CN101023057A - Certain chemical entities, compositions, and methods - Google Patents
Certain chemical entities, compositions, and methods Download PDFInfo
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Abstract
Compounds useful for treating cellular proliferative diseases and disorders by modulating the activity of one or more mitotic kinesins are disclosed.
Description
This application requires the rights and interests of the 60/569th, No. 510 U.S. Patent application submitting on May 6th, 2004, and this patent application is incorporated this paper into for your guidance.
Technical field
The present invention relates to chemical, it is the inhibitor of one or more mitotic kinesins, and is used to treat cell proliferation disorders, for example cancer, hyperplasia, restenosis, megalocardia, Immunological diseases, fungi illness and inflammation.
Background technology
Be used for the treatment of in the middle of the treatment for cancer agent, taxanes (taxanes) and catharanthus alkaloid are to act on the microtubule.Microtubule is the primary structure element of mitotic spindle.Mitotic spindle is that the replica of being responsible for genome respectively is distributed to two by on the daughter cell that cell fission caused.Suppose that mitotic spindle is decomposed by these medicines, cause bringing out of inhibition of cancer cell splitted and cancer cell death.Yet microtubule forms the cellularstructure of other types, is included in the path of transmitting in the cell in the neural process.Because these medicines are not to be target with the mitotic spindle specifically, so it has the side effect that limits its use.
In the improvement that is used for the treatment of on the drug specificity of cancer is quite attractive, and this is because if the side effect relevant with these medicines of administration can be reduced, then can realize treating benefit.Traditionally, the unusual improvement on the treatment cancer is relevant with the medicine that identifies via the new mechanism effect.This example does not include only taxanes, also comprises camptothecine (camptothecin) class of topology isomerase (topoisomerase) I inhibitor.From these two viewpoints, mitotic kinesins is attractive new anti-cancer drug thing target.
Mitotic kinesins is the combination of mitotic spindle and the enzyme of function basically, but is not the some of other micro-tubular structures usually, as in neural flow process.Mitotic kinesins is played the part of necessary role during mitotic all stages.These enzymes are " molecular motors ", and it changes the energy discharged by the ATP hydrolysis and becomes mechanical force, and this mechanical force then drives the cell object and moves along the directivity of microtubule.For the enough catalysis regions of this task is about 340 amino acid whose imporositys.During mitotic division, kinesin organizes microtubule to become bipolarity structure for mitotic spindle.Kinesin is regulated karyomit(e) along the moving of spindle microtubule, and the structural modification relevant with the specific phase of cell mitogen on mitotic spindle.
The experiment disturbance of mitotic kinesins function causes mitotic spindle deformity or dysfunction, often causes cell cycle to stop and necrocytosis.
Summary of the invention
In one aspect, the present invention relates to be used for the treatment of cell proliferation disorders method, and treat disorderly method by the activity that suppresses one or more mitotic kinesins.
The invention provides at least a chemical and the acceptable salt of pharmacology, solvate, inner complex, non-covalent complex, prodrug and the mixture that are selected from formula I compound:
Formula I
Wherein:
R
1Be the optional aryl that replaces, the optional Heterocyclylalkyl that replaces or the optional heteroaryl that replaces;
X is-CO or-SO
2-;
R
2Be hydrogen or the optional low alkyl group that replaces;
W is-CR
4-,-CH
2CR
4-or N;
R
3For-CO-R
7-, hydrogen, the optional alkyl that replaces, the optional heterocyclic radical that replaces, cyano group, the optional alkylsulfonyl that replaces or the optional aryl that replaces;
R
4Be hydrogen or the optional alkyl that replaces;
R
5Be hydrogen, hydroxyl, the optional amino that replaces, the optional heterocyclic radical that replaces or the optional low alkyl group that replaces;
R
6Be hydrogen, the optional alkyl that replaces, the optional alkoxyl group that replaces, the optional aryloxy that replaces, the optional heteroaryl oxygen base that replaces, the optional alkoxy carbonyl that replaces, the optional aminocarboxyl that replaces, the optional aryl that replaces, the optional heteroaryl that replaces, the optional heterocyclic radical that replaces or the optional alkaryl that replaces; And
R
7Be the optional low alkyl group that replaces, the optional aryl that replaces, hydroxyl, the optional amino that replaces, the optional aralkyl oxy that replaces or the optional alkoxyl group that replaces.
In some specific embodiments, if W is N, then R
5Not hydroxyl or the optional amino that replaces, and R
6Not the optional alkoxyl group that replaces, the optional aralkyl oxy that replaces, the optional assorted aralkoxy that replaces or the optional amino that replaces.
The present invention also provides at least a chemical and the acceptable salt of pharmacology, solvate, inner complex, non-covalent complex, prodrug and the mixture that is selected from formula II compound:
(formula II)
Wherein
R
2, R
3, R
5, R
6And W is as described in to formula I compound, and
R
11Be the optional heterocyclic radical that replaces, optional low alkyl group, nitro, cyano group, hydrogen, alkylsulfonyl or the halogen that replaces;
R
12Be hydrogen, halogen, the optional alkyl that replaces, the optional amino that replaces, the optional sulfane base that replaces, the optional alkoxyl group that replaces, the optional aryloxy that replaces, the optional heterocyclic radical that replaces or the optional heteroaryloxy that replaces; And
R
13For hydrogen, acyl group, the optional alkyl that replaces-, the optional alkoxyl group that replaces, halogen, hydroxyl, nitro, cyano group, the optional amino that replaces, alkyl sulphonyl, amino-alkyl sulfinyl, alkyl sulphonyl, carboxyalkyl, aminocarboxyl, the optional aryl that replaces or the optional heteroaryl that replaces.
The present invention also provides at least a chemical and the acceptable salt of pharmacology, solvate, inner complex, non-covalent complex, prodrug and the mixture that is selected from the formula III compound:
(formula III)
R wherein
2, R
3, R
6, R
11, R
12And R
13Be as described in to formula II compound.
The present invention also provides at least a chemical and the acceptable salt of pharmacology, solvate, inner complex, non-covalent complex, prodrug and the mixture that is selected from formula IV compound:
(formula IV)
R wherein
2, R
6, R
11, R
12And R
13Be as described in to the formula III compound.
The present invention also provides at least a chemical and the acceptable salt of pharmacology, solvate, inner complex, non-covalent complex, prodrug and the mixture that is selected from formula V compound:
(formula V)
Wherein
R
2, R
3, R
11, R
12And R
13Be as described in to the formula III compound, and wherein
R
14Be the optional heteroaryl that replaces; And
R
15Be to be selected from hydrogen, halogen, hydroxyl and low alkyl group.
The present invention also provides at least a chemical and the acceptable salt of pharmacology, solvate, inner complex, non-covalent complex, prodrug and the mixture that is selected from formula VI compound:
(formula VI)
R wherein
2, R
6, R
11, R
12And R
13Be as described in to the formula III compound.
The present invention also provides at least a chemical and the acceptable salt of pharmacology, solvate, inner complex, non-covalent complex, prodrug and the mixture that is selected from formula VII compound:
(formula VII)
R wherein
2, R
6, R
11, R
12And R
13Be as described in to the formula III compound, and wherein:
R
9Be to be selected from optional amino that replaces and the optional low alkyl group that replaces.
The present invention also provides a kind of composition, and it comprises a drug excipient and at least a said chemical.
The present invention also provides a kind of adjusting CENP-E kinesin active method, and it comprises this kinesin is contacted with the chemical at least a described herein of significant quantity.
The present invention also provides the method for a kind of CENP-E of inhibition, and it comprises this kinesin is contacted with the chemical at least a described herein of significant quantity.
The present invention also provides a kind of method for the treatment of cell proliferation disorders, and it comprises at least a said chemical of patient's administration that these needs are arranged.
The present invention also provides a kind of method for the treatment of cell proliferation disorders, and it comprises a kind of composition that comprises drug excipient and at least a said chemical of patient's administration that these needs are arranged.
The present invention also provides at least a said chemical to be used for the treatment of application in the medicine of cell proliferation disorders in preparation.
The present invention also provides at least a said chemical to be used for the treatment of application in the medicine with the active relevant disease of CENP-E kinesin in preparation.
As used in this manual, following words is intended to have the meaning shown in following usually, has the explanation in addition in literary composition.Following abbreviation and term be whole to have pointed meaning:
As used in this, when any variation in chemical formula took place more than one time, it was defined in each nidus and independently is the definition at each its other nidus.
Following abbreviation and term be whole to have pointed meaning:
The Ac=ethanoyl
The Boc=t-butoxy carbonyl
The Bu=butyl
The c-=ring
The CBZ=benzyloxycarbonyl
DBU=diazabicylo [5.4.0] 11 carbon-7-alkene
DCM=diamino methane CH
2Cl
2
DCE=diamino ethene
DEAD=azoethane dicarboxylic ester
DIC=di-isopropyl carbodiimide
DIEA=N, the N-diisopropyl ethyl amine
DMAP=4-N, the N-dimethyl aminopyridine
DMF=N, dinethylformamide
The DMSO=dimethyl sulfoxide (DMSO)
The Et=ethyl
Fmoc=9-fluorenyl methoxy carbonyl
The GC=gas-chromatography
HATU=O-(7-azepine benzo triazol-1-yl)-1,1,3,3-tetramethyl-hexafluoro
Phosphoric acid urine
HOAc=acetate
The HOBt=hydroxybenzotriazole
The LAH=lithium aluminium hydride
The Me=methyl
The mesyl=methylsulfonyl
The NCS=N-chloro-succinimide
The Ph=phenyl
The Py=pyridine
The rt=room temperature
Sat ' d=is saturated
The s-=secondary
Three grades of t-=
The TES=triethyl silicane
The TFA=trifluoroacetic acid
The THF=tetrahydrofuran (THF)
The TMS=trimethyl silyl
The tosyl=p-toluenesulfonyl
The dash ("-") between two letters or symbol is not used to point out substituent tie point.For example-CONH
2Connect via carbon atom.
Incident or environment that " optional " or " randomly " means follow-up narration might take place or might not take place, and this narration comprises example that this incident wherein or environment take place and the example that does not take place thereof.For example, " optional be substituted alkyl " comprise as give a definition it " alkyl " reach " alkyl that is substituted " both.It will be understood by those skilled in the art that for comprising one or more substituent any groups that this type of group is not intended to import is unactual on the solid, syntheticly infeasible and/or natural unsettled any replacement or the substitution pattern.
" alkyl " comprise the straight chain of the carbon atom with indication number and side chain arranged, from 1 to 20 carbon atom normally, and 1 to 8 carbon atom for example is as 1 to 6 carbon atom.C for example
1-C
6Alkyl comprise the straight chain of from 1 to 6 carbon atom and branched-chain alkyl both.The example of alkyl comprises methyl, ethyl, propyl group, sec.-propyl, normal-butyl, sec-butyl, the tertiary butyl, amyl group, 2-amyl group, isopentyl, neo-pentyl, hexyl, 2-hexyl, 3-hexyl, 3-methyl amyl and analogue etc.Alkylidene group is another time family of alkyl, means the identical residue as alkyl, but has two tie points.Alkylidene group has from 2 to 20 carbon atoms usually, and 2 to 8 carbon atoms for example are as from 2 to 6 carbon atoms.C for example
0Alkylidene group is meant a covalent linkage, and C
1Alkylidene group is a methylene radical.When the alkyl residue with given number carbon atom was censured, all geometrical isomers with this carbon atom number were intended to comprise it; Therefore, for example " butyl " means and comprises normal-butyl, sec-butyl, the tertiary butyl, and " propyl group " comprises n-propyl and sec.-propyl." low alkyl group " means has one to four carbon atom " alkyl.
" cycloalkyl " means the stable hydrocarbon cyclic group, has the carbon atom of given number, normally from 3 to 7 carbon atoms.The example of cycloalkyl comprises cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl and bridge formation and cage shape saturated rings group, as bornylane.
" alkoxyl group " means the alkyl via the indication number carbon atom of oxygen bridge formation connection, for example methoxyl group, oxyethyl group, propoxy-, isopropoxy, n-butoxy, sec-butoxy, tert.-butoxy, pentyloxy, 2-pentyloxy, isopentyloxy, neopentyl oxygen, hexyloxy, 2-hexyloxy, 3-hexyloxy, 3-methyl pentyloxy and analogue etc.Alkoxy grp has from 1 to 6 carbon atom of building bridge and connecting via oxygen usually, and " lower alkoxy " means has an alkoxyl group to four carbon atom.
" acyl group " mean (alkyl)-C (O)-, (cycloalkyl)-C (O)-, (aryl)-C (O)-, (heteroaryl)-C (O)-and (Heterocyclylalkyl)-C (O)-group; wherein be connected on the precursor structure by the carbonyl functional group on this group, and wherein alkyl, cycloalkyl, aryl, heteroaryl and Heterocyclylalkyl are as said.Acyl group has the carbon atom of indication number, and wherein the carbon of ketone groups is included in the carbon atom of being counted.C for example
2Acyl group is for having formula CH
3(C=O)-ethanoyl.
" alkoxy carbonyl " mean the formula (alkoxyl group) that connects via carbonyl carbon (C=O)-ester group, wherein alkoxyl group has the carbon atom of indication number.Therefore, C
1-C
6Alkoxy carbonyl is to have from 1 to 6 carbon atom that connects to carbonyl linking via its oxygen.
" amino " means-NH
2Group.
Term " aminocarboxyl " means-CONR
bR
c, wherein
R
bBe to be selected from H, the optional C that replaces
1-C
6Alkyl, the optional aryl that replaces and the optional heteroaryl that replaces; And
R
cBe to be selected from hydrogen and the optional C that replaces
1-C
4Alkyl; Or
R
bAnd R
cForm optional 5-to the 7-member nitrogen heterocyclic ring alkyl that replaces with the nitrogen of bond on it, it randomly comprises 1 or 2 extra heteroatoms that is selected from O, N and S in heterocycloalkyl ring; Its each group that replaces is independent of one or more following substituting group replacement: C that are independently selected from
1-C
4Alkyl, aryl, heteroaryl, aryl-C
1-C
4Alkyl, heteroaryl-C
1-C
4Alkyl, C
1-C
4Haloalkyl-,-OC
1-C
4Alkyl ,-OC
1-C
4Alkyl phenyl ,-C
1-C
4Alkyl-OH ,-OC
1-C
4Haloalkyl-, halogen ,-OH ,-NH
2, C
1-C
4Alkyl-NH
2,-N (C
1-C
4Alkyl) (C
1-C
4Alkyl) ,-NH (C
1-C
4Alkyl) ,-N (C
1-C
4Alkyl) (C
1-C
4Alkyl phenyl) ,-NH (C
1-C
4Alkyl phenyl), cyano group, nitro, oxo (to the substituting group of heteroaryl) ,-CO
2H ,-C (O) OC
1-C
4Alkyl ,-CON (C
1-C
4Alkyl) (C
1-C
4Alkyl) ,-CONH (C
1-C
4Alkyl) ,-CONH
2,-NHC (O) (C
1-C
4Alkyl) ,-NHC (O) (phenyl) ,-N (C
1-C
4Alkyl) C (O) (C
1-C
4Alkyl), N (C
1-C
4Alkyl) C (O) (phenyl) ,-C (O) C
1-C
4Alkyl ,-C (O) C
1-C
4Phenyl ,-C (O) C
1-C
4Haloalkyl ,-OC (O) C
1-C
4Alkyl ,-SO
2(C
1-C
4Alkyl) ,-SO
2(phenyl) ,-SO
2(C
1-C
4Haloalkyl) ,-SO
2NH
2,-SO
2NH (C
1-C
4Alkyl) ,-SO
2NH (phenyl) ,-NHSO
2(C
1-C
4Alkyl) ,-NHSO
2(phenyl) reaches-NHSO
2(C
1-C
4Haloalkyl).
" aryl " comprises 5-and 6-person's carbocyclic ring aromatic nucleus, for example benzene; The dicyclo loop systems, wherein at least one ring is for carbocyclic ring and fragrance, for example naphthalene, indane, and naphthane (tetralin); Reach three ring loop systems, wherein at least one ring is carbocyclic ring and fragrant, for example fluorenes.For example aryl comprise condense comprise 1 or heteroatomic 5-to the 7-element heterocycle alkyl ring of a plurality of O of being selected from, N and S on 5-and 6-person's carbocyclic ring aromatic nucleus.To this type of condensed-bicyclic loop systems that wherein to have only a ring be the carbocyclic ring aromatic nucleus, tie point can be at carbocyclic ring aromatic nucleus or heterocycloalkyl ring.Form and have the divalent group of free valence mumber by the benzene derivative that is substituted, be called as the phenylene that is substituted at the annular atoms place.Encircle the name tail end derived from unit price is the divalent group of the hydrocarbyl group of " yl " more, be that carbon atom from the free valence mumber of tool removes hydrogen atom, to add " idene " to its corresponding monoradical nominally, the naphthylene group that for example has two tie points is called as naphthylidene by name.Yet aryl is not included in down the heteroaryl of definition in addition or repeats with heteroaryl by any way.Therefore, if one or more carbocyclic ring aromatic nucleus and Heterocyclylalkyl aromatic nucleus condense, the gained loop systems is a heteroaryl, is not aryl, as defined in this.
Term " aryloxy " means-the O-aryl.
Term " alkaryl " means aryl moiety wherein is connected in precursor structure via alkyl group.Example comprise benzyl-, styroyl-, phenyl vinyl-, phenyl allyl group-and analogue.
Term " heteroaralkyl " means heteroaryl moieties wherein is connected in precursor structure via alkyl group.Example comprise furyl methyl-, pyridylmethyl-, pyrimidinylethyl and analogue.
Term " halo " means fluorine, chlorine, bromine and iodine, and term " halogen " means fluorine, chlorine, bromine and iodine.
" haloalkyl " means the alkyl with institute's given number carbon atom of as above definition, with 1 or a plurality of halogen atom replace high halogen atom to the maximum admissible number.The example of haloalkyl includes but not limited to trifluoromethyl, difluoromethyl, 2-fluoro ethyl and pentafluoroethyl group.
" heteroaryl " comprises 5-to 7-member fragrance, single cyclic rings, comprises the heteroatoms that one or more is selected from N, O and S, and for example from 1 to 4 or some specific embodiments from 1 to 3, surplus annular atoms is a carbon; And bicyclic heterocycle alkyl ring, comprise the heteroatoms that one or more is selected from N, O and S, for example from 1 to 4 or some specific embodiments from 1 to 3, surplus annular atoms is a carbon, and wherein at least one heteroatoms is present in the aromatic nucleus.For example heteroaryl comprises the aromatic nucleus of 5-to the 7-element heterocycle alkyl that condenses on 5-to 7-member cycloalkyl ring.Wherein have only a ring to comprise one or more heteroatomic condensed-bicyclic heteroaryl system to this type of, tie point can be on assorted aromatic nucleus or cycloalkyl ring.When the S in heteroaryl and O total atom number surpassed 1, those heteroatomss were contiguous mutually.In some specific embodiments, S in heteroaryl and O total atom number no more than 2.In some specific embodiments, S in aromatic heterocycle and O total atom number no more than 1.In some specific embodiments, the example of heteroaryl includes but not limited to (suppose to be decided to be preferential 1 from link position and be numbering) 2-pyridyl, the 3-pyridyl, the 4-pyridyl, 2, the 3-pyrazinyl, 3, the 4-pyrazinyl, 2, the 4-pyrimidyl, 3, the 5-pyrimidyl, 2, the 3-pyrazolinyl, 2,4-imidazolinyl isoxazoline-3-yl oxazolinyl, thiazolinyl, the Thiadiazoline base, tetrazyl, thienyl, benzothienyl, furyl, benzofuryl, the benzimidazoline base, indolinyl, pyridizinyl, triazolyl, quinolyl, pyrazolyl, imidazopyridyl and 5,6,7, the 8-tetrahydroisoquinoline.By the name tail end is the unit price heteroaryl deutero-divalent group of " yl ", be that atom from the free valence mumber of tool removes a hydrogen atom, to add " idene " to its corresponding monoradical nominally, the pyridyl that for example has two tie points is called as pyridylidene by name.Heteroaryl does not comprise the aryl of above-mentioned definition or repeats with it.
In term " heteroaralkyl ", heteroaryl and alkyl are as defined herein, and tie point is on alkyl.This term includes but not limited to pyridylmethyl, thienyl methyl and (pyrryl)-ethyl.
" leavings group " or " atom " is any group or the atom that can be removed and be promoted at specific position thus reaction under reaction conditions by initiator.Except as otherwise noted, the suitable example of these groups is halogen atom, mesyloxy, p-nitrophenyl sulfonyloxy or tosyloxy.
" choose wantonly " and be meant that described subsequently incident or environment may take place or also may not take place, and this statement comprises the situation of described incident or environment generation and the situation that it does not take place.For example, " the optional alkyl that replaces " comprises " alkyl " and " alkyl of replacement " that this paper defines.About containing one or more substituent any groups, it will be appreciated by persons skilled in the art that this group is not intended to three-dimensional unpractiaca and/or synthetic unpractiaca and/or unsettled any replacement own or the replacement mode of that of introducing.
" protecting group " has and its relevant implication in organic synthesis usually; be one or more reactive sites of selective exclusion polyfunctional compound, thus the group that makes chemical reaction optionally carry out and can after selective reaction is finished, easily remove at another not protected reactive site.Many protecting groups are open in such as following document: T.H.Greene and P.G.M.Wuts, Protective Groups in Organic Synthesis, ThirdEdition, John Wiley ﹠amp; Sons, New York (1999), the full content of the document is hereby incorporated by.For example, in the hydroxyl protection form, at least one hydroxyl that exists in the compound is protected by hydroxyl protecting group.Equally, amine and other reactive group can be protected similarly.
" Heterocyclylalkyl " means single aliphatic series ring, and 3 to 7 annular atomses are arranged usually, except 1-3 heteroatoms that independently is selected from oxygen, sulphur and nitrogen, comprises at least 2 carbon atoms and comprises at least a aforementioned heteroatomic combination.Suitably Heterocyclylalkyl for example comprises (suppose to be decided to be preferential 1 from link position and be numbering): 2-pyrrolinyl, 2,4-imidazolidyl, 2,3-pyrazolidyl, 2-piperidyl, 3-piperidyl, 4-piperidyl and 2,5-piperazinyl.Morpholinyl also is considered, and comprises 2-morpholinyl and morpholinyl (wherein oxygen is decided to be preferential 1 numbering).
As used in this, " adjusting " means the change on the CENP-E activity, as the direct or indirect reaction that at least a said chemical is existed, with respect to the non-existent CENP-E activity of chemical.This change can increase on the activity or reduce on activity, and can be owing to the direct interaction of the chemical of CENP-E or because compound and one or more influence the interaction of other factors of CENP-E activity in regular turn.
Term " sulfane base " comprises-S-(optional (C that replaces
1-C
6) alkyl) ,-S-(optional replace aryl) ,-S-(the optional heteroaryl that replaces) and-group of S-(the optional Heterocyclylalkyl that replaces).Therefore, the sulfane base comprises C
1-C
6Alkyl alkylthio base.
Term " sulfinyl " comprises-S (O)-H ,-S (O)-(optional (C that replaces
1-C
6) alkyl) ,-S (O)-(optional replace aryl) ,-S (O)-(the optional heteroaryl that replaces) ,-S (O)-(the optional Heterocyclylalkyl that replaces) and-group of S (O)-(the optional amino that replaces).
Term " alkylsulfonyl " comprises-S (O
2)-H ,-S (O
2Optional (the C that replaces of)-(
1-C
6) alkyl) ,-S (O
2The optional aryl that replaces of)-() ,-S (O
2The optional heteroaryl that replaces of)-() ,-S (O
2The optional Heterocyclylalkyl that replaces of)-() ,-S (O
2The optional alkoxyl group that replaces of)-() ,-S (O
2The optional aryloxy that replaces of)-() ,-S (O
2The optional heteroaryloxy that replaces of)-() ,-S (O
2The optional heterocycle alkoxyl group that replaces of)-() reaches-S (O
2The optional amino that replaces of)-() group.
As used in this, term " is substituted " any one or more hydrogen that means on atom of being decided or group and is replaced from the selection in the pointed group, and its restricted condition can not surpass for the normal valence mumber of the atom decided.When substituting group is that oxo (promptly=O) time, then replaced by 2 atoms on atom.The combination of substituting group and/or variation is admissible, as long as this type of combination causes stable compound or useful synthetic intermediate.It is enough by force to retaining from reaction mixture and follow-up preparation separates, as having the medicine of practical use at least that stable compound or stable structure mean the hint compound.Unless state in addition, substituting group is named as core texture.For example will understand, when (cycloalkyl) alkyl was done possible substituting group by row, this substituting group was at alkyl partly to the tie point of core texture.
Unless performance definition in addition, term " is substituted " alkyl, cycloalkyl, aryl, Heterocyclylalkyl and heteroaryl and means one or more (as height to 5, for example high to 3) hydrogen atom wherein and be independently selected from alkyl, cycloalkyl, aryl, Heterocyclylalkyl and the heteroaryl that the substituting group in following group replaces:
-R
a,-OR
b,-O (C
1-C
2Alkyl) O-(for example methylene radical dioxy base-) ,-SR
b, guanidine radicals, wherein one or more guanidine radicals hydrogen by low alkyl group metathetical guanidine radicals ,-NR
bR
c, halogen, cyano group, nitro ,-COR
b,-CO
2R
b,-CONR
bR
c,-OCOR
b,-OCO
2R
a,-OCONR
bR
c,-NR
cCOR
b,-NR
CCO
2R
a,-NR
cCONR
bR
c,-OCO
2R
b,-CONR
bR
c,-NR
CCOR
b,-SOR
a,-SO
2R
a,-SO
2NR
bR
cAnd-NR
cSO
2R
a,
R wherein
aBe to be selected from the optional C that replaces
1-C
6Alkyl, the optional aryl that replaces and the optional heteroaryl that replaces;
R
bBe to be selected from H, the optional C that replaces
1-C
6Alkyl, the optional aryl that replaces and the optional heteroaryl that replaces; And
R
cBe to be selected from hydrogen and the optional C that replaces
1-C
4Alkyl;
Wherein each optional group that replaces is to be unsubstituted or independent by one or more, replace as one, two or three substituting group that is independently selected from following group: C
1-C
4Alkyl, aryl, heteroaryl, aryl-C
1-C
4Alkyl, heteroaryl-C
1-C
4Alkyl, C
1-C
4Haloalkyl ,-OC
1-C
4Alkyl ,-OC
1-C
4Alkyl phenyl ,-C
1-C
4Alkyl-OH ,-OC
1-C
4Haloalkyl, halogen ,-OH ,-NH
2,-C
1-C
4Alkyl-NH
2,-N (C
1-C
4Alkyl) (C
1-C
4Alkyl) ,-NH (C
1-C
4Alkyl) ,-N (C
1-C
4Alkyl) (C
1-C
4Alkyl phenyl) ,-NH (C
1-C
4Alkyl phenyl), cyano group, nitro, oxo (as the substituting group of heteroaryl) ,-CO
2H ,-C (O) OC
1-C
4Alkyl ,-CON (C
1-C
4Alkyl) (C
1-C
4Alkyl) ,-CONH (C
1-C
4Alkyl) ,-CONH
2,-NHC (O) (C
1-C
4Alkyl) ,-NHC (O) (phenyl) ,-N (C
1-C
4Alkyl) C (O) (C
1-C
4Alkyl) ,-N (C
1-C
4Alkyl) C (O) (phenyl) ,-C (O) C
1-C
4Alkyl ,-C (O) C
1-C
4Phenyl ,-C (O) C
1-C
4Haloalkyl ,-OC (O) C
1-C
4Alkyl ,-SO
2(C
1-C
4Alkyl) ,-SO
2(phenyl) ,-SO
2(C
1-C
4Haloalkyl) ,-SO
2NH
2,-SO
2NH (C
1-C
4Alkyl) ,-SO
2NH (phenyl) ,-NHSO
2(C
1-C
4Alkyl) ,-NHSO
2(phenyl) reaches-NHSO
2(C
1-C
4Haloalkyl).
Term " acyl group that is substituted " mean (alkyl that is substituted)-C (O)-; (cycloalkyl that is substituted)-C (O)-; (aryl that is substituted)-C (O)-; (heteroaryl that is substituted)-C (O)-and (Heterocyclylalkyl that is substituted)-C (O)-group; wherein this group is to invest precursor structure via the carbonyl functional group; and the alkyl that wherein is substituted; cycloalkyl; aryl; heteroaryl and Heterocyclylalkyl mean wherein respectively, and one or more (as height to 5, for example high to 3) hydrogen atom independently is selected from the substituting group metathetical alkyl in following group; cycloalkyl; aryl; heteroaryl and Heterocyclylalkyl:
-R
a,-OR
b,-O (C
1-C
2Alkyl) O-(for example methylene radical dioxy base-) ,-SR
b, guanidine radicals, wherein one or more guanidine radicals hydrogen by low alkyl group metathetical guanidine radicals ,-NR
bR
c, halogen, cyano group, nitro ,-COR
b,-CO
2R
b,-CONR
bR
c,-OCOR
b,-OCO
2R
a,-OCONR
bR
c,-NR
CCOR
b,-NR
CCO
2R
a,-NR
cCONR
bR
c,-OCO
2R
b,-CONR
bR
c,-NR
cCOR
b,-SOR
a,-SO
2R
a,-SO
2NR
bR
cAnd-NR
cSO
2R
a,
R wherein
aBe to be selected from the optional C that replaces
1-C
6Alkyl, the optional aryl that replaces and the optional heteroaryl that replaces;
R
bBe to be selected from H, the optional C that replaces
1-C
6Alkyl, the optional aryl that replaces and the optional heteroaryl that replaces; And
R
cBe to be selected from hydrogen and the optional C that replaces
1-C
4Alkyl;
Wherein each optional group that replaces is to be unsubstituted or independent by one or more, replace as one, two or three substituting group that is independently selected from following group: C
1-C
4Alkyl, aryl, heteroaryl, aryl-C
1-C
4Alkyl-, heteroaryl-C
1-C
4Alkyl-, C
1-C
4Haloalkyl-,-OC
1-C
4Alkyl ,-OC
1-C
4Alkyl phenyl ,-C
1-C
4Alkyl-OH ,-OC
1-C
4Haloalkyl, halogen ,-OH ,-NH
2,-C
1-C
4Alkyl-NH
2,-N (C
1-C
4Alkyl) (C
1-C
4Alkyl) ,-NH (C
1-C
4Alkyl) ,-N (C
1-C
4Alkyl) (C
1-C
4Alkyl phenyl) ,-NH (C
1-C
4Alkyl phenyl), cyano group, nitro, oxo (as the substituting group of heteroaryl) ,-CO
2H ,-C (O) OC
1-C
4Alkyl ,-CON (C
1-C
4Alkyl) (C
1-C
4Alkyl) ,-CONH (C
1-C
4Alkyl) ,-CONH
2,-NHC (O) (C
1-C
4Alkyl) ,-NHC (O) (phenyl) ,-N (C
1-C
4Alkyl) C (O) (C
1-C
4Alkyl) ,-N (C
1-C
4Alkyl) C (O) (phenyl) ,-C (O) C
1-C
4Alkyl ,-C (O) C
1-C
4Phenyl ,-C (O) C
1-C
4Haloalkyl ,-OC (O) C
1-C
4Alkyl ,-SO
2(C
1-C
4Alkyl) ,-SO
2(phenyl) ,-SO
2(C
1-C
4Haloalkyl) ,-SO
2NH
2,-SO
2NH (C
1-C
4Alkyl) ,-SO
2NH (phenyl) ,-NHSO
2(C
1-C
4Alkyl) ,-NHSO
2(phenyl) reaches-NHSO
2(C
1-C
4Haloalkyl).
Term " alkoxyl group that is substituted " means wherein the substituted alkoxyl group of alkyl component (promptly-O-(alkyl that is substituted)), wherein " alkyl that is substituted " means wherein that one or more (as height to 5, for example high to 3) hydrogen atom is independently selected from the substituting group metathetical alkyl in following group:
-R
a,-OR
b,-O (C
1-C
2Alkyl) O-(for example methylene radical dioxy base-) ,-SR
b, guanidine radicals, wherein one or more guanidine radicals hydrogen by low alkyl group metathetical guanidine radicals ,-NR
bR
c, halogen, cyano group, nitro ,-COR
b,-CO
2R
b,-CONR
bR
c,-OCOR
b,-OCO
2R
a,-OCONR
bR
c,-NR
CCOR
b,-NR
CCO
2R
a,-NR
CCONR
bR
c,-OCO
2R
b,-CONR
bR
c,-NR
cCOR
b,-SOR
a,-SO
2R
a,-SO
2NR
bR
cAnd-NR
CSO
2R
a,
R wherein
aBe to be selected from the optional C that replaces
1-C
6Alkyl, the optional aryl that replaces and the optional heteroaryl that replaces;
R
bBe to be selected from H, the optional C that replaces
1-C
6Alkyl, the optional aryl that replaces and the optional heteroaryl that replaces; And
R
cBe to be selected from hydrogen and the optional C that replaces
1-C
4Alkyl;
Wherein each optional group that replaces is to be unsubstituted or independent by one or more, replace as one, two or three substituting group that is independently selected from following group: C
1-C
4Alkyl, aryl, heteroaryl, aryl-C
1-C
4Alkyl-, heteroaryl-C
1-C
4Alkyl-, C
1-C
4Haloalkyl-,-OC
1-C
4Alkyl ,-OC
1-C
4Alkyl phenyl ,-C
1-C
4Alkyl-OH ,-OC
1-C
4Haloalkyl, halogen ,-OH ,-NH
2,-C
1-C
4Alkyl-NH
2,-N (C
1-C
4Alkyl) (C
1-C
4Alkyl) ,-NH (C
1-C
4Alkyl) ,-N (C
1-C
4Alkyl) (C
1-C
4Alkyl phenyl) ,-NH (C
1-C
4Alkyl phenyl), cyano group, nitro, oxo (as the substituting group of heteroaryl) ,-CO
2H ,-C (O) OC
1-C
4Alkyl ,-CON (C
1-C
4Alkyl) (C
1-C
4Alkyl) ,-CONH (C
1-C
4Alkyl) ,-CONH
2,-NHC (O) (C
1-C
4Alkyl) ,-NHC (O) (phenyl) ,-N (C
1-C
4Alkyl) C (O) (C
1-C
4Alkyl) ,-N (C
1-C
4Alkyl) C (O) (phenyl) ,-C (O) C
1-C
4Alkyl ,-C (O) C
1-C
4Phenyl ,-C (O) C
1-C
4Haloalkyl ,-OC (O) C
1-C
4Alkyl ,-SO
2(C
1-C
4Alkyl) ,-SO
2(phenyl) ,-SO
2(C
1-C
4Haloalkyl) ,-SO
2NH
2,-SO
2NH (C
1-C
4Alkyl) ,-SO
2NH (phenyl) ,-NHSO
2(C
1-C
4Alkyl) ,-NHSO
2(phenyl) reaches-NHSO
2(C
1-C
4Haloalkyl).In some specific embodiments, the alkoxyl group that is substituted is " poly-alkoxyl group " or-O-(the optional alkylidene group that replaces)-(the optional alkoxyl group that replaces), and comprise as-OCH
2CH
2OCH
3Reach as polyoxyethylene glycol and reach-O (CH
2CH
2O)
xCH
3The group of glycol ethers residue, wherein x is the integer of 2-20, as 2-10, and 2-5 for example.Another alkoxyl group that is substituted be the hydroxy alkoxy base or-OCH
2(CH
2)
yOH, wherein y is the integer of 1-10, as 1-4.
Term " alkoxy carbonyl that is substituted " mean (alkyl that is substituted)-O-C (O)-group, wherein this group is to invest precursor structure via the carbonyl functional group, and what wherein be substituted means wherein that one or more (as height to 5, for example high to 3) hydrogen atom is independently selected from the substituting group metathetical alkyl in following group:
-R
a,-OR
b,-O (C
1-C
2Alkyl) O-(for example methylene radical dioxy base-) ,-SR
b, guanidine radicals, wherein one or more guanidine radicals hydrogen with low alkyl group metathetical guanidine radicals ,-NR
bR
c, halogen, cyano group, nitro ,-COR
b,-CO
2R
b,-CONR
bR
c,-OCOR
b,-OCO
2R
a,-OCONR
bR
c,-NR
CCOR
b,-NR
CCO
2R
a,-NR
cCONR
bR
c,-OCO
2R
b,-CONR
bR
c,-NR
CCOR
b,-SOR
a,-SO
2R
a,-SO
2NR
bR
cAnd-NR
cSO
2R
a,
R wherein
aBe to be selected from the optional C that replaces
1-C
6Alkyl, the optional aryl that replaces and the optional heteroaryl that replaces;
R
bBe to be selected from H, the optional C that replaces
1-C
6Alkyl, the optional aryl that replaces and the optional heteroaryl that replaces; And
R
cBe to be selected from hydrogen and the optional C that replaces
1-C
4Alkyl;
Wherein each optional group that replaces is to be unsubstituted or independent by one or more, replace as one, two or three substituting group that is independently selected from following group: C
1-C
4Alkyl, aryl, heteroaryl, aryl-C
1-C
4Alkyl-, heteroaryl-C
1-C
4Alkyl-, C
1-C
4Haloalkyl-,-OC
1-C
4Alkyl ,-OC
1-C
4Alkyl phenyl ,-C
1-C
4Alkyl-OH ,-OC
1-C
4Haloalkyl, halogen ,-OH ,-NH
2,-C
1-C
4Alkyl-NH
2,-N (C
1-C
4Alkyl) (C
1-C
4Alkyl) ,-NH (C
1-C
4Alkyl) ,-N (C
1-C
4Alkyl) (C
1-C
4Alkyl phenyl) ,-NH (C
1-C
4Alkyl phenyl), cyano group, nitro, oxo (as the substituting group of heteroaryl) ,-CO
2H ,-C (O) OC
1-C
4Alkyl ,-CON (C
1-C
4Alkyl) (C
1-C
4Alkyl) ,-CONH (C
1-C
4Alkyl) ,-CONH
2,-NHC (O) (C
1-C
4Alkyl) ,-NHC (O) (phenyl) ,-N (C
1-C
4Alkyl) C (O) (C
1-C
4Alkyl) ,-N (C
1-C
4Alkyl) C (O) (phenyl) ,-C (O) C
1-C
4Alkyl ,-C (O) C
1-C
4Phenyl ,-C (O) C
1-C
4Haloalkyl ,-OC (O) C
1-C
4Alkyl ,-SO
2(C
1-C
4Alkyl) ,-SO
2(phenyl) ,-SO
2(C
1-C
4Haloalkyl) ,-SO
2NH
2,-SO
2NH (C
1-C
4Alkyl) ,-SO
2NH (phenyl) ,-NHSO
2(C
1-C
4Alkyl) ,-NHSO
2(phenyl) reaches-NHSO
2(C
1-C
4Haloalkyl).
Term " amino that is substituted " means-NHR
dOr-NR
dR
dGroup, each R wherein
dBe independently to be selected from the alkyl that is substituted, the optional cycloalkyl that replaces, the optional acyl group that replaces, the optional aryl that replaces, the optional heteroaryl that replaces, optional Heterocyclylalkyl, alkoxy carbonyl, sulfinyl and the alkylsulfonyl that replaces; the alkyl that wherein is substituted, cycloalkyl, aryl, Heterocyclylalkyl and heteroaryl mean wherein respectively, and one or more (as height to 5, for example high to 3) hydrogen atom is independently selected from substituting group metathetical alkyl, cycloalkyl, aryl, Heterocyclylalkyl and the heteroaryl in following group:
-R
a,-OR
b,-O (C
1-C
2Alkyl) O-(for example methylene radical dioxy base-) ,-SR
b, guanidine radicals, wherein one or more guanidine radicals hydrogen by low alkyl group metathetical guanidine radicals ,-NR
bR
c, halogen, cyano group, nitro ,-COR
b,-CO
2R
b,-CONR
bR
c,-OCOR
b,-OCO
2R
a,-OCONR
bR
c,-NR
cCOR
b,-NR
cCO
2R
a,-NR
cCONR
bR
c,-OCO
2R
b,-CONR
bR
c,-NR
cCOR
b,-SOR
a,-SO
2R
a,-SO
2NR
bR
cAnd-NR
cSO
2R
a,
R wherein
aBe to be selected from the optional C that replaces
1-C
6Alkyl, the optional aryl that replaces and the optional heteroaryl that replaces;
R
bBe to be selected from H, the optional C that replaces
1-C
6Alkyl, the optional aryl that replaces and the optional heteroaryl that replaces; And
R
cBe to be selected from hydrogen and the optional C that replaces
1-C
4Alkyl;
Wherein each optional group that replaces is to be unsubstituted or independent by one or more, replace as one, two or three substituting group that is independently selected from following group: C
1-C
4Alkyl, aryl, heteroaryl, aryl-C
1-C
4Alkyl-, heteroaryl-C
1-C
4Alkyl-, C
1-C
4Haloalkyl-,-OC
1-C
4Alkyl ,-OC
1-C
4Alkyl phenyl ,-C
1-C
4Alkyl-OH ,-OC
1-C
4Haloalkyl, halogen ,-OH ,-NH
2,-C
1-C
4Alkyl-NH
2,-N (C
1-C
4Alkyl) (C
1-C
4Alkyl) ,-NH (C
1-C
4Alkyl) ,-N (C
1-C
4Alkyl) (C
1-C
4Alkyl phenyl) ,-NH (C
1-C
4Alkyl phenyl), cyano group, nitro, oxo (as the substituting group of heteroaryl) ,-CO
2H ,-C (O) OC
1-C
4Alkyl ,-CON (C
1-C
4Alkyl) (C
1-C
4Alkyl) ,-CONH (C
1-C
4Alkyl) ,-CONH
2,-NHC (O) (C
1-C
4Alkyl) ,-NHC (O) (phenyl) ,-N (C
1-C
4Alkyl) C (O) (C
1-C
4Alkyl) ,-N (C
1-C
4Alkyl) C (O) (phenyl) ,-C (O) C
1-C
4Alkyl ,-C (O) C
1-C
4Phenyl ,-C (O) C
1-C
4Haloalkyl ,-OC (O) C
1-C
4Alkyl ,-SO
2(C
1-C
4Alkyl) ,-SO
2(phenyl) ,-SO
2(C
1-C
4Haloalkyl) ,-SO
2NH
2,-SO
2NH (C
1-C
4Alkyl) ,-SO
2NH (phenyl) ,-NHSO
2(C
1-C
4Alkyl) ,-NHSO
2(phenyl) reaches-NHSO
2(C
1-C
4Haloalkyl); And
Wherein optional acyl group, alkoxyl group, sulfinyl and the alkylsulfonyl that replaces is as defined herein.
Term " amino that is substituted " also means-NR
eR
fGroup, R wherein
eAnd R
fForm optional nitrogenous, the nonaromatic heterocycles of 5-to 7-member that replaces with the nitrogen of bond on it, it randomly comprises 1 or 2 extra heteroatoms that is selected from nitrogen, oxygen and sulphur.
The compound of formula I-XIII includes but not limited to optical isomer, racemoid and their other mixtures of formula I-XIII compound.Under those situations, single enantiomer or diastereomer, i.e. optical activity form, can asymmetric synthesis or the fractionation of racemoid obtain.The fractionation of racemoid can for example be finished as the ordinary method of crystallization in the presence of resolving agent or stratographic analysis, uses for example to chirality high-pressure liquid stratographic analysis (HPLC) post.In addition, formula I-XIII compound includes the compound of the Z-of carbon-to-carbon double bond and E-form (or suitable-and anti--form).Its Chinese style I-XIII compound exists with various change forms, and the present invention's chemical comprises all tautomeric forms of compound.Formula I-XIII compound also comprises the crystallized form as polymorph and inclusion compound.
The present invention's chemical includes but not limited to formula I-XIII compound and the acceptable form of all pharmacology thereof.Comprise the acceptable salt of its pharmacology, solvate, inner complex, non-covalent complex, prodrug and mixture in the acceptable form of the pharmacology of this compound of quoting from.In some specific embodiments, be the form of the acceptable salt of its pharmacology at the compound of this narration.Therefore, term " chemical " also comprises the acceptable salt of pharmacology, solvate, inner complex, non-covalent complex, prodrug and mixture.
" the acceptable salt of pharmacology " includes but not limited to the salt with mineral acid, example hydrochloric acid salt, phosphoric acid salt, diphosphate, hydrobromate, vitriol, sulfonate, nitrate and analogue; And with the organic acid salt, as apple salt, maleic acid salt, fumarate, tartrate, succinate, Citrate trianion, acetate, lactic acid salt, methane sulfonates, right-tosylate, 2-isethionate, benzoate, salicylate, stearate and alkyl salt, as acetate, HOOC-(CH
2)
n-COOH, wherein n is 0-4; And similar salt.Similarly, the acceptable positively charged ion of pharmacology includes but not limited to sodium, potassium, calcium, aluminium, lithium and ammonium.
In addition, if formula I-XIII compound obtains with acid salt, free alkali can obtain by the alkalization acid salt solution.On the contrary, if product is free alkali, additive salt, particularly pharmacology acceptable addition salt can be prepared as follows according to the conventional steps that is used for preparing from free alkali acid salt: dissolve free alkali at suitable organic solvent, and with acid treatment.Those skilled in the art can the cognitive various synthetic methods that can be used for preparing nontoxic pharmacology acceptable addition salt class.
As above annotate, prodrug also drops on the category of chemical, for example the ester of formula I-XIII compound or amide derivatives.Term " prodrug " comprise any compound that when delivering medicine to the patient, becomes formula I-XIII compound, for example in the metabolic process of prodrug.The example of prodrug includes but not limited to the like derivatives of acetic ester, manthanoate and benzoic ether and the functional group in formula I-XIII compound (as alcohol or amine groups).In some specific embodiments, prodrug is a phosphoric acid ester.The complete discussion of prodrug is provided in the Pro-drugs as Novel Delivery Systems of T.Higuchi and V.Stella, the 14th of A.C.S. symposial series; The Bioreversible Carriers in Drug Design that Edward B.Roche edits, American pharmaceutical Association and Pergamon Press, 1987; And Design of Prodrugs, editor: H.Bundgaard, Elsevier is in 1985; Its integral body at this and in this paper as a reference.
Term " solvate " means the chemical that the interaction by solvent and compound forms.The appropriate solvent thing is the acceptable solvate of pharmacology, as hydrate, comprises monohydrate and semihydrate.
Term " inner complex " means by compound and the metal formed chemical of coordination at two (or many) points.
Term " non-covalent complex " means the chemical that the interaction by compound and another molecule forms, and wherein covalent linkage does not form between compound and this molecule.For example compound action can take place via van der Waals interaction, hydrogen bond and electrostatic interaction (being also referred to as the ion bond).
Term " promoting agent " is used to point out the chemical of biologically active.In some specific embodiments, " promoting agent " is the compound with medicinal use.For example promoting agent can be anticancer therapeutic agent.
Term " antimitotic agent " is meant and is used for for example by making metaphase stop to suppress or preventing mitotic medicine.Some antitumor drug blocking-up proliferation functions, and be considered to antimitotic agent.
" the treatment significant quantity " of term the present invention's chemical, meaning provides when delivering medicine to the mankind or non-human patients as improving symptom, slowing down the significant quantity of the treatment benefit of progression of disease or preventing disease, for example treats the amount that significant quantity can be to be enough to alleviate to the disease symptoms of CENP-E inhibited reaction.In some specific embodiments, the treatment significant quantity is the amount that is enough to reduce cancer symptoms.In some specific embodiments, the treatment significant quantity is to be enough to reduce the amount that can detect the cancer cell number in organ, can detect slowly or stop the cancer growth.In some specific embodiments, the treatment significant quantity is the amount that is enough to dwindle cancer.
The active great minimizing of the baseline of biological activity or process pointed out in term " inhibition "." suppress the CENP-E activity " and mean the reaction that at least a said chemical is existed as directly or indirectly, with respect to the CENP-E activity that no at least a this chemical exists, CENP-E is active to be reduced.Active minimizing can owing to the direct interaction of this chemical and CENP-E or because said chemical and one or more influence the interaction of other factors of CENP-E activity in regular turn.For example the existence meeting of this chemical is by directly bond reduces the CENP-E activity to CENP-E, (directly or indirectly) causes another factor to reduce the CENP-E activity or (directly or indirectly) reduces the CENP-E amount that exists in cell or the organ that is present in.
" disease that CENP-E is suppressed " for wherein suppressing the disease of CENP-E, provide as improve symptom, slow down progression of disease, prevention or postpone the treatment benefit that disease begins or suppress the abnormal activity of some cell type.
Any disease that " treatment " means on the patient is handled, and comprises
A) preventing disease just causes the clinical symptom of disease not develop;
B) suppress disease;
C) slow down or stop the development of clinical symptom; And/or
D) palliate a disease, just cause the recovery of clinical symptom.
" patient " mean a kind of maybe will be for the animal of treatment, observation or object of experiment, as Mammals.Method of the present invention can be used for human treatment and veterinary purpose.In some specific embodiments, the patient is a Mammals; In some specific embodiments, the patient is human; And in some specific embodiments, the patient is selected from cat and dog.
The present invention points out the novel chemical of a class, and it is the inhibitor of one or more mitotic kinesins.According to some specific embodiments, said chemical suppresses mitotic division, CENP-E, particularly Ren Lei CENP-E.CENP-E is the prime mover that increases on the microtubule of end guiding, for realizing necessity in the chromosomal arrangement of metaphase in cell division.CENP-E accumulates at interkinesis, and decomposes after mitotic division is finished.The overexpression of the microinjection of the antibody of anti-CENP-E or the main negative mutant of CENP-E causes mitotic division to stop, and metaphase in cell division karyomit(e) is dispersed on the spindle body of the two poles of the earth.The tail region of CENP-E is regulated and is localized to kinetochore (kinetochores), and also interacts with mitotic division check point kinases hBubR1.The CENP-E also activity form with map kinase is relevant.Human CENP-E duplicates by report (people such as Yen, Nature, 359 (6395): 436-9 (1992)).At people EMBO J. such as Thrower, reported the partly human CENP-E of purifying natural among the 14:918-26 (1995).Moreover it is the prime mover that reduces on the microtubule of holding guiding that research report CENP-E is arranged.People's such as Wood Cell, 91; 357-66 (1997) is disclosed in the Xenopus CENP-E that expresses on the intestinal bacteria, and XCENP-E has the prime mover of motility for the end of the increase in test tube guiding.CENP-E sees: No. 99/13061, the open WO of PCT, it at this and in this paper as a reference.
In some specific embodiments, this chemical suppresses mitotic kinesins, CENP-E, and regulate one or more be selected from HSET (see: United States Patent (USP) 6,361, No. 993, its at this and as a reference in this paper); MCAK (see: United States Patent (USP) 6,331, No. 424, its at this and as a reference in this paper); RabK-6 (see: United States Patent (USP) 6,544, No. 766, its at this and as a reference in this paper); Kif4 (see: United States Patent (USP) 6,440, No. 684, its at this and as a reference in this paper); MKLP1 (see: United States Patent (USP) 6,448, No. 025, its at this and as a reference in this paper); Kif15 (see: United States Patent (USP) 6,355, No. 466, its at this and as a reference in this paper); Kid (see: United States Patent (USP) 6,387, No. 644, its at this and as a reference in this paper); Mppl, CMKrp, KinI-3 (see: United States Patent (USP) 6,461, No. 855, its at this and as a reference in this paper); Kip3a (see: PCT publishes WO No. 01/96593, its and as a reference) in this paper at this; Kip3d (see: United States Patent (USP) 6,492, No. 151, its at this and as a reference in this paper) and KSP (see: United States Patent (USP) 6,617, No. 115, its at this and as a reference in this paper) human mitotic kinesins.
The method that suppresses mitotic kinesins comprises the present invention's inhibitor and one or more mitotic kinesins or its segment or variant contacted, particularly Ren Lei kinesin.ATP hydrolytic activity and/or mitotic spindle that inhibition can be mitotic kinesins form activity, make mitotic spindle be interrupted.
The invention provides the inhibitor of one or more mitotic kinesins, particularly one or more human mitotic kinesins is used for the treatment of the imbalance relevant with hyperplasia.Said chemical composition and method can be different on its selectivity, and are used for the treatment of cell proliferation disorders, include but not limited to cancer, hyperplasia, restenosis, megalocardia, Immunological diseases, fungal disease and inflammation.
Therefore, the invention provides at least a chemical and the acceptable salt of pharmacology, solvate, inner complex, non-covalent complex, prodrug and the mixture that is selected from formula I compound:
Formula I
Wherein:
R
1Be the optional aryl that replaces, the optional Heterocyclylalkyl that replaces or the optional heteroaryl that replaces;
X is-CO or-SO
2-;
R
2Be hydrogen or the optional low alkyl group that replaces;
W is-CR
4-,-CH
2CR
4-or N;
R
3For-CO-R
7-, hydrogen, the optional alkyl that replaces, the optional heterocyclic radical that replaces, cyano group, the optional alkylsulfonyl that replaces or the optional aryl that replaces;
R
4Be hydrogen or the optional alkyl that replaces;
R
5Be hydrogen, hydroxyl, the optional amino that replaces, the optional heterocyclic radical that replaces or the optional low alkyl group that replaces;
R
6For hydrogen, the optional alkyl that replaces, the optional alkoxyl group that replaces, the optional aryloxy that replaces, the optional heteroaryl oxygen base that replaces, the optional alkoxy carbonyl that replaces-, the optional aminocarboxyl that replaces-, the optional aryl that replaces, the optional heteroaryl that replaces, the optional heterocyclic radical that replaces or the optional alkaryl that replaces; And
R
7Be the optional low alkyl group that replaces, the optional aryl that replaces, hydroxyl, the optional amino that replaces, the optional aralkyl oxy that replaces or the optional alkoxyl group that replaces;
Its restricted condition is if W is N, then R
5Not hydroxyl or the optional amino that replaces, and R
6Not the optional alkoxyl group that replaces, the optional aralkyl oxy that replaces, the optional heteroaryl alkoxyl group that replaces or the optional amino that replaces.
In some specific embodiments, R
1Be the optional aryl that replaces.In some specific embodiments, R
1Be the optional phenyl that replaces.In some specific embodiments, R
1For optional by one, two or three independently be selected from the optional heterocyclic radical that replaces, the optional alkyl that replaces, alkylsulfonyl, halogen, the optional amino that replaces, the optional sulfane base that replaces, the optional alkoxyl group that replaces, the optional aryloxy that replaces, the optional heteroaryl oxygen base that replaces, acyl group, hydroxyl, nitro, cyano group, the optional aryl that replaces and the optional heteroaryl that replaces-the phenyl that replaces of group.In some specific embodiments, R
1Be 3-halogen-4-isopropoxy-phenyl, 3-cyano group-4-isopropoxy-phenyl, 3-cyano group-4-sec.-propyl amino-phenyl, 3-chloro-4-sec.-propyl amino-phenyl, 3-cyano group-4-trifluoro isopropoxy-phenyl, 3-chloro-4-trifluoro isopropoxy-phenyl, 3-cyano group-4-cyclobutyl oxygen base-phenyl, 3-chloro-4-cyclobutyl oxygen base-phenyl, 3-cyano group-4-cyclopropyl oxygen base-phenyl and 3-chloro-4-cyclopropyl oxygen base-phenyl.In some specific embodiments, R
1Be 3-halogen-4-isopropoxy-phenyl or 3-cyano group-4-isopropoxy-phenyl.
In some specific embodiments, R
2Be hydrogen.
In some specific embodiments, X is-CO-.
In some specific embodiments, W is-CR
4-and R
4Be hydrogen.
In some specific embodiments, said compound has a potential chiral centre, and for example W is-CR
4-.The present invention considers the purposes of pure enantiomer and enantiomeric mixture, comprises racemic mixture, goes up preferred usually though be roughly the purposes of the enantiomer of optical purity.Term " is roughly optically pure " or " enantiomeric pure " means the described enantiomer that has at least about 95%, does not have single impurity greater than about 1%, and particularly excessive at least about 97.5% enantiomerism.In some specific embodiments, as follows at the three-dimensional center of W:
In some specific embodiments, R
3For-CO-R
7-, hydrogen, the optional low alkyl group that replaces, cyano group, the optional alkylsulfonyl that replaces, the optional aryl that replaces or the optional heterocyclic radical that replaces.In some specific embodiments, R
3Be the optional low alkyl group that replaces.In some specific embodiments, R
3By the low alkyl group of hydroxyl or the replacement of its phosphoric acid ester, randomly the low alkyl group that is replaced by lower alkoxy is chosen the low alkyl group of the amino replacement that is optionally substituted wantonly, or is chosen wantonly by CO-R for optional
8The low alkyl group that replaces, wherein R
8For hydroxyl or for choosing the amino that replaces wantonly.
In some specific embodiments, R
5Be hydrogen, hydroxyl or the optional low alkyl group that replaces.In some specific embodiments, R
5Be hydrogen.
In some specific embodiments, work as R
5When being not hydrogen, said compound has a potential chiral centre.The present invention considers the purposes of pure enantiomer and enantiomeric mixture, comprises racemic mixture, though it is normally preferred to be roughly the purposes of enantiomer of optical purity.Term " be roughly optically pure " or enantiomeric pure " mean the described enantiomer that has at least about 95%, do not have single impurity greater than about 1%, and particularly excessive at least about 97.5% enantiomerism.
In some specific embodiments, R
6Be the optional aryl that replaces, the optional heteroaryl that replaces, the optional heterocyclic radical that replaces or the optional alkyl that replaces (amino that is optionally substituted as alkyl wherein replaces, or wherein cycloalkyl-replacement of being optionally substituted of alkyl).In some specific embodiments, R
6Be the phenyl that replaced by one or two following substituting group: the optional heteroaryl that replaces, the optional amino that replaces, aralkoxy, halogen, methylol-, hydroxyl, cyano group, alkoxyl group, phenyl, phenoxy group, methylene radical dioxy base, ethylenedioxy, alkylsulfonyl, aminocarboxyl, carboxyl, alkoxy carbonyl, nitro, assorted aralkoxy, aralkoxy and the optional heterocyclic radical that replaces.
The present invention also provides at least a chemical and the acceptable salt of pharmacology, solvate, inner complex, non-covalent complex, prodrug and the mixture that is selected from formula II compound:
Wherein
R
2, R
3, R
5, R
6And W is as described in to formula I compound, and wherein
R
11Be the optional heterocyclic radical that replaces, optional low alkyl group, nitro, cyano group, hydrogen, alkylsulfonyl or the halogen that replaces;
R
12Be hydrogen, halogen, the optional alkyl that replaces, the optional amino that replaces, the optional sulfane base that replaces, the optional alkoxyl group that replaces, the optional aryloxy that replaces, the optional heterocyclic radical that replaces or the optional heteroaryloxy that replaces; And
R
13For hydrogen, acyl group, the optional alkyl that replaces-, the optional alkoxyl group that replaces, halogen, hydroxyl, nitro, cyano group, the optional amino that replaces, alkyl sulphonyl-, alkyl sulfonyl amino-, alkyl sulphonyl-, carboxyalkyl-, aminocarboxyl-, the optional aryl that replaces or the optional heteroaryl that replaces-.
In some specific embodiments, R
11Be hydrogen, cyano group, nitro or halogen.In some specific embodiments, R
11Be chlorine or cyano group.
In some specific embodiments, R
12Be the optional lower alkoxy that replaces, the optional low alkyl group that replaces or the optional amino that replaces.In some specific embodiments, R
12Be selected from isopropoxy, sec.-propyl amino, trifluoro isopropoxy, cyclobutoxy group and ring propoxy-.In some specific embodiments, R
12Be low alkyl group (as propoxy-) or 2,2,2-three fluoro-1-methyl-oxyethyl groups.In some specific embodiments, R
12Be not-O-(CH
2)
nNH
2Or-O-(CH
2)
4NH (CH
3), wherein n is 4 or 5.
In some specific embodiments, R
11And R
12Form optional carbocyclic ring or the heterocycle that replaces together.In some specific embodiments, R
11And R
12Form methylene radical dioxy base or ethylenedioxy ring together.In some specific embodiments, R
12And R
13Optional together carbocyclic ring or the heterocycle that replaces.In some specific embodiments, R
11And R
13Form optional carbocyclic ring or the heterocycle that replaces together.
In some specific embodiments, R
13Be hydrogen.
In some specific embodiments, R
12And R
13Form optional carbocyclic ring or the heterocycle that replaces together, i.e. R
1, X, N and R
2Form optional carbocyclic ring or the heterocycle that replaces together.In some specific embodiments, form be substituted 2,4-dioxo-1,4-dihydro-2H-quinazoline-3-basic ring, for example
Wherein phenyl ring is optional is substituted.In some specific embodiments, form 4-oxo-4H-quinazoline-3-basic ring, for example
Wherein phenyl ring is optional is substituted.In some specific embodiments, form 4-oxo-4H-Pyridopyrimidine-3-basic ring, for example
Wherein one of R, S, T and U are nitrogen, and other are-CH, and wherein pyridine ring is optional is substituted.
The present invention also provides at least a chemical and the acceptable salt of pharmacology, solvate, inner complex, non-covalent complex, prodrug and the mixture that is selected from the formula III compound:
R wherein
2, R
3, R
6, R
11, R
12And R
13Be as described in to formula II compound.
