CN102464631B - Piperazine substituted 1,3-2-substituted carbamide compounds and the substituted amides compound of piperazine and its production and use - Google Patents

Piperazine substituted 1,3-2-substituted carbamide compounds and the substituted amides compound of piperazine and its production and use Download PDF

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CN102464631B
CN102464631B CN201010535107.8A CN201010535107A CN102464631B CN 102464631 B CN102464631 B CN 102464631B CN 201010535107 A CN201010535107 A CN 201010535107A CN 102464631 B CN102464631 B CN 102464631B
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piperazine
compound
substituted
dichloromethane
adamantyl
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CN102464631A (en
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龙亚秋
黄少胥
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Shanghai Institute of Materia Medica of CAS
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Shanghai Institute of Materia Medica of CAS
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Abstract

The present invention relates to the piperazine substituted 1 that a class is represented by below general formula (I), 3 2-substituted carbamide compounds and the substituted amides compound of piperazine or its pharmaceutically acceptable salt and preparation method thereof, comprise the pharmaceutical composition of this compound, and the purposes that these compounds are in preparation solubility epoxide hydrolase inhibitor.The compound of the present invention has with prior art a kind of compound quite or higher activity, and has suitable formulations and the water solublity of administration and outstanding pharmacokinetic property.

Description

Piperazine substituted 1,3-2-substituted carbamide compounds and piperazine substituted amide-type chemical combination Thing and its production and use
Technical field
The present invention relates to piperazine substituted 1,3-2-substituted carbamide compounds and the substituted amides compound of piperazine or its Pharmaceutically acceptable salt and preparation method thereof, comprise the pharmaceutical composition of this compound, and these compounds can in preparation Purposes in dissolubility epoxide hydrolase inhibitor.
Background technology
Epoxide hydrolase (EC 3.3.2.3) catalyzing hydrolysis epoxide and arene oxide generate corresponding bishydroxy Compound [Xenobiotica 1973,3,305-340], gets involved the metabolic pathway of many bioactive compounds.Microsome epoxy Hydrolytic enzyme and solubility epoxide hydrolase are that two classes study to obtain the most deep epoxide hydrolase.The dependency of this two fermentoid is not Height, has different intracellular distributions and substrate selective that is different but that overlap.
The important function of solubility epoxide hydrolase is metabolism lipid epoxide, including arachidonic acid [J.Bioi.Chern.1993,268,6402-6407], linoleic acid [Nat.Med.1997,3,562-567] and some are endogenous The chemical mediator [Thorax 2000,55, S13-16] of property.Arachidonic epoxide (i.e. epoxy 20 carbon-trienic acid) And other lipid epoxide and dihydroxyl compound be have been found to blood pressure effect thing [J.Lipid.Res.2000, 41,163-181] and the regulation matter [CircRes.1998,83,932-939] of vascular permeability.Arachidonic acid epoxide Vasodilation performance can increase the relevant [Nature 1999,401,493-of open state probability of potassium-channel with it 497], this passage is by calcium ion activated, and ultimately results in the hyperpolarization of vascular smooth muscle.Once arachidonic acid epoxide Being hydrolyzed by solubility epoxide hydrolase, it promotes that angiectatic activity disappears [J.Lipid.Res.2000,41,163-181]. Solubility epoxide hydrolase hydrolysis arachidonic acid epoxide also can regulate the latter simultaneously and be placed in the phospholipid of cardiac endothelial, The regulation effect [Am. J.Physiol.1992,277, H2098-2108] of prompting solubility epoxide hydrolase Endothelial Function. Research shows that essential hypertension Mus imposes selectivity solubility epoxide hydrolase inhibitor can significantly decrease its blood pressure [Circ.Res.2000,87,992-998]；The male mice additionally having knocked out solubility epoxide hydrolase gene is little with wild type Mus is compared, and the former has the lowest blood pressure [J.Biol.Chem.2000,275,40504-40510].
Arachidonic acid epoxide also show in endotheliocyte antiinflammatory character [Science 1999,285, 1276-1279；Trends Pharmacol.Sci.2000,21,125-127].In contrast, (the whitest by epoxy-linoleate Cytotoxin) diol compound that is derived can upset membrane passage and calcium ion balance, thus cause inflammation The generation [Nat.Med.1997,3,562-567] of disease.According to the literature, the leukotoxin of micro-molar concentration just with inflammation and Anoxia is relevant [Chern.Phys.Lipids1996,82,39-51], suppresses mitochondrial breathing in vitro simultaneously [Am.J.Physiol.1995,269, L326-331], causes the cardiopulmonary toxicity of mammal in vivo [Am.J.Physiol.1995,269, L65-70；Cardiovasc.Res.1988,22,213-218； Am.J.Physiol.1995,268, L123-128].The symptom that the toxicity of leukotoxin shows and multiple organ failure, MOF and Acute respiratory distress syndrome similar [Am.Rev.Respir.Dis.1988,137,535-540].At cell and living model In, the toxicity that leukotoxin causes all depend on its epoxy moieties hydrolysis [Nat.Med.1997,3,562-567； Proc.Natl.Acad.Sci.USA 1999,96,8849-8854；Am.J.Respir.Cell Mol.Bioi.2001,25, 434-438], this suggests that solubility epoxide hydrolase plays an important role in the regulation of inflammation and vascular permeability.This The biosynthesis of the biological activity prompting suppression o-dihydroxy lipid of a little epoxyfatty acids is likely to be of therapeutic value so that solvable Property epoxide hydrolase becomes a Drug therapy target being rich in prospect.
Recently, 1,3-2-substituted carbamide class, carbamates and amides compound are reported as novel, stable effective Solubility epoxide hydrolase inhibitor [U.S.Patent No.6,150,415].These compounds are competitive inhibitors, tool There is the Ki value [Proc.Natl.Acad.Sci.USA 1999,96,8849-8854] of nanomole level.Can by X-ray crystal structure To find, these ureas inhibitor by the residue of its urea functional group and solubility epoxide hydrolase avtive spot formed hydrogen bond and Salt bridge, simulates state [Proc.Natl.Acad.Sci.USA during solubility epoxide hydrolase catalyzing hydrolysis epoxide 1999,96,10637-10642；J.Bioi.Chern.2000,275,15265-15270].Internal and external models at some In, these inhibitor effectively reduce epoxide hydrolysis [Circ.Res.2000,87,992-998； Proc.Natl.Acad.Sci.USA 1999,96,8849-8854；Environ.Health Perspect.2001,109,61- 66].Although these inhibitor have high activity, but its poorly water-soluble, fusing point stability high, internal is low, therefore, and the present invention Compound have quite or more high activity, and have suitable formulations and the water solublity of administration and outstanding medicine for power Learn character.
Summary of the invention
It is an object of the invention to provide and there is containing shown in the below formula (I) that suppression solubility epoxide hydrolase is active The 1 of piperazine structure, 3-2-substituted carbamide compounds or amides compound.
It is yet another object of the invention to provide and comprise the compound shown in logical formula (I), its pharmaceutically acceptable salt or medicine On, acceptable solvate or its mixture are as the pharmaceutical composition of active component.
It is a further object of the present invention to provide the preparation method of the compound shown in above-mentioned logical formula (I).
Another object of the present invention is to provide the compound shown in above-mentioned logical formula (I) and presses down at preparation solubility epoxide hydrolase Purposes in preparation.
Another object of the present invention is to provide the compound shown in above-mentioned logical formula (I) at preparation treatment hypertension, vasculitis Purposes in the medicine of disease, obstructive pulmonary disease, interstitial lung disease, asthma or nephropathy.
Described obstructive pulmonary disease refers to, but is not limited to chronic obstructive pulmonary disease, emphysema or bronchitis.Chromic fibrous lung Disease refers to, but is not limited to idiopathic fibrosis or occupational pneumoconiosis.
The present invention is pharmacophore model (the Journal of at solubility epoxide hydrolase inhibitor MedicalChemistry 2004, Vol.47, pp.2110-2122) on the basis of, for improving the activity of this compounds simultaneously Improve its patent medicine physical property (including fusing point, water solublity and pharmacokinetics) and will usually improve compound patent medicine physics The piperazine ring of character is directly inserted main pharmacodynamics group and uses different connected modes that piperazine ring is inserted second or the 3rd medicine Effect group, investigates the piperazine ring impact in different pharmacophore regions on compound inhibitory activity, water solublity and pharmacokinetics, To obtain various structures, activity is more preferable, patent medicine physical property more preferably solubility epoxide hydrolase inhibitor.
Carbamide compounds containing piperazine structure involved in the present invention has a following general structure (I):
Wherein,
Y is CH2, NH or O；It is preferably CH2Or NH；
M is the integer of 0 or 1；
N is the integer of 0 to 5；It is preferably the integer of 0 to 3；
A is C6～C10Aryl, C5～C9Heteroaryl or C4～C8Heterocyclic radical, above-mentioned heteroaryl and heterocyclic radical contain 1～3 Hetero atom in N, O and S and above-mentioned group are not necessarily by 1～2 R1Replaced；It is preferably phenyl, C5～C9Nitrogenous Heteroaryl or C4～C8Nitrogen heterocycle；
X not necessarily exists or is singly-bound ,-O-,-NR1-,-CO-or-SOm-, wherein m is integer 0,1 or 2；It is preferably single Key ,-O-or-CO-；
X ' not necessarily exists or is singly-bound ,-CO-,-COO-or-SO2-；
StructureForOr direct singly-bound；
R is H, C1～C8Alkyl, C1～C8Alkyl oxy, C2～C6Thiazolinyl, C2～C6Alkynyl, C1～C8Miscellaneous alkyl, C6～C10 Aryl, C5～C10Heteroaryl, C3～C12Cycloalkyl or C3～C12Heterocyclic radical, above-mentioned heteroaryl and heterocyclic radical contain 1～3 and are selected from Hetero atom in N, O and S, above-mentioned group in addition to H not necessarily by 1～3 R2Replaced；R is preferably H, C1～C4Alkyl or benzene Base；
R1For H, halogen, trifluoromethyl, C1～C8Alkoxyl or C1～C8Alkyl；
R2For halogen, nitro, amino, C1～C8Alkyl, C1～C8Haloalkyl, C1～C8Alkyl amino, hydroxyl, C1～C8 Alkoxyl, C6～C10Aryl, C6～C10Aryloxy, C3～C12Cycloalkyl, C2～C8Thiazolinyl, C2～C8Alkynyl, C1～C8Alkyl Carbonyl, C6～C10Aryl carbonyl or C6～C10Arylamino；R2It is preferably halogen, C1～C4Alkyl, C1～C8Haloalkyl or C1 ～C4Alkoxyl；
Described halogen is fluorine, chlorine, bromine or iodine；It is preferably fluorine or chlorine.
Carbamide compounds containing piperazine structure the most of the present invention is in following compound:
The invention provides and piperazine is placed in two grades of pharmacophore parts of solubility epoxide hydrolase inhibitor or three grades of medicines The synthetic method that effect regiment headquarters divides, the preparation method one of compound shown in the most described logical formula (I), the method comprises the steps:
1) simultaneous with the compound (iv) of nitro and carboxyl in dichloromethane, deposit at organic base condensing agent and activator Under the conditions, the piperazine (i) with single Boc protection is condensed to yield compound (v)；
2) with 10% Pd/C as catalyst, hydrogenolysis nitro in methanol or ethanol, make compound (v) be reduced into accordingly Amino-compound (vi)；
3) compound (vi) reacts with 1-adamantyl isocyanate and obtains corresponding 1,3-disubstituted ureas compound (vii)；
4) remove Boc blocking group in carbamide compounds (vii) with trifluoroacetic acid or HCl, obtain N on piperazine4Exposed Compound (viii)；
5) compound (viii) is in DMF, at K2CO3Or Na2CO3Effect under, react with halides RX and obtain on piperazine N4The compound (d) being replaced, wherein X is fluorine, chlorine, bromine or iodine；
6) compound (viii) is in dichloromethane, under the effect of organic base, with chloride compoundsOr acid Acid anhydrideReaction,
Or, compound (viii) is in dichloromethane, under conditions of organic base condensing agent and activator exist, with acid RCOOH is condensed to yield N on piperazine4The compound (e) being acylated；
7) compound (viii) is in dichloromethane, under the effect of organic base, with sulfonyl chloride compoundReaction Obtain N on piperazine4By the compound (f) of sulfonylation；
Wherein, identical defined in A with R and logical formula (I)；The described organic base used in each step is triethylamine, two different Ethylamine, morpholine or N-methylmorpholine；Described condensing agent is 1-ethyl-(3-dimethylaminopropyl) carbodiimide, N, N '-carbonyl dimidazoles or N, N '-dicyclohexylcarbodiimide, described activator is 1-hydroxyl-BTA (HOBt) or 1- Hydroxyl-7-azo BTA (HOAt).
Or, prepare compound shown in described logical formula (I) by following preparation method two, the method comprises the steps:
1) simultaneous with the compound (iv) of nitro and hydroxyl in DMF, under the effect of potassium carbonate or sodium carbonate, and α, ω-saturated dihalide or alpha-halogen-ω acid (ester)Reaction, obtains halides or carboxylic acid (ester) (ix), wherein, q be 1 to The integer of 4；
2) piperazine (i) that halides (ix) and single Boc protect refluxes in oxolane and obtains compound (x) or carboxylic acid (ester) (ix) obtains compound (x) with the piperazine (i) of single Boc protection under coupling reagent activates；
3) with 10% Pd/C as catalyst, hydrogenolysis nitro in methanol or ethanol, make compound (x) be reduced into accordingly Amino-compound (xi)；
4) amino-compound (xi) obtains corresponding 1 with 1-adamantyl isocyanate or 1-adamantyl acetic acidreaction, 3-disubstituted ureas and amides compound (xii)；
5) remove the Boc blocking group in compound (xii) with trifluoroacetic acid or HCl, obtain N on piperazine4Exposed change Compound (xiii)；
6) compound (xiii) is in DMF, at K2CO3Or Na2CO3Effect under, react with halides RX and obtain on piperazine N4The compound (g) being replaced, wherein the X in RX is fluorine, chlorine, bromine or iodine；
7) compound (xiii) is in dichloromethane, under the effect of organic base, with chloride compoundsOr acid Acid anhydrideIt is condensed to yield N on piperazine4The compound (h) being acylated；
Or, in dichloromethane, under conditions of organic base, condensing agent and activator exist, it is condensed with acid RCOOH N on piperazine4The compound (h) being acylated；
8) compound (xiii) is in dichloromethane, under the effect of organic base, with sulfonyl chloride compoundReaction Obtain N on piperazine4By the compound (i) of sulfonylation；
Wherein, identical defined in R and logical formula (I), structureForOr direct singly-bound；At α, ω-saturated dihalide Or alpha-halogen-ω acid (ester)Middle X is halogen, and X ' is halogen, hydroxyl or C1-C8Alkoxyl, fixed in Z and logical formula (I) Justice is identical；Defined in Y and logical formula (I) identical, described halogen is fluorine, chlorine, bromine or iodine；
The described organic base used in each step is triethylamine, diisopropyl ethyl amine, morpholine or N-methylmorpholine；Institute Stating condensing agent is 1-ethyl-(3-dimethylaminopropyl) carbodiimide, N, N '-carbonyl dimidazoles or N, N '-dicyclohexyl carbon Diimine, described activator is 1-hydroxyl-BTA (HOBt) or 1-hydroxyl-7-azo BTA (HOAt).
Or, prepare compound shown in described logical formula (I) by following preparation method three, the method comprises the steps:
Heterocycle with amino reacts with 1-adamantyl isocyanate and obtains corresponding 1,3-disubstituted ureas (xiv), React the corresponding 4-ketobutyric acid of generation again with succinic anhydride, then pass through the method that said method one is same, in organic base, condensation Under conditions of agent and activator exist, it is condensed to yield compound (xvi) with the piperazine (i) of single N-protected, sloughs the guarantor on piperazine N After protecting base, use the acylated or alkylated reaction in method two, obtain compound K,
The described organic base wherein used in each step is triethylamine, diisopropyl ethyl amine, morpholine or N-methyl Quinoline；Described condensing agent is 1-ethyl-(3-dimethylaminopropyl) carbodiimide, N, N '-carbonyl dimidazoles or N, N '-two hexamethylene Base carbodiimide, described activator is 1-hydroxyl-BTA (HOBt) or 1-hydroxyl-7-azo BTA (HOAt)。
The present invention to having 1, the change of 3-2-substituted carbamide (or corresponding amide, formic acid esters, i.e. main pharmacodynamics group) structure The further functionalization of compound is higher to obtain activity, simultaneously the suppression of patent medicine physical property improved solubility epoxide hydrolase Agent.Introduce piperazine structure and can increase the water solublity of solubility epoxide hydrolase inhibitor, improve its oral bioavailability simultaneously Degree.By 1,3-2-substituted carbamide (or corresponding amide, formic acid esters) and piperazine ring structure insert solubility epoxide hydrolase jointly To reach to improve activity in inhibitor, improve the purpose of patent medicine physical property simultaneously.Solubility epoxide hydrolase inhibitor can be used Regulated the disease caused, such as (but not limited to) hypertension and inflammation by solubility epoxide hydrolase in treatment.
Pharmacological datum shows, the compound involved by this patent has the highest pressing down for human soluble epoxide hydrolase System activity.Wherein the inhibitory activity of most preferred compound has reached 0.4nM.The compound of this class formation has the system of being especially suitable for The melting range (60～100 DEG C) of agent, good water solublity and internal medicine are for character.
Detailed description of the invention
Below in conjunction with embodiment, the present invention is described further, but is not intended to the present invention.
Prepare example
Example 1:4-{3-[3-(1-adamantyl) urea groups] benzoyl } piperazine-1-t-butyl formate (LH-82)
Step one: 4-(3-nitro benzoyl) piperazine-1-t-butyl formate (2)
At 0 DEG C, by EDCI (403mg, 2.1mmol), HOBt (284mg, 2.1mmol) and triethylamine (0.29mL, 2.1mmol) join in the 3-nitrobenzoic acid (351mg, 2.1mmol) being dissolved in 50mL anhydrous methylene chloride.Stir 30 minutes After, add 1-tert-butoxycarbonyl-piperazine (373mg, 2.0mmol).Reaction is warmed to room temperature, after 5 hours, and stopped reaction, use dichloromethane Alkane extraction (3 × 30mL).Merging organic facies, saturated sodium bicarbonate solution washes (2 × 30mL) and Sal washing (2 × 30mL), nothing Aqueous sodium persulfate is dried.Reduce pressure and solvent rotary evaporation is removed, column chromatography purification (CH2Cl2∶CH3OH=50: 1), whitely final Pulverulent solids 577mg, yield 86%.
1H NMR(CDCl3): δ 1.46 (s, 9H), 1.75 (s, 2H), 2.80 (t, 2H, J=4.8Hz), 3.37～3.75 (m, 4H), 7.61～7.66 (m, 1H), 7.73～7.74 (m, 1H), 8.27～8.29 (m, 2H).
Step 2: 4-(3-amino benzoyl) piperazine-1-t-butyl formate (3)
4-(3-nitro benzoyl) piperazine-1-t-butyl formate (2) (134mg, 0.4mmol) that will obtain in step one It is dissolved in 20mL absolute methanol, adds 10%Pd/C (10% (w/w), 14mg) hydrogenation catalyst.Evacuation, pours into hydrogen, stirs Mix reaction overnight.After 12 hours, filter off Pd/C, reduce pressure and solvent rotary evaporation is removed, obtain white solid 120mg, yield 98%.
Step 3: 4-{3-[3-(1-adamantyl) urea groups] benzoyl } piperazine-1-t-butyl formate (LH-82)
Diamantane (obsolete)-1-isocyanates (103mg, 0.58mmol) is dissolved in the anhydrous dichloromethane of 10mL.At 0 DEG C, to In solution, dropping is dissolved in 4-(3-amino benzoyl) piperazine-1-formic acid obtained by step 2 of the anhydrous dichloromethane of 10mL The tert-butyl ester (3) (177mg, 0.58mmol).Reaction system is appreciated room temperature, be stirred overnight.After about 12 hours, stopped reaction, subtract Press and solvent rotary evaporation is removed, column chromatography purification (CH2Cl2∶CH3OH=40: 1), 211mg white powdery solids, yield are obtained 75%.
1H NMR (300MHz, CDCl3) δ 1.47 (s, 9H), 1.59 (br s, 6H), 1.68 (br s, 6H), 2.07 (br s, 3H), 3.38～3.72 (m, 8H), 4.89 (s, 1H), 6.71 (d, 1H, J=7.5Hz), 6.92 (d, 1H, J=8.1Hz), 7.14 (s, 1H), 7.17～7.27 (m, 1H), 7.45 (d, 1H, J=7.8Hz)；Mp114～117 DEG C；EI-MS m/z:482 (M+).
