CN100469770C - 5-substituted-pyrazine or -pyridine glucokinase activators - Google Patents
5-substituted-pyrazine or -pyridine glucokinase activators Download PDFInfo
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- CN100469770C CN100469770C CNB2003801058705A CN200380105870A CN100469770C CN 100469770 C CN100469770 C CN 100469770C CN B2003801058705 A CNB2003801058705 A CN B2003801058705A CN 200380105870 A CN200380105870 A CN 200380105870A CN 100469770 C CN100469770 C CN 100469770C
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- methylsulfonyl
- phenyl
- cyclopentyl
- pyrazine
- propionic acid
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Abstract
The present invention provides a compound according to formula (I) where the substituent designations are provided in the specification. Pharmaceutical compositions comprising a compound according to formula (I) are also provided, said compounds being glucokinase activators which are useful in the treatment of type II diabetes.
Description
[0001] glucokinase (GK) is one of four kinds of hexokinase finding in the mammalian body [Colowick, S.P., The Enzymes, the 9th volume (P.Boyer edits) Academic Press, NewYork, NY, 1-48 page or leaf, 1973].The first step of hexokinase catalysis glucose metabolism, being about to conversion of glucose is G-6-P.Glucokinase distributes limited in cell, finds mainly to be present in pancreas beta cell and hepatic parenchymal cells.In addition, GK is the rate-limiting enzyme of glucose metabolism in this two classes cell, and [Chipkin plays a significant role in the running balance of whole body glucose, S.R., Kelly, K.L., and Ruderman, N.B.Joslin ' s Diabetes (C.R.Khan and G.C.Wier, editor), Lea and Febiger, Philadelphia, PA, P.97-115,1994].The glucose concn of GK performance half maximum activity is about 8mM.Other three kinds of hexokinase under the relatively very low concentration of glucose (＜1mM) just reach saturated.Therefore, along with blood sugar concentration is increased to the state after the meal (≈ 10-15mM) of carbohydrate containing food from fasting state (5mM), the glucose flow by the GK approach also increases [Printz thereupon, R.G., Magnuson, M.A., and Granner, D.K.Ann.Rev.Nutrition the 13rd volume (R.E.Olson, D.M.Bier, edit with D.B.McCormick), Annual Review, Inc., Palo Alto, CA, P.463-496,1993].These conclusions formed such hypothesis before 10 years, promptly GK brings into play the function (Meglasson, M.D. and Matschinsky, F.M., Amer.J.Physiol.246, E1-E13,1984) of glucose sensor in beta cell and hepatic parenchymal cells.The GK that studies confirm that in transgenic animal brought into play keying action really in the running balance of whole body glucose in recent years.Do not express animal a couple of days internal cause severe diabetes mellitus death after birth of GK, and sugar tolerance (Grupe, A., Hultgren, B., Ryan, A. etc., Cell83,69-78,1995 that the performance of the animal of overexpression GK improves; Ferrie, T., Riu, E., Bosch, F. etc., FASERJ., 10,1213-1218,1996).The increase that glucose exposes in beta cell causes insulin secretion to increase by GK, and the increase of glucose causes glycogen deposition to increase and may cause glucose to produce by GK reducing in liver cell.
[0002] young adult's II type maturity-onset diabetes (MODY-2) is because the GK transgenation causes that this conclusion shows due to the afunction, function (Liang, Y., the Kesavan of GK same performance glucose sensor in human body, P., Wang, L. etc., Biochem.J.309,167-173,1995).The another one evidence of supporting GK to have vital role in the metabolic adjusting of human glucose is to have identified the patient who expresses the GK mutant of the enzymic activity with increase.These patients show the fasting hypoglycemia (Glaser, B., Kesavan, P., Heyman, M. etc., NewEngland J.Med.338,226-230,1998) of plasma insulin level due to too high.Find no the GK transgenation among most of type ii diabetes patients, activate GK and increase the compound of GK sensor system sensitivity thus still useful in the hyperglycemia symptom of all II diabetes of treatment.Glucokinase activating agents will increase the flow of glucose metabolism in beta cell and the hepatic parenchymal cells, and this will cause the increase of insulin secretion.These materials will play a role in the treatment type ii diabetes.
[0003] the invention provides a kind of compound, comprise acid amides or its pharmaceutical salts of following formula:
R wherein
1It is the low alkyl group that contains 1-5 carbon atom;
R
2Be hydrogen, halogen, nitro, cyano group, methyl, trifluoromethyl, hydroxyl, or methoxyl group;
R
3It is the cycloalkyl that contains 4-6 carbon;
Y is independently selected from CH and the N that forms pyridine or pyrazine ring respectively;
[0004] R
4Be the substituting group on pyridine or pyrazine ring 5, it is selected from
—(CH
2)
n-U-CH
3；
—ZCH
2CH
2-OR
9；
[0005]-(CH
2)
n-Q, wherein Q is the heterocycle that passes through the ring carbon atom connection that 5-unit is saturated, replace, described heterocycle contains two heteroatomss that are selected from nitrogen, sulphur and oxygen, and two the ring carbon each on replaced by oxo group, and randomly be substituted base and replace on the ring carbon that connects, this substituting group is methyl or amino;
[0006]-(CH
2)
n-V, wherein V is unsubstituted or mono-substituted five or hexa-atomic saturated or undersaturated by encircling the heterocycle that carbon connects, described heterocycle contains 1-3 heteroatoms that is selected from sulphur, oxygen or nitrogen; Described mono-substituted heterocycle is with the mono-substituted heterocycle of substituting group that is selected from cyano group, halogen, nitro, amino, methyl, methoxyl group and hydroxyl;
[0007] or nine or ten yuan of bicyclic heterocycles that connect by ring carbon atom, described bicyclic heterocycles contains a heteroatoms that is selected from oxygen, nitrogen or sulphur;
[0008] the unsubstituted or mono-substituted hexa-atomic aromatic ring that connects by ring carbon atom, described mono-substituted aromatic ring is substituted the single replacement of base on the position of the ring carbon atom except the carbon atom of described connection, this substituting group is selected from cyano group, halogen, nitro, amino, methyl, methoxyl group, and hydroxyl;
R
5Be hydrogen or low alkyl group;
R
6It is low alkyl group;
R
7Be low alkyl group, cyano group, or-C (=O) NH
2
R
8Be hydroxyl, methoxyl group, or dimethylamine;
R
9Be hydrogen or methyl;
R
10Be low alkyl group, cyano group, or-NH
2
R
11Be hydrogen, low alkyl group, or NHOH;
M is 0,1,2, or 3;
N is 0 or 1;
P is 1 or 2;
U is S, SO, or SO
2
Z is O, S, or NH;
The optional key of----expression;
*The expression unsymmetrical carbon.
[0009] has been found that the external activation glucokinase of compound of formula I.Glucokinase activating agents is used to increase insulin secretion in the treatment type ii diabetes.
[00010] the invention still further relates to the pharmaceutical composition that contains formula I compound or pharmaceutically acceptable salt thereof and pharmaceutical carrier and/or assistant agent.In addition, the invention still further relates to of the application of these compounds, and they are used for the treatment of or prevent application in the medicine of type ii diabetes in preparation as therapeutic active substance.The invention still further relates to the preparation method of formula I compound.In addition, the present invention relates to be used to prevent or treat the method for type ii diabetes, this method comprises the compound to human or animal's Medicine-feeding type I.
[00011] more specifically, the invention provides a kind of compound, comprise acid amides or its pharmaceutical salts of following formula:
Wherein
R
1It is the low alkyl group that contains 1-5 carbon atom;
R
2Be hydrogen, halogen, nitro, cyano group, methyl, trifluoromethyl, hydroxyl, or methoxyl group;
R
3It is the cycloalkyl that contains 4-6 carbon;
Y is independently selected from CH and the N that forms pyridine or pyrazine ring respectively;
R
4Be the substituting group (N on 1 on ring and Y on 4 on ring) on pyridine or pyrazine ring 5, it is selected from
—ZCH
2CH
2-OR
9；
-(CH
2)
n-Q, wherein Q is the heterocycle that passes through the ring carbon atom connection that 5-unit is saturated, replace, described heterocycle contains two heteroatomss that are selected from nitrogen, sulphur and oxygen, and two the ring carbon each on replaced by oxo group, and randomly be substituted base and replace on the ring carbon that connects, this substituting group is methyl or amino;
-(CH
2)
n-V, wherein V is unsubstituted or mono-substituted five or hexa-atomic saturated or undersaturated by encircling the heterocycle that carbon connects, described heterocycle contains 1-3 heteroatoms that is selected from sulphur, oxygen or nitrogen; Described mono-substituted heterocycle is with the mono-substituted heterocycle of substituting group that is selected from cyano group, halogen, nitro, amino, methyl, methoxyl group and hydroxyl;
Or nine or ten yuan of bicyclic heterocycles that connect by ring carbon atom, described bicyclic heterocycles contains a heteroatoms that is selected from oxygen, nitrogen or sulphur;
Unsubstituted or the mono-substituted hexa-atomic aromatic ring that connects by ring carbon atom, described mono-substituted aromatic ring are substituted the single replacement of base on the position of the ring carbon atom except the carbon atom of described connection, this substituting group is selected from cyano group, halogen, nitro, amino, methyl, methoxyl group, and hydroxyl;
R
5Be hydrogen or low alkyl group;
R
6It is low alkyl group;
R
7Be low alkyl group, cyano group, or-C (=O) NH
2
R
8Be hydroxyl, methoxyl group, or dimethylamine;
R
9Be hydrogen or methyl;
R
10Be low alkyl group, cyano group, or-NH
2
R
11Be hydrogen, low alkyl group, or NHOH;
M is 0,1,2, or 3;
N is 0 or 1;
P is 1 or 2;
U is S, SO, or SO
2
Z is O, S, or NH;
The optional key of----expression;
*The expression unsymmetrical carbon.
[00012] in the compound of formula I, " * " represents asymmetric carbon.The compound of formula I can be used as racemoid or exists with " R " configuration of asymmetric carbon shown in independent.In a preferred embodiment, preferred " R " enantiomer.In a further preferred embodiment, the compound of formula I is at-CH
2R
3Sentencing racemic mixture as substituent chiral carbon exists.
[00013] run through term ＂ low alkyl group ＂ used in this application and comprise straight or branched alkyl with 1-7 carbon atom, as methyl, ethyl, propyl group, sec.-propyl, preferable methyl and ethyl.As used herein, ＂ perfluor-low alkyl group ＂ represents any low alkyl group, and wherein all hydrogen is replaced by fluorine or replaces in the low alkyl group.Preferred perfluor low alkyl group is a trifluoromethyl in them, pentafluoroethyl group, seven fluoropropyls etc.
[00014] the ＂ cycloalkyl ＂ that uses in this article represents to have the stable hydrocarbon ring of 3-10 carbon atom.Preferred cycloalkyl has 4-6 carbon atom.Preferred cycloalkyl is a cyclopentyl.
[00015] " halogen " and " halo " that uses in this article represented all four kinds of halogens, i.e. fluorine, chlorine, bromine and iodine except as otherwise noted.Preferred halogen is a chlorine.
[00016] according to R
4" heterocycle " ring of definition can be saturated or unsaturated five or six-ring, contains 1-3 heteroatoms that is selected from oxygen, nitrogen or sulphur, and randomly is connected by connecting methyl and pyridine shown in the formula I or pyrazine ring 5 by ring carbon atom.Undersaturated heterocycle can fractional saturation or is aromatic.Heterocycle comprises for example pyridyl and furyl.The heterocycle that replaces is the heterocycle that can for example be replaced by oxo, low alkyl group, amino, cyano group, halogen, nitro, amino, methoxyl group and hydroxyl on ring carbon.Preferred low-grade alkyl substituent is a methyl.Preferred halogenic substituent is chlorine and bromine.For aromatic heterocycle, randomly can not contain any substituting group with the ring carbon that the rest part of formula I is connected by connecting methyl
[00017] according to R
4The bicyclic heterocycles of definition can be nine or ten yuan of two ring, contains a heteroatoms that is selected from oxygen, nitrogen and sulphur, and randomly is connected through ring carbon atom 5 with pyridine or pyrazine ring by connecting methyl.This bicyclic heterocycles comprises indole ring.
[00018] the unsubstituted aromatics mononuclear aromatic alkyl of term " aryl " expression that uses in this article.The aryl that replaces has cyano group, halogen, nitro, amino, low alkyl group, lower alkoxy or hydroxyl substituent in one or more positions ring replaces, except as otherwise noted.The multinuclear aryl also represented in term " aryl ", as for example naphthyl, and anthryl, phenanthryl, it can be unsubstituted or be replaced by one or more above-mentioned group.The example of aryl and substituted aryl comprises phenyl and tolyl.Preferred phenyl.Term " aralkyl " expression alkyl, preferred low alkyl group, one of them hydrogen atom can be replaced by aryl.The example of aralkyl is a benzyl, 2-phenylethyl, 3-phenyl propyl, 4-benzyl chloride base, 4-methoxy-benzyl etc.
[00019] the term ＂ lower alkoxy ＂ that uses in this article comprises the straight or branched alkoxyl group with 1-7 carbon atom, as methoxyl group, and oxyethyl group, propoxy-, isopropoxy, preferred methoxyl group and oxyethyl group.
[00020] term ＂ lower alkanols alkanoic acid ＂ used herein represents to contain the lower alkanols alkanoic acid of 2-7 carbon atom, as propionic acid, acetate etc.Term ＂ low-grade alkane acidyl ＂ is meant the monovalence alkyloyl with 2-7 carbon atom, as propionyl, ethanoyl etc.Term ＂ aromatic acid (aroic acids) ＂ is meant aryl-alkanoic, wherein aryl as defined above, alkane (alkanoic) contains 1-6 carbon atom.Term ＂ aroyl ＂ is meant aromatic acid (aroic acids), wherein aryl as defined above, wherein-oh group in the COOH part is removed.Wherein, preferred aroyl has benzoyl.
[00021] ＂ lower alkylthio ＂ used herein represents that aforesaid low alkyl group is connected on the sulfenyl, and this sulfenyl is connected on the rest part of molecule, for example methylthio group.＂ low alkyl group sulfinyl ＂ used herein represents that aforesaid low alkyl group is connected on the sulfinyl (sulfoxide), and this sulfinyl is connected on the rest part of molecule.＂ low alkyl group alkylsulfonyl ＂ used herein represents that aforesaid low alkyl group is connected on the alkylsulfonyl, and this alkylsulfonyl is connected on the rest part of molecule.
[00022] in the process of building-up reactions, a plurality of functional groups such as free carboxylic acid or oh group can be protected by the blocking group of conventional hydrolyzable ester or ether.The blocking group ＂ of hydrolyzable ester of term ＂ used herein or ether is meant that any routine is used to protect the ester or the ether of carboxylic acid or alcohol, and it can hydrolysis produce hydroxyl or carboxylic group respectively.The example that is used for the ester group group of this purpose has acyl moiety to be derived from those of lower alkane, aryl lower alkane or lower alkane dicarboxylic acid.Wherein, the activatory acid that can be used to form these groups has acid anhydrides, acyl halide, preferably is derived from the chloride of acid or the acid bromide of aryl or lower alkanols alkanoic acid.The example of acid anhydrides has the acid anhydrides that is derived from monocarboxylic acid, as diacetyl oxide, and benzoyl oxide and lower alkane dicarboxylic anhydride, for example succinyl oxide and chloro-formic ester, for example preferred superpalite and Vinyl chloroformate.The suitable ether protecting group of alcohol for example can be THP trtrahydropyranyl ether, as 4-methoxyl group-5, and 6-dihydroxyl-2H-pyranyl ether.Other suitable ether is the aroyl methyl ether, as benzyl, and diphenyl-methyl or trityl ether or α-lower alkoxy lower alkyl ether, for example, methoxymethyl or allyl ethers or alkyl silyl ether are as trimethyl silyl ether.
[00023] term ＂ amido protecting group ＂ is meant the amido protecting group that can cracking produces any routine of free amine group.Preferred blocking group is for being used for the conventional amido protecting group of peptide synthetic.Especially preferred is those amido protecting groups of cleavable under the moderate acid condition of pH=2-3.Especially preferred amido protecting group comprises carboxylamine tert-butyl ester (BOC), carboxylamine benzyl ester (CBZ) and carboxylamine 9-fluorenyl (flurorenyl) methyl ester (FMOC).
[00024] term used herein " pharmaceutical salts " comprises any salt with inorganic or organic medicinal acid, example hydrochloric acid, Hydrogen bromide, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, toxilic acid, acetate, succsinic acid, tartrate, methylsulfonic acid, right-toluenesulphonic acids etc.Term " pharmaceutical salts " also comprises any medicinal alkali salt, as amine salt, and trialkyl amine salt etc.Those of ordinary skills' application standard technology can form these salt at an easy rate.
[00025] compound of preferred formula I comprises wherein R
1Be those of methyl, wherein R2 is those and R wherein of hydrogen or halogen such as chlorine
3Be those of cyclopentyl.
[00026] compound of preferred formula I comprises wherein R
4Be following those:
-(CH
2)
n-U-CH
3As-SCH
3-SO
2CH
3With-SOCH
3-ZCH
2CH
2-OR
9As-SCH
2CH
2OH;-(CH
2)
m-N (CH
3) CH
3-C (=O) R
11-(CH
2)
n-C (OR
6) OR
6As
-(CH
2)
n-C (OCH
3) OCH
3-C (OH) R
7With-C ≡ C-C (CH
3)
2-OH;-NHSO
2CH
3With-SO
2NR
5R
6
[00027] compound of preferred formula I also comprises wherein R
4Be-(CH
2)
nThose of-Q, described-(CH
2)
n-Q as
[00028] compound of preferred formula I also comprises wherein R
4Be-(CH
2)
nThose of-V.Preferred R wherein
4Be-(CH
2)
nThe compound of-V comprises wherein ((CH
2)
n-V's) n is 0 to be those of 5 unsubstituted five or hexa-member heterocycles that are connected by ring carbon atom and pyridine shown in the formula I or pyrazine ring with V, described five or six-membered Hetero-aromatic contain a heteroatoms that is selected from sulphur, oxygen or nitrogen.
[00029] compound of in addition preferred formula I comprises wherein R
4Be those of unsubstituted or mono-substituted 5 the hexa-atomic aromatic ring that is connected to pyridine shown in the formula I or pyrazine ring by ring carbon atom, described mono-substituted aromatic ring is substituted the single replacement of base on the position of the ring carbon atom except the carbon atom of described connection, described substituting group is selected from chlorine, bromine, nitro, amino, methyl, or methoxyl group or hydroxyl.
[00030] compound of in addition preferred formula I comprises wherein R
4Be those of unsubstituted or mono-substituted 6-unit aromatic ring, be selected from unsubstituted aryl, aryl that is replaced by methoxyl group and the aryl that is replaced by hydroxyl.
[00031] compound of in addition preferred formula I comprises wherein R
4Those of the hetero-aromatic ring that is unsubstituted or replaces are selected from following:
[00032] compound of other preferred formula I comprises wherein R
4Be those of following formula,
R wherein
4Be those of hetero-aromatic ring that are selected from following replacement:
R wherein
4Be that two of following formula encircles those of hetero-aromatic rings:
[00033] compound of in addition preferred formula I comprises wherein R
4Be those of following formula:
R wherein
12Be the alkyl chain of 2 or 3 carbon atoms of straight chain, wherein the Sauerstoffatom of this chain and its bonding is common forms five or six-ring.
[00034] compound of in addition preferred formula I comprises wherein R
6Be those of methyl or ethyl.
[00035] compound of in addition preferred formula I comprises those shown in the formula II:
R wherein
10As implied above.
[00036] R of preferred formula II
10Group be methyl or-NH
2
[00037] compound of in addition preferred formula I comprises those shown in the formula III:
Wherein p and R
8As implied above.In formula III, preferred p value is 1.Preferred R
8Be hydroxyl or dimethylamine.
[00038] compound of in addition preferred formula I is at R
4The chiral carbon place be those of racemic mixture, R wherein
4Be
[00039] compound of in addition preferred formula I is those compounds, wherein works as R
4For
With n be 1 o'clock, described being configured as
In preferred embodiments, R
4The chiral carbon place be configured as R.
[00040] in also having another preferred embodiment, R
4Be
N is 0, is configured as
In a preferred embodiment, R
4The chiral carbon place be configured as R.
[00041] compound of in addition preferred formula I comprises wherein R
4Be those of following formula:
In a preferred embodiment, the compound of formula I is R wherein
4Be those of following formula
It is at R
4The chiral carbon place be racemize.In also having another preferred embodiment, R
4Be
More preferably, R wherein
4It is the S configuration.
[00042] preferably be selected from down group according to compound of the present invention:
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(N-hydroxyl amino formyl imino-(carbamimidoyl))-pyrazine-2-yl]-propionic acid amide,
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(N-hydroxyl amino formyl imino-)-pyridine-2-yl]-propionic acid amide,
3-cyclopentyl-2 (R)-N-[5-(N-hydroxyl amino formyl imino-)-pyrazine-2-yl]-2-(4-methylsulfonyl-phenyl)-propionic acid amide,
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-methylthio group-pyrazine-2-yl)-propionic acid amide,
3-cyclopentyl-2 (R)-(4-methylsulfonyl-phenyl)-N-(5-methylthio group-pyrazine-2-yl)-propionic acid amide,
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(2-hydroxyl-ethylmercapto group)-pyrazine-2-yl]-propionic acid amide,
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-methylsulfinyl-pyrazine-2-yl)-propionic acid amide,
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-methyl sulfamyl-pyrazine-2-yl)-propionic acid amide,
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-dimethylamino alkylsulfonyl-pyrazine-2-yl)-propionic acid amide,
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(3-hydroxyl-third-1-alkynyl)-pyrazine-2-yl]-propionic acid amide,
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(3-dimethylamino-third-1-alkynyl)-pyrazine-2-yl]-propionic acid amide,
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-methylsulfonyl amino-pyridine-2-yl)-propionic acid amide,
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-methylsulfonyl amino-pyrazino-2-yl)-propionic acid amide,
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-dimethylamino-pyridine-2-yl)-propionic acid amide,
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-dimethylamino-pyrazine-2-yl)-propionic acid amide,
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(3-dimethylamino-propyl group)-pyrazine-2-yl]-propionic acid amide,
N-[5-(5-amino-[1,2,4] oxadiazole-3-yls)-pyrazine-2-yl]-2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-propionic acid amide,
2-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-formyl radical-pyrazine-2-yl)-propionic acid amide,
2-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(2,4-dioxo thiazolidine-5-ylmethyl)-pyrazine-2-yl]-propionic acid amide,
2-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(2,5-dioxo-imidazolidine-4-ylmethyl)-pyrazine-2-yl]-propionic acid amide,
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-dimethoxy-methyl-pyrazine-2-yl)-propionic acid amide,
2-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(1-hydroxyl-ethyl) pyrazine-2-yl]-propionic acid amide,
N-(5-ethanoyl-pyrazine-2-yl)-2-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl propionic acid amide,
2-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(1-hydroxy-2-methyl-propyl group)-pyrazine-2-yl]-propionic acid amide,
2-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-isobutyryl-pyrazine-2-yl)-propionic acid amide,
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-N-[5-(cyano group-hydroxyl-methyl)-pyrazine-2-yl]-3-cyclopentyl-propionic acid amide,
N-[5-(formamyl-hydroxyl-methyl)-pyrazine-2-yl]-2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-propionic acid amide,
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(1-(Z)-oxyimino-ethyl)-pyrazine-2-yl]-propionic acid amide,
5-[2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-propionyl amino]-pyrazine-2-carboxylic acid hydroxamides,
2-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-methylthiomethyl-pyrazine-2-yl)-propionic acid amide,
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-methylsulfonyl methyl-pyrazine-2-yl)-propionic acid amide,
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-dimethylaminomethyl-pyrazine-2-yl)-propionic acid amide,
2-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(the 5-methyl-[1,2,4] oxadiazole-3-yls)-pyrazine-2-yl]-propionic acid amide,
3-cyclopentyl-N-[5-(1-oxyimino-ethyl)-pyrazine-2-yl]-2 (R)-(4-methylsulfonyl-phenyl)-propionic acid amide,
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(the 3-methyl-[1,2,4] oxadiazole-5-yls)-pyrazine-2-yl]-propionic acid amide,
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-methylthiomethyl-pyrazine-2-yl)-propionic acid amide,
2-(3-chloro-4-methylsulfonyl-phenyl)-N-[5-(cyano group-oxyimino-methyl)-pyrazine-2-yl]-3-cyclopentyl-propionic acid amide,
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-methylsulfinyl ylmethyl-pyrazine-2-yl)-propionic acid amide,
N-(5-ethanoyl-pyrazine-2-yl)-2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-propionic acid amide,
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(2-hydroxyl-1-methylol-ethyl)-pyrazine-2-yl]-propionic acid amide,
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-[1,3] dioxolane-2-base-pyrazine-2-yl)-propionic acid amide,
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-[1,3] dioxolane-2-ylmethyl-pyrazine-2-yl)-propionic acid amide,
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-5-(2-methoxy ethoxy-pyrazine-2-yl)-propionic acid amide,
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-2 (R), 3-dihydroxyl-propoxy-)-pyrazine-2-yl)-propionic acid amide,
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(2,2-dimethoxy-ethyl)-pyrazine-2-yl)-propionic acid amide,
3-cyclopentyl-N-5-[(4-hydroxyl-tetrahydropyran-4-base-ethynyl) pyrazine-2-yl]-2 (R)-(4-methylsulfonyl-phenyl)-propionic acid amide,
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(3-methoxyl group-third-1-alkynyl)-pyrazine-2-yl)-propionic acid amide,
3-cyclopentyl-2 (R)-(4-methylsulfonyl-phenyl)-N-[5-(3-methoxy propyl-1-alkynyl)-pyrazine-2-yl]-propionic acid amide,
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(2 (S), 3-dihydroxyl-propoxy-)-pyrazine-2-yl]-propionic acid amide,
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(4-hydroxyl-tetrahydropyran-4-base-ethynyl)-pyrazine-2-yl]-propionic acid amide,
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(4-hydroxyl-tetrahydropyran-4-base-ethyl)-pyrazine-2-yl]-propionic acid amide,
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(3-hydroxy-3-methyl-Ding-1-alkynyl)-pyrazine-2-yl]-propionic acid amide,
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(4-hydroxyl-Ding-]-alkynyl)-pyrazine-2-yl]-propionic acid amide,
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(1 (S), 2-dihydroxyl-ethyl)-pyrazine-2-yl]-propionic acid amide,
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(1 (R), 2-dihydroxyl-ethyl)-pyrazine-2-yl]-propionic acid amide,
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(2-hydroxyl-1-methylol-oxyethyl group)-pyrazine-2-yl]-propionic acid amide,
3-cyclopentyl-N-[5-(3-hydroxy-3-methyl-Ding-1-alkynyl)-pyrazine-2-yl]-2 (R)-(4-methylsulfonyl-3-methyl-phenyl)-propionic acid amide,
3-cyclopentyl-N-[5-1 (S), 2-dihydroxyl-ethyl]-2 (R)-(4-methylsulfonyl-3-methyl) propionic acid amide,
3-cyclopentyl-N-[5-(4-hydroxyl-tetrahydrochysene-pyrans-4-ethyl-acetylene base)-pyrazine-2-yl]-2 (R)-(4-methylsulfonyl-3-methyl-phenyl)-propionic acid amide,
3-cyclopentyl-N-[5-1 (R), 2-dihydroxyl-ethyl]-2 (R)-(4-methylsulfonyl-3-methyl)-propionic acid amide,
3-cyclopentyl-2 (R)-(4-methylsulfonyl-phenyl)-N-[5-(3-hydroxy-3-methyl-Ding-1-alkynyl)-pyrazine-2-yl]-propionic acid amide,
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(2-hydroxyl-oxyethyl group)-pyrazine-2-yl]-propionic acid amide,
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(2-p-methoxy-phenyl)-pyrazine-2-yl]-propionic acid amide,
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(2-hydroxy phenyl)-pyrazine-2-yl]-propionic acid amide,
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(1,2-dihydroxyl-ethyl)-pyrazine-2-yl]-propionic acid amide,
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(1 (S), 2-dihydroxyl-2-methyl-propyl group)-pyrazine-2-yl]-propionic acid amide,
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(1 (R), 2-dihydroxyl-2-methyl-propyl group)-pyrazine-2-yl]-propionic acid amide,
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(4-methyl-2,5-dioxo-imidazolidine-4-yl)-pyrazine-2-yl]-propionic acid amide,
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(tetrahydrochysene-furans-2-yl)-pyridine-2-yl]-propionic acid amide,
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-furans-2-base-pyrazine-2-yl)-propionic acid amide,
2 (R)-(3-chloro-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(3-methoxyl group-phenyl)-pyrazine-2-yl]-propionic acid amide,
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(2-methoxyl group-ethylamino)-pyrazine-2-yl]-propionic acid amide,
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(2-hydroxyl-ethylamino)-pyrazine-2-yl]-propionic acid amide,
2 (R)-(3-chloro-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(1H-indoles-5-yl)-pyrazine-2-yl]-propionic acid amide,
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(5,6-dihydro-4H-pyrans-2-yl)-pyrazine-2-yl]-propionic acid amide,
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-thiophene-2-base-pyrazine-2-yl)-propionic acid amide,
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-thiene-3-yl--pyrazine-2-yl)-propionic acid amide,
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-furans-3-base-pyrazine-2-yl)-propionic acid amide,
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-N-[5-(5-cyano group-thiophene-2-yl)-pyrazine-2-yl]-3-cyclopentyl-propionic acid amide,
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-{5-(4,5-dihydro-1H-imidazoles-2-yl)-pyrazine-2-yl }-propionic acid amide three fluoro-acetates,
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(2 (S), 3-dihydroxyl-propyl group)-pyrazine-2-yl]-propionic acid amide,
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(2 (R), 3-dihydroxyl-propyl group)-pyrazine-2-yl]-propionic acid amide,
And pharmaceutical salts.
[00043] in a preferred embodiment, be selected from according to compound of the present invention:
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(N-hydroxyl amino formyl imino-)-pyrazine-2-yl]-propionic acid amide;
3-cyclopentyl-2 (R)-N-[5-(N-hydroxyl amino formyl imino-)-pyrazine-2-yl]-2-(4-methylsulfonyl-phenyl)-propionic acid amide;
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-methylthio group-pyrazine-2-yl)-propionic acid amide;
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(2-hydroxyl-ethylmercapto group)-pyrazine-2-yl]-propionic acid amide;
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-methanesulfinyl-pyrazine-2-yl)-propionic acid amide;
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(3-hydroxyl-third-1-alkynyl)-pyrazine-2-yl]-propionic acid amide;
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(3-dimethylamino-third-1-alkynyl)-pyrazine-2-yl]-propionic acid amide;
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-methylsulfonyl amino-pyridine-2-yl)-propionic acid amide;
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-dimethylamino-pyridine-2-yl)-propionic acid amide;
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-dimethylamino-pyrazine-2-yl)-propionic acid amide;
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(3-dimethylamino-propyl group)-pyrazine-2-yl]-propionic acid amide;
N-[5-(5-amino-[1,2,4] oxadiazole-3-yls)-pyrazine-2-yl]-2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-propionic acid amide;
2-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-formyl radical-pyrazine-2-yl)-propionic acid amide;
2-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(2,4-dioxo-thiazolidine-5-ylmethyl)-pyrazine-2-yl]-propionic acid amide;
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-dimethoxy-methyl-pyrazine-2-yl)-propionic acid amide;
N-(5-ethanoyl-pyrazine-2-yl)-2-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-propionic acid amide;
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-N-[5-(cyano group-hydroxyl-methyl)-pyrazine-2-yl]-3-cyclopentyl-propionic acid amide;
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(1-(Z)-oxyimino-ethyl)-pyrazine-2-yl]-propionic acid amide;
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(1 (S), 2-dihydroxyl-ethyl)-pyrazine-2-yl]-propionic acid amide;
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(1 (S), 2-dihydroxyl-2-methyl-propyl group)-pyrazine-2-yl]-propionic acid amide;
And pharmaceutical salts.
[00044] in also having the preferred embodiment of another one, compound of the present invention is selected from:
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(1 (S), 2-dihydroxyl-ethyl)-pyrazine-2-yl]-propionic acid amide;
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(1 (S), 2-dihydroxyl-2-methyl-propyl group)-pyrazine-2-yl]-propionic acid amide, and pharmaceutical salts.
[00045] can begin compound from the compound of formula V by following reaction scheme preparation formula I:
Reaction scheme
R wherein
20It is functional group's (as methylthio group or halogen group, preferred chlorine or fluorine) that the low alkyl group alkylsulfonyl maybe will change the low alkyl group sulfone into;
R
1, R
2, R
3, R
4, R
6And Y as above.
[00046] R wherein
2Be hydrogen and R
20The carboxylic acid of formula V that is sulfydryl [4-(sulfydryl) phenylacetic acid], methylthio group [4-(methylthio group) phenylacetic acid] or methylsulfonyl [4-(methylsulfonyl) phenylacetic acid] is commercially available.R wherein
2Be trifluoromethyl and R
20Be carboxylic acid and the R wherein of the formula V of fluoro [4-fluoro-3-(trifluoromethyl) phenylacetic acid]
2Be nitro and R
20The carboxylic acid of formula V that is chloro [4-chloro-3-nitrophenyl acetate] is also commercially available.If desired further chemically modified with at R
20And R
2The required replacement of last generation, carboxylic acid can use any conventional esterification process to be converted into the ester of corresponding lower alkyl alcohol.
[00047] is on the lower alkyl esters of the carboxylic acid of formula VI or VIII, to carry out to this reaction, perhaps can on the carboxylic acid itself of formula V or IX, carries out.
[00048] if wherein R is produced in expectation
2Be hydrogen and R
20Be the compound of the formula V of low alkyl group alkylsulfonyl, known 4-(sulfydryl) phenylacetic acid can be used as starting material.R wherein
2Be hydrogen and R
20The compound that is the formula V of sulfydryl can be by the lower alkylthio compound of the corresponding formula V of ordinary method alkylation (for example using low alkyl group halogen) one-tenth.The lower alkylthio compound can be the low alkyl group sulfonyl compound of corresponding formula V by oxidation conversion then.The method that the alkylthio substituting group is oxidized to corresponding sulfuryl group of any routine can be used to implement this conversion.
[00049] if wherein R is produced in expectation
2Be halogen and R
20Be the compound of the formula V of low alkyl group alkylsulfonyl, known 2-halogeno-benzene thiophenol can be used as starting material.In this reaction sequence, sulfydryl can become corresponding 2-halo-1-lower alkylthio benzene by ordinary method alkylation (for example using low alkyl group halogen).These compounds can be converted into corresponding 3-halo-4-(lower alkylthio)-phenylacetic acid then.At first, 2-halogen-1-lower alkylthio benzene can use (low alkyl group) oxalyl chloride (as methyl oxalyl chloride or ethyl oxalyl chloride) by friedel-crafts acylation reaction acidylate, produces the alpha-keto carboxylic acid ester in the contraposition of described lower alkylthio functional group.The alpha-keto carboxylic acid ester can be converted into alpha-keto carboxylic acid with the alpha-keto carboxylic acid ester by any ordinary method hydrolysis then.The Wolff-Kishner reduction of the alpha-keto carboxylic acid that obtains is with the compound of production V, wherein R
2Be halogen and R
20Be lower alkylthio (similar reaction sequence is referring to for example J.Med.Chem.1972,15,1029-1032).The lower alkylthio compound can be the low alkyl group sulfonyl compound of corresponding formula V by oxidation conversion then.The method that the alkylthio substituting group is oxidized to corresponding sulfuryl group of any routine can be used to implement this conversion.
[00050] on the other hand, produce wherein R when expectation
2Be bromine and R
20When being the compound of formula V of low alkyl group alkylsulfonyl, R wherein
2Be hydrogen and R
20Be the compound of lower alkylthio, the compound of Sheng Chaning also can be used as starting material as mentioned above.R wherein
2Be hydrogen and R
20The phenyl acetic acid derivatives that is the formula V of lower alkylthio can be by bromination.The method of the aromatics bromination of any routine can be used to implement this conversion (J.Med.Chem.1989,32,2493-2500).In case R wherein
2Be bromine and R
20The compound that is the formula V of lower alkylthio can obtain, and they can be R wherein accordingly by oxidation conversion
2Be bromine and R
20It is the compound of the formula V of low alkyl group alkylsulfonyl.The method that the alkylthio substituting group is converted into corresponding sulfuryl group of any routine can be used to implement this conversion.
[00051] if wherein R is produced in expectation
2Be cyano group and R
20Be the compound of the formula V of low alkyl group alkylsulfonyl, these compounds can be as mentioned above from R wherein
2Be bromine and R
20It is the compound of low alkyl group alkylsulfonyl.Any routine can be used to implement this conversion with cyano group transfering reagent [as cupric cyanide (I)] the substituent method of nucleophilic displacement aromatic bromine.
[00052] if wherein R is produced in expectation
2Be nitro and R
20Be the compound of the formula V of low alkyl group alkylsulfonyl, known 4-chloro-3-nitrophenyl acetate can be used as starting material.These compounds can be converted into the compound of formula V, wherein R
2Be nitro and R
20It is lower alkylthio.The method with low alkyl group mercaptan nucleophilic displacement aromatics cl radical of any routine can be used to implement this conversion (Synthesis1983,751-755).In case R wherein
2Be nitro and R
20The compound that is the formula V of lower alkylthio can obtain, and they can be R wherein accordingly by oxidation conversion
2Be nitro and R
20It is the compound of the formula V of lower alkylthio.The method that the alkylthio substituting group is oxidized to corresponding sulfuryl group of any routine can be used to implement this conversion.On the other hand, if expectation from R wherein
2Be nitro and R
20Be the compound direct production R wherein of the formula V of chlorine
2Be nitro and R
20Be the compound of the formula V of low alkyl group alkylsulfonyl, the method with lower alkane-sulfinate (as methyl-sulfinic acid sodium) nucleophilic displacement aromatics cl radical of any routine can be used to implement this conversion (J.Org.Chem., 1989,54,4691-4692).
[00053] if wherein R is produced in expectation
2Be fluorine and R
20Be the compound of the formula V of low alkyl group alkylsulfonyl, these compounds can be alternatively from R wherein
2Be nitro and R
20It is the above-claimed cpd preparation of low alkyl group alkylsulfonyl.The aromatic nitro substituting group at first is converted into aromatic amine.The method with nitroreduction one-tenth amino of any routine can be used to implement this conversion.Amino can be converted into fluorin radical then, to produce wherein R
2Be fluorine and R
20It is the compound of the formula V of low alkyl group alkylsulfonyl.The method that aromatic amine is converted into the aromatics fluorine of any routine can be used to implement this conversion (Synthetic Commun.1992,22,73-82; J.Fluorine Chem.1991,51,299-304).
[00054] on the other hand, if wherein R is produced in expectation
2Be trifluoromethyl and R
20Be the compound of the formula V of low alkyl group alkylsulfonyl, known 4-fluoro-3-(trifluoromethyl) phenylacetic acid can be used as starting material.In this reaction, the method with low alkyl group mercaptan nucleophilic displacement aromatics fluorin radical of any routine can be used to implement this conversion (J.Org.Chem.1995,60,6592-6594; J.Org.Chem.1982,47,4341-4344).In case R wherein
2Be trifluoromethyl and R
20The compound that is the formula V of lower alkylthio can obtain, and they can use conventional method for oxidation to be converted into accordingly wherein R
2Be trifluoromethyl and R
20It is the compound of the formula V of low alkyl group alkylsulfonyl.
[00055] if wherein R is produced in expectation
2Be methyl and R
20Be the compound of the formula V of low alkyl group alkylsulfonyl, can be with commercially available 2-methylbenzene thiophenol as starting material.In this reaction sequence, sulfydryl can become corresponding 2-methyl isophthalic acid-low alkyl group sulfo-benzene by ordinary method alkylation (for example using low alkyl group halogen).These compounds can be converted into corresponding 3-methyl-4-(lower alkylthio)-phenylacetic acid then.At first, 2-methyl isophthalic acid-low alkyl group sulfo-benzene can use (low alkyl group) oxalyl chloride (as methyl oxalyl chloride or ethyl oxalyl chloride) by friedel-crafts acylation reaction acidylate, produces the alpha-keto carboxylic acid ester in the contraposition of described lower alkylthio functional group.The alpha-keto carboxylic acid ester can be converted into alpha-keto carboxylic acid with the alpha-keto carboxylic acid ester by any ordinary method hydrolysis then.The Wolff-Kishner reduction of the alpha-keto carboxylic acid that obtains is with the compound of production V, wherein R
2Be methyl and R
20It is lower alkylthio.The lower alkylthio compound can be the low alkyl group sulfonyl compound of corresponding formula V by oxidation conversion then.The method that the alkylthio substituting group is oxidized to corresponding sulfuryl group of any routine can be used to implement this conversion.
[00056] if wherein R is produced in expectation
2Be methoxyl group and R
20Be the compound of the formula V of low alkyl group alkylsulfonyl, these compounds also can be as mentioned above by R wherein
2Be halogen and R
20It is the compound of low alkyl group alkylsulfonyl.In this reaction, the method with sodium methylate nucleophilic displacement aromatic halogen group of any routine can be used to implement this conversion.In case R wherein
2Be methoxyl group and R
20The compound that is the formula V of low alkyl group alkylsulfonyl can obtain, and they can be converted into accordingly wherein R
2Be hydroxyl and R
20It is the compound of the formula V of low alkyl group alkylsulfonyl.Any routine be that the method for aromatic hydroxy can be used to implement this conversion with aromatics methoxyl group demethylation.This R
2Be hydroxyl and R
20The compound that is the formula V of low alkyl group alkylsulfonyl must be protected in remaining reaction scheme.Aromatic hydroxy can be protected by the hydrolyzable ether protecting group of routine.When reaction scheme finished, the ether protecting group can be removed then to produce the wherein R corresponding to expectation
2It is the hydroxyl separately of compound of the formula I of hydroxyl.Alternatively, in case prepare wherein R according to reaction scheme
2Be the compound of the formula I of methoxyl group, this compound can be converted into the wherein R of expectation then
2It is the compound of the formula I of hydroxyl.Any routine be that the method for aromatic hydroxy can be used to implement this conversion with aromatics methoxyl group demethylation.
[00057] for the alkylated reaction of the alkylogen that uses formula VII, the directly alkylation or at first use the esterification process of any routine to be converted into the ester of the lower alkyl alcohol of corresponding formula VI, alkylation then of the carboxylic acid of formula V.In the alkylation step of reaction scheme, the compound of the dianion of the alkylogen of formula VII and formula V reaction production formula IX, or with the compound of the anionic reactive production formula VIII of formula VI.The compound of formula V and VI represents to have the organic acid and the organic acid derivatives of alpha-carbon atom, and the compound of formula VII is an alkylogen, so alkylation occurs on the alpha-carbon atom of carboxylic acid and carboxylicesters.This reaction is undertaken by the alkylating mode of alpha-carbon atom with the lower alkyl esters of carboxylic acid or carboxylic acid of any routine.Usually, in these alkylated reactions, the dianion of alkylogen and acetate or the anionic reactive that produces by acetic ester.Negatively charged ion can produce by using strong organic bases such as LDA or n-Butyl Lithium and other organolithium alkali.In carrying out this reaction, at low temperature, preferred-80 ℃ to-10 ℃ are used the lower boiling ether solvents down, as tetrahydrofuran (THF).Yet, can use-80 ℃ of any temperature to room temperature.If desired, alkylated reaction can use fluoroform sulphonate alkylation subunit to replace the halogen alkylation subunit of compound VI I to carry out.These fluoroform sulphonate alkylated reactions can carry out according to known method in the synthetic organic chemistry field.
[00058] compound of formula VIII can be converted into the compound of formula IX by the method that carboxylicesters is converted into carboxylic acid of any routine.The compound of formula IX passes through the peptide coupling condensation of routine, the compound of production formula I then with the compound of formula X.In carrying out this reaction, the method with primary amine and carboxylic acid condensation of any routine can be used to implement this conversion.
[00059] R wherein
3The alkylogen that is cyclobutyl [cyclobutylmethyl bromine] or cyclohexyl [cyclohexyl methyl bromine] is commercially available.R wherein
3The alkylogen of formula VII that is cyclopentyl [iodo-methyl pentamethylene] is known in chemical literature, and the synthetic of this compound described in an embodiment.
[00060] the amino heteroaromatics of formula X is known or can be by those skilled in the art by use the synthetic improvement preparation that transforms of the standard report in chemical literature in chemical literature.For the compound of production formula I, synthetic conversion as herein described is to produce the R of expectation
4The compound that substituting group can occur in formula X is converted into before or after the compound of formula I.
[00061] for example, if wherein R is produced in expectation
4Be the amino heteroaromatics of the formula X of methylthio group, known wherein R
4Be that the amino heteroaromatics of the formula X of bromine can be used as starting material (if Y=CH, the compound of formula X is commercially available 2-amino-5-bromopyridine so; If Y=N, the compound of formula X is known 2-amino-5-bromo-pyrazine so, and it can be according to Tetrahedron 1988,44, the 2977-2983 preparation).In this reactions steps, bromine substituent can be converted into wherein R
4It is the compound of the substituent formula X of methylthio group.Can being used to implement this conversion with the substituent method of sulfo-sodium methylate nucleophilic displacement aromatic bromine (Tetrahedron 2002,58,1125-1129) of any routine.The wherein R that produces
4The compound that is the formula X of methylthio group can pass through conventional peptide coupling condensation with the compound of formula IX then, produces the wherein R of expectation
4It is the compound of the formula I of methylthio group.In carrying out this reaction, any ordinary method with primary amine and carboxylic acid condensation can be used to implement this conversion.
[00062] in case R wherein
4The compound that is the formula I of methylthio group can obtain, and they can be converted into accordingly wherein R
4It is the compound of the formula I of methylsulfinyl.Any ordinary method that the methylthio group substituting group is oxidized to methylsulfinyl substituting group (sulfoxide) can be used to implement this conversion.On the other hand, if wherein R is produced in expectation
4Be the compound of the formula I of methylsulfonyl, wherein R
4The compound that is the formula I of methylthio group also can be used as starting material.The methylthio group substituting group being oxidized to methyl-sulphoxide substituting group method and can being used to implement this conversion of any routine.
[00063] if wherein R is produced in expectation
4It is the amino heteroaromatics of the formula X of (methylthio group) methyl, following known heteroaromatics can be used as starting material: (1) is in formula X, if Y=CH, so known 5-picoline-2-carboxylic acid, it can be according to J.Am.Chem.Soc.1956,78,1932-1934 can be used as starting material; (2) in formula X, if the so commercially available 5-methylpyrazine of Y=N-2-carboxylic acid can be used as starting material.5-(methyl) hetero-aromatic ring-2-carboxylic acid can be converted into corresponding acylazide.The method that carboxylic acid is converted into acylazide of any routine can be used to implement this conversion.The pyrolytic Ku Ertisi of acylazide in the presence of the trimethyl carbinol that relates to acquisition resets wherein R can be provided
4It is the compound of methyl and wherein amino formula X as the t-butyl carbamate protection.5-(methyl) hetero-aromatic ring-2-t-butyl carbamate then can bromination so that 5-(brooethyl) hetero-aromatic ring-2-t-butyl carbamate to be provided.The benzylic bromination process of any routine can be used to implement this conversion.5-(brooethyl) substituting group that obtains can be converted into corresponding 5-[(methylthio group then) methyl] substituting group.In this reaction, the method with sulfo-sodium methylate nucleophilic displacement benzylic bromide of any routine can be used to implement this conversion.Under standard conditions, the t-butyl carbamate deprotection can be provided the wherein R of expectation
4It is the amino heteroaromatics of the formula X of (methylthio group) methyl.The wherein R that obtains
4The compound that is the formula X of (methylthio group) methyl can pass through conventional peptide coupling condensation with the compound of formula IX then, produces the wherein R of expectation
4It is the compound of the formula I of (methylthio group) methyl.When carrying out this reaction, the method with primary amine and carboxylic acid condensation of any routine can be used to implement this conversion.
[00064] in case R wherein
4The compound that is the formula I of (methylthio group) methyl can obtain, and they can be converted into accordingly wherein R
4It is the compound of the formula I of (methylsulfinyl) methyl.The method that the methylthio group substituting group is oxidized to methylsulfinyl substituting group (sulfoxide) of any routine can be used to implement this conversion.On the other hand, if wherein R is produced in expectation
4Be the compound of the formula I of (methylsulfonyl) methyl, wherein R
4The compound that is the formula I of (methylthio group) methyl also can be used as starting material.The methylthio group substituting group being oxidized to the substituent method of methyl-sulphoxide and can being used to implement this conversion of any routine.
[00065] if wherein R is produced in expectation
4Be the compound of formula I of the substituting group (amidoxim substituting group) of N-(hydroxyl)-Imidamide (carboximidamide), wherein R
4The compound that is the formula I of bromine can be used as starting material.In this reaction sequence, above-mentioned known wherein R
4Be bromine formula X compound can with the compound of formula IX by conventional peptide coupling condensation, to produce the wherein R of expectation
4It is the compound of the formula X of bromine.In carrying out this reaction, the method with primary amine and carboxylic acid condensation of any routine can be used to implement this conversion.In case R wherein
4The compound that is the formula I of bromine can obtain, and bromine substituent can be converted into wherein R then
4It is the compound of the formula I of cyano group.Any routine with cyano group transfering reagent [as cupric cyanide (I)] method of aromatic bromine substituting group nucleophilic displacement can be used to implement this conversion.Finally, the cyano group substituting group of acquisition can be converted into wherein R then
4It is the compound of the formula I of N-(hydroxyl)-Imidamide substituting group (amidoxim substituting group).Any routine the cyano group substituting group is converted into N-(hydroxyl)-the method for Imidamide substituting group (amidoxim substituting group) can be used to implement this conversion.
[00066] on the other hand, if wherein R is produced in expectation
4Be 5-amino-[compound of the formula I of 1,2,4] oxadiazole rings, wherein R
4The compound that is N-(hydroxyl)-substituent above-mentioned formula I of Imidamide can be used as starting material.R wherein
4The compound that is N-(hydroxyl)-substituent formula I of Imidamide can be handled with N-cyano group piperidines, so that wherein R to be provided
4Be 5-amino-[compound of the formula I of 1,2,4] oxadiazole rings (and Nippon Kagaku Kaishi 1987,10,1807-1812).
[00067] if wherein R is produced in expectation
4Be 5-methyl-[compound of the formula I of 1,2,4] oxadiazole rings, wherein R
4The compound that is N-(hydroxyl)-substituent above-mentioned formula I of Imidamide also can be used as starting material.R wherein
4The compound that is N-(hydroxyl)-substituent formula I of Imidamide can be handled so that wherein R to be provided with acetic anhydride
4Be the 5-methyl-[compound of the formula I of 1,2,4] oxadiazole rings, (and J.Med.Chem.1991,34,2726-2735).
[00068] if wherein R is produced in expectation
4Be the compound of (cyano group-oxyimino-methyl) substituent formula I, wherein R
4The compound that is methyl and wherein amino protected above-mentioned formula I for t-butyl carbamate can be used as starting material.5-(methyl) hetero-aromatic ring-2-t-butyl carbamate then can bromination, so that 5-(brooethyl) hetero-aromatic ring-2-t-butyl carbamate to be provided.The method of the benzylic bromination of any routine can be used to implement this conversion.5-(brooethyl) substituting group that produces can be converted into corresponding 5-(cyano methyl) substituting group then.In this reaction, the method with cyano group transfering reagent nucleophilic displacement benzylic bromide of any routine can be used to implement this conversion.T-butyl carbamate deprotection under standard conditions can provide the wherein R of expectation
4It is the amino heteroaromatics of the formula X of cyano methyl.The wherein R that produces
4The compound that is the formula X of cyano methyl can pass through conventional peptide coupling condensation with the compound of formula IX then, produces the wherein R of expectation
4It is the compound of the formula I of cyano methyl.In carrying out this reaction, the method with primary amine and carboxylic acid condensation of any routine can be used to implement this conversion.In case R wherein
4The compound that is the formula X of cyano methyl can obtain, and the cyano methyl substituting group can be converted into wherein R then
4It is the compound of (cyano group-oxyimino-methyl) substituent formula I.The cyano methyl substituting group being converted into (cyano group-oxyimino-methyl) substituent method and can being used to implement this conversion (US4539328) of any routine.
[00069] if expectation generates wherein R
4Be the compound of 2-hydroxyl ethylmercapto group substituting group or the substituent formula I of 2-methoxyl group ethylmercapto group, wherein R
4The compound that is the above-mentioned formula I of bromine can be used as starting material.Bromine substituent in the compound of formula I can be converted into wherein R
4It is the compound of 2-hydroxyl ethylmercapto group substituting group or the substituent formula I of 2-methoxyl group ethylmercapto group.Any routine can be used to implement this conversion with mercaptoethanol or the substituent method of 2-methoxyl group sulfur alcohol nucleophilic displacement aromatic bromine.
[00070] if expectation generates wherein R
4Be 3-replacement-1-propine substituting group or 4-replacement-ethyl acetylene substituting group ,-C ≡ C-(CH
2)
p-R
8The compound of formula I, R wherein
8Be that hydroxyl, methoxyl group or dimethylamine and p are 1 or 2, R wherein
4The compound that is the above-mentioned formula I of bromine can be used as starting material.Bromine substituent in the compound of formula I can be converted into wherein R
4Be 3-replacement-1-propine substituting group or 4-replacement-ethyl acetylene substituting group ,-C ≡ C-(CH
2)
p-R
8The compound of formula I, R wherein
8Be that hydroxyl, methoxyl group or dimethylamine and p are 1 or 2.The method (for example propargyl alcohol and 3-butine-1-alcohol) with aryl bromide catalysis replaced acetylene hydrogen of any routine, as the Sonogashira reaction, can be used to implement this conversion (about summary, referring to Campbell, I.B.Organocopper Reagents 1994,217-235).
[00071] if wherein R is produced in expectation
4Be the compound of 4-ethynyl tetrahydropyrans-substituent formula I of 4-alcohol, wherein R
4The compound that is the above-mentioned formula I of bromine also can be used as starting material.In this reactions steps, commercially available tetrahydrochysene-4H-pyrans-4-ketone can generate the compound with acetylene hydrogen of expectation, 4-ethynyl tetrahydrochysene-2H-pyrans-4-alcohol with commercially available ethynyl bromination reactive magnesium.R wherein
4The compound that is the above-mentioned formula I of bromine can generate wherein R with 4-ethynyl tetrahydrochysene-2H-pyrans-4-alcohol reaction then
4It is the compound of 4-ethynyl tetrahydropyrans-substituent formula I of 4-alcohol.The method with aryl bromide catalysis replaced acetylene hydrogen of any routine, the reaction as Sonogashira can be used to implement this conversion.
[00072] in case R wherein
4The compound that is 4-ethynyl tetrahydropyrans-substituent formula I of 4-alcohol can obtain, and they can be converted into accordingly wherein R
4It is the compound of 4-ethyl tetrahydropyrans-substituent formula I of 4-alcohol.Hetero-aromatic ring 4-ethynyl tetrahydropyrans-4-alcohol substituting group can reduce to produce corresponding hetero-aromatic ring 4-ethyl tetrahydropyrans-4-alcohol substituting group.The method that alkynes is reduced into stable hydrocarbon of any routine can be used to implement this conversion.
[00073] on the other hand, if expectation generates wherein R
4Be-C ≡ C-C (CH
3)
2The compound of the substituent formula I of-OH, wherein R
4The compound that is the above-mentioned formula I of bromine also can be used as starting material.R wherein
4The compound that is the formula I of bromine can generate wherein R with 2-methyl-3-butyne-2-alcohol reaction
4Be-C ≡ C-C (CH
3)
2The compound of the substituent formula I of-OH.The method with aryl bromide catalysis displacement acetylene hydrogen of any routine as the Sonogashira reaction, can be used to implement this conversion.
