CN101006085A - Substituted hydantoins - Google Patents

Substituted hydantoins Download PDF

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Publication number
CN101006085A
CN101006085A CN 200580027708 CN200580027708A CN101006085A CN 101006085 A CN101006085 A CN 101006085A CN 200580027708 CN200580027708 CN 200580027708 CN 200580027708 A CN200580027708 A CN 200580027708A CN 101006085 A CN101006085 A CN 101006085A
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China
Prior art keywords
phenyl
imidazolidine
dioxo
thiazol
butyramide
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CN 200580027708
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Chinese (zh)
Inventor
褚新阶
N·佛投赫
N·J·S·于比
N·孔
L·A·麦克德莫特
J·A·莫利泰尔尼
张筑明
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F Hoffmann La Roche AG
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F Hoffmann La Roche AG
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Abstract

The present invention relates to compounds of the formula (I), which are useful in treating diseases characterized by, the hyperactivity of MEK. Accordingly the compounds are useful in the treatment of diseases, such as, cancer, cognative and CNS disorders and inflammatory/autoimmune diseases.

Description

The hydantoins that replaces
Technical field
The present invention relates to be used for the treatment of the hydantoin derivatives of human diseases such as cancer, described hydantoin derivatives is the inhibitor of two kinds of protein kinases of so-called MEK1 and MEK2.MEK is kinase whose general the writing a Chinese character in simplified form of map kinase/ERK, and to be again that mitogen-activated protein(MAP)/extracellular signal-regulated kinase is kinase whose write a Chinese character in simplified form described map kinase/ERK kinases.Sometimes also MEK is called mapk kinase or map kinase.
Background of invention
Cancer is to be the disease of feature with malignant cell with non-limiting growth, differential expansion and whole body metastatic potential and tumor proliferation.This uncontrolled growth derive from normal cell in those the different signal transduction pathways found and unusual to various somatomedins responses.Unusually be included in the intrinsic activity of one or more signal proteins in the signal cascade amplification or the change of cell concn.These changes are caused by the proteic genetic mutation of intracellular signal or the overexpression that can cause short cell fission signal false in the cell.
Mitogen-activated protein(MAP) (MAP) kinase pathways represents to participate in one of the development of human cancer and the signal transduction pathway that is characterized by the best of process (J.M.English etc., Trends in Pharm.Sci.2002,23 (1), 40).This approach amplifies by the Ras/Raf/MEK/ERK signal cascade, is responsible for urging the cell fission signal and transmits and be amplified to nucleus from cell surface, expresses and determines cell fate in this activatory transcription factor regulatory gene.It is enough that the composing type activation of this approach transforms for inducing cell.Because the unusual adjusting activation of the map kinase approach that abnormal receptor tyrosine-kinase enzyme activation, Ras sudden change or Raf sudden change cause is found in the human cancer of being everlasting, and the main factor of misgrowth control is determined in representative.In human carcinomas, the Ras sudden change is common, is identified (J.L.Bos, Cancer Res.1989,49,4682) in about 30% cancer.The gtpase protein of Ras family (guanosine triphosphate being converted into the albumen of guanosine diphosphate(GDP)) is relayed partner in the born of the same parents in downstream with signal from activating growth factor receptors.The dominant Raf of being family serine/threonine protein kitase in the target spot of raising by active membrane bonded Ras.Raf family is made of the three kinds of associated kinases (A-, B-and C-Raf) that play the effect of Ras downstream effect thing.The activation of Raf activation the initiation again MEK1 and the MEK2 (MAP/ERK kinases 1 and 2) of Ras-mediation, its again will be simultaneously on tyrosine-185 and Threonine-183 with ERK1 and ERK2 (extracellular signal-regulated kinase 1 and 2) phosphorylation.Activatory ERK1 and ERK2 are shifted in nucleus and accumulate, and they can the various substrates of phosphorylation at this, comprise the transcription factor (A.Bonni etc., Science 1999,286,1358) of growth of control cell and survival.Recently, the B-Raf somatic mutation in kinase domain also is found in 60% the malignant melanoma, and is found (H.Davies etc., Nature 2002,417,949) with lower frequency in the human cancer of wide region more.As the Ras of sudden change, in various animal models, the sudden change Raf of constitutive activity can transformant outer cell, and bring out cancer (H.Davies etc., Nature 2002,417,949).Consider that the Ras/Raf/MEK/ERK approach is in the developing importance of human cancer, kinases component during this signal cascade amplifies (R.Herrera etc. occur as the potential important target spot of the progression of disease that is used for regulating cancer and other proliferative disease, Trends Mol.Med.2002,8 (4, Suppl.), S27).
MEK1 and MEK2 are the members of dual-specificity kinase (MEK1-7) of the more extended familys of the Threonine of the various map kinases of phosphorylation and tyrosine residues.MEK1 and MEK2 are by different genes encodings, but they are shared in terminal catalysis kinase domain of C-and the terminal high homology (80%) (C.F.Zheng etc., J.Biol.Chem.1993,268,11435) of regulating in the territory of most of N-.In human cancer, also do not find the MEK1 and 2 of carcinogenic form.But the composing type activation that has shown MEK causes cell transformation (S.Cowley etc., Cell 1994,77,841).Except Raf, MEK also can be activated by other oncogene.Up to now, MEK1 and 2 unique known substrates are ERK1 and 2 (R.Seger etc., J.Biol.Chem.1992,267,14373).Except the unique ability of while phosphorylated tyrosine and threonine residues, this uncommon substrate specificity places the key point place of signal transduction cascade system with MEK1 and 2, and this makes them that many extracellular signals are integrated in the MAPK approach.
With being also referred to as CI-1040 (Pfizer Inc., be described in PCT and announce WO 99/01426) mek inhibitor 2-(2-chloro-4-iodo-phenyl amino)-N-cyclo propyl methoxy-3, the research of report formerly of 4-two fluoro-benzamide provides following further evidence, promptly, for the hyperactivity with MEK is that pharmacology in the cancer of feature or other human diseases and the disease of being regulated by the MAPK approach is interfered MEK1 and the attractive target spot of 2 representatives.
Previously reported that the compound relevant with The compounds of this invention is glucokinase activators (F.Hoffmann-La Roche AG, the open WO01/83478 of PCT).The previous compound of having reported is defined as containing the methylene radical spacer (CH between the other substituting group that comprises the aryl rings that does not replace or replace in glycolylurea ring and the substituting group in other qualification 2Group).Claimed compound is included in the compound that does not have the methylene radical spacer between glycolylurea ring and replacement or unsubstituted aryl or replacement or the unsubstituted heteroaryl ring among qualification the present invention.
Summary of the invention
The present invention relates to the compound of at least a formula I:
Figure A20058002770800161
Or its pharmaceutical salts,
R wherein 1, R 2, R 3, R 4, R 5And R 6Described in the application.Think that these compounds suppress MEK 1/2, a kind of dual specificity protein kinases, described MEK 1/2 are the basal components of map kinase signal transduction pathway, and therefore described compound can have anti-high proliferation cytoactive.
Detailed Description Of The Invention
The present invention is the new compound of following formula I:
Figure A20058002770800162
Wherein:
R 1Be selected from: replace or unsubstituted aryl or replacement or unsubstituted heteroaryl;
R 2Be hydrogen
R 3Be alkyl;
R 4Be selected from: replace or unsubstituted aryl hydroxyl, alkoxyl group, the alkoxyl group of replacement or replacement or unsubstituted heteroaryl or alkyl;
R 5Be selected from: COOR, COR, CON (R 7) 2, CHOHR or S (O) nR, wherein n is 0-2, and R is the alkyl that alkyl or alkoxy replace; And
R 6And R 7Be selected from: hydrogen or alkyl,
The form of described compound randomly is their racemoid, their enantiomer, and their diastereomer or its mixture,
Or its medicinal salt or ester or prodrug.
The preferred compound of the present invention is the novel cpd of formula I:
Figure A20058002770800171
Wherein:
R 1Be selected from: replace or unsubstituted aryl or replacement or unsubstituted heteroaryl;
R 2Be hydrogen
R 3Be single-or two-alkyl;
R 4Be selected from: replace or unsubstituted aryl hydroxyl, alkoxyl group, the alkoxyl group of replacement or replacement or unsubstituted heteroaryl or alkyl;
R 5Be selected from: COOR, COR, CON (R 7) 2Or CHOHR, wherein R is the alkyl that alkyl or alkoxy replace; And
R 6And R 7Be selected from: hydrogen or alkyl,
Or its medicinal salt or ester or prodrug.
The preferably compound of formula I, wherein R 1For phenyl or be substituted the phenyl that base replaces, described substituting group is selected from: hydroxyl; Alkoxyl group; The alkoxyl group that replaces;-P (O) (O-alkyl) 2-NH-alkyl;-N (alkyl) 2The heterocyclic radical that optional quilt-OH replaces (preferred piperidyl, morpholino or pyrrolidyl);-S (O) 2-alkyl;-NHC (O)-alkyl;
-O-alkyl, this alkyl randomly are substituted base and replace once or twice, and described substituting group is selected from: NH 2The NH-alkyl, this alkyl is chosen quilt-O-methyl substituted wantonly; N (alkyl) 2Hydroxyl; Heterocyclic radical (preferred piperidyl, morpholino or pyrrolidyl);-O-alkyl;-COOH; Oxo;-C (O)-heterocyclic radical (preferred piperidyl, morpholino or pyrrolidyl);-C (O)-N (alkyl) 2-C (O)-NH-alkyl, this alkyl is chosen quilt-O-methyl substituted wantonly; Or-C (O)-NH 2
The equally preferably compound of formula I, wherein R 1Be 2,3-dihydro-benzo [1,4] dioxine-6-base.
The equally preferably compound of formula I, wherein R 3Be methyl.
The equally preferably compound of formula I, wherein R 4For replacing or unsubstituted aryl.
The equally preferably compound of formula I, wherein R 5For COR and R are methyl or ethyl.
The equally preferably compound of formula I, wherein R 5Be cyclopropyl.
The equally preferably compound of formula I, wherein R 6Be hydrogen.
The more preferably compound of formula I, wherein R 4Be phenyl.
The more preferably compound of formula I, wherein R 3Be methyl, and R 4Be phenyl.
The more preferably compound of formula I, wherein R 5For COR and R are methyl or ethyl or R wherein 5Be cyclopropyl and R 6Be hydrogen.
The compound of formula I more preferably, wherein any form in the above-claimed cpd randomly is their racemoid, their enantiomer, the form of their diastereomer or its mixture.
The compound of Formula Il equally preferably:
Figure A20058002770800181
Wherein:
R 8Be hydrogen; Alkyl; Cycloalkyl;-O-alkyl; NH alkyl or N (alkyl) 2
R 9Be alkyl and preferable methyl;
R 10Be hydrogen; Alkyl; The alkyl or the halogen that replace, and preferred hydrogen or halogen are preferably selected from: fluorine and chlorine;
R 11Be selected from: hydroxyl; Alkoxyl group; The alkoxyl group that replaces;-P (O) (O-alkyl) 2-NH-alkyl;-N (alkyl) 2The heterocyclic radical that is replaced by-OH (preferred piperidyl, morpholino or pyrrolidyl) randomly;-S (O) 2-alkyl;-NHC (O)-alkyl;
-O-alkyl, the optional base that is substituted of this alkyl replaces once or twice, and described substituting group is selected from: NH 2The NH-alkyl, this alkyl is chosen quilt-O-methyl substituted wantonly; N (alkyl) 2Hydroxyl; Heterocyclic radical (preferred piperidyl, morpholino or pyrrolidyl);-O-alkyl;-COOH; Oxo;-C (O)-heterocyclic radical (preferred piperidyl, morpholino or pyrrolidyl);-C (O)-N (alkyl) 2-C (O)-NH-alkyl, this alkyl is chosen quilt-O-methyl substituted wantonly; Or-C (O)-NH 2
The form of described compound randomly is their racemoid, their enantiomer, and their diastereomer or its mixture,
Or its medicinal salt or ester or prodrug.
The compound of following formula most preferably:
(2S, 3S)-N-(4-ethanoyl-thiazol-2-yl)-2-[(R)-4-(4-methoxyl group-phenyl)-2,5-dioxo-imidazolidine-1-yl]-3-phenyl-butyramide;
(2S, 3S)-N-(4-ethanoyl-thiazol-2-yl)-2-[(R)-4-(4-hydroxyl-phenyl)-2,5-dioxo-imidazolidine-1-yl]-3-phenyl-butyramide;
(2S, 3S)-N-(4-ethanoyl-thiazol-2-yl)-2-{ (R)-4-[4-(2-hydroxyl-oxyethyl group)-phenyl]-2,5-dioxo-imidazolidine-1-yl }-3-phenyl-butyramide;
(2S, 3S)-N-(4-ethanoyl-thiazol-2-yl)-2-{ (R) 4-[4-(2-methoxyl group-oxyethyl group)-phenyl]-2,5-dioxo-imidazolidine-1-yl }-3-phenyl-butyramide;
(2S, 3S)-N-(4-ethanoyl-thiazol-2-yl)-2-((R)-4-{4-[2-(2-methoxyl group-oxyethyl group)-oxyethyl group]-phenyl }-2,5-dioxo-imidazolidine-1-yl)-3-phenyl-butyramide;
(2S, 3S)-N-(4-ethanoyl-thiazol-2-yl)-2-{ (R)-4-[4-(2-oxyethyl group-oxyethyl group)-phenyl]-2,5-dioxo-imidazolidine-1-yl }-3-phenyl-butyramide;
(2S, 3S)-N-(4-ethanoyl-thiazol-2-yl)-2-{ (R)-4-[4-(2-dimethylamino-oxyethyl group)-phenyl]-2,5-dioxo-imidazolidine-1-yl }-3-phenyl-butyramide; Compound with trifluoroacetic acid
(2S, 3S)-N-(4-ethanoyl-thiazol-2-yl)-2-{ (R)-4-[4-(2-diethylamino-oxyethyl group)-phenyl]-2,5-dioxo-imidazolidine-1-yl }-3-phenyl-butyramide; Compound with trifluoroacetic acid
(2S, 3S)-N-(4-ethanoyl-thiazol-2-yl)-2-[(R)-4-(4-oxyethyl group-phenyl)-2,5-dioxo-imidazolidine-1-yl]-3-phenyl-butyramide;
(2S, 3S)-N-(4-ethanoyl-thiazol-2-yl)-2-{ (S)-4-[4-(2-dimethylamino-oxyethyl group)-phenyl]-2,5-dioxo-imidazolidine-1-yl }-3-phenyl-butyramide; Compound with trifluoroacetic acid
(4-{1-[(1S, 2S)-1-(4-ethanoyl-thiazol-2-yl formamyl)-2-phenyl-propyl group]-2,5-dioxo-imidazolidine-4-yl }-phenyl)-diethyl phosphonate;
(2S, 3S)-N-(4-ethanoyl-thiazol-2-yl)-2-[4-(4-dimethylamino-phenyl)-2,5-dioxo-imidazolidine-1-yl]-3-phenyl-butyramide;
(2S, 3S)-2-[(R)-4-(4-methoxyl group-phenyl)-2,5-dioxo-imidazolidine-1-yl]-3-phenyl-pentanoic acid (4-ethanoyl-thiazol-2-yl)-acid amides;
(2S, 3S)-2-[(R)-4-(4-methoxyl group-phenyl)-2,5-dioxo-imidazolidine-1-yl]-3-phenyl-N-(4-propionyl-thiazol-2-yl)-butyramide;
(2S, 3S)-2-[(R)-4-(2,3-dihydro-benzo [1,4] dioxine-6-yl)-2,5-dioxo-imidazolidine-1-yl]-3-phenyl-N-(4-propionyl-thiazol-2-yl)-butyramide;
(2S, 3S)-2-[(R)-4-(4-oxyethyl group-phenyl)-2,5-dioxo-imidazolidine-1-yl]-3-phenyl-N-(4-propionyl-thiazol-2-yl)-butyramide;
(2S, 3S)-2-[(R)-4-(4-hydroxyl-phenyl)-2,5-dioxo-imidazolidine-1-yl]-3-phenyl-N-(4-propionyl-thiazol-2-yl)-butyramide;
(2S, 3S)-2-{ (R)-4-[4-(2-methoxyl group-oxyethyl group)-phenyl]-2,5-dioxo-imidazolidine-1-yl }-3-phenyl-N-(4-propionyl-thiazol-2-yl)-butyramide;
(2S, 3S)-2-{ (S)-4-[4-(2-methoxyl group-oxyethyl group)-phenyl]-2,5-dioxo-imidazolidine-1-yl }-3-phenyl-N-(4-propionyl-thiazol-2-yl)-butyramide;
(2S, 3S)-2-{ (R)-4-[4-(2-hydroxyl-oxyethyl group)-phenyl]-2,5-dioxo-imidazolidine-1-yl }-3-phenyl-N-(4-propionyl-thiazol-2-yl)-butyramide;
(2S, 3S)-2-((R)-4-{4-[2-(2-methoxyl group-oxyethyl group)-oxyethyl group]-phenyl }-2,5-dioxo-imidazolidine-1-yl)-3-phenyl-N-(4-propionyl-thiazol-2-yl)-butyramide;
(2S, 3S)-2-{ (R)-4-[4-(2-oxyethyl group-oxyethyl group)-phenyl]-2,5-dioxo-imidazolidine-1-yl }-3-phenyl-N-(4-propionyl-thiazol-2-yl)-butyramide;
(2S, 3S)-2-{ (R)-4-[4-(2-dimethylamino-oxyethyl group)-phenyl]-2,5-dioxo-imidazolidine-1-yl }-3-phenyl-N-(4-propionyl-thiazol-2-yl)-butyramide; Compound with trifluoroacetic acid
(4-{ (R)-2,5-dioxo-1-[(1S, 2S)-2-phenyl-1-(4-propionyl-thiazol-2-yl formamyl)-propyl group]-imidazolidine-4-yl }-phenoxymethyl)-dimethyl phosphonate;
(2S, 3S)-N-(4-isobutyryl-thiazol-2-yl)-2-{4-[4-(2-methoxyl group-oxyethyl group)-phenyl]-2,5-dioxo-imidazolidine-1-yl }-3-phenyl-butyramide;
(2S, 3S)-N-(4-isobutyryl-thiazol-2-yl)-2-[(R)-4-(4-methoxyl group-phenyl)-2,5-dioxo-imidazolidine-1-yl]-3-phenyl-butyramide;
(2S, 3S)-2-{ (S)-4-[4-(2-dimethylamino-oxyethyl group)-phenyl]-2,5-dioxo-imidazolidine-1-yl }-3-phenyl-N-(4-propionyl-thiazol-2-yl)-butyramide; Compound with trifluoroacetic acid;
(2S, 3S)-2-{2,5-dioxo-4-[4-(2-piperidines-1-base-oxyethyl group)-phenyl]-imidazolidine-1-yl }-3-phenyl-N-(4-propionyl-thiazol-2-yl)-butyramide;
(2S, 3S)-2-{4-[4-(2-morpholine-4-base-oxyethyl group)-phenyl]-2,5-dioxo-imidazolidine-1-yl }-3-phenyl-N-(4-propionyl-thiazol-2-yl)-butyramide;
(2S, 3S)-3-(3-fluoro-phenyl)-2-{ (R)-4-[4-(2-methoxyl group-oxyethyl group)-phenyl]-2,5-dioxo-imidazolidine-1-yl }-N-(4-propionyl-thiazol-2-yl)-butyramide;
(2S, 3S)-2-[(R)-4-(4-methoxyl group-3-methyl-phenyl)-2,5-dioxo-imidazolidine-1-yl]-3-phenyl-N-(4-propionyl-thiazol-2-yl)-butyramide;
(2S, 3S)-2-{ (S)-4-[4-(2-hydroxyl-oxyethyl group)-phenyl]-2,5-dioxo-imidazolidine-1-yl }-3-phenyl-N-(4-propionyl-thiazol-2-yl)-butyramide;
(2S, 3S)-2-((R)-2,5-dioxo-4-phenyl-imidazolidine-1-yl)-3-phenyl-N-(4-propionyl-thiazol-2-yl)-butyramide;
(2S, 3S)-2-[4-(4-dimethylamino-phenyl)-2,5-dioxo-imidazolidine-1-yl]-3-phenyl-N-(4-propionyl-thiazol-2-yl)-butyramide;
(2S, 3S)-2-[4-(4-morpholine-4-base-phenyl)-2,5-dioxo-imidazolidine-1-yl]-3-phenyl-N-(4-propionyl-thiazol-2-yl)-butyramide;
(2S, 3S)-2-{4-[4-(4-hydroxy-piperdine-1-yl)-phenyl]-2,5-dioxo-imidazolidine-1-yl }-3-phenyl-N-(4-propionyl-thiazol-2-yl)-butyramide;
(2S, 3S)-2-(4-{4-[(2-methoxyl group-ethyl)-methyl-amino]-phenyl }-2,5-dioxo-imidazolidine-1-yl)-3-phenyl-N-(4-propionyl-thiazol-2-yl)-butyramide;
(2S, 3S)-N-(4-cyclopropane carbonyl-thiazol-2-yl)-2-{ (R)-4-[4-(2-methoxyl group-oxyethyl group)-phenyl]-2,5-dioxo-imidazolidine-1-yl }-3-phenyl-butyramide;
(2S, 3S)-2-{4-[4-(2-methoxyl group-oxyethyl group)-phenyl]-2,5-dioxo-imidazolidine-1-yl }-3-methyl-valeric acid (4-propionyl-thiazol-2-yl)-acid amides;
(2S, 3R)-3-benzyloxy-2-{ (R)-4-[4-(2-methoxyl group-oxyethyl group)-phenyl]-2,5-dioxo-imidazolidine-1-yl }-N-(4-propionyl-thiazol-2-yl)-butyramide;
(2S, 3S)-N-[4-(2-methoxyl group-ethanoyl)-thiazol-2-yl]-2-[(R)-and 4-(4-methoxyl group-phenyl)-2,5-dioxo-imidazolidine-1-yl]-3-phenyl-butyramide;
2-{ (2S, 3S)-2-[(R)-4-(2,3-dihydro-benzo [1,4] dioxine-6-yl)-2,5-dioxo-imidazolidine-1-yl]-3-phenyl-butyrylamino }-thiazole-4-carboxylic acid's methyl esters;
2-[(2S, 3S)-2-((R)-2,5-dioxo-4-phenyl-imidazolidine-1-yl)-3-phenyl-butyrylamino]-thiazole-4-carboxylic acid's methyl esters;
2-{ (2S, 3S)-2-[(R)-4-(4-methoxyl group-phenyl)-2,5-dioxo-imidazolidine-1-yl]-3-phenyl-butyrylamino }-thiazole-4-carboxylic acid's methyl esters;
2-{ (2S, 3S)-2-[(R)-4-(4-hydroxyl-phenyl)-2,5-dioxo-imidazolidine-1-yl]-3-phenyl-butyrylamino }-thiazole-4-carboxylic acid's methyl esters;
2-((2S, 3S)-2-{ (R)-4-[4-(2-methoxyl group-oxyethyl group)-phenyl]-2,5-dioxo-imidazolidine-1-yl }-3-phenyl-butyrylamino)-thiazole-4-carboxylic acid's methyl esters;
2-((2S, 3S)-2-{ (R)-4-[4-(2-hydroxyl-oxyethyl group)-phenyl]-2,5-dioxo-imidazolidine-1-yl }-3-phenyl-butyrylamino)-thiazole-4-carboxylic acid's methyl esters;
2-{ (2S, 3S)-2-[(R)-4-(4-isopropoxy-phenyl)-2,5-dioxo-imidazolidine-1-yl]-3-phenyl-butyrylamino }-thiazole-4-carboxylic acid's methyl esters;
2-{ (2S, 3S)-2-[(R)-4-(4-methoxyl group-3-methyl-phenyl)-2,5-dioxo-imidazolidine-1-yl]-3-phenyl-butyrylamino }-thiazole-4-carboxylic acid's methyl esters;
2-((2S, 3S)-2-{ (R)-4-[4-(dimethoxy-phosphoryl methoxy base)-phenyl]-2,5-dioxo-imidazolidine-1-yl }-3-phenyl-butyrylamino)-thiazole-4-carboxylic acid's methyl esters;
2-{ (2S, 3S)-3-(2-methoxyl group-phenyl)-2-[4-(4-methoxyl group-phenyl)-2,5-dioxo-imidazolidine-1-yl]-butyrylamino }-thiazole-4-carboxylic acid's methyl esters;
2-((2S, 3S)-3-(4-fluoro-phenyl)-2-{ (R)-4-[4-(2-methoxyl group-oxyethyl group)-phenyl]-2,5-dioxo-imidazolidine-1-yl }-butyrylamino)-thiazole-4-carboxylic acid's methyl esters;
2-{ (2S, 3S)-2-[(R)-4-(4-methoxyl group-phenyl)-2,5-dioxo-imidazolidine-1-yl]-3-methyl-pentanoyl amino }-thiazole-4-carboxylic acid's methyl esters;
2-[(2S, 3S)-2-((R)-2,5-dioxo-4-phenyl-imidazolidine-1-yl)-3-methyl-pentanoyl amino]-thiazole-4-carboxylic acid's methyl esters;
2-((2S, 3S)-2-{ (R)-4-[4-(2-methoxyl group-oxyethyl group)-phenyl]-2,5-dioxo-imidazolidine-1-yl }-3-methyl-pentanoyl amino)-thiazole-4-carboxylic acid's methyl esters;
2-{ (2S, 3R)-the 3-hydroxyl-2-[(R)-4-(4-methoxyl group-phenyl)-2,5-dioxo-imidazolidine-1-yl]-butyrylamino }-thiazole-4-carboxylic acid's methyl esters;
2-((2S, 3R)-3-hydroxyl-2-{ (R)-4-[4-(2-methoxyl group-oxyethyl group)-phenyl]-2,5-dioxo-imidazolidine-1-yl }-butyrylamino)-thiazole-4-carboxylic acid's methyl esters;
2-((2S, 3R)-3-tert.-butoxy-2-{ (R)-4-[4-(2-methoxyl group-oxyethyl group)-phenyl]-2,5-dioxo-imidazolidine-1-yl }-butyrylamino)-thiazole-4-carboxylic acid's methyl esters;
2-{ (2S, 3R)-the 3-methoxyl group-2-[(R)-4-(4-methoxyl group-phenyl)-2,5-dioxo-imidazolidine-1-yl]-butyrylamino }-thiazole-4-carboxylic acid's methyl esters;
2-((2S, 3R)-3-methoxyl group-2-{ (R)-4-[4-(2-methoxyl group-oxyethyl group)-phenyl]-2,5-dioxo-imidazolidine-1-yl }-butyrylamino)-thiazole-4-carboxylic acid's methyl esters;
2-((2S, 3R)-3-benzyloxy-2-{ (R)-4-[4-(2-methoxyl group-oxyethyl group)-phenyl]-2,5-dioxo-imidazolidine-1-yl }-butyrylamino)-thiazole-4-carboxylic acid's methyl esters;
2-((2S, 3R)-3-(4-chloro-benzyloxy)-2-{ (R)-4-[4-(2-methoxyl group-oxyethyl group)-phenyl]-2,5-dioxo-imidazolidine-1-yl }-butyrylamino)-thiazole-4-carboxylic acid's methyl esters
2-{ (2S, 3R)-2-[(R)-4-(4-methoxyl group-phenyl)-2,5-dioxo-imidazolidine-1-yl]-3-methyl-pentanoyl amino }-thiazole-4-carboxylic acid's methyl esters
2-((2S, 3R)-2-{ (R)-4-[4-(2-methoxyl group-oxyethyl group)-phenyl]-2,5-dioxo-imidazolidine-1-yl }-3-methyl-pentanoyl amino)-thiazole-4-carboxylic acid's methyl esters;
2-((2S, 3R)-2-{ (R)-4-[4-(2-methoxyl group-oxyethyl group)-phenyl]-2,5-dioxo-imidazolidine-1-yl }-3-methyl-pentanoyl amino)-thiazole-4-carboxylic acid's methyl esters;
2-{ (2S, 3S)-2-[4-(4-methylsulfonyl-phenyl)-2,5-dioxo-imidazolidine-1-yl]-3-phenyl-butyrylamino }-thiazole-4-carboxylic acid's methyl esters;
2-{ (S)-2-[(R)-4-(4-methoxyl group-phenyl)-2,5-dioxo-imidazolidine-1-yl]-3-methyl-3-phenyl-butyrylamino }-thiazole-4-carboxylic acid's methyl esters;
2-{ (2S, 3R)-2-[(R)-4-(2,3-dihydro-benzo [1,4] dioxine-6-yl)-2,5-dioxo-imidazolidine-1-yl]-3-phenyl-butyrylamino }-thiazole-4-carboxylic acid's methyl esters;
2-{ (2S, 3S)-2-[(R)-4-(4-acetylamino-phenyl)-2,5-dioxo-imidazolidine-1-yl]-3-phenyl-butyrylamino }-thiazole-4-carboxylic acid's methyl esters;
N-[4-(1-hydroxyl-1-methyl-ethyl)-thiazol-2-yl]-2-[(R)-and 4-(4-methoxyl group-phenyl)-2,5-dioxo-imidazolidine-1-yl]-3-phenyl-butyramide;
(2S, 3S)-2-[(R)-4-(2,3-dihydro-benzo [1,4] dioxine-6-yl)-2,5-dioxo-imidazolidine-1-yl]-N-[4-(1-hydroxyl-propyl group)-thiazol-2-yl]-3-phenyl-butyramide;
(2S, 3S)-N-[4-(1-hydroxyl-ethyl)-thiazol-2-yl]-2-[(R)-and 4-(4-methoxyl group-phenyl)-2,5-dioxo-imidazolidine-1-yl]-3-phenyl-butyramide;
2-{ (2S, 3S)-2-[(R)-4-(4-methoxyl group-phenyl)-2,5-dioxo-imidazolidine-1-yl]-3-phenyl-butyrylamino }-thiazole-4-carboxylic acid's dimethylformamide;
(2S, 3S)-N-(4-ethylmercapto group-thiazol-2-yl)-2-{ (R)-4-[4-(2-methoxyl group-oxyethyl group)-phenyl]-2,5-dioxo-imidazolidine-1-yl }-3-phenyl-butyramide;
(2S, 3S)-N-(4-second sulfinyl-thiazol-2-yl)-2-{ (R)-4-[4-(2-methoxyl group-oxyethyl group)-phenyl]-2,5-dioxo-imidazolidine-1-yl }-3-phenyl-butyramide;
(2S, 3S)-N-(4-ethylsulfonyl-thiazol-2-yl)-2-{ (R)-4-[4-(2-methoxyl group-oxyethyl group)-phenyl]-2,5-dioxo-imidazolidine-1-yl }-3-phenyl-butyramide;
(2S, 3S)-N-[4-(2-hydroxyl-ethanoyl)-thiazol-2-yl]-2-{ (R)-4-[4-(2-methoxyl group-oxyethyl group)-phenyl]-2,5-dioxo-imidazolidine-1-yl }-3-phenyl-butyramide;
(4-{ (R)-1-[(1S, 2S)-1-(4-ethanoyl-thiazol-2-yl formamyl)-2-phenyl-propyl group]-2,5-dioxo-imidazolidine-4-yl }-phenoxy group)-methyl acetate;
(4-{ (R)-2,5-dioxo-1-[(1S, 2S)-2-phenyl-1-(4-propionyl-thiazol-2-yl formamyl)-propyl group]-imidazolidine-4-yl }-phenoxy group)-methyl acetate;
(4-{2,5-dioxo-1-[(1S, 2S)-2-phenyl-1-(4-propionyl-thiazol-2-yl formamyl)-propyl group]-imidazolidine-4-yl }-phenoxy group)-acetate;
(2S, 3S)-N-(4-ethanoyl-thiazol-2-yl)-2-[(R)-4-(4-formyl-dimethylamino methoxyl group-phenyl)-2,5-dioxo-imidazolidine-1-yl]-3-phenyl-butyramide;
(2S, 3S)-N-(4-ethanoyl-thiazol-2-yl)-2-[(R)-4-(4-methylamino formyl radical methoxyl group-phenyl)-2,5-dioxo-imidazolidine-1-yl]-3-phenyl-butyramide;
(2S, 3S)-N-(4-ethanoyl-thiazol-2-yl)-2-[(R)-4-(4-carbamyl ylmethoxy-phenyl)-2,5-dioxo-imidazolidine-1-yl]-3-phenyl-butyramide;
(2S, 3S)-N-(4-ethanoyl-thiazol-2-yl)-2-((R)-4-{4-[(2-methoxyl group-ethylamino formyl radical)-methoxyl group]-phenyl }-2,5-dioxo-imidazolidine-1-yl)-3-phenyl-butyramide;
(2S, 3S)-N-(4-ethanoyl-thiazol-2-yl)-2-((R)-4-{4-[(2-methoxyl group-ethylamino formyl radical)-methoxyl group]-phenyl }-2,5-dioxo-imidazolidine-1-yl)-3-phenyl-butyramide;
(2S, 3S)-N-(4-ethanoyl-thiazol-2-yl)-2-{ (R)-4-[4-(2-morpholine-4-base-2-oxo-oxyethyl group)-phenyl]-2,5-dioxo-imidazolidine-1-yl }-3-phenyl-butyramide;
(2S, 3S)-N-(4-ethanoyl-thiazol-2-yl)-2-{ (R)-2,5-dioxo-4-[4-(2-oxo-2-tetramethyleneimine-1-base-oxyethyl group)-phenyl]-imidazolidine-1-yl }-3-phenyl-butyramide;
(2S, 3S)-2-[(R)-4-(4-formyl-dimethylamino methoxyl group-phenyl)-2,5-dioxo-imidazolidine-1-yl]-3-phenyl-N-(4-propionyl-thiazol-2-yl)-butyramide;
(2S, 3S)-2-[(R)-4-(4-methylamino formyl radical methoxyl group-phenyl)-2,5-dioxo-imidazolidine-1-yl]-3-phenyl-N-(4-propionyl-thiazol-2-yl)-butyramide;
(2S, 3S)-2-((R)-4-{4-[(2-methoxyl group-ethylamino formyl radical)-methoxyl group]-phenyl }-2,5-dioxo-imidazolidine-1-yl)-3-phenyl-N-(4-propionyl-thiazol-2-yl)-butyramide;
(2S, 3S)-2-{ (R)-4-[4-(2-morpholine-4-base-2-oxo-oxyethyl group)-phenyl]-2,5-dioxo-imidazolidine-1-yl }-3-phenyl-N-(4-propionyl-thiazol-2-yl)-butyramide;
(2S, 3S)-2-{ (R)-2,5-dioxo-4-[4-(2-oxo-2-tetramethyleneimine-1-base-oxyethyl group)-phenyl]-imidazolidine-1-yl }-3-phenyl-N-(4-propionyl-thiazol-2-yl)-butyramide;
(2S, 3S)-2-{ (R)-4-[4-(2-azetidine-1-base-2-oxo-oxyethyl group)-phenyl]-2,5-dioxo-imidazolidine-1-yl }-3-phenyl-N-(4-propionyl-thiazol-2-yl)-butyramide; And
(2S, 3S)-N-(4-cyclopropane carbonyl-thiazol-2-yl)-2-[(R)-4-(4-methylamino formyl radical methoxyl group-phenyl)-2,5-dioxo-imidazolidine-1-yl]-3-phenyl-butyramide.
