CN101258137A - Dicycloalkyl urea glucokinase activators - Google Patents
Dicycloalkyl urea glucokinase activators Download PDFInfo
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Abstract
Dicycloalkyl urea glucokinase activators compounds are glucokinase inhibitors useful for the treatment of diabetes.
Description
Invention field
The application relates to new Dicycloalkyl urea glucokinase activators and the purposes in the multiple disease of treatment thereof.
Background of invention
Glucokinase (GK) is one of four kinds of hexokinase finding in Mammals [Colowick, S.P. are stated from The Enzymes, the 9th volume (P.Boyer edits) AcademicPress, New York, N.Y., 1-48 page or leaf, 1973].The first step of hexokinase catalysis glucose metabolism is about to conversion of glucose and becomes G-6-P.Glucokinase has limited cell distribution, mainly is present in pancreas beta cell and the hepatic parenchymal cells.In addition, GK is the rate-limiting enzyme of glucose metabolism in this two classes cell, and known this two classes cell is at [the Chipkin that plays an important role aspect the whole body glucose stable state, S.R., Kelly, K.L. and Ruderman, N.B., be stated from Joslin ' sDiabetes (C.R.Khan and G.C.Wier write), Lea and Febiger, Philadelphia, Pa., the 97-115 page or leaf, 1994].Demonstrate the most highly active half at GK, glucose concn is approximately 8mM.Other three kinds of hexokinase much lower glucose concn (＜saturated 1mM) time.Therefore, when feed contains sugar after the meal, along with glucose concn in the blood increases to after the meal (≈ 10-15mM) level from empty stomach (5mM), glucose flow by the GK approach improves [Printz, R.G., Magnuson, M.A. and Granner, D.K. is stated from Ann.Rev.Nutrition the 13rd volume (R.E.Olson, D.M.Bier and D.B.McCormick write), Annual Review, Inc., Palo Alto, Calif., 463-496 page or leaf, 1993].These discoveries have facilitated the hypothesis before 10 years: GK to play glucose sensor (Meglasson, M.D. and Matschinsky, F.M.Amer.J.Physiol.246, E1-E13,1984) in beta cell and liver cell.In recent years, the research in transgenic animal has confirmed that GK brings into play keying action really in whole body glucose stable state.The animal of not expressing GK dies from serious diabetes in birth after several days, and the animal of overexpression GK has been improved glucose tolerance (Grupe, A., Hultgren, B., Ryan, A. etc., Cell83,69-78,1995; Ferrie, T., Riu, E., Bosch, F. etc., FASEB J., 10,1213-1218,1996).The increase that glucose exposes is by the GK in the beta cell and the insulin secretion coupling of increase, by the glucose generation coupling of the glycogen deposition of GK in the liver cell and increase and perhaps reduction.
Find that the adult morbidity type diabetes (MODY-2) of II type young adult are caused that by the afunction that the GK transgenation causes prompting GK also plays glucose sensor (Liang, Y., Kesavan in human body, P., Wang, L. etc., Biochem.J.309,167-173,1995).Be tested and appraised the patient who expresses mutant GK and follow the enzymic activity of increase, provide extra evidence to support the key player of GK in people's glucose metabolism is regulated.These patients show the fasting hypoglycemia relevant with the plasma insulin level that is not suitable for improving (Glaser, B., Kesavan, P., Heyman, M. etc., New England J.Med.338,226-230,1998).Although do not find the sudden change of GK gene in most of diabetes B patients, the compound that activates GK and increase the susceptibility of GK sensing system thus will be used for the treatment of the hyperglycemia symptom of all diabetes Bs.Activators of glucokinase will increase the glucose metabolism flow in beta cell and the liver cell, and it can be coupled to the insulin secretion of increase.These activators can be used for the treatment of type ii diabetes.Some GK activators are known, referring to for example US 2004/0014968 (Hofmann-LaRoche Inc.), WO 2003/055482 (Novo Nordisk A/S) and WO 2004/002481 (Novo Nordisk A/S).Diabetes are feature with the glucose metabolism attenuating, especially show as glucose level and raise in the diabetic subject.Can be divided into two big classes to diabetes according to these defectives: type 1 diabetes is insulin requirements type diabetes (IDDM), this disease takes place when the patient lacks the beta cell that produces Regular Insulin in their pancreas, with diabetes B be non insulin dependent diabetes (NIDDM), this disease occur in except a series of other unusual in addition among the impaired patient of beta cell function.
The present insulinize of type 1 diabetes patient, and most of diabetes B patient is with the sulfonylurea that stimulates the beta cell function or with strengthening medicine or the insulinize of patient to the structure sensitive properties of Regular Insulin.At the medicine that is used for strengthening to the structure sensitive properties of Regular Insulin, N1,N1-Dimethylbiguanide is a representative example.
Although sulfonylurea is widely used in treating NIDDM, but this therapy makes us not too satisfied in most cases: in a large amount of NIDDM patients, the sulfonylurea deficiency is so that glucose level normalizing, so the patient faces the high-risk of suffering from diabetic complication.In addition, a lot of patients lose the ability in response to the sulfonylurea treatment gradually, thereby are forced to accept insulinize gradually.The patient from oral hypoglycemic to this transformation of insulin treatment usually owing to NIDDM patient's body in the exhausting of beta cell.
In normal subjects and diabetic subject, for fear of hypoglycemia, liver can produce glucose.The generation of this glucose comes from the release of glucose from glycogen storage or glyconeogenesis, and the latter is synthesizing in capitulum of glucose.But in diabetes B, the regulation and control of hepatic glucose output are relatively poor and be increased, and may double behind overnight fasting.And, in these patients, between increase of fasting plasma glucose level and hepatic glucose generation speed, exist strong reciprocity.Similarly, hepatic glucose produces will be increased in type 1 diabetes, and prerequisite is the appropriate control that this disease is not subjected to insulinize.Because the diabetotherapy of existing form is controlling blood sugar fully not, therefore can't be satisfactory, there is huge demand in the treatment means of novelty.
Atherosclerosis is a kind of artery disease, is considered to the major causes of death in the U.S. and West Europe.Cause that the cardiopathic pathology of atherosclerosis and occlusive is widely known by the people in proper order.The very early time stage of this order is the generation that reaches " fatty streak " in the aorta in carotid artery, coronary artery and the cerebral arteries.Because the existence of lipid deposits, the color of these focuses are yellow, are mainly seen in the smooth muscle cell and scavenger cell of artery and aortic tunica intima layer.In addition, infer that the most of cholesterol that is present in the fatty streak causes the formation of " fibrous plaque " then, it is made up of the intimal smooth muscle cells of being accumulated, and wherein is full of lipid, and around extracellular lipid, collagen protein, elastin and proteoglycan are arranged.Cell adds matrix and forms fibrous cap, covers the deep settling and the more extracellular lipid of cell debris.Lipid mainly is the cholesterol of free and esterification.Fibrous plaque slowly forms, and might become calcification sooner or later with necrosis, develop into " plyability pathology " at last, this has explained that arterial occlusion and mural thrombus form the trend with the artery muscle spasm, these are that late arterial is atherosis peculiar.The epidemiology evidence has confirmed that hyperlipidaemia is the primary hazard factor that causes the cardiovascular disorder (CVD) that caused by atherosclerosis.In recent years, the medical circle authoritative sources to reemphasize the level that reduces plasma cholesterol, particularly low density lipoprotein cholesterol be essential step in the CVD prevention.The upper limit of " normally " is the known understanding that significantly is lower than before this now.The result is that most of westerner is considered to face extra high danger now.Independently Hazard Factor comprise the not anti-disease of glucose, left ventricular hypertrophy, hypertension and male gender.Cardiovascular disorder is especially general in the diabetic subject, is being because there are a plurality of independent hazard factors in this group people on the part degree at least.Therefore, the successful treatment of hyperlipidaemia has especially medical importance in the general population, particularly diabetic.
Hypertension (or hyperpiesia) is as various other diseases such as renal artery stenosis, pheochromocytoma or dyshormonal secondary symptom and occur in disease among some crowd.But, hypertension also has obvious performance in the patient of a lot of origin causes of formation or obstacle the unknown.Although this class " primary " hypertension is often with relevant such as diseases such as obesity, diabetes and hypertriglyceridemias, but the relation between these diseases is not illustrated as yet.In addition, a lot of patients also demonstrate the symptom of hyperpiesia fully without any other disease or obstacle sign the time.
Known hypertension can directly cause heart failure, renal failure and apoplexy (hematencephalon).These illnesss can cause patient's dead (short-term death) in very short time.Hypertension also can promote the generation of atherosclerosis and coronary disease.These illnesss make patient's weakness gradually, can cause death (long-term dead) after long-time.
The definite reason of essential hypertension is unknown, but believes that many factors facilitate the generation of this disease.Salinity and the excess moisture that this class factor has stress reaction, loses one's temper, hormone discharges imbalance (feritin, Angiotensin aldosterone system), caused by the kidney dysfunction, cause vasoconstrictive vascular system wall thickening and hypertrophy and inherited genetic factors.
When carrying out the essential hypertension treatment, considered above-mentioned factor.Thereby medicine such as miscellaneous β-blocade, vasoconstrictor, angiotensin-converting enzyme inhibitor has been developed listing as antihypertensive drug.Utilize the verified prevention that is of value to short-term death of these compounds for treating hypertension, for example heart failure, renal failure and hematencephalon.But, atherosclerosis or the heart trouble that is caused by long-time hypertension remains a problem.Be lowered although this means hypertension, the basic reason of essential hypertension is not in response to this treatment.
Hypertension and blood insulin level raise-and a kind of disease that is called as hyperinsulinemia is relevant.Regular Insulin is a kind of peptide hormone, and its main effect is generation and the storage that promotes glucose utilization, protein synthesis and neutral lipid, also promotes vascular cell growth and increases kidney sodium retention or the like.Latter's function can realize under the situation of affecting glucose level not, be hypertensive known reason.For example, the growth of peripheral vasculature can cause the periphery capillary vessel to shrink, and the sodium retention meeting increases blood volume.Thereby the abnormal vascular that the insulin level that reduces the hyperinsulinemia patient can prevent to be caused by high insulin levels is grown and the kidney sodium retention, thus alleviating hypertension.
Cardiac hypertrophy is the substantial risk factor during sudden death, myocardial infarction and congestive heart failure take place.These cardiac events are owing to ischemic at least on the part degree and the perfusion back is to the susceptibility increase of myocardial damage again, and this may occur in out-patient and intra-operative.Medically satisfy as yet for preventing bad myocardium peri-operation period consequence, particularly peri-operation period myocardial infarction or making its minimized needs.Non-heart is all relevant with the substantive danger of myocardial infarction or death with heart operation.About 7,000,000 patients that accept non-cardiac surgery are considered to face a danger, and the incidence of the dead and serious cardiac complication of intra-operative is up to 20-25% in some series operation.In addition, accept among 400,000 patients of heart bypass operation in every year, the incidence of perioperative myocardial infarction is 5% according to estimates, and mortality ratio is 1-2%.There is not at present pharmacotherapy can reduce the intra-operative myocardial ischemia to the infringement of heart tissue or strengthen the resistivity of heart to ischemic stroke in this field.The expection of this therapy can be saved life, reduces being hospitalized for treatment, improving the quality of living and reducing overall health care cost of high-risk patient.
Obesity be a lot of very common diseases (for example atherosclerosis, hypertension and diabetes) take place know Hazard Factor.Population of being obese and these disease incidence rate that cause in addition thus increase day by day in the whole industrialization world.Except taking exercise, go on a diet and limitting the food, there is not compellent pharmacological treatment to lose weight at present effective and reasonablely.But, since as Hazard Factor in fatal and common disease indirectly but significant effects finds that the therapy of obesity and/or the means of appetite stimulator will be important.
The term obesity is meant that fatty tissue is excessive.What in this article, obesity preferably was regarded as any degree brings dangerous obesity to health.Boundary line between normal individual and the obese individuals only is proximate, but the health risk that is brought by obesity probably continues along with increasing the weight of gradually of obesity.Framingham studies have shown that, surpasses ideal body weight 20% and will obviously bring health risk (Mann GV N.Engl.J.Med 291:226,1974).In the U.S., the fat common recognition council of NIH (NIH) is consistent think young adult's relative body weight increase by 20% or constitutional index (BMI=body weight kilogram number divided by height rice number square) more than 85 percentage points health is constituted dangerous.Utilize these standards, there are 20%～30% adult man and adult female's obesity (NIH, Ann Intern Med 103:147,1985) of 30%～40% in the U.S..
Even slight obesity also can increase the danger of premature dead, diabetes, hypertension, atherosclerosis, gallbladder disease and some types of cancer.In the industrialization the Western countries, fat ubiquity significantly increases in the past few decades.Because fat high ubiquity and its consequence to health, its prevention and treatment should be paying the utmost attention to of public health.
When energy take in to surpass consumed, too much heat was stored in the fatty tissue, if be in for a long time in this clean positive balance, then causes fat, and that is to say that there are two portions in the body weight balance, any side (take in or consume) can both cause obesity unusually.
The adjusting of feed behavior is not understood as yet fully.To a certain extent, appetite is subjected to the control of zone of dispersion in the hypothalamus: the full sense maincenter in feeding center in the hypothalamus ventral lateral nucleus of thalamus (VLH) and the ventromedial hypothalamus VMH (VMH).Pallium receives the positive signal from the stimulation feed of feeding center, and full sense maincenter is regulated and control this process by sending the inhibition pulse to feeding center.Some regulate processes can influence these hypothalamic cellses.Full sense maincenter can be by the increase activation of plasma glucose and/or Regular Insulin after the meal.The gastric dilatation that dining is brought out is another kind of possible damper.In addition, hypothalamic cells is to the catecholamine sensitivity, and the beta-adrenergic hormesis suppresses the feed behavior.Finally, pallium control feed behavior only is an input signal from feeding center to corticocerebral pulse.Psychology, society and inherited genetic factors also influence food intake.
There are multiple technologies to can be used for realizing preliminary weight reduction at present.What something lost was shaken is that preliminary weight reduction is not best therapeutic goal.On the contrary, problem is that the final body weight of most of obese patients increases again.The effective means of setting up and/or keep loss of weight is the significant challenge in the current obesity treatment.
Summary of the invention
The invention provides the compound of following general formula (I):
Wherein each substituent definition sees below, and its more embodiment also is documented in the appended embodiment.
The present invention also provides The compounds of this invention to be used for the treatment of purposes in the multiple disease medicine of (for example being used for the treatment of diabetes B) in preparation.
Definition
Here with the given structural formula of whole specification sheets in, following term has described implication:
Term used herein " the optional replacement " is meant that the optional part that replaces is unsubstituted or is replaced by one or more appointment substituting groups.When described part was replaced by a more than substituting group, substituting group can be identical or different.
Term used herein " adjacent () " relate to the relative position of two atoms or variable, these two an atoms or variable shared key, perhaps a variable was right after before or after another variable in variable declaration.For example, " atom A is adjacent with atom B " is meant two atom A and the shared key of B.
Term " halogen " or " halo " are meant fluorine, chlorine, bromine or iodine.
Term " perhalogeno methyl " is meant trifluoromethyl, trichloromethyl, trisbromomethyl or three iodomethyls.
C
X-y-alkyl, C
X-y-thiazolinyl, C
X-y-alkynyl, C
X-y-cycloalkyl or C
X-y-cycloalkyl-C
X-y-thiazolinyl-wait the use of this class formation prefix to be meant that the group of specified type has x to y carbon atom.
Term used herein " alkyl " single with or be meant the saturated monovalence alkyl of straight or branched during coupling, have one to ten carbon atom, for example C
1-8-alkyl or C
1-6-alkyl.Typical C
1-8-alkyl and C
1-6-alkyl includes but not limited to for example methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, sec-butyl, isobutyl-, the tertiary butyl, n-pentyl, 2-methyl butyl, 3-methyl butyl, 4-methyl amyl, neo-pentyl, n-pentyl, n-hexyl, 1,2-dimethyl propyl, 2,2-dimethyl propyl, 1,2,2-trimethylammonium propyl group etc.Term " C used herein
1-8-alkyl " also comprise C
3-8-secondary alkyl and C
4-8-tertiary alkyl.Term " C used herein
1-6-alkyl " also comprise C
3-6-secondary alkyl and C
4-6-tertiary alkyl.
Term used herein " thiazolinyl " single with or be meant straight or branched monovalence alkyl during coupling, contain two to ten carbon atoms and at least one carbon-to-carbon double bond, for example C
2-8-thiazolinyl or C
2-6-thiazolinyl.Typical C
2-8-thiazolinyl and C
2-6-thiazolinyl includes but not limited to vinyl, 1-propenyl, 2-propenyl, pseudoallyl, 1,3-butadienyl, 1-butylene base, crotyl, 3-butenyl, 2-methyl isophthalic acid-propenyl, 1-pentenyl, pentenyl, 3-pentenyl, 4-pentenyl, 3-methyl-2-butene base, 1-hexenyl, 2-hexenyl, 3-hexenyl, 2,4-hexadienyl, 5-hexenyl etc.
Term used herein " alkynyl " single with or be meant straight or branched monovalence alkyl during coupling, contain two to ten carbon atoms and at least one carbon-to-carbon triple bond, for example C
2-8-alkynyl or C
2-6-alkynyl.Typical C
2-8-alkynyl and C
2-6-alkynyl includes but not limited to ethynyl, 1-proyl, 2-propynyl, ethyl acetylene base, 2-butyne base, 3-butynyl, 1-pentynyl, valerylene base, 3-pentynyl, 4-pentynyl, 1-hexin base, 2-hexin base, 3-hexin base, 5-hexin base, 2,4-hexadiyne base etc.
Term used herein " cycloalkyl " single with or be meant during coupling saturated mono-, two-or three-carbocylic radical, have three to 12 carbon atoms, for example C
3-8-cycloalkyl.Typical C
3-8-cycloalkyl includes but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, ring octyl group, two ring [3.2.1] octyl groups, two ring [2.2.1] heptyl, falls pinane base (norpinyl), norcamphyl (norbonyl), norcaryl (norcaryl), adamantyl etc.
Term used herein " cycloalkenyl group " single with or be meant during coupling the unsaturated list of non-aromatics-, two-or three-carbocylic radical, have three to 12 carbon atoms, for example C
3-8-cycloalkenyl group.Typical C
3-8-cycloalkenyl group includes but not limited to cyclohexenyl, cycloheptenyl and cyclopentenyl etc.
Term used herein " heterocycle (heterocyclic) " or term " heterocyclic radical (heterocyclyl) " single with or be meant during coupling saturated mono-, two-or three-carbocylic radical, have three to 12 carbon atoms and be selected from nitrogen, oxygen, sulphur, SO or SO in addition with one or two
2Heteroatoms or group, C for example
3-8-heterocyclic radical.Typical C
3-8-heterocyclic radical includes but not limited to tetrahydrofuran base, tetrahydro-thienyl, THP trtrahydropyranyl, tetrahydro thiapyran base, 1,4-alkyl dioxin, 1,3-alkyl dioxin, piperidyl, pyrrolidyl, morpholinyl, piperazinyl etc.
Term used herein " heterocycloalkenyl " single with or be meant during coupling the unsaturated list of non-aromatics-, two-or three-cyclic group, have three to 12 carbon atoms and be selected from nitrogen, oxygen, sulphur, SO or SO in addition with one or two
2Heteroatoms or group, C for example
3-8-heterocycloalkenyl.Typical C
3-8-heterocycloalkenyl includes but not limited to tetrahydro pyridyl, azepine base, 2-pyrrolinyl, 3-pyrrolinyl, 2-pyrazolinyl, imidazolinyl, 4H-pyranyl etc.
Term " alkoxyl group (alkoxy) " or " alkyl oxy (alkyloxy) " are used interchangeably at this paper, single with or be meant univalent perssad R during coupling
aO-, wherein R
aBe alkyl as defined above, for example by C
1-8-alkyl obtains C
1-8-alkoxyl group.Typical C
1-8-alkoxyl group includes but not limited to methoxyl group, oxyethyl group, positive propoxy, isopropoxy, butoxy, sec-butoxy, tert.-butoxy, pentyloxy, isopentyloxy, hexyloxy, different hexyloxy etc.
Term " alkene oxygen base " single with or be meant univalent perssad R during coupling
aO-, wherein R
aBe thiazolinyl as defined above, for example by C
2-8-alkyl obtains C
2-8-alkene oxygen base.Typical C
2-8-alkene oxygen base includes but not limited to vinyloxy group, propenyloxy group, 2-methyl-propenyloxy group, butenyloxy etc.
Term used herein " alkylthio " single with or be meant the straight or branched monad radical during coupling, contain aforesaid alkyl by the bivalent sulfur atom connection, have free valence bond, for example C from this sulphur atom
1-6-alkylthio.Typical C
1-6-alkylthio includes but not limited to methylthio group, ethylmercapto group, rosickyite base, butylthio, penta sulfenyl, own sulfenyl etc.
Term used herein " alkoxy carbonyl " is meant univalent perssad R
aOC (O)-, R wherein
aBe aforesaid alkyl, for example C
1-8-alkoxy carbonyl.Typical C
1-8-alkoxy carbonyl includes but not limited to methoxycarbonyl, ethoxy carbonyl, propoxycarbonyl, isopropoxy carbonyl, n-butoxy carbonyl, sec-butoxy carbonyl, tert-butoxycarbonyl, 3-methyl butoxy carbonyl, positive hexyloxy carbonyl etc.
Term used herein " aryl " is meant carbocyclic aromatic cyclic group or aromatic ring system base.Aryl also is used to comprise the partial hydrogenation derivative of carbon-loop system.
Term used herein " heteroaryl " single with or be meant aromatics cyclic group during coupling or have for example aromatic ring system base of 7-18 annular atoms with 5-7 annular atoms for example, contain one or more heteroatomss that are selected from nitrogen, oxygen or sulfur heteroatom, wherein N-oxide compound and sulphur monoxide and sulphur dioxide are that admissible heteroaromatic replaces; For example furyl, thienyl (thienyl), thienyl (thiophenyl), pyrryl, imidazolyl, pyrazolyl, triazolyl, tetrazyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazole base, thiadiazolyl group, isothiazolyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl, benzofuryl, benzothienyl, indyl and indazolyl etc.Heteroaryl also is used to comprise the partial hydrogenation derivative of following heterocyclic system.
The example of " aryl " and " heteroaryl " includes but not limited to phenyl, xenyl, indenyl, fluorenyl, naphthyl (1-naphthyl, the 2-naphthyl), anthryl (1-anthryl, the 2-anthryl, the 3-anthryl), thienyl (2-thienyl, the 3-thienyl), furyl (2-furyl, the 3-furyl), indyl oxadiazole base isoxazolyl, thiadiazolyl group oxatriazole base, the thiatriazole base, quinazolyl, fluorenyl, xanthenyl, different dihydro indenyl, diphenyl-methyl, acridyl, thiazolyl, pyrryl (1-pyrryl, the 2-pyrryl, the 3-pyrryl), pyrazolyl (1-pyrazolyl, the 3-pyrazolyl, the 4-pyrazolyl, the 5-pyrazolyl), imidazolyl (1-imidazolyl, the 2-imidazolyl, the 4-imidazolyl, the 5-imidazolyl), triazolyl (1,2, the 3-triazol-1-yl, 1,2,3-triazole-4-base, 1,2,3-triazole-5-base, 1,2,4-triazole-3-base, 1,2,4-triazole-5-yl) oxazolyl (2-oxazolyl, the 4-oxazolyl, the 5-oxazolyl) isoxazolyl (isoxazole-3-base isoxazole-4-base isoxazole-5-base), isothiazolyl (isothiazole-3-base, isothiazole-4-base, isothiazole-5-yl), thiazolyl (2-thiazolyl, the 4-thiazolyl, the 5-thiazolyl), pyridyl (2-pyridyl, the 3-pyridyl, the 4-pyridyl), pyrimidyl (2-pyrimidyl, the 4-pyrimidyl, the 5-pyrimidyl, the 6-pyrimidyl), pyrazinyl, pyridazinyl (3-pyridazinyl, the 4-pyridazinyl, the 5-pyridazinyl), quinolyl (2-quinolyl, the 3-quinolyl, the 4-quinolyl, the 5-quinolyl, the 6-quinolyl, the 7-quinolyl, the 8-quinolyl), isoquinolyl (1-isoquinolyl, the 3-isoquinolyl, the 4-isoquinolyl, the 5-isoquinolyl, the 6-isoquinolyl, the 7-isoquinolyl, the 8-isoquinolyl), benzo [b] furyl (2-benzo [b] furyl, 3-benzo [b] furyl, 4-benzo [b] furyl, 5-benzo [b] furyl, 6-benzo [b] furyl, 7-benzo [b] furyl, 2, (2-(2 for 3-dihydro-benzo [b] furyl, 3-dihydro-benzo [b] furyl), 3-(2,3-dihydro-benzo [b] furyl), 4-(2,3-dihydro-benzo [b] furyl), 5-(2,3-dihydro-benzo [b] furyl), 6-(2,3-dihydro-benzo [b] furyl), 7-(2,3-dihydro-benzo [b] furyl), benzo [b] thienyl (benzo [b] thiophene-2-base, benzo [b] thiene-3-yl-, benzo [b] thiophene-4-base, benzo [b] thiophene-5-base, benzo [b] thiophene-6-base, benzo [b] thiophene-7-yl), 2,3-dihydro-benzo [b] thienyl (2,3-dihydro-benzo [b] thiophene-2-base, 2,3-dihydro-benzo [b] thiene-3-yl-, 2,3-dihydro-benzo [b] thiophene-4-base, 2,3-dihydro-benzo [b] thiophene-5-base, 2,3-dihydro-benzo [b] thiophene-6-base, 2,3-dihydro-benzo [b] thiophene-7-yl), indyl (1-indyl, the 2-indyl, the 3-indyl, the 4-indyl, the 5-indyl, the 6-indyl, the 7-indyl), indazolyl (1-indazolyl, the 3-indazolyl, the 4-indazolyl, the 5-indazolyl, the 6-indazolyl, the 7-indazolyl), benzimidazolyl-(1-benzimidazolyl-, the 2-benzimidazolyl-, the 4-benzimidazolyl-, the 5-benzimidazolyl-, the 6-benzimidazolyl-, the 7-benzimidazolyl-, the 8-benzimidazolyl-) benzoxazolyl (2-benzoxazolyl, the 3-benzoxazolyl, the 4-benzoxazolyl, the 5-benzoxazolyl, the 6-benzoxazolyl, the 7-benzoxazolyl), benzothiazolyl (2-[4-morpholinodithio base, the 4-benzothiazolyl, the 5-benzothiazolyl, the 6-benzothiazolyl, the 7-benzothiazolyl), carbazyl (1-carbazyl, the 2-carbazyl, the 3-carbazyl, the 4-carbazyl), 5H-dibenzo [b, f] azepine
Base (5H-dibenzo [b, f] azepine
-1-base, 5H-dibenzo [b, f] azepine
-2-base, 5H-dibenzo [b, f] azepine
-3-base, 5H-dibenzo [b, f] azepine
-4-base, 5H-dibenzo [b, f] azepine
-5-yl), 10,11-dihydro-5H-dibenzo [b, f] azepine
Base (10,11-dihydro-5H-dibenzo [b, f] azepine
-1-base, 10,11-dihydro-5H-dibenzo [b, f] azepine
-2-base, 10,11-dihydro-5H-dibenzo [b, f] azepine
-3-base, 10,11-dihydro-5H-dibenzo [b, f] azepine
-4-base, 10,11-dihydro-5H-dibenzo [b, f] azepine
-5-yl), benzo [1,3] dioxa cyclopentenyl (2-benzo [1,3] dioxa cyclopentenyl, 4-benzo [1,3] dioxa cyclopentenyl, 5-benzo [1,3] dioxa cyclopentenyl, 6-benzo [1,3] dioxa cyclopentenyl, 7-benzo [1,3] dioxa cyclopentenyl), purine radicals and tetrazyl (5-tetrazyl, N-tetrazyl).
The invention still further relates to the partially or completely saturated analogue of above-mentioned member ring systems.
When the term of definition is used in combination more than two or more, for example aryl-alkyl, heteroaryl-alkyl, cycloalkyl-C
1-6-alkyl etc., obvious last group are the substituting group of back on one group, wherein replace a little, promptly with the tie point of molecule another part, are positioned on one group of back, for example
Aryl-alkyl:
Cycloalkyl-aryl:
With
Aryl-alkoxyl group:
Term used herein " fused-aryl cycloalkyl " is meant aryl and Cycloalkylfused as defined above as defined above, and has the carbon atom that specifies number, shared two atoms of this aryl and cycloalkyl, and wherein cycloalkyl is to replace point.The example of " fused-aryl cycloalkyl " used herein comprise 1-dihydro indenyl, 2-dihydro indenyl, 1-(1,2,3, the 4-tetralyl),
Deng.
Term used herein " condensed heteroaryl cycloalkyl " is meant heteroaryl and Cycloalkylfused as defined above as defined above, and has the carbon atom that specifies number, shared two atoms of this aryl and cycloalkyl, and wherein cycloalkyl is to replace point.The example of condensed heteroaryl cycloalkyl used herein comprises 6,7-dihydro-5H-cyclopenta [b] pyridyl, 5,6,7,8-tetrahydric quinoline group, 5,6,7,8-tetrahydro isoquinolyl, 5,6,7,8-tetrahydro quinazoline base etc.
Term used herein " alkylthio (alkylsulfanyl) " is meant R
aS-, wherein R
aBe aforesaid alkyl.
Term used herein " alkyl sulphinyl (alkylsulfeny) " is meant R
aS (O)-, R wherein
aBe aforesaid alkyl.
Term used herein " alkyl sulphonyl (alkylsulfonyl) " is meant R
aSO
2-, R wherein
aBe aforesaid alkyl.
Term used herein " alkyl amino sulfonyl (alkylsulfamoyl) " is meant R
aNHSO
2-, R wherein
aBe aforesaid alkyl.
Term used herein " dialkyl amino sulfonyl " is meant R
aR
bNSO
2-, R wherein
aAnd R
bBe aforesaid alkyl.
Term used herein " alkylamino sulfinyl " is meant R
aNHSO-, wherein R
aBe aforesaid alkyl.
Term used herein " dialkyl amido sulfinyl " is meant R
aR
bNSO-, wherein R
aAnd R
bBe aforesaid alkyl.
Term used herein " alkylamino " is meant R
aNH-, wherein R
aBe aforesaid alkyl.
Term used herein " acyl group " is meant R
aC (O)-, R wherein
aBe aforesaid alkyl, thiazolinyl, alkynyl, cycloalkyl, cycloalkenyl group or heterocyclic radical.
Term used herein " heteroaryloxy " single with or be meant monad radical R during coupling
aO-, wherein R
aBe aforesaid heteroaryl.
Term used herein " aryloxycarbonyl " is meant R
a-O-C (O)-, R wherein
aBe aforesaid aryl.
Term used herein " acyloxy " is meant R
aC (O) O-, wherein R
aBe aforesaid alkyl, thiazolinyl, alkynyl, cycloalkyl, cycloalkenyl group or heterocyclic radical.
Term used herein " aryloxy " is meant R
a-O-, wherein R
aBe aforesaid aryl.
Term used herein " aryl acyloxy " is meant R
aC (O) O-, wherein R
aBe aforesaid aryl.
Term used herein " assorted aryl acyloxy " is meant R
aC (O) O-, wherein R
aBe aforesaid heteroaryl.
No matter when term " alkyl ", " cycloalkyl ", " aryl ", " heteroaryl " etc. or their prefix root appear in the substituting group title (for example alkoxy aryl aryloxy), and they all should be interpreted as comprising above about those given restrictions of " alkyl " and " aryl ".
Term used herein " oxo " should refer to substituting group=O.
Term used herein " sulfydryl " should refer to substituting group-SH.
Term used herein " carboxyl " should refer to substituting group-C (O) OH.
Term used herein " cyano group " should refer to substituting group-CN.
Term used herein " nitro " should refer to substituting group-NO
2
Term used herein " amino-sulfonyl " should refer to substituting group-SO
2NH
2
Term used herein " sulfenyl " should refer to substituting group-S-.
Term used herein " sulfinyl " should refer to substituting group-S (O)-.
Term used herein " alkylsulfonyl " should refer to substituting group-S (O)
2-.
Term used herein " directly key (direct bond) " is meant substituent directly connection of the variable side (before with afterwards) that is regarded as " direct key " for structure variable explanation a part of the time.
Term used herein " rudimentary " is meant the group with 1-6 carbon atom, can use prefix C
X-6-expression.Therefore, low alkyl group can be expressed as C
1-6-alkyl, and low-grade alkylidene can be expressed as C
2-6-alkylidene group.
Such as C
X-y-cycloalkyl-C
A-bThe group of-thiazolinyl should refer to that the tie point of this group is the part of back one base.
Term used herein " optional () " be meant that the incident of describing subsequently may take place or may not take place, and comprises the generation incident and these two kinds of situations of incident do not take place.
Term used herein " replacement " is meant by specified one or more substituting groups and replaces, allows a plurality of substitution values unless otherwise prescribed.
Term used herein " connection " or "-" (for example-C (O) R
11, be meant the carbonyl tie point on the skeleton) and the stable covalent linkage of expression.
Term used herein " contain " can refer to along any position of alkyl, thiazolinyl, alkynyl or naphthenic substituent as defined above by O, S, SO, SO
2, any one or a plurality of online replacement (in-line substitution) in N or the N-alkyl, for example comprise-CH
2-O-CH
2-,-CH
2-SO
2-CH
2-,-CH
2-NH-CH
3Deng.
Some as defined above term can in structural formula, occur once incessantly, each term all should be independent of other term definition when this class occurs.
Term used herein " solvate " is the variable mixture of stoichiometry that is generated by solute (being formula (I) compound in the present invention) and solvent.This kind solvent can not disturb the biological activity of solute for the object of the invention.Solvent for example can be water, ethanol or acetate.
Term used herein " biological hydrolyzable ester " is the ester of medicine (being formula (I) compound in the present invention), it a) does not disturb the biological activity of parent material, but give this material favourable body internal characteristic, for example the time length of onset, onset begins etc., perhaps b) lifeless matter activity, but be converted into bioactive ingredients in the subject easily.Advantage is that the hydrolyzable ester per os of biological example by intestinal absorption, is converted into (I) in blood plasma.A lot of such examples all are known in the art, for example comprise lower alkyl esters (C for example
1-4), low-grade acyloxy alkyl ester, lower alkoxy acyloxy alkyl ester, alkoxyl group acyloxyate, alkyl amido alkyl ester and cholinesterase.
Term used herein " biological hydrolyzable acid amides " is the acid amides of medicine (being formula (I) compound in the present invention), it a) does not disturb the biological activity of parent material, but give this material favourable body internal characteristic, for example the time length of onset, onset begins etc., perhaps b) lifeless matter activity, but be converted into bioactive ingredients in the subject easily.Advantage is that the hydrolyzable acid amides per os of biological example by intestinal absorption, is converted into (I) in blood plasma.A lot of such examples all are known in the art, for example comprise low alkyl group acid amides, alpha-amino acid amides, alkoxyl group acyl group acid amides and alkylamino alkyl-carbonyl acid amides.
Term used herein " prodrug " comprises biological hydrolyzable acid amides and biological hydrolyzable ester, contain also a) that some is included in the compound of biological hydrolyzable functional group in this precursor medicine in formula (I) compound, and b) some can be obtained the compound of formula (I) medicine in given functional group by bio-oxidation or reduction.The example of these functional groups includes but not limited to 1,4-dihydropyridine, N-alkyl-carbonyl-1,4-dihydropyridine, 1, the tertiary butyl etc.
Term " significant quantity on the pharmacology " should refer to be caused in tissue, animal or human by researchist or the determined active medicine of clinician or medicinal ingredients the amount of biological respinse or drug reaction.This amount can be the treatment significant quantity.Term " treatment significant quantity " should refer to that determined medicine or medicinal ingredients cause the amount of therapeutic response in animal or human's body.
Term used herein " treatment " is meant processing and the nursing of the patient being carried out for the purpose of antagonism disease, obstacle or illness.This term is used to comprise the full spectrum treatment of given disease that the patient is suffered from, for example delays the progress of disease, obstacle or illness, alleviate or relief of symptoms and complication, preventing disease and/or healing or eliminate a disease, obstacle or illness.The patient who treats is Mammals, particularly people preferably.
Term used herein " pharmacy acceptable salt " comprises pharmaceutically-acceptable acid addition, pharmaceutically acceptable base addition salt, pharmaceutically acceptable metal-salt, ammonium salt and alkylated ammonium.Acid salt comprises the salt and the organic acid salt of mineral acid.The representative example of suitable mineral acid comprises: hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, phosphoric acid, sulfuric acid and nitric acid.Suitable organic acid representative example comprises: formic acid, acetate, trichoroacetic acid(TCA), trifluoroacetic acid, propionic acid, phenylformic acid, styracin, citric acid, fumaric acid, oxyacetic acid, lactic acid, toxilic acid, oxysuccinic acid, propanedioic acid, amygdalic acid, oxalic acid, picric acid, pyruvic acid, Whitfield's ointment, succsinic acid, methylsulfonic acid, ethyl sulfonic acid, tartrate, xitix, pamoic acid, the dimethylene Whitfield's ointment, ethane disulfonic acid, glyconic acid, citraconic acid (citraconic acid), aspartic acid, stearic acid, palmitinic acid, EDTA, oxyacetic acid, para-amino benzoic acid, L-glutamic acid, Phenylsulfonic acid, tosic acid, sulfuric acid, nitric acid, phosphoric acid, perchloric acid, boric acid, acetate, phenylformic acid, hydroxynaphthoic acid, Phosphoric acid glycerol esters and ketoisocaproic.Other example of pharmaceutically acceptable inorganic acid addition salt or organic acid addition salt comprises and is listed in J.Pharm.Sci.1977, the pharmacy acceptable salt of enumerating in 66,2, and the document is attached to herein by reference.The example of metal-salt comprises: lithium salts, sodium salt, sylvite, magnesium salts, zinc salt and calcium salt.The example of amine and organic amine comprises: ammonium salt, methylamine, dimethylamine, Trimethylamine 99, ethamine, diethylamine, propylamine, butylamine, tetramethylammonium, thanomin, diethanolamine, trolamine, meglumine, quadrol, choline, N, N '-dibenzyl-ethylenediamin, N-benzyl-1-phenylethylamine, N-methyl D-glycosamine and guanidine.The example of cationic amino acid comprises Methionin, arginine and Histidine.
Pharmacy acceptable salt makes by the normal alkali of formula I compound and 1-4 is reacted in solvent, described alkali for example is sodium hydroxide, sodium methylate, sodium hydride, potassium tert.-butoxide, calcium hydroxide and magnesium hydroxide, and described solvent for example is ether, THF, methyl alcohol, trimethyl carbinol, diox, Virahol, ethanol etc.Can use solvent mixture.Also can use organic bases, for example Methionin, arginine, diethanolamine, choline, guanidine and derivative thereof etc.Alternatively, by in such as the solvent of ethyl acetate, ether, ethanol, acetone, THF, diox etc., no matter being applied in acid salt where with all example hydrochloric acids, Hydrogen bromide, nitric acid, sulfuric acid, phosphoric acid, tosic acid, methylsulfonic acid, acetate, citric acid, toxilic acid, Whitfield's ointment, hydroxynaphthoic acid, xitix, palmitinic acid, succsinic acid, phenylformic acid, Phenylsulfonic acid and tartaric acid treatment preparation.Also can use solvent mixture.
Term used herein " combination therapy ", " coupling ", " with ... coupling " etc. are meant and give a kind of pharmaceutical dosage form that comprises activators of glucokinase compound of the present invention and other promoting agent, and every kind of promoting agent is with himself independent pharmaceutical dosage form medication.Under the situation of using separate dosage forms, compound of the present invention and other promoting agent can (simultaneously promptly) give the patient in the essentially identical time, and perhaps (being sequential ground) gives the patient in different staggered times.When giving different formulations, the route of administration of every kind of medicine can be identical or different.Any route of administration that known or imagination is used for each medicine all is applicable to enforcement the present invention.
Invention is described
In embodiment 1, the compound that the invention provides following general formula (I) with and with the salt of pharmaceutically acceptable acid or alkali, or the mixture of any optically active isomer or optically active isomer comprises racemic mixture, or any tautomer:
R wherein
1Be C
3-8-cycloalkyl, C
3-8-cycloalkenyl group, C
3-8-heterocyclic radical, C
3-8-heterocycloalkenyl, fused-aryl-C
3-8-cycloalkyl or fused-aryl-C
3-8-cycloalkenyl group, described each group is randomly by one or more substituent R
3, R
4, R
5And R
6Replace;
R
2Be C
3-8-cycloalkyl, C
3-8-cycloalkenyl group, C
3-8-heterocyclic radical, C
3-8-heterocycloalkenyl, fused-aryl-C
3-8-cycloalkyl or condensed heteroaryl-C
3-8-cycloalkyl, described each group is randomly by one or more substituent R
30, R
31, R
32And R
33Replace;
A is a heteroaryl, and it is randomly by one or more R that are independently selected from
7, R
8And R
9Substituting group replace; With
R
1And R
2In at least one must have 1 and be selected from R
3, R
4, R
5, R
6, R
30, R
31, R
32And R
33Substituting group; With
R
3, R
4, R
5, R
6, R
30, R
31, R
32And R
33In at least one be independently selected from C
3-8-cycloalkyl-C
3-6-thiazolinyl, aryl-C
2-6-thiazolinyl, heteroaryl-C
2-6-thiazolinyl, C
3-6-alkene oxygen base, C
3-8-cycloalkyl-C
3-6-alkene oxygen base, aryl-C
3-6-alkene oxygen base, heteroaryl-C
3-6-alkene oxygen base, C
3-8-cycloalkenyl group-C
1-6-alkoxyl group, C
3-8-heterocyclic radical-C
1-6-alkoxyl group, fused-aryl-C
3-8-cycloalkenyl group-C
1-6-alkoxyl group, C
3-8-heterocyclic radical-C
3-6-alkene oxygen base, fused-aryl-C
3-8-cycloalkenyl group-C
3-6-alkene oxygen base, C
1-6-alkoxy-C
3-6-alkene oxygen base, C
3-8-alkene oxygen base-C
1-6-alkoxyl group, aryloxy-C
1-6-alkyl, aryloxy-C
3-6-thiazolinyl, heteroaryl oxygen base-C
1-6-alkyl, heteroaryl oxygen base-C
3-6-thiazolinyl, aryl-C
1-6-alkoxy-C
1-6-alkyl, aryl-C
3-6-alkene oxygen base-C
1-6-alkyl, aryl-C
1-6-alkoxy-C
3-6-thiazolinyl, heteroaryl-C
1-6-alkoxy-C
1-6-alkyl, heteroaryl-C
3-6-alkene oxygen base-C
1-6-alkyl, heteroaryl-C
1-6-alkoxy-C
3-6-thiazolinyl, C
3-8-cycloalkyl-C
1-6-alkoxy-C
1-6-alkyl, C
3-8-cycloalkyl-C
3-6-alkene oxygen base-C
1-6-alkyl, C
3-8-cycloalkyl-C
1-6-alkoxy-C
3-6-thiazolinyl, C
3-8-heterocyclic radical-C
1-6-alkoxy-C
1-6-alkyl, C
3-8-heterocyclic radical-C
3-6-alkene oxygen base-C
1-6-alkyl, C
3-8-heterocyclic radical-C
1-6-alkoxy-C
3-6-thiazolinyl, fused-aryl-C
3-8-cycloalkenyl group-C
1-6-alkoxy-C
1-6-alkyl, fused-aryl-C
3-8-cycloalkenyl group-C
3-6-alkene oxygen base-C
1-6-alkyl, fused-aryl-C
3-8-cycloalkenyl group-C
1-6-alkoxy-C
3-6-thiazolinyl, C
3-6-alkenylthio group, C
3-8-cycloalkyl-C
3-6-alkenylthio group, aryl-C
3-6-alkenylthio group, heteroaryl-C
3-6-alkenylthio group, C
3-8-cycloalkenyl group-C
1-6-alkylthio (alkthio), C
3-8-heterocyclic radical-C
1-6-alkylthio (alkthio), fused-aryl-C
3-8-cycloalkenyl group-C
1-6-alkylthio (alkthio), C
1-6-alkylthio-C
3-6-alkene oxygen base, C
1-6-alkoxy-C
3-6-alkenylthio group, C
3-8-alkenylthio group-C
1-6-alkoxyl group, C
3-8-alkene oxygen base-C
1-6-alkylthio, arylthio-C
1-6-alkyl, arylthio-C
3-6-thiazolinyl, heteroarylthio-C
1-6-alkyl, heteroarylthio-C
3-6-thiazolinyl, aryl-C
1-6-alkylthio-C
1-6-alkyl, aryl-C
3-6-alkenylthio group-C
1-6-alkyl, aryl-C
1-6-alkylthio-C
3-6-thiazolinyl, heteroaryl-C
1-6-alkylthio-C
1-6-alkyl, heteroaryl-C
3-6-alkenylthio group-C
1-6-alkyl, heteroaryl-C
1-6-alkylthio-C
3-6-thiazolinyl, C
3-8-cycloalkyl-C
1-6-alkylthio-C
1-6-alkyl, C
3-8-cycloalkyl-C
3-6-alkenylthio group-C
1-6-alkyl, C
3-8-cycloalkyl-C
1-6-alkylthio-C
3-6-thiazolinyl, C
3-8-heterocyclic radical-C
1-6-alkylthio-C
1-6-alkyl, C
3-8-heterocyclic radical-C
3-6-alkenylthio group-C
1-6-alkyl, C
3-8-heterocyclic radical-C
1-6-alkylthio-C
3-6-thiazolinyl, fused-aryl-C
3-8-cycloalkenyl group-C
1-6-alkylthio-C
1-6-alkyl, fused-aryl-C
3-8-cycloalkenyl group-C
3-6-alkenylthio group-C
1-6-alkyl, fused-aryl-C
3-8-cycloalkenyl group-C
1-6-alkylthio-C
3-6-thiazolinyl, described each group are randomly by one or more R that are independently selected from
12Substituting group replace; With
If R
3, R
4, R
5, R
6In have more than one or R
30, R
31, R
32And R
33In have more than one, R then
3, R
4, R
5, R
6, or R
30, R
31, R
32Or R
33In remaining can be independently selected from:
● halogen, nitro, cyano group, hydroxyl, oxo, carboxyl ,-CF
3Or
●-NR
10R
11Or
● C
1-6-alkyl, C
2-6-thiazolinyl, C
2-6-alkynyl, C
3-8-cycloalkyl, C
3-8-cycloalkyl-C
1-6-alkyl, aryl, aryl-C
1-6-alkyl, heteroaryl-C
1-6-alkyl, C
1-6-alkoxyl group, C
3-6-cycloalkyl-C
1-6-alkoxyl group, aryl-C
1-6-alkoxyl group, heteroaryl, heteroaryl-C
1-6-alkoxyl group, aryloxy, heteroaryloxy, C
1-6-alkylthio, arylthio, heteroarylthio, C
3-8-cycloalkylthio, aryl-C
1-6-alkylthio, heteroaryl-C
1-6-alkylthio, C
1-6-alkyl sulphinyl, C
3-6-cycloalkyl-C
1-6-alkylthio, C
1-6-alkyl-C (O)-O-C
1-6-alkyl, C
1-6-alkoxy-C
1-6-alkyl, C
1-6-alkylthio-C
1-6-alkyl, carboxyl-C
1-6-alkoxyl group, amino-C
1-6-alkyl, C
1-6-alkylamino-C
1-6-alkyl, two-(C
1-6-alkyl) amino-C
1-6-alkyl, C
1-6-alkyl amino sulfonyl, two (C
1-6-alkyl) amino-sulfonyl, C
1-6-alkylamino sulfinyl or two (C
1-6-alkyl) amino sulfinyl, described each group are randomly by one or more R that are independently selected from
12Substituting group replace; Or
●-C (O)-R
27,-S (O)
2-R
27,-C (O)-NR
13R
14,-S (O)
2-NR
13R
14,-C
1-6-alkyl-C (O)-NR
13R
14Or
● be selected from R
3, R
4, R
5And R
6Or R
30, R
31, R
32And R
33Two substituting groups, they are connected to form with same atom or adjacent atom-O-(CH together
2)
1-3-O-; With
R
27Be C
1-6-alkyl, C
1-6-alkoxyl group, C
2-6-thiazolinyl, C
2-6-alkynyl, C
3-8-cycloalkyl, C
3-8-cycloalkyl-C
1-6-alkyl, C
3-8-cycloalkyl-C
2-6-thiazolinyl, aryl, aryl-C
1-6-alkyl, aryloxy-C
1-6-alkyl, aryl-C
2-6-thiazolinyl, heteroaryl, C
3-8-heterocyclic radical, heteroaryl-C
1-6-alkyl, C
3-8-heterocyclic radical-C
1-6-alkyl, heteroaryloxy-C
1-6-alkyl, carboxyl-C
1-6-alkyl, carboxyl-C
2-6-thiazolinyl, C
1-6-alkoxy-C
1-6-alkyl, C
1-6-alkoxy-C
2-6-thiazolinyl, C
1-6-alkylthio-C
1-6-alkyl, R
10HN-C
1-6-alkyl, R
10R
11N-C
1-6-alkyl, R
10R
11N-C
2-6-thiazolinyl, R
10R
11N-S (O)
2-C
1-6-alkyl, R
10R
11N-C (O)-C
1-6-alkyl, C
1-6-alkyl-C (O)-NH-C
1-6-alkyl, aryl-C (O)-NH-C
1-6-alkyl, heteroaryl-C (O)-NH-C
1-6-alkyl, C
3-8-cycloalkyl-C (O)-NH-C
1-6-alkyl, C
1-6-alkyl-S (O)
2-NH-C
1-6-alkyl, aryl-S (O)
2-NH-C
1-6-alkyl, heteroaryl-S (O)
2-NH-C
1-6-alkyl or C
3-8-cycloalkyl-S (O)
2-NH-C
1-6-alkyl, described each group are randomly by one or more R that are independently selected from
12Substituting group replace; With
R
12For halogen, cyano group, hydroxyl ,-C (O)-O-C
1-6-alkyl, carboxyl ,-CF
3, C
1-6-alkyl, C
1-6-alkoxyl group, C
2-6-alkene oxygen base, C
3-8-cycloalkyloxy, cyclenes oxygen base, heterocyclic oxy group, aryloxy, heteroaryloxy, aryl-C
1-6-alkoxyl group, aryl-C
1-6-alkene oxygen base, heteroaryl-C
1-6-alkoxyl group, heteroaryl-C
1-6-alkene oxygen base, C
3-8-cycloalkyl-C
1-6-alkoxyl group, C
3-8-cycloalkyl-C
1-6-alkene oxygen base, heterocyclic radical-C
1-6-alkoxyl group, heterocyclic radical-C
1-6-alkene oxygen base, fused-aryl-cycloalkyl-C
1-6-alkoxyl group, fused-aryl-cycloalkyl-C
1-6-alkene oxygen base, C
1-6-alkylthio, C
2-6-alkenylthio group, C
3-8-cycloalkylthio, cyclenes sulfenyl, heterocycle sulfenyl, arylthio, heteroarylthio, aryl-C
1-6-alkylthio, aryl-C
1-6-alkenylthio group, heteroaryl-C
1-6-alkylthio, heteroaryl-C
1-6-alkenylthio group, C
3-8-cycloalkyl-C
1-6-alkylthio, C
3-8-cycloalkyl-C
1-6-alkenylthio group, heterocyclic radical-C
1-6-alkylthio, heterocyclic radical-C
1-6-alkenylthio group, fused-aryl-cycloalkyl-C
1-6-alkylthio, fused-aryl-cycloalkyl-C
1-6-alkenylthio group ,-NR
10R
11,-S (O)
2CH
3,-S (O)
2CF
3,-(O)
2CH
2CF
3Or-S (O)
2NH
2With
R
10And R
11Be H, C independently
1-6-alkyl ,-C (O)-C
1-6-alkyl ,-C (O)-O-C
1-6-alkyl, carboxyl-C
1-6-alkyl ,-C (O)-C
1-6-alkyl-C (O) OH ,-S (O)
2-C
1-6-alkyl or aryl; With
R
13And R
14Be independently selected from H, C
1-6-alkyl, hydroxyl-C
1-6-alkyl, carboxyl-C
1-6-alkyl, aryl or heteroaryl, described each group are randomly by one or more R that are independently selected from
15Substituting group replace; Perhaps R
13And R
14Form the 3-8 unit heterocycle with described nitrogen-atoms with the nitrogen-atoms that they connected, this heterocycle randomly contains one or two extra heteroatoms that is selected from nitrogen, oxygen and sulphur; With
R
15For halogen, cyano group, hydroxyl, carboxyl ,-CF
3, C
1-6-alkyl ,-S (O)
2CH
3Or-S (O)
2NH
2With
R
7, R
8And R
9Be independently selected from:
● halogen, carboxyl, cyano group, nitro, hydroxyl ,-CF
3,-SCN; Or
● C
1-6-alkyl, C
2-6-thiazolinyl, C
2-6-alkynyl, C
1-6-alkoxyl group, C
1-6-alkylthio, C
2-6-alkenylthio group, C
1-6-alkylamino, C
1-6-alkyl sulphinyl ,-C (O)-O-C
1-6-alkyl, formyl radical ,-C (O)-C
1-6-alkyl ,-C
1-6-alkyl-C (O)-O-C
1-6-alkyl ,-C
1-6-alkyl-O-C (O)-C
1-6-alkyl ,-NH-C (O)-C
1-6-alkyl ,-C
1-6-alkoxy-C
1-6-alkyl ,-C
1-6-alkyl-S-C
1-6-alkyl, carboxyl-C