Example 2:1-(1-adamantyl)-3-[3-(piperazine-1-formoxyl) phenyl] urea (LH-83)
Under ice bath, 4-{3-[3-(1-adamantyl) urea groups] benzoyl that will obtain in example 1 } piperazine-1-formic acid uncle Butyl ester (LH-82) (145mg, 0.3mmol) is dissolved in 5mL dichloromethane.About 0.9mL trifluoroacetic acid is added at 0 DEG C.Stirring is anti- After answering 3 hours, remove solvent under vacuum, add 10mL dchloromethane.Organic facies saturated sodium bicarbonate solution wash (2 × 10mL).Merge organic facies, anhydrous Na2SO4It is dried.Reduce pressure and solvent rotary evaporation is removed, obtain faint yellow solid 92mg, yield 80%.
1H NMR (300MHz, CDCl3) δ 1.67 (s, 6H), 1.98 (br s, 6H), 2.07 (br s, 3H), 2.76～2.93 (m, 4H), 3.26～3.30 (m, 4H), 5.16 (s, 1H), 6.88 (d, 1H, J=10.5Hz), 7.08 (s, 1H), 7.21～7.23 (m, 1H), 7.36 (s, 1H), 7.52 (d, 1H, J=9.3Hz)；Mp138～140 DEG C；EI-MS m/z:382 (M+).
Example 3:1-[3-(4-Acetylpiperazine-1-formoxyl) phenyl]-3-(1-adamantyl) urea (LH-84)
Under room temperature, 1-(1-adamantyl)-3-[3-(piperazine-1-formoxyl) phenyl] urea (LH-that will obtain in example 2 83), during (37mg, 0.10mmol) is dissolved into 3mL dichloromethane, acetic anhydride (11.2mg, 0.11mmol) is added.After 10 hours, subtract Press and solvent rotary evaporation is removed, column chromatography purification (CH2Cl2∶CH3OH=30: 1), final white powdery solids 23mg, Yield 54%.
1H NMR (300MHz, CDCl3) δ 1.66 (br s, 6H), 1.96 (br s, 6H), 2.06～2.13 (m, 6H), 3.44 ～3.70 (m, 8H), 5.13 (s, 1H), 6.91 (d, 1H, J=8.7Hz), 7.19～7.38 (m, 4H)；Mp 140～144 DEG C； EI-MS m/z:424 (M+).
Example 4:1-[3-(4-Nmethanesulphonylpiperazine-1-formoxyl) phenyl]-3-(1-adamantyl) urea (LH-85)
Under room temperature, 1-(1-adamantyl)-3-[3-(piperazine-1-formoxyl) phenyl] urea (LH-that will obtain in example 2 83), during (23mg, 0.06mmol) is dissolved into 5mL dichloromethane, mesyl chloride (7.5mg, 0.07mmol) is added.After 2 hours, subtract Press and solvent rotary evaporation is removed, column chromatography purification (CH2Cl2∶CH3OH=30: 1), final pale yellow powder shape solid 20mg, yield 72%.
1H NMR (300MHz, CDCl3) δ 1.67～1.69 (m, 6H), 1.98～1.99 (m, 6H), 2.08 (br s, 3H), 2.82 (s, 3H), 3.20～3.86 (m, 8H), 4.71 (s, 1H), 6.65 (s, 1H), 6.96 (dt, 1H, J1=5.1Hz, J2= 1.2Hz), 7.27～7.33 (m, 2H), 7.38 (m, 1H)；Mp 112～114 DEG C；EI-MS m/z:460 (M+).
Example 5:4-{4-[3-(1-adamantyl) urea groups] benzoyl } piperazine-1-t-butyl formate (LH-86)
Step one: 4-(4-nitro benzoyl) piperazine-1-t-butyl formate (4)
Operating procedure is with the step one in example 1.Substrate and consumption thereof are as follows: 1-tert-butoxycarbonyl-piperazine (373mg, 2mmol), 4-nitrobenzoic acid (351mg, 2.1mmol), EDCI (403mg, 2.1mmol), HOBt (284mg, 2.1mmol) and Triethylamine (0.29mL, 2.1mmol).Final white powdery solids 630mg, yield 94%.
Step 2: 4-(4-amino benzoyl) piperazine-1-t-butyl formate (5)
By molten for 4-(4-nitro benzoyl) piperazine-1-t-butyl formate (4) (335mg, 1mmol) that obtains in step one In 30mL absolute methanol, add 10%Pd/C (10% (w/w), 34mg) hydrogenation catalyst.Evacuation, pours into hydrogen, stirring Reaction is overnight.After 12 hours, filter off Pd/C, reduce pressure and solvent rotary evaporation is removed, obtain white solid, the most purified directly enter Next step reaction of row.
Step 3: 4-{4-[3-(1-adamantyl) urea groups] benzoyl } piperazine-1-t-butyl formate (LH-86)
Diamantane (obsolete)-1-isocyanates (157mg, 0.88mmol) is dissolved in the anhydrous dichloromethane of 5mL.At 0 DEG C, Xiang Rong In liquid, dropping is dissolved in 4-(4-amino benzoyl) piperazine-1-formic acid uncle obtained by step 2 of the anhydrous dichloromethane of 5mL Butyl ester (5) (270mg, 0.88mmol).Reaction system is appreciated room temperature, be stirred overnight.After about 12 hours, stopped reaction, concentrate, Column chromatography purification (CH2Cl2∶CH3OH=40: 1), final 320mg white powdery solids, yield 66%.
1H NMR (300MHz, CDCl3) δ 1.46 (s, 9H), 1.66 (br s, 6H), 1.98 (br s, 6H), 2.06 (br s, 3H), 3.43～3.61 (m, 8H), 5.46 (s, 1H), 7.12～7.26 (m, 4H), 7.73 (s, 1H)；Mp 130～132 DEG C；EI- MS m/z:482 (M+).
Example 6:1-(1-adamantyl)-3-[4-(piperazine-1-formoxyl) phenyl] urea (LH-87)
Operating procedure is with example 2.Substrate and consumption thereof are as follows: 4-{4-[3-(1-adamantyl) urea groups] benzoyl } piperazine Piperazine-1-t-butyl formate (LH-86 prepares from example 5) (130mg, 0.27mmol), trifluoroacetic acid (0.6mL).Final in vain Color pulverulent solids 68mg, yield 66%.
1H NMR (300MHz, CDCl3) δ 1.67 (s, 6H), 1.98 (br s, 6H), 2.07 (br s, 3H), 2.76～2.93 (m, 4H), 3.26～3.30 (m, 4H), 5.16 (s, 1H), 6.88 (d, 1H, J=10.5Hz), 7.08 (s, 1H), 7.21～7.23 (m, 1H), 7.36 (s, 1H), 7.52 (d, 1H, J=9.3Hz)；Mp143～145 DEG C；ESI-MS m/z:383.2 ([M+1]+).
Example 7:1-[4-(4-Acetylpiperazine-1-formoxyl) phenyl]-3-(1-adamantyl) urea (LH-88)
Operating procedure is with example 3.Substrate and consumption thereof are as follows: 1-(1-adamantyl)-3-[4-(piperazine-1-formoxyl) Phenyl] urea (LH-87 prepares from example 10) (23mg, 0.06mmol), acetic anhydride (6 μ L, 0.07mmol) and triethylamine (0.1mL).Final white powdery solids 22mg, yield 86%.
1H NMR (300MHz, CDCl3) δ 1.68 (br s, 6H), 2.00 (br s, 6H), 2.07 (br s, 3H), 2.13 (s, 3H), 3.48～3.61 (m, 8H), 5.31 (s, 1H), 7.16～7.23 (m, 4H), 7.53 (s, 1H)；Mp 118～121 DEG C；EI- MS m/z:424 (M+).
Example 8:1-[4-(4-Nmethanesulphonylpiperazine-1-formoxyl) phenyl]-3-(1-adamantyl) urea (LH-89)
Operating procedure is with example 4.Substrate and consumption thereof are as follows: 1-(1-adamantyl)-3-[4-(piperazine-1-formoxyl) Phenyl] urea (LH-87 prepares from example 6) (23mg, 0.06mmol), mesyl chloride (7.5mg, 0.07mmol) and triethylamine (0.05mL).Final white powdery solids 26mg, yield 98%.
1H NMR (300MHz, CDCl3) δ 1.68 (br s, 6H), 2.00 (br s, 6H), 2.08 (br s, 3H), 2.81 (s, 3H), 3.22 (br s, 4H), 3.70 (br s, 4H), 5.12 (s, 1H), 7.17～7.24 (m, 4H)；Mp 113～115 DEG C；EI- MS m/z:460 (M+).
Example 9:1-(1-adamantyl)-3-{2-[3-(4-methylpiperazine-1-yl) propoxyl group] phenyl } urea (LH-23)
Step one: 1-(3-bromine propoxyl group)-2-Nitrobenzol (6)
2-nitrophenol (2.782g, 20mmol) and potassium carbonate (3.317g, 24mmol) are dissolved in 30mL DMF, room temperature After lower stirring 1 hour, add 1,3-dibromopropane (6.460g, 32mmol).After reacting 16 hours, pour reactant liquor into 200mL In water, extract (3 × 100mL) with dichloromethane.Merge organic facies, with 2% sodium hydroxide (3 × 100mL) and water (2 × 100mL) wash.Organic facies anhydrous sodium sulfate is dried.Reduce pressure and solvent rotary evaporation is removed, column chromatography purification (petroleum ether: acetic acid Ethyl ester=50: 1), finally give pale yellow oily liquid body 3.740g, yield 72%.
1H NMR (300MHz, CDCl3) δ 2.36 (pent, 2H), 3.66 (t, 2H), 4.25 (t, 2H), 7.01～7.12 (m, 2H), 7.50～7.56 (m, 1H), 7.82～7.86 (dd, 1H).
Step 2: 1-methyl-4-[3-(2-nitro-phenoxy) propyl group] piperazine (7)
By 1-(3-the bromopropyl)-2-Nitrobenzol (6) (270mg, 1mmol) obtained in step one and 1-methyl piperazine (310mg, 3.1mmol) is dissolved in 30mL oxolane, and return stirring is overnight.Rotary evaporation removes solvent, and residue is dissolved in 30mL dilute hydrochloric acid stirs 10 minutes.After acid solution ether washes (2 × 30mL), with 10% sodium hydroxide solution regulation pH value extremely 10～12.Aqueous phase ether extracts (3 × 20mL).Merging organic facies, after washing (1 × 30mL) with water, anhydrous sodium sulfate is dried.Subtract Press and solvent rotary evaporation is removed, the final oily liquids 274mg obtaining yellow, yield 94%.
1H NMR (300MHz, CDCl3) δ 2.01 (pent, 2H), 2.28 (s, 3H), 2.46～2.57 (m, 10H), 4.16 (t, 2H), 7.00 (t, 1H), 7.08 (d, 1H), 7.50 (td, 1H), 7.81 (dd, 1H).
Step 3: 2-[3-(4-methylpiperazine-1-yl) propoxyl group] aniline (8)
By step 2 obtains 1-methyl-4-[3-(2-nitro-phenoxy) propyl group] piperazine (7) (200mg, 0.72mmol) in 15mL methanol, add 10%Pd/C (10% (w/w), 20mg) hydrogenation catalyst.Evacuation, pours into hydrogen, stirs Mix reaction overnight.Filter off Pd/C, reduce pressure and solvent rotary evaporation is removed, obtain brown solid 174mg, yield 97%.
1H NMR (300MHz, CDCl3) δ 2.01 (pent, 2H), 2.31 (s, 3H), 2.49～2.59 (m, 10H), 4.04 (t, 2H), 6.69～6.73 (m, 2H), 6.76～6.81 (m, 2H).
Step 4: 1-(1-adamantyl)-3-{2-[3-(4-methylpiperazine-1-yl) propoxyl group] phenyl } urea (LH-23)
At 0 DEG C, by step 3 obtains 2-[3-(4-methylpiperazine-1-yl) propoxyl group] aniline (8) (100mg, 0.40mmol) being dissolved in 10mL anhydrous methylene chloride, the diamantane (obsolete)-1-being added dropwise over being dissolved in 10mL anhydrous methylene chloride is different Cyanate (85mg, 0.48mmol).Reaction is stirred overnight.Reduce pressure and solvent rotary evaporation is removed, column chromatography purification (dichloromethane Alkane: methanol=10: 1), finally give white powdery solids 134mg, yield 79%.
1H NMR (300MHz, CDCl3) δ 1.69 (s, 6H), 2.07～2.09 (m, 11H), 2.31 (s, 3H), 2.53～ 2.61 (m, 10H), 4.05 (t, 2H, J=6.3Hz), 4.73 (br s, 1H), 6.78～6.85 (m, 2H), 6.88～6.93 (m, 2H), 8.01～8.05 (m, 1H)；Mp 154～156 DEG C；ESI-MS m/z:427.3 ([M+1]+).
Example 10:1-(1-adamantyl)-3-{2-[3-(4-tert-butoxycarbonyl-piperazine-1-base) propoxyl group] phenyl } urea (LH-25)
Step one: 4-[3-(2-nitro-phenoxy) propyl group] piperazine-1-t-butyl formate (9)
By 1-(3-bromopropyl)-2-Nitrobenzol (6) (301mg, 1.2mmol) (reference example 9 step one), 1-tertiary butyloxycarbonyl Base piperazine (1) (431mg, 2.3mmol) and triethylamine (234mg, 2.3mmol) are dissolved in 20mL oxolane, under nitrogen protection, Backflow, is stirred overnight.Reducing pressure and removed by solvent rotary evaporation, residue is dissolved in saturated sodium bicarbonate, extracts with dichloromethane Take (3 × 50mL).Merging organic facies, after washing with saturated aqueous common salt (1 × 50mL), anhydrous sodium sulfate is dried.Reduce pressure and solvent is revolved Turn evaporation to remove, column chromatography purification (dichloromethane: methanol=10: 1), finally give glassy yellow oily liquids 355mg, yield 84%.
1H NMR (300MHz, CDCl3) δ 1.44 (s, 9H), 1.99 (pent, 2H), 2.54 (t, 2H), 3.40 (t, 4H), 4.16 (t, 2H), 6.99 (td, 1H), 7.07 (dd, 1H), 7.48 (td, 1H), 7.79 (dd, 1H).
Step 2: 4-[3-(2-amino-benzene oxygen) propyl group] piperazine-1-t-butyl formate (10)
Operating procedure is with the step 3 in example 9.Substrate and consumption thereof are as follows: 4-[3-(the 2-Nitrobenzol that step one obtains Epoxide) propyl group] piperazine-1-t-butyl formate (9) (186mg, 0.51mmol) and 10%Pd/C (10%, 19mg).Brownly final Color pulverulent solids 154mg, yield 66%.
1H NMR (300MHz, CDCl3) δ 1.46 (s, 9H), 2.01 (pent, 2H), 2.42 (t, 4H), 2.56 (t, 2H), 3.45 (t, 4H), 4.05 (t, 2H), 6.67～6.73 (m, 2H), 6.77～6.81 (m, 2H).
Step 3: 1-(1-adamantyl)-3-{2-[3-(4-tert-butoxycarbonyl-piperazine-1-base) propoxyl group] phenyl } urea (LH-25)
Operating procedure is with the step 4 in example 9.Substrate and consumption thereof are as follows: 4-[3-(the 2-aminobenzene that step 2 obtains Epoxide) propyl group] piperazine-1-t-butyl formate (10) (152mg, 0.45mmol) and diamantane (obsolete)-1-isocyanates (96mg, 0.54mmol).Final white powdery solids 209mg, yield 90%.
1H NMR (300MHz, CDCl3) δ 1.46 (s, 9H), 1.69 (s, 6H), 1.94～2.03 (m, 8H), 2.09 (s, 3H), 2.45 (br s, 4H), 2.54 (t, 2H, J=6.3Hz), 4.07 (br s, 4H), 4.07 (t, 2H, J=6.3Hz), 4.60 (br s, 1H, NH), 6.69 (br s, 1H, NH), 6.82～6.85 (m, 1H), 6.89～6.94 (m, 2H), 7.98～8.01 (m, 1H)；Mp 88～90 DEG C；EI-MS m/z:512 (M+).
Example 11:1-(1-adamantyl)-3-{2-[3-(piperazine-1-base) propoxyl group] phenyl } urea (LH-24)
By 1-(1-adamantyl)-3-{2-[3-(4-tert-butoxycarbonyl-piperazine-1-base) propoxyl group] phenyl } urea (LH-25) (101mg, 0.2mmol) (reference example 10) is dissolved in 6mL dichloromethane.At 0 DEG C, add trifluoroacetic acid (0.3mL).Reaction rises To room temperature, it is stirred overnight.Reducing pressure and removed by solvent rotary evaporation, residue is dissolved in 10mL water, with 5% sodium hydroxide solution alkali Change solution.Aqueous phase dichloromethane extracts (3 × 20mL).Merge organic facies, after saturated aqueous common salt (2 × 20mL) is washed, anhydrous sulfur Acid sodium is dried.Reduce pressure and solvent rotary evaporation is removed, final white powdery solids 70mg, yield 86%.
1H NMR (300MHz, CDCl3) δ 1.69 (s, 6H), 2.04 (s, 6H), 2.08～2.17 (m, 3H), 2.57～2.65 (m, 6H), 2.98 (t, 4H), 4.05 (t, 2H), 5.29 (br s, 1H), 6.80～6.83 (m, 1H), 6.89～6.92 (m, 3H), 8.04～8.07 (m, 1H)；Mp 162～164 DEG C；EI-MS m/z:412 (M+).
Example 12:1-(1-adamantyl)-3-{2-[3-(4-Acetylpiperazine-1-base) propoxyl group] phenyl } urea (LH- 26)
By 1-(1-adamantyl)-3-{2-[3-(piperazine-1-base) propoxyl group] phenyl } urea (LH-24) (43mg, 0.10mmol) (reference example 11) and acetic anhydride (13mg, 0.13mmol) are dissolved in 8mLDMF.Stirring reaction 10 hours.Decompression Being removed by solvent rotary evaporation, residue is dissolved in 30mL ether, and after washing (1 × 30mL), anhydrous sodium sulfate is dried.Decompression will Solvent rotary evaporation removes, and column chromatography purification (dichloromethane: methanol=10: 1) finally gives white powdery solids 21mg, Yield 44%.
1H NMR (300MHz, CDCl3) δ 1.69 (s, 6H), 2.04～2.11 (m, 14H), 2.75 (m, 4H), 2.87 (t, 2H, J=7.8Hz), 3.63 (t, 2H, J=5.1Hz), 3.99 (t, 2H, J=5.4Hz), 6.22 (s, 1H), 6.72～6.75 (m, 1H), 6.82～6.93 (m, 2H), 7.37 (s, 1H), 8.23～8.26 (m, 1H)；Mp 86～88 DEG C；EI-MS m/z:454 (M+).
Example 13:1-(1-adamantyl)-3-{3-[3-(4-methylpiperazine-1-yl) propoxyl group] phenyl } urea (LH-27)
Step one: 1-(3-bromine propoxyl group)-3-Nitrobenzol (11)
3-nitrophenol (2.782g, 20mmol) and potassium carbonate (3.317g, 24mmol) are dissolved in 30mL DMF, room temperature After lower stirring 1 hour, add 1,3-dibromopropane (6.460g, 32mmol).Stirred overnight is reacted, and pours reactant liquor into 200mL In water, extract (3 × 100mL) with dichloromethane.Merge organic facies, with 2% sodium hydroxide (3 × 100mL) and water (2 × 100mL) wash.Organic facies anhydrous sodium sulfate is dried.Reduce pressure and solvent rotary evaporation is removed, column chromatography purification (petroleum ether: acetic acid Ethyl ester=50: 1), finally give pale yellow oily liquid body 2.162g, yield 42%.
1H NMR (300MHz, CDCl3) δ 2.36 (pent, 2H), 3.62 (t, 2H), 4.19 (t, 2H), 7.24 (td, 1H), 7.43 (t, 1H), 7.74 (t, 1H), 7.82 (dd, 1H).
Step 2: 1-methyl-4-[3-(3-nitro-phenoxy) propyl group] piperazine (12)
By 1-(3-bromine the propoxyl group)-3-Nitrobenzol (11) (600mg, 2.31mmol) obtained in step one and 1-methyl piperazine Piperazine (693mg, 6.92mmol) is dissolved in 30mL oxolane, and return stirring is overnight.Rotary evaporation removes solvent, and residue dissolves Stir 10 minutes in 30mL dilute hydrochloric acid.After acid solution ether washes (2 × 30mL), with 10% sodium hydroxide solution regulation pH value To 10～12.Aqueous phase ether extracts (3 × 20mL).Merging organic facies, after washing (1 × 30mL) with water, anhydrous sodium sulfate is dried. Reduce pressure and solvent rotary evaporation is removed, final flaxen oily liquids 621mg, yield 96%.
