CN101490064B - Novel glucokinase activators and methods of using same - Google Patents

Abstract

Compounds are provided which are phosphonate and phosphinate activators and thus are useful in treating diabetes and related diseases and have the structure of Formula (I), wherein Formula (II) is a heteroaryl ring; R4 is -(CH2)n-Z-(CH2)m-PO(OR7)(OR8), -(CH2)nZ-(CH2)m-PO(OR7)R9, -(CH2)n-Z-(CH2)m-OPO(OR7)R9, -(CH2)nZ-(CH2)m-OPO(R9)(R10), or -(CH2)nZ-(CH2)m-PO(R9)(R10); R5 and R6 are independently selected from H, alkyl and halogen; Y is R7(CH2)s or is absent; and X, n, Z, m, R4, R5, R6, R7, and s are as defined herein; or a pharmaceutically acceptable salt thereof. A method for treating diabetes and related diseases employing the above compounds is also provided.

Description

Novel glucokinase activators and method of use thereof

The right of priority of the U.S. Provisional Application case that the application advocates to propose on July 6th, 2006 number 60/818,912, its whole disclosure and for reference in this paper.

Technical field

The present invention is about novel phosphonic acid ester and phosphinate compounds, and it is the acvator of enzymatic glucose kinases, and therefore can be used for treating mellitus, and uses this kind compound with the treatment mellitus especially method of type ii diabetes.

Background technology

Enzymatic glucose kinases (GK), it mainly is found in pancreas beta cell and the liver parenchyma cell, and it can the catalysis conversion of glucose become G-6-P, and this is first step in the glucose metabolism.For the glucose metabolism in pancreas beta cell and the liver parenchyma cell, gk also is the rate-controlling enzyme, and it is played an important role on whole body glucose stable state.

Liag; Y. wait people (Biochem.J., 1995,309:167-173) discovery below the report; Youngster's II type (ripening stage-expansion) mellitus (MODY-2) cause because of the forfeiture of function mutation in the glucokinase gene, and this shows that gk also uses glucose sensor as in the mankind.Therefore, activation gk and therefore increase the susceptibility of gk sensing system and use the compound that causes the insulin secretion increase will can be used for treating hyperglycemia and type ii diabetes.

Glucokinase activators has been proved and can have strengthened effectively: 1) glucose effect that the Regular Insulin from the rat of isolation and human pancreas island is disengaged, with 2) bring out (Matschinsky for example, people such as F.M. at the glucose of pancreas island gk in the rat Langerhans islet of isolating cultivation; Mellitus; 2006,55:1 and " gk and blood sugar disorders, from basically to novel therapeutic agents "; Publish 2004 by Karger; F.M.Matschinsky and M.A.Magnuson are compiling, the 6th chapter, 360-378 page or leaf).In diabetes animal model research, glucokinase activators has been proved meeting in pancreas clamping research stimulate Regular Insulin to disengage, and strengthens the synthetic and minimizing hepatic glucose production of glycogen.Importantly, glucokinase activators has been proved can be in the different standards animal model of diabetes B, dose-dependently ground lowering blood glucose content; Such as ob/ob mouse, db/db mouse and Zucker in acute single dose research, and also in the test of oral glucose permission, in normal C57/BL6J and ob/ob mouse; (for example exist " gk and blood sugar disorders; from basically to novel therapeutic agents " published 2004 by Karger to improve glucose drift effectively; F.M.Matschinsky and M.A.Magnuson are compiling, the 6th chapter, and 360-378 page or leaf, and Fyfe, people such as M.C., Diabetologia, 2007, among the 50:1277).

Glucokinase activators also in the chronic animal model of type ii diabetes, confirms the effect of anti-diabetic.For example, in research in 9 days, in the ob/ob mouse; Glucokinase activators can improve overall glucose effect form, simultaneously in the test of oral glucose permission, when research begins and finish; Show suitable anti-high-blood-sugar function (Fyfe, people such as M.C., Diabetologia; 2007,50:1277).In another kind of situation, in chronic 40 weeks research, glucokinase activators can prevent the development of hyperglycemia in the fat mouse that the diet of not allowing glucose causes.With respect to control group; Diet with the glucokinase activators treatment is caused fat mouse, in the test of oral glucose permission, when research finishes; What show the glucose drift significantly improves (" gk and blood sugar disorders; from basically to novel therapeutic agents ", publish 2004 by Karger; F.M.Matschinsky and M.A.Magnuson are compiling, the 6th chapter, 360-378 page or leaf).

Summary of the invention

On the one hand, the compound with structure I is provided according to the present invention R wherein ₁Be heteroaryl, by R ₄Replace, and (promptly choose wantonly) by one or two substituent R according to circumstances ₅And/or R ₆Replace, wherein heteroaryl has nitrogen-atoms, and its vicinity is engaged to this heteroaryl

Atom; R ₄For-(CH ₂) _n-Z-(CH ₂) _m-PO (OR ₇) (OR ₈), or-(CH ₂) _nZ-(CH ₂) _m-PO (OR ₇) R ₉, or-(CH ₂) _n-Z-(CH ₂) _m-O-PO (OR ₇) R ₉, or-(CH ₂) _nZ-(CH ₂) _m-O-PO-(R ₉) R ₁₀, or-(CH ₂) _nZ-(CH ₂) _m-PO (R ₉) R ₁₀R ₇With R ₈For identical or different, and independently be selected from hydrogen and alkyl; R ₉With R ₁₀For identical or different, and independently be selected from alkyl, aryl, aralkyl, heteroaryl and heteroaralkyl, wherein any can be according to circumstances through replacing; In addition, R ₇With R ₈Can be cyclized into ring

Wherein q=1-3 likewise, R ₇With R ₉Can be cyclized into ring

Wherein q=1-3 or wherein q=1-3; Likewise, R ₉With R ₁₀Can be cyclized into ring

Wherein q=1-3 or wherein q=1-3; Z is selected from key, alkylidene group and an alkenylene, its each can choose wantonly and be substituted (for example hydroxyl, alkoxyl group, aminoalkyl group, amino aralkyl, amino heteroaralkyl, aminoaryl, aminoheteroaryl or carboxyl); M is 0,1 or 2; N is 0,1 or 2; And when m is 1 or 2, n is 0,1 or 2 o'clock, and Z can be O, S, SO ₂, R ₅With R ₆For identical or different, and independently be selected from hydrogen, alkyl, halogen or carboxyl, or for not existing; X is selected from And when Y when not existing, X is selected from

R ₂Be selected from hydrogen, alkyl, naphthenic base, heterocyclic radical, aryl, heteroaryl, alkynyl and thiazolinyl (its all according to circumstances can through replacing); P is 0 or 1; Q is selected from O, S (O) _qAnd CO, wherein q is 0,1 or 2; Q ₁Be selected from hydrogen and fluorine; R ₁₁Be selected from hydrogen, low-carbon alkyl, naphthenic base, aryl and heteroaryl; R ₁₂Be selected from hydrogen and low-carbon alkyl, or R ₁₁With R ₁₂The carbon atom that is connected with they forms the cycloalkyl ring of 5 to 7 carbon atoms together; R ₁₃Be selected from halogen, nitro, amino, cyanic acid, methyl, trifluoromethyl, hydroxyl, methoxyl group, trifluoromethoxy, methylthio group, methylsulfinyl and methylsulfonyl; T is selected from aryl and heteroaryl, its each warp replacement according to circumstances; Y is R ₃-(CH ₂) _s-or for not existing; R wherein ₃Be aryl or heteroaryl, its each warp replacement according to circumstances; S is 0 or 1; Its all stereoisomerses, its prodrug ester or its pharmaceutically acceptable salt.

Preferable case is that X does in formula I compound

, wherein p is more preferred from 1, and R ₂Be naphthenic base, be preferably cyclopentyl or cyclohexyl, or R ₂Be heterocyclic radical, for example have naphthenic base through heteroatoms such as the Sauerstoffatom or the sulphur atom of embedding, for example tetrahydropyrans, THF,

Be preferably tetrahydropyrans; Y is aryl or heteroaryl or for not existing, and is more preferred from aryl again, is more preferred from phenyl, is more preferred from again

Or X is a key, and Y does

R ₄Be (CH ₂) _n-Z-(CH ₂) _m-PO (OR ₇) (OR ₈), wherein Z is alkylidene group or alkenylene, wherein n is 0, m is 0, and Z be a key ,-CH ₂-,-CH ₃-CH=CH-,-CH ₂CH ₂-or

And R ₅With R ₆Respectively be H; R ₇Be H or alkyl; And R ₈Be H or alkyl.

The following section?

preferably?

R ₄Be more preferred from

The preferred specific embodiment of Y-X-CO-; Wherein X is X-1, includes but not limited to:

The preferred specific embodiment of Y-X-CO-; Wherein X=X-2 includes but not limited to:

The preferred specific embodiment of Y-X-CO-; Wherein X=X-3 includes but not limited to:

The preferred specific embodiment of Y-X-CO-; Wherein X=X-4 includes but not limited to:

The preferred specific embodiment of Y-X-CO-; Wherein X=X-5 includes but not limited to:

The preferred specific embodiment of Y-X-CO-; Wherein X=X-6 (wherein X is a key) includes but not limited to:

The preferred specific embodiment of Y-X-CO-; Wherein X=X-7 includes but not limited to:

The preferred specific embodiment of Y-X-CO-; Wherein X=X-8 includes but not limited to:

The preferred specific embodiment of Y-X-CO-; Wherein X=X-9 includes but not limited to:

Preferred compounds according to the present invention include, but are not limited to the following:?

The activity of The compounds of this invention meeting activation or enhancing enzymatic glucose kinases.Therefore; The compounds of this invention can be used for treatment and gk not enough relevant more than heavy disease or illness; Such as mellitus and relevant symptoms, the microvascular complication relevant, relevant vascular complication, cardiovascular disorder, metabolic syndrome and composition symptom thereof, and other sick illness with mellitus with mellitus.Can prevent according to the present invention, suppress or treatment and instance not enough related disease of enzymatic glucose kinase activity or illness, include but not limited to mellitus, hyperglycemia, the glucose tolerance that weakens, insulin resistance, hyperinsulinism, retinopathy, neuropathy, ephrosis, delay wound healing, atherosclerosis and sequela thereof, abnormal heart function, myocardial ischemia, apoplexy, metabolic syndrome, hypertension, obesity, dyslipidemia, hyperlipemia, hypertriglyceridemia, hypercholesterolemia, low HDL, high LDL, non-heart ischemia, infection, cancer, vascular restenosis, pancreatitis, neurodegenerative disease, lipid disorders, cognitive power weakens and dementia, bone diseases, lipodystrophy and the glaucoma relevant with hiv protease.

The present invention provides formula I compound, adopts the pharmaceutical composition of this kind compound, and uses the method for this kind compound.In specific words, the present invention provides a kind of pharmaceutical composition, and it contains the formula I compound that significant quantity is gone up in treatment, separately or and with the carrier that pharmaceutically can accept.

Moreover; According to the present invention; The not enough relevant disease of a kind of prevention, inhibition or treatment and enzymatic glucose kinase activity or the progress of illness or the method for beginning are provided; This disease such as preceding text and the civilian definien of institute in back, the formula I compound that wherein will treat significant quantity throw give need treatment Mammals to anticipate be human sufferer.

The compounds of this invention can use separately, and with other compound of the present invention, or and with one or more other therapeutical agent.

Moreover; The present invention provides a kind of prevention, inhibition or treatment as the preceding text method with back literary composition institute definition disease, the combination throwing that wherein will treat formula I compound and another kind of formula I compound and/or at least a other type therapeutical agent of significant quantity give need treatment Mammals to anticipate be human sufferer.

In another specific embodiment, the compound that the present invention's compound is selected from the instance to be given an example.

In another specific embodiment, the present invention is about pharmaceutical composition, and it comprises the The compounds of this invention that significant quantity is gone up in treatment, separately or according to circumstances and with the carrier that pharmaceutically can accept and/or one or more other medicament.

In another specific embodiment; The present invention is about strengthening the method for enzymatic glucose kinase activity; It may further comprise the steps, to the Mammals sufferer of needs being arranged, for example human sufferer; The The compounds of this invention that significant quantity is gone up in treatment is given in throwing, separately or according to circumstances and with the therapeutical agent of another kind of The compounds of this invention and/or at least a other type.

In another specific embodiment; The present invention is about a kind of prevention, inhibition or treatment and the not enough relevant disease of enzymatic glucose kinase activity or illness progress or initial method; It may further comprise the steps, to the Mammals sufferer of needs prevention, inhibition or treatment, for example human sufferer; The The compounds of this invention that significant quantity is gone up in treatment is given in throwing, separately or according to circumstances and with the therapeutical agent of another kind of The compounds of this invention and/or at least a other type.

Can prevent according to the present invention, suppress or treatment and instance not enough relevant disease of enzymatic glucose kinase activity or illness, include but not limited to disease or illness that preceding text propose.

In another specific embodiment; Progress that the present invention weakens about a kind of prevention, inhibition or treatment mellitus, hyperglycemia, obesity, dyslipidemia, hypertension and cognitive power or the method that starts; It may further comprise the steps, to the Mammals sufferer of needs prevention, inhibition or treatment, for example human sufferer; The The compounds of this invention that significant quantity is gone up in treatment is given in throwing, separately or according to circumstances and with the therapeutical agent of another kind of The compounds of this invention and/or at least a other type.

In another specific embodiment again; The present invention is about a kind of prevention, inhibition or the progress of treatment mellitus or the method that starts; It may further comprise the steps, and is loyal to the mammalian disease of needs prevention, inhibition or treatment, for example human sufferer; The The compounds of this invention that significant quantity is gone up in treatment is given in throwing, separately or according to circumstances and with the therapeutical agent of another kind of The compounds of this invention and/or at least a other type.

In again again in another specific embodiment; The present invention is about a kind of prevention, inhibition or the progress of treatment hyperglycemia or the method for beginning; It may further comprise the steps, and is to the Mammals sufferer of needs prevention, inhibition or treatment, for example human sick loyal; The The compounds of this invention that significant quantity is gone up in treatment is given in throwing, separately or according to circumstances and with the therapeutical agent of another kind of The compounds of this invention and/or at least a other type.

In another specific embodiment; The present invention is about a kind of prevention, inhibition or the progress of treatment obesity or the method that starts; It may further comprise the steps, to the Mammals sufferer of needs prevention, inhibition or treatment, for example human sufferer; The The compounds of this invention that significant quantity is gone up in treatment is given in throwing, separately or according to circumstances and with the therapeutical agent of another kind of The compounds of this invention and/or at least a other type.

In a specific embodiment; The present invention is about a kind of prevention, inhibition or the progress of treatment dyslipidemia or the method for beginning; It may further comprise the steps, to the Mammals sufferer of needs prevention, inhibition or treatment, for example human sufferer; The The compounds of this invention that significant quantity is gone up in treatment is given in throwing, separately or according to circumstances and with the therapeutical agent of another kind of The compounds of this invention and/or at least a other type.

Detailed Description Of The Invention

Compound described herein can have asymmetric center.The The compounds of this invention that contains asymmetric replacement atom can be separated with optical activity or racemic form.The well known optical activity form that how to prepare is for example passed through the parsing of racemic form, or through synthetic from the optical activity starting substance.Many rotamerism things of alkene, the two keys of C=N etc. also can be present in the compound described herein, and all this kind desmotropism things all are intended to covered among the present invention.The cis of The compounds of this invention and trans rotamerism thing are described, and can be separated into the mixture of isomer or the isomeric form of warp separation.All chiralitys of a kind of structure, diastereoisomerism, racemic form and all rotamerism forms are and are intended to, only if specifically indicate specific stereochemistry or isomeric form.

In this paper, use its " through replace " speech, mean any or a plurality of hydrogen on specified atom or ring and be selected from indicated group and replace, its condition must not be the normal valency that surpasses specified atom, and this replaces and forms stable compound.When substituting group is that ketone group (when anticipating promptly=O), then replaced by 2 hydrogen on atom.

As any variable (R for example ^a) when on any composition of compound or chemical formula, taking place to surpass one time, its definition in each existence place has nothing to do with its definition in each other existence place.Therefore, for example, if a kind of group is illustrated as by 0-2 R ^aReplace, then this group can be according to circumstances by two R at the most ^aGroup replaces, and R ^aIndependently be selected from R in each existence place ^aDefinition.And the combination of substituting group and/or variable only is combined to form under the stable compound at this kind and just can allows.

When a key to substituting group, when being shown as the key of crossing two atoms in the shack, then this kind substituting group can be incorporated in to the last any atom of ring.When substituting group be listed and do not show that this kind substituting group is incorporated in to given chemical formula compound all the other partly institute via atomic time, then this kind substituting group can combine through any atom of planting thus in the substituting group.The combination of substituting group and/or variable only is combined to form under the stable compound at this kind and just can allows.

Only if point out in addition; Otherwise " low-carbon alkyl ", " alkyl " or " alkane " term are when adopting in this paper; Separately or as the some of another kind of group; Comprise straight chain and side chain hydro carbons; Contain 1 to 20 carbon; Be preferably 1 to 10 carbon, be more preferred from 1 to 8 carbon, in normal chain; For example methyl, ethyl, propyl group, sec.-propyl, butyl, the tertiary butyl, isobutyl-, amyl group, hexyl, isohexyl, heptyl, 4; 4-dimethyl-amyl group, octyl group, 2,2,4-trimethylammonium-amyl group, nonyl, decyl, undecyl, dodecyl; Its various side chain isomers etc.; And this kind group can comprise 1 to 4 substituting group according to circumstances, such as halogen, for example F, Br, Cl or I; Or CF3, alkyl, alkoxyl group, aryl, aryloxy, aryl (aryl) or diaryl, aralkyl, aralkyl oxy, thiazolinyl, naphthenic base, cycloalkylalkyl, cycloalkyl alkoxy, amino, hydroxyl, hydroxyalkyl, acyl group, heteroaryl, heteroaryl oxygen base, heteroaralkyl, heteroaryl alkoxyl group, aryloxy alkyl, alkylthio, aromatic alkyl sulfurio, aryloxy aryl, alkylamidoalkyl, alkyl amide, aryl-amino-carbonyl, nitro, cyanic acid, mercaptan, alkylhalide group, three alkylhalide groups and/or alkylthio; And (=O), ORa, SRa, (=S) ,-NRaRb ,-N (alkyl) 3+ ,-NRaSO2 ,-NRaSO2Rc ,-SO2Rc-SO2NRaRb ,-SO2NRaC (=O) Rb, SO3H ,-PO (OH) 2 ,-C (=O) Ra ,-CO2Ra ,-C (=O) NRaRb ,-C (=O) (C1-4 alkylidene group) NRaRb ,-C (=O) NRa (SO2) Rb ,-CO2 (C1-4 alkylidene group) NRaRb ,-NRaC (=O) Rb ,-NRaCO2Rb ,-NRa (C1-4 alkylidene group) CO2Rb ,=N-OH ,=the N-O-alkyl, wherein Ra and Rb are identical or different, and independently be selected from hydrogen, alkyl, thiazolinyl, CO2H, CO2 (alkyl), C3-7 naphthenic base, phenyl, phenmethyl, phenylethyl, naphthyl, four to seven membered heterocyclic base or five to six membered heteroaryl; Maybe when being connected to identical nitrogen-atoms; Can engage forming heterocyclic radical or heteroaryl, and Rc is selected from the group identical with Ra and Rb, but is not hydrogen.Each radicals R a and Rb; When not being hydrogen; And each Rc group has three other substituting groups at the most according to circumstances; In the time of on any available carbon that is connected Ra, Rb and/or Rc or nitrogen-atoms; This substituting group is identical or different, and independently be selected from (C1-6) alkyl, (C2-6) thiazolinyl, hydroxyl, halogen, cyanic acid, nitro, CF3, O (C1-6 alkyl), OCF3, C (=O) H, C (=O) (C1-6 alkyl), CO2H, CO2 (C1-6 alkyl), NHCO2 (C1-6 alkyl) ,-S (C1-6 alkyl) ,-NH2, NH (C1-6 alkyl), N (C1-6 alkyl) 2, N (CH3) 3+, SO2 (C1-6 alkyl), C (=O) (C1-4 alkylidene group) NH2, C (=O) (C1-4 alkylidene group) NH (alkyl), C (=O) (C1-4 alkylidene group) N (C1-4 alkyl) 2, C3-7 naphthenic base, phenyl, benzyl, phenylethyl, phenoxy, benzyloxy, naphthyl, four to seven membered heterocyclic base or five to six membered heteroaryl.When the alkyl through replacement was replaced by aryl, heterocyclic radical, naphthenic base or heteroaryl, this ring system such as hereinafter defined, and therefore can have zero, one, two or three substituting group, also define like hereinafter.

Only if point out in addition; Otherwise " naphthenic base " speech is when adopting in this paper; Separately or as the some of another kind of group; Comprise saturated or partly unsaturated (containing 1 or 2 two key) cyclic hydrocarbon group; Contain 1 to 3 ring; Comprise monocycle shape alkyl, double-ring alkyl (or bicyclic alkyl) and three cyclic alkyls; Contain and amount to 3 to 20 these rings of carbon formation; Be preferably 3 to 10 carbon and form this ring; And it can be fused to 1 or 2 as about the said aromatic ring of aryl; Naphthenic base comprise cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, ring octyl group, ring decyl, ring dodecyl, cyclohexenyl, ring octyl group, ring decyl and ring dodecyl, cyclohexenyl, this group of

any can be replaced by 1 to 4 substituting group according to circumstances; Substituting group such as halogen, alkyl, alkoxyl group, hydroxyl, aryl, aryloxy, aralkyl, naphthenic base, alkylamidoalkyl, alkyl amide, ketone group, acyl group, aryl-amino-carbonyl, amino, nitro, cyanic acid, mercaptan and/or alkylthio, and/or about any substituting group of alkyl.

Only if point out in addition; Otherwise in this paper, use it " low-carbon (LC) thiazolinyl " or " thiazolinyl " term, alone or as the some of another kind of group, refer to the straight or branched group; 2 to 20 carbon; Be preferably 2 to 12 carbon, and be more preferred from 1 to 8 carbon in normal chain, it comprises one to six two key in normal chain; For example vinyl, 2-propenyl, 3-crotonyl, crotyl, 4-pentenyl, 3-pentenyl, 2-hexenyl, 3-hexenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 3-octenyl, 3-nonene base, 4-decene base, 3-hendecene base, 4-laurylene base, 4; 8,12-tetradecane trialkenyl etc., and it can be replaced by 1 to 4 substituting group according to circumstances; Be the assorted alkyl of halogen, alkylhalide group, alkyl, alkoxyl group, thiazolinyl, alkynyl, aryl, aralkyl, naphthenic base, amino, hydroxyl, heteroaryl, ring, alkyl amido, alkyl amido, aryl carbonyl-amino, nitro, cyanic acid, mercaptan, alkylthio, and/or any of the alkyl substituent that proposes among this paper.

Only if point out in addition; Otherwise in this paper, use it " low-carbon (LC) alkynyl " or " alkynyl " term; Alone or as the some of another kind of group; Refer to the straight or branched group, 2 to 20 carbon are preferably 2 to 12 carbon; And be more preferred from 2 to 8 carbon in normal chain; It comprises a triple bond in normal chain, such as 2-propynyl, 3-butynyl, 2-butyne base, 4-pentynyl, 3-pentynyl, 2-hexyn, 3-hexyn, 2-heptyne base, 3-heptyne base, 4-heptyne base, 3-octyne base, 3-n-heptylacetylene base, 4-decynyl, 3-undecyne base, 4-dodecyne base etc., and it can be replaced by 1 to 4 substituting group according to circumstances; Meaning is the assorted alkyl of halogen, alkylhalide group, alkyl, alkoxyl group, thiazolinyl, alkynyl, aryl, aralkyl, naphthenic base, amino, heteroaryl, ring, hydroxyl, alkyl amido, alkyl amido, aryl-amino-carbonyl, nitro, cyanic acid, mercaptan and/or alkylthio, and/or any of the alkyl substituent that proposes among this paper.

Have the singly-bound that supplies to be connected to other group under the situation on two different carbon atoms at the alkyl like the preceding text definition, it is called as " alkylidene group ", and can be according to circumstances as above literary composition be substituted about the definition of " alkyl ".

Like the thiazolinyl of preceding text definition and alkynyl like the preceding text definition; The singly-bound that has the confession connection respectively is under the situation on two different carbon atoms; It is called as " alkenylene " and " alkynylene " respectively, and can as above civilianly according to circumstances replace about " thiazolinyl " definition warp with " alkynyl ".

In this paper, use it " halogen " or " halogen " term, separately or as the some of another kind of group, refer to chlorine, bromine, fluorine and iodine, and CF ₃, wherein chlorine or fluorine are preferred.

Only if point out in addition; Otherwise " aryl " speech is when adopting in this paper; Separately or as the some of another kind of group; Mean monocycle shape and double-ring aromatic group; Contain 6 to 10 carbon (such as phenyl, xenyl or naphthyl in ring portion part; Comprise 1-naphthyl and 2-naphthyl); And can comprise 1 to 3 other ring according to circumstances; Through being fused to carbocyclic ring or heterocycle (such as the assorted alkyl ring of aryl, naphthenic base, heteroaryl or ring); For example

aryl can pass through the carbon atom that can adopt according to circumstances; By 1; 2; Or 3 substituting groups replace; The for example assorted alkyl of hydrogen, halogen, alkylhalide group, alkyl, alkylhalide group, alkoxyl group, halogen alkoxyl group, thiazolinyl, trifluoromethyl, trifluoromethoxy, alkynyl, naphthenic base-alkyl, naphthenic base, ring, the assorted alkyl-alkyl of ring, aryl, heteroaryl, aralkyl, aryloxy, aryloxy alkyl, alkoxy aryl, artyl sulfo, arylazo base, heteroaralkyl, heteroaryl thiazolinyl, heteroaryl heteroaryl, heteroaryl oxygen base, hydroxyl, nitro, cyanic acid, amino; Amino through replacement; Wherein amino comprises 1 or 2 substituting group (it is alkyl, aryl, or in the definition mentioned any other aryl compound), mercaptan, alkylthio, artyl sulfo, heteroaryl sulfenyl, artyl sulfo alkyl, alkoxy aryl sulfenyl, alkyl carbonyl, aryl carbonyl, alkyl-aminocarboxyl, aromatic aminocarbonyl, carbalkoxy, aminocarboxyl, alkyl carbonyl oxygen base, aryl carbonyl oxygen base, alkyl carbonyl amino, aryl-amino-carbonyl, aryl sulfonyl kia, aryl sulfonyl kia alkyl, arlysulfonylamino or Arenesulfonyl amino carbonyl, ORa, SRa, (=S) ,-NRaRb ,-N (alkyl) 3+ ,-NRaSO2 ,-NRaSO2Rc ,-SO2Rc-SO2NRaRb ,-SO2NRaC (=O) Rb, SO3H ,-PO (OH) 2 ,-C (=O) Ra ,-CO2Ra ,-C (=O) NRaRb ,-C (=O) (C1-4 alkylidene group) NRaRb ,-C (=O) NRa (SO2) Rb ,-CO2 (C1-4 alkylidene group) NRaRb ,-NRaC (=O) Rb ,-NRaCO2Rb or-NRa (C1-4 alkylidene group) CO2Rb; Wherein Ra, Rb and Rc all like preceding text about definition through substituted alkyl, and also according to circumstances and for example preceding text narrate through replacing.In addition,, can engage, for example condense or volution for example cyclopentyl or cyclohexyl, or annelated heterocycles base or heteroaryl to form another ring through being connected to two substituting groups of aryl (particularly phenyl).When aryl is replaced (or having second ring on being fused to it) by another ring; This ring again according to circumstances by one or two (C1-4) alkyl, (C2-4) thiazolinyl, halogen, hydroxyl, cyanic acid, nitro, CF3, O (C1-4 alkyl), OCF3, C (=O) H, C (=O) (C1-4 alkyl), CO2H, CO2 (C1-4 alkyl), NHCO2 (C1-4 alkyl) ,-S (C1-4 alkyl) ,-NH2, NH (C1-4 alkyl), N (C1-4 alkyl) 2, N (C1-4 alkyl) 3+, SO2 (C1-4 alkyl), C (=O) (C1-4 alkylidene group) NH2, C (=O) (C1-4 alkylidene group) NH (alkyl) and/or C (=O) (C1-4 alkylidene group) N (C1-4 alkyl) 2, and/or any replacement of the alkyl substituent that proposes among this paper.

Only if point out in addition; Otherwise " low-carbon alkoxy ", " alkoxyl group ", " aryloxy " or " aralkoxy " term; When in this paper, adopting, separately or as the some of another kind of group, comprise through being linked to any abovementioned alkyl, aralkyl or the aryl of Sauerstoffatom.

Only if point out in addition; Otherwise " " speech is when adopting in this paper for amino; Separately or as the some of another kind of group; Meaning can be by the amino of one or two substituting group replacement, and this substituting group can be identical or different, such as alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, the assorted alkyl of ring, the assorted alkyl-alkyl of ring, naphthenic base, cycloalkylalkyl, alkylhalide group, hydroxyalkyl, alkoxyalkyl or sulfenyl alkyl.These substituting groups can be further by carboxylic acid and/or like any R of preceding text proposition ₃Group or about R ₃Substituting group replace.In addition; Amino substituting group can adopt with the nitrogen-atoms that they connected; To form 1-pyrrolidyl, piperidino, 1-azepine base (1-azepinyl), 4-morpholinyl, 4-sulfenyl morpholinyl, 1-piperazinyl, 4-alkyl-1-piperazinyl, 4-aralkyl-1-piperazinyl, 4-alkyl diaryl-1-piperazinyl, 1-pyrrolidyl, piperidino or 1-azepine base, replaced by alkyl, alkoxyl group, alkylthio, halogen, trifluoromethyl or hydroxyl according to circumstances.

Only if point out in addition; Otherwise " lower alkanes sulfenyl ", " alkylthio ", " artyl sulfo " or " aromatic alkylthio " term; When in this paper, adopting, separately or as the some of another kind of group, comprise through being linked to any abovementioned alkyl, aralkyl or the aryl of sulphur atom.

Only if point out in addition; Otherwise " lower alkanes is amino ", " alkylamino ", " virtue is amino " or " aryl alkyl amino " term; When in this paper, adopting, separately or as the some of another kind of group, comprise through being linked to any abovementioned alkyl, the aryl or aralkyl of nitrogen-atoms.

" acyl group " speech separately or as the some of another kind of group, refers to through being linked to the carbonyl of organic group, is more especially group C (=O) R _e, and divalent group-C (=O)-or-C (=O) R _e-, it is linked to organic group.Radicals R _eThe alkyl of optional this paper freely definition, thiazolinyl, alkynyl, aminoalkyl group, alkyl, the thiazolinyl of warp replacement or the alkynyl of warp replacement through replacement, or when suitable, be its corresponding divalent group, for example alkylidene group, alkenylene etc.

" heterocycle " or " heterocycle family " or " heterocyclic radical " or " the assorted alkyl of ring " term; Mean that through replacement and without 3 to 7 yuan of monocycle shape groups of non-aromatics of replacement, 7 to 11 yuan of double-ring groups and 10 to 15 yuan of three cyclic groups wherein at least one ring has at least one heteroatoms (O, S or N) (also being called as assorted alkyl of ring or Heterocyclylalkyl).Each ring that contains the heterocyclic radical of heteroatoms can contain one or two oxygen or sulphur atom and/or one to four nitrogen-atoms, its condition be in each ring heteroatoms add up to four or less, and further condition is that this ring contains at least one carbon atom.The fused rings of accomplishing double-ring and three cyclic groups can only contain carbon atom, and can be saturated, partly saturated or unsaturated.Nitrogen and sulphur atom can be oxidized according to circumstances, and nitrogen-atoms can be according to circumstances by quaternized.Heterocyclic radical can be connected on any nitrogen or carbon atom that adopts.Heterocyclic ring can contain odd, one, two or three substituting group; Be selected from halogen, trifluoromethyl, trifluoromethoxy, alkyl, alkyl, thiazolinyl, warp replacement through replacements thiazolinyl, alkynyl, nitro, cyanic acid, ketone group (=O), ORa, SRa, (=S) ,-NRaRb ,-N (alkyl) 3+ ,-NRaSO2 ,-NRaSO2Rc ,-SO2Rc-SO2NRaRb ,-SO2NRaC (=O) Rb, SO3H ,-PO (OH) 2 ,-C (=O) Ra ,-CO2Ra ,-C (=O) NRaRb ,-C (=O) (C1-4 alkylidene group) NRaRb ,-C (=O) NRa (SO2) Rb ,-CO2 (C1-4 alkylidene group) NRaRb ,-NRaC (=O) Rb ,-NRaCO2Rb ,-NRa (C1-4 alkylidene group) CO2Rb ,=N-OH ,=N-O-alkyl, aryl, naphthenic base, heterocyclic radical and/or heteroaryl; Wherein Ra, Rb and Rc all like preceding text about definition through substituted alkyl, and also again according to circumstances such as preceding text narration through replacing.When heterocyclic radical is replaced by another ring, this ring again according to circumstances by one or two (C1-4) alkyl, (C2-4) thiazolinyl, halogen, hydroxyl, cyanic acid, nitro, CF3, O (C1-4 alkyl), OCF3, C (=O) H, C (=O) (C1-4 alkyl), CO2H, CO2 (C1-4 alkyl), NHCO2 (C1-4 alkyl) ,-S (C1-4 alkyl) ,-NH2, NH (C1-4 alkyl), N (C1-4 alkyl) 2, N (C1-4 alkyl) 3+, SO2 (C1-4 alkyl), C (=O) (C1-4 alkylidene group) NH2, C (=O) (C1-4 alkylidene group) NH (alkyl) and/or C (=O) (C1-4 alkylidene group) N (C1-4 alkyl) ₂Replace.

Monocycle shape group for example comprises azetidinyl, pyrrolidyl, oxetanyl, imidazolidyl, oxazolidinyl, isoxazole alkyl, thiazolidyl, isothiazole alkyl, tetrahydrofuran base, piperidyl, piperazinyl, 2-oxo piperazinyl, 2-oxo-piperidine base, 2-oxo-pyrrolidine base, 2-oxo azepine base, azepine base, 4-piperidone base, THP trtrahydropyranyl, morpholinyl, sulfenyl morpholinyl, sulfenyl morpholinyl sulfoxide, sulfenyl morpholinyl sulfone, 1; 3-dioxolane and tetrahydrochysene-1,1-dioxo thienyl etc.Double-ring heterocyclic radical for example comprises Kui quinoline cyclic group.

In the formula (I) is preferably a heterocyclic group of the compounds include?

which, as the case may be substituted.

" heteroaryl " speech; Separately or as the some of another kind of group; Mean that it has at least one heteroatoms (O, S or N) at least one encircles through replacing and aromatics 5 or 6 yuan of monocycle shape groups, 9 or 10 yuan of double-ring groups and 11 to 14 yuan of three cyclic groups without replacements.Each ring that contains the heteroaryl of heteroatoms can contain one or two oxygen or sulphur atom and/or one to four nitrogen-atoms, its condition be in each ring heteroatoms add up to four or less, and each ring has at least one carbon atom.The fused rings of accomplishing double-ring and three cyclic groups can only contain carbon atom, and can be saturated, part is saturated or unsaturated, and can comprise aryl, naphthenic base, heteroaryl or ring heteroaryl.Nitrogen and sulphur atom can be oxidized according to circumstances, and nitrogen-atoms can be according to circumstances by quaternized.For the heteroaryl of double-ring or three ring-types must comprise at least one full aromatic ring, but one or more other fused rings can be aromatics or non-aromatics.Heteroaryl can be connected any of any ring and adopt on nitrogen or the carbon atom.The heteroaryl ring system can contain odd, one, two or three substituting group; It can be any about substituting group that alkyl proposed; And can be selected from halogen, trifluoromethyl, trifluoromethoxy, alkyl, alkyl, thiazolinyl, warp replacement through replacements thiazolinyl, alkynyl, nitro, cyanic acid, ORa, SRa, (=S) ,-NRaRb ,-N (alkyl) 3+ ,-NRaSO2 ,-NRaSO2Rc ,-SO2Rc-SO2NRaRb ,-SO2NRaC (=O) Rb, SO3H ,-PO (OH) 2 ,-C (=O) Ra ,-CO2Ra ,-C (=O) NRaRb ,-C (=O) (C1-4 alkylidene group) NRaRb ,-C (=O) NRa (SO2) Rb ,-CO2 (C1-4 alkylidene group) NRaRb ,-NRaC (=O) Rb ,-NRaCO2Rb ,-NRa (C1-4 alkylidene group) CO2Rb, aryl, naphthenic base, heterocyclic radical and/or heteroaryl; Wherein Ra, Rb and Rc all like preceding text about definition through substituted alkyl, and also again according to circumstances such as preceding text narration through replacing.When heteroaryl is replaced by another ring, this ring again according to circumstances by one or two (C1-4) alkyl, (C2-4) thiazolinyl, halogen, hydroxyl, cyanic acid, nitro, CF3, O (C1-4 alkyl), OCF3, C (=O) H, C (=O) (C1-4 alkyl), CO2H, CO2 (C1-4 alkyl), NHCO2 (C1-4 alkyl) ,-S (C1-4 alkyl) ,-NH2, NH (C1-4 alkyl), N (C1-4 alkyl) 2, N (C1-4 alkyl) 3+, SO2 (C1-4 alkyl), C (=O) (C1-4 alkylidene group) NH2, C (=O) (C1-4 alkylidene group) NH (alkyl) and/or C (=O) (C1-4 alkylidene group) N (C1-4 alkyl) ₂Replace.

Monocycle shape heteroaryl for example comprises pyrryl, pyrazolyl, pyrazolinyl, imidazolyl 、 oxazolyl 、 isoxazolyl, thiazolyl, thiadiazolyl group, isothiazolyl, furyl, thienyl 、 oxadiazole base, pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, triazinyl etc.

Double-ring heteroaryl for example comprises indyl, benzothiazolyl, benzo dioxa penta cycloalkenyl group, benzoxazolyl, benzothienyl, quinolyl, tetrahydro isoquinolyl, isoquinolyl, benzimidazolyl-, benzopyranyl, pyrrocoline base, benzofuryl, chromone base, tonka-bean base, benzopyranyl, cinnolines base, quinoxalinyl, indazolyl, pyrrolopyridinyl, furo pyridyl, dihydro-iso indolyl, tetrahydric quinoline group etc.

Three ring-type heteroaryls for example comprise carbazyl, benzindole base, phenanthroline base, acridyl, coffee pyridine base, xanthenyl etc.

In formula (I) compound, preferred heteroaryl comprises

etc.

In this paper, use it " heterocyclic radical alkyl " or " Heterocyclylalkyl " or " ring assorted alkyl-alkyl " term, separately or as the some of another kind of group, refer to heterocyclic radical, pass through C atom or heteroatoms and be linked to alkyl chain like preceding text definition.

In this paper, use it " heteroaralkyl " or " heteroaryl thiazolinyl " term, separately or as the some of another kind of group, refer to heteroaryl, pass through C atom or heteroatoms and be linked to alkyl chain, alkylidene group or alkenylene like the preceding text definition like preceding text definition.

In this paper, use its " cyanic acid " speech, refer to-the CN group.

In this paper, use its " nitro " speech, refer to-NO ₂Group.

In this paper, use its " hydroxyl " speech, refer to-the OH group.

Only if point out in addition; Otherwise when censuring through the aryl (for example phenyl) of naming clearly, naphthenic base (for example cyclohexyl), heterocyclic radical (for example pyrrolidyl) or heteroaryl (for example imidazolyl); Only if clearly indication is arranged in addition, otherwise this denotion is intended to comprise to have 0 to 3, is preferably the ring of 0-2 substituting group; Substituting group is selected from preceding text about the cited person of aryl, naphthenic base, heterocyclic radical and/or heteroaryl, by suitable mode.

" heteroatoms " speech comprises oxygen, sulphur and nitrogen.

That " carbocyclic ring family " speech means is saturated or unsaturated, monocycle shape or double-ring ring, and wherein whole atoms of all rings are carbon.Therefore, this term comprises naphthenic base and aryl rings.Carbocyclic ring can be through replacing, and in this kind situation, substituting group is selected from preceding text about naphthenic base and the cited person of aryl.

When " unsaturated " speech in this paper during in order to finger ring or group, this ring or group can be unsaturated fully or partly unsaturated.

In whole patent specification; Group and substituting group thereof can be selected by those skilled in the art; Partly and compound and can be used as the compound of pharmaceutically acceptable compound use to provide stable, and/or compound between can be used for making among the pharmaceutically acceptable compound.

In this paper, adopt wording " pharmaceutically acceptable "; To refer to these compounds, material, compsn and/or formulation; It contacts in the scope of safe and reliable medical judgment, being applicable to the tissue of the mankind and animal; And do not have excessive toxicity, pungency, supersensitivity response or other problem or complication, be accompanied by rational interests/risk ratio.

In this paper, use it " pharmaceutically acceptable salt " to refer to the verivate of the compound that discloses, wherein parent compound is modified via making its acid or alkali salt.

Pharmaceutically acceptable it " salt " and " salt " term can refer to the basic salt that formed with organic bases with inorganic.This kind salt comprises ammonium salt; An alkali metal salt, such as lithium, sodium and sylvite (it is preferred); Alkaline earth salt, such as calcium and magnesium salts; With the salt of organic bases, such as amine salt (for example dicyclohexyl amine salt, benzyl star (benzathine), N-methyl D-glycamine and sea crust amine salt); And with the salt of amino acid, for example l-arginine, Methionin etc.; And zwitter-ion, so-called " inner salt ".The pharmaceutically acceptable salt of nontoxicity is preferred, though other salt also can use, for example in the isolated or purified product.

Pharmaceutically acceptable it " salt " also comprises acid salt with " salt " term.It forms like this, for example uses the strong inorganic acid class, such as mineral acid, for example sulfuric acid, phosphoric acid; Or haloid acid, such as HCl or HBr, use strong organic carboxyl acid class, for example the alkane carboxylic-acid of 1 to 4 carbon atom; It is without replacing or for example replaced by halogen, for example acetic acid, such as saturated or unsaturated dicarboxylic acid class; For example oxalic acid, propanedioic acid, succsinic acid, maleic acid, FUMARIC ACID TECH GRADE, phthalic acid or terephthalic acid, such as hydroxycarboxylic acid, for example xitix, oxyacetic acid, lactic acid, oxysuccinic acid, tartrate or Hydrocerol A; For example amino acid (for example aspartic acid or L-glutamic acid or Methionin or l-arginine), or phenylformic acid, or use organic sulfonic acid; (C1-C4) alkyl or aryl sulfonic acid for example, it is without replacing or for example replaced by halogen, for example methanesulfonic or right-toluenesulphonic acids.

The present invention's pharmaceutically-acceptable salts can contain the parent compound of alkalescence or acid part certainly, is synthesized into through traditional chemical process.Generally speaking, the free acid that this kind salt can be through making these compounds or the suitable alkali or the acid of alkali form and stoichiometry, reaction and processing in both mixtures in water or in organic solvent or at this; Generally speaking, non-hydrophily for example is situated between ether, vinyl acetic monomer, ethanol, Virahol or acetonitrile for preferred.Suitably the inventory of salt can be consulted the RemingtonShi medical science, and the 17th edition, Mack publishing company, Easton, PA, 1985, the 1418 pages, its disclosure is in view of the above and for reference in this paper.

In whole patent specification; Group and substituting group thereof can be selected by those skilled in the art; Partly and compound and can be used as the compound of pharmaceutically acceptable compound uses to provide stable, and/or compound between can being used among the pharmaceutically acceptable compound of manufacturing.

Can in body, be transformed so that any compound of biologically active agent (meaning is a formula I compound) to be provided, be to be the prodrug in the scope of the invention and spirit.

A kind of compound of " prodrug " construed when it gives sufferer in throwing, carries out chemical conversion through metabolism or chemical process, and produces compound and/or its salt and/or the solvate of this chemical formula.For example, the compound that contains carboxyl can form hydrolyzable ester class on the physiology, and it uses prodrug as, through in health, being hydrolyzed to produce chemical formula compound itself.This kind prodrug is preferably thrown with the per os mode and is given, and because of in many cases, hydrolytic action mainly takes place under the influence of digestive ferment.Under this situation of ester, or occur under the situation in the blood, can use and non-ly offer medicine through intestines in hydrolytic action as activity.

" prodrug " speech; When in this paper, adopting; System comprises ester class and carbonates; Its one or more hydroxyls and acylating agent of alkyl, alkoxyl group or aryl replacement through making formula I compound adopts the known program of those skilled in the art and forms, to produce acetic ester, pivalate, methyl carbonic, benzoic ether etc.

The prodrug of various forms is well known, and is described in: a) medical chemistry practice, people such as Camille G.Wermuth, the 31st chapter, (university press, 1996); B) design of prodrug is being compiled (Elsevier, 1985) by H.Bundgaard; C) textbook of medicinal design and development, P.Krogsgaard-Larson and H.Bundgaard are compiling, the 5th chapter, 113-191 page or leaf (Harwood university press, 1991); And d) hydrolytic action and the prodrug metabolism of medicine, Bernard Testa and Joachim M.Mayer, (Wiley-VCh2003).Said reference all and for reference in this paper.

The instance of hydrolyzable ester class comprises C on the physiology of formula (I) compound _1-6Alkyl benzyl, 4-methoxy-benzyl, 2,3-hydrogenation indenyl, phthaloyl, methoxymethyl, C _1-6Alkanoyloxy-C _1-6Alkyl, for example acetoxy-methyl, oxy acid methyl neopentyl or propionyloxy methyl, C _1-6Alkoxycarbonyloxy-C _1-6Alkyl; For example methoxycarbonyl-oxygen ylmethyl or ethoxycarbonyl-oxygen ylmethyl, glycyl oxygen ylmethyl, phenyl glycyl oxygen ylmethyl, (5-methyl-2-oxo-1; 3-dioxy thing penta cyclenes-4-yl)-methyl, and hydrolyzable ester class on other physiology known that for example in penicillium mould and cynnematin field, is used.This kind ester class can be processed through routine techniques known in this area.

Prodrug ester instance comprises following groups: (1-alkanoyloxy) alkyl, for example

R wherein ^z, R ^tAnd R ^yBe H, alkyl, aryl or aralkyl; But, R ^zO can not be HO.

The instance of this kind prodrug ester class comprises CH ₃CO ₂CH ₂-,

T-C ₄H ₉CO ₂CH ₂-or

Suitably other instance of prodrug ester class comprises

R wherein ^zCan be H, alkyl (such as methyl or tertiary butyl), aralkyl (such as benzyl) or aryl (such as phenyl); R ^vBe H, alkyl, halogen or alkoxyl group, R ^uBe alkyl, aryl, aralkyl or alkoxyl group, and n1 is 0,1 or 2.

" compounds tautomeric " speech mean can its tautomeric form existence formula I compound and salt thereof, wherein Wasserstoffatoms by changed to molecule other partly, and therefore the chemical bond between the atom of molecule is reset.What should understand is that all tautomeric forms with regard to it possibly exist, are comprised in the present invention.

In addition, formula I compound after its preparation, preferably through isolation and purification, to obtain to contain the constituent that is equal to or greater than 99% amount formula I compound (" pure basically " compound I) by weight, press use described in this paper then or is prepared.The formula I compound of this kind " pure basically " also is intended to be included among this paper, as the present invention's some.

In all stereoisomerses of The compounds of this invention all are intended to be encompassed in, no matter be to be to mix thing mutually or be pure or pure basically form.The compounds of this invention can have asymmetric center, at any carbon atom place, comprises any R substituting group, and/or shows polymorphism.Therefore, formula I compound can enantiomerism or diastereo-isomerism form, or exists with its mixture.Preparing method's racemoid capable of using, enantiomer or diastereoisomer are as starting substance.When preparation diastereo-isomerism or enantiomerism product, available ordinary method is separated, for example chromatography or fractional crystallization.

" stable compound " and " rock steady structure " are intended to represent such compound, and it is enough strong and from reaction mixture, retaining, and is separated to useful purity, and is deployed into effective therapeutical agent.This invention is intended to specialize the performance stable compound.

" significant quantity in the treatment " is intended to comprise the amount of independent The compounds of this invention, or the amount of the combination of the compound of asking for protection, or the amount of The compounds of this invention and other active ingredient of usefulness, with effective treatment or prevent diabetes and/or obesity.

In this paper, use it " to treat " or " treatment " is encompassed in the Mammals; The particularly treatment of the morbid state in the mankind; And comprise: (a) the preventing disease state betides in the Mammals; Particularly work as this kind Mammals and be prone to suffer from this morbid state, but be not diagnosed as as yet when having this disease; (b) suppress this morbid state, meaning is promptly contained its development; And/or (c) alleviating this morbid state, meaning promptly causes the degeneration of this morbid state.

Synthetic

Shown in formula I and Ia compound can and be explained by following reaction scheme, and can be processed by the relevant literature method of those skilled in the art's use.About the reagent and the method for example of these reactions, be presented in the back literary composition and reach in an embodiment.Protection in graphic hereinafter can be carried out (consult, Greene for example, T.W. and Wuts, P.G.M., the protection of organic synthesis is basic, the 3rd edition, 1999 [Wiley]) through general known method in this area with going protection.

Formula I amide compound is synthetic; Wherein X=

and when Y when not existing,

is described in graphic 1.Make carboxylic acid 1 and amine 2 couplings, according to the normative document condition, for example: oxalyl chloride and catalytic DMF are used in (1), to form the acyl chlorides intermediate, then under amine alkali exists, carry out subsequent reactions with amine 2; Or (2) 1 and 2 mixture, with coupler such as DEPBT handle (people such as Li, Org.Lett., 1999,1:91).Heteroaromatic rings R wherein ₁Be depicted in and reach in all said hereinafter subsequent drawings optional ring substituents R in graphic 1 ₅With R ₆Can exist.Graphic 1

The method that is used for the related example of synthesis of carboxylic acid 1 can be consulted document, and reference includes but not limited to following PCT international application case: about X-1, WO 2000/058293, and WO 2001/083465; WO2001/085706, WO 2001/085707, and WO 2002/046173, and WO 2003/095438; WO2004/052869, WO 2004/072031, and WO 2004/063194, and WO 2004/072066; WO2005/103021, WO 2006/016194, and WO 2006/016174, and WO 2006/016178; About X-2, WO 2002/008209, and WO 2004/063194; About X-4, WO 2001/044216, WO2004/072031, and WO 2004/072066, and WO 2004/063194, and WO 2002/014312, WO2005/103021, WO 2006/016194; About X-5, WO 2004/063179; About X-6, WO2003/000262, WO 2003/000267, and WO 2003/080585, and WO 2003/015774, WO2004/045614, WO 2004/046139, and WO 2004/076420, and WO 2005/121110; WO2006/040528, WO 2006/040529, and WO 2006/125972, and WO 2007/007040, WO2007/007041, WO 2007/007042, and WO 2007/0017649; About X-7, WO 2001/083478; About X-8, WO 2002/048106; About X-9, WO 2004/031179.

Formula I carbamide compound is synthetic, and wherein

is described in graphic 2.Amine 3 can agent treated, such as carbonyl dimidazoles, chloroformic acid 4-nitro phenyl ester, phosgene, or the phosgene verivate, such as trichloromethylchloroformate or TRIPHOSGENE 99.5, then adds amine 2, with the formula I urea product that obtains to be wanted.Perhaps, amine 2 can be at first with agent treated, such as carbonyl dimidazoles (or other similar reagents as indicated above), then adds amine 3, so that formula I-A to be provided ureas.Graphic 2

The method that is used for the related example of synthetic amine 3 can obtain that (bibliography comprises PCT international application case WO 2003/055482 and WO 2004/002481 in document; Reach people such as Castellano, Bioorg.Med. Chem.Lett.2005,15:1501).

Approach, wherein R as one of synthetic amine 2A of graphic 3 descriptions ₄The n-Z-of=-(CH2) (CH2) m-PO (OR ₇) (OR ₈) Z=key m and n=0 promptly, the phosphonate groups that is wherein formed is connected directly to heteroaromatic rings R ₁Heteroaryl 4 with amino replacement of warp protection of suitably activated hydrogen substituting group is with highly basic such as LDA or n-Butyl Lithium deprotonation.Make the negatively charged ion that formed and 5 reactions of chloro phosphoric acid dialkyl, make phosphonate groups and R ₁Directly connect.Removing of protection base provides amine 2A.Perhaps, the heteroaryl 6 of halogen replacement also can through reacting with alkali such as n-Butyl Lithium, be converted to identical anionic property intermediate via halogen-metal exchange.It is synthetic that this approach also can be extended to the phospho acid class, and it utilizes reagent such as N, N-diethylammonium chloromethyl phosphonamide, with the reaction of negatively charged ion intermediate (people such as Rumthao, Bioorg.Med.Chem.Lett., 2004,14:5165-5170).For example, the thiazole amine 7 through protection can use alkali such as LDA or n-BuLi deprotonation by shown in graphic 3; And by said phosphonic acidsization, after removing protection, obtain the thiazole amine 2B (people such as South of 5-phosphonic acid ester-replacement; J.Het.Chem., 1991,28:1017).Graphic 3

At preceding text graphic 3 and hereinafter graphic 4,5,6; Reaction described in 7 and 8; Also can on compound, carry out, wherein group Y-X-CO-is changed into amine 2 by acyl group, and this chemical reaction of uses permission of the compatible structure through in Y-X-CO-and/or due care base wherein.

Graphic 4 describe the another kind of approach of synthetic amine 2A.The warp protection heteroaryl amine 8 that contains substituting group such as bromo, iodo or trifluoromethayl sulfonic acid ester; Palladium (O) catalyzer such as four-triphenyl phosphine palladium (O) in catalytic amount exist down, are coupled to phosphorous acid dialkyl 9, and after removing protection; The heteroaryl amine 2A (people such as Hirao of phosphonate substituted is provided; Synthesis, 1981,56-57).In this reaction, use reagent 10, provide its corresponding phosphinate 2C (people such as Rumthao, Bioorg.Med.Chem.Lett., 2004,14:5165-5170).As an example, between bromo pyridine 11 and phosphorous acid dialkyl 9, through Pd (Ph ₃P) ₄The reaction of catalysis provides phosphine acidifying pyridine compounds I-B.Compound 11 obtains through making acid 1 be coupled to the amino pyrazine of 5-bromo-2-with the mode described in graphic 1.Graphic 4

Graphic 5 to describe formula I compound synthetic, wherein R ₄The n-Z-of=-(CH2) (CH ₂) m-PO (OR ₇) (OR ₈) Z=alkene or ethylidene m and n=0 therefore, phosphonate groups is connected to has the hetero-aromatic ring that two carbochains connect.Through the heteroaryl amine 8 of due care at the Pd of catalytic amount (II) catalyzer such as Pd (OAc) ₂, with phosphine ligand for example three-neighbour-tolylphosphine exist down, be coupled to vinyl phosphonate 12, and obtain through protection the vinyl phosphonate intermediate product (people such as Xu, Synthesis, 1983,556-558).Removing of protection base produces vinyl phosphonate amine 2D, and it is converted to I-D through the mode described in graphic 1 and 2, the respective compound of formula I, wherein Z=alkene (vinyl).The phosphonate compound 2E and the I-E of its corresponding ethylidene (two carbon) binding are provided with the hydrogenization in the presence of the Pd (0) in the catalysis of 2D and 1D.Of preamble, these conversions can carried out on the intermediate that fully exquisiteness is processed, and for example described amino pyrazinoic acid amide 11 changes into the pyrazine product I-F of vinyl phosphonate replacement.Graphic 5

Graphic 6 to describe formula I compound synthetic, wherein R ₄In phosphonic acid ester or phosphinate group use Arbusov (Engel, R., organophosphorus chemistry handbook, 1992 [Marcel Dekker]) or Michaelis-Becker (Engel, R., organophosphorus chemistry handbook, 1992 [Marcel Dekker]) reaction and be merged in.In the Arbusov reaction, alkyl halide 13 after removing the protection base, produces amine 2F with 14 heating of tricresyl phosphite alkane ester.Amine 2F is converted to formula IG compound through the mode described in graphic 1 and 2.When using R ₉P (OR ₇) ₂When replacing tricresyl phosphite alkane ester 14 to carry out, obtain its corresponding phosphinate product (i.e. R wherein ₄=-(CH ₂) n-Z-(CH ₂) m-PO-(R ₉) (OR ₇) (people such as Kapustin, Org.Lett., 2003,5:3053-3057).In the Michaelis-Becker reaction, there are reaction down in compound 13 and phosphorous acid dialkyl 15 in alkali, and after removing the protection base, produce amine 2F.Amine 2F can be converted to formula I-G compound through the mode described in graphic 1 and 2.As an example, can heat with tricresyl phosphite alkane ester 14 through the 5-of Boc-protection bromo methylpyrazine, and after removing the Boc group, obtain the pyrazine amine 2G of phosphonate group methyl substituted, it can be by the above-mentioned formula I compound that is converted to.Graphic 6

Graphic 7 to describe formula I compound synthetic, wherein R ₁Hetero-aromatic ring is a thiazole.In this was graphic, phosphonic acid ester or phosphinate were merged in the non-annularity precursor, to form hetero-aromatic ring.In standard Hantzsch thiazole was synthetic, halogen ketone 16 and thiocarbamide 17 reactions were to form the thiazolamine 2H of 4-replacement.As an example, ethanoyl phosphonic acids 18 is handled with bromine, to form α-halogen ketone 19.19 with the reaction of thiocarbamide 17 acquisition 5-phosphonate group-thiazolamine 2I (people such as Ohler, Chem.Ber., 1984,117:3034-3047).Basedol 2H and 2I can be converted to formula I compound through the mode described in graphic 1 and 2.Graphic 7

Graphic 8 to describe formula I compound synthetic, wherein R ₄=-(CH ₂) n-Z-(CH ₂) m-PO (OR ₇) (OR ₈) Z=CH (OH) m=0,1n=0,1,2 is following compound, wherein R ₄Contain the methylene radical [Z=CH (OH)] of hydroxyl replacement, be positioned at hetero-aromatic ring R ₁And between the phosphonate groups.In reaction formula (1), reaction acquisition hydroxyethylidene diphosphonic acid ester products I-H in the presence of alkali such as triethylamine or DBN of phosphorous acid dialkyl 9 and aldehyde 22 (people such as Caplan, J.Chem.Soc.Perkin I, 2000; 3:421-437), represent formula I compound, Z=CH (OH) wherein, n=0; 1,2, and m=0.In reaction formula (2), phosphonic acids alkane ester 23 usefulness alkali such as n-BuLi handle, and then add aldehyde 22, obtain hydroxyethylidene diphosphonic acid ester products I-I (people such as Mikolajczyk, Synthesis; 1984,691-694), represent formula I compound, wherein Z=CH (OH); N=0,1,2, and m=1.As an example, pyrazine 24 and thiazole 25 as shown in be converted to its corresponding hydroxy phosphonate I-J and I-K.Graphic 8

Graphic 9 to describe formula I compound synthetic, wherein R ₄=-(CH ₂) n-Z-(CH ₂) m-PO (OR ₇) (OR ₈) Z=CH (OR ₉) m=0 n=0,1,2 is following compound, wherein R ₄Methylene radical [Z=CH (the OR that contains the alkoxyl group replacement ₉)], be positioned at hetero-aromatic ring R ₁And between the phosphonate groups.In reaction formula (1), graphic 8 hydroxyethylidene diphosphonic acid ester products can be used suitable active alkyl halide 26 alkylations, and obtain alpha-alkoxy base phosphonic acid ester I-L (people such as Wrobleski, TetrahedronAsymmetry, 2002,13:845-850).Perhaps, reaction formula (2) describe alcohols 28 and α-diazo phosphonic acid ester 27 through the catalytic insertion reaction of rhodium, it also provides compound I-L (Cox, people such as G., Tetrahedron, 1994,50:3195-3212; Moody, people such as C., TetrahedronAsymmetry, 2001,12:1657-1661).The preparation of α-diazo phosphonic acid ester 28 by direct diazo transfer describe to its corresponding ketone 29a (Regitz, M., Tetrahedron Lett., 1968,9:3171-3174).Perhaps, diazo phosphonic acid ester 28 can be via the α-tosyl group hydrazides derived from its corresponding ketone group phosphonic acid ester 29b, through base catalysis decompose and obtain (Marmor, people such as R., J.Org.Chem., 1971,36:128-136).α-ketone group phosphonic acid ester 29a can pass through oxygenizement, uses reagent such as CrO ₃, directly synthetic from Alpha-hydroxy phosphonic acid ester (I-H) (Kaboudin, people such as B., Tetrahedron Lett., 2000,41:3169-2171).Perhaps, and its corresponding α-ketone group phosphonic acid ester of Arbusov reaction generation between chloride of acid and tricresyl phosphite alkane ester (Marmor, people such as R., J.Org.Chem., 1971,36:128-136).Be used for the method for synthetic phosphonic acid ester such as 29a, be described in preceding text.Graphic 9

Graphic 10 to describe formula I compound synthetic, wherein R ₄=-(CH ₂) n-Z-(CH ₂) m-PO (OR ₇) (OR ₈) Z=CH (NHR ₉) m=0n=0,1,2 is following compound, wherein R ₄Methylene radical [Z=CH (the NHR that contains amino replacement ₉)], at hetero-aromatic ring R ₁And between the phosphonate groups.In graphic 10, aldehyde 22 can with 30 reactions of phosphorous acid dialkyl 9 and amine, and the phosphonic acid ester I-M of alpha-amino group replacement, its mode be in the presence of silica gel and microwave irradiation, react (people such as Zhan, Chem.Lett., 2005,34:1042-1043).Other method relates to because aldehyde 22 forms corresponding imines in advance with amine 30 condensations, and it then reacts (Laschat and Kunz, Synthesis, 1992,90) with phosphorous acid dialkyl 9 in the presence of various catalyzer such as Lewis acid.Moreover other catalyzer can be used for synthetic (for example, the SmI of single pot described in graphic 10 ₂Use be described in people such as Xu, Eur.J.Org.Chem., 2003,4728) in.Graphic 10

Graphic 11 to describe formula I compound synthetic, wherein R ₄=-(CH ₂) n-Z-(CH ₂) m-O-PO (OR ₇) R ₉With-(CH ₂) nZ-(CH ₂) m-O-PO-R ₉R ₁₀

Alcohol precursor 31 and chlorination phosphono 32 or chlorination time phosphono 33, the reaction in the presence of alkali such as pyridine or triethylamine produces phosphonate compound I-N (reaction formula 1) or phosphinate compounds I-O (reaction formula 2).Except shown in be used for the reaction of synthetic phosphonic acid ester I-N, other method comprise phosphonic acids direct esterification or Mitsunobu reaction use (people such as Saady, Tetrahedron Lett., 1995,36:2239-2242).The phosphinic acid ester of dimethyl-phospho acid (I-O, wherein R ₉And R ₁₀=Me) preparation has been described to use chlorination dimethyl-time phosphono and tetrazolium, exists down in pyridine, produces intermediate phospho acid base tetrazolium things (PCT international application case WO 2000/078763).Graphic 11

Graphic 12 to describe formula I compound synthetic, wherein R ₄=-(CH ₂) n-Z-(CH ₂) m-O-PO (OR ₇) R ₉With-(CH ₂) nZ-(CH ₂) m-O-PO-(R ₉) R ₁₀, and Z=S or SO ₂, and m=1 or 2, and n=0,1 or 2.

Through substituted heteroaromatic intermediate 8 of the halogen of suitably activation and the reaction of sulfenyl potassium cyanate, obtain thiocyanate-intermediate 34.At this moment, the protection base can be removed, and the amino heteroaromatics that is formed, and uses standard method such as EDC-HOBt, with sour 1 coupling, obtains intermediate 35.Thiocyanate-35 is with NaBH ₄Handle, produce its corresponding mercaptan intermediate, it is with halogenide 36 alkylations through replacements, and must formula I compound, wherein Z=S (I-P).Product I-P obtains formula I compound, wherein Z=SO with oxygenant such as hydrogen peroxide or oxone (oxone) processing ₂(I-Q).As an example, the HBr salt of 2-amino-5-bromo thiazole (37) is handled with for example sulfenyl potassium cyanate, obtains thiocyanate-38.Amino thiocyanate-product uses acid 1, adopts the standard method acylations, and gets acid amides 39.39 thiocyanate ion group is with reagent such as NaBH ₄Reduction is followed formed free mercaptan and is carried out alkylation with phosphonic acids iodo methyl esters 40, acquisition formula I phosphonate compound, Z=S wherein, m=1, and n=0 (I-P).Graphic 12

Graphic 13 to describe formula I compound synthetic, wherein R ₄=-(CH ₂) n-Z-(CH ₂) m-O-PO (OR ₇) R ₉With-(CH ₂) nZ-(CH ₂) m-O-PO-(R ₉) R ₁₀, and Z=O, and m=1 or 2, and n=1 or 2.

Through substituted heteroaromatic intermediate 41 of the halogen of suitably activation and the substituted phosphonic acid ester intermediate 42 of hydroxyl, reaction in the presence of silver suboxide produces I-R, is formula I phosphonate compound; Z=O wherein, m=1 or 2, and n=1 or 2 (people such as Flor; J.Med.Chem., 1999,42:2633-2640).Graphic 13

Graphic 14 describe the general synthetic of amine 2D, wherein phosphonic acid ester or phosphinate partly (here by the phosphonic acid ester explanation) via nitrogen-atoms but not carbon atom is linked to heterocycle R1.The for example 43 available bases deprotonations of (Pro) amino-heterocycle of warp protection are then carried out alkylating with the suitable halogenide that contains phosphonic acid ester/phosphinate part, then remove protection, and get amine 2D.It is through the instance explanation of the triazole 44 of N-Boc protection, and it uses 45 alkylations of phosphonic acids iodo methyl esters then with alkali (for example NaH) deprotonation.Then, remove to protect the N-Boc group, obtain aminotriazole phosphonic acid ester 46.On the other hand, in some situation, amino-heterocycle does not need to be protected, as shown in the situation of pyrazoles 47, its available bases such as KOtBu deprotonation, and preferentially on ring nitrogen with electrophilic reagent such as 45 alkylations of phosphonic acids iodo methyl esters, to form product 48.Graphic 14

-for example,

The representative approach that substitutes through the phosphonic acid ester/phosphinate of N-alkylation is shown in graphic 15.Amine 43 can be used suitable alkali deprotonation, and reacts with iodide such as 49 (containing functional group Xa, for example Cl, Br, OTs), and must be through the heterocycle 51 of N-alkylation.Perhaps, amine can (contain the for example hydroxyl OP of warp protection with iodide such as 50 ₂, it can then be removed protection, and passes through for example Ph of currently known methods ₃P/CBr ₄Be converted to halogenide) reaction, so that the heterocycle 51 through the N-alkylation to be provided.Then, this intermediate can with tricresyl phosphate alkane ester reaction (Arbusov reaction), described in graphic 6, so that phosphonic acid ester to be provided, or react shown in Clicking here.When halogenide 51 during with phosphinate 52 reactions, product be its corresponding phosphinate 2E (reference: people such as Kapustin, Org.Lett., 2003,5:3053-3057).Graphic 15

Graphic 16 to describe formula I-S compound synthetic, and it contains annular phosphonate.The phosphonic acid diester 2F of intermediate amine is through protection (for example as t-butyl carbamate, or as benzyl carbamate), and phosphonic acid ester 53, it carries out dealkylation with reagent such as bromo trimethyl silane.Form two-the TMS phosphonic acid ester directly with the oxalyl chloride reaction, and must dichloride phosphinylidyne 54.Intermediate 54 is through reacting in the presence of alkali with suitable glycol 54a, and be converted to the annular phosphonate 55 wanted (reference: people such as Notter, Bioorg.Med.Chem.Lett., 2007,17:113-117).55 go protection to obtain its corresponding amine, and it easily transforms accepted way of doing sth I-S compound through the method that before was described in graphic 1 and 2 then.Graphic 16

Likewise, graphic 17 to describe formula I-T compound synthetic, and it contains the cyclic phosphines oxide compound.Dichloride phosphinylidyne 54 can with form from the Grignard of dibromide 56 and magnesium reagent react, with provide ring-type phosphine oxide 57 (reference: people such as R.Polniaszek, J.Org.Chem., 1991,56:3137-3146).57 go protection to obtain its corresponding amine, and it transforms accepted way of doing sth I-T compound through the method that before was described in graphic 1 and 2 then.Graphic 17

Graphic 18 to describe formula I-U compound synthetic, and it contains the ring-type phosphinate.The dichloro etherophosphoric acid with form from the Grignard of dibromide 56 and magnesium reagent react, and ring-type phosphinate 58 (reference: people such as R.Polniaszek, J.Org.Chem., 1991,56:3137-3146).Ester 58 is by dealkylation (for example using the bromo trimethyl silane).The TMS phosphonic acid ester that is formed directly with chlorizating agent (for example oxalyl chloride) reaction, and phosphoryl chloride 59, it reacts in the presence of alkali with alcohol 31 then, and gets formula I-U compound.Graphic 18

Effectiveness and combination

A. effectiveness

The present invention's compound has the activity as the toughener of enzymatic glucose kinase activity, therefore, can be used for treatment and glucokinase enzymic activity diseases associated.