The present invention also provides at least a chemical and the acceptable salt of pharmacology, solvate, inner complex, non-covalent complex, prodrug and the mixture that is selected from formula IV compound:
(formula IV)
R wherein
2, R
6, R
11, R
12And R
13Be as described in to the formula III compound.
The present invention also provides at least a chemical and the acceptable salt of pharmacology, solvate, inner complex, non-covalent complex, prodrug and the mixture that is selected from formula V compound:
(formula V)
R wherein
2, R
3, R
11, R
12And R
13Be as described in to the formula III compound, and wherein:
R
14Be the optional heteroaryl that replaces; And
R
15Be to be selected from hydrogen, halogen, hydroxyl and low alkyl group.
In some specific embodiments, R
14Be to be selected from:
7, the 8-dihydro-imidazol-also [1,2-c] [1,3] oxazine-2-base,
3a, 7a-dihydro-1H-benzimidazolyl-2 radicals-Ji,
Imidazo [2,1-b] oxazole-6-base,
Oxazole-4-base,
5,6,7,8-tetrahydrochysene-imidazo [2,1-b] pyridine-2-base,
1H-[1,2,4]-triazole-3-base,
2,3-dihydro-imidazol--4-base,
The 1H-imidazol-4 yl,
Imidazo [2,1-b] pyridine-2-base,
Thiazol-2-yl,
Thiazole-4-base,
Pyrazole-3-yl, and
1H-imidazoles 4-base,
Its each optionally be selected from the optional low alkyl group that replaces, halogen, acyl group, alkylsulfonyl, cyano group, nitro, the optional amino that replaces and the optional heteroaryl that replaces by one, two or three and replace.
In some specific embodiments, R
14Be to be selected from:
1H-imidazoles-2-base,
Imidazo [2,1-b] pyridine-2-base reaches
The 1H-imidazol-4 yl,
Its each optional being selected from one or two is chosen low alkyl group, halogen and the acyl substituted that replaces wantonly.
In some specific embodiments, R
15Be to select hydrogen.
The present invention also provides at least a chemical and the acceptable salt of pharmacology, solvate, inner complex, non-covalent complex, prodrug and the mixture that is selected from formula VI compound:
(formula VI)
R wherein
2, R
6, R
11, R
12And R
13Be as described in to the formula III compound.
The present invention also provides at least a chemical and the acceptable salt of pharmacology, solvate, inner complex, non-covalent complex, prodrug and the mixture that is selected from formula VII compound:
(formula VII)
R wherein
2, R
6, R
11, R
12And R
13Be as described in to the formula III compound, and wherein
R
9Be to be selected from the optional alkoxyl group that replaces, the optional cycloalkyloxy that replaces, the optional aralkoxy that replaces, the optional amino that replaces and the optional low alkyl group that replaces.
In some specific embodiments, R
9It is the optional low alkyl group that replaces or choose wantonly the amino replacement that is substituted through hydroxyl.In some specific embodiments, R
9By hydroxyl, amino, N-methylamino-or N, the low alkyl group that the N-dimethylamino replaces.
The present invention also provides at least a chemical and the acceptable salt of pharmacology, solvate, inner complex, non-covalent complex, prodrug and the mixture that is selected from formula VIII compound:
(formula VIII)
R wherein
1, X, W, R
3, R
4, R
6And R
7Be as defined to formula I compound, and R wherein
2And R
5Form optional 5-to the 7-element heterocycle that replaces with the atom of bond on it, it randomly can comprise one or two extra heteroatoms.
In some specific embodiments, R
2With R
5Form optional tetramethyleneimine basic ring that replaces or optional piperidine ring together through the hydroxyl replacement.
The present invention also provides at least a chemical and the acceptable salt of pharmacology, solvate, inner complex, non-covalent complex, prodrug and the mixture that is selected from formula IX compound:
(formula IX)
R wherein
1, X, W, R
2, R
3, R
4And R
7Be as defined to formula I compound, and R wherein
5And T
6Form optional 5-to the 7-element heterocycle that replaces with the atom of bond on it, it randomly can comprise one or two extra heteroatoms.
In some specific embodiments, R
5With R
6Form the optional 2H-[1 that replaces with the atom that they connected, 2,3]-triazole-4-base, the optional 1H-benzimidazolyl-2 radicals-Ji that replaces, the optional piperazine ring that replaces, the optional morpholine ring that replaces or the optional 1H-imidazol-4 yl ring that replaces, the optional isoxazole-4-base ring that replaces.
The present invention also provides at least a chemical and the acceptable salt of pharmacology, solvate, inner complex, non-covalent complex, prodrug and the mixture that is selected from formula X compound:
(formula X)
R wherein
1, X, W, R
4, R
5, R
6And R
7Be as defined to formula I compound, and wherein
R
2And R
3Form optional 3-to the 7-element heterocycle that replaces with the atom that they connected.
In some specific embodiments, R
2With R
3Form optional 3-to the 7-element heterocycle that replaces with the atom that they connected.In some specific embodiments, it forms the ethylene imine basic ring.
The present invention also provides at least a chemical and the acceptable salt of pharmacology, solvate, inner complex, non-covalent complex, prodrug and the mixture that is selected from formula XI compound:
(formula XI)
Wherein W, R
3, R
4, R
5, R
6And R
7Be as defined to formula I compound, and wherein
R
1, X, N and R
2Form together be substituted 2,4-dioxo-1,4-dihydro-2H-quinazoline-3-base, 4-oxo-4H-quinazoline-3-base or 4-oxo-4H-Pyridopyrimidine-3-basic ring.
The present invention also provides at least a chemical and the acceptable salt of pharmacology, solvate, inner complex, non-covalent complex, prodrug and the mixture that is selected from formula XII compound
(formula XII)
R wherein
1, W, R
4, R
5And R
6Be as defined to formula I compound, and wherein
-X-N (R
2)-be-C=N-; And
X and R
3Form the optional heterocycle that replaces together;
Under each situation, its restricted condition is if W is N, then R
5Not hydroxyl or the optional amino that replaces, and R
6Not the optional alkoxyl group that replaces, the optional aralkoxy that replaces, the optional assorted aralkoxy that replaces or the optional amino that replaces.
In some specific embodiments ,-X-N (R
2)-be-C=N-; And X and R
3Form the optional heterocycle that replaces together, include but not limited to 3H-[1,3,4]-oxadiazoles-2-ketone, 4,5-dihydro-oxazoles, triazole, imidazoles, 3,5-dihydro-imidazol--4-ketone or 3H-pyrimidin-4-one, its each optional for being substituted.
The present invention also provides at least a chemical and the acceptable salt of pharmacology, solvate, inner complex, non-covalent complex, prodrug and the mixture that is selected from formula XIII compound:
(formula XIII)
R wherein
1, X, W, R
2, R
4, R
5And R
7Be as defined to formula I compound, and R wherein
3And R
6Form optional 5-to the 7-element heterocycle that replaces with the atom of bond on it, it randomly can comprise one or two extra heteroatoms.
In some specific embodiments, R
3With R
6Form the piperidine ring of choosing the tetramethyleneimine basic ring that replaces, optional replacement wantonly or choose 1,2,3 of replacement, 4-tetrahydrochysene-quinoline-3-basic ring wantonly with the atom that they connected.
The present invention also provides at least a chemical and the acceptable salt of pharmacology, solvate, inner complex, non-covalent complex, prodrug and the mixture that is selected from the compound in the table 1,2,3,4,5 or 6.
Compound can be named, and uses AutoNom 2.1 editions, ChemDraw Ultra 6.0, Cambridgesoft, Cambridge, MA; ChemDraw Ultra 9.0 Cambridgesoft, Cambridge, the Struct of MA＜=Name logic or ISIS-DRAW.
Table 1
(S)-3-chloro-N-(1-(4-(1-ethyl-2-(2-hydroxy propane-2-yl)-1H-imidazol-4 yl) phenyl-4-hydroxyl butane-2-yl)-4-isopropoxy benzamide
(S)-N-(1-(4-(2-ethanoyl-1-ethyl-1H-imidazol-4 yl) phenyl-4-hydroxyl butane-2-yl)-3-chloro-4-isopropoxy benzamide
N-((S)-1-(4-(1-kharophen ethyl)-1-ethyl-1H-imidazol-4 yl) phenyl)-4-hydroxyl butane-2-yl)-3-chloro-4-isopropoxy benzamide
3-chloro-N-((S)-1-(4-(1-ethyl-2-(2-hydroxy propane-2-yl)-1H-imidazol-4 yl) phenyl)-4-hydroxyl butane-2-yl)-4-(1,1,1-trifluoro propane-2-base oxygen base) benzamide
N-((S)-1-(4-(1-kharophen ethyl)-1-ethyl-1H-imidazol-4 yl) phenyl)-4-hydroxyl butane-2-yl)-3-chloro-4-(1,1,1-trifluoro propane-2-base oxygen base) benzamide
(S)-N-(1-(4-(2-ethanoyl-1-(2,2, the 2-trifluoroethyl)-1H-imidazol-4 yl) phenyl)-4-hydroxyl butane-2-yl)-3-chloro-4-isopropoxy benzamide
3-chloro-N-((S)-4-hydroxyl-1-(4-(8-(1-hydroxyethyl) imidazo [1,2-a] pyridine-2-yl) phenyl)-butane-2-yl)-4-isopropoxy benzamide
(S)-3-chloro-N-(1-(2-(dimethylamino) acetyl amido-3-(4-(the 8-Methylimidazole is [1,2-a] pyridine-2-yl also) phenyl) propane-2-yl)-4-isopropoxy benzamide
3-chloro-N-((S)-(1-(2-(dimethylamino) acetyl amido-3-(4-(8-hydroxyethyl) imidazo [1,2-a] pyridine-2-yl) phenyl) propane-2-yl)-4-isopropoxy benzamide
3-cyano group-N-((1S)-3-hydroxyl-1-{[4-(the 8-Methylimidazole is [1,2-a] pyridine-2-yl also) phenyl] methyl } propyl group)-the 4-[(1-methylethyl) the oxygen base] benzamide;
3-chloro-N-[(1S)-3-hydroxyl-1-(4-[8-(1-hydroxyethyl) imidazo [1,2-a] pyridine-2-yl) and phenyl] methyl } propyl group]-the 4-[(1-methylethyl) the oxygen base] benzamide
3-chloro-N-[(1S)-and 2-[(N, N-dimethyl glycyl (glycyl) amino]-1-(4-[8-(1-hydroxyethyl) imidazo [1,2-a] pyridine-2-yl] and phenyl } methyl) ethyl]-the 4-[(1-methylethyl) the oxygen base] benzamide
N-((1S)-2-(D-alanyl (alanyl) amino)-1-{[4-(8 bromine imidazos [1,2-a] pyridine-2-yl) phenyl] methyl } ethyl)-3-chloro-4-[(1-methylethyl) the oxygen base] benzamide
3-chloro-N-[(1S)-and 2-[(2-methyl-prop aminoacyl) amino]-1-{[4-(the 8-Methylimidazole is [1,2-a] pyridine-2-yl also) phenyl] methyl } ethyl]-the 4-[(1-methylethyl) the oxygen base] benzamide
3-chloro-N-[(1S)-and 2-[(N, N-dimethyl glycyl) amino]-1-{[4-(the 8-Methylimidazole is [1,2-a] pyridine-2-yl also) phenyl] methyl } ethyl]-the 4-[(1-methylethyl) the oxygen base] benzamide
N-[(1R)-and 4-amino-1-{[4-(the 8-Methylimidazole is [1,2-a] pyridine-2-yl also) phenyl] methyl }-4-oxo butyl)-3-chloro-4-[(1-methylethyl) the oxygen base] benzamide
N-((1R)-{ [4-(2-ethanoyl-1-methyl isophthalic acid H-imidazol-4 yl) phenyl] methyl }-4-amino-4-oxo butyl)-3-chloro-4-[(1-methylethyl) oxygen base] benzamide
3-cyano group-N-[(1S)-3-hydroxyl-1-(4-[8-(1-hydroxyethyl) imidazo [1,2-a] pyridine-2-yl] and phenyl } methyl) propyl group]-the 4-[(1-methylethyl) the oxygen base] benzamide
3-chloro-N-((1S)-3-hydroxyl-1-{[4-(the 8-Methylimidazole is [1,2-a] pyridine-2-yl also) phenyl] methyl } propyl group)-the 4-[(1-methylethyl) the oxygen base] benzamide
3-cyano group-N-[(1S)-2-[(N, N-dimethyl glycyl) amino]-1-(4-[8-(1-hydroxyethyl) imidazo [1,2-a] pyridine-2-yl] and phenyl } methyl) ethyl]-the 4-[(1-methylethyl) the oxygen base] benzamide
3-cyano group-N-((1S)-2-[(N, N-dimethyl glycyl) amino]-1-{[4-(the 8-Methylimidazole is [1,2-a] pyridine-2-yl also) phenyl] methyl } ethyl)-the 4-[(1-methylethyl) the oxygen base] benzamide;
N-((1R)-{ [4-(2-ethanoyl-1-methyl isophthalic acid H-imidazol-4 yl) phenyl] methyl }-4-amino-4-oxo butyl)-3-cyano group-4-[(1-methylethyl) oxygen base] benzamide
N-[(1R)-4-amino-1-(4-[2-(1-hydroxyl-1-methylethyl)-1-methyl isophthalic acid H-imidazol-4 yl] and phenyl } methyl)-4-oxo butyl]-3-cyano group-4-[(1-methylethyl) the oxygen base] benzamide
N-((1S)-2-(D-alanyl amino)-1-(4-[1-(2-amino-ethyl)-2-(1, the 1-dimethyl ethyl)-1H-imidazol-4 yl] and phenyl } methyl) ethyl]-3-chloro-4-[(1-methylethyl) the oxygen base] benzamide
N-((1S)-2-{4-[1-(2-amino-ethyl)-2-(1, the 1-dimethyl ethyl)-1H-imidazol-4 yl] phenyl }-1-{[2-(methyl-prop aminoacyl) amino] methyl } ethyl)-3-chloro-4-[(1-methylethyl) the oxygen base] benzamide
N-((1S)-2-{4-[1-(2-amino-ethyl)-2-(1, the 1-dimethyl ethyl)-1H-imidazol-4 yl] phenyl }-the 1-{[(hydroxyacetyl) amino] methyl } ethyl)-3-cyano group-4-[(1-methylethyl) the oxygen base] benzamide
N-((1S)-2-{4-[1-(2-amino-ethyl)-2-(1, the 1-dimethyl ethyl)-1H-imidazol-4 yl] phenyl }-1-{[(2-methyl-prop aminoacyl) amino] methyl } ethyl)-3-cyano group-4-[(1-methylethyl) the oxygen base] benzamide
N-((1S)-2-{4-[1-(2-amino-ethyl)-2-(1, the 1-dimethyl ethyl)-1H-imidazol-4 yl] phenyl }-1-{[(N, N-dimethyl glycyl) amino] methyl } ethyl)-3-cyano group-4-[(1-methylethyl) the oxygen base] benzamide
3-chloro-N-[(1S)-and 2-{4-[8-(1-hydroxyethyl) imidazo [1,2-a] pyridine-2-yl] phenyl }-1-([(2R)-and 2-hydroxyl propionyl] amino } methyl) ethyl]-the 4-[(1-methylethyl) the oxygen base] benzamide
N-((1S)-2-[(4-aminocarboxyl) amino]-1-{[4-(8-bromine imidazo [1,2-a] pyridine-2-yl) phenyl] methyl } ethyl)-3-chloro-4-[(1-methylethyl) the oxygen base] benzamide
N-{ (1S)-2-[4-(8-bromine imidazo [1,2-a] pyridine-2-yl) phenyl]-1-[(2-oxo tetrahydrochysene-1 (2H)-pyrimidyl) methyl] ethyl }-3-chloro-4-[(1-methylethyl) the oxygen base] benzamide
N-{ (1S)-2-[4-(8-bromine imidazo [1,2-a] pyridine-2-yl) phenyl]-1-[(2-oxo tetrahydrochysene-1H-1,3-Diazesuberane-1-yl) methyl] ethyl }-3-chloro-4-[(1-methylethyl) the oxygen base] benzamide
N-((1S)-2-[(amino-carbon sulfonyl) amino]-1-{[4-(8-bromine imidazo [1,2-a] pyridine-2-yl) phenyl] methyl } ethyl)-the 4-[(1-methylethyl) the oxygen base] benzamide
2-(4-{ (2S)-2-[({3-cyano group-4-[(1-methylethyl) oxygen base] phenyl } carbonyl) amino]-3-[(1,2,3-thiadiazoles-4-base carbonyl) amino] propyl group } phenyl) imidazo [1,2-a] pyridine-8-methane amide
N-((1S)-2-[(amino-sulfonyl) amino]-1-{[4-(the 8-Methylimidazole is [1,2-a] pyridine-2-yl also) phenyl] methyl } ethyl)-3-cyano group-4-[(1-methylethyl) the oxygen base] benzamide
(3S)-and 3-[({3-chloro-4-[(1-methylethyl) the oxygen base] phenyl } amino]-4-{4-[2-(1, the 1-dimethyl ethyl)-1-methyl isophthalic acid H-imidazol-4 yl] phenyl } butyric acid
N-[(1S)-and the 2-[(amino-sulfonyl) amino]-1-(4-[2-(1, the 1-dimethyl ethyl)-1-methyl isophthalic acid H-imidazol-4 yl] and phenyl } methyl) ethyl]-3-cyano group-4-[(1-methylethyl) the oxygen base] benzamide
N-((1S)-1-{[4-(phenyl of 1H-benzimidazolyl-2 radicals-yl)] methyl }-the 3-hydroxypropyl)-3-chloro-4-[(1-methylethyl) the oxygen base] benzamide
3-chloro-N-[(1S)-3-hydroxyl-1-(4-[5-(trifluoromethyl)-1H-benzimidazolyl-2 radicals-yl] and phenyl } methyl) propyl group]-the 4-[(1-methylethyl) the oxygen base] benzamide
3-chloro-N-((1S)-1-{[4-(5, the phenyl of 6-dimethyl-1H-benzimidazolyl-2 radicals-yl)] methyl }-the 3-hydroxypropyl)-the 4-[(1-methylethyl) the oxygen base] benzamide
3-chloro-N-[(1S)-3-hydroxyl-1-(4-[5-(methoxyl group)-1H-benzimidazolyl-2 radicals-yl] and phenyl } methyl) propyl group]-the 4-[(1-methylethyl) the oxygen base] benzamide
3-chloro-N-((1S)-1-{[4-(phenyl of 5-chloro-1H-benzimidazolyl-2 radicals-yl)] methyl }-the 3-hydroxypropyl)-the 4-[(1-methylethyl) the oxygen base] benzamide
3-chloro-N-((1S)-1-{[4-(phenyl of 4-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl)] methyl } propyl group)-the 4-[(1-methylethyl) the oxygen base] benzamide
3-chloro-N-((1S)-1-{[4-(6-chloro-imidazo [4,5-b] pyridine-2-yl) phenyl] methyl }-the 3-hydroxypropyl)-the 4-[(1-methylethyl) the oxygen base] benzamide
2-(4-{ (2S)-2-[({3-chloro-4-[(1-methylethyl) oxygen base] phenyl } carbonyl) amino]-4-hydroxyl butyl } phenyl)-1H-benzoglyoxaline-5-carboxylic acid, ethyl ester
2-(4-{ (2S)-2-[({3-chloro-4-[(1-methylethyl) oxygen base] phenyl } carbonyl) amino]-4-hydroxyl butyl } phenyl)-1H-benzoglyoxaline-5-carboxylic acid
N-((1S)-3-amino-1-{[4-(phenyl of 1H-benzimidazolyl-2 radicals-yl)] methyl } propyl group)-3-chloro-4-[(1-methylethyl) the oxygen base] benzamide
3-cyano group-N-((1S)-1-([4-(8-cyano group imidazo [1,2-a] pyridine-2-yl) phenyl]) methyl }-the 3-hydroxypropyl)-the 4-[(1-methylethyl) the oxygen base] benzamide
N-((1S)-1-{[4-(8-chlorine imidazo [1,2-a] pyridine-2-yl) phenyl] methyl }-the 3-hydroxypropyl)-3-cyano group-4-[(1-methylethyl) the oxygen base] benzamide
3-cyano group-N-[(1S)-3-hydroxyl-1-(4-[8-(trifluoromethyl) imidazo [1,2-a] pyridine-2-yl] and phenyl } methyl) propyl group]-the 4-[(1-methylethyl) the oxygen base] benzamide
3-cyano group-N-((1S)-3-hydroxyl-1-{[4-(8-hydroxyl imidazo [1,2-a] pyridine-2-yl) phenyl] methyl } propyl group)-the 4-[(1-methylethyl) the oxygen base] benzamide
2-(4-{ (2S)-2-[({3-cyano group-4-[(1-methylethyl) oxygen base] phenyl } carbonyl) amino]-4-hydroxyl butyl } phenyl) imidazo [1,2-a] pyridine-7-methane amide
2-(4-{ (2S)-2-[({3-cyano group-4-[(1-methylethyl) oxygen base] phenyl } carbonyl) amino]-4-hydroxyl butyl } phenyl) imidazo [1,2-a] pyridine-7-carboxylic acid ethyl ester
3-cyano group-N-((1S)-3-hydroxyl-1-{[4-(the 8-nitroimidazole is [1,2-a] pyridine-2-yl also) phenyl] methyl } propyl group)-the 4-[(1-methylethyl) the oxygen base] benzamide
N-((1S)-1-{[4-(the 8-aminooimidazole is [1,2-a] pyridine-2-yl also) phenyl] methyl }-the 3-hydroxypropyl)-3-cyano group-4-[(1-methylethyl) the oxygen base] benzamide
2-(4-{ (2S)-2-[({3-cyano group-4-[(1-methylethyl) oxygen base] phenyl } carbonyl) amino]-4-hydroxyl butyl } phenyl) imidazo [1,2-a] pyridine-8-methane amide
3-cyano group-N-[(1S)-3-hydroxyl-1-({ 4-(8-hydroxyl imidazo [1,2-a] pyridine-2-yl) phenyl } methyl) propyl group]-the 4-[(1-methylethyl) the oxygen base] benzamide
N-[(1S)-1-({ 4-(the 8-aminooimidazole is [1,2-a] pyridine-2-yl also) phenyl } methyl)-3-hydroxypropyl]-3-cyano group-4-[(1-methylethyl) the oxygen base] benzamide
N-((1S)-1-{[4-(the 8-acetyl imidazole is [1,2-a] pyridine-2-yl also) phenyl] methyl }-the 3-hydroxypropyl)-3-cyano group-4-[(1-methylethyl) the oxygen base] benzamide
3-cyano group-N-[(1S)-3-hydroxyl-1-(4-[8-(1-hydroxyl-1-methylethyl) imidazo [1,2-a] pyridine-2-yl] and phenyl } methyl) propyl group]-the 4-[(1-methylethyl) the oxygen base] benzamide
3-cyano group-N-[(1S)-3-hydroxyl-1-(4-[8-(1-hydroxyethyl) imidazo [1,2-a] pyridine-2-yl] and phenyl } methyl) propyl group]-the 4-[(1-methylethyl) the oxygen base] benzamide
3-cyano group-N-[(1S)-3-hydroxyl-1-{[4-(8-methyl-5,6,7,8-imidazolidine be [1,2-a] pyridine-2-yl also) phenyl] methyl } propyl group]-the 4-[(1-methylethyl) the oxygen base] benzamide
3-cyano group-N-[(1S)-(4-[2-(1, the 1-dimethyl ethyl)-1-(2-hydroxyethyl)-1H-imidazol-4 yl] and phenyl } methyl)-the 3-hydroxypropyl]-the 4-[(1-methylethyl) the oxygen base] benzamide
N-[(1S)-1-(4-[1-[2-(acetylamino) ethyl]-2-(1, the 1-dimethyl ethyl)-1H-imidazol-4 yl] phenyl } methyl)-the 3-hydroxypropyl)-3-cyano group-4-[(1-methylethyl) the oxygen base] benzamide
3-cyano group-N-{ (1S)-3-hydroxyl-1-[(4-{8-[(1R)-the 1-hydroxyethyl] imidazo [1,2-a] pyridine-2-yl } phenyl) methyl] propyl group }-the 4-[(1-methylethyl) the oxygen base] benzamide
3-cyano group-N-{ (1S)-3-hydroxyl-1-[(4-{8-[(1S)-the 1-hydroxyethyl] imidazo [1,2-a] pyridine-2-yl } phenyl) methyl] propyl group }-the 4-[(1-methylethyl) the oxygen base] benzamide
3-chloro-N-[(1S)-3-hydroxyl-1-(4-[8-(1-hydroxypropyl) imidazo [1,2-a] pyridine-2-yl] and phenyl } methyl) propyl group]-the 4-[(1-methylethyl) the oxygen base] benzamide
N-[(1S)-and 1-{[4-(8-bromine imidazo [1,2-a] pyridine-2-yl) phenyl] methyl }-the 3-hydroxypropyl]-3-chloro-4-[(1-methylethyl) the oxygen base] benzamide
3-chloro-N-((1S)-1-{[4-(8-chlorine imidazo [1,2-a] pyridine-2-yl) phenyl] methyl }-the 3-hydroxypropyl)-the 4-[(1-methylethyl) the oxygen base] benzamide
3-chloro-N-[(1S)-3-hydroxyl-1-(4-[8-(1-hydroxy-2-methyl propyl group) imidazo [1,2-a] pyridine-2-yl] and phenyl } methyl) propyl group]-the 4-[(1-methylethyl) the oxygen base] benzamide
N-[(1R)-4-amino-1-(4-[8-(1-hydroxyethyl) imidazo [1,2-a] pyridine-2-yl] and phenyl } methyl)-4-oxo butyl]-3-chloro-4-[(1-methylethyl) the oxygen base] benzamide
N-[(1R)-4-amino-1-(4-[8-(1-hydroxyethyl) imidazo [1,2-a] pyridine-2-yl] and phenyl } methyl)-4-oxo butyl]-3-cyano group-4-[(1-methylethyl) the oxygen base] benzamide
3-chloro-N-((1S)-1-{[4-(3-fluoro-8-Methylimidazole is [1,2-a] pyridine-2-yl also) phenyl] methyl }-the 3-hydroxypropyl)-the 4-[(1-methylethyl) the oxygen base] benzamide
3-cyano group-N-[(1S)-1-{[4-(3-fluoro-8-Methylimidazole is [1,2-a] pyridine-2-yl also) phenyl] methyl }-the 3-hydroxypropyl)-the 4-[(1-methylethyl) the oxygen base] benzamide
3-chloro-N-((1S)-2-hydroxyl-1-{[4-(the 8-Methylimidazole is [1,2-a] pyridine-2-yl also) phenyl] methyl }-ethyl)-the 4-[(1-methylethyl) the oxygen base] benzamide
3-chloro-4-[(1-methylethyl) oxygen base]-N-[(1S)-2-[4-(the 8-Methylimidazole is [1,2-a] pyridine-2-yl also) phenyl]-1-(4-morpholinyl methyl) ethyl] benzamide
3-chloro-N-((1S)-2-(4-hydroxyl-piperidino)-1-{[4-(the 8-Methylimidazole is [1,2-a] pyridine-2-yl also) phenyl] methyl } ethyl)-the 4-[(1-methylethyl) the oxygen base] benzamide
3-chloro-N-((1S)-2-(3-fluoro-1-pyrrolidyl)-1-{[4-(the 8-Methylimidazole is [1,2-a] pyridine-2-yl also) phenyl] methyl } ethyl)-the 4-[(1-methylethyl) the oxygen base] benzamide
3-chloro-N-((1S)-2-[(2S)-2-methylol-1-pyrrolidyl)-1-{[4-(the 8-Methylimidazole is [1,2-a] pyridine-2-yl also) phenyl] methyl } ethyl)-the 4-[(1-methylethyl) the oxygen base] benzamide
3-chloro-N-((1S)-2-[(2R)-2-methylol-1-pyrrolidyl)-1-{[4-(the 8-Methylimidazole is [1,2-a] pyridine-2-yl also) phenyl] methyl } ethyl)-the 4-[(1-methylethyl) the oxygen base] benzamide
3-chloro-4-[(1-methylethyl) oxygen base]-N-((1S)-2-[4-(the 8-Methylimidazole is [1,2-a] pyridine-2-yl also) phenyl]-1-{[(2,2, the 2-trifluoroethyl) amino] methyl } ethyl) benzamide
3-chloro-N-((1S)-2-[(2-hydroxyethyl) amino]-1-{[4-(the 8-Methylimidazole is [1,2-a] pyridine-2-yl also) phenyl] methyl } ethyl)-the 4-[(1-methylethyl) the oxygen base] benzamide
3-cyano group-N-((1S)-{ [4-(8-ethyl-5-Methylimidazole is [1,2-a] pyridine-2-yl also) phenyl] methyl }-3-hydroxypropyl)-4-[(1-methylethyl) oxygen base] benzamide
(3S)-and 3-[({3-chloro-4-[(1-methylethyl) the oxygen base] phenyl } carbonyl) amino]-the 4-{4-[(phenylcarbonyl group) amino] phenyl } the butanone methyl esters
3-chloro-N-[(1S)-3-hydroxyl-1-(the 4-[(phenylcarbonyl group) and amino] phenyl } methyl) propyl group]-the 4-[(1-methylethyl) the oxygen base] benzamide
3-chloro-N-{ (1S)-1-[(4-{[(4-chloro-phenyl-) carbonyl] amino } phenyl) methyl]-the 3-hydroxypropyl }-the 4-[(1-methylethyl) the oxygen base] benzamide
(4-{ (2S)-2-[({3-chloro-4-[(1-methylethyl) oxygen base] phenyl } carbonyl) amino]-4-hydroxyl butyl } phenyl) amine formic acid phenyl methyl esters
3-chloro-N-((1S)-3-hydroxyl-1-{[4-({ [2-(methylamino-) phenyl] carbonyl } amino) phenyl] methyl } propyl group)-the 4-[(1-methylethyl) the oxygen base] benzamide
N-(4-{ (2S)-2-[({3-chloro-4-[(1-methylethyl) oxygen base] phenyl } carbonyl) amino]-4-hydroxyl butyl } phenyl)-the 4-pyridine carboxamides
3-chloro-N-[(1S)-1-(the 4-[(cyclohexyl-carbonyl) and amino] phenyl } methyl)-the 3-hydroxypropyl]-the 4-[(1-methylethyl) the oxygen base] benzamide
3-chloro-N-[(1S)-(4-[(3,3-dimethyl butyrate acyl group) and amino] phenyl } methyl)-the 3-hydroxypropyl]-the 4-[(1-methylethyl) the oxygen base] benzamide
3-chloro-N-[(1S)-3-hydroxyl-1-(the 4-[(phenyl acetyl) and amino] phenyl } methyl) propyl group]-the 4-[(1-methylethyl) the oxygen base] benzamide
3-chloro-N-{ (1S)-3-hydroxyl-1-[(4-{[(phenyl amino) carbonyl] amino } phenyl) methyl] propyl group }-the 4-[(1-methylethyl) the oxygen base] benzamide
3-cyano group-N-((1S)-3-hydroxyl-1-{[4-(8-methyl-5-oxo-5,6-glyoxalidine be [1,2-c] pyrimidine-2-base also) phenyl] methyl } propyl group)-the 4-[(1-methylethyl) the oxygen base] benzamide
3-cyano group-N-((1S)-3-hydroxyl-1-{[4-(1-methyl-3-oxo-2,3-dihydro-1H-imidazo [1,2-a] imidazoles-6-yl) phenyl] methyl } propyl group)-the 4-[(1-methylethyl) the oxygen base] benzamide
3-cyano group-N-((1S)-3-hydroxyl-1-{[4-(8-oxo-7,8-glyoxalidine be [1,2-c] pyrazine-2-yl also) phenyl] methyl } propyl group)-the 4-[(1-methylethyl) the oxygen base] benzamide
2,3-two chloro-N-((1S)-3-hydroxyl-1-{[4-(the 8-Methylimidazole is [1,2-a] pyridine-2-yl also) phenyl] methyl } propyl group)-the 4-[(1-methylethyl) the oxygen base] benzamide
N-((1S)-3-hydroxyl-{ [4-(the 8-Methylimidazole is [1,2-a] pyridine-2-yl also) phenyl] methyl } propyl group)-4-[(1-methylethyl) oxygen base]-the 3-nitrobenzamide
3-chloro-N-[(1S)-and the 2-[(hydroxyacetyl) amino]-1-(4-[8-(1-hydroxyethyl) imidazo [1,2-a] pyridine-2-yl] and phenyl } methyl) ethyl]-the 4-[(1-methylethyl) the oxygen base] benzamide
3-chloro-N-[(1S)-and 2-{4-[8-(1-hydroxyethyl) imidazo [1,2-a] pyridine-2-yl] phenyl }-1-([(2R)-and 2-hydroxyl propionyl] amino } methyl) ethyl]-the 4-[(1-methylethyl) the oxygen base] benzamide
3-chloro-N-[(1S)-and 2-{4-[8-(1-hydroxyethyl) imidazo [1,2-a] pyridine-2-yl] phenyl }-1-([(2S)-and 2-hydroxyl propionyl] amino } methyl) ethyl]-the 4-[(1-methylethyl) the oxygen base] benzamide
3-chloro-N-[(1S)-and 2-[(N, N-dimethyl glycyl) amino]-1-(4-[8-(1-hydroxyethyl) imidazo [1,2-a] pyridine-2-yl] and phenyl } methyl) ethyl]-the 4-[(1-methylethyl) the oxygen base] benzamide
N-[(1S)-2-(D-alanyl amino)-1-(4-[8-(1-hydroxyethyl) imidazo [1,2-a] pyridine-2-yl] and phenyl } methyl) ethyl]-3-chloro-4-[(1-methylethyl) the oxygen base] benzamide
3-chloro-N-[(1S)-3-hydroxyl-1-(4-[8-(1-hydroxyethyl) imidazo [1,2-a] pyridine-2-yl] and phenyl } methyl) propyl group]-the 4-[(1-methylethyl) the oxygen base] benzamide
3-chloro-N-((1S)-2-{4-[8-(1-hydroxyethyl) imidazo [1,2-a] pyridine-2-yl] phenyl }-1-{[(2-methyl-prop aminoacyl) amino] methyl } ethyl)-the 4-[(1-methylethyl) the oxygen base] benzamide
(3S)-and 3-[({3-chloro-4-[(1-methylethyl) the oxygen base] phenyl } carbonyl) amino]-the 4-{4-[(phenylcarbonyl group) amino] phenyl } butyric acid 3-chloro-N-{ (1S)-3-hydroxyl-1-{ (4-imidazo [1,2-a] pyridine-6-base phenyl) methyl } propyl group }-the 4-[(1-methylethyl) the oxygen base] benzamide
3-chloro-N-[(1S)-1-(4-[2-(1, the 1-dimethyl ethyl) imidazo [1,2-a] pyridine-6-yl] and phenyl } methyl)-the 3-hydroxypropyl]-the 4-[(1-methylethyl) the oxygen base] benzamide
3-chloro-N-{ (1S)-3-hydroxyl-1-[(4-imidazo [1,2-a] pyridine-2-base phenyl) methyl] propyl group }-the 4-[(1-methylethyl) the oxygen base] benzamide
3-chloro-N-{ (1S)-3-hydroxyl-1-[(4-imidazo [1,2-a] pyrimidine-2-base phenyl) methyl] propyl group }-the 4-[(1-methylethyl) the oxygen base] benzamide
3-chloro-N-((1S)-3-hydroxyl-1-{[4-(the 5-Methylimidazole is [1,2-a] pyridine-2-yl also) phenyl] methyl } propyl group)-the 4-[(1-methylethyl) the oxygen base] benzamide
3-chloro-N-((1S)-3-hydroxyl-1-{[4-(the 7-Methylimidazole is [1,2-a] pyrimidine-2-base also) phenyl] methyl } propyl group)-the 4-[(1-methylethyl) the oxygen base] benzamide
3-cyano group-N-{ (1S)-3-hydroxyl-1-[(4-imidazo [2,1-b] [1,3] thiazole-6-base phenyl) methyl] butyl }-the 4-[(1-methylethyl) the oxygen base] benzamide
3-cyano group-N-((1S)-3-hydroxyl-1-{[4-(the 3-Methylimidazole is [2,1-b] [1,3] thiazole-6-yl also) phenyl] methyl } butyl)-the 4-[(1-methylethyl) the oxygen base] benzamide
3-cyano group-N-((1S)-1{[4-(2, the 3-glyoxalidine is [2,1-b] [1,3] thiazole-6-yl also) phenyl] methyl }-3-hydroxyl butyl)-the 4-[(1-methylethyl) the oxygen base] benzamide
3-cyano group-N-((1S)-1-{[4-(1,1-dioxido-2,3-glyoxalidine be [2,1-b] [1,3] thiazole-6-yl also) phenyl] methyl }-3-hydroxyl butyl)-the 4-[(1-methylethyl) the oxygen base] benzamide
N-[(1S)-1-(4-[1-(3-aminopropyl)-2-(1, the 1-dimethyl ethyl)-1H-imidazol-4 yl] and phenyl } methyl)-the 3-hydroxypropyl]-3-cyano group-4-[(1-methylethyl) the oxygen base] benzamide
3-cyano group-4-[(1-methylethyl) oxygen base]-N-[(1S)-2-[4-(the 8-Methylimidazole is [2,1-a] pyridine-2-yl also) phenyl]-1-(5-methyl isophthalic acid, 2,4-oxadiazole-3-yl) ethyl] benzamide
3-cyano group-N-[(1S)-1-(4-[8-(3,5-dimethyl-4-isoxazolyl) imidazo [2,1-a] pyridine-2-yl] and phenyl } methyl)-the 3-hydroxypropyl]-the 4-[(1-methylethyl) the oxygen base] benzamide
3-cyano group-N-((1S)-3-hydroxyl-1-{[4-[8-phenylimidazole is [2,1-a] pyridine-2-yl also] phenyl] methyl } propyl group)-the 4-[(1-methylethyl) the oxygen base] benzamide
3-cyano group-N-[(1S)-3-hydroxyl-1-(4-[8-(1H-pyrazoles-4-yl) imidazo [2,1-a] pyridine-2-yl] and phenyl } methyl) propyl group]-the 4-[(1-methylethyl) the oxygen base] benzamide
3-cyano group-N-[(1S)-3-hydroxyl-1-(4-[8-(4-isoxazolyl) imidazo [2,1-a] pyridine-2-yl] and phenyl } methyl) propyl group]-the 4-[(1-methylethyl) the oxygen base] benzamide
N-((1S)-1-{[4-[8-acetyl imidazole is [2,1-a] pyridine-2-yl also] phenyl] methyl }-the 3-hydroxypropyl)-3-chloro-4-[(1-methylethyl) the oxygen base] benzamide
(2E)-and 3-[2-(4-{ (2S)-2-[({3-cyano group-4-[(1-methylethyl) oxygen base] phenyl } carbonyl) amino]-4-hydroxyl butyl } phenyl) imidazo [2,1-a] pyridine-8-yl]-the 2-ethyl propenoate
(2E)-and 3-[2-(4-{ (2S)-2-[({3-cyano group-4-[(1-methylethyl) oxygen base] phenyl } carbonyl) amino]-4-hydroxyl butyl } phenyl) imidazo [2,1-a] pyridine-8-yl]-2-vinylformic acid
N-{ (1S)-1-[(4-{8-[(1E)-amino-3-oxo-1-propylene-1-yl] imidazo [2,1-a] pyridine-2-yl } phenyl) methyl]-the 3-hydroxypropyl }-3-cyano group-4-[(1-methylethyl) the oxygen base] benzamide
N-[(1S)-1-(4-[8-(3-amino-3-oxopropyl) imidazo [2,1-a] pyridine-2-yl] and phenyl } methyl)-the 3-hydroxypropyl]-3-cyano group-4-[(1-methylethyl) the oxygen base] benzamide
3-chloro-N-((1S)-1-{[4-(3-chloro-8-Methylimidazole is [2,1-a] pyridine-2-yl also) phenyl] methyl }-the 3-hydroxypropyl)-the 4-[(1-methylethyl) the oxygen base] benzamide
N-((1S)-1-{[4-(3-chloro-8-Methylimidazole is [2,1-a] pyridine-2-yl also) phenyl] methyl }-the 3-hydroxypropyl)-3-cyano group-4-[(1-methylethyl) the oxygen base] benzamide
3-cyano group-N-[(1S)-(3-fluoro-4-[2-(1-hydroxyl-1-methylethyl)-1-methyl isophthalic acid H-imidazol-4 yl] and phenyl } methyl)-the 3-hydroxypropyl]-the 4-[(1-methylethyl) the oxygen base] benzamide
3-chloro-N-((1S)-2-hydroxyl-1-{[5-(the 8-Methylimidazole is [2,1-a] pyridine-2-yl also) phenyl] methyl } ethyl)-the 4-[(1-methylethyl) the oxygen base] benzamide
3-chloro-N-((1S)-2-hydroxyl-1-{[5-(the 8-Methylimidazole is [2,1-a] pyridine-2-yl also) fen base] methyl } ethyl)-the 4-[(1-methylethyl) the oxygen base] benzamide
3-chloro-N-[(1S)-1-(4-[2-(1, the 1-dimethyl ethyl)-1-methyl isophthalic acid H-imidazol-4 yl]-the 2-fluorophenyl } methyl)-the 3-hydroxypropyl]-the 4-[(1-methylethyl) the oxygen base] benzamide
3-chloro-N-[(1S)-1-(4-[2-(1, the 1-dimethyl ethyl)-1-methyl isophthalic acid H-imidazol-4 yl] and-2, the 6-difluorophenyl } methyl)-the 3-hydroxypropyl]-the 4-[(1-methylethyl) the oxygen base] benzamide
3-chloro-N-[(1S)-1-(2-chloro-4-[2-(1, the 1-dimethyl ethyl)-1-methyl isophthalic acid H-imidazol-4 yl] and phenyl) methyl)-the 3-hydroxypropyl]-the 4-[(1-methylethyl) the oxygen base] benzamide
3-chloro-N-[(1S)-1-(5-[2-(1, the 1-dimethyl ethyl)-1-methyl isophthalic acid H-imidazol-4 yl]-the 2-pyridyl } methyl)-the 3-hydroxypropyl]-the 4-[(1-methylethyl) the oxygen base] benzamide
3-chloro-N-((1S)-1-{[2-chloro-4-(the 8-Methylimidazole is [1,2-a] pyridine-2-yl also) phenyl] methyl }-the 3-hydroxypropyl)-the 4-[(1-methylethyl) the oxygen base] benzamide
3-chloro-N-((1S)-1-{[2-chloro-4-(8-chlorine imidazo [1,2-a] pyridine-2-yl) phenyl] methyl }-the 3-hydroxypropyl)-the 4-[(1-methylethyl) the oxygen base] benzamide
3-chloro-N-((1S)-{ [2,5-two fluoro-4-(the 8-Methylimidazole is [1,2-a] pyridine-2-yl also) phenyl] methyl }-3-hydroxypropyl)-4-[(1-methylethyl) oxygen base] benzamide
3-chloro-N-((1S)-{ [3-chloro-4-(the 8-Methylimidazole is [1,2-a] pyridine-2-yl also) phenyl] methyl }-3-hydroxypropyl)-4-[(1-methylethyl) oxygen base] benzamide
3-chloro-N-[(1S)-(4-[2-(1, the 1-dimethyl ethyl)-1-methyl isophthalic acid H-imidazol-4 yl] and phenyl } methyl)-3-(methylamino-)-3-oxopropyl]-the 4-[(1-methylethyl) the oxygen base] benzamide
3-cyano group-N-[(1S)-2-{4-[2-(1, the 1-dimethyl ethyl)-1-methyl isophthalic acid H-imidazol-4 yl] phenyl }-1-({ [(phenyl amino) carbonyl] amino } methyl) ethyl]-the 4-[(1-methylethyl) the oxygen base] benzamide
3-cyano group-N-[(1S)-2-{4-[2-(1, the 1-dimethyl ethyl)-1-methyl isophthalic acid H-imidazol-4 yl] phenyl }-1-({ [(ethylamino) carbonyl] amino } methyl) ethyl]-the 4-[(1-methylethyl) the oxygen base] benzamide
N-[(1S)-2-(4-amino-sulfonyl)-1-(4-[2-(1, the 1-dimethyl ethyl)-1-methyl isophthalic acid H-imidazol-4 yl] and phenyl } methyl) ethyl]-3-chloro-4-[(1-methylethyl) the oxygen base] benzamide
3-cyano group-N-((1S)-2-{4-[2-(1, the 1-dimethyl ethyl)-1-methyl isophthalic acid H-imidazol-4 yl] phenyl }-1-({ [(methyl sulphonyl) amino] methyl } ethyl)-4-[(1-methylethyl) the oxygen base] benzamide
3-cyano group-N-{ (1S)-2-{4-[2-(1, the 1-dimethyl ethyl)-1-methyl isophthalic acid H-imidazol-4 yl] phenyl }-the 1-[({[(2-hydroxyethyl) amino] carbonyl } amino) methyl] ethyl }-the 4-[(1-methylethyl) the oxygen base] benzamide
N-[(S)-1-[4-(the 2-tertiary butyl-1-methyl isophthalic acid H-imidazol-4 yl)-benzyl]-2-(2-methoxyl group-acetylamino)-ethyl]-3-cyano group-4-isopropoxy-benzamide
(4R)-and 4-[({3-cyano group-4-[(1-methylethyl) the oxygen base] phenyl } carbonyl) amino]-5-{4-[2-(1, the 1-dimethyl ethyl)-1-methyl isophthalic acid H-imidazol-4 yl] phenyl } valeric acid
N-((1S)-2-amino-1-{[4-(the 8-Methylimidazole is [1,2-a] pyridine-2-yl also) phenyl] methyl } ethyl)-3-cyano group-4-[(1-methylethyl) the oxygen base] benzamide
N-((1S)-2-(acetylamino)-1-{[4-(the 8-Methylimidazole is [1,2-a] pyridine-2-yl also) phenyl] methyl } ethyl)-3-cyano group-4-[(1-methylethyl) the oxygen base] benzamide
3-chloro-N-((1S)-2-{[(2R)-2-hydroxyl propionyl] amino }-1-{[4-(the 8-Methylimidazole is [1,2-a] pyridine-2-yl also) phenyl] methyl } ethyl)-the 4-[(1-methylethyl) the oxygen base] benzamide
3-chloro-N-[(1S)-and 2-[(N, N-dimethyl glycyl) amino]-1-(4-[2-(1-hydroxyl-1-methylethyl)-1-methyl isophthalic acid H-imidazol-4 yl] and phenyl } methyl) ethyl]-the 4-[(1-methylethyl) the oxygen base] benzamide
3-cyano group-N-[(1S)-2-[(N, N-dimethyl glycyl) amino]-1-(4-[2-(1-hydroxyl-1-methylethyl)-1-methyl isophthalic acid H-imidazol-4 yl] and phenyl } methyl) ethyl]-the 4-[(1-methylethyl) the oxygen base] benzamide
3-chloro-N-((S)-4-hydroxyl-1-(4-(1-methyl-2-((R)-1-(2-oxo-pyrrolidine-1-yl) ethyl)-1H-imidazol-4 yl) phenyl) butane-2-yl)-4-isopropoxy benzamide
3-chloro-N-((S)-4-hydroxyl-1-(4-(1-methyl-2-((R)-1-(2-oxo-pyrrolidine-1-yl) ethyl)-1H-imidazol-4 yl) phenyl) butane-2-yl)-(1,1,1-trifluoro propane-2-base oxygen base) benzamide
3-chloro-N-((S)-4-hydroxyl-1-(4-(1-methyl-2-((R)-1-(2-oxygen is for oxazolidine-3-yl)-1H-imidazol-4 yl) phenyl) butane-2-yl)-4-isopropoxy benzamide
3-chloro-N-((S)-4-hydroxyl-1-(4-(1-methyl-2-((R)-1-(2-oxygen is for oxazolidine-3-yl) ethyl)-1H-imidazol-4 yl) phenyl) butane-2-yl)-(1,1,1-trifluoro propane-2-base oxygen base) benzamide.