1H NMR (300MHz, CDCl3) δ 1.99 (pent, 2H), 2.28 (s, 3H), 2.47～2.55 (m, 10H), 4.08 (t, 2H), 7.20 (ddd, 1H, J=5.1Hz, J=1.8Hz, J=0.6Hz), 7.40 (t, 1H, J=8.2Hz), 7.71 (t, 1H, J=2.4Hz), 7.82 (dq, 1H, J=5.1Hz, J=0.9Hz).
Step 3: 3-[3-(4-methylpiperazine-1-yl) propoxyl group] aniline (13)
By step 2 obtains 1-methyl-4-[3-(3-nitro-phenoxy) propyl group] piperazine (12) (168mg, 0.6mmol) in 15mL methanol, add 10%Pd/C (10% (w/w), 17mg) hydrogenation catalyst.Evacuation, pours into hydrogen, stirs Mix reaction overnight.Filter off Pd/C, reduce pressure and solvent rotary evaporation is removed, obtain brown oil liquid 145mg, yield 97%.
1H NMR (300MHz, CDCl3) δ 1.94 (pent, 2H), 2.29 (s, 3H), 2.49～2.54 (m, 10H), 3.96 (t, 2H), 6.22～6.32 (m, 3H), 7.03 (t, 1H).
Step 4: 1-(1-adamantyl)-3-{3-[3-(4-methylpiperazine-1-yl) propoxyl group] phenyl } urea (LH-27)
At 0 DEG C, by step 3 obtains 3-[3-(4-methylpiperazine-1-yl) propoxyl group] aniline (13) (135mg, 0.54mmol) it is dissolved in 10mL anhydrous methylene chloride, is added dropwise over being dissolved in the diamantane (obsolete)-1-of 10mL anhydrous methylene chloride Isocyanates (106mg, 0.60mmol).Reaction is stirred overnight.Reduce pressure and solvent rotary evaporation is removed, column chromatography purification (dichloro Methane: methanol=10: 1), finally give white powdery solids 120mg, yield 97%.
1H NMR (300MHz, CDCl3) δ 1.67 (s, 6H), 1.90～2.00 (m, 8H), 2.07 (s, 3H), 2.31 (s, 3H), 2.51～2.56 (m, 10H), 3.97 (t, 2H, J=6.3Hz), 4.69 (s, 1H, NH), 6.37 (s, 1H, NH), 6.57 (dd, 1H, J=6.0Hz, J=1.8Hz), 6.77 (dd, 1H, J=6.0Hz, J=1.8Hz), 6.97 (t, 1H, J=2.1Hz), 7.15 (t, 1H, J=8.1Hz)；Mp 144～146 DEG C；EI-MSm/z:426 (M+).
Example 14:4-{3-{3-[3-(1-adamantyl) urea groups] phenoxy group } propyl group } piperazine-1-t-butyl formate (LH- 29)
Step one: 4-[3-(3-nitro-phenoxy) propyl group] piperazine-1-t-butyl formate (14)
By 1-(3-bromine propoxyl group)-3-Nitrobenzol (11) (400mg, 1.54mmol) (reference example 13 step one), uncle 1- Butoxy carbonyl piperazine (1) (430mg, 2.31mmol) and triethylamine (234mg, 2.3mmol) are dissolved in 20mL oxolane, nitrogen Under protection, backflow, it is stirred overnight.Reducing pressure and removed by solvent rotary evaporation, residue is dissolved in saturated sodium bicarbonate, uses dichloro Methane extraction (3 × 50 mL).Merging organic facies, after washing with saturated aqueous common salt (1 × 50mL), anhydrous sodium sulfate is dried.Decompression will Solvent rotary evaporation removes, and column chromatography purification (dichloromethane: methanol=10: 1) finally gives white waxy solid 369mg, receives Rate 66%.
1H NMR (300MHz, CDCl3) δ 1.44 (s, 9H), 2.00 (pent, 2H), 2.39 (t, 4H), 2.51 (t, 2H), 3.42 (t, 4H), 4.08 (t, 2H), 6.99 (ddd, 1H, J=4.8Hz, J=1.8Hz, J=0.9Hz), 7.39 (t, 1H, J= 8.4Hz), 7.70 (t, 1H, J=2.4Hz), 7.79 (ddd, 1H, J=5.1Hz, J=1.5Hz, J=0.9Hz).
Step 2: 4-[3-(3-amino-benzene oxygen) propyl group] piperazine-1-t-butyl formate (15)
Operating procedure is with the step 2 in example 10.Substrate and consumption thereof are as follows: 4-[3-(the 3-nitro that step one obtains Phenoxy group) propyl group] piperazine-1-t-butyl formate (14) (183mg, 0.5mmol) and 10%Pd/C (10%, 18mg).Final White waxy solid 160mg, yield 95%.
1H NMR (300MHz, CDCl3) δ 1.46 (s, 9H), 1.94 (pent, 2H), 2.40 (t, 4H), 2.51 (t, 2H), 3.41 (t, 4H), 3.97 (t, 2H), 6.23～6.32 (m, 3H), 7.04 (t, 1H).
Step 3: 4-{3-{3-[3-(1-adamantyl) urea groups] phenoxy group } propyl group } piperazine-1-t-butyl formate (LH- 29)
Operating procedure is with the step 3 in example 10.Substrate and consumption thereof are as follows: 4-[3-(the 3-amino that step 2 obtains Phenoxy group) propyl group] piperazine-1-t-butyl formate (15) (158mg, 0.47mmol) and diamantane (obsolete)-1-isocyanates (92mg, 0.52mmol).Final white powdery solids 89mg, yield 37%.
1H NMR (300MHz, CDCl3) δ 1.47 (s, 9H), 1.68 (s, 6H), 1.93～2.00 (m, 8H), 2.08 (s, 3H), 2.43 (t, 4H, J=4.2Hz), 2.53 (t, 2H, J=7.2Hz), 3.45 (t, 4H, J=5.7Hz), 3.99 (t, 2H, J= 5.7Hz), 4.65 (s, 1H, NH), 6.32 (s, 1H, NH), 6.57 (d, 1H, J=7.2Hz), 6.74 (d, 1H, J=7.2Hz), 7.01 (s, 1H), 7.15 (t, 1H, J=7.8Hz)；Mp150～153 DEG C；EI-MS m/z:512 (M+).
Example 15:1-(1-adamantyl)-3-{3-[3-(piperazine-1-base) propoxyl group] phenyl } urea (LH-28)
By 4-{3-{3-[3-(1-adamantyl) urea groups] phenoxy group } propyl group } piperazine-1-t-butyl formate (LH-29) (89mg, 0.17mmol) (reference example 14) is dissolved in 5mL dichloromethane.At 0 DEG C, add trifluoroacetic acid (0.25mL).Reaction It is warmed to room temperature, is stirred overnight.Reducing pressure and removed by solvent rotary evaporation, residue is dissolved in 10mL water, uses 5% sodium hydroxide solution Alkalizing solution.Aqueous phase dichloromethane extracts (3 × 15mL).Merge organic facies, after saturated aqueous common salt (2 × 20mL) is washed, anhydrous Sodium sulfate is dried.Reduce pressure and solvent rotary evaporation is removed, final white powdery solids 52mg, yield 72%.
1H NMR (300MHz, CDCl3) δ 1.68 (s, 6H), 1.88～2.00 (m, 11H), 2.50～2.55 (m, 6H), 2.95 (t, 4H, J=4.8Hz), 3.99 (t, 2H, J=6.3Hz), 4.61 (s, 1H, NH), 6.25 (s, 1H, NH), 6.57 (ddd, 1H, J=4.8Hz, J=1.5Hz, J=0.9Hz), 6.77 (ddd, 1H, J=5.4Hz, J=1.5Hz, J=0.9Hz), 6.96 (t, 1H, J=2.1Hz), 7.16 (t, 1H, J=8.1Hz)；Mp 84～86 DEG C；EI-MS m/z:412 (M+).
Example 16:1-(1-adamantyl)-3-{3-[3-(4-Acetylpiperazine-1-base) propoxyl group] phenyl } urea (LH- 30)
Step one: 1-{4-[3-(3-nitro-phenoxy) propyl group] piperazine-1-base } ethyl ketone (17)
By acetic anhydride (27mg, 0.26mmol), triethylamine (0.5mL) and 1-(3-(3-nitro-phenoxy) propyl group) piperazine 16 (58mg, 0.22mmol) is dissolved in 5mL dichloromethane.Stirring reaction 3 hours under room temperature.Reduce pressure and solvent rotary evaporation removed, Residue adds ether (30mL) and water (30mL) layering.Organic facies anhydrous sodium sulfate is dried.Reduce pressure to rotate solvent and steam Send out and remove, column chromatography purification (dichloromethane: methanol=20: 1), finally give yellow oily liquid 54mg, yield 80%.
1H NMR (300MHz, CDCl3) δ 2.03～2.10 (m, 5H), 2.46～2.53 (m, 4H), 2.60 (t, 2H, J= 7.5Hz), 3.51 (t, 2H, J=4.8Hz), 3.66 (t, 2H, J=3.6Hz), 4.11 (t, 2H, J=6.0Hz), 7.19～7.23 (m, 1H), 7.42 (t, 1H, J=8.4Hz), 7.73 (t, 1H, J=2.1Hz), 7.80～7.82 (m, 1H).
Step 2: 1-{4-[3-(3-amino-benzene oxygen) propyl group] piperazine-1-base } ethyl ketone (18)
1-{4-[3-(3-nitro-phenoxy) propyl group] piperazine-1-base that will obtain in step one } ethyl ketone (17) (54mg, 0.18mmol) in methanol (10mL), add 10%Pd/C (10% (w/w), 6mg) hydrogenation catalyst.Evacuation, is passed through hydrogen, Stirring reaction is overnight.Filter off Pd/C, reduce pressure and solvent rotary evaporation is removed, obtain yellow oily liquid 42mg, yield 86%.
1H NMR (300MHz, CDCl3) δ 1.95～1.98 (m, 2H), 2.09 (s, 3H), 2.43～2.50 (m, 4H), 2.53 ～2.58 (m, 2H), 3.49 (t, 2H, J=4.2Hz), 3.65 (t, 2H, J=4.8Hz), 3.99 (t, 2H, J=6.3Hz), 6.23 ～6.24 (m, 1H), 6.27～6.33 (m, 2H), 7.04 (t, 1H, J=7.8Hz).
Step 3: 1-(1-adamantyl)-3-{3-[3-(4-Acetylpiperazine-1-base) propoxyl group] phenyl } urea (LH- 30)
At 0 DEG C, 1-{4-[3-(3-amino-benzene oxygen) propyl group] piperazine-1-base that will obtain in step 2 } ethyl ketone (18) (42mg, 0.15mmol) is dissolved in 5mL anhydrous methylene chloride, is added dropwise over being dissolved in the Buddha's warrior attendant of 10mL anhydrous methylene chloride Alkane-1-isocyanates (29mg, 0.17mmol).Reaction is stirred overnight.Reduce pressure and solvent rotary evaporation is removed, column chromatography purification (dichloromethane: methanol=10: 1), finally gives white powdery solids 39mg, yield 57%.
1H NMR (300MHz, CDCl3) δ 1.68 (s, 6H), 1.95～2.01 (m, 8H), 2.09 (m, 6H), 2.45～2.59 (m, 6H), 3.50 (t, 2H, J=4.5Hz), 3.64～3.67 (m, 2H), 4.01 (t, 2H, J=6.0Hz), 4.51 (s, 1H), 6.12 (s, 1H), 6.57 (dd, 1H, J=2.7Hz, J=5.1Hz), 6.72 (d, 1H, J=8.1Hz), 7.15 (t, 1H, J= 8.4Hz)；Mp 96～98 DEG C；EI-MS m/z:454 (M+).
Example 17:1-(1-adamantyl)-3-{4-[3-(4-methylpiperazine-1-yl) propoxyl group] phenyl } urea (LH-31)
Step one: 1-(3-bromopropyl)-4-Nitrobenzol (19)
4-nitrophenol (6.956g, 50mmol) and potassium carbonate (8.293g, 60mmol) are dissolved in 70mL DMF, room temperature After lower stirring 2 hours, add 1,3-dibromopropane (15.949g, 79mmol).Stirred overnight is reacted, and pours reactant liquor into 300mL In water, extract (3 × 100mL) with dichloromethane.Merge organic facies, with 2% sodium hydroxide (3 × 100mL) and water (2 × 100mL) wash.Organic facies anhydrous sodium sulfate is dried.Reduce pressure and solvent rotary evaporation is removed, column chromatography purification (petroleum ether: acetic acid Ethyl ester=50: 1), finally give pale yellow oily liquid body 7.538g, yield 58%.
1H NMR (300MHz, CDCl3) δ 2.37 (pent, 2H), 3.61 (t, 2H), 4.21 (t, 2H), 6.94～6.99 (m, 2H), 8.18～8.23 (m, 2H).
Step 2: 1-methyl-4-[3-(4-nitrophenoxy) propyl group] piperazine (20)
By 1-(3-the bromopropyl)-4-Nitrobenzol (19) (1.000g, 3.85mmol) obtained in step one and 1-methyl piperazine Piperazine (1.155g, 11.54mmol) is dissolved in 100mL oxolane, and return stirring is overnight.Rotary evaporation removes solvent, residue It is dissolved in 60mL dilute hydrochloric acid stirring 30 minutes.After acid solution ether washes (2 × 60mL), with 10% sodium hydroxide solution regulation pH Value is to 10～12.Aqueous phase ether extracts (3 × 60mL).Merging organic facies, after washing (1 × 50mL) with water, anhydrous sodium sulfate is done Dry.Reduce pressure and solvent rotary evaporation is removed, the final oily liquids 889mg obtaining yellow, yield 83%.
1H NMR (300MHz, CDCl3) δ 2.01 (pent, 2H), 2.30 (s, 3H), 2.38～2.55 (m, 10H), 4.10 (t, 2H), 6.91～6.95 (m, 2H), 8.15～8.19 (m, 2H).
Step 3: 4-[3-(4-methylpiperazine-1-yl) propoxyl group] aniline (21)
By step 2 obtains 1-methyl-4-[3-(4-nitrophenoxy) propyl group] piperazine (20) (559mg, 2.0mmol) in 20mL methanol, add 10%Pd/C (10% (w/w), 55mg) hydrogenation catalyst.Evacuation, pours into hydrogen, stirs Mix reaction 4 hours.Filter off Pd/C, reduce pressure and solvent rotary evaporation is removed, obtain clear, colorless oily liquids 222mg, yield 45%.
1H NMR (300MHz, CDCl3) δ 1.93 (pent, 2H), 2.28 (s, 3H), 2.38～2.66 (m, 10H), 3.93 (t, 2H), 6.60～6.65 (m, 2H), 6.71～6.75 (m, 2H).
Step 4: 1-(1-adamantyl)-3-{4-[3-(4-methylpiperazine-1-yl) propoxyl group] phenyl } urea (LH-31)
At 0 DEG C, by step 3 obtains 4-[3-(4-methylpiperazine-1-yl) propoxyl group] aniline (21) (111mg, 0.45mmol) being dissolved in 10mL anhydrous methylene chloride, the diamantane (obsolete)-1-being added dropwise over being dissolved in 10mL anhydrous methylene chloride is different Cyanate (95mg, 0.45mmol).Reaction is stirred overnight.Reduce pressure and solvent rotary evaporation is removed, column chromatography purification (dichloromethane : methanol=10: 1), finally give white powdery solids 107mg, yield 56%.
1H NMR (300MHz, CDCl3) δ 1.64 (s, 6H), 1.92～1.99 (m, 8H), 2.04 (s, 3H), 2.30 (s, 3H), 2.49～2.54 (m, 10H), 3.96 (t, 2H, J=6.3Hz), 4.59 (s, 1H, NH), 6.26 (s, 1H, NH), 6.82 (d, 2H, J=8.7Hz), 7.15 (d, 2H, J=8.4Hz)；Mp 98～100 DEG C；EI-MS m/z:426 (M+).
Example 18:1-(1-adamantyl)-3-{4-[3-(4-tert-butoxycarbonyl-piperazine-1-base) propoxyl group] phenyl } urea (LH-33)
Step one: 1-[3-(4-nitrophenoxy) propyl group] piperazine (22)
By 1-(3-bromopropyl)-4-Nitrobenzol (19) (1.000g, 3.8mmol) (reference example 17 step one) and piperazine (1.656g, 19.2mmol) is dissolved in 60mL oxolane, under nitrogen protection, and backflow, it is stirred overnight.Reduce pressure to rotate solvent and steam Sending out and remove, residue 50mL dilute hydrochloric acid dilutes, and after stirring 10 minutes, aqueous phase ether (3 × 50mL) is washed.Use 10% hydroxide Sodium solution regulation aqueous pH values is to 10～12, and ether extracts (3 × 50mL).Merge organic facies, after washing (1 × 100mL), anhydrous Sodium sulfate is dried.Reduce pressure and solvent rotary evaporation is removed, finally give yellow powdery solid 646mg, yield 63%.
1H NMR (300MHz, CDCl3) δ 1.82 (s, 1H), 1.99 (pent, 2H), 2.43～2.52 (m, 6H), 2.89 (t, 4H), 4.10 (t, 2H), 6.92～6.97 (m, 2H), 8.16～8.20 (m, 2H).
Step 2: 4-[3-(4-nitrophenoxy) propyl group] piperazine-1-t-butyl formate (23)
Bis(tert-butoxycarbonyl)oxide (691mg, 3.2mmol) is dissolved in 20mL methanol, at 0 DEG C, is slowly dropped to and stirreds It is dissolved in the 1-[3-(4-nitrophenoxy) propyl group] piperazine (22) (646mg, 2.4mmol) of 25mL methanol.Reaction is warmed to room temperature, It is stirred overnight.Reduce pressure and solvent rotary evaporation is removed, column chromatography purification (dichloromethane: methanol=50: 1 → 30: 1), final To pale yellow powder shape solid 542mg, yield 61%.
1H NMR (300MHz, CDCl3) δ 1.46 (s, 9H), 2.01 (pent, 2H), 2.41 (t, 4H), 2.53 (t, 2H), 3.44 (t, 4H), 4.12 (t, 2H), 6.93～6.96 (m, 2H), 8.18～8.22 (m, 2H).
Step 3: 4-[3-(4-amino-benzene oxygen) propyl group] piperazine-1-t-butyl formate (24)
Operating procedure is with the step 2 in example 10.Substrate and consumption thereof are as follows: 4-[3-(the 4-nitro that step 2 obtains Phenoxy group) propyl group] piperazine-1-t-butyl formate (23) (183mg, 0.5mmol) and 10%Pd/C (10%, 18mg).Final Brown oil liquid 159mg, yield 95%.
1H NMR (300MHz, CDCl3) δ 1.46 (s, 9H), 1.93 (pent, 2H), 2.41 (t, 4H), 2.52 (t, 2H), 3.44 (t, 4H), 3.94 (t, 2H), 6.61～6.64 (m, 2H), 6.72～6.75 (m, 2H).
Step 4: 1-(1-adamantyl)-3-{4-[3-(4-tert-butoxycarbonyl-piperazine-1-base) propoxyl group] phenyl } urea (LH-33)
Operating procedure is with the step 3 in example 10.Substrate and consumption thereof are as follows: 4-[3-(the 4-amino that step 3 obtains Phenoxy group) propyl group] piperazine-1-t-butyl formate (24) (150mg, 0.45mmol) and diamantane (obsolete)-1-isocyanates (95mg, 0.54mmol).Final white powdery solids 158mg, yield 68%.
1H NMR (300MHz, CDCl3) δ 1.46 (s, 9H), 1.66 (s, 6H), 1.96～2.01 (m, 8H), 2.06 (s, 3H), 2.44 (br s, 4H), 2.53 (t, 2H, J=7.2Hz), 3.46 (br s, 4H), 3.99 (t, 2H, J=6.3Hz), 4.38 (s, 1H, NH), 5.92 (s, 1H, NH), 6.81～6.86 (m, 2H), 7.12～7.17 (m, 2H)；Mp 92～94 DEG C；EI-MS M/z:512 (M+).