Therefore; Can The compounds of this invention be thrown and give Mammals; Be preferably the mankind; To treat multiple symptom and illness, include but not limited to treat, prevent or slow down mellitus and relevant symptoms, the microvascular complication relevant, huge vascular complication, cardiovascular disorder, metabolic syndrome and the composition symptom thereof relevant and the progress of other sick illness with mellitus with mellitus.Therefore, believe The compounds of this invention can be used for preventing, suppress or treat wound healing, atherosclerosis and the sequela thereof of mellitus, hyperglycemia, impaired glucose tolerance, insulin resistance, hyperinsulinism, retinopathy, neuropathy, ephrosis, delay, abnormal heart function, myocardial ischemia, apoplexy, metabolic syndrome, hypertension, obesity, lipidemia obstacle, blood fat fat too much, the blood triglyceride too much, hypercholesterolemia, low HDL, high LDL, non-heart ischemia, infection, cancer, vascular restenosis, pancreatitis, neurodegenerative disease, lipid disorders, cognitive power weakens and dementia, bone diseases, lipodystrophy and the glaucoma relevant with hiv protease.

Metabolic syndrome or " syndrome X " are described in people such as Ford, J.Am.Med.Assoc., and 2002, people such as 287:356-359 and Arbeeny, Curr.Med.Chem.-Imm., Endoc.& Metab.Agents, 2001, among the 1:1-24.

B. combination

The present invention comprises pharmaceutical composition in its scope, it comprises at least a formula I compound as significant quantity in the treatment of active ingredient, independent or and medicament carrier or thinner.The compounds of this invention can use separately according to circumstances, and uses other The compounds of this invention, or and with one or more other therapeutical agent, for example antidiabetic or other medicinal activity material.

The compounds of this invention can with other toughener of glucokinase enzymic activity or one or more other can be used for treating the mentioned illness of preamble suitable therapeutical agent merge and adopt, comprising: antidiabetic, antihyperglycemic agents, anti-hyperinsulinism agent, anti-retinopathy agent, anti-neuropathy agent, anti-ephrosis agent, antiatherosclerotic, anti-infection agent, antiischemic agents, hypotensive agent, antiobesity agent, the agent of lipotropism mass formed by blood stasis obstacle, anti-lipid unusual agent, anti-hypertriglyceridemia agent, anti-hypercholesterolemiccompounds agent, anti-exhausted blood agent, carcinostatic agent, anti-cell toxic agent, anti-restenosis agent, anti-pancreas agent, lipid depressant, appetite-inhibiting agent, hypermnesia agent and cognitive agent.

Merge the instance of the suitable antidiabetic of use with The compounds of this invention, comprise Regular Insulin and insulin analog: the suction preparation of LysPro Regular Insulin, insulin-containing; Like glucagon-like peptide; Alkylsulfonyl ureas and analogue: P-607, Glyburide (glibenclamide), tolbutamide, first sulphur nitrogen grass urea, acetohexamide, Glipizide (glypizide), glyburide (glyburide), glimepiride (glimepiride), repaglinide (repaglinide), meglitinide (meglitinide); Biguanides: N1,N1-Dimethylbiguanide (metformin), phenformin (phenformin), buformin (buformin); α 2 antagonists and tetrahydroglyoxaline: midaglizole (midaglizole), isaglidole (isaglidole), SL 86-0715 (deriglidole), Racemic idazoxan (idazoxan), efaroxan (efaroxan), fluparoxan (fluparoxan); Other insulin secretagogue: linogliride (linogliride), pancreotropic hormone, Exendin (exendin)-4, BTS-67582, A-4166; U 25560 (PPAR gamma agonist): ciglitazone (ciglitazone), pioglitazone (pioglitazone), troglitazone (troglitazone), rosiglitazone (rosiglitazone); Non-U 25560 PPAR-gamma agonist; Selective PPAR gamma modulators (SPPARM; For example, the layout row that derive from Metabolex reach mountain (metaglidasen)); The PPAR-alfa agonists; PPAR α/γ dual agonists; PPAR delta agonists, the general agonist of PPAR α/gamma/delta; The SGLT2 suppressor factor; Dipeptidyl peptidase-IV (DPP4) suppressor factor; Aldose reductase inhibitor; Rxr agonist: JTT-501, MX-6054, DRF2593, LG100268; Fatty acid oxidation inhibitors: clomoxir (clomoxir), etomoxir (etomoxir); α-Pu Taotang enzyme inhibitors: acarbose (precose), Acarbose (acarbose), miglitol (miglitol), emiglitate (emiglitate), voglibose (voglibose), MDL-25; 637, MDL 73945 (camiglibose), MDL-73,945; Beta-2-agonists: BRL 35135, BRL 37344, Ro 16-8714, ICI D7114, CL 316,243, TAK-667, AZ40140; Phosphodiesterase inhibitor, two kinds of cAMP and cGMP type: 'Xiduofeng ' (sildenafil), L686398:L-386,398; Dextrin antagonist: tripro-amylin (pramlintide), AC-137; Lipoxygenase inhibitors: Ma Suopu Rocca (masoprocal); Stilamin analogue: BM-23014, seglitide (seglitide), Sostatin (octreotide); Glucagon antagonist: BAY 276-9955; Insulin signaling conduction agonist, Regular Insulin are intended like thing, PTP1B suppressor factor: L-783281, TER17411, TER17529; Glyconeogenesis suppressor factor: GP3034; Stilamin analogue and antagonist; Lipotropism fat decomposition agent: niacin, acipimox (acipimox), WAG 994; Glucose is carried stimulant: BM-130795; Glucose synthase kinase enzyme inhibitors: lithium chloride, CT98014, CT98023; And galanin receptors agonist.

Other suitable U 25560 comprises that the MCC-555 of Mitsubishi (is disclosed in USP 5; 594; In 016), the farglitazar (farglitazar) of Glaxo-Wellcome (GI-262570), englitazone (englitazone) (CP-68722; Pfizer) or darglitazone (darglitazone) (CP-86325, Pfizer), Ai Shagelie ketone (isaglitazone) (MIT/J&J), JTT-501 (JPNT/P&U), L-895645 (Merck), R-119702 (Sankyo/WL), NN-2344 or Ba Gelie ketone (balaglitazone) (Dr.Reddy/NN) or YM-440 (Yamanouchi).

Suitable substance P PAR α/γ dual agonists comprise Mo Geliezha (muraglitazar) (Bristol-Myers, Squibb), for Ge Liezha (tesaglitazar) (Astra/Zeneca), Na Weigeliezha (naveglitazar) (Lilly/Ligand); AVE-0847 (Sanofi-Aventis); TAK-654 (Takeda), and by people such as Murakami, " novel insulin sensitizer serves as outgrowth ligand-activated acceptor α (PPAR α) and the PPAR γ altogether of peroxysome; PPAR α activation is to the metabolic effect of abnormal lipids in the Zucker obese rat liver "; mellitus 47:1841-1847 (1998), WO 01/21602 and U.S.6; 414,002 disclosed those, its disclosure is also for reference in this paper; adopt such as wherein the dosage of proposition, be called as preferred compound and preferably supply this paper to use.Suitable substance P PAR delta agonists comprises for example GW-501516 (Glaxo).The general agonist of suitable substance P PAR α/gamma/delta comprises for example GW-677954 (Glaxo).

Suitable α 2 antagonists also are included in announcement person among the WO 00/59506, adopt such as this paper the dosage of proposition.

Suitable SGLT2 suppressor factor comprises that T-1095, phlorizin (phlorizin), WAY-123783 reach person described in the WO 01/27128.

Suitable DPP4 suppressor factor comprise picogram Sha Lieting (saxagliptin) (Bristol-MyersSquibb), row spit of fland, Victor (vildagliptin) (Novartis) and sitagliptin (sitagliptin) (Merck), and at WO 99/38501, WO 99/46272, WO 99/67279 (PROBIODRUG); Announcement person among the WO 99/67278 (PROBIODRUG), WO 99/61431 (PROBIODRUG), and NVP-DPP728A (1-[[[2-[(5-cyanopyridine-2-yl) amino] ethyl] amino] ethanoyl]-2-cyanic acid-(S)-tetramethyleneimine) (Novartis); As by people such as Hughes, Biochemistry, 38 (36): 11597-11603; 1999 announcement persons, TSL-225 (tryptophyl-1,2; 3,4-tetrahydroisoquinoline-3-carboxylic acid), as by people such as Yamada; Bioorg.&Med.Chem.Lett., 8:1537-1540 (1998) announcement person, 2-cyanic acid Pyrrolidine thing and 4-cyanic acid Pyrrolidine thing; As by people such as Ashworth, Bioorg.& Med.Chem.Lett., the 6th volume; The 22nd phase, 1163-1166 and 2745-2748 page or leaf (1996) announcement person, adopt such as in the above-mentioned reference the dosage of proposition.

Suitable aldose reductase inhibitor is included in announcement person among the WO 99/26659.

Suitable meglitinide (meglitinide) comprises that Starsis (nateglinide) (Novartis) or KAD 1229 (PF/Kissei).

Comprise that like the instance of glucagon-like peptide-1 (GLP-1) GLP-1 (1-36) acid amides, GLP-1 (7-36) acid amides, GLP-1 (7-37) are (as at the USP of giving Habener 5; 614; And AC2993 (Amylin) and LY-315902 (Lilly) announcement person in 492).

The antidiabetic that other can merge use with The compounds of this invention comprises supple and graceful fruit Xie Te (ergoset) and D-inositol.

Suitable antiischemic agents includes but not limited to person described in the RM on doctor's table (Physician ' s DeskReference), and the NHE suppressor factor, is included in announcement person among the WO 99/43663.

The instance of suitable anti-infection agent is an antiseptic-germicide, includes but not limited to person described in the RM on doctor's table (Physicians ' Desk Reference).

Merge the instance of the suitable lipid depressant of uses with The compounds of this invention, comprise upwards regulator, bile acid multivalent chelator (sequestrant), cholestery ester transfer protein inhibitors (for example appropriate western Zhuo than (torcetrapib) (Pfizer)) and/or the niacin and the verivate thereof of one or more MTP suppressor factor, HMG CoA reductase inhibitor, inhibitor for squalene synthetic enzyme, fiber acid derivative, ACAT suppressor factor, fats oxidn enzyme inhibitors, cholesterol absorption inhibitor, ileum Na+/bile acide cotransporter suppressor factor, ldl receptor activity.

Can be included in USP 5,595 like the above-mentioned MTP suppressor factor that is used, 872, USP 5,739,135, USP 5; 712,279, USP 5,760, and 246, USP 5,827; 875, USP 5,885,983 and USP 5,962,440 in announcement person.

Can merge the HMG CoA reductase inhibitor of employing with one or more formulas I compound, comprise mevastatin (mevastatin) and related compound, as at USP 3,983; Announcement person in 140, lovastatin (lovastatin) (Mei Wennuolin (mevinolin)) and related compound are as at USP 4,231; Announcement person in 938, pravastatin (pravastatin) and related compound are for example at USP 4,346; Announcement person in 227, SV (simvastatin) and related compound are as in USP case numbers 4,448; Disclose in 784 and 4,450,171.Other HMG CoA reductase inhibitor that can in this paper, adopt includes but not limited to fluvastatin (fluvastatin), is disclosed in USP 5,354, in 772; Cerivastatin (cerivastatin) is like announcement person in USP case number 5,006,530 and 5,177,080; Atorvastatin (atorvastatin) is like announcement person in USP case numbers 4,681,893,5,273,995,5,385,929 and 5,686,104; Ah he cuts down his spit of fland (atavastatin) (Buddhist nun of Nissan/Sankyo cut down him spit of fland (nisvastatin) (NK-104)), as at USP 5,011, and announcement person in 930; Wei Shatating (visastatin) (Shionogi-Astra/Zeneca (ZD-4522)), as at USP 5,260, announcement person in 440; And relevant statin compound, be disclosed in USP 5,753, in 675; The pyrazole analogs of mevalonolactone (mevalonolactone) verivate, as at USP 4,613, announcement person in 610; The indenes analogue of mevalonolactone verivate is like announcement person in PCT application case WO 86/03488; 6-[2-(substituted azole-1-yl) alkyl) pyran-2-one and verivate thereof, as at USP 4,647, announcement person in 576; The SC-45355 of Searle (3-substituent glutaric acid verivate) dichloroacetic acid salt; The imidazoles analogue of mevalonolactone is like announcement person in PCT application case WO 86/07054; 3-carboxyl-2-hydroxyl-propane-phosphonate derivative, as in FRP 2,596, announcement person in 393; 2,3-disubstituted pyrroles, furans and thiophene derivant are like announcement person in european patent application number 0221025; The naphthyl analogue of mevalonolactone, as at USP 4,686, announcement person in 237; The octahydro naphthalene, for example in USP 4,499, announcement person in 289; The ketone group analogue of Mei Wennuolin (lovastatin) is like announcement person in european patent application number 0142146 A2; And quinoline and pyridine derivate, like announcement person in USP case numbers 5,506,219 and 5,691,322.

Preferred hypolipidemic is that pravastatin, lovastatin, SV, atorvastatin, fluvastatin, Cerivastatin, Ah he cut down Ta Ting and ZD-4522.

In addition, can be used for suppressing the phosphinic compounds of HMG CoA reductase enzyme, for example announcement person in GB 2205837 is fit to merge use with the present invention's compound.

Be suitable for the inhibitor for squalene synthetic enzyme here, include but not limited to α-phosphono sulphonate, it is disclosed in USP 5,712, in 396; By people such as Biller, J.Med.Chem., 1988, the 31 volumes, the 10th phase, 1869-1871 page or leaf announcement person comprises isoprenoid (phosphinyl-methyl) phosphonic acid ester; And other known inhibitor for squalene synthetic enzyme, for example, as at USP 4,871,721 and 4; 924,024 and at Biller, S.A., Neuenschwander, K.; Ponpipom, M.M. and Poulter, C.D., existing medicine design, announcement person among the 2:1-40 (1996).

In addition, be suitable for other inhibitor for squalene synthetic enzyme here, comprise the terpenoid pyrophosphate salt, by people such as P.Ortiz de Montellano, J.Med.Chem., 1977,20:243-249 announcement person; The farnesyl diphosphate analogue AWith preceding Supraene pyrophosphate salt (PSQ-PP) analogue, as by Corey and Volante, J.Am.Chem.Soc., 1976,98:1291-1293 announcement person; The phosphinyl phosphonic acid ester, by McClard, people such as R.W., J.A.C.S., 1987, the reporter of 109:5544 institute; And cyclopropanes, by Capson, T.L., Ph.D. paper, in June, 1987, the Dept.Med.Chem. of Utah university, summary, contents table, the 16th, 17,40-43, the 48-51 page or leaf general introduction reporter of institute.

The fiber acid derivative that can merge employing with one or more formulas I compound; Comprise fenofibrate (fenofibrate), gemfibrozil (gemfibrozil), chlorine Bei Te (clofibrate), bezafibrate (bezafibrate), Win-35833 (ciprofibrate), S-8527 (clinofibrate) and analogue thereof, probucol (probucol) and related compound; As at USP 3; 674; Announcement person in 836; Probucol and gemfibrozil are preferred, bile acid multivalent chelator, such as QUESTRAN (cholestyramine), colestipol (colestipol) and DEAE-sephadex (Sephadex) (

); And protect fat appropriate (lipostabil) (Rhone-Poulenc), Eisai E-5050 (ethanolamine derivant of N-replacement), imanixil (imanixil) (HOE-402), orlistat (THL), different beans fat alkyl PC (SPC; Roche), amino Schardinger dextrins (Tanabe Seiyoku), Ajinomoto AJ-814 (azulene derivatives), AC-233 (melinamide) (Sumitomo), Sandoz 58-035, american cyanamide CL-277,082 and CL-283,546 (urea derivativess of two replacements), niacin, acipimox (acipimox), AY-25712 (acifran), Xin Meisu, right-aminosallcylic acid, Frosst), gather (diallyl methylamine) verivate; For example at USP 4; Announcement person in 759,923, quaternary amine gathers (chlorination diallyl dimethyl ammonium) and ionene (ionenes); For example at USP 4; Announcement person in 027,009, and other known serum cholesterol lowering agent.

Can merge the ACAT suppressor factor of employing with one or more formulas I compound, comprise being disclosed in following person future drugs 24:9-15 (1999) (avasimibe (Avasimibe)); " effective in the prevention in ACAT inhibitor C l-1011 aorta lipid layer zone in hamster and the degeneration ", people such as Nicolosi, atherosclerosis (Shannon, Irel). (1998), 137 (1): 77-85; " the pharmacotoxicological effect form of FCE 27677: a kind of liver secretion novel ACAT suppressor factor that mediates that suppresses to contain ApoB100 lipoprotein through selectivity " with effective hypolipidemic activity, Ghiselli, Giancarlo; Cardiovasc.Drug Rev. (1998), 16 (1): 16-30, " RP73163: biological alkyl sulphinyl-diphenyl-imidazole ACAT suppressor factor capable of using "; Smith, people such as C., Bioorg.Med.Chem.Lett. (1996); 6 (1), 47-50; " ACAT suppressor factor: the physiological mechanism of reducing blood-fat and atherosclerosis activity in laboratory animal ", people such as Krause, editor: Ruffolo, Robert R., Jr.; Hollinger, Mannfred A., inflammation: amboceptor approach (1995), 173-98, press: CRC, BocaRaton, Fla.; " ACAT suppressor factor: potential antiatherosclerotic ", people such as Sliskovic, Curr.Med.Chem. (1994), 1 (3): 204-25; " acyl group-CoA: the suppressor factor of SUV O-acyltransferase (ACAT) reduces agent .6. as blood cholesterol and has the first water-soluble ACAT suppressor factor that lipid is regulated activity.Acyl group-CoA: the suppressor factor .7. of cholesterol acyltransferase (ACAT) has the exploitation of a series of substituted N-phenyl-N '-[(1-benzyl ring amyl group) methyl] ureas of strengthening blood cholesterol minimizing activity "; people such as Stout; Chemtracts:Org.Chem. (1995), 8 (6): 359-62 or TS-962 (Taisho pharmaceuticals).

Lipid-lowering agent can be the upwards regulator of LD2 receptor active, such as MD-700 (Taisho pharmaceuticals) and LY295427 (Eli Lilly).

Merge the instance of the suitable cholesterol absorption inhibitor of uses with The compounds of this invention, comprise SCH48461 (Schering-Plough), and in atherosclerosis 115:45-63 (1995) and J.Med.Chem.41:973 (1998) announcement person.

Merge the instance of the suitable ileum Na+/bile acide cotransporter suppressor factor of use with The compounds of this invention, comprise as being disclosed in Drugs ofthe Future, the compound among the 24:425-430 (1999).

The lipoxygenase inhibitors that can merge employing with one or more formulas I compound; Comprise 15-lipoxygenase (15-LO) suppressor factor; The benzimidizole derivatives that for example in WO 97/12615, is disclosed, the 15-LO suppressor factor that in WO 97/12613, is disclosed, the isothiazolones that in WO 96/38144, is disclosed; And by people such as Sendobry " weakening of the high selectivity 15-fats oxidn enzyme inhibitors of the remarkable antioxidation property of atherosclerosis use shortage that diet causes in rabbit "; People such as Brit.J.Pharmacology (1997) 120:1199-1206 and Comicelli, " 15-lipoxidase and inhibition thereof: the novelty treatment target of vascular disease ", existing medicine design; 1999, the 15-LO suppressor factor that 5:11-20 disclosed.

Merge the instance of the suitable hypotensive agent of use with The compounds of this invention, comprise Beta-3 adrenergic blocker, calcium channel blocker (L-type and T-type; For example Odizem (diltiazem), verapamil (verapamil), nifedipine (nifedipine), amlodipine (amlodipine) and Mai Beifu Lardy (mybefradil)), diuretic(s) (for example chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methyl chlorothiazide, trichloromethiazide, many thiazines, benzthiazide, Uregit three can sharp that fens (tricrynafen), Rorer), furosemide, order Suo Limin (musolimine), bumetanide (bumetanide), three peaces urge peaceful (triamtrenene), guanamprazine, spironolactone), renin inhibitor, ACE inhibitor (for example captopril (captopril), zofenopril (zofenopril), fosinopril (fosinopril), enalapril (enalapril), Xie Lanuo Puli (ceranopril), hila are sat Puli (cilazopril), delapril (delapril), pentopril (pentopril), quinapril (quinapril), ramipril (ramipril), lisinopril (lisinopril)), AT-1 receptor antagonist (losartan (losartan), irbesartan (irbesartan), valsartan (valsartan), ET receptor antagonist (for example western tower celestial being smooth (sitaxsentan), Aunar celestial being smooth (atrsentan) and be disclosed in USP case numbers 5 for example; 612; 359 and 6; Compound in 043,265), dual ET/AII antagonist (for example being disclosed in the compound among the WO00/01389), neutral endopeptidase (NEP) suppressor factor, vasopeptidase inhibitors (dual NEP-ACE suppressor factor) (for example omapatrilat (omapatrilat) and Ji not song draw (gemopatrilat)) and nitrate salt.

Merge the instance of the suitable antiobesity agent of use, type of comprising Cannabined receptor 1 antagonist or inverse agonists, 'beta '3 adrenergic agonists, lipase inhibitor, serotonin (with Dopamine HCL) reuptake inhibitor, thryoid receptor β medicine and/or anoretics with The compounds of this invention.

Can merge employing and so on Cannabined receptor 1 antagonist and inverse agonists with The compounds of this invention according to circumstances; Comprise that SR141716A (rimonabant), SLV 319 reach at D.L.Hertzog; Expert Opin.Ther.Patents, 2004, the debater of institute among the 14:1435-1452.

The 'beta '3 adrenergic agonists that can be according to circumstances merges employing with The compounds of this invention comprises AJ9677 (Takeda/Dainippon), L750355 (Merck) or CP331648 (Pfizer) or other known β 3 agonists, as in USP case numbers 5,541,204,5; 770,615,5,491,134; 5,776,983 and 5,488; Announcement person in 064, AJ9677 wherein, L750,355 and CP331648 be preferred.

Can merge the instance of the lipase inhibitor of employing according to circumstances with The compounds of this invention, comprise orlistat (orlistat) or ATL-962 (Alizyme), wherein orlistat is preferred.

Serotonin (with the Dopamine HCL) reuptake inhibitor that can be according to circumstances merges employings with formula I compound can be sibutramine (sibutramine), topiramate (topiramat) (Johnson&Johnson) or the York rope live element (axokine) (Regeneron), wherein sibutramine and topiramate are preferred.

The instance that can merge the thryoid receptor beta compounds of employing according to circumstances with The compounds of this invention; Comprise thryoid receptor ligands; Announcement person in WO 97/21993 (U.Cal SF), WO 99/00353 (KaroBio) and WO 00/039077 (KaroBio) for example, wherein the compound of KaroBio application case is preferred.

Can merge the anoretics of employing according to circumstances with The compounds of this invention, comprise dextroamphetamine, phentermine (phentermine), Phenylpropanolamine or SaH-42548 (mazindol), wherein dextroamphetamine is preferred.

Can merge other compound of use with The compounds of this invention, comprise cck receptor agonist (for example SR-27895B); The galanin receptors antagonist; MCR-4 antagonist (for example HP-228); Leptin or plan are like thing; 11-beta-hydroxysteroid dehydrogenase type-1 suppressor factor; Urocortin is intended like thing, CRF antagonist and CRF conjugated protein (for example RU-486, Urocortin).

Moreover The compounds of this invention can merge use with carcinostatic agent and cytotoxic agent, includes but not limited to alkylating agent, such as nitrogen mustard, AS, nitrosoureas, Soluol XC 100 and triazines; Metabolic antagonist, such as folate antagonist, purine analogue and pyrimidine analogue; Microbiotic, such as anthracycline antibiotics, bleomycin, MTC, gengshengmeisu and Plicamycin; Enzyme, such as altheine enzyme; Farnesyl protein transferase inhibitor; 5 alpha reductase inhibitors; The suppressor factor of 17beta-Hydroxysteroid dehydrogenase type 3; Hormone preparation, such as glucocorticosteroid, oestrogenic hormon/estrogen antagonist agent, male sex hormone/androgen antagonist agent, Progesterone and r-hLH antagonist, Sostatin acetate; Microtubule is disintegrated agent, such as ETM775 (ecteinascidin) or its analogue and verivate; Microtubule stabilizer; Such as taxanes; For example taxol (paclitaxel) (

), how western purple mountain alcohol (docetaxel) ( ) and analogue thereof; And ebormycine (epothilone), such as ebomycin A-F and analogue thereof; The product of plant origin, such as vinca alkaloids, Zuyeyidal, taxanes; And topology isomerase inhibitors; Prenyl-protein transferase inhibitor; And miscellaneous medicament, such as hydroxyurea, Procarbazine, mitotane (mitotane), hexamethylmelamine, platinum coordination complex, such as cis-platinum and carboplatin; Reach other medicament, such as biological response changes agent, growth factor as carcinostatic agent and cytotoxic agent use; Immunomodulator; And monoclonal antibody.Other carcinostatic agent is disclosed among the EP1177791.The compounds of this invention also can combine radiotherapy to use.

Merge the instance of suitable hypermnesia agent, anti-dementia agent or the cognitive agent of use with The compounds of this invention, include but not limited to bright (rivastigmine), lycoremine, memantine (memantine), tacrine (tacrine), Metrifonate (metrifonate), muscarine, Zhan Nuo Merrill Lynch (xanomelline), selegiline (deprenyl) and the Physostigmine of E2020 (donepezil), Li Fansi.

Aforementioned patent and patent application case are all and for reference in this paper.

Above-mentioned other therapeutical agent; When merging employing with The compounds of this invention; Can be for example use with amount indicated in the RM on doctor's table (Physicians ' Desk Reference), such as preceding text person in the patent of proposition, or like the otherwise measured person of those of ordinary skills.

Formula I compound can be offerd medicine through any suitable mode, uses for the purposes described in any this paper, and is for example oral, for example is tablet, capsule, particle or powder type; The hypogloeeis mode; The cheek mode; The parenteral mode is for example through subcutaneous, intravenously, intramuscular or breastbone inner injection or perfusion technique (for example as sterile injectable water-based or non-aqueous solution or suspension-s); The intranasal mode comprises the dispensing of nose film, for example through sucking spraying; Local mode for example is emulsifiable paste or ointment; Or rectal, for example be suppository form; In the dosage unit preparations that contains pharmaceutically acceptable carrier of nontoxicity or thinner.

The method of carrying out the present invention with treatment mellitus and relative disease on; The pharmaceutical composition that employing is contained formula I compound; Use or do not use other antidiabetic and/or lipidemia agent and/or other type therapeutical agent, be accompanied by medical carrier or thinner.Pharmaceutical composition can be through allotment, and adopting expectation dispensing pattern is conventional solid or liquid vehicle or the thinner and the auxiliary pharmaceutical adjuvant of suitable type, for example pharmaceutically acceptable carrier, vehicle, tamanori etc.Compound can be made an excuse the clothes approach and thrown and to give the Mammals sufferer, comprises the mankind, monkey, dog etc., for example is the form of tablet, capsule, bead, particle or powder.For adult's dosage, between every day 0.25 and 2,000 milligrams, preferably between 1 and 500 milligram, it can be in single dose or with indivedual dosage forms, and every day, throwing was given 1-4 time.

Supply the typical capsule of oral administration medicine supplying, contain compound (250 milligrams), lactose (75 milligrams) and the Magnesium Stearate (15 milligrams) of structure I.Make mixture pass through 60 mesh screen clothes, and be packaged in numbering 1 gelatine capsule.

Typical case's injectable formulation also seals and processes with the sterile manner lyophilize through being placed in the bottle with the structure I compound of sterile manner with 250 milligrams.In order to use, mix with 2 ml physiological salines tolerant within the bottle, to make injectable formulation.

Abbreviation

Following abbreviation is used among the embodiment and this paper other places: Ph=phenyl Bn=benzyl t-Bu=tertiary butyl i-Bu=isobutyl-Me=methyl Et=ethyl Pr=propyl group iPr=sec.-propyl Bu=butyl AIBN=2,2 '-azobis isobutyronitrile TMS=TMS TMSCHN ₂=(TMS) diazomethane TMSN ₃=trimethylsilyl azide thing TBS=tertiary butyl dimethylsilyl FMOC=fluorenylmethyloxycarbonyl Boc or BOC=tertbutyloxycarbonyl Cbz=carbonyl benzyl oxygen base or carbonyl benzyloxy or carbobenzoxy-(Cbz) THF=THF Et ₂O=ether hex=hexane EtOAc=vinyl acetic monomer DMF=N MeOH=methyl alcohol EtOH=ethanol DCM=methylene dichloride i-PrOH=Virahol DMSO=methyl-sulphoxide DME=1; 2-glycol dimethyl ether DMA=N; N-dimethyl-ethanoyl acid amides DCE=1,2-ethylene dichloride HMPA=hexamethylphosphorictriamide HOAc or AcOH=acetic acid TFA=trifluoracetic acid DIEA or DIPEA or i-Pr ₂NEt or HunigShi alkali=diisopropylethylamine TEA or Et ₃N=triethylamine NMM=N-methylmorpholine NBS=N-bromo succinimide NCS=N-chloro succinimide DMAP=4-Dimethylamino pyridine DEPBT=3-diethoxy phosphoryl Oxy-1; 2,3-phentriazine-4 [3H]-ketone mCPBA=3-chloro benzoyl hydroperoxide NaBH ₄=Peng Qinghuana NaBH (OAc) ₃=sodium triacetoxy borohydride NaN ₃=sodiumazide DIBALH=diisobutylaluminium hydride LiAlH ₄=lithium aluminium hydride n-BuLi=just-butyllithium

=single persulphate Pd/C=palladium/carbon PXPd ₂=dichloro (chloro two-tertiary butyl phosphine) palladium (II) dimer or [PdCl ₂(t-Bu) ₂PCl] ₂PtO ₂=platinum oxide KOH=Pottasium Hydroxide NaOH=sodium hydroxide LiOH=Lithium Hydroxide MonoHydrate LiOH.H ₂O=lithium hydroxide monohydrate HCl=hydrochloric acid H ₂SO4=sulfuric acid H ₂O ₂=hydrogen peroxide Al ₂O ₃=aluminum oxide K ₂CO ₃=salt of wormwood Cs ₂CO ₃=cesium carbonate NaHCO ₃=sodium hydrogencarbonate ZnBr ₂=zinc bromide MgSO ₄=sal epsom Na ₂SO ₄=sodium sulfate KSCN=sulfenyl potassium cyanate NH ₄Cl=ammonium chloride DBU=1,8-diaza-bicyclo also [5.4.0] 11-7-alkene EDC (or EDC.HCl) or EDCI (or EDCI.HCl) or EDAC=3-ethyl-3 '-(dimethylamino) propyl group-carbodiimide hydrochloride (or 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride) HOBT or HOBT.H ₂O=1-hydroxy benzotriazole hydrate HOAT=1-hydroxyl-7-pyridine and triazole PyBOP reagent or bop reagent=phosphofluoric acid benzotriazole-1-base oxygen base-three (dimethylamino) Phosphonium NaN (TMS) ₂Two (TMS) amine Ph of=hexamethyl two silicon sodium nitrides or sodium ₃P=triphenyl phosphine Pd (OAc) ₂=palladium (Ph ₃P) ₄Pd ⁰=four-triphenyl phosphine palladium Pd ₂(dba) ₃=three (dibenzyl acetone) two palladium DPPF=1,1 '-two (diphenylphosphino) Dicyclopentadiene (DCPD) iron HATU=phosphofluoric acid 2-(7-nitrogen-1H-benzotriazole-1-yl)-1,1; 3; 3-tetramethyl-urea, phosphofluoric acid (V) 2-(3H-[1,2,3] triazolo [4; 5-b] pyridin-3-yl)-1; 1,3,3-tetramethyl-isourea DEAD=diethylazodicarboxylate DIAD=diisopropyl azo-2-carboxylic acid Cbz-Cl=chloroformic acid benzyl ester CAN=ceric ammonium nitrate SAX=strong anion exchanger SCX=strong cation exchanger H ₂=hydrogen Ar=argon N ₂Min=minute h of=nitrogen Equiv=equivalent or hr=hour L=rise mL=milliliter μ L=microlitre g=gram mg=milligram mol=mole mmol=mmole meq=milli-equivalent RT or R.T.=room temperature AT=envrionment temperature sat or the saturated aq.=aqueous solution of sat ' d=TLC=thin layer chromatography HPLC=high performance liquid chromatography (HPLC) HPLC Rt=HPLC RT LC/MS=high performance liquid chromatography (HPLC)/mass spectroscopy MS or Mass Spec=mass spectroscopy NMR=nuclear magnetic resonance nmr spectrum data: the s=singlet; The d=doublet; The m=multiplet; Br=is broad; The t=triplet, the mp=fusing point

Embodiment

Following work embodiment is used for explaining and some preferred implementations of unrestricted the present invention better.

General remark

HPLC one speech refers to the Shimadzu high performance liquid chromatography (HPLC), uses one of following method: 50 millimeters posts of 5 micron 4.6 X of method A:YMC or Phenomenex C18, use 0-100% solvent B [90%MeOH:10%H ₂O:0.2%H ₃PO ₄] and 100-0% solvent orange 2 A [10%MeOH:90%H ₂O:0.2%H ₃PO ₄] 4 minutes gradient liquid, use 4 ml/min flow velocitys and 1 minute to keep, be set in UV-light (uv) detector under 220 millimicrons.30 millimeters posts of method B:Phenomenex S5 ODS 4.6 x, gradient eluent, 0-100%B/A; (solvent orange 2 A=10%MeOH/H2O contains 0.1%TFA, solvent B=90%MeOH/H2O to go through 2 minutes; Contain 0.1%TFA), flow velocity 5 ml/min detect at 220 millimicrons of following UV.50 millimeters posts of method C:YMC S7 ODS 3.0 x, gradient eluent, 0-100%B/A; (solvent orange 2 A=10%MeOH/H2O contains 0.1%TFA, solvent B=90%MeOH/H2O to go through 2 minutes; Contain 0.1%TFA), flow velocity 5 ml/min detect at 220 millimicrons of following UV.

Preparation HPLC one speech refers to robotization Shimadzu HPLC system, uses the mixture of solvent orange 2 A (10%MeOH/90%H2O/0.2%TFA) and solvent B (90%MeOH/10%H2O/0.2%TFA).Preparation property post is with YMC or Phenomenex ODS C18 5 submicron resins or coordinator filling.

Following embodiment explains preferred compound of the present invention.Embodiment 1

A.

With (3.83 milliliters of trimethylammonium acetyl chlorides; 31.1 mmole) dropwise be added into 4-methylthio group-phenyl acetic acid (5.40 grams; 29.6 mmole) with K2CO3 (12.3 grams; 88.8 mmole) in acetone (40 milliliters), in they-10 ℃ of mixtures, maintain the temperature at simultaneously＜-10 ℃ under.In-10 ℃ after following 10 minutes, make reactant be warmed to 0 ℃.At 0 ℃ after following 10 minutes, make reactant be cooled to-10 ℃.Add (1R, 2R)-(-)-pseudo-ephedrine (7.34 grams; 44.4 mmole).In-10 ℃ after following 10 minutes, make reaction mixture be warmed to room temperature.After 4 hours, make reactant between EtOAc (60 milliliters) and H2O (30 milliliters), make separatory and handle.With EtOAc (30 milliliters) aqueous phase extracted.Merge whole organic phases, with salt solution (30 milliliters) washing, dehydrate (MgSO4), and concentrate in a vacuum.Make crude product from warm EtOAc/ hexane recrystallize, and get the partly compound of A (PartA) (7.3 grams; 75%), is crystalline solid.B.?

Compound (7.0 grams with part A; 21.27 the solution in THF (51 milliliters) mmole), in 45 minutes, be added into LiN (TMS) 2 (44.7 milliliters, the 1.0M solution in THF; 44.7 mmole) in they-70 ℃ of solution, keep internal temperature to be lower than-65 ℃ simultaneously.After interpolation, reaction mixture was stirred 15 minutes down in-70 ℃, make it be warmed to 0 ℃ then.At 0 ℃ after following 20 minutes, make reactant be cooled to-70 ℃ again.Add cyclopentyl methyl iodide (6.70 grams; 31.91 mmole) (5.4 milliliters of DMPU; 44.68 the solution mmole).Reactant was stirred 30 minutes down at-70 ℃, then make it be warmed to room temperature.After 20 hours, through adding saturated NH ₄The Cl aqueous solution (20 milliliters) makes the reaction mixture cancellation.With EtOAc (175 milliliters) extraction solution.Separate organic phase,, dehydrate (MgSO4), and concentrate with saturated NH4Cl (50 milliliters) and salt solution (50 milliliters) washing.Make crude product through hurried formula chromatography purification (SiO2; Continuous gradient liquid, from 0 to 90% solvent B went through 75 minutes, wherein, solvent orange 2 A=hexane, and solvent B=EtOAc), and get the partly compound of B (Part B) (6.94 grams; 79%).C.?

Compound (5.44 grams with part B; 13.22 mmole) 1, the solution in the 4-diox (24 milliliters) is handled with the 9N H2SO4 aqueous solution (15 milliliters).Then, reaction mixture is heated down at 105 ℃.After 20 hours, stop heating, and make solution be cooled to room temperature.Add H2O (100 milliliters), so that the product deposition.By the filtering separation solid, and dried in vacuum, and get the partly compound of C (3.40 grams; 97%).D.?

(17.64 grams with

; 28.70 mmole) be added into partly C compound (3.30 grams; 12.48 mmole) in the mixture in 2-propyl alcohol (90 milliliters) and H2O (45 milliliters).After following 20 hours, remove the 2-propyl alcohol in room temperature in a vacuum.With EtOAc (175 milliliters) extraction water solution.Organic phase with H2O (50 milliliters) and salt solution (50 milliliters) washing, is dehydrated (MgSO4), and in vacuum, concentrates, and get the partly compound of D (3.60 grams; 97%), is white solid.(partly the compound of D is processed through revising the method described in the patent WO 02/46173 a little).E.?

With two carbonic acid, two-tert-butyl ester (2.40 grams; 11.00 mmole) be added into thiazolamine (1.00 grams; 9.99 mmole) in the solution in THF (5 milliliters).Add (1.67 milliliters of TEA; 11.98 mmole), then be the 4-DMAP of catalytic amount (2.0 milligrams).After 4 hours, concentrated reaction mixture in a vacuum.Making residue between the EtOAc (20 milliliters) and the 0.1N HCl aqueous solution (15 milliliters), make separatory handles.Organic phase with salt solution (15 milliliters) washing, is dehydrated (MgSO4), and concentrate in a vacuum.Make crude product chromatography (SiO2; Continuous gradient liquid, from 0 to 100% solvent B went through 25 minutes; Under 100% solvent B, kept 5 minutes, wherein, solvent orange 2 A=hexane, and solvent B=EtOAc), and get the partly compound of E (0.77 gram; 39%), is white solid.F.?

With LDA (1.44 milliliters, the 2.0M solution in THF/ heptane/ethylbenzene; 2.88 mmole) they-78 ℃ of solution are added into partly A compound (0.25 gram with sleeve pipe; 1.25 mmole) in THF (4 milliliters) in they-78 ℃ of solution.After 30 minutes, slowly add ClPO ₃Et ₂(270 microlitres; 1.87 the solution in THF (0.5 milliliter) mmole).Make reaction mixture slowly be warmed to ambient temperature overnight.After 16 hours, through adding H ₂O (0.5 milliliter) makes the reaction cancellation.Making solution between EtOAc (5 milliliters) and salt solution (5 milliliters), make separatory handles.Make organic phase dehydrate (MgSO4), and concentrate in a vacuum.Make crude product chromatography (SiO2; Continuous gradient liquid, from 0 to 100% solvent B went through 10 minutes, under 100% solvent B, kept 10 minutes, wherein, solvent orange 2 A=hexane, and solvent B=EtOAc), and get the partly compound of F (0.12 gram; 29%).G.?

TFA (0.40 milliliter) is added into partly B compound (0.12 gram; 0.37 mmole) in 0 ℃ of solution in DCM (0.80 milliliter).After adding completion, make reaction mixture be warmed to room temperature, and at room temperature stirred 4 hours.In vacuum, remove volatile matter, and residue is dissolved among the EtOAc (3 milliliters).EtOAc solution is washed with the saturated NaHCO3 aqueous solution (3 milliliters).With EtOAc (2 milliliters) aqueous layer extracted.The organic extract liquid of merging is dehydrated (MgSO4), and concentrates in a vacuum, and (83.0 milligrams of the compounds of G partly; 96%).H.?

With (47.8 milligrams of DEPBT; 0.16 mmole) be added into (23.7 milligrams of part D compounds; 0.08 mmole) with (20.8 milligrams of part G compounds; 0.09 mmole) in the solution in THF (0.40 milliliter).Add DIPEA (27.0 microlitres; 0.16 mmole).After following 24 hours, reaction mixture is concentrated in room temperature in a vacuum.Residue is dissolved among the EtOAc (3 milliliters).The EtOAc layer with the 1N HCl aqueous solution (2 milliliters), H2O (2 milliliters), the saturated NaHCO3 aqueous solution (2 milliliters of 2 x) and salt solution (2 milliliters) washing, is dehydrated (MgSO4), and concentrates in a vacuum.Crude product is dissolved among the DCM (3 milliliters).With (40 milligrams of solution and amino methyl polystyrene resins; To remove the Acibenzolar of unreacted) stirred together 20 minutes, filter then.Concentrated filtrate in a vacuum.Make residue through preparing HPLC purifying (YMC anti-phase ODS-A-5u 30 x100 millimeter posts; Flow velocity=40 ml/min, 10 to 100% solvent B went through 12 minutes, were retained to 16 minutes, wherein, solvent orange 2 A=90: 10: 0.1 H2O: MeOH: TFA, and solvent B=90: 10: 0.1 MeOH: H2O: TFA), and get (15 milligrams of title compounds; 37%), is colorless solid.[M+H]+＝515.2；1H?NMR(400MHz，CD3OD)：δ1.19(m，2H)，1.33(m，6H)，1.50(m，2H)，1.64(m，3H)，1.80(m，2H)，1.89(m，1H)，2.23(m，1H)，3.10(s，3H)，4.00(t，1H)，4.12(m，4H)，7.69(d，2H)，7.89(d，J＝4.8?Hz，1H)，7.93(d，2H)。Embodiment 2 A.

With (0.68 milliliter of oxalyl chloride (2.0M is in DCM); 1.35 mmole) be added into (200 milligrams of embodiment 1 part D compounds; 0.68 mmole) in the mixture in DCM (1 milliliter).Add DMF (5 microlitre).Generation gas disengages.In room temperature after following 2 hours, concentrated reaction mixture in a vacuum.With residue from CHCl ₃(2 milliliters of 2 x) stripping is dissolved among the DCM (2.5 milliliters) then.Make solution be cooled to 0 ℃, and add (175 milligrams of 2-amino-5-bromo pyridine; 1.01 mmole), then be pyridine (82 microlitres; 1.01 mmole).Reaction mixture was stirred under room temperature 16 hours, concentrate in a vacuum then.Making residue between the EtOAc (5 milliliters) and the 0.1N HCl aqueous solution (4 milliliters), make separatory handles.Organic phase with salt solution (4 milliliters) washing, is dehydrated (MgSO4), and concentrate in a vacuum.Make crude product chromatography (SiO2; Continuous gradient liquid, from 0 to 80% solvent B went through 18 minutes, wherein, solvent orange 2 A=hexane, and solvent B=EtOAc), and get (250 milligrams of part A compounds; 82%).B.?

THF (through the degassing) (0.50 milliliter) is added into (28.9 milligrams of part A compounds; 0.064 mmole) with (Ph ₃P) ₄Pd ⁰(14.8 milligrams; 0.013 mmole).Add H (O) P (OEt) ₂(10.3 microlitres; 0.079 mmole), then be TEA (13.7 microlitres; 0.098 mmole).Container is added a cover, and reaction mixture was heated 9 hours down in 75 ℃, be cooled to room temperature then, and concentrate in a vacuum.Make crude product through preparing HPLC purifying (100 millimeters posts of YMC anti-phase ODS-A-5u 30 x; Flow velocity=40 ml/min, 20 to 100% solvent B went through 12 minutes; Under 100% solvent B, kept 17 minutes, wherein, solvent orange 2 A=90: 10: 0.1 H2O: MeOH: TFA; And solvent B=90: 10: 0.1 MeOH: H2O: TFA), and get (18 milligrams of title compounds; 55%), is amorphous solid.[M+H]+＝509.2；1H?NMR(400MHz，CD3OD)：δ1.19(m，2H)，1.32(t，6H)，1.51(m，2H)，1.64(m，3H)，1.84(m，3H)，2.22(m，1H)，3.09(s，3H)，4.02(t，1H)，4.12(m，4H)，7.70(d，2H)，7.92(d，2H)，8.08(ddd，1H)，8.26(dd，1H)，8.60(dd，1H)。Embodiment 3

(14.3 milligrams of title compounds; 44%; Yellow amorphous solid) adopt the method described in the embodiment 2, synthetic from 5-bromo-2-pyrazine amine.[M+H] +=510.2; 1H NMR (400MHz, CD3OD): δ 1.19 (m, 2H), 1.33 (t, 6H), 1.51 (m; 2H), 1.64 (m, 3H), 1.84 (m, 3H), 2.22 (m; 1H), 3.09 (s, 3H), 4.03 (t, 1H); 4.21 (m, 4H), 7.71 (d, 2H), 7.92 (d; 2H), 8.71 (s, 1H), 9.59 (s, 1H). embodiment 4

With CH ₃CN (150 microlitre) is added into (30 milligrams of embodiment 2 part A compounds; 0.066 Pd (OAc) mmole), ₂(0.30 milligram; 0.0013 mmole) and (0.80 milligram of three-neighbour-tolylphosphine; 0.0026 in mixture mmole).Add vinyl phosphoric acid diethyl ester (10.7 microlitres; 0.083 mmole), then be TEA (27.7 microlitres; 0.199 mmole).Reaction mixture was heated 4 hours down at 95 ℃, be cooled to room temperature then.Making solution between EtOAc (3 milliliters) and salt solution (2 milliliters), make separatory handles.Make organic phase dehydrate (MgSO4), and concentrate in a vacuum.Make residue chromatography (SiO2; Continuous gradient liquid, from 0 to 100% solvent B went through 12 minutes, kept wherein solvent orange 2 A=hexane, and solvent B=EtOAc 8 minutes at 100% time), and get (24 milligrams of title compounds; 68%), is amorphous solid.[M+H] +=535.3; 1HNMR (400MHz, CDCl3): δ 1.15 (m, 2H), 1.36 (t, 6H), 1.48 (m, 2H), 1.61 (m; 3H), 1.74 (m, 2H), 1.92 (m, 1H), 2.23 (m, 1H), 3.05 (s; 3H), 3.68 (t, 1H), 4.14 (m, 4H), 6.25 (t, 1H), 7.42 (d; J=22.4 Hz, 2H), 7.59 (d, 2H), 7.85 (dd, 1H), 7.92 (d; 2H), 8.23 (s, 1H), 8.24 (d, 2H), 8.31 (d, 1H). embodiment 5

10%Pd/C (5 milligrams) is added into (20 milligrams of embodiment 4 compounds; 0.037 mmole) in the solution in MeOH (0.30 milliliter).With H ₂Atmosphere is introduced via gas cylinder.After 8 hours, filter reaction mixture.Catalyzer is washed with MeOH (1.5 milliliters), and the filtrating of merging is concentrated in a vacuum.Make crude product chromatography (SiO2; Continuous gradient liquid, from 0 to 100% solvent B went through 6 minutes, under 100% solvent B, kept 15 minutes, wherein, solvent orange 2 A=hexane, and solvent B=EtOAc), and get (14.5 milligrams of title compounds; 73%), is colorless solid.[M+H]+＝537.2；1H?NMR(400MHz，CDCl3)：δ1.13(m，2H)，1.31(t，6H)，1.47(m，2H)，1.61(m，2H)，1.74(m，3H)，1.90(m，1H)，2.00(m，2H)，2.21(m，1H)，2.87(m，2H)，3.05(s，3H)，3.65(t，1H)，4.10(m，4H)，7.56(dd，1H)，7.58(d，2H)，7.90(d，2H)，8.08(d，1H)，8.13(d，1H)，8.20(s，1H)。Embodiment 6

A.

Under Ar, in (S)-3-cyclohexyl-2-(1-oxo-1,3-xylylenimine-2-yl)-propionic acid (144 milligrams, 0.5 mmole is processed described in WO 2002/048106) and oxalyl chloride (0.38 milliliter, the 2M solution in DCM; 0.75 mmole) in 0 ℃ of solution in DCM (1 milliliter), add DMF (1).After 30 minutes, make reactant be warmed to room temperature, and at room temperature stirred 4 hours.Remove volatile matter in a vacuum; Rough chloride of acid is dissolved among the DCM (3 milliliters) again.Under Ar, amino pyrazine of 5-bromo-2-(130 milligrams, 0.75 mmole) and pyridine (0.061 milliliter, 0.75 mmole) are added in the acyl chloride solution that in ice bath, has cooled off.Make reaction mixture be warmed to ambient temperature overnight; Then with DCM (6 milliliters) dilution, and with the 0.5NHCl aqueous solution (1 milliliter, 2x), water (1 milliliter), the saturated NaHCO3 aqueous solution (1 milliliter), salt solution (1 milliliter) flushing; Then dehydrate (MgSO4), and concentrate in a vacuum.Make residue chromatography (40 gram SiO2,0-50%EtOAc-hexane gradient liquid), obtain partly A compound of 188 milligrams of (84%) racemizes.B.?

THF (through the degassing) (0.40 milliliter) is added into contains partly (25.0 milligrams of A compounds; 0.056 mmole) with (Ph ₃P) ₄(12.9 milligrams of Pd (0); 0.011 in reaction flask mmole).Add diethyl phosphite (8.72 microlitres; 0.068 mmole), then be TEA (10.9 microlitres; 0.078 mmole).Reaction vessel is added a cover, and reaction mixture was heated 6 hours down in 85 ℃, be cooled to room temperature then, and concentrate in a vacuum.Making residue between EtOAc (2 milliliters) and salt solution (1.5 milliliters), make separatory handles.Separate organic phase, dehydrate (MgSO4), concentrate in a vacuum.Make crude product through preparing HPLC purifying (100 millimeters posts of YMC anti-phase ODS-A-5u 30 x; Flow velocity=40 ml/min, 45 to 100% solvent B went through 12 minutes, were retained to 16 minutes, wherein, solvent orange 2 A=90: 10: 0.1 H2O: MeOH: TFA, and solvent B=90: 10: 0.1 MeOH: H2O: TFA), and get (8 milligrams of title compounds; 29%; Colorless solid), be racemic mixture.[M+H]+＝501.3；1H?NMR(400MHz，CDCl3)：δ1.00(m，2H)，1.20(m，4H)，1.35(m，6H)，1.65(m，3H)，1.85(m，3H)，2.05(m，1H)，4.22(m，4H)，4.54(q，2H)，5.23(t，1H)，7.50(m，3H)，7.60(dd，1H)，7.92(d，1H)，8.75(s，1H)，9.52(s，1H)，9.62(s，1H)。Embodiment 7

A.

With (EtO) ₃(0.60 milliliter of P; 3.47 mmole) be added into and contain 5-(bromo methyl) pyrazine-2-aminocarbamic acid tert-butyl ester (Bioorg.Med.Chem.Lett., 2002,12:1203-1208) (125 milligrams; 0.434 mmole) in the reaction flask of the solution in THF (1.0 milliliters).Reaction vessel is added a cover, and reaction mixture was heated 16 hours down at 80 ℃, be cooled to room temperature then, and concentrate in a vacuum.Make crude product chromatography (SiO2; Continuous gradient liquid, from 0 to 100% solvent B went through 8 minutes, under 100% solvent B, kept 8 minutes, wherein, solvent orange 2 A=hexane, and solvent B=EtOAc), and get (145 milligrams of part A compounds; 96%).B.?

TFA (0.30 milliliter) is added into (144 milligrams of part A compounds; 0.417 mmole) in cold (0 ℃) solution in DCM (1.2 milliliters).Then reaction mixture was stirred under room temperature 16 hours, then concentrate in a vacuum.Making residue between the EtOAc (4 milliliters) and the saturated NaHCO3 aqueous solution (3 milliliters), make separatory handles.Separate organic phase, with salt solution (3 milliliters) washing, dehydrate (MgSO4), and concentrate in a vacuum, and get (51 milligrams of part B compounds; 50%).C.?

With oxalyl chloride (0.84 microlitre, the 2.0M solution in DCM; 0.168 mmole) be added into (25 milligrams of embodiment 1 part D compounds; 0.084 mmole) in the mixture in DCM (0.15 milliliter).Add DMF (5 microlitre).Generation gas disengages.In room temperature after following 1.5 hours, concentrated reaction mixture in a vacuum.With residue from CHCl ₃(0.8 milliliter of 2 x) stripping.Rough chloride of acid is dissolved among the DCM (0.25 milliliter).Add (24.8 milligrams of part B compounds; 0.101 mmole), then be pyridine (10.2 microlitres; 0.126 mmole).After stirring 16 hours under the room temperature, concentration response thing in a vacuum.Making residue between EtOAc (4 milliliters) and salt solution (2 milliliters), make separatory handles.Make organic phase dehydrate (MgSO4), and concentrate in a vacuum.Make crude product through preparing HPLC purifying (100 millimeters posts of YMC anti-phase ODS-A-5u 30 x; Flow velocity=40 ml/min, 10 to 100% solvent B went through 12 minutes, were retained to 16 minutes, wherein, solvent orange 2 A=90: 10: 0.1 H2O: MeOH: TFA, and solvent B=90: 10: 0.1 MeOH: H2O: TFA), and get (18 milligrams of title compounds; 41%), is amorphous solid.[M+H]+＝524.4；1H?NMR(400MHz，CD3OD)：δ1.18(m，2H)，1.27(t，6H)，1.51(m，2H)，1.64(m，2H)，1.72(m，1H)，1.83(m，3H)，2.22(m，1H)，3.09(s，3H)，3.46(d，2H)，4.00(t，1H)，4.09(m，4H)，7.70(d，2H)，7.92(d，2H)，8.32(s，1H)，9.30(s，1H)。Embodiment 8

(11 milligrams of title compounds; 19%; Colorless solid) adopt about said order of synthesizing of embodiment 7, synthetic from trimethyl phosphite.[M+H]+＝496.3；1H?NMR(400MHz，CD3OD)：δ1.19(m，2H)，1.51(m，2H)，1.64(m，2H)，1.72(m，1H)，1.84(m，3H)，2.23(m，1H)，3.09(s，3H)，3.50(d，2H)，3.73(s，3H)，3.76(s，3H)，4.00(t，1H)，7.69(d，2H)，7.91(d，2H)，8.31(s，1H)，9.29(s，1H)。Embodiment 9

A.

With bromine (145 microlitres; 2.82 mmole) at CCl ₄Solution in (5 milliliters) dropwise is added into ethanoyl-phosphonic acids two-ethyl ester (0.508 gram; 2.82 mmole) at CCl ₄In 0 ℃ of solution in (5 milliliters).Then, reaction mixture was stirred under room temperature 2 hours, then concentrate in a vacuum.Make residue chromatography (SiO2; Continuous gradient liquid, from 0 to 100% solvent B went through 10 minutes, under 100% solvent B, kept 10 minutes, wherein, solvent orange 2 A=hexane, and solvent B=EtOAc), and get (250 milligrams of part A compounds; 34%).B.?

With (43.9 milligrams of thiocarbamides; 0.577 mmole) be added in the solution of part A compound (135 milligram of 0.52 mmole) in EtOH (1.0 milliliters).Reaction mixture was stirred under room temperature 48 hours, concentrate in a vacuum then.Making residue between the EtOAc (5 milliliters) and the saturated NaHCO3 aqueous solution (3 milliliters), make separatory handles.Separate organic phase, with salt solution (3 milliliters) washing, dehydrate (MgSO4), and concentrate in a vacuum.Make residue chromatography (SiO2; Continuous gradient liquid, from 0 to 100% solvent B went through 2 minutes, under 100% solvent B, kept 10 minutes, wherein, solvent orange 2 A=hexane, and solvent B=EtOAc), and get (22 milligrams of part B compounds; 18%).C.?

With (50 milligrams of DEPBT; 0.168 mmole) be added into (25 milligrams of embodiment 1 part D compounds; 0.084 mmole) with (21.9 milligrams of part B compounds; 0.093 mmole) in THF (0.40 milliliter) in stirred solution.Add DIPEA (28.4 microlitres; 0.168 mmole).In room temperature after following 96 hours, concentrated reaction mixture in a vacuum.Residue is dissolved among the EtOAc (3 milliliters).EtOAc solution with salt solution (2 milliliters) washing, is dehydrated (MgSO4), filter, and concentrate in a vacuum.Make crude product through preparing HPLC purifying (100 millimeters posts of YMC anti-phase ODS-A-5u 30 x; Flow velocity=40 ml/min, 20 to 100% solvent B went through 12 minutes, were retained to 15 minutes, wherein, solvent orange 2 A=90: 10: 0.1 H2O: MeOH: TFA, and solvent B=90: 10: 0.1 MeOH: H2O: TFA), and get (13 milligrams of title compounds; 30%), is white solid.[M+H]+＝515.2；1H?NMR(400MHz，CD3OD)：δ1.18(m，2H)，1.31(m，6H)，1.51(2H)，1.64(m，3H)，1.81(m，2H)，1.88(m，1H)，2.23(m，1H)，3.10(s，3H)，3.96(t，1H)，4.14(m，4H)，7.68(d，2H)，7.86(d，J＝4.95Hz，1H)，7.93(d，2H)。Embodiment 10

A.

With (162 milligrams of DEPBT; 0.540 mmole) be added into (80 milligrams of embodiment 1 part D compounds; 0.270 mmole) with (51.4 milligrams of 2-amino-6-bromo pyridine; 0.297 mmole) in THF (1.0 milliliters) in stirred solution.Add DIPEA (91.0 microlitres; 0.540 mmole).In room temperature after following 48 hours, add (93.0 milligrams of more 2-amino-6-bromo pyridine; 0.537 mmole).Again after 48 hours, concentrated reaction mixture in a vacuum.Making residue between the EtOAc (6 milliliters) and the 0.1N HCl aqueous solution (3 milliliters), make separatory handles.Organic phase with salt solution (3 milliliters) washing, is dehydrated (MgSO4), and concentrate in a vacuum.Make crude product through preparing HPLC purifying (1 00 millimeters posts of YMC anti-phase ODS-A-5u 30 x; Flow velocity=40 ml/min, 35 to 100% solvent B went through 10 minutes, were retained to 13 minutes, wherein, solvent orange 2 A=90: 10: 0.1 H2O: MeOH: TFA, and solvent B=90: 10: 0.1 MeOH: H2O: TFA), and get (16 milligrams of part A compounds; 13%).B.?

THF (through the degassing) (0.50 milliliter) is added into contains partly (14.0 milligrams of A compounds; 0.031 mmole) with (Ph ₃P) ₄(7.2 milligrams of Pd (0); 0.006 in reaction flask mmole).Add diethyl phosphite (4.8 microlitres; 0.037 mmole), then be Et ₃N (6.0 microlitres; 0.043 mmole).Reaction vessel is added a cover, and reaction mixture was heated 12 hours down at 75 ℃, be cooled to room temperature then.Concentrated reaction mixture in vacuum.Make crude product through preparing HPLC purifying (100 millimeters posts of YMC anti-phase ODS-A-5u 20 x; Flow velocity=40 ml/min, 20 to 100% solvent B went through 12 minutes, were retained to 15 minutes, wherein, solvent orange 2 A=90: 10: 0.1 H2O: MeOH: TFA, and solvent B=90: 10: 0.1 MeOH: H2O: TFA), and get (3.6 milligrams of title compounds; 23%), is colorless solid.[M+H]+＝509.3；1H?NMR(400MHz，CD3OD)：δ1.20(m，2H)，1.33(m，6H)，1.53(m，2H)，1.65(m，2H)，1.72(m，1H)，1.83(m，3H)，2.22(m，1H)，3.09(s，3H)，4.01(t，1H)，4.19(m，4H)，7.61(t，1H)，7.71(d，2H)，7.91(m，3H)，8.32(d，1H)。Embodiment 11 A.

In 4-methylsulfonyl anilinechloride (1.06 grams, 5.10 mmoles), pentamethylene carboxylic aldehyde (0.5 gram, 5.10 mmoles) and Et ₃In 0 ℃ of mixture of N (1 milliliter, 7.14 mmoles) in 20 milliliters of ethylene dichloride, add NaBH (OAc) ₃(1.51 grams, 7.14 mmoles).Make reactant be warmed to room temperature, and under room temperature, stirred two days, handle with the excessive saturated NaHCO3 aqueous solution then.With the EtOAc aqueous layer extracted.Organic extract liquid with normal saline washing, is dehydrated (MgSO4), and concentrate in a vacuum.Through hurried formula chromatography purification (120 gram silica gel, continuous gradient liquid is from the 0-100%EtOAc-hexane), obtain partly A compound (904 milligrams, 70% productive rate).B.?

Part 1: with (49.3 milligrams of chloroformic acid 4-nitro phenyl esters; 0.245 mmole) be added into (60 milligrams of embodiment 7 part B compounds; 0.245 in cold (0 ℃) solution mmole).Add pyridine (20.8 microlitres; 0.257 mmole).Reaction mixture was stirred under room temperature 1 hour, concentrate in a vacuum then, and get rough carbamate.

Part 2: make rough carbamate be dissolved in CH ₃Among the CN (1.0 milliliters).Add (62 milligrams of part A compounds; 0.245 mmole).Reaction mixture was heated 2 hours down at 40 ℃, be cooled to room temperature then, and in vacuum, concentrate.Make crude product chromatography (SiO2; Continuous gradient liquid, from 0 to 100% solvent B went through 4 minutes, was converted to solvent C, under 100% solvent C, kept 8 minutes, wherein, solvent orange 2 A=hexane, solvent B=EtOAc, and the 10%MeOH among solvent C=EtOAc), and get (30 milligrams of title compounds; Two steps of 23%-), be amorphous solid.[M+H]+＝525.3；1H?NMR(400MHz，CD3OD)：δ1.28(t，8H)，1.54(m，2H)，1.67(m，4H)，2.10(m，1H)，3.17(s，3H)，3.45(d，2H)，3.83(d，2H)，4.09(m，4H)，7.65(d，2H)，8.05(d，2H)，8.19(s，1H)，9.12(s，1H)。Embodiment 12

A.

With (8.05 milliliters of DIPEA; 46.24 mmole) be added into 2-amino-5-picoline (2.50 grams; 23.12 mmole) in cold (0 ℃) solution in DCM (30 milliliters).Add two carbonic acid, two-tert-butyl ester (12.61 grams; 57.80 the solution in DCM (17 milliliters) mmole) then is 4-DMAP (2.82 grams; 23.12 mmole).Then, reaction mixture was stirred under room temperature 16 hours, then, be concentrated into half volume in a vacuum.With EtOAc (125 milliliters) diluting soln.With organic solution with saturated NH ₄The Cl aqueous solution (45 milliliters of 3 x), salt solution (45 milliliters), the saturated NaHCO3 aqueous solution (45 milliliters of 2 x) and salt solution (45 milliliters) washing.Then, make solution dehydrates dry (MgSO4), and in vacuum, concentrate.Make crude product chromatography (SiO2; Continuous gradient liquid, in hexane 15 to 20%EtOAc), and A compound (2.70 grams partly; 38%).B.?

With N-bromo succinimide (1.56 grams; 8.76 mmole) be added into partly A compound (2.70 grams; 8.76 mmole) at CCl ₄In the solution in (40 milliliters).Add BPO (0.21 gram; 0.88 mmole).Reaction mixture is heated to backflow (80 ℃), went through 7 hours, be cooled to room temperature then.Filter reaction mixture, and filtrating is concentrated in a vacuum.Make crude product chromatography (SiO2; 5%EtOAc in DCM), get partly B compound (1.48 grams; 44%) (Bioorg.Med.Chem.Lett, 2004,14:2227-2231).C.?

With (1.2 milliliters of triethyl-phosphites; 6.97 mmole) be added into partly B compound (0.45 gram; 1.16 mmole) in the solution in THF (2.5 milliliters).Reaction vessel is added a cover, and reaction mixture was heated 16 hours down in 80 ℃, be cooled to room temperature then.Enriching soln in a vacuum.Make crude product chromatography (SiO2; Continuous gradient liquid, from 0 to 100% solvent B went through 8 minutes, under 100% solvent B, kept 6 minutes, wherein, solvent orange 2 A=hexane, and solvent B=EtOAc), and get partly C compound (0.52 gram; 100%).D.?

TFA (1.5 milliliters) is added into partly C compound (0.52 gram; 1.17 mmole) in cold (0 ℃) solution in DCM (3 milliliters).Then, reaction mixture was stirred under room temperature 3 hours, then concentrate in a vacuum.Make residue in CHCl ₃Making separatory between (10 milliliters) and the saturated NaHCO3 aqueous solution (8 milliliters) handles.With CHCl ₃(8 milliliters) aqueous phase extracted.The organic extract liquid of merging is dehydrated (MgSO4), and concentrate in a vacuum, and get partly D compound (0.25 gram; 88%).E.?

With oxalyl chloride (2.0M is in DCM) (104 microlitres; 0.208 mmole) be added into (30.9 milligrams of embodiment 1 part D compounds; 0.104 mmole) in 0 ℃ of solution in DCM (0.3 milliliter).Add DMF (5 microlitre).Generation gas disengages.In room temperature after following 1 hour, concentrated reaction mixture in a vacuum.With residue from CHCl ₃(1 milliliter of 2 x) stripping.Rough chloride of acid is dissolved among the DCM (0.42 milliliter).Add (25.5 milligrams of part D compounds; 0.104 mmole), then be pyridine (12.6 microlitres; 0.156 mmole).After stirring 16 hours, concentration response thing in a vacuum.Making residue between EtOAc (5 milliliters) and salt solution (4 milliliters), make separatory handles.Make organic phase dehydrate (MgSO4), and concentrate in a vacuum.Make crude product through preparing HPLC purifying (100 millimeters posts of YMC anti-phase ODS-A-5u 30 x; Flow velocity=40 ml/min, 20 to 100% solvent B went through 15 minutes, were retained to 20 minutes, wherein, solvent orange 2 A=90: 10: 0.1 H2O: MeOH: TFA, and solvent B=90: 10: 0.1 MeOH: H2O: TFA), and get (19 milligrams of title compounds; 34%), is amorphous solid.[M+H]+＝523.4；1H?NMR(400MHz，CD3OD)：δ1.20(m，2H)，1.27(t，6H)，1.51(m，2H)，1.65(m，2H)，1.71(m，1H)，1.85(m，3H)，2.21(m，1H)，3.10(s，3H)，3.30(d，2H)，3.98(t，1H)，4.07(m，4H)，7.70(d，2H)，7.92(m，4H)，8.23(s，1H)。Embodiment 13

A.

With two carbonic acid, two-tert-butyl ester (11.3 grams; 51.83 mmole) solution in THF (50 milliliters) is added into thiazolamine-4-carboxylic acid, ethyl ester (8.59 grams; 49.36 mmole) in cold (0 ℃) solution in THF (150 milliliters).Add (7.57 milliliters of TEA; 54.30 mmole), then be the 4-DMAP of catalytic amount (30 milligrams).Reaction mixture was stirred under room temperature 16 hours, concentrate in a vacuum then.Residue is distributed between the EtOAc (300 milliliters) and the 0.5N HCl aqueous solution (250 milliliters).Organic phase with salt solution (150 milliliters) washing, is dehydrated (MgSO4), and concentrate in a vacuum, and get partly A compound (12.38 grams; Productive rate is shown among the hereinafter part B).This crude product is used in the next step, need not to be further purified.B.?

With LiAlH ₄(1.0M is in THF) (48.0 milliliters; 48.0 solution mmole) is added into partly A compound (12.38 grams; 45.3 mmole) in cold (0 ℃) solution in THF (130 milliliters).In 0 ℃ after following 3 hours,, make the reaction cancellation carefully through dropwise adding H2O (5 milliliters).After 10 minutes, add the 5N NaOH aqueous solution (2.5 milliliters).Again after 10 minutes, enriching soln in a vacuum.Making residue between EtOAc (300 milliliters) and H2O (200 milliliters), make separatory handles.With EtOAc (100 milliliters) aqueous phase extracted.The organic phase of merging is dehydrated (MgSO4), and concentrate in a vacuum.Make crude product chromatography (SiO2; Continuous gradient liquid, from 0 to 100% solvent B went through 16 minutes, under 100% solvent B, kept 5 minutes, wherein, solvent orange 2 A=hexane, and solvent B=EtOAc), and get partly B compound (8.67 grams; Two steps of 67%-).C.?

Method 1: with chloromethane sulphonyl (318 microlitres; 4.10 mmole) solution in DCM (3 milliliters) slowly is added into (900 milligrams of part B compounds; 3.91 mmole) with TEA (600 microlitres; 4.30 mmole) in 0 ℃ of solution in DCM (10 milliliters).After stirring 25 minutes, reaction mixture is diluted with acetone (13 milliliters).Add LiBr (2.03 grams; 23.46 mmole).Reactant was at room temperature stirred 1 hour, extract then with the saturated NH4Cl aqueous solution (20 milliliters) dilution, and with Et2O (40 milliliters of 2 x).The organic extract liquid that will merge is with the saturated NH4Cl aqueous solution (20 milliliters of 2 x) and salt solution (20 milliliters) washing.Make solution dehydrates dry (MgSO4), and concentrate in a vacuum, and get partly C compound (1.03 grams; 89%).Crude product is continued to adopt, need not to be further purified.

Method 2: with (428 milligrams of N-Boc thiocarbamides; 2.427 mmole) be added into 1, (524 milligrams of 3-dibromoacetones; 2.427 mmole) in the solution in acetone (9.7 milliliters)., reaction mixture is concentrated in a vacuum, and get partly C compound (0.78 gram after following 24 hours in room temperature; Quantitatively), be brown foam thing.Crude product is continued to adopt, need not to be further purified.D.?