The specilization compound comprises and is shown in the following table those:
Table 2
| R 11 | R 3 | R 8 | R 9 | R 5 | R 10 |
| Cl | Phenyl | H | H | 4-isopropoxy-3-chloro-benzoyl-amino- | H |
| Cl | Methylol- | The 2-tertiary butyl-3H-imidazoles-4-base | H | H | H |
| Cl | Methylol- | Benzylamino- | H | H | H |
| Cl | H | The 2-tertiary butyl-3H-imidazoles-4-base | H | H | H |
| Cl | Methylol- | The 4-tertiary butyl-5-methyl isophthalic acid H-imidazoles-2-base | H | H | H |
| Cl | Methylol- | The 5-tertiary butyl-4H-[1,2,4] triazole-3-base | H | H | H |
| Cl | Methylol- | 1H-benzimidazolyl-2 radicals-Ji | H | H | H |
| Cl | Methylol- | The 4-tertiary butyl-imidazoles-1-base | H | H | H |
| Cl | H | 1H-benzimidazolyl-2 radicals-Ji | H | H | H |
| Cl | Methoxymethyl- | The 2-tertiary butyl-3H-imidazoles-4-base | H | H | H |
| Cl | The 3-hydroxypropyl- | Benzyloxy- | H | H | H |
| Cl | H | 2-methylamino--benzoyl-amido- | H | H | H |
| Cl | Methylol- | Benzyloxy- | Cl | H | H |
| Cl | Methylol- | Benzyloxy- | Methylol- | H | H |
| Cl | Methylol- | The 4-tertiary butyl-1H-imidazoles-2-base | H | H | H |
| Cl | The 2-hydroxyethyl- | Benzyloxy- | H | H | H |
| Cl | H | Benzyloxy- | H | H | H |
| Cl | Methylol- | Tert-butoxycarbonyl-amino- | H | H | H |
| Cl | H | OH | H | H | H |
| Cyano group | Methylol- | Benzyloxy- | Cyano group | H | H |
| Cl | Methylol- | Benzyloxy- | Cyano group | H | H |
| Cl | H | Amino | H | H | H |
| Cyano group | The 2-hydroxyethyl- | 4-cyano group-benzyl- | H | H | H |
| Cl | Methylol- | The 4-tertiary butyl-1-methyl isophthalic acid H-imidazoles-2-base | H | H | H |
| Cyano group | Methylol- | Benzyloxy- | Cl | H | H |
| Cl | Methylol- | H | H | H | H |
| Cl | H | H | H | OH | H |
| Cl | H | H | Methoxyl group- | H | H |
| Cl | H | F | H | H | H |
| Cl | Pyridin-4-yl-methyl-amino-methyl- | Phenyl | H | H | H |
| Cl | Cyano group | H | H | H | H |
| Cl | Methylol- | Benzyloxy- | Cl | H | H |
| Cl | Dimethylamino-methyl- | Phenyl | H | H | H |
| Cl | Pyridin-3-yl-methyl-amino-methyl- | Phenyl | H | H | H |
| Cl | Methylol- | 2-methylamino--benzoyl-amido | H | H | H |
| Cl | Methylol- | The 2-tertiary butyl-2H-tetrazolium-5-base | H | H | H |
| Cl | (1,3-dioxo-1,3-dihydro-isoindole-2-yl)-methyl- | 4-sec.-propyl-4,5-dihydro-oxazole-2-base | H | H | H |
| Cl | Amino methyl- | Phenyl | H | H | H |
| Cl | (1,3-dioxo-1,3-dihydro-isoindole-2-yl)-methyl- | Phenyl | H | H | H |
| Cl | Phenyl | H | Amino | H | H |
| Cl | Methylol- | Hydroxyl | H | H | H |
| Cl | Amino methyl- | H | H | H | H |
| Cl | 1H-tetrazolium-5-base | H | H | H | H |
| Cl | Dimethylamino- | H | H | H | H |
| Cl | H | Phenoxy group- | H | H | H |
| Cl | H | Cl | H | H | H | |
| Cl | H | H | H | Morpholinyl | H | |
| Cl | H | Methoxyl group | H | H | H | |
| Cl | Methylol- | Cl | H | H | H | |
| Cl | H | Methylene radical dioxy base- | H | H | ||
| Cl | H | H | Cl | H | H | |
| Cl | Pyridine-2-ylmethyl-amino-methyl- | Phenyl | H | H | H | |
| Cl | Cyano group-(pyridine-2-base methylamino-)-methyl- | Phenyl | H | H | H | |
| Cl | 2-hydroxyethyl-amino methyl- | Phenyl | H | H | H | |
| Cl | Methylol- | H | H | OH | H | |
| Cl | Amino-ethyl-amino methyl- | Phenyl | H | H | H | |
| Cl | Methoxymethyl- | H | H | H | H | |
| Cl | Chloromethyl- | Phenyl | H | H | H | |
| Cl | Methylol- | Phenyl | H | H | H | |
| Cl | Methylol- | Benzyloxy- | H | H | H | |
| Cl | H | Amino-sulfonyl- | H | H | H | |
| Cl | Methylol- | Cyano group | H | H | H | |
| Cl | Methylol- | Carbamyl- | H | H | H | |
| Cl | I-propyl group amino-methyl- | Cyclopropyl-methoxyl group- | H | H | H | |
| Cl | Methylamino--methyl- | Phenyl | H | H | H | |
| Cl | Methylamino--methyl- | Methylol- | H | H | H | |
| Cl | Amino methyl- | Cyclopropyl-methoxyl group- | H | H | H | |
| Cl | Ethylamino-methyl- | Phenyl- | H | H | H |
| Cl | Benzylamino-methyl- | Phenyl | H | H | H |
| Cl | N-(2-hydroxypropyl)-amino methyl- | Phenyl | H | H | H |
| Cl | The 2-hydroxyethyl- | The 5-tertiary butyl-4-methyl isophthalic acid H-imidazoles-2-base | H | H | H |
| Cl | Methylol- | The 2-tertiary butyl-1-methyl isophthalic acid H-imidazol-4 yl | H | H | H |
| Cl | Methyl- | The 2-tertiary butyl-1H-imidazol-4 yl | H | H | H |
| Cl | Methylol- | 5-methyl-4-Trifluoromethyl-1 H-imidazoles-2-base | H | H | H |
| Cl | Methylol- | The 1-tertiary butyl-2-methyl isophthalic acid H-imidazol-4 yl | H | H | H |
| Cyano group | The 2-hydroxyethyl- | 3-hydroxy-2-methyl-propoxy-- | H | H | H |
| Cl | The 2-amino-ethyl- | The 4-tertiary butyl-5-methyl isophthalic acid H-imidazoles-2-base | H | H | H |
| Cyano group | The 2-hydroxyethyl- | The 5-tertiary butyl-isoxzzole-3-base | H | H | H |
| Cyano group | Methylol- | 1H-benzimidazolyl-2 radicals-Ji | H | H | H |
| Cyano group | Methylol- | 1-methoxymethyl-1H-benzimidazolyl-2 radicals-Ji | H | H | H |
| Cyano group | Methylol- | The 4-tertiary butyl-5-methyl isophthalic acid H-imidazoles-2-base | H | H | H |
| Cl | Methylol- | Cyclo propyl methoxy- | H | H | H |
| Cl | H | Tert-butoxycarbonyl- | H | H | H |
| Cl | Amino methyl- | The 2-tertiary butyl-1H-imidazol-4 yl | H | H | H |
| Cyano group | Methylamino-- | The 5-tertiary butyl-4-methyl isophthalic acid H-imidazoles-2-base | H | H | H |
| Cyano group | H | Benzyloxy- | H | H | H |
| Cyano group | The 2-hydroxyethyl- | The 5-tertiary butyl-4-methyl isophthalic acid H-imidazoles-2-base | H | H | H |
| Cyano group | Methylol- | Benzyloxy- | F | H | H |
| Cl | Methylol- | Benzyloxy- | The dimethylamino formyl radical- | H | H |
| Cl | Methylol- | Benzyloxy- | Carboxyl- | H | H |
| Cl | Methylol- | Benzyloxy- | F | H | H |
| Cyano group | Methylol- | Benzyloxy- | Cl | H | H |
| Cyano group | Methylol- | The 2-tertiary butyl-1-methyl isophthalic acid H-imidazol-4 yl | H | H | H |
| Cyano group | Methyl- | The 2-tertiary butyl-1H-imidazol-4 yl | H | H | H |
| Cyano group | Methylol- | The 1-tertiary butyl-2-methyl isophthalic acid H-imidazol-4 yl | H | H | H |
| Cyano group | Methylol- | Benzyloxy- | Carboxyl | H | H |
| Cyano group | The 2-hydroxyethyl- | 2-cyano group-benzyloxy- | H | H | H |
| Cyano group | The 2-hydroxyethyl- | 3-cyano group-benzyloxy- | H | H | H |
| Cyano group | The 2-amino-ethyl- | The 4-tertiary butyl-5-methyl isophthalic acid H-imidazoles-2-base | H | H | H |
| Cyano group | Methylol- | Benzyloxy- | The dimethylamino formyl radical- | H | H |
| Cyano group | Methylol- | Benzyloxy- | The methyl carbamyl- | H | H |
| Cl | Amino- | Benzyloxy- | H | H | H |
| Cl | 2-(acetylamino)-ethyl- | The 4-tertiary butyl-5-methyl isophthalic acid H-imidazoles-2-base | H | H | H |
| Cyano group | The 2-hydroxyethyl- | Benzyloxy- | H | H | H |
| Cl | Amino methyl- | The 5-tertiary butyl-4-methyl isophthalic acid H-imidazoles-2-base | H | H | H |
| Cyano group | 2-(methoxycarbonyl amino)-ethyl- | The 4-tertiary butyl-5-methyl isophthalic acid H-imidazoles-2-base | H | H | H |
| Cyano group | Methylol- | Benzyloxy- | Acetylamino- | H | H |
| Cl | H | 2-methylamino--benzoyl-amido- | H | H | H |
| Cl | H | Benzyloxy- | H | H | H |
| Cyano group | The 2-amino-ethyl- | The 4-tertiary butyl-5-methyl isophthalic acid H-imidazoles-2-base | H | H | H |
| Cyano group | Methylol- | Benzyloxy- | Hydroxyl | H | H |
| Cl | Amino methyl- | 1H-benzimidazolyl-2 radicals-Ji | H | H | H |
| Cl | Methylol- | Benzyloxy- | H | H | H |
| Cl | Methylol- | Hydroxyl | H | H | H |
| Cl | H | Amino | H | H | H |
| Cl | H | Tert-butoxycarbonyl- | H | H | H |
| Cl | H | Hydroxyl | H | H | H |
| Cl | H | Nitro | H | H | H |
| Cl | Methylol- | The 4-tertiary butyl-1H-imidazoles-2-base | H | H | H |
| Cl | Methylol- | Benzyloxy- | The dimethylamino formyl radical- | H | H |
| Cl | Methylol- | The 4-tertiary butyl-1-methyl isophthalic acid H-imidazoles-2-base | H | H | H |
| Cyano group | Methylol- | Benzyloxy- | Carboxyl- | H | H |
| Cyano group | The 2-hydroxyethyl- | The 4-cyano benzyloxy- | H | H | H |
| Cyano group | The 2-hydroxyethyl- | The 3-cyano benzyloxy- | H | H | H |
| Cyano group | Methylol- | Benzyloxy- | Cyano group | H | H |
| Cl | Amino | Benzyloxy- | H | H | H |
| Cyano group | The 2-hydroxyethyl- | The 2-cyano benzyloxy- | H | H | H |
| Cyano group | Methylol- | The 3-tertiary butyl-3H-imidazol-4 yl | H | H | H |
| Cyano group | Methylol- | Benzyloxy- | Acetylamino- | H | H |
| Cyano group | H | Benzyloxy- | H | H | H |
| Cl | Methylol- | Benzyloxy- | F | H | H |
| Cyano group | The 2-hydroxyethyl- | The 5-tertiary butyl-4-methyl isophthalic acid H-imidazoles-2-base | H | H | H |
| Cl | Methylol- | The 2-tertiary butyl-3H-imidazol-4 yl | H | H | H |
| Cl | Methylol- | Benzyloxy- | Dimethylamino-methyl- | H | H |
| Cyano group | Methylol- | Benzyloxy- | Cl | H | H |
| Cyano group | Methylol- | Benzyloxy- | Fluorine | H | H |
| Cl | Methylol- | The 4-tertiary butyl-imidazoles-1-base | H | H | H |
| Cl | Methoxymethyl- | The 2-tertiary butyl-3H-imidazol-4 yl | H | H | H |
| Cl | H | 1H-benzimidazolyl-2 radicals-Ji | H | H | H |
| Cl | Amino methyl- | The 5-tertiary butyl-4-methyl isophthalic acid H-imidazoles-2-base | H | H | H |
| Cl | Methylol- | Benzyloxy- | Cyano group | H | H |
| Cl | Methylol- | Benzyloxy- | Carboxyl- | H | H |
| Cyano group | Amino methyl- | The 5-tertiary butyl-4-methyl isophthalic acid H-imidazoles-2-base | H | H | H |
| Cyano group | Methylol- | Benzyloxy- | The methyl carbamyl- | H | H |
| Cyano group | Methylol- | Benzyloxy- | The dimethylamino formyl radical- | H | H |
| Iodine | The 2-hydroxyethyl- | The 5-tertiary butyl-4-methyl isophthalic acid H-imidazoles-2-base | H | H | H |
| Cl | The 2-hydroxyethyl- | The 5-tertiary butyl-4-methyl isophthalic acid H-imidazoles-2-base | H | H | H |
| Cl | Methylol- | The 1-tertiary butyl-2-methyl isophthalic acid H-imidazol-4 yl | H | H | H |
| Cyano group | The 2-hydroxyethyl- | Hydroxyl- | H | H | H |
| Cyano group | The 2-hydroxyethyl- | 3-hydroxy-2-methyl-propoxy-- | H | H | H |
| Cyano group | Methylol- | The 2-tertiary butyl-1-methyl isophthalic acid H-imidazol-4 yl | H | H | H |
| Cl | Methylol- | 5-methyl-4-Trifluoromethyl-1 H-imidazoles-2-base | H | H | H |
| Cyano group | Methylol- | 5-methyl-4-Trifluoromethyl-1 H-imidazoles-2-base | H | H | H |
| Cl | Methyl- | The 2-tertiary butyl-1H-imidazol-4 yl | H | H | H |
| Cyano group | Methylol- | The 1-tertiary butyl-2-methyl isophthalic acid H-imidazol-4 yl | H | H | H |
| Cl | H | The 2-tertiary butyl-3H-imidazol-4 yl | H | H | H |
| Cl | The 2-amino-ethyl- | The 4-tertiary butyl-5-methyl isophthalic acid H-imidazoles-2-base | H | H | H |
| Cl | Amino methyl- | Cyclopropyl-methoxyl group- | H | H | H |
| Cl | The sec.-propyl amino-methyl- | Cyclopropyl-methoxyl group- | H | H | H |
| Cyano group | Methylol- | The 4-tertiary butyl-5-methyl isophthalic acid H-imidazoles-2-base | H | H | H |
| Cl | Methylol- | The 2-tertiary butyl-2H-tetrazolium-5-base | H | H | H |
| Cl | Methylol- | Benzyloxy- | Methylol- | H | H |
| Cl | Amino methyl- | Carbamyl- | H | H | H |
| Cl | Methylol | Benzylamino- | H | H | H |
| Cl | Methylol | 2-methylamino--benzoyl-amido- | H | H | H |
| Cl | Amino methyl- | 4-sec.-propyl-4,5-dihydro-oxazole-2-base | H | H | H |
| Cl | The 2-hydroxyethyl- | Benzyloxy- | H | H | H |
| Cl | Methylol- | The 5-tertiary butyl-4H-[1,2,4] triazole-3-base | H | H | H |
| Cl | Methylol- | The 4-tertiary butyl-5-methyl isophthalic acid H-imidazoles-2-base | H | H | H |
| Cl | Methylol- | Tert-butoxycarbonyl amino- | H | H | H |
| Cl | Methylol- | Cyclo propyl methoxy- | H | H | H |
| Cl | (1,3-dioxo-1,3-dihydro-isoindole-2-yl)-methyl- | Carbamyl- | H | H | H |
| Cl | Methylol- | Cyano group | H | H | H |
| Cl | The 3-hydroxypropyl- | Benzyloxy- | H | H | H |
| Cyano group | Methylol- | 1-methoxymethyl-1H-benzimidazolyl-2 radicals-Ji | H | H | H |
| Cl | (1,3-dioxo-1,3-dihydro-isoindole-2-yl)-methyl- | 1H-benzimidazolyl-2 radicals-Ji | H | H | H |
| Cyano group | Methylol- | The 2-tertiary butyl-3H-imidazol-4 yl | H | H | H |
| Cyano group | The 2-hydroxyethyl- | Hydroxyl- | H | H | H |
| Cyano group | Methylol- | 1H-benzimidazolyl-2 radicals-Ji | H | H | H |
| Cl | Methylol- | 2H-tetrazolium-5-base | H | H | H |
| Cl | Amino methyl- | The 2-tertiary butyl-1H-imidazol-4 yl | H | H | H |
| Cyano group | The 2-hydroxyethyl- | Benzyloxy- | H | H | H |
| Cl | Methylol- | Benzyloxy | H | H | H |
| Cl | Methylol- | The 2-tertiary butyl-1-methyl isophthalic acid H-imidazol-4 yl | H | H | H |
| Cl | The 2-hydroxyethyl- | The 5-tertiary butyl-[1,2,4] oxadiazoles-3-ylmethoxy- | H | H | H |
| Cl | H | H | H | H | Cl |
| Cl | H | H | H | H | Methoxyl group- |
| Cl | 4-methyl-piperazine-1-ylmethyl- | Phenyl | H | H | H |
| Cl | (2-amino-ethyl amino)-cyano group-methyl- | Phenyl | H | H | H |
| Cl | (piperazine-1-yl)-cyano group-methyl- | Phenyl | H | H | H |
| Cl | Cyano group-(2-hydroxyl-2-phenyl-ethylamino)-methyl- | Phenyl | H | H | H |
| Cl | (2-hydroxyl-2-phenyl-ethylamino)-methyl- | Phenyl | H | H | H |
| Cl | Methylol- | 4-sec.-propyl-4,5-dihydro-oxazole-2-base | H | H | H |
| Cl | Amino methyl- | 1H-benzimidazolyl-2 radicals-Ji | H | H | H |
| Cl | 1H-tetrazolium-5-base | Phenyl | H | H | H |
| Cl | Morpholine-4-ylmethyl- | Phenyl | H | H | H |
| Cl | [2-(2-oxo-imidazolidine-1-yl)-ethylamino]-methyl- | Phenyl | H | H | H |
Table 3
| R 11 | R 7 | R 5 | R 6 |
| Cl | Methylamino-- | H | 4-(the 1H-benzimidazolyl-2 radicals-yl)-phenyl- |
| Cl | (pyridin-4-yl) methyl-amino- | H | Fen-3-base |
| Cl | Amino | H | The 4-hydroxyphenyl- |
| Cl | Methylamino-- | H | The 3-chloro-phenyl-- |
| Cl | Methylamino-- | H | 4-(N=N=N)-phenyl- |
| Cl | Methylamino-- | H | Benzo [b] thiene-3-yl- |
| Cl | Methylamino-- | H | Pyridine-2-base |
| Cl | Methylamino-- | H | Pyridin-3-yl |
| Cl | Methylamino-- | H | Cyclohexyl- |
| Cl | Methylamino-- | H | Naphthalene-1-base |
| Cl | Sec.-propyl amino- | H | Phenyl |
| Cl | Methylamino-- | H | The 4-xenyl- |
| Cl | Methylamino-- | H | Thiazole-4-base |
| Cl | Methylamino-- | H | The 4-xenyl- |
| Cl | Amino | H | The 4-xenyl- |
| Cl | Methoxyl group- | H | The 4-xenyl- |
| Cl | Methylamino-- | H | Phenyl |
| Cl | Methylamino- | H | 4-isobutyl-sulfamyl-phenyl- |
| Cl | (1-carbamyl-2-methyl-propyl group)-amino- | H | The 4-xenyl |
| Cl | Carbamyl methyl-amino- | H | 4-tert.-butoxy phenyl- |
| Cl | Methyl-amino- | H | 4-sec.-propyl sulfamyl-phenyl- |
| Cl | Amino | H | 4-cyclohexyl oxygen base-phenyl- |
| Cl | Methyl-amino | H | 4-(1-oxo-1H-phthalazines-2-yl)-phenyl- |
| Cl | Methyl-amino | H | 4-(2-oxo-piperidines-1-yl)-phenyl- |
| Cl | Methyl-amino | H | 4-dibenzyl amino-phenyl- |
| Cl | Methylamino-- | H | The 4-chloro-phenyl- |
| Cl | Methylamino-- | H | Pyridin-4-yl |
| Cl | Methylamino-- | H | 5-methoxyl group-1H-indol-3-yl |
| Cl | Amino | H | Phenyl |
| Cl | OH | H | Phenyl |
| Cl | Methylamino-- | H | Phenyl |
| Cl | Carbamyl methyl-amino- | H | 4-isobutyryl amino-phenyl- |
| Cl | Carbamyl methyl-amino- | H | 4-(3-methyl-butyryl radicals amino)-phenyl- |
| Cl | Carbamyl methyl-amino- | H | 4-(2,2-dimethyl-propionyl amino)-phenyl- |
| Cl | Carbamyl methyl-amino- | H | 4-[(morpholine-4-carbonyl)-amino]-phenyl- |
| Cl | Methylamino- | H | 4-(benzylamino)-phenyl- |
| Cl | Carbamyl methyl-amino- | H | 4-(hexanaphthene carbonyl-amino)-phenyl- |
| Cl | Methylamino-- | H | 4-(benzyl oxygen base)-phenyl- |
| Cl | Carbamyl methyl-amino- | H | 4-(4-sec.-propyl-4,5-dihydro-oxazoles-2-yl)-phenyl- |
| Cl | Tert.-butoxy | H | 4-(4-morpholine-4-yl)-[1,2,5]-thiadiazoles-3-base oxygen base)-phenyl- |
| Cl | Methoxyl group- | H | 4-(4-sec.-propyl-4,5-dihydro-oxazoles-2-yl)-phenyl- |
| Cl | Carbamyl methyl-amino- | H | 4-(cyclopropyl-methoxyl group)-phenyl- |
| Cl | Amino- | H | 4-(2-oxo-3-phenyl-cyclopentyloxy)-phenyl- |
| Cl | Amino- | H | 4-(3-bromo-[1,2,4]-thiadiazoles-5-base oxygen base)-phenyl- |
| Cl | Methylamino- | H | 2-phenyl-1H-benzoglyoxaline-5-base |
| Cl | Oxyethyl group- | H | 4-(the 4-tertiary butyl-5-methyl isophthalic acid H-imidazoles-2-yl)-phenyl- |
| Cyano group | Methylamino-- | H | 4-benzyl oxygen base-phenyl- |
| Cl | Methylamino-- | H | The 4-[(3-fluorophenyl)-carbonylamino]-cyclohexyl- |
| Cl | Methylamino-- | H | 4-(the 1H-benzimidazolyl-2 radicals-yl)-phenyl- |
| Cl | Methylamino- | H | 4-benzyloxy-phenyl- |
| Cl | Methylamino- | H | 4-(the 1H-benzimidazolyl-2 radicals-yl)-phenyl- |
| Cl | Amino | H | 4-(1-methoxymethyl-1H-benzimidazolyl-2 radicals-yl)-phenyl- |
| Cl | Methylamino-- | H | 4-(tert-butoxycarbonyl)-amino methyl-phenyl- |
| Cl | Methylamino-- | H | 4-(4-amino methyl-benzyl acyl amino)-phenyl- |
| Cl | Methoxyl group- | H | 4-(methoxycarbonyl)-phenyl- |
| Cl | Methylamino-- | H | 4-(4-allyl group carbamyl-1H-imidazoles-2-yl)-phenyl- |
| Cl | Methylamino- | H | 4-[(6-morpholine-4-base-pyridine-3-carbonyl)-amino]-phenyl- |
| Cl | Methylamino- | H | 4-(4-chloro-benzyl acyl amino)-phenyl- |
| Cl | Methylamino- | H | (the 3-tertiary butyl-urea groups)-hexanaphthene-4-base |
| Cl | Methylamino- | H | 4-(4-dimethylamino formyl radical-1H-imidazoles-2-yl)-phenyl- |
| Cl | Methylamino- | H | (the 1H-benzimidazolyl-2 radicals-yl)-hexanaphthene-4-base |
| Cl | Methylamino- | H | Carbamyl-1-hexanaphthene-4-base |
| Cl | Methylamino- | H | 4-(2-chloro-benzoyl)-amino-phenyl- |
| Cl | Methylamino- | H | 4-[4-(morpholine-4-carbonyl)-1H-imidazoles-2-yl]-phenyl- |
| Methoxyl group | Methylamino- | H | 4-benzyl oxygen base-phenyl- |
| Cl | Methylamino- | H | Carbamyl-hexanaphthene-4-base |
| Cl | Methylamino- | H | 4-(3-chloro-benzoyl)-amino-phenyl- |
| Cl | Methylamino- | H | Tert-butoxycarbonyl-amino-hexanaphthene-4-base |
| Cl | Methylamino- | H | Benzyl carbamyl-hexanaphthene-4-base |
| Cl | Methylamino- | H | 4-[4-(1-hydroxyl-1-methyl-ethyl)-thiazol-2-yl]-phenyl- |
| Cl | Methylamino- | H | 4-[4-(2-carboxyl-1,1-dimethyl-ethyl)-1H-imidazoles--2-yl]-phenyl- |
| Cl | Methylamino-- | H | 4-tert-butoxycarbonyl amino-phenyl- |
| Cl | Methylamino- | H | Tert-butoxycarbonyl amino-hexanaphthene-4-base |
| Cl | Methylamino- | H | (the 4-tertiary butyl-1H-imidazoles--2-yl)-hexanaphthene-4-base |
| Cl | Methylamino- | H | 4-[4-(2-ethoxy carbonyl-1,1-dimethyl-ethyl)-1H-imidazoles-2-yl]-phenyl- |
| Cl | Methylamino-- | H | The 4-aminocyclohexyl- |
| Cl | Methylamino- | H | 4-(pyridin-3-yl carbamyl)-cyclohexyl- |
| Cl | Methylamino- | H | 4-(4-oxo-1,4-dihydro-chinazoline-2-yl)-phenyl- |
| Cl | Methylamino- | H | 4-[4-(1H-pyrazole-3-yl carbamyl)-1H-imidazoles-2-yl]-phenyl- |
| Cl | Methylamino- | H | 4-(4-propyl group carbamyl-1H-imidazoles-2-yl)-phenyl- |
| Cl | Methylamino- | H | 4-(4-cyclopropyl carbamyl-1H-imidazoles-2-yl)-phenyl- |
| Fluorine | Methylamino- | H | 4-benzyl oxygen base phenyl- |
| Cl | Methylamino- | H | 4-(4-Trifluoromethyl-1 H-imidazoles-2-yl)-phenyl- |
| Cl | Methylamino- | H | 4-(4-cyclopropyl methyl-carbamyl-1H-imidazoles-2-yl)-phenyl- |
| Cl | Methylamino- | H | 4-benzoglyoxaline-1-base-phenyl- |
| Cl | Methylamino- | H | 4-[4-(2-methoxyl group-ethyl carbamyl)-1H-imidazoles-2-yl]-phenyl- |
| Cl | Methylamino- | H | 4-(4-sec.-propyl carbamyl-1H-imidazoles-2-yl)-phenyl- |
| Cl | Methylamino- | H | 4-[4-(2-methoxyl group-phenyl)-1H-imidazoles-2-yl]-phenyl- |
| Cl | Methylamino- | H | 4-(pyridin-4-yl carbamyl)-cyclohexyl- |
| Cl | Methylamino- | H | 4-[4-(3-methoxyl group-propyl group carbamyl)-1H-imidazoles-2-yl]-phenyl- |
| Cl | Methylamino- | H | 4-(4-methylol-thiazol-2-yl)-phenyl- |
| Cl | Methylamino- | H | 4-[4-(4-fluoro-phenyl)-1H-imidazoles-2-yl]-phenyl- |
| Cl | Methylamino- | H | 4-(sec.-propyl carbonyl-amino)-cyclohexyl- |
| Cl | Methylamino- | H | 4-[4-(pyridin-4-yl carbamyl)-1H-imidazoles-2-yl]-phenyl- |
| Cl | Methylamino- | H | 4-[4-(3-methyl-butyl carbamyl)-1H-imidazoles-2-yl]-phenyl- |
| Cl | Methylamino- | H | 4-[4-(3-methoxyl group-phenylamino formyl radical)-1H-imidazoles-2-yl]-phenyl- |
| Cl | Methylamino- | H | 4-isobutyl-carbonyl-amino-cyclohexyl- |
| Cl | Methylamino- | H | 4-(2-fluoro-benzyl acyl amino)-cyclohexyl- |
| Cl | Methylamino- | H | 4-[4-(2-dimethylamino-ethyl carbamyl)-1H-imidazoles-2-yl]-phenyl- |
| Cl | Methylamino- | H | 4-(6-sec.-propyl-4-oxo-1,4-dihydro-pyrimidine-2-yl)-phenyl- |
| Cl | Methylamino- | H | 4-(4-morpholine-4-base-benzyl acyl amino)-phenyl- |
| Cl | Amino | H | The 4-hydroxy-cyclohexyl- |
| Cl | Methylamino-- | H | 4-(4-ethoxy carbonyl-1H-imidazoles-2-yl)-phenyl- |
| Cl | Methylamino- | H | 4-(5-benzyl-[1,3,4] thiadiazoles-2-yl)-phenyl- |
| Cl | Methylamino- | H | The 4-cyano-phenyl- |
| Cl | (pyridin-3-yl-methyl)-amino | H | Phenyl |
| Cl | Methylamino- | H | Right-tolyl- |
| Cl | Methylamino- | H | The 3-hydroxy phenyl- |
| Cl | Methylamino- | H | Thiophene-2-base- |
| Cl | Methylamino- | H | The 2-hydroxy phenyl- |
| Cl | Methylamino- | H | The 4-xenyl- |
| Cl | Methylamino- | H | 1-methyl isophthalic acid H-imidazol-4 yl- |
| Cl | Methylamino- | H | 4-(4-cyano-phenyl)-phenyl- |
| Cl | Methylamino- | H | The 3-p-methoxy-phenyl- |
| Cl | (furans-2-base-methyl)-amino | H | Phenyl |
| Cl | Methylamino- | H | 4-(2-hydroxyphenyl)-phenyl- |
| Cl | Methylamino- | H | The 2-fluorophenyl- |
| Cl | Methylamino- | H | The 4-tert-butyl-phenyl- |
| Cl | Methylamino- | H | The 4-xenyl- |
| Cl | Methylamino- | H | Naphthalene-2-base |
| Cl | Methylamino- | H | The 4-xenyl- |
| Cl | Indane-2-base-amino- | H | Phenyl |
| Cl | Methylamino- | H | 4-(3-fluorophenyl)-phenyl- |
| Cl | Methylamino- | H | 4-(4-hydroxyphenoxy)-phenyl- |
| Cl | Methylamino- | H | 4-(3-p-methoxy-phenyl)-phenyl- |
| Cl | Pyridine-2-base-amino- | H | Phenyl |
| Cl | Methylamino- | H | 1H-[1,2,4]-triazol-1-yl |
| Cl | (2-methyl-propyl group)-amino- | H | Phenyl |
| Cl | Methylamino- | H | 4-(2-fluorophenyl)-phenyl- |
| Cl | Methylamino- | H | Isoquinoline 99.9-3-base |
| Cl | Methylamino- | H | The 3-fluorophenyl- |
| Cl | Dimethylamino | H | The 4-xenyl- |
| Cl | Methylamino- | H | 4-(phenylcarbonyl group)-phenyl- |
| Cl | Methylamino- | H | The 4-fluorophenyl- |
| Cl | OH | H | The 4-xenyl- |
| Cl | Ethylamino | H | The 4-xenyl- |
| Cl | Methylamino- | H | The 4-hydroxybenzyl- |
| Cl | Methylamino- | Methyl | Hydroxyl |
| Cl | Methylamino- | H | 1H-indoles-2-base |
| Cl | Amino | H | Sec.-propyl |
| Cl | Methylamino- | H | 1H-pyrrolo-[2,3-b] pyridine-2-base |
| Cl | (2-dimethylamino)-ethyl-amino- | H | Phenyl |
| Cl | Methylamino- | H | The 2-chloro-phenyl- |
| Cl | (3-hydroxypropyl)-amino | H | Phenyl |
| Cl | Methylamino- | Methyl | Phenyl |
| Cl | Amino | H | 4-(pyrimidine-2-yloxy)-phenyl- |
| Cl | Methylamino- | H | Benzyl- |
| Cl | Methylamino- | H | The 4-carboxyl phenyl- |
| Cl | Methylamino- | H | The 4-bromophenyl- |
| Cl | Methylamino- | H | Benzyl- |
| Cl | Methylamino- | H | 4-(tert-butoxycarbonyl amino methyl)-phenyl- |
| Cl | Methylamino- | H | 4-amine phenyl- |
| Cl | Pyridine-2-ylmethyl-amino- | H | Phenyl |
| Cl | Methylamino- | H | 4-amino methyl-phenyl- |
| Cl | Methylamino- | H | 4-acetylamino-phenyl- |
| Cl | Methylamino- | H | 4-(thiophene-2-yl)-phenyl- |
| Cl | Methylamino- | H | 4-(hydroxyl-phenyl-methyl)-phenyl- |
| Cl | Methylamino- | H | The 2-bromophenyl- |
| Cl | Amino | H | 4-(5-methyl-isoxazole-3-base methoxyl groups)-phenyl- |
| Cl | Methylamino- | H | 4-(4-aminomethyl phenyl)-phenyl- |
| Cl | Methylamino- | H | 4-(3-hydroxyphenyl)-phenyl- |
| Cl | Methylamino- | H | 4-benzyloxy-phenyl- |
| Cl | Methylamino- | H | 4-(the 5-methyl-[1,2,4] oxadiazole-3-yls)-phenyl- |
| Cl | Methylamino- | H | The 4-hydroxyphenyl- |
| Cl | Cyclopropyl amino- | H | Phenyl |
| Cl | Methoxyl group | H | The 4-hydroxyphenyl- |
| Cl | (tetrahydrochysene-furans-2-base-methyl)-amino | H | Phenyl |
| Cl | Methylamino- | H | The 4-trifluoromethyl- |
| Cl | Methylamino- | H | 4-[(6-morpholine-4-base-pyridine-3-carbonyl)-amino]-phenyl- |
| Cl | Methylamino- | H | 4-(3-oxo-[1,2,4] triazolo [4,3-a]-pyridine-2-yl)-phenyl- |
| Cl | Methylamino- | H | 4-[4-(tert-butoxycarbonyl amino-methyl)-benzoyl-amido]-phenyl- |
| Cl | Methylamino- | H | 4-(4-amino methyl-benzoyl-amido)-phenyl- |
| Cl | Methylamino- | H | 4-(4-carboxyl-thiazol-2-yl)-phenylformic acid |
| Cl | Methylamino- | H | 4-(6-oxo-1,6-dihydro-pyrimidine-2-base)-phenyl- |
| Cl | Methylamino- | H | The 4-bromophenyl |
| Cl | Methylamino- | H | 4-[4-(2-methoxyl group-ethyl carbamyl)-azoles-2-yl]-phenyl- |
| Cl | Methylamino- | H | 4-[4-(sec.-propyl carbamyl)-thiazol-2-yl]-phenyl- |
| Cl | Methylamino- | H | 4-[4-(dimethylamino formyl radical)-thiazol-2-yl]-phenyl- |
| Cl | Methylamino- | H | 4-[4-(4-methyl-piperazine-1-carbonyl)-thiazol-2-yl]-phenyl- |
| Cl | Methylamino- | H | 4-[4-(morpholine-4-carbonyl)-thiazol-2-yl]-phenyl |
| Cl | Methylamino- | H | 4-benzyloxy-3-p-methoxy-phenyl |
| Cl | Methylamino- | H | 4-(2-furans-2-base-thiazole-4-yl)-phenyl |
| Cl | 1-carbamyl-2-methyl-third amino | H | The 4-xenyl- |
| Cl | Methylamino- | H | 4-(dibenzyl amino)-phenyl- |
| Cl | Methylamino- | H | 4-(1-oxo-1H-phthalazines-2-yl)-phenyl- |
| Cl | Methylamino- | H | 4-(benzylamino)-phenyl- |
| Cl | Methylamino- | H | 4-(2-oxo-piperidines-1-yl)-phenyl- |
| Cl | Carbamyl-methylamino- | H | 4-[(morpholine-4-carbonyl)-amino]-phenyl |
| Cl | Carbamyl-methylamino- | H | The 4-[(cyclohexyl-carbonyl)-amino]-phenyl |
| Cl | Carbamyl-methylamino- | H | 4-(3-methyl-butynyl amino)-phenyl |
| Cl | Amino | H | 4-(piperidin-4-yl carbamyl methoxyl group)-phenyl |
| Cl | Amino | H | 4-(sec-butyl carbamyl-methoxyl group)-phenyl |
| Cl | Methylamino- | H | 4-isobutyl-sulfonamido-phenyl |
| Cl | Methylamino- | H | 4-isobutyl-sulfonamido-phenyl |
| Cl | Amino | H | 4-(4-chloro-[1,2,5]-thiadiazoles-3-base oxygen base)-phenyl |
| Cl | Carbamyl-methylamino- | H | 4-(tert-butoxycarbonyl)-phenyl |
| Cl | Carbamyl-methylamino- | H | 4-(4-morpholine-4-base-[1,2,5]-thiadiazoles-3-base oxygen base)-phenyl |
| Cl | Amino | H | 4-(cyclohexyl oxygen base)-phenyl |
| Cl | Methylamino- | H | 4-(4-oxo-4H-quinazoline-3-yl)-phenyl |
| Cl | Tert.-butoxy | H | 4-(4-morpholine-4-base-[1,2,5]-thiadiazoles-3-base oxygen base)-phenyl |
| Cl | Amino | H | 4-(3-bromo-[1,2,4]-thiadiazoles-5-base oxygen base)-phenyl |
| Cl | Amino | H | 4-(2-oxo-1-phenyl-pyrrolidyl-3-base oxygen base)-phenyl |
| Cl | Methylamino- | H | 4-(4-fluoro-benzoyl-amido)-phenyl |
| Cl | Methylamino- | H | 4-(3-fluoro-benzoyl-amido)-phenyl |
| Cl | Carbamyl-methylamino- | H | 4-(the 1H-benzimidazolyl-2 radicals-yl)-phenyl |
| Cl | Hydroxyl | H | 4-(the 1H-benzimidazolyl-2 radicals-yl)-phenyl |
| Cl | Methoxyl group | H | 4-(the 1H-benzimidazolyl-2 radicals-yl)-phenyl |
| Cl | Carbamyl-methylamino- | H | 4-(4-sec.-propyl-4,5-dihydro-oxazoles-2-yl)-phenyl |
| Cl | Hydroxyl | H | 4-(4-sec.-propyl-4,5-dihydro-oxazoles-2-yl)-phenyl |
| Cl | Methoxyl group | H | 4-(4-sec.-propyl-4,5-dihydro-oxazoles-2-yl)-phenyl |
| Cl | Carbamyl-methylamino- | H | 4-(cyclo propyl methoxy)-phenyl- |
| Cl | Tert.-butoxy | H | 4-(pyridin-3-yl methoxyl group)-phenyl |
Table 4
| R 11 | T | R 14 | R 6 |
| Cl | -CH 2NH- | Amino methyl- | 4-(cyclopropyl-methoxyl group)-phenyl- |
| Cl | -CH 2- | Methylamino-- | The 3-chloro-phenyl-- |
| Cl | -CH 2NH- | 2-hydrazino carbonyl-phenyl- | 4-(4-sec.-propyl-4,5-dihydro-oxazoles-2-yl)-phenyl- |
| Cl | -CH 2NH- | Amino methyl- | 4-(the 1H-benzimidazolyl-2 radicals-yl)-phenyl |
| Cl | -CH 2NH- | Amino methyl- | 4-(carbamyl)-phenyl |
| Cl | -CH 2NH- | Amino methyl- | 4-(4-sec.-propyl-4,5-dihydro-oxazoles-2-yl)-phenyl- |
| Cl | -CH 2NH- | Amino methyl- | 4-(cyclo propyl methoxy-phenyl- |
| Cl | -CH 2O- | Methylamino- | 4-(the 2-tertiary butyl-1H-imidazol-4 yl)-phenyl- |
| Cl | -CH 2NH- | Methylamino- | 4-(the 2-tertiary butyl-1H-imidazol-4 yl)-phenyl- |
| Cyano group | -CH 2NH- | Methylamino- | 4-(the 2-tertiary butyl-5-methyl isophthalic acid H-imidazoles-2-yl)-phenyl |
| Cl | -CH 2O- | Methoxyl group- | 4-(the 2-tertiary butyl-1H-imidazol-4 yl)-phenyl- |
| Cl | -CH 2NH- | Methyl | The 4-xenyl |
| Cl | -CH 2NH- | Methyl | Phenyl |
| Cl | -CH 2CH 2- | Methylamino- | 4-benzyloxy-phenyl- |
| Cl | -CH 2- | Methylamino- | The 2-chloro-phenyl-- |
| Cl | -CH 2- | Methylamino- | Phenyl |
| Cl | -CH 2- | Methylamino- | The 4-xenyl |
| Cl | -CH 2CH 2- | Methylamino- | 4-benzyloxy-phenyl- |
| Cl | Lack | Amino | Tert-butoxycarbonyl- |
| Cl | -CH 2NH- | Amino methyl- | 4-carbamyl-phenyl |
| Cl | -CH 2NH- | Amino methyl- | 4-(the 1H-benzimidazolyl-2 radicals-yl)-phenyl- |
| Cl | -CH 2O- | (2-methyl-amino)-phenyl- | 4-[(2-methylamino-benzoyl)-amino]-phenyl- |
| Cl | Lack | Amino | Benzyloxy oxygen base carbonyl- |
| Cl | -CH 2- | OH | The 4-xenyl- |
Table 5
| W | R 3 | R 6 |
| CH | Hydrogen | Tert-butoxycarbonyl- |
| CH | 2-(methyl carbamyl)-ethyl- | Phenyl |
| CH | 2-(carboxyl)-ethyl- | Phenyl |
| -CH 2CH- | Carboxyl | Phenyl |
| N | Methylamino-carbonyl- | 2-phenyl-3H-benzoglyoxaline-5-base |
| C | Methylol- | Hydroxyl |
| C | Hydrogen | Methylamino--carbonyl- |
| C | Hydrogen | (dimethylamino)-carbonyl- |
| C | Amino-carbonyl- | (methyl sulfane base)-methyl- |
| N | Methylamino--carbonyl- | 4-benzyloxy-3-methoxyl group-phenyl- |
| N | Methylamino--carbonyl- | 4-benzyloxy-phenyl- |
| N | Methylamino--carbonyl- | 4-(benzoyl-amido)-phenyl- |
| N | Methylamino--carbonyl- | The 4-bromophenyl- |
| N | Methylamino--carbonyl- | 2-phenyl-thiazole-4-base |
| N | Methylamino--carbonyl- | Phenyl |
| N | Methylamino--carbonyl- | 5-phenyl-[1,2,4] oxadiazole-3-bases |
| N | Methylamino--carbonyl- | 4-(the 1H-benzimidazolyl-2 radicals-yl)-phenyl- |
| CH | Methyl--sulfuryl amino-methyl- | The 4-xenyl- |
Table 6
| N-[2-(4-benzyloxy-phenyl)-1-methyl carbamyl)-and ethyl]-2,3-dihydro-isopropoxy-benzamide |
| 3-(3H-imidazol-4 yl)-2-(4-trifluoromethyl-benzenesulfonyl amino)-propionic acid |
| N-2-(xenyl-4-base-1-methyl carbamyl)-ethyl)-benzamide |
| N-(1-carbamyl-2-phenyl-ethyl)-3-chloro-4-(2,2,2-three fluoro-1-methyl-oxyethyl groups)-benzamide; N-(1-carbamyl-2-phenyl-ethyl)-4-chloro-benzamide |
| 4-[2-(4-tert.-butoxy-3-chloro-benzoyl-amido)-2-methyl carbamyl]-ethyl]-t-butyl perbenzoate |
| N-[2-(4-benzyloxy-phenyl)-1-methyl carbamyl-ethyl]-3-chloro-4-isopropylamino-benzamide |
| 2-benzyl-3-(3-chloro-4-isopropoxy-benzoyl-amido)-propionic acid |
| Naphthalene-2-carboxylic acid [2-(4-benzyloxy-phenyl)-1-methyl carbamyl-ethyl]-acid amides |
| Quinoline-7-carboxylic acid [2-(4-benzyloxy-phenyl)-1-methyl carbamyl-ethyl]-acid amides |
| 1-sec.-propyl-1H-benzoglyoxaline-5-carboxylic acid [2-(4-benzyloxy-phenyl)-1-methyl carbamyl-ethyl]-acid amides |
| 5-xenyl-4-ylmethyl-2-(3-chloro-4-isopropoxy-3,5-dihydro-imidazol--4-ketone |
| 5-xenyl-4-ylmethyl-2-(3-chloro-4-isopropoxy-3H-imidazoles-4-carboxylate methyl ester |
| 5-xenyl-4-ylmethyl-2-(3-chloro-4-isopropoxy-3H-imidazoles-4-carboxylic acid methane amide |
| 4-(4-{4-[2-(3-chloro-4-sec.-propyl-phenyl)-4,5-dihydro-oxazoles-4-ylmethyl]-phenoxy group }-[1,2,5]-thiadiazoles-3-yl)- |
| 4-(4-benzyloxy-benzyl)-2-(3-chloro-4-isopropoxy-phenyl)-4,5-dihydro-oxazoles |
| 3-xenyl-4-ylmethyl-5-(3-chloro-4-isopropoxy-phenyl)-3H-[1,3,4]-oxadiazoles-2-ketone |
| 1-(3-chloro-4-isopropoxy-benzoyl)-3-(4-iodo-phenyl)-tetramethyleneimine-2-carboxylic acid methane amide |
| 3-(4-bromo-phenyl)-1-(3-chloro-4-isopropoxy-benzoyl)-tetramethyleneimine-2-carboxylate methyl ester |
| 3-xenyl-4-base-1-(3-chloro-4-isopropoxy-benzoyl)-tetramethyleneimine-2-carboxylic acid methane amide |
| 1-(3-chloro-4-isopropoxy-benzoyl)-3-phenyl-piperidines-2-carboxylic acid methane amide |
| 1-(3-chloro-4-isopropoxy-benzoyl)-4-phenyl-piperidines-2-carboxylic acid methane amide |
| 1-(3-chloro-4-isopropoxy-benzoyl)-4-phenyl-Piperazine-2-carboxylic acid methane amide |
| (2-xenyl-4-base-1-aziridine-1-yl)-(3-chloro-4-isopropoxy-benzoyl)-ketone |
| 3-xenyl-4-base-N-carbamyl methyl-2-(6-chloro-7-isopropoxy-2,4-dioxo-1,4-dihydro-2H-quinazoline-3-yl)-propionic acid amide |
| 3-xenyl-4-base-N-carbamyl methyl-2-(6-chloro-7-isopropoxy-4-oxo-4H-quinazoline-3-yl)-propionic acid amide |
| 3-xenyl-4-base-N-carbamyl methyl-2-(8-chloro-7-isopropoxy-4-oxo-4H-quinazoline-3-yl)-propionic acid amide |
| 3-chloro-4-isopropoxy-N-(1,2,3,4-tetrahydrochysene-quinoline-3-yl)-benzamide |
| 3-chloro-4-isopropoxy-N-(4-phenyl-tetramethyleneimine-3-yl)-benzamide |
| 3-chloro-4-isopropoxy-N-(5-methyl-3-phenyl-isoxazole-4-base methyl)-benzamide |
| 3-chloro-4-isopropoxy-N-(1-methyl isophthalic acid H-imidazol-4 yl methyl)-benzamide |
| 3-chloro-4-isopropoxy-N-(2-phenoxy group-ethyl)-benzamide |
| N-[2-(4-benzyl-piperazine-1-yl)-ethyl]-3-chloro-4-isopropoxy-benzamide |
| N-(1H-benzimidazolyl-2 radicals-ylmethyl)-3-chloro-4-isopropoxy-benzamide |
| 3-chloro-4-isopropoxy-N-(5-methyl-2-phenyl-2H-[1,2,3] triazole-4-ylmethyl)-benzamide |
In some specific embodiments, chemical is the prodrug of listing in one of compound in the table 1,2,3,4,5 or 6, as phosphoric acid ester.In some specific embodiments, this chemical is to be selected from (3S)-4-[4-(2-ethanoyl-1-methyl isophthalic acid H-imidazol-4 yl) phenyl]-3-[({3-chloro-4-[(1-methylethyl) the oxygen base] phenyl } carbonyl) amino] butyl dihydrogen phosphoric acid ester; And (3S)-3-[({3-chloro-4-[(1-methylethyl) the oxygen base] phenyl } carbonyl) amino]-4-[4-(the 8-Methylimidazole is [1,2-a] pyridine-2-yl also)-benzyl] butyl dihydrogen phosphoric acid ester.
Can prepare by the method for for example describing in PCT WO 99/13061, No. 6,420,561, US patent and PCTWO 98/56756 at the chemical of this narration, these documents at this and in this paper as a reference.Initial substance and other reactants are commercial obtainable, Aldrich Chemical Company for example, and Wilwaukee, WI, or those skilled in the art use general used synthetic method and preparation easily.
Unless otherwise indicated, term " solvent ", " inert organic solvents " or " inert solvent " are meant and are the inert solvent under the reaction conditionss of associated description, for example comprise benzene, toluene, acetonitrile, tetrahydrofuran (THF) (" THF "), dimethyl formamide (" DMF "), chloroform, methylene dichloride (or carrene), ether, methyl alcohol, pyridine etc.Unless opposite explanation is arranged, the solvent that is used for reaction of the present invention is an inert organic solvents.
Generally speaking, the ester of carboxylic acid can prepare by conventional esterification process, and for example alkyl ester can be handled required carboxylic acid and prepare usually by with suitable alkanol under acidic conditions.Equally, acid amides can use conventional amidation method to prepare, and for example acid amides can prepare by handling relevant carboxylic acid with suitable amine.Perhaps, can choose wantonly in the presence of trimethyl aluminium, according to Tetrahedron Lett.48,4171-4173,1977 described methods, the lower alkyl esters with amine processing such as the methyl esters of acid obtains required acid amides.Carboxyl can be protected with the form of alkyl ester such as methyl esters, and described ester can and be removed with the preparation of the method for routine, and a kind of method easily that is used for methoxycarbonyl is changed into carboxyl is to use lithium hydroxide aqueous solution.
Salt that this paper mentions and solvate can be as required with the ordinary method productions in this area.For example, if compound of the present invention is acid, then can be by with inorganic or organic bases, prepare required base addition salt as processing free acids such as amine (primary, the second month in a season or uncle), basic metal or alkaline earth metal hydroxidess.The illustrative example of suitable salt comprises by following material deutero-organic salt: amino acid such as glycine and arginine; Ammonia; The primary, the second month in a season and tertiary amine; As quadrol and cyclammonium such as hexahydroaniline, piperidines, morpholine and piperazine; And by sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminium and lithium deutero-inorganic salt.
If compound is an alkali, then required acid salt can be by any suitable method preparation as known in the art, comprise and use the mineral acid example hydrochloric acid, Hydrogen bromide, sulfuric acid, nitric acid, phosphoric acid etc. are perhaps used organic acid such as acetate, toxilic acid, succsinic acid, mandelic acid, fumaric acid, propanedioic acid, pyruvic acid, oxalic acid, oxyacetic acid, Whitfield's ointment, pyranose thuja acid such as glucuronic acid or galacturonic acid, alpha hydroxy acid such as citric acid or tartrate, amino acid such as aspartic acid or L-glutamic acid, aromatic acid such as phenylformic acid or styracin, sulfonic acid such as tosic acid, methylsulfonic acid, ethyl sulfonic acids etc. are handled free alkali.
If necessary, compound as herein described and intermediate separate and purifying can be realized by any suitable isolated or purified method, for example filter, the combination of extraction, crystallization, column chromatography, tlc or thick layer chromatography method or these methods.Can come the suitable separation method of particular instantiation with reference to the embodiment below this paper.But other separation method that is equal to can certainly use.
Reaction process 1
Reference reaction flow process 1, step 1 are to as 103 compound solutions of the formula in the inert solvent of DCM, at 0 ℃ of five fluorine triflutate that add excessive (1.2 equivalents according to appointment) down and as the alkali of triethylamine.Reaction mixture is stirred about 1 hour.Separated and the purifying of product formula 105 compounds.
Reference reaction flow process 1, step 2 to 105 compound solutions of the formula in polar aprotic solvent, are added the formula R of excessive (1.2 equivalents according to appointment)
7(CO)-CH (NHR
2)-CH (R
5) (R
6) compound and as N, the alkali of N-diisopropyl ethyl amine.Reaction is with for example LC/MS monitoring, production 107 compounds, wherein R
7Be NH
2, it is separated and randomly be purified.
Reaction process 2
Reference reaction flow process 2 to as 201 compound solutions of the formula in the polar aprotic solvent of DMF, is at room temperature added formula 105 compounds of excessive (1.2 equivalents according to appointment) and as the alkali of diisopropyl ethyl amine.Reaction mixture is with for example LC/MS monitoring.When finishing, be added in the reaction soln as the one-level in the inert solvent of THF or secondary amine and HBTU.Reaction mixture is stirred about 2 days.Separated and the purifying of product formula 203 compounds, wherein R
7Be the optional amine that replaces.
In some specific embodiments, the R in formula 203 compounds
6Be halogenide, alkyl halide or aryl halide.This halogenide can use various reactions, uses the known technology of narrating at other that reaches in this area in the following example, changes into various other substituting groups.
In other specific embodiments, the R in formula 203 compounds
6Be alkyl or aryl amine.Moreover amine moiety can use in this skill known and in other technology in following narration, by alkanisation, acidylate, change into sulphonamide and analogue.
In other specific embodiments, the R in formula 203 compounds
6Be alkyl alcohol or aryl alcohol.Hydroxylic moiety can use known technology in this skill, changes into corresponding ether or ester.
Reaction process 3
Reference reaction flow process 3 to as 301 compound solutions of the formula in the polar aprotic solvent of DMF, is added glycyl amide hydrochloride, as the alkali and the HBTU of diisopropyl ethyl amine.Reaction mixture is stirred about 15 hours.Separated and the purifying of product formula 303 compounds.
Reaction process 4
Reference reaction flow process 4, to as the 401 compound stirred solutions of the formula in the inert solvent of THF, wherein n is 0,1 or 2, at about 0 ℃ of LAH (1.0 volumetric molar concentrations in THF) that adds excessive (1.2 equivalents according to appointment) down.After stir about 2 hours, product formula 403 compounds are separated and be used and do not have and be further purified.
Reference reaction flow process 4, step 2 to as the 403 compound stirred solutions of the formula in the inert solvent of THF, are added the isoindole-1 of excessive (1.1 equivalents according to appointment), 3-diketone and triphenylphosphine.Dropwise add the DEAD of excessive (1.1 equivalents according to appointment) then, and reaction is stirred about 30 minutes.Product, the separated and purifying of formula 405 compounds.
Reference reaction flow process 4, step 3, the Boc blocking group is removed then, forms corresponding unhindered amina.Those skilled in the art can understand that this must finish through protection amine complete mode to stay other.For example, add acid as TFA at room temperature to as 405 compound solutions of the formula in the polar aprotic solvent of DCM.Reaction mixture is stirred about 20 minutes.Product formula 407 compounds are separated and be used and do not have and be further purified.
Reference reaction flow process 4, step 4, at room temperature to as 407 compound solutions of the formula in the inert solvent of DMF, adding type 105 compounds and as the alkali of diisopropyl ethyl amine.Reaction mixture is stirred and spends the night.Separated and the purifying of product formula 409 compounds.
Reference reaction flow process 4, step 5, PG amine protecting group group is removed then.If the PG of amine protecting group group is the O-phthalic sulfilimine, it can followingly be removed.To as 409 compound solutions of the formula in the polar aprotic solvent of methyl alcohol, add the hydrazine hydrate of excessive (10 equivalents according to appointment).Reaction mixture is stirred about 5 hours under about 50 ℃, and cool to room temperature then.The condition that removes other blocking groups is known to those skilled in the art.
The unhindered amina of formula 411 compounds can use technology well known by persons skilled in the art by alkanisation, acidylate, reductibility alkanisation or sulfonylation.
Reaction process 5
In some compound of the present invention, special steric configuration can be preferably formula I-XIII compound.For the cause that the surplus narration of the synthetic institute of formula I-XIII compound is simplified, must understanding can use individual isomer or mixture of isomers to produce corresponding product.
Special steric isomer can use technology known in the art to obtain from mixture.For example in some specific embodiments, formula 605 unhindered aminas are dissolved in the inert solvent (as IPA) and are warmed to 60 ℃.In dividing other container, resolving agent (as dibenzoyl-D-tartrate) is dissolved in as in the identical solvent of heating, and adds (stirring is arranged) then fast in the amine aqueous solution of heating.Reaction mixture was left continuously stirring 16 hours, the crystallization with cool to room temperature.The isomer of being wanted is separated and with common mode purifying.
In some specific embodiments, the optically active amines of formula 607 can be from corresponding aryl aldehyde preparation, shown in reaction process 5.
Reference reaction flow process 5, step 1, formula 601 compounds and excessive Spirit of Mindererus in nitroethane are heated to and reflux about 8 hours approximately.Separated and optional being purified of product formula 603 compounds.
Reference reaction flow process 5, step 2 in the inert solvent as tetrahydrofuran (THF), as about 0 ℃ of solution of the reductive agent of sodium borohydride, are added the borine-tetrahydrofuran (THF) mixture of excessive (1.2 equivalents according to appointment).Gained solution is stir about 15 minutes at room temperature.Dropwise added as 603 compounds of the formula in the inert solvent of tetrahydrofuran (THF), and gained solution was refluxed about 4 hours.Separated and optional being purified of product formula 605 compounds.
Formula 605 amine can use technology known in the art to be split then.For example, saturated with spirit of salt (gas) as 0 ℃ of solution of 605 amine of the formula in the inert solvent of vinyl acetic monomer.Gained salt is to filter collection and dry in a vacuum.The bright amino acid sodium salt of L-N-ethanoyl is slowly added to the aforementioned stirred solution in water.The formation crystallization of spending the night, and with filtration remove, with the small amount of water washing, and crystallization from absolute methyl alcohol.Separated and optional being purified of the crystal salt of formula 607a.
Be rich in mixed, the one-tenth strong basicity of mother liquor of formula 607b compound, and with diethyl ether washing three times.Organic layer through merging is with water washing, and dry on sodium sulfate.Spirit of salt is by solution, up to the hydrochloride precipitation fully.Above-mentioned same steps as is used to the bright amino acid salt of D-N-ethanoyl.Separated and optional being purified of the crystalline compounds of formula 607b.
Reaction process 6
Reference reaction flow process 6, step 1 to as 701 compound solutions of the formula in the polar aprotic solvent of methyl alcohol, are added the SOCl of excessive (2 equivalents according to appointment)
2At room temperature stir spend the night after, product formula 703 compounds are separated and be used and do not have and be further purified.
Reference reaction flow process 6, step 2 to as 703 compound solutions of the formula in the polar aprotic solvent of ethanol, are added the N of excessive (5 equivalents according to appointment)
2H
4H
2O.Reaction mixture is heated to backflow, and stir about 3 hours.When cooling, the separated and purifying of product formula 705 compounds.
Reference reaction flow process 6, step 3 to as 705 compound solutions of the formula in the inert solvent of THF, are added the carbonyl dimidazoles of excessive (1.1 equivalents according to appointment).Reaction mixture is heated to backflow, and stir about 1.5 hours.When cooling, the separated and purifying of product formula 707 compounds.
Reference reaction flow process 6, step 4 to as 707 compound solutions of the formula in the inert solvent of nitrile, are added the R of excessive (1.1 equivalents according to appointment)
5R
6CH-Z reaches as K
2CO
3Alkali, wherein Z is a leavings group.Reaction mixture is heated about 30 minutes to about 80 ℃ under microwave radiation, continuous to filter and to concentrate in a vacuum.Separated and optional being purified of product formula 709 compounds.
Reference reaction flow process 6, step 5 to as 709 compound solutions of the formula in the inert solvent of THF, are added excessive primary amine.Reaction mixture is heated about 4 hours to about 100 ℃ under microwave radiation.Separated and the purifying of product formula 711 compounds.
Reaction process 7
Reference reaction flow process 7, step 1 use the known in the art and following method activated zinc powder that further describes in an embodiment at anhydrous and the polar aprotic solvent of the degassing such as the suspensoid among the DMF.Under nitrogen, glycol dibromide is added in this zinc powder solution.Use heating gun with about 30 seconds of this mixture heating up, in gas begins by solution, produce, show the activation of zinc.Make this mixture be cooled to room temperature, add TMSCl subsequently, at room temperature stirred then 30 minutes.Adding type 701 compounds are in the polar aprotic solvent such as the solution among the DMF of anhydrous and the degassing in this zinc solution, and this reaction mixture at room temperature stirred 1 hour.702 solution is used for next step.
Reference reaction flow process 7, step 2, adding type 703 compounds are at polar aprotic solvent such as the solution among the DMF and palladium catalyst and part such as Pd2 (dba3) and tri-o-tolyl the phosphine anhydrous and degassing in 702 solution.Reaction mixture stirred 3 hours.Separated and the purifying of product formula 704 compounds.
After the preparation, chemical of the present invention can be used for various relating in the mitotic application of change.It will be appreciated by persons skilled in the art that mitotic division can change by several different methods; That is to say, can change by the activity that increases or reduce the component in the mitotic division approach.Different is that mitotic division can be by suppressing or activate some component to disturb its balance to influence (as destroyed).Similarly method also can be used for changing reduction division.
In some specific embodiments, chemical of the present invention is used to suppress the formation of mitotic spindle, causes prolonging in the mitotic division cell cycle thus to stop.Be meant the formation of reduction or interference mitotic spindle or make mitotic spindle generation dysfunction at this used term " inhibition ".Be meant by mitotic kinesins at this used term " formation of mitotic spindle " microtubule is combined into dipolar configuration.Be meant that at this used term " mitotic spindle dysfunction " mitotic division stops.
Chemical of the present invention can be used for combining with mitotic kinesins and/or suppressing its activity.In one embodiment, mitotic kinesins is people's a mitotic kinesins, but also can make compound combination or inhibition derive from the mitotic kinesins of other biological body.In the present invention, " inhibition " is meant that increasing or reduce spindle pole separates, and causes the deformity (as opening) of mitotic division spindle pole, perhaps mitotic spindle produced form and disturbs.For this purpose, also comprise these proteic variant and/or fragments in the definition of mitotic kinesins, more especially this proteic motion field.
Chemical of the present invention is used for the treatment of cell proliferation disorders.The morbid state of available chemical treatment of the present invention includes but not limited to the proliferation function that cancer (further as described below), autoimmune disease, fungal disease, sacroiliitis, transplant rejection, inflammatory bowel disease, medical procedure (including but not limited to operation, angioplasty etc.) bring out.Treatment comprises the inhibition cel l proliferation.Be understandable that in some cases, cell might not be to be in error state (ERST), and still need treatment.Therefore, in some specific embodiments, the present invention includes the cell that is applied to suffer from one of these diseases or individual or prevent that it from suffering from one of these diseases.
Chemical of the present invention, composition and method are considered to useful especially for the treatment cancer, comprise solid tumor, as skin, mammary gland, brain, cervical cancer, carcinoma of testis etc.More specifically, medicable cancer includes but not limited to:
The heart: sarcoma (angiosarcoma, fibrosarcoma, rhabdosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma;
Lung: bronchogenic carcinoma (squamous cell, do not break up minicell, do not break up maxicell, gland cancer), alveolar (bronchiole) cancer, bronchial adenoma, sarcoma, lymphoma, cartilage progonoma, mesothelioma;
Gi tract: oesophagus (squamous cell carcinoma, gland cancer, leiomyosarcoma, lymphoma), stomach (cancer, lymphoma, leiomyosarcoma), pancreas (ductal pancreatic adenocarcinoma, nesidioblastoma, glucagonoma, gastrinoma, carcinoid tumor, Vipoma), small intestine (gland cancer, lymphoma, carcinoid tumor, kaposi's sarcoma, leiomyoma, vascular tumor, lipoma, neurofibroma, fibroma), large intestine (gland cancer, pipe adenoma, fine hair adenoma, progonoma, leiomyoma);
Genitourinary tract: kidney (gland cancer, wilms' tumor [nephroblastoma], lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transition cell cancer, gland cancer), prostate gland (gland cancer, sarcoma), testis (spermocytoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, mesenchymal cell cancer, fibroma, fibroadenoma, adenoma sample tumour, lipoma);
Liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, adenoma, vascular tumor;
Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple spinal cord knurl, pernicious giant cells tumour chordoma, chondrosteoma (osteocartilaginous exostosis), optimum chondroma, chondroblastoma, chondromyxoid fibroma, osteoid osteoma and giant cells tumour;
Neural system: skull (osteoma, vascular tumor, granuloma, vitiligoidea, osteitis deformans), meninx (meningioma, meningosarcoma, neurogliosis), brain (astrocytoma, medulloblastoma, neurospongioma, chamber tuberculation, germinoma (pinealoma), glioblastoma multiforme, Oligodendroglioma, schwannoma, retinoblastoma, congenital tumor), notochord (neurofibroma, meningioma, neurospongioma, sarcoma);
Gynaecology: uterus (uterus meninx cancer), uterine cervix (uterine cervix heteroplasia before cervical cancer, the tumour), ovary (ovarian cancer [serocyst gland cancer, pseudomucinous cystadenocarcinoma, non-classified cancer], granulosa-theca cell tumour, Sai Ertuoli-Leydig cell tumour, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, gland cancer, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, grape bunch shape sarcoma [embryonal rhabdomyosarcoma]), uterine tube (cancer);
Blood: blood (myelocyte sample leukemia [acute and chronic], acute lymphoblastic leukemia, lymphocytic leukemia, marrow and bone marrow proliferative disease, multiple myeloma, myelodysplasia syndromes), Hodgkin, non Hodgkin lymphoma (malignant lymphoma);
Skin: malignant melanoma, rodent cancer, squamous cell carcinoma, kaposi's sarcoma, mole dysplastic nevus, lipoma, vascular tumor, dermatofibroma, keloid, psoriasis; And
Body of gland: neuroblastoma.
As used in this, treatment for cancer comprises the cancer cells treatment, comprises the cell that is subjected to any aforesaid illness influence.Therefore, comprise the cell that is subjected to any aforesaid illness influence at this used term " cancer cells ".
Another useful aspect of the present invention is to have at least a said chemical, and the test kit of packing inset or other labels, and described packing inset or other labels comprise the indication for the treatment of cell proliferation disorders by at least a chemical of effective dosage.At least a chemical in the present invention's test kit is one or more dosage that provides especially during the treatment that is used as cell proliferation disorders, and each dosage is the pharmaceutical preparation that comprises drug excipient and at least a chemical described herein.
Regulate active analysis for mitotic kinesins, mitotic kinesins or chemical of the present invention be non-can being combined on the insoluble carrier diffusely usually, and this carrier has sample region of acceptance (as microtiter plate, array (array) etc.) separately.Insoluble carrier can be made in conjunction with material thereon by any compound of the present invention, is easy to separate with soluble material, perhaps matches with total screening method.The surface of these carriers can be a solid or porous, and can be Any shape.The example of suitable insoluble carrier comprises microtiter plate, array, film and pearl.These materials are normally by glass, plastics (as polystyrene), polysaccharide, nylon or Nitrocellulose, Teflon
TMDeng making.Microtiter plate and array are especially easily, because use a spot of reagent and sample can carry out a large amount of tests simultaneously.The concrete combination of The compounds of this invention is not critical, needs only itself and reagent and total method of the present invention and is complementary, and keeps the active of sample and can not spread getting final product.Preferred combining method comprises that use antibody is (when protein bound is on carrier, it can three-dimensional ground block ligand binding site or activation sequences), directly be combined on " viscosity " or the ionophore chemically crosslinked, synthetic protein or medicine etc. from the teeth outwards.Behind conjugated protein or medicine, remove excessive not bond material by washing.The sample region of acceptance then can be by being blocked with bovine serum albumin (BSA), casein or other inoculation albumen or the insulation of other materials.
Chemical of the present invention can use separately to suppress the activity of mitotic kinesins.In some specific embodiments, chemical of the present invention mixes with mitotic kinesins, analyzes the activity of mitotic kinesins then.The activity of kinesin is well known in the art, and comprises one or more kinesin activity.The kinesin activity comprises the ability that influences the ATP hydrolysis; The microtubule combination; Slide and polymerization/depolymerization (to the microtubule effect of kinetics); With other combination of proteins of spindle body; With the protein bound that relates in the cell cycle control; Substrate as other enzymes; As kinases or proteolytic enzyme; And specific kinesin cytoactive such as spindle pole separate.
The method of analyzing is well-known (for example referring to people such as Hall (1996), Biophys.J., 71:3467-3476 to those skilled in the art; People such as Turner, 1996, Anal Biochem.242 (1): 20-5; People such as Gittes, 1996, Biophys.J.70 (1): 418-29; People such as Shirakawa, 1995, J.Exp.Biol 198:1809-15; People such as Winkelmann, 1995, Biophys.J.68:2444-53; People such as Winkelmann, 1995, Biophys.J.68:72S).
Also can use the active method of mensuration ATP enzymic hydrolysis as known in the art.Preferably, use is based on the experiment of solution.United States Patent (USP) 6,410,254 (its content is incorporated herein by reference at this) have been described these experiments.Perhaps, use conventional method.For example, can carry out quantitatively the release of the Pi in the kinesin.In a preferred embodiment, ATP enzymic hydrolysis activity experiment uses PCA (perchloric acid) and the Victoria Green WPB reagent (the Victoria Green WPB oxalate of the sour sodium of 8.27mM molybdenum (II), 0.33mM and the Triton X-100 of 0.8mM) of 0.3M.When carrying out this experiment, the cancellation in the cold 0.3M PCA of 90 μ l of the reaction mixture of 10 μ l.Use the phosphoric acid salt standard substance, so can be the inorganic phosphate that mM discharged with data conversion.When all reactants and standard substance all during cancellation, add the Victoria Green WPB reagent of 100 μ l in the associated orifices of for example microtiter plate in PCA.Make mixture colour developing 10-15 minute, read the absorbancy of plate then at the 650nm place.If use the phosphoric acid salt standard substance, then the absorbancy reading can be converted into mM P
i, and the relative time mapping.In addition, ATP enzyme experiment as known in the art comprises the luciferase experiment.
The atpase activity of kinesin motion field also can be used for monitoring the effect of medicament.In some specific embodiments, do not having to carry out the experiment of kinesin ATP enzyme in the presence of the microtubule.In some specific embodiments, when having microtubule to exist, carry out the experiment of ATP enzyme.In above-mentioned experiment, can detect dissimilar medicaments.The effect of medicament does not rely on the concentration of microtubule and ATP in some specific embodiments.In some specific embodiments,, can reduce the effect of conditioning agent to kinesin ATP enzyme by increasing ATP, microtubule or the two concentration.In some specific embodiments,, can increase the effect of medicament by increasing ATP, microtubule or the two concentration.
The chemical of the biochemical activity of vitro inhibition mitotic kinesins can be followed in vivo and screen.Intravital screening method comprises the experiment of existence, form, activity, distribution or the amount of relevant cell cycle distribution, cell survival rate or mitotic spindle.For example the method by the distribution of wandering cells meter monitoring cell quantity in the cell cycle is known for those skilled in the art, and the method for measuring cell survival rate also is like this.For example referring to United States Patent (USP) 6,437,115, its content is incorporated herein by reference at this.The monitoring formation of spindle body and odd-shaped microscopy also are known (for example referring to Whitehead and Rattner (1998), J.Cell Sci.111:2551-61 for those skilled in the art; People such as Galgio, (1996) J.Cell Biol., 135:399-414), the full content in the document is incorporated herein by reference at this.
Chemical of the present invention suppresses mitotic kinesins.Inhibiting one to measure be IC
50, its activity that is defined as KSP is lowered 50% o'clock compound concentration with respect to contrast.In some specific embodiments, the IC of at least a chemical
50Preferably be lower than about 1mM.In some specific embodiments, the IC of at least a chemical
50Be lower than about 100 μ M.In some specific embodiments, the IC of at least a chemical
50Be lower than about 10 μ M.In some specific embodiments, the IC of at least a chemical
50Be lower than about 1 μ M.In some specific embodiments, the IC of at least a chemical
50Be lower than about 100nM.In some specific embodiments, the IC of at least a chemical
50Be lower than about 10nM.IC
50Measurement carry out with for example ATP enzyme described here experiment.
Another inhibiting measuring is K
iTo IC
50Be lower than the chemical of about 1 μ M concentration, K
iOr K
dBe defined as the interactional dissociation rate constant of said compound and mitotic kinesins.In some specific embodiments, at least a chemical has K
iBe lower than about 100 μ M concentration.In some specific embodiments, at least a chemical has K
iBe lower than about 10 μ M concentration.In some specific embodiments, at least a chemical has K
iBe lower than about 1 μ M concentration.In some specific embodiments, at least a chemical has K
iBe lower than about 100nM concentration.In some specific embodiments, at least a chemical has K
iBe lower than about 10nM concentration.
The K of chemical
iBe by IC according to three hypothesis and Michaelis-Menten equation
50Measure.The first, only a compound molecule is combined on the enzyme, and does not have cooperative.The second, the concentration of organized enzyme and test compounds are known (impurity or the inactivation forms that for example, do not have significant quantity in preparation).The 3rd, the enzymatic speed of enzyme-inhibitor complex is zero.The data fitting of speed (being compound concentration) is in following equation:
Wherein: V observes speed, V
MaxBe the speed of resolvase, I
0Be inhibitor concentration, E
0Be enzyme concn, and K
dIt is the dissociation constant of enzyme-inhibitor complex.
