CN101636397B - Urea compounds, preparation methods and pharmaceutical uses thereof - Google Patents

Urea compounds, preparation methods and pharmaceutical uses thereof Download PDF

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CN101636397B
CN101636397B CN2008800089963A CN200880008996A CN101636397B CN 101636397 B CN101636397 B CN 101636397B CN 2008800089963 A CN2008800089963 A CN 2008800089963A CN 200880008996 A CN200880008996 A CN 200880008996A CN 101636397 B CN101636397 B CN 101636397B
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chromenyl
urea
pyrazolyl
tertiary butyl
oxyethyl group
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CN101636397A (en
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李松
周新明
钟武
郑志兵
肖军海
***
刘洪英
谢云德
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Institute of Pharmacology and Toxicology of AMMS
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    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
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    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Abstract

The urea compounds of formula I, pharmaceutically acceptable salts and solvates, their preparation methods, the pharmaceutical compositions comprising the said compounds and the uses as p38 kinase inhibitors thereof. The substituents are defined as the description.

Description

Carbamide compounds, its preparation method and medicinal use thereof
Technical field
The present invention relates to suppress the carbamide compounds of p38 protein kinase, contain their pharmaceutical composition, prepare the method for these compounds and their medicinal use.
Background technology
TNF becomes the core participant with IL-1 in many chronic inflammatory diseasess pathologic process relevant with autoimmune disorder.IL-1 relates to mediation or worsens disease, and (referring to, Arend, W.P.Arthritis&Rheumatism 38 (2): 151-160 like rheumatoid arthritis; (1995)), osteo-arthritis, bone resorption, toxic shock syndrome; White plaque, atherosclerosis, mellitus, Hokdkin disease; (referring to, Benharroch .Euro.Cytokine Network such as D. 7 (1): 51-57) and alzheimer's disease.Have been found that excessively or the TNF of imbalance production is participated in mediation or worsened disease, as rheumatoid arthritis ((referring to, Maini, APMIS.105 such as R.N. (4): 257-263, (1997); Feldmann, M., J.of the Royal College of Physicians ofLondon 30 (6): 560-570, (1996); Lorenz, J.ofImmunology such as H.M. 156 (4): 1646-1653, (1996)), osteo-arthritis, spondylitis; Sepsis, septic shock ((referring to, Abraham, E waits JAMA.277 (19): 1531-1538; (1997), adult respiratory distress syndrome, asthma ((referring to, Shah .Clin.& Exp.Allergy 1038-1044 such as A.; (1995) and Lassalle, Clin.& Exp.Allergy such as P. 94 (1): 105-110, (1993)), bone absorpting disease; Pyreticosis ((referring to, Cooper, Am.J.of Physiology 267 (6Pt.2) such as A.L.: 1431-1436)), encephalomyelitis; Demyelinization (referring to, Klindert, J.of Neuroimmunol.72 (2): 163-168 such as W.E., (1997)) and periodontal.
The clinical trial of IL-1 and TNF receptor antagonist shows, blocks these cytokines and can in human body, obviously improve inflammatory diseases through the ability that its acceptor sends signal.So the regulation and control of these inflammatory cytokine are considered to a kind of strategy of the most effectively blocking chronic inflammatory diseases and having the positive treatment effect.
Silk splits plain activated protein kinase (mitogen-activated proteinkinase; MAPK) cascade is a main signal transduction system in the cell; The extracellular stimulus signal arrives nucleus through this systems communicate, and then causes the cell growth, grows; Division, a series of physiology and pathologic processes such as cytokine secretion and vicious transformation.
Most of protein kinases are in inactive state in the cell, when specific upper reaches kinase signal activates, cause this kinases generation Serine (seriene, S), Threonine (threonine, T) or tyrosine (tyrosine, Y) residue phosphorylation and activating.Different with other protein kinase; All MAPK family members' activation all needs Threonine and tyrosine residues dibit point phosphorylation are accomplished; MAPK dibit point phosphorylation group has the sequence signature (referring to Seger R, Krebs EG.TheMAPK singaling cascade.FASEB J.19959:726-735) of Thr-Xaa-Tyr (T-X-Y).The activation of MAPK and phosphorylation have passed through to comprise the cascade reaction of the multistage kinases in the upper reaches; Comprising three grades of crucial kinases: MAPK, mapk kinase (MAPK kinase, MAPKK or MEK/MKK); The mapk kinase kinases (MAPK kinase kinase, MAPKKK).MAPKKK is to the Serine of MAPKK, Threonine dibit point phosphorylation and with its activation; Activatory MAPKK further carries out Serine to MAPK, Threonine dibit point phosphorylation and with its activation.(referring to Boulton T.G., Nye S.H. .Cell 1991 such as Bobbins D.J., 65:663:675).
Mammalian cell MAPK family comprises four subfamilies at least, i.e. ERK (extracelluar regulated protein kinase), JNK (c-JunN-terminal kinase), p38, ERK5.Different subfamilies are mainly distinguished through the kinase whose difference of the Xaa between the bis phosphoric acid site and/or the upper reaches.
Han equals at first in the post-stimulatory pre B cell of intracellular toxin LPS (LPS), to find and cloned in 1993 the MAPK of a kind of 38kDa.P38MAPK bis phosphoric acid site is positioned at the 180th site and the 182nd 's tyrosine and Threonine.The specificity bis phosphoric acid group of p38MAPK is Thr-Gly-Tyr.Oneself finds four p38MAPK hypotypes so far: p38 α, p38 β, p38 γ, p3 δ.Between four kinds of isomer 60% homology is arranged approximately, the homology of 40-45% is then arranged approximately with other type MAPKs, all have in the structure of four kinds of p38 one contain TGY tripeptides module the ring-type active site, be the specificity bis phosphoric acid site of upper reaches molecule.P38 α, p38 β extensively exist in human body, and p38 γ mainly is present in the Skelettmuskel, and p3 δ mainly is distributed in lung, kidney, and testis is in pancreas and the small intestine.The p38 of different subtype distributes different in different cells.Non-activated p38 is arranged in endochylema, and activatory p38 all can express at endochylema and karyon.
Lee is through finding as the independent of target molecule of one type of new anti-inflammatory agent the p38 kinases; The definite evidence 5 [Lee etc. that cause the signal conducting path that the pro-inflammatory cytokine biosynthesizing produces that provide that the p38 kinases participates in that LPS one excites; Nature, 372,739 (1994)].The discovery of p38 (Lee is with its called after CSBP1 and 2) provides the mechanism of action of one type of anti-inflammatory compound, and wherein SK&F 86002 is prototype instances.These compounds suppress IL-1 and the synthetic [Lee etc. of TNF among the person monocytic cell in low μ M concentration range; Int.J.Immunopharmac.10 (7); 835 (1988)] and in animal model, show activity, these animal models have resistance [Lee etc., Annals N.Y.Acad.Sci. to cyclooxygenase inhibitors; 696,10149 (1993)].Be sure of now CSBP/p38 be participate in stress response signal conducting path one of several kinds of kinases its be parallel to and be independent of similar silk to a great extent and split plain activated protein kinase cascade.The stress response signal comprises LPS, pro-inflammatory cytokine, and oxygenant, UV line and osmotic pressure begin to activate upper reaches kinases by CSBP/p38, and it at Soviet Union's atmosphere acid 180 and tyrosine 182 site phosphorylation CSBP/p38, causes the CSBP/p38 activation successively.Confirmed MAPKAP kinases-2, MAPKAP kinases-3 is the downstream substrate of CSBP/p38, and it is phosphorylation HSP Hsp27 successively.Known other downstream substrate by the p38 phosphorylation comprises kinases (Mnk 1/2, MSK1/2 and PRAK) and transcription factor (CHOP, MEF2, ATF2 and CREB).Though need the biosynthetic a lot of signal paths of cytokine still to belong to the unknown, as if clear substrate [Cohen, the P.Trends Cell Biol. that wherein relates to a lot of above-mentioned p38; 353-361 (1997) and Lee; J.C. etc., Pharmacol.Ther.82:389-397, (1999)].
Except suppressing IL-1 and TNF, p38 SU11752 (SK&F86002 and SB203580) also reduces multiple proinflammatory protein and comprises IL-6, IL-8, and GM-CSF and COX-2's is synthetic.Shown that also CSBP/p 38 kinase whose suppressor factor suppress the expression of VCAM-1 on endotheliocyte that TNF-α brings out, the phosphorylation of the cell cytoplasm PLA2 that TNF-α brings out and activation and the collagenase of IL-1 stimulation and synthesizing of stromelysin.These and other data show that p38 not only participates in the synthetic of cytokine, and [relevant CSBP/P38 kinases summary is seen [Cohen, P.Trends Cell Biol., 353-361 (1997)] also to relate to cytokine signaling
Summary of the invention
The objective of the invention is to seek and exploitation has p38MAPK and suppresses active micromolecular compound, be used for treating the disease of cytokine (TNF-α, IL-1 etc.) mediation, risk factor or illness, as be arthritic psoriasis, conjunctivo-urethro-synovial syndrome; Gout, traumatic arthritis, rubella arthritis, acute synovitis, rheumatoid arthritis, the rheumatoid ridge pushes away inflammation; Osteo-arthritis, urarthritis and other joint disease, septicemia, septic shock, endotoxin shock, Gram-negative; Septicemia, toxic shock syndrome, cerebral malaria, meningitis, ischemic stroke and hemorrhagic stroke, neurotrauma/closed trauma of head; Asthma, adult respiratory distress syndrome, chronic pneumonia, chronic obstructive pulmonary disease, silicosis, lung sarcosis; Bone absorpting disease, osteoporosis, restenosis, heart and brain and renal reperfusion injury, congestive heart failure, coronary artery bypass bridging (CABG) art; Blood examination forms, glomerulonephritis, chronic renal failure, mellitus, diabetic retinopathy, degeneration of macula; Graft-vs-host reaction, homograft rejection, inflammatory bowel disease, Crohn disease, ulcerative colitis neurodegenerative disease; Muscle deterioration, diabetic retinopathy, degeneration of macula, tumor growth and transfer, vasculogenesis disease; The pneumonia that influenza causes, eczema, contact dermatitis, psoriasis, sunburn or conjunctivitis etc.
The inventor has been found that the compound of general formula I can be used for various diseases, risk factor or the illness of treatment or prevention cytokine (TNF-α, IL-1 etc.) mediation.
Therefore, in one aspect of the invention, the present invention provides general formula (I) compound, or its pharmacologically acceptable salt or solvolyte,
Wherein:
Ar 1Be C 6-C 10Aromatic carbocyclic includes but not limited to phenyl ring, substituted benzene ring, cyclooctatetraene, ring pentaene in the last of the ten Heavenly stems etc.; Or C 3-C 10Saturated or undersaturated non-aromatic carbocyclic includes but not limited to pentamethylene, hexanaphthene, cyclopentenes, tetrahydrobenzene, cyclopentadiene, cyclohexadiene etc.; C 5-C 10Aromatic heterocycle comprises that one or more are selected from O, N, the heteroatoms of S, include but not limited to imidazoles, pyrazoles, thiophene, thiazole, Azoles, pyrazine, morpholine pyridine, pyrimidine, indoles, indazole, quinoline etc.; Perhaps C 5-C 8Single heterocycle or C 8-C 11Two heterocycles, comprise that one or more are selected from O, N, the heteroatoms of S includes but not limited to THF, THTP, piperidines, hexahydropyrimidine, octahydro indoles etc.; Said Ar 1Independent also optionally by one or more R 1, R 2Replace;
Ar 2Be benzo five-membered or hexa-member heterocycle.When being five-membered ring; Comprise on the ring that 1-3 is selected from O; N; The heteroatoms of S includes but not limited to cumarone, thionaphthene, benzopyrrole, benzopyrazoles, coumaran, thiaindan, benzo pyrrolin, benzo pyrazoline, benzothiazole, benzo thiazoline etc.; When being hexa-member heterocycle, there is one to be selected from O on the ring, the heteroatoms of S or 2-4 is selected from O, N, the heteroatoms of S includes but not limited to chromene, benzo thiapyran, benzo pyrimidine, benzo
Figure GPA00000702890000053
Piperazine, chroman, benzo dihydro thiapyran, benzo piperidines, benzo dihydro thiazine, benzo morpholine etc.; Said Ar 2Optionally being selected from following substituting group by 1-4 replaces: C 1-C 6The straight or branched alkyl, C 2-C 6The straight or branched thiazolinyl, C 1-C 6The straight or branched alkoxyl group, C 2-C 6Straight or branched alkene oxygen base, trifluoromethyl, trifluoromethoxy, ethanoyl, aroyl, halogen, methoxycarbonyl, ethoxycarbonyl, benzenesulfonyl, hydroxyl, amino, single or two C 1-C 4The substituted amino of alkyl, single or two C 1-C 4The substituted amino-sulfonyl of alkyl, itrile group, nitro, amino-sulfonyl;
L independently does
(1) key;
(2) C 1-C 10Saturated or undersaturated, the straight or branched carbochain; One or more methylene radical independences wherein and selectivity be by O, NH, S (O) mPerhaps 0-2 carbonyl substitutes; And said spacer group alternative is replaced by one or more halogen atoms;
M is 0,1 or 2;
P is a phenyl, naphthyl, and quinolyl, isoquinolyl, pyridyl, pyrimidyl, pyridazinyl, imidazolyl,
Figure GPA00000702890000061
The azoles base, different The azoles base, thiazolyl, isothiazolyl, pyrryl, benzimidazolyl-, furyl, thienyl, pyranyl, naphthyridinyl; Piperazinyl, pyrazolyl, thiazolyl, purine radicals, pyrazolo [3,4-b] pyrimidyl, pyrrolo-[2,3-b] pyridyl, pyrrolo-[3; 4-b] pyridyl, 1,3-oxygen azepine is [4,5-b] pyridyl also, and 1,2,3-triazol radical, 1,2; 4-three ammonia azoles bases, tetrazole base, THP trtrahydropyranyl, tetrahydrofuran base, dihydro naphthyl, tetralyl, EEDQ base, tetrahydric quinoline group; The dihydro-isoquinoline base, tetrahydro isoquinolyl, 1,3-dioxy ketopentamethylene base, 1,3-dioxy hexamethylene ketone group, 1,4-dioxane base; Morpholinyl, thio-morpholinyl, sulfoxide be for morpholinyl, and sulfone is for morpholinyl, piperidyl, piperidone base, piperidines alcohol radical, tetrahydropyrimidine ketone group; The hexamethylene ketone group, hexamethylene alcohol radical, pentamethylene sulfide base, pentamethylene sulfoxide group, pentamethylene sulfuryl, tetrahydro-thienyl, tetramethylene sulfoxide base, tetramethylene sulfuryl; Said group can be chosen wantonly by 1-3 and be selected from following substituting group replacement: C 1-C 6The straight or branched alkyl, C 2-C 6The straight or branched thiazolinyl, C 1-C 6The straight or branched alkoxyl group, C 2-C 6Straight or branched alkene oxygen base, trifluoromethyl, trifluoromethoxy, ethanoyl, aroyl, halogen, benzenesulfonyl, hydroxyl, amino, single or two C 1-C 4The substituted amino of alkyl, single or two C 1-C 4The substituted aminoacyl of alkyl, C 1-C 4Carbalkoxy, C 1-C 5Acyloxy, single or two C 1-C 4The substituted amino-sulfonyl of alkyl, itrile group, nitro, amino-sulfonyl;
R 1Independently do
(1) C 1-C 10Straight or branched alkyl, said alkyl can be partly or entirely by halos, and alternative by 1-3 phenyl, naphthyl or following heterocyclic substituted: quinolyl, isoquinolyl; Pyridyl, pyrimidyl, pyridazinyl, piperazinyl, pyrryl; Imidazolyl, pyrazolyl, furyl, thienyl, different
Figure GPA00000702890000071
The azoles base, isothiazolyl; Above-mentioned phenyl, naphthyl or heterocycle can be replaced by 0-5 following radicals: halogen, C 1-C 6The straight or branched alkyl, C 3-C 8Naphthenic base, C 5-C 8Cycloalkenyl group, hydroxyl, itrile group, C 1-C 6The straight or branched alkoxyl group, trifluoromethyl, trifluoromethoxy, aminocarboxyl, two C 1-C 4The substituted aminocarboxyl of alkyl;
(2) C 3-C 10Naphthenic base or cycloalkenyl group, said group can be partly or entirely by halos, or selectivity is by 1-3 C 1-C 6Alkyl or C 1-C 6Alkoxyl group replaces; Above-mentioned naphthenic base or the 1-3 of cycloalkenyl group methylene radical alternative be by O, NH, S, SO, SO 2, carbonyl, methylol substitutes; Above-mentioned naphthenic base or cycloalkenyl group can independently be replaced by 0-5 following group: halogen, C 1-C 6The straight or branched alkyl, C 1-C 6The straight or branched alkoxyl group;
(3) C 3-C 10Straight or branched thiazolinyl, said alkyl can be partly or entirely by halos, and alternative by 1-3 C 1-C 6The straight or branched alkyl, phenyl, naphthyl or following heterocyclic substituted: quinolyl, isoquinolyl, pyridyl, pyrimidyl, pyridazinyl, piperazinyl, pyrryl, imidazolyl, pyrazolyl, furyl, thienyl, different
Figure GPA00000702890000072
The azoles base, isothiazolyl; Above-mentioned phenyl, naphthyl or heterocycle can be replaced by 0-5 following radicals: halogen, C 1-C 6The straight or branched alkyl, C 3-C 10Naphthenic base, C 5-C 8Cycloalkenyl group, hydroxyl, itrile group, C 1-C 6The straight or branched alkoxyl group, trifluoromethyl, trifluoromethoxy, aminocarboxyl, two C 1-C 4The substituted aminocarboxyl of alkyl;
(4) halogen, nitro, carboxyl, hydroxyl, itrile group, trifluoromethyl, trifluoromethoxy;
(5)NH 2-，R 3NH-，R 3 2N-，R 3NCO-R 3CONH-，R 3COO-，R 3OCO-，R 3S(O) m，R 3S(O) mNH，R 3NHS(O) m-；
R 2Independently do
(1) aromatic ring, aromatic heterocyclic or fused aromatic rings comprise phenyl, naphthyl, quinolyl; Isoquinolyl, pyridyl, pyrimidyl, pyridazinyl, imidazolyl;
Figure GPA00000702890000081
azoles base, different azoles base, thiazolyl, isothiazolyl, pyrryl; Furyl, thienyl, pyranyl, naphthyridinyl, piperazinyl; Pyrazolyl, thiazolyl, purine radicals, indyl, benzimidazolyl-; Benzofuryl, benzopyrazoles base, benzothienyl, benzo azoles base, benzisoxa
Figure GPA00000702890000084
azoles base; Benzothiazolyl, benzisothiazole base, pyrazolo [3,4-b] pyrimidyl, pyrrolo-[2; 3-b] pyridyl, pyrrolo-[3,4-b] pyridyl, 1,3-oxygen azepine also [4; 5-b] pyridyl, 1,2,3-triazol radical, 1; 2,4-triazol radical, tetrazole base, THP trtrahydropyranyl, tetrahydrofuran base; The dihydro naphthyl, tetralyl, EEDQ base, tetrahydric quinoline group, dihydro-isoquinoline base; Tetrahydro isoquinolyl, benzocyclobutane base, indenyl, indenes thiazolinyl.Above-mentioned aromatic ring, fragrant heterocycle or fused aromatic rings base can be independently by 0-5 R 4Group replaces;
(2) C 3-C 10Naphthenic base or cycloalkenyl group, said group can be partly or entirely by halos, or selectivity is by 1-3 C 1-C 6Alkyl or C 1-C 6Alkoxyl group replaces;
(3) C 1-C 10The straight or branched alkyl, said alkyl can be partly or entirely by halo;
(4)NH 2-，R 3NH-，R 3 2N-，R 3NCO-R 3CONH-，R 3COO-，R 3OCO-，R 3S(O) m，R 3S(O) mNH，R 3NHS(O) m-；
R 3Independently do
Wasserstoffatoms, C 1-C 6The straight or branched alkyl, C 1-C 6The straight or branched thiazolinyl, phenyl, naphthyl, single or two C 1-C 4Alkylamino C 1-C 6Alkyl; M is 0,1 or 2;
R 4Independently do
A) halogen, nitro, carboxyl, C 1-C 6The straight or branched alkyl, C 1-C 6The straight or branched thiazolinyl, C 3-C 10Naphthenic base, C 5-C 8Cycloalkenyl group, hydroxyl, itrile group, C 1-C 6The straight or branched alkoxyl group, trifluoromethyl, trifluoromethoxy;
b)NH 2-，R 3NH-，R 3 2N-，R 3NCO-R 3CONH-，R 3COO-，R 3OCO-，R 3S(O) m，R 3S(O) mNH，R 3NHS(O) m-。
On the other hand, the present invention provides the medicinal compsns that comprises general formula of the present invention (I) compound, and it contains at least a general formula (I) compound or pharmaceutically acceptable salt thereof, solvolyte, and one or more pharmaceutical carriers or vehicle.