Example 19:1-(1-adamantyl)-3-{4-[3-(piperazine-1-base) propoxyl group] phenyl } urea (LH-32)
By 1-(1-adamantyl)-3-{4-[3-(4-tert-butoxycarbonyl-piperazine-1-base) propoxyl group] phenyl } urea (LH-33) (100mg, 0.20mmol) (reference example 18) is dissolved in 5mL dichloromethane.At 0 DEG C, add trifluoroacetic acid (0.30mL).Reaction It is warmed to room temperature, is stirred overnight.Reducing pressure and removed by solvent rotary evaporation, residue is dissolved in 10mL water, uses 5% sodium hydroxide solution Alkalizing solution.Aqueous phase dichloromethane extracts (3 × 15mL).Merge organic facies, after saturated aqueous common salt (2 × 20mL) is washed, anhydrous Sodium sulfate is dried.Reduce pressure and solvent rotary evaporation is removed, final white powdery solids 42mg, yield 52%.
1H NMR (300MHz, CDCl3) δ 1.67 (s, 6H), 1.91～2.08 (m, 11H), 2.43～2.56 (m, 6H), 2.97 (t, 4H, J=4.8Hz), 3.99 (t, 2H, J=6.3Hz), 4.37 (s, 1H, NH), 5.90 (s, 1H, NH), 6.84 (dd, 2H, J=4.5Hz, J=2.1Hz), 7.15 (dd, 2H, J=5.1Hz, J=2.1Hz)；Mp 104～106 DEG C；EI-MS m/z: 412(M+).
Example 20:1-(1-adamantyl)-3-{4-[3-(4-Acetylpiperazine-1-base) propoxyl group] phenyl } urea (LH- 34)
By 1-(1-adamantyl)-3-{4-[3-(piperazine-1-base) propoxyl group] phenyl } urea (LH-32) (37mg, 0.09mmol) (reference example 19), acetic anhydride (11mg, 0.11mmol) and triethylamine (1mL) are dissolved in DMF (5mL).Stirring is anti- Answer 4 hours.Reducing pressure and removed by solvent rotary evaporation, residue is dissolved in 30mL ether, after washing (1 × 30mL), and anhydrous slufuric acid Sodium is dried.Reduce pressure and solvent rotary evaporation is removed, column chromatography purification (dichloromethane: methanol=10: 1), finally give white powder Powder solid 30mg, yield 73%.
1H NMR (300MHz, CDCl3) δ 1.66 (m, 6H), 1.96～2.09 (m, 14H), 2.48～2.60 (m, 6H), 3.50 (t, 2H, J=4.5Hz), 3.65 (s, 2H), 3.99 (t, 2H, J=6.3Hz), 4.40 (s, 1H), 5.99 (s, 1H), 6.82 ～6.85 (m, 2H), 7.14～7.17 (m, 2H)；Mp 170～172 DEG C；EI-MSm/z:454 (M+).
Example 21:1-(1-adamantyl)-3-{2-[4-(4-methylpiperazine-1-yl) butoxy] phenyl } urea (LH-35)
Step one: 1-(4-bromine propoxyl group)-2-Nitrobenzol (25)
Operating procedure is with the compound 6 in example 9 step one.Substrate and consumption thereof are as follows: 2-nitrophenol (2.782g, 20mmol) with potassium carbonate (3.317g, 24mmol).Final pale yellow oily liquid body 4.800g, yield 88%.
1H NMR (300MHz, CDCl3) δ 1.96～2.16 (m, 4H), 3.50 (t, 2H, J=6.3Hz), 4.14 (t, 2H, J =5.7Hz), 6.99～7.07 (m, 2H), 7.49～7.55 (m, 1H), 7.83 (dd, 1H, J=6.6Hz, J=1.5Hz).
Step 2: 1-methyl-4-[4-(2-nitro-phenoxy) butyl] piperazine (26)
Operating procedure is with the compound 7 in example 9 step 2.Substrate and consumption thereof are as follows: 1-(the 4-bromine that step one obtains Butoxy)-2-Nitrobenzol (25) (504mg, 1.84mmol) and 1-methyl piperazine (553mg, 5.52mmol).Final yellow oil Shape liquid 469mg, yield 87%.
1H NMR (300MHz, CDCl3) δ 1.68 (pent, 2H), 1.86 (pent, 2H), 2.27 (s, 3H), 2.30～2.44 (m, 10H), 4.11 (t, 2H, J=6.3Hz), 6.96～7.07 (m, 2H), 7.46～7.52 (m, 1H), 7.40 (t, 1H, J= 8.2Hz), 7.80 (dd, 1H, J=6.6Hz, J=1.5Hz).
Step 3: 2-[4-(4-methylpiperazine-1-yl) butoxy] aniline (27)
Operating procedure is with the compound 8 in example 9 step 3.Substrate and consumption thereof are as follows: the 1-methyl that step 2 obtains- 4-[4-(2-nitro-phenoxy) butyl] piperazine (26) (176mg, 0.6mmol) and 10%Pd/C (10% (w/w), 18mg).? Obtain yellow oily liquid 200mg, yield 94% eventually.
1H NMR (300MHz, CDCl3) δ 1.69 (pent, 2H), 1.84 (pent, 2H), 2.30 (s, 3H), 2.39～2.53 (m, 10H), 3.76 (br, 2H, NH2), 4.01 (t, 2H, J=6.3Hz), 6.67～6.73 (m, 2H), 6.75～6.81 (m, 2H).
Step 4: 1-(1-adamantyl)-3-{2-[4-(4-methylpiperazine-1-yl) butoxy] phenyl } urea (LH-35)
Operating procedure is with the compound L H-23 in example 9 step 4.Substrate and consumption thereof are as follows: the 2-that step 3 obtains [4-(4-methylpiperazine-1-yl) butoxy] aniline (27) (149mg, 0.57mmol) and diamantane (obsolete)-1-isocyanates (130mg, 0.75mmol).Final white powdery solids 172mg, yield 68%.
1H NMR (300MHz, CDCl3) δ 1.66～1.75 (m, 8H), 1.86 (pent, 2H), 2.04 (d, 6H, J= 2.4Hz), 2.09 (s, 3H), 2.30 (s, 3H), 2.43～2.52 (m, 10H), 4.02 (t, 2H, J=6.3Hz), 4.71 (s, 1H, NH), 6.70 (s, 1H, NH), 6.80～6.83 (m, 1H), 6.87～6.92 (m, 2H), 8.00～8.03 (m, 1H)；Mp 120～ 122℃；EI-MS m/z:440 (M+).
Example 22:1-(1-adamantyl)-3-{2-[4-(4-tert-butoxycarbonyl-piperazine-1-base) butoxy] phenyl } urea (LH-37)
Step one: 4-[4-(2-nitro-phenoxy) butyl] piperazine-1-t-butyl formate (28)
Operating procedure is with the compound 9 in example 10 step one.Substrate and consumption thereof are as follows: 1-(4-bromine butoxy)-2- Nitrobenzol (25) (427mg, 1.56mmol) (reference example 21 step one), 1-tert-butoxycarbonyl-piperazine (1) (436mg, 2.34mmol) with triethylamine (237mg, 2.34mmol).Final yellow oily liquid 430mg, yield 73%.
1H NMR (300MHz, CDCl3) δ 1.45 (s, 9H), 1.70 (pent, 2H), 1.87 (pent, 2H), 2.36～2.43 (m, 6H), 3.41 (t, 4H, J=4.8Hz), 4.12 (t, 2H, J=6.3Hz), 7.00～7.07 (m, 2H), 7.47～7.53 (m, 1H), 7.81 (dd, 1H, J=6.6Hz, J=1.5Hz).
Step 2: 4-[4-(2-amino-benzene oxygen) butyl] piperazine-1-t-butyl formate (29)
Operating procedure is with the compound 10 in example 10 step 2.Substrate and consumption thereof are as follows: the 4-[4-that step one obtains (2-nitro-phenoxy) butyl] piperazine-1-t-butyl formate (28) (228mg, 0.60mmol) and 10%Pd/C (10%, 23mg).Final white waxy solid 200mg, yield 95%.
1H NMR (300MHz, CDCl3) δ 1.46 (s, 9H), 1.71 (pent, 2H), 1.87 (pent, 2H), 2.41～2.46 (m, 6H), 3.45 (t, 4H, J=4.2Hz), 3.77 (br, 2H, NH2), 4.01 (t, 2H, J=6.3Hz), 6.67～6.73 (m, 2H), 6.76～6.81 (m, 2H).
Step 3: 1-(1-adamantyl)-3-{2-[4-(4-tert-butoxycarbonyl-piperazine-1-base) butoxy] phenyl } urea (LH-37)
Operating procedure is with the compound L H-25 in example 10 step 3.Substrate and consumption thereof are as follows: step 2 obtains 4-[4-(2-amino-benzene oxygen) butyl] piperazine-1-t-butyl formate (29) (140mg, 0.40mmol) and diamantane (obsolete)-1-isocyanide Acid esters (92mg, 0.52mmol).Final white powdery solids 163mg, yield 77%.
1H NMR (300MHz, CDCl3) δ 1.46 (s, 9H), 1.62～1.95 (m, 10H), 2.04 (s, 6H), 2.09 (s, 3H), 2.50 (br s, 6H), 3.51 (br s, 4H), 4.03 (t, 2H, J=6.3Hz), 4.73 (br s, 1H, NH), 6.71 (br S, 1H, NH), 6.80～6.83 (m, 1H), 6.88～6.93 (m, 2H), 7.99～8.02 (m, 1H)；Mp 84～86 DEG C；EI-MS M/z:526 (M+).
Example 23:1-(1-adamantyl)-3-{2-[4-(piperazine-1-base) butoxy] phenyl } urea (LH-36)
By 1-(1-adamantyl)-3-{2-[4-(4-tert-butoxycarbonyl-piperazine-1-base) butoxy] phenyl } urea (LH-37) (125mg, 0.24mmol) (reference example 22) is dissolved in 15mL dichloromethane.At 0 DEG C, add trifluoroacetic acid (0.5mL).Reaction It is warmed to room temperature, is stirred overnight.Reducing pressure and removed by solvent rotary evaporation, residue is dissolved in 10mL water, uses 5% sodium hydroxide solution Alkalizing solution.Aqueous phase dichloromethane extracts (3 × 20mL).Merge organic facies, after saturated aqueous common salt (2 × 20mL) is washed, anhydrous Sodium sulfate is dried.Reduce pressure and solvent rotary evaporation is removed, final white powdery solids 83mg, yield 81%.
1H NMR (300MHz, CDCl3) δ 1.69 (s, 6H), 1.77 (pent, 2H), 1.88 (pent, 2H), 2.05 (s, 6H), 2.08 (s, 3H), 2.31 (br s, 1H, NH), 2.50～2.58 (m, 6H), 3.00 (t, 4H, J=4.8Hz), 4.03 (t, 2H, J=6.3Hz), 4.92 (br s, 1H, NH), 6.78～6.84 (m, 2H), 6.88～6.93 (m, 2H), 8.01～8.04 (m, 1H)；Mp 147～149 DEG C；EI-MS m/z:426 (M+).
Example 24:1-(1-adamantyl)-3-{2-[4-(4-Acetylpiperazine-1-base) butoxy] phenyl } urea (LH- 38)
By 1-(1-adamantyl)-3-{2-[4-(piperazine-1-base) butoxy] phenyl } urea (LH-36) (55mg, 0.13mmol) (reference example 23) and acetic anhydride (16mg, 0.16mmol) are dissolved in 6mL dichloromethane.Stirring reaction 4 hours. Reducing pressure and removed by solvent rotary evaporation, residue is dissolved in 30mL ether, and after washing (1 × 30mL), anhydrous sodium sulfate is dried.Subtract Press and solvent rotary evaporation is removed, column chromatography purification (dichloromethane: methanol=10: 1), finally give white powdery solids 36mg, yield 59%.
1H NMR (300MHz, CDCl3) δ 1.68～1.74 (m, 8H), 1.87 (m, 2H), 2.02～2.08 (m, 12H), 2.43～2.48 (m, 6H), 3.48 (t, 2H, J=5.1Hz), 3.65 (s, 2H), 4.03 (t, 2H, J=6.3Hz), 4.62 (s, 1H), 6.62 (s, 1H), 6.80～6.83 (m, 1H), 6.89～6.92 (m, 2H), 7.94～7.98 (m, 1H)；Mp 98～100 ℃；EI-MS m/z:468 (M+).
Example 25:1-(1-adamantyl)-3-{3-[4-(4-methylpiperazine-1-yl) butoxy] phenyl } urea (LH-39)
Step one: 1-(4-brombutyl)-3-Nitrobenzol (30)
3-nitrophenol (2.782g, 20mmol) and potassium carbonate (3.317g, 24mmol) are dissolved in 30mL DMF, room temperature After lower stirring 1 hour, add Isosorbide-5-Nitrae-dibromopropane (6.909g, 32mmol).Stirred overnight is reacted, and pours reactant liquor into 200mL In water, extract (3 × 100mL) with dichloromethane.Merge organic facies, with 2% sodium hydroxide (3 × 100mL) and water (2 × 100mL) wash.Organic facies anhydrous sodium sulfate is dried.Reduce pressure and solvent rotary evaporation is removed, column chromatography purification (petroleum ether: acetic acid Ethyl ester=50: 1), finally give pale yellow oily liquid body 5.102g, yield 93%.
1H NMR (300MHz, CDCl3) δ 1.95～2.14 (m, 4H), 3.50 (t, 2H, J=6.3Hz), 4.08 (t, 2H, J =5.7Hz), 7.21 (dd, 1H, J=6.0Hz, J=2.4Hz), 7.42 (t, 1H, J=8.4Hz), 7.80～7.83 (m, 1H).
Step 2: 1-methyl-4-[4-(3-nitro-phenoxy) butyl] piperazine (31)
Operating procedure is with the compound 12 in example 13 step 2.Substrate and consumption thereof are as follows: the 1-(4-that step one obtains Brombutyl)-3-Nitrobenzol (30) (1.008g, 3.68mmol) and 1-methyl piperazine (1.105g, 11.03mmol).Yellowly final Color oily liquids 698mg, yield 65%.
1H NMR (300MHz, CDCl3) δ 1.68 (pent, 2H), 1.84 (pent, 2H), 2.28 (s, 3H), 2.39～2.54 (m, 10H), 4.05 (t, 2H, J=6.3Hz), 7.20 (ddd, 1H, J=4.8Hz, J=1.5Hz, J=0.9Hz), 7.40 (t, 1H, J=8.4Hz), 7.70 (t, 1H, J=2.4Hz), 7.80 (dq, 1H, J=5.1Hz, J=0.9Hz).
Step 3: 1-methyl-4-[4-(3-amino-benzene oxygen) butyl] piperazine (32)
By step 2 obtains 1-methyl-4-[4-(3-nitro-phenoxy) butyl] piperazine (31) (303mg, 1.0mmol) in 10mL methanol, add 10%Pd/C (10% (w/w), 30mg) hydrogenation catalyst.Evacuation, pours into hydrogen, stirs Mix reaction overnight.Filter off Pd/C, reduce pressure and solvent rotary evaporation is removed, obtain pale yellow oily liquid body 254mg, yield 94%.
1H NMR (300MHz, CDCl3) δ 1.65 (pent, 2H), 1.77 (pent, 2H), 2.29 (s, 3H), 2.37～2.48 (m, 10H), 3.63 (br, 2H, NH2), 3.92 (t, 2H, J=6.3Hz), 6.22～6.32 (m, 3H), 7.03 (t, 1H, J= 8.1Hz).
Step 4: 1-(1-adamantyl)-3-{3-[4-(4-methylpiperazine-1-yl) butoxy] phenyl } urea (LH-39)
At 0 DEG C, by step 3 obtains 1-methyl-4-[4-(3-amino-benzene oxygen) butyl] piperazine (32) (243mg, 0.92mmol) being dissolved in 10mL anhydrous methylene chloride, the diamantane (obsolete)-1-being added dropwise over being dissolved in 10mL anhydrous methylene chloride is different Cyanate (164mg, 0.92mmol).Reaction is stirred overnight.Reduce pressure and solvent rotary evaporation is removed, column chromatography purification (dichloromethane Alkane: methanol=10: 1), finally give white powdery solids 240mg, yield 59%.
1H NMR (300MHz, CDCl3) δ 1.59～1.81 (m, 10H), 1.99 (d, 6H, J=3.0Hz), 2.07 (s, 3H), 2.30 (s, 3H), 2.38～2.50 (m, 10H), 3.93 (t, 2H, J=6.3Hz), 4.75 (s, 1H, NH), 6.46 (s, 1H, NH), 6.55 (ddd, 1H, J=4.5Hz, J=1.5Hz, J=0.9Hz), 6.77 (ddd, 1H, J=5.4Hz, J=1.2Hz, J= 0.9Hz), 6.95 (t, 1H, J=2.1Hz), 7.14 (t, 1H, J=8.1Hz)；Mp 115～117 DEG C；EI-MS m/z:440 (M+).
Example 26:1-(1-adamantyl)-3-{3-[4-(4-tert-butoxycarbonyl-piperazine-1-base) butoxy] phenyl } urea (LH-41)
Step one: 4-[4-(3-nitro-phenoxy) butyl] piperazine-1-t-butyl formate (33)
Operating procedure is with the compound 14 in example 14 step one.Substrate and consumption thereof are as follows: 1-(4-bromine butoxy)-3- Nitrobenzol (30) (548mg, 2mmol) (reference example 25 step one), 1-tert-butoxycarbonyl-piperazine (1) (559mg, 3mmol) and Triethylamine (304mg, 3mmol).Final yellow oily liquid 444mg, yield 59%.
1H NMR (300MHz, CDCl3) δ 1.45 (s, 9H), 1.69 (pent, 2H), 1.86 (pent, 2H), 2.38～2.45 (m, 6H), 3.44 (t, 4H, J=5.1Hz), 4.05 (t, 2H, J=6.3Hz), 7.20 (ddd, 1H, J=5.4Hz, J=1.8Hz, J=0.6Hz), 7.41 (t, 1H, J=8.0Hz), 7.70 (t, 1H, J=1.8Hz), 7.80 (ddd, 1H, J=5.1Hz, J= 1.5Hz, J=0.9Hz).
Step 2: 4-[4-(3-amino-benzene oxygen) butyl] piperazine-1-t-butyl formate (34)
Operating procedure is with the compound 15 in example 14 step 2.Substrate and consumption thereof are as follows: the 4-[4-that step one obtains (3-nitro-phenoxy) butyl] piperazine-1-t-butyl formate (33) (444mg, 1.17mmol) and 10%Pd/C (10%, 44mg).Final yellow oily liquid 387mg, yield 95%.
1H NMR (300MHz, CDCl3) δ 1.46 (s, 9H), 1.67 (pent, 2H), 1.75 (pent, 2H), 2.37～2.42 (m, 6H), 3.43 (t, 4H, J=5.1Hz), 3.92 (t, 2H, J=6.3Hz), 6.21～6.31 (m, 3H), 7.02 (t, 1H, J= 8.1Hz).
Step 3: 1-(1-adamantyl)-3-{3-[4-(4-tert-butoxycarbonyl-piperazine-1-base) butoxy] phenyl } urea (LH-41)
Operating procedure is with the compound L H-29 in example 14 step 2.Substrate and consumption thereof are as follows: the 4-that step 2 obtains [4-(3-amino-benzene oxygen) butyl] piperazine-1-t-butyl formate (34) (187mg, 0.54mmol) and diamantane (obsolete)-1-Carbimide. Ester (104mg, 0.59mmol).Final white powdery solids 282mg, yield 99%.
1H NMR (300MHz, CDCl3) δ 1.46 (s, 9H), 1.68～1.78 (m, 10H), 2.01 (s, 6H), 2.08 (s, 3H), 2.56 (br s, 6H), 3.56 (br s, 4H), 3.95 (t, 2H, J=6.3Hz), 4.67 (br s, 1H, NH), 6.39 (br S, 1H, NH), 6.55 (dd, 1H, J=6.0Hz, J=3.0Hz), 6.79 (dd, 1H, J=5.7Hz, J=3.3Hz), 6.95 (t, 1H, J=1.8Hz), 7.14 (t, 1H, J=7.8Hz)；Mp135～137 DEG C；EI-MS m/z:527 (M+).
Example 27:1-(1-adamantyl)-3-{3-[4-(piperazine-1-base) butoxy] phenyl } urea (LH-40)
By 1-(1-adamantyl)-3-{3-[4-(4-tert-butoxycarbonyl-piperazine-1-base) butoxy] phenyl } urea (LH-41) (241mg, 0.46mmol) (reference example 26) is dissolved in 10mL dichloromethane.At 0 DEG C, add trifluoroacetic acid (0.50mL).Instead Should be warmed to room temperature, be stirred overnight.Reducing pressure and removed by solvent rotary evaporation, residue is dissolved in 20mL water, molten with 5% sodium hydroxide Basified solution.Aqueous phase dichloromethane extracts (3 × 15mL).Merge organic facies, after saturated aqueous common salt (3 × 20mL) is washed, nothing Aqueous sodium persulfate is dried.Reduce pressure and solvent rotary evaporation is removed, final white powdery solids 134mg, yield 68%.
