CN103664996A - Indole derivative and preparation method thereof - Google Patents
Indole derivative and preparation method thereof Download PDFInfo
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- CN103664996A CN103664996A CN201310388834.XA CN201310388834A CN103664996A CN 103664996 A CN103664996 A CN 103664996A CN 201310388834 A CN201310388834 A CN 201310388834A CN 103664996 A CN103664996 A CN 103664996A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/06—Peri-condensed systems
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- 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
-
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- 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
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- 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
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/06—Peri-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/12—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
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- 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
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- 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 System
- 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
Abstract
The invention relates to a novel antibacterial compound, i.e. an indole derivative, a three-dimensional isomerism or medical salt, solvent compound or aquo-complex as well as a preparation method, a medicine composition containing the compound and an application of the compound in preparing an antibiotic drug.
Description
Technical field
The present invention relates to the antimicrobial compounds that a class is new, i.e. a class indole derivatives, its stereoisomerism or their pharmacologically acceptable salt or solvate or hydrate; The preparation method of these compounds, the pharmaceutical composition that contains these compounds, these compounds are in the purposes for the preparation of in antibacterials, and described antibacterials preferred pin is to bacillus or gram-bacteria, more preferably for tubercule bacillus or Gram-negative bacteria or gram-positive microorganism.
Background technology
Resistant strain seriously jeopardizes the treatment of anti-infective disease to antibiotic resistance especially multiple drug resistance, and becomes one of important public hygiene problem of global concern.In recent years, the infection that Resistant strain causes is the one of the main reasons that causes infectious diseases high mortality, as seriously jeopardized the methicillin-resistant staphylococcus aureus (MRSA) of clinical treatment and staphylococcus epidermidis (MRSE), penicillin resistance pneumococcus (PRSP), vancomycin-resistant enterococcus (VRE), cause the use of antibacterials to be very restricted, even invalid.Clinical very urgent to the demand of new effective antibacterials, people are just sparing no effort actively to find and develop each kind new medicine that can resist resistant organism.
In the soil of creatmycin Shi Cong China Jinan, Shandong Province, isolate the antibacterium microbiotic of a kind of tool new chemical structure of a strain actinoplanes generation; part Gram-positive and negative bacterium are had to restraining effect; toxicity is very low; to infecting dysentery bacterium or colibacillary mouse, abdominal cavity or oral administration have provide protection.Septicemia, urinary system infection that creatmycin causes intestinal bacteria clinically have good therapeutic effect.The molecular structure β monomethyl indolepopionic acid of desulfurization creatmycin does not have the thiapyran ring in creatmycin, identical with creatmycin to the anti-microbial activity of E.coli B.Qi Tianqing etc. have studied desulfurization creatmycin to the anti-microbial effect of E.coli B and antibacterial primary action, result shows that creatmycin and desulfurization creatmycin are all that biosynthesizing by anti-bacteria tryptophane produces anti-microbial activity, its anti-microbial effect mechanism be antagonism suppress tryptophane path enzyme synthetic (Qi Changqing etc. microbiotic 1984,9(5): 401).This result shows, seems thiapyran ring inessential group in creatmycin molecule.The novel structure of creatmycin, its main core is being chemically a new heterocyclic system.But from finding that, so far not yet for clinical, its reason, except fermentative production cost height, is also that its antimicrobial spectrum is narrower, only can be oral, can not intramuscular injection, and anti-microbial activity is lower than other antibacterials clinically at present.Therefore scientific worker has carried out many structure of modification to creatmycin, and Su Shenghui etc. have carried out the transformation of following several aspects according to the chemical structure characteristic of creatmycin: synthesized the derivative of some carboxylic acids, comprised ester and acid amides; Some derivatives that replace have been synthesized on the NH of indoles; Some replacements in whole ring system, have been carried out.The test of these derivatives shows, except N-formyl radical creatmycin has the anti-microbial effect close to creatmycin, other derivative all without obvious anti-microbial effect [Su Shenghui etc. medicine industry, 1984,139(2): 17)].
Therefore, in prior art, also need new antimicrobial compounds.
Summary of the invention
Technical problem underlying solved by the invention is the structure effect research by Some Derivatives of Chuangxinmycin, screens and synthesizes the antimicrobial compounds that a class is new.This compounds not only has significant anti-microbial activity, and has advantages of that molecular weight is little, synthetic simply, toxic side effect is little.
The present invention also provides the synthetic method of described indole derivatives or its pharmaceutical salts, by the selection to reaction scheme, obtains described compound.
The present invention also provides described indole derivatives or its pharmaceutical salts in the application of antibiosis, studies show that it has significant antibacterial activity, and then provides and take the antibacterial combination that this indole derivatives is activeconstituents.The present invention also provides the compounds of this invention in the purposes for the preparation of in antibacterials, and described antibacterials preferred pin is to bacillus or gram-bacteria, more preferably for tubercule bacillus or Gram-negative bacteria or gram-positive microorganism.
On the one hand, the invention provides there is general formula indole derivatives, its steric isomer or their pharmacologically acceptable salt or solvate or the hydrate of (I):
Wherein,
R
1for H, C
1-6alkyl, C
1-6alkyloyl or C
1-6alkylamino;
R
2for H, C
1-6alkyl, C
3-6cycloalkyl, C
1-6alkoxyl group, C
1-6alkyloyl, halogen, cyano group, nitro, CF
3, amino, N (R
5)
2, COR
6, CO
2r
6, or CON (R
6)
2;
R
3for H, C
1-6alkyl, C
3-6cycloalkyl, C
1-6alkoxyl group, C
1-6alkyloyl, halogen, cyano group, nitro, CF
3, amino, N (R
5)
2, COR
6, CO
2r
6, or CON (R
6)
2;
R
4for H, C
1-6alkyl, C
3-6cycloalkyl, C
1-6alkoxyl group, C
1-6alkyloyl, halogen, cyano group, nitro, CF
3, amino, N (R
5)
2, COR
6, CO
2r
6, or CON (R
6)
2;
Each R
5be H independently, C
1-6alkyl, or COCH
2n(R
7)
2;
Each R
6be H independently, or C
1-6alkyl;
Each R
7be H independently, or C
1-6alkyl;
A, B, D is carbon or nitrogen-atoms independently of each other;
X is NH, O, S or do not exist;
Y is OR
8or N (R
8)
2;
Each R
8independently selected from
(1) H or C
1-6alkyl,
Wavy line is expressed as key place,
R
11represent H or C
1-6alkyl;
R
12representative
I) be not substituted or by 1-3 R
9the C replacing
1-6alkyl;
II) be not substituted or by halogen, C
1-6alkyl, C1-6 alkylamino, hydroxyl or C
1-6the C that alkoxyl group replaces
3-8cycloalkyl;
III) be not substituted or by 1-3 R
106 to the 18 yuan of aryl or 5 to the 14 yuan of heteroaryls that replace;
Iv) adamantyl;
Each R
8can be independently by 1-3 R
9replace,
Each R
9independently selected from halogen, C
1-6alkyl, C
1-6alkylamino, two (C
1-6alkyl) amino, hydroxyl, hydroxyl C
1-6alkyl, amino, amino C
1-6alkyl, C
1-6alkyl-carbonyl, C
1-6alkyl carbonyl oxy, amino-sulfonyl, formamyl, C
1-6alkyl-carbamoyl, C
3-8cycloalkyl; 6 to 18 yuan of aryl-carbonyl oxygens; 6 to 18 yuan of aryl or 5 to 14 yuan of heteroaryls, or R
106 to the 18 yuan of aryl or 5 to the 14 yuan of heteroaryls that replace; The non-aromatic heterocycle that contains 5 or 6 annular atomses; Butyrolactam-1-base; And phosphate;
R
10be selected from halogen, hydroxyl, amino, C
1-6alkyl-carbonyl, C
1-6alkyl, C1-6 alkoxyl group, C1-6 alkylamino and C
1-6alkyl carbonyl oxy;
Condition is that described formula (I) compound does not comprise following compound:
The substituting group of above formula is as shown in the table
2) compound of following formula 3
R
1methyl and R
2it is hydroxyl; Or
R
1methyl and R
2it is oxyethyl group; With
3) compound of formula 4
R
1methyl and R
2it is hydroxyl.
In a preferred embodiment, formula (I) compound has following logical formula II
R
1, R
2, R
3, R
4, A, B, D, X, Y define as general formula (I).
In a further preferred embodiment, R
3be substituted on A.
In a further preferred embodiment, R
3be substituted on B.
In a further preferred embodiment, R
3be substituted on D.
In a further preferred embodiment, formula (I) compound has following general formula X V
R
1, R
2, R
3, R
4, A, B, D, Y define as general formula (I).
In a further preferred embodiment, in formula (I) or formula (II) compound,
A, B and D are carbon atom;
B and D are carbon atom, and A is nitrogen-atoms;
D is carbon atom, and A and B are nitrogen-atoms;
A and D are carbon atom, and B is nitrogen-atoms;
A and B are 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) compound,
R
1for H, C
1-4alkyl, C
1-4alkyloyl or C
1-4alkylamino;
R
2for H, C
1-4alkyl, C
3-4cycloalkyl, C
1-4alkoxyl group, C
1-4alkyloyl, halogen, cyano group, nitro, CF
3, amino, N (R
5)
2, COR
6, CO
2r
6, or CON (R
6)
2;
R
3for H, C
1-4alkyl, C
3-6cycloalkyl, C
1-6alkoxyl group, C
1-4alkyloyl, halogen, cyano group, nitro, CF
3, amino, N (R
5)
2, COR
6, CO
2r
6, or CON (R
6)
2;
R
4for H, C
1-4alkyl, C
3-4cycloalkyl, C
1-4alkoxyl group, C
1-4alkyloyl, halogen, cyano group, nitro, CF
3, amino, N (R
5)
2, COR
6, CO
2r
6, or CON (R
6)
2;
Each R
5be H independently, C
1-4alkyl, or COCH
2n(R
7)
2;
Each R
6be H independently, C
1-4alkyl;
Each R
7be H independently, C
1-4alkyl;
A, B, D is carbon or nitrogen-atoms;
X is NH, O, S or do not exist;
Y is OR
8or N (R
8)
2;
Each R
8independently selected from
(1) H or C
1-6alkyl,
Wavy line is expressed as key place,
R
11represent H or C
1-6alkyl;
R
12representative
I) be not substituted or by 1-3 R
9the C replacing
1-6alkyl;
II) be not substituted or by halogen, C
1-6alkyl, C1-6 alkylamino, hydroxyl or C
1-6the C that alkoxyl group replaces
3-8cycloalkyl;
III) be not substituted or by 1-3 R
106 to the 18 yuan of aryl or 5 to the 14 yuan of heteroaryls that replace;
Iv) adamantyl;
Each R
8can be independently by 1-3 R
9replace,
Each R
9independently selected from halogen, C
1-6alkyl, C
1-6alkylamino, two (C
1-6alkyl) amino, hydroxyl, hydroxyl C
1-6alkyl, amino, amino C
1-6alkyl, C
1-6alkyl-carbonyl, C
1-6alkyl carbonyl oxy, amino-sulfonyl, formamyl, C
1-6alkyl-carbamoyl, C
3-8cycloalkyl; 6 to 18 yuan of aryl-carbonyl oxygens, 6 to 18 yuan of aryl or 5 to 14 yuan of heteroaryls, or R
106 to the 18 yuan of aryl or 5 to the 14 yuan of heteroaryls that replace; Non-aromatic heterocycle containing 5 or 6 annular atomses; Butyrolactam-1-base and phosphate;
R
10be selected from halogen, hydroxyl, amino, C
1-6alkyl-carbonyl, C
1-6alkyl, C1-6 alkoxyl group, C1-6 alkylamino and C
1-6alkyl carbonyl oxy.
In a further preferred embodiment, Y is OR
8, R
8for C
1-6alkyl, each R
8can be independently by 1-3 R
9replace each R
9independently selected from halogen, C
1-6alkyl, C
1-6alkylamino, two (C
1-6alkyl) amino, hydroxyl, hydroxyl C
1-6alkyl, amino, amino C
1-6alkyl, C
1-6alkyl-carbonyl, C
1-6alkyl carbonyl oxy, amino-sulfonyl, formamyl, C
1-6alkyl-carbamoyl, C
3-8cycloalkyl; 6 to 18 yuan of aryl-carbonyl oxygens, 6 to 18 yuan of aryl or 5 to 14 yuan of heteroaryls, or R
106 to the 18 yuan of aryl or 5 to the 14 yuan of heteroaryls that replace; Non-aromatic heterocycle containing 5 or 6 annular atomses; Butyrolactam-1-base and phosphate.
In a further preferred embodiment, Y is OR
8, R
8for C
1-6alkyl, each R
8can be independently by 1-3 R
9replace each R
9independently selected from 6 to 18 yuan of aryl-carbonyl oxygens.
In a further preferred embodiment, in formula (I) or formula (II) compound, R
12represent unsubstituted C
3-8cycloalkyl, each R
8can be independently by 1-3 R
9replace each R
9independently selected from hydroxyl, and C
1-6alkylamino, preferably, R
9be substituted in R
12on.