On the other hand, the invention still further relates to the method for preparing general formula (I) compound or its pharmacologically acceptable salt or solvolyte.
Again on the one hand, the present invention relates to general formula (I) compound and be used for the purposes of medicine that preparation treats and/or prevents disease or the illness of cytokine (TNF-α, IL-1 etc.) mediation.
Aspect another, the invention provides the method for the disease, risk factor or the illness that treat and/or prevent cytokine (TNF-α, IL-1 etc.) mediation, comprise that the object that these needs are arranged treats and/or prevents the The compounds of this invention of significant quantity.Disease, risk factor or the illness of the cytokine described in the present invention (TNF-α, IL-1 etc.) mediation comprise arthritic psoriasis, conjunctivo-urethro-synovial syndrome, gout, traumatic arthritis, rubella arthritis; Acute synovitis, rheumatoid arthritis, the rheumatoid ridge pushes away inflammation, osteo-arthritis, urarthritis and other joint disease, septicemia; Septic shock, endotoxin shock, Gram-negative, septicemia, toxic shock syndrome, cerebral malaria; Meningitis, ischemic stroke and hemorrhagic stroke, neurotrauma/closed trauma of head, asthma, adult respiratory distress syndrome, chronic pneumonia; Chronic obstructive pulmonary disease, silicosis, lung sarcosis, bone absorpting disease, osteoporosis, restenosis; Heart and brain and renal reperfusion injury, congestive heart failure, coronary artery bypass bridging (CABG) art, blood examination forms, glomerulonephritis, chronic renal failure; Mellitus, diabetic retinopathy, degeneration of macula, graft-vs-host reaction, homograft rejection, inflammatory bowel disease; Crohn disease, ulcerative colitis neurodegenerative disease, muscle deterioration, diabetic retinopathy, degeneration of macula, tumor growth and transfer; The pneumonia that vasculogenesis disease, influenza cause, eczema, contact dermatitis
Psoriasis, sunburn or conjunctivitis etc.
In an embodiment of the invention, the invention provides compound of Formula I, its pharmacologically acceptable salt or solvolyte,
Figure GPA00000702890000101
Wherein:
Ar 1Be C 6-C 10Aromatic carbocyclic includes but not limited to phenyl ring, substituted benzene ring, cyclooctatetraene, ring pentaene in the last of the ten Heavenly stems etc.; Or C 3-C 10Saturated or undersaturated non-aromatic carbocyclic includes but not limited to pentamethylene, hexanaphthene, cyclopentenes, tetrahydrobenzene, cyclopentadiene, cyclohexadiene etc.; C 5-C 10Aromatic heterocycle comprises that one or more are selected from O, N, the heteroatoms of S, include but not limited to imidazoles, pyrazoles, thiophene, thiazole,
Figure GPA00000702890000102
Azoles, pyrazine, morpholine pyridine, pyrimidine, indoles, indazole, quinoline etc.; Perhaps C 5-C 8Single heterocycle or C 8-C 11Two heterocycles, comprise that one or more are selected from O, N, the heteroatoms of S includes but not limited to THF, THTP, piperidines, hexahydropyrimidine, octahydro indoles etc.; Said Ar 1Independent also optionally by one or more R 1, R 2Replace;
Ar 2Be benzo five-membered or hexa-member heterocycle.When being five-membered ring; Comprise on the ring that 1-3 is selected from O; N; The heteroatoms of S includes but not limited to cumarone, thionaphthene, benzopyrrole, benzopyrazoles, coumaran, thiaindan, benzo pyrrolin, benzo pyrazoline, benzothiazole, benzo thiazoline etc.; When being hexa-member heterocycle, there is one to be selected from O on the ring, the heteroatoms of S or 2-4 are selected from O, N, the heteroatoms of S, fierce, include but not limited to chromene, benzo thiapyran, benzo pyrimidine, benzo Piperazine, chroman, benzo dihydro thiapyran, benzo piperidines, benzo dihydro thiazine, benzo morpholine etc.; Said Ar 2Optionally being selected from following substituting group by 1-4 replaces: C 1-C 6The straight or branched alkyl, C 2-C 6The straight or branched thiazolinyl, C 1-C 6The straight or branched alkoxyl group, C 2-C 6Straight or branched alkene oxygen base, trifluoromethyl, trifluoromethoxy, ethanoyl, aroyl, halogen, methoxycarbonyl, ethoxycarbonyl, benzenesulfonyl, hydroxyl, amino, single or two C 1-C 4The substituted amino of alkyl, single or two C 1-C 4The substituted amino-sulfonyl of alkyl, itrile group, nitro, amino-sulfonyl;
L independently does
(1) key;
(2) C 1-C 10Saturated or undersaturated, the straight or branched carbochain; One or more methylene radical wherein are independently by O, NH, S (O) mPerhaps 0-2 carbonyl substitutes; And said spacer group can be replaced by one or more halogen atoms;
M is 0,1 or 2;
P is a phenyl, naphthyl, and quinolyl, isoquinolyl, pyridyl, pyrimidyl, pyridazinyl, imidazolyl, The azoles base, different
Figure GPA00000702890000112
The azoles base, thiazolyl, isothiazolyl, pyrryl, benzimidazolyl-, furyl, thienyl, pyranyl, naphthyridinyl; Piperazinyl, pyrazolyl, thiazolyl, purine radicals, pyrazolo [3,4-b] pyrimidyl, pyrrolo-[2,3-b] pyridyl, pyrrolo-[3; 4-b] pyridyl, 1,3-oxygen azepine is [4,5-b] pyridyl also, and 1,2,3-triazol radical, 1,2; The 4-triazol radical, tetrazole base, THP trtrahydropyranyl, tetrahydrofuran base, dihydro naphthyl, tetralyl, EEDQ base, tetrahydric quinoline group; The dihydro-isoquinoline base, tetrahydro isoquinolyl, 1,3-dioxy ketopentamethylene base, 1,3-dioxy hexamethylene ketone group, 1,4-dioxane base; Morpholinyl, thio-morpholinyl, sulfoxide be for morpholinyl, and sulfone is for morpholinyl, piperidyl, piperidone base, piperidines alcohol radical, tetrahydropyrimidine ketone group; The hexamethylene ketone group, hexamethylene alcohol radical, pentamethylene sulfide base, pentamethylene sulfoxide group, pentamethylene sulfuryl, tetrahydro-thienyl, tetramethylene sulfoxide base, tetramethylene sulfuryl; Said group can be chosen wantonly by 1-3 and be selected from following substituting group replacement: C 1-C 6The straight or branched alkyl, C 2-C 6The straight or branched thiazolinyl, C 1-C 6The straight or branched alkoxyl group, C 2-C 6Straight or branched alkene oxygen base, trifluoromethyl, trifluoromethoxy, ethanoyl, aroyl, halogen, benzenesulfonyl, hydroxyl, amino, single or two C 1-C 4The substituted amino of alkyl, single or two C 1-C 4The substituted aminoacyl of alkyl, C 1-C 4Carbalkoxy, C 1-C 5Acyloxy, single or two C 1-C 4The substituted amino-sulfonyl of alkyl, itrile group, nitro, amino-sulfonyl;
R 1Independently do
(1) C 1-C 10Straight or branched alkyl, said alkyl can be partly or entirely by halos, and can be by 1-3 phenyl, naphthyl or following heterocyclic substituted: quinolyl, isoquinolyl; Pyridyl, pyrimidyl, pyridazinyl, piperazinyl, pyrryl; Imidazolyl, pyrazolyl, furyl, thienyl, different
Figure GPA00000702890000121
The azoles base, isothiazolyl; Above-mentioned phenyl, naphthyl or heterocycle can be replaced by 0-5 following radicals: halogen, C 1-C 6The straight or branched alkyl, C 3-C 8Naphthenic base, C 5-C 8Cycloalkenyl group, hydroxyl, itrile group, C 1-C 6The straight or branched alkoxyl group, trifluoromethyl, trifluoromethoxy, aminocarboxyl, two C 1-C 4The substituted aminocarboxyl of alkyl;
(2) C 3-C 10Naphthenic base or cycloalkenyl group, said group can be partly or entirely by halos, or by 1-3 C 1-C 6Alkyl or C 1-C 6Alkoxyl group replaces; Above-mentioned naphthenic base or the 1-3 of cycloalkenyl group methylene radical can be by O, NH, S, SO, SO 2, carbonyl, methylol substitutes; Above-mentioned naphthenic base or cycloalkenyl group can independently be replaced by 0-5 following group: halogen, C 1-C 6The straight or branched alkyl, C 1-C 6The straight or branched alkoxyl group;
(3) C 3-C 10Straight or branched thiazolinyl, said alkyl can be partly or entirely by halos, and can be by 1-3 C 1-C 6The straight or branched alkyl, phenyl, naphthyl or following heterocyclic substituted: quinolyl, isoquinolyl, pyridyl, pyrimidyl, pyridazinyl, piperazinyl, pyrryl, imidazolyl, pyrazolyl, furyl, thienyl, different
Figure GPA00000702890000122
The azoles base, isothiazolyl; Above-mentioned phenyl, naphthyl or heterocycle can be replaced by 0-5 following radicals: halogen, C 1-C 6The straight or branched alkyl, C 3-C 10Naphthenic base, C 5-C 8Cycloalkenyl group, hydroxyl, itrile group, C 1-C 6The straight or branched alkoxyl group, trifluoromethyl, trifluoromethoxy, aminocarboxyl, two C 1-C 4The substituted aminocarboxyl of alkyl;
(4) halogen, nitro, carboxyl, hydroxyl, itrile group, trifluoromethyl, trifluoromethoxy;
(5)NH 2-，R 3NH-，R 3 2N-，R 3NCO-R 3CONH-，R 3COO-，R 3OCO-，R 3S(O) m，R 3S(O) mNH，R 3NHS(O) m-；
R 2Independently do
(1) phenyl ring, aromatic heterocyclic or fused aromatic rings comprise phenyl, naphthyl, quinolyl; Isoquinolyl, pyridyl, pyrimidyl, pyridazinyl, imidazolyl;
Figure GPA00000702890000131
azoles base, different
Figure GPA00000702890000132
azoles base, thiazolyl, isothiazolyl, pyrryl; Furyl, thienyl, pyranyl, naphthyridinyl, piperazinyl; Pyrazolyl, thiazolyl, purine radicals, indyl, benzimidazolyl-; Benzofuryl, benzopyrazoles base, benzothienyl, benzo
Figure GPA00000702890000133
azoles base, benzisoxa
Figure GPA00000702890000134
azoles base; Benzothiazolyl, benzisothiazole base, pyrazolo [3,4-b] pyrimidyl, pyrrolo-[2; 3-b] pyridyl, pyrrolo-[3,4-b] pyridyl, 1,3-oxygen azepine also [4; 5-b] pyridyl, 1,2,3-triazol radical, 1; 2,4-triazol radical, tetrazole base, THP trtrahydropyranyl, tetrahydrofuran base; The dihydro naphthyl, tetralyl, EEDQ base, tetrahydric quinoline group, dihydro-isoquinoline base; Tetrahydro isoquinolyl, benzocyclobutane base, indenyl, indenes thiazolinyl.Above-mentioned aromatic ring, fragrant heterocycle or fused aromatic rings base can be independently by 0-5 R 4Group replaces;
(2) C 3-C 10Naphthenic base or cycloalkenyl group, said group can be partly or entirely by halos, or by 1-3 C 1-C 6Alkyl or C 1-C 6Alkoxyl group replaces;
(3) C 1-C 10The straight or branched alkyl, said alkyl can be partly or entirely by halo;
(4)NH 2-，R 3NH-，R 3 2N-，R 3NCO-R 3CONH-，R 3COO-，R 3OCO-，R 3S(O) m，R 3S(O) mNH，R 3NHS(O) m-；
R 3Independently do
Wasserstoffatoms, C 1-C 6The straight or branched alkyl, C 1-C 6The straight or branched thiazolinyl, phenyl, naphthyl, single or two C 1-C 4Alkylamino C 1-C 6Alkyl; M is 0,1 or 2;
R 4Independently do
A) halogen, nitro, carboxyl, C 1-C 6The straight or branched alkyl, C 1-C 6The straight or branched thiazolinyl, C 3-C 10Naphthenic base, C 5-C 8Cycloalkenyl group, hydroxyl, itrile group, C 1-C 6The straight or branched alkoxyl group, trifluoromethyl, trifluoromethoxy;
b)NH 2-，R 3NH-，R 3 2N-，R 3NCO-R 3CONH-，R 3COO-，R 3OCO-，R 3S(O) m，R 3S(O) mNH，R 3NHS(O) m-；
In a preferred implementation of the present invention, the invention provides the compound of general formula I representative, its pharmacologically acceptable salt or solvolyte,
Figure GPA00000702890000141
Wherein:
Ar 1Be C 6-C 10Aromatic carbocyclic includes but not limited to phenyl ring, substituted benzene ring, cyclooctatetraene, ring pentaene in the last of the ten Heavenly stems etc.; Or C 3-C 10Saturated or undersaturated non-aromatic carbocyclic includes but not limited to pentamethylene, hexanaphthene, cyclopentenes, tetrahydrobenzene, cyclopentadiene, cyclohexadiene etc.; C 5-C 10Aromatic heterocycle comprises that one or more are selected from O, N, the heteroatoms of S, include but not limited to imidazoles, pyrazoles, thiophene, thiazole,
Figure GPA00000702890000142
Azoles, pyrazine, morpholine pyridine, pyrimidine, indoles, indazole, quinoline etc.; Perhaps C 5-C 8Single heterocycle or C 8-C 11Two heterocycles, comprise that one or more are selected from O, N, the heteroatoms of S includes but not limited to THF, THTP, piperidines, hexahydropyrimidine, octahydro indoles etc.; Said Ar 1Independent also optionally by one or more R 1, R 2Replace;
Ar 2Be chromene or chromanyl; Said Ar2 can be selected from following substituting group by 1-4 and replace: C 1-C 6The straight or branched alkyl, C 2-C 6The straight or branched thiazolinyl, C 1-C 6The straight or branched alkoxyl group, C 2-C 6Straight or branched alkene oxygen base, trifluoromethyl, trifluoromethoxy, ethanoyl, aroyl, halogen, methoxycarbonyl, ethoxycarbonyl, benzenesulfonyl, hydroxyl, amino, single or two C 1-C 4The substituted amino of alkyl, single or two C 1-C 4The substituted amino-sulfonyl of alkyl, itrile group, nitro, amino-sulfonyl;
L independently does
(1) key;
(2) C 1-C 10Saturated or undersaturated, the straight or branched carbochain; One or more methylene radical wherein are independently by O, NH, S (O) mPerhaps 0-2 carbonyl substitutes; And said spacer group can be replaced by one or more halogen atoms;
M is 0,1 or 2;
P is a phenyl, naphthyl, and quinolyl, isoquinolyl, pyridyl, pyrimidyl, pyridazinyl, imidazolyl, The azoles base, different
Figure GPA00000702890000152
The azoles base, thiazolyl, isothiazolyl, pyrryl, benzimidazolyl-, furyl, thienyl, pyranyl, naphthyridinyl; Piperazinyl, pyrazolyl, thiazolyl, purine radicals, pyrazolo [3,4-b] pyrimidyl, pyrrolo-[2,3-b] pyridyl, pyrrolo-[3; 4-b] pyridyl, 1,3-oxygen azepine is [4,5-b] pyridyl also, and 1,2,3-triazol radical, 1,2; The 4-triazol radical, tetrazole base, THP trtrahydropyranyl, tetrahydrofuran base, dihydro naphthyl, tetralyl, EEDQ base, tetrahydric quinoline group; The dihydro-isoquinoline base, tetrahydro isoquinolyl, 1,3-dioxy ketopentamethylene base, 1,3-dioxy hexamethylene ketone group, 1,4-dioxane base; Morpholinyl, thio-morpholinyl, sulfoxide be for morpholinyl, and sulfone is for morpholinyl, piperidyl, piperidone base, piperidines alcohol radical, tetrahydropyrimidine ketone group; The hexamethylene ketone group, hexamethylene alcohol radical, pentamethylene sulfide base, pentamethylene sulfoxide group, pentamethylene sulfuryl, tetrahydro-thienyl, tetramethylene sulfoxide base, tetramethylene sulfuryl; Said group can be chosen wantonly by 1-3 and be selected from following substituting group replacement: C 1-C 6The straight or branched alkyl, C 2-C 6The straight or branched thiazolinyl, C 1-C 6The straight or branched alkoxyl group, C 2-C 6Straight or branched alkene oxygen base, trifluoromethyl, trifluoromethoxy, ethanoyl, aroyl, halogen, benzenesulfonyl, hydroxyl, amino, single or two C 1-C 4The substituted amino of alkyl, single or two C 1-C 4The substituted aminoacyl of alkyl, C 1-C 4Carbalkoxy, C 1-C 5Acyloxy, single or two C 1-C 4The substituted amino-sulfonyl of alkyl, itrile group, nitro, amino-sulfonyl;
R 1Independently do
(1) C 1-C 10Straight or branched alkyl, said alkyl can be partly or entirely by halos, and can be by 1-3 phenyl, naphthyl or following heterocyclic substituted: quinolyl, isoquinolyl; Pyridyl, pyrimidyl, pyridazinyl, piperazinyl, pyrryl; Imidazolyl, pyrazolyl, furyl, thienyl, different
Figure GPA00000702890000161
The azoles base, isothiazolyl; Above-mentioned phenyl, naphthyl or heterocycle can be replaced by 0-5 following radicals: halogen, C 1-C 6The straight or branched alkyl, C 3-C 8Naphthenic base, C 5-C 8Cycloalkenyl group, hydroxyl, itrile group, C 1-C 6The straight or branched alkoxyl group, trifluoromethyl, trifluoromethoxy, aminocarboxyl, two C 1-C 4The substituted aminocarboxyl of alkyl;
(2) C 3-C 10Naphthenic base or cycloalkenyl group, said group can be partly or entirely by halos, or by 1-3 C 1-C 6Alkyl or C 1-C 6Alkoxyl group replaces; Above-mentioned naphthenic base or the 1-3 of cycloalkenyl group methylene radical can be by O, NH, S, SO, SO 2, carbonyl, methylol substitutes; Above-mentioned naphthenic base or cycloalkenyl group can independently be replaced by 0-5 following group: halogen, C 1-C 6The straight or branched alkyl, C 1-C 6The straight or branched alkoxyl group;
(3) C 3-C 10Straight or branched thiazolinyl, said alkyl can be partly or entirely by halos, and can be by 1-3 C 1-C 6The straight or branched alkyl, phenyl, naphthyl or following heterocyclic substituted: quinolyl, isoquinolyl, pyridyl, pyrimidyl, pyridazinyl, piperazinyl, pyrryl, imidazolyl, pyrazolyl, furyl, thienyl, different
Figure GPA00000702890000162
The azoles base, isothiazolyl; Above-mentioned phenyl, naphthyl or heterocycle can be replaced by 0-5 following radicals: halogen, C 1-C 6The straight or branched alkyl, C 3-C 10Naphthenic base, C 5-C 8Cycloalkenyl group, hydroxyl, itrile group, C 1-C 6The straight or branched alkoxyl group, trifluoromethyl, trifluoromethoxy, aminocarboxyl, two C 1-C 4The substituted aminocarboxyl of alkyl;
(4) halogen, nitro, carboxyl, hydroxyl, itrile group, trifluoromethyl, trifluoromethoxy;
(5)NH 2-，R 3NH-，R 3 2N-，R 3NCO-R 3CONH-，R 3COO-，R 3OCO-，R 3S(O) m，R 3S(O) mNH，R 3NHS(O) m-；
R 2Independently do
(1) ring, aromatic heterocyclic or fused aromatic rings comprise phenyl, naphthyl, quinolyl; Isoquinolyl, pyridyl, pyrimidyl, pyridazinyl, imidazolyl;
Figure GPA00000702890000163
azoles base, different
Figure GPA00000702890000164
azoles base, thiazolyl, isothiazolyl, pyrryl; Furyl, thienyl, pyranyl, naphthyridinyl, piperazinyl; Pyrazolyl, thiazolyl, purine radicals, indyl, benzimidazolyl-; Benzofuryl, benzopyrazoles base, benzothienyl, benzo
Figure GPA00000702890000171
azoles base, benzisoxa azoles base; Benzothiazolyl, benzisothiazole base, pyrazolo [3,4-b] pyrimidyl, pyrrolo-[2; 3-b] pyridyl, pyrrolo-[3,4-b] pyridyl, 1,3-oxygen azepine also [4; 5-b] pyridyl, 1,2,3-triazol radical, 1; 2,4-triazol radical, tetrazole base, THP trtrahydropyranyl, tetrahydrofuran base; The dihydro naphthyl, tetralyl, EEDQ base, tetrahydric quinoline group, dihydro-isoquinoline base; Tetrahydro isoquinolyl, benzocyclobutane base, indenyl, indenes thiazolinyl.Above-mentioned aromatic ring, fragrant heterocycle or fused aromatic rings base can be independently by 0-5 R 4Group replaces;
(2) C 3-C 10Naphthenic base or cycloalkenyl group, said group can be partly or entirely by halos, or by 1-3 C 1-C 6Alkyl or C 1-C 6Alkoxyl group replaces;
