CN1771237A - Pyrazolidine-1,2-dicarboxyldiphenylamide derivatives as coagulation factor xa inhibitors for the treatment of thromboses. - Google Patents

Pyrazolidine-1,2-dicarboxyldiphenylamide derivatives as coagulation factor xa inhibitors for the treatment of thromboses. Download PDF

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CN1771237A
CN1771237A CNA2004800093547A CN200480009354A CN1771237A CN 1771237 A CN1771237 A CN 1771237A CN A2004800093547 A CNA2004800093547 A CN A2004800093547A CN 200480009354 A CN200480009354 A CN 200480009354A CN 1771237 A CN1771237 A CN 1771237A
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phenyl
chloro
diformamide
tetramethyleneimine
oxo
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C·察克拉基迪斯
D·多尔施
W·梅德尔斯基
B·切赞尼
J·格莱茨
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Merck Patent GmbH
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    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no 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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Abstract

The invention relates to the compounds of formula (I), wherein W represents N, CR<3>, or a sp<2 >hybridized C atom, E, together with W, represents a 3- to 7-membered saturated carbocylic or heterocyclic ring having 0 to 3 N atoms, 0 to 2 O atoms and/or 0 to 2 S atoms, which ring may contain a double bond, D represents a mononuclear or binuclear unsubstituted aromatic carbocycle or heterocycle having 0 to 4 N atoms, O atoms and/or S atoms or being monosubstituted or polysubstituted by Hal, A, OR<3>, N(R<3>)2, NO2, CN, COOR<3> or CON(R<3>)2, G represents -[C(R<4>)2]n-, -[C(R<4>)2]nNR<3>-, -[C(R<4>)2]nO-, -[C(R<4>)2]nS- or -[C(R<4>)=C(R<4>)]n-, X represents -[C(R<4>)2]nCONR<3>[C(R<4>)2]n-, -[C(R<4>)2]nNR<3>CO[C(R<4>)2]n-, -[C(R<4>)2]nNR<3>[C(R<4>)2]n-, -[C(R<4>)2]nO[C(R<4>)2]n-, -[C(R<4>)2]nCO[C(R<4>)2]n- or -[C(R<4>)2]nCOO[C(R<4>)2]n-, Y represents alkylene, cycloalkylene, Het-diyl or Ar-diyl, T represents a mononuclear or binuclear saturated or unsaturated carbocycle or heterocycle having 0 to 4 N atoms, O atoms and/or S atoms, which is monosubstituted or polysubstituted by =O, =S, =NR<3>, =N-CN, =N-NO2, =NOR<3>, =NCOR<3>, =NCOOR<3>, =NOCOR<3> and which may further be monosubstituted, disubstituted or trisubstituted by R<3>, Hal, A,-[C(R<4>)2]n, -Ar, -[C(R<4>)2]n-het, -[C(R<4>)2]n-cycloalkyl, OR<3>, N(R<3>)2, NO2, CN, COOR<3>, CON(R<3>)2, NR<3>COA, NR<3>CON(R<3>)2, NR<3>SO2A, COR<3>, SO2NR<3> and/or S(O)nA, and R<1> and R<2> are defined as in claim 1. The inventive compounds inhibit coagulation factor Xa and can be used in the prophylaxis and/or therapy of thrombo-embolic diseases and for treating tumors.