In a further preferred embodiment, the present invention relates to a kind of indole derivatives or its steric isomer or their pharmacologically acceptable salt or solvate or hydrate as shown in the formula (I):
Wherein,
R
1for H, C
1-6alkyl, or C
1-6alkyloyl;
R
2for H, C
1-6alkyl or halogen;
R
3for H, C
1-6alkyl, C
1-6alkoxyl group, halogen, CF
3, or N (R
5)
2;
R
4for C
1-6alkyl;
Each R
5be H independently, or C
1-6alkyl;
A, B, D is carbon or nitrogen-atoms independently of each other;
X is O, S, or do not exist;
Y is OR
8, or N (R
8)
2;
Each R
8independently selected from
(1) H, or C
1-6alkyl,
Wavy line is expressed as key place,
R
11represent H or C
1-6alkyl;
R
12representative
I) unsubstituted or by 1-3 R
9the C replacing
1-6alkyl;
II) be not substituted or by halogen, C
1-6alkyl, C
1-6alkylamino, hydroxyl or C
1-6the C that alkoxyl group replaces
3-8cycloalkyl;
III) unsubstituted or by 1-3 R
106 to 18 yuan of aryl that replace,
Iv) adamantyl;
V) unsubstituted 5 to 14 yuan of heteroaryls;
Each R
8can be independently by 1-3 R
9replace,
Each R
9independently selected from halogen, C
1-6alkyl, C
1-6alkylamino, two (C
1-6alkyl) amino, hydroxyl, 6 to 18 yuan of aryl-carbonyl oxygens, the non-aromatic heterocycle that contains 5 or 6 annular atomses, butyrolactam-1-base and phosphates;
R
10be selected from halogen, hydroxyl, C
1-6alkyl, C
1-6alkoxyl group, C
1-6alkoxyl group, C
1-6alkylamino and C
1-6alkylamino;
Condition is that described formula (I) compound does not comprise following compound:
1) formula 2 compounds
The substituting group of above formula is as shown in the table
2) compound of following formula 3
R
1methyl and R
2it is hydroxyl; Or
R
1methyl and R
2it is oxyethyl group; With
3) compound of following formula 4
R
1methyl and R
2it is hydroxyl.
In a further preferred embodiment, R
1for H, C
1-6alkyl, or C
1-6alkyloyl.
In a further preferred embodiment, R
2for H, C
1-6alkyl or halogen.
In a further preferred embodiment, R
3for H, C
1-6alkyl, C
1-6alkoxyl group, halogen, CF
3, or N (R
5)
2.
In a further preferred embodiment, R
4for C
1-6alkyl.
In a further preferred embodiment, each R
5be H independently, or C
1-6alkyl.
In a further preferred embodiment, A, B, D is carbon or nitrogen-atoms independently of each other.
In a further preferred embodiment, X is O, S, or do not exist.
In a further preferred embodiment, Y is OR
8, or N (R
8)
2,
Each R
8independently selected from
(1) H, or C
1-6alkyl,
Wavy line is expressed as key place,
R
11represent H or C
1-6alkyl.
In a further preferred embodiment, R
12representative
I) unsubstituted or by 1-3 R
9the C replacing
1-6alkyl;
II) be not substituted or by halogen, C
1-6alkyl, C
1-6alkylamino, hydroxyl or C
1-6the C that alkoxyl group replaces
3-8cycloalkyl;
III) unsubstituted or by 1-3 R
106 to 18 yuan of aryl that replace,
Iv) adamantyl;
V) unsubstituted 5 to 14 yuan of heteroaryls.
In a further preferred embodiment, each R
8independently selected from
(1) H, or C
1-6alkyl,
Wavy line is expressed as key place,
R
11represent H or C
1-6alkyl.
In a further preferred embodiment, R
12representative
I) unsubstituted or by 1-3 R
9the C replacing
1-6alkyl;
II) be not substituted or by halogen, C
1-6alkyl, C
1-6alkylamino, hydroxyl or C
1-6the C that alkoxyl group replaces
3-8cycloalkyl;
III) unsubstituted or by 1-3 R
106 to 18 yuan of aryl that replace,
Iv) adamantyl;
V) unsubstituted 5 to 14 yuan of heteroaryls.
In a further preferred embodiment, each R
8independently selected from
(1) H, or C
1-6alkyl,
Wavy line is expressed as key place,
R
11represent H or C
1-6alkyl;
R
12representative
I) unsubstituted or by 1-3 R
9the C replacing
1-6alkyl;
II) be not substituted or by halogen, C
1-6alkyl, C
1-6alkylamino, hydroxyl or C
1-6the C that alkoxyl group replaces
3-8cycloalkyl;
III) unsubstituted or by 1-3 R
106 to 18 yuan of aryl that replace,
Iv) adamantyl;
V) unsubstituted 5 to 14 yuan of heteroaryls.
In a further preferred embodiment, each R
8can be independently by 1-3 R
9replace each R
9independently selected from halogen, C
1-6alkyl, C
1-6alkylamino, two (C
1-6alkyl) amino, hydroxyl, 6 to 18 yuan of aryl-carbonyl oxygens, the non-aromatic heterocycle that contains 5 or 6 annular atomses, butyrolactam-1-base and phosphates.Aspect preferred, R
9be substituted in R
12on.
In a further preferred embodiment, R
10be selected from halogen, hydroxyl, C
1-6alkyl, C
1-6alkoxyl group, C
1-6alkoxyl group, C
1-6alkylamino and C
1-6alkylamino.
In a further preferred embodiment, formula (I) compound has the structure of formula VIII
R wherein
1, R
2, R
3, R
4, A, B, D define suc as formula (I), X is NH, O or S.
In a further preferred embodiment, formula I compound has formula IX structure
R wherein
1, R
2, R
3, R
4, A, B, D define suc as formula (I).
In a further preferred embodiment, formula I compound has formula X structure
Wherein, Z is O or N, and R
8for not being substituted or by 1-3 R
9the C replacing
1-6alkyl, R
4, R
9, A, B, D define suc as formula I, X is NH, O or S.
In a further preferred embodiment, formula I compound has formula XI structure
Wherein, Z is O or N, and R
8for not being substituted or by 1-3 R
9the C replacing
1-6alkyl, R
4, R
9, A, B, D define suc as formula I.
In a further preferred embodiment, formula I compound has formula XIII structure
Wherein, R
1, R
2, R
3, R
4, R
11, R
12, A, B, D and X define suc as formula I.
In a further preferred embodiment, formula I compound has formula XIV structure
Wherein, R
1, R
2, R
3, R
4, R
11, R
12, A, B and D define suc as formula I.
Preferred compound of the present invention is compound or steric isomer and their pharmacologically acceptable salt and solvate or the hydrate in lower list 1 and table 2.
Table 1
Table 2
Term related definition of the present invention is as follows.
Term " alkyl " used in the application means saturated straight chain or the alkyl of branching, refers in particular to the alkyl that carbonatoms is the straight or branched of 1-6.Specific examples includes, but are not limited to methyl, ethyl, sec.-propyl, n-propyl, cyclopropyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, n-pentyl, isopentyl, n-hexyl, isohexyl.Be preferably methyl, ethyl or propyl group.The alkyl replacing can be dihalo or tri haloalkyl, such as trifluoromethyl, trifluoroethyl, trichloromethyl, three chloroethyls, trisbromomethyl, three bromomethyl etc.
Term " halogen ", " halo " and " halogen " represent F, Cl, Br or I.
Term " cycloalkyl " refers to that non-aromatic monocyclic contains carbocyclic ring, and it is saturated, has 3-8 ring carbon atom.Specific examples includes, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
Term used herein " heterocyclic radical " or " heterocycle " refer to aromatics and the non--aromatics cyclic group as ring members with at least one heteroatoms.Preferred heterocyclic radical is those at least one heteroatomic heterocyclic radicals that comprises that contains 5 or 6 annular atomses, 5 or 6 yuan of heterocyclic radicals that more preferably contain 1 nitrogen-atoms and 1 Sauerstoffatom, or 5 or 6 yuan of heterocyclic radicals that contain 1 nitrogen-atoms or 1 Sauerstoffatom, or 5 or 6 yuan of non-aromatic heterocycles that contain 1 nitrogen-atoms and 1 Sauerstoffatom, or 5 or 6 yuan of non-aromatic heterocycles that contain 1 nitrogen-atoms or 1 Sauerstoffatom, and described " heterocyclic radical " comprising: cyclic amine group, such as morpholinyl, preferred morpholino, piperidyl, preferred piperidino-(1-position only), pyrrolidyl, preferred pyrrolidino etc., with cyclic ethers class group, such as tetrahydrofuran base, THP trtrahydropyranyl etc.Aromatic heterocyclic radical, also referred to as " heteroaryl ", is to comprise 1-3 mix-aromatic group of heteroatomic list-ring, such as pyrroles, furans, thiophene, imidazoles, oxazole, thiazole, triazole, pyrazoles, pyridine, pyrazine, pyridazine, pyrimidine group etc.Term used herein " heteroatoms " comprises nitrogen-atoms, Sauerstoffatom and sulphur atom.Term heteroaryl used herein also comprises the mix-aromatic systems of many rings with two or more rings, two atoms are wherein that two adjacent rings share (these rings are " condensing "), wherein at least one in ring is heteroaryl, and for example other ring can be cycloalkyl, cycloalkenyl group, aryl, heterocycle and/or heteroaryl.Heteroaryl comprises the mix-aromatic group of 5 or 6 yuan of list-rings that contains 1 or 2 nitrogen-atoms, Sauerstoffatom or sulphur atom.Mix-aromatic systems of many rings with two rings comprises benzo five-membered heteroaryl, and described quinary heteroaryl contains nitrogen-atoms, Sauerstoffatom or a sulphur atom.The example of many ring heteroaromatic systems comprises quinoline, isoquinoline 99.9, tetrahydroisoquinoline, quinoxaline, benzoglyoxaline, cumarone, purine, imidazopyridine, benzotriazole etc.The example of heteroaryl also comprises pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, imidazolyl, pyrryl, pyrazolyl, triazolyl, tetrazyl,
azoles base, different
azoles base,
di azoly, thiazolyl, isothiazolyl or thiadiazolyl group, for example comprise, 2-furyl, 3-furyl, TMSIM N imidazole base, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-are different
azoles base, 4-are different
azoles base, 5-are different
azoles base, 2-
di azoly, 5-
di azoly, 2-
azoles base, 4-
azoles base, 5-
azoles base, 3-pyrazolyl, 4-pyrazolyl, 1-pyrryl, 2-pyrryl, 3-pyrryl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, 3-pyridazinyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-triazolyl, 5-triazolyl, tetrazyl, 2-thienyl, 3-thienyl, carbazyl, benzimidazolyl-, benzothienyl, benzofuryl, indyl, benzotriazole base, benzothiazolyl, benzo
azoles base, benzimidazolyl-, isoquinolyl, indyl, pseudoindoyl, acridyl, benzisoxa
azoles base, isothiazolyl, 1,2,3-
di azoly, 1,2,5-
di azoly, 1,2,4-
di azoly, 1,2,3-triazolyl, 1,2,3-thiadiazolyl group, 1,3,4-thiadiazolyl group, 1,2,5-thiadiazolyl group, purine radicals, pyrazinyl, 1,3,5-triazinyl, quinolyl (for example 2-quinolyl, 3-quinolyl, 4-quinolyl) and isoquinolyl (for example 1-isoquinolyl, 3-isoquinolyl or 4-isoquinolyl).
Term " phosphate " expression-PO (OH) used in application
2.
In the application term " alkoxyl group " used represent by oxygen (" alkoxyl group ", for example-O-alkyl) atom and minute sub-connection as defined alkyl above.Specific examples comprises, but be not limited to methoxyl group, oxyethyl group, isopropoxy, positive propoxy, n-butoxy, isobutoxy, sec-butoxy, tert.-butoxy, n-pentyloxy, isopentyloxy, positive hexyloxy, different hexyloxy etc., when being the alkoxyl group replacing, substituting group can be such as halogen or amino etc.
Mean-C of term " alkyloyl " (O) R, wherein R is defined alkyl in the application.Specific examples includes, but are not limited to formyl radical, ethanoyl, sec.-propyl acyl group, n-propyl acyl group, normal-butyl acyl group, isobutyl-acyl group, sec-butyl acyl group, tertiary butyl acyl group, n-pentyl acyl group, isopentyl acyl group, n-hexyl acyl group, isohexyl acyl group etc.
Term " aryl " refers to carbocyclic aromatic cyclic group.Described carbocyclic aromatic cyclic group only has carboatomic ring atom (being generally 6-18) and comprises monocyclic aromatic ring for example phenyl and the polycyclic aromatic ring system condensing, one of them carbocyclic aromatic ring and one or more aromatic ring condense, and the group wherein connecting or point are on carbocyclic aromatic ring.Example comprises 1-naphthyl, 2-naphthyl, 1-anthryl and 2-anthryl.While using in this application, in term " carbocyclic aromatic ring " scope, also comprise such group, wherein aromatic ring is fused to one or more non-aromatic rings (carbocyclic ring or heterocycle), for example, at indanyl, phthalimide group, naphthalimide (naphthimidyl), phenanthridinyl or tetralyl, the group or the point that wherein connect are positioned on carbocyclic aromatic ring.