1-6-alkyl or hydroxyl-C
1-6-alkyl, described each group are randomly by one or more R that are independently selected from
16Substituting group replace; Or
● aryl, heteroaryl, aryl-C
1-6-alkyl, heteroaryl-C
1-6-alkyl, aryl-C
1-6-alkoxyl group, heteroaryl-C
1-6-alkoxyl group, aryl-C
1-6-alkylthio, heteroaryl-C
1-6-alkylthio, heteroaryl-sulfenyl-C
1-6-alkyl, heteroaryl-oxygen base-C
1-6-alkyl, aryloxy, heteroaryloxy, arylthio, heteroarylthio, aryl-C
1-6-alkylamino ,-C (O)-aryl or-C (O)-heteroaryl, described each group randomly on aryl or heteroaryl moieties by one or more R that are independently selected from
17Substituting group replace; Or
● C
3-8-cycloalkyl, C
3-8-cycloalkenyl group, C
3-8-cycloalkylthio, C
3-8-cycloalkyl-C
1-6-alkyl, C
3-8-cycloalkenyl group-C
1-6-alkyl, C
3-6-cycloalkyl-C
1-6-alkoxyl group, C
3-6-cycloalkyl-C
1-6-alkylthio, described each group randomly on cycloalkyl moiety by one or more R that are independently selected from
18Substituting group replace; Or
● C
3-8-heterocyclic radical, C
3-8-heterocyclic radical-C
1-6-alkyl, C
3-8-heterocyclic radical-C
1-6-alkylthio, C
3-8-heterocycle sulfenyl, C
3-8-heterocyclic radical-amino-C
1-6-alkyl or-C (O)-C
3-8-heterocyclic radical, described each group are randomly by one or more R that are independently selected from
16Substituting group replace; Or
●-NR
19R
20,-C
1-6-alkyl-NR
19R
20,-C
2-6-thiazolinyl-NR
19R
20,-C
1-6-alkyl-S-R
21,-C
1-6-alkyl-S (O)-R
21,-C
1-6-alkyl-S (O)
2-R
21,-S (O)
2-R
21,-S (O)
2-N (R
19) (C
1-6-alkyl-C (O) NR
22R
23) or-S (O)
2-NR
19R
20, wherein each moieties all can be by one or more R that are independently selected from
25Substituting group replace; Or
●-C (O) NR
22R
23,-C
1-6-alkyl-C (O) NR
22R
23,-C
1-6-alkyl-NH-NR
22R
23,-C
1-6-alkyl-NH-C (O)-C
1-6-alkyl-NR
22R
23, described each group is randomly by one or more R that are independently selected from
26Substituting group replace; Or
R
7, R
8And R
9In two can form C together
2-5-alkylidene bridge; C
2-5-alkylidene bridge is randomly by one or more R that are independently selected from
16Substituting group replace; With
R
16, R
17And R
18Be C independently
1-6-alkyl, halogen, nitro, cyano group, hydroxyl, carboxyl, oxo ,-CF
3, carboxyl-C
1-6-alkyl, hydroxyl-C
1-6-alkyl ,-C
1-6-alkyl-C (O)-O-C
1-6-alkyl ,-C
1-6-alkyl-C (O)-NR
19R
20,-C (O)-O-C
1-6-alkyl ,-C (O)-C
1-6-alkyl-C (O)-C
1-6-alkyl ,-NR
19R
20,-NHS (O)
2C
1-6-alkyl ,-NHS (O)
2CF
3,-NHS (O)
2CH
2CF
3,-C (O) NR
19R
20,-S (O)
2C
1-6-alkyl ,-S (O)
2CF
3,-S (O)
2CH
2CF
3Or-S (O)
2NR
19R
20With
R
19And R
20Be H, C independently
1-6-alkyl, C
2-6-thiazolinyl, C
3-8-cycloalkyl, C
3-8-cycloalkyl-C
1-6-alkyl, hydroxyl-C
1-6-alkyl, carboxyl-C
1-6-alkyl, aryl, heteroaryl, C
3-8-heterocyclic radical, aryl-C
1-6-alkyl, C
3-8-heterocyclic radical-C
1-6-alkyl ,-C (O)-O-C
1-6-alkyl ,-C
1-6-alkyl-C (O)-O-C
1-6-alkyl ,-C
1-6-alkyl-NR
22R
23Or-S (O)
2-C
1-6-alkyl, described each group are randomly by one or more R that are independently selected from
24Substituting group replace perhaps R
19And R
20Form the 3-8 unit heterocycle with described nitrogen-atoms with the nitrogen-atoms that they connected, this heterocycle randomly contains one or two extra heteroatoms that is selected from nitrogen, oxygen and sulphur, and described heterocycle is randomly by one or more R that are independently selected from
24Substituting group replace; With
R
21Be selected from:
● C
1-6-alkyl, C
2-6-thiazolinyl, carboxyl-C
1-6-alkyl, C
1-6-alkylamino-C
1-6-alkyl or hydroxyl-C
1-6-alkyl ,-C
1-6-alkyl-NR
22R
23Or
● aryl, heteroaryl, aryl-C
1-6-alkyl or heteroaryl-C
1-6-alkyl, wherein said aryl or heteroaryl moieties are randomly by one or more R that are independently selected from
24Substituting group replace; Or
● C
3-8-cycloalkyl, C
3-8-cycloalkenyl group, C
3-8-cycloalkyl-C
1-6-alkyl, C
3-8-cycloalkenyl group-C
1-6-alkyl; With
R
22And R
23Be independently selected from H, C
1-6-alkyl, carboxyl-C
1-6-alkyl, hydroxyl-C
1-6-alkyl ,-C
1-6-alkyl-C (O)-O-C
1-6-alkyl ,-C (O)-O-C
1-6-alkyl ,-C
1-6-alkyl-S (O)
2-C
1-6-alkyl, C
3-8-cycloalkyl, aryl or heteroaryl; Perhaps R
22And R
23Form the 3-8 unit heterocycle with described nitrogen-atoms with the nitrogen-atoms that they connected, this heterocycle randomly contains one or two extra heteroatoms that is selected from nitrogen, oxygen and sulphur, and described heterocycle is randomly by one or more R that are independently selected from
24Substituting group replace; With
R
24For halogen, nitro, cyano group, hydroxyl, carboxyl, oxo ,-CF
3, C
1-6-alkyl, hydroxyl-C
1-6-alkyl, carboxyl-C
1-6-alkyl ,-C (O)-C
1-6-alkyl ,-C (O)-C
3-8-cycloalkyl ,-C (O)-aryl ,-C (O)-heteroaryl ,-C (O)-C
3-8-heterocyclic radical-C (O)-O-C
1-6-alkyl ,-C
1-6-alkyl-C (O)-O-C
1-6-alkyl, aryl, heteroaryl, aryl-C
1-6-alkyl, heteroaryl-C
1-6-alkyl, C
3-8-cycloalkyl, C
3-8-heterocyclic radical, C
3-8-cycloalkyl-C
1-6-alkyl, C
3-8-heterocyclic radical-C
1-6-alkyl ,-C
1-6-alkyl-C (O)-C
3-8-heterocyclic radical ,-C (O)-O-C
1-6-alkyl-aryl ,-NH-S (O)
2R
28Or-S (O)
2R
28, wherein each cyclic group part is all randomly by one or more R that are independently selected from
29Substituting group replace; With
R
25And R
26Be C independently
1-6-alkyl, halogen, nitro, cyano group, hydroxyl ,-C (O)-O-C
1-6-alkyl, carboxyl ,-C
1-6-alkyl-C (O)-O-C
1-6-alkyl, carboxyl-C
1-6-alkyl ,-CF
3,-S (O)
2CH
3Or-S (O)
2NH
2With
R
28Be C
1-6-alkyl, carboxyl-C
1-6-alkyl ,-C
1-6-alkyl-C (O)-O-C
1-6-alkyl, C
3-8-cycloalkyl, aryl, aryl-C
1-6-alkyl, randomly by C
1-6The heteroaryl that-alkyl replaces ,-NH
2Or-N (CH
3)
2With
R
29For halogen, nitro, cyano group, hydroxyl, carboxyl, oxo ,-CF
3, C
1-6-alkyl or C
1-6-alkoxyl group;
Or
R
3, R
4, R
5, R
6, R
30, R
31, R
32And R
33Be independently selected from:
● halogen, nitro, cyano group, hydroxyl, oxo, carboxyl ,-CF
3Or
●-NR
10R
11Or
● C
1-6-alkyl, C
2-6-thiazolinyl, C
2-6-alkynyl, C
3-8-cycloalkyl, C
3-8-cycloalkyl-C
1-6-alkyl, aryl, aryl-C
1-6-alkyl, heteroaryl-C
1-6-alkyl, C
1-6-alkoxyl group, C
3-6-cycloalkyl-C
1-6-alkoxyl group, aryl-C
1-6-alkoxyl group, heteroaryl, heteroaryl-C
1-6-alkoxyl group, aryloxy, heteroaryloxy, C
1-6-alkylthio, arylthio, heteroarylthio, C
3-8-cycloalkylthio, aryl-C
1-6-alkylthio, heteroaryl-C
1-6-alkylthio, C
1-6-alkyl sulphinyl, C
3-6-cycloalkyl-C
1-6-alkylthio, C
1-6-alkyl-C (O)-O-C
1-6-alkyl, C
1-6-alkoxy-C
1-6-alkyl, C
1-6-alkylthio-C
1-6-alkyl, carboxyl-C
1-6-alkoxyl group, amino-C
1-6-alkyl, C
1-6-alkylamino-C
1-6-alkyl, two-(C
1-6-alkyl) amino-C
1-6-alkyl, C
1-6-alkyl amino sulfonyl, two (C
1-6-alkyl) amino-sulfonyl, C
1-6-alkylamino sulfinyl or two (C
1-6-alkyl) amino sulfinyl, described each group are randomly by one or more R that are independently selected from
12Substituting group replace; Or
●-C (O)-R
27,-S (O)
2-R
27,-C (O)-NR
13R
14,-S (O)
2-NR
13R
14,-C
1-6-alkyl-C (O)-NR
13R
14Or
● be selected from R
3, R
4, R
5And R
6Or R
30, R
31, R
32And R
33Two substituting groups, they are connected to form with same atom or adjacent atom-O-(CH together
2)
1-3-O-; With
R
10And R
11Be H, C independently
1-6-alkyl ,-C (O)-C
1-6-alkyl ,-C (O)-O-C
1-6-alkyl, carboxyl-C
1-6-alkyl ,-C (O)-C
1-6-alkyl-C (O) OH ,-S (O)
2-C
1-6-alkyl or aryl; With
R
27Be C
1-6-alkyl, C
1-6-alkoxyl group, C
2-6-thiazolinyl, C
2-6-alkynyl, C
3-8-cycloalkyl, C
3-8-cycloalkyl-C
1-6-alkyl, C
3-8-cycloalkyl-C
2-6-thiazolinyl, aryl, aryl-C
1-6-alkyl, aryloxy-C
1-6-alkyl, aryl-C
2-6-thiazolinyl, heteroaryl, C
3-8-heterocyclic radical, heteroaryl-C
1-6-alkyl, C
3-8-heterocyclic radical-C
1-6-alkyl, heteroaryloxy-C
1-6-alkyl, carboxyl-C
1-6-alkyl, carboxyl-C
2-6-thiazolinyl, C
1-6-alkoxy-C
1-6-alkyl, C
1-6-alkoxy-C
2-6-thiazolinyl, C
1-6-alkylthio-C
1-6-alkyl, R
10HN-C
1-6-alkyl, R
10R
11N-C
1-6-alkyl, R
10R
11N-C
2-6-thiazolinyl, R
10R
11N-S (O)
2-C
1-6-alkyl, R
10R
11N-C (O)-C
1-6-alkyl, C
1-6-alkyl-C (O)-NH-C
1-6-alkyl, aryl-C (O)-NH-C
1-6-alkyl, heteroaryl-C (O)-NH-C
1-6-alkyl, C
3-8-cycloalkyl-C (O)-NH-C
1-6-alkyl, C
1-6-alkyl-S (O)
2-NH-C
1-6-alkyl, aryl-S (O)
2-NH-C
1-6-alkyl, heteroaryl-S (O)
2-NH-C
1-6-alkyl or C
3-8-cycloalkyl-S (O)
2-NH-C
1-6-alkyl, described each group are randomly by one or more R that are independently selected from
12Substituting group replace; With
R
12For halogen, cyano group, hydroxyl ,-C (O)-O-C
1-6-alkyl, carboxyl ,-CF
3, C
1-6-alkyl, C
1-6-alkoxyl group ,-NR
10R
11,-S (O)
2CH
3Or-S (O)
2NH
2With
R
13And R
14Be independently selected from H, C
1-6-alkyl, hydroxyl-C
1-6-alkyl, carboxyl-C
1-6-alkyl, aryl or heteroaryl, described each group are randomly by one or more R that are independently selected from
15Substituting group replace; Perhaps R
13And R
14Form the 3-8 unit heterocycle with described nitrogen-atoms with the nitrogen-atoms that they connected, described heterocycle randomly contains one or two extra heteroatoms that is selected from nitrogen, oxygen and sulphur; With
R
15For halogen, cyano group, hydroxyl, carboxyl ,-CF
3, C
1-6-alkyl ,-S (O)
2CH
3Or-S (O)
2NH
2With
A must have at least one and be selected from R
7, R
8And R
9Substituting group; With
R
7, R
8And R
9In at least one be independently selected from:
● C
1-6-alkoxyl group, C
1-6-alkylthio, C
2-6-alkenylthio group, described each group are randomly by one or more R that are independently selected from
16Substituting group replace; Or
●-NR
19R
20,-C
1-6-alkyl-NR
19R
20,-C
2-6-thiazolinyl-NR
19R
20,-C
1-6-alkyl-S-R
21,-C
1-6-alkyl-S (O)-R
21,-C
1-6-alkyl-S (O)
2-R
21,-S (O)
2-R
21,-S (O)
2-NR
19R
20Or-S (O)
2NR
19(C
1-6-alkyl-C (O) NR
22R
23), wherein each moieties all can be by one or more R that are independently selected from
25Substituting group replace;
If R
7, R
8And R
9In have more than one, R then
7, R
8And R
9In other one or more being independently selected from:
● halogen, carboxyl, cyano group, nitro, hydroxyl ,-CF
3,-SCN; Or
● C
1-6-alkyl, C
2-6-thiazolinyl, C
2-6-alkynyl, C
1-6-alkoxyl group, C
1-6-alkylthio, C
2-6-alkenylthio group, C
1-6-alkylamino, C
1-6-alkyl sulphinyl ,-C (O)-O-C
1-6-alkyl, formyl radical ,-C (O)-C
1-6-alkyl ,-C
1-6-alkyl-C (O)-O-C
1-6-alkyl ,-C
1-6-alkyl-O-C (O)-C
1-6-alkyl ,-NH-C (O)-C
1-6-alkyl ,-C
1-6-alkoxy-C
1-6-alkyl ,-C
1-6-alkyl-S-C
1-6-alkyl, carboxyl-C
1-6-alkyl or hydroxyl-C
1-6-alkyl, described each group are randomly by one or more R that are independently selected from
40Substituting group replace; Or
● aryl, heteroaryl, aryl-C
1-6-alkyl, heteroaryl-C
1-6-alkyl, aryl-C
1-6-alkoxyl group, heteroaryl-C
1-6-alkoxyl group, aryl-C
1-6-alkylthio, heteroaryl-C
1-6-alkylthio, heteroaryl-sulfenyl-C
1-6-alkyl, heteroaryl-oxygen base-C
1-6-alkyl, aryloxy, heteroaryloxy, arylthio, heteroarylthio, aryl-C
1-6-alkylamino ,-C (O)-aryl or-C (O)-heteroaryl, described each group randomly on aryl or heteroaryl moieties by one or more R that are independently selected from
41Substituting group replace; Or
● C
3-8-cycloalkyl, C
3-8-cycloalkenyl group, C
3-8-cycloalkylthio, C
3-8-cycloalkyl-C
1-6-alkyl, C
3-8-cycloalkenyl group-C
1-6-alkyl, C
3-6-cycloalkyl-C
1-6-alkoxyl group, C
3-6-cycloalkyl-C
1-6-alkylthio, described each group randomly on cycloalkyl moiety by one or more R that are independently selected from
42Substituting group replace; Or
● C
3-8-heterocyclic radical, C
3-8-heterocyclic radical-C
1-6-alkyl, C
3-8-heterocyclic radical-C
1-6-alkylthio, C
3-8-heterocycle sulfenyl, C
3-8-heterocyclic radical-amino-C
1-6-alkyl or-C (O)-C
3-8-heterocyclic radical, described each group are randomly by one or more R that are independently selected from
40Substituting group replace; Or
●-NR
43R
44,-C
1-6-alkyl-NR
43R
44,-C
2-6-thiazolinyl-NR
43R
44,-C
1-6-alkyl-S-R
45,-C
1-6-alkyl-S (O)-R
45,-C
1-6-alkyl-S (O)
2-R
45,-S (O)
2-R
45,-S (O)
2-N (R
43) (C
1-6-alkyl-C (O) NR
46R
47) or-S (O)
2-NR
43R
44, wherein each moieties all can be by one or more R that are independently selected from
49Substituting group replace; Or
●-C (O) NR
46R
47,-C
1-6-alkyl-C (O) NR
46R
47,-C
1-6-alkyl-NH-NR
46R
47,-C
1-6-alkyl-NH-C (O)-C
1-6-alkyl-NNR
46R
47, described each group is randomly by one or more R that are independently selected from
50Substituting group replace; With
R
16For-NR
19R
20,-NHS (O)
2CF
3,-NHS (O)
2CH
2CF
3,-C (O) NR
19R
20,-S (O)
2CF
3,-S (O)
2CH
2CF
3Or-S (O)
2NR
19R
20R
19Represent H, C
1-6-alkyl, C
2-6-thiazolinyl, C
3-8-cycloalkyl, C
3-8-cycloalkyl-C
1-6-alkyl, hydroxyl-C
1-6-alkyl, hydroxyl-C
2-6-thiazolinyl, carboxyl-C
1-6-alkyl, aryl, heteroaryl, C
3-8-heterocyclic radical, aryl-C
1-6-alkyl, C
3-8-heterocyclic radical-C
1-6-alkyl ,-C (O)-O-C
1-6-alkyl ,-C
1-6-alkyl-C (O)-O-C
1-6-alkyl ,-C
1-6-alkyl-NR
22R
23Or-S (O)
2-C
1-6-alkyl, described each group are randomly by one or more R that are independently selected from
24Substituting group replace; With
R
20Represent C
2-6-thiazolinyl, C
3-8-cycloalkyl, C
3-8-cycloalkyl-C
1-6-alkyl, described each group are randomly by one or more R that are independently selected from
24Substituting group replace; With
R
21Be selected from C
3-8-cycloalkyl, C
3-8-cycloalkenyl group, C
3-8-cycloalkyl-C
1-6-alkyl, C
3-8-cycloalkenyl group-C
1-6-alkyl, C
2-6-thiazolinyl, carboxyl-C
1-6-alkyl, C
1-6-alkylamino-C
1-6-alkyl or hydroxyl-C
1-6-alkyl ,-C
1-6-alkyl-NR
22R
23, described each group is randomly by one or more R that are independently selected from
24Substituting group replace; With
R
22And R
23Be independently selected from H, C
1-6-alkyl, carboxyl-C
1-6-alkyl, hydroxyl-C
1-6-alkyl ,-C
1-6-alkyl-C (O)-O-C
1-6-alkyl ,-C (O)-O-C
1-6-alkyl ,-C
1-6-alkyl-S (O)
2-C
1-6-alkyl, C
3-8-cycloalkyl, aryl or heteroaryl; Perhaps R
22And R
23Form the 3-8 unit heterocycle with described nitrogen-atoms with the nitrogen-atoms that they connected, described heterocycle randomly contains one or two extra heteroatoms that is selected from nitrogen, oxygen and sulphur, and described heterocycle is randomly by one or more R that are independently selected from
24Substituting group replace; With
R
24For halogen, nitro, cyano group, hydroxyl, carboxyl, oxo ,-CF
3, C
1-6-alkyl, hydroxyl-C
1-6-alkyl, carboxyl-C
1-6-alkyl ,-C (O)-C
1-6-alkyl ,-C (O)-C
3-8-cycloalkyl ,-C (O)-aryl ,-C (O)-heteroaryl ,-C (O)-C
3-8-heterocyclic radical-C (O)-O-C
1-6-alkyl ,-C
1-6-alkyl-C (O)-O-C
1-6-alkyl, aryl, heteroaryl, aryl-C
1-6-alkyl, heteroaryl-C
1-6-alkyl, C
3-8-cycloalkyl, C
3-8-heterocyclic radical, C
3-8-cycloalkyl-C
1-6-alkyl, C
3-8-heterocyclic radical-C
1-6-alkyl ,-C
1-6-alkyl-C (O)-C
3-8-heterocyclic radical ,-C (O)-O-C
1-6-alkyl-aryl ,-NH-S (O)
2R
28Or-S (O)
2R
28, wherein each loop section is all randomly by one or more R that are independently selected from
29Substituting group replace; With
R
25Be C
1-6-alkyl, halogen, nitro, cyano group, hydroxyl ,-C (O)-O-C
1-6-alkyl, carboxyl ,-C
1-6-alkyl-C (O)-O-C
1-6-alkyl, carboxyl-C
1-6-alkyl ,-CF
3,-S (O)
2CH
3Or-S (O)
2NH
2With
R
28Be C
1-6-alkyl, carboxyl-C
1-6-alkyl ,-C
1-6-alkyl-C (O)-O-C
1-6-alkyl, C
3-8-cycloalkyl, aryl, aryl-C
1-6-alkyl, randomly by C
1-6The heteroaryl that-alkyl replaces ,-NH
2Or-N (CH
3)
2With
R
29For halogen, nitro, cyano group, hydroxyl, carboxyl, oxo ,-CF
3, C
1-6-alkyl or C
1-6-alkoxyl group; With
R
40, R
41And R
42Be C independently
1-6-alkyl, halogen, nitro, cyano group, hydroxyl, carboxyl, oxo ,-CF
3, carboxyl-C
1-6-alkyl, hydroxyl-C
1-6-alkyl ,-C
1-6-alkyl-C (O)-O-C
1-6-alkyl ,-C
1-6-alkyl-C (O)-NR
43R
44,-C (O)-O-C
1-6-alkyl ,-C (O)-C
1-6-alkyl-C (O)-C
1-6-alkyl ,-NR
43R
44,-NHS (O)
2C
1-6-alkyl ,-NHS (O)
2CF
3,-NHS (O)
2CH
2CF
3,-C (O) NR
43R
44,-S (O)
2C
1-6-alkyl ,-S (O)
2CF
3,-S (O)
2CH
2CF
3Or-S (O)
2NR
43R
44With
R
43And R
44Be H, C independently
1-6-alkyl, C
2-6-thiazolinyl, C
3-8-cycloalkyl, C
3-8-cycloalkyl-C
1-6-alkyl, hydroxyl-C
1-6-alkyl, carboxyl-C
1-6-alkyl, aryl, heteroaryl, C
3-8-heterocyclic radical, aryl-C
1-6-alkyl, C
3-8-heterocyclic radical-C
1-6-alkyl ,-C (O)-O-C
1-6-alkyl ,-C
1-6-alkyl-C (O)-O-C
1-6-alkyl ,-C
1-6-alkyl-NR
46R
47Or-S (O)
2-C
1-6-alkyl, described each group are randomly by one or more R that are independently selected from
48Substituting group replace perhaps R
43And R
44Form the 3-8 unit heterocycle with described nitrogen-atoms with the nitrogen-atoms that they connected, described heterocycle randomly contains one or two extra heteroatoms that is selected from nitrogen, oxygen and sulphur, and described heterocycle is randomly by one or more R that are independently selected from
48Substituting group replace; With
R
45Be selected from:
● C
1-6-alkyl, C
2-6-thiazolinyl, carboxyl-C
1-6-alkyl, C
1-6-alkylamino-C
1-6-alkyl or hydroxyl-C
1-6-alkyl ,-C
1-6-alkyl-NR
46R
47Or
● aryl, heteroaryl, aryl-C
1-6-alkyl or heteroaryl-C
1-6-alkyl, wherein aryl or heteroaryl moieties are randomly by one or more R that are independently selected from
48Substituting group replace; Or
● C
3-8-cycloalkyl, C
3-8-cycloalkenyl group, C
3-8-cycloalkyl-C
1-6-alkyl, C
3-8-cycloalkenyl group-C
1-6-alkyl; With
R
46And R
47Be independently selected from H, C
1-6-alkyl, carboxyl-C
1-6-alkyl, hydroxyl-C
1-6-alkyl ,-C
1-6-alkyl-C (O)-O-C
1-6-alkyl ,-C (O)-O-C
1-6-alkyl ,-C
1-6-alkyl-S (O)
2-C
1-6-alkyl, C
3-8-cycloalkyl, aryl or heteroaryl; Perhaps R
46And R
47Form the 3-8 unit heterocycle with described nitrogen-atoms with the nitrogen-atoms that they connected, described heterocycle randomly contains one or two extra heteroatoms that is selected from nitrogen, oxygen and sulphur, and described heterocycle is randomly by one or more R that are independently selected from
48Substituting group replace; With
R
48For halogen, nitro, cyano group, hydroxyl, carboxyl, oxo ,-CF
3, C
1-6-alkyl, hydroxyl-C
1-6-alkyl, carboxyl-C
1-6-alkyl ,-C (O)-C
1-6-alkyl ,-C (O)-C
3-8-cycloalkyl ,-C (O)-aryl ,-C (O)-heteroaryl ,-C (O)-C
3-8-heterocyclic radical-C (O)-O-C
1-6-alkyl ,-C
1-6-alkyl-C (O)-O-C
1-6-alkyl, aryl, heteroaryl, aryl-C
1-6-alkyl, heteroaryl-C
1-6-alkyl, C
3-8-cycloalkyl, C
3-8-heterocyclic radical, C
3-8-cycloalkyl-C
1-6-alkyl, C
3-8-heterocyclic radical-C
1-6-alkyl ,-C
1-6-alkyl-C (O)-C
3-8-heterocyclic radical ,-C (O)-O-C
1-6-alkyl-aryl ,-NH-S (O)
2R
52Or-S (O)
2R
52, wherein each cyclic group part is all randomly by one or more R that are independently selected from
53Substituting group replace; With
R
49And R
50Be C independently
1-6-alkyl, halogen, nitro, cyano group, hydroxyl ,-C (O)-O-C
1-6-alkyl, carboxyl ,-C
1-6-alkyl-C (O)-O-C
1-6-alkyl, carboxyl-C
1-6-alkyl ,-CF
3,-S (O)
2CH
3Or-S (O)
2NH
2With
R
52Be C
1-6-alkyl, carboxyl-C
1-6-alkyl ,-C
1-6-alkyl-C (O)-O-C
1-6-alkyl, C
3-8-cycloalkyl, aryl, aryl-C
1-6-alkyl, randomly by C
1-6The heteroaryl that-alkyl replaces ,-NH
2Or-N (CH
3)
2With
R
53For halogen, nitro, cyano group, carboxyl, oxo ,-CF
3, C
1-6-alkyl or C
1-6-alkoxyl group.
Embodiment 2. is according to the compound of embodiment 1, wherein R
1Be C
3-8-cycloalkyl, C
3-8-cycloalkenyl group, indenyl, tetrahydrofuran base, tetrahydrochysene thio-furan base, tetrahydro-thienyl, THP trtrahydropyranyl, tetrahydro thiapyran base, 1,4-alkyl dioxin, 1,3-alkyl dioxin, piperidyl, pyrrolidyl, morpholinyl or piperazinyl, described each group is randomly by one or more substituent R
3, R
4, R
5And R
6Replace.
Embodiment 3. is according to each compound among the embodiment 1-2, wherein R
1For cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, suberyl, cycloheptenyl, ring octyl group, two ring [3.2.1] octyl groups, two are encircled [2.2.1] heptyl, are fallen pinane base (norpinyl), norcamphyl (norbonyl), norcaryl (norcaryl), adamantyl, dihydro indenyl, tetrahydrofuran base, tetrahydrochysene thio-furan base, tetrahydro-thienyl, THP trtrahydropyranyl, tetrahydro thiapyran base, 1,4-alkyl dioxin, 1,3-alkyl dioxin, piperidyl, pyrrolidyl, morpholinyl or piperazinyl, described each group is randomly by one or more substituent R
3, R
4, R
5And R
6Replace.
Embodiment 4. is according to the compound of embodiment 3, wherein R
1Be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, suberyl, two ring [3.2.1] octyl groups, two ring [2.2.1] heptyl, adamantyl, dihydro indenyl, tetrahydrofuran base, tetrahydro-thienyl, THP trtrahydropyranyl, tetrahydro thiapyran base, piperidyl, pyrrolidyl, morpholinyl or piperazinyl, described each group is randomly by one or more substituent R
3, R
4, R
5And R
6Replace.
Embodiment 5. is according to the compound of embodiment 4, wherein R
1Be cyclopentyl, cyclohexyl, cyclohexenyl, suberyl, two ring [2.2.1] heptyl, tetrahydrofuran base, tetrahydro-thienyl, THP trtrahydropyranyl, tetrahydro thiapyran base, piperidyl, pyrrolidyl, morpholinyl or piperazinyl, described each group is randomly by one or more substituent R
3, R
4, R
5And R
6Replace.
Embodiment 6. is according to the compound of embodiment 5, wherein R
1Be selected from:
Embodiment 7. is according to the compound of embodiment 6, wherein R
1Be selected from:
Embodiment 8. is according to the compound of embodiment 7, wherein R
1Be selected from:
Embodiment 9. is according to the compound of embodiment 8, wherein R
1Be selected from:
Embodiment 10. is according to the compound of embodiment 9, wherein R
1Be selected from:
Embodiment 11. is according to the compound of embodiment 10, wherein R
1For:
Embodiment 12. is according to the compound of embodiment 10, wherein R
1For:
Embodiment 13. is according to the compound of embodiment 10, wherein R
1For:
Embodiment 14. is according to each compound among the embodiment 1-13, wherein R
2Be C
3-8-cycloalkyl, C
3-8-cycloalkenyl group, tetrahydrofuran base, tetrahydrochysene thio-furan base, tetrahydro-thienyl, THP trtrahydropyranyl, tetrahydro thiapyran base, 1,4-alkyl dioxin, 1,3-alkyl dioxin, piperidyl, pyrrolidyl, morpholinyl or piperazinyl, described each group is randomly by one or more substituent R
30, R
31, R
32And R
33Replace.
Embodiment 15. is according to the compound of embodiment 14, wherein R
2For cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, suberyl, cycloheptenyl, ring octyl group, two ring [3.2.1] octyl groups, two are encircled [2.2.1] heptyl, are fallen pinane base (norpinyl), norcamphyl (norbonyl), norcaryl (norcaryl), adamantyl, tetrahydrofuran base, tetrahydrochysene thio-furan base, tetrahydro-thienyl, THP trtrahydropyranyl, tetrahydro thiapyran base, 1,4-alkyl dioxin, 1,3-alkyl dioxin, piperidyl, pyrrolidyl, morpholinyl or piperazinyl, described each group is randomly by one or more substituent R
30, R
31, R
32And R
33Replace.
Embodiment 16. is according to the compound of embodiment 15, wherein R
2Be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, suberyl, two ring [3.2.1] octyl groups, two ring [2.2.1] heptyl, adamantyl, tetrahydrofuran base, tetrahydro-thienyl, THP trtrahydropyranyl, tetrahydro thiapyran base, piperidyl, pyrrolidyl, morpholinyl or piperazinyl, described each group is randomly by one or more substituent R
30, R
31, R
32And R
33Replace.
Embodiment 17. is according to the compound of embodiment 16, wherein R
2Be cyclopentyl, cyclohexyl, cyclohexenyl, two ring [2.2.1] heptyl, tetrahydrofuran base, tetrahydro-thienyl, THP trtrahydropyranyl, tetrahydro thiapyran base, piperidyl, pyrrolidyl, morpholinyl or piperazinyl, described each group is randomly by one or more substituent R
30, R
31, R
32And R
33Replace.
Embodiment 18. is according to the compound of embodiment 17, wherein R
2Be selected from:
Embodiment 19. is according to the compound of embodiment 17, wherein R
2Be selected from:
Embodiment 20. is according to the compound of embodiment 19, wherein R
2Be selected from:
Embodiment 21. is according to the compound of embodiment 20, wherein R
2Be selected from:
Embodiment 22. is according to the compound of embodiment 21, wherein R
2Be selected from:
Embodiment 23. is according to the compound of embodiment 22, wherein R
2For:
Embodiment 24. is according to the compound of embodiment 22, wherein R
2For:
Embodiment 25. is according to the compound of embodiment 22, wherein R
2For:
Embodiment 26. is according to each compound among the embodiment 1-25, wherein R
1For:
R
2Be suberyl.
Embodiment 27. is according to each compound among the embodiment 1-25, wherein R
1For:
R
2Be cyclohexyl.
Embodiment 28. is according to each compound among the embodiment 1-27, wherein A is thiazolyl, thiadiazolyl group, pyrazinyl, pyridyl, benzothiazolyl, 5,6-dihydro-4H-cyclopentadiene benzothiazolyl, 4,5,6, the 7-tetrahydrochysene-benzothiazole also-pyridyl, 6,7-dihydro-pyrans benzothiazolyl or 4,5,6,7-tetrahydro benzothiazol base, it is randomly by one or more R that are independently selected from
7, R
8And R
9Substituting group replace.
Embodiment 29. is according to the compound of embodiment 28, and wherein A is:
Embodiment 30. is according to the compound of embodiment 28, and wherein A is thiazolyl or thiadiazolyl group, and it is randomly by one or more R that are selected from
7, R
8And R
9Substituting group replace.
Embodiment 31. is according to the compound of embodiment 30, and wherein A is a thiazolyl, 1,2,4-thiadiazolyl group or 1,3, and the 4-thiadiazolyl group, it is randomly by one or more R that are selected from
7, R
8And R
9Substituting group replace.
Embodiment 32. is according to the compound of embodiment 31, and wherein A is:
Embodiment 33. is according to the compound of embodiment 32, and wherein A is:
Embodiment 34. is according to the compound of embodiment 33, and wherein A is:
Embodiment 35. is according to each compound among the embodiment 1-34, wherein R
3, R
4, R
5, R
6, R
30, R
31, R
32And R
33In at least one be independently selected from C
3-8-cycloalkyl-C
3-6-thiazolinyl, aryl-C
2-6-thiazolinyl, C
3-6-alkene oxygen base, C
3-8-cycloalkyl-C
3-6-alkene oxygen base, aryl-C
3-6-alkene oxygen base, C
3-8-cycloalkenyl group-C
1-6-alkoxyl group, C
3-8-heterocyclic radical-C
1-6-alkoxyl group, C
3-8-heterocyclic radical-C
3-6-alkene oxygen base, C
1-6-alkoxy-C
3-6-alkene oxygen base, C
3-8-alkene oxygen base-C
1-6-alkoxyl group, aryloxy-C
1-6-alkyl, aryloxy-C
3-6-thiazolinyl, aryl-C
1-6-alkoxy-C
1-6-alkyl, heteroaryl-C
1-6-alkoxy-C
1-6-alkyl, aryl-C
3-6-alkene oxygen base-C
1-6-alkyl, aryl-C
1-6-alkoxy-C
3-6-thiazolinyl, C
3-8-cycloalkyl-C
1-6-alkoxy-C
1-6-alkyl, C
3-8-cycloalkyl-C
3-6-alkene oxygen base-C
1-6-alkyl, C
3-8-cycloalkyl-C
1-6-alkoxy-C
3-6-thiazolinyl, C
3-8-heterocyclic radical-C
1-6-alkoxy-C
1-6-alkyl, C
3-8-heterocyclic radical-C
3-6-alkene oxygen base-C
1-6-alkyl, C
3-8-heterocyclic radical-C
1-6-alkoxy-C
3-6-thiazolinyl, C
3-6-alkenylthio group, C
3-8-cycloalkyl-C
3-6-alkenylthio group, aryl-C
3-6-alkenylthio group, heteroaryl-C
3-6-alkenylthio group, C
3-8-cycloalkenyl group-C
1-6-alkylthio, C
3-8-heterocyclic radical-C
1-6-alkylthio, C
1-6-alkylthio-C
3-6-alkene oxygen base, C
1-6-alkoxy-C
3-6-alkenylthio group, C
3-8-alkenylthio group-C
1-6-alkoxyl group, C
3-8-alkene oxygen base-C
1-6-alkylthio, arylthio-C
1-6-alkyl, arylthio-C
3-6-thiazolinyl, heteroaryloxy-C
1-6-alkyl, heteroarylthio-C
1-6-alkyl, heteroarylthio-C
3-6-thiazolinyl, aryl-C
1-6-alkylthio-C
1-6-alkyl, aryl-C
3-6-alkenylthio group-C
1-6-alkyl, aryl-C
1-6-alkylthio-C
3-6-thiazolinyl, heteroaryl-C
1-6-alkylthio-C
1-6-alkyl, heteroaryl-C
3-6-alkenylthio group-C
1-6-alkyl, heteroaryl-C
1-6-alkylthio-C
3-6-thiazolinyl, C
3-8-cycloalkyl-C
1-6-alkylthio-C
1-6-alkyl, C
3-8-cycloalkyl-C
3-6-alkenylthio group-C
1-6-alkyl, C
3-8-cycloalkyl-C
1-6-alkylthio-C
3-6-thiazolinyl, C
3-8-heterocyclic radical-C
1-6-alkylthio-C
1-6-alkyl, C
3-8-heterocyclic radical-C
3-6-alkenylthio group-C
1-6-alkyl, C
3-8-heterocyclic radical-C
1-6-alkylthio-C
3-6-thiazolinyl, described each group are randomly by one or more R that are independently selected from
12Substituting group replace.
Embodiment 36. is according to the compound of embodiment 35, wherein R
3, R
4, R
5, R
6, R
30, R
31, R
32And R
33In at least one be independently selected from C
3-8-cycloalkyl-C
3-6-thiazolinyl, aryl-C
2-6-thiazolinyl, C
3-6-alkene oxygen base, C
3-8-cycloalkyl-C
3-6-alkene oxygen base, aryl-C
3-6-alkene oxygen base, C
3-8-cycloalkenyl group-C
1-6-alkoxyl group, C
3-8-heterocyclic radical-C
1-6-alkoxyl group, C
3-8-heterocyclic radical-C
3-6-alkene oxygen base, C
1-6-alkoxy-C
3-6-alkene oxygen base, C
3-8-alkene oxygen base-C
1-6-alkoxyl group, aryloxy-C
1-6-alkyl, aryloxy-C
3-6-thiazolinyl, aryl-C
1-6-alkoxy-C
1-6-alkyl, heteroaryl-C
1-6-alkoxy-C
1-6-alkyl, aryl-C
3-6-alkene oxygen base-C
1-6-alkyl, aryl-C
1-6-alkoxy-C
3-6-thiazolinyl, C
3-8-cycloalkyl-C
1-6-alkoxy-C
1-6-alkyl, C
3-8-cycloalkyl-C
3-6-alkene oxygen base-C
1-6-alkyl, C
3-8-cycloalkyl-C
1-6-alkoxy-C
3-6-thiazolinyl, C
3-8-heterocyclic radical-C
1-6-alkoxy-C
1-6-alkyl, C
3-8-heterocyclic radical-C
3-6-alkene oxygen base-C
1-6-alkyl, C
3-8-heterocyclic radical-C
1-6-alkoxy-C
3-6-thiazolinyl, heteroaryloxy-C
1-6-alkyl, C
3-6-alkenylthio group, C
3-8-cycloalkyl-C
3-6-alkenylthio group, aryl-C
3-6-alkenylthio group, C
3-8-cycloalkenyl group-C
1-6-alkylthio, C
3-8-heterocyclic radical-C
1-6-alkylthio, C
1-6-alkylthio-C
3-6-alkene oxygen base, C
1-6-alkoxy-C
3-6-alkenylthio group, C
3-8-alkenylthio group-C
1-6-alkoxyl group, C
3-8-alkene oxygen base-C
1-6-alkylthio, arylthio-C
1-6-alkyl, arylthio-C
3-6-thiazolinyl, aryl-C
1-6-alkylthio-C
1-6-alkyl, aryl-C
3-6-alkenylthio group-C
1-6-alkyl, aryl-C
1-6-alkylthio-C
3-6-thiazolinyl, C
3-8-cycloalkyl-C
1-6-alkylthio-C
1-6-alkyl, C
3-8-cycloalkyl-C
3-6-alkenylthio group-C
1-6-alkyl, C
3-8-cycloalkyl-C
1-6-alkylthio-C
3-6-thiazolinyl, C
3-8-heterocyclic radical-C
1-6-alkylthio-C
1-6-alkyl, C
3-8-heterocyclic radical-C
3-6-alkenylthio group-C
1-6-alkyl, C
3-8-heterocyclic radical-C
1-6-alkylthio-C
3-6-thiazolinyl, described each group are randomly by one or more R that are independently selected from
12Substituting group replace.
Embodiment 37. is according to the compound of embodiment 36, wherein R
3, R
4, R
5, R
6, R
30, R
31, R
32And R
33In at least one be independently selected from C
3-8-cycloalkyl-C
3-6-thiazolinyl, aryl-C
2-6-thiazolinyl, C
3-6-alkene oxygen base, C
3-8-cycloalkyl-C
3-6-alkene oxygen base, aryl-C
3-6-alkene oxygen base, C
3-8-cycloalkenyl group-C
1-6-alkoxyl group, C
3-8-heterocyclic radical-C
1-6-alkoxyl group, C
3-8-heterocyclic radical-C
3-6-alkene oxygen base, C
1-6-alkoxy-C
3-6-alkene oxygen base, C
3-8-alkene oxygen base-C
1-6-alkoxyl group, aryloxy-C
1-6-alkyl, aryloxy-C
3-6-thiazolinyl, aryl-C
1-6-alkoxy-C
1-6-alkyl, heteroaryl-C
1-6-alkoxy-C
1-6-alkyl, aryl-C
3-6-alkene oxygen base-C
1-6-alkyl, aryl-C
1-6-alkoxy-C
3-6-thiazolinyl, C
3-8-cycloalkyl-C
1-6-alkoxy-C
1-6-alkyl, C
3-8-cycloalkyl-C
3-6-alkene oxygen base-C
1-6-alkyl, C
3-8-cycloalkyl-C
1-6-alkoxy-C
3-6-thiazolinyl, C
3-8-heterocyclic radical-C
1-6-alkoxy-C
1-6-alkyl, C
3-8-heterocyclic radical-C
3-6-alkene oxygen base-C
1-6-alkyl, C
3-8-heterocyclic radical-C
1-6-alkoxy-C
3-6-thiazolinyl, C
3-6-alkenylthio group, C
3-8-cycloalkyl-C
3-6-alkenylthio group, aryl-C
3-6-alkenylthio group, C
3-8-cycloalkenyl group-C
1-6-alkylthio, C
3-8-heterocyclic radical-C
1-6-alkylthio, C
1-6-alkylthio-C
3-6-alkene oxygen base, C
1-6-alkoxy-C
3-6-alkenylthio group, C
3-8-alkenylthio group-C
1-6-alkoxyl group, C
3-8-alkene oxygen base-C
1-6-alkylthio, arylthio-C
1-6-alkyl, arylthio-C
3-6-thiazolinyl, aryl-C
1-6-alkylthio-C
1-6-alkyl, aryl-C
3-6-alkenylthio group-C
1-6-alkyl, aryl-C
1-6-alkylthio-C
3-6-thiazolinyl, C
3-8-cycloalkyl-C
1-6-alkylthio-C
1-6-alkyl, C
3-8-cycloalkyl-C
3-6-alkenylthio group-C
1-6-alkyl, C
3-8-cycloalkyl-C
1-6-alkylthio-C
3-6-thiazolinyl, C
3-8-heterocyclic radical-C
1-6-alkylthio-C
1-6-alkyl, C
3-8-heterocyclic radical-C
3-6-alkenylthio group-C
1-6-alkyl, C
3-8-heterocyclic radical-C
1-6-alkylthio-C
3-6-thiazolinyl or heteroaryloxy-C
1-6-alkyl, described each group are randomly by one or more R that are independently selected from
12Substituting group replace.
Embodiment 38. is according to the compound of embodiment 37, wherein R
3, R
4, R
5, R
6, R
30, R
31, R
32And R
33In at least one be independently selected from C
3-6-alkene oxygen base, aryloxy-C
1-6-alkyl, C
3-8-cycloalkyl-C
1-6-alkoxy-C
1-6-alkyl, aryl-C
1-6-alkoxy-C
1-6-alkyl, heteroaryl-C
1-6-alkoxy-C
1-6-alkyl, C
3-6-alkenylthio group, arylthio-C
1-6-alkyl, C
3-8-cycloalkyl-C
1-6-alkylthio-C
1-6-alkyl or heteroaryloxy-C
1-6-alkyl, described each group are randomly by one or more R that are independently selected from
12Substituting group replace, wherein each aryl all is a phenyl, each heteroaryl all is a pyridyl.
Embodiment 39. is according to the compound of embodiment 38, wherein R
3, R
4, R
5, R
6, R
30, R
31, R
32And R
33In at least one be independently selected from C
3-6-alkene oxygen base, phenoxy group-C
1-6-alkyl, benzyloxy-C
1-6-alkyl, C
3-8-cycloalkyl-C
1-6-alkoxy-C
1-6-alkyl.
Embodiment 40. is according to the compound of embodiment 39, wherein R
3, R
4, R
5, R
6, R
30, R
31, R
32And R
33In at least one be independently selected from C
3-6-alkene oxygen base, phenoxy group-methyl, benzyloxy-methyl or cyclopropyl-methoxymethyl.
Embodiment 41. is according to each compound among the embodiment 35-40, if R wherein
3, R
4, R
5, R
6, R
30, R
31, R
32And R
33In have more than one, R then
3, R
4, R
5, R
6, R
30, R
31, R
32Or R
33In remaining is independently selected from:
● halogen, oxo, cyano group, hydroxyl, carboxyl ,-CF
3Or
●-NR
10R
11Or
● C
1-6-alkyl, C
2-6-thiazolinyl, C
3-8-cycloalkyl, C
3-8-cycloalkyl-C
1-6-alkyl, aryl, aryl-C
1-6-alkyl, C
1-6-alkoxyl group, C
3-6-cycloalkyl-C
1-6-alkoxyl group, aryl-C
1-6-alkoxyl group, C
1-6-alkylthio, arylthio ,-C (O)-O-C
1-6-alkyl or C
1-6-alkyl-C (O)-O-C
1-6-alkyl, described each group are randomly by one or more R that are independently selected from
12Substituting group replace; Or
●-C (O)-R
27,-S (O)
2-R
27,-C (O)-NR
13R
14,-S (O)
2-NR
13R
14,-C
1-6-alkyl-C (O)-NR
13R
14Or
Be selected from R
3, R
4, R
5And R
6Or R
30, R
31, R
32And R
33Two substituting groups, they are connected to form with same atom or adjacent atom-O-(CH together
2)
1-3-O-.
Embodiment 42. is according to the compound of embodiment 41, wherein R
3, R
4, R
5, R
6, R
30, R
31, R
32And R
33In remaining is independently selected from:
● halogen, oxo ,-CF
3Or
●-NR
10R
11Or
● C
1-6-alkyl, C
3-8-cycloalkyl, C
1-6-alkoxyl group, C
3-6-cycloalkyl-C
1-6-alkoxyl group, aryl-C
1-6-alkoxyl group, C
1-6-alkylthio, aryl, aryl-C
1-6-alkyl, arylthio ,-C (O)-O-C
1-6-alkyl or C
1-6-alkyl-C (O)-O-C
1-6-alkyl, described each group are randomly by one or more R that are independently selected from
12Substituting group replace; Or
●-C (O)-R
27,-S (O)
2-R
27Or-S (O)
2-R
27Or
Be selected from R
3, R
4, R
5And R
6Or R
30, R
31, R
32And R
33Two substituting groups, they are connected to form with same atom or adjacent atom-O-(CH together
2)
1-3-O-.
Embodiment 43. is according to the compound of embodiment 42, wherein R
3, R
4, R
5, R
6, R
30, R
31, R
32And R
33In remaining is independently selected from:
● halogen ,-CF
3Or
● methyl, ethyl, propyl group, sec.-propyl, butyl, the tertiary butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, benzyl, phenyl-ethyl, methoxyl group, oxyethyl group, propoxy-, cyclopropyl-methoxyl group, benzyloxy, thiophenyl (phenylthio) ,-C (O)-O-CH
3Or-C (O)-O-CH
2CH
3, described each group is randomly by one or more R that are independently selected from
12Substituting group replace; Or
●-C (O)-R
27,-S (O)
2-R
13R
14Or-S (O)
2-R
27Or
Be selected from R
3, R
4, R
5And R
6Or R
30, R
31, R
32And R
33Two substituting groups, they are connected to form with same atom or adjacent atom-O-(CH together
2)
1-3-O-.
Embodiment 44. is according to the compound of embodiment 43, wherein R
3, R
4, R
5, R
6, R
30, R
31, R
32And R
33In remaining is independently selected from:
● halogen ,-CF
3Or
● methyl, ethyl, propyl group, sec.-propyl, butyl, the tertiary butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, benzyl, phenyl-ethyl, methoxyl group, oxyethyl group, propoxy-, thiophenyl ,-C (O)-O-CH
3Or-C (O)-O-CH
2CH
3, described each group is randomly by one or more R that are independently selected from
12Substituting group replace; Or
●-C (O)-R
27,-S (O)
2-NR
13R
14Or-S (O)
2-R
27
Embodiment 45. is according to the compound of embodiment 44, wherein R
3, R
4, R
5, R
6, R
30, R
31, R
32And R
33In remaining be independently selected from F, Cl ,-CF
3, methyl, ethyl, propyl group, sec.-propyl, butyl, the tertiary butyl, methoxyl group, oxyethyl group, propoxy-,-C (O)-R
27,-S (O)
2-NR
13R
14Or-S (O)
2-R
27
Embodiment 46. is according to each compound among the embodiment 35-45, wherein R
12For halogen, cyano group, hydroxyl, carboxyl ,-CF
3, C
1-6-alkoxyl group, C
3-8-cycloalkyloxy, aryloxy, aryl-C
1-6-alkoxyl group or C
1-6-alkyl.
Embodiment 47. is according to the compound of embodiment 46, wherein R
12For halogen, cyano group, hydroxyl, carboxyl ,-CF
3, methoxyl group, oxyethyl group, propoxy-, ring propoxy-, cyclobutoxy group, cyclopentyloxy, cyclohexyloxy, ring oxygen in heptan base, phenoxy group, benzyloxy, phenyl-oxyethyl group, phenyl-propoxy-, methyl, ethyl or propyl group.
Embodiment 48. is according to the compound of embodiment 47, wherein R
12Be halogen, carboxyl, oxyethyl group, propoxy-, ring propoxy-, cyclobutoxy group, cyclopentyloxy, cyclohexyloxy, ring oxygen in heptan base, phenoxy group, benzyloxy, phenyl-oxyethyl group, phenyl-propoxy-, methyl, ethyl or propyl group.
Embodiment 49. is according to each compound among the embodiment 35-48, wherein R
10And R
11Be independently H, methyl, ethyl, propyl group ,-C (O)-CH
3,-C (O)-CH
2CH
3,-CH
2C (O) OH ,-CH
2CH
2C (O) OH ,-C (O)-CH
2-C (O) OH ,-C (O)-CH
2CH
2-C (O) OH ,-S (O)
2CH
3Or phenyl.
Embodiment 50. is according to the compound of embodiment 49, wherein R
10And R
11Be independently H, methyl, ethyl ,-C (O)-CH
3,-CH
2C (O) OH ,-C (O)-CH
2-C (O) OH ,-S (O)
2CH
3Or phenyl.
Embodiment 51. is according to the compound of embodiment 50, wherein R
10And R
11Be H, methyl, ethyl or phenyl independently.
Embodiment 52. is according to each compound among the embodiment 35-51, wherein R
27Be C
1-6-alkyl, C
1-6-alkoxyl group, C
2-6-thiazolinyl, C
2-6-alkynyl, C
3-8-cycloalkyl, C
3-8-cycloalkyl-C
1-6-alkyl, aryl, aryl-C
1-6-alkyl, aryl-C
2-6-thiazolinyl, heteroaryl, heteroaryl-C
1-6-alkyl, carboxyl-C
1-6-alkyl, C
1-6-alkoxy-C
1-6-alkyl, C
1-6-alkylthio-C
1-6-alkyl, R
10HN-C
1-6-alkyl, R
10R
11N-C
1-6-alkyl, R
10R
11N-S (O)
2-C
1-6-alkyl or R
10R
11N-C (O)-C
1-6-alkyl, described each group are randomly by one or more R that are independently selected from
12Substituting group replace.
Embodiment 53. is according to the compound of embodiment 52, wherein R
27Be C
1-6-alkyl, C
1-6-alkoxyl group, C
3-8-cycloalkyl, C
3-8-cycloalkyl-C
1-6-alkyl, aryl-C
2-6-thiazolinyl, aryl, heteroaryl, heteroaryl-C
1-6-alkyl, carboxyl-C
1-6-alkyl, carboxyl-C
1-6-alkyl, C
1-6-alkoxy-C
1-6-alkyl, R
10HN-C
1-6-alkyl, R
10R
11N-C
1-6-alkyl, R
10R
11N-S (O)
2-C
1-6-alkyl or R
10R
11N-C (O)-C
1-6-alkyl, described each group are randomly by one or more R that are independently selected from
12Substituting group replace.
Embodiment 54. is according to the compound of embodiment 53, wherein R
27Be C
1-6-alkyl, C
1-6-alkoxyl group, C
3-8-cycloalkyl, C
3-8-cycloalkyl-C
1-6-alkyl, aryl, heteroaryl-C
1-6-alkyl, aryl-C
1-6-alkyl, C
1-6-alkoxy-C
1-6-alkyl, carboxyl-C
1-6-alkyl or heteroaryl, described each group are randomly by one or more R that are independently selected from
12Substituting group replace.
Embodiment 55. is according to the compound of embodiment 54, wherein R
27Be methyl, ethyl, propyl group, normal-butyl, isobutyl-, 1,1,1-trifluoroethyl, cyclopropyl, cyclopentyl, cyclopropyl methyl, phenyl, pyridyl, thienyl, imidazolyl or thiazolyl, described each group are randomly by one or more R that are independently selected from
12Substituting group replace.
Embodiment 56. is according to the compound of embodiment 55, wherein R
27Be methyl, ethyl, propyl group, normal-butyl, isobutyl-, 1,1,1-trifluoroethyl, cyclopropyl, cyclopentyl, cyclopropyl methyl, phenyl or pyridyl, thienyl, imidazolyl or thiazolyl.
Embodiment 57. is according to the compound of embodiment 56, wherein R
27Be methyl, ethyl or propyl group.
Embodiment 58. is according to each compound among the embodiment 35-57, wherein R
13And R
14Be independently selected from: H, C
1-6-alkyl, hydroxyl-C
1-6-alkyl, carboxyl-C
1-6-alkyl, phenyl or naphthyl, described each group are randomly by one or more R that are independently selected from
15Substituting group replace; Perhaps R
13And R
14Form the 3-8 unit heterocycle with described nitrogen-atoms with the nitrogen-atoms that they connected, this heterocycle randomly contains one or two extra heteroatoms that is selected from nitrogen, oxygen and sulphur.
Embodiment 59. is according to the compound of embodiment 58, wherein R
13And R
14Be independently selected from: H, methyl, ethyl, propyl group, hydroxyl-methyl, hydroxyl-ethyl, carboxyl-methyl, carboxyl-ethyl, phenyl or naphthyl, described each group are randomly by one or more R that are independently selected from
15Substituting group replace; Perhaps R
13And R
14Form the 3-8 unit heterocycle with described nitrogen-atoms with the nitrogen-atoms that they connected, this heterocycle randomly contains one or two extra heteroatoms that is selected from nitrogen, oxygen and sulphur.
Embodiment 60. is according to the compound of embodiment 59, wherein R
13And R
14Be independently selected from: H, methyl, ethyl, propyl group or phenyl, described each group are randomly by one or more R that are independently selected from
15Substituting group replace.
Embodiment 61. is according to each compound among the embodiment 35-60, wherein R
15For H, cyano group, hydroxyl, carboxyl ,-CF
3, methyl, ethyl or propyl group.
Embodiment 62. is according to the compound of embodiment 61, wherein R
15For H, hydroxyl, carboxyl ,-CF
3, methyl or ethyl.
Embodiment 63. is according to each compound among the embodiment 1-34, wherein R
7, R
8And R
9Be independently selected from:
● halogen, carboxyl, cyano group, nitro, hydroxyl ,-CF
3,-SCN; Or
● C
1-6-alkyl, C
2-6-thiazolinyl, C
1-6-alkoxyl group, C
1-6-alkylthio, C
1-6-alkylamino, C
1-6-alkyl sulphinyl ,-C (O)-O-C
1-6-alkyl ,-C (O)-C
1-6-alkyl ,-C
1-6-alkyl-C (O)-O-C
1-6-alkyl ,-C
1-6-alkyl-O-C (O)-C
1-6-alkyl ,-NH-C (O)-C
1-6-alkyl ,-C
1-6-alkoxy-C
1-6-alkyl ,-C
1-6-alkyl-S-C
1-6-alkyl, C
3-8-cycloalkyl-C
1-6-alkyl, C
3-6-cycloalkyl-C
1-6-alkoxyl group, C
3-6-cycloalkyl-C
1-6-alkylthio, described each group are randomly by one or more R that are independently selected from
16Substituting group replace; Or
● aryl, heteroaryl, aryl-C
1-6-alkyl, heteroaryl-C
1-6-alkyl, aryl-C
1-6-alkoxyl group, heteroaryl-C
1-6-alkoxyl group, heteroaryl-sulfenyl-C
1-6-alkyl, aryloxy, heteroaryloxy, heteroarylthio, described each group randomly on aryl or heteroaryl moieties by one or more R that are independently selected from
17Substituting group replace; Or
● C
3-8-cycloalkyl, C
3-8-cycloalkenyl group, C
3-8-cycloalkyl-C
1-6-alkyl, C
3-8-cycloalkenyl group-C
1-6-alkyl, described each group randomly on cycloalkyl moiety by one or more R that are independently selected from
18Substituting group replace; Or
● C
3-8-heterocyclic radical, C
3-8-heterocyclic radical-C
1-6-alkyl, C
3-8-heterocycle sulfenyl or-C (O)-C
3-8-heterocyclic radical, described each group are randomly by one or more R that are independently selected from
16Substituting group replace; Or
●-NR
19R
20,-C
1-6-alkyl-NR
19R
20,-C
1-6-alkyl-S-R
21,-C
1-6-alkyl-S (O)-R
21,-C
1-6-alkyl-S (O)
2-R
21,-S (O)
2-R
21,-S (O)
2-N (R
19) (C
1-6-alkyl-C (O) NR
22R
23) or-S (O)
2-NR
19R
20, wherein each moieties all can be by one or more R that are independently selected from
25Substituting group replace; Or
●-C (O) NR
22R
23,-C
1-6-alkyl-C (O) NR
22R
23, they are randomly by one or more R that are independently selected from
26Substituting group replace; Or
R
7, R
8And R
9In two can form C together
2-5-alkylidene bridge.
Embodiment 64. is according to the compound of embodiment 63, wherein R
7, R
8And R
9Be independently selected from:
● halogen, carboxyl, cyano group or-CF
3Or
● C
1-6-alkyl, C
2-6-thiazolinyl, C
1-6-alkoxyl group, C
1-6-alkylthio ,-C (O)-O-C
1-6-alkyl ,-C (O)-C
1-6-alkyl ,-C
1-6-alkyl-C (O)-O-C
1-6-alkyl ,-C
1-6-alkyl-O-C (O)-C
1-6-alkyl ,-C
1-6-alkoxy-C
1-6-alkyl, C
3-8-cycloalkyl-C
1-6-alkyl, described each group are randomly by one or more R that are independently selected from
16Substituting group replace; Or
● aryl, heteroaryl, aryl-C
1-6-alkyl, heteroaryl-C
1-6-alkyl, described each group randomly on aryl or heteroaryl moieties by one or more R that are independently selected from
17Substituting group replace; Or
● C
3-8-cycloalkyl, C
3-8-cycloalkyl-C
1-6-alkyl, described each group randomly on cycloalkyl moiety by one or more R that are independently selected from
18Substituting group replace; Or
● C
3-8-heterocyclic radical, C
3-8-heterocyclic radical-C
1-6-alkyl or-C (O)-C
3-8-heterocyclic radical, described each group are randomly by one or more R that are independently selected from
16Substituting group replace; Or
●-NR
19R
20,-C
1-6-alkyl-NR
19R
20,-S (O)
2-R
21,-S (O)
2-N (R
19) (C
1-6-alkyl-C (O) NR
22R
23) or-S (O)
2-NR
19R
20, wherein each moieties all can be by one or more R that are independently selected from
25Substituting group replace; Or
●-C (O) NR
22R
23,-C
1-6-alkyl-C (O) NR
22R
23, they are randomly by one or more R that are independently selected from
26Substituting group replace; Or
R
7, R
8And R
9In two can form C together
2-5-alkylidene bridge.
Embodiment 65. is according to the compound of embodiment 64, wherein R
7, R
8And R
9Be independently selected from:
● halogen, carboxyl or-CF
3Or
● C
1-6-alkyl, C
1-6-alkoxyl group, C
1-6-alkylthio ,-C
1-6-alkyl-C (O)-O-C
1-6-alkyl ,-C
1-6-alkyl-O-C (O)-C
1-6-alkyl or-C (O)-O-C
1-6-alkyl, described each group are randomly by one or more R that are independently selected from
16Substituting group replace; Or
● phenyl, benzyl or heteroarylthio, wherein heteroaryl is pyridyl or imidazolyl, wherein each aryl or heteroaryl randomly on aryl or heteroaryl moieties by one or more R that are independently selected from
17Substituting group replace; Or
● cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, described each group randomly on cycloalkyl moiety by one or more R that are independently selected from
18Substituting group replace; Or
● pyrrolidyl, piperidyl, piperazinyl or morpholinyl, described each group are randomly by one or more R that are independently selected from
16Substituting group replace; Or
●-C (O) NR
22R
23,-S (O)
2-R
21,-S (O)
2-N (R
19) (C
1-6-alkyl-C (O) NR
22R
23) or-S (O)
2-NR
19R
20Or
R
7, R
8And R
9In two can form C together
2-5-alkylidene bridge.
Embodiment 66. is according to the compound of embodiment 65, wherein R
7, R
8And R
9Be independently selected from: halogen, carboxyl ,-CF
3,-S-CH
3,-S-CH
2CH
3,-S-CH
2CH
2CH
3, methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, methoxyl group, oxyethyl group ,-CH
2-C (O)-O-CH
3,-CH
2-C (O)-O-CH
2CH
3,-CH
2CH
2-C (O)-O-CH
3,-CH
2CH
2-C (O)-O-CH
2CH
3,-CH
2-O-C (O)-CH
3,-CH
2-O-C (O)-CH
2CH
3,-CH
2CH
2-O-C (O)-CH
3,-CH
2CH
2-O-C (O)-CH
2CH
3,-C (O)-O-CH
3,-C (O)-O-CH
2CH
3, described each group is randomly by one or more R that are independently selected from
16Substituting group replace; Or heteroarylthio, wherein heteroaryl is pyridyl or imidazolyl, described each group randomly on heteroaryl moieties by one or more R that are independently selected from
17Substituting group replace, or pyrrolidyl, piperidyl, piperazinyl or morpholinyl, described each group is randomly by one or more R that are independently selected from
16Substituting group replace; Or-S (O)
2-NR
19R
20Or-S (O)
2-R
21
Embodiment 67. is according to the compound of embodiment 66, wherein R
7, R
8And R
9Be independently selected from: Cl ,-S-CH
3,-S-CH
2CH
3,-S-CH
2CH
2CH
3,-S-CH (CH
3)
2,-S-CH
2CH (CH
3)
2, methyl or ethyl, described each group is randomly by one or more R that are independently selected from
16Substituting group replace;-S (O)
2-NR
19R
20Or-S (O)
2-R
21
Embodiment 68. is according to the compound of embodiment 67, wherein R
7, R
8And R
9Be independently selected from :-S-CH
3,-S-CH
2CH
3,-S-CH (CH
3)
2Or-S-CH
2CH (CH
3)
2, described each group is randomly by one or more R that are independently selected from
16Substituting group replace.
Embodiment 69. is according to each compound among the embodiment 1-68, wherein R
16, R
17And R
18Be C independently
1-6-alkyl, halogen, hydroxyl, oxo, carboxyl ,-CF
3, carboxyl-C
1-6-alkyl, hydroxyl-C
1-6-alkyl ,-C
1-6-alkyl-C (O)-O-C
1-6-alkyl ,-C (O)-O-C
1-6-alkyl ,-NR
19R
20,-C (O) NR
19R
20Or-S (O)
2-C
1-6-alkyl.
Embodiment 70. is according to the compound of embodiment 69, wherein R
16, R
17And R
18Be independently methyl, ethyl, propyl group, halogen, hydroxyl, oxo, carboxyl ,-CF
3, carboxyl-methyl, carboxyl-ethyl, carboxyl-propyl group, hydroxyl-methyl, hydroxyl-ethyl, hydroxyl-propyl group ,-CH
2-C (O)-O-CH
3,-CH
2-C (O)-O-CH
2CH
3,-CH
2CH
2-C (O)-O-CH
3,-CH
2CH
2-C (O)-O-CH
2CH
3,-C (O)-O-CH
3,-C (O)-O-CH
2CH
3,-C (O)-O-CH
2CH
2CH
3Or-S (O)
2CH
3
Embodiment 71. is according to the compound of embodiment 70, wherein R
16, R
17And R
18Be independently methyl, ethyl, propyl group, halogen, oxo, carboxyl, carboxyl-methyl, carboxyl-ethyl, carboxyl-propyl group, hydroxyl-methyl, hydroxyl-ethyl, hydroxyl-propyl group ,-CH
2-C (O)-O-CH
3,-CH
2-C (O)-O-CH
2CH
3,-CH
2CH
2-C (O)-O-CH
3,-CH
2CH
2-C (O)-O-CH
2CH
3,-C (O)-O-CH
3,-C (O)-O-CH
2CH
3,-C (O)-O-CH
2CH
2CH
3Or-S (O)
2CH
3
Embodiment 72. is according to the compound of embodiment 69, wherein R
16, R
17And R
18Be independently methyl, ethyl, propyl group, sec.-propyl, isobutyl-, halogen, hydroxyl, oxo, carboxyl ,-CF
3, carboxyl-methyl, carboxyl-ethyl, carboxyl-propyl group, hydroxyl-methyl, hydroxyl-ethyl, hydroxyl-propyl group ,-CH
2-C (O)-O-CH
3,-CH
2-C (O)-O-CH
2CH
3,-CH
2CH
2-C (O)-O-CH
3,-CH
2CH
2-C (O)-O-CH
2CH
3,-C (O)-O-CH
3,-C (O)-O-CH
2CH
3,-C (O)-O-CH
2CH
2CH
3Or-S (O)
2CH
3
Embodiment 73. is according to the compound of embodiment 72, wherein R
16, R
17And R
18Be independently methyl, ethyl, propyl group, sec.-propyl, isobutyl-, halogen, oxo, carboxyl, carboxyl-methyl, carboxyl-ethyl, carboxyl-propyl group, hydroxyl-methyl, hydroxyl-ethyl, hydroxyl-propyl group ,-CH
2-C (O)-O-CH
3,-CH
2-C (O)-O-CH
2CH
3,-CH
2CH
2-C (O)-O-CH
3,-CH
2CH
2-C (O)-O-CH
2CH
3,-C (O)-O-CH
3,-C (O)-O-CH
2CH
3,-C (O)-O-CH
2CH
2CH
3Or-S (O)
2CH
3
Embodiment 74. is according to the compound of embodiment 69, wherein R
16, R
17And R
18Be C independently
1-6-alkyl, carboxyl ,-NR
19R
20,-C (O)-O-C
1-6-alkyl ,-S (O)
2CH
3Or-C (O) NR
19R
20
Embodiment 75. is according to the compound of embodiment 74, wherein R
16, R
17And R
18Be carboxyl.