With (3.6 milliliters of triethyl-phosphites; 20.96 mmole) be added into (878 milligrams of part C compounds; 2.99 mmole) in the solution in THF (6 milliliters).Reaction vessel is added a cover, and reaction mixture was heated 16 hours down in 80 ℃, be cooled to room temperature then.Enriching soln in a vacuum.Make crude product chromatography (SiO2; Continuous gradient liquid, from 0 to 100% solvent B went through 8 minutes, under 100% solvent B, kept 10 minutes, wherein, solvent orange 2 A=hexane, and solvent B=EtOAc), and get partly D compound (0.86 gram; 82%).E.?

TFA (3.0 milliliters) is added into partly D compound (0.86 gram; 2.45 mmole) in 0 ℃ of solution in DCM (7 milliliters).Reaction mixture was stirred under room temperature 2.5 hours, concentrate in a vacuum then.Making residue between the EtOAc (15 milliliters) and the saturated NaHCO3 aqueous solution (10 milliliters), make separatory handles.With EtOAc (10 milliliters) aqueous phase extracted.The organic extract liquid of merging is dehydrated (MgSO4), and concentrate in a vacuum, and get (488 milligrams of part E compounds; 80%).1H NMR (400MHz, CDCl3) δ 6.17 (1H, d, J=3.95Hz), 5.85 (2H, broad s.), 3.92-4.05 (4H, m), 3.08 (2H, d, J=21.09Hz), 1.18 (6H, t, J=7.03Hz).F.?

With (0.63 milliliter of oxalyl chloride (2.0M is in DCM); 1.26 mmole) be added into (250 milligrams of embodiment 1 part D compounds; 0.844 mmole) in 0 ℃ of mixture in DCM (2.5 milliliters).Add DMF (10 microlitre).Generation gas disengages.In room temperature after following 1.5 hours, concentrated reaction mixture in a vacuum.With residue from CHCl3 (3 milliliters of 2 x) stripping.Rough chloride of acid is dissolved among the DCM (3.0 milliliters).Add (253 milligrams of part E compounds; 1.013 mmole), then be pyridine (205 microlitres; 2.532 mmole).In room temperature after following 2 hours, concentration response thing in a vacuum.Making residue between the EtOAc (15 milliliters) and the 0.5N HCl aqueous solution (10 milliliters), make separatory handles.Organic phase is washed with the 0.5N HCl aqueous solution (10 milliliters) and salt solution (10 milliliters).Make solution dehydrates dry (MgSO4), and concentrate in a vacuum.Make crude product chromatography (SiO2; Continuous gradient liquid, from 0 to 100% solvent B went through 3 minutes, under 100% solvent B, kept 14 minutes, wherein, solvent orange 2 A=hexane, and solvent B=EtOAc), and get title compound (0.40 gram; 89%), is amorphous solid.[M+H]+＝529.2；1H?NMR(400MHz，CD3OD)：δ1.18(m，2H)，1.26(t，6H)，1.51(m，2H)，1.64(m，3H)，1.83(m，3H)，2.22(m，1H)，3.09(s，3H)，3.31(d，2H)，3.95(t，1H)，4.07(m，4H)，6.89(d，J＝4.03Hz，1H)，7.67(d，2H)，7.92(d，2H)。Embodiment 14

With the 1N NaOH aqueous solution (136 microlitres; 0.136 mmole) be added into (50.5 milligrams of embodiment 13 part F compounds; 0.096 mmole) in the solution in EtOH (100 microlitre).Reaction mixture was heated 48 hours down in 80 ℃, be cooled to room temperature then, and concentrate in a vacuum.Make crude product through preparing HPLC purifying (100 millimeters posts of YMC anti-phase ODS-A-5u 30x; Flow velocity=40 ml/min, 10 to 100% solvent B went through 16 minutes, were retained to 20 minutes, wherein, solvent orange 2 A=90: 10: 0.1H2O: MeOH: TFA, and solvent B=90: 10: 0.1MeOH: H2O: TFA), and get (12.5 milligrams of title compounds; 26%), is amorphous solid.[M+H]+＝501.1；1H?NMR(400MHz，CDCl3)：δ1.13(m，2H)，1.30(t，3H)，1.48(m，2H)，1.60(m，3H)，1.78(m，2H)，1.90(m，1H)，2.23(m，1H)，3.04(s，3H)，3.28(d，2H)，4.05(m，3H)，6.68(d，1H)，7.68(d，2H)，7.88(d，2H)。Embodiment 15

A.

With two carbonic acid, two-tert-butyl ester (1.66 grams; 7.59 mmole) solution in THF (10 milliliters) is added into thiazolamine-5-carboxylate methyl ester (1.20 grams; 7.59 mmole) in 0 ℃ of solution in THF (20 milliliters).Add (1.11 milliliters of TEA; 7.97 mmole), then be the 4-DMAP of catalytic amount (10 milligrams).Then reaction mixture was stirred under room temperature 20 hours, then concentrate in a vacuum.Making residue between the EtOAc (80 milliliters) and the 0.2N HCl aqueous solution (40 milliliters), make separatory handles.Organic phase with salt solution (40 milliliters) washing, is dehydrated (MgSO4), and concentrate in a vacuum, and get partly A compound (1.70 grams; Productive rate system is shown among the hereinafter part B).Crude product is continued to adopt, need not to be further purified.B.?

With LiAlH ₄(7.60 milliliters, the 1.0M solution in THF; 7.60 solution mmole) is added into partly A compound (1.70 grams; 6.58 mmole) in 0 ℃ of solution in THF (30 milliliters).Reaction mixture was stirred under room temperature 1 hour, be cooled to 0 ℃ then, and, make the reaction cancellation carefully through dropwise adding H2O (0.76 milliliter).After 10 minutes, add the 5N NaOH aqueous solution (0.38 milliliter).Again after 10 minutes, solution is filtered through Celite pad (Celite), and concentrated filtrate in a vacuum.Make crude product chromatography (SiO2; Continuous gradient liquid, from 0 to 100% solvent B went through 13 minutes, under 100% solvent B, kept 6 minutes, wherein, solvent orange 2 A=hexane, and solvent B=EtOAc), and get partly B compound (0.80 gram; Two steps of 46%-).C.?

Part 1: with dichloride thionyl (253 microlitres; 3.47 mmole) be added into (200 milligrams of part B compounds; 0.869 mmole) in 0 ℃ of mixture in DCM (0.40 milliliter).Reaction mixture was stirred 2 hours down in 0 ℃, concentrate in a vacuum then, and get rough muriate.

Part 2: rough muriate is dissolved among the THF (3.0 milliliters).Add (EtO) ₃(1.20 milliliters of P; 6.95 mmole).Reaction mixture was heated 16 hours down at 80 ℃, be cooled to room temperature then, and in vacuum, concentrate.Make crude product chromatography (SiO2; Continuous gradient liquid, from 0 to 100% solvent B went through 8 minutes, was converted to solvent C, under 100% solvent C, kept 7 minutes, wherein, solvent orange 2 A=hexane, solvent B=EtOAc, and the 3%MeOH among solvent C=EtOAc), and get (270 milligrams of part C compounds; Two steps of 89%-).D.?

TFA (0.80 milliliter) is added into partly C compound (0.31 gram; 0.885 the Bo mole) in 0 ℃ of solution in DCM (2.4 milliliters).Reaction mixture was stirred under room temperature 3 hours, concentrate in a vacuum then.Making residue between the CHCl3 (10 milliliters) and the saturated NaHCO3 aqueous solution (10 milliliters), make separatory handles.With CHCl3 (10 milliliters) aqueous phase extracted.The organic extract liquid of merging is dehydrated (MgSO4), and concentrate in a vacuum, and get (198 milligrams of part D compounds; 89%).E.?

With oxalyl chloride (2.0M is in DCM) (101 microlitres; 0.202 mmole) be added into (40 milligrams of embodiment 1 part D compounds; 0.135 mmole) in 0 ℃ of mixture in DCM (0.35 milliliter).Add DMF (6 microlitre).Generation gas disengages.Then, reaction mixture was stirred under room temperature 1.5 hours, then concentrate in a vacuum.With residue from CHCl3 (1 milliliter of 2 x) stripping.Rough chloride of acid is dissolved among the DCM (0.45 milliliter).Add (47.3 milligrams of part D compounds; 0.189 mmole), then be pyridine (33.0 microlitres; 0.405 mmole).In room temperature after following 4 hours, concentration response thing in a vacuum.Making residue between EtOAc (6 milliliters) and salt solution (4 milliliters), make separatory handles.Make organic phase dehydrate (MgSO4), and concentrate in a vacuum.Make crude product through preparing HPLC purifying (100 millimeters posts of YMC anti-phase ODS-A-5u 30 x; Flow velocity=40 ml/min, 15 to 100% solvent B went through 10 minutes, were retained to 15 minutes, wherein, solvent orange 2 A=90: 10: 0.1H2O: MeOH: TFA, and solvent B=90: 10: 0.1MeOH: H2O: TFA), and get (46 milligrams of title compounds; 65%), is white solid.[M+H]+＝529.1；1H?NMR(400MHz，CD3OD)：δ1.18(m，2H)，1.29(t，6H)，1.49(m，2H)，1.63(m，3H)，1.80(m，3H)，2.22(m，1H)，3.09(s，3H)，3.43(d，2H)，3.96(t，1H)，4.09(m，4H)，7.26(d，J＝4.4Hz，1H)，7.67(d，2H)，7.92(d，2H)。Embodiment 16 A.

With oxalyl chloride (169 microlitres, the 2M solution in DCM; 0.338 mmole) be added into (50 milligrams of embodiment 1 part D compounds; 0.169 mmole) in the mixture in DCM (0.35 milliliter).Make solution be cooled to 0 ℃.Add DMF (5 microlitre).Generation gas disengages.In room temperature after following 2 hours, concentrated reaction mixture in a vacuum.With residue from CHCl3 (1 milliliter of 2 x) stripping.Rough chloride of acid is dissolved among the DCM (0.5 milliliter).Add (44 milligrams of 5-bromos-2-pyrazine amine; 0.253 mmole), then be pyridine (20.5 microlitres; 0.253 mmole).Reaction mixture was stirred under room temperature 3 hours, concentrate in a vacuum then.Making residue between EtOAc (6 milliliters) and salt solution (4 milliliters), make separatory handles.Make organic phase dehydrate (MgSO4), and concentrate in a vacuum.Make crude product chromatography (SiO2; Continuous gradient liquid, from 0 to 30% solvent B went through 30 minutes, and 30% to 65% solvent B went through 5 minutes then, then under 65% solvent B, kept 5 minutes, wherein, solvent orange 2 A=hexane, and solvent B=EtOAc), and get (64 milligrams of part A compounds; 84%).B.?

Partly the A compound is (44 milligrams; 0.097 mmole) solution in THF (through the degassing) (0.50 milliliter) is added into and contains (Ph ₃P) ₄(22.4 milligrams of Pd (0); 0.019 in reaction flask mmole).Add (MeO) ₃P (11.6 microlitres; 0.126 mmole), then be TEA (21.6 microlitres; 0.155 mmole).Reaction vessel is added a cover, and reaction mixture was heated 6 hours down in 75 ℃, be cooled to room temperature then, and concentrate in a vacuum.Make crude product through preparing HPLC purifying (100 millimeters posts of YMC anti-phase ODS-A-5u 30 x; Flow velocity=40 ml/min, 15 to 100% solvent B went through 10 minutes, were retained to 13 minutes, wherein, solvent orange 2 A=90: 10: 0.1H2O: MeOH: TFA, and solvent B=90: 10: 0.1MeOH: H2O: TFA), and get (17 milligrams of part B compounds; 38%).C.?

With TMSCHN ₂(2.0M is in hexane) (73 microlitres; 0.145 mmole) be added into (17 milligrams of part B compounds; 0.036 mmole) at Et ₂In the mixture among O (75 microlitre) and the THF (250 microlitre).After stirring 1 hour under the room temperature, concentrated reaction mixture in a vacuum.Make crude product through preparing HPLC purifying (100 millimeters posts of YMC anti-phase ODS-A-5u 20 x; Flow velocity=20 ml/min, 20 to 100% solvent B went through 10 minutes, were retained to 15 minutes, wherein, solvent orange 2 A=90: 10: 0.1H2O: MeOH: TFA, and solvent B=90: 10: 0.1MeOH: H2O: TFA), and get (9 milligrams of title compounds; 51%), is colorless solid.[M+H]+＝482.2；1H?NMR(400MHz，CD3OD)：δ1.19(m，2H)，1.51(m，2H)，1.64(m，3H)，1.83(m，3H)，2.22(m，1H)，3.09(s，3H)，3.83(d，3H)，3.86(d，3H)，4.04(t，1H)，7.70(d，2H)，7.92(d，2H)，8.71(s，1H)，9.59(s，1H)。Embodiment 17

A.

With TEA (311 microlitres; 2.23 mmole) be added into (450 milligrams of 4-bromo-VPPs; 2.23 mmole) in the mixture in toluene (6.7 milliliters).Add azide phenylbenzene phosphinylidyne (480 microlitres; 2.23 mmole), and reactant stirred under room temperature 30 minutes, adds the trimethyl carbinol (427 microlitres then; 4.46 mmole).Reaction mixture was heated 2 hours down at 90 ℃, then be cooled to room temperature.Solution with EtOAc (15 milliliters) dilution, with the 10%Na2CO3 aqueous solution (3 milliliters of 3 x) and salt solution (10 milliliters) washing, is dehydrated (MgSO4), and concentrates in a vacuum.Make crude product chromatography (SiO2; Continuous gradient liquid, from 0 to 75% solvent B went through 15 minutes, wherein, solvent orange 2 A=hexane, and solvent B=EtOAc), and get partly A compound (0.39 gram; 65%).B.?

HCl (1 milliliter, 1, the 4.0M solution in the 4-diox) is added into contains partly (106.5 milligrams of A compounds; 0.390 in reaction vessel mmole).After stirring 20 hours under the room temperature, concentrated reaction mixture in a vacuum.Crude product is stirred with hexane (3 milliliters).Through filtering separation (81 milligrams of the HCl salt of B compound partly; 100%).C.?

With oxalyl chloride (152 microlitres, the 2M solution in DCM; 0.304 mmole) be added into (60 milligrams of embodiment 1 part D compounds; 0.202 mmole) in the mixture in DCM (0.4 milliliter).Make solution be cooled to 0 ℃.Add DMF (7 microlitre).Generation gas disengages.In room temperature after following 2 hours, concentrated reaction mixture in a vacuum.With residue from CHCl3 (1 milliliter of 2 x) stripping.Then, rough chloride of acid is dissolved among the DCM (0.5 milliliter).Add (53 milligrams of part B compounds; 0.253 mmole), then be pyridine (49 microlitres; 0.606 mmole).Reaction mixture was stirred under room temperature 2 hours, concentrate in a vacuum then.Making residue between EtOAc (8 milliliters) and salt solution (4 milliliters), make separatory handles.Make organic phase dehydrate (MgSO4), and concentrate in a vacuum.Make crude product chromatography (SiO2; Continuous gradient liquid, from 0 to 100% solvent B went through 10 minutes, wherein, solvent orange 2 A=hexane, and solvent B=EtOAc), and get (72 milligrams of part C compounds; 79%).D.?

Partly the C compound is (66 milligrams; 0.146 mmole) solution in THF (through the degassing) (0.38 milliliter) is added into and contains (Ph ₃P) ₄(34 milligrams of Pd (0); 0.029 in reaction flask mmole).Add H (O) P (OEt) ₂(21 microlitres; 0.161 mmole), then be TEA (24.4 microlitres; 0.175 mmole).Reaction vessel is added a cover, and reaction mixture was heated 16 hours down in 75 ℃, be cooled to room temperature then, and concentrate in a vacuum.Make crude product through preparing HPLC purifying (100 millimeters posts of YMC anti-phase ODS-A-5u 30 x; Flow velocity=40 ml/min, 35 to 100% solvent B went through 12 minutes, were retained to 14 minutes, wherein, solvent orange 2 A=90: 10: 0.1H2O: MeOH: TFA, and solvent B=90: 10: 0.1MeOH: H2O: TFA), and get (49 milligrams of title compounds; 66%), is white solid.[M+H]+＝509.1；1H?NMR(400MHz，CD3OD)：δ1.19(m，2H)，1.34(m，6H)，1.52(m，2H)，1.65(m，3H)，1.84(m，3H)，2.23(m，1H)，3.09(s，3H)，4.01(t，1H)，4.16(m，4H)，7.38(dd，1H)，7.71(d，2H)，7.92(d，2H)，8.47(m，2H)。Embodiment 18 A.

With two carbonic acid, two-tert-butyl ester (1.03 grams; 4.73 mmole) solution in toluene (15 milliliters) is added into and contains 2-(thiazolamine-4-yl) vinyl acetic monomer (0.80 gram; 4.30 in reaction vessel mmole).Reaction mixture was heated 24 hours down in 85 ℃, be cooled to room temperature then, and concentrate in a vacuum, and get partly A compound (1.14 grams; Quantitative yield).Crude compound is proceeded, need not to be further purified.B.?

With LiAlH ₄(4.30 milliliters, the 1M solution in THF; 4.40 solution mmole) is added into rough part A compound (1.14 grams; 3.98 mmole) in 0 ℃ of solution in THF (13 milliliters).Reaction mixture was stirred 2 hours down in 0 ℃, then, through dropwise adding saturated NH ₄The Cl aqueous solution (0.6 milliliter) makes the reaction cancellation carefully.Making solution between EtOAc (20 milliliters) and salt solution (10 milliliters), make separatory handles.Organic phase with salt solution (10 milliliters) washing, is dehydrated (MgSO4), and concentrate in a vacuum.Make crude product chromatography (SiO2; Continuous gradient liquid, from 0 to 100% solvent B went through 8 minutes, under 100% solvent B, kept 8 minutes, wherein, solvent orange 2 A=hexane, and solvent B=EtOAc), and get partly B compound (0.42 gram; 43%).C.?

With CH ₃SO ₂Cl (140 microlitres; 1.81 mmole) solution in DCM (1.7 milliliters) is added into partly B compound (0.42 gram; 1.72 mmole) with TEA (264 microlitres; 1.89 mmole) in 0 ℃ of solution in DCM (4.0 milliliters).In 0 ℃ after following 30 minutes, reaction mixture is diluted with acetone (5.7 milliliters).Add (896 milligrams of LiBr; 10.32 mmole).Reactant was at room temperature stirred 1 hour, between the Et2O (10 milliliters) and the saturated NH4Cl aqueous solution (10 milliliters), make separatory then and handle.Organic phase with the saturated NH4Cl aqueous solution (10 milliliters) and salt solution (10 milliliters) washing, is dehydrated (MgSO4), and concentrates in a vacuum, and get partly C compound (0.50 gram; 94%).D.?

Part 1: make partly C compound (0.50 gram; 1.63 mmole) be dissolved in and do not contain solvent (EtO) ₃Among the P (1.0 milliliters).Reaction mixture was heated 2 hours down at 130 ℃; Analyze HPLC and show multiple absorption peak this moment.Make reactant be cooled to room temperature, and concentrate in a vacuum.Make crude product chromatography (SiO2; Continuous gradient liquid, from 0 to 100% solvent B went through 7 minutes, was converted to solvent C, under 100% solvent C, kept 7 minutes, wherein, solvent orange 2 A=hexane, solvent B=EtOAc, and the 3%MeOH among solvent C=EtOAc).This moment, compound was impure (65% purity).

Part 2: in the 0 ℃ solution of impure intermediate in DCM (0.8 milliliter) that derives from part 1, add TFA (0.4 milliliter).Make reactant be warmed to room temperature, and under room temperature, stirred 2 hours, concentrate in a vacuum then.Making residue between the EtOAc (10 milliliters) and the saturated NaHCO3 aqueous solution (10 milliliters), make separatory handles.Make organic phase dehydrate (MgSO4), and concentrate in a vacuum, and get (73 milligrams of part D compounds; Two steps of 17%-) (65% purity).E.?

With oxalyl chloride (2.0M is in DCM) (78 microlitres; 0.155 mmole) be added into (33 milligrams of embodiment 1 part D compounds; 0.111 mmole) in the mixture in DCM (0.25 milliliter).Make solution be cooled to 0 ℃.Add DMF (7 microlitre).Generation gas disengages.In room temperature after following 1.5 hours, concentrated reaction mixture in a vacuum.With residue from CHCl ₃(0.8 milliliter of 2 x) stripping.Rough chloride of acid is dissolved among the DCM (0.25 milliliter).Add (38 milligrams of part D compounds; 0.144 mmole), then be pyridine (27 microlitres; 0.333 mmole).Reaction mixture was stirred under room temperature 2 hours, concentrate in a vacuum then.Making residue between the EtOAc (8 milliliters) and the 0.5N HCl aqueous solution (4 milliliters), make separatory handles.Organic phase with salt solution (4 milliliters) washing, is dehydrated (MgSO4), and concentrate in a vacuum.Make crude product through preparing HPLC purifying (100 millimeters posts of YMC anti-phase ODS-A-5u 30 x; Flow velocity=40 ml/min, 20 to 100% solvent B went through 10 minutes, were retained to 14 minutes, wherein, solvent orange 2 A=90: 10: 0.1H2O: MeOH: TFA, and solvent B=90: 10: 0.1MeOH: H2O: TFA), and get (29 milligrams of title compounds; 48%), is amorphous solid.[M+H]+＝543.0；1H?NMR(400MHz，CD3OD)：δ1.19(m，2H)，1.27(t，6H)，1.50(m，2H)，1.63(m，3H)，1.81(m，3H)，2.20(m，3H)，2.87(m，2H)，3.09(s，3H)，3.95(t，1H)，4.06(m，4H)，6.77(s，1H)，7.67(d，2H)，7.92(d，2H)。Embodiment 19

A.

With DMF (20 milliliters) be added into contain 5-bromo-2-pyrazine amine (1.00 the gram; 5.75 (Ph mmole), ₃P) ₄(199 milligrams of Pd (0); 0.173 mmole) and (853 milligrams of LiCl; 20.13 in reaction flask mmole).Add (2.50 milliliters of DIPEA; 14.38 mmole), then be (2.52 milliliters in tributyl (vinyl) tin; 8.62 mmole).Reaction mixture was heated 4 hours down in 120 ℃, be cooled to room temperature then.Add the saturated KF aqueous solution (20 milliliters).After stirring 16 hours, with EtOAc (80 milliliters) diluted mixture thing, and through diatomite filtration.To filtrate with H2O (80 milliliters) washing, dehydrate (MgSO4), and concentrate in a vacuum.Make crude product chromatography (SiO2; Continuous gradient liquid, from 0 to 100% solvent B went through 13 minutes, kept 4 minutes at 100% time, wherein, solvent orange 2 A=hexane, and solvent B=EtOAc), and get partly A compound (0.41 gram; 59%).B.?

With oxalyl chloride (127 microlitres, the 2M solution in DCM; 0.253 mmole) be added into (50 milligrams of embodiment 1 part D compounds; 0.169 mmole) in the mixture in DCM (0.5 milliliter).Make solution be cooled to 0 ℃.Add DMF (7 microlitre).Generation gas disengages.In room temperature after following 1.5 hours, concentrated reaction mixture in a vacuum.With residue from CHCl3 (1 milliliter of 2 x) stripping.Rough chloride of acid is dissolved among the DCM (0.6 milliliter).Add (24.5 milligrams of part A compounds; 0.202 mmole), then be pyridine (41 microlitres; 0.507 mmole).Reaction mixture was stirred under room temperature 1.5 hours, concentrate in a vacuum then.Make crude product chromatography (SiO2; Continuous gradient liquid, from 0 to 100% solvent B went through 12 minutes, under 100% solvent B, kept 3 minutes, wherein, solvent orange 2 A=hexane, and solvent B=EtOAc), and get (70 milligrams of part B compounds; 100%).C.?

Acetic acid (15 microlitre) is added into (70 milligrams of part B compounds; 0.175 mmole) in the solution in DCM (0.50 milliliter).Make solution be cooled to-78 ℃ (dry ice/acetone).Ozone is bubbled through this solution, up to its be transformed into light blue till (～4 minutes).Remove dry ice/acetone batch, and make reactant be warmed to room temperature.After stirring 5 minutes under the room temperature, with DCM (3 milliliters) diluting soln.Add the saturated NaHCO3 aqueous solution (3 milliliters) (formation emulsion).Mixture is concentrated in a vacuum, to remove DCM.Then with EtOAc (4 milliliters) extraction water solution.Make organic phase dehydrate (MgSO4), and concentrate in a vacuum, and get (55 milligrams of part C compounds; 78%).D.?

With diethyl phosphite (8.0 microlitres; 0.062 mmole) be added into (25 milligrams of part C compounds; 0.062 mmole) in the solution in THF (0.30 milliliter).Add TEA (8.68 microlitres then; 0.062 mmole).In room temperature after following 8 hours, enriching soln in a vacuum.Make crude product through preparing HPLC purifying (100 millimeters posts of YMC anti-phase ODS-A-5u 30 x; Flow velocity=40 ml/min, 15 to 100% solvent B went through 15 minutes, were retained to 20 minutes, wherein, solvent orange 2 A=90: 10: 0.1H2O: MeOH: TFA, and solvent B=90: 10: 0.1MeOH: H2O: TFA), and get (15 milligrams of title compounds; 45%; Amorphous solid), be 1: 1 mixture of diastereomer.[M+H]+＝540.2；1H?NMR(400MHz，CDCl3)：δ1.15(m，2H)，1.31(m，6H)，1.48(m，2H)，1.62(m，3H)，1.78(m，2H)，1.93(m，1H)，2.22(m，1H)，3.88(m，1H)，4.20(m，4H)，5.13(dd，1H)，7.63(d，2H)，7.89(d，2H)，8.34(d，1H)，9.11(d，1H)，9.43(s，1H)。Embodiment 20

A.

With (26 milligrams of embodiment 19 part C compounds; 0.065 mmole) solution in DCM (150 microlitre) is added into CH ₂(PO ₃Et ₂) ₂(16.2 microlitres; 0.065 mmole) in the solution in the 5N NaOH aqueous solution (150 microlitre).After at room temperature 1 hour, make reaction mixture between DCM (3 milliliters) and H2O (2 milliliters), make separatory and handle.Make organic phase dehydrate (MgSO4), and concentrate in a vacuum, and get (35 milligrams of part A compounds; 100%).B.?

10%Pd/C (3 milligrams) is added into (35 milligrams of part A compounds; 0.065 mmole) in the solution in MeOH (0.30 milliliter).With H ₂Atmosphere is introduced via gas cylinder.After 6 hours, filter reaction mixture, and concentrated filtrate in a vacuum.Make crude product through preparing HPLC purifying (100 millimeters posts of YMC anti-phase ODS-A-5u 30 x; Flow velocity=40 ml/min, 20 to 100% solvent B went through 11 minutes, were retained to 15 minutes, wherein, solvent orange 2 A=90: 10: 0.1H2O: MeOH: TFA, and solvent B=90: 10: 0.1MeOH: H2O: TFA), and get (11 milligrams of title compounds; 31%), is amorphous solid.[M+H]+＝538.2；1H?NMR(400MHz，CDCl3)：δ1.15(m，2H)，1.30(m，8H)，1.48(m，2H)，1.61(m，3H)，1.76(m，2H)，1.93(m，1H)，2.22(m，3H)，3.05(s，3H)，3.74(m，1H)，4.09(m，4H)，7.61(d，2H)，7.92(d，2H)，8.08(s，1H)，8.29(s，1H)，9.44(s，1H)。Embodiment 21

A.

With oxalyl chloride (203 microlitres, the 2M solution in DCM; 0.406 mmole) be added into (80 milligrams of embodiment 1 part D compounds; 0.270 mmole) in 0 ℃ of mixture in DCM (0.70 milliliter).Add DMF (10 microlitre).Generation gas disengages.Reaction mixture was stirred under room temperature 1.5 hours, concentrate in a vacuum then.With residue from CHCl ₃(2 milliliters of 2 x) stripping.Rough chloride of acid is dissolved among the DCM (0.90 milliliter).Add (45.0 milligrams of 2-amino-5-formyl thiazole; 0.351 mmole), then be pyridine (66.0 microlitres; 0.810 mmole).In room temperature after following 16 hours, concentration response thing in a vacuum.Make crude product chromatography (SiO2; Continuous gradient liquid, from 0 to 100% solvent B went through 6 minutes, under 100% solvent B, kept 8 minutes, wherein, solvent orange 2 A=hexane, and solvent B=EtOAc), and get (27 milligrams of part A compounds; 25%).B.?

With H (O) P (OEt) ₂(8.9 microlitres; 0.069 mmole) be added into (27 milligrams of part A compounds; 0.066 mmole) in the solution in THF (0.30 milliliter).Add TEA (9.6 microlitres; 0.069 mmole).Reaction mixture was stirred under room temperature 20 hours, add more H (O) P (OEt) then ₂(8.89 microlitres; 0.069 mmole) with TEA (9.62 microlitres; 0.069 mmole), be accompanied by THF (0.10 milliliter).After 20 hours, reactant was heated 16 hours down at 45 ℃, then be cooled to room temperature.After two weeks under the room temperature, make the residue that forms through preparation HPLC purifying (100 millimeters posts of YMC anti-phase ODS-A-5u 30 x; Flow velocity=40 ml/min, 15 to 100% solvent B went through 20 minutes, wherein, solvent orange 2 A=90: 10: 0.1 H2O: MeOH: TFA, and solvent B=90: 10: 0.1MeOH: H2O: TFA), and get (27 milligrams of title compounds; 75%; Amorphous solid), be 1: 1 mixture of diastereoisomer.[M+H]+＝540.2；1HNMR(400MHz，CDCl3)：δ1.16(m，2H)，1.32(m，6H)，1.49(m，2H)，1.62(m，3H)，1.78(m，2H)，1.95(m，1H)，2.24(m，1H)，3.04(s，3H)，4.01(t，1H)，4.21(m，4H)，5.18(d，1H)，7.37(s，1H)，7.65(d，2H)，7.91(d，2H)。Embodiment 22 A.

In the solution of 2-amino-5-bromo thiazole hydrobromide salt (10.0 grams, 38.4 Bo moles) in MeOH (50 milliliters), add KSCN (15.0 grams, 160 mmoles).Reaction mixture was stirred under room temperature 18 hours, concentrate in a vacuum then, and H2O (40 milliliters) is added in the residue.Mixture is adjusted to pH 12 with the 1NNaOH aqueous solution.Form throw out, it is collected through suction filtration, and with H2O (3x) and Et2O (3x) washing.Making the solid dried in vacuum 18 hours, and get partly A compound, is brown solid (2.8 grams, 47%).B.?

In the thiocyanate-(800 milligrams, 5.09 Bo moles) and the solution of embodiment 1D (1.51 grams, 5.09 mmoles) in THF (20 milliliters) of part A, add DEPBT (3.05 grams, 10.18 mmoles) and iPr ₂NEt (1.8 milliliters, 10.18 mmoles).Reaction mixture was stirred under room temperature 18 hours, concentrate in a vacuum then.Residue is dissolved in EtOAc and the salt solution, and with EtOAc extraction (3x).The organic extract liquid that will merge dehydrates (MgSO4) with the 1N HCl aqueous solution, H2O, the 5%NaHCO3 aqueous solution, H2O and brine wash, and concentrates in a vacuum.Make residue chromatography (SiO2; Continuous gradient liquid, the 10%EtOAc/ hexane is to the 100%EtOAc/ hexane), and get partly B compound (927 milligrams, 42%), be the orange solid.C.?

In the 0 ℃ solution of thiocyanate-B (50 milligrams, 0.11 mmole) in anhydrous EtOH (2 milliliters), add NaBH ₄(7 milligrams, 0.22 mmole).Mixture was stirred 1 hour down at 0 ℃, make excessive NaBH carefully with acetone then ₄(0.5 milliliter) cancellation.Make mixture be warmed to room temperature, and be added into ICH is housed ₂PO ₃Et ₂In the flask of (41 milligrams, 0.15 mmole).Reactant was stirred under room temperature 18 hours, then concentrate in a vacuum.Make residue through preparing HPLC purifying (Phenomenex Luna 5u C1821.2x100 millimeter post; Detect down at 220 millimicrons; Flow velocity=20 ml/min; Continuous gradient liquid from 70%A to 100%B, is gone through 8 minutes+7 minute hold-time under 100%B; Wherein, A=90: 10: 0.1H2O: MeOH: TFA, and B=90: 10: 0.1MeOH: H2O: TFA), so that (25.1 milligrams of title compounds to be provided; 39% productive rate), be the pearl lyophilized products.[M+H]+＝561.1；1H?NMR(400MHz，DMSO-D6)：δ7.83(d，J＝8.4，2H)，7.58(d，J＝8.3，2H)，7.51(s，1H)，3.92(m，5H)，3.15(s，2H)，3.12(s，3H)，2.09-1.36(m，11H)，1.12(m，6H)。Embodiment 23

In the solution of embodiment 22 compounds (20 milligrams, 0.04 mmole) in MeOH (1 milliliter) and THF (1 milliliter), add ptoluene-sulfonyl imidazoles (24 milligrams, 0.11 mmole), 30%H ₂O ₂The aqueous solution (0.02 milliliter, 0.14 mmole) and the 1N NaOH aqueous solution (1.0 milliliters).Reactant was at room temperature stirred 3 hours, concentrate in a vacuum then.Make residue through preparing HPLC purifying (100 millimeters posts of Phenomenex Luna 5u,C18 21.2 x; Detect down at 220 millimicrons; Flow velocity=20 ml/min; Continuous gradient liquid from 70%A to 100%B, is gone through 8 minutes+7 minute hold-time under 100%B; Wherein, A=90: 10: 0.1H2O: MeOH: TFA, and B=90: 10: 0.1MeOH: H2O: TFA); So that title compound (12 milligrams, 57% productive rate) to be provided, be white lyophilized products.[M+H]+＝593.2；1H?NMR(400MHz，DMSO-D6)：δ8.00(s，1H)，7.84(d，J＝8.4，2H)，7.59(d，J＝8.4，2H)，4.08-3.94(m，5H)，3.13(s，2H)，3.10(s，3H)，2.02-1.10(m，11H)，1.10-1.06(m，6H)。Embodiment 24 A.

In 3,5-mesitylenic acid (800 milligrams, 5.3 mmoles) is at CH ₂C1 ₂In the solution in (20 milliliters), add oxalyl chloride (0.51 milliliter, 5.8 mmoles) and DMF (0.1 milliliter).Reaction mixture was stirred under room temperature 2 hours, concentrate in a vacuum then.Residue is dissolved among the THF (20 milliliters), and adds the embodiment 22 partly amine (922 milligrams, 5.8 mmoles) and pyridine (0.86 milliliter, 10.6 mmoles) of A.Mixture was stirred under room temperature 18 hours, then with EtOAc (60 milliliters) dilution, with H2O and brine wash, and with EtOAc extraction (2x).The organic extract liquid of merging is dehydrated (MgSO4), and concentrate in a vacuum.Make residue chromatography (the 10%EtOAc/ hexane is to the 100%EtOAc/ hexane), and get the partly compound (770 milligrams, 51% productive rate) of A, be brown solid.B.?

In the 0 ℃ solution of compound (50 milligrams, 0.17 mmole) in anhydrous EtOH (2 milliliters) of part A, add NaBH ₄(13 milligrams, 0.35 mmole), and mixture stirred 1 hour down at 0 ℃.Make excessive NaBH with acetone (0.5 milliliter) ₄Cancellation, and make mixture be warmed to room temperature.Mixture is added into ICH is housed ₂PO ₃Et ₂In the flask of (62 milligrams, 0.22 mmole).Reactant was stirred under room temperature 18 hours, concentrate in a vacuum then.Make residue through preparing HPLC purifying (100 millimeters posts of 5 microns C1821.2 x of Phenomenex Luna; Detect down at 220 millimicrons; Flow velocity=20 ml/min; Continuous gradient liquid from 70%A to 100%B, is gone through 8 minutes+7 minute hold-time under 100%B; Wherein, A=90: 10: 0.1H2O: MeOH: TFA, and B=90: 10: 0.1MeOH: H2O: TFA); So that title compound (22.4 milligrams, 32% productive rate) to be provided, be white solid.[M+H]+＝415.1；1H?NMR(400MHz，DMSO-D6)：δ7.71(s，1H)，7.66(s，2H)，7.27(s，1H)，4.02(m，4H)，3.27(s，2H)，2.34(s，6H)，1.21(m，6H)。Embodiment 25

A.

With 5-(bromo methyl) pyrazine-2-aminocarbamic acid tert-butyl ester (399 milligrams, 1.23 mmoles) with (iPrO) ₃The mixture of P (2 milliliters) is in 100 ℃ of following heated overnight.Make reaction mixture be cooled to room temperature, then chromatography (120 gram SiO2; The continuous gradient liquid of 0-50%EtOAc in DCM then is the continuous gradient liquid of 0-10%MeOH in DCM), and get 399 milligrams (86% productive rate) partly A compound, be faint yellow solid (88% purity is through HPLC).[M+H]+＝374.3；1H-NMR(400MHz，CDCl3)：δ9.18(s，1H)，8.24(s，1H)，7.32(s，1H)，4.67(m，2H)，3.33(d，2H)，1.54(s，9H)，1.25-1.30(m，12H)。B.?

Under Ar, partly the 0 ℃ solution of A compound (200 milligrams, 0.535 mmole) in DCM (1 milliliter) is handled with the 4N HCl aqueous solution in 1 milliliter of diox.Make reaction mixture be warmed to ambient temperature overnight, concentrate in a vacuum then.Make in the residue water-soluble (5 milliliters), and with the Et2O extraction, to remove impurity.Make the aqueous solution with the alkalization of the 1N NaOH aqueous solution, and extract with DCM (2 milliliters of 3x).To merge with organic extract liquid with normal saline washing, dehydrate (MgSO4), and concentrate in a vacuum, so that 103 milligrams (71% productive rates) (amino pyrazine of 5--2-yl) diisopropylmethylpho-sphonate(DIMP) to be provided, be yellow waxy solid.[M+H]+＝274.3。This material directly is used in the next step, need not to be further purified.

Use oxalyl chloride to change into its corresponding chloride of acid (pressing embodiment 2 partly described in the A) embodiment 1D acid; Under Ar; Chloride of acid is transferred to (45 milligrams of the amine of preceding text with two parts of 0.3 milliliter of DCM; 0.165 mmole) with the 0 ℃ mixture of pyridine (53.4 microlitres, 0.66 mmole) in DCM (0.7 milliliter) in.Make reactant be warmed to ambient temperature overnight, extract with DCM (5 milliliters) then.Organic extract liquid with each 2 milliliters of the 0.1N HCl aqueous solution, water and brine wash, is dehydrated (MgSO4), and concentrate in a vacuum, and get 142 milligrams of crude products.Make crude material chromatography (40 gram SiO2; Continuous gradient liquid, the 10-100%EtOAc in DCM), and get title compound (25.6 milligrams, 28% productive rate), be water white oil.[M+H]+＝552.4；1H-NMR(400MHz，CDCl3)：δ9.40(s，1H)，8.24(s，2H)，7.93(d，2H)，7.61(d，2H)，4.68(m，2H)，3.74(m，1H)，3.34(d，2H)，3.05(s，3H)，2.22(m，1H)，1.95(m，1H)，1.10-2.83(m，9H)，1.25-1.29(m，12H)。Embodiment 26

A.

In under 120 ℃ and Ar 3 of heating, 5-methyl dihydroxy benzoate (38 grams, 0.226 mole) and K ₂CO ₃In (47.7 grams, 0.345 mole) warp in DMF (150 milliliters) stirs the mixture fast, add the solution of 1-fluoro-4-(methylsulfonyl) benzene (20 grams, 0.115 mole) in DMF (50 milliliters), went through 3 hours.After 120 ℃ of following heated overnight; Make reaction mixture be cooled to room temperature; With DMF (300 milliliters) dilution, handle as flocculating aids with then.Filter heterogeneous reaction mixture, and with the abundant flush cake of more DMF.The filtrating of merging is concentrated in a vacuum, and make residue between the 1N HCl aqueous solution (200 milliliters) and EtOAc (250 milliliters), do the separatory processing.Add 100 other ml waters.With EtOAc (200 milliliters) aqueous layer extracted, and the organic extract liquid that will merge is with water and salt solution (each 250 milliliters) flushing, and dehydrates (MgSO4).Remove volatile matter in a vacuum.With residue with 3 chromatographies partly.Each partly is adsorbed on the SiO2 (～20 gram), and chromatography (330 gram SiO2; With 0-20%EtOAc at CH ₂Cl ₂In continuous gradient liquid, then be constant composition 20%EtOAc:CH ₂Cl ₂Wash-out), get the partly compound of A (14.77 grams; Merge productive rate 40%), be white solid.[M+H]+＝323.0；1H-NMR(400MHz，CDCl3)：δ7.89(d，2H)，7.33(s，1H)，7.22(s，1H)，7.11(dd，2H)，6.89(d，1H)，3.89(s，3H)，3.07(s，3H)。B.?

Under Ar, in the Ph of part A compound (5 grams, 15.5 mmoles), (R)-(-)-1-methoxyl group-2-propyl alcohol (2 milliliters, 20.4 mmoles) and polymer load ₃In 5 ℃ of mixtures of P (13.4 gram, 3 mmole/grams, 40.2 mmoles) in THF (175 milliliters), dropwise add the solution of DIAD (4.5 milliliters, 23.2 mmoles) in THF (25 milliliters), go through 25 minutes (internal temperature remain on≤5 ℃ under).Make reaction mixture be warmed to ambient temperature overnight, filter then.With THF and CH ₂Cl ₂The thorough washing solid.The filtrating of merging is concentrated in a vacuum, be dissolved among the CH2Cl2 again, and be divided into 2 equal portions.Make the first part chromatography (330 gram SiO2; With the continuous gradient liquid wash-out of 0-10%EtOAc in CH2Cl2, went through 40 minutes), and get the pure part B compound of 2.53 grams, be water white oil.Feasible not pure products fraction of post since then and all the other of crude product partly merge, and make this mixture as above be set forth in upward chromatography of 330 gram SiO2, but use the continuous gradient liquid of 0-8%EtOAc in CH2Cl2, and get part B compound (3.02 gram), are water white oil.Partly the merging productive rate of B compound is 5.55 grams (90%).[M+H]+＝395.0；1H-NMR(400MHz，CDCl3)：δ7.90(d，2H)，7.48(s，1H)，7.30(s，1H)，7.11(dd，2H)，6.86(d，1H)，4.61(m，1H)，3.90(s，3H)，3.49-3.62(m，2H)，3.40(s，3H)，3.07(s，3H)，1.32(d，3H)。C.?

In the 0 ℃ solution of part B compound (4.24 grams, 10.75 mmoles) in THF (50 milliliters) and water (15 milliliters), add LiOH.H ₂O (1.287 grams, 53.7 mmoles).Make reaction mixture be warmed to ambient temperature overnight (accomplishing) through the LC/MS detection reaction.Concentrated reaction mixture in a vacuum, and add 50 milliliters of H2O; Make the solution acidifying with the 5N HCl aqueous solution.With EtOAc (100 milliliters of 2 x) extraction mixture.The EtOAc extraction liquid that will merge dehydrates (MgSO4) with salt solution (50 milliliters) washing, and concentrates in a vacuum, so that partly C compound (3.95 grams, 96.5% productive rate) to be provided, is the flint glass material.[M+H]+＝381.1；1H-NMR(400MHz，CDCl3)：δ7.91(d，2H)，7.52(s，1H)，7.35(s，1H)，7.13(dd，2H)，6.90(s，1H)，4.61(m，1H)，3.52-3.64(m，2H)，3.42(s，3H)，3.07(s，3H)，1.33(d，3H)。D.?

Under Ar, in the 0 ℃ solution of embodiment 25A compound (199 milligrams, 0.533 mmole) in DCM (1 milliliter), add TFA (1 milliliter).Make reaction mixture be warmed to room temperature.After 5.5 hours, concentrated reaction mixture in a vacuum, and between the 0.5N HCl aqueous solution and Et2O (each 4 milliliters), make separatory and handle.Make the water layer alkalization with solid K 2CO3, then with DCM extraction (3x).The organic extract liquid that will merge dehydrates (MgSO4) with brine wash, and concentrates in a vacuum, so that 108 milligrams (74%) (amino pyrazine of 5--2-yl) diisopropylmethylpho-sphonate(DIMP) to be provided, is separated into yellow solid.[M+H]+＝274.3。

Partly C acid (32 milligrams, 0.0841 mmole) uses oxalyl chloride to change into its corresponding chloride of acid (described in embodiment 2 part A).Under Ar; Rough chloride of acid is transferred to (25.3 milligrams of (the amino pyrazine of 5--2-yl) diisopropylmethylpho-sphonate(DIMP)s with two parts of (each 0.2 milliliter) DCM; 0.0926 mmole) with pyridine (27.2 microlitres, 0.370 mmole) in DCM (0.4 milliliter) through being cooled to 0 ℃ mixture.Make reactant be warmed to ambient temperature overnight.Then, reaction mixture with DCM (4 milliliters) extraction, with each 2 milliliters of 0.5NHCl aqueous solution, water, the saturated NaHCO3 aqueous solution and brine wash, is dehydrated (MgSO4), and concentrate in a vacuum.Make crude product (47 milligrams) chromatography (12 gram SiO2; With 15 to 100%EtOAc continuous gradient liquid wash-outs in DCM), so that 17.6 milligrams of (30%) title compounds to be provided, be water white oil.[M+H]+＝636.3；1H-NMR(400MHz，CDCl3)：δ9.57(s，1H)，8.46(s，1H)，8.34(s，1H)，7.93(d，2H)，7.36(s，1H)，7.18(s，1H)，7.17(d，2H)，6.87(s，1H)，4.60-4.75(m，3H)，3.52-3.63(m，2H)，3.41(s，3H)，3.39(d，2H)，3.08(s，3H)，1.25-1.36(m，15H)。Embodiment 27; (isomer A) and embodiment 28; (isomer B) A.

With (300 milligrams of 5-(bromo methyl) pyrazines-2-aminocarbamic acid tert-butyl ester; 1.04 mmole) with the mixture of methyl phosphonous acid diethyl ester (0.2 milliliter) in THF (0.2 milliliter) 100 ℃ of following heated overnight; Be cooled to room temperature then, and be dissolved among the EtOAc (15 milliliters).Solution with water (5 milliliters of 3 x) and salt solution (5 milliliters) washing, is dehydrated (MgSO4), and concentrates in a vacuum.Make crude product (279 milligrams) chromatography (SiO2; 80 grams; With the continuous gradient liquid wash-out of 0-100%EtOAc in DCM), and get partly A compound (114 milligrams), being wax shape white solid, it still contains some by products from methyl phosphonous acid diethyl ester reagent.[M+H]+＝316.3。B.?

Partly the 4N HCl (1 milliliter) in 0 ℃ of solution Yi diox of A compound (114 milligrams, 0.361 mmole) in DCM (1 milliliter) handles.Make reactant be warmed to ambient temperature overnight, then with Et ₂O dilution, so that the product HCl salt of being wanted fully precipitates, and decant.This process is repeated for several times, and produce (82 milligrams of part B compounds; 90%), is white solid.LC/MS shows about correct [M+H] +=216.3 of free state amine.C.?

Use oxalyl chloride to change into its corresponding chloride of acid (described in embodiment 2 part A) embodiment 1 part D compound (91.9 milligrams, 0.310 mmole).Rough chloride of acid is dissolved among the DCM of minimum volume, and under Ar, is added in part B compound (52 milligrams, 0.242 mmole) and 0 ℃ of mixture of pyridine (78.2 microlitres, 0.968 mmole) in DCM (1 milliliter).Make reactant be warmed to ambient temperature overnight, then with DCM (7 milliliters) dilution, and, dehydrate (MgSO4), and concentrate in a vacuum with the two parts 2 milliliters 0.5N HCl aqueous solution, water, the saturated NaHCO3 aqueous solution and brine wash.Make crude material (150 milligrams) chromatography (40 gram SiO2; With 0 to 100%EtOAc continuous gradient liquid in DCM, then with the continuous gradient liquid wash-out of 0-10%MeOH in DCM), and product diastereoisomer (43 milligrams), be mixture.Preparation property reversed-phase HPLC on 100 millimeters posts of YMC ODS-A 5 μ, 30 x is (with 90: 10: 0.1 to 10: 90: 0.1; The continuous 40-100% gradient liquid wash-out of water: MeOH: TFA), obtain 17.9 milligrams of faster isomer A and 18.3 milligrams of isomer B of wash-out than slow wash-outs.Above-mentioned each sample is dissolved among 6 milliliters of DCM, and with 2 milliliters of saturated NaHCO3 aqueous solution flushings, to remove TFA.DCM solution with normal saline washing, is dehydrated (MgSO4), and concentrate in a vacuum, and get isomer A and the B that is wanted.

Isomer A (embodiment 27) obtains with 16.8 milligrams of flint glass materials.[M+H]+＝494.4；1H-NMR(400MHz，CD3OD)：δ9.31(s，1H)，8.31(s，1H)，7.92(m，2H)，7.72(m，2H)，3.96-4.12(m，3H)，3.44(d，2H)，3.30(s，3H)，2.18-2.26(m，1H)，1.13-1.89(m，9H)，1.56(d，3H)，1.27(m，3H)。

Isomer B (embodiment 28) obtains with 15.6 milligrams of flint glass materials: [M+H] +=494.4; 1H-NMR (400MHz, CD3OD): δ 9.31 (s, 1H), 8.31 (s, 1H), 7.91 (m, 2H), 7.70 (m; 2H), 3.97-4.12 (m, 3H), 3.44 (d, 2H), 3.30 (s, 3H), 2.16-2.26 (m; 1H), 1.13-1.88 (m, 9H), 1.54 (d, 3H), 1.28 (m, 3H).Embodiment 29

Under Ar; With (19.7 milligrams of EDC; 0.100 mmole) be added into (24.4 milligrams of acid (34.6 milligrams, 0.091 mmole), HOAT (14.8 milligrams, 0.109 mmole), (6-EL-970-3-yl) methyl-phosphorous acid diethyl esters of embodiment 26C; 0.100 mmole) and in 0 ℃ of mixture of Et3N (12.6 microlitres, 0.091 mmole) in 0.7 milliliter of DCM.Make reaction mixture be warmed to ambient temperature overnight.Add 12 milligrams of other amine, and continue to stir 4 days.Reactant is extracted with 3 milliliters of DCM, and, dehydrate (MgSO4), and concentrate in a vacuum with each 1 milliliter of 0.5N HCl aqueous solution, water, the saturated NaHCO3 aqueous solution and brine wash.Make crude product (34 milligrams) on 100 millimeters Phenomenex Axia of 30 x Luna, 5 μ C18 posts; Through preparation reversed-phase HPLC purifying (continuous gradient liquid; 30-100%90: 10: 0.1 to 10: 90: 0.1, water: CH3CN: TFA), so that 29 milligrams of products of being wanted to be provided.This material is dissolved among 3 milliliters of DCM, and with the two parts 1 milliliter saturated NaHCO3 aqueous solution, brine wash, and dehydrates (MgSO4).Concentrate in a vacuum, 20.8 milligrams of (38% productive rate) title compounds are provided, be water white oil.[M+H]+＝607.3；1H-NMR(400MHz，CDCl3)：δ8.54(s，1H)，8.30(d，1H)，8.20(s，1H)，7.91(d，2H)，7.72(d，1H)，7.34(s，1H)，7.12-7.17(m，3H)，6.85(s，1H)，4.62(m，1H)，4.06(m，4H)，3.50-3.62(m，2H)，3.41(s，3H)，3.11(d，2H)，3.08(s，3H)，1.23-1.35(m，9H)。Embodiment 30

A.

Under room temperature, imidazoles (1.86 grams, 27.4 mmoles) is added into (R)-propane-1, in 2-glycol (1 milliliter, 13.7 mmoles) and the mixture of TBSCl (4.1 milliliters, 16.44 mmoles) in DMF (13 milliliters).With reactant stirred overnight at room temperature, in vacuum, concentrate then.Residue is extracted with DCM (25 milliliters), and wash with water (20 milliliters).With DCM (25 milliliters) aqueous layer extracted again, and the organic extract liquid that will merge dehydrates (MgSO4) with salt solution (20 milliliters) washing, and concentrates in a vacuum.Make rough oily product (6 gram) chromatography (120 gram SiO2; Continuous gradient liquid, the 0-20%EtOAc in hexane), and get partly A compound (3.69 grams, 86% productive rate), be water white oil.In LC/MS, do not find [M+H]+.1H-NMR(400MHz，CDCl3)：δ7.67(m，4H)，7.41(m，6H)，3.91(m，1H)，3.61(dd，1H)，3.45(dd，1H)，2.58(d，1H)，1.10(d，3H)，1.07(s，9H)。B.?

Under Ar; The solution of DIAD (0.216 milliliter, 1.12 mmoles) in THF (0.5 milliliter) dropwise is added into (240 milligrams of part A compound (304 milligrams, 0.967 mmole), 3-hydroxyl-5-(4-(methylsulfonyl) phenoxy) oil of Niobe; 0.744 mmole) and the Ph3P of polymkeric substance load (1.6 mmoles/gram loadings; 1.2 gram, 1.92 mmoles) in 0 ℃ of mixture in 10 milliliters of THF, went through 3 minutes.Make reactant be warmed to room temperature.In room temperature after following 3 hours, the filtering reaction thing, and fully wash resin with THF and DCM.The filtrating of merging is concentrated in a vacuum.Make residue chromatography (SiO2; 40 grams; Continuous gradient liquid is at the 0-40%EtOAc of hexane), and must it be used in the next step through the product (through 1H-NMR, containing some DIAD through reduction) of part purifying, need not to be further purified.

LiOH.H2O (93 milligrams, 2.22 mmoles) is added in 0 ℃ of mixture of methyl esters (nominal 0.744 mmole) in 4 milliliters of THF and 1 ml water that derives from preceding text.Make reactant be warmed to ambient temperature overnight.Analyze HPLC to show～16% starting substance is residual, therefore adds more LiOH.H2O (31 milligrams).After 4.5 hours, reaction mixture is concentrated in a vacuum again, between water and EtOAc (each 15 milliliters), make separatory then and handle.With 15 milliliters of EtOAc aqueous layer extracted.The organic extract liquid that will merge is with 10%KHSO ₄The aqueous solution (10 milliliters), each 10 ml waters and brine wash dehydrate (MgSO4), and concentrate in a vacuum, and get partly B compound (402 milligrams, 90% productive rate), and it still contains some DIAD through reduction.1HNMR (400MHz, CDCl ₃) partly specify: δ 7.90 (d, 2H), 7.63 (d, 4H), 7.46 (s, 1H), 7.30-7.43 (m, 7H), 7.10 (d, 2H), 6.82 (s, 1H), 4.58 (m, 1H), 3.77 (dd, 2H), 3.06 (s, 3H), 1.01 (s, 9H).C.?

Under Ar, EDC (26.1 milligrams, 0.136 mmole) is added into partly B compound (75 milligrams, 0.124 mmole), HOAT (20.2 milligrams, 0.149 mmole), (6-EL-970-3-yl) methyl-phosphorous acid diethyl ester (39.3 milligrams, 0.161 mmole) and Et ₃In 0 ℃ of mixture of N (19 microlitres, 0.136 mmole) in 1.5 milliliters of DCM.After 5 days, about 62: 9 of the ratio of LC/MS analysis demonstration expectation product and the HOAT ester that partly B is sour.After 24 hours, reaction mixture is diluted with 7 milliliters of DCM again, and, dehydrate (MgSO4), and concentrate in a vacuum with each 2 milliliters of 0.5N HCl aqueous solution, water, the saturated NaHCO3 aqueous solution and brine wash.Make crude product (85 milligrams) chromatography (12 gram SiO2; Continuous gradient liquid wash-out with 0-5%MeOH to DCM), so that (46 milligrams of part C compounds to be provided; 45%), is water white oil.[M+H]+＝831.4；1H-NMR(400MHz，CDCl3)：δ8.57(s，1H)，8.31(d，1H)，8.21(s，1H)，7.90(d，2H)，7.74(d，1H)，7.63(m，4H)，7.32-7.43(m，6H)，7.28(s，1H)，7.07-7.14(m，3H)，6.79(s，1H)，4.59(m，1H)，4.08(m，4H)，3.78(dd，2H)，3.12(d，2H)，3.07(s，3H)，1.33(d，?3H)，1.25-1.30(m，6H)，1.02(s，9H)。D.?

Under Ar, in the 0 ℃ solution of part C compound (46 milligrams, 0.0553 mmole) in 1.5 milliliters of THF, add Bu ₄NF (0.11 milliliter, the 1M solution in THF, 0.11 mmole).Make reactant be warmed to room temperature.After 4 hours, reaction mixture is concentrated in a vacuum, and between 6 milliliters of EtOAc and 2 ml waters, make separatory and handle.Organic extract liquid with each 2 ml waters and brine wash, is dehydrated (MgSO4), and concentrate in a vacuum.Make residue (44 milligrams) on 100 millimeters PhenomenexAxiaLuna of 30 x, 5 μ C18 posts through preparation reversed-phase HPLC purifying (linear 20-100% gradient liquid, from 90: 10: 0.1 to 10: 90: 0.1, water: CH ₃CN: TFA).Purified material is dissolved among the DCM (6 milliliters), and, dehydrates (MgSO4), and concentrate in a vacuum, and produce (25 milligrams of title compounds with each the 2 milliliters saturated NaHCO3 aqueous solution and brine wash; 76%), is water white oil.[M+H]+＝593.2；1H-NMR(400MHz，CDCl3)：δ8.85(s，1H)，8.31(d，1H)，8.17(s，1H)，7.92(d，2H)，7.72(d，1H)，7.34(s，1H)，7.16(s，1H)，7.12(d，2H)，6.81(s，1H)，4.58(m，1H)，4.07(m，4H)，3.77(m，2H)，3.08(s，3H)，1.27(m，6H)。Embodiment 31

A.

In 3-amino-1,2, in the room temperature slurries of 4-triazole (1.0 grams, 11.9 mmoles) in hexane (20 milliliters), add TMEDA (0.07 gram, 0.6 mmole) and two carbonic acid, two-tert-butyl ester (3.89 restrain 17.8 mmoles).Reaction mixture was at room temperature stirred 24 hours, pour in the saturated NaHCO3 aqueous solution (150 milliliters), and with EtOAc (25 milliliters of 2 x) extraction product.Merge organic extract liquid, dehydrate (MgSO4), and in vacuum, concentrate.Make the residue chromatography (SiO2: continuous gradient liquid, from the 0%EtOAc/ hexane to the 100%EtOAc/ hexane), and the part A compound (1.33 restrain, 61% productive rate) that wanted, be white solid.[M+H]+＝185.0；1H?NMR(400MHz，CDCl3)：δ7.48(s，1H)，1.66(s，9H)。B.?

In the 0 ℃ solution of part A compound (0.500 gram, 2.71 mmoles) in DMF (5 milliliters), with 1 part of 60%NaH (0.119 gram, 2.99 mmoles) that adds in the oil, and with the stirring 1 hour under 0 ℃ of the slurries of institute formations.Add ICH ₂PO ₃Et ₂(0.830 gram, 2.99 mmoles), and with reaction mixture stirred overnight under room temperature.Reaction mixture is poured in the salt solution (35 milliliters); And extract with EtOAc (25 milliliters of 4x); The organic extract liquid of merging is dehydrated (MgSO4), and concentrate in a vacuum.Make residue through preparing HPLC purifying (100 millimeters posts of Phenomenex Luna AXIA 30 x; Detect down at 220 millimicrons; Flow velocity=40 ml/min; Continuous gradient liquid, from 100%A to 100%B, go through 15 minutes+under 100%B, kept 2 minutes, wherein, A=90: 10H2O: MeOH, and B=90: 10MeOH: H2O),, be white solid so that partly B compound (0.059 gram, 6.5% productive rate) to be provided.[M+H]＝335.1；1H?NMR(400MHz，DMSO-D6)：δ9.59(s，1H)，8.24(d，J＝1.76Hz，1H)，4.75(d，J＝11.87Hz，2H)，4.10-4.00(m，4H)，1.42(s，9H)，1.21(t，J＝7.03Hz，6H)。C.?

In the solution at room temperature of part B compound (0.059 gram, 0.177 mmole) in CH2Cl2 (1 milliliter), add TFA (2.04 milliliters, 3.13 mmoles).Reaction mixture was at room temperature stirred 2 hours, in vacuum, concentrate then.Make residue through preparing HPLC purifying (100 millimeters posts of Phenomenex Luna 21.2x; Detect down at 220 millimicrons; Flow velocity=20 ml/min; Continuous gradient liquid, from 100%A to 100%B, go through 15 minutes+under 100%B, kept 2 minutes; Wherein, A=90: 10: 0.1H2O: MeOH: TFA, and B=90: 10: 0.1MeOH: H2O: TFA); So that partly C compound (0.050 gram, 81% productive rate) to be provided, be clean oil.1H?NMR(400MHz，CDCl3)δ7.27(s，1H)，6.78(s，2H)，4.43(d，J＝13.62Hz，2H)，4.24-4.15(m，4H)，1.32-1.38(m，6H)。D.?

In embodiment 26 part C compound (0.023 grams; 0.060 mmole) in the solution at room temperature in CH2Cl2 (1 milliliter), add oxalyl chloride (10.6 microlitres, 0.121 mmole) and DMF (0.9 microlitre; 0.012 mmole), and with reaction mixture at room temperature stirred 1 hour.In vacuum, remove volatile matter,, be yellow oil so that rough part D compound (0.060 gram) to be provided.E.?

In the solution at room temperature of rough part D compound (0.060 gram, 0.24 mmole) in CH2Cl2 (1 milliliter), add partly C compound (0.031 gram, 0.090 mmole) and the solution of pyridine (0.019 milliliter, 0.241 mmole) in CH2Cl2 (1 milliliter).With reaction mixture stirred overnight at room temperature, between the saturated NaHCO3 aqueous solution (1 milliliter) and EtOAc (2 milliliters), make separatory then and handle; Organic phase with the saturated NaHCO3 aqueous solution (1 milliliter) washing, is dehydrated (MgSO4), and concentrate in a vacuum.Make residue through preparing HPLC purifying (100 millimeters posts of Phenomenex Luna AXIA 21.2 x; Detect down at 220 millimicrons; Flow velocity=40 ml/min; Continuous gradient liquid, from 100%A to 100%B, go through 15 minutes+under 100%B, kept 2 minutes, wherein, A=90: 10H2O: MeOH, and B=90: 10MeOH: H2O),, be white solid so that title compound (0.007 gram, 19.0% productive rate) to be provided.[M+H]+＝597.3；1H?NMR(400MHz，CDCl3)：δ9.65(s，1H)，8.42(d，J＝1.76Hz，1H)，7.92(t，J＝1.76Hz，1H)，7.90(t，J＝1.76Hz，7.45(t，J＝1.75Hz，1H)，7.32(t，J＝1.76Hz，1H)，7.15(t，J＝1.761H)，7.14(t，J＝1.76Hz)，6.88(t，J＝2.19Hz，1H)，4.80-4.75(m，1H)，4.70(d，J＝13.18Hz，2H)，4.29-4.19(m，4H)，3.64-3.54(m，2H)，3.42(s，3H)，3.07(s，3H)，1.35(t，J＝7.03，9H)。Embodiment 32

A.

In the 0 ℃ solution of 1H-pyrazoles-3-amine (1.00 grams, 12.03 mmoles) in DMF (25 milliliters), add potassium tert.-butoxide (2.70 grams, 24.07 mmoles), and reaction mixture was stirred 1 hour down at 0 ℃.Add ICH ₂PO ₃Et ₂(3.35 gram, 12.03 mmoles), and reaction mixture stirred 1.5 hours down at 0 ℃ make it be warmed to room temperature then, and under room temperature stirred overnight.Remove volatile matter in a vacuum, and make residue between salt solution (30 milliliters) and EtOAc (30 milliliters), do the separatory processing.With EtOAc (30 milliliters of 5 x) extraction product; The organic extract liquid of merging is dehydrated (MgSO4), and concentrate in a vacuum.Make residue through preparing HPLC purifying (100 millimeters posts of 5 microns C 1830x of Phenomenex Luna AXIA; Detect down at 220 millimicrons; Flow velocity=40 ml/min; Continuous gradient liquid, from 100%A to 20%B, go through 25 minutes+under 20%B, kept 2 minutes, wherein, A=90: 10H2O: MeCN, and B=90: 10MeCN: H2O),, be light yellow oil so that partly A compound (0.470 gram, 16.8% productive rate) to be provided.[M+H]+＝233.9；1H?NMR(400MHz，CDCl3)：δ7.29(s，1H)，5.66(d，J＝2.20Hz，1H)，4.36(d，J＝11.55Hz，2H)，4.10(m，4H)，3.76(s，2H)，1.29(t，J＝7.15Hz，6H)。B.?

In the solution at room temperature of embodiment 26 part C compounds (0.16 gram, 0.421 mmole) in DMF (8 milliliters), add EDAC (0.161 gram, 0.841 mmole), HOAT (0.114 gram, 0.841 mmole) and iPr ₂NEt (0.185 milliliter, 1.05 mmoles), and reaction mixture at room temperature stirred 30 minutes.Add the partly solution of A compound (0.123 gram, 0.526 mmole) in DMF (2 milliliters), and, pour into then among the H2O (40 milliliters) reaction mixture stirred overnight under room temperature.With EtOAc (15 milliliters of 2 x) extraction mixture; The organic extract liquid of merging is dehydrated (MgSO4), and concentrate in a vacuum.Make residue through preparing HPLC purifying (100 millimeters posts of Phenomenex Luna 5 μ C18,30 x; Detect down at 220 millimicrons; Flow velocity=40 ml/min; Continuous gradient liquid, from 100%A to 1000%B, go through 25 minutes+under 100%B, kept 10 minutes, wherein, A=90: 10H2O: MeCN, and B=90: 10MeCN: H2O),, be white solid so that title compound (0.149 gram, 59.4% productive rate) to be provided.[M+H]+＝596.3；1H?NMR(400MHz，CDCl3)：δ8.98(s，1H)，7.92(t，J＝1.65Hz，J＝3.3Hz，1H)，7.90(t，J＝2.70Hz，J＝2.2Hz，1H)7.47(d，J＝2.2Hz，1H)，7.35(t，J＝1.65Hz，1H)，7.20(t，J＝2.2Hz，1H)，7.14(t，J＝2.75Hz，J＝2.2Hz，1H)，7.12(t，J＝2.75Hz，J＝2.20Hz，6.90(d，J＝2.20Hz，1H)，6.82(t，J＝2.20Hz，1H)，4.67-4.59(m，1H)，4.51(d，J＝12.09Hz，2H)，4.13-4.03(m，4H)，3.58(dd，J＝10.44Hz，J＝6.05Hz，1H)，3.51(dd，J＝10.44Hz，J＝3.85Hz，1H)，3.40(s，3H)，3.08(s，3H)，1.33(d，J＝6.05Hz，3H)，1.27(t，J＝7.14Hz，6H)。Example 33?

A.?

i.?

Under Ar and room temperature,, in the solution of 5-methyl dihydroxy benzoate (10.0 grams, 59.5 mmoles) in DMF (60.0 milliliters), add K2CO3 (12.4 grams, 89.7 mmoles) in 3.Slowly add the benzyl bromine (10.0 milliliters, 84.2 mmoles; Before using, filter through parlkaline Al2O3), went through 10 minutes.Reaction mixture was stirred under room temperature 12 hours,, then make the reaction cancellation carefully with H2O (350 milliliters) then with the saturated NH4Cl aqueous solution (50 milliliters).With CH2Cl2 (30 milliliters of 1 x, 50 milliliters of 2 x) extraction aq suspension.The organic extract liquid that will merge dehydrates [MgSO4] with H2O (100 milliliters) and brine wash, and concentrates in a vacuum, and gets crude product (27.0 gram), is golden oil.Make crude material chromatography (during the 30%EtOAc/ hexane part of stepwise gradient liquid (10-50%EtOAc/ hexane), making the product wash-out), and produce partly A (i) compound (4.6 grams, 30%), be the milk yellow powder.ii.?

In the 0 ℃ solution of part A (i) compound (1.0 grams, 3.9 mmoles) in THF (16.8 milliliters), add (R)-(-)-1-methoxyl group-2-propyl alcohol (0.5 gram, 5.8 mmoles) and Ph continuously ₃P (1.5 grams, 5.8 mmoles) then slowly adds DIAD (1.1 milliliters, 5.8 mmoles).Make reaction mixture be warmed to room temperature, and under room temperature, stirred 2 days.With the H2O diluted reaction mixture, and extract with Et2O.Make organic layer dehydrate [MgSO4], and concentrate in a vacuum, and get dense thick light yellow oil.Make this crude material chromatography (during the 10%EtOAc/ hexane of the stepwise gradient liquid of 10-30%EtOAc/ hexane is partly, making the product wash-out), and (ii) compound (1.1 grams, 85% productive rate) of A partly, be water white oil.iii.?

To contain among the MeOH (45.4 milliliters) part A (ii) the flask of compound (1.2 gram, 3.6 mmoles) bleed, and wash with Ar.Add 10%Pd/C (0.38 gram, 0.36 mmole) with portion.Mixture was stirred 12 hours under H2 atmosphere and room temperature; Pass through

then and filter, it is washed with EtOAc.Concentrate the filtrating of merging in a vacuum, and get (iii) compound (0.81 gram, 93% productive rate) of part A, be yellow oil.iv.?