" alkyl " expression straight chain, side chain or ring-type saturated aliphatic hydrocarbon.Preferably, alkyl is represented low alkyl group, that is, and and the C1-C6 alkyl, and comprise methyl, ethyl, propyl group, sec.-propyl, butyl, the tertiary butyl, 2-butyl, amyl group, hexyl etc.Usually, low alkyl group is preferably the C1-C4 alkyl, and C1-C3 alkyl more preferably.The example of cycloalkyl is to contain 3 to 10, and the part of preferred 3 to 7 carbon atoms comprises cyclopropyl, cyclopentyl and cyclohexyl.
" aryl " is meant the aromatic carbocyclic alkyl of univalent, monocycle or dicyclo, the first aromatic ring of preferred 6-10 system.Preferred aryl groups includes but not limited to phenyl, naphthyl, tolyl and xylyl.
" heteroatoms " is meant the atom that is selected among N, O and the S.
" heteroaryl " is meant and contains the most nearly aromatic heterocycle system of two rings.Preferred heteroaryl includes but not limited to thienyl, furyl, indyl, pyrryl, pyridyl, pyrazinyl ， oxazolyl, thiazolyl (thiaxolyl), quinolyl, pyrimidyl, imidazolyl and tetrazyl.
As the list on aryl or heteroaryl ring-, two-or three-substituting group, can comprise hydroxyl, alkoxyl group, hydroxy alkoxy base, halogen, alkylamine, anils, the amide derivatives of anils, carboxylic acid, carboxylicesters, carboxylic acid amide and methylsulfonyl.When having two or more substituting groups on aryl or heteroaryl ring, they also can exist with the form of condensed ring.This condensed ring includes but not limited to 3,4-methylenedioxyphenyl and 3,4-ethylenedioxy phenyl.
" alkoxyl group or lower alkoxy " is meant any in the above-mentioned lower alkyl level that is connected with Sauerstoffatom.Typical lower alkoxy comprises methoxyl group, oxyethyl group, isopropoxy or propoxy-, butoxy etc.Also be included in having in the implication of alkoxyl group: many alkoxyl groups side chain, as ethoxy ethoxy, methoxy ethoxy; methoxy ethoxy oxyethyl groups etc., and the alkoxyl group side chain that replaces are as dimethylamino ethoxy; the diethyl amino base oxethyl, dimethoxy-phosphoryl methoxy base etc.Be included in having in the implication of alkoxyl group equally: have other substituent alkoxyl group side chain, as carboxylic acid, carboxylicesters and carboxylic acid amide.
" medicinal ester " is meant the compound of the formula I that contains carboxyl of conventional esterification, the biological effectiveness and the character of this ester hold mode I compound, and in vivo (in organism) is cracked into corresponding active carboxylic acid.
Provide in Design ofProdrugs.Bundgaard H ed. (Elsevier, 1985) about the example of the ester that is used for the delivering drugs compound and the more information of application.Also referring to H.Ansel etc., Pharmaceutical Dosage Forms and Drug Delivery Systems (6th Ed.1995) 108-109 page or leaf; Krogsgaard-Larsen, etc., Textbook of Drug Design andDevelopment (2d Ed.1996) 152-191 page or leaf.
" pharmaceutical salts " referred to keep the biological efficacy and the character of The compounds of this invention, and the conventional acid additive salt or the base addition salt that are formed by suitable non-toxicity organic or inorganic acid or organic or inorganic alkali.The example of acid salt comprises from mineral acid example hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, sulfuric acid, dithiocarbamic acid, phosphoric acid and those salt of nitric acid deutero-with from those salt of deutero-such as organic acid such as right-toluenesulphonic acids, Whitfield's ointment, methylsulfonic acid, oxalic acid, succsinic acid, citric acid, oxysuccinic acid, lactic acid, fumaric acid, trifluoroacetic acids.The example of base addition salt comprises from the oxyhydroxide of ammonium, potassium, sodium and quaternary ammonium, tetramethylammonium hydroxide for example, those salt of deutero-.For physics and chemical stability, water absorbability, flowability and the solvability of the compound that is improved, the salifiable chemically modified of medical compounds (that is medicine) shape is the Pharmaceutical Chemist technique known.Referring to, H.Ansel etc. for example, Pharmaceutical Dosage Forms and DrugDelivery Systems (the 6th edition, 1995) the 196th and 1456-1457 page or leaf.
" medicinal " as pharmaceutical carrier, vehicle etc., refers on the pharmacology acceptable and essentially no toxic to the patient of administration particular compound.
" replacement " as in substituted aryl or heteroaryl, is meant that replacement can occur in one or more positions, and except as otherwise noted, is independently selected from concrete option at the substituting group of each the position of substitution.
" treatment significant quantity " is meant obvious inhibition human tumor cells, comprises human tumour cell line's propagation and/or prevents the human tumor cell, comprises the amount of at least a appointed compound of human tumour cell line's differentiation.
Compound of the present invention can be used for the treatment of or control cell proliferation disorders, as inflammatory/autoimmune disease such as restenosis, and cognitive disorder such as dementia and Alzheimer, CNS illness such as neuropathic pain, particularly tumour illness.These compounds can be used for the treatment of or the controlled entity knurl with the preparation that contains described compound, as breast, rectum, lung and tumor of prostate.
Compound of the present invention can also be used for preparation and be used for the treatment of or control cell proliferation disorders, as inflammatory/autoimmune disease such as restenosis, and cognitive disorder such as dementia and Alzheimer, CNS illness such as neuropathic pain, the particularly medicine of tumour illness.These compounds can be used for preparation in addition with the preparation that contains described compound and be used for the treatment of or the controlled entity knurl, as the medicine of breast, rectum, lung and tumor of prostate.
The compound of formula I and their salt have at least one unsymmetrical carbon, therefore, can be that the form of mixtures of different steric isomers exists.Can separate various isomer by separation known method such as chromatography.
Treatment significant quantity according to compound of the present invention refers to can effectively prevent, slow down or improve the amount of being treated patient disease symptom or extended treatment patient survival time.Those of ordinary skills can determine to treat significant quantity.
Treatment significant quantity or dosage according to compound of the present invention can change in very wide scope, and can determine according to methods known in the art.Regulate this dosage according to the individual need of each concrete case, described individual need comprises one or more particular compound of administration, route of administration, the disease condition of treatment, and the patient of treatment.In general, under the situation to the one-tenth human oral of the about 70Kg of body weight or administered parenterally, the about 10mg of per daily dose is to about 10,000mg, and preferably about 200mg is to about 1, and 000mg will be suitable, although the upper limit can be exceeded when indicating.Per daily dose can be used as single dose or with the divided dose administration, perhaps for administered parenterally, can be used as continuous infusion provides.
Reaction scheme
Formula 6 compounds that can prepare the alkyl of R8=alkyl wherein or replacement according to the method for in scheme 1, being summarized.Described in scheme 1, compound known 1 obtains compound 2 when handling with tert-Butyl dicarbonate in the pyridine that refluxes.Then, in the mixture of tetrahydrofuran (THF) and water,, obtain corresponding carboxylic acid 3 with compound 2 lithium hydroxide hydrolysis.Compound 3 at first in tetrahydrofuran (THF) with 2-chloro-4, the reaction of 5-dimethoxy-1,3,5-triazines and N-methylmorpholine, then with N, O-dimethyl hydroxyl amine hydrochlorate and triethylamine reaction obtain the compound of formula 4.Can compound 4 be converted into the ketone of formula 5 by using alkyl magnesium chloride in ether solvents or bromine salt (Grignard reagent).Then, after the compound of handling formula 5 with sour for example trifluoroacetic acid is with the removal of carrying out tertbutyloxycarbonyl, obtain the compound of formula 6.
Figure A20058002770800281
Described in scheme 2, a kind of alternative approach of functionalized compounds 4 is for generating two-t-butoxycarbonyl amino derivative 7 by employing tert-Butyl dicarbonate and salt of wormwood.Then, can be with compound 7 by reacting the ketone that is converted into formula 8 with the organometallic reagent that suits such as organic lithium reagent.By the compound of formula 8, after for example trifluoroacetic acid is handled with the removal of carrying out tertbutyloxycarbonyl with acid, obtain the compound of formula 6.
Figure A20058002770800291
Substituent R 8 contains under the situation of active function groups therein, uses known method and chemical transformation aptly by those skilled in the art, this substituting group further can be modified.After the substituent introducing of R8, can carry out this modification immediately, perhaps can be in any having on this substituent derivative and carry out this modification subsequently.
In addition, the ketone that exists in the compound of formula 5,6 and 8 is active function groups and can uses in the organic chemistry filed known method and carry out further chemical transformation by the person skilled in art.After the introducing of ketone, can carry out this modification immediately, perhaps can be in any having on this substituent derivative and carry out this modification subsequently.
Described in scheme 3, will be for example-78 ℃ at low temperature, the 2-vinylformic acid 9 and the solution of triethylamine in anhydrous tetrahydro furan that replace are handled with trimethyl-acetyl chloride, use (S)-(+)-4-phenyl-2-oxazolidone anionic (producing) anionic treatments then, obtain the compound of formula 10 with n-Butyl Lithium.In the presence of cuprous bromide (I)-dimethyl sulphide title complex, the compound of formula 10 reacts with the Grignard reagent that suits, and obtains the compound of formula 11.The Grignard reagent that is used for this conversion can contain the heteroaryl of aryl, heteroaryl or the replacement of aryl in the compound of the formula of being incorporated into 11, replacement.By at first handling with highly basic such as hexamethyldisilane base amination potassium, use 2,4,6 tri isopropyl benzenesulfonyl base nitrine to handle then, the compound of formula 11 is converted into the compound of formula 12.In the presence of tert-Butyl dicarbonate and palladium carbon,, obtain the compound of formula 13 with the compound hydrogenolysis of formula 12.By the compound of formula 13,, obtain the compound of formula 14 by handling with hydrogen peroxide and lithium hydroxide.
R9 group shown in the scheme 3 can be the alkyl of alkyl or replacement.Therein under the situation of R9 for the alkyl of replacement, substituting group is a non-activity for the condition that is adopted in the chemical transformation subsequently on the remote part of molecule, so the R9 group can be retained in the compound of the presently claimed invention with chemically unaltered form.Alternatively, the R9 group can contain the lateral reactivity functional group that exists with protected form, and by this protected form, this functional group is released at suitable point in chemical transformation process subsequently.For the more fully description that utilizes blocking group, referring to ProtectingGroups in Organic Synthesis, 3 RdEdition, T.W.Greene and P.G.M.Wuts, Wiley-Interscience.
R10 group shown in the scheme 3 can be a hydrogen, alkyl, the alkyl of replacement or halogen.
Described in scheme 4, in methylene dichloride, in the presence of pyridine, use cyanuric fluoride, the compound of formula 14 is converted into the acid fluoride of formula 15.With the compound of formula 15 compound treatment in the presence of N-methylmorpholine with formula 6, and adding and microwave exposure to obtain interior reaction temperature 100 and 120 ℃ between the catalysis of this reaction by 4-dimethylaminopyridine.The compound of formula 6 can be a compound known, as the compound of R8=OMe, or according to the compound of known method preparation, or according to the compound of the method preparation of in scheme 1 and 2, being summarized.So, obtain the compound of formula 16.With the compound of formula 16 trifluoroacetic acid deprotection, obtain the compound of formula 17.Compound and alpha-amino acid derivatives with formula 17, the phenylglycine derivatives of preferred enantiomorph enrichment (compound known or the compound for preparing by known method), with I-hydroxybenzotriazole and O-benzotriazole-1-base-N, N, N ', N '-tetramethyl-urea hexafluorophosphate coupling obtains the compound of formula 18.At employed alpha-amino acid derivatives is under the situation of phenylglycine derivatives, and R11 can be a hydroxyl, alkoxyl group, the alkoxyl group of replacement, acylated amine, the sulfone of replacement and phosphoric acid ester.Be that these compounds can be prepared easily by 4-hydroxy phenyl glycine, because two kinds of enantiomers all are commercially available under the situation of phenylglycine derivatives of enantiomorph enrichment at alpha-amino acid derivatives.The compound of formula 18 is handled with trifluoroacetic acid,, obtained the compound of formula 19 by removing tertiary butyl carboxylamine ester protecting group.At solvent such as methylene dichloride, tetrahydrofuran (THF), or handle with trichloromethylchloroformate and diisopropylethylamine in the mixture of tetrahydrofuran (THF) and toluene obtains the hydantoins of the replacement of formula 20 with the compound of formula 19.
Figure A20058002770800311
The reaction conditions that is used for above-mentioned reaction can change to a certain extent.
Be used to prepare method according to formula II compound of the present invention, wherein:
A) compound of formula 17:
With the compound reaction of following formula,
Figure A20058002770800322
Obtain the compound of formula 18:
Figure A20058002770800323
B) compound of described formula II again with CF 3CO 2The H reaction,
Obtain the compound of formula 19:
Figure A20058002770800331
C) in the solvent in the mixture that is selected from methylene dichloride, tetrahydrofuran (THF) and tetrahydrofuran (THF) and toluene, the compound of described formula 19 again with the reaction of trichloromethylchloroformate and diisopropylethylamine, removing tertiary butyl carboxylamine ester protecting group,
Figure A20058002770800332
Obtain the compound of formula II:
Figure A20058002770800333
R wherein 8, R 9, R 10And R 11Has the above-mentioned implication that provides.
The method and the technology of carrying out above-mentioned reaction are as known in the art, can be similar to maybe that embodiment derives.Raw material is commercially available, perhaps can be prepared by those methods described in the embodiment that are similar to.
Embodiment 1
(2S, 3S)-N-(4-ethanoyl-thiazol-2-yl)-2-[(R)-4-(4-methoxyl group-phenyl)-2,5-dioxo-imidazolidine-1-yl]-3-phenyl-butyramide.
Figure A20058002770800341
(1) use 3 one step process of being summarized in the step (1a) to (1c) to prepare 1-(2-amino-thiazolyl--4-yl)-ethyl ketone; then according to the method for in step (2) to (7), being summarized; be converted into (2S; 3S)-and N-(4-ethanoyl-thiazol-2-yl)-2-[(R)-4-(4-methoxyl group-phenyl)-2,5-dioxo-imidazolidine-1-yl]-3-phenyl-butyramide.
(1a) in 1 hour, (18.7mL 226mmol) is added drop-wise to 60 ℃, 2, and (20g 225mmol) in the stirred solution in benzene (80mL), and stirs mixture and to spend the night 3-dimethyl diketone (97% purity) under this temperature with SULPHURYL CHLORIDE (97% purity).Vacuum is removed benzene, and by the distillation purifying resistates, obtains 1-chloro-2, and the 3-dimethyl diketone is yellow liquid, b.p.=95 to 105 ℃ (≈ 10mmHg), (16.2g, 60%).
(1b) (8.87g 115mmol) in the stirring the mixture in ethanol (20.9mL), drips 1-chloro-2, and (13.90g 115mmmol), causes slight thermopositive reaction to the 3-dimethyl diketone to thiocarbamide.Mixture was stirred 1 hour in envrionment temperature.Reaction mixture is filtered, and settling washs with ether (2 *).With dark brown solid air drying, dried overnight under the high vacuum obtains 1-(2-amino-thiazolyl--4-yl)-acetophenone hydrochloride then, is dark brown solid (21.5g, 97%).
(1c) 1-(2-amino-thiazolyl--4-yl)-acetophenone hydrochloride (5.6g 29.1mmol) is dissolved in water (15mL), and cools off in ice bath.To wherein, drip 17N ammonium hydroxide (15mL, 105mmol).The mixture that obtains was stirred 15 minutes, filter then, and with cold water (3 *), (3 * 50mL), (3 * 10mL) wash ether cold methanol.Throw out is passed through material and drying by making air, and vacuum-drying then obtains 1-(2-amino-thiazolyl--4-yl)-ethyl ketone, is faint yellow solid (2.6g, 57%).
In-10 ℃, will (2S, 3S)-2-t-butoxycarbonyl amino-3-phenyl-butyric acid (1.94g, 6.93mmol) and pyridine (0.63mL 7.74mmol) is dissolved in methylene dichloride (50mL).The dropping cyanuric fluoride (1.80mL, 21.1mmol).Mixture was stirred 1 hour, and add ice-water.Mixture is extracted with methylene dichloride (2x).With the organic extract water, salt water washing, and dry (sodium sulfate).That evaporating solvent obtains is rough ((1S, 2S)-1-fluorine carbonyl-2-phenyl-propyl group)-t-butyl carbamate (2.2g), be muddy oil, it is used to next step.
With rough ((1S, 2S)-1-fluorine carbonyl-2-phenyl-propyl group)-t-butyl carbamate (2.2g, ≈ 6.93mol), 1-(2-amino-thiazolyl--4-yl)-ethyl ketone (1.0g, 7.0mmol), the 4-methylmorpholine (1.56mL, 14mmol) and N, (10mg 0.082mmol) is dissolved in the tetrahydrofuran (THF) (20mL) the N-dimethyl aminopyridine.With mixture in 120 ℃ of microwaves 15 minutes.Solution is diluted with ethyl acetate, and use the 1.5M aqueous potassium hydrogen sulfate, water and salt water washing.At dry (sodium sulfate), after filtration and the solvent evaporation, obtain [(1S, 2S)-1-(4-ethanoyl-thiazol-2-yl formamyl)-2-phenyl-propyl group]-t-butyl carbamate (2.8g, 89%), be yellow foam.
Will [(1S, 2S)-1-(4-ethanoyl-thiazol-2-yl formamyl)-2-phenyl-propyl group]-(2.8g 6.25mmol) is dissolved in the methylene dichloride (42mL) in the ice bath t-butyl carbamate.Add trifluoroacetic acid (35mL).After 30 minutes, evaporation reaction mixture, and with resistates hexane/ether sedimentation.With mixture vigorous stirring 10 minutes, filter then.Solid is distributed between sodium bicarbonate aqueous solution and methylene dichloride.Separate organic layer, and with the water layer dichloromethane extraction.With the organic extract salt water washing that merges, and dry (sodium sulfate).Evaporating solvent obtains that (2S 3S)-N-(4-ethanoyl-thiazol-2-yl)-2-amino-3-phenyl-butyramide (1.9g, 95%), is white solid.
(5) incite somebody to action (2S, 3S)-N-(4-ethanoyl-thiazol-2-yl)-2-amino-3-phenyl-butyramide (1.8g, 5.64mmol), (R)-t-butoxycarbonyl amino-4-p-methoxy-phenyl glycine (according to Hyun, M.H., etc., J.Liq.Chrom.﹠amp; Rel.Technol.2002,25, the method preparation of 573-588) (1.67g, 5.9mmol), O-benzotriazole-1-base-N, N, N ', N '-tetramethyl-urea hexafluorophosphate (2.35g, 6.2mmol) and diisopropylethylamine be dissolved in the dimethyl formamide (20mL) in the ice bath.The I-hydroxybenzotriazole of dropping in dimethyl formamide (5mL) (0.84g, 6.2mmol).To stir continuation 30 minutes in 0 ℃.Reaction mixture is diluted with ethyl acetate, and with mixture water and salt water washing.Organic layer is diluted with isopyknic methylene dichloride, filter, use 1: 1 ethyl acetate/dichloromethane wash-out then by the silicagel pad that has the sodium sulfate layer at the top.Evaporating solvent obtains white solid; itself and ether/hexane are ground; obtain [(R)-[(1S, 2S)-1-(4-ethanoyl-thiazol-2-yl formamyl)-2-phenyl-propyl group formamyl]-(4-methoxyl group-phenyl)-methyl]-t-butyl carbamate (3.1g, 97%).
(6) incite somebody to action [(R)-[(1S; 2S)-1-(4-ethanoyl-thiazol-2-yl formamyl)-2-phenyl-propyl group formamyl]-(4-methoxyl group-phenyl)-methyl]-(3.1g 5.2mmol) stirs in the methylene dichloride in ice bath (50mL) t-butyl carbamate.Add trifluoroacetic acid (50mL), and with solution stirring 1 hour.Evaporation reaction mixture, and with resistates hexane/ether sedimentation.With mixture vigorous stirring 10 minutes, filter then.Solid is distributed between sodium bicarbonate aqueous solution and methylene dichloride.Organic layer is separated, and the water layer dichloromethane extraction.With the organic extract salt water washing that merges, and dry (sodium sulfate).Evaporating solvent obtain (2S, 3S)-N-(4-ethanoyl-thiazol-2-yl)-2-[(R)-2-amino-2-(4-methoxyl group-phenyl)-acetylamino]-3-phenyl-butyramide (2.7g, 90% is pure), be white solid.
(7) in 10 minutes; in 0 ℃; will be at (the 2S in the tetrahydrofuran (THF) (50mL); 3S)-N-(4-ethanoyl-thiazol-2-yl)-2-[(R)-2-amino-2-(4-methoxyl group-phenyl)-acetylamino]-3-phenyl-butyramide (2.7g; 90% purity; 5.2mmol) and diisopropylethylamine (4.2mL, 23.6mmol) be added to trichloromethylchloroformate in the mixture of toluene (50mL) and tetrahydrofuran (THF) (50mL) (0.48mL, 4mmol) in.Mixture was stirred 20 minutes in 0 ℃, and the ethyl acetate dilution.With the mixture water, salt water washing, and dry (sodium sulfate).Evaporating solvent and resistates separate by the silica gel chromatography that is used in the 0.4-1%v/v methyl alcohol in the methylene dichloride; obtain (2S; 3S)-N-(4-ethanoyl-thiazol-2-yl)-2-[(R)-4-(4-methoxyl group-phenyl)-2; 5-dioxo-imidazolidine-1-yl]-3-phenyl-butyramide (2.36g; 92%), is white solid.
HRMS: the quality of actual measurement, 493.1538.The quality of calculating, 493.1540 (M+H).
Embodiment 2
To be similar to the mode described in the embodiment 1, the preparation following compounds.
A) (2S, 3S)-N-(4-ethanoyl-thiazol-2-yl)-2-[(R)-4-(4-hydroxyl-phenyl)-2,5-dioxo-imidazolidine-1-yl]-3-phenyl-butyramide.
HRMS: the quality of actual measurement, 479.1385.The quality of calculating, 479.1384 (M+H).
B) (2S, 3S)-N-(4-ethanoyl-thiazol-2-yl)-2-{ (R)-4-[4-(2-hydroxyl-oxyethyl group)-phenyl]-2,5-dioxo-imidazolidine-1-yl }-3-phenyl-butyramide.
Figure A20058002770800371
Be prepared as follows (the R)-t-butoxycarbonyl amino of (R)-t-butoxycarbonyl amino-4-p-methoxy-phenyl glycine that is used for replacing embodiment 1d-{ 4-[2-(tetrahydrochysene-pyrans-2-base oxygen base)-oxyethyl group]-phenyl }-acetate.