Inhibiting another measured and is GI
50, be defined as and cause cell growth rate to reduce by 50% o'clock chemical concentration.In some specific embodiments, at least a chemical has GI
50Be lower than about 1mM concentration.。In some specific embodiments, at least a chemical has GI
50Be lower than about 20 μ M concentration.In some specific embodiments, at least a chemical has GI
50Be lower than about 10 μ M concentration.In some specific embodiments, at least a chemical has GI
50Be lower than about 1 μ M concentration.In some specific embodiments, at least a chemical has GI
50Be lower than about 100nM concentration.In some specific embodiments, at least a chemical has GI
50Be lower than about 10nM concentration.GI
50Measure by using cell proliferation experiment for example described here.Find that such chemical suppresses cell proliferation.
The vitro efficacy of micromolecular inhibitor is for example to measure in the survival rate of compound after 72 hours of a series of 9 somes dilutions of contact by analyst's ovarian cancer cell (SKOV3).Cell survival rate is that the absorbancy of the product formazon that forms when measuring biological reducing commercial reagent MTS/PMS is measured.Each point that is calculated on dosage-response curve is that the percentage ratio subtracting background of undressed control cells in the time of 72 hours absorbs (cell kills fully).
The anti-proliferative compounds (cancer chemotherapeutic agent) that successfully is used for the treatment of cancer in clinical has the bigger GI of variation
50For example, in the A549 cell, taxol GI
50Be 4nM, Dx is 63nM, and 5 FU 5 fluorouracil is 1 μ M, and hydroxyurea be 500 μ M (data are by National Cancer Institute, and Developmental TherapeuticProgram provides,
Http:// dtp.nci.nih.gov/).Therefore, suppress the compound of cell proliferation, no matter whether this concentration shows restraining effect, all has the potential clinical application.
Being used for screening when using chemical of the present invention in conjunction with the method for the compound of mitotic kinesins, mitotic kinesins is combined on the carrier, in experiment, add compound of the present invention then.Perhaps, chemical of the present invention is combined on the carrier, adds mitotic kinesins then.The non-natural wedding agent that the compounds category that can seek new wedding agent therein comprises specific antibody, differentiated in chemical library screening, peptide analogs etc.Filter out that to have hypotoxic drug candidate for people's cell be the useful especially aspect of screening experiment.Can use kinds of experiments for this purpose, the protein-protein that comprises external mark is in conjunction with experiment, and electrophoresis movability displacement experiment is used for protein bound immunization experiment, functional group's experiment (phosphorylation experiment etc.), or the like.
Can several different methods measure combining of chemical of the present invention and mitotic kinesins.In preferred embodiments, compound of the present invention for example with fluorescence or radioactivity group mark, is directly measured combination then.For example, this can followingly carry out: mitotic kinesins used or part is connected on the solid carrier, interpolation is through the test compounds of mark (for example wherein the The compounds of this invention replaced by detectable isotropic substance of at least one atom), wash away excessive reagent, measure the amount of the marker that exists on the solid carrier then.
Term used herein " mark " is meant compound directly or indirectly with the marker mark that detection signal can be provided, and described marker for example is emitting isotope, fluorescent mark, enzyme, antibody, particle (as magnetic-particle), chemiluminescent labeling or specific binding molecules etc.Specific binding molecules comprises a pair of material, as vitamin H and streptavidin, and digoxin and anti-digoxin etc.For specificity junction mixture, according to aforesaid currently known methods, complementary square tube molecule normal and to be detected combines.Marker can be directly or detectable signal is provided indirectly.
In some specific embodiments, one of them compound of mark only.For example, available
125I or fluorophore are at tyrosine position mark kinesin.Perhaps, with the different more than one components of marker mark, for example protein is used
125I, and antimitotic agent fluorophore.
Competitor when chemical of the present invention also can be used as other drug candidates of screening.The speech that is equal on this used term " drug candidate " or " drug candidate person " or grammer is meant its bioactive any molecule to be detected, as protein, oligopeptides, little organic molecule, polysaccharide, polynucleotide etc.They can be directly or change the expression of cell proliferation phenotype or cell proliferation sequence indirectly, and described cell proliferation sequence comprises nucleotide sequence and protein sequence.In other cases, screening changes cell proliferation protein binding and/or activity.The screening of the type can be carried out when having or do not have microtubule to exist.In the screening protein binding or when active, embodiment preferred do not comprise any known can be in conjunction with concrete proteic molecule, for example polymer architecture (as microtubule) and energy source (as ATP).The preferred embodiment of experiment is included in the drug candidate (being called " exogenous " medicine at this) of debond molecule proliferin under its endogenous native state.In some specific embodiments, exogenous medicine is further got rid of the antibody of mitotic kinesins.
Drug candidate can comprise the chemical class of plurality of classes, but normally molecular weight is the daltonian little organic molecule of 100-2500.Drug candidate comprises and proteic structural interaction necessary functional group, particularly hydrogen bond and lipotropy bonded functional group that it comprises amine, carbonyl, hydroxyl, ether or carboxyl usually at least, has two at least in the preferred functional group.Drug candidate often comprises ring-type carbon or heterocycle structure and/or fragrance or many aromatic structures, and they are replaced by one or more above-mentioned functional group.Drug candidate also can be selected in biomolecules, and described biomolecules comprises peptide, sugar, lipid acid, steroidal compounds, purine, pyrimidine and their derivative, analog or combination.
Drug candidate is that the multiple source by the library that comprises synthetic or natural compounds obtains.For example, at random multiple mode can be arranged, and relate to the synthetic of multiple organic compound and biomolecules, comprise the expression of random oligonucleotide.Perhaps, the natural compounds library of bacterium, fungi, plant and animal form of extract also can utilize or be easy to generate.In addition, natural or synthetic library and compound can be easily chemistry, physics and biochemical method by routine carry out modification.Known drug can be carried out specific aim or chemical modification at random, as acylations, alkylation, esterification, amidation, to produce analog.
Competitive screening experiment can be undertaken by mixing mitotic kinesins and drug candidate in first sample.Second sample comprises chemical of the present invention, mitotic kinesins and drug candidate.This can carry out when having or do not have microtubule to exist.Measure the drug candidate combination in these two samples, and between two samples in conjunction with changing or difference shows that existence can be in conjunction with mitotic kinesins and its active medicine of potential inhibition.That is to say,, show that then drug candidate can be in conjunction with mitotic kinesins if the combination of drug candidate is different from first sample in second sample.
In some specific embodiments, drug candidate is by using competitive binding experiment to measure with combining of mitotic kinesins.In some specific embodiments, competitor is known and mitotic kinesins bonded binding substance, as antibody, peptide, binding partners, part etc.In some cases, for example between drug candidate and binding substance,, can there be competitive combination with binding substance replacement candidate medicine.
In some specific embodiments, drug candidate is through mark.Two of this drug candidate or competitor or they at first are added in the mitotic kinesins, and its time is enough to carry out combination.Can under any temperature that helps optimum activity, be incubated, usually between 4-40 ℃.
The time of insulation is selected according to optimum activity, but also can carry out optimizing, to help high fast output screening.Usually 0.1-1 hour is enough.Excessive reagent is removed usually or washes off.Then adding second component, is the component that has or do not pass through mark, to show combination then.
In some specific embodiments, at first add competitor, add drug candidate then.The replacement of competitor be drug candidate combine with mitotic kinesins and thus can in conjunction with and the active index of potential inhibition mitotic kinesins.In this embodiment, component can be carried out mark.Therefore, for example,, replaces competitor if through mark, then existing marker to show by medicine in washing soln.Perhaps, if drug candidate is labeled, on carrier, exists marker to show and replace.
In some specific embodiments, drug candidate at first adds, and is incubated and washs, and is competitor then.Do not exist the combination of competitor to show that drug candidate combines with mitotic kinesins with higher affinity.Therefore,, on carrier, there is marker, do not have the combination of competitor, might show that drug candidate can combine with mitotic kinesins if drug candidate is a mark.
Restraining effect can suppress the active drug candidate of mitotic kinesins by screening and test, it may further comprise the steps: mix drug candidate and mitotic kinesins as mentioned above, measure the bioactive variation of mitotic kinesins then.Therefore, in this embodiment, drug candidate should combine (though this not necessarily) with mitotic kinesins, and changes its biology or biochemical activity in this definition.This method comprises sieve method in cells in vitro sieve method and the body, comprising cell cycle distribution, cell survival rate, mitotic spindle whether exist, the variation of form, activity, distribution or amount.
Perhaps, can use different screenings, with identify combine with natural mitotic kinesins but not with modification mitotic kinesins bonded drug candidate.
Can in experiment, use positive control and negative control.Suitably, all contrasts and specimen are all carried out three times at least, to obtain the significant result of statistics.The soaking time of all samples should be enough to make medicine and protein bound.After insulation, wash all samples, making does not have the material of non-specific binding, measure then in conjunction with and also the amount of the medicine that is labeled usually.For example, when using radioactively labelled substance, sample can be counted in scintillometer, to measure the amount of binding compounds.
In screening experiment, can comprise multiple other reagent.These reagent comprise for example salt, neutral protein matter (as albumin), washing composition etc., and they can help best protein-protein combination and/or reduce non-specific or the background interaction.Also can use the reagent that can improve service efficiency, as proteinase inhibitor, nucleic acid inhibitor, microbicide etc.Can any order add the mixture of component, so that required combination to be provided.
Therefore, chemical of the present invention can deliver medicine to cell.Term " administration " is the chemical at least a of the present invention that points to the cell drug treatment significant quantity among cell culture medium and the patient.Term " treatment significant quantity " is meant can be to the dosage of the individual generation effect of administration.Accurate dose depends on therapeutic purpose, and can be determined by known method by those skilled in the art.Well-known in the artly be, must be according to whole body and topical, age, body weight, total healthy state, sex, diet, administration time, the interaction of medicine and the severity of disease, dosage is adjusted, and can be determined with conventional experiment by those skilled in the art.Be meant at this used term " cell " and can change wherein mitotic division or maiotic any cell.
In the present invention, " patient " comprises people and other animals (particularly Mammals) and other biological body.Therefore, method of the present invention can be applicable in people's the treatment and veterinary applications.In preferred embodiments, the patient is a Mammals, and in the most preferred embodiment, the patient is the people.
In some specific embodiments, the chemical of the present invention with desirable pharmacologically active can comprise the form administration of the pharmaceutical composition of acceptable carrier on the pharmacology in the patient.According to the mode of introducing, compound of the present invention can several different methods as described below be prepared.The concentration of therapeutical active compound in preparation can be 0.1-100 weight %.
Medicine can be separately or with other treatment (as radiotherapy) or other chemotherapeutics (as if act on taxone that microtubule forms or as the camptothecine of topoisomerase I inhibitor) combination carries out.If use, the administration of other chemotherapeutics can be before at least a chemical administration of the present invention, simultaneously or carry out afterwards.In one aspect of the invention, at least a chemical of the present invention and one or more other chemotherapeutic co-administereds.Term " co-administered " is meant that at least a chemical of the present invention delivers medicine to the patient, make the compound of compound of the present invention and co-administered can be present in patient's the blood simultaneously, no matter these compounds are actually suitable administration, comprise administration simultaneously.
Chemical of the present invention can carry out administration by number of ways, include but not limited in oral, subcutaneous, intravenously, the nose, in the transdermal, intraperitoneal, intramuscular, lung, vagina, rectum or intraocular.In some cases, for example when treatment wound and inflammation, compound of the present invention or composition can be directly with solution or sprays administrations.
Pharmaceutical dosage form comprises at least a chemical described here and one or more pharmaceutical excipients.As known in the art, pharmaceutical excipient is an ancillary component, and its function is to impel or promote various formulations (for example: oral dosage form such as tablet, capsule and liquid; Topical formulations such as skin, eyes and ear formulation; Suppository; Injection; Breathing is with formulation etc.) medicament or the sending of medicine.Pharmaceutical excipient comprises inertia or non-active ingredient, synergistic agent or helps the chemical substance of the medical effect of activeconstituents in fact.For example, pharmaceutical excipient can be used to improve flow performance, product homogeneity, stability, taste or outward appearance, so that dose operation and administration are easy, thereby convenient the use perhaps controlled bioavailability.Though pharmaceutical excipient often is described to inertia or non-activity, can recognize in the character of pharmaceutical excipient in the art and contain between their formulation to have certain relation.
Be suitable for the pharmaceutical excipient of making carrier or thinner and be well known in the art, and be used for multiple formulations.For example referring to Remington ' s Pharmaceutical Sciences, the 18th edition, A.R.Gennaro edits, MackPublishing Company (1990); Remington:The Science and Practice of Pharmacy, the 20th edition, A.R.Gennaro, editor, Lippincott Williams ﹠amp; Wilkins (2000); Handbook of PharmaceuticalExcipients, the 3rd edition, A.H.Kibbe edits, American Pharmaceutical Association, andPharmaceutical Press (2000); With Handbook of Pharmaceutical Additives, compiled byMichael and Irene Ash, Gower (1995), more than each document all be hereby incorporated by.
Oral dosage form such as tablet comprise one or more pharmaceutical excipients usually, and they for example can help to give gratifying processing and compressive features, perhaps provide additional required physical features to tablet.These pharmaceutical excipients can be selected from thinner, tackiness agent, glidant, lubricant, disintegrating agent, tinting material, seasonings, sweeting agent, polymkeric substance, wax or other delay dissolved substances.
The composition that is used for intravenous administration generally comprises intravenous fluid, and promptly simple chemical substance is as sugar, amino acid or electrolytical sterile solution, and they can easily be recycled system and send and digest these liquid and can prepare with injection USP water.
The composition that is used for parenteral administration generally comprises intravenous fluid, and promptly simple chemical substance is as sugar, amino acid or electrolytical sterile solution, and they can easily be recycled system and send and digest.These liquid can prepare with injection USP water.The liquid that is usually used in intravenously (IV) is disclosed in Remington, the complete quoted passage that the Science and Practice ofPharmacy[provides previously] in, and comprise:
Alcohol, for example 5% alcohol (for example the D/W in dextrose and water (" D/W ") or in normal saline solution (" NSS ") is included in 5% dextrose and the water (" D5/W "), or the D5/W in NSS);
Synthesizing amino acid such as amino syn, FreAmine, Travasol for example are respectively 3.5 or 7; 8.5; 3.5,5.5 or 8.5%;
Ammonium chloride, for example 2.14%;
Gentran 40, in NSS, for example 10%, perhaps in D5/W, for example 10%;
Macrodex, in NSS, for example 6%, perhaps in D5/W, for example 6%;
Dextrose (glucose, D5/W), 2.5-50% for example;
Dextrose and sodium-chlor, for example 5-20% dextrose and 0.22-0.9%NaCl;
Lactic acid Ringer ' s (Hartmann ' s), for example NaCl 0.6%, KCl 0.03%, CaCl
20.02%;
Lactic acid salt 0.3%;
Mannitol, for example 5%, optional and dextrose, for example 10%, perhaps NaCl, for example 15 or 20% combination;
The multiple electrolyte solution that contains the various combination of ionogen, dextrose, fructose, Nulomoline Ringer ' s, for example NaCl 0.86%, KCl 0.03%, CaCl
20.033%;
Sodium bicarbonate, for example 5%;
Sodium-chlor, for example 0.45,0.9,3 or 5%;
Sodium.alpha.-hydroxypropionate, for example 1/6M; With
Sterile water for injection.
The pH of these liquid can change, and as known in the art, between 3.5-8, change usually.
Chemical of the present invention can be individually dosed or with the other treatment combination, other treatment for example is radiation or other treatment agent, as the medicine of taxanes, it occurs is to act on microtubule to form; Or the topology isomerase I inhibitor of camptothecin.When so employed, the other treatment medicine can be before the present invention's active medicine administration, (no matter dosage form or unitized dose form) respectively or administration afterwards simultaneously.
Following examples are used for describing in more detail the mode of the present invention of implementing, and the best mode of implementing each side of the present invention.It should be understood that these embodiment never are the restrictions to true scope of the present invention, and only be to be used for illustration purpose.All be incorporated herein by reference in full at these all reference of quoting.
Embodiment
Following examples are used for describing in more detail the mode of the present invention of implementing, and the best mode of implementing each side of the present invention.It should be understood that these embodiment never are the restrictions to true scope of the present invention, and only be to be used for illustration purpose.All be incorporated herein by reference in full at these all reference of quoting.
Embodiment 1
To the 4-isopropoxy phenylformic acid in DMF (150 milliliters) (25 grams, 140 mmoles) solution, add NCS (24 grams, 182 mmoles).Reaction mixture is stirred and spends the night.H
2O (500 milliliters) is added in the reaction mixture.Precipitation is collected and with water washing, and dry under vacuum, is produced as 2 (26.4 grams, 88%) of white solid, and it is used in next step and does not have and be further purified.LRMS(M+H
+)m/z 213.0。
2 (20 grams, 93 mmoles) solution in DCM adds five fluorine triflutates (20 milliliters, 112 mmoles) and triethylamine (17 milliliters, 112 mmoles) down at 0 ℃.Solution is concentrated, and mixture is produced as 3 (35 grams, full doses) of white solid with flash column chromatography analysis (100%DCM) purifying.LRMS(M+H
+)m/z 586.3。
To 3 solution in DMF (2.0 volumetric molar concentration), add amino acid (1.2 equivalent) and N, N-diisopropyl ethyl amine (3 equivalent).Reaction is monitored with LC/MS.When finishing, methylamine (2 volumetric molar concentrations in THF, 1.5 equivalents) and HBTU (1.5 equivalent) are added in the reaction soln.Reaction mixture stirred 4 hours.Product is analyzed purifying with HPLC or flash column chromatography, produces 4.
Embodiment 2
To H-Phe-(the 4-Br)-OH in DMF (20 milliliters) (2,2.5 grams, 10 mmoles) solution, at room temperature add 3 (4.7 grams, 12 mmoles) and diisopropyl ethyl amines (5.4 milliliters, 30 mmoles).Reaction mixture is monitored with LC/MS.When finishing, methylamine (2 volumetric molar concentrations in THF, 7.7 milliliters, 15 mmoles) and HBTU (5.8 milliliters, 15 mmoles) are added in the reaction soln.Reaction mixture is stirred 2 days.Mixture is filtered, and filtrate is with RP-HPLC, use acetonitrile and H
2The O purifying mixture produces 4 (2.3 grams, 50%).LRMS(M+H
+)m/z 455.0。
To (71 milligrams of 4 in the Zai dioxs (1 milliliter), 0.16 suspension mmole), add (16 milligrams of piperazines, 0.19 milli palladium (II) (4 milligrams, 0.016 dicyclohexyl phosphino--2 '-(N mmole),, N '-dimethylamino)-xenyl (6 milligrams, 0.016 mmole) and cesium carbonate (104 milligrams, 0.32 mmole).The gained mixture stirred 36 hours down at 110 ℃.Reaction mixture dilutes with EtOAc.Organic layer is with saturated NaHCO
3(20 milliliters) and salt water washing, at Na
2SO
4Last dry and concentrated.Resistates is with RP-HPLC, use acetonitrile and H
2The O purifying mixture produces 1a (6 milligrams, 8%).LRMS(M+H
+)m/z 459.2。
Embodiment 3
To the H-Tyr-NH in DMF (5 milliliters)
2HCl (2,830 milligrams, 3.8 mmoles) solution at room temperature adds 3 (1.8 grams, 4.5 mmoles) and diisopropyl ethyl amines (3.4 milliliters, 19 mmoles).Reaction is stirred 20 hours, and filters after adding water.White precipitate is recrystallize in DCM and methyl alcohol, is produced as 4 (1.120 grams, 78%) of white crystals.LRMS(M+H
+)m/z 377.1。
To 4 (50 milligrams, the 0.13 mmole) solution in DMF (1 milliliter), add (s)-(+)-3-bromo-2-methyl isophthalic acid-propyl alcohol (0.083 milliliter, 0.8 mmole) and salt of wormwood (110 milligrams, 0.8 mmole).The gained mixture is stirred 15 hours under 0 ℃.Mixture is filtered, and filtrate is with RP-HPLC, use acetonitrile and H
2The O purifying mixture produces 1b (30 milligrams, 51%).LRMS(M+H
+)m/z 499.1。
Embodiment 4
To the H-Tyr-OBut in DMF (50 milliliters) (2,1.9 grams, 8 mmoles) solution, at room temperature add 3 (2.4 grams, 6.2 mmoles) and diisopropyl ethyl amines (3.3 milliliters, 19 mmoles).Reaction is stirred 2 hours.Gained solution dilutes with EtOAc (200 milliliters), and with saturated NaHCO
3(50 milliliters) washing.Organic layer is separated, with the salt water washing, at Na
2SO
4Last dry and concentrated, produce yellow solid.Yellow solid in methylene dichloride (10 milliliters) is added trifluoracetic acid (30 milliliters).Mixture at room temperature stirs 12 hours, and under reduced pressure is concentrated then.Resistates is dry in a vacuum, produces 4 (3.1 grams), and it is used in next step and does not have and be further purified.LRMS(M+H
+)m/z 376.1。
4 (3.1 grams, 8 mmoles) solution in DMF (25 milliliters) adds G-NH2 (3.6 grams, 9.6 mmoles), diisopropyl ethyl amine (7 milliliters, 40 mmoles) and HBTU (3.6 grams, 9.6 mmoles).Reaction mixture is stirred 15 hours, and solution dilutes with vinyl acetic monomer afterwards, and with saturated NaHCO
3Washing.Organic layer is separated, with the salt water washing, at Na
2SO
4Last dry and concentrated.The rough thing of gained on RP-HPLC, use acetonitrile and H
2The O purifying mixture produces 5 (38 milligrams, 35%).LRMS(M+H
+)m/z 434.1。
To 5 (100 milligrams, the 0.23 mmole) solution in DMF (1 milliliter), add cyclopropyl monobromomethane (0.18 milliliter, 1.84 mmoles) and salt of wormwood (317 milligrams, 2.3 mmoles).The gained mixture is stirred 10 hours under 80 ℃.Mixture is filtered, and filtrate on RP-HPLC, use acetonitrile and H
2The O purifying mixture produces 1c (36 milligrams, 34%).LRMS(M+H
+)m/z 488.1。
Embodiment 5
To 4 (80 milligrams, the 0.2 mmole) solution in DMF (1 milliliter), add (±)-3-bromo-1-phenyl-2-tetrahydro pyrrolidine ketone (250 milligrams, 1 mmole) and salt of wormwood (235 milligrams, 1.7 mmoles).The gained mixture is stirred 10 hours under 110 ℃.Mixture is filtered, and filtrate on RP-HPLC, use acetonitrile and H
2The O purifying mixture produces 5 (38 milligrams, 35%).LRMS(M+H
+)m/z 536.1。
Embodiment 6
To 4 (70 milligrams in DMF (1 milliliter), 0.19 solution mmole) adds (100 milligrams of 3-(hydroxymethyl) pyridine (0.023 milliliter, 0.23 mmole), triphenylphosphines, 0.38 mmole) and di-isopropyl azodicarboxylate (0.055 milliliter, 0.38 mmole).The gained mixture at room temperature is stirred 20 hours.Reaction mixture is filtered, and via the flash column chromatography analysis, use vinyl acetic monomer and hexanes mixtures to be the elutriant purifying, produce 1f (22 milligrams, 25%).LRMS(M+H
+)m/z 468.2。
Embodiment 7
To 4 (50 milligrams in toluene (2 milliliters), 0.12 solution mmole) adds (42 milligrams of 2-(fluorophenyl) boric acid (20 milligrams, 0.14 mmole), four (triphenylphosphine) palladiums (0), 0.04 mmole) and 2 volumetric molar concentration yellow soda ash (0.18 milliliter, 0.36 mmole).Reaction mixture is stirred 90 minutes under 100 ℃.Gained solution on RP-HPLC, use acetonitrile and H
2The O purifying mixture produces 5 (22 milligrams, 40%).LRMS(M+H
+)m/z 469.2。
Embodiment 8
To 4 (45 milligrams in DMF (1 milliliter), 0.1 solution mmole), add (30 milligrams of two (pyrrole any acid (pinacolate)) two boron, 0.12 mole), 1, (17 milligrams in 1 '-two (diphenylphosphino) ferrocene-palladium chloride (II) methylene dichloride complex compound, 0.02 mmole) and Potassium ethanoate (39 milligrams, 0.4 mmole).Reaction mixture is stirred 1 hour under 80 ℃.The gained mixture is added 4-bromo-3,5-dimethyl isoxazole (35 milligrams, 0.2 mmole) and 2 volumetric molar concentration yellow soda ash (0.4 milliliter, 0.8 mmole).Reaction mixture is stirred 90 minutes under 80 ℃.The gained resistates is filtered, and filtrate on RP-HPLC, use acetonitrile and H
2The O purifying mixture produces 1h (23 milligrams, 49%).LRMS(M+H
+)m/z 470.1。
Embodiment 9
To 4 (62 milligrams in DMF (1 milliliter), 0.14 solution mmole), add (42 milligrams of two (pyrrole any acid) two boron, 0.16 mole), 1, (34 milligrams in 1 '-two (diphenylphosphino) ferrocene-palladium chloride (II) methylene dichloride complex compound, 0.04 mmole) and Potassium ethanoate (54 milligrams, 0.55 mmole).Reaction mixture is stirred 1 hour under 80 ℃.The gained mixture is added N-methyl-2-bromobenzene and imidazoles (58 milligrams, 0.27 mmole) and 2 volumetric molar concentration yellow soda ash (0.54 milliliter, 1.08 mmoles).Mixture is stirred 60 minutes under 80 ℃.Gained solution dilutes with vinyl acetic monomer (20 milliliters), and with saturated NaHCO
3(20 milliliters) washing.Organic layer is separated, with the salt water washing, at Na
2SO
4Last dry and concentrated.The gained resistates on RP-HPLC, use acetonitrile and H
2The O purifying mixture produces 1i (44 milligrams, 64%).LRMS(M+H
+)m/z 505.1。
Embodiment 10
To 4 (50 milligrams in DMF (1 milliliter), 0.13 the solution Bo mole), add (34 milligrams of two (pyrrole any acid) two boron, 0.13 mole), 1, (27 milligrams in 1 '-two (diphenylphosphino) ferrocene-palladium chloride (II) methylene dichloride complex compound, 0.03 mmole) and Potassium ethanoate (43 milligrams, 0.44 mmole).Reaction mixture is stirred 1 hour under 80 ℃.The gained mixture is added 3-bromine fen-2-carbon (41 milligrams, 0.22 mmole) and 2 volumetric molar concentration yellow soda ash (0.44 milliliter, 0.88 mmole).Mixture is stirred 90 minutes under 80 ℃.The gained resistates is filtered, and filtrate is with RP-HPLC, use acetonitrile and H
2The O purifying mixture produces 5 (20 milligrams, 37%).LRMS(M+H
+)m/z 482.1。
Embodiment 11
To 4 (85 milligrams in toluene (2 milliliters), 0.2 solution mmole), add the 1-tertiary butyl-1, (53 milligrams of 3-dihydro-imidazol-s-2-ketone, 0.4 mmole), cuprous iodide (I) (18 milligrams, 0.1 mmole), anti--1, (11 milligrams of 2-diamino-hexanaphthenes, 0.1 mmole) and cesium carbonate (124 milligrams, 0.4 mmole).Reaction mixture is stirred 4 hours under 100 ℃.Mixture is filtered, and filtrate is with RP-HPLC, use acetonitrile and H
2The O purifying mixture produces 1k (27 milligrams, 28%).LRMS(M+H
+)m/z 513.1。
Embodiment 12
To (100 milligrams of 4 in the Zai dioxs (2 milliliters), 0.2 solution mmole), add (39 milligrams of benzoglyoxalines, 0.33 mmole), cuprous iodide (I) is (8.4 milligrams, 0.04 mmole), 1,10-o-phenanthroline (16 milligrams, 0.1 mmole) and cesium carbonate (144 milligrams, 0.44 mmole).Reaction mixture is stirred 15 hours under 100 ℃.Mixture is filtered, and filtrate is concentrated.The gained resistates is filtered, and filtrate on RP-HPLC, use acetonitrile and H
2The O purifying mixture produces 1l (5.7 milligrams, 6%).LRMS(M+H
+)m/z 491.1。
Embodiment 13
To 4 (60 milligrams, the 0.16 mmole) solution in toluene (1 milliliter), add 2-chloro benzimidazole (50 milligrams, 0.32 mmole), cuprous iodide (I) (9 milligrams, 0.05 mmole) and cesium carbonate (105 milligrams, 0.32 mmole).Reaction mixture is stirred 28 hours under 110 ℃.Mixture is filtered, and filtrate on RP-HPLC, use acetonitrile and H
2The O purifying mixture produces 1m (8 milligrams, 10%).LRMS(M+H
+)m/z493.0。
Embodiment 14
To 4 (50 milligrams, the 0.1 mmole) solution in toluene (1 milliliter), add phenol (21 milligrams, 0.2 mmole), cuprous iodide (I) (6 milligrams, 0.03 mmole) and cesium carbonate (72 milligrams, 0.2 mmole).Reaction mixture is stirred 5 hours under 115 ℃.Mixture is filtered, and filtrate is concentrated.The gained resistates via the flash column chromatography analysis, use vinyl acetic monomer and hexanes mixtures to be the elutriant purifying, produce 1n (23 milligrams, 45%).LRMS(M+H
+)m/z467.1。
Embodiment 15
1 (2.3 grams, 12.6 mmoles) solution in DMF (30 milliliters) adds 2 (4.0 grams, 10.5 mmoles) and N, N-diisopropyl ethyl amine (5.2 milliliters, 30 mmoles).Reaction is monitored with LC/MS.Gained solution is used to next step and does not have be further purified.LRMS(M+H
+)m/z 377.1。
To rough 3 solution in DMF (6 milliliters ,～2 mmoles), add G-NH2 HCl (330 milligrams, 3 mmoles), HBTU (1.14 milligrams, 3 mmoles) and N, N-diisopropyl ethyl amine (522 microlitres, 3 mmoles).Reaction is stirred spends the night.The gained raw product is via RP-HPLC, use acetonitrile and H
2The O purifying mixture produces 4 (600 milligrams is 69% from 2).LRMS(M+H
+)m/z 433.1。
Embodiment 16
To rough 3 solution in DMF (15 milliliters ,～5.25 mmoles), add methylamine (2 volumetric molar concentrations in THF, 4 milliliters, 8 mmoles) and HBTU (3 grams, 7.9 mmoles).Reaction is stirred spends the night.Mixture dilutes with vinyl acetic monomer (200 milliliters).Organic layer is with H
2O, salt water washing, dry and concentrated on sodium sulfate.Gained raw product 5 is used to next step and does not have be further purified.LRMS(M+H
+)m/z 390.1。
To rough 5 solution in DCM (2 milliliters), add benzyl chloride of acid (23 microlitres, 0.2 mmole) and N, N-diisopropyl ethyl amine (35 microlitres, 0.2 mmole).Reaction mixture is stirred and spends the night.Solution is concentrated, and uses acetonitrile and H on RP-HPLC
2The O purifying mixture produces 6 (36 milligrams is 40% from 2).LRMS(M+H
+)m/z 494.1。
Embodiment 17
To 5 (75 milligrams ,～0.2 mmole) solution in DCM (2 milliliters), add phenylcarbimide (26 microlitres, 0.24 mmole).Reaction mixture is stirred and spends the night.Gained solution is concentrated, and on RP-HPLC, use acetonitrile and H
2The O purifying mixture produces 7 (40 milligrams is 39% from 2).LRMS(M+H
+)m/z 509.1。
Embodiment 18
To 5 (75 milligrams, the 0.19 mmole) solution in DCM (3 milliliters), add isobutyl chlorocarbonate (38 microlitres, 0.29 mmole) and N, N-diisopropyl ethyl amine (50 microlitres, 0.29 mmole).Reaction mixture is stirred and spends the night.Solution is concentrated, and on RP-HPLC, use acetonitrile and H
2The O purifying mixture produces 8 (45 milligrams is 48% from 2).LRMS(M+H
+)m/z 490.1。
Embodiment 19
To 5 (75 milligrams, the 0.19 mmole) solution in DCM (5 milliliters), add dimethylamino SULPHURYL CHLORIDE (30 microlitres, 0.29 mmole), N, N-diisopropyl ethyl amine (50 microlitres, 0.29 mmole) and DMAP (50 milligrams, 0.4 mmole).Reaction mixture is stirred and spends the night.Reaction mixture is heated to 30 ℃, and continues to stir 8 hours.Gained solution is concentrated, and on RP-HPLC, use acetonitrile and H
2The O purifying mixture produces 9 (30 milligrams, 30%).LRMS(M+H
+)m/z 497.1。
Embodiment 20
To H-Phe-(the 4-COOtBu)-OH in vinyl acetic monomer (60 milliliters) and water (20 milliliters) (5.8 grams, 22 mmoles) solution, add platinum oxide (IV) (400 milligrams, 1.8 mmoles) and acetic acid (50 milliliters).Reaction mixture is at H
2Stream (60psi) stirred 20 hours down.Filter removes with filtration catalyzer, and solvent evaporation through PTFE (0.45 micron), produces 2 (5.9 grams), and it is used to next step and does not have and be further purified.LRMS(M+H
+)m/z 272.1。
2 (6.9 grams, 18 mmoles) solution in DMF (30 milliliters) adds 3 (5.9 grams, 21.8 mmoles) and diisopropyl ethyl amines (9.5 milliliters, 54.3 mmoles).Reaction is monitored with LC/MS.When finishing, 2 volumetric molar concentration methylamine in THF (13.6 milliliters, 27 mmoles), HOBt (4 grams, 27 mmoles) and HBTU (10 grams, 27 mmoles) are added in the reaction soln.Reaction is stirred 4 hours.Mixture dilutes with vinyl acetic monomer (60 milliliters), and with saturated NaHCO
3(20 milliliters) washing.Organic layer is separated, and water extracts with vinyl acetic monomer (2 * 50 milliliters).Organic layer through merging is with salt water washing, dry and concentrated on sodium sulfate.The gained raw product with the flash column chromatography analysis, use vinyl acetic monomer and hexanes mixtures to be the elutriant purifying, produce 4 (along 808 milligrams on isomer, 1.68 mmoles, 300 milligrams of trans isomers, 0.64 mmoles).LRMS(M+H
+)m/z 481.1。
To the solution of 4 (290 milligrams, 0.6 mmole) in methylene dichloride (20 milliliters), add trifluoracetic acid (5 milliliters).Gained solution at room temperature is stirred 1 hour, and under reduced pressure is concentrated then.Resistates via the flash column chromatography analysis, use 99% vinyl acetic monomer and 1% acetic acid to be the elutriant purifying, be produced as 5 (140 milligrams, 55%) of white solid.LRMS(M+H
+)m/z 425.1。
To the solution of 5 (330 milligrams, 0.7 mmole) in DMSO (5 milliliters), add ammonium chloride (83 milligrams, 1.5 mmoles), diisopropyl ethyl amine (0.27 milliliter, 1.5 mmoles) and HBTU (580 milligrams, 1.5 mmoles).The gained mixture at room temperature stirred 15 hours.Add extra ammonium chloride (37 milligrams, 0.7 mmole), diisopropyl ethyl amine (0.12 milliliter, 0.75 mmole) and HBTU (266 milligrams, 0.7 mmole).Continue to stir again 5 hours, and mixture is with vinyl acetic monomer (50 milliliters) dilution, and with saturated NaHCO
3(20 milliliters) washing.Organic layer is separated, and water extracts with vinyl acetic monomer (2 * 50 milliliters).Organic layer through merging is with salt water washing, dry and be condensed into the rough thing of little yellow on sodium sulfate.Resistates on RP-HPLC, use acetonitrile and H
2The O purifying mixture produces 6 (128 milligrams, 30%).LRMS(M+H
+)m/z 424.1。
To the solution of 6 (94 milligrams, 0.2 mmole) in DMF (2 milliliters), add cyanic acid chlorine (45 milligrams, 0.2 mmole) down at 0 ℃, and reaction mixture stirs under nitrogen.After 1 hour, reaction soln is concentrated, and produces 7 (79 milligrams), and it is used in next step and does not have and be further purified.LRMS(M+H
+)m/z 406.1。
To the solution of 7 (17 milligrams, 0.04 mmole) in methyl alcohol (2 milliliters), flow down stirring 15 minutes at HCl.Under nitrogen, frothed in the reaction mixture then.After 1 hour, reaction soln is concentrated, and produces 8, and it is used in next step and does not have and be further purified.LRMS(M+H
+)m/z 438.1。
To the solution of rough 8 (17 milligrams ,～0.04 mmole) in acetic acid (2 milliliters), add neighbour-phenylenediamine (50 milligrams, 0.46 mmole), and gained solution flows down stirring 1 hour at 80 ℃.Reaction mixture is concentrated, and via the preparation of lamina stratographic analysis, use 5% methyl alcohol in methylene dichloride as the elutriant purifying, be produced as white solid.This solid on RP-HPLC, use acetonitrile and H
2The O purifying mixture produces 9 (9 milligrams, 45%).LRMS(M+H
+)m/z 497.1。
Embodiment 21
To the solution of 5 (50 milligrams, 0.12 mmole) in DMF (1 milliliter), add benzyl amine (16 milligrams, 0.14 mmole) and HATU (57 milligrams, 0.14 mmole).Reaction mixture at room temperature stirred 3 hours.Gained solution is filtered, and filtrate is with RP-HPLC, use acetonitrile and H
2The O purifying mixture produces 6 (16 milligrams, 26%).LRMS(M+H
+)m/z 514.1。
Embodiment 22-24
To H-Phe (the 4-NHBoc)-OH in ethanol (60 milliliters), methyl alcohol (20 milliliters), acetic acid (60 milliliters) and water (30 milliliters) (4.8 grams, 17.1 mmoles) solution, add platinum oxide (IV) (360 milligrams, 1.6 mmoles).Reaction mixture is at H
2Stream (45psi) stirred 20 hours down.Filter removes with filtration catalyzer, and solvent evaporation through PTFE (0.45 micron), produces 2 (5 grams), and it is used to next step and does not have and be further purified.LRMS(M+H
+)m/z 287.1。
Rough 2 (3.2 grams, 11.2 mmoles) solution in DMF (20 milliliters) adds 3 (3.8 grams, 10 mmoles) and N, N-diisopropyl ethyl amine (5.2 milliliters, 30 mmoles).Reaction is monitored with LC/MS.When finishing, methylamine (2 volumetric molar concentrations in THF, 7.5 milliliters, 15 mmoles) and HBTU (5.7 grams, 15 mmoles) are added in the reaction soln.Reaction is stirred spends the night.Mixture dilutes with vinyl acetic monomer (60 milliliters), and with saturated NaHCO
3(20 milliliters) washing.Organic layer is separated, and water extracts with vinyl acetic monomer (2 * 50 milliliters).Organic layer through merging is with salt water washing, dry and concentrated on sodium sulfate.The rough thing of gained is via RP-HPLC, use acetonitrile and H
2The O purifying mixture produces 4 (1.0 milligrams is 18% from 1).LRMS(M+H
+)m/z 496.1。
To the solution of 4 (1.0 milligrams, 2.0 mmoles) in methylene dichloride (25 milliliters), add trifluoracetic acid (8 milliliters).Gained solution at room temperature is stirred 4 hours, and under reduced pressure is concentrated then.Resistates is via RP-HPLC, use acetonitrile and H
2The O purifying mixture produces 5 (820 milligrams, 79%).LRMS(M+H
+)m/z 396.1。
To 5 (75 milligrams, the 0.16 mmole) solution in THF (3 milliliters), add 4-fluorine benzyl chloride of acid (28 microlitres, 0.23 mmole) and N, N-diisopropyl ethyl amine (100 microlitres, 0.57 mmole).Reaction mixture is stirred and spends the night.Gained solution is concentrated, and on RP-HPLC, use acetonitrile and H
2The O purifying mixture produces 6 (65 milligrams, 78%).LRMS(M+H
+)m/z 518.1。
To 5 (75 milligrams, the 0.16 mmole) solution in THF (3 milliliters), add isobutyl chlorocarbonate (30 microlitres, 0.23 mmole) and N, N-diisopropyl ethyl amine (100 microlitres, 0.57 mmole).Reaction mixture is stirred and spends the night.Gained solution is concentrated, and on RP-HPLC, use acetonitrile and H
2The O purifying mixture produces 7 (62 milligrams, 78%).LRMS(M+H
+)m/z 496.1。
To 5 (75 milligrams, the 0.16 mmole) solution in THF (3 milliliters), add tert-butyl isocyanate (26 microlitres, 0.23 mmole) and N, N-diisopropyl ethyl amine (100 microlitres, 0.57 mmole).Reaction mixture is stirred and spends the night.Gained solution is concentrated, and on RP-HPLC, use acetonitrile and H
2The O purifying mixture produces 7 (55 milligrams, 69%).LRMS(M+H
+)m/z 495.1。
Embodiment 25
To the Boc-L-Serine-β-lactone in acetonitrile (5 milliliters) (200 milligrams, 1.07 mmoles) solution, add 29 (154 milligrams, 1.07 mmoles).Mixture is stirred under 56 ℃ and spends the night.Under reduced pressure be concentrated, produce 30.
Rough 30 by solution in DMF (1 milliliter), handle with methylamine (2 volumetric molar concentrations in THF) (0.54 milliliter, 1.08 mmoles) and HBTU (404 milligrams, 1.07 mmoles).Mixture is stirred 1 hour, and it is filtered afterwards, and filtrate is with reversed-phase HPLC (C18), use acetonitrile and H
2The O purifying mixture produces 31 (50.0 grams, 14%).
31 (50.0 grams, 0.145 mmole) solution in DCM (5 milliliters) at room temperature adds TFA (5 milliliters).Reaction mixture is stirred 20 minutes.Solvent under reduced pressure is evaporated, and resuspending in DMF (100 milliliters), continuous at room temperature to add 6 (66.3 milligrams, 0.174 mmole) and diisopropyl ethyl amine (51 microlitres, 0.290 mmole).Reaction mixture is stirred 1 hour, under reduced pressure concentrates then, and with quick silica gel (hexane: EtOAc, 1: 1) purifying, produces 32 (50.0 milligrams, 78.2%).LRMS(M+H
+)m/z 441.1。
Embodiment 26
40 (50.0 grams, 0.0874 mmole) solution in water (1 milliliter) and methyl alcohol (1 milliliter) adds EDTA sodium (88.1 milligrams, 0.262 mmole) and HOAc (83.7 milligrams, 0.262 mmole).Reaction mixture stirred 1 hour down at 100 ℃, and under reduced pressure concentrated then.Resistates produces 41 (29.6 milligrams, 71%) with quick silicagel column (DCM: MeOH, 10: 1) purifying.LRMS(M+H
+)m/z 472.4。
Embodiment 27
51 (1.0 grams, 8.76 mmoles) solution in DMF (20 milliliters) at room temperature adds 6 (3.34 grams, 8.76 mmoles) and diisopropyl ethyl amines (2.30 milliliters, 13.1 mmoles).Reaction mixture is with reversed-phase HPLC/MS monitoring.When finishing, 2 volumetric molar concentration methylamine in THF (8.8 milliliters, 17.5 mmoles) and HBTU (4.97 grams, 13.1 mmoles) are added in the reaction soln.After stirring 1 hour, reaction mixture is concentrated, and with quick silicagel column (hexane: EtOAc, 1: 1) purifying, produces 53 (1.0 grams, 35.3%).
53 (1.0 grams, 3.09 mmoles) solution in ethanol (20 milliliters) adds triethylamine (0.517 milliliter, 3.17 mmoles) and oxammonium hydrochloride (258 milligrams, 3.71 mmoles).After stirring 24 hours under refluxing, solvent under reduced pressure is evaporated.Resistates is gone up purifying at reversed-phase HPLC (C18), is used acetonitrile and H
2The O purifying mixture produces 54 (280 milligrams, 25%).
54 (280 milligrams, 0.875 mmole) solution in THF (50 milliliters) at room temperature adds diisopropyl ethyl amine (64 microlitres, 0.942 mmole) and benzyl chloride of acid (100 microlitres, 0.864 mmole).After stirring 30 minutes, reaction mixture is concentrated, and resistates is dissolved among the HOAc (100 milliliters), and mixture stirred 5 hours under refluxing.Solvent under reduced pressure is removed, and resistates is gone up purifying at quick silicagel column (hexane: EtOAc, 1: 1), generation 56 (49 milligrams, 14.1%).LRMS(M+H
+)m/z 443.1。
Embodiment 28
57 (3.0 grams, 10.4 mmoles) solution in DMF (50 milliliters) adds 58 (1.69 grams, 12.4 mmoles) and HBTU (5.92 grams, 15.6 mmoles).Reaction mixture is with reversed-phase HPLC/MS monitoring.After stirring 5 hours, solvent under reduced pressure is evaporated, and resistates is gone up purifying at quick silicagel column (hexane: EtOAc, 1: 1), generation 59 (3.50 grams, 82%).
To 59 (200 milligrams, the 0.491 mmole) solution in toluene (5 milliliters), add Lawesson ' s reagent (109 milligrams, 0.270 mmole).After 100 ℃ were stirred 30 minutes down, solvent under reduced pressure was evaporated.Resistates is gone up purifying at quick silicagel column (hexane: EtOAc, 1: 1), produces 60 (160 milligrams, 80%).
60 (150 milligrams, 0.431 mmole) solution in DCM (5 milliliters) at room temperature adds TFA (5 milliliters).Reaction mixture is stirred 2 hours.Solvent under reduced pressure is evaporated, and resistates dried overnight in a vacuum.
To 61 (0.395 mmole) solution in DMF (5 milliliters), at room temperature add 6 (180 milligrams, 0.473 mmole) and diisopropyl ethyl amine (138 microlitres, 0.970 mmole).Reaction mixture is monitored with HPLC/MS.When finishing, 2 volumetric molar concentration methylamine in THF (395 microlitres, 0.970 mmole) and HBTU (225 milligrams, 0.593 mmole) are added in the reaction soln.Reaction mixture is stirred 30 minutes, and mixture is filtered afterwards, and filtrate is with reversed-phase HPLC (C18), use acetonitrile and H
2The O purifying mixture produces 62 (70.0 milligrams, 38.6%).LRMS(M+H
+)m/z 469.0。
Embodiment 29
The solution of the nitrile 1 in MeOH (25 milliliters) (640 milligrams, 1.6 mmoles) is saturated with HCl gas under 0 ℃.Reaction vessel is allowed to be warmed to 23 ℃.At 23 ℃ after following 2 hours, reaction mixture is concentrated in a vacuum, and gained resistates 2 is used and does not have and is further purified.
The solution of rough imidate 2 (50 milligrams, 0.12 mmole), 2-amino-3-methyl-propyl alcohol (36 milligrams, 0.35 mmole) and THF (1 milliliter) is stirred 30 minutes under 80 ℃.Reaction mixture is concentrated in a vacuum then, and the gained resistates is dissolved among the EtOAc (10 milliliters), and with 1 equivalent concentration NaOH (5 milliliters) and salt solution (5 milliliters) washing.Organic phase (the MgSO that is dried
4), filter and concentrate in a vacuum.(silica gel 100%EtOAc), is produced as 25 milligrams of De oxazoles 3 (43%) to the gained resistates with the flash column chromatography analysis.LRMS(M+H
+)m/z 486.3。
Embodiment 30
The solution of rough imidate 2 (50 milligrams, 0.12 mmole), phenylenediamine (36 milligrams, 0.32 mmole) and acetic acid (1 milliliter) is stirred 30 minutes under 80 ℃.Reaction mixture is concentrated in a vacuum then, and the gained resistates is dissolved among the EtOAc (10 milliliters), and with 1 equivalent concentration NaOH (5 milliliters) and salt solution (5 milliliters) washing.Organic phase (the MgSO that is dried
4), filter and concentrate in a vacuum.The gained resistates is with flash column chromatography analysis (silica gel, 1: 3 hexane: EtOAc), be produced as the benzoglyoxaline 3 of 20 milligrams (34%).LRMS(M+H
+)m/z 491.2。
Embodiment 31
(500 milligrams of bromides 4,1.1 mmole), 4-methyl-1-pentene alkynes-3-alcohol (0.15 milliliter, 1.32 mmoles), two (triphenylphosphinyl) palladiums (II) of chlorination are (390 milligrams, 0.55 mmole), cuprous iodide is (52 milligrams, 0.28 mmole), triethylamine (5 milliliters) and DMF (10 milliliters) solution, under 100 ℃, be stirred 3 hours.Reaction mixture is concentrated in a vacuum then, and the gained resistates is dissolved among the EtOAc (50 milliliters), and with 1 equivalent concentration HCl (3 * 20 milliliters) and salt solution (20 milliliters) washing.Organic layer (the MgSO that is dried
4), filter and concentrate in a vacuum.The gained resistates is with flash column chromatography analysis (silica gel, 1: 1 hexane: EtOAc), be produced as the acetylene 5 of 200 milligrams (42%).LRMS(M+H
+)m/z 471.2。
Alcohol 5 (50 milligrams, 0.12 mmole), Dess-Martin periodinane (90 milligrams, 0.21 mmole) and CH
2Cl
2(3 milliliters) solution is stirred 2 hours under 23 ℃.Reaction mixture dilutes with EtOAc (20 milliliters), and with saturated NaHCO
3(10 milliliters) and salt solution (20 milliliters) washing.Organic layer (the MgSO that is dried
4), filter and concentrate in a vacuum.The gained resistates is directly used.
Rough ketone 6 (30 milligrams, 0.06 mmole), hydrazine (0.13 milliliter, 1.0 volumetric molar concentrations in THF) and DMF (1 milliliter) solution are stirred 12 hours under 23 ℃.Reaction mixture dilutes with EtOAc (10 milliliters) then, and with 0.1 equivalent concentration HCl (5 milliliters) and salt solution (5 milliliters) washing.Organic phase (the MgSO that is dried
4), filter and concentrate in a vacuum.The gained resistates produces the pyrazine 7 of 5 milligrams (18%) with reversed-phase HPLC (C18, acetonitrile/water) purifying.LRMS(M+H
+)m/z 483.2。
Embodiment 32
(500 milligrams of bromides 4,1.1 mmole), two (which acid of pyrrole) two boron are (420 milligrams, 1.65 mmole), Potassium ethanoate is (433 milligrams, 4.4 mmole), [1,1 '-two (diphenylphosphino) ferrocene]-dichloro closes (180 milligrams of palladiums (II), 0.22 mmole) and DMF (5 milliliters) solution, under 80 ℃, be stirred 3 minutes.Add bromide 9 (366 milligrams, 4.65 mmoles) and Na then
2CO
3(4.4 milliliters, at H
22.0 volumetric molar concentrations among the O), and mixture stirred 2 hours down at 80 ℃.Reaction mixture is with EtOAc (50 milliliters) dilution then, and layer separates, and organic phase is with 0.1 equivalent concentration HCl (10 milliliters) and salt solution (10 milliliters) washing.Organic layer (the MgSO that is dried
4), filter and concentrate in a vacuum.The gained resistates produces the triazole 10 of 165 milligrams (28%) with reversed-phase HPLC (C18, acetonitrile/water) purifying.LRMS(M+H
+)m/z 531.2。
Ester 10 (165 milligrams, 0.31 mmole), sodium hydroxide (35 milligrams, 0.62 mmole), H
2O (1 milliliter), MeOH (1 milliliter) and THF (2 milliliters) solution are stirred 2 hours under 50 ℃.Reaction mixture dilutes with EtOAc (20 milliliters) then, and with 1 equivalent concentration HCl (5 milliliters) and salt solution (10 milliliters) washing.Organic layer (the MgSO that is dried
4), filter and concentrate in a vacuum.The gained resistates is directly used.
Acid 11 (140 milligrams, 0.28 mmole), pentafluranol triflutate 12 (96 microlitres, 0.56 mmole), triethylamine (77 microlitres, 0.56 mmole) and DMF (4 milliliters) solution stirred 2 hours down at 23 ℃.Reaction mixture dilutes with EtOAc (20 milliliters) then, and with 1 equivalent concentration HCl (5 milliliters) and saturated water-based NaHCO
3(5 milliliters) and salt solution (10 milliliters) washing.Organic layer (the MgSO that is dried
4), filter and concentrate in a vacuum.The gained resistates is with flash column chromatography analysis (silica gel, 1: 1 hexane: EtOAc), be produced as 80 milligrams ester 13.
Ester 13 (20 milligrams, 0.03 mmole), isopropylamine (5 microlitres, 0.06 mmole) and THF (1 milliliter) solution stirred 12 hours down at 23 ℃.Reaction mixture dilutes with EtOAc (20 milliliters) then, and with 1 equivalent concentration HCl (5 milliliters), saturated water-based NaHCO
3(5 milliliters) and salt solution (10 milliliters) washing.Organic layer (the MgSO that is dried
4), filter and concentrate in a vacuum.The gained resistates is with flash column chromatography analysis (silica gel, 1: 3 hexane: EtOAc), be produced as 9 milligrams acid amides 14.LRMS(M+H
+)m/z 543.2。
Embodiment 33
Imidate 2 in MeOH (10 milliliters) (1.6 grams, 4.0 mmoles) and 2.0 volumetric molar concentration NH
3Solution, stirred 12 hours down at 23 ℃.Reaction mixture concentrates in a vacuum then, and the gained resistates is with flash column chromatography analysis (silica gel, 1: 10 CH
2Cl
2: MeOH), be produced as the amidine 17 of 1.3 grams (78%).LRMS(M+H
+)m/z 417.2。
Amidine 17 (50 milligrams, 0.12 mmole), isobutyryl ritalin (17 microlitres, 0.12 mmole) and NaOMe (0.5 volumetric molar concentration in MeOH, 0.72 milliliter) stirred 1 hour down at 120 ℃.Reaction mixture concentrates in a vacuum then, and the gained resistates produces the pyrimidine 18 of 10 milligrams (16%) with reversed-phase HPLC (C18, acetonitrile/water) purifying.LRMS(M+H
+)m/z 511.2。
Embodiment 34
Bromide 4 (1.0 grams, 2.20 mmoles), two (triphenylphosphine) palladiums (II) (154 milligrams, 0.220 mole) of dichloro, tributyl (1-vinyl ethyl ether base) tin (1.49 milliliters, 4.41 mmoles) and toluene (15 milliliters) solution are at N
2Down, 100 ℃ were stirred 6 hours.When finishing, with the LCMS monitoring, reaction mixture is cooled, filters via Celite, and concentrates in a vacuum.The gained resistates is with flash column chromatography analysis (silica gel, 2: 1: 0.1 EtOAc: hexane: triethylamine), produce the vinylbenzene 19 of 540 milligrams (55%).LRMS(M+H
+)m/z 445.2。
Compound 19 (540 milligrams, 1.21 mmoles), THF: H
2With N-bromo-succinimide (216 milligrams, 1.21 mmoles) solution, stirred 15 minutes down among the O (3: 1,12 milliliters) at 23 ℃.Reaction mixture concentrates under vacuum then, and rough thing is with EtOAc (30 milliliters) dilution, with salt solution (10 milliliters) washing and concentrated under vacuum.The gained resistates is with flash column chromatography analysis (silica gel, 1: 1 EtOAc: hexane), produce the bromoketone 20 of 210 milligrams (35%).LRMS(M+H
+)m/z 495.1。
Bromoketone 20 (210 milligrams, 0.42 mmole), K
2CO
3(174 milligrams, 1.26 mmoles), tertiary butyl guanidinesalt hydrochlorate (115 milligrams, 0.84 mmole) and DMF (4 milliliters) solution are at 23 ℃, N
2Under stirred 18 hours.Reaction mixture concentrates in high vacuum (0.1 mm Hg), and the gained resistates is with column chromatography analysis (silica gel, 4: 1 EtOAc: hexane), produce the imidazoles 21 of 50 milligrams (24%).LRMS(M+H
+)m/z 497.2。
Embodiment 35
Bromoketone 20 (25 milligrams, 0.05 mmole), K
2CO
3(14 milligrams, 0.1 mmole), ethanamide (6 milligrams, 0.1 mmole) and DMF (1 milliliter) solution stirred 4 hours down at 100 ℃.Reaction mixture is with EtOAc (15 milliliters) dilution, with salt solution (3 * 10 milliliters) washing and concentrated under vacuum.The gained resistates is with column chromatography analysis (silica gel, 2: 1 EtOAc: hexane), produce 5 milligrams of (22%) De oxazoles 22.LRMS(M+H
+)m/z 446.2。
Embodiment 36
Bromoketone 20 (25 milligrams, 0.05 mmole), K
2CO
3(14 milligrams, 0.1 mmole), cyano-thioacetamide (10 milligrams, 0.1 mmole) and DMF (1 milliliter) solution stirred 4 hours down at 100 ℃.Reaction mixture is with EtOAc (15 milliliters) dilution, with salt solution (3 * 10 milliliters) washing and concentrated under vacuum.The gained resistates is with reversed-phase HPLC (C18, acetonitrile and H
2O) purifying, the thiazole 23 of generation 5 milligrams (20%).LRMS(M+H
+)m/z 497.2。
Embodiment 37
Bromoketone 20 (30 milligrams, 0.06 mmole), K
2CO
3(25 milligrams, 0.18 mmole), phenyl sulfenyl urea (18 milligrams, 0.12 mmole) and DMF (1 milliliter) solution stirred 4 hours down at 100 ℃.Reaction mixture is with EtOAc (15 milliliters) dilution, with salt solution (3 * 10 milliliters) washing and concentrated under vacuum.The gained resistates produces the aminothiazole 24 of 10 milligrams (30%) with reversed-phase HPLC (C18, acetonitrile/water) purifying.LRMS(M+H
+)m/z 549.2。
Embodiment 38
Aniline 25 (100 milligrams, 0.25 mmole), dense HCl (1 milliliter) and AcOH (1 milliliter) solution are cooled to-5 ℃.In 1 minute, slowly add NaNO then
2(20 milligrams, 0.29 mmole) are in this solution.Reaction soln stirred 45 minutes down at-5 ℃, so that two diazo salt solution to be provided.
In another reaction vessel, SO
2Blow in AcOH (1 milliliter) and cuprous chloride (I) (6 milligrams, 0.06 mmole) solution, continue up to blue-greenish colour.This two diazo salts solution slowly added SO in 1 minute then
2In/CuCl the solution.The internal temperature of reaction soln is being lower than 30 ℃ of stirrings down.The gained reaction soln is introduced into cold H then
2Among the O (10 milliliters), with diethyl ether (3 * 10 milliliters) extraction, and the organic layer (MgSO that is dried
4), filter and concentrate in a vacuum.Rough alkylsulfonyl chlorine 26 is used and does not have and is further purified.
Alkylsulfonyl chlorine 26 (74 milligrams, 0.16 mmole), diisopropyl ethyl amine (81 milliliters, 0.16 mmole), benzyl amine (17 milliliters, 0.16 mmole) and THF (1 milliliter) solution stirred 18 hours down at 23 ℃.Reaction mixture dilutes with EtOAc (15 milliliters), and with salt solution (3 * 10 milliliters) washing and concentrated in a vacuum.The gained resistates is produced as 25 milligrams sulphonamide 27 with column chromatography analysis (silica gel, 1: 1 EtOAc/ hexane).LRMS(M+H
+)m/z544.2。
Embodiment 39
To amino acid 64 (2.20 grams, 8.27 mmoles), pentafluorophenyl group ester 28 (3.0 grams, 7.88 mmoles), diisopropyl ethyl amine (5.5 milliliters, 31.5 mmoles) and DMF (30 milliliters) solution, stir down at 23 ℃.After 18 hours, add H
2NMe (2.0 volumetric molar concentrations in THF, 3.94 milliliters), O-benzotriazole-N, N, N ', N '-tetramethyl--urea-hexafluoro-phosphoric acid salt (HBTU, 6.0 grams, 15.75 mmoles).After 4 hours, reaction soln is dissolved among the HOAc (200 milliliters), with salt solution (3 * 200 milliliters) washing and concentrated in a vacuum.The gained resistates is produced as the acid amides 30 of 3.5 grams (93%) with column chromatography analysis (silica gel, 2: 1 EtOAc/ hexanes).LRMS(M+H
+)m/z 475.2。
Ester 66 (3.5 grams, 7.36 mmoles), TFA: H
2O (97.5; 2.5,10 milliliters) in CH
2Cl
2(10 milliliters) solution stirred 3 hours down at 23 ℃.Reaction soln concentrates under vacuum, and the gained resistates was placed in high vacuum following 2 hours, and is used then and does not have and be further purified.
Acid 67 (4.7 grams, 11.2 mmoles), pentafluranol triflutate 12 (3.86 milliliters, 22.4 mmoles), triethylamine (4.7 milliliters, 33.6 mmoles) and DMF (25 milliliters) solution stirred 18 hours down at 23 ℃.Reaction mixture dilutes with EtOAc (200 milliliters) then, and with 1 equivalent concentration HCl (50 milliliters) and saturated water-based NaHCO
3(50 milliliters) and salt solution (100 milliliters) washing.Organic layer (the MgSO that is dried
4), filter and concentrate in a vacuum.The gained resistates is with flash column chromatography analysis (silica gel, 2: 1 hexanes: EtOAc), be produced as the ester 68 of 1.1 grams (17%).