Under Ar, (iii) in 0 ℃ of solution of compound (0.14 gram, 0.59 mmole) in THF (2.9 milliliters), add Ph in part A ₃P (0.4 gram, 1.3 mmoles) with (R)-1-phenyl propan-2-ol (0.2 gram, 1.3 mmoles).Reaction mixture was stirred 5 minutes down at 0 ℃, dropwise add DIAD (0.3 milliliter, 1.3 mmoles) then.Reaction mixture was stirred under room temperature 12 hours, then with the H2O dilution, and with EtOAc extraction (2x).The organic extract liquid that will merge dehydrates [MgSO4] with the 1N NaOH aqueous solution and brine wash, and concentrates in a vacuum, and gets light yellow oil (1.0 gram).Make this crude material chromatography (during the 10%EtOAc/ hexane of the stepwise gradient liquid of 5-20%EtOAc/ hexane is partly, making the product wash-out), and (iv) compound (0.17 gram, 81% productive rate) of A partly, near water white oil.v.?

At room temperature, in part A (iv) compound (0.17 gram, 0.5 mmole) in the solution among THF (1.8 milliliters) and the H2O (0.6 milliliter), add LiOH.H2O (0.02 gram, 0.52 Bo mole).Reaction mixture was stirred 1 hour down at 45 ℃; Add another part LiOH.H2O, and continue down to stir at 45 ℃.After 6 hours, starting substance is consumed, and makes reactant be cooled to room temperature.Remove volatile matter in a vacuum, and make remaining aqueous layer with 0.5N HCl acidified aqueous solution to pH 2, then with EtOAc extraction (3x).The organic extract liquid that will merge dehydrates [MgSO4] with brine wash, and concentrates in a vacuum, and (v) compound (0.16 gram, 86%) is light yellow oil and get rough part A.B.?

(v) in the solution at room temperature of compound (0.030 gram, 0.087 mmole) in DMF (1.5 milliliters), add EDAC (0.033 gram, 0.174 mmole), HOAt (0.024 gram, 0.174 mmole) and DIEA (0.038 milliliter, 0.218 mmole) in part A.Reaction mixture was at room temperature stirred 30 minutes, add the partly solution of A compound (0.025 gram, 0.109 mmole) in DMF (0.5 milliliter) of embodiment 32 then.With reaction mixture stirred overnight under room temperature, then pour in the water (7 milliliters); With EtOAc (10 milliliters of 2 x) extraction mixture.The organic extract liquid of merging is dehydrated (MgSO4), and concentrate in a vacuum.Make residue through preparing HPLC purifying (Phenomenex Luna AXIA 100A 5 μ C18 posts; Detect down at 220 millimicrons; Flow velocity=40 ml/min; Continuous gradient liquid, from 100%A to 100%B, go through 25 minutes+under 100%B, kept 2 minutes, wherein, A=90: 10H2O: MeCN, and B=90: 10MeCN: H2O),, be clean oil so that title compound (0.027 gram, 56.3% productive rate) to be provided.[M+H]+＝560.4；1H?NMR(400MHz，CDCl3)：δ8.59(s，1H)，7.44-7.46(m，1H)，7.32-7.19(m，5H)，7.00(t，J＝1.65Hz，1H)，6.97(t，J＝2.2Hz，1H)，6.91(d，J＝2.2Hz，1H)，6.63(t，J＝2.2?Hz，1H)，4.65-4.53(m，2H)，4.44(d，J＝11.54Hz，2H)，4.14-4.04(m，4H)，3.56(dd，J＝9.9Hz，J＝5.5Hz，1H)，3.49(dd，J＝9.89Hz，J＝3.84Hz，1H)，3.41(s，3H)，3.06(dd，J＝13.74Hz，J＝6.04Hz，1H)，2.85(dd，J＝13.74Hz，J＝6.04Hz，1H)，1.26(m，12H)。Embodiment 34 A.

In 3, in two 0 ℃ of solution of (trifluoromethyl) phenylformic acid (129 milligrams, 0.50 mmole) in CH2Cl2 (1 milliliter) of 5-, the interpolation oxalyl chloride (0.375 milliliter, 0.75 mmole, 2M is in CH2Cl2) and DMF (1).Reactant was stirred 30 minutes down at 0 ℃, be warmed to room temperature then, and stirred 4 hours.Enriched mixture in a vacuum.In the solution of chloride of acid residue in CH2Cl2 (3 milliliters), add 5-bromo pyrazine-2-amine (130 milligrams, 0.75 mmole) and pyridine (0.061 milliliter, 0.75 mmole).Reactant was at room temperature stirred 18 hours, and with CH2Cl2 (6 milliliters) dilution, and with the 0.5N HCl aqueous solution (1 milliliter, 2x), water (1 milliliter), the saturated NaHCO3 aqueous solution (1 milliliter) and brine wash.Make organic layer dehydrate (MgSO4), filter, and in vacuum, concentrate.Make residue chromatography (SiO2),, be white solid so that partly A compound (40 milligrams, 19% productive rate) to be provided.B.?

THF (through the degassing) (0.40 milliliter) is added into (25.0 milligrams of part A compounds; 0.060 mmole) with (Ph ₃P) ₄Pd ⁰(13.9 milligrams; 0.012 mmole).Add H (O) P (OEt) 2 (9.33 microlitres; 0.072 mmole), then be TEA (11.7 microlitres; 0.084 mmole).Reaction mixture was heated 5 hours down at 85 ℃, be cooled to room temperature then, and between EtOAc (3 milliliters) and salt solution (3 milliliters), make separatory and handle.Make organic phase dehydrate (MgSO4), and concentrate in a vacuum.Make crude product through preparing HPLC purifying (100 millimeters posts of YMC anti-phase ODS-A-5 micron 30x; Flow velocity=40 ml/min, 45 to 100% solvent B went through 12 minutes, were retained to 15 minutes, wherein, solvent orange 2 A=90: 10: 0.1H2O: MeOH: TFA, and solvent B=90: 10: 0.1MeOH: H2O: TFA), and get (11.6 milligrams of title compounds; 41%), is faint yellow solid.[M+H]+＝472.2；1H?NMR(400MHz，CDCl3)：δ1.37(t，6H)，4.27(m，4H)，8.12(s，1H)，8.53(s，2H)，8.82(s，1H)，9.53(s，1H)，9.80(s，1H)。Embodiment 35

A.

With DIPEA (66 microlitres; 0.378 mmole) be added into (80 milligrams of embodiment 1 part D compounds; 0.270 mmole), 2-amino-5-formyl thiazole is (43.3 milligrams; 0.338 mmole) and (44.0 milligrams of HOAt; 0.324 mmole) in DMF (1.0 milliliters) in stirred solution.Add (62.0 milligrams of EDAC; 0.324 mmole).After at room temperature 3 hours, make reaction mixture between EtOAc (8 milliliters) and H2O (8 milliliters), make separatory and handle.Organic phase with the 1N HCl aqueous solution (5 milliliters), the saturated NaHCO3 aqueous solution (5 milliliters) and salt solution (5 milliliters) washing, is dehydrated (MgSO4), and concentrates in a vacuum.Make crude product chromatography (SiO2; Continuous gradient liquid, in hexane 0 to 100%EtOAc, went through 11 minutes, under 100%EtOAc, kept 4 minutes), and (81 milligrams of A compounds partly; 74%), is the foam thing.B.?

With CH ₂(PO ₃Et) ₂(59.4 microlitres; 0.239 mmole) be added into (10.13 milligrams of Powdered LiCl; 0.239 mmole) in the mixture in CH3CN (1.0 milliliters).Add DBU (35.7 microlitres; 0.239 mmole), then be (81.0 milligrams of part A compounds; 0.199 the solution in CH3CN (1.0 milliliters) mmole).After following 24 hours, add more CH in room temperature ₂(PO ₃Et) 2 (9.92 microlitres; 0.040 DBU (5.96 microlitres mmole); 0.040 mmole) and (1.7 milligrams of LiCl; 0.040 mmole).After 72 hours, concentrated reaction mixture in a vacuum.Making residue between the EtOAc (8 milliliters) and the 0.2N HCl aqueous solution (8 milliliters), make separatory handles.Organic phase with salt solution (6 milliliters) washing, is dehydrated (MgSO4), and concentrate in a vacuum.Make crude product chromatography (SiO2; Continuous gradient liquid, in hexane 0% to 100%EtOAc, went through 6 minutes, be converted to the 2%MeOH among the EtOAc, and kept 8 minutes), and (67 milligrams of title compounds; 62%), is colorless solid.[M+H]+＝541.1；1H?NMR(400MHz，CDCl3)(19∶1，E/Z)：δ1.15(m，2H)，1.37(m，6H)，1.48(m，2H)，1.66(m，3H)，1.78(m，2H)，1.92(m，1H)，2.27(m，1H)，3.03(s，3H)，4.12(m，5H)，5.88(dd，J＝17.3Hz，1H)，7.58(s，1H)，7.66(d，2H)，7.89(d，2H)，8.14(dd，J＝17.1Hz，1H)。Embodiment 36

With 20%Pd (OH) ₂(16 milligrams) are added into (35 milligrams of embodiment 35 compounds; 0.065 mmole) in the solution in MeOH (0.40 milliliter).H2 (gas) atmosphere is introduced via gas cylinder.After stirring 48 hours, filter reaction mixture.Catalyzer is washed with MeOH (1.5 milliliters), EtOAc (1.5 milliliters) and CHCl3 (1.5 milliliters), and concentrate the filtrating of merging in a vacuum.Make crude product through preparing HPLC purifying (100 millimeters posts of YMC anti-phase ODS-A-5u 20x; Flow velocity=20 ml/min, 15 to 100% solvent B went through 10 minutes, were retained to 12 minutes, wherein, solvent orange 2 A=90: 10: 0.1H2O: MeOH: TFA, and solvent B=90: 10: 0.1MeOH: H2O: TFA), so that (18 milligrams of title compounds to be provided; 51%).[M+H]+＝543.2；1H?NMR(400MHz，CD3OD)：δ1.19(m，2H)，1.29(t，6H)，1.51(m，2H)，1.64(m，3H)，1.80(m，3H)，2.17(m，3H)，3.05(m，2H)，3.09(s，3H)，3.96(t，1H)，4.07(m，4H)，7.20(s，1H)，7.67(d，2H)，7.92(d，2H)。Embodiment 37

With DIPEA (387 microlitres; 2.22 mmole) be added into (704 milligrams of embodiment 26 part C compounds; 1.85 mmole), embodiment 13 part E compounds are (556 milligrams; 2.22 mmole) and (302 milligrams of HOAt; 2.22 mmole) in cold (0 ℃) solution in DMF (7.4 milliliters).Add (426 milligrams of EDAC; 2.22 mmole).After at room temperature 24 hours, make reaction mixture between EtOAc (100 milliliters) and H2O (75 milliliters), make separatory and handle.Organic phase with the 0.5N HCl aqueous solution (50 milliliters), the saturated NaHCO3 aqueous solution (50 milliliters) and salt solution (50 milliliters) washing, is dehydrated (MgSO4), and concentrates in a vacuum.Make crude product through preparing HPLC purifying (250 millimeters posts of YMC anti-phase ODS-A-5u 30 x; Flow velocity=30 ml/min, 15 to 100% solvent B went through 25 minutes, were retained to 30 minutes, wherein, solvent orange 2 A=90: 10: 0.1H2O: CH3CN: TFA, and solvent B=90: 10: 0.1CH3CN: H2O: TFA).Make product through preparing HPLC purifying for the second time, use the same terms, but use MeOH replaced C H3CN, and get (778 milligrams of title compounds; 69%), is the white foam thing.[M+H]+＝613.2；1H?NMR(400MHz，CDCl3)：δ1.26(t，6H)，1.35(d，3H)，3.08(s，3H)，3.34(d，2H)，3.41(s，3H)，3.55(m，2H)，4.08(m，4H)，4.69(m，1H)，6.88(s，2H)，7.14(d，2H)，7.30(s，1H)，7.48(s，1H)，7.92(d，2H)。Embodiment 38

(39 milligrams of title compounds; 78%; Yellow solid) adopt said method about embodiment 37, synthetic from embodiment 15 D compounds partly.[M+H]+＝613.3；1H?NMR(400MHz，CDCl3)：δ1.34(m，9H)，3.08(s，3H)，3.28(d，2H)，3.41(s，3H)，3.59(m，2H)，4.15(m，4H)，4.84(m，1H)，6.93(s，1H)，7.15(d，2H)，7.34(d，1H)，7.40(s，1H)，7.63(s，1H)，7.92(d，2H)。Embodiment 39

A.

With embodiment 13 part B compound (0.94 grams; 4.08 mmole) solution in DCM (8 milliliters) dropwise is added into Dess-Martin periodo alkane (1.82 grams; 4.28 mmole) in 0 ℃ of solution in DCM (8 milliliters)., after following 20 hours reactant is diluted with the 1.0N NaOH aqueous solution (6 milliliters) with DCM (4 milliliters) in room temperature.After stirring 10 minutes, mixture is filtered through

.Organic phase with salt solution (10 milliliters) washing, is dehydrated (MgSO4), and concentrate in a vacuum.Make residue chromatography (SiO2; Continuous gradient liquid, in hexane 0 to 50%EtOAc, went through 12 minutes, kept 8 minutes under the 50%EtOAc in hexane), and A compound (0.65 gram partly; 70%), is white solid.B.?

TFA (2.0 milliliters) is added into partly A compound (0.64 gram; 2.80 mmole) in 0 ℃ of solution in DCM (4.0 milliliters).In room temperature after following 20 hours, concentrated reaction mixture in a vacuum.Making residue between the EtOAc (10 milliliters) and the saturated NaHCO3 aqueous solution (8 milliliters), make separatory handles.Water phase separated, and extract with EtOAc (8 milliliters of 5 x).The organic extract liquid of merging is dehydrated (MgSO4), and concentrate in a vacuum, and get partly B compound (0.30 gram; 83%), is yellow solid.C.?

With DIPEA (88.7 microlitres; 0.509 mmole) be added into (130 milligrams of embodiment 1 part D compounds; 0.439 mmole), part B compound is (67.4 milligrams; 0.526 mmole) and (69.3 milligrams of HOAt; 0.509 mmole) in DMF (1.5 milliliters) in stirred solution.Add (97.6 milligrams of EDAC; 0.509 mmole).After stirring 20 hours under the room temperature, make reaction mixture between EtOAc (12 milliliters) and H2O (12 milliliters), make separatory and handle.Organic phase with the 0.5N HCl aqueous solution (8 milliliters), the saturated NaHCO3 aqueous solution (8 milliliters) and salt solution (8 milliliters) washing, is dehydrated (MgSO4), and concentrates in a vacuum.Make crude product chromatography (SiO2; Continuous gradient liquid, in hexane 0 to 80%EtOAc, went through 13 minutes, kept 3 minutes under the 80%EtOAc in hexane), and (100 milligrams of C compounds partly; 56%), is yellow foam thing.D.?

With H (O) P (OEt) ₂(10.0 microlitres; 0.078 mmole) be added into (30.0 milligrams of part C compounds; 0.074 mmole), then be pyridine (6.6 microlitres; 0.081 mmole).Reaction mixture was heated 5 hours down in 70 ℃, be cooled to room temperature then.After 48 hours, add more H (O) P (OEt) 2 (10.0 microlitres; 0.078 mmole) with pyridine (10.0 microlitres; 0.123 mmole), and continue 70 ℃ of down heating.After 7 hours, make reactant be cooled to room temperature, and,, dehydrate (MgSO4), and concentrate in a vacuum with the 1.0N HCl aqueous solution (1.5 milliliters) and salt solution (1.5 milliliters) washing with EtOAc (3 milliliters) dilution.Make crude product chromatography (SiO2; Continuous gradient liquid, in hexane 0 to 100%EtOAc, went through 3 minutes, be converted to the 3%MeOH among the EtOAc, and kept 8 minutes).Then, make product through preparing HPLC purifying (100 millimeters posts of YMC anti-phase ODS-A-5u 20 x; Flow velocity=20 ml/min, 10 to 100% solvent B went through 10 minutes, were retained to 12 minutes, wherein, solvent orange 2 A=90: 10: 0.1H2O: MeOH: TFA, and solvent B=90: 10: 0.1MeOH: H2O: TFA), and get (14 milligrams of title compounds; 35%), is faint yellow solid (diastereo-isomerism mixture).[M+H]+＝545.2；1H?NMR(400MHz，CDCl3)：δ1.13(m，2H)，1.28(m，6H)，1.49(m，2H)，1.60(m，3H)，1.76(m，2H)，1.96(m，1H)，2.23(m，1H)，3.04(s，3H)，4.01(t，1H)，4.16(m，4H)，5.18(dd，1H)，7.03(d，1H)，7.65(d，2H)，7.90(d，2H)。Embodiment 40

With oxalyl chloride (2.0M is in DCM) (45.0 microlitres; 0.091 solution mmole) is added into (23.0 milligrams of embodiment 26 part C compounds; 0.060 mmole) in the solution in DCM (0.20 milliliter).Add DMF (5 microlitre).Generation gas disengages.Reaction mixture was stirred under room temperature 1 hour, concentrate in a vacuum then.With residue from DCM (1 milliliter of 2 x) stripping.Rough chloride of acid is dissolved among the DCM (0.25 milliliter).Add (16.2 milligrams of embodiment 7 part B compounds; 0.066 mmole), then be pyridine (14.6 microlitres; 0.180 mmole).In room temperature after following 20 hours, concentration response thing in a vacuum.Making residue between the EtOAc (4 milliliters) and the 0.5N HCl aqueous solution (3 milliliters), make separatory handles.Organic phase with the saturated NaHCO3 aqueous solution (3 milliliters) and salt solution (3 milliliters) washing, is dehydrated (MgSO4), and concentrates in a vacuum.Make crude product through preparing HPLC purifying (100 millimeters posts of YMC anti-phase ODS-A-5u 30 x; Flow velocity=40 ml/min, 15 to 100% solvent B went through 12 minutes, were retained to 14 minutes, wherein, solvent orange 2 A=90: 10: 0.1H2O: MeOH: TFA, and solvent B=90: 10: 0.1MeOH: H2O: TFA), and get (13 milligrams of title compounds; 36%), is white solid.[M+H]+＝608.2；1H?NMR(400MHz，CDCl3)：δ1.32(m，9H)，3.07(s，3H)，3.40(s，3H)，3.44(d，2H)，3.57(q，2H)，4.13(m，4H)，4.63(m，1H)，6.88(s，1H)，7.16(d，2H)，7.19(s，1H)，7.35(s，1H)，7.93(d，2H)，8.32(s，1H)，8.53(s，1H)，9.59(s，1H)。Embodiment 41

A.

With nBuLi (575 microlitres, the 1.6M solution in hexane; 0.920 mmole) dropwise be added into Me (O) P (OEt) 2 (134 microlitres; 0.920 mmole) in cold (78 ℃) solution in THF (0.30 milliliter).After 20 minutes, dropwise add (100 milligrams of embodiment 39 part A compounds; 0.438 the solution in THF (0.70 milliliter) mmole).In-78 ℃ after following 1 hour, through adding AcOH (63 microlitres; 1.10 mmole) make the reaction cancellation.Make reactant be warmed to room temperature, and use the Ar air-flow to concentrate.Making residue between EtOAc (5 milliliters) and salt solution (4 milliliters), make separatory handles.Make organic phase dehydrate (MgSO4), and concentrate in a vacuum.Make crude product chromatography (SiO2; Continuous gradient liquid, in hexane 0 to 100%EtOAc, went through 8 minutes, be converted to the 4%MeOH among the EtOAc, and kept 6 minutes), and (104 milligrams of A compounds partly; 62%), is slurries.B.?

HCl (100 microlitres, 1, the 4.0N solution in the 4-diox) is added into partly (104 milligrams of A compounds; 0.273 mmole).After 20 hours, reaction mixture is concentrated in a vacuum, and get (64 milligrams of part B compounds; 75%), is oily matter, it is used in the next step, need not to be further purified.C.?

With DIPEA (56.0 microlitres; 0.324 mmole) be added into (32.0 milligrams of embodiment 1 part D compounds; 0.108 mmole), part B compound is (48.0 milligrams; 0.151 mmole) and (16.9 milligrams of HOAt; 0.124 mmole) in DMF (0.42 milliliter) in stirred solution.Add (23.8 milligrams of EDAC; 0.124 mmole).After at room temperature 2 hours, make reaction mixture between the EtOAc (4 milliliters) and the 0.5N HCl aqueous solution (3 milliliters), make separatory and handle.Organic phase with the saturated NaHCO3 aqueous solution (3 milliliters) and salt solution (3 milliliters) washing, is dehydrated (MgSO4), and concentrates in a vacuum.Make crude product through preparing HPLC purifying (100 millimeters posts of YMC anti-phase ODS-A-5u 20 x; Flow velocity=20 ml/min, 15 to 100% solvent B went through 12 minutes, were retained to 14 minutes, wherein, solvent orange 2 A=90: 10: 0.1H2O: MeOH: TFA, and solvent B=90: 10: 0.1MeOH: H2O: TFA), and get (27 milligrams of title compounds; 45%), is white solid.[M+H]+＝559.3；1HNMR(400MHz，CDCl3)：δ1.15(m，2H)，1.27(m，3H)，1.35(t，3H)，1.49(m，2H)，1.62(m，3H)，1.78(m，2H)，1.95(m，1H)，2.25(m，1H)，2.41(m，2H)，3.04(s，3H)，4.03(t，1H)，4.16(m，4H)，5.19(t，1H)，6.93(s，1H)，7.65(d，2H)，7.90(d，2H)。Embodiment 42 A.

Under N2 (gas), in the Ph of embodiment 26A (3.7 grams, 11.5 mmoles), (R)-(-)-1-benzyloxy-2-propyl alcohol (2.5 grams, 15 mmoles) and polymkeric substance load ₃In P (30 gram, 1 mmole/gram, 30 mmoles) cold (internal temperature remain on≤5 ℃ under) solution in THF (150 milliliters), dropwise add the solution of DIAD (3.4 milliliters, 17.3 mmoles), went through 15 minutes.Make reaction mixture be warmed to room temperature, and stirred 18 hours, filter then.With solid with THF and CH2Cl2 thorough washing.Concentrate the filtrating of merging in a vacuum.Make mixture chromatography (SiO2; EtOAc/ hexane 1: 1), and gets partly A compound (6.0 grams, 110%), be water white oil.[M+H]＝471.2；1H?NMR(400MHz，CDCl3)δ7.90(2H，d，J＝8.79Hz)，7.48(1H，s)，7.27-7.37(6H，m)，7.09(2H，d，J＝8.79Hz)，6.83-6.89(1H，m)，4.60-4.69(1H，m)，4.58(2H，s)，3.90(3H，s)，3.54-3.70(2H，m)，3.06(3H，s)，1.34(3H，d，J＝6.15Hz)。B.?

Partly A (6 grams, 13 mmoles), LiOH (1.6 grams, 39 mmoles) and the solution of H2O (50 milliliters) in THF (20 milliliters) stirred 3 hours under room temperature, concentrated in a vacuum then.The aqueous solution with Et2O (15 milliliters of x 4) washing, is acidified to pH 4 with dense HCl, and extracts with EtOAc (50 milliliters).Organic layer is washed with H2O, dehydrate (MgSO4), filter, and concentrate in a vacuum, and get partly B compound (5 grams, 95%), be white solid.[M+H]＝457.2；1H?NMR(400MHz，CDCl3)δ7.91(2H，d，J＝8.79Hz)，7.52(1H，s)，7.27-7.38(6H，m)，7.11(2H，d，J＝8.79Hz)，6.90(1H，t，J＝2.20Hz)，4.61-4.70(1H，m)，4.59(2H，s)，3.56-3.70(2H，m)，3.07(3H，s)，1.35(3H，d，J＝6.59Hz)。C.?

With DIPEA (22.0 microlitres; 0.127 mmole) be added into (50 milligrams of part C compounds; 0.110 mmole), embodiment 13 part E compounds are (33.0 milligrams; 0.131 mmole) and (17.0 milligrams of HOAt; 0.127 mmole) in 0 ℃ of solution in DMF (0.44 milliliter), then be (24.0 milligrams of EDAC; 0.127 mmole)., make reaction mixture between the EtOAc (7 milliliters) and the 0.5N HCl aqueous solution (5 milliliters), make separatory and handle after following 24 hours in room temperature.Organic phase with the saturated NaHCO3 aqueous solution (5 milliliters) and salt solution (5 milliliters) washing, is dehydrated (MgSO4), and concentrates in a vacuum.Make crude product chromatography (SiO2; Continuous gradient liquid, in hexane 0 to 100%EtOAc, went through 12 minutes, under 100%EtOAc, kept 4 minutes).Make product through being dissolved among the MeOH (1 milliliter), and be filled on 0.5 gram SAX (reinforcing yin essence IX) post and be further purified.Make post with MeOH (4 milliliters) wash-out.Concentrated filtrate, and get (50 milligrams of title compounds; 67%), is faint yellow residue.[M+H]+＝689.3；1H?NMR(400MHz，CDCl3)：δ1.26(t，6H)，1.34(m，3H)，3.08(s，3H)，3.34(d，2H)，3.62(m，2H)，4.06(m，4H)，4.58(s，2H)，4.68(m，1H)，6.85(s，1H)，6.88(s，1H)，7.14(d，2H)，7.20(s，1H)，7.27(m，5H)，7.39(s，1H)，7.92(d，2H)。Example 43?

A.?

Annotate: following process is revised from WO 2006/016178 and WO 2006/016174.i.?

In the 0 ℃ suspension-s of NH4Cl (8.44 grams, 63.3 mmoles) in DCM (40 milliliters), add 2-chloro-2-oxo vinyl acetic monomer (5.53 milliliters, 49.7 mmoles), went through 10 minutes.Reactant was stirred 30 minutes down at 0 ℃.Add cyclopropyl-phenyl thioether (6.5 milliliters, 45.2 mmoles) then, during going through 45 minutes, temperature is remained under 0 ℃.[annotate: when adding sulfide, reactant is transformed into grape/redness immediately on color].Make reactant be warmed to room temperature, and at room temperature stirred 18 hours.Under 0 ℃, frozen water (100 milliliters) slowly is added in the mixture.Organic phase is washed, and washed with H2O again with H2O (2x), the saturated NaHCO3 aqueous solution (2x).Make organic layer dehydrate [MgSO4], and concentrate in a vacuum, and get rough part A (i) compound (6.1 grams, 54%), be yellow oil.ii.?

Partly the solution of A (i) compound (6.1 grams, 24.37 mmoles) in toluene (50 milliliters) is heated to 50 ℃, and stirs.Dropwise add the 3N NaOH aqueous solution (9.75 milliliters, 29.2 mmoles), maintain the temperature at simultaneously≤60 ℃ under.After adding completion, reactant was stirred 4 hours down at 50 ℃, be cooled to room temperature then, and neutralize through careful interpolation dense HCl (0.821 milliliter, 26.8 mmoles).Reactant was stirred under room temperature 18 hours.Concentrate organic phase in a vacuum, and get (ii) compound (6.0 grams, 111%) of rough part A, be yellow solid.iii.?

Under-78 ℃, in NH ₂NH ₂.H ₂Among the O (5.89 milliliters, 121 mmoles), add partly A compound (5.4 grams, 24.30 mmoles) (ii) with portion, and with reaction mass heated to 80 ℃, and stir, be cooled to room temperature then.Add KOH (0.818 gram, 14.58 mmoles); With reactant stirred for several minute under room temperature, then add second part of KOH (0.818 gram, 14.58 mmoles).With reactant stirred for several minute at room temperature, add the 3rd part of KOH (0.818 gram, 14.58 mmoles) then.With reactant stirred for several minute again under room temperature, and add the 4th part of KOH (0.818 gram, 14.58 mmoles).Then, reactant is heated down at 100 ℃, and stirred 18 hours.Make reactant be cooled to room temperature, and dilute with H2O.Making reaction mixture between Et2O and H2O, make separatory handles.Separate liquid layer, and water layer is transferred to round-bottomed flask.With H2O washing organic layer, and the water layer that will merge is with heptane (～50 milliliters) processing, and with the mixture high degree of agitation.To under 0 ℃, dropwise handle through the solution of stirring, go through 30 minutes with dense HCl (11.66 milliliters, 384 mmoles).Make this suspension-s be warmed to room temperature, and stirred for several hour at room temperature.Form yellow mercury oxide, and leach; With this material with the 1N HCl aqueous solution and heptane wash, in vacuum dry 48 hours then.Therefore, partly A (iii) compound (3.7 grams, 73% productive rate) be to be separated into faint yellow solid.iv.?

Partly A (iii) compound from toluene stripping (2x).In part A (iii) compound (3.7 the gram; 17.76 mmole) in anhydrous propanone (50 milliliters), in they-10 ℃ of mixtures, dropwise add (2.297 milliliters of trimethylammonium acetyl chlorides with K2CO3 (7.37 grams, 53.3 mmoles); 18.65 mmole), maintain the temperature at simultaneously≤-10 ℃ under.Reactant was stirred 30 minutes down in-10 ℃, be warmed to 0 ℃ then, went through 1 hour, and be warmed to room temperature at last, went through 30 minutes.Make mixture be cooled to-10 ℃ again, and with (1R, 2R)-(-)-pseudo-ephedrine (4.40 grams, 26.6 mmoles) processing.Reactant was stirred 1 hour down at-10 ℃, then be warmed to 25 ℃, and stirred 18 hours down in 25 ℃.Make the reaction cancellation with H2O (25 milliliters), and extract with EtOAc.Organic phase with 1N HCl solution washing, is dehydrated (MgSO4), and concentrates in a vacuum, and the compound of rough part D.Rough part D compound is dissolved among the CH2Cl2, and chromatography (SiO2; 120 grams; Gradient liquid, from the 30%EtOAc/ hexane to 100%EtOAc).The wash-out fraction of merging is concentrated in a vacuum, and get (iv) compound (1.16 grams, 18.4% productive rate) of part A, be white solid.v.?

a.?

In the solution of THF-4-MeOH (5.0 grams, 43 mmoles) in CH2Cl2 (30 milliliters), add Et ₃N (7.2 milliliters, 51.6 mmoles).Make mixture be cooled to 0 ℃, and add chloromethane sulphonyl (4.0 milliliters, 51.6 mmoles).Mixture in 0 ℃ of following stirred for several hour, slowly is warmed to room temperature then.Reactant was at room temperature stirred 18 hours, then concentrate in a vacuum.Residue is dissolved among the EtOAc, and with saturated NaHCO3 washing.Make organic layer dehydrate [MgSO4], and concentrate in a vacuum, (v) (a) compound (8.3 grams, quantitative yield) is the white needles solid and get methane sulfonate part A.b.?

(v) the mixture of (a) compound (8.3 grams, 43.0 mmoles) and NaI (12.8 grams, 85.5 mmoles) refluxed 18 hours in acetone (100 milliliters) under 65 ℃, was cooled to room temperature then, and filtration to make methane sulfonate part A.With the washing with acetone filter cake.Concentrate the filtrating that makes merging in a vacuum, and make residue between Et2O and water, do the separatory processing.With Et2O extraction (3x) water layer.The organic extract liquid that will merge is with 10%Na ₂S ₂O ₃The aqueous solution and water washing dehydrate [MgSO4], and concentrate in a vacuum, and (v) (b) compound (7.1 grams, 74% productive rate) is yellow oil and get part A.vi.?

Make all starting substances and toluene evaporates for several times, and make whole glass waress dried overnight in baking oven.In THF (15 milliliters), in they-78 ℃ of solution, dropwise add the (iv) solution of compound (1.0 grams, 2.81 mmoles) in THF (15 milliliters) of part A in LiHMDS (5.91 milliliters, 5.91 mmoles), went through 15 minutes.Reactant was stirred 15 minutes down in-78 ℃, be warmed to 0 ℃ then, went through 45 minutes, and be cooled to again-78 ℃.Add DMPU (0.714 milliliter, 5.91 mmoles), and reactant was stirred～15 minutes down at-78 ℃, then add partly A (iodide v) (0.954 gram, 4.22 mmoles) through distillation.Reactant was stirred 1 hour down in-78 ℃, slowly be warmed to room temperature then, and stirred 18 hours.Make the reaction cancellation with the saturated NH4Cl aqueous solution (～10 milliliters), and dilute with EtOAc.With the H2O purging compound.With the EtOAc aqueous layer extracted, and the organic extract liquid that will merge dehydrates [MgSO4] with brine wash, and concentrates in a vacuum, and partly A (vi) compound (1.3 grams, 100%) is yellow oil.vii.?

(vi) (10.4 milliliters, the solution in the 94 mmole) Zai dioxs (20 milliliters) is cooled to room temperature then in 110 ℃ of refluxed 18 hours for compound (1.3 grams, 2.87 mmoles) and the dense H2SO4 of 9N to make partly A.Solution is diluted with EtOAc (50 milliliters), and with H2O (40 milliliters of x 2) and salt solution (20 milliliters) washing.Make organic layer dehydrate [MgSO4], and concentrate in a vacuum, (vii) compound (1.17 grams, 133% productive rate) is yellow gumminess oil and get part A.viii.?

(vii) in the solution of compound (0.9 gram, 2.94 mmoles) in Virahol (20 milliliters) and water (10 milliliters), add oxone (oxone) (4.15 grams, 6.76 mmoles) in part A.Reactant was at room temperature stirred 18 hours, filter then, and concentrated filtrate in a vacuum.Residue is dissolved among the EtOAc, and with H2O and brine wash.Make organic layer dehydrate [MgSO4], and concentrate in a vacuum, (viii) compound (0.9 gram, 91% productive rate) is the weak yellow foam thing and get part A.B.?

With oxalyl chloride (58.0 microlitres, the 2.0M solution in DCM; 0.116 mmole) be added into (26.0 milligrams of part A compounds; 0.077 mmole) in the solution in DCM (0.25 milliliter).Add DMF (5 microlitre).Generation gas disengages.Reaction mixture was stirred under room temperature 1 hour, concentrate in a vacuum then.With residue from DCM (1 milliliter of 2 x) stripping.Rough chloride of acid is dissolved among the DCM (0.32 milliliter).Add (23.0 milligrams of embodiment 13 part E compounds; 0.092 mmole), then be pyridine (18.7 microlitres; 0.231 mmole).In room temperature after following 20 hours, concentration response thing in a vacuum.Making residue between the EtOAc (4 milliliters) and the 0.5N HCl aqueous solution (3 milliliters), make separatory handles.Organic phase with the saturated NaHCO3 aqueous solution (3 milliliters) and salt solution (3 milliliters) washing, is dehydrated (MgSO4), and concentrates in a vacuum.Make crude product through preparing HPLC purifying (100 millimeters posts of YMC anti-phase ODS-A-5 micron 30 x; Flow velocity=40 ml/min, 15 to 100% solvent B went through 16 minutes, were retained to 20 minutes, wherein, solvent orange 2 A=90: 10: 0.1H2O: MeOH: TFA, and solvent B=90: 10: 0.1MeOH: H2O: TFA), and get (17 milligrams of title compounds; 39%), is faint yellow solid.[M+H]+＝571.4；1H?NMR(400MHz，CDCl3)：δ1.04(m，2H)，1.33(m，11H)，1.63(m，2H)，1.87(m，1H)，2.21(m，1H)，2.46(m，1H)，3.28(m，4H)，3.92(m，2H)，4.02(t，1H)，4.11(m，4H)，6.88(d，1H)，7.61(d，2H)，7.88(d，2H)。Embodiment 44

(22 milligrams of title compounds; 51%; Faint yellow solid) adopt method about synthetic embodiment 43 compounds, synthetic from embodiment 7 B compounds and embodiment 43 part A (viii) compound partly.[M+H]+＝566.4；1H?NMR(400MHz，CDCl3)：δ1.05(m，2H)，1.34(m，10H)，1.48(m，1H)，1.67(m，2H)，1.79(m，1H)，2.22(m，1H)，2.46(m，1H)，3.35(m，4H)，3.92(d，2H)，4.04(t，1H)，4.14(m，4H)，7.62(d，2H)，7.85(d，2H)，8.20(s，1H)，9.34(s，1H)，9.36(s，1H)。Example 45?

A.?

With (iPrO) ₃(2.02 milliliters of P; 8.20 mmole) be added into and contain partly (600 milligrams of C compounds of embodiment 13; 2.05 in container mmole).Reaction vessel is added a cover, and mixture was heated 16 hours down in 85 ℃, be cooled to room temperature then.Make the direct chromatography (SiO2 of solution; Continuous gradient liquid, in hexane 0 to 100%EtOAc, went through 7 minutes, be converted to the 4%MeOH among the EtOAc, and kept 12 minutes), and (607 milligrams of A compounds partly; 78%), is sticky solid.B.?

TFA (2.0 milliliters) is added into (559 milligrams of part A compounds; 1.48 mmole) in 0 ℃ of solution in DCM (4 milliliters).Make reaction mixture be warmed to room temperature, and under room temperature, stirred 2 hours, concentrate in a vacuum then.Making residue between the EtOAc (15 milliliters) and the saturated NaHCO3 aqueous solution (10 milliliters), make separatory handles.With EtOAc (10 milliliters) aqueous phase extracted.The organic extract liquid that will merge dehydrates (MgSO4) with salt solution (10 milliliters) washing, and concentrates in a vacuum, and gets partly B compound (0.41 gram; 100%), is yellow solid.C.?

With DIPEA (81.3 microlitres; 0.467 mmole) be added into (135.6 milligrams of part B compounds; 0.487 mmole), embodiment 26 part C compounds are (154.5 milligrams; 0.406 mmole) and (63.6 milligrams of HOAt; 0.467 mmole) in the solution in DMF (1.5 milliliters).Add (89.5 milligrams of EDAC; 0.467 mmole)., make reaction mixture between EtOAc (15 milliliters) and H2O (12 milliliters), make separatory and handle after following 48 hours in room temperature.Organic phase with the 0.5N HCl aqueous solution (10 milliliters), the saturated NaHCO3 aqueous solution (10 milliliters) and salt solution (10 milliliters) washing, is dehydrated (MgSO4), and concentrates in a vacuum.Make crude product through preparing HPLC purifying (250 millimeters posts of YMC anti-phase ODS-A-5u 30 x; Flow velocity=30 ml/min, 20 to 100% solvent B went through 18 minutes, were retained to 25 minutes, wherein, solvent orange 2 A=90: 10: 0.1H2O: MeOH: TFA, and solvent B=90: 10: 0.1MeOH: H2O: TFA), and get title compound (0.24 gram; 92%), is faint yellow solid.[M+H]+＝641.3；1H?NMR(400MHz，CDCl3)：δ1.25(m，6H)，1.31(m，9H)，3.08(s，3H)，3.27(d，2H)，3.41(s，3H)，3.58(m，2H)，4.71(m，2H)，4.80(m，1H)，6.92(s，1H)，6.99(s，1H)，7.15(d，2H)，7.37(s，1H)，7.58(s，1H)，7.92(d，2H)。Example 46? A.?

With 10%Pd/C (100 milligrams) and embodiment 42 part B compound (1.03 grams; 2.26 mmole) mixture in EtOAc (6 milliliters) stirred 8 hours under H2 atmosphere, then, and filter reaction mixture.With MeOH (10 milliliters) flushing catalyzer, and the filtrating of merging is concentrated in a vacuum, and get partly A compound (0.82 gram; 99%).B.?

With TBSCl (1.01 grams; 6.71 mmole) solution in DMF (6 milliliters) is added into partly A compound (0.82 gram; 2.24 mmole), then be imidazoles (0.91 gram; 13.43 mmole).After 20 hours, make reaction mixture between the EtOAc (50 milliliters) and the saturated NH4Cl aqueous solution (50 milliliters), make separatory and handle.Organic phase with the saturated NH4Cl aqueous solution (25 milliliters) and salt solution (25 milliliters) washing, is dehydrated (MgSO4), and concentrates in a vacuum.Make crude product chromatography (SiO2; Continuous gradient liquid, in hexane 0 to 100%EtOAc, went through 14 minutes, under 100%EtOAc, kept 4 minutes), and (725 milligrams of B compounds partly; 68%), is the white foam thing.C.?

With DIPEA (14.5 microlitres; 0.083 mmole) be added into (30.8 milligrams of part B compounds; 0.064 mmole), embodiment 13 part E compounds are (21.6 milligrams; 0.086 mmole) and (10.9 milligrams of HOAt; 0.080 mmole) in the solution at room temperature in DMF (0.33 milliliter).Add (15.3 milligrams of EDAC then; 0.080 mmole).After at room temperature 48 hours, make reaction mixture between EtOAc (3 milliliters) and H2O (3 milliliters), make separatory and handle.Organic phase with salt solution (30 milliliters) washing, is dehydrated (MgSO4), and concentrate in a vacuum, and get (53 milligrams of part C compounds; 100%), is slurries.This crude product is used in the next step, need not to be further purified.D.?

With TBAF (1.0M is in THF) (152 microlitres; 0.152 mmole) be added into (54 milligrams of part C compounds; 0.76 mmole) in 0 ℃ of solution in THF (0.22 milliliter).Make reactant be warmed to room temperature, and under room temperature, stirred 2 hours, concentrate in a vacuum then.Making residue between EtOAc (2.5 milliliters) and salt solution (2.5 milliliters), make separatory handles.Make organic phase dehydrate (MgSO4), and concentrate in a vacuum.Make crude product through preparing HPLC purifying (100 millimeters posts of YMC anti-phase ODS-A-5u 30 x; Flow velocity=40 ml/min, 10 to 100% solvent B went through 10 minutes, were retained to 13 minutes, wherein, solvent orange 2 A=90: 10: 0.1H2O: MeOH: TFA, and solvent B=90: 10: 0.1MeOH: H2O: TFA), and get (23 milligrams of title compounds; 51%), is colourless slurries.[M+H]+＝599.3；1H?NMR(400MHz，CDCl3)∶δ1.33(m，9H)，3.07(s，3H)，3.33(d，2H)，3.79(q，2H)，4.15(m，4H)，4.82(m，1H)，6.93(s，1H)，7.05(d，1H)，7.15(d，2H)，7.44(s，1H)，7.70(s，1H)，7.92(d，1H)。Example 47?

A.?

With (141 milligrams of Powdered KOH; 2.51 mmole) be added into partly B compound (0.41 gram of embodiment 46; 1.12 mmole) in the solution in DMSO-D6 (2.5 milliliters).Add 4-methoxybenzyl bromine (0.47 gram; 2.35 the solution in DMSO-D6 (1 milliliter) mmole).After 2 hours, add H2O (0.5 milliliter).After 30 minutes, make solution between EtOAc (20 milliliters) and H2O (20 milliliters), make separatory and handle.Make organic phase dehydrate (MgSO4), and concentrate in a vacuum.Make crude product chromatography (SiO2; Continuous gradient liquid, in hexane 0 to 70%EtOAc, went through 13 minutes, under 70%EtOAc, kept 4 minutes), and (195 milligrams of A compounds partly; 33%).B.?

With oxalyl chloride (2.0M is in DCM) (72 microlitres; 0.144 mmole) be added into (43.9 milligrams of part A compounds; 0.096 mmole) in 0 ℃ of solution in DCM (0.33 milliliter).Add DMF (5 microlitre).Generation gas disengages.After stirring 1.5 hours under the room temperature, enriching soln in a vacuum.With residue from CHCl3 (2 milliliters) stripping.Rough chloride of acid is dissolved among the DCM (0.40 milliliter).Add (29.4 milligrams of embodiment 7 part B compounds; 0.120 mmole), then be pyridine (23.3 microlitres; 0.288 mmole).In room temperature after following 14 hours, concentration response thing in a vacuum.Making residue between the EtOAc (3 milliliters) and the 0.5N HCl aqueous solution (2 milliliters), make separatory handles.Organic phase with the saturated NaHCO3 aqueous solution (2 milliliters) and salt solution (2 milliliters) washing, is dehydrated (MgSO4), and concentrates in a vacuum.Make crude product chromatography (SiO2; Continuous gradient liquid, in hexane 0 to 100%EtOAc, went through 13 minutes, be converted to the 3%MeOH among the EtOAc, and kept 7 minutes), and (28 milligrams of B compounds partly; 40%).C.?

With (9.4 milligrams of DDQ; 0.041 mmole) be added into (28 milligrams of part B compounds; 0.039 mmole) in the solution in DCM (400 microlitre) and H2O (25 microlitre).After stirring 1 hour under the room temperature, enriched mixture in a vacuum.Making residue between the EtOAc (3 milliliters) and the saturated NaHCO3 aqueous solution (2 milliliters), make separatory handles.Organic phase with the saturated NaHCO3 aqueous solution (2 milliliters) and salt solution (2 milliliters) washing, is dehydrated (MgSO4), and concentrates in a vacuum.Make crude product through preparing HPLC purifying (100 millimeters posts of YMC anti-phase ODS-A-5u 30 x; Flow velocity=40 ml/min, 10 to 100% solvent B went through 10 minutes, were retained to 14 minutes, wherein, solvent orange 2 A=90: 10: 0.1H2O: ACN: TFA, and solvent B=90: 10: 0.1ACN: H2O: TFA), and get 20 milligrams of slurries.Make the further chromatography of this material, to remove aldehyde pollutent (SiO2; With the 100%EtOAc wash-out,, be converted to the 5%MeOH among the EtOAc then, with eluted product to remove aldehyde), and get (12 milligrams of title compounds; 52%), is colourless slurries.[M+H]+＝594.3；1H?NMR(400MHz，CDCl3)：δ1.29(m，9H)，2.29(s，1H)，3.08(s，3H)，3.42(d，2H)，3.77(m，2H)，4.11(m，4H)，4.59(m，1H)，6.86(s，1H)，7.14(d，2H)，7.19(s，1H)，7.37(s，1H)，7.93(d，2H)，8.30(s，1H)，8.68(s，1H)，9.57(s，1H)。Embodiment 48

Under room temperature, with (13.1 milligrams of NCS; 0.098 mmole) be added into (52.0 milligrams of embodiment 13 compounds; 0.098 mmole) in the solution in MeOH (0.5 milliliter), and at room temperature stirred 48 hours.In vacuum, remove volatile matter.Make residue through preparing HPLC purifying (100 millimeters posts of YMC anti-phase ODS-A-5u 30 x; Flow velocity=40 ml/min, 20 to 100% solvent B went through 12 minutes, were retained to 18 minutes, wherein, solvent orange 2 A=90: 10: 0.1H2O: MeOH: TFA, and solvent B=90: 10: 0.1MeOH: H2O: TFA), and get (42 milligrams of title compounds; 76%), is white solid.[M+H]+＝563.3；1H?NMR(400MHz，CDCl3)：δ1.13(m，2H)，1.29(m，6H)，1.48(m，2H)，1.60(m，3H)，1.74(m，2H)，1.92(m，1H)，2.20(m，1H)，3.06(s，3H)，3.33(d，2H)，3.84(t，1H)，4.11(m，4H)，7.59(d，2H)，7.89(d，2H)。Embodiment 49

(23 milligrams of title compounds; 69%; White solid) employing is synthesized into like the synthetic same procedure about embodiment 48, only uses NBS to replace NCS.Bromination reaction was accomplished in 1 hour.[M+H]+＝607.3；1H?NMR(400MHz，CDCl3)：δ1.13(m，2H)，1.28(m，6H)，1.48(m，2H)，1.59(m，3H)，1.76(m，2H)，1.92(m，1H)，2.20(m，1H)，3.06(s，3H)，3.31(d，2H)，3.83(t，1H)，4.09(m，4H)，7.59(d，2H)，7.89(d，2H)。Embodiment 50

With (8.55 milligrams of NCS; 0.064 mmole) be added into (39.0 milligrams of embodiment 37 compounds; 0.064 mmole) in the solution in MeOH (0.4 milliliter).In room temperature after following 48 hours, concentrated reaction mixture in a vacuum.Make crude product through preparing HPLC purifying (100 millimeters posts of YMC anti-phase ODS-A-5u 30 x; Flow velocity=40 ml/min, 25 to 100% solvent B went through 10 minutes, were retained to 13 minutes, wherein, solvent orange 2 A=90: 10: 0.1H2O: MeOH: TFA, and solvent B=90: 10: 0.1MeOH: H2O: TFA), and get (27 milligrams of title compounds; 66%), is white solid.[M+H]+＝647.2；1H?NMR(400MHz，CDCl3)：δ1.29(t，6H)，1.35(d，3H)，3.09(s，3H)，3.29(d，2H)，3.41(s，3H)，3.56(q，2H)，4.10(m，4H)，4.65(m，1H)，6.89(s，1H)，7.15(d，2H)，7.19(s，1H)，7.36(s，1H)，7.94(d，2H)。Embodiment 51

(32 milligrams of title compounds; 78%; White solid) employing is synthesized into like the synthetic said same procedure about embodiment 50, only uses NBS to replace NCS.Bromination reaction was accomplished in 1 hour.[M+H]+＝691.3；1H?NMR(400MHz，CDCl3)：δ1.29(t，6H)，1.34(d，3H)，3.09(s，3H)，3.33(d，2H)，3.41(s，3H)，3.55(q，2H)，4.09(m，4H)，4.65(m，1H)，6.89(s，1H)，7.14(d，2H)，7.21(s，1H)，7.38(s，1H)，7.94(d，2H)。Example 52? A.?

(120 milligrams of compd As; 16%, go through 5 steps; Soft white solid) adopt in order to prepare the partly same procedure of E compounds of embodiment 13, synthetic from 2-amino-5-sec.-propyl-1,3-thiazoles-4-carboxylate methyl ester.B.?

With DIPEA (19.2 microlitres; 0.110 mmole) be added into (33.6 milligrams of part A compounds; 0.115 mmole), embodiment 26 part C compounds are (36.4 milligrams; 0.096 mmole) and (15.0 milligrams of HOAt; 0.110 mmole) in the solution in DMF (0.35 milliliter), then be (21.1 milligrams of EDAC; 0.110 mmole).After at room temperature 24 hours, make reaction mixture between the EtOAc (15 milliliters) and the 0.5N HCl aqueous solution (10 milliliters), make separatory and handle.Organic phase with the saturated NaHCO3 aqueous solution (10 milliliters) and salt solution (10 milliliters) washing, is dehydrated (MgSO4), and concentrates in a vacuum.Make crude product through preparing HPLC purifying (100 millimeters posts of YMC anti-phase ODS-A-5u 30 x; Flow velocity=40 ml/min, 15 to 100% solvent B went through 10 minutes, were retained to 12 minutes, wherein, solvent orange 2 A=90: 10: 0.1H2O: ACN: TFA, and solvent B=90: 10: 0.1ACN: H2O: TFA), and get (49 milligrams of title compounds; 75%), is colourless residue.[M+H]+＝655.3；1H?NMR(400MHz，CDCl3)：δ1.29(t，6H)，1.35(m，9H)，3.07(s，3H)，3.28(d，2H)，3.31(m，1H)，3.41(s，3H)，3.57(m，2H)，4.13(m，4H)，4.84(m，1H)，6.92(s，1H)，7.15(d，2H)，7.38(s，1H)，7.62(s，1H)，7.92(d，2H)。Example 53?

A.?

With (690 milligrams of methyl phosphonous acid diethyl esters; 5.07 mmole) be added into (496 milligrams of embodiment 13 part C compounds; 1.69 mmole) in the solution in THF (0.5 milliliter).Reaction mixture was heated 16 hours down in 75 ℃, be cooled to room temperature then.Solution directly is filled on the 12 gram SiO2 posts, and make the crude product chromatography (continuous gradient liquid, in hexane 0 to 100%EtOAc, went through 4 minutes, be converted to the 5%MeOH among the EtOAc, and kept 10 minutes), and (493 milligrams of A compounds partly; 91%), is faint yellow solid.B.?

TFA (2.0 milliliters) is added into (768 milligrams of part A compounds; 2.40 mmole) in 0 ℃ of solution in DCM (6 milliliters).Reaction mixture was stirred under room temperature 3 hours, concentrate in a vacuum then.Making residue between the EtOAc (15 milliliters) and the saturated NaHCO3 aqueous solution (10 milliliters), make separatory handles.With EtOAc (10 milliliters of 2 x) aqueous phase extracted.The organic extract liquid of merging is dehydrated (MgSO4), and concentrate in a vacuum, and get (203 milligrams of part B compounds; 38%).C.?

With DIPEA (228 microlitres; 1.31 mmole) be added into (369 milligrams of part B compounds; 1.67 mmole), embodiment 26 part C compounds are (415 milligrams; 1.09 mmole) and (178 milligrams of HOAt; 1.31 mmole) in the solution in DMF (4.0 milliliters).Add (251 milligrams of EDAC; 1.31 mmole)., make reaction mixture between EtOAc (15 milliliters) and H2O (12 milliliters), make separatory and handle after following 48 hours in room temperature.Organic phase with the 0.5N HCl aqueous solution (10 milliliters), the saturated NaHCO3 aqueous solution (10 milliliters) and salt solution (10 milliliters) washing, is dehydrated (MgSO4), and concentrates in a vacuum.Make crude product chromatography (SiO2; Continuous gradient liquid, in hexane 0 to 100%EtOAc, went through 6 minutes, be converted to the 1%MeOH among the EtOAc, and kept 4 minutes, be converted to the 4%MeOH among the EtOAc then, and kept 10 minutes), and (354 milligrams of title compounds; 56%), is white solid (diastereo-isomerism mixture).[M+H] +=583.3; 1H NMR (400MHz, CDCl3): δ 1.34 (m, 6H), 1.50 (d, 3H); 3.08 (s, 3H), 3.32 (m, 1H), 3.41 (s; 3H), 3.57 (m, 3H), 4.06 (m, 2H); 4.76 (m, 1H), 6.89 (s, 2H); 7.15 (d, 2H), 7.44 (s, 1H); 7.61 (s, 1H), 7.92 (d, 2H). embodiment 54

A. isomer 1 isomer 2

With embodiment 53 part A compound (2.6 grams; 8.12 two kinds of isomer mmole) prepare HPLC through chirality and separate (Chiralpak AD, 50 centimetres of posts of 5 x, 20 μ, the constant composition under 15%50/50MeOH:EtOH; 85% heptane, 50 ml/min were gone through 2 hours).Make this material purifying in three operations.Isomer 1 had RT 38 minutes, and isomer 2 had RT 52 minutes.The wash-out fraction that contains isomer 1 is concentrated in vacuum, and get 1.07 gram (82%) glassy solids.The wash-out fraction that contains isomer 2 is concentrated in vacuum, and get 1.09 gram (84%) glassy solids.B.

isomer 2

HCl (6.0 milliliters, 1, the 4.0N solution in the 4-diox) is added into partly A compound isomers 2 (1.05 grams; 3.28 mmole).After stirring 5 hours under the room temperature, concentrated reaction mixture in a vacuum.Residue is dissolved among the H2O (20 milliliters), freezing, and freeze-drying.Lyophilized products is dissolved among the MeOH (25 milliliters), and concentrates in a vacuum, and get partly B compound (0.85 gram; 100%), is the white foam thing.C.?

With (1.45 milliliters of DIPEA; 8.28 mmole) be added into partly B compound (0.85 gram; 3.31 embodiment 26 part C compound (1.05 grams mmole); 2.76 mmole) and (526 milligrams of HOAt; 3.86 mmole) in the solution in DMF (10.0 milliliters).Add (741 milligrams of EDAC; 3.86 mmole)., make reaction mixture between EtOAc (140 milliliters) and H2O (120 milliliters), make separatory and handle after following 72 hours in room temperature.Organic phase with the 0.5N HCl aqueous solution (100 milliliters), the saturated NaHCO3 aqueous solution (100 milliliters) and salt solution (80 milliliters) washing, is dehydrated (MgSO4), and concentrates in a vacuum.Crude product is divided into 4 parts, and through preparation HPLC purifying (250 millimeters posts of YMC anti-phase ODS-A-5u 30 x; Flow velocity=30 ml/min, 20 to 100% solvent B went through 20 minutes, were retained to 25 minutes, wherein, solvent orange 2 A=90: 10: 0.1H2O: MeOH: TFA, and solvent B=90: 10: 0.1MeOH: H2O: TFA).Make product through preparing HPLC purifying for the second time, use the same terms, but use CH3CN to replace MeOH, and get (920 milligrams of title compounds; 57%), is white solid.[M+H]+＝583.0；1H?NMR(400MHz，CDCl3)：δ1.33(m，6H)，1.45(d，3H)，3.07(s，3H)，3.34(m，1H)，3.40(s，3H)，3.55(q，2H)，3.86(m，1H)，4.05(m，2H)，4.70(m，1H)，6.77(d，1H)，6.86(s，1H)，7.14(d，2H)，7.49(s，1H)，7.62(s，1H)，7.91(d，2H)。Embodiment 55

Title compound (133 milligrams, 44% thick productive rate, white solid) adopts method described in the embodiment 54, and system is from embodiment 54 part A isomer 1.[M+H]+＝583.2；1H?NMR(400MHz，CDCl3)：δ1.33(m，6H)，1.45(d，3H)，3.07(s，3H)，3.32(m，1H)，3.40(s，3H)，3.55(q，2H)，3.77(m，1H)，4.06(m，2H)，4.70(m，1H)，6.77(d，1H)，6.86(s，1H)，7.14(d，2H)，7.47(s，1H)，7.59(s，1H)，7.91(d，2H)。Embodiment 56

With the 2.0N NaOH aqueous solution (81 microlitres; 0.162 mmole) be added into (31.5 milligrams of embodiment 55 compounds; 0.054 mmole) in the mixture in EtOH (70 microlitre) and THF (70 microlitre).After 16 hours, make mixture between the EtOAc (2 milliliters) and the 0.5N HCl aqueous solution (1 milliliter), make separatory and handle.Organic phase with salt solution (1 milliliter) washing, is dehydrated (MgSO4), and concentrate in a vacuum, and get (27.4 milligrams of title compounds; 91%), is white solid.[M+H]+＝555.0；1H?NMR(400MHz，CDCl3)：δ1.28(d，3H)，1.37(d，3H)，3.10(s，3H)，3.21(d，2H)，3.43(s，3H)，3.59(q，2H)，4.77(m，1H)，6.74(s，1H)，6.92(s，1H)，7.20(d，2H)，7.70(s，1H)，7.77(s，1H)，7.93(d，2H)。Embodiment 57

With the 2.5N NaOH aqueous solution (131 microlitres; 0.328 mmole) be added into (67 milligrams of embodiment 37 compounds; 0.109 mmole) in the solution in MeOH (130 microlitre) and THF (130 microlitre).Solution was heated 20 hours down at 50 ℃, be cooled to room temperature then, and between the EtOAc (4 milliliters) and the 1.0N HCl aqueous solution (2 milliliters), make separatory and handle.Organic phase with salt solution (2 milliliters) washing, is dehydrated (MgSO4), and concentrate in a vacuum.Make crude product through preparing HPLC purifying (100 millimeters posts of YMC anti-phase ODS-A-5 micron 30 x; Flow velocity=40 ml/min, 15 to 100% solvent B went through 10 minutes, were retained to 12 minutes, wherein, solvent orange 2 A=90: 10: 0.1H2O: ACN: TFA, and solvent B=90: 10: 0.1ACN: H2O: TFA), and get white solid.Make this material pass through preparation HPLC purifying (, but using MeOH to replace ACN) for the second time, and get (30 milligrams of title compounds like above-mentioned the same terms; 47%), is white solid.[M+H]+＝585.0；1HNMR(400MHz，CD3OD)：δ1.30(m，6H)，3.12(s，3H)，3.28(d，2H)，3.37(s，3H)，3.56(m，2H)，4.05(m，2H)，4.71(m，1H)，6.96(m，2H)，7.24(d，2H)，7.31(s，1H)，7.48(s，1H)，7.97(d，2H)。Examples 58 and 59?

A.?

Stir in 0 ℃ of solution in the warp of 5-methyl isophthalic acid H-pyrazoles-3-amine (260 milligrams, 2.68 mmoles) in DMF (4 milliliters), add KOtBu (601 milligrams, 5.35 mmoles).Reactant was stirred 30 minutes down in 0 ℃, dropwise add ICH then ₂PO ₃Et ₂(1116 milligrams, 4.02 mmoles).Reactant was stirred 1 hour down at 0 ℃, then be warmed to room temperature, and under room temperature, stirred 18 hours.Under 50 ℃, remove volatile matter in a vacuum.Making residue between EtOAc and salt solution, make separatory handles.With EtOAc extraction (4x) water layer, and the organic extract liquid of merging is dehydrated (MgSO4), and concentrate in a vacuum, and get brown oil.Make rough residue through preparation HPLC purifying (100 millimeters posts of Luna 5u 21.2 x; Flow velocity=20 ml/min, 0 to 100% solvent B went through 12 minutes; Be retained to 15 minutes, wherein, solvent orange 2 A=90: 10: 0.1H2O: MeOH: TFA; And solvent B=90: 10: 0.1MeOH: H2O: TFA), and get partly A compound (1: 1 mixture, 80 milligrams; 12%), is white solid.B.?

In the solution at room temperature of embodiment 26C acid (0.110 gram, 0.288 mmole) in DMF (4.5 milliliters), add EDC (0.110 gram, 0.576 mmole), HOAT (0.078 gram, 0.576 mmole) and DIEA (0.088 milliliter, 0.5004 mmole).Even yellow solution was stirred 30 minutes down in 25 ℃.Add the partly solution of A compound (0.100 gram, 288 mmoles) in DIEA (0.088 milliliter, 0.5004 mmole) and DMF (1.5 milliliters), and even yellow reaction mixture was stirred 2 hours down in 25 ℃, pour into then in the water (15 milliliters).With EtOAc (10 milliliters) extraction mixture; Make organic phase dehydrate (MgSO4), and concentrate in a vacuum.Make residue through preparing HPLC purifying (250 millimeters posts of Phenomenex Luna 5 μ C1830 x; Under 220 nanometers, detect; Flow velocity=20 ml/min; Continuous gradient liquid, from 100%A to 100%B, go through 30 minutes+under 100%B, kept 7 minutes, wherein, A=90: 10H2O: MeOH, and B=90: 10MeOH: H2O), so that yellow foam thing (mixtures of two kinds of regional isomers) to be provided.

Regional isomer is prepared the HPLC separation through chirality, and (50 centimetres of AD posts of 5 centimetres of x detect constant composition 50: 50EtOH: MeOH moving phase under 220 nanometers; 50 ml/min flows), so that title compound 58 (27 milligrams, 15.2% productive rate) to be provided; Be the tawny solid; With title compound 59 (64 milligrams, 36.3% productive rate), be pale solid.

Embodiment 58: [M+H] +=610.4; 1H NMR (400MHz, CDCl3) δ 10.56 (s, 1H), 7.91 (d, J=8.79Hz, 2H), 7.52 (t, J=1.75,1.76Hz; 1H), 7.37 (t, J=1.75,1.32Hz, 1H), 7.15 (d, J=8.79Hz, 2H), 6.83 (t; J=2.20Hz, 1H), 6.44 (s, 1H), 4.64-4.74 (m, 1H), 4.50 (d, J=10.55Hz, 2H); 3.97-4.17 (m, 4H), 3.49-3.64 (m, 2H), 3.42 (s, 3H), 3.07 (s, 3H); 2.26 (s, 3H), 1.36 (d, J=6.15Hz, 3H), 1.27 (t, J=7.03Hz, 6H).

Embodiment 59: [M+H] +=610.4; 1H NMR (400MHz, CDCl3) δ 8.6 (s, 1H), 7.92 (d, J=8.79Hz, 2H), 7.31 (t, J=1.76Hz, 1H), 7.12-7.17 (m; 3H), 6.83 (t, J=2.19,1.76Hz, 1H), 6.66 (s, 1H), 4.57-4.69 (m, 1H), 4.37 (d; J=11.42Hz, 2H), 4.01-4.15 (m, 4H), 3.48-3.63 (m, 2H), 3.42 (s, 3H), 3.09 (s; 3H), 2.34 (s, 3H), 1.34 (d, J=6.59Hz, 3H), 1.29 (t, J=7.03Hz, 6H).Example 60?

A.?

In the suspension-s of 3-nitro-1H-pyrazoles (1.00 grams, 8.84 mmoles) in water (31 milliliters), interpolation formaldehyde (37 weight %, in water, 1.317 milliliters, 17.69 mmoles).With reaction mixture in stirring 48 hours (after 2 hours, this reaction mixture becomes even yellow solution) under the room temperature.Reaction mixture is diluted with the saturated NaHCO3 aqueous solution (20 milliliters), and with CH2Cl2 (40 milliliters of 4 x) and EtOAc (50 milliliters of 3 x) extraction.The organic extract liquid of merging is dehydrated (MgSO4), and concentrate in a vacuum,, be white solid so that partly A compound (1.26 grams, 99% productive rate) to be provided.1H?NMR(400MHz，CD3OD)δ7.69(d，J＝2.20Hz，1H)，6.95(d，J＝2.75Hz，1H)，5.62(d，J＝7.70Hz，2H)，4.40(t，J＝7.70，7.69Hz，1H)。B.?

In the 75 ℃ solution of part A compound (1.809 grams, 12.64 mmoles) in MeCN (54 milliliters), dropwise add PBr ₃(1.788 milliliters, 18.96 mmoles) were gone through 10 minutes.Reaction mixture was stirred 15 minutes down at 75 ℃, be cooled to room temperature then, and filter.With CH3CN (2 milliliters of 2 x) washing leaching cake, and concentrate the filtrating of merging in a vacuum.Making residue between the EtOAc (50 milliliters) and the saturated NaHCO3 aqueous solution (30 milliliters), make separatory handles.Organic phase with salt solution (20 milliliters) washing, is dehydrated (MgSO4), and concentrate in a vacuum.Make residue chromatography (SiO2: continuous gradient liquid, the 0%EtOAc/ hexane is to the 70%EtOAc/ hexane),, be light yellow oil so that partly B compound (1.693 grams, 65% productive rate) to be provided.1H?NMR(400MHz，CDCl3)δ7.80(d，J＝2.20Hz，1H)，7.01(d，J＝2.75Hz，1H)，5.98(s，2H)。C.?

In the solution of part B compound (1.7366 grams, 8.43 mmoles) in THF (4 milliliters), add CH ₃P (OEt) ₂(1.377 grams, 10.12 mmoles).Reaction mixture was stirred 15 hours down in 75 ℃.Add other CH ₃P (OEt) ₂(0.53 gram, 3.89 mmoles), and reaction mixture stirred 24 hours down at 75 ℃, be cooled to room temperature then.Removing volatile matter in a vacuum, and make residue chromatography (SiO2: continuous gradient liquid, from 0%MeOH/CH2Cl2 to 15%MeOH/CH2Cl2), so that partly C compound (1.56 grams, 80% productive rate) to be provided, is orange oil.[M+H]+＝234.1；1H?NMR(400MHz，CDCl3)δ7.71(d，J＝3.30Hz，1H)，6.96(d，J＝2.75Hz，1H)，4.63(d，J＝9.34Hz，2H)，4.03-4.20(m，4H)，1.57(d，J＝14.85Hz，3H)，1.30-1.37(m，6H)。D.?

In the solution of part C compound (1.60 grams, 6.86 mmoles) in MeOH (190 milliliters), add 10%Pd/C (0.730 gram, 0.686 mmole).Reaction mixture was stirred 3 hours under H2 (gas) atmosphere.Reaction mixture is filtered through

, and concentrated filtrate in a vacuum.Indivedual steric isomers are separated on Chiralcel OJ post (50 centimetres of 5 centimetres of x, constant group becomes condition: the 40%IPA in heptane, detect under 220 nanometers; 50 ml/min flows), so that isomer D1 to be provided (0.59 gram, 42.3% productive rate); Be pale solid; With isomer D2 (0.56 gram, 40% productive rate), be the tawny solid.

Isomer D1: [M+H] +=204.1; 1H NMR (400MHz, CDCl3) δ 7.24 (d, J=2.19Hz, 1H), 5.66 (d, J=2.20Hz, 1H); 4.32 (d, J=8.79Hz, 2H), 4.02-4.17 (m, 2H), 3.59-3.81 (s, 2H); 1.48 (d, J=14.50Hz, 3H), 1.33 (t, J=7.03Hz, 3H), specific rotation=48.5 °.

Isomer D2: [M+H] +=204.1; 1H NMR (400MHz, CDCl3) δ 7.21-7.27 (m, 1H), 5.62-5.70 (m, 1H), 4.32 (d, J=8.79Hz; 2H), and 4.01-4.19 (m, 2H), 3.55-3.81 (s, 2H), 1.48 (d; J=14.50Hz, 3H), 1.33 (t, J=7.03Hz, 3H), specific rotation=-49.6 °.E.?