Description

In the treatment thrombotic disease, be used as 1-(phenyl amino formyl radical)-2-(4-(3-oxo-morpholine-4-yl)-phenyl amino formyl radical) pyrrolidin derivatives and the related compound of inhibitors of coagulation factor XA
The steric isomer that the present invention relates to formula I compound and pharmaceutically spendable derivative thereof, solvate, salt and comprise its various mixed things:
Figure A20048000935400381
Wherein
R 1, R 2Independently of one another, respectively do for oneself H ,=O, Hal, A, ethynyl, OR 3, N (R 3) 2, NO 2, CN, N 3, COOR 3, CON (R 3) 2,-[C (R 4) 2] n-Ar ,-[C (R 4) 2] n-Het ,-[C (R 4) 2] n-cycloalkyl ,-OCOR 3, NR 3COA or NR 3SO 2A,
Perhaps, R 1With R 2Be 3-7 unit's carbocyclic ring or the heterocycle that dicyclo or volution connect together, have 0-3 N, O and/or S atom,
R 3Be H, A, H-C ≡ C-CH 2-, CH 3-C ≡ C-CH 2-,-CH 2-CH (OH)-CH 2OH ,-CH 2-CH (OH)-CH 2NH 2,-CH 2-CH (OH)-CH 2Het ' ,-[C (R 4) 2] n-Ar ' ,-[C (R 4) 2] n-Het ' ,-[C (R 4) 2] n-cycloalkyl ,-[C (R 4) 2] n-COOA or-[C (R 4) 2] nN (R 4) 2,
R 4Be H or A,
W is N, CR 3Or sp 2-hydridization carbon atom,
E is first saturated carbon ring of the 3-7 with 0-3 N, a 0-2 O and/or 0-2 S atom or heterocycle with W,
It can contain two keys,
D is monocycle or dicyclo aromatic carbon ring or the heterocycle with 0-4 N, O and/or S atom, and it does not replace or replaced by following group list or be polysubstituted: Hal, A, OR 3, N (R 3) 2, NO 2, CN, COOR 3Or CON (R 3) 2,
G is-[C (R 4) 2] n-,-[C (R 4) 2] nNR 3-,-[C (R 4) 2] nO-,-[C (R 4) 2] nS-or-[C (R 4)=C (R 4)] n-,
X is-[C (R 4) 2] nCONR 3[C (R 4) 2] n-,-[C (R 4) 2] nNR 3CO[C (R 4) 2] n-,-[C (R 4) 2] nNR 3[C (R 4) 2] n-,-[C (R 4) 2] nO[C (R 4) 2] n-,-[C (R 4) 2] nCO[C (R 4) 2] n-or-[C (R 4) 2] nCOO[C (R 4) 2] n-,
Y is alkylidene group, cycloalkylidene, Het-two bases or Ar-two bases,
T has the monocycle of 0-4 N, O and/or S atom or dicyclo, saturated or unsaturated carbocyclic or a heterocycle, and it is replaced by following group list or two replaces :=O ,=S ,=NR 3,=N-CN ,=N-NO 2,=NOR 3,=NCOR 3,=NCOOR 3Or=NOCOR 3, and can further be replaced or three replacement: R by following group list replacement, two 3, Hal, A ,-[C (R 4) 2] n-Ar ,-[C (R 4) 2] n-Het ,-[C (R 4) 2] n-cycloalkyl, OR 3, N (R 3) 2, NO 2, CN, COOR 3, CON (R 3) 2, NR 3COA, NR 3CON (R 3) 2, NR 3SO 2A, COR 3, SO 2NR 3And/or S (O) nA,
A is non-side chain or the branched-chain alkyl with 1-10 carbon atom, one of them or two CH 2Group can by O or S atom and/or-the CH=CH-group is replaced, and/or 1-7 H atom can be replaced by F in addition,
Ar is phenyl, naphthyl or xenyl, and they do not replace separately or are replaced or three replacements by following group list replacement, two: Hal, A, OR 3, N (R 3) 2, NO 2, CN, COOR 3, CON (R 3) 2, NR 3COA, NR 3CON (R 3) 2, NR 3SO 2A, COR 3, SO 2N (R 3) 2, S (O) nA ,-[C (R 4) 2] n-COOR 3Or-O[C (R 4) 2] o-COOR 3,
Ar ' is phenyl, naphthyl or xenyl, and they do not replace separately or are replaced or three replacements by following group list replacement, two: Hal, A, OR 4, N (R 4) 2, NO 2, CN, COOR 4, CON (R 4) 2, NR 4COA, NR 4CON (R 4) 2, NR 4SO 2A, COR 4, SO 2N (R 4) 2, S (O) nA ,-[C (R 4) 2] n-COOR 4Or-O[C (R 4) 2] o-COOR 4,
Het has the monocycle of 1-4 N, O and/or S atom or dicyclo, saturated, a unsaturated or aromatic heterocycle, its can not replace or by following group list replace, two replace or three replacements: Hal, A ,-[C (R 4) 2] n-Ar ,-[C (R 4) 2] n-Het ' ,-[C (R 4) 2] n-cycloalkyl, OR 3, N (R 3) 2, NR 3CON (R 3) 2, NO 2, CN ,-[C (R 4) 2] n-COOR 3,-[C (R 4) 2] n-CON (R 3) 2, NR 3COA, NR 3SO 2A, COR 3, SO 2NR 3, S (O) mA and/or ketonic oxygen,
Het ' is for having the monocycle of 1-4 N, O and/or S atom or dicyclo, saturated, unsaturated or aromatic heterocycle, and it can not replace or by following group list replacement or two replacements: ketonic oxygen ,=S ,=N (R 4) 2, Hal, A, OR 4, N (R 4) 2, NO 2, CN, COOR 4, CON (R 4) 2, NR 4COA, NR 4CON (R 4) 2, NR 4SO 2A, COR 4, SO 2NR 4And/or S (O) nA,
Hal is F, Cl, Br or I,
N is 0,1 or 2,
O is 1,2 or 3.