Term DMAP is DMAP.
Term DIC is N, N-DIC.
Term DMF is dimethyl formamide.
Term " racemic mixture " indicates the molar mixture that waits without two or more enantiomer materials of opticity.The present invention includes all steric isomers of compound described herein.
The salt or the solvate that the present invention includes compound described herein, comprise their combination, such as the solvate of salt.Compound of the present invention can for example,, with solvate forms (hydrate forms) and not solvate forms existence, the present invention includes all such forms.
Conventionally, but be not utterly, salt of the present invention is pharmacy acceptable salt.Be included in the non-toxic salt that the interior salt of term " pharmacy acceptable salt " represents compound of the present invention.
The example of suitable pharmacy acceptable salt comprises inorganic acid addition salt, such as hydrochloride, bromate, vitriol, phosphoric acid salt and nitrate; Organic acid addition salt, such as acetate, mutate, propionic salt, succinate, lactic acid salt, glycollate, malate, tartrate, Citrate trianion, maleate, fumarate, mesylate, tosilate and ascorbate salt; With the salt of acidic amino acid formation, such as aspartate and glutaminate; An alkali metal salt, such as sodium salt and sylvite; Alkaline earth salt, such as magnesium salts and calcium salt; Ammonium salt; Organic alkali salt, such as front three amine salt, triethylamine salt, pyridinium salt, picoline salt, dicyclohexyl amine salt and N, N'-dibenzyl ethylene amine salt; With the salt with basic aminoacids formation, such as lysine salt and arginic acid salt.In some cases, described salt can be hydrate or alcohol solvent compound.
The qualifier using together with quantity " approximately " comprises described value, and has the implication (for example, comprising the error degree relevant with the measurement of specific quantity) of context appointment.
The present invention also provides the synthetic method of formula I compound.
Described method can be reacted according to following scheme, thereby prepares described formula I compound.
Wherein, R
1, R
2, R
3, A, B, D, Y definition as above formula (I) defined, each R ' wherein
1be independently-COR
4, R
4suc as formula (I), define, X is NH, O or S.
The inventive method can be reacted according to following scheme, formula (I) compound with formula VIII structure is converted into formula (I) compound with formula IX structure
Wherein, R
1, R
2, R
3, R
4, A, B, D definition suc as formula (I), define.
The inventive method can also be reacted according to following scheme, thereby formula VIII compound is converted into formula X compound
Wherein, wherein, Z is O or N, and R
8for not being substituted or by 1-3 R
9the C replacing
1-6alkyl, R
1, R
2, R
3, R
4, R
9, A, B, D define suc as formula (I), X is NH, O or S.
The inventive method can also be reacted according to following scheme, thereby formula IX compound is converted into formula XI compound
Wherein, Z is O or N, and R
8for not being substituted or by 1-3 R
9the C replacing
1-6alkyl, R
1, R
2, R
3, R
4, R
9, A, B, D define suc as formula (I).
The inventive method can also be reacted according to following scheme, thereby formula VIII compound is converted into XIII compound
Wherein, R
1, R
2, R
3, R
4, R
11, R
12, A, B and D define suc as formula (I), X is NH, O or S.
The inventive method also can also be reacted according to following scheme, thereby formula IX compound is converted into XIV compound
Wherein, R
1, R
2, R
3, R
4, R
11, R
12, A, B and D define suc as formula (I).
The method of the invention can comprise the steps:
Step 1) makes formula III compound
React with formula 1 compound,
(R '
1)
2o formula 1
Thereby production IV compound,
Each R ' wherein
1be independently-COR
4, R
1, R
2, R
3, R
4, A, B, D define suc as formula (I), R
13for halogen or nitro;
Step 2) make formula IV compound and HXCH
2cOY ' reaction, obtains formula V compound,
Wherein Y ' is C
1-6alkoxyl group, R
1, R
2, R
3, R
4, A, B, D define suc as formula (I), X is NH, O or S;
Step 3), by formula V compound and acid and reactant salt thereof, obtains formula VI compound
Wherein Y ' defines suc as formula V, R
1, R
2, R
3, R
4, A, B, D define suc as formula (I), X is NH, O or S;
Step 4), by formula VI hydrogenation of compounds, obtains formula VII compound
Wherein Y ' defines suc as formula V, R
1, R
2, R
3, R
4, A, B, D define suc as formula (I), X is NH, O or S;
Step 5), by formula VII compound and alkali reaction, obtains formula (I) compound, and it has the structure of formula VIII
R wherein
1, R
2, R
3, R
4, A, B, D define suc as formula (I), X is NH, O or S.
Method of the present invention can also comprise the steps:
Step 6), under catalyzer exists, will have formula (I) compound of formula VIII structure
Be converted into formula (I) compound with formula IX structure
R wherein
1, R
2, R
3, R
4, A, B, D define suc as formula (I).
Method of the present invention can also comprise the steps:
Step 7) is under the existence of suitable alkali, by formula VIII compound
With R
8zH reaction, obtains formula X compound
Wherein, Z is O or N, and R
8for not being substituted or by 1-3 R
9the C replacing
1-6alkyl, R
1, R
2, R
3, R
4, R
9, A, B, D define suc as formula (I), X is NH, O or S.
The method that the present invention states can also comprise the steps:
Step 8) is by formula IX compound
With R
8zH reaction, obtains formula XI compound.
Wherein, Z is O or N, and R
8for not being substituted or by 1-3 R
9the C replacing
1-6alkyl, R
1, R
2, R
3, R
4, R
9, A, B, D define suc as formula (I).
Method of the present invention can also comprise the steps:
Step 9) is by formula VIII compound
With
reaction, obtains formula XIII compound
Wherein, R
1, R
2, R
3, R
4, R
11, R
12, A, B, D and X define suc as formula (I).
Method of the present invention can also comprise the steps:
Step 10) is by formula IX compound
With
reaction, obtains formula XIV compound
Wherein, R
1, R
2, R
3, R
4, R
11, R
12, A, B and D define suc as formula (I).
In an embodiment of method of the present invention, step 1) is carried out as follows, at rare gas element, under preferred nitrogen exists, at organic solvent, in preferred methylene dichloride, at catalyzer, preferred tin tetrachloride, and/or under Nitromethane 99Min. existence, preferably at room temperature, formula III compound reacts with formula 1 compound, thus production IV compound.
In an embodiment of method of the present invention, step 2) carry out as follows, at rare gas element, under preferred nitrogen exists, by formula IV compound, HXCH
2cOY ' and suitable alkali, anhydrous pyridine for example, in appropriate solvent, for example anhydrous methanol, preferably for example,, at optimal temperature, approximately 90 ℃ of reaction appropriate times, for example 48h, obtains formula V compound.
In an embodiment of method of the present invention, step 3) is carried out as follows, and at rare gas element, under preferred nitrogen exists, by formula V compound and acid and salt thereof, preferably ammonium acetate and Glacial acetic acid reaction, obtain formula VI compound.
In an embodiment of method of the present invention, step 4) is carried out as follows, for example, at catalyzer, under 10% Pd-C exists, in organic solvent, for example ethyl acetate, preferably for example,, at suitable pressure, 45 normal atmosphere, by formula VI hydrogenation of compounds, obtain formula VII compound.
In an embodiment of method of the present invention, step 5) is carried out as follows, by formula VII compound and suitable alkali, for example sodium hydroxide, in appropriate solvent, for example ethanol, water and/or tetrahydrofuran (THF), preferably at proper temperature, for example room temperature reaction appropriate time, for example 5h, obtain formula (I) compound, it has the structure of formula VIII.
In an embodiment of method of the present invention, described method also comprises the steps 6):
Under catalyzer, for example Raney's nickel exist, preferably, at suitable alkali, for example sodium hydroxide, in suitable solvent, for example water, formula (I) compound with formula VIII structure is converted into formula (I) compound with formula IX structure.
In an embodiment of method of the present invention, described method also comprises the steps 7):
Under the existence of DIC and DMAP, by formula VIII compound and R
8zH reaction, obtains formula X compound.
In an embodiment of method of the present invention, described method also comprises the steps 8):
At rare gas element for example nitrogen, suitable alkali under for example triethylamine exists, at appropriate solvent for example in DMF, by formula IX compound and R
8zH reaction, obtains formula XI compound.
In an embodiment of method of the present invention, described method also comprises the steps 9):
At rare gas element, under preferred nitrogen exists, under suitably alkali, for example triethylamine exist, in appropriate solvent, for example DMF, preferably at proper temperature, for example room temperature reaction appropriate time 5min for example, by formula VIII compound with
reaction, obtains formula XIII compound.
In an embodiment of method of the present invention, described method also comprises the steps 10):
At rare gas element, under preferred nitrogen exists, under suitably alkali, for example triethylamine exist, in appropriate solvent, for example DMF, preferably in proper temperature, for example room temperature, by formula IX compound with
reaction appropriate time is 5min for example, obtains formula XIV compound.
The preparation of steric isomer
The steric isomer of the compounds of this invention can be prepared with reference to the routine techniques means of prior art, for example, the exploration of the complete synthesis route of creatmycin of Guo Xialing etc. and the research of steric isomer thereof (Acta Pharmaceutica Sinica, 1987,22(9): 671-678).Specifically, according to aforesaid method, prepared the steric isomer of the compound in table 1, it has suc as formula the steric configuration described in (II) or XV, especially table 2 compound.
Those skilled in the art know salt or solvate how to prepare compound of the present invention.
The present invention also provides and contains in formula I compound defined above or its pharmacodynamics acceptable salt as the antimicrobial compound of activeconstituents.The weight ratio of the indole derivatives that pharmaceutical composition contains in composition is 0.7-99.9%, and the weight ratio of medicine acceptable carrier in composition is 0.1-99.9%.Pharmaceutical composition exists to be applicable to medicinal dosage form.Medicinal dosage form can be for tablet, sugar coated tablet, film coated tablet, enteric coated tablet, slow releasing tablet, capsule, hard capsule, soft capsule, slow releasing capsule, oral liquid, mixture, suck agent, granule, electuary, pill, powder, paste, sublimed preparation, suspensoid, solution, injection, powder injection, lyophilized injectable powder, cachet, suppository, ointment, plaster, creme, sprays, aerosol, drops, patch.
Pharmaceutical composition of the present invention, as dosage form, the significant quantity of the invention compound containing in every dose is 0.1-1000mg, described every dose refers to each preparation unit, as every of tablet, and every of capsule, also can refer to each taking dose, as each serving using 100mg.
Pharmaceutical composition of the present invention being prepared into pulvis, tablet, dispersible pulvis, when the solid of capsule, cachet, suppository and ointment or semisolid pharmaceutical formulation, can use solid carrier.Spendable solid carrier is preferably one or more materials that are selected from thinner, seasonings, solubilizing agent, lubricant, suspension agent, tackiness agent, exapnsion agent etc.; or can be encapsulating substance. in powderous preparations, in carrier, contain 5% to 70% micronize activeconstituents.Suitable solid carrier comprises magnesiumcarbonate, Magnesium Stearate, talcum powder, sucrose, lactose, fructose, dextrin, starch, gelatin, methylcellulose gum, Xylo-Mucine, lower boiling wax, theobroma oil etc.Because they are easy to administration, tablet, pulvis, cachet and capsule represent best oral administration solid system profit.
Liquid preparation of the present invention comprises solution, suspension and emulsion.For example, the injection formulations of parenteral administration can be water or water-propylene glycol solution form, and regulate its etc. degree of oozing, pH etc. make to be suitable for the physiological condition of live body; Liquid preparation also can be made into the solution form in polyoxyethylene glycol, the aqueous solution.Can, by activeconstituents being dissolved in water, adding appropriate tinting material, seasonings, stablizer and thickening material again, prepare oral aqueous solution.Micronized activeconstituents can be dispersed in to viscous substance as prepared and be suitable for oral aqueous suspensions in natural and synthetical glue, methylcellulose gum, Xylo-Mucine and other known suspension agent.
For ease of administration and dosage homogeneous, it is particularly advantageous that said medicine preparation is mixed with to dosage unit form.The dosage unit form of preparation refers to be suitable for the physical sepn unit as single dose, the activeconstituents that each unit contains the predetermined amount calculating that produces desired result for the treatment of.This dosage unit form can be packaged form, as tablet, capsule be contained in tubule or bottle in pulvis be contained in pipe or bottle in ointment, gel or creme.
Although the amount of contained activeconstituents can change in dosage unit form, general according to the effect of selected activeconstituents, be adjusted within the scope of 1-800mg.
When medicine that formula of the present invention (I) active compound infects as treatment bacterium, preferably carry out administration with the amount of 6-14mg/kg body weight.But dosage can change along with the seriousness of the infection of sick human needs, wish treatment, selected compounds etc.