Embodiment 76. is according to each compound among the embodiment 1-75, wherein R
19And R
20Be H, C independently
1-6-alkyl, hydroxyl-C
1-6-alkyl, carboxyl-C
1-6-alkyl, phenyl, naphthyl, C
3-8-cycloalkyl, C
3-8-heterocyclic radical, phenyl-C
1-6-alkyl, C
3-8-heterocyclic radical-C
1-6-alkyl ,-C (O)-O-C
1-6-alkyl ,-C
1-6-alkyl-C (O)-O-C
1-6-alkyl ,-C
1-6-alkyl-NR
22R
23Or-S (O)
2-C
1-6-alkyl, described each group are randomly by one or more R that are independently selected from
24Substituting group replace; Perhaps R
19And R
20Form the 3-8 unit heterocycle with described nitrogen-atoms with the nitrogen-atoms that they connected, this heterocycle randomly contains one or two extra heteroatoms that is selected from nitrogen, oxygen and sulphur, and described heterocycle is randomly by one or more R that are independently selected from
24Substituting group replace.
Embodiment 77. is according to the compound of embodiment 76, wherein R
19And R
20Be H, methyl, ethyl, propyl group, carboxyl-methyl, carboxyl-ethyl, carboxyl-propyl group, hydroxyl-methyl, hydroxyl-ethyl, hydroxyl-propyl group, phenyl, C independently
3-8-cycloalkyl, phenyl-C
1-6-alkyl, C
3-8-heterocyclic radical-C
1-6-alkyl ,-C (O)-O-C
1-6-alkyl ,-C
1-6-alkyl-C (O)-O-C
1-6-alkyl ,-C
1-6-alkyl-NR
22R
23,-S (O)
2-C
1-6-alkyl or naphthyl, perhaps R
19And R
20Form the 3-8 unit heterocycle with described nitrogen-atoms with the nitrogen-atoms that they connected, this heterocycle randomly contains one or two extra heteroatoms that is selected from nitrogen, oxygen and sulphur, and described heterocycle is randomly by one or more R that are independently selected from
24Substituting group replace.
Embodiment 78. is according to the compound of embodiment 76, wherein R
19And R
20Be H, C independently
1-6-alkyl ,-S (O)
2-C
1-6-alkyl, perhaps R
19And R
20Form the 3-8 unit heterocycle with described nitrogen-atoms with the nitrogen-atoms that they connected, this heterocycle randomly contains one or two extra heteroatoms that is selected from nitrogen, oxygen and sulphur, and described heterocycle is randomly by one or more R that are independently selected from
24Substituting group replace.
Embodiment 79. is according to the compound of embodiment 78, wherein R
19And R
20Be independently H, methyl, ethyl or propyl group ,-S (O)
2-CH
3, perhaps R
19And R
20Form the 3-8 unit heterocycle with described nitrogen-atoms with the nitrogen-atoms that they connected, wherein said heterocycle is pyrrolidyl, piperidyl, piperazinyl, high piperazinyl or morpholinyl, and described heterocycle is randomly by one or more R that are independently selected from
24Substituting group replace.
Embodiment 80. is according to each compound among the embodiment 1-79, wherein R
21Be selected from:
● C
1-6-alkyl, carboxyl-C
1-6-alkyl ,-C
1-6-alkyl-NR
22R
23Or hydroxyl-C
1-6-alkyl; Or
● phenyl, naphthyl or phenyl-C
1-6-alkyl, wherein said aryl moiety are randomly by one or more R that are independently selected from
24Substituting group replace; Or
● C
3-8-cycloalkyl or C
3-8-cycloalkyl-C
1-6-alkyl.
Embodiment 81. is according to the compound of embodiment 80, wherein R
21Be selected from:
● methyl, ethyl, propyl group, carboxyl-methyl, carboxyl-ethyl, carboxyl-propyl group, hydroxyl-methyl, hydroxyl-ethyl, hydroxyl-propyl group; Or
● phenyl, naphthyl or phenyl-C
1-6-alkyl, wherein said aryl moiety are randomly by one or more R that are independently selected from
24Substituting group replace; Or
● C
3-8-cycloalkyl or C
3-8-cycloalkyl-C
1-6-alkyl.
Embodiment 82. is according to the compound of embodiment 81, wherein R
21Be selected from:
● methyl, ethyl, carboxyl-methyl, carboxyl-ethyl, carboxyl-propyl group; Or
● phenyl, naphthyl or phenyl-C
1-6-alkyl, wherein said aryl moiety are randomly by one or more R that are independently selected from
24Substituting group replace.
Embodiment 83. is according to the compound of embodiment 82, wherein R
21Be selected from carboxyl-methyl, carboxyl-ethyl or carboxyl-propyl group.
Embodiment 84. is according to each compound among the embodiment 1-83, wherein R
22And R
23Be independently selected from H, C
1-6-alkyl, carboxyl-C
1-6-alkyl, hydroxyl-C
1-6-alkyl ,-C
1-6-alkyl-C (O)-O-C
1-6-alkyl ,-C (O)-O-C
1-6-alkyl, C
3-8-cycloalkyl, phenyl, naphthyl, perhaps R
22And R
23Form the 3-8 unit heterocycle with described nitrogen-atoms with the nitrogen-atoms that they connected, this heterocycle randomly contains one or two extra heteroatoms that is selected from nitrogen, oxygen and sulphur, and described heterocycle is randomly by one or more R that are independently selected from
24Substituting group replace.
Embodiment 85. is according to the compound of embodiment 84, wherein R
22And R
23Be independently selected from H, methyl, ethyl, propyl group, butyl, carboxymethyl, propyloic, carboxylic propyl group, methylol, hydroxyethyl, hydroxypropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, phenyl, naphthyl, perhaps R
22And R
23Form the 3-8 unit heterocycle with described nitrogen-atoms with the nitrogen-atoms that they connected, wherein said heterocycle is pyrrolidyl, piperidyl, piperazinyl, high piperazinyl or morpholinyl, and described heterocycle is randomly by one or more R that are independently selected from
24Substituting group replace.
Embodiment 86. is according to the compound of embodiment 85, wherein R
22And R
23Form the 3-8 unit heterocycle with described nitrogen-atoms with the nitrogen-atoms that they connected, wherein said heterocycle is pyrrolidyl, piperidyl, piperazinyl, high piperazinyl or morpholinyl, and described heterocycle is randomly by one or more R that are independently selected from
24Substituting group replace.
Embodiment 87. is according to the compound of embodiment 85, wherein R
22And R
23Be selected from methyl, ethyl or propyl group.
Embodiment 88. is according to each compound among the embodiment 1-87, wherein R
24For halogen, hydroxyl, carboxyl, oxo ,-CF
3, C
1-6-alkyl, hydroxyl-C
1-6-alkyl, carboxyl-C
1-6-alkyl ,-C (O)-C
1-6-alkyl ,-C (O)-O-C
1-6-alkyl ,-C
1-6-alkyl-C (O)-O-C
1-6-alkyl, aryl, heteroaryl, aryl-C
1-6-alkyl, heteroaryl-C
1-6-alkyl, C
3-8-cycloalkyl, C
3-8-heterocyclic radical, C
3-8-cycloalkyl-C
1-6-alkyl, C
3-8-heterocyclic radical-C
1-6-alkyl ,-C (O)-O-C
1-6-alkyl-aryl or-S (O)
2R
28, wherein aryl is a phenyl or naphthyl, and heteroaryl is pyridyl or pyrimidyl, and wherein each loop section is all randomly by one or more R that are independently selected from
29Substituting group replace.
Embodiment 89. is according to the compound of embodiment 88, wherein R
24For halogen, hydroxyl, carboxyl, oxo ,-CF
3, C
1-6-alkyl, hydroxyl-C
1-6-alkyl, carboxyl-C
1-6-alkyl ,-C (O)-C
1-6-alkyl ,-C (O)-O-C
1-6-alkyl, aryl, heteroaryl, aryl-C
1-6-alkyl, heteroaryl-C
1-6-alkyl, C
3-8-cycloalkyl, C
3-8-heterocyclic radical, C
3-8-cycloalkyl-C
1-6-alkyl, C
3-8-heterocyclic radical-C
1-6-alkyl or-S (O)
2R
28, wherein aryl is a phenyl or naphthyl, and heteroaryl is pyridyl or pyrimidyl, and wherein each loop section is all randomly by one or more R that are independently selected from
29Substituting group replace.
Embodiment 90. is according to the compound of embodiment 89, wherein R
24For halogen, carboxyl, oxo ,-CF
3, C
1-6-alkyl, carboxyl-C
1-6-alkyl ,-C (O)-C
1-6-alkyl ,-C (O)-O-C
1-6-alkyl, aryl, aryl-C
1-6-alkyl, C
3-8-cycloalkyl, C
3-8-heterocyclic radical, C
3-8-heterocyclic radical-C
1-6-alkyl or-S (O)
2R
28, wherein aryl is a phenyl or naphthyl, wherein each loop section is all randomly by one or more R that are independently selected from
29Substituting group replace.
Embodiment 91. is according to the compound of embodiment 88, wherein R
24Be halogen, carboxyl, C
1-6-alkyl, carboxyl-C
1-6-alkyl or-C (O)-C
1-6-alkyl.
Embodiment 92. is according to each compound among the embodiment 1-91, wherein R
25And R
26Be C independently
1-6-alkyl, halogen, hydroxyl, carboxyl or-CF
3
Embodiment 93. is according to the compound of embodiment 92, wherein R
25And R
26Be independently methyl, ethyl, propyl group, halogen, hydroxyl, carboxyl or-CF
3
Embodiment 94. is according to each compound among the embodiment 1-93, wherein R
28Be C
1-6-alkyl ,-C
1-6-alkyl-C (O)-O-C
1-6-alkyl, phenyl, phenyl-C
1-6-alkyl, randomly by C
1-6The heteroaryl that-alkyl replaces or-N (CH
3)
2, wherein heteroaryl is imidazolyl, pyridyl or pyrimidyl.
Embodiment 95. is according to the compound of embodiment 94, wherein R
28Be C
1-6-alkyl ,-C
1-6-alkyl-C (O)-O-C
1-6-alkyl or-N (CH
3)
2
Embodiment 96. is according to each compound among the embodiment 1-95, wherein R
29For halogen, carboxyl ,-CF
3, C
1-6-alkyl or C
1-6-alkoxyl group.
Embodiment 97. is according to each compound among the embodiment 1-34, wherein R
3, R
4, R
5, R
6, R
30, R
31, R
32And R
33Be independently selected from:
● halogen, nitro, cyano group, hydroxyl, oxo, carboxyl ,-CF
3Or
●-NR
10R
11Or
● C
1-6-alkyl, C
2-6-thiazolinyl, C
2-6-alkynyl, C
3-8-cycloalkyl, C
3-8-cycloalkyl-C
1-6-alkyl, aryl, aryl-C
1-6-alkyl, heteroaryl-C
1-6-alkyl, C
1-6-alkoxyl group, C
3-6-cycloalkyl-C
1-6-alkoxyl group, aryl-C
1-6-alkoxyl group, heteroaryl, heteroaryl-C
1-6-alkoxyl group, aryloxy, heteroaryloxy, C
1-6-alkylthio, arylthio, heteroarylthio, C
3-8-cycloalkylthio, aryl-C
1-6-alkylthio, heteroaryl-C
1-6-alkylthio, C
1-6-alkyl sulphinyl, C
3-6-cycloalkyl-C
1-6-alkylthio, C
1-6-alkyl-C (O)-O-C
1-6-alkyl, C
1-6-alkoxy-C
1-6-alkyl, C
1-6-alkylthio-C
1-6-alkyl, carboxyl-C
1-6-alkoxyl group, amino-C
1-6-alkyl, C
1-6-alkylamino-C
1-6-alkyl, two-(C
1-6-alkyl) amino-C
1-6-alkyl, C
1-6-alkyl amino sulfonyl, two (C
1-6-alkyl) amino-sulfonyl, C
1-6-alkylamino sulfinyl or two (C
1-6-alkyl) amino sulfinyl, described each group are randomly by one or more R that are independently selected from
12Substituting group replace; Or
●-C (O)-R
27,-S (O)
2-R
27,-C (O)-NR
13R
14,-S (O)
2-NR
13R
14,-C
1-6-alkyl-C (O)-NR
13R
14Or
● be selected from R
3, R
4, R
5And R
6Or R
30, R
31, R
32And R
33Two substituting groups, they are connected to form with same atom or adjacent atom-O-(CH together
2)
1-3-O-; With
R
10And R
11Be H, C independently
1-6-alkyl ,-C (O)-C
1-6-alkyl ,-C (O)-O-C
1-6-alkyl, carboxyl-C
1-6-alkyl ,-C (O)-C
1-6-alkyl-C (O) OH ,-S (O)
2-C
1-6-alkyl or aryl; With
R
27Be C
1-6-alkyl, C
1-6-alkoxyl group, C
2-6-thiazolinyl, C
2-6-alkynyl, C
3-8-cycloalkyl, C
3-8-cycloalkyl-C
1-6-alkyl, C
3-8-cycloalkyl-C
2-6-thiazolinyl, aryl, aryl-C
1-6-alkyl, aryloxy-C
1-6-alkyl, aryl-C
2-6-thiazolinyl, heteroaryl, C
3-8-heterocyclic radical, heteroaryl-C
1-6-alkyl, C
3-8-heterocyclic radical-C
1-6-alkyl, heteroaryloxy-C
1-6-alkyl, carboxyl-C
1-6-alkyl, carboxyl-C
2-6-thiazolinyl, C
1-6-alkoxy-C
1-6-alkyl, C
1-6-alkoxy-C
2-6-thiazolinyl, C
1-6-alkylthio-C
1-6-alkyl, R
10HN-C
1-6-alkyl, R
10R
11N-C
1-6-alkyl, R
10R
11N-C
2-6-thiazolinyl, R
10R
11N-S (O)
2-C
1-6-alkyl, R
10R
11N-C (O)-C
1-6-alkyl, C
1-6-alkyl-C (O)-NH-C
1-6-alkyl, aryl-C (O)-NH-C
1-6-alkyl, heteroaryl-C (O)-NH-C
1-6-alkyl, C
3-8-cycloalkyl-C (O)-NH-C
1-6-alkyl, C
1-6-alkyl-S (O)
2-NH-C
1-6-alkyl, aryl-S (O)
2-NH-C
1-6-alkyl, heteroaryl-S (O)
2-NH-C
1-6-alkyl or C
3-8-cycloalkyl-S (O)
2-NH-C
1-6-alkyl, described each group are randomly by one or more R that are independently selected from
12Substituting group replace; With
R
12For halogen, cyano group, hydroxyl ,-C (O)-O-C
1-6-alkyl, carboxyl ,-CF
3, C
1-6-alkyl, C
1-6-alkoxyl group ,-NR
10R
11,-S (O)
2CH
3Or-S (O)
2NH
2With
R
13And R
14Be independently selected from H, C
1-6-alkyl, hydroxyl-C
1-6-alkyl, carboxyl-C
1-6-alkyl, aryl or heteroaryl, described each group are randomly by one or more R that are independently selected from
15Substituting group replace; Perhaps R
13And R
14Form the 3-8 unit heterocycle with described nitrogen-atoms with the nitrogen-atoms that they connected, described heterocycle randomly contains one or two extra heteroatoms that is selected from nitrogen, oxygen and sulphur; With
R
15For halogen, cyano group, hydroxyl, carboxyl ,-CF
3, C
1-6-alkyl ,-S (O)
2CH
3Or-S (O)
2NH
2With
R
7, R
8And R
9In at least one be independently selected from:
● C
1-6Alkoxyl group, C
1-6Alkylthio, C
2-6Alkenylthio group, described each group is by one or more R that are independently selected from
16Substituting group replace;
●-NR
19R
20,-C
1-6-alkyl-NR
19R
20,-C
2-6-thiazolinyl-NR
19R
20,-C
1-6-alkyl-S-R
21,-C
1-6-alkyl-S (O)-R
21,-C
1-6-alkyl-S (O)
2-R
21,-S (O)
2-R
21,-S (O)
2-NR
19R
20Or-S (O)
2NR
19(C
1-6-alkyl-C (O) NR
22R
23), wherein each moieties all can be by one or more R that are independently selected from
25Substituting group replace;
If R
7, R
8And R
9In have more than one, R then
7, R
8And R
9In other one or more can being independently selected from addition:
● halogen, carboxyl, cyano group, nitro, hydroxyl ,-CF
3,-SCN; Or
● C
1-6-alkyl, C
2-6-thiazolinyl, C
2-6-alkynyl, C
1-6-alkoxyl group, C
1-6-alkylthio, C
2-6-alkenylthio group, C
1-6-alkylamino, C
1-6-alkyl sulphinyl ,-C (O)-O-C
1-6-alkyl, formyl radical ,-C (O)-C
1-6-alkyl ,-C
1-6-alkyl-C (O)-O-C
1-6-alkyl ,-C
1-6-alkyl-O-C (O)-C
1-6-alkyl ,-NH-C (O)-C
1-6-alkyl ,-C
1-6-alkoxy-C
1-6-alkyl ,-C
1-6-alkyl-S-C
1-6-alkyl, carboxyl-C
1-6-alkyl or hydroxyl-C
1-6-alkyl, described each group are randomly by one or more R that are independently selected from
40Substituting group replace; Or
● aryl, heteroaryl, aryl-C
1-6-alkyl, heteroaryl-C
1-6-alkyl, aryl-C
1-6-alkoxyl group, heteroaryl-C
1-6-alkoxyl group, aryl-C
1-6-alkylthio, heteroaryl-C
1-6-alkylthio, heteroaryl-sulfenyl-C
1-6-alkyl, heteroaryl-oxygen base-C
1-6-alkyl, aryloxy, heteroaryloxy, arylthio, heteroarylthio, aryl-C
1-6-alkylamino ,-C (O)-aryl or-C (O)-heteroaryl, described each group randomly on aryl or heteroaryl moieties by one or more R that are independently selected from
41Substituting group replace; Or
● C
3-8-cycloalkyl, C
3-8-cycloalkenyl group, C
3-8-cycloalkylthio, C
3-8-cycloalkyl-C
1-6-alkyl, C
3-8-cycloalkenyl group-C
1-6-alkyl, C
3-6-cycloalkyl-C
1-6-alkoxyl group, C
3-6-cycloalkyl-C
1-6-alkylthio, described each group randomly on cycloalkyl moiety by one or more R that are independently selected from
42Substituting group replace; Or
● C
3-8-heterocyclic radical, C
3-8-heterocyclic radical-C
1-6-alkyl, C
3-8-heterocyclic radical-C
1-6-alkylthio, C
3-8-heterocycle sulfenyl, C
3-8-heterocyclic radical-amino-C
1-6-alkyl or-C (O)-C
3-8-heterocyclic radical, described each group are randomly by one or more R that are independently selected from
40Substituting group replace; Or
●-NR
43R
44,-C
1-6-alkyl-NR
43R
44,-C
2-6-thiazolinyl-NR
43R
44,-C
1-6-alkyl-S-R
45,-C
1-6-alkyl-S (O)-R
45,-C
1-6-alkyl-S (O)
2-R
45,-S (O)
2-R
45,-S (O)
2-N (R
43) (C
1-6-alkyl-C (O) NR
46R
47) or-S (O)
2-NR
43R
44, wherein each moieties all can be by one or more R that are independently selected from
49Substituting group replace; Or
●-C (O) NR
46R
47,-C
1-6-alkyl-C (O) NR
46R
47,-C
1-6-alkyl-NH-NR
46R
47,-C
1-6-alkyl-NH-C (O)-C
1-6-alkyl-NNR
46R
47, described each group is randomly by one or more R that are independently selected from
50Substituting group replace; With
R
16For-NR
19R
20,-NHS (O)
2CF
3,-NHS (O)
2CH
2CF
3,-C (O) NR
19R
20,-S (O)
2CF
3,-S (O)
2CH
2CF
3Or-S (O)
2NR
19R
20With
R
19Represent H, C
1-6-alkyl, C
2-6-thiazolinyl, C
3-8-cycloalkyl, C
3-8-cycloalkyl-C
1-6-alkyl, hydroxyl-C
1-6-alkyl, hydroxyl-C
2-6-thiazolinyl, carboxyl-C
1-6-alkyl, aryl, heteroaryl, C
3-8-heterocyclic radical, aryl-C
1-6-alkyl, C
3-8-heterocyclic radical-C
1-6-alkyl ,-C (O)-O-C
1-6-alkyl ,-C
1-6-alkyl-C (O)-O-C
1-6-alkyl ,-C
1-6-alkyl-NR
22R
23Or-S (O)
2-C
1-6-alkyl, described each group are randomly by one or more R that are independently selected from
24Substituting group replace; With
R
20Represent C
2-6-thiazolinyl, C
3-8-cycloalkyl, C
3-8-cycloalkyl-C
1-6-alkyl, described each group are randomly by one or more R that are independently selected from
24Substituting group replace; With
R
21Be selected from:
● C
3-8-cycloalkyl, C
3-8-cycloalkyl-C
1-6-alkyl, C
2-6-thiazolinyl, carboxyl-C
1-6-alkyl, C
1-6-alkylamino-C
1-6-alkyl or hydroxyl-C
1-6-alkyl ,-C
1-6-alkyl-NR
22R
23, they are by one or more R that are independently selected from
24Substituting group replace; Or
● C
3-8-cycloalkyl, C
3-8-cycloalkenyl group, C
3-8-cycloalkyl-C
1-6-alkyl, C
3-8-cycloalkenyl group-C
1-6-alkyl, they are randomly by one or more R that are independently selected from
24Substituting group replace;
R
22And R
23Be independently selected from H, C
1-6-alkyl, carboxyl-C
1-6-alkyl, hydroxyl-C
1-6-alkyl ,-C
1-6-alkyl-C (O)-O-C
1-6-alkyl ,-C (O)-O-C
1-6-alkyl ,-C
1-6-alkyl-S (O)
2-C
1-6-alkyl, C
3-8-cycloalkyl, aryl or heteroaryl; Perhaps R
22And R
23Form the 3-8 unit heterocycle with described nitrogen-atoms with the nitrogen-atoms that they connected, described heterocycle randomly contains one or two extra heteroatoms that is selected from nitrogen, oxygen and sulphur, and described heterocycle is randomly by one or more R that are independently selected from
24Substituting group replace; With
R
24For halogen, nitro, cyano group, hydroxyl, carboxyl, oxo ,-CF
3, C
1-6-alkyl, hydroxyl-C
1-6-alkyl, carboxyl-C
1-6-alkyl ,-C (O)-C
1-6-alkyl ,-C (O)-C
3-8-cycloalkyl ,-C (O)-aryl ,-C (O)-heteroaryl ,-C (O)-C
3-8-heterocyclic radical-C (O)-O-C
1-6-alkyl ,-C
1-6-alkyl-C (O)-O-C
1-6-alkyl, aryl, heteroaryl, aryl-C
1-6-alkyl, heteroaryl-C
1-6-alkyl, C
3-8-cycloalkyl, C
3-8-heterocyclic radical, C
3-8-cycloalkyl-C
1-6-alkyl, C
3-8-heterocyclic radical-C
1-6-alkyl ,-C
1-6-alkyl-C (O)-C
3-8-heterocyclic radical ,-C (O)-O-C
1-6-alkyl-aryl ,-NH--S (O)
2R
28Or-S (O)
2R
28, wherein each loop section is all randomly by one or more R that are independently selected from
29Substituting group replace; With
R
25Be C
1-6-alkyl, halogen, nitro, cyano group, hydroxyl ,-C (O)-O-C
1-6-alkyl, carboxyl ,-C
1-6-alkyl-C (O)-O-C
1-6-alkyl, carboxyl-C
1-6-alkyl ,-CF
3,-S (O)
2CH
3Or-S (O)
2NH
2With
R
28Be C
1-6-alkyl, carboxyl-C
1-6-alkyl ,-C
1-6-alkyl-C (O)-O-C
1-6-alkyl, C
3-8-cycloalkyl, aryl, aryl-C
1-6-alkyl, randomly by C
1-6The heteroaryl that-alkyl replaces ,-NH
2Or-N (CH
3)
2With
R
29For halogen, nitro, cyano group, hydroxyl, carboxyl, oxo ,-CF
3, C
1-6-alkyl or C
1-6-alkoxyl group; With
R
40, R
41And R
42Be C independently
1-6-alkyl, halogen, nitro, cyano group, hydroxyl, carboxyl, oxo ,-CF
3, carboxyl-C
1-6-alkyl, hydroxyl-C
1-6-alkyl ,-C
1-6-alkyl-C (O)-O-C
1-6-alkyl ,-C
1-6-alkyl-C (O)-NR
43R
44,-C (O)-O-C
1-6-alkyl ,-C (O)-C
1-6-alkyl-C (O)-C
1-6-alkyl ,-NR
43R
44,-NHS (O)
2C
1-6-alkyl ,-NHS (O)
2CF
3,-NHS (O)
2CH
2CF
3,-C (O) NR
43R
44,-S (O)
2C
1-6-alkyl ,-S (O)
2CF
3,-S (O)
2CH
2CF
3Or-S (O)
2NR
43R
44With
R
43And R
44Be H, C independently
1-6-alkyl, C
2-6-thiazolinyl, C
3-8-cycloalkyl, C
3-8-cycloalkyl-C
1-6-alkyl, hydroxyl-C
1-6-alkyl, carboxyl-C
1-6-alkyl, aryl, heteroaryl, C
3-8-heterocyclic radical, aryl-C
1-6-alkyl, C
3-8-heterocyclic radical-C
1-6-alkyl ,-C (O)-O-C
1-6-alkyl ,-C
1-6-alkyl-C (O)-O-C
1-6-alkyl ,-C
1-6-alkyl-NR
46R
47Or-S (O)
2-C
1-6-alkyl, described each group are randomly by one or more R that are independently selected from
48Substituting group replace; Perhaps R
43And R
44Form the 3-8 unit heterocycle with described nitrogen-atoms with the nitrogen-atoms that they connected, described heterocycle randomly contains one or two extra heteroatoms that is selected from nitrogen, oxygen and sulphur, and described heterocycle is randomly by one or more R that are independently selected from
48Substituting group replace; With
R
45Be selected from:
● C
1-6-alkyl, C
2-6-thiazolinyl, carboxyl-C
1-6-alkyl, C
1-6-alkylamino-C
1-6-alkyl or hydroxyl-C
1-6-alkyl ,-C
1-6-alkyl-NR
46R
47Or
● aryl, heteroaryl, aryl-C
1-6-alkyl or heteroaryl-C
1-6-alkyl, wherein aryl or heteroaryl moieties are randomly by one or more R that are independently selected from
48Substituting group replace; Or
● C
3-8-cycloalkyl, C
3-8-cycloalkenyl group, C
3-8-cycloalkyl-C
1-6-alkyl, C
3-8-cycloalkenyl group-C
1-6-alkyl; With
R
46And R
47Be independently selected from H, C
1-6-alkyl, carboxyl-C
1-6-alkyl, hydroxyl-C
1-6-alkyl ,-C
1-6-alkyl-C (O)-O-C
1-6-alkyl ,-C (O)-O-C
1-6-alkyl ,-C
1-6-alkyl-S (O)
2-C
1-6-alkyl, C
3-8-cycloalkyl, aryl or heteroaryl; Perhaps R
46And R
47Form the 3-8 unit heterocycle with described nitrogen-atoms with the nitrogen-atoms that they connected, described heterocycle randomly contains one or two extra heteroatoms that is selected from nitrogen, oxygen and sulphur, and described heterocycle is randomly by one or more R that are independently selected from
48Substituting group replace; With
R
48For halogen, nitro, cyano group, hydroxyl, carboxyl, oxo ,-CF
3, C
1-6-alkyl, hydroxyl-C
1-6-alkyl, carboxyl-C
1-6-alkyl ,-C (O)-C
1-6-alkyl ,-C (O)-C
3-8-cycloalkyl ,-C (O)-aryl ,-C (O)-heteroaryl ,-C (O)-C
3-8-heterocyclic radical-C (O)-O-C
1-6-alkyl ,-C
1-6-alkyl-C (O)-O-C
1-6-alkyl, aryl, heteroaryl, aryl-C
1-6-alkyl, heteroaryl-C
1-6-alkyl, C
3-8-cycloalkyl, C
3-8-heterocyclic radical, C
3-8-cycloalkyl-C
1-6-alkyl, C
3-8-heterocyclic radical-C
1-6-alkyl ,-C
1-6-alkyl-C (O)-C
3-8-heterocyclic radical ,-C (O)-O-C
1-6-alkyl-aryl ,-NH-S (O)
2R
52Or-S (O)
2R
52, wherein each loop section is all randomly by one or more R that are independently selected from
53Substituting group replace; With
R
49And R
50Be C independently
1-6-alkyl, halogen, nitro, cyano group, hydroxyl ,-C (O)-O-C
1-6-alkyl, carboxyl ,-C
1-6-alkyl-C (O)-O-C
1-6-alkyl, carboxyl-C
1-6-alkyl ,-CF
3,-S (O)
2CH
3Or-S (O)
2NH
2With
R
52Be C
1-6-alkyl, carboxyl-C
1-6-alkyl ,-C
1-6-alkyl-C (O)-O-C
1-6-alkyl, C
3-8-cycloalkyl, aryl, aryl-C
1-6-alkyl, randomly by C
1-6The heteroaryl that-alkyl replaces ,-NH
2Or-N (CH
3)
2With
R
53For halogen, nitro, cyano group, hydroxyl, carboxyl, oxo ,-CF
3, C
1-6-alkyl or C
1-6-alkoxyl group.
Embodiment 98. is according to the compound of embodiment 97, wherein R
7, R
8And R
9In at least one be independently selected from:
● C
1-6-alkoxyl group, C
1-6-alkylthio, described each group is by one or more R that are independently selected from
16Substituting group replace; Or
●-NR
19R
20,-C
1-6-alkyl-NR
19R
20,-C
1-6-alkyl-S-R
21,-C
1-6-alkyl-S (O)
2-R
21,-S (O)
2-R
21,-S (O)
2-NR
19R
20Or-S (O)
2NR
19(C
1-6-alkyl-C (O) NR
22R
23), wherein each moieties is by one or more R that are independently selected from
25Substituting group replace.
Embodiment 99. is according to the compound of embodiment 98, wherein R
7, R
8And R
9In at least one be independently selected from:
● C
1-6-alkoxyl group, C
1-6-alkylthio, described each group is by one or more R that are independently selected from
16Substituting group replace; Or
●-C
1-6-alkyl-S-R
21,-C
1-6-alkyl-S (O)
2-R
21,-S (O)
2-R
21,-S (O)
2-NR
19R
20Or-S (O)
2NR
19(C
1-6-alkyl-C (O) NR
22R
23), wherein each moieties is by one or more R that are independently selected from
25Substituting group replace.
Embodiment 100. is according to the compound of embodiment 99, wherein R
7, R
8And R
9In at least one be independently selected from:
● C
1-6-alkoxyl group, C
1-6-alkylthio, described each group is by one or more R that are independently selected from
16Substituting group replace; Or
●-S (O)
2-R
21,-S (O)
2-NR
19R
20Or-S (O)
2NR
19(C
1-6-alkyl-C (O) NR
22R
23), wherein each moieties is by one or more R that are independently selected from
25Substituting group replace.
Embodiment 101. is according to the compound of embodiment 100, wherein R
7, R
8And R
9In at least one be independently selected from C
1-6-alkylthio, it is by one or more R that are independently selected from
16Substituting group replace; Or-S (O)
2-R
21,-S (O)
2-NR
19R
20Or-S (O)
2NR
19(C
1-6-alkyl-C (O) NR
22R
23), wherein each moieties is by one or more R that are independently selected from
25Substituting group replace.
Embodiment 102. is according to the compound of embodiment 101, wherein R
7, R
8And R
9In at least one be independently selected from-S-CH
3,-S-CH
2CH
3,-S-CH
2CH
2CH
3, described each group is by one or more R that are independently selected from
16Substituting group replace, or-S (O)
2-R
21,-S (O)
2-NR
19R
20Or-S (O)
2NR
19(CH
3-C (O) NR
22R
23).
Embodiment 103. is according to each compound among the embodiment 97-102, if R
7, R
8And R
9In have more than one, R then
7, R
8And R
9In other one or more being independently selected from:
● halogen, carboxyl, cyano group, nitro, hydroxyl ,-CF
3,-SCN; Or
● C
1-6-alkyl, C
2-6-thiazolinyl, C
2-6-alkynyl, C
1-6-alkoxyl group, C
1-6-alkylthio, C
2-6-alkenylthio group, C
1-6-alkylamino, C
1-6-alkyl sulphinyl ,-C (O)-O-C
1-6-alkyl, formyl radical ,-C (O)-C
1-6-alkyl ,-C
1-6-alkyl-C (O)-O-C
1-6-alkyl ,-C
1-6-alkyl-O-C (O)-C
1-6-alkyl ,-NH-C (O)-C
1-6-alkyl ,-C
1-6-alkoxy-C
1-6-alkyl ,-C
1-6-alkyl-S-C
1-6-alkyl, carboxyl-C
1-6-alkyl or hydroxyl-C
1-6-alkyl, described each group are randomly by one or more R that are independently selected from
40Substituting group replace; Or
● aryl, heteroaryl, aryl-C
1-6-alkyl, heteroaryl-C
1-6-alkyl, aryl-C
1-6-alkoxyl group, heteroaryl-C
1-6-alkoxyl group, aryl-C
1-6-alkylthio, heteroaryl-C
1-6-alkylthio, heteroaryl-sulfenyl-C
1-6-alkyl, heteroaryl-oxygen base-C
1-6-alkyl, aryloxy, heteroaryloxy, arylthio, heteroarylthio, aryl-C
1-6-alkylamino ,-C (O)-aryl or-C (O)-heteroaryl, described each group randomly on aryl or heteroaryl moieties by one or more R that are independently selected from
41Substituting group replace; Or
● C
3-8-cycloalkyl, C
3-8-cycloalkenyl group, C
3-8-cycloalkylthio, C
3-8-cycloalkyl-C
1-6-alkyl, C
3-8-cycloalkenyl group-C
1-6-alkyl, C
3-6-cycloalkyl-C
1-6-alkoxyl group, C
3-6-cycloalkyl-C
1-6-alkylthio, described each group randomly on cycloalkyl moiety by one or more R that are independently selected from
42Substituting group replace; Or
● C
3-8-heterocyclic radical, C
3-8-heterocyclic radical-C
1-6-alkyl, C
3-8-heterocyclic radical-C
1-6-alkylthio, C
3-8-heterocycle sulfenyl, C
3-8-heterocyclic radical-amino-C
1-6-alkyl or-C (O)-C
3-8-heterocyclic radical, described each group are randomly by one or more R that are independently selected from
40Substituting group replace; Or
●-NR
43R
44,-C
1-6-alkyl-NR
43R
44,-C
2-6-thiazolinyl-NR
43R
44,-C
1-6-alkyl-S-R
45,-C
1-6-alkyl-S (O)-R
45,-C
1-6-alkyl-S (O)
2-R
45,-S (O)
2-R
45,-S (O)
2-N (R
43) (C
1-6-alkyl-C (O) NR
46R
47) or-S (O)
2-NR
43R
44, wherein each moieties all can be by one or more R that are independently selected from
49Substituting group replace; Or
●-C (O) NR
46R
47,-C
1-6-alkyl-C (O) NR
46R
47,-C
1-6-alkyl-NH-NR
46R
47,-C
1-6-alkyl-NH-C (O)-C
1-6-alkyl-NNR
46R
47, described each group is randomly by one or more R that are independently selected from
50Substituting group replace.
Embodiment 104. is according to the compound of embodiment 103, wherein R
7, R
8And R
9In other one or more being independently selected from:
● halogen, carboxyl, cyano group, nitro, hydroxyl ,-CF
3,-SCN; Or
● C
1-6-alkyl, C
2-6-thiazolinyl, C
1-6-alkoxyl group, C
1-6-alkylthio, C
1-6-alkylamino, C
1-6-alkyl sulphinyl ,-C (O)-O-C
1-6-alkyl ,-C (O)-C
1-6-alkyl ,-C
1-6-alkyl-C (O)-O-C
1-6-alkyl ,-C
1-6-alkyl-O-C (O)-C
1-6-alkyl ,-NH-C (O)-C
1-6-alkyl ,-C
1-6-alkoxy-C
1-6-alkyl ,-C
1-6-alkyl-S-C
1-6-alkyl, C
3-8-cycloalkyl-C
1-6-alkyl, C
3-6-cycloalkyl-C
1-6-alkoxyl group, C
3-6-cycloalkyl-C
1-6-alkylthio, described each group are randomly by one or more R that are independently selected from
40Substituting group replace; Or
● aryl, heteroaryl, aryl-C
1-6-alkyl, heteroaryl-C
1-6-alkyl, aryl-C
1-6-alkoxyl group, heteroaryl-C
1-6-alkoxyl group, heteroaryl-sulfenyl-C
1-6-alkyl, aryloxy, heteroaryloxy, heteroarylthio, described each group randomly on aryl or heteroaryl moieties by one or more R that are independently selected from
42Substituting group replace; Or
● C
3-8-cycloalkyl, C
3-8-cycloalkenyl group, C
3-8-cycloalkyl-C
1-6-alkyl, C
3-8-cycloalkenyl group-C
1-6-alkyl, described each group randomly on cycloalkyl moiety by one or more R that are independently selected from
42Substituting group replace; Or
● C
3-8-heterocyclic radical, C
3-8-heterocyclic radical-C
1-6-alkyl, C
3-8-heterocycle sulfenyl or-C (O)-C
3-8-heterocyclic radical, described each group are randomly by one or more R that are independently selected from
40Substituting group replace; Or
●-NR
43R
44,-C
1-6-alkyl-NR
43R
44,-C
1-6-alkyl-S-R
45,-C
1-6-alkyl-S (O)-R
45,-C
1-6-alkyl-S (O)
2-R
45,-S (O)
2-R
45Or-S (O)
2-NR
43R
44, wherein each moieties all can be by one or more R that are independently selected from
49Substituting group replace; Or
●-C (O) NR
46R
47,-C
1-6-alkyl-C (O) NR
46R
47, they are randomly by one or more R that are independently selected from
50Substituting group replace; Or
R
7, R
8And R
9In two can form C together
2-5-alkylidene bridge.
Embodiment 105. is according to the compound of embodiment 104, wherein R
7, R
8And R
9In other one or more being independently selected from:
● halogen, carboxyl, cyano group or-CF
3Or
● C
1-6-alkyl, C
2-6-thiazolinyl, C
1-6-alkoxyl group, C
1-6-alkylthio ,-C (O)-O-C
1-6-alkyl ,-C (O)-C
1-6-alkyl ,-C
1-6-alkyl-C (O)-O-C
1-6-alkyl ,-C
1-6-alkyl-O-C (O)-C
1-6-alkyl ,-C
1-6-alkoxy-C
1-6-alkyl, C
3-8-cycloalkyl-C
1-6-alkyl, described each group are randomly by one or more R that are independently selected from
40Substituting group replace; Or
● aryl, heteroaryl, aryl-C
1-6-alkyl, heteroaryl-C
1-6-alkyl, described each group randomly on aryl or heteroaryl moieties by one or more R that are independently selected from
41Substituting group replace; Or
● C
3-8-cycloalkyl, C
3-8-cycloalkyl-C
1-6-alkyl, described each group randomly on cycloalkyl moiety by one or more R that are independently selected from
42Substituting group replace; Or
● C
3-8-heterocyclic radical, C
3-8-heterocyclic radical-C
1-6-alkyl or-C (O)-C
3-8-heterocyclic radical, described each group are randomly by one or more R that are independently selected from
40Substituting group replace; Or
●-NR
43R
44,-C
1-6-alkyl-NR
43R
44,-S (O)
2-R
45Or-S (O)
2-NR
43R
44, wherein each moieties all can be by one or more R that are independently selected from
49Substituting group replace; Or
●-C (O) NR
46R
47,-C
1-6-alkyl-C (O) NR
46R
47, they are randomly by one or more R that are independently selected from
50Substituting group replace; Or
R
7, R
8And R
9In two can form C together
2-5-alkylidene bridge.
Embodiment 106. is according to the compound of embodiment 105, wherein R
7, R
8And R
9In other one or more being independently selected from:
● halogen, carboxyl or-CF
3Or
● C
1-6-alkyl, C
1-6-alkoxyl group, C
1-6-alkylthio ,-C
1-6-alkyl-C (O)-O-C
1-6-alkyl ,-C
1-6-alkyl-O-C (O)-C
1-6-alkyl or-C (O)-O-C
1-6-alkyl, described each group are randomly by one or more R that are independently selected from
40Substituting group replace; Or
● phenyl, benzyl or heteroarylthio, wherein heteroaryl is pyridyl or imidazolyl, wherein each aryl or heteroaryl all randomly on aryl or heteroaryl moieties by one or more R that are independently selected from
41Substituting group replace; Or
● cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, described each group randomly on cycloalkyl moiety by one or more R that are independently selected from
42Substituting group replace; Or
● pyrrolidyl, piperidyl, piperazinyl or morpholinyl, described each group are randomly by one or more R that are independently selected from
40Substituting group replace; Or
●-C (O) NR
46R
47,-S (O)
2-R
45Or-S (O)
2-NR
43R
44Or
R
7, R
8And R
9In two can form C together
2-5-alkylidene bridge.
Embodiment 107. is according to the compound of embodiment 106, wherein R
7, R
8And R
9In other one or more be independently selected from halogen, carboxyl ,-CF
3,-S-CH
3,-S-CH
2CH
3,-S-CH
2CH
2CH
3, methyl, ethyl, propyl group, sec.-propyl, butyl, the tertiary butyl, methoxyl group, oxyethyl group ,-CH
2-C (O)-O-CH
3,-CH
2-C (O)-O-CH
2CH
3,-CH
2CH
2-C (O)-O-CH
3,-CH
2CH
2-C (O)-O-CH
2CH
3,-CH
2-O-C (O)-CH
3,-CH
2-O-C (O)-CH
2CH
3,-CH
2CH
2-O-C (O)-CH
3,-CH
2CH
2-O-C (O)-CH
2CH
3,-C (O)-O-CH
3,-C (O)-O-CH
2CH
3, described each group is randomly by one or more R that are independently selected from
40Substituting group replace; Or heteroarylthio, wherein heteroaryl is pyridyl or imidazolyl, described each group randomly on heteroaryl moieties by one or more R that are independently selected from
41Substituting group replace, or pyrrolidyl, piperidyl, piperazinyl or morpholinyl, described each group is randomly by one or more R that are independently selected from
40Substituting group replace S (O)
2-R
45Or-S (O)
2-NR
43R
44
Embodiment 108. is according to the compound of embodiment 107, wherein R
7, R
8And R
9In other one or more be independently selected from halogen ,-S-CH
3,-S-CH
2CH
3,-S-CH
2CH
2CH
3, methyl or ethyl ,-S (O)
2-R
45Or-S (O)
2-NR
43R
44
Embodiment 109. is according to each compound among the embodiment 97-108, wherein R
40, R
41And R
42Be C independently
1-6-alkyl, halogen, hydroxyl, oxo, carboxyl ,-CF
3, carboxyl-C
1-6-alkyl, hydroxyl-C
1-6-alkyl ,-C
1-6-alkyl-C (O)-O-C
1-6-alkyl ,-C (O)-O-C
1-6-alkyl ,-NR
43R
44,-C (O) NR
43R
44Or-S (O)
2C
1-6-alkyl.
Embodiment 110. is according to the compound of embodiment 109, wherein R
40, R
41And R
42Be independently methyl, ethyl, propyl group, halogen, hydroxyl, oxo, carboxyl ,-CF
3, carboxyl-methyl, carboxyl-ethyl, carboxyl-propyl group, hydroxyl-methyl, hydroxyl-ethyl, hydroxyl-propyl group ,-CH
2-C (O)-O-CH
3,-CH
2-C (O)-O-CH
2CH
3,-CH
2CH
2-C (O)-O-CH
3,-CH
2CH
2-C (O)-O-CH
2CH
3,-C (O)-O-CH
3,-C (O)-O-CH
2CH
3,-C (O)-O-CH
2CH
2CH
3Or-S (O)
2CH
3
Embodiment 111. is according to the compound of embodiment 110, wherein R
40, R
41And R
42Be independently methyl, ethyl, propyl group, halogen, oxo, carboxyl, carboxyl-methyl, carboxyl-ethyl, carboxyl-propyl group, hydroxyl-methyl, hydroxyl-ethyl, hydroxyl-propyl group ,-CH
2-C (O)-O-CH
3,-CH
2-C (O)-O-CH
2CH
3,-CH
2CH
2-C (O)-O-CH
3,-CH
2CH
2-C (O)-O-CH
2CH
3,-C (O)-O-CH
3,-C (O)-O-CH
2CH
3,-C (O)-O-CH
2CH
2CH
3Or-S (O)
2CH
3
Embodiment 112. is according to the compound of embodiment 111, wherein R
40, R
41And R
42Be C independently
1-6-alkyl, carboxyl ,-NR
43R
44,-C (O)-O-C
1-6-alkyl or-C (O) NR
43R
44
Embodiment 113. is according to each compound among the embodiment 97-112, wherein R
19, R
43And R
44Be H, C independently
1-6-alkyl, hydroxyl-C
1-6-alkyl, C
3-8-cycloalkyl, C
3-8-cycloalkyl-C
1-6-alkyl, carboxyl-C
1-6-alkyl, phenyl, naphthyl, C
3-8-heterocyclic radical, phenyl-C
1-6-alkyl, C
3-8-heterocyclic radical-C
1-6-alkyl ,-C (O)-O-C
1-6-alkyl ,-C
1-6-alkyl-C (O)-O-C
1-6-alkyl ,-C
1-6-alkyl-NR
46R
47Or-S (O)
2-C
1-6-alkyl, described each group are randomly by one or more R that are independently selected from
48Substituting group replace; Perhaps R
43And R
44Form the 3-8 unit heterocycle with described nitrogen-atoms with the nitrogen-atoms that they connected, described heterocycle randomly contains one or two extra heteroatoms that is selected from nitrogen, oxygen and sulphur, and described heterocycle is randomly by one or more R that are independently selected from
48Substituting group replace.
Embodiment 114. is according to the compound of embodiment 113, wherein R
19, R
43And R
44Be H, methyl, ethyl, propyl group, carboxyl-methyl, carboxyl-ethyl, carboxyl-propyl group, hydroxyl-methyl, hydroxyl-ethyl, hydroxyl-propyl group, phenyl, phenyl-C independently
1-6-alkyl, C
3-8-heterocyclic radical-C
1-6-alkyl ,-C (O)-O-C
1-6-alkyl ,-C
1-6-alkyl-C (O)-O-C
1-6-alkyl ,-C
1-6-alkyl-NR
46R
47,-S (O)
2-C
1-6-alkyl or naphthyl, perhaps R
43And R
44Form the 3-8 unit heterocycle with described nitrogen-atoms with the nitrogen-atoms that they connected, described heterocycle randomly contains one or two extra heteroatoms that is selected from nitrogen, oxygen and sulphur, and described heterocycle is randomly by one or more R that are independently selected from
48Substituting group replace.
Embodiment 115. is according to the compound of embodiment 114, wherein R
19, R
43And R
44Be H, C independently
1-6-alkyl ,-S (O)
2-C
1-6-alkyl, perhaps R
43And R
44Form the 3-8 unit heterocycle with described nitrogen-atoms with the nitrogen-atoms that they connected, described heterocycle randomly contains one or two extra heteroatoms that is selected from nitrogen, oxygen and sulphur, and described heterocycle is randomly by one or more R that are independently selected from
48Substituting group replace.
Embodiment 116. is according to the compound of embodiment 115, wherein R
19, R
43And R
44Be independently H, methyl, ethyl or propyl group ,-S (O)
2-CH
3, perhaps R
43And R
44Form the 3-8 unit heterocycle with described nitrogen-atoms with the nitrogen-atoms that they connected, wherein said heterocycle is pyrrolidyl, piperidyl, piperazinyl, high piperazinyl or morpholinyl, and described heterocycle is randomly by one or more R that are independently selected from
48Substituting group replace.
Embodiment 117. is according to each compound among the embodiment 97-116, wherein R
45Be selected from:
● C
1-6-alkyl, carboxyl-C
1-6-alkyl ,-C
1-6-alkyl-NR
46R
47Or hydroxyl-C
1-6-alkyl; Or
● phenyl, naphthyl or phenyl-C
1-6-alkyl, wherein aryl moiety is randomly by one or more R that are independently selected from
48Substituting group replace; Or
● C
3-8-cycloalkyl or C
3-8-cycloalkyl-C
1-6-alkyl.
Embodiment 118. is according to the compound of embodiment 117, wherein R
45Be selected from:
● methyl, ethyl, propyl group, carboxyl-methyl, carboxyl-ethyl, carboxyl-propyl group, hydroxyl-methyl, hydroxyl-ethyl, hydroxyl-propyl group; Or
● phenyl, naphthyl or phenyl-C
1-6-alkyl, wherein aryl moiety is randomly by one or more R that are independently selected from
48Substituting group replace; Or
● C
3-8-cycloalkyl or C
3-8-cycloalkyl-C
1-6-alkyl.
Embodiment 119. is according to the compound of embodiment 118, wherein R
45Be selected from:
● methyl, ethyl, carboxyl-methyl, carboxyl-ethyl, carboxyl-propyl group; Or
● phenyl, naphthyl or phenyl-C
1-6-alkyl, wherein aryl moiety is randomly by one or more R that are independently selected from
48Substituting group replace.
Embodiment 120. is according to the compound of embodiment 119, wherein R
45Be selected from carboxyl-methyl, carboxyl-ethyl, carboxyl-propyl group.
Embodiment 121. is according to each compound among the embodiment 97-120, wherein R
46And R
47Be independently selected from H, C
1-6-alkyl, hydroxyl-C
1-6-alkyl, carboxyl-C
1-6-alkyl ,-C
1-6-alkyl-C (O)-O-C
1-6-alkyl ,-C (O)-O-C
1-6-alkyl, C
3-8-cycloalkyl, phenyl, naphthyl; Perhaps R
46And R
47Form the 3-8 unit heterocycle with described nitrogen-atoms with the nitrogen-atoms that they connected, described heterocycle randomly contains one or two extra heteroatoms that is selected from nitrogen, oxygen and sulphur, and described heterocycle is randomly by one or more R that are independently selected from
48Substituting group replace.
Embodiment 122. is according to the compound of embodiment 121, wherein R
46And R
47Be independently selected from H, methyl, ethyl, propyl group, butyl, carboxymethyl, propyloic, carboxylic propyl group, methylol, ethoxycarbonyl propyl, hydroxypropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, phenyl, naphthyl, perhaps R
46And R
47Form the 3-8 unit heterocycle with described nitrogen-atoms with the nitrogen-atoms that they connected, wherein said heterocycle is pyrrolidyl, piperidyl, piperazinyl, high piperazinyl or morpholinyl, and described heterocycle is randomly by one or more R that are independently selected from
48Substituting group replace.
Embodiment 123. is according to the compound of embodiment 122, wherein R
46And R
47Form the 3-8 unit heterocycle with described nitrogen-atoms with the nitrogen-atoms that they connected, wherein said heterocycle is pyrrolidyl, piperidyl, piperazinyl, high piperazinyl or morpholinyl, and described heterocycle is randomly by one or more R that are independently selected from
48Substituting group replace.
Embodiment 124. is according to each compound among the embodiment 97-123, wherein R
48For halogen, hydroxyl, carboxyl, oxo ,-CF
3, C
1-6-alkyl, hydroxyl-C
1-6-alkyl, carboxyl-C
1-6-alkyl ,-C (O)-C
1-6-alkyl ,-C (O)-O-C
1-6-alkyl ,-C
1-6-alkyl-C (O)-O-C
1-6-alkyl, aryl, heteroaryl, aryl-C
1-6-alkyl, heteroaryl-C
1-6-alkyl, C
3-8-cycloalkyl, C
3-8-heterocyclic radical, C
3-8-cycloalkyl-C
1-6-alkyl, C
3-8-heterocyclic radical-C
1-6-alkyl ,-C (O)-O-C
1-6-alkyl-aryl or-S (O)
2R
52, wherein aryl is a phenyl or naphthyl, and heteroaryl is pyridyl or pyrimidyl, and wherein each loop section is all randomly by one or more R that are independently selected from
53Substituting group replace.
Embodiment 125. is according to the compound of embodiment 124, wherein R
48For halogen, hydroxyl, carboxyl, oxo ,-CF
3, C
1-6-alkyl, hydroxyl-C
1-6-alkyl, carboxyl-C
1-6-alkyl ,-C (O)-C
1-6-alkyl ,-C (O)-O-C
1-6-alkyl, aryl, heteroaryl, aryl-C
1-6-alkyl, heteroaryl-C
1-6-alkyl, C
3-8-cycloalkyl, C
3-8-heterocyclic radical, C
3-8-cycloalkyl-C
1-6-alkyl, C
3-8-heterocyclic radical-C
1-6-alkyl or-S (O)
2R
52, wherein aryl is a phenyl or naphthyl, and heteroaryl is pyridyl or pyrimidyl, and wherein each loop section is all randomly by one or more R that are independently selected from
53Substituting group replace.
Embodiment 126. is according to the compound of embodiment 125, wherein R
48For halogen, carboxyl, oxo ,-CF
3, C
1-6-alkyl, carboxyl-C
1-6-alkyl ,-C (O)-C
1-6-alkyl ,-C (O)-O-C
1-6-alkyl, aryl, aryl-C
1-6-alkyl, C
3-8-cycloalkyl, C
3-8-heterocyclic radical, C
3-8-heterocyclic radical-C
1-6-alkyl or-S (O)
2R
52, wherein aryl is a phenyl or naphthyl, wherein each loop section is all randomly by one or more R that are independently selected from
53Substituting group replace.
Embodiment 127. is according to the compound of embodiment 126, wherein R
48Be halogen, carboxyl, oxo, C
1-6-alkyl or carboxyl-C
1-6-alkyl.
Embodiment 128. is according to each compound among the embodiment 97-127, wherein R
49And R
50Be C independently
1-6-alkyl, halogen, hydroxyl, carboxyl or-CF
3
Embodiment 129. is according to the compound of embodiment 128, wherein R
49And R
50Be independently methyl, ethyl, propyl group, halogen, hydroxyl, carboxyl or-CF
3
Embodiment 130. is according to each compound among the embodiment 97-129, wherein R
52Be C
1-6-alkyl ,-C
1-6-alkyl-C (O)-O-C
1-6-alkyl, phenyl, phenyl-C
1-6-alkyl, randomly by C
1-6The heteroaryl that-alkyl replaces or-N (CH
3)
2, wherein heteroaryl is imidazolyl, pyridyl or pyrimidyl.
Embodiment 131. is according to the compound of embodiment 130, wherein R
52Be C
1-6-alkyl ,-C
1-6-alkyl-C (O)-O-C
1-6-alkyl or-N (CH
3)
2
Embodiment 132. is according to each compound among the embodiment 97-131, wherein R
53For halogen, carboxyl ,-CF
3, C
1-6-alkyl or C
1-6-alkoxyl group.
Embodiment 133. is according to each compound among the embodiment 97-132, wherein R
3, R
4, R
5, R
6, R
30, R
31, R
32And R
33Be independently selected from:
● halogen, oxo, cyano group, hydroxyl, carboxyl ,-CF
3Or
●-NR
10R
11Or
● C
1-6-alkyl, C
2-6-thiazolinyl, C
3-8-cycloalkyl, C
3-8-cycloalkyl-C
1-6-alkyl, aryl, aryl-C
1-6-alkyl, C
1-6-alkoxyl group, C
3-6-cycloalkyl-C
1-6-alkoxyl group, aryl-C
1-6-alkoxyl group, heteroaryl-C
1-6-alkoxyl group, C
1-6-alkylthio, aryloxy, arylthio ,-C (O)-O-C
1-6-alkyl or C
1-6-alkyl-C (O)-O-C
1-6-alkyl, described each group are randomly by one or more R that are independently selected from
12Substituting group replace; Or
●-C (O)-R
27,-S (O)
2-R
27,-C (O)-NR
13R
14,-S (O)
2-NR
13R
14,-C
1-6-alkyl-C (O)-NR
13R
14Or
Be selected from R
3, R
4, R
5And R
6Or R
30, R
31, R
32And R
33Two substituting groups, they are connected to form with same atom or adjacent atom-O-(CH together
2)
1-3-O-.
Embodiment 134. is according to the compound of embodiment 133, wherein R
3, R
4, R
5, R
6, R
30, R
31, R
32And R
33Be independently selected from:
● halogen, oxo ,-CF
3Or
●-NR
10R
11Or
● C
1-6-alkyl, C
3-8-cycloalkyl, C
1-6-alkoxyl group, C
1-6-alkylthio, aryl, aryl-C
1-6-alkyl, arylthio ,-C (O)-O-C
1-6-alkyl or C
1-6-alkyl-C (O)-O-C
1-6-alkyl, described each group are randomly by one or more R that are independently selected from
12Substituting group replace; Or
●-C (O)-R
27,-S (O)
2-NR
13R
14Or-S (O)
2-R
27Or
Be selected from R
3, R
4, R
5And R
6Or R
30, R
31, R
32And R
33Two substituting groups, they are connected to form with same atom or adjacent atom-O-(CH together
2)
1-3-O-.
Embodiment 135. is according to the compound of embodiment 134, wherein R
3, R
4, R
5, R
6, R
30, R
31, R
32And R
33Be independently selected from:
● halogen ,-CF
3Or
● methyl, ethyl, propyl group, sec.-propyl, butyl, the tertiary butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, benzyl, phenyl-ethyl, methoxyl group, oxyethyl group, propoxy-, thiophenyl ,-C (O)-O-CH
3Or-C (O)-O-CH
2CH
3, described each group is randomly by one or more R that are independently selected from
12Substituting group replace; Or
●-C (O)-R
27,-S (O)
2-NR
13R
14Or-S (O)
2-R
27Or
Be selected from R
3, R
4, R
5And R
6Or R
30, R
31, R
32And R
33Two substituting groups, they are connected to form with same atom or adjacent atom-O-(CH together
2)
1-3-O-.
Embodiment 136. is according to the compound of embodiment 135, wherein R
3, R
4, R
5, R
6, R
30, R
31, R
32And R
33Be independently selected from:
● halogen ,-CF
3Or
● methyl, ethyl, propyl group, sec.-propyl, butyl, the tertiary butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, benzyl, phenyl-ethyl, methoxyl group, oxyethyl group, propoxy-, thiophenyl ,-C (O)-O-CH
3Or-C (O)-O-CH
2CH
3, described each group is randomly by one or more R that are independently selected from
12Substituting group replace; Or
●-C (O)-R
27,-S (O)
2-NR
13R
14Or-S (O)
2-R
27
Embodiment 137. is according to the compound of embodiment 136, wherein R
3, R
4, R
5, R
6, R
30, R
31, R
32And R
33Be independently selected from F, Cl ,-CF
3, methyl, ethyl, propyl group, sec.-propyl, butyl, the tertiary butyl, methoxyl group, oxyethyl group, propoxy-,-C (O)-R
27,-S (O)
2-NR
13R
14Or-S (O)
2-R
27
Embodiment 138. is according to each compound among the embodiment 97-137, wherein R
12For halogen, cyano group, hydroxyl, carboxyl ,-CF
3, C
1-6-alkoxyl group, C
3-8-cycloalkyloxy, aryloxy, aryl-C
1-6-alkoxyl group or C
1-6-alkyl.
Embodiment 139. is according to the compound of embodiment 138, wherein R
12For halogen, cyano group, hydroxyl, carboxyl ,-CF
3, methoxyl group, oxyethyl group, propoxy-, ring propoxy-, cyclobutoxy group, cyclopentyloxy, cyclohexyloxy, ring oxygen in heptan base, phenoxy group, phenyl-methoxyl group, phenyl-oxyethyl group, phenyl-propoxy-, methyl, ethyl or propyl group.
Embodiment 140. is according to the compound of embodiment 139, wherein R
12Be halogen, carboxyl, oxyethyl group, propoxy-, ring propoxy-, cyclobutoxy group, cyclopentyloxy, cyclohexyloxy, ring oxygen in heptan base, phenoxy group, phenyl-methoxyl group, phenyl-oxyethyl group, phenyl-propoxy-, methyl, ethyl or propyl group.
Embodiment 141. is according to each compound among the embodiment 97-140, wherein R
10And R
11Be independently H, methyl, ethyl, propyl group ,-C (O)-CH
3,-C (O)-CH
2CH
3,-CH
2C (O) OH ,-CH
2CH
2C (O) OH ,-C (O)-CH
2-C (O) OH ,-C (O)-CH
2CH
2-C (O) OH ,-S (O)
2CH
3Or phenyl.