(3) C 1-C 10The straight or branched alkyl, said alkyl can be partly or entirely by halo;
(4)NH 2-，R 3NH-，R 3 2N-，R 3NCO-R 3CONH-，R 3COO-，R 3OCO-，R 3S(O) m，R 3S(O) mNH，R 3NHS(O) m-；
R 3Independently do
Wasserstoffatoms, C 1-C 6The straight or branched alkyl, C 1-C 6The straight or branched thiazolinyl, phenyl, naphthyl, single or two C 1-C 4Alkylamino C 1-C 6Alkyl; M is 0,1 or 2;
R 4Independently do
A) halogen, nitro, carboxyl, C 1-C 6The straight or branched alkyl, C 1-C 6The straight or branched thiazolinyl, C 3-C 10Naphthenic base, C 5-C 8Cycloalkenyl group, hydroxyl, itrile group, C 1-C 6The straight or branched alkoxyl group, trifluoromethyl, trifluoromethoxy;
b)NH 2-，R 3NH-，R 3 2N-，R 3NCO-R 3CONH-，R 3COO-，R 3OCO-，R 3S(O) m，R 3S(O) mNH，R 3NHS(O) m-；
The preferred compound of the present invention comprises:
1-[the 3-tertiary butyl-1-(4-aminomethyl phenyl)-1H-5-pyrazolyl]-3-[8-(3,4-dihydro-5-methoxyl group-2H-chromenyl)] urea
1-[the 3-tertiary butyl-1-(4-chloro-phenyl-)-1H-5-pyrazolyl]-3-[8-(5-methoxyl group-2H-chromenyl)] urea
1-[the 3-tertiary butyl-1-(4-aminomethyl phenyl)-1H-5-pyrazolyl]-3-[8-(5-methoxyl group-2H-chromenyl)] urea
1-[the 3-tertiary butyl-1-(4-aminomethyl phenyl)-1H-5-pyrazolyl]-3-{5-{8-[2-(4-morphine quinoline base) kharophen]-2H-chromenyl } } urea
1-[the 3-tertiary butyl-1-phenyl-1H-5-pyrazolyl]-3-[8-(3,4-dihydro-5-methoxyl group-2H-chromenyl)] urea
1-[the 3-tertiary butyl-1-(4-aminomethyl phenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } urea
1-[the 3-tertiary butyl-1-(4-aminomethyl phenyl)-1H-5-pyrazolyl]-3-[8-(5-nitro-2H-chromenyl)] urea
1-[the 3-tertiary butyl-1-phenyl-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } urea
1-[the 3-tertiary butyl-1-(4-fluorophenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } urea
1-[the 3-tertiary butyl-1-(4-chloro-phenyl-)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } urea
1-[the 3-tertiary butyl-1-(4-bromophenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } urea
1-[the 3-tertiary butyl-1-(4-p-methoxy-phenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } urea
1-[the 3-tertiary butyl-1-(4-amino-sulfonyl phenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } urea
1-[the 3-tertiary butyl-1-(4-nitrophenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } urea
1-[the 3-tertiary butyl-1-(4-aminomethyl phenyl)-1H-5-pyrazolyl]-3-{8-[3,4-dihydro-5-(4-morphine quinoline base acyl group methoxyl group)-2H-chromenyl] } urea
1-(the 3-tertiary butyl-5-different
Figure GPA00000702890000191
azoles base)-3-{8-{3,4-dihydro-5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } urea
1-(the 5-tertiary butyl-3-different
Figure GPA00000702890000192
azoles base)-3-{8-{3,4-dihydro-5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } urea
1-[the 1-tertiary butyl-3-(4-aminomethyl phenyl)-1H-4-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } urea
1-[the 4-tertiary butyl-1-(4-aminomethyl phenyl)-1H-2-imidazolyl]-3-{8-{3,4-dihydro-5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } urea
1-[the 3-tertiary butyl-1-(4-aminomethyl phenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-(4-pyridyl) oxygen base oxethyl]-2H-chromenyl } urea
1-[the 3-tertiary butyl-1-(4-aminomethyl phenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-{2-[4-(cis-2,6-dimethyl-) morphine quinoline base] oxyethyl group }-the 2H-chromenyl } urea
1-[the 3-tertiary butyl-1-(4-aminomethyl phenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-(1-imidazolyl) oxyethyl group]-2H-chromenyl } urea
1-[the 3-tertiary butyl-1-(4-aminomethyl phenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-(1-1,2,4-triazol radical) oxyethyl group]-2H-chromenyl } urea
1-[the 3-tertiary butyl-1-(4-chloro-phenyl-)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-{2-[4-(cis-2,6-dimethyl-) morphine quinoline base] oxyethyl group }-the 2H-chromenyl } urea
1-[the 3-tertiary butyl-1-(3, the 4-3,5-dimethylphenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } urea
1-[the 3-tertiary butyl-1-(3, the 4-dichlorophenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } urea
1-[the 3-tertiary butyl-1-(3-aminomethyl phenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } urea
1-[(the 3-tertiary butyl-1-naphthyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } urea
1-[the 3-tertiary butyl-1-(4-aminomethyl phenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-(1-pyrazolyl) oxyethyl group]-2H-chromenyl } urea
1-[the 3-tertiary butyl-1-(4-aminomethyl phenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-(1-piperidin-4-one-base) oxyethyl group]-2H-chromenyl } urea
1-[the 3-tertiary butyl-1-(4-aminomethyl phenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-(4-morphine quinoline base) kharophen]-2H-chromenyl } urea
1-[the 3-tertiary butyl-1-(4-trifluoromethyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } urea
1-[the 3-tertiary butyl-1-(4-ethylphenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } urea
1-[the 3-tertiary butyl-1-(4-tert-butyl-phenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } urea
1-[the 3-tertiary butyl-1-(4-trifluoromethyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-(1-imidazolyl) oxyethyl group]-2H-chromenyl } urea
1-[the 3-tertiary butyl-1-(4-aminomethyl phenyl)-1H-5-pyrazolyl]-3-{8-{5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } } urea
1-[the 3-tertiary butyl-1-(4-aminomethyl phenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-(4-pyridyl) oxyethyl group]-2H-chromenyl } urea
1-[the 3-tertiary butyl-1-(4-itrile group phenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } urea
1-[the 3-tertiary butyl-1-(3-chloro-4-fluorophenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } urea
1-[the 3-tertiary butyl-1-(4-aminomethyl phenyl)-1H-5-pyrazolyl]-3-{8-{5-[(4-p-methoxy-phenyl) methoxyl group]-2H-chromenyl } } urea
1-[the 3-tertiary butyl-1-(4-aminomethyl phenyl)-1H-5-pyrazolyl]-3-{8-[5-(4-morphine quinoline base acyl group methoxyl group)-2H-chromenyl] } urea
1-[the 3-tertiary butyl-1-(4-fluorophenyl)-1H-5-pyrazolyl]-3-{8-{5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } } urea
1-[the 3-tertiary butyl-1-(4-chloro-phenyl-)-1H5-pyrazolyl]-3-{8-{5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } } urea
1-[the 3-tertiary butyl-1-(4-bromophenyl)-1H-5-pyrazolyl]-3-{8-{5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } } urea
1-(the 3-tertiary butyl-1-phenyl-1H-5-pyrazolyl)-3-{8-{5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } } urea
1-[the 3-tertiary butyl-1-(4-p-methoxy-phenyl)-1H-5-pyrazolyl]-3-{8-{5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } } urea
1-[the 3-tertiary butyl-1-(4-trifluoromethyl)-1H-5-pyrazolyl]-3-{8-{5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } } urea
1-[the 3-tertiary butyl-1-(4-nitrophenyl)-1H-5-pyrazolyl]-3-{8-{5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } } urea
1-[the 3-tertiary butyl-1-(4-itrile group phenyl)-1H-5-pyrazolyl]-3-{8-{5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } } urea
1-[the 3-tertiary butyl-1-(4-aminomethyl phenyl)-1H-5-pyrazolyl]-3-{8-{5-[2-(1-1,2,4-triazol radical) oxyethyl group]-2H-chromenyl } } urea
1-[the 3-tertiary butyl-1-(4-ethylphenyl)-1H-5-pyrazolyl]-3-{8-{5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } } urea
1-[the 3-tertiary butyl-1-(4-tert-butyl-phenyl)-1H-5-pyrazolyl]-3-{8-{5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } } urea
1-[the 3-tertiary butyl-1-(3-chloro-4-fluorophenyl)-1H-5-pyrazolyl]-3-{8-{5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } } urea
1-[the 3-tertiary butyl-1-(3, the 4-3,5-dimethylphenyl)-1H-5-pyrazolyl]-3-{8-{5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } } urea
1-[the 3-tertiary butyl-1-(3, the 4-dichlorophenyl)-1H-5-pyrazolyl]-3-{8-{5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } } urea
1-(the 3-tertiary butyl-5-different
Figure GPA00000702890000221
azoles base)-3-{8-{5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } } urea
1-(the 5-tertiary butyl-3-different
Figure GPA00000702890000222
azoles base)-3-{8-{5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } } urea
1-[the 1-tertiary butyl-3-(4-aminomethyl phenyl)-1H-4-pyrazolyl]-3-{8-{5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } } urea
1-[the 3-tertiary butyl-1-(3-aminomethyl phenyl)-1H-5-pyrazolyl]-3-{8-{5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } } urea
1-[(the 3-tertiary butyl-1-naphthyl)-1H-5-pyrazolyl]-3-{8-{5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } } urea
1-[the 4-tertiary butyl-1-(4-aminomethyl phenyl)-1H-2-imidazolyl]-3-{8-{5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } } urea
1-[the 3-tertiary butyl-1-(4-aminomethyl phenyl)-1H-5-pyrazolyl]-3-{8-{5-{2-[4-(cis-2,6-dimethyl-) morphine quinoline base] oxyethyl group }-the 2H-chromenyl } urea
With and pharmacologically acceptable salt or solvolyte.
The preparation of the compound of formula I:
The compound of formula I can be by following several method preparation, preferred method 3.
Method 1
Figure GPA00000702890000231
Method 2
Figure GPA00000702890000232
Method 3
R 6＝CCl 3，C 6H 4NO 2，OC 2H 5，Imidiazole，Triazole
The response hierarchy of above-mentioned three kinds of methods can be put upside down, i.e. phosgene, and chloro-formic ester or carbonic ether can elder generation and P-L-Ar 2-NH 2The reaction, the midbody of generation again with Ar 1NH 2Reaction.Ar 1, Ar 2, L, the same general formula I of the definition of P.
In method 1, a kind of heterocyclic amine is dissolved in methylene dichloride, in chloroform or the ethylene dichloride, adds the aqueous solution of sodium hydrogencarbonate or salt of wormwood; Cool off in the ice-water bath, add phosgene, stirred 5-30 minute; The midbody that obtains and another heterocyclic amine in anhydrous non-protonic solvent (like THF, ether, toluene; Dioxane, methylene dichloride, ETHYLE ACETATE etc.) react the compound that obtained formula I in 2-24 hour in 0-45 ℃.
In method 2, a kind of heterocyclic amine is dissolved in methylene dichloride, in chloroform or the ethylene dichloride; Add suitable alkali (like triethylamine etc.), add chloro-formic ester then, in 0-85 ℃ of reaction 2-24 hour; The midbody that obtains and another heterocyclic amine in anhydrous non-protonic solvent (like THF, ether, toluene; Dioxane, methylene dichloride, ETHYLE ACETATE etc.) react the compound that obtained formula I in 2-24 hour in 0-110 ℃.
In method 3, a kind of heterocyclic amine is dissolved in methylene dichloride, in chloroform or the ethylene dichloride; Add suitable alkali (like triethylamine etc.), add carbonic ether then, in-20-45 ℃ reaction 2-24 hour; The midbody that obtains and another heterocyclic amine in anhydrous non-protonic solvent (like THF, ether, toluene; Dioxane, methylene dichloride, ETHYLE ACETATE etc.) react the compound that obtained formula I in 2-240 hour in 0-110 ℃.
Ar 1NH 2According to the difference of structure, synthetic by following route respectively.R1, R2 define same general formula I.
(1) 3-amino pyrazoles
Figure GPA00000702890000241
Figure GPA00000702890000242
Amine obtains diazonium salt in-10-10 ℃ through a diazotization reaction, and diazonium salt obtains hydrazine II through S-WAT or tin protochloride reduction.Substituted chloromethyl ester obtains intermediate III with the anhydrous acetonitrile back flow reaction under the effect of alkali such as sodium hydride in anhydrous tetrahydro furan; III and II at reflux in ethanol 16-48 hour, obtain 3-amino-pyrazol IV under acidic conditions.
(2) the amino furans of 3-
Figure GPA00000702890000251
The acyl acetic acid ethyl ester is at highly basic (sodium; Sodium hydride; Sodium ethylate etc.) the following and alpha-brominated reactive ketone of effect; The two ketone ester V that obtain obtain 3-furyl ethyl formate VI in ethanol equal solvent neutralisation of sulphuric acid or hydrochloric acid reaction, and 3-furyl ethyl formate VI and Hydrazine Hydrate 80 and formic acid reaction obtain the amino furfuran compound VII of 3-.
(3) 3-aminothiophene class
Figure GPA00000702890000252
Diketone and Lawesson ' s reagent obtained substituted thiophene in back flow reaction 1-10 hour in anhydrous non-protonic solvent, nitrated through concentrated nitric acid then, and iron/hydrochloric acid or catalytic hydrogenation reduction obtain 3-aminothiophene compounds VIII.
(4) 2-aminopyrrole
Figure GPA00000702890000261
Itrile group aldehyde and substituted amine obtained amino-nitrile IX in 5-30 minute in 50-90 ℃ of reaction in acetic acid/water, IX generates 2-aminopyrrole compound X in the room temperature cyclization in the presence of sodium ethylate.
(5) amino
Figure GPA00000702890000262
azole of 4-
Figure GPA00000702890000263
The acyl group nitrile; Aldehyde; Anhydrous acetic acid ammonium in acetate backflow 3-6 hour obtains 4-amino
Figure GPA00000702890000264
azole compounds XI.
(6) amino
Figure GPA00000702890000265
azole of 5-
Acyl chlorides and itrile group amine are at 0 ℃; Reaction obtains acid amides XII in the THF equal solvent; XII is dissolved in the exsiccant diamino methane, adds sulfur alcohol, feeds dry hydrogen chloride gas; Reacted 5-30 minute; The product XIII that obtains feeds hydrogen sulfide to saturated in 0 ℃ in the exsiccant pyridine, obtain 5-amino
Figure GPA00000702890000271
azole compounds XIV after 4 hours.
(7) 5-Basedol class
Figure GPA00000702890000272
Aldehyde, amino-nitrile, sulphur are dissolved in exsiccant methyl alcohol or ethanol, drip triethylamine, are heated to 50 ℃, react 1-3 hour, obtain product X V, and XV obtains 5-Basedol XVI through hydrochloric acid or tosic acid hydrolysis.
(8) 2-aminooimidazole class
Exist down at alkali (saleratus, salt of wormwood etc.), alpha-chloro ketone and substituted amine react in the DMF equal solvent and obtain alpha-amino group ketone XVII, and backflow obtained 2-aminooimidazole XVIII in 12 hours to XVII with nitrile amine in the ethanol equal solvent.
(9) 4-amino pyrazoles
Figure GPA00000702890000281
Chloro ketone and potassium phthalimide in 70 ℃ of reactions 2 hours, obtain compounds X IX in DMF, XIX and N, dinethylformamide dimethylacetal in 100 ℃ of reactions 12 hours, obtain compounds X X in DMF.XX and substituted hydrazine obtained compounds X XI in 12 hours in 90% reflux in ethanol, and XXI hydrazinolysis in ethanol obtains 4-amino-pyrazol XXII.
(10) 5-amino different azole
Figure GPA00000702890000283
Itrile group ketone reacts with oxammonium hydrochloride in 50-100 ℃ under the alkaline condition again, obtains 5-amino different
Figure GPA00000702890000284
azoles XXIII.
It will be appreciated by those skilled in the art that The compounds of this invention also can use with its pharmacologically acceptable salt or solvate forms.Acceptable salt comprises the salt of the routine that is formed by pharmaceutically acceptable mineral acid or organic acid or mineral alkali or organic bases and the acid salt of quaternary ammonium on the physiology of compound of Formula I.The example more specifically of suitable hydrochlorate comprises hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid, nitric acid, perchloric acid, fumaric acid, acetate, propionic acid, succsinic acid, oxyacetic acid, formic acid, lactic acid, toxilic acid, tartrate, Hydrocerol A, pounces on the salt of acid, propanedioic acid, hydroxymaleic acid, toluylic acid, L-glutamic acid, phenylformic acid, Whitfield's ointment, fumaric acid, toluenesulphonic acids, methylsulfonic acid, naphthalene-2-sulfonic acid, Phenylsulfonic acid, hydroxynaphthoic acid, hydroiodic acid HI, oxysuccinic acid, steroic, tannic acid etc.Other acid like oxalic acid, though itself be not pharmaceutically acceptable, can be used to prepare the salt as midbody, to obtain The compounds of this invention and pharmacologically acceptable salt thereof.The example more specifically of suitable alkali salt comprises sodium, lithium, potassium, magnesium, aluminium, calcium, zinc, N, N '-dibenzyl-ethylenediamin, chloro PROCAINE HCL, PHARMA GRADE, choline, diethylolamine, quadrol, N-NMG and procaine salt.When after this relating to compound of the present invention, comprise compound of Formula I and pharmacologically acceptable salt thereof and solvolyte.
The present invention also comprises the prodrug of The compounds of this invention, and this prodrug promptly carries out chemical conversion through metabolic process once administration, becomes afterwards to have active medicine.Usually, this type prodrug is the functional derivatives of The compounds of this invention, and it changes into the compound of required formula (I) in vivo easily.For example, at " Design Of Prodrugs ", H BundSaard, Elsevier edits, and has described in 1985 and has selected and the ordinary method of the suitable prodrug derivant of preparation.
The present invention also comprises the active metabolite of The compounds of this invention.
Another aspect of the present invention relates to pharmaceutical composition, and it contains The compounds of this invention and at least a pharmaceutically acceptable carrier, and it can be used for interior therapeutic and has biocompatibility.Said pharmaceutical composition can be prepared into various forms according to different way of administration.The mentioned compound of the present invention also can be prepared to various pharmacologically acceptable salts.
Compound of the present invention can be measured with following method the agonism of PPAR.In containing 15% foetal calf serum, in the RMPI substratum of 0.02nM 2 mercapto ethanol, cell concn is 1-2 * 10 with the THP-1 cell suspension 6Individual cell/mL, bed board (every hole contains 0.2mL) on 96 hole flat boards then.Experimental compound dissolves in DMSO, and with the substratum dilution, the final concentration that makes DMSO is 5% then.Add 25 μ L experimental compound solution or the substratum (contrast) of DMSO is only arranged to every hole.