In the solution at room temperature of embodiment 26 part C compounds (0.120 gram, 0.315 mmole) in DMF (6 milliliters), add EDAC (0.121 gram, 0.631 mmole), HOAT (0.086 gram, 0.631 mmole) and DIEA (0.165 milliliter, 0.946 mmole).Reaction mixture was at room temperature stirred 30 minutes, and add partly D1 compound (0.064 gram, 0.315 mmole).Reaction mixture was stirred under room temperature 18 hours.Reaction mixture is poured in the water (40 milliliters), and with EtOAc (15 milliliters of 3 x) extraction mixture.Concentrate the organic extract liquid of merging in a vacuum.Make residue through preparing HPLC purifying (100 millimeters posts of Phenomenex Luna5 micron C1830x; Under 220 nanometers, detect; Flow velocity=40 ml/min; Continuous gradient liquid, from 100%A to 100%B, go through 20 minutes+under 100%B, kept 2 minutes; Wherein, A=90: 10: 0.1H2O: MeOH: TFA, and B=90: 10: 0.1MeOH: H2O: TFA); So that title compound (0.121 gram, 68.1% productive rate) to be provided, be white solid.[M+H]+＝566.3；1H?NMR(400MHz，?CDCl3)：δ9.24(s，1H)，7.91(d，J＝8.78Hz，2H)，7.46(d，J＝1.76Hz，1H)，7.38(t，J＝1.76Hz，1H)，7.23(t，J＝1.76Hz，1H)，7.13(d，J＝8.79Hz，2H)，6.96(d，J＝2.19Hz，1H)，6.84(t，J＝2.20Hz，1H)，4.73-4.63(m，1H)，4.56(dd，J＝16.25，8.35Hz，1H)，4.46(dd，J＝15.82，8.35，9.67Hz，1H)，4.20-4.05(m，2H)，3.63-3.50(m，2H)，3.42(s，3H)，3.08(s，3H)，1.51(d，J＝14.5Hz，3H)，1.39-1.29(m，6H)。Embodiment 61

In the solution at room temperature of embodiment 26C acid (0.120 gram, 0.315 mmole) in DMF (6 milliliters), add EDAC (0.121 gram, 0.631 mmole), HOAT (0.086 gram, 0.631 mmole) and DIEA (0.165 milliliter, 0.946 mmole).Reaction mixture was at room temperature stirred 30 minutes, and add partly D2 compound (0.064 gram, 0.315 mmole) of embodiment 60.Reaction mixture was stirred under room temperature 18 hours, pour into then in the water (40 milliliters).With EtOAc (15 milliliters of 3 x) extraction mixture; Concentrate the organic extract liquid of merging in a vacuum.Make residue through preparing HPLC purifying (5 microns C of Phenomenex Luna, 18 30x100 millimeter posts; Under 220 nanometers, detect; Flow velocity=40 ml/min; Continuous gradient liquid, from 100%A to 100%B, go through 20 minutes+under 100%B, kept 2 minutes; Wherein, A=90: 10: 0.1H2O: MeOH: TFA, and B=90: 10: 0.1MeOH: H2O: TFA); So that title compound (0.117 gram, 65.4% productive rate) to be provided, be white solid.[M+H]+＝566.3；1H?NMR(400MHz，CDCl3)：δ9.19(s，1H)，7.92(d，J＝9.22Hz，2H)，7.46(d，J＝1.76Hz，1H)，7.37(t，J＝1.76Hz，1H)，7.22(t，J＝1.76Hz，1H)，7.13(d，J＝8.78Hz，2H)，6.96(d，J＝2.63Hz，1H)，6.85(t，J＝2.20Hz，1H)，4.72-4.62(m，1H)，4.56(dd，J＝16.25，8.35Hz，1H)，4.46(dd，J＝15.82，8.35，9.67Hz，1H)，4.19-4.05(m，2H)，3.63-3.50(m，2H)，3.42(s，3H)，3.08(s，3H)，1.51(d，J＝14.5Hz，3H)，1.38-1.29(m，6H)。Embodiment 62

In the solution at room temperature of partly A acid of embodiment 33 (0.030 gram, 0.087 mmole) in DMF (2.0 milliliters), add EDAC (0.033 gram, 0.174 mmole), HOAt (0.024 gram, 0.174 mmole) and DIEA (0.046 milliliter, 0.261 mmole).Reaction mixture was at room temperature stirred 30 minutes, add partly D1 compound (0.018 gram, 0.087 mmole) of embodiment 60 then.Reaction mixture was stirred under room temperature 18 hours, then pour in the water (20 milliliters).Mixture is extracted with EtOAc (10 milliliters of 2 x); The organic extract liquid of merging is dehydrated (MgSO4), and concentrate in a vacuum.Make residue through preparing HPLC purifying (100 millimeters posts of Phenomenex Luna 5 μ C1821.2x; Under 220 nanometers, detect; Flow velocity=40 ml/min; Continuous gradient liquid, from 100%A to 100%B, go through 15 minutes+under 100%B, kept 2 minutes; Wherein, A=90: 10: 0.1H2O: MeOH: TFA, and B=90: 10: 0.1MeOH: H2O: TFA); So that title compound (0.034 gram to be provided; Gram, 74.8% productive rate), be the stickiness pale solid.[M+H]+＝530.4；1H?NMR(400MHz，CDCl3)：δ9.16(s，1H)，7.45(d，J＝1.65Hz，1H)，7.32-7.18(m，5H)，7.06(t，J＝1.65Hz，1H)，7.03(t，J＝1.65Hz，1H)，6.98(d，J＝2.19Hz，1H)，6.64(t，J＝2.2Hz，1H)，4.69-4.56(m，2H)，4.55-4.40(m，2H)，4.18-4.04(m，2H)，3.57(dd，J＝10.45Hz，J＝6.04Hz，1H)，3.50(dd，J＝9.89Hz，J＝3.85Hz，1H)，3.41(s，3H)，3.06(dd，J＝13.74Hz，J＝6.04Hz，1H)，2.86(dd，J＝13.75Hz，J＝6.05Hz，1H)，1.53(d，J＝14.84Hz，3H)，1.35-1.27(m，9H)。Embodiment 63

(in (0.030 gram, 0.087 mmole) solution at room temperature in DMF (2.0 milliliters), add EDAC (0.033 gram, 0.174 mmole), HOAt (0.024 gram, 0.174 mmole) and DIEA (0.046 milliliter, 0.261 mmole) in partly A acid of embodiment 33.Reaction mixture was at room temperature stirred 30 minutes, add partly D2 compound (0.018 gram, 0.087 mmole) of embodiment 60 then.Reactant was stirred under room temperature 18 hours, then pour in the water (20 milliliters).With EtOAc (10 milliliters of 2x) extraction mixture, and the organic extract liquid of merging is dehydrated (MgSO4), and concentrate in a vacuum.Make residue through preparing HPLC purifying (100 millimeters posts of Phenomenex Luna 5 μ C1821.2 x; Under 220 nanometers, detect; Flow velocity=40 ml/min; Continuous gradient liquid, from 100%A to 100%B, go through 15 minutes+under 100%B, kept 2 minutes; Wherein, A=90: 10: 0.1H2O: MeOH: TFA, and B=90: 10: 0.1MeOH: H2O: TFA); So that title compound (0.03626 gram, 79% productive rate) to be provided, be the stickiness white solid.[M+H]+＝530.4；1H?NMR(400MHz，CDCl3)：δ9.17(s，1H)，7.45(d，J＝2.20Hz，1H)，7.32-7.17(m，5H)，7.06(t，J＝2.2Hz，1H)，7.03(t，J＝2.2Hz，1H)，6.98(d，J＝2.19Hz，1H)，6.64(t，J＝2.2Hz，1H)，4.70-4.57(m，2H)，4.54-4.40(m，2H)，4.17-4.03(m，2H)，3.57(dd，J＝9.90Hz，J＝6.04Hz，1H)，3.50(dd，J＝10.44Hz，J＝3.38Hz，1H)，3.41(s，3H)，3.06(dd，J＝13.74Hz，J＝6.59Hz，1H)，2.85(dd，J＝13.75Hz，J＝6.05Hz，1H)，1.52(d，J＝14.29Hz，3H)，1.36-1.26(m，9H)。Example 64? A.?

With 3,5-methyl dihydroxy benzoate (350 milligrams, 2.082 mmoles), 5-(chloro methyl) oxazolidine-2-ketone (1.0 grams; 7.38 mmole) and K2CO3 (5.75 the gram; 41.6 mmole) mixture in DMF (10 milliliters) stirred 18 hours down in 80 ℃, was cooled to room temperature then, and filtered.With the EtOAc washing leaching cake, and concentrate the filtrating of mergings in a vacuum, and must brown oil.The oil of Niobe of rough pair of alkylation is dissolved among the THF (1 milliliter), and adds the 1NNaOH aqueous solution (1 milliliter, 1.00 mmoles).Mixture was stirred under room temperature 18 hours, then concentrate in a vacuum.Make residue with the TFA acidifying, then through preparation HPLC purifying (100 millimeters posts of PhenomenexAXIA 5u C18 30 x; Under 220 nanometers, detect; Flow velocity=40 ml/min; Continuous gradient liquid from 30%A to 100%B, is gone through 10 minutes+1 minute hold-time under 100%B; Wherein, A=90: 10: 0.1H2O: MeOH: TFA, and B=90: 10: 0.1MeOH: H2O: TFA); And get partly A compound (83 milligrams, 9% productive rate), be red solid.[M+H]+＝353.1；1H?NMR(400MHz，MEOH-d4)δ3.56(dd，J＝8.79，6.60Hz，2H)3.75(t，J＝9.07Hz，2H)4.10-4.30(m，4H)4.96-5.07(m，2H)6.77-6.85(m，0H)7.22(d，J＝2.75Hz，2H)。B.?

Partly the A compound is (13 milligrams; 0.037 mmole), embodiment 13 part E compounds are (23 milligrams; 0.037 mmole), HOAt is (10 milligrams; 0.072 mmole), EDCI (20 milligrams, 0.500 mmole) and the mixture of DIPEA (0.2 milliliter, 1.148 mmoles) in DMF (0.5 milliliter) stirred 18 hours down in 21 ℃.With EtOAc (1 milliliter) diluted reaction mixture, and wash with the 1N HCl aqueous solution (1 milliliter).Make organic layer dehydrate (MgSO4), and concentrate in a vacuum.Make residue through preparing HPLC purifying (100 millimeters posts of Phenomenex AXIA 5u C18 30 x; Under 220 nanometers, detect; Flow velocity=40 ml/min; Continuous gradient liquid from 30%A to 100%B, is gone through 10 minutes+1 minute hold-time under 100%B; Wherein, A=90: 10: 0.1H2O: MeOH: TFA, and B=90: 10: 0.1MeOH: H2O: TFA); And get title compound (12.5 milligrams, 58.0% productive rate), be white solid.[M+H] +=585.3; 1H NMR (400MHz, CDCl3) δ 1.33 (t, J=7.15Hz, 6H) 3.35 (d, J=21.44Hz; 2H) 3.63 (dd, J=8.25,6.60Hz, 2H) 3.79 (t, J=8.79Hz; 2H) 4.11-4.20 (m, 4H) 4.21-4.37 (m, 4H) 4.96-5.04 (m, 2H) 5.76 (broad s., 2H) 6.80 (broad s.; 1H) 7.04 (d, J=3.85Hz, 1H) 7.44 (s, 2H).Example 65? A.?

With the suspension-s of NaH (70 milligrams of 60% suspension-s in oil, 1.750 mmoles) in THF (3 milliliters), stirred 15 minutes in 0 ℃ and N2 (gas) time.Make reactant be cooled to-30 ℃, and Tian Jia oxazolidine-2-ketone (125 milligrams, 1.436 mmoles).Mixture was stirred 30 minutes down at-30 ℃, be warmed to room temperature then, and stirred 30 minutes.Make mixture be cooled to-30 ℃ again, and add the solution of 3-(bromo methyl)-5-methoxyl methyl benzoate (200 milligrams, 0.772 mmole) in THF (2 milliliters).Mixture was stirred under room temperature 5 days, then be cooled to-30 ℃, and add the saturated NH4Cl aqueous solution (1 milliliter).With EtOAc (5 milliliters of 2 x) counterextraction water layer, and the organic extract liquid of merging is dehydrated (Na2SO4), and concentrate in a vacuum.Make residue chromatography [SiO2; EtOAc/ hexane (1: 1)], and get 184 milligrams of part A compounds, 90% productive rate), be clean oil.[M+H]+＝266.01；1H?NMR(500MHz，CDCl3)δ3.46(t，J＝7.70Hz，2H)3.85(s，3H)3.92(s，3H)4.33(t，J＝7.70Hz，2H)4.44(s，2H)7.05(s，1H)7.50(s，1H)7.54(s，1H)。B.?

Partly A compound (50 milligrams, 0.188 mmole) stirred 2 hours under room temperature with the mixture of NaOH (1 milliliter, 1.00 mmoles) in THF (2 milliliters), then with the 1N HCl aqueous solution (0.5 milliliter) acidifying.Filtering mixt, and concentrate in a vacuum; Make residue through preparing HPLC purifying (100 millimeters posts of Phenomenex AXIA 5u C18 30 x; Under 220 nanometers, detect; Flow velocity=40 ml/min; Continuous gradient liquid from 30%A to 100%B, is gone through 10 minutes+1 minute hold-time under 100%B; Wherein, A=90: 10: 0.1H2O: MeOH: TFA, and B=90: 10: 0.1MeOH: H2O: TFA); And B compound partly; Be white solid (42 milligrams, 0.167 mmole, 89%).[M+H]+＝251.98；1H?NMR(400MHz，CD3OD)δ3.53(t，J＝8.24Hz，2H)，3.84(s，3H)，4.34(t，J＝8.24Hz，2H)，4.44(s，2H)，7.09(t，J＝1.65Hz，1H)，7.49(dd，J＝2.75，1.10Hz，1H)，7.55(s，1H)。C.?

Partly the B compound is (12 milligrams; 0.048 partly (0.2 milliliter of E compound (11.95 milligrams, 0.048 mmole), HOAt (10 milligrams, 0.072 mmole), DIPEA of embodiment 13 mmole); 1.148 mmole) and (20 milligrams of EDCI; 0.500 mmole) mixture in DMF (0.5 milliliter) stirred 18 hours under room temperature, washed then with EtOAc (1 milliliter) dilution, and with the 1N HCl aqueous solution (1 milliliter).Remove volatile matter in a vacuum.Make rough residue through preparation HPLC purifying (100 millimeters posts of Phenomenex AXIA 5u C1830 x; Under 220 nanometers, detect; Flow velocity=40 ml/min; Continuous gradient liquid from 30%A to 100%B, is gone through 10 minutes+1 minute hold-time under 100%B; Wherein, A=90: 10: 0.1H2O: MeOH: TFA, and B=90: 10: 0.1MeOH: H2O: TFA); And get title compound, be clean oil (20 milligrams, 87% productive rate).[M+H]+＝483.99；1H?NMR(400MHz，CDCl3)δ1.33(t，J＝7.15Hz，6H)，3.36(d，J＝21.44Hz，2H)，3.52(s，J＝8.24，8.24Hz，2H)，3.91(s，3H)，4.12-4.22(m，J＝7.35，7.35，7.28，7.15Hz，4H)4.33(t，J＝8.25Hz，2H)，4.46(s，2H)，7.05(d，J＝3.30Hz，1H)，7.17(s，1H)，7.66(s，1H)，7.68(d，J＝2.20Hz，1H)。Example 66?

A.?

In embodiment 64 partly B compounds (177 milligrams, 0.667 mmole) in DCM (1 milliliter), in 0 ℃ of solution, add BBr ₃(1 milliliter, 1.000 mmoles).Reactant was stirred 24 hours down at 0 ℃, remove volatile matter then in a vacuum.Residue is dissolved among the MeOH (3 milliliters), and the pH value is adjusted to pH～4 with the saturated NaHCO3 aqueous solution.Remove solid through filtration, and concentrated filtrate in a vacuum.Make residue through preparing HPLC purifying (100 millimeters posts of Phenomenex AXIA 5u C18 30 x; Under 220 nanometers, detect; Flow velocity=40 ml/min; Continuous gradient liquid from 30%A to 100%B, is gone through 10 minutes+1 minute hold-time under 100%B; Wherein, A=90: 10: 0.1H2O: MeOH: TFA, and B=90: 10: 0.1MeOH: H2O: TFA); And get partly A compound (67 milligrams, 40% productive rate), be white solid.[M+H]+＝252.19；1H?NMR(400MHz，CD3OD)δ3.52(t，J＝8.24Hz，2H)，3.88(s，3H)，4.34(t，J＝8.24Hz，2H)，4.40(s，2H)，6.97(s，1H)，7.36(s，1H)，7.42(s，1H)。B.?

Partly A compound (67 milligrams, 0.267 mmole), 1-fluoro-4-(methylsulfonyl) benzene (50 milligrams, 0.287 mmole) and K2CO3 are (300 milligrams; 2.171 the solution in DMF (3 milliliters) mmole); Under 100 ℃, in ST, stirred 18 hours, be cooled to room temperature then.Leach solid, and concentrated filtrate in a vacuum.Make residue with the TFA acidifying, then through preparation HPLC purifying (100 millimeters posts of 5 microns C18 of Phenomenex AXIA, 30 x; Under 220 nanometers, detect; Flow velocity=40 ml/min; Continuous gradient liquid from 30%A to 100%B, is gone through 10 minutes+1 minute hold-time under 100%B; Wherein, A=90: 10: 0.1H2O: MeOH: TFA, and B=90: 10: 0.1MeOH: H2O: TFA); And get partly B compound (73 milligrams, 69.9% productive rate), be white solid.[M+H]+＝392.01；1H?NMR(400MHz，CD3OD)δ3.12(s，3H)，3.57(t，J＝8.24Hz，2H)，4.36(t，J＝8.24Hz，2H)，4.50(s，2H)，7.20(d，J＝8.79Hz，2H)，7.32(s，1H)，7.63(s，1H)，7.84(s，1H)，7.96(d，J＝8.79Hz，2H)。C.?

Partly the B compound is (15 milligrams; 0.038 mmole), embodiment 13 part E compounds are (9.59 milligrams; 0.038 mmole), HOAt is (10 milligrams; 0.072 mmole), EDCI (20 milligrams, 0.500 mmole) and the mixture of DIPEA (0.2 milliliter, 1.148 mmoles) in DMF (0.5 milliliter) stirred 18 hours down in 25 ℃.With EtOAc (1 milliliter) diluted mixture thing, and wash with the 1N HCl aqueous solution (1 milliliter).Make organic phase dehydrate (MgSO4), and concentrate in a vacuum.Make residue through preparing HPLC purifying (100 millimeters posts of Phenomenex AXIA 5u C18 30 x; Under 220 nanometers, detect; Flow velocity=40 ml/min; Continuous gradient liquid from 30%A to 100%B, is gone through 10 minutes+1 minute hold-time under 100%B; Wherein, A=90: 10: 0.1H2O: MeOH: TFA, and B=90: 10: 0.1MeOH: H2O: TFA); And get title compound (17 milligrams, 70% productive rate), be white solid.[M+H]+＝624.2；1H?NMR(400MHz，CDCl3)(1.32(t，J＝7.15Hz，6H)，3.07(s，3H)，3.33(d，J＝21.44Hz，2H)，3.64(t，J＝7.70Hz，2H)，4.15(dd，J＝8.25，7.15Hz，4H)，4.35(t，J＝8.24Hz，2H)，4.51(s，2H)，7.05(d，J＝3.85Hz，1H)，7.14(d，J＝8.79Hz，2H)，7.40(s，1H)，7.76(t，J＝1.65Hz，1H)，7.89-7.96(m，3H)。Example 67?

A.?

With 3,5-methyl dihydroxy benzoate (10 grams, 59.5 mmoles) stirred 2 hours down in 120 ℃ with the mixture of K2CO3 (13 grams, 94 mmoles) in DMF (50 milliliters).Add the solution of 1-fluoro-4-(methylsulfonyl) benzene (5 grams, 28.7 mmoles) in DMF (10 milliliters), and with reactant 120 ℃ of following restir 24 hours.Filter reaction mixture, and the filter cake that is formed with DMF (50 milliliters) flushing.Concentrate the filtrating of merging in a vacuum.Making residue between the EtOAc (100 milliliters) and the 1N HCl aqueous solution (100 milliliters), make separatory handles.With EtOAc (50 milliliters of x 3) aqueous layer extracted, and the organic extract liquid that will merge dehydrates (Na2SO4) with water washing, filters, and concentrates in a vacuum.Make rough residue chromatography (SiO2; EtOAc/ hexane 1: 3), and gets partly A compound (4 grams, 43% productive rate), be yellow solid.[M+H]+＝323.0；1H?NMR(400MHz，CDCl3)δ3.08(s，3H)，3.91(s，3H)，6.13(s，1H)，6.80(t，J＝2.20Hz，1H)，7.11(d，J＝8.79Hz，2H)，7.27-7.28(m，1H)，7.41-7.44(m，1H)，7.91(d，J＝8.79Hz，2H)。B.?

Under 0 ℃, in 5-(chloromethyl)-2H-tetrazolium (0.5 gram, 4.22 mmoles) in Et2O (5 milliliters) in stirred solution; Dropwise add system from (700 milligrams of 1-methyl-3-nitros-1-nitrosoguanidine; 4.76 mmole) with the CH of the 40%KOH aqueous solution (4 gram, 28.5 mmoles, 10 ml waters) ₂N ₂At Et ₂Solution among the O (5 milliliters).Reaction soln is remained under 0 ℃ during adding, and reactant was at room temperature stirred 1 hour, use airflow to concentrate then.In vacuum, remove residual solvent, and get partly B isomeric compound, be yellow oils (400 milligrams, 71.5% productive rate).C.?

Partly the mixture of A compound (100 milligrams, 0.310 mmole), part B compound (41.1 milligrams, 0.310 mmole) and K2CO3 (300 milligrams, 2.17 mmoles) under 100 ℃, stirred 18 hours in ST, was cooled to room temperature then.With EtOAc (5 milliliters) diluted reaction mixture, and wash with H2O (5 milliliters of x 2); Make organic layer dehydrate (Na2SO4), and concentrate in a vacuum, and get yellow oil.This rough methyl esters was stirred 2 hours with THF (1 milliliter) is middle at the 1N NaOH aqueous solution (0.5 milliliter, 0.500 mmole).Reactant is concentrated in a vacuum, and with the TFA acidifying.Two kinds of isomer are separated (100 millimeters posts of Phenomenex AXIA 5u C18 30 x through preparation HPLC; Under 220 nanometers, detect; Flow velocity=40 ml/min; Continuous gradient liquid from 30%A to 100%B, is gone through 10 minutes+1 minute hold-time under 100%B; Wherein, A=90: 10: 0.1H2O: MeOH: TFA, and B=90: 10: 0.1MeOH: H2O: TFA); And get the partly compound (40 milligrams, 31% productive rate) of C1, be white solid; Compound (72 milligrams, 57% productive rate) with part C2 is white solid.

Part C1 compound: [M+H] +=405.1; 1H NMR (400MHz, DMSO-d6) δ 3.22 (s, 3H), 4.13 (s, 3H), 5.63 (s, 2H), 7.20-7.28 (m, 4H), 7.49 (s, 1H), 7.95 (d, J=8.79Hz, 2H), 13.35 (s, 1H).

Part C2 compound: [M+H] +=405.1; 1H NMR (400MHz, DMSO-d6) δ 3.21 (s, 3H), 4.38 (s, 3H), 5.47 (s, 2H), 7.18 (d, J=5.50Hz, 2H), 7.24 (d, J=8.79Hz, 2H), 7.44 (s, 1H), 7.94 (d, J=8.79Hz, 2H), 13.30 (s, 1H).D.?

Partly the C1 compound is (12 milligrams; 0.030 mmole), embodiment 13 part E compounds are (7.43 milligrams; 0.030 mmole), HOAt is (10 milligrams; 0.072 mmole), EDCI (20 milligrams, 0.500 mmole) and the mixture of DIPEA (0.2 milliliter, 1.148 mmoles) in DMF (0.5 milliliter) stirred 18 hours down in 25 ℃.With EtOAc (1 milliliter) diluted reaction mixture, and wash with the 1N HCl aqueous solution (1 milliliter).Make organic layer dehydrate (Na2SO4), and concentrate in a vacuum.Make residue through preparing HPLC purifying (100 millimeters posts of 5 microns C18 of PhenomenexAXIA, 30 x; Under 220 nanometers, detect; Flow velocity=40 ml/min; Continuous gradient liquid from 30%A to 100%B, is gone through 10 minutes+1 minute hold-time under 100%B; Wherein, A=90: 10: 0.1H2O: MeOH: TFA, and B=90: 10: 0.1MeOH: H2O: TFA); And get title compound (12 milligrams, 64% productive rate), be white solid.[M+H]+＝636.99；1H?NMR(400MHz，CDCl3)δ1.30(t，J＝6.87Hz，6H)，3.08(s，3H)，3.29(d，J＝21.44Hz，2H)，4.08-4.17(m，J＝7.56，7.56，7.42，7.15Hz，4H)，4.18(s，3H)，5.56(s，2H)，6.98(s，1H)，7.03(d，J＝3.30Hz，1H)，7.15(d，J＝8.79Hz，2H)，7.50(s，1H)，7.80(s，1H)，7.94(d，J＝8.79Hz，2H)。Embodiment 68

With (12 milligrams of embodiment 67 part C2 compounds; 0.030 mmole), embodiment 13 part E compounds are (7.43 milligrams; 0.030 mmole), HOAt is (10 milligrams; 0.072 mmole), DIPEA (0.2 milliliter, 1.148 mmoles) and the mixture of EDCI (0.500 milliliter, 0.500 mmole) in DMF (0.5 milliliter) stirred 18 hours down in 25 ℃.Reaction mixture is diluted with EtOAc (1 milliliter), and wash with the 1N HCl aqueous solution (1 milliliter).Make organic layer dehydrate (Na2SO4), and concentrate in a vacuum.Make residue through preparing HPLC purifying (100 millimeters posts of 5 microns C of Phenomenex AXIA, 18 30 x; Under 220 nanometers, detect; Flow velocity=40 ml/min; Continuous gradient liquid from 30%A to 100%B, is gone through 10 minutes+1 minute hold-time under 100%B; Wherein, A=90: 10: 0.1H2O: MeOH: TFA, and B=90: 10: 0.1MeOH: H2O: TFA); And get title compound (10 milligrams, 53% productive rate), be white solid.[M+H]+＝637.00；1H?NMR(400MHz，CDCl3)δ1.30(t，J＝7.15Hz，6H)，3.07(s，3H)，3.32(d，J＝21.44Hz，2H)，4.07-4.17(m，J＝7.35，7.35，7.28，7.15Hz，4H)，4.39(s，3H)，5.48(s，2H)，6.97-7.02(m，2H)，7.15(d，J＝8.79Hz，2H)，7.49(s，1H)，7.78(s，1H)，7.93(d，J＝8.79Hz，2H)。Example 69? A.?

With 1-(bromo methyl)-4-anisole (2.151 milliliters, 14.92 mmoles), 3,5-methyl dihydroxy benzoate (5 grams, 29.7 mmoles) and the mixture of K2CO3 (12.33 grams, 89 mmoles) in MeCN (100 milliliters) stirred 3 days down in 80 ℃.Reactant with water (50 milliliters) dilution, is acidified to pH～2 with 12N HCl (30 milliliters), and extracts with EtOAc (20 milliliters of x 3).The organic extract liquid that makes merging dehydrates (Na2SO4) with water washing, and concentrates in a vacuum.Make residue chromatography (SiO2: EtOAc/ hexane 1: 3), and get partly A compound (3.0 grams, 35% productive rate), be white solid.1H?NMR(400MHz，CDCl3)δ3.82(s，3H)，3.90(s，3H)，5.00(s，2H)，5.14(s，1H)，6.66(t，J＝2.20Hz，1H)，6.92(d，J＝8.35Hz，2H)，7.10-7.16(m，1H)，7.22-7.29(m，1H)，7.35(d，J＝8.35Hz，2H)。B.?

In Ph ₃P (1.820 gram, 6.94 mmoles), partly in A compound (1 gram, 3.47 mmoles) and (R)-0 ℃ of solution of 1-methoxyl group propan-2-ol (0.365 milliliter, 4.16 mmoles) in anhydrous THF (5 milliliters), add DIAD (1.012 milliliters, 5.20 mmoles).Reactant was at room temperature stirred 18 hours.Remove volatile matter in a vacuum, and make residue chromatography (SiO2; The EtOAc/ hexane, 1: 5), and get rough part B compound (1.7 grams, 136%), and it is used in the next step, need not to be further purified.C.?

Rough part B compound (1.75 grams, 4.86 mmoles) was stirred 2 hours under room temperature with the solution of TFA (3 milliliters, 38.9 mmoles) in anhydrous DCM (5 milliliters).Remove volatile matter in a vacuum, and make residue chromatography (SiO2; EtOAc/ hexane 1: 5), and gets partly C compound (407 milligrams, 35%), be clean oil.[M+H] +=241.27; 1H NMR (400MHz, CDCl3) δ 1.29 (d, J=6.05Hz, 3H), 3.41 (s, 3H), 3.47-3.62 (m, 2H), 3.88 (s, 3H), 4.51-4.62 (m, 1H), 4.95 (broad s., 1H), 6.65 (s, 1H), 7.13 (dd, J=5.22,1.37Hz, 2H).D.?

Partly (300 milligrams of B compounds (166 milligrams, 1.249 mmoles) and K2CO3 of C compound (300 milligrams, 1.249 mmoles), embodiment 67 partly; 2.171 the mixture in DMF (3 milliliters) mmole); Under 100 ℃, in ST, stirred 18 hours, be cooled to room temperature then.Leach solid, and concentrated filtrate in a vacuum.Make residue with the TFA acidifying, and two kinds of isomer are separated (100 millimeters posts of Phenomenex AXIA 5u C18 30 x through preparation HPLC; Under 220 nanometers, detect; Flow velocity=40 ml/min; Continuous gradient liquid from 30%A to 100%B, is gone through 10 minutes+1 minute hold-time under 100%B; Wherein, A=90: 10: 0.1H2O: MeOH: TFA, and B=90: 10: 0.1MeOH: H2O: TFA); And get partly D1 compound (160 milligrams, 40% productive rate), be white solid; With part D2 compound (33 milligrams, 8.2% productive rate), be white solid.

Part D1 compound: [M+H] +=323.15; 1H NMR (400MHz, CDCl3) δ 1.31 (d, J=6.05Hz, 3H), 3.43 (s, 3H), 3.50-3.64 (m, 2H); 4.18 (s, 3H), 4.57-4.67 (m, 1H), 5.47 (s, 2H), 6.82 (t, J=2.47Hz; 1H), 7.30 (dd, J=2.20,1.10Hz, 1H), 7.35 (s, 1H).

Part D2 compound: [M+H] +=323.18; 1H NMR (400MHz, CDCl3) δ 1.32 (d, J=6.05Hz, 3H), 3.42 (s, 3H), 3.48-3.62 (m, 2H); 4.39 (s, 3H), 4.55-4.64 (m, 1H), 5.35 (s, 2H), 6.86 (t, J=2.47Hz; 1H), 7.34 (s, 1H), 7.37 (dd, J=2.20,1.10Hz, 1H).E.?

Partly the D1 compound is (15 milligrams; 0.047 mmole), embodiment 13 part E compounds are (11.65 milligrams; 0.047 mmole), HOAt is (10 milligrams; 0.072 mmole), EDCI (20 milligrams, 0.500 mmole) and the mixture of DIPEA (0.2 milliliter, 1.148 mmoles) in DMF (0.5 milliliter) stirred 18 hours down in 25 ℃.With EtOAc (1 milliliter) diluted reaction mixture, and wash with the 1N HCl aqueous solution (1 milliliter).Make organic phase dehydrate (Na2SO4), and concentrate in a vacuum.Make residue through preparing HPLC purifying (100 millimeters posts of Phenomenex AXIA 5u C1830x; Under 220 nanometers, detect; Flow velocity=40 ml/min; Continuous gradient liquid from 30%A to 100%B, is gone through 10 minutes+1 minute hold-time under 100%B; Wherein, A=90: 10: 0.1H2O: MeOH: TFA, and B=90: 10: 0.1MeOH: H2O: TFA); And get title compound (13 milligrams, 50% productive rate), be white solid.[M+H]+＝555.3；1H?NMR(400MHz，CDCl3)δ1.28-1.35(m，9H)，3.29-3.36(m，2H)，3.40(s，3H)，3.49-3.61(m，2H)，4.09-4.19(m，7H)，4.74(td，J＝6.19，3.79Hz，1H)，5.49(s，2H)，6.84(t，J＝2.15Hz，1H)，7.03(d，J＝3.54Hz，1H)，7.47(t，J＝1.77Hz，1H)，7.49(dd，J＝2.02，1.52Hz，1H)。Embodiment 70

(10 milligrams of title compounds; 58% productive rate; Water white oil) adopts the method described in the embodiment 69 part E to be synthesized into, just in order, use embodiment 69 part D2 to replace embodiment 69 part D1.[M+H]+＝555.3；1H?NMR(400MHz，CDCl3)δ1.25-1.37(m，9H)，3.26-3.37(m，2H)，3.40(s，3H)，3.47-3.62(m，2H)，4.06-4.19(m，4H)，4.38(s，3H)，4.71(td，J＝6.19，4.04Hz，1H)，5.40(s，2H)，6.86(t，J＝2.27Hz，1H)，6.98(d，J＝3.54Hz，1H)，7.40(d，J＝1.52Hz，1H)，7.45(d，J＝1.52Hz，1H)。Example 71?

A.?

In FeCl ₃(100 milligrams, 0.62 mmole) add 2-(chloro methyl) oxyethane (111.2 grams, 1202 mmoles), and stir, during going through 10 minutes in the solution among the HOAc (68.8 milliliters, 1202 mmoles).Mixture is heated down at 70 ℃, and stirred 24 hours, be cooled to room temperature then, and filter, and get partly A compound (183 grams, 100% productive rate), be yellow oil.1H?NMR(400MHz，CDCl3)2.11(s，3H)，3.57-3.66(m，2H)，4.05-4.12(m，1H)，4.21(t，J＝4.83Hz，2H)。B.?

In rough part A compound (183 grams, 1202 mmoles), add pTsOH (1 gram, 5.26 mmoles), then dropwise add ethyl vinyl ether (118 milliliters, 1232 mmoles), during going through 2 hours.Making the flask cooling, is 35-37 ℃ to keep temperature of reaction.After adding completion, mixture was heated 18 hours down at 40-45 ℃, be cooled to room temperature then, and get rough part B compound (270 grams, 100%), be red liquid.C.?

In the 110 ℃ solution of NaOH (110 grams, 2750 mmoles) in water (110 milliliters), add partly B compound (270 grams, 1202 mmoles), during going through 1.5 hours.Reaction mixture was refluxed 4 hours again, be cooled to room temperature then, and wash with water (110 milliliters).With DCM (110 milliliters) aqueous layer extracted, and the organic extract liquid of merging is concentrated in a vacuum, and get brown oil.Distillation (boiling point=45-50 ℃, under 0.5 mm Hg) obtains partly C compound (15 grams, 8.5%), is clean oil.1H?NMR(400MHz，CDCl3)δ1.15(t，J＝7.15Hz，3H)，1.25(d，J＝5.50Hz，3H)，3.44(dd，J＝9.34，7.15Hz，1H)，3.56(q，J＝7.15Hz，1H)，4.55-4.84(m，4H)。D.?

Make the solution of part C compound (15 grams, 103 mmoles) in MeOH (5.26 milliliters, 125 mmoles) be cooled to 15-18 ℃, and add p-TsOH (100 milligrams, 0.581 mmole), and stir.Reaction mixture was stirred 45 minutes, add NaHCO3 (50 milligrams, 0.595 mmole) then.In 35-40 ℃ (0.1 mm Hg) distillation down, obtain rough part D compound (7.0 grams, 95%), be clean oil.E.?

In part D compound (7 gram, 94 mmoles) and p-TsCl (12.8 grams, 67.1 mmoles) in water (15 milliliters) in well-beaten 50 ℃ of solution, dropwise add the solution of NaOH (2.69 grams, 67.1 mmoles) in water (15 milliliters).Reactant was heated 1 hour down at 50 ℃, be cooled to room temperature then, and add toluene (10 milliliters).With toluene (5 milliliters of x 2) aqueous layer extracted.The organic extract liquid that will merge is with dense NH ₄OH (3x) and water (2x) washing then concentrate in a vacuum.Hexane (50 milliliters) is added in the residue, and forms solid, it is collected through filtering, dried in vacuum is 1 hour then, and gets partly E compound (10 grams, 65% productive rate), is white solid.[M+H]+＝229.1；1H?NMR(400MHz，CDCl3)δppm?2.46(s，3H)，4.64-4.75(m，4H)，5.27-5.34(m，1H)，7.37(d，J＝8.25Hz，2H)，7.78(d，J＝8.25Hz，2H)。F.?

With embodiment 67 part A compounds (450 milligrams, 1.396 mmoles), part E compound (500 milligrams, 2.190 mmoles) and K2CO3 (2.7 grams; 19.54 the mixture in DMF (5 milliliters) mmole); In ST, stirred 18 hours down at 110 ℃, be cooled to room temperature then.The filtering reaction thing with the DMF wash solids, and concentrates the filtrating of merging in a vacuum.Residue is neutralized with TFA, and through preparation HPLC purifying (100 millimeters posts of Phenomenex AXIA 5u C1830x; Under 220 nanometers, detect; Flow velocity=40 ml/min; Continuous gradient liquid from 30%A to 100%B, is gone through 10 minutes+100%B, 1 minute hold-time down; Wherein, A=90: 10: 0.1H2O: MeOH: TFA, and B=90: 10: 0.1MeOH: H2O: TFA); And get partly F compound (220 milligrams, 42% productive rate), be white solid.[M+H]+＝365.2；1H?NMR(400MHz，CDCl3)δ3.08(s，3H)，4.78(dd，J＝7.15，4.95Hz，2H)，5.02(t，J＝6.87Hz，2H)，5.23-5.31(m，1H)，6.75(t，J＝1.92Hz，1H)，7.13(d，J＝8.79Hz，2H)，?7.18(s，1H)，7.39(s，1H)，7.93(d，J＝8.24Hz，2H)。G.?

Partly the F compound is (14 milligrams; 0.038 mmole), embodiment 13 part E compounds are (9.62 milligrams; 0.038 mmole), HOAt (10 milligrams, 0.072 mmole), EDCI (20 milligrams, 0.500 mmole) and DIPEA are (0.2 milliliter; 1.148 mmole) mixture in DMF (0.5 milliliter) stirred 18 hours down in 40 ℃, was cooled to room temperature then.Making reaction mixture between the EtOAc (1 milliliter) and the 1N HCl aqueous solution (1 milliliter), make separatory handles.Make organic layer dehydrate (Na ₂SO4), and in a vacuum concentrate.Make residue through preparing HPLC purifying (100 millimeters posts of 5 microns C 1830x of Phenomenex AXIA; Under 220 nanometers, detect; Flow velocity=40 ml/min; Continuous gradient liquid from 30%A to 100%B, is gone through 10 minutes+1 minute hold-time under 100%B; Wherein, A=90: 10: 0.1H2O: MeOH: TFA, and B=90: 10: 0.1MeOH: H2O: TFA); And get title compound (13 milligrams, 55.6% productive rate), be white solid.[M+H]+＝597.2；1H?NMR(400MHz，CDCl3)δ1.28(t，J＝7.03Hz，6H)，3.08(s，3H)，3.34(d，J＝21.09Hz，2H)，4.04-4.16(m，4H)，4.75(dd，J＝7.47，4.83Hz，2H)，5.05(t，J＝6.81Hz，2H)，5.36-5.45(m，J＝5.49，5.38，5.33，5.33Hz，1H)，6.82(t，J＝2.20Hz，1H)，6.96(d，J＝3.52Hz，1H)，7.15(d，J＝8.79Hz，2H)，7.24(s，1H)，7.42(s，J＝1.76，1.76Hz，1H)，7.94(d，J＝9.23Hz，2H)。Example 72?

A.?

Under 0 ℃, the TFAA that will cool off in advance (25 milliliters, 177 mmoles) is added in the D-oxysuccinic acid (5 grams, 37.3 mmoles), and stirs.This suspension-s was at room temperature stirred 2 hours, in vacuum, concentrate then.Add anhydrous benzylalcohol (25 milliliters, 240 mmoles), and with solution stirred overnight at room temperature.Remove volatile matter (benzylalcohol and TFAA) in a vacuum.Make residue chromatography [SiO2; The EtOAc/ hexane (1: 1+0.5%TFA)], and get partly A compound (7.9 grams, 94% productive rate), be water white oil.1H NMR (400MHz, CDCl3) δ 2.80-2.96 (m, 2H), 4.55 (dd, J=6.19,4.42Hz, 1H), 5.24 (s, 2H), 7.30-7.38 (m, 5H); [a]=+ 12.191.4%w/v, in DMF, under 589 nanometers.B.?

In part A compound (7.9 grams, 35.2 mmoles) and the solution of Et3N (5.6 milliliters, 40.2 mmoles) in toluene (120 milliliters), slowly add Ph ₂PON ₃(8.64 milliliters, 40.0 mmoles) are gone through～30 minutes.Made reaction mixture refluxed 2 hours, and stirred 2 hours down, be cooled to room temperature then, and under room temperature, stirred 3 days at 70 ℃.Remove volatile matter in a vacuum; Make residue soluble in water, and extract with EtOAc (20 milliliters of x 3).The organic extract liquid that will merge dehydrates (Na2SO4) with saturated NaHCO3 solution washing, and concentrates in a vacuum.Make residue chromatography [SiO2; EtOAc/ hexane (1: 1)], and get partly B compound (2.28 grams, 27.5% productive rate), be the light color solid.[M+H] +=222.16; 1H NMR (400MHz, CDCl3) δ 3.58-3.73 (m, 1H), 3.86 (t, J=9.35Hz, 1H), 5.02 (dd, J=9.60,5.56Hz, 1H), 5.24 (d, J=1.77Hz, 2H), 6.40 (br.s., 1H), 7.36 (s, 5H); [a]=-4.561.2%w/v, in DMF, under 589 nanometers.C.?

In the 0 ℃ suspension-s of part B compound (2.28 grams, 10.31 mmoles) in EtOH (50 milliliters), slowly add NaBH ₄(0.390 gram, 10.31 mmoles).Mixture was stirred 3 hours down at 0 ℃, be warmed to room temperature then, and add saturated NH ₄The Cl aqueous solution (2 milliliters).Reactant was stirred 30 minutes, then leach solid, and concentrated filtrate in a vacuum.Make residue chromatography (SiO2; EtOAc/MeOH, 5: 1), and get partly C compound (0.966 gram, 80% productive rate), be white solid.1H NMR (400MHz, DMSO-d6) δ 3.20 (t, J=7.70Hz, 1H), 3.41-3.57 (m, 3H), 4.52 (dt, J=15.39,4.67Hz, 1H), 5.06 (t, J=5.77Hz, 1H), 7.39 (broad s., 1H); [a]=-33.111.1%w/v, in EtOH, under 589 nanometers.D.?

In DCM (15 milliliters), in they-5 ℃ of solution, slowly add MsCl (0.8 milliliter, 10.27 mmoles) in part C compound (966 milligrams, 8.25 mmoles) and pyridine (10 milliliters, 124 mmoles), went through 1 hour.After 3 hours, volatile matter is removed under minimum temperature in a vacuum.Make residue chromatography (SiO2; CH2Cl2/MeOH 95: 5v/v), and get partly D compound (1.5 grams, 93% productive rate), be colorless solid.1H NMR (400MHz, DMSO-d6) δ 3.21-3.27 (m, 4H), 3.58 (t, J=9.34Hz, 1H), 4.28-4.35 (m, 1H), 4.36-4.43 (m, 1H), 4.80-4.88 (m, 1H), 7.63 (br.s., 1H); [a]=-33.930.55%w/v, in EtOH, under 589 nanometers.E.?

With embodiment 26 part A compounds (400 milligrams, 1.241 mmoles), part D compound (242 milligrams, 1.241 mmoles) and K2CO3 (2.7 grams; 19.54 the mixture in DMF (5 milliliters) mmole) in ST, stirred 18 hours down at 110 ℃; Be cooled to room temperature then, and filter.Concentrated filtrate in a vacuum.Residue is neutralized, then through preparation HPLC purifying (100 millimeters posts of Phenomenex AXIA 5u C1830 x with TFA; Under 220 nanometers, detect; Flow velocity=40 ml/min; Continuous gradient liquid from 30%A to 100%B, is gone through 10 minutes+1 minute hold-time under 100%B; Wherein, A=90: 10: 0.1H2O: MeOH: TFA, and B=90: 10: 0.1MeOH: H2O: TFA); And get partly E compound (260 milligrams, 51.4% productive rate), be white solid.[M+H] +=408.1; 1H NMR (400MHz, CD3OD) δ 3.12 (s, 3H), 3.55 (dd, J=9.01,6.37Hz, 1H), 3.75 (t; J=9.23Hz, 1H), 4.17-4.24 (m, 1H), 4.26-4.33 (m, 1H), 4.97-5.05 (m; 1H), 6.98 (t, J=2.20Hz, 1H), 7.19 (d, J=8.79Hz, 2H); 7.30 (s, 1H), 7.47 (s, 1H), 7.95 (d, J=9.23Hz, 2H); [a]=-23.971.4%w/v, in MeOH, under 589 nanometers.F.?

Partly the E compound is (20 milligrams; 0.049 mmole), embodiment 13 part E compounds are (12.29 milligrams; 0.049 mmole), HOAt is (10 milligrams; 0.072 mmole), EDCI (20 milligrams, 0.500 mmole) and the mixture of DIPEA (0.2 milliliter, 1.148 mmoles) in DMF (0.5 milliliter) stirred 18 hours down in 25 ℃.Remove volatile matter in a vacuum, and make residue through preparing HPLC purifying (100 millimeters posts of 5 microns C18 of PhenomenexAXIA, 30 x; Under 220 nanometers, detect; Flow velocity=40 ml/min; Continuous gradient liquid from 30%A to 100%B, is gone through 10 minutes+1 minute hold-time under 100%B; Wherein, A=90: 10: 0.1H2O: MeOH: TFA, and B=90: 10: 0.1MeOH: H2O: TFA); And get title compound (17 milligrams, 51.4% productive rate), be white solid.[M+H] +=640.3; 1H NMR (400MHz, CDCl3) δ 1.31 (td, J=7.07,5.05Hz, 6H), 3.07 (s, 3H), 3.32 (d, J=21.22Hz; 2H), 3.64 (dd, J=8.84,6.32Hz, 1H), 3.82 (t, J=8.97Hz, 1H), 4.07-4.18 (m; 4H), 4.38 (d, J=4.55Hz, 2H), 4.96-5.06 (m, 1H), 6.12 (broad s., 1H), 6.93 (t; J=2.27Hz, 1H), 6.99 (d, J=3.79Hz, 1H), 7.15 (d, J=8.84Hz, 2H), 7.50 (dd; J=2.15,1.39Hz, 1H), 7.71 (t, J=1.77Hz, 1H), 7.92 (d, J=8.84Hz, 2H); E.e.=98.2% (Chiralpak AS, 4.6 millimeters internal diameters of 250 x; 10 microns, RT, 60% (50/50MeOH-EtOH): 40% heptane, 1 ml/min).Embodiment 73

(22 milligrams of title compounds; 58% productive rate; White solid) same procedure of employing described in embodiment 72, synthetic from L MALIC ACID.[M+H] +=640.3; 1H NMR (400MHz, CDCl3) δ 1.33 (t, J=7.07Hz, 6H), 3.07 (s, 3H), 3.38 (d, J=21.47Hz, 2H), 3.64 (dd; J=8.84,6.57Hz, 1H), 3.81 (t, J=8.97Hz, 1H), 4.17 (dd, J=8.21,7.20Hz, 3H); 4.29-4.37 (m, 1H), 4.40-4.48 (m, 1H), 4.99-5.08 (m, 1H), 5.91 (broad s., 1H), 6.96 (t; J=2.15Hz, 1H), 7.06 (d, J=3.79Hz, 1H), 7.15 (dq, J=8.84,4.80Hz, 1H); 7.51 (dd, 1H), 7.71 (t, J=1.52Hz, 1H), 7.93 (dq, J=8.84,4.80Hz, 1H); E.e. (chiral isomer is excessive)=99.9% (Chiralpak AS, 4.6 millimeters internal diameters of 250x; 10 microns, RT, 60% (50/50MeOH-EtOH): 40% heptane, 1 ml/min).Embodiment 74

With 2-(2; The 4-Dimethoxyphenyl) acetic acid is (20 milligrams; 0.12 partly (25 milligrams of E compounds (25 milligrams, 0.1 mmole), HOAt (20 milligrams, 0.015 mmole), EDCI of embodiment 13 mmole); 0.500 mmole) and the mixture of DIPEA (0.2 milliliter, 1.148 mmoles) in DMF (0.5 milliliter) stirred 18 hours down in 25 ℃.Concentrated reaction mixture in a vacuum, and make residue through preparing HPLC purifying (100 millimeters posts of 5 microns C of Phenomenex AXIA, 18 30 x; Under 220 nanometers, detect; Flow velocity=40 ml/min; Continuous gradient liquid from 30%A to 100%B, is gone through 10 minutes+1 minute hold-time under 100%B; Wherein, A=90: 10: 0.1H2O: MeOH: TFA, and B=90: 10: 0.1MeOH: H2O: TFA); And get title compound (2.6 milligrams, 6% productive rate), be yellow oil.[M+H]+＝429.4；1H?NMR(400MHz，CDCl3)δ1.31(t，J＝7.03Hz，6H)，3.25-3.34(d，J＝21.53Hz，2H)，3.79(s，3H)，3.80(s，3H)，3.83(s，2H)，4.09-4.18(m，4H)，6.46-6.50(m，2H)，6.91(d，J＝3.52Hz，1H)，7.15(d，1H)。Examples 75-77? Following Examples manner as in Example 74 prepared in the same manner:?

Example 78?

A.?

With embodiment 26C acid (146 milligrams, 0.384 mmole) with (COCl) ₂(2 milliliters, the 2M solution in DCM, 4 mmoles) solution in DCM (2 milliliters) stirred 18 hours under room temperature, concentrated in a vacuum then.Make rough chloride of acid be dissolved in Et ₂Among the O (5 milliliters), and the system that under 0 ℃, dropwise is added into is from the CH of 1-methyl-3-nitro-1-nitrosoguanidine (735 milligrams, 5 mmoles) with the 40%KOH aqueous solution (0.8 gram, 15 mmoles, 2 ml waters) ₂N ₂At Et ₂In 0 ℃ of solution among the O (5 milliliters).Reaction mixture was stirred under room temperature 1 hour, and under airflow, concentrate; Remove residual solvent in a vacuum.Make residue chromatography (SiO2; EtOAc/ hexane 5: 1), and gets partly A compound (130 milligrams, 84% productive rate), be yellow oil.[M+H]+＝405.2；1H?NMR(400MHz，CDCl3)δ1.28(d，J＝6.15Hz，3H)，3.03(s，3H)，3.36(s，3H)，3.43-3.57(m，2H)，4.51-4.62(m，1H)，5.86(s，1H)，6.79(t，J＝2.20Hz，1H)，?6.99(s，1H)，7.08(d，J＝8.79Hz，2H)，7.15(s，1H)，7.87(d，2H)。B.?

In anhydrous THF (2 milliliters), in they-25 ℃ of solution, add PhCO with BnOH (0.5 milliliter, 5 mmoles) in part A compound (130 milligrams, 0.321 mmole) ₂Ag (206.1 milligrams, 0.9 mmole) is at Et ₃Solution among the N (1.67 milliliters, 12 mmoles) was gone through 15 minutes.With reaction mixture at room temperature, in dark, stirred 5 hours.Make the reactant process

Filter; Concentrated filtrate in a vacuum, and make residue chromatography [SiO ₂EtOAc/ hexane (2: 1)], and get partly B compound (130 milligrams, 83.6%), be clean oil.[M+H]+＝485.2；1H?NMR(400MHz，CDCl3)δ1.28(d，J＝6.15Hz，3H)，3.05(s，3H)，3.39(s，3H)，3.44-3.50(m，1H)，3.52-3.58(m，1H)，3.62(s，2H)，4.45-4.54(m，1H)，5.14(s，2H)，6.56(t，J＝2.20Hz，1H)，6.59(t，J＝1.76Hz，1H)，6.73(d，J＝1.76Hz，1H)，7.08(d，J＝9.23Hz，2H)，7.28-7.38(m，5H)，7.86(d，J＝8.79Hz，2H)。C.?

Partly B compound (130 milligrams, 0.268 mmole) and the solution of 10%Pd-C (20 milligrams) in EtOAc (10 milliliters) are in H2 (gas; 60psi) stirred 18 hours down.Remove catalyzer through filtration, and filtrating is concentrated in a vacuum, and get partly C compound (86 milligrams, 81.4%), be clean oil.[M+H]+＝395.1；1H?NMR(400MHz，CDCl3)δ1.28(d，J＝6.15Hz，3H)，3.05(s，3H)，3.38(s，3H)，3.44-3.51(m，1H)，3.51-3.57(m，1H)，3.58(s，2H)，4.46-4.56(m，1H)，6.55(t，J＝2.20Hz，1H)，6.58(s，1H)，6.72(s，1H)，7.09(d，J＝8.79Hz，2H)，7.87(d，2H)。D.?

Partly C compound (43 milligrams, 0.109 mmole) stirred 18 hours under room temperature with (COCl) 2 (3.0 milliliters, the 2M solution in DCM, 6 mmoles) solution in DCM (3 milliliters), and is concentrated in a vacuum then.Rough chloride of acid is dissolved among the DCM (2 milliliters), and is added in embodiment 13 part E compounds (37 milligrams, 0.148 mmole) and 0 ℃ of solution of pyridine (0.2 milliliter, 2.5 mmoles) in DCM (3 milliliters), went through 15 minutes.Reactant was stirred 30 minutes down in 0 ℃, then concentrate in a vacuum.Make residue through preparing HPLC purifying (100 millimeters posts of 5 microns C18 of PhenomenexAXIA, 30 x; Under 220 nanometers, detect; Flow velocity=40 ml/min; Continuous gradient liquid from 30%A to 100%B, is gone through 10 minutes+1 minute hold-time under 100%B; Wherein, A=90: 10: 0.1H2O: MeOH: TFA, and B=90: 10: 0.1MeOH: H2O: TFA); And get title compound (20 milligrams, 29% productive rate), be yellow oil.[M+H]+＝627.3；1H?NMR(400MHz，CDCl3)δ1.21-1.34(m，6H)，3.06(s，3H)，3.23-3.34(m，2H)，3.38(s，3H)，3.44-3.51(m，1H)，3.51-3.59(m，1H)，3.77(s，2H)，4.03-4.15(m，4H)，4.46-4.58(m，1H)，6.58(t，J＝2.20Hz，1H)，6.64(s，1H)，6.79(s，1H)，6.85(d，J＝3.52Hz，1H)，7.11(d，J＝8.79Hz，2H)，7.88(d，2H)。Embodiment 79

With 2; 3-dihydrobenzo [b] [(20 milligrams of 1,4] dioxine-6-carboxylic acid (20 milligrams, 0.11 mmole), embodiment 13 part E compounds; 0.083 mmole), HOAt is (20 milligrams; 0.147 mmole), EDCI (40 milligrams, 0.21 mmole) and the solution of DIPEA (40 milligrams, 0.31 mmole) in DMF (1 milliliter) stirred 18 hours down in 25 ℃.Concentrated reaction mixture in a vacuum, and make residue through preparing HPLC purifying (100 millimeters posts of Phenomenex AXIA 5u C18 30 x; Under 220 nanometers, detect; Flow velocity=40 ml/min; Continuous gradient liquid from 30%A to 100%B, is gone through 10 minutes+1 minute hold-time under 100%B; Wherein, A=90: 10: 0.1H2O: MeOH: TFA, and B=90: 10: 0.1MeOH: H2O: TFA); And get title compound (8.2 milligrams, 24% productive rate), be white solid.[M+H]+＝413.3；1H?NMR(400MHz，CDCl3)δ1.29(t，J＝7.03Hz，6H)，3.27-3.36(d，J＝21.09Hz，2H)，4.06-4.16(m，4H)，4.28-4.37(m，4H)，6.94(d，J＝3.52Hz，1H)，6.99(d，J＝8.35Hz，1H)，7.64-7.71(m，2H)。Example 80?

A.?

With 3, (600 milligrams of 5-methyl dihydroxy benzoate (200 milligrams, 1.189 mmoles), embodiment 71 part E compounds; 2.63 mmole) and the mixture of K2CO3 (2 gram, 14.47 mmoles) in DMF (10 milliliters), in ST; Stirred 18 hours down at 115 ℃, be cooled to room temperature then.Remove solid through filtration, and wash with DMF.Concentrate the filtrating of merging in a vacuum.Residue is neutralized with TFA, and through preparation HPLC purifying (100 millimeters posts of Phenomenex AXIA 5u C 18 30 x; Under 220 nanometers, detect; Flow velocity=40 ml/min; Continuous gradient liquid from 30%A to 100%B, is gone through 10 minutes+1 minute hold-time under 100%B; Wherein, A=90: 10: 0.1H2O: MeOH: TFA, and B=90: 10: 0.1MeOH: H2O: TFA); And get partly A compound (60 milligrams, 19.0%), be white solid.[M+H]+＝267.2；1H?NMR(400MHz，CD3OD)δ4.68(dd，J＝7.15，4.95Hz，4H)，5.02(t，J＝6.60Hz，4H)，5.26-5.35(m，2H)，6.46(t，J＝2.20Hz，1H)，6.98(d，J＝2.20Hz，2H)。B.?

Partly the A compound is (21 milligrams; 0.079 mmole), embodiment 13 part E compounds are (19.74 milligrams; 0.079 mmole), HOAt (20 milligrams, 0.145 mmole), EDCI (20 milligrams, 0.500 mmole) and DIPEA are (0.2 milliliter; 1.148 mmole) mixture in DMF (0.5 milliliter) stirred 18 hours down in 25 ℃, concentrated in a vacuum then.Make residue through preparing HPLC purifying (100 millimeters posts of Phenomenex AXIA 5u C18 30 x; Under 220 nanometers, detect; Flow velocity=40 ml/min; Continuous gradient liquid from 30%A to 100%B, is gone through 10 minutes+1 minute hold-time under 100%B; Wherein, A=90: 10: 0.1H2O: MeOH: TFA, and B=90: 10: 0.1MeOH: H2O: TFA); And get title compound (25 milligrams, 63.6% productive rate), be white solid.[M+H]+＝499.3；1H?NMR(400MHz，CDCl3)(7.09(2H，d)，7.03(1H，d，J＝3.30Hz)，6.54(1H，t?J＝2.20Hz)，5.31-5.39(2H，m)，5.04(4H，t?J＝6.60Hz)，4.74(4H，dd，J＝7.70，4.95Hz)，4.10-4.19(4H，m)，3.36(1H，s)，3.31(1H，s)，1.32(6H，t?J＝6.87Hz)。Example 81?

A.?

With (100 milligrams of 3-hydroxyls-5-isopropoxy oil of Niobe; 0.476 mmole), embodiment 71 part E compounds are (180 milligrams; 0.789 mmole) and the mixture of K2CO3 (1 gram, 7.24 mmoles) in DMF (5 milliliters), in ST; Stirred 18 hours down at 115 ℃, be cooled to room temperature then.Leach solid, and wash with DMF.The filtrating of merging is concentrated in a vacuum.Residue is neutralized with TFA, and through preparation HPLC purifying (100 millimeters posts of 5 microns C18 of Phenomenex AXIA, 30 x; Under 220 nanometers, detect; Flow velocity=40 ml/min; Continuous gradient liquid from 30%A to 100%B, is gone through 10 minutes+1 minute hold-time under 100%B; Wherein, A=90: 10: 0.1H2O: MeOH: TFA, and B=90: 10: 0.1MeOH: H2O: TFA); And get partly A compound (100 milligrams, 83% productive rate), be white solid.1H?NMR(400MHz，CDCl3)δ1.35(d，J＝6.05Hz，6H)，4.59(dt，J＝12.09，6.05Hz，1H)，4.77(dd，J＝7.42，5.22Hz，2H)，5.01(t，J＝6.60Hz，2H)，5.19-5.27(m，1H)，6.52(t，J＝2.47Hz，1H)，6.94(s，1H)，7.27(s，1H)。B.?

Partly the A compound is (21 milligrams; 0.083 mmole), embodiment 13 part E compounds are (20.83 milligrams; 0.083 mmole), HOAt (20 milligrams, 0.145 mmole), EDCI (20 milligrams, 0.500 mmole) and DIPEA are (0.2 milliliter; 1.148 mmole) mixture in DMF (0.5 milliliter) stirred 18 hours down in 25 ℃, concentrated in a vacuum then.Residue is neutralized with TFA, and through preparation HPLC purifying (100 millimeters posts of 5 microns C18 of Phenomenex AXIA, 30 x; Under 220 nanometers, detect; Flow velocity=40 ml/min; Continuous gradient liquid from 30%A to 100%B, is gone through 10 minutes+1 minute hold-time under 100%B; Wherein, A=90: 10: 0.1H2O: MeOH: TFA, and B=90: 10: 0.1MeOH: H2O: TFA); And (28 milligrams of title compounds; 0.058 mmole, 69.4% productive rate), be clear wax.[M+H]+＝485.3；1H?NMR(400MHz，CDCl3)δ7.31(1H，t，J＝1.52Hz)，6.96-7.01(2H，m)，6.56(1H，t，J＝2.27Hz)，5.28-5.35(1H，m，J＝5.53，5.53，5.49，5.43Hz)，5.03(2H，t，J＝6.95Hz)，4.64-4.78(3H，m)，4.13(4H，dd，J＝8.21，7.20Hz)，3.36(1H，s)，3.30(1H，s)，1.35(6H，d，J＝6.06Hz)，1.30(6H，t，J＝7.07Hz)。Example 82?

A.?

Under Ar and room temperature, in 4-(chloro methyl) pyrazoles-2-aminocarbamic acid tert-butyl ester (249 milligrams, 1.00 mmoles) and CH ₃P (OEt) ₂In (124.2 milligrams, 1.00 mmoles) solution in MeCN (4.0 milliliters), interpolation crown-6 ethers of 18-(52.9 milligrams, 0.2 mmole), K2CO3 (138.2 milligrams, 1.00 mmoles) reach (n-Bu) 4NI (74.0 milligrams, 0.20 mmole).Reaction mixture was heated 2 hours down at 55 ℃, be cooled to room temperature then, and make the reaction cancellation with the saturated NaHCO3 aqueous solution.With EtOAc extraction (2x) mixture.The organic extract liquid that will merge dehydrates (MgSO4) with brine wash, and concentrates in a vacuum.Make oil residues chromatography (SiO2; Continuous gradient liquid, from the 0%EtOAc/ hexane to the 100%EtOAc/ hexane), so that A compound (171 milligrams, 51% material balance, 90% purity is through HPLC) to be provided partly, be water white oil.B.?

In the solution at room temperature of embodiment 82 part A compounds (171 milligrams ,～0.51 mmole) in CH2Cl2 (1.5 milliliters), [annotate: flask is installed the drying tube of CaCl2 filling ,], add TFA (0.5 milliliter) with protection separating atmospheric moisture.Reactant was at room temperature stirred 14 hours, concentrate in a vacuum then, then from the CH2Cl2 stripping.Use the oily residue, need not to be further purified or to characterize, supplying partly, C uses.C.?

With (193.4 milligrams of embodiment 26 part C acid; 0.51 mmole) solution at room temperature in CH2Cl2 (2.0 milliliters) [is annotated: the drying tube of flask being installed the CaCl2 filling; With protection separating atmospheric moisture] with (0.305 milliliter of oxalyl chloride; 2M solution in CH2Cl2,0.61 mmole) handle with DMF (0.020 milliliter).Reaction mixture was stirred under room temperature 2 hours, concentrate in a vacuum then, and be dissolved in again among the CH2Cl2 (2 milliliters).Under Ar, in this solution at room temperature, add the partly solution of B compound in CH2Cl2 (2 milliliters), then be Et3N (0.213 milliliter, 1.53 mmoles).After at room temperature 15 hours, with the CH2Cl2 diluted reaction mixture, and with saturated NaHCO3 solution washing.Make organic extract liquid dehydrate (Na2SO4), and concentrate in a vacuum.Make residue through preparing HPLC purifying (250 millimeters posts of Phenomenex Luna 5u C18 30 x; Under 220 nanometers, detect; Flow velocity=30 ml/min; Continuous gradient liquid from 20%B to 100%B, is gone through 20 minutes+5 minute hold-time under 100%B; Wherein, A=90: 10: 0.1 H2O: CH3CN: TFA, and B=10: 90: 0.1 H2O: CH3CN.TFA); So that title compound (33 milligrams, 11%) to be provided, be colourless dense viscous crude.[M+H]+＝599.2；1H?NMR(400MHz，CDCl3)∶δ11.23(br?s，1H)，7.92(d，J＝8.8Hz，2H)，7.57(t，J＝1.6Hz，1H)，7.47(t，J＝1.6Hz，1H)，7.13(d，J＝8.8Hz，2H)，6.95(s，1H)，6.87(t，J＝2.2Hz，1H)，5.22(m，2H)，4.68(m，1H)，4.05(m，2H)，3.56(ddd，J＝6.6，10.5，30.3Hz，2H)，3.39(s，1H)，3.09(s，1H)，1.51(dd，J＝13.7，17.6Hz，3H)，1.34(d，J＝6.6Hz，3H)，1.27(dt，J＝2.2，7.2Hz，3H)。Example 83?

A.?

Under Ar reaches-78 ℃; In 2-(t-butoxycarbonyl amino) thiazole-4-carboxylic acid ethyl ester (2.24 gram, 8.23 mmoles) in CH2Cl2 (25 milliliters) in stirred solution, add (25.5 milliliters of the solution of DiBALH; 1.0M; In CH2Cl2,25.5 mmoles), its speed for cause temperature keep≤-65 ℃.Reactant was stirred 20 minutes down at-65 ℃, make it be warmed to-30 ℃ then.After 30 minutes, make the reaction mixture cancellation with 1M sodium tartrate potassium solution (30 milliliters), be warmed to room temperature, and at room temperature stirred 2 hours.Make the mixture process Filter, with it with CH ₂Cl ₂Washing.Make the filtrating of merging dehydrate (Na ₂SO4), and in a vacuum concentrate.Make the oil reservoir that is formed analyse (SiO2; Continuous gradient liquid, from the 0%EtOAc/ hexane to the 100%EtOAc/ hexane), so that partly A compound (1.66 grams, 88% productive rate) to be provided, be the amorphousness white solid.B.?

Under Ar, in part A compound (310 milligrams, 1.35 mmoles) at CH ₂Cl ₂In 0 ℃ of solution in (5 milliliters), add dimethyl-chlorination time phosphono (182 milligrams, 1.62 mmoles), then be Et ₃N (0.244 milliliter, 1.75 mmoles) went through 2 minutes.Make reactant be warmed to room temperature, and under room temperature, stirred 14 hours, dilute with EtOAc then.With the 1%HCl aqueous solution and brine wash mixture.Make organic phase dehydrate (MgSO4), and concentrate in a vacuum, and get partly B compound, be water white oil (413 milligrams, 100% rough thing).This material is used in the next step, need not to be further purified.C.?

C1: at room temperature, in the solution that the warp of part B compound (410 milligrams, 1.34 mmoles) in CH2Cl2 (3 milliliters) stirs, [annotate: flask is installed the drying tube of CaCl2 filling ,], add TFA (1 milliliter) with protection separating atmospheric moisture.Reactant was stirred under room temperature 14 hours, and reaction mixture is concentrated in a vacuum, and be dissolved in again among the MeOH (5 milliliters).Make solution pass through 2 StratroSpheres ^TMPL-HCO ₃MP SPE cartridge case (0.9 milli-equivalent capacity), and evaporate eluent in a vacuum, so that partly C1 compound to be provided.The water white oil (225 milligrams) that is formed is dissolved among the CH2Cl2 (2 milliliters) again.Use this solution half the (weight ratio), and need not further characterized, supplying partly, C2 uses.

C2: under room temperature and Ar, stir in the slurries, add EDC (76.3 milligrams, 0.40 mmole) in embodiment 26 part C compounds (152 milligrams, 0.40 mmole) and the warp of HOAt (54.5 milligrams, 0.40 mmole) in CH2Cl2 (2.4 milliliters).Form clear solution soon.After 30 minutes, add the solution of part C1 compound in CH2Cl2 that derives from C1, then be iPr ₂NEt (0.028 milliliter, 0.20 mmole) and DMAP (5 milligrams, 0.04 mmole).Reactant was at room temperature stirred 16 hours, make the reaction cancellation with the saturated NH4Cl aqueous solution then, and with the EtOAc extracted twice.The organic extract liquid of merging is dehydrated (Na2SO4), and evaporation in a vacuum, and get orange oil.Make residue through preparing HPLC purifying (75 millimeters posts of Phenomenex AXIA Luna 5u 30 x; Under 220 nanometers, detect; Flow velocity=40 ml/min; Continuous gradient liquid from 0%B to 100%B, is gone through 10 minutes+10 minute hold-time under 60%B; Wherein, A=90: 10: 0.1H2O: CH3CN: TFA, and B=10: 90: 0.1H2O: CH3CN: TFA), so that (28.9 milligrams of title compounds to be provided; 13% productive rate), be wax shape white solid.[M+H]+＝569.0；1H?NMR(400MHz，CDCl3)δ11.75(br?s，1H)，7.92(d，J＝8.8Hz，2H)，7.63(t，J＝2.2Hz，1H)，7.49(t，J＝1.9Hz，1H)，7.14(d，J＝8.8Hz，2H)，6.94(s，1H)，6.87(t，J＝2.2Hz，1H)，5.20(d，J＝7.7Hz，2H)，4.70(m，1H)，3.55(ddd，J＝6.0，9.9，30.2Hz，2H)，3.40(s，1H)，3.08(s，1H)，1.53(dd，J＝2.8，14.3Hz，6H)，1.33(d，J＝6.6Hz，3H)。Example 84? A.?