1H NMR (300MHz, CDCl3) δ 1.61～1.80 (m, 10H), 2.00 (s, 6H), 2.08 (s, 3H), 2.41～ 2.53 (m, 6H), 2.96 (t, 4H, J=4.5Hz), 3.96 (t, 2H, J=6.3Hz), 4.69 (s, 1H, NH), 6.37 (s, 1H, NH), 6.56 (dd, 1H, J=6.3Hz, J=1.5Hz), 6.79 (dd, 1H, J=6.3Hz, J=1.5Hz), 6.93 (t, 1H, J= 2.1Hz), 7.15 (t, 1H, J=6.6Hz)；Mp94～96 DEG C；EI-MS m/z:426 (M+).
Example 28:1-(1-adamantyl)-3-{3-[4-(4-Acetylpiperazine-1-base) butoxy] phenyl } urea (LH- 42)
By 1-(1-adamantyl)-3-{3-[4-(piperazine-1-base) butoxy] phenyl } urea (LH-40) (37mg, 0.09mmol) (reference example 27) and acetic anhydride (11mg, 0.10mmol) are dissolved in 5mL dichloromethane.Stirring reaction 3 hours. Reducing pressure and removed by solvent rotary evaporation, residue is dissolved in 30mL ether, and after washing (1 × 30mL), anhydrous sodium sulfate is dried.Subtract Press and solvent rotary evaporation is removed, column chromatography purification (dichloromethane: methanol=10: 1), finally give white powdery solids 28mg, yield 69%.
1H NMR (300MHz, CDCl3) δ 1.69 (s, 6H), 2.04～2.11 (m, 14H), 2.75 (m, 4H), 2.87 (t, 2H, J=7.8Hz), 3.63 (t, 2H, J=5.1Hz), 3.99 (t, 2H, J=5.4Hz), 6.22 (s, 1H), 6.72～6.75 (m, 1H), 6.82～6.93 (m, 2H), 7.37 (s, 1H), 8.23～8.26 (m, 1H)；Mp 76～78 DEG C；EI-MS m/z:468 (M+).
Example 29:1-(1-adamantyl)-3-{4-[4-(4-methylpiperazine-1-yl) butoxy] phenyl } urea (LH-43)
Step one: 1-(4-bromopropyl)-4-Nitrobenzol (35)
4-nitrophenol (6.956g, 50mmol) and potassium carbonate (8.293g, 60mmol) are dissolved in 70mL DMF, room temperature After lower stirring 2 hours, add Isosorbide-5-Nitrae-dibromopropane (17.026g, 79mmol).Stirred overnight is reacted, and pours reactant liquor into 300mL In water, extract (3 × 100mL) with dichloromethane.Merge organic facies, with 2% sodium hydroxide (3 × 100mL) and water (2 × 100mL) wash.Organic facies anhydrous sodium sulfate is dried.Reduce pressure and solvent rotary evaporation is removed, column chromatography purification (petroleum ether: acetic acid Ethyl ester=50: 1), finally give yellow, waxy solid 13.204g, yield 96%.
1H NMR (300MHz, CDCl3) δ 1.98～2.10 (m, 4H), 3.49 (t, 2H, J=6.3Hz), 4.09 (t, 2H, J =5.7Hz), 6.92～6.96 (m, 2H), 8.18～8.21 (m, 2H).
Step 2: 1-methyl-4-[4-(4-nitrophenoxy) butyl] piperazine (36)
Operating procedure is with the compound 20 in example 17 step 2.Substrate and consumption thereof are as follows: the 1-(4-that step one obtains Bromopropyl)-4-Nitrobenzol (35) (411mg, 1.5mmol) and 1-methyl piperazine (451mg, 4.5mmol).Final yellow oily Liquid 377mg, yield 86%.
1H NMR (300MHz, CDCl3) δ 1.68 (pent, 2H), 1.86 (pent, 2H), 2.29 (s, 3H), 2.31～2.58 (m, 10H), 4.08 (t, 2H, J=6.3Hz), 6.92～6.97 (m, 2H), 8.17～8.22 (m, 2H).
Step 3: 4-[4-(4-methylpiperazine-1-yl) butoxy] aniline (37)
By step 2 obtains 1-methyl-4-[4-(4-nitrophenoxy) butyl] piperazine (36) (147mg, 0.5mmol) in 20mL methanol, add 10%Pd/C (10% (w/w), 15mg) hydrogenation catalyst.Evacuation, pours into hydrogen, stirs Mix reaction overnight.Filter off Pd/C, reduce pressure and solvent rotary evaporation is removed, obtain pale brown oil liquid 120mg, yield 91%.
1H NMR (300MHz, CDCl3) δ 2.21～2.33 (m, 10H), 2.86 (s, 3H), 2.92～3.09 (m, 10H), 3.90 (br, 2H, NH2), 4.46 (m, 2H), 7.17～7.21 (m, 2H), 7.28～7.31 (m, 2H).
Step 4: 1-(1-adamantyl)-3-{4-[4-(4-methylpiperazine-1-yl) butoxy] phenyl } urea (LH-43)
At 0 DEG C, by step 3 obtains 4-[4-(4-methylpiperazine-1-yl) butoxy] aniline (37) (113mg, 0.43mmol) being dissolved in 10mL anhydrous methylene chloride, the diamantane (obsolete)-1-being added dropwise over being dissolved in 10mL anhydrous methylene chloride is different Cyanate (92mg, 0.52mmol).Reaction is stirred overnight.Reduce pressure and solvent rotary evaporation is removed, column chromatography purification (dichloromethane : methanol=10: 1), finally give white powdery solids 134mg, yield 71%.
1H NMR (300MHz, CDCl3) δ 1.61～1.70 (m, 8H), 1.78 (pent, 2H), 1.96 (d, 6H, J= 2.7Hz), 2.06 (s, 3H), 2.30 (s, 3H), 2.39～2.50 (m, 10H), 3.94 (t, 2H, J=6.3Hz), 4.42 (s, 1H, NH), 5.97 (s, 1H, NH), 6.79～6.85 (m, 2H), 7.11～7.17 (m, 2H)；Mp 118～121 DEG C；EI-MS m/z: 440(M+).
Example 30:1-(1-adamantyl)-3-{4-[4-(4-tert-butoxycarbonyl-piperazine-1-base) butoxy] phenyl } urea (LH-45)
Step one: 4-[4-(3-nitro-phenoxy) butyl] piperazine-1-t-butyl formate (38)
By 1-(4-bromine butoxy)-4-Nitrobenzol (35) (548mg, 2.0mmol) (reference example 29 step one), the tertiary fourth of 1- Oxygen carbonyl piperazine (1) (559mg, 3mmol) and triethylamine (304mg, 3.0mmo1) are dissolved in 30mL oxolane, and nitrogen is protected Under, backflow, it is stirred overnight.Reducing pressure and removed by solvent rotary evaporation, residue is dissolved in saturated sodium bicarbonate, uses dichloromethane Extraction (3 × 50mL).Merging organic facies, after washing with saturated aqueous common salt (1 × 50mL), anhydrous sodium sulfate is dried.Decompression is by solvent Rotary evaporation removes, and column chromatography purification (dichloromethane: methanol=10: 1) finally gives yellow powdery solid 588mg, yield 78%.
1H NMR (300MHz, CDCl3) δ 1.45 (s, 9H), 1.69 (pent, 2H), 1.86 (pent, 2H), 2.38～2.44 (m, 6H), 3.43 (t, 4H, J=5.1Hz), 4.07 (t, 2H, J=6.3Hz), 6.91～6.95 (m, 2H), 8.17～8.22 (m, 2H).
Step 2: 4-[4-(3-amino-benzene oxygen) butyl] piperazine-1-t-butyl formate (39)
By step one obtains 4-[4-(3-nitro-phenoxy) butyl] piperazine-1-t-butyl formate (38) (380mg, 1.0mmol) in 25mL methanol, add 10%Pd/C (10% (w/w), 38mg) hydrogenation catalyst.Evacuation, pours into hydrogen, stirs Mix reaction overnight.Filter off Pd/C, reduce pressure and solvent rotary evaporation is removed, obtain white waxy solid 211mg, yield 60%.
1H NMR (300MHz, CDCl3) δ 1.45 (s, 9H), 1.67 (pent, 2H), 1.74 (pent, 2H), 2.37～2.42 (m, 6H), 3.43 (t, 4H, J=5.1Hz), 3.89 (t, 2H, J=6.0Hz), 6.61～6.64 (m, 2H), 6.72～6.74 (m, 2H).
Step 3: 1-(1-adamantyl)-3-{4-[4-(4-tert-butoxycarbonyl-piperazine-1-base) butoxy] phenyl } urea (LH-45)
At 0 DEG C, 4-[4-(3-amino-benzene oxygen) butyl] piperazine-1-t-butyl formate (39) that will obtain in step 2 (221mg, 0.60mmol) is dissolved in 10mL anhydrous methylene chloride, is added dropwise over being dissolved in the Buddha's warrior attendant of 10mL anhydrous methylene chloride Alkane-1-isocyanates (107mg, 0.60mmol).Reaction is stirred overnight.Reduce pressure and solvent rotary evaporation is removed, column chromatography purification (dichloromethane: methanol=10: 1), finally gives white powdery solids 299mg, yield 95%.
1H NMR (300MHz, CDCl3) δ 1.67 (s, 6H), 1.90～2.00 (m, 8H), 2.07 (s, 3H), 2.31 (s, 3H), 2.51～2.56 (m, 10H), 3.97 (t, 2H, J=6.3Hz), 4.69 (s, 1H, NH), 6.37 (s, 1H, NH), 6.57 (dd, 1H, J=6.0Hz, J=1.8Hz), 6.77 (dd, 1H, J=6.0Hz, J=1.8Hz), 6.97 (t, 1H, J=2.1Hz), 7.15 (t, 1H, J=8.1Hz)；Mp 82～84 DEG C；EI-MSm/z:526 (M+).
Example 31:1-(1-adamantyl)-3-{4-[4-(piperazine-1-base) butoxy] phenyl } urea (LH-44)
By 1-(1-adamantyl)-3-{4-[4-(4-tert-butoxycarbonyl-piperazine-1-base) butoxy] phenyl } urea (LH-45) (150mg, 0.28mmol) (reference example 30) is dissolved in 25mL dichloromethane.At 0 DEG C, add trifluoroacetic acid (0.30mL).Instead Should be warmed to room temperature, be stirred overnight.Reducing pressure and removed by solvent rotary evaporation, residue is dissolved in 10mL water, molten with 5% sodium hydroxide Basified solution.Aqueous phase dichloromethane extracts (3 × 25mL).Merge organic facies, after saturated aqueous common salt (2 × 30mL) is washed, nothing Aqueous sodium persulfate is dried.Reduce pressure and solvent rotary evaporation is removed, final white powdery solids 87mg, yield 72%.
1H NMR (300MHz, CDCl3) δ 1.67 (s, 6H), 1.91～2.08 (m, 11H), 2.43～2.56 (m, 6H), 2.97 (t, 4H, J=4.8Hz), 3.99 (t, 2H, J=6.3Hz), 4.37 (s, 1H, NH), 5.90 (s, 1H, NH), 6.84 (dd, 2H, J=4.5Hz, J=2.1Hz), 7.15 (dd, 2H, J=5.1Hz, J=2.1Hz)；Mp 87～90 DEG C；ESI-MS m/z: 427.4([M+1]+).
Example 32:1-(1-adamantyl)-3-{4-[4-(4-Acetylpiperazine-1-base) butoxy] phenyl } urea (LH- 46)
By 1-(1-adamantyl)-3-{4-[4-(piperazine-1-base) butoxy] phenyl } urea (LH-44) (51mg, 0.12mmol) (reference example 31), acetic anhydride (15mg, 0.14mmol) and triethylamine (0.5mL) are dissolved in dichloromethane (10mL) In.Stirring reaction 4 hours.Reducing pressure and removed by solvent rotary evaporation, residue is dissolved in 30mL ether, after washing (1 × 30mL), Anhydrous sodium sulfate is dried.Reduce pressure and solvent rotary evaporation is removed, column chromatography purification (dichloromethane: methanol=10: 1), final To white powdery solids 51mg, yield 91%.
1H NMR (300MHz, CDCl3) δ 1.67～1.83 (m, 10H), 1.97 (s, 6H), 2.05～2.09 (m, 6H), 2.44～2.48 (m, 6H), 3.49 (s, 2H), 3.64 (s, 2H), 3.93 (t, 2H, J=7.8Hz), 4.40 (s, 1H), 6.03 (s, 1H), 6.81～6.84 (m, 2H), 7.14～7.17 (m, 2H)；Mp 150～152 DEG C；EI-MS m/z:468 (M+).
Example 33:1-(1-adamantyl)-3-{3-[2-(4-methylpiperazine-1-yl) ethyoxyl] phenyl } urea (LH-57)
Step one: 1-(2-bromine oxethyl)-3-Nitrobenzol (40)
3-nitrophenol (2.782g, 20mmol) and potassium carbonate (3.317g, 24mmol) are dissolved in 30mL DMF, room temperature After lower stirring 1 hour, add glycol dibromide (6.012g, 32mmol).Stirred overnight is reacted, and pours reactant liquor into 200mL In water, extract (3 × 100mL) with dichloromethane.Merge organic facies, with 2% sodium hydroxide (3 × 100mL) and water (2 × 100mL) wash.Organic facies anhydrous sodium sulfate is dried.Reduce pressure and solvent rotary evaporation is removed, column chromatography purification (petroleum ether: acetic acid Ethyl ester=50: 1), finally give pale yellow oily liquid body 787mg, yield 16%.
1H NMR (300MHz, CDCl3) δ 3.69 (t, 2H, J=6.0Hz), 4.38 (t, 2H, J=6.0Hz), 7.25～ 7.28 (m, 1H), 7.46 (t, 1H, J=8.4Hz), 7.74 (t, 1H, J=2.4Hz), 7.85～7.88 (m, 1H).
Step 2: 1-methyl-4-[2-(3-nitro-phenoxy) ethyl] piperazine (41)
By 1-(2-the bromine oxethyl)-3-Nitrobenzol (40) (257mg, 1.04mmol) obtained in step one and 1-methyl Piperazine (314mg, 3.13mmol) is dissolved in 25mL oxolane, stirring reaction 12 hours at 60 DEG C.Under negative pressure, rotary evaporation removes Solvent, residue is gone to be dissolved in stirring 20 minutes in 30mL dilute hydrochloric acid (2N).After acid solution ether washes (2 × 30mL), with 2N's Sodium hydroxide solution regulation pH value is to 10～12.Aqueous phase ether extracts (3 × 20mL).Merge organic facies, wash with water (1 × After 30mL), anhydrous sodium sulfate is dried.Reduce pressure and solvent rotary evaporation is removed, the final oily liquids 184mg obtaining yellow, yield 67%.
1H NMR (300MHz, CDCl3) δ 2.28 (s, 3H), 2.46～2.61 (m, 8H), 2.83 (t, 2H, J=5.7Hz), 4.16 (t, 2H, J=6.0Hz), 7.20～7.26 (m, 1H), 7.40 (t, 1H, J=8.1Hz), 7.73 (t, 1H, J=2.4Hz), 7.78～7.82 (m, 1H).
Step 3: 3-[2-(4-methylpiperazine-1-yl) ethyoxyl] aniline (42)
By step 2 obtains 1-methyl-4-[2-(3-nitro-phenoxy) ethyl] piperazine (41) (166mg, 0.63mmol) in 15mL methanol, add 10%Pd/C (10% (w/w), 17mg) hydrogenation catalyst.Evacuation, pours into hydrogen, stirs Mix reaction overnight.Filter off Pd/C, reduce pressure and solvent rotary evaporation is removed, obtain pale brown oil liquid 142mg, yield 96%.
1H NMR (300MHz, CDCl3) δ 2.28 (s, 3H), 2.45～2.48 (m, 8H), 2.77 (t, 2H, J=6.0Hz), 4.05 (t, 2H, J=6.0Hz), 6.22～6.32 (m, 3H), 7.02 (t, 1H, J=8.1Hz).
Step 4: 1-(1-adamantyl)-3-{3-[2-(4-methylpiperazine-1-yl) ethyoxyl] phenyl } urea (LH-57)
At 0 DEG C, by step 3 obtains 3-[2-(4-methylpiperazine-1-yl) ethyoxyl] aniline (42) (125mg, 0.53mmol) being dissolved in 10mL anhydrous methylene chloride, the diamantane (obsolete)-1-being added dropwise over being dissolved in 10mL anhydrous methylene chloride is different Cyanate (103mg, 0.58mmol).Stirring reaction 5 hours.Reduce pressure and solvent rotary evaporation is removed, column chromatography purification (dichloromethane Alkane: methanol=30: 1 → 10: 1), finally give white powdery solids 137mg, yield 63%.
1H NMR (300MHz, CDCl3) δ 1.67～1.68 (m, 6H), 1.99～2.00 (m, 6H), 2.07 (s, 3H), 2.36 (s, 3H), 2.51～2.69 (m, 8H), 2.80 (t, 2H, J=5.7Hz), 4.06 (t, 2H, J=5.7Hz), 4.82 (s, 1H), 6.56 (dd, 1H, J=6.0Hz, J=2.4Hz), 6.61 (s, 1H), 6.582 (dd, 1H, J=6.3Hz, J=1.5Hz), 6.97 (t, 1H, J=2.4Hz), 7.14 (t, 1H, J=8.1Hz)；Mp 94～96 DEG C；EI-MS m/z:412 (M+).
Example 34:1-(1-adamantyl)-3-{3-[2-(4-tert-butoxycarbonyl-piperazine-1-base) ethyoxyl] phenyl } urea (LH-59)
Step one: 4-[2-(3-nitro-phenoxy) ethyl] piperazine-1-t-butyl formate (43)
By 1-(2-bromoethyl)-3-Nitrobenzol (40) (492mg, 2.0mmol) (reference example 33 step one), 1-tertiary fourth oxygen Carbonyl piperazine (1) (559mg, 3.0mmol) and triethylamine (304mg, 3.0mmol) are dissolved in 25mL oxolane, and nitrogen is protected Under, it is stirred overnight reaction at 60 DEG C.Reducing pressure and removed by solvent rotary evaporation, residue is dissolved in saturated sodium bicarbonate, with two Chloromethanes extraction (3 × 50mL).Merging organic facies, after washing with saturated aqueous common salt (1 × 50mL), anhydrous sodium sulfate is dried.Decompression Solvent rotary evaporation is removed, column chromatography purification (dichloromethane: methanol=30: 1), finally gives white waxy solid 274mg, Yield 39%.
1H NMR (300MHz, CDCl3) δ 1.44 (s, 9H), 2.52 (t, 4H, J=5.1Hz), 2.83 (t, 2H, J= 5.7Hz), 3.44 (t, 4H, J=5.1Hz), 4.16 (t, 2H, J=5.4Hz), 7.20～7.25 (m, 1H), 7.41 (t, 1H, J= 8.1Hz), 7.73 (t, 1H, J=2.4Hz), 7.79～7.83 (m, 1H).
Step 2: 4-[2-(3-amino-benzene oxygen) ethyl] piperazine-1-t-butyl formate (44)
By step one obtains 4-[2-(3-nitro-phenoxy) ethyl] piperazine-1-t-butyl formate (43) (254mg, 0.72mmol) in methanol (15mL), add 10%Pd/C (10% (w/w), 26mg) hydrogenation catalyst.Evacuation, pours into hydrogen, Stirring reaction is overnight.Filter off Pd/C, reduce pressure and solvent rotary evaporation is removed, obtain brown oil liquid 232mg, yield 99%.
Step 3: 1-(1-adamantyl)-3-{3-[2-(4-tert-butoxycarbonyl-piperazine-1-base) ethyoxyl] phenyl } urea (LH-59)
At 0 DEG C, 4-[2-(3-amino-benzene oxygen) ethyl] piperazine-1-t-butyl formate (44) that will obtain in step 2 (232mg, 0.72mmol) is dissolved in 7mL anhydrous methylene chloride, after stirring half an hour, is added dropwise over being dissolved in 10mL anhydrous two The diamantane (obsolete)-1-isocyanates (153mg, 0.87mmol) of chloromethanes.Stirring reaction 11 hours, solvent rotary evaporation is removed by decompression Go, column chromatography purification (ethyl acetate: petroleum ether=2: 3 → 3: 1 → ethyl acetate: methanol=50: 1), finally give white powder Powder solid 321mg, yield 89%.