With (R)-t-butoxycarbonyl amino-(4-hydroxyl-phenyl)-acetate (2.67g, 10mmol) (Salituro, GM.; Townsend, C.A.J.Am.Chem.Soc.1990,112,760-770.) be dissolved in dimethyl formamide (70mL) in the ice bath.Aliquot ground adding sodium hydride (0.88g, 60%, in mineral oil, 22mmol).With mixture be warmed to 10 ℃ 1 hour.2-(2-bromo-the oxyethyl group)-tetrahydropyrans of dropping in dimethyl formamide (20mL) (1.7mol, 11mmol).Reaction mixture was stirred 24 hours, then with the dilution of ice-water.With the mixture ethyl acetate extraction.Water layer is cooled off in ice bath, and be acidified to pH=2-3 with 1.5 M aqueous potassium hydrogen sulfates.The mixture that obtains is extracted water (5 *), salt water washing, and dry (sodium sulfate) with ethyl acetate (5 *).Evaporating solvent obtains (R)-t-butoxycarbonyl amino-{ 4-[2-(tetrahydropyrans-2-base oxygen base)-oxyethyl group]-phenyl }-acetate, is solid white foam (3.2g, 82%).
HRMS: the quality of actual measurement, 523.1645.The quality of calculating, 523.1646 (M+H).
C) (2S, 3S)-N-(4-ethanoyl-thiazol-2-yl)-2-{ (R)-4-[4-(2-methoxyl group-oxyethyl group)-phenyl]-2,5-dioxo-imidazolidine-1-yl }-3-phenyl-butyramide.
Figure A20058002770800372
With as being used to synthesize (R)-t-butoxycarbonyl amino-{ 4-[2-(tetrahydrochysene-pyrans-2-base oxygen base)-oxyethyl group]-phenyl }-described similar fashion of acetate among the embodiment 2b, preparation replaces (R)-t-butoxycarbonyl amino-[4-(2-methoxyl group-oxyethyl group)-the phenyl]-acetate of (R)-t-butoxycarbonyl amino-4-p-methoxy-phenyl glycine among the embodiment 1d.
HRMS: the quality of actual measurement, 537.1803.The quality of calculating, 537.1803 (M+H).
D) (2S, 3S)-N-(4-ethanoyl-thiazol-2-yl)-2-((R)-4-{4-[2-(2-methoxyl group-oxyethyl group)-oxyethyl group]-phenyl }-2,5-dioxo-imidazolidine-1-yl)-3-phenyl-butyramide.
Figure A20058002770800381
With as being used to synthesize (R)-t-butoxycarbonyl amino-{ 4-[2-(tetrahydrochysene-pyrans-2-base oxygen base)-oxyethyl group]-phenyl }-described similar fashion of acetate among the embodiment 2b, preparation replaces (the R)-t-butoxycarbonyl amino of (R)-t-butoxycarbonyl amino-4-p-methoxy-phenyl glycine among the embodiment 1d-{ 4-[2-(2-methoxyl group-oxyethyl group)-oxyethyl group]-phenyl }-acetate.
HRMS: the quality of actual measurement, 581.2067.The quality of calculating, 581.2065 (M+H).
E) (2S, 3S)-N-(4-ethanoyl-thiazol-2-yl)-2-{ (R)-4-[4-(2-oxyethyl group-oxyethyl group)-phenyl]-2,5-dioxo-imidazolidine-1-yl }-3-phenyl-butyramide.
Figure A20058002770800382
With as being used to synthesize (R)-t-butoxycarbonyl amino-{ 4-[2-(tetrahydrochysene-pyrans-2-base oxygen base)-oxyethyl group]-phenyl }-described similar fashion of acetate among the embodiment 2b, preparation replaces (R)-t-butoxycarbonyl amino-[4-(2-oxyethyl group-oxyethyl group)-the phenyl]-acetate of (R)-t-butoxycarbonyl amino-4-p-methoxy-phenyl glycine among the embodiment 1d.
HRMS: the quality of actual measurement, 551.1963.The quality of calculating, 551.1959 (M+H).
F) (2S, 3S)-N-(4-ethanoyl-thiazol-2-yl)-2-{ (R)-4-[4-(2-dimethylamino-oxyethyl group)-phenyl]-2,5-dioxo-imidazolidine-1-yl }-3-phenyl-butyramide, three fluoro-acetates.
Figure A20058002770800391
With as being used to synthesize (R)-t-butoxycarbonyl amino-[4-(2-diethylamino-oxyethyl group)-phenyl]-described similar fashion of acetate among the embodiment 2g, prepare (R)-t-butoxycarbonyl amino-[4-(2-dimethylamino-oxyethyl group)-the phenyl]-acetate that replaces (R)-t-butoxycarbonyl amino-4-p-methoxy-phenyl glycine among the embodiment 1d.
HRMS: the quality of actual measurement, 550.2117, the quality of calculating, 550.2119 (M+H)
G) (2S, 3S)-N-(4-ethanoyl-thiazol-2-yl)-2-{ (R)-4-[4-(2-diethylamino-oxyethyl group)-phenyl]-2,5-dioxo-imidazolidine-1-yl }-3-phenyl-butyramide, three fluoro-acetates.
Figure A20058002770800392
Be prepared as follows (R)-t-butoxycarbonyl amino-[4-(2-diethylamino-oxyethyl group)-the phenyl]-acetate that replaces (R)-t-butoxycarbonyl amino-4-p-methoxy-phenyl glycine among the embodiment 1d.
(43.8mg is 95%Aldrich) at anhydrous N, in the suspension in the dinethylformamide (4mL), in 0 ℃ of dropping (R)-t-butoxycarbonyl amino-(4-hydroxy phenyl)-acetate (200.0mg, solution 0.749mmol) to sodium hydride.After adding, reaction mixture was stirred 20 minutes in envrionment temperature.With 2-bromotrifluoromethane-N, (234mg, 0.91mmol) at N, (23mg 1.00mmol) handles the cooling solution in the dinethylformamide (2mL) the N dimethylamine hydrochloride, then in 0 ℃, is added at leisure in the above-mentioned suspension with sodium hydride.To react on envrionment temperature and stir 17 hours, then with its quencher and neutralization by pouring into the 1N aqueous hydrochloric acid.With the mixture lyophilization that obtains, obtain described product (being polluted) by inorganic salt, it be not further purified use (619.5mg) down.
HRMS: the quality of actual measurement, 578.2430, the quality of calculating, 578.2432 (M+H).
H) (2S, 3S)-N-(4-ethanoyl-thiazol-2-yl)-2-[(R)-4-(4-oxyethyl group-phenyl)-2,5-dioxo-imidazolidine-1-yl]-3-phenyl-butyramide
Figure A20058002770800401
With as embodiment 2b) in be used to synthesize (R)-t-butoxycarbonyl amino-{ 4-[2-(tetrahydrochysene-pyrans-2-base oxygen base)-oxyethyl group]-phenyl }-described similar fashion of acetate, preparation replaces embodiment 1d) in (R)-t-butoxycarbonyl amino-(4-the ethoxyl phenenyl)-acetate of (R)-t-butoxycarbonyl amino-(4-p-methoxy-phenyl glycine).
HRMS: the quality of actual measurement, 507.1696.The quality of calculating, 507.1697 (M+H).
I) (2S, 3S)-N-(4-ethanoyl-thiazol-2-yl)-2-{ (S)-4-[4-(2-dimethylamino-oxyethyl group)-phenyl]-2,5-dioxo-imidazolidine-1-yl }-3-phenyl-butyramide, three fluoro-acetates.
Figure A20058002770800402
After the final step in the preparation described in the embodiment 2f; with (2S; 3S)-and N-(4-ethanoyl-thiazol-2-yl)-2-{ (S)-4-[4-(2-dimethylamino-oxyethyl group)-phenyl]-2,5-dioxo-imidazolidine-1-yl }-3-phenyl-butyramide is separated into less isomer.
HRMS: the quality of actual measurement, 550.2118, the quality of calculating, 550.2119 (M+H).
J) (4-{1-[(1S, 2S)-1-(4-ethanoyl-thiazol-2-yl formamyl)-2-phenyl-propyl group]-2,5-dioxo-imidazolidine-4-yl }-phenyl)-diethyl phosphonate.
Figure A20058002770800411
Be prepared as follows (R)-N-((±)-t-butoxycarbonyl amino of tertbutyloxycarbonyl-(4-p-methoxy-phenyl glycine)-{ 4-phenyl-phosphonic acid diethyl ester }-acetate that replaces among the embodiment 1d.
(l) to (R)-t-butoxycarbonyl amino-(4-hydroxy phenyl)-acetate benzyl ester (as J.Med.Chem.1991,34, prepare described in the 956-968) (2.0g, 5.60mmol) in the cold soln in anhydrous methylene chloride (60mL), add two (fluoroform the sulphonamide) (4.03g of N-phenyl, 11.28mmol) and diisopropylethylamine (1.0mL, 5.74mmol).With reaction mixture in stirring at room 48 hours.Solvent removed in vacuo, and resistates is dissolved in the ethyl acetate, with 10% wet chemical (2 *), water and salt water washing, and use dried over sodium sulfate.Solvent removed in vacuo; and product by the silica gel chromatography purifying, is wherein used 50% methylene dichloride in hexane, be used in 30% ethyl acetate in the hexane then; obtain t-butoxycarbonyl amino-(4-trifluoromethane-alkylsulfonyl oxygen base-phenyl)-jasmal (2.62g, 96%).
To t-butoxycarbonyl amino-(4-trifluoromethane-alkylsulfonyl oxygen base-phenyl)-jasmal (2.2g; 4.50mmol) solution in acetonitrile (10mL), add diethyl phosphite (643 μ L, 5.00mmol); then add N-methylmorpholine (691 μ L, 6.30mmol).With the mixture nitrogen purging, and add four-triphenyl phosphine palladium (260mg, 0.23mmol, 15mol%).Reaction mixture is heated to 75 ℃ spends the night, be cooled to room temperature then, and extract with ethyl acetate (50mL).Mixture is poured in the separating funnel that contains ethyl acetate (100mL), and with 0.2M aqueous hydrochloric acid (2 *), water (2 *), the salt water washing, and use dried over sodium sulfate.Solvent removed in vacuo, and product separated by silica gel column chromatography, wherein the ethyl acetate gradient elution in hexane between 10 to 75% obtains t-butoxycarbonyl amino-[4-(diethoxy-phosphoryl)-phenyl]-jasmal (2.0g, 93%).
(2.0g 4.2mmol) in the solution in ethanol (20mL), adds 10% palladium carbon (200mg) to t-butoxycarbonyl amino-[4-(diethoxy-phosphoryl)-phenyl]-jasmal.Mixture was stirred two days under atmospheric hydrogen atmosphere.Reaction mixture is filtered by Celite  pad.With the solid washing with alcohol, and, obtain (±)-t-butoxycarbonyl amino-{ 4-phenyl-phosphonic acid diethyl ester }-acetate (1.5g, 92%) the ethanol filtrate vacuum concentration that merges.
HRMS: the quality of actual measurement, 388.1516.The quality of calculating, 388.1520 (M+H).
HRMS: the quality of actual measurement, 599.1722.The quality of calculating, 599.1724 (M+H).
K) (2S, 3S)-N-(4-ethanoyl-thiazol-2-yl)-2-[4-(4-dimethylamino-phenyl)-2,5-dioxo-imidazolidine-1-yl]-3-phenyl-butyramide.
Figure A20058002770800421
Preparation as described in example 1 above, difference is: replace (R)-t-butoxycarbonyl amino-4-p-methoxy-phenyl glycine with t-butoxycarbonyl amino-(4-dimethylamino-phenyl)-acetate.
HRMS:HRMS: the quality of actual measurement, 506.1858.The quality of calculating, 506.1857 (M+H)
Embodiment 3
(2S, 3S)-N-(4-ethanoyl-thiazol-2-yl)-2-[(R)-4-(4-methoxyl group-phenyl)-2,5-dioxo-imidazolidine-1-yl]-3-phenyl-pentanoic acid (4-ethanoyl-thiazol-2-yl)-acid amides.
(1) under nitrogen ,-78 ℃ 2-pentenoic acid (5.44g, 54mmol) and triethylamine (6g, 60mmol) in the solution in anhydrous tetrahydro furan (120mL), add trimethyl-acetyl chloride (7.36mL, 60mmol).In-78 ℃ of stirrings 10 minutes, 0 ℃ was stirred 1 hour, and then is cooled to-78 ℃ with reaction mixture.Simultaneously, be equipped with under nitrogen, (8.86g 54mmol) in the separately flask of the solution in anhydrous tetrahydro furan (130mL), drips the solution of n-Butyl Lithium (2.5M is in the hexane for 22mL, 54mmol) in-78 ℃ (S)-(+)-4-phenyl-2-oxazolidone.Mixture in-78 ℃ of stirrings 20 minutes, is transferred to by sleeve pipe in the reaction flask of the mixed acid anhydride that contains-78 ℃ then.Reaction mixture in 0 ℃ of stirring 1 hour, is warmed to room temperature then, and stirred 18 hours.With mixture with saturated aqueous ammonium chloride (200mL) quencher, under reduced pressure be concentrated into initial volume pact half, to remove tetrahydrofuran (THF).With remaining mixture with ethyl acetate (2 * 250mL) extractions.Organic layer is separated, merge, use dried over sodium sulfate, and concentrating under reduced pressure.Resistates by silica gel chromatography, is wherein used 2: 1 ethyl acetate/hexane wash-outs and purifying obtains (S)-3-((E)-penta-2-enoyl-)-4-phenyl-oxazolidines-2-ketone, be white foam (9.9g, 75%).
(2) (12.4g 60.6mmol) in the suspension in anhydrous tetrahydro furan (150mL), adds phenyl magnesium chlorine solution (2M is in the tetrahydrofuran (THF) for 30.3mL, 60.6mmol) to-10 ℃ cuprous bromide (I) dimethyl sulphide title complex.Reaction mixture in-10 ℃ of stirrings 1 hour, is dripped (S)-3-((E)-penta-2-enoyl-)-4-phenyl-oxazolidines-2-ketone (9.9g, 40.4mmol) solution in tetrahydrofuran (THF) (100mL) by sleeve pipe then.Reaction mixture was stirred 0.5 hour in-10 ℃, then in stirring at room 2 hours.With mixture saturated aqueous ammonium chloride (150mL) quencher, decompression is concentrated into half of its volume down.(2 * 250mL) extract with ethyl acetate with mixture.Organic layer is separated, merge, and use dried over sodium sulfate, decompression concentrates down.Resistates by silica gel chromatography, is wherein used 2: 1 ethyl acetate/hexane wash-outs and purifying obtains (S)-4-phenyl-3-((R)-3-phenyl-pentanoyl)-oxazolidines-2-ketone, be water white oil, it solidifies (9.56g, 73%) by placing in room temperature.
(3) under nitrogen; (S)-4-phenyl-3-of-78 ℃ ((R)-3-phenyl-pentanoyl)-oxazolidines-2-ketone (8.81g; 27.2mmol) in the solution in anhydrous tetrahydro furan (200mL); add hexamethyl two silicon potassium azide (disilazide) (45mL; 40.8mmol; 0.91M, in the tetrahydrofuran (THF)).Reaction mixture was stirred 1 hour in-78 ℃, then by sleeve pipe drip-78 ℃ 2,4,6-tri isopropyl benzenesulfonyl nitrine (9.6g, 31mmol) the pre-cooled solution in tetrahydrofuran (THF) (200mL).Reaction mixture was stirred 1.5 hours in-78 ℃, add then acetate (7.5g, 125mmol).Reaction mixture is warmed to 35 ℃ in ice bath, and stirred 2 hours, during this period, thin-layer chromatographic analysis indicates needed product to generate as main ingredient.Reaction mixture is concentrated into still less volume, topples in the entry then, and with ethyl acetate (2 * 200mL) extractions.Organic layer is separated, merge, with dried over sodium sulfate and concentrated.Resistates by silica gel chromatography, is wherein used 2: 1 dichloromethane/hexane wash-outs and purifying, and ((2S, 3S)-2-azido--3-phenyl-pentanoyl)-4-phenyl-oxazolidines-2-ketone is white solid to obtain (S)-3-.By being further purified with the ethyl acetate solution that contains hexane, obtain described product, be white solid (6.08g, 36%).
(4) to (S)-3-((2S; 3 S)-2-azido--3-phenyl-pentanoyl)-4-phenyl-oxazolidines-2-ketone (4.0g; 11mmol) and tert-Butyl dicarbonate (4.8g 22mmol) in the solution in ethyl acetate (100mol), adds 10% palladium carbon (2g) under nitrogen.The suspension that obtains under hydrogen atmosphere (55psi), was acutely rocked in the Pa Er device 20 hours.Mixture is filtered by the short pad of diatomite, and filtrate is concentrated.Resistates is passed through silica gel chromatography, wherein use 1: 4 ethyl acetate/hexane wash-out and purifying, obtain [(1S, 2S)-1-((S)-2-oxo-4-phenyl-oxazolidines-3-carbonyl)-2-phenyl-butyl]-t-butyl carbamate, be white foam (4.38g, 90%).
(5) to-10 ℃ [(1S, 2S)-1-((S)-2-oxo-4-phenyl-oxazolidines-3-carbonyl)-2-phenyl-butyl]-t-butyl carbamate (4.38g, 10mmol) in the mixture of tetrahydrofuran (THF) and water (3: 1,60mL), the aqueous solution (the 11mL that adds hydrogen peroxide in succession, 100mmol, 30%) and lithium hydroxide monohydrate (1.23g, aqueous solution 30mmol) (15mL).Reaction mixture is stirred in-10 ℃, and by the progress of thin-layer chromatography monitoring reaction.After 3 hours, TLC analyzes the indication raw material and almost completely consumes.Add the saturated sodium sulfite aqueous solution (100mL).Mixture under reduced pressure is concentrated into half of its initial volume,, uses methylene dichloride (2 * 100mL) extractions then to remove tetrahydrofuran (THF).Water layer is separated, be acidified to pH=2-3, and (2 * 300mL) extract with ethyl acetate with aqueous citric acid solution.Organic layer is separated, merge, and use dried over sodium sulfate, decompression concentrates down, and vacuum-drying, obtain (2S, 3S)-2-t-butoxycarbonyl amino-3-phenyl-pentanoic acid, be white foam (1.7g, 58%).
(6) to be similar to the mode described in the embodiment 1; by (2S; 3S)-2-t-butoxycarbonyl amino-3-phenyl-pentanoic acid and 1-(2-amino-thiazolyl--4-yl)-ethyl ketone preparation (2S; 3S)-and N-(4-ethanoyl-thiazol-2-yl)-2-[(R)-4-(4-methoxyl group-phenyl)-2,5-dioxo-imidazolidine-1-yl]-3-phenyl-pentanoic acid (4-ethanoyl-thiazol-2-yl)-acid amides (RO4922706).
HRMS: the quality of actual measurement, 507.1701.The quality of calculating, 507.1697 (M+H).
Embodiment 4
(2S, 3S)-2-[(R)-4-(4-methoxyl group-phenyl)-2,5-dioxo-imidazolidine-1-yl]-3-phenyl-N-(4-propionyl-thiazol-2-yl)-butyramide.
Figure A20058002770800441
(1) will be at the 2-amino-thiazolyl-in the pyridine (1000mol)-4-carboxylic acid, ethyl ester (Kumar, R.; Rai, D. etc., Heterocyclic Communications 2002,8,521-530) (34.44g, 0.20mol) and tert-Butyl dicarbonate (65.47g, 0.30mol) reflux is 4.5 hours.(65.47g 0.3mol), and continues to reflux 1.5 hours to add more tert-Butyl dicarbonate.Reaction mixture is distributed between ethyl acetate and water.The organic phase water is washed well dry (sal epsom), and evaporation.Resistates separates by silica gel chromatography, uses 3: 1 ethyl acetate/dichloromethane, obtains 2-t-butoxycarbonyl amino-thiazole-4-carboxylic acid ethyl ester, is dark brown solid (52.35g, 96%).
(2) (20.16g, (52.35g is 0.192mol) in the stirred solution in the mixture of tetrahydrofuran (THF) (800mL) and water (200mL) 0.48mol) to be added to the 2-t-butoxycarbonyl amino-thiazole-4-carboxylic acid ethyl ester of stirring with lithium hydroxide monohydrate.The mixture stirring is spent the night.Add 1N aqueous hydrochloric acid (480mL), and with the reaction mixture vacuum concentration to remove tetrahydrofuran (THF).Then, with the mixture dilute with water, and filter.With the solid water, ether washing, and dried overnight obtain 2-t-butoxycarbonyl amino-thiazole-4-carboxylic acid (43.9g, 94%).
(3) with 2-t-butoxycarbonyl amino-thiazole-4-carboxylic acid (14g, 0.0573mol) and N-methylmorpholine (5.79g, 0.0573mol) solution in tetrahydrofuran (THF) was in stirring at room 2 hours.Add N, the O-dimethyl hydroxylamine hydrochloride (5.59g, 0.0573mmol) and triethylamine (5.59g, 0.0573mol), and with mixture stirring 3 days.Evaporation reaction mixture, and add ethyl acetate.Reaction mixture with the washing of 1N aqueous hydrochloric acid, is washed with saturated sodium bicarbonate aqueous solution then.After dry (sal epsom) and the evaporation, obtain [4-(methoxyl group-methyl-formamyl)-thiazol-2-yl]-t-butyl carbamate (14.5g, 88%), be dark brown tar.
(4) be cooled to-70 ℃ with the solution stirring of magnesium ethide chlorine (2M is in the tetrahydrofuran (THF) for 126mL, 0.252mol) and by dry ice/acetone batch.In about 5 minutes, drip [4-(methoxyl group-methyl-formamyl)-thiazol-2-yl]-t-butyl carbamate (14.5g, 0.0504mol) solution in tetrahydrofuran (THF) (200mL).Mixture was stirred 1 hour.Remove cooling bath, and continue to stir other 2 hours.Mixture is poured in the mixture of ice and saturated aqueous ammonium chloride, use ethyl acetate extraction then.Organic extract is merged; use the salt water washing; use dried over mgso, and evaporation, pale solid obtained; it is by the chromatogram of 350g silicagel pad; wherein use 4: 1 ethyl acetate/dichloromethane wash-outs, and purifying obtains (4-propionyl-thiazol-2-yl)-t-butyl carbamate (7.09g; 55%), is pale solid.
(5) in 0 ℃, (5.0g 19.5mmol) is suspended in the methylene dichloride (100mL) with (4-propionyl-thiazol-2-yl)-t-butyl carbamate.Add trifluoroacetic acid (100mL), and mixture was stirred 1.5 hours in 0 ℃.Remove cooling bath, and will stir and continue 1 hour, afterwards the vacuum concentration reaction mixture.Resistates is ground and filters with ether.Solid is dissolved in the mixture of methylene dichloride and saturated sodium bicarbonate aqueous solution.Separate organic layer, and with the water layer dichloromethane extraction.With the organic extract salt water washing that merges, use dried over sodium sulfate, and evaporation, obtain 1-(2-amino-thiazolyl--4-yl)-third-1-ketone (2.3g, 75%).
(6) with as described in example 1 above similar fashion; by (2S; 3S)-2-t-butoxycarbonyl amino-3-phenyl-butyric acid and 1-(2-amino-thiazolyl--4-yl)-third-1-ketone preparation (2S; 3S)-2-[(R)-and 4-(4-methoxyl group-phenyl)-2,5-dioxo-imidazolidine-1-yl]-3-phenyl-N-(4-propionyl-thiazol-2-yl)-butyramide.
HRMS: the quality of actual measurement, 507.1697.The quality of calculating, 507.1097 (M+H).
Embodiment 5
With similar fashion as described in example 4 above, the preparation following compounds.
A) (2S, 3S)-N-(4-ethanoyl-thiazol-2-yl)-2-[(R)-4-(2,3-dihydro-benzo [1,4] dioxine-6-yl)-2,5-dioxo-imidazolidine-1-yl]-3-phenyl-N-(4-propionyl-thiazol-2-yl)-butyramide.
Figure A20058002770800461
According to Bohme, E.H.W etc., J, Med, Chem, 1980,23, the described method of 405-412, preparation (2R)-t-butoxycarbonyl amino-(2,3-dihydro-benzo [1,4] dioxine-6-yl)-acetate.
HRMS: the quality of actual measurement, 535.1645.The quality of calculating, 535.1646 (M+H).
B) (2S, 3S)-2-[(R)-4-(4-oxyethyl group-phenyl)-2,5-dioxo-imidazolidine-1-yl]-3-phenyl-N-(4-propionyl-thiazol-2-yl)-butyramide.
With as being used to synthesize (R)-t-butoxycarbonyl amino-{ 4-[2-(tetrahydrochysene-pyrans-2-base oxygen base)-oxyethyl group]-phenyl }-described similar fashion of acetate among the embodiment 2b, preparation replaces (R)-t-butoxycarbonyl amino-{ 4-the ethoxyl phenenyl }-acetate of (R)-t-butoxycarbonyl amino-(the 4-p-methoxy-phenyl glycine) among the embodiment 1d.
HRMS: the quality of actual measurement, 611.2166.The quality of calculating, 611.2170 (M+H).
C) (2S, 3S)-2-[(R)-4-(4-hydroxyl-phenyl)-2,5-dioxo-imidazolidine-1-yl]-3-phenyl-N-(4-propionyl-thiazol-2-yl)-butyramide.
Figure A20058002770800472
LR-MS：493(M+H)。
D) (2S, 3S)-2-{ (R)-4-[4-(2-methoxyl group-oxyethyl group)-phenyl]-2,5-dioxo-imidazolidine-1-yl }-3-phenyl-N-(4-propionyl-thiazol-2-yl)-butyramide.
Figure A20058002770800473
With as being used to synthesize (R)-t-butoxycarbonyl amino-{ 4-[2-(tetrahydrochysene-pyrans-2-base oxygen base)-oxyethyl group]-phenyl }-described similar fashion of acetate among the embodiment 2b, preparation replaces (R)-t-butoxycarbonyl amino-[4-(2-methoxyl group-oxyethyl group)-the phenyl]-acetate of (R)-t-butoxycarbonyl amino-4-p-methoxy-phenyl glycine among the embodiment 1d.
HRMS: the quality of actual measurement, 551.1958.The quality of calculating, 551.1959 (M+H).
E) conduct is from synthetic (2S; 3S)-and 2-{ (R)-4-[4-(2-methoxyl group-oxyethyl group)-phenyl]-2; 5-dioxo-imidazolidine-1-yl }-by product of 3-phenyl-N-(4-propionyl-thiazol-2-yl)-butyramide; isolate (2S; 3S)-and 2-{ (S)-4-[4-(2-methoxyl group-oxyethyl group)-phenyl]-2,5-dioxo-imidazolidine-1-yl }-3-phenyl-N-(4-propionyl-thiazol-2-yl)-butyramide.
Figure A20058002770800481
HRMS: the quality of actual measurement, 551.1692.The quality of calculating, 551.1959 (M+H).
F) (2S, 3S)-2-{ (R)-4-[4-(2-hydroxyl-oxyethyl group)-phenyl]-2,5-dioxo-imidazolidine-1-yl }-3-phenyl-N-(4-propionyl-thiazol-2-yl)-butyramide.
Figure A20058002770800482
In embodiment 2b, preparation is used for replacing (the R)-t-butoxycarbonyl amino of (R)-t-butoxycarbonyl amino-4-p-methoxy-phenyl glycine among the embodiment 1d-{ 4-[2-(tetrahydrochysene-pyrans-2-base oxygen base)-oxyethyl group]-phenyl }-acetate.
HRMS: the quality of actual measurement, 537.1804.The quality of calculating, 537.1803 (M+H).
[0023] g) (2S, 3S)-2-((R)-4-{4-[2-(2-methoxyl group-oxyethyl group)-oxyethyl group]-phenyl }-2,5-dioxo-imidazolidine-1-yl)-3-phenyl-N-(4-propionyl-thiazol-2-yl)-butyramide.
With as being used to synthesize (R)-t-butoxycarbonyl amino-{ 4-[2-(tetrahydrochysene-pyrans-2-base oxygen base)-oxyethyl group]-phenyl }-described similar fashion of acetate among the embodiment 2b, preparation replaces (the R)-t-butoxycarbonyl amino of (R)-t-butoxycarbonyl amino-4-p-methoxy-phenyl glycine among the embodiment 1d-{ 4-[2-(2-methoxyl group-oxyethyl group)-oxyethyl group]-phenyl }-acetate.
HRMS: the quality of actual measurement, 595.2217.The quality of calculating, 595.2221 (M+H).
H) (2S, 3S)-2-{ (R)-4-[4-(2-oxyethyl group-oxyethyl group)-phenyl]-2,5-dioxo-imidazolidine-1-yl }-3-phenyl-N-(4-propionyl-thiazol-2-yl)-butyramide.
Figure A20058002770800491
With as being used to synthesize (R)-t-butoxycarbonyl amino-{ 4-[2-(tetrahydrochysene-pyrans-2-base oxygen base)-oxyethyl group]-phenyl }-described similar fashion of acetate among the embodiment 2b, preparation replaces (R)-t-butoxycarbonyl amino-[4-(2-oxyethyl group-oxyethyl group)-the phenyl]-acetate of (R)-t-butoxycarbonyl amino-4-p-methoxy-phenyl glycine among the embodiment 1d.