In embodiment 26 part A compounds (100 milligrams, 0.310 mmole), Ph ₃In P (150 milligrams, 0.572 mmole) and trimethylene oxide-0 ℃ of solution of 2-base methyl alcohol (40 milligrams, 0.454 mmole) in THF (5 milliliters), add DIAD (0.2 milliliter, 1.029 mmoles).Reactant is at room temperature stirred 18 hours, and in vacuum, remove volatile matter.Make residue chromatography (EtOAc/ hexane, 1: 1), and get rough methyl esters.In the solution of this material in MeOH (1 milliliter), add the 1N NaOH aqueous solution (1 milliliter).Reactant was at room temperature stirred 2 hours,, and concentrate in a vacuum then with the TFA acidifying.Make residue through preparing HPLC purifying (100 millimeters posts of Phenomenex AXIA 5u C18 30 x; Under 220 nanometers, detect; Flow velocity=40 ml/min; Continuous gradient liquid from 30%A to 100%B, is gone through 10 minutes+1 minute hold-time under 100%B; Wherein, A=90: 10: 0.1H20: MeOH: TFA, and B=90: 10: 0.1MeOH: H2O: TFA); And get partly A compound (40 milligrams, 34.1% productive rate), be white solid.[M+H]+＝377.2；1H?NMR(400MHz，CDCl3)δ2.66-2.88(m，2H)，3.08(s，3H)，4.20(d，J＝3.85Hz，2H)，4.66-4.81(m，2H)，5.16-5.25(m，1H)，6.92(t，J＝2.47Hz，1H)，7.11(d，J＝8.79Hz，2H)，7.36(d，J＝2.20Hz，1H)，7.52(dd，J＝2.20，1.10Hz，1H)，7.92(d，J＝8.79Hz，2H)。B.?

Partly the A compound is (15 milligrams; 0.040 mmole), embodiment 13 part E compounds are (20 milligrams; 0.080 mmole), HOAt is (20 milligrams; 0.145 mmole), EDCI (40 milligrams, 1.000 mmoles) and the mixture of DIPEA (0.2 milliliter, 1.148 mmoles) in DMF (0.5 milliliter) stirred 18 hours down in 25 ℃.Concentrated reaction mixture in a vacuum, and make rough residue through preparation HPLC purifying (100 millimeters posts of Phenomenex AXIA 5u C18 30 x; Under 220 nanometers, detect; Flow velocity=40 ml/min; Continuous gradient liquid from 30%A to 100%B, is gone through 10 minutes+1 minute hold-time under 100%B; Wherein, A=90: 10: 0.1H2O: MeOH: TFA, and B=90: 10: 0.1MeOH: H2O: TFA); So that (9.8 milligrams of title compounds to be provided; 0.016 mmole, 39.7% productive rate), be white solid.[M+H]+＝611.3；1HNMR(400MHz，CDCl3)δ7.93(2H，d，J＝8.79Hz)，7.59(1H，s)，7.39(1H，s)，7.15(2H，d，J＝8.79Hz)，6.94-6.98(2H，m)，5.12-5.20(1H，m)，4.62-4.78(2H，m)，4.22-4.32(2H，m)，4.06-4.17(4H，m，J＝7.35，7.35，7.28，7.15Hz)，3.32(2H，d，J＝20.89Hz)，3.08(3H，s)，2.64-2.86(2H，m)，1.30(6H，t，J＝6.87Hz)。Example 85?

A.?

In the solution of KOtBu (17.1 milliliters, 17.1 mmoles) in t-BuOH (10 milliliters), dropwise add methyl-malonate (2.0 milliliters, 17.1 mmoles).In the mixture that is formed, add the warm solution of 1-chloro-4-(methylsulfonyl) 2-oil of mirbane (2.0 grams, 8.6 mmoles) in t-BuOH (10 milliliters).Reaction mixture in the heating down 15 hours that refluxes, is cooled to room temperature then, and,, dehydrates (MgSO4), and concentrate in a vacuum, so that partly A compound (2.8 grams, 100%) to be provided with water and salt solution (each 30 milliliters) washing with EtOAc (50 milliliters) dilution.B.?

In the solution of part A compound (2.8 grams, 8.6 mmoles) in DMSO (10 milliliters), add NaCl (1.0 grams, 17.1 mmoles) and water (2 milliliters, 111 mmoles).Mixture was heated 5 hours down at 120 ℃, be cooled to room temperature then, and dilute with EtOAc (50 milliliters).Organic layer with water and salt solution (each 35 milliliters) washing, is dehydrated (MgSO4), and concentrates in a vacuum.Make residue chromatography (SiO2; 30 minutes gradient liquid, from 100% to 0% hexane/EtOAc), so that partly B compound (863 milligrams, 37% productive rate is gone through 2 steps) to be provided.C.?

In part B compound (830 milligrams, 3.0 mmoles) and the solution of Ac2O (2.0 milliliters, 21.6 mmoles) in toluene (10 milliliters), slowly add 10%Pd/C (200 milligrams, 1.7 mmoles).Reactant was stirred 4 hours under H2 atmosphere (gas) (1 normal atmosphere) and room temperature.Leach catalyzer, and wash with toluene (2x).The filtrating of merging is concentrated in a vacuum, so that rough part C compound (398 milligrams, 46%) to be provided.D.?

In the 90-95 ℃ solution of part C compound (398 milligrams, 1.4 mmoles) in AcOH (6 milliliters), dropwise add nitrite tert-butyl (0.18 milliliter, 1.5 mmoles).Reactant was stirred 30 minutes down at 95 ℃.Make reactant be cooled to room temperature, and dilute with EtOAc (30 milliliters).Organic layer with water (15 milliliters) and salt solution (15 milliliters) washing, is dehydrated (MgSO4), and concentrates in a vacuum, till solid precipitation.Collect this solid sediment through filtering, and with toluene wash, and get partly D compound (280 milligrams, 79% productive rate), and it is used in the next step, need not to be further purified.E.?

In the solution of part D compound (30 milligrams, 0.12 mmole) in CH3CN (1.5 milliliters), interpolation 1-(chloro methyl)-4-(methylsulfonyl) benzene (72.4 milligrams, 0.35 mmole), K2C03 (48.9 milligrams, 0.35 mmole) reach (n-Bu) ₄NI (3.5 milligrams, 9.4 micromoles).Reactant was stirred 3 hours down at 80 ℃, be cooled to room temperature then.Leach solid, and with washing with acetone.The filtrating of merging is concentrated in a vacuum, and get the partly mixture of E compound.F.?

In the solution of part E compound (0.12 mmole theoretical yield) in THF (1 milliliter), add the 1NNaOH aqueous solution (0.4 milliliter, 0.40 mmole).Reactant was at room temperature stirred 15 hours, then with EtOAc (4 milliliters) dilution, and with the 1N HCl aqueous solution (0.45 milliliter) acidifying.Organic layer with brine wash, is dehydrated (MgSO4), and concentrate in a vacuum.Make crude mixture through preparing HPLC purifying (100 millimeters posts of Phenomenex Luna AXIA 30x; Under 220 nanometers, detect; Flow velocity=25 ml/min; Continuous gradient liquid from 60%A to 100%B, was gone through 10 minutes; Wherein, A=90: 10: 0.1H2O: MeOH: TFA, and B=90: 10: 0.1MeOH: H2O: TFA); So that partly F1 compound (15.2 milligrams, 32% productive rate is gone through 2 steps) to be provided; With part F2 compound (9.0 milligrams, 19% productive rate is gone through 2 steps).G.?

In the solution of part F1 compound (7 milligrams, 0.02 mmole) in CH2Cl2 (0.8 milliliter), add oxalyl chloride (0.03 milliliter, the 2M solution in DCM, 0.05 mmole) and DMF (1.3 microlitres, 0.02 mmole).Reactant was stirred under room temperature 1 hour, concentrate in a vacuum then.Residue is dissolved among the THF (0.4 milliliter), and is added into embodiment 13 partly E compound (17.2 milligrams, 0.07 mmole) and NaHCO ₃(7.2 milligrams, 0.09 mmole) are in the solution among the THF/H2O (1: 1,0.8 milliliter).Reactant was at room temperature stirred 2 hours, then with EtOAc (4 milliliters) and water (1 milliliter) dilution.Concentrate organic layer in a vacuum.Make residue through preparing HPLC purifying (100 millimeters posts of Phenomenex LunaAXIA30 x; Under 220 nanometers, detect; Flow velocity=40 ml/min; Continuous gradient liquid from 70%A to 100%B, was gone through 10 minutes, wherein, and A=90: 10: 0.1H20: MeOH: TFA, and B=90: 10: 0.1MeOH: H2O: TFA),, be white solid so that title compound (0.63 milligram, 5.7% productive rate) to be provided.[M+H]+＝641.2；1H?NMR(400MHz，CDCl3)δ8.63(1H，d，J＝8.35Hz)，8.21(1H，s)，7.96(2H，d，J＝8.35Hz)，7.90(1H，d，J＝8.35Hz)，7.63(2H，d，J＝8.35Hz)，6.94-7.04(1H，m)，5.81(2H，s)，4.05-4.21(4H，m)，3.35(2H，d，J＝21.09Hz)，3.16(3H，s)，3.05(3H，s)，1.33(6H，t，J＝7.03Hz)。Embodiment 86 to 92

Following embodiment adopt about from embodiment 85 partly D compound embodiment 85 compounds one of said as route of synthesis, synthetic from embodiment 85 D compounds partly.

Example 93?

In the solution of embodiment 13 part E compounds (50 milligrams, 0.20 mmole) in DCM (1 milliliter), add the 1-benzyl-3-tertiary butyl-1H-pyrazoles-5-carbonyl chloride (71.9 milligrams, 0.26 mmole) and pyridine (0.02 milliliter, 0.26 mmole).Reactant was at room temperature stirred 16 hours, in vacuum, concentrate then.Make residue through preparing HPLC purifying (100 millimeters posts of Phenomenex Luna AXIA 30 x; Under 220 nanometers, detect; Flow velocity=40 ml/min; Continuous gradient liquid from 50%A to 100%B, was gone through 10 minutes, wherein, and A=90: 10: 0.1H2O: MeOH: TFA, and B=90: 10: 0.1MeOH: H2O: TFA), and get title compound (64 milligrams, 65% productive rate), be oily matter.[M+H]+＝491.1；1H?NMR(400MHz，CDCl3)δ7.31(1H，s)，7.17-7.30(5H，m)，6.96(1H，d，J＝3.52Hz)，5.81(2H，s)，4.05-4.19(4H，m)，3.31(2H，d，J＝21.09Hz)，1.36(9H，s)，1.29(6H，t，J＝7.03Hz)。Example 94? A.?

In the solution of pivalyl Pyruvic Acid Ethyl ester (205 milligrams, 1.02 mmoles) in anhydrous EtOH (1 milliliter), add O-methyl hydroxylamine hydrochloride (90 milligrams, 1.07 mmoles) and 3A molecular sieve.Reactant was at room temperature stirred 15 hours, filter then, and wash with EtOH.Concentrated filtrate in a vacuum, and make residue between the Et2O and the saturated NaHCO3 aqueous solution, make separatory to handle.The Et2O layer with water and brine wash, being dehydrated (MgSO4), and concentrate in a vacuum, and get partly A compound (176 milligrams, 75%), is red orange oil.B.?

In the solution of part A compound (176 milligrams, 0.77 mmole) in AcOH: EtOH (1.5 milliliters), add (4-(methylsulfonyl) phenyl) hydrazine (286 milligrams, 1.54 mmoles).Reactant was stirred 10 hours down at 90 ℃, be cooled to room temperature then.Concentrated reaction mixture in a vacuum, and make residue between the EtOAc and the 0.2N HCl aqueous solution, make separatory to handle.Organic layer with water and brine wash, is dehydrated (MgSO4), and concentrate in a vacuum.Make residue chromatography (SiO2; 15 minutes gradient liquid, from the 0%EtOAc/ hexane to the 100%EtOAc/ hexane), so that B1 compound (214 milligrams, 80%) and B2 compound (20 milligrams, 7%) partly to be provided partly.C.?

In the solution of part B1 compound (23 milligrams, 0.07 mmole) in THF (1 milliliter), add the 1N NaOH aqueous solution.Mixture was stirred under room temperature 15 hours, then with EtOAc (4 milliliters) dilution, and with the 1N HCl aqueous solution (0.5 milliliter) acidifying.Organic layer with brine wash, is dehydrated (MgSO4), and concentrate in a vacuum, and get rough part C compound (23 milligrams, 109% reclaims).D.?

In (21.3 milligrams of part C compounds; 0.07 mmole) in the solution in DMF (1 milliliter); Add embodiment 13 partly (20.2 milligrams of E compounds (33.0 milligrams, 0.13 mmole), EDCI (25.3 milligrams, 0.13 mmole), HOBT; 0.13 mmole) and HunigShi alkali (0.034 milliliter, 0.20 mmole).Reaction mixture was stirred under room temperature 4 days, and through preparation HPLC direct purification (100 millimeters posts of Phenomenex Luna AXIA 30 x; Under 220 nanometers, detect; Flow velocity=40 ml/min; Continuous gradient liquid from 50%A to 100%B, was gone through 10 minutes, wherein, and A=90: 10: 0.1H2O: MeOH: TFA, and B=90: 10: 0.1MeOH: H2O: TFA),, be yellow oil so that title compound (14 milligrams, 38% productive rate) to be provided.[M+H]+＝555.1；1H?NMR(500MHz，CDCl3)δ8.11(2H，d)，7.71(2H，d，J＝8.25Hz)，6.99(1H，s)，6.98(1H，d，J＝3.85Hz)，4.10-4.18(4H，m)，3.98(1H，s)，3.35(2H，d，J＝21.44Hz)，3.13(3H，s)，1.30(6H，t，J＝7.15Hz)，1.27(9H，s)。Embodiment 95

Title compound (10 milligrams, 32% productive rate, brown solid) uses the method that is adopted among the embodiment 94, and is synthetic from embodiment 94 part B2 compounds.[M+H]+＝555.1；1H?NMR(500MHz，CDCl3)δ8.04(2H，d，J＝8.80Hz)，7.68(2H，d，J＝8.80Hz)，7.49(1H，s)，7.01(1H，d，J＝3.85Hz)，4.15-4.22(4H，m)，3.37(2H，d，J＝21.44Hz)，3.11(3H，s)，1.40(9H，s)，1.34(6H，t，J＝6.87Hz)。Example 96?

A.?

In benzyl acetone (0.54 milliliter, 3.6 mmoles) and the 0 ℃ solution of oxalic acid diethyl ester (0.53 milliliter, 3.9 mmoles) in anhydrous EtOH (6 milliliters), add NaOEt (0.31 milliliter, 3.9 mmoles).Make reactant slowly be warmed to room temperature, and at room temperature stirred 15 hours, then with EtOAc (20 milliliters) dilution, and with brine wash.Make organic layer dehydrate (MgSO4), and concentrate in a vacuum,, be yellow oil so that partly A compound (0.65 gram, 73% productive rate) to be provided.B.?

In the solution of part A compound (0.65 gram, 2.6 mmoles) in anhydrous EtOH (5 milliliters), add O-methyl hydroxylamine hydrochloride (0.31 gram, 3.7 mmoles) and 3A molecular sieve (2 gram).Reactant was at room temperature stirred 15 hours, filter then, and wash with EtOH.Concentrate the filtrating of merging in a vacuum, and make residue between the Et2O and the saturated NaHCO3 aqueous solution, do the separatory processing.The Et2O layer with water and brine wash, is dehydrated (MgSO4), and concentrate in a vacuum.Make residue chromatography (SiO2; 16 minutes gradient liquid, from the 0%EtOAc/ hexane to the 100%EtOAc/ hexane), so that partly B compound (117 milligrams, 16%) to be provided.C.?

In the solution of part B compound (117 milligrams, 0.42 mmole) in AcOH: EtOH (1.5 milliliters), add (4-(methylsulfonyl) phenyl) hydrazine (157 milligrams, 0.84 mmole).Reactant was stirred 10 hours down at 100 ℃, be cooled to room temperature then, and concentrate in a vacuum.Making residue between the EtOAc and the 0.2NHCl aqueous solution, make separatory handles.Organic layer with water and brine wash, is dehydrated (MgSO4), filter, and concentrate in a vacuum.Make residue chromatography (SiO2; 22 minutes continuous gradient liquid, from the 0%EtOAc/ hexane to the 100%EtOAc/ hexane), and partly C1 compound (20 milligrams, 12%) and C2 compound (95 milligrams, 57%) partly.D.?

In the solution of compound (28 milligrams, 0.07 mmole) in THF (1 milliliter) of part C2, add the NaOH aqueous solution (0.3 milliliter of 1M solution, 0.30 mmole).Reactant was at room temperature stirred 15 hours, then with EtOAc (4 milliliters) dilution, and with the 1N HCl aqueous solution (0.5 milliliter) acidifying.Organic layer with brine wash, is dehydrated (MgSO4), and concentrate in a vacuum, and get the partly compound (29 milligrams, 111% rough thing) of D.E.?

In (25.9 milligrams of part D compounds; 0.07 mmole) in the solution in DMF (1 milliliter); Add embodiment 13 partly (21.4 milligrams of E compounds (35.0 milligrams, 0.14 mmole), EDCI (26.8 milligrams, 0.14 mmole), HOBT; 0.14 mmole) and HunigShi alkali (0.037 milliliter, 0.21 mmole).Reactant was at room temperature stirred 2 days, in vacuum, concentrate then.Make residue through preparing HPLC direct purification (100 millimeters posts of Phenomenex Luna AXIA 30 x; Under 220 nanometers, detect; Flow velocity=40 ml/min; Continuous gradient liquid from 50%A to 100%B, was gone through 10 minutes, wherein, and A=90: 10: 0.1H2O: MeOH: TFA, and B=90: 10: 0.1MeOH: H2O: TFA),, be gray solid so that title compound (7 milligrams, 17% productive rate) to be provided.[M+H] +=603.0; 1H NMR (500MHz, CDCl3) δ 8.04 (2H, d, J=8.80Hz), 7.67 (2H, d, J=8.25Hz), 7.18-7.36 (5H; M), 7.14 (1H, broad s.), 6.90 (1H, s), 4.01-4.17 (4H, m); 3.32 (2H, d, J=21.44Hz), 3.00-3.15 (7H, m), 1.22-1.35 (6H, m).Example 97? A.?

In (6.09 milliliters of sulphonamide; 102.0 mmole) in anhydrous pyridine (109.0 milliliters) just in reflux solution, dropwise add 2-methylpropane-1 via syringe pump, (10.7 milliliters of 2-diamines; 102.0 mmole), go through 30 minutes.Made reaction mixture refluxed 16 hours, and be cooled to room temperature then, and concentrate in a vacuum.Residue is developed with hexane, up to filtrating near till colourless.Make the solid dried in vacuum that is formed, and get partly A compound (14.89 grams, 97%), be the rice brown solid.B.?

Under Ar, in Ph ₃P (26.0 grams; 99.0 mmole) with part A compound (14.89 grams; 99.0 mmole) in anhydrous THF (300 milliliters) in stirred solution, dropwise add (19.3 milliliters of DIAD; 99.0 mmole), go through 5 minutes.Reaction mixture was stirred under room temperature 16 hours.Leach the pale solid that is formed, with anhydrous THF and anhydrous Et2O washing, dried in vacuum then, and B compound (36.68 grams, 90%) partly, be pale solid.C.?

In part B compound (1.4 grams; 3.5 mmole) in the suspension-s in DCM (6 milliliters); Add embodiment 26A compound (141 milligrams, 0.44 mmole) with (R)-(-)-solution of 3-hydroxyl tetrahydrofuran (0.08 milliliter, 1.0 mmoles) in toluene (2 milliliters).Reactant was at room temperature stirred 15 hours, then with the EtOAc dilution, and with water and brine wash.Make organic layer dehydrate (MgSO4), filter, and concentrate in a vacuum.Make residue chromatography (SiO2; 19 minutes gradient liquid, from the 0%EtOAc/ hexane to the 100%EtOAc/0% hexane), so that partly C compound (254 milligrams, 148% productive rate) to be provided.D.?

In the mixture of part C compound (254 milligrams, 0.65 mmole) in THF (2 milliliters), add the 1N NaOH aqueous solution (1 milliliter, 1.0 mmoles).Reactant was at room temperature stirred 15 hours, then with EtOAc (6 milliliters) dilution, and with the 1N HCl aqueous solution (0.5 milliliter) acidifying.Organic layer with brine wash, is dehydrated (MgSO4), and concentrate in a vacuum.Make residue through preparing HPLC purifying (100 millimeters posts of Phenomenex Luna AXIA 30 x; Under 220 nanometers, detect; Flow velocity=40 ml/min; Continuous gradient liquid from 70%A to 100%B, was gone through 10 minutes, wherein, and A=90: 10: 0.1H2O: MeOH: TFA, and B=90: 10: 0.1MeOH: H2O: TFA), and get partly D compound (90 milligrams, 54% productive rate is gone through 2 steps), be water white oil.E.?

In (43.0 milligrams of part D compounds; 0.11 mmole) in the solution in DMF (1 milliliter); Add embodiment 13 partly (34.8 milligrams of E compounds (56.9 milligrams, 0.23 mmole), EDCI (43.6 milligrams, 0.23 mmole), HOBT; 0.23 mmole) and HunigShi alkali (0.059 milliliter, 0.34 mmole).Reactant was at room temperature stirred 24 hours, and through preparation HPLC direct purification (100 millimeters posts of Phenomenex Luna AXIA30x; Under 220 nanometers, detect; Flow velocity=40 ml/min; Continuous gradient liquid from 70%A to 100%B, was gone through 10 minutes, wherein, and A=90: 10: 0.1H2O: MeOH: TFA, and B=90: 10: 0.1MeOH: H2O: TFA),, be white solid so that title compound (36 milligrams, 52% productive rate) to be provided.[M+H]+＝611.3；1H?NMR(500MHz，CDCl3)δ7.94(2H，d，J＝8.80Hz)，7.63(1H，s)，7.49(1H，s)，7.16(2H，d，J＝8.80Hz)，7.07(1H，d，J＝3.85Hz)，6.91(1H，s)，5.22-5.33(1H，m)，4.12-4.24(4H，m)，3.85-4.08(4H，m)，3.37(2H，d，J＝20.89Hz)，3.08(3H，s)，2.08-2.41(2H，m)，1.34(6H，t，J＝7.15Hz)。Embodiment 98

Title compound (10 milligrams, 16% productive rate, white solid) adopts like the synthetic same procedure about embodiment 97 compounds, and system is from (S)-(+)-3-hydroxyl tetrahydrofuran.[M+H]+＝611.3；1H?NMR?(500MHz，CDCl3)δ7.94(2H，d，J＝8.80Hz)，7.57(1H，s)，7.44(1H，s)，7.16(2H，d，J＝8.80Hz)，7.00(1H，d，J＝3.30Hz)，6.89(1H，s)，5.15-5.26(1H，m)，4.06-4.19(4H，m)，3.86-4.06(4H，m)，3.32(2H，d，J＝20.89Hz)，3.08(3H，s)，2.06-2.39(2H，m)，1.30(6H，t，J＝7.15Hz)。Embodiment 99

Title compound (24 milligrams, 42% productive rate, white solid) adopts like the synthetic same procedure about embodiment 97 compounds, and system is from 3-methyl-3-trimethylene oxide-methyl alcohol.[M+H]+＝625.3；1HNMR(500MHz，CDCl3)δ7.94(2H，d，J＝8.80Hz)，7.70(1H，s)，7.51(1H，s)，7.13-7.20(2H，m)，7.07(1H，d，J＝3.30Hz)，6.97(1H，s)，4.70(2H，d，J＝6.05Hz)，4.51(2H，d，J＝6.05Hz)，4.13-4.26(6H，m)，3.98(1H，s)，3.38(2H，d，J＝21.44Hz)，3.08(3H，s)，1.47(3H，s)，1.34(6H，t，J＝7.15Hz)。Embodiment 100

In (61 milligrams of 1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazoles-5-carboxylic acid; 0.213 in the solution of mmole) [consulting WO 1998/57937] in DMF (1 milliliter); Add embodiment 13 partly (65.3 milligrams of E compounds (107 milligrams, 0.426 mmole), EDC (82 milligrams, 0.426 mmole), HOBT; 0.426 mmole) and DIPEA (0.111 milliliter, 0.639 mmole).Reaction mixture was at room temperature stirred 4 days.Make reaction mixture through preparing HPLC direct purification (100 millimeters posts of Phenomenex Luna AXIA 30 x; Under 220 nanometers, detect; Flow velocity=40 ml/min; Continuous gradient liquid from 50%B to 100%B, was gone through 10 minutes, wherein, and A=90: 10: 0.1H2O: MeOH: TFA, and B=90: 10: 0.1MeOH: H2O: TFA),, be gray solid so that title compound (13 milligrams, 12% productive rate) to be provided.[M+H]+＝519.0；?1H?NMR(400MHz，CDCl3)δ7.59(1H，s)，7.33-7.46(2H，m)，6.91-7.02(2H，m)，6.80(1H，d，J＝3.52Hz)，3.99-4.15(4H，m)，3.86(3H，s)，3.51(2H，d，J＝21.53Hz)，1.26(6H，t，J＝7.03Hz)。Example 101? A.?

In 3,5-methyl dihydroxy benzoate (2.7 grams, 16.06 mmoles) is at CH ₃In the solution among the CN (35 milliliters), add K2CO3 (2.70 grams, 19.54 mmoles), then slowly add 2-N-PROPYLE BROMIDE (1.975 grams, 16.06 mmoles).Reaction mixture is heated to 80 ℃, went through 3 days.Reaction mixture is diluted with water, and with EtOAc extraction (3x).The organic layer that will merge dehydrates (MgSO4) with H2O and brine wash, filters, and concentrates in a vacuum.Make residue pass through column chromatography purification (SiO2; Continuous gradient liquid, the 15%EtOAc/ hexane is to the 60%EtOAc/ hexane), and get partly A compound (1.22 grams, 36% productive rate), be yellow solid.[M+H]+＝211.0；1H?NMR(400MHz，CDCl3)δ1.33(d，J＝6.15Hz，6H)，3.89(s，3H)，4.51-4.62(m，1H)，5.21(s，1H)，6.59(t，J＝2.42Hz，1H)，7.08-7.12(m，1H)，7.13-7.17(m，1H)。B.?

In (300 milligrams of part A compounds; 1.427 mmole) with 4-hydroxyl six hydrogen piperidines-1-carboxylic acid tert-butyl ester (1.15 grams; 5.7 mmole) in the solution in toluene (2 milliliters), add the suspension-s of compound (2.34 grams, 5.7 mmoles) in DCM (2 milliliters) of embodiment 97B.Reaction mixture was stirred under room temperature 3 hours, concentrate in a vacuum then.Make residue chromatography (SiO2; Continuous gradient liquid, from the 10%EtOAc/ hexane to the 60%EtOAc/ hexane), and B compound (490 milligrams, 87%) partly, be faint yellow solid.[M+H]+＝294.0；1H?NMR(500MHz，CDCl3)δ1.32(d，J＝6.05Hz，6H)，1.45(s，9H)，1.66-1.78(m，2H)，1.85-1.96(m，2H)，3.26-3.38(m，3H)，3.62-3.72(m，3H)，3.86-3.90(m，3H)，4.44-4.51(m，1H)，4.52-4.62(m，1H)，6.61(t，J＝2.20Hz，1H)，7.10-7.19(m，2H)。C.?

In 0 ℃ of solution in the THF/ water (1/1,4 milliliter), add LiOH.H2O (209 milligrams, 4.98 mmoles) in part B compound (490 milligrams, 1.245 mmoles).Mixture was at room temperature stirred 18 hours, then with EtOAc dilution, and with 1N HCl acidified aqueous solution to pH～4-5.With EtOAc extraction (2x) water layer.The organic extract liquid that will merge dehydrates (MgSO4) with the 1N HCl aqueous solution, H2O and brine wash, and concentrates in a vacuum, so that partly C compound (440 milligrams, 93% productive rate) to be provided, is white solid.[M+H]+＝561.1.?D.?

In (200 milligrams of part C compounds; 0.527 mmole) with (132 milligrams of embodiment 13 part E compounds; 0.527 mmole) in (with the DIEA buffering) solution in DCM/DMF (1/1), add (202 milligrams of HOAT (201 milligrams, 1.476 mmoles), EDCI continuously; 1.054 mmole) and DIEA (641 microlitres, 3.69 mmoles).Reaction mixture was stirred under room temperature 18 hours, dilute with DCM then.Organic layer with water (2x) and brine wash, is dehydrated (MgSO4), and concentrate in a vacuum.Make residue chromatography (SiO2; Continuous gradient liquid, 0%DCM/MeOH to 5%DCM/MeOH), and get title compound (140 milligrams, 43% productive rate), be white solid.[M+H]+＝612；1H?NMR(500MHz，CDCl3)δ1.26(t，J＝7.15Hz，6H)，1.33(d，J＝6.05Hz，6H)，1.45(s，9H)，1.63(s，2H)，1.67-1.80(m，2H)，1.92(dd，J＝12.65，3.85Hz，2H)，3.21-3.39(m，4H)，3.63-3.76(m，2H)，4.00-4.14(m，4H)，4.44-4.53(m，1H)，4.53-4.62(m，1H)，6.63(t，J＝2.20Hz，1H)，6.84(d，J＝3.85Hz，1H)，8.00(s，1H)。Embodiment 102

In the solution of embodiment 101 compounds (15 milligrams, 0.025 mmole) in DCM (0.5 milliliter), add TFA (0.15 milliliter).Reaction mixture was stirred under room temperature 2 hours, concentrate in a vacuum then.Make residue through preparing HPLC purifying (100 millimeters posts of Phenomenex AXIA 5u C18 30 x; Under 220 nanometers, detect; Flow velocity=40 ml/min; Continuous gradient liquid from 35%B to 100%B, was gone through 10 minutes, wherein, and A=90: 10: 0.1H2O: MeOH: TFA, and B=90: 10: 0.1MeOH: H2O: TFA), obtain title compound (11 milligrams, 85% productive rate), be white solid.[M+H]+＝512；1H?NMR(500MHz，CDCl3)δ1.29(t，J＝7.15Hz，6H)，1.33(d，J＝5.50Hz，6H)，2.08-2.16(m，2H)，2.16-2.26(m，2H)，3.22(d，J＝9.90Hz，2H)，3.30(d，J＝21.44Hz，2H)，3.35(d，J＝7.70Hz，2H)，4.02-4.17(m，4H)，4.60-4.73(m，1H)，4.82(s，1H)，6.69(t，J＝2.20Hz，1H)，6.96(d，J＝3.30Hz，1H)，7.36(d，J＝8.80Hz，2H)，9.37(s，1H)，9.47(s，1H)。Embodiment 103

In the solution of embodiment 102 compounds (30 milligrams, 0.059 mmole) in the THF (1 milliliter) and the saturated NaHCO3 aqueous solution (1 milliliter), add methyl-chloroformate (6.77 microlitres, 0.088 mmole).Reaction mixture was stirred under room temperature 18 hours, dilute with EtOAc then.With EtOAc extraction (2x) water layer, and the organic extract liquid of merging is concentrated in a vacuum.Make residue through preparing HPLC purifying (100 millimeters posts of Phenomenex AXIA 5u C18 30 x; Under 220 nanometers, detect; Flow velocity=40 ml/min; Continuous gradient liquid from 35%B to 100%B, was gone through 10 minutes, wherein, and A=90: 10: 0.1H2O: MeOH: TFA, and B=90: 10: 0.1MeOH: H2O: TFA), and get title compound (16 milligrams, 48% productive rate), be white solid.[M+H]+＝570.3；1H?NMR(500MHz，CDCl3)δ1.30?(t，J＝7.15Hz，6H)，1.33(d，J＝6.05Hz，6H)，1.76(s，2H)，1.91(s，2H)，3.31(d，J＝20.89Hz，2H)，3.31(d，J＝20.89Hz，2H)，3.44(s，2H)，3.66(d，J＝5.50Hz，2H)，3.69(s，3H)，4.10-4.17(m，4H)，4.64-4.75(m，2H)，6.69(t，J＝2.20Hz，1H)，7.01(d，J＝3.30Hz，1H)，7.33(dd，J＝4.67，1.92Hz，2H)。Embodiment 104

In the solution of embodiment 102 compounds (30 milligrams, 0.059 mmole) in DCM (1 milliliter), add pyridine (0.1 milliliter) and acetyl chloride (6.90 milligrams, 0.088 mmole).Reactant was at room temperature stirred 18 hours, dilute with EtOAc then.With EtOAc extraction (2x) water layer, and the organic extract liquid of merging is concentrated in a vacuum.Make residue through preparing HPLC purifying (100 millimeters posts of Phenomenex AXIA 5u C18 30x; Under 220 nanometers, detect; Flow velocity=40 ml/min; Continuous gradient liquid from 35%B to 100%B, was gone through 10 minutes, wherein, and A=90: 10: 0.1H2O: MeOH: TFA, and B=90: 10: 0.1MeOH: H2O: TFA), and get title compound (22 milligrams, 68% productive rate), be white solid.[M+H]+＝554.4；1HNMR(500MHz，CDCl3)δ1.34(t，J＝7.15Hz，6H)，1.36(d，J＝6.05Hz，6H)，1.79-2.04(m，4H)，2.17(s，3H)，3.36(d，J＝21.44Hz，2H)，3.43-3.54(m，1H)，3.63-3.86(m，3H)，4.12-4.24(m，4H)，4.68-4.86(m，2H)，6.73(s，1H)，7.06(d，J＝3.30Hz，2H)，7.39(s，2H)。Embodiment 105

Embodiment 102 compounds (50 milligrams, 0.098 mmole) and the solution of Et3N (10 milligrams, 0.098 mmole) in DCM (0.5 milliliter) are added in the solution of chloromethane sulphonyl (11.20 milligrams, 0.098 mmole) in DCM (0.5 milliliter).Reactant was at room temperature stirred 18 hours, dilute with EtOAc then.With EtOAc extraction (2x) water layer, and the organic extract liquid of merging is concentrated in a vacuum.Make residue through preparing HPLC purifying (100 millimeters posts of 5 microns C of Phenomenex AXIA, 18 30 x; Under 220 nanometers, detect; Flow velocity=40 ml/min; Continuous gradient liquid from 35%B to 100%B, was gone through 10 minutes, wherein, and A=90: 10: 0.1H2O: MeOH: TFA, and B=90: 10: 0.1MeOH: H2O: TFA), and get title compound (19.5 milligrams, 34% productive rate), be water white oil.[M+H]+＝590.3；1H?NMR(500MHz，CDCl3)δ1.28-1.38(m，12H)，1.93-2.10(m，4H)，2.97(s，3H)，3.29-3.40(m，6H)，4.12-4.22(m，4H)，4.68-4.75(m，2H)，6.70(t，J＝2.20Hz，1H)，7.03(d，J＝3.85Hz，1H)，7.337(d，1.10Hz，2H)。Embodiment 106

In (25.0 milligrams of embodiment 26 part C compounds; 0.066 mmole), embodiment 18 part D compounds are (20.9 milligrams; 0.079 mmole) and (10.3 milligrams of HOAt; 0.076 mmole) in the solution in DMF (0.25 milliliter), add DIPEA (13.2 microlitres continuously; 0.076 mmole) with (14.6 milligrams of EDAC; 0.076 mmole).Reactant was at room temperature stirred 20 hours, between EtOAc (4 milliliters) and H2O (3 milliliters), make separatory then and handle.Organic layer with the 0.5N HCl aqueous solution (3 milliliters), the saturated NaHCO3 aqueous solution (3 milliliters) and salt solution (3 milliliters) washing, is dehydrated (MgSO4), and concentrates in a vacuum.Make residue through preparing HPLC purifying (100 millimeters posts of YMC anti-phase ODS-A-5 micron 20 x; Flow velocity=20 ml/min, 15 to 100% solvent B went through 10 minutes, were retained to 14 minutes, wherein, solvent orange 2 A=90: 10: 0.1H2O: MeOH: TFA, and solvent B=90: 10: 0.1MeOH: H2O: TFA), and get (22.0 milligrams of title compounds; 54%), is faint yellow solid.[M+H]+＝627.1；1H?NMR(400MHz，?CDCl3)：δ1.34(m，9H)，2.19(m，2H)，3.07(m，5H)，3.41(s，3H)，3.57(m，2H)，4.12(m，4H)，4.89(m，1H)，6.81(s，1H)，6.94(s，1H)，7.15(d，2H)，7.44(s，1H)，7.69(s，1H)，7.92(d，2H)。Embodiment 107

Title compound (20 milligrams, 65% productive rate, white solid) adopts as in order to prepare the identical general sequence of embodiment 58, system is from racemize-(3-amino-1H-pyrazol-1-yl) methyl (methyl) phosphinicacid ethyl ester.[M+H]+＝566.3；1H?NMR(400MHz，CD3OD)：δ1.33(d，J＝6.6Hz，3H)，1.34(t，J＝6.6Hz，3H)，1.57(d，J＝14.3Hz，3H)，3.01(s，3H)，3.42(s，3H)，3.53-3.63(m，2H)，4.08-4.21(m，2H)，4.52(dd，J＝2.4，6.0Hz，2H)，4.71(m，1H)，6.86(d，J＝2.2Hz，1H)，7.03(s，1H)，7.14(d，J＝8.8Hz，2H)，7.24(s，1H)，7.39(s，1H)，7.52(d，J＝2.2Hz，1H)，7.91(d，J＝8.8Hz，2H)。Example 108?

A.?

Stir in 10 ℃ of solution in the warp of chloro methyl (methyl) chlorination time phosphono (2 grams, 13.61 mmoles) in Et2O (10 milliliters), dropwise add MeMgBr (4.54 milliliters, the 3M solution in Et2O, 13.61 mmoles).Reactant is transformed into muddiness and thickness, makes it slowly be warmed to room temperature then, goes through 1 hour.Remove volatile matter in a vacuum, and make the residue cancellation carefully with the saturated NaHCO3 aqueous solution, and with CHCl ₃Extraction (4x).The organic extract liquid of merging is dehydrated (MgSO4), and concentrate in a vacuum.In the clean oil that is formed, add hexane (50 milliliters); Form white depositions.Filtering precipitate to collect white solid (the fine spicule of crystallization), is part A compound (360 milligrams, 21%).B.?

In 3-nitro-1H-pyrazoles (45 milligrams, 0.398 mmole) in DMF (2 milliliters) in stirred solution, add K2CO3 (70 milligrams, 0.506 mmole) and A compound (70 milligrams, 0.553 mmole) partly.Reactant was stirred 16 hours down at 75 ℃, be cooled to room temperature then, and between the EtOAc and the saturated NH4Cl aqueous solution, make separatory and handle.With CHCl3 extraction (10x) water layer, and the organic extract liquid of merging is dehydrated (MgSO4), and concentrate in a vacuum, and get partly B compound (50 milligrams, 62% productive rate), be white solid.C.?

In part B compound (50 milligrams, 0.246 mmole) in MeOH (3 milliliters) in stirred solution, add Pd/C (26.2 milligrams, 0.025 mmole).Reactant was stirred 1 hour down in H2 atmosphere (gas cylinder); Pass through

then and filter; And concentrate in a vacuum; And get partly C compound (35 milligrams, 82%), be light yellow oil.D.?

In embodiment 26 partly C acid (77 milligrams, 0.202 mmole) in DMF (2 milliliters) in stirred solution, add HOBT (55.0 milligrams, 0.404 mmole), EDC (77 milligrams, 0.404 mmole) and HunigShi alkali (0.106 milliliter, 0.606 mmole).Reactant was stirred under room temperature 30 minutes, add partly C compound (35 milligrams, 0.202 mmole) then.Reactant was at room temperature stirred 20 hours, then between the 1N HCl aqueous solution and CH2Cl2, make separatory and handle.Organic phase with the saturated NH4Cl aqueous solution and brine wash, is dehydrated (MgSO4), and concentrate in a vacuum.Make residue through preparing HPLC purifying (100 millimeters posts of Luna5 micron 21.2 x; Flow velocity=20 ml/min, 0 to 100% solvent B went through 12 minutes, was retained to 15 minutes; Wherein, solvent orange 2 A=90: 10: 0.1H2O: MeOH: TFA, and solvent B=90: 10: 0.1MeOH: H2O: TFA); And get title compound (59 milligrams, 55% productive rate), be white solid.[M+H]+＝536.3；1H?NMR(400MHz，CD3OD)：δ1.31(d，J＝6.9Hz，3H)，1.64(d，J＝13.2Hz，6H)，2.99(s，3H)，3.40(s，3H)，3.48-3.61(m，2H)，4.60(d，J＝6.6Hz，2H)，4.68(m，1H)，6.84(s，1H)，6.96(d，J＝2.2Hz，1H)，7.11(d，J＝8.8Hz，2H)，7.21(s，1H)，7.34(s，1H)，7.52(d，J＝2.2Hz，1H)，7.88(d，J＝8.8Hz，2H)。Example 109?

A.?

In (300 milligrams of embodiment 101 part A compounds; 1.427 mmole) with (R)-(534 milligrams of 3-hydroxyl pyrrolidine-carboxylic acid tert-butyl esters; 2.85 mmole) in the solution in toluene (2 milliliters); Add the partly suspension-s of B compound (1.17 grams, 2.85 mmoles) in DCM (2 milliliters) of embodiment 97.Reaction mixture was stirred under room temperature 3 hours, concentrate in a vacuum then.Make residue chromatography (SiO2; Continuous gradient liquid, the 10%EtOAc/ hexane is to the 60%EtOAc/ hexane), and get partly A compound (500 milligrams, 92%), be white solid.[M+H]+＝402；1H?NMR(400MHz，CDCl3)δ1.25(d，J＝6.15Hz，6H)，1.39(d，J＝7.47Hz，9H)，1.95-2.22(m，2H)，3.25-3.46(m，4H)，3.47-3.58(m，1H)，3.82(s，3H)，4.61-4.73(m，1H)，5.07(s，1H)，6.76(t，J＝2.42Hz，1H)，7.00(s，1H)，7.03(s，1H)。B.?

In 0 ℃ of solution in the THF/ water (1/1,4 milliliter), add LiOH.H2O (270 milligrams, 6.59 mmoles) in part A compound (500 milligrams, 1.318 mmoles).Mixture was at room temperature stirred 18 hours, then with EtOAc dilution, and with 1N HCl acidified aqueous solution to pH～4-5.With EtOAc extraction (2x) water layer.The organic extract liquid that will merge dehydrates (MgSO4) with the 1N HCl aqueous solution, H2O and brine wash, and concentrates in a vacuum, so that partly B compound (480 milligrams, 100% productive rate) to be provided, is white solid.MS[M-H]-＝364.4。C.?

In part B compound (200 milligrams, 0.547 mmole) and embodiment 13 partly E compounds (137 milligrams, 0.547 mmole) at DCM/DMF (1/1; With DIEA buffering) in solution in, add HOAT (208 milligrams, 1.53 mmoles), EDCI (210 milligrams, 1.094 mmoles) and DIPEA (665 microlitres, 3.83 mmoles) continuously.Reaction mixture was stirred under room temperature 18 hours, dilute with DCM then.Organic phase with water (2x) and brine wash, is dehydrated (MgSO4), and concentrate in a vacuum.Make residue chromatography (SiO2; Continuous gradient liquid is from 0%DCM/MeOH to 5%DCM/MeOH), and get title compound (160 milligrams, 49% productive rate), be white solid.[M+H]+＝598.3；1H?NMR(500MHz，CDCl3)δ1.26(t，J＝7.15Hz，6H)，1.33(d，J＝6.05Hz，6H)，1.45(s，9H)，1.64(s，2H)，2.02-2.24(m，2H)，3.28(d，J＝21.44Hz，2H)，3.41-3.70(m，4H)，4.01-4.16(m，4H)，4.51-4.63(m，1H)，6.98(s，1H)，7.03(s，1H)，9.71(s，1H)。Embodiment 110

Title compound (10.4 milligrams, 71% productive rate, white solid) adopts as in order to prepare the identical general sequence of embodiment 102, system is from embodiment 109 compounds.[M+H]+＝498.0；1H?NMR(500MHz，CDCl3)δ1.24-1.29(m，6H)，1.32(d，J＝6.05Hz，6H)，2.22-2.44(m，2H)，3.26(d，J＝21.44Hz，2H)，4.01-4.16(m，4H)，4.58-4.70(m，1H)，5.24(s，1H)，6.66(s，?1H)，6.93(d，J＝3.30Hz，1H)，7.29(s，1H)，7.33(s，1H)，9.81(s，1H)，10.30(s，1H)。Embodiment 111

Title compound (22.5 milligrams, 68% productive rate, water white oil) adopts as in order to prepare the identical general sequence of embodiment 103, system is from embodiment 110 compounds.[M+H]+＝556.3；1H?NMR(500MHz，CDCl3)δ1.29-1.35(m，12H)，2.13(s，1H)，2.20(s，1H)，3.35(d，J＝21.44Hz，2H)，3.48-3.65(m，J＝28.04Hz，4H)，3.70(d，J＝11.55Hz，4H)，4.13-4.20(m，4H)，4.64-4.74(m，1H)，5.14(s，1H)，6.66(t，J＝1.92Hz，1H)，7.03(d，J＝3.30Hz，1H)，7.31-7.41(m，2H)。Embodiment 112

Title compound (24 milligrams, 74% productive rate, light yellow oil) adopts as in order to prepare the identical general sequence of embodiment 104, system is from embodiment 110 compounds.[M+H]+＝540.4；1H?NMR(500MHz，CDCl3)δ1.32-1.35(m，6H)，1.35-1.39(m，6H)，2.09-2.20(m，J＝23.09Hz，3H)，2.21-2.43(m，2H)，3.37(d，J＝21.44Hz，2H)，3.55-3.92(m，4H)，4.13-4.24(m，4H)，4.66-4.76(m，1H)，5.19-5.30(m，1H)，6.67-6.72(m，1H)，7.07(d，J＝3.85Hz，1H)，7.39(s，1H)，7.40-7.44(m，1H)。Embodiment 113

Title compound (28 milligrams, 43% productive rate, white solid) adopts as in order to prepare the identical general sequence of embodiment 105, system is from embodiment 110 compounds.[M+H]+＝576.3；1H?NMR(500MHz，CDCl3)δ1.32(t，J＝7.15Hz，6H)，1.35(dd，J＝6.05，1.10Hz，6H)，2.17-2.37(m，2H)，2.83(s，3H)，3.34(d，J＝20.89Hz，2H)，3.42-3.52(m，1H)，3.54-3.71(m，3H)，4.11-4.23(m，4H)，4.65-4.77(m，1H)，5.16(s，1H)，6.64(t，J＝2.20Hz，1H)，7.35(s，1H)，7.41(d，J＝3.30Hz，1H)。Embodiment 114

Title compound (176 milligrams, 32% productive rate, white solid) adopts as in order to prepare the identical general sequence of embodiment 109, system is from (S)-3-hydroxyl pyrrolidine-carboxylic acid tert-butyl ester.[M+H]+＝598.4；1HNMR(500MHz，CDCl3)δ1.26(t，J＝7.15Hz，6H)，1.34(d，J＝5.50Hz，6H)，1.45(s，9H)，1.63(s，2H)，2.00-2.27(m，2H)，3.28(d，J＝20.89Hz，2H)，3.39-3.70(m，4H)，3.99-4.18(m，4H)，4.50-4.66(m，1H)，4.91(s，1H)，6.59(s，1H)，6.84(s，1H)，6.96-7.10(m，2H)。Embodiment 115

Title compound (13.4 milligrams, 67% productive rate, white solid) adopts as in order to prepare the identical general sequence of embodiment 110, system is from embodiment 114 compounds.[M+H]+＝498.3；1H?NMR(500MHz，CDCl3)δ1.22-1.28(m，6H)，1.32(d，J＝6.05Hz，6H)，2.24-2.40(m，2H)，3.24(d，J＝21.44Hz，2H)，3.41-3.69(m，4H)，3.97-4.13(m，4H)，4.56-4.69(m，1H)，5.22(s，1H)，6.64(t，J＝2.20Hz，1H)，6.89(d，J＝3.85Hz，1H)，7.28(s，1H)，7.32(s，1H)。Embodiment 116

Title compound (32.5 milligrams, 83% productive rate, water white oil) adopts as in order to prepare the identical general sequence of embodiment 111, system is from embodiment 115 compounds.[M+H]+＝554；1H?NMR(500MHz，CDCl3)δ1.29-1.32(m，6H)，1.33(d，J＝5.50Hz，6H)，2.05-2.28(m，2H)，3.35(d，J＝21.44Hz，2H)，3.45-3.74(m，7H)，4.11-4.22(m，4H)，4.65-4.74(m，1H)，5.14(s，1H)，6.66(t，J＝1.92Hz，1H)，7.03(d，J＝3.30Hz，1H)，7.33(s，1H)，7.38(s，1H)。Embodiment 117

Title compound (28.5 milligrams, 75% productive rate, light yellow oil) adopts as in order to prepare the identical general sequence of embodiment 112, system is from embodiment 115 compounds.[M+H]+＝540.2；1H?NMR(500MHz，CDCl3)δ1.29-1.32(m，6H)，1.32-1.36(m，6H)，2.12(d，J＝23.09Hz，3H)，2.19-2.39(m，2H)，3.34(d，J＝21.44Hz，2H)，3.55-3.88(m，4H)，4.11-4.21(m，4H)，4.64-4.73(m，1H)，5.17-5.28(m，1H)，6.64-6.69(m，1H)，7.04(d，J＝2.75Hz，1H)，7.35(d，J＝1.10Hz，1H)，7.39(d，J＝9.35Hz，1H)。Embodiment 118

Title compound (12 milligrams, 30% productive rate, light yellow oil) adopts as in order to prepare the identical general sequence of embodiment 113, system is from embodiment 115 compounds.[M+H]+＝576.2；1H?NMR(500MHz，CDCl3)δ1.31-1.34(m，6H)，1.36(d，J＝6.05Hz，6H)，2.08-2.39(m，2H)，2.85(s，3H)，3.37(d，J＝21.44Hz，2H)，3.44-3.54(m，1H)，3.56-3.72(m，3H)，4.13-4.25(m，4H)，4.68-4.80(m，1H)，5.18(s，1H)，6.66(s，1H)，7.07(d，J＝3.30Hz，1H)，7.37(s，1H)，7.43(s，1H)。Example 119?

A.?

Under Ar, in the solution at room temperature of embodiment 101 part A esters (94.7 milligrams, 0.450 mmole) in MeCN (2.2 milliliters); Add 1,4,7; 10,13, (16 milligrams of 16-six oxygen ring octadecanes; 0.061 mmole), K2CO3 (178 milligrams, 1.288 mmoles) and bromo methyl phenyl sulfone (120 milligrams, 0.510 mmole).Mixture was heated 6 hours down at 70 ℃, following 4 hours at 90 ℃ then.Add DMF (1 milliliter), and reactant was heated 24 hours down at 115 ℃.After 24 hours, add more bromo methyl phenyl sulfones (90 milligrams, 0.382 mmole), and reactant was stirred 3 days down at 115 ℃, then be cooled to room temperature, and under room temperature, stirred 2 days.Make the Vandyke brown mixture in EtOAc and saturated NaHCO ₃Making separatory between the aqueous solution handles.Organic layer with the saturated NaHCO3 aqueous solution, water and brine wash, is dehydrated (Na2SO4), and concentrate in a vacuum.Make residue chromatography (SiO2,12 grams are from 0-10% 35%EtOAc then: the hexane wash-out, at last with the 100%EtOAc flushing), and impure part A compound (70 milligrams), be oily matter.Make residue through the preparation HPLC be further purified (Phenomenex AXIA Luna 5 μ, 30 millimeters of 75 x detect under 220 nanometers; Flow velocity=40 ml/min; Continuous gradient liquid from 40%A to 100%B, is gone through 15 minutes+3 minute hold-time under 100%B; Wherein, A=90: 10: 0.1H2O: CH3CN: TFA, and B=90: 10: 0.1CH3CN: H2O: TFA); And get partly A compound (9.2 milligrams, 5.5%), be oily solid.B.?

Under Ar, in the solution at room temperature of part A compound (9 milligrams, 0.025 mmole) in THF (0.2 milliliter) and MeOH (0.1 milliliter), add the 4N LiOH aqueous solution (0.062 milliliter, 0.247 mmole).Reactant was at room temperature stirred 8 hours, store 18 hours down in-20 ℃ then.In being warmed to room temperature and, removing volatile matter in a vacuum with after the EtOAc dilution, and colorless solid.Residue is suspended in water, reach pH 1 with the 1N HCl aqueous solution (0.3 milliliter), and with EtOAc extraction (2x) water layer.The organic extract liquid that will merge dehydrates (Na2SO4) with brine wash, and concentrates in a vacuum, and gets partly B compound (10.6 milligrams,＞100% reclaims), is colorless solid.C.?

Under Ar, in part B acid (8.76 milligrams, 0.025 mmole), add the partly solution at room temperature of E amine (21 milligrams, 0.084 mmole) in CH2Cl2 (0.800 milliliter) of embodiment 13.In the mixture that is formed, add iPr ₂NEt (0.030 milliliter, 0.175 mmole) then adds HATU (14.2 milligrams, 0.037 mmole).This solution was at room temperature stirred 18 hours, add partly E amine (15 milligrams, 0.06 mmole) of another part embodiment 13 then, and at room temperature continue to stir 18 hours.After stirring 15 minutes, make reactant between the EtOAc and the saturated NaHCO3 aqueous solution, make separatory and handle.Organic layer with the saturated NaHCO3 aqueous solution and brine wash, is dehydrated (Na2SO4), and concentrate in a vacuum.(100 millimeters posts of 5 micron 21.2 x of Phenomenex Luna detect under 220 nanometers through preparing the HPLC purifying to make residue; Flow velocity=20 ml/min; Continuous gradient liquid from 60%A to 100%B, is gone through 10 minutes+2 minute hold-time under 100%B, wherein, and A=90: 10: 0.1H2O: MeOH: TFA, and B=90: 10: 0.1MeOH: H2O: TFA).Make material through preparation HPLC be further purified (Phenomenex Luna, 100 millimeters of 5 micron 21.2 x detect under 220 nanometers; Flow velocity=20 ml/min; Continuous gradient liquid from 35%A to 100%B, is gone through 10 minutes+2 minute hold-time under 100%B, wherein, and A=90: 10: 0.1H2O: MeOH: TFA, and B=90: 10: 0.1MeOH: H2O: TFA).Make material at last through cartridge case purifying, with the MeOH thorough washing through the MeOH processing through Polymer Lab StratoSpheres TM SPE PL-HCO3 MP SPE resin (500 milligrams).Concentrated filtrate in a vacuum, and the solid that is formed is dissolved among the CH2Cl2/MeOH filters, and concentrates in a vacuum, and title compound (5 milligrams, 34%), be the tawny solid.[M+H]+＝583.3；1H?NMR(400MHz，CDCl3)δ1.27(t，J＝6.87Hz，6H)，1.33(d，J＝6.05Hz，6H)，3.33(d，J＝20.89Hz，2H)，4.07(td，J＝7.15，4.40Hz，4H)，4.55-4.58(m，1H)，5.11(s，2H)，6.67(s，1H)，6.83(d，J＝3.30Hz，1H)，7.08(s，1H)，7.16(s，1H)，7.59(t，J＝7.70Hz，2H)，7.69(t，J＝7.15Hz，1H)，7.97(d，J＝7.15Hz，2H)。Example 120? A.?

Under Ar, in the 0 ℃ solution of embodiment 101 part A compounds (183.9 milligrams, 0.875 mmole) in DMPU (4.5 milliliters), add NaH (35.0 milligrams of 60% dispersion liquids in oil, 0.875 mmole).In the solution that is formed, add 2-bromoacetophenone (174 milligrams, 0.875 mmole).Reactant in 0 ℃ of following stirred for several minute, is warmed to room temperature then, and under room temperature, stirred 1.5 hours.Add more 2-bromoacetophenones (39 milligrams, 0.19 mmole), and reactant was at room temperature stirred 1 hour.Make the reaction cancellation with water, and add EtOAc.Organic layer with water (2x) and salt solution (1x) washing, is dehydrated (Na2SO4), and concentrates in a vacuum.Make residue chromatography (SiO2,12 grams are from 0-5%EtOAc: the CH2Cl2 wash-out, then with the 90%EtOAc flushing), and A compound (274 milligrams, 95%) partly, be yellow oil.B.?

Under Ar, in the solution at room temperature of part A compound (101.4 milligrams, 0.309 mmole) in TF (2.4 milliliters), add water (0.6 milliliter), then be LiOH.H2O (54.7 milligrams, 1.304 mmoles).Reactant was at room temperature stirred 18 hours, and add the LiOH aqueous solution (0.2 milliliter of 4M solution, 0.8 mmole).After stirring 5.5 hours, add MeOH (0.5 milliliter); At room temperature continue to stir 2.5 hours, and reactant is stored 18 hours down at-20 ℃.After being warmed to room temperature, with reactant restir 4.5 hours.Remove volatile matter in a vacuum, and get the orange aqueous mixture, make it, between EtOAc and water, make separatory then and handle with the 1N HCl aqueous solution (1.9 milliliters) acidifying.Organic layer with water and brine wash, is dehydrated (Na2SO4), and concentrate in a vacuum, and get rough part B compound (88 milligrams, 49%), be yellow oil.C.?

Under Ar; In (≤88 milligrams of the acid of part B; ≤0.280 mmole) in the solution at room temperature in CH2Cl2 (1.4 milliliters), adds (0.34 milliliter of HATU (166 milligrams, 0.437 mmole), DIPEA continuously; 1.952 mmole) and embodiment 13 solution of E compounds (162 milligrams, 0.445 mmole) in CH2Cl2 (0.6 milliliter) partly.Reactant was at room temperature stirred 65 hours, between the EtOAc and the saturated NaHCO3 aqueous solution, make separatory then and handle.Organic layer with the saturated NaHCO3 aqueous solution and brine wash, is dehydrated (Na2SO4), and concentrate in a vacuum.(250 millimeters posts of YMCODS S5 30 x detect under 220 nanometers through preparing the HPLC purifying to make residue; Flow velocity=25 ml/min; Continuous gradient liquid from 50%A to 100%B, is gone through 20 minutes+5 minute hold-time under 100%B; Wherein, A=90: 10: 0.1H2O: CH3CN: TFA, and B=90: 10: 0.1CH3CN: H2O: TFA); And get title compound (33 milligrams, 22%), be the thickness yellow solid.[M+H]+＝545.3；1H?NMR(400MHz，CD3OD)：δ1.28(t，J＝7.15Hz，6H)，1.34(d，J＝6.05Hz，6H)，3.36(d，J＝16.49Hz，2H)，4.04-4.14(m，4H)，4.64-4.86(m，1H)，5.55(s，2H)，6.78-6.80(m，1H)，6.95-6.97(m，1H)，7.18-7.21(m，2H)，7.50-7.58(t，J＝7.97Hz，2H)，7.65-7.70(m，1H)，8.07(d，J＝7.15Hz，2H)。Embodiment 121

Under Ar, in the 0 ℃ solution of embodiment 120 ketone (28 milligrams, 0.051 mmole) in MeOH (1 milliliter), add NaBH ₄(10 milligrams, 0.264 mmole).After 15 minutes, make reactant be warmed to room temperature, and under room temperature, stirred 4 hours.Mixture is stored 18 hours down at-20 ℃, handle with pH 3 water-bearing phosphate salt buffer agents then, make it be warmed to room temperature, and under room temperature, stirred 40 minutes.Remove volatile matter in a vacuum, and make the aqueous mixture that is formed between water, phosphate buffer and EtOAc, do the separatory processing.Organic layer with water and brine wash, is dehydrated (Na2SO4), and concentrate in a vacuum.(30 millimeters of 5 micron 75 x of Phenomenex AXIA Luna detect under 220 nanometers through preparing the HPLC purifying to make residue; Flow velocity=40 ml/min; Continuous gradient liquid from 40%A to 100%B, is gone through 15 minutes+3 minute hold-time under 100%B; Wherein, A=90: 10: 0.1H2O: CH3CN: TFA, and B=90: 10: 0.1CH3CN: H2O: TFA), and get two kinds of wash-out fractions that contain the title compound of wanting to some extent.Make the cartridge case through MeOH processing of two kinds of wash-out fractions, with the MeOH thorough washing through Polymer Lab StratoSpheres TM SPE PL-HCO3 MPSPE resin (500 milligrams).Concentrated filtrate in a vacuum, and the solid that is formed is dissolved among the CH2Cl2/MeOH, and concentrating in a vacuum, and title compound (17 milligrams, 60%), be the tawny solid.[M+H]+＝549.2；[M-H]-＝547.2；1H?NMR(400MHz，CD3OD)：δ1.28(t，J＝6.87Hz，6H)，1.33(d，J＝6.05Hz，6H)，3.35(d，J＝20.89Hz，2H)，4.05-4.17(m，6H)，4.63-4.69(m，1H)，5.02-5.07(m，1H)，6.71-6.73(m，1H)，6.95(d，J＝3.85Hz，1H)，7.13-7.15(m，2H)，7.27-7.30(m，1H)，7.37(t，J＝7.42Hz，2H)，7.48(d，J＝7.15Hz，2H)。Example 122?

A.?

Under Ar, in the solution at room temperature of embodiment 120 part A compounds (53.7 milligrams, 0.164 mmole) in CH2Cl2 (0.5 milliliter), add two-(2-methoxy ethyl) amino sulfur trifluoride (0.3 milliliter, 1.627 mmoles).Orange solution was stirred 18 hours under room temperature and Ar, then with CH2Cl2 dilution, and carefully be added into ice and the saturated NaHCO3 aqueous solution in stirring the mixture.Mixture was stirred 1 hour, then between the CH2Cl2 and the saturated NaHCO3 aqueous solution, make separatory and handle.With CH2Cl2 extraction (2x) water layer, and the organic extract liquid that will merge dehydrates (Na2SO4) with brine wash, and concentrates in a vacuum, and rough part A ester (54.4 milligrams, 95% recovery), be yellow oil.B.?

Under Ar, in the solution at room temperature of part A ester (54.4 milligrams, 0.155 mmole) in THF (0.8 milliliter) and MeOH (0.4 milliliter), add the 4N LiOH aqueous solution (0.35 milliliter, 1.4 mmoles).Reactant was stirred under room temperature 6 hours, and remove volatile matter in a vacuum.Make the orange aqueous mixture with the 1N HCl aqueous solution (1.5 milliliters) acidifying.Making the mixture that is formed between water and EtOAc, make separatory handles.Organic layer with water and brine wash, is dehydrated (Na2SO4), and concentrate in a vacuum, and get partly B compound (46.7 milligrams, 89% reclaims), be yellow oily solid.C.?

Under Ar; In (21.2 milligrams of part B compounds; 0.063 mmole) in the solution at room temperature in CH2Cl2 (0.6 milliliter), add HATU (34 milligrams, 0.089 mmole), iPr2NEt (35 microlitres continuously; 0.201 mmole) and embodiment 32 solution of A amine (20.6 milligrams, 0.088 mmole) in CH2Cl2 (0.3 milliliter) partly.Reactant was at room temperature stirred 41 hours, with CH2Cl2, the saturated NaHCO3 aqueous solution and EtOAc dilution, then stirred 15 minutes then, and between the EtOAc and the NaHCO3 aqueous solution, make separatory and handle.With EtOAc extraction (2x) water layer, and the organic extract liquid that will merge dehydrates (Na2SO4) with brine wash, and concentrated in a vacuum.(250 millimeters posts of YMC ODS 30 x detect under 220 nanometers through preparing the HPLC purifying to make residue; Flow velocity=25 ml/min; Continuous gradient liquid from 50%A to 100%B, is gone through 25 minutes+7 minute hold-time under 100%B; Wherein, A=90: 10: 0.1H2O: CH3CN: TFA, and B=90: 10: 0.1CH3CN: H2O: TFA); And get impure a little title compound (34.3 milligrams), be water white oil.Make residue be further purified through preparation HPLC that (100 millimeters posts of 5 microns C18 of Phenomenex AXIA, 30 x detect under 220 nanometers; Flow velocity=40 ml/min; Continuous gradient liquid from 60%A to 100%B, is gone through 10 minutes+5 minute hold-time under 100%B, wherein; A=90: 10: 0.1H2O: MeOH: TFA, and B=90: 10: 0.1MeOH: H2O: TFA), and get (25 milligrams of title compounds; 59%, tfa salt), be water white oil.[M+H]+＝552.2；[M-H]-＝550.3；1H?NMR(400MHz，CDCl3)：δ1.28(t，J＝7.15Hz，6H)，1.32(d，J＝6.05Hz，6H)，4.04-4.14(m，4H)，4.37-4.48(m，4H)，4.59(dt，J＝12.09，6.05Hz，1H)，6.60(s，1H)，6.94(s，1H)，7.01(s，1H)，7.08(s，1H)，7.43-7.49(m，4H)，7.55-7.61(m，2H)，9.10(s，1H)，19F?NMR(400MHz，CDCl3)：δ-75.98，-103.82，-103.86。Example 123? A.?

Under Ar, in embodiment 122 part B acid (46.7 milligrams, 0.139 mmole) 0 ℃ of solution in CH2Cl2 (1.5 milliliters), dropwise add oxalyl chloride (250 microlitres, the 2M solution in CH2Cl2 continuously; 0.5 mmole) with DMF (15 microlitre).After 15 minutes, make reactant be warmed to room temperature, and the yellow reaction thing was at room temperature stirred 3 hours.In vacuum, remove volatile matter, and get partly A compound (68.8 milligrams,＞100% reclaims), be the orange oily solid.B.?

Under Ar, in the 0 ℃ solution of embodiment 13 part E amine (36.7 milligrams, 0.147 mmole) in THF (0.4 milliliter), add iPr continuously ₂NEt (120 microlitres, 0.689 mmole), solution and the last DMAP (1.7 milligram, 0.014 mmole) of part A compound (24.7 milligrams, 0.0695 mmole) in CH2Cl2 (0.4 milliliter).Make reactant be warmed to room temperature, and at room temperature stirred 20 hours,, and use partly A chloride of acid (24.7 milligrams, 0.0695 mmole) and the crude reaction mixture merging that derives from similar experiment then with the water dilution.Make the reaction mixture of merging between rare NaHCO3 aqueous solution and CH2Cl2, do the separatory processing.Water layer is extracted (2x) with CH2Cl2, and the organic layer of merging is dehydrated (Na2SO4), and concentrate in a vacuum.At first (250 millimeters posts of YMC ODS 30 x detect under 220 nanometers through preparation HPLC purifying to make residue; Flow velocity=25 ml/min; Continuous gradient liquid from 50%A to 100%B, is gone through 30 minutes+7 minute hold-time under 100%B, wherein, and A=90: 10: 0.1H2O: CH3CN: TFA, and B=90: 10: 0.1CH3CN: H2O: TFA).Residue is dissolved among the MeOH, and passes through the cartridge case through the MeOH processing of PolymerLab StratoSpheres TM SPE PL-HCO3MP SPE resin, with the MeOH thorough washing.Concentrated filtrate in a vacuum.Residue is dissolved among the CH2Cl2/MeOH, filters, and concentrate in a vacuum, and get title compound (5.6 milligrams, 7%), be the tawny sticky solid.[M+H]+＝569.3；[M-H]-＝567.3；1H?NMR(400MHz，CDCl3)：δ1.24(t，J＝7.15Hz，6H)，1.30(d，J＝6.05Hz，6H)，3.28(d，J＝20.89Hz，2H)，3.98-4.09(m，4H)，4.36(t，J＝12.37Hz，2H)，4.53(dt，J＝12.09，6.05Hz，1H)，6.57(s，1H)，6.77(d，J＝3.30Hz，1H)，7.02(s，1H)，7.09(s，1H)，7.41-7.49(m，3H)，7.51-7.59(m，2H)，8.01(d，J＝7.15Hz，1H)；19F?NMR(400MHz，CDCl3)：δ-103.73，-103.76，-103.80。Example 124?

A.?

Under Ar, in 3,5-methyl dihydroxy benzoate (10.00 grams; 59.5 mmole) in the solution in DMF (60.0 milliliters), add K2CO3 (12.4 grams; 89.7 mmole), then slowly add (10.0 milliliters of benzyl bromines; 84.2 mmole), go through 10 minutes.Reaction mixture was stirred 16 hours down at 25 ℃, make the reaction cancellation with the saturated NH4Cl aqueous solution (50 milliliters) and water (350 milliliters) then.With CH2Cl2 (50 milliliters of 3 x) extraction aq suspension.The organic extract liquid that will merge dehydrates (MgSO4) with water and brine wash, and concentrates in a vacuum.Make crude product chromatography (SiO2; Stepwise gradient liquid, 10-20-30-50% solvent B, wherein, solvent orange 2 A=hexane, and solvent B=EtOAc), and get partly A compound (4.599 grams; 30%), is pale powder.B.?

In part A compound (3.130 grams; 12.12 mmole) in 0 ℃ of solution in THF (52.7 milliliters), add (R)-1-methoxyl group propan-2-ol (1.64 grams; 18.18 mmole) and Ph ₃P (4.77 grams; 18.18 mmole), then slowly add (3.53 milliliters of DIAD via syringe pump; 18.18 mmole).Reaction mixture was stirred 16 hours under 25 ℃ and Ar, then with the water dilution, and with EtOAc extraction (3x).The organic extract liquid that will merge dehydrates (MgSO4) with the 1NNaOH aqueous solution and brine wash, and concentrates in a vacuum.Make crude product chromatography (SiO2; Stepwise gradient liquid, 5-10-30-50% solvent B, wherein, solvent orange 2 A=hexane, and solvent B=EtOAc), and get partly B compound (2.892 grams; 53%), is clear, colorless oil.C.?