Those skilled in the art can determine the preferred dose that is suitable for certain situation according to a conventional method.Generally, the amount of begin treatment, lower than the optimal dose of activeconstituents, then increases dosage, gradually until reach optimum therapeuticing effect.For simplicity, total per daily dose can be divided into several parts, minute administration for several times.
Embodiment
Below by further detailed explanation the present invention of embodiment, these embodiment can make the present invention of those skilled in the art comprehend, but enforcement of the present invention is not limited in these embodiment, and these embodiment can not limit the present invention by any way.Below corresponding product, write related datas such as understanding corresponding nuclear-magnetism, mass-spectrometric data, the concrete isomer that the title compound of described racemic mixture form is corresponding with it has identical nuclear-magnetism and mass-spectrometric data.The relevant concrete isomer structure of title compound of mentioning in Preparation Example is below compound represented in table 2, the numbering of the concrete isomer of described title compound and its correspondence is specified as follows: the upper right corner of the numbering of title compound is added to " ' ", thus the concrete isomer numbering that described title compound is corresponding obtained.For example, the concrete isomer numbering of compound 1 is compound 1 '.
Embodiment 1:2-carboxylic acid-3-methyl-3,5-dihydro-2H-sulphur pyrans is [4,3,2-cd] indoles (Compound C) also
Under step 1) nitrogen protection, in methylene dichloride (75ml) solution of the 4-iodine indoles (7.5g, 30mmol) of 0 ℃, slowly add tin tetrachloride (4.5ml, 36mmol), room temperature reaction 30min, then adds Ac
2o(2.9g, 30mmol) and Nitromethane 99Min. (46.5ml), room temperature reaction 1h, uses frozen water cancellation, filters, and filter cake washs with a small amount of ether, and organic layer extracts by ethyl acetate, anhydrous Na
2sO
4dry, be spin-dried for after solvent with obtaining compound 3-acetyl-4-iodine indoles (6.9g, 78%) after ethyl acetate and sherwood oil recrystallization.
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; anhydrous methanol 17mmol) (100ml) solution reacts 48h at 90 ℃, and reaction finishes rear evaporate to dryness methyl alcohol, adds 100ml acetic acid ethyl dissolution resistates; washing ethyl acetate layer (80ml * 3), by ethyl acetate layer anhydrous Na
2sO
4dry, with ethyl acetate and sherwood oil recrystallization, obtain compound 3-acetyl-4-ethoxy carbonyl methylthio group indoles (1.93g, 70%) after being spin-dried for solvent.
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]+。
Under step 3) nitrogen protection; by 3-acetyl-4-ethoxy carbonyl methylthio group indoles (2.63g; 10mmol), ammonium acetate (3.51g; 46mmol) and Glacial acetic acid (5.54g; 93mmol) at 110 ℃, react 15h, after reaction finishes, add water, by ethyl acetate, extract water layer (80ml * 3); washing ethyl acetate layer (80ml * 3), by ethyl acetate layer anhydrous Na
2sO
4dry, by sherwood oil and ethyl acetate column chromatography for separation, obtain also [4,3,2-cd] Ethyl indole-2-carboxylate (1.23g, 50%) of compound 3-methyl-5H-sulphur pyrans after being spin-dried for solvent.
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) is to 3-methyl-5H-sulphur pyrans also [4,3,2-cd] Ethyl indole-2-carboxylate (1.23g, in ethyl acetate 5mmol) (50ml) solution, add 10% Pd-C(324mg, 0.30mmol), then catalytic hydrogenation 20h under 45 normal atmosphere, reaction finishes by diatomite filtration, ethyl acetate washing leaching cake, after filtrate concentrated solvent, by sherwood oil and ethyl acetate column chromatography for separation, obtain compound 3-methyl-3,5-dihydro-2H-sulphur pyrans also [4,3,2-cd] Ethyl indole-2-carboxylate's (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) is by 3-methyl-3,5-dihydro-2H-sulphur pyrans is [4,3,2-cd] Ethyl indole-2-carboxylate (0.5g also, 2mmol) and the ethanol of sodium hydroxide (1.21g, 30mmol) (30ml), water (18ml) and tetrahydrofuran (THF) (80ml) solution room temperature reaction 5h.Reaction finishes to add salt solution to dilute in backward reaction solution, then the hydrochloric acid soln (20ml) that adds 2M, with dichloromethane extraction (80ml * 3), anhydrous magnesium sulfate drying, ethyl acetate washing leaching cake, obtains racemic mixture 2-carboxylic acid-3-methyl-3 with methylene dichloride and toluene recrystallization after being spin-dried for solvent, 5-dihydro-2H-sulphur pyrans also [4,3,2-cd] indoles (0.30g, 66%).
By above-mentioned gained racemic mixture 2-carboxylic acid-3-methyl-3,5-dihydro-2H-sulphur pyrans also [4,3,2-cd] indoles (0.3g) is dissolved in anhydrous methanol (8ml), be heated to boiling, drip (-)-α-phenylethylamine (0.18ml), filtered while hot, after cooling, separate out (S)-α-phenylethylamine (2R, 3S)-2-carboxylic acid-3-methyl-3,5-dihydro-2H-sulphur pyrans also [4,3,2-cd] indoles, the excellent brilliant 0.20g of white.Mother liquor is retained.Heavy 0.17g after anhydrous methanol recrystallization secondary for crystallization.
By this crystallization and H
2o(9ml) mixture is with 49%H
2sO
4-H
2o processes, and by ether extraction, is washed to pH5, anhydrous MgSO
4dry.Concentrated, chloroform-ether recrystallization once, obtain (2R, 3S)-2-carboxylic acid-3-methyl-3,5-dihydro-2H-sulphur pyrans is [4,3,2-cd] indoles 0.1g also, is white imperfect crystal formation.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 is [4,3,2-cd] Indoline-2-carboxylic acid benzoxy methyl ester (CV2) also
Under nitrogen protection; by racemic mixture 2-carboxylic acid-3-methyl-3; 5-dihydro-2H-sulphur pyrans also [4; 3,2-cd] indoles or (2R, 3S)-2-carboxylic acid-3-methyl-3; 5-dihydro-2H-sulphur pyrans also [4; 3,2-cd] indoles (0.23g, 1mmol) and triethylamine (0.10g; 1mmol) be dissolved in DMF solution (6ml) solution; room temperature reaction 5min, then adds phenylformic acid chloromethyl ester (0.17g, 1mmol); room temperature reaction 24h; after reaction finishes, add ethyl acetate 50ml, washing ethyl acetate layer (80ml * 3), by ethyl acetate layer anhydrous Na
2sO
4dry, after being spin-dried for solvent, with ethanol and sherwood oil recrystallization, obtain racemic mixture 3-methyl-3,5-dihydro-2H-sulphur pyrans is [4,3,2-cd] Indoline-2-carboxylic acid benzoxy methyl ester or (2R also, 3S)-3-methyl-3,5-dihydro-2H-sulphur pyrans is [4,3,2-cd] Indoline-2-carboxylic acid benzoxy methyl ester (0.22g also, 60%), related data is as follows:
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)
By sodium hydroxide (0.19g, 4.8mmol) be dissolved in water (50ml), under agitation add racemic mixture 2-carboxylic acid-3-methyl-3, 5-dihydro-2H-sulphur pyrans also [4, 3, 2-cd] indoles or (2R, 3S)-2-carboxylic acid-3-methyl-3, 5-dihydro-2H-sulphur pyrans also [4, 3, 2-cd] indoles (1g, 4.3mmol), add wherein freshly prepd Raney's nickel (Raney nickel) (10g, weight in wet base, containing dehydrated alcohol) and water (50ml), reflux 1 hour, cold filtration, sodium hydroxide solution washing (20ml * 2) with 0.02%, washing lotion and filtrate merge, add 0.2 gram of activated carbon decolorizing, filter, filtrate is with using ether extraction (20ml * 3) after concentrated hydrochloric acid acidifying, ether extracted liquid washes (10ml * 3) with water, anhydrous sodium sulfate drying spends the night, after concentrated solvent with obtaining yellow crystal after ether and sherwood oil recrystallization, it is racemic mixture 3-(indol-3-yl)-butyric acid or (S)-3-(indol-3-yl)-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-yl)-butyric acid benzoxy methyl ester (Compound D SCV)
Under nitrogen protection; by racemic mixture 3-(indol-3-yl)-butyric acid or (S)-3-(indol-3-yl)-butyric acid (0.20g; 1mmol) and triethylamine (0.10g, 1mmol) be dissolved in DMF solution (6ml) solution, room temperature reaction 5min; then add phenylformic acid chloromethyl ester (0.17g; 1mmol), room temperature reaction 24h, adds ethyl acetate 50ml after reaction finishes; washing ethyl acetate layer (80ml * 3), by ethyl acetate layer anhydrous Na
2sO
4dry, obtain target compound 3-(indol-3-yl)-butyric acid benzoxy methyl ester (0.23g, 70%) after being spin-dried for the separation of solvent rear pillar level, it is racemic mixture or (S) isomer, 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 is [4,3,2-cd]-6-azaindole (compound 1) also
With the iodo-1H-pyrrolo-of 4-[3,2-c] pyridine, for raw material, according to the method that is similar to embodiment 1, prepare title compound, it is racemic mixture or (2R, 3S) isomer, 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 is [4,3,2-cd]-6 also, 7-diaza indoles (compound 2)
With the iodo-1H-pyrrolo-of 4-[3,2-d] pyridazine, for raw material, according to the method that is similar to embodiment 1, prepare title compound, it is racemic mixture or (2R, 3S) isomer, 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 is [4,3,2-cd]-6 also, 7-diaza indoles (compound 3)
Think the iodo-1H-pyrrolo-of 4-[3,2-d] pyridazine raw material, by being similar to the method for embodiment 1, prepare title compound, it is racemic mixture or (2R, 3S) isomer, 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 is [4,3,2-cd] Indoline-2-carboxylic acid (compound 4) also
Think the iodo-7-methoxyl group-1H-of 4-indoles raw material, by being similar to the method for embodiment 1, prepare title compound, it is racemic mixture or (2R, 3S) isomer, 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 is [4,3,2-cd] Indoline-2-carboxylic acid (compound 5) also
The iodo-N-Methyl-1H-indole-7-of the 4-of take amine is raw material, by being similar to the method for embodiment 1, prepares title compound, and it is racemic mixture or (2R, 3S) isomer, 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 is [4,3,2-cd] indoles (compound 7) also
The iodo-6-of 2-methyl-4-(the trifluoromethyl)-1H-indoles of take is raw material, by being similar to the method for embodiment 1, prepares title compound, and it is racemic mixture or (2R, 3S) isomer, 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 is [4,3,2-cd] Indoline-2-carboxylic acid (3 '-morpholino) propyl ester (compound 75) also
By 2-carboxylic acid-3-methyl-3, 5-dihydro-2H-sulphur pyrans also [4, 3, 2-cd] indoles or (2R, 3S)-2-carboxylic acid-3-methyl-3, 5-dihydro-2H-sulphur pyrans also [4, 3, 2-cd] indoles (2.55g, 11mmol) be dissolved in methylene dichloride (50ml), add DIC (1.51g, 11.98mmol), after stirring at normal temperature 1h, add DMAP (0.24g, 1.96mmol) with 3-morpholino-propyl alcohol (1.59g, 10.95mmol), water and saturated common salt washing reaction solution after reflux 6h, anhydrous magnesium sulfate drying, evaporate to dryness after filtering, ethyl acetate petroleum ether system recrystallization, obtain 3-methyl-3, 5-dihydro-2H-sulphur pyrans also [4, 3, 2-cd] Indoline-2-carboxylic acid (3 '-morpholino) propyl ester or (2R, 3S)-3-methyl-3, 5-dihydro-2H-sulphur pyrans also [4, 3, 2-cd] Indoline-2-carboxylic 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 13:3-methyl-7-is fluoro-3, and 5-dihydro-2H-sulphur pyrans is [4,3,2-cd] Indoline-2-carboxylic acid (2 '-morpholino) ethyl ester (compound 76) also
With compound 2-morpholino ethanol and 2-carboxylic acid-3-methyl-7-fluoro-3,5-dihydro-2H-sulphur pyrans also [4,3,2-cd] indoles is raw material, it is racemic mixture or (2R, 3S) isomer, method according to similar embodiment 12 is prepared title compound, it is racemic mixture or (2R, 3S) isomer, 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 is [4,3,2-cd] Indoline-2-carboxylic acid (2 '-morpholino) ethyl ester (compound 77) also
With compound 2-morpholino ethanol and 2-carboxylic acid-3-methyl-3,5-dihydro-2H-pyrans also [4,3,2-cd] indoles is raw material, it is racemic mixture or (2R, 3S) isomer, method according to similar embodiment 12 is prepared title compound, it is racemic mixture or (2R, 3S) isomer, 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 is [4,3,2-cd] Indoline-2-carboxylic acid (2 '-dimethylamino) ethyl ester (compound 78) also
With compound 2-methylethylolamine and 2-carboxylic acid-3-methyl-3,5-dihydro-2H-sulphur pyrans also [4,3,2-cd] indoles is raw material, it is racemic mixture or (2R, 3S) isomer, title compound is prepared in method reaction according to similar embodiment 12, it is racemic mixture or (2R, 3S) isomer, 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 is [4,3,2-cd]-6 also, 8-diaza indoles-2-formyl (2 '-dimethylaminoethyl) amine (compound 79)
With compound N, N-dimethyl-ethylenediamine and 2-carboxylic acid-3-methyl-3,5-dihydro-2H-sulphur pyrans also [4,3,2-cd]-6,8-diaza indoles is raw material, and it is racemic mixture or (2R, 3S) isomer, method according to similar embodiment 12 is prepared title compound, it is racemic mixture or (2R, 3S) isomer, 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 is [4,3,2-cd]-8-azaindole-2-carbonyl oxygen base also) ethylphosphonic acid (compound 80)