The solution of ester 68 (20 milligrams, 0.03 mmole), benzyl amine (6 micrograms, 0.05 mmole) and THF (0.5 milliliter) stirred 18 hours down at 23 ℃.Reaction mixture dilutes with EtOAc (10 milliliters) then, and with 1 equivalent concentration HCl (5 milliliters), saturated water-based NaHCO
3(5 milliliters) and salt solution (5 milliliters) washing.Organic layer (the MgSO that is dried
4), filtration and filtrate concentrates in a vacuum.The gained resistates produces the acid amides 14 of 13 milligrams (85%) with reversed-phase HPLC (C18, acetonitrile/water) purifying.LRMS(M+H
+)m/z 508.2。
Embodiment 40
Ester 66 (50 milligrams, 0.1 mmole), LiAlH
4(1.0 volumetric molar concentrations in THF, 0.21 milliliter) and THF (1 milliliter) solution stirred 2 hours down at 23 ℃.Reaction mixture dilutes, washs with 1 equivalent concentration HCl (5 milliliters) and salt solution (5 milliliters) with EtOAc (10 milliliters) then with MeOH (1 milliliter) stopped reaction.Organic layer (the MgSO that is dried
4), filter, and filtrate concentrates in a vacuum.The gained resistates produces the alcohol 70 of 2 milligrams (5%) with reversed-phase HPLC (C18, acetonitrile/water) purifying.LRMS(M+H
+)m/z 405.2。
Embodiment 41
71 (108 milligrams, 0.27 mmole), LiAlH
4(1.0 volumetric molar concentrations in THF, 1.0 milliliters) and THF (2 milliliters) solution stirred 2 hours down at 23 ℃.Reaction mixture dilutes, washs with 1 equivalent concentration HCl (5 milliliters) and salt solution (5 milliliters) with EtOAc (10 milliliters) then with the MeOH stopped reaction.Organic layer (the MgSO that is dried
4), filter, and filtrate concentrates in a vacuum.The gained resistates produces the amine 72 of 30 milligrams (28%) with reversed-phase HPLC (C18, acetonitrile/water) purifying.LRMS(M+H
+)m/z 404.2。
Amine 72 (10 milligrams, 0.22 mmole), benzyl chloride of acid (2.3 microlitres, 0.03 mmole), triethylamine (50 microlitres, 0.36 mmole) and CH
2Cl
2(0.5 milliliter) solution stirred 2 hours down at 23 ℃.Reaction mixture dilutes with EtOAc (15 milliliters), and with 1 equivalent concentration HCl (2 milliliters), saturated water-based NaHCO
3(2 milliliters) and salt solution (5 milliliters) washing.Organic layer (the MgSO that is dried
4), filter and concentrate in a vacuum.The gained resistates is with flash column chromatography analysis (silica gel, 2: 1 hexane classes: EtOAc), produce the acid amides 73 of 5 milligrams (49%).LRMS(M+H
+)m/z 508.2。
Embodiment 42
71 (300 milligrams, 0.75 mmole), oxammonium hydrochloride (156 milligrams, 2.25 mmoles), K
2CO
3(726 milligrams, 5.25 mmoles) and EtOH (10 milliliters) solution stirred 18 hours down at 80 ℃.Reaction mixture concentrates in a vacuum.The gained resistates dilutes with EtOAc (15 milliliters), and washs with salt solution (15 milliliters).Organic layer (the MgSO that is dried
4), filtration and filtrate concentrates in a vacuum.The gained resistates is with flash column chromatography analysis (silica gel, 1: 20 MeOH: EtOAc), produce the hydroxyamidines 74 of 80 milligrams (25%).LRMS(M+H
+)m/z 433.2。
Hydroxyamidines 74 (20 milligrams, 0.05 mmole), carbonyl dimidazoles (CDI, 15 milligrams, 0.09 mmole), triethylamine (13 microlitres, 0.09 mmole) and DMF (1 milliliter) solution stirred 2 hours under 100C.Organic layer (the MgSO that is dried
4), filter and concentrate in a vacuum.The gained resistates is with flash column chromatography analysis (silica gel, 1: 20MeOH: EtOAc), produce 10 milligrams of (44%) De oxadiazole ketone 75.LRMS(M+H
+)m/z 459.2。
Embodiment 43
Hydroxyamidines 74 (20 milligrams, 0.05 mmole), triethylamine (13 microlitres, 0.09 mmole), acetic anhydride (0.5 milliliter) and DMF (0.5 milliliter) solution stirred 2 hours down at 100 ℃.The gained resistates dilutes with EtOAc (15 milliliters), and washs with salt solution (3 * 5 milliliters).Organic layer (the MgSO that is dried
4), filter and concentrate in a vacuum.The gained resistates is with flash column chromatography analysis (silica gel, 1: 20 MeOH: EtOAc), produce 13 milligrams of (67%) De oxadiazoles 75.LRMS(M+H
+)m/z 457.2。
Embodiment 44
To 63 (100 milligrams in DCM (10 milliliters), 0.367 solution mmole), add Benzoyl chloride (93.8 microlitres, 0.808 mmole) and diisopropyl ethyl amine (192 microlitres, 1.10 mmoles) after stirring 10 minutes, be added on 2 equivalent concentration methylamine (550 microlitres, 1.10 mmoles) among the THF in reaction soln.Reaction mixture is stirred 30 minutes and concentrates.Resistates is gone up purifying at quick silicagel column (hexane: EtOAc 1: 1), produces 66 (100 milligrams, 70%).
66 (100 milligrams, 0.257 mmole) solution in DCM (5 milliliters) at room temperature adds TFA (5 milliliters).Reaction mixture is stirred 100 minutes.Solvent vapourisation under reduced pressure, and resistates dried overnight under high vacuum.Resistates is dissolved among the DCM (2 milliliters), at room temperature stirs with 6 (117 milligrams, 0.308 mmole) and diisopropyl ethyl amine (90 microlitres, 0.515 mmole) then.Reaction mixture is with reversed-phase HPLC/MS monitoring.Reaction mixture is stirred 30 minutes, afterwards its be filtered and filtrate with reversed-phase HPLC (C18), use acetonitrile and H
2The O purifying mixture produces 67 (100 milligrams, 52.9%).LRMS(M+H
+)m/z 486.2。
Embodiment 45
68 (500 milligrams, 1.23 mmoles) solution in DCM (10 milliliters) at room temperature adds TFA (5 milliliters).Reaction mixture is stirred 10 minutes, and the solvent vapourisation under reduced pressure, and its interpolation 6 (562 milligrams, 1.48 mmoles) and diisopropyl ethyl amine (429 microlitres, 2.46 mmoles) are at room temperature stirred.Reaction mixture is monitored with reversed-phase HPLC MS.After initial substance no longer is observed, solution is added on 2 equivalent concentration methylamine (1.23 milliliters, 2.46 mmoles) among the THF and HBTU (702 milligrams, 1.85 mmoles) in solution.After stirring 30 minutes, the solvent vapourisation under reduced pressure, and the resistates flash column chromatography is analyzed (hexane: EtOAc, 1: 1) upward purifying, generation 69 (450 milligrams, 71%).LCMS(M+H
+)m/z 516.2。
69 (400 milligrams, 0.775 mmole) are dissolved in the HBr/HOAc solution (10 milliliters).After being stirred 10 minutes, resistates is dissolved in the sodium hydrogen carbonate solution (50 milliliters), and with DCM (50 milliliters) extraction three times.Through the dry and filtration on sodium sulfate of the DCM of combination layer, and filtrate under reduced pressure concentrates generation 70 (285 milligrams, 96%).
Solution 70 (82.5 milligrams, 0.216 mmole) is added bromotoluene (30.8 microlitres, 0.259 mmole) and diisopropyl ethyl amine (75.3 microlitres, 0.432 mmole).Reaction mixture is with reversed-phase HPLC/MS monitoring.After being stirred 2 hours, mixture be filtered and filtrate with reversed-phase HPLC (C18), use acetonitrile and H
2The O purifying mixture produces 71 (183 milligrams, 90%).LCMS(M+H
+)m/z 472.1。
To 71 (128 milligrams, the 0.271 mmole) solution in water (1 milliliter) and methyl alcohol (1 milliliter), add EDTA (273 milligrams, 0.814 mmole), HOAc (20 microlitre) and Hg (OAc)
2(259 milligrams, 0.814 mmole).Reaction mixture stirred 8 hours down at 100 ℃, afterwards the solvent vapourisation under reduced pressure.Resistates is dissolved among the DMF (2 milliliters) again, be filtered and filtrate with reversed-phase HPLC (C18), use acetonitrile and H
2The O purifying mixture produces 72 (37.6 milligrams, 28.5%).LCMS(M+H
+)m/z 486.1。
Embodiment 46
42 (1.0 grams, 3.24 mmoles) solution in methanol (2/1,20 milliliter) adds sodium hydrogen carbonate solution (327 milligrams, 3.24 mmoles).When on ice bath, stirring, dropwise add bromine (200 microlitres, 3.89 mmoles) in reaction mixture.Reaction mixture is monitored with reversed-phase HPLC MS.After initial substance no longer is observed, the solvent vapourisation under reduced pressure.Resistates is dissolved in the water (100 milliliters), and with DCM (50 milliliters) extraction three times., mixture dry on sodium sulfate through the DCM of combination layer is filtered, and filtrate is concentrated generation 43.
To rough 43 (3.24 mmole) solution in methyl alcohol (50 milliliters), add diisopropyl ethyl amine (1.14 milliliters, 6.4 mmoles) and benzyl thioamides 44 (445 milligrams, 3.24 mmoles).After refluxing 24 hours, the solvent vapourisation under reduced pressure.Resistates is with reversed-phase HPLC/MS monitoring.Reaction mixture is stirred 30 minutes, afterwards its be filtered and filtrate with reversed-phase HPLC (C18), use acetonitrile and H
2The O purifying mixture produces 45 (200 milligrams, 18%).
45 (150 milligrams, 0.431 mmole) solution in DCM (5 milliliters) at room temperature adds TFA (5 milliliters).Reaction mixture is stirred 10 minutes.Solvent vapourisation under reduced pressure, and resistates then 46 (107 milligrams, 100%) dried overnight under high vacuum.
To 46 (0.431 mmole) stirred solution in DMF (20 milliliters), at room temperature add 6 (197 milligrams, 0.517 mmole) and diisopropyl ethyl amine (150 microlitres, 0.862 mmole).Reaction mixture is with reversed-phase HPLC/MS monitoring.After initial substance no longer is observed, solution is added on 2 equivalent concentration methylamine (0.431 milliliter, 0.862 mmole) among the THF and HBTU (245 milligrams, 0.647 mmole) in solution.Reaction mixture is stirred 30 minutes, and mixture is filtered afterwards, and filtrate is with reversed-phase HPLC (C18), use acetonitrile and H
2The O purifying mixture produces 47 (80.0 milligrams, 40.5%).LCMS(M+H
+)m/z 458.1。
Same steps as is used to 47, is used to make 50 (58.3 milligrams).LCMS(M+H
+)m/z 441.4。
Embodiment 47
To the Boc-in THF (200 milliliters) right-stirred solution of biphenyl alanine (3.0 gram, 8.79 mmoles) on ice bath, add LAH (1.0 volumetric molar concentrations in THF, 17.6 milliliters, 17.6 mmoles).After stirring 2 hours, reaction mixture is with MeOH (10 milliliters) stopped reaction, and is continuous with NaOH solution (17.6 milliliters, 35.1 mmoles).Mixture filters through Celite, and filtrate under reduced pressure concentrates.Resistates is dissolved in the water (200 milliliters), and with DCM (200 milliliters) extraction three times.Through the DCM of the combination layer (Na that is dried
2SO
4), filter and under reduced pressure be concentrated, produce 10 (2.85 grams, 98%).
The stirred solution of 10 (2.85 milligrams, 8.70 mmoles) in THF (250 milliliters) is dropwise added 11 (1.54 milligrams, 10.4 mmoles) and triphenylphosphine (2.51 milligrams, 9.57 mmoles), DEAD (1.49 milliliters, 9.57 mmoles), and reaction mixture is stirred 30 minutes, concentrate in a vacuum, and resistates is at quick silicagel column (hexane: EtOAc, 6: 1) last purifying, obtain product 12 (2.0 grams, 50%).
12 (2.0 grams, 4.38 mmoles) solution in DCM (50 milliliters) at room temperature adds TFA (05 milliliter).Reaction mixture is stirred 20 minutes, and solvent concentrates in a vacuum then, produces 13 (1.56 grams, 100%).
To 13 solution in DMF (100 milliliters), at room temperature add 6 (2.0 grams, 4.38 mmoles) and diisopropyl ethyl amines (1.53 milliliters, 8.72 mmoles).Reaction mixture is stirred and spends the night.The solvent vapourisation under reduced pressure, and resistates is gone up purifying at silica gel (hexane: EtOAc, 1: 1), generation 14 (1.5 grams, 61.9%).LCMS(M+H
+)m/z553.1。
14 (1.5 grams, 2.71 mmoles) solution in methyl alcohol (20 milliliters) is added diamine hydrate (0.845 milliliter, 27.1 mmoles).Reaction mixture stirred 5 hours down at 0 ℃, and cool to room temperature.Solid is filtered, and filtrate under reduced pressure concentrates generation 15 (1.0 grams, 87.2%).LCMS(M+H
+)m/z 423.1。
Embodiment 48
To 15 (20.0 milligrams, the 0.0473 mmole) solution in DCM (10 milliliters), add diisopropyl ethyl amine (24.7 microlitres, 0.142 mmole) and ethanoyl chlorine (5.0 microlitres, 0.0709 mmole).Reaction mixture is stirred 10 minutes, under reduced pressure concentrates then, and with reversed-phase HPLC (C18, acetonitrile/water) purifying, produces 16 (8.0 milligrams, 36.4%).LCMS(M+H
+)m/z 465.2。
To 15 (60.0 milligrams, the 0.142 mmole) solution in DCM (2 milliliters), add diisopropyl ethyl amine (49.5 microlitres, 0.282 mmole), 17 (32.2 milligrams, 0.170 mmole) and HBTU (80.8 milligrams, 0.213 mmole).Reaction mixture is stirred 10 minutes, and under reduced pressure concentrates then, and product produces 19 (25.0 milligrams, 35.6%) with reversed-phase HPLC (C18, acetonitrile/water) purifying.LCMS(M+H
+)m/z 494.2。
To 15 (35.0 milligrams, the 0.0828 mmole) solution in DCM (2 milliliters), add diisopropyl ethyl amine (28.8 microlitres, 0.166 mmole) and methyl sulphonyl chlorine (9.64 microlitres, 0.124 mmole).Reaction mixture is stirred 10 minutes, and under reduced pressure concentrates then, and product produces 20 (25.0 milligrams, 60.3%) with reversed-phase HPLC (C18, acetonitrile/water) purifying.LCMS(M+H
+)m/z 501.2。
To 15 (60.0 milligrams, the 0.142 mmole) solution in DCM (2 milliliters), add diisopropyl ethyl amine (49.5 microlitres, 0.282 mmole) and trimethyl silyl isocyanide (19.6 milligrams, 0.170 mmole).Reaction mixture is stirred 10 minutes, and under reduced pressure concentrates then, and product produces 21 (20.6 milligrams, 31.1%) with reversed-phase HPLC (C18, acetonitrile/water) purifying.LCMS(M+H
+)m/z 466.1。
To 15 (60.0 milligrams, the 0.142 mmole) solution in DCM (2 milliliters), add diisopropyl ethyl amine (49.5 microlitres, 0.282 mmole) and methyl-chloroformate (13.1 microlitres, 0.170 mmole).Reaction mixture is stirred 10 minutes, under reduced pressure concentrate then, and resistates produces 22 (19.9 milligrams, 29.1%) with reversed-phase HPLC (C18, acetonitrile/water) purifying.LCMS(M+H
+)m/z 481.1。
Embodiment 49
4-bromobenzaldehyde (14.8 grams, 80 mmoles) and ammonium acetate (14.0 grams, 180 mmoles) in the nitroethane (50.0 gram) are heated to and refluxed 8 hours.Be cooled to room temperature then, in methylene dichloride (150 milliliters) and water (30 milliliters), distribute.Be separated, afterwards organic layer and concentrated in a vacuum.Resistates downwards by one silicagel column (vinyl acetic monomer/hexane is an elutriant), continuous with recrystallize from methyl alcohol, produce intermediate 2 (9.8 restrain 51%), it is measured as enough pure and is used for follow-up conversion (LC/MS LRMS (M+H
+) m/z 240.97).
0 ℃ of solution to the sodium borohydride in tetrahydrofuran (THF) (100 milliliters) (4.6 grams, 124 mmoles) adds boron-tetrahydrofuran complex (150 milliliters, 150 mmoles, 1.0 volumetric molar concentrations).Gained solution restir 15 minutes at room temperature then.Mesosome 2 among in tetrahydrofuran (THF) (30 milliliters) (6.5 grams, 27 mmoles) is dropwise added, and gained solution was refluxed 4 hours.Cool to room temperature, and react with water and end, and extract with methylene dichloride (3 * 80 milliliters).Organic layer through merging is dry and concentrate in a vacuum on sodium sulfate, and resistates provides intermediate 3 (5.2 grams, 90%) with flash column chromatography analysis (silica gel, hexane/ethyl acetate) purifying, and it is with LC/MS (LRMS (M+H
+) m/z213.02 characterizes.
0 ℃ of solution of the amine 3 in vinyl acetic monomer (30 milliliters) (4.0 grams, 16 mmoles) is saturated with spirit of salt (gas).Gained salt is collected and drying under vacuum to filter.
L-N-ethanoyl leucine sodium salt (8.0 mmole) (adds L-N-ethanoyl leucine in 5 ml waters (1.39 grams to 1 equivalent concentration sodium hydroxide solution; 8.0 mmole) suspended substance prepares up to pH=7), slowly added to the stirred solution of aforementioned 3 hydrochlorides in water (10 milliliters).The formation crystallization of spending the night, and remove with filtration, with the small amount of water washing, and crystallization from absolute methyl alcohol.Crystallization 4a is collected and is dry under vacuum.
The mother liquor that is rich in (S)-3 is mixed, becomes strong basicity with 5 equivalent concentration sodium hydroxide solutions, and with diethyl ether washing three times.Organic layer through merging is with water washing, and dry on sodium sulfate.After removing sodium sulfate, spirit of salt is finished up to the preparation of hydrochloride by solution.Above-mentioned identical step is used to D-N-ethanoyl leucine salt.Crystallization 4b is collected and is dry under vacuum.
The diastereo-isomerism salt of each enantiomer is distributed between 20 ml waters, becomes strong basicity with 5 equivalent concentration sodium hydroxide solutions, and extracts with diethyl ether.Organic layer through merging is with water washing, and dry on sodium sulfate.Solvent is removed, and two kinds of products are measured as enough pure and are used for follow-up conversion (4a:1.3 gram, 32%, 4b:0.9 gram, 22%).(
1H-NMR and LC/MS LRMS (M+H
+) m/z 213.02).Capillary electrophoresis is pointed out＞98.0%e.e..
To the solution at room temperature of the amine 4 in dimethyl formamide (50 milliliters) (111 milligrams, 0.52 mmole), be added on the diisopropyl ethyl amine (99 microlitres, 0.57 mmole) in the dimethyl formamide (5 milliliters).Gained solution is stirred 5 minutes, and adds intermediate 5 (217 milligrams, 0.57 mmole).Reaction mixture is stirred 30 minutes under nitrogen pressure.And solvent is removed in a vacuum.Resistates is distributed between vinyl acetic monomer (20 milliliters) and the aqueous citric acid solution (20 milliliters, 10%).Layer separates, and organic phase is with aqueous citric acid solution (20 milliliters, 10%) and potassium hydroxide aqueous solution (2 * 20 milliliters) washing.It is dry on sodium sulfate then, and it is measured as enough pure and is used for follow-up conversion (LRMS (M+H
+) m/z 410.1.
To (212 milligrams of the bromides 6 in the Zai diox (10 milliliters), 0.53 solution at room temperature mmole), add two (triphenylphosphine) palladiums (II) (37 milligrams, 10 moles of %) of anti--dichloro and 1-vinyl ethyl ether base-normal-butyl tin (481 milligrams, 1.33 mmoles) continuously.Gained solution be heated to 100 ℃ 4 hours.It is cooled to room temperature, and solvent is removed in a vacuum.Resistates provides intermediate 7 (250 milligrams) with flash column chromatography analysis (silica gel, vinyl acetic monomer add 5% triethylamine), and it is unsettled, and is measured as enough pure and is used for follow-up conversion (LC/MS LRMS (M+H
+) m/z402.8).
Intermediate 7 is fed in (10 milliliters) and the water (3 milliliters) at the tetrahydrochysene furan and was stirred 2 hours down at 50 ℃ with N-bromine succinimide (190 milligrams, 1.1 mmoles).Solvent is removed in a vacuum, and extracts with vinyl acetic monomer (3 * 50 milliliters).Organic layer through merging is dry and concentrated in a vacuum on sodium sulfate.Resistates provides intermediate 8 (55 milligrams, 23%) with flash column chromatography analysis (silica gel, hexane/ethyl acetate) purifying, and it is with LC/MS (LRMS (M+H
+) m/z 452.1 characterizes.
To the solution at room temperature of mesosome 9 (55 milligrams, 0.24 mmole) among in dimethyl formamide (3 milliliters), add salt of wormwood (34 milligrams, 0.24 mmole) and tertiary butyl carb amidine (31 milligrams, 0.30 mmole).Reaction mixture is stirred 1.5 hours under nitrogen pressure, 50 ℃.It is cooled to room temperature, and solvent is removed in a vacuum.Resistates is distributed between vinyl acetic monomer (15 milliliters) and the water (15 milliliters).Layer separates and water extracts with vinyl acetic monomer (2 * 20 milliliters).Organic layer through merging is dry and concentrated in a vacuum on sodium sulfate.Resistates provides intermediate 9 (35 milligrams, 67%) with flash column chromatography analysis (silica gel, hexane/ethyl acetate) purifying then, its with
1H-NMR and LC/MS (LRMS (M+H
+) m/z 452.1) characterize.
Embodiment 50
Solution at room temperature to the acid 1 in methyl alcohol (15 milliliters) (2.98 grams, 9.2 mmoles) dropwise be added on TMS two azo-group methane (9.2 milliliters, 18.4 mmoles, the 2.0 volumetric molar concentrations) solution in the hexane, and solvent is removed in a vacuum.Remaining thickness oily matter 2 (3.10 grams, 8.0 mmoles) is dried, and is measured as enough pure and is used for follow-up conversion (LC/MS LRMS (M+H
+) m/z 339.10).
Palladium (310 milligrams) mixture on mesosome 2 among in methyl alcohol (30 milliliters) (3.10 grams, 8.0 mmoles) and the carbon stirred 2 hours at room temperature, hydrogen.It filters and concentrates through Celite, is provided as the aniline 3 (2.47 grams, 8.0 mmoles) of thickness oily matter, and it is measured as enough pure and is used for follow-up conversion (LC/MS LRMS (M+H
+) m/z 309.20).
Solution at room temperature to the aniline 3 in methylene dichloride (20 milliliters) (2.47 grams, 8.0 mmoles) adds trifluoracetic acid (20 milliliters).Gained solution is stirred 45 minutes, and solvent is removed in a vacuum.Resistates is distributed between methylene dichloride (75 milliliters) and the saturated sodium bicarbonate aqueous solution (25 milliliters), and layer separates.Water is saturated with sodium-chlor, and with methylene dichloride (3 * 75 milliliters) and tetrahydrofuran (THF) (2 * 50 milliliters) extraction.Organic layer through merging is dry and concentrated in a vacuum on sodium sulfate, is provided as 4 (1.30 grams, 6.3 mmoles) of thickness oily matter, and it is with LC/MS (LRMS (M+H
+) m/z 290.30) characterize.
Solution to the aniline 4 in dimethyl formamide (20 milliliters) (1.30 grams, 6.25 mmoles) at room temperature stirred 5 minutes with diisopropyl ethyl amine (3.27 milliliters, 18.80 moles), and is continuous to add intermediate 5 (2.38 grams, 6.25 mmoles).Reaction mixture is stirred 30 minutes again, and solvent is removed in a vacuum.Resistates is distributed between vinyl acetic monomer (50 milliliters) and the water (50 milliliters).Layer separates and water extracts with vinyl acetic monomer (3 * 50 milliliters).Organic layer through merging is dry and concentrated in a vacuum on sodium sulfate.Resistates is provided as 6 (1.47 grams, 58%) of spumescence white solid with flash column chromatography analysis (silica gel, hexane/ethyl acetate) purifying, and it is with LC/MS (LRMS (M+H
+) m/z 405.15) characterize.
To (131 milligrams of the aniline 6 in tetrahydrofuran (THF) (5 milliliters), 0.32 solution at room temperature mmole), add diisopropyl ethyl amine (85 microlitres, 0.48 mole), 4-(dimethylamino) pyridine (15 milligrams, 0.12 mmole) and dimethyl dicarbonate butyl ester (851 milligrams, 0.39 mmole).Gained solution is stirred and spends the night, and with vinyl acetic monomer (20 milliliters) dilution, with the spirit of salt aqueous solution (2 * 15 milliliters, 1.0 volumetric molar concentrations) washing, and dry on sodium sulfate.Remove solvent, be produced as the carbamate 7 (139 milligrams, 88%) of vitreous solid, it is measured as enough pure and is used for follow-up conversion (LC/MS LRMS (M+H
+) m/z 505/10).
To the solution at room temperature of the carbamate 7 (139 milligrams, 0.28 mmole) in methyl alcohol (2 milliliters) and tetrahydrofuran (THF) (2 milliliters), add sodium borohydride (261 milligrams, 6.9 mmoles).The gained mixture is distributed between vinyl acetic monomer (15 milliliters) and the water (15 milliliters).Layer separates, and water extracts with vinyl acetic monomer (3 * 15 milliliters).Organic layer through merging is dry and concentrated in a vacuum on sodium sulfate.Then resistates with reversed-phase HPLC, use acetonitrile and water gradient to be the moving phase purifying.Pure product 8 is separated, and with
1H-NMR and LC/MS (LRMS (M+H
+) m/z 477.20) characterize.
To 0 ℃ of solution of the triphosgene in tetrahydrofuran (THF) (15 milliliters) (37 milligrams, 0.13 mmole), dropwise be added on 6 and diisopropyl ethyl amine (130 microlitres, the 0.75 mmole) solution in the tetrahydrochysene furan food in one's mouth (5 milliliters).The gained mixture was maintained at nitrogen pressure and uniform temp following 30 minutes, and with methyl-tert-butylamine (215 microlitres, 1.80 mmoles) stopped reaction.Reaction mixture restir 30 minutes, continuous to remove solvent in a vacuum.Resistates is distributed between the vinyl acetic monomer (15 milliliters) and the spirit of salt aqueous solution (15 milliliters, 0.1 volumetric molar concentration), and layer separates, and water extracts with vinyl acetic monomer (2 * 15 milliliters).Organic layer through merging is dry and concentrated in a vacuum on sodium sulfate, is produced as the urea of vitreous solid, and it is measured as enough pure and is used for follow-up conversion (LRMS (M+H
+) m/z 518.2).
To the solution at room temperature of the urea 9 (150 milligrams, 0.29 mmole) in methyl alcohol (2 milliliters) and tetrahydrofuran (THF) (2 milliliters), add sodium borohydride (260 milligrams, 6.90 mmoles).The gained mixture stirred 2 hours under nitrogen pressure and room temperature.Removing solvent and resistates is distributed between vinyl acetic monomer (15 milliliters) and the water (15 milliliters).Layer separates, and water extracts with vinyl acetic monomer (3 * 15 milliliters).Organic layer through merging is dry and concentrated in a vacuum on sodium sulfate.Then resistates with reversed-phase HPLC, use acetonitrile and water gradient to be the moving phase purifying.Pure product 10 (4 milligrams, 28%) is separated, and with
1H-NMR and LC/MS (LRMS (M+H
+) m/z 490.1) characterize.
Embodiment 51
Solution to the carboxylic acid 1 in anhydrous diethyl ether (200 milliliters) (10.0 grams, 28 mmoles) dropwise is added on lithium aluminum hydride (40 milliliters, 40 mmoles, the 1 volumetric molar concentration) solution in the tetrahydrofuran (THF) under 0 ℃.Gained solution restir 2 hours under uniform temp then.Carefully with water (2.5 milliliters), aqueous sodium hydroxide solution (2.5 milliliters, 1 volumetric molar concentration), water (3.0 milliliters) stopped reaction.Solution is dry and remove solvent on sodium sulfate then, produces intermediate 2 (9.2 grams, 96%), its be measured as enough pure and be used for follow-up conversion (
1H-NMR and LC/MS (LRMS (M+H
+) m/z344.08).
To the solution at room temperature of mesosome 2 among in no Shui diox (200 milliliters), add triethylamine (6 milliliters, 40 mmoles) and t-butyldimethylsilyl trifluoromethayl sulfonic acid ester (8.6 grams, 32 mmoles).Gained solution is stirred and spends the night then, and with the saturated sodium bicarbonate solution stopped reaction.It is with methylene dichloride (3 * 100 milliliters) extraction, and the organic layer through merging is dry on sodium sulfate, and concentrates in a vacuum.Resistates provides intermediate 3 (9.2 grams, integral body is 72%) with flash column chromatography analysis (silica gel, hexane/ethyl acetate), and it is with LC/MS (LRMS (M+H
+) m/z 458.16) characterize.
To the solution at room temperature of the bromide 3 in the Zai diox (100 milliliters), add two (triphenylphosphine) palladiums (I) (500 milligrams) of anti--dichloro and 1-vinyl ethyl ether base-normal-butyl tin (12.3 grams, 34 mmoles) continuously.Gained solution be heated to 100 ℃ 4 hours.Remove solvent in a vacuum, continuous with flash column chromatography analysis (silica gel, hexane/ethyl acetate add 5% triethylamine), intermediate 4 (5.4 gram) is provided, it is with LC/MS (LRMS (M+H
+) m/z 450.30) characterize.Product is found to be unsettled, and is used to follow-up conversion at once.
Mesosome 4 among in methyl alcohol (100 milliliters) and water (50 milliliters) stirred 4 hours down at 50 ℃ with N-bromine succinimide (5.9 grams, 33 mmoles).Remove solvent in a vacuum, and the gained resistates extracts with vinyl acetic monomer (3 * 50 milliliters).Organic layer through merging is dry and concentrated in a vacuum on sodium sulfate.Resistates provides intermediate 5 (4.5 grams, integral body is 69%) with flash column chromatography analysis (silica gel, hexane/ethyl acetate) then, and it is with LC/MS (LRMS (M+H
+) m/z 500.54) characterize.
Under nitrogen pressure, will be with the funnel such as pressure titration such as grade that invests 150 ml flasks in the brooethyl ketone 5 in the methylene dichloride (40 milliliters) (2.5 grams, 5.0 mmoles) charging, this flask comprises methylamine (15 milliliters, 30 mmoles, 1 volumetric molar concentration in THF).Flask is cooled to 0 ℃, and bromine solutions was dropwise added in 2 hours.Gained solution is stirred 1 hour again, is added on triethylamine (1 milliliter) and pivaloyl chlorine (4.8 milliliters, 40 mmoles) solution in the methylene dichloride (10 milliliters) afterwards.The gained mixture is stirred 2 hours again, and then with the saturated sodium bicarbonate solution stopped reaction.Mixture is with vinyl acetic monomer (3 * 50 milliliters) extraction, and the organic layer through merging is dry and concentrated in a vacuum on sodium sulfate.Resistates is with flash column chromatography analysis (silica gel, vinyl acetic monomer/hexane) purifying then, and ester 6 (1.3 grams, integral body is 49%) is provided, its with
1H-NMR and LC/MS analyze (LRMS (M+H
+) m/z 535.35) characterize.
6 (1.3 gram, 2.6 mmoles) solution of methane amide in excessive ammonium acetate (10 milliliters), under nitrogen pressure, be heated to 130 ℃ 3 hours.The gained mixture is cooled to room temperature, distributes in water, is extracted with methylene dichloride (3 * 50 milliliters).Organic layer through merging is dry and concentrated in a vacuum on sodium sulfate.Resistates is with flash column chromatography analysis (silica gel, vinyl acetic monomer/hexane) purifying then, and imidazoles 7 (0.8 gram, 60%) is provided, its with
1H-NMR and LC/MS analyze (LRMS (M+H
+) m/z 516.35) characterize.
To the solution of 7 (800 milligrams, 1.55 mmoles) in tetrahydrofuran (THF) (10 milliliters), at room temperature stirred one hour with hydrogenchloride (10 milliliters, 4.0 volumetric molar concentrations) in the Zai diox.Remove solvent in a vacuum, and resistates is dried in high vacuum and spends the night, produce intermediate 8 (600 milligrams), its be measured as enough pure and be used for next the conversion (
1H-NMR and LC/MS (LRMS (M+H
+) m/z 302.22)).
To the solution at room temperature of the amine 8 in dimethyl formamide (3 milliliters) (60 milligrams, 0.02 mmole), be added on diisopropyl ethyl amine (53 microlitres, 0.30 mmole), and gained solution at room temperature is stirred 5 minutes.Add intermediate 9 (23 milligrams, 0.06 mmole) then, and reaction mixture is stirred 30 minutes under nitrogen pressure.Solvent is removed in a vacuum, and resistates is provided as 10 (25 milligrams, 26%) of vitreous solid with flash column chromatography analysis (silica gel, ethanol/methylene) purifying, its with
1H-NMR and LC/MS analyze (LRMS (M+H
+) m/z 489.28) characterize.
Embodiment 52
Solution at room temperature to 1 (4.96 grams, 17 mmoles) in methyl alcohol (15 milliliters) dropwise is added on TMS two azo-group methane (17.0 milliliters, 34 mmoles, the 2 volumetric molar concentrations) solution in the hexane.The gained yellow solution at room temperature is stirred 30 minutes.Solvent is removed in a vacuum, and thickness oily matter 2 (5.19 gram, 17 mmoles) is dried under high vacuum, and is measured as enough pure and is used for follow-up conversion (LC/MS (LRMS (M+H
+) m/z 305.3)).
Intermediate 2 (5.19 grams, 17 mmoles) and the sodium borohydride in methyl alcohol (50 milliliters) and tetrahydrofuran (THF) (50 milliliters) (3.23 grams, 85 mmoles) at room temperature stirred 2 hours.Solvent is removed in a vacuum, and resistates is distributed between vinyl acetic monomer (50 milliliters) and the water (50 milliliters).Layer separates, and water is with vinyl acetic monomer (3 * 50 milliliters) extraction, and the organic layer through merging is dry and concentrate in a vacuum on sodium sulfate.Be produced as 3 (4.71 grams, 17 mmoles) of white solid, it is measured as enough pure and is used for follow-up conversion (LC/MS (LRMS (M+H
+) m/z 277.3).
3 (1.92 gram, 6.9 mmoles) and first sodium oxide in methyl alcohol (27.7 milliliters, 13.9 mmoles, 0.5 volumetric molar concentration and oxammonium hydrochloride (964 milligrams, 13.9 mmoles) are stirred 2 hours under nitrogen pressure, 50 ℃.Cool to room temperature then, and solvent is removed in a vacuum.Resistates is distributed between saturated aqueous ammonium chloride (30 milliliters) and the vinyl acetic monomer (30 milliliters).Layer separates, and water extracts with vinyl acetic monomer (2 * 30 milliliters).Organic layer through merging is dry and concentrate in a vacuum on sodium sulfate, and resistates provides intermediate 4 (1.08 grams, 51%) with flash column chromatography analysis (silica gel, hexane/ethyl acetate) purifying, its with
1H-NMR and LC/MS (LRMS (M+H
+) m/z 310.2) characterize.
Solution at room temperature to 4 (1.08 grams, 3.5 mmoles) in methyl alcohol (30 milliliters) adds Raney nickel (200 milligrams) and acetic acid (1 milliliter).The gained mixture is stirred 2 hours under nitrogen pressure, room temperature.It filters through Celite, and concentrates in a vacuum.Be provided as the intermediate 5 (1.02 grams, 100%) of white solid, it is measured as enough pure and is used for follow-up conversion (LC/MS LRMS (M+H
+) m/z 294.3)).
Solution at room temperature to the amidine in dehydrated alcohol (15 milliliters) (304 milligrams, 1.0 mmoles), add 1,8-two azo dicyclo [5.4.0] undecane-7-alkene (622 microlitres, 4.2 mmoles) and 3-bromo-1,1,1-three fluoro-2-butanone (424 milligrams, 2.1 mmoles).The gained mixture is stirred 30 minutes under nitrogen pressure, 115 ℃.It is cooled to room temperature then, and solvent is removed in a vacuum.Resistates with reversed-phase HPLC, use acetonitrile and water gradient to be the moving phase purifying.Compound 6 (76 milligrams, 20%) is separated, and with
1H-NMR and LC/MS (LRMS (M+H
+) m/z 400.1) characterize.
The solution of 6 (76 milligrams, 0.2 mmole) in methylene dichloride (2 milliliters) at room temperature stirred 45 minutes with trifluoracetic acid (2 milliliters).Solvent is removed in a vacuum, is provided as 7 (57 milligrams, 100%), and it is measured as enough pure and is used for follow-up conversion (LC/MS LRMS (M+H
+) m/z 300.3)).
To the solution at room temperature of the amine 7 in dimethyl formamide (3 milliliters) (25 milligrams, 0.08 mmole), be added on diisopropyl ethyl amine (87 microlitres, 0.50 mmole).Gained solution at room temperature is stirred 5 minutes, and adds intermediate 8 (32 milligrams, 0.08 mmole).Reaction mixture is stirred 30 minutes under nitrogen pressure, and solvent is removed in a vacuum.Resistates is distributed between vinyl acetic monomer (5 milliliters) and the water (5 milliliters), and layer separates afterwards, and water extracts with vinyl acetic monomer (3 * 10 milliliters).Organic layer through merging is dry and concentrated in a vacuum on sodium sulfate.Resistates is provided as 9 (7 milligrams, 18%) of vitreous solid with flash column chromatography analysis (silica gel, vinyl acetic monomer) purifying, its with
1H-NMR and LC/MS (LRMS (M+H
+) m/z 496.64) characterize.
Embodiment 53
To the solution at room temperature of the aniline 1 in dimethyl formamide (3 milliliters) (500 milligrams, 1.3 mmoles), add salt of wormwood (1.5 gram) and 1-bromine pinacolone (pinacolone) (500 milligrams, 2.8 mmoles).Reaction mixture is stirred 4 hours under 50 ℃, and solvent is removed in a vacuum.Resistates is distributed in vinyl acetic monomer (3 * 50 milliliters) extraction.Organic layer through merging is dry and concentrated in a vacuum on sodium sulfate.Resistates provides 2 (320 milligrams, 51%) with flash column chromatography analysis (silica gel, vinyl acetic monomer) purifying, its with
1H-NMR and LC/MS (LRMS (M+H
+) m/z479.74) characterize.
Solution at room temperature to 2 (307 milligrams, 0.64 mmole) in triethyl orthoformate (20 milliliters) adds dense water-based HCl (25 microlitre).The gained mixture is stirred 3 hours under 90 ℃, and cool to room temperature then.Solvent is removed in a vacuum, and resistates is distributed between water (15 milliliters) and the vinyl acetic monomer (50 milliliters).Layer separates, and organic layer is with water (3 * 20 milliliters) and salt solution (3 * 20 milliliters) washing, and dry on sodium sulfate.Solvent is removed, and is produced as thickness buttery intermediate 3 (326 milligrams, 100%), and it is with LC/MS (LRMS (M+H
+) m/z 507.1) characterize.
Intermediate 3 (207 milligrams, 0.41 mmole) and ammonium acetate in methane amide are stirred 4.5 hours under nitrogen pressure, 130 ℃.Gained solution is cooled to room temperature, and is distributed between vinyl acetic monomer (50 milliliters) and the water (50 milliliters).Layer separates, and organic layer washs with water (4 * 10 milliliters) and salt solution (20 milliliters), and dry on sodium sulfate.Solvent is removed in a vacuum, and resistates with reversed-phase HPLC, use acetonitrile and water gradient to be the moving phase purifying, produce imidazoles 4 (159 milligrams, 80%), it is separated, and with
1H-NMR and LC/MS (LRMS (M+H
+) m/z 488.2) characterize.
The solution at room temperature of 4 (159 milligrams, 0.33 mmole) in methylene dichloride (4 milliliters) is added trifluoracetic acid (4 milliliters), and gained solution is stirred at room temperature and spends the night.Solvent is removed in a vacuum, is provided as the amine 5 (89 milligrams) of vitreous solid, and it is measured as enough pure and is used for follow-up conversion (LC/MS LRMS (M+H
+) m/z 274.1).
Rough amine (72 milligrams, 0.26 mmole) with the diisopropyl ethyl amine in dimethyl formamide (3 milliliters) (197 microlitres, 1.1 mmoles) was at room temperature stirred 5 minutes, add intermediate 6 (100 milligrams, 0.26 mmole) afterwards.The gained mixture is stirred 30 minutes again, and solvent is removed in a vacuum.Rough resistates with reversed-phase HPLC, use acetonitrile and water gradient to be the moving phase purifying, be produced as the compound 7 (10 milligrams, 8%) of vitreous solid, its with
1H-NMR and LC/MS (LRMS (M+H
+) m/z 470.2) characterize.
Embodiment 54
Solution at room temperature to the alcohol 1 in benzene (50 milliliters) (2.59 grams, 9.4 mmoles) is added on 2,2-Propanal dimethyl acetal (1.75 milliliters, 14.1 mmoles) and right-toluenesulphonic acids (179 milligrams, 0.94 mmole).Gained solution is stirred 1.5 hours under nitrogen pressure, 110 ℃.Solvent is removed in a vacuum, and resistates provides 2 (756 milligrams, 27%) with flash column chromatography analysis (silica gel, vinyl acetic monomer/hexane) purifying, and it is with LC/MS (LRMS (M+H
+) m/z 317.4) characterize.
2 (765 milligrams, 2.4 mmoles) and the oxammonium hydrochloride (336 milligrams, 4.8 mmoles) in methyl alcohol (10.0 milliliters, 5.0 mmoles, 0.5 volumetric molar concentration) are nitrogen pressure, 50 ℃ of following stirrings 2 hours.It is cooled to room temperature then, and solvent is removed in a vacuum.Resistates is distributed between saturated aqueous ammonium chloride (30 milliliters) and the vinyl acetic monomer (30 milliliters), and layer separates, and water extracts with vinyl acetic monomer (2 * 30 milliliters).Organic layer through merging is dry and concentrated in a vacuum on sodium sulfate.Resistates provides intermediate 3 (314 milligrams, 38%) with flash column chromatography analysis (silica gel, hexane/ethyl acetate) purifying, its with
1H-NMR and LC/MS (LRMS (M+H
+) m/z 350.1) characterize.
To the solution at room temperature of 3 (314 milligrams, 0.9 mmole) in methyl alcohol (15 milliliters), add Raney nickel (50 milligrams) and acetic acid (300 microlitre).The gained mixture is stirred 2 hours under nitrogen pressure, room temperature.It filters through Celite, and concentrates in a vacuum, is provided as 4 (275 milligrams, 0.83 mmole) of white solid, and it is measured as enough pure and is used for follow-up conversion (LC/MS LRMS (M+H
+) m/z 414.1)).
Solution at room temperature to the amidine 4 in dehydrated alcohol (15 milliliters) (138 milligrams, 0.4 mmole), add 1,8-two azo dicyclo [5.4.0] undecane-7-alkene (622 microlitres, 4.2 mmoles) and 3-bromo-1,1,1-three fluoro-2-butanone (84 microlitres, 0.6 mmole).The gained mixture is stirred 30 minutes under nitrogen pressure, 115 ℃.It is cooled to room temperature then, and solvent is removed in a vacuum.Resistates with reversed-phase HPLC, use acetonitrile and water gradient to be the moving phase purifying, produce compound 5 (29 milligrams, 17%), its with
1H-NMR and LC/MS (LRMS (M+H
+) m/z 414.1) characterize.
To the solution of the imidazoles 5 in anhydrous dimethyl formamide (5 milliliters) (29 milligrams, 0.07 mmole), add salt of wormwood (39 milligrams, 0.28 mmole) and Dimethylsulfate (133 microlitres, 1.40 mmoles).The gained mixture is stirred 24 hours under 50 ℃, solvent is removed in a vacuum afterwards.Resistates uses flash column chromatography analysis (silica gel, vinyl acetic monomer/hexane) purifying, is provided as 6 (15 milligrams, 43%) of vitreous solid, its with
1H-NMR and LC/MS (LRMS (M+H
+) m/z 428.3) characterize.
The solution of 6 (15 milligrams, 0.04 mmole) in anhydrous methanol (3 milliliters) at room temperature stirred 16 hours with DOWEX 50WX8-400 ion exchange resin (100 milligrams).Resin is removed with filtration, and washs with triethylamine (3 milliliters).Solvent is removed under high vacuum, and 7 (12 milligrams, 0.04 mmole) are provided, and it is measured as enough pure and is used for the next (LRMS (M+H of conversion
+) m/z 288.2).
To the solution at room temperature of the amine 7 in dimethyl formamide (3 milliliters) (12 milligrams, 0.04 mmole), be added on diisopropyl ethyl amine (20 microlitres, 0.10 mmole).Gained solution at room temperature is stirred 5 minutes, adds intermediate 8 (16 milligrams, 0.04 mmole) afterwards.Reaction mixture is stirred 30 minutes again.Solvent is removed in a vacuum, and resistates is provided as 9 (10 milligrams, 50%) of vitreous solid with flash column chromatography analysis (silica gel, ethanol/methylene) purifying, its with
1H-NMR and LC/MS analyze (LRMS (M+H
+) m/z 484.2) characterize.
Embodiment 55
Solution to the Boc-L-β-Gao tyrosine in methyl alcohol (200 milliliters) (5 grams, 13 mmoles) dropwise adds trimethyl silyl two azomethanes (2 volumetric molar concentrations in hexane, 40 milliliters, 78 mmoles).If need, reagent is added continuously, stops up to bubble.Mixture is concentrated, and produces 2 (5.5 grams), and it is used to next step and does not have and be further purified.LRMS(M+H
+)m/z 300.3。
Solution to 2 (5.5 grams, 13.76 mmoles) in THF (100 milliliters) adds LAH (1.0 volumetric molar concentrations in THF, 13.7 milliliters, 13.7 mmoles).Gained solution is stirred 2 hours, and comes stopped reaction to add MeOH (～20 milliliters).Solvent is evaporated then, obtains little yellow solid, and it dilutes with vinyl acetic monomer, and with saturated NaHCO
3Washing.Organic layer is with the salt water washing, at Na
2SO
4On be dried and under reduced pressure be concentrated, resistates is produced as 3 (3.5 grams, 70%) of white solid, LRMS (M+H via washing away column chromatography analysis, using vinyl acetic monomer and hexane class mixture to be elutriant
+) m/z 394.4.
The solution of 3 (1.9 grams, 5 mmoles) in MeOH (40 milliliters) is at H
2There are stirring down 30 hours in stream (50psi), 10%Pd/C.Filter removes with filtration catalyzer, and solvent evaporation through PTFE (0.45 micron), produces white solid (1.5 gram), and it stirred 2 hours in TFA (1 milliliter) and DCM (9 milliliters) mixture.Gained solution is concentrated, and is used to next step and does not have be further purified.LRMS(M+H
+)m/z 182.3。
To the solution of 4 (926 milligrams, 5 mmoles) in THF (10 milliliters), add 5 (950 milligrams, 2.6 mmoles) and N, N-diisopropyl ethyl amine (4.5 milliliters, 25.5 mmoles).Reaction mixture at room temperature is stirred 10 hours.Mixture is concentrated, and dry on high vacuum.The gained raw product via quick silicagel column, use vinyl acetic monomer to be elutriant, produce 6 (710 milligrams, 74%), LRMS (M+H
+) m/z 370.4.
To the solution of 6 (70 milligrams, 0.2 mmole) in DMF (1 milliliter), add 4-fluoro benzyl bromide (0.15 milliliter, 1.2 mmoles) and salt of wormwood (166 milligrams, 1.2 mmoles).The gained mixture at room temperature is stirred 12 hours.Mixture is filtered, and filtrate on RP-HPLC, use the purifying mixture of acetonitrile and water.Produce 1c (35 milligrams, 37%).LRMS(M+H
+)m/z 477.5。
Embodiment 56
Imidate 15 (20 milligrams, 0.05 mmole), PIVALIC ACID CRUDE (25) hydrazides (hydrazide) (9 milligrams, 0.08 mmole) and acetic acid (1 milliliter) solution stirred 1 hour down at 80 ℃.Reaction mixture concentrates in a vacuum then.The gained resistates produces the tetrazolium 16 of 10 milligrams (43%) with reversed-phase HPLC (C18, acetonitrile/water) purifying.LRMS(M+H
+)m/z 471.2。
Embodiment 57
Pentafluorophenyl group ester 29 (1.0 grams, 2.62 mmoles), amine 29 (0.49 milliliter, 3.15 mmoles) and THF (10 milliliters) solution stirred 4 hours down at 23 ℃.Reaction soln concentrates in a vacuum, and the gained resistates is with column chromatography analysis (silica gel, 1: 1 EtOAc: hexane), produce the acid amides 30 of 1.1 grams (88%).LRMS(M+H
+)m/z 396.1。
Bromide 30 (200 milligrams, 0.51 mmole), two (triphenylphosphine) palladiums (II) (35 milligrams, 0.05 mole) of dichloro, tributyl (1-vinyl ethyl ether base) tin (0.34 milliliter, 1.0 mmoles) and toluene (2 milliliters) solution are at N
2Down, 100 ℃ were stirred 4 hours.When finishing, with the LCMS monitoring, reaction mixture is cooled, filters via cotton, and concentrates in a vacuum.The gained resistates is with flash column chromatography analysis (silica gel, 1: 4: 0.1 EtOAc: hexane class: triethylamine), produce the vinylbenzene 31 of 100 milligrams (52%).LRMS(M+H
+)m/z 388.2。
Compound 31 (100 milligrams, 0.25 mmole), THF: H
2O (3: 1,4 milliliters) and N-bromine succinimide (46 milligrams, 0.25 mmole) stirred 15 minutes down at 23 ℃.Reaction mixture concentrates in a vacuum then, and rough resistates is with EtOAc (30 milliliters) dilution, with water (10 milliliters) washing, and concentrates in a vacuum.The gained resistates is with flash column chromatography analysis (silica gel, 4: 1 EtOAc: the hexane class), produce the bromoketone 32 of 50 milligrams (46%).LRMS(M+H
+)m/z 438.1。
Bromoketone 32 (50 milligrams, 0.11 mmole), K
2CO
3(47 milligrams, 0.34 mmole), tertiary butyl amidine hydrochloride (21 milligrams, 0.23 mmole) and DMF (2 milliliters) solution stirred 18 hours down at 23 ℃.Reaction mixture concentrates down in high vacuum (0.1 mm Hg), and the gained resistates is with column chromatography analysis (silica gel, 2: 1 EtOAc: the hexane class) purifying, the imidazoles 34 of generation 35 milligrams (72%).LRMS(M+H
+)m/z 440.2。
Embodiment 58
Chloroform (20 milliliters) was slowly added at H in 2 hours
2In Boc-tyrosine among the O (400 milliliters) (20 grams, 71 mmoles) and the 10%NaOH solution.After totally 4 hours, reaction soln is with 3 equivalent concentration HCl (200 milliliters) acidifying, and extracts with EtOAc (3 * 150 milliliters).Organic layer (the MgSO that is dried
4), filter, and concentrate in a vacuum.The gained resistates is with flash column chromatography analysis (silica gel, 1: 1: 0.1 hexane class: EtOAc: AcOH), produce 34 of 6.3 aldehyde 35 that restrain and some recovery.
Aldehyde 35 (having 34 to pollute, 6.3 grams, 20 mmoles), K
2CO
3(5.8 grams, 42 mmoles), bromotoluene (5.0 milliliters, 42 mmoles) and DMF (100 milliliters) solution stirred 18 hours down at 23 ℃.Reaction mixture dilutes with EtOAc (200 milliliters), and washs, filters with 1 equivalent concentration HCl (3 * 200 milliliters) and salt solution (3 * 200 milliliters), and concentrates in a vacuum.The gained resistates is with column chromatography analysis (silica gel, 1: 4 EtOAc: hexane), produce the ester 36 of 2.2 grams (22%).LRMS(M+H
+)m/z 490.2。
Aldehyde 36 (570 milligrams, 1.16 mmoles), KMnO
4(368 milligrams, 2.32 mmole), dioxs (3 milliliters) and water (10 milliliters) solution stirred 3 hours down at 23 ℃.Reaction mixture concentrates in a vacuum, and the gained resistates is with column chromatography analysis (silica gel, 1: 1 EtOAc: hexane), produce the acid 37 of 350 milligrams (60%).LRMS(M+H
+)m/z506.2。
Acid 37 (115 milligrams, 0.23 mmole), dimethyl amine (0.23 milliliter, in THF 2.0 volumetric molar concentrations), 1-ethyl-3-(3-dimethyl amine propyl group) carbodiimide hydrochloride (65 milligrams, 0.34 mmole), diisopropyl ethyl amine (0.12 milliliter, 0.68 mmole) and CH
2Cl
2(1 milliliter) solution stirred 4 hours down at 23 ℃.Reaction mixture dilutes with EtOAc (10 milliliters) then, and with 1 equivalent concentration HCl (5 milliliters) and salt solution (5 milliliters) washing.Organic layer (the MgSO that is dried
4), filter and concentrate in a vacuum.The gained resistates is with flash column chromatography analysis (silica gel, 1: 1 hexane class: EtOAc), produce the acid amides 38 of 60 milligrams (49%).LRMS(M+H
+)m/z 533.3。
Acid amides 38 (60 milligrams, 0.11 mmole), TFA: H
2O (97.5: 2.5,1 milliliter) and CH
2Cl
2(1 milliliter) solution stirred 30 minutes down at 23 ℃.Reaction soln concentrates in a vacuum, and the gained resistates was placed in the high vacuum 2 hours, and is used then and does not have and be further purified.
Amine 39 (69 milligrams, 0.16 mmole), pentafluorophenyl group ester 40 (71 milligrams, 0.19 mmole), diisopropyl ethyl amine (83 microlitres, 0.68 mmole) and DMF (10 milliliters) solution stirred 4 hours down at 23 ℃.Reaction soln dilutes with vinyl acetic monomer (10 milliliters) then, and with 1 equivalent concentration HCl (5 milliliters) and salt solution (5 milliliters) washing.Organic layer (the MgSO that is dried
4), filter, and filtrate concentrates in a vacuum.The gained resistates is with flash column chromatography analysis (silica gel, 1: 1 hexane class: EtOAc), produce the esteramides 41 of 60 milligrams (60%).LRMS(M+H
+)m/z 620.3。
Ester 41 (50 milligrams, 0.08 mmole), NaBH
4(24 milligrams, 0.63 mmole), THF (1 milliliter) and MeOH (1 milliliter) solution stirred 18 hours down at 23 ℃.Reaction mixture dilutes with EtOAc (10 milliliters) then, and with 1 equivalent concentration HCl (5 milliliters) and salt solution (5 milliliters) washing.Organic layer (the MgSO that is dried
4), filter, and filtrate concentrates in a vacuum.The gained resistates
With flash column chromatography analysis (silica gel, 1: 50 MeOH: EtOAc), produce the alcohol 42 of 31 milligrams (75%).LRMS(M+H
+)m/z 516.3。
Embodiment 59
Acid 43 (300 milligrams, 1.0 mmoles), K
2CO
3(276 milligrams, 2.0 mmoles), bromotoluene (0.24 milliliter, 2.0 mmoles) and DMF (4 milliliters) solution stirred 18 hours down at 23 ℃.Reaction mixture dilutes with EtOAc (30 milliliters), and with 1 equivalent concentration HCl (10 milliliters) and salt solution (3 * 15 milliliters) washing.Organic layer (the MgSO that is dried
4), filter, and filtrate concentrates in a vacuum.The gained resistates is with flash column chromatography analysis (silica gel, 1: 3 EtOAc: the hexane class), produce the ester 44 of 400 milligrams (83%).LRMS(M+H
+)m/z 480.2。
Ester 44 (100 milligrams, 0.21 mmole), NaBH
4(30 milligrams, 0.81 mmole), THF (0.5 milliliter) and MeOH (0.5 milliliter) solution stirred 2 hours down at 23 ℃.Reaction soln dilutes with EtOAc (10 milliliters) then, and with 1 equivalent concentration HCl (5 milliliters) and salt solution (5 milliliters) washing.Organic layer (the MgSO that is dried
4), filter, and filtrate concentrates in a vacuum.The gained resistates is used and does not have and is further purified.
Alcohol 45 (100 milligrams, 0.27 mmole) and TFA: H
2O (97.5: 2.5,1 milliliter) solution stirred 30 minutes down at 23 ℃.Reaction soln concentrates in a vacuum, and the gained resistates was placed in the high vacuum 2 hours, and is used then and does not have and be further purified.
Amine 46 (40 milligrams, 0.15 mmole), pentafluorophenyl group ester 40 (43 milligrams, 0.12 mmole), triethylamine (51 microlitres, 0.29 Bo mole) and DMF (0.6 milliliter) solution stirred 4 hours down at 23 ℃.Reaction soln dilutes with EtOAc (10 milliliters) then, and with 1 equivalent concentration HCl (5 milliliters) and salt solution (5 milliliters) washing.Organic layer (the MgSO that is dried
4), filter, and filtrate concentrates in a vacuum.The gained resistates is with flash column chromatography analysis (silica gel, 1: 2 hexane class: EtOAc), produce the esteramides 47 of 30 milligrams (43%).LRMS(M+H
+)m/z 463.2。
Embodiment 60
Aldehyde 36 (300 milligrams, 0.6 mmole), dimethyl hydrazides (47 microlitres, 0.6 mmole) and MeOH (2.5 milliliters) solution stirred 2 hours down at 0 ℃, allows then to be warmed to 23 ℃, and restir 15 hours.Reaction soln concentrates in a vacuum, and the gained resistates is used and does not have and be further purified.
To at-5 ℃ of rough hydrazones (hydrazone) 48 (325 milligrams, 0.6 mmole) and CHCl
3(2 milliliters) solution, between dropwise adding-chlorine peroxy phenylformic acid (212 milligrams, 1.23 mmoles) and CHCl
3(2 milliliters).Reaction mixture is allowed to be warmed to 23 ℃, and restir 2 days.Reaction mixture dilutes with EtOAc (10 milliliters) then, and with saturated water-based NaHCO
3(5 milliliters) and salt solution (5 milliliters) washing.Organic layer (the MgSO that is dried
4), filter and concentrate in a vacuum.The gained resistates is with flash column chromatography analysis (silica gel, 1: 2 hexane class: EtOAc), produce the nitrile 49 of 100 milligrams (34%).LRMS(M+H
+)m/z 487.2。
Nitrile 49 (60 milligrams, 0.27 mmole) and TFA: H
2O (97.5: 2.5,2 milliliters) solution stirred 30 minutes down at 23 ℃.Reaction soln concentrates in a vacuum, and the gained resistates was placed in the high vacuum 2 hours, and is used then and does not have and be further purified.
Amine 50 (100 milligrams, 0.25 mmole), pentafluorophenyl group ester 40 (85 milligrams, 0.22 mmole), triethylamine (96 microlitres, 0.74 mmole) and DMF (1 milliliter) solution stirred 4 hours down at 23 ℃.Reaction mixture dilutes with EtOAc (10 milliliters) then, and with 1 equivalent concentration HCl (5 milliliters) and salt solution (5 milliliters) washing.Organic layer (the MgSO that is dried
4), filter and concentrate in a vacuum.The gained resistates with the flash column chromatography analysis (silica gel, 1: 1 hexane class: EtOAc), produce 60 milligrams (42%) 51.LRMS(M+H
+)m/z 574.2。
Ester 51 (60 milligrams, 0.1 mmole), NaBH
4(12 milligrams, 0.3 mmole), THF (1 milliliter) and MeOH (1 milliliter) solution, be maintained at 23 ℃ following 18 hours.Reaction mixture dilutes with EtOAc (10 milliliters) then, and with 1 equivalent concentration HCl (5 milliliters) and salt solution (5 milliliters) washing.Organic layer (the MgSO that is dried
4), filter, and filtrate concentrates in a vacuum.The gained resistates is with flash column chromatography analysis (silica gel, 1: 2 hexane class: EtOAc), produce the alcohol 52 of 30 milligrams (64%).LRMS(M+H
+)m/z 470.2。
Embodiment 61
Acid amides 52 (1.6 gram, 4.38 mmoles) and Diethyl Aniline (5 milliliters) solution, be maintained at 240 ℃ following 18 hours.Reaction mixture is cooled to 23 ℃, dilutes with EtOAc (30 milliliters), and with 1 equivalent concentration HCl (3 * 50 milliliters) and salt solution (2 * 50 milliliters) washing.Organic layer (the MgSO that is dried
4), filter, and filtrate concentrates in a vacuum.The gained resistates is with flash column chromatography analysis (silica gel, 2: 1 hexane classes: EtOAc), produce the phenol 56 of 1 gram (63%).LRMS(M+H
+)m/z 365.2。
Phenol 56 (700 milligrams, 1.92 mmoles), Cs
2CO
3(1.25 milligrams, 3.84 mmoles), bromotoluene (0.46 milliliter, 3.84 mmoles) and DMF (10 milliliters) solution stirred 2 hours down at 50 ℃.Reaction mixture is with EtOAc (30 milliliters) dilution, with 1 equivalent concentration HCl (20 milliliters) and salt solution (3 * 30 milliliters) washing.Organic layer (the MgSO that is dried
4), filter, and filtrate concentrates in a vacuum.The gained resistates is with flash column chromatography analysis (silica gel, 1: 3 EtOAc: the hexane class), produce the acid amides 57 of 500 milligrams (57%).LRMS(M+H
+)m/z 455.2。
Acid amides 57 (150 milligrams, 0.33 mmole), perosmic anhydride (8 milligrams, 0.03 mmole), N-methylmorpholine-N-oxide compound (182 milligrams, 1.55 mmoles), pyridine (2.4 microlitres, 0.03 mmole), THF (2 milliliters) and H
2The solution of O (2 milliliters) is maintained under 23 ℃.After 2 hours, add Celite (1 gram), NaHSO
3(1 gram) and EtOAc (20 milliliters), and gained solution is stirred.After 30 minutes, reaction mixture is filtered and gained filtrate concentrates in a vacuum.The gained resistates produces the glycol 58 of 100 milligrams (62%) with flash column chromatography analysis (silica gel, 3: 1 EtOAc/ hexane classes).LRMS(M+H
+)m/z 489.2。
Glycol 58 (52 milligrams, 0.11 mmole), Pb (OAc)
4And CH
2Cl
2(2 milliliters) solution stirred 30 minutes down at 23 ℃.Reaction mixture is concentrated with post Celite filtration and gained filtrate then, and the aldehyde of colorless oil is provided.