Embodiment 142. is according to the compound of embodiment 141, wherein R
10And R
11Be independently H, methyl, ethyl ,-C (O)-CH
3,-CH
2C (O) OH ,-C (O)-CH
2-C (O) OH ,-S (O)
2CH
3Or phenyl.
Embodiment 143. is according to the compound of embodiment 142, wherein R
10And R
11Be H, methyl, ethyl or phenyl independently.
Embodiment 144. is according to each compound among the embodiment 97-143, wherein R
27Be C
1-6-alkyl, C
1-6-alkoxyl group, C
2-6-thiazolinyl, C
2-6-alkynyl, C
3-8-cycloalkyl, C
3-8-cycloalkyl-C
1-6-alkyl, aryl, aryl-C
1-6-alkyl, aryl-C
2-6-thiazolinyl, heteroaryl, heteroaryl-C
1-6-alkyl, carboxyl-C
1-6-alkyl, C
1-6-alkoxy-C
1-6-alkyl, C
1-6-alkylthio-C
1-6-alkyl, R
10HN-C
1-6-alkyl, R
10R
11N-C
1-6-alkyl, R
10R
11N-S (O)
2-C
1-6-alkyl or R
10R
11N-C (O)-C
1-6-alkyl, described each group are randomly by one or more R that are independently selected from
12Substituting group replace.
Embodiment 145. is according to the compound of embodiment 144, wherein R
27Be C
1-6-alkyl, C
1-6-alkoxyl group, C
3-8-cycloalkyl, C
3-8-cycloalkyl-C
1-6-alkyl, aryl-C
2-6-thiazolinyl, aryl, heteroaryl, heteroaryl-C
1-6-alkyl, carboxyl-C
1-6-alkyl, carboxyl-C
1-6-alkyl, C
1-6-alkoxy-C
1-6-alkyl, R
10HN-C
1-6-alkyl, R
10R
11N-C
1-6-alkyl, R
10R
11N-S (O)
2-C
1-6-alkyl or R
10R
11N-C (O)-C
1-6-alkyl, described each group are randomly by one or more R that are independently selected from
12Substituting group replace.
Embodiment 146. is according to the compound of embodiment 145, wherein R
27Be C
1-6-alkyl, C
1-6-alkoxyl group, C
3-8-cycloalkyl, C
3-8-cycloalkyl-C
1-6-alkyl, aryl, heteroaryl-C
1-6-alkyl, aryl-C
1-6-alkyl, C
1-6-alkoxy-C
1-6-alkyl, carboxyl-C
1-6-alkyl or heteroaryl, described each group are randomly by one or more R that are independently selected from
12Substituting group replace.
Embodiment 147. is according to the compound of embodiment 146, wherein R
27Be methyl, ethyl, propyl group, normal-butyl, isobutyl-, 1,1,1-trifluoroethyl, cyclopropyl, cyclopentyl, cyclopropyl methyl, phenyl, pyridyl, thienyl, imidazolyl or thiazolyl, described each group are randomly by one or more R that are independently selected from
12Substituting group replace.
Embodiment 148. is according to the compound of embodiment 147, wherein R
27Be methyl, ethyl, propyl group, normal-butyl, isobutyl-, 1,1,1-trifluoroethyl, cyclopropyl, cyclopentyl, cyclopropyl methyl, phenyl or pyridyl, thienyl, imidazolyl or thiazolyl.
Embodiment 149. is according to the compound of embodiment 148, wherein R
27Be methyl, ethyl or propyl group.
Embodiment 150. is according to each compound among the embodiment 97-149, wherein R
13And R
14Be independently selected from: H, C
1-6-alkyl, hydroxyl-C
1-6-alkyl, carboxyl-C
1-6-alkyl, phenyl or naphthyl, described each group are randomly by one or more R that are independently selected from
15Substituting group replace; Perhaps R
13And R
14Form the 3-8 unit heterocycle with described nitrogen-atoms with the nitrogen-atoms that they connected, this heterocycle randomly contains one or two extra heteroatoms that is selected from nitrogen, oxygen and sulphur.
Embodiment 151. is according to the compound of embodiment 150, wherein R
13And R
14Be independently selected from: H, methyl, ethyl, propyl group, hydroxyl-methyl, hydroxyl-ethyl, carboxyl-methyl, carboxyl-ethyl, phenyl or naphthyl, described each group are randomly by one or more R that are independently selected from
15Substituting group replace; Perhaps R
13And R
14Form the 3-8 unit heterocycle with described nitrogen-atoms with the nitrogen-atoms that they connected, this heterocycle randomly contains one or two extra heteroatoms that is selected from nitrogen, oxygen and sulphur.
Embodiment 152. is according to the compound of embodiment 151, wherein R
13And R
14Be independently selected from: H, methyl, ethyl, propyl group or phenyl, described each group are randomly by one or more R that are independently selected from
15Substituting group replace.
Embodiment 153. is according to each compound among the embodiment 97-152, wherein R
15For H, cyano group, hydroxyl, carboxyl ,-CF
3, methyl, ethyl or propyl group.
Embodiment 154. is according to the compound of embodiment 153, wherein R
15For H, hydroxyl, carboxyl ,-CF
3, methyl or ethyl.
Embodiment 155. is according to each compound among the embodiment 97-154, wherein R
16For-NR
19R
20,-NHS (O)
2CF
3,-NHS (O)
2CH
2CF
3Or-C (O) NR
19R
20
Embodiment 156. is according to each compound among the embodiment 97-155, wherein R
20Representative is randomly by one or more R that are independently selected from
24The C that replaces of substituting group
3-8-cycloalkyl.
Embodiment 157. is according to each compound among the embodiment 97-156, wherein R
21Be selected from:
● C
3-8-cycloalkyl, C
3-8-cycloalkyl-C
1-6-alkyl, carboxyl-C
1-6-alkyl, hydroxyl-C
1-6-alkyl or-C
1-6-alkyl-NR
22R
23, they are by one or more R that are independently selected from
24Substituting group replace.
Embodiment 158. is according to the compound of embodiment 157, wherein R
21Be C
3-8-cycloalkyl.
Embodiment 159. is according to each compound among the embodiment 97-158, wherein R
22And R
23Be independently selected from H, C
1-6-alkyl, carboxyl-C
1-6-alkyl, hydroxyl-C
1-6-alkyl ,-C
1-6-alkyl-C (O)-O-C
1-6-alkyl ,-C (O)-O-C
1-6-alkyl, C
3-8-cycloalkyl, phenyl, naphthyl, perhaps R
22And R
23Form the 3-8 unit heterocycle with described nitrogen-atoms with the nitrogen-atoms that they connected, this heterocycle randomly contains one or two extra heteroatoms that is selected from nitrogen, oxygen and sulphur, and described heterocycle is randomly by one or more R that are independently selected from
24Substituting group replace.
Embodiment 160. is according to the compound of embodiment 159, wherein R
22And R
23Be independently selected from H, methyl, ethyl, propyl group, butyl, carboxymethyl, propyloic, carboxylic propyl group, methylol, hydroxyethyl, hydroxypropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, phenyl, naphthyl, perhaps R
22And R
23Form the 3-8 unit heterocycle with described nitrogen-atoms with the nitrogen-atoms that they connected, wherein said heterocycle is pyrrolidyl, piperidyl, piperazinyl, high piperazinyl or morpholinyl, and described heterocycle is randomly by one or more R that are independently selected from
24Substituting group replace.
Embodiment 161. is according to the compound of embodiment 160, wherein R
22And R
23Form the 3-8 unit heterocycle with described nitrogen-atoms with the nitrogen-atoms that they connected, wherein said heterocycle is pyrrolidyl, piperidyl, piperazinyl, high piperazinyl or morpholinyl, and described heterocycle is randomly by one or more R that are independently selected from
24Substituting group replace.
Embodiment 162. is according to the compound of embodiment 160, wherein R
22And R
23Be H, methyl, ethyl or propyl group independently.
Embodiment 163. is according to each compound among the embodiment 97-162, wherein R
24For halogen, hydroxyl, carboxyl, oxo ,-CF
3, C
1-6-alkyl, hydroxyl-C
1-6-alkyl, carboxyl-C
1-6-alkyl ,-C (O)-C
1-6-alkyl ,-C (O)-O-C
1-6-alkyl ,-C
1-6-alkyl-C (O)-O-C
1-6-alkyl, aryl, heteroaryl, aryl-C
1-6-alkyl, heteroaryl-C
1-6-alkyl, C
3-8-cycloalkyl, C
3-8-heterocyclic radical, C
3-8-cycloalkyl-C
1-6-alkyl, C
3-8-heterocyclic radical-C
1-6-alkyl ,-C (O)-O-C
1-6-alkyl-aryl or-S (O)
2R
28, wherein aryl is a phenyl or naphthyl, and heteroaryl is pyridyl or pyrimidyl, and wherein each loop section is all randomly by one or more R that are independently selected from
29Substituting group replace.
Embodiment 164. is according to the compound of embodiment 163, wherein R
24For halogen, hydroxyl, carboxyl, oxo ,-CF
3, C
1-6-alkyl, hydroxyl-C
1-6-alkyl, carboxyl-C
1-6-alkyl ,-C (O)-C
1-6-alkyl ,-C (O)-O-C
1-6-alkyl, aryl, heteroaryl, aryl-C
1-6-alkyl, heteroaryl-C
1-6-alkyl, C
3-8-cycloalkyl, C
3-8-heterocyclic radical, C
3-8-cycloalkyl-C
1-6-alkyl, C
3-8-heterocyclic radical-C
1-6-alkyl or-S (O)
2R
28, wherein aryl is a phenyl or naphthyl, and heteroaryl is pyridyl or pyrimidyl, and wherein each loop section is all randomly by one or more R that are independently selected from
29Substituting group replace.
Embodiment 165. is according to the compound of embodiment 164, wherein R
24For halogen, carboxyl, oxo ,-CF
3, C
1-6-alkyl, carboxyl-C
1-6-alkyl ,-C (O)-C
1-6-alkyl ,-C (O)-O-C
1-6-alkyl, aryl, aryl-C
1-6-alkyl, C
3-8-cycloalkyl, C
3-8-heterocyclic radical, C
3-8-heterocyclic radical-C
1-6-alkyl or-S (O)
2R
28, wherein aryl is a phenyl or naphthyl, wherein each loop section is all randomly by one or more R that are independently selected from
29Substituting group replace.
Embodiment 166. is according to the compound of embodiment 165, wherein R
24Be carboxyl, oxo, C
1-6-alkyl, carboxyl-C
1-6-alkyl ,-C (O)-C
1-6-alkyl, aryl, aryl-C
1-6-alkyl, C
3-8-cycloalkyl, C
3-8-heterocyclic radical, C
3-8-heterocyclic radical-C
1-6-alkyl or-S (O)
2R
28, wherein aryl is a phenyl or naphthyl, wherein each loop section is all randomly by one or more R that are independently selected from
29Substituting group replace.
Embodiment 167. is according to the compound of embodiment 166, wherein R
24Be carboxyl.
Embodiment 168. is according to each compound among the embodiment 97-167, wherein R
25Be C independently
1-6-alkyl, halogen, hydroxyl, carboxyl or-CF
3
Embodiment 169. is according to the compound of embodiment 168, wherein R
25Be independently methyl, ethyl, propyl group, halogen, hydroxyl, carboxyl or-CF
3
Embodiment 170. is according to each compound among the embodiment 97-169, wherein R
28Be C
1-6-alkyl ,-C
1-6-alkyl-C (O)-O-C
1-6-alkyl, carboxyl-C
1-6-alkyl, phenyl, phenyl-C
1-6-alkyl, randomly by C
1-6The heteroaryl that-alkyl replaces or-N (CH
3)
2, wherein heteroaryl is imidazolyl, pyridyl or pyrimidyl.
Embodiment 171. is according to the compound of embodiment 170, wherein R
28Be C
1-6-alkyl, carboxyl-C
1-6-alkyl or-N (CH
3)
2
Embodiment 172. is according to each compound among the embodiment 97-171, wherein R
29For halogen, carboxyl ,-CF
3, C
1-6-alkyl or C
1-6-alkoxyl group.
On the one hand, the invention provides a kind of compound, described compound is:
(1) 1,1-two cyclopentyl-3-thiazol-2-yl-urea
(2) 1-cyclopentyl-1-((R, S)-3,5-dimethyl-cyclohexyl)-3-thiazol-2-yl-urea
(3) 1-(1,4-two oxa-s-spiral shell [4.5] last of the ten Heavenly stems-8-yl)-1-(4-methyl-cyclohexyl base)-3-thiazol-2-yl-urea
(4) 1-cyclopentyl-1-(1,4-two oxa-s-spiral shell [4.5] last of the ten Heavenly stems-8-yl)-3-thiazol-2-yl-urea
(5) 1-(4-methyl-cyclohexyl base)-3-(5-methyl-thiazol-2-yl)-1-(4-oxo-cyclohexyl)-urea
(6) 2-[3-dicyclohexyl urea groups]-5-[4-methylpiperazine-1-yl]-thiazole-4-yl }-ethyl acetate
(7) 1,1-dicyclohexyl-3-(5-imidazoles-1-base-thiazol-2-yl)-urea
(8) 3-(5-chloro-thiazol-2-yl)-1,1-pair-(tetrahydrochysene-pyrans-4-yl)-urea
(9) 3-[2-(3,3-dicyclohexyl-urea groups)-thiazole-4-methylthiol]-propionic acid
(10) [2-(3,3-dicyclohexyl-urea groups)-thiazole-4-base methylsulfonyl]-acetate
(11) 1-(4-amino-cyclohexyl)-1-cyclohexyl-3-(5-methyl-thiazol-2-yl)-urea
(12) 1-(1-ethanoyl-piperidin-4-yl)-1-cyclopentyl-3-thiazol-2-yl-urea
(13) trans-3-(5-chloro-thiazol-2-yl)-1-cyclohexyl-1-[1-(3-phenyl-acryl)-piperazine fixed-the 4-yl]-urea
(14) 3-(5-chloro-thiazol-2-yl)-1-cyclohexyl-1-[1-(2-phenoxy group-ethanoyl)-piperidin-4-yl]-urea
(15) 1-(1-ethanoyl-piperidin-4-yl)-3-(5-chloro-thiazol-2-yl)-1-suberyl-urea
(16) 3-(5-chloro-thiazol-2-yl)-1-(1-methylsulfonyl-piperidin-4-yl)-1-(trans-4-methyl-cyclohexyl base)-urea
(17) 3-(5-chloro-thiazol-2-yl)-1-(1-ethylsulfonyl-piperidin-4-yl)-1-(trans-4-methyl-cyclohexyl base)-urea
(18) 3-(5-chloro-thiazol-2-yl)-1-cyclohexyl-1-[1-(third-1-alkylsulfonyl)-piperidin-4-yl]-urea
(19) 2-[2-(3,3-dicyclohexyl-urea groups)-thiazole-5-base sulfenyl]-2-methyl-propionic acid
(20) 2-[2-(3,3-dicyclohexyl-urea groups)-thiazole-5-base sulfenyl]-propionic acid
(21) [2-(3-hexamethylene-3-thiazolinyl-3-cyclohexyl-urea groups)-thiazole-5-base sulfenyl]-acetate
(22) 2-[3-cyclohexyl-3-(1-dimethylamino alkylsulfonyl-piperidin-4-yl)-urea groups]-thiazole-5-base sulfenyl }-acetate
(23) 3-(2-{3-cyclohexyl-3-[1-(morpholine-4-carbonyl)-piperidin-4-yl]-urea groups-thiazole-5-base sulfenyl)-propionic acid
(24) (2-{3-cyclohexyl-3-[1-(morpholine-4-carbonyl)-piperidin-4-yl]-urea groups }-thiazole-5-base sulfenyl)-acetate
(25) 3-{2-[3-cyclohexyl-3-(1-dimethylamino alkylsulfonyl-piperidin-4-yl)-urea groups]-thiazole-5-base sulfenyl }-propionic acid
(26) 2-[3-cyclohexyl-3-(1-formyl-dimethylamino-piperidin-4-yl)-urea groups]-thiazole-5-base sulfenyl }-acetate
(27) 3-{2-[3-cyclohexyl-3-(1-formyl-dimethylamino-piperidin-4-yl)-urea groups]-thiazole-5-base sulfenyl }-propionic acid
(28) 6-{4-[3-(5-chloro-thiazol-2-yl)-1-cyclohexyl-urea groups]-piperidines-1-yl }-the 6-oxo-oneself-the 3-olefin(e) acid
(29) 1-(1-ethanoyl-piperidin-4-yl)-1-(trans-4-methyl-cyclohexyl base)-3-[5-(2-oxo-2-piperidines-1-base-ethylmercapto group)-thiazol-2-yl]-urea
(30) 2-{2-[3-(1-ethanoyl-piperidin-4-yl)-3-(trans-4-methyl-cyclohexyl base)-urea groups]-thiazole-5-base sulfenyl }-N, N-diethyl-ethanamide
(31) 1-(1-ethanoyl-piperidin-4-yl)-1-(trans-4-methyl-cyclohexyl base)-3-{5-[2-(4-methyl-piperazine-1-yl)-2-oxo-ethylmercapto group]-thiazol-2-yl }-urea
(32) 1-(1-ethanoyl-piperidin-4-yl)-1-(trans-4-methyl-cyclohexyl base)-3-{5-[2-oxo-2-(4-pyrimidine-2-base-piperazine-1-yl)-ethylmercapto group]-thiazol-2-yl }-urea
(33) 1-(1-ethanoyl-piperidin-4-yl)-1-(trans-4-methyl-cyclohexyl base)-3-thiazol-2-yl-urea
(34) 2-[3-cyclohexyl-3-(trans-4-methoxymethyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate
(35) 2-[3-cyclopentyl-3-(trans-4-ethyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate
(36) 2-[3-cyclopentyl-3-(trans-4-sec.-propyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate
(37) 3-{2-[3-cyclopentyl-3-(trans-4-ethyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-propionic acid
(38) 3-{2-[3-cyclopentyl-3-(trans-4-sec.-propyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-propionic acid
(39) 2-[3-cyclohexyl-3-(trans-4-ethoxyl methyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate
(40) 2-[3-cyclopentyl-3-(trans-4-methoxyl group-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate
(41) 2-[3-suberyl-3-(trans-4-methoxyl group-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate
(42) 2-[3-cyclopentyl-3-(trans-4-oxyethyl group-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate
(43) 2-[3-cyclohexyl-3-(trans-4-oxyethyl group-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate
(44) 2-[3-suberyl-3-(trans-4-oxyethyl group-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate
(45) 3-{2-[3-cyclohexyl-3-(trans-4-methoxymethyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-propionic acid
(46) 2-[3-(trans-the 4-tertiary butyl-cyclohexyl)-3-cyclopentyl-urea groups]-thiazole-5-base sulfenyl }-acetate
(47) 2-[3-(trans-the 4-tertiary butyl-cyclohexyl)-3-cyclohexyl-urea groups]-thiazole-5-base sulfenyl }-acetate
(48) 2-[3-is trans-the 4-tertiary butyl-cyclohexyl)-3-suberyl-urea groups]-thiazole-5-base sulfenyl }-acetate
(49) 2-[3-suberyl-3-(trans-4-methoxymethyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate
(50) 3-{2-[3-suberyl-3-trans-4-methoxymethyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl-propionic acid
(51) 3-{2-[3-cyclohexyl-3-(trans-4-ethoxyl methyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-propionic acid
(52) 3-{2-[3-(trans-the 4-tertiary butyl-cyclohexyl)-3-cyclopentyl-urea groups]-thiazole-5-base sulfenyl }-propionic acid
(53) 3-{2-[3-(trans-the 4-tertiary butyl-cyclohexyl)-3-cyclohexyl-urea groups]-thiazole-5-base sulfenyl }-propionic acid
(54) 3-{2-[3-(trans-the 4-tertiary butyl-cyclohexyl)-3-suberyl-urea groups]-thiazole-5-base sulfenyl }-propionic acid
(55) 2-{2-[3-(trans-the 4-tertiary butyl-cyclohexyl)-3-cyclopentyl-urea groups]-thiazole-5-base sulfenyl }-2-methyl-propionic acid
(56) 2-{2-[3-(trans-the 4-tertiary butyl-cyclohexyl)-3-cyclohexyl-urea groups]-thiazole-5-base sulfenyl }-2-methyl-propionic acid
(57) 2-[3-suberyl-3-(trans-4-ethoxyl methyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate
(58) 2-[3-cyclohexyl-3-(trans-4-cyclo propyl methoxy-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate
(59) 3-{2-[-3-cyclohexyl-3-(trans-4-cyclo propyl methoxy-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-propionic acid
(60) 3-{2-[3-cyclopentyl-3-(trans-4-methoxyl group-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-propionic acid
(61) 3-{2-[3-cyclohexyl-3-(trans-4-methoxyl group-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-propionic acid
(62) 3-{2-[3-suberyl-3-(trans-4-methoxyl group-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-propionic acid
(63) 3-{2-[3-cyclopentyl-3-(trans-4-oxyethyl group-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-propionic acid
(64) 3-{2-[3-cyclohexyl-3-(trans-4-oxyethyl group-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-propionic acid
(65) 3-{2-[3-suberyl-3-(trans-4-oxyethyl group-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-propionic acid
(66) (2-{3-cyclohexyl-3-[is trans-4-(2-methoxyl group-oxyethyl group)-cyclohexyl]-urea groups }-thiazole-5-base sulfenyl)-acetate
(67) 3-(2-{3-cyclohexyl-3-[is trans-4-(2-methoxyl group-oxyethyl group)-cyclohexyl]-urea groups-thiazole-5-base sulfenyl)-propionic acid
(68) 2-[3-cyclopentyl-3-(trans-4-methoxymethyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate
(69) 3-{2-[3-suberyl-3-(trans-4-ethoxyl methyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-propionic acid
(70) 3-{2-[3-cyclopentyl-3-(trans-4-methoxymethyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-propionic acid
(71) 2-{2-[3-cyclohexyl-3-(trans-4-cyclo propyl methoxy-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-2-methyl-propionic acid
(72) 2-(2-{3-cyclohexyl-3-[is trans-4-(2-methoxyl group-oxyethyl group)-cyclohexyl]-urea groups-thiazole-5-base sulfenyl)-2-methyl-propionic acid
(73) [2-(3,3-dicyclohexyl-urea groups)-thiazole-5-sulfonamido]-acetate
(74) 2-[3-(1-ethanoyl-piperidin-4-yl)-3-cyclohexyl-urea groups]-thiazole-5-sulfonamido }-acetate
(75) 2-{2-[3-suberyl-3-(trans-4-ethoxyl methyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-2-methyl-propionic acid
(76) 2-{2-[3-suberyl-3-(trans-4-methoxymethyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-2-methyl-propionic acid
(77) 2-[3-cyclohexyl-3-(trans-4-methyl-cyclohexyl base)-urea groups]-thiazole-5-sulfonamido }-acetate
(78) 3-[2-(3,3-dicyclohexyl-urea groups)-thiazole-5-sulfonamido]-propionic acid
(79) 3-{2-[3-cyclohexyl-3-(trans-4-methyl-cyclohexyl base)-urea groups]-thiazole-5-sulfonamido }-propionic acid
(80) { [2-(3,3-dicyclohexyl-urea groups)-thiazole-5-alkylsulfonyl]-methyl-amino }-acetate
(81) (2-[3-cyclohexyl-3-(trans-4-methyl-cyclohexyl base)-urea groups]-thiazole-5-alkylsulfonyl }-methyl-amino)-acetate
(82) (S)-1-[2-(3,3-dicyclohexyl-urea groups)-thiazole-5-alkylsulfonyl]-tetramethyleneimine-2-formic acid
(83) (S)-1-{2-[3-cyclohexyl-3-(trans-4-methyl-cyclohexyl base)-urea groups]-thiazole-5-alkylsulfonyl }-tetramethyleneimine-2-formic acid
(84) 2-[3-suberyl-3-(trans-4-propoxy--cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate
(85) 2-[3-cyclopentyl-3-(trans-4-propoxy--cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate
(86) 2-[3-cyclohexyl-3-(trans-4-isobutoxy-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate
(87) 2-{2-[3-cyclohexyl-3-(trans-4-propoxy--cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-2-methyl-propionic acid
(88) 3-{2-[3-cyclohexyl-3-(trans-4-isobutoxy-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-propionic acid
(89) 3-{2-[3-suberyl-3-(trans-4-propoxy--cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-propionic acid
(90) 3-{2-[3-cyclopentyl-3-(trans-4-propoxy--cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-propionic acid
(91) 2-{2-[3-cyclohexyl-3-(trans-4-ethoxyl methyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-2-methyl-propionic acid
(92) 2-[3-cyclohexyl-3-(trans-4-phenyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate
(93) 3-{2-[3-cyclohexyl-3-(trans-4-phenyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-propionic acid
(94) 2-[3-suberyl-3-(trans-4-phenyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate
(95) 3-{2-[3-suberyl-3-(trans-4-phenyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-propionic acid
(96) 2-{2-[3-cyclohexyl-3-(4-phenyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-2-methyl-propionic acid
(97) 2-{2-[3-suberyl-3-(4-phenyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-2-methyl-propionic acid
(98) (E)-6-[4-(1-cyclohexyl-3-thiazol-2-yl-urea groups)-piperidines-1-yl]-the 6-oxo-oneself-the 3-olefin(e) acid
(99) 2-[3-cyclohexyl-3-(trans-4-sec.-propyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate
(100) 2-[3-suberyl-3-(trans-4-sec.-propyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate
(101) 2-[3-cyclohexyl-3-(trans-4-ethyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate
(102) 2-[3-cyclohexyl-3-(trans-4-propoxy--cyclohexyl)-urea groups]-thiazole-5-sulfonamido }-acetate
(103) 3-{2-[3-cyclohexyl-3-(trans-4-propoxy--cyclohexyl)-urea groups]-thiazole-5-sulfonamido }-propionic acid
(104) (2-[3-cyclohexyl-3-(trans-4-propoxy--cyclohexyl)-urea groups]-thiazole-5-alkylsulfonyl }-methyl-amino)-acetate
(105) 2-[3-(trans-4-tert.-butoxy-cyclohexyl)-3-suberyl-urea groups]-thiazole-5-base sulfenyl }-acetate
(106) 2-[3-(trans-4-tert.-butoxy-cyclohexyl)-3-cyclohexyl-urea groups]-thiazole-5-base sulfenyl }-acetate
(107) 3-{2-[3-(trans-4-tert.-butoxy-cyclohexyl)-3-suberyl-urea groups]-thiazole-5-base sulfenyl }-propionic acid
(108) 3-{2-[3-(trans-4-tert.-butoxy-cyclohexyl)-3-cyclohexyl-urea groups]-thiazole-5-base sulfenyl }-propionic acid
(109) 2-[3-(trans-4-benzyloxy-cyclohexyl)-3-cyclohexyl-urea groups]-thiazole-5-base sulfenyl }-acetate
(110) 2-[3-(trans-4-benzyloxy-cyclohexyl)-3-suberyl-urea groups]-thiazole-5-base sulfenyl }-acetate
(111) 3-{2-[3-(trans-4-benzyloxy-cyclohexyl)-3-cyclohexyl-urea groups]-thiazole-5-base sulfenyl }-propionic acid
(112) 3-{2-[3-(trans-4-benzyloxy-cyclohexyl)-3-suberyl-urea groups]-thiazole-5-base sulfenyl }-propionic acid
(113) 2-{2-[3-cyclohexyl-3-(trans-4-methyl-cyclohexyl base)-urea groups]-thiazole-5-sulfonamido }-2-methyl-propionic acid
(114) (R)-1-{2-[3-cyclohexyl-3-(trans-4-methyl-cyclohexyl base)-urea groups]-thiazole-5-alkylsulfonyl }-tetramethyleneimine-2-formic acid
(115) 2-{2-[3-cyclohexyl-3-(trans-4-propoxy--cyclohexyl)-urea groups]-thiazole-5-sulfonamido }-2-methyl-propionic acid
(116) (R)-1-{2-[3-cyclohexyl-3-(trans-4-propoxy--cyclohexyl)-urea groups]-thiazole-5-alkylsulfonyl }-tetramethyleneimine-2-formic acid
(117) 2-[3-cyclohexyl-3-(trans-4-isopropoxy-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate
(118) 2-[3-suberyl-3-(trans-4-isopropoxy-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate
(119) 3-{2-[3-cyclohexyl-3-(trans-4-isopropoxy-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-propionic acid
(120) 3-{2-[3-suberyl-3-(trans-4-isopropoxy-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-propionic acid
(121) 3-(2-{3-cyclohexyl-3-[4-(trans-2-methoxyl group-ethoxyl methyl)-cyclohexyl]-urea groups-thiazole-5-base sulfenyl)-acetate
(122) 3-(2-{3-cyclohexyl-3-[4-(trans-2-methoxyl group-ethoxyl methyl)-cyclohexyl]-urea groups-thiazole-5-base sulfenyl)-propionic acid
(123) (2-{3-suberyl-3-[4-(trans-2-methoxyl group-ethoxyl methyl)-cyclohexyl]-urea groups }-thiazole-5-base sulfenyl)-acetate
(124) 3-(2-{3-suberyl-3-[4-(trans-2-methoxyl group-ethoxyl methyl)-cyclohexyl]-urea groups-thiazole-5-base sulfenyl)-propionic acid
(125) (2-{3-cyclohexyl-3-[4-(trans-2,2,2-three fluoro-ethoxyl methyls)-cyclohexyl]-urea groups }-thiazole-5-base sulfenyl)-acetate
(126) (2-{2-[3-cyclohexyl-3-(trans-4-propoxy--cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-ethanoyl)-Toluidrin
(127) 2-(2-{3-cyclohexyl-3-[4-(trans-2-methoxyl group-ethoxyl methyl)-cyclohexyl]-urea groups-thiazole-5-base sulfenyl)-2-methyl-propionic acid
(128) 2-(2-{3-suberyl-3-[4-(trans-2-methoxyl group-ethoxyl methyl)-cyclohexyl]-urea groups-thiazole-5-base sulfenyl)-2-methyl-propionic acid
(129) 2-{2-[3-cyclohexyl-3-(trans-4-methoxymethyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-2-methyl-propionic acid
(130) 2-[3-cyclohexyl-3-(cis-4-propoxy--cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate
(131) 2-[3-cyclohexyl-3-(trans-4-phenoxy group-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate
(132) (2-{3-cyclohexyl-3-[is trans-4-(pyridine-2-base oxygen base)-cyclohexyl]-urea groups }-thiazole-5-base sulfenyl)-acetate
(133) 3-(2-{3-cyclohexyl-3-[is trans-4-(pyridine-2-base oxygen base)-cyclohexyl]-urea groups-thiazole-5-base sulfenyl)-propionic acid
(134) (2-{3-cyclohexyl-3-[is trans-4-(2,2,2-three fluoro-oxyethyl groups)-cyclohexyl]-urea groups }-thiazole-5-base sulfenyl)-acetate
(135) 2-[3-cyclohexyl-3-(trans-4-methyl-cyclohexyl base)-urea groups]-thiazole-5-N-sulfonyloxy methyl amine.
On the other hand, the invention provides a kind of compound, described compound is:
(1) 2-(3,3-dicyclohexyl urea groups)-4-methylthiazol-5-N-(2-hydroxyethyl) methane amide
(2) (2-{3-cyclohexyl-3-[-4-(2-methyl-allyloxy)-cyclohexyl]-urea groups }-thiazole-5-base sulfenyl)-acetate
(3) 3-(2-{3-cyclohexyl-3-[is trans-4-(2-methyl-allyloxy)-cyclohexyl]-urea groups-thiazole-5-base sulfenyl)-propionic acid
(4) 2-(2-{3-cyclohexyl-3-[is trans-4-(2-methyl-allyloxy)-cyclohexyl]-urea groups-thiazole-5-base sulfenyl)-2-methyl-propionic acid
(5) 2-[3-cyclohexyl-3-(trans-4-phenoxymethyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate
(6) 3-{2-[3-cyclohexyl-3-(trans-4-cyclo propyl methoxy methyl-cyclohexyl base)-urea groups]-thiazole-5-base sulfenyl }-propionic acid
(7) 3-{2-[3-suberyl-3-(trans-4-cyclo propyl methoxy methyl-cyclohexyl base)-urea groups]-thiazole-5-base sulfenyl }-propionic acid
(8) (2-{3-cyclohexyl-3-[4-(trans-4-methoxyl group-phenoxymethyl)-cyclohexyl]-urea groups }-thiazole-5-base sulfenyl)-acetate
(9) (2-{3-cyclohexyl-3-[is trans-4-(4-fluoro-phenoxymethyl)-cyclohexyl]-urea groups }-thiazole-5-base sulfenyl)-acetate
(10) (2-{3-cyclohexyl-3-[is trans-4-(4-imidazoles-1-base-phenoxymethyl)-cyclohexyl]-urea groups }-thiazole-5-base sulfenyl)-acetate
(11) 2-({ 2-[3-cyclohexyl-3-(trans-4-methyl-cyclohexyl base)-urea groups]-thiazole-5-alkylsulfonyl }-methyl-amino)-N, N-diethyl-ethanamide
(12) 1-{2-[3-cyclohexyl-3-(trans-4-methyl-cyclohexyl base)-urea groups]-thiazole-5-sulfonamido }-cyclobutane formate
(13) 1-{2-[3-cyclohexyl-3-(trans-4-methyl-cyclohexyl base)-urea groups]-thiazole-5-sulfonamido }-cyclopropane-carboxylic acid
(14) 1-{2-[3-cyclohexyl-3-(trans-4-propoxy--cyclohexyl)-urea groups]-thiazole-5-sulfonamido }-cyclobutane formate
(15) 2-[3-cyclohexyl-3-(trans-4-cyclo propyl methoxy methyl-cyclohexyl base)-urea groups]-thiazole-5-base sulfenyl }-acetate
(16) 2-[3-suberyl-3-(trans-4-cyclo propyl methoxy methyl-cyclohexyl base)-urea groups]-thiazole-5-base sulfenyl }-acetate
(17) 2-[3-(trans-4-benzyloxymethyl-cyclohexyl)-3-cyclohexyl-urea groups]-thiazole-5-base sulfenyl }-acetate
(18) 2-[3-suberyl-3-(trans-4-phenoxymethyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate
(19) (2-{3-suberyl-3-[is trans-4-(4-methoxyl group-phenoxymethyl)-cyclohexyl]-urea groups }-thiazole-5-base sulfenyl)-acetate
(20) (2-{3-suberyl-3-[is trans-4-(4-fluoro-phenoxymethyl)-cyclohexyl]-urea groups }-thiazole-5-base sulfenyl)-acetate
(21) (2-{3-suberyl-3-[is trans-4-(4-trifluoromethyl-phenoxymethyl)-cyclohexyl]-urea groups }-thiazole-5-base sulfenyl)-acetate
(22) (2-{3-cyclohexyl-3-[is trans-4-(4-trifluoromethyl-phenoxymethyl)-cyclohexyl]-urea groups }-thiazole-5-base sulfenyl)-acetate
(23) 3-{2-[3-cyclohexyl-3-(trans-4-phenoxymethyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-propionic acid
(24) 3-(2-{3-cyclohexyl-3-[is trans-4-(4-methoxyl group-phenoxymethyl)-cyclohexyl]-urea groups-thiazole-5-base sulfenyl)-propionic acid
(25) 3-(2-{3-cyclohexyl-3-[is trans-4-(4-fluoro-phenoxymethyl)-cyclohexyl]-urea groups-thiazole-5-base sulfenyl)-propionic acid
(26) 2-{2-[3-cyclohexyl-3-(trans-4-cyclo propyl methoxy methyl-cyclohexyl base)-urea groups]-thiazole-5-base sulfenyl }-2-methyl-propionic acid
(27) 2-{2-[3-cyclohexyl-3-(trans-4-methyl-cyclohexyl base)-urea groups]-thiazole-5-sulfonamido }-N, N-diethyl-ethanamide
(28) 2-{2-[3-cyclohexyl-3-(trans-4-methyl-cyclohexyl base)-urea groups]-thiazole-5-sulfonamido }-N-methyl-ethanamide
(29) 2-{2-[3-cyclohexyl-3-(trans-4-methyl-cyclohexyl base)-urea groups]-thiazole-5-sulfonamido }-N-sec.-propyl-ethanamide
(30) 2-[3-cyclohexyl-3-(trans-4-methyl-cyclohexyl base)-urea groups]-thiazole-5-N-(2-morpholine-4-base-2-oxo-ethyl)-sulphonamide.
On the other hand, the invention provides a kind of compound, described compound is:
(1) 1,1-two cyclopentyl-3-thiazol-2-yl-urea
(2) 1-cyclopentyl-1-((R, S)-3,5-dimethyl-cyclohexyl)-3-thiazol-2-yl-urea
(3) 1-(1,4-two oxa-s-spiral shell [4.5] last of the ten Heavenly stems-8-yl)-1-(4-methyl-cyclohexyl base)-3-thiazol-2-yl-urea
(4) 1-cyclopentyl-1-(1,4-two oxa-s-spiral shell [4.5] last of the ten Heavenly stems-8-yl)-3-thiazol-2-yl-urea
(5) 1-(4-methyl-cyclohexyl base)-3-(5-methyl-thiazol-2-yl)-1-(4-oxo-cyclohexyl)-urea
(6) 2-[3-dicyclohexyl urea groups]-5-[4-methylpiperazine-1-yl]-thiazole-4-yl }-ethyl acetate
(7) 1,1-dicyclohexyl-3-(5-imidazoles-1-base-thiazol-2-yl)-urea
(8) 3-(5-chloro-thiazol-2-yl)-1,1-pair-(tetrahydrochysene-pyrans-4-yl)-urea
(9) 3-[2-(3,3-dicyclohexyl-urea groups)-thiazole-4-methylthiol]-propionic acid
(10) [2-(3,3-dicyclohexyl-urea groups)-thiazole-4-base methylsulfonyl]-acetate
(11) 1-(4-amino-cyclohexyl)-1-cyclohexyl-3-(5-methyl-thiazol-2-yl)-urea
(12) 1-(1-ethanoyl-piperidin-4-yl)-1-cyclopentyl-3-thiazol-2-yl-urea
(13) trans-3-(5-chloro-thiazol-2-yl)-1-cyclohexyl-1-[1-(3-phenyl-acryl)-piperidin-4-yl]-urea
(14) 3-(5-chloro-thiazol-2-yl)-1-cyclohexyl-1-[1-(2-phenoxy group-ethanoyl)-piperidin-4-yl]-urea
(15) 1-(1-ethanoyl-piperidin-4-yl)-3-(5-chloro-thiazol-2-yl)-1-suberyl-urea
(16) 3-(5-chloro-thiazol-2-yl)-1-(1-methylsulfonyl-piperidin-4-yl)-1-(trans-4-methyl-cyclohexyl base)-urea
(17) 3-(5-chloro-thiazol-2-yl)-1-(1-ethylsulfonyl-piperidin-4-yl)-1-(trans-4-methyl-cyclohexyl base)-urea
(18) 3-(5-chloro-thiazol-2-yl)-1-cyclohexyl-1-[1-(third-1-alkylsulfonyl)-piperidin-4-yl]-urea
(19) 2-[2-(3,3-dicyclohexyl-urea groups)-thiazole-5-base sulfenyl]-2-methyl-propionic acid
(20) 2-[2-(3,3-dicyclohexyl-urea groups)-thiazole-5-base sulfenyl]-propionic acid
(21) [2-(3-hexamethylene-3-thiazolinyl-3-cyclohexyl-urea groups)-thiazole-5-base sulfenyl]-acetate
(22) 2-[3-cyclohexyl-3-(1-dimethylamino alkylsulfonyl-piperidin-4-yl)-urea groups]-thiazole-5-base sulfenyl }-acetate
(23) 3-(2-{3-cyclohexyl-3-[1-(morpholine-4-carbonyl)-piperidin-4-yl]-urea groups-thiazole-5-base sulfenyl)-propionic acid
(24) (2-{3-cyclohexyl-3-[1-(morpholine-4-carbonyl)-piperidin-4-yl]-urea groups }-thiazole-5-base sulfenyl)-acetate
(25) 3-{2-[3-cyclohexyl-3-(1-dimethylamino alkylsulfonyl-piperidin-4-yl)-urea groups]-thiazole-5-base sulfenyl }-propionic acid
(26) 2-[3-cyclohexyl-3-(1-formyl-dimethylamino-piperidin-4-yl)-urea groups]-thiazole-5-base sulfenyl }-acetate
(27) 3-{2-[3-cyclohexyl-3-(1-formyl-dimethylamino-piperidin-4-yl)-urea groups]-thiazole-5-base sulfenyl }-propionic acid
(28) 6-{4-[3-(5-chloro-thiazol-2-yl)-1-cyclohexyl-urea groups]-piperidines-1-yl }-the 6-oxo-oneself-the 3-olefin(e) acid
(29) 1-(1-ethanoyl-piperidin-4-yl)-1-(trans-4-methyl-cyclohexyl base)-3-[5-(2-oxo-2-piperidines-1-base-ethylmercapto group)-thiazol-2-yl]-urea
(30) 2-{2-[3-(1-ethanoyl-piperidin-4-yl)-3-(trans-4-methyl-cyclohexyl base)-urea groups]-thiazole-5-base sulfenyl }-N, N-diethyl-ethanamide
(31) 1-(1-ethanoyl-piperidin-4-yl)-1-(trans-4-methyl-cyclohexyl base)-3-{5-[2-(4-methyl-piperazine-1-yl)-2-oxo-ethylmercapto group]-thiazol-2-yl }-urea
(32) 1-(1-ethanoyl-piperidin-4-yl)-1-(trans-4-methyl-cyclohexyl base)-3-{5-[2-oxo-2-(4-pyrimidine-2-base-piperazine-1-yl)-ethylmercapto group]-thiazol-2-yl }-urea
(33) 1-(1-ethanoyl-piperidin-4-yl)-1-(trans-4-methyl-cyclohexyl base)-3-thiazol-2-yl-urea
(34) 2-[3-cyclohexyl-3-(trans-4-methoxymethyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate
(35) 2-[3-cyclopentyl-3-(trans-4-ethyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate
(36) 2-[3-cyclopentyl-3-(trans-4-sec.-propyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate
(37) 3-{2-[3-cyclopentyl-3-(trans-4-ethyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-propionic acid
(38) 3-{2-[3-cyclopentyl-3-(trans-4-sec.-propyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-propionic acid
(39) 2-[3-cyclohexyl-3-(trans-4-ethoxyl methyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate
(40) 2-[3-cyclopentyl-3-(trans-4-methoxyl group-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate
(41) 2-[3-suberyl-3-(trans-4-methoxyl group-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate
(42) 2-[3-cyclopentyl-3-(trans-4-oxyethyl group-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate
(43) 2-[3-cyclohexyl-3-(trans-4-oxyethyl group-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate
(44) 2-[3-suberyl-3-(trans-4-oxyethyl group-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate
(45) 3-{2-[3-cyclohexyl-3-(trans-4-methoxymethyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-propionic acid
(46) 2-[3-(trans-the 4-tertiary butyl-cyclohexyl)-3-cyclopentyl-urea groups]-thiazole-5-base sulfenyl }-acetate
(47) 2-[3-(trans-the 4-tertiary butyl-cyclohexyl)-3-cyclohexyl-urea groups]-thiazole-5-base sulfenyl }-acetate
(48) 2-[3-is trans-the 4-tertiary butyl-cyclohexyl)-3-suberyl-urea groups]-thiazole-5-base sulfenyl }-acetate
(49) 2-[3-suberyl-3-(trans-4-methoxymethyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate
(50) 3-{2-[3-suberyl-3-trans-4-methoxymethyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl-propionic acid
(51) 3-{2-[3-cyclohexyl-3-(trans-4-ethoxyl methyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-propionic acid
(52) 3-{2-[3-(trans-the 4-tertiary butyl-cyclohexyl)-3-cyclopentyl-urea groups]-thiazole-5-base sulfenyl }-propionic acid
(53) 3-{2-[3-(trans-the 4-tertiary butyl-cyclohexyl)-3-cyclohexyl-urea groups]-thiazole-5-base sulfenyl }-propionic acid
(54) 3-{2-[3-(trans-the 4-tertiary butyl-cyclohexyl)-3-suberyl-urea groups]-thiazole-5-base sulfenyl }-propionic acid
(55) 2-{2-[3-(trans-the 4-tertiary butyl-cyclohexyl)-3-cyclopentyl-urea groups]-thiazole-5-base sulfenyl }-2-methyl-propionic acid
(56) 2-{2-[3-(trans-the 4-tertiary butyl-cyclohexyl)-3-cyclohexyl-urea groups]-thiazole-5-base sulfenyl }-2-methyl-propionic acid
(57) 2-[3-suberyl-3-(trans-4-ethoxyl methyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate
(58) 2-[3-cyclohexyl-3-(trans-4-cyclo propyl methoxy-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate
(59) 3-{2-[-3-cyclohexyl-3-(trans-4-cyclo propyl methoxy-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-propionic acid
(60) 3-{2-[3-cyclopentyl-3-(trans-4-methoxyl group-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-propionic acid
(61) 3-{2-[3-cyclohexyl-3-(trans-4-methoxyl group-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-propionic acid
(62) 3-{2-[3-suberyl-3-(trans-4-methoxyl group-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-propionic acid
(63) 3-{2-[3-cyclopentyl-3-(trans-4-oxyethyl group-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-propionic acid
(64) 3-{2-[3-cyclohexyl-3-(trans-4-oxyethyl group-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-propionic acid
(65) 3-{2-[3-suberyl-3-(trans-4-oxyethyl group-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-propionic acid
(66) (2-{3-cyclohexyl-3-[is trans-4-(2-methoxyl group-oxyethyl group)-cyclohexyl]-urea groups }-thiazole-5-base sulfenyl)-acetate
(67) 3-(2-{3-cyclohexyl-3-[is trans-4-(2-methoxyl group-oxyethyl group)-cyclohexyl]-urea groups-thiazole-5-base sulfenyl)-propionic acid
(68) 2-[3-cyclopentyl-3-(trans-4-methoxymethyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate
(69) 3-{2-[3-suberyl-3-(trans-4-ethoxyl methyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-propionic acid
(70) 3-{2-[3-cyclopentyl-3-(trans-4-methoxymethyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-propionic acid
(71) 2-{2-[3-cyclohexyl-3-(trans-4-cyclo propyl methoxy-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-2-methyl-propionic acid
(72) 2-(2-{3-cyclohexyl-3-[is trans-4-(2-methoxyl group-oxyethyl group)-cyclohexyl]-urea groups-thiazole-5-base sulfenyl)-2-methyl-propionic acid
(73) [2-(3,3-dicyclohexyl-urea groups)-thiazole-5-sulfonamido]-acetate
(74) 2-[3-(1-ethanoyl-piperidin-4-yl)-3-cyclohexyl-urea groups]-thiazole-5-sulfonamido }-acetate
(75) 2-{2-[3-suberyl-3-(trans-4-ethoxyl methyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-2-methyl-propionic acid
(76) 2-{2-[3-suberyl-3-(trans-4-methoxymethyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-2-methyl-propionic acid
(77) 2-[3-cyclohexyl-3-(trans-4-methyl-cyclohexyl base)-urea groups]-thiazole-5-sulfonamido }-acetate
(78) 3-[2-(3,3-dicyclohexyl-urea groups)-thiazole-5-sulfonamido]-propionic acid
(79) 3-{2-[3-cyclohexyl-3-(trans-4-methyl-cyclohexyl base)-urea groups]-thiazole-5-sulfonamido }-propionic acid
(80) { [2-(3,3-dicyclohexyl-urea groups)-thiazole-5-alkylsulfonyl]-methyl-amino }-acetate
(81) (2-[3-cyclohexyl-3-(trans-4-methyl-cyclohexyl base)-urea groups]-thiazole-5-alkylsulfonyl }-methyl-amino)-acetate
(82) (S)-1-[2-(3,3-dicyclohexyl-urea groups)-thiazole-5-alkylsulfonyl]-tetramethyleneimine-2-formic acid
(83) (S)-1-{2-[3-cyclohexyl-3-(trans-4-methyl-cyclohexyl base)-urea groups]-thiazole-5-alkylsulfonyl }-tetramethyleneimine-2-formic acid
(84) 2-[3-suberyl-3-(trans-4-propoxy--cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate
(85) 2-[3-cyclopentyl-3-(trans-4-propoxy--cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate
(86) 2-[3-cyclohexyl-3-(trans-4-isobutoxy-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate
(87) 2-{2-[3-cyclohexyl-3-(trans-4-propoxy--cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-2-methyl-propionic acid
(88) 3-{2-[3-cyclohexyl-3-(trans-4-isobutoxy-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-propionic acid
(89) 3-{2-[3-suberyl-3-(trans-4-propoxy--cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-propionic acid
(90) 3-{2-[3-cyclopentyl-3-(trans-4-propoxy--cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-propionic acid
(91) 2-{2-[3-cyclohexyl-3-(trans-4-ethoxyl methyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-2-methyl-propionic acid
(92) 2-[3-cyclohexyl-3-(trans-4-phenyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate
(93) 3-{2-[3-cyclohexyl-3-(trans-4-phenyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-propionic acid
(94) 2-[3-suberyl-3-(trans-4-phenyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate
(95) 3-{2-[3-suberyl-3-(trans-4-phenyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-propionic acid
(96) 2-{2-[3-cyclohexyl-3-(4-phenyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-2-methyl-propionic acid
(97) 2-{2-[3-suberyl-3-(4-phenyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-2-methyl-propionic acid
(98) (E)-6-[4-(1-cyclohexyl-3-thiazol-2-yl-urea groups)-piperidines-1-yl]-the 6-oxo-oneself-3-alkyd
(99) 2-[3-cyclohexyl-3-(trans-4-sec.-propyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate
(100) 2-[3-suberyl-3-(trans-4-sec.-propyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate
(101) 2-[3-cyclohexyl-3-(trans-4-ethyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate
(102) 2-[3-cyclohexyl-3-(trans-4-propoxy--cyclohexyl)-urea groups]-thiazole-5-sulfonamido }-acetate
(103) 3-{2-[3-cyclohexyl-3-(trans-4-propoxy--cyclohexyl)-urea groups]-thiazole-5-sulfonamido }-propionic acid
(104) (2-[3-cyclohexyl-3-(trans-4-propoxy--cyclohexyl)-urea groups]-thiazole-5-alkylsulfonyl }-methyl-amino)-acetate
(105) 2-[3-(trans-4-tert.-butoxy-cyclohexyl)-3-suberyl-urea groups]-thiazole-5-base sulfenyl }-acetate
(106) 2-[3-(trans-4-tert.-butoxy-cyclohexyl)-3-cyclohexyl-urea groups]-thiazole-5-base sulfenyl }-acetate
(107) 3-{2-[3-(trans-4-tert.-butoxy-cyclohexyl)-3-suberyl-urea groups]-thiazole-5-base sulfenyl }-propionic acid
(108) 3-{2-[3-(trans-4-tert.-butoxy-cyclohexyl)-3-cyclohexyl-urea groups]-thiazole-5-base sulfenyl }-propionic acid
(109) 2-[3-(trans-4-benzyloxy-cyclohexyl)-3-cyclohexyl-urea groups]-thiazole-5-base sulfenyl }-acetate
(110) 2-[3-(trans-4-benzyloxy-cyclohexyl)-3-suberyl-urea groups]-thiazole-5-base sulfenyl }-acetate
(111) 3-{2-[3-(trans-4-benzyloxy-cyclohexyl)-3-cyclohexyl-urea groups]-thiazole-5-base sulfenyl }-propionic acid
(112) 3-{2-[3-(trans-4-benzyloxy-cyclohexyl)-3-suberyl-urea groups]-thiazole-5-base sulfenyl }-propionic acid
(113) 2-{2-[3-cyclohexyl-3-(trans-4-methyl-cyclohexyl base)-urea groups]-thiazole-5-sulfonamido }-2-methyl-propionic acid
(114) (R)-1-{2-[3-cyclohexyl-3-(trans-4-methyl-cyclohexyl base)-urea groups]-thiazole-5-alkylsulfonyl }-tetramethyleneimine-2-formic acid
(115) 2-{2-[3-cyclohexyl-3-(trans-4-propoxy--cyclohexyl)-urea groups]-thiazole-5-sulfonamido }-2-methyl-propionic acid
(116) (R)-1-{2-[3-cyclohexyl-3-(trans-4-propoxy--cyclohexyl)-urea groups]-thiazole-5-alkylsulfonyl }-tetramethyleneimine-2-formic acid
(117) 2-[3-cyclohexyl-3-(trans-4-isopropoxy-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate
(118) 2-[3-suberyl-3-(trans-4-isopropoxy-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate
(119) 3-{2-[3-cyclohexyl-3-(trans-4-isopropoxy-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-propionic acid
(120) 3-{2-[3-suberyl-3-(trans-4-isopropoxy-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-propionic acid
(121) 3-(2-{3-cyclohexyl-3-[4-(trans-2-methoxyl group-ethoxyl methyl)-cyclohexyl]-urea groups-thiazole-5-base sulfenyl)-acetate
(122) 3-(2-{3-cyclohexyl-3-[4-(trans-2-methoxyl group-ethoxyl methyl)-cyclohexyl]-urea groups-thiazole-5-base sulfenyl)-propionic acid
(123) (2-{3-suberyl-3-[4-(trans-2-methoxyl group-ethoxyl methyl)-cyclohexyl]-urea groups }-thiazole-5-base sulfenyl)-acetate
(124) 3-(2-{3-suberyl-3-[4-(trans-2-methoxyl group-ethoxyl methyl)-cyclohexyl]-urea groups-thiazole-5-base sulfenyl)-propionic acid
(125) (2-{3-cyclohexyl-3-[4-(trans-2,2,2-three fluoro-ethoxyl methyls)-cyclohexyl]-urea groups }-thiazole-5-base sulfenyl)-acetate
(126) (2-{2-[3-cyclohexyl-3-(trans-4-propoxy--cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-ethanoyl)-Toluidrin
(127) 2-(2-{3-cyclohexyl-3-[4-(trans-2-methoxyl group-ethoxyl methyl)-cyclohexyl]-urea groups-thiazole-5-base sulfenyl)-2-methyl-propionic acid
(128) 2-(2-{3-suberyl-3-[4-(trans-2-methoxyl group-ethoxyl methyl)-cyclohexyl]-urea groups-thiazole-5-base sulfenyl)-2-methyl-propionic acid
(129) 2-{2-[3-cyclohexyl-3-(trans-4-methoxymethyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-2-methyl-propionic acid
(130) 2-[3-cyclohexyl-3-(cis-4-propoxy--cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate
(131) 2-[3-cyclohexyl-3-(trans-4-phenoxy group-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate
(132) (2-{3-cyclohexyl-3-[is trans-4-(pyridine-2-base oxygen base)-cyclohexyl]-urea groups }-thiazole-5-base sulfenyl)-acetate
(133) 3-(2-{3-cyclohexyl-3-[is trans-4-(pyridine-2-base oxygen base)-cyclohexyl]-urea groups-thiazole-5-base sulfenyl)-propionic acid
(134) (2-{3-cyclohexyl-3-[is trans-4-(2,2,2-three fluoro-oxyethyl groups)-cyclohexyl]-urea groups }-thiazole-5-base sulfenyl)-acetate
(135) 2-[3-cyclohexyl-3-(trans-4-methyl-cyclohexyl base)-urea groups]-thiazole-5-N-sulfonyloxy methyl amine
(136) 2-{2-[3-suberyl-3-(trans-4-methoxyl group-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-2-methyl-propionic acid
(137) 2-{2-[3-cyclohexyl-3-(trans-4-methoxyl group-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-2-methyl-propionic acid
(138) 2-{2-[3-suberyl-3-(trans-4-oxyethyl group-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-2-methyl-propionic acid.
In another embodiment, the invention provides a kind of new pharmaceutical composition, it comprises: pharmaceutically acceptable carrier and The compounds of this invention or its pharmacy acceptable salt.
In another embodiment, the invention provides a kind of novel method for the treatment of diabetes B, this method comprises the The compounds of this invention that the patient treatment of needs significant quantity is arranged.
On the one hand, the invention provides a kind of method of preventing hypoglycemia, this method comprises and gives compound of the present invention.
On the other hand, the invention provides The compounds of this invention is used for preventing the medicine of hypoglycemia in preparation purposes.
On the other hand, the invention provides compound as described herein, it is a kind of medicine that is selected from following indication that can be used for treating: hyperglycemia, IGT, insulin resistance syndrome, X syndrome (syndrome X), diabetes B, type 1 diabetes, hyperlipemia (dyslipidemia), hypertension and obesity.
On the other hand, the invention provides a kind of compound, described compound is:
(1) 5-[3-cyclohexyl-3-(trans-4-methyl-cyclohexyl base)-urea groups]-[1,3,4] thiadiazoles-2-N-sulfonyloxy methyl amine
(2) 5-[3-cyclohexyl-3-(trans-4-methyl-cyclohexyl base)-urea groups]-[1,3,4] thiadiazoles-2-sulfuryl amino }-acetate
(3) (5-[3-cyclohexyl-3-(trans-4-methyl-cyclohexyl base)-urea groups]-[1,3,4] thiadiazoles-2-alkylsulfonyl }-methyl-amino)-acetate
(4) 2-[3-cyclohexyl-3-(trans-4-methyl-cyclohexyl base)-urea groups]-4-methyl-thiazole-5-N-sulfonyloxy methyl amine
(5) 2-[3-cyclohexyl-3-(trans-4-methyl-cyclohexyl base)-urea groups]-4-methyl-thiazole-5-sulfuryl amino }-acetate
(6) (2-[3-cyclohexyl-3-(trans-4-methyl-cyclohexyl base)-urea groups]-4-methyl-thiazole-5-alkylsulfonyl }-methyl-amino)-acetate
(7) 1-cyclohexyl-1-(trans-4-methyl-cyclohexyl base)-3-[5-(piperidines-1-alkylsulfonyl)-[1,3,4] thiadiazoles-2-yl]-urea
(8) 5-[3-cyclohexyl-3-(trans-4-methyl-cyclohexyl base)-urea groups]-[1,3,4] thiadiazoles-2-N-(2-methoxyl group-ethyl)-sulphonamide
(9) 5-[3-cyclohexyl-3-(trans-4-methyl-cyclohexyl base)-urea groups]-[1,3,4] thiadiazoles-2-N-sec.-propyl sulphonamide
(10) 5-[3-cyclohexyl-3-(trans-4-methyl-cyclohexyl base)-urea groups]-[1,3,4] thiadiazoles-2-N-phenyl-sulfamide
(11) 1-cyclohexyl-1-(trans-4-methyl-cyclohexyl base)-3-[5-(piperidines-1-alkylsulfonyl)-thiazol-2-yl]-urea
(12) 2-[3-cyclohexyl-3-(trans-4-methyl-cyclohexyl base)-urea groups]-thiazole-5-N-sec.-propyl sulphonamide
(13) 1-cyclohexyl-3-[5-(cis-2,6-dimethyl-piperidines-1-alkylsulfonyl)-thiazol-2-yl]-1-(trans-4-methyl-cyclohexyl base)-urea
(14) 2-[3-cyclohexyl-3-(trans-4-methyl-cyclohexyl base)-urea groups]-thiazole-5-N-tertiary butyl sulphonamide.
On the other hand, the invention provides The compounds of this invention as medicine.
On the other hand, the invention provides The compounds of this invention with following purposes: treatment hyperglycemia, treatment IGT, treatment X syndrome, treatment diabetes B, treatment type 1 diabetes, treatment hyperlipemia, treatment hyperlipidaemia, treatment hypertension, treatment of obesity, minimizing food intake, modulation of appetite, adjusting feeding behavior or strengthen incretin such as GLP-1 from secretion.
On the other hand, the invention provides a kind of pharmaceutical composition, it comprises at least a compound described herein as activeconstituents, and one or more pharmaceutically acceptable carrier or vehicle.
In one embodiment, described pharmaceutical composition can be unit dosage, comprises about 0.05mg to about 1000mg, preferred extremely about 500mg, especially preferred about 0.5mg The compounds of this invention of about 200mg extremely of about 0.1mg.
On the other hand, the invention provides the purposes of The compounds of this invention aspect increase glucokinase activity.