HRMS: the quality of actual measurement, 565.2120.The quality of calculating, 565.2116 (M+H).
I) (2S, 3S)-2-{ (R)-4-[4-(2-dimethylamino-oxyethyl group)-phenyl]-2,5-dioxo-imidazolidine-1-yl }-3-phenyl-N-(4-propionyl-thiazol-2-yl)-butyramide, three fluoro-acetates.
With as being used to synthesize (R)-t-butoxycarbonyl amino-[4-(2-diethylamino-oxyethyl group)-phenyl]-described similar fashion of acetate among the embodiment 2g, prepare (R)-t-butoxycarbonyl amino-[4-(2-dimethylamino-oxyethyl group)-the phenyl]-acetate that replaces (R)-t-butoxycarbonyl amino-4-p-methoxy-phenyl glycine among the embodiment 1d.
HRMS: the quality of actual measurement, 564.2266, the quality of calculating, 564.2275 (M+H).
J) (4-{ (R)-2,5-dioxo-1-[(1S, 2S)-2-phenyl-1-(4-propionyl-thiazol-2-yl formamyl)-propyl group]-imidazolidine-4-yl }-phenoxymethyl)-dimethyl phosphonate.
Figure A20058002770800501
Described in embodiment 8h, preparation is used for replacing (the R)-t-butoxycarbonyl amino of (R)-t-butoxycarbonyl amino-4-p-methoxy-phenyl glycine among the embodiment 1-{ 4-phenoxymethyl)-dimethyl phosphonate }-acetate.
HRMS: the quality of actual measurement, 615.1670.The quality of calculating, 615.1673 (M+H).
K) (2S, 3S)-N-(4-isobutyryl-thiazol-2-yl)-2-{ (R)-4-[4-(2-methoxyl group-oxyethyl group)-phenyl]-2,5-dioxo-imidazolidine-1-yl }-3-phenyl-butyramide.
With as being used to synthesize (R)-t-butoxycarbonyl amino-{ 4-[2-(tetrahydrochysene-pyrans-2-base oxygen base)-oxyethyl group]-phenyl }-described similar fashion of acetate among the embodiment 2b, preparation replaces (R)-t-butoxycarbonyl amino-[4-(2-methoxyl group-oxyethyl group)-the phenyl]-acetate of (R)-t-butoxycarbonyl amino-4-p-methoxy-phenyl glycine among the embodiment 1d.
With as being used for synthetic 1-(2-amino-thiazolyl--4-yl)-described similar fashion of third-1-ketone among the embodiment 4, prepare 1-(2-amino-thiazolyl--4-the yl)-2-methyl-third-1-ketone that replaces 1-(2-amino-thiazolyl--4-the yl)-ethyl ketone among the embodiment 1c.
L) (2S, 3S)-N-(4-isobutyryl-thiazol-2-yl)-2-[(R)-4-(4-methoxyl group-phenyl)-2,5-dioxo-imidazolidine-1-yl]-3-phenyl-butyramide.
Figure A20058002770800503
With as being used for synthetic 1-(2-amino-thiazolyl--4-yl)-described similar fashion of third-1-ketone among the embodiment 4, prepare 1-(2-amino-thiazolyl--4-the yl)-2-methyl-third-1-ketone that replaces 1-(2-amino-thiazolyl--4-the yl)-ethyl ketone among the embodiment 1c.
HRMS: the quality of actual measurement, 521.1852.The quality of calculating, 521.1853 (M+H).
M) (2S, 3S)-2-{ (S)-4-[4-(2-dimethylamino-oxyethyl group)-phenyl]-2,5-dioxo-imidazolidine-1-yl }-3-phenyl-N-(4-propionyl-thiazol-2-yl)-butyramide, three fluoro-acetate.
Figure A20058002770800511
After the final step in the preparation described in the embodiment 5i; with (2S; 3S)-and 2-{ (S)-4-[4-(2-dimethylamino-oxyethyl group)-phenyl]-2,5-dioxo-imidazolidine-1-yl }-3-phenyl-N-(4-propionyl-thiazol-2-yl)-butyramide is separated into less isomer.
HRMS: the quality of actual measurement, 564.2274, the quality of calculating, 564.2275 (M+H).
N) (2S, 3S)-2-{2,5-dioxo-4-[4-(2-piperidines-1-base-oxyethyl group)-phenyl]-imidazolidine-1-yl }-3-phenyl-N-(4-propionyl-thiazol-2-yl)-butyramide.
Figure A20058002770800512
(1) in 0 ℃, ((1g, 3.74mmol) at anhydrous N, (470mg 11.97mmol) handles the solution in the dinethylformamide (35mL) tertbutyloxycarbonyl-(4-hydroxy phenyl glycine) with sodium hydride (60% suspension at mineral oil) with (R)-N-.After 10 minutes, reaction mixture is warmed to room temperature, stirred other 10 minutes in this temperature, use then 1-(2-chloroethyl) piperidine hydrochlorate (720mg, 2.93mmol) and potassiumiodide (310mg 1.87mmol) handles.After stirring 15 minutes, add other anhydrous N, dinethylformamide (50mL), and will obtain slurries stirring 27.5 hours.Then, reaction mixture is distributed between ethyl acetate and water, and water layer is adjusted to pH=7 with the 1N aqueous hydrochloric acid.With the water layer freeze-drying, obtain solid residue then, it is suspended in the tetrahydrofuran (THF), and filter.Solid is washed with tetrahydrofuran (THF) (2 *), and the filtrate that merges is concentrated, obtain rough (R)-t-butoxycarbonyl amino-[4-(2-piperidines-1-base-oxyethyl group)-phenyl]-acetate (1.9g), it uses under not being further purified immediately.
(2) in 0 ℃; with (R)-t-butoxycarbonyl amino-[4-(2-piperidines-1-base-oxyethyl group)-phenyl]-acetate (740mg; ≈ 1.96mmol) is dissolved in the tetrahydrofuran (THF) (30mL); and add (2S; 3S)-2-amino-3-phenyl-N-(4-propionyl-thiazol-2-yl)-butyramide (250mg; 0.78mmol) (preparation as described in example 4 above), then add 1-[3-(dimethylamino) propyl group]-the 3-ethyl-carbodiimide hydrochloride (180mg, 0.94mmol).Reaction mixture is warmed to room temperature at leisure.After stirring 3.5 hours, other (R)-t-butoxycarbonyl amino-[4-(2-piperidines-1-base-oxyethyl group)-phenyl]-acetate (320mg, ≈ 0.85mmol) is added to reaction mixture.After stirring other 1.5 hours, with another part (R)-t-butoxycarbonyl amino-[4-(2-piperidines-1-base-oxyethyl group)-phenyl]-acetate (300mg, ≈ 0.82mmol) is added to reaction mixture, what add together also has other 1-[3-(dimethylamino) propyl group]-the 3-ethyl-carbodiimide hydrochloride (90mg, 4.72mmol).Be that stirring at room is after other 1 hour, mixture is distributed between ethyl acetate and salt solution, with the organic extract dried over sodium sulfate, vacuum concentration, and the resistates that obtains passes through silica gel chromatography, wherein at first use eluent ethyl acetate, then purifying with the dichloromethane gradient wash-out that contains 0 to 10% methyl alcohol.Obtain (R)-[(1S, 2S)-2-phenyl-1-(4-propionyl-thiazol-2-yl formamyl)-propyl group formamyl]-[4-(2-piperidines-1-base-oxyethyl group)-phenyl]-methyl }-t-butyl carbamate, be white solid (120mg, 24%).
HRMS: the quality of actual measurement, 678.3323.The quality of calculating, 678.3320 (M+H).
(3) in 0 ℃; will (R)-[(1S; 2S)-2-phenyl-1-(4-propionyl-thiazol-2-yl formamyl)-propyl group formamyl]-[4-(2-piperidines-1-base-oxyethyl group)-phenyl]-methyl }-(110mg 0.16mmol) is dissolved in the 30%v/v dissolving of trifluoroacetic acid in methylene dichloride (5mL) t-butyl carbamate.Stir after 1.5 hours, reaction mixture is distributed between ethyl acetate and saturated sodium bicarbonate aqueous solution.Water layer is adjusted to pH=8 by adding solid sodium bicarbonate.Water layer is used ethyl acetate (2 *) extraction again.With the organic layer dried over sodium sulfate that merges; filter; and vacuum concentration; obtain rough (2S; 3S)-2-{ (R)-2-amino-2-[4-(2-piperidines-1-base-oxyethyl group)-phenyl]-acetylamino }-3-phenyl-N-(4-propionyl-thiazol-2-yl)-butyramide, it be not further purified down use immediately.
(4) with rough (2S; 3S)-2-{ (R)-2-amino-2-[4-(2-piperidines-1-base-oxyethyl group)-phenyl]-acetylamino }-3-phenyl-N-(4-propionyl-thiazol-2-yl)-butyramide (≈ 0.16mmol) is dissolved in and contains diisopropylethylamine (142 μ L; 105mg; 0.81mmol) tetrahydrofuran (THF) (10mL) in; and in 0 ℃; (14 μ L, 23mg is 0.12mmol) in the solution in tetrahydrofuran (THF) (15mL) to be transferred to trichloromethylchloroformate by sleeve pipe.Reaction mixture was stirred 20 minutes, between ethyl acetate and water, distribute then.Organic layer is separated, and use dried over sodium sulfate, filter, and vacuum concentration.Resistates by silica gel chromatography, is wherein at first used eluent ethyl acetate, then purifying with the dichloromethane gradient wash-out that contains 0 to 10% methyl alcohol.From the methylene dichloride that contains excessive hexane, precipitate in the separated products; obtain (2S; 3S)-2-{2; 5-dioxo-4-[4-(2-piperidines-1-base-oxyethyl group)-phenyl]-imidazolidine-1-yl }-3-phenyl-N-(4-propionyl-thiazol-2-yl)-butyramide; be white solid (26mg, 27%).
HRMS: the quality of actual measurement, 604.2591.The quality of calculating, 604.2588 (M+H).
O) (2S, 3S)-2-{4-[4-(2-morpholine-4-base-oxyethyl group)-phenyl]-2,5-dioxo-imidazolidine-1-yl }-3-phenyl-N-(4-propionyl-thiazol-2-yl)-butyramide.
Figure A20058002770800531
(1) in 0 ℃, ((1g, 3.74mmol) at anhydrous N, (470mg 11.97mmol) handles tertbutyloxycarbonyl-(4-hydroxy phenyl glycine) with sodium hydride (60% in mineral oil suspension) for solution in the dinethylformamide (70mL) with (R)-N-.After 10 minutes, reaction mixture is warmed to room temperature, stirred other 10 minutes in this temperature, use then N-(2-chloroethyl) morpholine hydrochloride (720mg, 2.93mmol) and potassiumiodide (61mg 0.37mmol) handles.Reaction mixture was stirred 27.5 hours in envrionment temperature, between ethyl acetate and water, distribute then.Water layer is adjusted to pH=7 with the 1N aqueous hydrochloric acid.With the water layer freeze-drying, obtain solid residue then, it is suspended in tetrahydrofuran (THF), and filter.Solid is handled with tetrahydrofuran (THF) (2 *) and the filtrate that merges is concentrated, obtain rough (R)-t-butoxycarbonyl amino-[4-(2-morpholine-4-base-oxyethyl group)-phenyl]-acetate, it uses under not being further purified immediately.
(2) (R)-t-butoxycarbonyl amino-[4-(2-morpholine-4-base-oxyethyl group)-phenyl]-acetate (≈ 2.93mmol) is dissolved in the tetrahydrofuran (THF) (60mL); and in 0 ℃; add (2S; 3S)-2-amino-3-phenyl-N-(4-propionyl-thiazol-2-yl)-butyramide (500mg; 1.58mmol) (preparation as described in example 4 above); then add 1-[3-(dimethylamino) propyl group]-the 3-ethyl-carbodiimide hydrochloride (600mg, 3.12mmol).Reaction mixture is warmed to room temperature at leisure.Stirred 5.5 hours, reaction mixture is distributed between ethyl acetate and salt solution, with the organic extract dried over sodium sulfate, and vacuum concentration.The resistates that obtains is passed through silica gel chromatography, wherein at first use eluent ethyl acetate, then purifying with the dichloromethane gradient wash-out that contains 0 to 10% methyl alcohol.Obtain (R)-[4-(2-morpholine-4-base-oxyethyl group)-phenyl]-[(1S, 2S)-2-phenyl-1-(4-propionyl-thiazol-2-yl formamyl)-propyl group formamyl]-methyl }-t-butyl carbamate, be white solid (146mg, 14%).
HRMS: the quality of actual measurement, 680.3118.The quality of calculating, 680.3113 (M+H).
(3) in 0 ℃; will (R)-[4-(2-morpholine-4-base-oxyethyl group)-phenyl]-[(1S, 2S)-2-phenyl-1-(4-propionyl-thiazol-2-yl formamyl)-propyl group formamyl]-methyl }-carboxylamine-tert-butyl ester (0.19mmol) is dissolved in the 30%v/v solution of trifluoroacetic acid in methylene dichloride (5mL).After stirring 2 hours, reaction mixture is distributed between ethyl acetate and saturated sodium bicarbonate aqueous solution.Water layer is adjusted to pH=8 by adding solid sodium bicarbonate.Water layer is used ethyl acetate (2 *) extraction again.With the organic layer dried over sodium sulfate that merges; filter; and vacuum concentration; obtain rough (2S; 3S)-2-{ (R)-2-amino-2-[4-(2-morpholine-4-base-oxyethyl group)-phenyl]-acetylamino }-3-phenyl-N-(4-propionyl-thiazol-2-yl)-butyramide, it is used immediately and is not further purified.
(4) with rough (2S; 3S)-2-{ (R)-2-amino-2-[4-(2-morpholine-4-base-oxyethyl group)-phenyl]-acetylamino }-3-phenyl-N-(4-propionyl-thiazol-2-yl)-butyramide (≈ 0.19mmol) is dissolved in and contains diisopropylethylamine (160 μ L; 122mg; 0.94mmol) tetrahydrofuran (THF) (10mL) in; and in 0 ℃; (16 μ L, 26mg is 0.13mmol) in the solution in tetrahydrofuran (THF) (15mL) to be transferred to trichloromethylchloroformate by sleeve pipe.Reaction mixture was stirred 20 minutes, between ethyl acetate and water, distribute then.Organic layer is separated, and use dried over sodium sulfate, filter, and vacuum concentration.Resistates by silica gel chromatography, wherein is used in 0-100% ethyl acetate gradient elution in the hexane and purifying, and with isolating material by preparation of silica gel type tlc, wherein use eluent ethyl acetate and purifying.Isolating product is from containing the methylene dichloride precipitation of excessive hexane; obtain (2S, 3S)-2-{4-[4-(2-morpholine-4-base-oxyethyl group)-phenyl]-2,5-dioxo-imidazolidine-1-yl }-3-phenyl-N-(4-propionyl-thiazol-2-yl)-butyramide; be pale solid (32mg, 29%).
HRMS: the quality of actual measurement, 606.2384.The quality of calculating, 606.2381 (M+H).
P) (2S, 3S)-3-(3-fluoro-phenyl)-2-{ (R)-4-[4-(2-methoxyl group-oxyethyl group)-phenyl]-2,5-dioxo-imidazolidine-1-yl }-N-(4-propionyl-thiazol-2-yl)-butyramide.
Figure A20058002770800551
With as described in example 3 above synthetic (2S, 3S)-2-t-butoxycarbonyl amino-similar mode of 3-phenyl-pentanoic acid, preparation (2S, 3S)-2-t-butoxycarbonyl amino-3-(4-fluoro-phenyl)-butyric acid.
HRMS: the quality of actual measurement, 569.1866.The quality of calculating, 569.1865 (M+H).
Q) (2S, 3S)-2-[(R)-4-(4-methoxyl group-3-methyl-phenyl)-2,5-dioxo-imidazolidine-1-yl]-3-phenyl-N-(4-propionyl-thiazol-2-yl)-butyramide.
Figure A20058002770800552
As preparation (R)-t-butoxycarbonyl amino-(4-methoxyl group-3-methyl-phenyl)-acetate as described in the embodiment 8g.
HRMS: the quality of actual measurement, 543.1672.The quality of calculating, 543.1672 (M+H).
R) (2S, 3S)-2-{ (S)-4-[4-(2-hydroxyl-oxyethyl group)-phenyl]-2,5-dioxo-imidazolidine-1-yl }-3-phenyl-N-(4-propionyl-thiazol-2-yl)-butyramide.
Figure A20058002770800553
With with (2S; 3S)-and 2-{ (R)-4-[4-(2-hydroxyl-oxyethyl group)-phenyl]-2; 5-dioxo-imidazolidine-1-yl }-the similarly method preparation of 3-phenyl-N-(4-propionyl-thiazol-2-yl)-butyramide (embodiment 5f), difference is: replace (R)-4-hydroxy phenyl glycine with (S)-4-hydroxy phenyl glycine.
HRMS: the quality of actual measurement, 537.1802.The quality of calculating, 537.1803 (M+H).
S) (2S, 3S)-2-((R)-2,5-dioxo-4-phenyl-imidazolidine-1-yl)-3-phenyl-N-(4-propionyl-thiazol-2-yl)-butyramide.
Figure A20058002770800561
Preparation as described in example 4 above, difference is: replace (R)-t-butoxycarbonyl amino-4-p-methoxy-phenyl glycine with (R)-t-butoxycarbonyl amino-phenylglycocoll.
HRMS: the quality of actual measurement, 477.1595.The quality of calculating, 477.1591 (M+H).
T) (2S, 3S)-2-[4-(4-dimethylamino-phenyl)-2,5-dioxo-imidazolidine-1-yl]-3-phenyl-N-(4-propionyl-thiazol-2-yl)-butyramide.
Figure A20058002770800562
Preparation as described in example 4 above, difference is: replace (R)-t-butoxycarbonyl amino-4-p-methoxy-phenyl glycine with t-butoxycarbonyl amino-(4-dimethylamino-phenyl)-acetate.
HRMS: the quality of actual measurement, 520.2015.The quality of calculating, 520.2013 (M+H).
U) (2S, 3S)-2-[4-(4-morpholine-4-base-phenyl)-2,5-dioxo-imidazolidine-1-yl]-3-phenyl-N-(4-propionyl-thiazol-2-yl)-butyramide.
Preparation as described in example 4 above, difference is: replace (R)-t-butoxycarbonyl amino-4-p-methoxy-phenyl glycine with t-butoxycarbonyl amino-(4-morpholine-4-base-phenyl)-acetate.Prepare t-butoxycarbonyl amino-(4-morpholine-4-base-phenyl)-acetate with the similar fashion described in embodiment 9 steps 1, difference is: replace 4-sulphomethyl phenyl aldehyde with 4-morpholine-4-base-phenyl aldehyde.Be prepared as follows 4-morpholine-4-base-phenyl aldehyde:
With 2-(4-iodo-phenyl)-[1,3] dioxolane (960mg, 3.477mmol), 18-hat-6 ethers (1.021g, 3.85mmol), three (dibenzalacetones), two palladiums (0)-chloroform affixture (36.35mg, 0.0348mmol), rac-2,2 '-two (diphenylphosphino)-1-1 '-dinaphthalene (65.54mg, 0.104mmol) and sodium tert-butoxide (447.9mg, mixture 4.52mmol) thoroughly outgases with argon gas.In this mixture under argon gas, add firm distillatory morpholine (324.6mg, 3.651mmol) the argon-degassed solution in anhydrous tetrahydro furan (8mL).In stirring at room 2 hours, reflux was 2 hours then with it.Mixture is cooled to room temperature, puts into ethyl acetate (50mL), and water (3 * 50mL) washings, usefulness ethyl acetate (50mL) reextraction.With the organic extract dried over sodium sulfate that merges, filter, and simmer down to resistates (1.06g).With the silica gel column chromatography that resistates is deactivated by methyl alcohol, wherein be used in 0 to 25% ethyl acetate in the hexane with 5% stagewise gradient wash-out and activate.From post, be used in 20 in the hexane to 25% eluent ethyl acetate and go out 4-(4-[1,3] dioxolane-2-base-phenyl)-morpholine.By concentrating, obtain 4-(4-[1,3] dioxolane-2-base-phenyl)-morpholine, be dark brown solid (690mg, 84.3%).
With 4-(4-[1,3] dioxolane-2-base-phenyl)-morpholine (690mg, 2.933mmol) handle with 10 concentrated hydrochloric acid aqueous solutions by the mixture in methyl alcohol (5mL).With mixture in stirring at room 1 hour.In this solution, add 5 and drip, and will stir continuation 2 hours in envrionment temperature.Then, solution is poured into ethyl acetate (50mL), (2 * 50mL) wash, and (2 * 50mL) extract with ethyl acetate with saturated sodium bicarbonate aqueous solution.With the organic extract dried over sodium sulfate that merges, filter, and concentrate, obtain 4-morpholine-4-base-phenyl aldehyde, be dark brown waxy solid (550mg, 98%).
HRMS: the quality of actual measurement, 562.2120.The quality of calculating, 562.2119 (M+H).
V) (2S, 3S)-2-{4-[4-(4-hydroxy-piperdine-1-yl)-phenyl]-2,5-dioxo-imidazolidine-1-yl }-3-phenyl-N-(4-propionyl-thiazol-2-yl)-butyramide.
Figure A20058002770800571
Preparation as described in example 4 above, difference is: replace (R)-t-butoxycarbonyl amino-4-p-methoxy-phenyl glycine with t-butoxycarbonyl amino-[4-(4-hydroxy-piperdine-1-yl)-phenyl]-acetate.With the similar fashion described in the embodiment 5u, preparation t-butoxycarbonyl amino-[4-(4-hydroxy-piperdine-1-yl)-phenyl]-acetate, difference is: replace morpholine with piperidines-4-alcohol.
HRMS: the quality of actual measurement, 576.2275.The quality of calculating, 576.2275 (M+H).
W) (2S, 3S)-2-(4-{4-[(2-methoxyl group-ethyl)-methyl-amino]-phenyl }-2,5-dioxo-imidazolidine-1-yl)-3-phenyl-N-(4-propionyl-thiazol-2-yl)-butyramide.
Figure A20058002770800581
Preparation as described in example 4 above, difference is: the usefulness t-butoxycarbonyl amino-4-[(2-methoxyl group-ethyl)-methyl-amino]-phenyl }-acetate replacement (R)-t-butoxycarbonyl amino-4-p-methoxy-phenyl glycine.With the similar fashion described in the embodiment 5u, the preparation t-butoxycarbonyl amino-4-[(2-methoxyl group-ethyl)-methyl-amino]-phenyl }-acetate, difference is: replace morpholine with (2-methoxyl group-ethyl)-methyl-amine.
HRMS: the quality of actual measurement, 564.2279.The quality of calculating, 564.2275 (M+H)
X) (2S, 3S)-N-(4-cyclopropane carbonyl-thiazol-2-yl)-2-{ (R)-4-[4-(2-methoxyl group-oxyethyl group)-phenyl]-2,5-dioxo-imidazolidine-1-yl }-3-phenyl-butyramide.
Figure A20058002770800582
Preparation as described in example 4 above, difference is: use cyclopropyl magnesium chloro for the magnesium ethide chlorine in the step 4, and replace (R)-t-butoxycarbonyl amino-4-p-methoxy-phenyl glycine with (R)-t-butoxycarbonyl amino-[4-(2-methoxyl group-oxyethyl group)-phenyl]-acetate (preparing) described in embodiment 2c.
HRMS: the quality of actual measurement, 563.1955.The quality of calculating, 563.1959 (M+H).
Y) (2S, 3S)-2-{4-[4-(2-methoxyl group-oxyethyl group)-phenyl]-2,5-dioxo-imidazolidine-1-yl }-3-methyl-valeric acid (4-propionyl-thiazol-2-yl)-acid amides.
Figure A20058002770800591
Preparation as described in example 4 above, difference is: with (2S, 3S)-2-t-butoxycarbonyl amino-3-methyl-valeric acid replace (2S, 3S)-2-t-butoxycarbonyl amino-3-phenyl-butyric acid and (R)-t-butoxycarbonyl amino-[4-(2-methoxyl group-oxyethyl group)-phenyl]-acetate (preparing described in embodiment 2c) replaces (R)-t-butoxycarbonyl amino-4-p-methoxy-phenyl glycine.
HRMS: the quality of actual measurement, 503.1961 quality of calculating, 503.1959 (M+H).
Z) (2S, 3R)-3-benzyloxy-2-{ (R)-4-[4-(2-methoxyl group-oxyethyl group)-phenyl]-2,5-dioxo-imidazolidine-1-yl }-N-(4-propionyl-thiazol-2-yl)-butyramide.
Figure A20058002770800592
Preparation as described in example 4 above, difference is: with (2S, 3R)-3-benzyloxy-2-t-butoxycarbonyl amino-butyric acid replace (2S, 3S)-2-t-butoxycarbonyl amino-3-phenyl-butyric acid and (R)-t-butoxycarbonyl amino-[4-(2-methoxyl group-oxyethyl group)-phenyl]-acetate (preparing described in embodiment 2c) replaces (R)-t-butoxycarbonyl amino-4-p-methoxy-phenyl glycine.
HRMS: the quality of actual measurement, 581.2063 quality of calculating, 581.2065 (M+H).
Embodiment 6
(2S, 3S)-N-[4-(2-methoxyl group-ethanoyl)-thiazol-2-yl]-2-[(R)-and 4-(4-methoxyl group-phenyl)-2,5-dioxo-imidazolidine-1-yl]-3-phenyl-butyramide.
Figure A20058002770800601
(1) to [4-(methoxyl group-methyl-formamyl)-thiazol-2-yl]-carboxylamine-tert-butyl ester (17.0g; 59.2mmol) in (as preparation as described in the embodiment 4a-4c) solution in acetonitrile (250mL); add salt of wormwood (40.8g in room temperature; 295.2mmol) and 4-dimethylaminopyridine (1.4g; 11.5mmol); then add tert-Butyl dicarbonate (27.1g, 124.2mmol).Stir after 12 hours, will react by diatomite filtration, and solvent removed in vacuo.Crude product by silica gel chromatography, wherein is used in 30% in the hexane to 40% ethyl acetate gradient elution and purifying obtains [4-(methoxyl group-methyl-formamyl)-thiazol-2-yl]-two-(carboxylamine-tert-butyl ester) (20.1g, 88% yield).
(2) to speed be cooled to-78 ℃ lithium diisopropylamine (13.3g, 124.1mmol) in the solution in anhydrous tetrahydro furan (100mL), drip-78 ℃ the methoxy menthyl acetate in anhydrous tetrahydro furan (20mL) (12.9g, 124.3mmol).Mixture was stirred 15 minutes in-78 ℃.In-78 ℃, will be in anhydrous tetrahydro furan (20mL) [4-(methoxyl group-methyl-formamyl)-thiazol-2-yl]-(6.0g 15.5mmol) drops in the negatively charged ion two-(carboxylamine-tert-butyl ester).Mixture was stirred 30 minutes, use the saturated sodium bicarbonate aqueous solution quencher then, use ethyl acetate extraction, use the salt water washing, and use dried over sodium sulfate.Crude product by silica gel chromatography, wherein is used in 10% in the hexane to 30% ethyl acetate gradient elution and purifying.Obtain 3-(2-couple-t-butoxycarbonyl amino-thiazole-4-yl)-2-methoxyl group-3-oxo-methyl propionate, be white foam (1.54g, 23%).
(3) in 0 ℃, (1.54g 3.6mmol) in the solution in methylene dichloride (15mL), adds trifluoroacetic acid (7.2mL) to 3-(2-couple-t-butoxycarbonyl amino-thiazole-4-yl)-2-methoxyl group-3-oxo-methyl propionate.Reaction is warmed to room temperature, and stirred 4 hours.Solvent removed in vacuo, and resistates distributed between ethyl acetate and saturated sodium bicarbonate aqueous solution.With the water layer ethyl acetate extraction, and with the extract salt water washing that merges, and use dried over sodium sulfate.Remove and desolvate, obtain 3-(2-amino-thiazolyl--4-yl)-2-methoxyl group-3-oxo-methyl propionate, be oil (800mg, 97% yield).
(4) in room temperature, to 3-(2-amino-thiazolyl--4-yl)-2-methoxyl group-3-oxo-methyl propionate (765mg, 3.3mmol) in the solution in tetrahydrofuran (THF) (25ml), add the 1M aqueous sodium hydroxide solution (4.0ml, 4.0mmol).Mixture was stirred 2 hours, be cooled to 0 ℃ then.Add the 1N aqueous sulfuric acid (33mL, 33.2mmol), and with reaction be warmed to 40 ℃ 30 minutes.Then, reaction mixture is cooled to 0 ℃, and is alkalescence with saturated sodium bicarbonate aqueous solution.With the suspension ethyl acetate extraction, with the organic extract water that merges, the salt water washing, and use dried over mgso.Crude product by silica gel chromatography, is wherein used 7: 3 ethyl acetate/hexane wash-outs and purifying obtains 1-(2-amino-thiazolyl--4-yl)-2-methoxyl group-ethyl ketone, be yellow oil (240mg, 42% yield).