The serial dilutions one of cell and experimental compound is arised from 37 ℃ of insulations 30 minutes, add IFN-γ (100U/mL) and LPS (5mg/mL) then, and continue insulation 18-24 hour, stopped insulation in centrifugal 10 minutes in 1600RPM.With the commercially available ELISA test kit TNF-alpha content in the clear liquid analytically.The concentration of compound of the present invention with 0.1-3 μ M is experimentized.Representational compound of the present invention can suppress TNF-α and discharge in experiment.
Table 1 part The compounds of this invention is to the restraining effect (3 μ M) of TNF-α
Compound Inhibiting rate (%) Compound Inhibiting rate (%) Compound Inhibiting rate (%)
Embodiment 2 34.47 Embodiment 24 60.56 Embodiment 44 19.01
Embodiment 3 59.22 Embodiment 26 62.50 Embodiment 45 22.54
Embodiment 6 24.27 Embodiment 32 101.49 Embodiment 47 12.68
Embodiment 7 58.74 Embodiment 33 84.82 Embodiment 48 4.93
Embodiment 9 57.28 Embodiment 34 67.56 Embodiment 55 68.94
Embodiment 10 33.50 Embodiment 35 83.93 Embodiment 56 78.03
Embodiment 11 30.99 Embodiment 37 34.51 Embodiment 57 83.71
Embodiment 14 14.08 Embodiment 38 11.97 Embodiment 58 6.06
Embodiment 17 56.25 Embodiment 39 45.77 Embodiment 59 36.74
Embodiment 20 43.75 Embodiment 40 61.27 Embodiment 60 14.02
Embodiment 21 95.24 Embodiment 42 51.41 Embodiment 61 19.32
Embodiment 22 87.20 Embodiment 43 16.90 Embodiment 62 79.55
The pharmaceutical composition of The compounds of this invention can be used with following any-mode: oral, spraying sucks, rectal application; Nasal cavity applied medicine; The cheek medication, local application, non-enterally administer; As in subcutaneous, vein, intramuscular, intraperitoneal, the sheath, in the ventricle, in the breastbone and intracranial injection or input, or by the medication of a kind of outer planting reservoir.Wherein preferred oral, intraperitoneal or intravenous administration mode.
When medicine for oral use, The compounds of this invention can be made into oral acceptable dosage form arbitrarily, includes but not limited to tablet, capsule, the aqueous solution or aqeous suspension.Wherein, the carrier that tablet uses generally comprises lactose and W-Gum, also can add lubricant such as Magnesium Stearate in addition.The thinner that capsule preparations uses generally comprises lactose and dried corn starch.Aqueous suspension preparation then normally mixes use with activeconstituents with examples of suitable emulsifiers and suspension agent.If desired, also can add some sweeting agents, perfume compound or tinting material in the above oral prepns form.
During the Where topical medication; Particularly treat local external application easy to reach and suffer from face or organ; During like eyes, skin or lower intestinal tract nervous system disease, can The compounds of this invention be processed different local application's dosage forms, specify as follows according to different trouble faces or organ:
When the eye topical application, The compounds of this invention can be mixed with the dosage form of a kind of micronization suspension-s or solution, and the carrier that uses is the Sterile Saline of isoosmotic certain pH, wherein can add also not adding preservative agent such as zephiran chloride alkoxide.For eye usefulness, also can compound be processed paste form such as vaseline paste.
When topical application, The compounds of this invention can be made into suitable ointment, lotion or creme dosage form, wherein activeconstituents is suspended or is dissolved in one or more carriers.The spendable carrier of ointment formulation includes but not limited to: MO, Albolene, white vaseline, Ucar 35, polyoxyethylene, polyoxytrimethylene, emulsifying wax and water; The spendable carrier of lotion or creme includes but not limited to: MO, and sorbitan monostearate, polysorbate60, the n-Hexadecane ester type waxes, cetene is fragrant and mellow, 2-Standamul G, benzyl alcohol and water.
The all right aseptic injection preparation form medication of The compounds of this invention comprises aseptic injection water or oil suspension or aseptic injectable solution.Wherein, spendable carrier and solvent comprise water, Ringer's solution and isotonic sodium chlorrde solution.In addition, the fixed oil of sterilization also can be used as solvent or suspension medium, like direactive glyceride or two glyceryl ester.
It may be noted that in addition; The using dosage of The compounds of this invention and method of use depend on many factors, comprise activity intensity, Time of Administration, metabolic rate, the severity of illness and diagnosis and treatment doctor's the subjective judgement of patient's age, body weight, sex, natural health situation, nutritional status, compound.Preferred using dosage is between 0.01～100mg/kg body weight/day, and wherein optimal dosage is in the 5mg/kg-10mg/kg body weight/day.
Embodiment
The present invention further specifies with following midbody and embodiment, and these midbodys and embodiment are not construed as limiting the invention.
Melting point compound is measured by YRT-3 type fusing point appearance, and temperature is not calibrated. 1H-NMR
Spectrum is measured by Bruker ARX 400 type nuclear magnetic resonance spectrometers.The FAB mass spectrum is measured by Zabspect high resolution magnetic mass spectrometer.
The preparation of midbody
By aromatic amine preparation 2, the general operation A of the dibasic 3-amino-pyrazol of 5-
Figure GPA00000702890000321
Figure GPA00000702890000322
1. aromatic amine (0.04mol) adds in the 40mL concentrated hydrochloric acid, stirs, and is cooled to-5 ℃, separates out white fine particle shape crystal.Slowly drip sodium nitrite solution (the 2.90g Sodium Nitrite is dissolved in 20mL water), controlled temperature is no more than 0 ℃, adds afterreaction 1 hour.
2.18.0g tin protochloride is dissolved in the 50mL concentrated hydrochloric acid, is cooled to-5 ℃, drips the diazonium salt solution of step 1 preparation, separates out white crystal, reacts 1 hour, filters, filtration cakes torrefaction promptly gets product aryl hydrazine hydrochloride.
3.30mL anhydrous THF 0 ℃ add sodium hydride (0.6g, 60%, 0.015mol), stir add down substituted carboxylic acid chloromethyl ester (0.01mol) and anhydrous acetonitrile (0.82g, 0.02mol), first room temperature reaction is 1 hour after adding, reflux is 24 hours then.Cooling is poured in the 100mL frozen water, is transferred to pH 4 with Hydrogen chloride, ethyl acetate extraction, and drying concentrates, and obtains bullion.Purifying directly is not used for next step reaction.
4. (1.25g 0.01mol) joins in the 50mL ethanol with the aryl hydrazine hydrochloride that step 2 obtains the acyl group acetonitrile that obtains of step 3, drips the 2.0mL concentrated hydrochloric acid, reflux 12-24 hour.Cooling is poured in the 100mL frozen water, is transferred to pH 12 with dilute sodium hydroxide, ethyl acetate extraction, and drying through silica gel column chromatography, obtains the white solid product with the crude product that obtains.
Midbody 1
Figure GPA00000702890000331
Title compound is to be raw material such as general operation A to the tert-butyl chloride methyl esters, and the said preparation of step 3 gets light yellow oil.
Midbody 2
Title compound is with 3, and the 4-xylidine is raw material such as general operation A, step 1, and 2 said preparations get white solid.
Midbody 3
Figure GPA00000702890000333
Title compound is with 3, and the 4-dichlorphenamide bulk powder is raw material such as general operation A, step 1, and 2 said preparations get white solid.
Midbody 4
Title compound is raw material such as general operation A with the 3-monomethylaniline, step 1, and 2 said preparations get white solid.
Midbody 5
Figure GPA00000702890000341
Title compound is raw material such as general operation A with the naphthalidine, step 1, and 2 said preparations get white solid.
Midbody 6
Title compound is raw material such as general operation A with 3-chlorine 4-fluoroaniline, step 1, and 2 said preparations get white solid.
Midbody 7
Figure GPA00000702890000343
Title compound is raw material such as general operation A with the 4-MEA, step 1, and 2 said preparations get white solid.
Midbody 8
Figure GPA00000702890000344
Title compound is raw material such as general operation A with the 4-isopropyl aniline, step 1, and 2 said preparations get white solid.
Midbody 9
Figure GPA00000702890000351
Title compound is raw material such as general operation A with the 4-5-trifluoromethylaniline, step 1, and 2 said preparations get white solid.
Midbody 10
Title compound is raw material such as general operation A with 4-itrile group aniline, step 1, and 2 said preparations get white solid.
Midbody 11
Figure GPA00000702890000353
Title compound is raw material such as general operation A with midbody 1 with to procarbazine, and the said preparation of step 4 gets white solid.
1H-NMR(CDCl 3，400MHz)δ：7.40(d，2H，J＝8.4Hz)，7.25(d，2H，J＝3.08Hz)，5.50(s，1H)，3.72(s，2H)，2.37(s，3H)，1.32(s，9H)。
Midbody 12
Figure GPA00000702890000361
Title compound is raw material such as general operation A with midbody 1 with phenylhydrazine, and the said preparation of step 4 gets white solid.
Midbody 13
Title compound is raw material such as general operation A with midbody 1 with to the methoxyl group phenylhydrazine, and the said preparation of step 4 gets white solid.
Midbody 14
Figure GPA00000702890000363
Title compound is raw material such as general operation A with midbody 1 with to the fluorobenzene hydrazine, and the said preparation of step 4 gets white solid.
Midbody 15
Figure GPA00000702890000371
Title compound is raw material such as general operation A with midbody 1 with to chlorophenyl hydrazine, and the said preparation of step 4 gets white solid.
Midbody 16
Figure GPA00000702890000372
Title compound is raw material such as general operation A with midbody 1 with para-bromophenyl-hydrazine, and the said preparation of step 4 gets white solid.
Midbody 17
Figure GPA00000702890000373
Title compound is raw material such as general operation A with midbody 1 with paranitrophenylhydrazine, and the said preparation of step 4 gets yellow solid.
Midbody 18
Figure GPA00000702890000381
Title compound is raw material such as general operation A with midbody 1 with to the amino-sulfonyl phenylhydrazine, and the said preparation of step 4 gets white solid.
Midbody 19
Title compound is raw material such as general operation A with midbody 1 with midbody 2, and the said preparation of step 4 gets white solid.
1H-NMR(CDCl 3，400MHz)δ：7.18-7.30(m，3H)，5.49(s，1H)，3.70(s，2H)，2.28(s，3H)，2.27(s，3H)，1.32(s，9H)。
Midbody 20
Figure GPA00000702890000383
Title compound is raw material such as general operation A with midbody 1 with midbody 3, and the said preparation of step 4 gets white solid.
1H-NMR(CDCl 3，400MHz)δ：7.76(t，1H)，7.49(m，2H)，5.53(s，1H)，3.72(s，2H)，1.30(s，9H)。
Midbody 21
Figure GPA00000702890000391
Title compound is raw material such as general operation A with midbody 1 with midbody 4, and the said preparation of step 4 gets white solid.
1H-NMR(CDCl 3，400MHz)δ：7.38(s，1H)，7.31-7.33(m，2H)，7.13(m，1H)，5.51(s，1H)，3.73(s，2H)，2.39(s，3H)，1.31(s，9H)。
Midbody 22
Figure GPA00000702890000392
Title compound is raw material such as general operation A with midbody 1 with midbody 5, and the said preparation of step 4 gets white solid.
1H-NMR(CDCl 3，400MHz)δ：7.89-7.91(m，2H)，7.51-7.55(m，5H)，5.59(s，1H)，3.50(s，2H)，1.34(s，9H)。
Midbody 23
Figure GPA00000702890000393
Title compound is raw material such as general operation A with midbody 1 with midbody 6, and the said preparation of step 4 gets white solid.
Midbody 24
Figure GPA00000702890000401
Title compound is raw material such as general operation A with midbody 1 with midbody 7, and the said preparation of step 4 gets white solid.
Midbody 25
Figure GPA00000702890000402
Title compound is raw material such as general operation A with midbody 1 with midbody 8, and the said preparation of step 4 gets white solid.
1H-NMR(CDCl 3，400MHz)δ：7.44(d，2H，J＝8.4Hz)，7.29(d，2H，J＝8.4Hz)，5.51(s，1H)，3.72(s，2H)，2.93(m，1H)，1.31(s，9H)，1.25(d，3H)，1.24(d，3H)。
Midbody 26
Figure GPA00000702890000411
Title compound is raw material such as general operation A with midbody 1 with midbody 9, and the said preparation of step 4 gets white solid.
1H-NMR(CDCl 3，400MHz)δ：7.77(d，2H，J＝8.4Hz)，7.69(d，2H，J＝8.4Hz)，5.56(s，1H)，3.76(s，2H)，1.31(s，9H)。
Midbody 27
Figure GPA00000702890000412
Title compound is raw material such as general operation A with midbody 1 with midbody 10, and the said preparation of step 4 gets white solid.
Midbody 28
Figure GPA00000702890000413
In the 50mL round-bottomed bottle, add pivaloyl group acetonitrile (midbody 1) 1.25g (0.01mol), sodium hydroxide (0.84g 0.021mol) and water 10mL, stirs, and is heated to 50 ℃, add in batches oxammonium hydrochloride (0.76g, 0.011mol).Be warmed up to 100 ℃ after adding, reacted 4 hours, cooling, ethyl acetate extraction, drying, post separates, and gets white plates solid 1.23g, yield 88.0%.
1H-NMR(CDCl 3，400MHz)δ：5.03(s，1H)，4.32(s，2H)，1.27(s，9H)。
By alpha-chloro ketone preparation 1, the general operation B of 3-two substituted-4-amino pyrazoleses
Figure GPA00000702890000421
1. alpha-chloro ketone (0.01mol) is dissolved in 10mL DMF, adds potassium phthalimide (0.01mol), and 70 ℃ were reacted 2 hours, and cooling pours in the 100mL frozen water, separates out white solid, filters, and drying obtains product.
2. the product (0.01mol) that obtains of step 1 is dissolved in 20mL DMF, drips N, and the dinethylformamide dimethylacetal (1.44g, 0.012mol); 100 ℃ were reacted 12 hours, added N, and the dinethylformamide dimethylacetal (1.44g, 0.012mol); Continue reaction 24 hours, cooling pours in the 100mL frozen water ethyl acetate extraction; Drying, post separates, and obtains the white solid product.
3. the product (0.01mol) that obtains of step 2 is dissolved in 100mL 90% ethanol, adds substituted hydrazine (0.011mol), reflux 12 hours, and solid is separated out in cooling, filters, and filter cake washs with anhydrous diethyl ether, and drying obtains the white solid product.
4. the product (0.01mol) that obtains of step 3 is dissolved in 100mL ethanol, drips 85% hydrazine hydrate solution (0.04mol), and reflux 2 hours is separated out white solid; Cooling concentrates, and adds the 20mL ether; Filter, filter cake washs with anhydrous diethyl ether, merging filtrate; Concentrate, post separates, and obtains the white powder product.
Midbody 29
Figure GPA00000702890000431
Aluminum trichloride (anhydrous) (5.60g 0.04mol) is suspended in the 40mL dry toluene, stirs, slowly drip under the room temperature chloroacetyl chloride (4.52g, 0.04mol); Aluminum chloride dissolves gradually, slowly is warmed up to 80 ℃ of reactions 2 hours, and separatory is poured in the solution of 100g trash ice and 10mL concentrated hydrochloric acid formation in cooling into; Water layer is with methylbenzene extraction three times, and the combining methylbenzene layer is used 10% sodium hydroxide successively, water, saturated common salt water washing; Drying, post separates, and obtains product, yield 86.3%.
Midbody 30
Figure GPA00000702890000432
Title compound is raw material such as general operation B with midbody 29 with potassium phthalimide, and the said preparation of step 1 gets white solid, yield 87.8%.
1H-NMR(CDCl 3，400MHz)δ：7.88-7.91(m，4H)，7.76(m，2H)，7.30-7.32(m，2H)，5.51(s，2H)，2.44(s，3H)。
Midbody 31
Figure GPA00000702890000433
Title compound is raw material such as general operation B with midbody 30, and the said preparation of step 2 gets white solid, yield 61.5%.
Midbody 32
Figure GPA00000702890000441
Title compound is raw material such as general operation B with midbody 31, and the said preparation of step 3 gets white solid, yield 72.3%.
Midbody 33
Figure GPA00000702890000442
Title compound is raw material such as general operation B with midbody 32, and the said preparation of step 4 gets white solid, yield 82.6%.
1H-NMR(CDCl 3，400MHz)δ：7.21-7.26(m，5H)，2.68(s，2H)，2.41(s，3H)，1.41(s，9H)。
By alpha-chloro ketone preparation 1, the general operation C of 4-two replacement-2-aminooimidazole classes
Figure GPA00000702890000443
1. alpha-chloro ketone (0.012mol) is dissolved in 20mLDMF with arylamine (0.01mol), and the adding sodium hydrogencarbonate (1.26g, 0.015mol), 75 ℃ were reacted 48 hours, and cooling is poured in the 100mL frozen water, separates out solid, filters, and drying obtains product.Yield 99.2%.
2. the product (0.01mol) that obtains of step 1, (4.23g is 0.10mol) 100mL reflux in ethanol 12 hours for cyanamide.Concentrate, resistates adds entry, with ethyl acetate extraction three times, merges organic layer, uses diluted sodium hydroxide solution successively, water, and the saturated common salt water washing, drying, the post separation obtains the white solid product.
Midbody 34
Figure GPA00000702890000451
Title compound is to be raw material such as general operation C to monomethylaniline and pivaloyl group methyl chloride, and the said preparation of step 1 gets white solid, yield 99.2%.
Midbody 35
Title compound is raw material such as general operation C with midbody 35, and the said preparation of step 2 gets white solid, yield 56.7%.
1H-NMR(CDCl 3，400MHz)δ：7.26(m，4H)，6.35(s，1H)，4.18(s，2H)，2.39(s，3H)，1.27(s，9H)。
P-L-Ar 2NH 2According to the difference of structure, can be synthetic by following route.
1.8-amino-5-methoxyl group-2H-chromene is synthetic.
Figure GPA00000702890000461
(1) (4.96g 0.04mol) is dissolved in the 50mL propionic acid to the 3-methoxyphenol, is cooled to-10 ℃, drips the 0.5mL propionic anhydride; Add Sodium Nitrite (2.90g 0.042mol), separates out brown solid, reacts 1 hour in batches; Pour in the 250mL frozen water, filter, washing, drying obtains 4.03g Midbody 36, be pale brown look solid.
(2) (1.53g 0.01mol) is dissolved in the 16mL propionic acid to midbody 36, is cooled to-12 ℃, and (1.26g 0.02mol), stirred 2 hours, poured in the 50mL frozen water, separated out solid, filtered, and washed, and drying obtains 1.38g to drip nitrosonitric acid Midbody 37, be pale brown look solid, yield 77.4%.
(3) midbody 37 (1.69g 0.01mol) is dissolved in 15mLDMF, add the 3-propargyl bromide (1.43g, 0.012mol), 70 ℃ of reactions 6 hours, cooling is poured in the frozen water, separates out the khaki color solid, filter, washing, drying obtains 1.87g Midbody 38, be pale brown look solid, yield 90.3%.
(4) (8.46g 0.041mol) is dissolved in 88mL N to midbody 38, and the N-Diethyl Aniline is heated to 180-210 ℃ of reaction 1-6 hour; Cooling is poured in the 500mL cold dilute hydrochloric acid, filters, and filtrating is with ethyl acetate extraction three times; The combined ethyl acetate layer, the saturated common salt washing, drying, the post separation obtains 1.84g Midbody 39, be yellow solid, yield 21.8%.
(5) midbody 39 (1.24g 6mmol) is dissolved in 50mL ETHYLE ACETATE and 50mL ethanol, add in batches two hydrated stannous chlorides (5.41g, 24mmol), it is muddy that reaction solution becomes; Reflux 8 hours, cooling adds saturated sodium bicarbonate solution, until obvious layering occurring; Separatory, water layer merge organic layer with ethyl acetate extraction 2 times, use the saturated common salt water washing; Anhydrous sodium sulfate drying filters, and concentrates, and the post separation obtains 0.64g Midbody 40,Yield 59.9%.
(6) (1.04g 0.005mol) is dissolved in the 50mL absolute ethyl alcohol to midbody 39, if 0.2g palladium/charcoal is warmed up to 70 ℃, drips 1.0mL Hydrazine Hydrate 80 (85%), and temperature rising reflux 4 hours cools off, and filters, and filtrating is dry, concentrates to obtain 0.62g Midbody 41, yield 72.5%.