On the other hand, the invention provides The compounds of this invention and have purposes in the medicine of following effect: the treatment metabolic disturbance in preparation, lowering blood glucose, the treatment hyperglycemia, treatment IGT, the treatment X syndrome, treatment impaired fasting glucose (IFG), the treatment diabetes B, the treatment type 1 diabetes, the delay glucose tolerance lowers (IGT) and develops into diabetes B, delay non-insulin demand property diabetes B and develop into the insulin requirements diabetes B, the treatment hyperlipemia, the treatment hyperlipidaemia, treatment hypertension, reduce food intake, modulation of appetite, treatment of obesity, regulate the secretion of feeding behavior or enhancing incretin.On the other hand, the invention provides The compounds of this invention and be used for the purposes of type 1 diabetes assisting therapy with the medicine of prevent diabetes complication outbreak in preparation.
On the other hand, the invention provides The compounds of this invention and have purposes in the medicine of following effect: increase β cell quantity and/or size in the mammalian subject in preparation, treatment β cytopathy, the apoptosis of β cell particularly, perhaps treat functional dyspepsia, particularly irritable bowel syndrome.
In one embodiment, the invention provides above each purposes, be used for comprising the scheme of other antidiabetic medicine treatment.
On the one hand, the invention provides The compounds of this invention or pharmaceutical composition of the present invention purposes in the following areas: be used for the treatment of metabolic disturbance again, lowering blood glucose, the treatment hyperglycemia, treatment IGT, the treatment X syndrome, treatment impaired fasting glucose (IFG), the treatment diabetes B, the treatment type 1 diabetes, the delay glucose tolerance lowers (IGT) and develops into diabetes B, delay non-insulin demand property diabetes B and develop into the insulin requirements diabetes B, the treatment hyperlipemia, the treatment hyperlipidaemia, treatment hypertension, treatment or obesity prevention, reduce food intake, modulation of appetite, regulate the secretion of feeding behavior or enhancing incretin.
On the one hand, the invention provides The compounds of this invention or pharmaceutical composition of the present invention and be used for the type 1 diabetes assisting therapy again with the intraictal purposes of prevent diabetes complication.
Again on the one hand, the invention provides The compounds of this invention or pharmaceutical composition of the present invention purposes in the following areas: the β cell quantity and/or the size that are used for increasing mammalian subject, treatment β cytopathy, the apoptosis of β cell particularly, perhaps treat functional dyspepsia, particularly irritable bowel syndrome.
In another embodiment, the invention provides a kind of method that causes by glucokinase sudden change, lack the condition/disease of mediation by glucokinase that is used for the treatment of.
In another embodiment, the invention provides a kind of method, wherein the condition/disease of glucokinase shortage mediation is adult morbidity type diabetes, neonatal diabetes or a persistence neonatal diabetes of young adult.
In another embodiment; the invention provides a kind of pathogenetic method of glycosuria that is used to prevent or improve the experimenter who shows following symptom: impaired glucose tolerance, gestational diabetes, polycystic ovarian syndrome, hypercortisolism (Cushing syndrome) or metabolism syndrome; this method comprises the experimenter who needs this treatment compound of the present invention or its pharmaceutical composition, blood sugar normalizing and risk of hypoglycemia wherein occur and reduces.
In another embodiment, the invention provides a kind of be used for the prevention or improve microangiopathic method, this method comprises the experimenter who needs this treatment compound of the present invention or its pharmaceutical composition.
In another embodiment; the invention provides the method for a kind of experimenter's who is used to prevent to show following symptom macroangiopathic: impaired glucose tolerance, gestational diabetes or metabolism syndrome; this method comprises compound of the present invention or its pharmaceutical composition gives separately or unite the experimenter who needs this treatment with hypolipidemic, blood sugar normalizing and risk of hypoglycemia wherein occur and reduces.
In another embodiment; the invention provides a kind of method that is used to keep beta cell amount and function; this method comprises the experimenter who needs this treatment compound of the present invention or its pharmaceutical composition, blood sugar normalizing and risk of hypoglycemia wherein occur and reduces.
In another embodiment; the invention provides a kind of method that is used for the necrocytosis of prevention of amyloid β inducing peptide; this method comprises the experimenter who needs this treatment compound of the present invention or its pharmaceutical composition, blood sugar normalizing and risk of hypoglycemia wherein occur and reduces.
In another embodiment, the invention provides a kind of method, wherein said experimenter (patient) is vertebrate subject (patient).
In another embodiment, the invention provides a kind of method, compound wherein of the present invention gives as food additive.
In another embodiment; the invention provides a kind of method that is used for the treatment of because of the benefited hepatopathy of blood sugar normalizing; this method comprises the experimenter who needs this treatment compound of the present invention or its pharmaceutical composition, blood sugar normalizing and risk of hypoglycemia wherein occur and reduces.
In another embodiment, the invention provides a kind of method of improving the hepatopathy of being benefited because of liver function that is used for the treatment of, this method comprises the experimenter who needs this treatment compound of the present invention or its pharmaceutical composition.
In another embodiment; the invention provides a kind of being used for the treatment of by major disease causes or because the method for the hyperglycemia cause is intervened in treatment; this method comprises the experimenter who needs this treatment compound of the present invention or its pharmaceutical composition, blood sugar normalizing and risk of hypoglycemia wherein occur and reduces.
In another embodiment, the invention provides a kind of being used for the treatment of by major disease (for example cancer) causes or because the method for the hepatopathy that treatment (for example cancer therapy or HIV treatment) causes, this method comprises the experimenter who needs this treatment compound of the present invention or its pharmaceutical composition.
In another embodiment; the invention provides a kind of in the insulin requirements diabetes B auxiliary Regular Insulin methods of treatment or as the methods of treatment of insulin substitution therapy; this method comprises the experimenter who needs this treatment compound of the present invention or its pharmaceutical composition, blood sugar normalizing and risk of hypoglycemia wherein occur and reduces.
In another embodiment, the invention provides a kind of method that is used for the treatment of lipodystrophy, this method comprises the experimenter who needs this treatment compound of the present invention or its pharmaceutical composition, blood sugar normalizing and risk of hypoglycemia wherein occur and reduces.
In another embodiment; the invention provides a kind of being used for the treatment of stress be caused by serious health but not have the method for the hyperglycemia of liver failure symptom; this method comprises the experimenter who needs this treatment compound of the present invention or its pharmaceutical composition, blood sugar normalizing and risk of hypoglycemia wherein occur and reduces.
In another embodiment, the invention provides a kind of method, wherein said serious health stress be health many places wound or diabetic ketoacidosis.
In another embodiment, the invention provides a kind of method that is used to prevent the apoptosis liver damage, this method comprises the experimenter who needs this treatment compound of the present invention or its pharmaceutical composition.
In another embodiment, the invention provides a kind of method that is used to prevent hypoglycemia, this method comprises the experimenter who needs this treatment compound of the present invention or its pharmaceutical composition, blood sugar normalizing and risk of hypoglycemia wherein occur and reduces.
In another embodiment; the invention provides a kind of method that is used to increase beta cell amount and function; this method comprises the experimenter who needs this treatment compound of the present invention or its pharmaceutical composition, blood sugar normalizing and risk of hypoglycemia wherein occur and reduces.
In another embodiment, the invention provides a kind of method that is used to prevent type 1 diabetes, this method comprises the experimenter who needs this treatment compound of the present invention or its pharmaceutical composition, blood sugar normalizing and risk of hypoglycemia wherein occur and reduces.
In another embodiment, the invention provides a kind of be used to keep and/or the increase patient's who stands pancreatic islets transplantation the beta cell amount and the method for function, this method comprises the patient who needs this treatment compound of the present invention or its pharmaceutical composition.
In another embodiment, the invention provides a kind of method that is used to improve intra-operative and the glucose control of operation back, this method comprises the experimenter who needs this treatment compound of the present invention or its pharmaceutical composition.
In another embodiment, the invention provides and a kind ofly be used to improve the liver function of liver-transplantation patients and/or prolong the liver-transplantation patients method of lifetime, this method comprises the patient who needs this treatment compound of the present invention or its pharmaceutical composition.In another embodiment, the invention provides a kind of method, wherein this medication before transplanting, central or implement afterwards or in its any combination.
In another embodiment, the invention provides a kind of method that obtains blood sugar normalizing, this method comprises the experimenter who needs this treatment compound of the present invention or its pharmaceutical composition, blood sugar normalizing and risk of hypoglycemia wherein occur and reduces.
In another embodiment, the invention provides a kind of method of preventing or improving the advanced diabetes complication, this method comprises the patient who needs this treatment compound of the present invention or its pharmaceutical composition.
In another embodiment, the invention provides the method for a kind of treatment 1 type or diabetes B, this method comprises the patient who needs this treatment compound of the present invention or its pharmaceutical composition, and wherein said treatment can not cause weight increase.
In another embodiment, the invention provides a kind of method of prevent diabetes ketoacidosis, this method comprises the patient who needs this treatment compound of the present invention or its pharmaceutical composition.
Combination therapy
Of the present invention more on the one hand, other active substance of The compounds of this invention and one or more is with any suitable ratio drug combination.Other active substance of this class can be selected from antidiabetic drug, antihyperlipidemic drug, anti-obesity medicine, antihypertensive drug and treatment because of due to the diabetes or with the medicine of diabetes complications associated with arterial system.
Suitable antidiabetic drug comprises Regular Insulin, GLP-1 (glucagon-like-peptide-1) derivative, those disclosed antidiabetic drug in WO 98/08871 (Novo Nordisk A/S) for example, the document is hereby incorporated by, and the Orally active hypoglycemic agents.
Suitable Orally active hypoglycemic agents preferably includes imidazolines; Sulfonylurea; Biguanides; The mitiglinide class; Oxadiazole alkane two ketones; Thiazolidinediones; Euglycemic agent; Alpha-glucosidase inhibitor; Act on the medicine of the ATP dependent form potassium channel of pancreas β cell, potassium channel openers for example, for example be disclosed among WO 97/26265, WO 99/03861 and the WO00/37474 (Novo Nordisk A/S) those, these documents are hereby incorporated by, potassium channel openers, for example ormitiglinide; The potassium channel blocade, for example nateglinide or BTS-67582, glucagon antagonist, for example at WO 99/01423 and WO 00/39088 (Novo Nordisk A/S and Agouron Pharmaceuticals, Inc.) those disclosed in, all documents all are hereby incorporated by, the GLP-1 agonist, for example at WO 00/42026 (Novo Nordisk A/S and Agouron Pharmaceuticals, Inc.) those disclosed in, the document is hereby incorporated by, DPP-IV (dipeptidyl peptidase-IV) inhibitor, PTP enzyme (Protein Tyrosine Phosphatases) inhibitor, participate in stimulating the inhibitor of gluconeogenesis and/or glycogenolytic liver enzyme, the glucose uptake conditioning agent, GSK-3 (glycogen synthesizes kinases-3) inhibitor, change the compound of lipid metabolism, for example antihyperlipidemics and hypolipidemic, reduce the compound of food intake, and PPAR (peroxisome proliferation-activated receptor) and RXR (retinoid X acceptor) agonist, for example ALRT-268, LG-1268 or LG-1069.
In one embodiment of the invention, The compounds of this invention and sulfonylurea drug combination, for example tolbutamide, P-607, tolazamide, Glyburide (glibenclamide), Glipizide, glimepiride, gliclazide or Glyburide (glyburide).
In one embodiment of the invention, The compounds of this invention and biguanides N1,N1-Dimethylbiguanide drug combination for example.
In one embodiment of the invention, for example repaglinide or senaglinide (senaglinide)/nateglinide drug combination of The compounds of this invention and mitiglinide.
In one embodiment of the invention, The compounds of this invention and thiazolidinedione euglycemic agent drug combination, for example troglitazone, ciglitazone, pioglitazone, rosiglitazone, Netoglitazone, darglitazone, englitazone, CS-011/CI-1037 or T 174 or in WO 97/41097 (DRF-2344), WO 97/41119, WO 97/41120, WO 00/41121 and WO 98/45292 (Dr.Reddy ' s Research Foundation) disclosed compound, these documents are hereby incorporated by.
In one embodiment of the invention, The compounds of this invention can with the euglycemic agent drug combination, for example GI 262570, YM-440, MCC-555, JTT-501, AR-H039242, KRP-297, GW-409544, CRE-16336, AR-H049020, LY510929, MBX-102, CLX-0940, GW-501516 or at WO 99/19313 (NN622/DRF-2725), WO 00/50414, WO 00/63191, WO 00/63192, WO 00/63193 (Dr.Reddy ' s Research Foundation) and WO 00/23425, WO 00/23415, WO 00/23451, WO 00/23445, WO 00/23417, WO00/23416, WO 00/63153, WO 00/63196, WO 00/63209, disclosed compound among WO 00/63190 and the WO 00/63189 (Novo Nordisk A/S), these documents are hereby incorporated by.
In one embodiment of the invention, The compounds of this invention and alpha-glucosidase inhibitor drug combination, for example voglibose, emiglitate, miglitol or acarbose.
In one embodiment of the invention, The compounds of this invention and glycogen phosphorylase inhibitors drug combination for example are described in the compound among the WO 97/09040 (Novo Nordisk A/S).
In one embodiment of the invention, The compounds of this invention and the medication combined medication that acts on the ATP dependent form potassium channel of pancreas beta cell, for example tolbutamide, Glyburide (glibenclamide), Glipizide, gliclazide, BTS-67582 or repaglinide.
In one embodiment of the invention, The compounds of this invention and nateglinide drug combination.
In one embodiment of the invention, The compounds of this invention and antihyperlipidemics or hypolipidemic drug combination, for example Colestyramine, colestipol, chlorine Bei Te, gemfibrozil, lovastatin, Pravastatin, Simvastatin, probucol or dexadrine.
In addition, The compounds of this invention can with one or more anti-obesity medicines or appetite stimulator medicine drug combination.
This class medicine can be selected from: CART (transcript that the Cocaine amphetamine is regulated) agonist, NPY (neuropeptide tyrosine) antagonist, MC3 (melanocortin 3) agonist, MC4 (melanocortin 4) agonist, orexin antagonists, TNF (tumour necrosis factor) agonist, CRF (corticotropin releasing factor (CRF)) agonist, CRF BP (corticotropin releasing factor (CRF) is conjugated protein) antagonist, the Urocortin agonist, 'beta '3 adrenergic agonists (CL-316243 for example, AJ-9677, GW-0604, LY362884, LY377267 or AZ-40140), MSH (melanotropin) agonist, MCH (melanophore concentrates hormone) antagonist, CCK (cholecystokinin) agonist, serotonin reuptake inhibitor (fluoxetine, seroxat or citalopram), serotonin and NRI, 5HT (serotonin) agonist, the bombesin agonist, the galanin antagonist, tethelin, somatomedin (for example prolactin antagonist or galactagogin), tethelin release property compound, TRH (thyrotrophin-releasing hormone) agonist, UCP2 or 3 (uncoupling protein 2 or 3) conditioning agent, leptin (leptin) agonist, DA (Dopamine HCL) agonist (bromocriptine, doprexin), lipase/amylase inhibitor, the PPAR conditioning agent, the RXR conditioning agent, the TR beta-agonists, adrenergic CNS stimulant, AGRP (agouti dependency albumen) inhibitor, the H3 histamine antagonist (for example is disclosed in WO 00/42023, among WO 00/63208 and the WO00/64884 those, these documents are hereby incorporated by), Exendin-4 (exendin-4), the GLP-1 agonist, ciliary neurotrophic factor and oxyntomodulin.Other anti-obesity medicine is Bupropion (thymoleptic), topiramate (anticonvulsive drug), ecopipam (dopamine D 1/D5 antagonist) and TREXUPONT (OPIOIDS antagonist).
In one embodiment of the invention, the anti-obesity medicine is a leptin.
In one embodiment of the invention, the anti-obesity medicine is serotonin and NRI, for example sibutramine.
In one embodiment of the invention, the anti-obesity medicine is a lipase inhibitor, for example orlistat.
In one embodiment of the invention, the anti-obesity medicine is adrenergic CNS stimulant, for example Dextrofenfluramine, amphetamine, phentermine, Mazindol, phendimetrazine, Diethylpropion, Phenfluoramine or dexfenfluramine.
In addition, The compounds of this invention can with one or more antihypertensive drug drug combinations.The example of antihypertensive drug is β-blocade, for example alprenolol, atenolol USP 23, timolol, pindolol, Proprasylyte and metoprolol; ACE (angiotensin-converting enzyme) Depressant, for example benazepril, captopril, enalapril, fosinopril, lisinopril, quinapril and Ramipril; Calcium channel blocker, for example nifedipine, felodipine, nicardipine, Isradipine, nimodipine, diltiazem
And verapamil; With the blockade, medicine, for example Doxazosin, urapidil, Prazosin and terazosin.Can be further with reference to Remington:TheScience and Practice of Pharmacy, 19th Edition, Gennaro, Ed., MackPublishing Co., Easton, PA, 1995.
In one embodiment of the invention, The compounds of this invention and Regular Insulin, insulin derivates or insulin analog drug combination.
In one embodiment of the invention, Regular Insulin is to be selected from following insulin derivates: B29-N
ε-mnyristoyl-go (B30) insulin human, B29-N
ε-palmityl-go (B30) insulin human, B29-N
ε-mnyristoyl insulin human, B29-N
ε-palmityl insulin human, B28-N
ε-mnyristoyl Lys
B28Pro
B29Insulin human, B28-N
ε-palmityl Lys
B28Pro
B29Insulin human, B30-N
ε-mnyristoyl-Thr
B29Lys
B30Insulin human, B30-N
ε-palmityl-Thr
B29Lys
B30Insulin human, B29-N
ε-(N-palmityl-gamma-glutamyl)-go (B30) insulin human, B29-N
ε-(N-stone courage acyl-gamma-glutamyl)-go (B30) insulin human, B29-N
ε-(ω-carboxyl heptadecanoyl)-go (B30) insulin human and B29-N
ε-(ω-carboxyl heptadecanoyl)-insulin human.
In another embodiment of the invention, insulin derivates is B29-N
ε-mnyristoyl-go (B30) Regular Insulin.
In another embodiment of the present invention, Regular Insulin is a kind of sour stabilised insulin.The acid stabilised insulin can be selected from the human insulin analogue with one of following amino-acid residue replacement:
A21G
A21G、B28K、B29P
A21G、B28D
A21G、B28E
A21G、B3K、B29E
A21G、desB27
A21G、B9E
A21G、B9D
A21G, B10E Regular Insulin.
In yet another embodiment of the present invention, Regular Insulin is insulin analog.Insulin analog can be selected from:
A kind of analogue, wherein the B28 position is Asp, Lys, Leu, Val or Ala, the B29 position is Lys or Pro; With
Remove (B28-B30), remove (B27) or go (B30) insulin human.
In another embodiment, this analogue is a kind of human insulin analogue, and wherein the B28 position is Asp or Lys, and the B29 position is Lys or Pro.
In another embodiment, this analogue is (B30) insulin human.
In another embodiment, insulin analog is a kind of human insulin analogue, and wherein the B28 position is Asp.
In another embodiment, this analogue is a kind of like this analogue: wherein the B3 position is Lys, and the B29 position is Glu or Asp.
In another embodiment, with the GLP-1 derivative of The compounds of this invention coupling, be meant GLP-1 (1-37), Exendin-4 (1-39), its pancreotropic hormone fragment, its pancreotropic hormone analogue and its pancreotropic hormone derivative.The pancreotropic hormone fragment of GLP-1 (1-37) is to find the insulinoptropic peptides of its complete sequence in the sequence of GLP-1 (1-37), and wherein at least one end amino acid lacks.The pancreotropic hormone fragment instance of GLP-1 (1-37) has GLP-1 (7-37) that the 1-6 amino acids residue of GLP-1 (1-37) wherein lacked and wherein the 1-6 position of GLP-1 (1-37) and the GLP-1 (7-36) that 37 amino acids residues have been lacked.The pancreotropic hormone fragment instance of Exendin-4 (1-39) has Exendin-4 (1-38) and Exendin-4 (1-31).The pancreotropic hormone character of compound can by in the body well known in the art or the external test method measure.For example, can give animal with compound, the monitoring insulin concentration over time.The pancreotropic hormone analogue of GLP-1 (1-37) and Exendin-4 (1-39) is meant so separately molecule: wherein one or more amino-acid residues are by other radical amino acid replacement and/or one or more amino-acid residue has been lacked and/or one or more amino-acid residue has been added into wherein, as long as described analogue is insulinotropic or the prodrug of pancreotropic hormone compound.The pancreotropic hormone analogue example of GLP-1 (1-37) has for example Met
8-GLP-1 (7-37), wherein 8 L-Ala is replaced by methionine(Met), and the amino-acid residue of 1-6 position is lacked, and Arg
34-GLP-1 (7-37), wherein 34 Xie Ansuan is replaced by arginine, and the amino-acid residue of 1-6 position is lacked.The pancreotropic hormone analogue example of Exendin-4 (1-39) has Ser
2Asp
3-Exendin-4 (1-39), wherein 2 and 3 amino-acid residue is respectively by Serine and aspartic acid displacement (this special analogue is also referred to as Exendin-3 in the art).The pancreotropic hormone derivative of GLP-1 (1-37), Exendin-4 (1-39) and analogue thereof are considered as the derivative of these peptides by those skilled in the art, just have at least one and be not present in substituting group in female peptide molecule, as long as described derivative is insulinotropic or the prodrug of pancreotropic hormone compound.Substituent example is acid amides, sugar, alkyl and lipophilic substituent.The pancreotropic hormone derivative of GLP-1 (1-37), Exendin-4 (1-39) and the example of analogue thereof are GLP-1 (7-36)-acid amides, Arg
34, Lys
26(N
ε-(γ-Glu (N
α-hexadecanoyl)))-GLP-1 (7-37) and Tyr
31-Exendin-4 (1-31)-acid amides.Other case description of GLP-1 (1-37), Exendin-4 (1-39), its pancreotropic hormone fragment, its pancreotropic hormone analogue and its pancreotropic hormone derivative is in WO98/08871, WO 99/43706, US 5424286 and WO 00/09666.
In another aspect of this invention, The compounds of this invention and more than a kind of above-claimed cpd drug combination are for example with following drug regimen: N1,N1-Dimethylbiguanide and sulfonylurea, for example Glyburide; Sulfonylurea and acarbose; Nateglinide and N1,N1-Dimethylbiguanide; Acarbose and N1,N1-Dimethylbiguanide; Sulfonylurea, N1,N1-Dimethylbiguanide and troglitazone; Regular Insulin and sulfonylurea; Regular Insulin and N1,N1-Dimethylbiguanide; Regular Insulin, N1,N1-Dimethylbiguanide and sulfonylurea; Regular Insulin and troglitazone; Regular Insulin and lovastatin etc.
Should be appreciated that The compounds of this invention and diet and/or exercise, one or more above-claimed cpds and randomly any suitable combination of one or more other active substances all be regarded as belonging to scope of the present invention.In one embodiment of the invention, pharmaceutical composition of the present invention comprises for example combination of The compounds of this invention and N1,N1-Dimethylbiguanide and sulfonylurea such as Glyburide; The combination of The compounds of this invention and following medicine: sulfonylurea and acarbose; Nateglinide and N1,N1-Dimethylbiguanide; Acarbose and N1,N1-Dimethylbiguanide; Sulfonylurea, N1,N1-Dimethylbiguanide and troglitazone; Regular Insulin and sulfonylurea; Regular Insulin and N1,N1-Dimethylbiguanide; Regular Insulin, N1,N1-Dimethylbiguanide and sulfonylurea; Regular Insulin and troglitazone; Regular Insulin and lovastatin etc.
Pharmaceutical composition
The compounds of this invention medication or share with pharmaceutically acceptable carrier or vehicle separately divides single agent or multi-agent.Can be according to routine techniques, for example be disclosed in Remington:TheScience and Practice of Pharmacy, the 19th edition, Gennaro, Ed., MackPublishing Co., Easton, PA, those technology in 1995 are prepared pharmaceutical composition of the present invention with pharmaceutically acceptable carrier or thinner and any other known auxiliary agent and vehicle.
Pharmaceutical composition can specifically be mixed with by any suitable administration, in for example oral, rectum, nose, lung, part (comprising oral cavity and hypogloeeis), transdermal, the brain pond, intraperitoneal, vagina and parenteral (comprise in subcutaneous, intramuscular, the sheath, intravenously and intradermal) approach, the preferred oral approach.What recognize is that optimization approach will depend on curee's general situation and age, the sanatory character of institute and selected activeconstituents.
Be used for pharmaceutical composition for oral administration and comprise solid dosage, for example hard or soft capsule, tablet, dragee, dragee, pill, lozenge, pulvis and granule.In due course, they can have dressing, enteric coating for example, and perhaps they can be according to method preparation well known in the art, so that the sustained release of activeconstituents to be provided, for example release that continues or prolong.
The liquid dosage form that is used for oral administration comprises solution, emulsion, water-based or oiliness suspensoid, syrup and elixir.
The pharmaceutical composition that is used for parenteral admin comprises aseptic water-based and non-aqueous injectable solutions, dispersion liquid, suspensoid or emulsion, and reprovision is the sterile powder injection of sterile injectable solution agent or dispersion liquid before using.The slow release type injection also covered in the scope of the invention.
Other suitable form of administration comprises suppository, sprays, ointment, creme, gelifying agent, inhalation, skin patch, implant etc.
Typical oral dosage is that about 0.001mg/kg body weight/day is to about 100mg/kg body weight/day, preferred about 0.01mg/kg body weight/day is to about 50mg/kg body weight/day, more preferably from about the 0.05mg/kg body weight/day is divided potion or multi-agent administration, for example 1 to 3 dose to about 10mg/kg body weight/day.Accurate dose will depend on the frequency of administration and mode, curee sex, age, body weight and general situation, the illness for the treatment of and any disease accompanied character of being treated and seriousness and the other factors that it will be apparent to those skilled in the art.
By method known to those skilled in the art, preparation can provide with unit dosage easily.Medication every day one or repeatedly, for example every day 1-3 oral administration the typical flat formulation can contain 0.05mg to about 1000mg, preferably about 0.1mg is about 500mg extremely, more preferably from about 0.5mg about 200mg extremely.
With regard to the parenteral approach, for example in the intravenously, sheath, intramuscular and similar administration, typical dosage approximately is half of the used dosage of oral administration.
The compounds of this invention generally adopts dissociant or its pharmacy acceptable salt.Example has the acid salt of the compound with available free alkali and has the base addition salt of the compound of available free acid.Term " pharmacy acceptable salt " is meant the non-toxic salts of The compounds of this invention, and it generally is prepared as follows: make free alkali and appropriate organic or inorganic acid reaction, perhaps make acid and suitable organic bases or mineral alkali reaction.When The compounds of this invention contains free alkali, prepare this class salt in a usual manner by solution or suspension with stoichiometric pharmaceutically acceptable acid treatment compound.When The compounds of this invention contains free acid, prepare this class salt in a usual manner by solution or suspension with stoichiometric pharmaceutically acceptable alkaline purification compound.The physiologically acceptable salt of hydroxy-containing compounds comprises the combination of negatively charged ion and suitable positively charged ion such as the sodium ion or the ammonium ion of described compound.Other non-pharmacy acceptable salt also can be used for preparing The compounds of this invention, and these constitute one side more of the present invention.
With regard to parenteral admin, can use the solution of new (I) compound and aseptic aqueous solution, aqueous solution of propylene glycol or sesame or peanut oil.If necessary, this class aqueous solution should suitably be cushioned, and at first with capacity salt solution or glucose liquid diluent etc. is oozed.The aqueous solution is particularly suitable for intravenously, intramuscular, subcutaneous and intraperitoneal administration.The sterile aqueous media that is adopted all can easily obtain by standard technique well known by persons skilled in the art.
Suitable pharmaceutical carrier comprises inert solid diluent or weighting agent, aseptic aqueous solution and various organic solvent.The example of solid carrier has lactose, terra alba, sucrose, cyclodextrin, talcum powder, gelatin, agar, pectin, gum arabic, Magnesium Stearate, stearic acid and cellulosic lower alkyl ether.The example of liquid vehicle has syrup, peanut oil, sweet oil, phosphatide, lipid acid, fatty acid amine, polyoxyethylene and water.Similarly, carrier or thinner can comprise independent or with wax blended any lasting releasable material known in the art, for example Zerol or Stearic diglyceride.So, novel The compounds of this invention and pharmaceutically acceptable carrier are combined the pharmaceutical composition that constituted easily with the multiple formulation administration that is suitable for disclosed route of administration.According to the known method of pharmacy field, preparation can provide with unit dosage easily.
The preparation of the present invention that is suitable for oral administration can provide by discrete unit, for example capsule or tablet, and per unit all contains the activeconstituents of predetermined amount, and can contain suitable vehicle.In addition, oral preparations can be the form of pulvis or granule, the solution in water-based or non-aqueous liquid or suspensoid or oil-in-water-type or water-in-oil-type liquid emulsion.
The composition that the expection per os uses can be according to any currently known methods preparation, and this based composition can contain one or more materials that is selected from sweeting agent, correctives, tinting material and sanitas, so that good to eat preparation pharmaceutically attractive in appearance is provided.Tablet can contain the mixture of activeconstituents and nontoxic pharmaceutically acceptable vehicle, and described vehicle is suitable for the preparation of tablet.These vehicle for example can be inert diluent, for example lime carbonate, yellow soda ash, lactose, calcium phosphate or sodium phosphate; Granulating agent and disintegrating agent, for example W-Gum or alginic acid; Tackiness agent, for example starch, gelatin or gum arabic; And lubricant, for example Magnesium Stearate, stearic acid or talcum powder.Tablet can be a dressing not, and perhaps they can use the known technology dressing, delaying disintegration and the absorption in gi tract, thereby provides continuous action for a long time.For example, can use the time-delay material, for example Zerol or Stearic diglyceride.Also can utilize United States Patent (USP) 4,356,108,4,166,452 and 4,265, the described technology of 874 (being hereby incorporated by) is carried out dressing, makes the osmotic therapeutic sheet that is used for sustained release.
Mouth also can hard-gelatin capsules provide with preparation, wherein activeconstituents mixes with inert solid diluent such as lime carbonate, calcium phosphate or kaolin, perhaps provide, wherein activeconstituents and water or oily medium such as peanut oil, whiteruss or mixed with olive oil with Gelseal.
Aqueous suspension can contain active compound and be suitable for the mixture of the vehicle of aqueous suspension preparation.This class vehicle has suspension agent, for example Xylo-Mucine, methylcellulose gum, Vltra tears, sodiun alginate, polyvinylpyrrolidone, tragakanta and gum arabic; Dispersion agent or wetting agent can be naturally occurring phosphatide, Yelkin TTS for example, the perhaps condensation product of oxirane and lipid acid, polyoxyethylene stearic acid ester for example, the perhaps condensation product of oxirane and long chain aliphatic alcohol, 17 carbon vinyloxy group hexadecanols for example, the perhaps condensation product of oxirane and lipid acid and hexitol deutero-partial ester, polyoxyethylene sorbitol monoleate for example, the perhaps condensation product of oxirane and lipid acid and hexitan deutero-partial ester, for example polyoxyethylene sorbitan monooleate.Aqueous suspension can also contain one or more tinting materials, one or more correctivess and one or more sweeting agents, for example sucrose or asccharin.
Can prepare oil-based suspension by activeconstituents is suspended in vegetables oil or the mineral oil, described vegetables oil for example is peanut oil, sweet oil, sesame oil or Oleum Cocois, and described mineral oil for example is whiteruss.Oil-based suspension can contain thickening material, for example beeswax, paraffinum durum or hexadecanol.Can add sweeting agent, for example above-mentioned those, and correctives is to provide agreeable to the taste oral preparations.Can carry out anticorrosion to these compositions by adding antioxidant such as xitix.
But be suitable for preparing the dispersion powder of aqueous suspension and the mixture that granule provides active compound and dispersion agent or wetting agent, suspension agent and one or more sanitass by adding water.Suitable dispersion agent or wetting agent and suspension agent are example by those that above mentioned.Also can there be other vehicle, for example sweeting agent, correctives and tinting material.
Pharmaceutical composition of the present invention also can be the oil-in-water emulsion form.Oil phase can be a vegetables oil, for example sweet oil or peanut oil, perhaps mineral oil, for example whiteruss, or its mixture.Suitable emulsifying agent can be naturally occurring natural gum, for example gum arabic or tragakanta; Naturally occurring phosphatide, soybean lecithin for example, and the ester or the partial ester that are derived from lipid acid and hexitan, for example condensation product of polyoxyethylene-sorbitan mono-oleate and described partial ester and oxirane, for example polyoxyethylene sorbitan monooleate.Emulsion also can contain sweeting agent and correctives.
Syrup and elixir can be prepared with sweeting agent, for example glycerine, propylene glycol, Sorbitol Powder or sucrose.This class preparation can also contain negative catalyst, sanitas and flavoring and tinting material.Pharmaceutical composition can be the aseptic injectable water-based or the form of oil-based suspension.This suspension can use above-mentioned suitable dispersion agent or wetting agent and suspension agent to prepare according to currently known methods.Aseptic injectable formulation also can be sterile injectable solution agent or the suspensoid that contains nontoxic parenteral acceptable diluent or solvent, for example contains the solution of 1,3 butylene glycol.Spendablely accept solvent and solvent has water, woods Ge Shi (Ringer) solution and isotonic sodium chlorrde solution.In addition, aseptic expressed oil can be used as solvent or suspension medium easily.For this reason, can adopt the expressed oil of any brand of using synthetic monoglyceride or triglyceride.In addition, can be used for the preparation of injection such as oleic lipid acid.
Composition can be a suppository form also, is used for the rectal administration of The compounds of this invention.These compositions can be prepared as follows: medicine is mixed with suitable nonirritant excipient, and described vehicle is solid at normal temperatures, but is liquid under rectal temperature, thereby will melt in rectum, discharges medicine.This class material for example comprises theobroma oil and polyoxyethylene glycol.
With regard to use the part, consider creme, ointment, gelifying agent, solution or suspensoid etc., it contains compound of the present invention.For this application aims, topical application should comprise collutory and mouth wash shua.
The compounds of this invention can also the liposome delivery system form give for example small unilamellar vesicle, big unilamellar liposome and multilamellar liposome.Liposome can be made by multiple phosphatide, for example cholesterol, stearylamine or phosphatidylcholine.
In addition, some The compounds of this invention can generate solvate with water or ordinary organic solvents.This kind solvent thing is also contained within the scope of the invention.
Thereby, in another embodiment, providing a kind of pharmaceutical composition, it comprises The compounds of this invention or its pharmacy acceptable salt, solvate or its prodrug, and one or more pharmaceutically acceptable carriers, vehicle or thinner.
If use solid carrier to carry out oral administration, the prepared product compressing tablet can be placed hard gelatin capsule with powder or piller form, perhaps preparation can be the form of dragee or lozenge.The amount of solid carrier can alter a great deal, but is generally about 25mg to about 1g.If use liquid vehicle, preparation can be syrup, emulsion, Gelseal or aseptic injectable liquid body preparation, for example water-based or non-aqueous liquid suspensoid or solution.
Can contain by the typical tablet of conventional pressed disc technique preparation:
Plain sheet:
Active compound (free cpds or its salt) 5.0mg
Lactose, European Pharmacopoeia level 67.8mg
Microcrystalline Cellulose (Avicel) 31.4mg
IRP88
* 1.0mg
Magnesium Stearate, the European Pharmacopoeia level is an amount of
Coating material:
The about 9mg of Vltra tears
Mywacett 9-40 T
*About 0.9mg
*Polacrillin potassium NF, disintegrating tablet, Rohm and Haas.
*The acidylate monoglyceride is as the film-coat softening agent.
If necessary, pharmaceutical composition of the present invention can comprise the combination of The compounds of this invention and other active substance those materials as indicated above.
The present invention also provides the method for the synthetic compound that can be used as formula (I) compound intermediate and the method for preparation formula (I) compound.These compounds can use the raw material, reagent and the conventional synthesis technique that obtain easily easily to prepare (wherein all variable all defines as preamble, and other has except the indication) according to following reaction process.In these reactions, also might utilize some variations, they itself are that those of ordinary skills are known, but do not mention in more detail.
Pharmacological method
Glucokinase activation measurement (I)
The glucokinase activity is by spectrographic determination, and itself and the coupling of glucose 6-phosphate dehydrogenase are used to measure the activation of compound to glucokinase.Final mensuration thing contains 50mM Hepes (pH 7.1), 50mM KCl, 5mM MgCl
2, 2mM dithiothreitol (DTT), 0.6mM NADP, 1mM ATP, 0.195 μ M G-6-P desaturase (deriving from Roche, 127671), 15nM recombinant human glucokinase.Glucokinase is that the N-end is by the terminal His label ((His) of N-
8-VEQILA......Q466) the people liver glucokinase of brachymemma is a soluble protein at expression in escherichia coli, and enzymic activity is suitable with the GK that extracts from liver.
Following the carrying out of purifying of people's glucokinase (hGK) of His-mark: will be resuspended in extraction buffer A (25mM HEPES (pH 8.0), 1mM MgCl that 5ml adds 0.25mg/mL N,O-Diacetylmuramidase and 50 μ g/ml sodiumazide from the cell mass of 50mL culture of Escherichia coli
2, 150mM NaCl, 2mM mercaptoethanol) in.After at room temperature 5 minutes, add 5ml and extract buffer B (1.5M NaCl, 100mM CaCl
2, 100mM MgCl
2, the 0.02mg/mlDNA enzyme, the proteinase inhibitor sheet (
1697498): 1 to the 20ml damping fluid).Then, with extracting solution with 15, centrifugal 30 minutes of 000g.With sample on the gained supernatant liquor to being filled with Ni
2+1ml metal chelate affinity chromatography (MCAC) post.Pillar is washed with the 2 volume buffer A that contain the 20mM imidazoles, use the hGK of 20 minutes gradient elution bonded His-marks of the buffer A that contains the 20-500mM imidazoles subsequently.Utilize the SDS-gel electrophoresis to check each flow point, merge the flow point that contains hGK (MW:52KDa).At last, utilize the gel-filtration step to carry out final refining and buffer-exchanged.To contain on the flow point of hGK sample to Superdex 75 (16/60) gel-filtration columns, with buffer B (25mM HEPES (pH 8.0), 1mM MgCl
2, 150mM NaCl, 1mM dithiothreitol (DTT)) and wash-out.Check the hGK that purifying is crossed with SDS-gel electrophoresis and MALDI mass spectrum, before freezing, add 20% glycerine at last.The yield that is obtained by the 50mL culture of Escherichia coli generally is about 2-3mg hGK, purity＞90%.
DMSO final concentration with 2.5% adds testing compound in each hole, add-on is enough to obtain required compound concentration, for example 1 μ M, 5 μ M, 10 μ M, 25 μ M or 50 μ M.After adding glucose to final concentration is 2mM, 5mM, 10mM or 15mM, begin reaction.Measure and adopt 96 hole UV plates, used final mensuration volume is 200 μ l/ holes.This plate was hatched under 25 ℃ 5 minutes, in SpectraMax, measure kinetics, measured once, measured 5 minutes in per 30 seconds in 340nm.The result of every kind of compound is expressed as deduction " blank " (promptly do not have and have glucokinase and do not have compound) back glucokinase activity than the activation of the glucokinase activatory in not having the mensuration of compound multiple.Compound among each embodiment all shows the glucokinase activation in this assay method.Concentration below 30 μ M is produced as the activator that the 1.5 times of active compounds of high glucokinase of measurement result that do not have compound are regarded as glucokinase.
The glucose-sensitive of compound is measured under the glucose concn of 10 μ M compound concentrations and 5mM and 15mM.
Glucokinase activation measurement (II)
The mensuration of glycogen deposition in the isolating rat hepatocytes:
By two step perfusion techniques, isolating hepatocytes from the rat of ad libitum access.The cell viability of assessing according to trypan blue exclusion method is all the time greater than 80%.With cell with 30, the cell density in 000/ hole is inoculated into the basic medium (Medium 199 (5.5mM glucose) on 96 orifice plates that scribble collagen protein, add 0.1 μ M dexamethasone, 100 units/ml penicillin, 100mg/ml Streptomycin sulphate, 2mM L-glutaminate and 1nM Regular Insulin) in, this substratum contains 4%FCS.Substratum was replaced with basic medium in back 1 hour in initial inoculation, so that remove dead cell.After 24 hours substratum is replaced by the basic medium of adding 9.5mM glucose and 10nM Regular Insulin, synthetic to induce glycogen, experiment was carried out at second day.With buffer A (117.6mM NaCl, 5.4mM KCl, the 0.82mM Mg of liver cell with preheating (37 ℃)
2SO
4, 1.5mMKH
2PO
4, 20mM HEPES, 9mM NaHCO
3, the HAS of 0.1% weight/volume and 2.25mM CaCl
2, 7.4,37 ℃ of pH) and washed twice, in 100 μ l buffer A (test compound that contains 15mM glucose and progressive concentration, for example 1 μ M, 5 μ M, 10 μ M, 25 μ M, 50 μ M or 100 μ M), hatched 180 minutes.Utilize standard method (Agius, L. etc., Biochem J.
266, 91-102 (1990) detects glycogen content.When in this assay method, using, cause that glycogen content is regarded as having activity in this assay method than the compound of the remarkable increase of the result in the assay method that does not have compound.
Glucokinase activation measurement (III)
Activators of glucokinase stimulates the insulin secretion in the INS-1E cell
As Asfari M etc., Endocrinology,
130, 167-178 (1992) is described, and cultivating the glucose responding beta cell is INS-1E.Then, seed cells in the 96 porocyte culture plates, grow to density and be about 5 * 10
4Individual/hole.The stimulation of following test glucose dependency insulin secretion: add under the situation of glucokinase activated compounds that concentration for example is 1 μ M, 5 μ M, 10 μ M, 25 μ M, 50 μ M or 100 μ M being with or without, hatched 2 hours in Krebs Ringer Hepes damping fluid in the 2.5-15mM glucose concn, collect supernatant liquor, measure insulin concentration (n=4) by ELISA.When in this assay method, using, cause in response to the insulin secretion of glucose and be regarded as in this assay method, having activity than the compound of the remarkable increase of the result in the assay method that does not have compound.
Although the present invention is described and illustrates with reference to its some preferred embodiment, those of skill in the art will recognize that under situation without departing from the spirit and scope of the present invention, can carry out various variations, modification and replacement to the present invention.For example, the effective dose beyond the preferred dose described herein also is an available, and this is the discrepant result of mammiferous reactivity who treats at the disease that the glucokinase shortage is mediated.Equally, whether viewed concrete pharmacological reaction can or exist pharmaceutical carrier and the preparation type that is adopted and administering mode different because of selected concrete active compound, and according to purpose of the present invention and practice, in expection difference on these results or difference also are encompassed in.
Embodiment
The abbreviation that uses among schema and the embodiment is as follows:
D=days
The g=gram
H=hour
The MHz=megahertz
The L=liter
The M=volumetric molar concentration
The mg=milligram
Min=minute
The mL=milliliter
The mM=millimolar concentration
The mmol=mmole
The mol=mole
N=is normal
The ppm=PPM
The i.v.=intravenously
The m/z=mass-to-charge ratio
The mp=fusing point
The MS=mass spectrum
The HPLC=high pressure liquid chromatography
HPLC-MS=high pressure liquid chromatography-mass spectrum
The NMR=nuclear magnetic resonance spectroscopy(NMR spectroscopy)
P.o.=is oral
R
t=retention time
The rt=room temperature
S.c.=is subcutaneous
The TLC=thin-layer chromatography
The BuOK=potassium tert.-butoxide
The Boc=tertbutyloxycarbonyl
The CDI=carbonyl dimidazoles
DBU=1,8-diazabicyclo [5.4.0]-11 carbon-7-alkene
DCM (CH
2Cl
2)=methylene dichloride
DHOBt=3,4-dihydro-3-hydroxyl-4-oxo-1,2,3-phentriazine
DIC=1, the 3-DIC
DCC=1, the 3-dicyclohexylcarbodiimide
DIEA=N, the N-diisopropylethylamine
DIPEA=N, the N-diisopropylethylamine
DMA=N, the N-N,N-DIMETHYLACETAMIDE
DMAP=4-(N, N-dimethylamino) pyridine
DMF=N, dinethylformamide
DMF=N, dinethylformamide
DMPU=N, N '-dimethyl allene urea, 1,3-dimethyl-2-oxo hexahydropyrimidine
EDAC=1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride
Et
2The O=ether
The EtOAc=ethyl acetate
The HMPA=HMPA
The HOBt=N-hydroxybenzotriazole
HOAt=7-azepine-I-hydroxybenzotriazole
LAH, (LiAlH
4)=lithium aluminum hydride
The LDA=lithium diisopropylamine
The MeCN=acetonitrile
MeOH=methyl alcohol
NMP=N-methylpyrrolidin-2-ketone
The NaH=sodium hydride
NH
2The OH=azanol
PyBroP=phosphofluoric acid bromine tripyrrole Wan Ji Phosphonium
TEA (Et
3N)=triethylamine
The TFA=trifluoroacetic acid
The THF=tetrahydrofuran (THF)
CDCl
3=deuterate chloroform
CD
3OD=four deuterate methyl alcohol
DMSO-d
6=six deuterate dimethyl sulfoxide (DMSO)
NMR
At ambient temperature, utilize Brucker Avance DPX 200 (200MHz), BruckerAvance DPX 300 (300MHz) and Brucker Avance DPX 400 (400MHz) record proton N MR spectrum, with tetramethylsilane as interior mark.Chemical shift (δ) provides with ppm.
HPLC-MS
Use following instrument:
Hewlett Packard series 1100 G1312A Bin pumps
Hewlett Packard series 1100 column compartments
Hewlett Packard series 1100 G1315A DAD diode-array detectors
Hewlett Packard series 1100 MSD
Sedere 75 light scattering detectors
Instrument is subjected to HP Chemstation software control.
The HPLC pump links to each other with two elutriant banks, wherein is equipped with:
The aqueous solution of A:0.01%TFA
The acetonitrile solution of B:0.01%TFA
Followingly analyze: the sample (preferred 1 μ l) of proper volume is expelled on the pillar, with acetonitrile gradient wash-out pillar in 40 ℃.
Used HPLC condition, detector setting and mass spectrograph are arranged in the following table and provide.
Post Waters Xterra MS C-18 * 3mm, diameter 5 μ m
Gradient is 5%-100% acetonitrile linearity in 7.5 minutes, 1.5mL/ minute
Detect 210nm (the simulation output of DAD)
ELS (the simulation output of ELS)
MS ionization Mode A PI-ES
Scanning 100-1000amu, step pitch 0.1amu
Shunting after the DAD produced about 1mL/ minute for ELS, produced about 0.5mL/ minute for MS.
The preparation HPLC method
HPLC method 1
In Gilson system (3 Gilson, 306 pumps, Gilson 170 DAD detectors and Gilson215 liquid processor), carry out the RP-purifying, wherein use Waters X-terra RP (10 μ m, 30mm * 150mm), gradient elution, 5%-95% solvent B (acetonitrile solution of 0.05%TFA)/solvent orange 2 A (aqueous solution of 0.05%TFA), in 15 minutes, 40mL/ minute, detect room temperature in 210nm.The flow point vacuum-evaporation that merges is to doing, and perhaps vacuum-evaporation is until removing acetonitrile, freezing then and freeze-drying.
HPLC-MS method 2
Carrying out RP-in the Agilent HPLC system (1100 de-gassing vessels, 1100 pumps, 1100 syringes and 1100 DAD) that is furnished with Agilent MS detector system SL type (MW 0-3000) and S.E.D.E.R.ESedex 75 ELS type detector systems analyzes, wherein use Waters X-terraMS C18 post (5 μ m, 3.0mm * 50mm), gradient elution, 5%-100% solvent B (acetonitrile solution of 0.05%TFA)/solvent orange 2 A (aqueous solution of 0.05%TFA), in 6.75 minutes, 25 ℃ of 1.5mL/ minutes, temperature.
General provisions
Following embodiment and common processes relate to the general formula of differentiating (I) in specification sheets and synthesis flow midbody compound and final product.Use following examples to describe the preparation of general formula of the present invention (I) compound in detail.Sometimes, the reaction described every kind of compound that equally is applied to be included in the open scope of the present invention of may getting along well.Persons skilled in the art are known the compound that has this situation easily.In these cases, can successfully react by conventional modification well known by persons skilled in the art, this conventional modification is by the suitable protection of disturbing group, by changing into other conventional reagent or changing reaction conditions by routine.Alternatively, other reaction disclosed herein or opposite popular response will be applied to prepare corresponding The compounds of this invention.In all preparation methods, all raw materials all are known, perhaps can perhaps can be prepared by common processes A-G described herein by the similar approach preparation of those skilled in the art with the preparation method of similar known compound.
The structure of compound confirms by nucleus magnetic resonance (NMR) and/or by HPLS-MS.
Common processes (A)
The compound of formula of the present invention (Ia) can following general introduction preparation, wherein R
1, R
2With A with the same to the definition of formula (I):
Step 1
Can utilize normative document method (for example WO 2004/002481), with carbonyl dimidazoles (CDI) or its equivalent, in solvent such as methylene dichloride, ethylene dichloride, tetrahydrofuran (THF) or DMF, with amino-heterocycles (NH
2A) (III) (wherein A is with the same to the definition of formula (I)) is converted into the acylimidazole intermediate.Use R
1R
2NH (II) (R wherein
1And R
2As above definition) handles, obtain formula (Ia) compound.Amino-heterocycles (NH
2A) or secondary amine (R
1R
2NH) can be the commercial compound, perhaps can be according to the described method preparation of document, perhaps by relevant embodiment and the described method preparation of common processes.
Step 2
In some cases, after forming urea, produce R
1, R
2With the final substituting group on the A may be more convenient.If in example, the substituting group in the formula (Ia) on the A contains ester functional group, then can use the standard conditions of ester hydrolysis that it is hydrolyzed to corresponding carboxylic acid.The suitable alkali that is used for hydrolysis is the equivalent or their mixture (being dissolved in as the solvent of diox, THF, EtOH, MeOH and water) of NaOH and LiOH or these alkali.Reaction can be carried out in room temperature or high temperature.
Other case description is in common processes I and J.
Common processes (B)
The described required amine R of common processes (A)
1R
2NH can followingly prepare by reductive amination: the technology according to description in the document (Org.Prep.Proced.Int.1979,11,201) as follows makes primary amine R in the solvent such as tetrahydrofuran (THF)
1NH
2With ketone R
2=O or aldehyde and reductive agent such as sodium cyanoborohydride react.
Primary amine, ketone and aldehyde can be the commercial compound, perhaps can be according to the described method preparation of document, perhaps by related embodiment and the described method preparation of common processes.
Common processes (C)
The preparation of trans-compounds such as alkoxy methyl hexahydroaniline
The carbonyl of 4-oxo-pimelinketone methyl-formiate can be protected as ketone acetal by reacting in the benzene of azeotropic removal of water with ethylene glycol.Available then lithium aluminum hydride in The suitable solvent such as ether or tetrahydrofuran (THF), makes the ester group reduction.Can use sodium hydride and suitable alkylogen (R-X, wherein R is a kind of suitable group), in solvent such as tetrahydrofuran (THF) or DMF, make pure alkylation, perhaps can be in Mitsunobu condition (Mitsunobu, 1981,1, change alcohol into aryl ethers or heteroaryl ether under 1-28).The ketone acetal deprotection of the product of formula insulin receptor antagonists under the standard acidic condition obtains ketone, and ketone can change corresponding oxime into when handling with azanol and suitable alkali (for example sodium acetate).Use the ethanolic soln reduction oxime of sodium, obtain the trans-amine into main isomer, this trans-amine can be by the recrystallization purifying of corresponding HCl salt in case of necessity.
Common processes (D)
The reductive amination of trans-compounds such as alkoxy methyl hexahydroaniline
Use common processes (B) to carry out amine (wherein R is the group that suits) and ketone or aldehyde R
2The reductive amination of=O obtains trans-alkoxy methyl hexahydroaniline.
Common processes (E)
The preparation of 2-amino-thiazolyl--5-sulphonamide
In the presence of the DCM solution of alkali (for example DIPEA), make amine NHR
19R
20(R wherein
19And R
20As to the definition of formula (I)), mixture and 2-acetylaminohydroxyphenylarsonic acid thiazole-5-SULPHURYL CHLORIDE (J.Am.Chem.Soc, 1947,69., 2063) reaction of shielded amino acid etc.In the presence of HCl De diox/EtOH solution, when heating, realize that the N-of intermediate is deacetylated, obtain needed amino sulfinyl-thiazolamine.
Common processes (F)
The preparation of trans-compounds such as aryloxy hexahydroaniline
At Mitsunobu condition (PBu for example
3/ ADDP or DEAD/PPh
3) under, the cis-4-hydroxyl hexahydroaniline of N-Boc protection (as in preparation described in the WO 2005/019222) can change corresponding trans-trifluoro ethoxy or suitable aryloxy-hexahydroaniline, N-deprotection in TFA/DCM subsequently in example.
Common processes (G)
The preparation of cycloalkyl-[trans-4-(alkoxyl group)-cycloalkyl]-compounds such as amine
Can use alkali such as NaH, potassium tert.-butoxide, DBU etc., in the solvent of DMF, NMP, DMSO, THF and so on, temperature in-10 ℃ to 120 ℃, make 2-(trans-4-hydroxyl-cyclohexyl)-isoindole-1 with alkylating agent R-halogenide or its equivalent, 3-two ketoalkylations (Glennon etc., J.Med.Chem.1996,39,1,314-322).In example, can use the ethanolic soln of hydrazine,, realize trans-4-alkoxyl group-cyclohexyl-isoindole-1, the deprotection of 3-diketone in room temperature or high temperature.Can use suitable ketone and reductive agent such as sodium cyanoborohydride or its equivalent to carry out reductive amination, realize the alkanisation of trans-alkoxyl group-hexahydroaniline.Reaction can be used dewatering agent such as molecular sieve or MgSO in the solvent of for example THF, EtOH or MeOH or their mixture
4Or in the presence of acetate, carry out.Reaction can be carried out-10 ℃ to 120 ℃ temperature.
Common processes (H)
The preparation of trans-compounds such as 4-alkyl-hexahydroaniline
With oxammonium hydrochloride and suitable alkali such as sodium acetate, in the solvent mixture of for example water/MeOH, when pyroprocessing, the pimelinketone (wherein substituent R is the group that suits) that 4-replaces can change corresponding oxime into.In an embodiment, use the ethanolic soln of sodium to obtain to be to carry out purifying by the recrystallization of corresponding HCl salt to it in case of necessity by the trans-4-alkyl-hexahydroaniline of main isomer at the high temperature reduction oxime.
Common processes (I)
Acyl group-or alkylsulfonyl-piperidyl-(thiazolyl)-cycloalkyl urea is synthetic
Step 1
At room temperature, to being dissolved in methyl alcohol (50ml) and the middle Cycloalkyl amine (4.5g) that adds equimolar amount of the N-Boc-piperidin-4-one-(10g) in tetrahydrofuran (THF) (50ml) mixture.Add sodium cyanoborohydride (6.3g, 2 equivalents), reactant is at room temperature stirred spend the night.Crude product filters by diatomite (celite), and vacuum concentration dissolves/is suspended in the ether, stirs decant 1 hour.This step repeats 4 times, the ether phase that vacuum concentration merges, and the 4-cycloalkyl amino-piperidines that obtains suiting-1-t-butyl formate (light yellow oil) can be directly used in step 2.
Step 2
With 1,1-carbonyl dimidazoles, aminoheteroaryl compounds (R wherein
7And R
8With to the definition of formula (I) the same (for example 5-methyl-thiazolamine)) and 4-Dimethylamino pyridine (5mol%) in methylene dichloride etc. molar mixture in 80 ℃ the heating 4 hours, be cooled to room temperature then.Add the amine product (1 equivalent) of step 1, reaction stirred is spent the night.Aftertreatment and chromatography (hexane solution of 5% ethyl acetate) obtain the needed urea of being protected by Boc.
Step 3
Use the DCM solution of trifluoroacetic acid (TFA) to carry out the Boc deprotection in 2 hours in room temperature.Vacuum is removed excessive TFA and DCM, obtains the amine crude product, can be directly used in next step.
Step 4
Utilize existing literature method, with HOBt activatory carboxylic acid (RCO
2H) or SULPHURYL CHLORIDE (RSO
2Cl) (wherein R is the group that suits) carries out acetylize, obtains needed acid amides or sulphonamide respectively.
Step 5
If the substituting group on the aminoheteroaryl part contains ester functional group, then can use the methanol solution hydrolysis of lithium hydroxide, obtain corresponding acid.
Common processes (J)
Compounds such as thiazole Thiovanic acid, propionic acid change amide compound into
Originally use suitable acid amides coupling reagent such as DHOBt and EDAC in solvent, to handle carboxylic acid such as dimethyl formamide.After with HPLC or purification by flash chromatography, can add primary amine or secondary amine alkali (for example DIPEA) then, obtain required acid amides together with equivalence.
Common processes (K)
Can add 3-bromo-2 afterwards by the MeOH solution-treated with sodium borohydride, 2-dimethyl-propionic acid prepares 3-(2-amino-thiazolyl--5-base sulfenyl)-2,2-dimethyl-ethyl propionate by 5-thiocyano-thiazol-2-yl amine.After the water law aftertreatment, the EtOH solution-treated of the available HCl of intermediate acid obtains 3-(2-amino-thiazolyl--5-base sulfenyl)-2,2-dimethyl-ethyl propionate.
After common processes (A), the aminothiazole ester can be coupled to final urea derivatives.
Embodiment 1
1,1-two cyclopentyl-3-thiazol-2-yl-urea
(50mg, (81mg 0.5mmol) and Dimethylamino pyridine (3mg), at room temperature stirred solution 1 hour to add carbonyl dimidazoles in dichloromethane solution 0.5mmol) to thiazolamine.Add two cyclopentamine (77mg) then, reactant is at room temperature stirred spend the night.Reaction mixture is used 10% sodium pyrosulfate (3mL), water (3mL) washing successively with ethyl acetate (8mL) dilution then, through dried over mgso, and vacuum concentration, resistates purified by flash chromatography (elutriant: ethyl acetate: heptane (7: 3)).
HPLC-MS：m/z＝280(M+H)
Embodiment 2
1-cyclopentyl-1-((3S, 5R)-3,5-dimethyl-cyclohexyl)-3-thiazol-2-yl-urea
As ((3S, 5R)-3,5-dimethyl-cyclohexyl)-amine of preparation cyclopentyl-1-as described in the common processes (B).Synthesize 1 to be similar to, the mode of 1-two cyclopentyl-3-thiazol-2-yl-urea uses carbonylic imidazole and thiazolamine to carry out the urea coupling as raw material.
HPLC-MS：m/z＝322(M+H)
Embodiment 3
1-(1,4-two oxa-s-spiral shell [4.5] last of the ten Heavenly stems-8-yl)-1-(4-methyl-cyclohexyl base)-3-thiazol-2-yl-urea
To be similar to the mode of embodiment 2, according to common processes (A) and (B), use 1,4-dioxo spiro [4.5] last of the ten Heavenly stems-8-ketone, 4-methyl cyclohexylamine and thiazolamine are as feedstock production.
HPLC-MS：m/z＝380(M+H)
Embodiment 4
1-cyclopentyl-1-(1,4-two oxa-s-spiral shell [4.5] last of the ten Heavenly stems-8-yl)-3-thiazol-2-yl-urea
To be similar to the mode of embodiment 2, according to common processes (A) and (B), use 1,4-dioxo spiro [4.5] last of the ten Heavenly stems-8-ketone, 4-methyl cyclohexylamine, cyclopentanone and thiazolamine are as feedstock production.
HPLC-MS：m/z＝352(M+H)
Embodiment 5
1-(4-methyl-cyclohexyl base)-3-(5-methyl-thiazol-2-yl)-1-(4-oxo-cyclohexyl)-urea
To be similar to the mode of embodiment 2, according to common processes (A) and (B), use 1,4-dioxo spiro [4.5] last of the ten Heavenly stems-8-ketone, 4-methyl cyclohexylamine and 2-amino-5-methylthiazol prepare 1-(1,4-two oxa-s-spiral shell [4.5] last of the ten Heavenly stems-8-yl)-1-(4-methyl-cyclohexyl base)-3-(5-methyl-thiazol-2-yl)-urea.Hydrolysis acetate (acetale) in the following manner then:
(100mg, 80% acetic acid aqueous solution (1.15mL) 0.25mmol) is in 60 ℃ of heating 3 with 1-(1,4-two oxa-s-spiral shell [4.5] last of the ten Heavenly stems-8-yl)-1-(4-methyl-cyclohexyl base)-3-(5-methyl-thiazol-2-yl)-urea
1/
2Hour.Reaction mixture vacuum-evaporation obtains golden oily matter to doing.Crude product HPLC purifying obtains title compound.
1H-NMR (CDCl
3): 7.02 (d, 1H), 3.66 (wide unimodal, 2H), 2.66 (m, 3H), 2.46 (m, 3H), 2.37 (s, 3H), 1.98 (m, 4H), 1.76 (m, 3H), 1.59 (m, 2H), 1.39 (m, 2H), 1.05 (d, 1H), 0.91 (d, 2H).