(5) with the similar fashion described in the embodiment 1; by 1-(2-amino-thiazolyl--4-yl)-2-methoxyl group-ethyl ketone preparation (2S; 3S)-N-[4-(2-methoxyl group-ethanoyl)-thiazol-2-yl]-2-[(R)-and 4-(4-methoxyl group-phenyl)-2,5-dioxo-imidazolidine-1-yl]-3-phenyl-butyramide.
HRMS: the quality of actual measurement, 507.2888.The quality of calculating, 507.2887 (M+H).
Embodiment 7
2-{ (2S, 3S)-2-[(R)-4-(2,3-dihydro-benzo [1,4] dioxine-6-yl)-2,5-dioxo-imidazolidine-1-yl]-3-phenyl-butyrylamino }-thiazole-4-carboxylic acid's methyl esters.
Figure A20058002770800611
(1) will in ice bath, cool off in the 2-amino-thiazolyl-in the methyl alcohol (400mL)-4-carboxylic acid, ethyl ester (38g) (preparation as described in example 4 above), and, in 0.5 hour, add 25% sodium methylate to wherein.After 0.5 hour, remove ice bath.By removing by filter a small amount of insoluble substance, and in yellow solution, add saturated aqueous ammonium chloride, reaction mixture is concentrated, to remove excessive methanol.Mixture is alkalized to pH=9.0 with saturated sodium bicarbonate aqueous solution, and (3 * 200mL) extracted with 1: 1 ether/tetrahydrofuran (THF).With organic extract and the water washing that merges.With the organic solution dried over sodium sulfate, and concentrate, obtain faint yellow solid, it still contains some residual solvents.Solid suspension in hexane, is filtered by the 5.5cm funnel, and vacuum-drying then obtains 2-amino-thiazolyl--4-carboxylate methyl ester (15.6g), is faint yellow solid.
(2) will be at N, 2-amino-thiazolyl-in the dinethylformamide (8mL)-4-carboxylate methyl ester (0.57g, 3.62mmol) and (2S, 3S)-2-t-butoxycarbonyl amino-3-phenyl-butyric acid (Acros) (1.01g, 3.62mmol), I-hydroxybenzotriazole and (0.59g, 4.34mmol) and O-benzotriazole-1-base-N, N, N ', (1.65g 4.34mmol) stirred 24 hours in envrionment temperature N '-tetramethyl-urea hexafluorophosphate.Mixture is diluted water, salt water washing, and dry (sal epsom) with ethyl acetate.Evaporating solvent, and resistates separates by silica gel chromatography, wherein is used in the 0.2-1.5% methyl alcohol gradient elution in the methylene dichloride, obtains 2-((2S, 3S)-2-t-butoxycarbonyl amino-3-phenyl-butyrylamino)-thiazole-4-carboxylic acid's methyl esters (0.65g, 43%).
3) ((0.65g 1.54mmol) is blended in the methylene dichloride (5mL) in the ice bath (2S, 3S)-2-t-butoxycarbonyl amino-3-phenyl-butyrylamino)-thiazole-4-carboxylic acid's methyl esters with 2-.Add trifluoroacetic acid (5mL), and with solution stirring 2 hours.Evaporation reaction mixture, and with the resistates ether sedimentation.With mixture vigorous stirring 10 minutes, filter then.Solid is distributed between sodium bicarbonate aqueous solution and methylene dichloride.Separate organic layer, and with the water layer dichloromethane extraction.With the organic extract salt water washing that merges, and dry (sodium sulfate).Evaporating solvent obtains 2-((2S, 3S)-2-amino-3-phenyl-butyrylamino)-thiazole-4-carboxylic acid's methyl esters (0.35g, 71%).
(4) with 2-((2S, 3S)-2-amino-3-phenyl-butyrylamino)-thiazole-4-carboxylic acid's methyl esters (0.255g, 0.80mmol), (2R)-t-butoxycarbonyl amino-(2,3-dihydro-benzo [1,4] dioxine-6-yl)-and acetate (according to Bohme, E.H.W. etc., J.Med.Chem.1980,23, the method preparation of 405-412), O-benzotriazole-1-base-N, N, N ', and N '-tetramethyl-urea hexafluorophosphate (0.364g, 0.96mmol) and diisopropylethylamine (0.56mol, 3.2mmol) be dissolved in the N in ice bath, in the dinethylformamide (3mL).Dropping is at N, I-hydroxybenzotriazole (0.13g, 9.6mmol in the dinethylformamide (1mL).Continue to stir 30min in 0 ℃.Reaction mixture is diluted with ethyl acetate, and with mixture water and salt water washing.Organic layer is diluted with isopyknic methylene dichloride, filter by the silicagel pad that has the sodium sulfate layer at the top, and with 1: 1 ethyl acetate/dichloromethane wash-out.Evaporating solvent obtains white solid; it is ground with ether/hexane; obtain thick 2-{ (2S; 3S)-2-[(R)-2-t-butoxycarbonyl amino-2-(2; 3-dihydro-benzo [1,4] dioxine-6-yl)-acetylamino]-3-phenyl-butyrylamino }-thiazole-4-carboxylic acid's methyl esters (0.49g).
(5) with 2-{ (2S; 3S)-2-[(R)-2-t-butoxycarbonyl amino-2-(2; 3-dihydro-benzo [1,4] dioxine-6-yl)-acetylamino]-3-phenyl-butyrylamino }-(0.49g 0.80mmol) stirs in the methylene dichloride in ice bath (8mL) thiazole-4-carboxylic acid's methyl esters.Add trifluoroacetic acid (8mL), and with solution stirring 2 hours.Evaporation reaction mixture, and with resistates hexane/ether sedimentation.With mixture vigorous stirring 10 minutes, filter then.The solid that obtains is distributed between sodium bicarbonate aqueous solution and methylene dichloride.Separate organic layer, and with the water layer dichloromethane extraction.With the organic extract salt water washing that merges, and dry (sodium sulfate).Evaporating solvent obtain 2-{ (2S, 3S)-2-[(R)-2-amino-2-(2,3-dihydro-benzo [1,4] dioxine-6-yl)-acetylamino]-3-phenyl-butyrylamino-thiazole-4-carboxylic acid's methyl esters (0.384g, 94%).
(6) in 0 ℃; in 10 minutes; with 2-{ (2S; 3S)-2-[(R)-2-amino-2-(2; 3-dihydro-benzo [1,4] dioxine-6-yl)-acetylamino]-3-phenyl-butyrylamino }-thiazole-4-carboxylic acid's methyl esters (0.380g, 0.75mmol)) and diisopropylethylamine (0.52mL; 3mmol) solution in tetrahydrofuran (THF) (7.5mL) is added to trichloromethylchloroformate (0.48mL is 4mmol) in the solution in the mixture of toluene (7.5mol) and tetrahydrofuran (THF) (7.5mol).Mixture in 0 ℃ of stirring 20 minutes, is diluted with ethyl acetate then.With the mixture water, salt water washing, and dry (sodium sulfate).Evaporating solvent, and resistates is by the silicon chromatogram, wherein be used in the 0.2-1% methyl alcohol gradient elution in the methylene dichloride, obtain (2-{ (2S, 3S)-2-[(R)-4-(2,3-dihydro-benzo [1,4] dioxine-6-yl)-2,5-dioxo-imidazolidine-1-yl]-3-phenyl-butyrylamino }-thiazole-4-carboxylic acid's methyl esters (0.22g, 55%).
HRMS: the quality of actual measurement, 537.1438.The quality of calculating, 537.1439 (M+H).
Embodiment 8
To be similar to the mode described in the embodiment 7, the preparation following compounds.
A) 2-[(2S, 3S)-2-((R)-2,5-dioxo-4-phenyl-imidazolidine-1-yl)-3-phenyl-butyrylamino]-thiazole-4-carboxylic acid's methyl esters.
Figure A20058002770800631
For C 24H 22N 4O 5S.0.2C 6H 14The analytical calculation value: C, 61.05; H, 5.04; N, 11.30; S, 6.47.Measured value: C, 61.27; H, 5.25; N, 10.95; S, 6.10.
B) 2-{ (2S, 3S)-2-[(R)-4-(4-methoxyl group-phenyl)-2,5-dioxo-imidazolidine-1-yl]-3-phenyl-butyrylamino-thiazole-4-carboxylic acid's methyl esters.
Figure A20058002770800641
With (R)-t-butoxycarbonyl amino-4-p-methoxy-phenyl glycine (Hyun, M.H.; Cho, J.Liq.Chrom.﹠amp such as Y.K.; Rel.Technol.2002,25,573-588) replace embodiment 7 ((the 2R)-t-butoxycarbonyl amino in the step 4)-(2,3-dihydro-benzo [1,4] dioxine-6-yl)-acetate.
HRMS: the quality of actual measurement, 509.1485.The quality of calculating, 509.1490 (M+H).
C) 2-{ (2S, 3S)-2-[(R)-4-(4-hydroxyl-phenyl)-2,5-dioxo-imidazolidine-1-yl]-3-phenyl-butyrylamino-thiazole-4-carboxylic acid's methyl esters.
Figure A20058002770800642
HRMS: the quality of actual measurement, 495.1334.The quality of calculating, 495.1333 (M+H).
D) 2-((2S, 3S)-2-{ (R)-4-[4-(2-methoxyl group-oxyethyl group)-phenyl]-2,5-dioxo-imidazolidine-1-yl }-3-phenyl-butyrylamino)-thiazole-4-carboxylic acid's methyl esters.
Figure A20058002770800643
With as being used to synthesize (R)-t-butoxycarbonyl amino-{ 4-[2-(tetrahydrochysene-pyrans-2-base oxygen base)-oxyethyl group]-phenyl }-described similar fashion of acetate among the embodiment 2b, preparation replaces EXAMPLE Example 7 ((the 2R)-t-butoxycarbonyl amino-(2 in the step 4), 3-dihydro-benzo [1,4] dioxine-6-yl)-(R)-t-butoxycarbonyl amino-[4-(2-methoxyl group-oxyethyl group)-the phenyl]-acetate of acetate.
HRMS: the quality of actual measurement, 553.1753.The quality of calculating, 553.1752 (M+H).
E) 2-((2S, 3S)-2-{ (R)-4-[4-(2-hydroxyl-oxyethyl group)-phenyl]-2,5-dioxo-imidazolidine-1-yl }-3-phenyl-butyrylamino)-thiazole-4-carboxylic acid's methyl esters.
Figure A20058002770800651
Described in embodiment 2b, preparation replaces embodiment 7 ((the 2R)-t-butoxycarbonyl amino-(2 in the step 4), 3-dihydro-benzo [1,4] dioxine-6-yl)-(the R)-t-butoxycarbonyl amino of acetate-4-[2-(tetrahydrochysene-pyrans-2-base oxygen base)-oxyethyl group]-phenyl }-acetate.
HRMS: the quality of actual measurement, 539.1595.The quality of calculating, 539.1595 (M+H).
F) 2-{{2S, 3S)-2-[(R)-4-(4-isopropoxy-phenyl)-2,5-dioxo-imidazolidine-1-yl]-3-phenyl-butyrylamino }-thiazole-4-carboxylic acid's methyl esters.
Figure A20058002770800652
With as being used to synthesize (R)-t-butoxycarbonyl amino-{ 4-[2-(tetrahydrochysene-pyrans-2-base oxygen base)-oxyethyl group]-phenyl }-described similar fashion of acetate among the embodiment 2b, preparation replaces (R)-t-butoxycarbonyl amino-[4-(1-methyl-oxyethyl group)-the phenyl]-acetate of (R)-t-butoxycarbonyl amino-{ 4-[2-(tetrahydrochysene-pyrans-2-base oxygen base)-oxyethyl group]-the phenyl }-acetate among the embodiment 8e.
HRMS: the quality of actual measurement, 537.1803.The quality of calculating, 537.1803 (M+H).
G) 2-{ (2S, 3S)-2-[(R)-4-(4-methoxyl group-3-methyl-phenyl)-2,5-dioxo-imidazolidine-1-yl]-3-phenyl-butyrylamino-thiazole-4-carboxylic acid's methyl esters.
Figure A20058002770800653
Be prepared as follows (R)-t-butoxycarbonyl amino-(4-methoxyl group-3-methyl-phenyl)-acetate.
(1) under nitrogen, (4-methoxyl group-3-methyl-phenyl)-acetate of-78 ℃ (5.04g, 27.97mmol) and triethylamine (3.9mL is 27.97mmol) in the solution in anhydrous tetrahydro furan (100mL), the adding trimethyl-acetyl chloride (3.44mL, 27.97mmol).In-78 ℃ of stirrings 10 minutes, 0 ℃ was stirred 1 hour, and then is cooled to-78 ℃ with reaction mixture.Simultaneously, under nitrogen ,-78 ℃, (4.96g 27.97mmol) in the separately flask of the solution in anhydrous tetrahydro furan (100mL), drips n-butyllithium solution (2M is in the hexane for 14mL, 28mmol) to (R)-(+)-4-benzyl-2-oxazolidone is housed.Second reaction mixture in-78 ℃ of stirrings 20 minutes, is transferred to-78 ℃, contains in first reaction flask of mixed acid anhydride by sleeve pipe then.Reaction mixture in 0 ℃ of stirring 1 hour, is warmed to room temperature then, and stirred 18 hours.With mixture with saturated aqueous ammonium chloride (200mL) quencher, under reduced pressure be concentrated into its initial volume pact half, to remove tetrahydrofuran (THF).(2 * 250mL) extract with ethyl acetate with remaining mixture.Organic layer is separated, merge, use dried over sodium sulfate, and decompression concentrates down.Resistates by silica gel chromatography, is wherein used 1: 1 ethyl acetate/hexane wash-out and purifying obtains (R)-4-benzyl-3-[2-(4-methoxyl group-3-methyl-phenyl)-ethanoyl]-oxazolidines-2-ketone, be light yellow oil (8.5g, 89%).
(2) under nitrogen; (R)-4-benzyl-3-[2-of-78 ℃ (4-methoxyl group-3-methyl-phenyl)-ethanoyl]-oxazolidines-2-ketone (8.5g; 25mmol) in the solution in anhydrous tetrahydro furan (120mL); add hexamethyl two silicon potassium azide (36mL; 32.6mmol; 0.91M, in the tetrahydrofuran (THF)).Reaction mixture was stirred 1 hour in-78 ℃, then, by sleeve pipe drip-78 ℃ 2,4,6-tri isopropyl benzenesulfonyl nitrine (8.8g, 28.6mmol) the pre-cooled solution in tetrahydrofuran (THF) (80mL).Reaction mixture was stirred 1.5 hours in-78 ℃, add then acetate (5.4 equivalents, 8.2g, 136mmol).Reaction mixture is warmed to 35 ℃ in water-bath, and stirred 2 hours, during this period, show by thin-layer chromatographic analysis to have generated needed product, i.e. main ingredient.Reaction mixture is concentrated into still less volume, topples in the entry then, and with ethyl acetate (2 * 200mL) extractions.Organic layer is separated, merge, use dried over sodium sulfate, and concentrate.Resistates by silica gel chromatography, is wherein used 2: 1 dichloromethane/hexane wash-outs and purifying obtains (R)-3-[(R)-2-azido--2-(4-methoxyl group-3-methyl-phenyl)-ethanoyl]-4-benzyl-oxazolidines-2-ketone, be yellow oil (8.0g, 84%).
(3) under nitrogen; to (R)-3-[(R)-2-azido--2-(4-methoxyl group-3-methyl-phenyl)-ethanoyl]-4-benzyl-oxazolidines-2-ketone (8g; 21mmol) and tert-Butyl dicarbonate (9.2g; 42mmol) in the solution in ethyl acetate (100mL), add 10% palladium carbon (3g).The suspension that obtains was acutely rocked in the Pa Er device 20 hours.Mixture is filtered by the short pad of diatomite, and filtrate is concentrated.Resistates is passed through silica gel chromatography, wherein use 1: 4 ethyl acetate/hexane wash-out and purifying, obtain [(R)-2-((R)-4-benzyl-2-oxo-oxazolidines-3-yl)-1-(4-methoxyl group-3-methyl-phenyl)-2-oxo-ethyl]-t-butyl carbamate, be yellow oil (6.05g, 63%).
(4) to [(R)-2-((R)-4-benzyl-2-oxo-oxazolidines-3-yl)-1-(4-methoxyl group-3-methyl-phenyl)-2-oxo-ethyl]-t-butyl carbamate (6.05g of-10 ℃, 13.3mmol) 4: 1 tetrahydrofuran (THF)/water (200mL) solution in, add 30% aqueous hydrogen peroxide solution (15mL in succession, 133mmol) and lithium hydroxide monohydrate (1.63g, 40mmol) solution in water (20mL).With reaction mixture in-10 ℃ of stirrings, and by the progress of thin-layer chromatography monitoring reaction.After 4 hours, the completely consumed of thin-layer chromatography indication raw material is fallen.Add the saturated sodium sulfite aqueous solution (100mL).Under reduced pressure mixture is concentrated into half of its initial volume,, uses methylene dichloride (2 * 100mL) extractions then to remove tetrahydrofuran (THF).Water layer is separated, and be acidified to pH=4, with ethyl acetate (2 * 250mL) extractions with aqueous citric acid solution.Organic layer is separated, merge, use dried over sodium sulfate, decompression concentrates down, and vacuum-drying, obtains (R)-t-butoxycarbonyl amino-(4-methoxyl group-3-methyl-phenyl)-acetate, is white foam (2.2g, 58%).
HRMS: the quality of actual measurement, 523.1646.The quality of calculating, 523.1646 (M+H).
H) 2-((2S, 3S)-2-{ (R)-4-[4-(dimethoxy-phosphoryl methoxy base)-phenyl]-2,5-dioxo-imidazolidine-1-yl }-3-phenyl-butyrylamino)-thiazole-4-carboxylic acid's methyl esters.
Figure A20058002770800671
Be prepared as follows t-butoxycarbonyl amino-[(R)-4-(dimethoxy-phosphoryl methoxy base)-phenyl]-acetate.
With dimethylphosphite (2.0g, 18.2mmol), paraformaldehyde (574mg, 19.1mmol) and triethylamine (0.25mL 1.8mmol) merges, and is heated to 70 ℃, obtains clear solution.After 1 hour, will react cooling, and vacuum concentration spends the night, obtain thick hydroxymethyl-dimethyl phosphonate (2.5g).
(2) to hydroxymethyl-dimethyl phosphonate of-20 ℃ (2.0g, 14.5mmol) in the solution in anhydrous methylene chloride (50mL), add pyridine (1.4mL, 16.7mmol), then add trifluoromethanesulfanhydride anhydride (2.7mL, 15.9mmol)., after 0.5 hour mixture is filtered by having the diatomite filtration of thin silicon glue-line in 0 ℃ of stirring.With filtrate with cold 1.0N aqueous hydrochloric acid, water, saturated sodium bicarbonate aqueous solution washing, and use dried over sodium sulfate.Remove and desolvate, obtain three fluoro-methylsulfonic acid dimethoxy-phosphoryl methyl esters, be oil (2.1g, 53%).
(3) with sodium hydride (18.9mg 0.79mmol) is added in ice bath, (the R)-t-butoxycarbonyl amino in the anhydrous dimethyl formamide (2.5mL)-(4-hydroxyl-phenyl)-acetate (100mg, 0.37mmol) in.Mixture is warmed to room temperature, then add three fluoro-methylsulfonic acid dimethoxy-phosphoryl methyl esters (122mg, 0.45mmol).Continuing stirring in room temperature spends the night.Reaction is poured in the 0.2M aqueous hydrochloric acid (10mL), and with the mixture ethyl acetate extraction.With the extract saturated sodium bicarbonate aqueous solution that merges, the salt water washing, and use dried over sodium sulfate.Evaporating solvent obtains t-butoxycarbonyl amino-[(R)-4-(dimethoxy-phosphoryl methoxy base)-phenyl]-acetate (120mg, 83% yield).
HRMS: the quality of actual measurement, 617.1459.The quality of calculating, 617.1466 (M+H).
I) 2-{ (2S, 3S)-3-(2-methoxyl group-phenyl)-2-[4-(4-methoxyl group-phenyl)-2,5-dioxo-imidazolidine-1-yl]-butyrylamino-thiazole-4-carboxylic acid's methyl esters.
Figure A20058002770800681
With as described in example 3 above synthetic (2S, 3S)-2-t-butoxycarbonyl amino-similar mode of 3-phenyl-pentanoic acid, preparation (2S, 3S)-2-t-butoxycarbonyl amino-3-(2-methoxyl group-phenyl)-butyric acid.
HRMS: the quality of actual measurement, 539.1591.The quality of calculating, 539.1595 (M+H).
J) 2-((2S, 3S)-3-(4-fluoro-phenyl)-2-{ (R)-4-[4-(2-methoxyl group-oxyethyl group)-phenyl]-2,5-dioxo-imidazolidine-1-yl }-butyrylamino)-thiazole-4-carboxylic acid's methyl esters.
Figure A20058002770800682
With as described in example 3 above synthetic (2S, 3S)-2-t-butoxycarbonyl amino-similar mode of 3-phenyl-pentanoic acid, preparation (2S, 3S)-2-t-butoxycarbonyl amino-3-(4-fluoro-phenyl)-butyric acid.
With as being used to synthesize (R)-t-butoxycarbonyl amino-{ 4-[2-(tetrahydrochysene-pyrans-2-base oxygen base)-oxyethyl group]-phenyl }-described similar fashion of acetate among the embodiment 2b, preparation replaces embodiment 7 ((the 2R)-t-butoxycarbonyl amino-(2 in the step d), 3-dihydro-benzo [1,4] dioxine-6-yl)-(R)-t-butoxycarbonyl amino-[4-(2-methoxyl group-oxyethyl group)-the phenyl]-acetate of acetate.
HRMS: the quality of actual measurement, 571.1655.The quality of calculating, 571.1657 (M+H).
K) 2-{ (2S, 3S)-2-[(R)-4-(4-methoxyl group-phenyl)-2,5-dioxo-imidazolidine-1-yl]-3-methyl-pentanoyl amino-thiazole-4-carboxylic acid's methyl esters.
Figure A20058002770800691
Preparation as described in example 7 above, difference is: with (2S, 3S)-2-t-butoxycarbonyl amino-3-methyl-valeric acid replaces the (2S in the step 2,3S)-2-t-butoxycarbonyl amino-3-phenyl-butyric acid, and replace (the 2R)-t-butoxycarbonyl amino-(2 in the step 4 with (R)-t-butoxycarbonyl amino-4-p-methoxy-phenyl glycine (preparation described in embodiment 1 step 5), 3-dihydro-benzo [1,4] dioxine-6-yl)-acetate.
HRMS: the quality of actual measurement, 483.1312.The quality of calculating, 483.1309 (M+Na).
L) 2-[(2S, 3S)-2-((R)-2,5-dioxo-4-phenyl-imidazolidine-1-yl)-3-methyl-pentanoyl amino]-thiazole-4-carboxylic acid's methyl esters.
Figure A20058002770800692
Preparation as described in example 7 above, difference is: with (2S, 3S)-2-t-butoxycarbonyl amino-3-methyl-valeric acid replaces the (2S in the step 2,3S)-2-t-butoxycarbonyl amino-3-phenyl-butyric acid, and with (the 2R)-t-butoxycarbonyl amino-(2 in (R)-t-butoxycarbonyl amino-phenylglycocoll replacement step 4,3-dihydro-benzo [1,4] dioxine-6-yl)-acetate.
HRMS: the quality of actual measurement, 453.1205 quality of calculating, 453.1203 (M+Na).
M) 2-((2S, 3S)-2-{ (R)-4-[4-(2-methoxyl group-oxyethyl group)-phenyl]-2,5-dioxo-imidazolidine-1-yl }-3-methyl-pentanoyl amino)-thiazole-4-carboxylic acid's methyl esters.
Figure A20058002770800701
Preparation as described in example 7 above, difference is: with (2S, 3S)-2-t-butoxycarbonyl amino-3-methyl-valeric acid replaces the (2S in the step 2,3S)-2-t-butoxycarbonyl amino-3-phenyl-butyric acid, and with (the 2R)-t-butoxycarbonyl amino-(2 in (R)-t-butoxycarbonyl amino-[4-(2-methoxyl group-oxyethyl group)-phenyl]-acetate (described in embodiment 2c, preparing) replacement step 4,3-dihydro-benzo [1,4] dioxine-6-yl)-acetate.
HRMS: the quality of actual measurement, 505.1758 quality of calculating, 505.1752 (M+H).
N) 2-{ (2S, 3R)-the 3-hydroxyl-2-[(R)-4-(4-methoxyl group-phenyl)-2,5-dioxo-imidazolidine-1-yl]-butyrylamino-thiazole-4-carboxylic acid's methyl esters.
Figure A20058002770800702
Preparation as described in example 7 above, difference is: with (2S, 3R)-3-tert.-butoxy-2-t-butoxycarbonyl amino-butyric acid replaces the (2S in the step 2,3S)-2-t-butoxycarbonyl amino-3-phenyl-butyric acid, and replace (the 2R)-t-butoxycarbonyl amino-(2 in the step 4 with (R)-t-butoxycarbonyl amino-4-p-methoxy-phenyl glycine (preparation described in embodiment 1 step 5), 3-dihydro-benzo [1,4] dioxine-6-yl)-acetate.Before (R)-t-butoxycarbonyl amino-4-p-methoxy-phenyl glycine reactant, be used in 1 in the methylene dichloride: the 1v/v trifluoroacetic acid, in 0 ℃, about 30 minutes, (remove two tertiary butyls in (2S, 3R)-3-tert.-butoxy-2-t-butoxycarbonyl amino-butyrylamino)-thiazole-4-carboxylic acid's methyl esters from 2-.Remove desolvate after, compound dissolution in methylene dichloride, and is washed with saturated sodium bicarbonate and saturated sodium-chloride water solution.With the organic layer dried over sodium sulfate, filter, and concentrate.The crude product that obtains thus be not further purified use down.
HRMS: the quality of actual measurement, 449.1125 quality of calculating, 449.1126 (M+H).
O) 2-((2S, 3R)-3-hydroxyl-2-{ (R)-4-[4-(2-methoxyl group-oxyethyl group)-phenyl]-2,5-dioxo-imidazolidine-1-yl }-butyrylamino)-thiazole-4-carboxylic acid's methyl esters.
Figure A20058002770800711
Preparation as described in example 7 above, difference is: with (2S, 3R)-3-tert.-butoxy-2-t-butoxycarbonyl amino-butyric acid replaces the (2S in the step 2,3S)-2-t-butoxycarbonyl amino-3-phenyl-butyric acid, and with (the 2R)-t-butoxycarbonyl amino-(2 in (R)-t-butoxycarbonyl amino-[4-(2-methoxyl group-oxyethyl group)-phenyl]-acetate (described in embodiment 2c, preparing) replacement step 4,3-dihydro-benzo [1,4] dioxine-6-yl)-acetate.With (R)-t-butoxycarbonyl amino-[4-(2-methoxyl group-oxyethyl group)-phenyl]-acetic acidreaction before, be used in 1 in the methylene dichloride: the 1v/v trifluoroacetic acid, in 0 ℃, about 30 minutes, (remove two tertiary butyls in (2S, 3R)-3-tert.-butoxy-2-t-butoxycarbonyl amino-butyrylamino)-thiazole-4-carboxylic acid's methyl esters from 2-.Remove desolvate after, compound dissolution in methylene dichloride, and is washed with saturated sodium bicarbonate and saturated sodium-chloride water solution.With the organic layer dried over sodium sulfate, filter, and concentrate.The crude product that obtains thus be not further purified use down.
HRMS: the quality of actual measurement, 515.1210 quality of calculating, 515.1207 (M+H).
P) 2-((2S, 3R)-3-tert.-butoxy-2-{ (R)-4-[4-(2-methoxyl group-oxyethyl group)-phenyl]-2,5-dioxo-imidazolidine-1-yl }-butyrylamino)-thiazole-4-carboxylic acid's methyl esters.
Figure A20058002770800712
Preparation as described in example 7 above, difference is: with (2S, 3R)-3-tert.-butoxy-2-t-butoxycarbonyl amino-butyric acid replaces the (2S in the step 2,3S)-2-t-butoxycarbonyl amino-3-phenyl-butyric acid, and with (the 2R)-t-butoxycarbonyl amino-(2 in (R)-t-butoxycarbonyl amino-[4-(2-methoxyl group-oxyethyl group)-phenyl]-acetate (described in embodiment 2c, preparing) replacement step 4,3-dihydro-benzo [1,4] dioxine-6-yl)-acetate.With (R)-t-butoxycarbonyl amino-[4-(2-methoxyl group-oxyethyl group)-phenyl]-acetic acidreaction before, be used in 1 in the methylene dichloride: the 2v/v trifluoroacetic acid, in 0 ℃, about 30 minutes, (remove the t-butyl carbamate base in (2S, 3R)-3-tert.-butoxy-2-t-butoxycarbonyl amino-butyrylamino)-thiazole-4-carboxylic acid's methyl esters from 2-.Saturated sodium bicarbonate aqueous solution and ethyl acetate are added in the reaction soln of quick stirring, react with quencher.After further diluting with ethyl acetate and water, organic layer is separated, and, use dried over sodium sulfate with the saturated sodium-chloride washing, filter, and concentrate.
