CN1761655A

CN1761655A - Thiazole derivatives and their use as VAP-1 inhibitors

Info

Publication number: CN1761655A
Application number: CN 200480007682
Authority: CN
Inventors: 井上隆幸; 东条隆; 森田真正; 大久保充; 吉原耕生; 永岛亮
Original assignee: Yamanouchi Pharmaceutical Co Ltd
Current assignee: Fujisawa Pharmaceutical Co Ltd; Yamanouchi Pharmaceutical Co Ltd
Priority date: 2003-01-27
Filing date: 2004-01-27
Publication date: 2006-04-19
Anticipated expiration: 2024-01-27
Also published as: CN100491361C

Abstract

A compound of the formula (I): R<1>-NH-X-Y-Z (I) wherein R<1> is acyl; X is a bivalent residue derived from optionally substituted thiazole; Y is a bond, lower alkylene or -COHN-; and Z is a groupe of the formulae (II) or (III) wherein R<2> is a specified substituent or a pharmaceutically acceptable salt thereof useful as a vascular adhesion protein-1 (VAP-1) inhibitor for preventing or treating a VAP-1associated disease, especially macular edema.

Description

Thiazole derivative and as the purposes of VAP-1 inhibitor

The present invention relates to can be used as blood vessel attachment proteins-1 inhibitor compound or its pharmacy acceptable salt, comprise the purposes etc. of method, described compound, its salt or the composition of medicinal compositions as the described compound or its salt of activeconstituents, prevention or treatment blood vessel attachment proteins-1 relative disease (especially macular edema).

Background technology

Blood vessel attachment proteins-1 (being abbreviated as VAP-1 hereinafter) is that (the semicarbazide-sensitive amine oxydase, SSAO), it is present in human plasma to a kind of amine oxidase in a large number, and expresses significantly in the blood vessel endothelium at inflammatory position and vascular smooth muscle and increase.Though at present the physiological action of VAP-1 is not illustrated yet, clones the VAP-1 gene in 1998, it is reported that VAP-1 is a kind of membranin, as expression be subjected to inflammatory cytokine under regulating adhesion molecule adjusting lymphocyte and the rolling and the migration of NK cell.Although the amine as substrate is unknown, it is believed that it is the methylamine that biological certain body partly produces.Be known that equally because the important factor that hydrogen peroxide that the amine oxidase activity of VAP-1 molecule is produced and aldehydes are adhesive activity.

Up-to-date report proof I type and the VAP-1 enzymic activity in the type ii diabetes patient blood plasma strengthen, especially in the diabetic subject who suffers from the retinopathy complication, significantly strengthen (Diabetologia, 42 (1999) 233-237, Diabetic Medicine, 16 (1999) 514-521).

In addition, it is reported that VAP-1 is also relevant with following disease:

(1) liver cirrhosis, basicly stable hypertension, diabetes, joint disease (referring to JP-A-61-239891 and USP4,888,283);

(2) (diabetes, atherosclerosis and hypertensive) endothelial injury, diabetes and uremia with cardiovascular disorder, gout and arthritis pain, (diabetic subject's) retinopathy (referring to WO93/23023);

(3) (reticular tissue) inflammatory diseases or illness (rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis and osteoarthritis or degenerative osteoarthritis, Reiter syndrome, dry syndrome, Behcet, relapsing polychondritis, systemic lupus erythematosus, discoid lupus erythematosus, systemic sclerosis, eosinophilic fasciitis, polymyositis, dermatomyositis, polymyalgia rheumatica, vasculitis, temporal arteritis, polyarteritis nodosa, Wei Geneishi granuloma disease, mixed connective tissue disease and juvenile rheumatoid arthritis); Gastroenteritis disease or illness [Crohn disease, ulcerative colitis, irritable bowel syndrome (spastic colon), hepatic fibrosis disease, oral mucosa inflammation (stomatitis) and recurrent aphthous stomatitis]; Inflammatory disease of central nervous system or illness (multiple sclerosis, Alzheimer's and ischemia apoplexy with ischemia reperfusion injury); Pulmonary inflammation disease or illness (asthma, adult respiratory distress syndrome, chronic obstructive pulmonary disease); (chronic) inflammatory disease of the skin or illness (psoriasis, supersensitivity pathology, lichen planus, pityriasis rosea, contact dermatitis, atopic dermatitis, pityriasis rubra pilaris); Carbohydrate metabolism disease (complication of diabetes and diabetes) comprises capillary blood vessel and great vessels disease (atherosclerosis, retinal retinitis, retinopathy, ephrosis, nephrotic syndrome and neuropathy (polyneuropathy, mononeuropathy and autonomic neuropathy), ulcer of foot, joint problem and infection risk increase); Adipocyte differentiation or function or smooth muscle cell malfunction disease (atherosclerosis and obesity); Vascular disease [atherosclerotic arteriosclerosis, non-atherosclerotic arteriosclerosis, cardiac ischemia (comprising myocardial infarction) and peripheral arterial occlusion, Raynaud disease and phenomenon, thromboangiitis obliterans (Buerger's disease)]; Chronic arthritis; Inflammatory bowel; Tetter (disclosing 2002/0173521 A1) referring to WO02/02090, WO02/02541 and US patent application;

(4) diabetes (referring to WO02/38152);

(5) SSAO mediates property complication [diabetes (insulin-dependent diabetes (IDDM) and non-insulin-dependent diabetes mellitus (NIDDM) (NIDDM)) and vascular complication (heart attack, stenocardia, apoplexy, amputation, blind and renal failure)] (referring to WO02/38153) etc.

In the present circumstance, need pharmacological agent or prevent above-mentioned disease.

Macular edema is that the common eye that is caused by many causes of disease is unusual, is characterised in that the integrity and the optic disk that disturb the microvascular blood-retina barrier of perifovea.Known macular edema comprises diabetic and non-diabetic macular edema.Macular edema as diabetic complication is the disease that can appear at any stage of diabetic retinopathy, occurs before beginning to form neovascularity and causes a series of visual disorder.Macular area is amphiblestroid height evolution part, has vital role aspect the control eyesight.In case the macular area oedema, no matter how slight variation can cause that also eyesight obviously descends, if note handling, oedema causes the irreversible variation of macula lutea tissue, will promote the development of retinopathy.

At present, for macular edema, attempted using laser beam freezing method and operation on vitreous as symptomatiatria.But laser radiation is to macular area and be not easy, and unnecessary laser therapy may have side effects (for example may evoke oedema by causing inflammation).It is effective to 70% macular edema that operation on vitreous is considered to, but patient's body and economical load are big, and recurrence rate is also high.These methods of treatment are not usually used in the less relatively stage of the starting stage of macular edema, particularly visual deterioration.Therefore in the present circumstance, the commitment for macular edema also needs the relatively easy drug therapy of using.

Disclosure of the Invention

The inventor has furtherd investigate the problem of pharmacological agent VAP-1 relative disease, finds that the VAP-1 inhibitor can be used for prevention or treats described disease, especially macular edema, thereby has finished the present invention.Thus, the invention provides:

[1] a kind of following formula (I) compound [being sometimes referred to as compound (I) hereinafter] or its pharmacy acceptable salt:

R ^l-NH-X-Y-Z (I)

Wherein

R ¹Be acyl group;

X is the residue of divalent derived from the optional thiazole that replaces;

Y be chemical bond, low-grade alkylidene, lower alkenylene or-CONH-;

Z is the following formula group:

Or

R wherein ²Be following formula group :-A-B-D-E

Wherein A be chemical bond, low-grade alkylidene ,-NH-or-SO ₂-;

B be chemical bond, low-grade alkylidene ,-CO-or-O-;

D be chemical bond, low-grade alkylidene ,-NH-or-CH ₂NH-;

E for the amino of optional protection ,-N=CH ₂,

Or

Wherein

Q is-S-or-NH-;

R ³For hydrogen, low alkyl group, lower alkylthio or-NH-R ⁴, wherein

R ⁴For hydrogen ,-NH ₂Or low alkyl group.

[2] compound [1] or its pharmacy acceptable salt, wherein Z is the following formula group:

R wherein ²Be the following formula group:

(wherein G be chemical bond ,-NHCOCH ₂-or low-grade alkylidene, R ⁴For hydrogen ,-NH ₂Or low alkyl group);-NH ₂-CH ₂NH ₂-CH ₂ONH ₂-CH ₂ON=CH ₂

Or

[3] compound [2] or its pharmacy acceptable salt, wherein R ²Be the following formula group:

(wherein G be chemical bond ,-NHCOCH ₂-or low-grade alkylidene, R ⁴Be hydrogen or low alkyl group);-CH ₂NH ₂-CH ₂ONH ₂-CH ₂ON=CH ₂

Or

Arbitrary compound of [4] [1]-[3] or its pharmacy acceptable salt, wherein R ¹Be alkyl-carbonyl, X is replaced by the methyl sulphonyl benzyl derived from the residue of divalent of thiazole is also optional.

[5] compound [1], wherein said compound is

N-{4-[2-(4-{[amino (imino-) methyl] amino } phenyl) ethyl]-1,3-thiazoles-2-yl } ethanamide,

N-{4-[2-(4-{[amino (imino-) methyl] amino } phenyl) ethyl]-5-[4-(methyl sulphonyl) benzyl]-1,3-thiazoles-2-yl } ethanamide,

N-{4-[2-(4-{[diazanyl (imino-) methyl] amino } phenyl) ethyl]-5-[4-(methyl sulphonyl) benzyl]-1,3-thiazoles-2-yl } ethanamide,

N-{4-[2-(4-{[diazanyl (imino-) methyl] amino } phenyl) ethyl]-1,3-thiazoles-2-yl } ethanamide, or

N-(4-{2-[4-(2-{[amino (imino-) methyl] amino } ethyl) phenyl] ethyl }-1,3-thiazoles-2-yl) ethanamide;

Perhaps their pharmacy acceptable salt.

[6] compound [1] or its pharmacy acceptable salt are as the purposes of medicine.

[7] a kind of medicinal compositions, said composition comprise compound [1] or its pharmacy acceptable salt as activeconstituents.

[8] method of a kind of preparation formula (I) compound or its pharmacy acceptable salt:

R ¹-NH-X-Y-Z (I)

Wherein

R ¹Be acyl group;

X is the residue of divalent derived from the optional thiazole that replaces;

Y be chemical bond, low-grade alkylidene, lower alkenylene or-CONH-;

Z is the following formula group:

Or

R wherein ²Be following formula group :-A-B-D-E,

Wherein A be chemical bond, low-grade alkylidene ,-NH-or-SO ₂-;

B be chemical bond, low-grade alkylidene ,-CO-or-O-;

D be chemical bond, low-grade alkylidene ,-NH-or-CH ₂NH-;

E for the amino of optional protection ,-N=CH ₂,

Or

Wherein

Q is-S-or-NH-;

R ³For hydrogen, low alkyl group, lower alkylthio or-NH-R ⁴, wherein

R ⁴For hydrogen ,-NH ₂Or low alkyl group;

Described method comprise be selected from (i)-(at least one step v):

(i) make compound (1):

With compound (2) or its reactant salt:

L wherein ₁Be leavings group, Z is definition above;

(ii) make compound (3) or its salt: H ₂N-X-Z, wherein X and Z are definition above, react with compound (4): R ¹-L ₂, R wherein ¹Be definition above, L ₂Be leavings group;

(iii) make compound (6) or its salt: R ¹-NH-X-CHO, wherein R ¹With X be above definition, with compound (7) or its reactant salt: L ₃-CH ₂-Z, wherein L ₃Be leavings group, Z is definition above;

(iv) with compound (10) or its salt: R ¹-NH-X-(lower alkenylene)-Z, wherein R ¹, X and Z be definition above, is reduced to compound (11) or its salt: R ¹-NH-X-(low-grade alkylidene)-Z, wherein R ¹, X and Z be definition above;

(v) make compound (12) or its salt: R ¹-NH-X-COOH or its reactive derivatives, wherein R ¹With X be above definition, with compound (13) or its reactant salt: L ₄-NH-Z, wherein L ₄Be hydrogen atom or blocking group, Z is definition above.

[9] compound [1] or its pharmacy acceptable salt purposes in the preparation medicine, described medicine is the VAP-1 inhibitor.

[10] purposes [9], wherein said compound is

N-(4-{2-[4-(2-{[amino (imino-) methyl] amino } ethyl) phenyl] ethyl }-1,3-thiazoles-2-yl) ethanamide.

[11] compound [1] or its pharmacy acceptable salt purposes in the preparation medicine, described medicine are used for prevention or treatment VAP-1 relative disease.

[12] purposes [11], wherein said VAP-1 relative disease is selected from liver cirrhosis, basicly stable hypertension, diabetes, joint disease, (diabetes, atherosclerosis and hypertensive) endothelial injury, diabetes and uremia with cardiovascular disorder, gout and arthritis pain, (diabetic subject's) retinopathy, (reticular tissue) inflammatory diseases or illness (rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, osteoarthritis or degenerative osteoarthritis, Reiter syndrome, sjogren syndrome, Behcet, relapsing polychondritis, systemic lupus erythematosus, discoid lupus erythematosus, systemic sclerosis, eosinophilic fasciitis, polymyositis, dermatomyositis, polymyalgia rheumatica, vasculitis, temporal arteritis, polyarteritis nodosa, Wei Geneishi granuloma disease, mixed connective tissue disease and juvenile rheumatoid arthritis), gastroenteritis disease or illness [Crohn disease, ulcerative colitis, irritable bowel syndrome (spastic colon), the hepatic fibrosis disease, oral mucosa inflammation (stomatitis) and recurrent aphthous stomatitis], inflammatory disease of central nervous system or illness (multiple sclerosis, Alzheimer's and ischemia apoplexy with ischemia reperfusion injury), pulmonary inflammation disease or illness (asthma, adult respiratory distress syndrome, chronic obstructive pulmonary disease), (chronic) inflammatory disease of the skin or illness (psoriasis, the supersensitivity pathology, lichen planus, pityriasis rosea, contact dermatitis, atopic dermatitis, pityriasis rubra pilaris), (complication of diabetes and diabetes comprises capillary blood vessel and great vessels disease (atherosclerosis to the carbohydrate metabolism disease, retinal retinitis, retinopathy, ephrosis, nephrotic syndrome and neuropathy (polyneuropathy, mononeuropathy and autonomic neuropathy), ulcer of foot, joint problem and infection risk increase)), adipocyte differentiation or function or smooth muscle cell malfunction disease (atherosclerosis and obesity), vascular disease [atherosclerotic arteriosclerosis, non-atherosclerotic arteriosclerosis, cardiac ischemia (comprising myocardial infarction) and peripheral arterial occlusion, Raynaud disease and phenomenon, thromboangiitis obliterans (Buerger's disease)], chronic arthritis, inflammatory bowel, tetter, diabetes, [diabetes (insulin-dependent diabetes (IDDM) and non-insulin-dependent diabetes mellitus (NIDDM) (NIDDM)) and the vascular complication (heart attack of SSAO mediation property complication, stenocardia, apoplexy, amputation, lose one's sight and renal failure)] and macular edema (diabetic and non-diabetic macular edema).

[13] purposes [12], wherein said VAP-1 relative disease is a macular edema.

[14] purposes [13], wherein said macular edema is a diabetic macular edema.

[15] purposes [13], wherein said macular edema is non-diabetic macular edema.

[16] a kind of VAP-1 inhibitor, its inclusion compound [1] or its pharmacy acceptable salt.

[17] method of a kind of prevention or treatment macular edema, this method comprises that the VAP-1 inhibitor that needs the recipient of this treatment capacity is to treat described recipient's macular edema.

[18] method [17], wherein said VAP-1 inhibitor is

N-(4-{2-[4-(2-{[amino (imino-) methyl] amino } ethyl) phenyl] ethyl }-1,3-thiazoles-2-yl) ethanamide,

Perhaps their pharmacy acceptable salt.

[19] method of a kind of prevention or treatment VAP-1 relative disease, this method comprises compound [1] or its pharmacy acceptable salt that gives the Mammals significant quantity.

[20] method [19], wherein said VAP-1 relative disease is selected from liver cirrhosis, basicly stable hypertension, diabetes, joint disease, (diabetes, atherosclerosis and hypertensive) endothelial injury, diabetes and uremia with cardiovascular disorder, gout and arthritis pain, (diabetic subject's) retinopathy, (reticular tissue) inflammatory diseases or illness (rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis and osteoarthritis or degenerative osteoarthritis, Reiter syndrome, sjogren syndrome, Behcet, relapsing polychondritis, systemic lupus erythematosus, discoid lupus erythematosus, systemic sclerosis, eosinophilic fasciitis, polymyositis, dermatomyositis, polymyalgia rheumatica, vasculitis, temporal arteritis, polyarteritis nodosa, Wei Geneishi granuloma disease, mixed connective tissue disease and juvenile rheumatoid arthritis), gastroenteritis disease or illness [Crohn disease, ulcerative colitis, irritable bowel syndrome (spastic colon), the hepatic fibrosis disease, oral mucosa inflammation (stomatitis) and recurrent aphthous stomatitis], inflammatory disease of central nervous system or illness (multiple sclerosis, Alzheimer's and ischemia apoplexy with ischemia reperfusion injury), pulmonary inflammation disease or illness (asthma, adult respiratory distress syndrome, chronic obstructive pulmonary disease), (chronic) inflammatory disease of the skin or illness (psoriasis, the supersensitivity pathology, lichen planus, pityriasis rosea, contact dermatitis, atopic dermatitis, pityriasis rubra pilaris), (complication of diabetes and diabetes comprises capillary blood vessel and great vessels disease (atherosclerosis to the carbohydrate metabolism disease, retinal retinitis, retinopathy, ephrosis, nephrotic syndrome and neuropathy (polyneuropathy, mononeuropathy and autonomic neuropathy), ulcer of foot, joint problem and infection risk increase)), adipocyte differentiation or function or smooth muscle cell malfunction disease (atherosclerosis and obesity), vascular disease [atherosclerotic arteriosclerosis, non-atherosclerotic arteriosclerosis, cardiac ischemia (comprising myocardial infarction) and peripheral arterial occlusion, Raynaud disease and phenomenon, thromboangiitis obliterans (Buerger's disease)], chronic arthritis, inflammatory bowel, tetter, diabetes, [diabetes (insulin-dependent diabetes (IDDM) and non-insulin-dependent diabetes mellitus (NIDDM) (NIDDM)) and the vascular complication (heart attack of SSAO mediation property complication, stenocardia, apoplexy, amputation, lose one's sight and renal failure)] and macular edema (diabetic and non-diabetic macular edema).

[21] method [20], wherein said VAP-1 relative disease is a macular edema.

[22] method [21], wherein said macular edema is a diabetic macular edema.

[23] method [21], wherein said macular edema is non-diabetic macular edema.

Detailed Description Of The Invention

The present invention is based on following discovery: blood vessel attachment proteins-1 (VAP-1; Being also referred to as semicarbazide-sensitive amine oxydase (SSAO) or copper bearing amine oxidase) inhibitor can effectively treat or improve VAP-1 relative disease, especially macular edema etc.In view of the above, the invention provides compound (I) or its pharmacy acceptable salt, medicinal compositions, prevention that can be used as the VAP-1 inhibitor or the method for the treatment of the VAP-1 relative disease etc.

In the context of the present specification, be included in the scope of the invention various definition suitable example and the explanation elaborate hereinafter.

Suitable " halogen " comprises fluorine, chlorine, bromine and iodine.

Except as otherwise noted, otherwise term " rudimentary " be meant have 1-6, the group of preferred 1-4 carbon atom.

Suitable " low alkyl group " comprises the straight or branched alkyl of 1-6 carbon atom, and for example methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, tert-pentyl and hexyl wherein more select C ₁-C ₄Alkyl.

Suitable " lower alkylthio " comprises the lower alkylthio that contains above low alkyl group, for example methylthio group, ethylmercapto group, rosickyite base, iprotiazem base, butylthio, isobutyl sulfenyl, secondary butylthio, uncle's butylthio, penta sulfenyl, uncle's penta sulfenyl and own sulfenyl.

Suitable " low-grade alkylidene " comprises the straight or branched alkylidene group of 1-6 carbon atom, for example methylene radical, ethylene, trimethylene, fourth support, Propylene, ethylidene and propylidene, wherein more preferably C ₁-C ₄Alkylidene group.

Suitable " lower alkenylene " comprises the straight or branched alkenylene of 2-6 carbon atom, for example-CH=CH-,-CH ₂-CH=CH-,-CH ₂-CH=CH-CH ₂-,-CH ₂-CH ₂-CH=CH-,-CH=CH-CH=CH-,-CH=CH-CH ₂-CH ₂-CH ₂-,-CH=CH-CH=CH-CH ₂-CH ₂-and-CH=CH-CH=CH-CH=CH-, wherein more preferably C ₂-C ₄Alkenylene.

Above lower alkenylene can be respectively E type or Z type.Thus, those skilled in the art can understand when lower alkenylene contains more than 2 or 2 two key, comprise its all E types, Z type structure.

Suitable " aryl " comprises C ₆-C ₁₀Aryl, for example phenyl and naphthyl, wherein more preferably phenyl." aryl " can be replaced by 1-3 substituting group, and the position of substitution is not particularly limited.

Suitable " aralkyl " comprises such aralkyl: wherein to have 6-10 carbon atom [be that aryl moiety is the C of above-mentioned " aryl " to aryl moiety ₆-C ₁₀Aryl], it [is that moieties is the C of above-mentioned " low alkyl group " that moieties has 1-6 carbon atom ₁-C ₆Alkyl], for example benzyl, styroyl, 1-naphthyl methyl, 2-naphthyl methyl, 3-phenyl propyl, 4-phenyl butyl and 5-phenylpentyl.

" optional protection amino " is meant can be according to known method amino with the appropriate protection radical protection itself, for example the method for introduction such as Protective Groups in Organic Synthesis (JohnWiley and Sons publishes (1980)).Suitable " blocking group " comprise tert-butoxycarbonyl (being Boc), the acyl group of hereinafter mentioning, replacement or unsubstituted aryl (rudimentary) alkylidene group [for example benzylidene, hydroxyl benzylidene etc.], aryl (rudimentary) alkyl for example single-, two-or triphenyl-(rudimentary) alkyl [for example benzyl, styroyl, diphenyl-methyl, trityl etc.] etc.

Suitable " amino of optional protection " comprises amino and tert-butoxycarbonyl amino (promptly-NHBoc).

Suitable " heterocycle " comprises " aromatic heterocycle " and " non-aromatic heterocyclic ".

Suitable " aromatic heterocycle " comprises also contain the heteroatomic 5-10 unit aromatic heterocycle that 1-3 is selected from nitrogen, oxygen and sulphur except that carbon atom, comprises for example thiophene, furans, pyrroles, imidazoles, pyrazoles, thiazole, isothiazole, oxazole, isoxazole, pyridine, pyridazine, pyrimidine, pyrazine etc.

Suitable " non-aromatic heterocyclic " comprises that ring also contains 1-3 the first non-aromatic heterocyclic of heteroatomic 5-10 that is selected from nitrogen, oxygen and sulphur except that carbon atom, comprise for example tetramethyleneimine, tetrahydroglyoxaline, pyrazolidine, pyrazoline, piperidines, piperazine, morpholine, thiomorpholine, dioxolane, oxazolidine, thiazolidine, triazolidine etc.

Suitable " acyl group " comprises the acyl group of 1-20 carbon atom, for example formyl radical, alkyl-carbonyl, aryl carbonyl, alkoxy carbonyl and aralkyl oxy carbonyl.

Suitable " alkyl-carbonyl " comprises that it [is that moieties is the C of above " low alkyl group " that moieties has 1-6 carbon atom ₁-C ₆Alkyl] alkyl-carbonyl, for example ethanoyl, propionyl, butyryl radicals, isobutyryl, pentanoyl, isovaleryl, valeryl, caproyl and oenanthyl, wherein C more preferably ₁-C ₄Alkyl-carbonyl.

Suitable " aryl carbonyl " comprises that it [is that aryl moiety is the C of above " aryl " that aryl moiety has 6-10 carbon atom ₆-C _L0Aryl] aryl carbonyl, for example benzoyl and naphthoyl.

Suitable " alkoxy carbonyl " comprises that alkoxyl group partly has the alkoxy carbonyl of 1-6 carbon atom, for example methoxycarbonyl, ethoxy carbonyl, propoxycarbonyl, isopropoxy carbonyl, butoxy carbonyl, isobutoxy carbonyl, sec-butoxy carbonyl, tert-butoxycarbonyl, pentyloxy carbonyl, tert-pentyloxy carbonyl and hexyloxy carbonyl, wherein more preferably alkoxyl group partly has the alkoxy carbonyl of 1-4 carbon atom.

Suitable " aralkyl oxy carbonyl " comprises such aralkyl oxy carbonyl: wherein to have 6-10 carbon atom [be that aryl moiety is the C of above " aryl " to aryl moiety ₆-C ₁₀Aryl], it [is that moieties is the C of above " low alkyl group " that moieties has 1-6 carbon atom ₁-C ₆Alkyl], for example benzyloxycarbonyl, benzene ethoxy carbonyl, 1-naphthyl methoxycarbonyl, 2-naphthyl methoxycarbonyl, 3-phenyl propoxycarbonyl, 4-phenyl butoxy carbonyl and 5-phenyl pentyloxy carbonyl.

Suitable " derived from the residue of divalent of thiazole " of " derived from the residue of divalent of the optional thiazole that replaces " comprises

With

" thiazole " can have 1-3 substituting group, and each substituting group position is not particularly limited.

More than suitable " substituting group " of " optional replace thiazole " for example comprise:

(1) halogen defined above;

(2) alkoxy carbonyl defined above, for example ethoxy carbonyl;

(3) the optional aryl that replaces, this aryl is not particularly limited for definition and the position of substitution above, for example phenyl and 4-(methyl sulphonyl) phenyl;

(4)-CONR ^aR ^b, R wherein ^aBe hydrogen, low alkyl group, aryl or aralkyl, R ^bBe hydrogen, low alkyl group, aryl or aralkyl, wherein said low alkyl group, aryl and aralkyl are definition above, for example N-methylamino carbonyl, N-phenyl amino carbonyl, N, N-dimethylamino carbonyl and N-benzylamino carbonyl;

(5)-CONH-(CH ₂) _k-aryl, wherein k is integer 0-6; Described aryl is definition above, can have 1-5 to be selected from following substituting group :-NO ₂,-SO ₂-(low alkyl group) (low alkyl group is definition above) ,-CF ₃With-O-aryl (aryl is definition above), and the position of substitution is not particularly limited;

(6)-CONH-(CH ₂) _m-heterocycle, wherein m is integer 0-6; Described heterocycle is definition above, for example pyridine;

(7)-the CO-heterocycle, wherein heterocycle is definition above, for example tetramethyleneimine, piperidines, piperazine, thiomorpholine, described heterocycle can have 1-5 be selected from following substituting group :-CO-(low alkyl group) (low alkyl group for above definition) ,-CO-O-(low alkyl group) (low alkyl group for above definition) ,-SO ₂-(low alkyl group) (low alkyl group is definition above), oxo (promptly=O) and-CONR ^cR ^d, R wherein ^cBe hydrogen, low alkyl group, aryl or aralkyl, R ^dBe hydrogen, low alkyl group, aryl or aralkyl, wherein said low alkyl group, aryl and aralkyl are definition above, and the position of substitution is not particularly limited;

(8)-(CH ₂) _n-aryl, wherein n is integer 1-6; Described aryl is definition above, can have 1-5 be selected from following substituting group :-S-(low alkyl group) (low alkyl group for above definition) ,-SO ₂-(low alkyl group) (low alkyl group is definition above) ,-CO ₂-(low alkyl group) (low alkyl group is definition above) ,-NHCO-O-(low alkyl group) (low alkyl group for above definition) and-CONR ^eR ^f, R wherein ^eBe hydrogen, low alkyl group, aryl or aralkyl, R ^fBe hydrogen, low alkyl group, aryl or aralkyl, wherein said low alkyl group, aryl and aralkyl are definition above, and the position of substitution is not particularly limited;

(9)-(CH ₂) _o-heterocycle, wherein o is integer 0-6; Described heterocycle is definition above, and for example tetramethyleneimine, piperidines, piperazine, morpholine, thiomorpholine, described heterocycle can have 1-5 to be selected from following substituting group: oxo (promptly=O);-CO-(low alkyl group) (low alkyl group is definition above);-CO-O-(low alkyl group) (low alkyl group is definition above);-SO ₂-(low alkyl group) (low alkyl group is definition above);-CO-(heterocycle), wherein heterocycle is definition above, for example tetramethyleneimine, piperazine and morpholine, heterocycle can have 1-5 substituting group that is selected from low alkyl group and halogen (low alkyl group and halogen for above definition), and the position of substitution is not particularly limited; And-CONR ^gR ^h, R wherein ^gBe hydrogen, low alkyl group, aryl or aralkyl, R ^hBe hydrogen, low alkyl group, aryl or aralkyl, wherein said low alkyl group, aryl and aralkyl are definition above, and the position of substitution is not particularly limited;

(10)-(CH ₂) _p-NR ⁱR ^j, wherein p is integer 0-6; R ⁱBe hydrogen, acyl group, low alkyl group, aryl or aralkyl, R ^jBe hydrogen, acyl group, low alkyl group, aryl or aralkyl, wherein said acyl group, low alkyl group, aryl and aralkyl are definition above, and described low alkyl group can have 1-5 to be selected from following substituting group :-CONR ^kR ^l, R wherein ^kBe hydrogen, low alkyl group, aryl or aralkyl, R ^lBe hydrogen, low alkyl group, aryl or aralkyl, wherein said low alkyl group, aryl and aralkyl are definition above, and the position of substitution is not particularly limited;

(11)-CON (H or low alkyl group)-(CHR ^m) _q-T, wherein q is integer 0-6; Described low alkyl group is definition above; R ^mBe hydrogen, aralkyl defined above or alkyl defined above, R ^mCan be selected from by 1-3-OH and-CONH ₂Substituting group replace, and the position of substitution is not particularly limited; T is selected from hydrogen;-CONR ⁿR ^o, R wherein ⁿBe hydrogen, low alkyl group, aryl or aralkyl, R ^oBe hydrogen, low alkyl group, aryl or aralkyl, wherein said low alkyl group, aryl and aralkyl are definition above;-NH-CO-R ^p, R wherein ^pBe low alkyl group defined above or aralkyl defined above;-NH-SO ₂-(low alkyl group) (low alkyl group is definition above);-SO ₂-(low alkyl group) (low alkyl group is definition above);-heterocycle, wherein heterocycle is definition above, for example pyridine, tetramethyleneimine and morpholine, described heterocycle can have 1-3 substituting group (oxo (promptly=O)) for example, and the position of substitution is not particularly limited; Or-CO-(heterocycle), wherein said heterocycle is definition above, for example piperidines and morpholine;

(12)-(CH ₂) _r-CO-NR ^tR ^u, wherein r is integer 1-6; R ^tBe hydrogen, low alkyl group, aryl or aralkyl, R ^uBe hydrogen, low alkyl group, aryl or aralkyl, wherein said low alkyl group, aryl and aralkyl are definition above.

The position of substitution on aryl or the heterocycle is its any suitable position, is not particularly limited.

More than preferred " substituting group " of " optional replace thiazole " be the methyl sulphonyl benzyl.

R on the phenyl in the compound (I) ²The position of substitution be not particularly limited.

When Z is the following formula group:

The position of substitution on this group is not particularly limited.Preferred especially

The amino that compound (I) comprises (promptly-NH ₂), imino-(promptly=NH or-NH-) etc. any nitrogen-atoms can protect according to the procedure known to those skilled in the art, the method introduced such as ProtectiveGroups in Organic Synthesis (John Wiley and Sons publishes (1980)) for example.

Contain unsymmetrical carbon in the structure of compound (I), those skilled in the art should be appreciated that compound (I) comprises its all steric isomers.

" blood vessel attachment proteins-1 (VAP-1) relative disease " comprises and is selected from following disease: liver cirrhosis, basicly stable hypertension, diabetes, joint disease; (diabetes, atherosclerosis and hypertensive) endothelial injury, diabetes and uremia with cardiovascular disorder, gout and arthritis pain, (diabetic subject's) retinopathy; (reticular tissue) inflammatory diseases or illness (rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis and osteoarthritis or degenerative osteoarthritis, Reiter syndrome, dry syndrome, Behcet, relapsing polychondritis, systemic lupus erythematosus, discoid lupus erythematosus, systemic sclerosis, eosinophilic fasciitis, polymyositis, dermatomyositis, polymyalgia rheumatica, vasculitis, temporal arteritis, polyarteritis nodosa, Wei Geneishi granuloma disease, mixed connective tissue disease and juvenile rheumatoid arthritis); Gastroenteritis disease or illness [Crohn disease, ulcerative colitis, irritable bowel syndrome (spastic colon), hepatic fibrosis disease, oral mucosa inflammation (stomatitis) and recurrent aphthous stomatitis]; Inflammatory disease of central nervous system or illness (multiple sclerosis, Alzheimer's and ischemia apoplexy with ischemia reperfusion injury); Pulmonary inflammation disease or illness (asthma, adult respiratory distress syndrome, chronic obstructive pulmonary disease); (chronic) inflammatory disease of the skin or illness (psoriasis, supersensitivity pathology, lichen planus, pityriasis rosea, contact dermatitis, atopic dermatitis, pityriasis rubra pilaris); Carbohydrate metabolism disease (complication of diabetes and diabetes) comprises capillary blood vessel and great vessels disease (atherosclerosis, retinal retinitis, retinopathy, ephrosis, nephrotic syndrome and neuropathy (polyneuropathy, mononeuropathy and autonomic neuropathy), ulcer of foot, joint problem and infection risk increase); Adipocyte differentiation or function or smooth muscle cell malfunction disease (atherosclerosis and obesity); Vascular disease [atherosclerotic arteriosclerosis, non-atherosclerotic arteriosclerosis, cardiac ischemia (comprising myocardial infarction) and peripheral arterial occlusion, Raynaud disease and phenomenon, thromboangiitis obliterans (Buerger's disease)]; Chronic arthritis; Inflammatory bowel; Tetter; Diabetes; SSAO mediation property complication [diabetes (insulin-dependent diabetes (IDDM) and non-insulin-dependent diabetes mellitus (NIDDM) (NIDDM)) and vascular complication (heart attack, stenocardia, apoplexy, amputation, blind and renal failure)]; Macular edema (for example diabetic and non-diabetic macular edema) etc.

" prevention or treatment blood vessel attachment proteins-1 (VAP-1) relative disease ", especially " prevention or treatment macular edema " comprise for therapeutic purpose give the recipient having VAP-1 and suppress active compound (being the VAP-1 inhibitor), described therapeutic purpose can comprise prevention, improve, stop and cure above-mentioned VAP-1 relative disease, especially macular edema." recipient " used herein is meant the target that gives VAP-1 inhibitor of the present invention, particularly various animals, for example Mammals, for example people, mouse, rat, pig, dog, cat, horse, ox etc., especially people.

Described method comprises the VAP-1 inhibitor for the treatment of VAP-1 relative disease (especially macular edema) significant quantity.Any VAP-1 inhibitor may be used to the inventive method, as long as it is safe and effective." VAP-1 inhibitor " used herein is meant such compound: any point that comprises compound (I) and be included in the VAP-1 mechanism of action suppresses all compounds of VAP-1 enzymic activity.

By way of example, The compounds of this invention and derivative thereof, the compound that perhaps suppresses VAP-1 enzyme (SSAO) can comprise fluoro allyl amine derivative, semicarbazide derivative, hydrazide derivatives, the diazanyl derivative, 1,3,4-oxadiazine derivative, 2,6-diethoxy benzyl amine, 2,6-two (positive propoxy) benzyl amine, 2,6-diisopropoxy benzyl amine, 2,6-two (n-butoxy) benzyl amine, 2, two (methoxymethoxy) benzyl amine of 6-, 2, two (methoxymethyl) benzyl amine of 6-, 2,6-diethyl benzyl amine, 2,6-di benzyl amine, 2, two (2-hydroxyl-oxethyl) benzyl amine of 6-etc.

Above compound illustrates as follows.

1) fluoro allyl amine derivative, semicarbazide derivative and the hydrazide derivatives of WO93/23023 introduction,

2) the diazanyl derivative of WO02/02090 introduction,

3) 1,3 of the WO02/02541 introduction, 4-oxadiazine derivative,

4) the 4-alkyl-5-alkoxy carbonyl-4,5,6 of WO02/38153 introduction, the 7-imidazolidine is [4,5-c] pyridine derivate also,

5) USP4,2 of 888,283 introductions, 6-diethoxy benzyl amine, 2,6-two (positive propoxy) benzyl amine, 2,6-diisopropoxy benzyl amine, 2,6-two (n-butoxy) benzyl amine, 2, two (methoxymethoxy) benzyl amine, 2 of 6-, two (methoxymethyl) benzyl amine, 2 of 6-, 6-diethyl benzyl amine, 2,6-di benzyl amine and 2, two (2-hydroxyl-oxethyl) the benzyl amine of 6-.

Illustrated of the present invention is as the compound of VAP-1 inhibitor, the WO93/23023 illustrated is as the compound of SSAO inhibitor, for example the compound introduced of (Biochem.Pharmacol.36:2847,1987) and USP4650907, USP4916151 such as Lyles, USP4943593, USP4965288, USP5021456, USP5059714, USP4699928, european patent application 295604, european patent application 224924 and european patent application 168013 all belongs to the VAP-1 inhibitor.

In the above-claimed cpd, preferred compound (I), more preferably

N-{4-[2-(4-{[amino (imino-) methyl] amino } phenyl) ethyl]-1,3-thiazoles-2-yl } ethanamide (compd A hereinafter referred to as; Referring to preparation embodiment 1),

N-{4-[2-(4-{[amino (imino-) methyl] amino } phenyl) ethyl]-5-[4-(methyl sulphonyl) benzyl]-1,3-thiazoles-2-yl } ethanamide (referring to preparation embodiment 48),

N-{4-[2-(4-{[diazanyl (imino-) methyl] amino } phenyl) ethyl]-5-[4-(methyl sulphonyl) benzyl]-1,3-thiazoles-2-yl } ethanamide (referring to preparation embodiment 50),

N-{4-[2-(4-{[diazanyl (imino-) methyl] amino } phenyl) ethyl]-1,3-thiazoles-2-yl ethanamide (referring to preparation embodiment 58) and

N-(4-{2-[4-(2-{[amino (imino-) methyl] amino } ethyl) phenyl] ethyl }-1,3-thiazoles-2-yl) ethanamide (referring to preparation embodiment 110),

Especially N-{4-[2-(4-{[amino (imino-) methyl] amino }-phenyl) ethyl]-1,3-thiazoles-2-yl ethanamide and derivative thereof.

Term " derivative " comprises all compounds derived from original chemical.

In the present invention, can give recipient VAP-1 the prodrug of inhibitor.Term " prodrug " is included in all compounds that are converted into the VAP-1 inhibitor in the recipient's body that is given.Described prodrug can be any pharmaceutically acceptable prodrug of VAP-1 inhibitor.In addition, can give recipient VAP-1 the pharmacy acceptable salt of inhibitor.

The pharmacy acceptable salt of VAP-1 inhibitor of the present invention is nontoxic pharmaceutically acceptable conventional salt, for example with the salt of mineral alkali or organic bases, for example an alkali metal salt (for example sodium salt, sylvite etc.), alkaline earth salt (for example calcium salt, magnesium salts etc.), ammonium salt and amine salt (for example triethylamine salt, N-benzyl-N-methylamine salt etc.).

The VAP-1 inhibitor can also be formulated as pharmaceutically-acceptable acid addition.The example that is used for the pharmaceutically-acceptable acid addition of pharmaceutical compositions comprises the salt derived from mineral acid (for example hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, phosphoric acid, metaphosphoric acid, nitric acid and sulfuric acid) and organic acid (for example tartrate, acetate, citric acid, oxysuccinic acid, lactic acid, fumaric acid, phenylformic acid, oxyacetic acid, glyconic acid, Succinic Acid and aryl sulfonic acid (for example tosic acid)).

As the pharmacy acceptable salt of the VAP-1 inhibitor of formula (I) expression, preferred pharmaceutically-acceptable acid addition, for example (single-, two-or three-) hydrochloride and hydriodate, especially preferably salt hydrochlorate.

Above-mentioned VAP-1 inhibitor can obtain from commercial channels, perhaps can be according to known reference preparation.

In addition, compound (I) (especially compd A: N-{4-[2-(4-{[amino (imino-) methyl] amino } phenyl) ethyl]-1,3-thiazoles-2-yl ethanamide) can be synthetic according to following preparation method.

The compound or derivatives thereof that can not obtain from commercial channels can prepare with methodology of organic synthesis known in the art.

VAP-1 inhibitor or its pharmacy acceptable salt can give with any suitable way according to the inventive method.Suitable route of administration comprise general administration (for example oral) or by injection, local, near the eyes (for example subTenon ' s), under the conjunctiva, under the intraocular, retina, on the choroid and administration behind the eyeball.The treatment that the mode that gives of VAP-1 inhibitor depends in part on the VAP-1 relative disease is prophylactic treatment or therapeutic treatment.

Preferably after definite recipient (for example Mammals, particularly people) has VAP-1 relative disease (prophylactic treatment) risk of suffering from or begins to form VAP-1 relative disease (therapeutic treatment), give the VAP-1 inhibitor as early as possible.Methods of treatment will depend in part on the cause of disease and the degree (if suffering from any VAP-1 relative disease) of dosage, route of administration and the VAP-1 relative disease of employed concrete VAP-1 inhibitor, VAP-1 inhibitor.

Those skilled in the art can understand the appropriate method that existence gives VAP-1 inhibitor (the VAP-1 inhibitor that can be used for the inventive method).Although more than a kind of approach can be used for giving specific VAP-1 inhibitor, certain particular approach can provide than more direct, the more effective reaction of another kind of approach.Therefore, the route of administration of being introduced only is the example explanation, rather than restrictive.

The VAP-1 inhibitor dosage that gives recipient (animal that for example comprises the people, particularly people) according to the present invention should be enough to reasonably realizing required reaction in the time on the recipient.Those skilled in the art can understand dosage will depend on various factors, comprise the intensity of the concrete VAP-1 inhibitor of use, recipient's age, species, illness or disease and the degree of body weight and VAP-1 relative disease.The dosage size also depends on approach, time and the frequency of administration; May follow existence, character and the degree of any side effect that gives specific VAP-1 inhibitor; And required physiologic effect.Those of ordinary skills can understand the long-term treatment that different illnesss or disease may need to relate to multiple dosing.

Proper dosage and dosage can be determined by the known normal ranges searching of those of ordinary skills technology.Usually, the initial less dosage treatment of using less than the compound optimal dose.After this, dosage with little incremental increase up to reaching best effect in this case.

Usually, the VAP-1 inhibitor dosage that can give is about 1 μ g/kg/ days to about 300mg/kg/ days, and preferably about 0.1mg/kg/ days to about 10mg/kg/ days, described dosage was with every day potion or 2-4 agent or the mode medication that continues to give.

The medicinal compositions that uses in the inventive method preferably comprises " pharmaceutically acceptable carrier " and a certain amount of activeconstituents VAP-1 inhibitor, describedly a certain amount ofly is enough to preventative or therapeutic treatment VAP-1 relative disease (especially macular edema).Carrier can be any conventional carrier that uses, and only is subjected to the restriction of chemicophysics factor (for example solvability and do not have reactivity with described compound) and route of administration.

VAP-1 inhibitor medication in a different manner suppresses effect to reach required VAP-1.The VAP-1 inhibitor can give separately or give in conjunction with pharmaceutically acceptable carrier or thinner, and the characteristic of described carrier or thinner and character are determined by solvability and chemical property, selected route of administration and the standard drug practice of selected inhibitor.The VAP-1 inhibitor can solid dosage (for example capsule, tablet, powder) or liquid dosage form (for example solution or suspensoid) oral administration.Described inhibitor can also sterile solution agent or suspensoid parenteral drug administration by injection.Solid oral dosage form can comprise conventional excipients, for example raw materials such as lactose, sucrose, Magnesium Stearate, resin.Liquid oral dosage form can comprise various seasoningss, tinting material, sanitas, stablizer, solubilizing agent or suspension agent.Parenteral formulation is sterile aqueous or nonaqueous solution or suspensoid, and they can comprise various sanitass, stablizer, buffer reagent, solubilizing agent or suspension agent.If desired, the additive that can add such as salt solution or glucose makes solution etc. ooze.

The inventive method also relates to uniting and gives other medicinal activity compound." unite and give " be meant before giving above-mentioned VAP-1 inhibitor, (for example be combined into same preparation or for preparation independent of each other) or give afterwards simultaneously with the VAP-1 inhibitor.For example can unite and give corticosteroid (prednisone, methyl meticortelone, dexamethasone or Triamcinolone Acetonide) or non-corticosteroid anti-inflammatory compound (for example Ibuprofen BP/EP or flurbiprofen).Similarly, can unite and give vitamins and inorganics class (for example zinc), antioxidant (carotenoid for example, xenthophylls carotenoid for example is as zeaxanthin or progestin) and micronutrient.

In addition, VAP-1 inhibitor of the present invention can be used for preparation example such as therapeutic or preventive medicine, and described medicine is used for the treatment of the VAP-1 relative disease.

The preparation method of compound (I)

Compound (I) is according to (but being not limited to) following method preparation.Those skilled in the art can understand these methods and can improve according to known ordinary method itself.

Method A:

Synthetic Y is the compound (I) of chemical bond

Wherein

L ₁Be leavings group, for example halogen (for example chlorine, bromine, iodine);

Z is definition above;

X is definition above, is in this case

R ¹It is acyl group;

L ₂Be leavings group, for example-OH, halogen (for example chlorine, bromine, iodine) ,-the O-acyl group, wherein acyl group is definition (for example-O-ethanoyl etc.) above.

Preparation thiazole part X

Make compound (1) and compound (2) or its reactant salt obtain compound (3).

The acceptable acid addition salts of compound (2) can be the identical salt of illustrational compound (I).

Compound (1) and (2) or its salt can or can prepare (referring to preparation embodiment 11) according to known method itself by the commercial sources acquisition.

Described reaction is carried out in conventional solvent usually, for example ethanol, acetone, methylene dichloride, acetate, to described other organic solvent of deleterious effect or their mixture of instead would not producing.

Temperature of reaction and indecisive, reaction can be carried out being cooled under the heating condition.

Thus obtained compound (3) can separate or purification by separation known or method of purification, for example concentrate, vacuum concentration, solvent extraction, crystallization, recrystallize, phase transition, chromatography etc., and can be converted into the identical salt of illustrational compound (I).

Acylation reaction

Make the reaction of compound (3) or its salt and compound (4) obtain compound (5).Because R ¹Be acyl group, so this reaction is an acylation reaction.

Conventional process for acylating can be used for the present invention.

Compound (4) can or can prepare according to known method itself by the commercial sources acquisition.

Described reaction is carried out in conventional solvent usually, for example methylene dichloride, chloroform, methyl alcohol, to described other organic solvent of deleterious effect or their mixture of instead would not producing.

Described reaction is also preferably carried out in the presence of conventional alkali, for example 4-dimethylaminopyridine, pyridine etc.Liquid base also can be used as solvent.

Thus obtained compound (5) can separate or purification by separation known or method of purification, for example concentrate, vacuum concentration, solvent extraction, crystallization, recrystallize, phase transition, chromatography etc., and can be converted into the identical salt of illustrational compound (I).

Described acylation reaction can be used for compound (1) in advance.

Can be as required; with the nitrogen-atoms of compound (1), (2), (3) or (5) according to known method protection itself or slough protection, the method for introduction such as Protective Groups in OrganicSynthesis (John Wiley and Sons publishes (1980)) for example.

Method B:

Synthetic Y is the compound (I) of low-grade alkylidene or lower alkenylene, for example Y be ethylene (promptly-CH ₂-CH ₂-) or vinylidene is (promptly-CH=CH-), for example

Wherein

L ₃Be leavings group, for example halogen (for example chlorine, bromine, iodine);

R ¹, X and Z be definition above.

Generate olefin(e) compound

Make compound (6) or its salt and compound (7) or its reactant salt obtain olefin(e) compound (8).

The acceptable acid addition salts of compound (6) and (7) can be the identical salt of illustrational compound (I).

Compound (6) and (7) or their salt can or can prepare (referring to preparation embodiment 1 and 3) according to known method itself by the commercial sources acquisition.

Described reaction is carried out in conventional solvent usually, N for example, dinethylformamide, methyl-sulphoxide, tetrahydrofuran (THF), methylene dichloride, to described other organic solvent of deleterious effect or their mixture of instead would not producing.

Described reaction is also carried out in the presence of triphenylphosphine and conventional alkali (for example potassium tert.-butoxide, sodium hydride, sodium hydroxide etc.) usually.

Thus obtained compound (8) can separate or purification by separation known or method of purification, for example concentrate, vacuum concentration, solvent extraction, crystallization, recrystallize, phase transition, chromatography etc., and can be converted into the identical salt of illustrational compound (I).

Reduction reaction

Compound (8) or its salt are obtained compound (9) according to the ordinary method reduction.

The conventional reduction reaction comprises hydrogenation, catalytic hydrogenation etc.

Wherein, preferred catalytic hydrogenation.

Catalytic hydrogenation is carried out in the presence of catalyzer, for example palladium carbon, preferred 10% palladium carbon.

Catalytic hydrogenation is carried out in conventional solvent usually, for example tetrahydrofuran (THF), ethanol, ethyl acetate, to described other solvent of deleterious effect or their mixture of instead would not producing.

Catalytic hydrogenation is also preferably carried out in the presence of conventional acid, for example acetate, hydrochloric acid etc.Liquid acid also can be used as solvent.

Thus obtained compound (9) can separate or purification by separation known or method of purification, for example concentrate, vacuum concentration, solvent extraction, crystallization, recrystallize, phase transition, chromatography etc., and can be converted into the identical salt of illustrational compound (I).

Therefore, compound (11) or its salt can use compound (10) or its salt to prepare according to above-mentioned similar approach.The acceptable acid addition salts of compound (10) and (11) can be the identical salt of illustrational compound (I).

Can be as required; with the nitrogen-atoms of compound (6), (7), (8), (9), (10) or (11) according to known method protection itself or slough protection, the method for introduction such as Protective Groups inOrganic Synthesis (John Wiley and Sons publishes (1980)) for example.

Method C:

Synthetic Y is-compound (I) of CONH-,

(12) (13) (14)

L wherein ₄Be hydrogen atom or known blocking group itself, the tert-butoxycarbonyl (referring to Protective Groups in Organic Synthesis, John Wiley and Sons publication (1980) etc.) of for example above " the optional amino of protecting " introduction; R ¹, X and Z be definition above.

Amidate action

Make compound (12), its reactive derivatives or their salt and compound (13) or its reactant salt obtain amide compound (14).

The suitable reactivity derivative of compound (12) comprises acyl halide, acid anhydrides and Acibenzolar.

Suitable example can be a chloride of acid; Acid azide; With a kind of mixed acid anhydride of acid, described acid is phosphoric acid (for example dialkyl group phosphoric acid, phosphenylic acid, diphenylphosphoric acid, dibenzyl phosphoric acid, halophosphoric acid etc.), dialkyl group phosphorous acid, sulfurous acid, thiosulfuric acid, alkyl sulphur (for example methylsulfonic acid, ethyl sulfonic acid etc.), sulfuric acid, alkyl carbonic acid, the aliphatic carboxylic acid (for example PIVALIC ACID CRUDE (25), valeric acid, isovaleric acid, 2 Ethylbutanoic acid, trichoroacetic acid(TCA) etc.) that for example replaces; Aromatic carboxylic acid's (for example phenylformic acid etc.); Symmetric anhydride; The activating terephthalamide amine of imidazoles, dimethyl pyrazole, triazole or the tetrazolium that replaces with imidazoles, 4-; Acibenzolar (for example cyano methyl ester, methoxymethyl ester, dimethylimino methyl [(CH ₃) ₂N ⁺=CH-] ester, vinyl ester, propargyl ester, p-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester, five chlorophenyl ester, methylsulfonyl phenylester, phenyl phenylazo-ester, phenyl thioesters, p-nitrophenyl thioesters, p-methylphenyl thioesters, carboxyl methyl thioesters, pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolyl thioesters etc.); Perhaps with the ester of N-oxy-compound (for example N, N-dimethyl hydroxylamine, 1-hydroxyl-2-(1H)-pyridone, N-maloyl imines, N-hydroxybenzotriazole, N-hydroxyphthalimide, 1-hydroxyl-6-chloro-1H-benzotriazole etc.).Can from these reactive derivatives, choose arbitrarily according to the type of the compound (12) that will use.

The acceptable acid addition salts of the acceptable acid addition salts of compound (12) and reactive derivatives thereof and compound (13) can be the identical salt of illustrational compound (I).

Compound (12), its reactive derivatives and compound (13) or their salt can or can prepare (referring to preparation embodiment 7) according to known method itself by the commercial sources acquisition.

Conventional amidation method can use in the present invention.

Described reaction is carried out in conventional solvent usually, for example methylene dichloride, methyl alcohol, ethanol, acetone, tetrahydrofuran (THF), N, dinethylformamide, to described any other organic solvent or their mixture that instead would not produce harmful effect.

Described reaction is also preferably at conventional condensing agent (for example 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride, N, N '-dicyclohexyl carbodiimide, N, two (glyoxal ethyline) triphenylphosphines of N '-carbonyl) and additive (for example I-hydroxybenzotriazole, 1-maloyl imines, 3,4-dihydro-3-hydroxyl-4-oxo-1,2,3-phentriazine) carries out under existing.

Thus obtained compound (14) can separate or purification by separation known or method of purification, for example concentrate, vacuum concentration, solvent extraction, crystallization, recrystallize, phase transition, chromatography etc., and can be converted into the identical salt of illustrational compound (I).

Can be as required; with the nitrogen-atoms of compound (12), (13) or (14) according to known method protection itself or slough protection, the method for introduction such as Protective Groups in OrganicSynthesis (John Wiley and Sons publishes (1980)) for example.

Set forth the present invention in more detail by following preparation embodiment and embodiment, but they can not be interpreted as limitation of the present invention.

The test-compound that uses among the embodiment is N-{4-[2-(4-{[amino (imino-) methyl] amino } phenyl) ethyl]-1,3-thiazoles-2-yl } ethanamide (compd A hereinafter referred to as), synthetic in preparation embodiment 1.

Preparation embodiment 1:

Step 1

Mixture backflow 4h with acetate 3-chloro-2-oxopropyl ester (5g), thiocarbamide (2.5g) and ethanol (25ml).Reaction mixture is cooled to room temperature, filters and collect the gained crystalline deposit, obtain white crystal acetate (2-amino-1,3-thiazoles-4-yl) methyl ester hydrochloride (3.5g) with ethanol (20ml) washing.

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.07(3H，s)，4.92(2H，s)，6.87(1H，s)。

MS：173(M+H) ⁺

Step 2

In 5 ℃, 30min, add Acetyl Chloride 98Min. (23g) to the mixture of acetate (2-amino-1,3-thiazoles-4-yl) methyl ester hydrochloride (56g), pyridine (45g) and methylene dichloride (560ml), at uniform temp stirred reaction mixture 10min.In reaction mixture impouring water (500ml), with chloroform (1L) extraction.The organic layer dried over sodium sulfate, vacuum concentration.Residual solid and isopropyl ether filtration collection are obtained white crystal acetate (2-(acetylamino)-1,3-thiazoles-4-yl) methyl esters (47g).

¹H-NMR(CDCl ₃)，δ(ppm)：2.12(3H，s)，2.29(3H，s)，5.08(2H，s)，6.93(1H，s)。

MS：215(M+H) ⁺

Step 3

With the mixture of acetate (2-(acetylamino)-1,3-thiazoles-4-yl) methyl esters (46g), salt of wormwood (30g) and methyl alcohol (640ml) at stirring at room 3h.The vacuum concentration reaction mixture.Resistates dilutes with chloroform, the filtering insoluble substance.The silica gel flash column chromatography purification (methyl alcohol/chloroform 1/99) of gained solution.Gained solid and isopropyl ether are filtered collection, obtain white crystal N-(4-(hydroxymethyl)-1,3-thiazoles-2-yl) ethanamide (35g).

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.12(3H，s)，4.44(2H，d，J＝5.0Hz)，5.20(1H，t，J＝5.0Hz)，6.88(1H，s)，12.02(1H，brs)。

MS：173(M+H) ⁺

Step 4

N-(4-(hydroxymethyl)-1,3-thiazoles-2-yl) ethanamide (2.8g) is dissolved in methyl alcohol (10ml) and chloroform (200ml).Then manganese oxide (IV) (28.3g) is added solution under nitrogen atmosphere.At stirring at room reaction mixture 7h, filter by Celite pad.Vacuum concentrated filtrate.The gained solid washs with ether, obtains Off-white solid N-(4-formyl radical-1,3-thiazoles-2-yl) ethanamide (2.01g).mp.195.5-199℃。

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.17(3H，s)，8.28(1H，s)，9.79(1H，s)，12.47(1H，brs)。

Step 5

With 1-(brooethyl)-4-oil of mirbane (1.9g), triphenylphosphine (2.31g) and N, dinethylformamide (20ml) mixes under nitrogen atmosphere.At stirring at room reaction mixture 2.5h.Add potassium tert.-butoxide (1.19g) and N-(4-formyl radical-1,3-thiazoles-2-yl) ethanamide (1.5g) then, at stirring at room mixture 14h.In reaction mixture impouring frozen water, use ethyl acetate extraction.Organic layer is used anhydrous magnesium sulfate drying, vacuum concentration with 1N hydrochloric acid, water and saturated nacl aqueous solution washing.Resistates silica gel flash column chromatography purification (using n-hexane/ethyl acetate (1: 1) → (1: 2)) as eluent, grind with ether, obtain yellow solid N-{4-[(Z)-2-(4-nitrophenyl) vinyl]-1,3-thiazoles-2-yl } ethanamide (1.59g).mp.155-157℃

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.13(3H，s)，6.64(1H，d，J＝12.5Hz)6.71(1H，d，J＝12.5Hz)，7.18(1H，s)，7.79(2H，d，J＝9.0Hz)，8.17(2H，d，J＝9.0Hz)，12.02(1H，brs)。

MS：290(M+H) ⁺

Step 6

Under 4atm nitrogen atmosphere, room temperature, with N-{4-[(Z)-2-(4-nitrophenyl) vinyl]-1,3-thiazoles-2-yl } mixture of ethanamide (2g), 10% palladium carbon (400mg), methyl alcohol (25ml), tetrahydrofuran (THF) (25ml) and acetate (18ml) stirs 5h.By Celite pad filter reaction mixture, vacuum concentrated filtrate.Resistates is dissolved in ethyl acetate.Organic solution is used anhydrous magnesium sulfate drying, vacuum concentration with saturated sodium bicarbonate solution and saturated nacl aqueous solution washing.Resistates silica gel flash column chromatography purification (using n-hexane/ethyl acetate (1: 2) → ethyl acetate) as eluent, obtain Off-white solid N-(4-(2-(4-aminophenyl) ethyl)-1,3-thiazoles-2-yl) ethanamide (539.6mg) with ethanol/ether grinding.

mp.102.5-104℃

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.11(3H，s)，2.75(4H，brs)，4.82(2H，s)，6.46(2H，d，J＝8.5Hz)，6.69(1H，s)，6.83(2H，d，J＝8.5Hz)，12.07(1H，brs)。

MS：262(M+H) ⁺

Step 7

Compd A

Add 4N hydrogenchloride/ethyl acetate (25ml) and cyanamide (6.3g) in ethanol (500ml) suspension of N-(4-(2-(4-aminophenyl) ethyl)-1,3-thiazoles-2-yl) ethanamide (26g).With the mixture 26h that refluxes.Reaction mixture is cooled to room temperature, in the mixture of impouring ethyl acetate (500ml) and saturated sodium bicarbonate solution (500ml).Filter to collect the gained precipitation, water (300ml) and ethanol (300ml) wash, obtain white crystal N-{4-[2-(4-{[amino (imino-) methyl]-amino phenyl) ethyl]-1,3-thiazoles-2-yl ethanamide (18g).

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.10(3H，s)，2.85(4H，s)，6.79(1H，s)，6.83(2H，d，J＝7Hz)，7.10(2H，d，J＝7Hz)。

MS：304(M+H) ⁺

Preparation embodiment 2:

Synthetic N-(4-(2-(4-(4,5-dihydro-1,3-thiazoles-2-base is amino) phenyl) ethyl)-1,3-thiazoles-2-yl) ethanamide

With N-(4-(2-(4-aminophenyl) ethyl)-1, the 3-thiazol-2-yl) ethanamide (1.8g, similar approach preparation according to preparation embodiment 1 step 6), 2-(methyl sulfenyl)-4,5-dihydro-1,3-thiazole (918mg), concentrated hydrochloric acid (0.57ml) and 2-methyl cellosolve (28ml) mix under nitrogen atmosphere, stir 10h at 120 ℃.After being cooled to room temperature, the vacuum concentration reaction mixture.Resistates is dissolved in tetrahydrofuran (THF)/water, alkalizes with wet chemical.The mixture ethyl acetate extraction.The organic layer dried over mgso, vacuum-evaporation.Resistates silica gel flash column chromatography purification (using chloroform/methanol (30: 1 → 20: 1)) as eluent, grind with ethyl acetate, (((4-(4 for 2-for 4-to obtain Off-white solid N-, 5-dihydro-1,3-thiazol-2-yl amino) ethyl phenyl))-and 1,3-thiazoles-2-yl) ethanamide (484.7mg).

mp.218-219.5℃

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.11(3H，s)，2.84(4H，s)，3.26(2H，t，J＝7.5Hz)，3.35(2H，t，J＝7.5Hz)，4.02(1H，brs)，6.71(1H，brs)，7.05(2H，d，J＝8.5Hz)，7.51(1H，brs)，9.25(1H，brs)，12.10(1H，brs)。

MS：347(M+H) ⁺

Preparation embodiment 3:

Synthetic N-(4-{ (E)-2-[4-(4,5-dihydro-1,3-thiazoles-2-base is amino) phenyl] vinyl }-1,3-thiazoles-2-yl) ethanamide

Step 1

With 4-nitrobenzyl bromine (6.35g), triphenylphosphine (7.71g) and N, the mixture of dinethylformamide (50ml) is at stirring at room 5h.Add butanols potassium (3.96g), N-(4-formyl radical-1,3-thiazoles-2-yl) ethanamide (5.0g is according to the similar approach preparation of preparation embodiment 1 step 4) in the mixture successively, at the uniform temp 13h that stirs the mixture.In reaction mixture impouring ethyl acetate (200ml) and water (200ml).Organic layer water (20ml) washing concentrates with the dried over sodium sulfate final vacuum.Collect crystalline residue,, obtain N-{4-[(E with 30% ethyl acetate/diisopropyl ether washing)-2-(4-nitrophenyl) vinyl]-1,3-thiazoles-2-yl } ethanamide (7.8g).

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.16(3H，s)，7.29(1H，d，J＝16Hz)，7.48(1H，d，J＝16Hz)，7.88(2H，d，J＝7Hz)，8.22(2H，d，J＝7Hz)。

MS(M+H)＝290

Step 2

N-{4-[(E)-2-(4-nitrophenyl) vinyl]-1,3-thiazoles-2-yl } mixture of ethanamide (250mg), palladium carbon (25mg) and methyl alcohol (2.5ml) stirs 2h under nitrogen atmosphere, room temperature.Filtration catalizer, vacuum concentrated filtrate.Collect crystalline residue, obtain N-{44 (E)-2-(4-aminophenyl) vinyl with the isopropyl ether washing]-1,3-thiazoles-2-yl } ethanamide (160mg).

