CN105541828A - Acylaminoimidazole derivative and use thereof - Google Patents
Acylaminoimidazole derivative and use thereof Download PDFInfo
- Publication number
- CN105541828A CN105541828A CN201510895760.8A CN201510895760A CN105541828A CN 105541828 A CN105541828 A CN 105541828A CN 201510895760 A CN201510895760 A CN 201510895760A CN 105541828 A CN105541828 A CN 105541828A
- Authority
- CN
- China
- Prior art keywords
- base
- imidazoles
- propionate
- carboxamide
- chloro
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
- C07D233/61—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms not forming part of a nitro radical, attached to ring nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
Abstract
The invention belongs to the technical field of medicines and relates to an acylaminoimidazole derivative shown in the general formula I and its stereisomer and pharmaceutical acceptable salt, hydrate, solvate or prodrug. In the formula I, substituents R, R1, Ar, M and X are defined in the specification. The invention also relates to a method for preparing the compound shown in the formula I, a medicinal composition containing the compound and a use of the compound and the medicinal composition in preparation of drugs for treating and/or preventing cancers and other skin proliferative diseases. An antifungal experiment proves that the compound has strong resistance to shallow and deep fungi and can be used for preparation of an antibacterial drug.
Description
Technical field
The present invention relates to new imidazole derivative and pharmacy acceptable salt, hydrate, solvate or its prodrug, their preparation method and the pharmaceutical composition containing described compound.The present invention relates to imidazole derivative and pharmacy acceptable salt, hydrate, solvate or its prodrug at preparation treatment retinotic acid (ATRA) tachytrophism caused by CYP26A1 overexpression, thus make the purposes that retinotic acid pharmacologically active weakens, particularly preparing the purposes treated and/or prevented in the medicine of cancer.The invention still further relates to imdazole derivatives and pharmacy acceptable salt, hydrate, solvate or its prodrug purposes in the medicine preparing the various diseases that treatment causes due to fungi infestation thereof.
Background technology
Cancer is that current serious threatens one of important diseases of human health, and its treatment and prevention cause extensive attention.Current methods for the treatment of has excision, radiotherapy, chemotherapy etc., but still main based on chemotherapy.World Health Organization's latest data display, to the year two thousand twenty, the annual cancer morbidity in the whole world will increase by 50%, namely will increase 1,500 ten thousand cancer patientss newly every year.
Vitamin A acid (retinoicacid, RA), also known as vitamin A acid or retinoic acid, is the derivative of vitamin A, its structure by cyclohexene ring, side chain and polar group three part form.Due to polar group and pendant moiety difference, vitamin A acid comprises multiple isomers, wherein that important is 13-cisRA (3-cisretinoicacid, 13-cis-RA), 9-cis-retinoic acid (9-cisretinoicacid, 9-cis-RA) with all-trans-retinoic acid (alltransretinoicacid, ATRA).In body, certain density vitamin A acid can regulate the propagation of cell, differentiation, maturation, and it is that body normal growth is grown and the requisite important factor of physiological activity.Meanwhile, vitamin A acid has important effect in the treatment of malignant tumour.Research shows: retinoid compounds plays a significant role in cytodifferentiation, proliferation and apoptosis, has many application in the treatment of tumour, tetter and various diseases.All-trans-retinoic acid (ATRA), the metabolite that vitamin A biological activity is the strongest, has vital role in epithelial Differentiation and proliferation, has been successfully applied to the treatment of acute promyelocytic leukemia (APL).
Its mechanism of action is ATRA and cytoplasm vitamin A acid associated proteins (celllretinoicacidbindingprotein in cell, CRABP) combine, have been found that two species specific cytoplasm vitamin A acid associated proteins CRABPI and CRABPII participate in the transhipment of vitamin A acid in born of the same parents at present, ATRA and CRABP has two kinds of whereabouts after combining: one is that CRABPI is responsible for intracytoplasmic ATRA to be transferred to endoplasmic reticulum, and then by cytochrome P 450 enzymes (cytochromeP450, the CYPs) oxidative metabolism in microsome, two is that CRABPII is not combined by ATRA and 9-cis-RA of metabolism in endochylema, and be transported in nucleus, thus make ATRA and 9-cis-RA and nuclear receptor RARs (retinoicacidreceptor), RXRs (retinoidXreceptor) combines, ATRA is the native ligand of RARs, and 9-cis-RA is the part of RXRs, but 9-cis-RA also has higher avidity to RARs, with the vitamin A acid response element (retinoicacidresponseelement in the form of RXRs/RXRs homodimer or RARs/RXRs heterodimer and target gene DNA after these acceptors are activated, RARE) interact, transcribing of common promotion target gene, regulate the expression of different genes or enzyme in cell, make it activate or suppress, thus generation comprises antitumor a series of biological effects.
But the patient of application ATRA treatment, can be alleviated completely in a short time, but prolonged application easily causes recurrence, trace it to its cause, ectogenic ATRA enters human body later rapidly by cytochrome P 450 enzymes metabolism, and research finds that the newcomer CYP26 of CYP450 family is at liver, heart, hypophysis, suprarenal gland, testis, duodenum, colon, brain and placenta have expression.CYP26 has four hypotypes, and CYP26A1, CYP26B1, CYP26C1, CYP26D1, CYP26A1, zebra fish, have expression [33-38] in people and mouse organization.CYP26B1 and CYP26A1 has the similarity of 44%.CYP26A1 and CYP26B1 is can by a large amount of generation of ATRA induction, maximum to the contribution of ATRA4-hydroxylation, CYP26A1 and CYP26B1 is hydroxylation 9-cis-RA and 13-cis-RA not, and these enzymes show high selectivity to ATRA, and plays important regulating effect to ARTA level in cell.Retinoic acid metabolism blocker (retinoicacidmetabolismblockingagents, RAMBAs) metabolism of retinotic acid can be suppressed, the temporary transient ATRA level raised in tissue, increase its concentration in tumour cell, produce the effect of ATRA class medicine in local, thus show antitumour activity.Therefore, many medicine workers are devoted in the research of retinoic acid metabolism blocker.
Fungi infestation is a kind of common disease, can cause skin, and the fungi infestation at hair and the first-class shallow table place of finger (toe), also can cause subcutis, the fungi infestation of the deep tissues such as inner membrance, mainly be divided into superficial fungal infection and systemic fungal infection.Extensively carrying out in recent years along with organ transfer operation, the use of immunosuppressor increases considerably, and the insulting normal immunologic function of the Radiotherapy chemotherapy of malignant tumor patient, make the problem that fungi infestation becomes more and more general clinically, the health of the mankind in serious threat, thus find new, more preferably antifungal drug become the focus of research.
CYP51 is monooxygenase, catalysis sterol precursor 14 Alpha-Methyl hydroxylating in organism sterol route of synthesis.This process comprises 3 steps, and each step all needs a part oxygen and a part NADPH.Front 2 steps follow Cytochrome P450 superfamily albumen list oxidation cycle general formula, and 14 Alpha-Methyls successively coverlet are oxidized to 14 alpha-hydroxymethyls, 14 α-aldehyde radical, and final step 14 α-aldehyde radical discharges with formic form, and generates △ 14,15 double bonds.In fungus body, suppress the activity of CYP51, the synthesis of ergosterol can be reduced, block the synthesis of fungi inner cell film, reach the object of Antifungi growth.
Lanosterol 14 α-demethylase is that antifungal drug studies most active target spot, the especially research and development of some nitrogen azole drugs.Nitrogen azole is the class medicine that 20 generation develop the seventies from the Genes For Plant Tolerance Fungicide agricultural chemicals, and triazole antifungal agent thing is due to its has a broad antifungal spectrum, and anti-mycotic activity is better, and toxicity is low and become many class medicines clinically at present.Nitrogen azole compounds is as triazole species, imidazoles, benzimidazoless etc. have biological activity widely, vital role has been played clinical, as imidazoles miconazole (Miconazole), clotrimazole (Clotrimazole), econazole (Econazole), KETOKONAZOL (Ketoconazole) etc. with triazole type medicine as fluconazole (Fluconazole), itraconazole (Itraconazole), voriconazole (Voriconazole) and posaconazole (Posaconazole) etc. are all clinical widely used class synthetic antifunguses.Although azole drug has irreplaceable effect clinical, but such drug exposure goes out increasing deficiency, as single in narrow antimicrobial spectrum, resistance, toxic side effect, use formulation, drug interaction etc., the wide spectrum of development of new, the important topic that efficient, the diversified antifungal drug of low toxicity, administering mode is this area research always.
The present inventor, on the basis of reference, has designed and synthesized a series of new imidazole derivative.Through external activity screening, after showing this compounds and ATRA drug combination, have and strengthen ATRA Tumor suppression and differentiation-inducing activity.This compounds also through extracorporeal antifungal activity test, shows that this compounds has stronger anti-mycotic activity, in treatment fungal infection disease, have larger researching value.
Summary of the invention
The present invention relates to the glyoxaline compound shown in general formula I and pharmacy acceptable salt, hydrate, solvate or prodrug,
Wherein:
X is N, C;
N is the integer between 0-2; Be selected from 0,1,2, preferably 1;
R is (C
1-C
5) alkyl, (C
1-C
4) alkoxyl group, C
6-C
10aryl, carboxyl, (C
1-C
5) ester group, (C
1-C
5) acid amides, N-(C
6-C
10) arylamide; Described C
6-C
10aryl can be selected from hydroxyl, halogen, nitro, amino, cyano group, (C by 1-3
1-C
6) alkyl, (C
2-C
6) thiazolinyl, (C
2-C
6) alkynyl, (C
1-C
6) alkoxyl group, (C
1-C
6) replacement of alkyl sulfenyl.
Ar is C
6-C
10aryl, 5-10 unit heteroaryl, wherein, described heteroaryl contains the heteroatoms that 1-3 is selected from N, O or S, and the M replacement that the optional 1-4 of Ar identical or different;
M is hydrogen or is selected from hydroxyl, halogen, nitro, amino, cyano group, (C for 1-3 is individual
1-C
6) alkyl, (C
2-C
6) thiazolinyl, (C
2-C
6) alkynyl, (C
1-C
6) alkoxyl group, (C
1-C
6) alkyl sulfenyl, optionally by the (C of hydroxyl, amino or halogen substiuted
1-C
6) alkyl or (C
1-C
6) alkoxyl group or (C
1-C
6) alkyl sulfenyl, coverlet or two (C
1-C
6alkyl) the amino, (C that replace
1-C
6) alkyl amido, free, salify, esterification with amidated carboxyl, (C
1-C
6) alkyl sulphinyl, (C
1-C
6) alkyl sulphonyl, (C
1-C
6) alkyl acyl, formamyl, coverlet or two (C
1-C
6alkyl) the formamyl, (C that replace
1-C
3) alkylenedioxy group; M also may be 6-10 unit aryl, 5-10 unit heteroaryl, and described heteroaryl contains the heteroatoms that 1-3 is selected from O, N and S, described aryl and the optional 1-3 of a heteroaryl R
1replace;
R
1for hydrogen, hydroxyl, halogen, nitro, amino, cyano group, (C
1-C
6) alkyl, (C
2-C
6) thiazolinyl, (C
2-C
6) alkynyl, (C
1-C
6) alkoxyl group, optionally by the (C of hydroxyl, amino or halogen substiuted
1-C
6) alkyl or (C
1-C
6) alkoxyl group, coverlet or two (C
1-C
6alkyl) the amino, (C that replace
1-C
6) alkyl amido, free, salify, esterification with amidated carboxyl, (C
1-C
6) alkyl sulphinyl, (C
1-C
6) alkyl sulphonyl, (C
1-C
6) alkyl acyl, formamyl, coverlet or two (C
1-C
6alkyl) the formamyl, (C that replace
1-C
3) alkylenedioxy group.
The present invention preferably relates to the glyoxaline compound shown in general formula I and pharmacy acceptable salt, hydrate, solvate or prodrug,
X is N, C;
N is the integer between 0-1;
R is (C
1-C
5) alkyl, (C
1-C
4) alkoxyl group, C
6-C
10aryl, carboxyl, (C
1-C
5) ester group, (C
1-C
5) acid amides, N-(C
6-C
10) arylamide; Described C
6-C
10aryl can be selected from hydroxyl, halogen, nitro, amino, cyano group, (C by 1-3
1-C
6) alkyl, (C
2-C
6) thiazolinyl, (C
2-C
6) alkynyl, (C
1-C
6) alkoxyl group, (C
1-C
6) replacement of alkyl sulfenyl.
Ar is phenyl, naphthyl, pyrryl, furyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, 1, 2, 3-triazol radical, 1, 2, 4-triazol radical, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, benzothienyl, benzofuryl, indyl, benzimidazolyl-, benzopyrazoles base, benzothiazolyl, benzoxazolyl, quinolyl, isoquinolyl, benzo pyrimidyl, benzo pyridazinyl, benzopyrazines base, Thienopyrimidine base, pyrrolo-pyrimidine radicals, thienopyridine base, thienopyridine base, Ar can optionally replace by the individual identical or different M of 1-4,
M is hydrogen or is selected from hydroxyl, halogen, nitro, amino, cyano group, (C for 1-3 is individual
1-C
6) alkyl, (C
2-C
6) thiazolinyl, (C
2-C
6) alkynyl, (C
1-C
6) alkoxyl group, (C
1-C
6) alkyl sulfenyl, optionally by the (C of hydroxyl, amino or halo
1-C
6) alkyl or (C
1-C
6) alkoxyl group or (C
1-C
6) alkyl sulfenyl, coverlet or two (C
1-C
6alkyl) the amino, (C that replace
1-C
6) alkyl amido, free, salify, esterification with amidated carboxyl, (C
1-C
6) alkyl sulphinyl, alkylsulfonyl, (C
1-C
6) alkyl acyl, formamyl, coverlet or two (C
1-C
6alkyl) the formamyl, (C that replace
1-C
3) alkylenedioxy group; M also may be 6-10 unit aryl, 5-10 unit heteroaryl, and described heteroaryl contains the heteroatoms that 1-3 to be selected from O, N and S, and aryl and heteroaryl can optional 1-3 R
1replace;
R
1for hydrogen, hydroxyl, halogen, nitro, amino, cyano group, (C
1-C
6) alkyl, (C
2-C
6) thiazolinyl, (C
2-C
6) alkynyl, (C
1-C
6) alkoxyl group, optionally by the (C of hydroxyl, amino or halogen substiuted
1-C
6) alkyl or (C
1-C
6) alkoxyl group, coverlet or two (C
1-C
6alkyl) the amino, (C that replace
1-C
6) alkyl amido, free, salify, esterification with amidated carboxyl, (C
1-C
6) alkyl sulphinyl, (C
1-C
6) alkyl sulphonyl, (C
1-C
6) alkyl acyl, formamyl, coverlet or two (C
1-C
6alkyl) the formamyl, (C that replace
1-C
3) alkylenedioxy group.
The present invention preferably relates to the glyoxaline compound shown in general formula I and pharmacy acceptable salt, hydrate, solvate or prodrug,
Wherein
X is N, C;
N is the integer of 0 or 1;
R is phenyl, (C
1-C
5) ester group, (C
1-C
5) acid amides;
Ar is phenyl, naphthyl, pyrryl, furyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, 1,2,3-triazol radical, 1,2,4-triazol radical, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, benzothienyl, benzofuryl, indyl, benzimidazolyl-, benzopyrazoles base, benzothiazolyl, the individual identical or different M of the optional 1-4 of Ar replaces;
M is hydrogen or is selected from hydroxyl, halogen, nitro, amino, cyano group, (C for 1-3 is individual
1-C
6) alkyl, (C
2-C
6) thiazolinyl, (C
2-C
6) alkynyl, (C
1-C
6) alkoxyl group, (C
1-C
6) alkyl sulfenyl, optionally by the (C of hydroxyl, amino or halogen substiuted
1-C
6) alkyl or (C
1-C
6) alkoxyl group or (C
1-C
6) alkyl sulfenyl, coverlet or two (C1-C6 alkyl) the amino, (C that replace
1-C
6) alkyl amido, free, salify, esterification with amidated carboxyl, (C
1-C
6) alkyl sulphinyl, (C
1-C
6) alkyl sulphonyl, (C
1-C
6) alkyl acyl, formamyl, coverlet or two (C
1-C
6alkyl) the formamyl, (C that replace
1-C
3) alkylenedioxy group; M also may be 6-10 unit aryl, 5-10 unit heteroaryl, and described heteroaryl contains the heteroatoms that 1-3 is selected from O, N and S, described aryl and the optional 1-3 of a heteroaryl R
1replace;
R
1for hydrogen, hydroxyl, halogen, nitro, amino, cyano group, (C
1-C
6) alkyl, (C
2-C
6) thiazolinyl, (C
2-C
6) alkynyl, (C
1-C
6) alkoxyl group, optionally by the (C of hydroxyl, amino or halogen substiuted
1-C
6) alkyl or (C
1-C
6) alkoxyl group, coverlet or two (C
1-C
6alkyl) the amino, (C that replace
1-C
6) alkyl amido, free, salify, esterification with amidated carboxyl, (C
1-C
6) alkyl sulphinyl, (C
1-C
6) alkyl sulphonyl, (C
1-C
6) alkyl acyl, formamyl, coverlet or two (C1-C6 alkyl) formamyl, (C1-C3) alkylenedioxy group of replacing.
The present invention preferably relates to the glyoxaline compound shown in general formula I and pharmacy acceptable salt, hydrate, solvate or prodrug,
Wherein
X is C;
N is the integer of 1;
R is phenyl, (C
1-C
5) ester group, (C
1-C
5) acid amides;
Ar is phenyl, pyrryl, pyrazolyl, benzothiazolyl, and the individual identical or different M of the optional 1-4 of Ar replaces;
M is hydrogen or is selected from hydroxyl, halogen, nitro, amino, cyano group, (C for 1-3 is individual
1-C
6) alkyl, (C
2-C
6) thiazolinyl, (C
2-C
6) alkynyl, (C
1-C
6) alkoxyl group, (C
1-C
6) alkyl sulfenyl, optionally by the (C of hydroxyl, amino or halogen substiuted
1-C
6) alkyl or (C
1-C
6) alkoxyl group or (C
1-C
6) alkyl sulfenyl, coverlet or two (C
1-C
6alkyl) the amino, (C that replace
1-C
6) alkyl amido, free, salify, esterification with amidated carboxyl, (C
1-C
6) alkyl sulphinyl, (C
1-C
6) alkyl sulphonyl, (C
1-C
6) alkyl acyl, formamyl, coverlet or two (C
1-C
6alkyl) the formamyl, (C that replace
1-C
3) alkylenedioxy group; M also may be 6-10 unit aryl, 5-10 unit heteroaryl, and described heteroaryl contains the heteroatoms that 1-3 is selected from O, N and S, described aryl and the optional 1-3 of a heteroaryl R
1replace;
R
1for hydroxyl, halogen, nitro, amino, cyano group, (C
1-C
6) alkyl, (C
2-C
6) thiazolinyl, (C
2-C
6) alkynyl, (C
1-C
6) alkoxyl group, optionally by the (C of hydroxyl, amino or halogen substiuted
1-C
6) alkyl or (C
1-C
6) alkoxyl group, coverlet or two (C
1-C
6alkyl) the amino, (C that replace
1-C
6) alkyl amido, free, salify, esterification with amidated carboxyl, (C
1-C
6) alkyl sulphinyl, (C
1-C
6) alkyl sulphonyl, (C
1-C
6) alkoxyl group, (C
1-C
6) alkyl, (C
1-C
6) alkyl acyl, formamyl, coverlet or two (C
1-C
6alkyl) the formamyl, (C that replace
1-C
3) alkylenedioxy group.