2.8-amino-3,4-dihydro-5-substituted alkoxy-2H-chromene.The same general formula I of the definition of P.
Figure GPA00000702890000481
(1) Resorcinol (44.0g 0.40mol) is dissolved in 150mLDMF, add Anhydrous potassium carbonate (66.24g, 0.48mol); The ice-water bath cooling drips bromobenzyl down, and (47.88g 0.28mol), finishes reaction 5 hours, pours in the cold dilute hydrochloric acid; Make and show acid, ethyl acetate extraction three times, combined ethyl acetate layer; The saturated common salt washing, drying, the post separation obtains 26.25g Midbody 42, be colorless oil, become white solid after the placement, yield 46.9%.
(2) Midbody 43With midbody 42 is raw material, and the method preparation according to synthetic intermediate 37 is brown solid, yield 74.1%.
(3) Midbody 44With midbody 43 is raw material, and the method preparation according to synthetic intermediate 38 is brown solid, yield 89.0%.
(4) Midbody 45With midbody 44 is raw material, and the method preparation according to synthetic intermediate 39 is brown solid, yield 95.0%.
(5) Midbody 46With midbody 45 is raw material, and the method preparation according to synthetic intermediate 40 is yellow solid, yield 20-25%.
(6) 5.0g midbody 46 is dissolved in the 100mL absolute ethyl alcohol, drips 2 hydrochloric acid, adds 2.0g palladium/charcoal, is heated to 60 ℃; Drip 10.0mL Hydrazine Hydrate 80 (85%), temperature rising reflux 6 hours, cooling is filtered; Filtrating is dry, concentrates, and resistates is dissolved in the 100mL methylene dichloride; Add the 3.0mL triethylamine, the ice-water bath cooling drips 4.0g (Boc) 2O, room temperature reaction spends the night then, pour in the water, dichloromethane extraction, drying, the post separation obtains 1.69g Midbody 48, be the white powder solid.
(7) (2.20g 8.3mmol) is dissolved in the 50mL acetonitrile to midbody 48, adds the 1.37g Anhydrous potassium carbonate, drips 1; The 2-dibromopropane (6.23g, 33mmol), reflux 72 hours concentrates; Resistates adds 30mL water, ethyl acetate extraction three times, combined ethyl acetate layer; The saturated common salt washing, drying, the post separation obtains 0.83g Midbody 49, and reclaim raw material 1.61g.
(8) the general operation C of synthetic intermediate XXV.
A. midbody 49 (1.86g 5mmol) is dissolved in 20mL DMF, adds the 0.83g Anhydrous potassium carbonate, adds HP (6mmol), 80 ℃ of reactions 1-6 hour, cooling is poured in the cold water, ethyl acetate extraction, drying, post separates and obtains compounds X XIV.
B. compounds X XIV (2mmol) is dissolved in the 20mL methylene dichloride, is cooled to-5 ℃, drips the 2.0mL trifluoroacetic acid, reacts 2 hours; Concentrate, resistates adds 30mL water, is transferred to pH 10 with 1N sodium hydroxide; Ethyl acetate extraction, drying concentrates; Obtain the bullion of XXV, purifying directly is not used for next step reaction.
Midbody 50
Figure GPA00000702890000501
Title compound is raw material such as the said preparation of general operation C with midbody 49 with the morphine quinoline.
Midbody 51
Figure GPA00000702890000502
Title compound is raw material such as the said preparation of general operation C with midbody 49 with the 4-piperidone.
Midbody 52
Figure GPA00000702890000503
Title compound is raw material such as the said preparation of general operation C with midbody 49 with imidazoles.
Midbody 53
Figure GPA00000702890000504
Title compound is with midbody 49 and 1,2, and the 4-triazole is raw material such as the said preparation of general operation C.
Midbody 54
Figure GPA00000702890000511
Title compound is raw material such as the said preparation of general operation C with midbody 49 with pyrazoles.
Midbody 55
Title compound is with midbody 49 and cis-2, and 6-thebaine quinoline is raw material such as the said preparation of general operation C.
Midbody 56
Figure GPA00000702890000513
Title compound is raw material such as the said preparation of general operation C with midbody 49 with the 4-pyridone.
Midbody 57
Figure GPA00000702890000521
Midbody 48 (1.59g 6mmol) is dissolved in the 50mL anhydrous tetrahydro furan, add 4-(2-hydroxyethyl) pyridine (616mg, 5mmol), triphenyl phosphorus (1.57g, 5mmol) with DEAD (1.05g, 5mmol), reflux 3 hours, reaction completion.The post separation obtains 1.76g midbody 57, yield 95.0%.
Midbody 58
Figure GPA00000702890000522
Title compound is raw material such as general operation C with midbody 57, the said preparation of step b.
Midbody 59
Figure GPA00000702890000523
Title compound is raw material such as the said preparation of general operation C with midbody 48 and 4-(2-chloracetyl) pyridine.
3.8-amino-5-substituted alkoxy-2H-chromene.The same general formula I of the definition of P.
(1) midbody 45 (70.83g 0.25mol) is dissolved in 300mL ETHYLE ACETATE, adds the 300mL Hydrogen bromide, reflux 8 hours, underpressure distillation, the resistates post separates and obtains 31.1g Midbody 60, be the reddish-brown solid, yield 64.4%.
(2) (38.26g 0.198mol) is dissolved in 200mL DMF to midbody 60, and (32.84g 0.24mol), adds methoxyl group benzyl chloride (6mmol), and anti-8 hours of room temperature is poured in the cold water, separates out pale brown look solid, filters, and drying obtains 58.96g to add Anhydrous potassium carbonate Midbody 61, yield 95.0%.
(3) be raw material with midbody 61, adopt the preparation method of midbody 46, obtain xanchromatic Midbody 62, yield 20-45%.
(4) (18.2g 0.058mol) is dissolved in the 150mL methylene dichloride to midbody 61, is cooled to-10 ℃, drips the 10.0mL trifluoroacetic acid; Reacted 8 hours, and concentrated, resistates adds 50mL water, is transferred to pH 10 with 1N sodium hydroxide; Ethyl acetate extraction, drying concentrates, and the post separation obtains 7.5g Midbody 63, be yellow solid.
(5) (5.97g 31mmol) is dissolved in the 150mL acetonitrile to midbody 63, adds the 5.13g Anhydrous potassium carbonate, drips 1; The 2-dibromopropane (23.23g, 124mmol), reflux 2.5 hours concentrates; Resistates adds 50mL water, ethyl acetate extraction three times, combined ethyl acetate layer; The saturated common salt washing, drying, the post separation obtains 4.69g Midbody 64, be yellow solid, yield 34.4%.
(6) the general operation D of synthetic intermediate XXVII.
A. midbody 64 (1.50g 5mmol) is dissolved in 20mLDMF, adds the 0.83g Anhydrous potassium carbonate, adds HP (6mmol), 80 ℃ of reactions 2-6 hour, cooling is poured in the cold water, ethyl acetate extraction, drying, post separates and obtains compounds X XVI.
B. compounds X XVI (5mmol) is dissolved in 50mL ETHYLE ACETATE and 50mL ethanol, add in batches two hydrated stannous chlorides (4.50g, 20mmol), it is muddy that reaction solution becomes; Reflux 8 hours, cooling adds saturated sodium bicarbonate solution, until obvious layering occurring; Separatory, water layer merge organic layer with ethyl acetate extraction 2 times, use the saturated common salt water washing; Anhydrous sodium sulfate drying filters, and concentrates and obtains compounds X XVII, yield 85-95%.Purifying directly is not used for next step reaction.
Midbody 65
Title compound is raw material such as the said preparation of general operation D with midbody 64 with the morphine quinoline.
Midbody 66
Figure GPA00000702890000542
Title compound is with midbody 64 and cis-2, and 6-thebaine quinoline is raw material such as the said preparation of general operation D.
Midbody 67
Figure GPA00000702890000551
Title compound is raw material such as the said preparation of general operation D with midbody 64 with the 4-pyridone.
Midbody 68
Figure GPA00000702890000552
Title compound is raw material such as the said preparation of general operation D with midbody 63 and 4-(2-chloracetyl) pyridine.
Midbody 69
Figure GPA00000702890000553
Title compound is with midbody 64 and 1,2, and the 4-triazole is raw material such as the said preparation of general operation D.
Midbody 70
Figure GPA00000702890000554
Title compound is raw material such as the said preparation of general operation D with midbody 64 with the 4-piperidone.
4.8-amino-5-substituted-amino-2H-chromene.
Figure GPA00000702890000561
(1) (46.2g 0.30mol) is dissolved in the 300mL methylene dichloride to 2-amino-5-nitrophenols, is cooled to-5 ℃, and (36.3g 0.33mol), stirs and drips (Boc) down to add triethylamine 2(72.0g, 0.33mol), reflux is 6 hours then for O.Cooling is poured in the 500mL water, and separatory, water layer merge organic layer with dichloromethane extraction 2 times, saturated common salt water washing, anhydrous sodium sulfate drying, concentrated obtaining Midbody 71, be yellow heavy-gravity solid.
(2) upward go on foot the midbody 71 that obtains and be dissolved in 200mL DMF, (41.4g is 0.30mol) with 3-propargyl bromide (35.7g to add Anhydrous potassium carbonate; 0.30mol), be heated to 70 ℃ of reactions 8 hours, cooling; Pour in the water, separate out yellow solid, recrystallization from ethyl acetate/petroleum ether obtains 30.5g Midbody 72
(3) midbody 72 (15.32g) is dissolved in 100mL N, and the N-Diethyl Aniline is heated to 180 ℃ of reactions 4 hours, and underpressure distillation removes and desolvates, and resistates obtains 7.94g through the post separation Midbody 73, be yellow solid, yield 78.8%.
(4) midbody 73 (1.92g 10mmol) is dissolved in the 30mL methylene dichloride, is cooled to-5 ℃, add triethylamine (1.21g, 11mmol); (1.24g 11mmol), refluxed 24 hours, cooling to drip chloroacetyl chloride under stirring; Pour in the water, dichloromethane extraction, drying, the post separation obtains 1.53g Midbody 74, be yellow solid, yield 57.3%.
(5) midbody 74 (1.34g 5mmol) is dissolved in 10mL DMF, add Anhydrous potassium carbonate (0.83g, 6mmol) with the morphine quinoline (0.52g, 6mmol), 80 ℃ of reactions 4 hours are poured in the water, ethyl acetate extraction, drying, post separates and obtains 1.48g Midbody 75, be yellow solid, yield 92.7%.
(6) midbody 75 (640mg 2mmol) is dissolved in 30mL ETHYLE ACETATE and 30mL ethanol, add in batches two hydrated stannous chlorides (1.80g, 8mmol); It is muddy that reaction solution becomes, reflux 8 hours, and cooling adds saturated sodium bicarbonate solution; Until obvious layering occurring, separatory, water layer is with ethyl acetate extraction 2 times, merging organic layer; Use the saturated common salt water washing, anhydrous sodium sulfate drying filters, and concentrates and obtains 545mg Midbody 76, yield 94.3%.Purifying directly is not used for next step reaction.
5.5-amino-8-substituted-amino-2H-chromene.
Figure GPA00000702890000571
(1) (1.92g 10mmol) is dissolved in the 30mL methylene dichloride to midbody 73, is cooled to 0 ℃, and (1.21g 11mmol), stirs and drips (Boc) down to add triethylamine 2O (2.38g 11mmol), refluxed 48 hours, and cooling is poured in the water, dichloromethane extraction, and drying, the post separation obtains 1.34g Midbody 77, be yellow solid, yield 45.9%.
(2) (1.5g 5.14mmol) is dissolved in 50mL ethanol to midbody 77, adds 0.3g palladium/charcoal, is heated to 60 ℃, drips 2.0mL Hydrazine Hydrate 80 (85%), and temperature rising reflux 1 hour cools off, and filters, and filtrating is dry, concentrates, and obtains 1.39g Midbody 78
(3) midbody 78 is dissolved in the 30mL methylene dichloride, adds the 1.2mL triethylamine, the ice-water bath cooling, the dropping chloroacetyl chloride (0.68g 6mmol), reacted 2 hours, pours in the water, and dichloromethane extraction, drying, the post separation obtains 378mg Midbody 79, be the white powder solid.
(4) midbody 79 (534mg 1.57mmol) is dissolved in 10mL DMF, add Anhydrous potassium carbonate (324mg, 2.35mmol) with the morphine quinoline (204mg, 2.35mmol), 80 ℃ of reactions 4 hours are poured in the water, ethyl acetate extraction, drying, post separates and obtains 313mg Midbody 80, be the white granular solid, yield 50.9%.
(5) midbody 80 (313mg 0.8mmol) is dissolved in the 30mL methylene dichloride, is cooled to 0 ℃, drips the 1.5mL trifluoroacetic acid, react 4 hours, concentrates, and resistates adds 30mL water, is transferred to pH 10 with 1N sodium hydroxide, ethyl acetate extraction, drying, concentrated, obtain 176mg Midbody 81Bullion, purifying directly is not used for next step reaction.
Embodiment
Embodiment 1:1-[the 3-tertiary butyl-1-(4-aminomethyl phenyl)-1H-5-pyrazolyl]-3-[8-(3,4-dihydro-5-methoxyl group-2H-chromenyl)] urea
In the 50mL there-necked flask, add 20mL exsiccant methylene dichloride, be cooled to-10 ℃, add TRIPHOSGENE 99.5 (109mg; 0.36mmol), drip 0.4mL exsiccant triethylamine, slowly drip midbody 41 (180mg; 1.0mmol) be dissolved in the solution of 10mL dry methylene chloride, reacted 1 hour.(138mg 0.6mmol), is warming up to room temperature, and reflux is 48 hours then to add midbody 11.Cooling is poured in the 50mL water, with dichloromethane extraction 3 times; Organic layer is used the saturated common salt water washing; Anhydrous sodium sulfate drying, post separates (eluent system: petrol ether/ethyl acetate) obtain 1-[the 3-tertiary butyl-1-(4-aminomethyl phenyl)-1H-5-pyrazolyl]-3-[8-(3,4-dihydro-5-methoxyl group-2H-chromenyl)] urea 94mg; Be white crystal, yield 21.8%.
1H-NMR(DMSO，400MHz)δ：8.84(s，1H)，8.30(s，1H)，7.77(d，1H，J＝8.96Hz)，7.33-7.37(m，4H)，6.41(d，1H，J＝9.00Hz)，6.33(s，1H)，4.14(t，2H，J＝4.76Hz)，3.71(s，3H)，2.50(t，2H)，2.37(s，3H)，1.88(p，2H)，1.25(s，9H)。
MS(FAB)m/z：435.1[M+1] +。
Embodiment 2:1-[the 3-tertiary butyl-1-(4-chloro-phenyl-)-1H-5-pyrazolyl]-3-[8-(5-methoxyl group-2H-chromenyl)] urea
Adopt the preparation method of embodiment 1, change wherein midbody 11 into midbody 15, midbody 41 changes midbody 40 into, obtains title compound, is white solid.
1H-NMR(DMSO，400MHz)δ：8.91(s，1H)，8.31(s，1H)，7.82(d，1H)，7.52-7.60(m，4H)，6.65(d，1H，J＝10.08Hz)，6.50(d，1H，J＝9.28Hz)，6.36(s，1H)，5.87(m，1H)，4.76(t，2H，J＝1.68Hz)，3.74(s，3H)，1.26(s，9H)。
MS(FAB)m/z：453.0[M+1] +。
Embodiment 3:1-[the 3-tertiary butyl-1-(4-aminomethyl phenyl)-1H-5-pyrazolyl]-3-[8-(5-methoxyl group-2H-chromenyl)] urea
Adopt the preparation method of embodiment 1, change wherein midbody 41 into midbody 40, obtain title compound, be white solid.
1H-NMR(DMSO，400MHz)δ：8.83(s，1H)，8.35(s，1H)，7.81(d，1H，J＝9.24Hz)，7.33-7.37(m，4H)，6.65(d，1H，J＝8.12Hz)，6.50(d，1H，J＝9.24Hz)，6.33(s，1H)，5.85(m，1H)，4.75(t，2H，J＝1.68Hz)，3.74(s，3H)，2.37(s，3H)，1.26(s，9H)。
MS(FAB)m/z：433.1[M+1] +。
Embodiment 4:1-[the 3-tertiary butyl-1-(4-aminomethyl phenyl)-1H-5-pyrazolyl]-3-{5-{8-[2-(4-morphine quinoline base) acetamido]-2H-chromenyl } } urea
Adopt the preparation method of embodiment 1, change wherein midbody 41 into midbody 76, obtain title compound, be white solid.
1H-NMR(CDCl 3，400MHz)δ：9.46(s，1H)，7.96(s，1H)，7.17-7.26(m，4H)，6.85(d，1H)，6.71(d，1H，J＝1.36Hz)，6.40(s，1H)，6.36(d，1H，J＝10.64Hz)，5.76(m，1H)，4.76(t，2H)，3.78(t，4H)，3.04(s，2H)，2.62(t，4H)，2.35(s，3H)，1.33(s，9H)。
MS(FAB)m/z：545.1[M+1] +。
Embodiment 5:1-[the 3-tertiary butyl-1-phenyl-1H-5-pyrazolyl]-3-[8-(3,4-dihydro-5-methoxyl group-2H-chromenyl)] urea
The product 200mg that embodiment 2 obtains is dissolved in the 50mL absolute ethyl alcohol, adds 0.2g palladium/charcoal, is heated to 60 ℃, dropping 1.0mL Hydrazine Hydrate 80, and reflux is 6 hours then, and cooling is filtered, and filtrating concentrates, and the post separation obtains title compound 149mg, is white solid.
1H-NMR(CDCl 3，400MHz)δ：7.67(d，1H)，7.32-7.46(m，5H)，7.18(s，1H)，6.54(s，1H)，6.42(s，1H)，6.35(d，1H，J＝8.8Hz)，4.08(t，2H，J＝8.8Hz)，3.79(s，3H)，2.62(t，2H，J＝6.8Hz)，1.92(p，2H)，1.37(s，9H)。
MS(FAB)m/z：421.1[M+1] +。
Embodiment 6:1-[the 3-tertiary butyl-1-(4-aminomethyl phenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } urea
Adopt the preparation method of embodiment 1, change wherein midbody 41 into midbody 40, obtain title compound, be white solid.
1H-NMR(CDCl 3，400MHz)δ：7.69(d，1H，J＝8.4Hz)，7.29-7.31(m，3H)，7.16(m，2H)，6.84(s，1H)，6.31-6.34(m，2H)，4.04-4.07(m，4H)，3.72(t，4H)，2.80(t，2H，J＝5.2Hz)，2.60(t，2H)，2.59(t，4H)，2.31(s，3H)，1.91(p，2H)，1.34(s，9H)。
MS(FAB)m/z：534.2[M+1] +。
Embodiment 7:1-[the 3-tertiary butyl-1-(4-aminomethyl phenyl)-1H-5-pyrazolyl]-3-[8-(5-nitro-2H-chromenyl)] urea
Adopt the preparation method of embodiment 1, change wherein midbody 41 into midbody 73, obtain title compound, be white solid.
1H-NMR(CDCl 3，400MHz)δ：8.19(d，1H，J＝9.2Hz)，7.87(s，1H)，7.71(d，1H，J＝9.2Hz)，7.19-7.35(m，5H)，6.68(s，1H)，6.35(s，1H)，6.06(m，1H)，4.78(t，2H)，2.35(s，3H)，1.37(s，9H)。
MS(FAB)m/z：448.2[M+1] +。
Embodiment 8:1-[the 3-tertiary butyl-1-phenyl-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } urea
In the 50mL there-necked flask, add 20mL exsiccant methylene dichloride, be cooled to-10 ℃, add TRIPHOSGENE 99.5 (109mg; 0.36mmol), (280mg 1.0mmol) is dissolved in the solution of 10mL dry methylene chloride slowly to drip midbody 50; The adularescent deposition produces; Reacted 1 hour, and dripped 0.4mL exsiccant triethylamine, resolution of precipitate.(129mg 0.6mmol), is warming up to room temperature to add midbody 12; Reacted 5 days, and poured in the 50mL water, with dichloromethane extraction 3 times; Organic layer is used the saturated common salt water washing, anhydrous sodium sulfate drying, and post separates (eluent system: petrol ether/ethyl acetate) obtain title compound 136mg; Be white crystal, yield 26.2%.