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.14(3H，s)，5.33(2H，s)，6.55(2H，d，J＝7Hz)，6.82(1H，d，J＝10Hz)，6.44(1H，s)，7.09(1H，d，J＝10Hz)，7.20(2H，d，J＝7Hz)。

MS：260(M+H) ⁺

Step 3

With N-{4-[(E)-2-(4-aminophenyl) vinyl]-1, the 3-thiazol-2-yl } ethanamide (200mg), 2-(methyl sulfenyl)-4, the mixture of 5-dihydro-1,3-thiazoles (103mg), hydrochloric acid (0.064ml) and 2-methyl cellosolve (2ml) stirs 8h at 120 ℃.The vacuum concentration reaction mixture.Resistates silica gel flash column chromatography purification (use hexane: ethyl acetate (3: 1) is as eluent).Collect crystalline residue, with the ethyl acetate washing obtain N-(4-{ (E)-2-[4-(4,5-dihydro-1,3-thiazoles-2-base is amino) phenyl] vinyl }-1,3-thiazoles-2-yl) ethanamide (150mg).

¹H-NMR(CDCl ₃)，δ(ppm)：2.27(3H，s)，3.33-3.40(2H，m)，3.57-3.65(2H，m)，6.94(1H，s)，7.05(1H，d，J＝12Hz)，7.29(1H，d，J＝12Hz)，7.30(2H，d，J＝7Hz)，7.57(2H，d，J＝7Hz)。

MS：345(M+H) ⁺

Preparation embodiment 4:

Synthetic N-(4-{2-[2-(acetylamino)-1,3-thiazoles-4-tomb] ethyl } phenyl) sulfo-amino imido acid-S-methyl esters hydriodate

Step 1

N-(4-(2-(4-aminophenyl) ethyl)-1; the 3-thiazol-2-yl) ethanamide (300mg; similar approach preparation according to preparation embodiment 1 step 6) adds benzoyl lsothiocyanates (187mg) in the ice-cold solution of acetone (5ml), with the mixture 2h that refluxes.Reaction mixture to 0 ℃.The crystal that filtration is separated out with ice-cold washing with acetone, obtains N-{4-[2-(4-{[(benzoyl-amido) thiocarbonyl group] amino } phenyl) ethyl]-1,3-thiazoles-2-yl } ethanamide (359mg).

¹H-NMR(CDCl ₃)，δ(ppm)：2.25(3H，s)，2.90-3.05(4H，m)，6.51(1H，s)，7.21(2H，d，J＝7Hz)，7.50-7.70(5H，m)，7.89(2H，d，J＝7Hz)，9.03(1H，s)，9.12(1H，s)。

MS(M+H)＝425

Step 2

With N-{4-[2-(4-{[(benzoyl-amido) thiocarbonyl group] amino } phenyl) ethyl]-1,3-thiazoles-2-yl } mixture of ethanamide (200mg), 6N aqueous sodium hydroxide solution (0.19ml) and ethanol (2ml) stirs 2h at 60 ℃.Reaction mixture is to room temperature, with 1N hydrochloric acid (1.2ml) neutralization.The crystal that filtration is separated out washes with water and obtains N-[4-(2-{4-[(thiocarbamoyl)-amino] phenyl } ethyl)-1,3-thiazoles-2-yl] ethanamide (120mg).

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.11(3H，s)，2.88(4H，s)，6.75(1H，s)，7.15(2H，d，J＝7Hz)，7.27(2H，d，J＝7Hz)，9.60(1H，s)。

MS(M+H)＝321

Step 3

With N-[4-(2-{4-[(thiocarbamoyl) amino] phenyl } ethyl)-1,3-thiazoles-2-yl] the mixture backflow 3h of ethanamide (100mg), methyl-iodide (0.023ml) and methyl alcohol (2ml).The vacuum concentration reaction mixture.Resistates dilutes with ethyl acetate, stirs 30min.The crystal that filtration is separated out obtains N-(4-{2-[2-(acetylamino)-1,3-thiazoles-4-yl] ethyl } phenyl) sulfo-amino imido acid-S-methyl esters hydriodate (130mg) with ethyl acetate washing.

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.13(3H，s)，2.68(3H，s)，2.87-3.05(4H，m)，6.75(1H，s)，7.24(2H，d，J＝7Hz)，7.35(2H，d，J＝7Hz)。

MS(M+H)＝463

Preparation embodiment 5:

Synthetic N-(4-{2-[4-(4,5-dihydro-1H-imidazoles-2-base is amino) phenyl] ethyl }-1,3-thiazoles-2-yl) ethanamide

With N-(4-(2-(4-aminophenyl) ethyl)-1, the 3-thiazol-2-yl) ethanamide (65mg, similar approach preparation according to preparation embodiment 1 step 6), 2-(methyl sulfenyl)-4, the mixture of 5-dihydro-1H-imidazoles-1-ethyl formate (56mg), acetate (0.1ml), ethanol (0.9ml) stirs 6h at 65 ℃, and 5h then refluxes.In reaction mixture impouring ethyl acetate (5ml) and saturated sodium bicarbonate aqueous solution.The solid that filtration is separated out is dissolved in 50% methyl alcohol/chloroform with solid.The filtering insoluble substance, vacuum concentrated filtrate.Collect solid residue, with the ethyl acetate washing obtain N-(4-{2-[4-(4,5-dihydro-1H-imidazoles-2-base is amino) phenyl]-ethyl-1,3-thiazoles-2-yl) ethanamide (40mg).

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.11(3H，s)，2.72(4H，s)，3.33(4H，s)，6.73(1H，s)，6.85-7.08(4H，m)。

MS(M+H)＝330

Preparation embodiment 6:

Synthetic N-{4-[2-(4-{[amino (imino-) methyl] amino } phenyl) ethyl]-1,3-thiazoles-2-yl }-the 2-methyl propanamide

Step 1

Add isobutyryl chloride (0.91ml) in the ice-cold mixture of 2-amino-1,3-thiazoles-4-ethyl formate (2g is according to the similar approach preparation of following preparation embodiment 7 steps 1), pyridine (1.3ml) and methylene dichloride (20ml), stir 30min.Add saturated sodium bicarbonate aqueous solution (30ml) in the mixture, isolate organic layer, concentrate with the dried over sodium sulfate final vacuum.Collect crystalline residue, obtain 2-(isobutyryl amino)-1,3-thiazoles-4-ethyl formate (1.34g) with the ethyl acetate washing.

¹H-NMR(CDCl ₃)，δ(ppm)：1.30(6H，d，J＝7Hz)，1.40(3H，t，J＝7Hz)，2.57-2.73(1H，m)，4.41(2H，q，J＝7Hz)，7.83(1H，s)，8.98(1H，s)。

MS：243(M+H) ⁺

Step 2

Add lithium borohydride (252mg) by amount in the mixture of 2-(isobutyryl amino)-1,3-thiazoles-4-ethyl formate (1.4g) and tetrahydrofuran (THF) (28ml), with the mixture 6h that refluxes.Reaction mixture to 0 ℃ concentrates with methyl alcohol (5ml) quencher final vacuum.Make resistates be suspended in 10% methyl alcohol/chloroform (100ml), filtering insoluble substance.Filtrate is with silica gel flash column chromatography purify (with 5% methyl alcohol/chloroform as eluent).Collect crystalline residue, obtain N-[4-(hydroxymethyl)-1,3-thiazoles-2-yl with the diisopropyl ether washing]-2-methyl propanamide (1.0g).

¹H-NMR(CDCl ₃)，δ(ppm)：1.32(6H，d，J＝5Hz)，2.58-2.73(1H，m)，4.68(2H，s)，6.82(1H，s)。

MS(M+H)＝200

Step 3

With N-[4-(hydroxymethyl)-1,3-thiazoles-2-yl]-2-methyl propanamide (520mg), manganese oxide (IV) (2.26g), the mixture of methyl alcohol (0.5ml) and chloroform (5ml) is at stirring at room 18h.Reaction mixture filters by Celite pad, vacuum concentrated filtrate.Collect crystalline residue, obtain N-(4-formyl radical-1,3-thiazoles-2-yl)-2-methyl propanamide (365mg) with the diisopropyl ether washing.

¹H-NMR(CDCl ₃)，δ(ppm)：1.13(6H，d，＝5Hz)，2.60-2.77(1H，m)，7.86(1H，s)。

MS(M+H)＝199

Step 4

With 4-nitrobenzyl bromine (381mg), triphenylphosphine (463mg) and N, the mixture of dinethylformamide (3ml) is at stirring at room 5h.Add butanols potassium (238mg), N-(4-formyl radical-1,3-thiazoles-2-yl)-2-methyl propanamide (350mg) in the mixture successively, at the uniform temp 13h that stirs the mixture.In reaction mixture impouring ethyl acetate (20ml) and water (20ml).Organic layer water (20ml) washing concentrates with the dried over sodium sulfate final vacuum.Collect crystalline residue, washing obtains 2-methyl-N-{4-[(E)-2-(4-nitrophenyl) vinyl]-1,3-thiazoles-2-yl } propionic acid amide (360mg).

¹H-NMR(CDCl ₃)，δ(ppm)：1.25(6x2/3H，d，J＝5Hz)，1.30(6x1/3H，d，J＝5Hz)，2.50-5.70(1H，m)，6.63(1H，s)，6.79(1x2/3H，s)，6.97(1x2/3H，s)，7.14(1x1/3H，d，J＝12Hz)，7.33(1x1/3H，d，J＝12Hz)，7.53(2x2/3H，d，J＝7Hz)，7.62(2x1/3H，d，J＝7Hz)，8.13(2x2/3H，d，J＝7Hz)，8.22(2x1/3H，d，J＝7Hz)。

MS(M+H)＝318

Step 5

Under nitrogen atmosphere (4atm), room temperature, with 2-methyl-N-{4-[(E)-2-(4-nitrophenyl) vinyl]-1,3-thiazoles-2-yl } mixture of propionic acid amide (333mg), palladium carbon (33mg), acetate (1ml), methyl alcohol (2ml) and tetrahydrofuran (THF) (2ml) stirs 5h.Filtration catalizer, vacuum concentrated filtrate.Resistates is with silica gel flash column chromatography purify (with 5% methanol/ethyl acetate as eluent).Collect solid residue, obtain N-{4-[2-(4-aminophenyl) ethyl with the diisopropyl ether washing]-1,3-thiazoles-2-yl }-2-methyl propanamide (260mg).

¹H-NMR(CDCl ₃)，δ(ppm)：1.38(6H，d，J＝5Hz)，2.57-2.73(1H，m)，2.39-2.43(4H，m)，6.45(1H，s)，6.62(2H，d，J＝7Hz)，6.97(2H，d，J＝7Hz)。

MS(M+H)＝290

Step 6

Title compound is according to the similar approach preparation of preparation embodiment 1 step 7.

¹H-NMR(DMSO-d ₆)，δ(ppm)：1.01(6H，d，J＝5Hz)，2.62-2.78(1H，m)，2.83(4H，s)，6.72(2H，d，J＝7Hz)，6.75(1H，s)，7.04(2H，d，J＝7Hz)。

MS(M+H)＝332

Preparation embodiment 7:

Synthetic 2-(acetylamino)-N-(4-{[amino (imino-) methyl] amino } phenyl)-1,3-thiazoles-4-methane amide

Step 1

Mixture backflow 2h with 3-bromo-ethyl 2-oxopropanoate (100g), thiocarbamide (39g) and ethanol (500ml).The vacuum concentration reaction mixture.Collect crystalline residue, obtain 2-amino-1,3-thiazoles-4-ethyl formate hydrobromate (116g) with the ethyl acetate washing.

¹H-NMR(DMSO-d ₆)，δ(ppm)：1.28(3H，t，J＝7Hz)，4.26(2H，q，J＝7Hz)，7.60(1H，s)。

Step 2

At 0 ℃, dripping acetyl chloride (27.3g) in the ice-cold mixture of 2-amino-1,3-thiazoles-4-ethyl formate hydrobromate (80g), pyridine (52.5g) and methylene dichloride (800ml) is at the uniform temp 30min that stirs the mixture.Reaction mixture water (500ml) washing concentrates with the dried over sodium sulfate final vacuum.Collect crystalline residue, obtain 2-(acetylamino)-1,3-thiazoles-4-ethyl formate (60g) with the ethyl acetate washing.

¹H-NMR(DMSO-d ₆)，δ(ppm)：1.29(3H，t，J＝7Hz)，2.15(3H，s)，4.27(2H，q，J＝7Hz)，8.03(1H，s)。

MS(M+H)＝215

Step 3

With the mixture of 2-(acetylamino)-1,3-thiazoles-4-ethyl formate (2g), 2N sodium hydroxide (7ml) and methyl alcohol (13ml) at stirring at room 5h.Reaction mixture neutralizes with 1N hydrochloric acid (14ml).The crystal that filtration is separated out washes with water and obtains 2-(acetylamino)-1,3-thiazoles-4-formic acid (1.3g).

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.14(3H，s)，7.94(1H，s)。

Step 4

With the mixture of 2-(acetylamino)-1,3-thiazoles-4-formic acid (500mg), 4-aminophenyl t-butyl carbamate (615mg), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (566mg), I-hydroxybenzotriazole (399mg) and methylene dichloride (5ml) at stirring at room 3h.Reaction mixture washs with saturated sodium bicarbonate aqueous solution, the vacuum concentration organic layer.Resistates is with silica gel flash column chromatography purify (with 3% methyl alcohol/chloroform as eluent).Collect crystalline residue, obtain 4-({ [2-(acetylamino)-1,3-thiazoles-4-yl] carbonyl } amino) the phenylcarbamic acid tert-butyl ester (580mg) with the ethyl acetate washing.

¹H-NMR(DMSO-d ₆)，δ(ppm)：1.48(9H，s)，2.18(3H，s)，7.42(2H，d，J＝7Hz)，7.61(2H，d，J＝7Hz)，7.91(1H，s)，9.32(1H，s)，9.63(1H，s)。

MS(M+H)＝377

Step 5

Add 4N hydrogenchloride/ethyl acetate (1ml) in methyl alcohol (1ml) solution of 4-({ [2-(acetylamino)-1,3-thiazoles-4-yl] carbonyl } amino) phenylcarbamic acid tertiary butyl ester (85mg), at stirring at room mixture 1h.The vacuum concentration reaction mixture.Collect solid residue, obtain 2-(acetylamino)-N-(4-aminophenyl)-1,3-thiazoles-4-carboxamide hydrochloride (70mg) with the ethyl acetate washing.

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.15(3H，s)，7.42(2H，d，J＝7Hz)7.37(2H，d，J＝7Hz)，7.41(1H，s)。

MS(M+H)＝313

Step 6

The mixture of 2-(acetylamino)-N-(4-aminophenyl)-1,3-thiazoles-4-carboxamide hydrochloride (70mg), cyanamide (11mg) and 2-methyl cellosolve (2ml) is stirred 72h at 100 ℃.The vacuum concentration reaction mixture.Add ethyl acetate (5ml) and saturated sodium bicarbonate aqueous solution (5ml) in the resistates.The solid that filtration is separated out with ethyl acetate and water washing, obtains 2-(acetylamino)-N-(4-{[amino (imino-) methyl] amino } phenyl)-1,3-thiazoles-4-methane amide (45mg).

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.18(3H，s)，7.60-7.88(4H，br)，7.95(1H，s)。

MS(M+H)＝319

Preparation embodiment 8:

Synthetic N-(4-{2-[4-(acetimidoyl amino) phenyl] ethyl }-1,3-thiazoles-2-yl) ethanamide

N-(4-(2-(4-aminophenyl) ethyl)-1,3-thiazoles-2-yl) ethanamide (100mg is according to the similar approach preparation of preparation embodiment 1 step 6), second sulfo-imido acid-S-methyl esters hydriodate (166mg) and methyl alcohol (3ml) are mixed backflow 1.5h.After being cooled to room temperature, vacuum concentrated mixture.Resistates is purified (with chloroform/methanol (20: 1 → 10: 1) as eluent) with NH silica gel flash column chromatography, obtain light yellow amorphous substance N-(4-{2-[4-(acetimidoyl amino) phenyl] ethyl }-1,3-thiazoles-2-yl) ethanamide (165mg).

¹H-NMR(CDCl ₃)，δ(ppm)：2.03(3H，brs)，2.19(3H，s)，2.92(4H，s)，6.47(1H，s)，6.78(2H，d，J＝8.0Hz)，7.08(2H，d，J＝8.0Hz)。

MS：303(M+H) ⁺

Preparation embodiment 9:

Synthetic N-[4-(2-{4-[amino (imino-) methyl] phenyl } ethyl)-1,3-thiazoles-2-yl] acetamide hydrochloride

Step 1

With 4-(brooethyl) phenyl cyanide (1.73g), triphenylphosphine (2.31g) and N, dinethylformamide (20ml) mixes under nitrogen atmosphere.At stirring at room reaction mixture 1.5h.Then potassium tert.-butoxide (1.19g) and N-(4-formyl radical-1,3-thiazoles-2-yl) ethanamide (1.5g is according to the similar approach preparation of embodiment 1 step 4) are added mixture, at stirring at room 3h.In reaction mixture impouring frozen water, use ethyl acetate extraction.Organic layer is used anhydrous magnesium sulfate drying, vacuum concentration with 1N hydrochloric acid, water and saturated nacl aqueous solution washing.Resistates silica gel flash column chromatography purification (using n-hexane/ethyl acetate (1: 1)) as eluent, obtain N-{4-[(z with the ether grinding)-2-(4-cyano-phenyl) vinyl]-1, the 3-thiazol-2-yl } ethanamide and N-{4-[(E)-2-(4-cyano-phenyl) vinyl]-1,3-thiazoles-2-yl } the light yellow solid mixture (Z: E=3: 1) (1.63g) of ethanamide.

mp.175-176℃

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.13(3Hx3/4，s)，2.16(3Hx1/4，s)，6.59(1Hx3/4，d，J＝13.0Hz)，6.65(1Hx3/4，d，J＝13.0Hz)，7.11(1Hx3/4，s)，7.24(1Hx1/4，d，J＝16.0Hz)，7.28(1Hx1/4，s)，7.40(1Hx1/4，d，J＝16.0Hz)，7.65(2Hx3/4，d，J＝8.5Hz)，7.74(2Hx1/4，d，J＝8.5Hz)，7.75(2Hx3/4，d，J＝8.5Hz)，7.83(2Hx1/4，d，J＝8.5Hz)，12.00(1H，brs)。

MS：270(M+H) ⁺

Step 2

With N-{4-[(Z)-2-(4-cyano-phenyl) vinyl]-1, the 3-thiazol-2-yl } ethanamide and N-{4-[(E)-2-(4-cyano-phenyl) vinyl]-1,3-thiazoles-2-yl } ethanamide (Z: E=3: 1) (1.5g), 10% palladium carbon (323mg), methyl alcohol (20ml), tetrahydrofuran (THF) (10ml) and acetate (5ml) mixes.Reaction mixture is stirred 9h under 4atm nitrogen atmosphere, room temperature, filter by Celite pad.Vacuum concentrated filtrate.Resistates silica gel flash column chromatography purification (using n-hexane/ethyl acetate (1: 1) → chloroform/methanol (30: 1)) as eluent, obtain colorless solid N-{4-[2-(4-cyano-phenyl) ethyl with the ether grinding]-1,3-thiazoles-2 base } ethanamide (1.18g).

mp.205-206.5℃

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.11(3H，s)，2.90(2H，t，J＝8.0Hz)，3.01(2H，t，J＝8.0Hz)，6.73(1H，s)，7.40(2H，d，J＝8.0Hz)，7.74(2H，d，J＝8.0Hz)，12.09(1H，brs)。

MS：272(M+H) ⁺

Step 3

With N-{4-[2-(4-cyano-phenyl) ethyl]-1,3-thiazoles-2-yl } ethanamide (600mg) is dissolved in ethanol (5ml) and chloroform (5ml), feeds hydrogen chloride gas 5min at 0 ℃ then, stir simultaneously.With reaction mixture sat 15h, vacuum concentration.Residual solid obtains light green solid 4-{2-[2-(acetylamino)-1,3-thiazoles-4-yl with the ether washing] ethyl } phenyl azomethine acid ethyl ester hydrochloride salt (924.7mg).

mp.129-130℃

¹H-NMR(DMSO-d ₆)，δ(ppm)：1.48(3H，t，J＝7.0Hz)，2.12(3H，s)，2.95(2H，t，J＝8.0Hz)，3.07(2H，t，J＝8.0Hz)，4.61(2H，q，J＝7.0Hz)，6.72(1H，s)，7.46(2H，d，J＝8.5Hz)，8.02(2H，d，J＝8.5Hz)，11.25(1H，brs)，11.98(1H，brs)，12.11(1H，brs)。

MS:318 (M+H) ⁺(free type)

Step 4

With 4-{2-[2-(acetylamino)-1,3-thiazoles-4-yl] ethyl } phenyl azomethine acid ethyl ester hydrochloride salt (300mg) is dissolved in ethanol (6ml).The methanol solution (1ml) of ammonium chloride (68mg) and ammonia is added solution.The reaction mixture 5h that under nitrogen atmosphere, refluxes.After being cooled to room temperature, vacuum filtration suspension.Vacuum concentrated filtrate, resistates solidifies with ethanol/ether, obtains colorless solid N-[4-(2-{4-[amino (imino-) methyl] phenyl } ethyl)-1,3-thiazoles-2-yl] acetamide hydrochloride (234mg).

mp.229.5-231℃

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.12(3H，s)，2.94(2H，t，J＝8.0Hz)，3.06(2H，t，J＝8.0Hz)，6.75(1H，s)，7.44(2H，d，J＝8.5Hz)，7.76(2H，d，J＝8.5Hz)，12.10(1H，brs)。

MS:289 (M+H) ⁺(free type)

Preparation embodiment 10:

Synthetic N-(4-{2-[2-(acetylamino)-1,3-thiazoles-4-yl] ethyl } phenyl)-2-{[amino (imino-) methyl] amino }-acetamide hydrochloride

Step 1

With N-(4-(2-(4-aminophenyl) ethyl)-1, the 3-thiazol-2-yl) mixture of ethanamide (100mg is according to the similar approach preparation of preparation embodiment 1 step 6), ((tert-butoxycarbonyl) amino) acetate (74mg), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (81mg), I-hydroxybenzotriazole (57mg) and methylene dichloride (5ml) is at stirring at room 3h.Reaction mixture washs with saturated sodium bicarbonate aqueous solution, the vacuum concentration organic layer.Resistates is with silica gel flash column chromatography purify (with 3% methyl alcohol/chloroform as eluent).Collect crystalline residue,, obtain 2-[(4-{2-[2-(acetylamino)-1,3-thiazoles-4-yl with the ethyl acetate washing] ethyl } phenyl) amino]-2-oxoethyl t-butyl carbamate (580mg).

¹H-NMR(CDCl ₃)，δ(ppm)：1.47(9H，s)，2.25(3H，s)，2.92(4H，s)，3.92(2H，d，J＝5Hz)，6.46(1H，s)，7.10(2H，d，J＝7Hz)，7.38(2H，d，J＝7Hz)。

MS(M+H)＝419

Step 2

2-[(4-{2-[2-(acetylamino)-1; 3-thiazole-4-yl] ethyl } phenyl) amino]-add 4N hydrogenchloride/ethyl acetate (1ml) in ethyl acetate (1ml) solution of 2-oxoethyl t-butyl carbamate (100mg), at stirring at room mixture 103h.The solid that filtration is separated out obtains N-(4-{2-[2-(acetylamino)-1,3-thiazoles-4-yl] ethyl } phenyl)-2-glycyl amine hydrochlorate (80mg) with ethyl acetate washing.

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.11(3H，s)，2.87(4H，s)，6.70(1H，s)，7.17(2H，d，J＝7Hz)，7.49(2H，d，J＝7Hz)。

MS(M+H)＝319

Step 3

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.11(3H，s)，2.80-2.95(4H，m)，3.76(2H，s)，6.70(1H，s)，7.26(2H，d，J＝7Hz)，7.49(2H，d，J＝7Hz)，8.16(2H，s)。

MS(M+H)＝361

Preparation embodiment 11:

Synthetic N-{4-[4-(2-{[amino (imino-) methyl] amino } ethyl) phenyl]-1,3-thiazoles-2-yl } acetamide hydrochloride

Step 1

(1.63g) is dissolved in 1 with aluminum chloride, 2-ethylene dichloride (15mL).At 0 ℃ chloro-acetyl chloride (0.732mL) is added mixture, restir 20min drips 1 of N-(2-phenylethyl) ethanamide (1g) then, 2-ethylene dichloride (5mL) solution.At stirring at room mixture 1h, then in the impouring frozen water.The mixture chloroform extraction, water and saturated nacl aqueous solution washing concentrate with the dried over sodium sulfate final vacuum.Solid washs with ethyl acetate and ether, and vacuum-drying obtains white powder N-{2-[4-(2-chloracetyl) phenyl] ethyl }-ethanamide (1.18g, 80.4%).

¹H-NMR(300MHz，DMSO-d ₆)，δ(ppm)：7.92(2H，d，J＝6Hz)，7.34(2H，d，J＝6Hz)，5.66(1H，br)，4.70(2H，s)，3.55-3.60(2H，m)，2.90-2.94(2H，m)，1.98(3H，s)。

Step 2

With N-{2-[4-(2-chloracetyl) phenyl] ethyl } ethanamide (1.06g) and thiocarbamide (505mg) be dissolved in ethanol (20mL).With the mixture 1h that refluxes, allow it be cooled to room temperature.Filter and collect white solid, obtain N-{2-[4-(2-amino-1,3-thiazoles-4-yl) phenyl with washing with alcohol] ethyl } acetamide hydrochloride (1.19g, 90.4%).

MS m/z 262(M++1)。

¹H-NMR(300MHz，DMSO-d ₆)，δ(ppm)：7.93-7.96(2H，m)，7.69(2H，d，J＝6Hz)，7.30(2H，d，J＝6Hz)，7.16(1H，s)，3.23-3.30(2H，m)，2.70-2.76(2H，m)，1.78(3H，s)。

Step 3

With N-{2-[4-(2-amino-1,3-thiazoles-4-yl) phenyl] ethyl } ethanamide (0.6g) is dissolved in ethanol (10mL) and concentrated hydrochloric acid (10mL).With the mixture 5h that refluxes.Vacuum evaporating solvent.Resistates obtains 4-[4-(2-amino-ethyl) phenyl with the ether washing]-1,3-thiazoles-2-amine dihydrochloride (0.5g, 84.6%).

MS m/z 220(M++1)。

¹H-NMR(300MHz，DMSO-d ₆)，δ(ppm)：8.15(3H，br)，7.78(2H，d，J＝6Hz)，7.39(2H，d，J＝6Hz)，7.24(1H，s)，3.03-3.10(2H，m)，2.90-2.98(2H，m)。

Step 4

With 4-[4-(2-amino-ethyl) phenyl]-1,3-thiazoles-2-amine dihydrochloride (0.45g) is dissolved in 1,4-diox (10mL), water (3mL) and 1N sodium hydroxide solution (3.1mL).Add tert-Butyl dicarbonate (336mg) at 0 ℃.In the stirring at room mixture overnight, use ethyl acetate extraction then, water and saturated nacl aqueous solution washing concentrate with the dried over sodium sulfate final vacuum.Solid washs with ether, and vacuum-drying obtains white solid { 2-[4-(2-amino-1,3-thiazoles-4-yl) phenyl] ethyl }-t-butyl carbamate (311mg, 63.2%).

MS m/z 320(M++1)。

¹H-NMR(300MHz，DMSO-d ₆)，δ(ppm)：7.69(2H，d，J＝6Hz)，7.18(2H，d，J＝6Hz)，7.02(2H，br)，7.69(1H，s)，3.10-3.27(2H，m)，2.65-2.72(2H，m)，1.37(9H，s)。

Step 5

{ 2-[4-(2-amino-1,3-thiazoles-4-yl) phenyl] ethyl } t-butyl carbamate (290mg) is dissolved in methylene dichloride (5mL), adds acetic anhydride (0.103mL), 4-dimethylaminopyridine (10mg) and pyridine (0.147mL) then.Stir the mixture and spend the night.The mixture chloroform extraction, water and saturated nacl aqueous solution washing concentrate with the dried over sodium sulfate final vacuum.Solid washs with ether, and vacuum-drying obtains white solid (2-{4-[2-(acetylamino)-1,3-thiazoles-4-yl] phenyl } ethyl) t-butyl carbamate (280mg, 85.3%).

MS m/z 362(M++1)。

¹H-NMR(300MHz，DMSO-d ₆)，δ(ppm)：7.80(2H，d，J＝6Hz)，7.53(1H，s)，7.24(2H，d，J＝6Hz)，6.90(1H，m)，3.12-3.18(2H，m)，2.16-2.63(2H，m)，2.16(3H，s)，1.37(9H，s)。

Step 6

(2-{4-[2-(acetylamino)-1,3-thiazoles-4-yl] phenyl } ethyl) t-butyl carbamate (250mg) is dissolved in ethyl acetate (4mL) and 4N hydrogenchloride/ethyl acetate (2mL).Vacuum evaporating solvent.Solid obtains N-{4-[4-(2-amino-ethyl) phenyl with ethyl acetate and ether washing]-1,3-thiazoles-2-yl } acetamide hydrochloride (220mg, 106%).

MS m/z 262(M++1)。

¹H-NMR(300MHz，DMSO-d ₆)，δ(ppm)：8.05(3H，br)，7.85(2H，d，J＝6Hz)，7.58(1H，s)，7.32(2H，d，J＝6Hz)，3.12-3.18(2H，m)，2.88-2.94(2H，m)，2.16(3H，s)。

Step 7

With N-{4-[4-(2-amino-ethyl) phenyl]-1,3-thiazoles-2-yl } acetamide hydrochloride (200mg) and diisopropylethylamine (0.175mL) be dissolved in tetrahydrofuran (THF) (5mL).In stirring at room mixture overnight, vacuum-evaporation then.Resistates with silica gel chromatography purify (5% methyl alcohol/chloroform) obtain { [(2-{4-[2-(acetylamino)-1,3-thiazoles-4-yl] phenyl } ethyl) amino] methylene radical-diamino acid di tert butyl carbonate (268mg, 79.2%).

MS m/z 504(M++1)。

Step 8

Will { [(2-{4-[2-(acetylamino)-1,3-thiazoles-4-yl] phenyl } ethyl) amino] methylene radical } diamino acid di tert butyl carbonate (268mg, 79.2%) (170mg) is dissolved in 4N hydrogenchloride/1,4-diox (5mL).In stirring at room mixture 2 days, vacuum-evaporation then.Resistates washs with ether, and vacuum-drying obtains N-{4-[4-(2-{[amino (imino-) methyl] amino } ethyl) phenyl]-1,3-thiazoles-2-yl } acetamide hydrochloride (50mg, 43.6%).

MS m/z 304(M++1)。

¹H-NMR(300MHz，DMSO-d ₆)，δ(ppm)：7.83(2H，d，J＝8Hz)，7.62-7.66(1H，m)，7.56(1H，s)，7.34(2H，d，J＝8Hz)，3.37-3.45(2H，m)，2.78-2.85(2H，m)，2.16(3H，s)。

Preparation embodiment 12:

Synthetic N-(4-{2-[4-(amino methyl) phenyl] ethyl }-1,3-thiazoles-2-yl) ethanamide

Step 1

N-(4-{2-[4-(hydroxymethyl) phenyl] ethyl }-1, the 3-thiazol-2-yl) ethanamide (50mg, according to the preparation of the similar approach of following preparation embodiment 16 steps 3), add triphenylphosphine (71mg) in the mixture of carbon tetrabromide (72mg) and methylene dichloride (1ml), at stirring at room mixture 1h.Reaction mixture is with silica gel flash column chromatography purify (with 1% methyl alcohol/chloroform as eluent).Collect crystalline residue, with the diisopropyl ether washing obtain N-(4-{2-[4-(brooethyl) phenyl] ethyl }-1,3-thiazoles-2-yl) ethanamide (48mg).

¹H-NMR(CDCl ₃)，δ(ppm)：2.25(3H，s)，2.85-3.03(4H，m)，4.49(2H，s)，6.48(1H，s)，7.13(2H，d，J＝7Hz)，7.30(2H，d，J＝7Hz)。

MS(M+H)＝339

Step 2

N-(4-{2-[4-(brooethyl) phenyl] ethyl }-1, the 3-thiazol-2-yl) ethanamide (100mg), tetrahydrofuran (THF) (2ml) and N, add diformazan acylimino sodium (sodium diformylimide) (42mg) in the mixture of dinethylformamide (2ml), at stirring at room mixture 1h.The solid of separating out is filtered in reaction mixture water (3ml) dilution, washes with water and obtains N-[4-(2-{4-[(diformyl amino)-methyl] phenyl } ethyl)-1,3-thiazoles-2-tomb] ethanamide (80mg).

¹H-NMR(CDCl ₃)，δ(ppm)：2.23(3H，s)，2.83-3.00(4H，m)，4.72(2H，s)，6.48(1H，s)，7.10(2H，d，J＝7Hz)，7.38(2H，d，J＝7Hz)。

MS(M+H)＝318

Step 3

N-[4-(2-{4-[(diformyl amino) methyl]-phenyl } ethyl)-1,3-thiazoles-2-yl] add 4N hydrogenchloride/ethyl acetate (0.5ml) in methyl alcohol (0.5ml) solution of ethanamide (56mg), at stirring at room mixture 1h.The vacuum concentration reaction mixture.Resistates distributes between chloroform (5ml) and saturated sodium bicarbonate aqueous solution (5ml), and water layer extracts with chloroform (5ml).Organic layer dried over sodium sulfate, vacuum concentration obtain N-(4-{2-[4-(amino methyl) phenyl] ethyl }-1,3-thiazoles-2-yl) ethanamide (50mg).

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.12(3H，s)，2.80-3.00(4H，m)，3.92-4.05(2H，m)，6.72(1H，s)，7.24(2H，d，J＝7Hz)，7.37(2H，d，J＝7Hz)。

MS(M+H)＝276

Preparation embodiment 13:

Synthetic 4-[2-(4-{[amino (imino-) methyl] amino } phenyl) ethyl]-1,3-thiazoles-2-aminocarbamic acid carbethoxy hydrochloride

Step 1: 4-(hydroxymethyl)-1,3-thiazoles-2-aminocarbamic acid ethyl ester

With 4-(chloromethyl)-1,3-thiazoles-2-aminocarbamic acid ethyl ester (500mg), 1, the mixing solutions stirring and refluxing 3.5h of 4-diox (5ml) and water (10ml).After cooling, with its concentrating under reduced pressure.Mixture is distributed between ethyl acetate and water.Isolate organic phase, use the salt water washing, use dried over mgso, concentrating under reduced pressure.Resistates silica gel (10g) column chromatography purification (with the mixed solvent of hexane and ethyl acetate (2: 1)).Collection comprises the part of target compound, and reduction vaporization obtains colourless soup compound (450mg, 98.2%).

MS(ES+)；203(M+H) ⁺

¹H-NMR(CDCl ₃)，δ(ppm)：1.39(3H，t，J＝7.0Hz)，4.39(2H，q，J＝7.0Hz)，4.61(2H，s)，6.80(1H，s)。

Step 2:4-formyl radical-1,3-thiazoles-2-aminocarbamic acid ethyl ester

At room temperature, progressively add chemically treated manganese oxide (IV) (1.92g) in the mixing solutions of the chloroform (30ml) of 4-(hydroxymethyl)-1,3-thiazoles-2-aminocarbamic acid ethyl ester (446mg) and methyl alcohol (3ml).Mixture after uniform temp stirs 2h, is added chemically treated manganese oxide (IV) (250mg) to solution once more, stir 3h at 50 ℃.Remove by filter manganese oxide (IV), concentrating under reduced pressure filtrate.Resistates silica gel (10g) column chromatography purification (with the mixed solvent of hexane and ethyl acetate (4: 1)).Collection comprises the part of target compound, and reduction vaporization obtains colourless powder (470mg, 106.4%).

¹H-NMR(CDCl ₃)，δ(ppm)：1.36(3H，t，J＝7.0Hz)，4.34(2H，q，J＝7.0Hz)，7.83(1H，s)，9.54(1H，br)，9.88(1H，s)。

Step 3

4-[2-(4-nitrophenyl) vinyl]-1,3-thiazoles-2-aminocarbamic acid ethyl ester (E/Z mixture) obtains according to the similar approach of preparation embodiment 1 step 5.

¹H-NMR (CDCl ₃) (suitable/anti-mixture of products), δ (ppm): 1.20-1.40 (3H, m), 4.20-4.40 (2H, m), 6.60,6.66 (1.2H, ABq, J=13Hz), 6.74 (0.6H, s), 6.94 (0.4H, s), 7.12,7.30 (0.8H, ABq, J=16Hz), 7.53 (1.2H, d, J=8.9Hz), 7.61 (0.8H, d, J=8.9Hz), 8.11 (1.2H, d, J=8.9Hz), 8.22 (0.8H, d, J=8.9Hz).

Step 4

4-[2-(4-aminophenyl) ethyl]-1,3-thiazoles-2-aminocarbamic acid ethyl ester is real according to preparation

The similar approach of executing example 1 step 6 obtains.

MS(ES+)；292(M+H) ⁺

¹H-NMR(DMSO-d ₆)，δ(ppm)：1.24(3H，t，J＝7.1Hz)，2.65-2.80(4H，m)，4.18(2H，q，J＝7.1Hz)，4.82(2H，br)，6.46(2H，d，J＝8.5Hz)，6.69(1H，s)，6.84(2H，d，J＝8.5Hz)。

Step 5

4-[2-(4-{N ', N "-two (tert-butoxycarbonyls)-[amino (imino-) methyl] amino } phenyl) ethyl]-1,3-thiazoles-2-aminocarbamic acid ethyl ester obtains according to the similar approach of following preparation embodiment 14 steps 3.

¹H-NMR(CDCl ₃)，δ(ppm)：1.29(3H，t，J＝7.0Hz)，1.40-1.70(18H，m)，2.94(4H，s)，4.27(2H，q，J＝7.0Hz)，6.45(1H，s)，7.12(2H，d，J＝8.4Hz)，7.48(2H，d，J＝8.4Hz)，10.25(1H，s)。

Step 6

Title compound obtains according to the similar approach of following preparation embodiment 14 steps 5.

MS (ES+); 334 (M+H) ⁺(free type)

¹H-NMR(DMSO-d ₆)，δ(ppm)：1.24(3H，t，J＝7.0Hz)，2.80-3.00(4H，m)，4.19(2H，q，J＝7.0Hz)，6.76(1H，s)，7.14(2H，d，J＝8.4Hz)，7.28(2H，d，J＝8.4Hz)，7.46(3H，br)，9.91(1H，s)。

Preparation embodiment 14:

Synthetic N-{4-[2-(3-{[amino (imino-) methyl] amino } phenyl) ethyl]-5-bromo-1,3-thiazoles-2-yl } acetamide hydrochloride

Step 1:N-{4-[2-(3-nitrophenyl) vinyl]-1,3-thiazoles-2-yl } (E/Z mixes ethanamide Thing)

In room temperature,, add triphenylphosphine (335mg) in dinethylformamide (7mL) solution to the N of 1-(brooethyl)-3-oil of mirbane (276mg).After mixing solution 4h, potassium tert.-butoxide (172mg) and N-(4-formyl radical-1,3-thiazoles-2-yl) ethanamide (217mg) are added solution successively at uniform temp.Whole solution is behind stirring at room 5h, and in mixture impouring water, water layer pH is adjusted to 7 with 1N hydrochloric acid.Gained mixture ethyl acetate extraction.Extraction liquid salt water washing is used dried over sodium sulfate, reduction vaporization.Gained resistates silica gel (10g) column chromatography purification (with the mixed solvent of normal hexane and ethyl acetate (4: 1)).Collection comprises the part of target compound, and reduction vaporization obtains brown powder shape title compound (E/Z mixture) (323mg, 87.4%).

¹H-NMR (DMSO-d ₆) (suitable/anti-mixture of products), δ (ppm): 2.11 (2.49H, s), 2.16 (0.51H, s), 6.66 (1.66H, s), 7.13 (0.83H, s), 7.28 (0.17H, s), 7.29,7.46 (0.34H, ABq, J=16Hz), 7.60 (1H, t, J=7.9Hz), 7.91 (0.83H, d, J=7.9Hz), 8.01 (0.17H, d, J=7.9Hz), 8.09-8.13 (1H, m), 8.28 (0.83H, m), 8.38 (0.17H, m).

Step 2:N-{4-[2-(3-aminophenyl) ethyl]-1,3-thiazoles-2-yl } ethanamide

Under 4.3 normal atmosphere, room temperature, N-{4-[2-(3-nitrophenyl) vinyl]-1, the 3-thiazol-2-yl } ethanamide (E, the Z mixture) (315mg) solution in mixed solvent methyl alcohol (3ml), tetrahydrofuran (THF) (6ml) and acetate (1ml) (50% is moistening, 200mg) hydrogenation 3h by 10% palladium carbon.Filtration catalizer, vacuum-evaporation filtrate.In resistates impouring water, the pH of water layer is adjusted to 9 with sodium bicarbonate aqueous solution.Gained mixture ethyl acetate extraction.Extraction liquid salt water washing is used dried over mgso, reduction vaporization.Gained resistates silica gel (9g) column chromatography purification (with the mixed solvent of normal hexane and ethyl acetate (2: 1 to 1: 1)).Collection comprises the part of target compound, and reduction vaporization obtains soup compound.The soup compound of target compound becomes solid (275mg, 96.6%) in refrigerator.

MS(ES+)；262(M+H) ⁺

¹H-NMR(CDCl ₃)，δ(ppm)：2.23(3H，s)，2.80-3.00(4H，m)，3.60(2H，br)，6.51(1H，s)，6.45-6.65(3H，m)，7.06(1H，t，J＝7.9Hz)，9.45(1H，br)。

Step 3:N-{4-[2-(3-{[N ', N "-two (tert-butoxycarbonyl) amino-(imino-) methyl] amino } Phenyl) ethyl]-1,3-thiazoles-2-yl } ethanamide

At room temperature, to N-{4-[2-(3-aminophenyl) ethyl]-1,3-thiazoles-2-yl } add N, N '-two (tert-butoxycarbonyl)-1H-pyrazoles-1-carbonamidine (317mg) in tetrahydrofuran (THF) (3ml) solution of ethanamide (267mg).Mixing solutions after uniform temp stirred 3 days, reduction vaporization, the gained resistates is with silica gel (10g) column chromatography purify (with the mixed solvent of normal hexane and ethyl acetate (4: 1 to 3: 2)).Collection comprises the part of target compound, and reduction vaporization obtains colourless foam shape title compound (316mg, 61.4%).

MS(ES+)；504(M+H) ⁺

¹H-NMR(CDCl ₃)，δ(ppm)：1.40-1.80(18H，m)，2.25(3H，s)，2.97(4H，m)，6.37(1H，m)，6.53(1H，s)，6.91(1H，d，J＝7.9Hz)，7.23(1H，t，J＝7.9Hz)，7.34(1H，s)，7.52(1H，d，J＝7.9Hz)，7.63-7.64(1H，m)，10.28(1H，s)。

Step 4:N-{4-[2-(3-{[N ', N "-two (tert-butoxycarbonyl) amino-(imino-) methyl] amino } Phenyl) ethyl]-5-bromo-1,3-thiazoles-2-yl } ethanamide

Room temperature to N-{4-[2-(3-{[N ', N "-two (tert-butoxycarbonyl) amino (imino-) methyl] amino phenyl) ethyl]-1,3-thiazoles-2-yl methyl alcohol (3ml) suspension of ethanamide (115mg) adds N-bromo-succinimide (44.7mg).Mixing solutions filters and collects the gained precipitation after uniform temp stirs 1h, with the mixed solvent washing of diisopropyl ether and normal hexane (1: 1).Obtain white powder title compound (70mg, 52.6%).

MS(ES+)；582(M+H) ⁺

¹H-NMR(CDCl ₃)，δ(ppm)：1.40-1.75(18H，m)，2.21(3H，s)，2.85-3.00(4H，m)，6.93(1H，d，J＝7.9Hz)，7.23(1H，t，J＝7.9Hz)，7.30(1H，s)，7.51(1H，d，J＝7.9Hz)，9.26(1H，br)，10.26(1H，br)，11.63(1H，br)。

Step 5

Room temperature to N-{4-[2-(3-{[N '; N " amino (imino-) methyl of-two (tert-butoxycarbonyl)] amino } phenyl) ethyl]-5-bromo-1, the 3-thiazol-2-yl } drip 1 of 4N hydrogenchloride, 4-dioxane solution (2ml) in methylene dichloride (0.5ml) solution of ethanamide (64mg).After uniform temp stirs 20h, the concentrating under reduced pressure reaction mixture.The gained resistates is dissolved in minimum methyl alcohol, solution is progressively diluted with ethyl acetate.Filter and collect the gained precipitation, wash with diisopropyl ether.Obtain the title compound (37mg, 80.4%) of colourless powder shape.

MS (ES+); 382 (M+H) ⁺(free type)

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.14(3H，s)，2.80-3.00(4H，m)，7.00-7.15(3H，m)，7.35(1H，t，J＝7.9Hz)，7.51(4H，br)，10.01(1H，br)，12.42(1H，br)。

Preparation embodiment 15:

Synthetic N-{4-[2-(4-{[amino (imino-) methyl] amino } phenyl) ethyl]-5-bromo-1,3-thiazoles-2-yl } acetamide hydrochloride

Step 1-a

Will [(4-{2-[2-(acetylamino)-1,3-thiazoles-4-yl] ethyl } phenyl) amino] methylene radical } the similar approach preparation of the compound of embodiment 1 step 6 of diamino acid di tert butyl carbonate according to preparation embodiment 18 steps 5.

mp.275.5-276℃

¹H-NMR(DMSO-d ₆)，δ(ppm)：1.39(9H，s)，1.51(9H，s)，2.11(3H，s)，2.82-2.96(4H，m)，6.74(1H，s)，7.18(2H，d，J＝8.5Hz)，7.42(2H，d，J＝8.5Hz)，9.94(1H，brs)，11.44(1H，brs)，12.09(1H，brs)。

MS：504(M+H) ⁺

Step 1-b

Under nitrogen atmosphere; with { [(4-{2-[2-(acetylamino)-1; 3-thiazole-4-yl] ethyl } phenyl) amino] methylene radical } diamino acid di tert butyl carbonate (310mg is according to the preparation of the similar approach of following preparation embodiment 18 steps 5) is dissolved in methyl alcohol (6ml) and tetrahydrofuran (THF) (3ml).At 0 ℃ N-bromo-succinimide (164mg) is added solution then.At stirring at room reaction mixture 4h, vacuum concentration.Chloroform and saturated sodium bicarbonate solution are added in the resistates.Organic layer water and saturated nacl aqueous solution washing are used anhydrous magnesium sulfate drying, vacuum concentration.Resistates silica gel flash column chromatography purification (using n-hexane/ethyl acetate (2: 1)) as eluent; obtain colourless amorphous substance { [(4-{2-[2-(acetylamino)-5-bromo-1,3-thiazoles-4-yl] ethyl } phenyl) amino]-methylene radical } diamino acid di tert butyl carbonate (271.4mg).

¹H-NMR(CDCl ₃)，δ(ppm)：1.49(9H，s)，1.53(9H，s)，2.22(3H，s)，2.90(4H，s)，7.13(2H，d，J＝8.0Hz)，7.45(2H，d，J＝8.0Hz)。

MS：582(M+H) ⁺

Step 2

Will { [(4-{2-[2-(acetylamino)-5-bromo-1,3-thiazoles-4-yl] ethyl } phenyl) amino] methylene radical diamino acid di tert butyl carbonate (113mg) and 4N hydrochloric acid 1,4-dioxane solution (2ml) mixes under nitrogen atmosphere.At stirring at room reaction mixture 24h.Solvent removed in vacuo.Resistates washs with ethyl acetate, obtains light yellow amorphous solid N-{4-[2-(4-{[amino (imino-) methyl] amino } phenyl) ethyl]-5-bromo-1,3-thiazoles-2-yl } acetamide hydrochloride (16.8mg).

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.14(3H，s)，2.82-2.97(4H，m)，7.14(2H，d，J＝8.5Hz)，7.25(2H，d，J＝8.5Hz)，7.40(3H，brs)，9.81(1H，brs)，12.41(1H，brs)。

MS:382 (M+H) ⁺(free type)

Preparation embodiment 16:

Synthetic N-[4-(2-{4-[(amino oxygen base) methyl] phenyl } ethyl)-1,3-thiazoles-2-yl] ethanamide

Step 1

With [4-(methoxycarbonyl) benzyl] (triphenyl) phosphorus bromine (6.06g) and N, dinethylformamide (50ml) mixes under nitrogen atmosphere.At 0 ℃ potassium tert.-butoxide (1.66g) and N-(4-formyl radical-1,3-thiazoles-2-yl) ethanamide (2.1g is according to the similar approach preparation of preparation embodiment 1 step 4) are added suspension then.At stirring at room reaction mixture 6h, in the impouring frozen water, use ethyl acetate extraction.Organic layer is used anhydrous magnesium sulfate drying, vacuum concentration with 1N hydrochloric acid, water and saturated nacl aqueous solution washing.Resistates silica gel flash column chromatography purification (using chloroform/methanol (20: 1 → 10: 1)) as eluent; obtain 4-{ (Z)-2-[2-(acetylamino)-1 with the ether grinding; 3-thiazole-4-yl] vinyl } methyl benzoate and 4-{ (E)-2-[2-(acetylamino)-1,3-thiazoles-4-yl] vinyl } methyl benzoate (Z: E=3: colorless solid mixture (4.05g) 1).

mp.164-165.5℃

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.13(3Hx3/4，s)，2.16(3Hx1/4，s)，3.85(3H，s)，6.61(2Hx3/4，s)，7.05(1Hx3/4，s)，7.26(1Hx1/4，d，J＝15.5Hz)，7.27(1Hx1/4，s)，7.37(1Hx1/4，d，J＝15.5Hz)，7.64(2Hx3/4，d，J＝8.5Hz)，7.69(2Hx1/4，d，J＝8.5Hz)，7.90(2Hx3/4，d，J＝8.5Hz)，7.94(2Hx1/4，d，J＝8.5Hz)，12.05(1H，brs)。

MS：303(M+H) ⁺

Step 2

4-{2-[2-(acetylamino)-1,3-thiazoles-4-yl] ethyl } methyl benzoate is according to the similar approach preparation of preparation embodiment 9 steps 2.

mp.170-171℃

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.11(3H，s)，2.86-2.95(2H，m)，2.97-3.05(2H，m)，3.83(3H，s)，6.72(1H，s)，7.35(2H，d，J＝8.5Hz)，7.87(2H，d，J＝8.5Hz)，12.08(1H，brs)。

MS：305(M+H) ⁺

Step 3

Under nitrogen atmosphere ,-78 ℃; in 15min to 4-{2-[2-(acetylamino)-1,3-thiazoles-4-yl that stirs] ethyl drip the toluene solution (20.7ml) of 1.0M diisobutyl aluminium hydride in anhydrous tetrahydro furan (36ml) solution of methyl benzoate (1.8g).At stirring at room reaction mixture 1.5h, then with reactant water (1ml) quencher.At stirring at room mixture 30min, use anhydrous magnesium sulfate drying, filter by Celite pad.Vacuum evaporating solvent.Residual solid is washed with ether, obtain colorless solid N-(4-{2-[4-(hydroxymethyl) phenyl] ethyl }-1,3-thiazoles-2-yl) ethanamide (1.03g).

mp.162-165℃

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.11(3H，s)，2.80-2.95(4H，m)，4.44(2H，d，J＝5.5Hz)，5.09(1H，t，J＝5.5Hz)，6.72(1H，s)，7.14(2H，d，J＝8.0Hz)，7.21(2H，d，J＝8.0Hz)，12.08(1H，brs)。

MS：277(M+H) ⁺

Step 4

With N-(4-{2-[4-(hydroxymethyl) phenyl] ethyl-1, the 3-thiazol-2-yl) ethanamide (250mg), 2-hydroxyl-1H-isoindole-1,3 (2H)-diketone (155mg), triphenylphosphine (249mg) and tetrahydrofuran (THF) (5ml) mix under nitrogen atmosphere, at 0 ℃ diethyl azodiformate (0.15ml) are added solution then.At stirring at room reaction mixture 6h, in the impouring saturated sodium bicarbonate solution, use ethyl acetate extraction.Organic layer washs with saturated nacl aqueous solution, uses anhydrous magnesium sulfate drying, vacuum concentration.Resistates silica gel flash column chromatography purification (using chloroform/methanol (20: 1)) as eluent, obtain colorless solid N-{4-[2-(4-{[(1 with the ethyl acetate grinding, 3-dioxo-1,3-dihydro-2H-isoindole-2-yl) oxygen base] methyl } phenyl) ethyl]-1,3-thiazoles-2-yl } ethanamide (218.2mg).

mp.225-226℃

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.11(3H，s)，2.82-3.00(4H，m)，5.12(2H，s)，6.69(1H，s)，7.23(2H，d，J＝8.0Hz)，7.41(2H，d，J＝8.0Hz)，7.86(4H，s)，12.08(1H，brs)。

MS：422(M+H) ⁺

Step 5

With N-{4-[2-(4-{[(1,3-dioxo-1,3-dihydro-2H-isoindole-2-yl) oxygen base] methyl } phenyl) ethyl]-1,3-thiazoles-2-yl } ethanamide (200mg), methyl hydrazine (0.038ml) and methylene dichloride (4ml) mix under nitrogen atmosphere.In stirring at room reaction mixture 1.5h, vacuum filtration.Filtrate is used anhydrous magnesium sulfate drying, vacuum concentration with saturated sodium bicarbonate solution, water and saturated nacl aqueous solution washing.Residual solid is washed with acetonitrile, obtains colorless solid N-[4-(2-{4-[(amino oxygen base) methyl] phenyl } ethyl)-1,3-thiazoles-2-yl] ethanamide (81.8mg).

mp.130-130.5℃

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.11(3H，s)，2.82-2.97(4H，m)，4.51(2H，s)，6.01(2H，s)，6.73(1H，s)，7.17(2H，d，J＝8.0Hz)，7.22(2H，d，J＝8.0Hz)，12.09(1H，brs)。

MS：292(M+H) ⁺

Preparation embodiment 17:

Synthetic N-{4-[2-(4-{[(methene amido) oxygen base] methyl } phenyl) ethyl]-1,3-thiazoles-2-yl } ethanamide

With N-[4-(2-{4-[(amino oxygen base) methyl] phenyl } ethyl)-1,3-thiazoles-2-yl] ethanamide (30mg is according to the similar approach preparation of preparation embodiment 16), 37% formaldehyde (8 μ l) and anhydrous methanol (1ml) mix under nitrogen atmosphere.Behind stirring at room reaction mixture 6h, vacuum concentration.Resistates preparation type silica gel column chromatography purification (using chloroform/methanol (20: 1)) as eluent, obtain colorless solid N-{4-[2-(4-{[(methene amido) oxygen base with the ether grinding] methyl }-phenyl) ethyl]-1,3-thiazoles-2-yl } ethanamide (20.9mg).

mp.136.5-137℃

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.11(3H，s)，2.83-2.97(4H，m)，5.01(2H，s)，6.61(1H，d，J＝7.5Hz)，6.73(1H，s)，7.09(1H，d，J＝7.5Hz)，7.18(2H，d，J＝8.0Hz)，7.24(2H，d，J＝8.0Hz)，12.08(1H，brs)。

MS：304(M+H) ⁺

Preparation embodiment 18:

Synthetic N-{5-[2-(4-{[amino (imino-) methyl] amino } phenyl) ethyl]-1,3-thiazoles-2-yl } acetamide hydrochloride

Step 1

With 1,1,3, water (11ml) solution of 3-tetramethoxy propane (10g) and concentrated hydrochloric acid (0.43ml) is at stirring at room 10min.In room temperature bromine (3.14ml) is added drop-wise to solution in 50min.At stirring at room reaction mixture 20min, vacuum concentration.Residual solid washes with water and obtains yellow solid 2-bromine propionic aldehyde (3.6g).

mp.147-148℃

¹H-NMR(CDCl ₃)，δ(ppm)：4.73-4.80(1H，m)，8.47(2H，brs)。

MS：149(M-H) ⁺

Step 2

N '-((E)-ethanoyl) sulfo-amino imido acid-S-acid (2.74g) and acetone (20ml) are mixed under nitrogen atmosphere.Then 2-bromine propionic aldehyde (3.5g) is added the solution under refluxing.With reaction mixture refluxed 1h, be cooled to room temperature.Vacuum leaches precipitation.Solid water and washing with acetone, with the silica gel flash column chromatography purify (with chloroform/methanol (20: 1) as eluent) obtain Off-white solid N-(5-formyl radical-1,3-thiazoles-2-yl) ethanamide (1.21g).

mp.235-235.5℃

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.21(3H，s)，8.41(1H，s)，9.95(1H，s)，12.71(1H，brs)。

MS：169(M-H) ⁺

Step 3

N-{5-[(Z)-2-(4-nitrophenyl) vinyl]-1,3-thiazoles-2-yl } ethanamide is according to the similar approach preparation of preparation embodiment 1 step 5.

mp.221-223℃

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.07(3H，s)，6.63(1H，d，J＝12.0Hz)，6.92(1H，d，J＝12.0Hz)，7.55(1H，s)，7.62(2H，d，J＝9.0Hz)，8.24(2H，d，J＝9.0Hz)，12.16(1H，brs)。

MS：290(M+H) ⁺

Step 4

With N-{5-[(Z)-2-(4-nitrophenyl) vinyl]-1,3-thiazoles-2-yl } ethanamide (1g), 10% palladium carbon (1.04g), ethyl acetate (100ml) and N, the mixture of dinethylformamide (20ml) stirs 4h under 4atm nitrogen atmosphere, room temperature.Reaction mixture filters by Celite pad, vacuum concentrated filtrate.Resistates is purified (using chloroform/methanol (30: 1 → 20: 1) as eluent) with the silica gel flash column chromatography, grinds with ether and obtains Off-white solid N-{5-[2-(4-aminophenyl) ethyl]-1,3-thiazoles-2-yl } ethanamide (240.9mg).

mp.218-219.5℃

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.09(3H，s)，2.70(2H，t，J＝7.5Hz)，2.92(2H，t，J＝7.5Hz)，4.85(2H，s)，6.47(2H，d，J＝8.5Hz)，6.86(2H，d，J＝8.5Hz)，7.08(1H，s)，11.86(1H，brs)。

MS：262(M+H) ⁺

Step 5

With N-{5-[2-(4-aminophenyl) ethyl]-1, the 3-thiazol-2-yl } ethanamide (100mg), N, N '-two (tert-butoxycarbonyl)-1H-pyrazoles-1-carbonamidine (119mg), N, dinethylformamide (1ml) and tetrahydrofuran (THF) (2ml) mix under nitrogen atmosphere.Reaction mixture is stirred 5.5h at 50 ℃.After being cooled to room temperature, the vacuum concentration reaction mixture.Resistates preparation type silica gel column chromatography purification (using n-hexane/ethyl acetate (1: 2)) as eluent; obtain colorless solid { [(4-{2-[2-(acetylamino)-1,3-thiazoles-5-yl] ethyl } phenyl) amino]-methylene radical } diamino acid di tert butyl carbonate (93.9mg).

mp.203-205℃

¹H-NMR(DMSO-d ₆)，δ(ppm)：1.40(9H，s)，1.51(9H，s)，2.10(3H，s)，2.87(2H，t，J＝7.5Hz)，3.02(2H，t，J＝7.5Hz)，7.11(1H，s)，7.21(2H，d，J＝8.5Hz)，7.45(2H，d，J＝8.5Hz)，9.96(1H，brs)，11.43(1H，brs)，11.88(1H，brs)。

MS：504(M+H) ⁺

Step 6

Title compound is according to the similar approach preparation of preparation embodiment 15 steps 2.

mp.105-107℃

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.11(3H，s)，2.91(2H，t，J＝7.5Hz)，3.04(2H，t，J＝7.5Hz)，7.14(1H，s)，7.14(2H，d，J＝8.5Hz)，7.32(2H，d，J＝8.5Hz)，7.46(3H，brs)，9.89(1H，s)，11.95(1H，brs)。

MS:304 (M+H) ⁺(free type)

Preparation embodiment 19:

Synthetic N-{4-[2-(4-{[imino-(methylamino) methyl] amino } phenyl) ethyl]-1,3-thiazoles-2-yl } ethanamide

With N-(4-{2-[2-(acetylamino)-1; 3-thiazole-4-yl] ethyl } phenyl) mixture of sulfo-amino imido acid-S-methyl esters hydriodate (50mg is according to the similar approach preparation of preparation embodiment 4), 40% methylamine/methyl alcohol (0.056ml) and ethanol (1ml) is at stirring at room 20h.The crystal that filtration is separated out obtains N-{4-[2-(4-{[imino-(methylamino) methyl] amino } phenyl)-ethyl with washing with alcohol]-1,3-thiazoles-2-yl } ethanamide (18mg).

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.11(3H，s)，2.64(3H，s)，2.83(4H，s)，6.67(2H，d，J＝7Hz)，6.73(1H，s)，7.01(2H，d，J＝7Hz)。

MS(M+H)＝318

Preparation embodiment 20:

Synthetic N-{4-[2-(4-{[amino (imino-)-methyl] amino } phenyl) ethyl]-5-chloro-1,3-thiazoles-2-yl } acetamide hydrochloride

Step 1

Under nitrogen atmosphere with { [(4-{2-[2-(acetylamino)-1; 3-thiazole-4-yl] ethyl } phenyl) amino] methylene radical } diamino acid di tert butyl carbonate (150mg is according to the similar approach preparation of preparation embodiment 18 steps 5) is dissolved in methyl alcohol (1.5ml) and tetrahydrofuran (THF) (3ml).At 0 ℃ N-chlorosuccinimide (59.7mg) is added solution then.At stirring at room reaction mixture 29h, dilute with ethyl acetate.Organic solution is used anhydrous magnesium sulfate drying, vacuum concentration with saturated sodium bicarbonate solution, water and saturated nacl aqueous solution washing.Residual solid obtains Off-white solid { [(4-{2-[2-(acetylamino)-5-chloro-1,3-thiazoles-4-yl] ethyl } phenyl with ether washing) amino] methylene radical } diamino acid di tert butyl carbonate (111mg).

mp.220-221℃

¹H-NMR(DMSO-d ₆)，δ(ppm)：1.39(9H，s)，1.51(9H，s)，2.13(3H，s)，2.81-2.94(4H，m)，7.15(2H，d，J＝8.5Hz)，7.43(2H，d，J＝8.5Hz)，9.95(1H，brs)，11.43(1H，brs)，12.38(1H，brs)。

MS：538(M+H) ⁺

Step 2

mp.82-84℃

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.14(3H，s)，2.82-2.97(4H，m)，7.14(2H，d，J＝8.5Hz)，7.25(2H，d，J＝8.5Hz)，7.42(3H，brs)，9.85(1H，brs)，12.38(1H，brs)。

MS:338 (M+H) ⁺(free type)

Preparation embodiment 21:

Synthetic N-(4-{2-[4-({ [amino (imino-) methyl] amino } methyl) phenyl] ethyl }-1,3-thiazoles-2-yl) acetamide hydrochloride

Step 1

With N-(4-{2-[4-(amino methyl) phenyl] ethyl-1, the 3-thiazol-2-yl) ethanamide (20mg, similar approach preparation according to preparation embodiment 12), N, the mixture of N '-two (tert-butoxycarbonyl)-1H-pyrazoles-1-carbonamidine (23mg) and tetrahydrofuran (THF) (0.5ml) is at stirring at room 1h.Vacuum concentration reaction mixture, resistates silica gel flash column chromatography purification (using chloroform) as eluent.Collect crystalline residue, obtain { [(4-{2-[2-(acetylamino)-1,3-thiazoles-4-yl] ethyl } benzyl with the diisopropyl ether washing) amino] methylene radical } diamino acid di tert butyl carbonate (22mg).