Crude aldehyde (～50 milligrams ,～0.11 Bo mole), NaBH
4The solution of (24 milligrams, 0.63 mmole), THF (1 milliliter) and MeOH (1 milliliter) was kept under 23 ℃ 30 minutes.Reaction mixture is with EtOAc (10 milliliters) dilution, with 1 equivalent concentration HCl (5 milliliters) and salt solution (5 milliliters) washing then.Organic layer (the MgSO that is dried
4), filter, and filtrate concentrates in a vacuum.The gained resistates produces the glycol 59 of 20 milligrams (40%) with flash column chromatography analysis (silica gel, 2: 1 EtOAc/ hexane classes).LRMS(M+H
+)m/z 459.2。
Embodiment 62
The solution of benzoglycols (190 milligrams, 0.54 mmole), boron-THF (1.0 volumetric molar concentrations, 0.54 milliliter) was kept under 23 ℃ 2 hours.Add the boron-THF (0.54 milliliter) of extra deal then.After 2 hours, add the 3rd part (0.54 milliliter) again.Reaction soln kept 18 hours, be cooled to 0 ℃, add 3 equivalent concentration NaOH (0.5 milliliter) and H then
2O
2(0.5 milliliter).At 23 ℃ after following 2 hours, reaction mixture is with EtOAc (20 milliliters) dilution, and washs with salt solution (20 milliliters).Organic layer (the MgSO that is dried
4), filter, and filtrate concentrates in a vacuum.The gained resistates produces the alcohol 61 of 150 milligrams (75%) with flash column chromatography analysis (silica gel, 2: 1 EtOAc/ hexane classes).LRMS(M+H
+)m/z 372.2。
Alcohol 61 (120 milligrams, 0.32 mmole), TFA: H
2O (97.5: 2.5,4 milliliters) solution was kept under 23 ℃ 30 minutes.Reaction soln concentrates in a vacuum, and the gained resistates was placed in the high vacuum 2 hours, and is used then and does not have and be further purified.
Above-mentioned amine (50 milligrams, 0.18 mmole), pentafluorophenyl group ester (82 milligrams, 0.22 mmole), triethylamine (96 microlitres, 0.55 mmole) and DMF (1 milliliter) solution were kept under 23 ℃ 2 hours.Reaction mixture dilutes with EtOAc (10 milliliters) then, and with 1 equivalent concentration HCl (5 milliliters) and salt solution (5 milliliters) washing.Organic layer (the MgSO that is dried
4), filter and concentrate in a vacuum.The gained resistates produces the amine 63 of 6 milligrams (7%) with reversed-phase HPLC (C18, acetonitrile/water) purifying.LRMS(M+H
+)m/z 459.2
Embodiment 63
10 (1.15 grams, 2.71 mmoles) solution in DCM (100 milliliters) adds Dess-Martin Polyvinylpyrolidone (PVP) (periodinane) (2.30 grams, 5.24 mmoles).Reaction mixture is stirred 1 hour, and DCM solution washs with hypo solution and sodium hydrogen carbonate solution afterwards, and dry on sodium sulfate.Mixture is filtered and filtrate under reduced pressure concentrates, and produces 23 (1.0 grams, 87%).
To 23 (30.0 milligrams in DCM (2 milliliters), 0.0711 solution mmole), add diisopropyl ethyl amine (37.0 microlitres, 0.213 mmole), 24 (12.9 microlitres, 0.213 mmoles) and diacetoxy sodium borohydride (20.0 milligrams, 0.142 mmole).Reaction mixture is stirred and spends the night, and under reduced pressure concentrates then.Resistates is at reversed-phase HPLC (C18), use acetonitrile and H
2The O purifying mixture produces 25 (5.6 milligrams, 16.9%).LRMS(M+H
+)m/z467.4。
To 23 (50.0 milligrams, the 0.119 mmole) solution in methyl alcohol (2 milliliters), add diisopropyl ethyl amine (62.0 microlitres, 0.356 mmole), 26 (31.1 microlitres, 0.356 mmoles) and sodium cyanoborohydride (22.4 milligrams, 0.356 mmole).Reaction mixture is stirred and spends the night, and under reduced pressure concentrate then, and resistates is at reversed-phase HPLC (C18), use acetonitrile and H
2The O purifying mixture produces 27 (31.0 milligrams, 22.9%).LRMS(M+H
+)m/z 518.5。
Embodiment 64
1 (1.0 grams, 4.66 mmoles) solution in methyl alcohol (10.0 milliliters) adds SOCl
2(0.68 milliliter, 9.32 mmoles).After at room temperature stirring was spent the night, solution was concentrated in a vacuum, and is not used with having purifying.
To 2 (～1.065 milligrams of rough, the 4.66 mmoles) solution in EtOH (1.5 milliliters), add N
2H
4H
2O (1.13 milliliters, 2.3.3 mmole).Reaction mixture is heated to backflow, and stirs 3 hours.When cooling, solution is with H
2O handles, with the EtOAc extracting twice, at MgSO
4Last dry, filtration and concentrated.From CH
2Cl
2Middle recrystallize is produced as 1.01 of colourless crystallization and restrains 3; Two step 95% productive rates.
3 (0.477 gram, 2.09 mmoles) solution in THF (8.0 milliliters) is added carbonyl dimidazoles (0.379 gram, 2.29 mmoles).When cooling, solution concentrates in a vacuum, and (10-40%, EtOAc/Hex) purifying are produced as 4 of white solid 0.515 gram via the flash column chromatography analysis; 97% productive rate.
To at CH
34 (1.0 equivalents among the CN (2.0 milliliters); General 0.3-1.0 mmole) solution adds electrophilic base (1.1 equivalent) and K
2CO-
3(1.1 equivalent).Reaction mixture under microwave radiation, be heated to 80 ℃ 30 minutes, continuous to filter and to concentrate in a vacuum.Product does not have purifying and is used, or via flash column chromatography purifying (general 10-40%EtOAc/Hex) purifying, provides 5 of general＞90% productive rate.
To 5 (1.0 equivalents; General 0.3-1.0 mmole) adds methylamine (2.0 volumetric molar concentrations in THF, 10.0 equivalents).Reaction mixture under microwave radiation, be heated to 100 ℃ 4 hours, continuous to concentrate in a vacuum.Product provides 6 of general＞70-85% productive rate via flash column chromatography purifying (general 40-80%EtOAc/Hex) purifying.
Embodiment 65
To the 2-aminoacetonitriles hydrosulphite in DCM (50 milliliters) (2.9 grams, 0.013 mole) stirred solution, add benzophenone (3.48 milliliters, 0.0208 mole), continuous with DIEA (4.53 milliliters, 0.026 mole).After stirring 18 hours, DCM solution is with water (50 milliliters) washing, dry on sodium sulfate, filtration and under reduced pressure concentrated.Resistates is gone up purifying at quick silicagel column (hexane class: EtOAc, 1: 1), produces 3 (2.40 grams, 80%).
Two (trimethyl silyl) acid amides lithium (1.0 volumetric molar concentrations in THF) solution in THF (50 milliliters), on acetone-the dry ice bath, under the nitrogen pressure, slowly added to 3 (1.2 grams in THF (50 milliliters), 0.00545 mole) and in right-phenylbenzyl bromine (1.08 gram, 0.00436 mole) stirred solution.After 1 hour, reaction is with interpolation methyl alcohol stopped reaction, and solvent under reduced pressure is evaporated.Resistates is gone up purifying at quick silicagel column (hexane class: EtOAc, 1: 1), obtains 4.4 are suspended among the EtOAc (100 milliliters), and handle with dense HCl (5 milliliters).After stirring 1 hour, solvent under reduced pressure is evaporated, and gained solid 5 is with diethyl ether (50 milliliters) washing three times, and dry under vacuum (0.39 gram, 32.1%).
5 (0.39 gram, 1.75 mmoles) solution in DMF (10 milliliters) at room temperature adds 6 (0.801 gram, 2.11 mmoles) and diisopropyl ethyl amines (0.61 milliliter, 3.5 mmoles).Reaction mixture is stirred and spends the night.Solvent under reduced pressure is evaporated then, and resistates is gone up purifying at quick silicagel column (hexane class: EtOAc, 3: 1), generation 7 (0.40 gram, 54.5%).LCMS(M+H
+)m/z 419.1。
To 7 (50 milligrams, the 0.119 mmole) solution in DMF (2 milliliters), add sodiumazide (15.5 milligrams, 0.239 mmole) and ammonium chloride (12.8 milligrams, 0.238 mmole).Reaction mixture is stirred at 80 ℃ and spends the night, and filters.Filtrate goes up, uses acetonitrile and H at reversed-phase HPLC (C18)
2The O purifying mixture produces 8 (6.40 milligrams, 11.6%).LCMS(M+H
+)m/z 462.4。
Embodiment 66
Flow process A:
3-cyano group-4-[1-(methylethyl) oxygen base] methyl benzoate:
To the 3-cyano group-4-methyl hydroxybenzoate in dimethyl formamide (80 milliliters) (82 grams, 463 mmoles; J.Med.Chem.2002,45,5769) solution adds 2-iodopropane (93 milliliters, 926 mmoles) and salt of wormwood (190 grams, 1.4 moles).The gained mixture is 50 ℃ of down heating 16 hours, in that it was allowed cool to room temperature at that time.Reaction is filtered, and mother liquor dilutes with 0.5 equivalent concentration sodium hydroxide (1 liter).The gained mixture is with ether (2 * 1 liters) extraction, and organism is with 1 equivalent concentration HCl (1 liter) and salt solution (700 milliliters) washing, dry (MgSO
4) and concentrate, producing 100 grams (～100%) is 3-cyano group-4-[1-(methylethyl) oxygen base of yellow solid] methyl benzoate.
3-cyano group-4-[1-(methylethyl) oxygen base] phenylformic acid:
To 3-cyano group-4-[1-(methylethyl) oxygen base in tetrahydrofuran (THF) (500 milliliters)] 0 ℃ of solution of methyl benzoate (100 gram, 463 mmoles), add 10% potassium hydroxide (500 milliliters).Gained solution is allowed to be warmed to room temperature, and keeps 16 hours, in that it was concentrated at that time, to remove tetrahydrofuran (THF).Resistates dilutes with water (500 milliliters), and washs with ether (2 * 500 milliliters).Water layer is with 3 equivalent concentration HCl acidifyings then, and leaves standstill 2 hours.Solid is collected to filter, and with water washing several times, is dissolved in then in the methylene dichloride (1 liter).Most homogeneous mixture filters through Celite, and is concentrated to the methylene dichloride of minimum volume.Solid is collected to filter, and producing 82 grams (86%) is 3-cyano group-4-[1-(methylethyl) oxygen base of white solid] phenylformic acid.
Flow process B:
Reagent and condition: a) 4 equivalent concentration HCl/ dioxs, room temperature; B) HTBU, i-Pr
2NEt, DMF, room temperature; C) 1-vinyl ethyl ether base-normal-butyl tin, PdCl
2(PPh
3)
2, diox, 100 ℃; D) NBS, THF/H
2O (3: 1), room temperature; E) 2-amino-3-picoline (picoline), NaHCO
3, i-PrOH, 80 ℃.
(3S)-3-amino-4-(4-bromophenyl)-1-Kauri-butanol hydrochloric salt
(3S)-and the 1-[(4-bromophenyl) methyl]-the 3-hydroxypropyl } carboxylamine 1,1-dimethyl ethyl ester (4.4 grams, 12.8 mmoles) is dissolved in 4 equivalent concentration HCl/ dioxs (20 milliliters).After 2 hours, reaction mixture concentrates in a vacuum, and producing 3.69 grams (94%) is the title compound of white solid.LC/MS(ES)m/e 244.0(M+H
+)。
N-{ (1S)-1-[(4-bromophenyl) methyl-3-hydroxypropyl }-3-cyano group-4-[(1-methylethyl) the oxygen base] benzamide
To it (3S)-3-amino-4-(4-bromophenyl)-1-Kauri-butanol hydrochloric salt in dried DMF (32 milliliters) (1.80 grams, 6.42 mmoles) suspension, add N, N-diisopropyl ethyl amine (2.49 grams, 19.3 mmoles), and the gained settled solution is stirred 3 minutes.Add 3-cyano group-4-[1-(methylethyl) oxygen base] phenylformic acid (1.45 grams, 7.06 mmoles) and HBTU (2.68 grams, 7.06 mmoles), and be reflected at the stirring down of room temperature, nitrogen.After 1.5 hours, reaction mixture is with water (50 milliliters) stopped reaction, and extracts with EtOAc (3 * 30 milliliters).Extract (the Na that is dried
2SO
4), filter, and under reduced pressure concentrate.Resistates is with silica gel chromatography analysis (75%EtOAc/ hexane class) purifying, and producing 2.18 grams (78%) is the title compound of white solid.LC/MS(ES)m/e 431.2(M+H
+)。
N-((1S)-1-{[4-(bromophenyl ethanoyl) phenyl] methyl }-the 3-hydroxypropyl }-3-cyano group-4-[(1-methylethyl) the oxygen base] benzamide
One under argon gas with heating gun exsiccant flask, with N-{ (1S)-1-[(4-bromophenyl) methyl-3-hydroxypropyl }-3-cyano group-4-[(1-methylethyl) the oxygen base] (81 milligrams of benzamide (1.0 gram, 2.32 mmoles), two (the triphenylphosphine)-palladiums (II) of dichloro, 0.116 tributyl (1-vinyl ethyl ether base) tin (1.68 grams mmole),, 4.64 mmole) and 1,4-diox (15 milliliters) charging.Mixture stirred 2 hours under 100 ℃, argon gas.When finishing, with LCMS monitoring, reaction under reduced pressure concentrates, and resistates purifying (65%EtOAc/ hexane class adds 5% triethylamine) on not activated silica gel at once, producing 720 milligrams is the enol ether intermediate of colourless foam, and it is dissolved in THF: H at once
2Among the O (3: 1,18 milliliters), and with N-bromine succinimide (318 milligrams, 1.79 mmoles).After at room temperature 15 minutes, reaction mixture under reduced pressure concentrates, and rough resistates is with EtOAc (30 milliliters) dilution, with salt solution (10 milliliters) and water (10 milliliters) washing, and under reduced pressure concentrates.Resistates produces 651 milligrams of title compounds that (59%) is white sticky solid with silica gel chromatography analysis (80%EtOAc/ hexane class) purifying.LC/MS(ES)m/e 473.2(M+H
+)。
3-cyano group-N-((1S)-3-hydroxyl-1-{[4-(the 8-Methylimidazole is [1,2-a] pyridine-2-yl also) phenyl] methyl } propyl group)-the 4-[(1-methylethyl) the oxygen base] benzamide
To the N-in i-PrOH (6 milliliters) ((1S)-1-{[4-(bromophenyl ethanoyl) phenyl] methyl }-the 3-hydroxypropyl-3-cyano group-4-[(1-methylethyl) the oxygen base] benzamide (1.0 gram, 2.32 mmoles) solution; add 2-amino-3-picoline (Aldrich; 69 milligrams; 0.634 it is mmole), continuous with solid NaHCO
3(64 milligrams, 0.761 mmole).Gained suspension is heated to 80 ℃.After 7 hours, most i-PrOH under reduced pressure is removed, and resistates is dissolved among the 3%MeOH/EtOAc (30 milliliters), and with water (10 milliliters) and salt solution (10 milliliters) washing.Water layer through combination extracts with 3%MeOH/EtOAc (30 milliliters), and washs with water (10 milliliters) and salt solution (10 milliliters) through the extract of combination.Through the water layer extract of the combination (Na that is dried
2SO
4), filter and under reduced pressure be concentrated.Resistates is with reversed-phase HPLC (MeCN/H
2O has 0.1%TFA) purifying, and clarification is partly with saturated water-based NaHCO
3Adjust to pH～8, and extract with 3%MeOH/EtOAc (30 milliliters).Extract (the Na that is dried
2SO
4), filter and under reduced pressure be concentrated, producing 215 milligrams (70%) is lark solid title compound.LC/MS(ES)m/e483.2(M+H
+)。
Flow process C:
1-(2-amino-3-pyridyl) ethanol
Flask (under argon gas with the heating gun drying) is added dry THF (400 milliliters) and MeLi-LiBr (at Et via sleeve pipe
2Among the O in 1.5 volumetric molar concentrations 137 milliliters).When the amino pyridine of the 2-in THF (150 milliliters)-3-carboxylic aldehyde (10.0 grams, 82.0 mmoles) solution added via pressure equilibrium funnel in～45 minutes, have vigorous stirring ground dropwise to add (to observe heat release, orange is kept) time, this solution is cooled to-78 ℃.When finishing, solution is allowed at-78 ℃ to stir 1 hour, (KMnO under the heating is arranged at TLC at that time
4Dyeing) point out that most initial substance is converted to product.Reaction is ended carefully with water (200 milliliters, originally dropwise), extracts and allow with EtOAc (200 milliliters) to be warmed to room temperature.Layer separates and water layer extracts with 3%MeOH/EtOAc.The extract of combination is dry on sodium sulfate, filter and under reduced pressure be concentrated.Resistates is with silica gel chromatography analysis (Analogix: 0 to 5%MeOH in EtOAc) purifying, produce 7.78 grams (68%) by yellow oily wanted the racemization product, it solidified several days under high vacuum.This material with SFC, chiralcel OD-H (20 * 250 millimeters) post (0.1% isopropylamine/0.1% isopropylamine of 10%EtOH/ in heptane) be separated into its respectively enantiomer (＞98%ee).
Flow process D:
[(1S)-1-(4-[1-(oxyethyl group) vinyl] and phenyl } methyl)-the 3-hydroxypropyl } carboxylamine 1,1-dimethyl ethyl ester:
To in the Zai diox (500 milliliters) it (1S)-the 1-[(4-bromophenyl) methyl]-the 3-hydroxypropyl-carboxylamine 1,1-dimethyl ethyl ester (20 grams, 58 mmoles) solution adds tributyl [1-(oxyethyl group) vinyl] stannate (39 milliliters, 116 mmoles) and PdCl
2(PPh
3)
2Gained solution heated 5 hours down at 100 ℃.Reactant is concentrated then, and resistates is with flash column chromatography analysis (47.5%EtOAc, 47.5% hexane class, 5% triethylamine), produce 15 grams (77%) and be brown solid [(1S)-1-({ 4-[1-(oxyethyl group) vinyl] phenyl } methyl)-3-hydroxypropyl carboxylamine 1,1-dimethyl ethyl ester.
[(1S)-1-(4-[1-(acetyl bromide) phenyl] methyl }-the 3-hydroxypropyl } carboxylamine 1,1-dimethyl ethyl ester:
To in tetrahydrofuran (THF) (450 milliliters) and the water (150 milliliters) it [(1S)-1-({ 4-[1-(oxyethyl group) vinyl] phenyl } methyl)-3-hydroxypropyl carboxylamine 1,1-dimethyl ethyl ester (15 grams, 44 mmoles) cooling (0 ℃) solution adds N-bromine succinimide.Gained solution is allowed to be warmed to room temperature, and keeps 90 minutes.Reactant is concentrated then, and with vinyl acetic monomer dilution (1 liter).Gained solution is with the washing of water (1 liter) and salt solution (500 milliliters), dry (MgSO
4) and be concentrated, produce 19.5 grams (～100%) and be little yellow solid [(1S)-1-({ 4-[1-(acetyl bromide) phenyl] methyl }-3-hydroxypropyl } carboxylamine 1,1-dimethyl ethyl ester.ESMS[M+H]
+：386.2。
[(1S)-3-hydroxyl-1-(4-[8-(1-hydroxyethyl) imidazo [1,2-a] pyridine-2-yl] and phenyl } methyl) propyl group] carboxylamine 1,1-dimethyl ethyl ester:
In Virahol (25 milliliters) it [(1S)-1-({ 4-[1-(acetyl bromide) phenyl] methyl }-3-hydroxypropyl } carboxylamine 1; 1-dimethyl ethyl ester (1.00 grams, 2.59 mmoles), 1-(2-amino-3-pyridyl) ethanol (0.358 gram, 2.59 mmoles) and solid sodium bicarbonate (0.272 gram, 3.24 mmoles) mixture; heating is 3.5 hours under refluxing, and concentrates in a vacuum.Resistates is dissolved in the vinyl acetic monomer, Yi Shui and salt water washing, drying (Na
2SO
4) and concentrate.The gained yellow solid does not have to be further purified and is used to next reaction.MS(ES+)m/e 426[M+H]
+。
3-chloro-N-[(1S)-3-hydroxyl-1-(4-[8-(1-hydroxyethyl) imidazo [1,2-a] pyridine-2-yl] and phenyl } methyl) propyl group]-the 4-[(1-methylethyl) the oxygen base] benzamide:
[(1S)-3-hydroxyl-1-({ 4-[8-(1-hydroxyethyl) imidazo [1,2-a] pyridine-2-yl] phenyl } methyl) propyl group] carboxylamine 1,1-dimethyl ethyl ester (1.08 grams, 2.54 mmole) reach 1, the mixture of 4 equivalent concentration HCl in the 4-diox (8.0 milliliters, 32 mmoles) at room temperature is stirred 30 minutes.The reaction be concentrated into dried, be dissolved among the DMF (25 milliliters) again, and this solution is added N, N-diisopropyl ethyl amine (1.64 grams, 12.7 mmoles) and 3-chloro-4-[(1-methylethyl) the oxygen base] phenylformic acid pentafluorophenyl group ester (0.963 gram, 2.54 mmoles).Mixture at room temperature is stirred 3.0 hours, with the water dilution and with ethyl acetate extraction.Extract is with the washing of water and saturated sodium-chloride, dry (Na
2SO
4) and concentrate in a vacuum.(2%MeOH: EtOAc) purifying is produced as the title compound (0.7 gram, 53%) of lark powder to resistates with the fast chromatographic on silica gel.MS(ES+)m/e 522[M+H]
+。
Flow process E:
[(1S)-and 2-(4-bromophenyl)-1-(methylol) ethyl] carboxylamine 1,1-dimethyl ethyl ester:
To the 4-bromine N-{[(1 in the anhydrous diethyl ether (550 milliliters), 1-dimethyl ethyl) the oxygen base] carbonyl }-solution of L-phenylalanine (72.6 mmole) under 0 ℃, slowly add lithium aluminum hydride 95% (108.9 mmole).Gained solution was 0 ℃ of following restir 2 hours.React then and at room temperature stirred half an hour with saturated sodium bicarbonate aqueous solution (73 milliliters) carefully and end.Aluminium lithium salts class is forced out solution, and it removes with filtration.Filtrate is concentrated and vacuum pump 24 hours, is provided as the title compound (97%) of white solid.ESMS[M+H]
+：331.2。
(1S)-and 2-(4-bromophenyl)-1-[(1,3-dioxo-1,3-dihydro-2H-isoindole-2-yl) methyl] ethyl } carboxylamine 1,1-dimethyl ethyl ester:
To it [(1S)-2-(4-bromophenyl)-1-(methylol) ethyl] carboxylamine 1 in anhydrous tetrahydro furan (550 milliliters), 0 ℃ of solution of 1-dimethyl ethyl ester (70.6 mmole), triphenylphosphine (84.7 mmole) and O-phthalic sulfilimine (84.7 mmole) dropwise added diisopropyl azo-2-carboxylic acid's (84.7 mmole) in 10 minutes.Reaction continues to stir, and allows in 5 hours to be warmed to room temperature.Reaction is concentrated in a vacuum then, and product uses acetic ester (500 milliliters) to go out from solution triarated.Precipitation is filtered, extracts and drying with vinyl acetic monomer (3 * 100 milliliters), is produced as the title compound (57%) of white solid.ESMS[M+H]
+：460.4。
(1S)-and the 2-[4-acetyl bromide) phenyl]-1-[(1,3-dioxo-1,3-dihydro-2H-isoindole-2-yl) methyl] ethyl } carboxylamine 1,1-dimethyl ethyl ester:
(1S)-2-(4-bromophenyl)-1-[(1,3-dioxo-1,3-dihydro-2H-isoindole-2-yl) methyl] ethyl } carboxylamine 1, the solution of 1-dimethyl ethyl ester (21.7 mmole), 1-vinyl ethyl ether base-normal-butyl tin (43.5 mmole) and two (triphenylphosphine) palladiums (II) (5 moles of %) of anti--dichloro, in no Shui diox (300 milliliters), 100 ℃ stirred 3 hours down.Reaction is concentrated in a vacuum then, and is dissolved in tetrahydrofuran (THF) and the water (3: 1,400 milliliters) again, and handles with N-bromine succinimide (108.8 mmole), and at room temperature stirs half an hour.Then reaction soln be concentrated into dried, be dissolved in the vinyl acetic monomer (150 milliliters) again, and be deposited in and add hexane (350 milliliters) time and be found.Precipitation is filtered and is dry, is produced as the title compound (71%) of yellow solid.ESMS[M+H]
+：502.4。
(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindole-2-yl)-1-(4-[8-(1-hydroxyethyl) imidazo [1,2-a] pyridine-2-yl] and phenyl } methyl) ethyl] carboxylamine 1,1-dimethyl ethyl ester:
In Virahol (24 milliliters) it (1S)-the 2-[4-acetyl bromide) phenyl]-1-[(1; 3-dioxo-1; 3-dihydro-2H-is different-the 2-yl) and methyl] ethyl } carboxylamine 1; 1-dimethyl ethyl ester (1.90 grams, 3.799 mmoles), 1-(2-amino-3-pyridyl) ethanol (0.523 gram, 3.79 mmoles) and solid sodium bicarbonate (0.398 gram, 4.72 mmoles) mixture; refluxed 3.0 hours, and concentrated in a vacuum.Resistates is dissolved in the vinyl acetic monomer, with water and saturated sodium-chloride washing, dry (Na
2SO
4) and concentrate, be produced as baby pink solid title compound (1.79 grams, 87%).MS(ES+)m/e 541[M+H]
+。
3-chloro-N-[(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindole-2-yl)-1-(4-[8-(1-hydroxyethyl) imidazo [1,2-a] pyridine-2-yl] and phenyl } methyl) ethyl]-the 4-[(1-methylethyl) the oxygen base] benzamide:
(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindole-2-yl)-1-({ 4-[8-(1-hydroxyethyl) imidazo [1,2-a] pyridine-2-yl] phenyl } methyl) ethyl] carboxylamine 1,1-dimethyl ethyl ester (1.79 grams, 3.31 mmole) reach 1, the mixture of 4 equivalent concentration HCl in the 4-diox (20 milliliters, 80 mmoles) at room temperature is stirred 45 minutes.The reaction be concentrated into dried, be dissolved among the DMF (30 milliliters) again, and this solution is added N, N-diisopropyl ethyl amine (2.14 grams, 16.55 mmoles) and 3-chloro-4-[(1-methylethyl) the oxygen base] phenylformic acid pentafluorophenyl group ester (1.36 grams, 3.31 mmoles).Mixture at room temperature be stirred spend the night, with water dilution and with ethyl acetate extraction.Extract is with water washing, drying (Na
2SO
4) and concentrate in a vacuum, be produced as dark brown solid title compound (2.10 grams, 100%).MS(ES+)m/e 637[M+H]
+。
N-[(1S)-2-amino-1-(4-[8-(1-hydroxyethyl) imidazo [1,2-a] pyridine-2-yl] and phenyl } methyl) ethyl]-3-chloro-4-[(1-methylethyl) the oxygen base] benzamide:
3-chloro-N-[(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindole-2-yl)-1-({ 4-[8-(1-hydroxyethyl) imidazo [1,2-a] pyridine-2-yl] phenyl } methyl) ethyl]-the 4-[(1-methylethyl) the oxygen base] benzamide (2.10 grams, 3.30 (0.83 gram of the hydrazine monohydrate mmole) and in ethanol (30 milliliters), 16.5 mixture mmole) is stirred under 57 ℃ and spends the night.Reaction is cooled, with alcohol dilution, filtration and concentrate, be produced as lark solid title compound (1.67 grams, 100%).MS(ES+)m/e 507[M+H]
+。
3-chloro-N-[(1S)-and 2-[(N, N-dimethyl glycyl)-1-(4-[8-(1-hydroxyethyl) imidazo [1,2-a] pyridine-2-yl] and phenyl } methyl) ethyl]-the 4-[(1-methylethyl) the oxygen base] benzamide:
To the N-[(1S in methylene dichloride (17 milliliters))-2-amino-1-({ 4-[8-(1-hydroxyethyl) imidazo [1,2-a] pyridine-2-yl] phenyl } methyl) ethyl]-3-chloro-4-[(1-methylethyl) the oxygen base] benzamide (0.912 gram, 1.80 EDCI (0.69 gram mmole),, 3.6 N mmole),, N-diisopropyl ethyl amine (0.466 gram, 3.6 mmole) and N, the mixture of N-dimethyl propylene propylhomoserin (0.372 gram) at room temperature is stirred and spends the night.Reaction is with the water dilution, with salt water washing, drying (Na
2SO
4) and concentrate.Resistates is with the flash column chromatography analysis (8%-10%MOH: CH on silica gel
2Cl
2) purifying, be produced as lark solid title compound (0.515 gram, 48%).MS(ES+)m/e 592[M+H]
+。
(1S)-and 2-[4-[8-bromine imidazo [1,2-a] pyridine-2-yl] phenyl]-1-[(1,3-dioxo-1,3-dihydro-2H-isoindole-2-yl) methyl] ethyl } carboxylamine 1.1-dimethyl ethyl ester:
In Virahol (70 milliliters) it [(1S)-2-(4-[1-(acetyl bromide) phenyl]-1-[(1; 3-dioxo-1; 3-dihydro-2H-isoindole-2-yl) methyl] ethyl } carboxylamine 1; the solution of 1-dimethyl ethyl ester (6.9 mmole), 3-bromo-2-pyridine amine (8.4 mmole) and sodium bicarbonate (10.4 mmole) stirred 18 hours down at 80 ℃.Reaction is cooled to room temperature then, and the precipitation of formations is filtered, with cold hexane (3 * 100 milliliters) washing and drying, be produced as the title compound (72%) of light gray solid.ESMS[M+H]
+：576.2。
((1S)-1-[(1,3-dioxo-1,3-dihydro-2H-isoindole-2-yl)-1-{[4-(the 8-Methylimidazole is [1,2-a] pyridine-2-yl also) phenyl] methyl } ethyl) carboxylamine 1,1-dimethyl ethyl ester:
Follow above-mentioned step, with 3-methyl-2-pyridine amine but not 3-bromo-2-pyridine amine is provided as baby pink solid title product.ESMS[M+H]
+：511.0。
N-{ (1S)-2-[4-[8-bromine imidazo [1,2-a] pyridine-2-yl] phenyl]-1-[(1,3-dioxo-1,3-dihydro-2H-isoindole-2-yl) methyl] ethyl }-3-chloro-4-[(1-methylethyl) the oxygen base] benzamide:
(1S)-2-[4-[8-bromine imidazo [1,2-a] pyridine-2-yl] phenyl]-1-[(1,3-dioxo-1,3-dihydro-2H-isoindole-2-yl) methyl] ethyl } carboxylamine 1,1-dimethyl ethyl ester (3.5 mmole) reaches 1, the solution of the hydrogenchloride in the 4-diox (20 milliliters, 4.0 volumetric molar concentrations) at room temperature is stirred 1 hour.The reaction be concentrated into dried, be dissolved in N again, in the dinethylformamide (35 milliliters).This solution is added diisopropyl ethyl amine (10.5 mmole) and 3-chloro-4-[(1-methylethyl) the oxygen base] phenylformic acid pentafluorophenyl group ester (3.8 mmole), it at room temperature is stirred half an hour.Reaction is dissolved in the vinyl acetic monomer (80 milliliters), and with water (3 * 50 milliliters) and salt solution (1 * 50 milliliter) washing.When precipitation forms, for separating organic layer, add hexane (150 milliliters), filtration, drying, be produced as the title compound (65%) of pale solid.ESMS[M+H]
+672.2。
3-chloro-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindole-2-yl)-1-{[4-[8-Methylimidazole is [1,2-a] pyridine-2-yl also] phenyl] methyl } ethyl)-the 4-[(1-methylethyl) the oxygen base] benzamide:
Follow above-mentioned step, in case (1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindole-2-yl)-1-{[4-(8-Methylimidazole also [1,2-a] pyridine-2-yl] phenyl] methyl } ethyl) carboxylamine 1,1-dimethyl ethyl ester is provided as the title product of pale solid.ESMS[M+H]
+：608.2。
N-((1S)-2-amino-1-{[4-[8-bromine imidazo [1,2-a] pyridine-2-yl] phenyl] methyl } ethyl)-3-chloro-4-[(1-methylethyl) the oxygen base] benzamide:
N-{ (1S) in ethanol (10 milliliters)-2-{[4-[8-bromine imidazo [1,2-a] pyridine-2-yl] phenyl]-[(1,3-dioxo-1,3-dihydro-2H-isoindole-2-yl) methyl] ethyl }-3-chloro-4-[(1-methylethyl) the oxygen base] benzamide (1.5 mmole) solution, add hydrazine monohydrate (7.6 mmole).Be reflected at 50 ℃ and stirred 18 hours down, form precipitation and filtration.Filtrate concentrates in a vacuum.The gained light yellow solid is directly used in next reaction and is not had and be further purified.ESMS[M+H]
+：533.2。
N-((1S)-2-amino-1-{[4-[8-Methylimidazole is [1,2-a] pyridine-2-yl also] phenyl] methyl } ethyl)-3-chloro-4-[(1-methylethyl) the oxygen base] benzamide:
Follow above-mentioned step, with 3-chloro-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindole-2-yl)-1-{[4-(8-Methylimidazole also [1,2-a] pyridine-2-yl] phenyl] methyl } ethyl)-the 4-[(1-methylethyl) the oxygen base] benzamide, be provided as the title product of pale solid.ESMS[M+H]
+：478.2。
N-((1S)-2-(D-alanyl amino)-1-{[4-[8-Methylimidazole is [1,2-a] pyridine-2-yl also] phenyl] methyl } ethyl)-3-chloro-4-[(1-methylethyl) the oxygen base] benzamide:
To the N-[(1S in methylene dichloride (2 milliliters))-2-amino-1-{[4-(8-bromine imidazo [1,2-a] pyridine-2-yl) phenyl] methyl } ethyl)-3-chloro-4-[(1-methylethyl) the oxygen base] benzamide (0.28 mmole), N-{[(1, the 1-dimethyl ethyl) oxygen base] carbonyl }-solution of D-L-Ala (0.56 mmole), EDCI (0.56 mmole) and TEA (1.12 mmole), at room temperature be stirred 18 hours.React then with 1,4 equivalent concentration HCl in the 4-diox (2 milliliters) handle, and at room temperature are stirred 1 hour, and concentrate in a vacuum, are dissolved in the vinyl acetic monomer (25 milliliters) and with saturated sodium bicarbonate aqueous solution (1 * 10 milliliter) and wash.Organic layer concentrates in a vacuum.The purifying of resistates is the title product (25%) that the Gilson reversed-phase HPLC is provided as white solid.ESMS[M+H]
+：613.2。
3-chloro-N-((1S)-2-(methyl-prop aminoacyl) amino-1-{[4-[8-Methylimidazole is [1,2-a] pyridine-2-yl also] phenyl] methyl } ethyl)-the 4-[(1-methylethyl) the oxygen base] benzamide:
Follow above-mentioned step, with N-((1S)-2-amino-1-{[4-[8-Methylimidazole also [1,2-a] pyridine-2-yl] phenyl] methyl } ethyl)-3-chloro-4-[(1-methylethyl) the oxygen base] benzamide and N-{[(1, the 1-dimethyl ethyl) oxygen base] carbonyl }-the 2-methylalanine, be provided as the title product of white solid.ESMS[M+H]
+：563.2。
3-chloro-N-((1S)-2-[(N, N-dimethyl glycyl)-1-{[4-(8-(1-hydroxyethyl) imidazo [1,2-a] pyridine-2-yl] phenyl] methyl } ethyl)-the 4-[(1-methylethyl) the oxygen base] benzamide:
Follow above-mentioned step, with N-((1S)-2-amino-1-{[4-[8-Methylimidazole also [1,2-a] pyridine-2-yl] phenyl] methyl } ethyl)-3-chloro-4-[(1-methylethyl) the oxygen base] benzamide and N, N-dimethyl propylene propylhomoserin is provided as the title product of white solid.ESMS[M+H]
+：563.2。
Flow process F:
2-bromo-1-(4-iodophenyl) ethyl ketone:
The solution of 1-(4-iodophenyl) ethyl ketone (55.9 mmole) in the Zai diox (160 milliliters) is cooled to 10 ℃.Dropwise add bromine (1.1 equivalents, 61.6 moles of %) in reaction mixture.After 10 minutes, cooling bath is removed, and reaction mixture at room temperature is stirred.After 1.5 hours, reaction mixture is concentrated in a vacuum, pours in the water (100 milliliters), and extracts with vinyl acetic monomer (3 * 100 milliliters).Organic layer through merging is dry and be condensed to dark brown solid (18.2 gram) in a vacuum on sodium sulfate, and it is directly used in next step.
2-(4-iodophenyl)-8-Methylimidazole is [1,2-a] pyridine also:
The mixture of rough 2-bromo-1-(4-iodophenyl) ethyl ketone in Virahol (160 milliliters) (18.2 gram), 2-amino-3-picoline (1.1 equivalents, 61.6 mmoles) and sodium bicarbonate (1.3 equivalents, 72.8 mmoles) heated 16 hours down at 80 ℃.After reaction mixture concentrates in a vacuum, add water (100 milliliters), and the dark brown slurry of gained is filtered, wash with water (2 * 50 milliliters).Brown solid is by recrystallize from Virahol, and further dry in a vacuum, is provided as the title product of brown solid.ESMS[M+H]
+：335.0。
Flow process G:
4-(4-bromophenyl)-N, 1-dimethyl-N-(methoxyl group)-1H-imidazoles-2-methane amide:
The solution of 4-(4-bromophenyl) in MeOH (38 milliliters)-1-methyl isophthalic acid H-imidazoles-2-carboxylic acid, ethyl ester (1.66 grams, 5.37 mmoles) adds 1 equivalent concentration NaOH solution (19 milliliters).Reaction changes into muddy white, and at room temperature stirs 30 minutes.Reaction mixture is concentrated in a vacuum and high-vacuum pump spends the night, and is produced as 4-(4-the bromophenyl)-1-methyl isophthalic acid H-imidazoles-2-carboxylic acid sodium salt of white solid.4-(4-bromophenyl)-1-methyl isophthalic acid H-imidazoles-2-carboxylic acid sodium salt is dissolved in anhydrous CH under nitrogen ,-15 ℃ (ice/methanol bath)
2Cl
2In (40 milliliters), and add methyl (1.1 equivalents, 5.91 mmoles), continuous with isobutyl chlorocarbonate (1.1 equivalents, 5.91 mmoles).Reaction mixture stirred 15 minutes down at-15 ℃, and added N then, O-dimethyl oxammonium hydrochloride (1.0 equivalents, 5.37 Bo moles).Reaction is arrived room temperature by solvent heating, and stirs 17 hours.Reaction is with H
2O (10 milliliters) stopped reaction.Product is with EtOAc (3 * 30 milliliters) extraction, and the organic layer through merging is with salt solution (20 milliliters) washing, at MgSO
4Last dry and concentrated in a vacuum.With silica gel chromatography analysis (Analogix IF280,20-100%EtOAc/ hexane class), be produced as dark brown solid title product (32%).ESMS[M+H]
+：324.2。
Flow process H:
(4R)-and 4-({ [(1, the 1-dimethyl ethyl) oxygen base] carbonyl } amino)-5-hydroxypentanoic acid 1,1-dimethyl ethyl ester:
Triethylamine (11.49 milliliters, 82.4 mmoles) and Vinyl chloroformate (8.27 milliliters, 86.5 mmoles) by with syringe under＜0 ℃ (ice-salt bath), be added continuously in N-the 3rd-Boc-D-L-glutamic acid 5-tert-butyl ester (25 grams, 82.4 mmoles) in THF (588 milliliters).After stirring 40 minutes on ice bath, solid is filtered, and washs with THF (150 milliliters).Filtrate is transferred in 250 addition funnels, and adds at H under 0 ℃, in 1 hour
2In sodium borohydride among the O (114 milliliters) (8.42 grams, the 222.5 mmoles) solution.Reaction mixture be maintained at 0 ℃ 1.5 hours, yet and stir 16 hours (0 ℃ to room temperature).After a large amount of solvents removed with the rotation evaporation, concentrated solution was with frozen water (50 milliliters) and 1 equivalent concentration HCl (50 milliliters) stopped reaction.After with EtOAc (4 * 100 milliliters) extraction, extract is with 100 milliliters: 0.5 volumetric molar concentration citric acid, saturated NaHCO
3, H
2O and salt water washing, and concentrate in a vacuum, producing title compound, it is directly used in next step.ESMS[M+H]
+: 290.4[2M+H]
+=579.4 (document preparation: J.Med.Chem.1999,42 (1), 95-108 is other isomer).
(4R)-and 4-({ [(1, the 1-dimethyl ethyl) oxygen base] carbonyl } amino)-5-valeric acid 1,1-dimethyl ethyl ester:
To at 515 milliliters of anhydrous CH
2Cl
2In it (4R)-4-({ [(1, the 1-dimethyl ethyl) oxygen base] carbonyl } amino)-5-hydroxypentanoic acid 1,1-dimethyl ethyl ester (23.8 grams, 82.4 mmoles), triphenylphosphine (32.42 grams, 123.6 mmoles) and imidazoles (8.41 grams, 123.6 mmoles) solution are at N
2, divide under 0 ℃, in 15 minutes and partly add iodine.Ice bath is removed, and reaction allows and be warmed to room temperature, and stirs 30 minutes.Reaction is with 200 milliliters of H
2O ends.Water layer extracts with diethyl ether (2 * 150 milliliters).Organic layer through merging is with saturated water-based Na
2SO
3The washing of solvent (2 * 25 milliliters) and salt solution (25 milliliters), at MgSO
4Last dry and concentrated in a vacuum.(Analogix IF280 5%-50%EtOAc/Hex), is produced as the title product (25.34 grams, 77%) of white solid to resistates with the silica gel chromatography analysis.ESMS[M+H]
+：400.4。
(4R)-and 4-({ [(1, the 1-dimethyl ethyl) oxygen base] carbonyl } amino)-5-[4-(the 8-Methylimidazole is [1,2-a] pyridine-2-yl also) phenyl] valeric acid 1,1-dimethyl ethyl ester:
(flask Strem) heats with heating gun zincilate, bleeds simultaneously and with the nitrogen filling for 6.0 equivalents, 325 sieves.Under nitrogen, be added via syringe through the DMF of the degassing (14 milliliters), continuous with glycol dibromide (0.35 equivalent).The grey reaction mixture stirred 15 minutes in 100 ℃ of oil baths, and cool to room temperature.Add chlorine Trimethylamine (0.25 equivalent) in mixture via syringe, and reaction was stirred at room temperature 30 minutes.Be added on it (4R)-4-({ [(1, the 1-dimethyl ethyl) oxygen base] carbonyl } amino)-5-iodine valeric acid 1 among the DMF (14 milliliters) through the degassing via sleeve pipe, 1-dimethyl ethyl ester (20 grams, 1.2 equivalents) is in reaction mixture.The flask that contains solution is with through the DMF of the degassing (4 milliliters) washing, and cannulate is to reaction mixture.Reaction was at room temperature stirred 1 hour.Then, once add also [1,2-a] pyridine (1.4 grams, 1.0 equivalents) of ginseng (two benzal benzylacetones) two palladiums (0) (2.5 moles of %), three-o-tolylphosphine (10 moles of %) and 2-(4-iodophenyl)-8-Methylimidazole via the top.Reaction mixture at room temperature stirred 17 hours.Reaction is with EtOAc (40 milliliters) dilution, and process Celite filters.Filtrate is with H
2O (20 milliliters) and salt solution (20 milliliters) washing, and organic layer is at MgSO
4Last dry and concentrated in a vacuum.(Analogix IF280 5%-90%EtOAc/Hex), is produced as the title product (90%) of white solid with the silica gel chromatography analysis.ESMS[M+H]
+：480.4。
(4R)-4-({ [(1, the 1-dimethyl ethyl) oxygen base] carbonyl } amino)-5-[4-(1-methyl-2-{[methyl (methoxyl group) amino] carbonyl }-the 1H-imidazol-4 yl) phenyl] valeric acid 1,1-dimethyl ethyl ester:
Follow above-mentioned step, use 4-(4-bromophenyl)-N, 1-dimethyl-N-(methoxyl group)-1H-imidazoles-2-methane amide is provided as the solid title compound.ESMS[M+H]
+＝517.2。
(4R)-and 4-[({3-chloro-4-[(1-methylethyl) the oxygen base] phenyl } carbonyl) amino]-5-[4-(the 8-Methylimidazole is [1,2-a] pyridine-2-yl also) phenyl] valeric acid:
To at CH
2Cl
2It (4R)-4-({ [(1 in (14 milliliters), the 1-dimethyl ethyl) oxygen base] carbonyl } amino)-5-[4-(1-methyl-2-{[methyl (methoxyl group) amino] carbonyl }-the 1H-imidazol-4 yl) phenyl] valeric acid 1,1-dimethyl ethyl ester (1.35 grams, 2.82 mmoles) solution, add trifluoracetic acid (10 milliliters), continuous with triethyl silicane (2.5 equivalents, 7.05 mmoles).Reaction at room temperature is stirred 45 minutes, and is concentrated in a vacuum.Add DMF (35 milliliters) in resistates, continuous with diisopropyl ethyl amine under nitrogen (14.7 milliliters, 84.51 mmoles).Reaction is stirred 5 minutes, and adds 3-chloro-4-[(1-methylethyl) the oxygen base] phenylformic acid pentafluorophenyl group ester (1.1 equivalents, 3.10 mmoles).Reaction is stirred 45 minutes, and is concentrated in a vacuum.Add vinyl acetic monomer (50 milliliters) in resistates, and with H
2O (30 milliliters) washing.Water layer is with EtOAc (20 milliliters) extraction, and the organic layer through merging is at MgSO
4Last dry, and concentrate in a vacuum.With silica gel chromatography analysis (Analogix IF280,25%-100%EtOAc/ hexane class), be provided as white foam shape solid title compound (61%).ESMS[M+H]
+：520.2。
(4R)-and 4-[({3-chloro-4-[(1-methylethyl) the oxygen base] phenyl } carbonyl) amino]-5-[4-(1-methyl-2-{[methyl (methoxyl group) amino] carbonyl }-the 1H-imidazol-4 yl) phenyl] valeric acid:
Follow above-mentioned step, with (4R)-4-({ [(1, the 1-dimethyl ethyl) oxygen base] carbonyl } amino)-5-[4-(1-methyl-2-{[methyl (methoxyl group) amino] carbonyl }-the 1H-imidazol-4 yl) phenyl] valeric acid 1,1-dimethyl ethyl ester and aforementioned purifying are provided as the solid title compound.ESMS[M+H]
+＝557.2。
(4R)-5-[4-(2-ethanoyl-1-methyl isophthalic acid H-imidazol-4 yl) phenyl]-[(3-chloro-4-[(1-methylethyl) and the oxygen base] phenyl } carbonyl) amino] valeric acid:
To rough (the 4R)-4-[({3-chloro-4-[(1-methylethyl in THF (16 milliliters)) the oxygen base] phenyl } carbonyl) amino]-5-[4-(1-methyl-2-{[methyl (methoxyl group) amino] carbonyl }-the 1H-imidazol-4 yl) phenyl] solution of valeric acid (3.18 mmole) under nitrogen, 0 ℃, dropwise add (10.6 milliliters of methylmagnesium-bromides via syringe, 10 equivalents, 3.0 volumetric molar concentrations in ether).Be reflected at and be stirred 30 minutes under 0 ℃, and carefully with saturated NH
4The Cl aqueous solution (10 milliliters) is ended, and is continuous with 1 equivalent concentration HCl solution (60 milliliters), makes pH～5.5 of water layer.Product is with EtOAc (4 * 40 milliliters) extraction, and the organic layer through merging is at MgSO
4Last dry, and concentrate in a vacuum, be produced as white title compound, be directly used in next reaction.ESMS[M+H]
+：512.4。
N-((1R)-4-amino-1-{[4-(the 8-Methylimidazole is [1,2-a] pyridine-2-yl also) phenyl] methyl }-the 4-oxygen-butyl)-3-chloro-4-[(1-methylethyl) the oxygen base] benzamide:
To it (4R)-4-[({3-chloro-4-[(1-methylethyl in anhydrous THF (12.4 milliliters)) the oxygen base] phenyl } carbonyl) amino]-5-[4-(1-Methylimidazole also [1,2-a] pyridine-2-yl) phenyl] solution of valeric acid (900 milligrams, 1.73 mmoles) under nitrogen, 0 ℃, add triethylamine (242 microlitres, 1.73 mmoles), continuous with methyl-chloroformate (174 microlitres, 1.82 mmoles).Be reflected at and be stirred 40 minutes under 0 ℃, and solid is filtered then, and with 5 milliliters of THF washings.Filtrate being added to contains NH
4In OH (5 milliliters) flask at room temperature, and reaction mixture is stirred 1 hour.Product extracts with EtOAc (50 milliliters) from reaction mixture.Water layer extracts with EtOAc (20 milliliters), and then with 1 equivalent concentration HCl solution (30 milliliters) acidifying, and extract with EtOAc (10 milliliters) again.Organic layer through merging is at MgSO
4Last dry, and concentrate in a vacuum, white solid produced.The purifying of recrystallize from Virahol provides to be produced as white title compound (90%).ESMS[M+H]
+＝519.4。
N-(1R)-1-{[4-(2-ethanoyl-1-methyl isophthalic acid H-imidazol-4 yl) phenyl] methyl }-4-amino-4-oxo butyl)-3-chloro-4-[(1-methylethyl) the oxygen base] benzamide:
Follow above-mentioned step; with (4R)-5-[4-(2-ethanoyl-1-methyl isophthalic acid H-imidazol-4 yl) phenyl]-4-[({3-chloro-4-[(1-methylethyl) the oxygen base] phenyl } carbonyl) amino] valeric acid and with Gilson reversed-phase HPLC purifying, be provided as the title compound of white solid.ESMS[M+H]
+＝511.2。
Flow process I:
(3S)-4-{[4-(2-ethanoyl-1-methyl isophthalic acid H-imidazol-4 yl) phenyl]-3-[({3-chloro-4-[(1-methylethyl) the oxygen base] phenyl } carbonyl) amino] butyl dimethyl phosphoric acid ester:
At dry CH
2Cl
2N-in (10 milliliters) ((1S)-1-{[4-(2-ethanoyl-1-methyl isophthalic acid H-imidazol-4 yl) phenyl] methyl }-the 3-hydroxypropyl)-3-chloro-4-[(1-methylethyl) the oxygen base] benzamide (500 milligrams, 5.18 mmoles) solution, at room temperature, N
2Under add chlorine dimethyl phosphate (748 milligrams, 5.18 mmoles), continuous with DMAP (660 milligrams, 5.41 mmoles).After 30 minutes, TLC (95: 5 EtOAc/MeOH) shows that～50% transforms, so add extra chlorine dimethyl phosphate (748 milligrams, 5.18 mmoles) and DMAP (660 milligrams, 5.41 mmoles) partly.After 30 minutes, reaction is with saturated water-based NH again
4Cl ends, and CH
2Cl
2Dilution.Water layer is with CH
2Cl
2Reversed phase extraction, the and (Na that is dried of the organic layer through merging
2SO
4), filter and under reduced pressure be concentrated.Resistates is with silica gel chromatography analysis (100%EtOAc; At the first-class degree of Analogix) purifying, producing 475 milligrams (77%) is lark buttery title compound.LC/MS(ES)m/e 592.4(M+H
+)。Notice that product is so being carried out by～1 normal initial chlorine dimethyl phosphate/hydrogen dimethyl phosphate reagent contamination.
(3S)-4-[4-(2-ethanoyl-1-methyl isophthalic acid H-imidazol-4 yl) phenyl]-3-[({3-chloro-4-[(1-methylethyl) the oxygen base] phenyl } carbonyl) amino] butyl dihydrogen phosphoric acid ester:
It (3S)-4-[4-in AcOH, 30%HBr (2-ethanoyl-1-methyl isophthalic acid H-imidazol-4 yl) phenyl]-3-[({3-chloro-4-[(1-methylethyl) the oxygen base] phenyl } carbonyl) amino] yellow solution of butyl dimethyl phosphoric acid ester (475 milligrams, 0.804 mmole); be placed in preheating (60 ℃) and bathed 10 minutes, allow at once then to be cooled to room temperature.Reaction mixture under reduced pressure is concentrated, and resistates is dissolved among the DMSO (6 milliliters) again, filter and with Gilson reversed-phase HPLC (MeCN/H
2O has 0.1%TFA) purifying.Clarification MeCN partly under reduced pressure is removed, and the surplus aqueous solution is frozen, and freeze-drying spends the night, and produces 84 milligrams of title compounds that (19%) is yellow powder.LC/MS(ES)564.2(M+H)
+。
(3S)-and 3-[({3-chloro-4-[(1-methylethyl) the oxygen base] phenyl } carbonyl) amino]-4-[4-(the 8-Methylimidazole is [1,2-a] pyridine-2-yl also) phenyl] methyl } butyl dihydrogen phosphoric acid ester:
Follow above-mentioned step; except with 3-chloro-N-((1S)-3-hydroxyl-1-{[4-(8-Methylimidazole also [1; 2-a] pyridine-2-yl) phenyl] methyl } propyl group-4-[(1-methylethyl) the oxygen base] benzamide replacement N-((1S)-1-{[4-(2-ethanoyl-1-methyl isophthalic acid H-imidazol-4 yl) phenyl] methyl }-3-hydroxypropyl-3-chloro-4-[(1-methylethyl) the oxygen base] benzamide; and with the 3rd butoxy potassium replacement DMAP, title compound is prepared as white powder (35% productive rate).LC/MS(ES)563(M+H)
+。
Flow process J:
3-cyano group-N-[(1S)-1-(4-[8-(3,5-dimethyl-4-isoxazolyl) imidazo [1,2-a] pyridine-2-yl] and phenyl } methyl)-the 3-hydroxypropyl]-the 4-[(1-methylethyl) the oxygen base] benzamide:
To the N-[(1S in dry DMF (2 milliliters))-1-{[4-(8-bromine imidazo [1,2-a] pyridine-2-yl) phenyl] methyl }-the 3-hydroxypropyl]-the 3-hydroxypropyl)-3-cyano group-4-[(1-methylethyl) the oxygen base] benzamide (200 milligrams, 0.366 mmole) solution, at room temperature add 3 continuously, 5-dimethyl-isoxazolyls-4-boric acid (63 milligrams, 0.439 mmole), four triphenylphosphine palladiums (0) (21 milligrams, 0.018 mmole) and 2.0 volumetric molar concentration water-based K
2CO
3(0.46 milliliter).Reaction mixture exhaust under argon gas, and be heated to 100 ℃, stir 22 hours, cool to room temperature, filtration and directly with reversed-phase HPLC (MeCN/H
2O has 0.1%TFA) purifying.Clarification is partly with saturated water-based NaHCO
3Adjust to pH～8, and extract with 3%MeOH/EtOAc (3 * 30 milliliters).Extract (the Na that is dried
2SO
4), filter and under reduced pressure be concentrated, produce 45 milligrams of title compounds that (22%) is pale solid.LC/MS(ES) m/e564.2(M+H
+)。
Flow process K:
3-chloro-N-[(1S)-and 1-{[3-chloro-4-(the 8-Methylimidazole is [1,2-a] pyridine-2-yl also) phenyl] methyl }-the 3-hydroxypropyl)-the 4-[(1-methylethyl) the oxygen base] benzamide:
Follow in document (J.Org.Chem.2003,68,42; J.Org.Chem.2002,67,1738; J.Am.Chem.Soc.1972,94 6203) step and above-mentioned step, title compound is prepared as white solid.LC/MS(ES)m/e 526(M+H)
+。
Following compounds is used above-mentioned step preparation:
Embodiment 67
To the compound 1 in dimethyl formamide (200 milliliters) (10.7 grams, 61.37 mmoles), (R)-1,1,0 ℃ of solution of 1-trifluoropropanol (3.5 grams, 30.68 mmoles) added sodium hydride (3.7 grams, 92.05 mmoles) partly in 5 minutes.After 10 minutes, ice bath is removed and reaction mixture is stirred when being warmed to room temperature.Reaction mixture is heated to 80 ℃, and stirs and spend the night.Reaction is monitored with LC/MS.After reaction was finished, it was cooled to room temperature.Reaction mixture is with HCl (0.5 equivalent concentration, 200 milliliters) stopped reaction, and dilutes with vinyl acetic monomer (3 * 250 milliliters).Organic layer is dry on sodium sulfate, filtration, and filtrate is concentrated in a vacuum, produces crude compound 2 (8.2 gram), and it is directly used in next step, and nothing is not further purified.
To (4.1 grams of the compound 2 in methylene dichloride (200 milliliters), 15.34 mmole), 0 ℃ of solution of triethylamine (6.4 milliliters, 46.02 mmoles), in 3 minutes, add trifluoracetic acid pentafluorophenyl group ester (6.35 milliliters, 36.82 mmoles) via syringe.After 5 minutes, ice bath is removed and reaction mixture is stirred 2 hours again when being warmed to room temperature.Reaction mixture concentrates in a vacuum.The gained resistates is with fast chromatographic (silica gel, hexane class/EtOAc=1: 0,50; 1), produces compound 3 (3.5 grams, 50% productive rate).
Embodiment 68
4-hydroxyl-3-iodo-benzoic acid methyl esters 2:4-methyl hydroxybenzoate (35.5 grams, 0.233 mole) is dissolved in 200 milliliters of acetic acid, and is warmed to 65 ℃ through the mixture of stirring.ICI solution in AcOH (37.8 grams, 0.233 mole) was dropwise added in 40 minutes.Mixture stirred 5 hours down at 65 ℃, then restir 16 hours at room temperature.Precipitated product is via filtering separation, with water washing, and dry in a vacuum, produces the product of being wanted of 27.5 grams (pure by 99% with LCMS and HNMR).Mother liquor is evaporated, and the gained resistates produces the product of being wanted of 31 grams (pure by 95% with LCMS and HNMR) with water washing and dry in a vacuum.4-hydroxyl-3-iodo-benzoic acid methyl esters 2 through combined yield be 58.85 the gram (90.3% productive rate).LCMS m/z＝。
4-hydroxyl-3-iodo-benzoic acid the methyl esters 2 of 3-cyano group-4-hydroxy-benzoic acid methyl esters 3:28 gram (0.1 mole) is dissolved among 100 milliliters of DMF, handles with 9.92 gram (0.11 mole) CuCN and 0.49 gram (0.11 mole) NaCN.System washes away with nitrogen, and mixture is warmed to 105 ℃ afterwards, and stirs 18 hours.Mixture is allowed cool to room temperature, and any throw out is removed via filtration, and washs with EtOAc (2 * 200 milliliters).Dry on sodium sulfate through combination layer, filter and be evaporated to dried.After the drying, 3 of gained 18 grams (100% productive rate) are with LCMS and HNMR identification mark under vacuum.
3-cyano group-4-isopropoxy methyl benzoate 4:3-cyano group 4-hydroxy-benzoic acid methyl esters 3 (18 grams, 0.1 mole) is dissolved among 100 milliliters of DMF, handles with 14.2 milliliters of (0.15 mole) 2-N-PROPYLE BROMIDEs and 41.9 gram (0.3 mole) anhydrous sodium carbonates.System washes away with nitrogen, and mixture is warmed to 90 ℃, and stirs and spend the night.After being cooled to room temperature, mixture dilutes with 200 ml waters, with CH
2Cl
2(2 * 200 milliliters) extraction.Dry on sodium sulfate through the combination organic layer, filter and be evaporated to dried, producing 20.5 grams (99% productive rate) is buttery 4, it is with LCMS and HNMR identification mark.