The present invention preferably relates to the glyoxaline compound shown in general formula I and pharmacy acceptable salt, hydrate, solvate or prodrug,
Wherein
X is C;
N is the integer of 1;
R is phenmethyl, methyl esters, ethyl ester, propyl ester, isopropyl ester, isobutyl ester group, N-phenyl amide;
Ar is phenyl, pyrryl, pyrazolyl, benzothiazolyl, and the individual identical or different M of the optional 1-4 of Ar replaces;
M is hydrogen or is selected from hydroxyl, halogen, nitro, trifluoromethyl, (C for 1-3 is individual
1-C
4) alkyl, (C
1-C
4) alkoxyl group, phenyl, the optional 1-3 of a described phenyl R
1replace;
R
1for hydrogen or 1-3 the optional substituting group from halogen, (C1-C4) alkyl, (C1-C4) alkoxyl group, trifluoromethyl and trifluoromethoxy;
Compound of Formula I of the present invention and the preferred following compound of pharmacy acceptable salt, hydrate, solvate or prodrug thereof, but these compounds do not mean that any limitation of the invention:
(S)-2-(benzo [d] thiazole-2-formamido-)-3-(1H-imidazoles-1-base) methyl propionate
(S)-2-(benzo [d] thiazole-2-formamido-)-3-(1H-imidazoles-1-base) ethyl propionate
(S)-2-(benzo [d] thiazole-2-formamido-)-3-(1H-imidazoles-1-base) propyl propionate
(S)-2-(benzo [d] thiazole-2-formamido-)-3-(1H-imidazoles-1-base) isopropyl propionate
(S)-2-(benzo [d] thiazole-2-formamido-)-3-(1H-imidazoles-1-base) isobutyl propionate
(S)-N-(1-(1H-imidazoles-1-base)-3-phenylpropyl alcohol-2-base) benzo [d] thiazole-2-methane amide
(S)-2-(6-methyl benzo [d] thiazole-2-formamido-)-3-(1H-imidazoles-1-base) methyl propionate
(S)-2-(6-methyl benzo [d] thiazole-2-formamido-)-3-(1H-imidazoles-1-base) ethyl propionate
(S)-2-(6-methyl benzo [d] thiazole-2-formamido-)-3-(1H-imidazoles-1-base) propyl propionate
(S)-2-(6-methyl benzo [d] thiazole-2-formamido-)-3-(1H-imidazoles-1-base) isopropyl propionate
(S)-2-(6-methyl benzo [d] thiazole-2-formamido-)-3-(1H-imidazoles-1-base) isobutyl propionate
(S)-N-(1-(1H-imidazoles-1-base)-3-phenylpropyl alcohol-2-base)-6-methyl-benzo [d] thiazole-2-methane amide
(S)-2-(6-bromobenzene is [d] thiazole-2-formamido-also)-3-(1H-imidazoles-1-base) methyl propionate
(S)-2-(6-bromobenzene is [d] thiazole-2-formamido-also)-3-(1H-imidazoles-1-base) ethyl propionate
(S)-2-(6-bromobenzene is [d] thiazole-2-formamido-also)-3-(1H-imidazoles-1-base) propyl propionate
(S)-2-(6-bromobenzene is [d] thiazole-2-formamido-also)-3-(1H-imidazoles-1-base) isopropyl propionate
(S)-2-(6-bromobenzene is [d] thiazole-2-formamido-also)-3-(1H-imidazoles-1-base) isobutyl propionate
(S)-N-(1-(1H-imidazoles-1-base)-3-phenylpropyl alcohol-2-base) the bromo-benzo of-6-[d] thiazole-2-methane amide
(S)-2-(6-chlorobenzene is [d] thiazole-2-formamido-also)-3-(1H-imidazoles-1-base) methyl propionate
(S)-2-(6-chlorobenzene is [d] thiazole-2-formamido-also)-3-(1H-imidazoles-1-base) ethyl propionate
(S)-2-(6-chlorobenzene is [d] thiazole-2-formamido-also)-3-(1H-imidazoles-1-base) propyl propionate
(S)-2-(6-chlorobenzene is [d] thiazole-2-formamido-also)-3-(1H-imidazoles-1-base) isopropyl propionate
(S)-2-(6-chlorobenzene is [d] thiazole-2-formamido-also)-3-(1H-imidazoles-1-base) isobutyl propionate
(S)-N-(1-(1H-imidazoles-1-base)-3-phenylpropyl alcohol-2-base) the chloro-benzo of-6-[d] thiazole-2-methane amide
(S)-2-(6-methoxyl group benzo [d] thiazole-2-formamido-)-3-(1H-imidazoles-1-base) methyl propionate
(S)-2-(6-methoxyl group benzo [d] thiazole-2-formamido-)-3-(1H-imidazoles-1-base) ethyl propionate
(S)-2-(6-methoxyl group benzo [d] thiazole-2-formamido-)-3-(1H-imidazoles-1-base) propyl propionate
(S)-2-(6-methoxyl group benzo [d] thiazole-2-formamido-)-3-(1H-imidazoles-1-base) isopropyl propionate
(S)-2-(6-methoxyl group benzo [d] thiazole-2-formamido-)-3-(1H-imidazoles-1-base) isobutyl propionate
(S)-N-(1-(1H-imidazoles-1-base)-3-phenylpropyl alcohol-2-base)-6-methoxyl group-benzo [d] thiazole-2-methane amide
(S)-2-(6-trifluoromethyl benzo [d] thiazole-2-formamido-)-3-(1H-imidazoles-1-base) methyl propionate
(S)-2-(6-trifluoromethyl benzo [d] thiazole-2-formamido-)-3-(1H-imidazoles-1-base) ethyl propionate
(S)-2-(6-trifluoromethyl benzo [d] thiazole-2-formamido-)-3-(1H-imidazoles-1-base) propyl propionate
(S)-2-(6-trifluoromethyl benzo [d] thiazole-2-formamido-)-3-(1H-imidazoles-1-base) isopropyl propionate
(S)-2-(6-trifluoromethyl benzo [d] thiazole-2-formamido-)-3-(1H-imidazoles-1-base) isobutyl propionate
(S)-N-(1-(1H-imidazoles-1-base)-3-phenylpropyl alcohol-2-base)-6-trifluoromethyl-benzo [d] thiazole-2-methane amide
(S)-2-(4-methyl benzo [d] thiazole-2-formamido-)-3-(1H-imidazoles-1-base) methyl propionate
(S)-2-(4-methyl benzo [d] thiazole-2-formamido-)-3-(1H-imidazoles-1-base) ethyl propionate
(S)-2-(4-methyl benzo [d] thiazole-2-formamido-)-3-(1H-imidazoles-1-base) propyl propionate
(S)-2-(4-methyl benzo [d] thiazole-2-formamido-)-3-(1H-imidazoles-1-base) isopropyl propionate
(S)-2-(4-methyl benzo [d] thiazole-2-formamido-)-3-(1H-imidazoles-1-base) isobutyl propionate
(S)-N-(1-(1H-imidazoles-1-base)-3-phenylpropyl alcohol-2-base)-4-methyl-benzo [d] thiazole-2-methane amide
(S)-2-(4-methoxyl group benzo [d] thiazole-2-formamido-)-3-(1H-imidazoles-1-base) methyl propionate
(S)-2-(4-methoxyl group benzo [d] thiazole-2-formamido-)-3-(1H-imidazoles-1-base) ethyl propionate
(S)-2-(4-methoxyl group benzo [d] thiazole-2-formamido-)-3-(1H-imidazoles-1-base) propyl propionate
(S)-2-(4-methoxyl group benzo [d] thiazole-2-formamido-)-3-(1H-imidazoles-1-base) isopropyl propionate
(S)-2-(4-methoxyl group benzo [d] thiazole-2-formamido-)-3-(1H-imidazoles-1-base) isobutyl propionate
(S)-N-(1-(1H-imidazoles-1-base)-3-phenylpropyl alcohol-2-base)-4-methoxyl group-benzo [d] thiazole-2-methane amide
(S)-2-(4-trifluoromethyl benzo [d] thiazole-2-formamido-)-3-(1H-imidazoles-1-base) methyl propionate
(S)-2-(4-trifluoromethyl benzo [d] thiazole-2-formamido-)-3-(1H-imidazoles-1-base) ethyl propionate
(S)-2-(4-trifluoromethyl benzo [d] thiazole-2-formamido-)-3-(1H-imidazoles-1-base) propyl propionate
(S)-2-(4-trifluoromethyl benzo [d] thiazole-2-formamido-)-3-(1H-imidazoles-1-base) isopropyl propionate
(S)-2-(4-trifluoromethyl benzo [d] thiazole-2-formamido-)-3-(1H-imidazoles-1-base) isobutyl propionate
(S)-N-(1-(1H-imidazoles-1-base)-3-phenylpropyl alcohol-2-base)-4-trifluoromethyl-benzo [d] thiazole-2-methane amide
(S)-2-(4-chlorobenzene is [d] thiazole-2-formamido-also)-3-(1H-imidazoles-1-base) methyl propionate
(S)-2-(4-chlorobenzene is [d] thiazole-2-formamido-also)-3-(1H-imidazoles-1-base) ethyl propionate
(S)-2-(4-chlorobenzene is [d] thiazole-2-formamido-also)-3-(1H-imidazoles-1-base) propyl propionate
(S)-2-(4-chlorobenzene is [d] thiazole-2-formamido-also)-3-(1H-imidazoles-1-base) isopropyl propionate
(S)-2-(4-chlorobenzene is [d] thiazole-2-formamido-also)-3-(1H-imidazoles-1-base) isobutyl propionate
(S)-N-(1-(1H-imidazoles-1-base)-3-phenylpropyl alcohol-2-base)-4-Cl-benzo [d] thiazole-2-methane amide
(S)-2-(2,4,5-trimethylammonium-1-phenyl-1H-pyrrole-3-carboxamide base)-3-(1H-imidazoles-1-base) methyl propionate
(S)-2-(2,4,5-trimethylammonium-1-phenyl-1H-pyrrole-3-carboxamide base)-3-(1H-imidazoles-1-base) ethyl propionate
(S)-2-(2,4,5-trimethylammonium-1-phenyl-1H-pyrrole-3-carboxamide base)-3-(1H-imidazoles-1-base) propyl propionate
(S)-2-(2,4,5-trimethylammonium-1-phenyl-1H-pyrrole-3-carboxamide base)-3-(1H-imidazoles-1-base) isopropyl propionate
(S)-2-(2,4,5-trimethylammonium-1-phenyl-1H-pyrrole-3-carboxamide base)-3-(1H-imidazoles-1-base) isobutyl propionate
(S)-N-(1-(1H-imidazoles-1-base)-3-phenylpropyl alcohol-2-base)-2,4,5-trimethylammonium-1-phenyl-1H-pyrrole-3-carboxamides
(S)-2-[2,4,5 dimethyl-1-(4-aminomethyl phenyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) methyl propionate
(S)-2-[2,4,5 dimethyl-1-(4-aminomethyl phenyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) ethyl propionate
(S)-2-[2,4,5 dimethyl-1-(4-aminomethyl phenyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) propyl propionate
(S)-2-[2,4,5 dimethyl-1-(4-aminomethyl phenyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) isopropyl propionate
(S)-2-[2,4,5 dimethyl-1-(4-aminomethyl phenyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) isobutyl propionate
(S)-N-(1-(1H-imidazoles-1-base)-3-phenylpropyl alcohol-2-base)-2,4,5-trimethylammonium-1-(4-aminomethyl phenyl)-1H-pyrrole-3-carboxamide
(S)-2-[2,4,5-dimethyl-1-(4-bromophenyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) methyl propionate
(S)-2-[2,4,5-dimethyl-1-(4-bromophenyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) ethyl propionate
(S)-2-[2,4,5-dimethyl-1-(4-bromophenyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) propyl propionate
(S)-2-[2,4,5-dimethyl-1-(4-bromophenyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) isopropyl propionate
(S)-2-[2,4,5 dimethyl-1-(4-bromophenyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) isobutyl propionate
(S)-N-(1-(1H-imidazoles-1-base)-3-phenylpropyl alcohol-2-base)-2,4,5-trimethylammonium-1-(4-bromophenyl)-1H-pyrrole-3-carboxamide
(S)-2-[2,4,5-dimethyl-1-(4-chloro-phenyl-)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) methyl propionate
(S)-2-[2,4,5-dimethyl-1-(4-chloro-phenyl-)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) ethyl propionate
(S)-2-[2,4,5-dimethyl-1-(4-chloro-phenyl-)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) propyl propionate
(S)-2-[2,4,5-dimethyl-1-(4-chloro-phenyl-)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) isopropyl propionate
(S)-2-[2,5-dimethyl-1-(4-chloro-phenyl-)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) isobutyl propionate
(S)-N-(1-(1H-imidazoles-1-base)-3-phenylpropyl alcohol-2-base)-2,4,5-trimethylammonium-1-(4-chloro-phenyl-)-1H-pyrrole-3-carboxamide
(S)-2-[2,4,5-dimethyl-1-(4-p-methoxy-phenyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) methyl propionate
(S)-2-[2,4,5-dimethyl-1-(4-p-methoxy-phenyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) ethyl propionate
(S)-2-[2,4,5-dimethyl-1-(4-p-methoxy-phenyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) propyl propionate
(S)-2-[2,4,5-dimethyl-1-(4-p-methoxy-phenyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) isopropyl propionate
(S)-2-[2,4,5-dimethyl-1-(4-p-methoxy-phenyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) isobutyl propionate
(S)-N-(1-(1H-imidazoles-1-base)-3-phenylpropyl alcohol-2-base)-2,4,5-trimethylammonium-1-(4-p-methoxy-phenyl)-1H-pyrrole-3-carboxamide
(S)-2-[2,4,5-dimethyl-1-(4-trifluoromethyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) methyl propionate
(S)-2-[2,4,5-dimethyl-1-(4-trifluoromethyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) ethyl propionate
(S)-2-[2,4,5-dimethyl-1-(4-trifluoromethyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) propyl propionate
(S)-2-[2,4,5-dimethyl-1-(4-trifluoromethyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) isopropyl propionate
(S)-2-[2,4,5-dimethyl-1-(4-trifluoromethyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) isobutyl propionate
(S)-N-(1-(1H-imidazoles-1-base)-3-phenylpropyl alcohol-2-base)-2,4,5-trimethylammonium-1-(4-trifluoromethyl)-1H-pyrrole-3-carboxamide
(S)-2-[2,4,5-dimethyl-1-(4-ethylphenyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) methyl propionate
(S)-2-[2,4,5-dimethyl-1-(4-ethylphenyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) ethyl propionate
(S)-2-[2,4,5-dimethyl-1-(4-ethylphenyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) propyl propionate
(S)-2-[2,4,5-dimethyl-1-(4-ethylphenyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) isopropyl propionate
(S)-2-[2,4,5-dimethyl-1-(4-ethylphenyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) isobutyl propionate
(S)-2-[2,4,5-dimethyl-1-(4-nitrophenyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) methyl propionate
(S)-2-[2,4,5-dimethyl-1-(4-nitrophenyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) ethyl propionate
(S)-2-[2,4,5-dimethyl-1-(4-nitrophenyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) propyl propionate
(S)-2-[2,4,5-dimethyl-1-(4-nitrophenyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) isopropyl propionate
(S)-2-[2,4,5-dimethyl-1-(4-nitrophenyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) isobutyl propionate
(S)-2-[2,4,5-dimethyl-1-(2-aminomethyl phenyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) methyl propionate
(S)-2-[2,4,5-dimethyl-1-(2-aminomethyl phenyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) ethyl propionate
(S)-2-[2,4,5-dimethyl-1-(2-aminomethyl phenyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) propyl propionate
(S)-2-[2,4,5-dimethyl-1-(2-aminomethyl phenyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) isopropyl propionate
(S)-2-[2,4,5-dimethyl-1-(2-aminomethyl phenyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) isobutyl propionate
(S)-N-(1-(1H-imidazoles-1-base)-3-phenylpropyl alcohol-2-base)-2,4,5-trimethylammonium-1-(2-aminomethyl phenyl)-1H-pyrrole-3-carboxamide
(S)-2-[2,4,5-dimethyl-1-(2-chloro-phenyl-)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) methyl propionate
(S)-2-[2,4,5-dimethyl-1-(2-chloro-phenyl-)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) ethyl propionate
(S)-2-[2,4,5-dimethyl-1-(2-chloro-phenyl-)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) propyl propionate
(S)-2-[2,4,5-dimethyl-1-(2-chloro-phenyl-)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) isopropyl propionate
(S)-2-[2,4,5-dimethyl-1-(2-chloro-phenyl-)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) isobutyl propionate
(S)-N-(1-(1H-imidazoles-1-base)-3-phenylpropyl alcohol-2-base)-2,4,5-trimethylammonium-1-(2-chloro-phenyl-)-1H-pyrrole-3-carboxamide
(S)-2-[2,4,5-dimethyl-1-(2-p-methoxy-phenyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) methyl propionate
(S)-2-[2,4,5-dimethyl-1-(2-p-methoxy-phenyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) ethyl propionate
(S)-2-[2,4,5-dimethyl-1-(2-p-methoxy-phenyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) propyl propionate
(S)-2-[2,4,5-dimethyl-1-(2-p-methoxy-phenyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) isopropyl propionate
(S)-2-[2,4,5-dimethyl-1-(2-p-methoxy-phenyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) isobutyl propionate
(S)-N-(1-(1H-imidazoles-1-base)-3-phenylpropyl alcohol-2-base)-2,4,5-trimethylammonium-1-(2-p-methoxy-phenyl)-1H-pyrrole-3-carboxamide
(S)-2-[2,4,5-dimethyl-1-(2-trifluoromethyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) methyl propionate
(S)-2-[2,4,5-dimethyl-1-(2-trifluoromethyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) ethyl propionate
(S)-2-[2,4,5-dimethyl-1-(2-trifluoromethyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) propyl propionate
(S)-2-[2,4,5-dimethyl-1-(2-trifluoromethyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) isopropyl propionate
(S)-2-[2,4,5-dimethyl-1-(2-trifluoromethyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) isobutyl propionate
(S)-N-(1-(1H-imidazoles-1-base)-3-phenylpropyl alcohol-2-base)-2,4,5-trimethylammonium-1-(2-trifluoromethyl)-1H-pyrrole-3-carboxamide
(S)-2-[chloro-3 methyl isophthalic acids of 5--phenyl-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) methyl propionate
(S)-2-[chloro-3 methyl isophthalic acids of 5--phenyl-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) ethyl propionate
(S)-2-[chloro-3 methyl isophthalic acids of 5--phenyl-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) propyl propionate
(S)-2-[chloro-3 methyl isophthalic acids of 5--phenyl-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) isopropyl propionate
(S)-2-[chloro-3 methyl isophthalic acids of 5--phenyl-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) isobutyl propionate
(S)-N-(1-(1H-imidazoles-1-base)-3-phenylpropyl alcohol-2-base) chloro-3 methyl isophthalic acids of-5--phenyl-1H-pyrazole-4-carboxamide
(S)-2-[chloro-3 methyl isophthalic acids of 5--(4-aminomethyl phenyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) methyl propionate
(S)-2-[chloro-3 methyl isophthalic acids of 5--(4-aminomethyl phenyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) ethyl propionate
(S)-2-[chloro-3 methyl isophthalic acids of 5--(4-aminomethyl phenyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) propyl propionate
(S)-2-[chloro-3 methyl isophthalic acids of 5--(4-aminomethyl phenyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) isopropyl propionate
(S)-2-[chloro-3 methyl isophthalic acids of 5--(4-aminomethyl phenyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) isobutyl propionate
(S)-N-(1-(1H-imidazoles-1-base)-3-phenylpropyl alcohol-2-base) chloro-3 methyl isophthalic acids of-5--(4-aminomethyl phenyl)-1H-pyrazole-4-carboxamide
(S)-2-[chloro-3 methyl isophthalic acids of 5--(4-bromophenyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) methyl propionate
(S)-2-[chloro-3 methyl isophthalic acids of 5--(4-bromophenyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) ethyl propionate
(S)-2-[chloro-3 methyl isophthalic acids of 5--(4-bromophenyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) propyl propionate
(S)-2-[chloro-3 methyl isophthalic acids of 5--(4-bromophenyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) isopropyl propionate
(S)-2-[chloro-3 methyl isophthalic acids of 5--(4-bromophenyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) isobutyl propionate
(S)-N-(1-(1H-imidazoles-1-base)-3-phenylpropyl alcohol-2-base) chloro-3 methyl isophthalic acids of-5--(4-bromophenyl)-1H-pyrazole-4-carboxamide
(S)-2-[chloro-3 methyl isophthalic acids of 5--(4-chloro-phenyl-)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) methyl propionate
(S)-2-[chloro-3 methyl isophthalic acids of 5--(4-chloro-phenyl-)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) ethyl propionate
(S)-2-[chloro-3 methyl isophthalic acids of 5--(4-chloro-phenyl-)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) propyl propionate
(S)-2-[chloro-3 methyl isophthalic acids of 5--(4-chloro-phenyl-)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) isopropyl propionate
(S)-2-[chloro-3 methyl isophthalic acids of 5--(4-chloro-phenyl-)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) isobutyl propionate
(S)-N-(1-(1H-imidazoles-1-base)-3-phenylpropyl alcohol-2-base) chloro-3 methyl isophthalic acids of-5--(4-chloro-phenyl-)-1H-pyrazole-4-carboxamide
(S)-2-[chloro-3 methyl isophthalic acids of 5--(4-p-methoxy-phenyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) methyl propionate
(S)-2-[chloro-3 methyl isophthalic acids of 5--(4-p-methoxy-phenyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) ethyl propionate
(S)-2-[chloro-3 methyl isophthalic acids of 5--(4-p-methoxy-phenyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) propyl propionate
(S)-2-[chloro-3 methyl isophthalic acids of 5--(4-p-methoxy-phenyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) isopropyl propionate
(S)-2-[chloro-3 methyl isophthalic acids of 5--(4-p-methoxy-phenyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) isobutyl propionate
(S)-N-(1-(1H-imidazoles-1-base)-3-phenylpropyl alcohol-2-base) chloro-3 methyl isophthalic acids of-5--(4-p-methoxy-phenyl)-1H-pyrazole-4-carboxamide
(S)-2-[chloro-3 methyl isophthalic acids of 5--(4-trifluoromethyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) methyl propionate
(S)-2-[chloro-3 methyl isophthalic acids of 5--(4-trifluoromethyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) ethyl propionate
(S)-2-[chloro-3 methyl isophthalic acids of 5--(4-trifluoromethyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) propyl propionate
(S)-2-[chloro-3 methyl isophthalic acids of 5--(4-trifluoromethyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) isopropyl propionate
(S)-2-[chloro-3 methyl isophthalic acids of 5--(4-trifluoromethyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) isobutyl propionate
(S)-N-(1-(1H-imidazoles-1-base)-3-phenylpropyl alcohol-2-base) chloro-3 methyl isophthalic acids of-5--(4-trifluoromethyl)-1H-pyrazole-4-carboxamide
(S)-2-[chloro-3 methyl isophthalic acids of 5--(4-fluorophenyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) methyl propionate
(S)-2-[chloro-3 methyl isophthalic acids of 5--(4-fluorophenyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) ethyl propionate
(S)-2-[chloro-3 methyl isophthalic acids of 5--(4-fluorophenyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) propyl propionate
(S)-2-[chloro-3 methyl isophthalic acids of 5--(4-fluorophenyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) isopropyl propionate
(S)-2-[chloro-3 methyl isophthalic acids of 5--(4-fluorophenyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) isobutyl propionate
(S)-N-(1-(1H-imidazoles-1-base)-3-phenylpropyl alcohol-2-base) chloro-3 methyl isophthalic acids of-5--(4-fluorophenyl)-1H-pyrazole-4-carboxamide
(S)-2-[chloro-3 methyl isophthalic acids of 5--(4-nitrophenyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) methyl propionate
(S)-2-[chloro-3 methyl isophthalic acids of 5--(4-nitrophenyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) ethyl propionate
(S)-2-[chloro-3 methyl isophthalic acids of 5--(4-nitrophenyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) propyl propionate
(S)-2-[chloro-3 methyl isophthalic acids of 5--(4-nitrophenyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) isopropyl propionate
(S)-2-[chloro-3 methyl isophthalic acids of 5--(4-nitrophenyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) isobutyl propionate
(S)-N-(1-(1H-imidazoles-1-base)-3-phenylpropyl alcohol-2-base) chloro-3 methyl isophthalic acids of-5--(4-nitrophenyl)-1H-pyrazole-4-carboxamide
(S)-2-[chloro-3 methyl isophthalic acids of 5--(2-aminomethyl phenyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) methyl propionate
(S)-2-[chloro-3 methyl isophthalic acids of 5--(2-aminomethyl phenyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) ethyl propionate
(S)-2-[chloro-3 methyl isophthalic acids of 5--(2-aminomethyl phenyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) propyl propionate
(S)-2-[chloro-3 methyl isophthalic acids of 5--(2-aminomethyl phenyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) isopropyl propionate
(S)-2-[chloro-3 methyl isophthalic acids of 5--(2-aminomethyl phenyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) isobutyl propionate
(S)-N-(1-(1H-imidazoles-1-base)-3-phenylpropyl alcohol-2-base) chloro-3 methyl isophthalic acids of-5--(2-aminomethyl phenyl)-1H-pyrazole-4-carboxamide
(S)-2-[chloro-3 methyl isophthalic acids of 5--(2-chloro-phenyl-)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) methyl propionate
(S)-2-[chloro-3 methyl isophthalic acids of 5--(2-chloro-phenyl-)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) ethyl propionate
(S)-2-[chloro-3 methyl isophthalic acids of 5--(2-chloro-phenyl-)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) propyl propionate
(S)-2-[chloro-3 methyl isophthalic acids of 5--(2-chloro-phenyl-)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) isopropyl propionate
(S)-2-[chloro-3 methyl isophthalic acids of 5--(2-chloro-phenyl-)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) isobutyl propionate
(S)-N-(1-(1H-imidazoles-1-base)-3-phenylpropyl alcohol-2-base) chloro-3 methyl isophthalic acids of-5--(2-chloro-phenyl-)-1H-pyrazole-4-carboxamide
(S)-2-[chloro-3 methyl isophthalic acids of 5--(2-p-methoxy-phenyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) methyl propionate
(S)-2-[chloro-3 methyl isophthalic acids of 5--(2-p-methoxy-phenyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) ethyl propionate
(S)-2-[chloro-3 methyl isophthalic acids of 5--(2-p-methoxy-phenyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) propyl propionate
(S)-2-[chloro-3 methyl isophthalic acids of 5--(2-p-methoxy-phenyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) isopropyl propionate
(S)-2-[chloro-3 methyl isophthalic acids of 5--(2-p-methoxy-phenyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) isobutyl propionate
(S)-N-(1-(1H-imidazoles-1-base)-3-phenylpropyl alcohol-2-base) chloro-3 methyl isophthalic acids of-5--(2-p-methoxy-phenyl)-1H-pyrazole-4-carboxamide
(S)-2-[chloro-3 methyl isophthalic acids of 5--(2-trifluoromethyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) methyl propionate
(S)-2-[chloro-3 methyl isophthalic acids of 5--(2-trifluoromethyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) ethyl propionate
(S)-2-[chloro-3 methyl isophthalic acids of 5--(2-trifluoromethyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) propyl propionate
(S)-2-[chloro-3 methyl isophthalic acids of 5--(2-trifluoromethyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) isopropyl propionate
(S)-2-[chloro-3 methyl isophthalic acids of 5--(2-trifluoromethyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) isobutyl propionate
(S)-N-(1-(1H-imidazoles-1-base)-3-phenylpropyl alcohol-2-base) chloro-3 methyl isophthalic acids of-5--(2-trifluoromethyl)-1H-pyrazole-4-carboxamide
(S)-2-[(1,1'-xenyl)-4-formamido-]-3-(1H-imidazoles-1-base) methyl propionate
(S)-2-[(1,1'-xenyl)-4-formamido-]-3-(1H-imidazoles-1-base) ethyl propionate
(S)-2-[(1,1'-xenyl)-4-formamido-]-3-(1H-imidazoles-1-base) propyl propionate
(S)-2-[(1,1'-xenyl)-4-formamido-]-3-(1H-imidazoles-1-base) isopropyl propionate
(S)-2-[(1,1'-xenyl)-4-formamido-]-3-(1H-imidazoles-1-base) isobutyl propionate
(S)-N-(1-(1H-imidazoles-1-base)-3-phenylpropyl alcohol-2-base)-(1,1'-xenyl)-4-formamido-
(S)-2-[4'-fluoro-(1,1'-xenyl)-4-formamido-]-3-(1H-imidazoles-1-base) methyl propionate
(S)-2-[4'-fluoro-(1,1'-xenyl)-4-formamido-]-3-(1H-imidazoles-1-base) ethyl propionate
(S)-2-[4'-fluoro-(1,1'-xenyl)-4-formamido-]-3-(1H-imidazoles-1-base) propyl propionate
(S)-2-[4'-fluoro-(1,1'-xenyl)-4-formamido-]-3-(1H-imidazoles-1-base) isopropyl propionate
(S)-2-[4'-fluoro-(1,1'-xenyl)-4-formamido-]-3-(1H-imidazoles-1-base) isobutyl propionate
(S)-N-(1-(1H-imidazoles-1-base)-3-phenylpropyl alcohol-2-base)-4'-fluoro-(1,1'-xenyl)-4-formamido-
(S)-2-[4'-methyl-(1,1'-xenyl)-4-formamido-]-3-(1H-imidazoles-1-base) methyl propionate
(S)-2-[4'-methyl-(1,1'-xenyl)-4-formamido-]-3-(1H-imidazoles-1-base) ethyl propionate
(S)-2-[4'-methyl-(1,1'-xenyl)-4-formamido-]-3-(1H-imidazoles-1-base) propyl propionate
(S)-2-[4'-methyl-(1,1'-xenyl)-4-formamido-]-3-(1H-imidazoles-1-base) isopropyl propionate
(S)-2-[4'-methyl-(1,1'-xenyl)-4-formamido-]-3-(1H-imidazoles-1-base) isobutyl propionate
(S)-N-(1-(1H-imidazoles-1-base)-3-phenylpropyl alcohol-2-base)-4'-methyl-(1,1'-xenyl)-4-formamido-
(S)-2-[2'-fluoro-(1,1'-xenyl)-4-formamido-]-3-(1H-imidazoles-1-base) methyl propionate
(S)-2-[2'-fluoro-(1,1'-xenyl)-4-formamido-]-3-(1H-imidazoles-1-base) ethyl propionate
(S)-2-[2'-fluoro-(1,1'-xenyl)-4-formamido-]-3-(1H-imidazoles-1-base) propyl propionate
(S)-2-[2'-fluoro-(1,1'-xenyl)-4-formamido-]-3-(1H-imidazoles-1-base) isopropyl propionate
(S)-2-[2'-fluoro-(1,1'-xenyl)-4-formamido-]-3-(1H-imidazoles-1-base) isobutyl propionate
(S)-N-(1-(1H-imidazoles-1-base)-3-phenylpropyl alcohol-2-base)-2'-fluoro-(1,1'-xenyl)-4-formamido-
(S)-2-[2'-methyl-(1,1'-xenyl)-4-formamido-]-3-(1H-imidazoles-1-base) methyl propionate
(S)-2-[2'-methyl-(1,1'-xenyl)-4-formamido-]-3-(1H-imidazoles-1-base) ethyl propionate
(S)-2-[2'-methyl-(1,1'-xenyl)-4-formamido-]-3-(1H-imidazoles-1-base) propyl propionate
(S)-2-[2'-methyl-(1,1'-xenyl)-4-formamido-]-3-(1H-imidazoles-1-base) isopropyl propionate
(S)-2-[2'-methyl-(1,1'-xenyl)-4-formamido-]-3-(1H-imidazoles-1-base) isobutyl propionate
(S)-N-(1-(1H-imidazoles-1-base)-3-phenylpropyl alcohol-2-base)-2'-methyl-(1,1'-xenyl)-4-formamido-
(S)-N-methyl-2-[(1,1'-xenyl)-4-formamido-]-3-(1H-imidazoles-1-base) propionic acid amide
(S)-N-ethyl-2-[(1,1'-xenyl)-4-formamido-]-3-(1H-imidazoles-1-base) propionic acid amide
(S)-N-phenyl-2-[(1,1'-xenyl)-4-formamido-]-3-(1H-imidazoles-1-base) propionic acid amide
And according to some usual methods in field belonging to the present invention, in the present invention, the derivative of above formula I can generate pharmacy acceptable salt with acid.Pharmaceutically acceptable additive salt comprises mineral acid and organic acid addition salt, is particularly preferred: hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid, methylsulfonic acid, ethyl sulfonic acid, tosic acid, Phenylsulfonic acid, naphthalene disulfonic acid, acetic acid, propionic acid, lactic acid, trifluoroacetic acid, toxilic acid, citric acid, fumaric acid, oxalic acid, tartrate, phenylformic acid etc. with the salt of following sour addition.