The objective of the invention is to find the compound of new valuable characteristic, particularly can be used for preparing those compounds of medicine.
Discoverable type I compound and salt thereof have very valuable pharmacological characteristic and good tolerability.Specifically, they demonstrate the characteristic that suppresses Xa factor, therefore can be used for anti-and for example thrombosis, myocardial infarction, arteriosclerosis, inflammation, apoplexy, stenocardia, postangioplasty restenosis and intermittent claudication (claudicatiointermittens) of prevention of thromboembolic disorders.
Formula I compound of the present invention can also be the thrombin inhibitors in proconvertin a, the IXa factor and the blood coagulation cascade.
Arylamidine derivative with anti-thrombosis function is for example disclosing in the following patent: EP0540051B1, WO 98/28269, WO 00/71508, WO 00/71511, WO00/71493, WO 00/71507, WO 00/71509, WO 00/71512, WO 00/71515 and WO 00/71516.The ring-type guanidine that is used for the treatment of thrombotic disease is for example disclosing among the WO97/08165.Having the active aromatic heterocycle compounds of the Xa factor of inhibition is for example disclosing among the WO96/10022.The N-[(amino imino methyl that replaces) phenylalkyl] the nitrogen heterocyclic acid amides describes in WO 96/40679 as the Xa factor inhibitor.Other carboxamide derivative is open in WO02/48099 and WO 02/57236, and other pyrrolidin derivatives is described in WO 02/100830.
More multi-heterocycle derivant is open in WO 03/045912.
The antithrombotic of The compounds of this invention form and blood coagulation resisting function owing to restraining effect to the blood coagulating protein enzyme activation of Xa factor by name, or other is activated for example inhibition of the VIIa factor, the IXa factor or zymoplasm of serine protease.
Xa factor is a kind of proteolytic enzyme that relates to complicated blood coagulation process.Xa factor catalysis thrombogen is converted into zymoplasm.Zymoplasm is dissociated into fibrin monomer with Fibrinogen, and after crosslinked, fibrin monomer becomes thrombotic basis.Activate the generation that zymoplasm can cause thrombotic disease, form but Trombin inhibiting can suppress to relate to thrombotic scleroproein.For example by G.F.Cousins etc. at Circulation 1996,94, the method among the 1705-1712 can be measured the inhibition of zymoplasm.
Therefore suppress Xa factor and can prevent that zymoplasm from forming.
Formula I compound of the present invention and salt thereof participate in the blood coagulation process by suppressing Xa factor, therefore suppress thrombosis.
The compounds of this invention suppresses the measurement of Xa factor and anticoagulation and anti-thrombosis activity and can measure by method in conventional external or the body.For example J.Hauptmann etc. is at Thrombosis andHaemostasis 1990,63, the appropriate method of describing among the 220-223.
For example with T.Hara etc. at Thromb.Haemostas 1994,71, but the inhibition of the method measured X a factor of describing among the 314-319.