[00074] if expectation generates wherein R
4Be N-Toluidrin substituting group or N, the compound of the formula I of N-two Toluidrins, wherein R
4The compound that is the above-mentioned formula I of methylsulfinyl (methyl-sulphoxide) can be used as starting material.R wherein
4The compound that is the formula I of methylsulfinyl can be converted into wherein R then
4It is the compound of the formula I of mercaptan.A kind of two-stage process can be used to implement this conversion, relates to the Pummerer methyl-sulphoxide that uses trifluoacetic anhydride and reset in this two-stage process, then the intermediate of resetting with triethylamine and methyl alcohol hydrolysis Pummerer.In case R wherein
4The compound that is the formula I of mercaptan can obtain, and these compounds can be converted into wherein R
4It is the compound of the formula I of SULPHURYL CHLORIDE.The mercaptan substituting group being oxidized to the substituent method of SULPHURYL CHLORIDE and can being used to implement this conversion of any routine.Finally, the wherein R of generation
4Be the wherein R that the compound of the formula I of SULPHURYL CHLORIDE can be converted into expectation then
4Be N-Toluidrin substituting group or N, the compound of the formula I of N-diformazan sulfonamide substitutions base.The reaction of SULPHURYL CHLORIDE substituting group and methylamine being generated N-Toluidrin substituting group or generate N with the dimethylamine reaction of any routine, the method for N-diformazan sulfonamide substitutions base can be used to implement this conversion.
[00075] if expectation generates wherein R
4Be the compound of the formula I of dimethoxy-methyl, following known heteroaromatics can be used as starting material: (1) is in formula I, if Y=CH, so known 5-picoline-2-carboxylic acid can be used as starting material; (2) in formula I, if the so commercially available 5-methylpyrazine of Y=N-2-carboxylic acid can be used as starting material.Generating wherein R
4Be in this reactions steps of compound of formula I of dimethoxy-methyl, carboxylic acid can be esterified and methyl can use dimethylformamide dimethyl acetal to be converted into N simultaneously, N-dimethyl-vinyl-amine (ethenamine).Aromatics N, N-dimethyl-vinyl-amine functional group then can oxicracking to generate corresponding hetero-aromatic ring aldehyde.Any routine become the method for aldehyde can be used to implement this conversion vinyl-dimethyl amine oxicracking.The hetero-aromatic ring aldehyde that produces can be converted into corresponding hetero-aromatic ring dimethylacetal then.The method that aldehyde is converted into dimethylacetal of any routine can be used to implement this conversion.5-(dimethoxy-methyl) hetero-aromatic ring-2-carboxylate methyl ester that produces can be converted into corresponding carboxylic acid then.The method that carboxyester hydrolysis is become carboxylic acid under alkaline condition of any routine can be used to implement this conversion.Next, 5-(dimethoxy-methyl) hetero-aromatic ring-2-carboxylic acid can be converted into corresponding acylazide.The method that carboxylic acid is converted into acylazide of any routine can be used to implement this conversion.The Ku Ertisi that relates to the acylazide that pyrolysis produces in the presence of phenylcarbinol resets wherein R can be provided
4It is the compound of dimethoxy-methyl and wherein amino protected formula X for benzyl carbamate.The deprotection of benzyl carbamate under the standard hydrogenation conditions can provide the wherein R of expectation
4It is the compound of the formula X of dimethoxy-methyl.The wherein R that produces
4The compound that is the formula X of dimethoxy-methyl can pass through conventional peptide coupling condensation with the compound of formula IX then, generates the wherein R of expectation
4It is the compound of the formula I of dimethoxy-methyl.In carrying out this reaction, the method with primary amine and carboxylic acid condensation of any routine can be used to implement this conversion.
[00076] if expectation generates wherein R
4Be 1,3-dioxolane-2-base or R wherein
4Be 1, the compound of the formula I of 3-diox-2-base, these compounds can be according to above-mentioned reaction sequence preparation.For cyclic acetal rather than the acyclic dimethylacetal for preparing expectation, when separating the reactions steps of hetero-aromatic ring aldehyde therein behind oxicracking, the aldehyde of generation can be converted into 1 of expectation, 1 of 3-dioxolane cyclic acetal or expectation, 3-diox cyclic acetal.Any routine aldehyde and glycol reaction are generated 1,3-dioxolane cyclic acetal or with aldehyde and 1, ammediol reaction generation 1, the method for 3-diox cyclic acetal can be used to implement this conversion.In case generate the cyclic acetal of expectation, aforesaid remaining reaction sequence can be used to generate wherein R
4Be 1,3-dioxolane-2-base or R wherein
4Be 1, the compound of the formula I of 3-diox-2-base.
[00077] if expectation generates wherein R
4Be 2, the compound of the formula I of 2-(dimethoxy) ethyl, following known heteroaromatics can be used as starting material: (1) is in formula I, if Y=CH, so known 5-picoline-2-carboxylic acid can be used as starting material; (2) in formula I, if Y=N, so commercially available 5-methylpyrazine-2-carboxylic acid can be used as starting material.Generating wherein R
4Be 2, in this reactions steps of the compound of the formula I of 2-(dimethoxy) ethyl, carboxylic acid can be esterified and methyl can use dimethylformamide dimethyl acetal to be converted into N simultaneously, N-dimethyl-vinyl-amine.N, N-dimethyl-vinyl-amine functional group can hydrolysis generate corresponding aldehyde then.The method that enamine is hydrolyzed into aldehyde of any routine can be used to implement this conversion.The hetero-aromatic ring acetaldehyde that produces can be converted into corresponding dimethylacetal then.The method that aldehyde is converted into dimethylacetal of any routine can be used to implement this conversion.The 5-[2 that produces, 2-(dimethoxy) ethyl] hetero-aromatic ring-2-carboxylate methyl ester can be converted into corresponding carboxylic acid then.The method that carboxyester hydrolysis is become carboxylic acid under alkaline condition of any routine can be used to implement this conversion.Next, 5-[2,2-(dimethoxy) ethyl] hetero-aromatic ring-2-carboxylic acid can be converted into corresponding acylazide.The method that carboxylic acid is converted into acylazide of any routine can be used to implement this conversion.The Ku Ertisi that relates to the acylazide that pyrolysis produces in the presence of phenylcarbinol resets wherein R can be provided
4Be 2,2-(dimethoxy) ethyl and wherein amino protected be the compound of the formula X of benzyl carbamate.The deprotection of benzyl carbamate under the standard hydrogenation conditions can provide the wherein R of expectation
4Be 2, the compound of the formula X of 2-(dimethoxy) ethyl.The wherein R that produces
4Be 2, the compound of the formula X of 2-(dimethoxy) ethyl can pass through conventional peptide coupling condensation with the compound of formula IX then, generates the wherein R of expectation
4Be 2, the compound of the formula I of 2-(dimethoxy) ethyl.In carrying out this reaction, the method with primary amine and carboxylic acid condensation of any routine can be used to implement this conversion.
[00078] if expectation generates wherein R
4Be (1,3-dioxolane-2-yl) methyl or R wherein
4Be the compound of the formula I of (1,3-diox-2-yl) methyl, these compounds can be according to above-mentioned reaction sequence preparation.For cyclic acetal rather than the acyclic dimethylacetal for preparing expectation, when separating the reactions steps of hetero-aromatic ring acetaldehyde therein after hydrolysis, the acetaldehyde of generation can be converted into 1 of expectation, 1 of 3-dioxolane cyclic acetal or expectation, 3-diox cyclic acetal.Any routine aldehyde and glycol reaction are generated 1,3-dioxolane cyclic acetal or with aldehyde and 1, ammediol reaction generation 1, the method for 3-diox cyclic acetal can be used to implement this conversion.In case generate the cyclic acetal of expectation, aforesaid remaining reactions steps can be used to generate wherein R
4Be (1,3-dioxolane-2-yl) methyl or R wherein
4It is the compound of the formula I of (1,3-diox-2-yl) methyl.
[00079] if expectation generates wherein R
4Be (2,3-dihydroxyl-propoxy-) compound of formula I, following known heteroaromatics can be used as starting material: (1) is in formula I, if Y=CH, so known 5-chloro-pyridine-2-carboxylic acids methyl esters can be used as starting material, it can be according to Tetrahedron Lett.1999, and 40, the 3719-3722 preparation; (2) in formula I, if Y=N, so commercially available methyl 5-chloropyrazine-2-carboxylicesters can be used as starting material.In this reactions steps, under heating condition, preferred 90 ℃ to 100 ℃, use vinyl carbinol and potassium hydroxide simultaneously, the 5-chlorine substituent can be by displacement generating 5-allyloxy substituting group, 2-carboxylate methyl ester substituting group can hydrolysis to generate the 2-carboxylic acid.Next, 5-[allyloxy] hetero-aromatic ring-2-carboxylic acid can be converted into corresponding acylazide.The method that carboxylic acid is converted into acylazide of any routine can be used to implement this conversion.The Ku Ertisi that relates to the acylazide that pyrolysis produces in the presence of the trimethyl carbinol resets wherein R can be provided
4It is the compound of allyloxy substituting group and wherein amino protected formula X for t-butyl carbamate.The deprotection of t-butyl carbamate under the standard acidic condition can provide the wherein R of expectation
4It is the compound of the formula X of allyloxy.The wherein R that produces
4The compound that is the formula X of allyloxy can pass through conventional peptide coupling condensation with the compound of formula IX then, generates the wherein R of expectation
4It is the compound of the substituent formula I of allyloxy.In carrying out this reaction, the method with primary amine and carboxylic acid condensation of any routine can be used to implement this conversion.In case R wherein
4The compound that is the formula I of allyloxy can obtain, and they can be converted into the wherein R of expectation
4It is the compound of [2 (S), 3-dihydroxyl-propoxy-] substituting group, [2 (R), 3-dihydroxyl-propoxy-] substituting group or (2,3-dihydroxyl-propoxy-) substituent formula I.The allyloxy substituting group can stand the asymmetric bishydroxy condition of Sharpless to generate chiral diol (Chem.Rev.1994,94, the 2483-2547 of expectation; J.Chem.Soc., Perkin Trans.1,1999,3015-3018).R wherein
4The compound that is the formula I of allyloxy can use (DHQD)
2PHAL[hydroquinidine 1,4-phthalazines two basic diether] stand the asymmetric bishydroxy condition of Sharpless to generate the wherein R of expectation
4It is the compound of [2 (S), 3-dihydroxyl-propoxy-] substituent formula I.On the other hand, R wherein
4The compound that is the formula I of allyloxy can use (DHQD)
2PHAL[hydroquinidine 1,4-phthalazines two basic diether] stand the asymmetric bishydroxy condition of Sharpless to generate the wherein R of expectation
4It is the compound of [2 (R), 3-dihydroxyl-propoxy-] substituent formula I.If R wherein
4The compound that is the formula I of allyloxy stands conventional non--asymmetric bishydroxy condition, can prepare wherein R
4It is the racemic diol of (2,3-dihydroxyl-propoxy-) substituent formula I.According to the present invention, the preferred steric configuration at hydroxy functional group chiral centre place is " R ".
[00080] if expectation generates wherein R
4Be (2,3-dihydroxyl-propyl group) substituent compound, known wherein R
4The amino heteroaromatics that is the formula X of bromine can be used as starting material.In this reactions steps, bromine substituent can be converted into wherein R
4It is the compound of the substituent formula X of allyl group.The palladium mediated heteroaromatic bromine substituent and the Stille linked reaction of commercially available allyl group tri-n-butyl tin can be used to implement this conversion.The wherein R that produces
4The compound that is the substituent formula X of allyl group can pass through conventional peptide coupling condensation with the compound of formula IX then, to generate the wherein R of expectation
4It is the compound of the substituent formula I of allyl group.In carrying out this reaction, the method with primary amine and carboxylic acid condensation of any routine can be used to implement this conversion.In case R wherein
4The compound that is allylic formula I can obtain, and they can be converted into the wherein R of expectation
4It is the compound of [2 (R), 3-dihydroxyl-propyl group] substituting group, [2 (S), 3-dihydroxyl-propyl group] substituting group or (2,3-dihydroxyl-propyl group) substituent formula I.The allyl group substituting group can stand the asymmetric bishydroxy condition of Sharpless to generate the chiral diol of expectation.R wherein
4The compound that is allylic formula I can use (DHQD)
2PHAL stands the asymmetric bishydroxy condition of Sharpless to generate the wherein R of expectation
4It is the compound of [2 (R), 3-dihydroxyl-propyl group] substituent formula I.On the other hand, R wherein
4The compound that is allylic formula I can use (DHQD)
2PHAL stands the conventional asymmetric bishydroxy condition of Sharpless to generate the wherein R of expectation
4It is the compound of [2 (S), 3-dihydroxyl-propyl group] substituent formula I.If R wherein
4The compound that is allylic formula I stands conventional non--asymmetric bishydroxy condition, can prepare wherein R
4It is the racemic diol of (2,3-dihydroxyl-propyl group) substituent formula I.According to the present invention, the preferred steric configuration at hydroxy functional group chiral centre place is " R ".
[00081] if expectation generates wherein R
4Be the compound of (1,2-dihydroxyl-ethyl) substituent formula I, known wherein R
4The amino heteroaromatics that is the formula X of bromine also can be used as starting material.In this reactions steps, bromine substituent can be converted into wherein R
4It is the compound of the formula X of vinyl substituted base.The palladium mediated heteroaromatic bromine substituent and the Stille linked reaction of commercially available allyl group tri-n-butyl tin can be used to implement this conversion.The wherein R that produces
4The compound that is the substituent formula X of allyl group can pass through conventional peptide coupling condensation with the compound of formula IX then, to generate the wherein R of expectation
4It is the compound of the substituent formula I of allyl group.In carrying out this reaction, the method with primary amine and carboxylic acid condensation of any routine can be used to implement this conversion.In case R wherein
4The compound that is allylic formula I can obtain, and they can be converted into the wherein R of expectation
4It is the compound of [1 (R), 2-dihydroxyl-ethyl] substituting group, [1 (S), 2-dihydroxyl-ethyl] substituting group or (1,2-dihydroxyl-ethyl) substituent formula I.The allyl group substituting group can stand the asymmetric bishydroxy condition of Sharpless to generate the chiral diol of expectation.R wherein
4The compound that is allylic formula I can use (DHQD)
2PHAL stands the conventional asymmetric bishydroxy condition of Sharpless to generate the wherein R of expectation
4It is the compound of [1 (R), 2-dihydroxyl-ethyl] substituent formula I.On the other hand, R wherein
4The compound that is allylic formula I can use (DHQD)
2PHAL stands the conventional asymmetric bishydroxy condition of Sharpless to generate the wherein R of expectation
4It is the compound of [1 (S), 2-dihydroxyl-ethyl] substituent formula I.If R wherein
4The compound that is allylic formula I stands conventional non--asymmetric bishydroxy condition, can prepare wherein R
4It is the racemic diol of (1,2-dihydroxyl-ethyl) substituent formula I.According to the present invention, the preferred steric configuration at hydroxy functional group chiral centre place is " S ".
[00082] if expectation generates wherein R
4Be the compound of (1,2-dihydroxyl-2-methyl-propyl group) substituent formula I, known wherein R
4The amino heteroaromatics that is the formula X of bromine also can be used as starting material.In this reaction sequence, bromine substituent can be converted into wherein R
4It is the compound of the substituent formula X of isobutenyl.The palladium mediated heteroaromatic bromine substituent and the Stille linked reaction of known isobutenyl tri-n-butyl tin can be used to implement this conversion.The wherein R that produces
4The compound that is the substituent formula X of isobutenyl can pass through conventional peptide coupling condensation with the compound of formula IX then, to generate the wherein R of expectation
4It is the compound of the substituent formula I of isobutenyl.In carrying out this reaction, the method with primary amine and carboxylic acid condensation of any routine can be used to implement this conversion.In case R wherein
4The compound that is the formula I of isobutenyl can obtain, and they can be converted into the wherein R of expectation
4It is the compound of [1 (R), 2-dihydroxyl-2-methyl-propyl group] substituting group, [1 (S), 2-dihydroxyl-2-methyl-propyl group] substituting group or (1,2-dihydroxyl-2-methyl-propyl group) substituent formula I.The isobutenyl substituting group can stand the asymmetric bishydroxy condition of Sharpless to generate the chiral diol of expectation.R wherein
4The compound that is the formula I of isobutenyl can use (DHQD)
2PHAL stands the conventional asymmetric bishydroxy condition of Sharpless to generate the wherein R of expectation
4It is the compound of [1 (R), 2-dihydroxyl-2-methyl-propyl group] substituent formula I.On the other hand, R wherein
4The compound that is the formula I of isobutenyl can use (DHQD)
2PHAL stands the conventional asymmetric bishydroxy condition of Sharpless to generate the wherein R of expectation
4It is the compound of [1 (S), 2-dihydroxyl-2-methyl-propyl group] substituent formula I.If R wherein
4The compound that is the formula I of isobutenyl stands conventional non--asymmetric bishydroxy condition, can prepare wherein R
4It is the racemic diol of (1,2-dihydroxyl-2-methyl-propyl group) substituent formula I.According to the present invention, the preferred steric configuration at hydroxy functional group chiral centre place is " S ".
[00083] if expectation generates wherein R
4Be-NHCH
2CH
2OCH
3(2-methoxyl group-ethylamino) substituting group or R wherein
4Be-OCH
2CH
2OCH
3The compound of (2-methoxyl group-oxyethyl group) substituent formula I, following known heteroaromatics can be used as starting material: (1) is in formula I, if Y=CH, so commercially available 5-bromo-2-nitropyridine can be used as starting material; (2) in formula X, if the so known 2-bromo-of Y=N 5-nitro pyrazine can be used as starting material, it can be according to Tetrahedron1988, and 44, the 2977-2983 preparation.In this reaction sequence, bromine substituent can be converted into wherein R
4Be (2-methoxyl group-ethylamino) substituting group or R wherein
4It is the compound of (2-methoxyl group-oxyethyl group) substituent formula X.Any routine can be used to implement this conversion with 2-methoxyethyl amine or the substituent method of 2-methyl cellosolve nucleophilic displacement aromatic bromine respectively.In case the 5-[2-methoxyl group-ethylamino that produces]-the 5-[2-methoxyl group-oxyethyl group of 2-nitro-heteroaromatics and generation]-2-nitro-heteroaromatics can obtain, and nitro substituent can be converted into wherein R
4Be (2-methoxyl group-ethylamino) substituting group of expectation or the amino heteroaromatics of (2-methoxyl group-oxyethyl group) substituent formula X of expectation.Nitro substituent being reduced into amino substituent method and can being used to implement this conversion of any routine.These are R wherein
4Be-NHCH
2CH
2OCH
3Substituting group or R wherein
4Be-OCH
2CH
2OCH
3The compound of substituent formula X then can with the compound of formula IX by conventional peptide coupling condensation, generate the wherein R of expectation respectively
4Be-NHCH
2CH
2OCH
3Substituting group or R wherein
4Be-OCH
2CH
2OCH
3The compound of substituent formula I.In carrying out this reaction, the method with primary amine and carboxylic acid condensation of any routine can be used to implement this conversion.
[00084] if expectation generates wherein R
4Be-NHCH
2CH
2OH (2-hydroxyl-ethylamino) substituting group or R wherein
4Be-OCH
2CH
2The compound of the substituent formula I of OH (2-hydroxyl-oxyethyl group), following known heteroaromatics can be used as starting material: (1) is in formula X, if Y=CH, so commercially available 5-bromo-2-nitropyridine can be used as starting material; (2) in formula X, if the so known 2-bromo-of Y=N 5-nitro pyrazine can be used as starting material.In this reaction sequence, bromine substituent can be converted into wherein R
4Be [2-(tetrahydropyrans-2-base oxygen base)-ethylamino] substituting group or R wherein
4It is the compound of [2-(tetrahydropyrans-2-base oxygen base)-oxyethyl group] substituent formula X.Any routine use respectively known 2-tetrahydropyrans-2-base oxygen base-ethamine (J.Med.Chem.1999,42,1587-1603) or the substituent method of commercially available 2-(2-hydroxyl-oxethyl) tetrahydropyrans nucleophilic displacement aromatic bromine can be used to implement this conversion.In case the 5-[2-that produces (tetrahydropyrans-2-base oxygen base)-ethylamino]-5-[2-(tetrahydropyrans-2-base oxygen base)-oxyethyl group of 2-nitro-heteroaromatics and generation]-2-nitro-heteroaromatics can obtain, and nitro substituent can be converted into wherein R
4It is the amino heteroaromatics of [2-(tetrahydropyrans-2-base oxygen base)-ethylamino] substituting group or [2-(tetrahydropyrans-2-base oxygen base)-oxyethyl group] substituent formula X.Nitro substituent being reduced into amino substituent method and can being used to implement this conversion of any routine.These are R wherein
4Be [2-(tetrahydropyrans-2-base oxygen base)-ethylamino] substituting group or [2-(tetrahydropyrans-2-base oxygen base)-oxyethyl group] substituent formula X compound then can with the compound of formula IX by conventional peptide coupling condensation, generate the wherein R that expects respectively
4It is the compound of [2-(tetrahydropyrans-2-base oxygen base)-ethylamino] substituting group or [2-(tetrahydropyrans-2-base oxygen base)-oxyethyl group] substituent formula I.In carrying out this reaction, the method with primary amine and carboxylic acid condensation of any routine can be used to implement this conversion.In case R wherein
4The compound that is [2-(tetrahydropyrans-2-base oxygen base)-ethylamino] substituting group or [2-(tetrahydropyrans-2-base oxygen base)-oxyethyl group] substituent formula I can obtain, and they can be converted into the wherein R of expectation then
4Be-NHCH
2CH
2OH (2-hydroxyl-ethylamino) substituting group or R wherein
4Be-OCH
2CH
2The compound of the substituent formula I of OH (2-hydroxyl-oxyethyl group).Any routine THP trtrahydropyranyl ether deprotection can be used to implement this conversion with the method that generates hydroxyl.
[00085] if expectation generates wherein R
4Be the amino heteroaromatics of the amino substituent formula X of methylsulfonyl, following known heteroaromatics can be used as starting material: (1) is in formula X, if Y=CH, so commercially available 5-bromo-2-nitropyridine can be used as starting material; (2) in formula X, if the so known 2-bromo-of Y=N 5-nitro pyrazine can be used as starting material.In this reaction sequence, bromine substituent can be converted into wherein R
4It is the compound of the amino substituent formula X of methylsulfonyl.Any routine can be used to implement this conversion with the substituent method of Toluidrin displacement aromatic bromine.In case the 5-[methylsulfonyl amino that produces]-2-nitro-heteroaromatics can obtain, and nitro substituent can be converted into wherein R
4It is the amino heteroaromatics of the amino substituent formula X of methylsulfonyl of expectation.Nitro substituent being reduced into amino substituent method and can being used to implement this conversion of any routine.These are R wherein
4The compound that is the formula X of methylsulfonyl amino can pass through conventional peptide coupling condensation to generate the wherein R of expectation then with the compound of formula IX
4It is the compound of the amino substituent formula I of methylsulfonyl.In carrying out this reaction, the method with primary amine and carboxylic acid condensation of any routine can be used to implement this conversion.
[00086] if expectation generates wherein R
4Be the amino heteroaromatics of the formula X of dimethylamino, following known heteroaromatics can be used as starting material: (1) is in formula X, if Y=CH, so commercially available 5-bromo-2-nitropyridine can be used as starting material; (2) in formula X, if the so known 2-bromo-of Y=N 5-nitro pyrazine can be used as starting material.In this reaction sequence, bromine substituent can be converted into wherein R
4It is the compound of the substituent formula X of dimethylamino.Any routine can be used to implement this conversion with the substituent method of dimethyl amine nucleophilic displacement aromatic bromine.In case the 5-[dimethylamino that produces]-2-nitro-heteroaromatics can obtain, and nitro substituent can be converted into wherein R
4It is the hetero-aromatic ring amine compound of the formula X of dimethylamino.Nitro substituent being reduced into amino substituent method and can being used to implement this conversion of any routine.These are R wherein
4The compound that is the formula X of dimethylamino can pass through conventional peptide coupling condensation to generate the wherein R of expectation then with the compound of formula IX
4It is the compound of the formula I of dimethylamino.In carrying out this reaction, the method with primary amine and carboxylic acid condensation of any routine can be used to implement this conversion.
[00087] if expectation generates wherein R
4Be the amino heteroaromatics of the formula X of (dimethylamino) methyl, following known heteroaromatics can be used as starting material: (1) is in formula X, if Y=CH, so known 5-picoline-2 carboxylic acid can be used as starting material; (2) in formula X, if the so commercially available 5-methylpyrazine of Y=N-2-carboxylic acid can be used as starting material.Generating wherein R
4Be that carboxylic acid can be converted into corresponding methyl esters in this reaction sequence of compound of formula X of (dimethylamino) methyl.The esterification process that carboxylic acid is converted into carboxylate methyl ester of any routine can be used to implement this conversion.5-(methyl) hetero-aromatic ring-2-carboxylate methyl ester then can bromination so that 5-(brooethyl) hetero-aromatic ring-2-carboxylate methyl ester to be provided.The method of the benzylic bromination of any routine can be used to implement this conversion.The Bromomethyl Substituted base that produces can be converted into corresponding (dimethylamino) methyl substituents then.In this reaction, the method with dimethylamine nucleophilic displacement bromotoluene of any routine can be used to implement this conversion.The 5-[(dimethylamino that produces) methyl] hetero-aromatic ring-2-carboxylate methyl ester can be converted into corresponding carboxylic acid then.The method that carboxyester hydrolysis is become carboxylic acid of any routine can be used to implement this conversion.Next, methyl 5-[(dimethylamino)] hetero-aromatic ring-2-carboxylic acid can be converted into corresponding acylazide.The method that carboxylic acid is converted into acylazide of any routine can be used to implement this conversion.The pyrolytic Ku Ertisi of acylazide in the presence of phenylcarbinol that relates to acquisition resets wherein R can be provided
4It is the compound of (dimethylamino) methyl and wherein amino formula X as the benzyl carbamate protection.The deprotection of benzyl carbamate under the standard hydrogenation conditions can provide the wherein R of expectation
4It is the amino-heterocyclic compounds of the formula X of (dimethylamino) methyl.The wherein R that obtains
4The compound that is the formula X of (dimethylamino) methyl can pass through conventional peptide coupling condensation with the compound of formula IX then, produces the wherein R of expectation
4It is the compound of the formula I of (dimethylamino) methyl.When carrying out this reaction, the method with primary amine and carboxylic acid condensation of any routine can be used to implement this conversion.
[00088] if expectation generates wherein R
4Be the amino heteroaromatics of the formula X of 2-(dimethylamino) ethyl, following known heteroaromatics can be used as starting material: (1) is in formula X, if Y=CH, so known 5-picoline-2 carboxylic acid can be used as starting material; (2) in formula X, if the so commercially available 5-methylpyrazine of Y=N-2-carboxylic acid can be used as starting material.Generating wherein R
4Be in this reaction sequence of compound of formula X of 2-(dimethylamino) ethyl, carboxylic acid can be esterified and methyl can use dimethylformamide dimethyl acetal to be converted into N simultaneously, N-dimethyl-vinyl-amine.Hetero-aromatic ring N, N-dimethyl-vinyl-amine substituting group can reduce then and generate corresponding hetero-aromatic ring 2-(dimethylamino) ethyl substituting group.The method that carbon-carbon double bond is reduced into stable hydrocarbon of any routine can be used to implement this conversion.5-[2-(dimethylamino) ethyl that produces] hetero-aromatic ring-2-carboxylate methyl ester can be converted into corresponding carboxylic acid then.The method that carboxyester hydrolysis is become carboxylic acid of any routine can be used to implement this conversion.Next, 5-[2-(dimethylamino) ethyl] hetero-aromatic ring-2-carboxylic acid can be converted into corresponding acylazide.The method that carboxylic acid is converted into acylazide of any routine can be used to implement this conversion.The Ku Ertisi that relates to the acylazide that pyrolysis produces in the presence of phenylcarbinol resets wherein R can be provided
4It is the compound of 2-(dimethylamino) ethyl and wherein amino protected formula X for benzyl carbamate.The deprotection of benzyl carbamate under the standard hydrogenation conditions can provide the wherein R of expectation
4It is the compound of the formula X of 2-(dimethylamino) ethyl.The wherein R that produces
4The compound that is the formula X of 2-(dimethylamino) ethyl can pass through conventional peptide coupling condensation with the compound of formula IX then, generates the wherein R of expectation
4It is the compound of the formula I of 2-(dimethylamino) ethyl.In carrying out this reaction, the method with primary amine and carboxylic acid condensation of any routine can be used to implement this conversion.
[00089] if expectation generates wherein R
4Be the compound of the formula I of 3-(dimethylamino) propyl group, wherein R
4The compound that is the formula I of bromine can be used as starting material.In this reaction sequence, above-mentioned known wherein R
4Be bromine formula X compound can with the compound of formula IX by conventional peptide coupling condensation, generate the wherein R of expectation
4It is the compound of the formula I of bromine.In carrying out this reaction, the method with primary amine and carboxylic acid condensation of any routine can be used to implement this conversion.In case R wherein
4The compound that is the formula I of bromine can obtain, and bromine substituent can be converted into wherein R then
4It is the compound of 3-(dimethylamino)-substituent formula I of 1-propine.The method of the acetylene hydrogen of using aryl bromide catalysis displacement 1-dimethylamino-2-propine of any routine as the Sonogashira reaction, can be used to implement this conversion.In case R wherein
4The compound that is the formula I of 3-(dimethylamino)-1-propine can obtain, and they can be converted into the wherein R of expectation
4It is the compound of the formula I of 3-(dimethylamino) propyl group.Hetero-aromatic ring 3-(dimethylamino)-1-propine substituting group can reduce and generate corresponding hetero-aromatic ring 3-(dimethylamino) propyl group substituting group.The method that alkynyl is reduced into stable hydrocarbon of any routine can be used to implement this conversion.
[00090] if expectation generates wherein R
4Be the compound of the substituent formula I of formyl radical, wherein R
4The compound that is the above-mentioned formula I of bromine can be used as starting material.In case R wherein
4The compound that is the formula I of bromine can obtain, and bromine substituent can be converted into wherein R then
4It is the compound of the substituent formula I of formyl radical.The method with the aryl bromide carbonylation of any routine can be used to implement this conversion.
[00091] if expectation generates wherein R
4Be corresponding to-CH (OH)-R
7Secondary alcohol substituting group and R
7Be the compound of the formula I of low alkyl group, wherein R
4The compound that is the substituent above-mentioned formula I of formyl radical can be used as starting material.In this reaction sequence, the formyl radical substituting group can be converted into wherein R
4Be corresponding to-CH (OH)-R
7Secondary alcohol substituting group and R
7It is the compound of the formula I of low alkyl group.The method that aldehyde is converted into primary alconol of any routine as the Grignard reaction, can be used to implement this conversion.
[00092] in case R wherein
4Be-CH (OH)-R
7And R
7The compound that is the formula I of low alkyl group can obtain, and the secondary alcohol substituting group can be converted into the wherein R of expectation then
4Be-C (=O)-R
11And R
11It is the compound of the formula I of low alkyl group.Pure substituting group being oxidized to the substituent method of ketone and can being used to implement this conversion of any routine.
[00093] in case R wherein
4Be-C (=O)-R
11And R
11The compound that is the formula I of low alkyl group can obtain, and the ketone substituting group can be converted into the wherein R of expectation then
4Be-C (=NOH)-R
10And R
10It is the compound of the formula I of low alkyl group.The ketone substituting group being converted into the substituent method of oxime and can being used to implement this conversion of any routine.
[00094] on the other hand, if expectation generates wherein R
4Be corresponding to-CH (OH)-R
7Cyanohydrin substituting group and R
7Be the compound of the formula I of cyano group, wherein R
4The compound that is the substituent above-mentioned formula I of formyl radical also can be used as starting material.In this reaction sequence, the formyl radical substituting group can be converted into wherein R
4Be corresponding to-CH (OH)-R
7Cyanohydrin substituting group and R
7It is the compound of the formula I of cyano group.The aldehyde substituting group being converted into the substituent method of cyanohydrin and can being used to implement this conversion of any routine.In case R
4The compound that is the substituent formula I of cyanohydrin can obtain, and the cyano group substituting group can be converted into wherein R then
4Be-CH (OH)-R
7And R
7Be-C (=O) NH
2The compound of formula I.The method that nitrile is hydrolyzed into acid amides of any routine can be used to implement this conversion.
[00095] if expectation generates wherein R
4Be the compound of (2,4-dioxo-thiazolidine-5-ylmethyl) substituent formula I, wherein R
4The compound that is the substituent above-mentioned formula I of formyl radical can be used as starting material.In this reaction sequence, the formyl radical substituting group can be with 2, and the reaction of 4-thiazolidinedione provides accordingly wherein R
4Be compound (J.Med.Chem.1998,41, the 1619-1630 of (2,4-dioxo-thiazolidine-5-ylidenylmethyl) substituent formula I; PCT Intl.Appl.9743283,20 Nov.1997).R wherein
4The compound that is (2,4-dioxo-thiazolidine-5-ylidenylmethyl) substituent formula I then can be by using 2 in the toluene, 6-dimethyl-1, and 4-dihydro-pyridine-3,5-diethyl dicarboxylate and silica gel reduction carbon-to-carbon double bond are converted into the wherein R of expectation
4It is the compound of (2,4-dioxo-thiazolidine-5-ylmethyl) substituent formula I.
[00096] if expectation generates wherein R
4Be the compound of (2,5-dioxo-imidazolidine-4-ylmethyl) substituent formula I, wherein R
4The compound that is the substituent above-mentioned formula I of formyl radical also can be used as starting material.In this reaction sequence, the formyl radical substituting group can react so that corresponding wherein R to be provided with glycolylurea
4Be (2,5-dioxo-imidazolidine-4-ylidenylmethyl) substituent formula I compound (EgyptianJournal of Chemistry 1987,30,281-294).R wherein
4The compound that is (2,5-dioxo-imidazolidine-4-ylidenylmethyl) substituent formula I can pass through the catalytic hydrogenation carbon-to-carbon double bond then, is converted into the wherein R of expectation
4It is the compound of (2,5-dioxo-imidazolidine-4-ylmethyl) substituent formula I.
[00097] if expectation generates wherein R
4Be the compound of the substituent formula I of methyl glycolylurea, known wherein R
4Be that the amino heteroaromatics of the formula X of bromine can be used as starting material (if Y=CH, the compound of formula X is commercially available 2-amino-5-bromopyridine so; If Y=N, the compound of formula X is known 2-amino-5-bromo-pyrazine so).In this reaction sequence, amino can use the amino protecting group protection of any routine, and this protecting group can cracking and produce free amino, and preferred group is the trimethyl-acetyl protecting group.In case amino protected, bromine substituent can be converted into wherein R
4It is the compound of ethanoyl substituting group and wherein amino protected formula X for the pivaloyl acid amides.The Stille linked reaction of palladium mediated heteroaromatic bromine substituent and commercially available 1-vinyl ethyl ether base-tri-n-butyl tin, then acid hydrolysis intermediate ethyl enol ether can be used to implement this conversion (Synthesis 1997,1446-1450).Next, use the Bucherer-Bergs reaction conditions (Bioorg.Med.Chem, Lett.2001,11 (6), 777-780), R wherein
4The compound that is ethanoyl substituting group and wherein amino protected formula X for the pivaloyl acid amides can be converted into wherein R
4It is the compound of methyl glycolylurea substituting group and wherein amino protected formula X for the pivaloyl acid amides.The deprotection of pivaloyl acid amides can provide the wherein R of expectation under the standard alkaline type condition
4It is the amino heteroaromatics of the formula X of methyl glycolylurea.The wherein R that produces
4The compound that is the formula X of methyl glycolylurea can pass through conventional peptide coupling condensation with the compound of formula IX then, to generate the wherein R of expectation
4It is the compound of the substituent formula I of methyl glycolylurea.In carrying out this reaction, the method with primary amine and carboxylic acid condensation of any routine can be used to implement this conversion.
[00098] if expectation generates wherein R
4Be unsubstituted or mono-substituted by the amino heteroaromatics of ring carbon atom with the formula X of 5 five or six-membered Hetero-aromatics that are connected of pyridine or pyrazine ring, described five or six-membered Hetero-aromatic contain a heteroatoms that is selected from sulphur, oxygen or nitrogen; Described mono-substituted hetero-aromatic ring is substituted the single replacement of base on the position of the ring carbon atom except the carbon atom of described connection, described substituting group is selected from cyano group, chlorine, bromine, nitro, amino, methyl, methoxyl group or hydroxyl, known wherein R
4Be that the amino heteroaromatics of the formula X of bromine can be used as starting material (if Y=CH, the compound of formula X is commercially available 2-amino-5-bromopyridine so; IfY=N, the compound of formula X is known 2-amino-5-bromo-pyrazine so).In this reaction sequence, bromine substituent can be converted into wherein R
4Be above-mentioned unsubstituted or mono-substituted five or six-membered Hetero-aromatic.The palladium mediated aromatic bromine substituting group of any routine and heteroaromatic boric acid link coupled method (as the Suzuki linked reaction) or can be used to implement this conversion with hetero-aromatic ring stannyl reagent link coupled method (as the Stille linked reaction).The wherein R that produces
4Be expectation do not replace mono-substituted five or the compound of the formula X of six-membered Hetero-aromatic then can with the compound of formula IX by conventional peptide coupling condensation, generate the wherein R of expectation
4Be unsubstituted or mono-substituted by the compound of ring carbon atom with the formula I of 5 five or six-membered Hetero-aromatics that are connected of pyridine or pyrazine ring, described five or six-membered Hetero-aromatic contain a heteroatoms that is selected from sulphur, oxygen or nitrogen; Described mono-substituted hetero-aromatic ring is substituted the single replacement of base on the position of the ring carbon atom except the carbon atom of described connection, described substituting group is selected from cyano group, chlorine, bromine, nitro, amino, methyl, methoxyl group or hydroxyl.In carrying out this reaction, the method with primary amine and carboxylic acid condensation of any routine can be used to implement this conversion.On the other hand, if expectation generates wherein R
4Be to contain one to be selected from the heteroatoms of oxygen, nitrogen or sulphur and nine or ten yuan of two compound that encircles the formula I of hetero-aromatic ring that connects by ring carbon atom, these compounds can be according to above-mentioned reaction sequence, and that uses expectation condenses heteroaromatic boric acid or fused heteroaromatic ring stannyl reagent preparation.
[00099] if expectation generates wherein R
4Be unsubstituted or mono-substituted by the amino heteroaromatics of ring carbon atom with the formula X of 5 aromatic rings that are connected of pyridine or pyrazine ring, described aromatic ring contains six carbon atom; Described mono-substituted aromatic ring is substituted the single replacement of base on the position of ring carbon atom except described connection carbon atom, described substituting group is selected from cyano group, chlorine, bromine, nitro, amino, methyl, methoxyl group or hydroxyl, above-mentioned known wherein R
4The amino heteroaromatics that is the formula X of bromine can be used as starting material.In this reaction sequence, bromine substituent can be converted into wherein R
4It is above-mentioned unsubstituted or mono-substituted aromatic ring.The palladium mediated aromatic bromine substituting group of any routine and heteroaromatic boric acid link coupled method as the Suzuki linked reaction, can be used to implement this conversion.The wherein R that produces
4Be expectation do not replace or the compound of the formula X of mono-substituted aromatic ring then can with the compound of formula IX by conventional peptide coupling condensation, generate the wherein R of expectation
4It is unsubstituted or mono-substituted aromatic ring.In carrying out this reaction, the method with primary amine and carboxylic acid condensation of any routine can be used to implement this conversion.In case R wherein
4Be mono-substituted by the compound of ring carbon atom with the formula I of 5 aromatic rings that are connected of pyridine or pyrazine ring, described aromatic ring contains six carbon atom; Described mono-substituted aromatic ring is replaced by the nitro substituent list on the position of ring carbon atom except described connection carbon atom, and these compounds with nitro substituent can be converted into corresponding amino substituting group then.The method that nitro is converted into amino of any routine can be used to implement this conversion.On the other hand, in case R wherein
4Be mono-substituted by the compound of ring carbon atom with the formula I of 5 aromatic rings that are connected of pyridine or pyrazine ring, described aromatic ring contains six carbon atom; Described mono-substituted aromatic ring is replaced by methoxyl group substituting group list on the position of ring carbon atom except described connection carbon atom, and these have the substituent compound of methoxyl group can be converted into corresponding hydroxyl substituent then.Any routine be that the method for aromatic hydroxy can be used to implement this conversion with aromatics methoxyl group demethylation.
[000100] if expectation generates wherein R
4Be the amino heteroaromatics of (tetrahydrochysene-furans-2-yl) substituent formula X, above-mentioned known wherein R
4The amino heteroaromatics that is the formula X of bromine also can be used as starting material.In this reaction sequence, bromine substituent can be converted into wherein R
4It is the compound of (4,5-dihydro-furan-2-yl) substituent formula X.(Syn.Lett.1995 1227-1228) can be used to implement this conversion with the substituent Stille linked reaction of known tributyl (4,5-dihydro-2-furyl) to palladium mediated heteroaromatic bromine substituent.The wherein R that produces
4The amino heteroaromatics that is (4,5-dihydro-furan-2-yl) substituent formula X can be converted into wherein R then
4It is the amino heteroaromatics of (tetrahydrochysene-furans-2-yl) substituent formula X.The method that carbon-to-carbon double bond is reduced to stable hydrocarbon of any routine can be used to implement this conversion.In case R wherein
4The amino heteroaromatics that is (tetrahydrochysene-furans-2-yl) substituent formula X can obtain, and they can generate the wherein R of expectation then with the compound of formula IX by the peptide coupling condensation of routine
4It is the compound of (tetrahydrochysene-furans-2-yl) substituent formula I.In carrying out this reaction, the method with primary amine and carboxylic acid condensation of any routine can be used to implement this conversion.
[000101] if expectation generates wherein R
4Be the amino heteroaromatics of (5,6-dihydro-4H-pyrans-2-yl) substituent formula X, above-mentioned known wherein R
4The amino heteroaromatics that is the formula X of bromine also can be used as starting material.In this reaction sequence, bromine substituent can be converted into wherein R
4It is the compound of (5,6-dihydro-4H-pyrans-2-yl) substituent formula X.Palladium mediated heteroaromatic bromine substituent and commercially available 5, the Stille linked reaction of 6-dihydro-2-(tributyl stannyl)-4H-pyrans can be used to implement this conversion.The wherein R that produces
4The compound that is (5,6-dihydro-4H-pyrans-2-yl) substituent formula X can pass through conventional peptide coupling condensation with the compound of formula IX then, generates the wherein R of expectation
4It is the compound of (5,6-dihydro-4H-pyrans-2-yl) substituent formula I.In carrying out this reaction, the method with primary amine and carboxylic acid condensation of any routine can be used to implement this conversion.
[000102] if expectation generates wherein R
4Be the compound of the substituent formula I of tetrahydroglyoxaline, following known heteroaromatics can be used as starting material: (1) is in formula X, if Y=CH, so commercially available 2-amino-5-cyano pyridine can be used as starting material; (2) in formula X, if the so known 2-amino-5-cyano of Y=N pyrazine can be used as starting material, it can be according to J.Heterocyclic Chem.1987, and 24 (5), the 1371-1372 preparation.In this reaction sequence, the cyano group substituting group can be converted into wherein R
4It is the compound of the substituent formula X of tetrahydroglyoxaline.Any routine quadrol nucleophilic addition(Adn) to the method for aromatics cyano group can be used to implement this conversion (Bioorg.Med.Client.2001,9 (3), 585-592).R wherein
4The compound that is the substituent formula X of tetrahydroglyoxaline can pass through conventional peptide coupling condensation with the compound of formula IX then, generates the wherein R of expectation
4It is the compound of the substituent formula I of tetrahydroglyoxaline.In carrying out this reaction, the method with primary amine and carboxylic acid condensation of any routine can be used to implement this conversion.
[000103] if expectation generates wherein R
4Be corresponding to-C (=O) compound of the substituent formula I of NH-OH, following known heteroaromatic ring compounds can be used as starting material: (1) is in formula I, if Y=CH, so known 5-chloro-pyridine-2-carboxylic acids methyl esters can be used as starting material; (2) in formula I, if the so commercially available 5-chloropyrazine of Y=N-2-carboxylate methyl ester can be used as starting material.In this reaction sequence, known 5-[chlorine] hetero-aromatic ring-2-carboxylate methyl ester can be converted into corresponding carboxylic acid.Being hydrolyzed to carboxylic acid of carboxylate methyl ester and do not replace chlorine substituent can make salt of wormwood in water/tetrahydrofuran (THF) finish (Chem.Pharm.Bull.1980,28,3057-3063).The 5-[chlorine that obtains] hetero-aromatic ring-2-carboxylic acid can be converted into the corresponding tert-butyl ester.The esterification process that carboxylic acid is converted into carboxylic acid tert-butyl ester of any routine can be used to implement this conversion, and (Tetrahedron 1990,46,3019-3028).5-[chlorine] hetero-aromatic ring-2-carboxylic acid tert-butyl ester can use the silver fluoride (I) in the acetonitrile to be converted into corresponding 5-[chlorine then] hetero-aromatic ring-2-carboxylic acid tert-butyl ester (J.Med.Chem.1995,38,3902-3907).Next, 5-[chlorine] hetero-aromatic ring-2-carboxylic acid tert-butyl ester can be converted into wherein R then
4It is the compound of the substituent formula X of carboxylic acid tert-butyl ester.Any routine can be used to implement this conversion with ammonia nucleophilic displacement aromatics fluorin radical with the method that aromatic amine groups is provided.The wherein R that produces
4The compound that is the substituent formula X of carboxylic acid tert-butyl ester can pass through conventional peptide coupling condensation with the compound of formula IX then, generates the wherein R of expectation
4It is the compound of the substituent formula I of carboxylic acid tert-butyl ester.In carrying out this reaction, the method for any routine can be used the method for primary amine and carboxylic acid condensation and implement this conversion.In case R wherein
4The compound that is the substituent formula I of carboxylic acid tert-butyl ester can obtain, and they can be converted into wherein R
4It is the compound of the formula I of carboxyl.The method that the tert-butyl ester is hydrolyzed into carboxylic acid of any routine can be used to implement this conversion.In case R wherein
4The compound that is the formula I of carboxyl can obtain, and they can be converted into the wherein R of expectation
4Be corresponding to-C (=O) the compound of the formula I of NH-OH (carboxylic acid hydroxamides substituting group).In this reaction sequence, any routine the reaction of carboxylic acid and commercially available O-(tertiary butyl) hydroxylamine hydrochloride can be used to implement this conversion with the method that forms corresponding carboxylic acid tert.-butoxy amide analogue.The tert.-butoxy amide analogue that produces then can be at deprotection under the acidic conditions to provide the R of expectation
4Be corresponding to-C (=O) the compound of the formula I of NH-OH (carboxylic acid hydroxamides substituting group).
[000104] on the other hand, if expectation generates wherein R
4Be 3-methyl-[compound of the formula I of 1,2,4] oxadiazole rings, above-mentioned wherein R
4The compound that is the formula I of carboxyl substituent can be used as starting material.In this reaction sequence, R wherein
4The compound that is the formula I of carboxyl substituent can be converted into corresponding chloride of acid.The chloride of acid method that carboxylic acid is converted into of any routine can be used to implement this conversion.Next, chloride of acid can be handled with the acetyl amidoxime, and wherein R is provided
4It is the midbody compound of the compound of the substituent formula I of acetyl amidoxime ester.Finally, R wherein
4The compound that is the substituent formula I of acetyl amidoxime ester can dewater under heating condition, and the wherein R of expectation is provided
4Be the 3-methyl-[compound of the formula I of 1,2,4] oxadiazole rings (and J.Med.Chem.1991,34,2726-2735).
[000105] if expectation generates wherein R
4Be the compound of the formula I of (two-methylol) methyl substituents, following known heteroaromatics can be used as starting material: (1) is in formula X, if Y=CH, so commercially available 5-bromo-2-nitropyridine can be used as starting material; (2) in formula X, if Y=N, so known 2-bromo-5-nitro pyrazine can be used as starting material.In this reaction sequence, bromine substituent can be converted into wherein R
4It is the compound of (dialkyl malonate) substituent formula X.Any routine can be used to implement this conversion with the substituent method of dialkyl malonate displacement aromatic bromine.In case 5-(the dialkyl malonate)-2-nitro-heteroaromatic ring compounds that produces can obtain, nitro substituent can be converted into wherein R
4It is the amino heteroaromatics of (dialkyl malonate) substituent formula X of expectation.Nitro substituent being reduced into amino substituent method and can being used to implement this conversion of any routine.These are R wherein
4Be (dialkyl malonate) substituent formula X compound then can with the compound of formula IX by conventional peptide coupling condensation, to generate the wherein R of expectation
4It is the compound of (dialkyl malonate) substituent formula I.In carrying out this reaction, the method with primary amine and carboxylic acid condensation of any rule can be used to implement this conversion.In case R wherein
4The compound that is (dialkyl malonate) substituent formula I can obtain, and (dialkyl malonate) substituting group can be converted into wherein R then
4It is the compound of the formula I of (two-methylol) methyl substituents.The method that ester is reduced into alcohol of any routine can be used to implement this conversion.
[000106] if expectation generates wherein R
4Be the compound of the substituent formula I of (two-methylol) methoxyl group, following known heteroaromatics can be used as starting material: (1) is in formula I, if Y=CH, so known 5-chloro-pyridine-2-carboxylic acids methyl esters can be used as starting material; (2) in formula I, if the so commercially available 5-chloropyrazine of Y=N-2-carboxylate methyl ester can be used as starting material.In this reaction sequence, known 5-[chlorine] hetero-aromatic ring-2-carboxylate methyl ester can be converted into corresponding carboxylic acid.Being hydrolyzed to carboxylic acid of carboxylate methyl ester and do not replace chlorine substituent can make salt of wormwood in water/tetrahydrofuran (THF) finish (Chem.Pharm.Bull.1980,28,3057-3063).5-[chlorine] hetero-aromatic ring-2-carboxylic acid can be converted into (two-benzyloxymethyl) methyl esters accordingly.The esterification process that carboxylic acid is converted into carboxylicesters of any routine can be used to implement this conversion.Next, the 5-[chlorine that is obtaining] chlorine substituent on hetero-aromatic ring-2-carboxylic acid (two-benzyloxymethyl) methyl esters can be directly with 1,3-benzyloxy-2-propyl alcohol is replaced to generate corresponding 5-[(two-benzyloxymethyl) methoxyl group] hetero-aromatic ring-2-carboxylic acid (two-benzyloxymethyl) methyl esters replaces.The method with secondary alcohol nucleophilic displacement aromatics chlorine substituent of any routine can be used to implement this conversion.In case Bao Hu 5-[(two-benzyloxymethyl fully) methoxyl group] hetero-aromatic ring-2-carboxylic acid (two-benzyloxymethyl) methyl compound can obtain, and they can be converted into corresponding carboxylic acid.The method that ester is hydrolyzed into carboxylic acid of any routine can be used to implement this conversion.5-[(two-benzyloxymethyl) methoxyl group] hetero-aromatic ring-2-carboxylic acid can be converted into corresponding acylazide then.The method that carboxylic acid is converted into acylazide of any routine can be used to implement this conversion.The pyrolytic Ku Ertisi of acylazide in the presence of the trimethyl carbinol that relates to acquisition resets wherein R can be provided
4It is the compound of (two-benzyloxymethyl) methoxyl group and wherein amino formula X as the t-butyl carbamate protection.T-butyl carbamate deprotection under standard conditions can provide the wherein R of expectation
4It is the amino heteroaromatics of the formula X of (two-benzyloxymethyl) methoxyl group.The wherein R that produces
4Be (two-benzyloxymethyl) methoxyl group formula X compound then can with the compound of formula IX by conventional peptide coupling condensation, so that the wherein R of expectation to be provided
4It is the compound of the formula I of (two-benzyloxymethyl) methoxyl group.In carrying out this reaction, the method with primary amine and carboxylic acid condensation of any routine can be used to implement this conversion.Benzyl ester deprotection under the standard hydrogenation conditions can provide the wherein R of expectation
4It is the compound of the substituent formula I of (two-methylol) methoxyl group.
[000107] compound of formula I has a unsymmetrical carbon, group-CH
2R
3Be connected by this unsymmetrical carbon with amide substituents.According to the present invention, the preferred steric configuration of this carbon is " R ".
[000108] if expect the R isomer or the S isomer of production I compound, these compounds can be separated into the isomer of expectation by the conventional chemical method.Preferred chemical process be the asymmetric alkylation of the pseudoephedrine phenylacetic acid that is used as formula V the chirality assistant agent (J.Am.Chem.Soc.1997,119,6496-6511).For the R acid of the formula IX that forms expectation, wherein R
20Be lower alkylthio and R
2The compound of aforesaid formula V at first is converted into the pseudoephedrine acid amides, uses 1R, and 2R-(-)-pseudoephedrine is the enantiomorph of the pseudoephedrine of expectation.The method that carboxylic acid is converted into carboxylic acid amides of any routine can be used to implement this conversion.The pseudoephedrine acid amides can carry out the alkylation of height cis-selectivity with alkylogen, so that the amide product corresponding to the alpha-substitution of formula IX to be provided.By the acid hydrolysis process that carboxylic acid amides is converted into carboxylic acid of routine, the acid amides of these height diastereomer enrichments can be converted into the wherein R of enantiomorph enrichment
20Be lower alkylthio and R
2The R carboxylic acid of aforesaid formula IX.These are R wherein
20Be lower alkylthio and R
2The R carboxylic acid of aforesaid formula IX can be converted into wherein R
20Be lower alkylthio and R
2The R isomer of aforesaid formula I.In carrying out this reaction, with primary amine and carboxylic acid condensation and the not method of racemization of any routine can be used to implement this conversion.In case R wherein
20Be lower alkylthio and R
2The compound of aforesaid formula I can obtain, and they can be R wherein accordingly by oxidation conversion
20Be lower alkyl alkylsulfonyl and R
2The R compound of aforesaid formula I.The method that the alkylthio substituting group is oxidized to corresponding sulfuryl group of any routine can be used to implement this conversion.
[000109] on the other hand, R wherein
20Be lower alkylthio and R
2The compound of aforesaid formula IX can at first be oxidized to wherein R
20Be lower alkyl alkylsulfonyl and R
2The R compound of aforesaid formula IX.The method that the alkylthio substituting group is oxidized to corresponding sulfuryl group of any routine can be used to implement this conversion.These compounds can be converted into accordingly wherein R then
20Be lower alkyl alkylsulfonyl and R
2The R compound of aforesaid formula I.In carrying out this reaction, with primary amine and carboxylic acid condensation and the not method of racemization of any routine can be used to implement this conversion.
[000110] method of the R of the compound of another kind of production I or S isomer is compound and the optically-active alkali reaction with formula IX.The optically-active alkali of any routine can be used to implement this fractionation.Preferred optically-active alkali has optically active amine alkali such as Alpha-Methyl benzylamine, quinine, dehydroabietylamine and Alpha-Methyl naphthylamines.Any being used for can be used to carry out this reaction with optically-active organic amine alkali fractionation organic acid routine techniques.In this splitting step, the compound of formula IX and optically-active alkali react in the inert organic solvents medium, generate the salt of the optically active amine of the R of the compound contain formula IX and S isomer.In the formation of these salt, temperature and pressure is not critical, and salt formation can carry out under room temperature and barometric point.R can separate by any ordinary method such as fractional crystallization with S salt.After crystallization, every kind of salt can by be converted into acid hydrolysis separately R and the compound of the formula IX of S configuration.Preferred acid is rare aqueous acid, and the aqueous acid of promptly about 0.01N to 2N is as sulfuric acid or aqueous hydrochloric acid.The configuration of the formula IX that method by this fractionation generates runs through the entire reaction route to carry out, with R or the S configuration of the formula I that generates expectation.
[000111] fractionation of the racemoid of the compound of formula IX also can realize by forming corresponding non-mapping ester or acid amides.These non-mapping esters or acid amides can prepare with chiral alcohol or Chiral Amine coupling by the carboxylic acid with formula IX.This reaction can be used any routine carboxylic acid and alcohol or amine link coupled method are carried out.The diastereomer of the compound of corresponding formula IX can use the separation method of any routine to separate then.Pure non-mapping ester that produces or acid amides then can hydrolysis, produce corresponding pure R or S isomer.Hydrolysis reaction can use conventional known method ester hydrolysis or acid amides and not racemization carry out.Finally, also can use the separating of R and S isomer enzymatic ester hydrolysis corresponding to any lower alkyl esters of the compound of formula VIII realize (Tetrahedron Lett.1989,30,7053-7056), cause the formation of corresponding chiral acid and chiral ester.Ester and acid can be by any routine separates sour method separation from ester.The configuration of the formula VIII that produces by this method for splitting is implemented in the entire reaction route to generate R or the S isomer of the formula I that expects.