¹H-NMR(CDCl ₃)，δ(ppm)：1.47(9H，s)，1.50(9H，s)，2.24(3H，s)，2.87-3.03(4H，m)，6.50(1H，s)，7.13(2H，d，J＝7Hz)，7.22(2H，d，J＝7Hz)。

MS(M+H)＝518

Step 2

Will { [(4-{2-[2-(acetylamino)-1,3-thiazoles-4-tomb] ethyl } benzyl) amino] methylene radical } diamino acid di tert butyl carbonate (20mg), methylene dichloride (2) and 4N hydrogenchloride/1, the mixture stirring 15h of 4-diox (0.5ml).The crystal that filtration is separated out, with 1,4-diox washing obtain N-(4-{2-[4-({ [amino (imino-) methyl] amino }-methyl) phenyl] ethyl }-1,3-thiazoles-2-yl) acetamide hydrochloride (13mg).

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.12(3H，s)，2.80-3.00(4H，m)，4.32(2H，d，J＝7Hz)，6.73(1H，s)，7.20(4H，s)，8.04(1H，t，J＝7Hz)。

MS(M+H)＝318

Preparation embodiment 22:

Synthetic 2-(acetylamino)-4-[2-(4-{[amino (imino-) methyl] amino } phenyl) ethyl]-1,3-thiazoles-5-ethyl formate hydrochloride

Step 1

4-chloro-ethyl 3-oxobutanoate (35g) is dissolved in methylene dichloride (70ml), then under 0 ℃, nitrogen atmosphere, methylene dichloride (20ml) solution of sulfuryl chloride (17.1ml) is added drop-wise to solution in 15min.At stirring at room reaction mixture 3h, vacuum concentration.Remaining oily matter N '-((E)-ethanoyl) isothiourea (25.1g) and acetone (600ml) are mixed.With reaction mixture refluxed 2.5h.After being cooled to room temperature, vacuum concentrated mixture.Residual solid water and isopropyl ether washing obtain light yellow solid 2-(acetylamino)-4-(chloromethyl)-1,3-thiazoles-5-ethyl formate (21.2g).

mp.164-165℃

¹H-NMR(DMSO-d ₆)，δ(ppm)：1.30(3H，t，J＝7.0Hz)，2.19(3H，s)，4.29(2H，q，J＝7.0Hz)，5.00(2H，s)，12.72(1H，s)。

MS：263(M+H) ⁺

Step 2:2-(acetylamino)-4-[(E)-2-(4-nitrophenyl) vinyl]-1,3-thiazoles-5-formic acid Ethyl ester

2-(acetylamino)-4-(chloromethyl)-1,3-thiazoles-5-ethyl formate of room temperature under stirring (1.0g, N 3.81mmol), add in dinethylformamide (20mL) solution triphenylphosphine (1.2g, 4.57mmol).The gained mixture is stirred 5h at 65 ℃.(555mg 4.95mmol), stirs gained mixture 30min at 5 ℃ to add potassium tert.-butoxide at 5 ℃ in mixture.5 ℃ add paranitrobenzaldehydes (805mg, 5.33mmol).Behind stirring at room 1h, with the quencher of reactant water, filtering mixt obtains yellow solid title compound (1.0g, 72.7%).

¹H-NMR(CDCl ₃)，δ(ppm)：1.40(3H，t，J＝7.2Hz)，2.33(3H，s)，4.38(2H，q，J＝7.2Hz)，7.59(1H，d，J＝16.0Hz)，7.70(2H，d，J＝8.8Hz)，8.18(1H，d，J＝16.0Hz)，8.22(2H，d，J＝8.8Hz)，8.90(1H，m)。

Step 3

2-(acetylamino)-4-[2-(4-aminophenyl) ethyl]-1,3-thiazoles-5-ethyl formate is according to the similar approach preparation of preparation embodiment 1 step 6.

¹H-NMR(CDCl ₃)，δ(ppm)：1.35(3H，t，J＝7.0Hz)，2.27(3H，s)，2.84(2H，m)，3.28(2H，m)，3.56(2H，m)，4.31(2H，q，J＝7.0Hz)，6.61(2H，d，J＝8.3Hz)，7.01(2H，d，J＝8.3Hz)，9.12(1H，m)。

Step 4

2-(acetylamino)-4-{2-[4-({ (Z)-[(tert-butoxycarbonyl) amino] [(tert-butoxycarbonyl) imino-] methyl }-amino) phenyl] ethyl }-1,3-thiazoles-5-ethyl formate is according to the similar approach preparation of preparation embodiment 18 steps 5.

¹H-NMR(CDCl ₃)，δ(ppm)：1.36(3H，t，J＝7.4Hz)，1.49(9H，s)，1.53(9H，s)，2.25(3H，s)，2.94(2H，m)，3.34(2H，m)，4.31(2H，q，J＝7.4Hz)，7.15(2H，d，J＝8.4Hz)，7.41(2H，d，J＝8.4Hz)，9.69(1H，m)，10.20(1H，s)，11.63(1H，s)。

Step 5

¹H-NMR(DMSO-d ₆)，δ(ppm)：1.28(3H，t，J＝7.0Hz)，2.18(3H，s)，2.94(2H，m)，3.28(2H，m)，4.23(2H，q，J＝7.0Hz)，7.16(2H，d，J＝8.4Hz)，7.29(2H，d，J＝8.4Hz)，7.37(3H，s)，9.71(1H，s)，12.55(1H，s)。

Preparation embodiment 23:

Synthetic N-{4-[2-(4-{[(ethylamino) (imino-) methyl] amino } phenyl) ethyl]-1,3-thiazoles-2-yl } ethanamide

Title compound is according to the similar approach preparation of preparation embodiment 19.

¹H-NMR(DMSO-d ₆)，δ(ppm)：1.13(3H，t，J＝6Hz)，2.11(3H，s)，2.70-3.00(6H，m)，6.70(1H，s)，6.77(2H，d，J＝7Hz)，7.17(2H，d，J＝7Hz)。

MS(M+H)＝332

Preparation embodiment 24:

Synthetic 4-[2-(4-{[amino (imino-) methyl] amino } phenyl) ethyl]-1,3-thiazoles-2-benzyl carbamate

Step 1

Add benzyloxycarbonyl chlorine (3.1ml) in the ice-cold mixture of 2-amino-1,3-thiazoles-4-ethyl formate (5g), pyridine (3.36ml) and methylene dichloride (50ml), at stirring at room mixture 1h.Reaction mixture concentrates with the dried over sodium sulfate final vacuum with saturated sodium bicarbonate aqueous solution (30ml) washing.Collect crystalline residue, obtain the 2-{[(benzyloxy with the diisopropyl ether washing) carbonyl] amino }-1,3-thiazoles-4-ethyl formate (5.1g).

¹H-NMR(CDCl ₃)，δ(ppm)：1.48(3H，t，J＝7Hz)，4.38(2H，q，J＝7Hz)，5.27(2H，s)，7.36-7.44(5H，m)，7.82(1H，s)。

MS(M+H)＝307

Step 2

4-(hydroxymethyl)-1,3-thiazoles-2-aminocarbamic acid benzyl ester is according to the similar approach preparation of preparation embodiment 6 steps 2.

¹H-NMR(CDCl ₃)，δ(ppm)：4.56(2H，s)，5.27(2H，s)，6.80(1H，s)，7.30-7.46(5H，m)。

MS(M+H)＝265

Step 3

4-formyl radical-1,3-thiazoles-2-aminocarbamic acid benzyl ester is according to the similar approach preparation of preparation embodiment 6 steps 3.

¹H-NMR(CDCl ₃)，δ(ppm)：5.29(2H，s)，7.35-7.45(5H，m)，7.81(1H，s)，9.80(1H，s)。

MS(M+H)＝263

Step 4

4-[(E)-2-(4-nitrophenyl) vinyl]-1,3-thiazoles-2-aminocarbamic acid benzyl ester is according to the similar approach preparation of preparation embodiment 6 steps 4.

¹H-NMR(DMSO-d ₆)，δ(ppm)：5.23(2x3/5H，s)，5.25(2x2/5H，s)，6.56-6.70(1H，m)，7.23(1H，s)，7.30-7.50(5H，m)，7.82(2x2/5H，d，J＝7Hz)，7.92(2x3/5H，d，J＝7Hz)，8.14(2x3/5H，d，J＝7Hz)，8.21(2x2/5H，d，J＝7Hz)。

MS(M+H)＝382

Step 5

With 4-[(E)-2-(4-nitrophenyl) vinyl]-mixture of 1,3-thiazoles-2-aminocarbamic acid benzyl ester (1.4g), palladium carbon (140mg) and methyl alcohol (2ml) stirs 8h under nitrogen atmosphere (4atm), room temperature.Filtration catalizer, vacuum concentrated filtrate obtain 4-[2-(4-aminophenyl) ethyl]-1,3-thiazoles-2-aminocarbamic acid benzyl ester (1.2g).

¹H-NMR(CDCl ₃)，δ(ppm)：2.77-2.90(4H，m)，5.22(2H，s)，6.43(1H，s)，6.60(2H，d，J＝7Hz)，6.92(2H，d，J＝7Hz)，7.32-7.40(5H，m)。

MS(M+H)＝354

Step 6

With 4-[2-(4-aminophenyl) ethyl]-mixture of 1,3-thiazoles-2-aminocarbamic acid benzyl ester (25mg), cyanamide (6.0mg), 4N hydrogenchloride/ethyl acetate (0.018ml) and ethanol (1ml) stirs 72h at 100 ℃.The vacuum concentration reaction mixture.Add ethyl acetate (5ml) and saturated sodium bicarbonate aqueous solution (5ml) in the resistates.The solid that filtration is separated out with ethyl acetate and water washing, obtains 4-[2-(4-{[amino (imino-) methyl] amino } phenyl) ethyl]-1,3-thiazoles-2-benzyl carbamate (15mg).

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.63-2.75(4H，m)，5.07(2H，s)，6.40(1H，s)，6.94(2H，d，J＝7Hz)，7.25-7.40(7H，m)。

MS(M+H)＝396

Preparation embodiment 25:

Synthetic N-{4-[2-(4-{[amino (imino-) methyl] amino } phenyl) ethyl]-1,3-thiazoles-2-yl } benzamide hydrochloride salt

Step 1

With 4-[(E)-2-(4-nitrophenyl) vinyl]-1,3-thiazoles-2-aminocarbamic acid benzyl ester (2.7g is according to the similar approach preparation of preparation embodiment 24 steps 4) and 6N hydrochloric acid (50ml) mixing.With reaction mixture refluxed 3h.After being cooled to room temperature, vacuum leaches precipitation.Solid water and acetonitrile washing obtain yellow solid 4-[(E)-2-(4-nitrophenyl) vinyl]-1,3-thiazoles-2-amine (1.34g).

mp.278-278.5℃

¹H-NMR(DMSO-d ₆)，δ(ppm)：7.02(1H，s)，7.33(2H，s)，7.77(2H，d，J＝8.5Hz)，8.25(2H，d，J＝8.5Hz)。

MS：248(M+H) ⁺

Step 2

With 4-[(E)-2-(4-nitrophenyl) vinyl]-1,3-thiazoles-2-amine (300mg) and N, accelerine (4ml) mixes under nitrogen atmosphere, then Benzoyl chloride (0.31ml) is added drop-wise to suspension.Reaction mixture is stirred 2h at 110 ℃.After being cooled to room temperature, mixture dilutes with ethyl acetate.Organic solution is used anhydrous magnesium sulfate drying, vacuum concentration with 1N hydrochloric acid, water, saturated sodium bicarbonate solution and saturated nacl aqueous solution washing.Residual solid is washed with ether, obtains yellow solid N-{4-[(E)-2-(4-nitrophenyl) vinyl]-1,3-thiazoles-2-yl } benzamide (298.6mg).

mp.224.5-225℃

¹H-NMR(DMSO-d ₆)，δ(ppm)：7.40(1H，d，J＝16.0Hz)，7.45(1H，s)，7.53(1H，d，J＝16.0Hz)，7.56(2H，t，J＝7.0Hz)，7.66(1H，t，J＝7.0Hz)，7.84(2H，d，J＝8.5Hz)，8.13(2H，d，J＝7.0Hz)，8.23(2H，d，J＝8.5Hz)，12.80(1H，brs)。

MS：352(M+H) ⁺

Step 3

N-{4-[2-(4-aminophenyl) ethyl]-1,3-thiazoles-2-yl } benzamide is according to the similar approach preparation of preparation embodiment 9 steps 2.

¹H-NMR(CDCl ₃)，δ(ppm)：2.82(4H，s)，3.57(2H，brs)，6.53(1H，s)，6.61(2H，d，J＝8.0Hz)，6.92(2H，d，J＝8.0Hz)，7.50(2H，t，J＝7.0Hz)，7.60(1H，t，J＝7.0Hz)，7.93(2H，d，J＝7.0Hz)，10.15(1H，brs)。

MS：324(M+H) ⁺

Step 4

{ [(4-{2-[2-(benzoyl-amido)-1,3-thiazoles-4-yl] ethyl } phenyl) amino] methylene radical } the diamino acid di tert butyl carbonate is according to the similar approach preparation of preparation embodiment 18 steps 5.

mp.143-144℃

¹H-NMR(DMSO-d ₆)，δ(ppm)：1.39(9H，s)，1.51(9H，s)，2.95(4H，s)，6.86(1H，s)，7.22(2H，d，J＝8.5Hz)，7.44(2H，d，J＝8.5Hz)，7.54(2H，t，J＝7.5Hz)，7.63(1H，t，J＝7.5Hz)，8.10(2H，d，J＝7.5Hz)，9.94(1H，s)，11.44(1H，brs)，12.66(1H，brs)。

MS：566(M+H) ⁺

Step 5

mp.229-232℃

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.91-3.05(4H，m)，6.88(1H，s)，7.15(2H，d，J＝8.5Hz)，7.32(2H，d，J＝8.5Hz)，7.44(3H，brs)，7.54(2H，t，J＝7.5Hz)，7.64(1H，t，J＝7.5Hz)，8.10(2H，d，J＝7.5Hz)，9.88(1H，s)。

MS:366 (M+H) ⁺(free type)

Preparation embodiment 26:

Synthetic N-{4-[2-(4-{[amino (imino-) methyl] amino } phenyl) ethyl]-5-[4-(methyl sulphonyl) phenyl]-1,3-thiazoles-2-yl } acetamide hydrochloride

Step 1

4-(methyl sulfenyl) phenyl aldehyde (31.8g), (acetylamino) acetate (24.5g) and acetic anhydride (35ml) are mixed, under room temperature, nitrogen atmosphere, sodium acetate (8.57g) is added suspension then.With reaction mixture refluxed 3.5h.After being cooled to room temperature, under agitation with in mixture impouring frozen water and the ethyl acetate, vacuum filtration.Isolate filtrate.Organic layer washs with saturated nacl aqueous solution, uses anhydrous magnesium sulfate drying, vacuum concentration.Resistates and the solid that obtains are previously merged, mixture silica gel flash column chromatography purification (using chloroform/ethyl acetate (30: 1)) as eluent, obtain brown solid (4Z)-2-methyl-4-(4-(methyl sulfenyl) benzylidene)-1,3-oxazole-5 (4H)-ketone (17.8g) with the isopropyl ether grinding.

mp.154-155℃

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.38(3H，s)，2.53(3H，s)，7.19(1H，s)，7.36(2H，d，J＝8.5Hz)，8.12(2H，d，J＝8.5Hz)。

Step 2

With (4Z)-2-methyl-4-(4-(methyl sulfenyl) benzylidene)-1,3-oxazole-5 (4H)-ketone (17.5g), 1,4-diox (100ml) and 4N-hydrochloric acid (27ml) mix.With reaction mixture refluxed 3h.After being cooled to room temperature, vacuum concentrated mixture.Ethyl acetate and water are added in the resistates, and vacuum leaches precipitation, obtains light brown solid 3-(4-(methyl sulfenyl) phenyl)-2-oxo propionic acid (6.7g).

mp.165-167℃

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.48(3H，s)，6.37(1H，s)，7.23(2H，d，J＝8.5Hz)，7.70(2H，d，J＝8.5Hz)，9.44(1H，s)。

MS：209(M-H) ⁺

Step 3

Under 0 ℃, nitrogen atmosphere, with 3-(4-(methyl sulfenyl) phenyl)-2-oxo propionic acid (16.2g), N, N-: dimethyl formamide (81ml) and 1,8-diazabicylo [5.4.0] 11-7-alkene (11.5ml) mixes.Mixture is stirred 1h at uniform temp, at uniform temp methyl iodide (9.59ml) is added solution then.At stirring at room reaction mixture 4h, in the impouring 1N-hydrochloric acid, with ethyl acetate extraction (twice).The organic layer that merges washs with saturated nacl aqueous solution, uses anhydrous magnesium sulfate drying, vacuum concentration.Resistates is purified (using chloroform/ethyl acetate (30: 1) as eluent) with the silica gel flash column chromatography, grinds with isopropyl ether/normal hexane, obtains deep yellow solid 3-(4-(methyl sulfenyl) phenyl)-2-oxo methyl propionate (8.6g).

mp.112-113℃

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.48(3H，s)，3.79(3H，s)，6.41(1H，s)，7.24(2H，d，J＝8.5Hz)，7.72(2H，d，J＝8.5Hz)，9.52(1H，brs)。

MS：223(M-H) ⁺

Step 4

3-(4-(methyl sulfenyl) phenyl)-2-oxo methyl propionate (2.84g), tribromide pyridine (4.95g), methylene dichloride (140ml) and acetate (0.5ml) are mixed under 0 ℃, nitrogen atmosphere.At 0 ℃ of stirred reaction mixture 2h, in the impouring water.Mixture ethyl acetate extraction (twice).The organic layer anhydrous magnesium sulfate drying that merges, vacuum concentration.Remaining oily matter is dissolved in ethanol (55ml), then thiocarbamide (1.25g) is added solution.With the reaction mixture 1h that under nitrogen atmosphere, refluxes.After being cooled to 0 ℃, water is added in the solution.Vacuum leaches precipitation, obtains brown solid 2-amino-5-[4-(methylthio group) phenyl]-1,3-thiazoles-4-methyl-formiate (2.67g).

mp.184-185℃

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.50(3H，s)，3.64(3H，s)，7.25(2H，d，J＝8.5Hz)，7.34(2H，d，J＝8.5Hz)。

MS：281(M+H) ⁺

Step 5

With 2-amino-5-[4-(methylthio group) phenyl]-1,3-thiazoles-4-methyl-formiate (8.8g) is dissolved in pyridine (88ml), and under 0 ℃, nitrogen atmosphere, (6.7ml) is added drop-wise to solution with Acetyl Chloride 98Min. then.At stirring at room reaction mixture 30min, stir 2h at 50 ℃.After being cooled to 0 ℃, water is added solution.Vacuum leaches precipitation, and solid washs with ether, obtains Off-white solid 2-(acetylamino)-5-[4-(methylthio group) phenyl]-1,3-thiazoles-4-methyl-formiate (9.3g).

mp.253-254.5℃

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.16(3H，s)，2.52(3H，s)，3.70(3H，s)，7.30(2H，d，J＝8.5Hz)，7.44(2H，d，J＝8.5Hz)。

MS：323(M+H) ⁺

Step 6

With 2-(acetylamino)-5-[4-(methylthio group) phenyl]-1,3-thiazoles 14-methyl-formiate (200mg) is dissolved in tetrahydrofuran (THF) (2ml), at 0 ℃ lithium aluminum hydride (35.3mg) progressively added solution then.Reaction mixture is stirred 30min at 0 ℃,, use the methyl alcohol quencher at stirring at room 30min.Ethyl acetate and 1N hydrochloric acid are added mixture, extraction.Water layer ethyl acetate extraction (twice).The organic layer that merges washs with saturated nacl aqueous solution, uses anhydrous magnesium sulfate drying, vacuum concentration.Residual solid is dissolved in methyl alcohol (0.4ml) and chloroform (7ml).Under nitrogen atmosphere, manganese oxide (IV) (1.08g) is added solution then.At stirring at room reaction mixture 13h, filter by Celite pad.Vacuum concentrated filtrate.Resistates is purified (using chloroform/methanol (20: 1) as eluent) with the silica gel flash column chromatography, obtains light brown amorphous substance N-{4-formyl radical-5-[4-(methylthio group) phenyl]-1,3-thiazoles-2-yl) ethanamide (153.6mg).

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.18(3H，s)，2.54(3H，s)，7.38(2H，d，J＝8.5Hz)，7.58(2H，d，J＝8.5Hz)，9.77(1H，s)，12.59(1H，brs)。

MS：293(M+H) ⁺

Step 7

N-{5-[4-(methylthio group) phenyl]-4-[(E)-2-(4-nitrophenyl) vinyl]-1,3-thiazoles-2-yl } ethanamide is according to the similar approach preparation of preparation embodiment 9 steps 1.

mp.228-230℃

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.19(3H，s)，2.54(3H，s)，7.32(1H，d，J＝16.0Hz)，7.40(2H，d，J＝8.5Hz)，7.46(1H，d，J＝16.0Hz)，7.47(2H，d，J＝8.5Hz)，7.79(2H，d，J＝9.0Hz)，8.19(2H，d，J＝9.0Hz)，12.38(1H，brs)。

MS：412(M+H) ⁺

Step 8

Potassium hydrogen peroxymonosulfate (408mg) is suspended in water (1ml) and tetrahydrofuran (THF) (1ml), then at 0 ℃ with N-{5-[4-(methylthio group) phenyl]-4-[(E)-2-(4-nitrophenyl) vinyl]-1,3-thiazoles-2-yl tetrahydrofuran (THF) (3ml) drips of solution of ethanamide (182mg) is added to suspension.At stirring at room reaction mixture 2h, then water is added suspension.Vacuum leaches precipitation.Solid water and ethyl acetate washing obtain yellow solid N-{5-[4-(methyl sulphonyl) phenyl]-4-[(E)-2-(4-nitrophenyl) vinyl]-1,3-thiazoles-2-yl } ethanamide (83mg).

mp.294-295℃

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.21(3H，s)，3.30(3H，s)，7.40(1H，d，J＝16.0Hz)，7.54(1H，d，J＝16.0Hz)，7.82(2H，d，J＝8.5Hz)，7.84(2H，d，J＝8.5Hz)，8.05(2H，d，J＝8.5Hz)，8.20(2H，d，J＝8.5Hz)，12.51(1H，brs)。

MS：442(M-H) ⁺

Step 9

N-{4-[2-(4-aminophenyl) ethyl]-5-[4-(methyl sulphonyl) phenyl]-1,3-thiazoles-2-yl } ethanamide is according to the similar approach preparation of preparation embodiment 9 steps 2.

mp.202-204℃

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.17(3H，s)，2.77-2.88(4H，m)，3.24(3H，s)，6.84(2H，brs)，6.45(2H，d，J＝8.5Hz)，6.77(2H，d，J＝8.5Hz)，7.49(2H，d，J＝8.5Hz)，7.91(2H，d，J＝8.5Hz)，12.34(1H，brs)。

MS：416(M+H) ⁺

Step 10

{ [(4-{2-[2-(acetylamino)-5-(4-(methyl sulphonyl) phenyl)-1,3-thiazoles-4-yl] ethyl } phenyl) amino] methylene radical } the diamino acid di tert butyl carbonate is according to the similar approach preparation of preparation embodiment 18 steps 5.

¹H-NMR(DMSO-d ₆)，δ(ppm)：1.39(9H，s)，1.51(9H，s)，2.17(3H，s)，2.97(4H，s)，3.24(3H，s)，7.11(2H，d，J＝8.5Hz)，7.38(2H，d，J＝8.5Hz)，7.56(2H，d，J＝8.5Hz)，7.92(2H，d，J＝8.5Hz)，9.92(1H，s)，11.43(1H，brs)，12.34(1H，brs)。

MS：658(M+H) ⁺

Step 11

mp.145-146.5℃

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.18(3H，s)，2.99(4H，brs)，3.25(3H，s)，7.11(2H，d，J＝8.0Hz)，7.22(2H，d，J＝8.0Hz)，7.38(3H，brs)，7.57(2H，d，J＝8.0Hz)，7.94(2H，d，J＝8.0Hz)，9.79(1H，s)，12.36(1H，brs)。

MS:458 (M+H) ⁺(free type)

Preparation embodiment 27:

Synthetic 2-(acetylamino)-4-[2-(4-{[amino (imino-) methyl] amino } phenyl) ethyl]-the N-methyl isophthalic acid, 3-thiazole-5-carboxamide hydrochloride

Step 1

Under nitrogen atmosphere, with 2-(acetylamino)-4-[2-(4-aminophenyl) ethyl]-1,3-thiazoles-5-ethyl formate (310mg is according to the similar approach preparation of preparation embodiment 22 steps 3) is dissolved in tetrahydrofuran (THF) (6ml).In room temperature tetrahydrofuran (THF) (1ml) solution of tert-Butyl dicarbonate (223mg) is added above solution then.With reaction mixture refluxed 2h.After being cooled to room temperature, vacuum concentrated mixture.Residual solid is washed with ether, obtains Off-white solid 2-(acetylamino)-4-(2-{4-[(tert-butoxycarbonyl) amino] phenyl }-ethyl)-1,3-thiazoles-5-ethyl formate (370.7mg).

mp.213-214℃

¹H-NMR(DMSO-d ₆)，δ(ppm)：1.26(3H，t，J＝7.0Hz)，1.46(9H，s)，2.17(3H，s)，2.85(2H，t，J＝7.5Hz)，3.23(2H，t，J＝7.5Hz)，4.22(2H，q，J＝7.0Hz)，7.04(2H，d，J＝8.5Hz)，7.33(2H，d，J＝8.5Hz)，9.23(1H，brs)，12.55(1H，brs)。

MS：434(M+H) ⁺

Step 2

With 2-(acetylamino)-4-(2-{4-[(tert-butoxycarbonyl)-amino] phenyl } ethyl)-1,3-thiazoles-5-ethyl formate (3g), 1N aqueous sodium hydroxide solution (17.3ml) and ethanol (30ml) mixes, with the mixture 5h that refluxes.After being cooled to room temperature, vacuum is removed organic solvent.The aqueous solution is with 1N hcl acidifying (pH=4), with ethyl acetate extraction (twice).The organic layer anhydrous magnesium sulfate drying that merges, vacuum concentration.Residual solid is dissolved in pyridine (45ml), and under 0 ℃, nitrogen atmosphere, (1.48ml) is added drop-wise to solution with Acetyl Chloride 98Min. then.At stirring at room reaction mixture 13h, vacuum is removed pyridine.Water is added in the resistates, use the 1N hcl acidifying.The vacuum collection precipitation.Solid water and ether washing obtain Off-white solid 2-(acetylamino)-4-(2-{4-[(tert-butoxycarbonyl)-amino] phenyl } ethyl)-1,3-thiazoles-5-formic acid (2.23g).

mp.237-238℃

¹H-NMR(DMSO-d ₆)，δ(ppm)：1.46(9H，s)，2.16(3H，s)，2.85(2H，m)，3.23(2H，m)，7.04(2H，d，J＝8.5Hz)，7.33(2H，d，J＝8.5Hz)，9.24.(1H，s)，12.46(1H，s)。

MS：404(M-H) ⁺

Step 3

With 2-(acetylamino)-4-(2-{4-[(tert-butoxycarbonyl) amino] phenyl } ethyl)-1; 3-thiazole-5-formic acid (80mg), 30% methylamine/ethanolic soln (0.02ml), I-hydroxybenzotriazole (29.3mg), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (39.7mg), methylene dichloride (1ml) and N, the mixture of dinethylformamide (0.5ml) is at stirring at room 20h.In reaction mixture impouring saturated sodium bicarbonate solution, use chloroform extraction.Organic layer water and saturated nacl aqueous solution washing; use anhydrous magnesium sulfate drying; vacuum concentration obtains oyster white amorphous substance 4-(2-{2-(acetylamino)-5-[(methylamino) carbonyl]-1,3-thiazoles-4-yl } ethyl) the phenylcarbamic acid tert-butyl ester (92.8mg).

¹H-NMR(DMSO-d ₆)，δ(ppm)：1.46(9H，s)，2.15(3H，s)，2.69(3H，d，J＝4.5Hz)，2.78-2.86(2H，m)，3.12-3.20(2H，m)，7.06(2H，d，J＝8.5Hz)，7.33(2H，d，J＝8.5Hz)，7.91(1H，q，J＝4.5Hz)，9.22(1H，brs)，12.34(1H，brs)。

MS：419(M+H) ⁺

Step 4

With 4-(2-{2-(acetylamino)-5-[(methylamino) carbonyl]-1,3-thiazoles 4-yl } ethyl) the phenylcarbamic acid tert-butyl ester (95mg) and trifluoroacetic acid (2ml) be 0 ℃ of mixing.At stirring at room reaction mixture 1h, vacuum concentration.Resistates is dissolved in chloroform.Organic solution is used anhydrous magnesium sulfate drying, vacuum concentration with 1N sodium hydroxide solution, water and saturated nacl aqueous solution washing.Resistates with preparation type silica gel column chromatography purify (with chloroform/methanol (10: 1) as eluent) obtain oyster white amorphous substance 2-(acetylamino)-4-[2-(4-aminophenyl) ethyl]-the N-methyl isophthalic acid, 3-thiazole-5-methane amide (49mg).

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.15(3H，s)，2.68(3H，d，J＝4.5Hz)，2.67-2.75(2H，m)，3.05-3.15(2H，m)，4.83(2H，brs)，6.47(2H，d，J＝8.5Hz)，6.84(2H，d，J＝8.5Hz)，7.85(1H，q，J＝4.5Hz)，12.33(1H，brs)。

MS：319(M+H) ⁺

Step 5

{ [(4-{2-[2-(acetylamino)-5-(methylamino carbonyl)-1,3-thiazoles-4-yl] ethyl } phenyl) amino]-methylene radical } the diamino acid di tert butyl carbonate is according to the similar approach preparation of preparation embodiment 18 steps 5.

mp.245-246℃

¹H-NMR(DMSO-d ₆)，δ(ppm)：1.40(9H，s)，1.51(9H，s)，2.14(3H，s)，2.68(3H，d，J＝4.5Hz)，2.85-2.94(2H，m)，3.14-3.25(2H，m)，7.17(2H，d，J＝8.5Hz)，7.41(2H，d，J＝8.5Hz)，7.88(1H，q，J＝4.5Hz)，9.94(1H，s)，11.44(1H，brs)，12.38(1H，brs)。

MS：561(M+H) ⁺

Step 6

mp.101-104℃

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.16(3H，s)，2.67(3H，d，J＝4.5Hz)，2.86-2.96(2H，m)，3.16-3.26(2H，m)，7.14(2H，d，J＝8.5Hz)，7.26(2H，d，J＝8.5Hz)，7.41(3H，brs)，7.99(1H，q，J＝4，5Hz)，9.81(1H，s)，12.36(1H，brs)。

MS:361 (M+H) ⁺(free type)

Preparation embodiment 28:

Synthetic 2-(acetylamino)-4-[2-(4-{[amino (imino-) methyl] amino } phenyl) ethyl]-N-phenyl-1,3-thiazoles-5-carboxamide hydrochloride

Step 1

With 2-(acetylamino)-4-(2-{4-[(tert-butoxycarbonyl) amino] phenyl } ethyl)-1; 3-thiazole-5-formic acid (80mg), aniline (0.019ml), benzotriazole-1-base-oxygen base-three-pyrrolidyl-phosphorus hexafluorophosphate (113mg), N; N-diisopropylethylamine (0.076ml) and N; the mixture of dinethylformamide (2ml) stirs 3h at stirring at room 21h at 55 ℃.In reaction mixture impouring 1N hydrochloric acid, use chloroform extraction.Organic layer water, saturated sodium bicarbonate solution and saturated nacl aqueous solution washing are used anhydrous magnesium sulfate drying, vacuum concentration.Residual solid is washed with ether, obtains colorless solid 4-{2-[2-(acetylamino)-5-(anilino carbonyl)-1,3-thiazoles-4-yl] ethyl } the phenylcarbamic acid tert-butyl ester (57.2mg).

mp.199-200℃

¹H-NMR(DMSO-d ₆)，δ(ppm)：1.46(9H，s)，2.18(3H，s)，2.81-2.91(2H，m)，3.14-3.24(2H，m)，7.05(2H，d，J＝8.5Hz)，7.08(1H，t，J＝8.5Hz)，7.26-7.36(4H，m)，7.64(2H，d，J＝8.5Hz)，9.22(1H，brs)，9.95(1H，brs)，12.44(1H，brs)。

MS：481(M+H) ⁺

Step 2

2-(acetylamino)-4-[2-(4-aminophenyl) ethyl]-N-phenyl-1; 3-thiazole-5-methane amide is with 4-{2-[2-(acetylamino)-5-(anilino carbonyl)-1,3-thiazoles-4-yl] ethyl } the phenylcarbamic acid tert-butyl ester is according to the similar approach preparation of preparation embodiment 27 steps 4.

mp.104-105℃

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.18(3H，s)，2.71-2.81(2H，m)，3.09-3.18(2H，m)，5.07(2H，brs)，6.48(2H，d，J＝8.0Hz)，6.85(2H，d，J＝8.0Hz)，7.08(1H，t，J＝8.0Hz)，7.33(2H，t，J＝8.0Hz)，7.65(2H，d，J＝8.0Hz)，9.93(1H，brs)，12.44(1H，brs)。

MS：381(M+H) ⁺

Step 3

(Z)-[(4-{2-[2-(acetylamino)-5-(anilino carbonyl)-1; 3-thiazole-4-yl] ethyl } phenyl) amino] methylene radical } the diamino acid di tert butyl carbonate is with 2-(acetylamino)-4-[2-(4-aminophenyl) ethyl]-N-phenyl-1,3-thiazoles-5-methane amide is according to the similar approach preparation of preparation embodiment 18 steps 5.

¹H-NMR(DMSO-d ₆)，δ(ppm)：1.39(9H，s)，1.51(9H，s)，2.18(3H，s)，2.87-2.98(2H，m)，3.17-3.29(2H，m)，7.08(1H，t，J＝8.0Hz)，7.16(2H，d，J＝8.5Hz)，7.31(2H，t，J＝8.0Hz)，7.41(2H，d，J＝8.5Hz)，7.64(2H，d，J＝8.0Hz)，9.93(2H，s)，11.43(1H，brs)，12.46(1H，brs)。

MS：623(M+H) ⁺

Step 4

Title compound is with { (Z)-[(4-{2-[2-(acetylamino)-5-(anilino carbonyl)-1,3-thiazoles-4-yl] ethyl } phenyl) amino] methylene radical } the diamino acid di tert butyl carbonate is according to the similar approach preparation of preparation embodiment 27 steps 6.

mp.152-155℃

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.19(3H，s)，2.90-3.01(2H，m)，3.17-3.29(2H，m)，7.09(1H，t，J＝8.0Hz)，7.13(2H，d，J＝8.0Hz)，7.26(2H，d，J＝8.0Hz)，7.33(2H，t，J＝8.0Hz)，7.40(3H，brs)，7.64(2H，d，J＝8.0Hz)，9.79(1H，s)，10.02(1H，s)，12.46(1H，s)。

MS:423 (M+H) ⁺(free type)

Preparation embodiment 29:

Synthetic 2-(acetylamino)-4-[2-(4-{[amino (imino-) methyl] amino } phenyl) ethyl]-N, N-dimethyl-1,3-thiazoles-5-carboxamide hydrochloride

Step 1

[4-(2-{2-(acetylamino)-5-[(dimethylamino) carbonyl]-1,3-thiazoles-4-yl } ethyl) phenyl] the t-butyl carbamate similar approach preparation of the compound of preparation embodiment 27 steps 2 according to preparation embodiment 27 steps 3.

¹H-NMR(DMSO-d ₆)，δ(ppm)：1.46(9H，s)，2.14(3H，s)，2.84(4H，s)，2.85(6H，s)，7.01(2H，d，J＝8.5Hz)，7.31(2H，d，J＝8.5Hz)，9.21(1H，brs)，12.33(1H，brs)。

MS：433(M+H) ⁺

Step 2

2-(acetylamino)-4-[2-(4-aminophenyl) ethyl]-N; N-dimethyl-1; 3-thiazole-5-methane amide is with [4-(2-{2-(acetylamino)-5-[(dimethylamino) carbonyl]-1,3-thiazoles-4-yl } ethyl) phenyl] t-butyl carbamate is according to the similar approach preparation of preparation embodiment 27 steps 4.

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.14(3H，s)，2.70-2.77(4H，m)，2.86(6H，s)，4.83(2H，s)，6.45(2H，d，J＝8.5Hz)，6.78(2H，d，J＝8.5Hz)，12.32(1H，brs)。

MS：333(M+H) ⁺

Step 3

((Z)-{ [4-(2-{2-(acetylamino)-5-[(dimethylamino) carbonyl]-1; 3-thiazole-4-yl } ethyl) phenyl] amino } methylene radical) diamino acid di tert butyl carbonate 2-(acetylamino)-4-[2-(4-aminophenyl) ethyl]-N; N-dimethyl-1,3-thiazoles-5-methane amide is according to the similar approach preparation of preparation embodiment 18 steps 5.

¹H-NMR(DMSO-d ₆)，δ(ppm)：1.39(9H，s)，1.51(9H，s)，2.14(3H，s)，2.85(6H，s)，2.89(4H，s)，7.12(2H，d，J＝8.5Hz)，7.40(2H，d，J＝8.5Hz)，9.92(1H，s)，11.43(1H，brs)，12.36(1H，brs)。

MS：575(M+H) ⁺

Step 4

Title compound is with ((Z)-{ [4-(2-{2-(acetylamino)-5-[(dimethylamino) carbonyl]-1,3-thiazoles-4-tomb } ethyl) phenyl] amino } methylene radical) the diamino acid di tert butyl carbonate is according to the similar approach preparation of preparation embodiment 27 steps 6.

mp.78-80℃

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.15(3H，s)，2.81-2.96(4H，m)，2.88(6H，s)，7.11(2H，d，J＝8.5Hz)，7.18(2H，d，J＝8.5Hz)，7.38(3H，brs)，9.77(1H，s)，12.34(1H，s)。

MS:375 (M+H) ⁺(free type)

Preparation embodiment 30:

Synthetic 2-(acetylamino)-4-[2-(4-{[amino (imino-) methyl] amino } phenyl) ethyl]-N-benzyl-1,3-thiazoles-5-carboxamide hydrochloride

Step 1

[4-(2-{2-(acetylamino)-5-[(benzylamino) carbonyl]-1,3-thiazoles-4-yl } ethyl) phenyl] the t-butyl carbamate similar approach preparation of the compound of preparation embodiment 27 steps 2 according to preparation embodiment 27 steps 3.

mp.184-185℃

¹H-NMR(DMSO-d ₆)，δ(ppm)：1.46(9H，s)，2.15(3H，s)，2.79-2.87(2H，m)，3.12-3.22(2H，m)，4.37(2H，d，J＝6.5Hz)，7.02(2H，d，J＝8.5Hz)，7.18-7.36(7H，m)，8.56(1H，t，J＝6.5Hz)，9.22(1H，brs)，12.37(1H，brs)。

MS：495(M+H) ⁺

Step 2

2-(acetylamino)-4-[2-(4-aminophenyl) ethyl]-N-benzyl-1; 3-thiazole-5-methane amide is with [4-(2-{2-(acetylamino)-5-[(benzylamino) carbonyl]-1,3-thiazoles-4-yl } ethyl) phenyl] t-butyl carbamate is according to the similar approach preparation of preparation embodiment 27 steps 4.

mp.200-201℃

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.15(3H，s)，2.66-2.76(2H，m)，3.07-3.15(2H，m)，4.38(2H，d，J＝6.0Hz)，4.83(2H，s)，6.46(2H，d，J＝8.5Hz)，6.81(2H，d，J＝8.5Hz)，7.20-7.36(5H，m)，8.52(1H，t，J＝6.0Hz)，12.32(1H，brs)。

MS：395(M+H) ⁺

Step 3

((z)-{ [4-(2-{2-(acetylamino)-5-[(benzylamino) carbonyl]-1; 3-thiazole-4-yl } ethyl) phenyl] amino } methylene radical) the diamino acid di tert butyl carbonate is with 2-(acetylamino)-4-[2-(4-aminophenyl) ethyl]-N-benzyl-1,3-thiazoles-5-methane amide is according to the similar approach preparation of preparation embodiment 18 steps 5.

¹H-NMR(DMSO-d ₆)，δ(ppm)：1.39(9H，s)，1.51(9H，s)，2.15(3H，s)，2.85-2.94(2H，m)，3.16-3.25(2H，m)，4.37(2H，d，J＝6.0Hz)，7.12(2H，d，J＝8.5Hz)，7.22-7.36(5H，m)，7.40(2H，d，J＝8.5Hz)，8.32(1H，s)，8.54(1H，t，J＝6.0Hz)，9.94(1H，brs)，11.44(1H，brs)。

MS：637(M+H) ⁺

Step 4

Title compound is with ((Z)-{ [4-(2-{2-(acetylamino)-5-[(benzylamino) carbonyl]-1,3-thiazoles-4-yl } ethyl) phenyl] amino } methylene radical) the diamino acid di tert butyl carbonate is according to the similar approach preparation of preparation embodiment 27 steps 6.

mp.128-130℃

¹HNMR(DMSO-d ₆)，δ(ppm)：2.17(3H，s)，2.85-2.96(2H，m)，3.16-3.27(2H，m)，4.36(2H，d，J＝6.0Hz)，7.12(2H，d，J＝8.5Hz)，7.17-7.35(7H，m)，7.40(3H，brs)，8.66(1H，t，J＝6.0Hz)，9.78(1H，s)，12.38(1H，s)。

MS:437 (M+H) ⁺(free type)

Preparation embodiment 31:

Synthetic 2-(acetylamino)-4-[2-(4-{[amino (imino-) methyl] amino } phenyl) ethyl]-N-(4-nitrobenzyl)-1,3-thiazoles-5-carboxamide hydrochloride

Step 1

With 2-(acetylamino)-4-(2-{4-[(tert-butoxycarbonyl) amino] phenyl } ethyl)-mixture of 1,3-thiazoles-5-formic acid (100mg), (4-nitrobenzyl) amine hydrochlorate (46.5mg), I-hydroxybenzotriazole (36.7mg), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (40.2mg) and DMF (2ml) is at stirring at room 73h.In reaction mixture impouring saturated sodium bicarbonate, use chloroform extraction.Organic layer water and salt water washing; use anhydrous magnesium sulfate drying; vacuum concentration obtains light yellow solid { 4-[2-(2-(acetylamino)-5-{[(4-nitrobenzyl) amino] carbonyl }-1,3-thiazoles-4-yl) ethyl] phenyl } t-butyl carbamate (123.7mg).

mp.204-205℃

¹H-NMR(DMSO-d ₆)，δ(ppm)：1.46(9H，s)，2.16(3H，s)，2.77-2.91(2H，m)，3.12-3.27(2H，m)，4.49(2H，d，J＝5.5Hz)，7.01(2H，d，J＝8.5Hz)，7.32(2H，d，J＝8.5Hz)，7.52(2H，d，J＝8.5Hz)，8.21(2H，d，J＝8.5Hz)，8.68(1H，t，J＝5.5Hz)，9.21(1H，s)，12.40(1H，s)。

MS：540(M+H) ⁺

Step 2

Will { 4-[2-(2-(acetylamino)-5-{[(4-nitrobenzyl) amino] carbonyl }-1,3-thiazoles-4-yl) ethyl] phenyl } t-butyl carbamate (135mg) and TFA (2ml) be 0 ℃ of mixing.At stirring at room reaction mixture 1h, vacuum concentration.Resistates is dissolved in MeOH and CHCl ₃, with 1N NaOH alkalization (pH=8).Vacuum concentrated mixture.Residual solid washes with water and obtains light yellow solid 2-(acetylamino)-4-[2-(4-aminophenyl) ethyl]-N-(4-nitrobenzyl)-1,3-thiazoles-5-methane amide (92.5mg).

mp.120-121℃

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.16(3H，s)，2.65-2.81(2H，m)，3.04-3.21(2H，m)，4.49(2H，d，J＝5.5Hz)，5.65(2H，brs)，6.54(2H，d，J＝8.0Hz)，6.86(2H，d，J＝8.0Hz)，7.54(2H，d，J＝8.5Hz)，8.21(2H，d，J＝8.5Hz)，8.67(1H，t，J＝5.5Hz)，12.39(1H，s)。

MS：440(M+H) ⁺

Step 3

With 2-(acetylamino)-4-[2-(4-aminophenyl) ethyl]-N-(4-nitrobenzyl)-1,3-thiazoles-5-methane amide (83mg), N, N '-two (tert-butoxycarbonyl)-1H-pyrazoles-1-carbonamidine (58.6mg) and THF (1ml) mix under nitrogen atmosphere.At stirring at room reaction mixture 2h, vacuum concentration.Residual solid is washed with AcOEt, obtains Off-white solid [(Z)-({ 4-[2-(2-(acetylamino)-5-{[(4-nitrobenzyl) amino] carbonyl }-1,3-thiazoles-4-yl) ethyl] phenyl } amino) methylene radical] diamino acid di tert butyl carbonate (95.4mg).

mp.251-253℃

¹H-NMR(DMSO-d ₆)，δ(ppm)：1.38(9H，s)，1.51(9H，s)，2.16(3H，s)，2.81-2.98(2H，m)，3.16-3.29(2H，m)，4.49(2H，d，J＝5.5Hz)，7.12(2H，d，J＝8.0Hz)，7.40(2H，d，J＝8.0Hz)，7.53(2H，d，J＝8.5Hz)，8.20(2H，d，J＝8.5Hz)，8.67(1H，t，J＝5.5Hz)，9.93(1H，s)，11.44(1H，s)，12.42(1H，s)。

MS：682(M+H) ⁺

Step 4

Will [(Z)-(4-[2-(2-(acetylamino)-5-{[(4-nitrobenzyl) amino] carbonyl }-1; 3-thiazole-4-yl) ethyl] phenyl } amino) methylene radical] diamino acid di tert butyl carbonate (70mg) and 4NHCl/1,4-dioxane solution (1.5ml) mixes under nitrogen atmosphere.At stirring at room reaction mixture 14h.Solvent removed in vacuo.Resistates washs with AcOEt, obtains light green solid 2-(, acetylamino)-4-[2-(4-{[amino (imino-) methyl] amino } phenyl) ethyl]-N-(4-nitrobenzyl)-1,3-thiazoles-5-carboxamide hydrochloride (63.7mg).

mp.138-140℃

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.17(3H，s)，2.81-3.00(2H，m)，3.17-3.30(2H，m)，4.48(2H，d，J＝5.5Hz)，7.12(2H，d，J＝8.0Hz)，7.25(2H，d，J＝8.0Hz)，7.40(3H，s)，7.55(2H，d，J＝8.0Hz)，8.21(2H，d，J＝8.0Hz)，8.80(1H，t，J＝5.5Hz)，9.81(1H，s)，12.42(1H，s)。

MS:482 (M+H) ⁺(free type)

Preparation embodiment 32:

Synthetic 2-(acetylamino)-4-[2-(4-{[amino (imino-) methyl] amino } phenyl) ethyl]-N-[4-(methyl sulphonyl) benzyl]-1,3-thiazoles-5-carboxamide hydrochloride

Step 1

With 2-(acetylamino)-4-(2-{4-[(tert-butoxycarbonyl) amino] phenyl } ethyl)-mixture of 1,3-thiazoles-5-formic acid (120mg), [4-(methylthio group) benzyl] amine (45.4mg), I-hydroxybenzotriazole (44mg), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (59.6mg) and DMF (2ml) is at stirring at room 17h.In reaction mixture impouring saturated sodium bicarbonate, use chloroform extraction.Organic layer water and salt water washing are used anhydrous magnesium sulfate drying, vacuum concentration.Resistates is purified with preparation type silica gel chromatography and (is used CHCl ₃/ AcOEt (1: 1) is as eluent), obtain Off-white solid (4-{2-[2-(acetylamino)-5-({ [4-(methylthio group) benzyl] amino } carbonyl)-1,3-thiazoles-4-yl] ethyl } phenyl) t-butyl carbamate (163.5mg).

mp.182-183℃

¹H-NMR(DMSO-d ₆)，δ(ppm)：1.46(9H，s)，2.15(3H，s)，2.45(3H，s)，2.77-2.91(2H，m)，3.09-3.24(2H，m)，4.32(2H，d，J＝5.5Hz)，7.02(2H，d，J＝8.5Hz)，7.22(4H，s)，7.33(2H，d，J＝8.5Hz)，8.54(1H，t，J＝5.5Hz)，9.22(1H，s)，12.36(1H，s)。

MS：541(M+H) ⁺

Step 2

At 0 ℃ potassium hydrogen peroxymonosulfate (264mg) is suspended in water (1ml) and THF (1ml); THF (2ml) drips of solution that then will (4-{2-[2-(acetylamino)-5-({ [4-(methylthio group) benzyl] amino } carbonyl)-1,3-thiazoles-4-yl] ethyl } phenyl) t-butyl carbamate (155mg) is added to suspension.At stirring at room reaction mixture 1h, then water is added suspension.Solution extracts (twice) with AcOEt.The organic layer salt water washing that merges; use anhydrous magnesium sulfate drying; vacuum concentration obtains Off-white solid (4-{2-[2-(acetylamino)-5-({ [4-(methyl sulphonyl) benzyl] amino } carbonyl)-1,3-thiazoles-4-yl] ethyl } phenyl) t-butyl carbamate (140.6mg).

mp.192.5-193℃

¹H-NMR(DMSO-d ₆)，δ(ppm)：1.46(9H，s)，2.16(3H，s)，2.73-2.90(2H，n)，3.11-3.27(2H，m)，3.18(3H，s)，4.47(2H，d，J＝5.5Hz)，7.03(2H，d，J＝8.5Hz)，7.33(2H，d，J＝8.5Hz)，7.53(2H，d，J＝8.5Hz)，7.89(2H，d，J＝8.5Hz)，8.68(1H，t，J＝5.5Hz)，9.22(1H，s)，12.39(1H，s)。

MS：573(M+H) ⁺

Step 3

2-(acetylamino)-4-[2-(4-aminophenyl) ethyl]-N-[4-(methyl sulphonyl) benzyl]-1,3-thiazoles-5-methane amide is according to the similar approach preparation of preparation embodiment 31 steps 2.

mp.78-80℃

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.16(3H，s)，2.65-2.80(2H，m)，3.04-3.22(2H，m)，3.19(3H，s)，4.46(2H，d，J＝5.5Hz)，4.82(2H，s)，6.46(2H，d，J＝8.0Hz)，6.81(2H，d，J＝8.0Hz)，7.53(2H，d，J＝8.0Hz)，7.89(2H，d，J＝8.0Hz)，8.63(1H，t，J＝5.5Hz)，12.39(1H，s)。

MS：473(M+H) ⁺

Step 4

{ (Z)-[(4-{2-[2-(acetylamino)-5-({ [4-(methyl sulphonyl) benzyl] amino } carbonyl)-1,3-thiazoles-4-yl] ethyl } phenyl) amino] methylene radical } the diamino acid di tert butyl carbonate is according to the similar approach preparation of preparation embodiment 31 steps 3.

¹H-NMR(DMSO-d ₆)，δ(ppm)：1.39(9H，s)，1.51(9H，s)，2.16(3H，s)，2.81-2.98(2H，m)，3.18(3H，s)，3.18-3.29(2H，m)，4.46(，2H，d，J＝5.5Hz)，7.14(2H，d，J＝8.5Hz)，7.41(2H，d，J＝8.5Hz)，7.54(，2H，d，J＝8.5Hz)，7.88(2H，d，J＝8.5Hz)，8.67(1H，t，J＝5.5Hz)，9.94(1H，s)，11.44(1H，s)，12.41(1H，s)。

MS：715(M+H) ⁺

Step 5

Title compound is according to the similar approach preparation of preparation embodiment 31 steps 4.

mp.94-96℃

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.17(3H，s)，2.85-2.99(2H，m)，3.19(3H，s)，3.19-3.30(2H，m)，4.46(2H，d，J＝5.5Hz)，7.13(2H，d，J＝8.5Hz)，7.25(2H，d，J＝8.5Hz)，7.40(3H，s)，7.54(2H，d，J＝8.5Hz)，7.89(2H，d，J＝8.5Hz)，8.78(1H，t，J＝5.5Hz)，9.80(1H，s)，12.41(1H，s)。

MS:515 (M+H) ⁺(free type)

Preparation embodiment 33:

Synthetic 2-(acetylamino)-4-[2-(4-{[amino (imino-) methyl] amino } phenyl) ethyl]-N-[4-(trifluoromethyl) benzyl]-1,3-thiazoles-5-carboxamide hydrochloride

Step 1

(4-{2-[2-(acetylamino)-5-({ [4-(trifluoromethyl) benzyl] amino } carbonyl)-1; 3-thiazole-4-yl] ethyl } phenyl) t-butyl carbamate is with 2-(acetylamino)-4-(2-{4-[(tert-butoxycarbonyl) amino] phenyl } ethyl)-1,3-thiazoles-5-formic acid is according to the similar approach preparation of preparation embodiment 32 steps 1.

¹H-NMR(DMSO-d ₆)，δ(ppm)：1.46(9H，s)，2.16(3H，s)，2.73-2.92(2H，m)，3.12-3.25(2H，m)，4.45(2H，d，J＝5.5Hz)，7.01(2H，d，J＝8.5Hz)，7.33(2H，d，J＝8.5Hz)，7.47(2H，d，J＝8.5Hz)，7.69(2H，d，J＝8.5Hz)，8.64(1H，t，J＝5.5Hz)，9.22(1H，s)，12.39(1H，s)。

MS：563(M+H) ⁺

Step 2

2-(acetylamino)-4-[2-(4-aminophenyl) ethyl]-N-[4-(trifluoromethyl) benzyl]-1,3-thiazoles-5-methane amide is according to the similar approach preparation of preparation embodiment 31 steps 2.

mp.199-201℃

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.10(3H，s)，2.63-2.78(2H，m)，3.02-3.18(2H，m)，4.44(2H，d，J＝5.5Hz)，4.81(2H，s)，6.46(2H，d，J＝8.Hz)，6.81(2H，d J＝8.0Hz)，7.49(2H，d，J＝8.0Hz)，7.69(2H，d，J＝8.0Hz)，8.44(1H，t，J＝5.5Hz)，12.39(1H，s)。

MS：463(M+H) ⁺

Step 3

{ (Z)-[(4-{2-[2-(acetylamino)-5-({ [4-(trifluoromethyl) benzyl] amino } carbonyl)-1,3-thiazoles-4-yl] ethyl } phenyl) amino] methylene radical } the diamino acid di tert butyl carbonate is according to the similar approach preparation of preparation embodiment 31 steps 3.

mp.188-190℃

¹H-NMR(DMSO-d ₆)，δ(ppm)：1.39(9H，s)，1.51(9H，s)，2.16(3H，s)，2.83-2.97(2H，m)，3.17-3.29(2H，m)，4.44(2H，d，J＝5.5Hz)，7.12(2H，d，J＝8.5Hz)，7.40(2H，d，J＝8.5Hz)，7.48(2H，d，J＝8.0Hz)，7.69(2H，d，J＝8.0Hz)，8.63(1H，t，J＝5.5Hz)，9.94(1H，s)，11.44(1H，s)，12.40(1H，s)。

MS：705(M+H) ⁺

Step 4

mp.156-158℃

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.17(3H，s)，2.82-2.99(2H，m)，3.18-3.31(2H，m)，4.44(2H，d，J＝5.5Hz)，7.12(2H，d，J＝8.0Hz)，7.25(2H，d，J＝8.0Hz)，7.40(3H，s)，7.51(2H，d，J＝8.0Hz)，7.71(2H，d，J＝8.0Hz)，8.76(1H，t，J＝5.5Hz)，9.81(1H，s)，12.41(1H，s)。

MS:505 (M+H) ⁺(free type)

Preparation embodiment 34:

Synthetic 2-(acetylamino)-4-[2-(4-{[amino (imino-) methyl] amino } phenyl) ethyl]-N-(3-pyridyl)-1,3-thiazoles-5-methane amide dihydrochloride

Step 1

2-(acetylamino)-4-[2-(4-aminophenyl) ethyl]-1; 3-thiazole-5-formic acid is with 2-(acetylamino)-4-(2-{4-[(tert-butoxycarbonyl) amino] phenyl } ethyl)-1,3-thiazoles-5-formic acid is according to the similar approach preparation of preparation embodiment 31 steps 2.

mp.211.5-212℃

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.15(3H，s)，2.67-2.80(2H，m)，3.09-3.23(2H，m)，6.51(2H，d，J＝8.0Hz)，6.85(2H，d，J＝8.0Hz)，12.44(1H，brs)。

MS：306(M+H) ⁺

Step 2

Under nitrogen atmosphere with 2-(acetylamino)-4-[2-(4-aminophenyl) ethyl]-1,3-thiazoles-5-formic acid (106mg) is suspended in THF (2ml).In room temperature two (trimethyl silyl) ethanamides (0.253ml) are added suspension, at stirring at room mixture 15min.Then in room temperature with N, N '-two (tert-butoxycarbonyl)-1H-pyrazoles-1-carbonamidine (119mg) adds solution, at stirring at room reaction mixture 20h, vacuum concentration.Resistates is dissolved in CHCl ₃Organic solution is used anhydrous magnesium sulfate drying, vacuum concentration with 1NHCl, water and salt water washing.Residual solid is washed with ether, obtains filbert solid 2-(acetylamino)-4-{2-[4-({ (Z)-[(tert-butoxycarbonyl) amino] (tert-butoxycarbonyl) iminomethyl } amino) phenyl] ethyl }-1,3-thiazoles-5-formic acid (115.8mg).

mp.221.5-223℃

¹H-NMR(DMSO-d ₆)，δ(ppm)：1.44(18H，brs)，2.16(3H，s)，2.91(2H，t，J＝7.0Hz)，3.26(2H，t，J＝7.0Hz)，7.17(2H，d，J＝8.5Hz)，7.43(2H，d，J＝8.5Hz)，9.95(1H，brs)，11.43(1H，brs)，12.48(1H，s)。

MS：548(M+H) ⁺

Step 3

((Z)-{ [4-(2-{2-(acetylamino)-5-[(3-pyridinylamino) carbonyl]-1,3-thiazoles-4-yl } ethyl) phenyl] amino } methylene radical) the diamino acid di tert butyl carbonate is according to the similar approach preparation of preparation embodiment 32 steps 1.

¹H-NMR(DMSO-d ₆)，δ(ppm)：1.39(9H，s)，1.51(9H，s)，2.19(3H，s)，2.87-3.00(2H，m)，3.19-3.32(2H，m)，7.16(2H，d，J＝8.5Hz)，7.35(1H，dd，J＝8.5，4.5Hz)，7.41(2H，d，J＝8.5Hz)，8.07(1H，m)，8.28(1H，dd，J＝4.5，1.5Hz)，8.81(1H，d，J＝1.5Hz)，9.93(1H，s)，10.11(1H，s)，11.43(1H，s)，12.51(1H，s)。

MS：624(M+H) ⁺

Step 4

¹H-NMR(DMSO-d ₆)，6(ppm)：2.21(3H，s)，2.84-3.07(2H，m)，3.19-3.39(2H，m)，7.13(2H，d，J＝7.5Hz)，7.28(2H，d，J＝7.5Hz)，7.45(3H，brs)，7.37-8.81(4H，m)，9.93(1H，s)，10.75(1H，s)，12.61(1H，s)。

MS:424 (M+H) ⁺(free type)

Preparation embodiment 35:

Synthetic 2-(acetylamino)-4-[2-(4-{[amino (imino-) methyl] amino } phenyl) ethyl]-N-(4-phenoxy benzyl)-1,3-thiazoles-5-carboxamide hydrochloride

Step 1

[(Z)-(and 4-[2-(2-(acetylamino)-5-{[(4-phenoxy benzyl) amino] carbonyl }-1,3-thiazoles-4-yl) ethyl] phenyl } amino) methylene radical] the similar approach preparation of the compound of preparation embodiment 34 steps 2 of diamino acid di tert butyl carbonate according to preparation embodiment 32 steps 1.

¹H-NMR(DMSO-d ₆)，δ(ppm)：1.38(9H，s)，1.51(9H，s)，2.15(3H，s)，2.81-2.97(2H，m)，3.13-3.28(2H，m)，4.35(2H，d，J＝5.5Hz)，6.97(4H，d，J＝8.5Hz)，7.11(1H，t，J＝8.5Hz)，7.13(2H，d，J＝8.5Hz)，7.29-7.41(6H，m)，8.54(1H，t，J＝5.5Hz)，9.93(1H，s)，11.44(1H，brs)，12.37(1H，brs)。

MS：729(M+H) ⁺

Step 2

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.17(3H，s)，2.81-3.00(2H，m)，3.13-3.30(2H，m)，4.35(2H，d，J＝5.5Hz)，6.98(4H，d，J＝8.5Hz)，7.12(2H，d，J＝8.5Hz)，7.13(1H，t，J＝8.5Hz)，7.25(2H，d，J＝8.5Hz)，7.32(2H，d，J＝8.5Hz)，7.40(2H，t，J＝8.5Hz)，7.46(3H，brs)，8.67(1H，t，J＝5.5Hz)，9.92(1H，s)，12.39(1H，brs)。

MS:529 (M+H) ⁺(free type)

Preparation embodiment 36:

Synthetic 4-(2-(acetylamino)-4-[2-(4-{[amino (imino-) methyl] amino } phenyl) ethyl]-1,3-thiazoles-5-yl } carbonyl)-1-piperazinecarboxylic acid ethyl ester

Step 1

4-[(2-(acetylamino)-4-{2-[4-({ (Z)-[(tert-butoxycarbonyl) amino] [(tert-butoxycarbonyl) imino-] methyl } amino) phenyl] ethyl }-1,3-thiazoles-5-yl) carbonyl]-the similar approach preparation of the compound of preparation embodiment 34 steps 2 of 1-piperazinecarboxylic acid ethyl ester according to preparation embodiment 32 steps 1.