Proconvertin a and tissue factor cause the X factor activator in conjunction with the external source part of back startup coagulation cascade, discharge Xa factor.Therefore suppress the VIIa factor can prevent Xa factor form with and subsequent zymoplasm form.The compounds of this invention suppresses the measurement of the VIIa factor and anticoagulation and anti-thrombosis activity and can measure by method in conventional external or the body.For example H.F.Ronning etc. describes among the 73-81 and measures the ordinary method that suppresses the VIIa factor at Thrombosis Research 1996,84.
Factor IXa produces in the intrinsic coagulation cascade, relates to equally activating the X factor, discharges Xa factor.Therefore suppress the IXa factor and can prevent in different approach that Xa factor from forming.The compounds of this invention suppresses the measurement of the IXa factor and anticoagulation and anti-thrombosis activity and can measure by method in conventional external or the body.For example J.Chang etc. is at Journal of BiologicalChemistry 1998,273, the appropriate method of describing among the 12089-12094.
The compounds of this invention also can be used for treating tumour, tumor disease and/or tumor metastasis.T.Taniguchi and N.R.Lemoine be at Biomed.Health Res. (2000) 41 (MolecularPathogenesis of Pancreatic Cancer (molecular pathology of carcinoma of the pancreas)), pointed out the tissue factor TF/VIIa factor among the 57-59 and mutual relationship between the various cancers takes place.Following publication has been described TF-VII and the Xa factor inhibitor antitumor action to various tumours:
Thromb.Haemost.1998 such as K.M.Donnelly; 79:1041-1047;
J.Clin.Invest.104:1213-1221 such as E.G.Fischer (1999);
J.Clin.Invest.101:1372-1378 such as B.M.Mueller (1998);
Thromb.Haemost.1999 such as M.E.Bromberg; 82:88-92.
Formula I compound can be in people and veterinary drug uses as active constituents of medicine, particularly for example thrombosis, myocardial infarction, arteriosclerosis, inflammation, apoplexy, stenocardia, postangioplasty restenosis, intermittent claudication, venous thrombosis, pulmonary infarction, artery thrombosis, myocardial ischemia, unstable angina pectoris and based on thrombotic apoplexy of treatment and prevention of thromboembolic disorders.The compounds of this invention also can be used for treatment or prevention of arterial atherosclerotic disease for example coronary artery disease, cerebral arteries disease or peripheral arterial disease.Described compound also can be united use with other thrombolytic drug in myocardial infarction, also can prevent inaccessible again after the thrombolysis, percutaneous transluminal angio plasty (PTCA) and coronary artery bypass bypass surgery.
The compounds of this invention also is used for preventing the micrurgy thrombus to form again; And can be used as anticoagulant and artificial organ or hemodialysis associating.Described compound also is used to clean intravital conduit of patient and medical assistor, or is used for external preservation blood, blood plasma and other blood products as anticoagulant.The compounds of this invention also is used for the disease that wherein blood coagulation is the lysis important factor, or typical example comprises the disease of the Secondary cases cause of disease in sacroiliitis and the diabetes as comprise transfer, inflammatory diseases in cancer.
The compounds of this invention also be used for the treatment of migraine (F.Morales-Asin etc., Headache, 40,2000,45-47).
When the described disease of treatment, The compounds of this invention also can for example be united use with t-PA, streptokinase or the urokinase of " tissue plasmin activator " t-PA, modification with other thrombolysis activity medicine.The compounds of this invention can with described other material simultaneously or administration before or after other material.Preferred especially and acetylsalicylic acid administration simultaneously forms with the prevention grumeleuse again and takes place.The compounds of this invention also can use with platelet glycoprotein acceptor (IIb/IIIa) antagonist combination of anticoagulant.