HRMS: the quality of actual measurement, 549.2015 quality of calculating, 549.2014 (M+H).
Q) 2-{ (2S, 3R)-the 3-methoxyl group-2-[(R)-4-(4-methoxyl group-phenyl)-2,5-dioxo-imidazolidine-1-yl]-butyrylamino-thiazole-4-carboxylic acid's methyl esters.
Figure A20058002770800721
Preparation as described in example 7 above, difference is: with (2S, 3R)-2-t-butoxycarbonyl amino-3-methoxyl group-butyric acid replaces the (2S in the step 2,3S)-2-t-butoxycarbonyl amino-3-phenyl-butyric acid, and replace (the 2R)-t-butoxycarbonyl amino-(2 in the step 4 with (R)-t-butoxycarbonyl amino-4-p-methoxy-phenyl glycine (as preparation as described in embodiment 1 step 5), 3-dihydro-benzo [1,4] dioxine-6-yl)-acetate.
HRMS: the quality of actual measurement, 463.1284 quality of calculating, 463.1282 (M+H).
R) 2-((2S, 3R)-3-methoxyl group-2-{ (R)-4-[4-(2-methoxyl group-oxyethyl group)-phenyl]-2,5-dioxo-imidazolidine-1-yl }-butyrylamino)-thiazole-4-carboxylic acid's methyl esters.
Figure A20058002770800722
Preparation as described in example 7 above, difference is: with (2S, 3R)-2-t-butoxycarbonyl amino-3-methoxyl group-butyric acid replaces the (2S in the step 2,3S)-2-t-butoxycarbonyl amino-3-phenyl-butyric acid, and with (the 2R)-t-butoxycarbonyl amino-(2 in (R)-t-butoxycarbonyl amino-[4-(2-methoxyl group-oxyethyl group)-phenyl]-acetate (described in embodiment 2c, preparing) replacement step 4,3-dihydro-benzo [1,4] dioxine-6-yl)-acetate.
HRMS: the quality of actual measurement, 507.1547 quality of calculating, 507.1544 (M+H).
S) 2-((2S, 3R)-3-benzyloxy-2-{ (R)-4-[4-(2-methoxyl group-oxyethyl group)-phenyl]-2,5-dioxo-imidazolidine-1-yl }-butyrylamino)-thiazole-4-carboxylic acid's methyl esters.
Figure A20058002770800731
Preparation as described in example 7 above, difference is: with (2S, 3R)-3-benzyloxy-2-t-butoxycarbonyl amino-butyric acid replaces the (2S in the step 2,3S)-2-t-butoxycarbonyl amino-3-phenyl-butyric acid, and with (the 2R)-t-butoxycarbonyl amino-(2 in (R)-t-butoxycarbonyl amino-[4-(2-methoxyl group-oxyethyl group)-phenyl]-acetate (described in embodiment 2c, preparing) replacement step 4,3-dihydro-benzo [1,4] dioxine-6-yl)-acetate.
HRMS: the quality of actual measurement, 583.1860 quality of calculating, 583.1857 (M+H).
T) 2-((2S, 3R)-3-(4-chloro-benzyloxy)-2-{ (R)-4-[4-(2-methoxyl group-oxyethyl group)-phenyl]-2,5-dioxo-imidazolidine-1-yl }-butyrylamino)-thiazole-4-carboxylic acid's methyl esters.
Figure A20058002770800732
Preparation as described in example 7 above, difference is: with (2S, 3R)-2-t-butoxycarbonyl amino-3-(4-chloro-benzyloxy)-butyric acid replaces the (2S in the step 2,3S)-2-t-butoxycarbonyl amino-3-phenyl-butyric acid, and with (the 2R)-t-butoxycarbonyl amino-(2 in (R)-t-butoxycarbonyl amino-[4-(2-methoxyl group-oxyethyl group)-phenyl]-acetate (described in embodiment 2c, preparing) replacement step 4,3-dihydro-benzo [1,4] dioxine-6-yl)-acetate.
HRMS: the quality of actual measurement, 617.1465 quality of calculating, 617.1468 (M+H).
U) 2-{ (2S, 3R)-2-[(R)-4-(4-methoxyl group-phenyl)-2,5-dioxo-imidazolidine-1-yl]-3-methyl-pentanoyl amino-thiazole-4-carboxylic acid's methyl esters.
Preparation as described in example 7 above, difference is: with (2S, 3R)-2-t-butoxycarbonyl amino-3-methyl-valeric acid replaces the (2S in the step 2,3S)-2-t-butoxycarbonyl amino-3-phenyl-butyric acid, and replace (the 2R)-t-butoxycarbonyl amino-(2 in the step 4 with (R)-t-butoxycarbonyl amino-4-p-methoxy-phenyl glycine (preparation described in embodiment 1 step 5), 3-dihydro-benzo [1,4] dioxine-6-yl)-acetate.
HRMS: the quality of actual measurement, 461.1490 quality of calculating, 461.1490 (M+H).
V) 2-((2S, 3R)-2-{ (R)-4-[4-(2-methoxyl group-oxyethyl group)-phenyl]-2,5-dioxo-imidazolidine-1-yl }-3-methyl-pentanoyl amino)-thiazole-4-carboxylic acid's methyl esters.
Figure A20058002770800742
Preparation as described in example 7 above, difference is: with (2S, 3R)-2-t-butoxycarbonyl amino-3-methyl-valeric acid replaces the (2S in the step 2,3S)-2-t-butoxycarbonyl amino-3-phenyl-butyric acid, and with (the 2R)-t-butoxycarbonyl amino-(2 in (R)-t-butoxycarbonyl amino-[4-(2-methoxyl group-oxyethyl group)-phenyl]-acetate (described in embodiment 2c, preparing) replacement step 4,3-dihydro-benzo [1,4] dioxine-6-yl)-acetate.
HRMS: the quality of actual measurement, 505.1754 quality of calculating, 505.1752 (M+H).
Embodiment 9
2-{ (2S, 3S)-2-[4-(4-methylsulfonyl-phenyl)-2,5-dioxo-imidazolidine-1-yl]-3-phenyl-butyrylamino }-thiazole-4-carboxylic acid's methyl esters.
Figure A20058002770800751
(1) (2.0g, 13.00mmol) (7mL, the solution in 52.5mmol) is handled with the zinc iodide of catalytic amount, and in stirring at room 18 hours at cyaniding three silicomethanes with 4-sulphomethyl phenyl aldehyde.Decompression removes down and desolvates, and resistates is dissolved in the solution of ammonia in methyl alcohol (9mL) of 7N.With the mixture that obtains at sealed tube in 45 ℃ of heating 2 hours, be cooled to-20 ℃ then.Precipitated solid is collected by filtering, and with the ether washing, dry air is dissolved in the 6N aqueous hydrochloric acid then.With mixture at sealed tube in 110 ℃ of heating 5 hours, cooling then, and decompression concentrates down, obtains solid residue.Solid is ground with ether, dry air, and be suspended in the diox.To suspend, (3.4g 15.6mmol) handles, and stirs and spend the night for usefulness saturated aqueous sodium carbonate (10mL) and tert-Butyl dicarbonate.Mixture is distributed between ethyl acetate and 2N aqueous hydrochloric acid.With the organic layer dried over sodium sulfate, filter, concentrate, and solid residue is ground with hexane, obtain t-butoxycarbonyl amino-(4-methylthio group-phenyl)-acetate, be Huang/brown solid (2.3g, 59%).
(2) with 0 ℃ 2-((2S, 3S)-2-amino-3-phenyl-butyrylamino)-thiazole-4-carboxylic acid's methyl esters (75mg, 0.24mmol) and t-butoxycarbonyl amino-(4-methylthio group-phenyl)-acetate (77mg, 0.26mmol) (50mg 0.26mmol) handles with 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride for solution in methylene dichloride (10mL).To react and be warmed to room temperature at leisure, and stir 60 hours.Then, mixture is distributed between ethyl acetate and water.With the organic layer dried over sodium sulfate, filter, and concentrate.Resistates by silica gel chromatography, is wherein used up to 7: 3 ethyl acetate/hexane gradient elutions and purifying.The material that obtains after the chromatogram is precipitated and further processing by using the dichloromethane solution that contains excessive hexane; obtain 2-{ (2S; 3S)-2-[2-t-butoxycarbonyl amino-2-(4-methylthio group-phenyl)-acetylamino]-3-phenyl-butyrylamino }-thiazole-4-carboxylic acid's methyl esters; be white amorphous solid (115mg, 80%).
(3) in 0 ℃; with 2-{ (2S; 3S)-2-[2-t-butoxycarbonyl amino-2-(4-methylthio group-phenyl)-acetylamino]-3-phenyl-butyrylamino }-(110mg 0.18mmol) is dissolved in 30% the solution of trifluoroacetic acid in methylene dichloride thiazole-4-carboxylic acid's methyl esters.2.5 after hour, reaction mixture is distributed between ethyl acetate and saturated sodium bicarbonate aqueous solution.By adding solid sodium bicarbonate, water layer is adjusted to pH=8, use ethyl acetate extraction then.With the organic layer dried over sodium sulfate that merges, filter, and be concentrated into pale solid.Solid is dissolved in diisopropylethylamine, and (0.16mL 0.92mmol) in the solution in methylene dichloride (5mL), and will obtain solution and be added to 0 ℃ trichloromethylchloroformate in the mode that drips (16 μ L are 0.13mmol) in the mixture in methylene dichloride (5mL).Mixture was stirred 20 minutes, between methylene dichloride and water, distribute then.With the organic layer dried over sodium sulfate, filter, and the simmer down to crude product.Using silica gel chromatography, it is to use up to 3: 2 ethyl acetate/hexane gradient elutions and material post precipitation from the methylene dichloride that contains excessive hexane of obtaining from chromatogram, isolate 2-{ (2S, 3S)-2-[4-(4-methylthio group-phenyl)-2,5-dioxo-imidazolidine-1-yl]-3-phenyl-butyrylamino }-thiazole-4-carboxylic acid's methyl esters, be white amorphous solid (45mg, 46%).
(4) in 0 ℃, with 2-{ (2S, 3S)-2-[4-(4-methylthio group-phenyl)-2,5-dioxo-imidazolidine-1-yl]-3-phenyl-butyrylamino }-thiazole-4-carboxylic acid's methyl esters (RO4919362-000) (40mg, 0.08mmol) (40mg 0.17mmol) handles with 3-chlorine peroxybenzoic acid (75% purity) for solution in 1: 1 mixture of tetrahydrofuran (THF) and methylene dichloride (20mL).After stirring 30 minutes, add other tetrahydrofuran (THF) (6mL), then mixture is warmed to room temperature at leisure, and stirred other 6 hours.Then, reaction mixture is distributed between ethyl acetate and saturated aqueous sodium carbonate.With the organic layer dried over sodium sulfate, filter, concentrate, and resistates separated by silica gel chromatography, wherein use in the methylene dichloride up to 1: 1 ethyl acetate gradient elution.The material that will obtain after chromatogram precipitates from the methylene dichloride that contains excessive hexane; obtain 2-{ (2S, 3S)-2-[4-(4-methylsulfonyl-phenyl)-2,5-dioxo-imidazolidine-1-yl]-3-phenyl-butyrylamino-thiazole-4-carboxylic acid's methyl esters; be white amorphous solid (29mg, 65%).
HRMS: the quality of actual measurement, the quality of calculating, (M+H).
Embodiment 10
2-{ (S)-2-[(R)-4-(4-methoxyl group-phenyl)-2,5-dioxo-imidazolidine-1-yl]-3-methyl-3-phenyl-butyrylamino }-thiazole-4-carboxylic acid's methyl esters.
Figure A20058002770800771
With with similar mode described in the embodiment 1, use according to Nieman J.A.; Coleman, J.E.et al.J.Nat.Prod.2003,66, (S)-N-tertbutyloxycarbonyl-3 of the described method preparation of 183-199,3-3,5-dimethylphenyl L-Ala, preparation 2-{ (S)-2-[(R)-4-(4-methoxyl group-phenyl)-2,5-dioxo-imidazolidine-1-yl]-3-methyl-3-phenyl-butyrylamino }-thiazole-4-carboxylic acid's methyl esters.
HRMS: the quality of actual measurement, 523.1645.The quality of calculating, 523.1646 (M+H).
Embodiment 11
2-{ (2S, 3R)-2-[(R)-4-(2,3-dihydro-benzo [1,4] dioxine-6-yl)-2,5-dioxo-imidazolidine-1-yl]-3-phenyl-butyrylamino }-thiazole-4-carboxylic acid's methyl esters.
Figure A20058002770800772
(1) in-78 ℃, (1.3mL, (1.0g, 6.1mmol), (0.83ml 6.7mmol), obtains white solid then to drip pivalyl chloride 9.1mmol) to be added to (S)-3-phenylbutyric acid in anhydrous tetrahydro furan (60mL) with triethylamine.Reaction was warmed to room temperature 10 minutes, and cooling is got back to-78 ℃ then.In the flask that separates, n-Butyl Lithium (2.5M is in the hexane for 4.6mL, 11.6mmol) is added to-78 ℃ of (S)-(+)-4-phenyl-2-oxazolidones in anhydrous tetrahydro furan, and (2.0g 12.2mmol), and stirs them 10 minutes.Lithiumation De oxazolidone is transferred to by sleeve pipe in-78 ℃ the mixed acid anhydride, and continues to stir 2 hours.To react water (25mL) quencher, and use ethyl acetate extraction.With the extract water that merges, the salt water washing, and use dried over sodium sulfate.Crude product is passed through silica gel chromatography; wherein use 2: 3 ethyl acetate/hexane wash-outs and purifying; and, obtain (S)-4-phenyl-3-((S)-3-phenyl-butyryl radicals)-oxazolidines-2-ketone (1.63g, 88% yield) with the solid recrystallization from ethyl acetate/hexane that obtains.
In-78 ℃, with two (trimethylsilyl) potassium amide (2.0mL, 1.8mmol; 0.91M; in the tetrahydrofuran (THF)) (500mg 1.6mmol), and stirred 1 hour to be added to (S)-4-phenyl-3-((S)-3-phenyl-butyryl radicals)-oxazolidines-2-ketone in anhydrous tetrahydro furan (8mL).In the flask that separates, with-78 ℃ 2,4, (625mg, 2.0mmol) solution in anhydrous tetrahydro furan (10mL) is added to by sleeve pipe in-78 ℃ the negatively charged ion 6-tri isopropyl benzenesulfonyl nitrine, and continues to stir 2 hours.(0.45mL 7.8mmol) is added in-78 ℃ the reaction, and mixture is warmed to room temperature, and stirs and spend the night with acetate.Mixture is toppled over entry (30mL), and use ethyl acetate extraction.With the extract salt water washing that merges, and use dried over sodium sulfate.Crude product by silica gel chromatography, with 2: 1 dichloromethane/hexane purifying, is obtained (S)-3-((2S, 3R)-2-azido--3-phenyl-butyryl radicals)-4-phenyl-oxazolidines-2-ketone (230mg, 41%).
(3) to (S)-3-((2S; 3R)-2-azido--3-phenyl-butyryl radicals)-(595mg 1.7mmol) in the solution in ethyl acetate (25mL), adds tert-Butyl dicarbonate (815mg to 4-phenyl-oxazolidines-2-ketone; 3.7mmol), then add 10% palladium carbon (90mg).Mixture hydrogenation under normal atmosphere and room temperature is spent the night.Mixture is passed through diatomite filtration, and remove and desolvate, obtain [(1S, 2R)-1-((S)-2-oxo-4-phenyl-oxazolidine-3-carbonyl)-2-phenyl-propyl group]-t-butyl carbamate, be oil (710mg, 99%).
(4) to 0 ℃ [(1S, 2R)-1-((S)-2-oxo-4-phenyl-oxazolidines-3-carbonyl)-2-phenyl-propyl group]-t-butyl carbamate (710mg, 1.7mmol) in the solution in tetrahydrofuran (THF) (18mL) and water (4ml), add 30% aqueous hydrogen peroxide solution (1.5mL, 15.1mmol), then add the 1M lithium hydroxide aqueous solution (5.0mL, 5.0mmol).With mixture in stirred overnight at room temperature.With excessive hydrogen peroxide 2.0M aqueous solution of sodium bisulfite (15mL, 30.1mmol) quencher.To stir and continue 1 hour, then use dichloromethane extraction.Water layer with 10% aqueous citric acid solution acidifying, and is used ethyl acetate extraction.With the acetic acid ethyl ester extract water that merges, the salt water washing, and use dried over mgso, and evaporation, obtain (2S, 3R)-2-t-butoxycarbonyl amino-3-phenyl-butyric acid (420mg, 90% yield).
(5) with the similar fashion described in the embodiment 1, by (2S, 3R)-2-t-butoxycarbonyl amino-3-phenyl-butyric acid, preparation 2-{ (2S, 3R)-2-[(R)-4-(2,3-dihydro-benzo [1,4] dioxine-6-yl)-2,5-dioxo-imidazolidine-1-yl]-3-phenyl-butyrylamino }-thiazole-4-carboxylic acid's methyl esters.HRMS: the quality of actual measurement, 537.1439.The quality of calculating, 537.1439 (M+H).
Embodiment 12
2-{ (2S, 3S)-2-[(R)-4-(4-acetylamino-phenyl)-2,5-dioxo-imidazolidine-1-yl]-3-phenyl-butyrylamino }-thiazole-4-carboxylic acid's methyl esters.
Figure A20058002770800791
(1) to amino-(4-amino-phenyl)-acetate dihydrochloride (600mg, 2.51mmol) (described in US3527793, preparing) and triethylamine (1.1mL, 7.53mmol) in 3: 1 mixtures of tetrahydrofuran (THF)/water (60mL), and the adding tert-Butyl dicarbonate (1.4g, 6.27mmol).The reaction mixture stirring is spent the night, between ethyl acetate and 1N aqueous hydrochloric acid, distribute then.With the organic layer dried over sodium sulfate, filter, and concentrate.Resistates is dissolved in a small amount of methylene dichloride, and, obtains (R)-t-butoxycarbonyl amino-(4-t-butoxycarbonyl amino-phenyl)-acetate, be white solid (730mg, 79%) with excessive hexane precipitation.
HRMS: the quality of actual measurement, 389.1681.The quality of calculating, 389.1683 (M+H).
(2) to (R)-t-butoxycarbonyl amino-(4-t-butoxycarbonyl amino-phenyl)-acetate (420mg, 1.13mmol) and (2S, 3S)-2-(2-amino-3-phenyl-butyrylamino)-thiazole-4-carboxylic acid's methyl esters (300mg, 0.94mmol) in (preparation) as described in example 7 above solution in methylene dichloride (50mL), add 1-[3-(dimethylamino) propyl group in 0 ℃]-the 3-ethyl-carbodiimide hydrochloride (220mg, 1.13mmol).Reaction mixture slowly is warmed to envrionment temperature, and stirring is spent the night, and distributes between methylene dichloride and water then.With the organic layer dried over sodium sulfate, filter, and concentrate, obtain crude product.Crude product passes through silica gel chromatography; wherein be used in the ethyl acetate gradient elution between 0 and 60% in the hexane; then from the methylene dichloride that contains excessive hexane, precipitate and purifying; obtain 2-{ (2S; 3S)-2-[(R)-2-t-butoxycarbonyl amino-2-(4-t-butoxycarbonyl amino-phenyl)-acetylamino]-3-phenyl-butyrylamino }-thiazole-4-carboxylic acid's methyl esters; be white solid (520mg, 82%).
HRMS: the quality of actual measurement, 668.2746.The quality of calculating, 668.2749 (M+H).
(3) in 0 ℃; with 2-{ (2S; 3S)-2-[(R)-2-t-butoxycarbonyl amino-2-(4-t-butoxycarbonyl amino-phenyl)-acetylamino]-3-phenyl-butyrylamino }-(510mg 0.76mmol) is dissolved in 30%v/v trifluoroacetic acid in dichloromethane solution (10mL) to thiazole-4-carboxylic acid's methyl esters.Mixture in 0 ℃ of stirring 2.5 hours, is distributed between ethyl acetate and saturated aqueous sodium carbonate then.By adding solid sodium carbonate, water layer is adjusted to pH=9, and collected organic layer, use dried over sodium sulfate, filter, and concentrate.Resistates is dissolved in tetrahydrofuran (THF) (50mL) under not being further purified, and the solution that obtains is cooled to 0 ℃.Drip tert-Butyl dicarbonate (167mg; 0.76mmol) solution in tetrahydrofuran (THF) (5mL); and after stirring is spent the night; with reaction mixture evaporation, and with resistates by silica gel chromatography, wherein be used in 0 in the hexane to 100% ethyl acetate gradient elution and purifying; obtain 2-{ (2S; 3S)-2-[(R)-2-(4-amino-phenyl)-2-t-butoxycarbonyl amino-acetylamino]-3-phenyl-butyrylamino }-thiazole-4-carboxylic acid's methyl esters, be white solid (250mg, 58%).
HRMS: the quality of actual measurement, 568.2223.The quality of calculating, 568.2225 (M+H).
(4) to 2-{ (2S; 3S)-2-[(R)-2-(4-amino-phenyl)-2-t-butoxycarbonyl amino-acetylamino]-3-phenyl-butyrylamino }-thiazole-4-carboxylic acid's methyl esters (100mg; 0.177mmol) in the solution in methylene dichloride (10mL); add triethylamine (50 μ L; 0.354mmol); then add diacetyl oxide (22 μ L, 0.212mmol).Then, with reaction mixture in stirred overnight at room temperature.Solvent removed in vacuo; and resistates is passed through silica gel chromatography; wherein be used in 10% in the hexane to 75% ethyl acetate gradient elution and purifying; obtain 2-{ (2S; 3S)-2-[(R)-2-(4-acetylamino-phenyl)-2-t-butoxycarbonyl amino-acetylamino]-3-phenyl-butyryl radicals-amino }-thiazole-4-carboxylic acid's methyl esters; it is used for next synthesis step (107mg, 98%) immediately.
(5) to 2-{ (2S; 3S)-2-[(R)-2-(4-acetylamino-phenyl)-2-t-butoxycarbonyl amino-acetylamino]-3-phenyl-butyryl radicals-amino }-thiazole-4-carboxylic acid's methyl esters (107mg; 0.175mmol) in the cold soln in methylene dichloride (6mL), add trifluoroacetic acid (4mL).In stirring at room 45 minutes, then vacuum was removed volatile matter with reaction mixture.To resistates, add diethyl ether (10mL), and with the suspension that obtains by centrifugation.Solid is dissolved in the ethyl acetate, and washs with saturated sodium bicarbonate aqueous solution.(2 * 50mL) extract with ethyl acetate with water layer.With the organic layer dried over sodium sulfate that merges; filter, and concentrate, obtain thick 2-{ (2S; 3S)-2-[(R)-2-(4-acetylamino-phenyl)-2-amino-acetylamino]-3-phenyl-butyrylamino }-thiazole-4-carboxylic acid's methyl esters, it is used for next synthesis step immediately.
6) with thick 2-{ (2S; 3S)-2-[(R)-2-(4-acetylamino-phenyl)-2-amino-acetylamino]-3-phenyl-butyrylamino }-thiazole-4-carboxylic acid's methyl esters (≈ 0.175mmol) is dissolved in the methylene dichloride (10mL); and the adding diisopropylethylamine (72 μ L, 0.41mmol).The mixture that obtains is added to trichloromethylchloroformate, and (13 μ L are 0.109mmol) in the ice-cooled solution in methylene dichloride (10mL).Reaction mixture was stirred 15 minutes,, and use the 0.2M aqueous hydrochloric acid with ethyl acetate (100mL) dilution, saturated sodium bicarbonate aqueous solution, the salt water washing, and use dried over sodium sulfate.Solution is filtered, and solvent removed in vacuo.Resistates is passed through silica gel chromatography; wherein be used in 50% in the hexane to 100% ethyl acetate school degree wash-out and purifying; obtain 2-{ (2S; 3S)-2-[(R)-4-(4-acetylamino-phenyl)-2; 5-dioxo-imidazolidine-1-yl]-3-phenyl-butyrylamino }-thiazole-4-carboxylic acid's methyl esters (70mg, 74%).
HRMS: the quality of actual measurement, 536.1599.The quality of calculating, 536.1599 (M+H).
Embodiment 13
N-[4-(1-hydroxyl-1-methyl-ethyl)-thiazol-2-yl]-2-[(R)-and 4-(4-methoxyl group-phenyl)-2,5-dioxo-imidazolidine-1-yl]-3-phenyl-butyramide.
Figure A20058002770800811
(1) with embodiment 4a-4d in about the described similar approach of (4-propionyl-thiazol-2-yl)-t-butyl carbamate, the preparation (4-ethanoyl-thiazol-2-yl)-t-butyl carbamate.
(2) (500mg 2.06mmol) puts into anhydrous tetrahydro furan (8mL), and cools off in ice bath with (4-ethanoyl-thiazol-2-yl)-t-butyl carbamate.To wherein, in 5 minutes, add solution (2.752mL, 8.256mmol) the solution in ether of 3M methyl magnesium bromine in ether.After 30 minutes, add the solution of more 3M methyl magnesium bromine in ether (1mL, 3mmol).After 30 minutes, add the solution of another part 3M methyl magnesium bromine in ether (1mL, 3mmol).After other 30 minutes, observe the reaction mixture group and do not change again.Reaction mixture is diluted with tetrahydrofuran (THF) (5mL), and it is warmed to room temperature.After 2 hours, thin-layer chromatography shows that the composition of reaction mixture does not change.Reaction mixture is cooled off in ice bath, and add saturated aqueous ammonium chloride at leisure.With the mixture dilute with water, use ethyl acetate extraction, and use the salt water washing.With the organic extract dried over sodium sulfate that merges, and concentrate, obtain viscous oil.Crude product is separated by silica gel chromatography, wherein use 1: 19 to 1: 4 ethyl acetate/dichloromethane gradient elution, obtain [4-(1-hydroxyl-1-methyl-ethyl)-thiazol-2-yl]-t-butyl carbamate, be white foam (250mg, 47%).
(3) (250mg 0.92mmol) puts into anhydrous methylene chloride, and cools off in ice bath with [4-(1-hydroxyl-1-methyl-ethyl)-thiazol-2-yl]-t-butyl carbamate.To wherein, add trifluoroacetic acid, and mixture was stirred 4 hours in 0 ℃.Mixture is evaporated, and resistates is distributed between methylene dichloride and saturated sodium bicarbonate aqueous solution.Organic layer is isolated, and with the water layer dichloromethane extraction.With the organic extract dried over sodium sulfate that merges, and evaporation.Resistates is by silica gel chromatography, wherein use 1: 99 to 3: 97 in methylene dichloride the methyl alcohol gradient elution and purifying obtains [4-(1-hydroxyl-1-methyl-ethyl)-thiazol-2-yl]-carboxylamine (56mg, 39%), be white solid.
(4) by [4-(1-hydroxyl-1-methyl-ethyl)-thiazol-2-yl]-carboxylamine and 2-t-butoxycarbonyl amino-3-phenyl-butyric acid, with similar fashion as described in example 1 above, preparation N-[4-(1-hydroxyl-1-methyl-ethyl)-thiazol-2-yl]-2-[(R)-and 4-(4-methoxyl group-phenyl)-2,5-dioxo-imidazolidine-1-yl]-3-phenyl-butyramide.
HRMS: the quality of actual measurement, 509.1853.The quality of calculating, 509.1853 (M+H).
Embodiment 14
(2S, 3S)-2-[(R)-4-(2,3-dihydro-benzo [1,4] dioxine-6-yl)-2,5-dioxo-imidazolidine-1-yl]-N-[4-(1-hydroxyl-propyl group)-thiazol-2-yl]-3-phenyl-butyramide.
Figure A20058002770800821
With (2S; 3S)-N-(4-ethanoyl-thiazol-2-yl)-2-[(R)-4-(2; 3-dihydro-benzo [1; 4] dioxine-6-yl)-2; 5-dioxo-imidazolidine-1-yl]-(20mg 0.037mmol) is dissolved in warm anhydrous methanol (5mL) to 3-phenyl-N-(4-propionyl-thiazol-2-yl)-butyramide (from embodiment 5a).Then reaction mixture is cooled off in ice bath, and the adding sodium borohydride (1.56mg, 0.041mmol).React on 5 ℃ and stirred 30 minutes, (1.56mg 0.041mmol), and continues to stir 1 hour to add other sodium borohydride.Clear solution is handled with the 1.5N potassium hydrogen phosphate aqueous solution (1mL), and with muddy mixture stirred for several minute, (3 * 25mL) extract then with the saturated brine dilution, and with ethyl acetate.The organic extract that merges is washed with saturated brine, use dried over sodium sulfate, and vacuum concentration.Faint yellow resistates is put into a small amount of methylene dichloride (0.5ml), use ether (2mL) to handle then, and this opaque solution is further precipitated with hexane (3mL).Mixture was stirred 5 minutes, filter with the 1.7cm funnel then, use hexane wash, and dry air, (2S obtained, 3S)-2-[(R)-4-(2,3-dihydro-benzo [1,4] dioxine-6-yl)-2,5-dioxo-imidazolidine-1-yl]-N-[4-(1-hydroxyl-propyl group)-thiazol-2-yl]-3-phenyl-butyramide, be white solid (14.5mg, 73%).