¹H-NMR(DMSO-d ₆)，δ(ppm)：1.17(3H，t，J＝7.0Hz)，1.39(9H，brs)，1.50(9H，brs)，2.15(3H，s)，2.90(4H，m)，3.38(8H，brs)，4.03(2H，q，J＝7.0Hz)，7.12(2H，d，J＝8.5Hz)，7.41(2H，d，J＝8.5Hz)，9.94(1H，s)，11.46(1H，brs)，12.40(1H，brs)。

MS：688(M+H) ⁺

Step 2

Title compound is according to the similar approach preparation of following preparation embodiment 48 steps 2.

mp.180-1-82.5℃

¹H-NMR(DMSO-d ₆)，δ(ppm)：1.18(3H，t，J＝7.0Hz)，2.07(3H，s)，2.77(4H，s)，3.43(8H，brs)，4.05(2H，q，J＝7.0Hz)，6.89(2H，d，J＝7.5Hz)，7.02(2H，d，J＝7.5Hz)。

MS：488(M+H) ⁺

Preparation embodiment 37:

Synthetic N-{5-[(4-ethanoyl-1-piperazinyl) carbonyl]-4-[2-(4-{[amino (imino-) methyl] amino } phenyl) ethyl]-1,3-thiazoles-2-yl } ethanamide

Step 1

((Z)-{ [4-(2-{2-(acetylamino)-5-[(4-ethanoyl-1-piperazinyl) carbonyl]-1,3-thiazoles-4-yl } ethyl) phenyl] amino } methylene radical) the similar approach preparation of the compound of preparation embodiment 34 steps 2 of diamino acid di tert butyl carbonate according to preparation embodiment 32 steps 1.

¹H-NMR(DMSO-d ₆)，δ(ppm)：1.39(9H，brs)，1.50(9H，brs)，1.98(3H，s)，2.15(3H，s)，2.90(4H，m)，3.40(8H，brs)，7.13(2H，d，J＝8.5Hz)，7.41(2H，d，J＝8.5Hz)，9.93(1H，s)，11.43(1H，brs)，12.40(1H，brs)。

MS：658(M+H) ⁺

Step 2

mp.206-207.5℃

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.01(3H，s)，2.05(3H，s)，2.73(4H，s)，3.42(8H，brs)，6.77-7.08(4H，m)。

MS：458(M+H) ⁺

Preparation embodiment 38:

Synthetic N-(4-[2-(4-{[amino (imino-) methyl] amino } phenyl) ethyl]-5-{[4-(methyl sulphonyl)-1-piperazinyl] carbonyl }-1,3-thiazoles-2-yl) acetamide hydrochloride

Step 1

[(Z)-(4-[2-(2-(acetylamino)-5-{[4-(methyl sulphonyl)-1-piperazinyl] carbonyl }-1,3-thiazoles-4-yl) ethyl] phenyl } amino) methylene radical] the similar approach preparation of the compound of preparation embodiment 34 steps 2 of diamino acid di tert butyl carbonate according to preparation embodiment 31 steps 1.

¹H-NMR(DMSO-d ₆)，δ(ppm)：1.39(9H，s)，1.51(9H，s)，2.15(3H，s)，2.89(3H，s)，2.82-2.96(4H，m)，3.01-3.13(4H，m)，3.44-3.59(4H，m)，7.14(2H，d，J＝8.5Hz)，7.42(2H，d，J＝8.5Hz)，9.94(1H，s)，11.44(1H，brs)，12.40(1H，brs)。

MS：694(M+H) ⁺

Step 2

mp.118-119℃

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.16(3H，s)，2.90(3H，s)，2.83-2.98(4H，m)，3.06-3.18(4H，m)，3.50-3.61(4H，m)，7.12(2H，d，J＝8.5Hz)，7.21(2H，d，J＝8.5Hz)，7.43(3H，s)，9.90(1H，s)，12.41(1H，s)。

MS:494 (M+H) ⁺(free type)

Preparation embodiment 39:

Synthetic N-[4-[2-(4-{[amino (imino-) methyl] amino } phenyl) ethyl]-5-(4-thio-morpholinyl carbonyl tomb)-1,3-thiazoles-2-yl] acetamide hydrochloride

Step 1

(Z)-[(4-{2-[2-(acetylamino)-5-(4-thio-morpholinyl carbonyl)-1,3-thiazoles-4-yl] ethyl } phenyl) amino] methylene radical } the similar approach preparation of the compound of preparation embodiment 34 steps 2 of diamino acid di tert butyl carbonate according to preparation embodiment 32 steps 1.

¹H-NMR(DMSO-d ₆)，δ(ppm)：1.39(9H，s)，1.51(9H，s)，2.15(3H，s)，2.45-2.61(4H，m)，2.79-2.99(4H，m)，3.55-3.70(4H，m)，7.13(2H，d，J＝8.5Hz)，7.41(2H，d，J＝8.5Hz)，9.92(1H，s)，11.44(1H，brs)，12.38(1H，brs)。

Step 2

mp.134-135.5℃

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.16(3H，s)，2.47-2.62(4H，m)，2.80-3.00(4H，m)，3.59-3.73(4H，m)，7.12(2H，d，J＝8.5Hz)，7.20(2H，d，J＝8.5Hz)，7.39(3H，s)，9.80(1H，s)，12.38(1H，s)。

MS:433 (M+H) ⁺(free type)

Preparation embodiment 40:

Synthetic N-{4-[2-(4-{[amino (imino-) methyl] amino } phenyl) ethyl]-5-[(1,1-titanium dioxide-4-thio-morpholinyl) carbonyl]-1,3-thiazoles-2-yl } acetamide hydrochloride

Step 1

((Z)-{ [4-(2-{2-(acetylamino)-5-[(1; 1-titanium dioxide-4-thio-morpholinyl) carbonyl]-1,3-thiazoles-4-yl } ethyl) phenyl] amino } methylene radical) the similar approach preparation of the compound of preparation embodiment 39 steps 1 of diamino acid di tert butyl carbonate according to preparation embodiment 32 steps 2.

mp.270-271.5℃

¹H-NMR(DMSO-d ₆)，δ(ppm)：1.39(9H，s)，1.51(9H，s)，2.15(3H，s)，2.85-2.96(4H，m)，3.09-3.21(4H，m)，3.69-3.83(4H，m)，7.13(2H，d，J＝8.5Hz)，7.40(2H，d，J＝8.5Hz)，9.93(1H，s)，11.47(1H，brs)，12.42(1H，brs)。

MS：665(M+H) ⁺

Step 2

mp.185-186℃

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.16(3H，s)，2.92(4H，s)，3.11-3.28(4H，m)，3.76-3.91(4H，m)，7.12(2H，d，J＝8.5Hz)，7.22(2H，d，J＝8.5Hz)，7.40(3H，s)，9.84(1H，s)，12.40(1H，s)。

MS:465 (M+H) ⁺(free type)

Preparation embodiment 41:

Synthetic 1-(2-(acetylamino)-4-[2-(4-{[amino (imino-) methyl] amino } phenyl) ethyl]-1,3-thiazoles-5-yl } carbonyl)-4-piperidine ethyl formate hydrochloride

Step 1

1-{[2-(acetylamino)-4-{2-[4-({ (Z)-[(tert-butoxycarbonyl) amino] [(tert-butoxycarbonyl) imino-] methyl } amino) phenyl] ethyl }-1,3-thiazoles-5-yl] carbonyl }-the similar approach preparation of the compound of preparation embodiment 34 steps 2 of 4-piperidine ethyl formate according to preparation embodiment 32 steps 1.

¹H-NMR(DMSO-d ₆)，δ(ppm)：1.17(3H，t，J＝7.0Hz)，1.32-1.56(2H，m)，1.39(9H，s)，1.50(9H，s)，1.73-1.89(2H，m)，2.15(3H，s)，2.44-2.64(1H，m)，2.80-3.01(6H，m)，3.74-3.93(2H，m)，4.06(2H，q，J＝7.0Hz)，7.11(2H，d，J＝8.5Hz)，7.41(2H，d，J＝8.5Hz)，9.93(1H，s)，11.45(1H，brs)，12.36(1H，brs)。

MS：687(M+H) ⁺

Step 2

¹H-NMR(DMSO-d ₆)，δ(ppm)：1.18(3H，t，J＝7.0Hz)，1.29-1.54(2H，m)，1.73-1.93(2H，m)，2.15(3H，s)，2.44-2.71(1H，m)，2.79-3.09(6H，m)，3.79-3.96(2H，m)，4.09(2H，q，J＝7.0Hz)，7.11(2H，d，J＝8.5Hz)，7.19(2H，d，J＝8.5Hz)，7.40(3H，s)，9.83(1H，s)，12.37(1H，s)。

MS:487 (M+H) ⁺(free type)

Preparation embodiment 42:

Synthetic 1-(2-(acetylamino)-4-[2-(4-{[amino (imino-) methyl] amino } phenyl) ethyl]-1,3-thiazoles-5-yl } carbonyl)-4-piperidine formyl amine hydrochlorate

Step 1

With 1-[(2-(acetylamino)-4-{2-[4-({ (Z)-[(tert-butoxycarbonyl) amino] [(tert-butoxycarbonyl) imino-] methyl } amino) phenyl] ethyl }-1; 3-thiazole-5-yl) carbonyl]-4-piperidine ethyl formate (277.9mg), 1N NaOH (1.01ml) and 1; 4-diox (3ml) is 0 ℃ of mixing, at stirring at room reaction mixture 3h.Mixture neutralizes with 1N HCl, the vacuum-evaporation organic solvent.Residual water solution extracts with AcOEt.Organic layer water and salt water washing; use anhydrous magnesium sulfate drying; vacuum concentration obtains light yellow amorphous substance 1-[(2-(acetylamino)-4-{2-[4-({ (Z)-[(tert-butoxycarbonyl) amino] [(tert-butoxycarbonyl) imino-] methyl } amino) phenyl] ethyl }-1,3-thiazoles-5-yl) carbonyl]-4-piperidine carboxylic acid (262.4mg).

¹H-NMR(DMSO-d ₆)，δ(ppm)：1.28-1.59(2H，m)，1.45(18H，s)，1.72-1.90(2H，m)，2.15(3H，s)，2.40-2.59(1H，m)，2.78-3.03(6H，m)，3.77-3.94(2H，m)，7.12(2H，d，J＝8.5Hz)，7.40(2H，d，J＝8.5Hz)，9.94(1H，brs)，11.44(1H，brs)，12.36(1H，s)。

MS：659(M+H) ⁺

Step 2

[(Z)-({ 4-[2-(2-(acetylamino)-5-{[4-(aminocarboxyl)-piperidino] carbonyl }-1,3-thiazoles-4-yl) ethyl] phenyl } amino) methylene radical] the diamino acid di tert butyl carbonate is according to the similar approach preparation of preparation embodiment 32 steps 1.

¹H-NMR(DMSO-d ₆)，δ(ppm)：1.29-1.55(2H，m)，1.39(9H，s)，1.50(9H，s)，1.62-1.79(2H，m)，2.14(3H，s)，2.22-2.43(1H，m)，2.78-2.99(6H，m)，3.89-4.07(2H，m)，6.80(1H，s)，7.14(2H，d，J＝8.5Hz)，7.27(1H，s)，7.41(2H，d，J＝8.5Hz)，9.93(1H，s)，11.44(1H，brs)，12.36(1H，s)。

MS：658(M+H) ⁺

Step 3

¹H-NMR(200MHz，DMSO-d ₆)，δ(ppm)：1.27-1.52(2H，m)，1.64-1.79(2H，m)，-2.15(3H，s)，2.25-2.44(2H，m)，2.76-3.02(6H，m)，6.82(1H，br)，7.11(2H，d，J＝8.5Hz)，7.19(2H，d，J＝8.5Hz)，7.34(1H，br)，7.41(4H，s)，9.83(1H，s)，12.36(1H，s)。

MS:458 (M+H) ⁺(free type)

Preparation embodiment 43:

Synthetic 1-(2-(acetylamino)-4-[2-(4-{[amino (imino-) methyl] amino } phenyl) ethyl]-1,3-thiazoles-5-yl } carbonyl)-N-methyl-4-piperidine formyl amine hydrochlorate

Step 1

(Z)-[(4-{2-[2-(acetylamino)-5-(the 4-[(methylamino) carbonyl]-piperidino } carbonyl)-1,3-thiazoles-4-yl] ethyl) phenyl) amino] methylene radical } the similar approach preparation of the compound of preparation embodiment 42 steps 1 of diamino acid di tert butyl carbonate according to preparation embodiment 32 steps 1.

¹H-NMR(DMSO-d ₆，δ(ppm)：1.30-1.75(4H，m)，1.39(9H，s)，1.50(9H，s)，2.14(3H，s)，2.22-2.42(1H，m)，2.55(2H，d，J＝4.5Hz)，2.78-2.99(6H，m)，3.90-4.03(2H，m)，7.14(2H，d，J＝8.5Hz)，7.41(2H，d，J＝8.5Hz)，7.73(1H，q，J＝4.5Hz)，9.93(1H，s)，11.43(1H，brs)，12.36(1H，brs)。

MS：672(M+H) ⁺

Step 2

¹H-NMR(200MHz，DMSO-d ₆)，δ(ppm)：1.29-1.52(2H，m)，1.60-1.77(2H，m)，2.15(3H，s)，2.55(3H，d，J＝4.5Hz)，2.78-2.98(6H，m)，3.88-4.06(3H，m)，7.11(2H，d，J＝8.5Hz)，7.19(2H，d，J＝8.5Hz)，7.37(4H，br)，7.81(1H，m)，9.75(1H，s)，12.36(1H，s)。

MS:472 (M+H) ⁺(free type)

Preparation embodiment 44:

Synthetic 1-(2-(acetylamino)-4-[2-(4-{[amino (imino-) methyl] amino } phenyl) ethyl]-1,3-thiazoles-5-yl } carbonyl)-N, N-dimethyl-4-piperidine carboxamide hydrochloride

Step 1

(Z)-[(4-{2-[2-(acetylamino)-5-(the 4-[(dimethylamino) carbonyl]-piperidino } carbonyl)-1,3-thiazoles-4-yl] ethyl } phenyl) amino] methylene radical } the similar approach preparation of the compound of preparation embodiment 42 steps 1 of diamino acid di tert butyl carbonate according to preparation embodiment 32 steps 1.

¹H-NMR(DMSO-d ₆)，δ(ppm)：1.30-1.70(4H，m)，1.39(9H，s)，1.50(9H，s)，2.15(3H，s)，2.80(3H，s)，2.79-3.01(7H，m)，3.00(3H，s)，3.88-4.06(2H，m)，7.13(2H，d，J＝8.5Hz)，7.41(2H，d，J＝8.5Hz)，9.92(1H，s)，11.42(1H，brs)，12.36(1H，brs)。

MS：686(M+H) ⁺

Step 2

¹H-NMR(200MHz，DMSO-d ₆)，δ(ppm)：1.27-1.51(2H，m)，1.55-1.72(2H，m)，2.15(3H，s)，2.80(3H，s)，2.81-3.00(6H，m)，3.03(3H，s)，3.89-3.96(3H，m)，7.11(2H，d，J＝8.5Hz)，7.20(2H，d，J＝8.5Hz)，7.37(4H，br)，9.79(1H，s)，12.36(1H，s)。

MS：486(M+H) ⁺

Preparation embodiment 45:

Synthetic N-{4-[2-(4-{[amino (imino-) methyl] amino } phenyl) ethyl]-5-phenyl-1,3-thiazoles-2-yl } acetamide hydrochloride

Step 1

2-oxo-3-phenylpropionic acid (20g), DMF (100ml) and DBU (18.2ml) are mixed under 0 ℃, nitrogen atmosphere, mixture is stirred 1h at 0 ℃.At 0 ℃ methyl iodide (15.2ml) is added solution then.At stirring at room reaction mixture 3h, among the impouring 1N HCl.Mixture extracts (twice) with AcOEt.The organic layer salt water washing that merges is used anhydrous magnesium sulfate drying, vacuum concentration.Resistates is purified with the silica gel flash column chromatography and (is used CHCl ₃/ AcOEt (30: 1) is as eluent), obtain light yellow wax shape 2-oxo-3-phenylpropionic acid methyl esters (11.2g) with the grinding of IPE/ normal hexane.

¹H-NMR(CDCl ₃)，δ(ppm)：3.92(3H，s)，6.42(1H，s)，6.53(1H，s)，7.28-7.42(3H，m)，7.77(2H，dd，J＝8.5，1.5Hz)。

MS：179(M+H) ⁺

Step 2

With 2-oxo-3-phenylpropionic acid methyl esters (11g), tribromide pyridine (24.1g), CH ₂Cl ₂(490ml) and AcOH (1.5ml) under 0 ℃, nitrogen atmosphere, mix.Reaction mixture is stirred 1.5h at 0 ℃, in the impouring water, distribute.The organic layer anhydrous magnesium sulfate drying, vacuum concentration.Remaining oily matter is dissolved in EtOH (190ml), then thiocarbamide (6.11g) is added solution.With the reaction mixture 1h that under nitrogen atmosphere, refluxes.After being cooled to 0 ℃, water is added solution.Vacuum leaches precipitation, obtains Off-white solid 2-amino-5-phenyl-1,3-thiazoles-4-methyl-formiate (6.63g).

mp.208-208.5℃

¹H-NMR(DMSO-d ₆)，δ(ppm)：3.67(3H，s)，7.38-7.53(5H，m)。

MS：235(M+H) ⁺

Step 3

2-amino-5-phenyl-1,3-thiazoles-4-methyl-formiate (3g) is dissolved in pyridine (30ml), under 0 ℃, nitrogen atmosphere, Acetyl Chloride 98Min. (2.73ml) is added drop-wise to solution then.At stirring at room reaction mixture 1.5h.At 0 ℃ water is added solution.Vacuum leaches precipitation, and solid washs with ether, obtains light brown solid 2-(acetylamino)-5-phenyl-1,3-thiazoles-4-methyl-formiate (2.37g).

mp.224.5-225.5℃

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.16(3H，s)，3.68(3H，s)，7.39-7.57(5H，m)，12.56(1H，s)。

MS：277(M+H) ⁺

Step 4

2-(acetylamino)-5-phenyl-1,3-thiazoles-4-methyl-formiate (2.34g) is suspended in THF (23ml), at 0 ℃ lithium aluminum hydride (482mg) is progressively added solution then.At 0 ℃ of stirred reaction mixture 1.5h, use the MeOH quencher.AcOEt and 1N HCl are added mixture, the extraction mixture.Water layer extracts (twice) with AcOEt.The organic layer salt water washing that merges is used anhydrous magnesium sulfate drying, vacuum concentration.Residual solid is dissolved in MeOH (5ml) and CHCl ₃(90ml).Under nitrogen atmosphere, manganese oxide (IV) (11g) is added solution then.At stirring at room reaction mixture 13h, filter by Celite pad.Vacuum concentrated filtrate.Resistates is purified with the silica gel flash column chromatography and (is used CHCl ₃/ MeOH (20: 1) is as eluent), obtain brown amorphous substance N-(4-formyl radical-5-phenyl-1,3-thiazoles-2-yl) ethanamide (705.2mg).

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.19(3H，s)，7.49-7.58(3H，m)，7.60-7.69(2H，m)，9.78(1H，s)，12.60(1H，s)。

MS：247(M+H) ⁺

Step 5

1-(brooethyl)-4-oil of mirbane (1.03g), triphenylphosphine (1.25g) and DMF (14ml) are mixed under nitrogen atmosphere.At stirring at room reaction mixture 6h.Then potassium tert.-butoxide (629mg) and N-(4-formyl radical-5-phenyl-1,3-thiazoles-2-yl) ethanamide (690mg) are added mixture, at stirring at room mixture 13h.In reaction mixture impouring frozen water, extract with AcOEt.Organic layer is used anhydrous magnesium sulfate drying, vacuum concentration with 1N HCl, water and salt water washing.Resistates is purified with the silica gel flash column chromatography and (is used CHCl ₃/ AcOEt (1: 1) is as eluent), obtain N-{4-[(E)-2-(4-nitrophenyl) vinyl]-5-phenyl-1, the 3-thiazol-2-yl } ethanamide and N-{4-[(Z)-2-(4-nitrophenyl) vinyl]-5-phenyl-1,3-thiazoles-2-yl } the orange wax shape mixture (E: Z=2: 1) (1.02g) of ethanamide.

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.13(3Hx1/3，s)，2.19(3Hx2/3，s)，6.65(1Hx1/3，d，J＝12.5Hz)，6.78(1Hx1/3，d，J＝12.5Hz)，7.32(1Hx2/3，d，J＝15.5Hz)，7.39-7.59(5H+1Hx2/3，m)，7.61(2Hx1/3，d，J＝9.0Hz)，7.77(2Hx2/3，d，J＝9.0Hz)，8.13(2Hx1/3，d，J＝9.0Hz)8.19(2Hx2/3，d，J＝9.0Hz)，12.33(1H，brs)。

MS：366(M+H) ⁺

Step 6

With N-{4-[(E)-2-(4-nitrophenyl) vinyl]-5-phenyl-1, the 3-thiazol-2-yl } ethanamide and N-{4-[(Z)-2-(4-nitrophenyl) vinyl]-5-phenyl-1,3-thiazoles-2-yl } mixture (E: Z=2: 1) (600mg), 10% palladium carbon (657mg), MeOH (6rml), THF (6ml) and AcOH (1ml) mix of ethanamide.Stirred reaction mixture 3.5h under 3atm nitrogen atmosphere, room temperature filters by Celite pad.Vacuum concentrated filtrate.1N NaOH is added resistates, and mixture extracts with AcOEt.Dried over mgso is used in organic layer water and salt water washing, and vacuum concentration obtains light brown amorphous substance N-{4-[2-(4-aminophenyl) ethyl]-5-phenyl-1,3-thiazoles-2-yl } ethanamide (528.6mg).

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.15(3H，s)，2.80(4H，s)，4.82(2H，s)，6.45(2H，d，J＝8.5Hz)，6.78(2H，d，J＝8.5Hz)，7.21-7.44(5H，m)，12.18(1H，brs)。

MS：338(M+H) ⁺

Step 7

{ (Z)-[(4-{2-[2-(acetylamino)-5-phenyl-1,3-thiazoles-4-yl] ethyl } phenyl) amino] methylene radical } the diamino acid di tert butyl carbonate is according to the similar approach preparation of preparation embodiment 31 steps 3.

¹H-NMR(DMSO-d ₆)，δ(ppm)：1.21(9H，s)，1.44(9H，s)，2.15(3H，s)，2.83-2.98(4H，m)，7.10(2H，d，J＝8.5Hz)，7.22-7.47(7H，m)，9.92(1H，s)，11.43(1H，s)，12.22(1H，s)。

MS：580(M+H) ⁺

Step 8

mp.80-82℃

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.16(3H，s)，2.83-3.08(4H，m)，7.11(2H，d，J＝8.0Hz)，7.21(2H，d，J＝8.0Hz)，7.29-7.54(8H，m)，9.94(1H，s)，12.22(1H，brs)。

MS:380 (M+H) ⁺(free type)

Preparation embodiment 46:

Synthetic N-{4-[2-(4-{[amino (imino-) methyl] amino } phenyl) ethyl]-5-benzyl-1,3-thiazoles-2-yl } acetamide hydrochloride

Step 1

The 75ml CHCl that adds 2-oxo-4-phenylbutyrate (3g) in cupric bromide (II) AcOEt (150ml) suspension (9.75g) ₃Solution.With reaction mixture refluxed 23h, be cooled to room temperature, filter (with AcOEt/ normal hexane (1: 1) wash-out) by short silicagel pad.Solvent removed in vacuo obtains yellow liquid 3-bromo-2-oxo-4-phenylbutyrate (4.2g).

¹H-NMR(CDCl ₃)，δ(ppm)：1.37(3H，t，J＝7.0Hz)，3.25(1H，dd，J＝14.5，7.5Hz)，3.54(1H，dd，J＝14.5，7.5Hz)，4.35(2H，q，J＝7.0Hz)，5.27(1H，d，J＝7.5Hz)，7.18-7.41(5H，m)。

Step 2

3-bromo-2-oxo-4-phenylbutyrate (5.8g) is dissolved in EtOH (110ml), then thiocarbamide (3.1g) is added solution.With the reaction mixture 2h that under nitrogen atmosphere, refluxes.Vacuum-evaporation refrigerative reaction mixture.Residual solid is suspended in (pH=8) saturated sodium bicarbonate and water.Solid collected by filtration (is used CHCl with the purification of silica gel flash column chromatography ₃/ MeOH (10: 1) is as eluent), obtain yellow wax shape 2-amino-5-benzyl-1,3-thiazoles-4-ethyl formate (808.2mg).

¹H-NMRR(DMSO-d ₆)，δ(ppm)：1.25(3H，t，J＝7.0Hz)，4.21(2H，q，.＝7.0Hz)，4.33(2H，s)，7.02(2H，s)，7.11-7.39(5H，m)。

MS：263(M+H) ⁺

Step 3

2-(acetylamino)-5-benzyl-1,3-thiazoles-4-ethyl formate is according to the similar approach preparation of preparation embodiment 45 steps 3.

mp.178-180℃

¹H-NMR(DMSO-d ₆)，δ(ppm)：1.28(3H，t，J＝7.0Hz)，2.09(3H，s)，4.28(2H，q，J＝7.0Hz)，4.48(2H，s)，7.19-7.39(5H，m)，12.41(1H，s)。

MS：305(M+H) ⁺

Step 4

2-(acetylamino)-5-benzyl-1,3-thiazoles-4-ethyl formate (1.0g) is dissolved in THF (20ml), at 0 ℃ lithium borohydride (124mg) is progressively added solution then.With reaction mixture refluxed 4.5h, use the MeOH quencher.Vacuum concentrated mixture (is used CHCl with the purification of silica gel flash column chromatography ₃/ MeOH (20: 1) is as eluent).Remaining amorphous substance is dissolved in MeOH (1ml) and CHCl ₃(8ml).Under nitrogen atmosphere, manganese oxide (IV) (1.26g) is added solution then.At stirring at room reaction mixture 12h, filter by Celite pad.Vacuum concentrated filtrate.Resistates is purified with the silica gel flash column chromatography and (is used CHCl ₃/ MeOH (20: 1) is as eluent), obtain light yellow solid N-(5-benzyl-4-formyl radical-1,3-thiazoles-2-yl) ethanamide (251mg).

mp.191-192.5℃

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.12(3H，s)，4.53(2H，s)，7.19-7.40(5H，m)，10.04(1H，s)，12.34(1H，s)。

MS：261(M+H) ⁺

Step 5

N-{5-benzyl-4-[(Z)-2-(4-nitrophenyl) vinyl]-1,3-thiazoles-2-yl } ethanamide is according to the similar approach preparation of preparation embodiment 45 steps 5.

Z∶E＝2∶1

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.08(3Hx2/3，s)，2.12(3Hx1/3，s)，4.08(2Hx2/3，s)，4.34(2Hx1/3，s)，6.72(1Hx2/3，d，J＝12.5Hz)，6.86(1Hx2/3，d，J＝12.5Hz)，7.17-7.39(5H+2Hx1/3，m)，7.66(2Hx2/3，d，J＝9.0Hz)，7.92(2Hx1/3，d，J＝9.0Hz)，8.14(2Hx2/3，d，J＝9.0Hz)，8.22(2Hx1/3，d，J＝9.0Hz)，11.85(1Hx2/3，s)，12.16(1Hx1/3，s)。

MS：380(M+H) ⁺

Step 6

N-{4-[2-(4-aminophenyl) ethyl]-5-benzyl-1,3-thiazoles-2-yl } ethanamide is according to the similar approach preparation of preparation embodiment 45 steps 6.

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.07(3H，s)，2.59-2.85(4H，m)，3.85(2H，s)，4.84(2H，s)，6.46(2H，d，J＝8.5Hz)，6.78(2H，d，J＝8.5Hz)，7.07(2H，d，J＝8.0Hz)，7.16-7.31(3H，m)，11.96(1H，s)。

MS：352(M+H) ⁺

Step 7

{ (Z)-[(4-{2-[2-(acetylamino)-5-benzyl-1,3-thiazoles-4-yl] ethyl } phenyl) amino] methylene radical } the diamino acid di tert butyl carbonate is according to the similar approach preparation of preparation embodiment 31 steps 3.

¹H-NMR(DMSO-d ₆)，δ(ppm)：1.39(9H，s)，1.51(9H，s)，2.07(3H，s)，2.85(4H，s)，3.89(2H，s)，7.05-7.33(7H，m)，7.42(2H，d，J＝8.5Hz)，9.95(1H，s)，11.44(1H，s)，11.99(1H，s)。

MS：594(M+H) ⁺

Step 8

mp.97-99℃

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.09(3H，s)，2.86(4H，s)，3.93(2H，s)，7.05-7.37(9H，m)，7.47(3H，s)，9.98(1H，s)，12.01(1H，brs)。

MS:394 (M+H) ⁺(free type)

Preparation embodiment 47:

Synthetic N-{4-[2-(4-aminophenyl) ethyl]-5-[4-(methyl sulphonyl) benzyl]-1,3-thiazoles-2-yl } ethanamide

Step 1

With 3-(4-sulfydryl phenyl) propionic acid (5g), K ₂CO ₃(11.4g) and DMF (30ml) mix, under 0 ℃, nitrogen atmosphere, (5.12ml) is added drop-wise to mixture with methyl iodide.At stirring at room reaction mixture 13h, in the impouring frozen water.Mixture extracts with AcOEt.Anhydrous magnesium sulfate drying is used in organic layer water (twice) and salt water washing, and vacuum concentration obtains faint yellow oily thing 3-[4-(methylthio group) phenyl] methyl propionate (4.19g).

¹H-NMR(CDCl ₃)，δ(ppm)：2.47(3H，s)，2.61(2H，t，J＝8.0Hz)，2.91(2H，t，J＝8.0Hz)，3.67(3H，s)，7.12(2H，d，J＝8.5Hz)，7.20(2H，d，J＝8.5Hz)。

Step 2

0 ℃, stir under, with sodium methylate (28%MeOH solution 3.67ml) is added drop-wise to 3-[4-(methylthio group) phenyl] mixture of methyl propionate (4g) and diethyl oxalate (5.17ml).65 ℃, the decompression under stirred reaction mixture 30min.15% aqueous sulfuric acid (35ml) is added mixture, with the mixture 15h that refluxes.After being cooled to room temperature, mixture extracts with AcOEt.Organic layer water and salt water washing are used anhydrous magnesium sulfate drying, vacuum concentration.Remaining oily matter is dissolved in EtOH (20ml), and (0.4ml) is added drop-wise to solution with the vitriol oil.With reaction mixture refluxed 2h.After being cooled to room temperature, vacuum is removed EtOH.AcOEt and water are added in the resistates extraction.Organic layer water and salt water washing are used anhydrous magnesium sulfate drying, vacuum concentration.Resistates is purified (using normal hexane/AcOEt (6: 1) as eluent) with the silica gel flash column chromatography, obtains yellow liquid 4-[4-(methylthio group) phenyl]-2-ketobutyric acid ethyl ester (2.43g).

¹H-NMR(CDCl ₃)，δ(ppm)：1.35(3H，t，J＝7.0Hz)，2.46(3H，s)，2.92(2H，t，J＝7.0Hz)，3.16(2H，t，J＝7.0Hz)，4.31(2H，q，J＝7.0Hz)，7.13(2H，d，J＝8.5Hz)，7.20(2H，d，J＝8.5Hz)。

Step 3

3-bromo-4-[4-(methylthio group) phenyl]-2-ketobutyric acid ethyl ester is according to the similar approach preparation of preparation embodiment 46 steps 1.

¹H-NMR(CDCl ₃)，δ(ppm)：1.37(3H，t，J＝7.0Hz)，2.47(3H，s)，3.20(1H，dd，J＝14.5，7.5Hz)，3.49(1H，dd，J＝14.5，7.5Hz)，4.35(2H，q，J＝7.0Hz)，5.22(1H，d，J＝7.5Hz)，7.17(2H，d，J＝8.5Hz)，7.20(2H，d，J＝8.5Hz)。

Step 4

2-amino-5-[4-(methylthio group) benzyl]-1,3-thiazoles-4-ethyl formate is according to the similar approach preparation of preparation embodiment 46 steps 2.

¹H-NMR(DMSO-d ₆)，δ(ppm)：1.25(3H，t，J＝7.0Hz)，2.44(3H，s)，4.20(2H，q，J＝7.0Hz)，4.28(2H，s)，7.02(2H，s)，7.19(4H，s)。

MS：309(M+H) ⁺

Step 5

2-(acetylamino)-5-[4-(methylthio group) benzyl]-1,3-thiazoles-4-ethyl formate is according to the similar approach preparation of preparation embodiment 45 steps 3.

mp.205-206℃

¹H-NMR(DMSO-d ₆)，δ(ppm)：1.28(3H，t，J＝7.0Hz)，2.09(3H，s)，2.45(3H，s)，4.27(2H，q，J＝7.0Hz)，4.43(2H，s)，7.22(4H，s)，12.41(1H，s)。

MS：351(M+H) ⁺

Step 6

N-{4-formyl radical-5-[4-(methylthio group) benzyl]-1,3-thiazoles-2-tomb } ethanamide is according to the similar approach preparation of preparation embodiment 46 steps 4.

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.12(3H，s)，2.45(3H，s)，4.48(2H，s)，7.23(4H，s)，10.03(1H，s)，12.33(1H，s)。

MS：307(M+H) ⁺

Step 7

N-{5-[4-(methylthio group) benzyl]-4-[(Z)-2-(4-nitrophenyl) vinyl]-1,3-thiazoles-2-yl } ethanamide is according to the similar approach preparation of preparation embodiment 45 steps 5.

Z∶E＝2∶1

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.08(3Hx2/3，s)，2.12(3Hx1/3，s)，2.44(3H，s)，4.04(2Hx2/3，s)，4.30(2Hx1/3，s)，6.71(1Hx2/3，d，J＝12.5Hz)，6.84(1Hx2/3，d，J＝12.5Hz)，7.18(4Hx2/3，s)，7.23(4Hx1/3，s)，7.24(1Hx1/3，d，J＝15.5Hz)，7.40(1Hx1/3，d，J＝15.5Hz)，7.65(2Hx2/3，d，J＝9.0Hz)，7.92(2Hx1/3，d，J＝9.0Hz)，8.12(2Hx2/3，d，J＝9.0Hz)，8.22(2Hx1/3，d，J＝9.0Hz)，11.85(1Hx2/3，brs)，12.16(1Hx1/3，brs)。

MS：426(M+H) ⁺

Step 8

N-{5-[4-(methyl sulphonyl) benzyl]-4-[(Z)-2-(4-nitrophenyl) vinyl]-1,3-thiazoles-2-yl } ethanamide is according to the similar approach preparation of preparation embodiment 32 steps 2.

Z∶E＝2∶1

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.09(3Hx2/3，s)，2.13(3Hx1/3，s)，3.18(3H，s)，4.24(2Hx2/3，s)，4.49(2Hx1/3，s)，6.73(1Hx2/3，d，J＝12.5Hz)，6.86(1Hx2/3，d，J＝12.5Hz)，7.33(1Hx1/3，d，J＝15.5Hz)，7.41-7.97(5/3H，m)，7.48(2Hx2/3，d，J＝9.0Hz)，7.55(2Hx1/3，d，J＝9.0Hz)，7.65(2Hx2/3，d，J＝9.0Hz)，7.85(2Hx2/3，d，J＝9.0Hz)，8.14(2Hx2/3，d，J＝9.0Hz)，8.22(2Hx1/3，d，J＝9.0Hz)，11.90(1Hx2/3，s)，12.22(1Hx1/3，s)。

MS：458(M+H) ⁺

Step 9

Title compound is according to the similar approach preparation of preparation embodiment 45 steps 6.

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.08(3H，s)，2.58-2.87(4H，m)，3.18(3H，s)，3.98(2H，s)，4.85(2H，s)，6.46(2H，d，J＝8.5Hz)，6.77(2H，d，J＝8.5Hz)，7.27(2H，d，J＝8.5Hz)，7.82(2H，d，J＝8.5Hz)，12.02(1H，s)。

MS：430(M+H) ⁺

Preparation embodiment 48:

Synthetic N-{4-[2-(4-{[amino (imino-) methyl] amino } phenyl) ethyl]-5-[4-(methyl sulphonyl) benzyl]-1,3-thiazoles-2-yl } ethanamide

Step 1

((Z)-[and 4-(2-{2-(acetylamino)-5-[4-(methyl sulphonyl) benzyl-1,3-thiazoles-4-yl } ethyl) phenyl] amino } methylene radical) the similar approach preparation of the compound of embodiment 47 of diamino acid di tert butyl carbonate according to preparation embodiment 31 steps 3.

¹H-NMR(DMSO-d ₆)，δ(ppm)：1.39(9H，s)，1.51(9H，s)，2.08(3H，s)，2.86(4H，s)，3.16(3H，s)，4.03(2H，s)，7.13(2H，d，J＝8.5Hz)，7.33(2H，d，J＝8.5Hz)，7.43(2H，d，J＝8.5Hz)，7.81(2H，d，J＝8.5Hz)，9.97(1H，s)，11.45(1H，s)，12.05(1H，s)。

MS：672(M+H) ⁺

Step 2

Will ((Z)-[and 4-(2-{2-(acetylamino)-5-[4-(methyl sulphonyl) benzyl]-1; 3-thiazole-4-yl } ethyl) phenyl] amino } methylene radical) diamino acid di tert butyl carbonate (953mg) and 4NHCl/1,4-dioxane solution (10ml) mixes under nitrogen atmosphere.At stirring at room reaction mixture 7h.Solvent removed in vacuo.Water-soluble and the AcOEt with resistates.Solution is with saturated sodium bicarbonate alkalization (pH=8).Vacuum leaches precipitation, obtains light yellow solid N-{4-[2-(4-{[amino (imino-) methyl] amino } phenyl) ethyl]-5-[4-(methyl sulphonyl) benzyl]-1,3-thiazoles-2-yl } ethanamide (667.7mg).

mp.228-229.5℃

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.08(3H，s)，2.79(4H，m)，3.18(3H，s)，4.05(2H，s)，6.72(2H，d，J＝8.0Hz)，6.99(2H，d，J＝8.0Hz)，7.37(2H，d，J＝8.5Hz)，7.84(2H，d，J＝8.5Hz)。

MS：472(M+H) ⁺

Preparation embodiment 49:

Synthetic N-{4-[2-(4-{[amino (imino-) methyl] amino } phenyl) ethyl]-5-[4-(methyl sulphonyl) benzyl]-1,3-thiazoles-2-yl } acetamide hydrochloride

Title compound prepares according to the similar approach for preparing embodiment 31 steps 4 with the compound of preparation embodiment 48 steps 1.

mp.107-110℃

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.09(3H，s)，2.87(4H，s)，3.19(3H，s)，4.08(2H，s)，7.13(2H，d，J＝8.5Hz)，7.25(2H，d，J＝8.5Hz)，7.40(2H，d，J＝8.5Hz)，7.44(3H，s)，7.85(2H，d，J＝8.5Hz)，9.94(1H，s)，12.05(1H，brs)。

MS:472 (M+H) ⁺(free type)

Preparation embodiment 50:

Synthetic N-{4-[2-(4-{[diazanyl (imino-) methyl] amino } phenyl) ethyl]-5-[4-(methyl sulphonyl) benzyl]-1,3-thiazoles-2-yl } ethanamide

Step 1

N-{4-[2-(4-aminophenyl) ethyl]-5-[4-(methyl sulphonyl) benzyl]-1,3-thiazoles-2-yl } add benzoyl lsothiocyanates (94.1mg) in the ice-cold solution of acetone (4.8ml) of ethanamide (247.6mg), at stirring at room mixture 1h.Water is added mixture, and mixture extracts with AcOEt.Organic layer water and salt water washing are used anhydrous magnesium sulfate drying, vacuum concentration.Remaining amorphous substance is dissolved in EtOH (5ml), 6N NaOH (0.288ml) is added solution at 0 ℃.At stirring at room reaction mixture 2h, neutralize with 1N HCl at 0 ℃.Mixture extracts with AcOEt.Organic layer water and salt water washing are used anhydrous magnesium sulfate drying, vacuum concentration.Resistates solidifies with ether, obtains Off-white solid N-{4-(2-{4-[(thiocarbamoyl) amino] phenyl } ethyl)-5-[4-(methyl sulphonyl) benzyl]-1,3-thiazoles-2-yl } ethanamide (290.7mg).

mp.102-103℃

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.09(3H，s)，2.85(4H，s)，3.18(3H，s)，4.03(2H，s)，7.11(2H，d，J＝8.5Hz)，7.30(2H，d，J＝8.5Hz)，7.36(2H，d，J＝8.5Hz)，7.84(2H，d，J＝8.5Hz)，9.64(1H，s)，12.04(1H，s)。

MS：489(M+H) ⁺

Step 2

With N-{4-(2-{4-[(thiocarbamoyl) amino] phenyl } ethyl)-5-[4-(methyl sulphonyl) benzyl]-1,3-thiazoles-2-yl } the mixture backflow 3.5h of ethanamide (281.8mg), methyl-iodide (0.0431ml) and MeOH (3ml).The vacuum concentration reaction mixture.Resistates dilutes with AcOEt, stirs 30min.The crystal that filtration is separated out; wash with AcOEt; obtain oyster white amorphous solid N-[4-(2-{2-(acetylamino)-5-[4-(methyl sulphonyl) benzyl]-1,3-thiazoles-4-yl ethyl) phenyl] sulfo-amino imido acid-S-methyl esters hydriodate (291.5mg).

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.09(3H，s)，2.68(3H，s)，2.90(4H，s)，3.18(3H，s)，4.07(2H，s)，7.22(2H，d，J＝8.5Hz)，7.32(2H，d，J＝8.5Hz)，7.39(2H，d，J＝8.5Hz)，7.86(2H，d，J＝8.5Hz)，9.22(1H，brs)，11.11(1H，brs)，12.03(1H，s)。

MS:503 (M+H) ⁺(free type)

Step 3

Title compound is according to the similar approach preparation of preparation embodiment 58. ¹H-NMR(DMSO-d ₆)，δ(ppm)：2.09(3H，s)，2.87(4H，s)，3.19(3H，s)，4.08(2H，s)，7.12(2H，d，J＝8.5Hz)，7.23(2H，d，J＝8.5Hz)，7.41(2H，d，J＝8.5Hz)，7.85(2H，d，J＝8.5Hz)，8.92(2H，brs)，12.03(1H，brs)。

MS：487(M+H) ⁺

Preparation embodiment 51:

Synthetic N-{4-[2-(4-{[amino (imino-) methyl] amino } phenyl) ethyl]-5-[4-(ethylsulfonyl) benzyl]-1,3-thiazoles-2-yl } acetamide hydrochloride

Step 1

3-[4-(ethylmercapto group) phenyl] the ethyl propionate similar approach preparation of 4-(2-carboxy ethyl) thiophenol according to preparation embodiment 47 steps 1.

¹H-NMR(CDCl ₃)，δ(ppm)：1.23(3H，t，J＝7.0Hz)，1.29(3H，t，J＝7.0Hz)，2.60(2H，t，J＝8.5Hz)，2.82-2.99(4H，m)，4.12(2H，q，J＝7.0Hz)，7.12(2H，d，J＝8.5Hz)，7.26(2H，d，J＝8.5Hz)。

Step 2

4-[4-(ethylmercapto group) phenyl]-2-ketobutyric acid ethyl ester is according to the similar approach preparation of preparation embodiment 47 steps 2.

¹H-NMR(CDCl ₃)，δ(ppm)：1.31(3H，t，J＝7.0Hz)，1.36(3H，t，J＝7.0Hz)，2.92(2H，q，J＝7.0Hz)，2.93(2H，t，J＝7.0Hz)，3.16(2H，t，J＝7.0Hz)，4.27(2H，q，J＝7.0Hz)，7.08(2H，d，J＝9.0Hz)，7.26(2H，d，J＝9.0Hz)。

Step 3

3-bromo-4-[4-(ethylmercapto group) phenyl]-2-ketobutyric acid ethyl ester is according to the similar approach preparation of preparation embodiment 46 steps 1.

¹H-NMR(CDCl ₃)，δ(ppm)：1.31(3H，t，J＝7.5Hz)，1.38(3H，t，J＝7.5Hz)，2.93(2H，q，J＝7.5Hz)，3.21(1H，dd，J＝14.5，7.5Hz)，3.49(1H，dd，J＝14.5，7.5Hz)，4.35(2H，q，J＝7.5Hz)，5.23(1H，t，J＝7.5Hz)，7.16(2H，d，J＝8.5Hz)，7.27(2H，d，J＝8.5Hz)。

Step 4

2-amino-5-[4-(ethylmercapto group) benzyl]-1,3-thiazoles-4-ethyl formate is according to the similar approach preparation of preparation embodiment 46 steps 2.

¹H-NMR(DMSO-d ₆)，δ(ppm)：1.22(6H，t，J＝7.0Hz)，2.94(2H，q，J＝7.0Hz)，4.20(2H，q，J＝7.0Hz)，4.29(2H，s)，7.03(2H，s)，7.18(2H，d，J＝8.5Hz)，7.26(2H，d，J＝8.5Hz)。

MS：323(M+H) ⁺

Step 5

2-(acetylamino)-5-[4-(ethylmercapto group) benzyl]-1,3-thiazoles-4-ethyl formate is according to the similar approach preparation of preparation embodiment 45 steps 3.

mp.189.5-190℃

¹H-NMR(DMSO-d ₆)，δ(ppm)：1.21(3H，t，J＝7.5Hz)，1.28(3H，t，J＝7.0Hz)，2.09(3H，s)，2.95(2H，q，J＝7.5Hz)，4.27(2H，q，J＝7.0Hz)，4.44(2H，s)，7.22(2H，d，J＝8.5Hz)，7.26(2H，d，J＝8.5Hz)，12.42(1H，s)。

MS：365(M+H) ⁺

Step 6

N-{5-[4-(ethylmercapto group) benzyl]-4-formyl radical-1,3-thiazoles-2-yl } ethanamide is according to the similar approach preparation of preparation embodiment 46 steps 4.

¹H-NMR(DMSO-d ₆)，δ(ppm)：1.21(3H，t，J＝7.5Hz)，2.17(3H，s)，2.95(2H，q，J＝7.5Hz)，4.49(2H，s)，7.26(4H，s)，10.03(1H，s)，12.34(1H，s)。

Step 7

N-{5-[4-(ethylmercapto group) benzyl]-4-[(Z)-2-(4-nitrophenyl) vinyl]-1,3-thiazoles-2-yl } ethanamide is according to the similar approach preparation of preparation embodiment 45 steps 5.

Z∶E＝3∶2

¹H-NMR(DMSO-d ₆)，δ(ppm)：1.20(3H，t，J＝7.5Hz)，2.08(3Hx3/5，s)，2.12(3Hx2/5，s)，2.93(2H，q，J＝7.5Hz)，4.05(2Hx3/5，s)，4.31(2Hx2/5，s)，6.71(1Hx3/5，d，J＝12.5Hz)，6.84(1Hx3/5，d，J＝12.5Hz)，7.13-8.16(6H+4/5H，m)，8.12(2Hx3/5，d，J＝9.0Hz)，8.22(2Hx2/5，d，J＝9.0Hz)，11.86(1Hx3/5，brs)，12.18(1Hx2/5，brs)。

MS：440(M+H) ⁺

Step 8

N-{5-[4-(ethylsulfonyl) benzyl]-4-[(Z)-2-(4-nitrophenyl) vinyl]-1,3-thiazoles-2-yl } ethanamide is according to the similar approach preparation of preparation embodiment 32 steps 2.

Z∶E＝3∶2

¹H-NMR(DMSO-d ₆)，δ(ppm)：1.06(3H，t，J＝7.5Hz)，2.09(3Hx3/5，s)，2.13(3Hx2/5，s)，3.25(2H，q，J＝7.5Hz)，4.24(2Hx3/5，s)，4.50(2Hx2/5，s)，6.73(1Hx3/5，d，J＝12.5Hz)，6.87(1Hx3/5，d，J＝12.5Hz)，7.43-8.31(8H+4/5H，m)，11.91(1Hx3/5，brs)，12.22(1Hx2/5，brs)。

MS：472(M+H) ⁺

Step 9

(ethyl (Z)-{ [4-(2-{2-(acetylamino)-5-[4-(ethylsulfonyl) benzyl-1,3-thiazoles-4-yl }) phenyl] amino } methylene radical) the diamino acid di tert butyl carbonate is according to the similar approach preparation of preparation embodiment 31 steps 3.

¹H-NMR(DMSO-d ₆)，δ(ppm)：1.05(3H，t，J＝7.5Hz)，1.39(9H，s)，1.51(9H，s)，2.09(3H，s)，2.85(4H，s)，3.22(2H，q，J＝7.5Hz)，4.04(2H，s)，7.11(2H，d，J＝8.5Hz)，7.32(2H，d，J＝8.5Hz)，7.43(2H，d，J＝8.5Hz)，7.77(2H，d，J＝8.5Hz)，9.97(1H，s)，11.44(1H，s)，12.05(1H，s)。

MS：686(M+H) ⁺

Step 10

¹H-NMR(DMSO-d ₆)，δ(ppm)：：1.07(3H，t，J＝7.5Hz)，2.09(3H，s)，2.86(4H，s)，3.26(2H，q，J＝7.5Hz)，4.09(2H，s)，7.13(2H，d，J＝8.0Hz)，7.24(2H，d，J＝8.0Hz)，7.44(3H，brs)，7.60(2H，d，J＝8.0Hz)，7.81(2H，d，.＝8.0Hz)，9.89(1H，s)，12.05(1H，brs)。

MS:486 (M+H) ⁺(free type)

Preparation embodiment 52:

Synthetic 4-[2-(4-{[amino (imino-) methyl] amino } phenyl) ethyl]-5-[4-(methyl sulphonyl) benzyl]-1,3-thiazoles-2-yl } urethanum

Step 1

With N-{4-[2-(4-aminophenyl) ethyl]-5-[4-(methyl sulphonyl) benzyl]-1,3-thiazoles-2-yl } ethanamide (300mg) is dissolved in THF (3ml) under nitrogen atmosphere.Then at THF (3ml) the solution adding solution of room temperature, at stirring at room reaction mixture 14h, vacuum concentration with tert-Butyl dicarbonate (168mg).Resistates is purified with the silica gel flash column chromatography and (is used CHCl ₃/ AcOEt (1: 1) is as eluent), obtain oyster white amorphous substance [4-(2-{2-(acetylamino)-5-[4-(methyl sulphonyl)-benzyl-1,3-thiazoles-4-yl } ethyl) phenyl] t-butyl carbamate (248.5mg).

¹H-NMR(DMSO-d ₆)，δ(ppm)：1.47(9H，s)，2.08(3H，s)，2.82(4H，s)，3.16(3H，s)，3.99(2H，s)，7.00(2H，d，J＝8.5Hz)，7.25(2H，d，J＝8.5Hz)，7.33(2H，d，J＝8.5Hz)，7.79(2H，d，J＝8.5Hz)，9.24(1H，s)，12.03(1H，s)。

MS：530(M+H) ⁺

Step 2

Will [4-(2-{2-(acetylamino)-5-[4-(methyl sulphonyl) benzyl]-1,3-thiazoles-4-yl } ethyl) phenyl]-t-butyl carbamate (230mg), 1N NaOH (1.09ml) and EtOH (5ml) mixing, with the mixture 16h that refluxes.After being cooled to room temperature, vacuum is removed organic solvent.The aqueous solution extracts with AcOEt with 1N HCl neutralization.Organic layer water and salt water washing are used anhydrous magnesium sulfate drying, vacuum concentration.Resistates is purified with preparation type silica gel chromatography and (is used CHCl ₃/ MeOH (30: 1) is as eluent), obtain oyster white amorphous substance [4-(2-{2-amino-5-[4-(methyl sulphonyl) benzyl]-1,3-thiazoles-4-yl } ethyl) phenyl] t-butyl carbamate (151.2mg).

¹H-NMR(DMSO-d ₆)，δ(ppm)：1.47(9H，s)，2.58-2.82(4H，m)，3.16(3H，s)，3.84(2H，s)，6.73(2H，s)，7.02(2H，d，J＝8.5Hz)，7.21(2H，d，J＝8.5Hz)，7.33(2H，d，J＝8.5Hz)，7.77(2H，d，J＝8.5Hz)，9.24(1H，s)。

MS：488(M+H) ⁺

Step 3

Will [4-(2-{2-amino-5-[4-(methyl sulphonyl) benzyl]-1,3-thiazoles-4-yl under nitrogen atmosphere } ethyl) phenyl] t-butyl carbamate (140mg) is dissolved in pyridine (2ml).Then, at 0 ℃ Vinyl chloroformate (30.2ml) is added solution.At stirring at room reaction mixture 2h, vacuum concentration.Resistates is dissolved in AcOEt, with 1N HCl, water and salt water washing.Organic layer anhydrous magnesium sulfate drying, vacuum concentration obtain oyster white amorphous substance { 4-(2-{4-[(tert-butoxycarbonyl) amino] phenyl } ethyl)-5-[4-(methyl sulphonyl) benzyl]-1,3-thiazoles-2-yl } urethanum (155.8mg).

¹H-NMR(DMSO-d ₆)，δ(ppm)：1.21(3H，t，J＝7.0Hz)，1.47(9H，s)，2.79(4H，s)，3.16(3H，s)，3.97(2H，s)，4.14(2H，q，J＝7.0Hz)，7.00(2H，d，J＝8.5Hz)，7.24(2H，d，J＝8.5Hz)，7.33(2H，d，J＝8.5Hz)，7.79(2H，d，J＝8.5Hz)，9.54(1H，s)，11.64(1H，brs)。

MS：560(M+H) ⁺

Step 4

Will { 4-(2-{4-[(tert-butoxycarbonyl) amino] phenyl } ethyl under nitrogen atmosphere)-5-[4-(methyl sulphonyl) benzyl]-1,3-thiazoles-2-yl urethanum (140mg) and 4N HC1 1,4-dioxane solution (3ml) mixing.At stirring at room reaction mixture 2h.Solvent removed in vacuo.Water-soluble and the AcOEt with resistates.Mixture 1N NaOH alkalization (pH=8).Anhydrous magnesium sulfate drying is used in organic layer water and salt water washing, vacuum concentration obtain the oyster white amorphous substance 4-[2-(4-aminophenyl) ethyl]-5-[4-(methyl sulphonyl) benzyl]-1,3-thiazoles-2-yl urethanum (125.6mg).

¹H-NMR(DMSO-d ₆)，δ(ppm)：1.21(3H，t，J＝7.0Hz)，2.60-2.80(4H，m)，3.18(3H，s)，3.97(2H，s)，4.14(2H，q，J＝7.0ho)4.85(2H，brs)，6.46(2H，d，J＝8.5Hz)，6.77(2H，d，J＝8.5Hz)，7.29(2H，d，J＝8.5Hz)，7.82(2H，d，J＝8.5Hz)，11.62(1H，brs)。

MS：460(M+H) ⁺

Step 5

((Z)-{ [4-(2-{2-[(ethoxy carbonyl) amino]-5-[4-(methyl sulphonyl) benzyl]-1,3-thiazoles-4-yl } ethyl) phenyl] amino } methylene radical) the diamino acid di tert butyl carbonate is according to the similar approach preparation of preparation embodiment 31 steps 3.

¹H-NMR(DMSO-d ₆)，δ(ppm)：1.21(3H，t，J＝7.0Hz)，1.39(9H，s)，1.51(9H，s)，2.84(4H，s)，3.16(3H，s)，4.01(2H，s)，4.14(2H，q，J＝7.0Hz)，7.13(2H，d，J＝8.5Hz)，7.33(2H，d，J＝8.5Hz)，7.43(2H，d，J＝8.5Hz)，7.81(2H，d，J＝8.5Hz)，9.97(1H，s)，11.45(1H，s)，11.61(1H，brs)。

MS：702(M+H) ⁺

Step 6

Title compound is according to the similar approach preparation of preparation embodiment 48 steps 2.

¹H-NMR(DMSO-d ₆)，δ(ppm)：1.17(3H，t，J＝7.0Hz)，2.57(4H，s)，3.17(3H，s)，4.01(2H，q，J＝7.0Hz)，4.03(2H，s)，7.00(4H，s)，7.42(2H，d，J＝8.5Hz)，7.83(2H，d，J＝8.5Hz)。

MS：502(M+H) ⁺

Preparation embodiment 53:

Synthetic N-{4-{2-[4-(amino methyl) phenyl] ethyl }-5-[4-(methyl sulphonyl) benzyl]-1,3-thiazoles-2-yl } ethanamide

Step 1

[4-(methoxycarbonyl) benzyl] (triphenyl) phosphorus bromine (4.81g) and DMF (60ml) are mixed under nitrogen atmosphere.Then at 0 ℃ with potassium tert.-butoxide (1.32g) and N-{4-formyl radical-5-[4-(methylthio group) benzyl]-1,3-thiazoles-2-yl ethanamide (3g) adds suspension.At stirring at room reaction mixture 18h, in the impouring frozen water, extract with AcOEt.Organic layer water and salt water washing are used anhydrous magnesium sulfate drying, vacuum concentration.Resistates is purified with the silica gel flash column chromatography and (is used CHCl ₃/ AcOEt (2: 1) is as eluent).Solid suspension in AcOEt, is leached suspension.Vacuum concentrated filtrate, obtain yellow amorphous substance 4-((Z)-2-{2-(acetylamino)-5-[4-(methylthio group) benzyl]-1,3-thiazoles-4-yl vinyl) methyl benzoate (4.16g).

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.08(3H，s)，2.43(3H，s)，3.84(3H，s)，3.96(2H，s)，6.67(1H，d，J＝12.5Hz)，6.74(1H，d，J＝12.5Hz)，7.11(2H，d，J＝8.5Hz)，7.17(2H，d，J＝8.5Hz)，7.50(2H，d，J＝8.5Hz)，7.85(2H，d，J＝8.5Hz)，11.88(1H，s)。

MS：439(M+H) ⁺

Step 2

4-((Z)-2-{2-(acetylamino)-5-[4-(methyl sulphonyl) benzyl]-1,3-thiazoles-4-yl } vinyl) methyl benzoate is according to the similar approach preparation of preparation embodiment 32 steps 2.

Z∶E＝2∶1

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.08(3Hx2/3，s)，2.12(3Hx1/3，s)，3.18(3H，s)，3.84(3Hx2/3，s)，3.86(3Hx1/3，s)，4.15(2Hx2/3，s)，4.47(2Hx1/3，s)，6.68(1Hx2/3，d，J＝12.5Hz)，6.77(1Hx2/3，d，J＝12.5Hz)，7.30(1Hx1/3，d，J＝15.5Hz)，7.43(2H，d，J＝8.5Hz)，7.50-7.97(19/3H，m)，11.93(1Hx2/3，s)，12.19(1Hx1/3，s)。

MS：471(M+H) ⁺

Step 3

4-(2-{2-(acetylamino)-5-[4-(methyl sulphonyl) benzyl]-1,3-thiazoles-4-yl } ethyl) methyl benzoate is according to the similar approach preparation of preparation embodiment 45 steps 6.

mp.209-210℃

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.09(3H，s)，2.94(4H，m)，3.17(3H，s)，3.84(3H，s)，4.01(2H，s)，7.25(2H，d，J＝8.5Hz)，7.28(2H，d，J＝8.5Hz)，7.76(2H，d，J＝8.5Hz)，7.85(2H，d，J＝8.5Hz)，12.05(1H，brs)。

MS：473(M+H) ⁺

Step 4

Under-78 ℃, nitrogen atmosphere; 4-(2-{2-(acetylamino)-5-[4-(methyl sulphonyl) benzyl]-1,3-thiazoles-4-yl } ethyl) drip the toluene solution (14.8ml) of 1.0M diisobutyl aluminium hydride in anhydrous THF (40ml) stirred solution of methyl benzoate (2g).At stirring at room reaction mixture 4h, use the MeOH quencher then.Ac0Et and 1N HCl are added mixture, extraction.Organic layer salt water washing is used anhydrous magnesium sulfate drying, vacuum concentration.Resistates is purified with the silica gel flash column chromatography and (is used CHCl ₃/ MeOH (20: 1) is as eluent), obtain colorless solid N-{4-{2-[4-(hydroxymethyl) phenyl] ethyl }-5-[4-(methyl sulphonyl) benzyl]-1,3-thiazoles-2-yl } ethanamide (552.3mg).

mp.209.5-211℃

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.09(3H，s)，2.86(4H，s)，3.17(3H，s)，4.01(2H，s)，4.46(2H，d，J＝5.5Hz)，5.12(1H，t，J＝5.5Hz)，7.09(2H，d，J＝8.0Hz)，7.20(2H，d，J＝8.0Hz)，7.28(2H，d，J＝8.5Hz)，7.80(2H，d，J＝8.5Hz)，12.04(1H，brs)。

MS：445(M+H) ⁺

Step 5

With N-{4-{2-[4-(hydroxymethyl) phenyl] ethyl }-5-[4-(methyl sulphonyl) benzyl]-1,3-thiazoles-2-yl } ethanamide (539.5mg), CH ₂Cl ₂(5ml) and DMF (5ml) under nitrogen atmosphere, mix.Then at 0 ℃ with Et ₃N (0.211ml) and MsCl (0.108ml) add suspension.At stirring at room reaction mixture 3.5h.In reaction mixture impouring water, use chloroform extraction.Organic layer salt water washing is used anhydrous magnesium sulfate drying, vacuum concentration.Residual solid is washed with ether, obtains Off-white solid N-{4-{2-[4-(chloromethyl) phenyl] ethyl }-5-[4-(methyl sulphonyl) benzyl]-1,3-thiazoles-2-yl } ethanamide (537.5mg).

mp.202-203℃

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.09(3H，s)，2.88(4H，s)，3.17(3H，s)，4.01(2H，s)，4.73(2H，s)，7.15(2H，d，J＝8.0Hz)，7.30(2H，d，J＝8.5Hz)，7.34(2H，d，J＝8.0Hz)，7.81(2H，d，J＝8.5Hz)，12.05(1H，brs)。

MS：463(M+H) ⁺

Step 6

With N-{4-{2-[4-(chloromethyl) phenyl] ethyl }-5-[4-(methyl sulphonyl) benzyl]-1,3-thiazoles-2-yl } ethanamide (150mg) is suspended in CH ₃CN (6ml) adds suspension at 0 ℃ with 28% ammonia soln (0.4ml) then.At stirring at room reaction mixture 16h, vacuum concentration.Residual solid washes with water, purifies with preparation type silica gel chromatography and (uses CHCl ₃/ MeOH (10: 1) is as eluent), obtain light yellow amorphous substance N-{4-{2-[4-(amino methyl) phenyl] ethyl }-5-[4-(methyl sulphonyl) benzyl]-1,3-thiazoles-2-yl } ethanamide (32.1mg).

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.09(3H，s)，2.85(4H，s)，3.17(3H，s)，3.69(2H，s)，4.01(2H，s)，7.07(2H，d，J＝8.0Hz)，7.21(2H，d，J＝8.0Hz)，7.29(2H，d，J＝8.5Hz)，7.80(2H，d，J＝8.5Hz)。

MS：444(M+H) ⁺

Preparation embodiment 54:

Synthetic N-{4-{2-[4-(4,5-dihydro-1,3-thiazoles-2-base is amino) phenyl] ethyl }-5-[4-(methyl sulphonyl) benzyl]-1,3-thiazoles-2-yl } ethanamide

With N-{4-[2-(4-aminophenyl) ethyl]-5-[4-(methyl sulphonyl) benzyl]-1; the 3-thiazol-2-yl }-ethanamide (200mg), 2-(methyl sulfenyl)-4; the mixture of 5-dihydro-1,3-thiazoles (62mg), concentrated hydrochloric acid (0.064ml) and 2-methyl cellosolve (3ml) stirs 13h under 120 ℃, nitrogen atmosphere.After being cooled to room temperature, reaction mixture alkalizes with saturated sodium bicarbonate.Mixture extracts with AcOEt.The organic layer anhydrous magnesium sulfate drying, vacuum concentration.Resistates is purified with preparation type silica gel chromatography and (is used CHCl ₃/ MeOH (10: 1) is as eluent), obtain light yellow amorphous substance N-{4-{2-[4-(4,5-dihydro-1,3-thiazoles-2-base is amino) phenyl] ethyl }-5-[4-(methyl sulphonyl) benzyl]-1,3-thiazoles-2-yl } ethanamide (139.8mg).