The present invention relates to formula I compound and salt thereof and relate to the formula I compound of preparation claim 1-16 and the method for pharmaceutically spendable derivative, solvate, salt and steric isomer thereof, it is characterized in that:
A) for preparing with the following formula I compound, wherein
W is N, and
G is NH,
Make formula II compound
Figure A20048000935400431
Wherein
R 1, R 2, E, X, Y and T definition be with claim 1,
And W is N,
React with the formula III compound
D-N＝C＝O III
Wherein
D defines with claim 1,
Or
B) be preparation following formula I compound, wherein
X is-[C (R 4) 2] nCONR 3[C (R 4) 2] n-,
Make formula IV compound
HNR 3-[C(R 4) 2] n-Y-T IV
R wherein 3, n, Y and T definition is with claim 1,
React with formula V compound
Figure A20048000935400441
Wherein
L is Cl, Br, I or OH group free or that active function groups is modified, and
R 1, R 2, R 4, D, E, G, W and n definition be with claim 1,
Or
C) W is the formula I compound of N in order to prepare wherein,
Make formula II compound
Figure A20048000935400442
Wherein
R 1, R 2, E, X, Y and T definition be with claim 1,
And W is N,
React with formula VI compound
D-G-CO-L VI
Wherein D and G define with claim 1, and
L is Cl, Br, I or OH group free or that active function groups is modified,
And/or
Alkali or the acid of formula I are converted into a kind of of its salt.
The invention still further relates to optically-active form (steric isomer), enantiomorph, racemic modification, diastereomer, hydrate and the solvate of these compounds.Term " solvate of compound " expression is because their power that attracts each other forms the adducts of inert solvent molecule and compound.Solvate is for example one or dihydrate or alcoholate.
The for example salt of The compounds of this invention and alleged prodrug compound represented in term " pharmaceutically spendable derivative ".Term " prodrug derivatives " is represented with for example alkyl or acyl group, sugar or oligopeptides modification, dissociating rapidly in organism forms the formula I compound of active compound of the present invention.These compounds also comprise the biodegradable polymer derivant of The compounds of this invention, for example at Int.J.Pharm.115, describe among the 61-67 (1995).
According to the present invention, the invention still further relates to the mixture of formula I compound, the mixture of two kinds of diastereomers for example, for example ratio is the mixture of 1: 1,1: 2,1: 3,1: 4,1: 5,1: 10,1: 100 or 1: 1000.Preferred especially these mixtures are the mixture of Stereoisomeric compounds.
The invention still further relates to the steric isomer that is selected from following pyrrolidine carboxylic acid derivatives and pharmaceutically spendable derivative, solvate, salt, comprises its various mixed things:
1) 1-N-[(4-chloro-phenyl-)]-2-N-[(1 '-methyl-[1,4 '] connection piperidin-4-yl)]-(2R, 4R)-4-hydroxyl pyrrolidine-1, the 2-diformamide,
2) 1-N-[(4-chloro-phenyl-)]-and 2-N-[(3,4,5,6-tetrahydrochysene-2H-[1,4 '] dipyridyl-4-yl)]-(2R, 4R)-4-hydroxyl pyrrolidine-1, the 2-diformamide,
3) 1-N-[(4-chloro-phenyl-)]-and 2-N-[(3,4,5,6-tetrahydrochysene-2H-[1,4 '] dipyridyl-4-yl)-(2R, 4R)-4-oxyethyl group tetramethyleneimine-1, the 2-diformamide,
4) N-(4-chloro-phenyl-)-(2R, 4R)-4-hydroxyl-2-(4-pyridin-4-yl piperazine-1-carbonyl) tetramethyleneimine-1-methane amide,
5) N-(4-chloro-phenyl-)-(2R, 4R)-4-hydroxyl-2-[4-(2-p-methoxy-phenyl)-piperazine-1-carbonyl] tetramethyleneimine-1-methane amide,