HPLC-MS：m/z＝350(M+H)
Embodiment 6
2-[3-dicyclohexyl urea groups]-5-[4-methylpiperazine-1-yl]-thiazole-4-yl }-ethyl acetate
Step 1
Use dicyclohexyl amine, carbonyl dimidazoles and 2-amino-4-thiazole ethyl acetate, synthesize 1 to be similar to, the mode of 1-two cyclopentyl-3-thiazol-2-yl-urea prepares [2-(3,3-dicyclohexyl-urea groups)-thiazole-4-yl]-ethyl acetate.
Step 2
To 2-(3,3-dicyclohexyl-urea groups)-thiazole-4-yl]-ethyl acetate (3.0g, add in acetate 7.62mmol) (250mL) solution N-chloro-succinimide (1.32g, 9.91mmol).Reaction mixture stirred 20 hours under nitrogen atmosphere, room temperature.The vacuum-evaporation mixture is to doing.Resistates is dissolved in the methylene dichloride (100mL), wash with the 10% sodium pyrosulfate aqueous solution (50mL), (50mL) is saturated with sodium bicarbonate, through dried over mgso, vacuum-evaporation obtains thick intermediate to doing, and it is further purified (elutriant: ethyl acetate/heptane (1: 4)) on silicagel column, obtain 5-chloro-2-[3-dicyclohexyl urea groups]-thiazole-4-yl }-ethyl acetate, be yellow crystals (output: 1.89g (58%)).Crystal contains 10% the chloro-of having an appointment { 2-[3-dicyclohexyl urea groups]-thiazole-4-yl }-ethyl acetate.
Step 3
To { 5-chloro-2-[3-dicyclohexyl urea groups]-thiazole-4-yl }-ethyl acetate (100mg, add in methylene dichloride 0.234mmol) (5mL) solution DIPEA (60 μ l, 0.35mmol) and N methyl piperazine (33 μ l, 0.298).Reaction mixture was at room temperature stirred 48 hours, filter, vacuum-evaporation is to doing.Crude product HPLC purifying, obtain 2-[3,3-dicyclohexyl urea groups]-5-[4-methylpiperazine-1-yl]-thiazole-4-yl }-ethyl acetate.Output: 13mg (11%)..
1H-NMR (CD
3OD): δ 4.15 (q, 2H), 3.67 (s, 2H), 3.55 (m, 2H), 3.47 (m, 2CH), 3.28 (m, 2H), 3.06 (t, 2H), 2.96 (s, 3H), 1.96 (m, 4H), 1.82 (wide bimodal, 5H), 1.66 (wide bimodal, 6H), 1.32-1.40 (4H, m), 1.25 (t, 3H), 1.10-1.30 (m, 1H).
HPLC-MS：m/z＝492(M+H)
Embodiment 7
1,1-dicyclohexyl-3-(5-imidazoles-1-base-thiazol-2-yl)-urea
Step 1
With 2-amino-5-bromo thiazole hydrobromate (0.5g, 1.92mmol), DMF (6mL), salt of wormwood (1.0g, 7.2mmol) and imidazoles (132mg, mixture 1.94mmol) at room temperature stirred 6 hours.Filtering mixt, filtered solution vacuum-evaporation is to doing.Crude product is purifying (elutriant: the gradient of 100% methylene dichloride to 100% Virahol), obtain 5-imidazoles-1-base-thiazol-2-yl amine on silicagel column.Output: 0.16g (50%).
Step 2
In the mode identical with embodiment 1, use carbonyl dimidazoles, 2-amino-5-imidazol-thiazole and dicyclohexyl amine to carry out the urea coupling, obtain 1,1-dicyclohexyl-3-(5-imidazoles-1-base-thiazol-2-yl)-urea.
1H-NMR (CDCl
3): δ 7.96 (wide unimodal, 1H), 7.69 (s, 1H), 7.32 (s, 1H), 7.17 (s, 1H), 7.13 (s, 1H), 3.43 (m, 2H), 1.95-1.60 (m, 14H), 1.40-1.10 (m, 6H).
HPLC-MS：m/z＝375(M+H)
Embodiment 8
3-(5-chloro-thiazol-2-yl)-1,1-pair-(tetrahydrochysene-pyrans-4-yl)-urea
To be similar to the mode of embodiment 2, according to common processes (A) and (B), use Tetrahydro-pyran-4-one, 4-amino tetrahydro pyran and the preparation of 5-chloro-2 aminothiazoles.
HPLC-MS：m/z＝346(M+H)
Embodiment 9
3-[2-(3,3-dicyclohexyl-urea groups)-thiazole-4-methylthiol]-propionic acid
Synthesis technique according to { 2-[3-cyclopentyl-3-(trans-4-methoxyl group-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate uses dicyclohexyl amine and 3-(2-amino-thiazolyl--4-methylthiol)-ethyl propionate (according to the method preparation that is similar to the methyl esters of record among the WO 2004/002481) preparation.
HPLC-MS：m/z?426(M+H)。
Embodiment 10
[2-(3,3-dicyclohexyl-urea groups)-thiazole-4-base methylsulfonyl]-acetate
Montmorillonite (161mg) and water (38 μ L) were stirred 10 minutes, add then oxone (187mg, 0.30mmol) and DCM (200 μ L).Then add 3-[2-(3,3-dicyclohexyl-urea groups)-thiazole-4-methylthiol]-(50mg, DCM 0.12mmol) (1mL) solution at room temperature stirred reaction mixture 3 days propionic acid.Leach solid, with MeOH washing, filtered solution vacuum concentration.Crude product preparation HPLC purifying obtains 20mg[2-(3,3-dicyclohexyl-urea groups)-thiazole-4-base methylsulfonyl]-acetate.
HPLC-MS：m/z?444(M+H)
Embodiment 11
1-(4-amino-cyclohexyl)-1-cyclohexyl-3-(5-methyl-thiazol-2-yl)-urea
Synthesis technique according to { 2-[3-cyclopentyl-3-(trans-4-methoxyl group-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate uses 4-tertbutyloxycarbonyl amine-pimelinketone, hexahydroaniline and 5-methyl-thiazol-2-yl amine preparation.
HPLC-MS：m/z?337(M+H)
Embodiment 12
1-(1-ethanoyl-piperidin-4-yl)-1-cyclopentyl-3-thiazol-2-yl-urea
Prepare according to common processes (I).In N-ethanoyl-piperidone (1.4g) and cyclopentamine (0.9g) and the mixture of molecular sieve (5g) in THF (8mL) and methyl alcohol (8mL), add sodium cyanoborohydride (2.1g), reactant is at room temperature stirred spend the night.By removing by filter insoluble substance, isolate crude product secondary amine (0.57g) after the solvent removed in vacuo.Synthesize 1 to be similar to, the mode of 1-two cyclopentyl-3-thiazol-2-yl-urea uses carbonylic imidazole and thiazolamine to carry out the urea coupling as raw material.
HPLC-MS：m/z＝359(M+Na)
Embodiment 13
Trans-3-(5-chloro-thiazol-2-yl)-1-cyclohexyl-1-[1-(3-phenyl-acryl)-piperidin-4-yl]-urea
To be similar to the synthetic mode of embodiment 12,, use 4-Boc-amino piperidine hydrochloride, hexahydroaniline, 5-chloro-thiazolamine and styracin as feedstock production according to common processes (I).
HPLC-MS：m/z＝495(M+Na)
Embodiment 14
3-(5-chloro-thiazol-2-yl)-1-cyclohexyl-1-[1-(2-phenoxy group-ethanoyl)-piperidin-4-yl]-urea
To be similar to the synthetic mode of embodiment 12,, use 4-Boc-amino piperidine hydrochloride, hexahydroaniline, 5-chloro-thiazolamine and phenylium as feedstock production according to common processes (I).
HPLC-MS：m/z＝477(M+Na)
Embodiment 15
2-(3,3-dicyclohexyl urea groups)-4-methylthiazol-5-N-(2-hydroxyethyl) methane amide
In the mixture of 2-amino-4-methyl-thiazole-N-(2-hydroxyethyl)-methane amide (0.2g) and methylene dichloride, add N, O-pair-(trimethyl silyl)-ethanamide (0.2g), stirred the mixture 12 hours.Add CDI (0.16g) and DMAP (6mg) then, stirred the mixture 12 hours, add dicyclohexyl amine (0.18g) afterwards.After stirring is spent the night, add entry, the water dichloromethane extraction concentrates, and uses chromatography purification, obtains title compound.
1H?NMR(DMSO)：δ0.95-2.18(m，20H)，3.20-3.60(m，6H)，2.42(s，3H)，10.80-11-03(bs，1H)。
Embodiment 16
1-(1-ethanoyl-piperidin-4-yl)-3-(5-chloro-thiazol-2-yl)-1-suberyl-urea
To be similar to the synthetic mode of embodiment 12,, use 4-ethanoyl-amino-piperadine, suberone and 5-chloro-thiazolamine as feedstock production according to common processes (I).
1H?NMR(CDCl
3)：δ1.37-2.18(m，16H)，2.13(s，3H)，2.49-2.67(m，1H)，3.07-3.22(m，1H)，3.33-3.43(m，1H)，3.85-3.96(1H，m)，3.97-4.28(m，1H)，4.70-4.81(m，1H)，7.17(s，1H)。
HPLC-MS：m/z＝399(M+H)
Embodiment 17
3-(5-chloro-thiazol-2-yl)-1-(1-methylsulfonyl-piperidin-4-yl)-1-(trans-4-methyl-cyclohexyl base)-urea
To be similar to the synthetic mode of embodiment 12,, use 4-Boc-amino-piperadine ketone, trans-the 4-methyl cyclohexylamine, 5-chloro-thiazolamine and methylsulfonyl chloride as feedstock production according to common processes (I).
HPLC-MS：m/z＝435(M+H)
Embodiment 18
3-(5-chloro-thiazol-2-yl)-1-(1-ethylsulfonyl-piperidin-4-yl)-1-(trans-4-methyl-cyclohexyl base)-urea
To be similar to the synthetic mode of embodiment 12,, use 4-Boc-amino piperidine hydrochloride, trans-the 4-methyl cyclohexylamine, 5-chloro-thiazolamine and ethyl sulfonyl chloride as feedstock production according to common processes (I).
HPLC-MS：m/z＝453(M+H)
Embodiment 19
3-(5-chloro-thiazol-2-yl)-1-cyclohexyl-1-[1-(third-1-alkylsulfonyl)-piperidin-4-yl]-urea
To be similar to the synthetic mode of embodiment 12,, use 4-Boc-amino-piperadine, pimelinketone, 5-chloro-thiazolamine and third SULPHURYL CHLORIDE as feedstock production according to common processes (I).
HPLC-MS：m/z＝449(M+H)
Embodiment 20
2-[2-(3,3-dicyclohexyl-urea groups)-thiazole-5-base sulfenyl]-2-methyl-propionic acid
Step 1
With 1,1-carbonyl dimidazoles, 5-thiocyano-thiazol-2-yl amine (commercially available prod or press document J.Am.Chem.Soc 71,4007,1949 or J.Med.Chem, 20, method described in 572,1977 preparation) and DMAP (5mol%) in THF etc. molar mixture heated 2 hours in 60-70 ℃, be cooled to room temperature then.Add dicyclohexyl amine (1 equivalent), reactant is at room temperature stirred spend the night.Water quencher reaction mixture.Separate organic phase, water CH
2Cl
2Extraction is with organic phase drying, the vacuum concentration that merges.Crude product obtains 1,1-dicyclohexyl-3-(5-thiocyano-thiazol-2-yl)-urea (oily matter) with purified by flash chromatography (heptane: EtOAc 100: 0 → 50: 50).
Step 2
Under nitrogen atmosphere, with 1,4-dithiothreitol (DTT) (DTT) and 1, the wait molar mixture of 1-dicyclohexyl-3-(5-thiocyano-thiazol-2-yl)-urea (as in preparation described in the step 1) in MeOH (4mL/mmol) at room temperature stirred 2 hours.Add K
2CO
3(3 equivalent) and 2 bromo 2 methyl propionic acid ethyl ester (1.1 equivalent).Reaction mixture at room temperature stirred spend the night the water quencher.Add CH
2Cl
2Separate organic phase, water CH
2Cl
2Extraction, the organic phase that vacuum concentration merges.Crude product is dissolved among the MeCN, and with anti-phase preparation method purifying (HPLC method 1), obtains 2-[2-(3,3-dicyclohexyl-urea groups)-thiazole-5-base sulfenyl]-2-methyl-ethyl propionate (oily matter).This product is dissolved among the MeOH, handles with 20 normal 1N NaOH, in stirred overnight at room temperature.MeOH is removed in evaporation.Add 1N HCl to pH＜1, produce precipitation.Throw out comes out by filtering separation, washes with water, and drying obtains title compound.
HPLC-MS method 2:m/z=426 (M+H).
1H?NMR(CDCl
3)δ7.09(s，1H)，3.50(br?s，2H)，1.87-1.12(m，20H)，1.60(s，6H)。
Embodiment 21
2-[2-(3,3-dicyclohexyl-urea groups)-thiazole-5-base sulfenyl]-propionic acid
To be similar to 2-[2-(3,3-dicyclohexyl-urea groups)-thiazole-5-base sulfenyl]-mode of 2-methyl-propionic acid, use the 2 bromopropionic acid ethyl ester to prepare title compound as alkylating agent.
HPLC-MS method 2:m/z=412 (M+H).
1H?NMR(CDCl
3)δ7.11(s，1H)，3.62(q，1H)，3.44(br?s，2H)，1.86-1.12(m，20H)，1.48(d，3H)。
Embodiment 22
[2-(3-hexamethylene-3-thiazolinyl-3-cyclohexyl-urea groups)-thiazole-5-base sulfenyl]-acetate
Synthetic method according to { 2-[3-cyclopentyl-3-(trans-4-methoxyl group-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate uses hexamethylene-3-enamine, pimelinketone and (2-amino-thiazolyl--5-base sulfenyl)-ethyl acetate as feedstock production.
HPLC-MS：m/z?396(M+H)。
Embodiment 23
2-[3-cyclohexyl-3-(1-dimethylamino alkylsulfonyl-piperidin-4-yl)-urea groups]-thiazole-5-base sulfenyl }-acetate
To be similar to the synthetic mode of embodiment 12, by N-Boc piperidone, hexahydroaniline and (2-amino-thiazolyl--5-base sulfenyl)-ethyl acetate preparation { 2-[3-cyclohexyl-3-piperidin-4-yl-urea groups]-thiazole-5-base sulfenyl }-ethyl acetate, slough Boc, react with the dimethylamino SULPHURYL CHLORIDE, as in ester hydrolysis part described in the common processes (I), obtain title compound.
1H?NMR(CDCl
3)：δ1.11-1.88(m，14H)，2.85(s，6H)，2.85-3.04(m，4H)，3.37(s，2H)，3.72-3.85(m，2H)，7.30(s，1H)。
HPLC-MS：m/z?506(M+H)。
Embodiment 24
3-(2-{3-cyclohexyl-3-[1-(morpholine-4-carbonyl)-piperidin-4-yl]-urea groups }-thiazole-5-base sulfenyl)-propionic acid
To be similar to the synthetic mode of embodiment 12, by N-Boc piperidone, hexahydroaniline and (2-amino-thiazolyl--5-base sulfenyl)-ethyl acetate preparation { 2-[3-cyclohexyl-3-piperidin-4-yl-urea groups]-thiazole-5-base sulfenyl }-ethyl propionate, slough Boc, react with 4-morpholine formyl chloride, as in ester hydrolysis part described in the common processes (I), obtain title compound.
1H?NMR(CDCl
3)：δ1.11-1.95(m，14H)，2.68-3.03(m，6H)，3.25-3.34(m，4H)，3.65-3.85(m，8H)，7.32(s，1H)。
HPLC-MS：m/z?527(M+H)。
Embodiment 25
(2-{3-cyclohexyl-3-[1-(morpholine-4-carbonyl)-piperidin-4-yl]-urea groups }-thiazole-5-base sulfenyl)-acetate
To be similar to the synthetic mode of embodiment 12, by N-Boc piperidone, hexahydroaniline and (2-amino-thiazolyl--5-base sulfenyl)-ethyl acetate preparation { 2-[3-cyclohexyl-3-piperidin-4-yl-urea groups]-thiazole-5-base sulfenyl }-ethyl acetate, slough Boc, react with 4-morpholine formyl chloride, as in ester hydrolysis part described in the common processes (I), obtain title compound.
1H?NMR(CDCl
3)：δ1.05-1.95(m，14H)，2.78-3.03(m，2H)，3.22-3.33(m，4H)，3.36(s，2H)，3.62-3.74(4H，m)，3.75-3.83(m，4H)，7.32(s，1H)。
HPLC-MS：m/z?512(M+H)。
Embodiment 26
3-{2-[3-cyclohexyl-3-(1-dimethylamino alkylsulfonyl-piperidin-4-yl)-urea groups]-thiazole-5-base sulfenyl }-propionic acid
To be similar to the synthetic mode of embodiment 12, by N-Boc piperidone, hexahydroaniline and (2-amino-thiazolyl--5-base sulfenyl)-ethyl acetate preparation { 2-[3-cyclohexyl-3-piperidin-4-yl-urea groups]-thiazole-5-base sulfenyl }-ethyl propionate, slough Boc, react with the dimethylamino SULPHURYL CHLORIDE, as in ester hydrolysis part described in the common processes (I), obtain title compound.
1H?NMR(CDCl
3)：δ1.11-2.00(m，14H)，2.85(s，6H)，2.70-3.24(m，6H)，3.69-3.90(m，4H)，7.29(s，1H)。
HPLC-MS：m/z?520(M+H)。
Embodiment 27
2-[3-cyclohexyl-3-(1-formyl-dimethylamino-piperidin-4-yl)-urea groups]-thiazole-5-base sulfenyl }-acetate
To be similar to the synthetic mode of embodiment 12, by N-Boc piperidone, hexahydroaniline and (2-amino-thiazolyl--5-base sulfenyl)-ethyl acetate preparation { 2-[3-cyclohexyl-3-piperidin-4-yl-urea groups]-thiazole-5-base sulfenyl }-ethyl acetate, slough Boc, react with the dimethylamino formyl chloride, as in ester hydrolysis part described in the common processes (I), obtain title compound.
1H?NMR(CDCl
3)：δ1.11-1.88(m，14H)，2.85(s，6H)，2.85-3.04(m，4H)，3.34(s，2H)，3.72-3.85(m，2H)，7.30(s，1H)。
HPLC-MS：m/z?471(M+H)。
Embodiment 28
3-{2-[3-cyclohexyl-3-(1-formyl-dimethylamino-piperidin-4-yl)-urea groups]-thiazole-5-base sulfenyl }-propionic acid
By N-Boc piperidone, hexahydroaniline and (2-amino-thiazolyl--5-base sulfenyl)-ethyl acetate preparation { 2-[3-cyclohexyl-3-piperidin-4-yl-urea groups]-thiazole-5-base sulfenyl }-ethyl propionate, slough Boc, react with the dimethylamino formyl chloride, as in ester hydrolysis part described in the common processes (I), obtain title compound.
HPLC-MS：m/z?485(M+H)。
Embodiment 29
6-{4-[3-(5-chloro-thiazol-2-yl)-1-cyclohexyl-urea groups]-piperidines-1-yl }-the 6-oxo-oneself-the 3-olefin(e) acid
As using 3-(5-chloro-thiazol-2-yl)-1-(trans-4-methyl-cyclohexyl base)-1-piperidin-4-yl-urea and trans-2-butene-1 described in the common processes (I), the preparation of 4-dioctyl phthalate.
1H?NMR(CDCl
3)：δ1.10-2.00(m，14H)，2.80-3.40(m，6H)，3.75(d，2H)，4.65(d，2H)，5.52-5.63(m，1H)，5.35-5.85(m，1H)，7.10(s，1H)。
HPLC-MS：m/z?469(M+H)。
Embodiment 30
1-(1-ethanoyl-piperidin-4-yl)-1-(trans-4-methyl-cyclohexyl base)-3-[5-(2-oxo-2-piperidines-1-base-ethylmercapto group)-thiazol-2-yl]-urea
As described in the common processes (I) by 1-[4-(trans-4-methyl-cyclohexyl base amino)-piperidines-1-yl]-ethyl ketone and the preparation of (2-amino-thiazolyl--5-base sulfenyl)-ethyl acetate { 2-[3-(1-ethanoyl-piperidin-4-yl)-3-(trans-4-methyl-cyclohexyl base)-urea groups]-thiazole-5-base sulfenyl }-acetate.Following then use common processes (J) is carried out the acid amides coupling: will { 2-[3-(1-ethanoyl-piperidin-4-yl)-3-(trans-4-methyl-cyclohexyl base)-urea groups]-thiazole-5-base sulfenyl }-acetate dissolve/be suspended among the 1ml DMF in the 4ml vial of being furnished with magnetic stirring bar and nut.Add 0.015g (0.088mmol) DHOBt+0.017g (0.088mmol) EDAC, at room temperature stir 1 hour (clarifying yellow mixture), after this add 0.088mmol piperidines and 0.015ml (0.088mmol) diisopropylethylamine.At room temperature stirred 3 days, and used the HPLC purifying, obtain title compound.
HPLC-MS：m/z?522(M+H)。
Embodiment 31
2-{2-[3-(1-ethanoyl-piperidin-4-yl)-3-(trans-4-methyl-cyclohexyl base)-urea groups]-thiazole-5-base sulfenyl }-N, N-diethyl-ethanamide
To be similar to 1-(1-ethanoyl-piperidin-4-yl)-1-(trans-4-methyl-cyclohexyl base)-3-[5-(2-oxo-2-piperidines-1-base-ethylmercapto group)-thiazol-2-yl]-mode of urea, use 2-[3-(1-ethanoyl-piperidin-4-yl)-3-(trans-4-methyl-cyclohexyl base)-urea groups]-thiazole-5-base sulfenyl }-acetate and diethylamine preparation.
HPLC-MS：m/z?510(M+H)。
Embodiment 32
1-(1-ethanoyl-piperidin-4-yl)-1-(trans-4-methyl-cyclohexyl base)-3-{5-[2-(4-methyl-piperazine-1-yl)-2-oxo-ethylmercapto group]-thiazol-2-yl }-urea
To be similar to 1-(1-ethanoyl-piperidin-4-yl)-1-(trans-4-methyl-cyclohexyl base)-3-[5-(2-oxo-2-piperidines-1-base-ethylmercapto group)-thiazol-2-yl]-mode of urea, use 2-[3-(1-ethanoyl-piperidin-4-yl)-3-(trans-4-methyl-cyclohexyl base)-urea groups]-thiazole-5-base sulfenyl }-acetate and N methyl piperazine preparation.
HPLC-MS：m/z?537(M+H)。
Embodiment 33
1-(1-ethanoyl-piperidin-4-yl)-1-(trans-4-methyl-cyclohexyl base)-3-{5-[2-oxo-2-(4-pyrimidine-2-base-piperazine-1-yl)-ethylmercapto group]-thiazol-2-yl }-urea
To be similar to 1-(1-ethanoyl-piperidin-4-yl)-1-(trans-4-methyl-cyclohexyl base)-3-[5-(2-oxo-2-piperidines-1-base-ethylmercapto group)-thiazol-2-yl]-mode of urea, use 2-[3-(1-ethanoyl-piperidin-4-yl)-3-(trans-4-methyl-cyclohexyl base)-urea groups]-thiazole-5-base sulfenyl }-acetate and the preparation of 2-(piperazinyl) pyrimidine.
HPLC-MS：m/z?601(M+H)。
Embodiment 34
1-(1-ethanoyl-piperidin-4-yl)-1-(trans-4-methyl-cyclohexyl base)-3-thiazol-2-yl-urea
To be similar to the synthetic mode of embodiment 12, use universal method (I), by 1-[4-(trans-4-methyl-cyclohexyl base amino)-piperidines-1-yl]-ethyl ketone and aminothiazole preparation.
1H-NMR (CDCl
3): δ 8.36 (wide unimodal, 1H), 7.33 (d, 1H), 6.85 (d, 1H), 4.76 (dm, 1H), 3.89 (dm, 1H), 3.78 (m, 1H), 3.30 (m, 1H), 3.08 (dt, 1H), 2.53 (dt, 1H), 2.1-2.2 (m, 2H), 2.12 (s, 3H), 1.95-1.64 (m, 8H), 1.36-1.45 (m, 1H), 1.04 (m, 2H), 0.92 (d, 3H).
HPLC-MS：m/z?365(M+H)。
Embodiment 35
2-[3-cyclohexyl-3-(trans-4-methyl-allyloxy-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate
Synthetic method preparation according to { 2-[3-cyclopentyl-3-(trans-4-methoxyl group-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate.
Step 1
Use (trans-4-hydroxyl-cyclohexyl)-isoindole-1,3-diketone, 3-bromo-2-methyl-propylene and pimelinketone prepare cyclohexyl-[trans-4-(2-methyl-allyloxy)-cyclohexyl]-amine.
Step 2
Use cyclohexyl-[trans-4-(2-methyl-allyloxy)-cyclohexyl]-amine and (amino-thiazolyl--5-base sulfenyl)-ethyl acetate preparation (2-{3-cyclohexyl-3-[is trans-4-(2-methyl-allyloxy)-cyclohexyl]-urea groups-thiazole-5-base sulfenyl)-acetate.
1H?NMR(CDCl
3)δ7.25(s，1H)，4.98(s，1H)，4.90(s，1H)，3.92(s，2H)，3.6-3.2(m，3H)，3.32(s，2H)，2.5-1.0(m，21H)。
HPLC-MS：m/z 469(M+H)。
Embodiment 36
3-(2-{3-cyclohexyl-3-[is trans-4-(2-methyl-allyloxy)-cyclohexyl]-urea groups }-thiazole-5-base sulfenyl)-propionic acid
Synthetic method preparation according to { 2-[3-cyclopentyl-3-(trans-4-methoxyl group-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate.
Step 1
Use (trans-4-hydroxyl-cyclohexyl)-isoindole-1,3-diketone, 3-bromo-2-methyl-propylene and pimelinketone prepare cyclohexyl-[trans-4-(2-methyl-allyloxy)-cyclohexyl]-amine.
Step 2
Use cyclohexyl-[trans-4-(2-methyl-allyloxy)-cyclohexyl]-amine and (amino-thiazolyl--5-base sulfenyl)-ethyl propionate prepare 3-(2-{3-cyclohexyl-3-[is trans-4-(2-methyl-allyloxy)-cyclohexyl]-urea groups-thiazole-5-base sulfenyl)-propionic acid.
1H?NMR(400MHz，DMSO-d
6)δ7.39(s，1H)，4.92(s，1H)，4.82(s，1H)，3.87(s，2H)，3.7-3.3(m，2H)，3.30-3.10(m，1H)，2.85(t，2H)，2.50(t，2H)，2.2-1.0(m，18H)，1.65(s，3H)。
HPLC-MS：m/z?483(M+H)。
Embodiment 37
2-[3-cyclohexyl-3-(trans-4-methoxymethyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate
Following use common processes (C), (D) and (A) preparation.
Step 1 and 2
With the mixture reflux of 4-carboxymethyl pimelinketone (21g), ethylene glycol (19g), the vitriol oil (0.3mL) and benzene (250mL) 20 hours, with Dean Stark azeotropic removal of water.After cooling, gained solution washs with sodium hydrogen carbonate solution, through dried over mgso, and concentrates.Then, thick ketone acetal is dissolved in the ether (250mL), adds lithium aluminum hydride (7g).Stir the mixture and spend the night, add entry (20mL), 10% sodium hydroxide (30mL) and water (30mL) then carefully.Add sodium sulfate (30g) then, stirred the mixture 20 minutes.By removing by filter insoluble substance, the vacuum concentration organic phase obtains (1,4-two oxa-s-spiral shell [4.5] last of the ten Heavenly stems-8-yl)-methyl alcohol (21g).
1H?NMR(CDCl
3)：δ1.20-1.80，(m，10H)，3.45(d，2H)，3.95(s，4H)。
Step 3 and 4
In tetrahydrofuran (THF) (300mL) solution of (1,4-two oxa-s-spiral shell [4.5] last of the ten Heavenly stems-8-the yl)-methyl alcohol (10g) in ice bath, add sodium hydride (3.6g, 60% mineral oil solution), stirred the mixture 30 minutes.Drip THF (20mL) solution of methyl-iodide 7.8mL, reactant is spent the night lentamente be warming up to room temperature.Add entry (20mL), the partial concentration reaction mixture distributes between water (100mL) and ether (300mL) then.Separate organic phase, drying, and vacuum concentration.Then, crude product is dissolved in the tetrahydrofuran (THF) (250mL), and adds the 3N HCl aqueous solution of 40mL.At room temperature reaction stirred is 2 hours, partial concentration, and crude product extracted with diethyl ether then, drying concentrates, and with purified by flash chromatography (elutriant: hexane: ethyl acetate (4: 1)), obtain 4-methoxymethyl-pimelinketone (4.9g).
1H?NMR(CDCl
3)：δ1.40-1.55(m，2H)，1.98-2.15(m，3H)，2.20-2.45(m，4H)，(d，2H)，3.36(d，4H)，3.31(s.3H)。
Step 5 and 6
4-methoxymethyl-pimelinketone (5g), oxammonium hydrochloride (4.7g) and sodium acetate (5.6g) mixture in water (125mL) and methyl alcohol (25mL) was heated 18 hours in 60 ℃.Add ether, separate organic phase, with the saturated sodium bicarbonate washing, through dried over mgso, and vacuum concentration.Add ethanol, add sodium (8g) then in batches.Then, mixture heating up to 65 ℃ is reached 1.5 hours, in ice bath, cool off, add entry (10mL) carefully.The partial concentration reactant adds entry (30mL), the water extracted with diethyl ether, and concentrate, obtain crude product.Add 6N HCl, obtain corresponding HCl salt,, obtain trans-4-methoxymethyl-cyclohexylamine hydrochloride (3g) by the acetonitrile recrystallization.
1H?NMR(DMSO-d
6)：δ0.90-1.15(m，2H)，1.20-1.37(m，2H)，1.38-1.54(m，1H)，1.73(d，2H)，1.95(d，2H)，2.80-2.95(m，1H)，3.12(d，2H)，3.22(s.3H)，8.21(s，3H)。
Step 7
In trans-4-methoxymethyl-cyclohexylamine hydrochloride (0.7g), pimelinketone (0.4g), diisopropylethylamine (0.5g) and the mixture of molecular sieve (5mL) in THF (5mL) and methyl alcohol, add sodium cyanoborohydride (0.49g), mixture is at room temperature stirred spend the night.By removing by filter insoluble substance, use the purified by flash chromatography crude product, obtain cyclohexyl-(trans-4-methoxymethyl-cyclohexyl)-amine (0.29g).
HPLC-MS：m/z?227(M+H)。
Step 8
(2-amino-thiazolyl--5-base sulfenyl)-ethyl acetate, carbonyl dimidazoles (0.34g) and the mixture of 4-Dimethylamino pyridine (12mg) in methylene dichloride (10mL) and tetrahydrofuran (THF) (10mL) were at room temperature stirred 5 hours.Add cyclohexyl-(trans-4-methoxymethyl-cyclohexyl)-amine, reactant is at room temperature stirred spend the night then.Obtain { 2-[3-cyclohexyl-3-(trans-4-methoxymethyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-ethyl acetate with purified by flash chromatography.
HPLC-MS：m/z?471(M+H)。
Step 9
Will { 2-[3-cyclohexyl-3-(trans-4-methoxymethyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetic acid ethyl dissolution in methyl alcohol (10mL), add 1N sodium hydroxide (5mL).At room temperature stirred 3 hours, and used the 1N hcl acidifying then.Filter white precipitate, and dry, obtain title compound (97mg).
1H?NMR(CDCl
3)：δ1.0-2.0(m，19H)，3.15-3.50(2H，m)，3.21(d，2H)，3.35(s，3H)，3.34(s，2H)，7.28(s，1H)。
HPLC-MS：m/z?443(M+H)。
Embodiment 38
2-[3-cyclopentyl-3-(trans-4-ethyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate
Step 1
To 4-ethyl cyclohexanone oxime (33g, 0.23mol) (according to document R.O.Hutchins etc., J.Org.Chem.60 (1995) 7396-7405 preparation) (45g 1.96mol), maintains the temperature at below 65 ℃ simultaneously slowly to add sodium in 99.9% ethanol (500mL) solution.Reaction mixture heats 1 under reflux temperature
1/
2Hour, restir 16 hours at room temperature then.The mixture that adds entry (500mL) and ethanol (100mL), (3 * 250mL) extract mixture with ether.Organic phase with salt solution (150mL) washing merges through anhydrous magnesium sulfate drying, is evaporated to dried.Resistates is dissolved in the ethanol (100mL), with 4N hydrochloric acid (60mL) with pH regulator to about 3, vacuum evaporated solution obtains the crude product ethyl cyclohexylamine to doing.This product is by carrying out purifying by ethanol/acetonitrile (4: 1) recrystallization, obtain 4-trans-the ethyl cyclohexylamine hydrochloride, be white crystal.
Step 2
To 4-trans-ethyl cyclohexylamine hydrochloride (in step 1 preparation), diisopropylethylamine and pimelinketone THF: MeOH (1: 1,2mL/mmol) and
Waiting in the molar mixture in the molecular sieve adds sodium cyanoborohydride (2 equivalent), mixture at room temperature stirred spend the night, and by diatomite filtration, adds DCM and water.Separate organic phase, wash with water, add 4N HCl, vacuum-evaporation subsequently is to doing.Add MeOH, be evaporated to driedly, obtain crude product secondary amine cyclopentyl-(trans-4-ethyl-cyclohexyl)-amine, need not to be further purified and just can be used for next step.
Step 3
With 1,1-carbonyl dimidazoles, (2-amino-thiazolyl--5-base sulfenyl)-ethyl acetate and DMAP (5mol%) molar mixture that waits in THF heated 5 hours in 50-60 ℃, cooled off in room temperature then.Then, add cyclopentyl-(trans-4-ethyl-cyclohexyl)-amine (1 equivalent is referring to step 2), reactant is at room temperature stirred spend the night.Water quencher reaction mixture.Separate organic phase, water CH
2Cl
2Extraction, the dry organic phase that merges, and vacuum concentration.Crude product is dissolved among the MeCN, and purifying (HPLC method 1), obtain 2-[3-cyclopentyl-3-(trans-4-ethyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-ethyl acetate.This product is dissolved among the MeOH, and at room temperature handles with 15 normal 1N NaOH and to spend the night.Remove MeOH by evaporation.Add 1N HCl to pH＜1, cause throw out.By filtering to isolate precipitation, wash with water, and dry, obtain title compound.
HPLC-MS method 2:m/z=412 (M+H).
1H?NMR(DMSO-d
6)δ12.0(br?s，1H)，7.40(s，1H)，3.85(br?s，1H)，3.60(br?s，1H)，3.48(s，2H)，1.88-1.42(m，14H)，1.25-0.99(m，5H)，0.86(t，3H)。
Embodiment 39
2-[3-cyclopentyl-3-(trans-4-sec.-propyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate
To be similar to the mode of { 2-[3-cyclopentyl-3-(trans-4-ethyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate, by cyclopentyl-(trans-4-sec.-propyl-cyclohexyl)-amine and (2-amino-thiazolyl--5-base sulfenyl)-ethyl acetate preparation, obtain title compound.
HPLC-MS method 2:m/z=426 (M+H).
1H?NMR(DMSO-d
6)δ12.35(br?s，1H)，7.39(s，1H)，3.84(br?s，1H)，3.61(br?s，1H)，3.48(s，2H)，1.90-1.40(m，15H)，1.20-0.99(m，3H)，0.86(d，6H)。
Embodiment 40
3-{2-[3-cyclopentyl-3-(trans-4-ethyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-propionic acid
To be similar to the mode of { 2-[3-cyclopentyl-3-(trans-4-ethyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate, by cyclopentyl-(trans-4-ethyl-cyclohexyl)-amine and 3-(2-amino-thiazolyl--5-base sulfenyl)-ethyl propionate preparation, obtain title compound.
HPLC-MS method 2:m/z=426 (M+H).
1H?NMR(DMSO-d
6)δ11.8(br?s，1H)，7.38(s，1H)，3.86(br?s，1H)，3.62(br?s，1H)，2.85(t，2H)，2.50(t，2H)，1.89-1.44(m，14H)，1.24-0.99(m，5H)，0.87(t，3H)。
Embodiment 41
3-{2-[3-cyclopentyl-3-(trans-4-sec.-propyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-propionic acid
To be similar to the mode of { 2-[3-cyclopentyl-3-(trans-4-ethyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate, by cyclopentyl-(trans-4-sec.-propyl-cyclohexyl)-amine and 3-(2-amino-thiazolyl--5-base sulfenyl)-ethyl propionate preparation, obtain title compound.
HPLC-MS method 2:m/z=440 (M+H).
1H?NMR(DMSO-d
6)δ11.6(br?s，1H)，7.38(s，1H)，3.86(br?s，1H)，3.62(br?s，1H)，2.85(t，2H)，2.50(t，2H)，1.91-1.39(m，15H)，1.20-0.99(m，3H)，0.85(d，6H)。
Embodiment 42
2-[3-cyclohexyl-3-(trans-4-ethoxyl methyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate
To be similar to the mode of { 2-[3-cyclohexyl-3-(trans-4-methoxymethyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate, by cyclohexyl-(trans-4-ethoxyl methyl-cyclohexyl)-amine and (2-amino-thiazolyl--5-base sulfenyl)-ethyl acetate preparation, obtain title compound.
1H?NMR(CDCl
3)：δ1.2(t，3H)，1.0-2.0(m，19H)，3.20-3.50(2H，m)，3.22(d，2H)，3.30(s，2H)，3.41(q，2H)，7.22(s，1H)。
HPLC-MS：m/z?456(M+H)。
Embodiment 43
2-[3-cyclopentyl-3-(trans-4-methoxyl group-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate
Step 1 (preparation of secondary amine):
To 2-(trans-4-hydroxyl-cyclohexyl)-isoindole-1,3-diketone (Glennon etc., J.Med.Chem.1996,39,1,314-322) (1.0g, and DMF 40.77mmol) (4,0mL) add NaH (60% oil solution in the solution, 0.41g, 10.2mmol), add again methyl iodide (5.79g, 40.7mmol).Reaction mixture was stirred 16 hours, add entry (15mL) and ethyl acetate (25mL) again, separate each phase then.(2 * 10mL) washings are through MgSO for the organic phase water
4Drying, solvent removed in vacuo.Resistates is purifying (EtOAc-heptane) on silica gel, obtains 0.810g (77%) 2-(trans-4-methoxyl group-cyclohexyl)-isoindole-1, the 3-diketone.
To 2-(trans-4-methoxyl group-cyclohexyl)-isoindole-1, (0.710g, (0.130g 4.11mmol), stirs reaction mixture 2 hours in 50 ℃ the 3-diketone to add hydrazine hydrate in dehydrated alcohol 2.74mmol) (10mL) solution.Remove oil bath, reaction mixture at room temperature stirred 16 hours.Vacuum is removed volatile matter, and (20mL, 10N), (3 * 10mL) extract with ether to add NaOH in resistates.Organic phase MgSO
4Drying, vacuum concentration, obtain 0.300g (85%) 4-trans-methoxyl group-hexahydroaniline.
In 15 minutes with aliquot to 4-trans-methoxyl group-hexahydroaniline (100mg, 0.78mmol) and cyclopentanone (72mg, add in the solution of THF-MeOH 0.85mmol) 2: 1 (2mL) and acetate (0.1mL) sodium cyanoborohydride (73mg, 1.02mmol).Stirred reaction mixture 16 hours, vacuum is removed volatile matter.(1N 50mL), at room temperature stirred 16 hours to add HCl in resistates.(10N, 2.5mL), (2 * 10mL) extractions are through MgSO with ether to add NaOH in mixture
4Dry.Solvent removed in vacuo obtains 134mg (88%) cyclopentyl-(4-methoxyl group-cyclohexyl)-amine.
Step 2 (coupling and hydrolysis):
To (amino-thiazolyl--5-base sulfenyl)-ethyl acetate (110mg, 0.51mmol)) THF (5mL) solution in add CDI (82mg, 0.51mmol) and DMAP (2mg, 0.017mmol), reaction mixture at room temperature stirred 2 hours, add afterwards cyclopentyl-(4-methoxyl group-cyclohexyl)-amine (66.5mg, 0.34mmol).Stirred reaction mixture 16 hours, solvent removed in vacuo afterwards.Add ethyl acetate (25mL) in resistates, (1N, 2 * 10mL) washings are through MgSO with HCl
4Dry.Solvent removed in vacuo, resistates be with preparation HPLC method 1 purifying, obtains 35mg (24%) { 2-[3-cyclopentyl-3-(trans-4-methoxyl group-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-ethyl acetate.
To 2-[3-cyclopentyl-3-(trans-4-methoxyl group-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-ethyl acetate (30mg, 0.068mmol) acetonitrile (1mL) solution in add NaOH (1N, 0.3mL), reaction mixture was at room temperature stirred 2 hours, afterwards solvent removed in vacuo.Under agitation add HCl (1N, 2.5mL), collecting precipitation, (3 * 2.5mL) washings, vacuum-drying obtain 18mg (64%) { 2-[3-cyclopentyl-3-(trans-4-methoxyl group-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate to water.
1H?NMR(400MHz，DMSO-d
6)δ7.4(s，1H)，3.87(bs，1H)，3.60(bs，1H)，3.49(s，2H)，3.22(s，3H)，3.15-3.04(m，1H)，2.05-1.40(m，14H)，1.32-1.18(m，2H)。
HPLC-MS：m/z?414(M+H)。
Embodiment 44
2-[3-suberyl-3-(trans-4-methoxyl group-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate
Synthesis technique preparation according to { 2-[3-cyclopentyl-3-(trans-4-methoxyl group-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate.
Step 1: use (trans-4-hydroxyl-cyclohexyl)-isoindole-1,3-diketone, methyl iodide and suberone prepare suberyl-[trans-4-methoxyl group-cyclohexyl]-amine.
Step 2: use suberyl-[trans-4-methoxyl group-cyclohexyl]-amine and (amino-thiazolyl--5-base sulfenyl)-ethyl acetate preparation 2-[3-suberyl-3-(trans-4-methoxyl group-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate.
1H?NMR(DMSO-d
6)δ7.40(s，1H)，3.9-3.4(bm，2H)，3.47(s，2H)，3.22(s，3H)，3.15-3.05(m，1H)，2.10-1.18(m，20H)。
HPLC-MS：m/z?442(M+H)。
Embodiment 45
2-[3-cyclopentyl-3-(trans-4-oxyethyl group-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate
Synthesis technique preparation according to { 2-[3-cyclopentyl-3-(trans-4-methoxyl group-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate.
Step 1: use (trans-4-hydroxyl-cyclohexyl)-isoindole-1,3-diketone, iodoethane and cyclopentanone prepare cyclopentyl-[trans-4-oxyethyl group-cyclohexyl]-amine.
Step 2: use cyclopentyl-[trans-4-oxyethyl group-cyclohexyl]-amine and (amino-thiazolyl--5-base sulfenyl)-ethyl acetate preparation 2-[3-cyclopentyl-3-(trans-4-oxyethyl group-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate.
1H?NMR(DMSO-d
6)δ7.40(s，1H)，3.9(bs，1H)，3.6(bs，1H)，3.47(s，2H)，3.42(q，2H)，3.25-3.15(m，1H)，2.0-1.2(m，16H)，1.08(t，3H)。
HPLC-MS：m/z?428(M+H)。
Embodiment 46
2-[3-cyclohexyl-3-(trans-4-oxyethyl group-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate
Synthesis technique preparation according to { 2-[3-cyclopentyl-3-(trans-4-methoxyl group-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate.
Step 1: use (trans-4-hydroxyl-cyclohexyl)-isoindole-1,3-diketone, iodoethane and pimelinketone prepare cyclohexyl-[trans-4-oxyethyl group-cyclohexyl]-amine.
Step 2: use cyclohexyl-[trans-4-oxyethyl group-cyclohexyl]-amine and (amino-thiazolyl--5-base sulfenyl)-ethyl acetate preparation 2-[3-cyclohexyl-3-(trans-4-oxyethyl group-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate.
1H?NMR(DMSO-d
6)δ7.40(s，1H)，3.7-3.3(m，2H)，3.49(s，2H)，3.40(q，2H)，3.20(m，1H)，2.15-1.15(m，18)，1.10(t，3H)。
HPLC-MS：m/z?442(M+H)。
Embodiment 47
2-[3-suberyl-3-(trans-4-oxyethyl group-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate
Synthesis technique preparation according to { 2-[3-cyclopentyl-3-(trans-4-methoxyl group-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate.
Step 1: use (trans-4-hydroxyl-cyclohexyl)-isoindole-1,3-diketone, iodoethane and suberone prepare suberyl-[trans-4-oxyethyl group-cyclohexyl]-amine.
Step 2: use suberyl-[trans-4-oxyethyl group-cyclohexyl]-amine and (amino-thiazolyl--5-base sulfenyl)-ethyl acetate preparation 2-[3-suberyl-3-(trans-4-oxyethyl group-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate.
HPLC-MS：m/z?456(M+H)。
Embodiment 48
3-{2-[3-cyclohexyl-3-(trans-4-methoxymethyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-propionic acid
To be similar to the mode of { 2-[3-cyclohexyl-3-(trans-4-methoxymethyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate, by cyclohexyl-(trans-4-methoxymethyl-cyclohexyl)-amine and (2-amino-thiazolyl--5-base sulfenyl)-ethyl propionate preparation, obtain title compound.
1H?NMR(CDCl
3)：δ1.0-2.0(m，19H)，2.68-2.76(m，2H)，2.95-3.03(m，2H)，3.24(d，2H)，3.10-3.70(m，2H)，3.36(s，3H)，7.30(s，1H)。
HPLC-MS：m/z?456(M+H)。
Embodiment 49
2-[3-(trans-the 4-tertiary butyl-cyclohexyl)-3-cyclopentyl-urea groups]-thiazole-5-base sulfenyl }-acetate
To be similar to the mode of { 2-[3-cyclopentyl-3-(trans-4-ethyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate, by (the 4-tertiary butyl-cyclohexyl)-cyclopentyl-amine and (2-amino-thiazolyl--5-base sulfenyl)-ethyl acetate preparation, obtain title compound.
HPLC-MS method 2:m/z=440 (M+H).
1H?NMR(DMSO-d
6)δ11.5(br?s，1H)，7.40(s，1H)，3.82(br?s，1H)，3.63(br?s，1H)，3.48(s，2H)，1.90-1.44(m，14H)，1.20-0.93(m，3H)，0.85(s，9H)。
Embodiment 50
2-[3-(trans-the 4-tertiary butyl-cyclohexyl)-3-cyclohexyl-urea groups]-thiazole-5-base sulfenyl }-acetate
To be similar to the mode of { 2-[3-cyclopentyl-3-(trans-4-ethyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate, by (the 4-tertiary butyl-cyclohexyl)-cyclohexyl-amine and (2-amino-thiazolyl--5-base sulfenyl)-ethyl acetate preparation, obtain title compound.
HPLC-MS method 2:m/z=454 (M+H).
1H?NMR(DMSO-d
6)δ11.5(br?s，1H)，7.40(s，1H)，3.65(br?s，2H)，3.48(s，2H)，2.05-0.95(m，19H)，0.84(s，9H)。
Embodiment 51
2-[3-(trans-the 4-tertiary butyl-cyclohexyl)-3-suberyl-urea groups]-thiazole-5-base sulfenyl }-acetate
To be similar to the mode of { 2-[3-cyclopentyl-3-(trans-4-ethyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate, by (the 4-tertiary butyl-cyclohexyl)-suberyl-amine and (2-amino-thiazolyl--5-base sulfenyl)-ethyl acetate preparation, obtain title compound.
HPLC-MS method 2:m/z=468 (M+H).
1H?NMR(DMSO-d
6)δ11.5(br?s，1H)，7.41(s，1H)，4.20(br?s，2H)，3.50(s，2H)，2.15(br?s，2H)，1.68-0.97(m，19H)，0.85(s，9H)。
Embodiment 52
2-[3-suberyl-3-(trans-4-methoxymethyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate
To be similar to the mode of { 2-[3-cyclohexyl-3-(trans-4-methoxymethyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate, by cyclohexyl-(trans-4-methoxymethyl-suberyl)-amine and (2-amino-thiazolyl--5-base sulfenyl)-ethyl acetate preparation, obtain title compound.
1H?NMR(CDCl
3)：δ1.0-2.0(m，21H)，3.21(d，2H)，3.37(s，3H)，3.39(s，2H)，3.15-3.35(m，1H)，3.55-3.85(m，1H)，7.27(s，1H)。
HPLC-MS：m/z?456(M+H)。
Embodiment 53
3-{2-[3-suberyl-3-(trans-4-methoxymethyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-propionic acid
To be similar to the mode of { 2-[3-cyclohexyl-3-(trans-4-methoxymethyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate, by cyclohexyl-(trans-4-methoxymethyl-suberyl)-amine and (2-amino-thiazolyl--5-base sulfenyl)-ethyl propionate preparation, obtain title compound.
1H?NMR(CDCl
3)：δ1.0-2.0(m，21H)，2.69-2.75(m，2H)，2.91-3.04(m，2H)，3.20-3.23(d，2H)，3.10-3.30(m，1H)，3.34(s，3H)，3.50-3.80(m，1H)，7.27(s，1H)。
HPLC-MS：m/z?470(M+H)。
Embodiment 54
3-{2-[3-cyclohexyl-3-(trans-4-ethoxyl methyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-propionic acid
To be similar to the mode of { 2-[3-cyclohexyl-3-(trans-4-methoxymethyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate, by cyclohexyl-(trans-4-ethoxyl methyl-cyclohexyl)-amine and (2-amino-thiazolyl--5-base sulfenyl)-ethyl propionate preparation, obtain title compound.
1H?NMR(CDCl
3)：δ1.2(t，3H)，1.0-2.0(m，19H)，2.69-2.81(m，2H)，2.91-3.05(2H，m)，3.25(d，2H)，3.10-3.60(m，2H)，3.38(q，2H)，7.22(s，1H)。
HPLC-MS：m/z?470(M+H)。
Embodiment 55
3-{2-[3-(trans-the 4-tertiary butyl-cyclohexyl)-3-cyclopentyl-urea groups]-thiazole-5-base sulfenyl }-propionic acid
To be similar to the mode of { 2-[3-cyclopentyl-3-(trans-4-ethyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate, by (the 4-tertiary butyl-cyclohexyl)-cyclopentyl-amine and 3-(2-amino-thiazolyl--5-base sulfenyl)-ethyl propionate preparation, obtain title compound.
HPLC-MS method 2:m/z=454 (M+H).
1H?NMR(DMSO-d
6)δ11.5(br?s，1H)，7.38(s，1H)，3.83(br?s，1H)，3.64(br?s，1H)，2.85(t，2H)，2.49(t，2H)，1.91-1.44(m，14H)，1.23-0.93(m，3H)，0.85(s，9H)。
Embodiment 56
3-{2-[3-(trans-the 4-tertiary butyl-cyclohexyl)-3-cyclohexyl-urea groups]-thiazole-5-base sulfenyl }-propionic acid
To be similar to the mode of { 2-[3-cyclopentyl-3-(trans-4-ethyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate, by (the 4-tertiary butyl-cyclohexyl)-cyclohexyl-amine and 3-(2-amino-thiazolyl--5-base sulfenyl)-ethyl propionate preparation, obtain title compound.
HPLC-MS method 2:m/z=468 (M+H).
1H?NMR(DMSO-d
6)δ11.5(br?s，1H)，7.38(s，1H)，3.55(br?s，2H)，2.85(t，2H)，2.49(t，2H)，2.05-0.95(m，19H)，0.85(s，9H)。
Embodiment 57
3-{2-[3-(trans-the 4-tertiary butyl-cyclohexyl)-3-suberyl-urea groups]-thiazole-5-base sulfenyl }-propionic acid
To be similar to the mode of { 2-[3-cyclopentyl-3-(trans-4-ethyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate, by (the 4-tertiary butyl-cyclohexyl)-suberyl-amine and 3-(2-amino-thiazolyl--5-base sulfenyl)-ethyl propionate preparation, obtain title compound.
HPLC-MS method 2:m/z=482 (M+H).
1H?NMR(DMSO-d
6)δ11.5(br?s，1H)，7.38(s，1H)，3.80(br?s，2H)，2.84(t，2H)，2.49(t，2H)，2.16(br?s，2H)，1.68-0.96(m，19H)，0.85(s，9H)。
Embodiment 58
2-{2-[3-(trans-the 4-tertiary butyl-cyclohexyl)-3-cyclopentyl-urea groups]-thiazole-5-base sulfenyl }-2-methyl-propionic acid
To be similar to the mode of { 2-[3-cyclopentyl-3-(trans-4-ethyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate (embodiment 38), by (the 4-tertiary butyl-cyclohexyl)-cyclopentyl-amine and 2-(2-amino-thiazolyl--5-base sulfenyl)-2-methyl-ethyl propionate preparation, obtain title compound.
HPLC-MS method 2:m/z=468 (M+H).
1H?NMR(DMSO-d
6)δ12.6(br?s，1H)，11.1(br?s，1H)，7.38(s，1H)，3.83(br?s，1H)，3.63(br?s，1H)，1.93-1.43(m，14H)，1.40(s，6H)，1.23-0.94(m，3H)，0.85(s，9H)。
Embodiment 59
2-{2-[3-(trans-the 4-tertiary butyl-cyclohexyl)-3-cyclohexyl-urea groups]-thiazole-5-base sulfenyl }-2-methyl-propionic acid
To be similar to the mode of { 2-[3-cyclopentyl-3-(trans-4-ethyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate (embodiment 38), by (the 4-tertiary butyl-cyclohexyl)-cyclohexyl-amine and 2-(2-amino-thiazolyl--5-base sulfenyl)-2-methyl-ethyl propionate preparation, obtain title compound.
HPLC-MS method 2:m/z=482 (M+H).
1H?NMR(DMSO-d
6)δ12.6(br?s，1H)，11.1(br?s，1H)，7.38(s，1H)，3.40(br?s，2H)，2.05-0.95(m，19H)，1.40(s，6H)，0.85(s，9H)。
Embodiment 60
2-[3-suberyl-3-(trans-4-ethoxyl methyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate
To be similar to the mode of { 2-[3-cyclohexyl-3-(trans-4-methoxymethyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate, by cyclohexyl-(trans-4-ethoxyl methyl-suberyl)-amine and (2-amino-thiazolyl--5-base sulfenyl)-ethyl acetate preparation, obtain title compound.
1H?NMR(CDCl
3)：δ1.21(t，3H)，1.0-2.4(m，21H)，3.23(d，2H)，3.33(s，2H)，3.30-3.70(m，2H)，3.43(q，2H)，7.22(s，1H)。
HPLC-MS：m/z?470(M+H)。
Embodiment 61
2-[3-cyclohexyl-3-(trans-4-cyclo propyl methoxy-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate
Synthesis technique preparation according to { 2-[3-cyclopentyl-3-(trans-4-methoxyl group-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate.
Step 1: use (trans-4-hydroxyl-cyclohexyl)-isoindole-1,3-diketone, cyclopropyl monobromomethane and pimelinketone prepare cyclohexyl-[trans-4-cyclo propyl methoxy-cyclohexyl]-amine.
Step 2: use cyclohexyl-[trans-4-cyclo propyl methoxy-cyclohexyl]-amine and (amino-thiazolyl--5-base sulfenyl)-ethyl acetate preparation 2-[3-cyclohexyl-3-(trans-4-cyclo propyl methoxy-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate.
1H?NMR(DMSO-d
6)δ7.40(s，1H)，3.6-3.2(m，3H)，3.47(s，2H)，3.23(d，3H)，2.2-0.9(m，19H)，0.45(m，2H)，0.14(m，2H)。
HPLC-MS：m/z?468(M+H)。
Embodiment 62
3-{2-[-3-cyclohexyl-3-(trans-4-cyclo propyl methoxy-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-propionic acid
Synthesis technique preparation according to { 2-[3-cyclopentyl-3-(trans-4-methoxyl group-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate.
Step 1: use (trans 4-hydroxyl-cyclohexyl)-isoindole-1,3-diketone, cyclopropyl monobromomethane and pimelinketone prepare cyclohexyl-[trans-4-cyclo propyl methoxy-cyclohexyl]-amine.
Step 2: use cyclohexyl-[trans-4-cyclo propyl methoxy-cyclohexyl]-amine and (amino-thiazolyl--5-base sulfenyl)-ethyl propionate preparation 2-[3-cyclohexyl-3-(trans-4-cyclo propyl methoxy-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-propionic acid.
1H?NMR(DMSO-d
6)δ7.37(s，1H)，3.7-3.2(m，3H)，3.24(d，3H)，2.85(t，2H)，2.50(t，2H)，2.2-0.9(m，19H)，0.45(m，2H)，0.14(m，2H)。
HPLC-MS：m/z?482(M+H)。
Embodiment 63
3-{2-[3-cyclopentyl-3-(trans-4-methoxyl group-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-propionic acid
Synthesis technique preparation according to { 2-[3-cyclopentyl-3-(trans-4-methoxyl group-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate.
Step 1: use (trans-4-hydroxyl-cyclohexyl)-isoindole-1,3-diketone, methyl iodide and cyclopentanone prepare cyclopentyl-[trans-4-methoxyl group-cyclohexyl]-amine.
Step 2: use cyclopentyl-[trans-4-methoxyl group-cyclohexyl]-amine and (amino-thiazolyl--5-base sulfenyl)-ethyl propionate to prepare 3-{2-[3-cyclopentyl-3-(trans-4-methoxyl group-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-propionic acid.
1H?NMR(DMSO-d
6)δ7.38(s，1H)，3.87(m，1H)，3.60(m，1H)，3.33(s，3H)，3.10(m，1H)，2.85(t，2H)，2.50(t，2H)，2.1-1.4(m，14H)，1.31-1.15(m，2H)。
HPLC-MS：m/z?428(M+H)。
Embodiment 64
3-{2-[3-cyclohexyl-3-(trans-4-methoxyl group-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-propionic acid
Synthesis technique preparation according to { 2-[3-cyclopentyl-3-(trans-4-methoxyl group-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate.
Step 1: use (trans-4-hydroxyl-cyclohexyl)-isoindole-1,3-diketone, methyl iodide and pimelinketone prepare cyclohexyl-[trans-4-methoxyl group-cyclohexyl]-amine.
Step 2: use cyclohexyl-[trans-4-methoxyl group-cyclohexyl]-amine and (amino-thiazolyl--5-base sulfenyl)-ethyl propionate to prepare 3-{2-[3-cyclohexyl-3-(trans-4-methoxyl group-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-propionic acid.
1H?NMR(DMSO-d
6)δ7.32(s，1H)，3.65-3.20(m，2H)3.20(s，2H)，3.05(m，1H)，2.80(t，2H)，2.45(t，2H)，2.15-1.00(m，18H)。
HPLC-MS：m/z?442(M+H)。
Embodiment 65
3-{2-[3-suberyl-3-(trans-4-methoxyl group-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-propionic acid
Synthesis technique preparation according to { 2-[3-cyclopentyl-3-(trans-4-methoxyl group-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate.
Step 1: use (trans-4-hydroxyl-cyclohexyl)-isoindole-1,3-diketone, methyl iodide and suberone prepare suberyl-[trans-4-methoxyl group-cyclohexyl]-amine.
Step 2: use suberyl-[trans-4-methoxyl group-cyclohexyl]-amine and (amino-thiazolyl--5-base sulfenyl)-ethyl propionate to prepare 3-{2-[3-suberyl-3-(trans-4-methoxyl group-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-propionic acid.
1H?NMR(DMSO-d
6)δ7.32(s，1H)，3.20(s，3H)，3.08(m，1H)，2.79(t，2H)，2.47(t，2H)，2.25-1.10(m，20H)。
HPLC-MS：m/z?456(M+H)。
Embodiment 66
3-{2-[3-cyclopentyl-3-(trans-4-oxyethyl group-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-propionic acid
Synthesis technique preparation according to { 2-[3-cyclopentyl-3-(trans-4-methoxyl group-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate.
Step 1: use (trans-4-hydroxyl-cyclohexyl)-isoindole-1,3-diketone, iodoethane and cyclopentanone prepare cyclopentyl-[trans-4-oxyethyl group-cyclohexyl]-amine.
Step 2: use cyclopentyl-[trans-4-oxyethyl group-cyclohexyl]-amine and (amino-thiazolyl--5-base sulfenyl)-ethyl propionate to prepare 3-{2-[3-cyclopentyl-3-(trans-4-oxyethyl group-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-propionic acid.