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.08(3H，s)，2.82(4H，s)，3.16(3H，s)，3.17-3.34(4H，m)，3.98(2H，s)，6.99(2H，d，J＝8.5Hz)，7.25(2H，d，J＝8.5Hz)，7.45(2H，brd，J＝8.5Hz)，7.80(2H，d，J＝8.5Hz)，9.24(1H，brs)，12.04(1H，s)。

MS：515(M+H) ⁺

Preparation embodiment 55:

Synthetic N-{4-{2-[4-(4,5-dihydro-1H-imidazoles-2-base is amino) phenyl] ethyl }-5-[4-(methyl sulphonyl) benzyl]-1,3-thiazoles-2-yl } ethanamide

With N-{4-[2-(4-aminophenyl) ethyl]-5-[4-(methyl sulphonyl) benzyl]-1; the 3-thiazol-2-yl } ethanamide (150mg), 2-(methylthio group)-4, the mixture of 5-dihydro-1H-imidazoles-1-ethyl formate (78.9mg), AcOH (0.3ml) and EtOH (3ml) 7h that under nitrogen atmosphere, refluxes.After being cooled to room temperature, reaction mixture alkalizes with saturated sodium bicarbonate.Mixture extracts with AcOEt.Organic layer salt water washing is used anhydrous magnesium sulfate drying, vacuum concentration.Resistates is purified with preparation type silica gel chromatography and (is used CHCl ₃/ MeOH (10: 1) is as eluent).Amorphous substance solidifies with ether, obtains oyster white amorphous solid N-{4-{2-[4-(4,5--dihydro-1H-imidazoles-2-base is amino) phenyl] ethyl }-5-[4-(methyl sulphonyl) benzyl]-1,3-thiazoles-2-yl } ethanamide (17.9mg).

mp.139-140℃

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.08(3H，s)，2.71-2.87(4H，m)，3.18(3H，s)，3.25-3.41(4H，m)，4.03(2H，s)，6.95(4H，s)，7.32(2H，d，J＝8.5Hz)，7.82(2H，d，J＝8.5Hz)。

MS：498(M+H) ⁺

Preparation embodiment 56:

Synthetic N-{4-{2-[4-(acetimidoyl amino) phenyl] ethyl }-5-[4-(methyl sulphonyl) benzyl]-1,3-thiazoles-2-yl } ethanamide

With N-{4-[2-(4-aminophenyl) ethyl]-5-[4-(methyl sulphonyl) benzyl]-1,3-thiazoles-2-yl } ethanamide (200mg), second sulfo-imido acid-S-methyl esters hydriodate (202mg) and MeOH (4ml) mix under nitrogen atmosphere.With reaction mixture refluxed 3h.After being cooled to room temperature, vacuum concentrated mixture.Resistates is purified with preparation type NH silica gel chromatography and (is used CHCl ₃/ MeOH (10: 1) is as eluent).Amorphous substance solidifies with ether, obtains light yellow amorphous solid N-{4-{2-[4-(acetimidoyl amino) phenyl] ethyl }-5-[4-(methyl sulphonyl) benzyl]-1,3-thiazoles-2-yl } ethanamide (102.4mg).

mp.81.5-83℃

¹H-NMR(CDCl ₃)，δ(ppm)：1.83(3H，brs)，2.08(3H，s)，2.81(4H，m)，3.18(3H，s)，4.02(2H，s)，6.64(2H，brd，J＝8.5Hz)，6.99(2H，d，J＝8.5Hz)，7.36(2H，d，J＝8.5Hz)，7.83(2H，d，J＝8.5Hz)，12.03(1H，brs)。

MS：471(M+H) ⁺

Preparation embodiment 57:

Synthetic N-[4-(2-{4-[(iminomethyl) amino] phenyl } ethyl)-1,3-thiazoles-2-yl] ethanamide

At 0 ℃ with N-{4-[2-(4-aminophenyl) ethyl]-1,3-thiazoles-2-yl ethanamide (150mg) is dissolved in the damping fluid (2ml) of THF (2ml) and pH=7.Then azomethine acid ethyl ester hydrochloride salt (1.26g) is added solution.At 0 ℃ of stirred reaction mixture 2h, vacuum concentration.Resistates is purified with the silica gel flash column chromatography and (is used CH ₃CN/ water (7: 3) is as eluent).Oily matter (is used CHCl with preparation type silica gel chromatography ₃/ MeOH (5: 1) is as eluent) purify once more, obtain light brown oily matter N-[4-(2-{4-[(iminomethyl) amino] phenyl } ethyl)-1,3-thiazoles-2-yl] ethanamide (110mg).

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.12(3H，s)，2.81-3.01(4H，m)，6.71(1H，s)，7.09-8.00(7H，m)，12.07(1H，s)。

MS：289(M+H) ⁺

Preparation embodiment 58:

Synthetic N-{4-[2-(4-{[diazanyl (imino-) methyl] amino } phenyl) ethyl]-1,3-thiazoles-2-yl } ethanamide

With the mixture of N-(4-{2-[2-(acetylamino)-1,3-thiazoles-4-yl] ethyl } phenyl) sulfo-amino imido acid-S-methyl esters hydriodate (100mg), hydrazine monohydrate (0.0525ml) and THF (3md) at stirring at room 95h.The filtering precipitation.Vacuum concentrated filtrate.Resistates is purified with preparation type silica gel chromatography and (is used CHCl ₃/ MeOH (10: 1) is as eluent), obtain pale pink look solid N-{4-[2-(4-{[diazanyl (imino-) methyl] amino } phenyl) ethyl]-1,3-thiazoles-2-yl } ethanamide (62.7mg).

mp.216.5-218℃

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.12(3H，s)，2.92(4H，m)，6.75(1H，s)，7.12(2H，d，J＝8.5Hz)，7.27(2H，d，J＝8.5Hz)，8.88(1H，brs)，12.07(1H，brs)。

MS：319(M+H) ⁺

Preparation embodiment 59:

Synthetic N-(4-{2-[4-(2-amino-2-imino-ethyl) phenyl] ethyl }-1,3-thiazoles-2-yl) ethanamide

Step 1

N-(4-{2-[4-(chloromethyl) phenyl] ethyl }-1,3-thiazoles-2-yl) ethanamide with N-(4-{2-[4-(hydroxymethyl) phenyl] ethyl }-1,3-thiazoles-2-yl) ethanamide is according to the similar approach preparation of preparation embodiment 53 steps 5.

mp.145-146℃

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.11(3H，s)，2.82-2.99(4H，m)，4.72(2H，s)，6.73(1H，s)，7.20(2H，d，J＝8.0Hz)，7.33(2H，d，J＝8.0Hz)，12.08(1H，brs)。

MS：295(M+H) ⁺

Step 2

At 0 ℃ NaCN (115mg), KI (130mg) and water (1.8ml) are mixed, then with N-(4-{2-[4-(chloromethyl) phenyl] ethyl }-1,3-thiazoles-2-yl) DMF (7ml) drips of solution of ethanamide (230mg) is added to mixture.At stirring at room reaction mixture 19h, in the impouring water, use chloroform extraction.Organic layer salt water washing concentrates with the anhydrous magnesium sulfate drying final vacuum.Residual solid is washed with ether, obtain colorless solid N-(4-{2-[4-(cyano methyl) phenyl] ethyl }-1,3-thiazoles-2-yl) ethanamide (149.1mg).

mp.160-161℃

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.11(3H，s)，2.82-2.97(4H，m)，3.97(2H，s)，6.73(1H，s)，7.21(2H，d，J＝8.5Hz)，7.25(2H，d，J＝8.5Hz)，12.08(1H，brs)。

MS：286(M+H) ⁺

Step 3

With N-(4-{2-[4-(cyano methyl) phenyl] ethyl }-1,3-thiazoles-2-yl) ethanamide (600mg) is dissolved in MeOH (5ml) and CHCl ₃(5ml), then 0 ℃, feed hydrogen chloride gas 5min under stirring.With reaction mixture sat 17h, vacuum concentration.Residual solid is washed with ether, obtains Off-white solid 2-(4-{2-[2-(acetylamino)-1,3-thiazoles-4-yl] ethyl } phenyl) ethanimidic acid methyl ester hydrochloride (632.5mg).

mp.77-78℃

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.12(3H，s)，2.88(4H，s)，4.92(6H，brs)，6.75(1H，s)，7.10-7.20(4H，m)，12.11(1H，brs)。

MS:318 (M+H) ⁺(free type)

Step 4

2-(4-{2-[2-(acetylamino)-1,3-thiazoles-4-yl] ethyl } phenyl) ethanimidic acid methyl ester hydrochloride (600mg) is dissolved in EtOH (12ml).Methanol solution (2ml) with ammonium chloride (136mg) and ammonia adds solution then.With the reaction mixture 4h that under nitrogen atmosphere, refluxes.After being cooled to room temperature, vacuum filtration suspension.Vacuum concentrated filtrate, resistates solidifies with the EtOH/ ether, obtain Off-white solid N-(4-{2-[4-(2-amino-2-imino-ethyl) phenyl] ethyl }-1,3-thiazoles-2-yl) acetamide hydrochloride (338.6mg).

mp.190.5-192℃

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.12(3H，s)，2.89(4H，m)，3.68(2H，s)，6.74(1H，s)，7.20(2H，d，J＝8.0Hz)，7.39(2H，d，J＝8.0Hz)。

MS:303 (M+H) ⁺(free type)

Step 5

With N-(4-{2-[4-(2-amino-2-imino-ethyl) phenyl] ethyl }-1,3-thiazoles-2-yl) acetamide hydrochloride (67mg) water-soluble (1ml) and CH ₃CN (1ml).Solution alkalizes (pH=8) with saturated sodium bicarbonate, vacuum concentration.Resistates is purified with preparation type NH silica gel chromatography and (is used CH ₃CN/ water (7: 3) is as eluent), obtain oyster white amorphous substance N-(4-{2-[4-(2-amino-2-imino-ethyl) phenyl] ethyl }-1,3-thiazoles-2-yl) ethanamide (26mg).

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.11(3H，s)，2.89(4H，m)，3.59(2H，s)，6.72(1H，s)，7.20(2H，d，J＝8.0Hz)，7.30(2H，d，J＝8.0Hz)，9.38(3H，brs)。

MS：303(M+H) ⁺

Preparation embodiment 60:

Synthetic N-{4-[2-(4-{[amino (imino-) methyl] amino } phenyl) ethyl]-5-[4-(methylthio group) benzyl]-1,3-thiazoles-2-yl } ethanamide

Step 1

With N-{5-[4-(methylthio group) benzyl]-4-[(Z)-and 2-(4-nitrophenyl) vinyl]-1, the 3-thiazol-2-yl } ethanamide and N-{5-[4-(methylthio group) benzyl]-4-[(E)-2-(4-nitrophenyl) vinyl]-1,3-thiazoles-2-yl } (Z: E=2: 1) mixture (570mg) is dissolved in CH to ethanamide under nitrogen atmosphere ₂Cl ₂(6ml).At 0 ℃ m-CPBA (254mg) is progressively added solution then.At stirring at room reaction mixture 1.5h, use MeOH/CHCl ₃Dilution.Organic solution 1NNa ₂CO ₃, water and salt water washing; use dried over mgso; vacuum concentration obtains N-{5-[4-(methylsulfinyl) benzyl]-44 (Z)-2-(4-nitrophenyl) vinyl]-1; the 3-thiazol-2-yl } ethanamide and N-{5-[4-(methylsulfinyl) benzyl]-44 (E)-2-(4-nitrophenyl) vinyl]-1,3-thiazoles-2-yl } the yellow amorphous mixture (Z: E=2: 1) (282.8mg) of ethanamide.

Z∶E＝2∶1

¹H-NMR(DMSO-d ₆)δ(ppm)：2.08(3Hx2/3，s)，2.13(3Hx1/3，s)，2.71(3H，s)，4.18(2Hx2/3，s)，4.44(2Hx1/3，s)，6.73(1Hx2/3，d，J＝12.5Hz)，6.87(1Hx2/3，d，J＝12.5Hz)，7.34(1Hx1/3，d，J＝15.5Hz)，7.41-8.17(7/3H，m)，7.41(2Hx2/3，d，J＝8.0Hz)，7.50(2Hx1/3，d，J＝8.0Hz)，7.63(2Hx2/3，d，J＝8.0Hz)，7.93(2Hx1/3，d，J＝8.0Hz)，8.14(2Hx2/3，d，J＝8.0Hz)，8.22(2Hx1/3，d，J＝8.0Hz)，11.89(1Hx2/3，s)，12.20(1Hx1/3，s)。

MS：442(M+H) ⁺

Step 2

N-{4-[2-(4-aminophenyl) ethyl]-5-[4-(methylsulfinyl) benzyl]-1,3-thiazoles-2-yl } ethanamide is according to the similar approach preparation of preparation embodiment 45 steps 6.

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.08(3H，s)，2.62-2.84(4H，m)，2.70(3H，s)，3.94(2H，s)，4.85(2H，s)，6.46(2H，d，J＝8.5Hz)，6.77(2H，d，J＝8.5Hz)，7.23(2H，d，J＝8.5Hz)，7.58(2H，d，J＝8.5Hz)，12.00(1H，s)。

MS：414(M+H) ⁺

Step 3

((Z)-{ [4-(2-{2-(acetylamino)-5-[4-(methylsulfinyl) benzyl]-1,3-thiazoles-4-yl } ethyl) phenyl] amino } methylene radical) the diamino acid di tert butyl carbonate is according to the similar approach preparation of preparation embodiment 31 steps 3.

¹H-NMR(DMSO-d ₆)，δ(ppm)：1.39(9H，s)，1.51(9H，s)，2.08(3H，s)，2.69(3H，s)，2.86(4H，s)，3.98(2H，s)，7.12(2H，d，J＝8.5Hz)，7.26(2H，d，J＝8.0Hz)，7.43(2H，d，J＝8.5Hz)，7.57(2H，d，J＝8.0Hz)，9.95(1H，s)，11.43(1H，s)，12.02(1H，s)。

MS：656(M+H) ⁺

Step 4

mp.159.5-161℃

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.07(3H，s)，2.44(3H，s)，2.79(4H，s)，3.86(2H，s)，6.78(2H，d，J＝8.5Hz)，7.02(2H，d，J＝8.5Hz)，7.04，(2H，d，J＝8.5Hz)，7.30(2H，d，J＝8.5Hz)。

MS：440(M+H) ⁺

Preparation embodiment 61:

Synthetic N-{4-[4-(3-{[amino (imino-) methyl] amino } propyl group) phenyl]-5-[4-(methyl sulphonyl) phenyl]-1,3-thiazoles-2-yl } acetamide hydrochloride

Step 1

At 0 ℃ to 4-{[4-(methylthio group) phenyl] ethanoyl add acetate (0.65ml) and tribromide pyridine (6.51g) in methylene dichloride (250ml) solution of methyl benzoate (5g), mixture is stirred 1h at uniform temp.In reaction mixture impouring water (250ml), with ethyl acetate (250ml) extraction.Organic layer water and salt water washing are with evaporating after the dried over mgso.Resistates filters collection and obtains Off-white solid 4-{2-bromine [4-(methylthio group) phenyl] ethanoyl with the washing of di-isopropyl ether } methyl benzoate.

¹H-NMR(CDCl ₃)，δ(ppm)：2.47(3H，s)，3.94(3H，s)，6.33(3H，s)，7.23(2H，d，J＝8.5Hz)，7.43(2H，d，J＝8.5Hz)。

Step 2

4-{2-amino-5-[4-(methylthio group) phenyl]-l, 3-thiazole-4-yl } methyl benzoate is according to the similar approach preparation of preparation embodiment 46 steps 2.

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.47(3H，s)，3.83(3H，s)，7.08-7.32(4H，m)，7.52(2H，d，J＝8.5Hz)，7.85(2H，d，J＝8.5Hz)。

MS：357.1(M+H) ⁺

Step 3

4-{2-amino-5-[4-(methylthio group) phenyl-1,3-thiazoles-4-yl } progressively add lithium aluminum hydride (21.3mg) in tetrahydrofuran (THF) (4ml) solution of methyl benzoate (100mg), at 20 ℃ of 1h that stir the mixture.Add ethyl acetate (10ml) and water (3ml) in the reaction mixture.Remove by filter gained precipitation, filtrate is used the salt water washing, with evaporating after the dried over sodium sulfate, obtains yellow solid (4-{2-amino-5-[4-(methylthio group) phenyl-1,3-thiazoles-4-yl } phenyl) methyl alcohol, and crude product is directly used in next step.

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.46(3H，s)，4.46(2H，d，J＝6.0Hz)，5.17(t，1H，J＝5.5Hz)，7.13(d，2H，J＝5.5Hz)，7.17(d，2H，J＝5.5Hz)，7.20(d，2H，J＝8.5Hz)，7.34(d，2H，J＝8.5Hz)。

MS：329.2(M+H) ⁺

Step 4

0 ℃ to (4-{2-amino-5-[4-(methylthio group) phenyl]-1,3-thiazoles-4-yl phenyl) add pyridine (0.11ml) and Acetyl Chloride 98Min. (42.5 μ l) in methylene dichloride (1ml) suspension of methyl alcohol (89.3mg), mixture is stirred 1h at uniform temp.Add 1N hydrochloric acid (10ml) in the reaction mixture, mixture extracts with ethyl acetate (20ml x 2).Organic layer water and salt water washing with evaporating after the dried over mgso, obtain rough green solid (77.6mg).In 0 ℃ of dichloromethane solution (3ml), add 3-chlorine peroxybenzoic acid (80.7mg), at 20 ℃ of 2h that stir the mixture to rough green solid.Add saturated sodium bicarbonate aqueous solution (10ml) in the reaction mixture; mixture extracts with ethyl acetate (20mlx 2); water and salt water washing; use dried over mgso; evaporation obtains brown solid acetate 4-{2-(acetylamino)-5-[4-(methyl sulphonyl) phenyl-1,3-thiazoles-4-yl } benzyl ester.

¹H-NMR(CDCl ₃)，δ(ppm)：1.77(3H，s)，2.14(3H，s)，3.10(3H，s)，5.12(2H，s)，7.32(2H，d，J＝8.5Hz)，7.45(2H，d，J＝8.5Hz)，7.52(2H，d，J＝8.5Hz)，7.88(2H，d，J＝8.5Hz)，11.1(1H，brs)。

MS：467.0(M+Na) ⁺

Step 5

At 20 ℃ to acetate 4-{2-(acetylamino)-5-[4-(methyl sulphonyl) phenyl-1,3-thiazoles-4-yl add salt of wormwood (379mg) in methyl alcohol (24ml) suspension of benzyl ester (1.218g), 1h stirs the mixture.Add 0.1N hydrochloric acid (27.4ml) in the reaction mixture; mixture extracts with chloroform (500ml); with evaporating after the dried over mgso, obtain yellow solid N-{4-[4-(hydroxymethyl) phenyl]-5-[4-(methyl sulphonyl) phenyl]-1,3-thiazoles-2-yl } ethanamide.

¹H-NMR(CDCl ₃)，δ(ppm)：1.87(3H，s)，3.09(3H，s)，4.72(2H，s)，7.31(2H，d，J＝8.5Hz)，7.42(2H，d，J＝8.5Hz)，7.51(2H，d，J＝8.5Hz)，7.87(2H，d，J＝8.5Hz)，10.83(1H，brs)。

MS：425.0(M+Na) ⁺

Step 6

Under 20 ℃, nitrogen atmosphere; N-{4-[4-(hydroxymethyl) phenyl]-5-[4-(methyl sulphonyl) phenyl]-1; the 3-thiazol-2-yl } add manganese oxide (IV) (6.65g) in the methyl alcohol (0.6ml) of ethanamide (867.4mg) and chloroform (10ml) solution, 19h stirs the mixture.Reaction mixture filters by Celite pad.Evaporated filtrate obtains yellow solid N-{4-(4-formyl radical phenyl)-5-[4-(methyl sulphonyl) phenyl]-1,3-thiazoles-2-yl } ethanamide, crude product is directly used in next step.

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.20(3H，s)，3.26(3H，s)，7.63(2H，d，J＝8.5Hz)，7.64(2H，d，J＝8.0Hz)，7.90(2H，d，J＝8.0Hz)，7.92(2H，d，J＝8.5Hz)，10.00(1H，s)，12.5(1H，brs)。

Step 7

At 20 ℃ to N-{4-(4-formyl radical phenyl)-5-[4-(methyl sulphonyl) phenyl]-1,3-thiazoles-2-yl add (ethoxycarbonyl methylene) triphenyl phosphorane (626mg) in chloroform (7ml) suspension of ethanamide (360mg), 1h stirs the mixture.Evaporation reaction mixture.Resistates is purified (with hexane/ethyl acetate (1: 1-1: 2) as eluent) with silica gel (150ml) column chromatography; obtain light yellow solid (2E)-3-(4-{2-(acetylamino)-5-[4-(methyl sulphonyl) phenyl-1,3-thiazoles-4-yl } phenyl) ethyl propenoate.

¹H-NMR(CDCl ₃)，δ(ppm)：1.34(3H，t，J＝7.0Hz)，1.93(3H，s)，3.10(3H，s)，4.28(2H，q，J＝7.0Hz)，6.45(1H，d，J＝16.1Hz)，7.48(4H，s)，7.54(2H，d，J＝8.5Hz)，7.67(2H，d，J＝16.1Hz)，7.89(2H，d，J＝8.5Hz)，10.39(1H，s)。

MS：493.1(M+Na) ⁺

Step 8

0 ℃ to (2E)-3-(4-{2-(acetylamino)-5-[4-(methyl sulphonyl) phenyl]-1; 3-thiazole-4-yl } phenyl) progressively add lithium borohydride (271mg) in tetrahydrofuran (THF) (3ml) suspension of ethyl propenoate (306.5mg), at 20 ℃ of 6.5h that stir the mixture.In 0 ℃ of mixture with reaction mixture impouring saturated aqueous ammonium chloride (50ml) and chloroform (50ml).Isolate organic layer, use dried over mgso, evaporation obtains rough yellow solid (300mg).Resistates silica gel (80ml) column chromatography purification (with hexane/ethyl acetate (1: 2-1 :), obtain light yellow solid N-{4-[4-(3-hydroxypropyl) phenyl 5) as eluent]-5-[4-(methyl sulphonyl) phenyl]-1,3-thiazoles-2-yl } ethanamide.

¹H-NMR(CDCl ₃)，δ(ppm)：1.71(3H，s)，1.80-1.99(2H，m)，2.61-2.82(2H，m)，3.09(3H，s)，3.69(2H，dd，J＝6.0，10.0Hz)，7.17(2H，d，J＝8.0Hz)，7.37(2H，d，J＝8.5Hz)，7.53(2H，d，J＝8.5Hz)，7.87(2H，d，J＝8.5Hz)，11.1(1H，s)。

MS：431.20(M+1) ⁺

Step 9

At 0 ℃ to N-{4-[4-(3-hydroxypropyl) phenyl]-5-[4-(methyl sulphonyl) phenyl]-1; the 3-thiazol-2-yl } add triphenylphosphine (68.5mg) and carbon tetrabromide (86.7mg) in tetrahydrofuran (THF) (0.7ml) solution of ethanamide (75mg), at 20 ℃ of 1h that stir the mixture.Reaction mixture is purified (using hexane/ethyl acetate (1: 2) as eluent) with preparation type silica gel thin-layer chromatography, obtains colorless oil N-{4-[4-(3-bromopropyl) phenyl]-5-[4-(methyl sulphonyl) phenyl]-1,3-thiazoles-2-yl } ethanamide.

¹H-NMR(DMSO-d ₆)，δ(ppm)：1.67(3H，s)，2.08-2.28(2H，m)，2.80(2H，t，J＝7.5Hz)，3.10(3H，s)，3.41(2H，t，J＝6.5Hz)，7.18(2H，d，J＝8.0Hz)，7.39(2H，d，J＝8.0Hz)，7.53(2H，d，J＝8.5Hz)，7.87(2H，d，J＝8.5Hz)，11.1(1H，s)。

MS：515.0(M+Na) ⁺

Step 10

N-{4-[4-(3-bromopropyl) phenyl]-5-[4-(methyl sulphonyl) phenyl]-1; the 3-thiazol-2-yl } N of ethanamide (82mg); add potassium phthalimide (30.8mg) in dinethylformamide (0.82ml) solution, at 50 ℃ of 2h that stir the mixture.Reaction mixture to 20 ℃ adds reaction mixture with water then, and the mixture ethyl acetate extraction is used the salt water washing, with evaporating after the dried over mgso, obtains crude product (92.0mg).Crude product is purified with preparation type silica gel thin-layer chromatography and is obtained N-{4-{4-[3-(1,3-dioxo-1,3-dihydro-2H-isoindole-2-yl) propyl group] phenyl }-5-[4-(methyl sulphonyl) phenyl]-1,3-thiazoles-2-yl } ethanamide.

¹H-NMR(CDCl ₃)，δ(ppm)：1.72(3H，s)，1.90-2.13(2H，m)，2.60-2.79(2H，m)，3.09(3H，s)，3.74(2H，t，J＝7.3Hz)，7.18(2H，d，J＝8.0Hz)，7.37(2H，d，J＝8.0Hz)，7.52(2H，d，J＝8.5Hz)，7.66-7.78(2H，m)，7.80-7.92(4H，m)，11.0(1H，s)。

MS：582.1(M+Na) ⁺

Step 11

N-{4-{4-[3-(1; 3-dioxo-1; 3-dihydro-2H-isoindole-2-yl) propyl group] phenyl }-5-[4-(methyl sulphonyl) phenyl]-1; the 3-thiazol-2-yl } add hydrazine monohydrate (46.1 μ l) in acetonitrile (0.5ml) solution of ethanamide (53.2mg), at 50 ℃ of 30min that stir the mixture.The evaporation volatile matter.Add chloroform (1ml) in the mixture, remove by filter insoluble substance.Filtrate is purified (using chloroform/methanol (10: 1) as eluent) with preparation type NH silica gel thin-layer chromatography, obtains yellow solid N-{4-[4-(3-aminopropyl) phenyl]-5-[4-(methyl sulphonyl) phenyl]-1,3-thiazoles-2-yl } ethanamide.

¹H-NMR(DMSO-d ₆)，δ(ppm)：1.69(3H，s)，1.69-1.88(2H，m)，2.60-2.74(2H，m)，2.76(2H，t，J＝7.0Hz)，3.09(3H，s)，7.15(2H，d，J＝8.5Hz)，7.36(2H，d，J＝8.5Hz)，7.53(2H，d，J＝8.5Hz)，7.86(2H，d，J＝8.5Hz)。

MS：428.2(M-H) ^-

Step 12

(phenyl (E)-{ [3-(4-{2-(acetylamino)-5-[4-(methyl sulphonyl) phenyl-1,3-thiazoles-4-yl }) propyl group] amino } methylene radical) the diamino acid di tert butyl carbonate is according to the similar approach preparation of preparation embodiment 31 steps 3.

¹H-NMR CDCl ₃)，δ(ppm)：1.49(9H，s)，1.50(9H，s)，1.87-1.97(2H，m)，2.01(3H，s)，2.69(2H，t，J＝8.1Hz)，3.09(3H，s)，3.41-3.54(2H，m)，7.16(2H，d，J＝8.1Hz)，7.36(2H，d，J＝8.1Hz)，7.54(2H，d，J＝8.5Hz)，7.87(2H，d，J＝8.4Hz)，8.38(1H，t，J＝5.1Hz)，9.87(1H，brs)，11.5(1H，s)。

MS：694.2(M+Na) ⁺

Step 13

¹H-NMR(DMSO-d ₆)，δ(ppm)：1.72-1.85(2H，m)，2.19(3H，s)，2.58-2.66(2H，m)，3.08-3.18(2H，m)，3.25(3H，s)，6.65-7.58(4H，brs)，7.21(2H，d，J＝8.4Hz)，7.36(2H，d，J＝8.1Hz)，7.56(2H，d，J＝8.4Hz)，7.67(1H，t，J＝5.1Hz)，7.89(2H，d，J＝8.4Hz)，12.4(1H，s)。

MS:472.1 (M+H) ⁺(free type)

Preparation embodiment 62:

Synthetic N-{4-(2-{4-[(amino oxygen base) methyl] phenyl } ethyl)-5-[4-(methyl sulphonyl) phenyl]-1,3-thiazoles-2-yl } ethanamide

Step 1

4-((E)-2-{2-(acetylamino)-5-[4-(methylthio group) phenyl]-1; 3-thiazole-4-yl } vinyl) methyl benzoate is with N-{5-[4-(methylthio group) phenyl]-4-formyl radical-1,3-thiazoles-2-yl } ethanamide is according to the similar approach preparation of preparation embodiment 53 steps 1.

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.12(3Hx1/3，s)，2.19(3Hx2/3，s)，2.54(3H，s)，3.85(3H，s)，6.55(1Hx1/3，d，J＝12.6Hz)，6.73(1Hx1/3，d，J＝12.6Hz)，7.17-7.72(8H+2Hx2/3，m)，7.84(2Hx1/3，d，J＝8.5Hz)，7.93(2Hx2/3，d，J＝8.5Hz)，12.31(1H，brs)。

MS：423.1(M-H) ^-

Step 2

4-((E)-2-{2-(acetylamino)-5-[4-(methyl sulphonyl) phenyl-1,3-thiazoles-4-yl } vinyl) methyl benzoate is according to the similar approach preparation of preparation embodiment 32 steps 2.

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.15(3Hx1/5，s)，2.21(3Hx4/5，s)，3.24(3Hx1/5，s)，3.30(3Hx4/5，s)，3.84(3Hx1/5，s)，3.85(3Hx4/5，s)，6.64(1Hx1/5，d，J＝12.6Hz)，6.81(1Hx1/5，d，J＝12.6Hz)，7.31(1Hx4/5，d，J＝15.6Hz)，7.52(1Hx4/5，d，J＝15.6Hz)，7.30-8.11(8H，m)，12.24(1Hx1/5，s)，12.49(1Hx4/5，s)。

MS：479.0(M+Na) ⁺

Step 3

4-(2-{2-(acetylamino)-5-[4-(methyl sulphonyl) phenyl]-1,3-thiazoles-4-yl } ethyl) methyl benzoate is according to the similar approach preparation of preparation embodiment 45 steps 6.

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.31(3H，s)，2.97-3.07(4H，m)，3.08(3H，s)，3.91(3H，s)，7.09(2H，d，J＝8.1Hz)，7.32(2H，d，J＝8.1Hz)，7.87(4H，d，J＝8.1Hz)，8.75(1H，s)。

MS：481.0(M+Na) ⁺

Step 4

N-{4-{2-[4-(hydroxymethyl) phenyl] ethyl }-5-[4-(methyl sulphonyl) phenyl]-1,3-thiazoles-2-yl } ethanamide is according to the similar approach preparation of preparation embodiment 53 steps 4.

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.17(3H，s)，2.96(4H，s)，3.24(3H，s)，4.43(2H，s)，7.06(2H，d，J＝8.1Hz)，7.18(2H，d，J＝8.1Hz)，7.50(2H，d，J＝8.4Hz)，7.91(2H，d，J＝8.4Hz)，12.33(1H，s)。

MS：453.1(M+Na) ⁺

Step 5

With N-{4-{2-[4-(hydroxymethyl) phenyl] ethyl }-5-[4-(methyl sulphonyl) phenyl]-1; the 3-thiazol-2-yl } ethanamide (100mg), N-hydroxyphthalimide (39.8mg), triphenylphosphine (64mg) and tetrahydrofuran (THF) (2ml) mix under nitrogen atmosphere; at 0 ℃ diethyl azodiformate (40wt% toluene solution) (0.111ml) is added solution then, mixture is stirred 5h at 20 ℃.In reaction mixture impouring saturated sodium bicarbonate aqueous solution, use chloroform extraction.Dried over mgso is used in organic layer salt water washing, filters the back evaporation.Crude product preparation type silica gel thin-layer chromatography purification (using chloroform/methanol (30: 1)) as eluent; obtain yellow spumescence N-{4-[2-(4-{[(1; 3-dioxo-1; 3-dihydro-2H-isoindole-2-yl) oxygen base] methyl } phenyl) ethyl]-5-[4-(methyl sulphonyl) phenyl]-1,3-thiazoles-2-yl } ethanamide.

¹H-NMR(CDCl ₃)，δ(ppm)：2.30(3H，s)，2.95-3.00(4H，m)，3.09(3H，s)，5.15(2H，s)，7.04(2H，d，J＝8.1Hz)，7.21-7.92(10H，m)，9.31(1H，brs)。

MS：598.1(M+Na) ⁺，574.0(M-H) ^-

Step 6

Under nitrogen atmosphere; to N-{4-[2-(4-{[(1; 3-dioxo-1; 3-dihydro-2H-isoindole-2-yl) oxygen base] methyl } phenyl) ethyl]-5-[4-(methyl sulphonyl) phenyl]-1; the 3-thiazol-2-yl } N of ethanamide (116.8mg); add methyl hydrazine (11.9 μ l) in dinethylformamide (1.1ml) solution, at 20 ℃ of 4h that stir the mixture.The vacuum concentration reaction mixture.Ethyl acetate is added resistates, the filtering precipitation.Vacuum concentrated filtrate obtains rough yellow solid (105.1mg).Crude product is purified (using chloroform/methanol (30: 1) as eluent) with preparation type silica gel thin-layer chromatography, obtains buff powder.The powder that obtains washs with acetonitrile, filters collecting precipitation, obtains white solid N-{4-(2-{4-[(amino oxygen base) methyl] phenyl } ethyl)-5-[4-(methyl sulphonyl) phenyl]-1,3-thiazoles-2-yl } ethanamide (8.4mg).

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.17(3H，s)，2.91-3.02(4H，m)，3.24(3H，s)，4.51(2H，s)，5.98(2H，s)，7.09(2H，d，J＝8.1Hz)，7.19(2H，d，J＝8.1Hz)，7.51(2H，d，J＝8.4Hz)，7.91(2H，d，J＝8.1Hz)，12.33(1H，brs)。

MS：468.0(M+H) ⁺

Preparation embodiment 63:

Synthetic N-{4-{2-[4-({ [amino (imino-) methyl] amino } methyl) phenyl] ethyl }-5-[4-(methyl sulphonyl) phenyl]-1,3-thiazoles-2-yl } acetamide hydrochloride

Step 1

N-{4-{2-[4-(brooethyl) phenyl] ethyl }-5-[4-(methyl sulphonyl) phenyl]-1; the 3-thiazol-2-yl } ethanamide with N-(4-[2-{4-(hydroxymethyl) phenyl } ethyl]-5-[4-(methyl sulphonyl) phenyl]-1,3-thiazoles-2-yl) ethanamide is according to the similar approach preparation of preparation embodiment 61 steps 9.

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.17(3H，s)，2.90-3.10(4H，m)，3.23(3H，s)，4.67(2H，s)，7.10(2H，d，J＝8.1Hz)，7.31(2H，d，J＝8.1Hz)，7.48(2H，d，J＝8.4Hz)，7.90(2H，d，J＝8.4Hz)，12.33(21H，s)。

MS：491.0(M-H) ^-

Step 2

N-{4-{2-[4-(brooethyl) phenyl] ethyl }-5-[4-(methyl sulphonyl) phenyl]-1; the 3-thiazol-2-yl } N of ethanamide (70mg); add diformazan acylimino (diformimide) sodium salt (13.5mg) in dinethylformamide (1ml) solution, at 20 ℃ of 10min that stir the mixture.Add entry in the reaction mixture, the mixture ethyl acetate extraction washes twice with water, uses dried over mgso, and evaporation obtains rough dicarboximide (diformimide) compound.The dicarboximide compound is suspended in concentrated hydrochloric acid (200 μ l), ethanol (2ml) and methyl alcohol (0.5ml).At 20 ℃ of stirred reaction mixture 3h, stir 3h at 50 ℃ then.The evaporation volatile matter.Add saturated sodium bicarbonate aqueous solution in the resistates; the mixture chloroform extraction with evaporating after the dried over mgso, obtains rough N-{4-(2-{4-[amino methyl] phenyl } ethyl)-5-[4-(methyl sulphonyl) phenyl]-1; the 3-thiazol-2-yl } ethanamide, crude product is directly used in next step.

MS：428.8(M+H) ⁺

Step 3

(ethyl (E)-{ [4-(2-{2-(acetylamino)-5-[4-(methyl sulphonyl) phenyl-1,3-thiazoles-4-yl }) benzyl] amino } methylene radical) the diamino acid di tert butyl carbonate is according to the similar approach preparation of preparation embodiment 31 steps 3.

¹H-NMR(CDCl ₃)，δ(ppm)：1.48(9H，s)，1.51(9H，s)，2.30(3H，s)，2.98(4H，s)，3.08(3H，s)，4.57(2H，d，J＝5.1Hz)，7.04(2H，d，J＝8.1Hz)，7.17(2H，d，J＝8.1Hz)，7.38(2H，d，J＝8.4Hz)，7.91(2H，d，J＝8.4Hz)，8.54(1H，t，J＝5.1Hz)，8.79(1H，s)，11.53(1H，s)。

MS：672.2(M+H) ⁺

Step 4

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.18(3H，s)，2.90-3.05(4H，m)，3.25(3H，s)，4.31(2H，d，J＝6.2Hz)，6.65-7.73(4H，brs)，7.14(2H，d，J＝8.1Hz)，7.18(2H，d，J＝8.1Hz)，7.52(2H，d，J＝8.4Hz)，7.93(2H，d，J＝8.4Hz)，12.35(1H，s)。

MS：506.0(M-H) ^-

Preparation embodiment 64:

Synthetic 4-(2-(acetylamino)-4-[2-(4-{[amino (imino-) methyl] amino } phenyl) ethyl]-1,3-thiazoles-5-yl } methyl) the methyl benzoate hydrochloride

Step 1

4-(4-iodophenyl)-2-ketobutyric acid ethyl ester prepares with the similar approach of 3-(4-iodophenyl) ethyl propionate according to preparation embodiment 47 steps 2.

¹H-NMR(CDCl ₃)，δ(ppm)：1.35(3H，t，J＝7.0Hz)，2.90(2H，t，J＝7.5Hz)，3.15(2H，t，J＝7.5Hz)，4.31(2H，q，J＝7.0Hz)，6.96(2H，d，J＝8.0Hz)，7.61(8.5Hz)。

MS：331.0(M-H) ^-

Step 2

3-bromo-4-(4-iodophenyl)-2-ketobutyric acid ethyl ester is according to the similar approach preparation of preparation embodiment 46 steps 1.

¹H-NMR(CDCl ₃)，δ(ppm)：1.38(3H，t，J＝7.0Hz)，3.19(1H，dd，J＝7.5，14.6Hz)，3.47(1H，dd，J＝7.5，14.6Hz)，4.36(2H，q，J＝7.0Hz)，5.21(1H，dd，J＝7.5，7.5Hz)，7.00(2H，d，J＝8.5Hz)，7.65(2H，d，J＝8.5Hz)。

MS：369.2

Step 3

3-bromo-4-(4-iodophenyl)-2-ketobutyric acid ethyl ester (1.32g) is dissolved in ethanol (26ml), then thiocarbamide (244mg) is added solution.With the reaction mixture 1h that under nitrogen atmosphere, refluxes.Vacuum-evaporation refrigerative reaction mixture.Crude product and ether grind and obtain light yellow solid 2-amino-5-(4-iodine benzyl)-1,3-thiazoles-4-ethyl formate hydrobromate.

¹H-NMR(DMSO-d ₆)，δ(ppm)：1.27(3H，t，J＝7.0Hz)，4.28(2H，q，J＝7.0Hz)，4.31(2H，s)，7.10(2H，d，J＝8.5Hz)，7.69(2H，d，J＝8.5Hz)。

MS：389.0(M+H) ⁺，411.0(M+Na) ⁺

Step 4

Under nitrogen atmosphere, 2-amino-5-(4-iodine benzyl)-1,3-thiazoles-4-ethyl formate hydrobromate (1.386g) is dissolved in methylene dichloride (14ml).At 0 ℃ pyridine (0.765ml) and Acetyl Chloride 98Min. (0.336ml) are added drop-wise to solution then.At 20 ℃ of stirred reaction mixture 1h.Organic solution is used dried over mgso, vacuum concentration with 1N hydrochloric acid, water and salt water washing.Resistates washs with diisopropyl ether, obtains white solid 2-(acetylamino)-5-(4-iodine benzyl)-1,3-thiazoles-4-ethyl formate.

¹H-NMR(DMSO-d ₆)，δ(ppm)：1.27(3H，t，J＝7.0Hz)，2.09(3H，s)，4.26(2H，q，J＝7.0Hz)，4.43(2H，s)，7.10(2H，d，J＝8.0Hz)，7.67(2H，d，J＝8.0Hz)，12.44(1H，s)。

MS：431.0(M+H) ⁺，453.0(M+Na) ⁺

Step 5

N-[4-formyl radical-5-(4-iodine benzyl)-1,3-thiazoles-2-yl] ethanamide is according to the similar approach preparation of preparation embodiment 46 steps 4.

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.11(3H，s)，4.48(2H，s)，7.11(2H，d，J＝8.5Hz)，7.68(2H，d，J＝8.5Hz)，10.00(1H，s)。

MS：409.0(M+Na) ⁺

Step 6

N-{5-(4-iodine benzyl)-4-[2-(4-nitrophenyl) vinyl]-1,3-thiazoles-2-yl } ethanamide is according to the similar approach preparation of preparation embodiment 45 steps 5.

¹H-NMR(CDCl ₃)，δ(ppm)：2.07(3Hx2/3，s)，2.15(3Hx1/3，s)，3.96(2Hx2/3，s)，4.12(2Hx1/3，s)，6.63(1Hx2/3，d，J＝12.6Hz)，6.70(1Hx2/3，d，J＝12.6Hz)，6.94(2Hx2/3，d，J＝8.0Hz)，6.99(2Hx1/3，d，J＝8.0Hz)，7.12(1Hx1/3，d，J＝15.6Hz)，7.25(1Hx1/3，d，J＝15.6Hz)，7.39(2Hx2/3，d，J＝9.0Hz)，7.56(2Hx1/3，d，J＝8.5Hz)，7.62(2Hx2/3，d，J＝8.0Hz)，7.65(2Hx1/3，d，J＝8.5Hz)，8.00(2Hx2/3，d，J＝8.5Hz)，8.22(2Hx1/3，d，J＝8.5Hz)，9.85(1Hx1/3，s)，10.18(1Hx2/3，s)。

MS：528.0(M+H) ⁺

Step 7

N-{5-(4-iodine benzyl)-4-[(Z)-2-(4-nitrophenyl) vinyl]-1, the 3-thiazol-2-yl } ethanamide and N-{5-(4-iodine benzyl)-4-[(E)-2-(4-nitrophenyl) vinyl]-1, the 3-thiazol-2-yl } mixture (Z: E=2: 1) methyl alcohol (558.2mg) (2.8ml) and N of ethanamide, add in dinethylformamide (5.5ml) solution acid chloride (II) (49.6mg), 1, two (diphenylphosphino) propane (109mg) of 3-and triethylamine (308 μ l).In solution, feed CO (carbon monoxide converter) gas 30min at 25 ℃.Stirred reaction mixture 6h under 70 ℃, carbon monoxide atmosphere then.Reaction mixture to 25 ℃ with the ethyl acetate dilution, is used the salt water washing, with evaporating after the dried over mgso, obtains rough yellow foam (645mg).Rough foam is purified (with toluene/ethyl acetate (2: 1-3: 2) as eluent) with the silica gel flash column chromatography, obtain N-{5-(4-(methoxycarbonyl) benzyl)-4-[(Z)-2-(4-nitrophenyl) vinyl with the ether grinding]-1, the 3-thiazol-2-yl } ethanamide and N-{5-(4-(methoxycarbonyl) benzyl)-4-[(E)-2-(4-nitrophenyl) vinyl]-1,3-thiazoles-2-yl } the yellow solid mixture (Z: E=2: 3) of ethanamide.

¹H-NMR(CDCl ₃)，δ(ppm)：2.09(3Hx2/5，s)，2.20(3Hx3/5，s)，3.91(3H，s)，4.10(2Hx2/5，s)，4.25(2Hx3/5，s)，7.27(2Hx2/5，s)，7.14(1Hx3/5，d，J＝15.6Hz)，7.25(2Hx2/5，d，J＝9.0Hz)，7.29(1Hx3/5，d，J＝15.6Hz)，7.31(2Hx3/5，d，J＝8.5Hz)，7.38(2Hx2/5，d，J＝9.0Hz)，7.57(2Hx3/5，d，J＝8.5Hz)，7.97(2Hx2/5，d，J＝8.5Hz)，7.99(2Hx2/5，d，J＝9.0Hz)，8.00(2Hx3/5，d，J＝8.5Hz)，8.20(2Hx3/5，d，J＝9.0Hz)，9.55(1Hx3/5，brs)，10.11(1Hx2/5，brs)。

MS：460.1(M+Na) ⁺

Step 8

4-({ 2-(acetylamino)-4-[2-(4-aminophenyl) ethyl]-1,3-thiazoles-5-yl } methyl) methyl benzoate is according to the similar approach preparation of preparation embodiment 45 steps 6.

¹H-NMR(CDCl ₃)，δ(ppm)：2.20(3H，s)，2.80(4H，s)，3.40-3.67(2H，m)，3.83(2H，s)，3.90(3H，s)，6.57(2H，d，J＝8.5Hz)，6.84(2H，d，J＝8.5Hz)，7.09(2H，d，J＝8.0Hz)，7.91(2H，d，J＝8.5Hz，8.96(1H，brs)。

MS：410.2(M+H) ⁺，432.2(M+Na) ⁺

Step 9

4-[(2-(acetylamino)-4-{2-[4-({ (Z)-[(tert-butoxycarbonyl) amino] [(tert-butoxycarbonyl) imino-] methyl } amino) phenyl] ethyl }-1,3-thiazoles-5-yl) methyl] methyl benzoate is according to the similar approach preparation of preparation embodiment 31 steps 3.

¹H-NMR(CDCl ₃)，δ(ppm)：1.49(9H，s)，1.54(9H，s)，2.20(2H，s)，2.83(4H，s)，3.88(2H，s)，3.89(3H，s)，7.03(2H，d，J＝8.5Hz)，7.17(2H，d，J＝8.0Hz)，7.44(2H，d，J＝8.0Hz)，7.93(2H，d，J＝8.5Hz)，9.09(1H，brs)，10.24(1H，s)，11.64(1H，s)。

MS：652.3(M+H) ⁺，652.3(M+Na) ⁺

Step 10

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.09(3H，s)，2.86(4H，s)，3.83(3H，s)，3.96-4.10(2H，m)，7.13(2H，d，J＝8.5Hz)，7.24(2H，d，J＝9.0Hz)，7.28(2H，d，J＝8.5Hz)，7.35(4H，s)，7.89(2H，d，J＝8.0Hz)，9.71(1H，s)，12.01(1H，s)。

MS:452.2 (M+H)-(free type)

Preparation embodiment 65:

Synthetic 4-(2-(acetylamino)-4-[2-(4-{[amino (imino-) methyl] amino } phenyl) ethyl]-1,3-thiazoles-5-yl } methyl)-N, N-dimethyl benzamide hydrochloride

Step 1

4-{[2-(acetylamino)-4-(2-{4-[(tert-butoxycarbonyl) amino] phenyl } ethyl)-1,3-thiazoles-5-yl] methyl } the methyl benzoate similar approach preparation of the compound of preparation embodiment 64 steps 8 according to preparation embodiment 52 steps 1.

¹H-NMR(CDCl ₃)，δ(ppm)：1.52(9H，s)，2.23(3H，s)，2.81(4H，s)，3.86(2H，s)，3.90(3H，s)，6.93(2H，d，J＝8.0Hz)，7.13(2H，d，J＝8.5Hz)，7.19(2H，d，J＝8.0Hz)，7.91(2H，d，J＝8.5Hz)，8.48-9.69(1H，brs)。

MS：510.2(M+H) ⁺，532.3(M+Na) ⁺

Step 2

With 4-{[2-(acetylamino)-4-(2-{4-[(tert-butoxycarbonyl) amino] phenyl } ethyl)-1,3-thiazoles-5-yl] methyl } methyl benzoate (287.7mg), 1N sodium hydroxide (1.41ml) and ethanol (2.9ml) mixes, with the mixture 3h that refluxes.After being cooled to 25 ℃, vacuum is removed organic solvent.The aqueous solution leaches precipitation and obtains the 312.5mg light yellow solid with 1N hcl acidifying (pH=4), vacuum.Under nitrogen atmosphere, solid is dissolved in pyridine (4.3ml), at 0 ℃ Acetyl Chloride 98Min. (0.12ml) is added drop-wise to solution then.At 25 ℃ of stirred reaction mixture 3h, vacuum is removed pyridine.Resistates is suspended in water, uses the 1N hcl acidifying.The vacuum collection precipitation.Solid water and ether washing obtain light yellow solid 4-{[2-(acetylamino)-4-(2-{4-[(tert-butoxycarbonyl) amino] phenyl } ethyl)-1,3-thiazoles-5-yl] methyl } phenylformic acid.

¹H-NMR(DMSO-d ₆)，δ(ppm)：1.47(9H，s)，2.08(3H，s)，2.70-2.90(4H，m)，3.92(2H，s)，6.99(2H，d，J＝8.4Hz)，7.10(2H，d，J＝8.0Hz)，7.33(2H，d，J＝8.0Hz)，7.81(2H，d，J＝8.4Hz)，9.24(1H，s)，12.00(1H，s)，12.84(1H，brs)。

MS：494.4(M-H) ^-

Step 3

4-{[2-(acetylamino)-4-(2-{4-[(tert-butoxycarbonyl) amino] phenyl } ethyl)-1; 3-thiazole-5-yl] methyl } add methylamine hydrochloride (10.7mg), I-hydroxybenzotriazole (20.4mg) and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (55.3 μ l) in the 0.5ml dichloromethane solution of phenylformic acid (50mg), then at 25 ℃ of 3h that stir the mixture.Reaction mixture dilutes with the 10ml chloroform, water and salt water washing.Organic layer evaporates with the dried over mgso final vacuum.Resistates and ethyl acetate and diisopropyl ether are ground, and filter to collect to obtain light yellow solid { 4-[2-(2-(acetylamino)-5-{4-[(dimethylamino) carbonyl] benzyl }-1,3-thiazoles-4-yl) ethyl] phenyl } t-butyl carbamate.

¹H-NMR(CDCl ₃)，δ(ppm)：1.51(9H，s)，2.23(3H，s)，2.83(4H，s)，2.95(3H，s)，3.09(3H，s)，3.82(2H，s)，6.47-6.81(1H，brs)，6.94(2H，d，J＝8.1Hz)，7.05(2H，d，J＝8.1Hz)，7.18(2H，d，J＝8.1Hz)，7.28(2H，d，J＝8.1Hz)，8.50-9.09(1H，brs)。

MS：523.3(M+H) ⁺，545.2(M+Na) ⁺

Step 4

To at 0 ℃ 4-[2-(2-(acetylamino)-5-{4-[(dimethylamino) carbonyl] benzyl-1,3-thiazoles-4-yl) ethyl] phenyl } t-butyl carbamate (39.1mg) and trifluoroacetic acid (1ml) mixing.At 25 ℃ of stirred reaction mixture 2h, vacuum concentration.Resistates is added chloroform (20ml) and 1N sodium hydroxide (10ml).Isolate organic layer, use dried over mgso, evaporation obtains yellow oil (33.3mg).With crude yellow oil shape thing N, N '-two (tert-butoxycarbonyl)-1H-pyrazoles-1-carbonamidine (45.8mg) and tetrahydrofuran (THF) (0.5ml) mix under nitrogen atmosphere, at 25 ℃ of 34h that stir the mixture.Add N in the reaction mixture, N '-two (tert-butoxycarbonyl)-1H-pyrazoles-1-carbonamidine (11mg) is at 50 ℃ of 3h that stir the mixture.Vacuum concentrated mixture then.Resistates preparation type silica gel thin-layer chromatography purification (using chloroform/methanol (20: 1)) as eluent; obtain colorless oil [(E)-({ 4-[2-(2-(acetylamino)-5-{4-[(dimethylamino) carbonyl] benzyl }-1,3-thiazoles-4-yl) ethyl] phenyl } amino) methylene radical] diamino acid di tert butyl carbonate (12.9mg).

¹H-NMR(CDCl ₃)，δ(ppm)：1.50(9H，s)，1.54(9H，s)，2.21(3H，s)，2.85(4H，s)，2.96(3H，brs)，3.08(3H，brs)，3.86(2H，s)，7.06(2H，d，J＝8.5Hz)，7.14(2H，d，J＝8.1Hz)，7.33(2H，d，J＝8.5Hz)，7.46(2H，d，J＝8.5Hz)，8.81-9.21(1H，brs)，10.25(1H，s)，11.63(1H，s)。

MS：665.3(M+H) ⁺，687.2(M+Na) ⁺

Step 5

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.09(3H，s)，2.86(4H，s)，2.88(3H，s)，2.96(3H，s)，3.97(2H，s)，7.12(2H，d，J＝8.4Hz)，7.16(2H，d，J＝8.1Hz)，7.23(2H，d，J＝8.4Hz)，7.32(2H，d，J＝8.1Hz)，7.34(4H，s)，9.70(1H，s)，12.01(1H，s)。

MS:465.2 (M+H) ⁺(free type)

Preparation embodiment 66:

Synthetic 4-(2-(acetylamino)-4-[2-(4-{[amino (imino-) methyl] amino } phenyl) ethyl]-1,3-thiazoles-5-yl } methyl)-the N-methyl-benzamide hydrochloride

Step 1

4-[2-(2-(acetylamino)-5-{4-[(methylamino) carbonyl] benzyl }-1,3-thiazoles-4-yl) ethyl] phenyl } the t-butyl carbamate similar approach preparation of the compound of preparation embodiment 65 steps 2 according to preparation embodiment 65 steps 3.

¹H-NMR(CDCl ₃)，δ(ppm)：1.52(9H，s)，2.23(3H，s)，2.78-2.89(4H，m)，3.00(3H，d，J＝4.8Hz)，3.83(2H，s)，6.20(2H，d，J＝4.8Hz)，6.36-6.78(1H，brs)，6.94(2H，d，J＝8.4Hz)，7.05(2H，d，J＝8.4Hz)，7.18(2H，d，J＝8.4Hz)，7.63(2H，d，J＝8.4Hz)，8.60-9.09(1H，brs)。

MS：509.2(M+H) ⁺，531.2(M+Na) ⁺

Step 2

[(E)-({ 4-[2-(2-(acetylamino)-5-{4-[(methylamino) carbonyl] benzyl }-1,3-thiazoles-4-yl) ethyl] phenyl } amino) methylene radical] the diamino acid di tert butyl carbonate is according to the similar approach preparation of preparation embodiment 65 steps 4.

¹H-NMR(CDCl ₃)，δ(ppm)：1.49(9H，s)，1.54(9H，s)，2.22(3H，s)，2.83(4H，s)，2.99(3H，d，J＝4.8Hz)，3.86(2H，s)，6.16(1H，d，J＝4.0Hz)，7.01(2H，d，J＝8.4Hz)，7.13(2H，d，.＝8.4Hz)，7.42(2H，d，J＝8.4Hz)，7.66(2H，d，J＝8.4Hz)，8.77-9.10(1H，brs)，10.24(1H，s)，11.62(1H，s)。

MS：651.3(M+H) ⁺，673.3(M+Na) ⁺

Step 3

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.08(3H，s)，2.76(3H，d，J＝4.8Hz)，2.86(4H，s)，3.98(2H，s)，7.13(2H，d，J＝8.4Hz)，7.19(2H，d，J＝8.1Hz)，7.23(2H，d，J＝8.4Hz)，7.30(4H，s)，7.74(2H，d，J＝8.1Hz)，8.38(2H，d，J＝4.4Hz)，9.62(1H，s)，11.99(1H，s)。

MS:451.3 (M+H) ^-(free type)

Preparation embodiment 67:

Synthetic N-{4-[2-(4-{[amino (imino-) methyl] amino } phenyl) ethyl]-the 5-[(dimethylamino) methyl]-1,3-thiazoles-2-yl } the ethanamide dihydrochloride

Step 1

N-{4-[(Z)-2-(4-nitrophenyl) vinyl]-1,3-thiazoles-2-yl } adding-dimethylamine hydrochloride (169mg) and Paraformaldehyde 96 (62.2mg) in acetate (3ml) solution of ethanamide (500mg), stir 2h with mixture 100 ℃ (bathing temperature).Solvent removed in vacuo, mixture is adjusted to pH=9 with saturated sodium bicarbonate aqueous solution, uses ethyl acetate extraction.Organic layer salt water washing is with evaporating after the dried over mgso.Crude compound silica gel flash column chromatography purification (using methylene chloride (100: 1) → (20: 1)) as eluent, obtain yellow amorphous substance N-{5-[(dimethylamino) methyl]-4-[(Z)-2-(4-nitrophenyl) vinyl]-1,3-thiazoles-2-yl } ethanamide.

¹H-NMR(CDCl ₃)，δ(ppm)：2.08(3H，s)，2.26(6H，s)，3.47(2H，s)，6.63(1H，d，J＝12.6Hz)，6.70(1H，d，J＝12.6Hz)，7.43(2H，d，J＝9.0Hz)，8.03(2H，d，J＝9.0Hz)，10.20(1H，brs)。

MS：347(M+H) ⁺，369(M+Na) ⁺

Step 2

N-{4-[2-(4-aminophenyl) ethyl]-the 5-[(dimethylamino) methyl]-1,3-thiazoles-2-yl } ethanamide is according to the similar approach preparation of preparation embodiment 45 steps 6.

¹H-NMR(CDCl ₃)，δ(ppm)：2.19(6H，s)，2.23(3H，s)，2.80(4H，s)，3.30(2H，s)，3.56(2H，s)，6.60(2H，d，J＝8.4Hz)，6.91(2H，d，J＝8.4Hz)，8.54-8.84(1H，brs)。

MS：317.2(M-H) ^-

Step 3

((Z)-{ [4-(2-{2-(acetylamino)-5-[(dimethylamino) methyl]-1,3-thiazoles-4-yl } ethyl) phenyl] amino } methylene radical) the diamino acid di tert butyl carbonate is according to the similar approach preparation of preparation embodiment 45 steps 7.

¹H-NMR(CDCl ₃)，δ(ppm)：1.50(9H，s)，1.53(9H，s)，2.21(6H，s)，2.22(3H，s)，2.87(4H，s)，3.36(2H，s)，7.09(2H，d，J＝8.5Hz)，7.46(2H，d，J＝8.5Hz)，8.89-9.97(1H，brs)，10.24(1H，s)，11.63(1H，s)。

MS：561.3(M+H) ⁺，583.3(M+Na) ⁺

Step 4

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.16(3H，s)，2.66(3H，s)，2.68(3H，s)，2.96(4H，s)，4.37(2H，d，J＝4.8Hz)，7.15(2H，d，J＝8.4Hz)，7.32(2H，d，J＝8.4Hz)，7.51(4H，s)，10.08(1H，s)，10.64(1H，t，J＝4.8Hz)，12.33(1H，s)。

MS：361.1(M+H) ⁺

Preparation embodiment 68:

Synthetic N-{5-[(4-ethanoyl-1-piperazinyl) methyl]-4-[2-(4-{[amino (imino-) methyl] amino } phenyl) ethyl]-1,3-thiazoles-2-yl } the ethanamide dihydrochloride

Step 1

N-{5-[(4-ethanoyl-1-piperazinyl) methyl]-4-[(Z)-and 2-(4-nitrophenyl) vinyl]-1; the 3-thiazol-2-yl } ethanamide N-{4-[(Z)-2-(4-nitrophenyl) vinyl]-1,3-thiazoles-2-yl } ethanamide is according to the similar approach preparation of preparation embodiment 67 steps 1.

¹H-NMR(CDCl ₃)，δ(ppm)：2.08(6H，s)，2.34-2.59(4H，m)，3.41-3.53(2H，m)，3.56(2H，s)，3.58-3.69(2H，m)，6.62(1H，d，J＝12.6Hz)，6.68(1H，d，J＝12.6Hz)，7.45(2H，d，J＝8.5Hz)，8.05(2H，d，J＝9.0Hz)，10.18(1H，s)。

MS：452.0(M+Na) ⁺

Step 2

Under nitrogen atmosphere with N-{5-[(4-ethanoyl-1-piperazinyl) methyl]-4-[(Z)-2-(4-nitrophenyl) vinyl]-1; the 3-thiazol-2-yl } ethanamide (1080mg), methyl alcohol (2ml), tetrahydrofuran (THF) (2ml), acetate (0.3ml) mix, mix with 10% palladium carbon (150mg) then.3h stirs the mixture under 3atm nitrogen atmosphere, 25 ℃.Reaction mixture filters by Celite pad, and vacuum concentrated filtrate obtains crude product (192.3mg).Add saturated sodium bicarbonate aqueous solution in the resistates, the mixture chloroform extraction.Dried over mgso is used in organic layer salt water washing, and vacuum concentration obtains pink amorphous substance (124.7mg).With pink amorphous substance (124.7mg), N, N '-two (tert-butoxycarbonyl)-1H-pyrazoles-1-carbonamidine (93.6mg) and tetrahydrofuran (THF) (2ml) mix under nitrogen atmosphere.At 25 ℃ of stirred reaction mixture 14h., vacuum concentration.Resistates preparation type silica gel thin-layer chromatography purification (using chloroform/methanol (20: 1)) as eluent; obtain colorless oil ((Z)-{ [4-(2-{2-(acetylamino)-5-[(4-ethanoyl-1-piperazinyl) methyl]-1,3-thiazoles-4-yl } ethyl) phenyl] amino } methylene radical) diamino acid di tert butyl carbonate (121.1mg).

¹H-NMR(CDCl ₃)，δ(ppm)：1.50(9H，s)，1.53(9H，s)，2.06(3H，s)，2.24(3H，s)，2.20-2.32(2H，m)，2.33-2.44(2H，m)，2.74-2.96(4H，m)，3.30-3.45(4H，m)，3.52-3.65(2H，m)，7.04(2H，d，J＝8.5Hz)，7.45(2H，d，J＝8.5Hz)，8.85-10.17(1H，brs)，10.25(1H，s)，11.63(1H，s)。

MS：644.3(M+H) ⁺，666.1(M+H) ⁺

Step 3

¹H-NMR (DMSO-d ₆), δ (ppm): 2.03 (3H, s), 2.16 (3H, s), 2.75-3.15 (8H, m), 3.16-3.63 (4H, m), 4.40 (2H, s), 7.15 (2H, d, J=8.0Hz), 7.32 (2H, d, J=8.0Hz), 7.49 (4H, s), 10.07 (1H, s), 11.29 (1H, brs), 12.33 (1H, s) MS:444.2 (M+H) ⁺(free type)

Preparation embodiment 69:

Synthetic N-(4-[2-(4-{[amino (imino-) methyl] amino } phenyl) ethyl]-5-{[4-(methyl sulphonyl)-1-piperazinyl] methyl }-1,3-thiazoles-2-yl) the ethanamide dihydrochloride

Step 1

N-{5-{[4-(methyl sulphonyl)-1-piperazinyl] methyl }-4-[(Z)-and 2-(4-nitrophenyl) vinyl]-1; the 3-thiazol-2-yl } ethanamide N-{4-[(Z)-2-(4-nitrophenyl) vinyl]-1,3-thiazoles-2-yl } ethanamide is according to the similar approach preparation of preparation embodiment 67 steps 1.