1H-NMR(CDCl 3，400MHz)δ：7.67(d，1H，J＝8.4Hz)，7.32-7.45(m，2H)，7.34(m，3H)，7.28(m，1H)，7.03(s，1H)，6.35(s，1H)，6.31(d，1H，J＝10.8Hz)，4.04-4.06(m，4H)，3.70(t，4H，J＝4.8Hz)，2.77(t，2H，J＝5.6Hz)，2.56-2.61(m，6H)，1.90(p，2H)，1.34(s，9H)。
MS(FAB)m/z：520.2[M+1] +。
Embodiment 9:1-[the 3-tertiary butyl-1-(4-fluorophenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } urea
Adopt the preparation method of embodiment 8, change wherein midbody 12 into midbody 14, obtain title compound, be white solid.
1H-NMR(CDCl 3，400MHz)δ：7.64(d，1H，J＝8.8Hz)，7.38-7.41(m，3H)，7.32(s，1H)，6.99(m，2H)，6.30-6.32(m，2H)，4.04-4.08(m，4H)，3.71(t，4H，J＝4.8Hz)，2.79(t，2H，J＝5.6Hz)，2.56-2.59(m，6H)，1.90(p，2H)，1.32(s，9H)。
MS(FAB)m/z：538.1[M+1] +。
Embodiment 10:1-[the 3-tertiary butyl-1-(4-chloro-phenyl-)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } urea
Adopt the preparation method of embodiment 8, change wherein midbody 12 into midbody 15, obtain title compound, be white solid.
1H-NMR(CDCl 3，400MHz)δ：7.63(d，1H，J＝8.0Hz)，7.42(m，2H)，7.35(m，2H)，7.11(s，1H)，6.55(s，1H)，6.37(s，1H)，6.34(d，1H)，4.08(m，4H)，3.74(t，4H，J＝4.4Hz)，2.82(t，2H，J＝5.6Hz)，2.62-2.65(m，6H)，1.94(p，2H)，1.36(s，9H)。
MS(FAB)m/z：554.0[M+1] +。
Embodiment 11:1-[the 3-tertiary butyl-1-(4-bromophenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } urea
Adopt the preparation method of embodiment 8, change wherein midbody 12 into midbody 16, obtain title compound, be white solid.
1H-NMR(CDCl 3，400MHz)δ：7.64(d，1H，J＝8.0Hz)，7.47(m，2H)，7.37(m，2H)，7.20(s，1H)，6.88(s，1H)，6.37(s，1H)，6.34(d，1H，J＝8.8Hz)，4.08(m，4H)，3.73(t，4H，J＝4.4Hz)，2.83(t，2H，J＝5.6Hz)，2.60-2.61(m，6H)，1.92(p，2H)，1.36(s，9H)。
MS(FAB)m/z：598.0[M+1] +。
Embodiment 12:1-[the 3-tertiary butyl-1-(4-p-methoxy-phenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } urea
Adopt the preparation method of embodiment 8, change wherein midbody 12 into midbody 13, obtain title compound, be white solid.
1H-NMR(CDCl 3，400MHz)δ：7.70(d，1H，J＝8.4Hz)，7.35(m，2H)，7.24(s，1H)，6.90(m，2H)，6.52(s，1H)，6.34(s，1H)，6.32(d，1H)，4.08(m，4H)，3.79(s，3H)，3.74(t，4H，J＝4.4Hz)，2.81(t，2H，J＝6.0Hz)，2.59-2.63(m，6H)，1.93(p，2H)，1.35(s，9H)。
MS(FAB)m/z：550.1[M+1] +。
Embodiment 13:1-[the 3-tertiary butyl-1-(4-amino-sulfonyl phenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } urea
Adopt the preparation method of embodiment 8, change wherein midbody 12 into midbody 18, obtain title compound, be white solid.
1H-NMR(CDCl 3，400MHz)δ：8.80(d，2H，J＝8.8Hz)，7.78(d，2H，J＝8.8Hz)，7.66(d，1H)，6.29(d，1H，J＝9.2Hz)，5.56(s，1H)，5.23(t，2H)，4.12(t，2H)，3.79(m，6H)，2.90(t，2H)，2.63-2.70(m，6H)，2.00(p，2H)，1.29(s，9H)。
MS(FAB)m/z：599.1[M+1] +。
Embodiment 14:1-[the 3-tertiary butyl-1-(4-nitrophenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } urea
Adopt the preparation method of embodiment 8, change wherein midbody 12 into midbody 17, obtain title compound, be yellow solid.
1H-NMR(CDCl 3，400MHz)δ：8.13(d，2H，J＝9.6Hz)，7.84(s，1H)，7.73(d，2H，J＝9.2Hz)，7.55(d，1H，J＝8.4Hz)，7.43(s，1H)，6.38(s，1H)，6.29(d，1H，J＝8.8Hz)，4.07(m，4H)，3.72(t，4H，J＝4.8Hz)，2.81(t，2H)，2.58-2.62(m，6H)，1.91(p，2H)，1.33(s，9H)。
MS(FAB)m/z：565.0[M+1] +。
Embodiment 15:1-[the 3-tertiary butyl-1-(4-aminomethyl phenyl)-1H-5-pyrazolyl]-3-{8-[3,4-dihydro-5-(4-morphine quinoline base acyl group methoxyl group)-2H-chromenyl] } urea
Adopt the preparation method of embodiment 8, change wherein midbody 12 into midbody 11, midbody 50 changes midbody 59 into, obtains title compound, is white solid.
1H-NMR(CDCl 3，400MHz)δ：7.75(d，1H，J＝9.2Hz)，7.34(d，2H，J＝8.4Hz)，7.25(d，2H)，6.38(s，1H)，6.34(d，1H，J＝9.2Hz)，4.64(s，2H)，4.11(t，2H，J＝3.6Hz)，3.63-3.67(m，8H)，2.67(t，2H，J＝6.4Hz)，2.37(s，3H)，1.95(p，2H)，1.36(s，9H)。
MS(FAB)m/z：548.1[M+1] +。
Embodiment 16:1-(the 3-tertiary butyl-5-different
Figure GPA00000702890000651
azoles base)-3-{8-{3,4-dihydro-5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } urea
Adopt the preparation method of embodiment 8, change wherein midbody 12 into midbody 28, obtain title compound, be white solid.
1H-NMR(CDCl 3，400MHz)δ：8.59(s，1H)，7.67(d，1H，J＝8.0Hz)，6.36(d，1H，J＝9.2Hz)，6.12(s，1H)，4.08-4.10(m，4H)，3.75(t，4H，J＝4.4Hz)，2.83(t，2H，J＝5.6Hz)，2.60-2.64(m，6H)，1.92(p，2H)，1.30(s，9H)。
MS(FAB)m/z：445.1[M+1] +。
Embodiment 17:1-(the 5-tertiary butyl-3-different
Figure GPA00000702890000652
azoles base)-3-{8-{3,4-dihydro-5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } urea
Adopt the preparation method of embodiment 8; Change midbody 12 wherein into 3-amino-5-tertiary butyl different
Figure GPA00000702890000653
azoles; Obtain title compound, be white solid.
1H-NMR(CDCl 3，400MHz)δ：8.75(s，2H)，7.86(d，1H，J＝8.8Hz)，6.37(d，1H，J＝8.8Hz)，6.07(s，1H)，4.23(t，2H，J＝4.8Hz)，4.10(t.2H)，3.74(t，4H，J＝4.4Hz)，2.82(t，2H，J＝5.2Hz)，2.61-2.67(m，6H)，1.99(p，2H)，1.34(s，9H)。
MS(FAB)m/z：445.1[M+1] +。
Embodiment 18:1-[the 1-tertiary butyl-3-(4-aminomethyl phenyl)-1H-4-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } urea
Adopt the preparation method of embodiment 8, change wherein midbody 12 into midbody 33, obtain title compound, be white solid.
1H-NMR(CDCl 3，400MHz)δ：7.70(s，1H)，7.63(d，1H，J＝9.2Hz)，7.14-7.17(m，4H)，6.86(s，1H)，6.29(d，1H，J＝8.4Hz)，5.80(s，1H)，4.04-4.06(m，4H)，3.71(t，4H，J＝4.0Hz)，2.78(t，2H)，2.56-2.58(m，6H)，2.36(s，3H)，1.92(p，2H)，1.43(s，9H)。
MS(FAB)m/z：534.2[M+1] +。
Embodiment 19:1-[the 4-tertiary butyl-1-(4-aminomethyl phenyl)-1H-2-imidazolyl]-3-{8-{3,4-dihydro-5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } urea
Adopt the preparation method of embodiment 8, change wherein midbody 12 into midbody 35, obtain title compound, be white solid.
1H-NMR(CDCl 3，400MHz)δ：11.56(s，1H)，7.98(d，1H，J＝9.2Hz)，7.21-7.26(m，4H)，6.75(s，1H)，6.45(s，1H)，6.37(d，1H，J＝8.8Hz)，4.29(t，2H)，4.08(t，2H，J＝5.6Hz)，3.71(t，4H，J＝4.8Hz)，2.79(t，2H)，2.70(t，2H)，2.58(t，4H，J＝4.4Hz)，2.39(s，3H)，2.32(p，2H)，1.34(s，9H)。
MS(FAB)m/z：534.2[M+1] +。
Embodiment 20:1-[the 3-tertiary butyl-1-(4-aminomethyl phenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-(4-pyridyl) oxygen base oxethyl]-2H-chromenyl } urea
Adopt the preparation method of embodiment 15, change wherein midbody 59 into midbody 56, obtain title compound, be white solid.
1H-NMR(CDCl 3，400MHz)δ：8.44(dd，2H，J＝4.8Hz，1.2Hz)，7.79(d，1H，J＝8.8Hz)，7.33(d，2H，J＝8.0Hz)，7.28(s，1H)，7.21(d，2H)，6.91(dd，2H，J＝4.8Hz，1.6Hz)，6.43(s，1H)，6.40(d，1H，J＝9.2Hz)，6.37(s，1H)，4.40(t，2H，J＝5.2Hz)，4.33(t，2H，J＝5.2Hz)，4.12(t，2H)，2.58(t，2H，J＝6.8Hz)，2.36(s，3H)，1.90(p，2H)，1.36(s，9H)。
MS(FAB)m/z：542.0[M+1] +。
Embodiment 21:1-[the 3-tertiary butyl-1-(4-aminomethyl phenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-{2-[4-(cis-2,6-dimethyl-) morphine quinoline base] oxyethyl group }-the 2H-chromenyl } urea
Adopt the preparation method of embodiment 15, change wherein midbody 59 into midbody 55, obtain title compound, be white solid.
1H-NMR(CDCl 3，400MHz)δ：7.71(d，1H，J＝9.2Hz)，7.31(d，2H，J＝8.4Hz)，7.21(d，2H)，7.17(s，1H)，6.31-6.36(m，3H)，4.08-4.10(m，4H)，3.71(m，2H)，2.80-2.86(m，4H)，2.63(t，2H，J＝6.4Hz)，2.36(s，3H)，1.92-1.95(m，4H)，1.35(s，9H)，1.17(d，3H)，1.15(d，3H)。
MS(FAB)m/z：562.2[M+1] +。
Embodiment 22:1-[the 3-tertiary butyl-1-(4-aminomethyl phenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-(1-imidazolyl) oxyethyl group]-2H-chromenyl } urea
Adopt the preparation method of embodiment 15, change wherein midbody 59 into midbody 52, obtain title compound, be white solid.
1H-NMR(CDCl 3，400MHz)δ：7.88(d，1H，J＝8.8Hz)，7.73(s，1H)，7.53(s，1H)，7.32(d，2H，J＝8.0Hz)，7.15(d，2H，J＝8.0Hz)，6.93(s，1H)，6.89(s，1H)，6.41(s，1H)，6.22(d，1H，J＝8.8Hz)，4.32(t，2H，J＝4.8Hz)，4.12(t，2H，J＝5.6Hz)，3.62(t，2H)，2.35(t，2H)，2.32(s，3H)，1.61(p，2H)，1.35(s，9H)。
MS(FAB)m/z：515.2[M+1] +。
Embodiment 23:1-[the 3-tertiary butyl-1-(4-aminomethyl phenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-(1-1,2,4-triazol radical) oxyethyl group]-2H-chromenyl } urea
Adopt the preparation method of embodiment 15, change wherein midbody 59 into midbody 53, obtain title compound, be white solid.
1H-NMR(CDCl 3，400MHz)δ：8.08(s?1H)，7.82-7.84(m，2H)，7.45(s，1H)，7.32(d，2H，J＝8.4Hz)，7.17(d，2H，J＝8.4Hz)，6.40(s，1H)，6.27(d，1H，J＝9.2Hz)，4.56(t，2H，J＝4.8Hz)，4.23(t，2H，J＝4.8Hz)，3.77(t，2H)，2.33-2.36(m，5H)，1.69(p，2H)，1.35(s，9H)。
MS(FAB)m/z：516.3[M+1] +。
Embodiment 24:1-[the 3-tertiary butyl-1-(4-chloro-phenyl-)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-{2-[4-(cis-2,6-dimethyl-) morphine quinoline base] oxyethyl group }-the 2H-chromenyl } urea
Adopt the preparation method of embodiment 8, change wherein midbody 12 into midbody 15, midbody 50 changes midbody 55 into, obtains title compound, is white solid.
1H-NMR(CDCl 3，400MHz)δ：7.63(d，1H，J＝8.4Hz)，7.42(d，2H，J＝8.4Hz)，7.34(d，2H，J＝8.8Hz)，7.16(s，1H)，6.96(s，1H)，6.37(s，1H)，6.34(d，1H，J＝8.8Hz)，4.06-4.09(m，4H)，3.70(m，2H)，2.80-2.85(m，4H)，2.63(t，2H，J＝6.4Hz)，1.91-1.95(m，4H)，1.34(s，9H)，1.17(d，3H)，1.15(d，3H)。
MS(FAB)m/z：582.1[M+1] +。
Embodiment 25:1-[the 3-tertiary butyl-1-(3, the 4-3,5-dimethylphenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } urea
Adopt the preparation method of embodiment 8, change wherein midbody 12 into midbody 19, obtain title compound, be white solid.
1H-NMR(CDCl 3，400MHz)δ：7.68(d，1H，J＝8.8Hz)，7.30(s，1H)，7.19(s，1H)，7.08-7.10(m，2H)，6.80(s，1H)，6.34(s，1H)，6.32(d，1H，J＝8.8Hz)，4.04-4.06(m，4H)，3.71(t，4H，J＝4.4Hz)，2.79(t，2H)，2..57-2.61(m，6H)，2.20-2.21(m，6H)，1.90(p，2H)，1.34(s，9H)。
MS(FAB)m/z：548.1[M+1] +。
Embodiment 26:1-[the 3-tertiary butyl-1-(3, the 4-dichlorophenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } urea
Adopt the preparation method of embodiment 8, change wherein midbody 12 into midbody 20, obtain title compound, be white solid.
1H-NMR(CDCl 3，400MHz)δ：7.76(d，1H，J＝2.0Hz)，7.58(d，1H)，7.43(d，1H，J＝8.4Hz)，7.37(d，1H)，7.17(s，1H)，6.81(s，1H)，6.37(s，1H)，6.34(d，1H，J＝8.8Hz)，4.09-4.11(m，4H)，3.74(t，4H，J＝4.4Hz)，2.83(t，2H，J＝5.2Hz)，2.61-2.64(m，6H)，1.94(p，2H)，1.34(s，9H)。
MS(FAB)m/z：588.0[M+1] +。
Embodiment 27:1-[the 3-tertiary butyl-1-(3-aminomethyl phenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } urea
Adopt the preparation method of embodiment 8, change wherein midbody 12 into midbody 21, obtain title compound, be white solid.
1H-NMR(CDCl 3，400MHz)δ：7.68(d，1H，J＝8.4Hz)，7.21-7.26(m，4H)，7.11(d，1H)，6.83(s，1H)，6.36(s，1H)，6.32(d，1H，J＝8.8Hz)，4.05-4.08(m，4H)，3.73(t，4H，J＝4.4Hz)，2.80(t，2H，J＝5.6Hz)，2..57-2.62(m，6H)，2.32(s，3H)，1.91(p，2H)，1.35(s，9H)。
MS(FAB)m/z：534.2[M+1] +。
Embodiment 28:1-[(the 3-tertiary butyl-1-naphthyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } urea
Adopt the preparation method of embodiment 8, change wherein midbody 12 into midbody 22, obtain title compound, be white solid.
1H-NMR(CDCl 3，400MHz)δ：7.85-7.89(m，2H)，7.43-7.45(m，4H)，7.37(d，1H)，7.04(s，1H)，6.46(m，2H)，6.19(d，1H，J＝8.8Hz)，4.03(t，2H，J＝5.6Hz)，3.97(t，2H，J＝4.8Hz)，3.70(t，4H，J＝4.4Hz)，2.80(t，2H，J＝5.2Hz)，2.55-2.57(m，6H)，1.85(p，2H)，1.38(s，9H)。
MS(FAB)m/z：570.1[M+1] +。
Embodiment 29:1-[the 3-tertiary butyl-1-(4-aminomethyl phenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-(1-pyrazolyl) oxyethyl group]-2H-chromenyl } urea
Adopt the preparation method of embodiment 15, change wherein midbody 59 into midbody 54, obtain title compound, be white solid.
1H-NMR(CDCl 3，400MHz)δ：7.71(d，1H)，7.50-7.53(m，2H)，7.31(d，2H)，7.21(d，2H，J＝8.0Hz)，6.37(s，1H)，6.30(d，1H，J＝8.4Hz)，6.26(t，1H)，4.52(t，2H，J＝5.2Hz)，4.28(t，2H，J＝5.2Hz)，4.07(t，2H，J＝5.6Hz)，2.54(t，2H，J＝6.4Hz)，2.35(s，3H)，1.91(p，2H)，1.36(s，9H)。
MS(FAB)m/z：515.1[M+1] +。
Embodiment 30:1-[the 3-tertiary butyl-1-(4-aminomethyl phenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-(1-piperidin-4-one-base) oxyethyl group]-2H-chromenyl } urea
Adopt the preparation method of embodiment 15, change wherein midbody 59 into midbody 51, obtain title compound, be white solid.
1H-NMR(CDCl 3，400MHz)δ：7.73(d，1H，J＝8.8Hz)，7.30-7.32(m，3H)，7.16(d，2H)，6.85(s，1H)，6.34-6.35(m，2H)，4.10(t，2H)，4.06(t，2H)，2.91-2.94(m，6H)，2.62(t，2H)，2.47(t，4H，J＝6.0Hz)，2.32(s，3H)，1.91(p，2H)，1.35(s，9H)。
MS(FAB)m/z：546.0[M+1] +。
Embodiment 31:1-[the 3-tertiary butyl-1-(4-aminomethyl phenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-(4-morphine quinoline base) acetamido]-2H-chromenyl } urea
Adopt the preparation method of embodiment 15, change wherein midbody 59 into midbody 81, obtain title compound, be white solid.
1H-NMR(CDCl 3，400MHz)δ：7.94(d，1H，J＝8.8Hz)，7.47(s，1H)，7.35(d，2H，J＝8.4Hz)，7.23(d，2H，J＝8.0Hz)，6.36-6.38(m，2H)，4.12(t，2H，J＝4.4Hz)，3.79(t，4H)，3.18(t，2H)，2.61-2.68(m，6H)，2.37(s，3H)，2.03(p，2H)，1.36(s，9H)。
MS(FAB)m/z：547.2[M+1] +。
Embodiment 32:1-[the 3-tertiary butyl-1-(4-trifluoromethyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } urea
Adopt the preparation method of embodiment 8, change wherein midbody 12 into midbody 26, obtain title compound, be white solid.
1H-NMR(CDCl 3，400MHz)δ：7.61-7.65(m，5H)，7.07(s，1H)，6.60(s，1H)，6.41(s，1H)，6.34(d，1H，J＝8.8Hz)，4.07-4.09(m，4H)，3.74(t，4H，J＝4.4Hz)，2.82(t，2H)，2.61-2.64(m，6H)，1.92(p，2H)，1.35(s，9H)。
MS(FAB)m/z：588.0[M+1] +。
Embodiment 33:1-[the 3-tertiary butyl-1-(4-ethylphenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } urea
Adopt the preparation method of embodiment 8, change wherein midbody 12 into midbody 24, obtain title compound, be white solid.