6) N-(4-chloro-phenyl-)-(2R, 4R)-2-[4-(4-fluorophenyl) piperazine-1-carbonyl]-4-hydroxyl pyrrolidine-1-methane amide,
7) N-(4-chloro-phenyl-)-(2R, 4R)-4-hydroxyl-2-[4-hydroxyl-4-(4-p-methoxy-phenyl) piperidines-1-carbonyl] tetramethyleneimine-1-methane amide,
8) N-(4-chloro-phenyl-)-(2R, 4R)-4-hydroxyl-2-(4-pyridine-2-base piperazine-1-carbonyl) tetramethyleneimine-1-methane amide,
9) N-(4-chloro-phenyl-)-(2R, 4R)-2-[4-(4-ethyl piperazidine-1-yl) piperidines-1-carbonyl]-4-hydroxyl pyrrolidine-1-methane amide,
10) N-(4-chloro-phenyl-)-(2R, 4R)-2-[4-(4,6-dimethyl pyrimidine-2-yl) piperazine-1-carbonyl]-4-hydroxyl pyrrolidine-1-methane amide,
11) N-(4-chloro-phenyl-)-(2R, 4R)-4-hydroxyl-2-[4-(1-methyl piperidine-4-yl) piperazine-1-carbonyl] tetramethyleneimine-1-methane amide;
12) 1-N-[(4-chloro-phenyl-)]-2-N-{[2-(2-dimethylamino oxyethyl group)-4-morpholine-4-base phenyl]-(2R, 4R)-4-hydroxyl pyrrolidine-1, the 2-diformamide,
13) 1-N-[(4-chloro-phenyl-)]-2-N-[(2-oxyethyl group-4-morpholine-4-base phenyl)]-(2R, 4R)-4-hydroxyl pyrrolidine-1, the 2-diformamide,
14) 1-N-[(4-chloro-phenyl-)]-2-N-[(4-morpholine-4-base-2-propoxy-phenyl)]-(2R, 4R)-4-hydroxyl pyrrolidine-1, the 2-diformamide.
The invention still further relates to the steric isomer that is selected from following Cyclopentane carboxylic acid derivative and pharmaceutically spendable derivative, solvate, salt, comprises its various mixed things:
N-[4-(3-oxo morpholine-4-yl) phenyl]-(rac)-and 2-[3-(4-chloro-phenyl-) urea groups] cyclopentane formamide,
N-[3-methyl-4-(3-oxo morpholine-4-yl) phenyl]-(rac)-and 2-[3-(4-chloro-phenyl-)-urea groups] cyclopentane formamide.
For for example A of all once above groups occurring, their implication is independently of one another.
In upper and lower literary composition, unless otherwise indicated, otherwise group or parameter D, E, G, W, X, Y, T, R 1And R 2Under the definition cotype I item.
A is non-side chain (straight chain) or the branched-chain alkyl with 1,2,3,4,5,6,7,8,9 or 10 carbon atom.Preferred A is a methyl, is ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl or the tertiary butyl in addition, also is amyl group in addition; 1-, 2-or 3-methyl butyl; 1,1-, 1,2-or 2,2-dimethyl propyl; 1-ethyl propyl, hexyl, 1-, 2-, 3-or 4-methyl amyl; 1,1-, 1,2-, 1,3-, 2,2-, 2,3-or 3,3-dimethylbutyl; 1-or 2-ethyl-butyl; 1-ethyl-1-methyl-propyl, 1-ethyl-2-methyl-propyl, 1,1,2-or 1,2,2-trimethylammonium propyl group; Preference such as trifluoromethyl in addition.Very particularly preferably A is the alkyl with 1,2,3,4,5 or 6 carbon atom, preferable methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, hexyl, trifluoromethyl, pentafluoroethyl group or 1,1,1-trifluoroethyl.
Preferred cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or suberyl.Preferred alkylidene group is methylene radical, ethylidene, propylidene, butylidene, pentylidene or hexylidene, is branched alkylidene in addition.
R 1And R 2Independently of one another, separately preference as be H ,=O, COOR 3, OH, OA, NH 2, have alkyl, a N of 1,2,3,4,5 or 6 carbon atom 3, ethynyl, vinyl, allyloxy, NHCOA, NHSO 2A, OCH 2COOA or OCH 2COOH.
Preferred R 1For H ,=O, COOR 3For example COOA, OH, OA, NH 2, have alkyl, a N of 1,2,3,4,5 or 6 carbon atom 3, ethynyl, vinyl, allyloxy ,-OCOR 3For example kharophen or NHSO of methyl ketonic oxygen base, NHCOA for example 2A is methylsulfonyl amino for example; OCH 2COOA is OCH for example 2COOCH 3Or OCH 2COOH.Preferred R 2For H ,=O, OH, OA methoxyl group or have the alkyl of 1,2,3,4,5 or 6 carbon atom for example.