In addition, the present invention also comprises the prodrug of derivative of the present invention.The prodrug of derivative of the present invention is the derivative of general formula I, they self may have more weak activity and even not have activity, but (such as by metabolism, solvolysis or other mode) is converted to corresponding biologically active form upon administration, in physiological conditions.
In the present invention, " halogen " refers to fluorine, chlorine, bromine or iodine generation; " alkyl " refers to the alkyl of straight or branched; " aryl " refers to two hydrogen atoms of in removing aromatic hydrocarbons or different positions and the organic group that obtains, as phenyl, naphthyl; " heteroaryl " refers to containing one or more ring-type system being selected from the heteroatomic monocycle of N, O, S or many rings, this ring-type system refers to have aromaticity, and two hydrogen atoms of that removes in ring-type system or different positions and the organic group obtained, as thiazolyl, imidazolyl, pyridyl, pyrazolyl, (1,2,3)-and (1,2,4)-triazolyl, furyl, thienyl, pyrryl, indyl, benzothiazolyl oxazolyl ， isoxazolyl, naphthyl, quinolyl, isoquinolyl, benzimidazolyl-, benzoxazolyl etc.
The present invention can contain the derivative of above formula I, and pharmacy acceptable salt, hydrate, solvate or prodrug are as active ingredient, composition is mixed with into pharmaceutically acceptable carrier or excipient, and being prepared into acceptable formulation clinically, above-mentioned pharmaceutically acceptable excipient refers to any thinner, auxiliary and/or the carrier that can be used for pharmaceutical field.Derivative of the present invention can combinationally use with other active ingredients, such as, as long as they do not produce other disadvantageous effect, anaphylaxis.
Medicinal compositions of the present invention can be mixed with several formulation, wherein containing some conventional vehicle in pharmaceutical field.Several formulation as above can adopt the drug forms such as injection, tablet, capsule, aerosol, suppository, film, pill, externally-applied liniment, ointment.
Carrier for pharmaceutical composition of the present invention is available common type in pharmaceutical field, comprising: tackiness agent, lubricant, disintegrating agent, solubility promoter, thinner, stablizer, suspension agent, non-pigment, correctives, sanitas, solubilizing agent and matrix etc.Pharmaceutical preparation can oral administration or parenteral (such as intravenously, subcutaneous, intraperitoneal or local) administration, if some drugs is unstable under stomach condition, can be mixed with enteric coated tablets.
Anti tumor activity in vitro test shows, when the derivative of general formula I of the present invention and ATRA (all-trans-retinoic acid) Combined Preparation, there is anti-tumor activity, therefore the compounds of this invention may be used for preparing the medicine treating and/or preventing various cancer, as cancer and leukemia, the neuroblastoma etc. of mammary gland, lung, liver, kidney, colon, rectum, stomach, prostate gland, bladder, uterus, pancreas, marrow, testis, ovary, lymph, soft tissue, neck, Tiroidina, esophagus.Be used in particular for preparation and treat and/or prevent the early leukemic medicine of young grain.
Extracorporeal antifungal activity experiment shows, the derivative of general formula I of the present invention has good anti-mycotic activity, therefore the present invention may be used for the various antimycotic medicine of preparation treatment, as the medicine such as anti-candida albicans, Candida parapsilosis bacterium, level and smooth candidiasis, cryptococcus neoformans, microsporon gypseum, trichophyton, Aspergillus fumigatus.
Active compound of the present invention or its pharmacologically acceptable salt and solvate thereof can be used as the antitumor drug of combining with ATRA and use.Combination therapy by by each treatment component simultaneously, order or separate administration to realize.
The embodiment hereinafter provided and preparation example are illustrated further and are illustrated the compounds of this invention and preparation method thereof.Should be appreciated that the scope of following example and preparation example and limit the scope of the invention never in any form.According to formula I of the present invention; all can pass through acylation reaction according to the method for route 1 by corresponding intermediate A and corresponding intermediate B; and the nucleophilic substitution preparation of imidazoles or triazole gets, the whole variable factors applied in these routes are as the definition in claim.
According to formula I derivative of the present invention, the EDCI of catalytic amount all can be added by corresponding intermediate A according to the method for route 1, HOBt; stirring at room temperature 2h, adds intermediate B and DIEA, and reflux about 5h; intermediate C is obtained by acylation reaction; add N again, N'-Carbonyldiimidazole, imidazoles or N; N'-Carbonylditriazole; triazole is in acetonitrile solvent, and backflow 5h, obtains target product I.Wherein, Ar, M, R and n in compound are as defined in the claims.
When Ar is benzothiazolyl, when n is 1, the synthetic method following (route 2) of intermediate A-1.
When Ar is pyrryl, when n is 1, the synthetic method following (route 3) of intermediate A-2 when M is phenyl.
When Ar is pyrazolyl, when n is 1, the synthetic method following (route 4) of intermediate A-2 when M is phenyl.
When Ar is phenyl, when n is 1, the synthetic method following (route 5) of intermediate A-2 when M is phenyl.
When n is 1, the synthetic method following (route 5) of intermediate A-2 when M is phenyl.
When R is ester group, the synthetic method of intermediate B-1 is as follows ":
When R is phenmethyl, the synthetic method of intermediate B-2 is as follows ":
The substituent R of all intermediates in above 7 routes
1, R, M, Ar and n as defined in the claims.
Embodiment:
Embodiment is intended to set forth instead of limit the scope of the invention.The proton nmr spectra BrukerARX-400 of compound measures, and mass spectrum Agilent1100LC/MSD measures; Agents useful for same is analytical pure or chemical pure.
The structural formula of table 1 embodiment 1 ~ 60
The structural formula of table 2 embodiment 61 ~ 130
The structural formula of table 3 embodiment 131 ~ 202
The structural formula of table 4 embodiment 203 ~ 241
Embodiment 1:(S) preparation of-2-(benzo [d] thiazole-2-formamido-)-3-(1H-imidazoles-1-base) methyl propionate
Steps A-12-oxo-2-amino phenyl acetate ethyl ester preparation (1)
Aniline 5.00g (53.8mmol) joins in the oxalic acid diethyl ester of 20mL, temperature control 150 DEG C, and after 5h, TLC monitoring reacts completely.Cooling reaction solution, adds 100mL sherwood oil, and stirring 10min has a large amount of white solid to generate, and suction filtration obtains white solid 8.52g, yield 82.1%.MS[M+H]+
+(m/z)：194。
The preparation (2) of steps A-22-sulfo--2-amino phenyl acetate ethyl ester
Join in 30mL toluene by intermediate 1 (2-oxo-2-amino phenyl acetate ethyl ester) 2.00g (10.4mmol) and lawesson reagent 2.10g (5.2mmol), 70 DEG C of reactions 3h, TLC monitor reaction and complete.Concentrating under reduced pressure solvent, column chromatography for separation obtains red oil 1.59g, yield 73.6%.MS[M+H]
+(m/z)：210。
The preparation (3) of steps A-32-sulfo--2-amino phenyl acetate
Be dissolved in 15mL methylene dichloride by intermediate 2 (sulfo--2-amino phenyl acetate ethyl ester) 1.5g (7.2mmol), add the NaOH of 30mL2N, stirred at ambient temperature 2h, TLC monitoring reacts completely.Remove methylene dichloride under reduced pressure.
The preparation (4) of steps A-4 benzo [d] thiazole-2-formic acid
Tripotassium iron hexacyanide 7.08g (21.6mmol) is dissolved in 21mL water, is added drop-wise in above-mentioned 3 (2-sulfo--2-amino phenyl acetate) reaction solution under room temperature, and after 3h, TLC monitoring reacts completely.Concentrated hydrochloric acid adjust ph to 1, has a large amount of solid to separate out, and stirs 30min, suction filtration, dry, obtains off-white color solid 0.93g, yield 72.1%.MS[M+H]
-(m/z)：178。
The preparation (5) of steps A-5L-serine methyl ester hydrochloride
Serine 4.00g (38.10mmol) joins in 40mL methyl alcohol, drips SOCl
28.3mL (114.30mmol), drip finish be warming up to backflow (65 DEG C), be stirred to reaction solution clarify.Concentrating under reduced pressure reaction solution obtains white solid 5.67g, yield 96.1%.MS[M+H]
-(m/z)：120。
The preparation (6) of steps A-6 (S)-2-(benzo [d] thiazole-2-formamido-)-3-hydroxy methyl propionate
Intermediate 4 benzo [d] thiazole-2-formic acid 0.70g (3.91mmol), EDCI0.82g (4.3mmol) and HOBt0.85g (4.3mmol) are dissolved in the DMF of 30mL, stirred at ambient temperature 2h, add intermediate 5L-serine methyl ester hydrochloride 0.67g (4.30mmol) and DIEA2mL, react 5h at 70 DEG C, TLC monitoring reacts completely.In reaction solution, add 100mL water, 56mLEA extracts, and saturated common salt water washing has basic unit, Na
2sO
4dried overnight.Filtering siccative, concentrating under reduced pressure obtains brown oil 0.56g, yield 51.4%.MS[M+H]
-(m/z)：281。
The preparation (7) of steps A-7 (S)-2-(benzo [d] thiazole-2-formamido-)-3-(1H-imidazoles-1-base) methyl propionate
Intermediate 6 (S)-2-(benzo [d] thiazole-2-formamido-)-3-hydroxy methyl propionate 0.50g (1.79mmol), CDI0.44g (2.69mmol) and imidazoles 0.18g (2.69mmol) are dissolved in 10mL acetonitrile, at 70 DEG C, react 4h, TLC monitoring reacts completely.Pressurization concentration of reaction solution, is dissolved in ethyl acetate by residue, washing, saturated common salt water washing, Na
2sO
4dried overnight.Filtering siccative, concentrating under reduced pressure obtains reddish-brown oily matter, and column chromatography obtains white solid 0.38g, yield 64.4%.m.p.147.0-147.3℃；
1H-NMR(CDCl
3,400MHz):δ:8.16-8.14(d,1H,J＝7.24hz),8.11-8.09(d,1H,J＝7.84hz),7.99-7.97(m,1H),7.73(s,1H),7.56-7.50(m,2H),7.10(s,1H),6.95(s,1H),5.17-5.09(m,1H),4.66-4.64(d,2H,J＝4.52hz),3.86(s,3H)；ESI-MSm/z:331.0[M+H]
+。
According to the method for embodiment 1, substituted aniline is used to be raw material respectively, react with oxalic acid diethyl ester and prepare intermediate 1, intermediate 2 is obtained respectively again through thio reaction, intermediate 2 obtains intermediate 4 through hydrolysis ring-closure reaction, intermediate 4 is obtained by reacting intermediate 6 with Serine ester again, and intermediate 6 prepares embodiment 2-50 through the nucleophilic substitution reaction of imidazole group.
Embodiment 2 (S)-2-(benzo [d] thiazole-2-formamido-)-3-(1H-imidazoles-1-base) ethyl propionate
ESI-MS[M+H]
+(m/z):345；
Embodiment 3 (S)-2-(benzo [d] thiazole-2-formamido-)-3-(1H-imidazoles-1-base) propyl propionate
ESI-MS[M+H]
+(m/z):359；
Embodiment 4 (S)-2-(benzo [d] thiazole-2-formamido-)-3-(1H-imidazoles-1-base) isopropyl propionate
ESI-MS[M+H]
+(m/z):359；
Embodiment 5 (S)-2-(benzo [d] thiazole-2-formamido-)-3-(1H-imidazoles-1-base) isobutyl propionate
ESI-MS[M+H]
+(m/z):373；
Embodiment 6 (S)-2-(6-methyl benzo [d] thiazole-2-formamido-)-3-(1H-imidazoles-1-base) methyl propionate
ESI-MS[[M+H]
+(m/z):345；
Embodiment 7 (S)-2-(6-methyl benzo [d] thiazole-2-formamido-)-3-(1H-imidazoles-1-base) ethyl propionate
ESI-MS[M+H]
+(m/z):359；
Embodiment 8 (S)-2-(6-methyl benzo [d] thiazole-2-formamido-)-3-(1H-imidazoles-1-base) propyl propionate
ESI-MS[M+H]
+(m/z):373；
Embodiment 9 (S)-2-(6-methyl benzo [d] thiazole-2-formamido-)-3-(1H-imidazoles-1-base) isopropyl propionate
ESI-MS[M+H]
+(m/z):373；
Embodiment 10 (S)-2-(6-methyl benzo [d] thiazole-2-formamido-)-3-(1H-imidazoles-1-base) isobutyl propionate
ESI-MS[M+H]
+(m/z):387；
Embodiment 11 (S)-2-(6-bromobenzene is [d] thiazole-2-formamido-also)-3-(1H-imidazoles-1-base) methyl propionate
ESI-MS[M+H]
+(m/z):409；
Embodiment 12 (S)-2-(6-bromobenzene is [d] thiazole-2-formamido-also)-3-(1H-imidazoles-1-base) ethyl propionate
ESI-MS[M+H](m/z):423；
Embodiment 13 (S)-2-(6-bromobenzene is [d] thiazole-2-formamido-also)-3-(1H-imidazoles-1-base) propyl propionate
ESI-MS[M+H]
+(m/z):437；
Embodiment 14 (S)-2-(6-bromobenzene is [d] thiazole-2-formamido-also)-3-(1H-imidazoles-1-base) isopropyl propionate
ESI-MS[M+H]
+(m/z):437；
Embodiment 15 (S)-2-(6-bromobenzene is [d] thiazole-2-formamido-also)-3-(1H-imidazoles-1-base) isobutyl propionate
ESI-MS[M+H]
+(m/z):451；
Embodiment 16 (S)-2-(6-chlorobenzene is [d] thiazole-2-formamido-also)-3-(1H-imidazoles-1-base) methyl propionate
ESI-MS[M+H]
+(m/z):365；
Embodiment 17 (S)-2-(6-chlorobenzene is [d] thiazole-2-formamido-also)-3-(1H-imidazoles-1-base) ethyl propionate
ESI-MS[M+H]
+(m/z):379；
Embodiment 18 (S)-2-(6-chlorobenzene is [d] thiazole-2-formamido-also)-3-(1H-imidazoles-1-base) propyl propionate
ESI-MS[M+H]
+(m/z):393；
Embodiment 19 (S)-2-(6-chlorobenzene is [d] thiazole-2-formamido-also)-3-(1H-imidazoles-1-base) isopropyl propionate
ESI-MS[M+H]
+(m/z):393；
Embodiment 20 (S)-2-(6-chlorobenzene is [d] thiazole-2-formamido-also)-3-(1H-imidazoles-1-base) isobutyl propionate
ESI-MS[M+H]
+(m/z):407；
Embodiment 21 (S)-2-(6-methoxyl group benzo [d] thiazole-2-formamido-)-3-(1H-imidazoles-1-base) methyl propionate
ESI-MS[M+H]
+(m/z):361；
Embodiment 22 (S)-2-(6-methoxyl group benzo [d] thiazole-2-formamido-)-3-(1H-imidazoles-1-base) ethyl propionate
ESI-MS[M+H]
+(m/z):375；
Embodiment 23 (S)-2-(6-methoxyl group benzo [d] thiazole-2-formamido-)-3-(1H-imidazoles-1-base) propyl propionate
ESI-MS[M+H]
+(m/z):389；
Embodiment 24 (S)-2-(6-methoxyl group benzo [d] thiazole-2-formamido-)-3-(1H-imidazoles-1-base) isopropyl propionate
ESI-MS[M+H]
+(m/z):389；
Embodiment 25 (S)-2-(6-methoxyl group benzo [d] thiazole-2-formamido-)-3-(1H-imidazoles-1-base) isobutyl propionate
ESI-MS[M+H]
+(m/z):403；
Embodiment 26 (S)-2-(6-trifluoromethyl benzo [d] thiazole-2-formamido-)-3-(1H-imidazoles-1-base) methyl propionate
ESI-MS[M+H]
+(m/z):399；
Embodiment 27 (S)-2-(6-trifluoromethyl benzo [d] thiazole-2-formamido-)-3-(1H-imidazoles-1-base) ethyl propionate
ESI-MS[M+H]
+(m/z):413；
Embodiment 28 (S)-2-(6-trifluoromethyl benzo [d] thiazole-2-formamido-)-3-(1H-imidazoles-1-base) propyl propionate
ESI-MS[M+H]
+(m/z):427；
Embodiment 29 (S)-2-(6-trifluoromethyl benzo [d] thiazole-2-formamido-)-3-(1H-imidazoles-1-base) isopropyl propionate
ESI-MS[M+H]
+(m/z):427；
Embodiment 30 (S)-2-(6-trifluoromethyl benzo [d] thiazole-2-formamido-)-3-(1H-imidazoles-1-base) isobutyl propionate
ESI-MS[M+H]
+(m/z):441；
Embodiment 31 (S)-2-(4-methyl benzo [d] thiazole-2-formamido-)-3-(1H-imidazoles-1-base) methyl propionate
ESI-MS[M+H]
+(m/z):345；
Embodiment 32 (S)-2-(4-methyl benzo [d] thiazole-2-formamido-)-3-(1H-imidazoles-1-base) ethyl propionate
ESI-MS[M+H]
+(m/z):359；
Embodiment 33 (S)-2-(4-methyl benzo [d] thiazole-2-formamido-)-3-(1H-imidazoles-1-base) propyl propionate
ESI-MS[M+H]
+(m/z):373；
Embodiment 34 (S)-2-(4-methyl benzo [d] thiazole-2-formamido-)-3-(1H-imidazoles-1-base) isopropyl propionate
ESI-MS[M+H]
+(m/z):373；
Embodiment 35 (S)-2-(4-methyl benzo [d] thiazole-2-formamido-)-3-(1H-imidazoles-1-base) isobutyl propionate
ESI-MS[M+H]
+(m/z):441；
Embodiment 36 (S)-2-(4-methoxyl group benzo [d] thiazole-2-formamido-)-3-(1H-imidazoles-1-base) methyl propionate
ESI-MS[M+H]
+(m/z):361；
Embodiment 37 (S)-2-(4-methoxyl group benzo [d] thiazole-2-formamido-)-3-(1H-imidazoles-1-base) ethyl propionate
ESI-MS[M+H]
+(m/z):375；
Embodiment 38 (S)-2-(4-methoxyl group benzo [d] thiazole-2-formamido-)-3-(1H-imidazoles-1-base) propyl propionate
ESI-MS[M+H]
+(m/z):389；
Embodiment 39 (S)-2-(4-methoxyl group benzo [d] thiazole-2-formamido-)-3-(1H-imidazoles-1-base) isopropyl propionate
ESI-MS[M+H]
+(m/z):389；
Embodiment 40 (S)-2-(4-methoxyl group benzo [d] thiazole-2-formamido-)-3-(1H-imidazoles-1-base) isobutyl propionate
ESI-MS[M+H]
+(m/z):403；
Embodiment 41 (S)-2-(4-trifluoromethyl benzo [d] thiazole-2-formamido-)-3-(1H-imidazoles-1-base) methyl propionate
ESI-MS[M+H]
+(m/z):399；
Embodiment 42 (S)-2-(4-trifluoromethyl benzo [d] thiazole-2-formamido-)-3-(1H-imidazoles-1-base) ethyl propionate
ESI-MS[M+H]
+(m/z):413；
Embodiment 43 (S)-2-(4-trifluoromethyl benzo [d] thiazole-2-formamido-)-3-(1H-imidazoles-1-base) propyl propionate
ESI-MS[M+H]
+(m/z):427；
Embodiment 44 (S)-2-(4-trifluoromethyl benzo [d] thiazole-2-formamido-)-3-(1H-imidazoles-1-base) isopropyl propionate
ESI-MS[M+H]
+(m/z):427；
Embodiment 45 (S)-2-(4-trifluoromethyl benzo [d] thiazole-2-formamido-)-3-(1H-imidazoles-1-base) isobutyl propionate
ESI-MS[M+H]
+(m/z):441；
Embodiment 46 (S)-2-(4-chlorobenzene is [d] thiazole-2-formamido-also)-3-(1H-imidazoles-1-base) methyl propionate
ESI-MS[M+H]
+(m/z):365；
Embodiment 47 (S)-2-(4-chlorobenzene is [d] thiazole-2-formamido-also)-3-(1H-imidazoles-1-base) ethyl propionate
ESI-MS[M+H]
+(m/z):379；
Embodiment 48 (S)-2-(4-chlorobenzene is [d] thiazole-2-formamido-also)-3-(1H-imidazoles-1-base) propyl propionate
ESI-MS[M+H]
+(m/z):393；
Embodiment 49 (S)-2-(4-chlorobenzene is [d] thiazole-2-formamido-also)-3-(1H-imidazoles-1-base) isopropyl propionate
ESI-MS[M+H]
+(m/z):393；
Embodiment 50 (S)-2-(4-chlorobenzene is [d] thiazole-2-formamido-also)-3-(1H-imidazoles-1-base) isobutyl propionate
ESI-MS[M+H]
+(m/z):407；
The preparation of embodiment 51 (S)-N-(1-(1H-imidazoles-1-base)-3-phenylpropyl alcohol-2-base) benzo [d] thiazole-2-methane amide;
First react with compound 1 and borine; reduction obtains intermediate 2; obtain intermediate 3 with Bao Ke anhydride reaction again, then bromo, obtain intermediate 4; with imidazoles generation nucleophilic substitution reaction; obtained intermediate 5, finally removes Bao Ke protection, obtains important intermediate 6; finally carry out acylation reaction with A-1 again, as shown in synthetic route 8.