1H NMR (300MHz, CDCl3) δ 1.46 (s, 9H), 1.67 (s, 6H), 2.05 (s, 6H), 2.07 (s, 3H), 2.50 (t, 4H, J=4.8Hz), 2.78 (t, 2H, J=5.4Hz), 3.44 (t, 4H, J=5.4Hz), 4.07 (t, 2H, J=5.4Hz), 4.77 (s, 1H, NH), 6.55～6.58 (m, 2H), 6.73～6.76 (m, 1H), 7.03 (s, 1H), 7.14 (t, 1H, J= 7.8Hz)；Mp 78～80 DEG C；EI-MS m/z:498 (M+).
Example 35:1-(1-adamantyl)-3-{3-[2-(piperazine-1-base) ethyoxyl] phenyl } urea (LH-58)
By 1-(1-adamantyl)-3-{3-[2-(4-tert-butoxycarbonyl-piperazine-1-base) ethyoxyl] phenyl } urea (LH-59) (190mg, 0.38mmol) (reference example 34) is dissolved in 8mL dichloromethane.After stirring 30 minutes at 0 DEG C, add trifluoroacetic acid (0.4mL).Reaction is warmed to room temperature, and is stirred overnight.Reducing pressure and removed by solvent rotary evaporation, residue is dissolved in 10mL water, with 5% Sodium hydroxide solution alkalizing solution.Aqueous phase dichloromethane extracts (3 × 20mL).Merging organic facies, saturated aqueous common salt (2 × After 20mL) washing, anhydrous sodium sulfate is dried.Reduce pressure and solvent rotary evaporation is removed, the final white powdery solids 133mg that obtains, receipts Rate 88%.
1H NMR (300MHz, CD3OD) δ 1.72 (s, 6H), 2.03～2.06 (m, 9H), 2.82～2.89 (m, 6H), 3.21 (t, 4H, J=5.4Hz), 4.11 (t, 2H, J=5.1Hz), 6.50～6.54 (m, 1H), 6.67～6.71 (m, 1H), 7.10 (t, 1H, J=8.1Hz), 7.18 (t, 1H, J=2.1Hz)；Mp 80～82 DEG C；EI-MS m/z:397 ([M-1]+).
Example 36:1-(1-adamantyl)-3-{3-[2-(4-Acetylpiperazine-1-base) ethyoxyl] phenyl } urea (LH- 60)
By 1-(1-adamantyl)-3-{3-[2-(piperazine-1-base) ethyoxyl] phenyl } urea (LH-58) (88mg, 0.22mmol) (reference example 35) and acetic anhydride (34mg, 0.33mmol) are dissolved in 5mL dichloromethane, add 0.5mL DMF and promote Molten.Stirring reaction 3 hours.Reduce pressure and solvent rotary evaporation is removed, residue adds water (30mL), molten with 2% sodium hydroxide Liquid regulation pH value is to 9～10.Dichloromethane extraction (3 × 30mL).Merging organic facies, anhydrous sodium sulfate is dried.Decompression is by solvent Rotary evaporation removes, and column chromatography purification (dichloromethane → dichloromethane: methanol=20: 1) finally gives white powdery solids 78mg, yield 80%.
1H NMR (300MHz, CDCl3) δ 1.66 (s, 6H), 2.00 (s, 6H), 2.07～2.09 (m, 6H), 2.51～2.58 (m, 4H), 2.79 (t, 2H, J=2.4Hz), 3.47 (t, 2H, J=4.8Hz), 3.63 (t, 2H, J=5.7Hz), 4.08 (t, 2H, J=5.4Hz), 4.75 (s, 1H), 6.54 (s, 1H), 6.56～6.57 (m, 1H), 6.72～6.75 (m, lH), 7.07～7.09 (m, lH), 7.14 (t, 1H, J=7.8Hz)；Mp 73～75 DEG C；EI-MS m/z:440 (M+).
Example 37:1-(1-adamantyl)-3-{3-[5-(4-methylpiperazine-1-yl) amoxy] phenyl } urea (LH-61)
Step one: 1-(5-bromine amoxy)-3-Nitrobenzol (45)
3-nitrophenol (2.782g, 20mmol) and potassium carbonate (3.317g, 24mmol) are dissolved in 30mL DMF, room temperature After lower stirring 1 hour, add pentamethylene bromide (7.358g, 32mmol).Stirred overnight is reacted, and pours reactant liquor into 200mL In water, extract (3 × 100mL) with dichloromethane.Merge organic facies, with 2% sodium hydroxide (3 × 100mL) and water (2 × 100mL) wash.Organic facies anhydrous sodium sulfate is dried.Reduce pressure and solvent rotary evaporation is removed, column chromatography purification (petroleum ether: acetic acid Ethyl ester=5: 1), finally give pale yellow oily liquid body 5.421g, yield 94%.
1H NMR (300MHz, CDCl3) δ 1.60～1.71 (m, 2H), 1.82～2.05 (m, 4H), 3.46 (t, 2H, J= 6.6Hz), 4.05 (t, 2H, J=6.3Hz), 7.20～7.24 (m, 1H), 7.42 (t, 1H, J=8.4Hz), 7.71 (t, 1H, J= 2.1Hz), 7.80～7.83 (m, 1H).
Step 2: 1-methyl-4-[5-(3-nitro-phenoxy) amyl group] piperazine (46)
By 1-(5-bromine the amoxy)-3-Nitrobenzol (45) (864mg, 3.0mmol) obtained in step one and 1-methyl piperazine Piperazine (901mg, 9.0mmol) is dissolved in 30mL oxolane, and at 60 DEG C, stirring reaction is overnight.Under negative pressure, rotary evaporation removes molten Agent, residue is dissolved in stirring 20 minutes in 60mL dilute hydrochloric acid (2N).After acid solution ether washes (2 × 30mL), with the hydrogen of 10% Sodium hydroxide solution regulation pH value is to 10～12.Aqueous phase ether extracts (3 × 30mL).Merge organic facies, wash (1 × 30mL) with water After, anhydrous sodium sulfate is dried.Reduce pressure and solvent rotary evaporation is removed, the final oily liquids 422mg obtaining yellow, yield 46%.
1H NMR (300MHz, CDCl3) δ 1.43～1.57 (m, 4H), 1.76～1.83 (m, 2H), 2.25 (s, 3H), 2.31 ～2.43 (m, 10H), 3.99 (t, 2H, J=5.7Hz), 7.15～7.19 (m, 1H), 7.37 (t, 1H, J=8.1Hz), 7.67 (t, 1H, J=2.1Hz), 7.74～7.78 (m, 1H).
Step 3: 1-methyl-4-[5-(3-amino-benzene oxygen) amyl group] piperazine (47)
By step 2 obtains 1-methyl-4-[5-(3-nitro-phenoxy) amyl group] piperazine (46) (154mg, 0.5mmol) in 10mL methanol, add 10%Pd/C (10% (w/w), 15mg) hydrogenation catalyst.Evacuation, pours into hydrogen, stirs Mix reaction 15 hours.Filter off Pd/C, reduce pressure and solvent rotary evaporation is removed, obtain pale brown oil liquid 133mg, yield 96%.Directly carry out next step reaction.
Step 4: 1-(1-adamantyl)-3-{3-[5-(4-methylpiperazine-1-yl) amoxy] phenyl } urea (LH-61)
At 0 DEG C, by step 3 obtains 1-methyl-4-[5-(3-amino-benzene oxygen) amyl group] piperazine (47) (133mg, 0.48mmol) being dissolved in 10mL anhydrous methylene chloride, the diamantane (obsolete)-1-being added dropwise over being dissolved in 10mL anhydrous methylene chloride is different Cyanate (93mg, 0.53mmol).Stirring reaction 5 hours.Reduce pressure and solvent rotary evaporation is removed, column chromatography purification (dichloromethane Alkane → dichloromethane: methanol=30: 1 → 20: 1 → 10: 1), finally give white powdery solids 143mg, yield 66%.
1H NMR (300MHz, CDCl3) δ 1.45～1.58 (m, 4H), 1.67 (s, 6H), 1.74～1.79 (m, 2H), 1.97 ～2.07 (m, 11H), 2.29 (s, 3H), 2.34～2.56 (m, 10H), 3.92 (t, 2H, J=6.3Hz), 4.67 (s, 1H), 4.67 (s, 1H), 6.34 (s, 1H), 6.55～6.57 (m, 1H), 6.77 (dd, 1H, J=6.9Hz, J=2.1Hz), 6.93 (t, 1H, J=2.1Hz), 7.14 (t, 1H, J=8.1Hz)；Mp134～137 DEG C；EI-MS m/z:454 (M+).
Example 38:1-(1-adamantyl)-3-{3-[5-(4-tert-butoxycarbonyl-piperazine-1-base) amoxy] phenyl } urea (LH-63)
Step one: 4-[5-(3-nitro-phenoxy) amyl group] piperazine-1-t-butyl formate (48)
By 1-(5-bromine amoxy)-3-Nitrobenzol (45) (1.153g, 4.0mmol) (reference example 37 step one), uncle 1- Butoxy carbonyl piperazine (1) (1.118g, 6.0mmol) and triethylamine (0.84mL, 6.0mmol) are dissolved in 30mL oxolane, nitrogen Under gas shielded, at 60 DEG C, it is stirred overnight reaction.Reducing pressure and removed by solvent rotary evaporation, residue is dissolved in saturated sodium bicarbonate In, extract (3 × 50mL) with dichloromethane.Merging organic facies, after washing with saturated aqueous common salt (1 × 50mL), anhydrous sodium sulfate is done Dry.Reduce pressure and solvent rotary evaporation is removed, column chromatography purification (dichloromethane: methanol=20: 1), finally give yellow oily liquid Body 544mg, yield 35%.
1H NMR (300MHz, CDCl3) δ 1.46 (s, 9H), 1.49～1.59 (m, 4H), 2.35～2.40 (m, 6H), 3.44 (t, 4H, J=5.1Hz), 4.04 (t, 2H, J=6.6Hz), 7.19～7.22 (m, 1H), 7.42 (t, 1H, J=8.1Hz), 7.71 (t, 1H, J=2.1Hz), 7.79～7.83 (m, 1H).
Step 2: 4-[5-(3-amino-benzene oxygen) amyl group] piperazine-1-t-butyl formate (49)
By step one obtains 4-[5-(3-nitro-phenoxy) amyl group] piperazine-1-t-butyl formate (48) (258mg, 0.66mmol) in methanol (15mL), add 10%Pd/C (10% (w/w), 25mg) hydrogenation catalyst.Evacuation, pours into hydrogen, Stirring reaction is overnight.Filter off Pd/C, reduce pressure and solvent rotary evaporation is removed, obtain light brown oily liquids 204mg, yield 86%.Directly carry out next step reaction.
Step 3: 1-(1-adamantyl)-3-{3-[5-(4-tert-butoxycarbonyl-piperazine-1-base) amoxy] phenyl } urea (LH-63)
At 0 DEG C, 4-[5-(3-amino-benzene oxygen) amyl group] piperazine-1-t-butyl formate (49) that will obtain in step 2 (204mg, 0.56mmol) is dissolved in 5mL anhydrous methylene chloride, after stirring half an hour, is added dropwise over being dissolved in 10mL anhydrous two The diamantane (obsolete)-1-isocyanates (109mg, 0.62mmol) of chloromethanes.Stirring reaction 14 hours, solvent rotary evaporation is removed by decompression Go, column chromatography purification (dichloromethane → dichloromethane: methanol=50: 1 → 20: 1), finally give white powdery solids 177mg, yield 58%.
1H NMR (300MHz, CDCl3) δ 1.45 (s, 9H), 1.48～1.56 (m, 4H), 1.70 (s, 6H), 1.72～1.81 (m, 2H), 2.00 (s, 6H), 2.07 (s, 3H), 2.32～2.39 (m, 6H), 3.43 (t, 4H, J=4.8Hz), 3.92 (t, 2H, J =6.6Hz), 4.62 (s, 1H), 6.24 (s, 1H), 6.56 (dd, 1H, J=6.6Hz, J=1.8Hz), 6.73 (dd, 1H, J= 6.6Hz, J=1.8Hz), 6.95 (t, 1H, J=1.8Hz), 7.14 (t, 1H, J=8.1Hz)；Mp 72～74 DEG C；ESI-MS m/ Z:541.3 ([M+1]+).
Example 39:1-(1-adamantyl)-3-{3-[5-(piperazine-1-base) amoxy] phenyl } urea (LH-62)
By 1-(1-adamantyl)-3-{3-[5-(4-tert-butoxycarbonyl-piperazine-1-base) amoxy] phenyl } urea (LH-63) (152mg, 0.28mmol) (reference example 38) is dissolved in 6mL dichloromethane.After stirring 30 minutes at 0 DEG C, add trifluoroacetic acid (0.3mL).Reaction is warmed to room temperature, and is stirred overnight.Reducing pressure and removed by solvent rotary evaporation, residue is dissolved in 10mL water, with 5% Sodium hydroxide solution alkalizing solution.Aqueous phase dichloromethane extracts (3 × 20mL).Merging organic facies, saturated aqueous common salt (2 × After 20mL) washing, anhydrous sodium sulfate is dried.Reduce pressure and solvent rotary evaporation is removed, column chromatography purification (dichloromethane: methanol=10: 1 → 5: 1), white powdery solids 116mg, yield 94% are finally given.
1H NMR (300MHz, CDCl3) δ 1.43～1.61 (m, 4H), 1.66～1.68 (m, 6H), 1.72～1.81 (m, 2H), 2.00～2.03 (m, 9H), 2.41 (t, 2H, J=6.9Hz), 2.55～2.58 (m, 4H), 3.01 (t, 4H, J= 4.8Hz), 3.94 (t, 2H, J=6.3Hz), 4.85 (s, 1H), 6.52～6.57 (m, 1H), 6.64 (s, 1H), 6.84～6.88 (m, 1H), 6.91 (t, 1H, J=2.1Hz), 7.15 (t, 1H, J=7.8Hz)；Mp 82～84 DEG C；ESI-MS m/z:441.4 ([M+1]+).
Example 40:1-(1-adamantyl)-3-{3-[5-(4-Acetylpiperazine-1-base) amoxy] phenyl } urea (LH- 64)
By 1-(1-adamantyl)-3-{3-[5-(piperazine-1-base) amoxy] phenyl } urea (LH-62) (63mg, 0.14mmol) (reference example 39) and acetic anhydride (22mg, 0.21mmol) are dissolved in 5mL dichloromethane.Stirring reaction 3 hours. Reduce pressure and solvent rotary evaporation is removed, residue adds water (30mL), washes (2 × 30mL) with semi-saturation sodium bicarbonate solution. Merging organic facies, anhydrous sodium sulfate is dried.Reduce pressure and solvent rotary evaporation is removed, column chromatography purification (dichloromethane → dichloromethane Alkane: methanol=20: 1), finally give white powdery solids 54mg, yield 78%.
1H NMR (300MHz, CDCl3) δ 1.46～1.55 (m, 4H), 1.75 (s, 6H), 1.75～1.79 (m, 2H), 1.99 ～2.00 (m, 6H), 2.05～2.09 (m, 6H), 2.34～2.45 (m, 6H), 3.47 (t, 2H, J=5.4Hz), 3.60 (t, 2H, J=5.1Hz), 3.93 (t, 2H, J=6.0Hz), 4.70 (s, 1H), 6.55 (tt, 1H, J1=6.3Hz, J2=1.5Hz), 7.30 (tt, 1H, J1=2.1Hz, J2=1.8Hz), 7.00 (t, 1H, J=2.1Hz), 7.14 (t, 2H, J=8.1Hz)；Mp 136～ 138℃；EI-MS m/z:482 (M+).
Example 41:4-{4-{3-[3-(1-adamantyl) urea groups] phenoxy group } bytyry } piperazine-1-t-butyl formate (LH-65)
Step one: 4-(3-nitro-phenoxy) tert-butyl acetate (50)
3-nitrophenol (209mg, 1.50mmol) and potassium carbonate (270mg, 1.95mmol) are dissolved in 10mL DMF, After stirring 1 hour under room temperature, add 4-iodine tert-butyl acetate (338mg, 1.25mmol).Stirring reaction 10 hours, by reactant liquor Pour in 100mL water, extract (3 × 50mL) with dichloromethane.Merge organic facies, with 2% sodium hydroxide (3 × 50mL) and water (2 × 50mL) wash.Organic facies anhydrous sodium sulfate is dried.Reduce pressure and solvent rotary evaporation is removed, column chromatography purification (petroleum ether: second Acetoacetic ester=25: 1), finally give colourless transparent oil liquid 266mg, yield 76%.
1H NMR (300MHz, CDCl3) δ 1.45 (s, 9H), 2.10 (pent, 2H), 2.44 (t, 2H, J=7.5Hz), 4.07 (t, 2H, J=7.2Hz), 7.19～7.23 (m, 1H), 7.41 (td, 1H, J1=8.1Hz, J2=0.9Hz), 7.71 (d, 1H, J= 1.2Hz), 7.81 (dd, 1H, J1=8.1Hz, J2=2.4Hz).
Step 2: 4-(3-nitro-phenoxy) butanoic acid (51)
4-(3-nitro-phenoxy) tert-butyl acetate (50) (248mg, 0.88mmol) step one obtained is dissolved in 10mL In dichloromethane.After stirring 30 minutes at 0 DEG C, add trifluoroacetic acid (2mL).Reaction is warmed to room temperature, stirring reaction 2 hours.Subtract Press and solvent rotary evaporation is removed, be directly used in next step reaction.
Step 3: 4-[4-(3-nitro-phenoxy) bytyry] piperazine-1-t-butyl formate (52)
4-(3-nitro-phenoxy) butanoic acid (51) (148mg, 0.66mmol) that step 2 is obtained, EDCI (127mg, 0.66mmol) it is dissolved in dry dichloromethane (15mL) with HOAt (90mg, 0.66mmol), after stirring 30 minutes at 0 DEG C, adds Enter 1-tert-butoxycarbonyl-piperazine (1) (135mg, 0.72mmol).Reaction is warmed to room temperature, and adds DIPEA (0.13mL).Stirring is anti- Answer 5 hours, extract (3 × 30mL) with dichloromethane.Merge organic facies, with saturated sodium bicarbonate (2 × 30mL) and saturated common salt Water (1 × 30mL) is washed, and anhydrous sodium sulfate is dried.Reduce pressure and solvent rotary evaporation is removed, column chromatography purification (dichloromethane: methanol =10: 1), white powdery solids 237mg, yield 91% are finally given.
1H NMR(CDCl3): δ 1.47 (s, 9H), 2.19 (t, 2H, J=6.6Hz), 2.55 (t, 2H, J=7.2Hz), 3.40 ～3.45 (m, 6H), 3.61 (t, 2H, J=4.5Hz), 4.12 (t, 2H, J=6.0Hz), 7.20～7.24 (m, 1H), 7.42 (t, 1H, J=8.1Hz), 7.23 (t, 1H, J=2.1Hz), 7.79～7.83 (m, 1H).
Step 4: 4-[4-(3-amino-benzene oxygen) bytyry] piperazine-1-t-butyl formate (53)
By step 3 obtains 4-[4-(3-nitro-phenoxy) bytyry] piperazine-1-t-butyl formate (52) (93mg, 0.25mmol) in methanol (10mL), add 10%Pd/C (10% (w/w), 10mg) hydrogenation catalyst.Evacuation, pours into hydrogen, Stirring reaction is overnight.Filter off Pd/C, reduce pressure and solvent rotary evaporation is removed, obtain white powdery solids 174mg, yield 97%.It is directly used in next step reaction.
Step 5: 4-{4-{3-[3-(1-adamantyl) urea groups] phenoxy group } bytyry } piperazine-1-t-butyl formate (LH-65)
At 0 DEG C, 4-[4-(3-amino-benzene oxygen) bytyry] piperazine-1-t-butyl formate (53) that will obtain in step 4 (91mg, 0.25mmol) is dissolved in 5mL anhydrous methylene chloride, after stirring half an hour, is added dropwise over being dissolved in 10mL anhydrous two The diamantane (obsolete)-1-isocyanates (49mg, 0.275mmol) of chloromethanes.Being stirred overnight reaction, solvent rotary evaporation is removed by decompression Go, column chromatography purification (dichloromethane: methanol=30: 1), finally give white powdery solids 118mg, yield 87%.
1H NMR (300MHz, CDCl3) δ 1.47 (s, 9H), 1.68 (s, 6H), 2.08 (s, 6H), 2.10～2.13 (m, 5H), 2.52 (t, 2H, J=7.5Hz), 3.40～3.44 (m, 6H), 3.58～3.61 (m, 2H), 3.99 (t, 2H, J= 5.7Hz), 4.63 (s, 1H), 6.32 (s, 1H), 6.55 (dd, 1H, J1=8.1Hz, J2=2.1Hz), 6.75 (dd, 1H, J1= 8.1Hz, J2=1.2Hz), 6.99 (s, 1H), 7.14 (t, 1H, J=7.8Hz)；Mp 100～104 DEG C；EI-MS m/z:450 (M+).