HRMS: the quality of actual measurement, 537.1801.The quality of calculating, 537.1803 (M+H).
B) (2S, 3S)-N-[4-(1-hydroxyl-ethyl)-thiazol-2-yl]-2-[(R)-and 4-(4-methoxyl group-phenyl)-2,5-dioxo-imidazolidine-1-yl]-3-phenyl-butyramide.
Figure A20058002770800831
With with the described similar mode of embodiment 14a; by again as preparation (2S as described in the embodiment 1; 3S)-N-(4-ethanoyl-thiazol-2-yl)-2-[(R)-4-(4-methoxyl group-phenyl)-2; 5-dioxo-imidazolidine-1-yl]-3-phenyl-butyramide; preparation (2S; 3S)-N-[4-(1-hydroxyl-ethyl)-thiazol-2-yl]-2-[(R)-and 4-(4-methoxyl group-phenyl)-2,5-dioxo-imidazolidine-1-yl]-3-phenyl-butyramide.
HRMS: the quality of actual measurement.The quality of calculating, (M+H).
Embodiment 15
2-{ (2S, 3S)-2-[(R)-4-(4-methoxyl group-phenyl)-2,5-dioxo-imidazolidine-1-yl]-3-phenyl-butyrylamino }-thiazole-4-carboxylic acid's dimethylformamide.
Figure A20058002770800832
To be similar to the mode described in the embodiment 1, prepare by 2-amino-thiazolyl--4-carboxylic acid dimethylformamide: 2-{ (2S, 3S)-2-[(R)-and 4-(4-methoxyl group-phenyl)-2,5-dioxo-imidazolidine-1-yl]-3-phenyl-butyrylamino }-thiazole-4-carboxylic acid's dimethylformamide.
Be prepared as follows 2-amino-thiazolyl--4-carboxylic acid dimethylformamide.
(1) (0.5g 2mmol) (prepares) vlil (80 ℃) 2 hours in thionyl (two) chlorine (10mL) described in embodiment 4a and 4b with 2-t-butoxycarbonyl amino-thiazole-4-carboxylic acid.Then, the reaction mixture decompression is concentrated down.In resistates, the dimethylamine that adds 2M tetrahydrofuran (THF) (10mL, 20mmol) and the solution in the methyl alcohol (10mL).With reaction mixture in stirring at room 20 hours with concentrate.Resistates by silica gel chromatography, is wherein used 2: 1 ethyl acetate/hexane wash-outs and purifying obtains (4-formyl-dimethylamino-thiazol-2-yl)-t-butyl carbamate, be yellow foam (0.26g, 48%).
(2) to (4-formyl-dimethylamino-thiazol-2-yl)-t-butyl carbamate (0.26g, 0.95mmol) in the solution in methylene dichloride (10mL), add trifluoroacetic acid (10mL, 130mmol).In stirring at room 2 hours, decompression concentrated down then with reaction mixture.Add saturated sodium bicarbonate aqueous solution (50mL), with in and resistates.With mixture ethyl acetate (2 * 100mL).With the organic layer separating and extracting, merge, and use dried over sodium sulfate, decompression concentrates down, and vacuum-drying, obtains thick 2-amino-thiazolyl--4-carboxylic acid dimethylformamide, is yellow glue, and it uses (0.14g, 86%) under not being further purified.
HRMS: the quality of actual measurement, 522.1803.The quality of calculating, 522.1806 (M+H).
Embodiment 16
(2S, 3S)-N-(4-ethylmercapto group-thiazol-2-yl)-2-{ (R)-4-[4-(2-methoxyl group-oxyethyl group)-phenyl]-2,5-dioxo-imidazolidine-1-yl }-3-phenyl-butyramide.
Figure A20058002770800841
As preparation as described in the embodiment 1, difference is: replace 1-(2-amino-thiazolyl--4-yl)-ethyl ketone and (R)-t-butoxycarbonyl amino-[4-(2-methoxyl group-oxyethyl group)-phenyl]-acetate (preparing described in embodiment 2c) to replace (R)-t-butoxycarbonyl amino-4-p-methoxy-phenyl glycine with 4-ethylmercapto group-thiazole-2-amine.Be prepared as follows 4-ethylmercapto group-thiazole-2-amine:
(1) N-tertbutyloxycarbonyl-thiocarbamide (0.600g, 3.40 moles) is suspended in the ethanol (5mL), and mixture is cooled off in ice-water-bath.In this mixture, adding bromo-thioacetic acid S-ethyl ester (0.880g[75% is pure]; 3.61 the solution in ethanol (5mL) mole).After adding is finished, mixture is warmed to room temperature, and stirs and spend the night.After 20 hours, will react concentrated.Resistates is distributed between methylene dichloride and water.With organic phase water and salt water washing.Then water is used the methylene dichloride backwash.Two kinds of waters are merged, with dried over sodium sulfate and concentrated.Roughage by silica gel chromatography, wherein is used in the 20%v/v eluent ethyl acetate in the hexane and purifying obtains (4-ethylmercapto group-thiazole-2 base)-t-butyl carbamate (0.514g, 58%).
(2) (4-ethylmercapto group-thiazole-2 base)-t-butyl carbamate (0.583g, 2.24 moles) is dissolved in the methylene dichloride (9mL), and will obtains solution and in ice-water-bath, cool off.(5mL) is added dropwise in this solution with trifluoroacetic acid.Solution was stirred 3 hours under argon gas atmosphere, cooling bath is warm at leisure.When reaction finished, bathing temperature was 12 ℃.To react and concentrate.Resistates is dissolved in methylene dichloride again, and concentrates.It is repeated other twice, to remove most of trifluoroacetic acids.After last concentrating, resistates is dissolved in methylene dichloride again, and uses saturated sodium bicarbonate, water and salt water washing.With the organic phase dried over sodium sulfate, and concentrate, obtain 4-ethylmercapto group-thiazole-2-amine (0.256g, 65%).
RMS: the quality of actual measurement, 555.1731.The quality of calculating, 555.1731 (M+H).
Embodiment 17
(2S, 3S)-N-(4-second sulfinyl-thiazol-2-yl)-2-{ (R)-4-[4-(2-methoxyl group-oxyethyl group)-phenyl]-2,5-dioxo-imidazolidine-1-yl }-3-phenyl-butyramide.
Figure A20058002770800851
With (2S, 3S)-and N-(4-ethylmercapto group-thiazol-2-yl)-2-{ (R)-4-[4-(2-methoxyl group-oxyethyl group)-phenyl]-2,5-dioxo-imidazolidine-1-yl }-3-phenyl-butyramide (0.135g, 0.24 mole) (preparation) as described in example 16 above is dissolved in the anhydrous tetrahydro furan (15mL).In this solution, between adding-solution of chloro-benzoic acid (0.066g, 0.27 mole) in tetrahydrofuran (THF) (8mL).After 30 minutes, will react concentrated in stirring at room.Resistates is dissolved in the cold methylene dichloride, and uses the saturated sodium bicarbonate washed twice, use the salt solution washed twice.With every kind of water with second part of methylene dichloride backwash.Two kinds of organic phases are merged, with dried over sodium sulfate and concentrated.Roughage passes through silica gel chromatography; wherein be used in the 50-100%v/v ethyl acetate in the hexane; be used in 5%v/v methyl alcohol gradient elution in the ethyl acetate then and purifying; obtain (2S; 3S)-and N-(4-second sulfinyl-thiazol-2-yl)-2-{ (R)-4-[4-(2-methoxyl group-oxyethyl group)-phenyl]-2; 5-dioxo-imidazolidine-1-yl }-3-phenyl-butyramide (0.103g, 75%).This material and another batch of material are merged; be dissolved in the methylene dichloride; and be added in the hexane; with precipitated product; (2S; 3S)-and N-(4-second sulfinyl-thiazol-2-yl)-2-{ (R)-4-[4-(2-methoxyl group-oxyethyl group)-phenyl]-2,5-dioxo-imidazolidine-1-yl }-3-phenyl-butyramide (0.117g).
HRMS: the quality of actual measurement, 571.1682.The quality of calculating, 571.1680 (M+H).
Embodiment 18
(2S, 3S)-N-(4-ethylsulfonyl-thiazol-2-yl)-2-{ (R)-4-[4-(2-methoxyl group-oxyethyl group)-phenyl]-2,5-dioxo-imidazolidine-1-yl }-3-phenyl-butyramide.
Figure A20058002770800861
With (2S, 3S)-and N-(4-ethylmercapto group-thiazol-2-yl)-2-{ (R)-4-[4-(2-methoxyl group-oxyethyl group)-phenyl]-2,5-dioxo-imidazolidine-1-yl }-3-phenyl-butyramide (0.128g, 0.23 mole) (preparation) as described in example 16 above is dissolved in anhydrous tetrahydro furan (15mL).In this solution, between adding-solution of chloroperoxybenzoic acid (0.133g, 0.46 mole) in tetrahydrofuran (THF) (8mL).After 18 minutes, will react concentrated in stirring at room.Resistates is dissolved in the cold methylene dichloride, and uses the saturated sodium bicarbonate washed twice, use the salt solution washed twice.With every kind of water with second part of methylene dichloride backwash.Two kinds of organic phases are merged, with dried over sodium sulfate and concentrated.Roughage wherein is used in the 50-100%v/v ethyl acetate in the hexane by silica gel chromatography, is used in 5%v/v methyl alcohol gradient elution in the ethyl acetate then and purifying.Pure fraction is merged, and concentrate.Resistates is dissolved in the methylene dichloride; and will obtain solution is added in the hexane; to be settled out product; (2S; 3S)-and N-(4-ethylsulfonyl-thiazol-2-yl)-2-{ (R)-4-[4-(2-methoxyl group-oxyethyl group)-phenyl]-2; 5-dioxo-imidazolidine-1-yl }-3-phenyl-butyramide (0.095g, 68%).
HRMS: the quality of actual measurement, 587.1631.The quality of calculating, 587.1629 (M+H).
Embodiment 19
(2S, 3S)-N-[4-(2-hydroxyl-ethanoyl)-thiazol-2-yl]-2-{ (R)-4-[4-(2-methoxyl group-oxyethyl group)-phenyl]-2,5-dioxo-imidazolidine-1-yl }-3-phenyl-butyramide.
Prepare described in embodiment 2c, difference is: replace 1-(2-amino-thiazolyl--4-yl)-ethyl ketone with 1-(2-amino-thiazolyl--4-yl)-2-hydroxyl-ethyl ketone.Preparation 1-as described below (2-amino-thiazolyl--4-yl)-2-hydroxyl-ethyl ketone.
(1) (4g 19.38mmol) puts into methyl alcohol (50mL), and (0.94g 0.25mmol) handled 1 hour in 85 ℃ with tosic acid with thiazolamine-4-phenylglyoxylic acid ethyl ester.To wherein, (3.1g 0.75mmol), and continues to stir 24 hours to add tosic acid.With 500mg criticize add tosic acid (24 and 48h after, add again twice), stirred 72 hours in 85 ℃ then, during this period, NMR indication＞50% is converted into needed product.Reaction mixture is concentrated into～10mL, uses ethyl acetate (200mL) dilution then, and with saturated sodium bicarbonate aqueous solution (～100mL is each) washing three times, with saturated brine (100mL) washing.Water layer is stripped three times with ethyl acetate (100mL is each).With the organic layer dried over sodium sulfate that merges, filter, and concentrate, obtain yellow residue, it is attracted on the silica gel, and by the silica gel column chromatography of methyl alcohol inactivation, be used in 40 in the hexane to the 70%v/v ethyl acetate with 10% step, use 100% ethyl acetate gradient elution then and purifying.The cut that will contain product merges, and vacuum concentration, obtains (2-amino-thiazolyl--4-yl)-dimethoxy-methyl acetate (1.73g, 39%).
(2) (850mg, 3.66mmol) (73mg 1.83mmol) in 5 minutes, handles by part in room temperature the solution in anhydrous tetrahydro furan (40mL) with lithium aluminum hydride with (2-amino-thiazolyl--4-yl)-dimethoxy-methyl acetate.Mixture was stirred 30 minutes, use lithium aluminum hydride (36mg 0.91mmol) by a part processing then, and stirred 4 hours.After storage was spent the night in refrigerator, (～10g) processing, water (20mL) diluted then with trash ice with reaction mixture.(～0.5mL) acidifying, vacuum concentration then is to remove tetrahydrofuran (THF) with the 2N aqueous sulfuric acid with mixture.Aqueous mixture is neutralized to pH 7 with saturated sodium bicarbonate aqueous solution, and (8 * 50mL) extract with ethyl acetate.With organic solution salt water washing, and use dried over sodium sulfate, filter, and concentrate, obtain viscous foam (650mg).Resistates is by the silica gel column chromatography of methyl alcohol inactivation, be used in methyl alcohol between 0 in the methylene dichloride and 6% with 1% step gradient elution purifying.From post in 4 to 6% methyl alcohol of the product of wash-out in methylene dichloride.After concentrating, obtain 1-(2-amino-thiazolyl--4-yl)-2-hydroxyl-ethyl ketone, be yellow foam (210mg, 28%).
HRMS: the quality of actual measurement, 553.1752.The quality of calculating, 553.1752 (M+H).
Embodiment 20
(4-{ (R)-1-[(1S, 2S)-1-(4-ethanoyl-thiazol-2-yl formamyl)-2-phenyl-propyl group]-2,5-dioxo-imidazolidine-4-yl }-phenoxy group)-methyl acetate.
Figure A20058002770800881
Preparation as described in example 1 above, difference is: replace (R)-t-butoxycarbonyl amino-4-p-methoxy-phenyl glycine with (R)-t-butoxycarbonyl amino-(4-methoxycarbonyl methoxyl group-phenyl)-acetate.Similar approach preparation (R)-t-butoxycarbonyl amino-(4-methoxycarbonyl methoxyl group-phenyl)-acetate as described in example 1 above, difference is: replace methyl-iodide with methyl bromoacetate.
HRMS: the quality of actual measurement, 551.1597.The quality of calculating, 551.1595 (M+H).
Embodiment 21
(4-{ (R)-2,5-dioxo-1-[(1S, 2S)-2-phenyl-1-(4-propionyl-thiazol-2-yl formamyl)-propyl group]-imidazolidine-4-yl }-phenoxy group)-methyl acetate.
Figure A20058002770800891
Preparation as described in example 4 above, difference is: replace (R)-t-butoxycarbonyl amino-4-p-methoxy-phenyl glycine with (R)-t-butoxycarbonyl amino-(4-methoxycarbonyl methoxyl group-phenyl)-acetate.Prepare (R)-t-butoxycarbonyl amino-(4-methoxycarbonyl methoxyl group-phenyl)-acetate as described in example 20 above.
HRMS: the quality of actual measurement, 565.1754.The quality of calculating, 565.1752 (M+H).
Embodiment 22
(4-{2,5-dioxo-1-[(1S, 2S)-2-phenyl-1-(4-propionyl-thiazol-2-yl formamyl)-propyl group]-imidazolidine-4-yl }-phenoxy group)-acetate.
Figure A20058002770800892
By (4-{ (R)-2; 5-dioxo-1-[(1S, 2S)-2-phenyl-1-(4-propionyl-thiazol-2-yl formamyl)-propyl group]-imidazolidine-4-yl }-phenoxy group)-methyl acetate (preparation) as described in example 21 above is with lithium hydroxide monohydrate hydrolysis and preparing in tetrahydrofuran aqueous solution.Under the condition that is used for the methyl esters hydrolysis, on the 4-position of imidazolidimedione ring racemization takes place.
HRMS: the quality of actual measurement, 551.1598.The quality of calculating, 551.1595 (M+H).
Embodiment 23
(2S, 3S)-N-(4-ethanoyl-thiazol-2-yl)-2-[(R)-4-(4-formyl-dimethylamino methoxyl group-phenyl)-2,5-dioxo-imidazolidine-1-yl]-3-phenyl-butyramide.
Figure A20058002770800901
Preparation as described in example 1 above, difference is: replace (R)-t-butoxycarbonyl amino-4-p-methoxy-phenyl glycine with (R)-t-butoxycarbonyl amino-(4-formyl-dimethylamino methoxyl group-phenyl)-acetate.Similar fashion preparation (R)-t-butoxycarbonyl amino-(4-formyl-dimethylamino methoxyl group-phenyl)-acetate as described in example 1 above, difference is: with known compound 2-chloro-N, N-dimethyl-ethanamide replaces methyl-iodide.
HRMS: the quality of actual measurement, 564.1912.The quality of calculating, 564.1912 (M+H).
Embodiment 24
Similar fashion as described in example 23 above, the preparation following compounds.
A) (2S, 3S)-N-(4-ethanoyl-thiazol-2-yl)-2-[(R)-4-(4-methylamino formyl radical methoxyl group-phenyl)-2,5-dioxo-imidazolidine-1-yl]-3-phenyl-butyramide.
Figure A20058002770800902
As preparing for the described similar fashion of (R)-t-butoxycarbonyl amino-(4-formyl-dimethylamino methoxyl group-phenyl)-acetate and using: (R)-t-butoxycarbonyl amino-(4-methylamino formyl radical methoxyl group-phenyl)-acetate.
HRMS: the quality of actual measurement, 550.1757.The quality of calculating, 550.1755 (M+H).
B) (2S, 3S)-N-(4-ethanoyl-thiazol-2-yl)-2-[(R)-4-(4-carbamyl ylmethoxy-phenyl)-2,5-dioxo-imidazolidine-1-yl]-3-phenyl-butyramide.
As preparing for the described similar fashion of (R)-t-butoxycarbonyl amino-(4-formyl-dimethylamino methoxyl group-phenyl)-acetate and using: (R)-t-butoxycarbonyl amino-(4-carbamyl ylmethoxy-phenyl)-acetate.
HRMS: the quality of actual measurement, 532.1628.The quality of calculating, 532.1625 (M+H).
C) (2S, 3S)-N-(4-ethanoyl-thiazol-2-yl)-2-((R)-4-{4-[(2-methoxyl group-ethylamino formyl radical)-methoxyl group]-phenyl }-2,5-dioxo-imidazolidine-1-yl)-3-phenyl-butyramide.
As preparing for the described similar fashion of (R)-t-butoxycarbonyl amino-(4-formyl-dimethylamino methoxyl group-phenyl)-acetate and using: (R)-t-butoxycarbonyl amino-4-[(2-methoxyl group-ethylamino formyl radical)-methoxyl group]-phenyl }-acetate.
HRMS: the quality of actual measurement, 594.2014.The quality of calculating, 594.2017 (M+H).
D) (2S, 3S)-N-(4-ethanoyl-thiazol-2-yl)-2-{ (R)-4-[4-(2-morpholine-4-base-2-oxo-oxyethyl group)-phenyl]-2,5-dioxo-imidazolidine-1-yl }-3-phenyl-butyramide.
Figure A20058002770800913
As preparing for the described similar fashion of (R)-t-butoxycarbonyl amino-(4-formyl-dimethylamino methoxyl group-phenyl)-acetate and using: (R)-t-butoxycarbonyl amino-[4-(2-morpholine-4-base-2-oxo-oxyethyl group)-phenyl]-acetate.
HRMS: the quality of actual measurement, 606.2009.The quality of calculating, 606.2017 (M+H).
E) (2S, 3S)-N-(4-ethanoyl-thiazol-2-yl)-2-{ (R)-2,5-dioxo-4-[4-(2-oxo-2-tetramethyleneimine-1-base-oxyethyl group)-phenyl]-imidazolidine-1-yl }-3-phenyl-butyramide.
Figure A20058002770800921
As preparing for the described similar fashion of (R)-t-butoxycarbonyl amino-(4-formyl-dimethylamino methoxyl group-phenyl)-acetate and using: (R)-t-butoxycarbonyl amino-[4-(2-oxo-2-tetramethyleneimine-1-base-oxyethyl group)-phenyl]-acetate.
HRMS: the HRMS of actual measurement: the quality of actual measurement, 590.2063.The quality of calculating, 590.2068 (M+H).
Embodiment 25
(2S, 3S)-2-[(R)-4-(4-formyl-dimethylamino methoxyl group-phenyl)-2,5-dioxo-imidazolidine-1-yl]-3-phenyl-N-(4-propionyl-thiazol-2-yl)-butyramide.
Figure A20058002770800922
Preparation as described in example 4 above, difference is: replace (R)-t-butoxycarbonyl amino-4-p-methoxy-phenyl glycine with (R)-t-butoxycarbonyl amino-(4-formyl-dimethylamino methoxyl group-phenyl)-acetate.Prepare (R)-t-butoxycarbonyl amino-(4-formyl-dimethylamino methoxyl group-phenyl)-acetate as described in example 23 above.
HRMS: the quality of actual measurement, 578.2066.The quality of calculating, 578.2068 (M+H).
Embodiment 26
As embodiment 25 described similar fashion preparations, preparation following compounds.
A) (2S, 3S)-2-[(R)-4-(4-methylamino formyl radical methoxyl group-phenyl)-2,5-dioxo-imidazolidine-1-yl]-3-phenyl-N-(4-propionyl-thiazol-2-yl)-butyramide.
Figure A20058002770800931
As preparation as described in the embodiment 24a: (R)-t-butoxycarbonyl amino-(4-methylamino formyl radical methoxyl group-phenyl)-acetate.
HRMS: the quality of actual measurement, 5641915.The quality of calculating, 564.1912 (M+H).
B) (2S, 3S)-2-[(R)-4-(4-carbamyl ylmethoxy-phenyl)-2,5-dioxo-imidazolidine-1-yl]-3-phenyl-N-(4-propionyl-thiazol-2-yl)-butyramide.
Figure A20058002770800932
As preparation as described in the embodiment 24b: (R)-t-butoxycarbonyl amino-(4-carbamyl ylmethoxy-phenyl)-acetate.
HRMS: the quality of actual measurement, 550.1755.The quality of calculating, 550.1755 (M+H).
C) (2S, 3S)-2-((R)-4-{4-[(2-methoxyl group-ethylamino formyl radical)-methoxyl group]-phenyl }-2,5-dioxo-imidazolidine-1-yl)-3-phenyl-N-(4-propionyl-thiazol-2-yl)-butyramide.
Figure A20058002770800933
As preparation as described in the embodiment 24c: (R)-t-butoxycarbonyl amino-4-[(2-methoxyl group-ethylamino formyl radical)-methoxyl group]-phenyl }-acetate.
HRMS: the quality of actual measurement, 608.2169.The quality of calculating, 608.2174 (M+H).
D) (2S, 3S)-2-{ (R)-4-[4-(2-morpholine-4-base-2-oxo-oxyethyl group)-phenyl]-2,5-dioxo-imidazolidine-1-yl }-3-phenyl-N-(4-propionyl-thiazol-2-yl)-butyramide.
Figure A20058002770800941
As preparation as described in the embodiment 24d: (R)-t-butoxycarbonyl amino-[4-(2-morpholine-4-base-2-oxo-oxyethyl group)-phenyl]-acetate.
HRMS: the quality of actual measurement, 620.2166.The quality of calculating, 620.2174 (M+H).
E) (2S, 3S)-2-{ (R)-2,5-dioxo-4-[4-(2-oxo-2-tetramethyleneimine-1-base-oxyethyl group)-phenyl]-imidazolidine-1-yl }-3-phenyl-N-(4-propionyl-thiazol-2-yl)-butyramide.
Figure A20058002770800942
As preparation as described in the embodiment 24e: (R)-t-butoxycarbonyl amino-[4-(2-oxo-2-tetramethyleneimine-1-base-oxyethyl group)-phenyl]-acetate.
HRMS: the quality of actual measurement, 604.2222.The quality of calculating, 604.2225 (M+H).
F) (2S, 3S)-2-{ (R)-4-[4-(2-azetidine-1-base-2-oxo-oxyethyl group)-phenyl]-2,5-dioxo-imidazolidine-1-yl }-3-phenyl-N-(4-propionyl-thiazol-2-yl)-butyramide.
Figure A20058002770800943
As preparing for the described similar fashion of (R)-t-butoxycarbonyl amino-(4-formyl-dimethylamino methoxyl group-phenyl)-acetate (preparation as described in example 23 above) and using: (R)-[4-(2-azetidine-1-base-2-oxo-oxyethyl group)-phenyl]-t-butoxycarbonyl amino-acetate.
HRMS: the quality of actual measurement, 612.1890.The quality of calculating, 612.1887 (M+Na)
Embodiment 27
(2S, 3S)-N-(4-cyclopropane carbonyl-thiazol-2-yl)-2-[(R)-4-(4-methylamino formyl radical methoxyl group-phenyl)-2,5-dioxo-imidazolidine-1-yl]-3-phenyl-butyramide.
Figure A20058002770800951
Prepare described in embodiment 5x, difference is: replace (R)-t-butoxycarbonyl amino-4-p-methoxy-phenyl glycine with (R)-t-butoxycarbonyl amino-(4-methylamino formyl radical methoxyl group-phenyl)-acetate (preparing described in embodiment 24a).
HRMS: the quality of actual measurement, 576.1910.The quality of calculating, 576.1912 (M+H).
Compound I C in the MEK cascade is analyzed 50Mensuration
In the FP based on bead that is called the IMAP analysis that uses MEK cascade component analyzes, carry out the assessment of compound as mek inhibitor.In brief, containing 10mM HEPES, pH7.0,10mM MgCl 2, 50mM NaCl, 0.1mM NaVO 4In the reaction soln of 1m M DTT, at 50uM ATP, 0.45nM c-RAF, 11.25nM MEK, 90.5nM the ERK of ERK and 0.5 μ MFITC-mark (under the existence of FITC-Aca-Ala-Ala-Ala-Thr-Gly-Pro-Leu-Ser-Pro-Gly-Pro-Phe-Ala-NH2), analyzes.With C-RAF, MEK, ERK and ERK peptide substrates join in the reaction buffer in succession.Activatory c-Raf phosphorylation MEK, activatory MEK phosphorylation ERK, and subsequently, its peptide substrates of activatory ERK phosphorylation.The peptide substrates of FITC-mark, by tyrosine phosphorylation the time, being attached to derive by metal-phosphorus ligand interaction has on the nanoparticle of trivalent metal cation.The result of the phosphorylation product of this combined with fluorescent is the enhancing by the polarization signal that causes in conjunction with the reduction of product molecular migration.With the compound of 10 point (ten-point) serial dilutions with join before ERK and ERK peptide substrates mix during the MEK cascade analyzes.To react on 37 ℃ of incubations, MEK activation 20 minutes, ERK activation 20 minutes, ERK peptide substrates phosphorylation 30 minutes is incubated overnight in room temperature then, with in conjunction with the IMAP bead.Carrying out IMAP in 384-orifice plate form analyzes.By the LJL instrument, excite and 530 emissions the change of measuring fluorescence polarization in 485nm.Polarization value (MP) is calculated as follows:
(MP)=1000 * (intensity Vertically-intensity Level)/(intensity Vertically+ intensity Level).
Use Excel guide XLfit3 to obtain IC 50Value.By with they the MP value with do not have those values (being 100% activity) of compound to compare, calculate the active and per-cent inhibition of per-cent of reaction in the presence of compound.
In above-mentioned analysis, formula I compound exhibits goes out IC 50Value be lower than 25 micromoles.

Claims (24)

1. the compound of formula I,
Figure A2005800277080002C1
Wherein:
R 1Be selected from: replace or unsubstituted aryl or replacement or unsubstituted heteroaryl;
R 2Be hydrogen
R 3Be alkyl;
R 4Be selected from: replace or unsubstituted aryl hydroxyl, alkoxyl group, the alkoxyl group of replacement or replacement or unsubstituted heteroaryl or alkyl;
R 5Be selected from: COOR, COR, CON (R 7) 2, CHOHR or S (O) nR, wherein n is 0-2, and wherein R is the alkyl that alkyl or alkoxy replace; And
R 6And R 7Be selected from: hydrogen or alkyl,
The form of described compound randomly is their racemoid, their enantiomer, and their diastereomer or its mixture,
Or its medicinal salt or ester or prodrug.
2. the compound of claim 1, wherein R 1For phenyl or be substituted the phenyl that base replaces, described substituting group is selected from: hydroxyl; Alkoxyl group; The alkoxyl group that replaces;-P (O) (O-alkyl) 2-NH-alkyl;-N (alkyl) 2The heterocyclic radical that is replaced by-OH (preferred piperidyl, morpholino or pyrrolidyl) randomly;-S (O) 2-alkyl;-NHC (O)-alkyl;-O-alkyl, this alkyl randomly are substituted base and replace once or twice, and described substituting group is selected from: NH 2The NH-alkyl, this alkyl is chosen usefulness-O-methyl substituted wantonly; N (alkyl) 2Hydroxyl; Heterocyclic radical (preferred piperidyl, morpholino or pyrrolidyl);-O-alkyl;-COOH; Oxo;-C (O)-heterocyclic radical (preferred piperidyl, morpholino or pyrrolidyl);-C (O)-N (alkyl) 2-C (O)-NH-alkyl, this alkyl is chosen usefulness-O-methyl substituted wantonly; Or-C (O)-NH 2
3. the compound of claim 1, wherein R 1Be 2,3-dihydro-benzo [1,4] dioxine-6-base.