Concrete preparation method is as follows:
The preparation 2 of step B-1 β-phenylalaninol
Borine (20ml, 0.12mol) is dissolved in 30mlTHF solvent, is cooled to 0 DEG C, slowly add compound 1 (5g, 30mmol), stir 15min, back flow reaction 4h, reaction is finished, and is cooled to 0 DEG C, add anhydrous methanol quencher, produce to bubble-free, stir 20min, steaming desolventizes, and DCM dissolves, washing, drying, obtains colorless oil 3.4g.Yield 75%.MS[M+H]
+(m/z)：152。
The preparation 3 of the step B-2 tertiary butyl (1-hydroxyl-3-phenyl third-2-base) t-butyl carbamate
Intermediate 2 (2.5g, 15.92mmol) is dissolved in 30mlMeOH, adds (Boc)
2o (3.9,17.89mmol), Na
2cO
3(7,66.04mmol), stirring at room temperature 10h, reaction is finished, and steaming desolventizes, and adds water, and separates out solid, suction filtration, washing filter cake, dry.Obtain white solid 3.04g, yield 76%, MS [M+H]
+(m/z): 252.
The preparation 4 of the step B-3 tertiary butyl (the bromo-3-phenyl-propane of 1--2-base) t-butyl carbamate
Intermediate 3 (0.4g, 1.59mmol) is dissolved in 15mlDCM, near-5 DEG C of cryosel bath.By PBr
3be scattered in DCM and slowly instill reaction system, insulation 2.5h, after reacting completely, slowly add water under ice bath quencher, and 30mlDCM dissolves, and washing is dry.Obtain colorless oil 034g, yield 69%, MS [M+H]
+(m/z): 314.
The preparation 5 of the step B-4 tertiary butyl (1-(1H-imidazoles-1-base)-3-phenyl-propane-2-base) t-butyl carbamate
Under condition of ice bath, NaH (0.12g, 5.1mmol) is dissolved in 30mlDMF solvent, add imidazoles (0.18g, 2.82mmol), stirring at room temperature 30min, adds intermediate 4 (0.8g, 2.56mmol), 80 DEG C of reaction 5h, after reacting completely, in impouring water, EA extracts, dry.Obtain colorless oil 0.56g, yield 73%, MS [M+H]
+(m/z): 302.
The preparation 6 of step B-51-(1H-imidazoles-1-base)-3-phenyl third-2-amine
Intermediate 5 (0.6g, 1.99mmol) is dissolved in 15mlHCl.EA, stirring at room temperature 10h, after reacting completely, separates out solid, suction filtration, washing filter cake, dry, obtain white solid 0.54g, yield 86%, MS [M+H]
+(m/z): 314.
The preparation 7 of step B-6 (S)-N-(1-(1H-imidazoles-1-base)-3-phenylpropyl alcohol-2-base) benzo [d] thiazole-2-methane amide
By intermediate A-1 benzo [d] thiazole-2-formic acid (0.70g, 3.91mmol), EDCI0.82g (4.3mmol) and HOBt0.85g (4.3mmol) is dissolved in the DMF of 30mL, stirred at ambient temperature 2h, add intermediate 6 (0.86g, 4.30mmol) and DIEA2mL, react 5h at 70 DEG C, TLC monitoring reacts completely.In reaction solution, add 100mL water, 56mLEA extracts, and saturated common salt water washing has basic unit, Na
2sO
4dried overnight.Filtering siccative, concentrating under reduced pressure obtains brown oil 0.8g, yield 57%.MS[M+H]
-(m/z)：363。
According to the method for embodiment 51, use phenylalanine is raw material, and through reduction, Boc protection, bromo, imidazoles nucleophilic substitution, deprotection, is finally obtained by reacting embodiment 52-60 with intermediate A-1 benzo [d] thiazole-2-formic acid replaced respectively again.
The preparation of embodiment 52 (S)-N-(1-(1H-imidazoles-1-base)-3-phenylpropyl alcohol-2-base)-6-methyl-benzo [d] thiazole-2-methane amide
ESI-MS[M+H]
+(m/z):377；
The preparation of embodiment 53 (S)-N-(1-(1H-imidazoles-1-base)-3-phenylpropyl alcohol-2-base) the bromo-benzo of-6-[d] thiazole-2-methane amide
ESI-MS[M+H]
+(m/z):441；
Embodiment 54 (S)-N-(1-(1H-imidazoles-1-base)-3-phenylpropyl alcohol-2-base) the chloro-benzo of-6-[d] thiazole-2-methane amide
ESI-MS[M+H]
+(m/z):397；
Embodiment 55 (S)-N-(1-(1H-imidazoles-1-base)-3-phenylpropyl alcohol-2-base)-6-methoxyl group-benzo [d] thiazole-2-methane amide
ESI-MS[M+H]
+(m/z):393；
Embodiment 56 (S)-N-(1-(1H-imidazoles-1-base)-3-phenylpropyl alcohol-2-base)-6-trifluoromethyl-benzo [d] thiazole-2-methane amide
ESI-MS[M+H]+(m/z):431；
Embodiment 57 (S)-N-(1-(1H-imidazoles-1-base)-3-phenylpropyl alcohol-2-base)-4-methyl-benzo [d] thiazole-2-methane amide
ESI-MS[M+H]
+(m/z):377；
Embodiment 58 (S)-N-(1-(1H-imidazoles-1-base)-3-phenylpropyl alcohol-2-base)-4-methoxyl group-benzo [d] thiazole-2-methane amide
ESI-MS[M+H]
+(m/z):393；
Embodiment 59 (S)-N-(1-(1H-imidazoles-1-base)-3-phenylpropyl alcohol-2-base)-4-trifluoromethyl-benzo [d] thiazole-2-methane amide
ESI-MS[M+H]
+(m/z):431；
Embodiment 60 (S)-N-(1-(1H-imidazoles-1-base)-3-phenylpropyl alcohol-2-base)-4-Cl-benzo [d] thiazole-2-methane amide
ESI-MS[M+H]
+(m/z):397；
The preparation of embodiment 61 (S)-2-(2,4,5-trimethylammonium-1-phenyl-1H-pyrrole-3-carboxamide base)-3-(1H-imidazoles-1-base) methyl propionate
The preparation 1 of step C-1 methyl aceto acetate sodium
Sodium (5.19g, 225.6mmol) is cut into small pieces and puts in 80mL dehydrated alcohol to its total overall reaction in batches, add methyl aceto acetate (28.7mL, 225.6mmol), stirring at room temperature 24h, concentrating under reduced pressure, obtain light yellow solid 33.70g, yield 98.2%.
Step C-22-ethanoyl-3-methyl-ethyl 4-oxopentanoate 2
Intermediate 1 methyl aceto acetate sodium salt 2.00g (9.56mmol) is dissolved in 20mL acetone, add NaI0.13g (0.96mmol), the chloro-2-butanone 0.76mL (9.56mmol) of 3-is dripped at 40 DEG C, drip to finish and be warming up to backflow (56 DEG C), after 5h, TCL monitoring reaction is complete.Cooling, filter, concentrating under reduced pressure reaction solution obtains the oily matter of reddish-brown.Column chromatography obtains pale yellow oil 1.46g, yield 76.4%.ESI-MS[M+H]
+(m/z):201；
The preparation 3 of step C-32,4,5-trimethylammonium-1-phenyl-1H-pyrroles-3-carboxylic acid
Intermediate 2 (1.00g, 5mmol) and aniline 0.49Ml (5.38mmol) are dissolved in 10mL ethanol, are heated to reflux (78 DEG C), after 3h, TLC monitoring reacts completely.In above-mentioned reaction solution, add NaOH0.86g (21.52mmol) and 10mL water, after 7h, TLC monitoring reacts completely.Remove ethanol under reduced pressure, concentrated hydrochloric acid adjust ph to 2, have solid to separate out, filter, dry, obtain off-white color solid 0.85g, yield 74.4%.ESI-MS[M+H]
+(m/z):230；
The preparation 4 of step C-4 (S)-2-(2,4,5-dimethyl-1-phenyl-1H-pyrrole-3-carboxamide base)-3-hydroxy methyl propionate
By intermediate 3 (0.53g, 2.3mmol), EDCHCl0.50g (2.6mmol) and HOBt0.35g (2.6mmol) is dissolved in 10mLDMF, stirred at ambient temperature 3h, TLC monitoring reacts completely, and adds Serine methyl ester hydrochloride 0.40g (2.6mmol) and DIEA0.79mL (5.2mmol), stirred at ambient temperature 5h, TLC monitoring reacts completely, and adds 30mL water, 40mL extraction into ethyl acetate, saturated common salt water washing organic layer, Na
2sO
4dried overnight.Filtering siccative, concentrating under reduced pressure obtains brown oil 0.53g, yield 69.4%.ESI-MS[M+H]
+(m/z):331；
The preparation 5 of step C-5 (S)-2-(2,4,5-trimethylammonium-1-phenyl-1H-pyrrole-3-carboxamide base)-3-(1H-imidazoles-1-base) methyl propionate
Be dissolved in 8mL acetonitrile by intermediate 4 (0.52g, 1.58mmol), CDI0.38g (2.37mmol) and imidazoles 0.16g (2.37mmol), at 50 DEG C, react 9h, TLC monitoring reacts completely.Pressurization concentration of reaction solution, is dissolved in ethyl acetate by residue, and washing, saturated common salt water washing is washed, Na
2sO
4dried overnight.Filtering siccative, concentrating under reduced pressure obtains reddish-brown oily matter, and column chromatography obtains off-white color solid 0.31g, yield 51.9%.m.p.79.6-81.0℃；
1H-NMR(CDCl
3,400MHz):δ:7.55-7.44(m,3H),7.43(s,1H),7.20-7.15(d,2H,J＝6.68hz),7.05(s,1H),6.87(s,1H),6.38-6.33(d,1H,J＝5.96hz),5.07-5.01(m,1H),4.72-4.54(m,2H),3.86(s,3H),2.23(s,3H),2.17(s,3H),1.91(s,3H)；ESI-MS[M+H]
+m/z:381.1。
According to the method for embodiment 61; substituted aniline is used to be raw material respectively; react with 2-ethanoyl-3-methyl-ethyl 4-oxopentanoate and prepare key intermediate 2; 4; 5-trimethylammonium-1-phenyl-1H-pyrroles-3-carboxylic acid; be obtained by reacting intermediate 4 with Serine ester again, intermediate 4 prepares embodiment 62-120 through the nucleophilic substitution reaction of imidazole group.
Embodiment 62 (S)-2-(2,4,5-trimethylammonium-1-phenyl-1H-pyrrole-3-carboxamide base)-3-(1H-imidazoles-1-base) ethyl propionate
ESI-MS[M+H]
+(m/z):395；
Embodiment 63 (S)-2-(2,4,5-trimethylammonium-1-phenyl-1H-pyrrole-3-carboxamide base)-3-(1H-imidazoles-1-base) propyl propionate
ESI-MS[M+H]
+(m/z):409；
Embodiment 64 (S)-2-(2,4,5-trimethylammonium-1-phenyl-1H-pyrrole-3-carboxamide base)-3-(1H-imidazoles-1-base) isopropyl propionate
ESI-MS[M+H]
+(m/z):409；
Embodiment 65 (S)-2-(2,4,5-trimethylammonium-1-phenyl-1H-pyrrole-3-carboxamide base)-3-(1H-imidazoles-1-base) isobutyl propionate
ESI-MS[M+H]
+(m/z):423；
Embodiment 66 (S)-2-[2,4,5 dimethyl-1-(4-aminomethyl phenyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) methyl propionate
ESI-MS[M+H]
+(m/z):395；
Embodiment 67 (S)-2-[2,4,5 dimethyl-1-(4-aminomethyl phenyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) ethyl propionate
ESI-MS[M+H]
+(m/z):409；
Embodiment 68 (S)-2-[2,4,5 dimethyl-1-(4-aminomethyl phenyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) propyl propionate
ESI-MS[M+H]
+(m/z):423；
Embodiment 69 (S)-2-[2,4,5 dimethyl-1-(4-aminomethyl phenyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) isopropyl propionate
ESI-MS[M+H]
+(m/z):423；
Embodiment 70 (S)-2-[2,4,5 dimethyl-1-(4-aminomethyl phenyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) isobutyl propionate
ESI-MS[M+H]
+(m/z):437；
Embodiment 71 (S)-2-[2,4,5-dimethyl-1-(4-bromophenyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) methyl propionate
ESI-MS[M+H]
+(m/z):459；
Embodiment 72 (S)-2-[2,4,5-dimethyl-1-(4-bromophenyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) ethyl propionate
ESI-MS[M+H]
+(m/z):473；
Embodiment 73 (S)-2-[2,4,5-dimethyl-1-(4-bromophenyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) propyl propionate
ESI-MS[M+H]
+(m/z):487；
Embodiment 74 (S)-2-[2,4,5-dimethyl-1-(4-bromophenyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) isopropyl propionate
ESI-MS[M+H]
+(m/z):487；
Embodiment 75 (S)-2-[2,4,5-dimethyl-1-(4-bromophenyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) isobutyl propionate
ESI-MS[M+H]
+(m/z):501；
Embodiment 76 (S)-2-[2,4,5-dimethyl-1-(4-chloro-phenyl-)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) methyl propionate
ESI-MS[M+H]
+(m/z):415；
Embodiment 77 (S)-2-[2,4,5-dimethyl-1-(4-chloro-phenyl-)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) ethyl propionate
ESI-MS[M+H]
+(m/z):429；
Embodiment 78 (S)-2-[2,4,5-dimethyl-1-(4-chloro-phenyl-)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) propyl propionate
ESI-MS[M+H]
+(m/z):443；
Embodiment 79 (S)-2-[2,4,5-dimethyl-1-(4-chloro-phenyl-)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) isopropyl propionate
ESI-MS[M+H]
+(m/z):443；
Embodiment 80 (S)-2-[2,4,5-dimethyl-1-(4-chloro-phenyl-)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) isobutyl propionate
ESI-MS[M+H]
+(m/z):457；
Embodiment 81 (S)-2-[2,4,5-dimethyl-1-(4-p-methoxy-phenyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) methyl propionate
ESI-MS[M+H]
+(m/z):411；
Embodiment 82 (S)-2-[2,4,5-dimethyl-1-(4-p-methoxy-phenyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) ethyl propionate
ESI-MS[M+H]
+(m/z):425；
Embodiment 83 (S)-2-[2,4,5-dimethyl-1-(4-p-methoxy-phenyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) propyl propionate
ESI-MS[M+H]
+(m/z):439；
Embodiment 84 (S)-2-[2,4,5-dimethyl-1-(4-p-methoxy-phenyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) isopropyl propionate
ESI-MS[M+H]
+(m/z):439；
Embodiment 85 (S)-2-[2,4,5-dimethyl-1-(4-p-methoxy-phenyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) isobutyl propionate
ESI-MS[M+H]
+(m/z):453；
Embodiment 86 (S)-2-[2,4,5-dimethyl-1-(4-trifluoromethyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) methyl propionate
ESI-MS[M+H]
+(m/z):449；
Embodiment 87 (S)-2-[2,4,5-dimethyl-1-(4-trifluoromethyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) ethyl propionate
ESI-MS[M+H]
+(m/z):463；
Embodiment 88 (S)-2-[2,4,5-dimethyl-1-(4-trifluoromethyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) propyl propionate
ESI-MS[M+H]
+(m/z):477；
Embodiment 89 (S)-2-[2,4,5-dimethyl-1-(4-trifluoromethyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) isopropyl propionate
ESI-MS[M+H]
+(m/z):477；
Embodiment 90 (S)-2-[2,4,5-dimethyl-1-(4-trifluoromethyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) isobutyl propionate
ESI-MS[M+H]
+(m/z):491；
Embodiment 91 (S)-2-[2,4,5-dimethyl-1-(4-ethylphenyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) methyl propionate
ESI-MS[M+H]
+(m/z):409；
Embodiment 92 (S)-2-[2,4,5-dimethyl-1-(4-ethylphenyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) ethyl propionate
ESI-MS[M+H]
+(m/z):423；
Embodiment 93 (S)-2-[2,4,5-dimethyl-1-(4-ethylphenyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) propyl propionate
ESI-MS[M+H]
+(m/z):437；
Embodiment 94 (S)-2-[2,4,5-dimethyl-1-(4-ethylphenyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) isopropyl propionate
ESI-MS[M+H]
+(m/z):437；
Embodiment 95 (S)-2-[2,4,5-dimethyl-1-(4-ethylphenyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) isobutyl propionate
ESI-MS[M+H]
+(m/z):451；
Embodiment 96 (S)-2-[2,4,5-dimethyl-1-(4-nitrophenyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) methyl propionate
ESI-MS[M+H]
+(m/z):426；
Embodiment 97 (S)-2-[2,4,5-dimethyl-1-(4-nitrophenyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) ethyl propionate
ESI-MS[M+H]
+(m/z):440；
Embodiment 98 (S)-2-[2,4,5-dimethyl-1-(4-nitrophenyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) propyl propionate
ESI-MS[M+H]
+(m/z):454；
Embodiment 99 (S)-2-[2,4,5-dimethyl-1-(4-nitrophenyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) isopropyl propionate
ESI-MS[M+H]
+(m/z):454；
Embodiment 100 (S)-2-[2,4,5-dimethyl-1-(4-nitrophenyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) isobutyl propionate
ESI-MS[M+H]
+(m/z):468；
Embodiment 101 (S)-2-[2,4,5-dimethyl-1-(2-aminomethyl phenyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) methyl propionate
ESI-MS[M+H]
+(m/z):395；
Embodiment 102 (S)-2-[2,4,5-dimethyl-1-(2-aminomethyl phenyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) ethyl propionate
ESI-MS[M+H]
+(m/z):409；
Embodiment 103 (S)-2-[2,4,5-dimethyl-1-(2-aminomethyl phenyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) propyl propionate
ESI-MS[M+H]
+(m/z):423；
Embodiment 104 (S)-2-[2,4,5-dimethyl-1-(2-aminomethyl phenyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) isopropyl propionate
ESI-MS[M+H]
+(m/z):423；
Embodiment 105 (S)-2-[2,4,5-dimethyl-1-(2-aminomethyl phenyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) isobutyl propionate
ESI-MS[M+H]
+(m/z):437；
Embodiment 106 (S)-2-[2,4,5-dimethyl-1-(2-p-methoxy-phenyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) methyl propionate
ESI-MS[M+H]
+(m/z):415；
Embodiment 107 (S)-2-[2,4,5-dimethyl-1-(2-p-methoxy-phenyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) ethyl propionate
ESI-MS[M+H]
+(m/z):429；
Embodiment 108 (S)-2-[2,4,5-dimethyl-1-(2-p-methoxy-phenyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) propyl propionate
ESI-MS[M+H]
+(m/z):443；
Embodiment 109 (S)-2-[2,4,5-dimethyl-1-(2-p-methoxy-phenyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) isopropyl propionate
ESI-MS[M+H]
+(m/z):437；
Embodiment 110 (S)-2-[2,4,5-dimethyl-1-(2-p-methoxy-phenyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) isobutyl propionate
ESI-MS[M+H]
+(m/z):457；
Embodiment 111 (S)-2-[2,4,5-dimethyl-1-(2-trifluoromethyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) methyl propionate
ESI-MS[M+H]
+(m/z):411；
Embodiment 112 (S)-2-[2,4,5-dimethyl-1-(2-trifluoromethyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) ethyl propionate
ESI-MS[M+H]
+(m/z):425；
Embodiment 113 (S)-2-[2,4,5-dimethyl-1-(2-trifluoromethyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) propyl propionate
ESI-MS[M+H]
+(m/z):439；
Embodiment 114 (S)-2-[2,4,5-dimethyl-1-(2-trifluoromethyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) isopropyl propionate
ESI-MS[M+H]
+(m/z):439；
Embodiment 115 (S)-2-[2,4,5-dimethyl-1-(2-trifluoromethyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) isobutyl propionate
ESI-MS[M+H]
+(m/z):453；
Embodiment 116 (S)-2-[2,4,5-dimethyl-1-(2-chloro-phenyl-)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) methyl propionate
ESI-MS[M+H]
+(m/z):449；
Embodiment 117 (S)-2-[2,4,5-dimethyl-1-(2-chloro-phenyl-)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) ethyl propionate
ESI-MS[M+H]
+(m/z):463；
Embodiment 118 (S)-2-[2,4,5-dimethyl-1-(2-chloro-phenyl-)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) propyl propionate
ESI-MS[M+H]
+(m/z):477；
Embodiment 119 (S)-2-[2,4,5-dimethyl-1-(2-chloro-phenyl-)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) isopropyl propionate
ESI-MS[M+H]
+(m/z):477；
Embodiment 120 (S)-2-[2,4,5-dimethyl-1-(2-chloro-phenyl-)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) isobutyl propionate
ESI-MS[M+H]
+(m/z):491；
The preparation of embodiment 121 (S)-N-(1-(1H-imidazoles-1-base)-3-phenylpropyl alcohol-2-base)-2,4,5-trimethylammonium-1-phenyl-1H-pyrrole-3-carboxamides
The preparation of step D-1 (S)-N-(1-(1H-imidazoles-1-base)-3-phenylpropyl alcohol-2-base)-2,4,5-trimethylammonium-1-phenyl-1H-pyrrole-3-carboxamides
By intermediate A-22,4,5-trimethylammonium-1-phenyl-1H-pyrroles-3-carboxylic acid (0.90g, 3.91mmol), EDCI0.82g (4.3mmol) and HOBt0.85g (4.3mmol) is dissolved in the DMF of 30mL, and stirred at ambient temperature 2h, adds intermediate 6,1-(1H-imidazoles-1-base)-3-phenyl third-2-amine (0.86g, 4.30mmol) and DIEA2mL, react 5h at 70 DEG C, TLC monitoring reacts completely.In reaction solution, add 100mL water, 56mLEA extracts, and saturated common salt water washing has basic unit, Na
2sO
4dried overnight.Filtering siccative, concentrating under reduced pressure obtains brown oil 0.9g, yield 56%.ESI-MS[M+H]
+(m/z):413。
According to the method for embodiment 121, different 2,4, the 5-trimethylammonium-1-phenyl-1H-pyrroles-3-carboxylic acids replaced are used to be that raw material and 1-(1H-imidazoles-1-base)-3-phenyl third-2-amine amide are obtained by reacting embodiment 122-130.