[000112] fractionation of the racemoid of the compound of formula IX also can realize by forming corresponding non-mapping ester or acid amides.These non-mapping esters or acid amides can prepare with chiral alcohol or Chiral Amine coupling by the carboxylic acid with formula IX.This reaction can be used any routine carboxylic acid and alcohol or amine link coupled method are carried out.The diastereomer of the compound of corresponding formula IX can use the separation method of any routine to separate then.Pure non-mapping ester that produces or acid amides then can hydrolysis, produce corresponding pure R or S isomer.Hydrolysis reaction can use conventional known method ester hydrolysis or acid amides and not racemization carry out.Finally, also can use the separating of R and S isomer enzymatic ester hydrolysis corresponding to any lower alkyl esters of the compound of formula VIII realize (Tetrahedron Lett.1989,30,7053-7056), cause the formation of corresponding chiral acid and chiral ester.Ester and acid can be by any routine separates sour method separation from ester.The configuration of the formula VIII that produces by this method for splitting is implemented in the entire reaction route to generate R or the S isomer of the formula I that expects.
[000113] U.S. Patent number 6,320, and 050 relates to as 2 of glucokinase activating agents, 3-two-replacement N hetero-aromatic ring propionic acid amide.U.S. Patent number 6,320,050 by with reference to being incorporated into this.Substituting group name for the functional group of formula I of the present invention provides in this article.
[000114] all The compounds of this invention of enumerating in this paper embodiment pass through the method for biological activity embodiment A at external activation glucokinase.In the method, they increase the flow of glucose metabolism, cause that insulin secretion increases.Therefore, formula I compound is the glucokinase activating agents that is used to increase insulin secretion.
[000115] when according to the oral administration of mensuration described in the biological activity Embodiment B, the discovery following compounds shows to be compared with vehicle, measures constantly the reduction of blood sugar statistics remarkable (p≤0.05) for two successive.
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(N-hydroxyl amino formyl imino-)-pyrazine-2-yl]-propionic acid amide;
3-cyclopentyl-2 (R)-N-[5-(N-hydroxyl amino formyl imino-)-pyrazine-2-yl]-2-(4-methylsulfonyl-phenyl)-propionic acid amide;
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-methylthio group-pyrazine-2-yl)-propionic acid amide;
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(2-hydroxyl-ethylmercapto group)-pyrazine-2-yl]-propionic acid amide;
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-methanesulfinyl-pyrazine-2-yl)-propionic acid amide;
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(3-hydroxyl-third-1-alkynyl)-pyrazine-2-yl]-propionic acid amide;
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(3-dimethylamino-third-1-alkynyl)-pyrazine-2-yl]-propionic acid amide;
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-methylsulfonyl amino-pyridine-2-yl)-propionic acid amide;
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-dimethylamino-pyridine-2-yl)-propionic acid amide;
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-dimethylamino-pyrazine-2-yl)-propionic acid amide;
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(3-dimethylamino-propyl group)-pyrazine-2-yl]-propionic acid amide;
N-[5-(5-amino-[1,2,4] oxadiazole-3-yls)-pyrazine-2-yl]-2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-propionic acid amide;
2-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-formyl radical-pyrazine-2-yl)-propionic acid amide;
2-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(2,4-dioxo-thiazolidine-5-ylmethyl)-pyrazine-2-yl]-propionic acid amide;
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-dimethoxy-methyl-pyrazine-2-yl)-propionic acid amide;
N-(5-ethanoyl-pyrazine-2-yl)-2-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-propionic acid amide;
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-N-[5-(cyano group-hydroxyl-methyl)-pyrazine-2-yl]-3-cyclopentyl-propionic acid amide;
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(1-(Z)-oxyimino-ethyl)-pyrazine-2-yl]-propionic acid amide,
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(1 (S), 2-dihydroxyl-ethyl)-pyrazine-2-yl]-propionic acid amide; With
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(1 (S), 2-dihydroxyl-2-methyl-propyl group)-pyrazine-2-yl]-propionic acid amide.
[000116] according to the ability of their activation glucokinases, above-mentioned formula I compound can be as the medicine of treatment type ii diabetes.Therefore, as mentioned above, the medicine that contains formula I compound also is an one object of the present invention, and similarly, prepare the method for this medicine in addition, it comprise with one or more formulas I compound and, in case of necessity, valuable material is made galenic (galenical) form of medication in one or more other the treatment, for example, and by with formula I compound and pharmaceutical carrier and/or assistant agent combination.
[000117] the present invention comprises pharmaceutical composition, and it comprises the compound or pharmaceutically acceptable salt thereof of formula I, and pharmaceutical carrier.Preferred pharmaceutical composition of the present invention comprise above-mentioned enumerate have an active compound or pharmaceutically acceptable salt thereof of glucokinase promoting agent in the preferred body.
[000118] pharmaceutical composition of the present invention can be taken orally, for example with tablet, and the tablet of dressing, dragee, hard or soft gelatin capsule, solution, the form of emulsion or suspensoid.Their administrations also can be undertaken by rectum, for example use suppository; Topical or through percutaneous drug delivery for example uses ointment, creme, gelifying agent or solution; Perhaps parenteral admin for example uses in the intravenously, intramuscular of Injectable solution, subcutaneous, the sheath or percutaneous dosing.And administration can be a sublingual administration or as the aerosol form of sprays for example.
[000119] pharmaceutical composition of the present invention contains compound and/or its salt of formula I, can prepare with manner known in the art, for example by routine mix, seal, dissolving, granulating, emulsification, embedding, system ingot or freeze drying process.These pharmaceutical preparations can with the treatment inert, the organic or inorganic bearer configuration.Lactose, W-Gum or derivatives thereof, talcum, stearic acid or its salt can be used as the carrier such as tablet, dragee and the hard gelatin capsule of tablet, dressing.The suitable carriers of soft gelatin capsule comprises for example vegetables oil, wax, fat, semisolid or liquid polyol etc.According to the character of this activeconstituents, in the situation of soft gelatin capsule, do not need carrier usually.In this case, pharmaceutical carrier is believed to comprise soft gelatin capsule.The suitable carrier of preparation solution and syrup has water, polyvalent alcohol, carbohydrate, Nulomoline and glucose.The suitable carrier of injection liquid has water, alcohol, polyvalent alcohol, glycerine, vegetables oil, phosphatide and tensio-active agent.The suitable carrier of suppository has natural or winterized stearin, wax, fat and semiliquid polyvalent alcohol.
[000120] pharmaceutical preparation can also contain sanitas, solubilizing agent, stablizer, wetting agent, emulsifying agent, sweeting agent, tinting material, seasonings, salt, buffer reagent, Drug coating or the antioxidant of change osmotic pressure.As previously mentioned, they also can contain valuable material in other the treatment, comprise except the other activeconstituents those of formula I.
[000121] the treatment significant quantity is meant amount for treatment of obesity and/or type ii diabetes compounds effective according to compound of the present invention.The mensuration of treatment significant quantity belongs in the technical scope of this area.Can in broad range, the changing and can measure of treatment significant quantity or dosage with manner known in the art according to compound of the present invention.This dosage will be adjusted at individual need in each concrete situation, comprise the particular compound of using, route of administration, treatment illness, and the patient who is treated.Usually, in the situation of the adult patient of heavily about 70Kg, about 100mg is to about 1 at oral or administered parenterally, and the per daily dose of 000mg should be suitable.Per daily dose can be used as single dose or divided dose is used, and perhaps for administered parenterally, it can be used as continuous infusion and gives.
[000122] preferred application form has intravenously, intramuscular or oral administration, most preferably oral administration.
[000123] will understand the present invention better from the following example, these embodiment illustrate for example rather than are intended to be limited in the present invention who defines in the appended claim.
Embodiment 1
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(N-hydroxyl amino formyl imino-(carbamimidoyl))-pyrazine-2-yl]-propionic acid amide
[000124] will the triphenyl phosphine in the methylene dichloride (160mL) (28.80g, 109.8mmol) and imidazoles (14.9g, solution 219.6mmol) are cooled to 0 ℃, and (27.87g 109.8mmol) handles at leisure to use iodine then.Then, (10.00g 99.8mmol) drips reaction mixture to be used in cyclopentyl carbinol in the methylene dichloride (10mL).Make the reaction mixture that obtains be warmed to 25 ℃, it was stirred 4 hours in this temperature.Then, water (50mL) diluted reaction mixture, and use methylene dichloride (3 * 20mL) extractive reaction mixtures again.Organic layer with dried over sodium sulfate merges filters, and in 25 ℃ of vacuum concentration.(4 * 50mL) wash the solid that obtains, and filter by silica gel plug with pentane.In 25 ℃ of vacuum concentration filtrates, iodomethyl pentamethylene (18.48g, 88%) is provided, be clear, colorless liquid: EI-HRMS m/e calculated value C
6H
11I (M
+) 209.9906, actual measurement 209.9911.
[000125] under argon atmospher, will (54.9g, solution 412mmol) be cooled to 0 ℃, and (24.3mL 264mmol) drips and handles to be used in chlorine oxo methyl acetate in the chloroform (180mL) then at the aluminum chloride in the chloroform (180mL).In 0 ℃ of stirred reaction mixture 30 minutes, (39.4g 247mmol) dripped and handles to be used in 2-chlorobenzene sulfenyl methane in the chloroform (180mL) then.The color transition of reaction mixture is red.Make the reaction mixture that obtains be warmed to 25 ℃, it was stirred 4 hours in this temperature.Then, reaction mixture is poured on the ice (700mL) at leisure.The yellow mixture that obtains was stirred 15 minutes, then by diatomite filtration, to remove aluminium salt.With methylene dichloride (3 * 50mL) extraction filtrates.With the saturated sodium bicarbonate aqueous solution (organic layer that 1 * 50mL) washing merges.Then, use the dried over mgso organic layer, filter, and vacuum concentration, (3-chloro-4-methylthio group-phenyl)-oxo-acetic acids methyl esters (36.4g, 60%) is provided, be light yellow oil: EI-HRMS m/e calculated value C
10H
9ClO
3S (M
+) 243.9961, actual measurement 243.9958.
[000126] will be in toluene (120mL) (3-chloro-4-methylthio group-phenyl)-(61.7g, solution 252mmol) are heated to 50 ℃ to the oxo-acetic acids methyl esters.Then, by dropping funnel, (105mL 313mmol) drips the solution of handling this heating, carefully keeps temperature of reaction to be lower than 60 ℃ with the 3M aqueous sodium hydroxide solution.Add finish after, in other 1.5 hours of 50 ℃ of stirred reaction mixtures, during this period, begin to generate yellow mercury oxide.After this, remove heat, and (10.6mL 290mmol) drips this warm solution of processing with concentrated hydrochloric acid.Make the reaction mixture that obtains be cooled to 25 ℃, stirred 16 hours in 25 ℃ then.Cross filter solid, water (50mL) and toluene (50mL) washing then.By this solid of suction dried 1 hour, dry in high-vacuum jar then, (3-chloro-4-methylthio group-phenyl)-oxo-acetic acids (57.22g, 98%) is provided, be 166 ℃ of white solid: mp (dec); FAB-HRMS m/e calculated value C
9H
7ClO
3S (M+Na)
+252.9702, actual measurement 252.9700.
[000127] (8.5mL 273mmol) is added in the reaction flask that is equipped with mechanical stirrer with hydrazine hydrate.Hydrazine hydrate is cooled to-50 ℃, (12.6g 54.6mmol) handles to use portion (3-chloro-4-methylthio group-phenyl)-oxo-acetic acids then.The result of heat release is the rising of temperature.Then, the oyster white that obtains is mixed and heated to 80 ℃.After reaching 80 ℃, remove heating unit, use a potassium hydroxide (2.09g, 31.7mmol) reaction mixture then.Observing heat emits.Then, in 25 ℃ of stirred reaction mixtures, get back to 80 ℃ up to temperature of reaction.At this moment, add another part potassium hydroxide (2.09g, 31.7mmol).Once more, observe heat and emit, make the reaction mixture cooling that obtains get back to 80 ℃.In case at 80 ℃, to reaction mixture add the 3rd part of potassium hydroxide (2.09g, 31.7mmol).Observe another time heat and emit, after cooling is got back to 80 ℃, add the 4th and last a potassium hydroxide (2.09g, 31.7mmol).In this, add heating unit, and in 100 ℃ of reacting by heating mixtures 16 hours.The homogeneous reaction mixture that obtains is cooled to 25 ℃, water (12mL) dilution then.Reaction mixture is transferred in the separating funnel, with other water (12mL) and diethyl ether (40mL) rinsing.Layer separates, and water layer is transferred in the flask.Water (2 * 15mL) extraction organic layers.Combining water layer is handled with heptane (20mL), and the powerful reaction mixture that obtains that stirs.Then, in 30 minutes, drip the solution that processing is stirred, keep temperature to be lower than 50 ℃ with ice bath simultaneously with concentrated hydrochloric acid (26mL).Form cloud suspension, and this suspension was stirred 3 hours in 25 ℃.By the solid that filter to collect forms, use in succession then the 1N aqueous hydrochloric acid (2 * 6mL), heptane (1 * 12mL) and heptane/diethyl ether (15mL, solution washing 4:1).The dry solid that obtains provides (3-chloro-4-methylthio group-phenyl)-acetate (10.48g, 89%) under high vacuum, is pale solid: mp105.6-108.4 ℃; EI-HRMS m/e calculated value C
9H
9ClO
2S (M
+) 216.0012, actual measurement 216.0022.
[000128] (3-chloro-4-methylthio group-phenyl)-acetate that will be in acetone (65mL) (10.48g, 48.4mmol) and salt of wormwood (20.1g, mixture 145.1mmol) are cooled to-10 ℃.Then, (6.25mL 50.8mmol) drips this faint yellow thin pulp of processing, keeps temperature to be lower than-10 ℃ simultaneously with trimethyl-acetyl chloride.The reaction mixture that obtains in-10 ℃ of stirrings 15 minutes is warmed to 0 ℃ then, stirs 10 minutes under this temperature.Reaction mixture is cooled to again-10 ℃, use then (1R, 2R)-(-)-(11.99g 72.5mmol) handles pseudoephedrine, causes heat to be emitted.In-10 ℃ of stirred reaction mixtures 10 minutes, be warmed to 25 ℃ then, in this temperature it was stirred 1 hour.After this, the thin-layer chromatographic analysis Indicator Reaction is finished.Then, water (50mL) quencher reaction mixture is used ethyl acetate (1 * 100mL) extraction afterwards.Water (2 * 40mL) washing organic layers.Combining water layer, (2 * 50mL) strip with ethyl acetate.Organic layer with dried over mgso merges filters and vacuum concentration.This thick material is recrystallization from ethyl acetate (45mL) and hexane (80mL), 2-(3-chloro-4-methylthio group-phenyl)-N-[2 (R)-hydroxyl-1 (R)-methyl-2 (R)-phenyl-ethyl is provided]-N-methyl-ethanamide (13.75g, 78%), is faint yellow solid: mp 111.5-112.9 ℃; FAB-HRMS m/e calculated value C
19H
22ClNO
2S (M+H)
+364.1138, actual measurement 364.1142.
[000129] will be in tetrahydrofuran (THF) (90mL) 1,1,1,3,3, (17.9mL, solution 85mmol) are cooled to-78 ℃ to the 3-hexamethyldisilazane, and (33.9mL, n-butyllithium solution 79.3mmol) is handled at hexane to use 2.34M then.In-78 ℃ of stirred reaction mixtures 15 minutes, be used in 2-(3-chloro-4-methylthio group-phenyl)-N-[2 (R)-hydroxyl-1 (R)-methyl-2 (R)-phenyl-ethyl in the tetrahydrofuran (THF) (90mL) then at leisure]-N-methyl-ethanamide (13.75g, 37.8mmol) solution-treated, keep temperature to be lower than-65 ℃ simultaneously.Huang-the orange reaction mixture that obtains in-78 ℃ of stirrings 15 minutes is warmed to 0 ℃ then, in this temperature it is stirred 20 minutes.Reaction mixture is cooled to-78 ℃ again, is used in 1 then, 3-dimethyl-3,4,5,6-tetrahydrochysene-2 (1H)-pyrimidone (9.6mL, 79.3mmol) in iodomethyl pentamethylene (11.9g, 56.7mmol) solution-treated.The reaction mixture that obtains in-78 ℃ of stirrings 30 minutes is warmed to 25 ℃ then, in this temperature it is stirred 16 hours.With ethyl acetate (200mL) diluted reaction mixture, use saturated aqueous ammonium chloride (1 * 100mL) washing then.Then, with ethyl acetate (2 * 50mL) aqueous layer extracted.(organic layer that 1 * 50mL) washing merges is used dried over sodium sulfate, filters and vacuum concentration with saturated sodium-chloride water solution.Then, the material that obtains is dissolved in the ethyl acetate again.With 10% aqueous sulfuric acid (2 * 100mL) and 10% sodium bicarbonate aqueous solution (2 * 100mL) washing organic phases, use dried over mgso, the filtration and vacuum concentration.From this thick material of ethyl acetate/hexane recrystallization, 2 (R)-(3-chloro-4-methylthio group-phenyl)-3-cyclopentyl-N-[2 (R)-hydroxyl-1 (R)-methyl-2 (R)-phenyl-ethyl is provided]-N-methyl-propionic acid amide (11.36g, 67%), is faint yellow solid: mp 113.8-117.6 ℃; FAB-HRMS m/e calculated value C
25H
32ClNO
2S (M-H)
+444.1764, actual measurement 444.1765.
[000130] with 2 (R)-(3-chloro-4-methylthio group-phenyl)-3-cyclopentyl-N-[2 (R)-hydroxyl-1 (R)-methyl-2 (R)-phenyl-ethyl in 9N aqueous sulfuric acid (28mL) the processing Zai diox (45mL)]-N-methyl-propionic acid amide (11.36g, solution 25.5mmol).Then, the reaction mixture that obtains was heated 16 hours in 105 ℃.Then, reaction mixture is cooled to 0 ℃, and makes the product precipitation by adding entry (200mL) with ice bath.In 0 ℃ of following stirred suspension, up to begin be muddy supernatant liquor become transparent and color yellowish.By suction filtration and drying solid.Solid matter is dissolved in the hot Glacial acetic acid (15mL), and water (10mL) is handled hot solution, to cause crystallization.Mixture is cooled to 25 ℃, then with water (20mL) processing of amount in addition.After 1 hour, pass through solid collected by filtration in 25 ℃ of stirrings.Drying solid in having the high-vacuum jar of Vanadium Pentoxide in FLAKES provides 2 (R)-(3-chloro-4-methylthio group-phenyl)-3-cyclopentyl-propionic acid (7.46g, 98%), is white solid: mp116.9-119.2 ℃; EI-HRMS m/e calculated value C
15H
19ClO
2S (M)
+298.0794, actual measurement 298.0804.
[000131] (15.68g, thin pulp 52.5mmol) are cooled to 0 ℃ to 2 (R)-(3-chloro-4-methylthio group-phenyl)-3-cyclopentyl-propionic acid that will be in formic acid (10mL), use 30% aqueous hydrogen peroxide solution (30mL) to handle then.Make the solution that obtains be warmed to 25 ℃, it was stirred 16 hours in this temperature.Make the solid precipitation that obtains by adding entry (120mL).Filter out solid, wash with water, and pass through suction dried.Flash chromatography (50/50 hexane/ethyl acetate adds 1% acetate for Merck silica gel 60,230-400 order) provides 2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-propionic acid (13.93g, 80%), is white solid: mp 123.9-126.2 ℃; FAB-HRMS m/e calculated value C
15H
19ClO
4S (M+H)
+331.0771, actual measurement 331.0776.
[000132] with 4-(dimethylamino) pyridine (305.1mg, 2.497mmol), N, N, N ', N '-tetramethylene-diamine (241.8mg, 2.081mmol) (2.9mL 12.49mmol) handles 1 with the heavy carbonic dibutylester, 2-amino-5-cyano pyrazine (500.0mg, solution 4.162mmol) in the 4-diox (8.3mL).In 25 ℃ of stirred reaction mixtures 20 hours, vacuum concentration then.Biotage chromatogram (FLASH40M, silicon-dioxide, 10% ethyl acetate/hexane) provides: 5-[[two [(1,1-dimethyl oxyethyl group) carbonyl]] amino]-2-pyrazine nitrile, be white solid: mp 67-68 ℃; (ES)
+-HRMS m/e calculated value C
15H
20N
4O
4(M+Na)
+343.1377, actual measurement 343.1379.
[000133] with azanol base hydrochloride (333.8mg, 4.804mmol) and piperidines (0.50,5.050mmol) 5-[[two [(1,1-dimethyl oxyethyl group) carbonyl] of processing in methyl-sulphoxide (5.8mL)] amino]-2-pyrazine nitrile (305.7mg, solution 0.954mmol).In 25 ℃ of stirred reaction mixtures 50 minutes, between ethyl acetate (100mL) and water (50mL), distribute then.Water (50mL) and saturated sodium-chloride water solution (50mL) washing organic layer are used dried over sodium sulfate, filter and vacuum concentration.Biotage chromatogram (FLASH 40L, silicon-dioxide, 25% ethyl acetate/hexane) provide: 5-[[two [(1,1-dimethyl oxyethyl group) carbonyl]] amino]-N-hydroxyl-2-pyrazine Imidamide (carboximidamide), be white solid (186.2mg, 55%): mp 185-186 ℃; (ES)
+-HRMS m/e calculated value C
15H
23N
5O
5(M+H)
+354.1772, actual measurement 354.1775.
[000134] under 25 ℃, with chloroformic acid (9-fluorenyl first) ester (68.0mg, 0.263mmol) 5-[[two [(1,1-dimethyl oxyethyl group) carbonyl] of processing in pyridine (2mL)] amino]-N-hydroxyl-2-pyrazine Imidamide (77.0mg, solution 0.218mmol).In 25 ℃ of stirred reaction mixtures 45 minutes.Then, with ethyl acetate, water and saturated sodium chloride aqueous solution diluted reaction mixture.Shake mixture and separation.Use the ethyl acetate extraction water layer.With the organic layer of anhydrous sodium sulfate drying merging, and vacuum concentration.Biotage chromatogram (FLASH40S, silicon-dioxide, 1/9 to 1/1 ethyl acetate/hexane) provides needed 5-[[two [(1,1-dimethyl oxyethyl group) carbonyl]] amino]-N-[[[(9H-fluorenes-9-yl) methoxyl group] carbonyl] the oxygen base]-2-pyrazine Imidamide.With this substance dissolves in methylene dichloride (0.5mL).Solution is cooled to 0 ℃, and (0.16mL 2.077mmol) handles to use trifluoroacetic acid then.In 0 ℃ of stirred reaction mixture 30 minutes, stirred 30 minutes in 25 ℃.Then, with other trifluoroacetic acid (1.0mL, 12.99mmol) reaction mixture, and stirred 2 hours in 25 ℃.Use trifluoroacetic acid (1.0mL, 12.99mmol) reaction mixture, and stirred 2 hours again in 25 ℃.Then, use the methylene dichloride diluted reaction mixture, with saturated sodium bicarbonate aqueous solution washing three times, use anhydrous sodium sulfate drying, filter vacuum concentration, dry in high vacuum then, 5-amino-N-[[[(9H-fluorenes-9-yl is provided) methoxyl group] carbonyl] the oxygen base]-2-pyrazine Imidamide (36.7mg, 44.9%), be white solid: LRVIS:C
20H
17N
5O
3(M+H)
+, at m/z=376
[000135] 2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-propionic acid (140.0mg that will be in methylene dichloride (2mL); 0.423mmol) solution be cooled to 0 ℃, use N then, dinethylformamide (1) is handled; then (0.08mL 0.917mmol) handles with oxalyl chloride.In 0 ℃ of stirred reaction mixture 30 minutes, stirred 2 hours in 25 ℃ then.The vacuum concentration reaction mixture provides a kind of oil.Will be in methylene dichloride (2mL) should oil solution be cooled to 0 ℃, be used in tetrahydrofuran (THF) (the 5-amino among the 2mL-N-[[[(9H-fluorenes-9-yl) methoxyl group then] carbonyl] the oxygen base]-2-pyrazine Imidamide (210mg, suppose 0.45mmol) and pyridine (0.04mL, 0.495mmol) thin pulp handle, then thin pulp is washed in the reaction mixture with tetrahydrofuran (THF) (1mL).(0.04mL 0.495mmol) handles the orange reaction mixture that obtains, and in 0 ℃ of stirring 30 minutes, stirs 22 hours in 25 ℃ then with pyridine.Use the ethyl acetate diluted reaction mixture,, use anhydrous sodium sulfate drying, filter and vacuum concentration with the saturated sodium bicarbonate aqueous solution washing.Biotage chromatogram (FLASH40S; silicon-dioxide; 1/4 to 1/1 ethyl acetate/hexane) provide: (R)-3-chloro-α-(cyclopentyl-methyl)-N-[2-[[[[[(9H-fluorenes-9-yl) methoxyl group] carbonyl] the oxygen base]-amino] the imino-ethyl]-the 5-pyrazinyl]-4-(methylsulfonyl) phenylacetamide (151.9mg; 52.2%), is canescence foam: LRMS:C
35H
34ClN
5O
6S (M+H)
+, at m/z=688.
[000136] with triethylamine (0.26mL; 1.865mmol) (R)-3-chloro-a-(the cyclopentyl-methyl)-N-[2-[[[[[(9H-fluorenes-9-yl of processing in pyridine (2mL)) methoxyl group] carbonyl] the oxygen base] amino] the imino-ethyl]-the 5-pyrazinyl]-4-(methylsulfonyl) phenylacetamide (130.0mg; 0.189mmol) solution, and stirred 2 hours in 25 ℃.The vacuum concentration reaction mixture.Dilute residuum with ethyl acetate.With 0.1N aqueous hydrochloric acid washing organic layer, then, use anhydrous sodium sulfate drying with copper sulfate (II) solution washing, filter and vacuum concentration.Biotage chromatogram (FLASH 40S, silicon-dioxide, 2/1 ethyl acetate/hexane) provide 2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(N-hydroxyl amino formyl imino-)-pyrazine-2-yl]-propionic acid amide (42.1mg, 47.8%), is white solid: mp 117-121 ℃; (ES)
+-HRMS m/e calculated value C
20H
24ClN
5O
4S (M+H)
+466.1311, actual measurement 466.1302.
Embodiment 2
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(N-hydroxyl amino formyl imino-)-pyridine-2-yl]-propionic acid amide
[000137] use 2.0M at methylene dichloride (0.52mL; 1.04mmol) in the oxalyl chloride solution-treated be cooled to 0 ℃ at methylene dichloride (10mL) and N; 2 (R) in the dinethylformamide (1)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-propionic acid are (according to preparation among the embodiment 1; 300mg, solution 0.91mmol).In 0 ℃ of stirred reaction mixture 30 minutes.At this moment, the vacuum concentration reaction mixture obtains a kind of light yellow oil.Be used in tetrahydrofuran (THF) (5mL) and pyridine (0.37mL, 4.5mmol) the 2-amino-5-cyano pyridine in (216mg, solution-treated residuum 1.80mmol).Then, in 25 ℃ of stirred reaction mixtures 16 hours.At this moment, water (15mL) diluted reaction mixture, and with methylene dichloride (3 * 25mL) extraction.Organic layer with dried over sodium sulfate merges filters, and vacuum concentration.Biotage chromatogram (FLASH 12M, silicon-dioxide, 70/30 hexane/ethyl acetate) provides 2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-N-(5-cyano group-pyridine-2-yl)-3-cyclopentyl-propionic acid amide (53mg, 86%), is water white oil: (ES)
+-HRMS m/e calculated value C
21H
22ClN
3O
3S (M+H)
+432.1143, actual measurement 432.1147.
[000138] with azanol base hydrochloride (14mg; 0.21mmol) and yellow soda ash (9mg; 0.08mmol) 2 (Rs)-(3-chloro-4-methylsulfonyl-phenyl)-N-(5-cyano group-pyridine-2-yl)-3-cyclopentyl-propionic acid amide (74mg, 0.17mmol) solution of processing in ethanol (1mL) and water (0.5mL).Then, in 70 ℃ of heating this solution 1.5 hours, after this, product is precipitated out from solution.Collect the solid that obtains by filtering; wash with water, vacuum-drying provides 2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(N-hydroxyl amino formyl imino-)-pyridine-2-yl]-propionic acid amide (27mg; 34%), is white solid: (ES)
+-HRMS m/e calculated value C
21H
25ClN
4O
4S (M+H)
+465.1358, actual measurement 465.1362.
Embodiment 3
3-cyclopentyl-2 (R)-N-[5-(N-hydroxyl amino formyl imino-)-pyrazine-2-yl]-2-(4-methylsulfonyl-phenyl)-propionic acid amide
[000139] with the salt of wormwood of just having pulverized (93.8g, 679mmol) 4-(methylthio group) phenylacetic acid (50g, 272mmol) the mixture of processing in tetrahydrofuran (THF) (250mL).Heat release as mild as a dove takes place in the result, and the white suspension that obtains in 25-26 ℃ of stirring 30 minutes.Then, reaction mixture is cooled to-10 ℃, and (35.5mL 285mmol) handles 30 minutes with the interior time with trimethyl-acetyl chloride.Add finish after, in-10 to-5 ℃ of stirred reaction mixtures are 30 minutes then, use afterwards (1R, 2R)-(-)-(59.5g 353mmol) handles 10 minutes with the interior time with many parts to pseudoephedrine, keeps temperature of reaction simultaneously between-10 to-4 ℃.Then, in-7 to-0 ℃ of stirred reaction mixtures are 3 hours.By adding entry (150mL), in 0 ℃ of quencher reaction mixture.After brute force stirred 10 minutes, add toluene (150mL), and stirred reaction mixture 5 minutes.Separate organic layer, and water (2 * 100mL) washings.With toluene (1 * 50mL) water layer of stripping and merging.Use in succession aqueous sulfuric acid (1 * 200mL), saturated sodium bicarbonate aqueous solution (1 * 200mL), and water/saturated sodium-chloride water solution (1:1, the organic layer that 1 * 50mL) solution washing merges.Then, the organic layer that vacuum concentration obtains provides a kind of white solid.Dry this white solid spends the night in high vacuum (0.4mm Hg), thick N-[2 (R)-hydroxyl-1 (R)-methyl-2 (R)-phenyl-ethyl is provided]-N-methyl-2-(4-methylthio group-phenyl)-ethanamide (82.8g, 92.6% is pure, by efficient liquid phase chromatographic analysis).In the toluene (225mL) of this substance dissolves under refluxing.In refrigerator, placed all last, collect the crystalline material that obtains by filtering, with cold toluene (3 * 35mL) washings, and it is dry in the high vacuum, provide: N-[2 (R)-hydroxyl-1 (R)-methyl-2 (R)-phenyl-ethyl]-N-methyl-2-(4-methylthio group-phenyl)-ethanamide (66.1g, 73.1%), is white crystal: mp 112-113 ℃; 99.6% purity is by efficient liquid phase chromatographic analysis.High-efficient liquid phase chromatogram condition is as follows:
Chromatographic column: ES Si, 3 μ, 5 * 150mm
Mobile phase: 30% tetrahydrofuran (THF) in heptane, 1mL/min
Detect: UV, 259nm
The residence time: 20 minutes
[000140] will be in tetrahydrofuran (THF) (400mL) 1,1,1,3,3,3-hexamethyldisilazane (98.4mL, solution 457mmol) is cooled to-20 ℃, (182mL, 418mmol) n-butyllithium solution in is handled the time within 35 minutes, maintains the temperature at simultaneously between-20 ℃ and-15 ℃ at hexane to use 2.29M then.In-20 ℃ of stirred reaction mixtures 30 minutes, be used in N-[2 (R)-hydroxyl-1 (R)-methyl-2 (R)-phenyl-ethyl in the tetrahydrofuran (THF) (500mL) then]-N-methyl-2-(4-methylthio group-phenyl)-ethanamide (66.1g, time within solution-treated 201mmol) 50 minutes, maintain the temperature at simultaneously between-20 ℃ and-15 ℃.The yellow solution that obtains in 0 ℃ of stirring 30 minutes uses 1,3-dimethyl-3 then, 4,5,6-tetrahydrochysene-2 (1H)-pyrimidone (51mL, 418mmol) and the iodomethyl pentamethylene (according to preparation among the embodiment 1,50.6g, 239mmol) aqueous premix is handled the time within 30 minutes.The reaction mixture that obtains in 0 ℃ of stirring 4 hours.At this moment, reaction mixture is poured in the toluene (400mL).Water/saturated sodium-chloride water solution (1:1 in succession, 1 * 1000mL) solution, water/saturated sodium-chloride water solution (1:2,1 * 1000mL) solution, 1M aqueous sulfuric acid (1 * 800mL), water (1 * 200mL) and saturated sodium bicarbonate aqueous solution (1 * 1000mL) washing organic phase.The organic layer that vacuum concentration obtains, thick 3-cyclopentyl-N-[2 (R)-hydroxyl-1 (R)-methyl-2 (R)-phenyl-ethyl is provided]-N-methyl-2 (R)-(4-methylthio group-phenyl)-propionic acid amide, be oily yellow residue (98.5%) by efficient liquid phase chromatographic analysis.In ethyl acetate (70mL), use hexane (200mL) to handle then this substance dissolves.Solution is stored in the refrigerator spends the night.Collect the solid that obtains by filtering, with (-10 ℃ approximately of cold hexanes, 3 * 30mL) washings, high vacuum dry then, 3-cyclopentyl-N-[2 (R)-hydroxyl-1 (R)-methyl-2 (R)-phenyl-ethyl is provided]-N-methyl-2 (R)-(4-methylthio group-phenyl)-propionic acid amide (48.8g, 59%), is white solid: mp 82-84 ℃; 100%, by efficient liquid phase chromatographic analysis.Filtrate and washings that vacuum concentration merges, and residuum (34.4g) is positioned over thin-layer chromatography level silica gel (2-25 μ, 70g) Sai top.Then, with hexane/ethyl acetate (4:1, solution washing silica gel plug 1.5L), the organism that vacuum concentration merges.The light yellow oil that obtains is dissolved in the ethyl acetate (35mL), uses hexane (100mL) to handle then.Solution is stored in refrigerator overnight.Collect the solid that obtains by filtering, with (-10 ℃ approximately of cold hexanes, 3 * 25mL) washings, and high vacuum dry, 3-cyclopentyl-N-[2 (R)-hydroxyl-1 (R)-methyl-2 (R)-phenyl-ethyl is provided]-N-methyl-2 (R)-(4-methylthio group-phenyl)-propionic acid amide (17.3g, 20.9%), is white solid: mp 83-85 ℃; 99.6%, by efficient liquid phase chromatographic analysis.Merge this two batches of products, needed diastereomer be provided: 3-cyclopentyl-N-[2 (R)-hydroxyl-1 (R)-methyl-2 (R)-phenyl-ethyl]-N-methyl-2 (R)-(4-methylthio group-phenyl)-propionic acid amide (66.1g, 79.9%), be white solid.High-efficient liquid phase chromatogram condition is as follows:
Chromatographic column: ES Si, 3 μ, 5 * 150mm
Mobile phase: 30% tetrahydrofuran (THF) in heptane, 1mL/min
Detect: UV, 259nm
The residence time: 9.2 minutes (undesirable diastereomer) and
Minute 14.4 (diastereomer that needs)
[000141] with 3-cyclopentyl-N-[2 (R)-hydroxyl-1 (R)-methyl-2 (R)-phenyl-ethyl in 9N aqueous sulfuric acid (7.7mL) the processing Zai diox (8mL)]-N-methyl-2 (R)-(4-methylthio group-phenyl)-propionic acid amide (4.00g, solution 9.72mmol).This two-phase mixture of heating obtains a kind of even colourless solution under refluxing.After 16 hours, with ice-water bath reaction mixture is cooled to 5 ℃ at reflux, water (20mL) drips and handles then, so that the product precipitation.With stirring the suspension obtain under the ice-water cooling after 1 hour, pass through solid collected by filtration, water (4 * 10mL) washings, and pass through suction dried, thick 3-cyclopentyl-2R-(4-methylthio group-phenyl)-propionic acid (2.57g, 96.6%, 96.3%ee is provided, by the chiral high performance liquid chromatography analysis), be the Sandy solid.With the Glacial acetic acid (5mL) of this substance dissolves under refluxing, water (1mL) is handled then, through causing crystallization.Remove heating bath, in suspension, drip water (4mL) then, to finish crystallization.Make mixture be cooled to envrionment temperature.After stirring 1 hour, pass through solid collected by filtration.With acetic acid/water (1:1, solution 10mL) and water (4 * 10mL) washing solids, dry then, 3-cyclopentyl-2 (R)-(4-methylthio group-phenyl)-propionic acid (2.24g, 87.2%) is provided, be white solid: mp75-76 ℃; 96.4%ee is by the chiral high performance liquid chromatography analysis.The chiral high performance liquid chromatography condition is as follows:
Chromatographic column: Chiralpak AS, 5 μ, 5 * 250mm
Mobile phase: 6% Virahol+0.1%TFA in hexane, 0.5mL/ minute
Detect: UV, 259nm
The residence time: 13.2 minutes (need R-isomer) and
Minute 17.1 (S-isomer)
[000142] will (50.03g, solution 189.21mmol) be cooled to 0 ℃, and (58mL 567.64mmol) handles at leisure to use 30% aqueous hydrogen peroxide solution then at the 3-cyclopentyl-2 (R) in the formic acid (189mL)-(4-methylthio group-phenyl)-propionic acid.The reaction mixture that obtains was stirred 1 hour in 0 ℃, be warmed to 25 ℃ then, it was stirred 3 hours in this temperature.Reaction mixture is cooled to 0 ℃ again, uses then that saturated aqueous solution of sodium bisulfite (500mL) is slow to be handled ashamedly.Generate throw out.The suspension that obtains was stirred 1 hour in 0 ℃, cross filter solid then.(4 * 700mL) washing solids by suction dried, provide 3-cyclopentyl-2 (R)-(4-methylsulfonyl phenyl)-propionic acid, are mp:138-140 ℃ of paste solid with cold water; EI-HRMS m/e calculated value C
15H
20O
4S (M
+) 296.1082, actual measurement 296.1080.
[000143] (3.86g 21.7mmol) handles triphenyl phosphine (5.75g, 21.7mmol) solution in the anhydrous methylene chloride (35mL) under 0 ℃, argon atmospher with N-bromo-succinimide.In 0 ℃ of stirring 15 minutes, (4.95g 16.7mmol) handled to use 3-cyclopentyl-2 (R)-(4-methylsulfonyl phenyl)-propionic acid then with mixture.Then, make the mixture that obtains be warmed to 25 ℃ 10 minutes.At this moment, add 2-amino-5-bromo-pyrazine (5.81g, 33.4mmol), then add at leisure pyridine (5.5mL, 68.0mmol).This mixture was stirred 3 hours in 25 ℃, at this moment, the vacuum concentration reaction mixture.Residuum is dissolved in the ethyl acetate, and with 1N aqueous hydrochloric acid (150mL),, 10% wet chemical (100mL) and saturated sodium-chloride water solution (250mL) washing.Use the dried over sodium sulfate organic layer; filter and vacuum concentration Biotage chromatogram (FLASH 75S; silicon-dioxide; 2.5% to 5% gradient ethyl acetate/dichloromethane) provides: 2 (R)-(4-methylsulfonyl-phenyl)-3-cyclopentyl-5-bromo-pyrazine-2-base-propionic acid amide (6.12g; 81%), it is a faint yellow solid.
[000144] under argon atmospher; will be at anhydrous N; 2 (R) in the dinethylformamide (30mL)-(4-methylsulfonyl-phenyl)-3-cyclopentyl-5-bromo-pyrazine-2-base-propionic acid amide (6.11g; 13.5mmol), potassium cyanide (2.27g; 33.8mmol), cuprous iodide (I) (6.43g; 33.8mmol), four (triphenyl phosphine) palladium (0) (320mg, 0.27mmol) and hexaoxacyclooctadecane-6-6 (365mg, solution 1.37mmol) are heated to 150 ℃.After 4 hours, mixture is cooled to 25 ℃.Mixture is concentrated into the volume of half approximately, adds chloroform (700mL) then, so that the mantoquita precipitation.By the Celite pad filtering mixt, and with warm chloroform (2 * 100mL) wash this salt.Then, vacuum concentration filtrate.Biotage chromatogram (FLASH75S, silicon-dioxide, 0% to 35% gradient ethyl acetate/hexane) provide: 2 (R)-(4-methylsulfonyl-phenyl)-3-cyclopentyl-5-cyano group-pyrazine-2-base-propionic acid amide (4.49g, 83%) are faint yellow solid: mp 229-231 ℃; (ES)
+-HRMS m/e calculated value C
20H
23N
4O
3S
2(M+H)
+399.1486, actual measurement 399.1488.
[000145] 2 (R)-(4-methylsulfonyl-phenyl)-3-cyclopentyl-5-cyano group-pyrazine-2-base-propionic acid amide (1.00g that will be in pH=7 damping fluid/ethanol (40mL); 2.51mmol) and azanol base hydrochloride (219mg, 3.15mmol) mixture is in 70 ℃ of heating.After 17 hours, make mixture be cooled to 25 ℃, then vacuum concentration.With ethyl acetate (3 * 50mL) extraction mixtures.With the organic layer that the saturated sodium-chloride water solution washing merges, use dried over sodium sulfate, filter and vacuum concentration.By RPLC (C-18, acetonitrile/water, 0.1% trifluoroacetic acid, 40% to 80% acetonitrile gradient) purifying crude product, vacuum concentration contains the fraction of product, and freeze-drying, and 3-cyclopentyl-2 (R)-N-[5-(N-hydroxyl amino formyl imino-)-pyrazine-2-yl is provided]-2-(4-methylsulfonyl-phenyl)-propionic acid amide (740mg, 68%), is pale solid: mp223 ℃ (dec.); (ES)
+-HRMS m/e calculated value C
20H
26N
5O
4S (M+H)
+432.1700, actual measurement 432.1706.
Embodiment 4
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-methylthio group-pyrazine-2-yl)-propionic acid amide
[000146] (4.24g 57.47mmol) handles at N, and (3.32g is 2.87mmol) with 2-amino-5-bromo-pyrazine (5.00g, mixture 28.73mmol) for four (triphenyl phosphine) palladium (0) in the dinethylformamide (144mL) with 95% sulfo-sodium methylate.The reaction mixture that obtains in 60 ℃ of heating 10 hours.Make reaction mixture be cooled to 25 ℃, pour into then in the saturated sodium bicarbonate aqueous solution (500mL).With ethyl acetate (5 * 200mL) extraction products.(organic layer that 1 * 200mL) washing merges is used dried over sodium sulfate, filters and vacuum concentration with saturated sodium-chloride water solution.Flash chromatography (Merck silica gel 60,230-400 order, 30% ethyl acetate/hexane) provides: 5-methylthio group-pyrazine-2-base amine (1.66g, 40.9%) is orange solids: mp 65-67 ℃; EI-HRMS m/e calculated value C
5H
7N
3S (M
+) 141.0361, actual measurement 141.0357.
[000147] (7.08mmol) and N, the solution of dinethylformamide (5) is cooled to 0 ℃ to 2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-propionic acid that will be in methylene dichloride (15mL) for preparation in according to embodiment 1,2.34g.Then, with oxalyl chloride (1.24mL, 14.16mmol) reaction mixture.In 0 ℃ of stirred reaction mixture 15 minutes, stirred 2 hours in 25 ℃ then.This solution of vacuum concentration should be dissolved in methylene dichloride (8mL) by the yellow semisolid.In 0 ℃, the solution that obtains dropped to by feed hopper (0.86mL, 10.6mmol) the 5-methylthio group-pyrazine in-(1.0g is in solution 7.08mmol) for 2-base amine at methylene dichloride (5mL) and pyridine.In 0 ℃ of stirred reaction mixture 2 hours, spend the night in 25 ℃ of stirrings then.1N aqueous citric acid solution (10mL) quencher reaction mixture, and stirred 10 minutes.Then, water (50mL), methylene dichloride (100mL) and 1N aqueous citric acid solution (25mL) diluted reaction mixture.Layer separates, and uses saturated sodium bicarbonate aqueous solution (50mL) and saturated sodium-chloride water solution (50mL) washing organic layer then, uses dried over mgso, filters and vacuum concentration.Biotage chromatogram (FLASH 40M, silicon-dioxide, 25% ethyl acetate/hexane) provides impure product.By Biotage chromatogram (FLASH 40M, silicon-dioxide, 50% ethyl acetate/hexane) purifying once more, provide: 2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-methylthio group-pyrazine-2-yl)-propionic acid amide (1.75g, 54%), is white foam: mp 65-70 ℃ (foam is to gel); (ES)
+-HRMS m/e calculated value C
20H
24ClN
3O
3S
2(M+H)
+454.1021, actual measurement 454.1026.
Embodiment 5
3-cyclopentyl-2 (R)-(4-methylsulfonyl-phenyl)-N-(5-methylthio group-pyrazine-2-yl)-propionic acid amide
[000148] will (4.07mmol) and N, the solution of dinethylformamide (5) be cooled to 0 ℃ for preparation in according to embodiment 3,1.21g at the 3-cyclopentyl-2 (R) in the methylene dichloride (10mL)-(4-methylsulfonyl phenyl)-propionic acid.With oxalyl chloride (0.53mL, 6.10mmol) reaction mixture, and the reaction mixture that obtains in 0 ℃ of stirring 1 hour.Then, vacuum concentrated solution should be dissolved in the methylene dichloride by orange-brown gel.The solution that obtains is added dropwise to by feed hopper (0.36mL, 4.48mmol) the 5-methylthio group-pyrazine in-(according to preparation among the embodiment 4,0.58g is in solution 4.07mmol) for 2-base amine at methylene dichloride (10mL) and pyridine.In 0 ℃ of stirred reaction mixture 30 minutes, be warmed to 25 ℃ then, in this temperature it was stirred 3 hours.With 1N aqueous citric acid solution (10mL) quencher reaction mixture, and stirred 15 minutes.Then, with ethyl acetate (75mL) and 1N aqueous citric acid solution (50mL) diluted reaction mixture.Layer separates, and uses saturated sodium bicarbonate aqueous solution (50mL), water (50mL) and saturated sodium-chloride water solution (50mL) washing organic layer then, uses dried over mgso, filters and vacuum concentration.Biotage chromatogram (FLASH 40M, silicon-dioxide, 50% ethyl acetate/hexane) provide: 3-cyclopentyl-2 (R)-(4-methylsulfonyl-phenyl)-N-(5-methylthio group-pyrazine-2-yl)-propionic acid amide (0.864g, 51%) is white foam: mp 71-77 ℃ (foam is to gel); (ES)
+-HRMS m/e calculated value C
20H
25N
3O
3S
2(M+H)
+420.1410, actual measurement 420.1415.
Embodiment 6
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(2-hydroxyl-ethylmercapto group)-pyrazine-2-yl]-propionic acid amide
[000149] (5.80g 32.6mmol) handles triphenyl phosphine (8.57g, stirred solution 32.6mmol) in the anhydrous methylene chloride (110mL) in 0 ℃, nitrogen with N-bromo-succinimide.After 15 minutes, in reaction mixture, adding 2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-propionic acid (according to preparation among the embodiment 1,9.00g, 27.2mmol).Mixture is warmed to 25 ℃.After 10 minutes, ((8.79mL 108.8mmol) handles to use pyridine then for 7.92g, 45.6mmol) reaction mixture with 2-amino-5-bromo-pyrazine in 25 ℃ of stirrings.Stirred the mixture 1.5 hours in 25 ℃.At this moment, use the methylene dichloride diluted reaction mixture, use 1N aqueous hydrochloric acid (200mL) washing then, then wash with 10% wet chemical (100mL).Use the dried over sodium sulfate organic layer, filter and vacuum concentration.Flash chromatography (Merck silica gel 60, the 70-230 order, 30% ethyl acetate/hexane) provides: N-(5-bromo-pyrazine-2-yl)-2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-propionic acid amide (10.02g, 76%), white foam: mp 77-82 ℃ (foam is to gel); (ES)
+-HRMS m/e calculated value C
19H
21BrClN
3O
3S (M+H)
+486.0249, actual measurement 486.0255.
[000150] in the test tube of sealing; in 120 ℃ of heating at anhydrous N; N-in the dinethylformamide (0.5mL) (5-bromo-pyrazine-2-yl)-2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-propionic acid amide (94mg; 0.19mmol), mercaptoethanol (0.031mL; 0.44mmol) and four (triphenyl phosphine) palladium (0) (111mg, mixture 0.097mmol).After 3 hours, mixture is cooled to 25 ℃, dilute with water extracts with diethyl ether then.Use the dried over sodium sulfate organic layer, filter and vacuum concentration.Flash chromatography (Merck silica gel 60, the 230-400 order, 55% ethyl acetate/hexane) provide: 2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(2-hydroxyl-ethylmercapto group)-pyrazine-2-yl]-propionic acid amide (58mg, 62%), be filbert foam: mp=78-81 ℃; (ES)
+-HRMSm/e calculated value C
21H
27ClN
3O
4S
2(M+H)
+484.1126, actual measurement 484.1131.
Embodiment 7
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-methanesulfinyl-pyrazine-2-yl)-propionic acid amide
[000151] sodium metaperiodate (0.189g among the Xiang Zaishui (1.5mL); 0.882mmol) solution in; 2 (Rs)-(3 chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-methylthio group-pyrazine-2-yl)-propionic acid amide (according to embodiment 4 in the preparation of dropping in tetrahydrofuran (THF) (3mL); 0.20g, solution 0.441mmol).The reaction mixture that obtains in 25 ℃ of stirrings 72 hours.Then, the vacuum concentration reaction mixture is used chloroform (25mL) dilution residuum afterwards.Water (25mL) washing organic layer is used dried over mgso, filters and vacuum concentration.Biotage chromatogram (FLASH 40S, silicon-dioxide, 67% ethyl acetate/hexane) provides: 2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-methanesulfinyl-pyrazine-2-yl)-propionic acid amide (96mg, 46%), white foam: mp 88-95 ℃ (foam is to gel); (ES)
+-HRMS m/e calculated value C
20H
24ClN
3O
4S
2(M+H)
+470.0970, actual measurement 470.0976.
Embodiment 8
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-methyl sulfamyl-pyrazine-2-yl)-propionic acid amide
[000152] with trifluoroacetic anhydride (0.40mL; 2.83mmol) 2 (Rs)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-methanesulfinyl-pyrazine-2-yl)-propionic acid amide (according to embodiment 7 in the preparation of processing in methylene dichloride (5.6mL); 0.30g, solution 0.65mmol).The reaction mixture that heating obtains under refluxing 90 minutes.Reaction mixture is cooled to 25 ℃, and vacuum concentration provides: three fluoro-acetate 5-[2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-propionyl amino then]-pyrazine-2-base-sulfane methyl esters, it uses under the condition that is not further purified.
[000153] in 25 ℃ of agitated methanol (2.5mL) and triethylamine (2.5mL; 17.9mmol) in thick three fluoro-acetate 5-[2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-propionyl amino]-pyrazine-2-base-sulfane methyl esters (0.37g; thick material based on 0.65mmol) solution 2 hours, vacuum concentration reaction mixture then.The orange oil that obtains is dissolved in the methylene dichloride (10mL), uses 0.5M aqueous hydrochloric acid (10mL) washing then.With methylene dichloride (3 * 3mL) aqueous layer extracted.Organic layer with dried over sodium sulfate merges filters, and vacuum concentration, provides: 2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-sulfydryl pyrazine-2-yl)-propionic acid amide, be orange solids, and it uses under the condition that is not further purified.
[000154] with powder saltpetre (0.192g; 1.90mmol) thick 2 (Rs)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-sulfydryl-pyrazine-2-yl)-propionic acid amide (0.29g of processing in acetonitrile (6.5mL); thick material based on 0.65mmol) solution; (0.150mL 1.87mmol) handles to use SULPHURYL CHLORIDE then.The solution that obtains in 25 ℃ of stirrings 15 minutes, at this moment, there is needed product: 5-[2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-propionyl amino in low resolution mass spectrum indication in solution]-pyrazine-2-SULPHURYL CHLORIDE.The solution of half volume is added to 2.0M, and (0.65mL, 1.30mmol) in the methylamine solution in, and 25 ℃ stirred 5 minutes, at this moment, generates throw out at tetrahydrofuran (THF).Dilute the reaction mixture that obtains with methylene dichloride (15mL), and wash organic phase with saturated sodium bicarbonate aqueous solution (10mL) and 1N aqueous citric acid solution (10mL).With methylene dichloride (2 * 5mL) water layers of stripping and merging.Then, the organic layer of vacuum concentration merging.Flash chromatography (Merck silica gel 60,75% ethyl acetate/hexane) provides impure product.The product that this is impure RPLC chromatogram (C-18, acetonitrile/water, 0.1% trifluoroacetic acid, 50% to 100% acetonitrile gradient) repurity.Vacuum concentration contains the fraction of product, and freeze-drying, and 2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-methyl sulfamyl-pyrazine-2-yl)-propionic acid amide (15mg ,～9% total recovery) is provided, and is yellow glue: (ES)
+-HRMS m/e calculated value C
20H
25ClN
4O
5S
2(M+Na)
+523.0847, actual measurement 523.0854.
Embodiment 9
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-dimethylamino alkylsulfonyl-pyrazine-2-yl)-propionic acid amide
[000155] with trifluoroacetic anhydride (0.25mL; 1.77mmol) 2 (Rs)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-methanesulfinyl-pyrazine-2-yl)-propionic acid amide (according to embodiment 7 in the preparation of processing in methylene dichloride (3.6mL); 199.9mg, solution 0.42mmol).The reaction mixture that obtains was heated 90 minutes under refluxing.Reaction mixture is cooled to 25 ℃, and vacuum concentration provides: three fluoro-acetate 5-[2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-propionyl amino then]-pyrazine-2-base-sulfane base methyl esters, be thick yellow foam (291.3mg, 121%).This material uses under the condition that is not further purified.
[000156] under 25 ℃, is stirred in methyl alcohol (1.7mL) and triethylamine (1.6mL; 11.48mmol) in three thick fluoro-acetate 5-[2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-propionyl amino]-pyrazine-2-base-sulfane base methyl esters (240.7mg; thick material based on 0.42mmol) solution 3 hours, vacuum concentration reaction mixture then.The orange oil that obtains is dissolved in the methylene dichloride (11mL), uses 0.5M aqueous hydrochloric acid (10mL) washing then.With methylene dichloride (3 * 3mL) reextraction water layers.Then, the organic layer with dried over sodium sulfate merges filters and vacuum concentration, and provide: 2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-sulfydryl-pyrazine-2-yl)-propionic acid amide are thick red-orange solids (289.1mg, 155%).This material uses under the condition that is not further purified.
[000157] with powder saltpetre (125.1mg; 1.24mmol); use SULPHURYL CHLORIDE (0.100mL then; 1.24mmol) handle the solution of 2 thick (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-sulfydryl-pyrazine-2-the yl)-propionic acid amide (187.1mg is based on the thick material of 0.42mmol) in acetonitrile (4.4mL).The solution that obtains in 25 ℃ of stirrings 30 minutes, at this moment, there is needed crude product: 5-[2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-propionyl amino in low resolution mass spectrum indication in solution]-pyrazine-2-SULPHURYL CHLORIDE.This solution is added to 2.0M, and (0.85mL is 1.70mmol) in the dimethylamine solution at tetrahydrofuran (THF).Spend the night in 25 ℃ of stirred reaction mixtures, add another 2.0M partly then at tetrahydrofuran (THF) (0.21mL, 0.42mmol) dimethylamine solution in.Obtain in 25 ℃ of stirrings reaction mixture 5-6 hour, (0.21mL, 0.42mmol) dimethylamine solution in was handled at tetrahydrofuran (THF) to use the 2.0M of last part then.Spend the night in 25 ℃ of stirred reaction mixtures, by low resolution mass spectrum monitoring.With the reaction mixture that ethyl acetate (10mL) dilution obtains, use saturated sodium bicarbonate aqueous solution (10mL) washing then.With ethyl acetate (10mL) reextraction water layer.With the organic layer that 1N aqueous citric acid solution (10mL) washing merges, use dried over sodium sulfate, filter and vacuum concentration on silica gel (Merck silica gel 60,230-400 order).Biotage chromatogram (FLASH 40S, silicon-dioxide, 40% ethyl acetate/hexane) provides impure product.This impure product is by RPLC (C-18, acetonitrile/water, 0.1% trifluoroacetic acid, 50% to 100% acetonitrile gradient) repurity.Vacuum concentration contains the fraction and the freeze-drying of product, and 2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-dimethylamino alkylsulfonyl-pyrazine-2-yl)-propionic acid amide (44.6mg, 20% total recovery) is provided, and is 100.2 ℃ of faint yellow solid: mp; (ES)
+-HRMS m/e calculated value C
21H
27ClN
4O
5S
2(M+H)
+515.1184, actual measurement 515.1189.