To contain part B compound (2.892 grams among the MeOH (109 milliliters); 8.75 flask mmole) is bled, and washes with Ar.Add 10%Pd/C (0.931 gram; 0.875 mmole), then flask is bled, and with H2 (gas; 1 normal atmosphere) filling again.Reactant was stirred 2 days under H2.Filter reaction mixture, and with the EtOAc washing catalyst.The filtrating of merging is concentrated in a vacuum, and get partly C compound (2.075 grams; 83%), is clear, colorless oil.D.?

In part C compound (0.125 gram; 0.519 mmole) in 0 ℃ of solution in THF (2.60 milliliters), add 2-(4-(ethylmercapto group) phenyl) ethanol (0.208 gram; 1.142 mmole) and Ph ₃P (0.299 gram; 1.142 mmole), then slowly add (0.222 milliliter of DIAD; 1.142 mmole).Reaction mixture was stirred 16 hours under 25 ℃ and Ar.Reaction mixture is diluted with water, and with EtOAc extraction (3x).The organic extract liquid that will merge dehydrates (MgSO4) with the 1N NaOH aqueous solution and brine wash, and concentrates in a vacuum.Make residue chromatography (SiO2; Stepwise gradient liquid, 5-10-20-30-50% solvent B, wherein, solvent orange 2 A=hexane, and solvent B=EtOAc), and get partly D compound (0.121 gram; 49%), is glassy yellow oil.E.?

In part D compound (0.1208 gram; 0.299 mmole) in the solution in THF (2.47 milliliters) and water (0.25 milliliter), add LiOH.H2O (0.014 gram; 0.597 mmole).Reaction mixture under 45 ℃, was stirred 1 hour in the little glass bottle of sealing, add the LiOH.H2O of another equivalent then.Reaction mixture was stirred 6 hours down at 45 ℃, then be cooled to room temperature.In vacuum, remove volatile matter, and make all the other aqueous solution with 0.5N HCl acidified aqueous solution to pH＜2.Extract (3x) water layer again with EtOAc.The organic extract liquid that will merge dehydrates (MgSO4) with brine wash, and concentrates in a vacuum, and gets partly E compound (0.1082 gram; 76%), is clear, colorless oil.F.?

In part E compound (0.160 gram; 0.411 mmole) in the solution in DMF (2.05 milliliters), add HOAT (0.064 gram; 0.47 embodiment 13 part E compound (0.123 grams mmole); 0.493 mmole) and (0.08 milliliter of DIPEA; 0.47 mmole), and at last be EDCI (0.091 gram; 0.47 mmole).Reaction mixture was stirred 16 hours down at 25 ℃.Add water, and with EtOAc extraction (3x) mixture.The organic extract liquid that will merge is with saturated NH ₄The Cl aqueous solution, saturated NaHCO ₃The aqueous solution and brine wash dehydrate (MgSO ₄), and concentrate in a vacuum.Make residue through preparing HPLC purifying (100 millimeters posts of YMC anti-phase ODS-5u 30x; Flow velocity=40 ml/min, 25 to 100% solvent B went through 12 minutes, wherein, solvent orange 2 A=90: 10: 0.1H ₂O: CH ₃CN: TFA, and solvent B=90: 10: 0.1CH ₃CN: H ₂O: TFA), and get (80.4 milligrams of title compounds; 31%), is clear, colorless oil.[M+H]+＝623.2。Example 125?

A.?

In embodiment 124 part C compound (0.125 grams; 0.519 mmole) in 0 ℃ of solution in THF (2.60 milliliters), add 2-(4-(methylthio group) phenyl) ethanol (0.208 gram; 1.142 mmole) and Ph ₃P (0.299 gram; 1.142 mmole), then slowly add (0.222 milliliter of DIAD; 1.142 mmole).Reaction mixture was stirred 16 hours under 25 ℃ and Ar, then with the water dilution, and with EtOAc extraction (3x).The organic extract liquid that will merge dehydrates (MgSO4) with the 1N NaOH aqueous solution and brine wash, and concentrates in a vacuum.Make crude product chromatography (SiO2; Gradient liquid progressively, 5-10-20-30-50% solvent B, wherein, solvent orange 2 A=hexane, and solvent B=EtOAc), and A compound (0.121 gram partly; 49%), is glassy yellow oil.B.?

In part A compound (0.1208 gram; 0.299 mmole) in the solution in THF (2.47 milliliters) and water (0.25 milliliter), add LiOH.H2O (0.014 gram; 0.597 mmole).Reaction mixture under 45 ℃, was stirred 1 hour in the little glass bottle of sealing, add the LiOH of another equivalent then.Reaction mixture was stirred 16 hours down at 45 ℃, then be cooled to room temperature.In vacuum, remove volatile matter, and make all the other aqueous solution with 0.5N HCl acidified aqueous solution to pH＜2.Extract (3x) water layer again with EtOAc.The organic extract liquid that will merge dehydrates (MgSO4) with brine wash, and concentrates in a vacuum, and gets partly B compound (0.1082 gram; 76%), is clear, colorless oil.C?

In embodiment 13 part E compound (0.13 grams; 0.51 mmole) in the solution in DMF (2.13 milliliters), add HOAT (0.067 gram; 0.49 part B compound (0.16 gram mmole); 0.43 mmole), DIPEA is (0.63 milliliter; 0.49 mmole) and last EDCI (0.094 the gram; 0.49 mmole).Reaction mixture was stirred 16 hours down in 25 ℃.Add water, and with EtOAc extraction (3x) mixture.The organic extract liquid that will merge dehydrates (MgSO4) with the saturated NH4Cl aqueous solution, the saturated NaHCO3 aqueous solution and brine wash, and concentrates in a vacuum.Make residue through preparing HPLC purifying (100 millimeters posts of YMC anti-phase ODS-5u 30x; Flow velocity=40 ml/min, 25 to 100% solvent B went through 12 minutes, wherein, solvent orange 2 A=90: 10: 0.1H2O: CH3CN: TFA, and solvent B=90: 10: 0.1CH3CN: H2O: TFA), and get (47.0 milligrams of title compounds; 17%), is clear, colorless oil.[M+H]+＝609.1。Embodiment 126

Embodiment 124 in iPrOH (1.46 milliliters) and water (0.73 milliliter) is F compounds (0.04 gram partly; 0.07 mmole), add oxone (oxone) (0.09 gram; 0.15 mmole).Reaction mixture was stirred 16 hours down at 25 ℃, filter then, and extract with EtOAc.Making filtrates does the separatory processing between water and salt solution.Make organic layer dehydrate (MgSO4), and concentrate in a vacuum.Make residue through preparing HPLC purifying (100 millimeters posts of YMC anti-phase ODS-5u 30x; Flow velocity=40 ml/min, 25 to 100% solvent B went through 12 minutes, wherein, solvent orange 2 A=90: 10: 0.1H2O: CH3CN: TFA, and solvent B=90: 10: 0.1CH3CN: H2O: TFA), and get (48.0 milligrams of title compounds; 55%), is white solid.[M+H]+＝655.3；1H?NMR(400MHz，CDCl3)：δ1.16-1.29(m，12H)，2.98-3.08(m，J＝7.33，7.33，7.33Hz，2H)，3.08-3.18(m，J＝6.32，6.32Hz，2H)，3.22(s，1H)，3.28(s，1H)，3.33(s，3H)，3.41-3.54(m，2H)，4.01-4.13(m，4H)，4.24(t，J＝6.32Hz，2H)，4.61-4.70(m，J＝10.17，6.32Hz，1H)，6.64-6.70(m，1H)，6.93-6.97(m，J＝3.30Hz，1H)，7.29(d，J＝17.59Hz，2H)，7.42(d，J＝8.24Hz，2H)，7.78(d，J＝8.25Hz，2H)。Embodiment 127

Embodiment 125 in iPrOH (1.46 milliliters) and water (0.73 milliliter) is C compounds (0.04 gram partly; 0.07 mmole), add oxone (oxone) (0.09 gram; 0.15 mmole).Reaction mixture was stirred 16 hours down in 25 ℃, filter then, and wash with EtOAc.To filtrate with water and brine wash, dehydrate (MgSO4), and concentrate in a vacuum.Make residue through preparing HPLC purifying (100 millimeters posts of YMC anti-phase ODS-5u 30 x; Flow velocity=40 ml/min, 25 to 100% solvent B went through 12 minutes, wherein, solvent orange 2 A=90: 10: 0.1H2O: CH3CN: TFA, and solvent B=90: 10: 0.1CH3CN: H2O: TFA), and get (14.2 milligrams of title compounds; 33%), is white solid.[M+H]+＝641.3；1H?NMR(400MHz，CDCl3)：δ1.21-1.30(m，J＝7.42，7.42Hz，9H)，2.97(s，3H)，3.12(t，J＝6.05Hz，2H)，3.26(s，1H)，3.29-3.36(m，4H)，3.41-3.55(m，2H)，4.03-4.16(m，4H)，4.25(t，J＝6.32Hz，2H)，4.60-4.72(m，1H)，6.62-6.71(m，1H)，6.91-7.01(m，J＝3.85Hz，1H)，7.32(d，J＝16.49Hz，2H)，7.43(d，J＝8.25Hz，2H)，7.81(d，J＝8.24Hz，2H)。Example 128? A.?

In embodiment 124 part C compound (0.100 grams; 0.416 mmole), add 2-(2-fluorophenyl) ethanol (0.24 gram; 1.67 mmole is in toluene; 2.08 milliliter), then be embodiment 97 part B compound (0.68 grams; 1.67 the suspension-s in CH2Cl2 (7.6 milliliters) mmole).Reaction mixture was stirred 16 hours down in 25 ℃, then with the water dilution, and with EtOAc extraction (3x).The organic extract liquid that will merge dehydrates (MgSO4) with the 1N NaOH aqueous solution and brine wash, and concentrates in a vacuum.Make crude product chromatography (SiO2; Gradient liquid progressively, 10-20-30% solvent B, wherein, solvent orange 2 A=hexane, and solvent B=EtOAc), and A compound (0.146 gram partly; 90%).B.?

In part A compound (0.100 gram; 0.27 mmole) in the solution in THF (2.23 milliliters) and water (0.22 milliliter), add LiOH.H2O (0.013 gram; 0.54 mmole).Reaction mixture under 45 ℃, was stirred 1 hour in the little glass bottle of sealing, add the LiOH.H2O of another equivalent then.Reaction mixture was stirred 16 hours down at 45 ℃, then be cooled to room temperature.In vacuum, remove volatile matter, and make all the other aqueous solution with 0.5N HCl acidified aqueous solution to pH＜2.Extract (3x) water layer again with EtOAc.The organic extract liquid that will merge dehydrates (MgSO4) with brine wash, and concentrates in a vacuum, and gets partly B compound (0.107 gram; 100%).C.?

In embodiment 13 part E compound (0.073 grams; 0.29 mmole) in the solution in DMF (1.21 milliliters), add HOAT (0.038 gram; 0.278 part B compound (0.084 gram mmole); 0.242 mmole) and (0.049 milliliter of DIPEA; 0.278 mmole), and last EDCI (0.053 gram; 0.278 mmole).Reaction mixture was stirred 16 hours down in 25 ℃.Add water, and with EtOAc extraction (3x) mixture.The organic extract liquid that will merge is with saturated NH ₄The Cl aqueous solution, the saturated NaHCO3 aqueous solution and brine wash dehydrate (MgSO4), and concentrate in a vacuum.Make residue through preparing HPLC purifying (100 millimeters posts of YMC anti-phase ODS-5 micron 30 x; Flow velocity=40 ml/min, 25 to 100% solvent B went through 12 minutes, wherein, solvent orange 2 A=90: 10: 0.1H2O: CH3CN: TFA, and solvent B=90: 10: 0.1CH3CN: H2O: TFA), and get (69.7 milligrams of title compounds; 49%), is clear, colorless oil.[M+H]+＝581.5；1H?NMR(400MHz，CDCl3)δ1.21-1.26(m，9H)，3.06(t，J＝6.87Hz，2H)，3.21(s，1H)，3.26(s，1H)，3.31-3.35(m，3H)，3.41-3.53(m，2H)，3.98-4.10(m，4H)，4.18(t，?J＝6.60Hz，2H)，4.61-4.71(m，1H)，6.63-6.70(m，1H)，6.84-7.06(m，3H)，7.10-7.17(m，1H)，7.18-7.25(m，J＝12.64Hz，3H)，7.26-7.30(m，1H)。Example 129? A.?

In embodiment 124 part C compound (0.100 grams; 0.416 mmole), add 2-(3-fluorophenyl) ethanol (0.24 gram; 1.67 mmole in toluene (2.08 milliliters), then is embodiment 97 part B compound (0.68 grams; 1.67 the suspension-s in CH2Cl2 (7.6 milliliters) mmole).Reaction mixture was stirred 16 hours down in 25 ℃, then with the water dilution, and with EtOAc extraction (3x).The organic extract liquid that will merge dehydrates (MgSO4) with the 1N NaOH aqueous solution and brine wash, and concentrates in a vacuum.Make crude product chromatography (SiO2; Gradient liquid progressively, 10-20-30% solvent B, wherein, solvent orange 2 A=hexane, and solvent B=EtOAc), and A compound (0.146 gram partly; 90%).B.?

In part A compound (0.100 gram; 0.27 mmole) in the solution in THF (2.23 milliliters) and water (0.22 milliliter), add LiOH.H2O (0.013 gram; 0.54 mmole).Reaction mixture under 45 ℃, was stirred 1 hour in the little glass bottle of sealing, add the LiOH.H2O of another equivalent then.Reaction mixture was stirred 16 hours down at 45 ℃, then be cooled to room temperature.In vacuum, remove volatile matter, and make all the other aqueous solution with 0.5N HCl acidified aqueous solution to pH＜2.Extract (3x) water layer again with EtOAc.The organic extract liquid that will merge dehydrates (MgSO4) with brine wash, and concentrates in a vacuum, and gets partly B compound (0.107 gram; 100%).C.?

In embodiment 13 part E compound (0.092 grams; 0.37 mmole) in the solution in DMF (1.54 milliliters), add HOAT (0.038 gram; 0.35 part B compound (0.107 gram mmole); 0.308 mmole), DIPEA is (0.062 milliliter; 0.35 mmole) and last EDCI (0.068 the gram; 0.35 mmole).Reaction mixture was stirred 16 hours down in 25 ℃.Add water, and with EtOAc extraction (3x) mixture.The organic extract liquid that will merge dehydrates (MgSO4) with the saturated NH4Cl aqueous solution, the saturated NaHCO3 aqueous solution and brine wash, and concentrates in a vacuum.Make residue through preparing HPLC purifying (100 millimeters posts of YMC anti-phase ODS-5 micron 30 x; Flow velocity=40 ml/min, 25 to 100% solvent B went through 12 minutes, wherein, solvent orange 2 A=90: 10: 0.1H2O: CH3CN: TFA, and solvent B=90: 10: 0.1CH3CN: H2O: TFA), and get (78.5 milligrams of title compounds; 44%), is clear, colorless oil.[M+H]+＝581.1；1H?NMR(400MHz，CDCl3)δ1.17-1.28(m，9H)，3.01(t，J＝6.32Hz，2H)，3.24(s，1H)，3.26-3.36(m，4H)，3.42-3.54(m，2H)，4.00-4.14(m，4H)，4.19(t，J＝6.32Hz，2H)，4.62-4.73(m，1H)，6.64-6.70(m，1H)，6.79-6.88(m，J＝8.52，8.52Hz，1H)，6.88-7.02(m，3H)，7.12-7.22(m，1H)，7.25-7.30(m，1H)，7.28(s，1H)，7.33(s，1H)，7.31-7.36(m，1H)。Example 130? A.?

In embodiment 124 part C compound (0.100 grams; 0.416 mmole), add 4-(2-hydroxyethyl) benzonitrile (0.09 gram in the toluene (2.08 milliliters); 0.62 mmole), then be embodiment 97 part B compound (0.26 grams; 0.62 the suspension-s in CH2Cl2 (7.14 milliliters) mmole).Reaction mixture was stirred 16 hours down in 25 ℃, then with the water dilution, and with EtOAc extraction (3x).The organic extract liquid that will merge dehydrates (MgSO4) with the 1NNaOH aqueous solution and brine wash, and concentrates in a vacuum.Make crude product chromatography (SiO2; Stepwise gradient liquid, 5-10-20% solvent B, wherein, solvent orange 2 A=hexane, and solvent B=EtOAc), and get partly A compound (0.100 gram; 63%).B.?

Compound (0.15 gram in part A; 0.40 mmole) in the solution in THF (3.27 milliliters) and water (0.33 milliliter), add LiOH.H2O (0.019 gram; 0.79 mmole).Reaction mixture under 45 ℃, was stirred 1 hour in the little glass bottle of sealing, add the LiOH of another equivalent then.Reaction mixture was stirred 16 hours down at 45 ℃, then be cooled to room temperature.In vacuum, remove volatile matter, and make all the other aqueous solution with 0.5N HCl acidified aqueous solution to pH＜2.Extract (3x) water layer again with EtOAc.The organic extract liquid that will merge dehydrates (MgSO4) with brine wash, and concentrates in a vacuum, and gets partly B compound (0.140 gram; 85%).C.?

In embodiment 13 part E compound (0.114 grams; 0.454 mmole) in the solution in DMF (1.89 milliliters), add HOAT (0.059 gram; 0.44 part B compound (0.134 gram mmole); 0.378 mmole), DIPEA is (0.076 milliliter; 0.35 mmole) and last EDCI (0.083 the gram; 0.435 mmole).Reaction mixture was stirred 16 hours down in 25 ℃.Add water, and with EtOAc extraction (3x) mixture.The organic extract liquid that will merge dehydrates (MgSO4) with the saturated NH4Cl aqueous solution, the saturated NaHCO3 aqueous solution and brine wash, and concentrates in a vacuum.Make residue through preparing HPLC purifying (100 millimeters posts of YMC anti-phase ODS-5u30x; Flow velocity=40 ml/min, 25 to 100% solvent B went through 12 minutes, wherein, solvent orange 2 A=90: 10: 0.1H2O: CH3CN: TFA, and solvent B=90: 10: 0.1CH3CN: H2O: TFA), and get (86.5 milligrams of title compounds; 39%), is the viscous transparent white solid.[M+H]+＝588.1；1H?NMR(400MHz，CDCl3)：δ1.18-1.27(m，9H)，3.07(t，J＝6.32Hz，2H)，3.20(s，1H)，3.25(s，1H)，3.33(s，3H)，3.40-3.53(m，2H)，3.97-4.09(m，4H)，4.19(t，J＝6.32Hz，2H)，4.55-4.66(m，J＝3.85Hz，1H)，6.63(s，1H)，6.84-6.90(m，J＝3.30Hz，1H)，7.17-7.21(m，J＝3.85Hz，1H)，7.24(s，1H)，7.33(d，J＝8.25Hz，2H)，7.53(d，J＝8.25Hz，2H)。Example 131?

A.?

In embodiment 124 part C compound (0.100 grams; 0.416 mmole), add 2-(4-fluorophenyl) ethanol (0.58 gram; 4.16 mmole) solution in toluene (2.18 milliliters) and embodiment 97 part B compound (1.71 grams; 4.16 the suspension-s in CH2Cl2 (7.60 milliliters) mmole).Reaction mixture was stirred 16 hours down in 25 ℃, then with the water dilution, and with EtOAc extraction (3x).The organic extract liquid that will merge dehydrates (MgSO4) with the 1NNaOH aqueous solution and brine wash, and concentrates in a vacuum.Make crude product chromatography (SiO2; Gradient liquid progressively, 5-10-15-20% solvent B, wherein, solvent orange 2 A=hexane, and solvent B=EtOAc), and A compound (0.137 gram partly; 86%).B.?

In part A compound (0.14 gram; 0.38 mmole) in the solution in THF (3.27 milliliters) and water (0.33 milliliter), add LiOH.H2O (0.010 gram; 0.38 mmole).Reaction mixture under 45 ℃, was stirred 1 hour in the little glass bottle of sealing, add the LiOH of another equivalent then.Reaction mixture was stirred 16 hours down at 45 ℃, then be cooled to room temperature.In vacuum, remove volatile matter, and make all the other aqueous solution with 0.5N HCl acidified aqueous solution to pH less than 2.Extract (3x) water layer again with EtOAc.The organic extract liquid that will merge dehydrates (MgSO4) with brine wash, and concentrates in a vacuum, and gets partly B compound (0.122 gram; 78%).C.?

In embodiment 13 part E compound (0.106 grams; 0.422 mmole) in the solution in DMF (1.76 milliliters), add HOAT (0.055 gram; 0.404 part B compound (0.122 gram mmole); 0.351 mmole), DIPEA is (0.071 milliliter; 0.404 mmole) and last EDCI (0.077 the gram; 0.404 mmole).Reaction mixture was stirred 16 hours down in 25 ℃.Add water, and with EtOAc extraction (3x) mixture.The organic extract liquid that will merge dehydrates (MgSO4) with the saturated NH4Cl aqueous solution, the saturated NaHCO3 aqueous solution and brine wash, and concentrates in a vacuum.Make residue through preparing HPLC purifying (100 millimeters posts of YMC anti-phase ODS-5u30 x; Flow velocity=40 ml/min, 25 to 100% solvent B went through 12 minutes, wherein, solvent orange 2 A=90: 10: 0.1H2O: CH3CN: TFA, and solvent B=90: 10: 0.1CH3CN: H2O: TFA), and get (80.0 milligrams of title compounds; 39%), is transparent light yellow oil.[M+H]+＝581.2；1H?NMR(400MHz，CDCl3)：δ1.21-1.33(m，9H)，3.06(t，2H)，3.25(s，1H)，3.31(s，1H)，3.39(s，3H)，3.45-3.60(m，2H)，4.00-4.15(m，4H)，4.19(t，2H)，4.60-4.70(m，1H)，6.65-6.72(m，1H)，6.88-6.94(m，1H)，6.99(t，2H)，7.13-7.27(m，4H)，11.77(s，1H)。Example 132?

A.?

In embodiment 124 part C compound (0.100 grams; 0.416 mmole) in the cold soln (0 ℃) in THF (2.08 milliliters), add (0.074 milliliter of (S)-(+)-3-hydroxyl tetrahydrofuran; 0.916 mmole) with Ph3P (0.24 gram; 0.916 mmole), then slowly add (0.178 milliliter of DIAD; 0.916 mmole).Reaction mixture was stirred 16 hours under 25 ℃ and Ar atmosphere.Reaction mixture is diluted with water, and with EtOAc extraction (3x).The organic extract liquid that will merge dehydrates (MgSO4) with the 1N NaOH aqueous solution and brine wash, and concentrates in a vacuum.Make crude product chromatography (SiO2; Stepwise gradient liquid, 10-15-20% solvent B, wherein, solvent orange 2 A=hexane, and solvent B=EtOAc), and get partly A compound (0.105 gram; 75%).B.?

In part A compound (0.105 gram; 0.337 mmole) in the solution in THF (2.79 milliliters) and water (0.279 milliliter), add LiOH.H2O (0.028 gram; 0.674 mmole).Reaction mixture under 45 ℃, was stirred 1 hour in the little glass bottle of sealing, add the LiOH of another equivalent then.Reaction mixture was stirred 16 hours down at 45 ℃, then be cooled to room temperature.In vacuum, remove volatile matter, and make all the other aqueous solution with 0.5N HCl acidified aqueous solution to pH＜2.Extract (3x) water layer again with EtOAc.The organic extract liquid that will merge dehydrates (MgSO4) with brine wash, and concentrates in a vacuum, and gets partly B compound (0.0964 gram; 97%).C.?

In embodiment 13 part E compound (0.098 grams; 0.390 mmole) in the solution in DMF (1.63 milliliters), add HOAT (0.051 gram; 0.374 part B compound (0.096 gram mmole); 0.325 mmole), DIPEA is (0.065 milliliter; 0.374 mmole) and last EDCI (0.072 the gram; 0.374 mmole).Reaction mixture was stirred 16 hours down in 25 ℃.Add water, and with EtOAc extraction (3x) mixture.The organic extract liquid that will merge dehydrates (MgSO4) with the saturated NH4Cl aqueous solution, the saturated NaHCO3 aqueous solution and brine wash, and concentrates in a vacuum.Make residue through preparing HPLC purifying (100 millimeters posts of YMC anti-phase ODS-5u30 x; Flow velocity=40 ml/min, 25 to 100% solvent B went through 12 minutes, wherein, solvent orange 2 A=90: 10: 0.1H2O: CH3CN: TFA, and solvent B=90: 10: 0.1CH3CN: H2O: TFA), and get (84.3 milligrams of title compounds; 49%), is clear, colorless oil.[M+H]+＝529.1；1H?NMR(400MHz，CDCl3)：δ1.19-1.34(m，9H)，2.06-2.30(m，2H)，3.25(s，1H)，3.30(s，1H)，3.39(s，3H)，3.43-3.61(m，2H)，3.84-4.00(m，4H)，4.00-4.13(m，4H)，4.54-4.64(m，1H)，4.91-5.00(m，1H)，6.62-6.70(m，1H)，6.80-6.88(m，J＝3.85Hz，1H)，7.06(s，1H)，7.13(s，1H)，10.53(s，1H)。Example 133? A.?

In embodiment 124 part C compound (0.100 grams; 0.416 mmole) in 0 ℃ of solution in THF (2.08 milliliters), add (0.033 milliliter of (R)-(-)-3-hydroxyl tetrahydrofuran; 0.416 mmole) and Ph ₃P (0.24 gram; 0.916 mmole), then slowly add (0.178 milliliter of DIAD; 0.916 mmole).Reaction mixture was stirred 16 hours under 25 ℃ and Ar, then with the water dilution, and with EtOAc extraction (3x).The organic extract liquid that will merge dehydrates (MgSO4) with the 1N NaOH aqueous solution and brine wash, and concentrates in a vacuum.Make crude product chromatography (SiO2; Stepwise gradient liquid, 10-15-20% solvent B, wherein, solvent orange 2 A=hexane, and solvent B=EtOAc), and get partly A compound (0.088 gram; 62%).B.?

In part A compound (0.088 gram; 0.282 mmole) in the solution in THF (2.33 milliliters) and water (0.233 milliliter), add LiOH.H2O (0.024 gram; 0.565 mmole).Reaction mixture under 45 ℃, was stirred 1 hour in the little glass bottle of sealing, add the LiOH of another equivalent then.Reaction mixture was stirred 16 hours down at 45 ℃, then be cooled to room temperature.In vacuum, remove volatile matter, and make all the other aqueous solution with 0.5N HCl acidified aqueous solution to pH＜2.Extract (3x) water layer again with EtOAc.The organic extract liquid that will merge dehydrates (MgSO4) with brine wash, and concentrates in a vacuum, and gets partly B compound (0.0654 gram; 74%).C.?

In embodiment 13 part E compound (0.066 grams; 0.265 mmole) in the solution in DMF (1.10 milliliters), add HOAT (0.035 gram; 0.254 part B compound (0.065 gram mmole); 0.221 mmole), DIPEA is (0.044 milliliter; 0.254 mmole) and last EDCI (0.049 the gram; 0.254 mmole).Reaction mixture was stirred 16 hours down in 25 ℃.Add water, and with EtOAc extraction (3x) mixture.The organic extract liquid that will merge dehydrates (MgSO4) with the saturated NH4Cl aqueous solution, the saturated NaHCO3 aqueous solution and brine wash, and concentrates in a vacuum.Make residue through preparing HPLC purifying (100 millimeters posts of YMC anti-phase ODS-5u30 x; Flow velocity=40 ml/min, 25 to 100% solvent B went through 12 minutes, wherein, solvent orange 2 A=90: 10: 0.1H2O: CH3CN: TFA, and solvent B=90: 10: 0.1CH3CN: H2O: TFA), and get (50.5 milligrams of title compounds; 43%), is clear, colorless oil.[M+H]+＝529.1；1H?NMR(400MHz，CDCl3)：δ1.21-1.33(m，9H)，2.03-2.17(m，1H)，2.17-2.28(m，1H)，3.25?(s，1H)，3.31(s，1H)，3.38(s，3H)，3.44-3.53(m，1H)，3.52-3.59(m，1H)，3.68(s，2H)，3.83-3.92(m，1H)，3.93-4.01(m，2H)，4.03-4.12(m，3H)，4.57-4.67(m，1H)，4.96-5.02(m，J＝2.20Hz，1H)，6.67(s，1H)，6.85-6.92(m，J＝3.85Hz，1H)，7.13(s，1H)，7.20(s，1H)。Example 134?

A.?

In embodiment 124 part C compound (0.125 grams; 0.519 mmole) in 0 ℃ of solution in THF (2.60 milliliters), add (0.105 milliliter of 2-(methylthio group) ethanol; 1.14 mmole) with Ph3P (0.30 gram; 1.142 mmole), then slowly add (0.222 milliliter of DIAD; 1.142 mmole).Reaction mixture was stirred 16 hours under 25 ℃ and Ar, then with the water dilution, and with EtOAc extraction (3x).The organic extract liquid that will merge dehydrates (MgSO4) with the 1N NaOH aqueous solution and brine wash, and concentrates in a vacuum.Make crude product chromatography (SiO2; Gradient liquid progressively, 20-30-50-60% solvent B, wherein, solvent orange 2 A=hexane, and solvent B=EtOAc), and (61.8 milligrams of A compounds partly; 38%).B.?

In part A compound (0.062 gram; 0.197 mmole) in the solution in THF (1.63 milliliters) and water (0.163 milliliter), add LiOH.H2O (0.016 gram; 0.393 mmole).Reaction mixture under 45 ℃, was stirred 1 hour in the little glass bottle of sealing, add the LiOH of another equivalent then.Reaction mixture was stirred 16 hours down at 45 ℃, then be cooled to room temperature.In vacuum, remove volatile matter, and make all the other aqueous solution with 0.5N HCl acidified aqueous solution to pH＜2.Extract (3x) water layer again with EtOAc.The organic extract liquid that will merge dehydrates (MgSO4) with brine wash, and concentrates in a vacuum, and gets partly B compound (0.052 gram; 88%).C.?

In embodiment 13 part E compound (0.059 grams; 0.236 mmole) in the solution in DMF (0.98 milliliter), add HOAT (0.031 gram; 0.226 part B compound (0.059 gram mmole); 0.196 mmole), DIPEA is (0.034 milliliter; 0.196 mmole) and last EDCI (0.043 the gram; 0.226 mmole).Reaction mixture was stirred 16 hours down in 25 ℃.Add water, and with EtOAc extraction (3x) mixture.The organic extract liquid that will merge dehydrates (MgSO4) with the saturated NH4Cl aqueous solution, the saturated NaHCO3 aqueous solution and brine wash, and concentrates in a vacuum.Make residue through preparing HPLC purifying (100 millimeters posts of YMC anti-phase ODS-5u30 x; Flow velocity=40 ml/min, 25 to 100% solvent B went through 12 minutes, wherein, solvent orange 2 A=90: 10: 0.1H2O: CH3CN: TFA, and solvent B=90: 10: 0.1CH3CN: H2O: TFA), and get (62.3 milligrams of title compounds; 60%), is clear, colorless oil.[M+H]+＝533.4；1H?NMR(400MHz，CDCl3)：δ1.23-1.31(m，9H)，2.15(s，3H)，3.27(s，1H)，3.31-3.37(m，4H)，3.44-3.56(m，2H)，3.99-4.15(m，4H)，4.19(t，2H)，4.65-4.77(m，1H)，6.69-6.74(m，1H)，6.95-7.00(m，1H)，7.28-7.33(m，1H)，7.35-7.40(m，1H)。Embodiment 135

In embodiment 134 part C compound (0.040 grams; 0.075 mmole) in 0 ℃ of solution in CH2Cl2 (0.75 milliliter), add mCPBA (0.026 gram; 0.15 mmole).Reaction mixture was stirred 1 hour down in 0 ℃, be warmed to room temperature then.Filter reaction mixture makes the reaction cancellation with the saturated NaHCO3 aqueous solution, and with CH2Cl2 extraction (3x).The organic extract liquid that will merge dehydrates (MgSO4) with brine wash, and concentrates in a vacuum.Make residue through preparing HPLC purifying (100 millimeters posts of YMC anti-phase ODS-5u 30x; Flow velocity=40 ml/min, 25 to 100% solvent B went through 12 minutes, wherein, solvent orange 2 A=90: 10: 0.1H2O: CH3CN: TFA, and solvent B=90: 10: 0.1CH3CN: H2O: TFA), and get (10.6 milligrams of title compounds; 25%), is clear, colorless oil.[M+H]+＝565.2；1H?NMR(400MHz，CDCl3)：δ1.26-1.34(m，9H)，3.05(s，3H)，3.29(s，1H)，3.34(s，1H)，3.39(s，4H)，3.43(t，3H)，3.49-3.60(m，2H)，4.07-4.18(m，4H)，4.52(t，J＝10.44Hz，3H)，4.69-4.79(m，1H)，6.72-6.78(m，1H)，6.99-7.05(m，1H)，7.40(s，1H)，7.45(s，1H)。Example 136? A.?

In phenylformic acid 2-hydroxyl-methyl esters (0.20 gram; 1.31 mmole) in the cold soln (0 ℃) in THF (5.70 milliliters), add (R)-(-)-1-methoxyl group-2-propyl alcohol (0.178 gram; 1.97 mmole) with Ph3P (0.517 gram; 1.97 mmole), then slowly add DIAD (0.398 gram; 1.97 mmole).Reaction mixture was stirred 16 hours under 25 ℃ and Ar, then with the water dilution, and with EtOAc extraction (3x).The organic extract liquid that will merge dehydrates (MgSO4) with the 1N NaOH aqueous solution and brine wash, and concentrates in a vacuum.Make residue chromatography (SiO2; Stepwise gradient liquid, 10-20-30% solvent B, wherein, solvent orange 2 A=hexane, and solvent B=EtOAc), and get partly A compound (0.219 gram; 74%).B.?

In part A compound (0.219 gram; 0.975 mmole) in the solution in THF (3.75 milliliters) and water (1.19 milliliters), add LiOH.H2O (0.049 gram; 1.07 mmole).Reaction mixture under 45 ℃, was stirred 1 hour in the little glass bottle of sealing, add the LiOH of another equivalent then.Reaction mixture was stirred 2 hours down at 50 ℃, then be cooled to room temperature.In vacuum, remove volatile matter, and make all the other aqueous solution with 0.5N HCl acidified aqueous solution to pH＜2.Extract (3x) water layer again with EtOAc.The organic extract liquid that will merge dehydrates (MgSO4) with brine wash, and concentrates in a vacuum, and gets partly B compound (0.221 gram; 100%).C.?

In embodiment 13 part E compound (0.043 grams; 0.171 mmole) in the solution in DMF (0.55 milliliter), add HOAT (0.022 gram; 0.164 part B compound (0.030 gram mmole); 0.143 mmole), DIPEA is (0.029 milliliter; 0.164 mmole) and last EDCI (0.031 the gram; 0.164 mmole).Reaction mixture was stirred 16 hours down in 25 ℃.Add water, and with EtOAc extraction (3x) mixture.The organic extract liquid that will merge dehydrates (MgSO4) with the saturated NH4Cl aqueous solution, the saturated NaHCO3 aqueous solution and brine wash, and concentrates in a vacuum.Make residue through preparing HPLC purifying (100 millimeters posts of YMC anti-phase ODS-5 micron 30 x; Flow velocity=40 ml/min, 25 to 100% solvent B went through 12 minutes, wherein, solvent orange 2 A=90: 10: 0.1H2O: CH3CN: TFA, and solvent B=90: 10: 0.1CH3CN: H2O: TFA), and get (17.3 milligrams of title compounds; 27%), is the stickiness light yellow oil.[M+H]+＝443.3；1H?NMR(400MHz，CDCl3)：δ1.22-1.30(m，9H)，3.30(s，1H)，3.35(s，3H)，3.35(s，4H)，3.47-3.58(m，2H)，4.01-4.16(m，4H)，4.75-4.83(m，1H)，6.96-7.00(m，J＝3.85Hz，1H)，7.14-7.18(m，J＝8.24，2.20Hz，1H)，7.37(t，J＝7.97Hz，1H)，7.70(d，J＝7.70Hz，2H)，7.70(d，J＝7.70Hz，1H)。Example 137?

A.?

Under Ar, in partly A acid of embodiment 33 (0.058 gram; 0.17 mmole) in the solution in Et2O (1.30 milliliters), add TMSI (0.203 gram; 1.01 mmole).Reaction mixture was stirred 16 hours down in 25 ℃, be cooled to-40 ℃ then, make the reaction cancellation carefully, and concentrate in a vacuum with water.Residue is diluted with the EtOAc and the 1N HCl aqueous solution.Organic layer with 10% (w/v) Na2S2O3 solution washing,, is dehydrated (MgSO4) with brine wash, and concentrate in a vacuum, and get partly A compound (0.056 gram; 99%), is yellow oil.B.?

With TBSCl (0.076 gram; 0.504 the solution in DMF (0.37 milliliter) mmole) is added into partly A compound (0.056 gram; 0.17 mmole).Add imidazoles (0.069 gram; 1.01 mmole), and reaction mixture stirred 2 hours down in 25 ℃, between EtOAc and the saturated NH4Cl aqueous solution, does the separatory processing then.Organic phase with the saturated NH4Cl aqueous solution and brine wash, is dehydrated (MgSO4), and concentrate in a vacuum.Make residue chromatography (SiO2; Stepwise gradient liquid, 20-25-30% solvent B, wherein, solvent orange 2 A=hexane, and solvent B=EtOAc), and get partly B compound (0.057 gram; 76%).C.?

In embodiment 13 part E compound (0.038 grams; 0.152 mmole) in the solution in DMF (0.49 milliliter), add HOAT (0.020 gram; 0.146 part B compound (0.057 gram mmole); 0.127 mmole), DIPEA is (0.026 milliliter; 0.146 mmole) and last EDCI (0.028 the gram; 0.146 mmole).Reaction mixture was stirred 16 hours down in 25 ℃.Add water, and with EtOAc extraction (3x) mixture.The organic extract liquid that will merge is with the saturated NH4Cl aqueous solution, the saturated NaHCO3 aqueous solution and brine wash.Make organic layer dehydrate (MgSO4), and concentrate in a vacuum, and get partly C compound (0.063 gram; 74%), is transparent golden oil.D.?

In part C compound (0.063 gram; 0.094 mmole) in 0 ℃ of solution in THF (0.47 milliliter), add TBAF (0.090 milliliter of 1M solution; 0.094 mmole).Reactant was stirred 1 hour down in 0 ℃, and add TBAF (0.090 milliliter of 1M solution of another equivalent; 0.094 mmole).Reactant in 0 ℃ of following restir 1 hour, is concentrated then in a vacuum.Making residue between EtOAc and salt solution, make separatory handles.Organic layer with brine wash, is dehydrated (MgSO4), and concentrate in a vacuum.Make residue through preparing HPLC purifying (100 millimeters posts of YMC anti-phase ODS-5 micron 30 x; Flow velocity=40 ml/min, 25 to 100% solvent B went through 12 minutes, wherein, solvent orange 2 A=90: 10: 0.1H2O: CH3CN: TFA, and solvent B=90: 10: 0.1CH3CN: H2O: TFA), and get (23.6 milligrams of title compounds; 45%), is clear, colorless oil.[M+H]+＝563.5；1H?NMR(400MHz，CDCl3)：δ1.16-1.31(m，?J＝11.82，6.32Hz，12H)，1.98(s，1H)，2.77-2.87(m，J＝13.74Hz，1H)，2.93-3.02(m，J＝13.74Hz，1H)，3.27(s，1H)，3.32(s，1H)，3.61-3.69(m，1H)，3.69-3.76(m，1H)，4.01-4.14(m，4H)，4.60-4.72(m，2H)，6.62-6.66(m，J＝2.20，2.20Hz，1H)，6.96(d，J＝3.85Hz，1H)，7.09-7.24(m，5H)，7.28(s，1H)7.32(s，1H)。Example 138?

A.?

With embodiment 124 part C compound (0.100 grams; 0.416 phenyl-boron dihydroxide (0.102 gram mmole); 0.832 neutralized verdigris (II) (0.151 gram mmole); 0.832 Et mmole), ₃N (0.211 gram; 2.08 mmole) reaching the solution of just activated 4A molecular sieve (1.2 gram) in CH2Cl2 (8.32 milliliters) stirred 16 hours down in 25 ℃.After 2 days, add boric acid, neutralized verdigris (II) and the Et of other solvent (8 milliliters), each two equivalent ₃N.In altogether after 5 days, find 70% transformation efficiency.Filter reaction mixture, and wash with CH2Cl2.Concentrate the filtrating of merging in a vacuum, and make residue between the EtOAc and the 1N HCl aqueous solution, do the separatory processing.Organic layer with the saturated NaHCO3 aqueous solution and brine wash, is dehydrated (MgSO4), and concentrate in a vacuum.Make crude product chromatography (SiO2; Gradient liquid progressively, 10-20-30% solvent B, wherein, solvent orange 2 A=hexane, and solvent B=EtOAc), and (70.2 milligrams of A compounds partly; 83% productive rate is a benchmark with the starting substance that is reclaimed).B.?

In part A compound (0.070 gram; 0.222 mmole) in the solution in THF (0.85 milliliter) and water (0.27 milliliter), add LiOH.H2O (0.010 gram; 0.244 mmole).Reaction mixture under 45 ℃, was stirred 1 hour in the little glass bottle of sealing, add the LiOH.H2O of another equivalent then.Reaction mixture in 45 ℃ of following restir 3 hours, then is cooled to room temperature.Remove volatile matter in a vacuum, and make all the other aqueous solution with 0.5N HCl acidified aqueous solution to pH＜2.Extract (3x) water layer again with EtOAc.The organic extract liquid that will merge dehydrates (MgSO4) with brine wash, and concentrates in a vacuum, and gets partly B compound (0.060 gram; 90%).C.?

In embodiment 13 part E compound (0.030 grams; 0.119 mmole) in the solution in DMF (0.38 milliliter), add HOAT (0.016 gram; 0.114 part B compound (0.03 gram mmole); 0.099 mmole), DIPEA is (0.020 milliliter; 0.114 mmole) and last EDCI (0.022 the gram; 0.114 mmole).Reaction mixture was stirred 16 hours down in 25 ℃.The embodiment 13 that adds another equivalent is the E compounds partly, and with reaction mixture in 25 ℃ of following restir 16 hours, use further to transform.Add water, and with EtOAc extraction (3x) mixture.The organic extract liquid that will merge dehydrates (MgSO4) with the saturated NH4Cl aqueous solution, the saturated NaHCO3 aqueous solution and brine wash, and concentrates in a vacuum.Make residue through preparing HPLC purifying (100 millimeters posts of YMC anti-phase ODS-5 micron 30 x; Flow velocity=40 ml/min, 25 to 100% solvent B went through 12 minutes, wherein, solvent orange 2 A=90: 10: 0.1H2O: CH3CN: TFA, and solvent B=90: 10: 0.1CH3CN: H2O: TFA), and get (0.010 milligram of title compound; 20%), is stickiness yellow glass material.[M+H]+＝535.5；1H?NMR(400MHz，CDCl3)：δ1.21-1.31(m，9H)，3.26(s，1H)，3.29-3.36(m，4H)，3.46-3.53(m，2H)，4.02-4.15(m，4H)，4.73-4.87(m，1H)，6.74-6.81(m，1H)，6.92-7.02(m，3H)，7.09(t，J＝7.42Hz，1H)，7.25-7.34(m，3H)，7.48(s，1H)。Example 139? A.?

In embodiment 124 part C compound (0.110 grams; 0.458 mmole) in 0 ℃ of solution in THF (2.29 milliliters), add (0.107 milliliter of 3-(methylthio group) third-1-alcohol; 1.01 mmole) with Ph3P (0.265 gram; 1.01 mmole), then slowly add (0.195 milliliter of DIAD; 1.01 mmole).Reaction mixture was stirred 16 hours under 25 ℃ and Ar, then with the water dilution, and with EtOAc extraction (3x).The organic extract liquid that will merge dehydrates (MgSO4) with the 1N NaOH aqueous solution and brine wash, and concentrates in a vacuum.Make crude product chromatography (SiO2; Stepwise gradient liquid, 10-20% solvent B, wherein, solvent orange 2 A=hexane, and solvent B=EtOAc), and get partly A compound (0.110 gram; 73%).B.?

In part A compound (0.110 gram; 0.334 mmole) in 0 ℃ of solution in CH2Cl2 (3.34 milliliters), add mCPBA (0.115 gram; 0.67 mmole).Reaction mixture was stirred 1 hour down in 0 ℃, add the saturated NaHCO3 aqueous solution then, and with CH2Cl2 extraction (3x) mixture.The organic extract liquid that will merge dehydrates (MgSO4) with brine wash, and concentrates in a vacuum, and gets partly B compound (0.161 gram; 88%).C.?

In part C compound (0.162 gram; 0.450 mmole) in the solution in THF (1.73 milliliters) and water (0.549 milliliter), add LiOH.H2O (0.021 gram; 0.495 mmole).Reaction mixture under 45 ℃, was stirred 1 hour in the little glass bottle of sealing, add the LiOH of another equivalent then.Reaction mixture was stirred 16 hours down at 45 ℃, then be cooled to room temperature.In vacuum, remove volatile matter, and make all the other aqueous solution with 0.5N HCl acidified aqueous solution to pH＜2.Extract (3x) water layer again with EtOAc.The organic extract liquid that will merge dehydrates (MgSO4) with brine wash, and concentrates in a vacuum, and gets partly C compound (0.147 gram; 94%).D.?

In embodiment 13 part E compound (0.026 grams; 0.104 mmole) in the solution in DMF (0.33 milliliter), add HOAT (0.014 gram; 0.100 part C compound (0.030 gram mmole); 0.087 mmole), DIPEA is (0.017 milliliter; 0.100 mmole) and last EDCI (0.019 the gram; 0.100 mmole).Reaction mixture was stirred 16 hours down in 25 ℃.Add water, and with EtOAc extraction (3x) mixture.The organic extract liquid that will merge dehydrates (MgSO4) with the saturated NH4Cl aqueous solution, the saturated NaHCO3 aqueous solution and brine wash, and concentrates in a vacuum.Make residue through preparing HPLC purifying (100 millimeters posts of YMC anti-phase ODS-5u30x; Flow velocity=40 ml/min, 25 to 100% solvent B went through 12 minutes; Wherein, solvent orange 2 A=90: 10: 0.1H2O: CH3CN: TFA, and solvent B=90: 10: 0.1CH3CN: H2O: TFA); And get title compound (8 milligrams, 16% productive rate), be the white solid lyophilized products.[M+H]+＝579.4；1H?NMR(400MHz，CDCl3)：δ1.14-1.28(m，9H)，2.20-2.33(m，2H)，2.89(s，3H)，3.13-3.26(m，4H)，3.33(s，3H)，3.40-3.54(m，2H)，3.92-4.05(m，4H)，4.05-4.12(m，J＝5.77，5.77Hz，2H)，4.53-4.63(m，1H)，6.61-6.65(m，1H)，6.78-6.86(m，J＝3.85Hz，1H)，7.14(s，1H)，7.19(s，1H)。Embodiment 140 A.

[00152] is in embodiment 124 part C compound (0.110 grams; 0.458 mM) at the THF(2.29 milliliter) in 0 ℃ of solution in; Add (0.138 milliliter of (S)-(+)-1- phenyl-2- propyl alcohol; 1.01 mM) with the Ph3P(0.265 gram; 1.01 mM), then slowly add the DIAD(0.195 milliliter; 1.01 mM).Reaction mixture was stirred 16 hours under 25 ℃ and Ar, then with the water dilution, and with EtOAc extraction (3x).The organic extract liquid that will merge dehydrates (MgSO4) with the 1N NaOH aqueous solution and brine wash, and concentrates in a vacuum.Make residue chromatography (SiO2; Stepwise gradient liquid, 5-10% solvent B, wherein, solvent orange 2 A=hexane, and solvent B=EtOAc), and get partly A compound (0.133 gram; 81%).B.?

In part A compound (0.133 gram; 0.371 mmole) in the solution in THF (1.43 milliliters) and water (0.45 milliliter), add LiOH.H2O (0.017 gram; 0.408 mmole).Reaction mixture under 45 ℃, was stirred 1 hour in the little glass bottle of sealing, add the LiOH of another equivalent then.Reaction mixture was stirred 16 hours down at 45 ℃, then be cooled to room temperature.In vacuum, remove volatile matter, and make all the other aqueous solution with 0.5N HCl acidified aqueous solution to pH＜2.Extract (3x) water layer again with EtOAc.The organic extract liquid that will merge dehydrates (MgSO4) with brine wash, and concentrates in a vacuum, and gets partly B compound (0.123 gram; 96%).C.?

In embodiment 13 part E compound (0.026 grams; 0.105 mmole) in the solution in DMF (0.34 milliliter), add HOAT (0.014 gram; 0.100 part B compound (0.030 gram mmole); 0.087 mmole), DIPEA is (0.017 milliliter; 0.100 mmole) and last EDCI (0.019 the gram; 0.100 mmole).Reaction mixture was stirred 16 hours down in 25 ℃.Add water, and with EtOAc extraction (3x) mixture.The organic extract liquid that will merge dehydrates (MgSO4) with the saturated NH4Cl aqueous solution, the saturated NaHCO3 aqueous solution and brine wash, and concentrates in a vacuum.Make residue through preparing HPLC purifying (100 millimeters posts of YMC anti-phase ODS-5u30 x; Flow velocity=40 ml/min, 25 to 100% solvent B went through 12 minutes, wherein, solvent orange 2 A=90: 10: 0.1H2O: CH3CN: TFA, and solvent B=90: 10: 0.1CH3CN: H2O: TFA), and get (16.4 milligrams of title compounds; 33%), is clear, colorless oil.[M+H]+＝577.4；1H?NMR(400MHz，CDCl3)：δ1.04-1.32(m，12H)，2.65-2.86(m，J＝13.74Hz，1H)，2.88-3.06(m，1H)，3.10-3.25(m，J＝20.89Hz，2H)，3.32(s，3H)，3.36-3.55(m，2H)，3.85-4.05?(m，J＝7.15Hz，4H)，4.34-4.63(m，2H)，6.41-6.66(m，1H)，6.67-6.81(m，1H)，6.95-7.07(m，2H)，7.08-7.29(m，5H)，10.44(s，1H)，10.44(s，1H)。Example 141?

A.?

In phenylformic acid 3-hydroxyl-methyl esters (0.500 gram; 3.29 mmole) in the solution in DMF (8.23 milliliters), add K2CO3 (0.908 gram; 6.57 mmole) with fluorine-based-4-(methylsulfonyl) benzene (0.573 gram; 3.29 mmole).Reaction mixture was stirred 2 days down in 120 ℃ and Ar, be cooled to room temperature then.Remove volatile matter in a vacuum.Making residue between the saturated NaHCO3 aqueous solution and EtOAc, make separatory handles.Organic layer with the 1N HCl aqueous solution and brine wash, is dehydrated (MgSO4), and concentrate in a vacuum.Make residue chromatography (SiO2; Stepwise gradient liquid, 20-30-40% solvent B, wherein, solvent orange 2 A=hexane, and solvent B=EtOAc), and get partly A compound (0.583 gram; 58%).B.?

In part A compound (0.200 gram; 0.653 mmole) in the solution in THF (2.51 milliliters) and water (0.80 milliliter), add LiOH.H2O (0.030 gram; 0.718 mmole).Reaction mixture under 45 ℃, was stirred 1 hour in the little glass bottle of sealing, add the LiOH of another equivalent then.Reaction mixture was stirred 2 hours down at 50 ℃, then be cooled to room temperature.In vacuum, remove volatile matter, and make all the other aqueous solution with 0.5N HCl acidified aqueous solution to pH＜2.Extract (3x) water layer again with EtOAc.The organic extract liquid that will merge dehydrates (MgSO4) with brine wash, and concentrates in a vacuum, and gets partly B compound (0.176 gram; 92%).C.?

In embodiment 13 part E compound (0.309 grams; 0.124 mmole) in the solution in DMF (0.40 milliliter), add HOAT (0.016 gram; 0.118 part B compound (0.030 gram mmole); 0.103 mmole), DIPEA is (0.021 milliliter; 0.118 mmole) and last EDCI (0.023 the gram; 0.118 mmole).Reaction mixture was stirred 16 hours down in 25 ℃.Add water, and with EtOAc extraction (3x) mixture.The organic extract liquid that will merge dehydrates (MgSO4) with the saturated NH4Cl aqueous solution, the saturated NaHCO3 aqueous solution and brine wash, and concentrates in a vacuum.Make residue through preparing HPLC purifying (100 millimeters posts of YMC anti-phase ODS-5u30 x; Flow velocity=40 ml/min, 25 to 100% solvent B went through 12 minutes, wherein, solvent orange 2 A=90: 10: 0.1H2O: CH3CN: TFA, and solvent B=90: 10: 0.1CH3CN: H2O: TFA), and get (14.7 milligrams of title compounds; 27%), is the stickiness white solid.[M+H]+＝525.3；1H?NMR(400MHz，CDCl3)：δ1.20(t，J＝7.15Hz，6H)，2.99(s，3H)，3.21(s，1H)，3.26(s，1H)，3.95-4.08(m，4H)，6.85-6.92(m，J＝3.30Hz，1H)，7.00-7.10(m，J＝8.79Hz，2H)，7.24-7.32(m，J＝7.70Hz，1H)，7.53(t，J＝7.97Hz，1H)，7.77(s，1H)，7.74-7.80(m，1H)，7.84(d，J＝8.79Hz，2H)，7.92(d，J＝7.70Hz，1H)。Example 142? A.?

In embodiment 124 part C compound (0.110 grams; 0.458 mmole) in 0 ℃ of solution in THF (2.29 milliliters), add (0.109 milliliter of benzylalcohol; 1.01 mmole) with Ph3P (0.265 gram; 1.01 mmole), then slowly add (0.195 milliliter of DIAD; 1.01 mmole).Reaction mixture was stirred 16 hours under 25 ℃ and Ar, then with the water dilution, and with EtOAc extraction (3x).The organic extract liquid that will merge dehydrates (MgSO4) with the 1NNaOH aqueous solution and brine wash, and concentrates in a vacuum.Make residue chromatography (SiO2; Gradient liquid progressively, 10-15-20% solvent B, wherein, solvent orange 2 A=hexane, and solvent B=EtOAc), and A compound (0.160 gram partly; 100%).B.?

In part A compound (0.160 gram; 0.483 mmole) in the solution in THF (1.86 milliliters) and water (0.59 milliliter), add LiOH.H2O (0.022 gram; 0.532 mmole).Reaction mixture under 45 ℃, was stirred 2 hours in the little glass bottle of sealing, add the LiOH of another equivalent then.Reaction mixture was stirred 16 hours down at 45 ℃, then be cooled to room temperature.In vacuum, remove volatile matter, and make all the other aqueous solution with 0.5N HCl acidified aqueous solution to pH＜2.Extract (3x) water layer again with EtOAc.The organic extract liquid that will merge dehydrates (MgSO4) with brine wash, and concentrates in a vacuum, and gets partly B compound (0.137 gram; 90%).C.?

In embodiment 13 part E compound (0.029 grams; 0.114 mmole) in the solution in DMF (0.37 milliliter), add HOAT (0.015 gram; 0.109 part B compound (0.030 gram mmole); 0.095 mmole), DIPEA is (0.019 milliliter; 0.109 mmole) and last EDCI (0.021 the gram; 0.109 mmole).Reaction mixture was stirred 16 hours down in 25 ℃.Add water, and with EtOAc extraction (3x) mixture.The organic extract liquid that will merge dehydrates (MgSO4) with the saturated NH4Cl aqueous solution, the saturated NaHCO3 aqueous solution and brine wash, and concentrates in a vacuum.Make residue through preparing HPLC purifying (100 millimeters posts of YMC anti-phase ODS-5u30x; Flow velocity=40 ml/min, 25 to 100% solvent B went through 12 minutes, wherein, solvent orange 2 A=90: 10: 0.1H2O: CH3CN: TFA, and solvent B=90: 10: 0.1CH3CN: H2O: TFA), and get (18.6 milligrams of title compounds; 36%), is clear, colorless oil.[M+H]+＝549.2；1H?NMR(400MHz，CDCl3)：δ1.13-1.29(m，9H)，3.19(s，1H)，3.24(s，2H)，3.33(s，3H)，3.39-3.46(m，1H)，3.46-3.53(m，1H)，3.89-4.04(m，4H)，4.48-4.58(m，J＝3.85Hz，1H)，5.01(s，2H)，6.69-6.74(m，1H)，6.75-6.80(m，J＝3.85Hz，1H)，7.11(s，1H)，7.23-7.38(m，5H)。Example 143?

A.?

In embodiment 124 part C compound (0.110 grams; 0.458 mmole) in 0 ℃ of solution in THF (2.29 milliliters), add (0.121 milliliter of 2-phenylethyl alcohol; 1.01 mmole) with Ph3P (0.265 gram; 1.01 mmole), then slowly add (0.195 milliliter of DIAD; 1.01 mmole).Reaction mixture was stirred 16 hours under 25 ℃ and Ar, then with the water dilution, and with EtOAc extraction (3x).The organic extract liquid that will merge dehydrates (MgSO4) with the 1N NaOH aqueous solution and brine wash, and in vacuum, concentrates.Make residue chromatography (SiO2; Stepwise gradient liquid, 10-15-20% solvent B, wherein, solvent orange 2 A=hexane, and solvent B=EtOAc), and get partly A compound (0.127 gram; 81%).B.?

In part A compound (0.127 gram; 0.370 mmole) in the solution in THF (1.42 milliliters) and water (0.45 milliliter), add LiOH.H2O (0.017 gram; 0.407 mmole).Reaction mixture under 45 ℃, was stirred 2 hours in the little glass bottle of sealing, add the LiOH of another equivalent then.Reaction mixture was stirred 16 hours down at 45 ℃, then be cooled to room temperature.In vacuum, remove volatile matter, and make all the other aqueous solution with 0.5N HCl acidified aqueous solution to pH＜2.Extract (3x) water layer again with EtOAc.The organic extract liquid that will merge dehydrates (MgSO4) with brine wash, and concentrates in a vacuum, and gets partly B compound (0.112 gram; 91%).C.?

In embodiment 13 part E compound (0.027 grams; 0.109 mmole) in the solution in DMF (0.35 milliliter), add HOAT (0.014 gram; 0.104 part B compound (0.030 gram mmole); 0.091 mmole), DIPEA is (0.018 milliliter; 0.104 mmole) and last EDCI (0.020 the gram; 0.104 mmole).Reaction mixture was stirred 16 hours down in 25 ℃.Add water, and with EtOAc extraction (3x) mixture.The organic extract liquid that will merge dehydrates (MgSO4) with the saturated NH4Cl aqueous solution, the saturated NaHCO3 aqueous solution and brine wash, and concentrates in a vacuum.Make residue through preparing HPLC purifying (100 millimeters posts of YMC anti-phase ODS-5u30 x; Flow velocity=40 ml/min.25 to 100% solvent B went through 12 minutes, wherein, and solvent orange 2 A=90: 10: 0.1H2O: CH3CN: TFA, and solvent B=90: 10: 0.1CH3CN: H2O: TFA), and get (24.5 milligrams of title compounds; 48%), is clear, colorless oil.[M+H]+＝563.2；1H?NMR(400MHz，CDCl3)：δ1.16-1.28(m，6H)，3.02(t，J＝6.60Hz，2H)，3.20(s，1H)，3.25(s，1H)，3.33(s，3H)，3.41-3.54(m，2H)，3.96-4.08(m，4H)，4.16(t，J＝6.87Hz，2H)，4.57-4.67(m，1H)，6.63-6.69(m，1H)，6.83-6.89(m，J＝3.85Hz，1H)，7.13-7.28(m，7H)。Embodiment 144

In embodiment 13 part E compound (0.100 grams; 0.400 mmole) in the solution in DMF (2.0 milliliters), add HOAT (0.052 gram; 0.383 3-isopropoxy phenylformic acid (0.060 gram mmole); 0.333 mmole), DIPEA is (0.07 milliliter; 0.383 mmole) and last EDCI (0.073 the gram; 0.383 mmole).Reaction mixture was stirred 16 hours down in 25 ℃.Add water, and with EtOAc extraction (3x) mixture.The organic extract liquid that will merge dehydrates (MgSO4) with the 0.5N HCl aqueous solution and brine wash, and concentrates in a vacuum.Make residue through preparing HPLC purifying (100 millimeters posts of YMC anti-phase ODS-5u 30 x; Flow velocity=40 ml/min, 25 to 100% solvent B went through 12 minutes, wherein, solvent orange 2 A=90: 10: 0.1H2O: CH3CN: TFA, and solvent B=90: 10: 0.1CH3CN: H2O: TFA), and get (9.4 milligrams of title compounds; 7%), is clear, colorless oil.[M+H]+＝413.1；1H?NMR(400MHz，CDCl3)：δ1.21-1.34(m，J＝7.15，7.15Hz，12H)，3.26(s，1H)，3.31(s，1H)，4.00-4.14(m，4H)，4.68-4.80(m，1H)，6.91-6.99(m，1H)，7.04-7.12(m，J＝8.25Hz，?1H)，7.31-7.41(m，1H)，7.62-7.72(m，2H)。Embodiment 145

In embodiment 13 part E compound (0.027 grams; 0.105 mmole) in the solution in DMF (0.34 milliliter), add HOAT (0.013 gram; 0.093 partly A acid of embodiment 33 (0.030 gram mmole); 0.087 mmole), DIPEA is (0.016 milliliter; 0.093 mmole) and last EDCI (0.018 the gram; 0.932 mmole).Reaction mixture was stirred 16 hours down in 25 ℃.Add water, and with EtOAc extraction (3x) mixture.The organic extract liquid that will merge dehydrates (MgSO4) with the saturated NH4Cl aqueous solution, the saturated NaHCO3 aqueous solution and brine wash, and concentrates in a vacuum.Make residue through preparing HPLC purifying (100 millimeters posts of YMC anti-phase ODS-5u 30x; Flow velocity=40 ml/min, 25 to 100% solvent B went through 12 minutes, wherein, solvent orange 2 A=90: 10: 0.1H2O: CH3CN: TFA, and solvent B=90: 10: 0.1CH3CN: H2O: TFA), and get (35.2 milligrams of title compounds; 70%), is clear, colorless oil.[M+H]+＝577.2；1H?NMR(400MHz，CDCl3)：δ1.21-1.37(m，12H)，2.82-2.93(m，J＝14.02，5.22Hz，1H)，2.99-3.09(m，1H)，3.32-3.48(m，5H)，3.51-3.66(m，2H)，4.06-4.26(m，4H)，4.68-4.84(m，2H)，6.68-6.77(m，1H)，6.96-7.07(m，J＝3.85Hz，1H)，7.13-7.41(m，7H)，10.77(s，1H)。Example 146?

A.?

In embodiment 26 part A compound (0.166 grams; 0.515 mmole) in 0 ℃ of solution in THF (2.60 milliliters), add (0.087 milliliter of iPrOH; 1.13 mmole) with Ph3P (0.30 gram; 1.13 mmole), then slowly add (0.219 milliliter of DIAD; 1.13 mmole).Reaction mixture was stirred 16 hours under 25 ℃ and Ar, then with the water dilution, and with EtOAc extraction (3x).The organic extract liquid that will merge dehydrates (MgSO4) with the 1NNaOH aqueous solution and brine wash, and in vacuum, concentrates.Make residue chromatography (SiO2; Stepwise gradient liquid, 20-40% solvent B, wherein, solvent orange 2 A=hexane, and solvent B=EtOAc), and get partly A compound (0.258 gram;＞100%, polluted by the DIAD through reduction).B.?

In part A compound (0.189 gram; 0.515 mmole) in the solution in THF (3.22 milliliters) and water (0.62 milliliter), add LiOH.H2O (0.024 gram; 0.567 mmole).Reaction mixture under 45 ℃, was stirred 1 hour in the little glass bottle of sealing, add the LiOH of another equivalent then.Reaction mixture was stirred 16 hours down at 45 ℃, then be cooled to room temperature.In vacuum, remove volatile matter, and make all the other aqueous solution with 0.5N HCl acidified aqueous solution to pH＜2.Extract (3x) water layer again with EtOAc.The organic extract liquid that will merge dehydrates (MgSO4) with brine wash, and concentrates in a vacuum, and gets partly B compound (0.214 gram;＞100%, polluted by the DIAD through reduction).C.?

In embodiment 13 part E compound (0.043 grams; 0.17 mmole) in the solution in DMF (0.55 milliliter), add HOAT (0.022 gram; 0.164 part B compound (0.050 gram mmole); 0.143 mmole), DIPEA is (0.029 milliliter; 0.164 mmole) and last EDCI (0.031 the gram; 0.164 mmole).Reaction mixture was stirred 16 hours down in 25 ℃.Add water, and with EtOAc extraction (3x) mixture.The organic extract liquid that will merge dehydrates (MgSO4) with the saturated NH4Cl aqueous solution, the saturated NaHCO3 aqueous solution and brine wash, and concentrates in a vacuum.Make residue through preparing HPLC purifying (100 millimeters posts of YMC anti-phase ODS-5u30x; Flow velocity=40 ml/min, 25 to 100% solvent B went through 12 minutes, wherein, solvent orange 2 A=90: 10: 0.1H2O: CH3CN: TFA, and solvent B=90: 10: 0.1CH3CN: H2O: TFA), and get (37.5 milligrams of title compounds; 60%), is clear, colorless oil.[M+H]+＝583.1；1H?NMR(400MHz，CDCl3)：δ1.17-1.38(m，12H)，3.04(s，3H)，3.27(s，1H)，3.32(s，1H)，3.99-4.14(m，4H)，4.64-4.77(m，1H)，6.79-6.83(m，1H)，6.88-6.96(m，J＝3.30Hz，1H)，7.07-7.15(m，J＝8.79Hz，2H)，7.30-7.36(m，1H)，7.47-7.54(m，1H)，7.84-7.92(m，J＝8.79Hz，2H)。Example 147?

A.?

In embodiment 124 part C compound (0.100 grams; 0.416 mmole) in 0 ℃ of solution in THF (2.08 milliliters), add (0.019 milliliter of iPrOH; 0.916 mmole) and Ph ₃P (0.240 gram; 0.916 mmole), then slowly add (0.177 milliliter of DIAD; 0.916 mmole).Reaction mixture was stirred 16 hours under 25 ℃ and Ar, then with the water dilution, and with EtOAc extraction (3x).The organic extract liquid that will merge dehydrates (MgSO4) with the 1N NaOH aqueous solution and brine wash, and concentrates in a vacuum.Make residue chromatography (SiO2; Stepwise gradient liquid, 5-10% solvent B, wherein, solvent orange 2 A=hexane, and solvent B=EtOAc), and get (82.2 milligrams of part A compounds; 70%).B.?

In part A compound (0.082 gram; 0.291 mmole) in the solution in THF (1.82 milliliters) and water (0.45 milliliter), add LiOH.H2O (0.014 gram; 0.32 mmole).Reaction mixture under 45 ℃, was stirred 3 hours in the little glass bottle of sealing, add the LiOH of another equivalent then.Reaction mixture was stirred 16 hours down at 45 ℃, then be cooled to room temperature.In vacuum, remove volatile matter, and make all the other aqueous solution with 0.5N HCl acidified aqueous solution to pH＜2.With EtOAc counterextraction (3x) water layer.The organic extract liquid that will merge dehydrates (MgSO4) with brine wash, and concentrates in a vacuum, and gets (83.0 milligrams of part B compounds; 100%).C.?

In embodiment 13 part E compound (0.034 grams; 0.134 mmole) in the solution in DMF (0.43 milliliter), add HOAT (0.018 gram; 0.129 part B compound (0.030 gram mmole); 0.112 mmole), DIPEA is (0.023 milliliter; 0.129 mmole) and last EDCI (0.025 the gram; 0.129 mmole).Reaction mixture was stirred 16 hours down in 25 ℃.Add water, and with EtOAc extraction (3x) mixture.The organic extract liquid that will merge dehydrates (MgSO4) with the saturated NH4Cl aqueous solution, the saturated NaHCO3 aqueous solution and brine wash, and concentrates in a vacuum.Make residue through preparing HPLC purifying (100 millimeters posts of YMC anti-phase ODS-5u30 x; Flow velocity=40 ml/min, 25 to 100% solvent B went through 12 minutes, wherein, solvent orange 2 A=90: 10: 0.1H2O: CH3CN: TFA, and solvent B=90: 10: 0.1CH3CN: H2O: TFA), and get (28.0 milligrams of title compounds; 50%), is clear, colorless oil.[M+H]+＝501.0；1H?NMR(400MHz，CDCl3)：δ1.20-1.30(m，15H)，3.22(s，1H)，3.27(s，1H)，3.34(s，3H)，3.42-3.56(m，2H)，4.00-4.12(m，4H)，4.56-4.70(m，2H)，6.64-6.69(m，1H)，6.88-6.95(m，J＝3.30Hz，1H)，7.21-7.28(m，J＝8.24Hz，2H)。Example 148?

A.?

In 3,5-dihydroxyl-oil of Niobe (1.00 grams; 5.95 mmole) in the cold soln (0 ℃) in THF (29.8 milliliters), add (0.787 milliliter of iPrOH; 13.10 mmole) with Ph3P (3.43 grams; 13.10 mmole), then slowly add (2.58 milliliters of DIAD; 13.1 mmole).Reaction mixture was stirred 16 hours down in 25 ℃ and Ar, then with the water dilution, and with EtOAc extraction (3x).The organic extract liquid that will merge dehydrates (MgSO4) with the 1N NaOH aqueous solution and brine wash, and concentrates in a vacuum.Make crude product chromatography (SiO2; Stepwise gradient liquid, 10-20-30% solvent B, wherein, solvent orange 2 A=hexane, and solvent B=EtOAc), and get partly A compound (1.27 grams; 85%).B.?