Embodiment 122 (S)-N-(1-(1H-imidazoles-1-base)-3-phenylpropyl alcohol-2-base)-2,4,5-trimethylammonium-1-(4-aminomethyl phenyl)-1H-pyrrole-3-carboxamide
ESI-MS[M+H]
+(m/z):427；
Embodiment 123 (S)-N-(1-(1H-imidazoles-1-base)-3-phenylpropyl alcohol-2-base)-2,4,5-trimethylammonium-1-(4-bromophenyl)-1H-pyrrole-3-carboxamide
ESI-MS[M+H]
+(m/z):491；
Embodiment 124 (S)-N-(1-(1H-imidazoles-1-base)-3-phenylpropyl alcohol-2-base)-2,4,5-trimethylammonium-1-(4-chloro-phenyl-)-1H-pyrrole-3-carboxamide
ESI-MS[M+H]
+(m/z):447；
Embodiment 125 (S)-N-(1-(1H-imidazoles-1-base)-3-phenylpropyl alcohol-2-base)-2,4,5-trimethylammonium-1-(4-p-methoxy-phenyl)-1H-pyrrole-3-carboxamide
ESI-MS[M+H]
+(m/z):443；
Embodiment 126 (S)-N-(1-(1H-imidazoles-1-base)-3-phenylpropyl alcohol-2-base)-2,4,5-trimethylammonium-1-(4-trifluoromethyl)-1H-pyrrole-3-carboxamide
ESI-MS[M+H]
+(m/z):481；
Embodiment 127 (S)-N-(1-(1H-imidazoles-1-base)-3-phenylpropyl alcohol-2-base)-2,4,5-trimethylammonium-1-(2-aminomethyl phenyl)-1H-pyrrole-3-carboxamide
ESI-MS[M+H]
+(m/z):427；
Embodiment 128 (S)-N-(1-(1H-imidazoles-1-base)-3-phenylpropyl alcohol-2-base)-2,4,5-trimethylammonium-1-(2-p-methoxy-phenyl)-1H-pyrrole-3-carboxamide
ESI-MS[M+H]
+(m/z):413；
Embodiment 129 (S)-N-(1-(1H-imidazoles-1-base)-3-phenylpropyl alcohol-2-base)-2,4,5-trimethylammonium-1-(2-trifluoromethyl)-1H-pyrrole-3-carboxamide
ESI-MS[M+H]
+(m/z):443；
Embodiment 130 (S)-N-(1-(1H-imidazoles-1-base)-3-phenylpropyl alcohol-2-base)-2,4,5-trimethylammonium-1-(2-chloro-phenyl-)-1H-pyrrole-3-carboxamide
ESI-MS[M+H]
+(m/z):447；
The preparation of embodiment 131 (S)-2-[chloro-3 methyl isophthalic acids of 5--phenyl-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) methyl propionate
Step e-1 hydrazinobenzene hydrochloride salt preparation 1
Aniline (0.41g, 4.4mmol) is dissolved in the concentrated hydrochloric acid of 5ml, stirs and be cooled to 0, drip NaNO
2the aqueous solution 2ml of (0.33g, 4.8mmo), then drip SnCl
2the concentrated hydrochloric acid 5ml of (2.36g, 10mmol), drip and finish 0 reaction 1h, sluggish rises to room temperature, suction filtration, concentrated hydrochloric acid washing leaching cake, obtains faint yellow solid 0.42g, yield 65.2%.
The preparation 2 of step e-23-methyl isophthalic acid-phenyl-5-pyrazolone
By intermediate 1 phenylhydrazine (21.6g, 200mmol) and 30mL dehydrated alcohol, be heated with stirring to 50 DEG C, drip methyl aceto acetate (26.0g, 200mmol), during dropping, control temperature is between 50-70 DEG C, drip and finish, backflow 5h, cooling, concentration of reaction solution, obtains red, transparent liquid, left undisturbed overnight, separate out yellow solid, suction filtration, after dry, use dehydrated alcohol recrystallization, obtain 29.3g faint yellow solid, yield 85.0%.mp128.0-130.3℃；ESI-MSm/z:175.1[M+H]
+；197.1[M+Na]
+；172.9[M-H]
-。
The preparation 3 of step e-33-methyl isophthalic acid-phenyl-5-chloro-4-pyrazoles formaldehyde
Add DMF (23mL, 300mmol) in 250mL three-necked bottle, ice-water bath is cooled to 0-5 DEG C, drips POCl
3(64mL, 700mmol), drips and finishes, intermediate 2 is added, 1-phenyl-3-methyl-5-pyrazolone (17.48g, 100mmol) in mixture, slowly be warming up to backflow, maintain 1h, cooling, slowly pours into it in 600mL mixture of ice and water under stirring, separate out solid, suction filtration, dry faint yellow solid 19.0g, yield 86.4%.mp139.0-140.8℃；ESI-MSm/z:221.1[M+H]
+；243.1[M+Na]
+。
The preparation 4 of the chloro-4-pyrazole carboxylic acid of step e-43-methyl isophthalic acid-phenyl-5-
Chloro-3-methyl isophthalic acid-phenyl-4-pyrazoles formaldehyde (16.85g, 76.4mmol) of intermediate 3,5-is added in 1000mL three-necked bottle, potassium permanganate (16.9g, 106.96mmol), 300mL water, be heated with stirring to 90-95 DEG C, keep this thermotonus 4h, stop heating, stirring at room temperature 2.5h, suction filtration, filtrate uses 2MHCl acidifying, separate out white solid, suction filtration, dry product 16.6g, yield 92.2%.mp232.1-234.7℃；
1HNMR(DMSO-d
6,300MHz):δ2.41(s,3H),7.56(s,5H),12.88(s,1H)；ESI-MSm/z:237.1[M+H]
+；259.1[M+Na]
+。
The preparation 5 of step e-5 (S)-2-(the chloro-3-methyl isophthalic acid of 5--phenyl-1H-pyrazoles-4-formamido group)-3-methyl propionate
By intermediate 4,3-methyl isophthalic acid-chloro-4-the pyrazole carboxylic acid of phenyl-5-(0.92g, 3.91mmol), EDCI0.82g (4.3mmol) and HOBt0.85g (4.3mmol) is dissolved in the DMF of 30mL, stirred at ambient temperature 2h, add intermediate 5L-serine methyl ester hydrochloride 0.67g (4.30mmol) and DIEA2mL, react 5h at 70 DEG C, TLC monitoring reacts completely.In reaction solution, add 100mL water, 56mLEA extracts, and saturated common salt water washing has basic unit, Na
2sO
4dried overnight.Filtering siccative, concentrating under reduced pressure obtains brown oil 0.70g, yield 53%.ESI-MS[M+H]
+(m/z)：338。
The preparation 6 of step e-6 (S)-2-[chloro-3 methyl isophthalic acids of 5--phenyl-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) methyl propionate
Intermediate 5 (S)-2-(the chloro-3-methyl isophthalic acid of 5--phenyl-1H-pyrazoles-4-formamido group)-3-methyl propionate 0.60g (1.79mmol), CDI0.44g (2.69mmol) and imidazoles 0.18g (2.69mmol) are dissolved in 10mL acetonitrile, at 70 DEG C, react 4h, TLC monitoring reacts completely.Pressurization concentration of reaction solution, is dissolved in ethyl acetate by residue, washing, saturated common salt water washing, Na
2sO
4dried overnight.Filtering siccative, concentrating under reduced pressure obtains reddish-brown oily matter, and column chromatography obtains white solid 0.46g, yield 67%.
m.p.147.0-147.3℃；
1H-NMR(CDCl
3,400MHz):δ:8.47-8.42(d,1H,J＝7.92hz),7.62(s,1H),7.59-7.52(d,1H,J＝1.64hz),7.56(s,1H),7.55-7.53(d,1H,J＝2.8hz),7.53-7.51(m,1H),4.89-4.82(m,1H),4.54-4.34(m,2H),3.71(s,3H),2.23(s,3H)；ESI-MS[M+H]
+(m/z)＝388。
According to the method for embodiment 131, substituted aniline is used to be raw material respectively, reduce through diazonium, cyclization, aldehyde radical, oxidizing reaction obtains the chloro-4-pyrazole carboxylic acid of key intermediate 3-methyl isophthalic acid-phenyl-5-, then is obtained by reacting intermediate 5 with Serine ester, and intermediate 5 prepares embodiment 132-190 through the nucleophilic substitution reaction of imidazole group.
Embodiment 132 (S)-2-[chloro-3 methyl isophthalic acids of 5--phenyl-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) ethyl propionate
ESI-MS[M+H]
+(m/z):402；
Embodiment 133 (S)-2-[chloro-3 methyl isophthalic acids of 5--phenyl-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) propyl propionate
ESI-MS[M+H]
+(m/z):416；
Embodiment 134 (S)-2-[chloro-3 methyl isophthalic acids of 5--phenyl-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) isopropyl propionate
ESI-MS[M+H]
+(m/z):416；
Embodiment 135 (S)-2-[chloro-3 methyl isophthalic acids of 5--phenyl-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) isobutyl propionate
ESI-MS[M+H]
+(m/z):444；
Embodiment 136 (S)-2-[chloro-3 methyl isophthalic acids of 5--(4-aminomethyl phenyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) methyl propionate
ESI-MS[M+H]
+(m/z):402；
Embodiment 137 (S)-2-[chloro-3 methyl isophthalic acids of 5--(4-aminomethyl phenyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) ethyl propionate
ESI-MS[M+H]
+(m/z):416；
Embodiment 138 (S)-2-[chloro-3 methyl isophthalic acids of 5--(4-aminomethyl phenyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) propyl propionate
ESI-MS[M+H]
+(m/z):430；
Embodiment 139 (S)-2-[chloro-3 methyl isophthalic acids of 5--(4-aminomethyl phenyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) isopropyl propionate
ESI-MS[M+H]
+(m/z):430；
Embodiment 140 (S)-2-[chloro-3 methyl isophthalic acids of 5--(4-aminomethyl phenyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) isobutyl propionate
ESI-MS[M+H]
+(m/z):458；
Embodiment 141 (S)-2-[chloro-3 methyl isophthalic acids of 5--(4-bromophenyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) methyl propionate
ESI-MS[M+H]
+(m/z):466；
Embodiment 142 (S)-2-[chloro-3 methyl isophthalic acids of 5--(4-bromophenyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) ethyl propionate
ESI-MS[M+H]
+(m/z):495；
Embodiment 143 (S)-2-[chloro-3 methyl isophthalic acids of 5--(4-bromophenyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) propyl propionate
ESI-MS[M+H]
+(m/z):494；
Embodiment 144 (S)-2-[chloro-3 methyl isophthalic acids of 5--(4-bromophenyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) isopropyl propionate
ESI-MS[M+H]
+(m/z):494；
Embodiment 145 (S)-2-[chloro-3 methyl isophthalic acids of 5--(4-bromophenyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) isobutyl propionate
ESI-MS[M+H]
+(m/z):522；
Embodiment 146 (S)-2-[chloro-3 methyl isophthalic acids of 5--(4-chloro-phenyl-)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) methyl propionate
ESI-MS[M+H]
+(m/z):422；
Embodiment 147 (S)-2-[chloro-3 methyl isophthalic acids of 5--(4-chloro-phenyl-)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) ethyl propionate
ESI-MS[M+H]
+(m/z):436；
Embodiment 148 (S)-2-[chloro-3 methyl isophthalic acids of 5--(4-chloro-phenyl-)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) propyl propionate
ESI-MS[M+H]
+(m/z):450；
Embodiment 149 (S)-2-[chloro-3 methyl isophthalic acids of 5--(4-chloro-phenyl-)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) isopropyl propionate
ESI-MS[M+H]
+(m/z):450；
Embodiment 150 (S)-2-[chloro-3 methyl isophthalic acids of 5--(4-chloro-phenyl-)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) isobutyl propionate
ESI-MS[M+H]
+(m/z):478；
Embodiment 151 (S)-2-[chloro-3 methyl isophthalic acids of 5--(4-p-methoxy-phenyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) methyl propionate
ESI-MS[M+H]
+(m/z):418；
Embodiment 152 (S)-2-[chloro-3 methyl isophthalic acids of 5--(4-p-methoxy-phenyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) ethyl propionate
ESI-MS[M+H]
+(m/z):432；
Embodiment 153 (S)-2-[chloro-3 methyl isophthalic acids of 5--(4-p-methoxy-phenyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) propyl propionate
ESI-MS[M+H]
+(m/z):446；
Embodiment 154 (S)-2-[chloro-3 methyl isophthalic acids of 5--(4-p-methoxy-phenyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) isopropyl propionate
ESI-MS[M+H]
+(m/z):446；
Embodiment 155 (S)-2-[chloro-3 methyl isophthalic acids of 5--(4-p-methoxy-phenyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) isobutyl propionate
ESI-MS[M+H]
+(m/z):474；
Embodiment 156 (S)-2-[chloro-3 methyl isophthalic acids of 5--(4-trifluoromethyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) methyl propionate
ESI-MS[M+H]
+(m/z):456；
Embodiment 157 (S)-2-[chloro-3 methyl isophthalic acids of 5--(4-trifluoromethyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) ethyl propionate
ESI-MS[M+H]
+(m/z):470；
Embodiment 158 (S)-2-[chloro-3 methyl isophthalic acids of 5--(4-trifluoromethyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) propyl propionate
ESI-MS[M+H]
+(m/z):484；
Embodiment 159 (S)-2-[chloro-3 methyl isophthalic acids of 5--(4-trifluoromethyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) isopropyl propionate
ESI-MS[M+H]
+(m/z):484；
Embodiment 160 (S)-2-[chloro-3 methyl isophthalic acids of 5--(4-trifluoromethyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) isobutyl propionate
ESI-MS[M+H]
+(m/z):512；
Embodiment 161 (S)-2-[chloro-3 methyl isophthalic acids of 5--(4-fluorophenyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) methyl propionate
ESI-MS[M+H]
+(m/z):406；
Embodiment 162 (S)-2-[chloro-3 methyl isophthalic acids of 5--(4-fluorophenyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) ethyl propionate
ESI-MS[M+H]
+(m/z):420；
Embodiment 163 (S)-2-[chloro-3 methyl isophthalic acids of 5--(4-fluorophenyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) propyl propionate
ESI-MS[M+H]
+(m/z):434；
Embodiment 164 (S)-2-[chloro-3 methyl isophthalic acids of 5--(4-fluorophenyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) isopropyl propionate
ESI-MS[M+H]
+(m/z):434；
Embodiment 165 (S)-2-[chloro-3 methyl isophthalic acids of 5--(4-fluorophenyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) isobutyl propionate
ESI-MS[M+H]
+(m/z):462；
Embodiment 166 (S)-2-[chloro-3 methyl isophthalic acids of 5--(4-nitrophenyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) methyl propionate
ESI-MS[M+H]
+(m/z):433；
Embodiment 167 (S)-2-[chloro-3 methyl isophthalic acids of 5--(4-nitrophenyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) ethyl propionate
ESI-MS[M+H]
+(m/z):447；
Embodiment 168 (S)-2-[chloro-3 methyl isophthalic acids of 5--(4-nitrophenyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) propyl propionate
ESI-MS[M+H]
+(m/z):461；
Embodiment 169 (S)-2-[chloro-3 methyl isophthalic acids of 5--(4-nitrophenyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) isopropyl propionate
ESI-MS[M+H]
+(m/z):461；
Embodiment 170 (S)-2-[chloro-3 methyl isophthalic acids of 5--(4-nitrophenyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) isobutyl propionate
ESI-MS[M+H]
+(m/z):489；
Embodiment 171 (S)-2-[chloro-3 methyl isophthalic acids of 5--(2-aminomethyl phenyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) methyl propionate
ESI-MS[M+H]
+(m/z):402；
Embodiment 172 (S)-2-[chloro-3 methyl isophthalic acids of 5--(2-aminomethyl phenyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) ethyl propionate
ESI-MS[M+H]
+(m/z):416；
Embodiment 173 (S)-2-[chloro-3 methyl isophthalic acids of 5--(2-aminomethyl phenyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) propyl propionate
ESI-MS[M+H]
+(m/z):430；
Embodiment 174 (S)-2-[chloro-3 methyl isophthalic acids of 5--(2-aminomethyl phenyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) isopropyl propionate
ESI-MS[M+H]
+(m/z):430；
Embodiment 175 (S)-2-[chloro-3 methyl isophthalic acids of 5--(2-aminomethyl phenyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) isobutyl propionate
ESI-MS[M+H]
+(m/z):458；
Embodiment 176 (S)-2-[chloro-3 methyl isophthalic acids of 5--(2-chloro-phenyl-)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) methyl propionate
ESI-MS[M+H]
+(m/z):422；
Embodiment 177 (S)-2-[chloro-3 methyl isophthalic acids of 5--(2-chloro-phenyl-)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) ethyl propionate
ESI-MS[M+H]
+(m/z):436；
Embodiment 178 (S)-2-[chloro-3 methyl isophthalic acids of 5--(2-chloro-phenyl-)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) propyl propionate
ESI-MS[M+H]
+(m/z):450；
Embodiment 179 (S)-2-[chloro-3 methyl isophthalic acids of 5--(2-chloro-phenyl-)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) isopropyl propionate
ESI-MS[M+H]
+(m/z):450；
Embodiment 180 (S)-2-[chloro-3 methyl isophthalic acids of 5--(2-chloro-phenyl-)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) isobutyl propionate
ESI-MS[M+H]
+(m/z):478；
Embodiment 181 (S)-2-[chloro-3 methyl isophthalic acids of 5--(2-p-methoxy-phenyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) methyl propionate
ESI-MS[M+H]
+(m/z):418；
Embodiment 182 (S)-2-[chloro-3 methyl isophthalic acids of 5--(2-p-methoxy-phenyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) ethyl propionate
ESI-MS[M+H]
+(m/z):432；
Embodiment 183 (S)-2-[chloro-3 methyl isophthalic acids of 5--(2-p-methoxy-phenyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) propyl propionate
ESI-MS[M+H]
+(m/z):446；
Embodiment 184 (S)-2-[chloro-3 methyl isophthalic acids of 5--(2-p-methoxy-phenyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) isopropyl propionate
ESI-MS[M+H]
+(m/z):446；
Embodiment 185 (S)-2-[chloro-3 methyl isophthalic acids of 5--(2-p-methoxy-phenyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) isobutyl propionate
ESI-MS[M+H]
+(m/z):474；
Embodiment 186 (S)-2-[chloro-3 methyl isophthalic acids of 5--(2-trifluoromethyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) methyl propionate
ESI-MS[M+H]
+(m/z):456；
Embodiment 187 (S)-2-[chloro-3 methyl isophthalic acids of 5--(2-trifluoromethyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) ethyl propionate
ESI-MS[M+H]
+(m/z):470；
Embodiment 188 (S)-2-[chloro-3 methyl isophthalic acids of 5--(2-trifluoromethyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) propyl propionate
ESI-MS[M+H]
+(m/z):484；
Embodiment 189 (S)-2-[chloro-3 methyl isophthalic acids of 5--(2-trifluoromethyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) isopropyl propionate
ESI-MS[M+H]
+(m/z):484；
Embodiment 190 (S)-2-[chloro-3 methyl isophthalic acids of 5--(2-trifluoromethyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) isobutyl propionate
ESI-MS[M+H]
+(m/z):512；
The preparation of embodiment 191 (S)-N-(1-(1H-imidazoles-1-base)-3-phenylpropyl alcohol-2-base) chloro-3 methyl isophthalic acids of-5--phenyl-1H-pyrazole-4-carboxamide
Step F-1 is by chloro-for intermediate A-33-methyl isophthalic acid-phenyl-5-4-pyrazole carboxylic acid (0.92g, 3.91mmol), EDCI0.82g (4.3mmol) and HOBt0.85g (4.3mmol) is dissolved in the DMF of 30mL, stirred at ambient temperature 2h, add intermediate 6,1-(1H-imidazoles-1-base)-3-phenyl third-2-amine (0.86g, 4.30mmol) and DIEA2mL, react 5h at 70 DEG C, TLC monitoring reacts completely.In reaction solution, add 100mL water, 56mLEA extracts, and saturated common salt water washing has basic unit, Na
2sO
4dried overnight.Filtering siccative, concentrating under reduced pressure obtains brown oil 0.9g, yield 55%.ESI-MS[M+H]
+(m/z):420。
According to the method for embodiment 191, the different chloro-4-pyrazole carboxylic acid of 3-methyl isophthalic acid-phenyl-5-replaced is used to be obtained by reacting embodiment 192-202 for raw material and 1-(1H-imidazoles-1-base)-3-phenyl third-2-amine amide.