4. the compound of any one, wherein R in the claim 1 to 3 3Be methyl.
5. the compound of any one, wherein R in the claim 1 to 4 4For replacing or unsubstituted aryl.
6. the compound of any one, wherein R in the claim 1 to 5 5For COR and R are methyl or ethyl.
7. the compound of any one, wherein R in the claim 1 to 5 5Be cyclopropyl.
8. the compound of any one, wherein R in the claim 1 to 7 6Be hydrogen.
9. the compound of formula II:
Figure A2005800277080003C1
Wherein:
R 8Be hydrogen; Alkyl; Cycloalkyl;-O-alkyl; NH alkyl or N (alkyl) 2
R 9Be alkyl and preferable methyl;
R 10Be hydrogen; Alkyl; The alkyl or the halogen that replace, and preferred hydrogen or halogen are preferably selected from: fluorine and chlorine;
R 11Be selected from: hydroxyl; Alkoxyl group; The alkoxyl group that replaces;-P (O) (O-alkyl) 2-NH-alkyl;-N (alkyl) 2The heterocyclic radical that is replaced by-OH (preferred piperidyl, morpholino or pyrrolidyl) randomly;-S (O) 2-alkyl;-NHC (O)-alkyl;-O-alkyl, the optional base that is substituted of this alkyl replaces once or twice, and described substituting group is selected from: NH 2The NH-alkyl, this alkyl is chosen quilt-O-methyl substituted wantonly; N (alkyl) 2Hydroxyl; Heterocyclic radical (preferred piperidyl, morpholino or pyrrolidyl);-O-alkyl;-COOH; Oxo;-C (O)-heterocyclic radical (preferred piperidyl, morpholino or pyrrolidyl);-C (O)-N (alkyl) 2-C (O)-NH-alkyl, this alkyl is chosen quilt-O-methyl substituted wantonly; Or-C (O)-NH 2
The form of described compound randomly is their racemoid, their enantiomer, and their diastereomer or its mixture,
Or its medicinal salt or ester or prodrug.
10. compound, it is selected from:
(2S, 3S)-N-(4-ethanoyl-thiazol-2-yl)-2-[(R)-4-(4-methoxyl group-phenyl)-2,5-dioxo-imidazolidine-1-yl]-3-phenyl-butyramide;
(2S, 3S)-N-(4-ethanoyl-thiazol-2-yl)-2-[(R)-4-(4-hydroxyl-phenyl)-2,5-dioxo-imidazolidine-1-yl]-3-phenyl-butyramide;
(2S, 3S)-N-(4-ethanoyl-thiazol-2-yl)-2-{ (R)-4-[4-(2-hydroxyl-oxyethyl group)-phenyl]-2,5-dioxo-imidazolidine-1-yl }-3-phenyl-butyramide;
(2S, 3S)-N-(4-ethanoyl-thiazol-2-yl)-2-{ (R)-4-[4-(2-methoxyl group-oxyethyl group)-phenyl]-2,5-dioxo-imidazolidine-1-yl }-3-phenyl-butyramide;
(2S, 3S)-N-(4-ethanoyl-thiazol-2-yl)-2-((R)-4-{4-[2-(2-methoxyl group-oxyethyl group)-oxyethyl group]-phenyl }-2,5-dioxo-imidazolidine-1-yl)-3-phenyl-butyramide;
(2S, 3S)-N-(4-ethanoyl-thiazol-2-yl)-2-{ (R)-4-[4-(2-oxyethyl group-oxyethyl group)-phenyl]-2,5-dioxo-imidazolidine-1-yl }-3-phenyl-butyramide;
(2S, 3S)-N-(4-ethanoyl-thiazol-2-yl)-2-{ (R)-4-[4-(2-dimethylamino-oxyethyl group)-phenyl]-2,5-dioxo-imidazolidine-1-yl }-3-phenyl-butyramide; Compound with trifluoroacetic acid
(2S, 3S)-N-(4-ethanoyl-thiazol-2-yl)-2-{ (R)-4-[4-(2-diethylamino-oxyethyl group)-phenyl]-2,5-dioxo-imidazolidine-1-yl }-3-phenyl-butyramide; Compound with trifluoroacetic acid
(2S, 3S)-N-(4-ethanoyl-thiazol-2-yl)-2-[(R)-4-(4-oxyethyl group-phenyl)-2,5-dioxo-imidazolidine-1-yl]-3-phenyl-butyramide;
(2S, 3S)-N-(4-ethanoyl-thiazol-2-yl)-2-{ (S)-4-[4-(2-dimethylamino-oxyethyl group)-phenyl]-2,5-dioxo-imidazolidine-1-yl }-3-phenyl-butyramide; Compound with trifluoroacetic acid
(4-{1-[(1S, 2S)-1-(4-ethanoyl-thiazol-2-yl formamyl)-2-phenyl-propyl group]-2,5-dioxo-imidazolidine-4-yl }-phenyl)-diethyl phosphonate;
(2S, 3S)-N-(4-ethanoyl-thiazol-2-yl)-2-[4-(4-dimethylamino-phenyl)-2,5-dioxo-imidazolidine-1-yl]-3-phenyl-butyramide;
(2S, 3S)-2-[(R)-4-(4-methoxyl group-phenyl)-2,5-dioxo-imidazolidine-1-yl]-3-phenyl-pentanoic acid (4-ethanoyl-thiazol-2-yl)-acid amides;
(2S, 3S)-2-[(R)-4-(4-methoxyl group-phenyl)-2,5-dioxo-imidazolidine-1-yl]-3-phenyl-N-(4-propionyl-thiazol-2-yl)-butyramide;
(2S, 3S)-2-[(R)-4-(2,3-dihydro-benzo [1,4] dioxine-6-yl)-2,5-dioxo-imidazolidine-1-yl]-3-phenyl-N-(4-propionyl-thiazol-2-yl)-butyramide;
(2S, 3S)-2-[(R)-4-(4-oxyethyl group-phenyl)-2,5-dioxo-imidazolidine-1-yl]-3-phenyl-N-(4-propionyl-thiazol-2-yl)-butyramide;
(2S, 3S)-2-[(R)-4-(4-hydroxyl-phenyl)-2,5-dioxo-imidazolidine-1-yl]-3-phenyl-N-(4-propionyl-thiazol-2-yl)-butyramide;
(2S, 3S)-2-{ (R)-4-[4-(2-methoxyl group-oxyethyl group)-phenyl]-2,5-dioxo-imidazolidine-1-yl }-3-phenyl-N-(4-propionyl-thiazol-2-yl)-butyramide;
(2S, 3S)-2-{ (S)-4-[4-(2-methoxyl group-oxyethyl group)-phenyl]-2,5-dioxo-imidazolidine-1-yl }-3-phenyl-N-(4-propionyl-thiazol-2-yl)-butyramide;
(2S, 3S)-2-{ (R)-4-[4-(2-hydroxyl-oxyethyl group)-phenyl]-2,5-dioxo-imidazolidine-1-yl }-3-phenyl-N-(4-propionyl-thiazol-2-yl)-butyramide;
(2S, 3S)-2-((R)-4-{4-[2-(2-methoxyl group-oxyethyl group)-oxyethyl group]-phenyl }-2,5-dioxo-imidazolidine-1-yl)-3-phenyl-N-(4-propionyl-thiazol-2-yl)-butyramide; With
(2S, 3S)-2-{ (R)-4-[4-(2-oxyethyl group-oxyethyl group)-phenyl]-2,5-dioxo-imidazolidine-1-yl }-3-phenyl-N-(4-propionyl-thiazol-2-yl)-butyramide.
11. a compound, it is selected from:
(2S, 3S)-2-{ (R)-4-[4-(2-oxyethyl group-oxyethyl group)-phenyl]-2,5-dioxo-imidazolidine-1-yl }-3-phenyl-N-(4-propionyl-thiazol-2-yl)-butyramide;
(2S, 3S)-2-{ (R)-4-[4-(2-dimethylamino-oxyethyl group)-phenyl]-2,5-dioxo-imidazolidine-1-yl }-3-phenyl-N-(4-propionyl-thiazol-2-yl)-butyramide; Compound with trifluoroacetic acid
(4-{ (R)-2,5-dioxo-1-[(1S, 2S)-2-phenyl-1-(4-propionyl-thiazol-2-yl formamyl)-propyl group]-imidazolidine-4-yl }-phenoxymethyl)-dimethyl phosphonate;
(2S, 3S)-N-(4-isobutyryl-thiazol-2-yl)-2-{4-[4-(2-methoxyl group-oxyethyl group)-phenyl]-2,5-dioxo-imidazolidine-1-yl }-3-phenyl-butyramide;
(2S, 3S)-N-(4-isobutyryl-thiazol-2-yl)-2-[(R)-4-(4-methoxyl group-phenyl)-2,5-dioxo-imidazolidine-1-yl]-3-phenyl-butyramide;
(2S, 3S)-2-{ (S)-4-[4-(2-dimethylamino-oxyethyl group)-phenyl]-2,5-dioxo-imidazolidine-1-yl }-3-phenyl-N-(4-propionyl-thiazol-2-yl)-butyramide; Compound with trifluoroacetic acid;
(2S, 3S)-2-{2,5-dioxo-4-[4-(2-piperidines-1-base-oxyethyl group)-phenyl]-imidazolidine-1-yl }-3-phenyl-N-(4-propionyl-thiazol-2-yl)-butyramide;
(2S, 3S)-2-{4-[4-(2-morpholine-4-base-oxyethyl group)-phenyl]-2,5-dioxo-imidazolidine-1-yl }-3-phenyl-N-(4-propionyl-thiazol-2-yl)-butyramide;
(2S, 3S)-3-(3-fluoro-phenyl)-2-{ (R)-4-[4-(2-methoxyl group-oxyethyl group)-phenyl]-2,5-dioxo-imidazolidine-1-yl }-N-(4-propionyl-thiazol-2-yl)-butyramide;
(2S, 3S)-2-[(R)-4-(4-methoxyl group-3-methyl-phenyl)-2,5-dioxo-imidazolidine-1-yl]-3-phenyl-N-(4-propionyl-thiazol-2-yl)-butyramide;
(2S, 3S)-2-{ (S)-4-[4-(2-hydroxyl-oxyethyl group)-phenyl]-2,5-dioxo-imidazolidine-1-yl }-3-phenyl-N-(4-propionyl-thiazol-2-yl)-butyramide;
(2S, 3S)-2-((R)-2,5-dioxo-4-phenyl-imidazolidine-1-yl)-3-phenyl-N-(4-propionyl-thiazol-2-yl)-butyramide;
(2S, 3S)-2-[4-(4-dimethylamino-phenyl)-2,5-dioxo-imidazolidine-1-yl]-3-phenyl-N-(4-propionyl-thiazol-2-yl)-butyramide;
(2S, 3S)-2-[4-(4-morpholine-4-base-phenyl)-2,5-dioxo-imidazolidine-1-yl]-3-phenyl-N-(4-propionyl-thiazol-2-yl)-butyramide;
(2S, 3S)-2-{4-[4-(4-hydroxy-piperdine-1-yl)-phenyl]-2,5-dioxo-imidazolidine-1-yl }-3-phenyl-N-(4-propionyl-thiazol-2-yl)-butyramide;
(2S, 3S)-2-(4-{4-[(2-methoxyl group-ethyl)-methyl-amino]-phenyl }-2,5-dioxo-imidazolidine-1-yl)-3-phenyl-N-(4-propionyl-thiazol-2-yl)-butyramide;
(2S, 3S)-N-(4-cyclopropane carbonyl-thiazol-2-yl)-2-{ (R)-4-[4-(2-methoxyl group-oxyethyl group)-phenyl]-2,5-dioxo-imidazolidine-1-yl }-3-phenyl-butyramide;
(2S, 3S)-2-{4-[4-(2-methoxyl group-oxyethyl group)-phenyl]-2,5-dioxo-imidazolidine-1-yl }-3-methyl-valeric acid (4-propionyl-thiazol-2-yl)-acid amides;
(2S, 3R)-3-benzyloxy-2-{ (R)-4-[4-(2-methoxyl group-oxyethyl group)-phenyl]-2,5-dioxo-imidazolidine-1-yl }-N-(4-propionyl-thiazol-2-yl)-butyramide;
(2S, 3S)-N-[4-(2-methoxyl group-ethanoyl)-thiazol-2-yl]-2-[(R)-and 4-(4-methoxyl group-phenyl)-2,5-dioxo-imidazolidine-1-yl]-3-phenyl-butyramide;
2-{ (2S, 3S)-2-[(R)-4-(2,3-dihydro-benzo [1,4] dioxine-6-yl)-2,5-dioxo-imidazolidine-1-yl]-3-phenyl-butyrylamino }-thiazole-4-carboxylic acid's methyl esters; With
2-[(2S, 3S)-2-((R)-2,5-dioxo-4-phenyl-imidazolidine-1-yl)-3-phenyl-butyrylamino]-thiazole-4-carboxylic acid's methyl esters.
12. a compound, it is selected from:
2-{ (2S, 3S)-2-[(R)-4-(4-methoxyl group-phenyl)-2,5-dioxo-imidazolidine-1-yl]-3-phenyl-butyrylamino }-thiazole-4-carboxylic acid's methyl esters;
2-{ (2S, 3S)-2-[(R)-4-(4-hydroxyl-phenyl)-2,5-dioxo-imidazolidine-1-yl]-3-phenyl-butyrylamino }-thiazole-4-carboxylic acid's methyl esters;
2-((2S, 3S)-2-{ (R)-4-[4-(2-methoxyl group-oxyethyl group)-phenyl]-2,5-dioxo-imidazolidine-1-yl }-3-phenyl-butyrylamino)-thiazole-4-carboxylic acid's methyl esters;
2-((2S, 3S)-2-{ (R)-4-[4-(2-hydroxyl-oxyethyl group)-phenyl]-2,5-dioxo-imidazolidine-1-yl }-3-phenyl-butyrylamino)-thiazole-4-carboxylic acid's methyl esters;
2-{ (2S, 3S)-2-[(R)-4-(4-isopropoxy-phenyl)-2,5-dioxo-imidazolidine-1-yl]-3-phenyl-butyrylamino }-thiazole-4-carboxylic acid's methyl esters;
2-{ (2S, 3S)-2-[(R)-4-(4-methoxyl group-3-methyl-phenyl)-2,5-dioxo-imidazolidine-1-yl]-3-phenyl-butyrylamino }-thiazole-4-carboxylic acid's methyl esters;
2-((2S, 3S)-2-{ (R)-4-[4-(dimethoxy-phosphoryl methoxy base)-phenyl]-2,5-dioxo-imidazolidine-1-yl }-3-phenyl-butyrylamino)-thiazole-4-carboxylic acid's methyl esters;
2-{ (2S, 3S)-3-(2-methoxyl group-phenyl)-2-[4-(4-methoxyl group-phenyl)-2,5-dioxo-imidazolidine-1-yl]-butyrylamino }-thiazole-4-carboxylic acid's methyl esters;
2-((2S, 3S)-3-(4-fluoro-phenyl)-2-{ (R)-4-[4-(2-methoxyl group-oxyethyl group)-phenyl]-2,5-dioxo-imidazolidine-1-yl }-butyrylamino)-thiazole-4-carboxylic acid's methyl esters;
2-{ (2S, 3S)-2-[(R)-4-(4-methoxyl group-phenyl)-2,5-dioxo-imidazolidine-1-yl]-3-methyl-pentanoyl amino }-thiazole-4-carboxylic acid's methyl esters;
2-[(2S, 3S)-2-((R)-2,5-dioxo-4-phenyl-imidazolidine-1-yl)-3-methyl-pentanoyl amino]-thiazole-4-carboxylic acid's methyl esters;
2-((2S, 3S)-2-{ (R)-4-[4-(2-methoxyl group-oxyethyl group)-phenyl]-2,5-dioxo-imidazolidine-1-yl }-3-methyl-pentanoyl amino)-thiazole-4-carboxylic acid's methyl esters;
2-{ (2S, 3R)-the 3-hydroxyl-2-[(R)-4-(4-methoxyl group-phenyl)-2,5-dioxo-imidazolidine-1-yl]-butyrylamino }-thiazole-4-carboxylic acid's methyl esters;
2-((2S, 3R)-3-hydroxyl-2-{ (R)-4-[4-(2-methoxyl group-oxyethyl group)-phenyl]-2,5-dioxo-imidazolidine-1-yl }-butyrylamino)-thiazole-4-carboxylic acid's methyl esters;
2-((2S, 3R)-3-tert.-butoxy-2-{ (R)-4-[4-(2-methoxyl group-oxyethyl group)-phenyl]-2,5-dioxo-imidazolidine-1-yl }-butyrylamino)-thiazole-4-carboxylic acid's methyl esters;
2-{ (2S, 3R)-the 3-methoxyl group-2-[(R)-4-(4-methoxyl group-phenyl)-2,5-dioxo-imidazolidine-1-yl]-butyrylamino }-thiazole-4-carboxylic acid's methyl esters;
2-((2S, 3R)-3-methoxyl group-2-{ (R)-4-[4-(2-methoxyl group-oxyethyl group)-phenyl]-2,5-dioxo-imidazolidine-1-yl }-butyrylamino)-thiazole-4-carboxylic acid's methyl esters;
2-((2S, 3R)-3-benzyloxy-2-{ (R)-4-[4-(2-methoxyl group-oxyethyl group)-phenyl]-2,5-dioxo-imidazolidine-1-yl }-butyrylamino)-thiazole-4-carboxylic acid's methyl esters;
2-((2S, 3R)-3-(4-chloro-benzyloxy)-2-{ (R)-4-[4-(2-methoxyl group-oxyethyl group)-phenyl]-2,5-dioxo-imidazolidine-1-yl }-butyrylamino)-thiazole-4-carboxylic acid's methyl esters
2-{ (2S, 3R)-2-[(R)-4-(4-methoxyl group-phenyl)-2,5-dioxo-imidazolidine-1-yl]-3-methyl-pentanoyl amino }-thiazole-4-carboxylic acid's methyl esters
2-((2S, 3R)-2-{ (R)-4-[4-(2-methoxyl group-oxyethyl group)-phenyl]-2,5-dioxo-imidazolidine-1-yl }-3-methyl-pentanoyl amino)-thiazole-4-carboxylic acid's methyl esters;
2-((2S, 3R)-2-{ (R)-4-[4-(2-methoxyl group-oxyethyl group)-phenyl]-2,5-dioxo-imidazolidine-1-yl }-3-methyl-pentanoyl amino)-thiazole-4-carboxylic acid's methyl esters;
2-{ (2S, 3S)-2-[4-(4-methylsulfonyl-phenyl)-2,5-dioxo-imidazolidine-1-yl]-3-phenyl-butyrylamino }-thiazole-4-carboxylic acid's methyl esters; With
2-{ (S)-2-[(R)-4-(4-methoxyl group-phenyl)-2,5-dioxo-imidazolidine-1-yl]-3-methyl-3-phenyl-butyrylamino }-thiazole-4-carboxylic acid's methyl esters.
13. a compound, it is selected from:
2-{ (2S, 3R)-2-[(R)-4-(2,3-dihydro-benzo [1,4] dioxine-6-yl)-2,5-dioxo-imidazolidine-1-yl]-3-phenyl-butyrylamino }-thiazole-4-carboxylic acid's methyl esters;
2-{ (2S, 3S)-2-[(R)-4-(4-acetylamino-phenyl)-2,5-dioxo-imidazolidine-1-yl]-3-phenyl-butyrylamino }-thiazole-4-carboxylic acid's methyl esters;
N-[4-(1-hydroxyl-1-methyl-ethyl)-thiazol-2-yl]-2-[(R)-and 4-(4-methoxyl group-phenyl)-2,5-dioxo-imidazolidine-1-yl]-3-phenyl-butyramide;
(2S, 3S)-2-[(R)-4-(2,3-dihydro-benzo [1,4] dioxine-6-yl)-2,5-dioxo-imidazolidine-1-yl]-N-[4-(1-hydroxyl-propyl group)-thiazol-2-yl]-3-phenyl-butyramide;
(2S, 3S)-N-[4-(1-hydroxyl-ethyl)-thiazol-2-yl]-2-[(R)-and 4-(4-methoxyl group-phenyl)-2,5-dioxo-imidazolidine-1-yl]-3-phenyl-butyramide;
2-{ (2S, 3S)-2-[(R)-4-(4-methoxyl group-phenyl)-2,5-dioxo-imidazolidine-1-yl]-3-phenyl-butyrylamino }-thiazole-4-carboxylic acid's dimethylformamide;
(2S, 3S)-N-(4-ethylmercapto group-thiazol-2-yl)-2-{ (R)-4-[4-(2-methoxyl group-oxyethyl group)-phenyl]-2,5-dioxo-imidazolidine-1-yl }-3-phenyl-butyramide;
(2S, 3S)-N-(4-second sulfinyl-thiazol-2-yl)-2-{ (R)-4-[4-(2-methoxyl group-oxyethyl group)-phenyl]-2,5-dioxo-imidazolidine-1-yl }-3-phenyl-butyramide;
(2S, 3S)-N-(4-ethylsulfonyl-thiazol-2-yl)-2-{ (R)-4-[4-(2-methoxyl group-oxyethyl group)-phenyl]-2,5-dioxo-imidazolidine-1-yl }-3-phenyl-butyramide;
(2S, 3S)-N-[4-(2-hydroxyl-ethanoyl)-thiazol-2-yl]-2-{ (R)-4-[4-(2-methoxyl group-oxyethyl group)-phenyl]-2,5-dioxo-imidazolidine-1-yl }-3-phenyl-butyramide;
(4-{ (R)-1-[(1S, 2S)-1-(4-ethanoyl-thiazol-2-yl formamyl)-2-phenyl-propyl group]-2,5-dioxo-imidazolidine-4-yl }-phenoxy group)-methyl acetate;
(4-{ (R)-2,5-dioxo-1-[(1S, 2S)-2-phenyl-1-(4-propionyl-thiazol-2-yl formamyl)-propyl group]-imidazolidine-4-yl }-phenoxy group)-methyl acetate;
(4-{2,5-dioxo-1-[(1S, 2S)-2-phenyl-1-(4-propionyl-thiazol-2-yl formamyl)-propyl group]-imidazolidine-4-yl }-phenoxy group)-acetate;
(2S, 3S)-N-(4-ethanoyl-thiazol-2-yl)-2-[(R)-4-(4-formyl-dimethylamino methoxyl group-phenyl)-2,5-dioxo-imidazolidine-1-yl]-3-phenyl-butyramide;
(2S, 3S)-N-(4-ethanoyl-thiazol-2-yl)-2-[(R)-4-(4-methylamino formyl radical methoxyl group-phenyl)-2,5-dioxo-imidazolidine-1-yl]-3-phenyl-butyramide;
(2S, 3S)-N-(4-ethanoyl-thiazol-2-yl)-2-[(R)-4-(4-carbamyl ylmethoxy-phenyl)-2,5-dioxo-imidazolidine-1-yl]-3-phenyl-butyramide; With
(2S, 3S)-N-(4-ethanoyl-thiazol-2-yl)-2-((R)-4-{4-[(2-methoxyl group-ethylamino formyl radical)-methoxyl group]-phenyl }-2,5-dioxo-imidazolidine-1-yl)-3-phenyl-butyramide.
14. a compound, it is selected from:
(2S, 3S)-N-(4-ethanoyl-thiazol-2-yl)-2-((R)-4-{4-[(2-methoxyl group-ethylamino formyl radical)-methoxyl group]-phenyl }-2,5-dioxo-imidazolidine-1-yl)-3-phenyl-butyramide;
(2S, 3S)-N-(4-ethanoyl-thiazol-2-yl)-2-((R)-4-{4-[(2-methoxyl group-ethylamino formyl radical)-methoxyl group]-phenyl }-2,5-dioxo-imidazolidine-1-yl)-3-phenyl-butyramide;
(2S, 3S)-N-(4-ethanoyl-thiazol-2-yl)-2-{ (R)-4-[4-(2-morpholine-4-base-2-oxo-oxyethyl group)-phenyl]-2,5-dioxo-imidazolidine-1-yl }-3-phenyl-butyramide;
(2S, 3S)-N-(4-ethanoyl-thiazol-2-yl)-2-{ (R)-2,5-dioxo-4-[4-(2-oxo-2-tetramethyleneimine-1-base-oxyethyl group)-phenyl]-imidazolidine-1-yl }-3-phenyl-butyramide;
(2S, 3S)-2-[(R)-4-(4-formyl-dimethylamino methoxyl group-phenyl)-2,5-dioxo-imidazolidine-1-yl]-3-phenyl-N-(4-propionyl-thiazol-2-yl)-butyramide;
(2S, 3S)-2-[(R)-4-(4-methylamino formyl radical methoxyl group-phenyl)-2,5-dioxo-imidazolidine-1-yl]-3-phenyl-N-(4-propionyl-thiazol-2-yl)-butyramide;
(2S, 3S)-2-((R)-4-{4-[(2-methoxyl group-ethylamino formyl radical)-methoxyl group]-phenyl }-2,5-dioxo-imidazolidine-1-yl)-3-phenyl-N-(4-propionyl-thiazol-2-yl)-butyramide;
(2S, 3S)-2-{ (R)-4-[4-(2-morpholine-4-base-2-oxo-oxyethyl group)-phenyl]-2,5-dioxo-imidazolidine-1-yl }-3-phenyl-N-(4-propionyl-thiazol-2-yl)-butyramide;
(2S, 3S)-2-{ (R)-2,5-dioxo-4-[4-(2-oxo-2-tetramethyleneimine-1-base-oxyethyl group)-phenyl]-imidazolidine-1-yl }-3-phenyl-N-(4-propionyl-thiazol-2-yl)-butyramide;
(2S, 3S)-2-{ (R)-4-[4-(2-azetidine-1-base-2-oxo-oxyethyl group)-phenyl]-2,5-dioxo-imidazolidine-1-yl }-3-phenyl-N-(4-propionyl-thiazol-2-yl)-butyramide; With
(2S, 3S)-N-(4-cyclopropane carbonyl-thiazol-2-yl)-2-[(R)-4-(4-methylamino formyl radical methoxyl group-phenyl)-2,5-dioxo-imidazolidine-1-yl]-3-phenyl-butyramide.
15. a treatment is by the method for the disease of MEK1/2 mediation, this method comprises: to needs its claim 1 of patient's drug treatment significant quantity or the compound of claim 9.
16. the compound of claim 1 or claim 9 is used for the treatment of by the application in the medicine of the disease of MEK1/2 mediation in preparation.
17. according to the application of claim 16, wherein the compound with claim 1 or claim 9 is used to prepare the medicine that is used for the treatment of cancer.
18. according to the application of claim 16, wherein the compound with claim 1 or claim 9 is used to prepare the medicine that is used for the treatment of inflammatory or autoimmune disease.
19. according to the application of claim 16, wherein the compound with claim 1 or claim 9 is used to prepare the medicine that is used for the treatment of cognitive disorder.
20. according to the application of claim 16, wherein the compound with claim 1 or claim 9 is used to prepare the medicine that is used for the treatment of the CNS illness.
21. a pharmaceutical composition is used in particular for the disease by the MEK1/2 mediation, this pharmaceutical composition comprises the compound and the pharmaceutical carrier of claim 1 or claim 9.
22. the compound of claim 1 or claim 9, it is as therapeutic active substance, especially for the treatment of diseases active substance by the MEK1/2 mediation.
23. be used to prepare method according to the formula II compound of claim 9, wherein:
A) compound of formula 17:
With the compound reaction of following formula,
Figure A2005800277080012C2
Obtain the compound of formula 18:
Figure A2005800277080012C3
B) compound of described formula 18 again with CF 3CO 2The H reaction,
Obtain the compound of formula 19:
C) in the solvent in the mixture that is selected from methylene dichloride, tetrahydrofuran (THF) and tetrahydrofuran (THF) and toluene, the compound of described formula 19 reacts with trichloromethylchloroformate and diisopropylethylamine again,
Removing tertiary butyl carboxylamine ester protecting group,
Figure A2005800277080013C1
Obtain the compound of formula II:
Figure A2005800277080013C2
R wherein 8, R 9, R 10And R 11Has the implication that in claim 9, provides.
24. aforesaid basically new compound, intermediate, preparation, technology, methods and applications.
CN 200580027708 2004-08-17 2005-08-09 Substituted hydantoins Pending CN101006085A (en)

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WO2013169858A1 (en) 2012-05-08 2013-11-14 The Broad Institute, Inc. Diagnostic and treatment methods in patients having or at risk of developing resistance to cancer therapy
US11078540B2 (en) 2010-03-09 2021-08-03 Dana-Farber Cancer Institute, Inc. Methods of diagnosing and treating cancer in patients having or developing resistance to a first cancer therapy

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US9084781B2 (en) 2008-12-10 2015-07-21 Novartis Ag MEK mutations conferring resistance to MEK inhibitors
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