Embodiment 10
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(3-hydroxyl-third-1-alkynyl)-pyrazine-2-yl]-propionic acid amide
[000158] with cuprous iodide (I) (19.2mg; 0.10mmol), trichlorine two (triphenyl phosphine) palladium (II) (36mg; 0.05mmol) and N; N-diisopropylethylamine (2ml) is handled N-(5-bromo-pyrazine-2-yl)-2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-propionic acid amide (preparation in according to embodiment 6 in toluene (6mL); 486mg; 1mmol) and propargyl alcohol (84mg, solution 1.5mmol).The mixture that obtains was stirred 1 hour in 25 ℃, be heated to then 60 ℃ 1 hour.At this moment, vacuum concentration reaction mixture.Residuum is extracted into the ethyl acetate from the 1N aqueous hydrochloric acid.With the organic layer that the saturated sodium-chloride water solution washing merges, drying, and vacuum concentration.Flash chromatography (Merck silica gel 60; the 230-400 order; 1/1 ethyl acetate/hexane) provide: 2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(3-hydroxyl-third-1-alkynyl)-pyrazine-2-yl]-propionic acid amide (275mg, 57%), be faint yellow solid: (ES)
+-HRMS m/e calculated value C
22H
24ClN
3O
4S (M+H)
+462.1249, actual measurement 462.1252.
Embodiment 11
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(3-dimethylamino-third-1-alkynyl)-pyrazine-2-yl]-propionic acid amide
[000160] uses N; N-diisopropylethylamine (1.5ml); cuprous iodide (I) (19.2mg; 0.10mmol) and dichloro two (triphenyl phosphine) palladium (II) (36.0mg; 0.05mmol) N-(5-bromo-pyrazine-2-yl)-2 (Rs)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-propionic acid amide (according to embodiment 1 in the preparation of processing in toluene (6ml); 486mg is 1.0mmol) with 1-dimethylamino-2-propine (830mg, solution 10.0mmol).The mixture that obtains was stirred 24 hours in 25 ℃.At this moment, vacuum concentration reaction mixture.Residuum is extracted in the methylene dichloride from water.Dry organic layer and the vacuum concentration that merges.Flash chromatography (Merck silica gel 60; the 230-400 order; 4/1 ethyl acetate/methanol) provide: 2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(3-dimethylamino-third-1-alkynyl)-pyrazine-2-yl]-propionic acid amide (360mg; 74%), be filbert solid: (ES)+-HRMS m/e calculated value C
24H
29ClN
4O
3S (M+H)
+489.1722, actual measurement 489.1725.
Embodiment 12
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-methylsulfonyl amino-pyridine-2-yl)-propionic acid amide
[000161] with 5-bromo-2-nitropyridine (2.0g, 9.85mmol), Toluidrin (2.81g, 29.55mmol) and salt of wormwood (3.43g, mixture process 24.8mmol) is heated to 90 ℃ fusion ethanamide (2.36g, solution 40.0mmol).The mixture that obtains is rapidly heated to 145 ℃.The solution that obtains in 145 ℃ of stirrings 30 minutes.At this moment, reaction mixture is cooled to 25 ℃, water (8mL) is handled then.This solution is cooled to 0 ℃, handles with the 1N aqueous hydrochloric acid then, up to the pH regulator of solution to pH=8.By removing by filter the throw out that obtains.Regulate filtrate to pH=4 by adding the 1N aqueous hydrochloric acid.The throw out that collection obtains, and vacuum-drying provide: N-(6-nitro-pyridin-3-yl)-Toluidrin (1.46g, 68%) is white solid: mp 187-189 ℃; (ES)
--HRMS m/e calculated value C
6H
7N
3O
4S (M-H)
-216.0084, actual measurement 216.0085.
[000162] is used in ammonium chloride (154mg, N-(6-nitro-pyridin-3-yl)-Toluidrin (298mg, 1.37mmol) the solution of solution-treated 2.88mmol) in methyl alcohol (8.3mL) in the water (1mL).Stirred this reaction mixture 5 minutes in 25 ℃.At this moment, in reaction mixture, add zinc powder (879mg, 13.44mmol).With the reaction mixture reflux that obtains 3 hours.At this moment, reaction mixture is cooled to 25 ℃, and filters by Celite pad (washing of 90/10 methylene chloride).The vacuum concentration filtrate.Flash chromatography (Merck silica gel 60,230-400 order, 90/10 methylene chloride) provides: N-(6-amino-pyridine-3-yl)-Toluidrin (196.3mg, 76.4%), for little red-brown oil: EI-HRMS m/e calculated value C
6H
9N
3O
2S (M
+) 184.0415, actual measurement 184.0415.
[000163] 2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-propionic acid that will be in methylene dichloride is (according to preparation among the embodiment 1; 224mg; 0.67mmol) solution be cooled to 0 ℃; use 2.0M at methylene dichloride (0.37mL then; 0.74mmol) and several N, the oxalyl chloride solution-treated in the dinethylformamide.In 0 ℃ of stirred reaction mixture 10 minutes, and stirred 20 minutes in 25 ℃.Then, be used in N-(6-amino-pyridine-3-yl)-Toluidrin in the tetrahydrofuran (THF) (3.38mL) (190mg, 1.01mmol) and pyridine (0.08mL, solution-treated reaction mixture 1.01mmol).In 25 ℃ of stirred reaction mixtures 18 hours.At this moment, vacuum concentration reaction mixture.Residuum is dissolved in methylene dichloride (50mL), use in succession the 1N aqueous hydrochloric acid (1 * 100mL) and saturated sodium bicarbonate aqueous solution (1 * 100mL) washing organic layer.Then, use the dried over sodium sulfate organic layer, filter and vacuum concentration.Flash chromatography (Merck silica gel 60, the 230-400 order, 75/25 ethyl acetate/hexane) provide: 2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-methylsulfonyl amino-pyridine-2-yl)-propionic acid amide (34.4mg, 10.2%) are the Sandy solid: mp 146-150 ℃; EI-HRMS m/e calculated value C
21H
26ClN
3O
5S
2(M+H)
+500.1075, actual measurement 500.1081.
Embodiment 13
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-methylsulfonyl amino-pyrazino-2-yl)-propionic acid amide
[000164] with 2-bromo-5-nitro pyrazine (1.34g, 6.58mmol), amsacrine (1.88g, 19.7mmol) and salt of wormwood (2.30g, mixture process 16.6mmol) is heated to 90 ℃ fusion ethanamide (2.36g, solution 40.0mmol).The mixture that obtains is rapidly heated to 145 ℃.The solution that obtains in 145 ℃ of stirrings 30 minutes.At this moment, reaction mixture is cooled to 25 ℃, water (4mL) is handled then.This solution is cooled to 0 ℃, handles with the 1N aqueous hydrochloric acid then, up to the pH regulator of solution to pH=8.With this solution of charcoal treatment, and filter with Celite pad (washing of 90/10 methylene chloride).Distribute filtrate, and with the solution extraction water layer of 90/10 methylene chloride.Organic layer with dried over sodium sulfate merges filters, and vacuum concentration.Flash chromatography (Merck silica gel 60,230-400 order, ethyl acetate) provides: N-(5-nitro-pyrazine-2-yl)-Toluidrin (583.9mg, 40.6%) is yellow solid: mp 204-207 ℃; EI-HRMS m/e calculated value C
5H
6N
4O
4S (M+H)
+219.0183, actual measurement 219.0185.
[000165] is used in ammonium chloride (300.6mg, N-(5-nitro-pyrazine-2-yl)-Toluidrin (583.9mg, 2.67mmol) the solution of solution-treated 5.62mmol) in methyl alcohol (26.8mL) in the water (2mL).Stirred this reaction mixture 5 minutes in 25 ℃.At this moment, in reaction mixture, add zinc powder (1.71g, 26.2mmol).The mixture heating up that obtains was refluxed 2 hours.At this moment, reaction mixture is cooled to 25 ℃, and filters by silicagel pad (washing of 90/10 methylene chloride).The vacuum concentration filtrate provides: N-(5-amino-pyrazino-2-yl)-Toluidrin (548.8mg, 100%), for secretly-brown size: EI-HRMS m/e calculated value C
5H
8N
4O
2S (M+H)
+189.0441, actual measurement 189.0442.
[000166] use 2.0M at methylene dichloride (0.80mL; 1.60mmol) and several N; oxalyl chloride solution-treated in the dinethylformamide is cooled to 2 (R) in methylene dichloride (14.6mL)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-propionic acid (preparation in according to embodiment 1 of 0 ℃; 482mg, solution 1.45mmol).In 0 ℃ of stirred reaction mixture 10 minutes, and stirred 30 minutes in 25 ℃.Then, be used in N-(5-amino-pyrazino-2-yl)-amsacrine in the tetrahydrofuran (THF) (7.29mL) (548.8mg, 2.91mmol) and pyridine (0.24mL, solution-treated reaction mixture 2.91mmol).In 25 ℃ of following stirred reaction mixtures 18 hours.At this moment, vacuum concentration reaction mixture.Residuum is dissolved in methylene dichloride (50mL), use in succession the 1N aqueous hydrochloric acid (1 * 100mL) and saturated sodium bicarbonate aqueous solution (1 * 100mL) washing organic layer.Use the dried over sodium sulfate organic layer, filter and vacuum concentration.Flash chromatography (Merck silica gel 60, the 230-400 order, 95/5 methylene chloride) provide: 2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-ring-amyl group-N-(5-methylsulfonyl amino-pyrazino-2-yl)-propionic acid amide (43.0mg, 5.9%) are pale solid: mp 108-110 ℃; EI-HRMS m/e calculated value C
20H
25ClN
4O
5S
2(M+H)
+501.1028, actual measurement 501.1031.
Embodiment 14
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-dimethylamino-pyridine-2-yl)-propionic acid amide
[000167] in the tubular unit of sealing, add 2-bromo-5-nitropyridine (1.02g, 5.02mmol) and 5.6M at ethanol (5.0mL, 28.0mmol) dimethylamine solution in.The solution that obtains in 90 ℃ of heating three days, is cooled to 0 ℃, dilutes with acetoneand ethyl acetate then.By removing by filter white depositions, and filtrate is adsorbed on the silica gel (Merck silica gel 60,230-400 order).Biotage chromatogram (FLASH 40S, silicon-dioxide, 33-75% ethyl acetate/hexane) provides: dimethyl-(6-nitro-pyridin-3-yl)-amine (0.64g, 76%) is mp199.8-200.5 ℃ of glassy yellow solid; EI-HRMS m/e calculated value C
7H
9N
3O
2(M
+) 167.0695, actual measurement 167.0697.
[000168] with 10% dimethyl-(6-nitro-pyridin-3-yl)-amine (0.64g, 3.83mmol) the solution of palladium processing in ethanol (45mL) at gac (203mg).In 25 ℃, stirred reaction mixture spends the night under the malleation (positive pressure) of hydrogen (balloon) and normal atmosphere.Then, filter out catalyzer, and wash Celite pad well with ethanol by Celite pad.The vacuum concentration filtrate provides N
5, N
5-dimethyl-pyridine-2,5-diamines (493.6mg, 94%) is dark red-violet oil: EI-HRMS m/e calculated value C
7H
11N
3(M
+) 137.0953, actual measurement 137.0957.
[000169] (preparation in according to embodiment 1,701mg, solution 2.12mmol) are cooled to 0 ℃ to 2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-propionic acid that will be in methylene dichloride (5.0mL).Then, with oxalyl chloride (0.43mL, 4.93mmol) and N, dinethylformamide (4) reaction mixture.In 0 ℃ of stirred reaction mixture, in 5 hours, be warmed to 25 ℃ at leisure then.This solution of vacuum concentration is dissolved in yellow thin pulp in the methylene dichloride (3mL).In 0 ℃, the solution that obtains is added to N in methylene dichloride (5mL) and pyridine (0.3mL) by addition funnel
5, N
5-dimethyl-pyridine-2, (287mg is in solution 2.09mmol) for the 5-diamines.In 0 ℃ of stirred reaction mixture, be warmed to 25 ℃ then and spend the night.Then, the vacuum concentration reaction mixture, and handle with ethyl acetate (75mL) and 1N aqueous citric acid solution (75mL).Layer separates.With ethyl acetate (2 * 50mL) aqueous layer extracted.Organic layer with saturated sodium bicarbonate aqueous solution (75mL) washing merging.Water layer with ethyl acetate (50mL) reextraction merging.With the organic layer that saturated sodium-chloride water solution (75mL) washing merges, use dried over sodium sulfate, filter and vacuum concentration.Biotage chromatogram (FLASH 40M, silicon-dioxide, the 33-50% ethyl acetate/hexane) provides: 2 (R)-(3-chloromethane alkylsulfonyl-phenyl)-3-cyclopentyl-N-(5-dimethylamino-pyridine-2-yl)-propionic acid amide (0.67g, 70%), 166.2 ℃ of white foam: mp (foam is to gel); (ES)
+-HRMS m/e calculated value C
22H
28ClN
3O
3S (M+H)
+450.1613, actual measurement 450.1618.
Embodiment 15
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-dimethylamino-pyrazine-2-yl)-propionic acid amide
[000170] in the tubular unit of sealing, add 2-bromo-5-nitropyridine (1.89g, 9.27mmol), water (6.5mL) and 40% is at water (2.2mL, 17.5mmol) dimethylamine solution in.The solution that obtains 110 ℃ of heating spends the night.Then, solution is cooled to 0 ℃, and generates throw out.By the filtering separation throw out, provide: dimethyl-(6-nitro-pyrazine-3-yl)-amine (1.28g, 82%) is tea-yellow powder: mp 221.4-222.7 ℃; EI-HRMS m/e calculated value C
6H
8N
4O
2(M
+) 168.0647, actual measurement 168.0648.
[000171] handles dimethyl-(6-nitro-pyrazine-3-yl)-amine (1.27g, solution 7.55mmol) in ethanol (90mL) with 10% at the palladium on the gac (0.40g).In 25 ℃, stirred reaction mixture spends the night under the malleation of hydrogen (balloon) and normal atmosphere.Then, filter out catalyzer, and wash Celite pad well with ethanol by Celite pad.The vacuum concentration filtrate is ground the black-orange solids that obtains with sherwood oil, and N is provided
5, N
5-dimethyl-pyrazine-2,5-diamines (0.78g, 75%) is black solid: mp 71.5-74.2 ℃; EI-HRMS m/e calculated value C
6H
10N
4(M
+) 138.0905, actual measurement 138.0903.
[000172] (preparation in according to embodiment 1,276.1mg, solution 0.83mmol) are cooled to 0 ℃ to 2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-propionic acid that will be in methylene dichloride (6mL).With oxalyl chloride (0.37mL, 4.15mmol) and N, dinethylformamide (2) reaction mixture.In 0 ℃ of stirred reaction mixture, in 2 hours, be warmed to 25 ℃ at leisure then.Then, this solution of vacuum concentration, and yellow thin pulp is dissolved in methylene dichloride (4mL) and the pyridine (0.5mL).Under 0 ℃, be used in N in the methylene dichloride (2mL) by feed hopper
5, N
5-dimethyl-pyrazine-2, (114.9mg, solution 0.83mmol) drip and handle this solution the 5-diamines, then with methylene dichloride (2 * 0.5mL) quick rinsings.In 0 ℃ of stirred reaction mixture, be warmed to 25 ℃ in 2.5 hours then.Water (1mL) quencher reaction mixture, and dilute with ethyl acetate (250mL).With saturated sodium bicarbonate aqueous solution (210mL), water (210mL) and saturated sodium-chloride water solution (210mL) washing organic layer, use dried over sodium sulfate, use carbon decoloring, by the Celite pad filtration, and on Celite pad vacuum concentration.Biotage chromatogram (FLASH 40S, silicon-dioxide, 33% ethyl acetate/hexane) provides: 2 (R)-(3-chloromethane alkylsulfonyl-phenyl)-3-cyclopentyl-N-(5-dimethylamino-pyrazine-2-yl)-propionic acid amide (0.189g, 50%), is weak yellow foam: mp 93.3-97.7 ℃ (foam is to gel); (ES)
+-HRMS m/e calculated value C
21H
27ClN
4O
3S (M+H)
+451.1565, actual measurement 451.1567.
Embodiment 16
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(3-dimethylamino-propyl group)-pyrazine-2-yl]-propionic acid amide
[000173] handle 2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(3-dimethylamino-third-1-alkynyl)-pyrazine-2-yl in methyl alcohol (20ml) with 10% palladium on activated carbon (65mg)]-propionic acid amide (preparation in according to embodiment 11; 190mg, solution 0.389mmol).Stirring the reaction mixture that obtains at the direct draught of hydrogen (balloon) spends the night.At this moment, remove by filter catalyzer by Celite pad, and the vacuum concentration filtrate.Flash chromatography (Merck silica gel 60; the 230-400 order; 1/1 methylene chloride) provide: 2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(3-dimethylamino-propyl group)-pyrazine-2-yl]-propionic acid amide (120mg; 63%), be solid: (ES)+-HRMS m/e calculated value C
24H
33ClN
4O
3S (M+H)
+493.2035, actual measurement 493.2041.
Embodiment 17
N-[5-(5-amino-[1,2,4] oxadiazole-3-yls)-pyrazine-2-yl]-2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-propionic acid amide
[000174] in the test tube of sealing; in 130 ℃ of 2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(N-hydroxyl amino formyl imino-)-pyrazine-2-yls that heat down in N-cyano group piperidines (25mL)]-propionic acid amide (preparation in according to embodiment 1; 7.00g, mixture 15.02mmol) 1.5 hours.Mixture is cooled to 25 ℃, in the air-flow of dry nitrogen, concentrates then and spend the night.Flash chromatography (Merck silica gel 60, the 230-400 order, 60% ethyl acetate/hexane) provides: N-[5-(5-amino-[1,2,4] oxadiazole-3-yl)-and pyrazine-2-yl]-2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-propionic acid amide (2.74g, 37%), is pale solid: mp 262-264 ℃; (ES)
+-HRMS m/e calculated value C
21H
23ClN
6O
4S
2(M+Na)
+513.1082, actual measurement 513.1088.
Embodiment 18
2-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-formyl radical-pyrazine-2-yl)-propionic acid amide
[000175] in the test tube of pressurization, under 65psi, 25 ℃ carbon monoxide; be stirred in anhydrous N; N-in the dinethylformamide (95mL) (5-bromo-pyrazine-2-yl)-2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-propionic acid amide are (according to preparation among the embodiment 6; 5.73g; 11.8mmol), potassiumiodide (2.2g; 13.0mmol), hexaoxacyclooctadecane-6-6 (0.62g; 2.4mmol), triethylamine (4.2mL; 29.5mmol), diphenyl propyl phosphine (81gL; 0.35mmol) and acid chloride (II) (80mg, mixture 0.35mmol) 30 minutes.At this moment, (8.42mL 23.6mmol) handles, and stirs 4 hours under 65psi, 110 ℃ carbon monoxide with three hexyl silanes.Then, reaction mixture is cooled to 25 ℃, and (2 * 200mL) extract with ethyl acetate.Use in succession saturated sodium bicarbonate aqueous solution (3 * 50mL) and water (organic layer that 3 * 50mL) washings merge use dried over sodium sulfate, filtration and vacuum concentration.Flash chromatography (Merck silica gel 60; 70-230 order, the 10%-70% ethyl acetate in hexane was with 30 minutes) provide: racemic 2-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-formyl radical-pyrazine-2-yl)-propionic acid amide (1.53g; 30%), is white solid.
Embodiment 19
2-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(2,4-dioxo-thiazolidine-5-ylmethyl)-pyrazine-2-yl]-propionic acid amide
[000176] will be in (the preparation in according to embodiment 18 of the 2-in the dehydrated alcohol (5mL) (3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-formyl radical-pyrazine-2-yl)-propionic acid amide; 44mg; 0.1mmol), 2; 4-thiazolidinedione (18mg; 0.15mmol), piperidines (2 μ L; 0.02mmol) and phenylformic acid (1.2mg, 0.01mmol) reflux is spent the night.Reaction mixture is cooled to 25 ℃, then vacuum concentration.Flash chromatography (Merck silica gel 60; the 230-400 order; the 0%-60% ethyl acetate/hexane) provides: 2-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(2; 4-dioxo-thiazolidine-5-ylmethyl)-pyrazine-2-yl]-propionic acid amide (40mg; 75%), is white solid: LC-MS m/e535 (MH
+).
[000177] will be at the 2-in the dry toluene (12mL) (3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(2; 4-dioxo-thiazolidine-5-ylmethyl)-pyrazine-2-yl]-propionic acid amide (150mg; 0.28mmol); 2; 6-dimethyl-1; 4-dihydro-pyridine-3, the 5-diethyl dicarboxylate (92.5mg, 0.37mmol) and the suspension of silica gel (450mg) stirred 12 hours in 90 ℃.Then, reaction mixture is cooled to 25 ℃, is acidified with acetic acid to pH=2 afterwards.Before removing by filter silicon, and wash with small amount of methanol.Then, use the ethyl acetate extraction product.Wash organic layer with water, use dried over sodium sulfate, filter and vacuum concentration.Flash chromatography (Merck silica gel 60; the 230-400 order; the 10%-70% ethyl acetate/hexane) provides: 2-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(2; 4-dioxo-thiazolidine-5-ylmethyl)-pyrazine-2-yl]-propionic acid amide (86.5mg; 57%), is white solid: LC-MS m/e 537 (MH
+).
Embodiment 20
2-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(2,5-dioxo-imidazolidine-4-ylmethyl)-pyrazine-2-yl]-propionic acid amide
[000178] will be in (the preparation in according to embodiment 18 of the 2-in the dehydrated alcohol (30mL) (3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-formyl radical-pyrazine-2-yl)-propionic acid amide; 217mg; 0.5mmol), glycolylurea (75mg; 0.75mmol), piperidines (10 μ L; 0.10mmol) and phenylformic acid (6.1mg, vlil 0.05mmol) 2 days.Reaction mixture is cooled to 25 ℃, then vacuum concentration.Flash chromatography (Merck silica gel 60; the 230-400 order; the 10%-65% ethyl acetate/hexane) provides: 2-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(2; 5-dioxo-Ya imidazolidine-4-ylmethyl)-pyrazine-2-yl]-propionic acid amide (84mg; 33%), is white solid: LC-MSm/e 518 (MH
+).
[000179] with 10% the palladium on the gac (260mg) handle in ethanol (5mL) solution 2-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(2; 5-dioxo-Ya imidazolidine-4-ylmethyl)-pyrazine-2-yl]-propionic acid amide (130mg, 0.25mmol).Stirred reaction mixture is 2 days under 25 ℃ hydrogen (65psi).Filter out catalyzer by Celite pad, wash Celite pad well with ethanol.The vacuum concentration filtrate.Flash chromatography (Merck silica gel 60; the 230-400 order; the 80%-100% ethyl acetate/hexane) provides: 2-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(2; 5-dioxo-imidazolidine-4-ylmethyl)-pyrazine-2-yl]-propionic acid amide (20mg; 15%), is white solid: LC-MS m/e520 (MH
+).
Embodiment 21
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-dimethoxy-methyl-pyrazine-2-yl)-propionic acid amide
[000180] handles at anhydrous N 5-methylpyrazine-2-carboxylic acid (1.38g, solution 10mmol) in the dinethylformamide (5mL) with dimethylformamide dimethyl acetal (5mL).With the mixture that obtains in 90 ℃ of heating 1 hour, then in 25 ℃ of heating 2 hours.Mixture is cooled to 25 ℃, topples over then in the entry (100mL).(3 * 50mL) extract this solution with ethyl acetate.Water (1 * 50mL) and saturated sodium-chloride water solution (organic layer that 1 * 50mL) washing merges use anhydrous magnesium sulfate drying, filtration and vacuum concentration.Grind the dark-coloured oil that obtains with diethyl ether/hexane (5/1), provide: 5-(2-dimethylamino-vinyl)-pyrazine-2-carboxylate methyl ester (1.3g, 63%), be orange solids, it uses under the condition that is not further purified.
[000181] in 0 ℃, water (80mL) drip to handle 5-(2-dimethylamino-vinyl)-pyrazine-2-carboxylate methyl ester in methyl alcohol (40mL) (3.00g, 14.5mmol) and sodium periodate (9.09g, mixture 43.5mmol).Stirred the mixture 30 minutes in 0 ℃, stirred 30 minutes in 25 ℃ then.Between saturated sodium bicarbonate aqueous solution (50mL) and ethyl acetate (50mL), distribute mixture.Separate water layer, and saturated with sodium-chlor.Then, with ethyl acetate (4 * 50mL) extractions.Organic extract liquid with anhydrous magnesium sulfate drying merges filters and vacuum concentration, and red solid is provided.The solid that obtains is merged with trimethyl orthoformate (15mL) and methyl alcohol (40mL), and (191mg 1mmol) handles to use the paratolunitrile monohydrate then.With reaction mixture reflux 1.5 hours, be cooled to 25 ℃ then.With ethyl acetate (100mL) diluted reaction mixture, with saturated sodium bicarbonate aqueous solution (50mL) washing.Separate organic layer, and with ethyl acetate (3 * 25mL) aqueous layer extracted.Organic layer with anhydrous sodium sulfate drying merges filters and vacuum concentration, provides: 5 dimethoxy-methyls-pyrazine-2-carboxylate methyl ester (2.26g, 73%), be yellow oil, and it uses under the condition that is not further purified.
[000182] with potassium hydroxide (365mg, 6.52mmol) 5-dimethoxy-methyl-pyrazine-2-carboxylate methyl ester (690mg, 3.26mmol) the mixture of processing in methyl alcohol/tetrahydrofuran (THF)/water (3:3:1.5mL).Mixture was stirred 2 hours in 25 ℃.At this moment, vacuum concentration reaction mixture.(concentrate residuum 3 * 5mL), be suspended in N then, in the dinethylformamide (30mL) from methyl alcohol.(0.92mL 4.24mmol) handles this solution, and stirs 5 hours in 25 ℃ with diphenylphosphine acylazide thing.The homogeneous solution that obtains is toppled in the entry (100mL), and (3 * 30mL) extract with ethyl acetate.Water (3 * 30mL) and saturated sodium-chloride water solution (organic layer that 1 * 30mL) washing merges use anhydrous magnesium sulfate drying, filtration and vacuum concentration.With the residuum that obtains be dissolved in benzylalcohol (0.66mL, 6.54mmol) in, and in 93 ℃ the heating 20 minutes.Mixture is cooled to 25 ℃, uses diethyl ether/hexane (2:1) to grind then, provide: (5-dimethoxy-methyl pyrazine-2-yl)-phenyl carbamate (552mg, 56%), be dark brown solid, it uses under the condition that is not further purified.
[000183] handles (5-dimethoxy-methyl pyrazine-2-yl)-phenyl carbamate (500mg, 2.2mmol) solution in ethanol (30mL) in ethanol (30mL) with 10% at the palladium on the gac.Wash reaction vessel with hydrogen, and under hydrogen (1atm), stirred the mixture 1 hour in 25 ℃.Excessive hydrogen is extracted out from reaction vessel, and by the Celite pad filtering mixt.The vacuum concentration filtrate provides: 5-dimethoxy-pyrazine-2-base amine (183mg, 76%), be dark brown solid, and it uses under the condition that is not further purified.
[000184] in 25 ℃; use N; dinethylformamide (2) is handled at methylene dichloride/toluene (1:1; 5mL) 2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-propionic acid is (according to preparation among the embodiment 1; 883mg; 2.67mmol) and oxalyl chloride (677mg, solution 5.34mmol).Reaction mixture was stirred 2 hours in 25 ℃.Vacuum concentrated solution, and from toluene (5mL), concentrate residuum three times.Residuum is suspended in 0 ℃ the tetrahydrofuran (THF) (5mL), be used in then 5-dimethoxy-methyl-pyrazine-2-base amine in the tetrahydrofuran (THF) (5mL) (451mg, 2.67mmol) and pyridine (0.216mL, the time in mixture process 2.67mmol) 5 minutes.At this moment, reaction mixture is warmed to 25 ℃, it was stirred 18 hours in this temperature.Between ethyl acetate (50mL) and rare aqueous ammonium chloride solution (50mL), distribute the mixture that obtains.Separate water layer.In succession water (1 * 25mL), saturated sodium bicarbonate aqueous solution (1 * 25mL), water (1 * 25mL), copper sulfate (II) aqueous solution (1 * 25mL) and saturated sodium-chloride water solution (1 * 25mL) washing organic layer.Then, use the anhydrous magnesium sulfate drying organic layer, filter and vacuum concentration.Flash chromatography (Merck silica gel 60; the 230-400 order; 40% ethyl acetate/hexane) provide: 2-(R)-(3-chloro-4-methylsulfonyl phenyl)-3-cyclopentyl-N-(5-dimethoxy-methyl pyrazine-2-yl)-propionic acid amide (890mg, 69%) is weak yellow foam: (ES)
+-HRMS m/e calculated value C
22H
28ClN
3O
5S (M+H)
+424.0729, actual measurement 424.0733.
Embodiment 22
2-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(1-hydroxyl-ethyl)-pyrazine-2-yl]-propionic acid amide
[000185] in 0 ℃; with 3.0M at diethyl ether (0.35mL; 1.05mmol) in the solution-treated of methylmagnesium-chloride 2-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-formyl radical-pyrazine-2-the yl)-propionic acid amide in diethyl ether (15mL) (according to embodiment 18 preparations; 218mg, solution 0.5mmol).After finishing adding, reaction mixture was stirred 1 hour in 0 ℃.Then, make the reaction quencher by dripping the 1N aqueous hydrochloric acid.Then, water (25mL) diluted reaction mixture, and with ethyl acetate (2 * 50mL) extraction.(organic layer that 2 * 20mL) washings merge is used dried over sodium sulfate, filters and vacuum concentration with saturated sodium-chloride water solution.Flash chromatography (Merck silica gel 60; the 230-400 order; the 30%-70% ethyl acetate/hexane) provide: 2-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(1-hydroxyl-ethyl)-pyrazine-2-yl]-propionic acid amide (140mg, 62%), be white solid: LC-MS m/e 451 (MH
+).
Embodiment 23
N-(5-ethanoyl-pyrazine-2-yl)-2-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-propionic acid amide
[000186] with Manganse Dioxide (200mg; 2.2mmol) 2-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(1-hydroxyl-ethyl-pyrazine-2-yl)-propionic acid amide (according to embodiment 22 in the preparation of processing in chloroform (20mL); 100mg, solution 0.22mmol).With reaction mixture reflux 12 hours.At this moment, by removing by filter the solid that obtains.The vacuum concentration filtrate.Flash chromatography (Merck silica gel 60; the 230-400 order; the 10%-30% ethyl acetate/hexane) provides N-(5-ethanoyl-pyrazine-2-yl)-2-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-propionic acid amide (90mg, 90%), be white solid: LC-MSm/e 450 (MH
+).
Embodiment 24
2-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(1-hydroxy-2-methyl-propyl group)-pyrazine-2-yl]-propionic acid amide
[000187] under-20 ℃; with 2.0M at diethyl ether (1.5mL; 3.0mmol) in isopropylmagnesium chloride handle 2-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-formyl radical-pyrazine-2-yl)-propionic acid amide (preparation in according to embodiment 18 handle at leisure in diethyl ether (15mL); 218mg, solution 0.5mmol).After finishing adding, reaction mixture was stirred 30 minutes in-20 ℃.Then, the dilute with water reaction mixture, and with ethyl acetate (2 * 50mL) extraction.(organic layer that 2 * 20mL) washings merge is used dried over sodium sulfate, filters and vacuum concentration with saturated sodium-chloride water solution.Flash chromatography (Merck silica gel 60; the 230-400 order; the 20%-50% ethyl acetate/hexane) provide: 2-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(1-hydroxy-2-methyl-propyl group-pyrazine-2-yl)]-propionic acid amide (110mg; 46%), is white solid: LC-MS m/e 479 (MH
+).
Embodiment 25
2-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-isobutyryl-pyrazine-2-yl)-propionic acid amide
[000188] with Manganse Dioxide (300mg; 3.3mmol) 2-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(1-hydroxy-2-methyl-propyl group-pyrazine-2-yl) of processing in chloroform (20mL)]-propionic acid amide (preparation in according to embodiment 24; 100mg, 0.21mmol) solution in chloroform (20mL).With reaction mixture reflux 24 hours.At this moment, by removing by filter the solid that obtains.The vacuum concentration filtrate.Flash chromatography (Merck silica gel 60; the 230-400 order; the 10%-40% ethyl acetate/hexane) provide: 2-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-isobutyryl-pyrazine-2-yl)-propionic acid amide (22mg, 22%) is white solid: LC-MS m/e 478 (MH
+).
Embodiment 26
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-N-[5-(cyano group-hydroxyl-methyl)-pyrazine-2-yl]-3-cyclopentyl-propionic acid amide
[000189] will be at acetone (20mL; 2-9:1) (R)-(3-chloro-4-methylsulfonyl phenyl)-3-cyclopentyl-N-(5-dimethoxy-methyl pyrazine-2-yl)-propionic acid amide is (according to preparation among the embodiment 21; 740mg; 1.53mmol) and the paratolunitrile monohydrate (80mg, solution 0.41mmol) in 60 ℃ the heating 30 minutes.Cooling mixture is used ethyl acetate (100mL) dilution then.Use in succession saturated sodium bicarbonate aqueous solution (1 * 30mL), water (1 * 30mL) and saturated sodium-chloride water solution (1 * 30mL) washing organic layer.Then, use anhydrous magnesium sulfate drying, filter and vacuum concentration, weak yellow foam is provided.(1:1 in mixture 10mL), is cooled to 0 ℃, and (69mg 1.5mmol) handles to use sodium bisulfite then in ethyl acetate/water with the substance dissolves that obtains.The reaction mixture that obtains was stirred 15 minutes in 0 ℃.At this moment, with sodium cyanide (73mg, 1.5mmol) reaction mixture, and reaction mixture stirred 30 minutes in 0 ℃.At this moment, between saturated sodium-chloride water solution (50mL) and ethyl acetate (50mL), distribute mixture.Separate organic layer, and with ethyl acetate (3 * 25mL) aqueous layer extracted.With saturated ammonium chloride solution (1 * 30mL), saturated sodium bicarbonate aqueous solution (1 * 30mL) and the saturated sodium-chloride water solution (organic layer that 1 * 30mL) washing merges.Then, use the anhydrous magnesium sulfate drying organic layer, filter and vacuum concentration.Flash chromatography (Merck silica gel 60; the 230-400 order; 50% ethyl acetate/hexane) provide: 2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-N-[5-(cyano group-hydroxyl-methyl)-pyrazine-2-yl]-3-cyclopentyl-propionic acid amide (230mg, 32%), be yellow foam: (ES)
+-HRMS m/e calculated value C
21H
23ClN
4O
4S (M+H)
+463.1208, actual measurement 463.1202.
Embodiment 27
N-[5-(formamyl hydroxyl-methyl)-pyrazine-2-yl]-2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-propionic acid amide
[000190] 2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-N-[5-(cyano group-hydroxyl-methyl)-pyrazine-2-yl that will be in methyl-sulphoxide (6mL)]-(preparation in according to embodiment 26 of 3-cyclopentyl-propionic acid amide; 100mg; 0.22mmol) and salt of wormwood (400mg; 2.9mmol) mixture be cooled to 0 ℃, use 30% aqueous hydrogen peroxide solution (2mL) drip to handle then.Reaction mixture was stirred 1 hour in 0 ℃.Between ethyl acetate (50mL) and water (50mL), distribute the mixture obtain, and with ethyl acetate (3 * 25mL) aqueous layer extracted.Water (3 * 30mL) and saturated sodium-chloride water solution (organic layer that 1 * 30mL) washing merges use anhydrous magnesium sulfate drying, filtration and vacuum concentration.Flash chromatography (Merck silica gel 60; the 230-400 order; ethyl acetate) provide: N-[5-(formamyl hydroxyl-methyl)-pyrazine-2-yl]-2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-propionic acid amide (30mg, 28%), be white solid: (ES)
+-HRMS m/e calculated value C
21H
25ClN
4O
5S (M+H)
+481.1314, actual measurement 481.1307.
Embodiment 28
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(1-(Z)-oxyimino-ethyl)-pyrazine-2-yl]-propionic acid amide
[000191] will the 2-amino-5-bromo-pyrazine in the methylene dichloride (144mL) (10.00g, 57.47mmol) and pyridine (5.6mL, solution 68.96mmol) are cooled to 0 ℃, and (8.6mL 68.96mmol) handles at leisure to use trimethyl-acetyl chloride then.The reaction mixture that obtains was stirred 30 minutes in 0 ℃, be warmed to 25 ℃ then, it was stirred 18 hours in this temperature.At this moment, reaction mixture still contains raw material: 2-amino-5-bromo-pyrazine.(4.3mL, 34.48mmol) reaction mixture stirred 4 hours in 25 ℃ then with the trimethyl-acetyl chloride of other amount.Then, the vacuum concentration reaction mixture is to remove methylene dichloride.Dilute the residuum that obtains with ethyl acetate (700mL).The 1N aqueous hydrochloric acid (2 * 200mL) and saturated sodium-chloride water solution (1 * 200mL) washing organic layer, use dried over sodium sulfate, the filtration and vacuum concentration.Biotage chromatogram (FLASH 65M, silicon-dioxide, 10% ethyl acetate/hexane) provides: N-(5-bromo-pyrazine-2-yl)-2, and 2-dimethyl-propionic acid amide (12.19g, 82%) is white solid: mp122-124 ℃; (ES)
+-HRMS m/e calculated value C
9H
12BrN
3O (M+H)
+258.0237, actual measurement 258.0240.
[000192] with tributyl (1-vinyl ethyl ether base) tin (2.00g, 5.54mmol) N-(5-bromo-pyrazine-2-yl)-2 of processing in toluene (10mL), (1.30g is 5.04mmol) with dichloro two (triphenyl phosphine) palladium (II) (35.3mg, thin pulp 0.05mmol) for 2-dimethyl-propionic acid amide.Then, will react the thin pulp reflux, obtain uniform yellow solution.After 15 hours, the black reaction mixture that obtains is cooled to 25 ℃ in reflux, is cooled to 0 ℃ with ice-water-bath then.(8.4mL) handles the refrigerative reaction mixture at leisure with 5% aqueous hydrochloric acid.Reaction mixture in 0 ℃ of stirring 30 minutes, is warmed to 25 ℃ then, it was stirred 24 hours in this temperature.Separate obtain two-layer, and further dilute organic layer with ethyl acetate (100mL).Then, dilute organic layer, and the mixture that obtains was stirred 5 hours in 25 ℃ with 10% ammonium fluoride aqueous solution (100mL).Then, cross filter solid, and separation leaches liquid layer.(1 * 100mL) washing organic layer is used dried over sodium sulfate, filters and vacuum concentration with saturated sodium-chloride water solution.Biotage chromatogram (FLASH 40M, silicon-dioxide, 15% ethyl acetate/hexane) provides: N-(5-ethanoyl-pyrazine-2-yl)-2, and 2-dimethyl-propionic acid amide (1.07g, 96%) is white solid: mp173-174 ℃; (ES)
+-HRMS m/e calculated value C
11H
15N
3O
2(M+H)
+222.1237, actual measurement 222.1240.
[000193] with O-(tertiary butyl) azanol base hydrochloride (681.1mg, the 5.42mmol) N-(5-ethanoyl-pyrazine-2-yl)-2 of processing in methyl alcohol (9mL) and pyridine (9mL), 2-dimethyl-propionic acid amide (800.0mg, solution 3.62mmol).With the reaction mixture reflux that obtains 30 minutes.Reaction mixture is cooled to 25 ℃, then vacuum concentration.With ethyl acetate (50mL) diluted reaction mixture.(1 * 50mL) washing organic layer is used dried over sodium sulfate, filters and vacuum concentration with the 1N aqueous hydrochloric acid.Biotage chromatogram (FLASH 40M, silicon-dioxide, 10% ethyl acetate/hexane) provides: N-[5-(1-tert.-butoxy imino--ethyl)-pyrazine-2-yl]-2,2-dimethyl-propionic acid amide (1.04g, 98%) is white solid: mp123-124 ℃; EI-HRMS m/e calculated value C
15H
24N
4O
2(M
+) 292.1899, actual measurement 292.1901.
[000194] with the N-[5-in Zai diox (5.8mL) and the hydrazine monohydrate (9.6mL) (1-tert.-butoxy imino--ethyl)-pyrazine-2-yl]-2,2-dimethyl-propionic acid amide (563.4mg, vlil 1.93mmol) 48 hours.Reaction mixture is cooled to 25 ℃, uses ethyl acetate (100mL) dilution then.(1 * 100mL) washing organic layer filters and vacuum concentration with saturated sodium-chloride water solution.Biotage chromatogram (FLASH40L, silicon-dioxide, 30% ethyl acetate/hexane) provides: (408.4g quant.), is faint yellow solid: mp113-115 ℃ to 1-(5-amino-pyrazino-2-the yl)-ethyl ketone O-tertiary butyl-oxime; EI-HRMS m/e calculated value C
10H
16N
4O (M
+) 208.1324, actual measurement 208.1325.
[000195] (preparation in according to embodiment 1,262.9mg, solution 0.79mmol) are cooled to 0 ℃ to 2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-propionic acid that will be in methylene dichloride (4mL).Then, with oxalyl chloride (275 μ L, 3.15mmol) and N, dinethylformamide (2) reaction mixture.Reaction mixture in 0 ℃ of stirring 30 minutes, slowly is warmed to 25 ℃ then, it was stirred 2.5 hours in this temperature.Then, vacuum concentrated solution desolvates to remove.The residuum that obtains is dissolved in the methylene dichloride (3mL), is cooled to 0 ℃ then.Be used in 1-(5-amino-pyrazino-2-the yl)-ethyl ketone O-tertiary butyl-oxime (150.2mg in the tetrahydrofuran (THF) (4mL), 0.72mmol) and 2, the solution of 6-lutidine (100 μ L) drips handles this refrigerative solution, uses methylene dichloride (1mL) rinsing fast then.Reaction mixture in 0 ℃ of stirring 30 minutes, is warmed to 25 ℃ then, its stirring is spent the night in this temperature.Water quencher reaction mixture, and in 25 ℃ of stirrings 30 minutes.Then, with ethyl acetate (300mL) and 1N aqueous citric acid solution (300mL) diluted reaction mixture, and shake and separating layer.With saturated sodium bicarbonate aqueous solution (1 * 300mL), water (1 * 300mL) and saturated sodium-chloride water solution (1 * 300mL) washing organic layer.Then, use the dried over sodium sulfate organic layer, filter and vacuum concentration.Biotage chromatogram (FLASH 40L, silicon-dioxide, 25% ethyl acetate/hexane) provide: N-[5-(1-tert.-butoxy imino--ethyl)-pyrazine-2-yl]-2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-propionic acid amide (216.5mg, 58%) white foam: mp 95.7-99.9 ℃ (foam is to gel); (ES)+-HRMS m/e calculated value C
25H
33ClN
4O
4S (M+H)
+521.1984, actual measurement 521.1994.
[000196] with N-[5-(the 1-tert.-butoxy imino-ethyl)-pyrazine-2-yl of trifluoroacetic acid (2.8mL) processing in methylene dichloride (1.4mL)]-2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-propionic acid amide (195.5mg, solution 0.38mmol).The reaction mixture that obtains was stirred 2 hours in 25 ℃, and at this moment, thin-layer chromatography is still indicated and is had raw material.Then, in 40 ℃ of reacting by heating mixtures, its stirring is spent the night in this temperature.At this moment, thin-layer chromatography is still also indicated and is had raw material.Then, in 60 ℃ of reacting by heating mixtures, it was stirred for second night in this temperature.Then, reaction mixture is cooled to 25 ℃.With ethyl acetate (50mL) diluted reaction mixture, and with saturated sodium bicarbonate aqueous solution (2 * 50mL) and saturated sodium-chloride water solution (1 * 50mL) washing organic layer, use dried over sodium sulfate, the filtration and vacuum concentration.Biotage chromatogram (FLASH 40L, silicon-dioxide, 33% ethyl acetate/hexane) provide: 2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(1 (Z)-oxyimino-ethyl)-pyrazine-2-yl]-propionic acid amide (110.0mg, 63%), is the pale powder solid: mp 94.2-102.5 ℃ (foam is to gel); (ES)
+-HRMS m/e calculated value C
21H
25ClN
4O
4S (M+H)
+465.1358, actual measurement 465.1363.
Embodiment 29
5-[2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-propionyl amino]-pyrazine-2-carboxylic acid hydroxamides
[000197] is used in salt of wormwood (72.08g, 5-chloropyrazine-2-carboxylate methyl ester (30.00g, 0.17mol) the solution of solution-treated 0.52mol) in tetrahydrofuran (THF) (87mL) in the water (261mL).The reaction mixture that obtains was stirred 42 hours in 25 ℃, with concentrated hydrochloric acid reaction mixture is acidified to pH then and is about 2,, and use ethyl acetate (4L total amount) extraction continuously, in water layer, do not have product with saturated sodium-chloride water solution (300mL) dilution.With the organic layer that dried over sodium sulfate merges, filter, and vacuum concentration provides: 5-chloro-pyrazine-2-carboxylic acid (26.54g, 96%) is pale solid: mp150-151 ℃; EI-HRMS m/e calculated value C
5H
3ClN
2O
2(M
+) 157.9883, actual measurement 157.9877.
[000198] is used in 2 in the hexanaphthene (126mL), 2, (tert-butyl 2 by tert.-butyl acetate for 2-trichlorine imido, 2,2-trichloroacetimidate) (23mL, 126.14mmol) 5-chloro-pyrazine-2-carboxylic acid (10.00g, 63.07mmol) the solution of solution-treated in tetrahydrofuran (THF) (126mL).In 25 ℃ of stirred reaction mixtures 5 minutes, (3.2mL 25.23mmol) handled to use boron trifluoride dimethyl ether compound then.The reaction mixture that obtains was stirred 16 hours in 25 ℃, use ethyl acetate (200mL) dilution then,, use dried over sodium sulfate, filtration and vacuum concentration with saturated sodium bicarbonate aqueous solution (200mL) and water (200mL) washing.Biotage chromatogram (FLASH 65M, silicon-dioxide, 10% ethyl acetate/hexane) provides: 5-chloro-pyrazine-2-carboxylic acid tert-butyl ester (12.73g, 94%) is water white oil: EI-HRMS m/e calculated value C
9H
11ClN
2O
2(M
+) 214.0502, actual measurement 214.0510.
[000199] with one bottle of fresh silver fluoride (I) (11.26g, 87.86mmol) 5-chloro-pyrazine-2-carboxylic acid tert-butyl ester (12.6g, 58.7mmol) the solution of processing in acetonitrile (150mL).Cover reaction unit with aluminium foil, and the reaction mixture reflux is spent the night.With decolorizing charcoal vortex mixed thing, filter by Celite pad, and with acetonitrile rinsing Celite pad.The vacuum concentration filtrate, and be adsorbed on the silica gel (Merck silica gel 60,230-400 order).Biotage chromatogram (FLASH65M, silicon-dioxide, 10-20% diethyl ether/sherwood oil) provides: 5-fluoro-pyrazine-2-carboxylic acid tert-butyl ester (9.19g, 79%) is cooled to 0 ℃ and is white crystal.By grinding with sherwood oil, obtain analytic sample, provide: 5-fluoro-pyrazine-2-carboxylic acid tert-butyl ester is white crystal: mp 26.5-28.1 ℃, EI-HRMS m/e calculated value C
9H
11FN
2O
2(M
+) 198.0799, actual measurement 198.0804.
[000200] in big sealing tubular reactor vessel, 5-fluoro-pyrazine-2-carboxylic acid tert-butyl ester (7.99g, 40.31mmol) the solution of preparation in tetrahydrofuran (THF) (20mL).Reaction soln is cooled to 0 ℃, uses ammonia saturated in 35 minutes then.Closely seal this pipe, and stirred reaction mixture.When reaction mixture is warmed to 25 ℃, generate throw out.By the filtering separation throw out, and use the sherwood oil rinsing, provide: 5-amino-pyrazino-2-carboxylic acid tert-butyl ester (5.63g, 71%) is white powder: mp190-193 ℃; EI-HRMS m/e calculated value C
9H
13N
3O
2(M
+) 195.1008, actual measurement 195.1009.
[000201] (preparation in according to embodiment 1,1.00g, solution 3.02mmol) are cooled to 0 ℃ to 2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-propionic acid that will be in methylene dichloride (15mL).With oxalyl chloride (1.10mL, 12.61mmol) and N, dinethylformamide (2) reaction mixture.Reaction mixture was stirred 30 minutes in 0 ℃.Then, in 45 minutes, slowly be warmed to 25 ℃.Then, vacuum concentrated solution.Yellow thin pulp is dissolved in the methylene dichloride (15mL), is cooled to 0 ℃ then.In this solution, be added in 5-amino-pyrazino-2-carboxylic acid tert-butyl ester in the tetrahydrofuran (THF) (15mL) (0.71g, 3.64mmol) and pyridine (295 μ L, solution 3.65mmol).Reaction mixture in 0 ℃, is warmed to 25 ℃ at leisure and spends the night.Then, with 1N aqueous citric acid solution (10mL) quencher reaction, in 25 ℃ of stirrings 3 minutes, vacuum concentration then.Between ethyl acetate (400mL) and 1N aqueous citric acid solution (200mL), distribute reactive material, and layer separates.Flat coexistence saturated sodium bicarbonate aqueous solution (200mL), water (200mL) and saturated sodium-chloride water solution (200mL) washing organic layer are used dried over sodium sulfate, and filtration and vacuum concentration are on silica gel (Merck silica gel 60,230-400 order).Biotage chromatogram (FLASH40L, silicon-dioxide, 33% ethyl acetate/hexane) provide: 5-[2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-propionyl amino]-pyrazine-2-carboxylic acid tert-butyl ester (0.80g, 52%), white foam: mp107-111 ℃ (foam is to gel); (ES)
+-HRMS m/e calculated value C
24H
30ClN
3O
5S (M+H)
+508.1668, actual measurement 508.1666.
[000202] with 5-[2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-propionyl amino of trifluoroacetic acid (60mL) processing in methylene dichloride (30mL)]-pyrazine-2-carboxylic acid tert-butyl ester (3.29g; 6.48mmol) solution, and stirred 65 minutes in 25 ℃.Then, vacuum concentration reaction soln.Dilute the oil that obtains with ethyl acetate (500mL), water (2 * 250mL) and saturated sodium-chloride water solution (5 * 250mL) washing, use dried over sodium sulfate, and handle with decolorizing charcoal, filter by Celite pad, and vacuum concentration, provide: 5-[2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-propionyl amino]-pyrazine-2-carboxylic acid (2.89g, 99%), is weak yellow foam: mp 121-127 ℃; (ES)
+-HRMS m/e calculated value C
20H
22ClN
3O
5S (M+H)
+452.1042, actual measurement 452.1046.This material uses under the condition that is not further purified.
[000203] will be at the 5-[2 (R) in the methylene dichloride (4.4mL)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-propionyl amino]-(401.6mg, solution 0.889mmol) are cooled to 0 ℃ to pyrazine-2-carboxylic acid.Then, with oxalyl chloride (310 μ L, 3.554mmol) and N, dinethylformamide (2) reaction mixture.Reaction mixture in 0 ℃ of stirring 45 minutes, was warmed to 25 ℃ then at leisure in 1 hour 45 minutes.Then, vacuum concentrated solution.Residuum is dissolved in methylene dichloride (3.4mL), and is cooled to 0 ℃.Then, be used in O-(tert.-butoxy) azanol base hydrochloride in the tetrahydrofuran (THF) (4.4mL) (133.3mg, 1.061mmol) and pyridine (180 μ L, the solution that mixture process 2.226mmol) obtains is then with methylene dichloride (1mL) rinsing.Reaction mixture in 0 ℃ of stirring 45 minutes, was stirred 2 hours 15 minutes in 25 ℃ then.Then, water (5mL) quencher reaction, and in 25 ℃ of stirrings 30-45 minute.Between ethyl acetate (300mL) and 1N aqueous citric acid solution (250mL), distribute reaction mixture, and layer separates.With saturated sodium bicarbonate aqueous solution (250mL), water (250mL) and saturated sodium-chloride water solution (250mL) washing organic layer, use dried over sodium sulfate, filter and vacuum concentration.Biotage chromatogram (FLASH 40L, silicon-dioxide, the 40-50% ethyl acetate/hexane) provide: 5-[2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-propionyl amino]-pyrazine-2-carboxylic acid tert.-butoxy-acid amides (338.8mg, 73%), is canescence foam: mp128-131 ℃ (foam is to gel); (ES)
+-HRMS m/e calculated value C
24H
31ClN
4O
5S (M+H)
+523.1777, actual measurement 523.1782.
[000204] with 5-[2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-propionyl amino of trifluoroacetic acid (4.6mL) processing in methylene dichloride (2.3mL)]-pyrazine-2-carboxylic acid tert.-butoxy-acid amides (318.3mg; 0.609mol) solution; and spend the night in 25 ℃ of stirrings; in 40 ℃ of stirrings 10-11 hour, then spend the night in 25 ℃ of stirrings more then.Then, vacuum concentration reaction soln.RPLC (Rainin Dynamax system, 60A C-18 post, 1=214nm, the 50-100% acetonitrile of 50mL/min and 0.1% trifluoroacetic acid/water and 0.1% trifluoroacetic acid, in the 55min) provide: 5-[2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-propionyl amino]-pyrazine-2-carboxylic acid hydroxamides (90.0mg, 32%), is pink foam: mp 134-139 ℃ (foam is to gel); (ES)
+-HRMS m/e calculated value C
20H
23ClN
4O
5S (M+H)
+467.1151, actual measurement 467.1155.
Embodiment 30
2-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-methylthiomethyl-pyrazine-2-yl)-propionic acid amide
[000205] with one bottle of fresh silver fluoride (I) (11.00g, 86.70mmol) 5-chloropyrazine-2-carboxylic acid tert-butyl ester (5.00g, 28.97mmol) the solution of processing in acetonitrile (290mL).Cover reaction unit with aluminium foil, and the reaction mixture reflux is spent the night.Filter by Celite pad, and with acetonitrile rinsing Celite pad.Vacuum concentration filtrate Biotage chromatogram (FLASH 40M, silicon-dioxide, 25% ethyl acetate/hexane) provides: 5-fluoro-pyrazine-2-carboxylate methyl ester (2.98g, 66%) is cooled to 0 ℃ and is pale solid.Grind by sherwood oil, obtain analytic sample, provide: 5-fluoro-pyrazine-2-carboxylate methyl ester is white crystal: mp 55.6-56.7 ℃, and EI-HRMS m/e calculated value C
6H
5FN
2O
2(M
+) 156.0335, actual measurement 156.0331.
[000206] in big steel reaction vessel, is added in 5-fluoro-pyrazine-2-carboxylate methyl ester (17.45g, solution 111.78mmol) in the tetrahydrofuran (THF) (200mL).Reaction soln is cooled to 0 ℃, and saturated in 2-3 hour with ammonia.Container is sealed tightly.Mechanical agitation reaction mixture then, and be warmed to 25 ℃ and spend the night.Then, container is cooled to-78 ℃ 15-20 minute, container is ventilated, and with the content of diethyl ether (100mL) cut-back tank.By the throw out that filtering separation obtains, (2 * 100mL) rinsings, and dry air provide: 5-amino-pyrazino-2-carboxylate methyl ester (16.97g, 99%) is pale solid: mp 229-231 ℃ with sherwood oil; EI-HRMS m/e calculated value C
6H
7N
3O
2(M
+) 153.0538, actual measurement 153.0537.