In a further preferred embodiment,
R 1For H ,=O, COOR 3, OH, OA, NH 2, have alkyl, a N of 1,2,3,4,5 or 6 carbon atom 3, ethynyl, vinyl, allyloxy ,-OCOR 3, NHCOA, NHSO 2A, H-C ≡ C-CH 2-, CH 3-C ≡ C-CH 2-O-,-O-CH 2-CH (OH)-CH 2OH ,-O-CH 2-CH (OH)-CH 2NH 2,-O-CH 2-CH (OH)-CH 2Het ', OCH 2COOCH 3Or OCH 2COOH;
R 2For H ,=O, OH, OA or have the alkyl of 1,2,3,4,5 or 6 carbon atom;
Het ' can not replace or replaced or two replacements by following group list: ketonic oxygen, Hal, A, OH, NH for the first heterocycle of the saturated 3-6 with 1-3 N and/or O atom 2, NO 2, CN, COOA or CONH 2
In another preferred embodiment,
R 1Be ethynyl, vinyl, allyloxy, CH 3-C ≡ C-CH 2-O-,-O-CH 2CH (OH)-CH 2OH ,-O-CH 2-CH (OH)-CH 2NH 2,-O-CH 2-CH (OH)-CH 2Het ', OCH 2COOCH 3Or OCH 2COOH,
R 2Be H, A or OH,
Het ' can not replace or replaced or two replacements by following group list: ketonic oxygen, Hal, A, OH, NH for the first heterocycle of the saturated 3-6 with 1-3 N and/or O atom 2, NO 2, CN, COOA or CONH 2
In a further preferred embodiment,
R 1Be ethynyl, vinyl, allyloxy, CH 3-C ≡ C-CH 2-O-,-O-CH 2-CH (OH)-CH 2OH ,-O-CH 2-CH (OH)-CH 2NH 2,-O-CH 2-CH (OH)-CH 2Het ', OCH 2COOCH 3Or OCH 2COOH,
R 2Be H, A or OH,
Het ' can not replace or replaced or two replacements by the ketonic oxygen list for the first heterocycle of the saturated 3-6 with 1-3 N and/or O atom.
In this connected, very particularly preferably Het ' was tetramethyleneimine, piperidines Huo oxazolidine, and they do not replace separately or are replaced by the ketonic oxygen list.
Perhaps, R 1And R 2For having the 3-6 unit's carbocyclic ring or the heterocycle of 0-3 N, O and/or S atom, their volutions or dicyclo connect (condensing) extremely together
Figure A20048000935400481
On the loop systems.
Here, 3-6 unit's carbocyclic ring or heterocycle are for example phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyridyl, imidazolyl, piperidyl or 1,3-dioxolanyl.
R 1And R 2Be in particular 3-6 unit carbocyclic ring together, its volution is connected to
Figure A20048000935400482
On the loop systems.
Here, the first carbocyclic ring of preferred 3-6 is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
Preferred R 3Being H or A, also is phenyl, benzyl or [C (R in addition 4) 2] nCOOA is CH for example 2COOCH 3
Preferred R 4Be H or A, very particularly preferably H.COR 2, COR 3And COR 4For for example CHO or-COA.Preferably-COA (acyl group) is ethanoyl, propionyl, also is butyryl radicals, pentanoyl, caproyl or benzoyl for example in addition.
Preferred Hal is F, Cl or Br, perhaps is I.