¹H-NMR(CDCl ₃)，δ(ppm)：2.08(3H，s)，2.54-2.66(4H，m)，2.80(3H，s)，3.19-3.34(4H，m)，3.58(2H，s)，6.61(1H，d，J＝12.1Hz)，6.69(1H，d，J＝12.1Hz)，7.45(2H，d，J＝8.5Hz)，8.04(2H，d，J＝8.5Hz)，10.09(1H，s)。

MS：467.2(M+H) ⁺，488.1(M+Na) ⁺

Step 2

[(Z)-({ 4-[2-(2-(acetylamino)-5-{[4-(methyl sulphonyl)-1-piperazinyl] methyl }-1,3-thiazoles-4-yl) ethyl] phenyl } amino) methylene radical] the diamino acid di tert butyl carbonate is according to the similar approach preparation of preparation embodiment 68 steps 2.

¹H-NMR(CDCl ₃)，δ(ppm)：1.50(9H，s)，1.54(9H，s)，2.23(3H，s)，2.41-2.56(4H，m)，2.76(3H，s)，2.80-2.89(4H，m)，3.12-3.27(4H，m)，3.42(2H，s)，7.05(2H，d，J＝8.5Hz)，7.45(2H，d，J＝8.5Hz)，8.57-9.61(1H，brs)，10.25(1H，s)，11.63(1H，s)。

MS：680.3(M+H) ^-，702.2(M+Na) ^-

Step 3

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.16(3H，s)，2.97(4H，s)，3.00(3H，s)，3.05-3.28(4H，m)，3.28-3.48(2H，m)，3.59-3.81(2H，m)，4.35-4.60(2H，brs)，7.16(2H，d，J＝8.1Hz)，7.32(2H，d，J＝8.1Hz)，7.39(4H，s)，9.84(1H，s)，10.64-10.89(1H，brs)，12.34(1H，s)。

MS:480.1 (M+H) ^-(free type)

Preparation embodiment 70:

Synthetic N-[4-[2-(4-{[amino (imino-) methyl] amino } phenyl) ethyl]-5-(4-thiomorpholine ylmethyl)-1,3-thiazoles-2-yl] the ethanamide dihydrochloride

Step 1

N-[4-[(Z)-2-(4-nitrophenyl) vinyl]-5-(4-thiomorpholine ylmethyl)-1, the 3-thiazol-2-yl] ethanamide N-{4-[(Z)-2-(4-nitrophenyl) vinyl]-1,3-thiazoles-2-yl } ethanamide is according to the similar approach preparation of preparation embodiment 67 steps 1.

¹H-NMR(CDCl ₃)，δ(ppm)：2.08(3H，s)，2.57-2.86(8H，m)，3.53(2H，s)，6.62(1H，d，J＝12.6Hz)，6.68(1H，d，J＝12.6Hz)，7.43(2H，d，J＝9.0Hz)，8.0332(2H，d，J＝9.0Hz)，10.16(1H，s)。

MS：405.1(M+H) ⁺，427.1(M+Na) ⁺

Step 2

{ (Z)-[(4-{2-[2-(acetylamino)-5-(4-thiomorpholine ylmethyl)-1,3-thiazoles-4-yl] ethyl } phenyl) amino] methylene radical } the diamino acid di tert butyl carbonate is according to the similar approach preparation of preparation embodiment 68 steps 2.

¹H-NMR(CDCl ₃)，δ(ppm)：1.50(9H，s)，1.53(9H，s)，2.22(3H，s)，2.63(8H，s)，2.80-2.90(4H，m)，3.39(2H，s)，7.06(2H，d，J＝8.5Hz)，7.45(2H，d，J＝8.5Hz)，8.82-9.39(1H，brs)，10.24(1H，s)，11.63(1H，s)。

MS：619.3(M+H) ⁺，641.2(M+Na) ⁺

Step 3

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.16(3H，s)，2.69-2.87(2H，m)，2.97(4H，s)，3.02-3.19(4H，m)，3.48-3.61(2H，m)，4.42(2H，s)，7.15(2H，d，J＝8.4Hz)，7.31(2H，d，J＝8.4Hz)，7.40(4H，s)，9.86(1H，s)，1051-10.69(1H，brs)，12.34(1H，s)。

MS:419.2 (M+H) ^-(free type)

Preparation embodiment 71:

Synthetic 2-(acetylamino)-4-[2-(4-{[amino (imino-) methyl] amino } phenyl) ethyl]-N-[2-(dimethylamino)-2-oxoethyl]-1,3-thiazoles-5-carboxamide hydrochloride

Step 1

(4-{2-[2-(acetylamino)-5-({ [2-(dimethylamino)-2-oxoethyl] amino } carbonyl)-1; 3-thiazole-4-yl] ethyl } phenyl) t-butyl carbamate is with 2-(acetylamino)-4-(2-{4-[(tert-butoxycarbonyl) amino] phenyl } ethyl)-1,3-thiazoles-5-formic acid is according to the similar approach preparation of preparation embodiment 32 steps 1.

¹H-NMR(200MHz，DMSO-d ₆)，δ(ppm)：1.46(9H，s)，2.15(3H，s)，2.72，2.85(3H，s)，2.89，2.98(3H，s)，3.16(4H，m)，4.01(2H，m)，7.07(2H，d，J＝8.2Hz)，7.32(2H，d，J＝8.2Hz)，7.87-7.95(1H，m)，9.21(1H，s)，12.36(1H，s)。

MS：490(M+H) ⁺

Step 2

2-(acetylamino)-4-[2-(4-aminophenyl) ethyl]-N-[2-(dimethylamino)-2-oxoethyl]-1,3-thiazoles-5-carboxamide hydrochloride is according to the similar approach preparation of preparation embodiment 31 steps 2.

White powder

¹H-NMR(200MHz，DMSO-d ₆)，δ(ppm)：2.16(3H，s)，2.85(3H，s)，2.86-2.98(5H，m)，3.22(2H，dd，J＝8.9，5.3Hz)，4.01(2H，d，J＝5.3Hz)，7.27(2H，d，J＝8.5Hz)，7.33(2H，d，J＝8.5Hz)，7.94(1H，t，J＝5.3Hz)，10.15(2H，br)，12.38(1H，s)。

MS:390 (M+H) ⁺(free type)

Step 3

{ (Z)-[(4-{2-[2-(acetylamino)-5-({ [2-(dimethylamino)-2-oxoethyl] amino } carbonyl)-1,3-thiazoles-4-yl] ethyl } phenyl) amino] methylene radical } the diamino acid di tert butyl carbonate is according to the similar approach preparation of preparation embodiment 31 steps 3.

White powder

¹H-NMR(200MHz，DMSO-d ₆)，δ(ppm)：1.39(9H，s)，1.51(9H，s)，2.15(3H，s)，2.85(3H，s)，2.85-2.94(2H，m)，2.97(3H，s)，3.17-3.26(2H，m)，4.00-4.04(2H，m)，7.19(1H，d，J＝8.0Hz)，7.42(2H，d，J＝8.0Hz)，7.88(1H，t，J＝5.4Hz)，9.93(1H，s)，11.43(1H，s)，12.38(1H，s)。

MS：632(M+H) ⁺

Step 4

White powder

¹H-NMR(200MHz，DMSO-d ₆)，δ(ppm)：2.16(3H，s)，2.84(3H，s)，2.89-2.695(2H，m)，2.98(3H，s)，3.19-3.26(2H，m)，3.99(2H，m)，7.13(2H，d，J＝8.0Hz)，7.28(2H，d，J＝8.0Hz)，7.43(4H，br)，7.97(1H，br)，9.86(1H，s)，12.38(1H，s)。

MS:432 (M+H) ⁺(free type)

Preparation embodiment 72:

Synthetic 2-(acetylamino)-4-[2-(4-{[amino (imino-) methyl] amino } phenyl) ethyl]-N-[3-(dimethylamino)-3-oxopropyl]-1,3-thiazoles-5-carboxamide hydrochloride

Step 1

(4-{2-[2-(acetylamino)-5-({ [3-(dimethylamino)-3-oxopropyl] amino } carbonyl)-1; 3-thiazole-4-yl] ethyl } phenyl) t-butyl carbamate is with 2-(acetylamino)-4-(2-{4-[(tert-butoxycarbonyl) amino] phenyl } ethyl)-1,3-thiazoles-5-formic acid is according to the similar approach preparation of preparation embodiment 32 steps 1.

¹H-NMR(200MHz，DMSO-d ₆)，δ(ppm)：1.46(9H，s)，2.14(3H，s)，2.55(2H，m)，2.73-2.94(8H，m)，3.14(2H，dd，J＝9.1，6.1Hz)，3.37(2H，m)，7.05(2H，d，J＝8.5Hz)，7.32(2H，d，J＝8.5Hz)，7.89(1H，m)，9.21(1H，s)，12.33(1H，s)。

MS：504(M+H) ⁺

Step 2

2-(acetylamino)-4-[2-(4-aminophenyl) ethyl]-N-[3-(dimethylamino)-3-oxopropyl]-1,3-thiazoles-5-carboxamide hydrochloride is according to the similar approach preparation of preparation embodiment 31 steps 2.

White powder

¹H-NMR(200MHz，DMSO-d ₆)，δ(ppm)：2.15(3H，s)，2.57(2H，m)，2.81(3H，s)，2.84-2.98(5H，m)，3.20(2H，dd，J＝8.9，5.4Hz)，3.36(2H，dd，J＝12.8，7.1Hz)，7.26(2H，d，J＝8.6Hz)，7.32(2H，d，J＝8.6Hz)，7.95(1H，t，J＝5.4Hz)，10.04(2H，br)，12.35(1H，br)。

MS:403 (M+H) ⁺(free type)

Step 3

{ (Z)-[(4-{2-[2-(acetylamino)-5-({ [3-(dimethylamino)-3-oxopropyl] amino } carbonyl)-1,3-thiazoles-4-yl] ethyl } phenyl) amino] methylene radical } the diamino acid di tert butyl carbonate is according to the similar approach preparation of preparation embodiment 31 steps 3.

White powder

¹H-NMR(200MHz，DMSO-d ₆)，δ(ppm)：1.39(9H，s)，1.50(9H，s)，2.14(3H，s)，2.80(3H，s)，2.81-2.93(2H，m)，2.94(3H，s)，3.13-3.29(6H，m)，3.34-3.43(2H，m)，7.17(2H，d)，7.42(2H，d)，7.89(1H，m)，9.93(1H，s)，11.43(1H，s)，12.34(1H，m)。

MS：646(M+H) ⁺

Step 4

White powder

¹H-NMR(200MHz，DMSO-d ₆)，δ(ppm)：2.16(3H，s)，2.56(2H，m)，2.81(3H，s)，2.87-2.95(5H，m)，3.19(2H，m)，3.34(2H，m)，7.11-7.38(4H，m)，7.43(4H，s)，8.02(1H，m)，8.55(1H，br)，9.88(1H，br)，12.36(1H，s)。

MS:445 (M+H) ⁺(free type)

Preparation embodiment 73:

Synthetic 2-(acetylamino)-N-[2-(acetylamino) ethyl]-4-[2-(4-{[amino (imino-) methyl] amino } phenyl) ethyl]-1,3-thiazoles-5-carboxamide hydrochloride

Step 1

(4-{2-[2-(acetylamino)-5-({ [2-(acetylamino) ethyl] amino } carbonyl)-1; 3-thiazole-4-yl] ethyl } phenyl) t-butyl carbamate is with 2-(acetylamino)-4-(2-{4-[(tert-butoxycarbonyl) amino] phenyl } ethyl)-1,3-thiazoles-5-formic acid is according to the similar approach preparation of preparation embodiment 32 steps 1.

¹H-NMR(200MHz，DMSO-d ₆)，δ(ppm)：1.46(9H，s)，1.79(3H，s)，2.14(3H，s)，2.84(2H，m)，3.16-3.22(6H，m)，7.06(2H，d，J＝8.5Hz)，7.33(2H，d，J＝8.5Hz)，7.99(2H，m)，9.21(1H，s)，12.33(1H，s)。

MS：490(M+H) ⁺

Step 2

2-(acetylamino)-N-[2-(acetylamino) ethyl]-4-[2-(4-aminophenyl) ethyl]-1,3-thiazoles-5-carboxamide hydrochloride is according to the similar approach preparation of preparation embodiment 31 steps 2.

White powder

¹H-NMR(200MHz，DMSO-d ₆)，δ(ppm)：1.79(3H，s)，2.15(3H，s)，2.90-2.98(2H，dd，J＝10.1，6.6Hz)，3.14-3.26(6H，m)，7.27(2H，d，J＝8.9Hz)，7.32(2H，d，J＝8.9Hz)，7.97-8.06(2H，m)，10.18(2H，br)，12.35(1H，s)。

MS:390 (M+H) ⁺(free type)

Step 3

{ (Z)-[(4-{2-[2-(acetylamino)-5-({ [2-(acetylamino) ethyl] amino } carbonyl)-1,3-thiazoles-4-yl] ethyl } phenyl) amino] methylene radical } the diamino acid di tert butyl carbonate is according to the similar approach preparation of preparation embodiment 31 steps 3.

White powder

¹H-NMR(200MHz，DMSO-d ₆)，δ(ppm)：1.39(9H，s)，1.51(9H，s)，1.79(3H，s)，2.15(3H，s)，2.89(2H，m)，3.18(6H，m)，7.18(2H，d，J＝8.0Hz)，7.42(2H，d，J＝8.0Hz)，7.95(2H，m)，9.93(1H，s)，11.43(1H，s)，12.35(1H，s)。

MS：632(M+H) ⁺

Step 4

White powder

¹H-NMR(200MHz，DMSO-d ₆)，δ(ppm)：1.79(9H，s)，2.16(9H，s)，2.91(2H，m)，3.10-3.25(6H，m)，7.14(2H，d，J＝8.2Hz)，7.27(2H，d，J＝8.2Hz)，7.42(4H，br)，7.97(1H，br)，8.08(1H，br)，9.83(1H，s)，12.36(1H，s)。

MS:432 (M+H) ⁺(free type)

Preparation embodiment 74:

Synthetic 2-(acetylamino)-4-[2-(4-{[amino (imino-) methyl] amino } phenyl) ethyl]-the N-{2-[(methyl sulphonyl) amino] ethyl }-1,3-thiazoles-5-carboxamide hydrochloride

Step 1

[4-(2-{2-(acetylamino)-5-[({2-[(methyl sulphonyl) amino] ethyl } amino) carbonyl]-1; 3-thiazole-4-yl } ethyl) phenyl] t-butyl carbamate is with 2-(acetylamino)-4-(2-{4-[(tert-butoxycarbonyl) amino] phenyl } ethyl)-1,3-thiazoles-5-formic acid is according to the similar approach preparation of preparation embodiment 32 steps 1.

¹H-NMR(200MHz，DMSO-d ₆)，δ(ppm)：1.46(9H，s)，2.15(3H，s)，2.79-2.89(5H，m)，3.05-3.32(6H，m)，7.04-7.14(3H，m)，7.33(2H，d，J＝8.3Hz)，8.01(1H，br)，9.20(1H，s)，12.35(1H，s)。

MS：526(M+H) ⁺

Step 2

2-(acetylamino)-4-[2-(4-aminophenyl) ethyl]-the N-{2-[(methyl sulphonyl) amino] ethyl }-1,3-thiazoles-5-carboxamide hydrochloride is according to the similar approach preparation of preparation embodiment 31 steps 2.

White powder

¹H-NMR(200MHz，DMSO-d ₆)，δ(ppm)：2.15(3H，s)，2.89(3H，s)，2.89-3.27(8H，m)，7.12(1H，t，J＝5.7Hz)，7.24(2H，d，J＝8.5Hz)，7.32(2H，d，J＝8.5Hz)，8.05(1H，t，J＝5.。4Hz)，9.95(2H，br)，12.36(1H，s)。

MS:425 (M+H) ⁺(free type)

Step 3

((Z)-{ [4-(2-{2-(acetylamino)-5-[({2-[(methyl sulphonyl) amino] ethyl } amino) carbonyl]-1,3-thiazoles-4-yl } ethyl) phenyl] amino } methylene radical) the diamino acid di tert butyl carbonate is according to the similar approach preparation of preparation embodiment 31 steps 3.

White powder

¹H-NMR(200MHz，DMSO-d ₆)，δ(ppm)：1.39(9H，s)，1.51(9H，s)，2.15(3H，s)，2.80-2.97(5H，m)，3.00-3.14(2H，m)，3.15-3.30(4H，m)，7.11(1H，m)，7.17(2H，d，J＝8.5Hz)，7.42(2H，d，J＝8.5Hz)，8.01(1H，m)，9.93(1H，s)，11.43(1H，s)，12.37(1H，s)。

MS：668(M+H) ⁺

Step 4

White powder

¹H-NMR(200MHz，DMSO-d ₆)，δ(ppm)：2.16(3H，s)，2.90-2.96(5H，m)，3.08(2H，m)，3.19-3.29(4H，q)，7.14(2H，d，J＝8.3Hz)，7.28(2H，d，J＝8.3Hz)，7.43(4H，br)，8.07(1H，m)，9.87(1H，s)，12.38(1H，s)。

MS:467 (M+H) ⁺(free type)

Preparation embodiment 75:

Synthetic 2-(acetylamino)-4-[2-(4-{[amino (imino-) methyl] amino } phenyl) ethyl]-N-[3-(dimethylamino)-3-oxopropyl]-the N-methyl isophthalic acid, 3-thiazole-5-carboxamide hydrochloride

Step 1

[(Z)-(4-[2-(2-(acetylamino)-5-{[[3-(dimethylamino)-3-oxopropyl] (methyl) amino] carbonyl }-1,3-thiazoles-4-yl) ethyl] phenyl } amino) methylene radical] the similar approach preparation of the compound of preparation embodiment 34 steps 2 of diamino acid di tert butyl carbonate according to preparation embodiment 32 steps 1.

¹H-NMR(200MHz，DMSO-d ₆)，δ(ppm)：1.39(9H，s)，1.50(9H，s)，2.14(3H，s)，2.56(2H，t，J＝7.3Hz)，2.78(3H，s)，2.84-2.88(6H，m)，2.93(3H，s)，3.47(3H，m)，7.12(2H，d，J＝8.4Hz)，7.40(2H，d，J＝8.4Hz)，9.92(1H，s)，11.43(1H，s)，12.34(1H，s)。

MS：659(M+Na) ⁺

Step 2

¹H-NMR(200MHz，DMSO-d ₆)，δ(ppm)：2.15(3H，s)，2.50-2.60(6H，m)，2.79(3H，s)，2.87(3H，s)，2.94(3H，s)，3.39-3.64(2H，m)，7.09-7.26(4H，m)，7.46(4H，br)，9.96(1H，s)，12.35(1H，s)。

MS:460 (M+H) ⁺(free type)

Preparation embodiment 76:

Synthetic 2-(acetylamino)-4-[2-(4-{[amino (imino-) methyl] amino } phenyl) ethyl]-N-{3-[benzyl (methyl) amino]-the 3-oxopropyl }-1,3-thiazoles-5-carboxamide hydrochloride

Step 1

((z)-[4-(2-{2-(acetylamino)-5-[({3-[benzyl (methyl) amino]-the 3-oxopropyl } amino) carbonyl]-1,3-thiazoles-4-yl } ethyl) phenyl] amino } methylene radical) the similar approach preparation of the compound of preparation embodiment 34 steps 2 of diamino acid di tert butyl carbonate according to preparation embodiment 32 steps 1.

¹H-NMR(200MHz，DMSO-d ₆)，δ(ppm)：1.83(9H，s)，1.50(9H，s)，1.98-2.15(3H，m)，2.60-2.63(2H，m)，2.80-2.90(5H，m)，3.17-3.21(2H，m)，3.42-3.47(2H，m)，4.50-4.57(2H，m)，7.12-7.43(9H，m)，7.95(1H，m)，9.93(1H，s)，11.44(1H，s)，12.4(1H，s)。

MS：722(M+H) ⁺

Step 2

¹H-NMR(200MHz，DMSO-d ₆)，δ(ppm)：2.16，2.30(3H，s)，2.64(2H，m)，2.64(2H，m)，2.80-2.90(5H，m)，3.14-3.25(2H，m)，3.43-3.47(2H，m)，4.51-4.57(2H，m)，7.08-7.42(9H，m)，8.02-8.04(1H，m)，9.83-9.87(1H，m)，12.36(1H，m)。

MS:522 (M+H) ⁺(free type)

Preparation embodiment 77:

Synthetic 2-(acetylamino)-4-[2-(4-{[amino (imino-) methyl] amino } phenyl) ethyl]-N-[4-(dimethylamino)-4-oxo butyl]-1,3-thiazoles-5-carboxamide hydrochloride

Step 1

(Z)-[(4-{2-[2-(acetylamino)-5-({ [4-(dimethylamino)-4-oxo butyl] amino } carbonyl)-1,3-thiazoles-4-yl] ethyl } phenyl) amino] methylene radical } the similar approach preparation of the compound of preparation embodiment 34 steps 2 of diamino acid di tert butyl carbonate according to preparation embodiment 32 steps 1.

¹H-NMR(200MHz，DMSO-d ₆)，δ(ppm)：1.39(9H，s)，1.50(9H，s)，1.68(2H，tt，J＝6.8Hz)，2.14(3H，s)，2.30(2H，t，J＝6.8Hz)，2.80(3H，s)，2.82-2.95(2H，m)，2.92(3H，s)，3.10-3.28(4H，m)，7.18(2H，d，J＝8.5Hz)，7.39(2H，d，J＝8.5Hz)，9.92(1H，s)，11.43(1H，br)，12.3(1H，br)。

MS：682(M+Na) ⁺

Step 2

¹H-NMR(200MHz，DMSO-d ₆)，δ(ppm)：1.69(2H，m)，2.16(2H，s)，2.31(2H，t，J＝7.2Hz)，2.81(3H，s)，2.87-2.95(2H，m)，2.93(3H，s)，3.16-3.24(4H，m)，3.57(3H，s)，7.11-7.44(4H，m)，8.06-8.23(1H，m)，9.83-9.92(1H，m)，12.35(1H，s)。

MS:460 (M+H) ⁺(free type)

Preparation embodiment 78:

Synthetic (2R)-1-(2-(acetylamino)-4-[2-(4-{[amino (imino-) methyl] amino } phenyl) ethyl]-1,3-thiazoles-5-yl } carbonyl)-N, N-dimethyl-2-pyrrolidine formyl amine hydrochlorate

Step 1

(Z)-[(4-{2-[2-(acetylamino)-5-((2R)-and the 2-[(dimethylamino) carbonyl]-the 1-pyrrolidyl } carbonyl)-1,3-thiazoles-4-yl] ethyl } phenyl) amino] methylene radical } the similar approach preparation of the compound of preparation embodiment 34 steps 2 of diamino acid di tert butyl carbonate according to preparation embodiment 32 steps 1.

¹H-NMR(200MHz，DMSO-d ₆)，δ(ppm)：1.39(9H，s)，1.50(9H，s)，1.60-1.93(3H，m)，2.06-2.30(1H，m)，2.14(3H，s)，2.66-3.14(10H，m)，3.20-3.50(2H，m)，4.89(1H，m)，7.16(2H，d，J＝8.0Hz)，7.41(2H，d，J＝8.0Hz)，9.92(1H，s)，11.41(1H，s)，12.34(1H，s)。

MS：694(M+Na) ⁺

Step 2

¹H-NMR(200MHz，DMSO-d ₆)，δ(ppm)：1.60-2.00(3H，m)，2.15，2.48(3H，s x2)，2.65-3.50(12H，m)，3.60-3.75(2H，m)，7.09-7.17(2H，d x2)，7.23-7.31(2H，d x2)，7.47(3H，br)，9.94(1H，br)，12.35，12.59(1H，s x2)。

MS:472 (M+H) ⁺(free type)

Preparation embodiment 79:

Synthetic (2S)-1-(2-(acetylamino)-4-[2-(4-{[amino (imino-) methyl] amino } phenyl) ethyl]-1,3-thiazoles-5-yl } carbonyl)-N, N-dimethyl-2-pyrrolidine formyl amine hydrochlorate

Step 1

(Z)-[(4-{2-[2-(acetylamino)-5-((2S)-and the 2-[(dimethylamino) carbonyl]-the 1-pyrrolidyl } carbonyl)-1,3-thiazoles-4-yl] ethyl } phenyl) amino] methylene radical } the similar approach preparation of the compound of preparation embodiment 34 steps 2 of diamino acid di tert butyl carbonate according to preparation embodiment 32 steps 1.

¹H-NMR(200MHz，DMSO-d ₆)，δ(ppm)：1.39(3H，s)，1.50(9H，s)，1.60-1.94(H，m)，2.14(3H，s)，2.10-2.36(1H，m)，2.67-3.11(10H，m)，3.30-3.52(2H，m)，4.88(1H，m)，7.16(2H，d，J＝8.0Hz)，7.41(2H，d，J＝8.0Hz)，9.92(1H，s)，11.41(1H，s)，12.34(1H，s)。

MS：694(M+Na) ⁺

Step 2

MS:472 (M+H) ⁺(free type)

Preparation embodiment 80:

Synthetic 2-(acetylamino)-4-[2-(4-{[amino (imino-) methyl] amino } phenyl) ethyl]-N-[2-(methyl sulphonyl) ethyl]-1,3-thiazoles-5-carboxamide hydrochloride

Step 1

(Z)-[(4-{2-[2-(acetylamino)-5-({ [2-(methyl sulphonyl) ethyl] amino } carbonyl)-1,3-thiazoles-4-yl] ethyl } phenyl) amino] methylene radical } the similar approach preparation of the compound of preparation embodiment 34 steps 2 of diamino acid di tert butyl carbonate according to preparation embodiment 32 steps 1.

¹H-NMR(200MHz，DMSO-d ₆)，δ(ppm)：1.39(9H，s)，1.57(9H，s)，2.15(3H，s)，2.87(2H，dd，J＝8.8，6.5Hz)3.02(3H，s)，3.19-3.28(2H，dd，J＝9.0，5.5Hz)，3.30-3.36(2H，m)，3.59(2H，dd，J＝12.0，6.0Hz)，7.17(2H，d，J＝8.4Hz)，7.42(2H，d，J＝8.4Hz)，8.17(1H，s)，9.93(1H，s)，11.44(1H，s)，12.40(1H，s)。

MS：675(M+Na) ⁺

Step 2

¹H-NMR(200MHz，DMSO-d ₆)，δ(ppm)：2.16(3H，s)，2.88-2.96(2H，m)，3.03(3H，s)，3.20-3.30(4H，m)，3.33-3.60(2H，m)，7.12-7.18(2H，m)，7.26-7.46(2H，d)，7.46(4H，br)，8.27(1H，t)，9.94(1H，s)，12.41(1H，s)。

MS:453 (M+H) ⁺(free type)

Preparation embodiment 81:

Synthetic 2-(acetylamino)-4-[2-(4-{[amino (imino-) methyl] amino } phenyl) ethyl]-N-(4-pyridylmethyl)-1,3-thiazoles-5-methane amide dihydrochloride

Step 1

[(Z)-(and 4-[2-(2-(acetylamino)-5-{[(4-pyridylmethyl) amino] carbonyl }-1,3-thiazoles-4-yl) ethyl] phenyl } amino) methylene radical] the similar approach preparation of the compound of preparation embodiment 34 steps 2 of diamino acid di tert butyl carbonate according to preparation embodiment 32 steps 1.

¹H-NMR(200MHz，DMSO-d ₆)，δ(ppm)：1.40-1.50(18H，br)，2.15(3H，s)，2.89(2H，m)，3.22(2H，m)，4.39(2H，d，J＝5.7Hz)，7.09-7.18(2H，m)，7.32-7.44(3H，m)，7.66(1H，m)，8.43-8.62(3H，m)，9.94(1H，s)，11.44(1H，s)，12.40(1H，s)。

MS：660(M+Na) ⁺

Step 2

¹H-NMR(200MHz，DMSO-d ₆)，δ(ppm)：2.18(3H，s)，2.92(2H，m)，3.13-3.28(2H，m)，4.63(2H，m)，7.12(2H，d，J＝8.4Hz)，7.24(2H，d，J＝8.4Hz)，7.47(4H，br)7.93(2H，d，J＝6.3Hz)，8.88(3H，m)，10.00(1H，s)，12.43(1H，s)。

MS:438 (M+H) ⁺(free type)

Preparation embodiment 82:

Synthetic 2-(acetylamino)-4-[2-(4-{[amino (imino-) methyl] amino } phenyl) ethyl]-N-(3-pyridylmethyl)-1,3-thiazoles-5-methane amide dihydrochloride

Step 1

[(Z)-(and 4-[2-(2-(acetylamino)-5-{[(3-pyridylmethyl) amino] carbonyl }-1,3-thiazoles-4-yl) ethyl] phenyl } amino) methylene radical] the similar approach preparation of the compound of preparation embodiment 34 steps 2 of diamino acid di tert butyl carbonate according to preparation embodiment 32 steps 1.

¹H-NMR(200MHz，DMSO-d ₆)，δ(ppm)：1.39(9H，s)，1.50(9H，s)，2.16(3H，s)，2.89(2H，dd，J＝8.6，6.7Hz)，3.22(2H，dd，J＝8.6，5.7Hz)，4.38(2H，d，J＝5.7Hz)，7.13(2H，d，J＝8.4Hz)，7.25(2H，s x2，J＝5.7Hz)，7.41(2H，d，J＝8.4Hz)，8.50(2H，s x2，J＝5.0Hz)，8.62(1H，dd，J＝5.0，5.7Hz)，9.93(1H，s)，11.43(1H，s)，12.41(1H，s)。

MS：660(M+Na) ⁺

Step 2

¹H-NMR(200MHz，DMSO-d ₆)，δ(ppm)：2.17(3H，s)，2.92(2H，m)，3.23(2H，m)，4.56(2H，m)，7.10-7.31(4H，m)，7.45(4H，br)，8.01(1H，dd，J＝8.1，5.9Hz)，8.82(1H，d，J＝8.0Hz)，8.84(2H，s)，8.96(1H，s)，12.45(1H，s)。

MS:438 (M+H) ⁺(free type)

Preparation embodiment 83:

Synthetic 2-(acetylamino)-4-[2-(4-{[amino (imino-) methyl] amino } phenyl) ethyl]-the N-{2-[(2-phenyl acetyl) amino] ethyl }-1,3-thiazoles-5-carboxamide hydrochloride

Step 1

((Z)-{ [4-(2-{2-(acetylamino)-5-[({2-[(2-phenyl acetyl) amino] ethyl } amino) carbonyl]-1,3-thiazoles-4-yl } ethyl) phenyl] amino } methylene radical) the similar approach preparation of the compound of preparation embodiment 34 steps 2 of diamino acid di tert butyl carbonate according to preparation embodiment 32 steps 1.

¹H-NMR(200MHz，DMSO-d ₆)，δ(ppm)：1.39(9H，s)，1.51(9H，s)，2.15(3H，s)，2.88(2H，m)，3.25-3.31(6H，m)，3.38(2H，s)，7.15-7.44(7H，m)，7.32(2H，d，J＝8.3Hz)，7.98(1H，br)，8.11(1H， br)，9.93(1H，s)，11.43(1H，s)，12.35(1H，s)。

MS：730(M+Na) ⁺

Step 2

¹H-NMR(200MHz，DMSO-d ₆)，δ(ppm)：2.16(3H，s)，2.90(2H，br)，3.20(6H，m)，7.11-7.31(9H，m)，7.38(3H，s)，8.06-8.16(2H，m)，9.75(1H，s)，12.33(1H，s)。

MS:508 (M+H) ⁺(free type)

Preparation embodiment 84:

Synthetic 2-(acetylamino)-4-[2-(4-{[amino (imino-) methyl] amino } phenyl) ethyl]-N-[5-(dimethylamino)-5-oxo amyl group]-1,3-thiazoles-5-carboxamide hydrochloride

Step 1

(Z)-[(4-{2-[2-(acetylamino)-5-({ [5-(dimethylamino)-5-oxo amyl group] amino } carbonyl)-1,3-thiazoles-4-yl] ethyl } phenyl) amino] methylene radical } the similar approach preparation of the compound of preparation embodiment 34 steps 2 of diamino acid di tert butyl carbonate according to preparation embodiment 32 steps 1.

¹H-NMR(200MHz，DMSO-d ₆)，δ(ppm)：1.39(9H，s)，1.39-1.50(4H，m)，1.57(9H，s)，2.14(3H，s)，2.29(2H，br)，2.79(3H，s)，2.84-2.94(2H，m)，2.94(3H，s)，3.15-3.23(4H，m)，7.16(2H，d，J＝8.3Hz)，7.42(2H，d，J＝8.3Hz)，7.97(1H，br)，9.93(1H，s)，11.44(1H，s)，12.35(1H，s)。

MS：696(M+Na) ⁺

Step 2

¹H-NMR(200MHz，DMSO-d ₆)，δ(ppm)：1，39-1.56(4H，m)，2.16(2H，m)，2.29(3H，s)，2.83-2.98(5H，m)，3.06-3.28(4H，m)，7.13(2H，d，J＝8.5Hz)，7.25(2H，d，J＝8.5Hz)，7.40(3H，br)，8.06(1H，br)，9.79(1H，s)。

MS:474 (M+H) ⁺(free type)

Preparation embodiment 85:

Synthetic 2-(acetylamino)-4-[2-(4-{[amino (imino-) methyl] amino } phenyl) ethyl]-N-[3-(benzylamino)-3-oxopropyl]-1,3-thiazoles-5-carboxamide hydrochloride

Step 1

(Z)-[(4-{2-[2-(acetylamino)-5-({ [3-(benzylamino)-3-oxopropyl] amino } carbonyl)-1,3-thiazoles-4-yl] ethyl } phenyl) amino] methylene radical } the similar approach preparation of the compound of preparation embodiment 34 steps 2 of diamino acid di tert butyl carbonate according to preparation embodiment 32 steps 1.

¹H-NMR(200MHz，DMSO-d ₆)，δ(ppm)：1.39(9H，s)，1.50(9H，s)，2.15(3H，s)，2.45(2H，t，J＝7.2Hz)，2.73(2H，m)，3.20(2H，m)，3.39(2H，m)，4.26(2H，d，J＝5.8Hz)，7.15-7.28(7H，m)，7.41(2H，d，J＝8.4Hz)，8.02(1H，t，J＝5.5Hz)，8.40(1H，t，J＝5.5Hz)，9.93(1H，s)，11.4(1H，br)，12.3(1H，br)。

MS：730(M+Na) ⁺

Step 2

¹H-NMR(200MHz，DMSO-d ₆)，δ(ppm)：2.16(3H，s)，2.41(2H，t，J＝7.0Hz)，2.90(2H，m)，3.20(2H，m)，3.39(2H，m)，3.63(2H，m)，4.27(2H，d，J＝5.8Hz)，7.11-7.37(9H，m)，7.37(4H，s)，8.09(1H，t，J＝5.5Hz)，8.43(1H，t，J＝6.0Hz)，9.74(1H，s)，12.35(1H，s)。

MS:508 (M+H) ⁺(free type)

Preparation embodiment 86:

Synthetic 2-(acetylamino)-4-[2-(4-{[amino (imino-) methyl] amino } phenyl) ethyl]-N-[6-(dimethylamino)-6-oxo-hexyl]-1,3-thiazoles-5-carboxamide hydrochloride

Step 1

(Z)-[(4-{2-[2-(acetylamino)-5-({ [6-(dimethylamino)-6-oxo-hexyl] amino } carbonyl)-1,3-thiazoles-4-yl] ethyl } phenyl) amino] methylene radical } the similar approach preparation of the compound of preparation embodiment 34 steps 2 of diamino acid di tert butyl carbonate according to preparation embodiment 32 steps 1.

¹H-NMR(200MHz，DMSO-d ₆)，δ(ppm)：1.13-1.50(24H，m)，2.14(3H，s)，2.24(2H，t，J＝8.0Hz)，2.78(3H，s)，2.88(2H，m)，2.92(3H，s)，3.07-3.25(4H，m)，7.16(2H，d，J＝8.5Hz)，7.42(2H，d，J＝8.5Hz)，7.95(1H，t，J＝5.52Hz)，9.94(1H，s)，11.4(1H，s)，12.3(1H，s)。

MS：710(M+Na) ⁺

Step 2

¹H-NMR(200MHz，DMSO-d ₆)，δ(ppm)：1.27-1.34(2H，m)，1.47(4H，m)，2.16(3H，s)，2.26(2H，t，J＝7.2Hz)，2.79(3H，s)，2.94(3H，s)，2.90-2.94(2H，m)，3.17(4H，m)，7.13(2H，d，J＝8.3Hz)，7.26(2H，d，J＝8.3Hz)，7.47(4H，br)，8.05(1H，t，J＝5.4Hz)，9.93(1H，s)。

MS:488 (M+H) ⁺(free type)

Preparation embodiment 87:

Synthetic 2-(acetylamino)-4-[2-(4-{[amino (imino-) methyl] amino } phenyl) ethyl]-N-[3-(4-morpholinyl) propyl group]-1,3-thiazoles-5-methane amide dihydrochloride

Step 1

(Z)-[(4-{2-[2-(acetylamino)-5-(([3-(4-morpholinyl) propyl group] amino } carbonyl)-1,3-thiazoles-4-yl] ethyl } phenyl) amino] methylene radical } the similar approach preparation of the compound of preparation embodiment 34 steps 2 of diamino acid di tert butyl carbonate according to preparation embodiment 32 steps 1.

¹H-NMR(200MHz，DMSO-d ₆)，δ(ppm)：1.58(9H，br)，1.62(2H，m)，2.14(3H，s)，2.31(6H，m)，2.88(2H，m)，2.19(4H，m)，3.58(4H，m)，7.14(2H，d，J＝8.4Hz)，7.41(2H，d，J＝8.4Hz)，7.95(1H，t，J＝5.2Hz)，9.94(1H，s)，11.45(1H，s)，12.30(1H，s)。

MS：696(M+Na) ⁺

Step 2

¹H-NMR(200MHz，DMSO-d ₆)，δ(ppm)：1.90-2.00(2H，br)，2.17(3H，s)，2.83-3.15(6H，m)，3.15-3.30(4H，m)，3.30-3.44(2H，m)，3.77-4.00(4H，m)，7.14(2H，d，J＝8.5Hz)，7.26(2H，d，J＝8.5Hz)，7.44(4H，br)，8.20(1H，t，J＝5.5Hz)，9.92(1H，s)，11.01(1H，s)，12.38(1H，s)。

MS:474 (M+H) ⁺(free type)

Preparation embodiment 88:

Synthetic 2-(acetylamino)-4-[2-(4-{[amino (imino-) methyl] amino } phenyl) ethyl]-N-[3-(2-OXo-1-pyrrolidine base) propyl group]-1,3-thiazoles-5-carboxamide hydrochloride

Step 1

(Z)-[(4-{2-[2-(acetylamino)-5-({ [3-(2-OXo-1-pyrrolidine base) propyl group] amino } carbonyl)-1,3-thiazoles-4-yl] ethyl } phenyl) amino] methylene radical } the similar approach preparation of the compound of preparation embodiment 34 steps 2 of diamino acid di tert butyl carbonate according to preparation embodiment 32 steps 1.

¹H-NMR(200MHz，DMSO-d ₆)，δ(ppm)：1.41(9H，br)，1.49(9H，br)，1.64(2H，t，J＝6.9Hz)，1.90(2H，m)，2.14(3H，s)，2.17(2H，m)，2.91(2H，m)，3.16(6H，m)，3.32(2H，m)，7.16(2H，d，J＝8.4Hz)，7.41(2H，d，J＝8.4Hz)，7.93(1H，t，J＝5.6Hz)，9.93(1H，br)，11.73(1H，br)。

MS：694(M+Na) ⁺

Step 2

¹H-NMR(200MHz，DMSO-d ₆)，δ(ppm)：1.65(2H，m)，1.91(2H，m)，2.16(3H，s)，2.20(2H，q，J＝7.5Hz)，2.90(2H，m)，3.02-3.27(6H，m)，3.33(2H，t，J＝7.5Hz)，7.16(2H，d，J＝8.5Hz)，7.26(2H，d，J＝8.5Hz)，8.03(1H，br)，9.92(1H，s)，12.35(1H，s)。

MS:472 (M+H) ⁺(free type)

Preparation embodiment 89:

Synthetic 2-(acetylamino)-4-[2-(4-{[amino (imino-) methyl] amino } phenyl) ethyl]-N-hexyl-1,3-thiazoles-5-carboxamide hydrochloride

Step 1

((Z)-{ [4-(2-{2-(acetylamino)-5-[(hexyl amino) carbonyl]-1,3-thiazoles-4-yl } ethyl) phenyl] amino } methylene radical) the similar approach preparation of the compound of preparation embodiment 34 steps 2 of diamino acid di tert butyl carbonate according to preparation embodiment 32 steps 1.

¹H-NMR(200MHz，DMSO-d ₆)，δ(ppm)：0.85(3H，t，J＝6.4Hz)，1.25(9H，s)，1.35-1.60(17H，br)，2.14(3H，s)，2.88(2H，m)，3.15(4H，m)，7.14(2H，d，J＝8.5Hz)，7.41(2H，d，J＝8.5Hz)，7.92(1H，t，J＝5.7Hz)，10.00(1H，br)，11.60(1H，br)。

MS：653(M+Na) ⁺

Step 2

¹H-NMR(200MHz，DMSO-d ₆(+D ₂O))，δ(ppm)：0.86(3H，t，J＝6.53Hz)，1.18-1.57(8H，m)，2.16(3H，s)，2.91(2H，dd，J＝9.5，6.0Hz)，3.16(4H，m)，7.13(2H，d，J＝8.5Hz)，7.25(2H，d，J＝8.5Hz)，8.05(1H，br)，9.91(1H，s)，12.33(1H，s)。

MS:431 (M+H) ⁺(free type)

Preparation embodiment 90:

Synthetic 2-(acetylamino)-4-[2-(4-{[amino (imino-) methyl] amino } phenyl) ethyl]-N-[4-oxo-4-(piperidino) butyl]-1,3-thiazoles-5-carboxamide hydrochloride

Step 1

{ (Z)-[(4-{2-[2-(acetylamino)-5-({ [4-oxo-4-(piperidino) butyl] amino } carbonyl)-1,3-thiazoles-4-yl] ethyl } phenyl) amino] methylene radical } the diamino acid di tert butyl carbonate prepares the similar approach preparation of 32 steps 1 according to preparation embodiment with the compound of preparation embodiment 34 steps 2.

¹H-NMR(200MHz，DMSO-d ₆)，δ(ppm)：1.29-1.59(20H，m)，1.69(2H，m)，2.14(3H，s)，2.30(2H，t，J＝7.5Hz)，2.89(4H，m)，3.32-3.45(4H，m)，7.16(2H，d，J＝8.0Hz)，7.41(2H，d，J＝8.0Hz)，7.99(1H，t，J＝5.2Hz)，9.94(1H，s)，11.43(1H，br)。

MS：722(M+Na) ⁺

Step 2

¹H-NMR(200MHz，DMSO-d ₆)，δ(ppm)：1.30-1.79(8H，m)，2.16(3H，s)，2.31(2H，t，J＝7.5Hz)，2.92(2H，m)，3.18(4H，m)，3.38(4H，m)，7.13(2H，d，J＝8.0Hz)，7.25(2H，d，J＝8.O Hz)，7.43(4H，br)，8.09(1H，t，J＝6.0Hz)，9.87(1H，s)，12.34(1H，s)。

MS:500 (M+H) ⁺(free type)

Preparation embodiment 91:

Synthetic 2-(acetylamino)-4-[2-(4-{[amino (imino-) methyl] amino } phenyl) ethyl]-N-[4-(4-morpholinyl)-4-oxo butyl]-1,3-thiazoles-5-carboxamide hydrochloride

Step 1

(Z)-[(4-{2-[2-(acetylamino)-5-({ [4-(4-morpholinyl)-4-oxo butyl] amino } carbonyl)-1,3-thiazoles-4-yl] ethyl } phenyl) amino] methylene radical } the similar approach preparation of the compound of preparation embodiment 34 steps 2 of diamino acid di tert butyl carbonate according to preparation embodiment 32 steps 1.

¹H-NMR(200MHz，DMSO-d ₆)，δ(ppm)：1.40(9H，s)，1.50(9H，s)，1.71(2H，m)，2.14(3H，s)，2.32(2H，t，J＝7.3Hz)，2.89(2H，dd，J＝10.1，6.9Hz)，3.19(4H，m)，3.42(4H，m)，3.51(4H，m)，7.16(2H，d，J＝8.3Hz)，7.42(2H，d，J＝8.3Hz)，7.99(2H，t，J＝5.3Hz)，9.94(1H，s)，11.44(1H，s)，12.33(1H，s)。

MS：724(M+Na) ⁺

Step 2

¹H-NMR(200MHz，DMSO-d ₆)，δ(ppm)：1.70(2H，m)，2.16(3H，s)，2.33(2H，t，J＝7.0Hz)，2.91(2H，m)，3.19(4H，m)，3.42(4H，m)，3.53(4H，m)，7.13(2H，d，J＝8.5Hz)，7.25(2H，d，J＝8.5Hz)，7.44(4H，br)，8.07(1H，t，J＝5.0Hz)，9.89(1H，s)，12.34(1H，s)。

MS:502 (M+H) ⁺(free type)

Preparation embodiment 92:

Synthetic 2-(acetylamino)-4-[2-(4-{[amino (imino-) methyl] amino } phenyl) ethyl]-N-[4-(methyl sulphonyl) phenyl]-1,3-thiazoles-5-carboxamide hydrochloride

Step 1

(Z)-[(4-{2-[2-(acetylamino)-5-({ [4-(methylthio group) phenyl] amino } carbonyl)-1,3-thiazoles-4-yl] ethyl } phenyl) amino] methylene radical } the similar approach preparation of the compound of preparation embodiment 34 steps 2 of diamino acid di tert butyl carbonate according to preparation embodiment 32 steps 1.

¹H-NMR(200MHz，DMSO-d ₆)，δ(ppm)：1.39(9H，s)，1.51(9H，s)，2.18(3H，s)，2.45(3H，s)，2.82-3.00(2H，m)，3.17-3.30(2H，m)，7.13(2H，d，J＝8.5Hz)，7.23(2H，d，J＝8.5Hz)，7.41(2H，d，J＝8.5Hz)，7.61(2H，d，J＝8.5Hz)，9.92(2H，s)，11.43(1H，s)，12.45(1H，s)。

MS：691(M+Na) ⁺

Step 2

{ (Z)-[(4-{2-[2-(acetylamino)-5-({ [4-(methyl sulphonyl) phenyl] amino } carbonyl)-1,3-thiazoles-4-yl] ethyl } phenyl) amino] methylene radical } the diamino acid di tert butyl carbonate is according to the similar approach preparation of preparation embodiment 32 steps 2.

¹H-NMR(200MHz，DMSO-d ₆)，δ(ppm)：1.39(9H，s)，1.51(9H，s)，2.18(3H，s)，2.81-3.03(2H，m)，3.18(3H，s)，3.19-3.30(2H，m)，7.16(2H，d，J＝8.5Hz)，7.41(2H，d，J＝8.5Hz)，7.86(2H，d，J＝9.0Hz)，7.93(2H，d，J＝9.0Hz)，9.92(1H，s)，10.34(1H，s)，11.42(1H，s)，12.52(1H，s)。

MS：723(M+Na) ⁺

Step 3

¹H-NMR(200MHz，DMSO-d ₆)，δ(ppm)：2.20(3H，s)，2.84-3.07(2H，m)，3.17-3.32(2H，m)，3.18(3H，s)，7.12(2H，d，J＝8.5Hz)，7.37(4H，br)，7.86(2H，d，J＝9.0Hz)，7.92(2H，d，J＝9.0Hz)，9.76(1H，s)，10.42(1H，s)。

MS:501 (M+H) ⁺(free type)

Preparation embodiment 93:

Synthetic 2-(acetylamino)-4-[2-(4-{[amino (imino-) methyl] amino } phenyl) ethyl]-N-[(1S)-2-(dimethylamino)-1-methyl-2-oxoethyl]-1,3-thiazoles-5-carboxamide hydrochloride

Step 1

(Z)-[(4-{2-[2-(acetylamino)-5-([(1S)-and 2-(dimethylamino)-1-methyl-2-oxoethyl] amino } carbonyl)-1,3-thiazoles-4-yl] ethyl } phenyl) amino] methylene radical } the similar approach preparation of the compound of preparation embodiment 34 steps 2 of diamino acid di tert butyl carbonate according to preparation embodiment 32 steps 1.

¹H-NMR(200MHz，CDCl ₃)，δ(ppm)：1.40(3H，d，J＝7.0Hz)，1.49(9H，s)，1.53(9H，s)，2.22(3H，s)，2.95(2H，m)，3.00(3H，s)，3.10(3H，s)，3.26(2H，m)，5.01(1H，dt，J＝7.0Hz)，6.87(1H，d，J＝7.5Hz)，7.14(2H，d，J＝8.5Hz)，7.40(2H，d，J＝8.5Hz)，9.57(1H，br)，10.20(1H，s)，11.62(1H，s)。

MS：646(M+H) ⁺

Step 2

¹H-NMR(200MHz，DMSO-d ₆)，δ(ppm)：1.23(3H，d)，2.16(3H，s)，2.84(3H，s)，2.87-2.95(2H，m)，3.03(3H，s)，3.15-3.24(2H，m)，3.56(1H，s)，4.78(3H，t，J＝7.0Hz)，7.13(2H，d，J＝8.4Hz)，7.25(2H，d，J＝8.4Hz)，8.09(1H，d，J＝7.0Hz)，9.67(1H，s)，12.35(1H，s)。

MS:446 (M+H) ⁺(free type)

Preparation embodiment 94:

Synthetic 2-(acetylamino)-4-[2-(4-{[amino (imino-) methyl] amino } phenyl) ethyl]-N-[(1S)-1-benzyl-2-(dimethylamino)-2-oxoethyl]-1,3-thiazoles-5-carboxamide hydrochloride

Step 1

(Z)-[(4-{2-[2-(acetylamino)-5-([(1S)-and 1-benzyl-2-(dimethylamino)-2-oxoethyl] amino } carbonyl)-1,3-thiazoles-4-yl] ethyl } phenyl) amino] methylene radical } the similar approach preparation of the compound of preparation embodiment 34 steps 2 of diamino acid di tert butyl carbonate according to preparation embodiment 32 steps 1.

¹H-NMR(200MHz，CDCl ₃)，δ(ppm)：1.48(9H，s)，1.52(9H，S)，2.22(3H，s)，2.68(3H，s)，2.84-2.97(5H，m)，3.06(2H，d，J＝7.5Hz)，3.17(H，dd，J＝8.0，6.0Hz)，5.26(1H，q，J＝7.5Hz)，6.80(1H，d，J＝8.0Hz)，7.08(2H，d，J＝8.0Hz)，7.14-7.33(5H，m)，7.39(2H，d，J＝8.0Hz)，9.96(1H，br)，10.19(1H，s)，11.61(1H，s)。

MS.722(M+H) ⁺

Step 2

¹H-NMR(200MHz，DMSO-d ₆)，δ(ppm)：2.15(3H，s)，2.82-3.15(13H，m)，4.91(1H，q，J＝6.7Hz)，7.09(4H，s)，7.16-7.31(5H，m)，7.36(4H，br)，8.31(1H，d，J＝7.7Hz)，9.71(1H，s)，12.33(1H，s)。

MS:522 (M+H) ⁺(free type)

Preparation embodiment 95:

Synthetic 2-(acetylamino)-4-[2-(4-{[amino (imino-) methyl] amino } phenyl) ethyl]-N-[(1S)-2-(dimethylamino)-1-(hydroxymethyl)-2-oxoethyl]-1,3-thiazoles-5-carboxamide hydrochloride

Step 1

(Z)-[(4-{2-[2-(acetylamino)-5-([(1S)-and 2-(dimethylamino)-1-(hydroxymethyl)-2-oxoethyl] amino } carbonyl)-1,3-thiazoles-4-yl] ethyl } phenyl) amino] methylene radical } the similar approach preparation of the compound of preparation embodiment 34 steps 2 of diamino acid di tert butyl carbonate according to preparation embodiment 32 steps 1.

¹H-NMR(200MHz，CDCl ₃)，δ(ppm)：1.48(9H，s)，1.52(9H，s)，2.23(3H，s)，2.94(2H，dd，J＝7.0Hz)，3.01(3H，s)，3.14(3H，s)，3.26(2H，dd，J＝7.0Hz)，3.78-3.86(3H，br)，5.04(1H，m)，6.85(1H，d，J＝7.5Hz)，7.08(2H，d，J＝8.5Hz)，7.37(2H，d，J＝8.5Hz)，9.70(1H，br)，10.20(1H，s)，11.61(1H，s)。

MS：662(M+H) ⁺

Step 2

¹H-NMR(200MHz，DMSO-d ₆)，δ(ppm)：2.16，2.19(3H，s x2)，2.85-3.50(10H，m)，3.60-3.69(2H，m)，4.81(1H，m)，7.14(2H，m)，2.27(2H，m)，7.39(4H，br)，7.91(1H，br)，8.48(1H，br)，9.77，9.94(1H，s x2)，12.37，12.61(1H，s x2)。

MS:462 (M+H) ⁺(free type)

Preparation embodiment 96:

Synthetic 2-(acetylamino)-4-[2-(4-{[amino (imino-) methyl] amino } phenyl) ethyl]-N-{ (1S, 2S)-the 1-[(dimethylamino) carbonyl]-the 2-hydroxypropyl }-1,3-thiazoles-5-carboxamide hydrochloride

Step 1

((z)-{ [4-(2-{2-(acetylamino)-5-[({ (1S; 2S)-and the 1-[(dimethylamino) carbonyl]-the 2-hydroxypropyl } amino) carbonyl]-1,3-thiazoles-4-yl } ethyl) phenyl] amino } methylene radical) the similar approach preparation of the compound of preparation embodiment 34 steps 2 of diamino acid di tert butyl carbonate according to preparation embodiment 32 steps 1.

¹H-NMR(200MHz，CDCl ₃)，δ(ppm)：1.18(3H，d，J＝6.5Hz)，1.48(9H，s)，1.52(9H，s)，2.22(3H，s)，2.95(2H，m)，2.99(3H，s)，3.16(3H，s)，3.20-3.32(2H，m)，4.06-4.12(2H，m)，5.02(1H，dd，J＝9.0，1.5Hz)，6.55(1H，d，J＝9.0Hz)，7.09(2H，d，J＝8.0Hz)，7.38(2H，d，J＝8.0Hz)，9.70(1H，br)，10.20(1H，s)，11.62(1H，s)。

MS：676(M+H) ⁺

Step 2

¹H-NMR(200MHz，DMSO-d ₆)，δ(ppm)：1.35(3H，d，J＝6.5Hz)，2.19(3H，s)，2.85-2.97(6H，m)，3.11(3H，s)，3.26(2H，m)，4.67(1H，br)，5.40(1H，m)，7.15(2H，d，J＝8.3Hz)，7.28(2H，d，J＝8.3Hz)，7.43(4H，br)，8.43(3H，br)，9.93(1H，s)，12.59(1H，s)。

MS:475 (M+H) ⁺(free type)

Preparation embodiment 97:

Synthetic (2S)-2-[({2-(acetylamino)-4-[2-(4-{[amino (imino-) methyl] amino } phenyl) ethyl]-1,3-thiazoles-5-yl } carbonyl) amino]-N1, N1-dimethyl-penten diamide hydrochloride

Step 1

((Z)-{ [4-(2-{2-(acetylamino)-5-[({ (1S)-4-amino-1-[(dimethylamino) carbonyl]-4-oxo butyl } amino) carbonyl]-1,3-thiazoles-4-yl } ethyl) phenyl] amino } methylene radical) the similar approach preparation of the compound of preparation embodiment 34 steps 2 of diamino acid di tert butyl carbonate according to preparation embodiment 32 steps 1.

¹H-NMR(200MHz，CDCl ₃)，δ(ppm)：1.49(9H，s)，1.53(9H，s)，1.86-2.19(2H，m)，2.22-2.37(5H，m)，2.89(2H，m)，2.99(3H，s)，3.05-3.16(5H，m)，3.20-3.41(1H，m)，5.06(1H，m)，6.27(1H，br)，6.35(1H，br)，6.81(1H，d，J＝7.5Hz)，7.09(2H，d，J＝8.5Hz)，7.41(2H，d，J＝8.5Hz)，10.21(1H，s)，10.55(1H，br)，11.62(1H，s)。

MS：703(M+H) ⁺

Step 2

¹H-NNR(200MHz，DMSO-d ₆)，δ(ppm)：1.70-2.00(2H，m)，2.16(5H，m)，2.84(3H，s)，2.91(2H，m)，3.08(3H，s)，3.19(2H，m)，4.75(1H，m)，6.79(1H，m)，7.12(2H，d，J＝8.3Hz)，7.25(2H，d，J＝8.3Hz)，7.39(4H，br)，8.13(1H，d)，9.77(1H，s)，12.35(1H，s)。

MS:503 (M+H) ⁺(free type)

Preparation embodiment 98:

Synthetic N-{4-[2-(4-{[imino-(methylamino) methyl] amino } phenyl) ethyl]-5-[4-(methyl sulphonyl) benzyl]-1,3-thiazoles-2-yl } ethanamide

Title compound prepares according to the similar approach for preparing embodiment 58 with the compound of preparation embodiment 50 steps 2.

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.09(3H，s)，2.79(3H，s)，2.86(4H，s)，3.18(3H，s)，4.08(2H，s)，4.43(2H，m)，7.08(2H，d，J＝8.5Hz)，7.22(2H，d，J＝8.5Hz)，7.39(2H，d，J＝8.5Hz)，7.85(2H，d，J＝8.5Hz)，12.05(1H，brs)。

MS：486(M+H) ⁺

Preparation embodiment 99:

Synthetic (2S)-1-(2-(acetylamino)-4-[2-(4-{[amino (imino-) methyl] amino } phenyl) ethyl]-1,3-thiazoles-5-yl } methyl)-N, N-dimethyl-2-pyrrolidine formamide dihydrochloride

Step 1

4-[2-(2-(acetylamino)-5-{[methoxyl group (methyl) amino] carbonyl }-1; 3-thiazole-4-yl) ethyl] phenyl } t-butyl carbamate is with 2-(acetylamino)-4-(2-{4-[(tert-butoxycarbonyl) amino] phenyl } ethyl)-1,3-thiazoles-5-formic acid is according to the similar approach preparation of preparation embodiment 32 steps 1.

¹H-NMR(CDCl ₃)，δ(ppm)：1.46(9H，s)，2.15(3H，s)，2.74-2.93(2H，m)，3.12-3.29(2H，m)，3.22(3H，s)，3.59(3H，s)，7.05(2H，d，J＝8.5Hz)，7.33(2H，d，J＝8.5Hz)，9.21(1H，s)，12.34(1H，s)。

MS：471.1(M+Na) ⁺

Step 2

At 5-10 ℃ (under ice-cooled), slow (in 15min) adds lithium aluminum hydride (499mg) in THF (80mL) solution of step 1 compound (3.93g).At 5 ℃ of 1h that stir the mixture.At the ice-cooled 30mL soluble tartrate sodium water solution (1M) that slowly adds down, then at stirring at room mixture 0.5h.The mixture ethyl acetate extraction, the organic layer dried over mgso, vacuum concentration obtains light yellow oil.Oily matter and IPE and EtOAc are ground, obtain buff powder (4-{2-[2-(acetylamino)-5-formyl radical-1,3-thiazoles-4-yl] ethyl } phenyl) t-butyl carbamate (2.67g).

¹H-NMR(200MHz，DMSO-d ₆)，δ(ppm)：1.46(9H，s)，2.19(3H，s)，2.90(2H，t，J＝7.3Hz)，3.22(2H，t，J＝7.3Hz)，7.01(2H，d，J＝8.5Hz)，7.32(2H，d，J＝8.5Hz)，9.22(1H，s)，9.77(1H，s)，12.68(1H，s)。

MS：390(M+H) ⁺

Step 3

At 5 ℃, add (2S)-2-(N, N-dimethylamino carbonyl) pyrrolidine hydrochloride and diisopropylethylamine (0.27ml) in methylene dichloride (6mL) solution of step 2 compound (200mg).At 5 ℃ of 10min that stir the mixture.Add sodium triacetoxy borohydride (327mg) then, 3h stirs the mixture.Add NH ₄The Cl aqueous solution, the mixture dichloromethane extraction.The organic layer dried over mgso.The concentrating under reduced pressure organic layer.The gained crude mixture is with silica gel column chromatography purify (with mixed solvent (methylene chloride=15/1) as eluent); obtain light yellow amorphous substance (4-{2-[2-(acetylamino)-5-((2S)-2-[(N; the N-dimethylamino) carbonyl]-the 1-pyrrolidyl } methyl)-1,3-thiazoles-4-yl] ethyl } phenyl) t-butyl carbamate.

¹H-NMR(200MHz，CDCl ₃)，δ(ppm)：1.67-1.99(4H，m)，2.24(3H，s)，2.04(4H，s)，2.14(3H，s)，2.95-3.14(5H，m)，3.42-3.58(2H，m)，3.68-3.83(1H，m)，6.97(2H，d，J＝8.3Hz)，7.94(2H，d，J＝8.3Hz)。

MS：516(M+H) ⁺

Step 4

(2S)-1-(2-(acetylamino)-4-[2-(4-aminophenyl) ethyl]-1,3-thiazoles-5-yl } methyl)-N, N-dimethyl-2-pyrrolidine formamide is according to the similar approach preparation of preparation embodiment 31 steps 2.

¹H-NMR(200MHz，CDCl ₃)，δ(ppm)：1.70-2.10(4H，m)，2.22(3H，s)，2.39(1H，q，J＝8.4Hz)，2.77(4H，m)，2.91(3H，s)，3.03(3H，s)，3.30-3.81(6H，m)，6.58(2H，d，J＝8.3Hz)，6.89(2H，d，J＝8.3Hz)，8.82(1H，br)。

MS；416(M+H) ⁺

Step 5

(Z)-[(4-{2-[2-(acetylamino)-5-((2S)-2-[(N; the N-dimethylamino) carbonyl]-the 1-pyrrolidyl } methyl)-1,3-thiazoles-4-yl] ethyl } phenyl) amino] methylene radical } the diamino acid di tert butyl carbonate is according to the similar approach preparation of preparation embodiment 31 steps 3.