The 3-cyano group 4-isopropoxy methyl benzoate 4 of 3-cyano group-4-isopropoxy phenylformic acid pentafluorophenyl esters 6:20.5 gram (0.093 mole) is dissolved in 200 milliliters of 6: 4 methyl alcohol and the water mixture.This is added 5.61 gram (0.14 mole) NaOH, and mixture stirred at room temperature 2 hours.Solution filters with silicagel column then, and solvent is removed in a vacuum.The gained solid is dissolved in 200 milliliters of CH again
2Cl
2In, and with 19.3 milliliters of (0.11 moles) 2,2,2-trifluoracetic acid pentafluorophenyl group ester and 19.5 milliliters of (0.14 mole) triethylamines are handled.After stirring is spent the night, solution be filtered and any solid with CH
2Cl
2Washing.Through the combination organic layer short silicagel column of flowing through, and be evaporated to driedly then, produce 6 of 29 grams (83.5% productive rate), it is with LCMS and HNMR identification mark.
Embodiment 69
To compound 1 in DMF (10 milliliters) (200 milligrams, 1.077 mmoles) and 2-iodopropane (322 microlitres, 3.23 mmoles) solution, add DIEA (750 microlitres, 4.31 mmoles).Reaction mixture is heated to 80 ℃, and stirs and spend the night.Reaction is monitored with LC/MS.After reaction was finished, it was cooled to room temperature.Reaction mixture is with HCl (0.5 equivalent concentration, 30 milliliters) stopped reaction, and extracts with vinyl acetic monomer (50 milliliters * 3).Organic layer is dry and concentrated on sodium sulfate, and dry in high vacuum.The gained resistates produces compound 2 (50 milligrams, 20%) with reverse-phase chromatography analysis (using acetonitrile and water mixture) purifying.
To the compound 2 in MeOH (1.0 milliliters) (50 milligrams, 0.22 mmole) solution, be added on the NaOH (1.0 volumetric molar concentrations, 330 microlitres, 0.330 mmole) in the water.Reaction mixture at room temperature stirred 2 hours.Reaction is monitored with LC/MS.Mixture is with HCl (0.5 equivalent concentration, 5 milliliters) stopped reaction, and extracts with vinyl acetic monomer (10 milliliters * 3).Organic layer is dry and concentrated on sodium sulfate, produces 2 (45 milligrams).LRMS(M-H
+)m/z212.0。
Embodiment 70
To compound 1 in DMF (10 milliliters) (200 milligrams, 1.077 mmoles) and 2-iodopropane (322 microlitres, 3.23 mmoles) solution, add DIEA (750 microlitres, 4.31 mmoles).Reaction mixture is heated to 80 ℃, and stirs and spend the night.Reaction is monitored with LC/MS.After reaction was finished, it was cooled to room temperature.Reaction mixture is with HCl (0.5 equivalent concentration, 30 milliliters) stopped reaction, and extracts with vinyl acetic monomer (50 milliliters * 3).Organic layer is dry and concentrated on sodium sulfate, and dry in high vacuum.The gained resistates produces compound 2 (50 milligrams, 20%) with reverse-phase chromatography analysis (using acetonitrile and water mixture) purifying.
To the compound 2 in MeOH (1.0 milliliters) (50 milligrams, 0.22 mmole) solution, be added on the NaOH (1.0 volumetric molar concentrations, 330 microlitres, 0.330 mmole) in the water.Reaction mixture at room temperature stirred 2 hours.Reaction is monitored with LC/MS.Mixture is with HCl (0.5 equivalent concentration, 5 milliliters) stopped reaction, and extracts with vinyl acetic monomer (10 milliliters * 3).Organic layer is dry and concentrated on sodium sulfate, produces 2 (45 milligrams).LRMS(M-H
+)m/z212.0。
Embodiment 71
Compound 1
4-bromo-2-chlorophenol (5.04 grams, 24.3 mmoles) is dissolved in DMF (30 milliliters), and adds K
2CO-
3(10.10 grams, 72.9 mmoles), continuous with 2-chloroethyl-right-tosylate (4.86 milliliters, 26.7 mmoles).The gained mixture be warmed to 60 ℃ 3 hours, be cooled to room temperature then.Reaction is diluted with EtOAc (350 milliliters), and washs with water (5 * 150 milliliters).Organic layer (the Na that is dried
2SO
4) and be condensed into the thickness oily, it is solidified into solid under high vacuum.Compound 1 (6.46 grams, 24.1 mmoles, full dose productive rate) uses
1The H-NMR identification mark, and be used to subsequent step and do not have be further purified.
Compound 1 (6.46 grams, 24.1 mmoles) is dissolved in DMF (30 milliliters), and adds sodium hydride (1.94 grams, 60% dispersion liquid in mineral oil, 48.6 mmoles).The gained mixture at room temperature stirred 16 hours.Reaction is with water (100 milliliters) and EtOAc (350 milliliters) dilution.Layer separates, and organic layer washs with water (4 * 150 milliliters).Organic layer (the Na that is dried
2SO
4) and be condensed into white solid.Compound 2 (5.56 grams, 24.0 mmoles, full dose productive rate) is dry under high vacuum, and uses
1The H-NMR identification mark.It is used to subsequent step and does not have be further purified.
Compound 2 (5.56 grams, 24.0 mmoles) and chloroiodomethane (5.59 milliliters, 76.8 mmoles) combination, and under nitrogen pressure, be dissolved in 1, in the 2-ethylene dichloride (35 milliliters).Solution is cooled to 0 ℃ with ice bath, and in 10 minutes, add zinc ethyl (38.4 milliliters, in hexane 1.0 volumetric molar concentrations, 38.4 mmoles).The gained mixture is stirred 30 minutes, and solvent heating is to room temperature.It is cooled to 0 ℃ with ice bath, and adds saturated water-based NH
4Cl (150 milliliters), continuous with dense water-based NH
4OH (25 milliliters) and EtOAc (200 milliliters).Layer separates, and water layer extracts with extra EtOAc (2 * 100 milliliters).Organic layer is combined, dry (Na
2SO
4) and be condensed into rough oily matter, it uses silica gel (100% hexane) purifying to use as the compound 3 (1.76 grams, 7.2 mmoles, 30% productive rate) of colorless oil
1The H-NMR identification mark.
In high-pressure reactor, compound 3 (1.76 grams, 7.2 mmoles) is dissolved among the EtOH (40 milliliters).Add triethylamine (5.0 milliliters, 35.8 mmoles), continuous with [1, two (diphenylphosphino) palladium ferrocene of 1-] dichloro palladium (II) (188 milligrams, 0.36 mmole).Reaction vessel with carbon monoxide pressurization (every square time 100 pounds), bleed, and again with carbon monoxide (every square time 100 pounds) pressurization.Container is bled, and again with carbon monoxide (every square time 350 pounds) pressurization.Reaction is heated to 90 ℃, and stirs 16 hours.It is cooled to room temperature, decompression and process Celite and filters.Solvent is evaporated, and the surplus resistates of institute is at methylene dichloride (150 milliliters) and 1.0 volumetric molar concentration water-based KHSO
4Distribute in (75 milliliters).Layer separates, and organic phase is with extra 1 volumetric molar concentration water-based KHSO
4(1 * 75 milliliter) washing.Organic phase (the Na that is dried
2SO
4) and be condensed into oily matter, it uses silica gel (EtOAc/ hexane) purifying, is provided as the compound 4 (648 milligrams, 2.70 mmoles, 38% productive rate) of white solid, uses
1The H-NMR identification mark.
Compound 4 (648 milligrams, 2.70 mmoles) solution in methylene dichloride (3 milliliters) and EtOH (15 milliliters) adds 1 volumetric molar concentration water-based KOH (7.0 milliliters, 7 mmoles).The gained turbid mixture be heated to 60 ℃ 1 hour.Methylene dichloride and EtOH vapourisation under reduced pressure, and the surplus aqueous solution of institute is with dense HCl acidifying.The gained precipitation is filtered.White solid is pure compound 5 (506 milligrams, 2.39 mmoles, 88% productive rate) after filtration, uses LC/MS (LRMS (M-H) 211.1 m/z) identification mark.
Embodiment 72
To amine (580 milligrams, 1.7 mmoles) in THF (8.5 milliliters, 0.2 volumetric molar concentration) and triethylamine (449 microlitres, 3.4 mmoles, 2 equivalents) solution, add ethyl chloroformate (278 microlitres, 2.6 mmoles, 1.5 equivalents).Mixture at room temperature is stirred 30 minutes.Then, it is with the vinyl acetic monomer dilution, with 1 equivalent concentration HCl and salt water washing.Organic layer is dried, filters and concentrates in a vacuum, is produced as the crude material (900 milligrams) of yellow oil.To the crude material solution in DMF (10 milliliters), add NaH (272 milligrams, 6.8 mmoles, 4 equivalents), and at room temperature be stirred 16 hours.Mixture dilutes with vinyl acetic monomer (100 milliliters), and washs with salt solution (5 * 50 milliliters).Organic layer is dried, filters and concentrates in a vacuum, is produced as the crude material (900 milligrams) of oily matter.With column chromatography analysis (1: 1 vinyl acetic monomer: the hexane class), produce the product of wanting of 80 milligrams (24%).m/z(+1)＝398.0。
Embodiment 73
(R)-4-chloro-N-(1-(4-(4-iodophenyl)-1-methyl isophthalic acid H-imidazoles-2-yl) ethyl) butyramide.To one 100 milliliters round-bottomed flask, add 1-(4-(4-iodophenyl)-1-methyl isophthalic acid H-imidazoles-2-yl) ethyl carbamic acid (R)-benzyl ester (1.50 grams, 3.27 mmoles, 1.0 equivalents), CH
3CN (20 milliliters) and TMSI (900 microlitres, 6.4 mmoles, 1.9 equivalents).Reaction mixture is added a cover, and stirs 2 hours.Add methyl alcohol (40 milliliters) then in flask, and mixture is concentrated, is dissolved in EtOAc (100 milliliters) and with water washing.Organic layer is at Na
2SO
4Last dry, filtration and concentrated.Resistates is dissolved among the DCM, and with silica gel chromatography analysis (35-60%CH
3CN/CH
2Cl
2, 20%MeOH/CH then
2Cl
2), provide 950 milligrams (90%) will main amine (M+H (m/z)=328 for the institute of oily matter.This amine is added CH in mode dropwise
2Cl
2(20 milliliters) and pyridine (260 microlitres, 1.1 equivalents), continuous with 4-chlorobutyryl chlorine (344 microlitres, 1.05 equivalents).Reaction is stirred 15 minutes, continues to add EtOAc (50 milliliters) and water (10 milliliters).Organic layer is separated, at Na
2SO
4Last dry, filtration and concentrated.Resistates is dissolved among the DCM, and with silica gel chromatography analysis (5-35%CH
3CN/CH
2Cl
2, provide 747 milligrams (60%) to be it (R)-4-chloro-of pale solid N-(1-(4-(4-iodophenyl)-1-methyl isophthalic acid H-imidazoles-2-yl) ethyl) butyramide (M+H (m/z)=432).
Embodiment 74
(R)-1-(1-(4-(4-iodophenyl)-1-methyl isophthalic acid H-imidazoles-2-yl) ethyl) tetrahydrochysene coughs up-2-ketone.To 20 milliliters of 7.5 milliliters of bottles, add (R)-4-chloro-N-(1-(4-(4-iodophenyl)-1-methyl isophthalic acid H-imidazoles-2-yl) ethyl) butyramide and THF (10 milliliters).This bottle is cooled to 0 ℃ under nitrogen pressure then, adds tertiary butyl potassium (214 milligrams, 1.91 mmoles).Reaction is stirred 1.5 hours.Reaction mixture is added EtOAc (50 milliliters) and water (10 milliliters).Organic layer is separated, at Na
2SO
4Last dry, filtration and concentrated.Resistates is dissolved among the DCM then, and with silica gel chromatography analysis (5-50%CH
3CN/CH
2Cl
2), provide 593 milligrams (86%) for being it (R)-1-of white solid (1-(4-(4-iodophenyl)-1-methyl isophthalic acid H-imidazoles-2-yl) ethyl) tetrahydro pyrrolidine-2-ketone (M+H (m/z)=396).
Embodiment 75
1 (10 grams, 45.7 mmoles) solution in DMF (150 milliliters) adds HBTU (26 milligrams, 68.5 mmoles), dimethyl hydroxyl amine HCl salt (5.35 grams, 54.8 mmoles) and DIEA (9.6 milliliters, 55.0 mmoles) down at 0 ℃.After being stirred 2 hours, mixture is allowed to be warmed to room temperature.Continuously stirring 2 days.Reaction mixture distributes in EtOAc (500 milliliters) and water (200 milliliters).Organic layer is with NaOH (2 equivalent concentration, 200 milliliters), HCl (2 equivalent concentration, 200 milliliters), H
2O, salt water washing are at Na
2SO
4Last dry and concentrate, produce 2 (9.6 grams), it is used and does not have and be further purified.LRMS(M+H
+)m/z 262.0。
At Et
2Among the O (100 milliliters) 2 (9.6 grams ,～36.8 mmoles) solution, add MeMgBr (Et down at 0 ℃
2Among the O in 3 volumetric molar concentrations, 27 milliliters).The gained mixture is stirred 4 hours, allows simultaneously to be warmed to room temperature.Reaction mixture is with saturated NH
4Cl (100 milliliters) ends.Organic layer is with H
2O, salt water washing, at Na
2SO
4Last dry and concentrated, produce 3 (7 grams are 71% from 1), with the NMR identification mark.
3 (6.5 grams, 30 mmoles) solution in DCM (200 milliliters) and MeOH (100 milliliters) adds tetrabutylammonium tribromide (14.5 grams, 30 mmoles).Reaction mixture is stirred 14 hours.Mixture is concentrated, and dry under high vacuum, produces 5 (with the NMR identification marks), and it is used and does not have and be further purified.
4 (5 grams ,～16.9 mmoles) solution in DCM (50 milliliters) adds vulkacit H (2.6 grams, 18.5 mmoles).Reaction mixture is stirred 2 hours.Mixture dilutes with DCM (500 milliliters).Precipitation is collected, is washed with DCM (500 milliliters * 2) to filter, and dry under high vacuum.The gained resistates is added EtOH (60 milliliters) and dense HCl (30 milliliters).Reaction mixture is stirred 2 hours.Mixture is concentrated, drying, produces 5, and it is used and does not have and be further purified.LRMS(M+H
+)m/z 231.9。
To the solution of rough 5 (～16.9 mmoles) in the Zai diox (50 milliliters), add NaOAc (6.93 grams, 84.5 mmoles), HOAc (4.8 milliliters, 84.5 mmoles) and 5.1. (5.93 grams, 84.5 mmoles).After 1 hour, reaction mixture is warmed to 80 ℃, and stirs 3 hours.Reaction mixture is distributed in EtOAc (500 milliliters) and saturated NaHCO
3Between (200 milliliters).Water layer extracts with EtOAc (300 milliliters * 2).Organic layer through merging is with the salt water washing, at Na
2SO
4Last dry and concentrated.The gained resistates is (hexane/EtOAc 1: 0,1: 2,1: 1,0: 1) purifying on silica gel, produces 6 (1.2 grams are 23% from 4).LRMS(M+H
+)m/z 312.9。
Embodiment 76
To the solution of the sulfo-ethyl oxalate in methylene dichloride (400 milliliters) (10.0 grams, 75 mmoles), slowly add Tetrafluoroboric acid trimethylammonium osmium (13.1 grams, 89 mmoles) down at 0 ℃.Solvent is removed, and is produced as 18.0 gram products 2 of white solid, and it is used and does not have and be further purified.
2-amino-4 '-bromoacetophenone hydrochloride in the Zai diox (70 milliliters) (10.0 grams, 40 mmoles), sodium-acetate (16.4 grams, 200 mmoles), acetic acid is (11.5 milliliters, 200 mmoles) and compound 2 (19.2 the gram, 80 mmoles) mixture, 65 ℃ of stirrings, show no compound 2 residual (about 2 hours) up to TLC.Reaction mixture is by carefully with saturated NaHCO
3The solution neutralization is with ethyl acetate extraction.Organic layer is at Na
2SO
4Last dry and concentrated.With flash column chromatography analysis (EtOAc: Hex 1: 1) purifying, be produced as the product 3 (9.11 grams, 79%) of white solid.
In a round-bottomed flask, product 3 (2.00 grams, 6.8 mmoles) is dissolved among the DMF (20 milliliters), and is continuous to add methyl iodide (5.1 milliliters, 10.1 mmoles) and K
2CO
3(1.4 grams, 10.1 mmoles).Mixture is allowed at 60 ℃ to mix 3 hours, up to being complete with TLC.Solution is with the salt solution stopped reaction, with EtOAc extraction three times, dry and concentrated on sodium sulfate.Via the column chromatography analysis purifying, used EtOAc: Hex 1: 1, produce the product 4 of 1.38 grams (66%).
To the compound 3 in DMF (15 milliliters) (3.174 grams, 10.8 mmoles) solution, add K
2CO
3(4.478 grams, 32.4 mmoles) and (2-bromine oxethyl)-tertiary butyl dimethylsilane (2.780 milliliters, 13.0 mmoles).The gained mixture stirs down at 55 ℃ and spends the night.Solution is concentrated, dilutes with water, and with EtOAc extraction (3 * 50 milliliters).Organic layer is combined, at Na
2SO
4Last dry.Solvent is removed, and is produced as heavy-gravity oily matter (4.805 gram, 10.6 mmoles, 98.4%), and it is used to subsequent step and does not have and be further purified.
To the compound 4 in anhydrous THF (25 milliliters) (2.174 gram, 4.8 mmoles) solution, under nitrogen, 0 ℃, dropwise add methylmagnesium-bromide (4.8 milliliters, 3 volumetric molar concentrations in diethyl ether, 14.4 mmoles).Being reflected at 0 ℃ stirred 15 minutes down.Reaction by carefully with saturated ammonium chloride solution (5 milliliters) and water (30 milliliters) stopped reaction, and with EtOAc extraction (3 * 50 milliliters).Organic layer is combined, at Na
2SO
4Last dry, and be condensed into heavy-gravity oily matter.Analyze purifying (15%EtOAc: hexane), be produced as the product of wanting 5 (1.371 grams, 65%) of the no crystalline solid of white with flash column chromatography.
To the compound 5 in THF (5 milliliters) (1.371 gram, 3.1 mmoles) solution, add 4 volumetric molar concentrations in 35 milliliters the HCl (Zai diox).Gained solution at room temperature stirs and spends the night.Solvent is removed, and is produced as the product 6 (1.0 grams, 99%) of white solid.
Compound 6 in toluene (60 milliliters) (0.5 gram, 1.54 mmoles) and the mixture of 1 milliliter of TFA are spent the night by backflow.Solid 6 does not dissolve, up to the boiling point of nearly toluene.Solvent is removed.Resistates dilutes with EtOAc, with NaHCO
3Solution washing, at Na
2SO
4On be dried and concentrate.With flash column chromatography analysis (EtOAc: hexane 1: 1), be produced as the product 7 (0.348 gram, 74%) of white solid.
Embodiment 77
1-(4-(4-iodophenyl)-1-methyl isophthalic acid H-imidazoles-2-yl) ethyl) (methyl) carboxylamine (R)-methyl estersTo one 250 milliliters round-bottomed flask, add (R)-1-(4-(4-iodophenyl)-1-methyl isophthalic acid H-imidazoles-2-yl)-N-methyl ethane amine (3.1 grams, 9.1 mmoles), methyl-chloroformate (0.84 milliliter, 10.9 mmoles), Na
2CO
3(1.15 grams, 10.9 mmoles) and THF (100 milliliters).Reaction is stirred 2 hours, and is continuous to add EtOAc (50 milliliters) and water (10 milliliters).Organic layer is at Na
2SO
4Last dry, filtration and concentrated, producing 1.50 grams (41%) is 1-(4-(4-the iodophenyl)-1-methyl isophthalic acid H-imidazoles-2-yl) ethyl of pale solid) (methyl) carboxylamine (R)-methyl esters (M+H (m/z)=400).
Embodiment 78
Reference: J.Med.Chem.2001,44,2990-3000.
Stirred solution to the right-iodine acetophenone 1 in the, diox on ice bath (200 milliliters) (30.0 grams, 122 mmoles) adds bromine (6.56 milliliters, 128 mmoles).Reaction mixture at room temperature stirs and monitors with LC/MS.After finishing (about 1 hour), solvent removes to rotate evaporation, and resistates is dry in a vacuum, produces solid 2 (40 grams, 100%).
(with J.Med.Chem.2001,44,2990-3000 is the basis).To the Cbz-D-Ala-OH 3 in NMP (100 milliliters) (5.0 grams, 22.4 mmoles) solution, add cesium carbonate (3.72 grams, 11.4 mmoles).After at room temperature stirring 1 hour, add 2 (7.60 grams, 22.4 mmoles).Reaction mixture dilutes with dimethylbenzene (100 milliliters) and ammonium acetate (9.25 grams, 120 mmoles), and stirs 4 hours down at 120 ℃ then.Can there be height to 50 equivalent ammonium acetates to be required, depend on the carrying out of reaction.Key be see the solid in the free inherent flask.After being cooled to room temperature, reaction mixture dilutes with vinyl acetic monomer (200 milliliters).EtOAc solution is with saturated sodium bicarbonate aqueous solution (200 milliliters) washed twice, and drying, filtration, and filtrate then under reduced pressure concentrate on sodium sulfate.Resistates is dissolved among the DCM (100 milliliters), is stirred 1 hour, produces precipitation, and solid 5 (4.0 gram) is filtered, and dry in a vacuum.Mother liquor is to rotate evaporation concentration, and resistates is purifying on Bio-tage, produces 5 (hexane: EtOAc 1: 1 to EtOAc 100%).Two products are combined, and dry in a vacuum 5 (5.8 grams, 58%) that produce.
Embodiment 79
1-(4-(4-iodophenyl)-1-methyl isophthalic acid H-imidazoles-2-yl) ethyl) (methyl) carboxylamine (R)-benzyl ester 2: to the 1-in 55 milliliters DMF (4-(4-iodophenyl)-1-methyl isophthalic acid H-imidazoles-2-yl) ethyl) carboxylamine (R)-benzyl ester 1 (55 grams, 11 mmoles) stirs the mixture, be cooled to 0 ℃, and with NaH (1.33 grams, 11 mmoles, 60% dispersion liquid in oil) little processing partially is to avoid foam.When the bubble from last part stops, once adding all MeI (2.1 milliliters, 34 mmoles), and mixture restir 30 minutes.Solution is removed in a vacuum, and resistates is dissolved among 200 milliliters of EtOAc.Solution is with saturated NH
4The Cl aqueous solution (4 * 100 milliliters) and NaCl (4 * 100 milliliters) washing, and filter then, and be concentrated into dried.Rough resistates produces 2 of 5.13 grams (97%) via column chromatography analysis, at the last purifying of silica gel (60: 40 EtOAc/ hexanes), and it is with the LCMS identification mark.
Embodiment 80
Ethanoyl chlorine (54. milliliters, 0.75 mmole) is dropwise added to ethanol (316 milliliters) herbal medicine under 0-5 ℃.When interpolation was finished, ice bath was removed, and solution allowed stirring, was warmed to room temperature simultaneously 30 minutes again.Add D-aspartic acid 1 (25 gram, 0.188 mole) then.Reaction mixture was refluxed 2 hours.Reaction soln concentrates in a vacuum then, and is placed under the high vacuum (0.5 mm Hg) and spends the night.Compound 2 obtains (42 grams, 99%) with white solid, and directly is used to next step.
(BOC)
2O (4.7 gram, 0.21 mole) was divided in 10 minutes in the 0 ℃ of solution that partly adds compound 1 (42 grams, 0.19 mole), triethylamine (51.9 milliliters, 0.37 mole), diox (140 milliliters) and water (56 milliliters) to.After 10 minutes, ice bath is removed again, and reaction mixture is stirred, and is warmed to room temperature simultaneously 2 hours again.Reaction mixture dilutes with EtOAc (150 milliliters), and washs with 0.5 equivalent concentration HCl (200 milliliters * 3).Organic layer drying, filtration and filtrate on sal epsom concentrate in a vacuum, produce compound 3 (52 grams, productive rate 97%), and it directly is used to next step.
NaBH
4(54.4 gram, 1.44 moles) were divided in 30 minutes in the 0 ℃ of solution that partly adds compound 3 (52 grams, 86.4 mmoles) and ethanol (600 milliliters) to.Reaction mixture is extremely heat release, and during adding reductive agent extreme care.After interpolation was finished, reaction mixture was heated to and refluxed 1 hour.Solution is cooled to room temperature, and reaction mixture cured.Solid is broken into slurry, and it is introduced in the salt solution (250 milliliters) then.The gained mixture is filtered, and filtrate concentrates in a vacuum.Gained resistates and ether (200 milliliters * 5) are by vigorous stirring.The ether layer is by continuously from the resistates decant.Dry on sal epsom, the filtration of ether layer extract through combination, and filtrate is concentrated in a vacuum, is produced as the compound 4 (25.2 grams, productive rate 68%) of white solid.[note: when with 25 grams (compound 3) when scale is carried out, productive rate is 89%].
Tert-butyl diphenyl chlorosilane (31.9 milliliters, 0.123 mole) is added in the solution of compound 4 (25.2 grams, 0.123 mole), diisopropyl ethyl amine (42.8 milliliters, 0.245 mole) and methylene dichloride (500 milliliters).Reaction solution at room temperature stirred 24 hours.Reaction solution is used 0.5N HCl (150 milliliters * 3) and salt solution (150 milliliters) washing subsequently.Organic layer is dry on sal epsom, filtration, and filtrate concentrates in a vacuum.The gained resistates is with flash column chromatography analysis (silica gel, 4: 1 hexanes: EtOAc), be produced as compound 5 (42 grams, productive rate 77%).[note: when with 15 grams (compound 4) when scale is carried out, productive rate is 85%].
Iodine (24 grams, 94.7 mmoles) was divided partly to add compound 5 (28 grams, 63.1 mmoles), Ph in 15 minutes
3In 0 ℃ of solution of P (24.8 grams, 94.7 mmoles), imidazoles (6.4 grams, 94.7 mmoles), diethyl ether (450 milliliters) and acetonitrile (150 milliliters).Ice bath is removed, and reaction soln is allowed in 30 minutes and is warmed to room temperature.(4: 1 hexanes: EtOAc) analysis and judgement is complete with TLC in reaction.Reaction is ended with water (400 milliliters).Layer separates, and water layer extracts with diethyl ether (100 milliliters).Organic layer through merging is with saturated water-based Na
2SO
3Solution (100 * 2) and salt solution (100 milliliters) washing.Organic layer drying, filtration and filtrate on sal epsom concentrate in a vacuum.The gained resistates is with flash column chromatography analysis (silica gel, 4: 1 hexanes: EtOAc), be produced as compound 6 (32 grams, 92%).
Embodiment 81
Under ice bath, the D-aspartic acid 1 in methyl alcohol (200 milliliters) (59 gram, 0.376 mole) was blown into HCl gas 10 minutes.At room temperature stir at reaction soln and to spend the night, solution is evaporated.The gained resistates is dry in a vacuum, has the product 2 (0.376 mole) for HCl salt.
To the stirred solution of 2 (0.376 mmoles), DIEA (196 milliliters, 1.13 moles) and THF (200 milliliters), splash into chloroformic acid benzyl ester (59 milliliters, 0.414 mole) solution.Reaction soln stirred 1 hour under room temperature after, solution concentrated on the rotation vaporizer.Resistates is dissolved in NaHCO then
3In (300 milliliters), and extract with DCM (100 milliliters * 3).Concentrate in a vacuum through the DCM of combination layer drying, filtration and filtrate on sodium sulfate, have product 3 (0.376 mole).
To the solution of 3 (0.376 mmoles), THF (200 milliliters) and water (100 milliliters), add lithium hydroxide (31.6 grams, 0.752 mole), and stirred 2 hours.Reaction mixture filters (pH of filtrate about 7) via silicagel column and concentrates.Resistates is dry in a vacuum, produces 4 (0.376 moles).
After 4 (0.376 mmoles) and acetic anhydride (200 milliliters) stirred 1 hour, resistates was dry in a vacuum, produces 5 (0.376 moles).
Under ice bath, to during 30 minutes, adding sodium borohydride (14.2 grams, 0.376 mole) at 5 (0.376 moles) and THF (1000 milliliters), and stirred 3 hours.HCl (4 equivalent concentration) is splashed into reaction soln then, up to pH about 2.Solution is concentrated to approximately and remains 1/4th, dilutes with water (300 milliliters), and extracts with ether (200 milliliters * 3).Ethereal solution drying, filtration and filtrate on sodium sulfate through combination concentrate in a vacuum.The gained resistates is dissolved in the benzene (300 milliliters), and adds TsOH (500 milligrams).Reaction mixture is stirred 3 hours under refluxing then.Solution is concentrated into about 100 milliliters, and adds ether (200 milliliters) to form the foam precipitation.White solid 6 (57.5 gram, be 65% from 1) is filtered out, with some ethers washings and dry in a vacuum.
To (30.0 grams, 0.128 mmole) and methyl alcohol (200 milliliters) solution 6, add triethylamine (142 milliliters, 1.02 moles) and stir and spend the night.Reaction mixture is concentrated.Resistates is dry in a vacuum, produces 7 (LC-MS shows that about 20% mole 6 stay), and it is directly used in next step.
Under ice bath, to the solution stirring of compound 7 (0.128 mole), Ph3P (50.4 grams, 0.192 mole), imidazoles (13.1 grams, 0.192 mole) and DCM (300 milliliters) 10 minutes.Iodine (48.7 gram, 0.192 mole) divided partly in 15 minutes and adds.Ice bath is removed, and reaction soln is allowed in 1 hour and is warmed to room temperature.Solid is filtered out.Filtrate is with saturated water-based Na
2SO
3(200 milliliters * 2) and salt solution (200 milliliters) washing.Organic layer drying, filtration and filtrate on sal epsom are concentrated.The gained resistates is produced as the compound 8 (27.5 grams are 59.2% from 6) of white solid with quick silica gel column chromatography analysis (hexane: EtOAc 4: 1 to 1: 1).
To the mixture of zinc powder (Strem, 10.1 grams, 0.154 mole) and DMF (15 milliliters), exhaust is 10 minutes under nitrogen, and adds glycol dibromide (0.758 milliliter, 8.80 mmoles).Mixture cooled down 5 minutes with heating gun heating～2 minutes, and again with the heating gun heating, was cooled to room temperature then.Add TMSCl (128 microlitres, 2.20 mmoles) in mixture.After mixture stirs 30 minutes, add 8 (9.98 grams, 26.5 mmoles).After 1 hour, LCMS shows 8 completely consumed.Above-mentioned reaction soln is added aryl iodide (7.50 grams, 22.0 mmoles), Pd
2(dba)
3(50.4 milligrams, 0.55 mmole) and three-neighbour-tolylphosphine (670 milligrams, 2.20 mmoles).Reaction mixture is kept 1 hour (with in the LC-MS monitoring) under 50 ℃.Reaction mixture directly is carried on the silicagel column, and with hexane: EtOAc (3: 1 to 1: 1) washing, produces compound 10 (5.0 grams, 49%).
Embodiment 82
To the round-bottomed flask of an oven drying, add zinc powder (1753 milligrams, 27 mmoles), continuous with DMF (15 milliliters).Flask is added a cover, and with nitrogen exhaust 10 minutes.This solution is added glycol dibromide (0.139 milliliter, 1.6 mmoles).Mixture uses heating gun to heat about 30 seconds then, begins to disengage up to gas, points out the activation of zinc.Mixture is allowed cooling, simultaneously its again with the heating gun heating, before gas disengages, stirred 1 minute.Mixture is allowed cool to room temperature then, and is continuous with interpolation TMSCl (0.042 milliliter, 0.33 mmole), and stirs 30 minutes.Reagent A is dissolved among the DMF, is blown into, adds zinc solution with nitrogen then, and at room temperature stirs 1 hour.Bromine 4 (1.381 grams, 4.5 mmoles) is dissolved among the DMF, and nitrogen is blown into and injects solution, and is continuous to add Pd
2(dba)
3(102 milligrams, 0.11 mmole) and three-neighbour-tolylphosphine (136 milligrams, 0.44 mmole).Solution mixture is blown into by nitrogen, and maintains under the nitrogen, at room temperature stirs 1 hour simultaneously.After 1 hour, through stirred solution be heated to 40 ℃ 2 hours, up to serving as complete with TLC and LC/MS.Solution is with the salt solution stopped reaction, and use EtOAc extracts five times.Dry and concentrated on sodium sulfate through the combination organic layer.Raw product 5 uses 1: 1 purifying of EtOAc: Hex via column chromatography analysis, obtains the pure products 5 of 2.0 grams (70% productive rate).
Embodiment 83
To the compound 6 in THF (5 milliliters) (940 milligrams, 1.78 mmoles) solution, be added on 1,4 equivalent concentration HCl in the 4-diox (20 milliliters, 80 Bo moles).The gained mixture at room temperature is stirred 1 hour.Solution is evaporated, and surplus compound 7 (726 milligrams, 1.78 mmoles, full dose productive rate) is whole dry under high vacuum.Compound 7 uses LCMS (LRMS (MH) 373 m/z) to be identification mark, and is used to next step and does not have be further purified.
To the compound 7 in DMF (5 milliliters) (662 milligrams, 1.62 mmoles) solution, add DIEA (930 microlitres, 5.34 mmoles) and compound 8 (678 milligrams, 1.78 mmoles).Gained solution at room temperature is stirred 1 hour.DMF is evaporated, and rough resistates directly used preparation property HPLC purifying, and compound 9 (425 milligrams, 0.77 mmole, 48% productive rate) is provided, its with
1H NMR and LCMS (LRMS (MH) 569 m/z).
Compound 9 (100 milligrams, 0.176 mmole) and HATU (134 milligrams, 0.352 mmole), HOAT (48 milligrams, 0.352 mmole) and NH
4Cl (50 milligrams, 0.944 mmole) combination.Solid is dissolved in N-methyl tetrahydrochysene
Cough up ketone (5 milliliters), and add DIEA (93 microlitres, 0.528 mmole).The gained mixture at room temperature is stirred 2 hours, and directly uses preparation property HPLC purifying then, is provided as the compound 10 (16 milligrams, 0.028 mmole, 16% productive rate) of vitreous solid, its with
1H NMR and LCMS (LRMS (MH) 568 m/z).
Compound 9 (91 milligrams, 0.160 mmole) and HBTU (121 milligrams, 0.320 mmole) and HOBt (43 milligrams, 0.320 mmole) combination.Solid is dissolved in DMF (3 milliliters), and adds dimethyl amine (400 microlitres, 0.800 mmole, 2 volumetric molar concentrations in THF) and DIEA (93 microlitres, 0.528 mmole).Gained solution at room temperature is stirred 2 hours.Raw product directly uses preparation property HPLC purifying, is provided as the compound 11 (25 milligrams, 0.042 mmole, 26% productive rate) of vitreous solid, its with
1H NMR and LCMS (LRMS (MH) 596 m/z).
Embodiment 84
To 0 ℃ of solution of 1 (100 milligrams, 117 mmoles) in THF (250 milliliters) and DIEA (11.4 milliliters, 175 mmoles), add methyl-chloroformate (21.2 milliliters, 163 mmoles).The gained mixture at room temperature is stirred 3 hours.Reaction is with gaseous ammonia exhaust 1 hour, and at room temperature is stirred 16 hours then.It is with water (200 milliliters), vinyl acetic monomer (200 milliliters) dilution, and filtration.White, solid is by being wanted product after filtration.Extra product obtains to separatory funnel and separating layer to shift two-phase filtrate.Water extracts with extra vinyl acetic monomer (3 * 150 milliliters).Organic layer is combined, dry (Na
2SO
4) and be condensed into white solid, it is recrystallize from vinyl acetic monomer, and the product of is provided.Pure products 2 (20.6 gram, 60 mmoles) with
1H-NMR and LC/MS (LRMS (MH) m/z:343.1) characterize.
Acid amides 2 (18.1 grams, 53 mmoles) is suspended in 1,4-diox (200 milliliters) and pyridine (10.7 milliliters, 132 mmoles).Add trifluoro-acetic anhydride (22 milliliters, 158 mmoles), and white is dissolved at once through suspended solids.Homogeneous phase solution at room temperature is stirred 30 minutes.Solvent under reduced pressure is removed, and surplus resistates is dissolved in the vinyl acetic monomer (200 milliliters), and with 1 volumetric molar concentration KHSO
4(2 * 100 milliliters) and saturated water-based NaHCO
3(2 * 100 milliliters) washing.Organic layer is at Na
2SO
4On be dried and be concentrated in a vacuum.The surplus product of wanting 3 (14.9 grams, 46 mmoles) determined enough pure and be used for next transform (LC/MS (LRMS (MH) m/z 198.0)).
Nitrile 3 (14.9 grams, 46 mmoles) is dissolved in 1,4-diox (100 milliliters), and add tributyl (1-vinyl ethyl ether base) tin (23.3 milliliters, 69 mmoles), continuous with PdCl
2(PPh
3)
2(1.6 grams, 5 moles of %).The gained mixture is heated to 90 ℃, and stirs 4 hours.It is cooled to room temperature, and solvent under reduced pressure is removed.Surplus resistates directly use the silica gel purification that is prepared in the slurry that uses 95% hexane/triethylamine.Wash-out is progressively, begins with 95% hexane/triethylamine, and changes over 50% vinyl acetic monomer/hexane/5% triethylamine.The product of wanting 4 with latter's moving phase wash-out, and be the thickness yellow oil, characterize with LC/MS (LRMS (MH) m/z:371.1).Product is used for next the conversion at once.
To the solution of vinyl ether 4 in THF (60 milliliters) and water (20 milliliters), add N-bromine succinimide (12.3 grams, 69 mmoles).The gained mixture stirred 30 minutes down at 50 ℃.It is cooled to room temperature, and with 2 volumetric molar concentration Na
2CO
3Dilution.Mixture is with vinyl acetic monomer (2 * 150 milliliters) extraction, and organic extract is through combination, at Na
2SO
4Last dry and be condensed into no crystalline solid, it is with silica gel (methylene dichloride/vinyl acetic monomer) purifying.For the institute of yellow solid want product 5 (10.6 grams, 29 mmoles) with
1H-NMR and LC/MS (LRMS (MH) m/z 239.9 characterizes).
Embodiment 85
1, the solution of the ketone 5 in the 4-diox (50 milliliters) (10.6 grams, 29 mmoles) is splashed into methylamine (72 milliliters, 144 mmoles, 2 volumetric molar concentrations in THF) in 0 ℃, 45 minutes.The gained turbid solution was at room temperature stirred 15 minutes.THF and methylamine vapourisation under reduced pressure, and do not evaporate 1 carefully, the 4-diox.The gained mixture is under reduced pressure added triethylamine (12 milliliters, 87 mmoles), continuous with pivaloyl chlorine (15 milliliters, 144 mmoles).Gained suspension at room temperature stirred 30 minutes.It dilutes with water (125 milliliters), and extracts with EtOAc (3 * 100 milliliters).Organic phase is combined, at Na
2SO
4Last dry and concentrated in a vacuum.(LRMS (MH) m/z 402.1 characterizes gained raw product 6, and down carries out and do not have being further purified with LC/MS.
Acid amides 6 (11.6 grams, 29 mmoles) and ammonium acetate (55 grams, 723 mmoles) and methane amide (150 milliliters) combination.The gained mixture is heated to 100 ℃, and stirs 3 hours.It is cooled to room temperature, dilutes with vinyl acetic monomer (500 milliliters), and washs with water (3 * 200 milliliters).Organic layer is at Na
2SO
4Last dry and under reduced pressure concentrated.The surplus resistates of institute uses silica gel (diethyl ether/hexane) purifying, is provided as pure 7 (6.1 grams, 16 mmoles) of foam yellow solid, with
1(LRMS (MH) m/z 383.2 characterizes for H-NMR and LC/MS.
Imidazoles 7 (1.316 grams, 3.4 mmoles) makes up with oxammonium hydrochloride (478 milligrams, 6.9 mmoles), and is dissolved in the sodium methoxide solution in methyl alcohol (14 milliliters, 69 mmoles, 0.5 volumetric molar concentration).Gained solution stirred 4 hours down at 50 ℃.It under reduced pressure concentrates, and directly uses silica gel (5% ethanol/methylene) purifying, and the institute that is provided as the foam white solid wants amidoxime 8 (913 milligrams, 2.2 moles), and (LRMS (MH) m/z 416.1 characterizes with LC/MS.
To the amidoxime 8 in methyl alcohol (10 milliliters) (652 milligrams, 1.6 mmoles) solution, add Raney nickel (50 milligrams) and acetic acid (20 microlitre).Mixture is 60 pounds of H in the time of every square
2Under stir 3 hours, and filter through Celite then.Under reduced pressure concentrate the pure amidine 9 (638 milligrams, 1.6 mmoles) that is provided as white solid, use LC/MS (LRMS (MH) m/z 400.2 characterizes).
Monochloroacetaldehyde (360 milliliters, 5.7 mmoles) is added to amidine 9 (283 milligrams, 0.71 mmole) and the K in DMF (4 milliliters)
2CO
3In (195 milligrams, 1.4 mmoles) solution.Mixture is heated to 50 ℃, and stirs 4 hours.Reaction is filtered, and the eluent gradient purifying of direct reversed-phase HPLC, use acetonitrile and water composition.Pure product 10 (25 milligrams, 0.06 Bo mole)
*Be vitreous solid, with
1H-NMR and LC/MS (LRMS (MH) m/z424.1) characterize.
To the acid amides 8 in trimethyl orthoacetate (5 milliliters) (148 milligrams, 0.35 mmole) solution, add Glacial acetic acid (100 microlitre).Gained solution stirred 16 hours down at 50 ℃.The solvent vapourisation under reduced pressure, and resistates is directly through silica gel (5% ethanol/methylene) purifying, the institute that is provided as vitreous solid wants product 9, and (LRMS (MH) m/z 440.1 characterizes with LC/MS.
Embodiment 86
1 (200 milligrams, 0.5 mmole) solution in THF (3 milliliters) at room temperature adds Bu
3P (150 microlitres, 0.6 mmole) and 2-nitrophenyl selenocyanate (136 milligrams, 0.6 mmole).Reaction mixture is stirred 14 hours.Mixture is at EtOAc (200 milliliters) and H
2Distribute among the O (50 milliliters).Organic layer and with the salt water washing, at Na
2SO
4On be dried and be concentrated.The gained resistates is used and does not have and is further purified.LRMS(M+H
+)m/z587.1。
To 2 (～0.5 mmole) solution in DCM (5 milliliters), add water-based KH
2PO
-4(2 volumetric molar concentrations, 1 milliliter) and MCPBA (77%, 135 milligram, 0.6 mmole).Reaction mixture is stirred 6 hours.Reaction mixture is with Na
2S
2O
4(10 milliliters) stopped reaction.Organic layer is with saturated water-based NaHCO
3, H
2O and salt water washing are at Na
2SO
4Last dry and concentrated.Resistates on RP-HPLC, use acetonitrile and H
2The O purifying mixture produces 3 (150 milligrams is 65% from 1).LRMS(M+H
+)m/z 384.2。
To 3 (150 milligrams, the 0.39 mmole) solution in DCM (8 milliliters), add TFA (1 milliliter).Reaction mixture is stirred 4 hours.Mixture is concentrated, and dry under high vacuum.Gained resistates in THF (4 milliliters) (90 milligrams, 0.32 mmole) is added DIEA (165 microlitres, 0.95 mole) and 4 (140 milligrams, 0.38 mmole).The gained mixture is stirred 14 hours.Reaction mixture is concentrated.Resistates on RP-HPLC, use acetonitrile and H
2The O purifying mixture produces 5 (120 milligrams, 65%).LRMS(M+H
+)m/z 471.2。
To at THF/H
25 (120 milligrams, 0.19 mmole) solution among the O (2 milliliters/2 milliliters) adds OsO-
4(4.8 milligrams, 0.019 mmole), NMO (117 milligrams, 0.95 mmole) and pyridine (1.5 microlitres, 0.019 mole).The gained mixture is stirred 6 hours.Add HaHSO
3(300 milligrams).Reaction mixture is concentrated.The gained solid washs with EtOAc (100 milliliters * 3).Filtrate is concentrated.(silica gel, 5: 1EtOAc/MeOH) purifying produces diastereomer 6a (23 milligrams, 24%) and 6b (2 milligrams, 2%) to the gained resistates with preparation property TLC plate.LRMS(M+H
+)m/z 505.2。
Embodiment 87
To at amine 1 (150 milligrams, 0.309 mmole), DCM (2 milliliters) and DIEA (53.8 microlitres, 0.309 mmole) solution, add ethanoyl chlorine (53.8 microlitres, 0.309 mmole).Gained solution at room temperature stirred 10 minutes.Solvent is evaporated, and the surplus resistates of institute provides 2 (42.7 milligrams, 26.8%) at the last purifying of anti-phase preparation HPLC (acetonitrile/water).MS(MW+1)：527.2。
Embodiment 88
To at amine 1 (150 milligrams, 0.309 mmole), DCM (2 milliliters) and DIEA (53.8 microlitres, 0.309 mmole) solution, add isocyanic acid trimethyl silyl ester (35.6 microlitres, 0.309 mmole).Gained solution at room temperature stirs and spends the night.Solvent is evaporated, and the surplus resistates of institute provides 3 (30.3 milligrams, 18.6%) at the last purifying of anti-phase preparation HPLC (acetonitrile/water).MS(MW+1)：528.2。
Embodiment 89
To at amine 1 (150 milligrams, 0.309 mmole), DCM (2 milliliters) and DIEA (53.8 microlitres, 0.309 mmole) solution, add methane sulfonyl chlorine (24 microlitres, 0.309 mmole).Gained solution at room temperature stirred 30 minutes.Solvent is evaporated, and the surplus resistates of institute provides 4 (18.4 milligrams, 10.6%) at the last purifying of anti-phase preparation HPLC (acetonitrile/water).MS(MW+1)：563.1。
Embodiment 90
To at amine 1 (150 milligrams, 0.309 mmole), DCM (2 milliliters) and DIEA (53.8 microlitres, 0.309 mmole) solution, add methyl-chloroformate (24 microlitres, 0.309 mmole).Gained solution at room temperature stirred 30 minutes.Solvent is evaporated, and the surplus resistates of institute provides 5 (CK1828648) (25.7 milligrams, 15.3%) at the last purifying of anti-phase preparation HPLC (acetonitrile/water).MS(MW+1)：543.1。
Embodiment 91
(S)-3-chloro-N-(4-hydroxyl-(1-(4-(2-(1-methoxyimino) ethyl)-1-methyl isophthalic acid H-imidazol-4 yl) phenyl) fourth-2-yl)-4-isopropoxy benzamide 2:
80 milligrams (0.031 mmoles) in 2 milliliters of pyridines (S)-N-(1-(4-hydroxyl (2-ethanoyl-1-methyl isophthalic acid H-imidazol-4 yl) phenyl)-4-hydroxyl fourth-2-yl)-3-chloro-4-isopropoxy benzamide, handle with the oxyamine methyl ether hydrochloride of 27.6 milligrams (0.033 mmoles).Reaction is stirred spends the night, and solvent is evaporated afterwards, and resistates is via reversed-phase HPLC (acetonitrile/water) purifying.Obtain 11.2 milligrams (70% productive rates) 2, and with LC/MS and HNMR identification mark.
Embodiment 92
(S)-3-chloro-N-(4-hydroxyl-1-(4-(2-(1-oxyimino) ethyl)-1-methyl isophthalic acid H-imidazol-4 yl) phenyl) fourth-2-yl)-4-isopropoxy benzamide 3:
100 milligrams (0.21 mmoles) in 2 milliliters of pyridines (S)-N-(1-(4-(2-ethanoyl-1-methyl isophthalic acid H-imidazol-4 yl) phenyl)-4-hydroxyl fourth-2-yl)-3-chloro-4-isopropoxy benzamide, handle with the oxammonium hydrochloride of 71.8 milligrams (1.0 mmoles).Reaction is stirred spends the night, and solvent is evaporated afterwards, and resistates is via reversed-phase HPLC (acetonitrile/water) purifying.Obtain 69.7 milligrams (67% productive rates) 3, and with LC/MS and HNMR identification mark.
Embodiment 93
(S)-3-chloro-N-(4-hydroxyl-1-(4-(1-methyl-2-(2-methyl isophthalic acid, 3-Dloxole alkane-2-yl)-1H-imidazol-4 yl) phenyl) fourth-2-yl)-4-isopropoxy benzamide 4:
150 milligrams (0.31 mmoles) in 2 milliliters of benzene (S)-N-(1-(4-(2-ethanoyl-1-methyl isophthalic acid H-imidazol-4 yl) phenyl)-4-hydroxyl fourth-2-yl)-3-chloro-4-isopropoxy benzamide; with the ethane-1 of 34.6 microlitres (0.62 mmole), the right-toluenesulphonic acids monohydrate of 2-glycol and 59 milligrams (0.31 mmoles) is handled.Be reflected at 70 ℃ and stirred 2 hours down, solvent is evaporated afterwards, and resistates is via reversed-phase HPLC (acetonitrile/water) purifying.Obtain 25.5 milligrams (16% productive rates) 4, and with LC/MS and HNMR identification mark.
Embodiment 94
1 (1.5 grams, 2.29 mmoles) solution in ethanol (5.0 milliliters) adds NaOH (1.0 volumetric molar concentrations, 3.7 milliliters, 2.80 mmoles).Reaction mixture at room temperature stirred 2 hours.After reaction was finished, it was concentrated, and produced 2 (1.49 grams), and it is used to next step and does not have and be further purified.
To (530 milligrams of 2 (1.49 grams, 2.29 mmoles) in DMF (20 milliliters), HBTU (1.3 grams, 3.44 mmoles), HOBt, 3.44 mmole) and N, O-dimethyl hydroxyl amine HCl salt (340 milligrams, 3.44 mmoles) solution adds DIEA (785 microlitres, 4.58 mmoles).The gained mixture at room temperature is stirred 2 hours.Reaction mixture is concentrated.The gained resistates uses silica gel, and (hexane/EtOAc=1: 3) purifying is produced as canescence spumescence solid pure compound 3 (1.20 grams, 78%).
0 ℃ of solution to 3 (1.20 grams, 1.79 mmoles) in anhydrous THF (20 milliliters) adds methylmagnesium-bromide (Et
23 volumetric molar concentrations among the O, 2.38 milliliters).Reaction mixture is stirred 1 hour under 0 ℃.Reaction mixture is with saturated NH
4Cl (5 milliliters) and water (20 milliliters) stopped reaction.Add EtOAc (50 milliliters), and layer separates.Water extracts with extra EtOAc (50 milliliters * 2).Organic layer is combined, dry (Na
2SO
4) and be condensed into rough oily matter, it uses silica gel (50%EtOAc/ hexane) purifying.The compound of wanting (0.82 gram, 73%) is a thickness oily matter, and it becomes the spumescence solid between dry epoch under high vacuum.
4 (0.82 gram, 1.31 mmoles) solution in methyl alcohol (10 milliliters) adds HCl (1,4 volumetric molar concentrations in the 4-diox, 20 milliliters).Reaction at room temperature is stirred spends the night.Mixture is concentrated, and dry under the high vacuum, produces 5, and it is used to subsequent step and does not have and be further purified.
To 5 (350 milligrams, the 1.09 mmoles) solution in DMF (5 milliliters), add DIEA (280 microlitres, 1.63 mmoles) and ester H (472 milligrams, 1.09 mmoles).Gained solution at room temperature stirred 1 hour.Crude solution is filtered, and then with reverse-phase chromatography analysis (using acetonitrile and water mixture) purifying, is provided as the CK1904250 (400 milligrams, 68%) of spumescence solid.LRMS(M+H
+)m/z 538.1。
Ester D (10.2 grams, 24.5 mmoles) is dissolved in EtOH (150 milliliters) and the water (50 milliliters).Add hydroxide first (4.1 grams, 73.5 mmoles), and reaction stirring is at room temperature spent the night.Reaction mixture is cooled to 0 ℃, and with dense HCl neutralization.Minimum heart do not allow pH during neutralizing, become＜7.Solvent evaporates in a vacuum, and resistates is dry under high vacuum.Acid E (9.5 gram, 24.5 mmoles) is used to next step and does not have and be further purified.
Acid E (9.5 grams, 24.5 mmoles) and HBTU (1.85 grams, 48.7 mmoles), HOBt (6.6 grams, 48.7 mmoles) and N, O-dimethyl hydroxyl amine HCl salt (4.8 grams, 48.7 mmoles) combination.The gained mixture at room temperature is stirred 4 hours.Most DMF is evaporated, and the surplus resistates of institute is with vinyl acetic monomer (300 milliliters) and water (300 milliliters) dilution.Layer separates, and water extracts with EtOAc (1 * 200 milliliter).Organic layer is through combination, with sodium bicarbonate aqueous solution (2 * 250 milliliters) washing, at Na
2SO
4Last dry.Under reduced pressure concentrate, be provided as the rough acid amides E of canescence spumescence solid (6.73 grams, 17.4 mmoles).
To the acid amides E in anhydrous THF (250 milliliters) (6.73 grams, 17.4 mmoles) solution, be cooled to 0 ℃ with ice bath.Add methylmagnesium-bromide (3 volumetric molar concentrations in diethyl ether, 52.2 milliliters, 156.6 mmoles), and stirred 15 minutes under being reflected at 0 ℃.With saturated ammonium chloride solution (20 milliliters) and water (100 milliliters) stopped reaction, and layer separates by carefully in reaction.Water extracts with extra EtOAc (2 * 200 milliliters).Organic layer is through combination, dry (Na
2SO
4) and be condensed into rough oily matter, it uses silica gel (50%EtOAc/ hexane) purifying.The ketone F that wants (4.45 gram, 11.5 mmoles) be a thickness oily matter, and it becomes white foam shape solid during drying under high vacuum.
Ketone F (4.45 grams, 11.5 mmoles) is dissolved in THF (25 milliliters) and reaches 14 volumetric molar concentration HCl (75 milliliters) lining in the 4-diox.Reaction at room temperature is stirred 1.5 hours.Solvent evaporates in a vacuum, and resistates integral body is dry under high vacuum, and amine G is provided.Amine G is used to subsequent step and does not have be further purified.
To 0 ℃ of solution of the amine G in DMF (50 milliliters) (3.30 grams, 11.5 mmoles), add DIEA (8.0 milliliters, 46.0 mmoles) and ester H (5.25 grams, 13.8 mmoles).Gained solution at room temperature is stirred 1 hour.Most DMF is evaporated, and the surplus resistates of institute is with EtOAc (250 milliliters) and water (200 milliliters) dilution.Layer separates, and organic phase is with extra water (2 * 150 milliliters) and salt solution (2 * 150 milliliters) washing.Organic phase (the Na that is dried
2SO
4) and concentrate.The surplus rough thickness oily matter of institute uses silica gel (100% hexane) purifying, proposes into spumescence solid CK1317644 (2.98 grams, 6.2 mmoles).
Embodiment 95
To the solution of the sulfo-ethyl oxalate in methylene dichloride (400 milliliters) (10.0 grams, 75 mmoles), slowly add Tetrafluoroboric acid trimethylammonium osmium (13.1 grams, 89 mmoles) down at 0 ℃.After 10 minutes, ice bath is removed, and reaction mixture is stirred and spends the night.Solvent is removed, and is produced as 18.0 gram products 2 of white solid, and it is used and does not have and be further purified.
2-amino 4 '-bromoacetophenone hydrochloride in the Zai diox (70 milliliters) (10.0 grams, 40 mmoles), sodium-acetate (16.4 grams, 200 mmoles), acetic acid is (11.5 milliliters, 200 mmoles) and compound 2 (19.2 the gram, 80 mmoles) mixture, 65 ℃ of stirrings, show no compound 2 residual (about 2 hours) up to TLC.Reaction mixture is by carefully with saturated NaHCO
3The solution neutralization, and with ethyl acetate extraction.Organic solution is at Na
2SO
4Last dry and concentrated.With flash column chromatography analysis (EtOAc: Hexs 1: 1) purifying, be produced as the product 3 (9.11 grams, 79%) of white solid.
To the compound 3 in DMF (15 milliliters) (3.174 grams, 10.8 mmoles) solution, add K
2CO
-3(4.478 grams, 32.4 moles) and (2-bromine oxethyl)-tertiary butyl dimethylsilane (2.780 milliliters, 13.0 mmoles).The gained mixture stirs down at 55 ℃ and spends the night.Solution is concentrated, extracts with the water dilution and with EtOAc (3 * 50 milliliters).Organic layer is through combination, and at Na
2SO
4Last dry.Solvent is removed, and produces thickness oily matter (4.805 grams, 10.6 moles, 98.4%), and it is used to subsequent step and does not have and be further purified.
To the solution of the compound 4 in anhydrous THF (25 milliliters) (2.174 gram, 4.8 mmoles), under 0 ℃, nitrogen, dropwise add methylmagnesium-bromide (4.8 milliliters, 3 volumetric molar concentrations in diethyl ether, 14.4 mmoles).Be reflected at and be stirred 15 minutes under 0 ℃.React carefully with saturated ammonium chloride (5 milliliters) and water (30 milliliters) stopped reaction, and extract with EtOAc (3 * 50 milliliters).Organic layer is combined, at Na
2SO
4Last dry and be condensed into rough oily matter.With flash column chromatography analysis (15%EtOAc/ hexane), be produced as the product of wanting 5 (1.371 grams, 65%) of the no crystalline solid of white.
To the compound 5 in THF (5 milliliters) (1.371 grams, 3.1 mmoles) solution, add 35 milliliters of HCl (1,4 volumetric molar concentrations in the 4-diox).Gained solution at room temperature is stirred and spends the night.Solvent is removed, and is produced as 6 (1.0 grams, 99%) of white solid.
Compound 6 in toluene (60 milliliters) (0.5 gram, 1.54 mmoles) and the mixture of 1 milliliter of TFA are spent the night by backflow.Solid 6 does not dissolve, up to the boiling point of nearly toluene.Solvent is removed.Resistates dilutes with EtOAc, with NaHCO
3Solution washing, at Na
2SO
4On be dried and concentrate.With flash column chromatography analysis (EtOAc: hexane 1: 1), be produced as the product 7 (0.348 gram, 74%) of white solid.
Suspension to the zinc powder (255 milligrams, 3.9 moles) in the DMF (15 milliliters) of anhydrous and the degassing adds 1,2-monobromethane (0.020 milliliter, 0.23 mmole) under nitrogen.Mixture uses heating gun to heat about 30 seconds, begins to disengage from solution up to gas, points out the activation of zinc.Mixture is allowed cool to room temperature then, and is continuous with interpolation TMSCl (6 microlitres, 0.05 mmole), and allows and at room temperature stir 30 minutes.Iodine compound solution A in degassing DMF is added to zinc solution then, and reaction mixture at room temperature stirred 1 hour.Compound 7 (200 milligrams, 0.65 mmole) in degassing DMF is added via syringe then, and is continuous to add Pd
2(dba)
3(14.9 milligrams, 0.016 mmole) and three-neighbour-tolylphosphine (19.8 milligrams, 0.065 mmole).Reaction mixture at room temperature stirred 1 hour, and is following 2 hours at 40 ℃ then.Reaction is presented on the TLC fully.Reaction is with the salt solution stopped reaction, and use EtOAc extraction (5 * 50 milliliters).Dry and concentrated on sodium sulfate through the combination organic layer.With flash column chromatography analysis (EtOAc: Hex 1: 1) purifying, produce the product 8 (373 milligrams, 88% productive rate) of colorless oil.
To the compound 8 in methyl alcohol (10 milliliters) (373 milligrams, 0.57 mmole) solution, add 2 milliliters of HCl (1,4 volumetric molar concentrations in the 4-diox).Solution is allowed at room temperature be stirred 2 hours.Solvent is removed, and produces raw product 9 (180 milligrams, 99%), and it is used and does not have and be further purified.
To the compound 9 in DMF (10 milliliters) (180 milligrams, 0.57 mmole) and contain ester reagent B (260 milligrams, the 0.68 mmole) mixture of triethylamine (0.24 milliliter, 1.71 mmoles), at room temperature be stirred and spend the night.Reaction soln dilutes with salt solution, and with EtOAc extraction (3 * 50 milliliters).Dry and concentrated on sodium sulfate through the combination organic layer.HPLC (C18 post) produce white solid product 10 (141 milligrams, 50% productive rate).
To the suspension of the NaH in DMF (15 milliliters) (0.39 gram, 9.3 mmoles), under nitrogen, 0 ℃, be added on 3 among the DMF (10 milliliters) (1.9 grams, 6.5 mmoles) solution.Reaction is stirred 1.5 hours, and adds (2-bromine oxethyl)-tertiary butyl dimethylsilane (2.09 milliliters, 9.7 mmoles).Reaction mixture be stirred spend the night, with EtOAc dilution, with the aqueous ammonium chloride solution stopped reaction, and extract with EtOAc (3 * 50 milliliters).Organic layer is combined, at Na
2SO
4Last dry.With Biotage (EtOAc), purifying is produced as the product 4 (1.2 gram, 41%) of light yellow solid.