[000207] (preparation in according to embodiment 1,196.4mg, solution 0.59mmol) are cooled to 0 ℃ to 2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-propionic acid that will be in methylene dichloride (3mL).Use N then, dinethylformamide (1) and oxalyl chloride (109 μ L, 1.25mmol) reaction mixture.Reaction mixture in 0 ℃ of stirring 15 minutes, was stirred 2 hours in 25 ℃ then.Then, vacuum concentrated solution.Yellow thin pulp is dissolved in the methylene dichloride (1mL), and is cooled to 0 ℃.In this solution, be added in 5-amino-pyrazino-2-carboxylate methyl ester in the warm methylene dichloride (2mL) (100.0mg, 0.65mmol) and pyridine (53PtL, suspension 0.6529mmol).Reaction mixture in 0 ℃ of stirring 30 minutes, was stirred 3 hours in 25 ℃ then.Then, vacuum concentration reaction mixture.With ethyl acetate (50mL) diluting reaction material, and with saturated sodium bicarbonate aqueous solution (100mL), saturated sodium-chloride water solution (100mL), 1N aqueous hydrochloric acid (100mL) and saturated sodium-chloride water solution (100mL) washing, use dried over sodium sulfate, filter, and vacuum concentration.Biotage chromatogram (FLASH 40S, silicon-dioxide, 50% ethyl acetate/hexane) provide: 5-[2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-propionyl amino]-pyrazine-2-carboxylate methyl ester (225.9mg, 82%), white foam: mp 94-97 ℃ (foam is to gel); (ES)
+-HRMS m/e calculated value C
21H
24ClN
3O
5S (M+H)
+466.1198, actual measurement 466.1204.
[000208] will be at the 5-[2 (R) in the methyl alcohol (2mL)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-propionyl amino]-pyrazine-2-carboxylate methyl ester (200mg; 0.43mmol) suspension be cooled to 0 ℃; (49.2mg 1.29mmol) handles to use sodium borohydride then.Reaction mixture in 0 ℃ of stirring 5 minutes, was stirred 1.5 hours in 25 ℃ then.Reaction mixture is cooled to 0 ℃, and the water quencher.Then, with ethyl acetate (75mL) diluted reaction mixture, with the 1N aqueous hydrochloric acid (3 * 75mL) and saturated sodium-chloride water solution (75mL) washing, use dried over sodium sulfate, filtration and vacuum concentration.Biotage chromatogram (FLASH 40S, silicon-dioxide, 60% ethyl acetate/hexane) provides: 2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-methylol-pyrazine-2-yl)-propionic acid amide (110.4mg, 59%), white foam: mp 78-81 ℃ (foam is to gel); (ES)
+-HRMSm/e calculated value C
20H
24ClN
3O
4S (M+H)
+438.1249, actual measurement 438.1252.
[000209] with triphenyl phosphine (573.5mg; 2.19mmol) and carbon tetrabromide (726.2mg; 2.19mmol) 2 (Rs)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-methylol-pyrazine-2-yl)-propionic acid amide (457.1mg, 1.04mmol) the solution of processing in tetrahydrofuran (THF) (10mL).Reaction soln was stirred 6 hours in 25 ℃, then vacuum concentration.Biotage chromatogram (FLASH 40L, silicon-dioxide, 33% ethyl acetate/hexane) provide: N-(5-brooethyl-pyrazine-2-yl)-2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-propionic acid amide (337.2mg, 65%) are the purple foam: mp 98-103 ℃ (foam is to gel); (ES)
+-HRMS m/e calculated value C
20H
23BrClN
3O
3S (M+H)
+500.0405, actual measurement 500.0410.
[000210] will be at the N-in the acetone (1mL) (5-brooethyl-pyrazine-2-yl)-2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-propionic acid amide (95.1mg; 0.19mmol) solution be cooled to 0 ℃; (12.9mg 0.18mmol) handles to use the sulfo-sodium methylate then.Reaction mixture in 0 ℃ of stirring 1.5 hours, is used second part sulfo-sodium methylate (3.6mg, 0.051mmol) processing then.Reaction mixture in 0 ℃ of stirring, was warmed to 25 ℃ then at leisure in 1.5 hours.(3-4mg, 0.042-0.057mmol), and in 25 ℃ of stirrings 1.5 hours, at this moment, the APCI-LRMS Indicator Reaction was finished to add the 3rd part of sulfo-sodium methylate.Then, with ethyl acetate (50mL) diluted reaction mixture, water (2 * 25mL) and saturated sodium-chloride water solution (25mL) washing, use dried over sodium sulfate, filtration and vacuum concentration.Biotage chromatogram (FLASH 40S, silicon-dioxide, 33% ethyl acetate/hexane) provides racemic 2-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-methylthiomethyl-pyrazine-2-yl)-propionic acid amide (51.9mg, 58%) white foam: mp70-75 ℃ (foam is to gel); (ES)
+-HRMS m/e calculated value C
21H
26ClN
3O
3S
2(M+H)
+468.1177, actual measurement 468.1179.
Embodiment 31
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-methylsulfonyl methyl-pyrazine-2-yl)-propionic acid amide
[000211] will be in (the preparation in according to embodiment 30 of the N-in the acetone (1mL) (5-brooethyl-pyrazine-2-yl)-2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-propionic acid amide; 102.2mg; 0.20mmol) solution be cooled to 0 ℃; use sodium salt (31.8mg, 0.30mmol) processing of methane-sulfinic acid then.Reaction mixture in 0 ℃ of stirring 1 hour, was stirred 4 hours 20 minutes in 25 ℃ then.(24.0mg 0.24mmol), and spends the night reaction mixture in 25 ℃ of stirrings to add the sodium salt of second part of methane-sulfinic acid.The vacuum concentration reaction mixture.With ethyl acetate (50mL) dilution residuum, and water (2 * 25mL) and saturated sodium-chloride water solution (25mL) washing, use dried over sodium sulfate, filtration and vacuum concentration.Biotage chromatogram (FLASH 40S, silicon-dioxide, 50% ethyl acetate/hexane) provides 2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-methylsulfonyl methyl-pyrazine-2-yl)-propionic acid amide (74.9mg, 73%), white foam: mp 91-95 ℃ (foam is to gel); (ES)
+-HRMS m/e calculated value C
21H
26ClN
3O
5S
2(M+H)
+500.1075, actual measurement 500.1080.
Embodiment 32
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-dimethylaminomethyl-pyrazine-2-yl)-propionic acid amide
[000212] will be in (the preparation in according to embodiment 30 of the N-in the tetrahydrofuran (THF) (2.6mL) (5-brooethyl-pyrazine-2-yl)-2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-propionic acid amide; 138.5mg; 0.28mmol) solution be cooled to 0 ℃; use 2.0M in tetrahydrofuran (THF) (275 μ L, 0.55mmol) solution-treated of the dimethylamine in then.Reaction mixture in 0 ℃ of stirring 30 minutes, was stirred 1 hour in 25 ℃ then.Add second part at 2.0M at tetrahydrofuran (THF) (275 μ L, the 0.55mmol) solution of the dimethylamine in, and stirred 1 hour in 25 ℃.Add the 3rd part at 2.0M (at this moment, the APCI-LRMS Indicator Reaction is finished for 138 μ L, the 0.28mmol) solution of the dimethylamine in, and stirred 1.5 hours in 25 ℃ at tetrahydrofuran (THF).The vacuum concentration reaction mixture is used ethyl acetate (50mL) dilution then, and dried over sodium sulfate is used in water (25mL) washing, filters and vacuum concentration.Biotage chromatogram (FLASH 40S, silicon-dioxide, 100% methyl alcohol) provides impure 2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-dimethylaminomethyl-pyrazine-2-yl)-propionic acid amide, is orange oil.This not pure products by RPLC (Waters symmetry packing, acetonitrile/water and 0.05% trifluoroacetic acid, 2% to 45% acetonitrile gradient) repurity.Vacuum concentration contains the fraction of product, provide: 2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-dimethylaminomethyl-pyrazine-2-yl)-propionic acid amide (50.4mg, 39%), is weak yellow foam: mp88.0-91.5 ℃ (foam is to gel); (ES)
+-HRMS m/e calculated value C
22H
29ClN
4O
3S (M+H)
+465.1722, actual measurement 465.1726.
Embodiment 33
2-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(the 5-methyl-[1,2,4] oxadiazole-3-yls)-pyrazine-2-yl]-propionic acid amide
[000213] (3-chloro-4-methylthio group-phenyl)-acetate of handling at leisure in methyl alcohol (200mL) with the vitriol oil (1mL) (prepares 8.00g, solution 36.92mmol) in according to embodiment 1.The reaction mixture reflux that obtains is spent the night.Reaction mixture is cooled to 25 ℃, and vacuum concentration is to remove methyl alcohol then.The residuum that obtains is dissolved in the ethyl acetate (50mL).Water (1 * 50mL) washing organic layer.With ethyl acetate (3 * 20mL) further aqueous layer extracted.With the saturated sodium bicarbonate aqueous solution (organic layer that 1 * 25mL) washing merges.Then, use the dried over sodium sulfate organic layer, filter and vacuum concentration, provide: (3-chloro-4-methylthio group-phenyl)-methyl acetate (7.28g, 85.5%), be yellow oil, it uses under the condition that is not further purified: EI-HRMS m/e calculated value C
10H
11ClO
2S (M
+) 230.0168, actual measurement 230.0166.
[000214] will (4.86mL, solution 34.70mmol) be cooled to-78 ℃, use 2.5M in hexane (13.88mL, 34.70mmol) solution-treated of the n-Butyl Lithium in then at the Diisopropylamine in the anhydrous tetrahydro furan (212.3mL).The reaction mixture that obtains was stirred 15 minutes in-78 ℃, be used in anhydrous tetrahydro furan (23.6mL) and 1 then, 3-dimethyl-3,4,5, in 6-tetrahydrochysene-2 (1H)-pyrimidone (9.43mL) (3-chloro-4-methylthio group-phenyl)-methyl acetate (7.28g, handle at leisure by solution 31.55mmol).The bright yellow solution that obtains was stirred 1 hour in-78 ℃, at this moment, be added in 1 at leisure, 3-dimethyl-3,4,5, the iodomethyl pentamethylene in 6-tetrahydrochysene-2 (1H)-pyrimidone (7.08mL) is (according to preparation among the embodiment 1,7.95g, solution 37.86mmol).Reaction mixture is warmed to 25 ℃, its stirring is spent the night in this temperature.Then, with saturated aqueous ammonium chloride (20mL) quencher reaction mixture, and layer separates.With ethyl acetate (3 * 20mL) aqueous layer extracted.Organic layer with dried over sodium sulfate merges filters, and vacuum concentration.Flash chromatography (Merck silica gel 60,230-400 order, 95/5 hexane/ethyl acetate) provides: 2-(3-chloro-4-methylthio group-phenyl)-3-cyclopentyl-methyl propionate (5.74g, 58.1%) is water white oil.
[000215] is used in potassium hydroxide (4.35g, 2-(3-chloro-4-methylthio group-phenyl)-3-cyclopentyl-methyl propionate (4.85g, 15.50mmol) the solution of solution-treated 77.50mmol) in ethanol (108mL) in the water (25.2mL).Reaction mixture was stirred 3 hours in 25 ℃.Then, the vacuum concentration reaction mixture is to remove ethanol.With the 1N aqueous hydrochloric acid water-based residuum that obtains is acidified to pH=2, uses methylene dichloride (3 * 15mL) extractions then.Then, the organic layer with dried over sodium sulfate merges filters and vacuum concentration, provides: 2-(3-chloro-4-methylthio group-phenyl)-3-cyclopentyl-propionic acid (4.14g, 89.4%), be white solid, and it uses under the condition that is not further purified.
[000216] will (4.14g, mixture 13.85mmol) be cooled to 0 ℃, use 30% aqueous hydrogen peroxide solution (7.85mL) to handle then at the 2-in the formic acid (7.08mL) (3-chloro-4-methylthio group-phenyl)-3-cyclopentyl-propionic acid.Add tetrahydrofuran (THF) (4mL), to help to stablize raw material.The reaction mixture that obtains is warmed to 25 ℃, its stirring is spent the night in this temperature.Then, reaction mixture is cooled to 0 ℃, handles with the saturated sodium sulfite aqueous solution at leisure.Product is extracted into ethyl acetate (in 3 * 20mL).Organic layer with dried over sodium sulfate merges filters, and vacuum concentration, and provide: 2-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-propionic acid (4.54g, 99.1%) is white solid: mp123.9-126.2 ℃; FAB-HRMS m/e calculated value C
15H
19ClO
4S (M+H)
+331.0771, actual measurement 331.0776.
[000217] will (3-chloro-4-methylsulfonyl-phenyl)-(1.00g, solution 3.023mmol) be cooled to 0 ℃ to 3-cyclopentyl-propionic acid at the 2-in the methylene dichloride (16mL).(1.15mL 13.18mmol), then uses N, dinethylformamide (2) reaction mixture to use oxalyl chloride then.Reaction mixture in 0 ℃ of stirring 20 minutes, was stirred 2 hours in 25 ℃ then.Then, vacuum concentrated solution.Residuum is dissolved in the methylene dichloride (16mL), and is cooled to 0 ℃.In this solution, in 1 minute, be added in 2-amino-5-bromo-pyrazine in the tetrahydrofuran (THF) (16mL) (530.0mg, 3.046mmol) and 2,6-lutidine (420 μ L, solution 3.606mmol).Reaction mixture in 0 ℃ of stirring 30 minutes, was stirred 3 hours in 25 ℃ then.Then, use ethyl acetate diluting reaction material, and wash with the 1N aqueous hydrochloric acid.With 1N aqueous hydrochloric acid reextraction water layer.With the organic layer that the saturated sodium bicarbonate aqueous solution washing merges, use dried over sodium sulfate, filter and vacuum concentration.Biotage chromatogram (FLASH40L, silicon-dioxide, 1/3 ethyl acetate/hexane) provides: N-(5-bromo-pyrazine-2-yl)-2-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-propionic acid amide (1.00g, 68%), white foam: (ES)
+-HRMS m/e calculated value C
19H
21BrClN
3O
3S (M+H)
+486.0249, actual measurement 486.0254.
[000218] under nitrogen; will be at anhydrous N; N-in the dinethylformamide (6mL) (5-bromo-pyrazine-2-yl)-2-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-propionic acid amide (616.0mg; 1.266mmol), potassium cyanide (210.0mg; 3.225mmol), four (triphenyl phosphine) palladium (0) (30.0mg; 0.026mmol), cuprous iodide (I) (605.0mg, 3.177mmol) and hexaoxacyclooctadecane-6-6 (33.0mg, solution 0.125mmol) is in 150 ℃ of heating.2.75 hour, mixture is cooled to 25 ℃.Then, vacuum concentrated mixture desolvates to remove.With methylene dichloride and ethyl acetate dilution residuum, filter by Celite pad then.Wash Celite pad well with methylene dichloride and ethyl acetate.Then, the vacuum concentration filtrate, and be adsorbed on the silica gel (Merck silica gel 60,230-400 order).Biotage chromatogram (FLASH40L, silicon-dioxide, 1/3 to 1/1 ethyl acetate/hexane) provides: 2-(3-chloro-4-methylsulfonyl-phenyl)-N-(5-cyano group-pyrazine-2-yl)-3-cyclopentyl-propionic acid amide (402.3mg, 73.4%) is the canescence foam: (ES)
+-HRMS m/e calculated value C
20H
21ClN
4O
3S (M+H)
+433.1096, actual measurement 433.1101.
[000219] with azanol base hydrochloride (330.0mg; 4.749mmol) 25 ℃ of 2-(3-chloro-4-methylsulfonyl-phenyl)-N-(5-cyano group-pyrazine-2-yl)-3-cyclopentyl-propionic acid amide (400.0mg, solution 0.924mmol) in methyl-sulphoxide (6mL) of processing.Then, (500 μ L, 5.056mmol) reaction mixture stirred 1 hour in 25 ℃ then with piperidines.Then, the dilute with water reaction mixture is used ethyl acetate extraction afterwards.Use the dried over sodium sulfate organic layer, filter and vacuum concentration.Biotage chromatogram (FLASH 40L; silicon-dioxide; 1/1 to 2/1 ethyl acetate/hexane) provide: 2-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(N-hydroxyl-carbamyl imino-)-pyrazine-2-yl]-propionic acid amide (274.5mg, 63.8%), be white solid: (ES)
+-HRMS m/e calculated value C
20H
24ClN
5O
4S (M+H)
+466.1311, actual measurement 466.1315.
[000220] in a cuvette; preparation 2-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(N-hydroxyl amino formyl imino-)-pyrazine-2-yl]-propionic acid amide (197.0mg; 0.423mmol) and diacetyl oxide (970 μ L, mixture 10.281mmol).Seal tightly this Glass tubing, and reaction mixture was stirred 3.5 hours in 120 ℃.With ethyl acetate (75mL) diluted reaction mixture, and with the washing of saturated sodium bicarbonate aqueous solution (50mL) and saturated sodium-chloride water solution (50mL).Water layer with ethyl acetate (50mL) reextraction merging.Merging organic layer with dried over sodium sulfate obtains filters and vacuum concentration.Biotage chromatogram (FLASH 40L, silicon-dioxide, 50% ethyl acetate/hexane) provides: 2-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(5-methyl-[1,2,4] oxadiazole-3-yl)-pyrazine-2-yl]-propionic acid amide (43.8mg, 21%), white foam; Mp 101.9-104.8 ℃ (foam is to gel); (ES)
+-HRMS m/e calculated value C
22H
24ClN
5O
4S (M+H)
+490.1311, actual measurement 490.1315.
Embodiment 34
3-cyclopentyl-N-[5-(1-oxyimino-ethyl)-pyrazine-2-yl]-2 (R)-(4-methylsulfonyl-phenyl)-propionic acid amide
[000221] will the 3-cyclopentyl-2 (R) in the methylene dichloride (4.2mL)-(4-methylsulfonyl phenyl)-propionic acid (in according to embodiment 3 preparation, 500.0mg, solution 1.687mmol) are cooled to 0 ℃.Use N, dinethylformamide (1) and oxalyl chloride (294gL, 3.374mmol) reaction mixture.Reaction mixture in 0 ℃ of stirring 15 minutes, is warmed to 25 ℃ then at leisure, it was stirred 3 hours in this temperature.Then, vacuum concentrated solution.The residuum that obtains is dissolved in the methylene dichloride (8.4mL), is cooled to 0 ℃ then.Then, be used in 1-(5-amino-pyrazino-2-the yl)-ethyl ketone O-tertiary butyl-oxime in the tetrahydrofuran (THF) (8.4mL) (according to preparation among the embodiment 28,351.4mg, 1.687mmol) and 2,6-lutidine (246 μ L, 2.109) drips handles this cooling solution.Reaction mixture in 0 ℃ of stirring 30 minutes, is warmed to 25 ℃ then, its stirring is spent the night in this temperature.Then, the vacuum concentration reaction mixture, with ethyl acetate (250mL) dilution, and with the 1N aqueous hydrochloric acid (3 * 100mL) and saturated sodium-chloride water solution (1 * 300mL) washs.Then, use the dried over sodium sulfate organic layer, filter and vacuum concentration.Biotage chromatogram (FLASH 40L; silicon-dioxide; 20% ethyl acetate/hexane) provide: N-[5-(1-tert.-butoxy imino-ethyl)-pyrazine-2-yl]-3-cyclopentyl-2 (R)-(4-methylsulfonyl-phenyl)-propionic acid amide (451.1mg, 55%), be yellow foam.This material is passed through Biotage chromatogram (FLASH 40L, silicon-dioxide, 5% ethyl acetate/dichloromethane) repurity, provide: N-[5-(1-tert.-butoxy imino-ethyl)-pyrazine-2-yl]-3-cyclopentyl-2 (R)-(4-methylsulfonyl-phenyl)-propionic acid amide (380.4mg, 46%) white foam: mp 81-83 ℃ (foam is to gel); (ES)
+-HRMS m/e calculated value C
25H
34N
4O
4S (M+H)
+487.2374, actual measurement 487.2377.
[000222] will be at the N-[5-in the methylene dichloride (1.4mL) (1-tert.-butoxy imino-ethyl)-pyrazine-2-yl]-3-cyclopentyl-2 (R)-(4-methylsulfonyl-phenyl)-propionic acid amide (342.6mg; 0.704mmol) solution be cooled to 0 ℃; (2.10mL, 2.10mmol) titanium tetrachloride solution in is handled at methylene dichloride to use 1.0M then.The solution that obtains was stirred 2 hours in 0 ℃, stirred 1 hour 50 minutes in 25 ℃ then.The vacuum concentration reaction soln distributes between ethyl acetate (210mL) and water (150mL) then.With saturated sodium-chloride water solution (150mL) washing organic layer, use dried over sodium sulfate, filter and vacuum concentration.Biotage chromatogram (FLASH 40L, silicon-dioxide, 60% ethyl acetate/hexane) provide: 3-cyclopentyl-N-[5-(1-oxyimino-ethyl)-pyrazine-2-yl]-2 (R)-(4-methylsulfonyl-phenyl)-propionic acid amide (276.3mg, 91%) white foam: mp 118.8-122.4 ℃ (foam is to gel); (ES)
+-HRMS m/e calculated value C
21H
26N
4O
4S (M+H)
+431.1748, actual measurement 431.1752.
Embodiment 35
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(the 3-methyl-[1,2,4] oxadiazole-5-yls)-pyrazine-2-yl]-propionic acid amide
[000223] will be at the 5-[2 (R) in the methylene dichloride (1.8mL)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-propionyl amino]-(preparation in according to embodiment 29,149.5mg, solution 0.331mmol) are cooled to 0 ℃ to pyrazine-2-carboxylic acid.Then, with oxalyl chloride (61 μ L, 0.699mmol) and N, dinethylformamide (1) reaction mixture.Reaction mixture was stirred 30 minutes in 0 ℃, be warmed at leisure then 25 ℃ 3 hours.Then, vacuum concentrated solution.Residuum is dissolved in the methylene dichloride (1.8mL), and is cooled to 0 ℃.Then, (27.4mg, 0.370mmol) and 2, (46 μ L, the solution that mixture process 0.395mmol) obtains is then with methylene dichloride (0.8mL) rinsing for the 6-lutidine to be used in acetyl amidoxime in the methylene dichloride (1.0mL).The pH of reaction mixture is about 3, and adds second part 2, and (23 μ L 0.198mmol), make pH be about 5 to the 6-lutidine.Reaction mixture in 0 ℃ of stirring 30 minutes, is spent the night in 25 ℃ of stirrings then.Water (3mL) quencher reaction, and between ethyl acetate (50mL) and water (25mL), distribute.With saturated sodium-chloride water solution (100mL) washing organic layer; use dried over sodium sulfate; filter and vacuum concentration; provide: (Z)-N-[[[5-[[2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-1-oxopropyl] amino]-the 2-pyrazinyl] carbonyl] the oxygen base] second Imidamide (ethanimidamide); be orange oil, it uses under the condition that is not further purified.
With 4
Molecular sieve is handled thick (Z)-N-[[[5-[[2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-1-oxopropyl in toluene (3.6mL)] amino]-the 2-pyrazinyl] carbonyl] the oxygen base] solution of second Imidamide (0.331mmol); and be warmed to 80 ℃, it stirred 48 hours in this temperature.Between ethyl acetate (25mL) and water (50mL), distribute reaction mixture.With 1N aqueous hydrochloric acid (50mL) washing organic layer.Then, the water layer of stripping and merging with ethyl acetate (50mL).With the organic layer that saturated sodium-chloride water solution (50mL) washing merges, use dried over sodium sulfate, filter and vacuum concentration.Biotage chromatogram (FLASH 40S; silicon-dioxide; 40% ethyl acetate/hexane) provides: 2 impure (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(3-methyl-[1; 2; 4] oxadiazole-5-yl)-pyrazine-2-yl]-propionic acid amide; be weak yellow foam (22.5mg, 13%).With this not pure products RPLC (Waters symmetry packing, acetonitrile/water and 0.05% trifluoroacetic acid, 2% to 45% acetonitrile gradient) repurity.Vacuum concentration contains the fraction and the freeze-drying of product, provide: 2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(3-methyl-[1,2,4] oxadiazole-5-yl)-pyrazine-2-yl]-propionic acid amide (12mg, 7%), is white lyophilized solid: mp 101-105 ℃ (foam is to gel); (ES)
+-HRMS m/e calculated value C
22H
24ClN
5O
4S (M+H)
+490.1311, actual measurement 490.1315.
Embodiment 36
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-methylthiomethyl-pyrazine-2-yl)-propionic acid amide
[000225] (0.33g, 4.473mmol) (5-brooethyl-pyrazine-2-yl)-t-butyl carbamate of handling in acetone (11.6mL) (prepares 1.03g, solution 3.575mmol) according to WO02/070494 with the sulfo-sodium methylate.Reaction mixture was stirred 5 hours 15 minutes in 25 ℃.Then, the vacuum concentration reaction mixture, and between ethyl acetate (200mL) and water (200mL), distribute residuum.With ethyl acetate (100mL) reextraction water layer.Organic layer with dried over mgso merges filters and vacuum concentration.Biotage chromatogram (FLASH 40L, silicon-dioxide, 5% ethyl acetate/dichloromethane) provides (5-methylthiomethyl-pyrazine-2-yl)-t-butyl carbamate, is natural white solid (0.45g, 49%) that it uses under the condition that is not further purified.
[000226] (1.4mL, 18.172mmol) (0.45g, solution 1.762mmol) stirred 2 hours 15 minutes in 25 ℃ (5-methylthiomethyl-pyrazine-2-the yl)-t-butyl carbamate of processing in methylene dichloride (18mL) then with trifluoroacetic acid.Then, with second part of trifluoroacetic acid (0.7mL, 9.086mmol) processing reaction solution, and stirred 5 hours in 25 ℃.At this moment, vacuum concentration reaction mixture.Biotage chromatogram (FLASH 40S, silicon-dioxide, 10% ethanol/methylene and 0.1% ammonium hydroxide) provides: 5-methylthiomethyl-pyrazine-(276.1mg quant.), is white solid: mp102.0-102.7 ℃ to 2-base amine; EI-HRMS m/e calculated value C
6H
9N
3S (M
+) 155.0517, actual measurement 155.0516.
[000227] (preparation in according to embodiment 1,581.7mg, solution 1.758mmol) are cooled to 0 ℃ to 2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-propionic acid that will be in methylene dichloride (8.6mL).With oxalyl chloride (310 μ L, 3.554mmol) and N, dinethylformamide (2) reaction mixture.Reaction mixture in 0 ℃ of stirring 45 minutes, was warmed to 25 ℃ then at leisure in 6 hours.Then, vacuum concentrated solution.The yellow thin pulp that obtains is dissolved in the methylene dichloride (7mL), is cooled to 0 ℃ then.In this solution, be added in 5-methylthiomethyl-pyrazine in the methylene dichloride (8.6mL)-2-base amine (267.2mg, 1.721mmol) and pyridine (174 μ L, solution 2.151mmol), the then rinsing of usefulness methylene dichloride (1.7mL).The pH of reaction mixture is about 3-4, and add second part of pyridine (50 μ L, 0.618mmol), to regulate pH to about 5.In 0 ℃ of stirring, waiting a moment is warmed to 25 ℃ slowly and spends the night with reaction mixture.Then, water quencher reaction, and in 25 ℃ of stirrings 10 minutes, and vacuum concentration.Between ethyl acetate (250mL) and 1N aqueous hydrochloric acid (250mL), divide the reactant ligand thin pulp.With 1N aqueous hydrochloric acid (250mL), saturated sodium bicarbonate aqueous solution (250mL), water (250mL) and saturated sodium-chloride water solution (250mL) washing organic layer, use dried over mgso, filter and vacuum concentration.Biotage chromatogram (FLASH 40L, silicon-dioxide, 33% ethyl acetate/hexane) provides: needed chirality 2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-methylthiomethyl-pyrazine-2-yl)-propionic acid amide (679.0mg, 84%) white foam: mp 75.0-76.7 ℃ (foam is to gel); (ES)
+-HRMSm/e calculated value C
21H
26ClN
3O
3S
2(M+H)
+468.1177, actual measurement 468.1180.
Embodiment 37
2-(3-chloro-4-methylsulfonyl-phenyl)-N-[5-(cyano group-oxyimino-methyl)-pyrazine-2-yl]-3-cyclopentyl-propionic acid amide
[000228] (350.7mg 6.940mmol) handles at N, and (5-brooethyl-pyrazine-2-the yl)-t-butyl carbamate in the dinethylformamide (6.9mL) is (according to WO 02/070494 preparation, 1.00g, solution 3.470mmol) with sodium cyanide.Reaction mixture was stirred 1 hour in 40 ℃.With saturated sodium-chloride water solution (100mL) diluted reaction mixture, use ethyl acetate (100mL) extraction then.Use the dried over mgso organic layer, filter and vacuum concentration.Biotage chromatogram (FLASH 40L, silicon-dioxide, 30% ethyl acetate/hexane) provides: (5-cyano methyl-pyrazine-2-yl)-t-butyl carbamate (807.6mg, 99%) is faint yellow solid: mp162-164 ℃; EI-HRMS m/e calculated value C
11H
14N
4O
2(M
+) 234.1117, actual measurement 234.1120.
[000229] with trifluoroacetic acid (2.7mL, 34.470mmol) (5-cyano methyl-pyrazine-2-yl)-t-butyl carbamate (807.6mg, 3.447mol) the solution of processing in methylene dichloride (4.3mL).Reaction mixture was stirred 2 hours in 25 ℃, then vacuum concentration.Biotage chromatogram (FLASH40S, silicon-dioxide, 10% ethanol/methylene and 0.1% ammonium hydroxide) provides: impure (5-amino-pyrazino-2-yl)-acetonitrile.Repurity by Biotage chromatogram (FLASH 40M, silicon-dioxide, 99/1 ethyl acetate/methanol) provides, and pure (5-amino-pyrazino-2-yl)-acetonitrile (281.4mg, 60.8%) is orange solids: mp 132-134 ℃; EI-HRMS m/e calculated value C
6H
6N
4(M
+) 134.0592, actual measurement 134.0593.
[000230] use N, (preparation in according to embodiment 33,663.1mg 2.004mmol), is cooled to 0 ℃ to 2-(3-chloro-4-methylthio group-phenyl)-3-cyclopentyl-propionic acid of dinethylformamide (2) processing in methylene dichloride (10mL) then.Then, with oxalyl chloride (357 μ L, 4.009mmol) reaction mixture.Reaction mixture in 0 ℃ of stirring, is warmed to 25 ℃ then, it was stirred 1.5 hours in this temperature.At this moment, vacuum concentration reaction mixture.Yellow thin pulp is dissolved in methylene dichloride (10mL), is cooled to 0 ℃ then.In this solution, be added in (5-amino-pyrazino-2-yl)-acetonitrile in the methylene dichloride (10mL) (268.9mg, 2.004mmol) and pyridine (324 μ L, 4.009mmol).Reaction mixture in 0 ℃ of stirring 30 minutes, is warmed to 25 ℃ then, it was stirred 16 hours in this temperature.Use methylene dichloride (100mL) and water (50mL) diluted reaction mixture then.With 1N aqueous hydrochloric acid (50mL), saturated sodium bicarbonate aqueous solution (50mL) and saturated sodium-chloride water solution (50mL) washing water layer, use dried over mgso, and vacuum concentration.Biotage chromatogram (FLASH 40L, silicon-dioxide, 10% ethyl acetate/dichloromethane) provides: 2-(3-chloro-4-methylsulfonyl-phenyl)-N-(5-cyano methyl-pyrazine-2-yl)-3-cyclopentyl-propionic acid amide (523.4mg, 58%), white foam: mp 79-82 ℃ (foam is to gel); (ES)
+-HRMS m/e calculated value C
21H
23ClN
4O
3S (M+H)
+447.1252, actual measurement 447.1255.
[000231] will be at the 2-in the methyl alcohol (671 μ L) (3-chloro-4-methylsulfonyl-phenyl)-N-(5-cyano methyl-pyrazine-2-yl)-3-cyclopentyl-propionic acid amide (300.0mg; 0.671mmol) solution be cooled to 0 ℃; use sodium hydride (26.8mg then; 0.671mmol); then (92.3mg 0.805mmol) handles with uncle's butyronitrile.Reaction mixture in 0 ℃ of stirring 30 minutes, is warmed to 25 ℃ then, it was stirred 16 hours in this temperature.At this moment, with the 1N aqueous hydrochloric acid reaction mixture is acidified to pH and is about 7.With saturated sodium-chloride water solution (50mL) washing organic layer, use dried over mgso, filter and vacuum concentration.Biotage chromatogram (FLASH 40S, silicon-dioxide, 50% ethyl acetate/hexane) provides: 2-(3-chloro-4-methylsulfonyl-phenyl)-N-[5-(cyano group-oxyimino-methyl)-pyrazine-2-yl]-3-cyclopentyl-propionic acid amide, be yellow oil.With this material high performance liquid chromatography (Metachem diol column, 10, the 10-50% ethyl acetate/hexane) repurity, provide: 2-(3-chloro-4-methylsulfonyl-phenyl)-N-[5-(cyano group-oxyimino-methyl)-pyrazine-2-yl]-3-cyclopentyl-propionic acid amide, be white lyophilized powder (35.5mg, 11%): mp 130-133 ℃ (foam is to gel); (ES)
+-HRMS m/e calculated value C
21H
22ClN
5O
4S (M+H)
+476.1154, actual measurement 476.1158.
Embodiment 38
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-methylsulfinyl ylmethyl-pyrazine-2-yl)-propionic acid amide
[000232] with 30% aqueous hydrogen peroxide solution (113 μ L; 1.106mmol) 2 (Rs)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N (5-methylthiomethyl-pyrazine-2-yl)-propionic acid amide (according to embodiment 36 in the preparation of processing in formic acid (11mL); 514.3mg, solution 1.099mmol).Reaction mixture was stirred 4 days in 25 ℃.Then, between ethyl acetate (250mL) and water (250mL), distribute reaction mixture.With saturated sodium bicarbonate aqueous solution (250mL) and saturated sodium-chloride water solution (150mL) washing organic layer, use dried over mgso, filter and vacuum concentration.Biotage chromatogram (FLASH 40S, silicon-dioxide, 5% ethanol/methylene) provides: 2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-methylsulfinyl ylmethyl-pyrazine-2-yl)-propionic acid amide (269.9mg, 51%), is weak yellow foam: mp102-106 ℃ (foam is to gel); (ES)
+-HRMS m/e calculated value C
21H
26ClN
3O
4S
2(M+H)
+484.1126, actual measurement 484.1134.
Embodiment 39
N-(5-ethanoyl-pyrazine-2-yl)-2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-propionic acid amide
[000233] with paratolunitrile monohydrate (174.5mg; 0.904mmol) N-(5-ethanoyl-pyrazine-2-yl)-2 of processing in trimethyl orthoformate (13.5mL) and methyl alcohol (36mL); 2-dimethyl-propionic acid amide is (according to preparation among the embodiment 28; 2.00g, suspension 9.038mmol).With the reaction mixture reflux that obtains 2.5 hours, vacuum concentration then.With ethyl acetate (200mL) dilution residuum.With saturated sodium bicarbonate aqueous solution (100mL) and saturated sodium-chloride water solution (100mL) washing organic layer, use dried over mgso, filter and vacuum concentration.Biotage chromatogram (FLASH 40L, silicon-dioxide, 20% ethyl acetate/hexane) provides: N-[5-(1,1-dimethoxy-ethyl)-pyrazine-2-yl]-2,2-dimethyl propylene acid amides is white solid (1.74g, 72%): mp 108-109 ℃; EI-HRMS m/e calculated value C
13H
21N
3O
3(M
+) 267.1583, actual measurement 267.1486.
[000234] with the 2N aqueous sodium hydroxide solution (11mL 22mmol) handles N-[5-(1,1-dimethoxy-ethyl)-pyrazine-2-yl in ethanol (13mL)]-2,2-dimethyl propylene acid amides (1.73g, solution 6.470mmol).Reaction mixture in 25 ℃ of stirrings 65 hours, was heated 1.5 hours in 65 ℃ then.With ethyl acetate (200mL) diluted reaction mixture, and wash with saturated sodium-chloride water solution (75mL).With ethyl acetate (100mL) reextraction water layer.Organic layer with dried over mgso merges filters and vacuum concentration.Biotage chromatogram (FLASH 40M, silicon-dioxide, 4% ethanol/methylene) provides: impure 5-(1,1-dimethoxy-ethyl)-pyrazine-2-base amine is yellow solid.This material is by Biotage chromatogram (FLASH 40L, silicon-dioxide, 70% ethyl acetate/hexane) repurity, still impure 5-(1 is provided, 1-dimethoxy-ethyl)-pyrazine-2-base amine, be faint yellow solid (880.4mg, 74%) that it uses under the condition that is not further purified and characterizes.
[000235] will be at methyl chloride (24mL) and N, (according to preparation among the embodiment 1,1.59g, solution 4.805mmol) are cooled to 0 ℃ to 2 (R) in the dinethylformamide (2)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-propionic acid.Then, with oxalyl chloride (855L, 9.609mmol) reaction mixture.Reaction mixture in 0 ℃ of stirring 30 minutes, is warmed to 25 ℃ then, it was stirred 2 hours in this temperature.Then, this solution of vacuum concentration.Yellow thin pulp is dissolved in the methylene dichloride (24mL), is cooled to 0 ℃ then.In this solution, be added in 5-(1,1-dimethoxy-ethyl)-pyrazine in the methylene dichloride (24mL)-2-base amine (880.4mg, 4.805mmol) and pyridine (466 μ L, solution 5.766mmol).Reaction mixture was stirred 1 hour in 0 ℃.Then, with saturated sodium-chloride water solution (50mL) quencher reaction, and layer separates.With methylene dichloride (50mL) reextraction water layer.With saturated sodium bicarbonate aqueous solution (75mL), copper sulfate (II) aqueous solution (2 * 50mL) and the organic layer that merges of saturated sodium-chloride water solution (75mL) washing, use dried over mgso, filtration and vacuum concentration.Biotage chromatogram (FLASH 40L, silicon-dioxide, 30% ethyl acetate/hexane) provides: 2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(1,1-dimethoxy-ethyl)-pyrazine-2-yl]-propionic acid amide (1.25g, 52%) white foam: mp85-88 ℃ (foam is to gel); (ES)
+-HRMS m/e calculated value C
23H
30ClN
3O
5S (M+Na)
+518.1487, actual measurement 518.1488.
[000236] with paratolunitrile monohydrate (142.5mg; 0.738mmol) 2 (Rs)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(1 of processing in acetone (28mL) and water (3mL); 1-dimethoxy-ethyl)-pyrazine-2-yl]-propionic acid amide (1.22g, solution 2.459mmol).With reaction mixture be heated to 60 ℃ 30 minutes, use ethyl acetate (100mL) dilution then.With saturated sodium bicarbonate aqueous solution (100mL), water (100mL) and saturated sodium-chloride water solution (100mL) washing organic layer, use dried over mgso, filter and vacuum concentration.Biotage chromatogram (FLASH 40M, silicon-dioxide, 25% ethyl acetate/hexane) provides: N-(5-ethanoyl-pyrazine-2-yl)-2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-propionic acid amide, white foam (1.07g, 96%): mp 77-80 ℃ (foam is to gel); (ES)
+-HRMS m/e calculated value C
21H
24ClN
3O
4S (M+H)
+450.1249, actual measurement 450.1253.
Embodiment 40
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(2-hydroxyl-1-methylol-ethyl)-pyrazine-2-yl]-propionic acid amide
[000237] with diethyl malonate (3.35mL, 22.0mmol) and salt of wormwood (5.08g, 36.7mmol) 2-bromo-5-nitro pyrazine (3.0g, 14.7mmol) the solution of processing in tetrahydrofuran (THF) (24.5mL).Then, spend the night in 90-95 ℃ of stirring.At this moment, reaction mixture is cooled to 25 ℃, pours into then in the 1N aqueous hydrochloric acid (60mL).(50mL) dilutes this solution with saturated sodium-chloride water solution, uses ethyl acetate (3 * 75mL) extractions then.Organic layer with dried over sodium sulfate merges filters, and vacuum concentration.Biotage chromatogram (FLASH 40M, Silica 25% ethyl acetate/hexane) provides 2-(5-nitro-pyrazine-2-yl)-diethyl malonate (3.28g, 78%), is light yellow oil: EI-HRMSm/e calculated value C
11H
13N
3O
6(M
+) 283.0804, actual measurement 283.0801.
[000238] with ammonium formiate (510mg, 8.1mmol) and 10% handle 2-(5-nitro-pyrazine-2-yl)-diethyl malonate (425mg, solution 1.5mmol) in the ethanol (10mL) at 25 ℃ at the palladium on the gac (51mg).With mixture heating up to 95-100 ℃ 4 hours, spend the night in 25 ℃ of stirrings then.At this moment, remove by filter catalyzer by Celite pad (washing with alcohol).The vacuum concentration filtrate.Biotage chromatogram (FLASH 40M, silicon-dioxide, 50% ethyl acetate/hexane) provides: 2-(5-amino-pyrazino-2-yl)-diethyl malonate (131.5mg, 37%) is the Sandy solid: EI-HRMSm/e calculated value C
11H
15N
3O
4(M
+) 253.1063, actual measurement 253.1065.
[000239] use 2.0M at methylene dichloride (385 μ L; 0.77mmol) and the N of catalytic amount; oxalyl chloride in the dinethylformamide is handled 2 (R) in methylene dichloride (10mL)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-propionic acid (preparation in according to embodiment 1 that is cooled to 0 ℃; 170mg, solution 0.51mmol).Reaction mixture was stirred 30 minutes in 0 ℃, and stirred 2 hours in 25 ℃.Then, vacuum concentrated solution.Residuum is dissolved in the methylene dichloride (10mL), be cooled to 0 ℃, be used in then 2-(5-amino-pyrazino-2-yl)-diethyl malonate in the tetrahydrofuran (THF) (10mL) (130mg, 0.51mmol) and 2,6-lutidine (120 μ L, solution-treated 1.03mmol).Reaction mixture was stirred 15 minutes in 0 ℃, and stirred 16 hours in 25 ℃.Then, vacuum concentration reaction mixture.Biotage chromatogram (FLASH 40M; silicon-dioxide; 50% ethyl acetate/hexane) provide: 2 (R)-5-[2-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-propionyl amino]-pyrazine-2-yl }-diethyl malonate (76.9mg, 26%), be light yellow oil.This material is further purified by it being dissolved in the methylene dichloride and with 1N aqueous hydrochloric acid (25mL) washing.Then, use the dried over mgso organic layer, filter and vacuum concentration, provide: 2 (R)-5-[2-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-propionyl amino]-pyrazine-2-yl }-diethyl malonate (51.3mg, 18%), be light yellow oil: (ES)
+-HRMS m/e calculated value C
26H
32ClN
3O
7S (M+H)
+566.1722, actual measurement 566.1726.
[000240] use 2.0M at hexane (1.84mL; 1.84mmol) in 2 (R) in being cooled to 0 ℃ tetrahydrofuran (THF) (5.0mL) of the solution-treated of hydrogenation two isobutyl ammoniums-{ 5-[2-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-propionyl amino]-pyrazine-2-yl }-diethyl malonate (189mg, solution 0.33mmol).Reaction mixture was stirred 1.25 hours in 0 ℃, and stirred 2 hours in 25 ℃.At this moment, reaction mixture is cooled to 0 ℃ again, uses the 2.0M that measures in addition then in hexane (0.92mL, 0.92mmol) solution-treated of the hydrogenation two isobutyl ammoniums in.Reaction mixture was stirred 15 minutes in 0 ℃, and stirred 1 hour in 25 ℃.At this moment, reaction mixture is poured in the mixture of ice, water and ethyl acetate.With ethyl acetate and diethyl ether aqueous layer extracted.With 1N aqueous citric acid solution, cold saturated sodium bicarbonate aqueous solution, the organic layer that the saturated sodium-chloride water solution washing merges, with sal epsom and dried over sodium sulfate, use charcoal treatment, filter and vacuum concentration.Biotage chromatogram (FLASH 40M, silicon-dioxide, 90% ethylacetate/acetonitrile) provide: 2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(2-hydroxyl-1-methylol-ethyl)-pyrazine-2-yl]-propionic acid amide (17.9mg, 11%), is weak yellow foam: mp 110-120 ℃; (ES)
+-HRMS m/e calculated value C
22H
28N
3O
5(M+H)
+482.1511, actual measurement 482.1512.
Embodiment 41
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-[1,3] dioxolane-2-base-pyrazine-2-yl)-propionic acid amide
[000241] under argon atmospher, in 90 ℃ oil bath, stirring heating 5-methylpyrazine-2-carboxylic acid (5.0g, 36.2mmol), N, the dinethylformamide dimethyl-acetal (15mL, 113mmol) and N, the solution of dinethylformamide (15mL) 60 minutes.The temperature of oil bath is increased to 120 ℃, and will will heat and stir and continue other 120 minutes.Then, reaction mixture is cooled to 25 ℃ and vacuum concentration, to remove the volume of about 10mL.Between water (50mL) and ethyl acetate (50mL), distribute the oily residuum.With ethyl acetate (2 * 50mL) further aqueous phase extracted, and handle each organic extract liquid with a saturated sodium-chloride water solution (25mL).With the organic extract liquid that dried over sodium sulfate merges, filtration and vacuum concentration are dark-coloured oil.(50mL, solution-treated residuum 3:2) generate orange solids with diethyl ether/hexane.By solid collected by filtration, and with diethyl ether/hexane (provide: 5-(2-dimethylamino-vinyl)-pyrazine-2-carboxylate methyl ester (4.94g, 66%) is the bright orange solid for 25mL, the washing of 1:1) mixture.
[000242] (1.3g 6.07mmol) handles at tetrahydrofuran (THF) and water (10mL, 1:1) 5-in (2-dimethylamino-vinyl)-pyrazine-2-carboxylate methyl ester (415mg, solution 2.0mmol) with the powder sodium periodate.Mixture was stirred 30 minutes in 25 ℃, and at this moment, thin-layer chromatography shows to have finished and changes into than the lower polar product of raw material.The reaction mixture vacuum concentration is extremely approaching dry, and between ethyl acetate (50mL) and saturated sodium bicarbonate aqueous solution (25mL), distribute residuum.With ethyl acetate (2 * 50mL) aqueous phase extracted.With the each organic extract liquid of saturated sodium-chloride water solution (25mL) washing.Organic extract liquid with dried over sodium sulfate merges filters and vacuum concentration, and thick aldehyde is provided: 5-formyl radical-pyrazine-2-carboxylate methyl ester (180mg), be orange oil, and it uses under the condition that does not have further sign and purifying.
[000243] by Dean-Rodney Stark condenser; will be at the 5-formyl radical-pyrazine in the benzene (10mL)-2-carboxylate methyl ester (325mg; 1.56mmol), ethylene glycol (100 μ L, 1.79mmol) and the paratolunitrile monohydrate (30mg, 0.157mmol) mixture heating up refluxed 17 hours.Cooling mixture, and dilute with benzene (25mL).With saturated sodium bicarbonate aqueous solution (25mL) and saturated sodium-chloride water solution (25mL) washing organic layer.The each water washing liquor of benzene reextraction with small portion.Organic layer with dried over sodium sulfate merges filters, and vacuum concentration, and provide: 5-[1,3 dioxolane-2-base-pyrazine-2-carboxylate methyl ester are orange-reddish oil (250mg).
[000244] with potassium hydroxide (150mg 2.27mmol), then handles 5-[1 in tetrahydrofuran (THF) (5mL) with methyl alcohol (2mL) and water (1mL), 3] dioxolane-2-base-pyrazine-2-carboxylate methyl ester (250mg, solution 1.19mmol).In 25 ℃ of stirrings 30 minutes, vacuum concentration was to dry then with mixture.Vacuum concentration is to dry from the benzene of 20mL part with residuum, and provide: (～280mg 1.19mmol), is brown solid to sylvite.In N, in the dinethylformamide (10mL), when stirring, (0.35mL 1.62mmol) handles with diphenylphosphine acylazide thing with this salt suspension.Mixture was stirred 18 hours in 25 ℃.Then, vacuum concentrated solution, and between ethyl acetate (50mL) and water (25mL), distribute residuum.With ethyl acetate (2 * 25mL) aqueous phase extracted.The each organic extract liquid of saturated sodium-chloride water solution washing with small portion.Filter the organic extract liquid that merges with sodium sulfate, filter and vacuum concentration, provide: acid azide (～240mg), be orange oil.With benzylalcohol (185 μ L 1.78mmol) handle acid azide, and with mixture in 85 ℃ of heated and stirred 30 minutes.Stir with the reaction mixture cooling and with diethyl ether (10mL).The solid that filtration obtains provides: carbamate (153mg, 43%) is filbert solid: mp 95-99 ℃.The vacuum concentration filtrate is to dry, and with residuum by flash chromatography (Merck silica gel 60, the 230-400 order is with the ethyl acetate/hexane wash-out of various concentration) purifying, the carbamate (60mg, 16%) of other amount is provided.
[000245] handles carbamate (200mg, solution 0.66mmol) in methyl alcohol (5mL) with 10% at the palladium on the gac (40mg).Then, in 25 ℃ and atmospheric hydrogen atmosphere, hydrogenation mixture 60 minutes, at this moment, thin-layer chromatography (1/1 ethyl acetate/hexane) shows the conversion of having finished to the polarity product.By the diatomite filtration mixture, and the vacuum concentration filtrate, needed amino pyrazines derivatives (110mg, 100%) is provided, be pale solid.
[000246] will be at methylene dichloride (5mL) and N; 2 (R) in the dinethylformamide (2)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-propionic acid are (according to preparation among the embodiment 1; 200mg; 0.604mmol) solution be cooled to 5 ℃; (105 μ L 1.2mmol) handle to use oxalyl chloride then.Solution in 5 ℃ of stirrings 5 minutes, is removed cooling bath, and continue to stir 10 minutes.At this moment, vacuum concentration reaction mixture, and residuum is dissolved in the benzene (10mL), vacuum concentration solvent once more.The acyl halide that obtains is dissolved in the methylene dichloride (5mL); be cooled to 5 ℃, be used in the 5-[1 in the methylene dichloride (5mL) then, 3] dioxolane-2-base-pyrazine-2-base amine (105 μ L; 0.628mmol), pyridine (100 μ L, solution-treated 1.23mmol).After 5 minutes, remove cooling bath, and continue to stir 18 hours.Then, with methylene dichloride (50mL) diluted reaction mixture, and with saturated sodium bicarbonate aqueous solution (25mL), 0.5M aqueous hydrochloric acid (25mL) and saturated sodium-chloride water solution (25mL) washing soln.With the each water-washing liquid of the washed with dichloromethane of small portion.Organic layer with dried over sodium sulfate merges filters, and vacuum concentration, provides: yellow oil.Flash chromatography (Merck silica gel 60; the 230-400 order, the ethyl acetate/hexane of various concentration) provide: 2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-[1,3] dioxolane-2-base-pyrazine-2-yl)-propionic acid amide (148mg; 51%), is colourless foam: (ES)
+-HRMSm/e calculated value C
22H
26ClN
3O
5S (M+H)
+480.1355, actual measurement 480.1357.
Embodiment 42
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-[1,3] dioxolane-2-ylmethyl-pyrazine-2-yl)-propionic acid amide
[000247] 5-(the 2-dimethylamino vinyl)-pyrazine-2-carboxylate methyl ester of solution-treated in benzene (5mL) with 1M aqueous hydrochloric acid (5mL) and water (5mL) (prepares in according to embodiment 41,600mg, 2.9mmol) solution, then in 50 ℃ of powerful stirrings 60 minutes.Cooling mixture uses sodium-chlor (2g) to handle then.With benzene (3 * 25mL) extraction mixtures.With saturated sodium-chloride water solution (the each extraction liquid of 2 * 20mL) washings.Organic extract liquid with dried over sodium sulfate merges filters and vacuum concentration, and provide: 5-(2-oxo-ethyl)-pyrazine-2-carboxylate methyl ester (295mg, 56%) is yellow crystals.
[000248] with paratolunitrile monohydrate (27mg, 0.142mmol) 5-(2-oxo-ethyl)-pyrazine-2-carboxylate methyl ester (295mg of processing in benzene (10mL), 1.42mmol) and 1,2-ethylidene glycol (100 μ L, 1.79mmol) solution, and, mixture heating up was refluxed 20 hours with Dean-Rodney Stark condenser.Cooling mixture with benzene (15mL) dilution, is used saturated sodium bicarbonate aqueous solution (10mL) then, then with saturated sodium-chloride water solution (10mL) washing.With the each water of small portion benzene extraction.With the organic extract liquid that dried over sodium sulfate merges, filtration and vacuum concentration provide: 5-[1,3 to dry] dioxolane-2-ylmethyl-pyrazine-2-carboxylate methyl ester, be orange oil (273mg, 86%).
[000249] with potassium hydroxide (150mg 2.3mmol) handles 5-[1 in methyl alcohol (1.5mL) and tetrahydrofuran (THF) (1.5mL), 3] dioxolane-2-ylmethyl-pyrazine-2-carboxylate methyl ester (273mg, solution 1.22mmol).In reaction mixture, drip water (0.2mL), dissolve up to potassium hydroxide.After 90 minutes, thin-layer chromatography indication raw material changes the polarity product fully into.The vacuum concentration reaction mixture.Residuum is suspended in the toluene (10mL), and further vacuum concentration obtains sylvite to dry, is dark brown solid (300mg, 100%).This salt uses under the condition that is not further purified or characterizes.With this salt (300mg, 1.2mmol) with at N, (0.4mL 1.85mmol) merges the diphenylphosphine acylazide thing in the dinethylformamide (10mL), and reaction mixture was stirred 18 hours in 25 ℃.Vacuum concentrated solution, and residuum distributed between ethyl acetate (25mL) and water (25mL).With ethyl acetate (25mL) strip aqueous, and with the each organic extract liquid of small portion saturated sodium-chloride water solution washing.The organic layer that merges is merged, use dried over sodium sulfate, filter and vacuum concentration, provide: acid azide is light yellow oil (263mg).(160 μ L 1.55mmol) handle this oil, and in 85 ℃ of heated and stirred 35 minutes with benzylalcohol.Stir residuum with diethyl ether (10mL), and filter, obtain carbamate, be pale solid (138mg, 36% yield).With filtrate by flash chromatography (Merck silica gel 60 (230-400 order, the gradient mixture of ethyl acetate/hexane) purifying provides the 5-[1 of other amount, 3] dioxolane-2-ylmethyl-pyrazine-2-base-benzyl carbamate (21mg, 5.5%).
[000250] handle 5-[1 in methyl alcohol (5mL) with 10% at the palladium on the gac (40mg), 3] dioxolane-2-ylmethyl-pyrazine-2-base-benzyl carbamate (240mg, solution 0.49mmol).Then, in 25 ℃ and atmospheric hydrogen atmosphere, hydrogenation mixture 60 minutes, at this moment, thin-layer chromatography (ethyl acetate) shows the conversion of having finished to the polarity product.By the diatomite filtration reaction mixture, and the vacuum concentration filtrate, provide: 5-[1,3] dioxolane-2-ylmethyl-pyrazine-2-base amine (140mg, 100%), be oil, its crystallization.