1H?NMR(400MHz，DMSO-d
6)δ7.33(s，1H)；3.82(m，1H)，3.55(M，1H)，3.40(q，2H)，3.15(m，1H)，2.80(t，2H)，2.45(t，2H)，2.05-1.10(m，16H)，1.05(t，3H)。
HPLC-MS：m/z?442(M+H)。
Embodiment 67
3-{2-[3-cyclohexyl-3-(trans-4-oxyethyl group-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-propionic acid
Synthesis technique preparation according to { 2-[3-cyclopentyl-3-(trans-4-methoxyl group-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate.
Step 1: use (trans-4-hydroxyl-cyclohexyl)-isoindole-1,3-diketone, iodoethane and pimelinketone prepare cyclohexyl-[trans-4-oxyethyl group-cyclohexyl]-amine.
Step 2: use cyclohexyl-[trans-4-oxyethyl group-cyclohexyl]-amine and (amino-thiazolyl--5-base sulfenyl)-ethyl propionate preparation 2-[3-cyclohexyl-3-(trans-4-oxyethyl group-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-propionic acid.
1H?NMR(DMSO-d
6)δ11.8(bs，1H)，7.38(s，1H)，3.7-3.2(m，2H)，3.40(q，2H)，3.20(m，1H)，2.84(t，2H)，2.50(t，2H)，2.20-1.15(m，18H)，1.10(t，3H)。
HPLC-MS：m/z?456(M+H)。
Embodiment 68
3-{2-[3-suberyl-3-(trans-4-oxyethyl group-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-propionic acid
Synthesis technique preparation according to { 2-[3-cyclopentyl-3-(trans-4-methoxyl group-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate.
Step 1: use (trans-4-hydroxyl-cyclohexyl)-isoindole-1,3-diketone, iodoethane and suberone prepare suberyl-[trans-4-oxyethyl group-cyclohexyl]-amine.
Step 2: use suberyl-[trans-4-oxyethyl group-cyclohexyl]-amine and (amino-thiazolyl--5-base sulfenyl)-ethyl propionate preparation 2-[3-suberyl-3-(trans-4-oxyethyl group-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-propionic acid.
1H?NMR(DMSO-d
6)δ7.32(s，1H)，3.7-3.3(m，2H)，3.38(q，2H)，3.15(m，1H)，2.80(t，2H)，2.45(t，2H)，2.2-1.1(m，20H)，1.03(t，3H)。
HPLC-MS：m/z?470(M+H)。
Embodiment 69
(2-{3-cyclohexyl-3-[is trans-4-(2-methoxyl group-oxyethyl group)-cyclohexyl]-urea groups }-thiazole-5-base sulfenyl)-acetate
Synthesis technique preparation according to { 2-[3-cyclopentyl-3-(trans-4-methoxyl group-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate.
Step 1: use (trans-4-hydroxyl-cyclohexyl)-isoindole-1,3-diketone, 1-bromo-2-methyl ethyl ether and pimelinketone prepare cyclohexyl-[trans-4-(2-methoxyl group-oxyethyl group)-cyclohexyl]-amine.
Step 2: use cyclohexyl-[trans-4-(2-methoxyl group-oxyethyl group)-cyclohexyl]-amine and (amino-thiazolyl--5-base sulfenyl)-ethyl acetate preparation (2-{3-cyclohexyl-3-[is trans-4-(2-methoxyl group-oxyethyl group)-cyclohexyl]-urea groups-thiazole-5-base sulfenyl)-acetate.
HPLC-MS：m/z?472(M+H)。
Embodiment 70
3-(2-{3-cyclohexyl-3-[is trans-4-(2-methoxyl group-oxyethyl group)-cyclohexyl]-urea groups }-thiazole-5-base sulfenyl)-propionic acid
Synthesis technique preparation according to { 2-[3-cyclopentyl-3-(trans-4-methoxyl group-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate.
Step 1: use (trans-4-hydroxyl-cyclohexyl)-isoindole-1,3-diketone, 1-bromo-2-methyl ethyl ether and pimelinketone prepare cyclohexyl-[trans-4-(2-methoxyl group-oxyethyl group)-cyclohexyl]-amine.
Step 2: use cyclohexyl-[trans-4-(2-methoxyl group-oxyethyl group)-cyclohexyl]-amine and (amino-thiazolyl--5-base sulfenyl)-ethyl propionate preparation (2-{3-cyclohexyl-3-[is trans-4-(2-methoxyl group-oxyethyl group)-cyclohexyl]-urea groups-thiazole-5-base sulfenyl)-propionic acid.
1H?NMR(400MHz，DMSO-d
6)δ7.37(s，1H)，3.7-3.3(m，2H)，3.52(t，2H)，3.42(t，2H)，3.25(s，3H)，3.3-3.18(m，1H)，2.85(t，2H)，2.50(t，2H)，2.2-1.0(m，18H)。
HPLC-MS：m/z?486(M+H)。
Embodiment 71
2-[3-cyclopentyl-3-(trans-4-methoxymethyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate
To be similar to the mode of { 2-[3-cyclohexyl-3-(trans-4-methoxymethyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate, by cyclohexyl-(trans-4-methoxymethyl-cyclopentyl)-amine and (2-amino-thiazolyl--5-base sulfenyl)-ethyl acetate preparation, obtain title compound.
1H?NMR(CDCl
3)：δ1.10-2.00(m，17H)，3.21(d，2H)，3.32(s，3H)，3.34(s，2H)，3.35-3.50(1H，m)，3.70-3.85(m，1H)，7.28(s，1H)。
HPLC-MS：m/z?428(M+H)。
Embodiment 72
3-{2-[3-suberyl-3-(trans-4-ethoxyl methyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-propionic acid
To be similar to the mode of { 2-[3-cyclohexyl-3-(trans-4-methoxymethyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate, by cyclohexyl-(trans-4-ethoxyl methyl-suberyl)-amine and (2-amino-thiazolyl--5-base sulfenyl)-ethyl propionate preparation, obtain title compound.
1H?NMR(CDCl
3)：δ1.22(t，3H)，1.0-2.4(m，21H)，2.65-2.76(2H，m)，2.91-3.03(m，2H)，3.23(d，2H)，3.1-3.6(m，2H)，3.44(q，2H)，7.22(s，1H)。
HPLC-MS：m/z?484(M+H)。
Embodiment 73
3-{2-[3-cyclopentyl-3-(trans-4-methoxymethyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-propionic acid
To be similar to the mode of { 2-[3-cyclohexyl-3-(trans-4-methoxymethyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate, by cyclohexyl-(trans-4-methoxymethyl-cyclopentyl)-amine and (2-amino-thiazolyl--5-base sulfenyl)-ethyl propionate preparation, obtain title compound.
1H?NMR(CDCl
3)：δ1.10-2.00(m，17H)，2.69-2.76(m，2H)，2.91-3.01(m，2H)，3.21(d，2H)，3.32(s，3H)，3.25-3.48(1H，m)，3.60-3.85(m，1H)，7.26(s，1H)。
HPLC-MS：m/z?443(M+H)。
Embodiment 74
2-{2-[3-cyclohexyl-3-(trans-4-cyclo propyl methoxy-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-2-methyl-propionic acid
Synthesis technique preparation according to { 2-[3-cyclopentyl-3-(trans-4-methoxyl group-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate.
Step 1: use (trans-4-hydroxyl-cyclohexyl)-isoindole-1,3-diketone, cyclopropyl monobromomethane and pimelinketone prepare cyclohexyl-[trans-4-cyclo propyl methoxy-cyclohexyl]-amine.
Step 2: use cyclohexyl-[trans-4-cyclo propyl methoxy-cyclohexyl]-amine and 2-(2-amino-thiazolyl--5-base sulfenyl)-2-methyl-ethyl propionate preparation 2-[3-cyclohexyl-3-(trans-4-cyclo propyl methoxy-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate.
HPLC-MS：m/z?496(M+H)。
Embodiment 75
2-(2-{3-cyclohexyl-3-[is trans-4-(2-methoxyl group-oxyethyl group)-cyclohexyl]-urea groups }-thiazole-5-base sulfenyl)-2-methyl-propionic acid
Synthesis technique preparation according to { 2-[3-cyclopentyl-3-(trans-4-methoxyl group-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate.
Step 1: use (trans-4-hydroxyl-cyclohexyl)-isoindole-1,3-diketone, 1-bromo-2-methyl ethyl ether and pimelinketone prepare cyclohexyl-[trans-4-(2-methoxyl group-oxyethyl group)-cyclohexyl]-amine.
Step 2: use cyclohexyl-[trans-4-(2-methoxyl group-oxyethyl group)-cyclohexyl]-amine and 2-(2-amino-thiazolyl--5-base sulfenyl)-2-methyl-ethyl propionate prepare 2-(2-{3-cyclohexyl-3-[is trans-4-(2-methoxyl group-oxyethyl group)-cyclohexyl]-urea groups-thiazole-5-base sulfenyl)-2-methyl-propionic acid.
HPLC-MS：m/z?500(M+H)。
Embodiment 76
[2-(3,3-dicyclohexyl-urea groups)-thiazole-5-sulfonamido]-acetate
Step 1
Glycine ethyl ester hydrochloride (15mmol), 2-acetylaminohydroxyphenylarsonic acid thiazole-5-SULPHURYL CHLORIDE (12mmol) (are pressed document J.Am.Chem.Soc 69, the preparation of method described in 2063,1947), the mixture of DIPEA (35mmol) and DCM (50mL) at room temperature stirs and spends the night.Add entry and 1N HCl to pH 2, cause precipitation.Throw out comes out by filtering separation, washes drying with water, obtain (2-acetylaminohydroxyphenylarsonic acid thiazole-5-sulfonamido)-ethyl acetate (64%, crystal), it is suspended among the EtOH (15mL), add 4N HCl De diox (15mL),, be cooled to room temperature then in 80 ℃ of heating 4 hours.Add water-based NaHCO
3To neutral pH.Separate organic phase, water CH
2Cl
2Extraction, the dry organic phase that merges, vacuum concentration obtains (2-amino-thiazolyl--5-sulfonamido)-ethyl acetate (80%, clear crystal).
Step 2
With 1,1-carbonyl dimidazoles, (2-amino-thiazolyl--5-sulfonamido)-ethyl acetate and DMAP (5mol%) in THF etc. molar mixture in 50-60 ℃ the heating 2 hours, be cooled to room temperature then.Then, add dicyclohexyl amine (1 equivalent), reactant is at room temperature stirred spend the night.Water quencher reaction mixture.Separate organic phase, water CH
2Cl
2Extraction, the dry organic phase that merges, vacuum concentration.Crude product is dissolved among the MeCN, and purifying (HPLC method 1), [2-(3,3-dicyclohexyl-urea groups)-thiazole-5-sulfonamido]-ethyl acetate obtained.This product is dissolved among the MeOH, at room temperature handles with 20 normal 1N NaOH and spend the night.MeOH is removed in evaporation.Add 1N HCl to pH＜1, cause precipitation.Throw out comes out by filtering separation, washes with water, and drying obtains title compound.
HPLC-MS method 2:m/z=445 (M+H).
1H?NMR(CDCl
3+2?dr?CD
3OD)δ7.79(s，1H)，3.80(s，2H)，3.40(br?s，2H)，1.90-1.64(m，13H)，1.42-1.13(m，7H)。
Embodiment 77
2-[3-(1-ethanoyl-piperidin-4-yl)-3-cyclohexyl-urea groups]-thiazole-5-sulfonamido }-acetate
[2-(3 to be similar to, 3-dicyclohexyl-urea groups)-thiazole-5-sulfonamido]-mode of acetate, by 1-(4-cyclohexyl amino-piperadine-1-yl)-ethyl ketone (common processes I) and the preparation of (2-amino-thiazolyl--5-sulfonamido)-ethyl acetate, obtain title compound.
1H?NMR(DMSO-d
6)δ12.7(br?s，1H)，11.4(br?s，1H)，8.16(br?t，1H)，8.78(s，1H)，4.45(br?d，1H)，3.85(br?d，1H)，3.63(d，2H)，3.10(t，1H)，2.59-2.45(m，1H)，2.25-1.05(m，16H)，2.02(s，3H)。
Embodiment 78
2-{2-[3-suberyl-3-(trans-4-ethoxyl methyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-2-methyl-propionic acid
To be similar to the mode of { 2-[3-cyclohexyl-3-(trans-4-methoxymethyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate, by suberyl-(trans-4-ethoxyl methyl-suberyl)-amine and 2-(2-amino-thiazolyl--5-base sulfenyl)-2-methyl-ethyl propionate preparation, obtain title compound.
1H?NMR(CDCl
3)：δ1.19(t，3H)，1.10-2.00(m，21H)，3.23(d，2H)，3.4(q，2H)，3.15-3.30(m，1H)，3.70-3.95(m，1H)，7.10(s，1H)。
HPLC-MS：m/z?498(M+H)。
Embodiment 79
2-{2-[3-suberyl-3-(trans-4-methoxymethyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-2-methyl-propionic acid
To be similar to the mode that { 2-[3-cyclohexyl-3-(trans-4-methoxymethyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate is similar to, by suberyl-(trans-4-methoxymethyl-suberyl)-amine and 2-(2-amino-thiazolyl--5-base sulfenyl)-2-methyl-ethyl propionate preparation, obtain title compound.
1H?NMR(CDCl
3)：δ1.00-2.00(m，21H)，3.18(d，2H)，3.32(s，3H)，3.10-3.30(m，1H)，3.65-3.95(m，1H)，7.08(s，1H)。
HPLC-MS：m/z?485(M+H)。
Embodiment 80
2-[3-cyclohexyl-3-(trans-4-methyl-cyclohexyl base)-urea groups]-thiazole-5-sulfonamido }-acetate
[2-(3 to be similar to, 3-dicyclohexyl-urea groups)-thiazole-5-sulfonamido]-mode of acetate (embodiment 76), by cyclohexyl-(trans-4-methyl-cyclohexyl base)-amine (common processes I) and the preparation of (2-amino-thiazolyl--5-sulfonamido)-ethyl acetate, obtain title compound.
HPLC-MS method 2:m/z=460 (M+H).
1H?NMR(DMSO-d
6)δ12.7(br?s，1H)，11.35(br?s，1H)，8.15(t，1H)，7.76(s，1H)，3.62(d，2H)，3.45(br?s，2H)，1.74-1.02(m，19H)，0.88(d，3H)。
Embodiment 81
3-[2-(3,3-dicyclohexyl-urea groups)-thiazole-5-sulfonamido]-propionic acid
To be similar to the mode of [2-(3,3-dicyclohexyl-urea groups)-thiazole-5-sulfonamido]-acetate,, obtain title compound by dicyclohexyl amine and 3-(2-amino-thiazolyl--5-sulfonamido)-ethyl propionate preparation.
1H?NMR(DMSO-d
6)δ12.05(br?s，2H)，7.79(s，1H)，7.75(t，1H)，3.48(br?s，2H)，3.02(q，2H)，2.42(t，2H)，2.06-1.04(m，20H)。
Embodiment 82
3-{2-[3-cyclohexyl-3-(trans-4-methyl-cyclohexyl base)-urea groups]-thiazole-5-sulfonamido }-propionic acid
To be similar to the mode of [2-(3,3-dicyclohexyl-urea groups)-thiazole-5-sulfonamido]-acetate,, obtain title compound by cyclohexyl-(trans-4-methyl-cyclohexyl base)-amine and 3-(2-amino-thiazolyl--5-sulfonamido)-ethyl propionate preparation.
1H?NMR(DMSO-d
6)δ12.3(br?s，1H)，11.5(br?s，1H)，7.78(s，1H)，7.75(t，1H)，3.5(br?s，2H)，3.01(q，2H)，2.41(t，2H)，2.10-1.05(m，19H)，0.87(d，3H)。
Embodiment 83
{ [2-(3,3-dicyclohexyl-urea groups)-thiazole-5-alkylsulfonyl]-methyl-amino }-acetate
To be similar to the mode of [2-(3,3-dicyclohexyl-urea groups)-thiazole-5-sulfonamido]-acetate,, obtain title compound by dicyclohexyl amine and the preparation of [(2-amino-thiazolyl--5-alkylsulfonyl)-methyl-amino]-methyl acetate.
HPLC-MS method 2:m/z=459 (M+H).
1H?NMR(CDCl
3)δ7.68(s，1H)，4.14(s，2H)，3.37(br?s，2H)，3.10(s，3H)，1.86-1.12(m，20H)。
Embodiment 84
(2-[3-cyclohexyl-3-(trans-4-methyl-cyclohexyl base)-urea groups]-thiazole-5-alkylsulfonyl }-methyl-amino)-acetate
[2-(3 to be similar to; 3-dicyclohexyl-urea groups)-thiazole-5-sulfonamido]-mode of acetate; by cyclohexyl-(trans-4-methyl-cyclohexyl base)-amine and the preparation of [(2-amino-thiazolyl--5-alkylsulfonyl)-methyl-amino]-methyl acetate, obtain title compound.
HPLC-MS method 2:m/z=473 (M+H).
1H?NMR(DMSO-d
6)δ12.8(br?s，1H)，11.5(br?s，1H)，7.87(s，1H)，3.87(s，2H)，3.48(br?s，2H)，2.81(s，3H)，1.95(br?s，3H)，1.76-0.99(m，16H)，0.87(d，3H)。
Embodiment 85
(S)-1-[2-(3,3-dicyclohexyl-urea groups)-thiazole-5-alkylsulfonyl]-tetramethyleneimine-2-formic acid
Being similar to the mode of [2-(3,3-dicyclohexyl-urea groups)-thiazole-5-sulfonamido]-acetate, by dicyclohexyl amine and (S)-1-(2-amino-thiazolyl--5-alkylsulfonyl)-tetramethyleneimine-2-methyl-formiate preparation, obtain title compound.
HPLC-MS method 2:m/z=485 (M+H).
1H?NMR(DMSO-d
6)δ12.78(br?s，1H)，11.48(br?s，1H)，7.92(s，1H)，4.02(dd，1H)，3.57-3.18(m，4H)，2.07-1.05(m，24H)。
Embodiment 86
(S)-1-{2-[3-cyclohexyl-3-(trans-4-methyl-cyclohexyl base)-urea groups]-thiazole-5-alkylsulfonyl }-tetramethyleneimine-2-formic acid
[2-(3 to be similar to; 3-dicyclohexyl-urea groups)-thiazole-5-sulfonamido]-mode of acetate; by cyclohexyl-(trans-4-methyl-cyclohexyl base)-amine and (S)-1-(2-amino-thiazolyl--5-alkylsulfonyl)-tetramethyleneimine-2-methyl-formiate preparation, obtain title compound.
HPLC-MS method 2:m/z=499 (M+H).
1H?NMR(DMSO-d
6)δ12.78(br?s，1H)，11.46(br?s，1H)，7.92(s，1H)，4.02(dd，1H)，3.60-3.18(m，4H)，2.06-0.99(m，23H)，0.88(d，3H)。
Embodiment 87
2-[3-suberyl-3-(trans-4-propoxy--cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate
Synthesis technique preparation according to { 2-[3-cyclopentyl-3-(trans-4-methoxyl group-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate.
Step 1: use (trans-4-hydroxyl-cyclohexyl)-isoindole-1,3-diketone, 1-N-PROPYLE BROMIDE and suberone prepare suberyl-[trans-4-propoxy--cyclohexyl]-amine.
Step 2: use suberyl-[trans-4-propoxy--cyclohexyl]-amine and (amino-thiazolyl--5-base sulfenyl)-ethyl acetate preparation 2-[3-suberyl-3-(trans-4-propoxy--cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate.
1H?NMR(DMSO-d
6)δ7.39(s，1H)，3.70-3.15(m，3H)，3.48(s，2H)，2.20-1.15(m，20)，0.87(t，3H)。
HPLC-MS：m/z?470(M+H)。
Embodiment 88
2-[3-cyclopentyl-3-(trans-4-propoxy--cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate
Synthesis technique preparation according to { 2-[3-cyclopentyl-3-(trans-4-methoxyl group-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate.
Step 1: use (trans-4-hydroxyl-cyclohexyl)-isoindole-1,3-diketone, 1-N-PROPYLE BROMIDE and cyclopentanone prepare cyclopentyl-[trans-4-propoxy--cyclohexyl]-amine.
Step 2: use cyclopentyl-[trans-4-propoxy--cyclohexyl]-amine and (amino-thiazolyl--5-base sulfenyl)-ethyl acetate preparation 2-[3-cyclopentyl-3-(trans-4-propoxy--cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate.
1H?NMR(DMSO-d
6)δ7.35(s，1H)，3.82(m，1H)，3.55(m，1H)，3.42(s，2H)，3.28(t，2H)，3.12(m，1H)，2.1-1.1(m，16H)，0.8(t，3H)。
HPLC-MS：m/z?442(M+H)。
Embodiment 89
2-[3-cyclohexyl-3-(trans-4-isobutoxy-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate
Synthesis technique according to { 2-[3-cyclopentyl-3-(trans-4-methoxyl group-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate, use 2-(trans-4-hydroxyl-cyclohexyl)-isoindole-1,3-diketone, 3-bromo-2-methacrylic suberone and 2-(2-amino-thiazolyl--5-base sulfenyl)-2-methyl-ethyl acetate preparation.Use following technology hydrolysis intermediate cyclohexyl-[trans-4-(2-methyl-allyloxy)-cyclohexyl]-amine: with cyclohexyl-[4-(2-methyl-allyloxy)-cyclohexyl]-(540mg 2.15mmol) is dissolved among the 10mL AcOH, with N amine
2Access equipment adds 50mg Pd/C afterwards.Balloon feed N
2, and link to each other with device.Reaction mixture was at room temperature stirred 3 days, use Celite pad to leach Pd then.Filtered solution is poured among the 1N NaOH (pH＞12), and mixture extracts with 3 * ether (50mL), dry (MgSO
4), obtain cyclohexyl-(trans-4-isobutoxy-cyclohexyl)-amine, change it into title compound according to the synthesis technique of { 2-[3-cyclopentyl-3-(trans-4-methoxyl group-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate.
1H?NMR(DMSO-d
6)δ7.35(s，1H)，3.7-3.1(m，3H)，3.43(s，2H)，3.13(d，2H)，2.2-0.9(m，18H)，0.82(d，6H)。
HPLC-MS：m/z?470(M+H)。
Embodiment 90
2-(2-{3-cyclohexyl-3-[is trans-4-(2-methyl-allyloxy)-cyclohexyl]-urea groups }-thiazole-5-base sulfenyl)-2-methyl-propionic acid
Synthesis technique preparation according to { 2-[3-cyclopentyl-3-(trans-4-methoxyl group-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate.
Step 1: use (trans-4-hydroxyl-cyclohexyl)-isoindole-1,3-diketone, 3-bromo-2-methyl-propylene and pimelinketone prepare cyclohexyl-[trans-4-(2-methyl-allyloxy)-cyclohexyl]-amine.
Step 2: use cyclohexyl-[trans-4-(2-methyl-allyloxy)-cyclohexyl]-amine and 2-(2-amino-thiazolyl--5-base sulfenyl)-2-methyl-ethyl propionate prepare 2-(2-{3-cyclohexyl-3-[is trans-4-(2-methyl-allyloxy)-cyclohexyl]-urea groups-thiazole-5-base sulfenyl)-2-methyl-propionic acid.
HPLC-MS：m/z?496(M+H)。
Embodiment 91
2-{2-[3-cyclohexyl-3-(trans-4-propoxy--cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-2-methyl-propionic acid
Synthesis technique preparation according to { 2-[3-cyclopentyl-3-(trans-4-methoxyl group-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate.
Step 1: use (trans-4-hydroxyl-cyclohexyl)-isoindole-1,3-diketone, 1-N-PROPYLE BROMIDE and pimelinketone prepare cyclohexyl-[trans-4-propoxy--cyclohexyl]-amine.
Step 2: use cyclohexyl-[trans-4-propoxy--cyclohexyl]-amine and 2-(2-amino-thiazolyl--5-base sulfenyl)-2-methyl-ethyl propionate to prepare 2-{2-[3-cyclohexyl-3-(trans-4-propoxy--cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-2-methyl-propionic acid.
1H?NMR(DMSO-d
6)δ7.38(s，1H)，3.7-3.2(m，2H)，3.50(t，2H)，3.18(m，1H)，2.2-1.0(m，18H)，1.39(s，6H)，0.85(t，3H)。
HPLC-MS：m/z?484(M+H)。
Embodiment 92
3-{2-[3-cyclohexyl-3-(trans-4-isobutoxy-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-propionic acid
As described in to { 2-[3-cyclohexyl-3-(trans-4-isobutoxy-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate synthetic, use 2-(the basic sulfenyl of 2-amino-thiazolyl--5-)-2-methyl-ethyl acetate in coupling step, to prepare.
1H?NMR(DMSO-d
6)δ7.32(s，1H)，4.0-3.2(m，3H)，3.12(d，2H)，2.80(t，2H)，2.48(t，2H)，2.2-0.9(m，18H)，0.80(d，6H)。
HPLC-MS：m/z?484(M+H)。
Embodiment 93
3-{2-[3-suberyl-3-(trans-4-propoxy--cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-propionic acid
Synthesis technique preparation according to { 2-[3-cyclopentyl-3-(trans-4-methoxyl group-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate.
Step 1: use (trans-4-hydroxyl-cyclohexyl)-isoindole-1,3-diketone, 1-N-PROPYLE BROMIDE and suberone prepare suberyl-[trans-4-propoxy--cyclohexyl]-amine.
Step 2: use suberyl-[trans-4-propoxy--cyclohexyl]-amine and (amino-thiazolyl--5-base sulfenyl)-ethyl propionate to prepare 3-{2-[3-suberyl-3-(trans-4-propoxy--cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-propionic acid.
1H?NMR(DMSO-d
6)δ7.32(s，1H)，3.7-3.2(m，3H)，3.30(t，2H)，2.80(t，2H)，2.45(t，2H)，2.3-1.0(m，m，20H)，0.82(t，3H)。
HPLC-MS：m/z?484(M+H)。
Embodiment 94
3-{2-[3-cyclopentyl-3-(trans-4-propoxy--cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-propionic acid
Synthesis technique preparation according to { 2-[3-cyclopentyl-3-(trans-4-methoxyl group-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate.
Step 1: use (trans-4-hydroxyl-cyclohexyl)-isoindole-1,3-diketone, 1-N-PROPYLE BROMIDE and cyclopentanone prepare cyclopentyl-[trans-4-propoxy--cyclohexyl]-amine.
Step 2: use cyclopentyl-[trans-4-propoxy--cyclohexyl]-amine and (amino-thiazolyl--5-base sulfenyl)-ethyl propionate to prepare 3-{2-[3-cyclopentyl-3-(trans-4-propoxy--cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-propionic acid.
1H?NMR(DMSO-d
6)δ7.32(s，1H)，3.9-2.9(m，3H)，2.80(t，2H)，2.44(t，2H)，2.1-1.0(m，16H)，0.80(t，3H)。
HPLC-MS：m/z?456(M+H)。
Embodiment 95
2-{2-[3-cyclohexyl-3-(trans-4-ethoxyl methyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-2-methyl-propionic acid
To be similar to the mode of { 2-[3-cyclohexyl-3-(trans-4-methoxymethyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate, by cyclohexyl-(trans-4-ethoxyl methyl-cyclohexyl)-amine and 2-(2-amino-thiazolyl--5-base sulfenyl)-2-methyl-ethyl propionate preparation, obtain title compound.
1H?NMR(CDCl
3)：δ1.05-1.95(19H，m)，1.18(t，3H)，1.58(6H，s)，1.0-2.4(m，21H)，3.15-3.55(m，2H)，3.23(d，2H)，3.46(q，2H)，7.09(s，1H)。
HPLC-MS：m/z?485(M+H)。
Embodiment 96
2-[3-cyclohexyl-3-(trans-4-phenyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate
To be similar to the mode of { 2-[3-cyclopentyl-3-(trans-4-ethyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate (embodiment 38), by cyclohexyl-(4-phenyl-cyclohexyl)-amine and (2-amino-thiazolyl--5-base sulfenyl)-ethyl acetate preparation, obtain title compound.
HPLC-MS method 2:m/z=474 (M+H).
1H?NMR(DMSO)δ12.4(br?s，1H)，7.41(s，1H)，7.31-7.16(m，5H)，3.58(br?s，2H)，3.49(s，2H)，2.25-1.10(m，19H)。
Embodiment 97
3-{2-[3-cyclohexyl-3-(trans-4-phenyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-propionic acid
To be similar to the mode of { 2-[3-cyclopentyl-3-(trans-4-ethyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate, by cyclohexyl-(4-phenyl-cyclohexyl)-amine and 3-(2-amino-thiazolyl--5-base sulfenyl)-ethyl propionate preparation, obtain title compound.
HPLC-MS method 2:m/z=488 (M+H).
1H?NMR(DMSO-d
6)δ11.8(br?s，1H)，7.39(s，1H)，7.30-7.17(m，5H)，3.55(br?s，2H)，2.87(t，2H)，2.50(t，2H)，2.25-1.07(m，19H)。
Embodiment 98
2-[3-suberyl-3-(trans-4-phenyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate
To be similar to the mode of { 2-[3-cyclopentyl-3-(trans-4-ethyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate, by suberyl-(4-phenyl-cyclohexyl)-amine and (2-amino-thiazolyl--5-base sulfenyl)-ethyl acetate preparation, obtain title compound.
HPLC-MS method 2:m/z=488 (M+H).
1H?NMR(DMSO-d
6)δ11.4(br?s，1H)，7.41(s，1H)，7.32-7.16(m，5H)，3.55(br?s，2H)，3.48(s，2H)，2.58-1.42(m，21H)。
Embodiment 99
3-{2-[3-suberyl-3-(4-phenyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-propionic acid
To be similar to the mode of { 2-[3-cyclopentyl-3-(trans-4-ethyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate, by suberyl-(4-phenyl-cyclohexyl)-amine and 3-(2-amino-thiazolyl--5-base sulfenyl)-ethyl propionate preparation, obtain title compound.
HPLC-MS method 2:m/z=502 (M+H).
1H?NMR(DMSO-d
6)δ11.8(br?s，1H)，7.39(s，1H)，7.31-7.17(m，5H)，3.87(br?s，2H)，2.85(t，2H)，2.50(t，2H)，2.25-1.45(m，21H)。
Embodiment 100
2-{2-[3-cyclohexyl-3-(4-phenyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-2-methyl-propionic acid
To be similar to the mode of { 2-[3-cyclopentyl-3-(trans-4-ethyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate, by cyclohexyl-(4-phenyl-cyclohexyl)-amine and 2-(2-amino-thiazolyl--5-base sulfenyl)-2-methyl-ethyl propionate preparation.
HPLC-MS method 2:m/z=502 (M+H).
1H?NMR(DMSO-d
6)δ12.2(br?s，1H)，7.40(s，1H)，7.31-7.17(m，5H)，3.60(br?s，2H)，2.25-1.08(m，19H)，1.41(s，6H)。
Embodiment 101
2-{2-[3-suberyl-3-(4-phenyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-2-methyl-propionic acid
To be similar to the mode of { 2-[3-cyclopentyl-3-(trans-4-ethyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate, by suberyl-(4-phenyl-cyclohexyl)-amine and 2-(2-amino-thiazolyl--5-base sulfenyl)-2-methyl-ethyl propionate preparation.
HPLC-MS method 2:m/z=516 (M+H).
1H?NMR(DMSO-d
6)δ12.6(br?s，1H)，11.2(br?s，1H)，7.40(s，1H)，7.31-7.17(m，5H)，3.90(br?s，2H)，2.60-1.42(m，21H)，1.40(s，6H)。
Embodiment 102
2-[3-cyclohexyl-3-(trans-4-phenoxymethyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate
Step 1
With 0.50g trans-(4-methylol cyclohexyl) t-butyl carbamate is dissolved in the 30mL tetrahydrofuran (THF), adds 0.881g (4.36mmol) three fourth phosphines.Cooling mixture in ice bath adds 1.10g 1, and 1-(azo dicarbapentaborane) two piperidines stirred 10 minutes, adds 0.226g phenol.Reaction stirred makes ice bath reach room temperature in about 2 hours, then in stirred overnight at room temperature simultaneously.
Add 50mL water, the water layer ethyl acetate extraction is used 10%NaHSO
4, the saturated NaHCO of 20mL
3, the water washing of 20ml salt, dry (MgSO
4), filter, and vacuum concentration, filter by silicagel pad, use ethyl acetate and hexane as elutriant, vacuum concentration obtains 0.6g (trans-4-phenoxymethyl-cyclohexyl)-t-butyl carbamate, is white solid.
HPLC-MS：m/z?328(M+Na)。
Step 2
380mg (trans-4-phenoxymethyl-cyclohexyl)-t-butyl carbamate is dissolved in the 5mL methylene dichloride, adds the 5ml trifluoroacetic acid.Stirred the mixture 2 hours, vacuum concentration, by dichloromethane extraction twice, obtain 250mg trans-4-phenoxymethyl hexahydroaniline trifluoroacetate, be white solid.
HPLC-MS：m/z?205(M+H)。
Step 3
Trans-4-phenoxymethyl hexahydroaniline trifluoroacetate (1.2mmol) is dissolved in the mixture of 4mlTHF and 4mL MeOH, and this mixture is contained in the 20ml vial of being furnished with magnetic stirring bar and nut.Add 117mg pimelinketone and 3g
Molecular sieve.Stirred the mixture 10 minutes, and after this added the tetrahydrofuran solution of 2.4mL 1N sodium cyanoborohydride.Reaction mixture was at room temperature stirred 4 days, by diatomite filtration, thoroughly wash then with the 30mL methylene dichloride.With 10mL water, 10mL salt water washing organic phase, dry (MgSO
4), filtering, vacuum concentration obtains 300mg cyclohexyl-(trans-4-phenoxymethyl-cyclohexyl)-amine.
HPLC-MS：m/z?288(M+H)。
Step 4
(2-amino-thiazolyl--5-base sulfenyl)-ethyl acetate (0.13g), carbonyl dimidazoles (0.11g) and the mixture of 4-Dimethylamino pyridine (4mg) in tetrahydrofuran (THF) (10mL) and tetrahydrofuran (THF) (10mL) were at room temperature stirred 2 hours.Add cyclohexyl-(trans-4-phenoxymethyl-cyclohexyl)-amine, reactant is at room temperature stirred spend the night.Use purified by flash chromatography, obtain 80mg{2-[3-cyclohexyl-3-(trans-4-phenoxymethyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-ethyl acetate.
HPLC-MS：m/z?532(M+H)。
Step 5
With 80mg{2-[3-cyclohexyl-3-(trans-4-phenoxymethyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl-acetic acid ethyl dissolution in tetrahydrofuran (THF) (1mL), add 1N sodium hydroxide (1mL).At room temperature stirred 2 hours, and used the 1N hcl acidifying then.Filter white precipitate, and dry, obtain title compound (73mg).
1H?NMR(DMSO-d
6)：δ1.0-2.2(m，19H)，3.30-3.50(m，2H)，3.49(s，2H)，3.80(d，2H)，6.85-6.95(m，3H)，7.25-7.33(m，2H)，7.39(s，1H)。
HPLC-MS：m/z?504(M+H)。
Embodiment 103
(E)-6-[4-(1-cyclohexyl-3-thiazol-2-yl-urea groups)-piperidines-1-yl]-the 6-oxo-oneself-the 3-olefin(e) acid
As using 1-cyclohexyl-1-piperidin-4-yl-3-thiazol-2-yl-urea, trans-2-butene-1 described in the common processes (I), the preparation of 4-dioctyl phthalate.
1H?NMR(CDCl
3)：δ1.00-2.80(m，14H)，3.00-3.25(4H，m)，3.15-3.40(m，1H)，3.80-3.95(m，3H)，4.65-4.80(m，2H)，5.60-5.70(m，1H)，5.73-5.85(m，1H)，6.88(d，1H)，7.35(d，1H)。
HPLC-MS：m/z?435(M+H)。
Embodiment 104
2-[3-cyclohexyl-3-(trans-4-sec.-propyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate
To be similar to the mode of { 2-[3-cyclopentyl-3-(trans-4-ethyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate, by cyclohexyl-(trans-4-sec.-propyl-cyclohexyl)-amine and (2-amino-thiazolyl--5-base sulfenyl)-ethyl acetate preparation, obtain title compound.
HPLC-MS：m/z＝440(M+H)。
1H?NMR(CDCl
3)δ7.30(s，1H)，3.38(br?s，2H)，3.35(s，2H)，2.12-1.08(m，20H)，0.87(d，6H)。
Embodiment 105
2-[3-suberyl-3-(trans-4-sec.-propyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate
To be similar to the mode of { 2-[3-cyclopentyl-3-(trans 4-ethyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate (embodiment 38), by suberyl-(trans-4-sec.-propyl-cyclohexyl)-amine and (2-amino-thiazolyl--5-base sulfenyl)-ethyl acetate preparation, obtain title compound.
HPLC-MS：m/z＝454(M+H)。
1H?NMR(CDCl
3)δ7.29(s，1H)，3.68(br?s，1H)，3.34(s，2H)，3.25(br?s，1H)，2.38(br?s，2H)，1.82-1.04(m，20H)，0.89(d，6H)。
Embodiment 106
2-[3-cyclohexyl-3-(trans-4-ethyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate
To be similar to the mode of { 2-[3-cyclopentyl-3-(trans-4-ethyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate, by cyclohexyl-(trans-4-ethyl-cyclohexyl)-amine and (2-amino-thiazolyl--5-base sulfenyl)-ethyl acetate preparation, obtain title compound.
HPLC-MS：m/z＝426(M+H)。
1H?NMR(400MHz，CDCl
3)δ7.34(s，1H)，3.42(br?s，2H)，3.37(s，2H)，2.20-1.00(m，21H)，0.90(t，3H)。
Embodiment 107
2-[3-cyclohexyl-3-(trans-4-propoxy--cyclohexyl)-urea groups]-thiazole-5-sulfonamido }-acetate
[2-(3 to be similar to, 3-dicyclohexyl-urea groups)-thiazole-5-sulfonamido]-mode of acetate, by cyclohexyl-(trans-4-propoxy--cyclohexyl)-amine (according to described { 2-[3-cyclopentyl-3-(trans-4-methoxyl group-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate (synthesis technique of step 1), use (trans-4-hydroxyl-cyclohexyl)-isoindole-1,3-diketone, 1-N-PROPYLE BROMIDE and pimelinketone) and the preparation of (2-amino-thiazolyl--5-sulfonamido)-ethyl acetate, title compound obtained.
HPLC-MS method 2:m/z=503 (M+H).
1H?NMR(DMSO-d
6)δ12.7(br?s，1H)，11.4(br?s，1H)，8.16(t，1H)，7.78(s，1H)，3.62(d，2H)，3.45(br?s，2H)，3.35(t，2H)，3.22-3.15(m，1H)，2.25-1.5(m，20H)，0.86(t，3H)。
Embodiment 108
3-{2-[3-cyclohexyl-3-(trans-4-propoxy--cyclohexyl)-urea groups]-thiazole-5-sulfonamido }-propionic acid
[2-(3 to be similar to, 3-dicyclohexyl-urea groups)-thiazole-5-sulfonamido]-mode of acetate, by cyclohexyl-(trans-4-propoxy--cyclohexyl)-amine (according to described { 2-[3-cyclopentyl-3-(trans-4-methoxyl group-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate (synthesis technique of step 1), use (trans-4-hydroxyl-cyclohexyl)-isoindole-1,3-diketone, 1-N-PROPYLE BROMIDE and pimelinketone preparation) and 3-(2-amino-thiazolyl--5-sulfonamido)-ethyl propionate preparation, title compound obtained.
HPLC-MS method 2:m/z=517 (M+H).
1H?NMR(CDCl
3)δ7.78(s，1H)，6.54(br?t，1H)，3.58-3.19(m，5H)，3.41(t，2H)，2.55(t，2H)，2.20-1.11(m，20H)，0.92(t，3H)。
Embodiment 109
(2-[3-cyclohexyl-3-(trans-4-propoxy--cyclohexyl)-urea groups]-thiazole-5-alkylsulfonyl }-methyl-amino)-acetate
[2-(3 to be similar to; 3-dicyclohexyl-urea groups)-thiazole-5-sulfonamido]-mode of acetate; by cyclohexyl-(trans-4-propoxy--cyclohexyl)-amine (according to described { 2-[3-cyclopentyl-3-(trans-4-methoxyl group-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate (synthesis technique of step 1); use (trans-4-hydroxyl-cyclohexyl)-isoindole-1; 3-diketone, 1-N-PROPYLE BROMIDE and pimelinketone preparation) and the preparation of [(2-amino-thiazolyl--5-alkylsulfonyl)-methyl-amino]-acetate methyl ethyl ester, title compound obtained.
HPLC-MS method 2:m/z=517 (M+H).
1H?NMR(CDCl
3)δ7.78(s，1H)，3.86(s，2H)，3.58-3.32(m，2H)，3.41(t，2H)，3.28(br?t，1H)，2.90(s，3H)，2.20-1.11(m，20H)，0.91(t，3H)。
Embodiment 110
3-{2-[3-cyclohexyl-3-(trans-4-cyclo propyl methoxy methyl-cyclohexyl base)-urea groups]-thiazole-5-base sulfenyl }-propionic acid
To be similar to the mode of { 2-[3-cyclohexyl-3-(trans-4-methoxymethyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate, by cyclohexyl-(trans-4-cyclo propyl methoxy methyl-cyclohexyl base)-amine and (2-amino-thiazolyl--5-base sulfenyl)-ethyl propionate preparation, obtain title compound.
1H?NMR(CDCl
3)：δ0.08-0.15(m，2H)，0.40-0.46(m，2H)，.0.75-1.80-2.4(m，20H)，2.49-2.53(m，2H)，2.70-2.85(m，2H)，3.00-3.15(m，6H)，7.15(s，1H)。
HPLC-MS：m/z?497(M+H)。
Embodiment 111
3-{2-[3-suberyl-3-(trans-4-cyclo propyl methoxy methyl-cyclohexyl base)-urea groups]-thiazole-5-base sulfenyl }-propionic acid
To be similar to the mode of { 2-[3-cyclohexyl-3-(trans-4-methoxymethyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate, by suberyl-(trans-4-cyclo propyl methoxy methyl-cyclohexyl base)-amine and (2-amino-thiazolyl--5-base sulfenyl)-ethyl propionate preparation, obtain title compound.
1H?NMR(CDCl
3)：δ0.08-0.14(m，2H)，0.39-0.46(m，2H)，.0.75-1.80-2.4(m，22H)，2.45-2.55(m，2H)，2.70-2.86(m，2H)，3.00-3.15(m，6H)，7.16(s，1H)。
HPLC-MS：m/z?511(M+H)。
Embodiment 112
(2-{3-cyclohexyl-3-[4-(trans-4-methoxyl group-phenoxymethyl)-cyclohexyl]-urea groups }-thiazole-5-base sulfenyl)-acetate
To be similar to the mode of { 2-[3-cyclohexyl-3-(trans-4-phenoxymethyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate, by cyclohexyl-[trans-4-(4-methoxyl group-phenoxymethyl)-cyclohexyl]-amine and (2-amino-thiazolyl--5-base sulfenyl)-ethyl acetate preparation, obtain title compound.
1H?NMR(DMSO-d
6)：δ1.0-2.2(m，19H)，3.30-3.50(m，2H)，3.47(s，2H)，3.68(s，3H)，3.72(d，2H)，6.80-6.90(m，4H)，7.22(s，1H)。
HPLC-MS：m/z?534(M+H)。
Embodiment 113
(2-{3-cyclohexyl-3-[is trans-4-(4-fluoro-phenoxymethyl)-cyclohexyl]-urea groups }-thiazole-5-base sulfenyl)-acetate
To be similar to the mode of { 2-[3-cyclohexyl-3-(trans-4-phenoxymethyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate, by cyclohexyl-[trans-4-(4-fluoro-phenoxymethyl)-cyclohexyl]-amine and (2-amino-thiazolyl--5-base sulfenyl)-ethyl acetate preparation, obtain title compound.
1H?NMR(DMSO-d
6)：δ1.0-2.2(m，19H)，3.30-3.65(m，2H)，3.52(s，2H)，3.76(d，2H)，6.90-6.99(m，2H)，7.05-7.15(m，2H)，7.22(s，1H)。
HPLC-MS：m/z?522(M+H)。
Embodiment 114
(2-{3-cyclohexyl-3-[is trans-4-(4-imidazoles-1-base-phenoxymethyl)-cyclohexyl]-urea groups }-thiazole-5-base sulfenyl)-acetate
To be similar to the mode of { 2-[3-cyclohexyl-3-(trans-4-phenoxymethyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate, by cyclohexyl-[trans-4-(4-imidazoles-1-base-phenoxymethyl)-cyclohexyl]-amine and (2-amino-thiazolyl--5-base sulfenyl)-ethyl acetate preparation, obtain title compound.
1H?NMR(DMSO-d
6)：δ1.0-2.2(m，19H)，3.30-3.66(m，6H)，6.90-6.99(m，2H)，7.19(d，2H)，7.38(s，1H)，7.71(d，2H)，7.81(s，1H)，8.20(s，1H)，9.59(s，1H)。
HPLC-MS：m/z?570(M+H)。
Embodiment 115
2-[3-(trans-4-tert.-butoxy-cyclohexyl)-3-suberyl-urea groups]-thiazole-5-base sulfenyl }-acetate
Synthesis technique preparation according to { 2-[3-cyclopentyl-3-(trans-4-methoxyl group-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate.
Step 1
Use trans-4-tert.-butoxy-hexahydroaniline and pimelinketone to prepare suberyl-[trans-4-tert.-butoxy-cyclohexyl]-amine.
Step 2
Use suberyl-[trans-4-tert.-butoxy-cyclohexyl]-amine and (amino-thiazolyl--5-base sulfenyl)-ethyl acetate preparation 2-[3-(trans-4-tert.-butoxy-cyclohexyl)-3-suberyl-urea groups]-thiazole-5-base sulfenyl }-acetate.
1H?NMR(CDCl
3)δ7.30(s，1H)，3.7-3.3(m，3H)，3.35(s，2H)，1.95-1.3(m，20H)，1.20(s，9H)。
HPLC-MS：m/z?484(M+H)。
Embodiment 116
2-[3-(4-tert.-butoxy-cyclohexyl)-3-cyclohexyl-urea groups]-thiazole-5-base sulfenyl }-acetate
Synthesis technique preparation according to { 2-[3-cyclopentyl-3-(trans-4-methoxyl group-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate.
Step 1
Use trans-4-tert.-butoxy-hexahydroaniline and pimelinketone to prepare cyclohexyl-[trans-4-tert.-butoxy-cyclohexyl]-amine.
Step 2
Use cyclohexyl-[trans-4-tert.-butoxy-cyclohexyl]-amine and (amino-thiazolyl--5-base sulfenyl)-ethyl acetate preparation 2-[3-(4-tert.-butoxy-cyclohexyl)-3-cyclohexyl-urea groups]-thiazole-5-base sulfenyl }-acetate.
1H?NMR(DMSO-d
6)δ7.39(s，1H)，3.7-3.3(m，3H)，3.48(s，2H)，2.2-1.2(m，18H)，1.13(s，9H)。
HPLC-MS：m/z?470(M+H)。
Embodiment 117
3-{2-[3-(trans-4-tert.-butoxy-cyclohexyl)-3-suberyl-urea groups]-thiazole-5-base sulfenyl }-propionic acid
Synthesis technique preparation according to { 2-[3-cyclopentyl-3-(trans-4-methoxyl group-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate.
Step 1: use trans-4-tert.-butoxy-hexahydroaniline and suberone to prepare suberyl-[trans-4-tert.-butoxy-cyclohexyl]-amine.
Step 2: use suberyl-[trans-4-tert.-butoxy-cyclohexyl]-amine and (amino-thiazolyl--5-base sulfenyl)-ethyl propionate to prepare 3-{2-[3-(trans-4-tert.-butoxy-cyclohexyl)-3-suberyl-urea groups]-thiazole-5-base sulfenyl }-propionic acid.
1H?NMR(DMSO-d
6)δ7.38(s，1H)，3.7-3.3(m，2H)，3.33(s，2H)，2.84(t，2H)，2.50(t，2H)，2.2-1.2(m，20H)，1.13(s，9H)。
HPLC-MS：m/z?498(M+H)。
Embodiment 118
3-{2-[3-(4-tert.-butoxy-cyclohexyl)-3-cyclohexyl-urea groups]-thiazole-5-base sulfenyl }-propionic acid
Synthesis technique preparation according to { 2-[3-cyclopentyl-3-(trans-4-methoxyl group-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate.
Step 1: use trans-4-tert.-butoxy-hexahydroaniline and pimelinketone to prepare cyclohexyl-[trans-4-tert.-butoxy-cyclohexyl]-amine.
Step 2: use cyclohexyl-[trans-4-tert.-butoxy-cyclohexyl]-amine and (amino-thiazolyl--5-base sulfenyl)-ethyl propionate to prepare 3-{2-[3-(4-tert.-butoxy-cyclohexyl)-3-cyclohexyl-urea groups]-thiazole-5-base sulfenyl }-propionic acid.
1H?NMR(DMSO-d
6)δ7.38(s，1H)，3.7-3.2(m，3H)，3.30(s，2H)，2.84(t，2H)，2.2-1.2(m，18H)，1.15(s，9H)。
HPLC-MS：m/z?485(M+H)。
Embodiment 119
2-[3-(trans-4-benzyloxy-cyclohexyl)-3-cyclohexyl-urea groups]-thiazole-5-base sulfenyl }-acetate
Synthesis technique preparation according to { 2-[3-cyclopentyl-3-(trans-4-methoxyl group-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate.
Step 1: use (trans-4-hydroxyl-cyclohexyl)-isoindole-1,3-diketone, bromotoluene and pimelinketone prepare cyclohexyl-[trans-4-benzyloxy-cyclohexyl]-amine.
Step 2: use cyclohexyl-[trans-4-benzyloxy-cyclohexyl]-amine and (amino-thiazolyl--5-base sulfenyl)-ethyl acetate preparation 2-[3-(trans-4-benzyloxy-cyclohexyl)-3-cyclohexyl-urea groups]-thiazole-5-base sulfenyl }-acetate.
1H?NMR(DMSO-d
6)δ7.39(s，1H)，7.39-7.22(m，5H)，4.50(s，2H)，3.7-3.2(m，3H)，3.48(s，2H)，2.2-1.0(m，18H)。
HPLC-MS：m/z?504(M+H)。
Embodiment 120
2-[3-(trans-4-benzyloxy-cyclohexyl)-3-suberyl-urea groups]-thiazole-5-base sulfenyl }-acetate
Synthesis technique preparation according to { 2-[3-cyclopentyl-3-(trans-4-methoxyl group-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate.
Step 1
Use (trans-4-hydroxyl-cyclohexyl)-isoindole-1,3-diketone, bromotoluene and suberone prepare suberyl-[trans-4-benzyloxy-cyclohexyl]-amine.
Step 2
Use suberyl-[trans-4-benzyloxy-cyclohexyl]-amine and (amino-thiazolyl--5-base sulfenyl)-ethyl acetate preparation 2-[3-(trans-4-benzyloxy-cyclohexyl)-3-suberyl-urea groups]-thiazole-5-base sulfenyl }-acetate.
1H?NMR(DMSO-d
6)δ7.39(s，1H)，7.4-7.2(m，5H)，4.51(s，2H)，3.48(s，2H)，3.7-3.2(m，3H)，2.2-1.1(m，20H)。
HPLC-MS：m/z?518(M+H)。
Embodiment 121
3-{2-[3-(trans-4-benzyloxy-cyclohexyl)-3-cyclohexyl-urea groups]-thiazole-5-base sulfenyl }-propionic acid
Synthesis technique preparation according to { 2-[3-cyclopentyl-3-(trans-4-methoxyl group-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate.
Step 1
Use (trans-4-hydroxyl-cyclohexyl)-isoindole-1,3-diketone, bromotoluene and pimelinketone prepare cyclohexyl-[trans-4-benzyloxy-cyclohexyl]-amine.
Step 2
Use cyclohexyl-[trans-4-benzyloxy-cyclohexyl]-amine and (amino-thiazolyl--5-base sulfenyl)-ethyl propionate to prepare 3-{2-[3-(trans-4-benzyloxy-cyclohexyl)-3-cyclohexyl-urea groups]-thiazole-5-base sulfenyl }-propionic acid.
1H?NMR(DMSO-d
6)δ7.40-7.24(m，6H)，4.51(s；2H)，3.7-3.3(m，3H)，2.84(t，2H)，2.50(t，2H)，2.2-1.0(m，18H)。
HPLC-MS：m/z?518(M+H)。
Embodiment 122
3-{2-[3-(trans-4-benzyloxy-cyclohexyl)-3-suberyl-urea groups]-thiazole-5-base sulfenyl }-propionic acid
Synthesis technique preparation according to { 2-[3-cyclopentyl-3-(trans-4-methoxyl group-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate.
Step 1: use (trans-4-hydroxyl-cyclohexyl)-isoindole-1,3-diketone, bromotoluene and suberone prepare suberyl-[trans-4-benzyloxy-cyclohexyl]-amine.
Step 2: use suberyl-[trans-4-benzyloxy-cyclohexyl]-amine and (amino-thiazolyl--5-base sulfenyl)-ethyl propionate to prepare 3-{2-[3-(trans-4-benzyloxy-cyclohexyl)-3-suberyl-urea groups]-thiazole-5-base sulfenyl }-propionic acid.
1H?NMR(DMSO-d
6)δ7.40-7.23(m，6H)，4.50(s，2H)，3.7-3.2(m，3H)，2.83(t，2H)，2.49(t，2H)，2.2-1.2(m，20H)。
HPLC-MS：m/z?532(M+H)。
Embodiment 123
2-(2-[3-cyclohexyl-3-(trans-4-methyl-cyclohexyl base)-urea groups]-thiazole-5-alkylsulfonyl }-methyl-amino)-N, N-diethyl-ethanamide
To HOBt, ({ 2-[3-cyclohexyl-3-(trans-4-methyl-cyclohexyl base)-urea groups]-thiazole-5-alkylsulfonyl }-methyl-amino)-acetate etc. add EDAC (1.5 equivalent) and diisopropylethylamine (1.2 equivalent) and dry DMF (10mL/mmol) in the molar mixture.At room temperature stirred solution is 30 minutes, adds diethylamine (1.5 equivalent) then, continues to stir and spends the night.
Water quencher reaction mixture.Separate organic phase, water CH
2Cl
2Extraction, the dry organic phase that merges, vacuum concentration.Crude product is dissolved among the MeCN, and purifying (HPLC method 1), title compound obtained.
HPLC-MS method 2:m/z=528 (M+H).
1H?NMR(CDCl
3)δ7.79(s，1H)，3.92(s，2H)，3.44-3.33(m，6H)，2.90(s，3H)，1.95-1.75(m，13H)，1.47-1.03(m，12H)，0.92(d，3H)。
Embodiment 124
2-{2-[3-cyclohexyl-3-(trans-4-methyl-cyclohexyl base)-urea groups]-thiazole-5-sulfonamido }-2-methyl-propionic acid
To be similar to the mode of [2-(3,3-dicyclohexyl-urea groups)-thiazole-5-sulfonamido]-acetate,, obtain title compound by cyclohexyl-(trans-4-methyl-cyclohexyl base)-amine and 2-(2-amino-thiazolyl--5-sulfonamido)-2-methyl-methyl propionate preparation.
HPLC-MS method 2:m/z=487 (M+H).
1H?NMR(CDCl
3)δ7.67(s，1H)，5.65(br?s，1H)，5.20(br?s，1H)，3.60-3.05(m，2H)，2.22-1.02(m，19H)，1.60(s，6H)，0.92(d，3H)。
Embodiment 125
1-{2-[3-cyclohexyl-3-(trans-4-methyl-cyclohexyl base)-urea groups]-thiazole-5-sulfonamido }-cyclobutane formate
To be similar to the mode of [2-(3,3-dicyclohexyl-urea groups)-thiazole-5-sulfonamido]-acetate,, obtain title compound by cyclohexyl-(trans-4-methyl-cyclohexyl base)-amine 1-(2-amino-thiazolyl--5-sulfonamido)-cyclobutane formate methyl esters preparation.
HPLC-MS method 2:m/z=500 (M+H).
1H?NMR(CDCl
3)δ7.60(s，1H)，5.23(br?s，1H)，3.55(br?s，1H)，3.05(br?s，1H)，2.68-2.52(m，5H)，2.18-1.05(m，20H)，0.91(d，3H)。
Embodiment 126
1-{2-[3-cyclohexyl-3-(trans-4-methyl-cyclohexyl base)-urea groups]-thiazole-5-sulfonamido }-cyclopropane-carboxylic acid
To be similar to the mode of [2-(3,3-dicyclohexyl-urea groups)-thiazole-5-sulfonamido]-acetate,, obtain title compound by cyclohexyl-(trans-4-methyl-cyclohexyl base)-amine and 1-(2-amino-thiazolyl--5-sulfonamido)-cyclopropane-carboxylic acid ethyl ester preparation.
HPLC-MS method 2:m/z=485 (M+H).
1H?NMR(DMSO-d
6)δ12.5(br?s，1H)，11.32(br?s，1H)，8.68(s，1H)，7.68(s，1H)，2.07-1.00(m，25H)，0.87(d，3H)。
Embodiment 127
(R)-1-{2-[3-cyclohexyl-3-(trans-4-methyl-cyclohexyl base)-urea groups]-thiazole-5-alkylsulfonyl }-tetramethyleneimine-2-formic acid
[2-(3 to be similar to; 3-dicyclohexyl-urea groups)-thiazole-5-sulfonamido]-mode of acetate; by cyclohexyl-(trans-4-methyl-cyclohexyl base)-amine and (R)-1-(2-amino-thiazolyl--5-alkylsulfonyl)-tetramethyleneimine-2-methyl-formiate preparation, obtain title compound.
HPLC-MS method 2:m/z=499 (M+H).
1H NMR is equal to (S)-1-{2-[3-cyclohexyl-3-(trans-4-methyl-cyclohexyl base)-urea groups]-thiazole-5-alkylsulfonyl }-tetramethyleneimine-2-formic acid
1H NMR.
Embodiment 128
1-{2-[3-cyclohexyl-3-(trans-4-propoxy--cyclohexyl)-urea groups]-thiazole-5-sulfonamido }-cyclobutane formate
[2-(3 to be similar to, 3-dicyclohexyl-urea groups)-thiazole-5-sulfonamido]-mode of acetate, by cyclohexyl-(trans-4-propoxy--cyclohexyl)-amine (according to described { 2-[3-cyclopentyl-3-(trans-4-methoxyl group-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate (synthesis technique of step 1), use (trans-4-hydroxyl-cyclohexyl)-isoindole-1,3-diketone, 1-N-PROPYLE BROMIDE and pimelinketone preparation) and 1-(2-amino-thiazolyl--5-sulfonamido)-cyclobutane formate methyl esters preparation, title compound obtained.
HPLC-MS method 2:m/z=543 (M+H).
1H?NMR(CDCl
3)δ7.60(s，1H)，5.50(br?s，1H)，3.59(br?s，1H)，3.42(t，2H)，3.31-3.22(m，1H)，2.68-2.51(m，4H)，2.18-1.11(m，22H)，0.93(t，3H)。
Embodiment 129
2-[3-cyclohexyl-3-(trans-4-cyclo propyl methoxy methyl-cyclohexyl base)-urea groups]-thiazole-5-base sulfenyl }-acetate
To be similar to the mode of { 2-[3-cyclohexyl-3-(trans-4-methoxymethyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate, by cyclohexyl-(trans-4-cyclo propyl methoxy methyl-cyclohexyl base)-amine and (2-amino-thiazolyl--5-base sulfenyl)-ethyl acetate preparation, obtain title compound.
1H?NMR(CDCl
3)：δ0.08-0.15(m，2H)，0.40-0.50(m，2H)，0.80-2.00(m，20H)，2.80-3.50(2H，m)，3.13(d，2H)，3.18(d，2H)，7.25(s，1H)。
HPLC-MS：m/z?483(M+H)。
Embodiment 130
2-[3-suberyl-3-(trans-4-cyclo propyl methoxy methyl-cyclohexyl base)-urea groups]-thiazole-5-base sulfenyl }-acetate
To be similar to the mode of { 2-[3-cyclohexyl-3-(trans-4-methoxymethyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate, by suberyl-(trans-4-cyclo propyl methoxy methyl-cyclohexyl base)-amine and (2-amino-thiazolyl--5-base sulfenyl)-ethyl acetate preparation, obtain title compound.