1H-NMR(CDCl 3，400MHz)δ：7.70(d，1H，J＝8.8Hz)，7.32(d，2H，J＝8.4Hz)，7.16(d，2H，J＝8.0Hz)，6.93(s，1H)，6.34(s，1H)，6.32(d，1H，J＝8.8Hz)，4.04-4.06(m，4H)，3.70(t，4H，J＝4.8Hz)，2.78(t，2H)，2.57-2.61(m，8H)，1.90(p，2H)，1.34(s，9H)，1.18(t，3H，J＝7.6Hz)。
MS(FAB)m/z：548.1[M+1] +。
Embodiment 34:1-[the 3-tertiary butyl-1-(4-tert-butyl-phenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } urea
Adopt the preparation method of embodiment 8, change wherein midbody 12 into midbody 25, obtain title compound, be white solid.
1H-NMR(CDCl 3，400MHz)δ：7.72(d，1H，J＝8.8Hz)，7.34(d，2H)，7.26(m，2H)，7.18(s，1H)，6.34-6.37(m，3H)，4.08-4.11(m，4H)，3.74(t，4H，J＝4.4Hz)，2.82(t，2H)，2.62-2.65(m，6H)，1.94(p，2H)，1.35(s，9H)，1.24(d，3H)，1.23(d，3H)。
MS(FAB)m/z：562.1[M+1] +。
Embodiment 35:1-[the 3-tertiary butyl-1-(4-trifluoromethyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-(1-imidazolyl) oxyethyl group]-2H-chromenyl } urea
Adopt the preparation method of embodiment 8, change wherein midbody 12 into midbody 26, midbody 50 changes midbody 52 into, obtains title compound, is white solid.
1H-NMR(CDCl 3，400MHz)δ：8.08(s，1H)，7.91(d，1H，J＝9.2Hz)，7.63(d，2H，J＝8.4Hz)，7.54(d，2H，J＝8.4Hz)，7.46(s，1H)，6.86(s，1H)，6.74(s，1H)，6.51(s，1H)，6.18(d，1H，J＝8.8Hz)，4.29(t，2H，J＝4.4Hz)，4.06(t，2H，J＝4.8Hz)，3.23(t，2H)，2.18(t，2H，J＝6.4Hz)，1.34(s，9H)。
MS(FAB)m/z：569.3[M+1] +。
Embodiment 36:1-[the 3-tertiary butyl-1-(4-aminomethyl phenyl)-1H-5-pyrazolyl]-3-{8-{5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } } urea
In the 50mL there-necked flask, add 20mL exsiccant methylene dichloride, be cooled to-10 ℃, add TRIPHOSGENE 99.5 (109mg; 0.36mmol), (277mg 1.0mmol) is dissolved in the solution of 10mL dry methylene chloride slowly to drip midbody 65; The adularescent deposition produces; Reacted 1 hour, and dripped 0.4mL exsiccant triethylamine, resolution of precipitate.(138mg 0.6mmol), is warming up to room temperature to add midbody 11; Reacted 5 days, and poured in the 50mL water, with dichloromethane extraction 3 times; Organic layer is used the saturated common salt water washing, anhydrous sodium sulfate drying, and post separates (eluent system: petrol ether/ethyl acetate=1: 1) obtain title compound 145mg; Be white crystal, yield 27.3%.
1H-NMR(CDCl 3，400MHz)δ：7.74(d，1H，J＝8.8Hz)，7.33(d，2H，J＝8.4Hz)，7.21(d，2H，J＝8.0Hz)，7.13(s，1H)，6.72-6.74(dd，1H，J＝8.4Hz，1.6Hz)，6.39(d，1H，J＝9.2Hz)，6.35(s，1H)，6.34(s，1H)，5.72(m，1H)，4.71(t，2H，J＝2.0Hz)，4.11(t，2H)，3.74(t，4H)，2.82(t，2H)，2.60(t，4H)，2.36(s，3H)，1.35(s，9H)。
MS(FAB)m/z：532.2[M+1] +。
Embodiment 37:1-[the 3-tertiary butyl-1-(4-aminomethyl phenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-(4-pyridyl) oxyethyl group]-2H-chromenyl } urea
Adopt the preparation method of embodiment 8, change wherein midbody 12 into midbody 11, midbody 50 changes midbody 58 into, obtains title compound, is white solid.
1H-NMR(CDCl 3，400MHz)δ：8.57(d，2H，J＝4.8Hz)，7.75(d，1H，J＝9.2Hz)，7.38(s，1H)，7.28-7.32(m，4H)，7.12(d，2H)，6.82(s，1H)，6.34(s，1H)，6.27(d，1H，J＝9.2Hz)，4.14(t，2H，J＝6.0Hz)，3.94(t，2H)，3.10(t，2H，J＝6.0Hz)，2.47(t，2H，J＝6.4Hz)，2.28(s，3H)，1.82(p，2H)，1.34(s，9H)。
MS(FAB)m/z：526.2[M+1] +。
Embodiment 38:1-[the 3-tertiary butyl-1-(4-itrile group phenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } urea
Adopt the preparation method of embodiment 8, change wherein midbody 12 into midbody 27, obtain title compound, be white solid.
1H-NMR(CDCl 3，400MHz)δ：7.63-7.70(m，5H)，7.18(s，1H)，6.96(s，1H)，6.40(s，1H)，6.35(d，1H，J＝9.2Hz)，4.08-4.11(m，4H)，3.73(t，4H，J＝4.4Hz)，2.84(t，2H)，2.61-2.65(m，6H)，1.95(p，2H)，1.35(s，9H)。
MS(FAB)m/z：545.3[M+1] +。
Embodiment 39:1-[the 3-tertiary butyl-1-(3-chloro-4-fluorophenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } urea
Adopt the preparation method of embodiment 8, change wherein midbody 12 into midbody 23, obtain title compound, be white solid.
1H-NMR(CDCl 3，400MHz)δ：7.59(m，2H)，7.36(m，1H)，7.10-7.14(m，2H)，6.88(s，1H)，6.33-6.36(m，2H)，4.08-4.11(m，4H)，3.72(t，4H，J＝4.0Hz)，2.81(t，2H)，2.61-2.64(m，6H)，1.93(p，2H)，1.34(s，9H)。
MS(FAB)m/z：572.2[M+1] +。
Embodiment 40:1-[the 3-tertiary butyl-1-(4-aminomethyl phenyl)-1H-5-pyrazolyl]-3-{8-{5-[(4-p-methoxy-phenyl) methoxyl group]-2H-chromenyl } } urea
Midbody 62 (617mg 2mmol) is dissolved in 25mL ETHYLE ACETATE and 25mL ethanol, add in batches two hydrated stannous chlorides (1.80g, 8mmol), it is muddy that reaction solution becomes; Reflux 8 hours, cooling adds saturated sodium bicarbonate solution, until obvious layering occurring; Separatory, water layer merge organic layer with ethyl acetate extraction 2 times, use the saturated common salt water washing; Anhydrous sodium sulfate drying filters, and concentrates and obtains 541mg reduzate, yield 95%.
In the 100mL there-necked flask, add 30mL exsiccant methylene dichloride, be cooled to-10 ℃, add TRIPHOSGENE 99.5 (208mg; 0.70mmol), (541mg 1.9mmol) is dissolved in the solution of 20mL dry methylene chloride slowly drip to go up the product that obtains in step; The adularescent deposition produces; Reacted 1 hour, and dripped 1.0mL exsiccant triethylamine, resolution of precipitate.(261mg 1.14mmol), is warming up to room temperature to add midbody 11; Reacted 5 days, and poured in the 50mL water, with dichloromethane extraction 3 times; Organic layer is used the saturated common salt water washing, anhydrous sodium sulfate drying, and post separates (eluent system: petrol ether/ethyl acetate=1: 1) obtain title compound 350mg; Be white crystal, yield 34.2%.
1H-NMR(CDCl 3，400MHz)δ：7.68(d，1H，J＝8.8Hz)，7.32-7.35(m，4H)，7.17(m，2H)，6.91(d，2H，J＝8.8Hz)，6.77(d，1H)，6.46(d，1H，J＝9.2Hz)，6.36(s，1H)，5.68(m，1H)，4.95(t，2H)，4.68(t，2H，J＝1.6Hz)，3.83(s，3H)，2.33(s，3H)，1.35(s，9H)。
MS(FAB)m/z：526.2[M+1] +。
Embodiment 41:1-[the 3-tertiary butyl-1-(4-aminomethyl phenyl)-1H-5-pyrazolyl]-3-{8-[5-(4-morphine quinoline base acyl group methoxyl group)-2H-chromenyl] } urea
Adopt the preparation method of embodiment 36, change wherein midbody 50 into midbody 59, obtain title compound, be white solid.
1H-NMR(CDCl 3，400MHz)δ：7.76(d，1H，J＝9.2Hz)，7.34(d，2H，J＝8.4Hz)，7.22(d，2H)，6.72(d，1H，J＝10.0Hz)，6.35-6.38(m，2H)，5.73(m，1H)，4.71(s，2H)，4.64(s，2H)，3.55-3.67(m，8H)，2.36(s，3H)，1.36(s，9H)。
MS(FAB)m/z：546.2[M+1] +。
Embodiment 42:1-[the 3-tertiary butyl-1-(4-fluorophenyl)-1H-5-pyrazolyl]-3-{8-{5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } } urea
Adopt the preparation method of embodiment 36, change wherein midbody 11 into midbody 14, obtain title compound, be white solid.
1H-NMR(CDCl 3，400MHz)δ：7.67(d，1H，J＝8.4Hz)，7.43(m，2H)，7.07-7.11(m，3H)，6.73(d，1H，J＝10.4Hz)，6.58(s，1H)，6.38(d，1H，J＝9.2Hz)，6.35(s，1H)，5.73(m，1H)，4.71(t，2H，J＝2.0Hz)，4.11(t，2H，J＝5.2Hz)，3.75(t，4H)，2.83(t，2H)，2.61(t，4H)，1.35(s，9H)。
MS(FAB)m/z：536.2[M+1] +。
Embodiment 43:1-[the 3-tertiary butyl-1-(4-chloro-phenyl-)-1H-5-pyrazolyl]-3-{8-{5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } } urea
Adopt the preparation method of embodiment 36, change wherein midbody 11 into midbody 15, obtain title compound, be white solid.
1H-NMR(CDCl 3，400MHz)δ：7.65(d，1H，J＝8.8Hz)，7.43(d，2H)，7.35(d，2H，J＝8.8Hz)，7.10(s，1H)，6.74(d，1H，J＝10.0Hz)，6.68(s，1H)，6.36-6.38(m，2H)，5.72(m，1H)，4.69(t，2H，J＝2.0Hz)，4.10(t，2H，J＝5.2Hz)，3.74(t，4H，J＝4.4Hz)，2.81(t，2H，J＝4.8Hz)，2.59(t，4H)，1.35(s，9H)。
MS(FAB)m/z：552.2[M+1] +。
Embodiment 44:1-[the 3-tertiary butyl-1-(4-bromophenyl)-1H-5-pyrazolyl]-3-{8-{5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } } urea
Adopt the preparation method of embodiment 36, change wherein midbody 11 into midbody 16, obtain title compound, be white solid.
1H-NMR(CDCl 3，400MHz)δ：7.65(d，1H)，7.50(d，2H，J＝8.8Hz)，7.36(d，2H，J＝8.8Hz)，7.12(s，1H)，6.77(s，1H)，6.73(d，1H，J＝10.4Hz)，6.38(d，1H，J＝7.2Hz)，6.36(s，1H)，5.72(m，1H)，4.69(t，2H，J＝1.6Hz)，4.10(t，2H，J＝1.6Hz)，3.74(t，4H，J＝4.4Hz)，2.82(t，2H，J＝4.8Hz)，2.60(t，4H)，1.34(s，9H)。
MS(FAB)m/z：598.0[M+1] +。
Embodiment 45:1-(the 3-tertiary butyl-1-phenyl-1H-5-pyrazolyl)-3-{8-{5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } } urea
Adopt the preparation method of embodiment 36, change wherein midbody 11 into midbody 12, obtain title compound, be white solid.
1H-NMR(CDCl 3，400MHz)δ：7.71(d，1H，J＝8.8Hz)，7.45(d，2H)，7.40(t，2H)，7.29(t，1H)，7.20(s，1H)，6.72(d，1H，J＝10.0Hz)，6.69(s，1H)，6.36-6.38(m，2H)，5.71(m，1H)，4.69(t，2H，J＝2.0Hz)，4.09(t，2H)，3.73(t，4H，J＝4.4Hz)，2.81(t，2H，J＝5.2Hz)，2.59(t，4H)，1.36(s，9H)。
MS(FAB)m/z：518.1[M+1] +。
Embodiment 46:1-[the 3-tertiary butyl-1-(4-p-methoxy-phenyl)-1H-5-pyrazolyl]-3-{8-{5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } } urea
Adopt the preparation method of embodiment 36, change wherein midbody 11 into midbody 13, obtain title compound, be white solid.
1H-NMR(CDCl 3，400MHz)δ：7.72(d，1H，J＝8.8Hz)，7.33(d，2H，J＝9.2Hz)，7.25(s，1H)，6.88(d，2H，J＝9.2Hz)，6.75(d，1H)，6.73(s，1H)，6.36(d，1H)，6.33(s，1H)，5.70(m，1H)，4.67(t，2H，J＝1.6Hz)，4.10(t，2H)，3.77(s，3H)，3.74(t，4H，J＝4.4Hz)，2.80(t，2H，J＝5.6Hz)，2.59(t，4H)，1.35(s，9H)。
MS(FAB)m/z：548.1[M+1] +。
Embodiment 47:1-[the 3-tertiary butyl-1-(4-trifluoromethyl)-1H-5-pyrazolyl]-3-{8-{5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } } urea
Adopt the preparation method of embodiment 36, change wherein midbody 11 into midbody 26, obtain title compound, be white solid.
1H-NMR(CDCl 3，400MHz)δ：7.65(m，5H)，7.07(s，1H)，6.76(s，1H)，6.73(d，1H，J＝9.6Hz)，6.40(s，1H)，6.38(d，1H，J＝8.8Hz)，5.70(m，1H)，4.70(t，2H，J＝1.6Hz)，4.10(t，2H，J＝5.2Hz)，3.74(t，4H，J＝4.0Hz)，2.82(t，2H)，2.60(t，4H)，1.36(s，9H)。
MS(FAB)m/z：586.1[M+1] +。
Embodiment 48:1-[the 3-tertiary butyl-1-(4-nitrophenyl)-1H-5-pyrazolyl]-3-{8-{5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } } urea
Adopt the preparation method of embodiment 36, change wherein midbody 11 into midbody 17, obtain title compound, be yellow solid.
1H-NMR(CDCl 3，400MHz)δ：8.18(d，2H，J＝9.2Hz)，7.74(d，2H，J＝8.8Hz)，7.55(d，1H)，7.30(s，1H)，6.71(d，1H，J＝10.0Hz)，6.39(s，1H)，6.34(d，1H，J＝9.2Hz)，5.70(m，1H)，4.68(t，2H，J＝1.6Hz)，4.09(t，2H，J＝6.0Hz)，3.74(t，4H，J＝4.4Hz)，2.81(t，2H，J＝6.0Hz)，2.60(t，4H)，1.34(s，9H)。
MS(FAB)m/z：563.0[M+1] +。
Embodiment 49:1-[the 3-tertiary butyl-1-(4-itrile group phenyl)-1H-5-pyrazolyl]-3-{8-{5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } } urea
Adopt the preparation method of embodiment 36, change wherein midbody 11 into midbody 27, obtain title compound, be white solid.
1H-NMR(CDCl 3，400MHz)δ：7.64-7.70(m，5H)，7.15(s，1H)，7.05(s，1H)，6.74(d，1H，J＝10.0Hz)，6.40(s，1H)，6.38(d，1H，J＝8.8Hz)，5.73(m，1H)，4.71(t，2H，J＝1.6Hz)，4.11(t，2H，J＝4.4Hz)，3.74(t，4H，J＝4.8Hz)，2.83(t，2H)，2.61(t，4H)，1.34(s，9H)。
MS(FAB)m/z：543.1[M+1] +。
Embodiment 50:1-[the 3-tertiary butyl-1-(4-aminomethyl phenyl)-1H-5-pyrazolyl]-3-{8-{5-[2-(1-1,2,4-triazol radical) oxyethyl group]-2H-chromenyl } } urea
Adopt the preparation method of embodiment 36, change wherein midbody 65 into midbody 69, obtain title compound, be white solid.
1H-NMR(CDCl 3，400MHz)δ：8.10(s，1H)，7.86(s，1H)，7.83(d，1H，J＝8.0Hz)，7.38(s，1H)，7.32(d，2H，J＝8.4Hz)，7.18(d，2H)，6.39(s，1H)，6.36(d，1H)，6.29(d，1H，J＝9.2Hz)，5.47(m，1H)，4.55(t，2H，J＝4.8Hz)，4.44(t，2H)，4.28(t，2H，J＝4.8Hz)，2.33(s，3H)，1.35(s，9H)。
MS(FAB)m/z：514.2[M+1] +。
Embodiment 51:1-[the 3-tertiary butyl-1-(4-ethylphenyl)-1H-5-pyrazolyl]-3-{8-{5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } } urea
Adopt the preparation method of embodiment 36, change wherein midbody 11 into midbody 24, obtain title compound, be white solid.
1H-NMR(CDCl 3，400MHz)δ：7.74(d，1H，J＝8.8Hz)，7.36(d，2H，J＝8.4Hz)，7.25(d，2H)，7.14(s，1H)，6.73(d，1H，J＝10.0Hz)，6.35-6.40(m，3H)，5.72(m，1H)，4.71(t，2H，J＝2.0Hz)，4.12(t，2H)，3.75(t，4H)，2.84(t，2H)，2.62-2.68(m，6H)，1.36(s，9H)，1.22(t，3H)。
MS(FAB)m/z：546.0[M+1] +。
Embodiment 52:1-[the 3-tertiary butyl-1-(4-tert-butyl-phenyl)-1H-5-pyrazolyl]-3-{8-{5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } } urea
Adopt the preparation method of embodiment 36, change wherein midbody 11 into midbody 25, obtain title compound, be white solid.
1H-NMR(CDCl 3，400MHz)δ：7.74(d，1H，J＝9.2Hz)，7.34(d，2H)，7.26(d，2H)，7.15(s，1H)，6.73(d，1H，J＝10.0Hz)，6.43(s，1H)，6.39(d，1H，J＝9.2Hz)，6.35(s，1H)，5.72(m，1H)，4.71(t，2H，J＝2.0Hz)，4.09(t，2H，J＝5.2Hz)，3.73(t，4H)，2.81(t，2H)，2.59(t，4H)，1.36(s，9H)，1.24(d，3H)，1.22(d，3H)。
MS(FAB)m/z：560.1[M+1] +。
Embodiment 53:1-[the 3-tertiary butyl-1-(3-chloro-4-fluorophenyl)-1H-5-pyrazolyl]-3-{8-{5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } } urea
Adopt the preparation method of embodiment 36, change wherein midbody 11 into midbody 23, obtain title compound, be white solid.
1H-NMR(CDCl 3，400MHz)δ：7.60(m，2H)，7.38(m，1H)，7.08-7.14(m，3H)，6.72(d，1H，J＝9.6Hz)，6.38(d，1H，J＝8.8Hz)，6.35(s，1H)，5.72(m，1H)，4.70(t，2H，J＝1.6Hz)，4.10(t，2H，J＝5.2Hz)，3.74(t，4H，J＝4.4Hz)，2.83(t，2H)，2.61(t，4H)，1.34(s，9H)。
MS(FAB)m/z：570.0[M+1] +。
Embodiment 54:1-[the 3-tertiary butyl-1-(3, the 4-3,5-dimethylphenyl)-1H-5-pyrazolyl]-3-{8-{5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } } urea
Adopt the preparation method of embodiment 36, change wherein midbody 11 into midbody 19, obtain title compound, be white solid.
1H-NMR(CDCl 3，400MHz)δ：7.72(d，1H，J＝8.8Hz)，7.12-7.21(m，4H)，6.72(d，1H，J＝10.4Hz)，6.60(s，1H)，6.38(d，1H)，6.34(s，1H)，5.70(m，1H)，4.68(t，2H，J＝2.0Hz)，4.10(t，2H，J＝5.6Hz)，3.74(t，4H，J＝4.4Hz)，2.82(t，2H，J＝5.6Hz)，2.60(t，4H)，2.23(s，3H)，2.21(s，3H)，1.35(s，9H)。
MS(FAB)m/z：546.0[M+1] +。
Embodiment 55:1-[the 3-tertiary butyl-1-(3, the 4-dichlorophenyl)-1H-5-pyrazolyl]-3-{8-{5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } } urea
Adopt the preparation method of embodiment 36, change wherein midbody 11 into midbody 20, obtain title compound, be white solid.