Embodiment 192 (S)-N-(1-(1H-imidazoles-1-base)-3-phenylpropyl alcohol-2-base) chloro-3 methyl isophthalic acids of-5--(4-aminomethyl phenyl)-1H-pyrazole-4-carboxamide
ESI-MS[M+H]
+(m/z):434；
Embodiment 193 (S)-N-(1-(1H-imidazoles-1-base)-3-phenylpropyl alcohol-2-base) chloro-3 methyl isophthalic acids of-5--(4-bromophenyl)-1H-pyrazole-4-carboxamide
ESI-MS[M+H]
+(m/z):498；
Embodiment 194 (S)-N-(1-(1H-imidazoles-1-base)-3-phenylpropyl alcohol-2-base) chloro-3 methyl isophthalic acids of-5--(4-chloro-phenyl-)-1H-pyrazole-4-carboxamide
ESI-MS[M+H]
+(m/z):454；
Embodiment 195 (S)-N-(1-(1H-imidazoles-1-base)-3-phenylpropyl alcohol-2-base) chloro-3 methyl isophthalic acids of-5--(4-p-methoxy-phenyl)-1H-pyrazole-4-carboxamide
ESI-MS[M+H]
+(m/z):450；
Embodiment 196 (S)-N-(1-(1H-imidazoles-1-base)-3-phenylpropyl alcohol-2-base) chloro-3 methyl isophthalic acids of-5--(4-trifluoromethyl)-1H-pyrazole-4-carboxamide
ESI-MS[M+H]
+(m/z):488；
Embodiment 197 (S)-N-(1-(1H-imidazoles-1-base)-3-phenylpropyl alcohol-2-base) chloro-3 methyl isophthalic acids of-5--(4-fluorophenyl)-1H-pyrazole-4-carboxamide
ESI-MS[M+H]
+(m/z):438；
Embodiment 198 (S)-N-(1-(1H-imidazoles-1-base)-3-phenylpropyl alcohol-2-base) chloro-3 methyl isophthalic acids of-5--(4-nitrophenyl)-1H-pyrazole-4-carboxamide
ESI-MS[M+H]
+(m/z):465；
Embodiment 199 (S)-N-(1-(1H-imidazoles-1-base)-3-phenylpropyl alcohol-2-base) chloro-3 methyl isophthalic acids of-5--(2-aminomethyl phenyl)-1H-pyrazole-4-carboxamide
ESI-MS[M+H]
+(m/z):434；
Embodiment 200 (S)-N-(1-(1H-imidazoles-1-base)-3-phenylpropyl alcohol-2-base) chloro-3 methyl isophthalic acids of-5--(2-p-methoxy-phenyl)-1H-pyrazole-4-carboxamide
ESI-MS[M+H]
+(m/z):450；
Embodiment 201 (S)-N-(1-(1H-imidazoles-1-base)-3-phenylpropyl alcohol-2-base) chloro-3 methyl isophthalic acids of-5--(2-trifluoromethyl)-1H-pyrazole-4-carboxamide
ESI-MS[M+H]
+(m/z):488；
Embodiment 202 (S)-N-(1-(1H-imidazoles-1-base)-3-phenylpropyl alcohol-2-base) chloro-3 methyl isophthalic acids of-5--(2-chloro-phenyl-)-1H-pyrazole-4-carboxamide
ESI-MS[M+H]
+(m/z):454；
The preparation of embodiment 203 (S)-2-[(1,1'-xenyl)-4-formamido-]-3-(1H-imidazoles-1-base) methyl propionate
The preparation 1 of step G-1 parabromobenzoic acid
P-bromobenzaldehyde 5.00g (27.17mmol), potassium permanganate 4.72 (29.89mmol) joins in the NaOH of the 2N of 30mL, temperature control 70 DEG C, and after 5h, TLC monitoring reacts completely.Cooling reaction solution, suction filtration, adjust pH value to 1, have a large amount of white solid to generate, suction filtration obtains white solid 4.59g, yield 85.1%.MS[M+H]
+(m/z)：201。
The preparation 2 of step G-21,1'-diphenic acid
Respectively by bromo-benzoic acid 2.58g (11.9mmol), phenylo boric acid 2g (16.39mmol) K
2cO
34g, four triphenyl phosphorus palladium 0.2g join in the dioxane solvent of 30mL, temperature control 75 DEG C, and after 5h, TLC monitoring reacts completely.Cooling reaction solution, suction filtration, adjust pH value to 1, have a large amount of white solid to generate, suction filtration obtains white solid 2.03g, yield 86.5%.MS[M+H]
+(m/z)：199。
The preparation 3 of step G-3 (S)-2-([1,1'-biphenyl]-4-base formamido group)-3-hydroxy methyl propionate
By intermediate 2 (1g, 5mmol), EDCHCl0.96g (5.5mmol) and HOBt0.74g (5.5mmol) is dissolved in 30mLDMF, stirred at ambient temperature 3h, TLC monitoring reacts completely, and adds Serine methyl ester hydrochloride 0.83g (5.5mmol) and DIEA1.58mL (11mmol), stirred at ambient temperature 5h, TLC monitoring reacts completely, and adds 30mL water, 40mL extraction into ethyl acetate, saturated common salt water washing organic layer, Na
2sO
4dried overnight.Filtering siccative, concentrating under reduced pressure obtains brown oil 1.08g, yield 66.2%.ESI-MS[M+H]
+(m/z):300；
The preparation 4 of step G-5 (S)-2-(2,4,5-trimethylammonium-1-phenyl-1H-pyrrole-3-carboxamide base)-3-(1H-imidazoles-1-base) methyl propionate
Be dissolved in 20mL acetonitrile by intermediate 4 (1.08g, 3.61mmol), CDI1.17g (7.22mmol) and imidazoles 0.74g (10.83mmol), at 70 DEG C, react 9h, TLC monitoring reacts completely.Pressurization concentration of reaction solution, is dissolved in ethyl acetate by residue, and washing, saturated common salt water washing is washed, Na
2sO
4dried overnight.Filtering siccative, concentrating under reduced pressure obtains reddish-brown oily matter, and column chromatography obtains off-white color solid 0.7g, yield 56.2%.[M+H]
+(m/z):350.m.p.147.0-147.3℃；
1H-NMR(DMSO,400MHz):δ:9.17-9.03(d,1H,J＝8hz),7.95-7.91(d,2H,J＝8hz),7.82-7.78(d,2H,J＝8hz),7.75-7.72(d,2H,J＝8hz),7.70(s,1H),7.52-7.48(m,2H),7.43-7.40(m,1H),7.24(s,1H)，6.89(s,1H),4.92-4.87(m,1H),4.60-4.41(m,2H),3.71(s,3H)。
According to the method for embodiment 203, use substituted benzene boric acid to be raw material respectively, react obtained key intermediate 1,1'-diphenic acid with parabromobenzoic acid, be obtained by reacting intermediate 3 with Serine ester again, intermediate 3 prepares embodiment 204-232 through the nucleophilic substitution reaction of imidazole group.
Embodiment 204 (S)-2-[(1,1'-xenyl)-4-formamido-]-3-(1H-imidazoles-1-base) ethyl propionate
ESI-MS[M+H]
+(m/z):364；
Embodiment 205 (S)-2-[(1,1'-xenyl)-4-formamido-]-3-(1H-imidazoles-1-base) propyl propionate
ESI-MS[M+H]
+(m/z):378；
Embodiment 206 (S)-2-[(1,1'-xenyl)-4-formamido-]-3-(1H-imidazoles-1-base) isopropyl propionate
ESI-MS[M+H]
+(m/z):378；
Embodiment 207 (S)-2-[(1,1'-xenyl)-4-formamido-]-3-(1H-imidazoles-1-base) isobutyl propionate
ESI-MS[M+H]
+(m/z):392；
Embodiment 208 (S)-2-[4'-fluoro-(1,1'-xenyl)-4-formamido-]-3-(1H-imidazoles-1-base) methyl propionate
ESI-MS[M+H]
+(m/z):368；
Embodiment 209 (S)-2-[4'-fluoro-(1,1'-xenyl)-4-formamido-]-3-(1H-imidazoles-1-base) ethyl propionate
ESI-MS[M+H]
+(m/z):382；
Embodiment 210 (S)-2-[4'-fluoro-(1,1'-xenyl)-4-formamido-]-3-(1H-imidazoles-1-base) propyl propionate
ESI-MS[M+H]
+(m/z):396；
Embodiment 211 (S)-2-[4'-fluoro-(1,1'-xenyl)-4-formamido-]-3-(1H-imidazoles-1-base) isopropyl propionate
ESI-MS[M+H]
+(m/z):396；
Embodiment 212 (S)-2-[4'-fluoro-(1,1'-xenyl)-4-formamido-]-3-(1H-imidazoles-1-base) isobutyl propionate
ESI-MS[M+H]
+(m/z):410；
Embodiment 213 (S)-2-[4'-methyl-(1,1'-xenyl)-4-formamido-]-3-(1H-imidazoles-1-base) methyl propionate
ESI-MS[M+H]
+(m/z):364；
Embodiment 214 (S)-2-[4'-methyl-(1,1'-xenyl)-4-formamido-]-3-(1H-imidazoles-1-base) ethyl propionate
ESI-MS[M+H]
+(m/z):378；
Embodiment 215 (S)-2-[4'-methyl-(1,1'-xenyl)-4-formamido-]-3-(1H-imidazoles-1-base) propyl propionate
ESI-MS[M+H]
+(m/z):392；
Embodiment 216 (S)-2-[4'-methyl-(1,1'-xenyl)-4-formamido-]-3-(1H-imidazoles-1-base) isopropyl propionate
ESI-MS[M+H]
+(m/z):392；
Embodiment 217 (S)-2-[4'-methyl-(1,1'-xenyl)-4-formamido-]-3-(1H-imidazoles-1-base) isobutyl propionate
ESI-MS[M+H]
+(m/z):406；
Embodiment 218 (S)-2-[2'-fluoro-(1,1'-xenyl)-4-formamido-]-3-(1H-imidazoles-1-base) methyl propionate
ESI-MS[M+H]
+(m/z):368；
Embodiment 219 (S)-2-[2'-fluoro-(1,1'-xenyl)-4-formamido-]-3-(1H-imidazoles-1-base) ethyl propionate
ESI-MS[M+H]
+(m/z):382；
Embodiment 220 (S)-2-[2'-fluoro-(1,1'-xenyl)-4-formamido-]-3-(1H-imidazoles-1-base) propyl propionate
ESI-MS[M+H]
+(m/z):396；
Embodiment 221 (S)-2-[2'-fluoro-(1,1'-xenyl)-4-formamido-]-3-(1H-imidazoles-1-base) isopropyl propionate
ESI-MS[M+H]
+(m/z):396；
Embodiment 222 (S)-2-[2'-fluoro-(1,1'-xenyl)-4-formamido-]-3-(1H-imidazoles-1-base) isobutyl propionate
ESI-MS[M+H]
+(m/z):410；
Embodiment 223 (S)-2-[2'-methyl-(1,1'-xenyl)-4-formamido-]-3-(1H-imidazoles-1-base) methyl propionate
ESI-MS[M+H]
+(m/z):364；
Embodiment 224 (S)-2-[2'-methyl-(1,1'-xenyl)-4-formamido-]-3-(1H-imidazoles-1-base) ethyl propionate
ESI-MS[M+H]
+(m/z):378；
Embodiment 225 (S)-2-[2'-methyl-(1,1'-xenyl)-4-formamido-]-3-(1H-imidazoles-1-base) propyl propionate
ESI-MS[M+H]
+(m/z):392；
Embodiment 226 (S)-2-[2'-methyl-(1,1'-xenyl)-4-formamido-]-3-(1H-imidazoles-1-base) isopropyl propionate
ESI-MS[M+H]
+(m/z):392；
Embodiment 227 (S)-2-[2'-methyl-(1,1'-xenyl)-4-formamido-]-3-(1H-imidazoles-1-base) isobutyl propionate
ESI-MS[M+H]
+(m/z):406；
Embodiment 228 (S)-2-[2,4'-dimethoxy-(1,1'-xenyl)-4-formamido-]-3-(1H-imidazoles-1-base) methyl propionate
ESI-MS[M+H]
+(m/z):410；
Embodiment 229 (S)-2-[2,4'-dimethoxy-(1,1'-xenyl)-4-formamido-]-3-(1H-imidazoles-1-base) ethyl propionate
ESI-MS[M+H]
+(m/z):424；
Embodiment 230 (S)-2-[2,4'-dimethoxy-(1,1'-xenyl)-4-formamido-]-3-(1H-imidazoles-1-base) propyl propionate
ESI-MS[M+H]
+(m/z):438；
Embodiment 231 (S)-2-[2,4'-dimethoxy-(1,1'-xenyl)-4-formamido-]-3-(1H-imidazoles-1-base) isopropyl propionate
ESI-MS[M+H]
+(m/z):438；
Embodiment 232 (S)-2-[2,4'-dimethoxy-(1,1'-xenyl)-4-formamido-]-3-(1H-imidazoles-1-base) isobutyl propionate
ESI-MS[M+H]
+(m/z):452；
The preparation of embodiment 233 (S)-N-(1-(1H-imidazoles-1-base)-3-phenylpropyl alcohol-2-base)-(1,1'-xenyl)-4-formamido-
Step H-1 is by intermediate A-4 diphenic acid (1g, 5mmol), EDCI0.82g (4.3mmol) and HOBt0.85g (4.3mmol) is dissolved in the DMF of 30mL, stirred at ambient temperature 2h, add intermediate 6,1-(1H-imidazoles-1-base)-3-phenyl third-2-amine (1.7g, 5.5mmol) and DIEA4mL, react 5h at 70 DEG C, TLC monitoring reacts completely.In reaction solution, add 100mL water, 56mLEA extracts, and saturated common salt water washing has basic unit, Na
2sO
4dried overnight.Filtering siccative, concentrating under reduced pressure obtains brown oil 1.05g, yield 55%.ESI-MS[M+H]
+(m/z):382。
According to the method for embodiment 233, the different diphenic acid replaced is used to be obtained by reacting embodiment 234-238 for raw material and 1-(1H-imidazoles-1-base)-3-phenyl third-2-amine amide.
Embodiment 234 (S)-N-(1-(1H-imidazoles-1-base)-3-phenylpropyl alcohol-2-base)-4'-fluoro-(1,1'-xenyl)-4-formamido-
ESI-MS[M+H]
+(m/z):400；
Embodiment 235 (S)-N-(1-(1H-imidazoles-1-base)-3-phenylpropyl alcohol-2-base)-4'-methyl-(1,1'-xenyl)-4-formamido-
ESI-MS[M+H]
+(m/z):396；
Embodiment 236 (S)-N-(1-(1H-imidazoles-1-base)-3-phenylpropyl alcohol-2-base)-2'-fluoro-(1,1'-xenyl)-4-formamido-
ESI-MS[M+H]
+(m/z):400；
Embodiment 237 (S)-N-(1-(1H-imidazoles-1-base)-3-phenylpropyl alcohol-2-base)-2'-methyl-(1,1'-xenyl)-4-formamido-
ESI-MS[M+H]
+(m/z):396；
Embodiment 238 (S)-N-(1-(1H-imidazoles-1-base)-3-phenylpropyl alcohol-2-base)-2,4'-dimethoxys-(1,1'-xenyl)-4-formamido-
ESI-MS[M+H]
+(m/z):442；
Obtain compound 203 according to the method for embodiment 203, with 203 for raw material, after hydrolysis, prepare embodiment 239-241 with various amine generation condensation reaction again.
Embodiment 239 (S)-N-methyl-2-[(1,1'-xenyl)-4-formamido-]-3-(1H-imidazoles-1-base) propionic acid amide
ESI-MS[M+H]
+(m/z):349；
Embodiment 240 (S)-N-ethyl-2-[(1,1'-xenyl)-4-formamido-]-3-(1H-imidazoles-1-base) propionic acid amide
ESI-MS[M+H]
+(m/z):363；
Embodiment 241 (S)-N-phenyl-2-[(1,1'-xenyl)-4-formamido-]-3-(1H-imidazoles-1-base) propionic acid amide
ESI-MS[M+H]
+(m/z):411。
The pharmacological research of portion of product of the present invention
Cell cultures extracorporeal anti-tumor cell and differentiation-inducing activity
Mankind APL cell line HL-60, suspension culture is in 10% foetal calf serum, 100U/mL penicillin, 100ug/mL Streptomycin sulphate, 0.2%NaHCO
3rPMI-1640 nutrient solution in.Culture condition is 37 DEG C, 5%CO
2, saturated humidity.ATRA cell growth inhibiting activity measures
1. take the logarithm proliferation period cell, piping and druming evenly becomes cell suspension, with every hole 4 × 10
4the density of cell/mL is inoculated in 24 well culture plates, 2mL/ hole.
2. set up the blank group not adding any reagent respectively, individually dosed group of the ATRA of 1 μM, the Combined Preparation group of ATRA and the 25 μM inhibitor of 1 μM.
3. after 72h is cultivated in dosing, 24 orifice plate supernatant liquors are taken out 1.7mL, then add 1.8mL fresh medium and continue incubated cell 24h.Take out cell suspension that 50 μ L suspend to join 50 μ L0.4% platforms and expect in blue solution and dye.
4. dead cell number and the total cellular score of control wells and medicine feeding hole is counted respectively with blood counting chamber.Following formula is utilized to try to achieve inhibitory rate of cell growth: (1-medicine feeding hole total cellular score/control wells total cellular score) × 100%.
When compound and ATRA drug combination, suppress HL-60 cell strain Activity Results in table 3.
The inhibit activities percentage of the anti-HL60 of table 1 embodiment Compound ira vitro
Cytodifferentiation induced activity measures
1. bury cell: with 4 × 10 after suspension cell counting
5individual/mL adds 24 orifice plates, 2mL/well.
2. dosing: add in hand-hole with certain concentration after Pharmaceutical formulations is good, set up negative control hole, positive drug control wells, drug level is 25 μMs.After dosing, drug solvent DMSO concentration wants <0.1%, alcohol concn <1%.96h counts.
3. develop the color: with 1mL rifle head suspension cell, get 1mL cell suspension and add centrifugal collecting cell in ep pipe.Add 1mL nitrite ion (14.7mL1640 nutrient solution adds 300 μ LNBT, 15 μ LPMC) 37 DEG C and hatch 20 minutes.Centrifugal 3 minutes of 2000r, removes supernatant, stays 50 μ L or adds 50 μ LPBS re-suspended cells.
4. count: get 20 μ L cell suspensions and add on the slide glass that coated, covered, counts total cell count and bluish voilet cell count under × 20 object lens.Obtain positive percentage.
5. independent 3 repeated experiments, gets average and variance.
The differentiation-inducing percent activity of the anti-HL60 of table 2 embodiment Compound ira vitro
Can clearly be seen that from above-mentioned test-results, the compound of the claimed general formula I of the present invention, after ATRA drug combination, have good extracorporeal anti-tumor and differentiation-inducing activity, therefore compound of the present invention has good prospects for commercial application.
Extracorporeal antifungal activity is tested
Experimental technique: adopt conventional extracorporeal bacteria inhibitor test method (antimicrobialagentsandchemotherapy, 1995,39 (5): 1169).
Experiment material and method:
(1) experimental strain
This experiment has selected following 6 kinds of common human body cause illness's standard fungal bacterial strains as screening object, and fungal bacterial strain is provided by Shenyang Pharmaceutical University.
| Strain name | Species | Bacterial strain is selected |
| Candida albicans | Candida albicans | SC5314 |
| Candida albicans | Candida albicans | Y0109 |
| Candida glabrata | Candida glabrata | 537 |
| Trichophyton | Trichophyton rubrum | Cmccftla |
| Trichophyton verrucosum | Trichophyton verrucosum | |
| Microsporon gypseum | Microsporum gypseum | Cmccfmza |
(2) experimental technique:
The preparation of RPMI-1640 substratum: RPMI1640 (Gibco) 10g, NaHCO
32.0g, three morpholino nitrogen quinoline propanesulfonic acid (sigma) 34.5g, add 800mL sterile distilled water and dissolve, after 1mol/LNaOH adjusts pH to 7.0, be settled to 1000mL, 0.22 μm of degerming rear placement 4 DEG C of filtering with microporous membrane saves backup.
The preparation of filamentous fungus bacteria suspension: double the going down to posterity such as filamentous fungus (trichophyton, Trichophyton verrucosum, microsporon gypseum) are inoculated in sabouraud culture medium flat board, 48h is cultivated in 35 DEG C of incubators, bacterium colony adds 0.85% physiological saline 5mL, preparation bacterium liquid.Adjust bacterial concentration with spectrophotometer, A value is adjusted to 0.3 ~ 0.5; 50 times are diluted as inoculation bacteria suspension again with substratum.
The preparation of spherical fungi bacteria suspension: spherical bacterium (Candida albicans, Candida glabrata).Bacterial strain streaking inoculation after activation is inoculated on Sharpe solid medium flat board, in 32 DEG C of constant temperature culture 2 ~ 3 days, get appropriate single bacterium colony access containing in the triangular flask of 10mL0.85% stroke-physiological saline solution, shake 15 minutes, take a morsel bacterium liquid on blood cell counting plate, counted under microscope with sterilizing rifle head.Add the dilution of RPMI-1640 substratum, make the concentration of final bacteria suspension be 1 × 10
6individual/mL.
Prepared by liquid: take each 6.40mg of above-mentioned chemical synthetic drug, add 1.0mL dimethyl sulfoxide (DMSO) (DMSO), 1.0mL polysorbas20 and 8.0mL sterile purified water successively, mixing.Being made into liquor strength is 0.64mg/mL.Prepare positive control drug fluconazole, voriconazole in the same way.
Inoculation: the first step, adds RPMI-1640 substratum: often the 1st hole of row adds 180 μ LRPMI1640 substratum, and 2-11 hole adds 100 μ LRPMI1640 substratum, and 12 holes add 200 μ LRPMI1640 substratum.Second step, dosing sample: add 20 μ L liquid to be measured in the 1st hole, with liquid-transfering gun mixing after draw 100 μ L to 2 holes, carry out successively 2 times be diluted to the 10th hole after mixing discard 100 μ L.3rd step, adds bacteria suspension: in 1 ~ 11 hole, respectively add 100 μ L inoculate bacteria suspension.11st hole is growth control, and the 12nd hole is blank cultures contrast.Blank drug control do not established by positive control medicine, namely from the 1st hole, does multiple proportions gradient dilution until the 10th hole, test concentrations (μ g/mL) scope 256,128,64,32,16,8,4,2,1,0.5.
Cultivate and detect: with blank asepsis growth, positive control well-grown is as judging the standard whether test operation is qualified.Every board test 8 samples, each bacterium all arranges positive drug control.Drug dilution method to be measured is the same.
Table 3 Compound of Example minimum inhibitory concentration (MIC, μ g/ml)
Remarks: FCZ: fluconazole; VCZ: voriconazole.
Can clearly be seen that from above-mentioned test-results; compound and its esters of the claimed general formula I of the present invention have good anti-mycotic activity; the anti-mycotic activity of multiple compound is better than contrast medicine; compared with existing antifungal drug; have the advantages such as novel structure, efficient, wide spectrum, therefore this compounds has good application prospect.
The compound of formula of I of the present invention can be used separately, but normally give with pharmaceutical carrier mixture, the selection of described pharmaceutical carrier will according to required route of administration and standard pharmaceutical practice, below respectively with the various pharmaceutical dosage forms of this compounds, the such as preparation method of tablet, capsule, injection, aerosol, suppository, film, pill, externally-applied liniment and ointment, illustrates its new opplication in pharmacy field.
Embodiment 232: tablet
With compound (for the embodiment 1 compound) 10g containing compound in claim 1, after adding auxiliary material 20g mixing according to the general pressed disc method of pharmaceutics, be pressed into 100, the heavy 300mg of every sheet.
Embodiment 233: capsule
With compound (for the embodiment 107 compound) 10g containing compound in claim 1, after being mixed by auxiliary material 20g according to the requirement of pharmaceutics capsule, load Capsules, the heavy 300mg of each capsule.
Embodiment 234: injection
With compound (for the embodiment 206 compound) 10g containing compound in claim 1, according to pharmaceutics ordinary method, carry out charcoal absorption, after 0.65 μm of filtering with microporous membrane, insert nitrogen pot and make hydro-acupuncture preparation, often only fill 2mL, filling 100 bottles altogether.
Embodiment 235: aerosol
With compound (for the embodiment 37 compound) 10g containing compound in claim 1, after dissolving with appropriate propylene glycol, after adding distilled water and other spoke material, make the settled solution of 500mL and get final product.
Embodiment 236: suppository
With compound (for the embodiment 113 compound) 10g containing compound in claim 1, it porphyrize is added glycerine in right amount, add the glycogelatin melted after grinding well, evenly, impouring has been coated with in the model of lubricant in grinding, obtained suppository 50
Embodiment 237: film
With compound (for the embodiment 117 compound) 10g containing compound in claim 1, polyvinyl alcohol, medicinal glycerin, water etc. are stirred expansion post-heating dissolve, 80 eye mesh screens filter, again embodiment 18 compound is joined stirring and dissolving in filtrate, film applicator masking 100.
Embodiment 238: pill
With compound (for the embodiment 147 compound) 10g containing compound in claim 1, after mixing with the matrix 50g heat fused such as gelatin, in instillation cryogenic liquid paraffin, obtained dripping pill 1000 ball altogether.
Embodiment 239: externally-applied liniment
With compound (for the embodiment 86 compound) 10g containing compound in claim 1, the conveniently auxiliary material such as practice of pharmacy and emulsifying agent 2.5g mixed grinding, then adding distil water obtains to 200mL.
Embodiment 240: ointment
With compound (for the embodiment 39 compound) 10g containing compound in claim 1, grind well obtained with oleaginous base 500g such as Vaseline after porphyrize.
Although describe the present invention by particular, amendment and equivalent variations are obvious for the technician being proficient in this field, and they are included in the scope of the invention.
Claims (12)
1. the compound shown in general formula I, and geometrical isomer or its pharmacy acceptable salt, hydrate, solvate or prodrug.