By 2-carboxylic acid-3-methyl-3, 5-dihydro-2H-sulphur pyrans also [4, 3, 2-cd]-8-azaindole or (2R, 3S)-2-carboxylic acid-3-methyl-3, 5-dihydro-2H-sulphur pyrans also [4, 3, 2-cd]-8-azaindole (2.57g, 11mmol) be dissolved in methylene dichloride (50ml), add DIC (1.51g, 11.98mmol), after stirring at normal temperature 1h, add DMAP (0.24g, 1.96mmol) with hydroxyethyl dimethyl phosphonate (1.84g, 10.95mmol), after reflux 6h, water and saturated common salt washing reaction solution, anhydrous magnesium sulfate drying, evaporate to dryness after filtering, ethyl acetate petroleum ether system recrystallization, obtain 3-methyl-3, 5-dihydro-2H-sulphur pyrans also [4, 3, 2-cd]-8-azaindole-2-carboxylic acid (2 '-dimethyl phosphonate) ethyl ester 3.50g, be dissolved in methylene dichloride (50ml), add bromotrimethylsilane (9.85g, 64.8mmol) stirring at normal temperature 3h, use methyl alcohol termination reaction, evaporate to dryness, obtain product 2-(3-methyl-3, 5-dihydro-2H-sulphur pyrans also [4, 3, 2-cd]-8-azaindole-2-carbonyl oxygen base) ethylphosphonic acid 2.53g(68%), it is racemic mixture or (2R, 3S) isomer, related data is 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 is [4,3,2-cd]-7-azaindole-2-carboxylate methyl ester (compound 8) also
With the iodo-1-methyl isophthalic acid of 4-H-pyrrolo-[3,2-c] pyridine, for raw material, by being similar to the method for embodiment 1 and 12, prepare title compound, it is racemic mixture or (2R, 3S) isomer, and 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-ethanoyl-3-methyl-3,5-dihydro-2H-sulphur pyrans is [4,3,2-cd]-7-azaindole-2-carboxylic acid, ethyl ester (compound 9) also
With 1-(the iodo-1H-pyrrolo-of 4-[2,3-c] pyridine-1-yl) ethyl ketone, for raw material, by being similar to the method for embodiment 1 and 12, prepare title compound, it is racemic mixture or (2R, 3S) isomer, 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 is [4,3,2-cd]-6 also, 7-diaza Ethyl indole-2-carboxylate (compound 10)
With the iodo-1H-pyrrolo-of 4-[3,2-d] pyridazine, for raw material, by being similar to the method for embodiment 1 and 12, prepare title compound, it is racemic mixture or (2R, 3S) isomer, 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 is [4,3,2-cd]-7-azaindole-2-carboxylic acid, ethyl ester (compound 11) also
With the iodo-1H-pyrrolo-of 4-[2,3-c] pyridine, for raw material, by being similar to the method for embodiment 1 and 12, prepare title compound, it is racemic mixture or (2R, 3S) isomer, 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 is [4,3,2-cd]-6 also, 7-diaza indoles-2-formyl ethamine (compound 12)
With the iodo-1H-pyrrolo-of 4-[3,2-d] pyridazine, for raw material, by being similar to the method for embodiment 1 and 12, prepare title compound, it is racemic mixture or (2R, 3S) isomer, 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 23:3-methyl-7-is fluoro-3, and 5-dihydro-2H-sulphur pyrans is [4,3,2-cd] Indoline-2-carboxylic acid tert-butyl ester (compound 13) also
The fluoro-1H-indoles of the iodo-6-of the 4-of take is raw material, by being similar to the method for embodiment 1 and 12, prepares title compound, and it is racemic mixture or (2R, 3S) isomer, 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 is [4,3,2-cd] indoles-2-formyl TERTIARY BUTYL AMINE (compound 14) also
The iodo-1H-indoles of the 4-of take is raw material, by being similar to the method for embodiment 1 and 12, prepares title compound, and it is racemic mixture or (2R, 3S) isomer, and related data is 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 is [4,3,2-cd]-6 also, 8-diaza indoles-2-formyl methylamine (compound 15)
With the iodo-7H-pyrrolo-of 4-[2,3-d] pyrimidine, for raw material, by being similar to the method for embodiment 1 and 12, prepare title compound, it is racemic mixture or (2R, 3S) isomer, 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 is [4,3,2-cd]-6-azaindole-2-formyl ethamine (compound 16) also
With the iodo-1H-pyrrolo-of 4-[3,2-c] pyridine, for raw material, by being similar to the method for embodiment 1 and 12, prepare title compound, it is racemic mixture or (2R, 3S) isomer, 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 27:3-methyl-3,5-dihydro-2H-pyrans is [4,3,2-cd]-6 also, 7-diaza indoles-2-formyl Isopropylamine (compound 17)
With the iodo-1H-pyrrolo-of 4-[3,2-d] pyridazine, for raw material, by being similar to the method for embodiment 1 and 12, prepare title compound, it is racemic mixture or (2R, 3S) isomer, 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-[2,3-c] pyridin-3-yl) butyric acid (compound 21)
With the iodo-1H-pyrrolo-of 1-methyl-4-[2,3-c] pyridine, for raw material, by being similar to the method for embodiment 1 and 3, prepare title compound, it is racemic mixture or (S) isomer, 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 group-1-methyl isophthalic acid H-pyrrolo-[3,2-c] pyridin-3-yl) butyric acid (compound 22)
With 4-iodo-7-methoxyl group-1-methyl isophthalic acid H-pyrrolo-[3,2-c] pyridine, for raw material, by being similar to the method for embodiment 1 and 3, prepare title compound, it is racemic mixture or (S) isomer, 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-(the fluoro-1H-pyrrolo-of 7-[2,3-c] pyridin-3-yl) butyric acid (compound 23)
With the fluoro-1H-pyrrolo-of the iodo-7-of 4-[2,3-c] pyridine, for raw material, by being similar to the method for embodiment 1 and 3, prepare title compound, it is racemic mixture or (S) isomer, 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-(the fluoro-1-methyl isophthalic acid of 7-H-pyrrolo-[2,3-c] pyridin-3-yl) butyric acid ethyl ester (compound 24)
With the fluoro-1H-pyrrolo-of the iodo-7-of 1-methyl-4-[2,3-c] pyridine, for raw material, by being similar to the method for embodiment 1,3 and 12, prepare title compound, it is racemic mixture or (S) isomer, 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-ethyl-3-(5-methyl isophthalic acid H-pyrrolo-[2,3-c] pyridin-3-yl) butyryl ethamine (compound 25)
With the iodo-5-methyl isophthalic acid of 4-H-pyrrolo-[2,3-c] pyridine, for raw material, by being similar to the method for embodiment 1,3 and 12, prepare title compound, it is racemic mixture or (S) isomer, 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-[2,3-c] pyridazine-5-yl) butyric acid tertiary butyl ester (compound 26)
With the iodo-7H-pyrrolo-of 4-[2,3-c] pyridazine, for raw material, by being similar to the method for embodiment 12, prepare title compound, it is racemic mixture or (S) isomer, 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-[2,3-d] pyrimidine-5-yl) butyric acid tertiary butyl ester (compound 27)
With 4-iodo-7-methyl-7H-pyrrolo-[2,3-d] pyrimidine, for raw material, by being similar to the method for embodiment 1,3 and 12, prepare title compound, it is racemic mixture or (S) isomer, 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-ethyl-3-(5-(methylamino)-1H-indol-3-yl) butyramide (compound 28)
The iodo-5-of the 4-of take (methylamino)-1H-indoles is raw material, by being similar to the method for embodiment 1,3 and 12, prepares title compound, and it is racemic mixture or (S) isomer, and 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-ethanoyl-6-Methyl-1H-indole-3-yl) butyric acid isopropyl esters (compound 29)
The iodo-6-Methyl-1H-indole of the 1-ethanoyl-4-of take is raw material, by being similar to the method for embodiment 1,3 and 12, prepares title compound, and it is racemic mixture or (S) isomer, 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 is [4,3,2-cd] Indoline-2-carboxylic acid (4 '-methylcyclohexane ketonic oxygen base) methyl ester (compound 30) also
By being similar to the method for embodiment 2, prepare title compound, it is racemic mixture or (2R, 3S) isomer, and 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:(3-methyl-7-is fluoro-3, and 5-dihydro-2H-sulphur pyrans is [4,3,2-cd] Indoline-2-carboxylic acid 4-methoxyl group hexanaphthene ketonic oxygen base also) methyl ester (compound 31)
The fluoro-1H-indoles of the iodo-6-of the 4-of take is raw material, by being similar to the method for embodiment 1 and 2, prepares title compound, and it is racemic mixture or (2R, 3S) isomer, and 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 is [4,3,2-cd] Indoline-2-carboxylic acid (cyclopropane carbonyl oxygen base) methyl ester (compound 32) also
The iodo-6-methoxyl group-1H-of the 4-of take indoles is raw material, by being similar to the method for embodiment 1 and 2, prepares title compound, and it is racemic mixture or (2R, 3S) isomer, 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 is [4,3,2-cd]-6 also, 8-diaza Indoline-2-carboxylic acid (pentamethylene methanoyl) methyl ester (compound 33)
With the iodo-7H-pyrrolo-of 4-[2,3-d] pyrimidine, for raw material, by being similar to the method for embodiment 1 and 2, prepare title compound, it is racemic mixture or (2R, 3S) isomer, 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 is [4,3,2-cd]-8-azaindole-2-carboxylic acid (tetramethylene methanoyl) methyl ester (compound 34) also
With the iodo-1H-pyrrolo-of 4-[2,3-b] pyridine, for raw material, by being similar to the method for embodiment 1 and 2, prepare title compound, it is racemic mixture or (2R, 3S) isomer, 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 is [4,3,2-cd]-8-azaindole-2-carboxylic acid (4 '-hydroxyl hexanaphthene methanoyl) methyl ester (compound 35) also
With the iodo-1H-pyrrolo-of 4-[2,3-b] pyridine, for raw material, by being similar to the method for embodiment 1 and 2, prepare title compound, it is racemic mixture or (2R, 3S) isomer, 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 is [4,3,2-cd] Indoline-2-carboxylic acid (1 '-methylcyclohexane ketonic oxygen base) methyl ester (compound 36) also
By being similar to the method for embodiment 2, prepare title compound, it is racemic mixture or (2R, 3S) isomer, and 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 is [4,3,2-cd] Indoline-2-carboxylic acid (4 '-methoxyl group hexanaphthene ketonic oxygen base) methyl ester (compound 37) also
The iodo-N-Methyl-1H-indole-6-of the 4-of take amine is raw material, by being similar to the method for embodiment 1 and 2, prepares title compound, and it is racemic mixture or (2R, 3S) isomer, 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 is [4,3,2-cd] Indoline-2-carboxylic acid (4 '-methylcyclohexane ketonic oxygen base) methyl ester (compound 38) also
The iodo-7-Methyl-1H-indole of the 4-of take is raw material, by being similar to the method for embodiment 1 and 2, prepares title compound, and it is racemic mixture or (2R, 3S) isomer, 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 is [4,3,2-cd]-6 also, 8-diaza Indoline-2-carboxylic acid (4 '-methoxyl group hexanaphthene ketonic oxygen base) methyl ester (compound 39)
With the iodo-7H-pyrrolo-of 4-[2,3-d] pyrimidine, for raw material, by being similar to the method for embodiment 1 and 2, prepare title compound, it is racemic mixture or (2R, 3S) isomer, 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 is [4,3,2-cd]-8-azaindole-2-carboxylic acid (4 '-hydroxyl hexanaphthene ketonic oxygen base) methyl ester (compound 40) also
With the iodo-1H-pyrrolo-of 4-[2,3-b] pyridine, for raw material, by being similar to the method for embodiment 1 and 2, prepare title compound, it is racemic mixture or (2R, 3S) isomer, 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 is [4,3,2-cd]-6 also, 8-diaza Indoline-2-carboxylic acid (4 '-hydroxyl hexanaphthene ketonic oxygen base) methyl ester (compound 41)
With the iodo-1H-pyrrolo-of 4-[2,3-b] pyrimidine, for raw material, by being similar to the method for embodiment 1 and 2, prepare title compound, it is racemic mixture or (2R, 3S) isomer, 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 is [4,3,2-cd] Indoline-2-carboxylic acid (4 '-methylcyclohexane ketonic oxygen base) methyl ester (compound 42) also
The iodo-5-methoxyl group-1H-of the 4-of take indoles is raw material, by being similar to the method for embodiment 1 and 2, prepares title compound, and it is racemic mixture or (2R, 3S) isomer, 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 is [4,3,2-cd] Indoline-2-carboxylic acid (4-fluorine hexanaphthene ketonic oxygen base) methyl ester (compound 43) also
By being similar to the method for embodiment 2, prepare title compound, it is racemic mixture or (2R, 3S) isomer, and 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 is [4,3,2-cd] Indoline-2-carboxylic acid (4 '-chlorine hexanaphthene ketonic oxygen base) methyl ester (compound 44) also
The iodo-6-Methyl-1H-indole of the 4-of take is raw material, by being similar to the method for embodiment 1 and 2, prepares title compound, and it is racemic mixture or (2R, 3S) isomer, 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 is [4,3,2-cd]-6 also, 8-diaza Indoline-2-carboxylic acid (4 '-methylamino-hexanaphthene ketonic oxygen base) methyl ester (compound 45)