Example 42:1-(1-adamantyl)-3-{3-[4-oxo-4-(piperazine-1-base) butoxy] phenyl } urea (LH-66)
By 4-{4-{3-[3-(1-adamantyl) urea groups] phenoxy group } bytyry } piperazine-1-t-butyl formate (LH-65) (81mg, 0.15mmol) (reference example 41) is dissolved in 5mL dichloromethane.At 0 DEG C, add trifluoroacetic acid (0.2mL).Reaction rises To room temperature, stirring reaction 10 hours.Reducing pressure and removed by solvent rotary evaporation, residue is dissolved in 20mL water, uses 5% sodium hydroxide Basified solution.Aqueous phase dichloromethane extracts (3 × 15mL).Merge organic facies, after saturated aqueous common salt (3 × 20mL) is washed, Anhydrous sodium sulfate is dried.Reduce pressure and solvent rotary evaporation is removed, final white powdery solids 58mg, yield 88%.
1H NMR (300MHz, CDCl3) δ 1.68 (s, 6H), 1.99～2.00 (m, 6H), 2.09～2.16 (m, 5H), 2.51 (t, 2H, J=6.6Hz), 2.83 (t, 4H, J=5.4Hz), 3.46 (t, 2H, J=5.1Hz), 3.60 (t, 2H, J=4.2Hz), 4.01 (t, 2H, J=6.0Hz), 4.53 (s, 1H), 6.16 (s, 1H), 6.56～6.59 (m, 1H), 6.73～6.77 (m, 1H), 6.97 (t, 1H, J=2.1Hz), 7.15 (t, 1H, J=8.1Hz)；Mp 78～80 DEG C；ESI-MS m/z:441.4 ([M+1]+).
Example 43:1-{3-[4-(4-Acetylpiperazine-1-base)-4-oxa-butoxy] phenyl }-3-(1-adamantyl) Urea (LH-67)
By 1-(1-adamantyl)-3-{3-[4-oxo-4-(piperazine-1-base) butoxy] phenyl } urea (LH-66) (30mg, 0.07mmol) (reference example 42), acetic anhydride (8mg, 0.08mmol) and triethylamine (12 μ L) are dissolved in 5mL dichloromethane In.Stirring reaction 2 hours.Reducing pressure and removed by solvent rotary evaporation, residue is dissolved in 30mL dichloromethane, washing (1 × After 30mL), anhydrous sodium sulfate is dried.Reduce pressure and solvent rotary evaporation is removed, column chromatography purification (dichloromethane: methanol=30: 1), white powdery solids 28mg, yield 85% are finally given.
1H NMR (300MHz, CDCl3) δ 1.67～1.69 (m, 6H), 1.99～2.00 (m, 6H), 2.08～2.16 (m, 8H), 2.53 (t, 2H, J=6.9Hz), 3.42～3.49 (m, 4H), 3.61～3.67 (m, 4H), 4.00 (t, 2H, J= 5.4Hz), 4.57 (s, 1H), 6.26 (s, 1H), 6.55 (d, 1H, J=8.4Hz), 6.72 (t, 1H, J=8.4Hz), 7.00 (s, 1H), 7.14 (t, 1H, J=7.8Hz)；Mp 90～92 DEG C；EI-MS m/z:482 (M+).
Example 44:4-{3-{3-[3-(1-adamantyl) urea groups] phenoxy group } propyl group } piperazine-1-methyl formate (LH-29)
By 1-(1-adamantyl)-3-{3-[3-(piperazine-1-base) propoxyl group] phenyl } urea (LH-28) (15mg, 0.04mmol) (reference example 15), methylchloroformate (3.3 μ L, 0.04mmol) and triethylamine (10.1 μ L, 0.07mmol) are dissolved in In 5mL dichloromethane.Stirring reaction 10 hours.Reduce pressure and solvent rotary evaporation is removed, residue adds water (30mL), dichloro Methane extraction (3 × 10mL).Merging organic facies, anhydrous sodium sulfate is dried.Reduce pressure and solvent rotary evaporation is removed, column chromatography purification (dichloromethane → dichloromethane: methanol=20: 1), finally gives white powdery solids 13mg, yield 76%.
1H NMR (300MHz, CDCl3) δ 1.67 (s, 6H), 1.75～2.07 (m, 11H), 2.41～2.53 (m, 6H), 3.48 (br s, 4H), 3.70 (s, 3H), 3.98 (t, 2H, J=6.0Hz), 4.74 (s, 1H), 6.48 (s, 1H), 6.55 (d, 1H, J=9.9Hz), 6.71 (d, 1H, J=7.5Hz), 7.03～7.04 (m, 1H), 7.13 (t, 1H, J=6.0Hz)；Mp 158～ 163℃；EI-MS m/z:470 (M+).
Example 45:4-{3-{2-[3-(1-adamantyl) urea groups] phenoxy group } propyl group } piperazine-1-methyl formate (LH-71)
By 1-(1-adamantyl)-3-{2-[3-(piperazine-1-base) propoxyl group] phenyl } urea (LH-24) (21mg, 0.05mmol) (reference example 11), methylchloroformate (4.7 μ L, 0.06mmol) and triethylamine (14.2 μ L, 0.10mmol) are dissolved in In 5mL dichloromethane.Stirring reaction 10 hours.Reduce pressure and solvent rotary evaporation is removed, residue adds water (30mL), dichloro Methane extraction (3 × 10mL).Merging organic facies, anhydrous sodium sulfate is dried.Reduce pressure and solvent rotary evaporation is removed, column chromatography purification (dichloromethane: methanol=20: 1), finally gives white powdery solids 21mg, yield 88%.
1H NMR (300MHz, CDCl3) δ 1.68 (s, 6H), 1.97～2.08 (m, 11H), 2.41～2.44 (m, 4H), 2.52 (t, 2H, J=6.9Hz), 3.50 (br s, 4H), 3.70 (s, 3H), 4.05 (t, 2H, J=6.0Hz), 4.77 (s, 1H), 6.78～6.84 (m, 2H), 6.89～6.92 (m, 1H), 6.89～6.92 (m, 1H), 8.00 (t, 1H, J=4.8Hz)；Mp 118 ～121 DEG C；EI-MS m/z:470 (M+).
Example 46:1-(1-adamantyl)-3-{3-[4-(4-p-toluenesulfonyl piperazine-1-base) butoxy] phenyl } urea (LH-72)
By 1-(1-adamantyl)-3-{3-[4-(piperazine-1-base) butoxy] phenyl } urea (LH-40) (22mg, 0.05mmol) (reference example 27), paratoluensulfonyl chloride (11mg, 0.06mmol) are dissolved in 5mL dichloromethane.Stirring reaction 3 Hour.After washing (2 × 20mL) with semi-saturation sodium bicarbonate, anhydrous sodium sulfate is dried.Reduce pressure and solvent rotary evaporation is removed, post layer Analysis purification (petroleum ether: ethyl acetate=5: 1 → dichloromethane: methanol=20: 1), finally gives white powdery solids 21mg, Yield 87%.
1H NMR (300MHz, CDCl3) δ 1.20～1.25 (m, 4H), 1.53～1.72 (m, 10H), 1.97 (s, 6H), 2.05 (s, 3H), 2.36 (t, 2H, J=8.1Hz), 2.42 (s, 3H), 2.50～2.51 (m, 4H), 3.00 (br s, 4H), 3.88 (t, 2H, J=7.5Hz), 6.50 (d, 1H, J=8.4Hz), 6.69 (d, 1H, J=8.1Hz), 7.00 (d, 1H, J=8.1Hz), 7.06～7.13 (m, 1H), 7.31 (d, 2H, J=7.8Hz), 7.62 (d, 2H, J=8.1Hz)；Mp 86～89 DEG C；ESI-MS M/z:581.5 ([M+1]+).
Example 47:1-(1-adamantyl)-3-{3-[4-(4-Nmethanesulphonylpiperazine-1-base) butoxy] phenyl } urea (LH- 73)
By 1-(1-adamantyl)-3-{3-[4-(piperazine-1-base) butoxy] phenyl } urea (LH-40) (22mg, 0.05mmol) (reference example 27), mesyl chloride (4.3 μ L, 0.06mmol) are dissolved in 5mL dichloromethane.Stirring reaction 3 is little Time.After washing (2 × 20mL) with semi-saturation sodium bicarbonate, anhydrous sodium sulfate is dried.Reduce pressure and solvent rotary evaporation is removed, column chromatography Purification (petroleum ether: ethyl acetate=5: 1 → dichloromethane: methanol=20: 1), finally gives white powdery solids 21mg, receives Rate 87%.
1H NMR (300MHz, CDCl3) δ 1.60～1.66 (m, 10H), 1.98 (s, 6H), 2.06 (s, 3H), 2.42 (t, 2H, J=6.9Hz), 2.53 (t, 4H, J=4.5Hz), 2.77 (s, 3H), 3.22 (t, 4H, J=4.5Hz), 3.94 (t, 2H, J= 6.0Hz), 4.82 (s, 1H), 6.53 (d, 1H, J=8.1Hz), 6.63 (s, 1H), 6.69 (d, 1H, J=8.1Hz), 7.07～ 7.14 (m, 2H)；Mp 63～65 DEG C；EI-MS m/z:504 (M+).
Example 48:1-(1-adamantyl)-3-{3-{4-[4-(3,4,5-trimethoxybenzoy) piperazine-1-base] fourth Epoxide } phenyl } urea (LH-74)
By 1-(1-adamantyl)-3-{3-[4-(piperazine-1-base) butoxy] phenyl } urea (LH-40) (43mg, 0.10mmol) (reference example 27) and 3,4,5-trimethoxybenzoic acids (25mg, 0.12mmol) are dissolved in 5mL dichloromethane. Add HOAt (18mg, 0.13mmol) and DIPEA (23 μ L, 0.13mmol), after stirring 10 minutes, addition EDCI (25mg, 0.13mmol).React 10 hours.Organic facies saturated sodium bicarbonate (2 × 20mL) and saturated aqueous common salt (1 × 20mL).Organic It is dried with anhydrous sodium sulfate.Column chromatography purification (dichloromethane: methanol=20: 1), finally gives white powdery solids 43mg, yield 69%.
1H NMR (300MHz, CDCl3) δ 1.62～1.82 (m, 10H), 1.99 (s, 6H), 2.07 (s, 3H), 2.39～ 2.50 (m, 6H), 3.47～3.75 (m, 4H), 3.85～3.86 (m, 9H), 3.96 (t, 2H, J=6.0Hz), 4.58 (s, 1H), 6.23 (s, 1H), 6.55 (dd, 1H, J=5.7Hz, J=2.1Hz), 6.62 (s, 2H), 6.69 (dd, 1H, J=8.1Hz, J= 0.9Hz), 7.02 (s, 1H), 7.14 (t, 1H, J=5.4Hz).
Example 49:1-(1-adamantyl)-3-{3-{4-[4-(4-TRIFLUOROMETHYLBENZOYL) piperazine-1-base] fourth oxygen Base } phenyl } urea (LH-75)
Operating procedure is with example 48.Substrate and consumption thereof are as follows: 1-(the 1-adamantyl)-3-{3-[4-that example 27 obtains (piperazine-1-base) butoxy] phenyl urea (LH-40) (43mg, 0.10mmol), 4-(Trifluoromethyl)benzoic acid. (23mg, 0.12mmol), HOAt (18mg, 0.13mmol), DIPEA (23 μ L, 0.13mmol) and EDCI (25mg, 0.13mmol).Finally Obtain white powdery solids 36mg, yield 60%.
1H NMR (300MHz, CDCl3) δ 1.68～1.82 (m, 10H), 1.99 (m, 6H), 2.08 (s, 3H), 2.38～ 2.54 (m, 6H), 3.38 (br s, 2H), 3.80 (br s, 2H), 3.97 (t, 2H, J=5.7Hz), 4.47 (s, 1H), 6.04 (s, 1H), 6.55～6.59 (m, 1H), 6.67～6.70 (m, 1H), 7.01 (t, 1H, J=2.4Hz), 7.15 (t, 1H, J= 8.7Hz), 7.52 (d, 2H, J=8.4Hz), 7.68 (d, 2H, J=8.1Hz).
Example 50:1-(1-adamantyl)-3-{3-{4-[4-(2-chloracetyl) piperazine-1-base] butoxy } phenyl } urea (LH-76)
Operating procedure is with example 47.Substrate and consumption thereof are as follows: 1-(the 1-adamantyl)-3-{3-[4-that example 27 obtains (piperazine-1-base) butoxy] phenyl } urea (LH-40) (43mg, 0.10mmol) and chloracetyl chloride (14mg, 0.12mmol).Finally Obtain white powdery solids 37mg, yield 74%.
1H NMR (300MHz, CDCl3) δ 1.65～1.82 (m, 10H), 1.99～2.00 (m, 6H), 2.05～2.08 (m, 3H), 2.40～2.51 (m, 6H), 3.52 (t, 2H, J=4.8Hz), 3.64 (t, 2H, J=4.8Hz), 3.96 (t, 2H, J= 6.0Hz), 4.07 (s, 1H), 6.19 (s, 1H), 6.71 (dd, 1H, J=6.0 Hz, J=2.1Hz), 6.71 (d, 1H, J= 8.1Hz), 7.02 (s, 1H), 7.15 (t, 1H, J=8.1Hz)；Mp 196～200 DEG C.
Example 51:1-(1-adamantyl)-3-{3-[4-(4-trifluoroacetyl group) piperazine-1-base] butoxy } phenyl } urea (LH-81)
Operating procedure is with example 28.Substrate and consumption thereof are as follows: 1-(the 1-adamantyl)-3-{3-[4-that example 27 obtains (piperazine-1-base) butoxy] phenyl } urea (LH-40) (43mg, 0.10mmol) and trifluoroacetic anhydride (25mg, 0.12mmol).? Obtain white powdery solids 26mg, yield 50% eventually.
1H NMR (300MHz, CDCl3) δ 1.61～1.71 (m, 10H), 1.99～2.00 (m, 6H), 2.08 (s, 3H), 2.43 (t, 2H, J=7.2Hz), 2.50 (t, 4H, J=5.1Hz), 3.60 (t, 2H, J=4.5Hz), 3.69 (t, 2H, J= 6.0Hz), 3.97 (t, 2H, J=6.0Hz), 4.50 (s, 1H), 6.13 (s, 1H), 6.56～6.59 (m, 1H), 6.68 (d, 1H, J =9.3Hz), 7.03 (m, 1H), 7.15 (t, 1H, J=8.1Hz)；EI-MS m/z:522 (M+).
Example 52:4-{4-{3-[2-(1-adamantyl) acetylamino] phenoxy group } butyl } piperazine-1-t-butyl formate (LH-90)
By diamantane (obsolete)-1-guanidine-acetic acid (189mg, 0.97mmol), HOBt (132mg, 0.97mmol), EDCI (187mg, 0.97mmol) it is dissolved in 10mL dichloromethane with triethylamine (0.14mL, 0.97mmol).After stirring 10 minutes, add and be dissolved in two 4-[4-(3-amino-benzene oxygen) butyl] piperazine-1-t-butyl formate (34) (324mg, the 0.93mmol) (ginseng of chloromethanes (5mL) Examine example 26 step 2).React 10 hours.Organic facies saturated ammonium chloride (2 × 15mL), saturated sodium bicarbonate (2 × 15mL) Wash with saturated aqueous common salt (1 × 20mL).Organic facies anhydrous sodium sulfate is dried.Column chromatography purification (dichloromethane: methanol=50: 1), white powdery solids 70mg, yield 14% are finally given.
1H NMR(CDCl3): δ 1.46 (s, 9H), 1.74～1.82 (m, 16H), 1.99 (br s, 3H), 2.08 (s, 2H), 2.38～2.42 (m, 6H), 3.43 (t, 4H, J=5.1Hz), 3.98 (t, 2H, J=6.3Hz), 6.63 (d, 1H, J=8.4Hz), 6.89 (d, 1H, J=6.6Hz), 7.01 (s, 1H), 7.18 (t, 1H, J=9.0Hz), 7.35 (s, 1H)；Mp 54～57 DEG C；EI- MS m/z:525 (M+).
Example 53:N-(3-(4-(4-Acetylpiperazine-1-base) butoxy) phenyl)-2-(1-adamantyl) acetamide (LH-91)
Step one: 2-(1-adamantyl)-N-(3-(4-(piperazine-1-base) butoxy) phenyl) acetamide (54)
By 4-{4-{3-[2-(1-adamantyl) acetylamino] phenoxy group } butyl } piperazine-1-t-butyl formate (LH- 90) (40mg, 0.08mmol) (reference example 52) is dissolved in 5mL dichloromethane.After stirring half an hour at 0 DEG C, add trifluoro second Acid (0.15mL).Reaction is warmed to room temperature, stirring reaction 10 hours.Reducing pressure and removed by solvent rotary evaporation, residue is dissolved in 10mL In water, with 5% sodium hydroxide solution alkalizing solution.Aqueous phase dichloromethane extracts (3 × 25mL).Merge organic facies, saturated food After saline (2 × 30mL) is washed, anhydrous sodium sulfate is dried.Reduce pressure and solvent rotary evaporation is removed, finally give pale yellow oily liquid Body 27mg, yield 83%.
Step 2: N-(3-(4-(4-Acetylpiperazine-1-base) butoxy) phenyl)-2-(1-adamantyl) acetamide (LH-91)
2-(1-adamantyl)-N-(3-(4-(piperazine-1-base) butoxy) phenyl) acetamide that step one is obtained (54) during (8mg, 0.019mmol) is dissolved in 5mL dichloromethane, add 1 triethylamine, after stirring 10 minutes, add acetic anhydride (2 μ L, 0.021mmol).Stirring reaction 2 hours.Reduce pressure and solvent rotary evaporation is removed, column chromatography purification (dichloromethane: methanol= 30: 1), thick white shape liquid 6mg, yield 68% are finally given.
1H NMR (300MHz, CDCl3) δ 1.62～1.85 (br s, 16H), 1.99 (br s, 3H), 2.08～2.11 (m, 5H), 2.39～2.46 (m, 6H), 3.45～3.48 (m, 2H), 3.60～3.64 (m, 2H), 3.99 (t, 2H, J=6.0Hz), 6.63 (dd, 1H, J1=5.7Hz, J2=2.7Hz) 6.86 (d, 1H, J=8.7Hz), 7.03 (s, 1H), 7.18 (t, 1H, J= 8.1Hz), 7.39 (s, 1H)；EI-MS m/z:467 (M+).
Example 54:N-(3-(4-(4-Nmethanesulphonylpiperazine-1-base) butoxy) phenyl)-2-(1-adamantyl) acetamide (LH-92)
By 2-(1-adamantyl)-N-(3-(4-(piperazine-1-base) butoxy) phenyl) acetamide (54) (16mg, 0.038mmol) (reference example 53 step one) is dissolved in 5mL dichloromethane, adds 1 triethylamine, adds after stirring 10 minutes Mesyl chloride (3.3 μ L, 0.041mmol).Stirring reaction 3 hours.Reduce pressure and solvent rotary evaporation is removed, column chromatography purification (two Chloromethanes → dichloromethane: methanol=50: 1 → dichloromethane: methanol=40: 1 → dichloromethane: methanol=30: 1), finally Obtain yellow powdery solid 17mg, yield 90%.
1H NMR (300MHz, CDCl3) δ 1.68～1.82 (m, 16H), 1.99 (br s, 3H), 2.08 (s, 2H), 2.46 (m, 2H), 2.54～2.58 (m, 4H), 2.77 (s, 3H), 3.23～3.26 (m, 4H), 3.99 (t, 2H, J=5.7Hz), 6.63 (dd, 1H, J1=6.3Hz, J2=1.8Hz), 6.84 (dd, 1H, J1=5.4Hz, J2=2.1Hz), 7.00 (s, 1H), 7.18 (t, 1H, J=8.4Hz), 7.41 (t, 1H, J=2.4Hz)；EI-MS m/z:503 (M+).