Suspension to the zinc powder in degassing DMF (15 milliliters) (1.2 grams, 18.4 mmoles) adds 1,2-monobromethane (0.13 milliliter, 1.5 mmoles) under nitrogen.Mixture uses heating gun to heat about 30 seconds, begins to disengage from solution up to gas, points out the activation of zinc.Mixture is allowed cool to room temperature then, and is continuous with interpolation TMSCl (100 microlitre), and allows and at room temperature stir 30 minutes.Iodine compound solution A in degassing DMF (1.71 grams, 3.1 mmoles) is added to zinc solution then, and reaction mixture at room temperature stirred 1 hour.Compound 4 in degassing IDMF (1.0 grams, 2.2 mmoles) is added via syringe then, and is continuous to add Pd
2(dba)
3(0.14 gram, 0.015 mmole) and three-neighbour-tolylphosphine (1.8 grams, 0.06 mmole).Reaction mixture at room temperature stirred one hour, spent the night under 60 ℃ then.Reaction is with the salt solution stopped reaction, and with EtOAc extraction (5 * 50 milliliters).Dry and concentrated on sodium sulfate through the combination organic layer.With flash column chromatography analysis (EtOAc: Hex 1: 1) purifying, produce the product 5 (346 milligrams, 20%) of colorless oil.
To compound 7 (346 milligrams) solution in methyl alcohol (10 milliliters), add 2 milliliters of HCl (1,4 volumetric molar concentrations in the 4-diox).Solution is allowed at room temperature be stirred 2 hours.Solvent is removed, and produces raw product 7, and it is used in next step and does not have and be further purified.
To the compound 7 in DMF (10 milliliters) and contain ester reagent B (200 milligrams, the 0.52 mmole) mixture of triethylamine (0.15 milliliter, 1.08 mmoles), at room temperature be stirred and spend the night.Reaction soln dilutes with salt solution, and with EtOAc extraction (3 * 50 milliliters).Dry and concentrated on sodium sulfate through the combination organic layer.HPLC (C18 post) produce white solid product 8 (0.2 gram, 87%) and white solid interior ester products 9 (15.4 milligrams, 7.3%).LC-MS(CI)m/z 389.1(MH
+)。
Embodiment 96
To the solution of the sulfo-ethyl oxalate in methylene dichloride (400 milliliters) (10.0 grams, 75 mmoles), slowly add Tetrafluoroboric acid trimethylammonium osmium (13.1 grams, 89 mmoles) down at 0 ℃.After 10 minutes, ice bath is removed, and reaction mixture is stirred and spends the night.Solvent is removed, and is produced as 18.0 gram products 2 of white solid, and it is used and does not have and be further purified.
2-amino-4 '-bromoacetophenone hydrochloride in the Zai diox (70 milliliters) (10.0 grams, 40 mmoles), sodium-acetate (16.4 grams, 200 mmoles), acetic acid is (11.5 milliliters, 200 mmoles) and compound 2 (19.2 the gram, 80 mmoles) mixture, 65 ℃ of stirrings, show no compound 2 residual (about 2 hours) up to TLC.Reaction mixture is by carefully with saturated NaHCO
3The solution neutralization is with ethyl acetate extraction.Organic solution is at Na
2SO
4Last dry and concentrated.With flash column chromatography analysis (EtOAc: Hex 1: 1) purifying, be produced as the product 3 (9.11 grams, 79%) of white solid.
To the compound 3 in DMF (15 milliliters) (5.307 grams, 18 mmoles) solution, add K
2CO
3(3.73 grams, 27 mmoles) and iodoethane (3.5 milliliters, 43.2 mmoles).The gained mixture stirred three hours down at 60 ℃.Mixture dilutes with water, and with EtOAc extraction (3 * 50 milliliters).Organic layer is combined, at Na
2SO
4Last dry and concentrated.With flash column chromatography analysis (hexane/EtOAc 50: 50) purifying, produce the product 4 (3.2 grams, 55%) of white solid.
Suspension at the zinc powder (3.90,49.6 mmole) of drying in degassing DMF (10 milliliters) adds 1,2-monobromethane (308 microlitres, 3.58 mmoles) under nitrogen.Mixture uses heating gun to heat about 30 seconds, begins to disengage from solution up to gas, points out the activation of zinc.Mixture is allowed cool to room temperature then, and is continuous with interpolation TMSCl (92 microlitres, 0.735 mmole), and allows and at room temperature stir 30 minutes.Iodine compound solution A in degassing DMF (6.6 grams, 11.9 mmoles) is added to zinc solution then, and reaction mixture at room temperature stirred 1 hour.Compound 4 in degassing DMF (3.2 grams, 9.93 mmoles) is added via syringe then, and is continuous to add Pd
2(dba)
3(223 milligrams, 0.244 mmole) and three-neighbour-tolylphosphine (302 milligrams, 0.0992 mmole).Reaction mixture at room temperature stirred one hour, and is following 2 hours at 60 ℃ then.Reaction is as being shown as on the TLC fully.Solution is with the salt solution stopped reaction, and with EtOAc extraction (3 * 80 milliliters).Dry and concentrated on sodium sulfate through the combination organic layer.With flash column chromatography analysis (EtOAc: Hex 1: 1) purifying, produce the product 5 (5.43 milligrams, 82%) of colorless oil.
Compound 5 in THF (50 milliliters) (5.43 gram, 8.1 mmoles) solution dropwise is added on the MeMgBr (9.0 milliliters, 27 mmoles) in the ether under 0 ℃, nitrogen.Reaction is finished in 10 minutes via TLC.Solution extracts with EtOAc (3 * 60 milliliters) in ice with the aqueous ammonium chloride solution stopped reaction simultaneously.Organic layer through merging is dry and concentrated on sodium sulfate.With column chromatography analysis (hexane/EtOAc 1: 1) purifying, produce the product 6 (4.86 grams, 91%) of colorless oil.
To the compound 6 in MeOH (10.0 milliliters) (4.86 gram, 7.4 mmoles) and 18 milliliters of HCl (1,4 volumetric molar concentrations in the 4-diox) at room temperature are stirred 1 hour, continuous with following 30 minutes at 60 ℃.Reaction via TLC and LC/MS for finishing.Solvent is removed, and produces product 7, and it is used and does not have and be further purified.
To the sour B in DMF (40 milliliters) (677 milligrams, 2.51 mmoles), HBTU (3.6 grams, 9.49 mmoles), HOBT (1.45 grams, 9.46 mmole) and the mixture of DIEA (2.20 milliliters, 12.6 mmoles), at room temperature be stirred 1 minute, continuous to add 7 (1.0 grams, 3.14 mmoles).Reaction is finished in one hour via TLC and LC/MS.Organic layer is dry and down concentrated on sodium sulfate.With the HPLC purifying, produce the product 8 (390 milligrams) of white solid.
To the compound 3 in DMF (15 milliliters) (2.66 grams, 7.27 mmoles) solution, add K
2CO
3(2.00 grams, 15 mmoles) and iodoethane (1.61 milliliters, 14.5 mmoles).The gained mixture stirred three hours down at 60 ℃.Mixture dilutes with water, and with EtOAc extraction (3 * 50 milliliters).Organic layer is combined, at Na
2SO
4Last dry and concentrated.With column chromatography analysis (hexane/EtOAc 50: 50) purifying, produce product 4 (3.02 grams, 91%).
Solution to the compound 4 in MeOH (20 milliliters) (3.02 grams, 6.7 mmoles) is added on 1, and the HCl (4 volumetric molar concentration) in the 4-diox (7.0 milliliters) is stirred one hour under 60 ℃.Mixture is concentrated, and does not have purifying and be carried out.Surplus oily matter is dissolved in DMF (15 milliliters), adds K
2CO
-3(2.0 grams, 14.7 mmoles) spend the night 60 ℃ of stirrings.Mixture dilutes with water (5 * 150 milliliters), and extracts with EtOAc (3 * 50 milliliters).Organic layer is combined, at Na
2SO
4Last dry and concentrated.With column chromatography analysis (hexane/EtOAc 50: 50) purifying, produce product 5 (1.80 grams, 88%).
To the compound 3 in DMF (15 milliliters) (5.00 grams, 17 mmoles) solution, add K
2CO
3(3.51 grams, 26 mmoles) and Boc-2-amino-ethyl bromine (4.56 grams, 20.35 mmoles).The gained mixture stirred three hours down at 60 ℃.Mixture dilutes with water, and with EtOAc extraction (3 * 50 milliliters).Organic layer is combined, at Na
2SO
4Last dry and concentrated.With column chromatography analysis (hexane/EtOAc 50: 50) purifying, produce the product 4 (4.08 grams, 55%) of white solid.
Embodiment 97
At MeOH/H
2The solution of among the O (60 milliliters/20 milliliters) 1 (10.7 grams, 34.6 mmoles) adds NaOH (2 equivalent concentration, 20.8 milliliters, 41.6 mmoles).Being reflected at 50 ℃ stirred 2 hours down.Solution is concentrated under high vacuum then, is produced as the light yellow solid (LRMS (M-H of 10.3 grams
+) m/z 278.9), it is used and does not have and is further purified.Crude mixture solution in DMF (50 milliliters) is added N continuously, O-dimethyl oxammonium hydrochloride (4.0 grams, 40.7 mmole), HBTU (4.0 grams, 40.7 mmoles), HOBt (6.2 grams, 40.7 mmoles) and DIEA (6.0 milliliters, 47.0 mmoles).Mixture at room temperature stirs and spends the night.Solution is at EtOAc and H then
2Distribute among the O.Organic layer is with NaOH (1 equivalent concentration), salt water washing, at Na
2SO
4Last dry, filtration and concentrated.The gained resistates uses hexane and EtOAc with the flash column chromatography analysis, produces 2 (8 grams, 72%).LRMS(M+H
+)m/z 324.0。
2 (3.7 grams, 11.4 mmoles) solution in THF (40 milliliters) dropwise is added on Et under 0 ℃
2MeMgBr among the O (3 volumetric molar concentrations, 11.4 milliliters, 34.2 mmoles).Mixture is stirred 30 minutes under 0 ℃.Solution under 0 ℃ with saturated NH
4The Cl stopped reaction, and at EtOAc and H
2Distribute among the O.Organic layer is with the salt water washing, at Na
2SO
4Last dry, filter and concentrate, do not have and be further purified and produce 3 (3.0 grams, 94%).LRMS(M+H
+)m/z279.0。
3 (3.0 grams, 10.8 mmoles) solution in THF/MeOH (10 milliliters/10 milliliters) slowly adds NaBH
4(407 milligrams, 10.8 mmoles).Mixture is stirred 10 minutes, with saturated NH
4The Cl stopped reaction, and be distributed in EtOAc and H
2Between the O.Organic layer is with saturated NaHCO
3, the salt water washing, at Na
2SO
4Last dry and concentrate, produce 4 (3.0 grams, 99%), it is used and does not have and be further purified.LRMS(M+H
+)m/z 281.0。
To the solution of 4 (3.0 grams, 10.7 mmoles) in DMF (20 milliliters), add TBDMSCl (1.6 grams, 10.7 mmoles) and DMAP (271 milligrams, 21.3 mmoles).Mixture at room temperature stirs and spends the night.Solution is distributed in EtOAc and H
2Between the O.Organic layer is with saturated NaHCO
3, H
2O, salt water washing, at Na
2SO
4Last dry, filtration and concentrated.Resistates is analyzed purifying with flash column chromatography, uses the mixture of hexane and EtOAc, produces product 5 (3.5 grams, 83%).LRMS(M+H
+)m/z 395.1。
Suspension to the Zn in DMF (20 milliliters) (4.8 grams, 74.4 mmoles) adds BrCH
2CH
2Br (320 microlitres, 3.7 mmoles).Mixture uses heating gun heating 4 minutes.Solution is cooled, and adds trimethyl silane (95 microlitres, 0.74 mmole).After 3 minutes, add BOC-β-iodo-Ala-OMe (5.2 grams, 16.0 mmoles), and reaction mixture stirred at room temperature 1 hour.Then this mixture is added Pd
2(dba)
3(243 milligrams, 0.27 mmole), (O-Tol)
3P (269 milligrams, 0.88 mmole) and 5 (3.5 grams, 8.9 mmoles).Mixture 50 ℃ stir down 2 hours, cool down and filter through Celite.Solution is distributed in EtOAc and H
2Between the O.Organic layer is with the salt water washing, at Na
2SO
4Last dry and concentrated.Resistates produces 6 (3.3 grams, 72%) with the purifying mixture of column chromatography analysis, use hexane and EtOAc.LRMS(M+H
+)m/z 518.2。
Solution to 6 (3.3 grams, 6.4 mmoles) in THF (20 milliliters) slowly adds LAH (1.0 volumetric molar concentrations, 6.4 milliliters, 6.4 mmoles) down at 0 ℃.Mixture stirred 20 minutes down at 0 ℃, with H
2O (240 microlitre), NaOH (3 equivalent concentration, 240 microlitres), H
2O (720 microlitre) stopped reaction, filtration.Organic layer is at Na
2SO
4Last dry, filtration and concentrated.Resistates is analyzed purifying with flash column chromatography, uses the mixture of hexane and EtOAc, produces product 7 (1.57 grams, 50%).LRMS(M+H
+)m/z 490.2。
7 (1.57 grams, 3.2 mmoles) solution in THF (20 milliliters) adds PPh
3(1.0 grams, 3.9 mmoles), DIAD (746 microlitres, 3.9 mmoles) and O-phthalic sulfilimine (567 milligrams, 3.9 mmoles).Solution is after room temperature ℃ following stirring 4 hours, and it is monitored with anti-phase LCMS, and reaction is distributed in EtOAc and H
2Between the O.Organic layer is with the salt water washing, at Na
2SO
4Last dry and concentrated.Resistates produces 8 (2.0 grams, 99%) with the purifying mixture of column chromatography analysis, use hexane and EtOAc.LRMS(M+H
+)m/z 619.2。
7 (2 grams, 3.2 mmoles) solution in MeOH (15 milliliters) adds NH
2-NH
2(1.01 milliliters, 32.3 mmoles).After reaction at room temperature was stirred about 4 hours, solution was precipitated, filter and with CH
2Cl
2, MeOH washing.Organic layer is concentrated, and produces 8 (2.5 grams), and it is used and does not have and be further purified.LRMS(M+H
+)m/z 489.2。
To at CH
2Cl
2/ CH
3Among the CN (15 milliliters/15 milliliters) 8 (1.5 grams, 3.1 mmoles) solution adds DIEA (588 microlitres, 3.4 mmoles) and chloracetyl chlorine (269 microlitres, 3.4 mmoles).After reaction was at room temperature stirred 10 minutes, add azetidine (2 milliliters, 30.7 mmoles) and DIEA (2.7 milliliters, 15.3 mmoles).Reaction mixture is stirred and spends the night.Solution is concentrated, and is diluted in EtOAc and H
2Between the O.Organic layer is with the salt water washing, at Na
2SO
4Last dry and concentrated.Resistates produces 9 (900 milligrams, 51%) with the purifying mixture of column chromatography analysis, use hexane and EtOAc.LRMS(M+H
+)m/z 586.3。
To 9 (900 milligrams, the 1.3 mmoles) solution in MeOH (1 milliliter), the HCl (4 equivalent concentration, 2 milliliters) that is added in the diox reaches at H
2HCl among the O (2 equivalent concentration, 1 milliliter).Reaction at room temperature is stirred to be spent the night, concentrates, and produces the white solid and the next coupling step that leads.To crude compound in DMF (10 milliliters) (655 milligrams, 1.53 mmoles) and DIEA (800 microlitres, 4.59 mmoles).Mixture at room temperature stirs 1 hour, and is distributed in EtOAc and H
2Between the O.Organic layer is with the salt water washing, at Na
2SO
4Last dry and concentrated.Resistates produces 10 (600 milligrams, 64%) with the reversed-phase HPLC purifying.LRMS(M+H
+)m/z 622.2。
To 10 (160 milligrams, the 0.24 mmole) solution in DCM (10 milliliters), add MnO
2(416 milligrams, 4.8 mmoles).This suspension is stirred 14 hours.Reaction mixture is filtered, and filtrate is concentrated, and with reversed-phase HPLC, use acetonitrile and H
2The O purifying mixture produces 11 (90 milligrams, 60%).LRMS(M+H
+)m/z620.1。
Embodiment 98
Following compounds is used above-mentioned step preparation:
| Title | MS(m/z) |
| N-(1-{4-[2-(1-acetylamino-ethyl)-1-ethyl-1H-imidazol-4 yl]-benzyl }-3-hydroxyl-propyl group)-3-chloro-4-(2; 2,2-three fluoro-1-methyl-oxyethyl groups)-benzamide | 498.1 |
| N-{1-[4-(8-pseudoallyl-imidazo [1,2-a] pyridine-2-yl)-benzyl]-3-hydroxyl-propyl group }-3-cyano group-4-isopropoxy-benzamide | 555.2 |
| N-(1-{4-[2-(1-acetylamino-propyl group)-1-ethyl-1H-imidazol-4 yl]-benzyl }-3-hydroxyl-propyl group)-3-chloro-4-(isopropoxy)-benzamide | 541.2 |
| N-[1-(4-{2-[1-(ethanoyl-methyl-amino)-ethyl]-1-ethyl-1H-imidazol-4 yl }-benzyl)-3-hydroxyl-propyl group]-3-chloro-4-(2; 2,2-three fluoro-1-methyl-oxyethyl groups)-benzamide | 555.2 |
| N-(1-{4-[2-(1-ethanoyl-methyl-amino)-ethyl]-1-ethyl-1H-imidazol-4 yl]-benzyl }-3-hydroxyl-propyl group)-3-cyano group-4-isopropoxy-benzamide | 546.2 |
| N-{1-[4-(8-bromo-imidazo [1,2-a] pyridine-2-yl)-benzyl]-3-hydroxyl-propyl group }-3-chloro-4-isopropoxy-benzamide | 555.3 |
| N-(1-{4-[2-(1-acetylamino-ethyl)-1-sec.-propyl]-the 1H-imidazol-4 yl]-benzyl }-3-hydroxyl-propyl group)-3-chloro-4-isopropoxy-benzamide | 595.2 |
| N-(1-{4-[2-(1-acetylamino-ethyl)-1-ethyl-1H-imidazol-4 yl]-benzyl }-3-hydroxyl-propyl group)-3-chloro-4-(2; 2,2-three fluoro-1-methyl)-oxyethyl group)-benzamide | 610.2 |
| N-(2-(2-dimethylamino-acetylamino)-1-{4-[8-methyl-imidazo [1,2-a] pyridine-2-yl]-benzyl } ethyl)-3-cyano group-4-isopropoxy-benzamide | 489.2 |
| N-(1-{4-[2-(1-acetylamino-2-methyl-propyl group)-1-ethyl-1H-imidazol-4 yl]-benzyl }-3-hydroxyl-propyl group)-3-chloro-4-(2; 2,2-three fluoro-1-methyl-oxyethyl groups)-benzamide | 629.2 |
| N-{1-[4-(8-chloro-imidazo [1,2-a] pyridine-2-yl)-benzyl]-3-hydroxyl-butyl }-3-cyano group-4-isopropoxy-benzamide | 639.2 |
| N-(2-(2-dimethylamino-acetylamino)-1-{4-[8-(1-hydroxyl-ethyl)-imidazo [1,2-a] pyridine-2-yl]-benzyl }-ethyl)-3-chloro-4-isopropoxy-benzamide | 567.2 |
| N-(2-(2-amino-2-methyl-propionyl amino)-1-{4-[8-bromo-imidazo [1,2-a] pyridine-2-yl]-benzyl }-ethyl)-3-cyano group-4-isopropoxy-benzamide | 527.2 |
| N-(1-{3-fluoro-4-[2-(1-methyl isophthalic acid-hydroxyl-amino)-1-ethyl-1H-imidazol-4 yl]-benzyl }-3-hydroxyl-propyl group)-3-chloro-4-isopropoxy-benzamide | 532.2 |
| N-{1-[2-fluoro-4-(8-methyl-imidazo [1,2-a] pyridine-2-yl)-benzyl]-3-hydroxyl-propyl group }-3-cyano group-4-isopropoxy-benzamide | 528.2 |
| N-{1-[4-(8-ethanoyl-5-methyl-imidazo [1,2-a] pyridine-2-yl)-benzyl]-3-hydroxyl-propyl group }-3-cyano group-4-isopropoxy-benzamide | 569.2 |
| N-(1-{4-[2-(1-acetylamino-2-methyl-propyl group)-1-ethyl-1H-imidazol-4 yl]-benzyl }-3-hydroxyl-propyl group)-3-chloro-4-isopropoxy-benzamide | 595.1 |
| N-(the 1-{4-[2-tertiary butyl-1-ethyl-1H-imidazol-4 yl]-benzyl }-3-hydroxyl-propyl group)-3-cyano group-4-isopropoxy-benzamide | 503.3 |
| N-(2-(2-dimethylamino-acetylamino)-1-{4-[8-bromo-imidazo [1,2-a] pyridine-2-yl]-benzyl } ethyl)-3-cyano group-4-isopropoxy-benzamide | 582.2 |
| N-(1-{4-[2-ethanoyl-1-methyl isophthalic acid H-imidazol-4 yl]-benzyl }-3-amine formyl-propyl group)-3-chloro-4-isopropoxy-benzamide | 512.1 |
| N-(1-{4-[2-isobutyl alkynyl-1-methyl isophthalic acid H-imidazol-4 yl]-benzyl }-3-hydroxyl-propyl group)-3-chloro-4-isopropoxy-benzamide | 514.3 |
| N-(1-{3-fluoro-4-[2-ethanoyl-1-methyl isophthalic acid H-imidazol-4 yl]-benzyl }-3-hydroxyl-propyl group)-3-cyano group-4-isopropoxy-benzamide | 533.3 |
| N-[1-[4-(8-bromo-imidazo [1,2-a] pyridine-2-yl)-benzyl]-2-(2-oxo-tetrahydrochysene-pyrimidine-1-yl)-ethyl]-3-cyano group-4-isopropoxy-benzamide | 568.2 |
| N-(1-{4-[2-ethanoyl-1-methyl isophthalic acid H-imidazol-4 yl]-benzyl }-3-hydroxyl-propyl group)-3-cyano group-4-(2,2,2-three fluoro-1-methyl-oxyethyl groups)-benzamide | (527.1 negative value) |
| N-(1-{4-[2-(1-hydroxyl-1-methyl-ethyl)-(2,2, the 2-trifluoroethyl)-1H-imidazol-4 yl]-benzyl }-3-hydroxyl-propyl group)-3-chloro-4-isopropoxy-benzamide | 541.2 |
| N-[1-[4-(2-ethanoyl-1-ethyl-1H-imidazol-4 yl)-benzyl]-2-(2-hydroxyl-acetylamino)-ethyl)-3-chloro-4-isopropoxy-benzamide | 568.2 |
| N-(1-{4-[2-ethanoyl-1-(2-methoxy ethyl)-1H-imidazol-4 yl]-benzyl }-3-hydroxyl-propyl group)-3-chloro-4-isopropoxy-benzamide | 528.2 |
| N-(2-(2-amino-propionyl amino)-1-{4-[8-(1-hydroxyl-ethyl)-imidazo [1,2-a] pyridine-2-yl]-benzyl }-ethyl)-3-chloro-4-isopropoxy-benzamide | 503.2 |
| N-(1-{4-[2-ethanoyl-1-methyl isophthalic acid H-imidazol-4 yl]-benzyl }-3-hydroxyl-propyl group)-3-cyano group-4-isopropoxy-benzamide | 512.2 |
| N-(1-{4-(8-methyl-5,6,7,8-tetrahydrochysene-imidazo [1,2-a] pyridine-2-yl)-benzyl }-3-hydroxyl-propyl group)-3-cyano group-4-isopropoxy-benzamide | 511.1 |
| N-(1-{4-[2-ethanoyl-1-propyl group-1H-imidazol-4 yl]-benzyl }-3-hydroxyl-propyl group)-3-chloro-4-isopropoxy-benzamide | 512.2 |
| N-(1-{4-[2-ethanoyl-1-methyl isophthalic acid H-imidazol-4 yl]-benzyl }-3-hydroxyl-propyl group)-3-chloro-4-isopropoxy-benzamide | 484.1 |
| N-(2-(2-amino-propionyl amino)-1-{4-[8-methyl-imidazo [1,2-a] pyridine-2-yl]-benzyl }-ethyl)-3-cyano group-4-isopropoxy-benzamide | 582.2 |
| N-(1-{4-[2-(1-hydroxy-2-methyl-propyl group)-1-ethyl-1H-imidazol-4 yl]-benzyl }-3-hydroxyl-propyl group)-3-chloro-4-(2,2,2-three fluoro-1-methyl-oxyethyl groups)-benzamide | 586.1 |
| N-(1-{3-fluoro-4-[2-(1-hydroxyl-1-methyl-ethyl)-1-ethyl-1H-imidazol-4 yl]-benzyl }-3-hydroxyl-propyl group)-3-chloro-4-(2,2,2-three fluoro-1-methyl-oxyethyl groups)-benzamide | 513.1 |
| N-(1-{4-[2-(1-hydroxyl-1-methyl-ethyl)-1-(2,2, the 2-trifluoroethyl)-1H-imidazol-4 yl]-benzyl }-3-hydroxyl-propyl group)-3-cyanogen-4-isopropoxy-benzamide | 559.2 |
| N-(1-{4-[2-(1-formyl radical-ethyl)-1-methyl isophthalic acid H-imidazol-4 yl]-benzyl }-3-hydroxyl-propyl group)-3-chloro-4-isopropoxy-benzamide | 489.2 |
| N-(2-(2-hydroxyl-acetylamino)-1-{4-[8-(1-hydroxyl-ethyl)-imidazo [1,2-a] pyridine-2-yl]-benzyl }-ethyl)-3-chloro-4-isopropoxy-benzamide | 527.1 |
| N-(the 1-{4-[2-tertiary butyl-1-methyl isophthalic acid H-imidazol-4 yl]-benzyl }-3-hydroxyl-propyl group)-3-cyano group-4-isopropoxy-benzamide | 490.2 |
| N-{1-[4-(8-methyl-imidazo [1,2-a] pyridine-2-yl)-benzyl]-3-amine formyl-propyl group }-3-chloro-4-isopropoxy-benzamide | 505.2 |
| N-(1-{4-[2-(1-hydroxyl-1-methyl-ethyl)-1-ethyl-1H-imidazol-4 yl]-benzyl }-3-hydroxyl-propyl group)-3-cyano group-4-isopropoxy-benzamide | 502.1 |
| N-(1-{4-[2-ethanoyl-1-methyl isophthalic acid H-imidazol-4 yl]-benzyl }-3-amine formyl-propyl group)-3-chloro-4-isopropoxy-benzamide | 516.1 |
| N-(1-{3-fluoro-4-[2-ethanoyl-1-ethyl-1H-imidazol-4 yl]-benzyl }-3-hydroxyl-propyl group)-3-chloro-4-isopropoxy-benzamide | 498.1 |
| N-(1-{4-[2-propionyl-1-methyl isophthalic acid H-imidazol-4 yl]-benzyl }-3-hydroxyl-propyl group)-3-chloro-4-isopropoxy-benzamide | 537.1 |
| N-(2-(2-hydroxyl-acetylamino)-1-{4-[8-methyl-imidazo [1,2-a] pyridine-2-yl]-benzyl }-ethyl)-3-chloro-4-isopropoxy-benzamide | 499.1 |
| N-(1-{4-[2-(3-hydroxyl-penta-3-yl)-1-ethyl-1H-imidazol-4 yl]-benzyl }-3-hydroxyl-propyl group)-3-chloro-4-isopropoxy-benzamide | 542.3 |
| N-(2-(2-dimethylamino-acetylamino)-1-{4-[8-methyl-imidazo [1,2-a] pyridine-2-yl]-benzyl }-ethyl)-3-chloro-4-isopropoxy-benzamide | 552.1 |
| N-{1-[4-(8-methyl-imidazo [1,2-a] pyridine-2-yl)-benzyl]-3-amine formyl-propyl group }-3-chloro-4-isopropoxy-benzamide | 514.2 |
| N-(1-{4-[2-(3-hydroxypropyl)-1-ethyl-1H-imidazol-4 yl]-benzyl }-3-hydroxyl-propyl group)-3-chloro-4-isopropoxy-benzamide | 497.1 |
| N-(2-(2-hydroxyl-acetylamino)-1-{4-[8-methyl-imidazo [1,2-a] pyridine-2-yl]-benzyl }-ethyl)-3-chloro-4-isopropoxy-benzamide | 538.1 |
| N-(1-{4-[2-ethanoyl-1-methyl isophthalic acid H-imidazol-4 yl]-benzyl }-3-hydroxyl-propyl group)-3-chloro-4-(2,2,2-three fluoro-1-methyl-oxyethyl groups)-benzamide | 526.2 |
| N-{1-[4-(8-(1-hydroxyl-ethyl)-imidazo [1,2-a] pyridine-2-yl)-benzyl]-3-amine formyl-propyl group }-3-chloro-4-isopropoxy-benzamide | 514.2 |
| N-{1-[2-fluoro-4-(8-(methyl-imidazo [1,2-a] pyridine-2-yl)-benzyl]-3-hydroxyl-propyl group }-3-chloro-4-isopropoxy-benzamide | 559.2 |
| N-{1-[4-(8-methyl-imidazo [1,2-a] pyridine-2-yl)-benzyl]-3-hydroxyl-propyl group }-3-chloro-4-(2,2,2-three fluoro-1-methyl-oxyethyl groups)-benzamide | 546.1 |
| N-(1-{4-[2-(1-hydroxyl-1-methyl-ethyl)-1-ethyl-1H-imidazol-4 yl]-benzyl }-3-hydroxyl-propyl group)-3-cyano group-4-(2,2,2-three fluoro-1-methyl-oxyethyl groups)-benzamide | 527.2 |
| N-(1-{2,3,5, the 6-tetrafluoro-4-[2-tertiary butyl-1-methyl isophthalic acid H-imidazol-4 yl]-benzyl }-3-hydroxyl-propyl group)-3-cyano group-4-isopropoxy-benzamide | 493.2 |
| N-(the 1-{4-tertiary butyl-1-methyl isophthalic acid H-imidazol-4 yl]-benzyl }-3-hydroxyl-propyl group)-3-chloro-4-isopropoxy-benzamide | 568.1 |
| N-{1-[4-(8-hydroxyl-ethyl)-imidazo [1,2-a] pyridine-2-yl)-benzyl]-3-amine formyl-propyl group }-3-cyano group-4-isopropoxy-benzamide | 473.3 |
| N-(1-{4-[2-(1-hydroxy-2-methyl-propyl group)-1-ethyl-1H-imidazol-4 yl]-benzyl }-3-hydroxyl-propyl group)-3-chloro-4-isopropoxy-benzamide | 500.2 |
| N-(1-{4-[2-(1-hydroxyl-1-methyl-ethyl)-1-methyl isophthalic acid H-imidazol-4 yl]-benzyl }-3-hydroxyl-propyl group)-3-chloro-4-isopropoxy-benzamide | 528.2 |
| N-(1-{4-[2-ethanoyl-1-sec.-propyl-1H-imidazol-4 yl]-benzyl }-3-hydroxyl-propyl group)-3-chloro-4-isopropoxy-benzamide | 512.2 |
| N-(1-{4-[2-Trifluoromethyl-1-methyl isophthalic acid H-imidazol-4 yl]-benzyl }-3-hydroxyl-propyl group)-3-cyano group-4-isopropoxy-benzamide | 512.2 |
| N-(the 1-hydroxyl-1-{4-[2-tertiary butyl-1-methyl isophthalic acid H-imidazol-4 yl]-phenyl }-4-hydroxyl-butyl)-3-chloro-4-isopropoxy-benzamide | 539.2 |
| N-[1-[4-(8-bromo-imidazo [1,2-a] pyridine-2-yl)-benzyl]-2-(the 3-methyl-yl)-ethyl]-3-cyano group-4-isopropoxy-benzamide | 491.2 |
| N-(1-{4-[2-(1-hydroxyl-1-methyl-ethyl)-1H-imidazol-4 yl]-benzyl }-3-hydroxyl-propyl group)-3-cyano group-4-isopropoxy-benzamide | 610.2 |
| The N-[1-[4-[2-tertiary butyl-1-methyl isophthalic acid H-imidazol-4 yl]-benzyl }-2-(the 3-methyl-yl)-ethyl]-3-cyano group-4-ring fourth propoxy--benzamide | 501.3 |
| N-(the 1-{4-[2-tertiary butyl-1-methyl isophthalic acid H-imidazol-4 yl]-benzyl }-3-hydroxyl-propyl group)-3-cyano group-4-ring fourth propoxy--benzamide | 527.2 |
| N-(1-{4-[2-(methyl sulphonyl)-1-methyl isophthalic acid H-imidazol-4 yl]-benzyl }-3-hydroxyl-propyl group)-3-chloro-4-isopropoxy-benzamide | 570.1 |
| N-[1-[4-(8-bromo-imidazo [1,2-a] pyridine-2-yl)-benzyl]-2-(the 3-methyl-yl)-ethyl]-3-cyano group-4-isopropoxy-benzamide | 527.2 |
| N-(1-{4-[2-(1-hydroxyl-2,2-dimethyl-propyl group)-1-methyl isophthalic acid H-imidazol-4 yl]-benzyl }-3-hydroxyl-propyl group)-3-cyano group-4-isopropoxy-benzamide | 513.1 |
| N-(1-{4-[2-(1-hydroxyl-1-methyl-ethyl)-1-methyl isophthalic acid H-imidazol-4 yl]-benzyl }-3-hydroxyl-propyl group)-3-chloro-4-(2,2,2-three fluoro-1-methyl-oxyethyl groups)-benzamide | 554.1 |
| N-(2-(2-amino-propionyl amino)-1-{4-[8-bromo-imidazo [1,2-a] pyridine-2-yl]-benzyl }-ethyl)-3-chloro-4-isopropoxy-benzamide | 568.2 |
| N-(2-(2-hydroxyl-propionyl amino)-1-{4-[8-methyl-imidazo [1,2-a] pyridine-2-yl]-benzyl }-ethyl)-3-cyano group-4-isopropoxy-benzamide | 593.2 |
| N-{1-[4-(8-methyl-imidazo [1,2-a] pyridine-2-yl)-benzyl]-3-hydroxyl-propyl group }-2,2-two chloro-4-isopropoxy-benzamide | 552.1 |
| N-(1-{4-[2-ethanoyl-1-ethyl-1H-imidazol-4 yl]-benzyl }-3-hydroxyl-propyl group)-3-chloro-4-(2,2,2-three fluoro-1-methyl-oxyethyl groups)-benzamide | 547.1 |
| N-{1-[4-(5-methyl-imidazo [1,2-a] pyridine-2-yl)-benzyl]-3-hydroxyl-propyl group }-3-cyano group-4-isopropoxy-benzamide | 474.2 |
| N-(1-{4-[2-ethanoyl-1-methyl isophthalic acid H-imidazol-4 yl]-benzyl }-3-hydroxyl-propyl group)-3-cyano group-4-(sec.-propyl amino)-benzamide | 478.1 |
| N-(the 1-{4-[2-tertiary butyl-1-methyl isophthalic acid H-imidazol-4 yl]-benzyl }-3-hydroxyl-propyl group)-2-amino-3-chloro-4-isopropoxy-benzamide | 622.2 |
| N-{1-[4-(8-(1-methyl isophthalic acid-hydroxyl-ethyl)-imidazo [1,2-a] pyridine-2-yl)-benzyl]-3-hydroxyl-propyl group }-3-cyano group-4-isopropoxy-benzamide | 543.1 |
| N-(1-{4-[2-(1-methoxycarbonyl amino)-ethyl-1-methyl isophthalic acid H-imidazol-4 yl]-benzyl }-3-hydroxyl-propyl group)-3-chloro-4-isopropoxy-benzamide | 611.2 |
| N-(2-(2-hydroxyl-acetylamino)-1-{4-[8-hydroxyl-ethyl]-imidazo [1,2-a] pyridine-2-yl]-benzyl }-ethyl)-3-cyano group-4-isopropoxy-benzamide | 625.2 |
| N-{1-[4-(imidazo [1,2-a] pyridine-2-yl)-benzyl]-3-hydroxyl-propyl group }-3-cyano group-4-isopropoxy-benzamide | 511.2 |
| N-{1-[4-(8-methyl-imidazo [1,2-a] pyridine-2-yl)-benzyl]-3-hydroxyl-propyl group }-3-chloro-4-(sec.-propyl amino)-benzamide | 491.1 |
| N-(2-(3-amino-propionyl amino)-1-{4-[8-bromo-imidazo [1,2-a] pyridine-2-yl]-benzyl }-ethyl)-3-chloro-4-isopropoxy-benzamide | 513.3 |
| N-{1-[2,6-two fluoro-4-(8-methyl-5,6,7,8-tetrahydrochysene-imidazo [1,2-a] pyridine-2-yl)-benzyl]-3-hydroxyl-propyl group }-3-chloro-4-isopropoxy-benzamide | 579.1 |
| N-[1-[4-(8-bromo-imidazo [1,2-a] pyridine-2-yl)-benzyl]-2-(2-oxo-imidazolidine)-ethyl]-3-chloro-4-isopropoxy-benzamide | 556.2 |
| N-[1-[4-(2-(1-hydroxyl-1-methyl-ethyl)-1-methyl isophthalic acid H-imidazol-4 yl)-benzyl]-2-(2-amino-propionyl amino)-ethyl]-3-chloro-4-isopropoxy-benzamide | 526.2 |
| N-(1-{4-[2-ethanoyl-1-butyl-1H-imidazol-4 yl]-benzyl }-3-hydroxyl-propyl group)-3-chloro-4-isopropoxy-benzamide | 554.2 |
| N-(1-{4-[2-(1-acetylamino-ethyl)-1-ethyl-1H-imidazol-4 yl]-benzyl }-2-amine formyl-ethyl)-3-chloro-4-isopropoxy-benzamide | 475.5 |
| N-(the 1-{4-[4-tertiary butyl-1H-imidazol-4 yl]-benzyl }-3-hydroxyl-propyl group)-3-cyano group-4-isopropoxy-benzamide | 503.3 |
| N-(2-(2-hydroxyl-propionyl amino)-1-{4-[8-(1-hydroxyl-ethyl)-imidazo [1,2-a] pyridine-2-yl]-benzyl }-ethyl)-3-cyano group-4-isopropoxy-benzamide | 566.1 |
| N-(1-{4-[2-isobutyl--1-methyl isophthalic acid H-imidazol-4 yl]-benzyl }-3-hydroxyl-propyl group)-3-chloro-4-(2,2,2-three fluoro-1-methyl-oxyethyl groups)-benzamide | 518.2 |
| N-(the 1-{4-[2-tertiary butyl-1-(2-amino-ethyl)-1H-imidazol-4 yl]-benzyl }-3-hydroxyl-propyl group)-3-cyano group-4-isopropoxy-benzamide | 513.1 |
| N-(2-(2-dimethylamino-acetylamino)-1-{4-[8-amine formyl-imidazo [1,2-a] pyridine-2-yl]-benzyl }-ethyl)-3-cyano group-4-isopropoxy-benzamide | 556.1 |
| N-(2-(2-amino-acetylamino)-1-{4-[8-bromo-imidazo [1,2-a] pyridine-2-yl]-benzyl }-ethyl)-3-cyano group-4-isopropoxy-benzamide | 513.2 |
| N-(2-{4-ethanoyl-1-methyl isophthalic acid H-imidazol-4 yl]-phenyl }-1-(5-methyl-[1,2,4]-oxadiazoles-3-yl)-ethyl)-3-cyano group-4-isopropoxy-benzamide | 530.3 |
| N-[1-[4-(the 2-tertiary butyl-1-methyl isophthalic acid H-imidazol-4 yl)-benzyl]-2-hydroxyl-3-azo-group-propyl group]-3-cyano group-4-isopropoxy-benzamide | 489.2 |
| N-{1-[4-(8-(1-hydroxyl-ethyl)-imidazo [1,2-a] pyridine-2-yl)-benzyl]-3-hydroxyl-propyl group }-3-cyano group-4-isopropoxy-benzamide | 498.1 |
| N-(the 1-{4-[5-tertiary butyl-4-methyl isophthalic acid H-imidazoles-2-yl]-benzyl }-3-hydroxyl-propyl group)-3-chloro-4-isopropoxy-benzamide | 581.1 |
| N-{1-[4-(8-imidazo [1,2-a] pyridine-2-yl)-benzyl]-3-hydroxyl-butyl }-3-cyano group-4-isopropoxy-benzamide | 489.2 |
| N-(2-(2-amino-propionyl amino)-1-{4-[8-bromo-imidazo [1,2-a] pyridine-2-yl]-benzyl }-ethyl)-3-chloro-4-isopropoxy-benzamide | 483.2 |
| N-(1-{4-(2-ethanoyl-1-methyl isophthalic acid H-imidazol-4 yl]-phenyl }-3-hydroxyl-propyl group)-3-chloro-4-sec.-propyl amino-benzamide | 475.5 |
Embodiment 99
The inhibition of the cell survival rate of the tumor cell line of handling with the mitotic kinesins inhibitor:
Raw material and solution:
Cell: SKOV3, ovarian cancer (people)
Substratum: do not have phenol red RPMI+5% foetal calf serum+2mM L-glutaminate
Be used to measure the ratio toner of cell survival rate: Promega MTS tetrazole compound
Be used for the control compound that maximum cell kills and wounds: Topotecan, 1 μ M
Method: the 1st day-the cell bed board
PBS with 10mL washs adherent SKOV3 cell, adds 2mL 0.25% trypsinase then, and 37 ℃ of following incubations 5 minutes.From flask, wash cell with 8mL substratum (not having phenol red RPMI+5%FBS), be transferred to then in the new flask.Measure cell concn with the Coulter counter, and calculate the suitable cell volume that obtains 1000 cell/100 μ L.With 100 μ L substratum cell suspending liquids (being adjusted to 1000 cells/100 μ L) add the institute of 96 hole flat boards porose in, then at 37 ℃, 100% humidity and 5%CO
2Following incubation 18-24 hour, make cell adhesion on flat board.
Method: the 2nd day-compound adds
Extremely pass through the test compounds that adds initial 2.5 μ L in the autoclaved mensuration storing solution with the amount of 400 * maximum target concentration to a round.1.25 μ L400 * (400 μ M) Topotecan added in other hole (deduct the background absorbancy of dead cell and carrier with the optical density(OD) in these holes).The 500 μ L substratum adding that does not contain DMSO is contained in the hole of test compounds, and 250 μ L are added in the Topotecan hole.250 μ L substratum+0.5%DMSO are added in remaining hole, the test compounds in the hole is carried out serial dilution.To duplicate (parallel two parts) to corresponding cell flat board from the substratum that contains compound of the measuring storing solution flat board of embarking on journey.With the cell flat board in 37 ℃, 100% humidity and 5%CO
2Following incubation 72 hours.
Method: the 4th day-MTS adds and the OD reading:
From incubator, take out flat board, and in each hole, add the MTS/PMS of 40 μ L.Dull and stereotyped at 37 ℃, 100% humidity, 5%CO
2The following incubation of condition 120 minutes, after 5 seconds cycle of oscillation, in 96 hole spectrophotometers, read the OD value at 490nm place then.
Data analysis
Calculate the normalized % (absorbancy-background) of contrast, and make dosage-response curve, required compound concentrations when suppressing survival rate 50% by this curve determination with XLfit.When testing by aforesaid method, compound of the present invention shows activity.
Embodiment 100
The purposes of mitotic kinesins inhibitor
Human tumor cells Skov-3 (ovary) is placed 96 orifice plates by plate, and density is 4,000 cells in every hole, allows to adhere to 24 hours, and handles 24 hours with the test compounds of various concentration.Cell is fixed in 4% formaldehyde, and with Antitubulin (antitubulin) antibody (the fluorescently-labeled less important antibody recognition of follow-up use) and Hoechst dyeing (its DNA that dyes).
As seen check shows that compound causes cell cycle to stop.
Embodiment 101
In the tumor cell line of handling with the mitotic kinesins inhibitor, suppress cell proliferation
With the density of 1000-2500 cells/well cell is put into the hole of 96 orifice plates, make then their dregs of rice attached/growth 24 hours.With the medicine of multiple concentration they were handled 48 hours then.Time when adding compound is as T
0The mensuration based on tetrazolium (patent No. 5,185,450) of use reagent 3-(4,5-dimethylthiazole-2-yl)-5-(3-carboxyl p-methoxy-phenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) (referring to Promega products catalogue #G3580, CellTiter96 AQ
UeousOne Solution Cell Proliferation Assay), be used to measure T
0The time cell survival quantity and the quantity of contact compound survivaling cell after 48 hours.Survivaling cell quantity when the survival cells amount is with the interpolation medicine after 48 hours is compared, to calculate the growth-inhibiting effect.
The growth of cell after 48 hours is considered to 100% growth in the control wells of only using carrier (0.25%DMSO) to handle, and the cell growth in the hole of interpolation compound compares with it.The mitotic kinesins inhibitor suppresses the cell proliferation in people's ovarian tumor cell system (SKOV-3).
GI
50Be the per-cent mapping of handling cell growth in the hole to be calculated by compound concentrations (μ M).GI for compound calculating
50Be to compare 50% estimated concentration when suppressing growth with control group, promptly, the concentration of time of representing of following equation:
100 * [(handle
48-T
0)/(contrast
48-T
0)]=50
Wherein handle
48Handle the value of cell when being 48 hours, and contrast
48The value of control cells when being 48 hours.
All compound concentration test doubles, and contrast is the mean value in 12 holes.National Cancer Institute has used very similar 96 orifice plate scheme and GI
50Method of calculation (referring to: people such as Monks, J.Natl.Cancer Inst.83:757-766 (1991)).But the method that National Cancer Institute is used for quantitative cell number is not to use MTS, and is to use other method.
Embodiment 102
IC
50Calculating
The compounds of this invention is to the active IC of KSP
50Value is to use the ATP enzyme to test and measures.Use following solution: solution 1 is made up of the magnesium chloride (VWR JT400301) of Pipes/KOH pH6.8 (Sigma P6757), the 2mM of the froth breaking 289 (SigmaA-8436) of the taxol (Sigma T-7402) of IDTT (Sigma D-9779), the 5 μ M of ATP (SigmaA-3377), the 1mM of the phosphorus olefin(e) acid alcohol potassium pyruvate salt (Sigma P-7127) of 3mM, 2mM, 10ppm, 25mM and the EGTA (Sigma E3889) of 1mM.Solution 2 is by the NADH (Sigma N8129) of 1mM, 0.2mg/ml BSA (SigmaA7906), pyruvate kinase 7U/ml, L-lactic dehydrogenase 10 U/ml (Sigma P0294), the KSP motion field of 100nM, the microtubule of 50 μ g/ml, the DTT of 1mM (Sigma D9779), the taxol of 5 μ M (Sigma T-7402), the froth breaking 289 (SigmaA-8436) of 10ppm, the Pipes/KOH pH6.8 of 25mM (Sigma P6757), the magnesium chloride of 2mM (VWR JT4003-01), and the EGTA of 1mM (Sigma E3889) forms.Use solution 1 to go up the serial dilutions (8-12 2 times of diluents) of preparation compound at 96 orifice plates (CorningCostar3695).Behind serial dilution, there is the solution 1 of 50 μ l in each hole.In each hole, add the solution 2 of 50 μ l, make the reaction beginning thus.This can realize by manual use hyperchannel transfer pipet or with the automated fluid treatment unit.Microtiter plate is transferred in the microplate absorbancy reader, and dynamically to read a plurality of absorbancy readings of each hole at the 340nm place.Viewed rate of change is directly proportional with the ATP enzyme, and draws the figure that it changes with compound concentration.For IC standard
50Measure, needed data are to carry out match by the equation use nonlinear fitting program (as Grafit 4) of following 4 parameters:
Wherein y is observed speed, and x is a compound concentration.
This type of chemical is found inhibition cell proliferation, though GI
50Value changes.The GI of tested chemical
50The value scope be from 200nM to greater than the test maximum concentration.Thus, suppress cell proliferation really, under the maximum concentration (general about 20 μ M) of test, some cell growth-inhibiting are lower than 50% though we mean on most active chemical biochemistry of inhibition mitotic kinesins.Many chemical have GI
50Value is lower than 10 μ M, and severally has a GI
50Value is lower than 1 μ M.Have success and apply to clinical anti-proliferative compounds for the treatment of cancer (cancer chemotherapeutic), have GI
50Alter a great deal.For example in the A549 cell, the GI of taxol
50Be 4nM, Dx is 63nM, and 5 FU 5 fluorouracil is 1Mm, provides and hydroxyurea is 500 μ M (data by National Cancer Institute, DevelopmentTherapeutic Program, http://dtp.nci.nih.gov/).Therefore the compound of the inhibition cell proliferation of actual any concentration can be useful.
Claims (46)
1, at least a chemical and the acceptable salt of pharmacology, solvate, inner complex, non-covalent complex, prodrug and the mixture that is selected from formula I compound:
Wherein
R
1Be the optional aryl that replaces, the optional heterocyclic radical that replaces or the optional heteroaryl that replaces;
X is-CO or-SO
2-;
R
2Be hydrogen or the optional low alkyl group that replaces;
W is-CR
4-,-CH
2CR
4-or N;
R
3For-CO-R
7-, hydrogen, the optional alkyl that replaces, the optional heterocyclic radical that replaces, cyano group, the optional alkylsulfonyl that replaces or the optional aryl that replaces;
R
4Be hydrogen or the optional alkyl that replaces;
R
5Be hydrogen, hydroxyl, the optional amino that replaces, the optional heterocyclic radical that replaces or the optional low alkyl group that replaces;
R
6Be hydrogen, the optional alkyl that replaces, the optional alkoxyl group that replaces, the optional aryloxy that replaces, the optional heteroaryl oxygen base that replaces, the optional alkoxy carbonyl that replaces, the optional aminocarboxyl that replaces, the optional aryl that replaces, the optional heteroaryl that replaces, the optional heterocyclic radical that replaces or the optional alkaryl that replaces; And
R
7Be the optional low alkyl group that replaces, the optional aryl that replaces, hydroxyl, the optional amino that replaces, the optional aralkoxy that replaces or the optional alkoxyl group that replaces;
Its restricted condition is, if W is N, then R
5Not hydroxyl or the optional amino that replaces, and R
6Not the optional alkoxyl group that replaces, the optional aralkoxy that replaces, the optional assorted aralkoxy that replaces or the optional amino that replaces.
2, at least a chemical as claimed in claim 1, wherein R
1Be the optional aryl that replaces.
3, at least a chemical as claimed in claim 2, wherein R
1Be the optional phenyl that replaces.
4, at least a chemical as claimed in claim 3, wherein R
1The phenyl that is replaced by one, two or three substituting group that independently is selected from following group: choosing is substituted heterocyclic radical, the optional alkyl that is substituted, alkylsulfonyl, halogen, the optional amino that is substituted, the optional sulfane base that is substituted, the optional alkoxyl group that is substituted, the optional aryloxy that is substituted, the optional heteroaryloxy that is substituted, acyl group, hydroxyl, nitro, cyano group, the optional aryl that is substituted and the optional heteroaryl that replaces.
5, at least a chemical as claimed in claim 4, wherein R
1Be 3-halogen-4-isopropoxy-phenyl or 3-cyano group-4-isopropoxy-phenyl.
6, as at least a chemical of one of claim 1 to 4, wherein X is-CO-.
7, at least a chemical as claimed in claim 1, its Chinese style I compound is to be selected from formula II compound
Wherein
R
11Be the optional heterocyclic radical that replaces, optional low alkyl group, nitro, cyano group, hydrogen, alkylsulfonyl or the halogen that replaces;
R
12Be hydrogen, halogen, the optional alkyl that replaces, the optional amino that replaces, the optional sulfane base that replaces, the optional alkoxyl group that replaces, the optional aryloxy that replaces, the optional heterocyclic radical that replaces or the optional heteroaryl oxygen base that replaces; And
R
13For hydrogen, acyl group, the optional alkyl that replaces-, the optional alkoxyl group that replaces, halogen, hydroxyl, nitro, cyano group, the optional amino that replaces, alkyl sulphonyl-, alkyl sulfonyl amino-, carboxyalkyl-, aminocarboxyl-, the optional aryl that replaces or the optional heteroaryl that replaces-.
8, as at least a chemical of one of claim 1 to 7, wherein W is-CR
4-.
9, as at least a chemical of one of claim 1 to 8, R wherein
4Be hydrogen.
10, as at least a chemical of one of claim 1 to 9, R wherein
5Be hydrogen, hydroxyl or the optional low alkyl group that replaces.
11, as at least a chemical of claim 10, R wherein
5Be hydrogen.
12, at least a chemical as claimed in claim 7, its Chinese style II compound is to be selected from the formula III compound
13, as at least a chemical of one of claim 1 or 12, R wherein
3Be-CO-R
7-, hydrogen, the optional low alkyl group that replaces, cyano group, the optional alkylsulfonyl that replaces or optional aryl that replaces or the optional heterocyclic radical that replaces.
14, as at least a chemical of claim 13, wherein it is the optional low alkyl group that replaces.
15, as at least a chemical of claim 14, R wherein
3Be optional by the low alkyl group of hydroxyl or the replacement of its phosphoric acid ester, the optional low alkyl group that is replaced by lower alkoxy, the low alkyl group that the optional amine groups that is optionally substituted replaces, or optional by CO-R
7The low alkyl group that replaces, wherein R
7Be hydroxyl or the optional amino that replaces.
16, as at least a chemical of claim 15, R wherein
3Be optional by the low alkyl group of hydroxyl or the replacement of its phosphoric acid ester, or the low alkyl group of the optional amine groups replacement that is optionally substituted.
17, as at least a chemical of claim 12, wherein the formula III compound is to be selected from formula IV compound
18, as at least a chemical of one of claim 1 to 17, R wherein
6Be the optional aryl that replaces, the optional heteroaryl that replaces, the optional heterocyclic radical that replaces or the optional alkyl that replaces.
19, as at least a chemical of claim 18, R wherein
6Be the phenyl that replaced by one or two following substituting group: the optional heteroaryl that replaces, the optional amino that replaces, aralkoxy, halogen, methylol-, hydroxyl, cyano group, alkoxyl group, phenyl, phenoxy group, methylene radical dioxy base, ethylenedioxy, alkylsulfonyl, aminocarboxyl, carboxyl, alkoxy carbonyl, nitro, assorted aralkoxy, aralkoxy and the optional heterocyclic radical that replaces.
20, as at least a chemical of claim 12, wherein the formula III compound is to be selected from formula V compound
Wherein
R
14Be the optional heteroaryl that replaces; And
R
15Be to be selected from hydrogen, halogen, hydroxyl and low alkyl group.
21, as at least a chemical of claim 20, R wherein
14Be selected from:
7, the 8-dihydro-imidazol-also [1,2-c] [1,3] oxazine-2-base,
3a, 7a-dihydro-1H-benzimidazolyl-2 radicals-Ji,
Imidazo [2,1-b] oxazole-6-base,
Oxazole-4-base,
5,6,7,8-tetrahydrochysene-imidazo [1,2-a] pyridine-2-base,
1H-[1,2,4]-triazole-3-base,
2,3-dihydro-imidazol--4-base,
1H-imidazoles-2-base,
Imidazo [1,2-a] pyridine-2-base, thiazol-2-yl,
Thiazole-4-base,
Pyrazole-3-yl, and
The 1H-imidazol-4 yl,
Its each optional by one, two or three be selected from the optional low alkyl group that replaces, halogen, acyl group, alkylsulfonyl, cyano group, nitro, the optional amino that replaces, and the optional heteroaryl that replaces replace.
22, as at least a chemical of claim 21, R wherein
14Be to be selected from
1H-imidazoles-2-base,
Imidazo [1,2-a] pyridine-2-base reaches
The 1H-imidazol-4 yl,
Its each optional being selected from by one or two is chosen low alkyl group, halogen and the acyl substituted that replaces wantonly.
23, as at least a chemical of one of claim 20 to 22, R wherein
15Be hydrogen.
24, as at least a chemical of claim 12, its Chinese style II compound is to be selected from formula VI compound
25, as at least a chemical of claim 12, its Chinese style II compound is to be selected from formula VII compound
Wherein
R
9Be to be selected from the optional alkoxyl group that replaces, the optional cycloalkyloxy that replaces, the optional alkoxy aryl that replaces, the optional amino that replaces and the optional low alkyl group that replaces.
26, as at least a chemical of claim 25, R wherein
9It is low alkyl group through hydroxyl or the optional amino replacement that replaces.
27, as at least a chemical of claim 26, R wherein
9By hydroxyl, amino, N-methylamino or N, the low alkyl group that the N-dimethylamino replaces.
28, as at least a chemical of one of claim 7 to 27, R wherein
11Be hydrogen, cyano group, nitro or halogen.
29, as at least a chemical of claim 28, R wherein
11Be chlorine or cyano group.
30, as at least a chemical of one of claim 7 to 29, R wherein
12For the optional lower alkoxy that replaces, the optional low alkyl group that replaces or the optional amino that replaces-.
31, as at least a chemical of claim 30, R wherein
12Be lower alkoxy or 2,2,2-three fluoro-1-methyl-oxyethyl groups.
32, as at least a chemical of claim 31, R wherein
12Be propoxy-or 2,2,2-three fluoro-1-methyl-oxyethyl groups.
33, as at least a chemical of one of claim 7 to 32, R wherein
13Be hydrogen.
34, as at least a chemical of one of claim 1 to 33, R wherein
2Be hydrogen.
35, be selected from the claimed at least a chemical of the compound described in the table 1,2,3,4,5 or 6 and the acceptable salt of pharmacology, solvate, inner complex, non-covalent complex, prodrug and mixture.
36. as at least a chemical of claim 35, it is the phosphoric acid ester that is selected from compound described in the table 1,2,3,4,5 or 6.
37, a kind of composition, it comprises drug excipient and as at least a chemical of one of claim 1 to 36.
38, as the composition of claim 37, wherein said composition further comprises the chemotherapeutic of non-formula I compound.
39, as the composition of claim 38, wherein said composition further comprises taxanes, catharanthus alkaloid or topology isomerase I inhibitor.
40, the active method of a kind of adjusting CENP-E kinesin, it comprises this kinesin is contacted with at least a chemical as one of claim 1 to 36 of significant quantity.
41, a kind of method that suppresses CENP-E, it comprises this kinesin is contacted with at least a chemical as one of claim 1 to 36 of significant quantity.
42, a kind of method for the treatment of cell proliferation disorders, it comprises at least a chemical to one of the individual administration that these needs are arranged such as claim 1 to 36.
43, a kind of method for the treatment of cell proliferation disorders, it comprises the composition to one of the individual administration that these needs are arranged such as claim 37 to 39.
44, as the method for claim 42 or 43, wherein this disease is selected from following group: cancer, hyperplasia, restenosis, megalocardia, Immunological diseases and inflammation.
45, be used for the treatment of application in the medicine of cell proliferation disorders as at least a chemical of one of claim 1 to 36 in preparation.
46, as the application of at least a chemical of claim 45, it is that preparation is used for the treatment of the medicine with the active relevant disease of CEMP-E kinesin.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US56951004P | 2004-05-06 | 2004-05-06 | |
| US60/569,510 | 2004-05-06 | ||
| US11/121,709 | 2005-05-03 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2011104057912A Division CN102557982A (en) | 2004-05-06 | 2005-05-06 | Certain chemical entities, compositions, and methods |
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| Publication Number | Publication Date |
|---|---|
| CN101023057A true CN101023057A (en) | 2007-08-22 |
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ID=38710375
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| ZA (1) | ZA200609808B (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106632061A (en) * | 2016-11-23 | 2017-05-10 | 上海皓元医药股份有限公司 | Synthesis method of 1-(4-phenyl-1-alkyl-1H-imidazol-2-yl)ethanone and derivative thereof |
| CN104968646B (en) * | 2012-12-13 | 2017-09-05 | 葛兰素史密斯克莱有限责任公司 | The inhibitor of Zeste homologues enhancer 2 |
| CN108276307A (en) * | 2018-01-17 | 2018-07-13 | 常熟浸大科技有限公司 | The synthetic method of 3- cyano -4- oxyl benzoic ethers |
| CN117603604A (en) * | 2023-11-16 | 2024-02-27 | 江苏众立生包装科技有限公司 | Preparation method of printing gloss oil with amino-terminated hyperbranched self-assembled polyamide as main component |
-
2005
- 2005-05-06 CN CN 200580021899 patent/CN101023057A/en active Pending
-
2006
- 2006-11-24 ZA ZA200609808A patent/ZA200609808B/en unknown
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104968646B (en) * | 2012-12-13 | 2017-09-05 | 葛兰素史密斯克莱有限责任公司 | The inhibitor of Zeste homologues enhancer 2 |
| CN106632061A (en) * | 2016-11-23 | 2017-05-10 | 上海皓元医药股份有限公司 | Synthesis method of 1-(4-phenyl-1-alkyl-1H-imidazol-2-yl)ethanone and derivative thereof |
| CN106632061B (en) * | 2016-11-23 | 2020-07-24 | 上海皓元医药股份有限公司 | Synthesis method of 1- (4-phenyl-1-alkyl-1H-imidazole-2-yl) ethanone and derivative thereof |
| CN108276307A (en) * | 2018-01-17 | 2018-07-13 | 常熟浸大科技有限公司 | The synthetic method of 3- cyano -4- oxyl benzoic ethers |
| CN117603604A (en) * | 2023-11-16 | 2024-02-27 | 江苏众立生包装科技有限公司 | Preparation method of printing gloss oil with amino-terminated hyperbranched self-assembled polyamide as main component |
| CN117603604B (en) * | 2023-11-16 | 2024-05-24 | 江苏众立生包装科技有限公司 | Preparation method of printing gloss oil with amino-terminated hyperbranched self-assembled polyamide as main component |
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| ZA200609808B (en) | 2008-01-30 |
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Application publication date: 20070822 |