With the iodo-7H-pyrrolo-of 4-[2,3-d] pyrimidine, for raw material, by being similar to the method for embodiment 1 and 2, prepare title compound, it is racemic mixture or (2R, 3S) isomer, 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 is [4,3,2-cd] Indoline-2-carboxylic acid (isobutyryl oxygen base) methyl ester (compound 46) also
By being similar to the method for embodiment 2, prepare title compound, it is racemic mixture or (2R, 3S) isomer, and 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 is [4,3,2-cd] Indoline-2-carboxylic acid (pivaloyl group oxygen base) methyl ester (compound 47) also
By being similar to the method for embodiment 2, prepare title compound, it is racemic mixture or (2R, 3S) isomer, and 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 is [4,3,2-cd] Indoline-2-carboxylic acid (pivaloyl group oxygen base) methyl ester (compound 48) also
The iodo-6-Methyl-1H-indole of the 4-of take is raw material, by being similar to the method for embodiment 1 and 2, prepares title compound, and it is racemic mixture or (2R, 3S) isomer, 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 59:3-methyl-6-is fluoro-3, and 5-dihydro-2H-sulphur pyrans is [4,3,2-cd] Indoline-2-carboxylic acid (1 '-(pivaloyl group oxygen base)) ethyl ester (compound 49) also
The fluoro-1H-indoles of the iodo-7-of the 4-of take is raw material, by being similar to the method for embodiment 1 and 2, prepares title compound, and it is racemic mixture or (2R, 3S) isomer, and 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 is [4,3,2-cd]-6 also, 8-diaza Indoline-2-carboxylic acid (1 '-(pivaloyl group oxygen base)) ethyl ester (compound 50)
With the iodo-7H-pyrrolo-of 4-[2,3-d] pyrimidine, for raw material, by being similar to the method for embodiment 1 and 2, prepare title compound, it is racemic mixture or (2R, 3S) isomer, 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 is [4,3,2-cd] Indoline-2-carboxylic acid (1 '-(propionyl oxygen base)) ethyl ester (compound 51) also
Take compound 4 as raw material, by being similar to the method for embodiment 2, prepare title compound, it is racemic mixture or (2R, 3S) isomer, and related data is 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 is [4,3,2-cd]-6 also, 8-diaza Indoline-2-carboxylic acid (1 '-(pivaloyl group oxygen base)) ethyl ester (compound 52)
By being similar to the method for embodiment 43, prepare title compound, it is racemic mixture or (2R, 3S) isomer, and 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 is [4,3,2-cd] Indoline-2-carboxylic acid benzoyloxy methyl ester (compound 55) also
By being similar to the method for embodiment 2, prepare title compound, it is racemic mixture or (2R, 3S) isomer, and 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 is [4,3,2-cd] Indoline-2-carboxylic acid (4 '-anisoyl oxygen base) methyl ester (compound 56) also
Take Compound C as raw material, and it is racemic mixture or (2R, 3S) isomer, by being similar to the method for embodiment 2, prepares title compound, and it is racemic mixture or (2R, 3S) isomer, 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 is [4,3,2-cd] Indoline-2-carboxylic acid (4 '-methyl benzoyl oxygen base) methyl ester (compound 57) also
Take Compound C as raw material, and it is racemic mixture or (2R, 3S) isomer, by being similar to the method for embodiment 2, prepares title compound, and it is racemic mixture or (2R, 3S) isomer, 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 68:3-methyl-7-is fluoro-3, and 5-dihydro-2H-sulphur pyrans is [4,3,2-cd] Indoline-2-carboxylic acid (3 '-fluoro benzoyl oxygen base) methyl ester (compound 58) also
By being similar to the method for embodiment 41, prepare title compound, it is racemic mixture or (2R, 3S) isomer, and 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 is [4,3,2-cd] Indoline-2-carboxylic acid (4 '-methylamino benzoyl oxygen base) methyl ester (compound 59) also
Take Compound C as raw material, and it is racemic mixture or (2R, 3S) isomer, by being similar to the method for embodiment 2, prepares title compound, and it is racemic mixture or (2R, 3S) isomer, 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 is [4,3,2-cd] Indoline-2-carboxylic acid (4 '-hydroxy benzoyl oxygen base) methyl ester (compound 60) also
By being similar to the method for embodiment 2, prepare title compound, it is racemic mixture or (2R, 3S) isomer, and 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 is [4,3,2-cd] Indoline-2-carboxylic acid (4 '-methyl benzoyl oxygen base) methyl ester (compound 61) also
Take Compound C as raw material, and it is racemic mixture or (2R, 3S) isomer, by being similar to the method for embodiment 2, prepares title compound, and it is racemic mixture or (2R, 3S) isomer, 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 is [4,3,2-cd] Indoline-2-carboxylic acid (1 '-(4 ' '-methyl benzoyl oxygen base)) ethyl ester (compound 62) also
The iodo-6-methoxyl group-1H-of the 4-of take indoles is raw material, by being similar to the method for embodiment 1 and 2, prepares title compound, and it is racemic mixture or (2R, 3S) isomer, 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 is [4,3,2-cd]-6 also, 8-diaza Indoline-2-carboxylic acid (1 '-(4 ' '-ethylamino benzonitrile acyl group oxygen base)) ethyl ester (compound 63)
With the iodo-7H-pyrrolo-of 2-methoxyl group-4-[2,3-d] pyrimidine, for raw material, by being similar to the method for embodiment 1 and 2, prepare title compound, it is racemic mixture or (2R, 3S) isomer, and 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 is [4,3,2-cd]-8-azaindole-2-carboxylic acid (1 '-(4 ' '-anisoyl oxygen base)) ethyl ester (compound 64) also
With the iodo-6-methyl isophthalic acid of 4-H-pyrrolo-[2,3-b] pyridine, for raw material, by being similar to the method for embodiment 1 and 2, prepare title compound, it is racemic mixture or (2R, 3S) isomer, 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 is [4,3,2-cd]-7 also, 8-diaza Indoline-2-carboxylic acid (1 '-benzoyl oxygen base) ethyl ester (compound 65)
With the iodo-7H-pyrrolo-of 4-[2,3-c] pyridazine, for raw material, by being similar to the method for embodiment 1 and 2, prepare title compound, it is racemic mixture or (2R, 3S) isomer, 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 is [4,3,2-cd]-6 also, 8-diaza Indoline-2-carboxylic acid (1 '-benzoyl oxygen base) ethyl ester (compound 66)
With the iodo-7H-pyrrolo-of 2-methyl-4-[2,3-d] pyrimidine, for raw material, by being similar to the method for embodiment 1 and 2, prepare title compound, it is racemic mixture or (2R, 3S) isomer, 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 77:3-methyl-7-is fluoro-3, and 5-dihydro-2H-pyrans is [4,3,2-cd] Indoline-2-carboxylic acid (3 '-fluoro benzoyl oxygen base) methyl ester (compound 67) also
By being similar to the method for embodiment 41, prepare title compound, it is racemic mixture or (2R, 3S) isomer, and 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 is [4,3,2-cd] Indoline-2-carboxylic acid (4 '-anisoyl oxygen base) methyl ester (compound 68) also
The iodo-1H-indoles of the 4-of take is raw material, by being similar to the method for embodiment 1 and 2, prepares title compound, and it is racemic mixture or (2R, 3S) isomer, and related data is 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: phenylformic acid (3-(1H-indol-3-yl) butyryl radicals oxygen base) methyl ester (compound 69)
By being similar to the method for embodiment 4, prepare title compound, it is racemic mixture or (2R, 3S) isomer, and 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-tolyl acid (3-(1H-indol-3-yl) butyryl radicals oxygen base) methyl ester (compound 70)
By being similar to the method for embodiment 4, prepare title compound, it is racemic mixture or (2R, 3S) isomer, and 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-methoxybenzoic acid (3-(1H-indol-3-yl) butyryl radicals oxygen base) methyl ester (compound 71)
By being similar to the method for embodiment 4, prepare title compound, it is racemic mixture or (2R, 3S) isomer, and 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-methoxyl group hexahydrobenzoic acid (3-(6-Methyl-1H-indole-3-yl) butyryl radicals oxygen base) methyl ester (compound 72)
The iodo-6-Methyl-1H-indole of the 2-of take is raw material, by being similar to the method for embodiment 1,3 and 4, prepares title compound, and it is racemic mixture or (2R, 3S) isomer, 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: hexahydrobenzoic acid (3-(7H-pyrrolo-[2,3-d] pyrimidine-5-yl) butyryl radicals oxygen base) methyl ester (compound 73)
With the iodo-7H-pyrrolo-of 6-[2,3-d] pyrimidine, for raw material, by being similar to the method for embodiment 1,3 and 4, prepare title compound, it is racemic mixture or (2R, 3S) isomer, and 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-[2,3-d] pyrimidine-5-yl) butyric acid (pivaloyl group oxygen base) methyl ester (compound 74)
By being similar to the method for embodiment 83, prepare title compound, it is racemic mixture or (2R, 3S) isomer, and 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 is [4,3,2-cd] Indoline-2-carboxylic acid (pyridine-2-base formyl radical oxygen base) methyl ester (compound 81) also
By being similar to the method for embodiment 2, prepare title compound, it is racemic mixture or (2R, 3S) isomer, and 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 is [4,3,2-cd] Indoline-2-carboxylic acid (cumarone-2-base formyl radical oxygen base) methyl ester (compound 82) also
By being similar to the method for embodiment 2, prepare title compound, it is racemic mixture or (2R, 3S) isomer, and 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 is [4,3,2-cd] Indoline-2-carboxylic acid (indol-3-yl formyl radical oxygen base) methyl ester (compound 83) also
By being similar to the method for embodiment 2, prepare title compound, it is racemic mixture or (2R, 3S) isomer, and 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 is [4,3,2-cd] indoles-2-formyl (2 '-morpholino ethyl) amine (compound 84) also
Take compound 2-morpholino-ethamine and Compound C as raw material, and it is racemic mixture or (2R, 3S) isomer, method according to similar embodiment 12 is prepared title compound, it is racemic mixture or (2R, 3S) isomer, and related data 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 is [4,3,2-cd] Indoline-2-carboxylic acid (2 '-morpholino) ethyl ester (compound 85) also
Take compound 2-morpholino-ethanol and Compound C as raw material, and it is racemic mixture or (2R, 3S) isomer, method according to similar embodiment 12 is prepared title compound, it is racemic mixture or (2R, 3S) isomer, and related data is 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 is [4,3,2-cd] indoles-2-formyl (3 '-dimethylamino-propyl) amine (compound 86) also
With N, N-dimethyl-1,3 propylene diamine and Compound C are raw material, it is racemic mixture or (2R, 3S) isomer, according to the method for similar embodiment 12, prepares title compound, it is racemic mixture or (2R, 3S) isomer, and related data is 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 is [4,3,2-cd] indoles-2-formyl (2 '-dimethylaminoethyl) amine (compound 87) also
With N, N-dimethyl-ethylenediamine and Compound C are raw material, and it is racemic mixture or (2R, 3S) isomer, according to the method for similar embodiment 12, prepares title compound, and it is racemic mixture or (2R, 3S) isomer, and related data is as follows:
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 is [4,3,2-cd] Indoline-2-carboxylic acid (4 '-fluoro benzoyl oxygen base) methyl ester (compound 88) also
Take 4-fluorobenzoic acid chloromethyl ester and Compound C is raw material, and it is racemic mixture or (2R, 3S) isomer, method according to similar embodiment 2 is prepared title compound, it is racemic mixture or (2R, 3S) isomer, and related data 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 is [4,3,2-cd] Indoline-2-carboxylic acid (diamantane-1-formyl radical oxygen base) methyl ester (compound 89) also
Take amantadine-1-base formic acid chloromethyl ester and Compound C is raw material, and it is racemic mixture or (2R, 3S) isomer, method according to similar embodiment 2 is prepared title compound, it is racemic mixture or (2R, 3S) isomer, and related data is 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 is [4,3,2-cd] Indoline-2-carboxylic acid hexanaphthene ketonic oxygen ylmethyl ester (compound 90) also
Take naphthenic acid chloromethyl ester and Compound C as raw material, and it is racemic mixture or (2R, 3S) isomer, by being similar to the method for embodiment 2, prepare title compound, it is racemic mixture or (2R, 3S) isomer, and related data is 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 is [4,3,2-cd] Indoline-2-carboxylic acid (1 '-benzoyl oxygen base) ethyl ester (compound 91) also