Example 55:4-{4-{4-[(3-tert-butyl group urea groups) methyl] piperidines-1-yl}-4-oxobutanoyl } piperazine-1-first Tert-butyl acrylate (LH-54)
Step one: 4-{4-[(3-tert-butyl group urea groups) methyl] piperidin-1-yl }-4-ketobutyric acid (55)
By 1-(1-adamantyl)-3-(piperidin-4-ylmethyl) urea hydrochlorate (164mg, 0.5mmol) and triethylamine (0.5mL) it is dissolved in 5mL dichloromethane.Add succinic anhydride (75mg, 0.75mmol).Stirring reaction is overnight.Organic facies 2N Hydrochloric acid (2 × 10mL) and water (1 × 10mL) are washed.Anhydrous sodium sulfate is dried, and reduces pressure and is removed by solvent rotary evaporation, obtains white powder Shape solid 160mg, yield 82%.
1H NMR (300MHz, DMSO-d6) δ 0.81～0.89 (m, 2H), 1.58～1.63 (m, 9H), 1.76 (s, 6H), 1.97 (s, 3H), 2.40～2.45 (m, 5H), 2.81 (d, 2H, J=6.0Hz), 2.89～2.97 (m, 1H), 3.82～3.87 (m, 1H), 4.30～4.34 (m, 1H), 5.72 (s, 1H).
Step 2: 4-{4-{4-[(3-tert-butyl group urea groups) methyl] piperidines-1-yl}-4-oxobutanoyl } piperazine-1-first Tert-butyl acrylate (LH-54)
Under ice bath, 4-{4-[(the 3-tert-butyl group urea groups) methyl] piperidin-1-yl that step one is obtained }-4-ketobutyric acid (55) (78mg, 0.20mmol) and DIPEA (0.5mL) are dissolved in 5mL dichloromethane.After stirring 10 minutes, add HOBt (32mg, 0.24mmol) and 1-tert-butoxycarbonyl-piperazine (1) (45mg, 0.24mmol).After stirring 20 minutes, add EDCI (46mg, 0.24mmol).It is stirred overnight reaction.Organic facies saturated ammonium chloride (2 × 20mL), saturated sodium bicarbonate (2 × 20mL) with saturated aqueous common salt (1 × 20mL).Organic facies anhydrous sodium sulfate is dried.Column chromatography purification (dichloromethane: methanol= 10: 1), white powdery solids 106mg, yield 95% are finally given.
1H NMR (300MHz, DMSO-d6) δ 1.06～1.21 (m, 2H), 1.46 (s, 9H), 1.66～1.77 (m, 9H), 1.95 (s, 6H), 2.06 (s, 3H), 2.54 (t, 1H, J=12.6Hz), 2.93～3.10 (m, 2H), 3.40～3.59 (m, 8H), 3.92～3.97 (m, 8H), 4.55～4.60 (m, 1H)；EI-MS m/z:559 (M+).
The example 56:1-tert-butyl group-3-{{1-[4-oxo-4-(piperazine-1-base) bytyry] piperidin-4-yl } methyl } urea (LH-53)
By 4-{4-{4-[(3-tert-butyl group urea groups) methyl] piperidin-1-yl }-4-oxobutanoyl } the tertiary fourth of piperazine-1-formic acid Ester (LH-54) (80mg, 0.14mmol) (reference example 55) is dissolved in 15mL dichloromethane.At 0 DEG C, add trifluoroacetic acid (0.15mL).Reaction is warmed to room temperature, and is stirred overnight.Reducing pressure and removed by solvent rotary evaporation, residue is dissolved in 10mL water, uses 5% sodium hydroxide solution alkalizing solution.Aqueous phase dichloromethane extracts (3 × 25mL).Merging organic facies, saturated aqueous common salt (2 × After 30mL) washing, anhydrous sodium sulfate is dried.Reduce pressure and solvent rotary evaporation is removed, column chromatography purification (dichloromethane: methanol=10: 1), white powdery solids 33mg, yield 50% are finally given.
1H NMR (300MHz, CDCl3) δ 1.06～1.22 (m, 2H), 1.56～1.78 (m, 11H), 1.94 (m, 6H), 2.06 (s, 3H), 2.14～2.25 (m, 4H), 2.50～2.60 (m, 1H), 2.66～2.68 (m, 2H), 2.95～3.05 (m, 5H), 3.61～3.71 (m, 3H), 3.94～3.97 (m, 1H), 4.27 (s, 1H), 4.49～4.58 (m, 1H).
The example 57:1-tert-butyl group-3-{{1-[4-oxo-4-(4-Acetylpiperazine-1-base) bytyry] piperidin-4-yl } Methyl } urea (LH-55)
By the 1-tert-butyl group-3-{{1-[4-oxo-4-(piperazine-1-base) bytyry] piperidin-4-yl } methyl } urea (LH-53) (24mg, 0.05mmol) (reference example 56), acetic anhydride (8mg, 0.08mmol) and triethylamine (8 μ L) are dissolved in dichloromethane (5mL) in.It is stirred overnight reaction.Reducing pressure and removed by solvent rotary evaporation, residue is dissolved in 30mL ether, washing (1 × After 30mL), anhydrous sodium sulfate is dried.Reduce pressure and solvent rotary evaporation is removed, column chromatography purification (dichloromethane: methanol=10: 1), white powdery solids 9mg, yield 35% are finally given.
1H NMR (300MHz, CDCl3) δ 1.07～1.22 (m, 2H), 1.65～1.67 (m, 9H), 1.94～1.95 (m, 6H), 2.03～2.08 (m, 3H), 2.11 (s, 3H), 2.51～2.59 (m, 1H), 2.68 (s, 4H), 2.95～3.05 (m, 3H), 3.43～3.66 (m, 8H), 3.92～3.97 (m, 1H), 4.55～4.60 (m, 1H).
Example 58:4-{3-{5-[3-(1-adamantyl) urea groups] quinoline-8-yl oxo } propyl group } the tertiary fourth of piperazine-1-formic acid Ester (LH-68)
Step one: 8-(3-bromine propoxyl group)-5-nitroquinoline (56)
5-nitroquinoline-8-alcohol (911mg, 5mmol) and potassium carbonate (1.037g, 7.5mmol) are dissolved in 30mL acetonitrile, After stirring 2 hours under room temperature, add 1,3-dibromopropane (5.047g, 25mmol).At 80 DEG C, stirred overnight is reacted, will reaction Liquid is poured in 100mL water, extracts (3 × 50mL) with dichloromethane.Merge organic facies, with 2% sodium hydroxide (3 × 50mL) and water (2 × 50mL) washes.Organic facies anhydrous sodium sulfate is dried.Reduce pressure and solvent rotary evaporation is removed, column chromatography purification (dichloromethane : methanol=30: 1), finally give pale yellow powder shape solid 432mg, yield 28%.
1H NMR (300MHz, CDCl3) δ 2.57 (pent, 2H), 3.69 (t, 2H, J=6.3Hz), 4.48 (t, 2H, J= 6.3Hz), 7.11 (d, 1H, J=9.0Hz), 7.67 (q, 1H), 8.50 (d, 1H, J=9.0Hz), 9.01 (dd, 1H, J= 2.7Hz, J=1.5Hz), 9.19 (dd, 1H, J=7.2Hz, J=1.5Hz).
Step 2: 4-(3-(5-nitroquinoline-8-base oxo) propyl group) piperazine-1-t-butyl formate (57)
8-(3-bromine propoxyl group)-5-nitroquinoline (56) (300mg, 0.96mmol) that step one is obtained, 1-tertiary fourth oxygen Carbonyl piperazine (1) (359mg, 1.93mmol) and triethylamine (195mg, 1.93mmol) are dissolved in 15mL oxolane, and nitrogen is protected Protect down, backflow, stirring reaction 16 hours.Reducing pressure and removed by solvent rotary evaporation, residue is dissolved in saturated sodium bicarbonate, uses Dichloromethane extraction (3 × 50mL).Merging organic facies, after washing with saturated aqueous common salt (1 × 50mL), anhydrous sodium sulfate is dried.Subtract Press and solvent rotary evaporation is removed, column chromatography purification (dichloromethane: methanol=10: 1), finally give yellow powdery solid 272mg, yield 68%.
1H NMR (300MHz, CDCl3) δ 1.39 (s, 9H), 2.23 (pent, 2H), 2.40 (br s, 4H), 2.58 (t, 2H, J=6.6Hz), 3.41 (br s, 4H), 4.42 (t, 2H, J=6.6Hz), 7.10 (d, 1H, J=9.0Hz), 7.64～7.68 (m, 1H), 8.49 (d, 1H, J=9.0Hz), 9.00～9.01 (m, 1H), 9.19 (d, 1H, J=9.0Hz).
Step 3: 4-(3-(5-quinolin-2-ylamine-8-base oxo) propyl group) piperazine-1-t-butyl formate (58)
4-(3-(5-nitroquinoline-8-base oxo) propyl group) piperazine-1-t-butyl formate (57) that will obtain in step 2 In (83mg, 0.2mmol) 10mL methanol, add 10%Pd/C (10% (w/w), 17mg) hydrogenation catalyst.Evacuation, pours into hydrogen Gas, stirring reaction is overnight.Filter off Pd/C, reduce pressure and solvent rotary evaporation is removed, be directly used in next step reaction.
Step 4: 4-{3-{5-[3-(1-adamantyl) urea groups] quinoline-8-yl oxo } propyl group } the tertiary fourth of piperazine-1-formic acid Ester (LH-68)
4-(3-(5-quinolin-2-ylamine-8-base oxo) propyl group) piperazine-1-t-butyl formate (58) that will obtain in step 3 It is dissolved in 5mL anhydrous methylene chloride, is added dropwise over being dissolved in the diamantane (obsolete)-1-isocyanates of 10mL anhydrous methylene chloride (39mg, 0.22mmol).Stirring reaction 6 hours.Reduce pressure and solvent rotary evaporation is removed, column chromatography purification (dichloromethane: methanol =30: 1 → 10: 1), khaki pulverulent solids 62mg, yield 55% are finally given.
1H NMR (300MHz, CDCl3) δ 1.46 (s, 9H), 1.62 (s, 6H), 1.87～1.88 (m, 6H), 2.02 (s, 3H), 2.16 (pent, 2H), 2.44 (t, 4H, J=4.5Hz), 2.62 (t, 2H, J=6.9Hz), 3.44 (t, 4H, J= 4.5Hz), 4.22 (s, 1H), 4.33 (t, 2H, J=6.9Hz), 6.03 (s, 1H), 7.05 (d, 1H, J=6.9Hz), 7.43 (d, 1H, J=8.1Hz), 7.50 (q, 1H), 8.37 (dd, 1H, J=6.9Hz, J=1.8Hz), 8.98 (dd, 1H, J=2.4Hz, J= 1.8Hz).
Example 59:1-{8-[3-(4-Acetylpiperazine-1-base) propoxyl group] quinoline-5-base }-3-(1-adamantyl) urea (LH-69)
Step one: 1-(1-adamantyl)-3-(8-(3-(piperazine-1-base) propoxyl group) quinoline-5-base) urea (59)
By 4-{3-{5-[3-(1-adamantyl) urea groups] quinoline-8-yl oxo } propyl group } piperazine-1-t-butyl formate (LH-68) (50mg, 0.089mmol) (reference example 58) is dissolved in 5mL dichloromethane.At 0 DEG C, add trifluoroacetic acid (0.1mL).Stirring reaction 3 hours.Reducing pressure and removed by solvent rotary evaporation, residue is dissolved in 10mL water, uses 5% sodium hydroxide Basified solution.Aqueous phase dichloromethane extracts (3 × 15mL).Merge organic facies, after saturated aqueous common salt (2 × 20mL) is washed, Anhydrous sodium sulfate is dried.Reduce pressure and solvent rotary evaporation is removed, final white powdery solids, it is directly used in next step anti- Should.
Step 2: 1-{8-[3-(4-Acetylpiperazine-1-base) propoxyl group] quinoline-5-base }-3-(1-adamantyl) urea (LH-69)
1-(1-adamantyl)-3-(8-(3-(piperazine-1-base) propoxyl group) quinoline-5-base) urea that step one is obtained (59), acetic anhydride (11mg, 0.11mmo1) and triethylamine (11mg, 0.11mmo1) are dissolved in dichloromethane (5mL).Stirring reaction 6 hours.Reducing pressure and removed by solvent rotary evaporation, residue is dissolved in 30mL ether, after washing (1 × 30mL), and anhydrous sodium sulfate It is dried.Reduce pressure and solvent rotary evaporation is removed, column chromatography purification (dichloromethane: methanol=10: 1), finally give white powder Shape solid 15mg, yield 33%.
1H NMR (300MHz, CDCl3) δ 1.62 (s, 6H), 1.90 (s, 6H), 2.02 (s, 3H), 2.08 (s, 3H), 2.22 (pent, 2H), 2.53～2.57 (m, 4H), 2.70 (t, 2H, J=6.9Hz), 3.50～3.52 (m, 2H), 3.64～3.66 (m, 2H), 4.29 (t, 2H, J=6.3Hz), 4.63 (s, 1H), 6.59 (s, 1H), 7.01 (d, 1H, J=8.4Hz), 7.40～7.48 (m, 2H), 8.39 (d, 1H, J=8.4Hz), 8.90～8.91 (m, 1H).
Active testing embodiment 1
Recombinant human soluble epoxide hydrolase is obtained by baculovirus expression system.Purification uses affinity chromatography, purity More than 97%.IC50The test following method of employing of value:
The method of test inhibitory activity is to be tested by high flux based on fluorescence.By molten for the dimethyl sulfoxide of inhibitor 10mM The BisTris-hydrochloric acid buffer solution (25mM, pH=7.0 comprise the BSA of 0.1mg/mL) that liquid is increased with 10 times amount continuously (buffer solution A) dilutes.In 96 orifice plates of a black, in each hole, add inhibitor solution or the buffer of 20 μ L dilutions, Add 130 μ L, concentration about 0.4 μ g/mL in the most each hole, be dissolved in the human soluble epoxide hydrolase of buffer solution A. Mix homogeneously, at room temperature preculture is after 5 minutes, adds 50 μ L, concentration is 200 μMs, is dissolved in buffer solution A: dimethyl sulfoxide Substrate ((3-benzyl ring epoxide) acetic acid-cyano group (6-methoxynaphthalene-2-base) methyl ester, PHOME) in the solution of=96: 4, finally Make [S]Finally=50 μMs, [E]Finally([S] refers to that the concentration of substrate (PHOME), [E] refer to the dense of human soluble epoxide hydrolase to ≈ 4nM Degree).After mix homogeneously, preculture 90 minutes under room temperature (25 DEG C) in darkroom.The test of activity is the 6-formed by detection The relative quantity of methoxy-2-naphthaldehyde obtains, and the excitation wavelength of its 316nm and the transmitting wavelength of 460nm are by SpectraMax M- 2 exometer detections.
Table 1: each compound activity and fusing point row
These ureas containing piperazine structure or amides compound to the inhibitory activity of epoxide hydrolase all at nanomole Rank, most 503nhibiting concentration IC50All below 10 nanomoles, and fusing point is generally below the 1 of document report, 3-bis- Substituted urea class epoxide hydrolase inhibitor (Kim, I.-H.；Morisseau, C.；Watanabe, T.；Hammock, B.D.Design, synthesis, and biological activity of1,3-disubstituted ureas as potent inhibitors of the soluble epoxide hydrolase ofincreased water Solubility.J.Med.Chem.2004,47,2110-2122.), there is potent activity and the thing of good suitable formulations Rationality matter.The existence of piperazine structure can increase polarity and the water solublity of molecule, thus reduces the fusing point of compound.
In these ureas containing piperazine structure or amides compound, we choose 11 compounds therein and test its water Dissolubility, and determine the drug metabolism parameter in the mouse body of wherein 6 compounds the most representational, data are as follows:
Table 2
Wherein AUDA isIt it is the generation of document report Table ureas epoxide hydrolase inhibitor, is incorporated by reference herein compound.(Kim, I.-H.；Tsai, H.-J.；Nishi, K.； Kasagami, T.；Morisseau, C.；Hammock, B.D.1,3-Disubstitutedureas functionalized with ether groups are potent inhibitors of the soluble epoxidehydrolase with Improved pharmacokinetic properties.J.Med.Chem.2007,50,5217-5226.).According in table Data, the compound of the present invention has a higher water solublity than AUDA, longer half-life (internal more stable) and higher Area AUC under drug-time curve.AUC represents that a medicine has quantity in vivo and how long stops, and it with medicine is System absorbs and metabolism, elimination are relevant.AUC is the biggest, shows that the dynamic metabolism character of this medicine is the best.
The compound of the present invention is by further functionalization to obtain higher activity, and introduced piperazine structure is obvious Improve water solublity, thus effectively improve the oral bioavailability of the epoxide hydrolase inhibitor prepared by this compound Degree.
Those skilled in the art it will be seen that examples detailed above is only exemplary, and the present invention does not constitute any restriction, Any modifications and variations without departing from the essence of the present invention are the most within the scope of the present invention.

Claims (6)

1. a piperazine substituted 1,3-2-substituted carbamide compounds and the substituted amides compound of piperazine or its pharmaceutically may be used The salt accepted, it is characterised in that: described compound is in following compound:
2. a piperazine according to claim 1 substituted 1,3-2-substituted carbamide compounds and the substituted amide-type of piperazine Compound or the preparation method of its pharmaceutically acceptable salt, said method comprising the steps of:
1) simultaneous with the compound (iv) of nitro and hydroxyl in DMF, under the effect of potassium carbonate or sodium carbonate, with α, ω- Saturated dihalide or alpha-halogen-ω acid or alpha-halogen-ω esterReaction, obtains halides or carboxylic acid or carboxylate (ix), its In, q is the integer of 1 to 4；
2) piperazine (i) of halides (ix) and single Boc protection refluxes in oxolane and obtains compound (x), or carboxylic acid or Carboxylate (ix) obtains compound (x) with the piperazine (i) of single Boc protection under coupling reagent activates；
3) with 10% Pd/C as catalyst, hydrogenolysis nitro in methanol or ethanol, make compound (x) be reduced into corresponding amino Compound (xi)；
4) amino-compound (xi) obtains corresponding 1,3-bis-with 1-adamantyl isocyanate or 1-adamantyl acetic acidreaction Substituted ureas or amides compound (xii)；
5) remove the Boc blocking group in compound (xii) with trifluoroacetic acid or HCl, obtain 4 chemical combination exposed for N on piperazine Thing (xiii)；
6) compound (xiii) is in DMF, at K2CO3Or Na2CO3Effect under, react with halides RX and obtain 4 N on piperazine The compound (g) being replaced, wherein the X in RX is fluorine, chlorine, bromine or iodine；
7) compound (xiii) is in dichloromethane, under the effect of organic base, with chloride compoundsOr anhydrideIt is condensed to yield the compound (h) that on piperazine, 4 N are acylated；
Or, in dichloromethane, under conditions of organic base, condensing agent and activator exist, it is condensed to yield piperazine with acid RCOOH The compound (h) that on piperazine, 4 N are acylated；
8) compound (xiii) is in dichloromethane, under the effect of organic base, with sulfonyl chloride compoundReaction obtains piperazine On piperazine, 4-position N is by the compound (i) of sulfonylation；
Wherein, the definition of A and R corresponds to corresponding linking group or substituent group, the structure of compound in claim 1ForOr direct singly-bound；At α, ω-saturated dihalide or alpha-halogen-ω acid or alpha-halogen-ω esterIn, X is halogen, X' is halogen, hydroxyl or C1-C6Alkoxyl；The definition of Y corresponds to the corresponding linking group of compound in claim 1, described Halogen is fluorine, chlorine, bromine or iodine；
The described organic base used in each step is triethylamine, diisopropyl ethyl amine, morpholine or N-methylmorpholine；Described contracting Mixture is that 1-ethyl-(3-dimethylaminopropyl) carbodiimide, N, N'-carbonyl dimidazoles or N, N'-dicyclohexyl carbon two are sub- Amine, described activator is 1-hydroxyl-BTA or 1-hydroxyl-7-azo BTA.
3. a pharmaceutical composition, it is characterised in that described pharmaceutical composition comprise as active component according to claim 1 Described piperazine substituted 1,3-2-substituted carbamide compounds and the substituted amides compound of piperazine or it is pharmaceutically acceptable Salt.
Piperazine the most according to claim 1 substituted 1,3-2-substituted carbamide compounds and piperazine substituted amide-type chemical combination Thing or its pharmaceutically acceptable salt purposes in preparation solubility epoxide hydrolase inhibitor.
Piperazine the most according to claim 1 substituted 1,3-2-substituted carbamide compounds and piperazine substituted amide-type chemical combination Thing or its pharmaceutically acceptable salt preparation treatment hypertension, vascular inflammation, obstructive pulmonary disease, interstitial lung disease, asthma or Purposes in the medicine of nephropathy.
Purposes the most according to claim 5, it is characterised in that described obstructive pulmonary disease is chronic obstructive pulmonary disease, emphysema Or bronchitis；Interstitial lung disease is idiopathic fibrosis or occupational pneumoconiosis.
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