[000251] will be at methylene dichloride (5mL) and N; 2 (R) in the dinethylformamide (2)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-propionic acid are (according to preparation among the embodiment 1; 160mg; 0.48mmol) solution be cooled to 5 ℃; (90 μ L 1.03mmol) handle to use oxalyl chloride then.After 5 minutes, remove cooling bath, will continue to stir 15 minutes.The vacuum concentration residuum is extremely dry, and further vacuum concentration is extremely dry from benzene (15mL) with residuum.The acyl halide that obtains is dissolved in the methylene dichloride (10mL), is cooled to 5 ℃, be used in the 5-[1 in the methylene dichloride (5mL) then, 3] dioxolane-2-ylmethyl pyrazine-2 bases-amine (0.49mmol), pyridine (100 μ L, solution-treated 1.23mmol).Mixture in 5 ℃ of stirrings 30 minutes, was stirred 18 hours in 25 ℃ then.Dilute residuum with methylene dichloride (25mL), and wash with saturated sodium bicarbonate aqueous solution (20mL), 0.5M aqueous hydrochloric acid (20mL) and saturated sodium-chloride water solution (20mL).With the each water of small portion ethyl acetate reextraction.Organic extract liquid with dried over sodium sulfate merges filters and vacuum concentration.Flash chromatography (Merck silica gel 60 (230-400 order; use the ethyl acetate/hexane gradient elution) provide: 2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-[1; 3] dioxolane-2-ylmethyl-pyrazine-2-yl)-and propionic acid amide (112mg, 47%), be colourless foam: (ES)
+-HRMS m/e calculated value C
23H
28ClN
3O
5S (M+H)
+494.1511, actual measurement 494.1517.
Embodiment 43
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-5-(2-methoxy ethoxy-pyrazine-2-yl)-propionic acid amide
[000252] with solid carbonic acid potassium (4.8g, 34.8mmol) 5-chloropyrazine-2-carboxylate methyl ester (2.0g, 11.63mmol) the solution of processing in 2-methyl cellosolve (20mL).Mixture in 95 ℃ of heating, and was stirred 4.5 hours in this temperature.Mixture is dissolved in the water (20mL), and extracts with diethyl ether.With in the 1N aqueous hydrochloric acid and water layer, and use ethyl acetate extraction.Wash organic layer with saturated sodium-chloride water solution, use dried over sodium sulfate, filter and vacuum concentration, provide: 5-methoxy ethoxy pyrazine-2-carboxylic acid is the faint yellow solid powder: (1.89g, 82.2%).
[000253] with diphenylphosphine acylazide thing (1.14mL, 5.30mmol) and triethylamine (1.40mL, 10.10mmol) 5-methoxy ethoxy pyrazine-2-carboxylic acid (1.0g, 5.05mmol) the mixture of processing in the trimethyl carbinol (20mL).Mixture heating up was refluxed 4 hours.The vacuum concentration solvent, and with ethyl acetate and saturated sodium bicarbonate aqueous solution extraction residuum.Wash organic layer with saturated sodium-chloride water solution, use dried over sodium sulfate, filter and vacuum concentration.Biotage chromatogram (FLASH 40S, silicon-dioxide, 3/1 hexane/ethyl acetate) provides: 2-N-tert-butoxycarbonyl amino-5-methoxy ethoxy pyrazine (259.4mg, 19.1%) is white solid.
[000254] with 2-N-tert-butoxycarbonyl amino-5-methoxy ethoxy pyrazine (254mg, 0.944mmol) the solution of trifluoroacetic acid (1mL) processing in methylene dichloride (3mL).Mixture was stirred 5 hours in 25 ℃.The vacuum concentration residuum is to drying, vacuum-drying then.Extract red oily residuum with ethyl acetate and saturated sodium bicarbonate aqueous solution.Wash organic layer with saturated sodium-chloride water solution, use dried over sodium sulfate, filter and vacuum concentration, provide: 2-amino-5-methoxy ethoxy pyrazine (148mg, 87.6%) is the oily residuum.
[000255] with oxalyl chloride (153 μ L; 1.7514mmol) and N; dinethylformamide (1) is handled 2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-propionic acid (preparation in according to embodiment 1,288.9mg, solution 0.8757mmol) in methylene dichloride (6mL).Mixture was stirred 2 hours in 25 ℃, at this moment, the vacuum concentration solvent, and residuum vacuum-drying spent the night.Then, residuum is dissolved in the benzene, and the vacuum concentration solvent, and the vacuum-drying residuum.This substance dissolves in methylene dichloride (4mL), is cooled to 0 ℃, be used in then 2-amino-5-methoxy ethoxy pyrazine in the methylene dichloride (5mL) (148mg, 0.8757mmol) and the solution-treated of pyridine (180 μ L).Remove ice bath, and solution is spent the night in 25 ℃ of stirrings.Then, vacuum concentration solvent.Flash chromatography (1.5/1 hexane/ethyl acetate) provides: 2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-5-(2-methoxy ethoxy-pyrazine-2-yl)-propionic acid amide (363mg, 86.2%) are soft solid: (ES)
+-HRMS m/e calculated value C
22H
28ClN
3O
5S (M+H)
+482.1511, actual measurement 482.1518.
Embodiment 44
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-2 (R), 3-dihydroxyl-propoxy-)-pyrazine-2-yl]-propionic acid amide
[000256] with 5-chloropyrazine-2-carboxylate methyl ester (1.7g, 10mmol) and vinyl carbinol (10mL, mixture heating up 147mmol) is stirred to 95 ℃, (1.3g 23mmol) handles with the potassium hydroxide of pulverizing then.In 10 minutes, thick thin pulp appears.Continue heating 2 hours.With the reaction mixture vacuum concentration to dry, and with residuum further (vacuum concentration is to drying 2 * 50mL) from toluene.Isolated 5-allyloxy-pyrazine-2-carboxylic acid sylvite (2.2g) is used under the condition that is not further purified and characterizes.
[000257] with 5-allyloxy-pyrazine-2-carboxylic acid sylvite (2.2g, 10mmol) with at N, (2.8mL 12.99mmol) merges the diphenylphosphine acylazide thing in the dinethylformamide (75mL), and suspended substance was stirred 18 hours in 25 ℃.The reaction mixture vacuum concentration that to clarify by stirring, and with ethyl acetate (50mL) and water (35mL) dilution residuum.With ethyl acetate (2 * 50mL) strip aqueous.Organic extract liquid with dried over sodium sulfate merges filters and vacuum concentration.Residuum is suspended in the trimethyl carbinol (25mL), and mixture heating up is refluxed, do not have gas to generate up to observing.Then, vacuum concentration solvent.Flash chromatography (Merck silica gel 60, the 230-400 order is with the mixture wash-out of ethyl acetate/hexane) provides: 5-allyloxy-pyrazine-2-base-t-butyl carbamate (480mg, 19%).
[000258] with 25% 5-allyloxy-pyrazine-2-base-t-butyl carbamate (400mg, 1.59mmol) the solution of solution-treated in methylene dichloride (2mL) of trifluoroacetic acid in methylene dichloride (5mL).Mixture in 25 ℃ of stirrings 90 minutes, is poured in the saturated sodium bicarbonate aqueous solution (50mL), add sodium-chlor (3g) then.(3 * 25mL) extract the mixture that obtains, and wash each organic extract liquid with the saturated sodium-chloride water solution of small portion with methylene dichloride.With the dry organic extract liquid that merges of salt of wormwood, filter and vacuum concentration, provide: 5-allyloxy-pyrazine-2-base amine (240mg, 100%) is light yellow crystal.
[000259] will be at methylene dichloride (15mL) and N; 2 (R) in the dinethylformamide (2)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-propionic acid are (according to preparation among the embodiment 1; 510mg; 1.54mmol) solution be cooled to 5 ℃; (0.27mL 3.09mmol) handles to use oxalyl chloride then.Stir after 5 minutes, remove cooling bath, and continue to stir 10 minutes in 25 ℃.Solvent removed in vacuo, and residuum is dissolved in the benzene (25mL), and vacuum concentration solvent once more.The acyl halide that obtains is dissolved in methylene dichloride (10mL), is cooled to 5 ℃, be used in then 5-allyloxy-pyrazine in the methylene dichloride (15mL)-2-base amine (238mg, 1.57mmol) and pyridine (0.32mL, solution-treated 3.96mmol).Mixture was further stirred 16 hours in 25 ℃.Then, use methylene dichloride (25mL) diluted reaction mixture, and wash with saturated sodium bicarbonate aqueous solution (25mL), 0.5M aqueous hydrochloric acid (25mL) and saturated sodium-chloride water solution (25mL).With the each water layer of another part methyl chloride (25mL) reextraction.With the organic phase that dried over sodium sulfate merges, filter and vacuum concentration.Flash chromatography (Merck silica gel 60; the 230-400 order; with the ethyl acetate/hexane wash-out that improves concentration gradually) provide: N-(5-allyloxy-pyrazine-2-yl)-2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-propionic acid amide, white foam (574mg, 80%).
[000260] water/trimethyl carbinol (10mL, solution-treated Tripotassium iron hexacyanide 1:1) (430mg, 1.3mmol), salt of wormwood (180mg, 1.3mmol) and (DHQ)
2PHAL (8mg, mixture 0.010mmol), and reaction mixture stirred 5 minutes in 25 ℃.Reaction mixture is cooled to 0 ℃; use 0.2M at toluene (20 μ L then; 0.004mmol) in the solution-treated of perosmic anhydride; then be used in water/trimethyl carbinol (3mL; N-1:1) (5-allyloxy-pyrazine-2-yl)-2 (R) (3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-propionic acid amide (210mg, solution-treated 0.452mmol).Multiphase mixture was stirred 5 minutes, and remove cooling bath, and continue to stir 2 hours.Then, when stirring, usefulness ethyl acetate (20mL) and sodium metabisulfite (150mg, 0.79mmol) treating mixture, and continue to stir 30 minutes.The color of reaction mixture becomes colorless from yellow, and the water of regulation occurs.Be separated, and water (25mL) dilution water, and (3 * 50mL) extract with ethyl acetate.With saturated sodium-chloride water solution (20mL) washing extract.With the organic phase that dried over sodium sulfate merges, filter and vacuum concentration.Flash chromatography (Merck silica gel 60; the 230-400 order; with the ethyl acetate/hexane wash-out that improves concentration gradually) provide: 2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-2 (R); 3-dihydroxyl-propoxy-)-pyrazine-2-yl]-propionic acid amide (110mg; 49%) white foam: (ES)
+-HRMS m/e calculated value C
22H
28ClN
3O
6S (M+H)
+498.1460, actual measurement 498.1462.Also obtain more impure a little material (75mg, 33%).
Embodiment 45
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(2,2-dimethoxy-ethyl)-pyrazine-2-yl]-propionic acid amide
[000261] with 5-(2-oxo-ethyl)-pyrazine-2-carboxylate methyl ester (according among the embodiment 42 preparation, 330mg, 1.83mmol), paratolunitrile monohydrate (35mg, 0.184mmol), trimethyl orthoformate (3mL, 137mmol) and the mixture heating up of methyl alcohol (10mL) refluxed 90 minutes.Vacuum concentrated mixture is to dry, and with residuum further from toluene (10mL) vacuum concentration to drying.Shake the residuum that obtains with methylene dichloride (25mL) and saturated sodium bicarbonate aqueous solution (10mL).With methylene dichloride (10mL) strip aqueous.With the each extraction liquid of saturated sodium-chloride water solution (5mL) washing.With the organic layer that dried over sodium sulfate merges, drying and vacuum concentration provide: 5-(2,2-dimethoxy-ethyl)-pyrazine-2-carboxylate methyl ester (325mg, 78%) is yellow oil.
[000262] (160mg 2.4mmol) handles at methyl alcohol/tetrahydrofuran (THF)/water (5mL, 3:3:1) 5-in the mixture (2,2-dimethoxy-ethyl)-pyrazine-2-carboxylate methyl ester (320mg, mixture 1.4mmol) with potassium hydroxide.After 60 minutes, the vacuum concentration solvent, and with residuum further (vacuum concentration 2 * 20mL) provides salt (380mg), is light brown solid, and it uses under the condition that is not further purified or characterizes from toluene.
[000263] with N, dinethylformamide (10mL), diphenylphosphine acylazide thing (0.45mL, 2.08mmol) and 5-(2,2-dimethoxy-ethyl)-pyrazine-2-carboxylic acid sylvite (380mg, suspension 1.4mmol) stirred 18 hours in 25 ℃.The reaction mixture vacuum concentration is extremely dry, and between ethyl acetate (50mL) and water (25mL), distribute residuum.Water (25mL) washing organic layer, and with the each water of another part ethyl acetate (25mL) reextraction.Organic extract liquid with dried over sodium sulfate merges filters and vacuum concentration, and provide: acid azide is orange oil (209mg).(160 μ L 1.54mmol) handle acid azide, and add heat power plant 5 minutes at 90 ℃ with benzylalcohol.(25C 1mmHg) vacuumizes 17 hours with vacuum pump with reaction mixture.Flash chromatography (Merck silica gel 60, the 230-400 order is with the gradient mixture wash-out of ethyl acetate/hexane) provides: 5-(2,2-dimethoxy-ethyl)-pyrazine-2-base-benzyl carbamate (132mg, 42%) is white solid.
[000264] handles 5-(2,2-dimethoxy-ethyl)-pyrazine-2-base-benzyl carbamate (130mg, solution 0.4096mmol) in methyl alcohol (5mL) with 10% at the palladium on the gac (30mg).With reaction mixture hydrogenation 60 minutes under 25 ℃ and atmospheric hydrogen atmosphere.By the diatomite filtration mixture, and the vacuum concentration filtrate, provide: 5-(2,2-dimethoxy-ethyl)-pyrazine-2-base amine (75mg, 100%) is light yellow oil.
[000265] will be at methylene dichloride (5mL) and N; (according to preparation among the embodiment 1,136mg, solution 0.41mmol) are cooled to 5 ℃ to 2 (R) in the dinethylformamide (2)-(3-chloro-4-methylsulfonyl-phenyl)-propionic acid; (75 μ L 0.86mmol) handle to use oxalyl chloride then.Mixture was stirred 5 minutes in 5 ℃, remove cooling bath, and with mixture restir 10 minutes.The vacuum concentration solvent.Residuum is dissolved in the benzene (10mL), and vacuum concentration solvent once more.The acyl halide that obtains is dissolved in the methylene dichloride (5mL), is cooled to 0 ℃, be used in then 5-(2,2-dimethoxy-ethyl)-pyrazine in the methylene dichloride (5mL)-2-base amine (75mg, 0.41mmol) and pyridine (85 μ L, solution-treated 1.05mmol).Reaction mixture in 0 ℃ of stirring 5 minutes, is removed cooling bath, and continue to stir 18 hours.With methylene dichloride (25mL) diluted mixture thing, and use saturated sodium bicarbonate aqueous solution (25mL), 0.5M aqueous hydrochloric acid and saturated sodium-chloride water solution (25mL) washing soln in succession.With the each water-washing liquid of the dichloromethane extraction of another small portion.Organic layer with dried over sodium sulfate merges filters, and vacuum concentration.Flash chromatography (Merck silica gel 60; the 230-400 order; with 1/3 to 1/1 ethyl acetate/hexane wash-out) provide: 2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(2,2-dimethoxy-ethyl)-pyrazine-2-yl]-propionic acid amide (120mg, 59%): (ES)
+-HRMS m/e calculated value C
23H
30ClN
3O
5S (M+H)
+496.1668, actual measurement 496.1672.
Embodiment 46
3-cyclopentyl-N-5-[(4-hydroxyl-tetrahydropyran-4-base-ethynyl) pyrazine-2-yl]-2 (R)-(4-methylsulfonyl-phenyl)-propionic acid amide
[000266] will (1.25g, solution 12.5mmol) be cooled to 0 ℃, use 0.5M in tetrahydrofuran (THF) (40mL, 20mmol) solution-treated of the protobromide magnesium ethide in then at the tetrahydro pyrone in the tetrahydrofuran (THF) (10mL).Mixture was stirred 2 hours in 0 ℃, and stirred 4 hours in 25 ℃.The mixture that obtains is cooled to 0 ℃, uses methyl alcohol (10ml) dilution then.The vacuum concentration solvent, and with saturated aqueous ammonium chloride and ethyl acetate extraction residuum.Wash organic layer with saturated sodium-chloride water solution, use dried over sodium sulfate, filter and vacuum concentration.The vacuum concentration residuum provides: solid 4-ethynyl-tetrahydrochysene-pyrans-4-alcohol (1.2g, 95.2%).
Use N; N-diisopropylethylamine (2mL), 4-ethynyl-tetrahydrochysene-pyrans-4-alcohol (252mg; 2.0mmol), dichloro two (triphenyl phosphine) palladium (II) (40mg) and cuprous iodide (I) (20mg) handle (preparation in according to embodiment 3 of 2 (R)-(4-methylsulfonyl-phenyl)-3-cyclopentyl-5-bromo-pyrazine-2-base-propionic acid amide in toluene (8mL); 452mg, suspension 1.0mmol).Mixture is spent the night in 25 ℃ of stirrings, and obtain the oily black precipitate.The clear liquid on decantation top, and at first use toluene (8ml) rinsing oily throw out, use hexane/ethyl acetate (2 * 8mL, 4:1) rinsing then.Residuum is dissolved in the methylene dichloride, and extracts with methylene dichloride and 0.2N aqueous hydrochloric acid.Wash organic layer with saturated sodium-chloride water solution, use dried over sodium sulfate, filter and vacuum concentration.Flash chromatography (ethyl acetate) provides: 3-cyclopentyl-N-5-[(4-hydroxyl-tetrahydropyran-4-base-ethynyl) pyrazine-2-yl]-2 (R)-(4-methylsulfonyl-phenyl)-propionic acid amide (390mg, 78.5%), be soft solid: (ES)
+-HRMS m/e calculated value C
26H
31N
3O
5S (M+H)
+498.2057, actual measurement 498.2063.
Embodiment 47
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(3-methoxyl group-third-1-alkynyl)-pyrazine-2-yl]-propionic acid amide
[000268] under 0 ℃, nitrogen, (5.80g 32.6mmol) handles triphenyl phosphine (8.57g, stirred solution 32.6mmol) in anhydrous methylene chloride (110mL) with N-bromo-succinimide.After 15 minutes, in reaction mixture, add 2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-propionic acid (9.00g, 27.2mmol).Mixture is warmed to 25 ℃.After 10 minutes, (7.92g 45.6mmol), then uses pyridine (8.79mL, 108.8mmol) reaction mixture with 2-amino-5-bromo-pyrazine in 25 ℃ of stirrings.Stirred the mixture 1.5 hours in 25 ℃.At this moment, use the methylene dichloride diluted reaction mixture, use 1N aqueous hydrochloric acid (200mL) then, then wash with 10% wet chemical (100mL).Use the dried over sodium sulfate organic layer, filter and vacuum concentration.Flash chromatography (Merck silica gel 60, the 70-230 order, 30% ethyl acetate/hexane) provides: N-(5-bromo-pyrazine-2-yl)-2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-propionic acid amide (10.02g, 76%), white foam: mp77-82 ℃ (foam is to gel); (ES)
+-HRMS m/e calculated value C
19H
21BrClN
3O
3S (M+H)
+486.0249, actual measurement 486.0255.
[000269] uses N; N-diisopropylethylamine (2mL), 3-methoxyl group propine (350mg; 10.0mmol), dichloro two (triphenyl phosphine) palladium (II) (40mg) and cuprous iodide (I) (20mg) handle N-(5-bromo-pyrazine-2-yl)-2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-propionic acid amide (486mg, suspension 1.0mmol) in toluene (8mL).Mixture is spent the night in 25 ℃ of stirrings, and obtain the oily black precipitate.The clear liquid on decantation top, and with toluene (4ml) rinsing oily throw out.Residuum is dissolved in the methylene dichloride, and extracts with methylene dichloride and 0.2N aqueous hydrochloric acid.Wash organic layer with saturated sodium-chloride water solution, use dried over sodium sulfate, filter and vacuum concentration.Flash chromatography (1/3 to 1/2 ethyl acetate/from alkane) provide: 2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(3-methoxyl group-third-1-alkynyl)-pyrazine-2-yl]-propionic acid amide (330mg, 69.5%), be soft solid: (ES)
+-HRMSm/e calculated value C
23H
26ClN
3O
4S (M+H)
+476.1406, actual measurement 476.1405.
Embodiment 48
3-cyclopentyl-2 (R)-(4-methylsulfonyl-phenyl)-N-[5-(3-methoxy propyl-1-alkynyl)-pyrazine-2-yl]-propionic acid amide
[000270] uses N; N-diisopropylethylamine (2mL), 3-methoxyl group propine (700mg; 10.0mmol), dichloro two (triphenyl phosphine) palladium (II) (40mg) and cuprous iodide (I) (20mg) handle (preparation in according to embodiment 3 of 2 (R)-(4-methylsulfonyl-phenyl)-3-cyclopentyl-5-bromo-pyrazine-2-base-propionic acid amide in toluene (8mL); 452mg, suspension 1.0mmol).Mixture is spent the night in 25 ℃ of stirrings, and obtain the oily black precipitate.The clear liquid on decantation top, and at first use toluene (8ml) rinsing oily throw out, use hexane/ethyl acetate (2 * 8mL, 8:1) rinsing then.Residuum is dissolved in the methylene dichloride, and extracts with methylene dichloride and 0.2N aqueous hydrochloric acid.Wash organic layer with saturated sodium-chloride water solution, use dried over sodium sulfate, filter and vacuum concentration.Flash chromatography (1/2 ethyl acetate/hexane) provides: 3-cyclopentyl-2 (R)-(4-methylsulfonyl-phenyl)-N-[5-(3-methoxy propyl-1-alkynyl)-pyrazine-2-yl]-propionic acid amide (217mg, 49.2%), be soft solid: (ES)
+-HRMS m/e calculated value C
23H
27N
3O
4S (M+H)
+442.1795, actual measurement 442.1800.
Embodiment 49
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-2 (S), 3-dihydroxyl-propoxy-)-pyrazine-2-yl]-propionic acid amide
[000271] water/trimethyl carbinol (10mL, solution-treated Tripotassium iron hexacyanide 1:1) (430mg, 1.3mmol), salt of wormwood (180mg, 1.3mmol) and (DHQD)
2PHIAL (8mg, mixture 0.010mmol), and reaction mixture stirred 5 minutes in 25 ℃.Reaction mixture is cooled to 0 ℃; use 0.2M at toluene (20 μ L then; 0.004mmol) in the solution-treated of perosmic anhydride; then be used in water/trimethyl carbinol (3mL; N-1:1) (5-allyloxy-pyrazine-2-yl)-2 (R) (3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-propionic acid amide are (according to preparation among the embodiment 44; 210mg, mixture process 0.452mmol).Non-homogeneous mixture was stirred 5 minutes, remove cooling bath, and continue to stir 2 hours.Then, when stirring, usefulness ethyl acetate (20mL) and sodium metabisulfite (150mg, 0.79mmol) treating mixture, and continue to stir 30 minutes.The color of reaction mixture is become colorless by yellow, and the water of regulation occurs.Be separated, and water (25mL) dilution water, and (3 * 50mL) extract with ethyl acetate.With saturated sodium-chloride water solution (20mL) washing extraction liquid.With the organic phase that dried over sodium sulfate merges, filter and vacuum concentration.Flash chromatography (Merck silica gel 60; the 230-400 order; with the ethyl acetate/hexane wash-out that improves concentration gradually) provide: 2 impure (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-2 (S); 3-dihydroxyl-propoxy-)-pyrazine-2-yl]-propionic acid amide (80mg), white foam.Purifying once more under the same conditions provides: 2 pure (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-2 (S), 3-dihydroxyl-propoxy-)-pyrazine-2-yl]-propionic acid amide (40mg, 18.6%), be colourless foam: (ES)
+-HRMS m/e calculated value C
22H
28ClN
3O
6S (M+H)
+498.1460, actual measurement 498.1468.
Embodiment 50
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(4-hydroxyl-tetrahydropyran-4-base-ethynyl)-pyrazine-2-yl]-propionic acid amide
[000272] uses N; N-diisopropylethylamine (2mL), 4-ethynyl-tetrahydropyrans-4-alcohol are (according to preparation among the embodiment 46; 252mg; 2.0mmol), cuprous iodide (I) (20mg) and dichloro two (triphenyl phosphine) palladium (II) (40mg) handles N-(5-bromo-pyrazine-2-yl)-2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-propionic acid amide in toluene (8mL) and (prepares in according to embodiment 47; 486mg, suspension 1.0mmol).Mixture is spent the night in 25 ℃ of stirrings, and obtain the oily black precipitate.The clear liquid on decantation top, and at first use toluene (5ml) rinsing oily throw out, use hexane (5mL) rinsing then.Residuum is dissolved in the methylene dichloride, and extracts with methylene dichloride and 0.2N aqueous hydrochloric acid.Wash organic layer with saturated sodium-chloride water solution, use dried over sodium sulfate, filter and vacuum concentration.Flash chromatography (2/1 ethyl acetate/hexane) provides: 2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(4-hydroxyl-tetrahydropyran-4-base-ethynyl)-pyrazine-2-yl]-propionic acid amide (474mg; 89.3%), is soft solid: (ES)
+-HRMS m/e calculated value C
23H
30ClN
3O
4S (M+H)
+532.1668, actual measurement 532.1675.
Embodiment 51
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(4-hydroxyl-tetrahydropyran-4-base-ethyl)-pyrazine-2-yl]-propionic acid amide
[000273] handle 2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(4-hydroxyl-tetrahydropyran-4-base-ethynyl)-pyrazine-2-yl in methyl alcohol (30mL) with 10% palladium on gac (39mg)]-propionic acid amide (preparation in according to embodiment 50; 200mg, solution 0.376mmol).Under the hydrogen atmosphere of 50psi, reaction mixture was placed 4 hours in the Parr wobbler.Filtering mixt, and vacuum concentration solvent.Flash chromatography (ethyl acetate) provides: 2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(4-hydroxyl-tetrahydropyran-4-base-ethyl)-pyrazine-2-yl]-propionic acid amide (169mg, 84%), be soft solid: (ES)
+-HRMS m/e calculated value C
26H
34ClN
3O
5S (M+H)
+536.1981, actual measurement 536.1988.
Embodiment 52
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(3-hydroxy-3-methyl-Ding-1-alkynyl)-pyrazine-2-yl]-propionic acid amide
[000274] uses N; N-diisopropylethylamine (2mL), 3-hydroxy-3-methyl butine (168mg; 2.0mmol), dichloro two (triphenyl phosphine) palladium (II) (40mg) and cuprous iodide (I) (20mg) handle (preparation in according to embodiment 47 of N-(5-bromo-pyrazine-2-yl)-2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-propionic acid amide in toluene (8mL); 486mg, suspension 1.0mmol).Mixture is spent the night in 25 ℃ of stirrings, and obtain the oily black precipitate.The clear liquid on decantation top, and at first use toluene (5ml) rinsing oily throw out, use hexane (5mL) rinsing then.Residuum is dissolved in the methylene dichloride, and extracts with methylene dichloride and 0.2N aqueous hydrochloric acid.Wash organic layer with saturated sodium-chloride water solution, use dried over sodium sulfate, filter and vacuum concentration.Flash chromatography (with 1/1 ethyl acetate/hexane wash-out) provides: 2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(3-hydroxy-3-methyl-Ding-1-alkynyl)-pyrazine-2-yl]-propionic acid amide (412mg; 84%), is soft solid: (ES)
+-HRMS m/e calculated value C
24H
28ClN
3O
4S (M+H)
+490.1562, actual measurement 490.1553.
Embodiment 53
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(4-hydroxyl-Ding-1-alkynyl)-pyrazine-2-yl]-propionic acid amide
[000275] uses N; N-diisopropylethylamine (2mL), 4-hydroxyl butine (210mg; 3.0mmol), dichloro two (triphenyl phosphine) palladium (II) (60mg) and cuprous iodide (I) (30mg) handle (preparation in according to embodiment 47 of N-(5-bromo-pyrazine-2-yl)-2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-propionic acid amide in toluene (8mL); 729mg, suspension 1.5mmol).Mixture is spent the night in 25 ℃ of stirrings, and obtain the oily black precipitate.The clear liquid on decantation top, and at first use toluene (5ml) rinsing oily throw out, use hexane (5mL) rinsing then.Residuum is dissolved in the methylene dichloride, and extracts with methylene dichloride and 0.2N aqueous hydrochloric acid.Wash organic layer with saturated sodium-chloride water solution, use dried over sodium sulfate, filter and vacuum concentration.Flash chromatography (with 1/1 ethyl acetate/hexane wash-out) provides: 2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(4-hydroxyl-Ding-1-alkynyl)-pyrazine-2-yl]-propionic acid amide (650mg, 88.4%), be soft solid: (ES)
+-HRMS m/e calculated value C
23H
26ClN
3O
4S (M+H)
+476.1406, actual measurement 476.1395.
Embodiment 54
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(1 (S), 2-dihydroxyl-ethyl)-pyrazine-2-yl]-propionic acid amide
[000276] this compound prepares by linear synthetic (method A) and convergent synthesis (method B).Method A:
[000277] with four (triphenyl phosphine) palladium (0) (66mg, 0.06mmol), N, N-diisopropylethylamine (1.25mL, 7.18mmol), lithium chloride (426mg, 0.06mmol) and vinyl three positive fourth tin (840 μ L 2.87mmol) handle at N the 2-amino in the dinethylformamide (15mL)-5-bromo-pyrazine (500mg, 2.87mmol) solution, and with reaction mixture in 120 ℃ the heating 4 hours.After this, reaction mixture is cooled to 25 ℃, and handles, and spent the night 16 hours in 25 ℃ of stirrings with saturated potassium fluoride aqueous solution (10mL).Then, with methylene dichloride (25mL) diluting soln, and methylene dichloride (3 * 15mL) extractions.Organic layer with dried over sodium sulfate merges filters, and vacuum concentration.Biotage chromatogram (FLASH40S, silicon-dioxide, 40/60 to 20/80 hexane/ethyl acetate) provides: 2-amino-5-vinylpyrazine (211mg, 61%) is faint yellow solid: EI-HRMS m/e calculated value C
6H
7N
3(M
+) 121.0640, actual measurement 121.0642.
[000278] 2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-propionic acid in methylene dichloride (7mL) (is prepared in according to embodiment 1; 470mg; 1.42mmol) solution be cooled to 0 ℃; and with 2.0M at methylene dichloride (817 μ L; 1.63mmol) and N, the oxalyl chloride solution-treated in the dinethylformamide (1mL).Reaction mixture was stirred 30 minutes in 0 ℃, vacuum concentration, and with methylene dichloride (3 * 2mL) azeotropic.The oil that obtains is dissolved in 25 ℃ the tetrahydrofuran (THF) (10mL), then by feed hopper, be used in 2-amino-5-vinylpyrazine in the tetrahydrofuran (THF) (8mL) (207mg, 1.71mmol) and 2,6-lutidine (198 μ L, solution-treated 1.71mmol).Then, the turbid solution that obtains was spent the night 16 hours in 25 ℃ of stirrings.After this, water (10mL) diluted reaction mixture is used methylene dichloride (3 * 25mL) extractions then.Organic layer with dried over sodium sulfate merges filters, and vacuum concentration.Biotage chromatogram (FLASH 40S; silicon-dioxide; 65/35 to 20/80 hexane/ethyl acetate) provide: 2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-vinyl-pyrazine-2-yl)-propionic acid amide (472mg, 77%) are faint yellow solid: (ES)
+-HRMS m/e calculated value C
21H
24ClN
3O
3S (M+H)
+434.1300, actual measurement 434.1301.
[000279] water/trimethyl carbinol (10mL, solution-treated Tripotassium iron hexacyanide 1:1) (375mg, 1.14mmol), salt of wormwood (160mg, 1.16mmol), and (DHQ)
2PHAL (7mg, mixture 0.00898mmol), and in 25 ℃ of stirrings 5 minutes.Reaction mixture is cooled to 0 ℃; use 0.2M at toluene (17 μ L then; 0.0034mmol) in the perosmic anhydride solution-treated; then be used in water/trimethyl carbinol (2mL; 1:1) 2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-vinyl-pyrazine-2-yl)-propionic acid amide (175mg, mixture process 0.374mmol).Non-homogeneous mixture was stirred 10 minutes, and remove cooling bath.After 30 minutes, undissolved vinyl substrate is arranged still, and in reaction mixture, add the trimethyl carbinol (2mL) of amount in addition.Continue to stir 18 hours.Then, when stirring, usefulness ethyl acetate (20mL) and sodium metabisulfite (150mg, 0.79mmol) treating mixture, and continue to stir 15 minutes.Be separated, and (2 * 25mL) wash organic layers with saturated sodium-chloride water solution.With the each water of ethyl acetate (25mL) reextraction.Organic layer with dried over sodium sulfate merges filters, and vacuum concentration.Flash chromatography (Merck silica gel 60; the 230-400 order; 1/3 to 1/1 ethyl acetate/hexane) provide: 2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(1 (S), 2-hydroxyl-ethyl)-pyrazine-2-yl]-propionic acid amide (50mg), be colourless foam: (ES)
+-HRMS m/e calculated value C
21H
26ClN
3O
5S (M+H)
+468.1355, actual measurement 468.1360.
Method B:
[000280] will the 2-amino-5-bromo-pyrazine in the methylene dichloride (144mL) (10.00g, 57.47mmol) and pyridine (5.6mL, solution 68.96mmol) are cooled to 0 ℃, and (8.6mL 68.96mmol) handles to use trimethyl-acetyl chloride then at leisure.The reaction mixture that obtains was stirred 30 minutes in 0 ℃, be warmed to 25 ℃ then, it was stirred 18 hours in this temperature.At this moment, reaction mixture still contains raw material 2-amino-5-bromo-pyrazine.(4.3mL, 34.48mmol) reaction mixture stirred 4 hours in 25 ℃ then with the trimethyl-acetyl chloride of other amount.Then, the vacuum concentration reaction mixture is to remove methylene dichloride.Dilute the residuum that obtains with ethyl acetate (700mL).With the 1N aqueous hydrochloric acid (2 * 200mL) and saturated sodium-chloride water solution (1 * 200mL) washing organic layer, use dried over sodium sulfate, the filtration and vacuum concentration.Biotage chromatogram (FLASH 65M, silicon-dioxide, 10% ethyl acetate/hexane) provides: N-(5-bromo-pyrazine-2-yl)-2, and 2-dimethyl-propionic acid amide (12.19g, 82%) is white solid: mp 122-124 ℃; (ES)
+-HRMS m/e calculated value C
9H
12BrN
3O (M+H)
+258.0237, actual measurement 258.0240.
[000281] will be at the N-in the ethanol (245mL) (5-bromo-pyrazine-2-yl)-2,2-dimethyl-propionic acid amide (29.67g, 114.9421mmol), dichloro [1,1 '-two (diphenylphosphino) ferrocene] palladium (II) methylene dichloride affixture (0.95g, 1.1633mmol), triethylamine (17.6mL, 126.2733mmol) and vinyl three potassium fluoborates (19.25g, 143.7103mmol) mixture in 100 ℃ the heating 90 minutes.At this moment, reaction mixture is cooled to 25 ℃, then vacuum concentration.Dilute the orange thin pulp that obtains with methylene dichloride (200mL).With the 1N aqueous hydrochloric acid (2 * 200mL), saturated sodium bicarbonate aqueous solution (1 * 200mL) and saturated sodium-chloride water solution (1 * 200mL) washing organic layer.With magnesium chloride and the dry organic layer that merges of decolorizing charcoal, filter and vacuum concentration.Biotage chromatogram (FLASH 75S, silicon-dioxide, 100% hexane to 10% ethyl acetate/hexane) provides: 2, and 2-dimethyl-N-(5-vinyl-pyrazine-2-yl)-propionic acid amide (21.64g, 92%) is pale solid: mp 80.4-81.8 ℃; EI-HRMS m/e calculated value C
11H
15N
3O (M
+) 205.1215, actual measurement 205.1214.
[000282] water/trimethyl carbinol (2L, solution-treated Tripotassium iron hexacyanide 1:1) (148.74g, 450mmol), salt of wormwood (62.25g, 450mmol) and (DHQ)
2PHAL (2.6g, solution 3.34mmol), and reaction mixture stirred 15 minutes in 25 ℃.Reaction mixture is cooled to 5 ℃, with 0.2M at toluene (7.5mL, 1.5mmol) in the solution-treated of perosmic anhydride, then with partly being dissolved in water/trimethyl carbinol (150mL, 1:1) 2, (30.8g 150mmol) handles 2-dimethyl-N-(5-vinyl-pyrazine-2-yl)-propionic acid amide.By using Neslab Endocal cooling system controlled temperature, mixture was stirred 18 hours in 4-5 ℃.In the time of 4-5 ℃ of stirring, so (35g 184mmol) handles at leisure, causes foaming with sodium metabisulfite.Remove cooling bath, and continue to stir 15 minutes.Layer separates, and with ethyl acetate (600mL) aqueous phase extracted.With the each organic layer of saturated sodium-chloride water solution (500mL) washing.Organic layer with dried over sodium sulfate merges filters, and vacuum concentration, provides: N-[5-(1 (S), 2-dihydroxyl-ethyl) pyrazine-2-yl]-2,2-dimethyl-propionic acid amide (46g, 100%) is reddish oil, it uses under the condition that is not further purified.
[000283] with 2,2-Propanal dimethyl acetal (225mL, 1.88mol) and paratolunitrile monohydrate (3.4g, 17.9mmol) N-[5-(1 (S) of processing in tetrahydrofuran (THF) (275mL), 2-dihydroxyl-ethyl)-and pyrazine-2-yl]-2,2-dimethyl propylene acid amides (46g, moistening a little by solvent ,～170mmol) solution.In 25 ℃ of stirrings 16.5 hours, at this moment, thin-layer chromatography shows to react to be finished, and generates lower polar product with reaction mixture.The vacuum concentration reaction mixture, and residuum is dissolved in the methylene dichloride (600mL).With saturated sodium-chloride water solution (250mL) and saturated sodium bicarbonate aqueous solution (250mL) washing organic layer.With the each water layer of methylene dichloride (250mL) reextraction.Stir the organic layer that merges with sodium sulfate (35mg) and Norit A charcoal (8g), filter by Celite pad then.With the weight of filtrate vacuum concentration to about 250g.(300mL) handles this material with diethyl ether, and once more with the weight of mixture vacuum concentration to about 250g, at this moment, the beginning crystallization.Mixture was stored 4 hours in refrigerator (4 ℃) and filtered.Drying solid is 16 hours in 30 ℃ vacuum oven, provides: white crystal (32.3g, 68%), mp 144-144.5 ℃.To the collection of another batch product, provide white crystal (9.5g, 20%) from mother liquor, its purity is comparable to first degree of purity of production.High performance liquid chromatography indication with chiral column: compare with real racemize sample, two batches of products all are 100%ee.Merge two batches of products, provide: needed N-[5-((S)-2,2-dimethyl-[1,3] dioxolane-4-yl)-pyrazine-2-yl]-2,2-dimethyl-propionic acid amide.
[000284] will be in N-[5-((S)-2 in the methyl alcohol (150mL), 2-dimethyl-[1,3] dioxolane-4-yl)-and pyrazine-2-yl]-2,2-dimethyl-propionic acid amide (8.4g, 30.7mmol) and salt of wormwood (4.32g, 31.2mmol) solution stirred 16.5 hours in 25 ℃, at this moment, the thin-layer chromatography indicating section changes higher polar product into.Avoiding in the epimeric effort that three-dimensional center (stereogenic center) locates, before finishing, no longer continuing reaction.Therefore, under 25 ℃ decompression, remove and desolvate.With the residuum that obtains vacuum concentration from ethyl acetate (50mL) once more.This material uses Biotage chromatogram (FLASH 40L, silicon-dioxide, ethyl acetate) to come purifying.It is white solid (2.0g, 24%) that the initial stage fraction of collecting can reclaim the new acyl group acid amides of unreacted raw material.The fraction in vacuum concentration later stage provides: 5-((S)-2,2-dimethyl-[1,3] dioxolane-4-yl)-pyrazine-2-base amine (3.7g, 63%) is light yellow oil.High performance liquid chromatography indication 100%ee with chiral column.
[000285] 2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-propionic acid in methylene dichloride (70mL) (is prepared in according to embodiment 1; 6.29g; 19.01mmol) and N; the solution of dinethylformamide (2) is in 2 ℃ of stirrings; (4.15mL 45.7mmol) handles to use oxalyl chloride then.Mixture was stirred 5 minutes in 2 ℃, and stirred 15 minutes in 25 ℃.Then, vacuum concentration reaction mixture.Residuum is dissolved in benzene (25mL), and repeated evaporation.The acyl halide that obtains is dissolved in the methylene dichloride (40mL); be cooled to 0 ℃; use ((S)-2 then by 5-; 2-dimethyl-[1; 3] dioxolane-4-yl)-pyrazine-2-base amine (3.65g; 18.95mmol), pyridine (4.6mL, 56.9mmol) and the solution-treated formed of methylene dichloride (40mL).Not replenishing under the condition of cooling bath, mixture was stirred 16 hours.Then, with 1N aqueous hydrochloric acid (100mL) reaction mixture.Layer separates, and with methylene dichloride (75mL) aqueous layer extracted.With saturated sodium bicarbonate aqueous solution (100mL) and saturated sodium-chloride water solution washing organic layer, filter, and vacuum concentration.Biotage chromatogram (FLASH 40L; silicon-dioxide; 1/1 ethyl acetate/hexane) provides: 2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-((S)-2; 2-dimethyl-[1; 3] dioxolane-4-yl)-pyrazine-2-yl]-propionic acid amide (8.9g; 92%) white foam: (ES)
+-HRMS m/e calculated value C
24H
30ClN
3O
5S (M+H)
+508.1668, actual measurement 508.1671.
[000286] with 2 (Rs)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-((S)-2 of 1N aqueous hydrochloric acid (50mL) processing in tetrahydrofuran (THF) (50mL); 2-dimethyl-[1; 3] dioxolane-4-yl)-pyrazine-2-yl]-propionic acid amide (8.85g, solution 17.4mmol).In 25 ℃ of stirrings, and in 15 minutes, it is clear that the emulsus reaction mixture becomes with the emulsus reaction mixture that obtains.Continuing at 25 ℃ stirred 16 hours.The vacuum concentration reaction mixture, and with methylene dichloride (1 * 100mL, then 2 * 50mL) extraction residuums.With saturated sodium bicarbonate aqueous solution (50mL) and the each organic extract liquid of saturated sodium-chloride water solution (50mL) washing.Organic layer with dried over sodium sulfate merges filters, and vacuum concentration.Biotage chromatogram (FLASH 40L; silicon-dioxide; 1/1 ethyl acetate/hexane; 100% ethyl acetate then) provides: 2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(1 (S); 2-dihydroxyl-ethyl)-pyrazine-2-yl]-propionic acid amide (7.15g; 88%), is colourless foam: (ES)
+-HRMS m/e calculated value C
21H
26ClN
3O
5S (M+H)
+468.1355, actual measurement 468.1360.
Embodiment 55
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-1 (R), 2-dihydroxyl-ethyl)-pyrazine-2-yl]-propionic acid amide
[000287] water/trimethyl carbinol (10mL, solution-treated Tripotassium iron hexacyanide 1:1) (365mg, 1.10mmol), salt of wormwood (155mg, 1.12mmol) and (DHQD)
2PHAL (7mg, mixture 0.00898mmol), and reaction mixture stirred 5 minutes in 25 ℃.Reaction mixture is cooled to 0 ℃; use 0.2M at toluene (17 μ L then; 0.0034mmol) in the perosmic anhydride solution-treated; then be used in water/trimethyl carbinol (2mL; 1:1) 2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-vinyl-pyrazine-2-yl)-propionic acid amide (175mg, mixture process 0.374mmol).Stir non-homogeneous mixture, remove cooling bath, and continue to stir 18 hours.Then, when stirring, usefulness ethyl acetate (20mL) and sodium metabisulfite (150mg, 0.79mmol) treating mixture, and continue to stir 15 minutes.Be separated, and (2 * 25mL) wash organic layers with saturated sodium-chloride water solution.With the each water of ethyl acetate (25mL) reextraction.Organic layer with dried over sodium sulfate merges filters, and vacuum concentration.Flash chromatography (Merck silica gel 60; the 230-400 order; 1/3 ethyl acetate/hexane to 100% ethyl acetate) provides: 2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(1 (S); 2-dihydroxyl-ethyl)-pyrazine-2-yl]-propionic acid amide (65mg), be colourless foam: (ES)+-HRMS m/e calculated value C
21H
26ClN
3O
5S (M+H)
+468.1355, actual measurement 468.1359.
Embodiment 56
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(2-hydroxyl-1-methylol-oxyethyl group)-pyrazine-2-yl]-propionic acid amide
[000288] with 1,3-benzyloxy-2-propyl alcohol (2.06g, 7.57mmol), the inferior phosphonyl chloride (1.61g of two (2-oxos-3-oxazolidinyl), 6.34mmol) and triethylamine (1.83mL, 12.66mmol) 5-chloro-pyrazine-2-carboxylic acid (according to embodiment 29 in the preparation of processing in methylene dichloride (30mL), 1.00g, suspension 6.33mmol).Mixture is spent the night in 25 ℃ of stirrings.With methylene dichloride and saturated sodium bicarbonate solution extraction solution.Water, saturated sodium-chloride water solution, 1N hydrochloric acid soln and saturated sodium-chloride water solution washing organic layer.Use the dried over sodium sulfate organic layer, filter and vacuum concentration.Biotage chromatogram (FLASH 40L, silicon-dioxide, 3/1 hexane/ethyl acetate) provides: 5-chloropyrazine-2-carboxylic acid 2-benzyloxy-1-benzyloxymethyl-ethyl ester (1.45g, 55.7%) is water white oil.
[000289] with sodium hydride (60% is dispersed in the mineral oil, 0.345g, 8.62mmol) handle in anhydrous tetrahydro furan (30mL) 1,3-benzyloxy-2-propyl alcohol (2.815g, solution 10.35mmol).Solution in 0 ℃ of stirring 10 minutes, was stirred 2 hours in 25 ℃ then.Then, be used in 5-chloropyrazine-2-carboxylic acid 2-benzyloxy-1-benzyloxymethyl-ethyl ester (1.43g, solution-treated reaction mixture 3.45mmol) in the anhydrous tetrahydro furan (10mL).In 25 ℃ of stirrings 1 hour, reflux was 2 hours then with mixture.The vacuum concentration reaction mixture is suspended in residuum in water (30mL) and the 1N aqueous sodium hydroxide solution (5mL).With this mixture heating up to 80 ℃, in this temperature it was stirred 3 hours, at this moment, thin-layer chromatography is indicated incomplete hydrolysis, thus add other tetrahydrofuran (THF) (10mL) and methyl alcohol (10mL), and with mixture heating up backflow 6 hours, be hydrolyzed up to ester.The vacuum concentration reaction mixture, and residuum is suspended in the water (100mL).Extract mixture with diethyl ether.With 1N aqueous hydrochloric acid acidifying water layer, and extract with diethyl ether.The vacuum concentration organic layer provides: 5-[(2-benzyloxy-1-benzyloxymethyl)-and oxyethyl group-pyrazine]-2-carboxylic acid (440mg, 32%), be a kind of oil.
[000290] with diphenylphosphine acylazide thing (0.24ml, 1.11mmol) and triethylamine (0.16ml, 1.11mmol) the 5-[(2-benzyloxy-1-benzyloxymethyl of processing in the trimethyl carbinol (5mL))-oxyethyl group-pyrazine]-2-carboxylic acid (0.44g, solution 1.11mmol).In 25 ℃ of stirrings 30 minutes, reflux was 5 hours then with mixture.Then, the vacuum concentration reaction mixture, and with methylene dichloride and 0.1N aqueous hydrochloric acid extraction residuum.Saturated sodium-chloride water solution and saturated sodium bicarbonate aqueous solution washing organic layer, vacuum concentration then.Biotage chromatogram (FLASH 40S, silicon-dioxide, 4/1 hexane/ethyl acetate) provides [5-(2-benzyloxy-1-benzyloxymethyl-oxyethyl group)-pyrazine-2-yl]-t-butyl carbamate (163.2mg, 31.4%), is light yellow oil.
[000291] use trifluoroacetic acid (1mL) to handle the solution of [5-(2-benzyloxy-1-benzyloxymethyl-oxyethyl group)-pyrazine-2-yl]-t-butyl carbamate (163mg) in methylene dichloride (4mL).Mixture is spent the night in 25 ℃ of stirrings, then vacuum concentration.With methylene dichloride and saturated sodium bicarbonate aqueous solution extraction residuum.Use the dried over sodium sulfate organic layer, filter and vacuum concentration, provide: 2-amino-5-[(2-benzyloxy-1-benzyloxymethyl)-oxyethyl group]-pyrazine, be a kind of oil (111mg).
[000292] (55 μ L, 0.6122mmol) and N, dinethylformamide (1) is handled 2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-propionic acid (101mg, solution 0.3061mmol) in methylene dichloride (3mL) with oxalyl chloride.Mixture was stirred 2 hours in 25 ℃, then vacuum concentration.The vacuum-drying residue is spent the night.Then, residuum is dissolved in the benzene vacuum concentration solvent.With the residuum vacuum-drying that obtains.This substance dissolves in methylene dichloride (4mL), is cooled to 0 ℃, is used in the 2-amino-5-[(2-benzyloxy-1-benzyloxymethyl in the methylene dichloride (2mL) then)-oxyethyl group]-pyrazine (111mg, 0.3041mmol) and the solution-treated of pyridine (50 μ L).Remove ice bath, and solution is spent the night in 25 ℃ of stirrings.With methylene dichloride and 0.2N aqueous hydrochloric acid extraction mixture.Wash organic layer with saturated sodium-chloride water solution, use dried over sodium sulfate, filter and vacuum concentration.Flash chromatography (using 2/1 hexane/ethyl acetate) provides: N-[5-(2-benzyloxy-1-benzyloxymethyl) oxyethyl group-pyrazine-2-base-2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-propionic acid amide (179.3mg, 87%) is a kind of oil.
[000293] with 10% solution at N-[5-(2-benzyloxy-1-benzyloxymethyl) oxyethyl group-pyrazine-2-base-2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-propionic acid amide (179mg) of the processing of the palladium on the gac (105mg) in methyl alcohol (30mL) and tetrahydrofuran (THF) (2mL).Then, under the hydrogen atmosphere of 50psi, reaction mixture was placed 5 hours in the Parr wobbler, up to consuming all raw materials.LC-MS indicates the by product (ratio of 5:1) of needed product and dechlorination.The isolating top condition of the thin-layer chromatography of two kinds of compounds is ethyl acetate/hexane/Virahol (20:5:1), and wherein the Rf value is 0.27 and 0.21.Use high performance liquid chromatography (dibasic alcohol post; use the ethyl acetate in hexane of 40% to 90% linear gradient; in 20 minutes) come the thick material of purifying; first kind of compound of wash-out provides: 2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(2-hydroxyl-1-methylol-oxyethyl group)-pyrazine-2-yl]-propionic acid amide, be colourless foam: (ES)
+-HRMS m/e calculated value C
22H
28ClN
3O
6S (M+H)
+498.1460, actual measurement 498.1451.
Embodiment 57
3-cyclopentyl-N-[5-(3-hydroxy-3-methyl-Ding-1-alkynyl)-pyrazine-2-yl]-2 (R)-(4-methylsulfonyl-3-methyl-phenyl)-propionic acid amide
[000294] (22g 159mmol), then uses methyl iodide (16mL, 257mmol) positive thiocresol (5g, 40mmol) the solution of processing in acetone (50mL) with salt of wormwood.Liberated heat guarantees elevated temperature (～38-40 ℃).The reaction mixture that obtains was stirred 17 hours in 25 ℃.The vacuum concentration reaction mixture, and methylene dichloride (100mL) and saturated sodium-chloride water solution (50mL) shake residuum.With methylene dichloride (50mL) strip aqueous.Use saturated sodium-chloride water solution (25mL) washing organic phase once more.Organic layer with dried over mgso merges filters and vacuum concentration, and provide: 1-methyl-2-sulphomethyl-benzene (5.5g, 100%) is light yellow oil.
[000295] will (7g, suspension 52.5mmol) be cooled to 3 ℃ at the aluminum chloride in the methylene dichloride (25mL).Individually, (5.5g 40mmol) is cooled to 5 ℃, and (4.7mL 42.06mmol) drips processing to use the ethyl oxalyl chloride then with neat liquid 1-methyl-2-sulphomethyl-benzene.When adding is finished, in refrigerative aluminum chloride-methylene dichloride suspension, add the mixture that forms thus by syringe.Observe acutely emitting of hydrogenchloride.Reaction mixture in 5 ℃ of stirrings 5 minutes, is removed cooling bath, and continue to stir 18 hours.Then, reaction mixture cooling got back to drop to 10 ℃, and drip processing with 2N aqueous hydrochloric acid (40mL).First 10mL for adding has gas to emit immediately.The separate dichloromethane phase, and with methylene dichloride (2 * 35mL) aqueous phase extracted.The organic layer that vacuum concentration merges provides: (4-methylthio group-3-methyl-phenyl)-oxo-acetic acids ethyl ester (～9.5g), being yellow oil, it uses under the condition that is not further purified.
[000296] with (4-methylthio group-3-methyl-phenyl)-oxo-acetic acids ethyl ester (9.5g, 39.8mmol) and the mixture heating up of 6N aqueous hydrochloric acid (25mL) reflux (104-105 ℃) 4 hours.At this moment, water (25mL) reaction mixture, and will bathe temperature rise to 125 ℃.Heating and stirring continued 8 hours.Then, no longer continue heating, and water (10mL) and toluene (10mL) diluted reaction mixture.The yellow solid precipitation.After placing a few hours, cross filter solid, wash with water, and dry air, provide: (4-methylthio group-3-methyl-phenyl)-oxo-acetic acids (9.5g, moistening a little), it uses under the condition that is not further purified.
[000297] (5mL 51.6mmol) handles (4-methylthio group-3-methyl-phenyl)-oxo-acetic acids in toluene (25mL) (9.0g, suspension 38mmol), and mixture becomes clear with cellosolvo.Then, (2.3mL 48mmol) dripped reaction mixture in 5 minutes with the hydrazine monohydrate.Reaction mixture becomes orange liquid from brown liquid, and finally becomes darkorange suspension.Reaction mixture is placed in the oil bath that is arranged at 105 ℃.The reaction mixture temperature inside was increased to 90 ℃ in 8 minutes.At this moment, (50%w/v, 62mmol) reaction mixture gradually in 10 minutes keep internal temperature to be higher than 90 ℃ with potassium hydroxide aqueous solution.To bathe temperature rise to 115 ℃, and observe controlled ammonia and emit.By Di Ke-Rodney Stark still head component distillation water.After 90 minutes, the inside temperature of reaction mixture reaches 106 ℃.With the reaction mixture cooling, vacuum concentration is to the volume of making an appointment with half then.Mixture is cooled to 80 ℃, uses 6N aqueous hydrochloric acid (12.5mL) to handle at leisure then.Reaction mixture is cooled to 25 ℃, and (3 * 50mL) extract with diethyl ether.With the each organic extract liquid of saturated sodium-chloride water solution (25mL) washing.Organic layer with dried over mgso merges filters and vacuum concentration, provides: yellow semi-solid (7g).This solid is dissolved in the diethyl ether (30mL), handles with hexane (40mL), and make its crystallization.Filter in two batches, provide: (3-methyl-4-methylthio group-phenyl)-acetate (4.27g, 54%) is yellow solid.
[000298] (3-methyl-4-methylthio group-phenyl)-acetate that will be in tetrahydrofuran (THF) (10mL) (1.55g, 7.89mmol) and salt of wormwood (2.75g, mixture 19.89mmol) stirred 15 minutes in 25 ℃.Under argon atmospher, suspended substance is cooled to-15 ℃, then by syringe, (1.02mL 8.28mmol) dripped processing in 2 minutes with trimethyl-acetyl chloride.Continue to stir 20 minutes, use then (1R, 2R)-(-)-(1.7g 10.28mmol) divides mode reaction mixture in 3 minutes of several parts to pseudoephedrine.Reaction mixture is positioned in 0 ℃ the cooling bath, and stirred 90 minutes.Then, water (10mL) and toluene (25mL) reaction mixture.Layer separates, and with toluene (2 * 25mL) aqueous layer extracted.With the each organic extract liquid of each 25mL washing of 1N aqueous sulfuric acid, saturated sodium-chloride water solution, saturated sodium bicarbonate aqueous solution and saturated sodium-chloride water solution.Organic layer with dried over sodium sulfate merges filters, and vacuum concentration, provides: unpurified crude product (2.75g), be amber oil, and it is by leaving standstill crystallization.Digestion of solid material and filtration in the diethyl ether (25mL) that stirs.With diethyl ether/hexane (1:1) washing solid product, and it is dry, provide: N-[2 (R)-hydroxyl-1 (R)-methyl-2 (R)-phenyl-ethyl]-N-methyl-2-(3-methyl-4-methylthio group-phenyl)-ethanamide (2.17g, 80%), be the canescence crystal: mp 104-105 ℃.