1H-NMR(CDCl 3，400MHz)δ：7.67(s，1H)，7.58(d，1H)，7.45(s，1H)，7.38(m，2H)，7.23(s，1H)，6.71(d，1H，J＝10.0Hz)，6.36(d，1H，J＝9.2Hz)，6.35(s，1H)，5.69(m，1H)，4.68(t，2H，J＝1.6Hz)，4.10(t，2H，J＝5.6Hz)，3.73(t，4H，J＝4.8Hz)，2.82(t，2H，J＝5.2Hz)，2.60(t，4H)，1.34(s，9H)。
MS(FAB)m/z：586.0[M+1] +。
Embodiment 56:1-(the 3-tertiary butyl-5-different
Figure GPA00000702890000821
azoles base)-3-{8-{5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } } urea
Adopt the preparation method of embodiment 36, change wherein midbody 11 into midbody 28, obtain title compound, be white solid.
1H-NMR(CDCl 3，400MHz)δ：9.27(s，1H)，7.74(d，1H，J＝8.8Hz)，7.40(s，1H)，6.67(d，1H，J＝10.0Hz)，6.37(d，1H，J＝9.2Hz)，6.13(s，1H)，5.63(m，1H)，4.62(t，2H，J＝1.6Hz)，4.10(t，2H，J＝5.6Hz)，3.77(t，4H，J＝4.4Hz)，2.83(t，2H，J＝5.2Hz)，2.69(t，4H)，1.30(s，9H)。
MS(FAB)m/z：443.0[M+1] +。
Embodiment 57:1-(the 5-tertiary butyl-3-different
Figure GPA00000702890000831
azoles base)-3-{8-{5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } } urea
Adopt the preparation method of embodiment 36; Change midbody 11 wherein into 3-amino-5-tertiary butyl different
Figure GPA00000702890000832
azoles; Obtain title compound, be white solid.
1H-NMR(CDCl 3，400MHz)δ：8.77(s，1H)，8.27(s，1H)，7.86(d，1H，J＝8.8Hz)，6.75(d，1H，J＝10.0Hz)，6.42(d，1H，J＝9.6Hz)，6.02(s，1H)，5.76(m，1H)，4.84(t，2H，J＝2.0Hz)，4.12(t，2H，J＝6.8Hz)，3.76(t，4H)，2.84(t，2H)，2.62(t，4H)，1.36(s，9H)。
MS(FAB)m/z：443.0[M+1] +。
Embodiment 58:1-[the 1-tertiary butyl-3-(4-aminomethyl phenyl)-1H-4-pyrazolyl]-3-{8-{5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } } urea
Adopt the preparation method of embodiment 36, change wherein midbody 11 into midbody 33, obtain title compound, be white solid.
1H-NMR(CDCl 3，400MHz)δ：7.67-7.70(m，2H)，7.18-7.20(m，4H)，6.73(d，1H，J＝10.0Hz)，6.68(s，1H)，6.36(d，1H，J＝9.2Hz)，5.72(m，1H)，5.49(s，1H)，4.71(t，2H，J＝2.0Hz)，4.11(t，2H)，3.76(t，4H)，2.83(t，2H)，2.62(t，4H)，2.39(s，3H)，1.46(s，9H)。
MS(FAB)m/z：532.1[M+1] +。
Embodiment 59:1-[the 3-tertiary butyl-1-(3-aminomethyl phenyl)-1H-5-pyrazolyl]-3-{8-{5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } } urea
Adopt the preparation method of embodiment 36, change wherein midbody 11 into midbody 21, obtain title compound, be white solid.
1H-NMR(CDCl 3，400MHz)δ：7.22(d，1H，J＝8.8Hz)，7.26-7.29(m，3H)，7.15(d，2H)，6.73(d，1H，J＝10.0Hz)，6.58(s，1H)，6.38(d，1H，J＝9.6Hz)，6.36(s，1H)，5.72(m，1H)，4.71(t，2H，J＝1.6Hz)，4.12(t，2H)，3.76(t，4H)，2.84(t，2H)，2.63(t，4H)，2.36(s，3H)，1.36(s，9H)。
MS(FAB)m/z：532.1[M+1] +。
Embodiment 60:1-[(the 3-tertiary butyl-1-naphthyl)-1H-5-pyrazolyl]-3-{8-{5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } } urea
Adopt the preparation method of embodiment 36, change wherein midbody 11 into midbody 22, obtain title compound, be white solid.
1H-NMR(CDCl 3，400MHz)δ：7.88-7.90(m，2H)，7.48-7.50(m，5H)，7.38(d，1H)，6.95(s，1H)，6.68(d，1H，J＝10.0Hz)，6.48(s，1H)，6.24-6.27(m，2H)，5.67(m，1H)，4.63(t，2H，J＝1.6Hz)，4.07(t，2H，J＝5.2Hz)，3.75(t，4H，J＝4.4Hz)，2.82(t，2H)，2.61(t，4H)，1.40(s，9H)。
MS(FAB)m/z：568.1[M+1] +。
Embodiment 61:1-[the 4-tertiary butyl-1-(4-aminomethyl phenyl)-1H-2-imidazolyl]-3-{8-{5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } } urea
Adopt the preparation method of embodiment 36, change wherein midbody 11 into midbody 35, obtain title compound, be white solid.
1H-NMR(CDCl 3，400MHz)δ：8.03(d，1H，J＝9.2Hz)，7.26-7.30(m，5H)，6.78(d，1H，J＝10.0Hz)，6.44(s，1H)，6.41(d，1H，J＝9.2Hz)，5.77(m，1H)，4.88(t，2H)，4.13(t，2H，J＝6.8Hz)，3.76(t，4H)，2.84(t，2H)，2.62(t，4H)，2.42(s，3H)，1.34(s，9H)。
MS(FAB)m/z：532.4[M+1] +。
Embodiment 62:1-[the 3-tertiary butyl-1-(4-aminomethyl phenyl)-1H-5-pyrazolyl]-3-{8-{5-{2-[4-(cis-2,6-dimethyl-) morphine quinoline base] oxyethyl group }-the 2H-chromenyl } urea
Adopt the preparation method of embodiment 36, change wherein midbody 50 into midbody 66, obtain title compound, be white solid.
1H-NMR(CDCl 3，400MHz)δ：7.74(d，1H，＝9.2Hz)，7.33(d，2H，J＝8.0Hz)，7.22(d，2H)，7.14(s，1H)，6.74(d，1H，J＝10.0Hz)，6.45(s，1H)，6.39(d，1H，J＝9.2Hz)，6.35(s，1H)，5.72(m，1H)，4.71(t，2H，J＝1.6Hz)，4.12(t，2H，J＝4.0Hz)，3.74(m，2H)，2.83(m，4H)，2.36(s，3H)，1.94(m，2H)，1.36(s，9H)，1.17(d，3H)，1.16(d，3H)。
MS(FAB)m/z：532.4[M+1] +。

Claims (11)

1. compound of Formula I, or its pharmacologically acceptable salt,
Figure FSB00000702384300011
Wherein:
Ar 1Be pyrazolyl, imidazolyl Huo isoxazolyl; Said Ar 1Independently by one or more R 1, R 2Replace;
Ar 2Be benzopyranyl or chromanyl;
L independently does
(1) key;
(2) C 1-C 4Saturated or undersaturated, the straight or branched carbochain; One or more methylene radical wherein are independent of O, and a NH or 0-2 carbonyl substitutes; And said spacer group can be replaced by one or more halogen atoms;
P is an imidazolyl, pyrazolyl, 1,2,4-triazol radical, morpholinyl or piperidone base; Said group can be chosen wantonly by 1-3 and be selected from following substituting group replacement: C 1-C 6The straight or branched alkyl;
R 1Independently be C 1-C 10The straight or branched alkyl;
R 2Independently be phenyl or naphthyl, said phenyl or naphthyl can be independently by 0-5 R 4Group replaces;
R 3It independently is Wasserstoffatoms;
R 4Independently be halogen, nitro, C 1-C 6The straight or branched alkyl, itrile group, C 1-C 6The straight or branched alkoxyl group, trifluoromethyl; R 3NHS (O) m-, m is 0,1 or 2.
2. following compound, it is selected from:
1-[the 3-tertiary butyl-1-(4-aminomethyl phenyl)-1H-5-pyrazolyl]-3-[8-(3,4-dihydro-5-methoxyl group-2H-chromenyl)] urea
1-[the 3-tertiary butyl-1-(4-chloro-phenyl-)-1H-5-pyrazolyl]-3-[8-(5-methoxyl group-2H-chromenyl)] urea
1-[the 3-tertiary butyl-1-(4-aminomethyl phenyl)-1H-5-pyrazolyl]-3-[8-(5-methoxyl group-2H-chromenyl)] urea
1-[the 3-tertiary butyl-1-(4-aminomethyl phenyl)-1H-5-pyrazolyl]-3-{5-{8-[2-(4-morphine quinoline base) acetamido]-2H-chromenyl } } urea
1-[the 3-tertiary butyl-1-phenyl-1H-5-pyrazolyl]-3-[8-(3,4-dihydro-5-methoxyl group-2H-chromenyl)] urea
1-[the 3-tertiary butyl-1-(4-aminomethyl phenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } urea
1-[the 3-tertiary butyl-1-(4-aminomethyl phenyl)-1H-5-pyrazolyl]-3-[8-(5-nitro-2H-chromenyl)] urea
1-[the 3-tertiary butyl-1-phenyl-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } urea
1-[the 3-tertiary butyl-1-(4-fluorophenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } urea
1-[the 3-tertiary butyl-1-(4-chloro-phenyl-)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } urea
1-[the 3-tertiary butyl-1-(4-bromophenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } urea
1-[the 3-tertiary butyl-1-(4-p-methoxy-phenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } urea
1-[the 3-tertiary butyl-1-(4-amino-sulfonyl phenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } urea
1-[the 3-tertiary butyl-1-(4-nitrophenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } urea
1-[the 3-tertiary butyl-1-(4-aminomethyl phenyl)-1H-5-pyrazolyl]-3-{8-[3,4-dihydro-5-(4-morphine quinoline base acyl group methoxyl group)-2H-chromenyl] } urea
1-(the 3-tertiary butyl-5-isoxazolyl)-3-{8-{3,4-dihydro-5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } urea
1-(the 5-tertiary butyl-3-isoxazolyl)-3-{8-{3,4-dihydro-5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } urea
1-[the 1-tertiary butyl-3-(4-aminomethyl phenyl)-1H-4-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } urea
1-[the 4-tertiary butyl-1-(4-aminomethyl phenyl)-1H-2-imidazolyl]-3-{8-{3,4-dihydro-5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } urea
1-[the 3-tertiary butyl-1-(4-aminomethyl phenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-(4-pyridyl) oxygen base oxethyl]-2H-chromenyl } urea
1-[the 3-tertiary butyl-1-(4-aminomethyl phenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-{2-[4-(cis-2,6-dimethyl-) morphine quinoline base] oxyethyl group }-the 2H-chromenyl } urea
1-[the 3-tertiary butyl-1-(4-aminomethyl phenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-(1-imidazolyl) oxyethyl group]-2H-chromenyl } urea
1-[the 3-tertiary butyl-1-(4-aminomethyl phenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-(1-1,2,4-triazol radical) oxyethyl group]-2H-chromenyl } urea
1-[the 3-tertiary butyl-1-(4-chloro-phenyl-)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-{2-[4-(cis-2,6-dimethyl-) morphine quinoline base] oxyethyl group }-the 2H-chromenyl } urea
1-[the 3-tertiary butyl-1-(3, the 4-3,5-dimethylphenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } urea
1-[the 3-tertiary butyl-1-(3, the 4-dichlorophenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } urea
1-[the 3-tertiary butyl-1-(3-aminomethyl phenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } urea
1-[(the 3-tertiary butyl-1-naphthyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } urea
1-[the 3-tertiary butyl-1-(4-aminomethyl phenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-(1-pyrazolyl) oxyethyl group]-2H-chromenyl } urea
1-[the 3-tertiary butyl-1-(4-aminomethyl phenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-(1-piperidin-4-one-base) oxyethyl group]-2H-chromenyl } urea
1-[the 3-tertiary butyl-1-(4-aminomethyl phenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-(4-morphine quinoline base) acetamido]-2H-chromenyl } urea
1-[the 3-tertiary butyl-1-(4-trifluoromethyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } urea
1-[the 3-tertiary butyl-1-(4-ethylphenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } urea
1-[the 3-tertiary butyl-1-(4-tert-butyl-phenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } urea
1-[the 3-tertiary butyl-1-(4-trifluoromethyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-(1-imidazolyl) oxyethyl group]-2H-chromenyl } urea
1-[the 3-tertiary butyl-1-(4-aminomethyl phenyl)-1H-5-pyrazolyl]-3-{8-{5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } } urea
1-[the 3-tertiary butyl-1-(4-aminomethyl phenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-(4-pyridyl) oxyethyl group]-2H-chromenyl } urea
1-[the 3-tertiary butyl-1-(4-itrile group phenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } urea
1-[the 3-tertiary butyl-1-(3-chloro-4-fluorophenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } urea
1-[the 3-tertiary butyl-1-(4-aminomethyl phenyl)-1H-5-pyrazolyl]-3-{8-{5-[(4-p-methoxy-phenyl) methoxyl group]-2H-chromenyl } } urea
1-[the 3-tertiary butyl-1-(4-aminomethyl phenyl)-1H-5-pyrazolyl]-3-{8-[5-(4-morphine quinoline base acyl group methoxyl group)-2H-chromenyl] } urea
1-[the 3-tertiary butyl-1-(4-fluorophenyl)-1H-5-pyrazolyl]-3-{8-{5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } } urea
1-[the 3-tertiary butyl-1-(4-chloro-phenyl-)-1H-5-pyrazolyl]-3-{8-{5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } } urea
1-[the 3-tertiary butyl-1-(4-bromophenyl)-1H-5-pyrazolyl]-3-{8-{5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } } urea
1-(the 3-tertiary butyl-1-phenyl-1H-5-pyrazolyl)-3-{8-{5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } } urea
1-[the 3-tertiary butyl-1-(4-p-methoxy-phenyl)-1H-5-pyrazolyl]-3-{8-{5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } } urea
1-[the 3-tertiary butyl-1-(4-trifluoromethyl)-1H-5-pyrazolyl]-3-{8-{5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } } urea
1-[the 3-tertiary butyl-1-(4-nitrophenyl)-1H-5-pyrazolyl]-3-{8-{5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } } urea
1-[the 3-tertiary butyl-1-(4-itrile group phenyl)-1H-5-pyrazolyl]-3-{8-{5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } } urea
1-[the 3-tertiary butyl-1-(4-aminomethyl phenyl)-1H-5-pyrazolyl]-3-{8-{5-[2-(1-1,2,4-triazol radical) oxyethyl group]-2H-chromenyl } } urea
1-[the 3-tertiary butyl-1-(4-ethylphenyl)-1H-5-pyrazolyl]-3-{8-{5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } } urea
1-[the 3-tertiary butyl-1-(4-tert-butyl-phenyl)-1H-5-pyrazolyl]-3-{8-{5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } } urea
1-[the 3-tertiary butyl-1-(3-chloro-4-fluorophenyl)-1H-5-pyrazolyl]-3-{8-{5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } } urea
1-[the 3-tertiary butyl-1-(3, the 4-3,5-dimethylphenyl)-1H-5-pyrazolyl]-3-{8-{5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } } urea
1-[the 3-tertiary butyl-1-(3, the 4-dichlorophenyl)-1H-5-pyrazolyl]-3-{8-{5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } } urea
1-(the 3-tertiary butyl-5-isoxazolyl)-3-{8-{5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } } urea
1-(the 5-tertiary butyl-3-isoxazolyl)-3-{8-{5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } } urea
1-[the 1-tertiary butyl-3-(4-aminomethyl phenyl)-1H-4-pyrazolyl]-3-{8-{5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } } urea
1-[the 3-tertiary butyl-1-(3-aminomethyl phenyl)-1H-5-pyrazolyl]-3-{8-{5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } } urea
1-[(the 3-tertiary butyl-1-naphthyl)-1H-5-pyrazolyl]-3-{8-{5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } } urea
1-[the 4-tertiary butyl-1-(4-aminomethyl phenyl)-1H-2-imidazolyl]-3-{8-{5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } } urea
1-[the 3-tertiary butyl-1-(4-aminomethyl phenyl)-1H-5-pyrazolyl]-3-{8-{5-{2-[4-(cis-2,6-dimethyl-) morphine quinoline base] oxyethyl group }-the 2H-chromenyl } urea
With and pharmacologically acceptable salt.
3. the method for preparing the said compound of Formula I of claim 1, this method comprises the compound of following formula:
Figure FSB00000702384300061
With P-L-Ar 2-NH 2At suitable solvent, obtained the compound of formula I in 1 hour to 120 hours in 0 ℃-100 ℃ reactions in the suitable alkali, wherein, Ar 1, Ar 2, L, the same general formula I of the definition of P, R 6Be trichloromethyl, p-nitrophenyl, oxyethyl group, imidazolyl or triazolyl.
4. the described method of claim 3, wherein said formula (A) compound is following:
Make the compound of following formula:
Figure FSB00000702384300062
With Ar 1NH 2At suitable solvent, obtained the compound of formula (A) in 10 minutes to 24 hours in-15 ℃-25 ℃ reactions in the suitable alkali, wherein, Ar 1The same general formula I of definition, R 6Be trichloromethyl, p-nitrophenyl, oxyethyl group, imidazolyl or triazolyl.
5. the method for preparing the said compound of Formula I of claim 1, this method comprises the compound of following formula:
Figure FSB00000702384300071
With Ar 1NH 2At suitable solvent, obtained the compound of formula I in 1 hour to 120 hours in 0 ℃-100 ℃ reactions in the suitable alkali, wherein, Ar 1, Ar 2, L, the same general formula I of the definition of P, R 6Be trichloromethyl, p-nitrophenyl, oxyethyl group, imidazolyl or triazolyl.
6. the described method of claim 5, wherein said formula (B) compound is following:
Make the compound of following formula:
Figure FSB00000702384300072
With P-L-Ar 2-NH 2At suitable solvent, obtained the compound of formula (B) in 10 minutes to 24 hours in-15 ℃-25 ℃ reactions in the suitable alkali, wherein, Ar 2, L, the same general formula I of the definition of P, R 6Be trichloromethyl, p-nitrophenyl, oxyethyl group, imidazolyl or triazolyl.
7. medicinal compsns, it contains claim 1 or 2 each compound or pharmaceutically acceptable salt thereof and at least a pharmaceutically acceptable carrier or vehicle.
8. the medicinal compsns of claim 7, wherein said vehicle is a thinner.
9. claim 1 or 2 each compounds are used to prepare the alpha mediated disease of treatment TNF-, the purposes of the medicine of risk factor or illness.
10. the purposes of claim 9, wherein said disease, risk factor or illness are arthritic psoriasis, conjunctivo-urethro-synovial syndrome, gout, traumatic arthritis, rubella arthritis, acute synovitis; Rheumatoid arthritis, osteo-arthritis, urarthritis, septic shock, endotoxin shock, Gram-negative, septicemia; Toxic shock syndrome, cerebral malaria, meningitis, ischemic stroke and hemorrhagic stroke, neurotrauma/closed trauma of head, asthma; Adult respiratory distress syndrome, chronic pneumonia, chronic obstructive pulmonary disease, silicosis, lung sarcosis, bone absorpting disease; Osteoporosis, restenosis, heart and brain and renal reperfusion injury, congestive heart failure, coronary artery bypass bridging (CABG) art, blood examination forms; Glomerulonephritis, chronic renal failure, mellitus, diabetic retinopathy, degeneration of macula, graft-vs-host reaction; Homograft rejection, inflammatory bowel disease, Crohn disease, ulcerative colitis neurodegenerative disease, muscle deterioration, tumor growth and transfer; The pneumonia that vasculogenesis disease, influenza cause, eczema, contact dermatitis, psoriasis, sunburn or conjunctivitis.
11. claim 1 or 2 each compounds are used to prepare the purposes that suppresses p38 protein kinase medicine.
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