Wherein:
X is N, C;
N is the integer between 0-2;
R is (C
1-C
5) alkyl, (C
1-C
4) alkoxyl group, C
6-C
10aryl, carboxyl, (C
1-C
5) ester group, (C
1-C
5) acid amides, N-(C
6-C
10) arylamide;
Ar is C
6-C
10aryl, 5-10 unit heteroaryl, wherein, described heteroaryl contains the heteroatoms that 1-3 is selected from N, O or S, and the M replacement that the optional 1-4 of Ar identical or different;
M is hydrogen or is selected from hydroxyl, halogen, nitro, amino, cyano group, (C for 1-3 is individual
1-C
6) alkyl, (C
2-C
6) thiazolinyl, (C
2-C
6) alkynyl, (C
1-C
6) alkoxyl group, (C
1-C
6) alkyl sulfenyl, optionally by the (C of hydroxyl, amino or halogen substiuted
1-C
6) alkyl or (C
1-C
6) alkoxyl group or (C
1-C
6) alkyl sulfenyl, coverlet or two (C
1-C
6alkyl) the amino, (C that replace
1-C
6) alkyl amido, free, salify, esterification with amidated carboxyl, (C
1-C
6) alkyl sulphinyl, (C
1-C
6) alkyl sulphonyl, (C
1-C
6) alkyl acyl, formamyl, coverlet or two (C
1-C
6alkyl) the formamyl, (C that replace
1-C
3) alkylenedioxy group; M also can be 6-10 unit aryl, 5-10 unit heteroaryl, and described heteroaryl contains the heteroatoms that 1-3 is selected from O, N and S, described aryl and the optional 1-3 of a heteroaryl R
1replace;
R
1for hydrogen, hydroxyl, halogen, nitro, amino, cyano group, (C
1-C
6) alkyl, (C
2-C
6) thiazolinyl, (C
2-C
6) alkynyl, (C
1-C
6) alkoxyl group, optionally by the (C of hydroxyl, amino or halogen substiuted
1-C
6) alkyl or (C
1-C
6) alkoxyl group, coverlet or two (C
1-C
6alkyl) the amino, (C that replace
1-C
6) alkyl amido, free, salify, esterification with amidated carboxyl, (C
1-C
6) alkyl sulphinyl, (C
1-C
6) alkyl sulphonyl (C
1-C
6) alkyl acyl, formamyl, coverlet or two (C
1-C
6alkyl) the formamyl, (C that replace
1-C
3) alkylenedioxy group.
2. the compound of Formula I of claim 1, and geometrical isomer or its pharmacy acceptable salt, hydrate, solvate or prodrug,
Ar is phenyl, naphthyl, pyrryl, furyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, 1, 2, 3-triazol radical, 1, 2, 4-triazol radical, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, benzothienyl, benzofuryl, indyl, benzimidazolyl-, benzopyrazoles base, benzothiazolyl, benzoxazolyl, quinolyl, isoquinolyl, benzo pyrimidyl, benzo pyridazinyl, benzopyrazines base, Thienopyrimidine base, pyrrolo-pyrimidine radicals, thienopyridine base, thienopyridine base, the individual identical or different M of the optional 1-4 of Ar replaces.
3. the compound of Formula I of claim 1 or 2, and geometrical isomer or its pharmacy acceptable salt, hydrate, solvate or prodrug,
Wherein
N is the integer of 0 or 1;
4. the compound of Formula I of claim 1-3 described in any one, and geometrical isomer or its pharmacy acceptable salt, hydrate, solvate or prodrug,
Wherein
R is phenyl, (C
1-C
5) ester group, (C
1-C
5) acid amides;
Ar is phenyl, pyrryl, pyrazolyl, benzothiazolyl, and the individual identical or different M of the optional 1-4 of Ar replaces;
5. any one compound of Formula I of claim 1-4, and geometrical isomer or its pharmacy acceptable salt, hydrate, solvate or prodrug,
Wherein
X is C;
N is the integer of 1;
R is phenmethyl, methyl esters, ethyl ester, propyl ester, isopropyl ester, isobutyl ester group, N-phenyl amide;
Ar is phenyl, pyrryl, pyrazolyl, benzothiazolyl, and the individual identical or different M of the optional 1-4 of Ar replaces;
M is hydrogen or is selected from hydroxyl, halogen, nitro, trifluoromethyl, (C for 1-3 is individual
1-C
4) alkyl, (C
1-C
4) alkoxy methyl, phenyl, the optional 1-3 of a described phenyl R
1replace;
R
1for hydrogen or 1-3 the optional substituting group from halogen, (C1-C4) alkyl, (C1-C4) alkoxyl group, trifluoromethyl and trifluoromethoxy.
6. any one compound of Formula I of claim 1-5, and geometrical isomer or its pharmacy acceptable salt, hydrate, solvate or prodrug, be selected from:
(S)-2-(benzo [d] thiazole-2-formamido-)-3-(1H-imidazoles-1-base) methyl propionate
(S)-2-(benzo [d] thiazole-2-formamido-)-3-(1H-imidazoles-1-base) ethyl propionate
(S)-2-(benzo [d] thiazole-2-formamido-)-3-(1H-imidazoles-1-base) propyl propionate
(S)-2-(benzo [d] thiazole-2-formamido-)-3-(1H-imidazoles-1-base) isopropyl propionate
(S)-2-(benzo [d] thiazole-2-formamido-)-3-(1H-imidazoles-1-base) isobutyl propionate
(S)-N-(1-(1H-imidazoles-1-base)-3-phenylpropyl alcohol-2-base) benzo [d] thiazole-2-methane amide
(S)-2-(6-methyl benzo [d] thiazole-2-formamido-)-3-(1H-imidazoles-1-base) methyl propionate
(S)-2-(6-methyl benzo [d] thiazole-2-formamido-)-3-(1H-imidazoles-1-base) ethyl propionate
(S)-2-(6-methyl benzo [d] thiazole-2-formamido-)-3-(1H-imidazoles-1-base) propyl propionate
(S)-2-(6-methyl benzo [d] thiazole-2-formamido-)-3-(1H-imidazoles-1-base) isopropyl propionate
(S)-2-(6-methyl benzo [d] thiazole-2-formamido-)-3-(1H-imidazoles-1-base) isobutyl propionate
(S)-N-(1-(1H-imidazoles-1-base)-3-phenylpropyl alcohol-2-base)-6-methyl-benzo [d] thiazole-2-methane amide
(S)-2-(6-bromobenzene is [d] thiazole-2-formamido-also)-3-(1H-imidazoles-1-base) methyl propionate
(S)-2-(6-bromobenzene is [d] thiazole-2-formamido-also)-3-(1H-imidazoles-1-base) ethyl propionate
(S)-2-(6-bromobenzene is [d] thiazole-2-formamido-also)-3-(1H-imidazoles-1-base) propyl propionate
(S)-2-(6-bromobenzene is [d] thiazole-2-formamido-also)-3-(1H-imidazoles-1-base) isopropyl propionate
(S)-2-(6-bromobenzene is [d] thiazole-2-formamido-also)-3-(1H-imidazoles-1-base) isobutyl propionate
(S)-N-(1-(1H-imidazoles-1-base)-3-phenylpropyl alcohol-2-base) the bromo-benzo of-6-[d] thiazole-2-methane amide
(S)-2-(6-chlorobenzene is [d] thiazole-2-formamido-also)-3-(1H-imidazoles-1-base) methyl propionate
(S)-2-(6-chlorobenzene is [d] thiazole-2-formamido-also)-3-(1H-imidazoles-1-base) ethyl propionate
(S)-2-(6-chlorobenzene is [d] thiazole-2-formamido-also)-3-(1H-imidazoles-1-base) propyl propionate
(S)-2-(6-chlorobenzene is [d] thiazole-2-formamido-also)-3-(1H-imidazoles-1-base) isopropyl propionate
(S)-2-(6-chlorobenzene is [d] thiazole-2-formamido-also)-3-(1H-imidazoles-1-base) isobutyl propionate
(S)-N-(1-(1H-imidazoles-1-base)-3-phenylpropyl alcohol-2-base) the chloro-benzo of-6-[d] thiazole-2-methane amide
(S)-2-(6-methoxyl group benzo [d] thiazole-2-formamido-)-3-(1H-imidazoles-1-base) methyl propionate
(S)-2-(6-methoxyl group benzo [d] thiazole-2-formamido-)-3-(1H-imidazoles-1-base) ethyl propionate
(S)-2-(6-methoxyl group benzo [d] thiazole-2-formamido-)-3-(1H-imidazoles-1-base) propyl propionate
(S)-2-(6-methoxyl group benzo [d] thiazole-2-formamido-)-3-(1H-imidazoles-1-base) isopropyl propionate
(S)-2-(6-methoxyl group benzo [d] thiazole-2-formamido-)-3-(1H-imidazoles-1-base) isobutyl propionate
(S)-N-(1-(1H-imidazoles-1-base)-3-phenylpropyl alcohol-2-base)-6-methoxyl group-benzo [d] thiazole-2-methane amide
(S)-2-(6-trifluoromethyl benzo [d] thiazole-2-formamido-)-3-(1H-imidazoles-1-base) methyl propionate
(S)-2-(6-trifluoromethyl benzo [d] thiazole-2-formamido-)-3-(1H-imidazoles-1-base) ethyl propionate
(S)-2-(6-trifluoromethyl benzo [d] thiazole-2-formamido-)-3-(1H-imidazoles-1-base) propyl propionate
(S)-2-(6-trifluoromethyl benzo [d] thiazole-2-formamido-)-3-(1H-imidazoles-1-base) isopropyl propionate
(S)-2-(6-trifluoromethyl benzo [d] thiazole-2-formamido-)-3-(1H-imidazoles-1-base) isobutyl propionate
(S)-N-(1-(1H-imidazoles-1-base)-3-phenylpropyl alcohol-2-base)-6-trifluoromethyl-benzo [d] thiazole-2-methane amide
(S)-2-(4-methyl benzo [d] thiazole-2-formamido-)-3-(1H-imidazoles-1-base) methyl propionate
(S)-2-(4-methyl benzo [d] thiazole-2-formamido-)-3-(1H-imidazoles-1-base) ethyl propionate
(S)-2-(4-methyl benzo [d] thiazole-2-formamido-)-3-(1H-imidazoles-1-base) propyl propionate
(S)-2-(4-methyl benzo [d] thiazole-2-formamido-)-3-(1H-imidazoles-1-base) isopropyl propionate
(S)-2-(4-methyl benzo [d] thiazole-2-formamido-)-3-(1H-imidazoles-1-base) isobutyl propionate
(S)-N-(1-(1H-imidazoles-1-base)-3-phenylpropyl alcohol-2-base)-4-methyl-benzo [d] thiazole-2-methane amide
(S)-2-(4-methoxyl group benzo [d] thiazole-2-formamido-)-3-(1H-imidazoles-1-base) methyl propionate
(S)-2-(4-methoxyl group benzo [d] thiazole-2-formamido-)-3-(1H-imidazoles-1-base) ethyl propionate
(S)-2-(4-methoxyl group benzo [d] thiazole-2-formamido-)-3-(1H-imidazoles-1-base) propyl propionate
(S)-2-(4-methoxyl group benzo [d] thiazole-2-formamido-)-3-(1H-imidazoles-1-base) isopropyl propionate
(S)-2-(4-methoxyl group benzo [d] thiazole-2-formamido-)-3-(1H-imidazoles-1-base) isobutyl propionate
(S)-N-(1-(1H-imidazoles-1-base)-3-phenylpropyl alcohol-2-base)-4-methoxyl group-benzo [d] thiazole-2-methane amide
(S)-2-(4-trifluoromethyl benzo [d] thiazole-2-formamido-)-3-(1H-imidazoles-1-base) methyl propionate
(S)-2-(4-trifluoromethyl benzo [d] thiazole-2-formamido-)-3-(1H-imidazoles-1-base) ethyl propionate
(S)-2-(4-trifluoromethyl benzo [d] thiazole-2-formamido-)-3-(1H-imidazoles-1-base) propyl propionate
(S)-2-(4-trifluoromethyl benzo [d] thiazole-2-formamido-)-3-(1H-imidazoles-1-base) isopropyl propionate
(S)-2-(4-trifluoromethyl benzo [d] thiazole-2-formamido-)-3-(1H-imidazoles-1-base) isobutyl propionate
(S)-N-(1-(1H-imidazoles-1-base)-3-phenylpropyl alcohol-2-base)-4-trifluoromethyl-benzo [d] thiazole-2-methane amide
(S)-2-(4-chlorobenzene is [d] thiazole-2-formamido-also)-3-(1H-imidazoles-1-base) methyl propionate
(S)-2-(4-chlorobenzene is [d] thiazole-2-formamido-also)-3-(1H-imidazoles-1-base) ethyl propionate
(S)-2-(4-chlorobenzene is [d] thiazole-2-formamido-also)-3-(1H-imidazoles-1-base) propyl propionate
(S)-2-(4-chlorobenzene is [d] thiazole-2-formamido-also)-3-(1H-imidazoles-1-base) isopropyl propionate
(S)-2-(4-chlorobenzene is [d] thiazole-2-formamido-also)-3-(1H-imidazoles-1-base) isobutyl propionate
(S)-N-(1-(1H-imidazoles-1-base)-3-phenylpropyl alcohol-2-base)-4-Cl-benzo [d] thiazole-2-methane amide
(S)-2-(2,4,5-trimethylammonium-1-phenyl-1H-pyrrole-3-carboxamide base)-3-(1H-imidazoles-1-base) methyl propionate
(S)-2-(2,4,5-trimethylammonium-1-phenyl-1H-pyrrole-3-carboxamide base)-3-(1H-imidazoles-1-base) ethyl propionate
(S)-2-(2,4,5-trimethylammonium-1-phenyl-1H-pyrrole-3-carboxamide base)-3-(1H-imidazoles-1-base) propyl propionate
(S)-2-(2,4,5-trimethylammonium-1-phenyl-1H-pyrrole-3-carboxamide base)-3-(1H-imidazoles-1-base) isopropyl propionate
(S)-2-(2,4,5-trimethylammonium-1-phenyl-1H-pyrrole-3-carboxamide base)-3-(1H-imidazoles-1-base) isobutyl propionate
(S)-N-(1-(1H-imidazoles-1-base)-3-phenylpropyl alcohol-2-base)-2,4,5-trimethylammonium-1-phenyl-1H-pyrrole-3-carboxamides
(S)-2-[2,4,5 dimethyl-1-(4-aminomethyl phenyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) methyl propionate
(S)-2-[2,4,5 dimethyl-1-(4-aminomethyl phenyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) ethyl propionate
(S)-2-[2,4,5 dimethyl-1-(4-aminomethyl phenyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) propyl propionate
(S)-2-[2,4,5 dimethyl-1-(4-aminomethyl phenyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) isopropyl propionate
(S)-2-[2,4,5 dimethyl-1-(4-aminomethyl phenyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) isobutyl propionate
(S)-N-(1-(1H-imidazoles-1-base)-3-phenylpropyl alcohol-2-base)-2,4,5-trimethylammonium-1-(4-aminomethyl phenyl)-1H-pyrrole-3-carboxamide
(S)-2-[2,4,5-dimethyl-1-(4-bromophenyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) methyl propionate
(S)-2-[2,4,5-dimethyl-1-(4-bromophenyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) ethyl propionate
(S)-2-[2,4,5-dimethyl-1-(4-bromophenyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) propyl propionate
(S)-2-[2,4,5-dimethyl-1-(4-bromophenyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) isopropyl propionate
(S)-2-[2,4,5 dimethyl-1-(4-bromophenyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) isobutyl propionate
(S)-N-(1-(1H-imidazoles-1-base)-3-phenylpropyl alcohol-2-base)-2,4,5-trimethylammonium-1-(4-bromophenyl)-1H-pyrrole-3-carboxamide
(S)-2-[2,4,5-dimethyl-1-(4-chloro-phenyl-)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) methyl propionate
(S)-2-[2,4,5-dimethyl-1-(4-chloro-phenyl-)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) ethyl propionate
(S)-2-[2,4,5-dimethyl-1-(4-chloro-phenyl-)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) propyl propionate
(S)-2-[2,4,5-dimethyl-1-(4-chloro-phenyl-)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) isopropyl propionate
(S)-2-[2,5-dimethyl-1-(4-chloro-phenyl-)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) isobutyl propionate
(S)-N-(1-(1H-imidazoles-1-base)-3-phenylpropyl alcohol-2-base)-2,4,5-trimethylammonium-1-(4-chloro-phenyl-)-1H-pyrrole-3-carboxamide
(S)-2-[2,4,5-dimethyl-1-(4-p-methoxy-phenyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) methyl propionate
(S)-2-[2,4,5-dimethyl-1-(4-p-methoxy-phenyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) ethyl propionate
(S)-2-[2,4,5-dimethyl-1-(4-p-methoxy-phenyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) propyl propionate
(S)-2-[2,4,5-dimethyl-1-(4-p-methoxy-phenyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) isopropyl propionate
(S)-2-[2,4,5-dimethyl-1-(4-p-methoxy-phenyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) isobutyl propionate
(S)-N-(1-(1H-imidazoles-1-base)-3-phenylpropyl alcohol-2-base)-2,4,5-trimethylammonium-1-(4-p-methoxy-phenyl)-1H-pyrrole-3-carboxamide
(S)-2-[2,4,5-dimethyl-1-(4-trifluoromethyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) methyl propionate
(S)-2-[2,4,5-dimethyl-1-(4-trifluoromethyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) ethyl propionate
(S)-2-[2,4,5-dimethyl-1-(4-trifluoromethyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) propyl propionate
(S)-2-[2,4,5-dimethyl-1-(4-trifluoromethyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) isopropyl propionate
(S)-2-[2,4,5-dimethyl-1-(4-trifluoromethyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) isobutyl propionate
(S)-N-(1-(1H-imidazoles-1-base)-3-phenylpropyl alcohol-2-base)-2,4,5-trimethylammonium-1-(4-trifluoromethyl)-1H-pyrrole-3-carboxamide
(S)-2-[2,4,5-dimethyl-1-(4-ethylphenyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) methyl propionate
(S)-2-[2,4,5-dimethyl-1-(4-ethylphenyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) ethyl propionate
(S)-2-[2,4,5-dimethyl-1-(4-ethylphenyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) propyl propionate
(S)-2-[2,4,5-dimethyl-1-(4-ethylphenyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) isopropyl propionate
(S)-2-[2,4,5-dimethyl-1-(4-ethylphenyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) isobutyl propionate
(S)-2-[2,4,5-dimethyl-1-(4-nitrophenyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) methyl propionate
(S)-2-[2,4,5-dimethyl-1-(4-nitrophenyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) ethyl propionate
(S)-2-[2,4,5-dimethyl-1-(4-nitrophenyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) propyl propionate
(S)-2-[2,4,5-dimethyl-1-(4-nitrophenyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) isopropyl propionate
(S)-2-[2,4,5-dimethyl-1-(4-nitrophenyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) isobutyl propionate
(S)-2-[2,4,5-dimethyl-1-(2-aminomethyl phenyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) methyl propionate
(S)-2-[2,4,5-dimethyl-1-(2-aminomethyl phenyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) ethyl propionate
(S)-2-[2,4,5-dimethyl-1-(2-aminomethyl phenyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) propyl propionate
(S)-2-[2,4,5-dimethyl-1-(2-aminomethyl phenyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) isopropyl propionate
(S)-2-[2,4,5-dimethyl-1-(2-aminomethyl phenyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) isobutyl propionate
(S)-N-(1-(1H-imidazoles-1-base)-3-phenylpropyl alcohol-2-base)-2,4,5-trimethylammonium-1-(2-aminomethyl phenyl)-1H-pyrrole-3-carboxamide
(S)-2-[2,4,5-dimethyl-1-(2-chloro-phenyl-)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) methyl propionate
(S)-2-[2,4,5-dimethyl-1-(2-chloro-phenyl-)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) ethyl propionate
(S)-2-[2,4,5-dimethyl-1-(2-chloro-phenyl-)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) propyl propionate
(S)-2-[2,4,5-dimethyl-1-(2-chloro-phenyl-)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) isopropyl propionate
(S)-2-[2,4,5-dimethyl-1-(2-chloro-phenyl-)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) isobutyl propionate
(S)-N-(1-(1H-imidazoles-1-base)-3-phenylpropyl alcohol-2-base)-2,4,5-trimethylammonium-1-(2-chloro-phenyl-)-1H-pyrrole-3-carboxamide
(S)-2-[2,4,5-dimethyl-1-(2-p-methoxy-phenyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) methyl propionate
(S)-2-[2,4,5-dimethyl-1-(2-p-methoxy-phenyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) ethyl propionate
(S)-2-[2,4,5-dimethyl-1-(2-p-methoxy-phenyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) propyl propionate
(S)-2-[2,4,5-dimethyl-1-(2-p-methoxy-phenyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) isopropyl propionate
(S)-2-[2,4,5-dimethyl-1-(2-p-methoxy-phenyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) isobutyl propionate
(S)-N-(1-(1H-imidazoles-1-base)-3-phenylpropyl alcohol-2-base)-2,4,5-trimethylammonium-1-(2-p-methoxy-phenyl)-1H-pyrrole-3-carboxamide
(S)-2-[2,4,5-dimethyl-1-(2-trifluoromethyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) methyl propionate
(S)-2-[2,4,5-dimethyl-1-(2-trifluoromethyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) ethyl propionate
(S)-2-[2,4,5-dimethyl-1-(2-trifluoromethyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) propyl propionate
(S)-2-[2,4,5-dimethyl-1-(2-trifluoromethyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) isopropyl propionate
(S)-2-[2,4,5-dimethyl-1-(2-trifluoromethyl)-1H-pyrrole-3-carboxamide base]-3-(1H-imidazoles-1-base) isobutyl propionate
(S)-N-(1-(1H-imidazoles-1-base)-3-phenylpropyl alcohol-2-base)-2,4,5-trimethylammonium-1-(2-trifluoromethyl)-1H-pyrrole-3-carboxamide
(S)-2-[chloro-3 methyl isophthalic acids of 5--phenyl-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) methyl propionate
(S)-2-[chloro-3 methyl isophthalic acids of 5--phenyl-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) ethyl propionate
(S)-2-[chloro-3 methyl isophthalic acids of 5--phenyl-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) propyl propionate
(S)-2-[chloro-3 methyl isophthalic acids of 5--phenyl-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) isopropyl propionate
(S)-2-[chloro-3 methyl isophthalic acids of 5--phenyl-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) isobutyl propionate
(S)-N-(1-(1H-imidazoles-1-base)-3-phenylpropyl alcohol-2-base) chloro-3 methyl isophthalic acids of-5--phenyl-1H-pyrazole-4-carboxamide
(S)-2-[chloro-3 methyl isophthalic acids of 5--(4-aminomethyl phenyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) methyl propionate
(S)-2-[chloro-3 methyl isophthalic acids of 5--(4-aminomethyl phenyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) ethyl propionate
(S)-2-[chloro-3 methyl isophthalic acids of 5--(4-aminomethyl phenyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) propyl propionate
(S)-2-[chloro-3 methyl isophthalic acids of 5--(4-aminomethyl phenyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) isopropyl propionate
(S)-2-[chloro-3 methyl isophthalic acids of 5--(4-aminomethyl phenyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) isobutyl propionate
(S)-N-(1-(1H-imidazoles-1-base)-3-phenylpropyl alcohol-2-base) chloro-3 methyl isophthalic acids of-5--(4-aminomethyl phenyl)-1H-pyrazole-4-carboxamide
(S)-2-[chloro-3 methyl isophthalic acids of 5--(4-bromophenyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) methyl propionate
(S)-2-[chloro-3 methyl isophthalic acids of 5--(4-bromophenyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) ethyl propionate
(S)-2-[chloro-3 methyl isophthalic acids of 5--(4-bromophenyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) propyl propionate
(S)-2-[chloro-3 methyl isophthalic acids of 5--(4-bromophenyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) isopropyl propionate
(S)-2-[chloro-3 methyl isophthalic acids of 5--(4-bromophenyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) isobutyl propionate
(S)-N-(1-(1H-imidazoles-1-base)-3-phenylpropyl alcohol-2-base) chloro-3 methyl isophthalic acids of-5--(4-bromophenyl)-1H-pyrazole-4-carboxamide
(S)-2-[chloro-3 methyl isophthalic acids of 5--(4-chloro-phenyl-)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) methyl propionate
(S)-2-[chloro-3 methyl isophthalic acids of 5--(4-chloro-phenyl-)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) ethyl propionate
(S)-2-[chloro-3 methyl isophthalic acids of 5--(4-chloro-phenyl-)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) propyl propionate