[000299] will be at the N-[2 (R) in the anhydrous tetrahydro furan (20mL)-hydroxyl-1 (R)-methyl-2 (R)-phenyl-ethyl]-N-methyl-2-(3-methyl-4-methylthio group-phenyl)-ethanamide (1.0g, 2.91mmol) solution under argon atmospher, be cooled to-25 ℃, use 1.0M at tetrahydrofuran (THF) (6.1mL then, 6.1mmol) in the solution of two (trimethylsilyl) lithium amide handle at leisure, keep temperature to be lower than-15 ℃ simultaneously.Remove cooling bath, and temperature of reaction is increased to 0 ℃, it was kept 20 minutes in this temperature.At this moment,, be used in 1 by syringe, 3-dimethyl-3,4,5,6-tetrahydrochysene-2 (1H)-pyrimidone (0.75mL, 6.2mmol) the iodomethyl pentamethylene in (according among the embodiment 1 preparation, 0.75g, solution-treated 3.57mmol) was 2 minutes reaction mixture.Mixture in 0 ℃ of stirring 2.5 hours, at this moment, is used saturated sodium-chloride water solution (30mL) quencher reaction mixture, and extracted with toluene (50mL).With 1N aqueous hydrochloric acid (30mL), saturated sodium-chloride water solution (30mL), saturated sodium bicarbonate aqueous solution (50mL) and saturated sodium-chloride water solution (30mL) washing organic phase.With the each water-washing liquid of toluene (20mL) reextraction.Organic layer with dried over sodium sulfate merges filters, and vacuum concentration, provides: thick white solid.This substance dissolves in the diethyl ether (20mL) of temperature, is handled with hexane (15mL), and made its crystallization.Cross filter solid, with cold diethyl ether/hexane (1:1) solution washing, and dry air, provide: 3-cyclopentyl-N-[2 (R)-hydroxyl-1 (R)-methyl-2 (R)-phenyl-ethyl]-N-methyl-2 (R)-(3-methyl-4-methylthio group-phenyl)-propionic acid amide (820mg, 66%), is the crystalline state solid.
[000300] with 3-cyclopentyl-N-[2 (R)-hydroxyl-1 (R)-methyl-2 (R)-phenyl-ethyl in 9N aqueous sulfuric acid (2mL) the processing Zai diox (2mL)]-N-methyl-2 (R)-(3-methyl-4-methylthio group-phenyl)-propionic acid amide (800mg, mixture 1.87mmol).The reaction mixture that obtains was heated 16 hours in 108-110 ℃.Between water (20mL) and ethyl acetate (30mL), distribute the refrigerative reaction mixture.And with ethyl acetate (2 * 30mL) aqueous phase extracted.The each organic layer of saturated sodium-chloride water solution washing with small portion.Organic layer with dried over sodium sulfate merges filters and vacuum concentration, and provide: 3-cyclopentyl-2 (R)-(3-methyl-4-methylthio group-phenyl)-propionic acid (550mg, 100%) is amber solid.
[000301] with 30% aqueous hydrogen peroxide solution (0.75mL, 6.2mmol) 3-cyclopentyl-2 (R)-(3-methyl-4-methylthio group-phenyl)-propionic acid (510mg, 1.83mmol) the suspension of processing in 98% formic acid (4mL).Mixture was stirred 90 minutes in 25 ℃.The vacuum concentration solvent, water (20mL) stirs residuum.Cross filter solid and wash with water.The substance dissolves that obtains in methylene dichloride, is used dried over mgso, filter and vacuum concentration.With exsiccant residuum recrystallization from diethyl ether/hexane, provide: 3-cyclopentyl-2 (R)-(4-methylsulfonyl-3-methyl-phenyl)-propionic acid (406mg, 71%) is white crystal: (ES)
+-HRMS m/e calculated value C
16H
22O
4S (M+Na)
+333.1131, actual measurement 333.1134.
[000302] (0.175mL, 2.0mmol) and N, dinethylformamide (1) is handled 3-cyclopentyl-2 (R)-(4-methylsulfonyl-3-methyl-phenyl)-propionic acid (310mg, solution 1.0mmol) in methylene dichloride (5mL) with oxalyl chloride.Solution was stirred 45 minutes in 25 ℃.The vacuum concentration reaction mixture, and residuum is suspended in the toluene.Further this toluene of vacuum concentration.The residuum that vacuum-drying obtains.Waxy substance is dissolved in the methylene dichloride (5mL), is cooled to 0 ℃, be used in then 2-amino-5-bromo-pyrazine in the methylene dichloride (5mL) (1.74g, 1.0mmol) and pyridine (0.121mL, solution-treated 1.5mmol).Mixture in 0 ℃ of stirring 20 minutes, was stirred 3 hours in 25 ℃ then.With methylene dichloride and water extraction solution.With 1N aqueous hydrochloric acid, saturated sodium-chloride water solution, saturated sodium bicarbonate aqueous solution and saturated sodium-chloride water solution washing organic layer.Use the dried over sodium sulfate organic layer, filter and vacuum concentration.Flash chromatography (Merck silica gel 60,230-400 order, 1/2 ethyl acetate/hexane) provides: N-(5-bromo-pyrazine-2-yl)-3-cyclopentyl-2 (R)-(4-methylsulfonyl-3-methyl-phenyl)-propionic acid amide (391mg, 84%) is soft solid.
[000303] with dichloro two (triphenyl phosphine) palladium (II) (11mg; 0.0157mmol) and cuprous iodide (I) (5.5mg; 0.0288mmol) N-(5-bromo-pyrazine-2-yl)-3-cyclopentyl-2 (R)-(4-methylsulfonyl-3-methyl-phenyl)-propionic acid amide (120mg of processing in toluene (2mL); 0.257mmol), N; N-diisopropylethylamine (0.5mL; 2.87mmol) and 3-hydroxy-3-methyl butine (90mg, mixture 1.07mmol).Mixture was stirred 18 hours in 25 ℃.Then, the vacuum concentration reaction mixture, and distribute residuum with methylene dichloride (25mL) and 0.2M aqueous hydrochloric acid (20mL).With saturated sodium-chloride water solution (20mL) washing organic layer, and with the each water of dichloromethane extraction of volume less.Organic layer with dried over sodium sulfate merges filters and vacuum concentration.Flash chromatography (Merck silica gel 60; the 230-400 order; with the ethyl acetate/hexane gradient elution that improves concentration gradually) provide: 3-cyclopentyl-N-[5-(3-hydroxy-3-methyl-Ding-1-alkynyl)-pyrazine-2-yl]-2 (R)-(4-methylsulfonyl-3-methyl-phenyl)-propionic acid amide (93mg; 77%), is yellow foam: (ES)
+-HRMS m/e calculated value C
25H
31N
3O
4S (M+H)
+470.2108, actual measurement 470.2113.
Embodiment 58
3-cyclopentyl-N-[5-1 (S), 2-dihydroxyl-ethyl]-2 (R)-(4-methylsulfonyl-3-methyl)-propionic acid amide
[000304] (0.3mL, 3.4mmol) and N, dinethylformamide (1-2 drips) is handled 3-cyclopentyl-2 (R)-(4-methylsulfonyl-3-methyl-phenyl)-propionic acid (465mg, solution 1.5mmol) in methylene dichloride (20mL) with oxalyl chloride.Solution in 0 ℃ of stirring 5 minutes, was stirred 15 minutes in 25 ℃ then.The vacuum concentration reaction mixture.Residuum is dissolved in methylene dichloride (20mL), is cooled to 0 ℃, be used in then 2-amino-5-vinylpyrazine in the methylene dichloride (5mL) (according to preparation among the embodiment 54,182mg, 1.5mmol) and pyridine (0.37mL, solution-treated 4.6mmol).Then, mixture in 0 ℃ of stirring, is spent the night in 25 ℃ of stirrings then.With 1N aqueous sodium hydroxide solution (25mL) and 1N aqueous hydrochloric acid (25mL) washing organic layer.With the each water of the dichloromethane extraction of small volume.Organic layer with dried over sodium sulfate merges filters, and vacuum concentration.Flash chromatography (Merck silica gel 60; the 230-400 order; 1/3 to 1/1 ethyl acetate/hexane) provides: 3-cyclopentyl-2 (R)-(4-methylsulfonyl-3-methyl-phenyl)-N-(5-vinyl-pyrazine-2-yl)-propionic acid amide (385mg, 63%), white foam: (ES)
+-HRMS m/e calculated value C
22H
27N
3O
3S (M+H)
+414.1846, actual measurement 414.1849.
[000305] water/trimethyl carbinol (10mL, solution-treated Tripotassium iron hexacyanide 1:1) (442mg, 1.34mmol), salt of wormwood (190mg, 1.37mmol) and (DHQ)
2PHAL (8mg, mixture 0.010mmol), and in 25 ℃ of stirrings 5 minutes.Reaction mixture is cooled to 0 ℃; use 0.2M at toluene (20 μ L then; 0.004mmol) in the perosmic anhydride solution-treated; then be used in water/trimethyl carbinol (5mL; 3-cyclopentyl-2 (R) 1:1)-(4-methylsulfonyl-3-methyl-phenyl)-N-(5-vinyl-pyrazine-2-yl)-propionic acid amide (185mg, mixture process 0.447mmol).The mixture that obtains was stirred 5 minutes in 0 ℃, stirred 5 hours in 25 ℃ then.Then, when stirring, usefulness ethyl acetate (25mL) and sodium metabisulfite (150mg, 0.79mmol) treating mixture, and continue to stir 30 minutes.Be separated, and wash organic layer with saturated sodium-chloride water solution (20mL).With the each water of ethyl acetate (25mL) reextraction.Organic layer with dried over sodium sulfate merges filters, and vacuum concentration.Flash chromatography (Merck silica gel 60; the 230-400 order, 25% ethyl acetate/hexane to 100% ethyl acetate) provide: 3-cyclopentyl-N-[5-1 (S), 2-dihydroxyl-ethyl]-2 (R)-(4-methylsulfonyl-3-methyl)-propionic acid amide (135mg; 67%), is colourless foam: (ES)
+-HRMS m/e calculated value C
22H
29N
3O
5S (M+H)
+448.1901, actual measurement 448.1904.
Embodiment 59
3-cyclopentyl-N-[5-(4-hydroxyl-tetrahydrochysene-pyrans-4-ethyl-acetylene base)-pyrazine-2-yl]-2 (R)-(4-methylsulfonyl-3-methyl-phenyl)-propionic acid amide
[000306] with dichloro two (triphenyl phosphine) palladium (II) (14mg; 0.02mmol) and cuprous iodide (I) (7mg; 0.0367mmol) N-(5-bromo-pyrazine-2-yl)-3-cyclopentyl-2 (R)-(4-methylsulfonyl-3-methyl-phenyl)-propionic acid amide (154mg of processing in toluene (2mL); 0.33mmol), N; N-diisopropylethylamine (0.6mL; 3.44mmol) and 4-ethynyl-tetrahydropyrans-4-alcohol (according among the embodiment 46 preparation, 85mg, mixture 0.67mmol).Mixture was stirred 17 hours in 25 ℃.Then, the vacuum concentration reaction mixture, and distribute residuum with methylene dichloride (50mL) and 0.2M aqueous hydrochloric acid (25mL), and layer separates.With methylene dichloride (25mL) aqueous phase extracted.Saturated sodium-chloride water solution (1) mL) the each water of washing.Organic layer with dried over sodium sulfate merges filters vacuum concentration.Flash chromatography (Merck silica gel 60; the 230-400 order; with ethyl acetate/the mixture gradient elution of hexane) provide: 3-cyclopentyl-N-[5-(4-hydroxyl-tetrahydrochysene-pyrans-4-ethyl-acetylene base)-pyrazine-2-yl]-2 (R)-(4-methylsulfonyl-3-methyl-phenyl)-propionic acid amide (93mg; 55%), is yellow foam: (ES)
+-HRMS m/e calculated value C
27H
33N
3O
5S (M+H)
+512.2214, actual measurement 512.2219.
Embodiment 60
3-cyclopentyl-N-[5-1 (R), 2-dihydroxyl-ethyl]-2 (R)-(4-methylsulfonyl-3-methyl)-propionic acid amide
[000307] water/trimethyl carbinol (10mL, solution-treated Tripotassium iron hexacyanide 1:1) (410mg, 1.24mmol), salt of wormwood (175mg, 1.26mmol) and (DHQD)
2PHAL (8mg, mixture 0.010mmol), and in 25 ℃ of stirrings 5 minutes.Reaction mixture is cooled to 0 ℃; use 0.2M at toluene (20 μ L then; 0.004mmol) in the perosmic anhydride solution-treated; then be used in water/trimethyl carbinol (5mL; 3-cyclopentyl-2 (R) 1:1)-(4-methylsulfonyl-3-methyl-phenyl)-N-(5-vinyl-pyrazine-2-yl)-propionic acid amide (170mg, mixture process 0.411mmol).The reaction mixture that obtains was stirred 5 minutes in 0 ℃, stirred 5 hours in 25 ℃ then.Then, when stirring, usefulness ethyl acetate (25mL) and sodium metabisulfite (150mg, 0.79mmol) treating mixture, and continue to stir 30 minutes.Be separated.Dilute water with saturated sodium-chloride water solution (20mL), and (2 * 25mL) extract with ethyl acetate.With the each organic layer of saturated sodium-chloride water solution washing.Organic layer with dried over sodium sulfate merges filters, and vacuum concentration.Flash chromatography (Merck silica gel 60,230-400 order are used the ethyl acetate/hexane wash-out) provides: 3-cyclopentyl-N-[5-1 (R), 2-dihydroxyl-ethyl]-2 (R)-(4-methylsulfonyl-3-methyl)-propionic acid amide (99mg, 54%), be colourless foam: (ES)
+-HRMS m/e calculated value C
22H
29N
3O
5S (M+H)
+448.1901, actual measurement 448.1900.
Embodiment 61
3-cyclopentyl-2 (R)-(4-methylsulfonyl-phenyl)-N-[5-(3-hydroxy-3-methyl-Ding-1-alkynyl)-pyrazine-2-yl]-propionic acid amide
[000308] uses N; N-diisopropylethylamine (2mL), 3-hydroxy-3-methyl butine (84mg; 1.0mmol), dichloro two (triphenyl phosphine) palladium (II) (19mg) and cuprous iodide (I) (9mg) handle 2 (R)-(4-methylsulfonyl-phenyl)-3-cyclopentyl-5-bromo-pyrazine-2-base-propionic acid amide in toluene (6mL) (according to embodiment 3 preparations; 226mg, mixture 0.5mmol).Mixture is spent the night in 25 ℃ of stirrings, and obtain the oily black precipitate.The clear liquid on decantation top, and at first use toluene (8mL) rinsing oily throw out, use hexane/ethyl acetate (2 * 8ml, 8:1) rinsing then.Residuum is dissolved in the methylene dichloride, and extracts with methylene dichloride and 0.2N aqueous hydrochloric acid.Wash organic layer with saturated sodium-chloride water solution, use dried over sodium sulfate, filter and vacuum concentration.Flash chromatography (Merck silica gel 60; the 230-400 order; 1/1 ethyl acetate/hexane) provide: 3-cyclopentyl-2 (R)-(4-methylsulfonyl-phenyl)-N-[5-(3-hydroxy-3-methyl-Ding-1-alkynyl)-pyrazine-2-yl]-propionic acid amide (100mg, 44%), be soft solid: (ES)
+-HRMS m/e calculated value C
24H
29N
3O
4S (M+H)
+456.1952, actual measurement 456.1943.
Embodiment 62
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(2-hydroxyl-oxyethyl group)-pyrazine-2-yl]-propionic acid amide
[000309] (2.91g, 19.94mmol) 5-chloro-pyrazine-2-carboxylic acid of handling in methylene dichloride (50mL) (prepares 3.15g, solution 19.94mmol) to ethanol in according to embodiment 29 with 2-(tetrahydropyrans-2-base oxygen base).Solution is cooled to 0 ℃, and (5.60mL, 39.88mmol) (5.07g 19.94mmol) handles with the inferior phosphonyl chloride of two (2-oxos-3-oxazolidinyl) to use triethylamine then.Mixture in 0 ℃ of stirring 15 minutes, was stirred 24 hours in 25 ℃ then.With methylene dichloride and water extraction mixture.Wash organic layer with saturated sodium-chloride water solution, use dried over sodium sulfate, filter and vacuum concentration.Flash chromatography (Merck silica gel 60,230-400 order, 2/1 hexane/ethyl acetate) provides: 5-chloro-pyrazine-2-carboxylic acid 2-(tetrahydrochysene-pyrans-2-base oxygen base)-ethyl ester is water white oil (3.41g, 60%).
[000310] with 2-(tetrahydropyrans-2-base oxygen base) ethanol (5.22g, 35.77mmol) the solution of sodium hydride (60% is scattered in the mineral oil for 1.43g, 35.75mmol, with hexane preliminary election washing) processing in 0 ℃ anhydrous tetrahydro furan.Mixture was stirred 10 minutes in 0 ℃, stirred 2 hours in 25 ℃ then, up to consuming all sodium hydrides.Reaction mixture is cooled to 0 ℃, is used in 5-chloro-pyrazine-2-carboxylic acid 2-(tetrahydrochysene-pyrans-2-base oxygen base)-ethyl ester (3.41g, solution-treated 11.92mmol) in the tetrahydrofuran (THF) (15mL) then.Mixture was stirred 20 minutes in 0 ℃, and spend the night in 25 ℃ of stirrings.Darkening of reaction mixture, and the completely consumed of thin-layer chromatography indication raw material is fallen.The reaction mixture vacuum concentration is extremely dry.Water (30mL) and 1N aqueous sodium hydroxide solution (15mL) dilution residuum is then with residuum reflux 2 hours.The solution that water (30mL) dilution obtains is used diethyl ether (3 * 30mL) extractions then.With 1N aqueous hydrochloric acid acidifying water layer, use ethyl acetate extraction then.Use the dried over sodium sulfate organic layer, filter and vacuum concentration, provide: a kind of oil (2.11g).
1H-NMR is designated as 5-[2-(tetrahydrochysene-pyrans-2-base oxygen base)-oxyethyl group]-mixture of pyrazine-2-carboxylic acid and unreacted 2-(tetrahydropyrans-2-base oxygen base) ethanol (1.4/1 ratio).This oil is scattered in the water (20mL), adds 1N aqueous sodium hydroxide solution (6.5mL) then to regulate pH value to 8.0.Vacuum concentrated solution, and dry remaining.The material that obtains is suspended in the diethyl ether and filters, provide: 5-[2-(tetrahydrochysene-pyrans-2-base oxygen base)-oxyethyl group]-sodium salt of pyrazine-2-carboxylic acid (1.74g, 50.3%), be solid.
[000311] with diphenylphosphine acylazide thing (1.40ml 6.50mmol) handles at N, the 5-[2-in the dinethylformamide (20mL) (tetrahydrochysene-pyrans-2-base oxygen base)-oxyethyl group]-pyrazine-2-carboxylic acid sodium salt (1.72g, suspension 5.93mmol).Reaction mixture is spent the night in 25 ℃ of stirrings, then vacuum concentration.Residuum is suspended in the ethyl acetate, and passes through solids removed by filtration.Wash organic filtrate with water, use dried over sodium sulfate, filter and vacuum concentration, provide: acid azide (1.80g), be a kind of oil, it uses under the condition that is not further purified.The benzylalcohol (0.64g) that is used in the toluene (15mL) is handled this acid azide (1.80g).Mixture was stirred 1 hour in 90 ℃, emit up to gas and finish.Reaction mixture is cooled to 25 ℃, and the curing reaction mixture.Biotage chromatogram (FLASH40L, silicon-dioxide, 2/1 hexane/ethyl acetate) provides: 5-[2-(tetrahydrochysene-pyrans-2-yl)-oxyethyl group]-pyrazine-2-yl }-benzyl carbamate (1.12g, 51%), be solid.
[000312] in methyl alcohol (5mL), handle { 5-[2-(tetrahydrochysene-pyrans-2-yl)-oxyethyl group]-pyrazine-2-yl }-benzyl carbamate (560mg, solution 1.5mmol) in tetrahydrofuran (THF) (5mL) and methyl alcohol (15mL) with 10% palladium in gac (110mg).At the direct draught of 25 ℃ hydrogen (balloon), stirred reaction mixture 2 hours, at this moment, thin-layer chromatography indication protecting group is removed fully.Filter reaction mixture and vacuum concentration provide: 5-[2-(tetrahydrochysene-pyrans-2-yl)-oxyethyl group]-pyrazine-2-base amine, be a kind of oil, it uses under the condition that is not further purified.
[000313] with oxalyl chloride (262 μ L; 3.0mmol) and N; dinethylformamide (1) is handled 2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-propionic acid (preparation in according to embodiment 1,495mg, solution 1.5mmol) in methylene dichloride (5mL).Mixture was stirred 2 hours in 25 ℃.The vacuum concentration reaction mixture, and residuum vacuum-drying spent the night.Residuum is dissolved in the benzene, and the vacuum concentration solvent.The vacuum-drying residuum.This substance dissolves in methylene dichloride (5mL), is cooled to 0 ℃, is used in 5-[2-(tetrahydrochysene-pyrans-2-the yl)-oxyethyl group in the methylene dichloride (7mL) then]-mixture process of pyrazine-2-base amine and pyridine (240 μ L).Remove ice bath, and solution was stirred 2 hours in 25 ℃.With methylene dichloride and 0.1N aqueous hydrochloric acid extraction mixture.Wash organic layer with saturated sodium-chloride water solution, use dried over sodium sulfate, filter and vacuum concentration.Flash chromatography (Merck silica gel 60; the 230-400 order; 1.5/1 hexane/ethyl acetate) provide 2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(2-tetrahydropyrans-2-base oxygen base) oxyethyl group-pyrazine-2-yl]-propionic acid amide (594mg, 72%), white foam.
[000314] handle 2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(2-tetrahydropyrans-2-base oxygen base) oxyethyl group-pyrazine-2-yl in methyl alcohol (8mL) with 6N aqueous hydrochloric acid (0.2mL)]-solution of propionic acid amide (300mg).Mixture was stirred 2 hours in 25 ℃, up to consuming all raw materials.Vacuum concentrated solution, and with ethyl acetate and saturated sodium bicarbonate aqueous solution extraction residuum.Use the dried over sodium sulfate organic layer, filter and vacuum concentration, provide: 2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(2-hydroxyl-oxyethyl group)-pyrazine-2-yl]-propionic acid amide (254mg, 100%), white foam: (ES)
+-HRMS m/e calculated value C
21H
26ClN
3O
5S (M+H)
+468.1355, actual measurement 468.1339.
Embodiment 63
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(2-p-methoxy-phenyl)-pyrazine-2-yl]-propionic acid amide
[000315] with four (triphenyl phosphine) palladium (0) (193mg, 0.17mmol) and salt of wormwood (1.87g 13.34mmol) handles at N the 2-amino in the dinethylformamide (15mL)-5-bromo-pyrazine (1.16g, 6.67mmol) and 2 anisole ylboronic acids (1.17g, solution 7.70mmol).With mixture in 110 ℃ of heated overnight.With chloroform and water extractive reaction mixture.Wash organic layer with saturated sodium-chloride water solution, use dried over sodium sulfate, filter and vacuum concentration.(2/1 ethyl acetate/hexane (2/1 ratio) provides the Biotage chromatogram for FLASH 40S, silicon-dioxide: 5-(2-methoxyl group-phenyl)-pyrazine-2-base amine (210mg, 16%).
[000316] with oxalyl chloride (182 μ L; 2.08mmol) and N; dinethylformamide (1) is handled 2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-propionic acid (preparation in according to embodiment 1,343mg, solution 1.04mmol) in methylene dichloride (5mL).Mixture was stirred 2 hours in 25 ℃.The vacuum concentration reaction mixture, and residuum vacuum-drying spent the night.Then, residuum is dissolved in the benzene, and the vacuum concentration solvent.The vacuum-drying residuum.This substance dissolves in methylene dichloride (5mL), is cooled to 0 ℃, is used in the mixture process of 5-(2-methoxyl group-phenyl)-pyrazine in the methylene dichloride (10mL)-2-base amine and pyridine (130 μ L) then.Remove ice bath, and solution is spent the night in 25 ℃ of stirrings.With methylene dichloride and 0.3N aqueous hydrochloric acid extraction residuum.Wash organic layer with saturated sodium-chloride water solution, use dried over sodium sulfate, filter and vacuum concentration.Flash chromatography (Merck silica gel 60; the 230-400 order; 2/1 hexane/ethyl acetate) provide: 2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(2-p-methoxy-phenyl)-pyrazine-2-yl]-propionic acid amide (378mg, 71%), be the canescence foam: (ES)
+-HRMS m/e calculated value C
26H
28ClN
3O
4S (M+H)
+514.1562, actual measurement 514.1547.
Embodiment 64
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(2-hydroxy phenyl)-pyrazine-2-yl]-propionic acid amide
[000317] merely hits to each of 8 microwave tubes, add 2-amino-5-bromo-pyrazine (174mg, 1.00mmol), 2-hydroxy phenyl boric acid (151mg, 1.10mmol), acetonitrile (3mL), dichloro two (triphenyl phosphine) palladium (II) (36mg, 0.05mmol) and 1M sodium bicarbonate aqueous solution (1mL).With this 8 by all means in 150 ℃ of microwave heatings 15 minutes.Reaction mixture pours in the solution of ethyl acetate and water then.Wash organic layer with saturated sodium-chloride water solution, use dried over sodium sulfate, filter and vacuum concentration.Residuum is dissolved in the hot methanol (100mL).The vacuum concentration methanol solution is up to observing throw out.Filtering precipitate.Further concentrating filtrate and filtration provides: 5-(2-hydroxyl-phenyl)-pyrazine-2-base amine (478mg, 32%) is solid.
[000318] with oxalyl chloride (175 μ L; 2.0mmol) and N; dinethylformamide (1) is handled 2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-propionic acid (preparation in according to embodiment 1,330mg, solution 1.0mmol) in methylene dichloride (5mL).Mixture was stirred 2 hours in 25 ℃.Vacuum concentration reaction mixture, and vacuum-drying residuum.Residuum is dissolved in the benzene, and the vacuum concentration solvent.The vacuum-drying residuum.This substance dissolves in methylene dichloride (5mL), is cooled to 0 ℃, is used in the mixture process of 5-(2-hydroxyl-phenyl)-pyrazine in the methylene dichloride (10mL)-2-base amine and pyridine (125 μ L) then.Remove ice bath, and solution is spent the night in 25 ℃ of stirrings.With methylene dichloride and 0.3N aqueous hydrochloric acid extraction residuum.Wash organic layer with saturated sodium-chloride water solution, use dried over sodium sulfate, filter and vacuum concentration.Flash chromatography (Merck silica gel 60; the 230-400 order; 2/1 hexane/ethyl acetate) provide: 2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(2-hydroxy phenyl)-pyrazine-2-yl]-propionic acid amide (256mg, 51%), be the canescence foam: (ES)
+-HRMS m/e calculated value C
25H
26ClN
3O
4S (M+H)
+500.1406, actual measurement 500.1395.
Embodiment 65
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(1,2-dihydroxyl-ethyl)-pyrazine-2-yl]-propionic acid amide
[000319] with 2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-vinyl-pyrazine-2-yl)-propionic acid amide (according among the embodiment 54 preparation; 50mg; 0.115mmol) the N-methylmorpholine oxide compound (27mg of processing in acetone (0.5mL) and water (0.5mL); 0.23mmol) solution and 0.2M at toluene (5 μ L, 0.001mmol) the perosmic anhydride solution in.Add two tetrahydrofuran (THF)s, dissolving substrate fully, and the residuum that obtains is spent the night in 25 ℃ of stirrings.Vacuum concentration residuum, and water (10mL) and methylene dichloride (25mL) washing residuum.With 1N aqueous hydrochloric acid (10mL) washing organic phase, and with the each water of small portion dichloromethane extraction.Organic layer with dried over sodium sulfate merges filters, and vacuum concentration.Biotage chromatogram (FLASH 12M, silicon-dioxide, ethyl acetate) provides: 2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(1,2-dihydroxyl-ethyl)-pyrazine-2-yl]-propionic acid amide (48mg), be colourless foam: (ES)
+-HRMS m/e calculated value C
21H
26N
3O
5S (M+H)
+468.1355, actual measurement 468.1357.
Embodiment 66
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(1 (S), 2-dihydroxyl-2-methyl-propyl group)-pyrazine-2-yl]-propionic acid amide
[000320] with the magnesium of a spot of iodinate in anhydrous tetrahydro furan (60mL) (2.64g, suspension 110mmol), then with several sections be added in 1-bromo-2-methacrylic in the tetrahydrofuran (THF) (30mL) (13.5g, 100mmol).Mixture heating up was refluxed 3 minutes.Mixture is cooled to 25 ℃, and (0.2mL 3.0mmol) handles to use methyl iodide then.In 25 ℃ of stirrings 30 minutes, reflux was 2 hours then, up to consuming all magnesium with reaction mixture.Mixture is cooled to 25 ℃, is used in tributyltin chloride (27mL, solution-treated 100mmol) in the tetrahydrofuran (THF) (30mL) then.Mixture heating up was refluxed 19 hours, be cooled to 25 ℃ then.With diethyl ether and saturated aqueous ammonium chloride extraction solution.Use the dried over sodium sulfate organic layer, filter and vacuum concentration, provide: isobutenyl tributyl tin (31.95g) is thick oil.Should be slightly oily
1The H-NMR data show that the purity of needed isobutenyl tributyl tin is 58%.
[000321] with lithium chloride (2.0g) and four (triphenyl phosphine) palladium (0) (381mg, 0.33mmol) handle at N, thick isobutenyl tributyl tin (6.90g in the dinethylformamide (50mL), 58 purity), 2-amino-5-bromo-pyrazine (1.92g, 11mmol) and N, the mixture of N-diisopropylethylamine (5mL).In 130 ℃ of stirrings 4 hours, at this moment, thin-layer chromatography was indicated the completely consumed raw material with mixture.The vacuum concentration residuum is handled residuum with saturated potassium fluoride solution, uses ethyl acetate extraction then.Wash organic layer with saturated sodium-chloride water solution, use dried over sodium sulfate, filter and vacuum concentration.Flash chromatography (Merck silica gel 60,230-400 order, 1.5/1 hexane/ethyl acetate) provides: 2-amino-5-(2,2-dimethyl vinyl)-pyrazine (420mg, 26%).
[000322] with oxalyl chloride (490 μ L; 5.64mmol) and N; dinethylformamide (1) is handled 2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-propionic acid (preparation in according to embodiment 1,930mg, solution 2.82mmol) in methylene dichloride (10mL).Mixture was stirred 2 hours in 25 ℃.Vacuum concentration reaction mixture, and vacuum-drying residuum.Residuum is dissolved in the benzene, and the vacuum concentration solvent.The vacuum-drying residuum.This substance dissolves in methylene dichloride (10mL), is cooled to 0 ℃, be used in then 2-amino-5-(2,2-dimethyl vinyl)-pyrazine in the methylene dichloride (10mL) (420mg, 2.82mmol) and the mixture process of pyridine (340 μ L).Remove ice bath, and solution is spent the night in 25 ℃ of stirrings.With methylene dichloride and 0.1N aqueous hydrochloric acid extraction residuum.Wash organic layer with saturated sodium-chloride water solution, use dried over sodium sulfate, filter and vacuum concentration.Flash chromatography (Merck silica gel 60; the 230-400 order; 2/1 hexane/ethyl acetate) provide: 2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(2-methylpropenyl)-pyrazine-2-yl]-propionic acid amide (1.10g, 85%), be weak yellow foam.
[000323] water/trimethyl carbinol (15mL, 1:1) handle the Tripotassium iron hexacyanide (738mg, 2.24mmol), salt of wormwood (310mg, 2.24mmol) and (DHQ)
2(11.7mg, mixture 0.015mmol) stir down in 25 ℃ PHAL, obtain clear liquid.Solution-treated reaction mixture with the perosmic anhydride of 0.2M in toluene (37.4 μ L).Reaction mixture is cooled to 0 ℃; use 2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(2-methylpropenyl)-pyrazine-2-yl then]-propionic acid amide (345mg; 0.748mmol) handle, then add amsacrine (71mg, 0.747mmol).Mixture was stirred 18 hours in 0 ℃ of stirring, up to all olefine reactions.With ethyl acetate (30mL) diluted mixture thing, and handle with S-WAT (1.0g).With ethyl acetate and water extraction solution.Use the dried over sodium sulfate organic layer, filter and vacuum concentration.Flash chromatography (Merck silica gel 60; the 230-400 order, 1/5 hexane/ethyl acetate) provide: 2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(1 (S), 2-dihydroxyl-2-methyl-propyl group)-pyrazine-2-yl]-propionic acid amide (255mg; 69%), is the canescence foam: (ES)
+-HRMS m/e calculated value C
23H
30ClN
3O
5S (M+H)
+496.1668, actual measurement 496.1657.
Embodiment 67
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(1 (R), 2-dihydroxyl-2-methyl-propyl group)-pyrazine-2-yl]-propionic acid amide
[000324] water/trimethyl carbinol (15mL, 1:1) handle the Tripotassium iron hexacyanide (738mg, 2.24mmol), salt of wormwood (310mg, 2.24mmol) and (DHQ)
2(11.7mg, mixture 0.015mmol) in 25 ℃ of stirrings, obtain clear liquid to PHAL.Solution-treated reaction mixture with the perosmic anhydride of 0.2M in toluene (37.4 μ L).Reaction mixture is cooled to 0 ℃; use 2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(2-methylpropenyl)-pyrazine-2-yl then]-propionic acid amide (according among the embodiment 66 preparation; 345mg; 0.748mmol) handle; then add amsacrine (71mg, 0.747mmol).Mixture was stirred 18 hours in 0 ℃ of stirring, up to all olefine reactions.With ethyl acetate (30mL) diluted mixture thing, and handle with S-WAT (1.0g).With ethyl acetate and water extraction solution.Use the dried over sodium sulfate organic layer, filter and vacuum concentration.Flash chromatography (Merck silica gel 60; the 230-400 order, 1/5 hexane/ethyl acetate) provide: 2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(1 (R), 2-dihydroxyl-2-methyl-propyl group)-pyrazine-2-yl]-propionic acid amide (255mg; 69%), is the canescence foam: (ES)
+-HRMS m/e calculated value C
23H
30ClN
3O
5S (M+H)
+496.1668, actual measurement 496.1654.
Embodiment 68
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(4-methyl-2,5-dioxo-imidazolidine-4-yl)-pyrazine-2-yl]-propionic acid amide
[000325] will be at the N-in the ethanol (32mL) (5-ethanoyl-pyrazine-2-yl)-2, and 2-dimethyl-propionic acid amide (according to preparation among the embodiment 28,884mg, suspension heating 4.0mmol) obtains clear liquid.With sodium cyanide (294mg, 6.0mmol) and volatile salt (1.54g, 16mmol) reaction mixture then add entry (32mL).Mixture was stirred 18 hours in 65 ℃.With 1N aqueous hydrochloric acid neutralization reaction mixture, be about 3.0 to pH.The mixture that obtains with ethyl acetate extraction.Wash organic layer with saturated sodium-chloride water solution, use dried over sodium sulfate, filter and vacuum concentration, provide: 2,2-dimethyl-N-[5-(4-methyl-2,5-dioxo-imidazolidine-4-yl)-pyrazine-2-yl] propionic acid amide (1.16g, 100%), be pale solid.
[000326] with N aqueous sodium hydroxide solution (15mL) handle in methyl alcohol (30mL) 2,2-dimethyl-N-[5-(4-methyl-2,5-dioxo-imidazolidine-4-yl)-pyrazine-2-yl]-propionic acid amide (1.16g, suspension 4.0mmol).Mixture in 65 ℃ of stirrings 4 hours, is spent the night in 25 ℃ of stirrings then.Vacuum concentrated mixture, and the vacuum-drying residuum spends the night, and obtains thick solid.With this solid matter be suspended in ethyl acetate and methanol mixture (100mL, 1:1) in, and mild heat.Filtering mixt, and vacuum concentration filtrate.Biotage chromatogram (FLASH 40L, silicon-dioxide, 10% to 30% methanol/ethyl acetate) provides: 5-(5-amino-pyrazino-2-yl)-5-methyl-imidazolidine-2,4-diketone (841mg, 100%) is solid.
[000327] with oxalyl chloride (116 μ L; 1.212mmol) and N; dinethylformamide (1) handle 2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-propionic acid in methylene dichloride (5mL) (preparation in according to embodiment 1,200mg, 0.606mmol).Mixture was stirred 1 hour in 25 ℃.Vacuum concentration reaction mixture, and vacuum-drying residuum.Residuum is dissolved in the benzene, and the vacuum concentration solvent.The vacuum-drying residuum.With this substance dissolves in methylene dichloride (5mL), be cooled to 0 ℃, be used in 5-(5-amino-pyrazino-2-the yl)-5-methyl-imidazolidine-2 of methylene dichloride (1mL) and methyl-sulphoxide (1mL) then, and the 4-diketone (150mg, 0.727mmol) and the mixture process of pyridine (98 μ L).Remove ice bath, and solution is spent the night in 25 ℃ of stirrings.The vacuum concentration reaction mixture is then with methylene dichloride and 0.1N aqueous hydrochloric acid extraction residuum.Wash organic layer with saturated sodium-chloride water solution, use dried over sodium sulfate, filter and vacuum concentration.Flash chromatography (Merck silica gel 60; the 230-400 order; 1/4 hexane/ethyl acetate) provides: 2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(4-methyl-2; 5-dioxo-imidazolidine-4-yl)-pyrazine-2-yl]-propionic acid amide (82mg; 26%), is faint yellow solid: (ES)
+-HRMS m/e calculated value C
23H
26ClN
5O
5S (M+H)
+520.1416, actual measurement 520.1403.
Embodiment 69
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(tetrahydrochysene-furans-2-yl)-pyridine-2-yl]-propionic acid amide
[000328] (5.00g, solution 28.90mmol) are dissolved in the tetrahydrofuran (THF) (80mL), are cooled to-78 ℃, use 2.5M in hexane (11.68mL, 29.19mmol) solution-treated of the n-Butyl Lithium in then with 2-amino-5-bromopyridine.The reaction mixture that obtains was stirred 1 hour, at this moment, in reaction mixture, drip in tetrahydrofuran (THF) (15mL) 1,2-two (Chlorodimethyl silyl) ethane (6.22g, solution 28.90mmol).In other 90 minutes of-78 ℃ of stirrings, the 2.5M that uses another part then was in hexane (11.68mL, 29.19mmol) solution-treated of the n-Butyl Lithium in reaction mixture.Reaction mixture is warmed to 25 ℃ at leisure, it was stirred 2 hours in this temperature.Then, will react quencher, use diethyl ether (2 * 200mL) extractions afterwards by adding saturated sodium-chloride water solution (50mL).Organic layer with dried over mgso merges filters and vacuum concentration.Kugelrohr distillation under 125-135 ℃, 0.5mmHg provides: 5-bromo-2-(2,2,5,5-tetramethyl--[1,2,5] azadisilolidin-1-yl)-pyridine (5.38g, 59%) is white solid: mp 50.4-55.8 ℃.
[000329] will the 2,3 dihydro furan in the methylene dichloride (80mL) (1.40g, 19.97mmol) and benzene sulfinic acid (3.12g, mixture 21.97mmol) stirred 2 hours in 25 ℃.Then, reaction mixture is transferred in the separating funnel, and washs with saturated aqueous sodium carbonate (15mL).Use the dried over sodium sulfate organic layer, filter and vacuum concentration.Then, use diethyl ether/sherwood oil to make the solid crystal that obtains, provide: 2-benzenesulfonyl-tetrahydrochysene-furans is white solid: mp 55.9-56.8 ℃.
[000330] use 1.7M at pentane (4.93mL, 8.39mmol) in tert-butyl lithium solution drip to handle-78 ℃ of 5-bromo-2-(2 in tetrahydrofuran (THF) (6mL), 2,5,5-tetramethyl--[1,2,5] azadisilolidin-1-yl)-pyridine (1.26g, 3.99mmol) solution, stirred then 10 minutes.Then, (539mg, 2.39mmol) (1.03g 3.99mmol) handles, and reaction mixture is warmed to 25 ℃, in this temperature it is stirred 30 minutes with magnesium bromide Anaesthetie Ether compound with zinc bromide.(424mg 1.99mmol) handles this solution, and reaction mixture was stirred 20 hours in 25 ℃ to be used in 2-benzenesulfonyl-tetrahydrochysene-furans in the tetrahydrofuran (THF) (10mL).Then, with saturated aqueous ammonium chloride (10mL) quencher reaction mixture, use ethyl acetate (3 * 15mL) extractions then.Organic layer with dried over sodium sulfate merges filters, and vacuum concentration.Biotage chromatogram (FLASH 40S, silicon-dioxide, 95/5 methylene chloride) provides: the inseparable mixture (227mg) of 5-(tetrahydrochysene-furans-2-yl)-pyridine-2-base amine and 2-aminopyridine is waxy solid.
[000331] 2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-propionic acid in methylene dichloride (5mL) (is prepared in according to embodiment 1; 250mg; 0.76mmol) solution be cooled to 0 ℃; use 2.0M at methylene dichloride (435 μ L then; 0.87mmol) and N, the oxalyl chloride solution-treated in the dinethylformamide (1).Reaction mixture was stirred 30 minutes in 0 ℃, then vacuum concentration.The oil that obtains is dissolved in 25 ℃ the tetrahydrofuran (THF) (2mL), pass through feed hopper then, be used in the inseparable mixture (224mg of 5-(tetrahydrochysene-furans-2-yl)-pyridine in the tetrahydrofuran (THF) (3mL)-2-base amine and 2-aminopyridine, 1.36mmol) and 2, (263 μ L, solution 2.27mmol) drip and handle the 6-lutidine.Then, the turbid solution that obtains was spent the night 16 hours in 25 ℃ of stirrings.After this, water (10mL) diluted reaction mixture is used methylene dichloride (3 * 25mL) extractions then.Organic layer with dried over sodium sulfate merges filters and vacuum concentration.Biotage chromatogram (FLASH 12M; silicon-dioxide; 65/35 to 50/50 hexane/ethyl acetate) provide: 2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(tetrahydrochysene-furans-2-yl)-pyridine-2-yl]-propionic acid amide (86mg, 24%), white foam: (ES)
+-HRMS m/e calculated value C
24H
29ClN
2O
4S (M+H)
+477.1610, actual measurement 477.1616.
Embodiment 70
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-furans-2-base-pyrazine-2-yl)-propionic acid amide
[000332] with four (triphenyl phosphine) palladium (0) (66mg, 0.06mmol), N, N-diisopropylethylamine (1.25mL, 7.18mmol), lithium chloride (426mg, 10.06mmol) and 2-(tributyl stannyl) furans (905 μ L, 2.87mmol) handle at N 2-amino-5-bromo-pyrazine (500mg, solution 2.87mmol) in the dinethylformamide (15mL).The reaction mixture that obtains was heated 4 hours in 120 ℃.After this, reaction mixture is cooled to 25 ℃, handles, spent the night 16 hours in 25 ℃ of stirrings then with saturated potassium fluoride solution (10mL).Then, with methylene dichloride (25mL) diluting soln, with methylene dichloride (3 * 15mL) extractions.Organic layer with dried over sodium sulfate merges filters, and vacuum concentration.Biotage chromatogram (FLASH 40S, silicon-dioxide, 98/2 to 96/4 methylene chloride) provides: 5-furans-2-base-pyrazine-2-base amine (356mg, 77%) is brown solid: mp 80.2-83.8 ℃.
[000333] use 2.0M at methylene dichloride (217 μ L; 0.44mmol) and N; oxalyl chloride solution-treated in the dinethylformamide (1) is cooled to 2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-propionic acid in 0 ℃ the methylene dichloride (2.5mL) (according to preparation among the embodiment 1; 125mg, solution 0.38mmol).Reaction mixture was stirred 30 minutes in 0 ℃, and vacuum concentration is with twice of toluene (2mL) azeotropic.Then, the oil that obtains is dissolved in 25 ℃ the tetrahydrofuran (THF) (1mL).Then, by feed hopper, (91mg, 0.57mmol) and 2, (66 μ L 0.57mmol) drip and handle this solution the 6-lutidine to be used in 5-furans-2-base-pyrazine in the tetrahydrofuran (THF) (1.5mL)-2-base amine.Then, the turbid solution that obtains was spent the night 16 hours in 25 ℃ of stirrings.After this, water (10mL) diluted reaction mixture is used methylene dichloride (3 * 25mL) extractions then.Organic layer with dried over sodium sulfate merges filters and vacuum concentration.Biotage chromatogram (FLASH 12M; silicon-dioxide; 80/20 to 60/40 hexane/ethyl acetate) provide: 2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-furans-2-base-pyrazine-2-yl)-propionic acid amide (124mg, 69%) are yellow foam: (ES)
+-HRMS m/e calculated value C
23H
24ClN
3O
4S (M+H)
+474.1249, actual measurement 474.1254.
Embodiment 71
2 (R)-(3-chloro-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(3-methoxyl group-phenyl)-pyrazine-2-yl]-propionic acid amide
[000334] with nitrogen bubble by 3-anisole ylboronic acid (393mg, 2.59mmol), 2-amino-5-bromo-pyrazine (300mg, 1.72mmol), yellow soda ash (603mg, 5.69mmol), the solution of glycol dimethyl ether (10mL) and water (3mL) 15 minutes.After this, with dichloro two (triphenyl phosphine) palladium (II) (121mg, 0.17mmol) treatment soln, and with the reaction mixture that obtains in 90 ℃ of heating two days.Then, reaction mixture is toppled in the entry (50mL), and (3 * 50mL) extract with ethyl acetate.Organic layer with dried over mgso merges filters and vacuum concentration.Biotage chromatogram (FLASH40S, silicon-dioxide, 40/60 hexane/ethyl acetate) provides: 5-(3-methoxyl group-phenyl)-pyrazine-2-base amine (218mg, 63%) is faint yellow solid: mp 113.2-115.5 ℃; EI-HRMS m/e calculated value C
11H
11N
3O (M
+) 201.0902, actual measurement 201.0905.
[000335] use 2.0M at methylene dichloride (522 μ L; 1.04mmol) and N; oxalyl chloride solution-treated in the dinethylformamide (1) is cooled to 2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-propionic acid in 0 ℃ the methylene dichloride (15mL) (according to preparation among the embodiment 1; 300mg, solution 0.91mmol).Reaction mixture was stirred 30 minutes in 0 ℃, vacuum concentration, and with twice of methylene dichloride (2mL) azeotropic.The oil that obtains is dissolved in 25 ℃ the tetrahydrofuran (THF) (5mL), then by feed hopper, be used in 5-(3-methoxyl group-phenyl)-pyrazine-2-base amine in the tetrahydrofuran (THF) (6mL) (201mg, 1.00mmol) and 2, (126 μ L, solution 1.09mmol) drip and handle the 6-lutidine.Then, the turbid solution that obtains was spent the night 16 hours in 25 ℃ of stirrings.After this, water (10mL) diluted reaction mixture is used methylene dichloride (3 * 25mL) extractions then.Organic layer with dried over sodium sulfate merges filters, and vacuum concentration.Biotage chromatogram (FLASH40S; silicon-dioxide; 75/25 to 60/40 hexane/ethyl acetate) provide: 2 (R)-(3-chloro-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(3-methoxyl group-phenyl)-pyrazine-2-yl]-propionic acid amide (388mg, 83%), be weak yellow foam: (ES)
+-HRMS m/e calculated value C
26H
28ClN
3O
4S (M+H)
+514.1562, actual measurement 514.1567.
Embodiment 72
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(2-methoxyl group-ethylamino)-pyrazine-2-yl]-propionic acid amide
[000336] will the 2-bromo-5-nitro pyrazine in the methyl alcohol (15mL) (500mg, 2.45mmol) and the 2-methoxyethyl amine (276mg, mixture 3.67mmol) stirred 5 hours in 25 ℃.After this, vacuum concentration reaction mixture.Biotage chromatogram (FLASH 40S, silicon-dioxide, 40/60 to 20/80 hexane/ethyl acetate) provides: (2-methoxyl group-ethyl)-(5-nitro-pyrazine-2-yl)-amine (291mg, 60%) is yellow solid: mp 116.0-117.3 ℃; EI-HRMS m/e calculated value C
7H
10N
4O
3(M
+) 198.0753, actual measurement 198.0751.
[000337] handles (2-methoxyl group-ethyl)-(5-nitro-pyrazine-2-yl)-amine (290mg, solution 1.46mmol) in ethyl acetate (25mL) with 10% at the palladium on the gac (40mg).Then, under the hydrogen atmosphere of 50psi, reaction mixture was placed 4 hours in the Parr wobbler.Then, filter out catalyzer, wash Celite pad well with ethyl acetate afterwards by Celite pad.Then, vacuum concentration filtrate.Biotage chromatogram (FLASH 12M, silicon-dioxide, 98/2 to 95/5 methylene chloride) provides: N-(2-methoxyl group-ethyl)-pyrazine-2,5-diamines (198mg, 80%) is orange solids: EI-HRMS m/e calculated value C
7H
12N
4O (M
+) 168.1011, actual measurement 168.1018.
[000338] use 2.0M at methylene dichloride (565 μ L; 1.13mmol) and N; 2 (Rs)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-propionic acid (according to embodiment 1 in the preparation of oxalyl chloride solution-treated in the dinethylformamide (1) in methylene dichloride (15mL); 325mg, solution 0.33mmol).Reaction mixture was stirred 30 minutes in 0 ℃, vacuum concentration, and with twice of methylene dichloride (2mL) azeotropic.By feed hopper, be used in N-(2-methoxyl group-ethyl)-pyrazine-2 in the tetrahydrofuran (THF) (6mL) with obtaining then in the tetrahydrofuran (THF) (5mL) that oil is dissolved in 25 ℃, 5-diamines (182mg, 1.08mmol) and 2, (137 μ L, solution 1.18mmol) drip and handle the 6-lutidine.Then, will obtain turbid solution spent the night 16 hours in 25 ℃ of stirrings.After this, water (10mL) diluted reaction mixture is used methylene dichloride (3 * 25mL) extractions afterwards.Organic layer with dried over sodium sulfate merges filters, and vacuum concentration.Biotage chromatogram (FLASH 40S; silicon-dioxide; 40/60 to 20/80 hexane/ethyl acetate) provide: 2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(2-methoxyl group-ethylamino)-pyrazine-2-yl]-propionic acid amide (295mg, 62%), white foam: (ES)
+-HRMS m/e calculated value C
22H
29ClN
4O
4S (M+H)
+481.1671, actual measurement 481.1678.
Embodiment 73
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(2-hydroxyl-ethylamino)-pyrazine-2-yl]-propionic acid amide
[000339] will the 2-bromo-5-nitro pyrazine in the methyl alcohol (15mL) (500mg, 2.45mmol) and thanomin (225mg, mixture 3.67mmol) stirred 5 hours in 25 ℃.After this, vacuum concentration reaction mixture.Biotage chromatogram (FLASH 40S, silicon-dioxide, 20/80 hexane/ethyl acetate to 97/3 ethyl acetate/methanol) provides: 2-(5-nitro-pyrazine-2-base is amino)-ethanol (375mg, 83%) is yellow solid: mp 157.5-159.8 ℃; EI-HRMS m/e calculated value C
6H
8N
4O
3(M
+) 184.0596, actual measurement 184.0603.
[000340] with chloro triethyl-silicane (371 μ L, 2.21mmol) and imidazoles (342mg, 5.02mmol) handle the N at 0 ℃, the 2-in the dinethylformamide (10mL) (5-nitro-pyrazine-2-base is amino)-ethanol (370mg, solution 2.01mmol).Then, reaction mixture is warmed to 25 ℃, its stirring was spent the night 16 hours in this temperature.After this, use ethyl acetate (20mL) and saturated sodium-chloride water solution (10mL) diluted reaction mixture, and then (2 * 10mL) extract with ethyl acetate.Organic layer with dried over sodium sulfate merges filters, and vacuum concentration.Biotage chromatogram (FLASH 40S, silicon-dioxide, 25/75 hexane/ethyl acetate) provides: (5-nitro-pyrazine-2-yl)-(2-silicoheptane alcoxyl base-ethyl)-amine (531mg, 89%) is faint yellow solid: (ES)
+-HRMS m/e calculated value C
12H
22N
4O
3Si (M+H)
+299.1534, actual measurement 299.1538.
[000341] handles (5-nitro-pyrazine-2-yl)-(2-silicoheptane alcoxyl base-ethyl)-amine (530mg, solution 1.78mmol) in ethyl acetate (25mL) with 10% at the palladium on the gac (60mg).Then, under the hydrogen atmosphere of 50psi, reaction mixture was placed 4 hours in the Parr wobbler.Then, filter out catalyzer, wash Celite pad well with ethyl acetate afterwards by Celite pad.Then, vacuum concentration filtrate.Biotage chromatogram (FLASH 40S, silicon-dioxide, ethyl acetate) provides: N-(2-silicoheptane alcoxyl base-ethyl)-pyrazine-2,5-diamines (459mg, 96%) is orange-brown solid: (ES)
+-HRMS m/e calculated value C
12H
24N
4O
2Si (M+H)
+269.1792, actual measurement 269.1794.
[000342] use 2.0M at methyl chloride (869 μ L; 1.74mmol) and N; 2 (Rs)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-propionic acid (according to embodiment 1 in the preparation of oxalyl chloride solution-treated in the dinethylformamide (1) in methylene dichloride (20mL); 500mg, solution 1.51mmol).Reaction mixture was stirred 30 minutes in 0 ℃, vacuum concentration, and with twice of methylene dichloride (2mL) azeotropic.To obtain in the tetrahydrofuran (THF) (10mL) that oil is dissolved in 25 ℃, pass through feed hopper then, be used in N-(2-silicoheptane alcoxyl base-ethyl)-pyrazine-2 in the tetrahydrofuran (THF) (15mL), 5-diamines (446mg, 1.66mmol) and 2, (211, μ L, solution 1.81mmol) drip and handle the 6-lutidine.Then, will obtain turbid solution spent the night 16 hours in 25 ℃ of stirrings.After this, water (10mL) diluted reaction mixture is used methylene dichloride (3 * 25mL) extractions afterwards.Organic layer with dried over sodium sulfate merges filters, and vacuum concentration.Biotage chromatogram (FLASH 40M; silicon-dioxide; 85/15 to 50/50 hexane/ethyl acetate) provide: 2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(2-silicoheptane alcoxyl base-ethylamino)-pyrazine-2-yl]-propionic acid amide (606mg; 69%), is weak yellow foam: (ES)
+-HRMS m/e calculated value C
27H
41ClN
4O
4SSi (M+H)
+581.2379, actual measurement 581.2386.
[000343] will be at 2 (R) in tetrahydrofuran (THF) (2mL), water (0.5mL) and the acetate (2mL)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(2-silicoheptane alcoxyl base-ethylamino)-pyrazine-2-yl]-(100mg, solution 0.17mmol) stirred 6 hours in 25 ℃ propionic acid amide.Then,, water (10mL) diluted reaction mixture is used methylene dichloride (3 * 20mL) extractions afterwards.With the organic layer that saturated sodium bicarbonate aqueous solution (10mL) washing merges, use dried over sodium sulfate, filter and vacuum concentration.Biotage chromatogram (FLASH 12M; silicon-dioxide; 40/60 hexane/ethyl acetate to 100% ethyl acetate) provide: 2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(2-hydroxyl-ethylamino)-pyrazine-2-yl]-propionic acid amide (69mg, 86%), white foam: (ES)
+-HRMS m/e calculated value C
21H
27ClN
4O
4S (M+H)
+467.1515, actual measurement 467.1517.