Take 1-phenylformic acid chloro-ethyl ester and Compound C as raw material, and it is racemic mixture or (2R, 3S) isomer, by being similar to the method for embodiment 2, prepare title compound, it is racemic mixture or (2R, 3S) isomer, and related data 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 is [4,3,2-cd] Indoline-2-carboxylic acid (1 '-hexanaphthene ketonic oxygen base) ethyl ester (compound 92) also
Take 1-naphthenic acid chloro-ethyl ester and Compound C as raw material, and it is racemic mixture or (2R, 3S) isomer, by being similar to the method for embodiment 2, prepare title compound, it is racemic mixture or (2R, 3S) isomer, and related data is 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 is [4,3,2-cd] indoles-2-formyl (3 '-imidazoles-1-base propyl group) amine (compound 93) also
Take compound 3-imidazoles-1-base propylamine and Compound C is raw material, and it is racemic mixture or (2R, 3S) isomer, method according to similar embodiment 12 is prepared title compound, it is racemic mixture or (2R, 3S) isomer, and related data is 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 is [4,3,2-cd] indoles-2-formyl (3 '-butyrolactam-1-base propyl group) amine (compound 94) also
Take compound 3-butyrolactam-1-base propylamine and Compound C is raw material, and it is racemic mixture or (2R, 3S) isomer, method according to similar embodiment 12 is prepared title compound, it is racemic mixture or (2R, 3S) isomer, and 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 is [4,3,2-cd] Indoline-2-carboxylic acid (2-benzoyloxy) ethyl ester (compound 95) also
Take 2-phenylformic acid chloro-ethyl ester and Compound C as raw material, and it is racemic mixture or (2R, 3S) isomer, by being similar to the method for embodiment 2, prepare title compound, it is racemic mixture or (2R, 3S) isomer, and related data 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 is [4,3,2-cd] Indoline-2-carboxylic acid (3-benzoyloxy) propyl diester (compound 96) also
Take 3-phenylformic acid chloropropyl ester and Compound C is raw material, and it is racemic mixture or (2R, 3S) isomer, by being similar to the method for embodiment 2, prepare title compound, it is racemic mixture or (2R, 3S) isomer, and related data 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 101:3-methyl-4,7,8 – tri-are bromo-3, and 5-dihydro-2H-sulphur pyrans is [4,3,2-cd] Indoline-2-carboxylic acid benzoyloxy methyl ester (compound 97) also
With compound phenylformic acid chloromethyl ester and 2-carboxylic acid-3-methyl-4,7,8-tri-is bromo-3,5-dihydro-2H-sulphur pyrans also [4,3,2-cd] indoles is raw material, it is racemic mixture or (2R, 3S) isomer, method according to similar embodiment 2 is prepared title compound, it is racemic mixture or (2R, 3S) isomer, 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 102:3-methyl-4-is bromo-3, and 5-dihydro-2H-sulphur pyrans is [4,3,2-cd] Indoline-2-carboxylic acid benzoyloxy methyl ester (compound 98) also
With compound phenylformic acid chloromethyl ester and 2-carboxylic acid-3-methyl-4 – bromo-3,5-dihydro-2H-sulphur pyrans also [4,3,2-cd] indoles is raw material, it is racemic mixture or (2R, 3S) isomer, method according to similar embodiment 2 is prepared title compound, it is racemic mixture or (2R, 3S) isomer, 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 anti-microbial activity of the compounds of this invention be by measure its to the bacterial strain of reference culture, clinical separation and the minimum inhibition concentration (MlC to the Resistant strain of some antiseptic-germicides, mg/L) measure: in this experiment, the glycine ring of new listing element class microbiotic Tigecycline (Tige) compares medicine recently.Minimal inhibitory concentration is measured as follows: in aseptic plate, add 1ml liquid, 50 ℃ of MH substratum 14ml that add again thawing, mix, make in its every ware that contained drug final concentration is followed successively by 128,64,32,16,8,4,2,1,0.5,0.25,0.125,0.06,0.03mg/L; With multiple spot, inoculate instrument (Denley A400, England) inoculation gram-bacteria, preferred Gram-negative bacteria or gram-positive microorganism after cooling, quantity of microorganism inoculated is about 10
5cFU/ml, covers ware lid.Above-mentioned bacterial strains is placed in cultivation 18-20h in 35-37 ℃ of incubator, observed and recorded result; In the plate of asepsis growth, the concentration of contained drug minimum is minimum inhibitory concentration (MIC).
Table 3 has been listed representation compound in the application's formula (I) the compound antibacterial activity in vitro to gram bacterial strain, and compares with the glycine ring element class microbiotic Tigecycline of nearest new listing.From table 3, formula of the present invention (I) compound is better than the glycine ring element microbiotic Tigecycline of nearest new listing to the external activity of these gram-bacterias, or suitable with it, formula of the present invention (I) compound is to increasing clinically MRSA(Mrsa In Rabbits) and MRSE(methicillin resistance form staph) also show good activity.For mushroom, especially gram-bacteria, preferred Gram-negative bacteria or gram-positive microorganism.
Table 3 preferred compound of the present invention is to the antibacterial activity in vitro of clinical separated gram-bacteria (MIC μ g/ml)
Applicant also adopts aforesaid method, with creatmycin (CD) and the positive contrast of desulfurization creatmycin (DSC, corresponding to the compound of numbering 20 in the present invention), has carried out simultaneous test, and acquired results is as shown in table 4-9.
Table 4
Table 5
Table 6
Table 7
As mentioned above, the compounds of this invention has stronger anti-microbial activity and wide antimicrobial spectrum to comprising the various pathogenic microorganisms of Gram-negative bacteria and gram-positive microorganism.The compounds of this invention is to gram bacterial strain, especially to comprising that the anti-microbial activity of the Staphylococcus of MRSA, MRSE is better than or is equivalent to the glycine ring element class microbiotic Tigecycline in nearest listing.The compounds of this invention is to gram bacterial strain, especially to comprising that the anti-microbial activity of the golden bacterium MRSA12-1 of Portugal, ATCC25923, MSSE12-8, Klebsiella Pneumoniae E-12-1, Pseudomonas aeruginosa 12-20, streptococcus pneumoniae 10-11 is better than positive control creatmycin and desulfurization creatmycin.
The anti-microbial activity of the anti-bacillus of the compounds of this invention, preferred anti-mycobacterium tuberculosis is to measure by measuring its minimum inhibition concentration (MlC, mg/L) to reference culture H37Rv: in this experiment, with Rifampin (RFP), compare medicine.Minimal inhibitory concentration is measured as follows: 200 μ l aqua sterilisas add in each hole of 96 orifice plates, to prevent the composition evaporation of each experimental port in culturing process, precision takes each compound 1mg respectively, adds sterile purified water 1ml, makes the storing solution of 1000 μ g/ml; RFP dissolves with dimethyl formamide; 0.22 μ m filtering with microporous membrane.Use respectively 7H9 substratum (not tween 80) dilution for each required two times of concentration, add 96 orifice plate 100 μ l, the final concentration of investigational agent (the compounds of this invention, especially table 1 or table 2 compound) is: 128.0,64.0,32.0,16.0,8.0,4.0,2.0,1.0,0.5,0.25,0.125,0.0625 μ g/ml.Contrast medicine RFP final concentration is: 32.0,16.0,8.0,4.0,2.0,1.0,0.5,0.25,0.125,0.0625,0.032 μ g/ml.Select eugonic each strain culture on modified Russell medium, make bacteria suspension, be inoculated in 7H9 liquid nutrient medium, hatch 10-14 hour for 37 ℃, making it grow to turbidity is that McFarland1(is equivalent to 107CUF/ml), after dilution, 100 μ l are inoculated, bacterium liquid final concentration in every hole
if 2 growth control holes that do not contain antimicrobial drug, are placed in 37 ℃ and hatch.After the 5th day, add growth control hole
blue(Setotec company product) and the mixed solution of 5% tween 80 50 μ l, hatch 24h for 37 ℃, if color becomes pink colour from blueness, the Alamar Blue and the tween 80 mixed solution that in the hole of each Experimental agents, add above-mentioned amount, hatch 24h for 37 ℃, record the color in each hole, MIC is defined as the lowest drug concentration that stops colour-change (becoming pink colour from blueness).Result shows that the compounds of this invention has positive effect aspect anti-bacillus, preferred Mycobacterium tuberculosis.
Table 8 has been listed representation compound CV2 in the application's formula (I) compound to bacillus, the preferred antibacterial activity in vitro of tubercule bacillus, and compares with Rifampin.From table 4, formula of the present invention (I) compound is suitable to external activity and the Rifampin of bacillus, preferred tubercule bacillus.Formula of the present invention (I) compound, especially table 1 compound be to bacillus, preferably the external activity MIC of tubercule bacillus is 0.25-8 μ g/ml, and steric isomer, especially table 2 compound with table 1 compound of concrete steric configuration shown in formula (II) or formula XV are to bacillus, preferably the external activity MIC of tubercule bacillus is 0.125-4 μ g/ml.Compare with creatmycin (CD) and desulfurization creatmycin (DSC, corresponding to the compound of numbering 20 in the present invention), the compounds of this invention has better anti-microbial activity.
Table 4 compound is to the antibacterial activity in vitro of tubercule bacillus (MIC μ g/ml)
| Compound number | Active | Compound number | Active | Compound number | Active | Compound number | Active |
| 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 about toxic side effect
Acute toxic test: adopt ICR mouse, body weight: 18-22g, male and female half and half, administration the compounds of this invention, preferably table 1 and 2 compound.Totally 20 animals.According to dosage compound described in gavage respectively, record abnormal response and the dead animal number of animal appearance in 14 days.Test-results shows, gavage of Compound C V2 gives mouse 2g/kg, has no animal dead, and the LD50 of ICR mouse stomach administration CV2 is greater than 2.0g/kg.Except Compound C V2, the compounds of this invention, preferably the LD50 of table 1 and 2 compound and Compound C V2 is suitable.
Claims (26)
1. indole derivatives or its steric isomer or their pharmacologically acceptable salt or solvate or a hydrate as shown in the formula (I):
Wherein,
R
1for H, C
1-6alkyl, C
1-6alkyloyl or C
1-6alkylamino;
R
2for H, C
1-6alkyl, C
3-6cycloalkyl, C
1-6alkoxyl group, C
1-6alkyloyl, halogen, cyano group, nitro, CF
3, amino, N (R
5)
2, COR
6, CO
2r
6, or CONR
6;
R
3for H, C
1-6alkyl, C
3-6cycloalkyl, C
1-6alkoxyl group, C
1-6alkyloyl, halogen, cyano group, nitro, CF
3, amino, N (R
5)
2, COR
6, CO
2r
6, or CON (R
6)
2;
R
4for H, C
1-6alkyl, C
3-6cycloalkyl, C
1-6alkoxyl group, C
1-6alkyloyl, halogen, cyano group, nitro, CF
3, amino, N (R
5)
2, COR
6, CO
2r
6, or CON (R
6)
2;
Each R
5be H independently, C
1-6alkyl, or COCH
2n(R
7)
2;
Each R
6be H independently, or C
1-6alkyl;
Each R
7be H independently, or C
1-6alkyl;
A, B, D is carbon or nitrogen-atoms independently of each other;
X is NH, O, S or do not exist;
Y is OR
8or N (R
8)
2;
Each R
8independently selected from
(1) H or C
1-6alkyl,
Wavy line is expressed as key place,
R
11represent H or C
1-6alkyl;
R
12representative
I) be not substituted or by 1-3 R
9the C replacing
1-6alkyl;
II) be not substituted or by halogen, C
1-6alkyl, C
1-6alkylamino, hydroxyl or C
1-6the C that alkoxyl group replaces
3-8cycloalkyl;
III) be not substituted or by 1-3 R
106 to the 18 yuan of aryl or 5 to the 14 yuan of heteroaryls that replace;
Iv) adamantyl;
Each R
8can be independently by 1-3 R
9replace,
Each R
9independently selected from halogen, C
1-6alkyl, C
1-6alkylamino, two (C
1-6alkyl) amino, hydroxyl, hydroxyl C
1-6alkyl, amino, amino C
1-6alkyl, C
1-6alkyl-carbonyl, C
1-6alkyl carbonyl oxy, amino-sulfonyl, formamyl, C
1-6alkyl-carbamoyl, C
3-8cycloalkyl; 6 to 18 yuan of aryl-carbonyl oxygens; 6 to 18 yuan of aryl or 5 to 14 yuan of heteroaryls, or R
106 to the 18 yuan of aryl or 5 to the 14 yuan of heteroaryls that replace; The non-aromatic heterocycle that contains 5 or 6 annular atomses; Butyrolactam-1-base; And phosphate;
R
10be selected from halogen, hydroxyl, amino, C
1-6alkyl-carbonyl, C
1-6alkyl, C
1-6alkoxyl group, C
1-6alkylamino and C
1-6alkyl carbonyl oxy;
Condition is that described formula (I) compound does not comprise following compound:
1) formula 2 compounds
The substituting group of above formula is as shown in the table
2) compound of following formula 3
R
1methyl and R
2it is hydroxyl; Or
R
1methyl and R
2it is oxyethyl group; With
3) compound of following formula 4
R
1methyl and R
2it is hydroxyl.