(S)-2-[chloro-3 methyl isophthalic acids of 5--(4-chloro-phenyl-)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) isopropyl propionate
(S)-2-[chloro-3 methyl isophthalic acids of 5--(4-chloro-phenyl-)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) isobutyl propionate
(S)-N-(1-(1H-imidazoles-1-base)-3-phenylpropyl alcohol-2-base) chloro-3 methyl isophthalic acids of-5--(4-chloro-phenyl-)-1H-pyrazole-4-carboxamide
(S)-2-[chloro-3 methyl isophthalic acids of 5--(4-p-methoxy-phenyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) methyl propionate
(S)-2-[chloro-3 methyl isophthalic acids of 5--(4-p-methoxy-phenyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) ethyl propionate
(S)-2-[chloro-3 methyl isophthalic acids of 5--(4-p-methoxy-phenyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) propyl propionate
(S)-2-[chloro-3 methyl isophthalic acids of 5--(4-p-methoxy-phenyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) isopropyl propionate
(S)-2-[chloro-3 methyl isophthalic acids of 5--(4-p-methoxy-phenyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) isobutyl propionate
(S)-N-(1-(1H-imidazoles-1-base)-3-phenylpropyl alcohol-2-base) chloro-3 methyl isophthalic acids of-5--(4-p-methoxy-phenyl)-1H-pyrazole-4-carboxamide
(S)-2-[chloro-3 methyl isophthalic acids of 5--(4-trifluoromethyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) methyl propionate
(S)-2-[chloro-3 methyl isophthalic acids of 5--(4-trifluoromethyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) ethyl propionate
(S)-2-[chloro-3 methyl isophthalic acids of 5--(4-trifluoromethyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) propyl propionate
(S)-2-[chloro-3 methyl isophthalic acids of 5--(4-trifluoromethyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) isopropyl propionate
(S)-2-[chloro-3 methyl isophthalic acids of 5--(4-trifluoromethyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) isobutyl propionate
(S)-N-(1-(1H-imidazoles-1-base)-3-phenylpropyl alcohol-2-base) chloro-3 methyl isophthalic acids of-5--(4-trifluoromethyl)-1H-pyrazole-4-carboxamide
(S)-2-[chloro-3 methyl isophthalic acids of 5--(4-fluorophenyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) methyl propionate
(S)-2-[chloro-3 methyl isophthalic acids of 5--(4-fluorophenyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) ethyl propionate
(S)-2-[chloro-3 methyl isophthalic acids of 5--(4-fluorophenyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) propyl propionate
(S)-2-[chloro-3 methyl isophthalic acids of 5--(4-fluorophenyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) isopropyl propionate
(S)-2-[chloro-3 methyl isophthalic acids of 5--(4-fluorophenyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) isobutyl propionate
(S)-N-(1-(1H-imidazoles-1-base)-3-phenylpropyl alcohol-2-base) chloro-3 methyl isophthalic acids of-5--(4-fluorophenyl)-1H-pyrazole-4-carboxamide
(S)-2-[chloro-3 methyl isophthalic acids of 5--(4-nitrophenyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) methyl propionate
(S)-2-[chloro-3 methyl isophthalic acids of 5--(4-nitrophenyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) ethyl propionate
(S)-2-[chloro-3 methyl isophthalic acids of 5--(4-nitrophenyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) propyl propionate
(S)-2-[chloro-3 methyl isophthalic acids of 5--(4-nitrophenyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) isopropyl propionate
(S)-2-[chloro-3 methyl isophthalic acids of 5--(4-nitrophenyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) isobutyl propionate
(S)-N-(1-(1H-imidazoles-1-base)-3-phenylpropyl alcohol-2-base) chloro-3 methyl isophthalic acids of-5--(4-nitrophenyl)-1H-pyrazole-4-carboxamide
(S)-2-[chloro-3 methyl isophthalic acids of 5--(2-aminomethyl phenyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) methyl propionate
(S)-2-[chloro-3 methyl isophthalic acids of 5--(2-aminomethyl phenyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) ethyl propionate
(S)-2-[chloro-3 methyl isophthalic acids of 5--(2-aminomethyl phenyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) propyl propionate
(S)-2-[chloro-3 methyl isophthalic acids of 5--(2-aminomethyl phenyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) isopropyl propionate
(S)-2-[chloro-3 methyl isophthalic acids of 5--(2-aminomethyl phenyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) isobutyl propionate
(S)-N-(1-(1H-imidazoles-1-base)-3-phenylpropyl alcohol-2-base) chloro-3 methyl isophthalic acids of-5--(2-aminomethyl phenyl)-1H-pyrazole-4-carboxamide
(S)-2-[chloro-3 methyl isophthalic acids of 5--(2-chloro-phenyl-)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) methyl propionate
(S)-2-[chloro-3 methyl isophthalic acids of 5--(2-chloro-phenyl-)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) ethyl propionate
(S)-2-[chloro-3 methyl isophthalic acids of 5--(2-chloro-phenyl-)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) propyl propionate
(S)-2-[chloro-3 methyl isophthalic acids of 5--(2-chloro-phenyl-)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) isopropyl propionate
(S)-2-[chloro-3 methyl isophthalic acids of 5--(2-chloro-phenyl-)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) isobutyl propionate
(S)-N-(1-(1H-imidazoles-1-base)-3-phenylpropyl alcohol-2-base) chloro-3 methyl isophthalic acids of-5--(2-chloro-phenyl-)-1H-pyrazole-4-carboxamide
(S)-2-[chloro-3 methyl isophthalic acids of 5--(2-p-methoxy-phenyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) methyl propionate
(S)-2-[chloro-3 methyl isophthalic acids of 5--(2-p-methoxy-phenyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) ethyl propionate
(S)-2-[chloro-3 methyl isophthalic acids of 5--(2-p-methoxy-phenyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) propyl propionate
(S)-2-[chloro-3 methyl isophthalic acids of 5--(2-p-methoxy-phenyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) isopropyl propionate
(S)-2-[chloro-3 methyl isophthalic acids of 5--(2-p-methoxy-phenyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) isobutyl propionate
(S)-N-(1-(1H-imidazoles-1-base)-3-phenylpropyl alcohol-2-base) chloro-3 methyl isophthalic acids of-5--(2-p-methoxy-phenyl)-1H-pyrazole-4-carboxamide
(S)-2-[chloro-3 methyl isophthalic acids of 5--(2-trifluoromethyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) methyl propionate
(S)-2-[chloro-3 methyl isophthalic acids of 5--(2-trifluoromethyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) ethyl propionate
(S)-2-[chloro-3 methyl isophthalic acids of 5--(2-trifluoromethyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) propyl propionate
(S)-2-[chloro-3 methyl isophthalic acids of 5--(2-trifluoromethyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) isopropyl propionate
(S)-2-[chloro-3 methyl isophthalic acids of 5--(2-trifluoromethyl)-1H-pyrazole-4-carboxamide base]-3-(1H-imidazoles-1-base) isobutyl propionate
(S)-N-(1-(1H-imidazoles-1-base)-3-phenylpropyl alcohol-2-base) chloro-3 methyl isophthalic acids of-5--(2-trifluoromethyl)-1H-pyrazole-4-carboxamide
(S)-2-[(1,1'-xenyl)-4-formamido-]-3-(1H-imidazoles-1-base) methyl propionate
(S)-2-[(1,1'-xenyl)-4-formamido-]-3-(1H-imidazoles-1-base) ethyl propionate
(S)-2-[(1,1'-xenyl)-4-formamido-]-3-(1H-imidazoles-1-base) propyl propionate
(S)-2-[(1,1'-xenyl)-4-formamido-]-3-(1H-imidazoles-1-base) isopropyl propionate
(S)-2-[(1,1'-xenyl)-4-formamido-]-3-(1H-imidazoles-1-base) isobutyl propionate
(S)-N-(1-(1H-imidazoles-1-base)-3-phenylpropyl alcohol-2-base)-(1,1'-xenyl)-4-formamido-
(S)-2-[4'-fluoro-(1,1'-xenyl)-4-formamido-]-3-(1H-imidazoles-1-base) methyl propionate
(S)-2-[4'-fluoro-(1,1'-xenyl)-4-formamido-]-3-(1H-imidazoles-1-base) ethyl propionate
(S)-2-[4'-fluoro-(1,1'-xenyl)-4-formamido-]-3-(1H-imidazoles-1-base) propyl propionate
(S)-2-[4'-fluoro-(1,1'-xenyl)-4-formamido-]-3-(1H-imidazoles-1-base) isopropyl propionate
(S)-2-[4'-fluoro-(1,1'-xenyl)-4-formamido-]-3-(1H-imidazoles-1-base) isobutyl propionate
(S)-N-(1-(1H-imidazoles-1-base)-3-phenylpropyl alcohol-2-base)-4'-fluoro-(1,1'-xenyl)-4-formamido-
(S)-2-[4'-methyl-(1,1'-xenyl)-4-formamido-]-3-(1H-imidazoles-1-base) methyl propionate
(S)-2-[4'-methyl-(1,1'-xenyl)-4-formamido-]-3-(1H-imidazoles-1-base) ethyl propionate
(S)-2-[4'-methyl-(1,1'-xenyl)-4-formamido-]-3-(1H-imidazoles-1-base) propyl propionate
(S)-2-[4'-methyl-(1,1'-xenyl)-4-formamido-]-3-(1H-imidazoles-1-base) isopropyl propionate
(S)-2-[4'-methyl-(1,1'-xenyl)-4-formamido-]-3-(1H-imidazoles-1-base) isobutyl propionate
(S)-N-(1-(1H-imidazoles-1-base)-3-phenylpropyl alcohol-2-base)-4'-methyl-(1,1'-xenyl)-4-formamido-
(S)-2-[2'-fluoro-(1,1'-xenyl)-4-formamido-]-3-(1H-imidazoles-1-base) methyl propionate
(S)-2-[2'-fluoro-(1,1'-xenyl)-4-formamido-]-3-(1H-imidazoles-1-base) ethyl propionate
(S)-2-[2'-fluoro-(1,1'-xenyl)-4-formamido-]-3-(1H-imidazoles-1-base) propyl propionate
(S)-2-[2'-fluoro-(1,1'-xenyl)-4-formamido-]-3-(1H-imidazoles-1-base) isopropyl propionate
(S)-2-[2'-fluoro-(1,1'-xenyl)-4-formamido-]-3-(1H-imidazoles-1-base) isobutyl propionate
(S)-N-(1-(1H-imidazoles-1-base)-3-phenylpropyl alcohol-2-base)-2'-fluoro-(1,1'-xenyl)-4-formamido-
(S)-2-[2'-methyl-(1,1'-xenyl)-4-formamido-]-3-(1H-imidazoles-1-base) methyl propionate
(S)-2-[2'-methyl-(1,1'-xenyl)-4-formamido-]-3-(1H-imidazoles-1-base) ethyl propionate
(S)-2-[2'-methyl-(1,1'-xenyl)-4-formamido-]-3-(1H-imidazoles-1-base) propyl propionate
(S)-2-[2'-methyl-(1,1'-xenyl)-4-formamido-]-3-(1H-imidazoles-1-base) isopropyl propionate
(S)-2-[2'-methyl-(1,1'-xenyl)-4-formamido-]-3-(1H-imidazoles-1-base) isobutyl propionate
(S)-N-(1-(1H-imidazoles-1-base)-3-phenylpropyl alcohol-2-base)-2'-methyl-(1,1'-xenyl)-4-formamido-.
(S)-N-methyl-2-[(1,1'-xenyl)-4-formamido-]-3-(1H-imidazoles-1-base) propionic acid amide
(S)-N-ethyl-2-[(1,1'-xenyl)-4-formamido-]-3-(1H-imidazoles-1-base) propionic acid amide
(S)-N-phenyl-2-[(1,1'-xenyl)-4-formamido-]-3-(1H-imidazoles-1-base) propionic acid amide
7. a medicinal compositions, to comprise in claim 1-6 any one compound and pharmacy acceptable salt, hydrate, solvate or prodrug as activeconstituents and pharmaceutically acceptable vehicle.
8. in claim 1-6, any one compound and pharmacy acceptable salt, hydrate, solvate or prodrug or composition according to claim 7 are preparing the application treated and/or prevented in proliferative disease medicine.
9. any one compound and pharmacy acceptable salt, hydrate, solvate or prodrug or composition according to claim 7 application in the medicine of preparation combination therapy and/or preventing cancer in claim 1-6.
10. any one compound and pharmacy acceptable salt, hydrate, solvate or prodrug or composition according to claim 7 application in the medicine of preparation combination therapy and/or prevention lung cancer, liver cancer, cancer of the stomach, colorectal carcinoma, mammary cancer in claim 1-6.
Any one compound and pharmacy acceptable salt, hydrate, solvate or prodrug or the application of composition according to claim 7 in preparation treatment antifungal drug in 11. claim 1-6.
Any one compound and pharmacy acceptable salt, hydrate, solvate or prodrug or the purposes of composition according to claim 7 in the medicine of preparation treatment anti-candida albicans, Candida parapsilosis bacterium, level and smooth candidiasis, cryptococcus neoformans, microsporon gypseum, trichophyton, Aspergillus fumigatus in 12. claim 1-6.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510895760.8A CN105541828B (en) | 2014-12-10 | 2015-12-08 | Amide imidazole derivative and application thereof |
| CN201811434187.0A CN109485645B (en) | 2014-12-10 | 2015-12-08 | Benzothiazole derivative and application thereof |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410756139.9A CN104530038A (en) | 2014-12-10 | 2014-12-10 | Amide imidazole derivative and application thereof |
| CN2014107561399 | 2014-12-10 | ||
| CN201510895760.8A CN105541828B (en) | 2014-12-10 | 2015-12-08 | Amide imidazole derivative and application thereof |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201811434187.0A Division CN109485645B (en) | 2014-12-10 | 2015-12-08 | Benzothiazole derivative and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN105541828A true CN105541828A (en) | 2016-05-04 |
| CN105541828B CN105541828B (en) | 2019-04-02 |
Family
ID=52845709
Family Applications (3)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410756139.9A Pending CN104530038A (en) | 2014-12-10 | 2014-12-10 | Amide imidazole derivative and application thereof |
| CN201510895760.8A Active CN105541828B (en) | 2014-12-10 | 2015-12-08 | Amide imidazole derivative and application thereof |
| CN201811434187.0A Active CN109485645B (en) | 2014-12-10 | 2015-12-08 | Benzothiazole derivative and application thereof |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410756139.9A Pending CN104530038A (en) | 2014-12-10 | 2014-12-10 | Amide imidazole derivative and application thereof |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201811434187.0A Active CN109485645B (en) | 2014-12-10 | 2015-12-08 | Benzothiazole derivative and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (3) | CN104530038A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109485607A (en) * | 2018-10-25 | 2019-03-19 | 沈阳药科大学 | β-azole-phenyl ketone derivatives and application thereof |
| CN109851560A (en) * | 2019-01-09 | 2019-06-07 | 河南新天地药业股份有限公司 | Biphenyl diazole analog derivative and its preparation method and application |
| CN110950845A (en) * | 2019-11-21 | 2020-04-03 | 聊城大学 | Formylacetamide azole derivative and application thereof |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104530038A (en) * | 2014-12-10 | 2015-04-22 | 沈阳药科大学 | Amide imidazole derivative and application thereof |
| RU2730492C1 (en) * | 2019-12-27 | 2020-08-24 | Федеральное государственное бюджетное образовательное учреждение высшего образования "Российский химико-технологический университет имени Д.И. Менделеева" | Method of producing alkyl 2-[([1,1'-biphenyl]-4-carbonyl)amino]-3-(1h-azol-1-yl) propanoates |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4124369A (en) * | 1976-06-01 | 1978-11-07 | Bayer Aktiengesellschaft | Combating fungi and controlling plant growth with 1-amido-1-azolyl-2-hydroxy- or -keto-alkanes |
| GB2136801A (en) * | 1983-03-11 | 1984-09-26 | Sandoz Ltd | Fungicidal N-acyl-1-aryl-2-azolyl-ethylamines |
| US4818748A (en) * | 1986-03-12 | 1989-04-04 | Bayer Aktiengesellschaft | Renin inhibitors and aminoacid and aminoaldehyde derivatives |
| JPH0226632B2 (en) * | 1981-10-06 | 1990-06-12 | Kureha Chemical Ind Co Ltd | |
| CN1060163C (en) * | 1994-05-18 | 2001-01-03 | 诺瓦蒂斯有限公司 | Acylated aminoalknimidazoles and-triazoles |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2006151812A (en) * | 2003-01-30 | 2006-06-15 | Meiji Seika Kaisha Ltd | New triazole derivative and antifungal agent having the same as active ingredient |
| JP2006523452A (en) * | 2003-03-25 | 2006-10-19 | スリーエム イノベイティブ プロパティズ カンパニー | Selective activation of cellular activity mediated through a common Toll-like receptor |
| CN104530038A (en) * | 2014-12-10 | 2015-04-22 | 沈阳药科大学 | Amide imidazole derivative and application thereof |
-
2014
- 2014-12-10 CN CN201410756139.9A patent/CN104530038A/en active Pending
-
2015
- 2015-12-08 CN CN201510895760.8A patent/CN105541828B/en active Active
- 2015-12-08 CN CN201811434187.0A patent/CN109485645B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4124369A (en) * | 1976-06-01 | 1978-11-07 | Bayer Aktiengesellschaft | Combating fungi and controlling plant growth with 1-amido-1-azolyl-2-hydroxy- or -keto-alkanes |
| JPH0226632B2 (en) * | 1981-10-06 | 1990-06-12 | Kureha Chemical Ind Co Ltd | |
| GB2136801A (en) * | 1983-03-11 | 1984-09-26 | Sandoz Ltd | Fungicidal N-acyl-1-aryl-2-azolyl-ethylamines |
| US4818748A (en) * | 1986-03-12 | 1989-04-04 | Bayer Aktiengesellschaft | Renin inhibitors and aminoacid and aminoaldehyde derivatives |
| CN1060163C (en) * | 1994-05-18 | 2001-01-03 | 诺瓦蒂斯有限公司 | Acylated aminoalknimidazoles and-triazoles |
Non-Patent Citations (8)
| Title |
|---|
| A. BENTAMA ET AL.: "Synthesis of new α-heterocyclic α-aminoesters", 《AMINO ACIDS》 * |
| BIN SUN ET AL.: "Design, synthesis, and biological evaluation of amide imidazole derivatives as novel metabolic enzyme CYP26A1 inhibitors", 《BIOORGANIC & MEDICINAL CHEMISTRY》 * |
| GALINA I. LEPESHEVA ET AL.: "CYP51: A Major Drug Target in the Cytochrome P450 Superfamily", 《LIPIDS》 * |
| GALINA I. LEPESHEVA ET AL.: "Sterol 14α-Demethylase as a Potential Target for Antitrypanosomal Therapy: Enzyme Inhibition and Parasite Cell Growth", 《CHEMISTRY & BIOLOGY》 * |
| SHUNSAKU OHTA ET AL.: "Reaction of 1-(1-Alkoxyalkyl)-1H-1,2,4-triazole with Amides", 《HETEROCYCLES》 * |
| UKRORGSYNTEZ LTD.等: "STN检索报告", 《数据库REGISTRY（在线）》 * |
| 任金红 等: "维甲酸代谢阻断剂的研究进展", 《中国药学杂志》 * |
| 赵冬梅 等: "以CYP26A1为靶点的维甲酸代谢阻断剂的设计、合成与活性研究", 《2011年全国药物化学学术会议》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109485607A (en) * | 2018-10-25 | 2019-03-19 | 沈阳药科大学 | β-azole-phenyl ketone derivatives and application thereof |
| CN109851560A (en) * | 2019-01-09 | 2019-06-07 | 河南新天地药业股份有限公司 | Biphenyl diazole analog derivative and its preparation method and application |
| CN110950845A (en) * | 2019-11-21 | 2020-04-03 | 聊城大学 | Formylacetamide azole derivative and application thereof |
| CN110950845B (en) * | 2019-11-21 | 2023-04-18 | 聊城大学 | Formylacetamide azole derivative and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN109485645A (en) | 2019-03-19 |
| CN109485645B (en) | 2020-08-04 |
| CN105541828B (en) | 2019-04-02 |
| CN104530038A (en) | 2015-04-22 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP2799435B1 (en) | Poly (adp-ribose) polymerase inhibitor | |
| TWI542590B (en) | 1,2-disubstituted heterocyclic compounds | |
| CN105541828A (en) | Acylaminoimidazole derivative and use thereof | |
| CN103415519B (en) | As 6,7-dihydro-pyrazol [1, the 5-a] pyrazine-4-yl amine derivatives that beta-secretase (BACE) inhibitor is useful | |
| US8129527B2 (en) | Analogs of dehydrophenylahistins and their therapeutic use | |
| CN109790169A (en) | With the Cyanopyrolidine derivatives as USP30 inhibitor activity | |
| CN105592888A (en) | Kdm1a inhibitors for the treatment of disease | |
| KR102166665B1 (en) | Benzylideneguanidine derivatives and therapeutic use for the treatment of protein misfolding diseases | |
| CN103502219A (en) | Novel small-molecules as therapeutics | |
| CN107074773A (en) | Substituted N, the formamide of 2 biaryl quinolin 4 and application thereof | |
| CN107311995A (en) | Three ring isoxazole class derivatives and its preparation method and application | |
| CN107151233B (en) | Hydrazone-containing pyrimidine derivative and application thereof | |
| Song et al. | Discovery of bazedoxifene analogues targeting glycoprotein 130 | |
| CN103739589A (en) | N-(2,3-dihydro benzo [b] thiapyran-4-imino)-N'-(4-methyl phenyl) guanidine derivative and application thereof | |
| US10793525B2 (en) | 13-cis-RAMBA retinamides that degrade MNKs for treating cancer | |
| CN108752412B (en) | Boswellic acid derivatives and their use | |
| CN101230045A (en) | Aromatic triazin derivatives and uses thereof | |
| WO2023276828A1 (en) | Pharmaceutical composition for preventing and/or treating kidney injury, and autophagy activator | |
| CN102617478B (en) | Synthesis of benzimidazole, oxazole and thiazole derivatives and application thereof | |
| BR112019022331A2 (en) | METHODS OF USE FOR BENZOTRIAZOL DERIVATIVES TRISUBSTITUTED AS INHIBITORS OF DI-HYDRO-OROTATE OXYGENASE | |
| US9381260B2 (en) | Hypoxia inducible factor-1 pathway inhibitors and uses as anticancer and imaging agents | |
| CN109721536A (en) | The fused tricyclic class compound and application thereof that phenyl replaces | |
| CN109096194A (en) | A kind of Biguanide derivative, pharmaceutical composition, preparation method and purposes | |
| CN111559982B (en) | 2- (2-substituted-4-hydroxypyrimidine-5-formamido) acetic acid compound and preparation method and application thereof | |
| Singh et al. | Novel pyrazole derivatives: rationale design, synthesis, sar study and biological potential based on In Vitro Study |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| CB03 | Change of inventor or designer information |
Inventor after: Zhao Dongmei Inventor after: Zhao Shizhen Inventor after: Sun Bin Inventor after: Cheng Maosheng Inventor after: Li Fengrong Inventor after: Zhao Liyu Inventor after: Hao Chenzhou Inventor after: Liu Chunchi Inventor after: Ren Jinhong Inventor before: Zhao Dongmei Inventor before: Sun Bin Inventor before: Zhao Shizhen Inventor before: Cheng Maosheng Inventor before: Li Fengrong Inventor before: Zhao Liyu Inventor before: Hao Chenzhou Inventor before: Liu Chunchi Inventor before: Ren Jinhong |
|
| CB03 | Change of inventor or designer information | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |