CN1261276A - Protease inhibitors - Google Patents

Protease inhibitors Download PDF

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CN1261276A
CN1261276A CN98806641A CN98806641A CN1261276A CN 1261276 A CN1261276 A CN 1261276A CN 98806641 A CN98806641 A CN 98806641A CN 98806641 A CN98806641 A CN 98806641A CN 1261276 A CN1261276 A CN 1261276A
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thiazol
hydrazide
carbonyl
leucyl
methyl
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S·M·哈尔伯特
E·米绍
S·K·汤普森
D·F·韦贝尔
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SmithKline Beecham Corp
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    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
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    • A—HUMAN NECESSITIES
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    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07K—PEPTIDES
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    • C07K5/06139—Dipeptides with the first amino acid being heterocyclic

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Abstract

The present invention provides compounds of formula (I) which inhibit proteases, including cathepsin K, pharmaceutical compositions of such compounds, and methods for treating diseases of excessive bone loss or cartilage or matrix degradation, including osteoporosis; gingival disease including gingivitis and periodontitis; arthritis, more specifically, osteoarthritis and rheumatoid arthritis; Paget's disease; hypercalcemia or malignancy; and metabolic bone disease therewith.

Description

Protease inhibitor
Field of the present invention
The present invention relates generally to heterocycle ketone group hydrazides protease inhibitor, relate to cysteine and serpin specifically, more particularly relate to the chemical compound that suppresses cysteine proteinase, even relate more specifically to suppress the cysteine proteinase of papain superfamily, the particularly chemical compound of the cysteine proteinase of histone enzyme family, more especially relate to the chemical compound of inhibition of histone enzyme K.This compounds pair is useful especially with disease such as osteoporosis, periodontitis and arthritic treatment that cysteine proteinase diseases associated, especially excessive bone or cartilage are lost.
Background of the present invention
Bone is by forming with fusiformis or the bonded albumen substrate of flaky hydroxyapatite crystal.Type i collagen albumen is represented the primary structure albumen of bone, and its structural protein by about 90% are formed.Remain 10% substrate and form, comprise osteocalcin, Dan Baijutang, osteopontin, osteonectin, thrombospondin, fibronectin and bone sialoprotein by some noncollagen protein matter.In the independent focus of whole life process, skeleton has experienced process of reconstruction.Described focus or reconstruction unit experienced by the bone resorption phase, the cycle for bone replacement period composition of continuing.
Carry out bone resorption by osteoclast, this cell is the apocyte of hemopoietic pedigree.Described osteoclast adheres to bone surface, forms the citadel, afterwards on its top end face, and large tracts of land film crumple (just absorbing again).Thus on the film of crumple, by the acidifying bone surface of proton pump produce airtight extracellular chamber every, and the excretory proteolytic enzyme of osteoclast enters wherein.The hydroxyapatite crystal body of chamber on the dissolving bone surface that pH value is low, described proteolytic enzyme digest albumen substrate simultaneously.Formed so again absorbing cavity every or cavity.When this stage in described cycle finished, osteoblast produced albumen substrate new, that mineralized subsequently.At several morbid states for example in osteoporosis and the PagetShi disease, bone resorption and form between normal equilibrium destroyed, all there be losing only of sclerotin in each cycle.At last, will cause bone to die down, and minimum wound can cause that fracture risk increases.
Some disclosed cystatins that studies confirm that are effectively to the bone resorption that suppresses osteoclast-mediation, and point out the important function of cysteine proteinase aspect bone resorption.For example, (Biochem.J., 1980 such as Delaisse, 192,365) a series of protease inhibitor that disclose in mice bone object official cultivating system are also pointed out under the invalid situation of serpin, and cystatin (as leupeptin, Z-Phe-Ala-CHN 2) can prevent the absorption again of bone.Open E-64 of Delaisse etc. (Biochem.Biophys.Res.Commun., 1984,125,441) and leupeptin also are effectively to the absorption again of prevention body internal skeleton, as the acute change of the serum calcium of the rat of feeding calcium deficiency food is measured.Lerner etc. (J.Bone Min.Res., 1992,7,433) disclose the absorption again of the mice cranium of cystatin (a kind of endogenous cystatin) inhibition PTH stimulation.Other research is (as Delaisse etc., Bone, 1987,8,305, Hill etc., J.Cell.Biochem., 1994,56,118 and Everts etc., J.Cell.Physiol., 1992,150,221) inhibition of cysteine protease activity and the dependency relation between the bone resorption have also been reported.(J.Biol.Chem. such as Tezuka, 1994,269,1106), (Biochem.Biophys.Res.Commun. such as Inaoka, 1995,206,89) and (FEBS Lett., 1995 such as Shi, 357,129) open cathepsin K (being also referred to as cathepsin O), a kind of cysteine proteinase, but under normal circumstances great expression in osteoclast and may be the main cysteine proteinase that is present in these cells.
Cathepsin K is a large amount of in osteoclast, optionally express strong this enzyme of prompting is very important for the absorption again of bone.Therefore, the disease that can excessively lose bone of inhibition of histone enzyme K optionally, the hypercalcemia and the metabolic osteopathy that include, but is not limited to osteoporosis, PagetShi disease, malignant tumor provide effective treatment.Confirmed also that in the chondroclast of osteoarthritis synovial membrane the level of cathepsin K raises.Therefore, optionally inhibition of histone enzyme K includes, but is not limited to osteoarthritis to the disease of the excessive degradation of treatment cartilage or substrate and rheumatoid arthritis also is useful.The tumor cell that shifts is also usually expressed the high-caliber degradable proteolytic enzyme of substrate on every side.Therefore, optionally inhibition of histone enzyme K also is useful to treating some tumor disease.
Palmer etc. (J.Med.Chem., 1995,38,3193) disclose some irreversible inhibition cysteine proteinase, as the vinyl sulfone of cathepsin B, L, S, O2 and cruzain.Chemical compound such as aldehyde, nitrile, a-ketone carbonyl compound, halogenated methyl ketone, dizaomethyl ketone, (acyloxy) methyl ketone, ketone methyl sulfonium salt and the epoxy succinic acyl compounds of also reporting other class can suppress cysteine proteinase.Han and Janda (J.Am.Chem.Soc., 1996,118,2539) disclose the synthetic of azatides (many acyl groups hydrazides) as peptide mimics recently.
Afridi, and A etc. (J.Chem.Soc.Perkin Trans.1,1976,3,315-20) the synthetic of N-phenyl-N '-(2-Ben Ji oxazole-4-base carbonyl) hydrazides and its N-(2, the 4-dinitrophenyl) derivant described.Benko, and A. etc. (Justus Liebigs Ann.Chem., 1968,717,148-53) preparation of N-(4-ethoxy carbonyl thiazol-2-yl)-N '-[2-(4-pyridine radicals) thiazole-4-base carbonyl] hydrazides is disclosed.
Therefore, identified the different cystatin of structure.Yet these known inhibitor do not think and are suitable as mammal, and Ren Lei therapeutic agent particularly is because they have many shortcomings.These shortcomings comprise and lack selectivity, have cytotoxicity, poorly soluble and too fast serum is removed.Thereby need find the protease of treatment by the pathology level, especially cysteine proteinase comprises the method for the disease that cathepsin (particularly cathepsin K) causes, and the new inhibitor compound that is used for these methods.
What our present discovery one class was new is protease inhibitor, is the heterocycle ketone group hydrazide compound of cathepsin K inhibitor the most specifically.
The present invention's general introduction
The purpose of this invention is to provide heterocycle ketone group hydrazides protease inhibitor, be cysteine and serpin specifically, it more particularly is this compounds that suppresses cysteine proteinase, it more particularly is this compounds that suppresses the cysteine proteinase of papain superfamily, even more particularly be this compounds of the cysteine proteinase of inhibition of histone enzyme family, be this compounds of inhibition of histone enzyme K the most specifically, the disease that these chemical compounds can be alleviated by changing these protease activities for treatment is useful.
Therefore, in first aspect, the invention provides formula I chemical compound.
On the other hand, the invention provides the Pharmaceutical composition that contains formula I chemical compound and pharmaceutically acceptable carrier, diluent or excipient.
On the other hand, the invention provides the intermediate that is used for preparation I compound.
Also have on the one hand, the invention provides the method for treatment disease, the pathological condition of wherein said disease can be eased by the treatment of Profilin enzyme, be specifically by suppress cysteine and serine protease, more particularly be cysteine proteinase, especially suppress the cysteine proteinase of papain superfamily, even more particularly be the cysteine proteinase of inhibition of histone enzyme family, be that the treatment by inhibition of histone enzyme K is eased the most specifically.
Another aspect, chemical compound of the present invention is disease such as the osteoporosis and the gingival disease (as gingivitis and periodontitis) of feature for treatment with the bone loss, or is that the disease of feature such as osteoarthritis and rheumatoid arthritis are useful especially with excessive cartilage or substrate degradation.Detailed description of the present invention
The invention provides formula I chemical compound:
Figure A9880664100381
Wherein: L is C 2-6Alkyl, Ar-C 0-6Alkyl, Het-C 0-6Alkyl, CH (R 4) NR 5R 6, CH (R 4) Ar, CH (R 4) OAr ' or NR 4R 7Ar is a phenyl or naphthyl, and is optional by one or more Ph-C 0-6Alkyl, Het-C 0-6Alkyl, C 1-6Alkyl, C 1-6Alkoxyl, Ph-C 0-6Alkoxyl, Het-C 0-6Alkoxyl, OH, (CH 2) 1-6NR 8R 9, O (CH 2) 1-6NR 8R 9, CO 2R ' or halogen independently replace.Two C 1-6Alkyl can condense saturated or undersaturated 5-7 unit ring on the Ar ring in conjunction with formation.Ph can choose wantonly by one or more C 1-6Alkyl, C 1-6Alkoxyl, OH, (CH 2) 1-6NR 8R 9, O (CH 2) 1-6NR 8R 9, CO 2R ' or halogen replace.Ar ' is a phenyl or naphthyl, and is optional by one or more Ph-C 0-6Alkyl, Het-C 0-6Alkyl, C 1-6Alkyl, C 1-6Alkoxyl, Ph-C 0-6Alkoxyl, Het-C 0-6Alkoxyl, OH, (CH 2) 1-6NR 8R 9, O (CH 2) 1-6NR 8R 9Or halogen independently replaces.Ph can choose wantonly by one or more C 1-6Alkyl, C 1-6Alkoxyl, OH, (CH 2) 1-6NR 8R 9, O (CH 2) 1-6NR 8R 9, CO 2R ' or halogen replace.Two C 1-6Alkyl can condense saturated or undersaturated 5-7 unit ring on Ar ' ring in conjunction with formation.
Het is stable 5-7 unit's monocyclic heterocycles or stable 7-10 unit bicyclic heterocycle, it is saturated or unsaturated, and form by carbon atom and 1-4 hetero atom that is selected from N, O and S, wherein nitrogen and sulfur heteroatom can be chosen wantonly oxidized, described nitrogen heteroatom can be chosen wantonly quaternary ammoniated, and comprising any bicyclic radicals, wherein any as defined above heterocycle and phenyl ring condense.Described heterocycle can be connected on any hetero atom or carbon atom that produces rock-steady structure, and can choose wantonly by one or more following part replacement: Ph-C that are selected from 0-6Alkyl, Het-C 0-6Alkyl, C 1-6Alkyl, C 1-6Alkoxyl, Ph-C 0-6Alkoxyl, Het-C 0-6Alkoxyl, OH, (CH 2) 1-6NR 8R 9, O (CH 2) 1-6NR 8R 9, CO 2R '.Two C 1-6Alkyl can condense saturated or undersaturated 5-7 unit ring on the Het ring in conjunction with formation.Ph can choose wantonly by one or more C 1-6Alkyl, C 1-6Alkoxyl, OH, (CH 2) 1-6NR 8R 9, O (CH 2) 1-6NR 8R 9, CO 2R ' or halogen replace.Preferred such heterocyclic radical is selected from: piperidyl, piperazinyl, 2-oxo piperazinyl, 2-oxo-piperidine base, 2-oxo-pyrrolidine base, 2-oxo azatropylidene base, the azatropylidene base, pyrrole radicals, the 4-piperidone base, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazole radicals, triazolyl, tetrazole radical, pyridine radicals, pyrazinyl, pyridazinyl (pryidazinyl), pyrimidine radicals, triazine radical, tetrazine base oxazolidinyl oxazolinyl oxazolyl, isothiazolyl isoxazolyl, morpholinyl, thiazolidinyl, thiazolinyl, thiazolyl, quininuclidinyl, indyl, quinolyl, isoquinolyl, benzimidazolyl, benzopyranyl benzoxazolyl, furyl, pyranose, tetrahydrofuran base, THP trtrahydropyranyl, thienyl benzoxazolyl, the thio-morpholinyl sulfoxide, the thio-morpholinyl sulfone, thiadiazolyl group is with the oxadiazole basic ring.W is C (O) or SO 2X, Y and Z independently are N, O, S or CR 10, condition is to have at least two to be that at least one is N among hetero atom and X, Y and the Z among X, Y and the Z, or among X, Y and the Z one is C=N, C=C or N=N and two other is CR 10Or N, further condition be among X, Y and the Z at least two be N; Refer to singly-bound or two key in 5 yuan of heterocycles; R ', R 1, R 2, R 5, R 8, R 9, R 10And R 12Independent is hydrogen, C 1-6Alkyl, C 2-6Alkenyl, Ar-C 0-6Alkyl or Het-C 0-6Alkyl; R 3Be C 3-6Alkyl, Ar, Het, CH (R 11) Ar, CH (R 11) OAr, NR 11R 12, CH (R 11) NR 12R 13Or
Figure A9880664100401
R 4, R 11And R 15Independent is hydrogen, C 1-6Alkyl, C 2-6Alkenyl, C 3-6Cycloalkyl-C 0-6Alkyl, Ar-C 0-6Alkyl or Het-C 0-6Alkyl; R 7Be C 1-6Alkyl, C 1-6Alkenyl, C 3-6Cycloalkyl-C 0-6Alkyl, Ar-C 0-6Alkyl or Het-C 0-6Alkyl; R 4And R 7Can replace by 1-4 following group in conjunction with forming 3-7 unit's monocycle or 7-10 unit's bicyclic carbocyclic or heterocycle, choosing wantonly independently: C 1-6Alkyl, Ar-C 0-6Alkyl, Het-C 0-6Alkyl, C 1-6Alkoxyl, Ar-C 0-6Alkoxyl, Het-C 0-6Alkoxyl, OH, (CH 2) 1-6NR 8R 9Or O (CH 2) 1-6NR 8R 9R 6And R 13Be R 14, R 14C (O), R 14C (S), R 14OC (O) or R 14OC (O) NR 9CH (R 15) (CO); And R 14Be C 1-6Alkyl, C 2-6Alkenyl, Ar-C 0-6Alkyl or Het-C 0-6Alkyl.
The preferred formula I chemical compound of Z=N, X=S and Y=CH (thiazolyl) wherein.More preferably wherein W is this compounds of C (O).Even more preferably R wherein 1And R 2This compounds for H.
Preferred also have such chemical compound, wherein R 3For: Wherein: R 16Be H or C 1-6Alkyl is preferably H or Me; R 17Be C 1-6Alkyl, C 2-6Alkenyl and C 3-11Cycloalkyl-C 1-6Alkyl is preferably n-pro-pyl, isopropyl, isopentyl, tert-butyl group methyl, cyclopropyl methyl, isobutyl group, normal-butyl or pi-allyl; And R 18Be C 3-6Alkyl, OC 3-6Alkyl, Ar, Het, O (CH 2) 0-3Ar or O (CH 2) 0-3Het, be preferably 2-pyridine radicals methoxyl group, 3-pyridine radicals methoxyl group, 4-pyridine radicals methoxyl group, tert-butoxy, the 2-pyridine radicals, the 3-pyridine radicals, the 4-pyridine radicals, the 2-pyrazinyl, 4-tert-butoxycarbonyl benzyloxy, the 4-carboxyl benzyloxy, 3-tert-butoxycarbonyl benzyloxy, the 3-carboxyl benzyloxy, 2-methyl-3-pyridine radicals methoxyl group, 6-methyl-3-pyridine radicals methoxyl group, benzyloxy, the 2-quinolyl, the 3-quinolyl, the 4-quinolyl, the 5-quinolyl, the 6-quinolyl, the 7-quinolyl, the 8-quinolyl, the 1-isoquinolyl, the 3-isoquinolyl, piperidyl, 4-methyl piperidine base, 4-methylimidazole-5-base, N-benzyl-pyrrolidinyl, N-methyl-pyrrolidinyl, 1-benzyl-5-Methylimidazole .-4-base, the 1-piperazinyl, 3-(2-pyridine radicals) benzyl, 2-methyl-3-pyridine radicals, 2-methyl-4-pyridine radicals, 6-methyl-3-pyridine radicals, 4-dimethylamino benzyloxy, 4-(4-morpholinyl methyl) phenyl, 5-hydroxymethyl imidazol-4 yl, 5-butyl-2-pyridine radicals, 4-fluoro phenyl, 3, the 4-difluorophenyl, 2-(1, the 8-naphthyridinyl) or 3,4-Dimethoxyphenyl.
Preferred also have such formula I chemical compound, wherein Z=N, X=S and Y=CH (thiazolyl), and W is C (O), R 1And R 2Be H, and L is 4-(suitable-2, the 6-dimethyl)-the 4-morpholinyl, N-cyclopropyl methyl-N-(2-methyl-propyl) amino, 4-methyl isophthalic acid-naphthyl, N-methyl-N-(2-methyl-propyl) amino, the 1-naphthyl, 5-acenaphthenyl (acenaphthyl), N-cyclopropyl-N-cyclopropyl methylamino, N, N-pair-(2-methyl-propyl) amino, 1-(1,2,3, the 4-tetrahydric quinoline group), N-cyclopropyl methyl-N-third amino, N-(2-methyl-propyl)-N-phenyl amino, 2-methoxyl group-1-naphthyl, 2-benzyloxy phenyl, 2-benzyloxy-1-naphthyl, the 9-phenanthryl, the 9-anthryl, phenyl, 2-(4-tert-butoxycarbonyl) benzyloxy phenyl, 2-(4-carboxyl benzyloxy) phenyl, N-cyclopropyl amino, the 8-quinolyl, N, N-pair-(cyclopropyl methyl) amino, 4-(2, the 2-dimethylamino ethoxy)-1-naphthyl or 1-(N-benzyloxycarbonyl amino)-3-methyl butyl.
Sulfonyl 2147 4 - piperidine-cyclopropylmethyl-styrylsulfonyl OH2148 4 - piperidine-cyclopropylmethyl-benzyloxy carbonyloxy-OH2149 4 - piperidine-cyclopropylmethyl-benzyloxy carbonyloxy-OMe2150 4 - piperidinopropyl methyl-n-butoxycarbonyl OH2151 4 - methyl-n-propyl-piperidin-butoxycarbonyl OMe2152 4 - amidino piperidinyl methyl n-butylsulfonyl OH2153 4 - amidino piperidinyl methyl n-butylsulfonyl OMe2154 4 - amidino piperidylmethyl 2 - tosyl OH2155 4 - amidino piperidylmethyl 2 - bromobenzenesulfonyl OH2156 4 - amidino piperidinyl Synthesis of methyl 3 - tosyl-OH2157 4 - amidino-piperidinyl Synthesis of methyl 3 - tosyl OMe2158 4 - amidino piperidinyl methyl 3,5 - dimethyl-isoxazole OH
Definition
The present invention includes all hydras, solvate, complex and the prodrug of The compounds of this invention.Prodrug is the chemical compound of any covalent bond, and it is release type I parent drug in vivo.If The compounds of this invention has the isomer center of chiral centre or another kind of form, then the form of ownership of this isomer comprises enantiomer and diastereomer, covers by this paper.The mixture that the The compounds of this invention that contains chiral centre can be used as racemic mixture, be rich in a kind of enantiomer use or racemic mixture can with the technical point of knowing from, single enantiomer can use separately.Chemical compound has under the situation of unsaturated carbon-to-carbon double bond therein, and cis (Z) and trans (E) two kinds of isomers are all within the scope of the present invention.Chemical compound exists under the situation of tautomer (as the ketoenol tautomerization body) therein, and every kind of tautomeric forms all is considered within the scope of the present invention, and no matter be to exist with equilibrium form or with the dominant situation of a kind of form.
Except as otherwise noted, any any substituent meaning that once occurs all has its independently meaning in formula I or its any inferior formula, or any other the substituent group meaning under what its situation in office.
The abbreviation and the symbol that generally are used for peptide and chemical field are used for this paper to describe chemical compound of the present invention.In general, amino acid abbreviations is according to IUPAC-IUB joint committee biological chemical name principle (as at Eur.J.Biochem, described in 158,9 (1984)).Refer to following amino acid whose D-or L-isomer at this used term " aminoacid ": alanine, arginine, agedoite, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine.
At this used " C 1-6Alkyl " be intended to comprise replacement with unsubstituted methyl, ethyl, just-propyl group, isopropyl, just-butyl, isobutyl group, the tert-butyl group, amyl group, n-pentyl, isopentyl, neopentyl and hexyl and simple aliphatic isomer thereof.Any C 1-6Alkyl group can be chosen wantonly by following radicals and independently replace: one or two halogen atoms, SR ', OR ', N (R ') 2, C (O) N (R ') 2, carbamoyl or C 1-4Alkyl, wherein R ' is C 1-6Alkyl.C 0Alkyl refers to not have alkyl in this part.Therefore, Ar-C 0Alkyl equals Ar.
At this used " C 3-11Cycloalkyl " be intended to comprise replacement with unsubstituted cyclopropane, Tetramethylene., Pentamethylene., cyclohexane extraction, cycloheptane, cyclooctane, cyclononane, cyclodecane, ring hendecane.When replacing, substituent group is as mentioned to C 1-6Alkyl defines.
At this used " C 2-6Alkenyl " refer to have 2 to 6 carbon atoms, alkyl that one of them carbon-to-carbon singly-bound is replaced by carbon-to-carbon double bond.C 2-6Alkenyl comprises the isomer of ethylene, 1-propylene, 2-propylene, 1-butylene, 2-butylene, isobutene. and several amylene and hexene.Also comprise cis and transisomer.
At this used " C 2-6Alkynyl " refer to have 2 to 6 carbon atoms, alkyl that one of them carbon-to-carbon singly-bound is replaced by carbon-to-carbon triple bond.C 2-6Alkynyl comprises the simple isomer of acetylene, 1-propine, 2-propine, ethyl acetylene, 2-butyne, 3-butine and pentyne and hexin.
" halogen " refers to F, Cl, Br and I.
" Ar " or " aryl " refers to by the optional independent phenyl or naphthyl that replaces of one or more following radicals: Ph-C 0-6Alkyl, Het-C 0-6Alkyl, C 1-6Alkyl, C 1-6Alkoxyl, Ph-C 0-6Alkoxyl, Het-C 0-6Alkoxyl, OH, (CH 2) 1-6NR 8R 9, O (CH 2) 1-6NR 8R 9, CO 2R ' or halogen.Two C 1-6Alkyl group can condense the saturated or unsaturated ring of 5-7 unit on the Ar ring in conjunction with formation.Ph can choose wantonly by one or more following groups and replace: C 1-6Alkyl, C 1-6Alkoxyl, OH, (CH 2) 1-6NR 8R 9, O (CH 2) 1-6NR 8R 9, CO 2R ' or halogen.
At this used " Het " or stable 5 to 7 yuan of monocycles or 7 to the 10 yuan of stable bicyclic heterocycles of " heterocyclic radical " representative, it is saturated or unsaturated, and form by carbon atom and 1 to 3 hetero atom that is selected from N, O and S, wherein nitrogen and sulfur heteroatom can be chosen wantonly oxidized, and nitrogen heteroatom can be chosen wantonly by quaternized, also comprises the heterocycle and the condensed bicyclic radicals of phenyl ring of wherein any above-mentioned definition.Heterocycle can be connected on any hetero atom or carbon atom that produces rock-steady structure, and can be by being selected from the optional replacement of 1 or 2 following part: Ph-C 0-6Alkyl, Het-C 0-6Alkyl, C 1-6Alkyl, C 1-6Alkoxyl, Ph-C 0-6Alkoxyl, Het-C 0-6Alkoxyl, OH, (CH 2) 1-6NR 8R 9, O (CH 2) 1-6NR 8R 9, CO 2R '.Two C 1-6Alkyl group can condense the saturated or unsaturated ring of 5-7 unit on the Het ring in conjunction with formation.Ph can choose wantonly by one or more following groups and replace: C 1-6Alkyl, C 1-6Alkoxyl, OH, (CH 2) 1-6NR 8R 9, O (CH 2) 1-6NR 8R 9, CO 2R ' or halogen.This type of heterocyclic example comprises piperidyl, piperazinyl, 2-oxo piperazinyl, 2-oxo-piperidine base, 2-oxo-pyrrolidine base (pyrrolodinyl), 2-oxo azatropylidene base, the azatropylidene base, pyrrole radicals, the 4-piperidone base, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazole radicals, pyridine radicals, pyrazinyl oxazolidinyl oxazolinyl oxazolyl isoxazolyl, morpholinyl, thiazolidinyl, thiazolinyl, thiazolyl, quininuclidinyl, indyl, quinolyl, isoquinolyl, benzimidazolyl, benzopyranyl benzoxazolyl, furyl, pyranose, tetrahydrofuran base, THP trtrahydropyranyl, thienyl benzoxazolyl, the thiomorpholine sulfoxide, thiomorpholine Feng is with the oxadiazole basic ring.
" HetAr " or " heteroaryl " means any heterocyclic moiety that the Het of above-mentioned definition comprises.It is aromatics on characteristics, as pyridine.
At some group of this paper is abbreviated form.T-Bu represents the tert-butyl group, and Boc represents uncle-butoxy carbonyl, and Fmoc represents the fluorenyl methoxy carbonyl, and Ph represents phenyl, and Cbz represents benzyloxycarbonyl.
Be abbreviation at some reagent of this paper.EDC refers to N-ethyl-N ' (dimethylamino-propyl)-carbodiimide.HOBT refers to I-hydroxybenzotriazole, DMF refers to dimethyl formamide, BOP refers to benzotriazole-1-base oxygen base-three (dimethylamino) Phosphonium hexafluorophosphate, and LawessonShi reagent is 2, two (the 4-methoxyphenyls)-1 of 4-, 3-dithia-2,4-diphosphane-2,4-disulphide, NMM are N-methylmorpholine, TFA refers to trifluoroacetic acid, and THF represents oxolane.Preparation method
Formula I chemical compound, wherein X=S, Y=CH, Z=N and L=NR 4R 7, by being similar to flow process 1 described method preparation.
Flow process 1 A) R 4NH 2, Py, dichloromethane; B) lithium aluminium hydride reduction, THF; C) i.Cl 2CS, Py, dichloromethane; Ii.NH 3, methanol or I, PhCONCS, CHCl 3Iii. potassium carbonate, methanol, water; D) EtO 2CCOCH 2Br, EtOH; E) H 2NNH 2H 2O, EtOH; F) R 3CO 2H, EDCHCl, 1-HOBT, DMF or R 11R 12NCOCl, Et 3N, dichloromethane, wherein W is C (O), or R 3SO 2Cl, NMM, dichloromethane, wherein W is a sulfur dioxide; G) R 4NH 2, CH 2Cl 2H) lithium aluminium hydride reduction, Et 2O; J) Na (OAc) 3BH, CH 2Cl 2
In aprotonic solvent (as dichloromethane), (obtain 2-flow process 1 as cyclopropane phosgene or isobutyryl chloride (1-flow process 1), it is handled through the lithium aluminium hydride reduction in THF and obtains 3-flow process 1 to handle acyl chlorides with primary amine (as aniline, cyclopropylamine, isobutyl amine or propylamine) and pyridine.Perhaps in dichloromethane, handle aldehyde (as cyclopropyl formaldehyde or isobutylaldehyde) (8-flow process 1) so that 9-flow process 1 to be provided, it can be prepared 3-flow process 1 with Reducing agent (as lithium aluminium hydride reduction in ether or the sodium triacetoxy borohydride in dichloromethane) processing with amine (as cyclopropylamine).The thiophosgene and the pyridine that are used in the dichloromethane are handled 3-flow process 1, and the ammonia treatment that then is used in the methanol obtains 4-flow process 1.Perhaps by handling 3-flow process 1 with the benzoyl isothiocyanate, the potassium carbonate processing intermediate benzoylthioureas that then is used in the methanol can prepare 4-flow process 1.The hydrazine hydrate processing 4-flow process 1 that is used in the ethanol obtains 5-flow process 1.In aprotonic solvent (as DMF), use carboxylic acid and peptide coupling agent (as EDCHCl/1-HOBT) or in dichloromethane, use carbamyl chloride (as N, N-diisobutyl carbamyl chloride) and triethylamine handle 5-flow process 1 and obtain 6-flow process 1, used carboxylic acid has N-(2-pyridine radicals methoxycarbonyl)-L-leucine, N-(3-pyridine radicals methoxycarbonyl)-L-leucine, N-(4-pyridine radicals methoxycarbonyl)-L-leucine, N-methyl-N-(4-pyridine radicals methoxycarbonyl)-L-leucine, N-methyl-N-(3-pyridine radicals methoxycarbonyl)-L-leucine, N-methyl-N-(2-pyridine radicals methoxycarbonyl)-L-leucine, 4-methyl-2-(3-phenyl) penta-obtusilic acid, 4-methyl-2-(3-phenyl) valeric acid, uncle N--butoxy carbonyl-L-leucine, N-(uncle 4--butoxy carbonyl benzyloxycarbonyl)-L-leucine, N-(6-methyl-3-pyridine radicals methoxycarbonyl)-L-leucine, N-(2-methyl-3-pyridine radicals methoxycarbonyl)-L-leucine, N-(uncle 4--butoxy carbonyl benzyloxycarbonyl)-L-leucine, uncle N--butoxy carbonyl-L-b-tert-butyl group alanine and uncle N--butoxy carbonyl-L-b-cyclopropyl alanine.Flow process 2
Figure A9880664100731
A) thiourea, EtOH; B) i.NaNO 2, 16% HBr aqueous solution; Ii.CuBr, the 16%HBr aqueous solution; Iii.HBr (catalyst), EtOH; C) ArB (OH) 2, Pd (PPh 3) 4, sodium bicarbonate, toluene, EtOH, water; D) H 2NNH 2H 2O, EtOH, e) R 3CO 2H, EDCHCl, 1-HOBT, DMF, wherein W is C (O), or R 3SO 2Cl, NMM, CH 2Cl 2, wherein W is SO 2
Formula I chemical compound, X=S wherein, Y=CH, Z=N and L=Ar or Het are by being similar to flow process 2 described methods preparations.In backflow ethanol, handle ethyl bromide acetone (1-flow process 2) and obtain 2-flow process 2 with thiourea, use sodium nitrite and cuprous bromide (I) in the aqueous solution of 16%HBr, to handle continuously in proper order it, in ethanol, this product heated with the HBr of catalytic amount and obtain 3-flow process 2.In the toluene/ethanol/water that refluxes; with aryl boric acid (as 2-benzyloxy phenylboric acid; 1-naphthyl boric acid; 4-methyl 1-naphthyl boric acid; 5-acenaphthenyl boric acid; 2-methoxyl group-1-naphthyl boric acid; 2-methoxymethoxy-1-naphthyl boric acid; 9-anthryl boric acid; 9-phenanthryl (phenanthenyl) boric acid; 2-(4-tert-butoxycarbonyl benzyloxy) phenylboric acid; 4-methoxymethoxy naphthyl boric acid or 8-quinolineboronic acid); four (triphenyl phasphine) palladium (O) and sodium bicarbonate are handled this material and are obtained 4-flow process 2; in ethanol, handle 4-flow process 2 with hydrazine hydrate and obtain 5-flow process 2; use carboxylic acid (as N-(2-pyridine radicals methoxycarbonyl)-L-leucine it; N-(3-pyridine radicals methoxycarbonyl)-L-leucine; N-(4-pyridine radicals methoxycarbonyl)-L-leucine; N-methyl-N-(3-pyridine radicals methoxycarbonyl)-L-leucine; N-benzyloxycarbonyl-L-leucine; 4-methyl-2-(3-phenyl) valeric acid; 4-methyl-2-(3-Phenoxyphenyl) valeric acid; 4-methyl-2-(4-Phenoxyphenyl) valeric acid; N-benzyloxycarbonyl-L-b-tert-butyl group alanine; N-benzyloxycarbonyl-L-b-cyclopropyl alanine; N-benzyloxycarbonyl-L-norvaline; N-benzyloxycarbonyl-L-nor-leucine; N-benzyloxycarbonyl-L-isoleucine; N-(4-dimethylaminomethyl benzyloxycarbonyl-L-leucine); uncle N--butoxy carbonyl-L-leucine; N-(6-methyl-3-pyridine radicals methoxycarbonyl)-L-leucine; N-(2-methyl-3-pyridine radicals methoxycarbonyl)-L-leucine; N-(8-quinoline acyl group)-L-leucine; N-(8-quinoline acyl group) glycine; uncle N--butoxy carbonyl-L-allylglycine; N-tert-butoxycarbonyl-L-nor-leucine; N-tert-butoxycarbonyl-L-norvaline; N-tert-butoxycarbonyl-L-b-tert-butyl group alanine; N-tert-butoxycarbonyl-L-b-cyclopropyl alanine) and a kind of peptide coupling agent (as EDCHCl/1-HOBT) in aprotonic solvent (as DMF); perhaps use carbamyl chloride (N-isobutyl group-N-phenyl amino formyl chloride) and triethylamine to handle in dichloromethane and obtain 6-flow process 2, wherein W is C (O).At W=SO 2The time, with corresponding sulfonic acid chloride R 3SO 2Cl and n-methyl morpholine (NMM) are handled 5-flow process 2 in dichloromethane.
Formula I chemical compound, X=S wherein, Y=CH and Z=N are by being similar to flow process 1 described method preparation.
Flow process 3
Figure A9880664100741
A) i-BuOCOCl, NMM, NH 3, THF; B) LawessonShi reagent, THF; C) i.EtO 2CCOCH 2Br; Ii.TFAA, Py, CH 2Cl 2D) H 2NNH 2H 2O, EtOH, e) R 3CO 2H, EDCHCl, 1-HOBT, DMF, wherein W is C (O), or R 3SO 2Cl, NMM, CH 2Cl 2, wherein W is SO 2
Carboxylic acid (as N-benzyloxycarbonyl-L-leucine) (1-flow process 3) can be converted into 2-flow process 3 by in THF, handling with carbonochloridic acid isobutyl ester, N-methylmorpholine and ammonia.In THF, handle 2-flow process 3 with LawessonShi reagent and obtain thioamides 3-flow process 3.This material is then handled in dichloromethane with trifluoroacetic anhydride and pyridine and is obtained 4-flow process 3 by being converted into thiazole with the condensation of a-ketone ester, and it can be converted into 5-flow process 3 through the processing of hydrazine monohydrate.Handle this material with carboxylic acid (as (1S)-1-benzyloxycarbonyl amino-1-(4-carboxyl thiazol-2-yl)-3-methybutane) and peptide coupling agent (as EDCHCl/1-HOBT) in aprotonic solvent (as DMF) and obtain 6-flow process 3, wherein W is C (O).At W=SO 2The time, with corresponding sulfonic acid chloride R 3SO 2Cl and n-methyl morpholine (NMM) are handled 5-flow process 3 in dichloromethane.
Flow process 4
Figure A9880664100751
A) TFA; B) R 14CO 2H, EDCHCl, 1-HOBT, DMF.
Formula I chemical compound, X=S wherein, Y=CH, Z=N, R 3=CH (R 11) NR 12R 13, R wherein 13=R 14CO is by being similar to flow process 4 described method preparations.Handle 1-flow process 4 with trifluoroacetic acid and obtain 2-flow process 4.This material uses carboxylic acid (as pyrazine carboxylic acid, pyridine carboxylic acid, the 2-quinolinecarboxylic acid, the 3-quinolinecarboxylic acid, the 4-quinolinecarboxylic acid, the 5-quinolinecarboxylic acid, the 6-quinolinecarboxylic acid, the 7-quinolinecarboxylic acid, the 8-quinolinecarboxylic acid, 1-isoquinolin formic acid, 3-isoquinolin formic acid, N-methyl piperidine formic acid, 4-methylimidazole-5-formic acid, N-benzyl proline, the N-methylproline, 1-benzyl-5-Methylimidazole .-4-formic acid, the 6-methylnicotinic acid, the 2-methylnicotinic acid, 2-methyl .gamma.-pyridinecarboxylic acid, 4-dimethylaminomethyl benzoic acid, 4-(4-morpholinyl) benzoic acid, 5-hydroxy methylimidazole-4-formic acid, 5-butyl picolinate or 4-fluorinated acid) and a kind of peptide coupling agent (as EDCHCl/1-HOBT) in aprotonic solvent (as DMF), handle and obtain 3-flow process 4.
At this used raw material is maybe can prepare by the conventional method that those of ordinary skills know from the aminoacid that commerce obtains, and can discovery in standard textbook such as COMPENDIUM OF ORGANIC SYNTHETIC METHODS I-VI volume (being published by Wiley-Interscience).
Normally well known in the art at this couling process that forms amido link.By (THE PRACTICE OF PEPTIDE SYNTHESIS such as Bodansky, Springer-Verlag, Berlin, 1984), E.Gross and J.Meienhofer (THE PEPTIDES, 1 volume, 1-284 page or leaf (1979)) and J.M.Stewart and J.D.Young (SOLID PHASE PEPTIDE SYNTHESIS, second edition, Pierce Chemical Co., Rockford, III., 1984) the peptide synthetic method that proposes has been summarized this technology, and these documents are incorporated herein by reference.
The synthetic method of preparation The compounds of this invention is usually used protecting group, to cover reactive functionality or to reduce unwanted side reaction as far as possible.This type of protecting group is by Green, and T.W describes in PROTECTIVE GROUPS IN ORGANIC SYNTHESIS (John Wiley and Sons, New York (1981)).Term " amino protecting group " refers generally to Boc known in the art, acetyl group, benzoyl, Fmoc, Cbz group and derivant thereof.For protecting and going to protect and all know with the method for other parts substituted-amino protecting group.
The acid-addition salts of formula (I) chemical compound be by its parent compound and excessive acid (example hydrochloric acid, hydrobromic acid, Fluohydric acid., sulphuric acid, phosphoric acid, acetic acid, trifluoroacetic acid, maleic acid, succinic acid or methanesulfonic acid) in suitable solvent with the method preparation of standard.Acceptable inner salt of some described compound formation or amphion.Cationic salts is as containing suitable cationic hydroxide, carbonate or alcoholates or handling the parent compound preparation with suitable organic amine with excessive alkaline reagent.Cation is (as Li +, Na +, K +, Ca ++, Mg ++And NH 4 +) for being present in the cationic particular example in the pharmaceutically-acceptable salts.Hydracid root, sulfate radical, phosphate radical, alkane acid group (as acetate and trifluoroacetic acid root), benzoate anion and sulfonate radical (as methanesulfonate) are for being present in the anionic example in the pharmaceutically-acceptable salts.
The present invention also provides Pharmaceutical composition, and it comprises chemical compound and pharmaceutically acceptable carrier, diluent or the excipient of formula (I).Therefore, formula (I) chemical compound can be used for producing medicine.The Pharmaceutical composition of formula (I) chemical compound (according to foregoing method preparation) can be mixed with solution or the freeze dried powder for parenteral.Powder can duplicate with preceding adding suitable diluent or other pharmaceutically acceptable carrier.Liquid preparation can be the isoosmotic aqueous solution of buffering.The example of suitable diluent oozes physiological solt solution, standard 5% D/W or sodium acetate or ammonium acetate buffer solution for waiting.This type of preparation is particularly suitable for parenteral, but also can be used for oral administration, or is loaded in the inhaler that has metering or the aerosol apparatus for being blown into administration.May need to add excipient such as polyvinylpyrrolidone, gelatin, hydroxylated cellulose, arabic gum, Polyethylene Glycol, mannitol, sodium chloride or sodium citrate.
Perhaps these compound are become capsule, tablet or be prepared into Emulsion or the syrup oral administration.Can add pharmaceutically acceptable solid or liquid-carrier strengthening or to stablize described compositions, or help described preparation of compositions.Solid carrier comprises starch, lactose, calcium sulfate dihydrate, Gypsum Fibrosum powder, magnesium stearate or stearic acid, Pulvis Talci, pectin, arabic gum, agar or gelatin.Liquid-carrier comprises syrup, Oleum Arachidis hypogaeae semen, olive oil, saline and water.Described carrier also can comprise sustained-release materials such as glyceryl monostearate or distearin, uses separately or uses with wax.The amount of solid carrier can change, but the about 20mg of preferred every dosage unit is to about 1g.For tablet in case of necessity, conventional pharmaceutical technology is followed in described pharmaceutical preparation, comprises grinding, mixing, granulation and tabletting preparation; Or the hard gelatin capsule form comprised grinding, mixes and fill.When using liquid-carrier, the dosage form of preparation is syrup, elixir, Emulsion or aqueous or non-aqueous suspending agent.This type of liquid preparation can the directly oral or interior administration of the Perle of packing into.
For rectally, also can and mould and make suppository The compounds of this invention and mixed with excipients, described excipient is as cocoa butter, glycerol, gelatin or Polyethylene Glycol.Purposes of the present invention
Formula (I) chemical compound useful as protease inhibitors, in particular to cysteine and serpin, it more particularly is the inhibitor of cysteine proteinase, even more particularly be the inhibitor of the cysteine proteinase of papain superfamily, also more particularly be the cystatin of histone enzyme family, in particular to the inhibitor of cathepsin K.The present invention also provides useful compositions of described chemical compound and preparation, comprises the Pharmaceutical composition and the preparation of described chemical compound.
Chemical compound of the present invention is used for the treatment of and the cysteine proteinase diseases associated, comprises the disease that Pneumocystis carinii, Ke Shi dimension worm, Bu Shi dimension worm and Crithidia fusiculata infect; And schistosomicide, malaria, neoplasm metastasis, metachromatic leukodystrophy, muscular dystrophy, amyotrophy; Particularly with the cathepsin K diseases associated, more especially excessive bone or cartilage are lost disease, (comprising osteoporosis), gingival disease (comprising gingivitis, periodontitis), arthritis (more particularly being osteoarthritis, rheumatoid arthritis) and Paget; The hypercalcemia of malignant tumor and metabolic bone disease.
The metastatic tumour cell is generally also expressed high-caliber proteolytic enzyme, the substrate around this enzyme degradable, and some tumor and metastatic tumour can be treated effectively with chemical compound of the present invention.
The present invention also provides the method for the treatment of the disease that is caused by the horizontal protease of pathology, specifically by cysteine and serine protease, more specifically say so by cysteine proteinase, even more specifically say so by the cysteine proteinase of papain superfamily, the treatment of diseases method that the cysteine proteinase by the histone enzyme family of also more specifically saying so causes, described method comprises the animal that needs treatment, mammal particularly, especially human effective dose chemical compound of the present invention or several compound compositions.The present invention provides the method for the disease that treatment causes by the cathepsin K of pathology level especially, this method comprises the animal that needs treatment, mammal particularly, the cathepsin K inhibitor of especially human effective dose (comprising chemical compound of the present invention or several compound compositions).The professional should be appreciated that, term " effective dose " means chemical compound of the present invention or several compound compositions by suppressing described targeting enzymes and be enough to improve or the amount of the unwanted clinical manifestation of cure diseases (bone easily crisp and reduction that causes as osteoporosis), and these diseases to be targeting enzymes by described pathology level cause as cathepsin K.The present invention provides the method for treatment and cysteine proteinase diseases associated especially, comprises the disease that is infected by Pneumocystis carinii, Ke Shi dimension worm, Bu Shi dimension worm and Crithidia fusiculata; And schistosomicide, malaria, neoplasm metastasis, metachromatic leukodystrophy, muscular dystrophy, amyotrophy, particularly with the cathepsin K diseases associated, the more especially hypercalcemia and the metabolic bone disease of the excessive disease of losing of bone or cartilage (comprising osteoporosis), gingival disease (comprising gingivitis and periodontitis), arthritis (particularly osteoarthritis, rheumatoid arthritis) and Paget, malignant tumor.
The present invention further provides the treatment osteoporosis or suppress the bone loss method, this method comprises the animal that needs treatment with for oral administration, mammal particularly, the formula of especially human effective dose (I) chemical compound or several compound compositions are taken separately or are given jointly with other bone resorption inhibitor such as diphosphonate (being fosamax (allendronate)), hormone replacement therapy, estrogen antagonist or calcitonin.In addition, can be used for stoping bone loss or improve sclerotin with chemical compound of the present invention and anabolism medicine (as bone morphogenetic protein and ipriflavone).
For acute treatment, preferably with formula (I) chemical compound parenteral.5% D/W of above-claimed cpd or the venoclysis of normal saline, or with the similar formulations of suitable vehicle for the most effective, although the intramuscular large bolus injection also is effective.In general, parenteral dosage is about 0.01 to about 100mg/kg; Preferred 0.1 to 20mg/kg, comes inhibition of histone enzyme K with the blood drug level of remaining valid.Described chemical compound administration every day 1 to 4 time is to reach total daily dose of about 0.4 to about 400mg/kg/ day.Blood levels by more described medicine with have the required concentration of therapeutical effect, those of ordinary skills can easily determine the optimal path that the The compounds of this invention treatment is effectively accurately measured and given this chemical compound.
But chemical compound of the present invention also per os gives the patient, so that drug level is enough to suppress bone resorption or acquisition gives in the mode of the treatment of this disclosed other indication.Generally speaking, the Pharmaceutical composition that contains described chemical compound gives with about oral dose of 0.1 to about 50mg/kg, and the mode to adapt with patient disease.Preferred oral dosage is about 0.5 to about 20mg/kg.
When giving chemical compound of the present invention, there is not unacceptable toxic action according to the present invention.Bioassay
Measuring biology to measure according to one of several bioassay provides certain required compound concentration of pharmacological action to detect The compounds of this invention.The mensuration of the Proteolytic enzyme catalytic activity of cathepsin K
The assay method of all cathepsin Ks recombinase of all choosing carries out.The standard conditions of the mensuration of kinetic constant are used fluorescence peptide substrates (being generally Cbz-Phe-Arg-AMC), and measure in pH5.5 contains the sodium acetate solution of 100mM of 20mM cysteine and 5mM EDTA.During these are measured the substrate stock solution concentration of preparation be 10 or the DMSO solution (substrate final concentration) of 20mM with 20 μ M in.All are measured and all contain 10% DMSO.Independent experiment finds that the level of DMSO does not influence enzymatic activity or kinetic constant.All mensuration are all at room temperature carried out.Reading plate instrument monitoring product fluorescence with Perceptive Biosystems Cytofluor II fluorescence (excites at 360nM; Be transmitted in 460nM).The progressive curve of product forms the back at the AMC product and produced in 20 to 30 minutes.Inhibiting research
Potential inhibitor is estimated by the progressive curve method.Assay method carries out under the compound concentration of various tests.By beginning reaction in the buffer that enzyme is added inhibitor and substrate.Data analysis is according to being undertaken by one of two kinds of methods of the measuring shape of progressive curve in the presence of inhibitor.For its progressive curve is those linear chemical compounds, apparent inhibition constant (K I, apparent) calculate (Brandt etc., Biochemistry, 1989,28,140) by equation 1:
V=V mA/[K a(I+I/K I, apparent)+A] (1) wherein v be V for having maximum reaction velocity mResponse speed, A is for having the Michaelis constant K aConcentration of substrate, I is an inhibitor concentration.
For its progressive curve time-the dependence inhibitory action shows those chemical compounds be bent downwardly characteristic, data of analyzing each group according to equation 2 obtain k Observe:
[AMC]=v SsT+ (v o-v Ss) [I-exp (k ObserveT)]/k Observe(2) wherein [AMC] is the production concentration of t formation in time, v oBe primary response speed, and v SsFinal homeostatic reaction speed.K is analyzed in linear function with inhibitor concentration ObserveValue, the inhibiting apparent secondary rate constant (k with time correlation to be described Observe/ inhibitor concentration or k Observe/ [I]).Existing describe fully (Morrison etc., Adv.Enzymol.Relat.Areas Mol.Biol., 1988,61,201) of the complete discussion of this dynamics calculation.The resorbent quantitative approach of human osteoclast
From the liquid nitrogen storage tank, take out and be divided into the deutero-cell suspending liquid of equal portions osteoclastoma, heat rapidly in 37 ℃, and in the RPMI-1640 culture medium, wash 1 time with centrifugal (1000rpm, in 4 ℃ 5 minutes).Sucking-off culture medium, and replace it with the antibody of mouse-anti-HLA-DR, again with 1: 3 ratio with the dilution of RPMI-1640 culture medium, hatched 30 minutes on ice.Frequent this cell suspending liquid of mixing.
With cold RPMI-1640 centrifuge washing cell 2 times (1000rpm, in 4 ℃ 5 minutes), cell is moved in the aseptic 15ml centrifuge tube then.Counting mononuclear cell number in the Neubauer counting chamber of improvement.
Be coated with goat anti--the capacity magnetic bead (5/mononuclear cell) of mice IgG takes out from its reservoir bottle, places 5mL fresh culture (the toxic azide antiseptic of flush away).Described magnetic bead is fixed on the magnet removing culture medium, and replaces with fresh culture.
With magnetic bead and mixing with cells, and suspension is put and is hatched 30 minutes on ice.Frequent this suspension of mixing.The cell fixation of magnetic bead bag quilt on magnet, and is inclined remaining cell (being rich in the osteoclast part) in aseptic 50mL centrifuge tube.Add in the fresh cell of cultivation, so that remove adsorbed osteoclast based on magnetic bead bag quilt.This washing process is repeated 10 times.Discard the cell of magnetic bead bag quilt.
With large aperture, disposable plastics pasteur pipet sample is full of counting chamber, in counting chamber, counts osteoclast.By the centrifugation osteoclast, and be 1.5 * 10 with the density that the EMEM culture medium that contains 10% hyclone and 1.7g/L sodium bicarbonate is regulated osteoclast 4/ mL.The cell suspending liquid (each processing) of 3mL equal portions is inclined in each 15mL centrifuge tube.Centrifugation cell.In every pipe, add suitable handled thing 3ml (being diluted to 50 μ M) with the EMEM culture medium.Comprise suitable solvent contrast, positive control (being diluted to the 87MEM1 of 100 μ g/mL) and homotype contrast (being diluted to the IgG2a of 100 μ g/mL) simultaneously.Each pipe was hatched 30 minutes in 37 ℃.
The cell inoculation of 0.5mL equal portions to the aseptic dentine section that is arranged in 48 well culture plates, was hatched 2 hours for 37 ℃.Quadruplicate each handled thing of screening.Replace washing slice 6 times (in 6 orifice plates, every hole 10mL) with warm PBS, then it is placed fresh processing sample or control sample, and hatched 48 hours in 37 ℃.Wash these sections with phosphate buffered saline (PBS) then, and fix 5 minutes, wash section subsequently with water, and in buffer, hatched 5 minutes in 37 ℃ with 2% glutaraldehyde (in the 0.2M sodium dimethylarsonate).Use the above-mentioned section of cold water washing then, and in cold acetate buffer/fast red garnet, hatching 5 minutes under 4 ℃.The buffer that sucking-off is excessive, and after washing with water, air-dry should the section.
By the positive osteoclast of bright field microscopy counting TRAP, by supersound process it is removed from dentin surface then.Measure the recess volume with Nikon/Lasertec ILM21W confocal microscope.Outline
Nuclear magnetic resoance spectrum uses Bruker AM 250 or Bruker AC 400 spectrometers 250 or the 400MHz record respectively.CDCl 3Be deteriochloroform, DMSO-d 6Be six deuterium dimethyl sulfoxine and CD 3OD is four deuterium methanol.Chemical shift is to represent to a few millionths (d) of low from interior mark tetramethylsilane.The abbreviation of NMR data is as follows: s=is unimodal, and d=is bimodal, t=three peaks, and q=four peaks, the m=multimodal, two of dd=are bimodal, two three peaks of dt=, app=is apparent, and br=broad peak, J are represented the NMR coupling constant with Hz mensuration.Infrared (IR) spectrum record on the Perkin-Elmer683 infrared spectrometer of continuous wave, also record Fourier transformation infrared (FTIR) spectrum on Nicolet Impact 400 D infrared spectrometers.IR and FTIR spectrum are pressed the emission mode record, and the position of band is with the inverse (cm of wave number -1) record.Mass spectrum adopts fast atom bombardment (FAB) or electronic spraying (ES) ionization techniques to carry out on VG 70 FE, PE Syx API III or VG ZABHF equipment.Chemical analysis uses Perkin-Elmer 240C elemental analyser to obtain.Fusing point is measured on Thomas-Hoover fusing point instrument, but does not proofread and correct.All temperature are all used a degree centigrade record.
Use Analtech silica gel G F and E.Merck silica gel 60F-254 lamellae to carry out thin layer chromatography.Quick and gravitational stratification all carries out on E.Merck Kieselgel 60 (230-400 order) silica gel.
Point out that in passing some material is available from Aldrich Chemical Co., Milwaukee, Wisconsin, Chemical Dynamics Corp., South Plainfield, New Jersey and Advanced Chemtech, Louisville, Kentucky.
Embodiment
In following synthetic embodiment, temperature be degree centigrade (℃).Unless otherwise indicated, all raw material sources are in commerce.Needn't further specify, believe that those skilled in the art can farthest use the present invention according to above description.Providing embodiment is used to the present invention is described and does not limit its scope.The claim that belongs to the inventor below the reference.
Embodiment 1N-[2-(suitable-2,6-dimethyl-4-morpholinyl) thiazole-4-base carbonyl]-preparation of N '-[N-(4-pyridine radicals methoxycarbonyl)-L-leucyl-] hydrazides is a) suitable-2,6-dimethyl-4-morpholinyl-N-benzoylthioureas
With suitable-2, the 6-thebaine (1.40g, 12.17mmol, 1.5ml) be dissolved in the chloroform (20ml) and add the benzoyl isothiocyanate (2.0g, 12.17mmol, 1.75ml).After 45 minutes, concentrated this solution obtains the title compound (3.94g, 100%) into yellow solid in stirring at room.MS(ESI)：279.2(M+H) +。B) suitable-2,6-dimethyl-4-morpholinyl thiourea
With the chemical compound of embodiment 1 (a) (3.38g, 12.17mmol) be dissolved in the methanol (40ml) and add entry (40ml), potassium carbonate (8.4g, 60.84mmol), with this solution heated overnight under refluxing.Concentrated reaction mixture makes it to be dissolved in the ethyl acetate again, uses sodium bicarbonate and water washing, then dry (magnesium sulfate), filtration and the concentrated title compound (1.7g, 80%) that obtains to beige solid.MS(ESI)：174.9(M+H) +。C) 2-(suitable-2,6-dimethyl-4-morpholinyl) thiazole-4-carboxylic acid ethyl ester
(1.7g 9.74mmol) is dissolved in the ethanol (25ml) under the heating with the chemical compound of embodiment 1 (b).This solution is cooled to room temperature and add ethyl bromide acetone (1.22ml, 9.74mmol).Reactant mixture was heated 10 minutes under refluxing, concentrate then.Residue is distributed between ethyl acetate and saturated sodium bicarbonate aqueous solution.Use the ethyl acetate extraction water, with the organic facies that saturated salt water washing merges, dry (magnesium sulfate), filtration and simmer down to orange.This crude product by silica gel, with ethyl acetate/hexane (1: 8,1: 3 then) eluting, is obtained the title compound (2.07g, 79%) into yellow solid.MS(ESI)：271.3(M+H) +。D) N-[2-(suitable-2,6-dimethyl-4-morpholinyl) thiazole-4-carbonyl] hydrazides
With the chemical compound of embodiment 1 (c) (2.07g, 7.65mmol) be dissolved in the ethanol (25ml) and add the hydrazine monohydrate (3.7ml, 76.56mmol).This solution was heated 2 hours under refluxing, concentrate then, obtain title compound (1.96g, 100%) into orange solids.MS(ESI)：257.2(M+H) +。E) a-isocyanato--L-leucine methyl ester
With L-leucine methyl ester hydrochloride (25g 0.14mol) is dissolved in the dichloromethane (450ml), is cooled to 0 ℃, add pyridine (43.5g, 0.55mol, 44.5ml), slowly add then the 1.93M phosgene toluene solution (0.18mol, 92.7ml).In 0 ℃ stir 2 hours after, with this mixed liquor impouring 0.5N HCl (1400ml) with ice in (900ml).With 0.5N HCl (1400ml) and ice (900ml) washing organic layer.With the organic layer that dichloromethane (450ml) extraction water-bearing layer also merges with saturated saline (1400ml) and frozen water (900ml) washing, dry (magnesium sulfate), filtration and concentrated then.Residue is through (56-58 ℃ of distillation; 0.78mmHg) be provided as the title compound (20.4g, 86%) of colourless liquid. 1H?NMR(250MHz，CDCl 3)d4.04(dd，1H)，3.82(s，3H)，1.92-1.72(m，1H)，1.69-1.62(m，2H)，0.96(d，3H)，0.94(d，3H)。F) N-(4-pyridine radicals methoxycarbonyl)-L-leucine methyl ester
With the chemical compound of embodiment 1 (e) (5.10g, 29.8mmol) and 4-pyridine radicals methanol (3.25g, toluene 29.8mmol) (30ml) solution is in the heating down 24 hours that refluxes.Concentrate this solution, residue through the flash chromatography purification, with 3: 1 ethyl acetate/hexane eluting, obtains title compound (7.86g, 94%) on the 230-400 of 250g order silica gel. 1H?NMR(250MHz，CDCl 3)d?8.59(d，2H)，7.24(d，2H)，5.33(d，1H)，5.13(s，3H)，4.40(dt，1H)，3.75(s，3H)，1.81-1.51(m，3H)，0.96(d，3H)，0.95(d，3H)。G) N-(4-pyridine radicals methoxycarbonyl)-L-leucine
(1.98g adds 7ml water in the agitating solution of THF 7.06mmol) (7ml), then add LiOHH to the chemical compound of embodiment 1 (f) 2O (325mg, 7.76mmol).This mixture was stirred 30 minutes, concentrate then.Make residue water-soluble again (10ml) and add 3NHCl (2.6ml).This solution of lyophilizing obtain white solid (2.015g, 6.44mmol).MS(ESI)：267.2(M+H) +。H) N-[2-(suitable-2,6-dimethyl-4-morpholinyl) thiazole-4-base carbonyl]-N '-[N-(4-pyridine radicals methoxycarbonyl)-L-leucyl-] hydrazides
Chemical compound (104mg to embodiment 1 (g), 0.39mmol) the agitating solution of DMF (2.5ml) in add the chemical compound (100mg of embodiment 1 (d), 0.39mmol), I-hydroxybenzotriazole (9.5mg, 0.07mmol) and 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (100mg, 0.39mmol).After stirring 16 hours under the room temperature, this solution is distributed between ethyl acetate and water.Use the ethyl acetate extraction water-bearing layer.With the organic layer that saturated salt water washing merges, dry (magnesium sulfate), filtration also concentrate.This crude product by silicagel column (6% methanol is in dichloromethane) chromatography purification, is obtained the title compound (125mg, 51%) into white solid.MS(ESI)：505.4(M+H) +。
Embodiment 2N-[2-(N-cyclopropyl methyl-N-(2-methyl-propyl) amino] thiazole-4-base carbonyl]-a) N-cyclopropyl methyl isobutyramide of the preparation of N '-[N-(4-pyridine radicals methoxycarbonyl)-L-leucyl-] hydrazides
With triethylamine (1.53g, 15.09mmol, 1.21ml) and isobutyl amine (1.10g, 15.09mmol 1.5ml) are dissolved in the dichloromethane (15ml), be cooled to 0 ℃ and drip the cyclopropane phosgene (1.58g, 15.09mmol, 1.4ml).After 1 hour, (60ml) dilutes this mixture with dichloromethane in 0 ℃ of stirring, and with sodium hydroxide (1M), washs with saturated brine then, and dry (magnesium sulfate), filtration also concentrate.Residue obtains the title compound (2.1g, 100%) into beige solid with ether washing and dry.MS(ESI)：141.9(M+H) +。B) N-cyclopropyl methyl isobutyl amine
With 20 minutes chemical compounds with embodiment 2 (a) (1.595g, THF 11.3mmol) (20ml) solution slowly add the 1M lithium aluminium hydride reduction that is cooled to 0 ℃ the THF agitating solution (11.3ml, 11.3mmol) in.After finishing, remove ice bath and also this solution was heated 30 minutes in 55 ℃.This mixture is cooled to 0 ℃ and water (0.43ml), 15% sodium hydrate aqueous solution (0.43ml) and water (1.29ml) quenching.Remove by filter this solid, with the ether washing, dry (magnesium sulfate) also filters.Evaporated filtrate is to the dried title compound (1.15g, 80%) that obtains to colourless liquid.MS(ESI)：128.0(M+H) +。C) N-[2-(N-cyclopropyl methyl-N-(2-methyl-propyl) amino] thiazole-4-base carbonyl]-N '-[N-(4-pyridine radicals methoxycarbonyl)-L-leucyl-] hydrazides
According to the step of embodiment 1 (a)-1 (h), but replace the suitable-2 of step (a) with N-cyclopropyl methyl isobutyl amine, the 6-thebaine is prepared as the title compound (60mg, 31%) of yellow solid.MS(ESI)：517.3(M+H) +。
Embodiment 3N-[2-(4-methyl isophthalic acid-naphthyl) thiazole-4-base carbonyl]-a) thiazolamine-4-carboxylic acid, ethyl ester hydrochlorate of the preparation of N '-[N-(4-pyridine radicals methoxycarbonyl)-L-leucyl-] hydrazides
To thiourea (46.7g, slowly add in the stirred suspension of ethanol 0.614mol) (640ml) ethyl bromide acetone (120g, 0.614mol, 77.2ml).In 45 ℃ stir 16 hours after, this solution is cooled to room temperature and places in the refrigerator spend the night.Filter this mixture,, obtain faint yellow crystalline product (132.74g, 85%) after air-dry with this crystallization of cold washing with alcohol.MS(ESI)：172.9(M+H) +。B) 2-bromethiazole-4-formic acid
In 0 ℃, with NaNO 2(9.11g, (32.11g is 0.127mol) in 16%HBr (water liquid) stirred suspension (400ml) for the chemical compound of water 0.132mol) (16ml) solution adding embodiment 3 (a).Stir after 35 minutes, (20.6g 0.144mol), then adds 16%HBr (aqueous solution) (150ml) again to add cuprous bromide.In 70 ℃ of these mixture of heating 1 hour and filtration immediately.(2 * 500ml) extract with the saturated filtrate of sodium chloride and with ethyl acetate.Merge organic facies, dry (magnesium sulfate), filtration and simmer down to brown solid.Itself and the solid merging of filtering collection also can be used for next step without being further purified or identifying.C) 2-bromethiazole-4-carboxylic acid, ethyl ester
The chemical compound of embodiment 1 (b) was heated 1 hour under refluxing in ethanol (1L), filter then.64 48%HBr (aqueous solution) are added in the filtrate.In refluxing stirring down after 24 hours, concentrate this solution and also make it to be dissolved in again in the ethyl acetate (1L).The order wash this solution with saturated sodium bicarbonate aqueous solution (1L) and saline (1L), the drying (magnesium sulfate), the filtration, use activated carbon decolorizing, by diatomite filtration and simmer down to faint yellow solid (16.95g, 56%). 1H?NMR(400MHz，CDCl 3)d?8.14(s，1H)，4.46(q，2H)，1.43(t，3H)。D) 4-methyl isophthalic acid-naphthyl boric acid
(1.0g is in the agitating solution of THF 4.52mmol) (5ml) in-78 ℃ N-butyl lithium (2.5M is in hexane for 1.8ml, 4.52mmol) to be added drop-wise to 1-bromo-4-methyl naphthalene.In-78 ℃ stir 1 hour after, add triisopropyl borate ester (4.52g, 22.6mmol).After stirring 3 hours under the room temperature, this solution is distributed between 3N HCl and ethyl acetate.Order is with saturated sodium bicarbonate aqueous solution and salt water washing organic facies, then dry (magnesium sulfate), filter and the simmer down to yellow solid, obtain title compound (0.5g, 59%) with hexane wash into faint yellow solid. 1H?NMR(400MHz，CDCl 3)d?9.35(d，1H)，8.58(d，1H)，8.14(d，1H)，7.64(m，2H)，7.54(d，1H)，2.82(s，3H)。E) 2-(4-methyl isophthalic acid-naphthyl) thiazole-4-carboxylic acid ethyl ester
With sodium bicarbonate (4.42ml, 1.0M is in water) add embodiment 1 (c) chemical compound (0.30g, 1.27mmol), the chemical compound of embodiment 1 (d) (0.355g, 1.91mmol) and Pd (Ph 3P) 4(0.059g is 0.05mmol) in the stirring the mixture in ethanol (4ml) and toluene (4ml).In refluxing stirring down after 4 hours, cool off this mixture and make it and between 1N HCl (25ml) and ethyl acetate (25ml), distribute.With this organic layer of salt water washing, dry (magnesium sulfate), filtration also concentrate.Residue obtains being the solid title compound of cystose (0.257g, 68%) through column chromatography (silica gel, ethyl acetate/hexane) purification.MS(ESI)：298.2(M+H) +。F) N-[2-(4-methyl isophthalic acid-naphthyl) thiazole-4-base carbonyl] hydrazides
According to the step of embodiment 1 (d), but replace 2-(suitable-2,6-dimethyl-4-morpholinyl) thiazole-4-carboxylic acid ethyl ester, be prepared as the title compound (0.245g, 100%) of faint yellow solid with 2-(4-methyl isophthalic acid-naphthyl) thiazole-4-carboxylic acid ethyl ester.MS(ESI)：284.2(M+H) +。G) N-[2-(4-methyl isophthalic acid-naphthyl) thiazole-4-base carbonyl]-N '-[N-(4-pyridine radicals methoxycarbonyl)-L-leucyl-] hydrazides
Step according to embodiment 1 (e)-1 (h), but with N-[2-(4-methyl isophthalic acid-naphthyl) thiazole-4-base carbonyl] hydrazides replaces the N-[2-(suitable-2 of step (h), 6-dimethyl-4-morpholinyl) thiazole-4-base carbonyl] hydrazides, be prepared as the title compound (0.122g, 48%) of white solid.MS(ESI)：532.1(M+H) +。
Embodiment 4N-[2-[N-methyl-N-(2-methyl-propyl) amino] thiazole-4-base carbonyl]-a) N-(4-pyridine radicals methoxycarbonyl)-L-leucine tert-butyl ester of the preparation of N '-[N-methyl-N-(4-pyridine radicals methoxycarbonyl)-L-leucyl-] hydrazides
According to the step of embodiment 1 (e)-1 (f), but replace the L-leucine methyl ester hydrochloride of step (e), be prepared as the title compound (2.945g, 64%) of colorless oil with L-leucine tert-butyl ester hydrochlorate.MS(ESI)：323.4(M+H) +。B) N-methyl-N-(4-pyridine radicals methoxycarbonyl)-L-leucine tert-butoxycarbonyl ester
With the chemical compound of embodiment 3 (a) (2.9g, 8.99mmol) be dissolved among the THF (40ml) and add methyl iodide (2.24ml, 35.98mmol).Reactant mixture is cooled to 0 ℃ in the flask of isolated moisture, careful sodium hydride dispersion (the 1.214mg that adds, 13.49mmol) and under room temperature, stirred 5 hours, add ethyl acetate (to consume the sodium hydroxide that forms by excessive sodium hydride) then, then add dropping water, to destroy excessive sodium hydride.This solution of vacuum concentration distributes the oily residue between ether and water.With saturated sodium bicarbonate aqueous solution washing ether layer.With this product of ethyl acetate extraction, wash this extract with water, dry (magnesium sulfate), filtration also concentrate.Crude product obtains yellow oil (2.07mg, 68%) through silica gel column chromatography (ethyl acetate/hexane 3: 1) purification.MS(ESI)：337.5(M+H) +。C) N-methyl-N-(4-pyridine radicals methoxycarbonyl)-L-leucine
With trifluoroacetic acid (3ml) be added in the embodiment 3 (b) in the dichloromethane (20ml) chemical compound (2.07g, 6.15mmol) in.After stirring 1 hour under the room temperature, concentrate this solution, residue is dissolved in the dichloromethane again, with the saturated sodium bicarbonate aqueous solution washing, dry (magnesium sulfate) also concentrates the title compound (1.72g, 100%) that obtains to white solid.MS(ESI)：281.3(M+H) +。D) N-[2-(N-methyl-N-(2-methyl-propyl) amino] thiazole-4-base carbonyl]-N '-[N-methyl-N-(4-pyridine radicals methoxycarbonyl)-L-leucyl-] hydrazides
Step according to embodiment 1 (a)-1 (h), but replace suitable-2 of step (a) with N-methyl isobutyl amine, the 6-thebaine, and with N-(4-pyridine radicals the methoxycarbonyl)-L-leucine of N-methyl-N-(4-pyridine radicals methoxycarbonyl)-L-leucine in place step (h), be prepared as the title compound (91.8mg, 43%) of faint yellow solid.MS(ESI)：491.3(M+H) +。
Embodiment 5N-[2-(1-naphthyl) thiazole-4-base carbonyl]-a) N-(3-pyridine radicals methoxycarbonyl)-L-leucine of the preparation of N '-[N-(3-pyridine radicals methoxycarbonyl)-L-leucyl-] hydrazides
According to the step of embodiment 1 (f)-1 (g), but replace the 4-pyridine radicals methanol of step (f), be prepared as the title compound of white solid with 3-pyridine radicals methanol.MS(ESI)：267.2(M+H) +。B) N-[2-(1-naphthyl) thiazole-4-base carbonyl]-N '-[N-(3-pyridine radicals methoxycarbonyl)-L-leucyl-] hydrazides
Step according to embodiment 3 (a)-3 (c) and 3 (e)-3 (g), but the 4-methyl isophthalic acid-naphthyl boric acid that replaces step (e) with 1-naphthyl boric acid, and with N-(4-pyridine radicals the methoxycarbonyl)-L-leucine of N-(3-pyridine radicals methoxycarbonyl)-L-leucine in place step (g), be prepared as the title compound (0.029g, 28%) of white solid.MS(ESI)：518.2(M+H) +。
Embodiment 6N-[2-(1-naphthyl) thiazole-4-base carbonyl]-preparation of N '-[N-(2-pyridine radicals methoxycarbonyl)-L-leucyl-] hydrazides
According to the step of embodiment 5 (a)-5 (b), but replace the 3-pyridine radicals methanol of step (a), be prepared as the title compound (0.084g, 82%) of white solid with 2-pyridine radicals methanol.MS(ESI)：518.2(M+H) +。
Embodiment 7N-[2-(5-acenaphthenyl) thiazole-4-base carbonyl]-preparation of N '-[N-(4-pyridine radicals methoxycarbonyl)-L-leucyl-] hydrazides
According to the step of embodiment 3 (a)-3 (g), but replace the 1-bromo-4-methyl naphthalene of step (d), be prepared as the title compound (0.166g, 74%) of white solid with 5-bromo acenaphthene.MS(ESI)：544.2(M+H) +。
Embodiment 8N-[2-[N-cyclopropyl methyl-N-(2-methyl-propyl) amino] thiazole-4-base carbonyl]-preparation of N '-[N-methyl-N-(4-pyridine radicals methoxycarbonyl)-L-leucyl-] hydrazides
According to the step of embodiment 2 (a)-2 (c), but with N-(4-pyridine radicals the methoxycarbonyl)-L-leucine of N-methyl-N-(4-pyridine radicals methoxycarbonyl)-L-leucine in place step (c), be prepared as the title compound (50mg, 25%) of yellow solid.MS(ESI)：531.3(M+H) +。
Embodiment 9N-[2-(N-cyclopropyl-N-cyclopropyl methylamino) thiazole-4-base carbonyl]-a) N-cyclopropyl methyl cyclopropylamine of the preparation of N '-[N-(4-pyridine radicals methoxycarbonyl)-L-leucyl-] hydrazides
With cyclopropylamine (1.14g, 20.0mmol, 1.4ml) and cyclopropyl formaldehyde (1.40g, 20.0mmol 1.5ml) are dissolved in the dichloromethane (10ml) and under room temperature and stir.After 2 hours, dry (magnesium sulfate) this solution, concentrating provides pure imines.This chemical compound is dissolved in the ether (10ml), this solution is cooled to 0 ℃ and the slow lithium aluminium hydride reduction (1M is in ether for 30ml, 30mmol) that adds.Stirred this solution 2 hours, then in 0 ℃, water (1.14ml), 15% sodium hydroxide (1.14ml), water (3.42ml) make it quenching.Solids removed by filtration is also washed with ether.Dry (magnesium sulfate) filtrate is filtered and the concentrated colourless liquid (1.58g, 71%) that obtains.MS(ESI)：111.9(M+H) +。B) N-[2-(N-cyclopropyl-N-cyclopropyl methylamino) thiazole-4-base carbonyl]-N '-[N-(4-pyridine radicals methoxycarbonyl)-L-leucyl-] hydrazides
According to the step of embodiment 1 (a)-1 (h), but replace the suitable-2 of step (a) with N-cyclopropyl methyl cyclopropylamine, the 6-thebaine is prepared as the title compound (165mg, yield 88%) of white solid.MS(ESI)：501.4(M+H) +。
Embodiment 10N-[2-[N-cyclopropyl methyl-N-(2-methyl-propyl) amino] thiazole-4-base carbonyl]-preparation of N '-[N-(3-pyridine radicals methoxycarbonyl)-L-leucyl-] hydrazides
According to the step of embodiment 2 (a)-2 (c), but with N-(4-pyridine radicals the methoxycarbonyl)-L-leucine of N-(3-pyridine radicals methoxycarbonyl)-L-leucine in place step (c), be prepared as the title compound (154mg, yield 89%) of yellow solid.MS(ESI)：517.4(M+H) +。
Embodiment 11N-[2-[N-cyclopropyl methyl-N-(2-methyl-propyl) amino] thiazole-4-base carbonyl]-preparation of N '-[N-(2-pyridine radicals methoxycarbonyl)-L-leucyl-] hydrazides
According to the step of embodiment 2 (a)-2 (c), but with N-(4-pyridine radicals the methoxycarbonyl)-L-leucine of N-(2-pyridine radicals methoxycarbonyl)-L-leucine in place step (c), be prepared as the title compound (100mg, yield 65%) of yellow solid.MS(ESI)：517.3(M+H) +。
Embodiment 12N-[2-[N-cyclopropyl methyl-N-(2-methyl-propyl) amino] thiazole-4-base carbonyl]-preparation of N '-[N-methyl-N-(3-pyridine radicals methoxycarbonyl)-L-leucyl-] hydrazides
According to the step of embodiment 4 (a)-4 (d), but replace the 4-pyridine radicals methanol of step (a) and with the N-methyl isobutyl amine of N-cyclopropyl methyl isobutyl amine replacement step (d), be prepared as the title compound (30mg, 22%) of yellow solid with 3-pyridine radicals methanol.MS(ESI)：531.4(M+H) +。
Embodiment 13N-[2-(N-cyclopropyl-N-cyclopropyl methylamino) thiazole-4-base carbonyl]-preparation of N '-[N-(3-pyridine radicals methoxycarbonyl)-L-leucyl-] hydrazides
Step according to embodiment 1 (a)-1 (h), but replace suitable-2 of step (a) with N-cyclopropyl methyl cyclopropylamine, 6-thebaine and replace the 4-pyridine radicals methanol of step (f) with 3-pyridine radicals methanol is prepared as the title compound (85mg, 43%) of white solid.MS(ESI)：501.4(M+H) +。
Embodiment 14N-[2-(N-cyclopropyl-N-cyclopropyl methylamino) thiazole-4-base carbonyl]-preparation of N '-[N-methyl-N-(4-pyridine radicals methoxycarbonyl)-L-leucyl-] hydrazides
According to the step of embodiment 4 (a)-4 (d), but replace the N-methyl isobutyl amine of step (d), be prepared as the title compound (58mg, 35%) of white solid with N-cyclopropyl methyl cyclopropylamine.MS(ESI)：515.3(M+H) +。
Embodiment 15N-[2-[N, N-is two-(2-methyl-propyl) amino] thiazole-4-base carbonyl]-preparation of N '-[N-(2-pyridine radicals methoxycarbonyl)-L-leucyl-] hydrazides
According to the step of embodiment 1 (a)-1 (h), but replace the suitable-2 of step (a) with di-iso-butylmanice, 6-thebaine and replace the 4-pyridine radicals methanol of step (f) with 2-pyridine radicals methanol is prepared as the title compound (140mg, 77%) of yellow solid.MS(ESI)：519.4(M+H) +。
Embodiment 16N-[N-(4-pyridine radicals methoxycarbonyl)-L-leucyl-]-preparation of N '-[2-[1-(1,2,3, the 4-tetrahydric quinoline group) thiazole-4-base carbonyl] hydrazides
According to the step of embodiment 1 (a)-1 (h), but with 1,2,3, the 4-tetrahydroquinoline replaces the suitable-2 of step (a), and the 6-thebaine is prepared as the title compound (168mg, 88%) of yellow solid.MS(ESI)：523.4(M+H) +。
Embodiment 17N-[4-methyl-2-(3-phenoxy group) phenyl valeryl]-a) 2-(3-Phenoxyphenyl)-4-methylpent-obtusilic acid of the preparation of N '-[2-(1-naphthyl) thiazole-4-base carbonyl] hydrazides
N-BuLi (2.5M is in hexane for 19.4ml, 48.5mmol) is added drop-wise to the diisopropylamine that is cooled to-78 ℃, and (4.99g is in the agitating solution of THF 49.3mmol) (50ml).After 15 minutes, drip 3-phenoxy group phenylacetic acid (5.0g, THF 21.9mmol) (20ml) solution in-78 ℃ of stirrings.This mixture is warmed to 0 ℃, be cooled to then-78 ℃ and with 3-bromo-2-metering system (4.4g is 32.9mmol) in this mixture of disposable adding.After 2 hours, make this reactant quenching in-78 ℃ of stirrings, concentrate then with 10ml water.Make residue soluble in water and extract with ether (200ml).Make water layer acidify (3N HCl) and use ether (2 * 200ml) extractions.Merge organic facies, dry (magnesium sulfate), filtration also concentrate the title compound (5.4g, 87%) that obtains white solid. 1H?NMR(400MHz，CDCl 3)d?7.36(m，3H)，7.14(m，2H)，7.01(m，4H)，4.78(d，2H)，3.82(t，1H)，2.83(dd，1H)，2.47(dd，1H)，1.75(s，3H)。B) 2-(3-Phenoxyphenyl)-4-methylvaleric acid
Palladium charcoal (2.0g) is added in the chemical compound of the embodiment 17 (a) in the ethyl acetate (75ml), and (5.4g is in agitating solution 19.1mmol).Under nitrogen atmosphere, stir after 16 hours, by this mixture of diatomite filtration.Concentrate this filtrate, residue obtains the title compound (2.1g, 39%) into white solid through column chromatography (silica gel, ethyl acetate/hexane) purification.MS(ESI)：283.2(M-H) -。C) (±)-N-[4-methyl-2-(3-phenoxy group) phenyl valeryl]-N '-[2-(1-naphthyl) thiazole-4-base carbonyl] hydrazides
Step according to embodiment 1 (h), but replace N-[2-(suitable-2 with 2-(1-naphthyl) thiazole-4-base carbonyl hydrazides, 6-dimethyl-4-morpholinyl) thiazole-4-base carbonyl] hydrazides and usefulness 2-(3-Phenoxyphenyl)-4-methylvaleric acid replacement N-(4-pyridine radicals methoxycarbonyl)-L-leucine, be prepared as the title compound (0.246g, 82%) of white solid.MS(ESI)：536.2(M+H) +。
Embodiment 18N-[2-[N-methyl-N-(2-methyl-propyl) amino] thiazole-4-base carbonyl]-a) 2-(3-phenyl)-4-methylpent-obtusilic acid of the preparation of N '-[4-methyl-2-(3-phenyl) phenyl penta-4-enoyl-] hydrazides
According to the step of embodiment 17 (a), but replace the 3-phenoxyacetic acid, be prepared as the title compound of white solid with the 3-biphenyl acetic acid.MS(ESI)：265.3(M-H) -。B) N-[2-[N-methyl-N-(2-methyl-propyl) amino] thiazole-4-base carbonyl]-N '-[4-methyl-2-(3-phenyl) phenyl penta-4-enoyl-] hydrazides
Step according to embodiment 1 (a)-1 (h), but replace suitable-2 of step (a) with N-methyl isobutyl amine, the 6-thebaine also replaces N-(4-pyridine radicals the methoxycarbonyl)-L-leucine of step (h) with 2-(3-phenyl)-4-methylpent-obtusilic acid, be prepared as the title compound of white solid.MS(ESI)：477.3(M+H) +。
Embodiment 19
N-[2-[N, N-is two-(2-methyl-propyl) amino] thiazole-4-base carbonyl]-preparation of N '-[N-methyl-N-(3-pyridine radicals methoxycarbonyl)-L-leucyl-] hydrazides
According to the step of embodiment 1 (a)-1 (h), but replace the suitable-2 of step (a) with di-iso-butylmanice, the 6-thebaine also replaces the 4-pyridine radicals methanol of step (f) with 3-pyridine radicals methanol, is prepared as the title compound (110mg, 30%) of yellow solid.MS(ESI)：519.4(M+H) +。
Embodiment 20
N-[2-(N-cyclopropyl-N-cyclopropyl methylamino] thiazole-4-base carbonyl]-preparation of N '-[N-methyl-N-(3-pyridine radicals methoxycarbonyl)-L-leucyl-] hydrazides
According to the step of embodiment 4 (a)-4 (d), but replace the 4-pyridine radicals methanol of step (a) also to use the N-methyl isobutyl amine of N-cyclopropyl methyl cyclopropylamine replacement step (d), be prepared as the title compound (33mg, 25%) of yellow solid with 3-pyridine radicals methanol.MS(ESI)：515.4(M+H) +。
Embodiment 21N-[2-(N-cyclopropyl methyl-N-cyclopropyl amino) thiazole-4-base carbonyl]-preparation of N '-[N-(3-pyridine radicals oxygen base carbonyl)-L-leucyl-] hydrazides
According to the step of embodiment 1 (a)-1 (h), but replace the suitable-2 of step (a) with N-cyclopropyl propylamine, 6-thebaine and with the 4-pyridine radicals methanol of 3-pyridine radicals methanol replacement step (f) is prepared as the title compound (40mg, 25%) of yellow solid.MS(ESI)：503.3(M+H) +。
Embodiment 22N-[2-[N-methyl-N-(2-methyl-propyl) amino] thiazole-4-base carbonyl]-a) 2-(3-phenyl)-4-methylvaleric acid of the preparation of N '-[4-methyl-2-(3-phenyl) phenyl valeryl] hydrazides
According to the step of embodiment 17 (a)-17 (b), but replace the 3-phenoxyacetic acid, be prepared as the title compound of white solid with the 3-biphenyl acetic acid.MS(ESI)：267.4(M-H) -。B) N-[2-[N-methyl-N-(2-methyl-propyl) amino] thiazole-4-base carbonyl]-preparation of N '-[4-methyl-2-(3-phenyl) phenyl) valeryl] hydrazides
Step according to embodiment 1 (a)-1 (h), but replace suitable-2 of step (a) with N-methyl isobutyl amine, the 6-thebaine also uses 2-(3-phenyl)-4-methylvaleric acid to replace N-(4-pyridine radicals the methoxycarbonyl)-L-leucine of step (h), be prepared as the title compound (185mg, 88%) of white solid.MS(ESI)：479.4(M+H) +。
Embodiment 23N-[N-(2-methyl-propyl)-N-(3-phenyl) carbamoyl]-a) 3-phenylaniline of the preparation of N '-[2-(1-naphthyl) thiazole-4-base carbonyl] hydrazides
(500mg, (1.2g is in agitating solution 6.0mmol) 40%w/w) to be added in 3-nitrobiphenyl in the ethyl acetate (25ml) with the palladium charcoal.Under nitrogen atmosphere, stir after 24 hours,, concentrate the title compound (0.956g, 94%) that obtains to white solid by this mixture of diatomite filtration.MS(ESI)：170.0(M+H) +。B) N-(3-phenyl) phenyl isobutyl amine
According to the step of embodiment 2 (a)-2 (b), but replace isobutyl amine and replace cyclopropane phosgene in the step (a), be prepared as the title compound (1.1g, 90%) of brown oil with isobutyryl chloride with the 3-phenylaniline.MS(ESI)：226.1(M+H) +。C) N-[2-(1-naphthyl) thiazole-4-base carbonyl]-N ' [[N-isobutyl group-N-(3-xenyl)] amide groups] hydrazine
With the chemical compound of embodiment 23 (b) (0.126g, 0.558mmol) and N-methylmorpholine (0.056g, 0.558mmol) mixture in dichloromethane (3ml) is added drop-wise in the solution of phosgene (0.289ml, 1.93M is in toluene).Stir after 20 minutes, be added in 2-(1-naphthyl) thiazole in the dichloromethane (3ml)-4-base carbonyl hydrazides (0.150g, 0.558mmol) and N-methylmorpholine (0.056g 0.558mmol), then adds DMF (3ml).After 16 hours, dilute this solution and order water, saturated sodium bicarbonate aqueous solution and salt water washing in 50 ℃ of stirrings with ethyl acetate.Dry (magnesium sulfate) organic layer filters and concentrates.Residue obtains the title compound (0.122g, 42%) into white solid through column chromatography (silica gel, ethyl acetate/hexane) purification.MS(ESI)：521.3(M+H) +。
Embodiment 24N-[4-methyl-2-(3-phenyl) phenyl valeryl]-preparation of N '-[2-(1-naphthyl) thiazole-4-base carbonyl] hydrazides
Step according to embodiment 3 (a)-3 (c) and 3 (e)-3 (g), but the 4-methyl isophthalic acid-naphthalene boronic acids that replaces step (e) with 1-naphthyl boric acid, and replace N-(4-pyridine radicals the methoxycarbonyl)-L-leucine of step (g) with 2-(3-phenyl)-4-methylvaleric acid, be prepared as the title compound (0.119g, 49%) of white solid.MS(ESI)：520.3(M+H) +。
Embodiment 25N-[4-methyl-2-(3-phenyl) phenyl valeryl]-N '-[2-[N-(2-methyl-propyl)-N-phenyl amino] thiazole-4-base carbonyl] preparation of hydrazides
Step according to embodiment 2 (a)-2 (c), but replace isobutyl amine and replace the cyclopropane phosgene of step (a) with isobutyryl chloride with aniline, and replace N-(4-pyridine radicals the methoxycarbonyl)-L-leucine of step (c) with 2-(3-phenyl)-4-methylvaleric acid, be prepared as the title compound (72mg, 52%) of white solid.MS(ESI)：541.3(M+H) +。
Embodiment 26N-[2-(2-methoxyl group-1-naphthyl) thiazole-4-base carbonyl]-preparation of N '-[N-(4-pyridine radicals methoxycarbonyl)-L-leucyl-] hydrazides
According to the step of embodiment 3 (a)-3 (g), but replace the 1-bromo-4-methoxynaphthalene of step (d), be prepared as the title compound (0.194g, 85%) of white solid with 1-bromo-2-methoxynaphthalene.MS(ESI)：548.3(M+H) +。
Embodiment 27N-[2-(2-benzyloxy phenyl) thiazole-4-base carbonyl]-N '-(4-methyl-2-(3-phenyl) phenyl valeryl] a) the 2-benzyloxy bromobenzene of preparation of hydrazides
With potassium carbonate (12.0g, 86.7mmol) add the 2-bromophenol (10.0g, 57.8mmol) and benzyl bromide a-bromotoluene (9.9g is in the agitating solution of acetone 57.8mmol) (150ml).Stirring distributed this mixture after 4 hours between ethyl acetate and water in refluxing down.With salt water washing organic layer, dry (magnesium sulfate), filtration also concentrate.Residue is through column chromatography (silica gel, ethyl acetate/hexane) purification, obtain into colorless oil title compound (15.2g, 57.8mmol). 1H?NMR(400MHz，CDCl 3)d?7.62(m，1H)，7.54(m，2H)，7.45(m，2H)，7.37(m，1H)，7.28(m，1H)，6.98(m，1H)，6.91(m，1H)，5.17(s，2H)。B) 2-benzyloxy phenylboric acid
(15.2g, (23.1ml, 2.5M is in hexane, 57.8mmol) to drip n-BuLi in the agitating solution of THF 57.8mmol) (100ml) in-78 ℃ of chemical compounds to embodiment 27 (a).This mixture in-78 ℃ by conduit join triisopropyl borate ester (54.4g, 289mmol) in the agitating solution of THF (100ml) in, stirred 25 minutes in-78 ℃.After being warmed to room temperature and stirring 3 hours, with (3 * 200ml) extract among this mixture impouring 3N HCl (100ml) and with ethyl acetate.Merge organic layer, order water, salt water washing, dry (magnesium sulfate) filters and concentrates.Residue is through column chromatography (silica gel, ethyl acetate/hexane) purification, obtain into faint yellow solid title compound (6.9g, 30.3mmol). 1H?NMR(400MHz，CDCl 3)d?7.90(d，1H)，7.42(m，6H)，7.07(t，1H)，7.02(d，1H)，6.05(s，2H)，5.16(s，2H)。C) N-[2-(2-benzyloxy phenyl) thiazole-4-base carbonyl]-N '-[4-methyl-2-(3-phenyl) phenyl valeryl] hydrazides
Step according to embodiment 3 (a)-3 (c) and 3 (e)-3 (g), but replace the 4-methyl isophthalic acid-naphthalene boronic acids of step (e) and use 2-(3-phenyl)-4-methylvaleric acid to replace N-(4-pyridine radicals the methoxycarbonyl)-L-leucine of step (g) with 2-benzyloxy phenylboric acid, be prepared as the title compound (0.194g, 85%) of white solid.MS(ESI)：576.3(M+H) +。
Embodiment 28N-[2-(2-benzyloxy-1-naphthyl) thiazole-4-base carbonyl]-a) 1-bromo-2-methoxymethoxy naphthalene of the preparation of N '-[N-(4-pyridine radicals methoxycarbonyl)-L-leucyl-] hydrazides
(5.0g 22.4mmol) is added drop-wise in the stirred suspension of DMF (150ml) of sodium hydride (1.6g, 40.3mmol, the dispersion in 60% mineral oil) with 1-bromo-beta naphthal in 0 ℃.Stir after 20 minutes, slowly add the bromomethyl methyl ether (2.8g, 22.4mmol).After being warmed to room temperature and stirring 4 hours, with in this mixture impouring water and use ethyl acetate extraction.Merge organic layer, with saturated sodium bicarbonate aqueous solution and salt water washing organic facies, dry (magnesium sulfate) then filters and simmer down to red oil (5.98g, 100%). 1H?NMR(400MHz，CDCl 3)d?8.27(d，1H)，7.79(d，2H)，7.60(t，1H)，7.46(m，2H)，5.38(s，2H)，3.61(s，3H)。B) 2-(2-methoxymethoxy-1-naphthyl) thiazole-4-carboxylic acid ethyl ester
According to the step of embodiment 3 (a)-3 (e), but replace the 1-bromo-4-methyl naphthalene of step (d), be prepared as the title compound (0.136g, 15%) of pale solid with 1-bromo-2-methoxymethoxy naphthalene.MS(ESI)：344.2(M+H) +。C) 2-(2-hydroxyl-1-naphthyl) thiazole-4-carboxylic acid ethyl ester
Concentrated hydrochloric acid (5) is added embodiment 28 (b) chemical compound, and (0.136g is in the agitating solution of ethanol 0.397mmol) (3ml).In refluxing stirring down after 3 hours, concentrate this solution, make it to be dissolved in again in the ethyl acetate, in proper order with saturated sodium bicarbonate aqueous solution and salt water washing.Dry (magnesium sulfate) organic layer filters and concentrates.Residue obtains the title compound (0.080g, 67%) into white solid through column chromatography (silica gel, ethyl acetate/hexane) purification.MS(ESI)：300.2(M+H) +。D) 2-(2-benzyloxy-1-naphthyl) thiazole-4-carboxylic acid ethyl ester
In 0 ℃ with diisopropyl azo-2-carboxylic acid (0.070g, 0.348mmol) be added drop-wise to embodiment 28 (c) chemical compound (0.080g, 0.268mmol), benzyl alcohol (0.038g, 0.348mmol) and triphenyl phasphine (0.091g is in the agitating solution of THF 0.348mmol) (3ml).After stirring 16 hours under the room temperature, concentrate this solution, residue obtains the title compound (0.060g, 58%) into white solid through column chromatography (silica gel, ethyl acetate/hexane) purification. 1H?NMR(400MHz，CDCl 3)d8.41(s，1H)，8.12(d，1H)，7.91(d，1H)，7.80(d，1H)，7.52(t，1H)，7.41(t，1H)，7.34(m，6H)，5.24(s，2H)，4.49(q，2H)，1.44(t，3H)。E) N-[2-(2-benzyloxy-1-naphthyl) thiazole-4-base carbonyl]-N '-[N-(4-pyridine radicals methoxycarbonyl)-L-leucyl-] hydrazides
Step according to embodiment 1 (d)-1 (h), but the 2-(suitable-2 that replaces step (d) with 2-(2-benzyloxy-1-naphthyl) thiazole-4-carboxylic acid ethyl ester, 6-dimethyl-4-morpholinyl) thiazole-4-carboxylic acid ethyl ester is prepared as the title compound (0.050g, 52%) of white solid.MS(ESI)：624.2(M+H) +。
Embodiment 29N-[2-[N, N-is two-(2-methyl-propyl) amino] thiazole-4-base carbonyl]-preparation of N '-[N-methyl-N-(2-pyridine radicals methoxycarbonyl)-L-leucyl-] hydrazides
According to the step of embodiment 4 (a)-4 (d), but replace the 4-pyridine radicals methanol of step (a) and replace the N-methyl isobutyl amine of step (d), be prepared as the title compound (40mg, 20%) of yellow solid with di-iso-butylmanice with 2-pyridine radicals methanol.MS(ESI)：533.4(M+H) +。
Embodiment 30N-[2-(9-phenanthryl) thiazole-4-base carbonyl]-preparation of N '-[N-(4-pyridine radicals methoxycarbonyl)-L-leucyl-] hydrazides
According to the step of embodiment 3 (a)-3 (g), but replace the 1-bromo-4-methyl naphthalene of step (d), be prepared as the title compound (0.085g, 48%) of pale solid with the 9-bromo phenanthrene.MS(ESI)：568.2(M+H) +。
Embodiment 31N-[2-(9-anthryl) thiazole-4-base carbonyl]-preparation of N '-[N-(4-pyridine radicals methoxycarbonyl)-L-leucyl-] hydrazides
According to the step of embodiment 3 (a)-3 (g), but replace the 1-bromo-4-methyl naphthalene of step (d), be prepared as the title compound (0.101g, 67%) of white solid with 9-bromo anthracene.MS(ESI)：568.2(M+H) +。
Embodiment 32N-[2-[N, N-is two-(2-methyl-propyl) amino] thiazole-4-base carbonyl]-preparation of N '-(tert-butoxycarbonyl-L-leucyl-) hydrazides
Step according to embodiment 1 (a)-1 (d) and 1 (h), but replace suitable-2 of step (a) with di-iso-butylmanice, the 6-thebaine is also used N-(4-pyridine radicals the methoxycarbonyl)-L-leucine of N-tert-butoxycarbonyl-L-leucine in place step (h), be prepared as the title compound (950mg, yield 78%) of yellow solid.MS(ESI)：484.3(M+H) +。
Embodiment 33N-[2-[N, N-is two-(2-methyl-propyl) amino] thiazole-4-base carbonyl]-preparation of N '-[N-(L-leucyl-)] hydrazides
Step according to embodiment 4 (c); but use N-[2-[N; N-pair-(2-methyl-propyl) amino] thiazole-4-base carbonyl]-N '-(tert-butoxycarbonyl-L-leucyl-) hydrazides replacement N-methyl-N-(4-pyridine radicals methoxycarbonyl)-L-leucine tert-butoxycarbonyl ester; be prepared as the title compound (370mg, 85%) of yellow solid.MS(ESI)：384.3(M+H) +。
Embodiment 34N-[2-(1-naphthyl) thiazole-4-base carbonyl]-preparation of N '-[N-methyl-N-(3-pyridine radicals methoxycarbonyl)-L-leucyl-] hydrazides
Step according to embodiment 3 (a)-3 (c) and 3 (e)-3 (g), but the 4-methyl isophthalic acid-naphthalene boronic acids that replaces step (e) with 1-naphthyl boric acid, and with N-(4-pyridine radicals the methoxycarbonyl)-L-leucine of N-methyl-N-(3-pyridine radicals methoxycarbonyl)-L-leucine in place step (g), be prepared as the title compound (0.100g, 59%) of white solid.MS(ESI)：532.2(M+H) +。
Embodiment 35N-[2-[N, N-is two-(2-methyl-propyl) amino] thiazole-4-base carbonyl]-preparation of N '-(N-picoline acyl group-L-leucyl-) hydrazides
Step according to embodiment 1 (h); but use N-[2-[N; N-pair-(2-methyl-propyl) amino] thiazole-4-base carbonyl]-N '-[N-(L-leucyl-)] hydrazides replacement N-[2-(suitable-2; 6-dimethyl-4-morpholinyl) hydrazides and replace N-(4-pyridine radicals methoxycarbonyl)-L-leucine thiazole-4-base carbonyl) with pyridine carboxylic acid; be prepared as the title compound (40mg, 30%) of yellow solid.MS(ESI)：489.3(M+H) +。
Embodiment 36N-[2-[N, N-is two-(2-methyl-propyl) amino] thiazole-4-base carbonyl]-preparation of N '-[N-(2-pyrazine carbonyl)-L-leucyl-] hydrazides
Step according to embodiment 1 (h); but use N-[2-[N; N-pair-(2-methyl-propyl) amino] thiazole-4-base carbonyl]-N '-[N-(L-leucyl-)] hydrazides replacement N-[2-(suitable-2; 6-dimethyl-4-morpholinyl) thiazole-4-base carbonyl] hydrazides and usefulness pyrazine carboxylic acid replacement N-(4-pyridine radicals methoxycarbonyl)-L-leucine; be prepared as the title compound (45mg, 35%) of yellow solid.MS(ESI)：490.3(M+H) +。
Embodiment 37N-[N, N-is two-(2-methyl-propyl) carbamoyl]-N '-[2-[N-(2-methyl-propyl)-N-phenyl amino] thiazole-4-base carbonyl] a) isobutyl-aniline of preparation of hydrazides
According to the step of embodiment 2 (a)-2 (d), but replace isobutyl amine and replace ring third phosgene of step (a), be prepared as the title compound (2.11g, yield 83%) of orange liquid with isobutyryl chloride with aniline.MS(ESI)：172.2(M+Na) +。B) N-[2-[N-(2-methyl-propyl)-N-phenyl] thiazole-4-base carbonyl] hydrazides
According to the step of embodiment 1 (a)-1 (d), but replace the suitable-2 of step (a) with isobutyl-aniline, the 6-thebaine is prepared as the title compound of white solid.MS(ESI)：291.3(M+H) +。C) N-[N, N-pair-(2-methyl-propyl) carbamoyl]-N '-[2-[N-(2-methyl-propyl)-N-phenyl amino] thiazole-4-base carbonyl] hydrazides
Step according to embodiment 23 (c), but with N-[2-[N-(2-methyl-propyl)-N-phenyl] thiazole-4-base carbonyl] hydrazides replaces 2-(1-naphthyl) thiazole-4-base carbonyl hydrazides and replaces N-(3-phenyl) phenyl isobutyl amine with di-iso-butylmanice, be prepared as the title compound (25mg, 25%) of white solid.MS(ESI)：446.3(M+H) +。
The preparation of embodiment 38N-(2-phenyl thiazole-4-base carbonyl)-N '-[N-(4-pyridine radicals methoxycarbonyl)-L-leucyl-] hydrazides
According to the step of embodiment 3 (a)-3 (c) and 3 (e)-3 (g), but replace the 4-methyl isophthalic acid-naphthalene boronic acids of step (e), be prepared as the title compound (0.077g, 27%) of white solid with phenylboric acid.MS(ESI)：468.2(M+H) +。
Embodiment 39N-[2-[2-(4-tert-butoxycarbonyl) benzyloxy phenyl] thiazole-4-base carbonyl]-a) 4-bromomethyl t-butyl perbenzoate of the preparation of N '-[N-(4-pyridine radicals methoxycarbonyl)-L-leucyl-] hydrazides
To 4-bromomethyl benzoic acid (4.0g, 18.6mmol) add the tert-butyl group-2 in the agitating solution in cyclohexane extraction (37ml), dichloromethane (19ml) and THF (2ml), 2,2-tribromo-acetyl imino-ester (trichloroacetimidate) (8.1g, 37.2mmol) the solution of cyclohexane extraction (12ml), then add the boron trifluoride etherate of catalytic amount.After stirring 18 hours under the room temperature, add sodium bicarbonate (4g) and filter this mixture.Filter this mixture and concentrate the title compound (3.6g, 71%) that obtains colorless oil (leaving standstill curable) by a short silica gel stick harness. 1H?NMR(400MHz，CDCl 3)d?7.98(d，2H)，7.44(d，2H)，4.50(s，2H)，1.59(s，9H)。B) 2-(2-hydroxy phenyl) thiazole-4-carboxylic acid ethyl ester
According to the step of embodiment 28 (a)-28 (c), but replace the 1-bromo-beta naphthal of step (a), be prepared as the title compound (0.560g, 53%) of white solid with the 2-bromophenol.MS(ESI)：250.1(M+H) +。C) 2-[2-(4-tert-butoxycarbonyl benzyloxy) phenyl] thiazole-4-carboxylic acid ethyl ester
To the chemical compound of embodiment 39 (b) (0.094g, 0.379mmol) and potassium carbonate (0.136g, add in the stirring the mixture of acetone 0.985mmol) (10ml) embodiment 39 (a) chemical compound (0.133g, 0.417mmol).Stirring distributed this mixture after 16 hours between ethyl acetate and water in refluxing down.With salt water washing organic layer, dry (magnesium sulfate), filtration also concentrate.Residue obtains the title compound (0.160g, 96%) into white solid through column chromatography (silica gel, ethyl acetate/hexane) purification.MS(ESI)：440.2(M+H) +。D) N-[2-[2-(4-tert-butoxycarbonyl) benzyloxy phenyl] thiazole-4-base carbonyl]-N '-[N-(4-pyridine radicals methoxycarbonyl)-L-leucyl-] hydrazides
Step according to embodiment 1 (d)-1 (h), but with 2-[2-(4-tert-butoxycarbonyl benzyloxy) phenyl] thiazole-4-carboxylic acid ethyl ester replaces the 2-(suitable-2 of step (d), 6-dimethyl-4-morpholinyl) thiazole-4-carboxylic acid ethyl ester is prepared as the title compound (0.124g, 47%) of white solid.MS(ESI)：674.2(M+H) +。
Embodiment 40N-[2-[2-(4-carboxyl benzyloxy) phenyl] thiazole-4-base carbonyl]-preparation of N '-[N-(4-pyridine radicals methoxycarbonyl)-L-leucyl-] hydrazides
Step according to embodiment 4 (c); but with N-[2-[2-(4-tert-butyl group carbonyl) benzyloxy phenyl] thiazole-4-base carbonyl]-N '-[N-(4-pyridine radicals methoxycarbonyl)-L-leucyl-] hydrazides replacement N-methyl-N-(4-pyridine radicals methoxycarbonyl)-L-leucine tert-butoxycarbonyl ester; be prepared as the title compound (0.130g, 100%) of faint yellow solid.MS(ESI)：618.2(M+H) +。
Embodiment 41N-[N-(4-tert-butoxycarbonyl benzyloxycarbonyl)-L-leucyl-]-N '-[2-[N-(2-methyl-propyl)-N-phenyl amino] thiazole-4-base carbonyl] a) isobutyl-aniline of preparation of hydrazides
According to the step of embodiment 2 (a)-2 (b), but replace isobutyl amine and replace ring third phosgene of step (a), be prepared as the title compound (2.11g, yield 83%) of orange liquid with isobutyryl chloride with aniline.MS(ESI)：335.3(M+Ha) +。B) (4-tert-butoxycarbonyl) benzyl alcohol
(710mg, (280mg is in the solution of dioxane 1.03mmol) (5ml) 5.15mmol) to add the chemical compound of embodiment 39 (a) with water (5ml) and potassium carbonate.In this mixture overnight of heating down that refluxes, dioxane is removed in decompression then.Add dichloromethane, then handle until all solid dissolvings with dilute hydrochloric acid.Separate organic facies, with the sodium bicarbonate aqueous solution washing, dry (magnesium sulfate), filtration also concentrate the title compound (214mg, 100%) that obtains to white solid. 1HNMR(400MHz，CDCl 3)d?7.89(d，2H)，7.33(d，2H)，4.67(s，2H)，3.08(s，1H)，1.57(s，9H)。C) N-[N-(4-tert-butoxycarbonyl benzyloxycarbonyl)-L-leucyl-]-N '-[2-[N-(2-methyl-propyl)-N-phenyl amino] thiazole-4-base carbonyl] hydrazides
Step according to embodiment 1 (a)-1 (h), but replace suitable-2 of step (a) with isobutyl-aniline, the 6-thebaine also replaces the 4-pyridine radicals methanol of step (f) with (4-tert-butoxycarbonyl) benzyl alcohol, be prepared as the title compound (15mg, 17%) of white solid.MS(ESI)：638.2(M+H) +。
Embodiment 42N-[2-[N, N-is two-(2-methyl-propyl) amino] thiazole-4-base carbonyl]-preparation of N '-[N-(4-tert-butoxycarbonyl benzyloxycarbonyl)-L-leucyl-] hydrazides
Step according to embodiment 1 (a)-1 (h), but replace suitable-2 of step (a) with di-iso-butylmanice, the 6-thebaine also replaces the 4-pyridine radicals methanol of step (f) with (4-tert-butoxycarbonyl) benzyl alcohol, be prepared as the title compound (35mg, 16%) of white solid.MS(ESI)：618.4(M+H) +。
Embodiment 43N-[N-(4-carboxyl benzyloxy carbonyl)-L-leucyl-]-N '-[2-[N-(2-methyl-propyl)-N-phenyl amino] thiazole-4-base carbonyl] preparation of hydrazides
Step according to embodiment 4 (c); but with N-[N-(4-tert-butoxycarbonyl benzyloxycarbonyl)-L-leucyl-]-N '-[2-[N-(2-methyl-propyl)-N-phenyl amino] thiazole-4-base carbonyl] hydrazides replacement N-methyl-N-(4-pyridine radicals methoxycarbonyl)-L-leucine tert-butoxycarbonyl ester; be prepared as the title compound (10mg, 85%) of yellow solid.MS(ESI)：582.2(M+H) +。
Embodiment 44N-(N-benzyloxycarbonyl-L-leucyl-)-N '-[2-[2-(4-tert-butoxycarbonyl) benzyloxy phenyl] thiazole-4-base carbonyl] preparation of hydrazides
Step according to embodiment 1 (d) and 1 (h), but with 2-[2-(4-tert-butoxycarbonyl benzyloxy) phenyl] thiazole-4-carboxylic acid ethyl ester replaces the 2-(suitable-2 of step (d), 6-dimethyl-4-morpholinyl) thiazole-4-carboxylic acid ethyl ester also uses N-(4-pyridine radicals the methoxycarbonyl)-L-leucine of N-benzyloxycarbonyl-L-leucine in place step (h), be prepared as the title compound (0.102g, 68%) of white solid.MS(ESI)：673.2(M+H) +。
Embodiment 45N-(N-benzyloxycarbonyl-L-leucyl-)-N '-[2-[2-(4-carbonyl benzyloxy) phenyl] thiazole-4-base carbonyl] preparation of hydrazides
Step according to embodiment 4 (c); but with N-(N-benzyloxycarbonyl-L-leucyl-)-N '-[2-[2-(4-tert-butoxycarbonyl) benzyloxy phenyl] thiazole-4-base carbonyl] hydrazides replacement N-methyl-N-(4-pyridine radicals methoxycarbonyl)-L-leucine tert-butoxycarbonyl ester; be prepared as the title compound (0.103mg, 100%) of faint yellow solid.MS(ESI)：632.2(M+H) +。
Embodiment 46N-[N-(6-methyl-3-pyridine radicals methoxycarbonyl)-L-leucyl-]-a) 6-methyl-3-pyridine radicals methanol of the preparation of N '-[2-(1-naphthyl) thiazole-4-base carbonyl] hydrazides
According to the step of embodiment 2 (b), but replace N-cyclopropyl methyl isobutyramide, be prepared as the title compound (4.32g, 83%) of yellow oil with 6-methylnicotinic acid methyl ester.MS(ESI)：123.8(M+H) +。B) N-[N-(6-methyl-3-pyridine radicals methoxycarbonyl)-L-leucyl-]-N '-[2-(1-naphthyl) thiazole-4-base carbonyl] hydrazides
According to the step of embodiment 5 (a)-5 (b), but replace the 3-pyridine radicals methanol of step (a), be prepared as the title compound (0.155g, 63%) of white solid with 6-methyl-3-idyl methanol.MS(ESI)：532.2(M+H) +。
The preparation of embodiment 47N-(N-benzyloxycarbonyl-L-leucyl-)-N '-[2-(N-cyclopropyl-N-cyclopropyl methylamino) thiazole-4-base carbonyl] hydrazides
Step according to embodiment 1 (a)-1 (d) and 1 (h), but replace suitable-2 of step (a) with N-cyclopropyl methyl cyclopropylamine, the 6-thebaine is also used N-(4-pyridine radicals the methoxycarbonyl)-L-leucine of N-benzyloxycarbonyl-L-leucine in place step (h), be prepared as the title compound (156mg, 75%) of white solid.MS(ESI)：500.3(M+H) +。
Embodiment 48N-[2-(N-cyclopropyl-N-cyclopropyl methylamino) thiazole-4-base carbonyl]-preparation of N '-[N-(2-pyridine radicals methoxycarbonyl)-L-leucyl-] hydrazides
Step according to embodiment 1 (a)-1 (h), but replace suitable-2 of step (a) with N-cyclopropyl methyl cyclopropylamine, the 6-thebaine also replaces the 4-pyridine radicals methanol of step (f) with 2-pyridine radicals methanol, be prepared as the title compound (260mg, 73%) of white solid.MS(ESI)：501.1(M+H) +。
Embodiment 49N-[2-(N-cyclopropyl-N-cyclopropyl methylamino) thiazole-4-base carbonyl]-preparation of N '-[N-(6-methyl-3-pyridine radicals methoxycarbonyl)-L-leucyl-] hydrazides
Step according to embodiment 1 (a)-1 (h), but replace suitable-2 of step (a) with N-cyclopropyl methyl cyclopropylamine, the 6-thebaine also replaces the 4-pyridine radicals methanol of step (f) with 6-methyl-3-pyridine radicals methanol, be prepared as the title compound (151mg, 71%) of white solid.MS(ESI)：515.3(M+H) +。
The preparation of embodiment 50N-(N-tert-butoxycarbonyl-L-leucyl-)-N '-[2-(N-cyclopropyl-N-cyclopropyl methylamino) thiazole-4-base carbonyl] hydrazides
Step according to embodiment 1 (a)-1 (d) and 1 (h), but replace suitable-2 of step (a) with N-cyclopropyl methyl cyclopropylamine, the 6-thebaine is also used N-(4-pyridine radicals the methoxycarbonyl)-L-leucine of N-tert-butoxycarbonyl-L-leucine in place step (h), be prepared as the title compound (1.2g, 72%) of white solid.MS(ESI)：466.3(M+H) +。
Embodiment 51N-[2-(N-cyclopropyl-N-cyclopropyl methylamino) thiazole-4-base carbonyl]-preparation of N '-[N-methyl-N-(2-pyridine radicals methoxycarbonyl)-L-leucyl-] hydrazides
According to the step of embodiment 4 (a)-4 (d), but replace the 4-pyridine radicals methanol of step (a) also to use the N-methyl isobutyl amine of cyclopropyl methyl cyclopropylamine replacement step (d), be prepared as the title compound (60mg, 25%) of white solid with 2-pyridine radicals methanol.MS(ESI)：515.3(M+H) +。
Embodiment 52N-[2-(2-benzyloxy phenyl) thiazole-4-base carbonyl]-a) N-(6-methyl-3-pyridine radicals methoxycarbonyl)-L-leucine of the preparation of N '-[N-(4-methyl-3-pyridine radicals methoxycarbonyl)-L-leucyl-] hydrazides
According to the step of embodiment 1 (f)-1 (g), but replace the 4-pyridine radicals methanol of step (f), be prepared as the title compound (5.8g, 100%) of pale solid with 6-methyl-3-pyridine radicals methanol. 1HNMR(400MHz，CDCl 3)d?8.36(s，1H)，7.61(d，1H)，7.15(d，1H)，5.85(d，1H)，5.01(s，2H)，4.20(m，1H)，2.50(s，3H)，1.62(m，2H)，1.49(m，1H)，0.87(t，6H)。B) N-[2-(2-benzyloxy phenyl) thiazole-4-base carbonyl]-N '-[N-(4-methyl-3-pyridine radicals methoxycarbonyl)-L-leucyl-] hydrazides
Step according to embodiment 3 (a)-3 (c) and 3 (e)-3 (g), but the 4-methyl isophthalic acid-naphthalene boronic acids that replaces step (e) with 2-benzyloxy phenylboric acid, and with the N-(N-of 6-methyl-3-pyridine radicals methoxycarbonyl-L-leucine in place step (g) (4-pyridine radicals methoxycarbonyl)-L-leucine, be prepared as the title compound (178mg, 99%) of white solid.MS(ESI)：588.3(M+H) +。
Embodiment 53N-[2-(2-benzyloxy phenyl) thiazole-4-base carbonyl]-a) 2-methyl-3-pyridine radicals methanol of the preparation of N '-[N-(2-methyl-3-pyridine radicals methoxycarbonyl)-L-leucyl-] hydrazides
According to the step of embodiment 2 (b), but replace N-cyclopropyl methyl isobutyramide, be prepared as the title compound (4.89g, 100%) of faint yellow oily thing with 2-methylnicotinic acid methyl ester.MS(ESI)：123.8(M+H) +。B) N-3-(6-methyl) pyridine radicals methoxycarbonyl-(L)-leucine
According to the step of embodiment 1 (f)-1 (g), but replace the 4-pyridine radicals methanol of step (f), be prepared as the title compound (6.73g, 100%) of white solid with 2-methyl-3-pyridine radicals methanol.MS(ESI)：281.3(M+H) +。C) N-[2-(2-benzyloxy phenyl) thiazole-4-base carbonyl]-N '-[N-(2-methyl-3-pyridine radicals methoxycarbonyl)-L-leucyl-] hydrazides
Step according to embodiment 3 (a)-3 (c) and 3 (e)-3 (g), but the 4-methyl isophthalic acid-naphthalene boronic acids that replaces step (e) with 2-benzyloxy phenylboric acid, and with the N-(N-of 2-methyl-3-pyridine radicals methoxycarbonyl-L-leucine in place step (g) (4-pyridine radicals methoxycarbonyl)-L-leucine, be prepared as the title compound (179.1mg, 99%) of faint yellow solid.MS(ESI)：588.3(M+H) +。
Embodiment 54N-[2-[N-methyl-N-(2-methyl-propyl) amino] thiazole-4-base carbonyl]-preparation of N '-[N-(6-methyl-3-pyridine radicals methoxycarbonyl)-L-leucyl-] hydrazides
Step according to embodiment 1 (a)-1 (h), but replace suitable-2 of step (a) with N-methyl isobutyl amine, the 6-thebaine also replaces the 4-pyridine radicals methanol of step (f) with 6-methyl-3-pyridine radicals methanol, be prepared as the title compound (215mg, 100%) of faint yellow solid.MS(ESI)：491.3(M+H) +。
Embodiment 55N-[2-[N-methyl-N-(2-methyl-propyl) amino] thiazole-4-base carbonyl]-preparation of N '-[N-(2-methyl-3-pyridine radicals methoxycarbonyl)-L-leucyl-] hydrazides
Step according to embodiment 1 (a)-1 (h), but replace suitable-2 of step (a) with N-methyl isobutyl amine, the 6-thebaine also replaces the 4-pyridine radicals methanol of step (f) with 2-methyl-3-pyridine radicals methanol, be prepared as the title compound (215mg, 100%) of faint yellow solid.MS(ESI)：491.3(M+H) +。
Embodiment 56N-[2-(N-cyclopropyl-N-cyclopropyl methylamino) thiazole-4-base carbonyl]-N '-(N-picoline acyl group-L-leucyl-] a) N-[2-(N-cyclopropyl-N-cyclopropyl methylamino) of preparation of hydrazides] thiazole-4-base carbonyl]-N '-(L-leucyl-) hydrazides
Step according to embodiment 4 (c); but replace N-methyl-N-(4-pyridine radicals methoxycarbonyl)-L-leucine tert-butoxycarbonyl ester with N-(N-tert-butoxycarbonyl-L-leucyl-)-N '-[2-(N-cyclopropyl-N-cyclopropyl methylamino) thiazole-4-base carbonyl] hydrazides; be prepared as the title compound (668mg, 81%) of white solid.MS(ESI)：366.3(M+H) +。B) N-[2-(N-cyclopropyl-N-cyclopropyl methylamino) thiazole-4-base carbonyl]-N '-(N-picoline acyl group-L-leucyl-] hydrazides
Step according to embodiment 1 (h); but with N-[2-(N-cyclopropyl-N-cyclopropyl methylamino) thiazole-4-base carbonyl]-N '-(the L-leucyl-] hydrazides replacement N-[2-(suitable-2; 6-dimethyl-4-morpholinyl) thiazole-4-base carbonyl] hydrazides and replace N-(4-pyridine radicals methoxycarbonyl)-L-leucine with pyridine carboxylic acid; be prepared as the title compound (183mg, 95%) of white solid.MS(ESI)：471.2(M+H) +。
Embodiment 57N-[2-(N-cyclopropyl-N-cyclopropyl methylamino) thiazole-4-base carbonyl]-preparation of N '-[N-(2-methyl-3-pyridine radicals methoxycarbonyl)-L-leucyl-] hydrazides
Step according to embodiment 1 (a)-1 (h), but replace suitable-2 of step (a) with N-cyclopropyl methyl cyclopropylamine, the 6-thebaine also replaces the 4-pyridine radicals methanol of step (f) with 2-methyl-3-pyridine radicals methanol, be prepared as the title compound (310mg, 84%) of white solid.MS(ESI)：515.4(M+H) +。
Embodiment 58N-[N-(3-tert-butoxycarbonyl benzyloxycarbonyl)-L-leucyl-]-a) 3-bromomethyl benzoic acid of the preparation of N '-[2-(N-cyclopropyl-N-cyclopropyl methylamino) thiazole-4-base carbonyl] hydrazides
With the 3-toluic acid (15.0g, 110mmol), N-bromosuccinimide (19.60g, 110mmol) and t-butyl peroxybenzoate (2.1ml, 110mmol) heated overnight under refluxing of the mixture in carbon tetrachloride (50ml).Cool off this mixture and concentrating under reduced pressure.Residue and vacuum filtration with carbon tetrachloride washing acquisition.Evaporated filtrate is to the dried white solid (12.57g, 53%) that obtains. 1H?NMR(400MHz，CDCl 3)d?7.93(m，2H)，7.43(m，2H)，4.55(s，2H)。B) 3-bromomethyl t-butyl perbenzoate
According to the step of embodiment 39 (a), but replace 4-bromomethyl benzoic acid, be prepared as the title compound (7.9g, 100%) of yellow oil with 3-bromomethyl benzoic acid. 1H?NMR(400MHz，CDCl 3)d?7.93(m，2H)，7.43(m，2H)，4.55(s，2H)，1.55(s，9H)。C) (3-tert-butoxycarbonyl) benzyl alcohol
According to the step of embodiment 41 (b), but replace 4-bromomethyl t-butyl perbenzoate, be prepared as the title compound (5.6g, 92%) of yellow oil with 3-bromomethyl t-butyl perbenzoate.MS(ESI)：208.1(M+H) +。D) N-[N-(3-tert-butoxycarbonyl benzyloxycarbonyl)-L-leucyl-]-N '-[2-(N-cyclopropyl-N-cyclopropyl methylamino) thiazole-4-base carbonyl] hydrazides
Step according to embodiment 1 (a)-1 (h), but replace suitable-2 of step (a) with N-cyclopropyl methyl cyclopropylamine, the 6-thebaine also replaces the 4-pyridine radicals methanol of step (f) with (3-tert-butoxycarbonyl) benzyl alcohol, be prepared as the title compound (90mg, 29%) of white solid.MS(ESI)：600.4(M+H) +。
Embodiment 59N-[2-(1-naphthyl) thiazole-4-base carbonyl]-a) N-[2-(1-naphthyl) thiazole-4-base carbonyl of the preparation of N '-[N-(8-quinoline acyl group)-L-leucyl-] hydrazides] hydrazides
According to the step of embodiment 3 (a)-3 (f), but replace the 4-methyl isophthalic acid-naphthalene boronic acids of step (e), be prepared as the title compound of faint yellow solid with the 1-naphthalene boronic acids.MS(ESI)：270.1(M+H) +。B) N-(N-tert-butoxycarbonyl-L-leucyl-)-N '-[2-(1-naphthyl) thiazole-4-base carbonyl] hydrazides
Step according to embodiment 1 (h), but with N-[2-(1-naphthyl) thiazole-4-base carbonyl] hydrazides replacement N-[2-(suitable-2,6-dimethyl-4-morpholinyl) thiazole-4-base carbonyl] hydrazides and usefulness N-tert-butoxycarbonyl-L-leucine in place N-(4-pyridine radicals methoxycarbonyl)-L-leucine, be prepared as the title compound (2.2g, 96%) of white solid.MS(ESI)：483.2(M+H) +。C) N-(L-leucyl-)-N '-[2-(1-naphthyl) thiazole-4-base carbonyl] hydrazides
Step according to embodiment 4 (c); but replace N-methyl-N-(4-pyridine radicals methoxycarbonyl)-L-leucine tert-butoxycarbonyl ester with N-(N-tert-butoxycarbonyl-L-leucyl-)-N '-[2-(1-naphthyl) thiazole-4-base carbonyl] hydrazides; be prepared as the title compound (1.7g, 97%) of pale solid.MS(ESI)：383.3(M+H) +。D) N-[2-(1-naphthyl) thiazole-4-base carbonyl]-N '-[N-(8-quinoline acyl group)-L-leucyl-] hydrazides
Step according to embodiment 1 (h); but replace N-[2-(suitable-2 with N-(L-leucyl-)-N '-[2-(1-naphthyl) thiazole-4-base carbonyl] hydrazides; 6-dimethyl-4-morpholinyl) thiazole-4-base carbonyl] hydrazides and replace N-(4-pyridine radicals methoxycarbonyl)-L-leucine with 8-Quinoline Carboxylic Acid; be prepared as the title compound (118mg, 84%) of white solid.MS(ESI)：538.2(M+H) +。
Embodiment 60N-[N-(2-methyl-3-pyridine radicals methoxycarbonyl)-L-leucyl-]-preparation of N '-[2-(1-naphthyl) thiazole-4-base carbonyl] hydrazides
According to the step of embodiment 5 (a)-5 (b), but replace 3-pyridine radicals methanol, be prepared as the title compound (0.160g, 65%) of white solid with 2-methyl-3-idyl methanol.MS(ESI)：532.2(M+H) +。
Embodiment 61N-[2-(1-naphthyl) thiazole-4-base carbonyl]-N '-(N-picoline acyl group-L-leucyl-] preparation of hydrazides
According to the step of embodiment 59 (a)-59 (c), but replace the 8-Quinoline Carboxylic Acid of step (d), be prepared as the title compound (0.086g, 54%) of white solid with pyridine carboxylic acid.MS(ESI)：488.3(M+H) +。
Embodiment 62N-[N-(3-carboxyl benzyloxy carbonyl)-L-leucyl-]-preparation of N '-[2-(N-cyclopropyl-N-cyclopropyl methylamino) thiazole-4-base carbonyl] hydrazides
Step according to embodiment 4 (c); but with N-[N-(3-tert-butoxycarbonyl benzyloxycarbonyl)-L-leucyl-]-N '-[2-(N-cyclopropyl-N-cyclopropyl methylamino) thiazole-4-base carbonyl] hydrazides replacement N-methyl-N-(4-pyridine radicals methoxycarbonyl)-L-leucine tert-butoxycarbonyl ester; be prepared as the title compound (21mg, 93%) of white solid.MS(ESI)：544.3(M+H) +。
Embodiment 63N-[2-(1-naphthyl) thiazole-4-base carbonyl]-preparation of N '-[N-(2-quinoline acyl group)-L-leucyl-] hydrazides
According to the step of embodiment 59 (a)-59 (d), but replace the 8-Quinoline Carboxylic Acid of step (d), be prepared as the title compound (0.123g, 80%) of white solid with quinaldinic acid.MS(ESI)：538.2(M+H) +。
Embodiment 64N-[2-(1-naphthyl) thiazole-4-base carbonyl]-preparation of N '-[N-(3-quinoline acyl group)-L-leucyl-] hydrazides
According to the step of embodiment 59 (a)-59 (d), but replace the 8-Quinoline Carboxylic Acid of step (d), be prepared as the title compound (0.109g, 77%) of white solid with the 3-quinoline carboxylic acid.MS(ESI)：538.2(M+H) +。
Embodiment 65N-[2-(1-naphthyl) thiazole-4-base carbonyl]-preparation of N '-[N-(4-methyl piperidine base carbonyl)-L-leucyl-] hydrazides
According to the step of embodiment 59 (a)-59 (d), but replace the 8-Quinoline Carboxylic Acid of step (d), be prepared as the title compound (0.059g, 45%) of white solid with 1-methyl piperidine-4-carboxylic acid.MS(ESI)：508.2(M+H) +。
Embodiment 66N-[2-(1-naphthyl) thiazole-4-base carbonyl]-preparation of N '-[N-(4-quinoline acyl group)-L-leucyl-] hydrazides
According to the step of embodiment 59 (a)-59 (d), but replace the 8-Quinoline Carboxylic Acid of step (d), be prepared as the title compound (0.096g, 68%) of white solid with the 4-quinoline carboxylic acid.MS(ESI)：538.3(M+H) +。
Embodiment 67N-[2-(1-naphthyl) thiazole-4-base carbonyl]-preparation of N '-[N-(5-quinoline acyl group)-L-leucyl-] hydrazides
According to the step of embodiment 59 (a)-59 (d), but replace the 8-Quinoline Carboxylic Acid of step (d), be prepared as the title compound (0.089g, 63%) of white solid with the 5-quinoline carboxylic acid.MS(ESI)：538.3(M+H) +。
Embodiment 68N-[2-(1-naphthyl) thiazole-4-base carbonyl]-preparation of N '-[N-(7-quinoline acyl group)-L-leucyl-] hydrazides
According to the step of embodiment 59 (a)-59 (d), but replace the 8-Quinoline Carboxylic Acid of step (d), be prepared as the title compound (0.106g, 75%) of white solid with the 7-quinoline carboxylic acid.MS(ESI)：538.2(M+H) +。
Embodiment 69N-[2-(1-naphthyl) thiazole-4-base carbonyl]-preparation of N '-[N-(6-quinoline acyl group)-L-leucyl-] hydrazides
According to the step of embodiment 59 (a)-59 (d), but replace the 8-Quinoline Carboxylic Acid of step (d), be prepared as the title compound (0.111g, 79%) of white solid with the 6-quinoline carboxylic acid.MS(ESI)：538.2(M+H) +。
Embodiment 70N-[N-(1-isoquinolin acyl group)-L-leucyl-]-preparation of N '-[2-(1-naphthyl) thiazole-4-base carbonyl] hydrazides
According to the step of embodiment 59 (a)-59 (d), but replace the 8-Quinoline Carboxylic Acid of step (d), be prepared as the title compound (0.076g, 54%) of white solid with the 1-isoquinolinecarboxylic acid.MS(ESI)：538.2(M+H) +。
Embodiment 71N-[N-(3-isoquinolin acyl group)-L-leucyl-]-preparation of N '-[2-(1-naphthyl) thiazole-4-base carbonyl] hydrazides
According to the step of embodiment 59 (a)-59 (d), but replace the 8-Quinoline Carboxylic Acid of step (d), be prepared as the title compound (0.055g, 39%) of white solid with the 3-isoquinolinecarboxylic acid.MS(ESI)：538.2(M+H) +。
Embodiment 72N-[N-(4-methylimidazole-5-base carbonyl)-L-leucyl-]-a) 4-methylimidazole-5-carboxylic acid of the preparation of N '-[2-(1-naphthyl) thiazole-4-base carbonyl] hydrazides
According to the step of embodiment 1 (g), but replace N-(4-pyridine radicals methoxycarbonyl)-L-leucine methyl ester, be prepared as the title compound (0.428g, 52%) of white solid with 4-methylimidazole-5-carboxylic acid, ethyl ester.MS(ESI)：126.8(M+H) +。B) N-[N-(4-methylimidazole-5-base carbonyl)-L-leucyl-]-N '-[2-(1-naphthyl) thiazole-4-base carbonyl] hydrazides
Step according to embodiment 1 (h); but replace N-[2-(suitable-2 with N-(L-leucyl-)-N '-[2-(1-naphthyl) thiazole-4-base carbonyl] hydrazides; 6-dimethyl-4-morpholinyl) thiazole-4-base carbonyl) hydrazides also replaces N-(4-pyridine radicals methoxycarbonyl)-L-leucine with 4-methylimidazole-5-carboxylic acid; be prepared as the title compound (0.108g, 84%) of white solid.MS(ESI)：491.3(M+H) +。
Embodiment 73N-(N-benzyl-L-prolyl-L-leucyl-]-preparation of N '-[2-(1-naphthyl) thiazole-4-base carbonyl] hydrazides
According to the step of embodiment 59 (a)-59 (d), but replace the 8-Quinoline Carboxylic Acid of step (d), be prepared as the title compound (0.075g, 50%) of white solid with N-benzyl proline.MS(ESI)：570.2(M+H) +。
Embodiment 74N-[N-(1-benzyl-5-Methylimidazole .-4-base carbonyl)-L-leucyl-]-preparation of N '-[2-(1-naphthyl) thiazole-4-base carbonyl] hydrazides
According to the step of embodiment 72 (a)-72 (b), but replace the 4-methylimidazole-5-carboxylic acid of step (a), be prepared as the title compound (0.115g, 75%) of white solid with 1-benzyl-5-Methylimidazole .-4-carboxylic acid.MS(ESI)：581.1(M+H) +。
Embodiment 75N-[N-(the different nicotinoyl of 3-methyl)-L-leucyl-]-a) 4-cyano group-2-picoline of the preparation of N '-[2-(1-naphthyl) thiazole-4-base carbonyl] hydrazides
Under room temperature, with iodoethane (51.5g, 330mmol) be added drop-wise to pure PICOLINE N-OXIDES (10.0g, 91.7mmol) in.After leaving standstill 24 hours, this salt of filtering also washs with ether.This solid is dissolved in the ethanol/water (70ml/30ml), in 48-50 ℃, with dripped in 100 minutes potassium cyanide in water (30ml) (11.0g, 172mmol).After adding finishes, under same temperature, continue to stir this solution 30 minutes.Then with this solution of chloroform extraction.With salt water washing organic layer, dry (magnesium sulfate), filtration also concentrate.Residue obtains being the solid title compound of faint yellow oily (3.9g, 36%) through column chromatography (silica gel, ethyl acetate/hexane) purification.MS(ESI)：118.8(M+H) +。B) 2-picoline-4-carboxylic acid
(0.300g 2.5mmol) is dissolved in the concentrated hydrochloric acid (3ml) with the chemical compound of embodiment 75 (a).In refluxing stirring down after 18 hours, concentrated this solution obtains the title compound (0.342g, 100%) into white solid.MS(ESI)：137.8(M+H) +。C) N-[N-(the different nicotinoyl of 3-methyl)-L-leucyl-]-N '-[2-(1-naphthyl) thiazole-4-base carbonyl] hydrazides
Step according to embodiment 1 (h); but replace N-[2-(suitable-2 with N-(L-leucyl-)-N '-[2-(1-naphthyl) thiazole-4-base carbonyl] hydrazides; 6-dimethyl-4-morpholinyl) thiazole-4-base carbonyl] hydrazides and usefulness 2-picoline-4-carboxylic acid replacement N-(4-pyridine radicals methoxycarbonyl)-L-leucine; be prepared as the title compound (0.095g, 72%) of white solid.MS(ESI)：502.2(M+H) +。
Embodiment 76N-[2-(N-cyclopropyl amino) thiazole-4-base carbonyl]-preparation of N '-[N-(2-pyridine radicals methoxycarbonyl)-L-leucyl-] hydrazides
According to the step of embodiment 1 (a)-1 (h), but replace the suitable-2 of step (a) with cyclopropylamine, the 6-thebaine also replaces the 4-pyridine radicals methanol of step (f) with 2-pyridine radicals methanol, is prepared as the title compound (140mg, 50%) of white solid.MS(ESI)：447.3(M+H) +。
Embodiment 77N-[N-(2-benzoxazolyl)-L-leucyl-]-preparation of N '-[2-(1-naphthyl) thiazole-4-base carbonyl] hydrazides
With the chemical compound of embodiment 59 (c) (100mg, 0.26mmol), 2-chloro benzoxazole (40.2mg, 0.26mmol, 0.03ml) and triethylamine (26.5mg, 0.26mmol, 0.365ml) 1: the solution of 1YHF/ methanol (1ml) be heated to 60 ℃ 48 hours.Dilute this solution with ethyl acetate, with saturated sodium bicarbonate aqueous solution, water (2 *) and saturated brine washing, dry (magnesium sulfate), filtration and concentrated then.Residue through the flash chromatography purification, with 1: 1 ethyl acetate/hexane eluting, obtains the title compound (50.2mg, 38%) into faint yellow solid on 230-400 order silica gel.MS(ESI)：500.2(M+H) +。
The preparation of embodiment 78N-(N-benzyloxycarbonyl-L-leucyl-)-N '-[2-[N, N-couple-(2-methyl-propyl) amino] oxazole-4-base carbonyl] hydrazides is N a), N-two isobutyl ureas
Under room temperature, with di-iso-butylmanice (4.5g, 34.8mmol, 6.08ml) and the chloro sulfonylisocyanates (THF 3.03ml) (200ml) solution stirring 20 minutes adds entry (10ml) then and stirred under room temperature 17 hours for 4.93g, 34.8mmol.Concentrate this solution, residue is dissolved in the ethyl acetate again, water, saturated sodium bicarbonate aqueous solution and saturated brine washing, dry (magnesium sulfate), filtration and the concentrated title compound (6.0g, 100%) that obtains to colorless oil leave standstill crystallizable then.MS(ESI)：173.3(M+H) +。B) N-(N-benzyloxycarbonyl-L-leucyl-)-N '-[2-[N, N-couple-(2-methyl-propyl) amino] oxazole-4-base carbonyl] hydrazides
Step according to embodiment 1 (c)-1 (d) and 1 (h), but use N, N-two isobutyl ureas replace suitable-2 of step (c), 6-dimethyl-4-morpholinyl thiourea is also used N-(4-pyridine radicals the methoxycarbonyl)-L-leucine of N-benzyloxycarbonyl-L-leucine in place step (h), be prepared as the title compound (126mg, 64%) of white solid.MS(ESI)：502.3(M+H) +。
Embodiment 79N-[2-[N-cyclopropyl-N-(2-methyl-propyl) amino] thiazole-4-base carbonyl]-a) N-cyclopropyl isobutyl amine of the preparation of N '-[N-(2-pyridine radicals methoxycarbonyl)-L-leucyl-] hydrazides
According to the step of embodiment 9 (a), but replace cyclopropyl formaldehyde, be prepared as the title compound (1.9g, 58%) of colorless oil with isobutylaldehyde.MS(ESI)：113.9(M+H) +。B) N-[2-[N-cyclopropyl-N-(2-methyl-propyl) amino] thiazole-4-base carbonyl]-N '-[N-(2-pyridine radicals methoxycarbonyl)-L-leucyl-] hydrazides
Step according to embodiment 1 (a)-1 (h), but replace suitable-2 of step (a) with N-cyclopropyl isobutyl amine, the 6-thebaine also replaces the 4-pyridine radicals methanol of step (f) with 2-pyridine radicals methanol, be prepared as the title compound (150mg, yield 69%) of white solid.MS(ESI)：503.2(M+H) +。
Embodiment 80N-[2-[N-cyclopropyl-N-(2-methyl-propyl) amino] thiazole-4-base carbonyl]-preparation of N '-[N-methyl-N-(2-pyridine radicals methoxycarbonyl)-L-leucyl-] hydrazides
According to the step of embodiment 4 (a)-4 (d), but replace the 4-pyridine radicals methanol of step (a) also to use the N-methyl isobutyl amine of N-cyclopropyl isobutyl amine replacement step (d), be prepared as the title compound (85mg, 32%) of white solid with 2-pyridine radicals methanol.MS(ESI)：517.3(M+H) +。
Embodiment 81N-[2-(1-naphthyl) thiazole-4-base carbonyl]-a) N-[2-(1-naphthyl) thiazole-4-base carbonyl of the preparation of N '-[N-(1-piperazine carbonyl)-L-leucyl-] hydrazides]-N '-[N-(4-tert-butoxycarbonyl-1-piperazine carbonyl)-L-leucyl-] hydrazides
According to the step of embodiment 23 (c), but replace N-(3-phenyl) phenyl isobutyl amine, be prepared as the title compound (131mg, 83%) of white solid with N-tert-butoxycarbonyl piperazine.MS(ESI)：595.2(M+H) +。B) N-[2-(1-naphthyl) thiazole-4-base carbonyl]-N '-[N-(1-piperazine carbonyl)-L-leucyl-] hydrazides
Step according to embodiment 4 (c); but with N-[2-(1-naphthyl) thiazole-4-base carbonyl]-N '-[N-(4-tert-butoxycarbonyl-1-piperazine carbonyl)-L-leucyl-] hydrazides replacement N-methyl-N-(4-pyridine radicals methoxycarbonyl)-L-leucine tert-butoxycarbonyl ester; be prepared as the title compound (47mg, 54%) of white solid.MS(ESI)：495.2(M+H) +。
Embodiment 82N-[4-methyl-2-(4-phenoxy group) phenyl valeryl]-preparation of N '-[2-(1-naphthyl) thiazole-4-base carbonyl] hydrazides
According to the step of embodiment 17 (a)-17 (c), but replace the 4-Phenoxyphenylacetic acid of step (a), be prepared as the title compound (134mg, 67%) of white solid with the 4-Phenoxyphenylacetic acid.MS(ESI)：536.2(M+H) +。
Embodiment 83N-[2-[N-is two-(cyclopropyl methyl) amino] and thiazole-4-base carbonyl]-a) two-(cyclopropyl methyl) amine of the preparation of N '-[N-(2-pyridine radicals methoxycarbonyl)-L-leucyl-] hydrazides
According to the step of embodiment 9 (a), but replace cyclopropylamine, be prepared as the title compound (2.5g, 96%) of colourless liquid with the amino methyl cyclopropane.MS(ESI)：125.8(M+H) +。B) N-[2-[N-pair-(cyclopropyl methyl) amino] thiazole-4-base carbonyl]-N '-[N-(2-pyridine radicals methoxycarbonyl)-L-leucyl-] hydrazides
Step according to embodiment 1 (a)-1 (h), but replace suitable-2 of step (a) with two-(cyclopropyl methyl) amine, the 6-thebaine also replaces the 4-pyridine radicals methanol of step (f) with 2-pyridine radicals methanol, be prepared as the title compound (115mg, 30%) of yellow solid.MS(ESI)：515.3(M+H) +。
Embodiment 84N-[2-[N-cyclopropyl-N-cyclopropyl methylamino) thiazole-4-base carbonyl]-preparation of N '-[N-(2-quinoline acyl group)-L-leucyl-] hydrazides
According to the step of embodiment 56 (a)-56 (b), but replace the pyridine carboxylic acid of step (b), be prepared as the title compound (125mg, 59%) of white solid with quinaldinic acid.MS(ESI)：521.2(M+H) +。
Embodiment 85N-[N-(8-quinoline acyl group)-L-leucyl-]-a) N-[2-(8-quinolyl) thiazole-4-base carbonyl of the preparation of N '-[2-(8-quinolyl) thiazole-4-base carbonyl] hydrazides] hydrazides
According to the step of embodiment 3 (a)-3 (f), but replace the 1-bromo-4-methyl naphthalene of step (d), be prepared as the title compound (0.306g, 100%) of faint yellow solid with 8-bromo quinoline.MS(ESI)：271.2(M+H) +。B) N-[N-(8-quinoline acyl group)-L-leucyl-]-N '-[2-(8-quinolyl) thiazole-4-base carbonyl] hydrazides
According to the step of embodiment 59 (b)-59 (d), but with N-[2-(8-quinolyl) thiazole-4-base carbonyl] hydrazides replaces N-[2-(1-naphthyl) thiazole-4-base carbonyl of step (b)] hydrazides, be prepared as the title compound (0111g, 66%) of white solid.MS(ESI)：539.2(M+H) +。
Embodiment 86N-(N-benzyloxycarbonyl-L-leucyl-]-preparation of N '-[2-(1-naphthyl) thiazole-4-base carbonyl] hydrazides
Step according to embodiment 3 (a)-3 (c) and 3 (e)-3 (g), but the 4-methyl isophthalic acid-naphthalene boronic acids that replaces step (e) with 1-naphthyl boric acid, and with N-(4-pyridine radicals the methoxycarbonyl)-L-leucine of N-benzyloxycarbonyl-L-leucine in place step (g), be prepared as the title compound (0.145g, 60%) of white solid.MS(ESI)：517.3(M+H) +。
Embodiment 87N-[2-(N-cyclopropyl-N-cyclopropyl methylamino) thiazole-4-base carbonyl]-preparation of N '-[N-(3-quinoline acyl group)-L-leucyl-] hydrazides
According to the step of embodiment 56 (a)-56 (b), but replace the pyridine carboxylic acid of step (b), be prepared as the title compound (150mg, 75%) of white solid with the 3-quinoline carboxylic acid.MS(ESI)：521.2(M+H) +。
Embodiment 88N-[2-(N-cyclopropyl-N-cyclopropyl methylamino) thiazole-4-base carbonyl]-preparation of N '-[N-(3-isoquinolin acyl group)-L-leucyl-] hydrazides
According to the step of embodiment 56 (a)-56 (b), but replace the pyridine carboxylic acid of step (b), be prepared as the title compound (187mg, 82%) of white solid with the 3-isoquinolinecarboxylic acid.MS(ESI)：521.1(M+H) +。
Embodiment 89N-[2-(N-cyclopropyl-N-cyclopropyl methylamino) thiazole-4-base carbonyl]-preparation of N '-[N-(6-quinoline acyl group)-L-leucyl-] hydrazides
According to the step of embodiment 56 (a)-56 (b), but replace the pyridine carboxylic acid of step (b), be prepared as the title compound (155mg, 59%) of white solid with the 6-quinoline carboxylic acid.MS(ESI)：521.3(M+H) +。
Embodiment 90N-[2-[N-is two-(cyclopropyl methyl) amino] and thiazole-4-base carbonyl]-preparation of N '-[N-(2-methyl-3-pyridine radicals methoxycarbonyl)-L-leucyl-] hydrazides
According to the step of embodiment 83 (a)-83 (b), but replace the 2-pyridine radicals methanol of step (b), be prepared as the title compound (105mg, 46%) of yellow solid with 2-methyl-3-pyridine radicals methanol.MS(ESI)：529.3(M+H) +。
The preparation of embodiment 91N-(N-benzyloxycarbonyl-L-b-tert-butyl group alanyl)-N '-[2-(1-naphthyl) thiazole-4-base carbonyl] hydrazides is the N-benzyloxycarbonyl-L-b-tert-butyl group alanine a)
In 0 ℃, with 1.5 hours, (1.3g, (1.0g is 6.89mmol) in the agitating solution in water (2.1ml) and 5N sodium hydroxide (1.38ml) 7.58mmol) to add L-b-tert-butyl group alanine with 2N sodium hydroxide (3.8ml) with benzyl chloroformate to divide very different parts.Add finish after, under room temperature with this mixture restir 30 minutes.PH is transferred to 10 also extract this mixture with ether (50ml).Water layer is acidified to pH 3 and uses ether (3 * 50ml) extractions with 3N hydrochloric acid.Merge organic layer, dry (magnesium sulfate) filters and concentrates the title compound (1.59g, 83%) that obtains colorless oil.MS(ESI)：278.2(M+H) -。B) N-(N-benzyloxycarbonyl-L-b-tert-butyl group alanyl)-N '-[2-(1-naphthyl) thiazole-4-base carbonyl] hydrazides
Step according to embodiment 3 (a)-3 (c) and 3 (e)-3 (g), but the 4-methyl isophthalic acid-naphthalene boronic acids that replaces step (e) with 1-naphthyl boric acid, and replace N-(4-pyridine radicals the methoxycarbonyl)-L-leucine of step (g) with N-benzyloxycarbonyl-L-tert-butyl group alanine, be prepared as the title compound (0.214g, 87%) of white solid.MS(ESI)：531.3(M+H) +。
The preparation of embodiment 92N-(N-benzyloxycarbonyl-L-cyclopropyl alanyl)-N '-[2-(1-naphthyl) thiazole-4-base carbonyl] hydrazides is N-benzyloxycarbonyl-L-allylglycine a)
According to the step of embodiment 91 (a), but replace L-tert-butyl group alanine, the preparation title compound with the L-allylglycine.B) N-benzyloxycarbonyl-L-cyclopropyl alanine methyl ester
Under room temperature, Azimethylene. (4.8mmol is in the 18ml ether) is added the chemical compound of embodiment 92 (a), and (0.210g is in the solution of 1ml ether 0.48mmol) and stirred 5 minutes.Add Pd (OAc) then 2(2mg), this reactant stirred spend the night, by filtered through silica gel, vacuum concentration obtains being used for without being further purified the required product (205mg, 95%) of next step reaction.MS(ESI)：300.1(M+Na) +。C) N-benzyloxycarbonyl-L-cyclopropyl alanine
According to the step of embodiment 1 (g), but replace N-(4-pyridine radicals methoxycarbonyl)-L-leucine methyl ester, be prepared as the title compound (165mg, 82%) of white solid with N-benzyloxycarbonyl-L-cyclopropyl alanine methyl ester.MS(ESI)：264.2(M+H) +。D) N-(N-benzyloxycarbonyl-L-cyclopropyl alanyl)-N '-[2-(1-naphthyl) thiazole-4-base carbonyl] hydrazides
Step according to embodiment 3 (a)-3 (c) and 3 (e)-3 (g), but the 4-methyl isophthalic acid-naphthalene boronic acids that replaces step (e) with 1-naphthyl boric acid, and replace N-(4-pyridine radicals the methoxycarbonyl)-L-leucine of step (g) with N-benzyloxycarbonyl-(L)-tert-butyl group alanine, be prepared as the title compound (0.054g, 67%) of white solid.MS(ESI)：515.2(M+H) +。
Embodiment 93N-[2-(1-naphthyl) thiazole-4-base carbonyl]-N '-[N-[3-(2-pyridine radicals) phenyl acetyl]-L-leucyl-] a) the 3-9 trifluoromethyl sulfonyloxy phenylacetic acid methyl ester of preparation of hydrazides
Under argon, anhydrous pentane (20ml) added contain sodium hydride (2.54g, 60% dispersion in mineral oil is in the flask of oven drying 63.5mmol).Stirred this slurry 5 minutes, and made precipitation, remove most of pentane and add anhydrous THF (40ml).(9.99g, anhydrous THF (20ml) solution 60.1mmol) also stirred this reactant 20 minutes under room temperature to add 3-hydroxyphenyl acetic acid methyl ester in this suspension.(22.53g, anhydrous THF (40ml) solution 63.1mmol) also stirs this reactant and analyzes indication raw material full consumption (1.5 hours) until TLC under room temperature to add N-phenyl trifluoromethyl sulfimide then in this mixture.Make this reactant quenching by adding entry (10ml), be concentrated into half of original volume.Use CHCl then 3(200ml) dilute and wash with water.With new CHCl 3(50ml) washing water layer, with the organic layer that 10% sodium carbonate, water and salt water washing merge, dry (magnesium sulfate) then filters and concentrates.Residue is through column chromatography (silica gel, 5: 95 ethyl acetate: hexane, 10: 90 ethyl acetate then: hexane), obtain the 17.47g title compound. 1H?NMR(400MHz，CDCl 3)d7.42(m，1H)，7.31-7.19(m，3H)，3.72(s，3H)，3.68(s，2H)。B) 3-(2-pyridine radicals) phenylacetic acid methyl ester
With 2-pyridine radicals stannane (8.89g, 24.1mmol), lithium chloride (2.94g, 69.3mmol), 2,6-di-tert-butyl-4-methy phenol (some crystallizations) and Pd (PPh 3) 4(632.1mg, 0.55mmol) (6.86g is in the solution of anhydrous dioxane (100ml) 23.0mmol) for the chemical compound of adding embodiment 93 (a).This reactant is used the metal forming shading and heated overnight under refluxing.This reactant is cooled to room temperature and concentrated.Residue is through column chromatography (silica gel, 1: 3 ethyl acetate: hexane, 1: 2 ethyl acetate then: hexane), obtain the 3.85g title compound, MS (ESI): 228.1 (M+H) +C) 3-(2-pyridine radicals) phenylacetic acid
According to the step of embodiment 1 (g), but replace N-(4-pyridine radicals methoxycarbonyl)-L-leucine methyl ester, the preparation title compound with 3-(2-pyridine radicals) phenylacetic acid methyl ester.MS(ESI)：214.3(M+H) +。E) N-[2-(1-naphthyl) thiazole-4-base carbonyl]-N '-[N-[3-(2-pyridine radicals) phenyl acetyl]-L-leucyl-] hydrazides
Step according to embodiment 3 (a)-3 (c) and 3 (e)-3 (g), but the 4-methyl isophthalic acid-naphthalene boronic acids that replaces step (e) with 1-naphthyl boric acid, and replace N-(4-pyridine radicals the methoxycarbonyl)-L-leucine of step (g) with 3-(2-pyridine radicals) phenylacetic acid, be prepared as the title compound (0.149g, 79%) of white solid.MS(ESI)：578.1(M+H) +。
Embodiment 94N-[2-[N-is two-(cyclopropyl methyl) amino] thiazole-4-base carbonyl]-N '-(N-picolyl-L-leucyl-] hydrazides preparation a) N-[2-[N-two-(cyclopropyl methyl) amino] thiazole-4-base carbonyl]-N '-(N-tert-butoxycarbonyl-L-leucyl-] hydrazides
Step according to embodiment 1 (a)-1 (d) and 1 (h), but replace suitable-2 of step (a) with two-(cyclopropyl methyl) amine cyclopropylamine, the 6-thebaine is prepared as the title compound of orange also with N-(4-pyridine radicals the methoxycarbonyl)-L-leucine of N-tert-butoxycarbonyl-L-leucine in place step (h).MS(ESI)：480.3(M+H) +。B) N-[2-[N-pair-(cyclopropyl methyl) amino] thiazole-4-base carbonyl]-N '-(N-picolyl-L-leucyl-] hydrazides
Step according to embodiment 56 (a)-56 (b); but with N-[2-[N-two-(cyclopropyl methyl) amino] thiazole-4-base carbonyl]-N '-(N-tert-butoxycarbonyl-L-leucyl-] hydrazides replaces N-[2-(N-cyclopropyl-N-cyclopropyl methylamino) thiazole-4-base carbonyl of step (a)]-N '-(N-tert-butoxycarbonyl-L-leucyl-] hydrazides; be prepared as the title compound (74mg, 41%) of yellow solid.MS(ESI)：485.3(M+H) +。
Embodiment 95N-(N-benzyloxycarbonyl-L-leucyl-)-N '-[2-[N-two-(cyclopropyl methyl) amino] thiazole-4-base carbonyl] preparation of hydrazides
Step according to embodiment 1 (a)-1 (d) and 1 (h), but replace suitable-2 of step (a) with two-(cyclopropyl methyl) amine, the 6-thebaine is also used N-(4-pyridine radicals the methoxycarbonyl)-L-leucine of N-benzyloxycarbonyl-L-leucine in place step (h), be prepared as the title compound (140mg, 69%) of yellow solid.MS(ESI)：514.3(M+H) +。
Embodiment 96N-[2-(N-cyclopropyl-N-cyclopropyl methylamino) thiazole-4-base carbonyl]-a) 6-methylnicotinic acid of the preparation of N '-[N-(6-methyl nicotinoyl)-L-leucyl-] hydrazides
According to the step of embodiment 1 (g), but replace N-(4-pyridine radicals methoxycarbonyl)-L-leucine methyl ester, be prepared as the title compound (506mg, 100%) of white solid with 6-methylnicotinic acid methyl ester.MS(ESI)：137.9(M+H) +。B) N-[2-(N-cyclopropyl-N-cyclopropyl methylamino) thiazole-4-base carbonyl]-N '-[N-(4-methyl nicotinoyl)-L-leucyl-] hydrazides
According to the step of embodiment 56 (a)-56 (b), but replace the pyridine carboxylic acid of step (b), be prepared as the title compound (150mg, 41%) of white solid with the 6-methylnicotinic acid.MS(ESI)：485.4(M+H) +。
Embodiment 97N-[2-(N-cyclopropyl-N-cyclopropyl methylamino) thiazole-4-base carbonyl]-a) 2-methylnicotinic acid of the preparation of N '-[N-(2-methyl nicotinoyl)-L-leucyl-] hydrazides
According to the step of embodiment 1 (g), but replace N-(4-pyridine radicals methoxycarbonyl)-L-leucine methyl ester, be prepared as the title compound (1.6g, 100%) of white solid with 2-methylnicotinic acid methyl ester.MS(ESI)：138.2(M+H) +。B) N-[2-(N-cyclopropyl-N-cyclopropyl methylamino) thiazole-4-base carbonyl]-N '-[N-(2-methyl nicotinoyl)-L-leucyl-] hydrazides
According to the step of embodiment 56 (a)-56 (b), but replace the pyridine carboxylic acid of step (b), be prepared as the title compound (170mg, 71%) of white solid with the 2-methylnicotinic acid.MS(ESI)：485.3(M+H) +。
Embodiment 98N-[2-(N-cyclopropyl-N-cyclopropyl methylamino) thiazole-4-base carbonyl]-N '-[N-(the different nicotinoyl of 3-methyl]-L-leucyl-] preparation of hydrazides
According to the step of embodiment 56 (a)-56 (b), but replace the pyridine carboxylic acid of step (b), be prepared as the title compound (120mg, 57%) of white solid with 2-picoline-4-carboxylic acid.MS(ESI)：485.2(M+H) +。
Embodiment 99N-[2-(N-cyclopropyl-N-cyclopropyl methylamino) thiazole-4-base carbonyl]-preparation of N '-[N-(8-quinoline acyl group)-L-leucyl-] hydrazides
According to the step of embodiment 56 (a)-56 (b), but replace the pyridine carboxylic acid of step (b), be prepared as the title compound (200mg, 94%) of white solid with 8-Quinoline Carboxylic Acid.MS(ESI)：521.2(M+H) +。
Embodiment 100N-[2-[N-is two-(cyclopropyl methyl) amino] and thiazole-4-base carbonyl]-preparation of N '-[N-(8-quinoline acyl group)-L-leucyl-] hydrazides
Step according to embodiment 56 (a)-56 (b); but with N-[2-[N-two-(cyclopropyl methyl) amino] thiazole-4-base carbonyl]-N '-(N-tert-butoxycarbonyl-L-leucyl-) hydrazides replaces N-[2-(N-cyclopropyl-N-cyclopropyl methylamino) thiazole-4-base carbonyl of step (a)]-N '-(N-tert-butoxycarbonyl-L-leucyl-) hydrazides; and replace the pyridine carboxylic acid of step (b) with 8-Quinoline Carboxylic Acid; be prepared as the title compound (25mg, 12%) of yellow solid.MS(ESI)：533.3(M+H) +。
Embodiment 101N-[2-[N-is two-(cyclopropyl methyl) amino] and thiazole-4-base carbonyl]-preparation of N '-[N-(3-isoquinolin acyl group)-L-leucyl-] hydrazides
Step according to embodiment 56 (a)-56 (b); but with N-[2-[N-two-(cyclopropyl methyl) amino] thiazole-4-base carbonyl]-N '-(N-tert-butoxycarbonyl-L-leucyl-] hydrazides replaces N-[2-(N-cyclopropyl-N-cyclopropyl methylamino) thiazole-4-base carbonyl of step (a)]-N '-(N-tert-butoxycarbonyl-L-leucyl-] hydrazides; and replace the pyridine carboxylic acid of step (b) to be prepared as the title compound (25mg, 10%) of yellow solid with the 3-isoquinolinecarboxylic acid.MS(ESI)：535.3(M+H) +。
Embodiment 102N-[2-[4-(2, the 2-dimethylamino ethoxy)-1-naphthyl] thiazole-4-base carbonyl]-N '-(N-(8-quinoline acyl group)-L-leucyl-] a) 4-bromo-1-naphthols of preparation of hydrazides
In-78 ℃, n-BuLi (2.5M is in hexane for 22.3ml, 56.4mmol) is added drop-wise to 1, (15.3g is in the suspension of the vigorous stirring of hexane/THF 53.7mmol) (300ml) for 4-two naphthalene bromides.After 30 minutes, slowly add two (TMS) peroxide (11g, 61.8mmol) [Taddei, M., Ricci, A., Synthesis, 1986,633] in-78 ℃ of restir by syringe.Be warmed to room temperature and restir after 3 hours, dilute this mixture and use 1NHCl, then use the salt water washing with ethyl acetate.Dry (magnesium sulfate) organic layer filters and concentrates.(silica gel, ethyl acetate: purification hexane) obtains the title compound (6.5g, 54%) into pale solid to residue through column chromatography.MS(ESI)：221.1(M+H) -。B) 4-bromo-1-naphthyl uncle butyl ether
According to the step of embodiment 39 (a), but replace 4-bromomethyl benzoic acid, be prepared as the title compound (2.34g, 62%) of colorless oil with 4-bromo-1-naphthols. 1H?NMR(400MHz，CDCl 3)d8.28(d，1H)，8.18(d，1H)，7.67(d，1H)，7.60(t，1H)，7.54(t，1H)，7.01(d，1H)，1.51(s，9H)。C) 2-(4-tert-butoxy-1-naphthyl] thiazole-4-carboxylic acid ethyl ester
According to the step of embodiment 3 (a)-3 (e), but replace the 1-bromo-4-methyl naphthalene of step (d), be prepared as the title compound (0.783g, 67%) of white solid with 4-bromo-1-naphthyl uncle butyl ether.MS(ESI)：356.2(M+H) +。D) 2-(4-hydroxyl-1-naphthyl) thiazole-4-carboxylic acid ethyl ester
Step according to embodiment 4 (c), but replace N-methyl-N-(4-pyridine radicals methoxycarbonyl)-L-leucine tert-butoxycarbonyl ester with 2-(4-tert-butoxy-1-naphthyl) thiazole-4-carboxylic acid ethyl ester, be prepared as the title compound (0.580g, 88%) of yellow solid.MS(ESI)：300.1(M+H) +。E) 2-[4-(2-N, N-dimethylamino ethoxy)-1-naphthyl] thiazole-4-carboxylic acid ethyl ester
Step according to embodiment 28 (d), but with 2-(4-hydroxyl-1-naphthyl] thiazole-4-carboxylic acid ethyl ester replaces 2-(2-hydroxyl-1-naphthyl) thiazole-4-carboxylic acid ethyl ester and with 2-(N, the N-dimethylamino) ethanol replaces benzyl alcohol, is prepared as the title compound (0.097g, 52%) of white solid.MS(ESI)：371.3(M+H) +。F) N-(8-quinoline acyl group)-L-leucine methyl ester
Step according to embodiment 1 (h), but replace N-[2-(suitable-2 with L-leucine methyl ester hydrochloride, 6-dimethyl-4-morpholinyl) thiazole-4-base carbonyl] hydrazides and replace N-(4-pyridine radicals methoxycarbonyl)-L-leucine with 8-Quinoline Carboxylic Acid, be prepared as the title compound (0.637g, 41%) of white solid.MS(ESI)：301.2(M+H) +。G) N-(8-quinoline acyl group)-L-leucine
According to the step of embodiment 1 (g), but replace N-(4-pyridine radicals methoxycarbonyl)-L-leucine methyl ester, be prepared as the title compound (0.150g, 25%) of white solid with N-(8-quinoline acyl group)-L-leucine methyl ester. 1H?NMR(400MHz，CDCl 3)d?8.89(t，1H)，8.78(d，1H)，8.21(d，1H)，7.90(d，1H)，7.57(t，1H)，7.43(t，1H)，4.88(m，1H)，1.92(m，3H)，1.03(m，6H)。H) N-[2-[4-(2, the 2-dimethylamino ethoxy)-1-naphthyl] thiazole-4-base carbonyl] hydrazides
Step according to embodiment 1 (d), but with 2-[4-(2-N, N-dimethylamino ethoxy)-1-naphthyl] thiazole-4-carboxylic acid ethyl ester replaces 2-(suitable-2,6-dimethyl-4-morpholinyl) thiazole-4-carboxylic acid ethyl ester, be prepared as the title compound (0.091g, 100%) of yellow solid.MS(ESI)：357.2(M+H) +。I) N-[2-[4-(2, the 2-dimethylamino ethoxy)-1-naphthyl] thiazole-4-base carbonyl]-N '-[N-(8-quinoline acyl group)-L-leucyl-] hydrazides
Step according to embodiment 1 (h); but with N-[2-[4-(2; the 2-dimethylamino ethoxy)-and the 1-naphthyl] thiazole-4-base carbonyl] hydrazides replacement N-[2-(suitable-2; 6-dimethyl-4-morpholinyl) thiazole-4-base carbonyl] hydrazides and usefulness N-(8-quinoline acyl group)-L-leucine in place N-(4-pyridine radicals methoxycarbonyl)-L-leucine; be prepared as the title compound (0.050g, 31%) of yellow solid.MS(ESI)：625.2(M+H) +。
Embodiment 103N-[2-(N-cyclopropyl-N-cyclopropyl methylamino) thiazole-4-base carbonyl]-N '-[N-(7-quinoline acyl group]-L-leucyl-] preparation of hydrazides
According to the step of embodiment 56 (a)-56 (b), but replace the pyridine carboxylic acid of step (b) to be prepared as the title compound (100mg, 50%) of white solid with the 7-quinoline carboxylic acid.MS(ESI)：521.2(M+H) +。
Embodiment 104N-[2-[N-is two-(cyclopropyl methyl) amino] and thiazole-4-base carbonyl]-preparation of N '-[N-(6-methyl nicotinoyl)-L-leucyl-] hydrazides
Step according to embodiment 56 (a)-56 (b); but with N-[2-[N-two-(cyclopropyl methyl) amino] thiazole-4-base carbonyl]-N '-(N-tert-butoxycarbonyl-L-leucyl-) hydrazides replaces N-[2-(N-cyclopropyl-N-cyclopropyl methylamino) thiazole-4-base carbonyl of step (a)]-N '-(N-tert-butoxycarbonyl-L-leucyl-) hydrazides; and replace the pyridine carboxylic acid of step (b) with the 6-methylnicotinic acid; be prepared as the title compound (40mg, 15%) of yellow solid.MS(ESI)：499.3(M+H) +。
Embodiment 105N-[2-[N-is two-(cyclopropyl methyl) amino] and thiazole-4-base carbonyl]-preparation of N '-(N-methyl-L-prolyl-L-leucyl-) hydrazides
According to the step of embodiment 56 (a)-56 (b), but replace the pyridine carboxylic acid of step (b), be prepared as the title compound (62mg, 48%) of white solid with N-methyl-L-proline.MS(ESI)：477.3(M+H) +。
The preparation of embodiment 106N-(N-benzyloxycarbonyl-L-is norvalyl)-N '-[2-(1-naphthyl) thiazole-4-base carbonyl] hydrazides
Step according to embodiment 3 (a)-3 (c) and 3 (e)-3 (g), but the 4-methyl isophthalic acid-naphthalene boronic acids that replaces step (e) with 1-naphthyl boric acid, and replace N-(4-pyridine radicals the methoxycarbonyl)-L-leucine of step (g) with N-benzyloxycarbonyl-L-norvaline, be prepared as the title compound (180mg, 96%) of white solid.MS(ESI)：503.2(M+H) +。
The preparation of embodiment 107N-(N-benzyloxycarbonyl-L-isoleucyl-)-N '-[2-(1-naphthyl) thiazole-4-base carbonyl] hydrazides
Step according to embodiment 3 (a)-3 (c) and 3 (e)-3 (g), but the 4-methyl isophthalic acid-naphthalene boronic acids that replaces step (e) with 1-naphthyl boric acid, and replace N-(4-pyridine radicals the methoxycarbonyl)-L-leucine of step (g) with N-benzyloxycarbonyl-L-isoleucine, be prepared as the title compound (167mg, 87%) of white solid.MS(ESI)：517.1(M+H) +。
Embodiment 108N-[N-(4-dimethylaminomethyl benzoyl)-L-leucyl-]-a) 4-(N, N-dimethylaminomethyl) essence of Niobe of the preparation of N '-[2-(1-naphthyl) thiazole-4-base carbonyl] hydrazides
(2.0g 8.73mmol) adds in the methanol solution of saturated dimethylamine with 4-(bromomethyl) essence of Niobe.Stir after 25 minutes, concentrate this solution and residue is distributed between 1N sodium hydroxide and ethyl acetate.Wash organic layer with saturated brine, dry (magnesium sulfate), filtration also concentrate the title compound (1.67g, 99%) that obtains to colourless liquid. 1H?NMR(250MHz，CDCl 3)d8.00(d，2E)，7.39(d，2H)，3.91(s，3H)，3.47(d，2H)，2.25(s，6H)。B) 4-(N, N-dimethylaminomethyl) benzoic acid
According to the step of embodiment 1 (g), but replace N-(4-pyridine radicals methoxycarbonyl)-L-leucine methyl ester, be prepared as the title compound (1.6g, 100%) of white solid with 4-(N, N-dimethylaminomethyl) essence of Niobe. 1H?NMR(400MHz，CD 3OD)d7.94(d，2H)，7.36(d，2H)，3.64(s，2H)，2.35(s，6H)。C) N-[N-(4-dimethylaminomethyl benzoyl)-L-leucyl-]-preparation of N '-[2-(1-naphthyl) thiazole-4-base carbonyl] hydrazides
According to the step of embodiment 59 (a)-59 (d), but replace the 8-Quinoline Carboxylic Acid of step (d), be prepared as the title compound (87mg, 61%) of white solid with 4-(N, N-dimethylaminomethyl) benzoic acid.MS(ESI)：544.2(M+H) +。
The preparation of embodiment 109N-(N-benzyloxycarbonyl-L-norleucyl-)-N '-[2-(1-naphthyl) thiazole-4-base carbonyl] hydrazides
Step according to embodiment 3 (a)-3 (c) and 3 (e)-3 (g), but the 4-methyl isophthalic acid-naphthalene boronic acids that replaces step (e) with 1-naphthyl boric acid, and replace N-(4-pyridine radicals the methoxycarbonyl)-L-leucine of step (g) with N-benzyloxycarbonyl-L-nor-leucine, be prepared as the title compound (184mg, 96%) of white solid.MS(ESI)：517.1(M+H) +。
Embodiment 110N-[N-(4-dimethylaminomethyl benzyloxycarbonyl)-L-leucyl-)-a) 4-(N, N-dimethylamino) benzyl alcohol of the preparation of N '-[2-(1-naphthyl) thiazole-4-base carbonyl] hydrazides
(8.4mmol, 8.4ml) solution adds embodiment 108 (a) chemical compound be cooled to 0 ℃ (1.63g is in the agitating solution of 25ml ether 8.4mmol) with the 1M lithium aluminium hydride reduction.After 5 minutes, make the reactant quenching by adding entry (0.33ml), 15% sodium hydrate aqueous solution (0.33ml) and water (1.0ml).Remove by filter precipitation, wash twice and concentrated filtrate with ether and obtain title compound (1.36g, 98%) into colorless oil. 1H?NMR(250MHz，CDCl 3)d7.32(d，2H)，7.28(d，2H)，4.68(s，2H)，3.41(s，2H)，2.22(s，6H)。B) N-[N-(4-dimethylaminomethyl benzyloxycarbonyl)-L-leucyl-]-N '-[2-(1-naphthyl) thiazole-4-base carbonyl] hydrazides
Step according to embodiment 1 (e)-1 (h), but with 4-(N, the N-dimethylamino) benzyl alcohol replaces the 4-pyridine radicals methanol of step (f) and uses N-[2-(1-naphthyl) thiazole-4-base carbonyl] hydrazides, replace N-[2-(suitable-2,6-dimethyl-4-morpholinyl) thiazole-4-base carbonyl] hydrazides, be prepared as the title compound (186mg, 87%) of white solid.MS(ESI)：574.3(M+H) +。
The preparation of embodiment 111N-(N-benzyloxycarbonyl-L-is norvalyl)-N '-[2-(2-benzyloxy phenyl) thiazole-4-base carbonyl] hydrazides
According to the step of embodiment 27 (a)-27 (c), but replace 2-(3-the phenyl)-4-methylvaleric acid of step (c), be prepared as the title compound of white solid with N-benzyloxycarbonyl-L-norvaline.MS(ESI)：559.0(M+H) +。
Embodiment 112N-[2-(N-cyclopropyl-N-cyclopropyl methylamino) thiazole-4-base carbonyl]-N '-[N-(4-methylimidazole-5-base carbonyl]-L-leucyl-] preparation of hydrazides
According to the step of embodiment 56 (a)-56 (b), but replace the pyridine carboxylic acid of step (b), be prepared as the title compound (100mg, 65%) of white solid with 4-methylimidazole-5-carboxylic acid.MS(ESI)：474.3(M+H) +。
Embodiment 113N-[N-[4-(4-morpholinyl methyl) benzoyl]-the L-leucyl-]-preparation of N '-[2-(1-naphthyl) thiazole-4-base carbonyl] hydrazides
According to the step of embodiment 108 (a)-108 (c), but with morpholino for the dimethylamine of step (a), be prepared as the title compound (0.097g, 51%) of white solid.MS(ESI)：586.2(M+H) +。
Embodiment 114N-[N-(2-methyl nicotinoyl)-L-leucyl-]-preparation of N '-[2-(1-naphthyl) thiazole-4-base carbonyl] hydrazides
According to the step of embodiment 59 (a)-59 (d), but replace the 8-Quinoline Carboxylic Acid of step (d), be prepared as the title compound (0.103g, 60%) of white solid with the 2-methylnicotinic acid.MS(ESI)：502.2(M+H) +。
Embodiment 115N-[N-(6-methyl nicotinoyl)-L-leucyl-]-preparation of N '-[2-(1-naphthyl) thiazole-4-base carbonyl] hydrazides
According to the step of embodiment 59 (a)-59 (d), but replace the 8-Quinoline Carboxylic Acid of step (d), be prepared as the title compound (0.134g, 79%) of white solid with the 6-methylnicotinic acid.MS(ESI)：502.2(M+H) +。
Embodiment 116N-[N-(4-methylimidazole-5-base carbonyl)-L-pi-allyl glycyl]-a) N-tert-butoxycarbonyl-L-allylglycine of the preparation of N '-[2-(1-naphthyl) thiazole-4-base carbonyl] hydrazides
(12.5g, (6.28g is in the agitating solution of dioxane/water 54.5mmol)/1N sodium hydroxide (110ml/55ml/55ml) 57.2mmol) to add the L-allylglycine with two carbonic acid, two-tert-butyl ester in 0 ℃.Stir after 30 minutes, concentrate this solution, and be dissolved in again in the 60ml water.Add ethyl acetate layer and use 0.3N potassium acid sulfate acidify water layer to pH 3.Extract the water-bearing layer with ethyl acetate (2 *).Merge organic layer, water (2 *) washing, dry (magnesium sulfate), filtration also concentrate the title compound (10.11g, 86%) that obtains to white solid.MS(ESI)：453.2(2M+Na) +。B) N-[N-(4-methylimidazole-5-base carbonyl)-L-pi-allyl glycyl]-N '-[2-(1-naphthyl) thiazole-4-base carbonyl] hydrazides
Step according to embodiment 59 (a)-59 (d), but replace the N-tert-butoxycarbonyl-L-leucine of step (b) and use 4-methylimidazole-5-carboxylic acid to replace the 8-Quinoline Carboxylic Acid of step (d) with N-tert-butoxycarbonyl-L-allylglycine, be prepared as the title compound (0.112g, 67%) of white solid.MS(ESI)：475.1(M+H) +。
The preparation of embodiment 117N-(N-b-tert-butoxycarbonyl-L-tert-butyl group alanyl)-N '-[2-(N-cyclopropyl-N-cyclopropyl methylamino) thiazole-4-base carbonyl] hydrazides is the N-tert-butoxycarbonyl-L-b-tert-butyl group alanine a)
According to the step of embodiment 116 (a), but replace the L-allylglycine, be prepared as the title compound (2.36g, 70%) of white solid with L-tert-butyl group alanine.MS(ESI)：268.3(M+Na) +。B) N-(N-b-tert-butoxycarbonyl-L-tert-butyl group alanyl)-N '-[2-(N-cyclopropyl-N-cyclopropyl methylamino) thiazole-4-base carbonyl] hydrazides
Step according to embodiment 1 (a)-1 (d) and 1 (h), but replace suitable-2 of step (a) with N-cyclopropyl methyl cyclopropylamine, the 6-thebaine also uses N-tert-butoxycarbonyl-L-b-tert-butyl group alanine to replace N-(4-pyridine radicals the methoxycarbonyl)-L-leucine of step (h), be prepared as the title compound (0.96g, 100%) of white solid.MS(ESI)：480.3(M+H) +。
Embodiment 118N-[2-(N-cyclopropyl-N-cyclopropyl methylamino) thiazole-4-base carbonyl]-preparation of N '-[N-(8-quinoline acyl group)-L-b-tert-butyl group alanyl] hydrazides
Step according to embodiment 56 (a)-56 (b); but with N-(N-b-tert-butoxycarbonyl-L-tert-butyl group alanyl]-N '-[2-(N-cyclopropyl-N-cyclopropyl methylamino) thiazole-4-base carbonyl] hydrazides replaces N-[2-(N-cyclopropyl-N-cyclopropyl methylamino) thiazole-4-base carbonyl of step (a)]-N '-(N-tert-butoxycarbonyl-L-leucyl-) hydrazides; and replace the pyridine carboxylic acid of step (b) with 8-Quinoline Carboxylic Acid; be prepared as the title compound (160mg, 82%) of white solid.MS(ESI)：535.3(M+H) +。
Embodiment 119N-[N-(4-methylimidazole-5-base carbonyl)-L-b-tert-butyl group alanyl]-preparation of N '-[2-(1-naphthyl) thiazole-4-base carbonyl] hydrazides
Step according to embodiment 59 (a)-59 (d), but replace the N-tert-butoxycarbonyl-L-leucine of step (b) and use 4-methylimidazole-5-carboxylic acid to replace the 8-Quinoline Carboxylic Acid of step (d) with N-tert-butoxycarbonyl-L-b-tert-butyl group alanine, be prepared as the title compound (0.096g, 58%) of white solid.MS(ESI)：505.2(M+H) +。
Embodiment 120N-[2-(N-cyclopropyl-N-cyclopropyl methylamino) thiazole-4-base carbonyl]-preparation of N '-[N-(4-methylimidazole-5-base carbonyl)-L-b-tert-butyl group alanyl] hydrazides
Step according to embodiment 56 (a)-56 (b); but replace N-[2-(N-cyclopropyl-N-cyclopropyl methylamino) thiazole-4-base carbonyl of step (a) with N-(N-b-tert-butoxycarbonyl-L-tert-butyl group alanyl)-N '-[2-(N-cyclopropyl-N-cyclopropyl methylamino) thiazole-4-base carbonyl] hydrazides]-N '-(N-tert-butoxycarbonyl-L-leucyl-] hydrazides; and replace the pyridine carboxylic acid of step (b) with 4-methylimidazole-5-carboxylic acid; be prepared as the title compound (180mg, 78%) of white solid.MS(ESI)：488.2(M+H) +。
Embodiment 121N-[2-(1-naphthyl) thiazole-4-base carbonyl]-preparation of N '-(N-picoline acyl group-L-b-tert-butyl group alanyl) hydrazides
Step according to embodiment 59 (a)-59 (d), but replace the N-tert-butoxycarbonyl-L-leucine of step (b) and replace the 8-Quinoline Carboxylic Acid of step (d) with pyridine carboxylic acid with N-tert-butoxycarbonyl-L-b-tert-butyl group alanine, be prepared as the title compound (0.098g, 62%) of white solid.MS(ESI)：502.3(M+H) +。
Embodiment 122N-[2-(1-naphthyl) thiazole-4-base carbonyl]-preparation of N '-[N-(8-quinoline acyl group)-L-b-tert-butyl group alanyl] hydrazides
According to the step of embodiment 59 (a)-59 (d), but replace the N-tert-butoxycarbonyl-L-leucine of step (b), be prepared as the title compound (0.083g, 46%) of white solid with N-tert-butoxycarbonyl-L-b-tert-butyl group alanine.MS(ESI)：552.2(M+H) +。
Embodiment 123N-[2-(1-naphthyl) thiazole-4-base carbonyl]-N '-(N-picoline acyl group-L-pi-allyl glycyl] preparation of hydrazides
Step according to embodiment 59 (a)-59 (d), but replace the N-tert-butoxycarbonyl-L-leucine of step (b) and replace the 8-Quinoline Carboxylic Acid of step (d) with pyridine carboxylic acid with N-tert-butoxycarbonyl-L-allylglycine, be prepared as the title compound (0.141g, 84%) of white solid.MS(ESI)：472.2(M+H) +。
Embodiment 124N-[2-(1-naphthyl) thiazole-4-base carbonyl]-N '-(N-picoline acyl group-L-b-cyclopropyl alanyl] a) N-tert-butoxycarbonyl-L-b-cyclopropyl alanine methyl ester of preparation of hydrazides
In 0 ℃, Azimethylene. (in 0 ℃ by the preparation of 10 eq 1-methyl-3-nitro-1-nitrosoguanidines in ether (500ml) and 40% sodium hydroxide (500ml)) solution is added the chemical compound of embodiment 116 (a), and (7.81g is in the agitating solution of ether 36.3mmol) (100ml).Stir after 10 minutes, Pd (OAc) 2(0.300g) add in this solution.After 20 minutes, concentrate this solution, residue filters to remove the not catalyst of usefulness by a short silica gel stick harness.Concentrate this solution and obtain being the buttery title compound of golden yellow (8.29g, 99%). 1HNMR(400MHz，CDCl 3)d5.17(d，1H)，4.39(m，1H)，3.73(s，3H)，1.66(t，2H)，1.44(s，9H)，0.68(m，1H)，0.49(m，2H)，0.08(m，2H)。B) N-tert-butoxycarbonyl-L-b-cyclopropyl alanine
According to the step of embodiment 1 (g), but replace N-(4-pyridine radicals methoxycarbonyl)-L-leucine methyl ester, be prepared as the title compound (6.37g, 82%) of golden yellow grease with N-tert-butoxycarbonyl-L-b-cyclopropyl alanine methyl ester.MS(ESI)：252.3(M+Na) +。C) N-[2-(1-naphthyl) thiazole-4-base carbonyl]-N '-(N-picoline acyl group-L-cyclopropyl alanyl) hydrazides
Step according to embodiment 59 (a)-59 (d), but replace the N-tert-butoxycarbonyl-L-leucine of step (b) and replace the 8-Quinoline Carboxylic Acid of step (d) with pyridine carboxylic acid with N-tert-butoxycarbonyl-L-b-cyclopropyl alanine, be prepared as the title compound (0.114g, 71%) of white solid.MS(ESI)：486.1(M+H) +。
Embodiment 125N-[N-(6-methyl nicotinoyl)-L-b-cyclopropyl alanyl]-preparation of N '-[2-(1-naphthyl) thiazole-4-base carbonyl] hydrazides
Step according to embodiment 59 (a)-59 (d), but replace the N-tert-butoxycarbonyl-L-leucine of step (b) and use the 6-methylnicotinic acid to replace the 8-Quinoline Carboxylic Acid of step (d) with N-tert-butoxycarbonyl-L-b-cyclopropyl alanine, be prepared as the title compound (0.097g, 59%) of white solid.MS(ESI)：500.1(M+H) +。
Embodiment 126N-[N-(4-methylimidazole-5-base carbonyl)-L-b-cyclopropyl alanyl]-preparation of N '-[2-(1-naphthyl) thiazole-4-base carbonyl] hydrazides
Step according to embodiment 59 (a)-59 (d), but replace the N-tert-butoxycarbonyl-L-leucine of step (b) and use 4-methylimidazole-5-carboxylic acid to replace the 8-Quinoline Carboxylic Acid of step (d) with N-tert-butoxycarbonyl-L-b-cyclopropyl alanine, be prepared as the title compound (0.095g, 59%) of white solid.MS(ESI)：489.1(M+H) +。
Embodiment 127N-[2-(1-naphthyl) thiazole-4-base carbonyl]-preparation of N '-[N-(8-quinoline acyl group)-L-b-cyclopropyl alanyl] hydrazides
According to the step of embodiment 59 (a)-59 (d), but replace the N-tert-butoxycarbonyl-L-leucine of step (b), be prepared as the title compound (0.138g, 78%) of white solid with N-tert-butoxycarbonyl-L-b-cyclopropyl alanine.MS(ESI)：536.2(M+H) +。
Embodiment 128N-[N-(6-methyl nicotinoyl)-L-b-tert-butyl group alanyl]-N '-(2-(1-naphthyl) thiazole-4-base carbonyl] preparation of hydrazides
Step according to embodiment 59 (a)-59 (d), but replace the N-tert-butoxycarbonyl-L-leucine of step (b) and use the 6-methylnicotinic acid to replace the 8-Quinoline Carboxylic Acid of step (d) with N-tert-butoxycarbonyl-L-b-tert-butyl group alanine, be prepared as the title compound (0.124g, 73%) of white solid.MS(ESI)：516.1(M+H) +。
Embodiment 129N-[2-(N-cyclopropyl-N-cyclopropyl methylamino) thiazole-4-base carbonyl]-preparation of N '-[N-picoline acyl group-L-b-tert-butyl group alanyl] hydrazides
Step according to embodiment 56 (a)-56 (b); but with N-(N-b-tert-butoxycarbonyl-L-tert-butyl group alanyl]-N '-[2-(N-cyclopropyl-N-cyclopropyl methylamino) thiazole-4-base carbonyl] hydrazides replaces N-[2-(N-cyclopropyl-N-cyclopropyl methylamino) thiazole-4-base carbonyl of step (a)]-N '-(N-tert-butoxycarbonyl-L-leucyl-) hydrazides; be prepared as the title compound (143mg, 83%) of white solid.MS(ESI)：485.1(M+H) +。
Embodiment 130N-[2-(N-cyclopropyl-N-cyclopropyl methylamino) thiazole-4-base carbonyl]-preparation of N '-[N-(3-isoquinolin acyl group)-L-b-tert-butyl group alanyl] hydrazides
Step according to embodiment 56 (a)-56 (b); but with N-(N-b-tert-butoxycarbonyl-L-tert-butyl group alanyl]-N '-[2-(N-cyclopropyl-N-cyclopropyl methylamino) thiazole-4-base carbonyl] hydrazides replaces N-[2-(N-cyclopropyl-N-cyclopropyl methylamino) thiazole-4-base carbonyl of step (a)]-N '-(N-tert-butoxycarbonyl-L-leucyl-] hydrazides; and replace the pyridine carboxylic acid of step (b) with the 3-isoquinolinecarboxylic acid; be prepared as the title compound (135mg, 85%) of white solid.MS(ESI)：535.1(M+H) +。
Embodiment 131N-(N-tert-butoxycarbonyl-L-b-cyclopropyl alanyl]-preparation of N '-[2-(N-cyclopropyl-N-cyclopropyl methylamino) thiazole-4-base carbonyl] hydrazides
Step according to embodiment 1 (a)-1 (d) and 1 (h), but replace suitable-2 of step (a) with N-cyclopropyl methyl cyclopropylamine, the 6-thebaine also uses N-tert-butoxycarbonyl-L-b-cyclopropyl alanine to replace N-(4-pyridine radicals the methoxycarbonyl)-L-leucine of step (h), be prepared as the title compound (1.375g, 76%) of white solid.MS(ESI)：464.2(M+H) +。
Embodiment 132N-[2-(N-cyclopropyl methyl-N-propyl group amino) thiazole-4-base carbonyl]-preparation of N '-[N-(6-methyl-3-pyridine radicals methoxycarbonyl)-L-leucyl-] hydrazides
Step according to embodiment 1 (a)-1 (h), but replace suitable-2 of step (a) with N-cyclopropyl propylamine, the 6-thebaine also replaces the 4-pyridine radicals methanol of step (f) with 6-methyl-3-pyridine radicals methanol, be prepared as the title compound (84mg, 33%) of orange solids.MS(ESI)：517.3(M+H) +。
Embodiment 133N-[N-(6-methyl nicotinoyl)-L-pi-allyl glycyl]-preparation of N '-[2-(1-naphthyl) thiazole-4-base carbonyl] hydrazides
Step according to embodiment 59 (a)-59 (d), but replace the N-tert-butoxycarbonyl-L-leucine of step (b) and use the 6-methylnicotinic acid to replace the 8-Quinoline Carboxylic Acid of step (d) with N-tert-butoxycarbonyl-L-allylglycine, be prepared as the title compound (0.097g, 66%) of white solid.MS(ESI)：486.1(M+H) +。
Embodiment 134N-[2-(1-naphthyl) thiazole-4-base carbonyl]-preparation of N '-[N-(8-quinoline acyl group)-L-pi-allyl glycyl] hydrazides
According to the step of embodiment 59 (a)-59 (d), but replace the N-tert-butoxycarbonyl-L-leucine of step (b), be prepared as the title compound (0.105g, 74%) of white solid with N-tert-butoxycarbonyl-L-allylglycine.MS(ESI)：522.1(M+H) +。
Embodiment 135N-[2-(1-naphthyl) thiazole-4-base carbonyl]-preparation of N '-[N-(2-quinoline acyl group)-L-b-cyclopropyl alanyl] hydrazides
Step according to embodiment 59 (a)-59 (d), but replace the N-tert-butoxycarbonyl-L-leucine of step (b) and replace the 8-Quinoline Carboxylic Acid of step (d) with quinaldinic acid with N-tert-butoxycarbonyl-L-b-cyclopropyl alanine, be prepared as the title compound (0.151g, 86%) of white solid.MS(ESI)：536.3(M+H) +。
Embodiment 136N-[N-(3-isoquinolin acyl group)-L-b-cyclopropyl alanyl]-preparation of N '-[2-(1-naphthyl) thiazole-4-base carbonyl] hydrazides
Step according to embodiment 59 (a)-59 (d), but replace the N-tert-butoxycarbonyl-L-leucine of step (b) also to replace the 8-Quinoline Carboxylic Acid of step (d) with the 3-isoquinolinecarboxylic acid with N-tert-butoxycarbonyl-L-b-cyclopropyl alanine, be prepared as the title compound (0.145g, 82%) of white solid.MS(ESI)：536.1(M+H) +。
Embodiment 137N-[N-(1-isoquinolin acyl group)-L-b-cyclopropyl alanyl]-preparation of N '-[2-(1-naphthyl) thiazole-4-base carbonyl] hydrazides
Step according to embodiment 59 (a)-59 (d), but replace the N-tert-butoxycarbonyl-L-leucine of step (b) also to replace the 8-Quinoline Carboxylic Acid of step (d) with the 1-isoquinolinecarboxylic acid with N-tert-butoxycarbonyl-L-b-cyclopropyl alanine, be prepared as the title compound (0.143g, 81%) of white solid.MS(ESI)：536.1(M+H) +。
Embodiment 138N-[2-(1-naphthyl) thiazole-4-base carbonyl]-preparation of N '-[N-(7-quinoline acyl group)-L-b-cyclopropyl alanyl] hydrazides
Step according to embodiment 59 (a)-59 (d), but replace the N-tert-butoxycarbonyl-L-leucine of step (b) also to replace the 8-Quinoline Carboxylic Acid of step (d) with the 7-quinoline carboxylic acid with N-tert-butoxycarbonyl-L-b-cyclopropyl alanine, be prepared as the title compound (0.138g, 78%) of white solid.MS(ESI)：536.1(M+H) +。
Embodiment 139N-[2-[N-cyclopropyl-N-cyclopropyl methylamino) thiazole-4-base carbonyl]-preparation of N '-[N-(8-quinoline acyl group)-L-b-cyclopropyl alanyl] hydrazides
Step according to embodiment 56 (a)-56 (b); but replace N-[2-(N-cyclopropyl-N-cyclopropyl methylamino) thiazole-4-base carbonyl of step (a) with N-(N-tert-butoxycarbonyl-L-b-cyclopropyl alanyl)-N '-[2-(N-cyclopropyl-N-cyclopropyl methylamino) thiazole-4-base carbonyl] hydrazides]-N '-(N-tert-butoxycarbonyl-L-leucyl-] hydrazides; and replace the pyridine carboxylic acid of step (b) with 8-Quinoline Carboxylic Acid; be prepared as the title compound (120mg, 73%) of white solid.MS(ESI)：519.1(M+H) +。
Embodiment 140N-[2-(N-cyclopropyl-N-cyclopropyl methylamino) thiazole-4-base carbonyl]-preparation of N '-[N-(4-methylimidazole-5-base carbonyl)-L-b-cyclopropyl alanyl] hydrazides
Step according to embodiment 56 (a)-56 (b); but replace N-[2-(N-cyclopropyl-N-cyclopropyl methylamino) thiazole-4-base carbonyl of step (a) with N-(N-tert-butoxycarbonyl-L-b-cyclopropyl alanyl)-N '-[2-(N-cyclopropyl-N-cyclopropyl methylamino) thiazole-4-base carbonyl] hydrazides]-N '-(N-tert-butoxycarbonyl-L-leucyl-] hydrazides; and replace the pyridine carboxylic acid of step (b) with 4-methylimidazole-5-carboxylic acid; be prepared as the title compound (120mg, 81%) of white solid.MS(ESI)：472.1(M+H) +。
Embodiment 141N-[2-(N-cyclopropyl-N-cyclopropyl methylamino) thiazole-4-base carbonyl]-preparation of N '-[N-(3-isoquinolin acyl group)-L-b-cyclopropyl alanyl] hydrazides
Step according to embodiment 56 (a)-56 (b); but replace N-[2-(N-cyclopropyl-N-cyclopropyl methylamino) thiazole-4-base carbonyl of step (a) with N-(N-tert-butoxycarbonyl-L-b-cyclopropyl alanyl)-N '-[2-(N-cyclopropyl-N-cyclopropyl methylamino) thiazole-4-base carbonyl] hydrazides]-N '-(N-tert-butoxycarbonyl-L-leucyl-] hydrazides; and replace the pyridine carboxylic acid of step (b) with 3-isoquinolin formic acid; be prepared as the title compound (140mg, 82%) of white solid.MS(ESI)：519.2(M+H) +。
Embodiment 142N-[2-(N-cyclopropyl-N-cyclopropyl methylamino) thiazole-4-base carbonyl]-preparation of N '-[N-(6-methyl nicotinoyl)-L-b-cyclopropyl alanyl] hydrazides
Step according to embodiment 56 (a)-56 (b); but with N-[2-(N-cyclopropyl-N-cyclopropyl methylamino) thiazole in N-(N-tert-butoxycarbonyl-L-b-cyclopropyl alanyl)-N '-[2-(N-cyclopropyl-N-cyclopropyl methylamino) thiazole-4-carbonyl] hydrazides replacement step (a)-4-base carbonyl]-N '-(N-tert-butoxycarbonyl-L-leucyl-] hydrazides; and replace pyridine carboxylic acid in the step (b) with the 6-methylnicotinic acid; be prepared as the title compound (105mg, 62%) of white solid.MS(ESI)：483.2(M+H) +。
Embodiment 143N-[N-(4-methylimidazole-5-base carbonyl)-L-norleucyl-]-preparation of N '-[2-(1-naphthyl) thiazole-4-base carbonyl] hydrazides
Step according to embodiment 59 (a)-59 (d), but replace the N-tert-butoxycarbonyl-L-leucine of step (b) and use 4-methylimidazole-5-carboxylic acid to replace the 8-Quinoline Carboxylic Acid of step (d) with N-tert-butoxycarbonyl-L-nor-leucine, be prepared as the title compound (0.112g, 70%) of white solid.MS(ESI)：491.1(M+H) +。
Embodiment 144N-[2-(1-naphthyl) thiazole-4-base carbonyl]-N '-(N-picoline acyl group-L-norleucyl-] preparation of hydrazides
Step according to embodiment 59 (a)-59 (d), but replace the N-tert-butoxycarbonyl-L-leucine of step (b) and replace the 8-Quinoline Carboxylic Acid of step (d) with pyridine carboxylic acid with N-tert-butoxycarbonyl-L-nor-leucine, be prepared as the title compound (0.114g, 72%) of white solid.MS(ESI)：488.2(M+H) +。
Embodiment 145N-[2-(1-naphthyl) thiazole-4-base carbonyl]-preparation of N '-[N-(8-quinoline acyl group)-L-norleucyl-] hydrazides
According to the step of embodiment 59 (a)-59 (d), but replace the N-tert-butoxycarbonyl-L-leucine of step (b), be prepared as the title compound (0.082g, 47%) of white solid with N-tert-butoxycarbonyl-L-nor-leucine.MS(ESI)：538.1(M+H) +。
Embodiment 146N-[2-(N-cyclopropyl-N-cyclopropyl methylamino) thiazole-4-base carbonyl]-preparation of N '-[N-(2-quinoline acyl group)-L-b-cyclopropyl alanyl] hydrazides
Step according to embodiment 56 (a)-56 (b); but replace N-[2-(N-cyclopropyl-N-cyclopropyl methylamino) thiazole-4-base carbonyl of step (a) with N-(N-tert-butoxycarbonyl-L-b-cyclopropyl alanyl)-N '-[2-(N-cyclopropyl-N-cyclopropyl methylamino) thiazole-4-base carbonyl] hydrazides]-N '-(N-tert-butoxycarbonyl-L-leucyl-] hydrazides; and replace the pyridine carboxylic acid of step (b) with quinaldinic acid; be prepared as the title compound (150mg, 81%) of white solid.MS(ESI)：519.2(M+H) +。
Embodiment 147N-[2-(N-cyclopropyl-N-cyclopropyl methylamino) thiazole-4-base carbonyl]-preparation of N '-[N-(1-isoquinolin acyl group)-L-b-cyclopropyl alanyl] hydrazides
Step according to embodiment 56 (a)-56 (b); but replace N-[2-(N-cyclopropyl-N-cyclopropyl methylamino) thiazole-4-base carbonyl of step (a) with N-(N-tert-butoxycarbonyl-L-b-cyclopropyl alanyl)-N '-[2-(N-cyclopropyl-N-cyclopropyl methylamino) thiazole-4-base carbonyl] hydrazides]-N '-(N-tert-butoxycarbonyl-L-leucyl-] hydrazides; and replace the pyridine carboxylic acid of step (b) with the 1-isoquinolinecarboxylic acid; be prepared as the title compound (130mg, 87%) of white solid.MS(ESI)：519.2(M+H) +。
Embodiment 148N-[2-[N-cyclopropyl-N-(2-methyl-propyl) amino] thiazole-4-base carbonyl]-preparation of N '-[N-(6-methyl-3-pyridine radicals methoxycarbonyl)-L-leucyl-] hydrazides
Step according to embodiment 1 (a)-1 (h), but replace suitable-2 of step (a) with N-isobutyl group cyclopropylamine, the 6-thebaine also replaces the 4-pyridine radicals methanol of step (f) with 6-methyl-3-pyridine radicals methanol, be prepared as the title compound (220mg, 88%) of white solid.MS(ESI)：517.2(M+H) +。
Embodiment 149N-(N-tert-butoxycarbonyl-L-leucyl-]-preparation of N '-[2-[N-cyclopropyl-N-(2-methyl-propyl) amino) thiazole-4-base carbonyl] hydrazides
Step according to embodiment 1 (a)-1 (d) and 1 (h), but replace suitable-2 of step (a) with N-cyclopropyl isobutyl amine, the 6-thebaine is also used N-(4-pyridine radicals the methoxycarbonyl)-L-leucine of N-tert-butoxycarbonyl-L-leucine in place step (h), be prepared as the title compound (1.01g, 89%) of white solid.MS(ESI)：466.3(M+H) +。
Embodiment 150N-[2-(1-naphthyl) thiazole-4-base carbonyl]-preparation of N '-[N-(7-quinoline acyl group)-L-b-tert-butyl group alanyl] hydrazides
Step according to embodiment 59 (a)-59 (d), but replace the N-tert-butoxycarbonyl-L-leucine of step (b) also to replace the 8-Quinoline Carboxylic Acid of step (d) with the 7-quinoline carboxylic acid with N-tert-butoxycarbonyl-L-b-tert-butyl group alanine, be prepared as the title compound (0.139g, 80%) of white solid.MS(ESI)：552.2(M+H) +。
Embodiment 151N-[2-(1-naphthyl) thiazole-4-base carbonyl]-preparation of N '-[N-(2-quinoline acyl group)-L-b-tert-butyl group alanyl] hydrazides
Step according to embodiment 59 (a)-59 (d), but replace the N-tert-butoxycarbonyl-L-leucine of step (b) and replace the 8-Quinoline Carboxylic Acid of step (d) with quinaldinic acid with N-tert-butoxycarbonyl-L-b-tert-butyl group alanine, be prepared as the title compound (0.158g, 91%) of white solid.MS(ESI)：552.2(M+H) +。
Embodiment 152N-[N-(1-isoquinolin acyl group)-L-b-tert-butyl group alanyl]-preparation of N '-[2-(1-naphthyl) thiazole-4-base carbonyl] hydrazides
Step according to embodiment 59 (a)-59 (d), but replace the N-tert-butoxycarbonyl-L-leucine of step (b) also to replace the 8-Quinoline Carboxylic Acid of step (d) with the 1-isoquinolinecarboxylic acid with N-tert-butoxycarbonyl-L-b-tert-butyl group alanine, be prepared as the title compound (0.143g, 82%) of white solid.MS(ESI)：552.2(M+H) +。
Embodiment 153N-[N-(3-isoquinolin acyl group)-L-b-tert-butyl group alanyl]-preparation of N '-[2-(1-naphthyl) thiazole-4-base carbonyl] hydrazides
Step according to embodiment 59 (a)-59 (d), but replace the N-tert-butoxycarbonyl-L-leucine of step (b) also to replace the 8-Quinoline Carboxylic Acid of step (d) with the 3-isoquinolinecarboxylic acid with N-tert-butoxycarbonyl-L-b-tert-butyl group alanine, be prepared as the title compound (0.130g, 75%) of white solid.MS(ESI)：552.2(M+H) +。
Embodiment 154N-[N-(6-methyl nicotinoyl)-L-norleucyl-]-preparation of N '-[2-(1-naphthyl) thiazole-4-base carbonyl] hydrazides
Step according to embodiment 59 (a)-59 (d), but replace the N-tert-butoxycarbonyl-L-leucine of step (b) and use the 6-methylnicotinic acid to replace the 8-Quinoline Carboxylic Acid of step (d) with N-tert-butoxycarbonyl-L-nor-leucine, be prepared as the title compound (0.109g, 67%) of white solid.MS(ESI)：502.2(M+H) +。
Embodiment 155N-[2-(1-naphthyl) thiazole-4-base carbonyl]-preparation of N '-[N-(7-quinoline acyl group)-L-norleucyl-] hydrazides
Step according to embodiment 59 (a)-59 (d), but replace the N-tert-butoxycarbonyl-L-leucine of step (b) also to replace the 8-Quinoline Carboxylic Acid of step (d) with the 7-quinoline carboxylic acid with N-tert-butoxycarbonyl-L-nor-leucine, be prepared as the title compound (0.104g, 59%) of white solid.MS(ESI)：538.1(M+H) +。
Embodiment 156N-[2-(1-naphthyl) thiazole-4-base carbonyl]-preparation of N '-[N-(2-quinoline acyl group)-L-norleucyl-] hydrazides
Step according to embodiment 59 (a)-59 (d), but replace the N-tert-butoxycarbonyl-L-leucine of step (b) and replace the 8-Quinoline Carboxylic Acid of step (d) with quinaldinic acid with N-tert-butoxycarbonyl-L-nor-leucine, be prepared as the title compound (0.153g, 87%) of white solid.MS(ESI)：538.1(M+H) +。
Embodiment 157N-[N-(1-isoquinolin acyl group)-L-norleucyl-]-preparation of N '-[2-(1-naphthyl) thiazole-4-base carbonyl] hydrazides
Step according to embodiment 59 (a)-59 (d), but replace the N-tert-butoxycarbonyl-L-leucine of step (b) also to replace the 8-Quinoline Carboxylic Acid of step (d) with the 1-isoquinolinecarboxylic acid with N-tert-butoxycarbonyl-L-nor-leucine, be prepared as the title compound (0.151g, 86%) of white solid.MS(ESI)：538.1(M+H) +。
Embodiment 158N-[N-(3-isoquinolin acyl group)-L-norleucyl-]-preparation of N '-[2-(1-naphthyl) thiazole-4-base carbonyl] hydrazides
Step according to embodiment 59 (a)-59 (d), but replace the N-tert-butoxycarbonyl-L-leucine of step (b) also to replace the 8-Quinoline Carboxylic Acid of step (d) with the 3-isoquinolinecarboxylic acid with N-tert-butoxycarbonyl-L-nor-leucine, be prepared as the title compound (0.126g, 72%) of white solid.MS(ESI)：538.1(M+H) +。
Embodiment 159N-[2-(N-cyclopropyl-N-cyclopropyl methylamino) thiazole-4-base carbonyl]-preparation of N '-[N-(5-hydroxy methylimidazole-4-base carbonyl)-L-b-cyclopropyl alanyl] hydrazides
Step according to embodiment 56 (a)-56 (b); but replace N-[2-(N-cyclopropyl-N-cyclopropyl methylamino) thiazole-4-base carbonyl of step (a) with N-(N-tert-butoxycarbonyl-L-b-cyclopropyl alanyl)-N '-[2-(N-cyclopropyl-N-cyclopropyl methylamino) thiazole-4-base carbonyl] hydrazides]-N '-(N-tert-butoxycarbonyl-L-leucyl-] hydrazides; and replace the pyridine carboxylic acid of step (b) with 5-hydroxymethyl imidazoles-4-carboxylic acid; be prepared as the title compound (50mg, 44%) of white solid.MS(ESI)：488.2(M+H) +。
Embodiment 160N-[2-[N-cyclopropyl-N-(2-methyl-propyl) amino] thiazole-4-base carbonyl]-a) N-(N-tert-butoxycarbonyl-L-b-cyclopropyl alanyl)-N '-[2-(N-cyclopropyl-N-(2-methyl-propyl) amino] thiazole-4-base carbonyl of the preparation of N '-[N-(8-quinoline acyl group)-L-b-cyclopropyl alanyl] hydrazides] hydrazides
Step according to embodiment 1 (a)-1 (d) and 1 (h), but replace suitable-2 of step (a) with N-cyclopropyl isobutyl amine, the 6-thebaine also uses N-tert-butoxycarbonyl-L-b-cyclopropyl alanine to replace N-(4-pyridine radicals the methoxycarbonyl)-L-leucine of step (h), be prepared as the title compound (1.01g, 89%) of white solid.MS(ESI)：466.3(M+H) +。B) N-[2-[N-cyclopropyl-N-(2-methyl-propyl) amino] thiazole-4-base carbonyl]-N '-[N-(8-quinoline acyl group)-L-b-cyclopropyl alanyl] hydrazides
Step according to embodiment 56 (a)-56 (b); but with N-(N-tert-butoxycarbonyl-L-b-cyclopropyl alanyl)-N '-[2-[N-cyclopropyl-N-(2-methyl-propyl) amino] thiazole-4-base carbonyl] hydrazides replaces N-[2-(N-cyclopropyl-N-cyclopropyl methylamino) thiazole-4-base carbonyl of step (a)]-N '-(N-tert-butoxycarbonyl-L-leucyl-] hydrazides; and replace the pyridine carboxylic acid of step (b) with 8-Quinoline Carboxylic Acid; be prepared as the title compound (135mg, 100%) of white solid.MS(ESI)：512.2(M+H) +。
Embodiment 161N-[2-(N-cyclopropyl-N-cyclopropyl methylamino) thiazole-4-base carbonyl]-preparation of N '-[N-(6-methyl nicotinoyl)-L-b-tert-butyl group alanyl] hydrazides
Step according to embodiment 56 (a)-56 (b); but with N-[2-(N-cyclopropyl-N-cyclopropyl methylamino) thiazole-4-base carbonyl]-N '-(N-tert-butoxycarbonyl-L-b-tert-butyl group alanyl] hydrazides replaces N-[2-(N-cyclopropyl-N-cyclopropyl methylamino) thiazole-4-base carbonyl of step (a)]-N '-(N-tert-butyl group carbonyl-L-leucyl-] hydrazides; and replace the pyridine carboxylic acid of step (b) with the 6-methylnicotinic acid; be prepared as the title compound (85mg, 79%) of white solid.MS(ESI)：499.2(M+H) +。
Embodiment 162N-[2-[N-cyclopropyl-N-(2-methyl-propyl) amino] thiazole-4-base carbonyl]-preparation of N '-[N-(4-methylimidazole-5-base carbonyl)-L-b-cyclopropyl alanyl] hydrazides
Step according to embodiment 56 (a)-56 (b); but with N-(N-tert-butoxycarbonyl-L-b-cyclopropyl alanyl)-N '-[2-[N-cyclopropyl-N-(2-methyl-propyl) amino] thiazole-4-base carbonyl] hydrazides replaces N-[2-(N-cyclopropyl-N-cyclopropyl methylamino) thiazole-4-base carbonyl of step (a)]-N '-(N-tert-butoxycarbonyl-L-leucyl-] hydrazides; and replace the pyridine carboxylic acid of step (b) with 4-methylimidazole-5-carboxylic acid; be prepared as the title compound (100mg, 73%) of white solid.MS(ESI)：474.2(M+H) +。
Embodiment 163N-[2-[N-cyclopropyl-N-(2-methyl-propyl) amino] thiazole-4-base carbonyl]-preparation of N '-[N-(2-quinoline acyl group)-L-b-cyclopropyl alanyl] hydrazides
Step according to embodiment 56 (a)-56 (b); but with N-(N-tert-butoxycarbonyl-L-b-cyclopropyl alanyl)-N '-[2-[N-cyclopropyl-N-(2-methyl-propyl) amino] thiazole-4-base carbonyl] hydrazides replaces N-[2-(N-cyclopropyl-N-cyclopropyl methylamino) thiazole-4-base carbonyl of step (a)]-N '-(N-tert-butoxycarbonyl-L-leucyl-] hydrazides; and replace the pyridine carboxylic acid of step (b) with quinaldinic acid; be prepared as the title compound (75mg, 59%) of white solid.MS(ESI)：521.2(M+H) +。
Embodiment 164N-[2-[N-cyclopropyl-N-(2-methyl-propyl) amino] thiazole-4-base carbonyl]-preparation of N '-[N-(6-methyl nicotinoyl)-L-b-cyclopropyl alanyl] hydrazides
Step according to embodiment 56 (a)-56 (b); but with N-(N-tert-butoxycarbonyl-L-b-cyclopropyl alanyl)-N '-[2-[N-cyclopropyl-N-(2-methyl-propyl) amino] thiazole-4-base carbonyl] hydrazides replaces N-[2-(N-cyclopropyl-N-cyclopropyl methylamino) thiazole-4-base carbonyl of step (a)]-N '-(N-tert-butoxycarbonyl-L-leucyl-] hydrazides; and replace the pyridine carboxylic acid of step (b) with the 6-methylnicotinic acid; be prepared as the title compound (112mg, 65%) of white solid.MS(ESI)：485.3(M+H) +。
Embodiment 165N-[2-(1-naphthyl) thiazole-4-base carbonyl]-a) N-(8-quinoline acyl group) glycine of the preparation of N '-[N-(8-quinoline acyl group) glycyl] hydrazides
According to the step of embodiment 102 (f)-102 (g), but replace the L-leucine methyl ester of step (f), be prepared as the title compound (0.207g, 95%) of faint yellow solid with glycine methyl ester hydrochloride.MS(ESI)：231.1(M+H) +。B) N-[2-(1-naphthyl) thiazole-4-base carbonyl]-preparation of N '-[N-(8-quinoline acyl group) glycyl] hydrazides
Step according to embodiment 1 (h); but with N-[2-(1-naphthyl) thiazole-4-base carbonyl] hydrazides replacement N-[2-(suitable-2; 6-dimethyl-4-morpholinyl) thiazole-4-base carbonyl] hydrazides and usefulness N-(8-quinoline acyl group) glycine replacement N-(4-pyridine radicals methoxycarbonyl)-L-leucine; be prepared as the title compound (0.028g, 12%) of brown solid.MS(ESI)：482.1(M+H) +。
Embodiment 166N-[2-(1-naphthyl) thiazole-4-base carbonyl]-preparation of N '-[(8-quinoline acyl group)-L-is norvalyl for N-] hydrazides
According to the step of embodiment 59 (a)-59 (d), but replace the N-tert-butoxycarbonyl-L-leucine of step (b), be prepared as the title compound (0.131g, 74%) of white solid with N-tert-butoxycarbonyl-L-norvaline.MS(ESI)：524.1(M+H) +。
Embodiment 167N-[2-(1-naphthyl) thiazole-4-base carbonyl]-preparation of N '-[(2-quinoline acyl group)-L-is norvalyl for N-] hydrazides
Step according to embodiment 59 (a)-59 (d), but replace the N-tert-butoxycarbonyl-L-leucine of step (b) and replace the 8-Quinoline Carboxylic Acid of step (d) with quinaldinic acid with N-tert-butoxycarbonyl-L-norvaline, be prepared as the title compound (0.135g, 75%) of white solid.MS(ESI)：524.1(M+H) +。
Embodiment 168N-[2-(1-naphthyl) thiazole-4-base carbonyl]-N '-(acyl group-L-is norvalyl for the N-picoline] preparation of hydrazides
Step according to embodiment 59 (a)-59 (d), but replace the N-tert-butoxycarbonyl-L-leucine of step (b) and replace the 8-Quinoline Carboxylic Acid of step (d) with pyridine carboxylic acid with N-tert-butoxycarbonyl-L-norvaline, be prepared as the title compound (0.126g, 79%) of white solid.MS(ESI)：474.2(M+H) +。
Embodiment 169N-[2-(1-naphthyl) thiazole-4-base carbonyl]-preparation of N '-[(6-methyl nicotinoyl)-L-is norvalyl for N-] hydrazides
Step according to embodiment 59 (a)-59 (d), but replace the N-tert-butoxycarbonyl-L-leucine of step (b) and use the 6-methylnicotinic acid to replace the 8-Quinoline Carboxylic Acid of step (d) with N-tert-butoxycarbonyl-L-norvaline, be prepared as the title compound (0.141g, 85%) of white solid.MS(ESI)：488.2(M+H) +。
Embodiment 170N-[2-(1-naphthyl) thiazole-4-base carbonyl]-preparation of N '-[(4-methylimidazole-5-base carbonyl)-L-is norvalyl for N-] hydrazides
Step according to embodiment 59 (a)-59 (d), but replace the N-tert-butoxycarbonyl-L-leucine of step (b) and use 4-methylimidazole-5-carboxylic acid to replace the 8-Quinoline Carboxylic Acid of step (d) with N-tert-butoxycarbonyl-L-norvaline, be prepared as the title compound (0.098g, 51%) of white solid.MS(ESI)：477.1(M+H) +。
Embodiment 171N-[2-(1-naphthyl) thiazole-4-base carbonyl]-preparation of N '-[(1-isoquinolin acyl group)-L-is norvalyl for N-] hydrazides
Step according to embodiment 59 (a)-59 (d), but replace the N-tert-butoxycarbonyl-L-leucine of step (b) also to replace the 8-Quinoline Carboxylic Acid of step (d) with the 1-isoquinolinecarboxylic acid with N-tert-butoxycarbonyl-L-norvaline, be prepared as the title compound (0.146g, 82%) of white solid.MS(ESI)：524.2(M+H) +。
Embodiment 172N-[2-(1-naphthyl) thiazole-4-base carbonyl]-preparation of N '-[(3-isoquinolin acyl group)-L-is norvalyl for N-] hydrazides
Step according to embodiment 59 (a)-59 (d), but replace the N-tert-butoxycarbonyl-L-leucine of step (b) also to replace the 8-Quinoline Carboxylic Acid of step (d) with the 3-isoquinolinecarboxylic acid with N-tert-butoxycarbonyl-L-norvaline, be prepared as the title compound (0.138g, 78%) of white solid.MS(ESI)：524.2(M+H) +。
Embodiment 173 (1S, 1 ' S)-N, N '-two-[4-[1-(N-benzyloxycarbonyl amino)-3-methyl butyl] thiazol-2-yl carbonyl] a) N-benzyloxycarbonyl-L-leucyl amine of preparation of hydrazides
(4.0ml) ((4.6g is in the agitating solution of THF 17.3mmol) 2.25ml) to add the N-benzyloxycarbonyl-L-leucine that is cooled to-40 ℃ for 2.37g, 17.3mmol with the carbonochloridic acid isobutyl ester for 3.68g, 36.4mmol with N-methylmorpholine.Stir after 15 minutes, blasted ammonia 5 minutes to this solution.Make this solution be warmed to room temperature, evaporate and residue is dissolved in the ethyl acetate,, filter and be concentrated into dried, obtain title compound (4.58g, 100%) into white solid with 0.1NHCl and saturated brine washing, dry (magnesium sulfate) then.B) N-benzyloxycarbonyl-L-leucine thioamides
Under room temperature, with the chemical compound of embodiment 1 (a) (4.58g, 17.3mmol) and LawessonShi reagent (4.21g, THF solution stirring 10.4mmol) 16 hours.Concentrate this solution, and with residue on 230-400 order silica gel through the flash chromatography purification, with 1: 3 ethyl acetate/hexane eluting, obtain title compound (3.74g, 77%) into faint yellow solid.C) (1S)-1-benzyloxycarbonyl amino-1-(4-carbonyl ethoxythiazole-2-yl)-3-methybutane
Make embodiment 1 (b) chemical compound (2.20g, 7.83mmol) be dissolved in the acetone (35ml) that is cooled to-10 ℃ and add ethyl bromide acetone (1.68g, 8.62mmol, 1.08ml).Stir after 1 hour, in this solution impouring dichloromethane/water, then in the impouring saturated sodium bicarbonate aqueous solution.Wash the organic layer that merges with the dichloromethane extraction water layer and with saturated brine, dry (magnesium sulfate) filters also concentrated.Residue is dissolved in be cooled in-20 ℃ the dichloromethane, add pyridine (1.36g, 17.2mmol, 1.39ml) and trifluoroacetic anhydride (1.81g, 8.62mmol, 1.22ml).Stir after 1 hour, with saturated sodium bicarbonate aqueous solution and saturated brine washing, dry (magnesium sulfate) then filters and concentrates.With residue on 90g 230-400 order silica gel through the flash chromatography purification, with 1: 3 ethyl acetate/hexane eluting, obtain title compound (2.36g, 80%) into faint yellow oily. 1H?NMR(400MHz，CDCl 3)d?8.08(s，1H)，7.38(m，5H)，5.42(s，3H)，5.23-5.07(m，3H)，4.42(q，2H)，2.01-1.62(m，3H)，1.41(t，3H)，0.99(d，6H)。D) (1S)-1-benzyloxycarbonyl amino-1-(4-diazanyl carbonyl thiazol-2-yl)-3-methybutane
Step according to embodiment 1 (d), but replace 2-(suitable-2 with (1S)-1-benzyloxycarbonyl amino-1-(4-carbonyl ethoxythiazole-2-yl)-3-methybutane, 6-dimethyl-4-morpholinyl) thiazole-4-carboxylic acid ethyl ester is prepared as the title compound (2.01g, 97%) of weak yellow foam shape. 1H?NMR(400MHz，CDCl 3)d?8.35(bs，1H)，8.03(s，1H)，7.37(m，5H)，5.29(d，1H)，5.14-5.09(m，3H)，4.07(bs，2H)，1.92-1.82(m，1H)，1.79-1.66(m，2H)，1.00(d，6H)。E) (1S)-1-benzyloxycarbonyl amino-1-(4-carboxyl thiazol-2-yl)-3-methybutane
According to the step of embodiment 1 (g), but replace N-(4-pyridine radicals methoxycarbonyl)-L-leucine methyl ester, be prepared as the title compound of white solid with (1S)-1-benzyloxycarbonyl amino-1-(4-carbonyl ethoxythiazole-2-yl)-3-methybutane.MS(ESI)：349.2(M+H) +。F) (1S, 1 ' S)-N, N '-two-[4-[1-(N-benzyloxycarbonyl amino)-3-methyl butyl] thiazol-2-yl carbonyl] hydrazides
Step according to embodiment 1 (h), but replace N-[2-(suitable-2 with (1S)-1-benzyloxycarbonyl amino-1-(4-diazanyl carbonyl thiazol-2-yl)-3-methybutane, 6-dimethyl-4-morpholinyl) thiazole-4-base carbonyl] hydrazides and usefulness (1S)-1-benzyloxycarbonyl amino-1-(4-carboxyl thiazol-2-yl)-3-methybutane replacement N-(4-pyridine radicals methoxycarbonyl)-L-leucine, be prepared as the title compound (0.028g, 59%) of white solid.MS(ESI)：693.1(M+H) +。
Embodiment 174N-[2-(N-cyclopropyl-N-(2-methyl-propyl) amino] thiazole-4-base carbonyl]-a) N-(N-tert-butoxycarbonyl-L-b-tert-butyl group alanyl)-N '-[2-[N-cyclopropyl-N-(2-methyl-propyl) amino] thiazole-4-base carbonyl of the preparation of N '-[N-(6-methyl nicotinoyl)-L-b-tert-butyl group alanyl] hydrazides] hydrazides
Step according to embodiment 1 (a)-1 (d) and 1 (h), but replace suitable-2 of step (a) with N-cyclopropyl isobutyl amine, the 6-thebaine also uses N-tert-butoxycarbonyl-L-b-tert-butyl group alanine to replace N-(4-pyridine radicals the methoxycarbonyl)-L-leucine of step (h), be prepared as the title compound (0.44g, 100%) of white solid.MS(ESI)：482.3(M+H) +。B) N-[2-(N-cyclopropyl-N-(2-methyl-propyl) amino] thiazole-4-base carbonyl]-N '-[N-(6-methyl nicotinoyl)-L-b-tert-butyl group alanyl] hydrazides
Step according to embodiment 56 (a)-56 (b); but with N-(N-tert-butoxycarbonyl-L-b-tert-butyl group alanyl]-N '-[2-[N-cyclopropyl-N-(2-methyl-propyl) amino] thiazole-4-base carbonyl] hydrazides replaces N-[2-(N-cyclopropyl-N-cyclopropyl methylamino) thiazole-4-base carbonyl of step (a)]-N '-(N-tert-butoxycarbonyl-L-leucyl-] hydrazides; and replace the pyridine carboxylic acid of step (b) with the 6-methylnicotinic acid; be prepared as the title compound (70mg, 66%) of white solid.MS(ESI)：501.2(M+H) +。
Embodiment 175N-[2-(N-cyclopropyl-N-(2-methyl-propyl) amino] thiazole-4-base carbonyl]-preparation of N '-[N-(4-methylimidazole-5-base carbonyl)-L-b-tert-butyl group alanyl] hydrazides
Step according to embodiment 56 (a)-56 (b); but with N-(N-tert-butoxycarbonyl-L-b-tert-butyl group alanyl]-N '-[2-[N-cyclopropyl-N-(2-methyl-propyl) amino] thiazole-4-base carbonyl] hydrazides replaces N-[2-(N-cyclopropyl-N-cyclopropyl methylamino) thiazole-4-base carbonyl of step (a)]-N '-(N-tert-butoxycarbonyl-L-leucyl-] hydrazides; and replace the pyridine carboxylic acid of step (b) with 4-methylimidazole-5-carboxylic acid; be prepared as the title compound (70mg, 39%) of white solid.MS(ESI)：490.2(M+H) +。
Embodiment 176N-[2-(N-cyclopropyl-N-cyclopropyl methylamino] thiazole-4-base carbonyl]-preparation of N '-[N-(1-isoquinolin acyl group)-L-b-tert-butyl group alanyl] hydrazides
Step according to embodiment 56 (a)-56 (b); but with N-(N-tert-butoxycarbonyl-L-b-tert-butyl group alanyl)-N '-[2-[N-cyclopropyl-N-(2-methyl-propyl) amino] thiazole-4-base carbonyl] hydrazides replaces N-[2-(N-cyclopropyl-N-cyclopropyl methylamino) thiazole-4-base carbonyl of step (a)]-N '-(N-tert-butoxycarbonyl-L-leucyl-) hydrazides; and replace the pyridine carboxylic acid of step (b) with the 1-isoquinolinecarboxylic acid; be prepared as the title compound (123mg, 88%) of white solid.MS(ESI)：535.3(M+H) +。
Embodiment 177N-[N-(5-butyl methyl pyridine acyl)-L-b-tert-butyl group alanyl]-preparation of N '-[2-(N-cyclopropyl-N-cyclopropyl methylamino) thiazole-4-base carbonyl] hydrazides
Step according to embodiment 56 (a)-56 (b); but with N-(N-tert-butoxycarbonyl-L-b-tert-butyl group alanyl)-N '-[2-[N-cyclopropyl-N-(2-methyl-propyl) amino] thiazole-4-base carbonyl] hydrazides replaces N-[2-(N-cyclopropyl-N-cyclopropyl methylamino) thiazole-4-base carbonyl of step (a)]-N '-(N-tert-butoxycarbonyl-L-leucyl-] hydrazides; and replace the pyridine carboxylic acid of step (b) with the 5-butyl picolinate; be prepared as the title compound (90mg, 85%) of white solid.MS(ESI)：541.3(M+H) +。
Embodiment 178N-[2-(N-cyclopropyl-N-cyclopropyl methylamino] thiazole-4-base carbonyl]-preparation of N '-[N-(6-methyl pyridine acyl)-L-b-tert-butyl group alanyl] hydrazides
Step according to embodiment 56 (a)-56 (b); but with N-(N-tert-butoxycarbonyl-L-b-tert-butyl group alanyl]-N '-[2-[N-cyclopropyl-N-(2-methyl-propyl) amino] thiazole-4-base carbonyl] hydrazides replaces N-[2-(N-cyclopropyl-N-cyclopropyl methylamino) thiazole-4-base carbonyl of step (a)]-N '-(N-tert-butoxycarbonyl-L-leucyl-] hydrazides; and replace the pyridine carboxylic acid of step (b) with 6-picoline formic acid; be prepared as the title compound (170mg, 86%) of white solid.MS(ESI)：499.2(M+H) +。
Embodiment 179N-[2-(N-cyclopropyl-N-cyclopropyl methylamino) thiazole-4-base carbonyl]-preparation of N '-[N-(4-fluorobenzene formoxyl)-L-leucyl-] hydrazides
According to the step of embodiment 56 (a)-56 (b), but replace the pyridine carboxylic acid of step (b), be prepared as the title compound (88mg, 97%) of white solid with the 4-fluorinated acid.MS(ESI)：488.2(M+H) +。
Embodiment 180N-[N-(4-fluoro benzoyl)-L-leucyl-]-preparation of N '-[2-(1-naphthyl) thiazole-4-base carbonyl] hydrazides
According to the step of embodiment 59 (a)-59 (d), but replace the 8-Quinoline Carboxylic Acid of step (d), be prepared as the title compound (0.113g, 69%) of white solid with the 4-fluorinated acid.MS(ESI)：505.1(M+H) +。
Embodiment 181N-[2-(1-naphthyl) thiazole-4-base carbonyl]-a) L-b-tert-butyl group methyl lactamine hydrochlorate of the preparation of N '-[N-(2-pyridine radicals methoxycarbonyl)-L-b-tert-butyl group alanyl] hydrazides
Concentrated hydrochloric acid (12ml) is added L-b-tert-butyl group alanine, and (2.0g is 13.8mmol) 2, in the suspension of 2-dimethoxy propane (75ml).After stirring 16 hours under the room temperature, concentrate this solution, and make it to be dissolved in again in the ethyl acetate and wash with 7.5% sodium carbonate (2 *).Dry (magnesium sulfate) organic layer, filter and concentrate obtain free alkali (1.3g, 8.2mmol).Be dissolved in it in ether and add HCl (8.2ml, 1.0M is in ether).Filter the precipitate of collecting white, obtain title compound (1.32g, 49%) into white solid.MS(ESI)：159.7(M+H) +。B) N-(2-pyridine radicals methoxycarbonyl)-L-b-tert-butyl group alanine
Step according to embodiment 1 (e)-5 (g), but replace the L-leucine methyl ester hydrochloride of step (e) and use 2-pyridine radicals methanol to replace the 4-pyridine radicals methanol of step (f) with L-b-tert-butyl group methyl lactamine hydrochlorate, be prepared as the title compound (0.55g, 100%) of white solid.MS(ESI)：281.3(M+H) +。C) N-[2-(1-naphthyl) thiazole-4-base carbonyl]-N '-[N-(2-pyridine radicals methoxycarbonyl)-L-b-tert-butyl group alanyl] hydrazides
Step according to embodiment 1 (h), but with N-[2-(1-naphthyl) thiazole-4-base carbonyl] hydrazides replacement N-[2-(suitable-2,6-dimethyl-4-morpholinyl) thiazole-4-base carbonyl] hydrazides and usefulness N-(2-pyridine radicals methoxycarbonyl)-L-b-tert-butyl group alanine replacement N-(4-pyridine radicals methoxycarbonyl)-L-leucine, be prepared as the title compound (0.155g, 47%) of white solid.MS(ESI)：532.2(M+H) +。
Embodiment 182N-[N-(2-methyl-3-pyridine radicals methoxycarbonyl)-L-b-tert-butyl group alanyl]-preparation of N '-[2-(1-naphthyl) thiazole-4-base carbonyl] hydrazides
According to the step of embodiment 181 (a)-181 (c), but replace the 2-pyridine radicals methanol of step (b), be prepared as the title compound (0.169g, 67%) of white solid with 2-methyl-3-pyridine radicals methanol.MS(ESI)：546.2(M+H) +。
Embodiment 183N-[2-(1-naphthyl) thiazole-4-base carbonyl]-a) L-b-cyclopropyl alanine methyl ester hydrochloride of the preparation of N '-[N-(2-pyridine radicals methoxycarbonyl)-L-b-cyclopropyl alanyl] hydrazides
According to the step of embodiment 181 (a), but replace L-b-tert-butyl group alanine, be prepared as the title compound (2.2g, 30%) of white solid with N-tert-butoxycarbonyl-L-b-cyclopropyl alanine methyl ester.MS(ESI)：144.0(M+H) +。B) N-[2-(1-naphthyl) thiazole-4-base carbonyl]-N '-[N-(2-pyridine radicals methoxycarbonyl)-L-b-cyclopropyl alanyl] hydrazides
According to the step of embodiment 181 (b)-181 (c), but replace the L-b-tert-butyl group methyl lactamine hydrochlorate of step (b), be prepared as the title compound (0.147g, 61%) of white solid with L-b-cyclopropyl alanine methyl ester hydrochloride.MS(ESI)：516.1(M+H) +。
Embodiment 184N-[N-(2-methyl-3-pyridine radicals methoxycarbonyl)-L-b-cyclopropyl alanyl]-preparation of N '-[2-(1-naphthyl) thiazole-4-base carbonyl] hydrazides
Step according to embodiment 181 (a)-181 (c), but replace the L-b-tert-butyl group alanine of step (a) and use 2-methyl-3-pyridine radicals methanol to replace the 2-pyridine radicals methanol of step (b) with N-tert-butoxycarbonyl-L-b-cyclopropyl alanine methyl ester, be prepared as the title compound (0.159g, 65%) of white solid.MS(ESI)：530.2(M+H) +。
Embodiment 185N-[N-(6-methyl-3-pyridine radicals methoxycarbonyl)-L-b-cyclopropyl alanyl]-preparation of N '-[2-(1-naphthyl) thiazole-4-base carbonyl] hydrazides
Step according to embodiment 181 (a)-181 (c), but replace the L-b-tert-butyl group alanine of step (a) and use 6-methyl-3-pyridine radicals methanol to replace the 2-pyridine radicals methanol of step (b) with N-tert-butoxycarbonyl-L-b-cyclopropyl alanine methyl ester, be prepared as the title compound (0.169g, 69%) of white solid.MS(ESI)：530.2(M+H) +。
Embodiment 186N-[N-(6-methyl-3-pyridine radicals methoxycarbonyl)-L-b-tert-butyl group alanyl]-preparation of N '-[2-(1-naphthyl) thiazole-4-base carbonyl] hydrazides
According to the step of embodiment 181 (a)-181 (c), but replace the 2-pyridine radicals methanol of step (b), be prepared as the title compound (0.194g, 77%) of white solid with 6-methyl-3-pyridine radicals methanol.MS(ESI)：546.2(M+H) +。
Embodiment 187N, the preparation of N '-two-[2-(1-naphthyl) thiazole-4-base carbonyl] hydrazides is ethyl 2-(1-naphthyl) thiazole-4-carbonohydrazides a)
According to the step of embodiment 3 (a)-3 (c) and 3 (e), but replace the 4-methyl isophthalic acid-naphthalene boronic acids of step (e), be prepared as the title compound of faint yellow solid with 1-naphthyl boric acid.MS(ESI)：270.1(M+H) +。A) ethyl 2-(1-naphthyl) thiazole-4-carbonohydrazides
According to the step of embodiment 1 (g), but replace N-(4-pyridine radicals methoxycarbonyl)-L-leucine methyl ester, be prepared as the title compound of white solid with ethyl 2-(1-naphthyl) thiazole-4-carbonohydrazides.MS(ESI)：256.0(M+H) +。
Embodiment 188N-[2-(N-cyclopropyl-N-cyclopropyl methylamino) thiazole-4-base carbonyl]-preparation of N '-[N-[2-(1,8-naphthyridines acyl group)-L-b-cyclopropyl alanyl] hydrazides
Step according to embodiment 56 (a)-56 (b); but replace N-[2-(N-cyclopropyl-N-cyclopropyl methylamino) thiazole-4-base carbonyl of step (a) with N-(N-tert-butoxycarbonyl-L-b-cyclopropyl alanyl)-N '-[2-(N-cyclopropyl-N-cyclopropyl methylamino) thiazole-4-base carbonyl] hydrazides]-N '-(N-tert-butoxycarbonyl-L-leucyl-) hydrazides; and with 1; 8-naphthyridines-2-formic acid replaces the pyridine carboxylic acid of step (b); be prepared as the title compound (100mg, 59%) of white solid.MS(ESI)：520.2(M+H) +。
Embodiment 189N-[2-[N-cyclopropyl-N-(2-methyl-propyl) amino] thiazole-4-base carbonyl]-preparation of N '-[N-(3, the 4-difluoro benzoyl)-L-b-cyclopropyl alanyl] hydrazides
Step according to embodiment 56 (a)-56 (b); but with N-(N-tert-butoxycarbonyl-L-b-cyclopropyl alanyl)-N '-[2-[N-cyclopropyl-N-(2-methyl-propyl) amino] thiazole-4-base carbonyl] hydrazides replaces N-[2-(N-cyclopropyl-N-cyclopropyl methylamino) thiazole-4-base carbonyl of step (a)]-N '-(N-tert-butoxycarbonyl-L-leucyl-] hydrazides; and with 3; the 4-difluoro-benzoic acid replaces the pyridine carboxylic acid of step (b); be prepared as the title compound (208mg, 100%) of white solid.MS(ESI)：506.1(M+H) +。
Embodiment 190N-[2-[N-cyclopropyl-N-(2-methyl-propyl) amino] thiazole-4-base carbonyl]-preparation of N '-[N-(4-fluoro benzoyl)-L-leucyl-] hydrazides
Step according to embodiment 56 (a)-56 (b); but with N-(N-tert-butoxycarbonyl-L-leucyl-]-N '-[2-[N-cyclopropyl-N-(2-methyl-propyl) amino] thiazole-4-base carbonyl] hydrazides replaces N-[2-(N-cyclopropyl-N-cyclopropyl methylamino) thiazole-4-base carbonyl of step (a)]-N '-(N-tert-butoxycarbonyl-L-leucyl-] hydrazides; and replace the pyridine carboxylic acid of step (b) with the 4-fluobenzoic acid; be prepared as the title compound (130mg, 70%) of white solid.MS(ESI)：490.2(M+H) +。
Embodiment 191N-[N-(5-butyl methyl pyridine acyl)-L-leucyl-]-preparation of N '-[2-(N-cyclopropyl-N-cyclopropyl methylamino) thiazole-4-base carbonyl] hydrazides
Step according to embodiment 56 (a)-56 (b); but with N-(N-tert-butoxycarbonyl-L-leucyl-)-N '-[2-[N-cyclopropyl-N-(2-methyl-propyl) amino] thiazole-4-base carbonyl] hydrazides replaces N-[2-(N-cyclopropyl-N-cyclopropyl methylamino) thiazole-4-base carbonyl of step (a)]-N '-(N-tert-butoxycarbonyl-L-leucyl-) hydrazides; and replace the pyridine carboxylic acid of step (b) with the 5-butyl picolinate; be prepared as the title compound (100mg, 63%) of white solid.MS(ESI)：529.3(M+H) +。
Embodiment 192N-[2-[N-cyclopropyl-N-(2-methyl-propyl) amino] thiazole-4-base carbonyl]-preparation of N '-[N-(3,4-dimethoxy benzoyl)-L-leucyl-] hydrazides
Step according to embodiment 56 (a)-56 (b); but with N-(N-tert-butoxycarbonyl-L-leucyl-)-N '-[2-[N-cyclopropyl-N-(2-methyl-propyl) amino] thiazole-4-base carbonyl] hydrazides replaces N-[2-(N-cyclopropyl-N-cyclopropyl methylamino) thiazole-4-base carbonyl of step (a)]-N '-(N-tert-butoxycarbonyl-L-leucyl-) hydrazides; and with 3; the 4-dimethoxybenzoic acid replaces the pyridine carboxylic acid of step (b); be prepared as the title compound (130mg, 84%) of white solid.MS(ESI)：532.2(M+H) +。
Embodiment 193N-[2-[N-cyclopropyl-N-(2-methyl-propyl) amino] thiazole-4-base carbonyl]-preparation of N '-[N-(3, the 4-difluoro benzoyl)-L-b-tert-butyl group alanyl] hydrazides
Step according to embodiment 56 (a)-56 (b); but with N-(N-tert-butoxycarbonyl-L-b-tert-butyl group alanyl)-N '-[2-[N-cyclopropyl-N-(2-methyl-propyl) amino] thiazole-4-base carbonyl] hydrazides replaces N-[2-(N-cyclopropyl-N-cyclopropyl methylamino) thiazole-4-base carbonyl of step (a)]-N '-(N-tert-butoxycarbonyl-L-leucyl-] hydrazides; and with 3; the 4-difluoro-benzoic acid replaces the pyridine carboxylic acid of step (b); be prepared as the title compound (120mg, 78%) of white solid.MS(ESI)：522.2(M+H) +。
Embodiment 194N-[2-[N-cyclopropyl-N-(2-methyl-propyl) amino] thiazole-4-base carbonyl]-preparation of N '-[N-(3,4-dimethoxy benzoyl)-L-b-tert-butyl group alanyl] hydrazides
Step according to embodiment 56 (a)-56 (b); but with N-(N-tert-butoxycarbonyl-L-b-tert-butyl group alanyl)-N '-[2-[N-cyclopropyl-N-(2-methyl-propyl) amino] thiazole-4-base carbonyl] hydrazides replaces N-[2-(N-cyclopropyl-N-cyclopropyl methylamino) thiazole-4-base carbonyl of step (a)]-N '-(N-tert-butoxycarbonyl-L-leucyl-] hydrazides; and with 3; the 4-dimethoxybenzoic acid replaces the pyridine carboxylic acid of step (b); be prepared as the title compound (73mg, 51%) of white solid.MS(ESI)：546.3(M+H) +。
Embodiment 195N-[N-(5-butyl methyl pyridine acyl)-L-b-tert-butyl group alanyl]-preparation of N '-[2-(N-cyclopropyl-N-cyclopropyl methylamino) thiazole-4-base carbonyl] hydrazides
Step according to embodiment 56 (a)-56 (b); but with N-(N-tert-butoxycarbonyl-L-b-tert-butyl group alanyl]-N '-[2-[N-cyclopropyl-N-(2-methyl-propyl) amino] thiazole-4-base carbonyl] hydrazides replaces N-[2-(N-cyclopropyl-N-cyclopropyl methylamino) thiazole-4-base carbonyl of step (a)]-N '-(N-tert-butoxycarbonyl-L-leucyl-] hydrazides; and replace the pyridine carboxylic acid of step (b) with the 5-butyl picolinate; be prepared as the title compound (120mg, 77%) of white solid.MS(ESI)：543.2(M+H) +。
Embodiment 196N-[2-[N-cyclopropyl-N-(2-methyl-propyl) amino] thiazole-4-base carbonyl]-preparation of N '-[N-(6-methyl pyridine acyl)-L-b-tert-butyl group alanyl] hydrazides
Step according to embodiment 56 (a)-56 (b); but with N-(N-tert-butoxycarbonyl-L-b-tert-butyl group alanyl)-N '-[2-[N-cyclopropyl-N-(2-methyl-propyl) amino] thiazole-4-base carbonyl] hydrazides replaces N-[2-(N-cyclopropyl-N-cyclopropyl methylamino) thiazole-4-base carbonyl of step (a)]-N '-(N-tert-butoxycarbonyl-L-leucyl-) hydrazides; and replace the pyridine carboxylic acid of step (b) with 6-picoline formic acid; be prepared as the title compound (104mg, 72%) of white solid.MS(ESI)：501.3(M+H) +。
Above-mentioned explanation and embodiment full disclosure how to prepare and use chemical compound of the present invention.Yet, the invention is not restricted to specific embodiment described above, but its all change includes in the scope of following claims.Quoting various periodicals, patent and other publication has herein comprised prior art and has been attached to herein by quoting fully.

Claims (58)

1. formula (I) chemical compound and pharmaceutically acceptable salt, hydras and solvate:
Figure A9880664100021
Wherein: L is C 2-6Alkyl, Ar-C 0-6Alkyl, Het-C 0-6Alkyl, CH (R 4) NR 5R 6, CH (R 4) Ar, CH (R 4) OAr ' or NR 4R 7Ar is a phenyl or naphthyl; Ar ' is a phenyl or naphthyl; Het is stable 5-7 unit's monocyclic heterocycles or stable 7-10 unit bicyclic heterocycle, it is saturated or unsaturated, and form by carbon atom and 1-4 hetero atom that is selected from N, O and S, described heterocycle can be connected on any hetero atom or carbon atom that produces rock-steady structure, or wherein any described monocyclic heterocycles condenses any bicyclic radicals on phenyl ring; W is C (O), SO 2X, Y and Z independently are N, O, S or CR 10, condition is to have at least two to be that at least one is N among hetero atom and X, Y and the Z among X, Y and the Z, or among X, Y and the Z one is C=N, C=C or N=N and two other is CR 10Or N, further condition be among X, Y and the Z at least two be N; Refer to singly-bound or two key in 5 yuan of heterocycles; R ', R 1, R 2, R 5, R 8, R 9, R 10And R 12Independent is hydrogen, C 1-6Alkyl, C 2-6Alkenyl, Ar-C 0-6Alkyl or Het-C 0-6Alkyl; R 3Be C 3-6Alkyl, Ar, Het, CH (R 11) Ar, CH (R 11) OAr, NR 11R 12, CH (R 11) NR 12R 13Or
Figure A9880664100022
R 4, R 11And R 15Independent is hydrogen, C 1-6Alkyl, C 2-6Alkenyl, C 3-6Cycloalkyl-C 0-6Alkyl, Ar-C 0-6Alkyl or Het-C 0-6Alkyl; R 7Be C 1-6Alkyl, C 1-6Alkenyl, C 3-6Cycloalkyl-C 0-6Alkyl, Ar-C 0-6Alkyl or Het-C 0-6Alkyl; R 6And R 13Be R 14, R 14C (O), R 14C (S), R 14OC (O) or R 14OC (O) NR 9CH (R 15) (CO); And R 14Be C 1-6Alkyl, C 2-6Alkenyl, Ar-C 0-6Alkyl or Het-C 0-6Alkyl.
2. the chemical compound of claim 1, wherein Ar independently replaces by being selected from following one or more parts: Ph-C 0-6Alkyl, Het-C 0-6Alkyl, C 1-6Alkyl, C 1-6Alkoxyl, Ph-C 0-6Alkoxyl, Het-C 0-6Alkoxyl, OH, (CH 2) 1-6NR 8R 9, O (CH 2) 1-6NR 8R 9, CO 2R ' or halogen.
3. the chemical compound of claim 2, wherein Ph independently replaces by being selected from following one or more parts: C 1-6Alkyl, C 1-6Alkoxyl, OH, (CH 2) 1-6NR 8R 9, O (CH 2) 1-6NR 8R 9, CO 2R ' and halogen.
4. the chemical compound of claim 2, wherein two C 1-6Alkyl can condense saturated or unsaturated 5-7 unit ring on the Ar ring in conjunction with formation.
5. the chemical compound of claim 1, wherein Ar ' independently replaces by being selected from following one or more parts: Ph-C 0-6Alkyl, Het-C 0-6Alkyl, C 1-6Alkyl, C 1-6Alkoxyl, Ph-C 0-6Alkoxyl, Het-C 0-6Alkoxyl, OH, (CH 2) 1-6NR 8R 9, O (CH 2) 1-6NR 8R 9, CO 2R ' or halogen.
6. the chemical compound of claim 5, wherein Ph independently replaces by being selected from following one or more parts: C 1-6Alkyl, C 1-6Alkoxyl, OH, (CH 2) 1-6NR 8R 9, O (CH 2) 1-6NR 8R 9, CO 2R ' and halogen.
7. the chemical compound of claim 5, wherein two C 1-6Alkyl can condense saturated or unsaturated 5-7 unit ring on Ar ' ring in conjunction with formation.
8. the chemical compound of claim 1, wherein Het is by being selected from following one or two part independent replacements: Ph-C 0-6Alkyl, Het-C 0-6Alkyl, C 1-6Alkyl, C 1-6Alkoxyl, Ph-C 0-6Alkoxyl, Het-C 0-6Alkoxyl, OH, (CH 2) 1-6NR 8R 9, O (CH 2) 1-6NR 8R 9Or CO 2R '.
9. the chemical compound of claim 8, wherein Ph independently replaces by being selected from following one or more parts: C 1-6Alkyl, C 1-6Alkoxyl, OH, (CH 2) 1-6NR 8R 9, O (CH 2) 1-6NR 8R 9, CO 2R ' and halogen.
10. the chemical compound of claim 8, wherein two C 1-6Alkyl can condense saturated or unsaturated 5-7 unit ring on the Het ring in conjunction with formation.
11. the chemical compound of claim 1, wherein Het is selected from: piperidyl, piperazinyl, 2-oxo piperazinyl, 2-oxo-piperidine base, 2-oxo-pyrrolidine base, 2-oxo azatropylidene base, the azatropylidene base, pyrrole radicals, the 4-piperidone base, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazole radicals, triazolyl, tetrazole radical, pyridine radicals, pyrazinyl, pyridazinyl (pryidazinyl), pyrimidine radicals, triazine radical, tetrazine base oxazolidinyl oxazolinyl oxazolyl, isothiazolyl isoxazolyl, morpholinyl, thiazolidinyl, thiazolinyl, thiazolyl, quininuclidinyl, indyl, quinolyl, isoquinolyl, benzimidazolyl, benzopyranyl benzoxazolyl, furyl, pyranose, tetrahydrofuran base, THP trtrahydropyranyl, thienyl benzoxazolyl, the thio-morpholinyl sulfoxide, the thio-morpholinyl sulfone, thiadiazolyl group is with the oxadiazole basic ring.
12. the chemical compound of claim 1, wherein R 4And R 7Can be in conjunction with forming 3-7 unit's monocycle or 7-10 unit's bicyclic carbocyclic or heterocycle.
13. the chemical compound of claim 12, wherein said 3-7 unit's monocycle or 7-10 unit's bicyclic carbocyclic or heterocycle are selected from following part by 1-4 independently and replace: C 1-6Alkyl, Ar-C 0-6Alkyl, Het-C 0-6Alkyl, C 1-6Alkoxyl, Ar-C 0-6Alkoxyl, Het-C 0-6Alkoxyl, OH, (CH 2) 1-6NR 8R 9And O (CH 2) 1-6NR 8R 9
14. the chemical compound of claim 1, wherein Z=N, X=S and Y=CH.
15. the chemical compound of claim 14, wherein R 3Be further defined as: Wherein: R 16Be H or C 1-6Alkyl; R 17Be C 1-6Alkyl, C 2-6Alkenyl or C 3-11Cycloalkyl; And R 18Be C 3-6Alkyl, OC 3-6Alkyl, Ar, Het, O (CH 2) 0-3Ar or O (CH 2) 0-3Het.
16. the chemical compound of claim 15, wherein R 16Be H or Me.
17. the chemical compound of claim 15, wherein R 17Be n-pro-pyl, isopropyl, isopentyl, tert-butyl group methyl, cyclopropyl methyl, isobutyl group, normal-butyl or pi-allyl.
18. the chemical compound of claim 15, wherein R 18Be selected from: 2-pyridine radicals methoxyl group, 3-pyridine radicals methoxyl group, 4-pyridine radicals methoxyl group, tert-butoxy, the 2-pyridine radicals, the 3-pyridine radicals, the 4-pyridine radicals, the 2-pyrazinyl, 4-tert-butoxycarbonyl benzyloxy, the 4-carboxyl benzyloxy, 3-tert-butoxycarbonyl benzyloxy, the 3-carboxyl benzyloxy, 2-methyl-3-pyridine radicals methoxyl group, 6-methyl-3-pyridine radicals methoxyl group, benzyloxy, the 2-quinolyl, the 3-quinolyl, the 4-quinolyl, the 5-quinolyl, the 6-quinolyl, the 7-quinolyl, the 8-quinolyl, the 1-isoquinolyl, the 3-isoquinolyl, piperidyl, 4-methyl piperidine base, 4-methylimidazole-5-base, N-benzyl-pyrrolidinyl, N-methyl-pyrrolidinyl, 1-benzyl-5-Methylimidazole .-4-base, the 1-piperazinyl, 3-(2-pyridine radicals) benzyl, 2-methyl-3-pyridine radicals, 2-methyl-4-pyridine radicals, 6-methyl-3-pyridine radicals, 4-dimethylamino benzyloxy, 4-(4-morpholinyl methyl) phenyl, 5-hydroxymethyl imidazol-4 yl, 5-butyl-2-pyridine radicals, 4-fluoro phenyl, 3, the 4-difluorophenyl, 2-(1, the 8-naphthyridinyl) or 3,4-Dimethoxyphenyl.
19. the chemical compound of claim 14, wherein L is selected from: 4-(suitable-2, the 6-dimethyl)-the 4-morpholinyl, N-cyclopropyl methyl-N-(2-methyl-propyl) amino, 4-methyl isophthalic acid-naphthyl, N-methyl-N-(2-methyl-propyl) amino, the 1-naphthyl, 5-acenaphthenyl (acenaphthyl), N-cyclopropyl-N-cyclopropyl methylamino, N, N-pair-(2-methyl-propyl) amino, 1-(1,2,3, the 4-tetrahydric quinoline group), N-cyclopropyl methyl-N-third amino, N-(2-methyl-propyl)-N-phenyl amino, 2-methoxyl group-1-naphthyl, 2-benzyloxy phenyl, 2-benzyloxy-1-naphthyl, the 9-phenanthryl, the 9-anthryl, phenyl, 2-(4-tert-butoxycarbonyl) benzyloxy phenyl, 2-(4-carboxyl benzyloxy) phenyl, N-cyclopropyl amino, the 8-quinolyl, N, N-pair-(cyclopropyl methyl) amino, 4-(2, the 2-dimethylamino ethoxy)-1-naphthyl or 1-(N-benzyloxycarbonyl amino)-3-methyl butyl.
20. A compound of claim 1 selected from: N-[2 - (cis-2 ,6 - dimethyl-4 - morpholinyl) thiazol-4 - yl-carbonyl]-N'-[N-(4 - pyridyl methyl -Butoxycarbonyl)-L-leucyl] hydrazide; N-[2 - (N-cyclopropylmethyl-N-(2 - methylpropyl) amino] thiazol-4 - yl-carbonyl]-N'-[N- (4 - pyridyl methoxycarbonyl)-L-leucyl] hydrazide; N-[2 - (4 - methyl-1 - naphthyl) thiazol-4 - yl-carbonyl]-N'-[N-(4 - pyridyl methoxycarbonyl Yl)-L-leucyl] hydrazide; N-[2 - (N-methyl-N-(2 - methylpropyl) amino] thiazol-4 - yl-carbonyl]-N'-[N-methyl-N- (4 - pyridyl methoxycarbonyl)-L-leucyl] hydrazide; N-[2 - (1 - naphthyl) thiazol-4 - yl-carbonyl]-N'-[N-(3 - pyridyl methoxycarbonyl)-L-leucyl Group] hydrazide; N-[2 - (1 - naphthyl) thiazol-4 - yl-carbonyl]-N'-[N-(2 - pyridyl methoxycarbonyl)-L-leucyl Group] hydrazide; N-[2 - (5 - acenaphthyl) thiazol-4 - yl-carbonyl]-N'-[N-(4 - pyridyl methoxycarbonyl)-L-leucyl Group] hydrazide; N-[2 - [N-cyclopropylmethyl-N-(2 - methylpropyl) amino] thiazol-4 - yl-carbonyl]-N'-[N- Methyl-N-(4 - pyridyl methoxycarbonyl)-L-leucyl] hydrazide; N-[2 - (N-cyclopropyl-N-cyclopropylmethyl-amino) thiazol-4 - yl-carbonyl]-N'-[N-(4 - pyridyl Methoxy carbonyl)-L-leucyl] hydrazide; N-[2 - [N-cyclopropylmethyl-N-(2 - methylpropyl) amino] thiazol-4 - yl-carbonyl]-N'-[N- (3 - pyridyl methoxycarbonyl)-L-leucyl] hydrazide; N-[2 - [N-cyclopropylmethyl-N-(2 - methylpropyl) amino] thiazol-4 - yl-carbonyl]-N'-[N- (2 - pyridyl methoxycarbonyl)-L-leucyl] hydrazide; N-[2 - [N-cyclopropylmethyl-N-(2 - methylpropyl) amino] thiazol-4 - yl-carbonyl]-N'-[N- Methyl-N-(3 - pyridyl methoxycarbonyl)-L-leucyl] hydrazide; N-[2 - (N-cyclopropyl-N-cyclopropylmethyl-amino) thiazol-4 - yl-carbonyl]-N'-[N-(3 - pyridyl Methoxy carbonyl)-L-leucyl] hydrazide; N-[2 - (N-cyclopropyl-N-cyclopropylmethyl-amino) thiazol-4 - yl-carbonyl]-N'-[N-methyl - N-(4 - pyridyl methoxycarbonyl)-L-leucyl] hydrazide; N-[2 - [N, N-bis - (2 - methylpropyl) amino] thiazol-4 - yl-carbonyl]-N'-[N-(2 - pyridyl Methoxycarbonyl)-L-leucyl] hydrazide; N-[N-(4 - pyridyl methoxycarbonyl)-L-leucyl]-N'-[2 - [1 - (1,2,3,4 - tetrahydro-quinoline Morpholinyl) thiazol-4 - ylcarbonyl] hydrazide; N-[2 - [N-methyl-N-(2 - methylpropyl) amino] thiazol-4 - yl-carbonyl]-N'-[4 - methyl-2 - (3 - phenyl)-phenyl-pent-4 - enoyl] hydrazide; N-[2 - [N, N-bis - (2 - methylpropyl) amino] thiazol-4 - yl-carbonyl]-N'-[N-methyl-N-(3 - Pyridyl methoxycarbonyl)-L-leucyl] hydrazide; N-[2 - (N-cyclopropyl-N-cyclopropylmethyl-amino) thiazol-4 - yl-carbonyl]-N'-[N-methyl - N-(3 - pyridyl methoxycarbonyl)-L-leucyl] hydrazide; N-[2 - (N-cyclopropylmethyl-N-propylamino) thiazol-4 - yl-carbonyl]-N'-[N-(3 - pyridyl Methoxycarbonyl)-L-leucyl] hydrazide; N-[2 - [N-methyl-N-(2 - methylpropyl) amino] thiazol-4 - yl-carbonyl]-N'-[4 - methyl-2 - (3 - phenyl) phenylpentanoyl] hydrazide; N-[N-(2 - methylpropyl)-N-(3 - phenyl-phenyl) carbamoyl]-N'-[2 - (1 - naphthyl) thiophene -4 - ylcarbonyl] hydrazide; N-[4 - methyl-2 - (3 - phenyl) phenylpentanoyl]-N'-[2 - (1 - naphthyl) thiazol-4 - yl-carbonyl] acid Hydrazine; N-[4 - methyl-2 - (3 - phenyl) phenylpentanoyl]-N'-[2 - [N-(2 - methylpropyl)-N-phenyl- Amino] thiazol-4 - ylcarbonyl] hydrazide; N-[2 - (2 - methoxy-1 - naphthyl) thiazol-4 - yl-carbonyl]-N'-[N-(4 - pyridyl methoxycarbonyl Yl)-L-leucyl] hydrazide; N-[2 - (2 - benzyloxy-phenyl)-thiazol-4 - yl-carbonyl]-N'-(4 - methyl -2 - (3 - phenyl) phenyl-pentyl Group] hydrazide; N-[2 - (2 - benzyloxy-1 - naphthyl) thiazol-4 - yl-carbonyl]-N'-[N-(4 - pyridyl methoxycarbonyl Yl)-L-leucyl] hydrazide; N-[2 - [N, N-bis - (2 - methylpropyl) amino] thiazol-4 - yl-carbonyl]-N'-[N-methyl-N-(2 - Pyridyl methoxycarbonyl)-L-leucyl] hydrazide; N-[2 - (9 - phenanthryl) thiazol-4 - yl-carbonyl]-N'-[N-(4 - pyridyl methoxycarbonyl)-L-leucyl Group] hydrazide; N-[2 - (9 - anthryl) thiazol-4 - yl-carbonyl]-N'-[N-(4 - pyridyl methoxycarbonyl)-L-leucyl Group] hydrazide; N-[2 - [N, N-bis - (2 - methylpropyl) amino] thiazol-4 - yl-carbonyl]-N'-(t-butoxycarbonyl Yl-L-leucyl) hydrazide; N-[2 - (N, N-bis - (2 - methylpropyl) amino] thiazol-4 - yl-carbonyl]-N'-[N-(L-leucyl Yl) hydrazide; N-[2 - (1 - naphthyl) thiazol-4 - yl-carbonyl]-N'-[N-methyl-N-(3 - pyridyl methoxycarbonyl Yl)-L-leucyl] hydrazide; N-[2 - [N, N-bis - (2 - methylpropyl) amino] thiazol-4 - yl-carbonyl]-N'-(N-methyl-pyridine Acyl-L-leucyl) hydrazide; N-[2 - [N, N-bis - (2 - methylpropyl) amino] thiazol-4 - yl-carbonyl]-N'-[N-(2 - pyrazinylcarbonyl Yl)-L-leucyl) hydrazide; N-[N, N-bis - (2 - methylpropyl) carbamoyl]-N'-[2 - [N-(2 - methylpropyl)-N-phenyl Ylamino]-thiazol-4 - ylcarbonyl] hydrazide; N-(2 - phenyl-thiazol-4 - yl-carbonyl)-N'-[N-(4 - pyridyl methoxycarbonyl)-L-leucyl Yl] hydrazide; N-[2 - [2 - (4 - tert-butoxycarbonyl) benzyloxyphenyl] thiazol-4 - yl-carbonyl]-N'-[N-(4 - pyrazol Piperidinyl methoxycarbonyl)-L-leucyl] hydrazide; N-[2 - [2 - (4 - carboxy-benzyloxy) phenyl] thiazol-4 - yl-carbonyl]-N'-[N-(4 - methoxy-pyridyl Ylcarbonyl)-L-leucyl] hydrazide; N-[N-(4 - tert-butoxycarbonyl-benzyloxycarbonyl)-L-leucyl]-N'-[2 - [N-(2 - methyl- Propyl)-N-phenylamino] thiazol-4 - ylcarbonyl] hydrazide; N-[2 - [N, N-bis - (2 - methylpropyl) amino] thiazol-4 - yl-carbonyl]-N'-[N-(4 - tert-Butoxy- Ylcarbonyl benzyloxycarbonyl)-L-leucyl) hydrazide; N-[N-(4 - carboxy-benzyloxy-carbonyl]-L-leucyl]-N'-[2 - [N-(2 - methylpropyl)-N- Phenylamino]-thiazol-4 - ylcarbonyl] hydrazide; N-(N-benzyloxycarbonyl-L-leucyl)-N'-[2 - [2 - (4 - tert-butoxycarbonyl) benzyloxy Phenyl] thiazol-4 - ylcarbonyl] hydrazide; N-(N-benzyloxycarbonyl-L-leucyl)-N'-[2 - [2 - (4 - carboxy-benzyloxy) phenyl] thiazole -4 - Yl-carbonyl] hydrazide; N-[N-(6 - methyl-3 - pyridyl methoxycarbonyl)-L-leucyl]-N'-[2 - (1 - naphthyl) thiophene -4 - ylcarbonyl] hydrazide; N-(N-benzyloxycarbonyl-L-leucyl)-N'-[2 - (N-cyclopropyl-N-cyclopropylmethyl-amino Yl) thiazol-4 - ylcarbonyl] hydrazide; N-[2 - (N-cyclopropyl-N-cyclopropylmethyl-amino) thiazol-4 - yl-carbonyl]-N'-[N-(2 - pyridyl Methoxy carbonyl)-L-leucyl] hydrazide; N-[2 - (N-cyclopropyl-N-cyclopropylmethyl-amino) thiazol-4 - yl-carbonyl]-N'-[N-(6 - methyl- -, Methyl group methoxycarbonyl)-L-leucyl] hydrazide; N-(N-t-butoxycarbonyl-L-leucyl)-N'-[2 - (N-cyclopropyl-N-cyclopropylmethyl Amino) thiazol-4 - ylcarbonyl] hydrazide; N-[2 - (N-cyclopropyl-N-cyclopropylmethyl-amino) thiazol-4 - yl-carbonyl]-N'-[N-methyl - N-(2 - pyridyl methoxycarbonyl)-L-leucyl] hydrazide; N-[2 - (2 - benzyloxy-phenyl)-thiazol-4 - yl-carbonyl]-N'-[N-(6 - methyl-3 - methoxy-pyridyl Ylcarbonyl)-L-leucyl] hydrazide; N-[2 - (2 - benzyloxy-phenyl)-thiazol-4 - yl-carbonyl]-N'-[N-(2 - methyl-3 - methoxy-pyridyl Ylcarbonyl)-L-leucyl] hydrazide; N-[2 - [N-methyl-N-(2 - methylpropyl) amino] thiazol-4 - yl-carbonyl]-N'-[N-(6 - methyl - 3 - pyridyl methoxycarbonyl)-L-leucyl] hydrazide; N-[2 - [N-methyl-N-(2 - methylpropyl) amino] thiazol-4 - yl-carbonyl]-N'-[N-()-L-bright Amino group] hydrazide; N-[2 - (N-cyclopropyl-N-cyclopropylmethyl-amino) thiazol-4 - yl-carbonyl]-N'-(N-methyl-pyridine Piperidine acyl-L-leucyl] hydrazide; N-[2 - (N-cyclopropyl-N-cyclopropylmethyl-amino) thiazol-4 - yl-carbonyl]-N'-[N-(2 - methyl- -, Methyl group methoxycarbonyl)-L-leucyl] hydrazide; N-[N-(3 - tert-butoxycarbonyl-benzyloxycarbonyl)-L-leucyl]-N'-[2 - (N-cyclopropyl - N-cyclopropylmethyl-amino) thiazol-4 - ylcarbonyl] hydrazide; N-[2 - (1 - naphthyl) thiazol-4 - yl-carbonyl]-N'-[N-(8 - quinolyl group)-L-leucyl] acid Hydrazine; N-[N-(2 - methyl-3 - pyridyl methoxycarbonyl)-L-leucyl]-N'-[2 - (1 - naphthyl) thiophene -4 - ylcarbonyl] hydrazide; N-[2 - (1 - naphthyl) thiazol-4 - yl-carbonyl]-N'-(N-methyl-pyridin-acyl-L-leucyl] acid Hydrazine; N-[N-(3 - carboxy-benzyloxycarbonyl)-L-leucyl]-N'-[2 - (N-cyclopropyl-N-cyclopropyl- Methyl-amino) thiazol-4 - ylcarbonyl] hydrazide; N-[2 - (1 - naphthyl) thiazol-4 - yl-carbonyl]-N'-[N-(2 - quinolyl group)-L-leucyl] acid Hydrazine; N-[2 - (1 - naphthyl) thiazol-4 - yl-carbonyl]-N'-[N-(3 - quinolyl group)-L-leucyl] acid Hydrazine; N-[2 - (1 - naphthyl) thiazol-4 - yl-carbonyl]-N'-[N-(4 - methyl-piperidinyl-carbonyl)-L-leucyl Yl] hydrazide; N-[2 - (1 - naphthyl) thiazol-4 - yl-carbonyl]-N'-[N-(4 - quinolyl group)-L-leucyl] acid Hydrazine; N-[2 - (1 - naphthyl) thiazol-4 - yl-carbonyl]-N'-[N-(5 - quinolyl group)-L-leucyl] acid Hydrazine; N-[2 - (1 - naphthyl) thiazol-4 - yl-carbonyl]-N'-[N-(7 - quinoline acid)-L-leucyl] acid Hydrazine; N-[2 - (1 - naphthyl) thiazol-4 - yl-carbonyl]-N'-[N-(6 - quinoline acid)-L-leucyl] acid Hydrazine; N-[N-(1 - isoquinolyl group)-L-leucyl]-N'-[2 - (1 - naphthyl) thiazol-4 - yl-carbonyl] Hydrazide; N-[N-(3 - isoquinoline group)-L-leucyl]-N'-[2 - (1 - naphthyl) thiazol-4 - yl-carbonyl] Hydrazide; N-[N-(4 - methyl-imidazol-5 - yl-carbonyl)-L-leucyl]-N'-[2 - (1 - naphthyl) thiazol-4 - Ylcarbonyl] hydrazide; N-(N-benzyl-L-prolyl-L-leucyl]-N'-[2 - (1 - naphthyl) thiazol-4 - yl-carbonyl] Hydrazide; N-[N-(1 - benzyl-5 - methyl-imidazol-4 - yl-carbonyl)-L-leucyl]-N'-[2 - (1 - naphthyl) Thiazol-4 - ylcarbonyl] hydrazide; N-[N-(3 - methyl-isonicotinic acid)-L-leucyl]-N'-[2 - (1 - naphthyl) thiazol-4 - yl-carbonyl Yl] hydrazide; N-[2 - (N-cyclopropylamino) thiazol-4 - yl-carbonyl)-N'-[N-(2 - pyridyl methoxycarbonyl Yl)-L-leucyl] hydrazide; N-[4 - methyl -2 - (3 - phenoxy) phenylpentanoyl]-N'-[2 - (1 - naphthyl) thiazol-4 - yl-carbonyl] Hydrazide; N-[N-(2 - benzoxazolyl)-L-leucyl]-N'-[2 - (1 - naphthyl) thiazol-4 - yl-carbonyl] Hydrazide; N-[N-benzyloxycarbonyl-L-leucyl]-N'-[2 - [N, N-bis - (2 - methylpropyl) amino] Oxazol-4 - ylcarbonyl] hydrazide; N-[2 - [N-cyclopropyl-N-(2 - methylpropyl) amino] thiazol-4 - yl-carbonyl]-N'-[N-(2 - pyridine Piperidinyl methoxycarbonyl)-L-leucyl] hydrazide; N-[2 - [N-cyclopropyl-N-(2 - methylpropyl) amino] thiazol-4 - yl-carbonyl]-N'-[N-methyl - (2 - pyridyl methoxycarbonyl)-L-leucyl] hydrazide; N-[2 - (1 - naphthyl) thiazol-4 - yl-carbonyl]-N'-[N-(1 - piperazinyl carbonyl)-L-leucyl] acid Hydrazine; N-[4 - methyl-2 - (4 - phenoxy) phenylpentanoyl]-N'-[N-(1 - naphthyl) thiazol-4 - yl-carbonyl Yl] hydrazide; N-[2 - [N-bis - (cyclopropylmethyl) amino] thiazol-4 - yl-carbonyl]-N'-[N-(2 - pyridyl methyl -Butoxycarbonyl)-L-leucyl] hydrazide; N-[2 - (N-cyclopropyl-N-cyclopropylmethyl-amino) thiazol-4 - yl-carbonyl]-N'-[N-(2 - quinolyl Acyl)-L-leucyl] hydrazide; N-[N-(8 - quinolyl group)-L-leucyl]-N'-[2 - (8 - quinolyl) thiazol-4 - yl-carbonyl] Hydrazide; N-(N-benzyloxycarbonyl-L-leucyl]-N'-[2 - (1 - naphthyl) thiazol-4 - yl-carbonyl] acid Hydrazine; N-[2 - (N-cyclopropyl-N-cyclopropylmethyl-amino) thiazol-4 - yl-carbonyl]-N'-[N-(3 - quinoline Acyl)-L-leucyl] hydrazide; N-[2 - (N-cyclopropyl-N-cyclopropylmethyl-amino) thiazol-4 - yl-carbonyl]-N'-[N-(3 - isoquinoline Morpholino group)-L-leucyl] hydrazide; N-[2 - (N-cyclopropyl-N-cyclopropylmethyl-amino) thiazol-4 - yl-carbonyl]-N'-[N-(6 - quinoline Acyl)-L-leucyl] hydrazide; N-[2 - [N-bis - (cyclopropylmethyl) amino] thiazol-4 - yl-carbonyl]-N'-[N-(2 - methyl-3 - pyridine Piperidinyl methoxycarbonyl)-L-leucyl] hydrazide; N-(N-benzyloxycarbonyl-Lb-t-butyl-alanyl)-N'-[2 - (1 - naphthyl) thiazol-4 - yl Carbonyl] hydrazide; N-(N-benzyloxycarbonyl-Lb-cyclopropyl-alanyl)-N'-[2 - (1 - naphthyl) thiazol-4 - yl Carbonyl] hydrazide; N-[2 - (1 - naphthyl) thiazol-4 - yl-carbonyl]-N'-[N-[3 - (2 - pyridyl) phenylacetyl]-L- Leucyl] hydrazide; N-[2 - [N-bis - (cyclopropylmethyl) amino] thiazol-4 - yl-carbonyl]-N'-(N-methyl-pyridyl - L-leucyl] hydrazide; N-(N-benzyloxycarbonyl-L-leucyl)-N'-[2 - [N-bis - (cyclopropylmethyl) amino] thiophene -4 - ylcarbonyl] hydrazide; N-[2 - (N-cyclopropyl-N-cyclopropylmethyl-amino) thiazol-4 - yl-carbonyl]-N'-[N-(6 - methyl- Nicotinoyl]-L-leucyl] hydrazide; N-[2 - (N-cyclopropyl-N-cyclopropylmethyl-amino) thiazol-4 - yl-carbonyl]-N'-[N-(2 - methyl- Nicotinoyl]-L-leucyl] hydrazide; N-[2 - (N-cyclopropyl-N-cyclopropylmethyl-amino) thiazol-4 - yl-carbonyl]-N'-[N-(3 - methyl- Isonicotinoyl)-L-leucyl] hydrazide; N-[2 - (N-cyclopropyl-N-cyclopropylmethyl-amino) thiazol-4 - yl-carbonyl]-N'-[N-(8 - quinolyl Acyl)-L-leucyl] hydrazide; N-[2 - [N-bis - (cyclopropylmethyl) amino] thiazol-4 - yl-carbonyl]-N'-(N-(8 - quinoline acid Yl)-L-leucyl] hydrazide; N-[2 - [N-bis - (cyclopropylmethyl) amino] thiazol-4 - yl-carbonyl]-N'-(N-(3 - isoquinoline acid Yl)-L-leucyl] hydrazide; N-[2 - [4 - (2,2 - dimethyl-amino-ethoxy)-1 - naphthyl] thiazol-4 - yl-carbonyl]-N'-(N-(8 - Quinoline acid)-L-leucyl] hydrazide; N-[2 - [N-cyclopropyl-N-cyclopropylmethyl-amino) thiazol-4 - yl-carbonyl]-N'-[N-(7 - quinoline Acyl]-L-leucyl] hydrazide; N-[2 - [N-bis - (cyclopropylmethyl) amino] thiazol-4 - yl-carbonyl]-N'-(N-(6 - methyl-nicotinoyl Yl)-L-leucyl] hydrazide; N-[2 - [N-bis - (cyclopropylmethyl) amino] thiazol-4 - yl-carbonyl]-N'-(N-methyl-L-prolyl Acyl)-L-leucyl] hydrazide; N-(N-benzyloxycarbonyl-L-n-valyl)-N'-[2 - (1 - naphthyl) thiazol-4 - yl-carbonyl] acid Hydrazine; N-(N-benzyloxycarbonyl-L-isoleucyl)-N'-[2 - (1 - naphthyl) thiazol-4 - yl-carbonyl] acid Hydrazine; N-[N-(4 - dimethylaminomethyl-benzoyl)-L-leucyl]-N'-(2 - (1 - naphthyl) thiophene -4 - ylcarbonyl] hydrazide; N-(N-benzyloxycarbonyl-L-norleucyl)-N'-[2 - (1 - naphthyl) thiazol-4 - yl-carbonyl] acid Hydrazine; N-[N-(4 - dimethylaminomethyl benzyloxycarbonyl)-L-leucyl]-N'-[2 - (1 - naphthyl) Thiazol-4 - ylcarbonyl] hydrazide; N-(N-benzyloxycarbonyl-L-n-valyl)-N'-[2 - (2 - benzyloxy-phenyl)-thiazol-4 - yl Carbonyl] hydrazide; N-[2 - (N-cyclopropyl-N-cyclopropylmethyl-amino) thiazol-4 - yl-carbonyl]-N'-[N-(4 - methyl- Imidazol-5 - yl-carbonyl)-L-leucyl] hydrazide; N-[N-[4 - (4 - morpholinyl) benzoyl]-L-leucyl]-N'-[2 - (1 - naphthyl) thiophene -4 - ylcarbonyl] hydrazide; N-[N-(2 - methyl-nicotinoyl)-L-leucyl]-N'-[2 - (1 - naphthyl) thiazol-4 - yl-carbonyl] Hydrazide; N-[N-(6 - methyl-nicotinoyl)-L-leucyl]-N'-[2 - (1 - naphthyl) thiazol-4 - yl-carbonyl] Hydrazide; N-(Nb-tert-butoxycarbonyl-L-tert-butyl-alanyl)-N'-[2 - (N-cyclopropyl-N-Ring Methyl-propyl-amino) thiazol-4 - ylcarbonyl] hydrazide; N-[2 - (N-cyclopropyl-N-cyclopropylmethyl-amino) thiazol-4 - yl-carbonyl]-N'-[N-(8 - quinolyl Acyl)-L-b-tert-butyl-alanyl] hydrazide; N-[N-(4 - methyl-imidazol-5 - yl-carbonyl)-L-allyl-glycyl)-N'-(2 - (1 - naphthyl) thiophene -4 - ylcarbonyl] hydrazide; N-[N-(4 - methyl-imidazol-5 - yl-carbonyl)-Lb-t-butyl-alanyl)-N'-[2 - (1 - naphthyl) Thiazol-4 - ylcarbonyl] hydrazide; N-[2 - (N-cyclopropyl-N-cyclopropylmethyl-amino) thiazol-4 - yl-carbonyl]-N'-[N-(4 - methyl- Imidazol-5 - yl-carbonyl)-Lb-t-butyl-alanyl] hydrazide; N-[2 - (1 - naphthyl) thiazol-4 - yl-carbonyl]-N'-(N-methyl-pyridin-acyl-Lb-t-butyl-C Amino group] hydrazide; N-[2 - (1 - naphthyl) thiazol-4 - yl-carbonyl]-N'-[N-(8 - quinolyl group)-Lb-alanine tert-butyl Group] hydrazide; N-[2 - (1 - naphthyl) thiazol-4 - yl-carbonyl]-N'-(N-methyl-pyridin-acyl-L-allyl glycine Group] hydrazide; N-[2 - (1 - naphthyl) thiazol-4 - yl-carbonyl]-N'-(N-methyl-pyridin-acyl-Lb-cyclopropyl-C Amino group] hydrazide; N-[N-(6 - methyl-nicotinoyl)-Lb-cyclopropyl-alanyl]-N'-[2 - (1 - naphthyl) thiazol-4 - Ylcarbonyl] hydrazide; N-[N-(4 - methyl-imidazol-5 - yl-carbonyl)-Lb-cyclopropyl-alanyl]-N'-[2 - (1 - naphthyl) Thiazol-4 - ylcarbonyl] hydrazide; N-[2 - (1 - naphthyl) thiazol-4 - yl-carbonyl]-N'-[N-(8 - quinolyl group)-Lb-cyclopropyl-alanyl Group] hydrazide; N-[N-(6 - methyl-nicotinoyl)-Lb-t-butyl-alanyl]-N'-[2 - (1 - naphthyl) thiazol-4 - Ylcarbonyl] hydrazide; N-[2 - (N-cyclopropyl-N-cyclopropylmethyl-amino) thiazol-4 - yl-carbonyl]-N'-[N-methyl-pyridine Piperidine acyl-L-b-tert-butyl-alanyl] hydrazide; N-[2 - (N-cyclopropyl-N-cyclopropylmethyl-amino) thiazol-4 - yl-carbonyl]-N'-[N-(3 - isoquinoline Morpholino group)-L-b-tert-butyl-alanyl] hydrazide; N-(N-t-butoxycarbonyl-Lb-cyclopropyl-alanyl]-N'-[2 - (N-cyclopropyl-N-Ring Methyl-propyl-amino) thiazol-4 - ylcarbonyl] hydrazide; N-[2 - (N-cyclopropylmethyl-N-propylamino) thiazol-4 - yl-carbonyl]-N'-[N-(6 - methyl - 3 - pyridyl methoxycarbonyl)-L-leucyl] hydrazide; N-[N-(6 - methyl-nicotinoyl)-L-allyl-glycyl]-N'-[2 - (1 - naphthyl) thiazol-4 - yl Carbonyl] hydrazide; N-[2 - (1 - naphthyl) thiazol-4 - yl-carbonyl]-N'-[N-(8 - quinolyl group)-L-allyl-glycyl Yl] hydrazide; N-[2 - (1 - naphthyl) thiazol-4 - yl-carbonyl]-N'-[N-(2 - quinolyl group)-Lb-cyclopropyl-alanyl Group] hydrazide; N-[N-(3 - isoquinoline group)-Lb-cyclopropyl-alanyl]-N'-[- [2 - (1 - naphthyl) thiazol - 4 - ylcarbonyl] hydrazide; N-[N-(1 - isoquinolyl group)-Lb-cyclopropyl-alanyl]-N'-[2 - (1 - naphthyl) thiazol-4 - Ylcarbonyl] hydrazide; N-[2 - (1 - naphthyl) thiazol-4 - yl-carbonyl]-N'-[N-(7 - quinoline acyl)-Lb-cyclopropyl-alanyl Group] hydrazide; N-[2 - (N-cyclopropyl-N-cyclopropylmethyl-amino) thiazol-4 - yl-carbonyl]-N'-[N-(8 - quinolyl Acyl)-L-b-cyclopropyl-alanyl] hydrazide; N-[2 - (N-cyclopropyl-N-cyclopropylmethyl-amino) thiazol-4 - yl-carbonyl]-N'-[N-(4 - methyl- Imidazol-5 - yl-carbonyl)-Lb-cyclopropyl-alanyl] hydrazide; N-[2 - [N-cyclopropyl-N-cyclopropylmethyl-amino) thiazol-4 - yl-carbonyl]-N'-[N-(3 - isoquinoline Morpholino group)-L-b-cyclopropyl-alanyl] hydrazide; N-[2 - (N-cyclopropyl-N-cyclopropylmethyl-amino) thiazol-4 - yl-carbonyl]-N'-[N-(6 - methyl- Nicotinoyl)-L-b-cyclopropyl-alanyl] hydrazide; N-[N-(4 - methyl-imidazol-5 - yl-carbonyl)-L-norleucyl]-N'-[2 - (1 - naphthyl) thiazol - 4 - ylcarbonyl] hydrazide; N-[2 - (1 - naphthyl) thiazol-4 - yl-carbonyl]-N'-(N-methyl-pyridin-acyl-L-norleucyl] Hydrazide; N-[2 - (1 - naphthyl) thiazol-4 - yl-carbonyl]-N'-[N-(8 - quinolyl group)-L-norleucyl] Hydrazide; N-[2 - (N-cyclopropyl-N-cyclopropylmethyl-amino) thiazol-4 - yl-carbonyl]-N'-[N-(2 - quinolyl Acyl)-L-b-cyclopropyl-alanyl] hydrazide; N-[2 - (N-cyclopropyl-N-cyclopropylmethyl-amino) thiazol-4 - yl-carbonyl]-N'-[N-(1 - isoquinoline Morpholino group)-L-b-cyclopropyl-alanyl] hydrazide; N-[2 - [N-cyclopropyl-N-(2 - methylpropyl) amino] thiazol-4 - yl-carbonyl]-N'-[N-(6 - methyl -3 - pyridyl methoxycarbonyl)-L-leucyl] hydrazide; N-(N-t-butoxycarbonyl-L-leucyl]-N'-[2 - [N-cyclopropyl-N-(2 - methylpropyl) Amino) thiazol-4 - ylcarbonyl] hydrazide; N-[2 - (1 - naphthyl) thiazol-4 - yl-carbonyl]-N'-[N-(7 - quinoline acyl)-Lb-alanine tert-butyl Group] hydrazide; N-[2 - (1 - naphthyl) thiazol-4 - yl-carbonyl]-N'-[N-(2 - quinolyl group)-Lb-alanine tert-butyl Group] hydrazide; N-[N-(1 - isoquinolyl group)-Lb-t-butyl-alanyl]-N'-[2 - (1 - naphthyl) thiazol-4 - Ylcarbonyl] hydrazide; N-[N-(3 - isoquinoline group)-Lb-t-butyl-alanyl]-N'-[2 - (1 - naphthyl) thiazol-4 - Ylcarbonyl] hydrazide; N-[N-(6 - methyl-nicotinoyl)-L-norleucyl]-N'-[2 - (1 - naphthyl) thiazol-4 - yl-carbonyl Yl] hydrazide; N-[2 - (1 - naphthyl) thiazol-4 - yl-carbonyl]-N'-[N-(7 - quinoline acid)-L-norleucyl] Hydrazide; N-[2 - (1 - naphthyl) thiazol-4 - yl-carbonyl]-N'-[N-(2 - quinolyl group)-L-norleucyl] Hydrazide; N-[N-(1 - isoquinolyl group)-L-norleucyl]-N'-[2 - (1 - naphthyl) thiazol-4 - yl-carbonyl Yl] hydrazide; N-[N-(3 - isoquinoline group)-L-norleucyl]-N'-[2 - (1 - naphthyl) thiazol-4 - yl-carbonyl Yl] hydrazide; N-[2 - (N-cyclopropyl-N-cyclopropylmethyl-amino) thiazol-4 - yl-carbonyl]-N'-[N-(5 - (hydroxymethyl) Yl imidazol-4 - yl-carbonyl)-Lb-cyclopropyl-alanyl] hydrazide; N-[2 - [N-cyclopropyl-N-(2 - methylpropyl) amino] thiazol-4 - yl-carbonyl]-N'-[N-(8 - quinolyl Morpholino group)-L-b-cyclopropyl-alanyl] hydrazide; N-[2 - (N-cyclopropyl-N-cyclopropylmethyl-amino) thiazol-4 - yl-carbonyl]-N'-[N-(6 - methyl- Nicotinoyl)-L-b-tert-butyl-alanyl] hydrazide; N-[2 - [N-cyclopropyl-N-(2 - methylpropyl) amino] thiazol-4 - yl-carbonyl]-N'-[N-(4 - A Yl-5 - ylcarbonyl)-Lb-cyclopropyl-alanyl] hydrazide; N-[2 - [N-cyclopropyl-N-(2 - methylpropyl) amino] thiazol-4 - yl-carbonyl]-N'-[N-(2 - quinolyl Morpholino group)-L-b-cyclopropyl-alanyl] hydrazide; N-[2 - [N-cyclopropyl-N-(2 - methylpropyl) amino] thiazol-4 - yl-carbonyl]-N'-[N-(6 - methyl Nicotinyl yl)-L-b-cyclopropyl-alanyl] hydrazide; N-[2 - (1 - naphthyl) thiazol-4 - yl-carbonyl]-N'-[N-(8 - quinolyl group) glycyl] hydrazide; N-[2 - (1 - naphthyl) thiazol-4 - yl-carbonyl]-N'-[N-(8 - quinolyl group)-L-n-valyl] Hydrazide; N-[2 - (1 - naphthyl) thiazol-4 - yl-carbonyl]-N'-[N-(2 - quinolyl group)-L-n-valyl] Hydrazide; N-[2 - (1 - naphthyl) thiazol-4 - yl-carbonyl]-N'-(N-methyl-pyridin-acyl-L-n-valyl] Hydrazide; N-[2 - (1 - naphthyl) thiazol-4 - yl-carbonyl]-N'-[N-(6 - methyl-nicotinoyl)-L-n-valyl Yl] hydrazide; N-[2 - (1 - naphthyl) thiazol-4 - yl-carbonyl]-N'-[N-(4 - methyl-imidazol-5 - yl-carbonyl)-L-n Valyl] hydrazide; N-[2 - (1 - naphthyl) thiazol-4 - yl-carbonyl]-N'-[N-(1 - isoquinolyl group)-L-n-valyl Yl] hydrazide; N-[2 - (1 - naphthyl) thiazol-4 - yl-carbonyl]-N'-[N-(3 - isoquinoline group)-L-n-valyl Yl] hydrazide; (1S, 1'S)-N, N'-bis - [4 - [1 - (N-benzyloxycarbonyl) -3 - methylbutyl] thiazol-2 - Ylcarbonyl] hydrazide; N-[2 - (N-cyclopropyl-N-(2 - methylpropyl) amino] thiazol-4 - yl-carbonyl]-N'-[N-(6 - methyl Nicotinyl yl)-L-b-tert-butyl-alanyl] hydrazide; N-[2 - (N-cyclopropyl-N-(2 - methylpropyl) amino] thiazol-4 - yl-carbonyl]-N'-[N-(4 - A Yl-5 - ylcarbonyl)-Lb-t-butyl-alanyl] hydrazide; N-[2 - (N-cyclopropyl-N-cyclopropylmethyl-amino]-thiazol-4 - yl-carbonyl]-N'-[N-(1 - isoquinoline Morpholino group)-L-b-tert-butyl-alanyl] hydrazide; N-[N-(5 - methylpyridine-butyl group)-Lb-t-butyl-alanyl]-N'-[2 - (N-cyclopropylmethyl Yl-N-cyclopropylmethyl-amino) thiazol-4 - ylcarbonyl] hydrazide; N-[2 - (N-cyclopropyl-N-cyclopropylmethyl-amino]-thiazol-4 - yl-carbonyl]-N'-[N-(6 - methyl- Picoline acyl)-Lb-t-butyl-alanyl] hydrazide; N-[2 - (N-cyclopropyl-N-cyclopropylmethyl-amino]-thiazol-4 - yl-carbonyl]-N'-[N-(4 - fluorophenyl Benzoyl)-L-leucyl] hydrazide; N-[N-(4 - fluoro-benzoyl)-L-leucyl]-N'-[2 - (1 - naphthyl) thiazol-4 - yl-carbonyl] Hydrazide; N-[2 - (1 - naphthyl) thiazol-4 - yl-carbonyl]-N'-[N-(2 - pyridyl methoxycarbonyl)-Lb-t Butyl-alanyl] hydrazide; N-[N-(2 - methyl-3 - pyridyl methoxycarbonyl)-Lb-t-butyl-alanyl]-N'-[2 - (1 - naphthyl) thiazol-4 - ylcarbonyl] hydrazide; N-[2 - (1 - naphthyl) thiazol-4 - yl-carbonyl]-N'-[N-(2 - pyridyl methoxycarbonyl)-Lb-Ring Propyl-alanyl] hydrazide; N-[N-(2 - methyl-3 - pyridyl methoxycarbonyl)-Lb-cyclopropyl-alanyl]-N'-[2 - (1 - naphthyl) thiazol-4 - ylcarbonyl] hydrazide; N-[N-(6 - methyl-3 - pyridyl methoxycarbonyl)-Lb-cyclopropyl-alanyl]-N'-[2 - (1 - naphthyl) thiazol-4 - ylcarbonyl] hydrazide; N-[N-(6 - methyl-3 - pyridyl methoxycarbonyl)-Lb-t-butyl-alanyl]-N'-[2 - (1 - naphthyl) thiazol-4 - ylcarbonyl] hydrazide; N, N'-bis - [2 - (1 - naphthyl) thiazol-4 - ylcarbonyl] hydrazide; N-[2 - (N-cyclopropyl-N-cyclopropylmethyl-amino]-thiazol-4 - yl-carbonyl]-N'-[N-[2 - (1,8 - Nalidixic acid)]-Lb-cyclopropyl-alanyl] hydrazide; N-[2 - [N-cyclopropyl-N-(2 - methylpropyl) amino] thiazol-4 - yl-carbonyl]-N'-[N-(3,4 - Difluoro-benzoyl)-Lb-cyclopropyl-alanyl] hydrazide; N-[2 - [N-cyclopropyl-N-(2 - methylpropyl) amino] thiazol-4 - yl-carbonyl]-N'-[N-(4 - fluoro- Benzoyl)-L-leucyl] hydrazide; N-[N-(5 - methylpyridine-butyl group)-L-leucyl]-N'-[2 - (N-cyclopropyl-N-cyclopropylmethyl Ylmethyl-amino) thiazol-4 - ylcarbonyl] hydrazide; N-[2 - [N-cyclopropyl-N-(2 - methylpropyl) amino] thiazol-4 - yl-carbonyl]-N'-[N-(3,4 - Dimethoxybenzoyl)-L-leucyl] hydrazide; N-[2 - [N-cyclopropyl-N-(2 - methylpropyl) amino] thiazol-4 - yl-carbonyl]-N'-[N-(3,4 - Difluoro-benzoyl)-Lb-t-butyl-alanyl] hydrazide; N-[2 - [N-cyclopropyl-N-(2 - methylpropyl) amino] thiazol-4 - yl-carbonyl]-N'-[N-(3,4 - Dimethoxybenzoyl)-Lb-t-butyl-alanyl] hydrazide; N-[N-(5 - methylpyridine-butyl group)-Lb-t-butyl-alanyl]-N'-[2 - (N-cyclopropylmethyl Yl-N-cyclopropylmethyl-amino) thiazol-4 - ylcarbonyl] hydrazide; and N-[2 - [N-cyclopropyl-N-(2 - methylpropyl) amino] thiazol-4 - yl-carbonyl]-N'-[N-(6 - methyl Pyridyl group ylmethyl)-Lb-t-butyl-alanyl] hydrazide. ...