2. compound according to claim 1 or its steric isomer or their pharmacologically acceptable salt or solvate or hydrate, wherein
A, B and D are carbon atom;
B and D are carbon atom, and A is nitrogen-atoms;
D is carbon atom, and A and B are nitrogen-atoms;
A and D are carbon atom, and B is nitrogen-atoms; Or
B is carbon atom, and A and D are nitrogen-atoms.
3. compound according to claim 1 or its steric isomer or their pharmacologically acceptable salt or solvate or hydrate, described compound has following logical formula II
R
1, R
2, R
3, R
4, A, B, D, Y as defined in claim 1, X is NH, O or S.
4. compound according to claim 1 or its steric isomer or their pharmacologically acceptable salt or solvate or hydrate, described compound has following general formula X V
R
1, R
2, R
3, R
4, A, B, D, Y as defined in claim 1.
5. the compound as described in claim 1 to 4 any one or its steric isomer or their pharmacologically acceptable salt or solvate or hydrate:
Wherein,
R
1for H, C
1-4alkyl, C
1-4alkyloyl or C
1-4alkylamino;
R
2for H, C
1-4alkyl, C
3-4cycloalkyl, C
1-4alkoxyl group, C
1-4alkyloyl, halogen, cyano group, nitro, CF
3, amino, N (R
5)
2, COR
6, CO
2r
6, or CON (R
6)
2;
R
3for H, C
1-4alkyl, C
3-6cycloalkyl, C
1-6alkoxyl group, C
1-4alkyloyl, halogen, cyano group, nitro, CF
3, amino, N (R
5)
2, COR
6, CO
2r
6, or CON (R
6)
2;
R
4for H, C
1-4alkyl, C
3-4cycloalkyl, C
1-4alkoxyl group, C
1-4alkyloyl, halogen, cyano group, nitro, CF
3, amino, N (R
5)
2, COR
6, CO
2r
6, or CON (R
6)
2;
Each R
5be H independently, C
1-4alkyl, or COCH
2n(R
7)
2;
Each R
6be H independently, C
1-4alkyl;
Each R
7be H independently, C
1-4alkyl;
X is NH, O, S or do not exist;
Y is OR
8or N (R
8)
2;
Each R
8independently selected from
(1) H or C
1-6alkyl,
Wavy line is expressed as key place,
R
11represent H or C
1-6alkyl;
R
12representative
I) be not substituted or by 1-3 R
9the C replacing
1-6alkyl;
II) be not substituted or by halogen, C
1-6alkyl, C1-6 alkylamino, hydroxyl or C
1-6the C that alkoxyl group replaces
3-8cycloalkyl;
III) be not substituted or by 1-3 R
106 to the 18 yuan of aryl or 5 to the 14 yuan of heteroaryls that replace;
Iv) adamantyl;
Each R
8can be independently by 1-3 R
9replace each R
9independently selected from halogen, C
1-6alkyl, C
1-6alkylamino, two (C
1-6alkyl) amino, hydroxyl, hydroxyl C
1-6alkyl, amino, amino C
1-6alkyl, C
1-6alkyl-carbonyl, C
1-6alkyl carbonyl oxy, amino-sulfonyl, formamyl, C
1-6alkyl-carbamoyl, C
3-8cycloalkyl; 6 to 18 yuan of aryl-carbonyl oxygens; 6 to 18 yuan of aryl or 5 to 14 yuan of heteroaryls, or R
106 to the 18 yuan of aryl or 5 to the 14 yuan of heteroaryls that replace; The non-aromatic heterocycle that contains 5 or 6 annular atomses; Butyrolactam-1-base; And phosphate;
R
10be selected from halogen, hydroxyl, amino, C
1-6alkyl-carbonyl, C
1-6alkyl, C1-6 alkoxyl group, C1-6 alkylamino or C
1-6alkyl carbonyl oxy.
6. compound and pharmaceutical salts thereof, solvate, hydrate or its isomer shown in general formula as claimed in claim 1 or 2 (I), described compound is the compound that is selected from table 1 and 2.
7. a method of preparing compound shown in general formula claimed in claim 1 (I) and pharmaceutical salts, solvate, hydrate or its isomer, is characterized in that described method comprises the steps:
Step 1) makes formula III compound
React with formula 1 compound,
(R '
1)
2o formula 1
Thereby production IV compound,
Each R ' wherein
1be independently-COR
4, R
1, R
2, R
3, R
4, A, B, D define suc as formula (I), R
13for halogen or nitro;
Step 2) make formula IV compound and HXCH
2cOY ' reaction, obtains formula V compound,
Wherein Y ' is C
1-6alkoxyl group, R
1, R
2, R
3, R
4, A, B, D define suc as formula (I), X is NH, O or S;
Step 3), by formula V compound and acid and reactant salt thereof, obtains formula VI compound
Wherein Y ' defines suc as formula V, R
1, R
2, R
3, R
4, A, B, D define suc as formula (I), X is NH, O or S;
Step 4), by formula VI hydrogenation of compounds, obtains formula VII compound
Wherein Y ' defines suc as formula V, R
1, R
2, R
3, R
4, A, B, D define suc as formula (I), X is NH, O or S; With
Step 5), by formula VII compound and alkali reaction, obtains formula (I) compound, and it has the structure of formula VIII
R wherein
1, R
2, R
3, R
4, A, B, D define suc as formula (I), X is NH, O or S.
8. method claimed in claim 7, can also comprise the steps:
Step 6), under catalyzer exists, will have formula (I) compound of formula VIII structure
Be converted into formula (I) compound with formula IX structure
R wherein
1, R
2, R
3, R
4, A, B, D define suc as formula (I).
9. method claimed in claim 7, can also comprise the steps:
Step 7) is under the existence of suitable alkali, by formula VIII compound
With R
8zH reaction, obtains formula X compound
Wherein, Z is O or N, and R
8for not being substituted or by 1-3 R
9the C replacing
1-6alkyl, R
1, R
2, R
3, R
4, R
9, A, B, D define suc as formula (I), X is NH, O or S.
10. method claimed in claim 8, can also comprise the steps:
Step 8) is by formula IX compound
With R
8zH reaction, obtains formula XI compound.
Wherein, Z is O or N, and R
8for not being substituted or by 1-3 R
9the C replacing
1-6alkyl, R
1, R
2, R
3, R
4, R
9, A, B, D define suc as formula (I).
11. methods claimed in claim 7, can also comprise the steps:
Step 9) is by formula VIII compound
With
reaction, obtains formula XIII compound
Wherein, R
1, R
2, R
3, R
4, R
11, R
12, A, B, D and X define suc as formula (I).
12. methods claimed in claim 8, can also comprise the steps:
Step 10) is by formula IX compound
With
reaction, obtains formula XIV compound
Wherein, R
1, R
2, R
3, R
4, R
11, R
12, A, B and D define suc as formula (I).
The method of any one in 13. claims 7 to 12, wherein, step 1) is carried out as follows, at rare gas element, under preferred nitrogen exists, at organic solvent, preferably in methylene dichloride, at catalyzer, under preferably tin tetrachloride, and/or Nitromethane 99Min. exists, preferably at room temperature, formula III compound reacts with formula 1 compound, thus production IV compound.
The method of any one in 14. claims 7 to 12, wherein, step 2) carry out as follows, at rare gas element, under preferred nitrogen exists, by formula IV compound, HXCH
2cOY ' and suitable alkali, anhydrous pyridine for example, in appropriate solvent, for example anhydrous methanol, preferably for example,, at optimal temperature, approximately 90 ℃ of reaction appropriate times, for example 48h, obtains formula V compound.
The method of any one in 15. claims 7 to 12, wherein, step 3) is carried out as follows, and at rare gas element, under preferred nitrogen exists, by formula V compound and acid and salt thereof, preferably ammonium acetate and Glacial acetic acid reaction, obtain formula VI compound.
The method of any one in 16. claims 7 to 12, wherein, step 4) is carried out as follows, for example, at catalyzer, under 10% Pd-C exists, in organic solvent, for example ethyl acetate, preferably for example, at suitable pressure, 45 normal atmosphere, by formula VI hydrogenation of compounds, obtain formula VII compound.
The method of any one in 17. claims 7 to 12, wherein, step 5) is carried out as follows, by formula VII compound and suitable alkali, for example sodium hydroxide, in appropriate solvent, for example ethanol, water and/or tetrahydrofuran (THF), preferably, at proper temperature, for example room temperature reaction appropriate time, for example 5h, obtain formula (I) compound, it has the structure of formula VIII.
The method of 18. claims 8, wherein,
Described method steps 6) carry out as follows:
Under catalyzer, for example Raney's nickel exist, preferably, at suitable alkali, for example sodium hydroxide, in suitable solvent, for example water, formula (I) compound with formula VIII structure is converted into formula (I) compound with formula IX structure.
The method of 19. claims 9, wherein,
Described method steps 7) carry out as follows:
Under the existence of DIC and DMAP, by formula VIII compound and R
8zH reaction, obtains formula X compound.
The method of 20. claims 10, wherein,
Described method steps 8) carry out as follows:
At rare gas element for example nitrogen, suitable alkali under for example triethylamine exists, at appropriate solvent for example in DMF, by formula IX compound and R
8zH reaction, obtains formula XI compound.
The method of 21. claims 11, wherein,
Described method steps 9) carry out as follows: at rare gas element, under preferred nitrogen exists, under suitably alkali, for example triethylamine exist, in appropriate solvent, for example DMF, preferably at proper temperature, for example room temperature reaction appropriate time 5min for example, by formula VIII compound with
reaction, obtains formula XIII compound.
The method of 22. claims 12, wherein,
Described method steps 10) carry out as follows:
At rare gas element, under preferred nitrogen exists, under suitably alkali, for example triethylamine exist, in appropriate solvent, for example DMF, preferably in proper temperature, for example room temperature, by formula IX compound with
reaction appropriate time is 5min for example, obtains formula XIV compound.
23. 1 kinds of pharmaceutical compositions, wherein contain indole derivatives described in the claim 1-6 any one for the treatment of significant quantity, its steric isomer or their pharmacologically acceptable salt or solvate or hydrate, and one or more pharmaceutically acceptable carriers.
24. indole derivatives, its steric isomer or their pharmacologically acceptable salt or solvate or the application of hydrate in preparation antibacterials as described in claim 1-6 any one.
25. application as claimed in claim 24, wherein said antibacterials are anti-bacillus or gram-bacteria medicine.
26. application as claimed in claim 24, wherein said antibacterials are anti-mycobacterium tuberculosis or Gram-negative bacteria or gram-positive microorganism medicine.
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| US9630968B1 (en) | 2015-12-23 | 2017-04-25 | Arqule, Inc. | Tetrahydropyranyl amino-pyrrolopyrimidinone and methods of use thereof |
| WO2020161209A1 (en) | 2019-02-06 | 2020-08-13 | Syngenta Crop Protection Ag | Herbicidal fused pyridazine compounds |
| US11020398B2 (en) | 2016-08-24 | 2021-06-01 | Arqule, Inc. | Amino-pyrrolopyrimidinone compounds and methods of use thereof |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9630968B1 (en) | 2015-12-23 | 2017-04-25 | Arqule, Inc. | Tetrahydropyranyl amino-pyrrolopyrimidinone and methods of use thereof |
| US10245263B2 (en) | 2015-12-23 | 2019-04-02 | Arqule, Inc. | Tetrahydropyranyl amino-pyrrolopyrimidinone and methods of use thereof |
| US10933065B2 (en) | 2015-12-23 | 2021-03-02 | Arqule Inc. | Tetrahydropyranyl amino-pyrrolopyrimidinone and methods of use thereof |
| US11020400B2 (en) | 2015-12-23 | 2021-06-01 | Arqule, Inc. | Tetrahydropyranyl amino-pyrrolopyrimidinone and methods of use thereof |
| US11020398B2 (en) | 2016-08-24 | 2021-06-01 | Arqule, Inc. | Amino-pyrrolopyrimidinone compounds and methods of use thereof |
| WO2020161209A1 (en) | 2019-02-06 | 2020-08-13 | Syngenta Crop Protection Ag | Herbicidal fused pyridazine compounds |
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