In part A compound (0.300 gram; 1.19 mmole) in the solution in THF (7.44 milliliters) and water (1.45 milliliters), add LiOH.H2O (0.055 gram; 1.31 mmole).Reaction mixture under 45 ℃, was stirred 3 hours in the little glass bottle of sealing, add the LiOH of another equivalent then.Reaction mixture was stirred 16 hours down at 45 ℃, then be cooled to room temperature.In vacuum, remove volatile matter, and make all the other aqueous solution with 0.5N HCl acidified aqueous solution to pH＜2.Extract (3x) water layer again with EtOAc.The organic extract liquid that will merge dehydrates (MgSO4) with brine wash, and concentrates in a vacuum, and gets partly B compound (0.290 gram; 100%).C.?

In embodiment 13 part E compound (0.167 grams; 0.668 mmole) in the solution in DMF (2.14 milliliters), add HOAT (0.087 gram; 0.641 part B compound (0.133 gram mmole); 0.557 mmole), DIPEA is (0.116 milliliter; 0.641 mmole) and last EDCI (0.123 the gram; 0.668 mmole).Reaction mixture was stirred 16 hours down in 25 ℃.Add water, and with EtOAc extraction (3x) mixture.The organic extract liquid that will merge dehydrates (MgSO4) with the saturated NH4Cl aqueous solution, the saturated NaHCO3 aqueous solution and brine wash, and concentrates in a vacuum.Make residue through preparing HPLC purifying (100 millimeters posts of YMC anti-phase ODS-5u30 x; Flow velocity=40 ml/min, 25 to 100% solvent B went through 12 minutes, wherein, solvent orange 2 A=90: 10: 0.1H2O: CH3CN: TFA, and solvent B=90: 10: 0.1CH3CN: H2O: TFA), and get (95.1 milligrams of title compounds; 36%), is white solid.[M+H]+＝471.5；1H?NMR(400MHz，CDCl3)：δ1.24-1.37(m，18H)，3.27(s，1H)，3.32(s，1H)，4.01-4.19(m，4H)，4.58-4.72(m，2H)，6.65(s，1H)，6.92-7.00(m，J＝3.85Hz，1H)，7.21-7.27(m，2H)。Example 149? A.?

In 3,5-methyl dihydroxy benzoate (1.75 grams; 10.41 mmole) in the solution in acetone (14 milliliters), add K2CO3 (2.88 grams; 20.82 mmole) with (384 milligrams of nBu4NI; 1.04 mmole), then be methyl-sulfate (985 microlitres; 10.41 mmole).Reaction mixture was heated 3 hours down in reflux (～65 ℃), be cooled to room temperature then.Filtering mixt, and concentrated filtrate in a vacuum.Make residue chromatography (SiO2; Continuous gradient liquid, from 0 to 45% solvent B went through 40 minutes, wherein, solvent orange 2 A=hexane, and solvent B=EtOAc), and get partly A compound (0.74 gram; 39%), is white solid.B.?

In (75 milligrams of part A compounds; 0.412 mmole), 4-fluorophenyl methyl sulfone is (72 milligrams; 0.412 mmole) and (114 milligrams of K2CO3; 0.824 in mixture mmole), add DMF (1.6 milliliters).Reaction mixture was heated 5 hours down at 120 ℃, be cooled to room temperature then.Making mixture between EtOAc (10 milliliters) and H2O (10 milliliters), make separatory handles.Organic phase with salt solution (5 milliliters) washing, is dehydrated (MgSO4), and concentrate in a vacuum.Make residue chromatography (SiO2; Continuous gradient liquid, from 0 to 80% solvent B went through 12 minutes, wherein, solvent orange 2 A=hexane, and solvent B=EtOAc), and get (119 milligrams of part B compounds; 86%), is colourless slurries.C.?

In (118 milligrams of part B compounds; 0.351 mmole) in the solution in THF (0.47 milliliter), MeOH (0.47 milliliter) and H2O (0.47 milliliter), add (44 milligrams of LiOH.H2O; 1.053 mmole).After stirring 1 hour, make mixture between the EtOAc (6 milliliters) and the 0.5N HCl aqueous solution (6 milliliters), make separatory and handle.With EtOAc (6 milliliters) aqueous phase extracted.The organic extract liquid that will merge dehydrates (MgSO4) with salt solution (6 milliliters) washing, and concentrates in a vacuum, and gets (94 milligrams of part C compounds; 83%), is white solid.D.?

In embodiment 13 part E compound (0.038 grams; 0.150 mmole) in the solution in DMF (0.48 milliliter), add HOAT (0.020 gram; 0.144 part C compound (0.040 gram mmole); 0.125 mmole), DIPEA is (0.025 milliliter; 0.144 mmole) and last EDCI (0.028 the gram; 0.144 mmole).Reaction mixture was stirred 16 hours down in 25 ℃.Add water, and with EtOAc extraction (3x) mixture.The organic extract liquid that will merge dehydrates (MgSO4) with the saturated NH4Cl aqueous solution, the saturated NaHCO3 aqueous solution and brine wash, and concentrates in a vacuum.Make residue through preparing HPLC purifying (100 millimeters posts of YMC anti-phase ODS-5u30 x; Flow velocity=40 ml/min, 25 to 100% solvent B went through 12 minutes, wherein, solvent orange 2 A=90: 10: 0.1H2O: CH3CN: TFA, and solvent B=90: 10: 0.1CH3CN: H2O: TFA), and get (27.6 milligrams of title compounds; 40%), is white solid.[M+H]+＝555.4；1H?NMR(400MHz，CDCl3)：δ1.20(t，J＝7.15Hz，6H)，3.01(s，3H)，3.24(s，1H)，3.30(s，1H)，3.83(s，3H)，3.94-4.09(m，4H)，6.73-6.87(m，2H)，7.08(d，J＝8.79Hz，2H)，7.22-7.28(m，1H)，7.36-7.43(m，1H)，7.86(d，J＝8.79Hz，2H)。Example 150? A.?

In (100 milligrams of embodiment 149 part A compounds; 0.549 R-(-)-1-methoxyl group-2-propyl alcohol (70 microlitres mmole); 0.714 mmole) and the PPh of polymkeric substance combination ₃(0.47 gram; 1.43 mmole) in 0 ℃ of mixture in THF (2 milliliters), dropwise add DIAD (162 microlitres; 0.823 the solution in THF (0.20 milliliter) mmole).Reactant was at room temperature stirred 18 hours, filter then.With THF (4 milliliters of 2 x) flushing resin, and the filtrating of concentrated merging in vacuum.Make residue chromatography (SiO2; Continuous gradient liquid, from 0 to 45% solvent B went through 20 minutes, wherein, solvent orange 2 A=hexane, and solvent B=EtOAc), and get (78 milligrams of part A compounds; 56%), is water white oil.B.?

In (74 milligrams of part A compounds; 0.291 mmole) in the solution in THF (0.39 milliliter), MeOH (0.39 milliliter) and H2O (0.39 milliliter), add (37 milligrams of LiOH.H2O; 0.873 mmole).Reactant was stirred 1 hour, between the EtOAc (5 milliliters) and the 0.5N HCl aqueous solution (5 milliliters), make separatory then and handle.With EtOAc (5 milliliters) aqueous phase extracted.The organic extract liquid that will merge dehydrates (MgSO4) with salt solution (5 milliliters) washing, and concentrates in a vacuum, and gets (68 milligrams of part B compounds; 97%), is colourless slurries.C.?

In embodiment 13 part E compound (0.041 grams; 0.164 mmole) in the solution in DMF (0.52 milliliter), add HOAT (0.087 gram; 0.641 part B compound (0.033 gram mmole); 0.137 mmole) and (0.028 milliliter of DIPEA; 0.158 mmole), and at last be EDCI (0.030 gram; 0.158 mmole).Reaction mixture was stirred 16 hours down in 25 ℃.Add water, and with EtOAc extraction (3x) mixture.The organic extract liquid that will merge dehydrates (MgSO4) with the saturated NH4Cl aqueous solution, the saturated NaHCO3 aqueous solution and brine wash, and concentrates in a vacuum.Make residue through preparing HPLC purifying (100 millimeters posts of YMC anti-phase ODS-5 micron 30 x; Flow velocity=40 ml/min, 25 to 100% solvent B went through 12 minutes, wherein, solvent orange 2 A=90: 10: 0.1H2O: CH3CN: TFA, and solvent B=90: 10: 0.1CH3CN: H2O: TFA), and get (38.1 milligrams of title compounds; 59%), is clear, colorless oil.[M+H]+＝473.4；1H?NMR(400MHz，CDCl3)：δ1.20-1.30(m，9H)，3.23(s，1H)，3.28(s，1H)，3.35(s，3H)，3.43-3.55(m，2H)，3.80(s，3H)，4.01-4.12(m，4H)，4.60-4.72(m，1H)，6.66-6.72(m，1H)，6.89-6.94(m，J＝3.30Hz，1H)，7.21-7.25(m，1H)，7.25-7.29(m，1H)。Example 151? A.?

In 2, two (2,2, the 2-trifluoro ethoxy) oil of Niobe of 5-(0.029 gram; 1.20 mmole) in the solution in THF (2.49 milliliters) and water (0.25 milliliter), add LiOH.H2O (0.100 gram; 0.301 mmole).Reaction mixture under 45 ℃, was stirred 3 hours in the little glass bottle of sealing, add the LiOH of another equivalent then.Reaction mixture was stirred 16 hours down at 45 ℃, then be cooled to room temperature.Remove solvent in a vacuum, and make all the other aqueous solution with 0.5N HCl acidified aqueous solution to pH＜2.Extract (3x) water layer again with EtOAc.The organic extract liquid that will merge dehydrates (MgSO4) with brine wash, and in vacuum, concentrates, and gets partly A compound (0.0954 gram; 99%).B.?

In embodiment 13 part E compound (0.029 grams; 0.114 mmole) in the solution in DMF (0.476 milliliter), add HOAT (0.015 gram; 0.11 part A compound (0.030 gram mmole); 0.095 mmole), DIPEA is (0.019 milliliter; 0.110 mmole) and last EDCI (0.021 the gram; 0.110 mmole).Reaction mixture was stirred 16 hours down in 25 ℃.Add water, and with EtOAc extraction (3x) mixture.The organic extract liquid that will merge dehydrates (MgSO4) with the saturated NH4Cl aqueous solution, the saturated NaHCO3 aqueous solution and brine wash, and concentrates in a vacuum.Make residue through preparing HPLC purifying (100 millimeters posts of YMC anti-phase ODS-5u30 x; Flow velocity=40 ml/min, 0 to 100% solvent B went through 12 minutes, wherein, solvent orange 2 A=90: 10: 0.1H2O: CH3CN: TFA, and solvent B=90: 10: 0.1CH3CN: H2O: TFA), and get (13.8 milligrams of title compounds; 26%), is white lyophilized products.[M+H]+＝551.2；1H?NMR(400MHz，CDCl3)δ1.23(t，J＝7.15Hz，6H)，3.23(s，1H)，3.28(s，1H)，3.94-4.10(m，4H)，4.27-4.39(m，J＝7.88，7.88，7.88Hz，2H)，4.46-4.58(m，J＝8.06，8.06，8.06Hz，2H)，6.81-6.86(m，J＝3.30Hz，1H)，6.93-6.98(m，J＝9.34Hz，1H)，7.12-7.18(m，?J＝9.34，3.30Hz，1H)，7.69-7.75(m，J＝3.30Hz，1H)。Example 152?

A.?

In embodiment 26 part A compound (0.130 grams; 0.403 mmole), add 2-methyl cellosolve (0.046 gram in the toluene (2.02 milliliters) continuously; 0.605 mmole) with embodiment 97 part B compound (0.248 grams; 0.605 the suspension-s in CH2Cl2 (1.1 milliliters) mmole).Reaction mixture was stirred 16 hours down in 25 ℃, then with the water dilution, and with EtOAc extraction (3x).The organic extract liquid that will merge dehydrates (MgSO4) with the 1NNaOH aqueous solution and brine wash, and concentrates in a vacuum.Make residue chromatography (SiO2; Gradient liquid progressively, 50-60% solvent B, wherein, solvent orange 2 A=hexane, and solvent B=EtOAc), and A compound (0.157 gram partly; 93%).B.?

In part A compound (0.157 gram; 0.413 mmole) in the solution in THF (3.42 milliliters) and water (0.342 milliliter), add LiOH.H2O (0.020 gram; 0.827 mmole).Reaction mixture under 45 ℃, was stirred 3 hours in the little glass bottle of sealing, be cooled to room temperature then.Remove volatile matter in a vacuum, and make all the other aqueous solution with 0.5N HCl acidified aqueous solution to pH＜2.Extract (3x) water layer again with EtOAc.The organic extract liquid that will merge dehydrates (MgSO4) with brine wash, and concentrates in a vacuum, and gets partly B compound (0.166 gram; 100%).C.?

In embodiment 13 part E compound (0.033 grams; 0.130 mmole) in the solution in DMF (0.542 milliliter), add HOAT (0.017 gram; 0.125 part B compound (0.040 gram mmole); 0.108 mmole), DIPEA is (0.022 milliliter; 0.125 mmole) and last EDCI (0.024 the gram; 0.125 mmole).Reaction mixture was stirred 5 hours down in 25 ℃.Add water, and with EtOAc extraction (3x) mixture.The organic extract liquid that will merge is with the saturated NH4Cl aqueous solution, saturated NaHCO ₃The aqueous solution and brine wash dehydrate (MgSO ₄), and concentrate in a vacuum.Make residue through preparing HPLC purifying (100 millimeters posts of YMC anti-phase ODS-5 micron 30 x; Flow velocity=40 ml/min, 0 to 100% solvent B went through 12 minutes, wherein, solvent orange 2 A=90: 10: 0.1H2O: CH3CN: TFA, and solvent B=90: 10: 0.1CH3CN: H2O: TFA), and get (34.4 milligrams of title compounds; 51%), is white lyophilized products.[M+H]+＝599.2；1H?NMR(400MHz，CDCl3)：δ1.25(t，J＝6.87Hz，6H)，3.00(s，3H)，3.24(s，1H)，3.29(s，1H)，3.39(s，3H)，3.67-3.77(m，2H)，4.00-4.15(m，4H)，4.18-4.28(m，2H)，6.86-6.93(m，1H)，6.94-7.00(m，J＝3.30Hz，1H)，7.04-7.12(m，J＝8.79Hz，2H)，7.38-7.45(m，1H)，7.58-7.64(m，1H)，7.81-7.88(m，J＝8.79Hz，2H)。Example 153?

A.?

In 3,5-methyl dihydroxy benzoate (0.100 gram; 0.595 mmole), add (0.134 gram of it (R)-1-methoxyl group-propan-2-ol in the toluene (2.97 milliliters); 1.487 mmole), then be embodiment 97 part B compound (0.610 grams; 1.487 the suspension-s in CH2Cl2 (2.72 milliliters) mmole).Reaction mixture was stirred 2 days down in 25 ℃, then in 45 ℃ following 2 days, then be cooled to room temperature.Reaction mixture is diluted with water, and with EtOAc extraction (3x).The organic extract liquid that will merge dehydrates (MgSO4) with the 1N NaOH aqueous solution and brine wash, and concentrates in a vacuum.Make residue chromatography (SiO2; Stepwise gradient liquid, 10-20% solvent B, wherein, solvent orange 2 A=hexane, and solvent B=EtOAc), and get partly A compound (0.080 gram; 40%).B.?

In part A compound (0.080 gram; 0.257 mmole) in the solution in THF (2.13 milliliters) and water (0.213 milliliter), add LiOH.H2O (0.012 gram; 0.514 mmole).Reaction mixture under 45 ℃, was stirred 3 hours in the little glass bottle of sealing, add the LiOH of another equivalent then.Reaction mixture was stirred 16 hours down at 45 ℃, then be cooled to room temperature.In vacuum, remove volatile matter, and make all the other aqueous solution with 0.5N HCl acidified aqueous solution to pH＜2.Extract (3x) water layer again with EtOAc.The organic extract liquid that will merge dehydrates (MgSO4) with brine wash, and concentrates in a vacuum, and gets partly B compound (0.082 gram; 100%).C.?

In embodiment 13 part E compound (0.036 grams; 0.142 mmole) in the solution in DMF (0.592 milliliter), add HOAT (0.019 gram; 0.136 part B compound (0.035 gram mmole); 0.118 mmole) and (0.024 milliliter of DIPEA; 0.136 mmole), and last EDCI (0.026 gram; 0.136 mmole).Reaction mixture was stirred 15 hours down in 25 ℃.Add water, and with EtOAc extraction (3x) mixture.The organic extract liquid that will merge dehydrates (MgSO4) with the saturated NH4Cl aqueous solution, the saturated NaHCO3 aqueous solution and brine wash, and concentrates in a vacuum.Make residue through preparing HPLC purifying (100 millimeters posts of YMC anti-phase ODS-5u 30 x; Flow velocity=40 ml/min, 0 to 100% solvent B went through 12 minutes, wherein, solvent orange 2 A=90: 10: 0.1H2O: CH3CN: TFA, and solvent B=90: 10: 0.1CH3CN: H2O: TFA), and get (28.2 milligrams of title compounds; 45%), is clear, colorless oil.[M+H]+＝531.3；?1H?NMR(400MHz，CDCl3)δ1.22-1.29(m，J＝6.87，6.87Hz，12H)，3.28(s，1H)，3.32-3.38(m，7H)，3.44-3.56(m，4H)，4.06-4.16(m，4H)，4.64-4.73(m，2H)，6.70-6.76(m，1H)，6.94-7.00(m，J＝3.85Hz，1H)，7.32-7.35(m，J＝2.20Hz，2H)。Example 154?

A.?

In embodiment 134 compounds (0.298 gram; 0.560 mmole) in the solution in iPrOH (12.43 milliliters) and water (6.22 milliliters), add oxone (oxone) (0.791 gram; 1.287 mmole).Reaction mixture was stirred 16 hours down in 25 ℃, filter then, and extract with EtOAc.The filtrating that will merge dehydrates (MgSO4) with water and brine wash, and concentrates in a vacuum, and gets partly A compound (0.206 gram; 38%).B.?

In part A compound (0.070 gram; 0.125 mmole) in the solution in THF (1.03 milliliters) and water (0.103 milliliter), add LiOH.H2O (0.006 gram; 0.249 mmole).Reaction mixture under 45 ℃, was stirred 1 hour in the little glass bottle of sealing, add the LiOH.H2O of other two equivalents then.Reaction mixture was stirred 20 minutes down at 45 ℃, then be cooled to room temperature.In vacuum, remove volatile matter, and make all the other aqueous solution with 0.5N HCl acidified aqueous solution to pH＜2.Extract (3x) water layer again with EtOAc.The organic extract liquid that will merge dehydrates (MgSO4) with brine wash, and concentrates in a vacuum, and gets partly B compound (0.082 gram; 87%).C.?

In part B compound (0.020 gram; 0.044 mmole) in 0 ℃ of solution in NMP (0.146 milliliter), (0.087 milliliter of the 1MLiHMDS among the interpolation THF; 0.087 mmole).After 15 minutes, add 2-bromo-1-phenyl ethyl ketone (0.017 gram; 0.087 mmole).Make reaction mixture be warmed to room temperature, and at room temperature stirred 15 hours, between the saturated NH4Cl aqueous solution and EtOAc, make separatory then and handle.Organic layer with water (2x) and brine wash, is dehydrated (MgSO4), and concentrate in a vacuum.Make residue through preparing HPLC purifying (100 millimeters posts of YMC anti-phase ODS-5u 30 x; Flow velocity=40 ml/min, 0 to 100% solvent B went through 12 minutes, wherein, solvent orange 2 A=90: 10: 0.1H2O: CH3CN: TFA, and solvent B=90: 10: 0.1CH3CN: H2O: TFA), and get (6.0 milligrams of title compounds; 24%), is yellow oil.[M+H]+＝577.3；1H?NMR(400MHz，CDCl3)δ1.05-1.12(m，J＝6.05Hz，3H)，1.24(t，6H)，3.06(s，1H)，3.11(s，1H)，3.23-3.35(m，4H)，3.36-3.42(m，1H)，3.93-4.10(m，4H)，4.24-4.35(m，1H)，5.92-5.99(m，J＝4.40Hz，2H)，6.41-6.48(m，1H)，6.50-6.57(m，1H)，7.11(s，1H)，7.19(s，1H)，7.44-7.54(m，J＝7.70Hz，2H)，7.56-7.66(m，J＝7.15Hz，1H)，7.99-8.08(m，J＝8.25Hz，2H)。Embodiment 155

In embodiment 137 compounds (0.021 gram; 0.036 mmole) in 0 ℃ of solution in anhydrous CH2Cl2 (0.369 milliliter), add (0.005 milliliter of DAST; 0.036 mmole).Reaction mixture was stirred 2 hours down at 0 ℃, the saturated NaHCO3 aqueous solution of then careful interpolation, and stirred 5 minutes, between the saturated NaHCO3 aqueous solution and CH2Cl2, make separatory then and handle.Extract (3x) water layer again with CH2Cl2.The organic extract liquid that will merge dehydrates (MgSO4) with brine wash, and concentrates in a vacuum.Make residue through (the 100 millimeters posts of YMC anti-phase ODS-5u 30 x that prepare the HPLC purifying twice; Flow velocity=40 ml/min, 20 to 100% solvent B went through 12 minutes, wherein, solvent orange 2 A=90: 10: 0.1H2O: CH3CN: TFA, and solvent B=90: 10: 0.1CH3CN: H2O: TFA), and get (6.0 milligrams of title compounds; 29%), is clear, colorless oil.[M+H]+＝565.2；1H?NMR(400MHz，CDCl3)δ1.22-1.32(m，12H)，2.75-2.87(m，J＝13.74，5.50Hz，2H)，2.92-3.03(m，J＝13.74，6.60Hz，1H)，3.29(s，1H)，3.34(s，1H)，4.06-4.17(m，4H)，4.33-4.45(m，1H)，4.45-4.57(m，1H)，4.63-4.74(m，1H)，4.74-4.87(m，1H)，6.64-6.69(m，J＝2.20，2.20Hz，1H)，6.94-7.00(m，J＝3.30Hz，1H)，7.12-7.24(m，5H)，7.30(s，1H)，7.33(s，1H)。Example 156?

A.?

In embodiment 97 part B compound (1.4 grams; 3.5 mmole) in the suspension-s in DCM (6 milliliters); Add embodiment 26 partly A compounds (141 milligrams, 0.44 mmole) with (R)-(-)-solution of 3-hydroxyl tetrahydrofuran (0.081 milliliter, 1.00 mmoles) in toluene (2 milliliters).Reactant was at room temperature stirred 15 hours, then with EtOAc (10 milliliters) dilution, and with water and brine wash.Make organic layer dehydrate (MgSO4), and concentrate in a vacuum.Make residue chromatography (SiO2; 40 grams, 19 minutes continuous gradient liquid is from 100% hexane/0%EtOAc to 0% hexane/100%EtOAc), (254 milligrams, 148% productive rate is with Ph so that part A compound to be provided ₃PO mixes), be water white oil.B.?

In the solution of part A compound (254 milligrams, 0.65 mmole) in THF (2 milliliters), add the 1N NaOH aqueous solution (1 milliliter, 1.00 mmoles).Reactant was at room temperature stirred 15 hours, then with EtOAc (6 milliliters) dilution, and with the 1N HCl aqueous solution (0.5 milliliter) acidifying.Organic layer with brine wash, is dehydrated (MgSO4), and concentrate in a vacuum.Make residue through preparing HPLC purifying (100 millimeters posts of Phenomenex LunaAXIA 30 x; Flow velocity=40 ml/min, 30 to 100% solvent B went through 10 minutes; Wherein, solvent orange 2 A=90: 10: 0.1H2O: MeOH: TFA, and solvent B=90: 10: 0.1MeOH: H2O: TFA); And get partly B compound (90 milligrams, 37% productive rate), be water white oil.C.?

In (25 milligrams of part B compounds; 0.066 mmole) in the solution in DMF (1 milliliter); Add embodiment 60 partly (20.2 milligrams of D2 amine (26.8 milligrams, 0.13 mmole), EDCI (25.3 milligrams, 0.13 mmole), HOBT; 0.13 mmole) and DIPEA (0.035 milliliter, 0.20 mmole).Reactant was at room temperature stirred 24 hours.Make reactant through preparing HPLC direct purification (100 millimeters posts of Phenomenex Luna AXIA30x; Flow velocity=40 ml/min, 30 to 100% solvent B went through 10 minutes; Wherein, solvent orange 2 A=90: 10: 0.1H2O: MeOH: TFA, and solvent B=90: 10: 0.1MeOH: H2O: TFA); So that title compound (24.6 milligrams, 66% productive rate) to be provided, be white solid.[M+H]+＝564.3；1H?NMR(500MHz，CDCl3)δ9.63(1H，s)，7.92(2H，d，J＝8.80Hz)，7.52(1H，d，J＝2.20Hz)，7.33(1H，s)，7.27(1H，s)，7.09-7.18(2H，m)，7.01(1H，d，J＝2.20Hz)，6.71-6.86(1H，m)，5.01-5.14(1H，m)，4.37-4.60(2H，m)，4.07-4.22(2H，m)，3.96-4.05(3H，m)，3.84-3.96(1H，m)，3.07(3H，s)，2.05-2.38(2H，m)，1.55(3H，d，J＝14.85Hz)，1.34(3H，t，J＝7.15Hz)。Embodiment 157

Title compound (27.4 milligrams, 73.6% productive rate; White solid) use the method that is adopted among the embodiment 156, synthetic from embodiment 60 part D1 amine.[M+H]+＝564.3；1H?NMR(500MHz，CDCl3)δ9.58(1H，s)，7.92(2H，d，J＝8.25Hz)，7.52(1H，s)，7.31(1H，s)，7.26(1H，s)，7.14(2H，d，J＝8.25Hz)，7.01(1H，s)，6.80(1H，s)，5.01-5.13(1H，m)，4.41-4.60?(2H，m)，4.06-4.21(2H，m)，3.96-4.05(3H，m)，3.86-3.96(1H，m)，3.07(3H，s)，2.09-2.35(2H，m)，1.55(3H，d，J＝14.30Hz)，1.27-1.39(3H，m)。Example 158?

A.?

Under Ar, in the solution at room temperature of embodiment 26 part A compounds (117.8 milligrams, 0.365 mmole) in NMP (1.8 milliliters), add Cs ₂CO ₃(357 milligrams, 1.096 mmoles) then dropwise add methanesulfonic 2,2,2-trifluoro ethyl ester (0.075 milliliter, 0.640 mmole).Mixture was stirred 18 hours down at 60 ℃, add more methanesulfonics 2,2,2-trifluoro ethyl ester (0.043 milliliter, 0.365 mmole) then.With reaction mass heated to 80 ℃, went through 29 hours, then be cooled to room temperature.With water diluting reaction thing, and stirred 1 hour, between the EtOAc and the saturated NaHCO3 aqueous solution, make separatory then and handle.With organic layer with water (2x) washing, and with the water layer of EtOAc counterextraction merging.The organic extract liquid that will merge dehydrates (Na2SO4) with brine wash, and concentrates in a vacuum.Make residue chromatography (12 gram SiO2 are from 0-10%EtOAc: the CH2Cl2 wash-out, then with the 90%EtOAc flushing), and A compound (44 milligrams, 29%) partly, be water white oil.B.?

Under Ar, in the solution at room temperature of part A ester (44 milligrams, 0.109 mmole) in THF (0.8 milliliter) and MeOH (0.4 milliliter), add the 4N LiOH.H2O aqueous solution (0.2 milliliter, 0.800 mmole).Form throw out immediately, and reactant was at room temperature stirred 6.5 hours,, and remove volatile matter in a vacuum then with the MeOH dilution.Make residue soluble in water, and with 1N HCl acidified aqueous solution.With the EtOAc aqueous layer extracted; Organic layer with brine wash, is dehydrated (Na2SO4), and concentrate in a vacuum, and get partly B acid (38.6 milligrams, 91%), be colorless solid.C.?

Under Ar, in part B acid (20 milligrams, 0.051 mmole) at CH ₂Cl ₂In the room temperature suspension-s in (0.3 milliliter), add HATU (36 milligrams, 0.095 mmole) and the solution of embodiment 13 part E compounds (18.6 milligrams, 0.074 mmole) in CH2Cl2 (0.3 milliliter), then be DIPEA (0.036 milliliter, 0.205 mmole).Reactant was at room temperature stirred 42 hours, add the EtOAc and the saturated NaHCO3 aqueous solution then.Reactant was stirred 1 hour, then between the EtOAc and the saturated NaHCO3 aqueous solution, make separatory and handle.Organic layer with the saturated NaHCO3 aqueous solution, brine wash, is dehydrated (Na2SO4), and concentrate in a vacuum.(100 millimeters posts of 5 micron 21.2 x of Phenomenex Luna detect under 220 nanometers through preparing the HPLC purifying to make residue; Flow velocity=20 ml/min; Continuous gradient liquid from 50%A to 100%B, is gone through 10 minutes+2 minute hold-time under 100%B, wherein, A=90: 10: 0.1H2O: MeOH: TFA, and B=90: 10: 0.1MeOH: H2O: TFA), and a kind of pure fraction.Make the fraction of being wanted pass through the cartridge case through the MeOH processing of Polymer Lab StratoSpheres TM SPE PL-HCO3 MP SPE resin (500 milligrams), with the MeOH thorough washing.Concentrated filtrate in a vacuum, then with the MeOH azeotropic for several times.Residue is dissolved among the CH2Cl2/MeOH; Leach solid, and filtrating is concentrated in a vacuum, and get title compound (14.8 milligrams, 46%), be the tawny solid.[M+H]+＝623.2；1H?NMR(400MHz，CDCl3)δ1.24(t，J＝7.15Hz，6H)，3.09(s，3H)，3.46(d，J＝21.5Hz，2H)，3.99-4.10(m，4H)，4.48(q，J＝7.70Hz，2H)，6.83(d，J＝3.30Hz，1H)，6.92(s，1H)，7.16(d，J＝8.79Hz，2H)，7.46(s，1H)，7.58(s，1H)，7.95(d，J＝8.79Hz，2H)，19FNMR(400MHz，CDCl3)：δ-73.66。Embodiment 159

Title compound (20 milligrams, 51% productive rate, yellow oil) adopt as the synthesizing of embodiment 74 described in identical general sequence process.[M+H]+＝485.18；1H?NMR(400MHz，CDCl3)δppm6.94(1H，d，J＝3.95Hz)，6.52(2H，d，J＝2.20Hz)，6.35(1H，t，J＝2.20Hz)，4.49-4.57(2H，m)，4.10-4.19(4H，m)，3.78(2H，s)，3.25-3.34(2H，m)，1.27-1.36(18H，m)。Embodiment 160

Title compound (15 milligrams, 45% productive rate, yellow oil) adopt as the synthesizing of embodiment 74 described in identical general sequence process.[M+H]+＝485.18；1H?NMR(400MHz，CDCl3)δ7.12(1H，d，J＝8.79Hz)，6.88(1H，d，J＝3.95Hz)，6.41-6.46(2H，m)，4.47-4.57(1H，m)，4.07-4.17(4H，m)，3.75(2H，s)，3.24-3.34(2H，m)，1.23-1.37(18H，m)。Example 161?

A.?

With 3; 5-methyl dihydroxy benzoate (2.5 grams; 14.9 mmole), 1-fluoro-4-(methylsulfonyl) benzene (5.18 grams, 29.8 mmoles) and the solution of anhydrous K 2CO3 (8.23 grams, 59.6 mmoles) in dry DMF (100 milliliters) heated 10 hours down in 120 ℃; Be cooled to room temperature then, and filter.Solid is washed with CH2Cl2 (100 milliliters), and concentrate the filtrating of merging in a vacuum.Make residue chromatography (SiO2; 80 grams; Continuous gradient liquid, was gone through 40 minutes to 100%EtOA from 100% hexane), so that partly A compound (6.1 grams, 86% productive rate) to be provided, be white solid.[M+H]+＝477.?B.?

Partly A compound (2.3 grams, 4.83 mmoles) stirred 2 hours under room temperature with the solution of LiOH.H2O (4.1 grams, 97.5 mmoles) in THF (10 milliliters)/H2O (5 milliliters).Make reactant with the 1NHCl acidified aqueous solution to pH 1, and extract with EtOAc (15 milliliters of 3 x).The organic extract liquid that will merge dehydrates (MgSO4) with salt solution (30 milliliters) washing, and concentrates in a vacuum, and gets partly B compound (2.2 grams, 99% productive rate), is white solid.[M-H]＝461。C.?

In the suspension-s of part B compound (50 milligrams, 0.11 mmole) in CH2Cl2 (3 milliliters), add embodiment 13 partly E compound (27 milligrams, 0.11 mmole), Et ₃N (30 microlitres, 0.22 mmole) and BOP (72 milligrams, 0.16 mmole).Reactant was stirred 16 hours, extract then with H2O (1 milliliter) dilution, and with CH2Cl2 (5 milliliters of 3 x).The organic extract liquid that will merge dehydrates (MgSO4) with salt solution (3 milliliters) washing, and concentrates in a vacuum.Make residue through preparing HPLC purifying (250 millimeters posts of YMC anti-phase ODS-A-5 micron 30x; Flow velocity=25 ml/min, 20 to 100% solvent B went through 30 minutes, were retained to 40 minutes; Wherein, solvent orange 2 A=90: 10: 0.1H2O: MeOH: TFA, and solvent B=90: 10: 0.1MeOH: H2O: TFA); And get title compound (50 milligrams, 65% productive rate), be white solid.[M+H]+＝695；1H?NMR(500MHz，CDCl3)：δ7.95(d，J＝8.8Hz，4H)，7.65(d，J＝2.2Hz，2H)，7.20(d，J＝8.8Hz，4H)，7.09(t，J＝2.2Hz，1H)，7.01(d，J＝3.3Hz，1H)，4.11(m，4H)，3.28(d，J＝22.0Hz，2H)，3.06(s，6H)，1.28(t，J＝6.9Hz，6H)。Example 162?

A.?

With 3-bromo-5-methyl hydroxybenzoate (2.13 grams; 9.21 1-fluoro-4-(methylsulfonyl) benzene (1.93 grams mmole); 11.1 mmole) and anhydrous K 2CO3 (2.55 the gram; 18.42 mmole) solution in dry DMF (15 milliliters) heated 20 hours down in 120 ℃, was cooled to room temperature then, and filtered.With CH2Cl2 (100 milliliters) wash solids, and concentrate the filtrating of merging in a vacuum.Make residue chromatography (SiO2; 80 grams; Continuous gradient liquid, was gone through 40 minutes to 100%EtOAc from 100% hexane), so that partly A compound (1.64 grams, 48% productive rate) to be provided, be white solid.[M-H]＝370。B.?

Partly A compound (124 milligrams, 0.322 mmole), the fluorine-based pyridin-4-yl boric acid of 2-(54.4 milligrams, 0.386 mmole), K2CO3 (89 milligrams, 0.644 mmole) reach (PPh ₃) ₄The solution at room temperature of Pd (18.6 milligrams, 16 micromoles) in DME (4 milliliters) and water (1 milliliter) stirred 5 minutes under the N2 air-flow.Then mixture is sealed; And under 150 ℃, heating is 30 minutes in Emrys .Make reactant be cooled to room temperature, and with 1N HCl acidified aqueous solution to pH 2.Make mixture between EtOAc (3 milliliters) and water (3 milliliters), make separatory and handle, and extract with EtOAc (10 milliliters of 3 x).The organic extract liquid of merging is dehydrated (MgSO4), and concentrate in a vacuum.Make residue through preparing HPLC purifying (250 millimeters posts of YMC anti-phase ODS-A-5 micron 30 x; Flow velocity=25 ml/min, 20 to 100% solvent B went through 30 minutes, kept then 10 minutes; Wherein, solvent orange 2 A=90: 10: 0.1H2O: MeOH: TFA, and solvent B=90: 10: 0.1MeOH: H2O: TFA); And get partly B compound (80 milligrams, 64%), be white solid.[M-H]＝386。C.?

In the suspension-s of part B compound (20 milligrams, 0.052 mmole) in CH2Cl2 (2 milliliters), add embodiment 13 partly E compound (13 milligrams, 0.052 mmole), Et3N (11 microlitres, 0.077 mmole) and BOP (27.4 milligrams, 0.062 mmole).Reactant was stirred 16 hours, extract then with H2O (1 milliliter) dilution, and with CH2Cl2 (5 milliliters of 3 x).The organic extract liquid that will merge dehydrates (MgSO4) with salt solution (3 milliliters) washing, and concentrates in a vacuum.Make residue through preparing HPLC purifying (250 millimeters posts of YMC anti-phase ODS-A-5 micron 30x; Flow velocity=25 ml/min, 20 to 100% solvent B went through 30 minutes, were retained to 40 minutes; Wherein, solvent orange 2 A=90: 10: 0.1H2O: MeOH: TFA, and solvent B=90: 10: 0.1MeOH: H2O: TFA); And get title compound (27 milligrams, 84% productive rate), be white solid.[M+H]+＝620；1H?NMR(500MHz，CD3OD)：δ8.32-8.29(m，2H)，8.0(d，J＝8.8Hz，2H)，7.85-7.82(m，2H)，7.72-7.69(m，1H)，7.51(s，1H)，7.30(d，J＝8.8Hz，2H)，7.00(d，J＝3.8Hz，1H)，4.12-4.05(m，4H)，3.37(d，J＝21.4Hz，2H)，3.13(s，3H)，1.28(t，J＝6.8Hz，6H)。Example 163? A.?

With 3-hydroxyl-5-isopropoxy oil of Niobe (Bioorg.Med.Chem.Lett.2005; 15:2103) (609 milligrams; 2.90 mmole), 5-chloro pyrazine-2-carboxylate methyl ester (500 milligrams, 2.90 mmoles) and K2CO3 (1.20 milligrams, 8.69 mmoles) are at CH ₃Solution among the CN (20 milliliters) is heated to 80 ℃ under Ar, went through 2 hours.Make reactant be cooled to room temperature,, filter with CH2Cl2 (50 milliliters) dilution, and concentrated filtrate in a vacuum.Make residue chromatography (SiO2; 40 grams; Continuous gradient liquid, was gone through 40 minutes to 100%EtOAc from 100% hexane), so that partly A compound (1.005 grams, 100% productive rate) to be provided, be water white oil.[M+H]+＝347。B.?

Partly the mixture of B compound (1.005 grams, 2.9 mmoles), azetidine hydrochloride (326 milligrams, 3.48 mmoles), Et3N (0.485 milliliter, 3.48 mmoles) and MgCl2 (332 milligrams, 3.48 mmoles) stirred under room temperature 5 hours.Add more polynitrogen heterocycle butane hydrochloride (326 milligrams, 3.48 mmoles), Et ₃N (0.485 milliliter, 3.48 mmoles) and MgCl ₂(332 milligrams, 3.48 mmoles).Reactant was at room temperature stirred 30 minutes,, then, filter with CH2Cl2 (50 milliliters) dilution then in 0 ℃ of following store overnight, and concentrated filtrate in a vacuum.Make residue chromatography (SiO2; 40 grams; Continuous gradient liquid, was gone through 40 minutes to 100%EtOAc from 100% hexane), so that partly B compound (267 milligrams, 25% productive rate) to be provided, be water white oil.[M+H]+＝372。C.?

Partly B compound (267 milligrams, 0.72 mmole) stirred 5 hours under room temperature with the solution of LiOH.H2O (90 milligrams, 2.16 mmoles) in THF (4 milliliters)/H2O (4 milliliters).Make reactant with 1N HCl acidified aqueous solution to pH 2, extract with EtOAc (10 milliliters of 3 x) then.The organic extract liquid that will merge dehydrates (MgSO4) with salt solution (10 milliliters) washing, and concentrates in a vacuum, and gets partly C compound (200 milligrams, 78% productive rate), is white solid.[M+H]+＝358。D.?

In (14 milligrams of part C compounds; 0.039 mmole) in the suspension-s in CH2Cl2 (1.5 milliliters), add embodiment 32 partly A compound (9.1 milligrams, 0.039 mmole), Et3N (11 microlitres; 0.078 mmole) and BOP (34.7 milligrams, 0.078 mmole).Reactant was at room temperature stirred 16 hours, extract then with H2O (1 milliliter) dilution, and with CH2Cl2 (5 milliliters of 3 x).The organic extract liquid that will merge dehydrates (MgSO4) with salt solution (3 milliliters) washing, and concentrates in a vacuum.Make residue through preparing HPLC purifying (250 millimeters posts of YMC anti-phase ODS-A-5u 30 x; Flow velocity=25 ml/min, 20 to 100% solvent B went through 30 minutes, were retained to 40 minutes; Wherein, solvent orange 2 A=90: 10: 0.1H2O: MeOH: TFA, and solvent B=90: 10: 0.1MeOH: H2O: TFA); And get title compound (9.5 milligrams, 43% productive rate), be white solid.[M+H]+＝573；1H?NMR(500MHz，CDCl3)：δ9.11(s，1H)，8.84(s，1H)，8.33(s，1H)，7.48(s，1H)，7.35(s，1H)，7.27(s，1H)，6.95(d，J＝2.2Hz，1H)，6.87(d，J＝2.2Hz，1H)，4.70-7.62(m，3H)，4.44(d，J＝8.0Hz，2H)，4.26(t，J＝7.7Hz，2H)，4.15-4.05(m，4H)，2.41-2.34(m，2H)，1.35(d，J＝6.1Hz，6H)，1.29(t，J＝7.2Hz，6H)。Example 164? A.?

In (2.9 milliliters of LDA; 5.79 mmole, 2N is in THF) with (1.75 milliliters of DMPU; 5.79 mmole) in THF (5.1 milliliters) in they-70 ℃ of solution; Slowly add 2-(4-(methylsulfonyl) phenyl) ritalin (1.27 grams, 5.55 mmoles) (consulting WO 00/58293), keep temperature to be lower than-65 ℃.Reactant was stirred 1 hour down at-70 ℃, and add 4-(iodo methyl) ring penta-1-alkene (1.38 grams, 6.58 mmoles), keep temperature to be lower than-60 ℃.Reaction mixture was stirred 30 minutes down at-70 ℃, be warmed to room temperature then, and stirred 18 hours.Reactant is cooled off in ice bath, and make the reaction cancellation with the saturated NH4Cl aqueous solution (20 milliliters).In vacuum, remove volatile matter, and with EtOAc extraction (2x) mixture.The organic layer that will merge dehydrates (MgSO4) with brine wash, filters, and concentrates in a vacuum.Make residue chromatography (SiO2), and get partly A compound (880 milligrams, 51% productive rate), be white solid.B.?

In the 0 ℃ solution of part A compound (880 milligrams, 2.85 mmoles) in MeOH (8 milliliters) and THF (4 milliliters), add the 1N NaOH aqueous solution (6 milliliters).Make reactant slowly be warmed to room temperature, and at room temperature stirred 18 hours.Remove volatile matter in a vacuum, and reactant is diluted with water,, and extract with EtOAc with the 2N HCl aqueous solution (5 milliliters) acidifying.Organic layer with brine wash, is dehydrated (MgSO4), filter, and concentrate in a vacuum, and get partly B compound (830 milligrams, 96% productive rate), be white solid.C.?

Under Ar, in the 0 ℃ solution of part B compound (29.4 milligrams, 0.1 mmole) in CH2Cl2 (0.5 milliliter), the interpolation oxalyl chloride (0.065 milliliter, 0.13 mmole, 2M is in CH2Cl2) and DMF (3 microlitre).Reactant was stirred 1 hour down at 0 ℃, be warmed to room temperature then, and stirred 2 hours.In vacuum, remove volatile matter.Under Ar, in the 0 ℃ solution of chloride of acid residue in CH2Cl2 (0.5 milliliter), add the solution of pyridine (32.3 microlitres, 0.4 mmole) in CH2Cl2 (0.25 milliliter), then add partly B compound (27 milligrams, 0.11 mmole) of embodiment 7.Reactant was stirred under room temperature 18 hours, and through the column chromatography direct purification (SiO2,0-10%MeOH:CH2Cl2).Product of being wanted and part B acid co-elute are so extract mixture with CH2Cl2.With organic layer with the 0.5N HCl aqueous solution, water, the saturated NaHCO3 aqueous solution and brine wash.Make organic layer dehydrate (MgSO4), filter, and concentrate in a vacuum, and get title compound (29 milligrams, 56% productive rate), be oily matter.[M+H]+＝522.2。Example 165?

A.?

In the solution of embodiment 26 part A compounds (80 milligrams, 0.248 mmole) in DMF (1 milliliter), add 2-chloropyridine (0.047 milliliter, 0.496 mmole) and K2CO3 (103 milligrams, 0.745 mmole).Reaction mixture was stirred 40 hours down at 120 ℃, be cooled to room temperature then, and filter.With MeOH dilution filtrating, then through preparation HPLC purifying (100 millimeters posts of Phenomenex Luna AXIA 30 x; Under 220 nanometers, detect; Flow velocity=40 ml/min; Continuous gradient liquid from 80%A to 100%B, was gone through 10 minutes, wherein, and A=10%MeOH/90%H2O/0.1%TFA, and B=90%MeOH/10%H2O/0.1%TFA), and get partly A compound (26 milligrams, 27%), be white solid.B.?

In (26 milligrams of part A compounds; 0.067 mmole) in the solution in DMF (1 milliliter); Add embodiment 13 partly (20.66 milligrams of E compounds (33.8 milligrams, 0.135 mmole), EDCI (25.9 milligrams, 0.135 mmole), HOBT; 0.135 mmole) and DIPEA (0.035 milliliter, 0.202 mmole).Reaction mixture was at room temperature stirred 2 days.Make reaction mixture through preparing HPLC direct purification (100 millimeters posts of Phenomenex Luna AXIA 30 x; Under 220 nanometers, detect; Flow velocity=40 ml/min; Continuous gradient liquid from 70%A to 100%B, was gone through 10 minutes, wherein, and A=10%MeOH/90%H2O/0.1%TFA, and B=90%MeOH/10%H2O/0.1%TFA), and get title compound (11 milligrams, 26% productive rate), be yellow oil.[M+H]+＝618.3；1H?NMR(500MHz，CDCl3)：δ8.24(1H，d，J＝4.95Hz)，7.95(2H，d，J＝8.80Hz)，7.78-7.84(2H，m)，7.71(1H，s)，7.20-7.25(3H，m)，7.13(1H，dd，J＝6.87，4.67Hz)，7.07(1H，d，J＝8.25Hz)，7.04(1H，d，J＝3.85Hz)，4.10-4.21(4H，m)，3.34(2H，d，J＝21.44Hz)，3.07(3H，s)，1.32(6H，t，J＝6.87Hz)。Embodiment 166

Title compound (5 milligrams, 24% productive rate, yellow oil) is made from 2-chloro pyrimidine according to as being used for the synthetic identical general method of embodiment 165.[M+H]+＝619.3；1H?NMR(500MHz，CDCl3)：δ8.63(2H，d，J＝4.95Hz)，7.88-7.99(3H，m)，7.78(1H，s)，7.27-7.28(1H，m)，7.24(2H，d，J＝9.35Hz)，7.15(1H，t，J＝4.95Hz)，7.05(1H，d，J＝3.30Hz)，4.11-4.21(4H，m)，3.34(2H，d，J＝21.44Hz)，3.08(3H，s)，1.32(6H，t，J＝7.15Hz)。Embodiment 167

Title compound (11.5 milligrams, 30% productive rate, yellow solid) is made from 2-chloro pyrazine according to as being used for the synthetic identical general method of embodiment 165.[M+H]+＝619.3；1H?NMR(500MHz，CDCl3)：δ8.54(1H，s)，8.37(1H，d，J＝2.75Hz)，8.16(1H，s)，7.96(2H，d，J＝8.80Hz)，7.89(1H，s)，7.77(1H，s)，7.25-7.27(1H，m)，7.24(2H，d，J＝8.80Hz)，7.05(1H，d，J＝3.85Hz)，4.10-4.21(4H，m)，3.34(2H，d，J＝21.44Hz)，3.08(3H，s)，1.32(6H，t，J＝6.87Hz)。Example 168? A.?

In the solution of 5-hydroxyisophthalic acid dimethyl ester (198 milligrams, 0.942 mmole) in DMF (2 milliliters), add 1-fluorine-based-4-(methylsulfonyl) benzene (197 milligrams, 1.130 mmoles) and K2CO3 (391 milligrams, 2.83 mmoles).Reaction mixture was stirred 41 hours down at 120 ℃, be cooled to room temperature then, and filter.To filtrate with the MeOH dilution, then through preparation HPLC purifying (100 millimeters posts of Phenomenex Luna AXIA 30x; Under 220 nanometers, detect; Flow velocity=40 ml/min; Continuous gradient liquid from 80%A to 100%B, was gone through 10 minutes, wherein, A=10%MeOH/90%H2O/0.1%TFA, and B=90%MeOH/10%H2O/0.1%TFA), so that partly A compound (176 milligrams, 53% productive rate) to be provided, be white solid.[M+H]+＝351.2。B.?

In the solution of part A compound (85 milligrams, 0.243 mmole) in CH2Cl2 (1.0 milliliters), add oxalyl chloride (0.243 milliliter, 0.485 mmole) and DMF (5.64 microlitres, 0.073 mmole).Mixture was at room temperature stirred 1 hour, concentrate in a vacuum then.Rough chloride of acid is dissolved among the THF (1.0 milliliters), and adds tetramethyleneimine (0.041 milliliter, 0.485 mmole) and pyridine (0.059 milliliter, 0.728 mmole).Reaction mixture was stirred under room temperature 3 hours, then,, dehydrate (MgSO4) with H2O and brine wash, and concentrate in a vacuum with EtOAc (10 milliliters) dilution.Make residue through preparing HPLC purifying (100 millimeters posts of Phenomenex Luna AXIA 30 x; Under 220 nanometers, detect; Flow velocity=40 ml/min; Continuous gradient liquid from 70%A to 100%B, was gone through 10 minutes, wherein, A=10%MeOH/90%H2O/0.1%TFA, and B=90%MeOH/10%H2O/0.1%TFA), so that partly B compound (93 milligrams, 95% productive rate) to be provided, be water white oil.[M+H]+＝404.3。C.?

In the solution of part B compound (8.5 milligrams, 0.021 mmole) in THF (1 milliliter), add the 1NNaOH aqueous solution (0.063 milliliter, 0.063 mmole).Reaction mixture was at room temperature stirred 15 hours, and,, and separate with the 1N HCl aqueous solution (0.050 milliliter) acidifying with EtOAc (6 milliliters) dilution.Organic layer with brine wash, is dehydrated (MgSO4), and concentrate in a vacuum, and get rough part C compound (10 milligrams), be white solid, it is used in the next step, need not to be further purified.[M+H]+＝390.2。D.?

In (10 milligrams of part C compounds; 0.026 mmole) in the solution in DMF (1 milliliter); Add embodiment 13 partly (7.9 milligrams of E compounds (12.9 milligrams, 0.051 mmole), EDCI (9.9 milligrams, 0.051 mmole), HOBT; 0.051 mmole) and DIPEA (0.013 milliliter, 0.077 mmole).Reaction mixture was at room temperature stirred 4 days, then through preparation HPLC direct purification (100 millimeters posts of Phenomenex LunaAXIA 30x; Under 220 nanometers, detect; Flow velocity=40 ml/min; Continuous gradient liquid from 70%A to 100%B, was gone through 10 minutes, wherein; A=10%MeOH/90%H2O/0.1%TFA, and B=90%MeOH/10%H2O/0.1%TFA), so that (3 milligrams of title compounds to be provided; 23% productive rate is gone through 2 steps), be white solid.[M+H]+＝622.3；1H?NMR(500MHz，CDCl3)：δ8.18(1H，s)，7.89-8.00(3H，m)，7.55(1H，s)，7.19(2H，d，J＝8.80Hz)，7.05(1H，d，J＝3.30Hz)，4.05-4.23(4H，m)，3.50-3.74(4H，m)，3.35(2H，d，J＝21.44Hz)，3.09(3H，s)，?1.85-2.04(4H，m)，1.32(6H，t，J＝7.15Hz)。

Example 169?

A.?

Under room temperature and Ar, in the solution of embodiment 13 part A compounds (377 milligrams, 1.08 mmoles) in CH2Cl2 (5 milliliters), add TMSBr (0.307 milliliter, 2.37 mmoles).After stirring 15 hours under the room temperature, make reaction mixture in a vacuum, concentrate down in careful drying conditions, so that partly A compound to be provided, be water white oil, it is used in the next step, need not to be further purified.B.?

In part A compound (5 milliliters of anhydrous CH2Cl2; The separating atmospheric through the drying tube protection of CaCl2 filling) in the solution in, adds oxalyl chloride (0.207 milliliter, 2.37 mmoles) and DMF (8 microlitres, 0.1 mmole).Find a large amount of the foaming, cause the formation of beige throw out at last.After stirring 3 hours under the room temperature, concentrated reaction mixture in a vacuum, and residue is dissolved among the THF (12 milliliters), and under Ar, be cooled to-65 ℃.In these slurries, add 1, the solution of ammediol (0.086 milliliter, 1.18 mmoles) in MeCN (6 milliliters) was gone through 2 minutes, and stirred 5 minutes down at-65 ℃.Add pyridine (0.183 milliliter, 2.26 mmoles) then, go through 1 minute, and make reaction mixture be warmed to room temperature, and at room temperature stirred 16 hours.Making mixture between the EtOAc and the 5%NaHSO4 aqueous solution (each 25 milliliters), make separatory handles.Make organic phase dehydrate (Na2SO4), and concentrate in a vacuum.Make residue through preparing HPLC purifying (100 millimeters posts of PhenomenexLuna 21.2 x; Under 254 nanometers, detect; Flow velocity=20 ml/min; Continuous gradient liquid from 0%A to 100%B, was gone through 10 minutes, wherein, A=10%MeCN/90%H2O/0.1%TFA, and B=90%MeCN/10%H2O/0.1%TFA), so that partly B compound (71 milligrams, 20% productive rate) to be provided, be white amorphous solid.[M+H]+＝335。C.?

At room temperature, in part B compound (71 milligrams, 0.21 mmole) (2 milliliters of anhydrous CH2Cl2; Drying tube protection through the CaCl2 filling and separating atmospheric) in stirred solution, add TFA (0.5 milliliter).Reactant was at room temperature stirred 4 hours, in vacuum, concentrate then.Residue is dissolved among the MeOH, and through StratoSpheres ^TMSPE PL-HCO ₃MP IX cartridge case (0.9 milli-equivalent capacity) is with the MeOH wash-out.Elutriant concentrates in vacuum, and partly C compound is provided, and is white amorphous solid (43 milligrams, 86% productive rate).[M+H]+＝235。

D.?

Under room temperature and Ar, stir in the slurries in the warp of embodiment 26C compound (69 milligrams, 0.18 mmole) in CH2Cl2 (2 milliliters), add HOAt (25 milligrams, 0.18 mmole) and EDC (35 milligrams, 0.18 mmole) continuously.In 5 minutes, form clear solution.After 30 minutes, under room temperature and Ar, this solution is added in the slurries (2 milliliters) of part C compound in THF, then be iPr ₂NEt (0.016 milliliter, 0.43 mmole) and DMAP (2.6 milligrams, 0.02 mmole).After stirring 18 hours under the room temperature, analyze HPLC and show to have no product to form.Reaction mixture is concentrated in a vacuum, and be dissolved among the anhydrous MeCN (3 milliliters), under Ar, be heated to backflow then, so form solution.After refluxing following 2 hours, analyze HPLC and show that nearly all amine is consumed.Make reaction mixture be cooled to room temperature, and concentrate in a vacuum.Making residue between the EtOAc and the saturated NaHCO3 aqueous solution (each 20 milliliters), make separatory handles.Organic phase with salt solution and 10%NaHSO3 solution washing, is dehydrated (Na2SO4), and concentrate in a vacuum.The oily residue is through purifying (100 millimeters posts of Phenomenex Luna 21.2 x of preparation HPLC; Under 220 nanometers, detect; Flow velocity=20 ml/min; Continuous gradient liquid from 0%A to 100%B, was gone through 10 minutes, wherein, A=10%MeCN/90%H2O/0.1%TFA, and B=90%MeCN/10%H2O/0.1% TFA), title compound (35 milligrams, 28% productive rate) is provided, be white amorphous solid.[M+H]+＝597.1H?NMR(400MHz，CDCl3)：δ7.92(2H，d，J＝7.1Hz)，7.59(1H，s)，7.42(1H，s)，7.17(2H，d，J＝8.80Hz)，6.85(2H，m)，4.73(1H，m)，4.35(2H，m)，4.12(2H，m)，3.66-3.51(3H，m)，3.41(3H，s)，3.07(3H，s)，1.92-1.72(2H，m)，1.34(3H，d，J＝6.0Hz)。

The detection of glucokinase enzyme activation

The present invention's formula I compound can the activation gk.The detection that on the activation gk, can be used for testing formula I compound of the present invention is known in the art, for example in USP case numbers 6,320,050,6,384,200 and 6,610,846 and WO 2004/052869; And at Castellano, A.L., Dong, H., Fyfe, M.C.T., Gardner, L.S., Kamikozawa; Y. wait people (2005) " glucokinase enzyme activation ureas ", Bioorg.Med.Chem.Letters, 15:1501-1504 and Grimsby, J., Sarabu, R., Corbett, W.L., Haynes; N-E., Bizzarro, F.T., Coffey, J.W., Guertin, K.R., Hilliard; D.W., Kester, R.F., Mahaney, P.E., Marcus, L., Qi; L., Spence C.L., Tengi, J., Magnuson, M.A., Chu, C.A.; Dvorozniak, M.T., Matschinsky, F.M., Grippo, J.F. (2003) " the dystopy acvator of gk: the latent effect on treating diabetes ", Science, announcement person among the 301:370-373.

Generally speaking; The present invention's compound; For example be disclosed in the specific compound among the following embodiment, be identified can be equivalent to 100 μ M or than it activity of enhancing gk under the more effective concentration, be preferably 10 μ M; 1 μ M more preferably is so confirm the toughener of the present invention's compound for effective especially glucokinase enzymic activity.Effect can be calculated, and with EC ₅₀(reaching the concentration of 50% complete activation) and/or the highest per-cent activation that is higher than background technology represent, and refer to the activity that adopts said detecting system measured.

Detect and biological data

The present invention's formula I compound comprises the compound described in the embodiment, and is to be tested in following detection, and turned out to be the acvator of gk.

Gk series connection enzymatic detects

The enzymic activity of human glucose kinases (GK) then makes the reaction cancellation with EDTA (YD 30) through cultivating GK, ATP and glucose discontinuous period, measures.Then; The operation detection test; Measure the relative quantity of product G-6-P (G6P); Its mode is to use the G6P desaturase, and under the wavelength of 405 nanometers, and that measures sulfenyl NAD (sulfenyl VITAMIN PP adenine dinucleotide) changes into sulfenyl NADH (sulfenyl dihydro VITAMIN PP adenine dinucleotide).The enzymatic reaction of this " uncoupling " detects expression with GK " series connection ".GK can use this detection assessment through the activation of compound.According to hereinafter described GK series connection detection scheme, use the activator compound concentration range of 0 to 100 μ M, 5 with 12mM glucose under carry out.(GK 15nM) with 5 or 12mM glucose, cultivates in having 384 hole black titer plate of clear bottom with human total length gk.Be starting GK reaction, magnesium-ATP (3mM ultimate density) is added into (final buffer reagent condition is a 25mM HEPES buffer reagent, and pH 7.1, contain 1mM disulfide group threitol and 5%DMSO) in the GK in the buffer reagent.Total reaction volume is 20 microlitres.Reaction was carried out ten minutes, made the reaction cancellation with 5 microlitre EDTA (final 45mM) then.Then add the composition of detection reaction together, sulfenyl NAD and G6PDH (glucose-6-phosphate dehydrogenase (G6PD)) (ultimate density is respectively 650 μ M and 3.33 units) are with the volume (and getting TV 50 microlitres) of 25 microlitres.Light absorption ratio is measured under 405 nanometers, goes up in Spectramax Plus 384 light absorption ratio plate readers (Molecular Devices) and implements.Read light absorption ratio, subtracting background G-6-P content is then with the percentage calculation activation of control group activity.Control activity is used GK to exist down in carrier (DMSO) and is measured, and wherein the background G-6-P is deducted.The background G-6-P is through before starting reaction with ATP, makes the GK cancellation in advance and records with EDTA.

Performance and the purifying of human GK

The human liver GK of total length (unmarked) is expressed under 25 ℃ in BL21 STAR (DE3) the pLysS cell (Invitrogen), presses people said (1) such as Mookhtiar.Protein is gone up basically and is pressed Lange said (2), changes a little, carries out purifying.In brief, make the cell pill freezing dissolved with thawing through three-wheel, centrifugal with clarification under 15000 grams, and with 40-65% (NH ₄) ₂The SO4 deposition.Make the pill resuspending that is formed in buffer reagent, dialysis, and be applied directly to Q-agarose (Sigma) post, then with linear 100-600mMKCl gradient liquid wash-out.Compile the fraction that contains GK, dialysis is spent the night to 25mM HEPES pH 7.2/1mM MgCl2/1mM EDTA/0.1M KCl/1mM DTT, then with identical buffer reagent and add 10% glycerine, dialysis again.Reference 1.Mookhtiar, K.A., Kalinowski, S.S., Brown; K.S., Tsay, Y.H., Smith-Monroy; C. reach Robinson, G.W. (1996) " the rats'liver gk is regulated the heterogenous expression and the sign of albumen ", Diabetes, 45:1670-1677.2.Lange, A.J., Xu, L.Z., Van Poelwijk, F., Lin, K., Granner, D.K. and Pilkis, S.J. (1991) " expression of hepatic glucose kinases and site guiding sudden change ", Biochem.J., 277:159-163.

About selecting the biological data of embodiment, be shown in the following table.

The embodiment numbering	The kinase whose EC of human glucose 50(nM) under 12mM glucose
		169	9
51	15
		82	18
137	21
		50	22
122	23
		145	24
33	26
		37	34
163	38
		54	49

32	65
		29	98
148	178
		22	402
112	428
		113	437
139	467
		116	469
134	476
		84	492
56	534
		44	564

About other embodiment, EC ₅₀Value can not be from the activation curve calculation, so for some maximum activation data (% with basic activation representes) of selecting embodiment, be shown in the following table.

The embodiment numbering	Maximum activation (%), the human glucose kinases is under 12mM glucose
		121	126％
65	162％
		35	133％
79	133％
		86	141％
123	135％
		74	142％
23	150％

Research in the body: oral glucose tolerance property test (OGTT)

The test of oral glucose tolerance property is before experiment, on the male DIO (obesity that diet causes) of feeding high fat diet (having 60% kilocalorie from fat) C57BL/6J mouse, carrying out for 26 weeks.Supplying before experiment uses, making that mouse is jejunitas to spend the night.Testing compound or carrier (not being 1) 40%PEG 400+10% cremophor (Cremophor)+50% water; Be exactly 2) 10% N,N-DIMETHYLACETAMIDE+10% ethanol+10% cremophor+70% water); Under the dosage of 2 gram/kg body weight; Before glucose solution is given in oral throwing 60 minutes give (oral glucose tolerance property test with the per os mode; OGTT).Blood-sugar content is from the afterbody sample measurement of taking a blood sample, this sample before glucose is given in throwing with the different time points of back under (2 hours time-histories) obtain.Produce the time curve of blood sugar, and calculate under 0-120 minute inner curve area from the variation (Δ AUC) (the glucose dispensing time is the time zero) of baseline.

Embodiment is in like above-mentioned OGTT test in the following table, in the DIO mouse, has reduced glucose AUC content.

The embodiment numbering	The reduction of glucose AUC under 30 milligrams of/kilogram dosage
		37	88％
148	60％
		145	71％
54	68-82％
		29	66-78％
44	62-80
		32	79%, under 30 micromole/kilograms
82	44%, under 10 micromole/kilograms

Claims (16)

1. compound, it has following structure:

Wherein

R ₁Be heteroaryl, by R ₄Replace, and optional by one or two substituent R ₅With R ₆Replace, wherein said heteroaryl has nitrogen-atoms, and this nitrogen-atoms vicinity is engaged to said heteroaryl

Atom; And Be

R ₄Be selected from

-(CH ₂) _n-Z-(CH ₂) _m-PO(OR ₇)(OR ₈)，

Or-(CH ₂) _nZ-(CH ₂) _m-PO (OR ₇) R ₉,

Or-(CH ₂) _n-Z-(CH ₂) _m-O-PO (OR ₇) R ₉,

Or-(CH ₂) _nZ-(CH ₂) _m-O-PO-(R ₉) R ₁₀,

Or-(CH ₂) _nZ-(CH ₂) _m-PO-(R ₉) R ₁₀

R ₇With R ₈For identical or different, and independently be selected from the straight or branched alkyl that contains 1 to 8 carbon, or R ₇With R ₈Can be cyclized into ring

be q=1-3 wherein

R ₉With R ₁₀For identical or different, and independently be selected from the straight or branched alkyl that contains 1 to 8 carbon;

Z is selected from a key, contain the straight or branched alkylidene group of 1 to 8 carbon and contain the straight or branched alkenylene of 2 to 8 carbon;

M is 0,1 or 2;

N is 0,1 or 2;

And when m was 1 or 2, Z also can be selected from O, S and SO ₂,

R ₅With R ₆For identical or different, and be selected from hydrogen, contain the straight or branched alkyl and the halogen of 1 to 8 carbon, or for not existing;

Y-X-CO-does

Or Y-X-CO-does

Its all stereoisomerses or its pharmacy acceptable salt.

2. compound as claimed in claim 1, wherein partly

3. compound as claimed in claim 1, wherein m is 1 or 2, and

(1) R ₄For-(CH ₂) _n-Z-(CH ₂) _m-PO (OR ₇) (OR ₈), wherein Z is that a key and n are 1 or 2; Or

(2) R ₄Be (CH ₂) _n-Z-(CH ₂) _m-PO (OR ₇) R ₉, wherein Z is that a key and n are 1 or 2; Or

(3) R ₄For-(CH ₂) _n-Z-(CH ₂) _m-OPO-(OR ₇) R ₉Or R ₄For

-(CH ₂) _n-Z-(CH ₂) _m-O-PO-(R ₉) R ₁₀, wherein Z is O.

4. compound as claimed in claim 1, wherein

R ₄Be (CH ₂) _n-Z-(CH ₂) _m-PO (OR ₇) (OR ₈), wherein Z is the straight or branched alkenylene that contains the straight or branched alkylidene group of 1 to 8 carbon or contain 2 to 8 carbon.

5. compound as claimed in claim 1, wherein

N is 0, and m is 0, and Z be a key ,-CH ₂-,-CH ₂-CH=CH-or-CH ₂CH ₂-; And

R ₅With R ₆Respectively be H;

R ₇For containing the straight or branched alkyl of 1 to 8 carbon; And

R ₈For containing the straight or branched alkyl of 1 to 8 carbon.

6. compound as claimed in claim 1, wherein

R ₄For

7. be selected from down the compound of group:

And all stereoisomerses or its pharmacy acceptable salt.

8. pharmaceutical composition; It comprises like claim 1 or 7 described compounds and combines and its pharmaceutically acceptable carrier separately or with another kind of therapeutical agent, and said another kind of therapeutical agent is antidiabetic, antihyperglycemic agents, anti-hyperinsulinism agent, anti-retinopathy agent, anti-neuropathy agent, anti-ephrosis agent, antiatherosclerotic, anti-infection agent, antiischemic agents, hypotensive agent, antiobesity agent, the agent of lipotropism mass formed by blood stasis obstacle, anti-lipid unusual agent, anti-exhausted blood agent, carcinostatic agent, anti-cell toxic agent, anti-restenosis agent, anti-pancreas agent, lipid depressant, appetite-inhibiting agent, hypermnesia agent or cognitive agent.

9. pharmaceutical composition, it comprises like claim 1 or 7 described compounds and combines separately or with another kind of therapeutical agent and the said another kind of therapeutical agent of its pharmaceutically acceptable carrier is anti-hypertriglyceridemia agent or anti-hypercholesterolemiccompounds agent.

Treatment claim 1 or the 7 described compounds of going up significant quantity preparation be used in the needs treatment the treatment of Mammals sufferer, prevent or slow down the purposes in the medicine of the PD that needs the glucokinase activators therapy.

11. purposes as claimed in claim 10, wherein said disease be mellitus, hyperglycemia, the glucose tolerance that weakens, insulin resistance, Hyperinsulinism, retinopathy, neuropathy, ephrosis, delay wound healing, atherosclerosis and sequela thereof, abnormal heart function, myocardial ischemia, apoplexy, metabolic syndrome, hypertension, obesity, lipidemia obstacle, hyperlipemia, non-heart ischemia, infection, cancer, vascular restenosis, pancreatitis, neurodegenerative disease, lipid disorders, cognitive power weakens and dementia, bone diseases, lipodystrophy and the glaucoma relevant with hiv protease.

12. purposes as claimed in claim 10, wherein said disease be the blood triglyceride too much, hypercholesterolemia, low HDL or high LDL.

13. be used for the purposes in the medicine of the sufferer treatment type ii diabetes that needs are treated in preparation like claim 1 or 7 described compounds.

14. compound as claimed in claim 1, wherein:

or its pharmacy acceptable salt.

15. compound as claimed in claim 14, wherein y-X-CO does

R ₄For

Or its pharmacy acceptable salt.

16. a compound, it has structure

Or its pharmacy acceptable salt.