¹H-NMR(200MHz，CDCl ₃)，δ(ppm)：1.50(9H，s)，1.52(9H，s)，1.76-1.92(4H，m)，2.04-2.14(1H，m)，2.43(1H，dd，J＝8.1，8.0Hz)，2.45(3H，s)，2.85(2H，s)，3.07(3H，s)，3.51(1H，dd，J＝5.7，8.0Hz)，3.60(1H，d，J＝14.3Hz)，3.84(1H，d，J＝14.3Hz)，6.37(1H，t，J＝2.0Hz)，7.08(2H，d，J＝8.4Hz)，7.44(2H，d，J＝8.4Hz)，7.63(1H，d，J＝2.0Hz)，10.23(1H，s)，11.62(1H，br)。

MS：658(M+H) ⁺

Step 6

¹H-NMR(200MHz，DMSO-d ₆)，δ(ppm)：1.60-1.98(2H，br)，1.98-2.16(1H，br)，2.16(3H，s)，2.85(3H，s)，2.95(7H，br)，3.00-3.30(1H，br)，7.15(2H，d，J＝8.3Hz)，7.30(2H，d，J＝8.3Hz)，7.55(4H，br)，7.85(1H，d，J＝2.2Hz)，9.65(1H，br)，10.21(1H，s)，12.35(1H，s)。

MS:458 (M+H) ⁺(free type)

Preparation embodiment 100:

Synthetic 3-[({2-(acetylamino)-4-[2-(4-{[amino (imino-) methyl] amino } phenyl) ethyl]-1,3-thiazoles-5-yl } methyl) (methyl) amino]-N, N-dimethyl propylene acid amides dihydrochloride

Step 1

(4-{2-[2-(acetylamino)-5-({ [3-(N; the N-dimethylamino)-and the 3-oxopropyl] amino } methyl)-1,3-thiazoles-4-yl] ethyl } phenyl) the t-butyl carbamate similar approach preparation of the compound of preparation embodiment 99 steps 2 according to preparation embodiment 99 steps 3.

¹H-NMR(200MHz，CDCl ₃)，δ(ppm)：1.50(9H，s)，2.24(3H，s)，2.47(2H，t，J＝6.2Hz)，2.74(2H，t，J＝6.2Hz)，2.82-2.88(4H，m)，2.93(3H，s)，2.97(3H，s)，3.59(2H，s)，6.94(2H，d，J＝8.3Hz)，7.21(2H，d，J＝8.3Hz)，8.02(1H，s)。

MS：490(M+H) ⁺

Step 2

Add formalin (35%, 87.6 μ l) in methylene dichloride (1.5mL) solution of step 1 compound (100mg).Add 0.05ml MeOH in this suspension.Add sodium triacetoxy borohydride (433mg) then, 12h stirs the mixture.Add entry and 1N NaOH in the mixture to regulate the pH (about pH 8-9) of water.The mixture dichloromethane extraction.The organic layer dried over mgso, concentrating under reduced pressure.Gained oily matter is purified (with mixed solvent C H with silica gel column chromatography ₂Cl ₂/ MeOH 15/1 is as eluent); obtain light yellow oil { 4-[2-(2-(acetylamino)-5-{[[3-(N; the N-dimethylamino)-and the 3-oxopropyl] (methyl) amino] methyl }-1,3-thiazoles-4-yl) ethyl] phenyl } t-butyl carbamate (90.4mg).

¹H-NMR(200MHz，CDCl ₃)，δ(ppm)：1.51(9H，s)，2.18(3H，s)，2.24(3H，s)，2.45(2H，m)，2.62(2H，m)，2.80(4H，s)，2.93(3H，s)，2.99(3H，s)，3.35(2H，s)，6.96(2H，d，J＝8.3Hz)，7.20(2H，d，J＝8.3Hz)。

MS：504(M+H) ⁺

Step 3

3-[({2-(acetylamino)-4-[2-(4-aminophenyl) ethyl]-1,3-thiazoles-5-yl } methyl) (methyl) amino]-N, N-dimethyl propylene acid amides is according to the similar approach preparation of preparation embodiment 31 steps 2.

¹H-NMR(200MHz，CDCl ₃)，δ(ppm)：2.19(3H，s)，2.22(2H，s)，2.43-2.51(2H，m)，2.62-2.71(4H，m)，2.78(3H，s)，2.93(3H，s)，2.99(3H，s)，3.33(2H，s)，3.65(1H，m)，3.75(1H，m)，6.58(2H，d，J＝8.3Hz)，6.87(2H，d，J＝8.3Hz)。

MS：404(M+H) ⁺

Step 4

[(Z)-({ 4-[2-(2-(acetylamino)-5-{[[3-(N; the N-dimethylamino)-and the 3-oxopropyl] (methyl) amino] methyl }-1,3-thiazoles-4-yl) ethyl] phenyl } amino) methylene radical] the diamino acid di tert butyl carbonate is according to the similar approach preparation of preparation embodiment 31 steps 3.

¹H-NMR(200MHz，CDCl ₃)，δ(ppm)：1.50(9H，s)，1.53(9H，s)，2.20(3H，s)，2.22(3H，s)，2.49(2H，dd，J＝6.5，5.5Hz)，2.71(2H，dd，J＝6.5，5.5Hz)，2.84(4H，s)，2.93(3H，s)，2.99(3H，s)，3.43(2H，s)，7.08(2H，d，J＝8.4Hz)，7.46(2H，d，J＝8.4Hz)，7.62(1H，s)，10.24(1H，s)，11.62(1H，s)。

MS：646(M+H) ⁺

Step 5

¹H-NMR(200MHz，DMSO-d ₆)，δ(ppm)：2.15(3H，s)，2.68(3H，d，J＝4.0Hz)，2.83-2.88(6H，m)，2.96(6H，s)，3.05-3.15(2H，m)，4.44(2H，m)，7.15(2H，d，J＝8.3Hz)，7.32(2H，d，J＝8.3Hz)，7.62(4H，br)，9.90(1H，s)，12.32(1H，s)。

MS:446 (M+H) ⁺(free type)

Preparation embodiment 101:

Synthetic 4-(2-{2-(acetylamino)-4-[2-(4-{[amino (imino-) methyl] amino } phenyl) ethyl]-1,3-thiazoles-5-yl } ethyl)-N, N-dimethyl benzamide hydrochloride

Step 1

4-{2-[2-(acetylamino)-4-(2-{4-[(tert-butoxycarbonyl) amino] phenyl } ethyl)-1,3-thiazoles-5-yl] vinyl } the methyl benzoate similar approach preparation of the compound of preparation embodiment 99 steps 2 according to preparation embodiment 53 steps 1.

¹H-NMR(CDCl ₃)，δ(ppm)：1.50(9Hx4/9，s)，1.51(9Hx5/9，s)，2.20(3Hx5/9，s)，2.29(3Hx4/9，s)，2.72-3.06(4H，m)，3.90(3Hx5/9，s)，3.92(3Hx4/9，s)，6.42-6.60(2Hx5/9，m)，6.69(1Hx4/9，d，J＝16.6Hz)，6.81-7.03(4H+1Hx4/9，m)，7.31(2Hx5/9，d，J＝8.0Hz)，7.39(2Hx4/9，d，J＝8.0Hz)，7.96(2Hx5/9，d，J＝8.0Hz)，7.99(2Hx4/9，d，J＝8.0Hz)。

MS：522.2(M+H) ⁺，544.2(M+Na) ⁺

Step 2

4-{2-[2-(acetylamino)-4-(2-{4-[(tert-butoxycarbonyl) amino] phenyl } ethyl)-1,3-thiazoles-5-yl] ethyl } methyl benzoate is according to the similar approach preparation of preparation embodiment 45 steps 6.

MS：524.25(M+H) ⁺

Step 3

4-{-[2-(acetylamino)-4-(2-{4-[(tert-butoxycarbonyl) amino] phenyl } ethyl)-1,3-thiazoles-5-yl] ethyl } phenylformic acid is according to the similar approach preparation 5 of preparation embodiment 65 steps 2.

¹H-NMR(DMSO-d ₆)，δ(ppm)：1.45(9H，s)，2.09(3H，s)，2.57-2.72(6H，m)，2.75-2.86(2H，m)，6.94(2H，d，J＝8.4Hz)，7.21(2H，d，J＝8.4Hz)，7.32(2H，d，J＝8.4Hz)，7.82(2H，d，J＝8.4Hz)，9.21(1H，s)，11.94(1H，s)，12.41-13.20(1H，brs)。

MS：510.2(M+H) ⁺，532.2(M+Na) ⁺

Step 4

(4-{2-[2-(acetylamino)-5-(2-{4-[(methylamino) carbonyl] phenyl } ethyl)-1,3-thiazoles-4-yl] ethyl } phenyl) t-butyl carbamate is according to the similar approach preparation of preparation embodiment 65 steps 3.

¹H-NMR(CDCl ₃)，δ(ppm)：1.51(9H，s)，2.24(3H，s)，2.56-2.73(4H，m)，2.73-2.86(4H，m)，2.99(3H，d，J＝4.8Hz)，6.05(1H，d，J＝4.4Hz)，6.25-6.75(1H，brs)，6.77(2H，d，J＝6.6Hz)，7.12(2H，d，J＝8.1Hz)，7.15-7.23(2H，m)，7.63(2H，d，J＝8.1Hz)，8.43-9.18(1H，brs)。

MS：523.29(M+H) ⁺

Step 5

{ (Z)-[(4-{2-[2-(acetylamino)-5-(2-{4-[(methylamino) carbonyl] phenyl } ethyl)-and 1,3-thiazoles-4-yl] ethyl } phenyl) amino] methylene radical } the diamino acid di tert butyl carbonate is according to the similar approach preparation of preparation embodiment 65 steps 4.

¹H-NMR(CDCl ₃)，δ(ppm)：1.48(9H，s)，1.54(9H，s)，2.22(3H，s)，2.51-2.61(2H，m)，2.61-2.71(2H，m)，2.79-2.90(4H，m)，2.97(3H，d，J＝4.8Hz)，6.20(1H，d，J＝4.8Hz)，6.98(2H，d，J＝8.4Hz)，7.13(2H，d，J＝8.1Hz)，7.40(2H，d，J＝8.4Hz)，7.64(2H，d，J＝8.4Hz)，8.83-9.42(1H，brs)，10.21(1H，s)，11.62(1H，s)。

MS：687.2(M+Na) ⁺

Step 6

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.09(3H，s)，2.58-2.79(6H，m)，2.80-3.02(8H，m)，7.13(2H，d，J＝8.4Hz)，7.19(2H，d，J＝8.1Hz)，7.20(2H，d，J＝8.4Hz)，7.29(2H，d，J＝8.1Hz)，7.32(4H，s)，9.66(1H，s)，11.93(1H，s)。

MS:479.2 (M+H) ⁺(free type)

Preparation embodiment 102:

Synthetic 4-(2-{2-(acetylamino)-4-[2-(4-{[amino (imino-) methyl] amino } phenyl) ethyl]-1,3-thiazoles-5-yl } ethyl)-the N-methyl-benzamide hydrochloride

Step 1

(4-{2-[2-(acetylamino)-5-(2-{4-[(dimethylamino) carbonyl] phenyl } ethyl)-1,3-thiazoles-4-yl] ethyl } phenyl) the t-butyl carbamate similar approach preparation of the compound of preparation embodiment 101 steps 3 according to preparation embodiment 65 steps 3.

¹H-NMR(CDCl ₃)，δ(ppm)：1.51(9H，s)，2.23(3H，s)，2.66(4H，s)，2.79(4H，s)，2.93(3H，s)，3.08(3H，s)，6.90(2H，d，J＝8.0Hz)，7.11(2H，d，J＝8.0Hz)，7.18(2H，d，J＝8.0Hz)，8.56-10.01(1H，brs)。

MS：537(M+H) ⁺，559.2(M+Na) ⁺

Step 2

{ (Z)-[(4-{2-[2-(acetylamino)-5-(2-{4-[(dimethylamino) carbonyl] phenyl } ethyl)-and 1,3-thiazoles-4-yl] ethyl } phenyl) amino] methylene radical } the diamino acid di tert butyl carbonate is according to the similar approach preparation of preparation embodiment 65 steps 4.

¹H-NMR(CDCl ₃)，δ(ppm)：1.49(9H，s)，1.53(9H，s)，2.21(3H，s)，2.57-2.78(4H，m)，2.82(4H，s)，2.94(3H，s)，3.08(3H，s)，7.03(2H，d，J＝8.5Hz)，7.13(2H，d，J＝8.0Hz)，7.33(2H，d，J＝8.0Hz)，7.45(2H，d，J＝8.5Hz)，8.28-9.61(1H，brs)，10.24(1H，s)，11.63(1H，s)。

MS：679.2(M+H) ⁺，701.2(M+Na) ⁺

Step 3

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.10(3H，s)，2.60-2.72(4H，m)，2.72-2.80(2H，m)，2.76(3H，d，J＝4.4Hz)，2.89(2H，t，J＝7.3Hz)，7.12(2H，d，J＝8.4Hz)，7.19(2H，d，J＝8.4Hz)，7.22(2H，d，J＝8.1Hz)，7.33(4H，s)，7.73(2H，d，J＝8.1Hz)，8.36(1H，d，J＝4.4Hz)，9.66(1H，s)，11.93(1H，s)。

MS:465.2 (M+H) ⁺(free type)

Preparation embodiment 103:

Synthetic N-[4-(2-(acetylamino)-4-[2-(4-{[amino (imino-) methyl] amino } phenyl) ethyl]-1,3-thiazoles-5-yl } methyl) phenyl] the Urethylane hydrochloride

Step 1

4-{[2-(acetylamino)-4-(2-{4-[(tert-butoxycarbonyl) amino] phenyl } ethyl)-1; 3-thiazole-5-yl] methyl } (0.5ml) is with add triethylamine (28.1 μ l) and diphenyl phosphate azide (39.1 μ l) in diox (0.5ml) suspension for the toluene of phenylformic acid (50mg); at 25 ℃ of 2h that stir the mixture, stir 1h at 100 ℃ then.Add methyl alcohol (1ml) in the reaction mixture, with the mixture 2h that refluxes, vacuum concentration.Resistates preparation type silica gel thin-layer chromatography purification (using chloroform/methanol (20: 1)) as eluent; obtain N-(4-{[2-(acetylamino)-4-(2-{4-[(tert-butoxycarbonyl) amino] phenyl } ethyl)-1,3-thiazoles-5-yl] methyl } phenyl) Urethylane (17.2mg).

¹H-NMR(CDCl ₃)，δ(ppm)：1.52(9H，s)，2.22(3H，s)，2.80(4H，s)，3.76(3H，s)，3.79(2H，s)，6.62-6.78(1H，brs)，6.83-7.05(1H，brs)，6.90(2H，d，J＝8.0Hz)，6.98(2H，d，J＝8.5Hz)，7.17(2H，d，J＝8.0Hz)，7.20-7.33(2H，m)。

MS：547.2(M+Na) ⁺

Step 2

[(Z)-({ 4-[2-(2-(acetylamino)-5-{4-[(methoxycarbonyl) amino] benzyl }-1,3-thiazoles-4-yl) ethyl] phenyl } amino) methylene radical] the diamino acid di tert butyl carbonate is according to the similar approach preparation of preparation embodiment 65 steps 4.

¹H-NMR(CDCl ₃)，δ(ppm)：1.49(9H，s)，1.54(9H，s)，2.19(3H，s)，2.82(4H，s)，3.76(3H，s)，3.80(2H，s)，6.72-6.90(1H，brs)，6.98(2H，d，J＝8.5Hz)，7.00(2H，d，J＝8.5Hz)，7.26(2H，d，J＝8.5Hz)，7.39(2H，d，J＝8.5Hz)，9.10-9.59(1H，brs)，10.19(1H，s)，11.64(1H，s)。

MS：667.2(M+H) ⁺，689.2(M+Na) ⁺

Step 3

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.08(3H，s)，2.85(4H，s)，3.64(3H，s)，3.85(2H，s)，7.04(2H，d，J＝8.5Hz)，7.14(2H，d，J＝8.4Hz)，7.24(2H，d，J＝8.4Hz)，7.28-7.47(6H，m)，9.58(1H，s)，9.70(1H，s)，11.96(1H，s)。

MS：467.2(M+H) ⁺

Preparation embodiment 104:

Synthetic 1-(2-(acetylamino)-4-[2-(4-{[amino (imino-) methyl] amino } phenyl) ethyl]-1,3-thiazoles-5-yl } methyl)-4-piperidine ethyl formate dihydrochloride

Step 1

1-(2-(acetylamino)-4-[(Z)-2-(4-nitrophenyl) vinyl]-1; 3-thiazole-5-yl } methyl)-4-piperidine ethyl formate N-{4-[(Z)-2-(4-nitrophenyl) vinyl]-1,3-thiazoles-2-yl } ethanamide is according to the similar approach preparation of preparation embodiment 67 steps 1.

MS：459.17(M+H) ⁺

Step 2

1-[(2-(acetylamino)-4-{2-[4-({ (Z)-[(tert-butoxycarbonyl) amino] [(tert-butoxycarbonyl) imino-] methyl } amino) phenyl] ethyl }-1,3-thiazoles-5-yl) methyl]-the 4-piperidine ethyl formate is according to the similar approach preparation of preparation embodiment 68 steps 2.

¹H-NMR(CDCl ₃)，δ(ppm)：1.24(3H，t，J＝7.2Hz)，1.50(9H，s)，1.53(9H，s)，1.65-2.09(6H，m)，2.13-2.34(4H，s)，2.71-2.95(6H，m)，3.39(2H，s)，4.12(2H，q，J＝7.2Hz)，7.07(2H，d，J＝8.5Hz)，7.46(2H-，d，J＝8.5Hz)，10.24(1H，s)，11.63(1H，brs)。

MS：673.3(M+H) ⁺，695.3(M+Na) ⁺

Step 3

¹H-NMR(DMSO-d ₆)，δ(ppm)：1.18(3H，t，J＝7.1Hz)，1.73-1.90(2H，m)，1.93-2.13(2H，m)，2.16(3H，s)，2.87-3.01(6H，m)，3.30-3.41(2H，m)，4.08(2H，q，J＝7.1Hz)，4.31-4.43(2H，m)，7.15(2H，d，J＝8.4Hz)，7.31(2H，d，J＝8.4Hz)，7.42(4H，s)，9.90(1H，s)，10.23-10.46(1H，brs)，12.3(1H，s)。

MS:473.2 (M+H) ⁺, 495.2 (M+Na) ⁺(free type)

Preparation embodiment 105:

Synthetic 1-(2-(acetylamino)-4-[2-(4-{[amino (imino-) methyl] amino } phenyl) ethyl]-1,3-thiazoles-5-yl } methyl)-4-piperidine ethyl formate hydrochloride

Title compound is according to the similar approach preparation of embodiment 104.

Preparation embodiment 106:

Synthetic 4-(2-{2-(acetylamino)-5-[4-(methyl sulphonyl) benzyl]-1,3-thiazoles-4-yl } ethyl)-N-[amino (imino-) methyl] benzamide

Guanidinesalt hydrochlorate (152mg) is dissolved in DMF (3ml); then at methanol solution (0.3ml) the adding solution of room temperature with 28% sodium methylate; with suspension at stirring at room 15min; room temperature with 4-(2-{2-(acetylamino)-5-[4-(methyl sulphonyl) benzyl]-1; 3-thiazole-4-yl } ethyl) methyl benzoate (150mg) adding mixture; at stirring at room reaction mixture 14h, vacuum concentration.Resistates is water-soluble, with 1N HCl neutralization.By filtering collecting precipitation, purify with preparation type silica gel chromatography and (use CHCl ₃/ MeOH (10: 1) is as eluent).Solid washs with ether, obtain Off-white solid 4-(2-{2-(acetylamino)-5-[4-(methyl sulphonyl) benzyl]-1,3-thiazoles-4-yl ethyl)-N-[amino (imino-) methyl] benzamide (36.6mg).

mp.108-109.5℃

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.09(3H，s)，2.89(4H，s)，3.16(3H，s)，4.06(2H，s)，7.15(2H，d，J＝8.0Hz)，7.27(2H，d，J＝8.0Hz)，7.78(2H，d，J＝8.0Hz)，7.95(2H，d，J＝8.0Hz)，12.04(1H，s)。

MS：500(M+H) ⁺

Preparation embodiment 107:

Synthetic (2-{[4-(2-{2-(acetylamino)-5-[4-(methyl sulphonyl) benzyl]-1,3-thiazoles-4-yl } ethyl) phenyl] amino }-the 2-oxoethyl) t-butyl carbamate

Title compound is with 2-(acetylamino)-4-[2-(4-aminophenyl) ethyl]-5-[4-(methyl sulphonyl) benzyl]-1,3-thiazoles is according to the similar approach preparation of preparation embodiment 10 steps 1.

mp.186-187.5℃

¹H-NMR(DMSO-d ₆)，δ(ppm)：1.39(9H，s)，2.08(3H，s)，2.84(4H，s)，3.17(3H，s)，3.71(2H，d，J＝6.0Hz)，4.00(2H，s)，7.01(1H，t，J＝6.0Hz)，7.06(2H，d，J＝8.5Hz)，7.28(2H，d，J＝8.5Hz)，7.46(2H，d，J＝8.5Hz)，7.79(2H，d，J＝8.5Hz)，9.86(1H，s)，12.04(1H，s)。

MS：587(M+H) ⁺

Preparation embodiment 108:

Synthetic N-[4-(2-{2-(acetylamino)-5-[4-(methyl sulphonyl) benzyl]-1,3-thiazoles-4-yl } ethyl) phenyl]-2-glycyl amine hydrochlorate

Title compound prepares according to the similar approach for preparing embodiment 10 steps 2 with the compound of preparation embodiment 107.

mp.142.5-144℃

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.09(3H，s)，2.85(4H，s)，3.18(3H，s)，3.78(2H，m)，4.00(2H，s)，7.10(2H，d，J＝8.5Hz)，7.26(2H，d，J＝8.5Hz)，7.50(2H，d，J＝8.5Hz)，7.79(2H，d，J＝8.5Hz)，8.22(3H，brs)，10.63(1H，s)，12.06(1H，s)。

MS:487 (M+H) ⁺(free type)

Preparation embodiment 109:

Synthetic N-(4-{2-[4-(2-amino-ethyl) phenyl] ethyl }-1,3-thiazoles-2-yl) acetamide hydrochloride

Step 1

With N-(4-{2-[4-(cyano methyl) phenyl] ethyl }-1,3-thiazoles-2-yl) ethanamide (1g), 1N NaOH (7ml) and EtOH (14ml) mix, with reaction mixture refluxed 8h.After being cooled to room temperature, vacuum is removed organic solvent.The aqueous solution extracts with AcOEt with 1N HCl neutralization.Organic layer water and salt water washing are used anhydrous magnesium sulfate drying, vacuum concentration.The yellow wax of remnants (1.03g) is dissolved in THF (10ml), at 0 ℃ lithium aluminum hydride (266mg) is added solution then.With reaction mixture refluxed 3h, use the MeOH quencher.Then with Na ₂SO ₄/ 10H ₂O adds mixture, at stirring at room mixture 1h, filters by Celite pad.Vacuum concentrated filtrate.Under nitrogen atmosphere, the yellow amorphous substance of remnants (835.5mg) is dissolved in THF (10ml) and DMF (10ml).Then at THF (5ml) the solution adding solution of room temperature with tert-Butyl dicarbonate (841mg), at stirring at room reaction mixture 12h, vacuum concentration obtains yellow oil (2-{4-[2-(2-amino-1,3-thiazoles-4-yl) ethyl] phenyl } ethyl) t-butyl carbamate (171.6mg).

¹H-NMR(DMSO-d ₆)，δ(ppm)：1.38(9H，s)，2.60-2.70(4H，m)，2.79-2.88(4H，m)，6.82(1H，s)，7.07(2H，d，J＝8.0Hz)，7.11(2H，d，J＝8.0Hz)。

MS：348(M+H) ⁺

Step 2

[2-(4-{2-[2-(acetylamino)-1,3-thiazoles-4-yl] ethyl } phenyl) ethyl] the t-butyl carbamate similar approach preparation of the compound of step 1 according to preparation embodiment 45 steps 3.

¹H-NMR(DMSO-d ₆)，δ(ppm)：1.36(9H，s)，2.11(3H，s)，2.58-2.70(1H，m)，2.80-2.97(6H，m)，3.02-3.18(1H，m)，6.72(1H，s)，7.08(2H，d，J＝8.0Hz)，7.23(2H，d，J＝8.0Hz)，12.08(1H，s)。

MS：390(M+H) ⁺

Step 3

Title compound prepares according to the similar approach for preparing embodiment 10 steps 2 with the compound of step 2.

mp.165-167℃

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.12(3H，s)，2.79-3.09(8H，m)，6.75(1H，s)，7.16(4H，s)，8.14(2H，brs)，12.13(1H，brs)。

MS:290 (M+H) ⁺(free type)

Preparation embodiment 110:

Synthetic N-(4-{2-[4-(2-{[amino (imino-) methyl] amino } ethyl) phenyl] ethyl }-1,3-thiazoles-2-yl) acetamide hydrochloride

Step 1

With N-(4-{2-[4-(2-amino-ethyl) phenyl] ethyl-1, the 3-thiazol-2-yl) acetamide hydrochloride (7mg), N, N '-two (tert-butoxycarbonyl)-1H-pyrazoles-1-carbonamidine (6.57mg), N, N-diisopropylethylamine (0.00748ml), THF (0.5ml) and DMF (0.1ml) mix under nitrogen atmosphere.At stirring at room reaction mixture 43h, vacuum concentration.Resistates preparation type silica gel chromatography purification (using normal hexane/AcOEt (1: 1)) as eluent; obtain colorless oil ((z)-{ [2-(4-{2-[2-(acetylamino)-1,3-thiazoles-4-yl] ethyl } phenyl) ethyl] amino }-methylene radical) diamino acid di tert butyl carbonate (5.9mg).

¹H-NMR[CD ₃Cl/CD ₃OD(1∶1)]，δ(ppm)：1.50(18H，s)，2.24(3H，s)，2.86(2H，t，J＝7.0Hz)，2.95(4H，s)，3.62(2H，t，J＝7.0Hz)，4.24(2H，s)，6.50(1H，s)，7.11(2H，d，J＝8.5Hz)，7.16(2H，d，J＝8.5Hz)。

MS：532(M+H) ⁺

Step 2

Title compound prepares according to the similar approach for preparing embodiment 31 steps 4 with the compound of step 1.

¹H-NMR[CD ₃Cl/CD ₃OD(1∶1)]，δ(ppm)：2.41(3H，s)，2.87(2H，t，J＝7.0Hz)，3.05(4H，s)，3.44(2H，t，J＝7.0Hz)，6.86(1H，s)，7.18(4H，s)。

MS:332 (M+H) ⁺(free type)

Preparation embodiment 111:

Synthetic N-(4-{4-[(2-{[amino (imino-) methyl] amino } ethyl) alkylsulfonyl] phenyl }-1,3-thiazoles-2-yl) acetamide hydrochloride

Step 1

With 1-[4-(methylthio group) phenyl] ethyl ketone (5.5g) is dissolved in AcOH (55ml), at 0 ℃ 90% tribromide pyridine (11.8g) and 30% Hydrogen bromide/AcOH (5.5ml) added solution then.At stirring at room reaction mixture 30min, in the impouring water.Mixture extracts with AcOEt.Organic layer is used anhydrous magnesium sulfate drying, vacuum concentration with saturated sodium bicarbonate and salt water washing.Residual solid (8.03g), thiocarbamide (3.78g) and EtOH (55ml) are mixed.With the reaction mixture 1.5h that under nitrogen atmosphere, refluxes.After being cooled to room temperature, vacuum leaches precipitation.Solid obtains light yellow solid 4-[4-(methylthio group) phenyl with EtOH and water washing]-1,3-thiazoles-2-amine (7.48g).

mp.245-246℃

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.51(3H，s)，7.18(1H，s)，7.35(2H，d，J＝8.5Hz)，7.67(2H，d，J＝8.5Hz)。

MS：223(M+H) ⁺

Step 2

N-{4-[4-(methylthio group) phenyl]-1,3-thiazoles-2-yl } the ethanamide similar approach preparation of the compound of step 1 according to preparation embodiment 45 steps 3.

mp.235-236℃

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.16(3H，s)，2.50(3H，s)，7.31(2H，d，J＝8.5Hz)，7.56(1H，s)，7.83(2H，d，J＝8.5Hz)，12.24(1H，brs)。

MS：265(M+H) ⁺

Step 3

With N-{4-[4-(methylthio group) phenyl]-1,3-thiazoles-2-yl } ethanamide (2g) is suspended in CH ₂Cl ₂(20ml), at 0 ℃ 3-chlorine peroxybenzoic acid (1.44g) is progressively added suspension then.At stirring at room reaction mixture 15min.Vacuum leaches precipitation, solid 1N Na ₂CO ₃, water and EtOH washing, obtain colorless solid N-{4-[4-(methylsulfinyl) phenyl]-1,3-thiazoles-2-yl ethanamide (2.80g).

mp.274-274.5℃

¹H-MR(DMSO-d ₆)，δ(ppm)：2.10(3H，s)，2.77(3H，s)，7.62(1H，s)，7.71(2H，d，J＝8.5Hz)，8.07(2H，d，J＝8.5Hz)。

MS：279(M-H) ⁺

Step 4

With N-{4-[4-(methylsulfinyl) phenyl]-1,3-thiazoles-2-yl } ethanamide (1.5g), sodium acetate (1.54g), acetic anhydride (30ml) mix under nitrogen atmosphere.With reaction mixture refluxed 2h.After being cooled to room temperature, mixture dilutes with AcOEt.Organic solution water and salt water washing are used anhydrous magnesium sulfate drying, vacuum concentration.Residual solid obtains Off-white solid acetate ({ 4-[2-(acetylamino)-1,3-thiazoles-4-yl] phenyl } sulfenyl) methyl esters (811.2mg) with the washing of ether/normal hexane.

mp.144-145℃

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.07(3H，s)，2.17(3H，s)，5.53(2H，s)，7.50(2H，d，J＝8.5Hz)，7.63(1H，s)，7.88(2H，d，J＝8.5Hz)，12.27(1H，brs)。

MS：323(M+H) ⁺

Step 5

Under nitrogen atmosphere, acetate ({ 4-[2-(acetylamino)-1,3-thiazoles-4-yl] phenyl } sulfenyl) methyl esters (40mg) is dissolved in CH ₂Cl ₂(0.6ml) and MeOH (0.3ml).At 0 ℃ monoperoxyphthalic acid magnesium (120mg) is added solution then.At stirring at room reaction mixture 2h.With water and CHCl ₃Add mixture, the extraction mixture.Organic layer is used anhydrous magnesium sulfate drying, vacuum concentration with saturated sodium bicarbonate and salt water washing.Residual solid is washed with ether, obtains colorless solid acetate ({ 4-[2-(acetylamino)-1,3-thiazoles-4-yl] phenyl } alkylsulfonyl) methyl esters (29.7mg).

mp.237-238℃

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.07(3H，s)，2.18(3H，s)，5.43(2H，s)，7.94(1H，s)，7.97(2H，d，J＝8.5Hz)，8.17(2H，d，J＝8.5Hz)，12.37(1H，brs)。

MS：355(M+H) ⁺

Step 6

Acetate ({ 4-[2-(acetylamino)-1,3-thiazoles-4-yl] phenyl } alkylsulfonyl) methyl esters (700mg), THF (8ml), MeOH (4ml) and 1N NaOH (1.98ml) are mixed.At stirring at room reaction mixture 1.5h, vacuum concentration.Residual solid is washed with ether, obtains colorless solid 4-[2-(acetylamino)-1,3-thiazoles-4-yl] Sodium phenylsulfinate (731mg).

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.16(3H，s)，7.52(2H，d，J＝8.0Hz)，7.54(1H，s)，7.84(2H，d，J＝8.0Hz)。

MS:281 (M-H) ⁺(free type)

Step 7

Under nitrogen atmosphere with 4-[2-(acetylamino)-1,3-thiazoles-4-yl] Sodium phenylsulfinate (600mg) is dissolved in DMF (2ml).At 0 ℃ ethylene bromohyrin (0.168ml) is added solution then.At 100 ℃ of stirred reaction mixture 7h.After being cooled to room temperature, water and AcOEt are added mixture.Vacuum leaches precipitation and obtains Off-white solid N-(4-{4-[(2-hydroxyethyl) alkylsulfonyl] phenyl }-1,3-thiazoles-2-yl) ethanamide (80.2mg).

mp.258-260℃

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.18(3H，s)，3.47(2H，t，J＝6.0Hz)，3.70(2H，q，J＝6.0Hz)，4.89(1H，t，J＝6.0Hz)，7.89(1H，s)，7.94(2H，d，J＝8.5Hz)，8.13(2H，d，J＝8.5Hz)，12.36(1H，brs)。

MS：325(M-H) ⁺

Step 8

With N-(4-{4-[(2-hydroxyethyl) alkylsulfonyl] phenyl }-1,3-thiazoles-2-yl) ethanamide (200mg), Et ₃N (0.102ml) and CH ₂Cl ₂(4ml) under nitrogen atmosphere, mix, at 0 ℃ MsCl (0.05ml) is added suspension then.At stirring at room reaction mixture 2h.With MeOH/CHCl ₃Add mixture with water, the extraction mixture.Organic layer salt water washing is used anhydrous magnesium sulfate drying, vacuum concentration.(221.6mg) is suspended in CH with residual solid ₃CN (10ml) adds suspension at 0 ℃ with 28% ammonia soln (0.5ml) then.At stirring at room reaction mixture 15h, vacuum concentration.Resistates is purified with the silica gel flash column chromatography and (is used MeOH/CHCl successively ₃(1: 30), NH ₄OH/MeOH/CHCl ₃(1: 10: 60) is as eluent), grind with the EtOH/ ether, obtain Off-white solid N-(4-{4-[(2-amino-ethyl) alkylsulfonyl] phenyl }-1,3-thiazoles-2-yl) ethanamide (60.4mg).

mp.287-288℃

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.18(3H，s)，2.79(2H，t，J＝6.5Hz)，3.36(2H，q，J＝6.5Hz)，7.90(1H，s)，7.94(2H，d，J＝8.5Hz)，8.15(2H，d，J＝8.5Hz)。

MS：326(M+H) ⁺

Step 9

((Z)-[2-(4-[2-(acetylamino)-1,3-thiazoles-4-yl] and phenyl } alkylsulfonyl) ethyl] amino } methylene radical) the similar approach preparation of the compound of step 8 of diamino acid di tert butyl carbonate according to preparation embodiment 31 steps 3.

mp.280-281℃

¹H-NMR(DMSO-d ₆)，δ(ppm)：1.38(9H，s)，1.39(9H，s)，2.18(3H，s)，3.65(4H，s)，7.88(1H，s)，7.93(2H，d，J＝8.5Hz)，8.13(2H，d，J＝8.5Hz)，8.32(1H，brs)，11.32(1H，brs)，12.35(1H，brs)。

MS：568(M+H) ⁺

Step 10

Title compound prepares according to the similar approach for preparing embodiment 31 steps 4 with the compound of step 9.

mp.188-189.5℃

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.18(3H，s)，3.51(2H，m)，3.59(2H，t，J＝6.0Hz)，7.28(3H，brs)，7.62(1H，t，J＝5.5Hz)，7.93(1H，s)，7.98(2H，d，J＝8.5Hz)，8.17(2H，d，J＝8.5Hz)，12.37(1H，brs)。

MS:368 (M+H) ⁺(free type)

Preparation embodiment 112:

Synthetic N-{4-[2-(4-{[amino (imino-) methyl] amino } phenyl) ethyl]-5-[3-(methyl sulphonyl) benzyl]-1,3-thiazoles-2-yl } acetamide hydrochloride

Step 1

N-methoxyl group-N-methyl-3-(methyl sulphonyl) benzamide prepares with the similar approach of 3-(methyl sulphonyl) phenylformic acid according to preparation embodiment 31 steps 1.

¹H-NMR(CDCl ₃)，δ(ppm)：3.08(3H，s)，3.40(3H，s)，3.55(3H，s)，7.64(1H，t，J＝8.0Hz)，7.99(1H，dt，J＝8.0，1.5Hz)，8.03(1H，dt，J＝8.0，1.5Hz)，8.28(1H，t，J＝1.5Hz)。

MS：244(M+H) ⁺

Step 2

Under-78 ℃, nitrogen atmosphere, in the anhydrous THF (100ml) of N-methoxyl group-N-methyl-3-(methyl sulphonyl) benzamide (5g) stirred solution, drip DIBALH (22.6ml).At stirring at room reaction mixture 4h, use MeOH then 0 ℃ of quencher.AcOEt and 1NHCl are added mixture, extraction.Organic layer salt water washing is used anhydrous magnesium sulfate drying, vacuum concentration.Remaining oily matter (3.38g), (triphenyl phosphinidene) methyl acetate (6.87g) and THF (68ml) are mixed under room temperature, nitrogen atmosphere, with reaction mixture refluxed 3h.Solvent removed in vacuo is suspended in AcOEt with resistates.The filtering solid, vacuum concentrated filtrate.Resistates is purified (using normal hexane/AcOEt (2: 1) as eluent) with the silica gel flash column chromatography, obtains yellow oil (2E)-3-[3-(methyl sulphonyl) phenyl] methyl acrylate (613.8mg).

¹H-NMR(DMSO-d ₆)，δ(ppm)：3.28(3H，s)，3.75(3H，s)，6.85(1H，d，J＝16.0Hz)，7.74(1H，s)，7.93(1H，t，J＝8.0Hz)，7.96(1H，d，J＝8.0Hz)，8.09(1H，d，J＝8.0Hz)，8.32(1H，d，J＝16.0Hz)。

Step 3

Successively with (2E)-3-[3-(methyl sulphonyl) phenyl] methyl acrylate (600mg), MeOH (6ml) and 10% palladium carbon (99.9mg) mixes under nitrogen atmosphere.Stirred reaction mixture 7h under room temperature, nitrogen atmosphere (1atm) filters by Celite pad.Vacuum concentrated filtrate.Resistates is purified (using normal hexane/AcOEt (1: 1 → 1: 2) as eluent) with the silica gel flash column chromatography, obtains colorless oil 3-[3-(methyl sulphonyl) phenyl] methyl propionate (283.3mg).

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.70(2H，t，J＝7.5Hz)，2.97(2H，t，J＝7.5Hz)，3.20(3H，s)，3.58(3H，s)，7.52-7.63(2H，m)，7.73-7.80(2H，m)。

Step 4

4-[3-(methyl sulphonyl) phenyl]-the similar approach preparation of the compound of step 3 of 2-ketobutyric acid ethyl ester according to preparation embodiment 47 steps 2.

¹H-NMR(CDCl ₃)，δ(ppm)：1.35(3H，t，J＝7.0Hz)，3.05(2H，t，J＝7.0Hz)，3.06(3H，s)，3.24(2H，t，J＝7.0Hz)，4.32(2H，q，J＝7.0Hz)，7.45-7.82(4H，m)。

Step 5

3-bromo-4-[3-(methyl sulphonyl) phenyl]-the similar approach preparation of the compound of step 4 of 2-ketobutyric acid ethyl ester according to preparation embodiment 46 steps 1.

¹H-NMR(CDCl ₃)，δ(ppm)：1.37(3H，t，J＝7.0Hz)，3.07(3H，s)，3.34(1H，dd，J＝14.5，8.0Hz)，3.60(1H，dd，J＝14.5，6.5Hz)，4.35(2H，q，J＝7.0Hz)，5.26(1H，dd，J＝8.0，6.5Hz)，7.49-7.88(4H，m)。

Step 6

2-amino-5-[3-(methyl sulphonyl) benzyl]-the similar approach preparation of the compound of step 5 of 1,3-thiazoles-4-ethyl formate according to preparation embodiment 46 steps 2.

¹H-NMR(DMSO-d ₆)，δ(ppm)：1.24(3H，t，J＝7.0Hz)，3.20(3H，s)，4.20(2H，q，J＝7.0Hz)，4.46(2H，s)，7.10(2H，s)，7.57-7.61(2H，m)，7.76-7.83(2H，m)。

MS：341(M+H) ⁺

Step 7

2-(acetylamino)-5-[3-(methyl sulphonyl) benzyl]-the similar approach preparation of the compound of step 6 of 1,3-thiazoles-4-ethyl formate according to preparation embodiment 45 steps 3.

¹H-NMR(DMSO-d ₆)，δ(ppm)：1.27(3H，t，J＝7.0Hz)，2.10(3H，s)，3.20(3H，s)，4.27(2H，q，J＝7.0Hz)，4.61(2H，s)，7.56-7.66(2H，m)，7.77-7.89(2H，m)，12.47(1H，s)。

MS：383(M+H) ⁺

Step 8

Under nitrogen atmosphere with 2-(acetylamino)-5-[3-(methyl sulphonyl) benzyl]-1,3-thiazoles-4-ethyl formate (54.7mg) is suspended in THF (1ml), at 0 ℃ lithium aluminum hydride (7.79mg) progressively added suspension then.With reaction mixture refluxed 2.5h, use MeOH and 1N HCl 0 ℃ of quencher.Anhydrous magnesium sulfate is added mixture, at stirring at room 1h.Vacuum filtration suspension.Vacuum concentrated filtrate.With remaining oily matter (114.8mg), CHCl ₃(1ml), CH ₃CN (1ml) and Dess-Martin periodinane (88mg) mix under 0 ℃, nitrogen atmosphere.At stirring at room reaction mixture 1h, use CHCl ₃Dilution.The saturated NaHCO of organic solution ₃, water and salt water washing, use anhydrous magnesium sulfate drying, vacuum concentration obtains yellow amorphous substance N-{4-formyl radical-5-[3-(methyl sulphonyl) benzyl]-1,3-thiazoles-2-yl ethanamide (61.2mg).

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.13(3H，s)，3.17(3H，s)，4.67(2H，s)，7.56-7.90(4H，m)，10.04(1H，s)，12.39(1H，s)。

Step 9

N-{5-[3-(methyl sulphonyl) benzyl]-4-[(Z)-2-(4-nitrophenyl) vinyl]-1,3-thiazoles-2-yl } the ethanamide similar approach preparation of the compound of step 8 according to preparation embodiment 45 steps 5.

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.08(3Hx2/3，s)，2.13(3Hx1/3，s)，3.18(3H，s)，4.23(2Hx2/3，s)，4.50(2Hx1/3，s)，6.69-8.31(10H，m)。

Step 10

N-{4-[2-(4-aminophenyl) ethyl]-5-[3-(methyl sulphonyl) benzyl]-1,3-thiazoles-2-yl } the ethanamide similar approach preparation of the compound of step 9 according to preparation embodiment 45 steps 6.

MS：430(M+H) ⁺

Step 11

((Z)-[4-(2-{2-(acetylamino)-5-[3-(methyl sulphonyl) benzyl]-1,3-thiazoles-4-yl } ethyl) phenyl] amino } methylene radical) the similar approach preparation of the compound of step 10 of diamino acid di tert butyl carbonate according to preparation embodiment 31 steps 3.

¹H-NMR[CD ₃Cl/CD ₃OD(1∶1)]，δ(ppm)：1.29(9H，s)，1.55(9H，s)，2.23(3H，s)，2.89(4H，m)，3.07(3H，s)，3.90(2H，s)，7.11-7.87(8H，m)。

MS：672(M+H) ⁺

Step 12

Title compound prepares according to the similar approach for preparing embodiment 31 steps 4 with the compound of step 11.

¹H-NMR(CD ₃OD)，δ(ppm)：2.08(3H，s)，2.98(4H，m)，3.10(3H，s)，3.98(2H，s)，7.10-7.88(8H，m)。

MS:472 (M+H) ⁺(free type)

Preparation embodiment 113:

Synthetic N-{4-[2-(4-{[amino (imino-) methyl] amino } phenyl) ethyl]-5-[(1,1-titanium dioxide-4-thio-morpholinyl) methyl]-1,3-thiazoles-2-yl } the ethanamide dihydrochloride

Step 1

N-{5-[(1,1-titanium dioxide-4-thio-morpholinyl) methyl]-4-[(Z)-and 2-(4-nitrophenyl) vinyl]-1, the 3-thiazol-2-yl } ethanamide N-{4-[(Z)-2-(4-nitrophenyl) vinyl]-1,3-thiazoles-2-yl } ethanamide is according to the similar approach preparation of preparation embodiment 67 steps 1.

MS：437.12(M+H) ⁺

Step 2

((Z)-{ [4-(2-{2-(acetylamino)-5-[(1; 1-titanium dioxide-4-thio-morpholinyl) methyl]-1,3-thiazoles-4-yl } ethyl) phenyl] amino } methylene radical) the similar approach preparation of the compound of step 1 of diamino acid di tert butyl carbonate according to preparation embodiment 68 steps 2.

¹H-NMR(CDCl ₃)，δ(ppm)：1.49(9H，s)，1.53(9H，s)，2.23(3H，s)，2.70-2.95(8H，m)，2.95-3.12(4H，s)，3.45(2H，s)，6.99(2H，d，J＝8.3Hz)，7.42(2H，d，J＝8.3Hz)，8.94-9.24(1H，brs)，10.24(1H，s)，11.63(1H，s)。

MS：651.1(M+H) ⁺，673.3(M+Na) ⁺

Step 3

Title compound prepares according to the similar approach for preparing embodiment 31 steps 4 with the compound of step 2.

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.15(3H，s)，2.97(4H，s)，3.77-4.63(8H，s)，4.45(2H，s)，7.15(2H，d，J＝8.3Hz)，7.32(2H，d，J＝8.3Hz)，7.46(4H，s)，9.96(1H，s)，12.29(1H，s)。

MS：451.3(M+H) ⁺，473.2(M+Na) ⁺

Preparation embodiment 114:

Synthetic N-[4-[2-(4-{[amino (imino-) methyl] amino } phenyl) ethyl]-5-(4-morpholinyl methyl)-1,3-thiazoles-2-yl] the ethanamide dihydrochloride

Step 1

N-{5-(4-morpholinyl methyl)-4-[(Z)-2-(4-nitrophenyl) vinyl]-1, the 3-thiazol-2-yl } ethanamide N-{4-[(Z)-2-(4-nitrophenyl) vinyl]-1,3-thiazoles-2-yl } ethanamide is according to the similar approach preparation of preparation embodiment 67 steps 1.

MS：389.16(M+H) ⁺

Step 2

(Z)-[(4-{2-[2-(acetylamino)-5-(4-morpholinyl methyl)-1,3-thiazoles-4-yl] ethyl } phenyl) amino] methylene radical } the similar approach preparation of the compound of step 1 of diamino acid di tert butyl carbonate according to preparation embodiment 68 steps 2.

¹H-NMR(CDCl ₃)，δ(ppm)：1.50(9H，s)，1.53(9H，s)，2.22(3H，s)，2.30-2.46(4H，m)，2.85(4H，s)，3.39(2H，s)，3.58-3.75(4H，m)，7.07(2H，d，J＝8.4Hz)，7.45(2H，d，J＝8.4Hz)，8.80-9.31(1H，brs)，10.24(1H，s)，11.63(1H，s)。

MS：603.3(M+H) ⁺

Step 3

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.16(3H，s)，2.97(4H，s)，3.00-3.12(2H，m)，3.16-3.27(2H，m)，3.65-3.76(2H，m)，3.86-3.97(2H，m)，4.43(2H，s)，7.15(2H，d，J＝8.4Hz)，7.31(2H，d，J＝8.4Hz)，7.40(4H，s)，9.86(1H，s)，10.54-10.84(1H，brs)，12.34(1H，s)。

MS：403.1(M+H) ⁺，426.1(M+Na) ⁺

Preparation embodiment 115:

Synthetic N-{4-[2-(4-{[amino (imino-) methyl] amino } phenyl) ethyl]-5-[(3-oxo-1-piperazinyl) methyl]-1,3-thiazoles-2-yl } the ethanamide dihydrochloride

Step 1

N-{4-[(Z)-2-(4-nitrophenyl) vinyl]-5-[(3-oxo-1-piperazinyl) methyl]-1, the 3-thiazol-2-yl } ethanamide N-{4-[(Z)-2-(4-nitrophenyl) vinyl]-1,3-thiazoles-2-yl } ethanamide is according to the similar approach preparation of preparation embodiment 67 steps 1.

Z∶E＝3∶1

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.10(3Hx3/4，s)，2.15(3Hx1/4，s)，2.54-2.59(2Hx3/4，m)，2.61-2.67(2Hx1/4，m)，2.93(2Hx3/4，s)，3.02(2Hx1/4，m)，3.08-3.19(2H，m)，3.64(2Hx3/4，s)，3.95(2Hx1/4，s)，6.72(1Hx3/4，d，J＝12.4Hz)，6.78(1Hx3/4，d，J＝12.4Hz)，7.34(1Hx1/4，d，J＝15.7Hz)，7.59(1x1/4，d，J＝15.7Hz)，7.62(2Hx3/4，d，J＝8.8Hz)，7.76(1Hx3/4，s)，7.78(1Hx1/4，s)，7.90(2Hx1/4，d，J＝8.8Hz)，8.14(2Hx3/4，d，J＝8.8Hz)，8.21(2Hx1/4，d，J＝8.8Hz)，11.75-12.06(1Hx3/4，brs)，

12.08-12.33(1Hx1/4，brs)。

MS：402.21(M+H) ⁺

Step 2

((2)-{ [4-(2-{2-(acetylamino)-5-[(3-oxo-1-piperazinyl) methyl]-1,3-thiazoles-4-yl } ethyl) phenyl] amino } methylene radical) the similar approach preparation of the compound of step 1 of diamino acid di tert butyl carbonate according to preparation embodiment 68 steps 2.

¹H-NMR(CDCl ₃)，δ(ppm)：1.49(9H，s)，1.53(9H，s)，2.24(3H，s)，2.47-2.55(2H，m)，2.80-2.93(4H，m)，3.13(2H，s)，3.24-3.32(2H，m)，3.43(2H，s)，6.02(1H，s)，7.04(2H，d，J＝8.4Hz)，7.44(2H，d，J＝8.3Hz)，9.02-9.26(1H，brs)，10.24(1H，s)，11.62(1H，s)。

MS：616.2(M+H) ⁺，638.2(M+Na) ⁺

Step 3

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.15(3H，s)，2.39-2.62(2H，m)，2.95(4H，s)，3.08-3.86(4H，m)，4.20-4.77(2H，brs)，7.15(2H，d，J＝8.3Hz)，7.30(2H，d，J＝8.0Hz)，7.35(4H，s)，8.04-8.62(1H，brs)，9.70(1H，s)，10.67-11.38(1H，brs)，11.97-12.72(1H，brs)。

MS:416.2 (M+H) ⁺(free type)

Preparation embodiment 116:

Synthetic 4-(2-(acetylamino)-4-[2-(4-{[amino (imino-) methyl] amino } phenyl) ethyl]-1,3-thiazoles-5-yl } methyl)-N, N-dimethyl-1-piperazine carboxamides dihydrochloride

Step 1

4-(2-(acetylamino)-4-[(Z)-2-(4-nitrophenyl) vinyl]-1; 3-thiazole-5-yl } methyl)-1-piperazinecarboxylic acid 9H-fluorenes-9-base methyl esters N-{4-[(Z)-2-(4-nitrophenyl) vinyl]-1,3-thiazoles-2-yl } ethanamide prepares according to the similar approach of preparation embodiment 67 steps 1.

¹H-NMR(CDCl ₃)，δ(ppm)：2.10(3H，s)，2.26-2.61(4H，m)，3.39-3.64(6H，m)，4.19-4.30(1H，m)，4.37-4.49(2H，m)，6.66(2H，s)，7.07-7.67(8H，m)，7.76(2H，d，J＝6.9Hz)，8.05(2H，d，J＝8.9Hz)，10.03(1H，s)。

MS：610.2(M+H) ⁺，632.2(M+Na) ⁺

Step 2

4-(2-(acetylamino)-4-[2-(4-aminophenyl) ethyl]-1,3-thiazoles-5-yl } methyl)-the similar approach preparation of the compound of step 1 of 1-piperazinecarboxylic acid 9H-fluorenes-9-base methyl esters according to preparation embodiment 45 steps 6.

¹H-NMR(CDCl ₃)，δ(ppm)：2.16-2.33(7H，m)，2.80(4H，s)，3.34(2H，s)，3.36-3.84(6H，m)，4.17-4.30(1H，m)，4.36-4.47(2H，m)，6.57(2H，d，J＝8.4Hz)，6.86(2H，d，J＝8.3Hz)，7.26-7.46(4H，m)，7.56(2H，d，J＝7.0Hz)，7.76(2H，d，J＝6.9Hz)，8.60-9.52(1H，brs)。

MS：582.2(M+H) ⁺，604.3(M+Na) ⁺

Step 3

4-[(2-(acetylamino)-4-{2-[4-({ (Z)-[(tert-butoxycarbonyl) amino] [(tert-butoxycarbonyl) imino-] methyl } amino) phenyl] ethyl }-1,3-thiazoles-5-yl) methyl]-the similar approach preparation of the compound of step 2 of 1-piperazinecarboxylic acid 9H-fluorenes-9-base methyl esters according to preparation embodiment 31 steps 3.

¹H-NMR(CDCl ₃)，δ(ppm)：1.50(9H，s)，1.52(9H，s)，2.23(3H，s)，2.28-2.43(4H，m)，2.86(4H，s)，3.36-3.55(6H，m)，4.18-4.29(1H，m)，4.35-4.48(2H，m)，7.05(2H，d，J＝8.5Hz)，7.13-7.66(8H，m)，7.75(2H，d，J＝7.0Hz)，8.85-9.76(1H，brs)，10.25(1H，Ss)，11.63(1H，s)。

MS：824.2(M+H) ⁺，847.3(M+Na) ⁺

Step 4

4-[(2-(acetylamino)-4-{2-[4-({ (Z)-[(tert-butoxycarbonyl) amino] [(tert-butoxycarbonyl) imino-] methyl } amino) phenyl] ethyl }-1; 3-thiazole-5-yl) methyl]-add piperidines (0.16ml) in DMF (0.8ml) solution of 1-piperazinecarboxylic acid 9H-fluorenes-9-base methyl esters (400mg), at 20 ℃ of 2h that stir the mixture.Add piperidines (0.16ml) in the reaction mixture, stir 1h at 20 ℃, stir 1h at 40 ℃, be cooled to 20 ℃ then, add AcOEt (50ml), dried over mgso is used in mixture water (10mlx3) and salt solution (10ml) washing, filters the concentrated rough light yellow oil (463mg) that obtains of final vacuum.Rough oily matter NH silica gel flash column chromatography purification (using methylene chloride (100: 0) → (100: 1)) as eluent; obtain colourless amorphous substance { (Z)-[(4-{2-[2-(acetylamino)-5-(1-piperazinyl methyl)-1,3-thiazoles-4-yl] ethyl } phenyl) amino] methylene radical } the diamino acid di tert butyl carbonate.

¹H-NMR(CDCl ₃)，δ(ppm)：1.50(9H，s)，1.53(9H，s)，2.21(3H，s)，2.27-2.47(4H，m)，2.71-3.00(8H，m)，3.40(2H，s)，7.07(2H，d，J＝8.4Hz)，7.45(2H，d，J＝8.4Hz)，10.24(1H，s)，11.47-11.74(1H，brs)。

MS：602.3(M+H) ⁺，624.2(M+Na) ⁺

Step 5

(Z)-[(4-{2-[2-(acetylamino)-5-(1-piperazinyl methyl)-1; 3-thiazole-4-yl] ethyl } phenyl) amino] methylene radical } add N in methylene dichloride (0.3ml) solution of diamino acid di tert butyl carbonate (30mg); N-diisopropylethylamine (9.55 μ l) and dimethylcarbamyl chloride (4.59 μ l) are at 20 ℃ of 14h that stir the mixture.Add saturated sodium bicarbonate aqueous solution (2ml) in the reaction mixture, mixture extracts with methylene dichloride (5mlx3) then, and extraction liquid is by the diatomite drying.The vacuum concentration organic layer obtains rough oily matter.Resistates preparation type silica gel thin-layer chromatography purification (using chloroform/methanol (20: 1)) as eluent; obtain colorless oil { (Z)-[(4-{2-[2-(acetylamino)-5-({ 4-[(dimethylamino) carbonyl]-1-piperazinyl } methyl)-1,3-thiazoles-4-yl] ethyl } phenyl) amino] methylene radical } the diamino acid di tert butyl carbonate.

¹H-NMR(CDCl ₃)，δ(ppm)：1.50(9H，s)，1.54(9H，s)，2.23(3H，s)，2.35-2.42(4H，m)，2.80(6H，s)，2.81-2.89(4H，m)，3.17-3.27(4H，m)，3.41(2H，s)，7.07(2H，d，J＝8.4Hz)，7.46(2H，d，J＝8.4Hz)，8.73-8.90(1H，brs)，10.25(1H，s)，11.63(1H，s)。

MS：673.3(M+H) ⁺，695.2(M+Na) ⁺

Step 6

Title compound prepares according to the similar approach for preparing embodiment 31 steps 4 with the compound of step 5.

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.16(3H，s)，2.76(6H，s)，2.91-3.06(6H，m)，3.07-3.19(2H，m)，3.20-3.30(2H，m)，3.57-3.65(2H，m)，4.36-4.51(2H，m)，7.15(2H，d，J＝8.4Hz)，7.31(2H，d，J＝8.4Hz)，7.41(4H，s)，9.87(1H，s)，10.51-10.69(1H，brs)，12.33(1H，s)。

MS：473.2(M+H) ⁺

Preparation embodiment 117:

Synthetic N-(4-[2-(4-{[amino (imino-) methyl] amino } phenyl) ethyl]-5-{[4-(4-morpholinyl carbonyl)-1-piperazinyl] methyl }-1,3-thiazoles-2-yl) the ethanamide dihydrochloride

Step 1

[(Z)-(4-[2-(2-(acetylamino)-5-{[4-(4-morpholinyl carbonyl)-1-piperazinyl] methyl }-1,3-thiazoles-4-yl) ethyl] phenyl } amino) methylene radical] the similar approach preparation of the compound of preparation embodiment 116 steps 4 of diamino acid di tert butyl carbonate according to preparation embodiment 116 steps 5.

¹H-NMR(CDCl ₃)，δ(ppm)：1.50(9H，s)，1.54(9H，s)，2.23(3H，s)，2.32-2.46(4H，m)，2.78-2.91(4H，m)，3.20-3.30(8H，m)，3.42(2H，s)，3.63-3.71(4H，m)，7.07(2H，d，J＝8.4Hz)，7.46(2H，d，J＝8.4Hz)，8.72-8.89(1H，brs)，10.25(1H，s)，11.64(1H，s)。

MS：715.3(M+H) ⁺，737.2(M+Na) ⁺

Step 2

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.16(3H，s)，2.90-3.07(6H，m)，3.11-3.32(8H，m)，3.48-3.76(6H，m)，4.42(2H，s)，7.15(2H，d，J＝8.4Hz)，7.31(2H，d，J＝8.4Hz)，7.40(4H，s)，9.85(1H，s)，10.51-10.72(1H，brs)，12.34(1H，s)。

MS:515.3 (M+H) ⁺(free type)

Preparation embodiment 118:

Synthetic N-(4-[2-(4-{[amino (imino-) methyl] amino } phenyl) ethyl]-5-{[4-(1-pyrrolidyl carbonyl)-1-piperazinyl] methyl }-1,3-thiazoles-2-yl) the ethanamide dihydrochloride

Step 1

[(Z)-(4-[2-(2-(acetylamino)-5-{[4-(1-pyrrolidyl carbonyl)-1-piperazinyl] methyl }-1,3-thiazoles-4-yl) ethyl] phenyl } amino) methylene radical] the similar approach preparation of the compound of preparation embodiment 116 steps 4 of diamino acid di tert butyl carbonate according to preparation embodiment 116 steps 5.

¹H-NMR(CDCl ₃)，δ(ppm)：1.50(9H，s)，1.54(9H，s)，1.72-1.89(4H，m)，2.23(3H，s)，2.28-2.48(4H，m)，2.84(4H，s)，3.19-3.39(8H，m)，3.41(2H，s)，7.07(2H，d，J＝8.4Hz)，7.46(2H，d，J＝8.4Hz)，8.71-8.99(1H，brs)，10.24(1H，s)，11.64(1H，s)。

MS：699.2(M+H) ⁺，721.3(M+Na) ⁺

Step 2

¹H-NMR(DMSO-d ₆)，δ(ppm)：1.70-1.83(4H，m)，2.16(3H，s)，2.89-3.05(6H，m)，3.06-3.19(2H，m)，3.20-3.32(6H，m)，3.64-3.84(2H，m)，4.36-4.50(2H，m)，7.15(2H，d，J＝8.2Hz)，7.31(2H，d，J＝8.3Hz)，7.42(4H，s)，9.88(1H，s)，10.50-10.75(1H，brs)，12.34(1H，s)。

MS:499.3 (M+H) ⁺(free type)

Preparation embodiment 119:

Synthetic N-[4-[2-(4-{[amino (imino-) methyl] amino } phenyl) ethyl]-5-(4-[(4-methyl isophthalic acid-piperazinyl) carbonyl]-the 1-piperazinyl } methyl)-1,3-thiazoles-2-yl] the ethanamide tri hydrochloride

Step 1

(Z)-[(4-{2-[2-(acetylamino)-5-(4-[(4-methyl isophthalic acid-piperazinyl) carbonyl]-the 1-piperazinyl } methyl)-1,3-thiazoles-4-yl] ethyl } phenyl) amino] methylene radical } the similar approach preparation of the compound of preparation embodiment 116 steps 4 of diamino acid di tert butyl carbonate according to preparation embodiment 116 steps 5.

¹H-NMR(CDCl ₃)，δ(ppm)：1.50(9H，s)，1.54(9H，s)，2.23(3H，s)，2.29(3H，s)，2.32-2.48(8H，m)，2.84(4H，s)，3.16-3.35(8H，m)，3.42(2H，s)，7.07(2H，d，J＝8.4Hz)，7.46(2H，d，J＝8.4Hz)，8.69-9.04(1H，brs)，10.24(1H，s)，11.64(1H，s)。

MS：728.2(M+H) ⁺，750.3(M+Na) ⁺

Step 2

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.16(3H，s)，2.76(3H，d，J＝4.6Hz)，2.89-3.09(8H，m)，3.17-3.39(8H，m)，3.62-3.77(4H，m)，4.34-4.51(2H，brs)，7.15(2H，d，J＝8.3Hz)，7.31(2H，d，J＝8.2Hz)，7.41(4H，s)，9.87(1H，s)，10.68-10.97(1H，brs)，12.34(1H，s)。

MS:528.3 (M+H) ⁺(free type)

Preparation embodiment 120:

Synthetic 3-{2-(acetylamino)-4-[2-(4-{[amino (imino-) methyl] amino } phenyl) ethyl]-1,3-thiazoles-5-yl }-N, N-dimethyl propylene amide hydrochloride

Step 1

3-[2-(acetylamino)-4-(2-{4-[(tert-butoxycarbonyl) amino] phenyl } ethyl)-1; 3-thiazole-5-yl] ethyl propenoate is with 2-(acetylamino)-4-(2-{4-[(tert-butoxycarbonyl) amino] phenyl } ethyl)-1,3-thiazoles-5-formaldehyde is according to the similar approach preparation of preparation embodiment 61 steps 7.