20. A compound of claim 1 selected from: N-[2 - (cis-2 ,6 - dimethyl-4 - morpholinyl) thiazol-4 - yl-carbonyl]-N'-[N-(4 - pyridyl methyl -Butoxycarbonyl)-L-leucyl] hydrazide; N-[2 - (N-cyclopropylmethyl-N-(2 - methylpropyl) amino] thiazol-4 - yl-carbonyl]-N'-[N- (4 - pyridyl methoxycarbonyl)-L-leucyl] hydrazide; N-[2 - (4 - methyl-1 - naphthyl) thiazol-4 - yl-carbonyl]-N'-[N-(4 - pyridyl methoxycarbonyl Yl)-L-leucyl] hydrazide; N-[2 - (N-methyl-N-(2 - methylpropyl) amino] thiazol-4 - yl-carbonyl]-N'-[N-methyl-N- (4 - pyridyl methoxycarbonyl)-L-leucyl] hydrazide; N-[2 - (1 - naphthyl) thiazol-4 - yl-carbonyl]-N'-[N-(3 - pyridyl methoxycarbonyl)-L-leucyl Group] hydrazide; N-[2 - (1 - naphthyl) thiazol-4 - yl-carbonyl]-N'-[N-(2 - pyridyl methoxycarbonyl)-L-leucyl Group] hydrazide; N-[2 - (5 - acenaphthyl) thiazol-4 - yl-carbonyl]-N'-[N-(4 - pyridyl methoxycarbonyl)-L-leucyl Group] hydrazide; N-[2 - [N-cyclopropylmethyl-N-(2 - methylpropyl) amino] thiazol-4 - yl-carbonyl]-N'-[N- Methyl-N-(4 - pyridyl methoxycarbonyl)-L-leucyl] hydrazide; N-[2 - (N-cyclopropyl-N-cyclopropylmethyl-amino) thiazol-4 - yl-carbonyl]-N'-[N-(4 - pyridyl Methoxy carbonyl)-L-leucyl] hydrazide; N-[2 - [N-cyclopropylmethyl-N-(2 - methylpropyl) amino] thiazol-4 - yl-carbonyl]-N'-[N- (3 - pyridyl methoxycarbonyl)-L-leucyl] hydrazide; N-[2 - [N-cyclopropylmethyl-N-(2 - methylpropyl) amino] thiazol-4 - yl-carbonyl]-N'-[N- (2 - pyridyl methoxycarbonyl)-L-leucyl] hydrazide; N-[2 - [N-cyclopropylmethyl-N-(2 - methylpropyl) amino] thiazol-4 - yl-carbonyl]-N'-[N- Methyl-N-(3 - pyridyl methoxycarbonyl)-L-leucyl] hydrazide; N-[2 - (N-cyclopropyl-N-cyclopropylmethyl-amino) thiazol-4 - yl-carbonyl]-N'-[N-(3 - pyridyl Methoxy carbonyl)-L-leucyl] hydrazide; N-[2 - (N-cyclopropyl-N-cyclopropylmethyl-amino) thiazol-4 - yl-carbonyl]-N'-[N-methyl - N-(4 - pyridyl methoxycarbonyl)-L-leucyl] hydrazide; N-[2 - [N, N-bis - (2 - methylpropyl) amino] thiazol-4 - yl-carbonyl]-N'-[N-(2 - pyridyl Methoxycarbonyl)-L-leucyl] hydrazide; N-[N-(4 - pyridyl methoxycarbonyl)-L-leucyl]-N'-[2 - [1 - (1,2,3,4 - tetrahydro-quinoline Morpholinyl) thiazol-4 - ylcarbonyl] hydrazide; N-[2 - [N-methyl-N-(2 - methylpropyl) amino] thiazol-4 - yl-carbonyl]-N'-[4 - methyl-2 - (3 - phenyl)-phenyl-pent-4 - enoyl] hydrazide; N-[2 - [N, N-bis - (2 - methylpropyl) amino] thiazol-4 - yl-carbonyl]-N'-[N-methyl-N-(3 - Pyridyl methoxycarbonyl)-L-leucyl] hydrazide; N-[2 - (N-cyclopropyl-N-cyclopropylmethyl-amino) thiazol-4 - yl-carbonyl]-N'-[N-methyl - N-(3 - pyridyl methoxycarbonyl)-L-leucyl] hydrazide; N-[2 - (N-cyclopropylmethyl-N-propylamino) thiazol-4 - yl-carbonyl]-N'-[N-(3 - pyridyl Methoxycarbonyl)-L-leucyl] hydrazide; N-[2 - [N-methyl-N-(2 - methylpropyl) amino] thiazol-4 - yl-carbonyl]-N'-[4 - methyl-2 - (3 - phenyl) phenylpentanoyl] hydrazide; N-[N-(2 - methylpropyl)-N-(3 - phenyl-phenyl) carbamoyl]-N'-[2 - (1 - naphthyl) thiophene -4 - ylcarbonyl] hydrazide; N-[4 - methyl-2 - (3 - phenyl) phenylpentanoyl]-N'-[2 - (1 - naphthyl) thiazol-4 - yl-carbonyl] acid Hydrazine; N-[4 - methyl-2 - (3 - phenyl) phenylpentanoyl]-N'-[2 - [N-(2 - methylpropyl)-N-phenyl- Amino] thiazol-4 - ylcarbonyl] hydrazide; N-[2 - (2 - methoxy-1 - naphthyl) thiazol-4 - yl-carbonyl]-N'-[N-(4 - pyridyl methoxycarbonyl Yl)-L-leucyl] hydrazide; N-[2 - (2 - benzyloxy-phenyl)-thiazol-4 - yl-carbonyl]-N'-(4 - methyl -2 - (3 - phenyl) phenyl-pentyl Group] hydrazide; N-[2 - (2 - benzyloxy-1 - naphthyl) thiazol-4 - yl-carbonyl]-N'-[N-(4 - pyridyl methoxycarbonyl Yl)-L-leucyl] hydrazide; N-[2 - [N, N-bis - (2 - methylpropyl) amino] thiazol-4 - yl-carbonyl]-N'-[N-methyl-N-(2 - Pyridyl methoxycarbonyl)-L-leucyl] hydrazide; N-[2 - (9 - phenanthryl) thiazol-4 - yl-carbonyl]-N'-[N-(4 - pyridyl methoxycarbonyl)-L-leucyl Group] hydrazide; N-[2 - (9 - anthryl) thiazol-4 - yl-carbonyl]-N'-[N-(4 - pyridyl methoxycarbonyl)-L-leucyl Group] hydrazide; N-[2 - [N, N-bis - (2 - methylpropyl) amino] thiazol-4 - yl-carbonyl]-N'-(t-butoxycarbonyl Yl-L-leucyl) hydrazide; N-[2 - (N, N-bis - (2 - methylpropyl) amino] thiazol-4 - yl-carbonyl]-N'-[N-(L-leucyl Yl) hydrazide; N-[2 - (1 - naphthyl) thiazol-4 - yl-carbonyl]-N'-[N-methyl-N-(3 - pyridyl methoxycarbonyl Yl)-L-leucyl] hydrazide; N-[2 - [N, N-bis - (2 - methylpropyl) amino] thiazol-4 - yl-carbonyl]-N'-(N-methyl-pyridine Acyl-L-leucyl) hydrazide; N-[2 - [N, N-bis - (2 - methylpropyl) amino] thiazol-4 - yl-carbonyl]-N'-[N-(2 - pyrazinylcarbonyl Yl)-L-leucyl) hydrazide; N-[N, N-bis - (2 - methylpropyl) carbamoyl]-N'-[2 - [N-(2 - methylpropyl)-N-phenyl Ylamino]-thiazol-4 - ylcarbonyl] hydrazide; N-(2 - phenyl-thiazol-4 - yl-carbonyl)-N'-[N-(4 - pyridyl methoxycarbonyl)-L-leucyl Yl] hydrazide; N-[2 - [2 - (4 - tert-butoxycarbonyl) benzyloxyphenyl] thiazol-4 - yl-carbonyl]-N'-[N-(4 - pyrazol Piperidinyl methoxycarbonyl)-L-leucyl] hydrazide; N-[2 - [2 - (4 - carboxy-benzyloxy) phenyl] thiazol-4 - yl-carbonyl]-N'-[N-(4 - methoxy-pyridyl Ylcarbonyl)-L-leucyl] hydrazide; N-[N-(4 - tert-butoxycarbonyl-benzyloxycarbonyl)-L-leucyl]-N'-[2 - [N-(2 - methyl- Propyl)-N-phenylamino] thiazol-4 - ylcarbonyl] hydrazide; N-[2 - [N, N-bis - (2 - methylpropyl) amino] thiazol-4 - yl-carbonyl]-N'-[N-(4 - tert-Butoxy- Ylcarbonyl benzyloxycarbonyl)-L-leucyl) hydrazide; N-[N-(4 - carboxy-benzyloxy-carbonyl]-L-leucyl]-N'-[2 - [N-(2 - methylpropyl)-N- Phenylamino]-thiazol-4 - ylcarbonyl] hydrazide; N-(N-benzyloxycarbonyl-L-leucyl)-N'-[2 - [2 - (4 - tert-butoxycarbonyl) benzyloxy Phenyl] thiazol-4 - ylcarbonyl] hydrazide; N-(N-benzyloxycarbonyl-L-leucyl)-N'-[2 - [2 - (4 - carboxy-benzyloxy) phenyl] thiazole -4 - Yl-carbonyl] hydrazide; N-[N-(6 - methyl-3 - pyridyl methoxycarbonyl)-L-leucyl]-N'-[2 - (1 - naphthyl) thiophene -4 - ylcarbonyl] hydrazide; N-(N-benzyloxycarbonyl-L-leucyl)-N'-[2 - (N-cyclopropyl-N-cyclopropylmethyl-amino Yl) thiazol-4 - ylcarbonyl] hydrazide; N-[2 - (N-cyclopropyl-N-cyclopropylmethyl-amino) thiazol-4 - yl-carbonyl]-N'-[N-(2 - pyridyl Methoxy carbonyl)-L-leucyl] hydrazide; N-[2 - (N-cyclopropyl-N-cyclopropylmethyl-amino) thiazol-4 - yl-carbonyl]-N'-[N-(6 - methyl- -, Methyl group methoxycarbonyl)-L-leucyl] hydrazide; N-(N-t-butoxycarbonyl-L-leucyl)-N'-[2 - (N-cyclopropyl-N-cyclopropylmethyl Amino) thiazol-4 - ylcarbonyl] hydrazide; N-[2 - (N-cyclopropyl-N-cyclopropylmethyl-amino) thiazol-4 - yl-carbonyl]-N'-[N-methyl - N-(2 - pyridyl methoxycarbonyl)-L-leucyl] hydrazide; N-[2 - (2 - benzyloxy-phenyl)-thiazol-4 - yl-carbonyl]-N'-[N-(6 - methyl-3 - methoxy-pyridyl Ylcarbonyl)-L-leucyl] hydrazide; N-[2 - (2 - benzyloxy-phenyl)-thiazol-4 - yl-carbonyl]-N'-[N-(2 - methyl-3 - methoxy-pyridyl Ylcarbonyl)-L-leucyl] hydrazide; N-[2 - [N-methyl-N-(2 - methylpropyl) amino] thiazol-4 - yl-carbonyl]-N'-[N-(6 - methyl - 3 - pyridyl methoxycarbonyl)-L-leucyl] hydrazide; N-[2 - [N-methyl-N-(2 - methylpropyl) amino] thiazol-4 - yl-carbonyl]-N'-[N-()-L-bright Amino group] hydrazide; N-[2 - (N-cyclopropyl-N-cyclopropylmethyl-amino) thiazol-4 - yl-carbonyl]-N'-(N-methyl-pyridine Piperidine acyl-L-leucyl] hydrazide; N-[2 - (N-cyclopropyl-N-cyclopropylmethyl-amino) thiazol-4 - yl-carbonyl]-N'-[N-(2 - methyl- -, Methyl group methoxycarbonyl)-L-leucyl] hydrazide; N-[N-(3 - tert-butoxycarbonyl-benzyloxycarbonyl)-L-leucyl]-N'-[2 - (N-cyclopropyl - N-cyclopropylmethyl-amino) thiazol-4 - ylcarbonyl] hydrazide; N-[2 - (1 - naphthyl) thiazol-4 - yl-carbonyl]-N'-[N-(8 - quinolyl group)-L-leucyl] acid Hydrazine; N-[N-(2 - methyl-3 - pyridyl methoxycarbonyl)-L-leucyl]-N'-[2 - (1 - naphthyl) thiophene -4 - ylcarbonyl] hydrazide; N-[2 - (1 - naphthyl) thiazol-4 - yl-carbonyl]-N'-(N-methyl-pyridin-acyl-L-leucyl] acid Hydrazine; N-[N-(3 - carboxy-benzyloxycarbonyl)-L-leucyl]-N'-[2 - (N-cyclopropyl-N-cyclopropyl- Methyl-amino) thiazol-4 - ylcarbonyl] hydrazide; N-[2 - (1 - naphthyl) thiazol-4 - yl-carbonyl]-N'-[N-(2 - quinolyl group)-L-leucyl] acid Hydrazine; N-[2 - (1 - naphthyl) thiazol-4 - yl-carbonyl]-N'-[N-(3 - quinolyl group)-L-leucyl] acid Hydrazine; N-[2 - (1 - naphthyl) thiazol-4 - yl-carbonyl]-N'-[N-(4 - methyl-piperidinyl-carbonyl)-L-leucyl Yl] hydrazide; N-[2 - (1 - naphthyl) thiazol-4 - yl-carbonyl]-N'-[N-(4 - quinolyl group)-L-leucyl] acid Hydrazine; N-[2 - (1 - naphthyl) thiazol-4 - yl-carbonyl]-N'-[N-(5 - quinolyl group)-L-leucyl] acid Hydrazine; N-[2 - (1 - naphthyl) thiazol-4 - yl-carbonyl]-N'-[N-(7 - quinoline acid)-L-leucyl] acid Hydrazine; N-[2 - (1 - naphthyl) thiazol-4 - yl-carbonyl]-N'-[N-(6 - quinoline acid)-L-leucyl] acid Hydrazine; N-[N-(1 - isoquinolyl group)-L-leucyl]-N'-[2 - (1 - naphthyl) thiazol-4 - yl-carbonyl] Hydrazide; N-[N-(3 - isoquinoline group)-L-leucyl]-N'-[2 - (1 - naphthyl) thiazol-4 - yl-carbonyl] Hydrazide; N-[N-(4 - methyl-imidazol-5 - yl-carbonyl)-L-leucyl]-N'-[2 - (1 - naphthyl) thiazol-4 - Ylcarbonyl] hydrazide; N-(N-benzyl-L-prolyl-L-leucyl]-N'-[2 - (1 - naphthyl) thiazol-4 - yl-carbonyl] Hydrazide; N-[N-(1 - benzyl-5 - methyl-imidazol-4 - yl-carbonyl)-L-leucyl]-N'-[2 - (1 - naphthyl) Thiazol-4 - ylcarbonyl] hydrazide; N-[N-(3 - methyl-isonicotinic acid)-L-leucyl]-N'-[2 - (1 - naphthyl) thiazol-4 - yl-carbonyl Yl] hydrazide; N-[2 - (N-cyclopropylamino) thiazol-4 - yl-carbonyl)-N'-[N-(2 - pyridyl methoxycarbonyl Yl)-L-leucyl] hydrazide; N-[4 - methyl -2 - (3 - phenoxy) phenylpentanoyl]-N'-[2 - (1 - naphthyl) thiazol-4 - yl-carbonyl] Hydrazide; N-[N-(2 - benzoxazolyl)-L-leucyl]-N'-[2 - (1 - naphthyl) thiazol-4 - yl-carbonyl] Hydrazide; N-[N-benzyloxycarbonyl-L-leucyl]-N'-[2 - [N, N-bis - (2 - methylpropyl) amino] Oxazol-4 - ylcarbonyl] hydrazide; N-[2 - [N-cyclopropyl-N-(2 - methylpropyl) amino] thiazol-4 - yl-carbonyl]-N'-[N-(2 - pyridine Piperidinyl methoxycarbonyl)-L-leucyl] hydrazide; N-[2 - [N-cyclopropyl-N-(2 - methylpropyl) amino] thiazol-4 - yl-carbonyl]-N'-[N-methyl - (2 - pyridyl methoxycarbonyl)-L-leucyl] hydrazide; N-[2 - (1 - naphthyl) thiazol-4 - yl-carbonyl]-N'-[N-(1 - piperazinyl carbonyl)-L-leucyl] acid Hydrazine; N-[4 - methyl-2 - (4 - phenoxy) phenylpentanoyl]-N'-[N-(1 - naphthyl) thiazol-4 - yl-carbonyl Yl] hydrazide; N-[2 - [N-bis - (cyclopropylmethyl) amino] thiazol-4 - yl-carbonyl]-N'-[N-(2 - pyridyl methyl -Butoxycarbonyl)-L-leucyl] hydrazide; N-[2 - (N-cyclopropyl-N-cyclopropylmethyl-amino) thiazol-4 - yl-carbonyl]-N'-[N-(2 - quinolyl Acyl)-L-leucyl] hydrazide; N-[N-(8 - quinolyl group)-L-leucyl]-N'-[2 - (8 - quinolyl) thiazol-4 - yl-carbonyl] Hydrazide; N-(N-benzyloxycarbonyl-L-leucyl]-N'-[2 - (1 - naphthyl) thiazol-4 - yl-carbonyl] acid Hydrazine; N-[2 - (N-cyclopropyl-N-cyclopropylmethyl-amino) thiazol-4 - yl-carbonyl]-N'-[N-(3 - quinoline Acyl)-L-leucyl] hydrazide; N-[2 - (N-cyclopropyl-N-cyclopropylmethyl-amino) thiazol-4 - yl-carbonyl]-N'-[N-(3 - isoquinoline Morpholino group)-L-leucyl] hydrazide; N-[2 - (N-cyclopropyl-N-cyclopropylmethyl-amino) thiazol-4 - yl-carbonyl]-N'-[N-(6 - quinoline Acyl)-L-leucyl] hydrazide; N-[2 - [N-bis - (cyclopropylmethyl) amino] thiazol-4 - yl-carbonyl]-N'-[N-(2 - methyl-3 - pyridine Piperidinyl methoxycarbonyl)-L-leucyl] hydrazide; N-(N-benzyloxycarbonyl-Lb-t-butyl-alanyl)-N'-[2 - (1 - naphthyl) thiazol-4 - yl Carbonyl] hydrazide; N-(N-benzyloxycarbonyl-Lb-cyclopropyl-alanyl)-N'-[2 - (1 - naphthyl) thiazol-4 - yl Carbonyl] hydrazide; N-[2 - (1 - naphthyl) thiazol-4 - yl-carbonyl]-N'-[N-[3 - (2 - pyridyl) phenylacetyl]-L- Leucyl] hydrazide; N-[2 - [N-bis - (cyclopropylmethyl) amino] thiazol-4 - yl-carbonyl]-N'-(N-methyl-pyridyl - L-leucyl] hydrazide; N-(N-benzyloxycarbonyl-L-leucyl)-N'-[2 - [N-bis - (cyclopropylmethyl) amino] thiophene -4 - ylcarbonyl] hydrazide; N-[2 - (N-cyclopropyl-N-cyclopropylmethyl-amino) thiazol-4 - yl-carbonyl]-N'-[N-(6 - methyl- Nicotinoyl]-L-leucyl] hydrazide; N-[2 - (N-cyclopropyl-N-cyclopropylmethyl-amino) thiazol-4 - yl-carbonyl]-N'-[N-(2 - methyl- Nicotinoyl]-L-leucyl] hydrazide; N-[2 - (N-cyclopropyl-N-cyclopropylmethyl-amino) thiazol-4 - yl-carbonyl]-N'-[N-(3 - methyl- Isonicotinoyl)-L-leucyl] hydrazide; N-[2 - (N-cyclopropyl-N-cyclopropylmethyl-amino) thiazol-4 - yl-carbonyl]-N'-[N-(8 - quinolyl Acyl)-L-leucyl] hydrazide; N-[2 - [N-bis - (cyclopropylmethyl) amino] thiazol-4 - yl-carbonyl]-N'-(N-(8 - quinoline acid Yl)-L-leucyl] hydrazide; N-[2 - [N-bis - (cyclopropylmethyl) amino] thiazol-4 - yl-carbonyl]-N'-(N-(3 - isoquinoline acid Yl)-L-leucyl] hydrazide; N-[2 - [4 - (2,2 - dimethyl-amino-ethoxy)-1 - naphthyl] thiazol-4 - yl-carbonyl]-N'-(N-(8 - Quinoline acid)-L-leucyl] hydrazide; N-[2 - [N-cyclopropyl-N-cyclopropylmethyl-amino) thiazol-4 - yl-carbonyl]-N'-[N-(7 - quinoline Acyl]-L-leucyl] hydrazide; N-[2 - [N-bis - (cyclopropylmethyl) amino] thiazol-4 - yl-carbonyl]-N'-(N-(6 - methyl-nicotinoyl Yl)-L-leucyl] hydrazide; N-[2 - [N-bis - (cyclopropylmethyl) amino] thiazol-4 - yl-carbonyl]-N'-(N-methyl-L-prolyl Acyl)-L-leucyl] hydrazide; N-(N-benzyloxycarbonyl-L-n-valyl)-N'-[2 - (1 - naphthyl) thiazol-4 - yl-carbonyl] acid Hydrazine; N-(N-benzyloxycarbonyl-L-isoleucyl)-N'-[2 - (1 - naphthyl) thiazol-4 - yl-carbonyl] acid Hydrazine; N-[N-(4 - dimethylaminomethyl-benzoyl)-L-leucyl]-N'-(2 - (1 - naphthyl) thiophene -4 - ylcarbonyl] hydrazide; N-(N-benzyloxycarbonyl-L-norleucyl)-N'-[2 - (1 - naphthyl) thiazol-4 - yl-carbonyl] acid Hydrazine; N-[N-(4 - dimethylaminomethyl benzyloxycarbonyl)-L-leucyl]-N'-[2 - (1 - naphthyl) Thiazol-4 - ylcarbonyl] hydrazide; N-(N-benzyloxycarbonyl-L-n-valyl)-N'-[2 - (2 - benzyloxy-phenyl)-thiazol-4 - yl Carbonyl] hydrazide; N-[2 - (N-cyclopropyl-N-cyclopropylmethyl-amino) thiazol-4 - yl-carbonyl]-N'-[N-(4 - methyl- Imidazol-5 - yl-carbonyl)-L-leucyl] hydrazide; N-[N-[4 - (4 - morpholinyl) benzoyl]-L-leucyl]-N'-[2 - (1 - naphthyl) thiophene -4 - ylcarbonyl] hydrazide; N-[N-(2 - methyl-nicotinoyl)-L-leucyl]-N'-[2 - (1 - naphthyl) thiazol-4 - yl-carbonyl] Hydrazide; N-[N-(6 - methyl-nicotinoyl)-L-leucyl]-N'-[2 - (1 - naphthyl) thiazol-4 - yl-carbonyl] Hydrazide; N-(Nb-tert-butoxycarbonyl-L-tert-butyl-alanyl)-N'-[2 - (N-cyclopropyl-N-Ring Methyl-propyl-amino) thiazol-4 - ylcarbonyl] hydrazide; N-[2 - (N-cyclopropyl-N-cyclopropylmethyl-amino) thiazol-4 - yl-carbonyl]-N'-[N-(8 - quinolyl Acyl)-L-b-tert-butyl-alanyl] hydrazide; N-[N-(4 - methyl-imidazol-5 - yl-carbonyl)-L-allyl-glycyl)-N'-(2 - (1 - naphthyl) thiophene -4 - ylcarbonyl] hydrazide; N-[N-(4 - methyl-imidazol-5 - yl-carbonyl)-Lb-t-butyl-alanyl)-N'-[2 - (1 - naphthyl) Thiazol-4 - ylcarbonyl] hydrazide; N-[2 - (N-cyclopropyl-N-cyclopropylmethyl-amino) thiazol-4 - yl-carbonyl]-N'-[N-(4 - methyl- Imidazol-5 - yl-carbonyl)-Lb-t-butyl-alanyl] hydrazide; N-[2 - (1 - naphthyl) thiazol-4 - yl-carbonyl]-N'-(N-methyl-pyridin-acyl-Lb-t-butyl-C Amino group] hydrazide; N-[2 - (1 - naphthyl) thiazol-4 - yl-carbonyl]-N'-[N-(8 - quinolyl group)-Lb-alanine tert-butyl Group] hydrazide; N-[2 - (1 - naphthyl) thiazol-4 - yl-carbonyl]-N'-(N-methyl-pyridin-acyl-L-allyl glycine Group] hydrazide; N-[2 - (1 - naphthyl) thiazol-4 - yl-carbonyl]-N'-(N-methyl-pyridin-acyl-Lb-cyclopropyl-C Amino group] hydrazide; N-[N-(6 - methyl-nicotinoyl)-Lb-cyclopropyl-alanyl]-N'-[2 - (1 - naphthyl) thiazol-4 - Ylcarbonyl] hydrazide; N-[N-(4 - methyl-imidazol-5 - yl-carbonyl)-Lb-cyclopropyl-alanyl]-N'-[2 - (1 - naphthyl) Thiazol-4 - ylcarbonyl] hydrazide; N-[2 - (1 - naphthyl) thiazol-4 - yl-carbonyl]-N'-[N-(8 - quinolyl group)-Lb-cyclopropyl-alanyl Group] hydrazide; N-[N-(6 - methyl-nicotinoyl)-Lb-t-butyl-alanyl]-N'-[2 - (1 - naphthyl) thiazol-4 - Ylcarbonyl] hydrazide; N-[2 - (N-cyclopropyl-N-cyclopropylmethyl-amino) thiazol-4 - yl-carbonyl]-N'-[N-methyl-pyridine Piperidine acyl-L-b-tert-butyl-alanyl] hydrazide; N-[2 - (N-cyclopropyl-N-cyclopropylmethyl-amino) thiazol-4 - yl-carbonyl]-N'-[N-(3 - isoquinoline Morpholino group)-L-b-tert-butyl-alanyl] hydrazide; N-(N-t-butoxycarbonyl-Lb-cyclopropyl-alanyl]-N'-[2 - (N-cyclopropyl-N-Ring Methyl-propyl-amino) thiazol-4 - ylcarbonyl] hydrazide; N-[2 - (N-cyclopropylmethyl-N-propylamino) thiazol-4 - yl-carbonyl]-N'-[N-(6 - methyl - 3 - pyridyl methoxycarbonyl)-L-leucyl] hydrazide; N-[N-(6 - methyl-nicotinoyl)-L-allyl-glycyl]-N'-[2 - (1 - naphthyl) thiazol-4 - yl Carbonyl] hydrazide; N-[2 - (1 - naphthyl) thiazol-4 - yl-carbonyl]-N'-[N-(8 - quinolyl group)-L-allyl-glycyl Yl] hydrazide; N-[2 - (1 - naphthyl) thiazol-4 - yl-carbonyl]-N'-[N-(2 - quinolyl group)-Lb-cyclopropyl-alanyl Group] hydrazide; N-[N-(3 - isoquinoline group)-Lb-cyclopropyl-alanyl]-N'-[- [2 - (1 - naphthyl) thiazol - 4 - ylcarbonyl] hydrazide; N-[N-(1 - isoquinolyl group)-Lb-cyclopropyl-alanyl]-N'-[2 - (1 - naphthyl) thiazol-4 - Ylcarbonyl] hydrazide; N-[2 - (1 - naphthyl) thiazol-4 - yl-carbonyl]-N'-[N-(7 - quinoline acyl)-Lb-cyclopropyl-alanyl Group] hydrazide; N-[2 - (N-cyclopropyl-N-cyclopropylmethyl-amino) thiazol-4 - yl-carbonyl]-N'-[N-(8 - quinolyl Acyl)-L-b-cyclopropyl-alanyl] hydrazide; N-[2 - (N-cyclopropyl-N-cyclopropylmethyl-amino) thiazol-4 - yl-carbonyl]-N'-[N-(4 - methyl- Imidazol-5 - yl-carbonyl)-Lb-cyclopropyl-alanyl] hydrazide; N-[2 - [N-cyclopropyl-N-cyclopropylmethyl-amino) thiazol-4 - yl-carbonyl]-N'-[N-(3 - isoquinoline Morpholino group)-L-b-cyclopropyl-alanyl] hydrazide; N-[2 - (N-cyclopropyl-N-cyclopropylmethyl-amino) thiazol-4 - yl-carbonyl]-N'-[N-(6 - methyl- Nicotinoyl)-L-b-cyclopropyl-alanyl] hydrazide; N-[N-(4 - methyl-imidazol-5 - yl-carbonyl)-L-norleucyl]-N'-[2 - (1 - naphthyl) thiazol - 4 - ylcarbonyl] hydrazide; N-[2 - (1 - naphthyl) thiazol-4 - yl-carbonyl]-N'-(N-methyl-pyridin-acyl-L-norleucyl] Hydrazide; N-[2 - (1 - naphthyl) thiazol-4 - yl-carbonyl]-N'-[N-(8 - quinolyl group)-L-norleucyl] Hydrazide; N-[2 - (N-cyclopropyl-N-cyclopropylmethyl-amino) thiazol-4 - yl-carbonyl]-N'-[N-(2 - quinolyl Acyl)-L-b-cyclopropyl-alanyl] hydrazide; N-[2 - (N-cyclopropyl-N-cyclopropylmethyl-amino) thiazol-4 - yl-carbonyl]-N'-[N-(1 - isoquinoline Morpholino group)-L-b-cyclopropyl-alanyl] hydrazide; N-[2 - [N-cyclopropyl-N-(2 - methylpropyl) amino] thiazol-4 - yl-carbonyl]-N'-[N-(6 - methyl -3 - pyridyl methoxycarbonyl)-L-leucyl] hydrazide; N-(N-t-butoxycarbonyl-L-leucyl]-N'-[2 - [N-cyclopropyl-N-(2 - methylpropyl) Amino) thiazol-4 - ylcarbonyl] hydrazide; N-[2 - (1 - naphthyl) thiazol-4 - yl-carbonyl]-N'-[N-(7 - quinoline acyl)-Lb-alanine tert-butyl Group] hydrazide; N-[2 - (1 - naphthyl) thiazol-4 - yl-carbonyl]-N'-[N-(2 - quinolyl group)-Lb-alanine tert-butyl Group] hydrazide; N-[N-(1 - isoquinolyl group)-Lb-t-butyl-alanyl]-N'-[2 - (1 - naphthyl) thiazol-4 - Ylcarbonyl] hydrazide; N-[N-(3 - isoquinoline group)-Lb-t-butyl-alanyl]-N'-[2 - (1 - naphthyl) thiazol-4 - Ylcarbonyl] hydrazide; N-[N-(6 - methyl-nicotinoyl)-L-norleucyl]-N'-[2 - (1 - naphthyl) thiazol-4 - yl-carbonyl Yl] hydrazide; N-[2 - (1 - naphthyl) thiazol-4 - yl-carbonyl]-N'-[N-(7 - quinoline acid)-L-norleucyl] Hydrazide; N-[2 - (1 - naphthyl) thiazol-4 - yl-carbonyl]-N'-[N-(2 - quinolyl group)-L-norleucyl] Hydrazide; N-[N-(1 - isoquinolyl group)-L-norleucyl]-N'-[2 - (1 - naphthyl) thiazol-4 - yl-carbonyl Yl] hydrazide; N-[N-(3 - isoquinoline group)-L-norleucyl]-N'-[2 - (1 - naphthyl) thiazol-4 - yl-carbonyl Yl] hydrazide; N-[2 - (N-cyclopropyl-N-cyclopropylmethyl-amino) thiazol-4 - yl-carbonyl]-N'-[N-(5 - (hydroxymethyl) Yl imidazol-4 - yl-carbonyl)-Lb-cyclopropyl-alanyl] hydrazide; N-[2 - [N-cyclopropyl-N-(2 - methylpropyl) amino] thiazol-4 - yl-carbonyl]-N'-[N-(8 - quinolyl Morpholino group)-L-b-cyclopropyl-alanyl] hydrazide; N-[2 - (N-cyclopropyl-N-cyclopropylmethyl-amino) thiazol-4 - yl-carbonyl]-N'-[N-(6 - methyl- Nicotinoyl)-L-b-tert-butyl-alanyl] hydrazide; N-[2 - [N-cyclopropyl-N-(2 - methylpropyl) amino] thiazol-4 - yl-carbonyl]-N'-[N-(4 - A Yl-5 - ylcarbonyl)-Lb-cyclopropyl-alanyl] hydrazide; N-[2 - [N-cyclopropyl-N-(2 - methylpropyl) amino] thiazol-4 - yl-carbonyl]-N'-[N-(2 - quinolyl Morpholino group)-L-b-cyclopropyl-alanyl] hydrazide; N-[2 - [N-cyclopropyl-N-(2 - methylpropyl) amino] thiazol-4 - yl-carbonyl]-N'-[N-(6 - methyl Nicotinyl yl)-L-b-cyclopropyl-alanyl] hydrazide; N-[2 - (1 - naphthyl) thiazol-4 - yl-carbonyl]-N'-[N-(8 - quinolyl group) glycyl] hydrazide; N-[2 - (1 - naphthyl) thiazol-4 - yl-carbonyl]-N'-[N-(8 - quinolyl group)-L-n-valyl] Hydrazide; N-[2 - (1 - naphthyl) thiazol-4 - yl-carbonyl]-N'-[N-(2 - quinolyl group)-L-n-valyl] Hydrazide; N-[2 - (1 - naphthyl) thiazol-4 - yl-carbonyl]-N'-(N-methyl-pyridin-acyl-L-n-valyl] Hydrazide; N-[2 - (1 - naphthyl) thiazol-4 - yl-carbonyl]-N'-[N-(6 - methyl-nicotinoyl)-L-n-valyl Yl] hydrazide; N-[2 - (1 - naphthyl) thiazol-4 - yl-carbonyl]-N'-[N-(4 - methyl-imidazol-5 - yl-carbonyl)-L-n Valyl] hydrazide; N-[2 - (1 - naphthyl) thiazol-4 - yl-carbonyl]-N'-[N-(1 - isoquinolyl group)-L-n-valyl Yl] hydrazide; N-[2 - (1 - naphthyl) thiazol-4 - yl-carbonyl]-N'-[N-(3 - isoquinoline group)-L-n-valyl Yl] hydrazide; (1S, 1'S)-N, N'-bis - [4 - [1 - (N-benzyloxycarbonyl) -3 - methylbutyl] thiazol-2 - Ylcarbonyl] hydrazide; N-[2 - (N-cyclopropyl-N-(2 - methylpropyl) amino] thiazol-4 - yl-carbonyl]-N'-[N-(6 - methyl Nicotinyl yl)-L-b-tert-butyl-alanyl] hydrazide; N-[2 - (N-cyclopropyl-N-(2 - methylpropyl) amino] thiazol-4 - yl-carbonyl]-N'-[N-(4 - A Yl-5 - ylcarbonyl)-Lb-t-butyl-alanyl] hydrazide; N-[2 - (N-cyclopropyl-N-cyclopropylmethyl-amino]-thiazol-4 - yl-carbonyl]-N'-[N-(1 - isoquinoline Morpholino group)-L-b-tert-butyl-alanyl] hydrazide; N-[N-(5 - methylpyridine-butyl group)-Lb-t-butyl-alanyl]-N'-[2 - (N-cyclopropylmethyl Yl-N-cyclopropylmethyl-amino) thiazol-4 - ylcarbonyl] hydrazide; N-[2 - (N-cyclopropyl-N-cyclopropylmethyl-amino]-thiazol-4 - yl-carbonyl]-N'-[N-(6 - methyl- Picoline acyl)-Lb-t-butyl-alanyl] hydrazide; N-[2 - (N-cyclopropyl-N-cyclopropylmethyl-amino]-thiazol-4 - yl-carbonyl]-N'-[N-(4 - fluorophenyl Benzoyl)-L-leucyl] hydrazide; N-[N-(4 - fluoro-benzoyl)-L-leucyl]-N'-[2 - (1 - naphthyl) thiazol-4 - yl-carbonyl] Hydrazide; N-[2 - (1 - naphthyl) thiazol-4 - yl-carbonyl]-N'-[N-(2 - pyridyl methoxycarbonyl)-Lb-t Butyl-alanyl] hydrazide; N-[N-(2 - methyl-3 - pyridyl methoxycarbonyl)-Lb-t-butyl-alanyl]-N'-[2 - (1 - naphthyl) thiazol-4 - ylcarbonyl] hydrazide; N-[2 - (1 - naphthyl) thiazol-4 - yl-carbonyl]-N'-[N-(2 - pyridyl methoxycarbonyl)-Lb-Ring Propyl-alanyl] hydrazide; N-[N-(2 - methyl-3 - pyridyl methoxycarbonyl)-Lb-cyclopropyl-alanyl]-N'-[2 - (1 - naphthyl) thiazol-4 - ylcarbonyl] hydrazide; N-[N-(6 - methyl-3 - pyridyl methoxycarbonyl)-Lb-cyclopropyl-alanyl]-N'-[2 - (1 - naphthyl) thiazol-4 - ylcarbonyl] hydrazide; N-[N-(6 - methyl-3 - pyridyl methoxycarbonyl)-Lb-t-butyl-alanyl]-N'-[2 - (1 - naphthyl) thiazol-4 - ylcarbonyl] hydrazide; N, N'-bis - [2 - (1 - naphthyl) thiazol-4 - ylcarbonyl] hydrazide; N-[2 - (N-cyclopropyl-N-cyclopropylmethyl-amino]-thiazol-4 - yl-carbonyl]-N'-[N-[2 - (1,8 - Nalidixic acid)]-Lb-cyclopropyl-alanyl] hydrazide; N-[2 - [N-cyclopropyl-N-(2 - methylpropyl) amino] thiazol-4 - yl-carbonyl]-N'-[N-(3,4 - Difluoro-benzoyl)-Lb-cyclopropyl-alanyl] hydrazide; N-[2 - [N-cyclopropyl-N-(2 - methylpropyl) amino] thiazol-4 - yl-carbonyl]-N'-[N-(4 - fluoro- Benzoyl)-L-leucyl] hydrazide; N-[N-(5 - methylpyridine-butyl group)-L-leucyl]-N'-[2 - (N-cyclopropyl-N-cyclopropylmethyl Ylmethyl-amino) thiazol-4 - ylcarbonyl] hydrazide; N-[2 - [N-cyclopropyl-N-(2 - methylpropyl) amino] thiazol-4 - yl-carbonyl]-N'-[N-(3,4 - Dimethoxybenzoyl)-L-leucyl] hydrazide; N-[2 - [N-cyclopropyl-N-(2 - methylpropyl) amino] thiazol-4 - yl-carbonyl]-N'-[N-(3,4 - Difluoro-benzoyl)-Lb-t-butyl-alanyl] hydrazide; N-[2 - [N-cyclopropyl-N-(2 - methylpropyl) amino] thiazol-4 - yl-carbonyl]-N'-[N-(3,4 - Dimethoxybenzoyl)-Lb-t-butyl-alanyl] hydrazide; N-[N-(5 - methylpyridine-butyl group)-Lb-t-butyl-alanyl]-N'-[2 - (N-cyclopropylmethyl Yl-N-cyclopropylmethyl-amino) thiazol-4 - ylcarbonyl] hydrazide; and N-[2 - [N-cyclopropyl-N-(2 - methylpropyl) amino] thiazol-4 - yl-carbonyl]-N'-[N-(6 - methyl Pyridyl group ylmethyl)-Lb-t-butyl-alanyl] hydrazide. ...
22. contain the chemical compound of claim 1 and the Pharmaceutical composition of pharmaceutically acceptable carrier, diluent or excipient.
23. contain the chemical compound of claim 21 and the Pharmaceutical composition of pharmaceutically acceptable carrier, diluent or excipient.
24. inhibition is selected from the method for the protease of cysteine proteinase and serine protease, this method comprises the chemical compound of the claim 1 of the patient's effective dose that needs.
25. inhibition is selected from the method for the protease of cysteine proteinase and serine protease, this method comprises the chemical compound of the claim 21 of the patient's effective dose that needs.
26. the method for claim 24, wherein said protease are cysteine proteinase.
27. the method for claim 25, wherein said protease are cysteine proteinase.
28. the method for claim 26, wherein said cysteine proteinase are cathepsin K.
29. the method for claim 27, wherein said cysteine proteinase are cathepsin K.
30. treatment is the method for the disease of feature with the bone loss, the chemical compound that comprises the claim 1 by patient's effective dose of needing is to suppress described bone loss.
31. the method for claim 30, wherein said disease are osteoporosis.
32. the method for claim 30, wherein said disease are periodontitis.
33. the method for claim 30, wherein said disease are gingivitis.
34. treatment is the method for the disease of feature with excessive cartilage or substrate degradation, the chemical compound that comprises the claim 1 by patient's effective dose of needing is to suppress described excessive cartilage or substrate degradation.
35. the method for claim 34, wherein said disease are osteoarthritis.
36. the method for claim 34, wherein said disease are rheumatoid arthritis.
37. treatment is the method for the disease of feature with the bone loss, the chemical compound that comprises the claim 21 by patient's effective dose of needing is to suppress described bone loss.
38. the method for claim 37, wherein said disease are osteoporosis.
39. the method for claim 37, wherein said disease are periodontitis.
40. the method for claim 37, wherein said disease are gingivitis.
41. treatment is the method for the disease of feature with excessive cartilage or substrate degradation, the chemical compound that comprises the claim 21 by patient's effective dose of needing is to suppress described excessive cartilage or substrate degradation.
42. the method for claim 41, wherein said disease are osteoarthritis.
43. the method for claim 41, wherein said disease are rheumatoid arthritis.
44. the method for the chemical compound of preparation claim 1 comprises making intermediate:
Figure A9880664100331
In aprotonic solvent with carboxylic acid R 3CO 2The step of H and the reaction of peptide coupling agent.
45. the method for claim 44, wherein said peptide coupling agent is EDCHCl/1-HOBT when using carboxylic acid.
46. the method for claim 45, wherein said aprotonic solvent are DMF.
47. the method for the chemical compound of preparation claim 1 comprises making intermediate:
Figure A9880664100332
In dichloromethane with carbamyl chloride R 3The step of COCl and triethylamine reaction.
48. the method for the chemical compound of preparation claim 1 comprises making intermediate: In dichloromethane with sulfonic acid chloride R 3SO 2The step of Cl and NMM reaction.
49. each chemical compound is used for the purposes of the medicine of Profilin enzyme in production among the claim 1-21, described protease is selected from cysteine proteinase and serine protease.
50. the purposes of claim 49, wherein said protease are cysteine proteinase.
51. the purposes of claim 51, wherein said cysteine proteinase are cathepsin K.
52. to be used for the treatment of with the bone loss in production be purposes in the medicine of disease of feature to each chemical compound among the claim 1-21.
53. the purposes of claim 52, wherein said disease are osteoporosis.
54. the purposes of claim 52, wherein said disease are periodontitis.
55. the purposes of claim 52, wherein said disease are gingivitis.
56. to be used for the treatment of with excessive cartilage or substrate degradation in production be purposes in the medicine of disease of feature to each chemical compound among the claim 1-21.
57. the purposes of claim 56, wherein said disease are osteoarthritis.
58. the purposes of claim 56, wherein said disease are rheumatoid arthritis.
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US10358453B2 (en) 2015-02-25 2019-07-23 Alios Biopharma, Inc. Antiviral compounds

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