Embodiment 74
2 (R)-(3-chloro-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(1H-indoles-5-yl)-pyrazine-2-yl]-propionic acid amide
[000344] with nitrogen bubble by 5-indyl boric acid (340mg, 2.11mmol), 2-amino-5-bromo-pyrazine (245mg, 1.41mmol), yellow soda ash (493mg, 4.65mmol), the solution of glycol dimethyl ether (12mL) and water (4mL) 15 minutes.After this, with dichloro two (triphenyl phosphine) palladium (II) (98mg, 0.14mmol) treatment soln, and with the reaction mixture that obtains in 90 ℃ of heating two days.Then, reaction mixture is toppled in the entry (50mL), and (3 * 50mL) extract with ethyl acetate.Organic layer with dried over mgso merges filters and vacuum concentration.Biotage chromatogram (FLASH 40S, silicon-dioxide, 35/65 hexane/ethyl acetate) provides 5-(1H-indoles-5-yl)-pyrazine-2-base amine (122mg, 41%), is brown solid: EI-HRMS m/e calculated value C
2H
10N
4(M
+) 210.0905, actual measurement 210.0901.
[000345] use 2.0M at methylene dichloride (313 μ L; 0.63mmol) and N; oxalyl chloride solution-treated in the dinethylformamide (1) is cooled to 2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-propionic acid in 0 ℃ the methylene dichloride (15mL) (according to preparation among the embodiment 1; 180mg, solution 0.54mmol).Reaction mixture was stirred 30 minutes in 0 ℃, vacuum concentration, and with twice of methylene dichloride (2mL) azeotropic.The oil that obtains is dissolved in 25 ℃ the tetrahydrofuran (THF) (4mL), then by feed hopper, be used in 5-(1H-indoles-5-yl)-pyrazine-2-base amine in the tetrahydrofuran (THF) (6mL) (126mg, 0.60mmol) and 2, (76 μ L, solution 0.65mmol) drip and handle the 6-lutidine.Then, the turbid solution that obtains was spent the night 16 hours in 25 ℃ of stirrings.After this, water (10mL) diluted reaction mixture is used methylene dichloride (3 * 25mL) extractions then.Organic layer with dried over sodium sulfate merges filters, and vacuum concentration.Biotage chromatogram (FLASH 40S, silicon-dioxide, 50/50 hexane/ethyl acetate) is dissolved in the methylene dichloride (30mL).With 1N aqueous citric acid solution (15mL) and saturated sodium bicarbonate aqueous solution (15mL) washing organic layer; use dried over sodium sulfate; filter and concentrate; provide: 2 (R)-(3-chloro-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(1H-indoles-5-yl)-pyrazine-2-yl]-propionic acid amide (203mg; 71%), is the canescence foam: (ES)
+-HRMS m/e calculated value C
27H
27ClN
4O
3S (M+H)
+523.1565, actual measurement 523.1567.
Embodiment 75
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(5,6-dihydro-4H-pyrans-2-yl)-pyrazine-2-yl]-propionic acid amide
[000346] with four (triphenyl phosphine) palladium (0) (13mg, 0.01mmol), N, N-diisopropylethylamine (250 μ L, 1.43mmol), lithium chloride (85mg, 2.01mmol) and 5, (214mg 0.58mmol) handles at N 6-dihydro-2-(tributyl tin silylation)-4H-pyrans, 2-amino-5-bromo-pyrazine (100mg, solution 0.58mmol) in the dinethylformamide (6mL).The reaction mixture that obtains was stirred 4 hours in 120 ℃.After this, reaction mixture is cooled to 25 ℃, handles, and spent the night 16 hours in 25 ℃ of stirrings with saturated potassium fluoride solution (10mL).Then, use methylene dichloride (25mL) diluting soln, and (3 * 15mL) extract with methylene dichloride.Organic layer with dried over sodium sulfate merges filters, and vacuum concentration.Biotage chromatogram (FLASH 12M, silicon-dioxide, 50/50 to 25/75 hexane/ethyl acetate) provides: 5-(5,6-dihydro-4H-pyrans-2-yl)-pyrazine-2-base amine (25mg, 25%) as a foam:EI-HRMS m/e calculated value C
9H
11N
3O (M
+) 177.0902, actual measurement 177.0906.
[000347] use 2.0M at methylene dichloride (70 μ L; 1.63mmol) and N; oxalyl chloride solution-treated in the dinethylformamide (1) is cooled to 2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-propionic acid in 0 ℃ the methylene dichloride (15mL) (according to preparation among the embodiment 1; 40mg, solution 0.12mmol).Reaction mixture was stirred 30 minutes in 0 ℃, vacuum concentration, and with twice of methylene dichloride (2mL) azeotropic.The oil that obtains is dissolved in 25 ℃ the tetrahydrofuran (THF) (1mL), pass through feed hopper then, be used in the 5-(5 in the tetrahydrofuran (THF) (1.5mL), 6-dihydro-4H-pyrans-2-yl)-pyrazine-2-base amine (24mg, 0.13mmol) and 2, (17 μ L, solution 0.15mmol) drip and handle the 6-lutidine.Then, the turbid solution that obtains was spent the night 16 hours in 25 ℃ of stirrings.After this, water (10mL) diluted reaction mixture is used methylene dichloride (3 * 25mL) extractions then.Organic layer with dried over sodium sulfate merges filters, and vacuum concentration.Biotage chromatogram (FLASH 12M; silicon-dioxide, 80/20 to 70/30 hexane/ethyl acetate) provide: 2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(5,6-dihydro-4H-pyrans-2-yl)-pyrazine-2-yl]-propionic acid amide (25mg; 42%) white foam: (ES)
+-HRMSm/e calculated value C
24H
28ClN
3O
4S (M+H)
+490.1562, actual measurement 490.1562.
Embodiment 76
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-thiophene-2-base-pyrazine-2-yl)-propionic acid amide
[0003408] will be at the 2-amino in glycol dimethyl ether (8mL) and the ethanol (8mL)-5-bromo-pyrazine (500mg, 2.874mmol), dichloro two (triphenyl phosphine) palladium (II) (290mg, 0.413mmol), the 2-thienyl boric acid (500mg, 3.907mmol) and the mixture heating up backheat of saturated aqueous sodium carbonate (4mL) spend the night.With the reaction mixture cooling, with ethyl acetate, water and saturated sodium-chloride water solution dilution.After the mixing, layer separates.Use the ethyl acetate extraction water.Organic layer with anhydrous sodium sulfate drying merges filters and vacuum concentration.Biotage chromatogram (FLASH 40M, silica 1/1 hexane/ethyl acetate) provides: 5-thiophene-2-base-pyrazine-2-base amine (267mg, 52.4%) is yellow solid: EI-HRMS m/e calculated value C
8H
7N
3S (M
+) 177.0361, actual measurement 177.0355.
[000349] (160.0mg 0.899mmol) handles triphenyl phosphine (230.0mg, solution 0.877mmol) in being cooled to 0 ℃ methylene dichloride (15mL) with N-bromo-succinimide.In 0 ℃ of stirring 5 minutes, (according to preparation among the embodiment 1,232.0mg 0.701mmol) handled to use 2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-propionic acid then with reaction mixture.In 15 minutes, be warmed to 25 ℃ at reaction mixture.Then, (260.0mg 1.467mmol), then uses pyridine (0.24mL, 2.967mmol) reaction mixture with 5-thiophene-2-base-pyrazine-2-base amine.The reaction mixture that obtains was stirred 1 hour in 25 ℃.Then, use the methylene dichloride diluted reaction mixture, and wash with diluted hydrochloric acid aqueous solution.Use the dichloromethane extraction water layer.With the organic layer that saturated sodium bicarbonate aqueous solution and water washing merge, use anhydrous sodium sulfate drying, filter and vacuum concentration.Biotage chromatogram (FLASH 40M, silicon-dioxide, 3/1 to 3/2 hexane/ethyl acetate) provides 2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-thiophene-2-base-pyrazine-2-yl)-propionic acid amide (202.3mg, 58.9%), is yellow foam: mp 97-99 ℃ (foam is to gel); (ES)
+-HRMS m/e calculated value C
23H
24ClN
3O
3S
2(M+H)
+490.1021, actual measurement 490.1026.
Embodiment 77
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-thiene-3-yl--pyrazine-2-yl)-propionic acid amide
[000350] will be at the 2-amino in glycol dimethyl ether (8mL) and the ethanol (8mL)-5-bromo-pyrazine (500mg, 2.874mmol), dichloro two (triphenyl phosphine) palladium (II) (290mg, 0.413mmol), 3 thienylboronic acid (500mg, 3.908mmol) and the mixture heating up of saturated aqueous sodium carbonate (4mL) refluxed 45 minutes.Then, with the reaction mixture cooling, with the ethyl acetate dilution, and water and saturated sodium-chloride water solution washing.Use the anhydrous sodium sulfate drying organic layer, filter and vacuum concentration.Biotage chromatogram (FLASH 40M, silicon-dioxide, 1/1 hexane/ethyl acetate) provides: 5-thiene-3-yl--pyrazine-2-base amine (351.3mg, 69%) is the lavender solid: EI-HRMS m/e calculated value C
8H
7N
3S (M
+) 177.0361, actual measurement 177.0358.
[000351] (103.0mg 0.579mmol) handles triphenyl phosphine (149.0mg, solution 0.568mmol) in being cooled to 0 ℃ methylene dichloride (8mL) with N-bromo-succinimide.In 0 ℃ of stirring 5 minutes, (according to preparation among the embodiment 1,150.0mg 0.453mmol) handled to use 2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-propionic acid then with reaction mixture.In 15 minutes, be warmed to 25 ℃ at reaction mixture.Then, (168.0mg 0.948mmol), then uses pyridine (0.16mL, 1.978mmol) reaction mixture with 5-thiene-3-yl--pyrazine-2-base amine.The reaction mixture that obtains was stirred 1.5 hours in 25 ℃.Then, use the methylene dichloride diluted reaction mixture, and wash with diluted hydrochloric acid aqueous solution.Use the dichloromethane extraction water layer.With the organic layer that the saturated sodium bicarbonate aqueous solution washing merges, use anhydrous sodium sulfate drying, filter and vacuum concentration.Biotage chromatogram (FLASH 40S, silicon-dioxide, 3/1 to 2/1 hexane/ethyl acetate) provides 2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-thiene-3-yl--pyrazine-2-yl)-propionic acid amide (105.6mg, 47.5%), is weak yellow foam: mp 96-102 ℃ (foam is to gel); (ES)
+-HRMS m/e calculated value C
23H
24ClN
3O
3S
2(M+H)
+490.1021, actual measurement 490.1023.
Embodiment 78
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-furans-3-base-pyrazine-2-yl)-propionic acid amide
[000352] will be at the 2-amino in glycol dimethyl ether (5mL) and the ethanol (5mL)-5-bromo-pyrazine (300mg, 1.724mmol), four (triphenyl phosphine) palladium (0) (340mg, 0.294mmol), furans-3-boric acid (300mg, 2.681mmol) and the mixture heating up of saturated aqueous sodium carbonate (2mL) refluxed 45 minutes.Then, with the reaction mixture cooling, with the ethyl acetate dilution, and water and saturated sodium-chloride water solution washing.Use the anhydrous sodium sulfate drying organic layer, filter and vacuum concentration.Biotage chromatogram (2/3 hexane/ethyl acetate is to ethyl acetate for FLASH 40M, silicon-dioxide) provides: 5-furans-3-base-pyrazine-2-base amine (256.9mg, 92.5%), be yellow solid: LRMS is for C
8H
7N
3O (M+H)
+At m/z=162.
[000353] (160.0mg 0.899mmol) handles triphenyl phosphine (230.0mg, solution 0.877mmol) in being cooled to 0 ℃ methylene dichloride (14mL) with N-bromo-succinimide.In 0 ℃ of stirring 5 minutes, (according to preparation among the embodiment 1,232.0mg 0.701mmol) handled to use 2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-propionic acid then with reaction mixture.In 15 minutes, be warmed to 25 ℃ at reaction mixture.Then, (250.0mg 1.551mmol), then uses pyridine (0.12mL, 1.484mmol) reaction mixture with 5-furans-3-base-pyrazine-2-base amine.The reaction mixture that obtains was stirred 2.5 hours in 25 ℃.Then, use the methylene dichloride diluted reaction mixture, and wash with diluted hydrochloric acid aqueous solution.Use the dichloromethane extraction water layer.With the organic layer that saturated sodium bicarbonate aqueous solution and water washing merge, use anhydrous sodium sulfate drying, filter and vacuum concentration.Biotage chromatogram (FLASH40M, silicon-dioxide, 3/2 to 45/55 hexane/ethyl acetate) provides: 2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-furans-3-base-pyrazine-2-yl)-propionic acid amide (161.1mg, 48.5%), is weak yellow foam: mp 97-101 ℃ (foam is to gel); (ES)
+-HRMS m/e calculated value C
23H
24ClN
3O
3S
2(M+H)
+474.1249, actual measurement 474.1252.
Embodiment 79
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-N-[5-(5-cyano group-thiophene-2-yl)-pyrazine-2-yl]-3-cyclopentyl-propionic acid amide
[000354] will be at the 2-amino in glycol dimethyl ether (5mL) and the ethanol (5mL)-5-bromo-pyrazine (300mg, 1.724mmol), dichloro two (triphenyl phosphine) palladium (II) (175mg, 0.249mmol), 5-cyano thiophene-2-boric acid (540mg, 3.53mmol) and the mixture heating up of saturated aqueous sodium carbonate (2mL) reflux and to spend the night.Then, with the reaction mixture cooling, with the ethyl acetate dilution, and water and saturated sodium-chloride water solution washing.Use the anhydrous sodium sulfate drying organic layer, filter and vacuum concentration.Biotage chromatogram (FLASH 40S, silicon-dioxide, 2/3 to 1/9 hexane/ethyl acetate) provides 5-(5-amino-pyrazino-2-yl)-thiophene-2-nitrile (49.1mg, 14.1%), and be yellow solid: LRMS is for C
9H
6N
4S (M+H)
+At m/z=203.
[000355] (35.0mg 0.197mmol) handles triphenyl phosphine (50.0mg, solution 0.191mmol) in being cooled to 0 ℃ methylene dichloride (2mL) with N-bromo-succinimide.In 0 ℃ of stirring 5 minutes, (according to preparation among the embodiment 1,51.0mg 0.154mmol) handled to use 2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-propionic acid then with reaction mixture.In 15 minutes, be warmed to 25 ℃ at reaction mixture.Then, (47.0mg 0.232mmol), then uses pyridine (30.0 μ L, 0.371mmol) reaction mixture with 5-(5-amino-pyrazino-2-yl)-thiophene-2-nitrile.The reaction mixture that obtains was stirred 2 hours in 25 ℃.Then, use the methylene dichloride diluted reaction mixture, and wash with diluted hydrochloric acid aqueous solution.Use the dichloromethane extraction water layer.With the organic layer that saturated sodium bicarbonate aqueous solution and water washing merge, use anhydrous sodium sulfate drying, filter and vacuum concentration.Biotage chromatogram (FLASH, 40S, silicon-dioxide, 1/1 hexane/ethyl acetate) provide: 2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-N-[5-(5-cyano group-thiophene-2-yl)-pyrazine-2-yl]-3-cyclopentyl-propionic acid amide (44.4mg, 55.9%), is yellow foam: mp101-107 ℃ (foam is to gel); (ES)
+-HRMS m/e calculated value C
24H
23ClN
4O
3S
2(M+H)
+515.0973, actual measurement 515.0974.
Embodiment 80
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-{5-(4,5-dihydro-1H-imidazoles-2-yl)-pyrazine-2-yl }-propionic acid amide three fluoro-acetates
[000356] with 2-amino-5-cyano pyrazine (500.0mg, 4.163mmol), 1 (3.0mL, 44.88mmol) and thiophosphoric anhydride (185.1mg, mixture 0.416mmol) is placed in the sealed tube, and in 120 ℃ the heating 3 hours.At this moment, reaction mixture is poured on ice.Dilute the reaction mixture that obtains with chloroform (50mL), water (10mL) and saturated sodium-chloride water solution (20mL).Layer separates.Wash organic layer with saturated sodium-chloride water solution, use anhydrous magnesium sulfate drying, filter and vacuum concentration, provide: 5-(4,5-dihydro-1H-imidazoles-2-yl)-pyrazine-2-base amine (327.0mg, 48.1%), be white solid, it uses under the condition that is not further purified.
[000357] uses N; dinethylformamide (1); then with oxalyl chloride (0.16mL; 1.834mmol) handle 2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-propionic acid (preparation in according to embodiment 1 in being cooled to 0 ℃ methylene dichloride (4mL); 288.0mg, solution 0.871mmol).Reaction mixture in 0 ℃ of stirring 15 minutes, was stirred 1 hour in 25 ℃ then.The vacuum concentration reaction mixture provides a kind of oil.Will be in methylene dichloride (4mL) should oil solution be cooled to 0 ℃, be used in the 5-(4 in the tetrahydrofuran (THF) (4mL) then, 5-dihydro-1H-imidazoles-2-yl)-pyrazine-2-base amine (150.0mg, 0.919mmol) and pyridine (0.08mL, 0.989mmol) thin pulp handle, then thin pulp is washed in the reaction mixture with tetrahydrofuran (THF) (2mL).(0.08mL 0.989mmol) handles the orange reaction mixture that obtains, and in 0 ℃ of stirring 30 minutes, spends the night in 25 ℃ of stirrings then with pyridine.Then, with 90/10/1 methylene chloride/dense ammonium hydroxide aqueous solution diluted reaction mixture, and water and saturated sodium-chloride water solution washing.With 90/10/1 methylene chloride/dense ammonium hydroxide aqueous solution washing water layer.Wash the organic layer of the merging that merges with saturated sodium-chloride water solution, use anhydrous sodium sulfate drying, filter and vacuum concentration.This crude product is provided by the RPLC purifying: 2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-{5-(4,5-dihydro-1H-imidazoles-2-yl)-pyrazine-2-yl }-propionic acid amide; With three fluoro-acetate (1.1mg, 0.21%) chemical combination, be white solid: LRMS is for C
22H
26ClN
5O
3S (M+H)
+At m/z=476.
Embodiment 81
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(2 (S), 3-dihydroxyl-propyl group)-pyrazine-2-yl]-propionic acid amide
[000358] will be at N, 2-amino in the dinethylformamide (29mL)-5-bromo-pyrazine (1.00g, 5.746mmol), four (triphenyl phosphine) palladium (0) (132mg, 0.114mmol), allyl group tri-n-butyl tin (2.2mL, 7.096mmol), lithium chloride (875.0mg, 20.64mmol) and N, (2.6mL, mixture 14.93mmol) stirred 45 minutes in 120 ℃ the N-diisopropylethylamine.Reaction mixture is cooled to 25 ℃, uses saturated potassium fluoride aqueous solution (20mL) to handle then.Mixture was stirred 3 hours.The solution-treated of water and saturated sodium-chloride water solution, and use ethyl acetate extraction.Organic layer with anhydrous sodium sulfate drying merges filters and vacuum concentration.Biotage chromatogram (FLASH 40L, silicon-dioxide, 1/1 hexane/ethyl acetate) provides: 5-allyl group-pyrazine-2-base amine (378.2mg, 48.7%), be yellow solid: LRMS is for C
7H
9N
3(M+H)
+At m/z=136.
[000359] under nitrogen; with oxalyl chloride (0.64mL; 7.336mmol); then use N; dinethylformamide (2) is handled 2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-propionic acid (preparation in according to embodiment 1 in being cooled to 0 ℃ methylene dichloride (12mL); 800.0mg, solution 2.418mmol).Reaction mixture in 0 ℃ of stirring 30 minutes, was stirred 1.25 hours in 25 ℃ then.The vacuum concentration reaction mixture.Residuum is dissolved in methylene dichloride (12mL), under nitrogen, is cooled to 0 ℃, be used in then 5-allyl group-pyrazine in the methylene dichloride (12mL)-2-base amine (0.37g, 2.737mmol) and pyridine (0.59mL, solution 7.295mmol) handled in 1 minute.The reaction mixture that obtains was stirred 30 minutes in 0 ℃, stirred 1 hour in 25 ℃ then.Then, use the ethyl acetate diluted reaction mixture, and wash with the 1N aqueous hydrochloric acid.Use the ethyl acetate extraction water layer.The organic layer that anhydrous sodium sulfate drying merges filters and vacuum concentration.Biotage chromatogram (FLASH, 40L, silicon-dioxide, 1/1 hexane/ethyl acetate) provides: N-(5-allyl group-pyrazine-2-yl)-2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl propionic acid amide (965mg, 89.1%), white foam: LRMS is for C
22H
26ClN
3O
3S (M-H)
+At m/z=446.
[000360] will butanol/water (16.0mL, 1:1) Tripotassium iron hexacyanide in (1.00g, 3.037mmol), salt of wormwood (430.0mg, 3.111mmol) and (DHQ)
2PHAL (19.0mg; 0.0244mmol) yellow solution be cooled to 0 ℃; use 0.2M at toluene (0.048mL then; 0.0096mmol) in the solution-treated of perosmic anhydride; then (446.0mg 0.996mmol) handles with N-(5-allyl group-pyrazine-2-yl)-2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl propionic acid amide.Reaction mixture was stirred 4 hours in 0 ℃.Then, and usefulness ethyl acetate and sodium metabisulfite (0.45g, 2.37mmol) diluted reaction mixture, and be warmed to 25 ℃, in this temperature it was stirred 15 minutes.Then, with saturated sodium-chloride water solution and water diluted mixture thing, and use ethyl acetate extraction.Organic layer with anhydrous sodium sulfate drying merges filters and vacuum concentration.Biotage chromatogram (FLASH 40M, silicon-dioxide, 2/3 hexane/ethyl acetate is to ethyl acetate) provide: 2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(2 (S), 3-dihydroxyl-propyl group)-pyrazine-2-yl]-propionic acid amide (370.2mg, 77.1%) white foam: mp 61-65 ℃ (foam is to gel); (ES)
+-HRMS m/e calculated value C
22H
28ClN
3O
5S (M+H)
+482.1511, actual measurement 482.1516.
Embodiment 82
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(2 (R), 3-dihydroxyl-propyl group)-pyrazine-2-yl]-propionic acid amide
[000361] will butanol/water (16.0mL, 1:1) Tripotassium iron hexacyanide in (1.00g, 3.037mmol), salt of wormwood (430.0mg, 3.111mmol) and (DHQD)
2PHAL (19.0mg; 0.0244mmol) yellow solution be cooled to 0 ℃; use 0.2M at toluene (0.048mL then; 0.0096mmol) in the solution-treated of perosmic anhydride; then use N-(5-allyl group-pyrazine-2-yl)-2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl propionic acid amide (according to preparation among the embodiment 81; 446.0mg, 0.996mmol) handle.Reaction mixture was stirred 4 hours in 0 ℃.Then, and usefulness ethyl acetate and sodium metabisulfite (0.45g, 2.37mmol) diluted reaction mixture, and be warmed to 25 ℃, in this temperature it was stirred 15 minutes.Then, with saturated sodium-chloride water solution and water diluted mixture thing, and use ethyl acetate extraction.Organic layer with anhydrous sodium sulfate drying merges filters and vacuum concentration.Biotage chromatogram (FLASH 40M, silicon-dioxide, 2/3 hexane/ethyl acetate is to ethyl acetate) provide: 2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(2 (R), 3-dihydroxyl-propyl group)-pyrazine-2-yl]-propionic acid amide (469.2mg, 89%) white foam: mp 64-69 ℃ (foam is to gel); (ES)
+-HRMS m/e calculated value C
22H
28ClN
3O
5S (M+H)
+482.1511, actual measurement 482.1511.
Biological activity
Embodiment A: external glucokinase activity
[000362] glucokinase analytical plan: by with the generation of G-6-P and the generation coupling mutually of NADH, analyze glucokinase (GK), wherein the generation of NADH has glucose-6-phosphate dehydrogenase (G6PD) (G6PDH, the 0.75-1k unit/mg from leuconostoc mesenteroides (Leuconostoc mesenteroides); Boehringer Mannheim, Indianapolis is IN) as conjugate enzyme (reaction scheme 2).
Reaction scheme 2
[000363] recombinant human liver GK1 is expressed [Liang etc. as glutathione S-transferase fusion rotein (GST-GK) in intestinal bacteria, 1995], and on glutathione agarose gel 4B affinity column with manufacturer (Amersham Pharmacia Biotech, Piscataway, the method chromatogram purification that NJ) provides.Character substantially the same (Liang etc., 1995 of the enzyme of verified natural GK of research in the past and GST-GK; Neet etc., 1990).
[000364] under 25 ℃, in that (Cambridge analyzes in the flat tissue culturing plate in 96 holes MA), and whole volume of culture is 120 μ l from Costar.Culturing mixt contains: 25mM Hepes damping fluid (pH, 7.1), 25mM KCl, 5mM D-glucose, 1mM ATP, 1.8mM NAD, 2mM MgCl
2, 1 μ M Sorbitol Powder-6-phosphoric acid, 1mM dithiothreitol (DTT), trial drug or 10%DMSO, 1.8 units/ml G6PDH, and GK (as follows).All organic reagent purity〉98%, except D-glucose and Hepes from Sigma Chemical Co, St Louis, MO, other is from Boehringer Mannheim.Test compounds is dissolved in DMSO, and adding volume then is the culturing mixt that does not contain GST-GK of 12 μ l, to the final concentration of DMSO be 10%.This mixture is placed SPECTRAmax 250 microplate spectrophotometers, and (pre-incubation is 10 minutes in temperature control tank CA), makes temperature equilibrium for Molecular DevicesCorporation, Sunnyvale, adds 20 μ l GST-GK initial actions then.
[000365] add enzyme after, monitor in 10 minutes the soak, the increase of the optical density(OD) at 340nm place (OD) is as the active measurement of GK.Add enough GST-GK the hole of not having test compounds so that contain 10%DMSO in 10 minutes soak, OD
340Be increased to 0.1 unit from 0.08.Preliminary experiment shows, GK is reflected at and is linear in this time period, even also like this when the activator that produces the GK activity and increased by 5 times exists.Control wells and the GK activity that contains in the hole of testing the GK activator have been compared.Calculating makes the concentration of the activator of the active increase by 50% of GK, is expressed as SC
1.5, promptly activate the required activator irritating concentration of GK enzyme 50%.All compounds that embodiment describes all have the SC of being less than or equal to 100 μ M
1.5
Reference:
[000366] Liang, Y., Kesavan, P., Wang, L., Niswender, K., Tanizawa, Y., Permut, M.A., Magnuson, M., and Matschinsky, F.M.Variable effects ofmaturity-onset-diabetes-of-youth (MODY)-associated glucokinase mutationson the substrate interactions and stability of the enzyme.Biochem.J.309:167-173,1995.
[000367] Neet, K., Keenan, R.P., and Tippett, P.S.Observation of akinetic slow transition in monomeric glucokinase.Biochemistry 29; 770-777,1990.
Biological activity Embodiment B: glucokinase activity in the body
[000368] screening scheme in the glucokinase activating agents body: by oral gavage dosed administration glucokinase (GK) activator, the 50mg/kg body weight is followed two hours fasting time with the C57BL/6J mouse.During studying behind the dosed administration in six hours, carry out blood sugar detection 5 times.
[000369] mouse (n=6) is weighed and fasting two hours before oral administration.The GK activator is formulated in Gelucire carrier (ethanol: Gelucire 44/14:PEG400q.s.4:66:30v/w/v) with 6.76mg/ml.The every g body weight of mouse oral administration 7.5 μ L preparations are equivalent to 50mg/kg dosage.Dosed administration at once before, by cut small portion animal tail (～1mm) and collect 15 μ L blood and in the kapillary of heparinization, be used for analyzing, obtain the glucose readings of (zero-time) before the dosed administration.After the administration of GK activator, behind dosed administration, obtained other glucose readings from the identical end portions wound in 1,2,4 and 6 hours.The average blood sugar value of the mouse that mouse by six vehicle treated relatively and six GK activator are handled in during research in six hours come analytical results.Think compare with carrier two METHOD FOR CONTINUOUS DETERMINATION blood sugar constantly show statistics significantly (p＜0.05) reduce those are preferred compounds.
The galenic embodiment A
[000370] can prepare the tablet that contain following composition according to ordinary method:
Composition
The mg/ sheet
Formula I compound 10.0-100.0
Lactose 125.0
W-Gum 75.0
Talcum 4.0
Magnesium Stearate 1.0
The galenic Embodiment B
[000371] can prepare the capsule that contain following composition according to ordinary method:
Composition
The Mg/ capsule
Formula I compound 25.0
Lactose 150.0
W-Gum 20.0
Talcum 5.0
Claims (74)
1. according to the compound or pharmaceutically acceptable salt thereof of formula I
R wherein
1It is the alkyl that contains 1-5 carbon atom;
R
2Be hydrogen, halogen, nitro, cyano group, methyl, trifluoromethyl, hydroxyl, or methoxyl group;
R
3It is the cycloalkyl that contains 4-6 carbon;
Y is independently selected from CH and the N that forms pyridine or pyrazine ring respectively;
R
4Be the substituting group on pyridine or pyrazine ring 5, it is selected from
-(CH
2)
n-Q, wherein Q is the heterocycle that passes through the ring carbon atom connection that 5-unit is saturated, replace, described heterocycle contains two heteroatomss that are selected from nitrogen, sulphur and oxygen, and on each of two ring carbon atoms, all replaced by oxo group, and randomly be substituted base and replace on the ring carbon that connects, this substituting group is methyl or amino;
-(CH
2)
n-V, wherein V is unsubstituted or mono-substituted five or hexa-atomic saturated or undersaturated by encircling the heterocycle that carbon connects, described heterocycle contains 1-3 heteroatoms that is selected from sulphur, oxygen or nitrogen; Described mono-substituted heterocycle is with the mono-substituted heterocycle of substituting group that is selected from cyano group, halogen, nitro, amino, methyl, methoxyl group and hydroxyl;
Or nine or ten yuan of bicyclic heterocycles that connect by ring carbon atom, described bicyclic heterocycles contains a heteroatoms that is selected from oxygen, nitrogen or sulphur;
Unsubstituted or the mono-substituted hexa-atomic aromatic ring that connects by ring carbon atom, described mono-substituted aromatic ring are substituted the single replacement of base on the position of the ring carbon atom except the carbon atom of described connection, this substituting group is selected from cyano group, halogen, nitro, amino, methyl, methoxyl group, and hydroxyl;
R
5Be hydrogen or alkyl with 1-7 carbon atom;
R
6It is alkyl with 1-7 carbon atom;
R
7Be alkyl with 1-7 carbon atom, cyano group, or-C (=O) NH
2
R
8Be hydroxyl, methoxyl group, or dimethylamine;
R
9Be hydrogen or methyl;
R
10Be alkyl with 1-7 carbon atom, cyano group, or-NH
2
R
11Be hydrogen, have the alkyl of 1-7 carbon atom, or NHOH;
M is 0,1,2, or 3;
N is 0 or 1;
P is 1 or 2;
U is S, SO, or SO
2
Z is O, S, or NH;
The optional key of----expression;
*The expression unsymmetrical carbon.
2. according to the compound of claim 1, R wherein
1It is methyl.
3. according to the compound of claim 1, R wherein
2It is hydrogen or halogen.
4. according to the compound of claim 3, wherein halogen is a chlorine.
5. according to the compound of claim 1, R wherein
3It is cyclopentyl.
6. according to the compound of claim 1, R wherein
4Be-(CH
2)
n-U-CH
3
7. according to the compound of claim 6, wherein U is S.
8. according to the compound of claim 7, it is selected from
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-methylthio group-pyrazine-2-yl)-propionic acid amide; With
3-cyclopentyl-2 (R)-(4-methylsulfonyl-phenyl)-N-(5-methylthio group-pyrazine-2-yl)-propionic acid amide.
9. according to the compound of claim 6, wherein U is SO.
10. according to the compound of claim 9, it is
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-methanesulfinyl-pyrazine-2-yl)-propionic acid amide.
11. according to the compound of claim 6, wherein U is SO
2
12. according to the compound of claim 1, wherein R
4Be-ZCH
2CH
2-OR
9
13. according to the compound of claim 12, wherein R
4Be-SCH
2CH
2OH.
14. according to the compound of claim 13, it is
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(2-hydroxyl-ethylmercapto group)-pyrazine-2-yl]-propionic acid amide.
15. according to the compound of claim 1, wherein R
4Be-NHSO
2CH
3
16. according to the compound of claim 15, wherein this compound is selected from
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-methylsulfonyl amino-pyridine-2-yl)-propionic acid amide; With
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-methylsulfonyl amino-pyrazino-2-yl)-propionic acid amide.
17. according to the compound of claim 1, wherein R
4Be-(CH
2)
m-N (CH
3) CH
3
18. according to the compound of claim 17, it is
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-dimethylamino-pyridine-2-yl)-propionic acid amide.
19. according to the compound of claim 17, it is
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-dimethylamino-pyrazine-2-yl)-propionic acid amide.
20. according to the compound of claim 17, it is
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(3-dimethylamino-propyl group)-pyrazine-2-yl]-propionic acid amide.
21. according to the compound of claim 1, wherein R
4Be-C (=O) R
11
22. according to the compound of claim 21, it is
2-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-formyl radical-pyrazine-2-yl)-propionic acid amide.
23. according to the compound of claim 21, it is
N-(5-ethanoyl-pyrazine-2-yl)-2-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-propionic acid amide.
24. according to the compound of claim 21, it is
2-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-isobutyryl-pyrazine-2-yl)-propionic acid amide.
25. according to the compound of claim 1, wherein R
4Be-(CH
2)
n-C (OCH
3) OCH
3
26. according to the compound of claim 25, it is
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-dimethoxy-methyl-pyrazine-2-yl)-propionic acid amide.
27. according to the compound of claim 1, wherein R
4Be-C (OH) R
7
28. according to the compound of claim 27, it is selected from
2-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(1-hydroxyl-ethyl)-pyrazine-2-yl]-propionic acid amide;
2-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(1-hydroxy-2-methyl-propyl group)-pyrazine-2-yl]-propionic acid amide;
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-N-[5-(cyano group-hydroxyl-methyl)-pyrazine-2-yl]-3-cyclopentyl-propionic acid amide; With
N-[5-(formamyl-hydroxyl-methyl)-pyrazine-2-yl]-2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-propionic acid amide.
29. according to the compound of claim 1, wherein R
4Be
30. according to the compound of claim 29, it is selected from
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-methyl sulfamyl-pyrazine-2-yl)-propionic acid amide; With
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-dimethylamino alkylsulfonyl-pyrazine-2-yl)-propionic acid amide.
31. according to the compound of claim 1, it has the structure of formula II:
32. according to the compound of claim 31, wherein R
10Be methyl or-NH
2
33. according to the compound of claim 32, it is
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(N-hydroxyl amino formyl imino-)-pyrazine-2-yl]-propionic acid amide.
34. according to the compound of claim 32, it is
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(N-hydroxyl amino formyl imino-)-pyridine-2-yl]-propionic acid amide.
35. according to the compound of claim 32, it is
3-cyclopentyl-2 (R)-N-[5-(N-hydroxyl amino formyl imino-)-pyrazine-2-yl]-2-(4-methylsulfonyl-phenyl)-propionic acid amide.
36. according to the compound of claim 32, it is
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(1-(Z)-oxyimino-ethyl)-pyrazine-2-yl]-propionic acid amide.
37. according to the compound of claim 1, it has the structure of formula III
38. according to the compound of claim 37, wherein p is 1.
39. according to the compound of claim 37, wherein R8 is hydroxyl or dimethylamine.
40. according to the compound of claim 37, it is
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(3-hydroxyl-third-1-alkynyl)-pyrazine-2-yl]-propionic acid amide.
41. according to the compound of claim 37, it is
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(3-dimethylamino-third-1-alkynyl)-pyrazine-2-yl]-propionic acid amide.
42. according to the compound of claim 1, wherein R
4Be selected from
Unsubstituted five or the hexa-member heterocycle that connects by ring carbon atom, described five or hexa-member heterocycle contain a heteroatoms that is selected from sulphur, oxygen or nitrogen;
Unsubstituted or the mono-substituted 6-unit aromatic ring that connects by ring carbon atom, described mono-substituted aromatic ring is to be substituted the single replacement of base on the position of the ring carbon atom except described connection carbon atom, and described substituting group is selected from chlorine, bromine, nitro, amino, methyl, methoxyl group or hydroxyl.
43. according to the compound of claim 42, wherein R
4Be the first aromatic ring of unsubstituted or mono-substituted 6-, it is selected from the aromatic ring of unsubstituted aromatic ring, methoxyl group replacement and the aromatic ring that hydroxyl replaces.
44. according to the compound of claim 1, wherein R
4Be heterocycle unsubstituted or that replace, it is selected from:
45. according to the compound of claim 44, wherein R
4Be
46. according to the compound of claim 45, it is
N-[5-(5-amino-[1,2,4] oxadiazole-3-yls)-pyrazine-2-yl]-2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-propionic acid amide.
47. according to the compound of claim 1, wherein R
4Be the heterocycle that replaces, be selected from:
With
48. according to the compound of claim 47, it is
2-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(2,4-dioxo thiazolidine-5-ylmethyl)-pyrazine-2-yl]-propionic acid amide.
49. according to the compound of claim 47, it is
2-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(2,5-dioxo alkyl imidazole-4-ylmethyl)-pyrazine-2-yl]-propionic acid amide.
50. according to the compound of claim 1, wherein R
4Be two ring hetero-aromatic rings, it is
51. according to the compound of claim 1, wherein R
6Be methyl or ethyl.
52. according to the compound of claim 1, wherein R
4Be
R wherein
12Be the straight chained alkyl of 2 or 3 carbon atoms, wherein the Sauerstoffatom of this chain and its bonding is common forms five or six-ring.
53. according to the compound of claim 1, it is at-CH
2R
3The place is a racemic mixture as substituent chiral carbon.
54. according to the compound of claim 1, it is at-CH
2R
3As substituent chiral carbon place is the R configuration.
55. according to the compound of claim 1, it is R
4The racemic mixture of chiral carbon, R wherein
4Be
56., wherein work as R according to the compound of claim 1
4Be
With n be 1 o'clock, configuration is
57. according to the compound of claim 56, wherein R
4It is the R configuration.
58., wherein work as R according to the compound of claim 1
4Be
With n be 0 o'clock, configuration is
59. according to the compound of claim 58, wherein R
4It is the R configuration.
60. according to the compound of claim 1, it is R
4The racemic mixture of chiral carbon, R wherein
4Be
61., wherein work as R according to the compound of claim 1
4Be
Configuration is
Or
62. according to the compound of claim 61, wherein R
4It is the S configuration.
63. according to the compound of claim 1, wherein R
4Be
64. according to the compound of claim 1, it is selected from:
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(N-hydroxyl amino formyl imino-)-pyrazine-2-yl]-propionic acid amide,
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(N-hydroxyl amino formyl imino-)-pyridine-2-yl]-propionic acid amide,
3-cyclopentyl-2 (R)-N-[5-(N-hydroxyl amino formyl imino-)-pyrazine-2-yl]-2-(4-methylsulfonyl-phenyl)-propionic acid amide,
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-methylthio group-pyrazine-2-yl)-propionic acid amide,
3-cyclopentyl-2 (R)-(4-methylsulfonyl-phenyl)-N-(5-methylthio group-pyrazine-2-yl)-propionic acid amide,
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(2-hydroxyl-ethylmercapto group)-pyrazine-2-yl]-propionic acid amide,
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-methylsulfinyl-pyrazine-2-yl)-propionic acid amide,
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-methyl sulfamyl-pyrazine-2-yl)-propionic acid amide,
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-dimethylamino alkylsulfonyl-pyrazine-2-yl)-propionic acid amide,
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(3-hydroxyl-third-1-alkynyl)-pyrazine-2-yl]-propionic acid amide,
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(3-dimethylamino-third-1-alkynyl)-pyrazine-2-yl]-propionic acid amide,
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-methylsulfonyl amino-pyridine-2-yl)-propionic acid amide,
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-methylsulfonyl amino-pyrazino-2-yl)-propionic acid amide,
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-dimethylamino-pyridine-2-yl)-propionic acid amide,
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-dimethylamino-pyrazine-2-yl)-propionic acid amide,
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(3-dimethylamino-propyl group)-pyrazine-2-yl]-propionic acid amide,
N-[5-(5-amino-[1,2,4] oxadiazole-3-yls)-pyrazine-2-yl]-2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-propionic acid amide,
2-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-formyl radical-pyrazine-2-yl)-propionic acid amide,
2-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(2,4-dioxo thiazolidine-5-ylmethyl)-pyrazine-2-yl]-propionic acid amide,
2-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(2,5-dioxo-imidazolidine-4-ylmethyl)-pyrazine-2-yl]-propionic acid amide,
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-dimethoxy-methyl-pyrazine-2-yl)-propionic acid amide,
2-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(1-hydroxyl-ethyl) pyrazine-2-yl]-propionic acid amide,
N-(5-ethanoyl-pyrazine-2-yl)-2-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl propionic acid amide,
2-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(1-hydroxy-2-methyl-propyl group)-pyrazine-2-yl]-propionic acid amide,
2-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-isobutyryl-pyrazine-2-yl)-propionic acid amide,
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-N-[5-(cyano group-hydroxyl-methyl)-pyrazine-2-yl]-3-cyclopentyl-propionic acid amide,
N-[5-(formamyl-hydroxyl-methyl)-pyrazine-2-yl]-2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-propionic acid amide,
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(1-(Z)-oxyimino-ethyl)-pyrazine-2-yl]-propionic acid amide,
5-[2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-propionyl amino]-pyrazine-2-carboxylic acid hydroxamides,
2-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-methylthiomethyl-pyrazine-2-yl)-propionic acid amide,
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-methylsulfonyl methyl-pyrazine-2-yl)-propionic acid amide,
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-dimethylaminomethyl-pyrazine-2-yl)-propionic acid amide,
2-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(the 5-methyl-[1,2,4] oxadiazole-3-yls)-pyrazine-2-yl]-propionic acid amide,
3-cyclopentyl-N-[5-(1-oxyimino-ethyl)-pyrazine-2-yl]-2 (R)-(4-methylsulfonyl-phenyl)-propionic acid amide,
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(the 3-methyl-[1,2,4] oxadiazole-5-yls)-pyrazine-2-yl]-propionic acid amide,
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-methylthiomethyl-pyrazine-2-yl)-propionic acid amide,
2-(3-chloro-4-methylsulfonyl-phenyl)-N-[5-(cyano group-oxyimino-methyl)-pyrazine-2-yl]-3-cyclopentyl-propionic acid amide,
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-methylsulfinyl ylmethyl-pyrazine-2-yl)-propionic acid amide,
N-(5-ethanoyl-pyrazine-2-yl)-2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-propionic acid amide,
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(2-hydroxyl-1-methylol-ethyl)-pyrazine-2-yl]-propionic acid amide,
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-[1,3] dioxolane-2-base-pyrazine-2-yl)-propionic acid amide,
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-[1,3] dioxolane-2-ylmethyl-pyrazine-2-yl)-propionic acid amide,
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-5-(2-methoxy ethoxy-pyrazine-2-yl)-propionic acid amide,
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-2 (R), 3-dihydroxyl-propoxy-)-pyrazine-2-yl)-propionic acid amide,
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(2,2-dimethoxy-ethyl)-pyrazine-2-yl)-propionic acid amide,
3-cyclopentyl-N-5-[(4-hydroxyl-tetrahydropyran-4-base-ethynyl) pyrazine-2-yl]-2 (R)-(4-methylsulfonyl-phenyl)-propionic acid amide,
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(3-methoxyl group-third-1-alkynyl)-pyrazine-2-yl)-propionic acid amide,
3-cyclopentyl-2 (R)-(4-methylsulfonyl-phenyl)-N-[5-(3-methoxy propyl-1-alkynyl)-pyrazine-2-yl]-propionic acid amide,
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(2 (S), 3-dihydroxyl-propoxy-)-pyrazine-2-yl]-propionic acid amide,
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(4-hydroxyl-tetrahydropyran-4-base-ethynyl)-pyrazine-2-yl]-propionic acid amide,
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(4-hydroxyl-tetrahydropyran-4-base-ethyl)-pyrazine-2-yl]-propionic acid amide,
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(3-hydroxy-3-methyl-Ding-1-alkynyl)-pyrazine-2-yl]-propionic acid amide,
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(4-hydroxyl-Ding-1-alkynyl)-pyrazine-2-yl]-propionic acid amide,
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(1 (S), 2-dihydroxyl-ethyl)-pyrazine-2-yl]-propionic acid amide,
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(1 (R), 2-dihydroxyl-ethyl)-pyrazine-2-yl]-propionic acid amide,
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(2-hydroxyl-1-methylol-oxyethyl group)-pyrazine-2-yl]-propionic acid amide,
3-cyclopentyl-N-[5-(3-hydroxy-3-methyl-Ding-1-alkynyl)-pyrazine-2-yl]-2 (R)-(4-methylsulfonyl-3-methyl-phenyl)-propionic acid amide,
3-cyclopentyl-N-[5-1 (S), 2-dihydroxyl-ethyl]-2 (R)-(4-methylsulfonyl-3-methyl) propionic acid amide,
3-cyclopentyl-N-[5-(4-hydroxyl-tetrahydrochysene-pyrans-4-ethyl-acetylene base)-pyrazine-2-yl]-2 (R)-(4-methylsulfonyl-3-methyl-phenyl)-propionic acid amide,
3-cyclopentyl-N-[5-1 (R), 2-dihydroxyl-ethyl]-2 (R)-(4-methylsulfonyl-3-methyl)-propionic acid amide,
3-cyclopentyl-2 (R)-(4-methylsulfonyl-phenyl)-N-[5-(3-hydroxy-3-methyl-Ding-1-alkynyl)-pyrazine-2-yl]-propionic acid amide,
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(2-hydroxyl-oxyethyl group)-pyrazine-2-yl]-propionic acid amide,
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(2-p-methoxy-phenyl)-pyrazine-2-yl]-propionic acid amide,
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(2-hydroxy phenyl)-pyrazine-2-yl]-propionic acid amide,
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(1,2-dihydroxyl-ethyl)-pyrazine-2-yl]-propionic acid amide,
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(1 (S), 2-dihydroxyl-2-methyl-propyl group)-pyrazine-2-yl]-propionic acid amide,
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(1 (R), 2-dihydroxyl-2-methyl-propyl group)-pyrazine-2-yl]-propionic acid amide,
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(4-methyl-2,5-dioxo-imidazolidine-4-yl)-pyrazine-2-yl]-propionic acid amide,
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(tetrahydrochysene-furans-2-yl)-pyridine-2-yl]-propionic acid amide,
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-furans-2-base-pyrazine-2-yl)-propionic acid amide,
2 (R)-(3-chloro-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(3-methoxyl group-phenyl)-pyrazine-2-yl]-propionic acid amide,
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(2-methoxyl group-ethylamino)-pyrazine-2-yl]-propionic acid amide,
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(2-hydroxyl-ethylamino)-pyrazine-2-yl]-propionic acid amide,
2 (R)-(3-chloro-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(1H-indoles-5-yl)-pyrazine-2-yl]-propionic acid amide,
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(5,6-dihydro-4H-pyrans-2-yl)-pyrazine-2-yl]-propionic acid amide,
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-thiophene-2-base-pyrazine-2-yl)-propionic acid amide,
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-thiene-3-yl--pyrazine-2-yl)-propionic acid amide,
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-furans-3-base-pyrazine-2-yl)-propionic acid amide,
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-N-[5-(5-cyano group-thiophene-2-yl)-pyrazine-2-yl]-3-cyclopentyl-propionic acid amide,
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-{5-(4,5-dihydro-1H-imidazoles-2-yl)-pyrazine-2-yl }-propionic acid amide three fluoro-acetates,
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(2 (S), 3-dihydroxyl-propyl group)-pyrazine-2-yl]-propionic acid amide,
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(2 (R), 3-dihydroxyl-propyl group)-pyrazine-2-yl]-propionic acid amide,
And pharmaceutical salts.
65. according to the compound and the pharmaceutical salts thereof of claim 1, described compound is selected from:
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(N-hydroxyl amino formyl imino-)-pyrazine-2-yl]-propionic acid amide;
3-cyclopentyl-2 (R)-N-[5-(N-hydroxyl amino formyl imino-)-pyrazine-2-yl]-2-(4-methylsulfonyl-phenyl)-propionic acid amide;
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-methylthio group-pyrazine-2-yl)-propionic acid amide;
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(2-hydroxyl-ethylmercapto group)-pyrazine-2-yl]-propionic acid amide;
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-methanesulfinyl-pyrazine-2-yl)-propionic acid amide;
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(3-hydroxyl-third-1-alkynyl)-pyrazine-2-yl]-propionic acid amide;
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(3-dimethylamino-third-1-alkynyl)-pyrazine-2-yl]-propionic acid amide;
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-methylsulfonyl amino-pyridine-2-yl)-propionic acid amide;
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-dimethylamino-pyridine-2-yl)-propionic acid amide;
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-dimethylamino pyrazine-2-yl)-propionic acid amide;
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(3-dimethylamino-propyl group)-pyrazine-2-yl]-propionic acid amide;
N-[5-(5-amino-[1,2,4] oxadiazole-3-yls)-pyrazine-2-yl]-2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-propionic acid amide;
2-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-formyl radical-pyrazine-2-yl)-propionic acid amide;
2-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(2,4-dioxo-thiazolidine-5-ylmethyl)-pyrazine-2-yl]-propionic acid amide;
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-dimethoxy-methyl-pyrazine-2-yl)-propionic acid amide;
N-(5-ethanoyl-pyrazine-2-yl)-2-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-propionic acid amide;
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-N-[5-(cyano group-hydroxyl-methyl)-pyrazine-2-yl]-3-cyclopentyl-propionic acid amide;
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(1-(Z)-oxyimino-ethyl)-pyrazine-2-yl]-propionic acid amide;
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(1 (S), 2-dihydroxyl-ethyl)-pyrazine-2-yl]-propionic acid amide;
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(1 (S), 2-dihydroxyl-2-methyl-propyl group)-pyrazine-2-yl]-propionic acid amide;
And pharmaceutical salts.
66. according to the compound of claim 1, wherein said compound is 2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(1 (S), 2-dihydroxyl-ethyl)-pyrazine-2-yl]-propionic acid amide or its pharmaceutical salts.
67. according to the compound of claim 1, wherein said compound is 2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(1 (S), 2-dihydroxyl-2-methyl-propyl group)-pyrazine-2-yl]-propionic acid amide or its pharmaceutical salts.
68. a pharmaceutical composition, it comprises according to any one compound or pharmaceutically acceptable salt thereof and pharmaceutical carrier among the claim 1-67.
69. according to the pharmaceutical composition of claim 68, wherein said compound is selected from:
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(N-hydroxyl amino formyl imino-)-pyrazine-2-yl]-propionic acid amide;
3-cyclopentyl-2 (R)-N-[5-(N-hydroxyl amino formyl imino-)-pyrazine-2-yl]-2-(4-methylsulfonyl-phenyl)-propionic acid amide;
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-methylthio group-pyrazine-2-yl)-propionic acid amide;
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(2-hydroxyl-ethylmercapto group)-pyrazine-2-yl]-propionic acid amide;
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-methanesulfinyl-pyrazine-2-yl)-propionic acid amide;
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(3-hydroxyl-third-1-alkynyl)-pyrazine-2-yl]-propionic acid amide;
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(3-dimethylamino-third-1-alkynyl)-pyrazine-2-yl]-propionic acid amide;
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-methylsulfonyl amino-pyridine-2-yl)-propionic acid amide;
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-dimethylamino-pyridine-2-yl)-propionic acid amide;
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-dimethylamino-pyrazine-2-yl)-propionic acid amide;
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(3-dimethylamino-propyl group)-pyrazine-2-yl]-propionic acid amide;
N-[5-(5-amino-[1,2,4] oxadiazole-3-yls)-pyrazine-2-yl]-2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-propionic acid amide;
2-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-formyl radical-pyrazine-2-yl)-propionic acid amide;
2-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(2,4-dioxo-thiazolidine-5-ylmethyl)-pyrazine-2-yl]-propionic acid amide;
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-(5-dimethoxy-methyl-pyrazine-2-yl)-propionic acid amide;
N-(5-ethanoyl-pyrazine-2-yl)-2-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-propionic acid amide;
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-N-[5-(cyano group-hydroxyl-methyl)-pyrazine-2-yl]-3-cyclopentyl-propionic acid amide;
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(1-(Z)-oxyimino-ethyl)-pyrazine-2-yl]-propionic acid amide;
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(1 (S), 2-dihydroxyl-ethyl)-pyrazine-2-yl]-propionic acid amide;
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(1 (S), 2-dihydroxyl-2-methyl-propyl group)-pyrazine-2-yl]-propionic acid amide; And pharmaceutical salts;
And pharmaceutical carrier.
70. according to the pharmaceutical composition of claim 69, wherein said compound is selected from:
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(N-hydroxyl amino formyl imino-)-pyrazine-2-yl]-propionic acid amide;
3-cyclopentyl-2 (R)-N-[5-(N-hydroxyl amino formyl imino-)-pyrazine-2-yl]-2-(4-methylsulfonyl-phenyl)-propionic acid amide;
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(3-hydroxyl-third-1-alkynyl)-pyrazine-2-yl]-propionic acid amide;
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(1-(Z)-oxyimino-ethyl)-pyrazine-2-yl]-propionic acid amide, and pharmaceutical salts;
And pharmaceutical carrier.
71. according to the pharmaceutical composition of claim 69, wherein said compound is selected from:
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(1 (S), 2-dihydroxyl-ethyl)-pyrazine-2-yl]-propionic acid amide; With
2 (R)-(3-chloro-4-methylsulfonyl-phenyl)-3-cyclopentyl-N-[5-(1 (S), 2-dihydroxyl-2-methyl-propyl group)-pyrazine-2-yl]-propionic acid amide; And pharmaceutical salts;
And pharmaceutical carrier.
72. according to any one the application of compound in the medicine of preparation treatment type ii diabetes among the claim 1-67.
73. according to any one the application of compound in the medicine of preparation prevention type ii diabetes among the claim 1-67.
74. a method for preparing according to the compound of the formula I of any one among the claim 1-67, described method comprises:
(a) with the compound of formula IX
R wherein
20Be C
1-5Alkyl sulphonyl maybe will change C into
1-5The functional group of alkyl sulfone, R
2And R
3As any one defines among the claim 1-67;
With the compound reaction of formula X,
Wherein Y and R
4As any one defines among the claim 1-67,
Compound with the formula I of any one among the production claim 1-67.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US43280602P | 2002-12-12 | 2002-12-12 | |
| US60/432,806 | 2002-12-12 | ||
| US60/524,531 | 2003-11-24 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1726197A CN1726197A (en) | 2006-01-25 |
| CN100469770C true CN100469770C (en) | 2009-03-18 |
Family
ID=35925145
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB2003801058705A Expired - Fee Related CN100469770C (en) | 2002-12-12 | 2003-12-11 | 5-substituted-pyrazine or -pyridine glucokinase activators |
Country Status (3)
| Country | Link |
|---|---|
| CN (1) | CN100469770C (en) |
| GT (1) | GT200300283A (en) |
| ZA (1) | ZA200504474B (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8258134B2 (en) * | 2008-04-16 | 2012-09-04 | Hoffmann-La Roche Inc. | Pyridazinone glucokinase activators |
| EP2870138B1 (en) * | 2012-07-06 | 2018-08-22 | Genentech, Inc. | N-substituted benzamides and methods of use thereof |
| EP3101007A1 (en) * | 2015-06-05 | 2016-12-07 | Lead Pharma Cel Models IP B.V. | Ror gamma (rory) modulators |
| EP3101005A1 (en) * | 2015-06-05 | 2016-12-07 | Lead Pharma Cel Models IP B.V. | Ror gamma (rory) modulators |
| CN106187838B (en) * | 2016-07-13 | 2018-05-01 | 广东东阳光药业有限公司 | Aryl alkynes compound and its preparation method and application |
-
2003
- 2003-12-11 CN CNB2003801058705A patent/CN100469770C/en not_active Expired - Fee Related
- 2003-12-11 GT GT200300283A patent/GT200300283A/en unknown
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2005
- 2005-05-31 ZA ZA200504474A patent/ZA200504474B/en unknown
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| Publication number | Publication date |
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| GT200300283A (en) | 2004-07-14 |
| CN1726197A (en) | 2006-01-25 |
| ZA200504474B (en) | 2006-02-22 |
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