¹H-NMR(CDCl ₃)，δ(ppm)：1.16-1.40(3H，m)，1.52(9H，s)，2.23-2.38(3H，m)，2.70-3.06(4H，m)，4.15-4.33(2H，m)，5.53-6.15(1H，m)，6.64-7.85(6H，m)。

MS：482.2(M+Na) ⁺

Step 2

With (2E)-3-[2-(acetylamino)-4-(2-{4-[(tert-butoxycarbonyl) amino] phenyl } ethyl)-1; 3-thiazole-5-yl] ethyl propenoate and (2Z)-3-[2-(acetylamino)-4-(2-{4-[(tert-butoxycarbonyl) amino] phenyl } ethyl)-1,3-thiazoles-5-yl] mixture (200mg), THF (7ml) and the 10%Pd/C (392mg) of ethyl propenoate mix under nitrogen atmosphere.3h stirs the mixture under 3atm nitrogen atmosphere, 20 ℃.By the Celite pad filter reaction mixture, vacuum concentrated filtrate obtains colourless amorphous substance 3-[2-(acetylamino)-4-(2-{4-[(tert-butoxycarbonyl) amino] phenyl } ethyl)-1,3-thiazoles-5-yl] ethyl propionate.

¹H-NMR(CDCl ₃)，δ(ppm)：1.24(3H，t，J＝7.0Hz)，1.51(9H，s)，2.24(3H，s)，2.41(2H，t，J＝7.5Hz)，2.73-2.93(6H，m)，4.12(2H，q，J＝7.0Hz)，6.95(2H，d，J＝7.2Hz)，7.23(2H，d，J＝7.7Hz)。

MS：484.1(M+Na) ⁺

Step 3

3-(2-(acetylamino)-4-{2-[4-({ (Z)-[(tert-butoxycarbonyl) amino] [(tert-butoxycarbonyl) imino-] methyl } amino) phenyl] ethyl }-1,3-thiazoles-5-yl) the ethyl propionate similar approach preparation of the compound of step 2 according to preparation embodiment 65 steps 4.

¹H-NMR(CDCl ₃)，δ(ppm)：1.24(3H，t，J＝7.1Hz)，1.50(9H，s)，1.53(9H，s)，2.21(3H，s)，2.41(2H，t，J＝7.6Hz)，2.70-3.00(6H，m)，4.12(2H，q，J＝7.2Hz)，7.07(2H，d，J＝8.4Hz)，7.46(2H，d，J＝8.4Hz)，8.80-9.20(1H，brs)，10.24(1H，s)，11.63(1H，s)。

MS：604.3(M+H) ⁺，626.2(M+Na) ⁺

Step 4

3-(2-(acetylamino)-4-{2-[4-({ (Z)-[(tert-butoxycarbonyl) amino] [(tert-butoxycarbonyl) imino-] methyl } amino) phenyl] ethyl }-1,3-thiazoles-5-yl) the propionic acid similar approach preparation of the compound of step 3 according to preparation embodiment 42 steps 1.

¹H-NMR(CDCl ₃)，δ(ppm)：1.47(9H，s)，1.53(9H，s)，2.19(3H，s)，2.25-2.45(2H，m)，2.60-3.00(6H，m)，6.9δ(2H，d，J＝8.3Hz)，7.34(2H，d，J＝8.3Hz)，10.17(1H，s)，11.30-11.90(1H，brs)。

MS：598.2(M+Na) ⁺

Step 5

((Z)-[4-(2-{2-(acetylamino)-5-[3-(dimethylamino)-3-oxopropyl]-1,3-thiazoles-4-yl } ethyl) phenyl] amino } methylene radical) the similar approach preparation of the compound of step 4 of diamino acid di tert butyl carbonate according to preparation embodiment 32 steps 1.

¹H-NMR(CDCl ₃)，δ(ppm)：1.49(9H，s)，1.53(9H，s)，2.21(3H，s)，2.28-2.43(2H，m)，2.79-2.99(12H，m)，7.05(2H，d，J＝8.5Hz)，7.44(2H，d，J＝8.5Hz)，8.85-9.37(1H，brs)，10.23(1H，s)，11.62(1H，s)。

MS：603.3(M+H) ⁺，625.3(M+Na) ⁺

Step 6

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.10(3H，s)，2.40(2H，t，J＝7.3Hz)，2.75(2H，t，J＝7.3Hz)，2.77-2.84(5H，m)，2.84-2.95(5H，m)，7.14(2H，d，J＝8.4Hz)，7.24(2H，d，J＝8.4Hz)，7.36(4H，s)，9.72(1H，s)，11.93(1H，s)。

MS:403.3 (M+H) ⁺(free type)

Preparation embodiment 121:

Synthetic 3-{2-(acetylamino)-4-[2-(4-{[amino (imino-) methyl] amino } phenyl) ethyl]-1,3-thiazoles-5-yl }-N-methyl propanamide hydrochloride

Step 1

((Z)-[4-(2-{2-(acetylamino)-5-[3-(methylamino)-3-oxopropyl]-1,3-thiazoles-4-yl } ethyl) phenyl] amino } methylene radical) the similar approach preparation of the compound of preparation embodiment 120 steps 4 of diamino acid di tert butyl carbonate according to preparation embodiment 32 steps 1.

¹H-NMR(CDCl ₃)，δ(ppm)：1.45(9H，s)，1.54(9H，s)，1.79-1.88(2H，s)，2.23(3H，s)，2.65(3H，d，J＝4.8Hz)，2.69-2.77(2H，m)，2.79-2.86(2H，m)，2.86-2.95(2H，m)，6.04(2H，d，J＝4.4Hz)，6.93(2H，d，J＝8.4Hz)，7.28(2H，d，J＝8.4Hz)，8.79-9.17(1H，brs)，10.28(1H，s)，11.60(1H，s)。

MS：589.3(M+H) ⁺，611.3(M+Na) ⁺

Step 2

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.10(3H，s)，2.22(2H，t，J＝7.3Hz)，2.53(3H，d，J＝4.8Hz)，2.72-2.82(4H，m)，2.82-2.90(2H，m)，7.15(2H，d，J＝8.4Hz)，7.26(2H，d，J＝8.4Hz)，7.38(4H，s)，7.79(1H，d，J＝4.5Hz)，9.76(1H，s)，11.95(1H，s)。

MS:389.2 (M+H) ⁺, 411.2 (M+Na) ⁺(free type)

Preparation embodiment 122:

Synthetic 3-{2-(acetylamino)-4-[2-(4-{[amino (imino-) methyl] amino } phenyl) ethyl]-1,3-thiazoles-5-yl } propionamide hydrochloride

Step 1

(Z)-[(4-{2-[2-(acetylamino)-5-(3-amino-3-oxopropyl)-1,3-thiazoles-4-yl] ethyl } phenyl) amino] methylene radical } the similar approach preparation of the compound of preparation embodiment 120 steps 4 of diamino acid di tert butyl carbonate according to preparation embodiment 32 steps 1.

¹H-NMR(CDCl ₃)，δ(ppm)：1.47(9H，s)，1.53(9H，s)，1.57-1.67(2H，m)，2.24(3H，s)，2.65-2.76(2H，m)，2.76-2.87(2H，m)，2.87-2.99(2H，m)，5.37(1H，s)，6.14(1H，s)，6.90(2H，d，J＝8.4Hz)，7.28(2H，d，J＝8.4Hz)，8.88-9.28(1H，brs)，10.12(1H，s)，11.58(1H，s)。

MS：575.0(M+H) ⁺，597.3(M+Na) ⁺

Step 2

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.10(3H，s)，2.23(2H，t，J＝7.3Hz)，2.71-2.83(4H，m)，2.83-2.91(2H，m)，6.81(1H，s)，7.14(2H，d，J＝8.4Hz)，7.26(2H，d，J＝8.4Hz)，7.31(1H，s)，7.35(4H，s)，9.70(1H，s)，11.94(1H，s)。

MS:375.2 (M+H) ⁺, 397.0 (M+Na) ⁺(free type)

Preparation embodiment 123:

Synthetic 1-(2-(acetylamino)-4-[2-(4-{[amino (imino-) methyl] amino } phenyl) ethyl]-1,3-thiazoles-5-yl } methyl)-N, N-dimethyl-4-piperidine methane amide dihydrochloride

Step 1

1-[(2-(acetylamino)-4-{2-[4-({ (Z)-[(tert-butoxycarbonyl) amino] [(tert-butoxycarbonyl) imino-] methyl } amino) phenyl] ethyl }-1; 3-thiazole-5-yl) methyl]-the 4-piperidine carboxylic acid is with 1-[(2-(acetylamino)-4-{2-[4-({ (Z)-[(tert-butoxycarbonyl) amino] [(tert-butoxycarbonyl) imino-] methyl } amino) phenyl] ethyl }-1,3-thiazoles-5-yl) methyl]-the 4-piperidine ethyl formate is according to the similar approach preparation of preparation embodiment 42 steps 1.

¹H-NMR(CDCl ₃)，δ(ppm)：1.49(9H，s)，1.51(9H，s)，1.76-2.49(10H，m)，2.69-3.00(6H，m)，3.71(2H，s)，7.04(2H，d，J＝8.5Hz)，7.42(2H，d，J＝8.5Hz)，10.23(1H，s)，11.13-12.07(1H，brs)。

MS：645.3(M+H) ⁺，667.2(M+Na) ⁺

Step 2

(Z)-[(4-{2-[2-(acetylamino)-5-(the 4-[(dimethylamino) carbonyl]-piperidino } methyl)-1,3-thiazoles-4-yl] ethyl } phenyl) amino] methylene radical } the similar approach preparation of the compound of step 1 of diamino acid di tert butyl carbonate according to preparation embodiment 32 steps 1.

¹H-NMR(CDCl ₃)，δ(ppm)：1.50(9H，s)，1.54(9H，s)，1.75-1.89(2H，m)，1.92-2.03(2H，m)，2.22(3H，s)，2.37-2.49(1H，m)，2.80-2.95(9H，m)，3.02(3H，s)，3.43(2H，s)，7.08(2H，d，J＝8.4Hz)，7.46(2H，d，J＝8.4Hz)，8.61-9.19(1H，brs)，10.24(1H，s)，11.63(1H，s)。

MS：672.2(M+H) ⁺，694.3(M+Na) ⁺

Step 3

¹H-NMR(DMSO-d ₆)，δ(ppm)：1.71-2.01(4H，m)，2.16(3H，s)，2.76-2.87(4H，m)，2.87-3.1(9H，m)，3.3-3.4(2H，m)，4.32-4.45(2H，m)，7.15(2H，d，J＝4.2Hz)，7.31(2H，d，J＝4.2Hz)，7.41(4H，s)，9.83-9.93(1H，m)，9.99-10.19(1H，m)，12.32-12.37(1H，m)。

MS:472.3 (M+H) ⁺, 494.0 (M+Na) ⁺(free type)

Preparation embodiment 124:

Synthetic 1-(2-(acetylamino)-4-[2-(4-{[amino (imino-) methyl] amino } phenyl) ethyl]-1,3-thiazoles-5-yl } methyl)-N-methyl-4-piperidyl urea dihydrochloride

Step 1

(Z)-[(4-{2-[2-(acetylamino)-5-(the 4-[(methylamino) carbonyl]-piperidino } methyl)-1,3-thiazoles-4-yl] ethyl } phenyl) amino] methylene radical } the similar approach preparation of the compound of preparation embodiment 123 steps 1 of diamino acid di tert butyl carbonate according to preparation embodiment 32 steps 1.

¹H-NMR(CDCl ₃)，δ(ppm)：1.5(9H，s)，1.54(9H，s)，1.65-1.74(2H，m)，1.75-1.84(2H，m)，1.87-1.98(2H，m)，2-2.11(1H，m)，2.22(3H，s)，2.8(3H，d，J＝4.8Hz)，2.82-2.91(6H，m)，3.39(2H，s)，5.5(1H，d，J＝4.4Hz)，7.07(2H，d，J＝8.4Hz)，7.45(2H，d，J＝8.4Hz)，8.72-8.99(1H，brs)，10.23(1H，s)，11.62(1H，s)。

MS：658.3(M+H) ⁺，680.3(M+Na) ⁺

Step 2

¹H-NMR(DMSO-d ₆)，δ(ppm)：1.71-2.04(4H，m)，2.16(3H，s)，2.25-2.37(1H，m)，2.54-2.61(3H，m)，2.82-2.94(2H，m)，2.96(4H，s)，3.27-3.37(2H，m)，4.31-4.44(2H，m)，7.15(2H，d，J＝8.4Hz)，7.30(2H，d，J＝8.4Hz)，7.41(4H，s)，7.89-8.00(1H，m)，9.83-10.16(2H，m)。

MS:458.2 (M+H) ⁺, 480.0 (M+Na) ⁺(free type)

Preparation embodiment 125:

Synthetic 1-(2-(acetylamino)-4-[2-(4-{[amino (imino-) methyl] amino } phenyl) ethyl]-1,3-thiazoles-5-yl } methyl)-4-piperidyl urea dihydrochloride

Step 1

[(Z)-(4-[2-(2-(acetylamino)-5-{[4-(aminocarboxyl)-piperidino] methyl }-1,3-thiazoles-4-yl) ethyl] phenyl } amino) methylene radical] the similar approach preparation of the compound of preparation embodiment 123 steps 1 of diamino acid di tert butyl carbonate according to preparation embodiment 32 steps 1.

¹H-NMR(CDCl ₃)，δ(ppm)：1.50(9H，s)，1.53(9H，s)，1.66-1.75(2H，m)，1.78-1.87(2H，m)，1.88-1.99(2H，m)，2.07-2.17(1H，m)，2.23(3H，s)，2.77-2.92(6H，m)，3.39(2H，s)，5.5(2H，s)，7.06(2H，d，J＝8.4Hz)，7.45(2H，d，J＝8.4Hz)，8.94-9.25(1H，brs)，10.23(1H，s)，11.61(1H，s)。

MS：644.2(M+H) ⁺，666.3(M+Na) ⁺

Step 2

¹H-NMR(DMSO-d ₆)，δ(ppm)：1.68-2.08(4H，m)，2.16(3H，s)，2.25-2.36(1H，m)，2.82-3.09(6H，m)，3.27-3.44(2H，m)，4.30-4.45(2H，m)，6.87-7.06(1H，m)，7.15(2H，d，J＝8.4Hz)，7.30(2H，d，J＝8.3Hz)，7.36-7.52(5H，m)，9.87-10.25(2H，m)，12.30-12.37(1H，m)。

MS:444.2 (M+H) ⁺, 466.2 (M+Na) ⁺(free type)

Preparation embodiment 126:

Synthetic (3R)-1-(2-(acetylamino)-4-[2-(4-{[amino (imino-) methyl] amino } phenyl) ethyl]-1,3-thiazoles-5-yl } methyl)-N, N-dimethyl-3-piperidyl urea dihydrochloride

Step 1

(3R)-and 1-(2-(acetylamino)-4-[(Z)-2-(4-nitrophenyl) vinyl]-1; 3-thiazole-5-yl } methyl)-the nipecotic acid ethyl ester is with preparation N-{4-[(Z)-2-(4-nitrophenyl) vinyl]-1,3-thiazoles-2-yl } ethanamide is according to the similar approach preparation of preparation embodiment 67 steps 1.

MS：459.20(M+H) ⁺

Step 2

(3R)-and 1-[(2-(acetylamino)-4-{2-[4-({ (Z)-[(tert-butoxycarbonyl) amino] [(tert-butoxycarbonyl) imino-] methyl } amino) phenyl] ethyl }-1,3-thiazoles-5-yl) methyl]-the similar approach preparation of the compound of step 1 of nipecotic acid ethyl ester according to preparation embodiment 68 steps 2.

¹H-NMR(CDCl ₃)，δ(ppm)：1.22(3H，t，J＝7.2Hz)，1.31-1.78(21H，m)，1.79-2.06(2H，m)，2.07-2.18(1H，m)，2.22(3H，s)，2.43-2.62(1H，m)，2.62-2.75(1H，m)，2.84(4H，s)，2.88-3.01(1H，m)，3.42(2H，s)，4.11(2H，q，J＝7.1Hz)，7.08(2H，d，J＝8.4Hz)，7.46(2H，d，J＝8.4Hz)，8.76-9.16(1H，brs)，10.24(1H，s)，11.64(1H，s)。

MS：673.3(M+H) ⁺，695.2(M+Na) ⁺

Step 3

(3R)-and 1-[(2-(acetylamino)-4-{2-[4-({ (Z)-[(tert-butoxycarbonyl) amino] [(tert-butoxycarbonyl) imino-] methyl } amino) phenyl] ethyl }-1,3-thiazoles-5-yl) methyl]-the nipecotic acid similar approach preparation of the compound of step 2 according to preparation embodiment 42 steps 1.

MS：645.37(M+H) ⁺

Step 4

(Z)-[(4-{2-[2-(acetylamino)-5-((3R)-and the 3-[(dimethylamino) carbonyl]-piperidino } methyl)-1,3-thiazoles-4-yl] ethyl } phenyl) amino] methylene radical } the similar approach preparation of the compound of step 3 of diamino acid di tert butyl carbonate according to preparation embodiment 32 steps 1.

¹H-NMR(CDCl ₃)，δ(ppm)：1.39-1.57(20H，m)，1.66-1.73(1H，m)，1.74-1.83(1H，m)，1.87-1.98(1H，m)，2.08-2.19(1H，m)，2.22(3H，s)，2.72-2.94(10H，m)，3.02(3H，s)，3.41(2H，s)，7.08(2H，d，J＝8.4Hz)，7.46(2H，d，J＝8.4Hz)，8.70-9.02(1H，brs)，10.24(1H，s)，11.63(1H，s)。

MS：672.41(M+H) ⁺

Step 5

Title compound prepares according to the similar approach for preparing embodiment 31 steps 4 with the compound of step 4.

¹H-NMR(DMSO-d ₆)，δ(ppm)：1.29-1.94(4H，m)，2.16(3H，s)，2.77-3.33(15H，m)，4.27-4.46(2H，m)，7.16(2H，d，J＝8.3Hz)，7.27-7.35(2H，m)，7.36-7.48(4H，m)，9.8-9.98(1H，m)，10.22-10.51(1H，brs)，12.29-12.36(1H，m)。

MS:472.3 (M+H) ⁺, 494.2 (M+Na) ⁺(free type)

Preparation embodiment 127:

Synthetic (3R)-1-(2-(acetylamino)-4-[-2-(4-{[amino (imino-) methyl] amino } phenyl) ethyl]-1,3-thiazoles-5-yl } methyl)-N-methyl-3-piperidyl urea dihydrochloride

Step 1

(Z)-[(4-{2-[2-(acetylamino)-5-((3R)-and the 3-[(methylamino) carbonyl]-piperidino } methyl)-1,3-thiazoles-4-yl] ethyl } phenyl) amino] methylene radical } the similar approach preparation of the compound of preparation embodiment 126 steps 3 of diamino acid di tert butyl carbonate according to preparation embodiment 32 steps 1.

¹H-NMR(CDCl ₃)，δ(ppm)：1.50(9H，s)，1.52-1.72(12H，m)，1.84-1.98(1H，m)，2.01-2.14(1H，m)，2.14-2.23(1H，m)，2.24(3H，s)，2.43-2.51(1H，m)，2.64-2.76(1H，m)，2.76-2.94(8H，m)，3.32(1H，d，J＝14Hz)，3.41(1H，d，J＝14Hz)，7.06(2H，d，J＝8.4Hz)，7.45(2H，d，J＝8.4Hs)，7.53(1H，brs)，8.84(1H，brs)，10.24(1H，s)，11.63(1H，s)。

MS：658.39(M+H) ⁺

Step 2

¹H-NMR(DMSO-d ₆)，δ(ppm)：1.31-1.94(4H，m)，2.16(3H，s)，2.54-3.36(12H，m)，4.27-4.48(2H，m)，7.12-7.19(2H，m)，7.25-7.35(2H，m)，7.35(4H，brs)，8.05-8.37(1H，m)，9.79-9.92(1H，m)，10.16-10.42(1H，brs)，12.29-12.37(1H，m)。

MS:458.2 (M+H) ⁺, 480.1 (M+Na) ⁺(free type)

Preparation embodiment 128:

Synthetic (3S)-1-(2-(acetylamino)-4-[2-(4-{[amino (imino-) methyl] amino } phenyl) ethyl]-1,3-thiazoles-5-yl } methyl)-N, N-dimethyl-3-piperidyl urea dihydrochloride

Step 1

(3S)-and 1-(2-(acetylamino)-4-[(Z)-2-(4-nitrophenyl) vinyl]-1; 3-thiazole-5-yl } methyl)-nipecotic acid ethyl ester N-{4-[(Z)-2-(4-nitrophenyl) vinyl]-1,3-thiazoles-2-yl } ethanamide is according to the similar approach preparation of preparation embodiment 67 steps 1.

MS：459.21(M+H) ⁺

Step 2

(3S)-and 1-[(2-(acetylamino)-4-{2-[4-({ (Z)-[(tert-butoxycarbonyl) amino] [(tert-butoxycarbonyl) imino-] methyl } amino) phenyl] ethyl }-1,3-thiazoles-5-yl) methyl]-the similar approach preparation of the compound of step 1 of nipecotic acid ethyl ester according to preparation embodiment 68 steps 2.

¹H-NMR(CDCl ₃)，δ(ppm)：1.22(3H，t，J＝7.2Hz)，1.3-1.79(21H，m)，1.8-2.06(2H，m)，2.08-2.18(1H，m)，2.22(3H，s)，2.43-2.62(1H，m)，2.62-2.75(1H，m)，2.84(4H，s)，2.88-3.01(1H，m)，3.42(2H，s)，4.11(2H，q，J＝7.1Hz)，7.08(2H，d，J＝8.4Hz)，7.46(2H，d，J＝8.4Hz)，8.71-9.23(1H，brs)，10.24(1H，s)，11.64(1H，s)。

MS：673.3(M+H) ⁺，695.2(M+Na) ⁺

Step 3

(3S)-and 1-[(2-(acetylamino)-4-{2-[4-({ (Z)-[(tert-butoxycarbonyl) amino] [(tert-butoxycarbonyl) imino-] methyl } amino) phenyl] ethyl }-1,3-thiazoles-5-yl) methyl]-the nipecotic acid similar approach preparation of the compound of step 2 according to preparation embodiment 42 steps 1.

MS：645.36(M+H) ⁺

Step 4

(Z)-[(4-{2-[2-(acetylamino)-5-((3S)-and the 3-[(dimethylamino) carbonyl]-piperidino } methyl)-1,3-thiazoles-4-yl] ethyl } phenyl) amino] methylene radical } the similar approach preparation of the compound of step 3 of diamino acid di tert butyl carbonate according to preparation embodiment 32 steps 1.

¹H-NMR(CDCl ₃)，δ(ppm)：1.4-1.64(20H，m)，1.65-1.73(1H，m)，1.73-1.82(1H，m)，1.86-1.97(1H，m)，2.08-2.18(1H，m)，2.22(3H，s)，2.7-2.93(10H，m)，3.02(3H，s)，3.41(2H，s)，7.08(2H，d，J＝8.4Hz)，7.46(2H，d，J＝8.3Hz)，8.61-8.99(1H，brs)，10.24(1H，s)，11.63(1H，s)。

MS：672.39(M+H) ⁺

Step 5

¹H-NMR(DMSO-d ₆)，δ(ppm)：1.29-1.93(4H，m)，2.16(3H，s)，2.77-3.35(15H，m)，4.27-4.45(2H，m)，7.16(2H，d，J＝8.4Hz)，7.28-7.35(2H，m)，7.35-7.47(4H，m)，9.8-9.96(1H，m)，10.21-10.46(1H，brs)，12.29-12.36(1H，m)。

MS:472.3 (M+H) ⁺, 494.2 (M+Na) ⁺(free type)

Preparation embodiment 129:

Synthetic (3S)-1-(2-(acetylamino)-4-[2-(4-{[amino (imino-) methyl] amino } phenyl) ethyl]-1,3-thiazoles-5-yl } methyl)-N-methyl-3-piperidyl urea dihydrochloride

Step 1

(Z)-[(4-{2-[2-(acetylamino)-5-((3S)-and the 3-[(methylamino) carbonyl]-piperidino } methyl)-1,3-thiazoles-4-yl] ethyl } phenyl) amino] methylene radical } the similar approach preparation of the compound of preparation embodiment 128 steps 3 of diamino acid di tert butyl carbonate according to preparation embodiment 32 steps 1.

¹H-NMR(CDCl ₃)，δ(ppm)：1.46-1.72(21H，m)，1.84-1.97(1H，m)，1.99-2.14(1H，m)，2.15-2.22(1H，m)，2.24(3H，s)，2.43-2.51(1H，m)，2.65-2.76(1H，m)，2.76-2.91(8H，m)，3.32(1H，d，J＝14Hz)，3.41(1H，d，J＝14Hz)，7.06(2H，d，J＝8.4Hz)，7.45(2H，d，J＝8.4Hz)，7.54(1H，brs)，8.84-9.02(1H，brs)，10.24(1H，s)，11.63(1H，s)。

MS：658.40(M+H) ⁺

Step 2

¹H-NMR(DMSO-d ₆)，δ(ppm)：1.31-1.94(4H，m)，2.16(3H，s)，2.53-3.36(12H，m)，4.24-4.46(2H，m)，7.12-7.19(2H，m)，7.25-7.35(2H，m)，7.36(4H，brs)，8.06-8.37(1H，m)，9.83-9.99(1H，m)，10.28-10.54(1H，brs)，12.33(1H，s)。

MS:458.2 (M+H) ⁺, 480.2 (M+Na) ⁺(free type)

Preparation embodiment 130:

Synthetic N-{4-[2-(2-amino-1H-benzoglyoxaline-6-yl) ethyl]-5-[4-(methyl sulphonyl) benzyl]-1,3-thiazoles-2-yl } ethanamide

Step 1

N-{4-[2-(3; the 4-dinitrophenyl) vinyl]-5-[4-(methylthio group) benzyl]-1; the 3-thiazol-2-yl } ethanamide is with 2-(acetylamino)-5-[4-(methylthio group) benzyl]-1,3-thiazoles-4-formaldehyde is according to the similar approach preparation of preparation embodiment 45 steps 5.

Z∶E＝3∶1

¹H-NMR(CDCl ₃)，δ(ppm)：2.08(3Hx3/4，s)，2.12(3Hx1/4，s)，2.44(3H，s)，4.13(2Hx3/4，s)，4.32(2Hx1/4，s)，6.71(1Hx3/4，d，J＝12.5Hz)，6.97(1Hx3/4，d，J＝12.3Hz)，7.06-8.61(7H+2Hx1/4，m)，11.85(1Hx3/4，s)，12.18(1Hx1/4，s)。

MS：471.1(M+H) ⁺，493.9(M+Na) ⁺

Step 2

N-{4-[2-(3, the 4-diamino-phenyl) ethyl]-5-[4-(methyl sulphonyl) benzyl]-1,3-thiazoles-2-yl } the ethanamide similar approach preparation of the compound of step 1 according to preparation embodiment 32 steps 2 and preparation embodiment 45 steps 6.

¹H-NMR(CDCl ₃)，δ(ppm)：2.23(3H，s)，2.70-2.85(4H，m)，3.03(3H，s)，3.88(2H，s)，6.34(1H，d，J＝1.8Hz)，6.39(1H，dd，J＝1.8，7.8Hz)，6.56(1H，d，J＝7.7Hz)，7.14(2H，d，J＝8.3Hz)，7.79(2H，d，J＝8.4Hz)，8.30-9.45(1H，brs)。

MS：445.0(M+H) ⁺，467.0(M+Na) ⁺

Step 3

N-{4-[2-(3, the 4-diamino-phenyl) ethyl]-5-[4-(methyl sulphonyl) benzyl]-1,3-thiazoles-2-yl } add cyanogen bromide (25.3mg) in MeOH (0.7ml) suspension of ethanamide (70.8mg), then at 20 ℃ of 14h that stir the mixture.Add 1N NaOH (0.239ml), vacuum concentrated mixture in the reaction mixture.Add CHCl in the resistates ₃: MeOH=10: 1 (10ml) removes by filter insoluble substance.Filtrate is purified with NH silica gel flash column chromatography and (is used CHCl ₃/ MeOH (100: 1 → 10: 1) is as eluent), obtain colorless oil.Oily matter CH ₂Cl ₂: Et ₂O=2: 1 solidifies, and obtains white solid N-{4-[2-(2-amino-1H-benzoglyoxaline-6-yl) ethyl]-5-[4-(methyl sulphonyl) benzyl]-1,3-thiazoles-2-yl } ethanamide.

¹H-NMR(CDCl ₃)，δ(ppm)：2.09(3H，s)，2.85(4H，s)，3.16(3H，s)，3.97(2H，s)，6.01(2H，s)，6.55-6.77(1H，m)，6.78-6.90(1H，m)，6.96(1H，d，J＝7.8Hz)，7.10-7.30(2H，brs)，7.72(2H，d，J＝8.1Hz)，10.55(1H，d，J＝10.5Hz)，11.50-12.20(1H，brs)。

MS：470.2(M+H) ⁺，492.1(M+Na) ⁺

Preparation embodiment 131:

Synthetic N-{4-[2-(2-amino-1H-benzoglyoxaline-6-yl) ethyl]-1,3-thiazoles-2-yl } ethanamide

Step 1

N-{4-[2-(3, the 4-dinitrophenyl) vinyl]-1,3-thiazoles-2-yl } the ethanamide similar approach preparation of 2-(acetylamino)-1,3-thiazoles-4-formaldehyde according to preparation embodiment 1 step 5.

Z∶E＝8∶1

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.13(3Hx8/9，s)，2.17(3Hx1/9，s)，6.64(1Hx8/9，d，J＝12.6Hz)，6.80(1Hx8/9，d，J＝12.6Hz)，7.29(1Hx1/9，d，J＝15.7Hz)，7.33(1Hx8/9，s)，7.39(1Hx1/9，s)，7.63(1Hx1/9，d，J＝15.7Hz)，8.00-8.50(3H，m)，11.97(1Hx8/9，s)，12.30(1Hx1/9，s)。

MS：335.0(M+H) ⁺，357.1(M+Na) ⁺

Step 2

N-{4-[2-(3, the 4-diamino-phenyl) ethyl]-1,3-thiazoles-2-yl) the ethanamide similar approach preparation of the compound of step 1 according to preparation embodiment 1 step 6.

¹H-NMR(CDCl ₃)，δ(ppm)：2.22(3H，s)，2.58-3.17(8H，m)，6.46-6.56(3H，m)，6.62(1H，d，J＝8.3Hz)，8.84-10.42(1H，brs)。

MS：277.1(M+H) ⁺，299.2(M+Na) ⁺

Step 3

Title compound prepares according to the similar approach for preparing embodiment 130 steps 3 with the compound of step 2.

¹H-NMR(CDCl ₃)，δ(ppm)：2.11(3H，s)，2.79-2.97(4H，m)，6(2H，s)，6.59-6.8(2H，m)，6.91(1H，s)，6.97(1H，d，J＝7.9Hz)，10.34-10.73(1H，brs)，11.94-12.22(1H，brs)。

MS：302.2(M+H) ⁺，324.1(M+Na) ⁺

Preparation embodiment 132:

Synthetic N-(2-(acetylamino)-4-[2-(4-{[amino (imino-) methyl] amino } phenyl) ethyl]-1,3-thiazoles-5-yl } methyl)-N-methylacetamide hydrochloride

Step 1

The N-{5-[(methylamino) methyl]-4-[(Z)-and 2-(4-nitrophenyl) vinyl]-1, the 3-thiazol-2-yl } ethanamide N-{4-[(Z)-2-(4-nitrophenyl) vinyl]-1,3-thiazoles-2-yl } ethanamide is according to the similar approach preparation of preparation embodiment 67 steps 1.

¹H-NMR(CDCl ₃)，δ(ppm)：2.05(3H，s)，2.46(3H，s)，3.75(2H，s)，6.67(2H，s)，7.41(2H，d，J＝8.9Hz)，8.01(2H，d，J＝8.8Hz)，9.7-11.69(1H，brs)。

MS：333.1(M+H) ⁺，355.1(M+Na) ⁺

Step 2

The N-{5-[(methylamino) methyl]-4-[(Z)-and 2-(4-nitrophenyl) vinyl]-1, the 3-thiazol-2-yl } add N in methylene dichloride (0.5ml) suspension of ethanamide (46.8mg), N-diisopropylethylamine (27 μ l) and Acetyl Chloride 98Min. (10 μ l) are at 20 ℃ of 2h that stir the mixture.Add methylene dichloride (5ml), N in the reaction mixture, N-diisopropylethylamine (27 μ l) and Acetyl Chloride 98Min. (10 μ l), at 20 ℃ of 5min that stir the mixture, use the washing of saturated sodium bicarbonate aqueous solution (5ml) and salt solution (5ml) then, use dried over mgso, filter the back evaporation, obtain yellow solid (67.8mg).Crude compound preparation type silica gel thin-layer chromatography purification (using chloroform/methanol (20: 1)) as eluent; obtain yellow solid N-({ 2-(acetylamino)-4-[(Z)-2-(4-nitrophenyl) vinyl]-1,3-thiazoles-5-yl } methyl)-N-methylacetamide.

¹H-NMR(CDCl ₃)，δ(ppm)：2.12(3Hx2/3，s)，2.13(3Hx1/3，s)，2.14(3Hx2/3，s)，2.24(3Hx1/3，s)，3.02(3Hx2/3，s)，3.05(3Hx1/3，s)，4.62(2Hx2/3，s)，4.79(2Hx1/3，s)，6.61(1Hx1/3，d，J＝12.6Hz)，6.70(1Hx2/3，d，J＝12.6Hz)，6.77(1Hx1/3，d，J＝12.6Hz)，6.82(1Hx2/3，d，J＝12.6Hz)，7.43(2Hx2/3，d，J＝8.8Hz)，7.65(2Hx1/3，d，J＝8.8Hz，8.06(2Hx2/3，d，J＝8.8Hz)，8.22(2Hx1/3，d，J＝8.8Hz，9.09-9.26(1Hx1/3，brs)，9.26-9.51(1Hx2/3，brs)。

MS：375.2(M+H) ⁺，397.1(M+Na) ⁺

Step 3

N-(2-(acetylamino)-4-[2-(4-aminophenyl) ethyl]-1,3-thiazoles-5-yl } methyl)-the similar approach preparation of the compound of step 2 of N-methylacetamide according to preparation embodiment 45 steps 6.

MS：347.25(M+H) ⁺

Step 4

[(Z)-(4-[2-(2-(acetylamino)-5-{[ethanoyl (methyl) amino] methyl }-1,3-thiazoles-4-yl) ethyl] phenyl } amino) methylene radical] the similar approach preparation of the compound of step 3 of diamino acid di tert butyl carbonate according to preparation embodiment 31 steps 3.

¹H-NMR(CDCl ₃)，δ(ppm)：1.49(9H，s)，1.53(9H，s)，2.06(3Hx3/4，s)，2.12(3Hx1/4，s)，2.23(3H，s)，2.77(3Hx1/4，s)，2.81(3Hx3/4，s)，2.90(4H，s)，4.20(2Hx1/4，s)，4.46(2Hx3/4，s)，7.01(2Hx1/4，d，J＝8.6Hz，7.07(2Hx3/4，d，J＝8.5Hz)，7.43(2Hx3/4，d，J＝8.5Hz)，7.46(2Hx1/4，d，J＝8.0Hz)，8.81-9.09(1H，brs)，10.22(1Hx3/4，s)，10.25(1Hx1/4，s)，11.62(1H，s)。

MS：589.2(M+H) ⁺，611.2(M+Na) ⁺

Step 5

¹H-NMR(DMSO-d ₆)，δ(ppm)：1.98(3Hx3/4，s)，2.02(3Hx1/4，s)，2.11(3Hx3/4，s)，2.12(3Hx1/4，s)，2.60(3Hx1/4，s)，2.82(3Hx3/4，s)，2.89(4H，s)，4.39(2Hx3/4，s)，4.45(2Hx1/4，s)，7.13(2Hx1/4，d，J＝8.1Hz)，7.14(2Hx3/4，d，J＝8.4Hz)，7.22(2Hx1/4，d，J＝8.4Hz)，7.25(2Hx3/4，d，J＝8.4Hz)，7.31(4H，s)，9.61(1H，s)，12.03(1Hx3/4，s)，12.13(1Hx1/4，s)。

MS:389.19 (M+H) ⁺(free type)

Preparation embodiment 133:

Synthetic N-[4-(2-{4-[(2-amino-ethyl) amino] phenyl } ethyl)-1,3-thiazoles-2-yl] the ethanamide dihydrochloride

Step 1

N-{4-[2-(4-aminophenyl) ethyl]-1,3-thiazoles-2-yl } add (2-bromotrifluoromethane) t-butyl carbamate (87.5mg) and N in the toluene suspension of ethanamide (100mg), N-diisopropylethylamine (52 μ 1) is at 80 ℃ of 24h that stir the mixture.Allow reaction mixture be cooled to room temperature; add entry (10ml); isolate organic layer; with saturated NaCl solution washing; use dried over mgso; filter, vacuum concentration obtains light brown amorphous substance { 2-[(4-{2-[2-(acetylamino)-1,3-thiazoles-4-yl] ethyl } phenyl) amino] ethyl } t-butyl carbamate.

¹H-NMR(CDCl ₃)，δ(ppm)：1.45(9H，s)，2.23(3H，s)，2.86(4H，s)，3.15-3.28(2H，m)，3.15-3.47(2H，m)，4.64-5.02(1H，brs)，6.49(1H，s)，6.52(2H，d，J＝8.0Hz)，6.95(2H，d，J＝8.0Hz)，9.22-10.10(1H，brs)。

MS：405.2(M+H) ⁺，427.3(M+Na) ⁺

Step 2

¹H-NMR(DMSO-d ₆)，δ(ppm)：2.11(3H，s)，2.81(4H，s)，2.92-3.05(2H，m)，3.29(2H，t，J＝6.2Hz)，6.67(2H，d，J＝7.7Hz)，7.01(2H，d，J＝8.1Hz)，7.87-8.24(3H，brs)，12.08(1H，s)。

MS：305.2(M+H) ⁺，327.2(M+Na) ⁺

Preparation embodiment 134:

Synthetic N-{4-[3-(2-{[amino (imino-) methyl] amino } ethyl) phenyl]-1,3-thiazoles-2-yl } acetamide hydrochloride

Step 1

Under ice-cooled, add tetrahydrofuran (THF) (100ml) solution of (3-bromophenyl) acetate (10g) in the anhydrous tetrahydro furan of lithium aluminum hydride (50ml) suspension.With the mixture 2h that refluxes.After cooling, add entry and Rochelle's salt solution in the reaction mixture.Restir mixture 30min.The water layer ethyl acetate extraction.Organic layer anhydrous magnesium sulfate drying, vacuum concentration obtain 2-(3-bromophenyl) ethanol.This compound is directly used in next reaction and need not to purify again.

¹H-NMR(200MHz，CDCl ₃)，δ(ppm)：1.66(1H，brs)，2.84(2H，dd，J＝6.5，14Hz)，3.85(2H，dt，J＝6.5，2.6Hz)，7.13-7.39(4H，m)。

Step 2

At 25 ℃ of N, add tert-butyldimethylsilyl chloride (5.77g) and imidazoles (2.84g) in dinethylformamide (100ml) solution to 2-(3-bromophenyl) ethanol (7g).At 25 ℃ of 12h that stir the mixture.In reaction mixture impouring water (500ml), with ethyl acetate (100mlx2) extraction.The organic layer that merges concentrates with the dried over mgso final vacuum.Resistates is purified by (the mixed solvent of normal hexane and ethyl acetate) with silica gel column chromatography, obtains colorless oil [2-(3-bromophenyl) oxyethyl group] (tertiary butyl) dimethylsilane.

¹H-NMR(200MHz，CDCl ₃)，δ(ppm)：0.01(6H，s)，0.88(9H，s)，2.81(2H，dt，J＝6.5，9.5Hz)，3.81(2H，dt，J＝3.0，6.5Hz)，7.14-7.39(5H，brs)。

Step 3

At-70 ℃ to 1.6g[2-(3-bromophenyl) oxyethyl group] (1.57M 3.88ml), stirs 30min with reaction mixture at uniform temp then to add the n-BuLi/ hexane in tetrahydrofuran (THF) (20ml) solution of (tertiary butyl) dimethylsilane.In solution, drip N,N-DIMETHYLACETAMIDE (1.42ml) at uniform temp.Restir mixture 1h.Under ice-cooled, add entry and 8ml 1N HCl in the reaction mixture.The 1h that stirs the mixture uses ethyl acetate extraction then.Organic layer salt water washing concentrates with the dried over mgso final vacuum.Resistates is purified (with normal hexane and ethyl acetate (20/1-10/1) as eluent) with silica gel column chromatography, obtains colorless oil 1-[3-(the 2-{[tertiary butyl (dimethyl) silyl] oxygen base } ethyl) phenyl] ethyl ketone (350mg).

¹H-NMR(200MHz，CDCl ₃)，δ(ppm)：0.03(6H，s)，0.85(9H，s)，2.61(3H，s)，2.87(2H，t，J＝6.7Hz)，3.82(2H，t，J＝6.7Hz)，7.20-7.24(1H，m)，7.35-7.44(2H，m)，7.77-7.82(2H，m)。

MS：279(M+H) ⁺

Step 4

At 0 ℃ to 1-[3-(the 2-{[tertiary butyl (dimethyl) silyl] oxygen base } ethyl) phenyl] dripping bromine (168ml) in tetrahydrofuran (THF) (4ml) solution of ethyl ketone (755mg).At 25 ℃ of 1h that stir the mixture.Add saturated sodium bicarbonate aqueous solution in the reaction mixture, the mixture ethyl acetate extraction.Dried over mgso is used in organic layer salt water washing, and concentrating under reduced pressure obtains rough colorless oil 2-bromo-1-[3-(2-hydroxyethyl) phenyl] ethyl ketone.This compound is directly used in next reaction and need not to purify again.

Step 5

At 25 ℃ to 2-bromo-1-[3-(2-hydroxyethyl) phenyl] ethyl ketone (and rough, add 1-ethanoyl-2-thiocarbamide (320mg) in tetrahydrofuran (THF) 658mg) (15ml) solution.At 60 ℃ of 2h that stir the mixture.Filter and collect remaining clear crystal.Crystal washs with isopropyl ether, and drying under reduced pressure obtains clear crystal N-{4-[3-(2-hydroxyethyl) phenyl]-1,3-thiazoles-2-yl } ethanamide (514mg).

¹H-NMR(200MHz，DMSO-d ₆)，δ(ppm)：2.16(3H，s)，2.76(2H，t，J＝6.9Hz)，3.63(2H，t，J＝6.9Hz)，4.89(1H，brs)，7.16(1H，d，J＝7.7Hz)，7.32(1H，dd，J＝7.7，7.6Hz)，7.56(1H，s)，7.70(2H，d，J＝7.6Hz)，7.76(1H，s)，12.24(1H，s)。

MS：263(M+H) ⁺

Step 6

At 5 ℃ to N-{4-[3-(2-hydroxyethyl) phenyl]-1,3-thiazoles-2-yl the CH of ethanamide (300mg) ₂Cl ₂(10ml) add methylsulfonyl chloride (106 μ l) and triethylamine (207 μ l) in the suspension.At 25 ℃ of 2h that stir the mixture.In reaction mixture impouring water, use dichloromethane extraction.Organic layer salt water washing is used dried over mgso, concentrating under reduced pressure.The gained resistates is purified (using normal hexane and ethyl acetate (1: 1) as eluent) with silica gel column chromatography, obtains colorless solid methylsulfonic acid 2-{3-[2-(acetylamino)-1,3-thiazoles-4-yl] phenyl } ethyl ester (388mg).

¹H-NMR(200MHz，DMSO-d ₆)，δ(ppm)：2.16(3H，s)，3.04(2H，t，J＝6.9Hz)，3.12(3H，s)，4.45(2H，t，J＝6.9Hz)，7.23-7.42(2H，m)，7.60(1H，s)，7.75-7.81(2H，m)，12.26(1H，s)。

MS：341(M+H) ⁺

Step 7

25 ℃ to methylsulfonic acid 2-(3-[2-(acetylamino)-1,3-thiazoles-4-yl] phenyl the N of ethyl ester (388mg), add iminodiformic acid di tert butyl carbonate (322mg) and K in dinethylformamide (5ml) solution ₂CO ₃(236mg).At 80 ℃ of 2h that stir the mixture.In reaction mixture impouring water, use ethyl acetate extraction.Organic layer salt water washing is used dried over mgso, concentrating under reduced pressure.Gained contains N-{4-(3-[2-{ two-(tert-butoxycarbonyl) amino } ethyl] phenyl)-1,3-thiazoles-2-yl } colorless oil of ethanamide is directly used in next reaction and need not to purify again.

Step 8

N-{4-[3-(2-amino-ethyl) phenyl]-1,3-thiazoles-2-yl } the ethanamide similar approach preparation of the compound of step 7 according to preparation embodiment 31 steps 2.

¹H-NMR(200MHz，DMSO-d ₆)，δ(ppm)：2.16(1H，s)，2.74(2H，dd，J＝6.8，6.2Hz)，2.88(2H，dd，J＝7，7.8Hz)，7.17(1H，d，J＝7.7Hz)，7.35(1H，dd，J＝7.7，8Hz)，7.58(1H，s)，7.73(1H，d，J＝8Hz)，7.74(1H，s)。

MS：262(M+H) ⁺

Step 9

(z)-[(2-{3-[2-(acetylamino)-1,3-thiazoles-4-yl] phenyl } ethyl) amino] methylene radical } the similar approach preparation of the compound of step 8 of diamino acid di tert butyl carbonate according to preparation embodiment 18 steps 5.

¹H-NMR(200MHz，CDCl ₃)，δ(ppm)：1.45(9H，s)，1.50(3H，s)，2.27(3H，s)，2.92(2H，t，J＝7.5Hz)，3.71(2H，dt，J＝7.5，7.2Hz)，7.11-7.41(4H，d)，7.65-7.78(1H，m)。

MS：504(M+H) ⁺

Step 10

¹H-NMR(200MHz，CDCl ₃)，δ(ppm)：2.16(3H，s)，2.83(2H，t，J＝6.9Hz)，3.41(2H，m)，7.23(1H，d，J＝7.7Hz)，7.38(1H，dd，J＝7.7，7.8Hz)，7.52(1H，t，J＝5.5Hz)，7.59(1H，s)，7.75(1H，d，J＝8.1Hz)，7.79(1H，s)，12.23(1H，s)。

MS:304 (M+H) ⁺(free type)

Preparation embodiment 135:

Synthetic N-(4-[2-(4-{[amino (imino-) methyl] amino } phenyl) ethyl]-5-{2-[4-(methyl sulphonyl) phenyl] ethyl }-1,3-thiazoles-2-yl) acetamide hydrochloride

Step 1

N-{4-[2-(2-(acetylamino)-5-{ (E)-2-[4-(methyl sulphonyl) phenyl] vinyl }-1; 3-thiazole-4-yl) ethyl] phenyl } t-butyl carbamate is with 2-(acetylamino)-4-{2-[4-(tert-butoxycarbonyl amino) phenyl] ethyl }-1,3-thiazoles-5-formaldehyde is according to the similar approach preparation of preparation embodiment 45 steps 5.

MS:542 (M+H) ⁺(free type),

Step 2

N-{4-[2-(2-(acetylamino)-5-{2-[4-(methyl sulphonyl) phenyl] ethyl }-1,3-thiazoles-4-yl) ethyl] phenyl } the t-butyl carbamate similar approach preparation of the compound of step 1 according to preparation embodiment 45 steps 6.

MS：544(M+H) ⁺

Step 3

N-(4-[2-(4-aminophenyl) ethyl]-5-{2-[4-(methyl sulphonyl) phenyl] ethyl }-1,3-thiazoles-2-yl) the ethanamide similar approach preparation of the compound of step 2 according to preparation embodiment 31 steps 2.

¹H-NMR(200MHz，CDCl ₃)，δ(ppm)：2.23(3H，s)，2.61(4H，s)，2.78(4H，s)，2.98(3H，s)，3.55(2H，brs)，6.57(2H，d，J＝8.5Hz)，6.81(2H，d，J＝8.5Hz)，7.25(2H，d，J＝8.5Hz)，7.82(2H，d，J＝8.5Hz)，8.80(1H，s)。

MS：444(M+H) ⁺

Step 4

[(E)-(4-[2-(2-(acetylamino)-5-{2-[4-(methyl sulphonyl) phenyl] ethyl }-1,3-thiazoles-4-yl) ethyl] phenyl } amino) methylene radical] the similar approach preparation of the compound of step 3 of diamino acid di tert butyl carbonate according to preparation embodiment 18 steps 5.

¹H-NMR(200MHz，CDCl ₃)，δ(ppm)：1.49(9H，s)，1.53(9H，s)，2.22(3H，s)，2.59-2.73(4H，m)，2.84(4H，s)，2.98(3H，s)，6.99(2H，d，J＝8.4Hz)，7.28(2H，d，J＝8.4Hz)，7.44(2H，d，J＝8.4Hz)，7.83(2H，d，J＝8.4Hz)，8.99(1H，bra)，10.23(1H，s)，11.62(1H，s)。

MS：686(M+H) ⁺

Step 5

¹H-NMR(200MHz，DMSO-d ₆)，δ(ppm)：2.16(3H，s)，2.67(4H，brs)，2.82-2.94(4H，m)，3.14(3H，s)，7.12(2H，d，J＝8.4Hz)，7.20(2H，d，J＝8.4Hz)，7.43(2H，d，J＝8.4Hz)，7.82(2H，d，J＝8.4Hz)，9.87(1H，s)，11.97(1H，s)。

MS：486(M+H) ⁺

What following table was listed is the The compounds of this invention that can be used as the VAP-1 inhibitor.

Embodiment 1

Compd A is to the active restraining effect of VAP-1 enzyme (SSAO) in people and the rat plasma

With ¹⁴The C-benzylamine is as artificial substrates, determines VAP-1 enzyme (SSAO) activity in people and the rat plasma by the radiological chemistry enzyme assay.Will with the described enzyme suspension of blood plasma preparation with compd A in 96 hole microplates under room temperature preincubation 30min.Then described enzyme suspension is used ¹⁴C-benzylamine (2 * 10 ^-5The mol/l final concentration) with final volume 50 μ l at 37 ℃ of incubation 1h.Add 2mol/l (50 μ l) citric acid and stop enzyme reaction.Oxidation products directly is extracted in the 200 μ l toluene scintillators, detects its radioactivity with scintillation spectrometer.Use respectively ¹⁴The C-phenyl-ethyl amine and ¹⁴The C-butanediamine detects the activity of monoamine oxidase (MAO) and diamine oxidase (DAO, histaminase) as substrate by similar method.The clone DAO that will obtain from the cDNA library is used for people DAO and analyzes.The inhibition activity expression is IC ₅₀(μ mol/l) value.

Compd A suppresses the enzymic activity of SSAO in people and the rat plasma fully, but does not suppress the enzymic activity of other amine oxidase (for example human blood platelets MAO and clone DAO), and is as shown in table 1.

Table 1. compd A is to the active restraining effect (IC of different amine oxidases ₅₀Value, μ M)

Human plasma SSAO	Rat plasma SSAO	Human blood platelets MAO	Clone's people DAO
Human plasma SSAO	Rat plasma SSAO	Human blood platelets MAO	Clone's people DAO	0.15	0.012	＞100	＞100

Embodiment 2

Compd A is to the influence of the eye permeability of diabetes rat

After rat is gone on a hunger strike 20h, bring out the diabetes of rat by the 2mmol/l citrate buffer (pH 4.5) of intraperitoneal (i.p.) injection 65mg/ml/kg U-9889 (STZ).Simultaneously, inject isopyknic 2mmol/l citrate buffer to control rats.Check the glucose level of blood plasma by colorimetry.Handled the back the 3rd day at 8TZ, diagnose out rat to suffer from diabetes, plasma glucose concentration is 350mg/dl.

After STZ handled for two weeks, give compd A every day, continued for 2 weeks.Compd A is handled back 24h the last time,, leaks into Vitrea amount of dye and studies ophthalmovascular permeability after 30 minutes according to intravenous injection luciferin solution (40mg/ml/kg).Permeability is expressed as the fluorescein concentration ratio of vitreum and blood plasma, and fluorescein concentration detects with fluorophotometer.Simultaneously, use ¹⁴The C-benzylamine is as substrate (2 * 10 ^-5The mol/l final concentration), detect blood plasma SSAO activity by the radiological chemistry enzyme assay.

The back is detected around STZ handles, and compares with normoglycemic rat, and the eye permeability of diabetes rat significantly increases.Compare with the STZ control group, after STZ handled for two weeks, (10mg/kg s.c.u.i.d.) improved eye permeability (table 2) to give compd A every day.After around STZ handles, the blood plasma SSAO enzymic activity of diabetes rat also increases, and with the compd A processing active the increasing of SSAO is had the restraining effect (table 3) that is independent of dosage.

Fluorescein concentration ratio (the x10 of table 2. vitreum/blood plasma ^-3)

Normally	The STZ control group	The compd A treatment group
Normally	The STZ control group	The compd A treatment group	3.30±0.38 ^**	8.93±1.14	5.39±0.73 ^**

Each value is mean value ± S.E.M. of 10 rats. ^*Compare with the analog value of STZ contrast (p＜0.01, Dunnett check).

Table 3. blood plasma SSAO activity (pmol/min/ml)

Normally	The STZ control group	The compd A treatment group
Normally	The STZ control group	The compd A treatment group	4.40±0.34 ^**	10.0±0.73	2.51±0.26 ^**

Commercial Application

The invention provides formula (I) compound or its pharmaceutically acceptable salt: the R that can be used as the VAP-1 inhibitor¹-NH-X-Y-Z (I), wherein each symbol is definition above; Pharmaceutical composition; The method of prevention or treatment VAP-1 relevant disease, especially treat for example method of diabetic macular edema and non-diabetic macular edema of macular edema, described method comprises the VAP-1 inhibitor that needs the patient of this treatment effective dose with treatment patient's VAP-1 relevant disease, etc.

Claims

1. following formula (I) compound or its pharmacy acceptable salt:

R ¹-NH-X-Y-Z (I)

Wherein

R ¹Be acyl group;

X is the residue of divalent derived from the optional thiazole that replaces;

Y be chemical bond, low-grade alkylidene, lower alkenylene or-CONH-;

Z is the following formula group:

Or

R wherein ²Be following formula group :-A-B-D-E

Wherein A be chemical bond, low-grade alkylidene ,-NH-or-SO ₂-;

B be chemical bond, low-grade alkylidene ,-CO-or-O-;

D be chemical bond, low-grade alkylidene ,-NH-or-CH ₂NH-;

E for the amino of optional protection ,-N=CH ₂,

Or

Wherein

Q is-S-or-NH-;

R ³For hydrogen, low alkyl group, lower alkylthio or-NH-R ⁴, wherein

R ⁴For hydrogen ,-NH ₂Or low alkyl group.

2. the compound of claim 1 or its pharmacy acceptable salt, wherein Z is the following formula group:

R wherein ²Be the following formula group:

Or

3. the compound of claim 2 or its pharmacy acceptable salt, wherein R ²Be the following formula group:

Or

4. each compound or its pharmacy acceptable salt, wherein R of claim 1-3 ¹Be alkyl-carbonyl, X is replaced by the methyl sulphonyl benzyl derived from the residue of divalent of thiazole is also optional.

5. the compound of claim 1 or its pharmacy acceptable salt, wherein said compound or its pharmacy acceptable salt are

N-(4-{2-[4-(2-{[amino (imino-) methyl] amino } ethyl) phenyl] ethyl }-1,3-thiazoles-2-yl) ethanamide; Perhaps their pharmacy acceptable salt.

6. be used as compound or its pharmacy acceptable salt of the claim 1 of medicine.

7. medicinal compositions, said composition comprises as the compound of the claim 1 of activeconstituents or its pharmacy acceptable salt.

8. method for preparing following formula (I) compound or its pharmacy acceptable salt:

R ¹-NH-X-Y-Z (I)

Wherein

R ¹Be acyl group;

X is the residue of divalent derived from the optional thiazole that replaces;

Y be chemical bond, low-grade alkylidene, lower alkenylene or-CONH-;

Z is the following formula group:

Or

R wherein ²Be following formula group :-A-B-D-E,

Wherein A be chemical bond, low-grade alkylidene ,-NH-or-SO ₂-;

B be chemical bond, low-grade alkylidene ,-CO-or-O-;

D be chemical bond, low-grade alkylidene ,-NH-or-CH ₂NH-;

E for the amino of optional protection ,-N=CH ₂,

Or

Wherein

Q is-S-or-NH-;

R ³For hydrogen, low alkyl group, lower alkylthio or-NH-R ⁴, wherein

R ⁴For hydrogen ,-NH ₂Or low alkyl group;

Described method comprise at least one be selected from (i)-(step v):

(i) make compound (1):

With compound (2) or its reactant salt:

L wherein ₁Be leavings group, Z is definition above;

9. the compound of claim 1 or its pharmacy acceptable salt are preparing as the purposes in the medicine of VAP-1 inhibitor.

10. the purposes of claim 9, wherein said compound is

11. the compound of claim 1 or its pharmacy acceptable salt purposes in the preparation medicine, described medicine are used for prevention or treatment VAP-1 relative disease.

12. the purposes of claim 11, wherein said VAP-1 relative disease is selected from liver cirrhosis, basicly stable hypertension, diabetes, joint disease, (diabetes, atherosclerosis and hypertensive) endothelial injury, diabetes and uremia with cardiovascular disorder, gout and arthritis pain, (diabetic subject's) retinopathy, (reticular tissue) inflammatory diseases or illness (rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, osteoarthritis or degenerative osteoarthritis, Reiter syndrome, sjogren syndrome, Behcet, relapsing polychondritis, systemic lupus erythematosus, discoid lupus erythematosus, systemic sclerosis, eosinophilic fasciitis, polymyositis, dermatomyositis, polymyalgia rheumatica, vasculitis, temporal arteritis, polyarteritis nodosa, Wei Geneishi granuloma disease, mixed connective tissue disease and juvenile rheumatoid arthritis), gastroenteritis disease or illness [Crohn disease, ulcerative colitis, irritable bowel syndrome (spastic colon), the hepatic fibrosis disease, oral mucosa inflammation (stomatitis) and recurrent aphthous stomatitis], inflammatory disease of central nervous system or illness (multiple sclerosis, Alzheimer's and ischemia apoplexy with ischemia reperfusion injury), pulmonary inflammation disease or illness (asthma, adult respiratory distress syndrome, chronic obstructive pulmonary disease), (chronic) inflammatory disease of the skin or illness (psoriasis, the supersensitivity pathology, lichen planus, pityriasis rosea, contact dermatitis, atopic dermatitis, pityriasis rubra pilaris), (complication of diabetes and diabetes comprises capillary blood vessel and great vessels disease (atherosclerosis to the carbohydrate metabolism disease, retinal retinitis, retinopathy, ephrosis, nephrotic syndrome and neuropathy (polyneuropathy, mononeuropathy and autonomic neuropathy), ulcer of foot, joint problem and infection risk increase)), adipocyte differentiation or function or smooth muscle cell malfunction disease (atherosclerosis and obesity), vascular disease [atherosclerotic arteriosclerosis, non-atherosclerotic arteriosclerosis, cardiac ischemia (comprising myocardial infarction) and peripheral arterial occlusion, Raynaud disease and phenomenon, thromboangiitis obliterans (Buerger's disease)], chronic arthritis, inflammatory bowel, tetter, diabetes, [diabetes (insulin-dependent diabetes (IDDM) and non-insulin-dependent diabetes mellitus (NIDDM) (NIDDM)) and the vascular complication (heart attack of SSAO mediation property complication, stenocardia, apoplexy, amputation, lose one's sight and renal failure)] and macular edema (diabetic and non-diabetic macular edema).

13. the purposes of claim 12, wherein said VAP-1 relative disease is a macular edema.

14. the purposes of claim 13, wherein said macular edema is a diabetic macular edema.

15. the purposes of claim 13, wherein said macular edema are non-diabetic macular edema.

16. a VAP-1 inhibitor, it comprises compound or its pharmacy acceptable salt of claim 1.

17. the method for preventing or treating macular edema, this method comprises that the VAP-1 inhibitor that needs the recipient of this treatment capacity is to treat described recipient's macular edema.

18. the method for claim 17, wherein said VAP-1 inhibitor is

N-(4-{2-[4-(2-{[amino (imino-) methyl] amino } ethyl) phenyl] ethyl }-1,3-thiazoles-2-yl) ethanamide, perhaps their pharmacy acceptable salt.

19. the method for preventing or treating the VAP-1 relative disease, this method comprises compound or its pharmacy acceptable salt of the claim 1 that gives the Mammals significant quantity.

20. the method for claim 19, wherein said VAP-1 relative disease is selected from liver cirrhosis, basicly stable hypertension, diabetes, joint disease, (diabetes, atherosclerosis and hypertensive) endothelial injury, diabetes and uremia with cardiovascular disorder, gout and arthritis pain, (diabetic subject's) retinopathy, (reticular tissue) inflammatory diseases or illness (rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis and osteoarthritis or degenerative osteoarthritis, Reiter syndrome, sjogren syndrome, Behcet, relapsing polychondritis, systemic lupus erythematosus, discoid lupus erythematosus, systemic sclerosis, eosinophilic fasciitis, polymyositis, dermatomyositis, polymyalgia rheumatica, vasculitis, temporal arteritis, polyarteritis nodosa, Wei Geneishi granuloma disease, mixed connective tissue disease and juvenile rheumatoid arthritis), gastroenteritis disease or illness [Crohn disease, ulcerative colitis, irritable bowel syndrome (spastic colon), the hepatic fibrosis disease, oral mucosa inflammation (stomatitis) and recurrent aphthous stomatitis], inflammatory disease of central nervous system or illness (multiple sclerosis, Alzheimer's and ischemia apoplexy with ischemia reperfusion injury), pulmonary inflammation disease or illness (asthma, adult respiratory distress syndrome, chronic obstructive pulmonary disease), (chronic) inflammatory disease of the skin or illness (psoriasis, the supersensitivity pathology, lichen planus, pityriasis rosea, contact dermatitis, atopic dermatitis, pityriasis rubra pilaris), (complication of diabetes and diabetes comprises capillary blood vessel and great vessels disease (atherosclerosis to the carbohydrate metabolism disease, retinal retinitis, retinopathy, ephrosis, nephrotic syndrome and neuropathy (polyneuropathy, mononeuropathy and autonomic neuropathy), ulcer of foot, joint problem and infection risk increase)), adipocyte differentiation or function or smooth muscle cell malfunction disease (atherosclerosis and obesity), vascular disease [atherosclerotic arteriosclerosis, non-atherosclerotic arteriosclerosis, cardiac ischemia (comprising myocardial infarction) and peripheral arterial occlusion, Raynaud disease and phenomenon, thromboangiitis obliterans (Buerger's disease)], chronic arthritis, inflammatory bowel, tetter, diabetes, [diabetes (insulin-dependent diabetes (IDDM) and non-insulin-dependent diabetes mellitus (NIDDM) (NIDDM)) and the vascular complication (heart attack of SSAO mediation property complication, stenocardia, apoplexy, amputation, lose one's sight and renal failure)] and macular edema (diabetic and non-diabetic macular edema).

21. the method for claim 20, wherein said VAP-1 relative disease is a macular edema.

22. the method for claim 21, wherein said macular edema is a diabetic macular edema.

23. the method for claim 21, wherein said macular edema are non-diabetic macular edema.