1H?NMR(CDCl
3)：δ0.08-0.15(m，2H)，0.40-0.50(m，2H)，0.80-1.90(m，20H)，2.80-3.50(2H，m)，3.13(d，2H)，3.15(d，2H)，3.30-(s，2H)，7.20(s，1H)。
HPLC-MS：m/z?497(M+H)。
Embodiment 131
2-{2-[3-cyclohexyl-3-(trans-4-propoxy--cyclohexyl)-urea groups]-thiazole-5-sulfonamido }-2-methyl-propionic acid
[2-(3 to be similar to, 3-dicyclohexyl-urea groups)-thiazole-5-sulfonamido]-mode of acetate, by cyclohexyl-(trans-4-propoxy--cyclohexyl)-amine (according to described { 2-[3-cyclopentyl-3-(trans-4-methoxyl group-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate (synthesis technique of step 1), use (trans-4-hydroxyl-cyclohexyl)-isoindole-1,3-diketone, 1-N-PROPYLE BROMIDE and pimelinketone preparation) and 2-(2-amino-thiazolyl--5-sulfonamido)-2-methyl-methyl propionate preparation, title compound obtained.
HPLC-MS method 2:m/z=531 (M+H).
1H?NMR(400MHz，CDCl
3)δ7.65(s，1H)，5.28(br?s，1H)，3.60(brs，1H)，3.42(t，2H)，3.30-3.02(m，2H)，2.47-1.11(m，20H)，1.61(s，6H)，0.92(d，3H)。
Embodiment 132
(R)-1-{2-[3-cyclohexyl-3-(trans-4-propoxy--cyclohexyl)-urea groups]-thiazole-5-alkylsulfonyl }-tetramethyleneimine-2-formic acid
[2-(3 to be similar to; 3-dicyclohexyl-urea groups)-thiazole-5-sulfonamido]-mode of acetate; by cyclohexyl-(trans-4-propoxy--cyclohexyl)-amine (according to described { 2-[3-cyclopentyl-3-(trans-4-methoxyl group-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate (synthesis technique of step 1); use (trans-4-hydroxyl-cyclohexyl)-isoindole-1; 3-diketone, 1-N-PROPYLE BROMIDE and pimelinketone preparation) and (R)-1-(2-amino-thiazolyl--5-alkylsulfonyl)-tetramethyleneimine-2-methyl-formiate preparation, obtain title compound.
HPLC-MS method 2:m/z=543 (M+H).
1H?NMR(400MHz，CDCl
3)δ7.83(s，1H)，4.18(dd，1H)，3.63-3.23(m，8H)，2.27-1.11(m，27H)，0.92(d，3H)。
Embodiment 133
2-[3-(trans-4-benzyloxymethyl-cyclohexyl)-3-cyclohexyl-urea groups]-thiazole-5-base sulfenyl }-acetate
To be similar to the mode of { 2-[3-cyclohexyl-3-(trans-4-methoxymethyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate, by (trans-4-benzyloxymethyl-cyclohexyl)-cyclohexyl-amine and (2-amino-thiazolyl--5-base sulfenyl)-ethyl acetate preparation, obtain title compound.
1H?NMR(DMSO-d
6)：δ1.00-2.10(m，19H)，3.15-3.55(m，2H)，3.20(d，2H)，3.47(s，2H)，4.45(s，2H)，7.20-7.45(m?6H)。
HPLC-MS：m/z?518(M+H)。
Embodiment 134
2-[3-cyclohexyl-3-(trans-4-isopropoxy-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate
Synthesis technique according to { 2-[3-cyclopentyl-3-(trans-4-methoxyl group-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate uses cyclohexyl-(4-isopropoxy-cyclohexyl)-amine and (amino-thiazolyl--5-base sulfenyl)-ethyl acetate preparation.
1H?NMR(400MHz，DMSO-d
6)δ7.39(s，1H)，3.65(h，1H)，3.6-3.2(m，3H)，3.48(s，2H)，2.2-1.0(m，18H)，1.07(d，6H)。
HPLC-MS：m/z?457(M+H)。
Embodiment 135
2-[3-suberyl-3-(trans-4-isopropoxy-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate
Synthesis technique according to { 2-[3-cyclopentyl-3-(trans-4-methoxyl group-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate uses suberyl-(4-isopropoxy-cyclohexyl)-amine and (amino-thiazolyl--5-base sulfenyl)-ethyl acetate preparation.
1H?NMR(DMSO-d
6)δ7.39(s，1H)，3.68(h，1H)，3.6-3.2(m，3H)，3.48(s，2H)，2.2-1.1(m，20H)，1.08(d，6H)。
HPLC-MS：m/z?471(M+H)。
Embodiment 136
2-[3-suberyl-3-(trans-4-phenoxymethyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate
To be similar to the mode of { 2-[3-cyclohexyl-3-(trans-4-phenoxymethyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate, by suberyl-(trans-4-phenoxymethyl-cyclohexyl)-amine and (2-amino-thiazolyl--5-base sulfenyl)-ethyl acetate preparation, obtain title compound.
1H?NMR(DMSO-d
6)：δ1.10-2.15(m，21H)，3.30-3.50(m，2H)，3.48(s，2H)，3.79(d，2H)，6.87-6.95(m，3H)，7.27(d，2H)，7.39(s，1H)。
HPLC-MS：m/z?518(M+H)。
Embodiment 137
(2-{3-suberyl-3-[is trans-4-(4-methoxyl group-phenoxymethyl)-cyclohexyl]-urea groups }-thiazole-5-base sulfenyl)-acetate
To be similar to the mode of { 2-[3-cyclohexyl-3-(trans-4-phenoxymethyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate, by suberyl-[trans-4-(4-methoxyl group-phenoxymethyl)-cyclohexyl]-amine and (2-amino-thiazolyl--5-base sulfenyl)-ethyl acetate preparation, obtain title compound.
1H?NMR(DMSO-d
6)：δ1.0-2.2(m，21H)，3.30-3.50(m，2H)，3.45(s，2H)，3.69(s，3H)，3.72(d，2H)，6.80-6.90(m，4H)，7.40(s，1H)。
HPLC-MS：m/z?548(M+H)。
Embodiment 138
(2-{3-suberyl-3-[is trans-4-(4-fluoro-phenoxymethyl)-cyclohexyl]-urea groups }-thiazole-5-base sulfenyl)-acetate
To be similar to the mode of { 2-[3-cyclohexyl-3-(trans-4-phenoxymethyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate, by suberyl-[trans-4-(4-fluoro-phenoxymethyl)-cyclohexyl]-amine and (2-amino-thiazolyl--5-base sulfenyl)-ethyl acetate preparation, obtain title compound.
1H?NMR(DMSO-d
6)：δ1.15-2.20(m，21H)，3.20-3.50(m，2H)，3.46(s，2H)，3.80(d，2H)，6.93(d，2H)，7.37(t，2H)，7.39(s，1H)。
HPLC-MS：m/z?536(M+H)。
Embodiment 139
(2-{3-suberyl-3-[is trans-4-(4-trifluoromethyl-phenoxymethyl)-cyclohexyl]-urea groups }-thiazole-5-base sulfenyl)-acetate
To be similar to the mode of { 2-[3-cyclohexyl-3-(trans-4-phenoxymethyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate, by suberyl-[trans-4-(4-trifluoromethyl-phenoxymethyl)-cyclohexyl]-amine and (2-amino-thiazolyl--5-base sulfenyl)-ethyl acetate preparation, obtain title compound.
1H?NMR(DMSO-d
6)：δ1.15-2.20(m，21H)，3.20-4.00(m，2H)，3.46(s，2H)，3.75(d，2H)，6.95(dd，2H)，7.12(t，2H)，7.40(s，1H)。
HPLC-MS：m/z?586(M+H)。
Embodiment 140
(2-{3-cyclohexyl-3-[is trans-4-(4-trifluoromethyl-phenoxymethyl)-cyclohexyl]-urea groups }-thiazole-5-base sulfenyl)-acetate
To be similar to the mode of { 2-[3-cyclohexyl-3-(trans-4-phenoxymethyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate, by cyclohexyl-[trans-4-(4-trifluoromethyl-phenoxymethyl)-cyclohexyl]-amine and (2-amino-thiazolyl--5-base sulfenyl)-ethyl acetate preparation, obtain title compound.
1H?NMR(DMSO)：δ1.15-2.20(m，19H)，3.10-3.60(m，2H)，3.48(s，2H)，3.88(d，2H)，7.12(d，2H)，7.40(s，1H)，7.61(d，2H)。
HPLC-MS：m/z?572(M+H)。
Embodiment 141
3-{2-[3-cyclohexyl-3-(trans-4-phenoxymethyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-propionic acid
To be similar to the mode of { 2-[3-cyclohexyl-3-(trans-4-phenoxymethyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate, by cyclohexyl-(trans-4-phenoxymethyl-cyclohexyl)-amine and (2-amino-thiazolyl--5-base sulfenyl)-ethyl propionate preparation, obtain title compound.
1H?NMR(DMSO-d
6)：δ1.05-2.00(m，19H)，2.50(t，2H)，2.82(t，2H)，3.30-3.50(m，2H)，3.78(d，2H)，6.91(d，3H)，7.25(d，2H)，7.38(s，1H)。
Embodiment 142
3-(2-{3-cyclohexyl-3-[is trans-4-(4-methoxyl group-phenoxymethyl)-cyclohexyl]-urea groups }-thiazole-5-base sulfenyl)-propionic acid
To be similar to the mode of { 2-[3-cyclohexyl-3-(trans-4-phenoxymethyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate, by cyclohexyl-[trans-4-(4-methoxyl group-phenoxymethyl)-cyclohexyl]-amine and (2-amino-thiazolyl--5-base sulfenyl)-ethyl propionate preparation, obtain title compound.
1H?NMR(DMSO-d
6)：δ1.0-2.2(m，19H)，2.50(t，2H)，2.82(t，2H)，3.20-3.90(m，2H)，3.68(s，3H)，3.72(d，2H)，6.82(m，4H)，7.37(s，1H)。
HPLC-MS：m/z?548(M+H)。
Embodiment 143
3-(2-{3-cyclohexyl-3-[is trans-4-(4-fluoro-phenoxymethyl)-cyclohexyl]-urea groups }-thiazole-5-base sulfenyl)-propionic acid
To be similar to the mode of { 2-[3-cyclohexyl-3-(trans-4-phenoxymethyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate, by cyclohexyl-[trans-4-(4-fluoro-phenoxymethyl)-cyclohexyl]-amine and (2-amino-thiazolyl--5-base sulfenyl)-ethyl propionate preparation, obtain title compound.
1H?NMR(DMSO-d
6)：δ1.05-2.20(m，19H)，2.50(t，2H)，2.82(t，2H)，3.20-3.90(m，2H)，3.72(d，2H)，6.92(dd，2H)，7.10(t，2H)，7.38(s，1H)。
HPLC-MS：m/z?536(M+H)。
Embodiment 144
3-{2-[3-cyclohexyl-3-(trans-4-isopropoxy-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-propionic acid
Synthesis technique according to { 2-[3-cyclopentyl-3-(trans-4-methoxyl group-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate uses cyclohexyl-(4-isopropoxy-cyclohexyl)-amine and (amino-thiazolyl--5-base sulfenyl)-ethyl propionate preparation.
1H?NMR(400MHz，DMSO-d
6)δ7.38(s，2H)，3.68(h，1H)，3.6-3.2(m，3H)，2.83(t，2H)，2.50(t，2H)，2.2-1.0(m，18H)，1.05(d，6H)。
HPLC-MS：m/z?470(M+H)。
Embodiment 145
3-{2-[3-suberyl-3-(trans-4-isopropoxy-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-propionic acid
Synthesis technique according to { 2-[3-cyclopentyl-3-(trans-4-methoxyl group-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate uses suberyl-(4-isopropoxy-cyclohexyl)-amine and (amino-thiazolyl--5-base sulfenyl)-ethyl propionate preparation.
1H?NMR(DMSO-d
6)δ7.38(s，1H)，3.68(h，1H)，3.8-3.1(m，3H)，2.85(t，2H)，2.50(t，2H)，2.2-1.12(m，20H)，1.08(d，6H)。
HPLC-MS：m/z?484(M+H)。
Embodiment 146
3-(2-{3-cyclohexyl-3-[4-(trans-2-methoxyl group-ethoxyl methyl)-cyclohexyl]-urea groups }-thiazole-5-base sulfenyl)-acetate
To be similar to the mode of { 2-[3-cyclohexyl-3-(trans-4-methoxymethyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate, by cyclohexyl-[4-(trans-2-methoxyl group-ethoxyl methyl)-cyclohexyl]-amine and (2-amino-thiazolyl--5-base sulfenyl)-ethyl acetate preparation, obtain title compound.
1H?NMR(CDCl
3)：δ1.0-2.0(m，19H)，3.0-3.60(m，2H)，3.28(d，2H)，3.39(s，3H)，3.50-3.60(m，4H)，7.36(m，1H)。
HPLC-MS：m/z?487(M+H)。
Embodiment 147
3-(2-{3-cyclohexyl-3-[4-(trans-2-methoxyl group-ethoxyl methyl)-cyclohexyl]-urea groups }-thiazole-5-base sulfenyl)-propionic acid
To be similar to the mode of { 2-[3-cyclohexyl-3-(trans-4-methoxymethyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate, by cyclohexyl-[4-(trans-2-methoxyl group-ethoxyl methyl)-cyclohexyl]-amine and (2-amino-thiazolyl--5-base sulfenyl)-ethyl propionate preparation, obtain title compound.
1H?NMR(CDCl
3)：δ1.0-2.0(m，19H)，2.9-3.60(m，2H)，2.70(t，2H)，2.95-3.03(m，2H)，3.30(d，2H)，3.40(s，3H)，3.50-3.60(m，4H)，7.31(m，1H)。
HPLC-MS：m/z?501(M+H)。
Embodiment 148
(2-{3-suberyl-3-[4-(trans-2-methoxyl group-ethoxyl methyl)-cyclohexyl]-urea groups }-thiazole-5-base sulfenyl)-acetate
To be similar to the mode of { 2-[3-cyclohexyl-3-(trans-4-methoxymethyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate, by suberyl-[4-(trans-2-methoxyl group-ethoxyl methyl)-cyclohexyl]-amine and (2-amino-thiazolyl--5-base sulfenyl)-ethyl acetate preparation, obtain title compound.
1H?NMR(CDCl
3)：
1.0-2.0(m，21H)，3.0-3.60(m，2H)，3.30(d，2H)，3.33-3.38(m，2H)，3.39(s，3H)，3.50-3.60(m，4H)，7.32(bs，1H)。
HPLC-MS：m/z?500(M+H)。
Embodiment 149
3-(2-{3-suberyl-3-[4-(trans-2-methoxyl group-ethoxyl methyl)-cyclohexyl]-urea groups }-thiazole-5-base sulfenyl)-propionic acid
To be similar to the mode of { 2-[3-cyclohexyl-3-(trans-4-methoxymethyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate, by suberyl-[4-(trans-2-methoxyl group-ethoxyl methyl)-cyclohexyl]-amine and (2-amino-thiazolyl--5-base sulfenyl)-ethyl propionate preparation, obtain title compound.
1H?NMR(CDCl
3)：δ1.0-2.0(m，21H)，2.9-3.80(m，2H)，2.71(t，2H)，2.95-3.00(m，2H)，3.32(d，2H)，3.40(s，3H)，3.51-3.60(m，4H)，7.30(m，1H)。
HPLC-MS：m/z?515(M+H)。
Embodiment 150
(2-{3-cyclohexyl-3-[4-(trans-2,2,2-three fluoro-ethoxyl methyls)-cyclohexyl]-urea groups }-thiazole-5-base sulfenyl)-acetate
To be similar to the mode of { 2-[3-cyclohexyl-3-(trans-4-phenoxymethyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate, by cyclohexyl-[trans-4-(2,2,2-three fluoro-ethoxyl methyls)-cyclohexyl]-amine and (2-amino-thiazolyl--5-base sulfenyl)-ethyl acetate preparation, obtain title compound.
1H?NMR(CDCl
3)：δ1.11-2.25(m，19H)，3.28-3.50(m，2H)，3.34(s，2H)，3.44(d，2H)，3.81(q，2H)，7.27(s，1H)。
HPLC-MS：m/z?511(M+H)。
Embodiment 151
(2-{2-[3-cyclohexyl-3-(trans-4-propoxy--cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-ethanoyl)-Toluidrin
To be similar to the mode of { 2-[3-cyclopentyl-3-(trans-4-methoxyl group-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate, by cyclohexyl-(trans-4-propoxy--cyclohexyl)-amine (according to described { 2-[3-cyclopentyl-3-(trans-4-methoxyl group-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate (synthesis technique of step 1), use (trans-4-hydroxyl-cyclohexyl)-isoindole-1, the 3-diketone, 1-N-PROPYLE BROMIDE and pimelinketone preparation) and (2-amino-thiazolyl--5-base sulfenyl)-ethyl acetate preparation 2-[3-cyclohexyl-3-(4-propoxy--cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate.Will { 2-[3-cyclohexyl-3-(4-propoxy--cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate (0.5mmol), 1,1 '-carbonyl dimidazoles (0.51mmol) and 4-lutidine (0.05mmol) be dissolved among the anhydrous THF (3mL).At room temperature stirred the mixture 1 hour.In this solution, add Toluidrin (0.95mmol), stirred 2-3 minute.Add 1, THF (0.5mL) solution of 8-diazabicyclo [5.4.0] 11 carbon-7-alkene (0.6mmol) at room temperature stirred the mixture 2 hours, and concentrated.Crude product obtains title compound, yield 45% with HPLC purifying (method 1).
1H NMR (CDCl
3): δ 7.44 (s, 1H), 3.49 (s, 2H), 3.41 (m, 3H), 3.33 (s, 3H), 3.23 (m, 2H), 2.30-2.09 (m, 4H), 1.85-1.65 (m, 10H), 1.57 (sextet, 2H), 1.42-1.30 (m, 4H), 1.15 (m, 1H), 0.91 (t, 3H).
HPLC-MS：m/z?534(M+1)。
Embodiment 152
2-{2-[3-cyclohexyl-3-(trans-4-cyclo propyl methoxy methyl-cyclohexyl base)-urea groups]-thiazole-5-base sulfenyl }-2-methyl-propionic acid
To be similar to the mode of { 2-[3-cyclohexyl-3-(trans-4-methoxymethyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate, by cyclohexyl-(trans-4-cyclo propyl methoxy methyl-cyclohexyl base)-amine and (2-amino-thiazolyl--5-base sulfenyl)-2-methyl-ethyl propionate preparation, obtain title compound.
1H?NMR(CDCl
3)：δ0.15-0.20(m，2H)，0.47-0.54(m，2H)，.0.75-1.80-2.4(m，26H)，3.00-3.60(m，6H)，7.15(s，1H)。
HPLC-MS：m/z?511(M+H)。
Embodiment 153
2-(2-{3-cyclohexyl-3-[4-(trans-2-methoxyl group-ethoxyl methyl)-cyclohexyl]-urea groups }-thiazole-5-base sulfenyl)-2-methyl-propionic acid
To be similar to the mode of { 2-[3-cyclohexyl-3-(trans-4-methoxymethyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate, by cyclohexyl-[4-(trans-2-methoxyl group-ethoxyl methyl)-cyclohexyl]-amine and (2-amino-thiazolyl--5-base sulfenyl)-2-methyl-ethyl propionate preparation, obtain title compound.
1H?NMR(CDCl
3)：δ1.0-2.0(m，25H)，3.0-3.85(m，2H)，3.29(d，2H)，3.39(s，3H)，3.52-3.59(m，4H)，7.06(bs，1H)。
HPLC-MS：m/z?515(M+H)。
Embodiment 154
2-(2-{3-suberyl-3-[4-(trans-2-methoxyl group-ethoxyl methyl)-cyclohexyl]-urea groups }-thiazole-5-base sulfenyl)-2-methyl-propionic acid
To be similar to the mode of { 2-[3-cyclohexyl-3-(trans-4-methoxymethyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate, by suberyl-[4-(trans-2-methoxyl group-ethoxyl methyl)-cyclohexyl]-amine and (2-amino-thiazolyl--5-base sulfenyl)-2-methyl-ethyl propionate preparation, obtain title compound.
1H?NMR(CDCl
3)：δ1.0-2.0(m，27H)，3.0-3.85(m，2H)，3.27(d，2H)，3.38(s，3H)，3.52-3.60(m，4H)，7.15(bs，1H)。
HPLC-MS：m/z?528(M+H)。
Embodiment 155
2-{2-[3-cyclohexyl-3-(trans-4-methoxymethyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-2-methyl-propionic acid
To be similar to the mode of { 2-[3-cyclohexyl-3-(trans-4-methoxymethyl-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate, by cyclohexyl-(trans-4-methoxymethyl-suberyl)-amine and 2-(2-amino-thiazolyl--5-base sulfenyl)-2-methyl-ethyl propionate preparation, obtain title compound.
1H?NMR(CDCl
3)：δ1.0-2.0(m，25H)，3.15-3.70(2H，m)，3.21(d，2H)，3.33(s，3H)，7.10(s，1H)。
HPLC-MS：m/z?470(M+H)。
Embodiment 156
2-[3-cyclohexyl-3-(cis-4-propoxy--cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate
Step 1
At N
2Down, with cis-4-Trans-4-Amino Cyclohexanol hydrochloride (4mmol) and pimelinketone (8mmol) and molecular sieve (
1g) mixture with anhydrous MeOH (10mL) at room temperature stirred 10 minutes.In mixture, add NaBH
3CN (8mmol) and Glacial acetic acid (0.1mL), restir 24 hours.Add NaBH
4(1.3mmol), restir 10 minutes afterwards.Filtering mixt, resistates is extremely done with MeOH (10mL) extraction, the filtered solution of evaporation merging.Resistates is dissolved in the 1M HCl aqueous solution (15mL), with TBME (15mL) washing.Add the 10%NaOH aqueous solution to water, until pH 14, with TBME (15mL) extraction.Organic phase H
2O (10ml) washing, dry (Na
2SO
4), reduction vaporization obtains crude product cyclohexyl-cis-(4-hydroxy-cyclohexyl) amine to doing, and need not to be further purified just to can be used for next step.
Step 2
To NaH (60% suspension, 1.4mmol) and add cyclohexyl-cis-(4-hydroxy-cyclohexyl)-amine (0.36mmol) in the mixture of glycol dimethyl ether (3mL), at N
2, stirred the mixture 5 minutes under the room temperature, then add N-PROPYLE BROMIDE (5.5mmol), with mixture at N
2Under refluxed 18 hours.Reaction mixture is cooled to room temperature, with anhydrous EtOH (0.5mL) quencher.Filtering mixt, resistates spent glycol dme (2mL) extraction.The reduction vaporization organic phase is to doing, with toluene (10Ll) coevaporation.(1.25M, 5mL), reduction vaporization obtains white solid to doing to the MeOH solution of adding HCl in resistates.Solid is dissolved in the mixture of the DCM (5mL) and the 1M NaOH aqueous solution (5mL) after washing with TBME (2mL).Organic phase H
2O (5mL) washing, dry (Na
2SO
4), reduction vaporization obtains cyclohexyl-cis-(4-propoxy-cyclohexyl) amine (oily matter) of needs to doing, and need not to be further purified just to can be used for next step.
Step 3 (coupling and hydrolysis)
To be similar to the mode of { 2-[3-cyclopentyl-3-(trans-4-methoxyl group-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate, use cyclohexyl-cis-(4-propoxy-cyclohexyl)-amine and (amino-thiazolyl--5-base sulfenyl)-ethyl acetate to prepare title compound.
1H-NMR(DMSO-d
6)δ11.50(br?s，1H)，7.38(s，1H)，3.64(m，1H)，3.46(s，2H)，3.45-3.25(m，4H)，2.14-1.93(m，4H)，1.92-1.84(m，2H)，1.78-1.69(m，2H)，1.60-1.40(m，7H)，1.36-1.18(m，4H)，1.16-1.03(m，1H)，0.93(t，3H)。
Embodiment 157
2-[3-cyclohexyl-3-(trans-4-phenoxy group-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate
Step 1
In 0 ℃; in the stirred solution of the cis-4-hydroxyl hexahydroaniline (1mmol is as preparing described in the WO2005/019222) of N-Boc protection and toluene (10mL) and THF (1mL), add triphenyl phosphine (1.5mmol), diisopropyl azo-2-carboxylic acid (1.7mmol) and phenol (2mmol).Mixture was at room temperature stirred 4 hours, and reduction vaporization is dissolved among the DCM then, uses Na
2CO
3Solution washing.With the organic phase drying, filter and concentrate, obtain crude product, use purified by flash chromatography, obtain the trans-4-phenoxy group hexahydroaniline of needed N-Boc protection, just need not to be further purified and can directly use.
Step 2
(4-phenoxy group-cyclohexyl)-t-butyl carbamate (1mmol) is dissolved in the 5mL methylene dichloride, adds the 5mL trifluoroacetic acid.Stirred the mixture 2 hours, vacuum concentration by dichloromethane extraction twice, obtains trans-4-phenoxy group-hexahydroaniline tfa salt, is white solid.
Step 3
In the trans-mixture of 4-phenoxy group hexahydroaniline (1mmol) in 6ml THF and 6ml MeOH, add pimelinketone (2mmol), NaOAc (2mmol) and 3g
Molecular sieve.Stirred the mixture 10 minutes, and after this added the tetrahydrofuran solution (2.4mmol) of 1N sodium cyanoborohydride.At room temperature reaction stirred is 1 day, by diatomite filtration, thoroughly washs with the 30mL methylene dichloride then.Organic phase is used 10ml water, the water washing of 10mL salt successively, dry (MgSO
4), filtering, vacuum concentration obtains crude product cyclohexyl-(trans-4-phenoxy group-cyclohexyl) amine, need not to be further purified just to can be used for next step.
Step 4 (coupling and hydrolysis)
To be similar to the mode of { 2-[3-cyclopentyl-3-(trans-4-methoxyl group-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate, use cyclohexyl-(trans-4-phenoxy group-cyclohexyl)-amine and (amino-thiazolyl--5-base sulfenyl)-ethyl acetate to prepare title compound.
HPLC-MS method 2:m/z=490 (M+H).
1H-NMR(DMSO-d
6)δ7.40(s，1H)，7.28(t，2H)，6.95(d，2H)，6.90(t，1H)，4.34-4.28(m，1H)，3.51(br?s，2H)，3.48(s，2H)，2.25-1.07(m，18H)。
Embodiment 158
(2-{3-cyclohexyl-3-[is trans-4-(pyridine-2-base oxygen base)-cyclohexyl]-urea groups }-thiazole-5-base sulfenyl)-acetate
To be similar to the mode of { 2-[3-cyclohexyl-3-(trans-4-phenoxy group-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate, by cyclohexyl-[trans-4-(pyridine-2-base oxygen base)-cyclohexyl]-amine and (2-amino-thiazolyl--5-base sulfenyl)-ethyl acetate preparation, obtain title compound.
HPLC-MS method 2:m/z=491 (M+H).
1H-NMR(DMSO-d
6)δ12.2(br?s，1H)，8.15(dd，1H)，7.69(dt，1H)，7.41(s，1H)，6.95(dt，1H)，6.76(d，1H)，5.00-4.92(m，1H)，3.55(br?s，2H)，3.48(s，2H)，2.28-1.05(m，18H)。
Embodiment 159
3-(2-{3-cyclohexyl-3-[is trans-4-(pyridine-2-base oxygen base)-cyclohexyl]-urea groups }-thiazole-5-base sulfenyl)-propionic acid
To be similar to the mode of { 2-[3-cyclohexyl-3-(trans-4-phenoxy group-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate, by cyclohexyl-[trans-4-(pyridine-2-base oxygen base)-cyclohexyl]-amine and 3-(2-amino-thiazolyl--5-base sulfenyl)-ethyl propionate preparation, obtain title compound.
HPLC-MS：m/z＝505(M+H)。
1H-NMR(DMSO-d
6)δ11.9(br?s，1H)，8.15(dd，1H)，7.69(dt，1H)，7.39(s，1H)，6.94(dd，1H)，6.77(d，1H)，5.01-4.93(m，1H)，3.58(br?s，2H)，2.85(t，2H)，2.50(t，2H)，2.28-1.05(m，18H)。
Embodiment 160
(2-{3-cyclohexyl-3-[is trans-4-(2,2,2-three fluoro-oxyethyl groups)-cyclohexyl]-urea groups }-thiazole-5-base sulfenyl)-acetate
To be similar to the mode of { 2-[3-cyclohexyl-3-(trans-4-phenoxy group-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate, by cyclohexyl-[trans-4-(2,2,2-three fluoro-oxyethyl groups)-cyclohexyl]-amine and (2-amino-thiazolyl--5-base sulfenyl)-ethyl acetate preparation, obtain title compound.
1H-NMR(CDCl
3)δ7.25(s，1H)，3.84(q，2H)，3.54-3.22(m，3H)，3.33(s，2H)，2.40-1.10(m，18H)。
Embodiment 161
2-[3-cyclohexyl-3-(trans-4-methyl-cyclohexyl base)-urea groups]-thiazole-5-N-sulfonyloxy methyl amine
Step 1
In-20 ℃, (the THF solution of 2M 40mmol) joins in 2-acetylaminohydroxyphenylarsonic acid thiazole-5-SULPHURYL CHLORIDE (10mmol) THF (10mL) suspension of (as at J.Am.Chem.Soc 69,2063, preparing described in 1947) with methylamine.Mixture at room temperature stirred spend the night, be evaporated to dried.Crude product sulfonyloxy methyl amine is suspended among the EtOH (15mL), adds 4N HCl De dioxane solution (15mL),, be cooled to room temperature then, be evaporated to driedly, obtain crude product 2-amino-thiazolyl--5-N-sulfonyloxy methyl amine in 80 ℃ of heating 4 hours.
Step 2
With 1,1-carbonyl dimidazoles, 2-amino-thiazolyl--5-N-sulfonyloxy methyl amine and DMAP (5mol%) in THF etc. molar mixture in 50-60 ℃ the heating 2 hours, be cooled to room temperature then.Then, add cyclohexyl-(trans-4-methyl-cyclohexyl base)-amine (1 equivalent; Common processes E), reactant is at room temperature stirred spend the night.Water quencher reaction mixture.Separate organic phase, water CH
2Cl
2Extraction, the dry organic phase that merges, vacuum concentration.Crude product is dissolved among the MeCN, and purifying (HPLC method 1), title compound obtained.
HPLC-MS：m/z＝415(M+H)。
1H?NMR(CDCl
3)δ7.80(s，1H)，5.46(br?q，1H)，3.40(br?s，2H)，2.74(d，3H)，1.99-1.62(m，11H)，1.45-1.01(m，8H)，0.90(d，3H)。
Embodiment 162
2-{2-[3-cyclohexyl-3-(trans-4-methyl-cyclohexyl base)-urea groups]-thiazole-5-sulfonamido }-N, N-diethyl-ethanamide
To be similar to 2-({ 2-[3-cyclohexyl-3-(trans-4-methyl-cyclohexyl base)-urea groups]-thiazole-5-alkylsulfonyl }-methyl-amino)-N; the mode of N-diethyl-ethanamide, use { 2-[3-cyclohexyl-3-(trans-4-methyl-cyclohexyl base)-urea groups]-thiazole-5-sulfonamido }-acetate and diethylamine prepare title compound.
HPLC-MS：m/z＝514(M+H)。
1H?NMR(CDCl
3)δ7.81(s，1H)，5.93(br?t，1H)，3.86(d，2H)，3.47-3.33(m，4H)，3.21(q，2H)，1.98-1.65(m，13H)，1.47-1.01(m，12H)，0.93(d，3H)。
Embodiment 163
2-{2-[3-cyclohexyl-3-(trans-4-methyl-cyclohexyl base)-urea groups]-thiazole-5-sulfonamido }-N-methyl-ethanamide
To be similar to 2-({ 2-[3-cyclohexyl-3-(trans-4-methyl-cyclohexyl base)-urea groups]-thiazole-5-alkylsulfonyl }-methyl-amino)-N; the mode of N-diethyl-ethanamide, use { 2-[3-cyclohexyl-3-(trans-4-methyl-cyclohexyl base)-urea groups]-thiazole-5-sulfonamido }-acetate and methylamine prepare title compound.
HPLC-MS：m/z＝472(M+H)。
1H?NMR(CDCl
3)δ7.80(s，1H)，6.50(br?q，1H)，6.28(br?s，1H)，3.66(br?s，2H)，3.42(br?s，2H)，2.84(d，3H)，1.99-1.65(m，13H)，1.47-1.00(m，6H)，0.91(d，3H)。
Embodiment 164
2-{2-[3-cyclohexyl-3-(trans-4-methyl-cyclohexyl base)-urea groups]-thiazole-5-sulfonamido }-N-sec.-propyl-ethanamide
To be similar to 2-({ 2-[3-cyclohexyl-3-(trans-4-methyl-cyclohexyl base)-urea groups]-thiazole-5-alkylsulfonyl }-methyl-amino)-N; the mode of N-diethyl-ethanamide, use { 2-[3-cyclohexyl-3-(trans-4-methyl-cyclohexyl base)-urea groups]-thiazole-5-sulfonamido }-acetate and Isopropylamine prepare title compound.
HPLC-MS：m/z＝500(M+H)。
1H NMR (CDCl
3) δ 7.80 (s, 1H), 6.68 (br s, 1H), 6.25 (br s, 1H), 4.05 (octet, 1H), 3.64 (br s, 2H), 3.42 (br s, 2H), 1.99-1.64 (m, 13H), 1.47-1.00 (m, 6H), 1.14 (d, 6H), 0.92 (d, 3H).
Embodiment 165
2-[3-cyclohexyl-3-(trans-4-methyl-cyclohexyl base)-urea groups]-thiazole-5-N-(2-morpholine-4-base-2-oxo-ethyl)-sulphonamide
To be similar to 2-({ 2-[3-cyclohexyl-3-(trans-4-methyl-cyclohexyl base)-urea groups]-thiazole-5-alkylsulfonyl }-methyl-amino)-N; the mode of N-diethyl-ethanamide, use { 2-[3-cyclohexyl-3-(trans-4-methyl-cyclohexyl base)-urea groups]-thiazole-5-sulfonamido }-acetate and morpholine prepare title compound.
HPLC-MS：m/z＝528(M+H)。
1H?NMR(CDCl
3)δ7.92(s，1H)，6.04(br?s，1H)，3.89(br?s，2H)，3.73-3.32(m，10H)，1.98-1.65(m，13H)，1.45-1.01(m，6H)，0.92(d，3H)。
Embodiment 166
2-{2-[3-cyclohexyl-3-(trans-4-oxyethyl group-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-2-methyl-propionic acid
Synthesis technique preparation according to { 2-[3-cyclopentyl-3-(trans-4-methoxyl group-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate.
Step 1: use (trans-4-hydroxyl-cyclohexyl)-isoindole-1,3-diketone, 1-iodoethane and pimelinketone prepare cyclohexyl-[trans-4-oxyethyl group-cyclohexyl]-amine.
Step 2: use cyclohexyl-[trans-4-oxyethyl group-cyclohexyl]-amine and 2-(2-amino-thiazolyl--5-base sulfenyl)-2-methyl-ethyl propionate to prepare 2-{2-[3-cyclohexyl-3-(4-oxyethyl group-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-2-methyl-propionic acid.
1H?NMR(DMSO-d
6)δ7.39(s，1H)，3.42(q，2H)，3.20(m，1H)，3.70-3.20(m，2H)，1.40(s，6H)，1.09(t，3H)，2.20-1.20(m，18H)。
HPLC-MS：m/z?470(M+H)。
Embodiment 167
2-{2-[3-suberyl-3-(trans-4-oxyethyl group-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-2-methyl-propionic acid
Synthesis technique preparation according to { 2-[3-cyclopentyl-3-(trans-4-methoxyl group-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate.
Step 1: use (trans-4-hydroxyl-cyclohexyl)-isoindole-1,3-diketone, 1-iodoethane and suberone prepare suberyl-[trans-4-oxyethyl group-cyclohexyl]-amine.
Step 2: use suberyl-[trans-4-oxyethyl group-cyclohexyl]-amine and 2-(2-amino-thiazolyl--5-base sulfenyl)-2-methyl-ethyl propionate to prepare 2-{2-[3-suberyl-3-(trans-4-oxyethyl group-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-2-methyl-propionic acid.
1H?NMR(DMSO-d
6)δ7.39(s，1H)，3.43(q，2H)，3.30-3.15(m，3H)，2.20-1.15(m，20H)，1.39(s，6H)，1.09(t，3H)。
HPLC-MS：m/z?484(M+H)。
Embodiment 168
2-{2-[3-cyclohexyl-3-(trans-4-methoxyl group-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-2-methyl-propionic acid
Synthesis technique preparation according to { 2-[3-cyclopentyl-3-(trans-4-methoxyl group-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate.
Step 1: use (trans-4-hydroxyl-cyclohexyl)-isoindole-1,3-diketone, 1-methyl iodide and pimelinketone prepare cyclohexyl-[trans-4-methoxyl group-cyclohexyl]-amine.
Step 2: use cyclohexyl-[trans-4-methoxyl group-cyclohexyl]-amine and 2-(2-amino-thiazolyl--5-base sulfenyl)-2-methyl-ethyl propionate to prepare 2-{2-[3-cyclohexyl-3-(trans-4-methoxyl group-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-2-methyl-propionic acid.
1H?NMR(DMSO-d
6)δ7.39(s，1H)，3.70-3.30(m，2H)，3.21(s，3H)；3.15-3.03(m，1H)，2.20-1.05(m，18H)；1.40(s，6H)。
HPLC-MS：m/z?456(M+H)。
Embodiment 169
2-{2-[3-suberyl-3-(trans-4-methoxyl group-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-2-methyl-propionic acid
Synthesis technique preparation according to { 2-[3-cyclopentyl-3-(trans-4-methoxyl group-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-acetate.
Step 1: use (trans-4-hydroxyl-cyclohexyl)-isoindole-1,3-diketone, 1-methyl iodide and suberone prepare suberyl-[trans-4-methoxyl group-cyclohexyl]-amine.
Step 2: use suberyl-[trans-4-methoxyl group-cyclohexyl]-amine and 2-(2-amino-thiazolyl--5-base sulfenyl)-2-methyl-ethyl propionate to prepare 2-{2-[3-suberyl-3-(trans-4-methoxyl group-cyclohexyl)-urea groups]-thiazole-5-base sulfenyl }-2-methyl-propionic acid.
1H?NMR(DMSO-d
6)δ7.39(s，1H)，3.23(s，3H)，3.20-3.04(m，3H)，2.20-1.05(m，20H)，1.40(s，6H)。
HPLC-MS：m/z?470(M+H)。
Embodiment 170
5-[3-cyclohexyl-3-(trans-4-methyl-cyclohexyl base)-urea groups]-[1,3,4] thiadiazoles-2-N-sulfonyloxy methyl amine
Step 1
In-20 ℃, (the THF solution of 2M 40mmol) adds 5-acetylaminohydroxyphenylarsonic acid 1,3, in THF (10mL) suspension of 4-thiadiazoles-2-SULPHURYL CHLORIDE (10mmol) (as at Bioorg.Med.Chem.5, preparing described in 515,1997) with methylamine.Mixture at room temperature stirred spend the night, be evaporated to dried.Crude product sulfonyloxy methyl amine is suspended among the EtOH (15mL), adds 4N HCl De dioxane solution (15mL),, be cooled to room temperature then, be evaporated to driedly, obtain crude product 5-amino-1,3,4-thiadiazoles-2-N-sulfonyloxy methyl amine in 80 ℃ of heating 4 hours.
Step 2
With 1,1-carbonyl dimidazoles (2 equivalent), 5-amino-1,3,4-thiadiazoles-2-N-sulfonyloxy methyl amine, cyclohexyl-(trans-4-methyl-cyclohexyl base)-amine (1 equivalent) and the mixture of DMAP (5mol%) in THF-toluene (1: 1) are cooled to room temperature then in 40 ℃ of heating 16 hours.The vacuum concentration reaction mixture is dissolved in crude product among the MeCN, and purifying (HPLC method 1), obtains title compound.
HPLC-MS：m/z＝417(M+H)。
1H?NMR(400MHz，CDCl
3)δ9.46(br?s，1H)，6.81(br?s，1H)，3.43(br?s，2H)，2.83(s，3H)，1.50-2.38(m，13H)，1.22-1.48(m，3H)，0.94-1.22(m，3H)，0.84(d，3H)。
Embodiment 171
5-[3-cyclohexyl-3-(trans-4-methyl-cyclohexyl base)-urea groups]-[1,3,4] thiadiazoles-2-sulfonamido }-acetate
[2-(3 to be similar to, 3-dicyclohexyl-urea groups)-thiazole-5-sulfonamido]-mode of acetate (embodiment 76), use 5-acetylaminohydroxyphenylarsonic acid 1,3,4-thiadiazoles-2-SULPHURYL CHLORIDE is then through cyclohexyl-(trans-4-methyl-cyclohexyl base)-amine and (5-amino-1,3,4-thiadiazoles-2-sulfonamido)-and the ethyl acetate preparation, obtain title compound.
HPLC-MS：m/z＝461(M+H)。
1H?NMR(400MHz，CDCl
3)δ3.93(s，2H)，3.48(br?s，2H)，1.52-2.22(m，12H)，0.96-1.51(m，7H)，0.87(d，3H)。
Embodiment 172
(5-[3-cyclohexyl-3-(trans-4-methyl-cyclohexyl base)-urea groups]-[1,3,4] thiadiazoles-2-alkylsulfonyl }-methyl-amino)-acetate
Be similar to 5-[3-cyclohexyl-3-(trans-4-methyl-cyclohexyl base)-urea groups]-[1; 3; 4] thiadiazoles-2-sulfonamido }-mode of acetate; by cyclohexyl-(trans-4-methyl-cyclohexyl base)-amine and [(5-amino-1; 3; 4-thiadiazoles-2-alkylsulfonyl)-methyl-amino]-the ethyl acetate preparation, obtain title compound.
HPLC-MS：m/z＝475(M+H)。
1H?NMR(400MHz，CDCl
3)δ10.84(br?s，1H)，4.26(s，2H)，3.52(brs，2H)，3.16(s，3H)，1.50-1.88(m，12H)，0.95-1.50(m，7H)，0.91(d，3H)。
Embodiment 173
2-[3-cyclohexyl-3-(trans-4-methyl-cyclohexyl base)-urea groups]-4-methyl-thiazole-5-N-sulfonyloxy methyl amine
To be similar to 2-[3-cyclohexyl-3-(trans-4-methyl-cyclohexyl base)-urea groups]-mode of thiazole-5-N-sulfonyloxy methyl amine, use 2-acetylaminohydroxyphenylarsonic acid 4-methyl-thiazole-5-SULPHURYL CHLORIDE to prepare title compound as SULPHURYL CHLORIDE.
HPLC-MS：m/z＝429(M+H)。
1H?NMR(400MHz，CDCl
3)δ8.16(br?s，1H)，3.39(br?s，2H)，2.74(d，3H)，2.52(s，3H)，0.96-2.00(m，19H)，0.91(d，3H)。
Embodiment 174
2-[3-cyclohexyl-3-(trans-4-methyl-cyclohexyl base)-urea groups]-4-methyl-thiazole-5-sulfonamido }-acetate
[2-(3 to be similar to, 3-dicyclohexyl-urea groups)-thiazole-5-sulfonamido]-mode of acetate (embodiment 76), use 2-acetylaminohydroxyphenylarsonic acid 4-methyl-thiazole-5-SULPHURYL CHLORIDE as SULPHURYL CHLORIDE, through cyclohexyl-(trans-4-methyl-cyclohexyl base)-amine (2-amino-4-methyl-thiazole-5-sulfonamido)-ethyl acetate preparation, obtain title compound then.
HPLC-MS：m/z＝473(M+H)。
1H NMR (400MHz, DMSO-d
6) (t, 1H), 3.63 (d, 2H), 2.38 (s, 3H), (m, 19H), 0.87 (d, 3H), two protons all do not observe 0.92-2.12 δ 8.15.
Embodiment 175
(2-[3-cyclohexyl-3-(trans-4-methyl-cyclohexyl base)-urea groups]-4-methyl-thiazole-5-alkylsulfonyl }-methyl-amino)-acetate
[2-(3 to be similar to; 3-dicyclohexyl-urea groups)-thiazole-5-sulfonamido]-mode of acetate (embodiment 76); use 2-acetylaminohydroxyphenylarsonic acid 4-methyl-thiazole-5-SULPHURYL CHLORIDE as SULPHURYL CHLORIDE; through cyclohexyl-(trans-4-methyl-cyclohexyl base)-amine [(2-amino-4-methyl-thiazole-5-alkylsulfonyl)-methyl-amino]-methyl acetate preparation, obtain title compound then.
HPLC-MS：m/z＝487(M+H)。
1H NMR (400MHz, DMSO-d
6) (br s, 1H), 11.40 (br s, 1H), 3.90 (s, 2H), 2.84 (s, 3H), 2.41 (s, 3H), (m, 19H), 0.87 (d, 3H), two protons all do not observe 0.95-2.21 δ 12.78.
Embodiment 176
1-cyclohexyl-1-(trans-4-methyl-cyclohexyl base)-3-[5-(piperidines-1-alkylsulfonyl)-[1,3,4] thiadiazoles-2-yl]-urea
To be similar to 5-[3-cyclohexyl-3-(trans-4-methyl-cyclohexyl base)-urea groups]-mode of [1,3,4] thiadiazoles-2-N-sulfonyloxy methyl amine; by cyclohexyl-(trans-4-methyl-cyclohexyl base)-amine and 5-(piperidines-1-alkylsulfonyl)-1; 3,4-thiadiazoles-2-base amine preparation obtains title compound.
HPLC-MS：m/z＝470(M+H)。
1H?NMR(400MHz，CD
3OD)δ3.49(br?s，2H)，3.27(t，4H)，2.03(brs，4H)，1.71-1.88(m，4H)，1.49-1.71(m，11H)，1.29-1.49(m，3H)，0.99-1.28(m，3H)，0.92(d，3H)。
Embodiment 177
5-[3-cyclohexyl-3-(trans-4-methyl-cyclohexyl base)-urea groups]-[1,3,4] thiadiazoles-2-N-(2-methoxyl group-ethyl)-sulphonamide
To be similar to 5-[3-cyclohexyl-3-(trans-4-methyl-cyclohexyl base)-urea groups]-[1,3,4] mode of thiadiazoles-2-N-sulfonyloxy methyl amine, by cyclohexyl-(trans-4-methyl-cyclohexyl base)-amine and 5-amino-1,3,4-thiadiazoles-2-N-(2-methoxyl group-ethyl)-sulphonamide preparation obtains title compound.
HPLC-MS：m/z＝460(M+H)。
1H?NMR(400MHz，CD
3OD)δ3.45(t，2H)，3.47(br?s，2H)，3.29-3.33(m，5H)，2.00(br?s，4H)，1.71-1.87(m，4H)，1.56-1.71(m，5H)，1.29-1.50(m，3H)，1.03-1.29(m，3H)，0.92(d，3H)。
Embodiment 178
5-[3-cyclohexyl-3-(trans-4-methyl-cyclohexyl base)-urea groups]-[1,3,4] thiadiazoles-2-N-sec.-propyl sulphonamide
To be similar to 5-[3-cyclohexyl-3-(trans-4-methyl-cyclohexyl base)-urea groups]-mode of [1,3,4] thiadiazoles-2-N-sulfonyloxy methyl amine, by cyclohexyl-(trans-4-methyl-cyclohexyl base)-amine and 5-amino-1,3,4-thiadiazoles-2-N-sec.-propyl sulphonamide preparation obtains title compound.
HPLC-MS：m/z＝444(M+H)。
1H?NMR(400MHz，CD
3OD)δ3.56-3.73(m，1H)，3.48(br?s，2H)，2.01(br?s，3H)，1.70-1.86(m，4H)，1.50-1.70(m，5H)，1.30-1.49(m，4H)，0.99-1.29(m，9H)，0.92(d，4H)。
Embodiment 179
5-[3-cyclohexyl-3-(trans-4-methyl-cyclohexyl base)-urea groups]-[1,3,4] thiadiazoles-2-N-phenyl-sulfamide
To be similar to 5-[3-cyclohexyl-3-(trans-4-methyl-cyclohexyl base)-urea groups]-mode of [1,3,4] thiadiazoles-2-N-sulfonyloxy methyl amine, by cyclohexyl-(trans-4-methyl-cyclohexyl base)-amine and 5-amino-1,3,4-thiadiazoles-2-N-phenyl-sulfamide preparation obtains title compound.
HPLC-MS：m/z＝478(M+H)。
1H?NMR(400MHz，CD
3OD)δ7.18-7.35(m，4H)，7.13(t，1H)，3.45(br?s，2H)，1.55-2.17(m，11H)，0.99-1.48(m，6H)，0.92(d，3H)。
Embodiment 180
1-cyclohexyl-1-(trans-4-methyl-cyclohexyl base)-3-[5-(piperidines-1-alkylsulfonyl)-thiazol-2-yl]-urea
To be similar to 2-[3-cyclohexyl-3-(trans-4-methyl-cyclohexyl base)-urea groups]-mode of thiazole-5-N-sulfonyloxy methyl amine; by cyclohexyl-(trans-4-methyl-cyclohexyl base)-amine and 5-(piperidines-1-alkylsulfonyl)-thiazol-2-yl amine preparation, obtain title compound.
HPLC-MS：m/z＝469(M+H)。
1H NMR (400MHz, benzene-d
6) δ 8.56 (br s, 1H), 7.75 (s, 1H), 3.41 (br s, 2H), 3.05 (t, 4H), 0.96-2.20 (m, 25H), 0.91 (d, 3H).
Embodiment 181
2-[3-cyclohexyl-3-(trans-4-methyl-cyclohexyl base)-urea groups]-thiazole-5-N-sec.-propyl sulphonamide
To be similar to 2-[3-cyclohexyl-3-(trans-4-methyl-cyclohexyl base)-urea groups]-mode of thiazole-5-N-sulfonyloxy methyl amine, by cyclohexyl-(trans-4-methyl-cyclohexyl base)-amine and 2-amino-thiazolyl--5-N-sec.-propyl sulphonamide preparation, obtain title compound.
HPLC-MS：m/z＝443(M+H)。
1H?NMR(300MHz，CDCl
3)δ8.68(br?s，1H)，7.80(s，1H)，5.05(d，1H)，3.47-3.66(m，1H)，3.41(br?s，2H)，1.52-2.14(m，13H)，0.96-1.52(m，12H)，0.90(d，3H)。
Embodiment 182
1-cyclohexyl-3-[5-(cis-2,6-dimethyl-piperidines-1-alkylsulfonyl)-thiazol-2-yl]-1-(trans-4-methyl-cyclohexyl base)-urea
To be similar to 2-[3-cyclohexyl-3-(trans-4-methyl-cyclohexyl base)-urea groups]-mode of thiazole-5-N-sulfonyloxy methyl amine; by cyclohexyl-(trans-4-methyl-cyclohexyl base)-amine and 5-(cis-2; 6-dimethyl-piperidines-1-alkylsulfonyl)-and the preparation of thiazol-2-yl amine, obtain title compound.
HPLC-MS：m/z＝497(M+H)。
1H?NMR(300MHz，CDCl
3)δ8.33(br?s，1H)，7.75(s，1H)，4.11-4.29(m，2H)，3.43(br?s，2H)，1.60-2.06(m，14H)，0.96-1.60(m，17H)，0.91(d，3H)。
Embodiment 183
2-[3-cyclohexyl-3-(trans-4-methyl-cyclohexyl base)-urea groups]-thiazole-5-N-tertiary butyl sulphonamide
2-[3-cyclohexyl-3-(trans-4-methyl-cyclohexyl base)-urea groups]-thiazole-5-N-sulfonyloxy methyl amine cyclohexyl-(trans-4-methyl-cyclohexyl base)-amine and 2-amino-thiazolyl--5-N-tertiary butyl sulphonamide, obtain title compound.
HPLC-MS：m/z＝457(M+H)。
1H?NMR(400MHz，CDCl
3)δ8.81(br?s，1H)，7.77(s，1H)，5.51-5.75(br?s，1H)，3.39(br?s，2H)，0.95-2.15(m，27H)，0.89(d，3H)。
Claims (11)
- The compound of general formula below a kind (I) with and with any salt of pharmaceutically acceptable acid or alkali, or the mixture of any optically active isomer or optically active isomer comprises racemic mixture, or any tautomer:
R wherein 1For And R 2Be cyclohexyl; WithA isWith
R 5Be selected from C 3-6-alkene oxygen base, aryloxy-C 1-6-alkyl, C 3-8-cycloalkyl-C 1-6-alkoxy-C 1-6-alkyl, aryl-C 1-6-alkoxy-C 1-6-alkyl, heteroaryl-C 1-6-alkoxy-C 1-6-alkyl, C 3-6-alkenylthio group, arylthio-C 1-6-alkyl, C 3-8-cycloalkyl-C 1-6-alkylthio-C 1-6-alkyl or heteroaryloxy-C 1-6-alkyl, described each group are randomly by one or more R that are independently selected from 12Substituting group replace, wherein each aryl all is a phenyl, each heteroaryl all is a pyridyl; WithR 12For halogen, cyano group, hydroxyl, carboxyl ,-CF 3, C 1-6-alkoxyl group, C 3-8-cycloalkyloxy, aryloxy, aryl-C 1-6-alkoxyl group or C 1-6-alkyl; WithR 8Be selected from halogen, carboxyl ,-CF 3,-S-CH 3,-S-CH 2CH 3,-S-CH 2CH 2CH 3, methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, methoxyl group, oxyethyl group ,-CH 2-C (O)-O-CH 3,-CH 2-C (O)-O-CH 2CH 3,-CH 2CH 2-C (O)-O-CH 3,-CH 2CH 2-C (O)-O-CH 2CH 3,-CH 2-O-C (O)-CH 3,-CH 2-O-C (O)-CH 2CH 3,-CH 2CH 2-O-C (O)-CH 3,-CH 2CH 2-O-C (O)-CH 2CH 3,-C (O)-O-CH 3,-C (O)-O-CH 2CH 3, described each group is randomly by one or more R that are independently selected from 16Substituting group replace; Or heteroarylthio, wherein heteroaryl is pyridyl or imidazolyl, described each group randomly on heteroaryl moieties by one or more R that are independently selected from 17Substituting group replace, or pyrrolidyl, piperidyl, piperazinyl or morpholinyl, described each group is randomly by one or more R that are independently selected from 16Substituting group replace; Or-S (O) 2-NR 19R 20Or-S (O) 2-R 21R 16And R 17Be C independently 1-6-alkyl, halogen, nitro, cyano group, hydroxyl, carboxyl, oxo ,-CF 3, carboxyl-C 1-6-alkyl, hydroxyl-C 1-6-alkyl ,-C 1-6-alkyl-C (O)-O-C 1-6-alkyl ,-C 1-6-alkyl-C (O)-NR 19R 20,-C (O)-O-C 1-6-alkyl ,-C (O)-C 1-6-alkyl-C (O)-C 1-6-alkyl ,-NR 19R 20,-NHS (O) 2C 1-6-alkyl ,-NHS (O) 2CF 3,-NHS (O) 2CH 2CF 3,-C (O) NR 19R 20,-S (O) 2C 1-6-alkyl ,-S (O) 2CF 3,-S (O) 2CH 2CF 3Or-S (O) 2NR 19R 20WithR 19Be H, methyl, ethyl or propyl group, S (O) independently 2-CH 3, perhaps R 19And R 20Form the 3-8 unit heterocycle with described nitrogen-atoms with the nitrogen-atoms that they connected, wherein said heterocycle is pyrrolidyl, piperidyl, piperazinyl, high piperazinyl or morpholinyl, and described heterocycle is randomly by one or more R that are independently selected from 24Substituting group replace; WithR 21Be selected from carboxyl-methyl, carboxyl-ethyl or carboxyl-propyl group; WithR 24Be halogen, carboxyl, C 1-6-alkyl, carboxyl-C 1-6-alkyl or-C (O)-O-C 1-6-alkyl. - 2. the compound of claim 1, wherein R 5Be selected from C 3-6-alkene oxygen base, phenoxy group-C 1-6-alkyl, benzyloxy-C 1-6-alkyl, C 3-8-cycloalkyl-C 1-6-alkoxy-C 1-6-alkyl.
- 3. the compound of claim 2, wherein R 5Be selected from C 3-4-alkene oxygen base, phenoxy group-methyl, benzyloxy-methyl or cyclopropyl-methoxymethyl.
- 4. each compound, wherein R among the claim 1-3 12For halogen, cyano group, hydroxyl, carboxyl ,-CF 3, methoxyl group, oxyethyl group, propoxy-, ring propoxy-, cyclobutoxy group, cyclopentyloxy, cyclohexyloxy, ring oxygen in heptan base, phenoxy group, benzyloxy, phenyl-oxyethyl group, phenyl-propoxy-, methyl, ethyl or propyl group.
- 5. the compound of claim 4, wherein R 12Be halogen, carboxyl, oxyethyl group, propoxy-, ring propoxy-, cyclobutoxy group, cyclopentyloxy, cyclohexyloxy, ring oxygen in heptan base, phenoxy group, benzyloxy, phenyl-oxyethyl group, phenyl-propoxy-, methyl, ethyl or propyl group.
- 6. each compound, wherein R among the claim 1-5 8Be selected from Cl ,-S-CH 3,-S-CH 2CH 3,-S-CH 2CH 2CH 3,-S-CH (CH 3) 2,-S-CH 2CH (CH 3) 2, methyl or ethyl, described each group is randomly by one or more R that are independently selected from 16Substituting group replace;-S (O) 2-NR 19R 20Or-S (O) 2-R 21
- 7. each compound, wherein R among the claim 1-6 16And R 17Be C independently 1-6-alkyl, halogen, hydroxyl, oxo, carboxyl ,-CF 3, carboxyl-C 1-6-alkyl, hydroxyl-C 1-6-alkyl ,-C 1-6-alkyl-C (O)-O-C 1-6-alkyl ,-C (O)-O-C 1-6-alkyl ,-NR 19R 20,-C (O) NR 19R 20Or-S (O) 2-C 1-6-alkyl.
- 8. the compound of claim 7, wherein R 16And R 17Be independently methyl, ethyl, propyl group, sec.-propyl, isobutyl-, halogen, hydroxyl, oxo, carboxyl ,-CF 3, carboxyl-methyl, carboxyl-ethyl, carboxyl-propyl group, hydroxyl-methyl, hydroxyl-ethyl, hydroxyl-propyl group ,-CH 2-C (O)-O-CH 3,-CH 2-C (O)-O-CH 2CH 3,-CH 2CH 2-C (O)-O-CH 3,-CH 2CH 2-C (O)-O-CH 2CH 3,-C (O)-O-CH 3,-C (O)-O-CH 2CH 3,-C (O)-O-CH 2CH 2CH 3Or-S (O) 2CH 3
- 9. the compound of claim 8, wherein R 16And R 17Be independently methyl, ethyl, propyl group, sec.-propyl, isobutyl-, halogen, oxo, carboxyl, carboxyl-methyl, carboxyl-ethyl, carboxyl-propyl group, hydroxyl-methyl, hydroxyl-ethyl, hydroxyl-propyl group ,-CH 2-C (O)-O-CH 3,-CH 2-C (O)-O-CH 2CH 3,-CH 2CH 2-C (O)-O-CH 3,-CH 2CH 2-C (O)-O-CH 2CH 3,-C (O)-O-CH 3,-C (O)-O-CH 2CH 3,-C (O)-O-CH 2CH 2CH 3Or-S (O) 2CH 3
- 10. the compound of claim 7, wherein R 16And R 17Be C independently 1-6-alkyl, carboxyl ,-NR 19R 20,-C (O)-O-C 1-6-alkyl ,-S (O) 2CH 3Or-C (O) NR 19R 20
- 11. the compound of claim 10, wherein R 16Or R 17Be carboxyl.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP05106284.2 | 2005-07-08 | ||
| EP05106284 | 2005-07-08 | ||
| EP05106519.1 | 2005-07-15 | ||
| EP05110779.5 | 2005-11-16 |
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| Publication Number | Publication Date |
|---|---|
| CN101258137A true CN101258137A (en) | 2008-09-03 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2006800324254A Pending CN101258137A (en) | 2005-07-08 | 2006-07-07 | Dicycloalkyl urea glucokinase activators |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN101258137A (en) |
| ZA (1) | ZA200800175B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104349790A (en) * | 2012-05-17 | 2015-02-11 | 转化技术制药有限责任公司 | Glucokinase activator compositions for the treatment of diabetes |
-
2006
- 2006-07-07 CN CNA2006800324254A patent/CN101258137A/en active Pending
-
2008
- 2008-01-08 ZA ZA200800175A patent/ZA200800175B/en unknown
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104349790A (en) * | 2012-05-17 | 2015-02-11 | 转化技术制药有限责任公司 | Glucokinase activator compositions for the treatment of diabetes |
Also Published As
| Publication number | Publication date |
|---|---|
| ZA200800175B (en) | 2008-12-31 |
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