Ar is for example phenyl, adjacent-,-or right-aminomethyl phenyl; Adjacent-,-or right-ethylphenyl; Adjacent-,-or right-propyl group phenyl; Adjacent-,-or right-isopropyl phenyl; Adjacent-,-or right-tert-butyl-phenyl; Adjacent-,-or right-hydroxy phenyl; Adjacent-,-or right-nitrophenyl; Adjacent-,-or right-aminophenyl; Adjacent-,-or right-(N-methylamino) phenyl; Adjacent-,-or right-(N-methylamino carbonyl) phenyl; Adjacent-,-or right-acetylamino phenyl; Adjacent-,-or right-p-methoxy-phenyl; Adjacent-,-or right-ethoxyl phenenyl; Adjacent-,-or right-ethoxy carbonyl phenyl; Adjacent-,-or right-(N, N-dimethylamino) phenyl; Adjacent-,-or right-(N, N-dimethylamino carbonyl) phenyl; Adjacent-,-or right-(N-ethylamino) phenyl; Adjacent-,-or right-(N, N-diethylamino) phenyl; Adjacent-,-or right-fluorophenyl; Adjacent-,-or right-bromophenyl; Adjacent-,-or right-chloro-phenyl-; Adjacent-,-or right-(methanesulfonamido) phenyl; Adjacent-,-or right-(methylsulfonyl) phenyl; Adjacent-,-or right-Phenoxyphenyl; Further preferred 2,3-, 2,4-, 2,5-, 2,6-, 3,4-or 3,5-difluorophenyl; 2,3-, 2,4-, 2,5-, 2,6-, 3,4-or 3,5-dichlorophenyl; 2,3-, 2,4-, 2,5-, 2,6-, 3,4-or 3,5-dibromo phenyl; 2,4-or 2,5-dinitrophenyl; 2,5-or 3,4-Dimethoxyphenyl; 3-nitro-4-chloro-phenyl; 3-amino-4-chloro-, 2-amino-3-chloro-, 2-amino-4-chloro-, 2-amino-5-chloro-or 2-amino-6-chloro-phenyl-; 2-nitro-4-N, the N-dimethylamino-or 3-nitro-4-N, the N-dimethylamino phenyl; 2, the 3-diamino-phenyl; 2,3,4-, 2,3,5-, 2,3,6-, 2,4,6-or 3,4,5-trichlorophenyl; 2,4,6-trimethoxyphenyl, 2-hydroxyl-3, the 5-dichlorophenyl, right-iodophenyl, 3,6-two chloro-4-aminophenyls, 4-fluoro-3-chloro-phenyl-, 2-fluoro-4-bromophenyl, 2,5-two fluoro-4-bromophenyls, 3-bromo-6-p-methoxy-phenyl, 3-chloro-6-p-methoxy-phenyl, 3-chloro-4-acetylamino phenyl, 3-fluoro-4-p-methoxy-phenyl, 3-amino-6-aminomethyl phenyl, 3-chloro-4-acetylamino phenyl or 2,5-dimethyl-4-chloro-phenyl-.
Preferred Ar for for example do not replace or by following group list replace, two replacements or trisubstd phenyl: Hal, A, OR 2, OR 3, SO 2A, COOR 2Or CN.Preferred especially Ar is not for for example replacing or by following group list replacement or dibasic phenyl: Hal, A, OA, phenoxy group, SO 2A, SO 2NH 2, COOR 2Or CN, for example phenyl, 2-methylsulfonyl phenyl, 2-amino-sulfonyl phenyl, Phenoxyphenyl, 2-, 3-or 4-chloro-phenyl-; 3,4-dichlorophenyl, 4-aminomethyl phenyl, 4-bromophenyl, 3-fluoro-4-p-methoxy-phenyl, 4-Trifluoromethoxyphen-l, 4-ethoxyl phenenyl, 2-p-methoxy-phenyl, 3-cyano group-phenyl, 4-ethoxy carbonyl phenyl, methoxycarbonyl phenyl, carboxyl phenyl or aminocarbonyl-phenyl.Very particularly preferably Ar is unsubstituted phenyl, 4-chloro-phenyl-or 2-methylsulfonyl phenyl.
Preferred especially G is (CH 2) n, (CH 2) nNH-,-CH=CH-or-CH=CH-CH=CH-.
Preferred especially X is-CONH-or-CON (CH 2COOA)-.
Preferred Y is preferably 1,4-phenylene: A, OA, Cl, F, COOCH especially for not replacing or being replaced or dibasic cycloalkylidene, Het-two bases or Ar-two bases by following group list 3, COOH, phenoxy group or aminocarboxyl, also be the preferred pyridines-2 of pyridine two bases in addition, 5-two bases, piperidines two bases or cyclohexylidene.Y is in particular not and replaces or to be replaced by following group list or Disubstituted pyridine two bases, piperidines two bases, cyclohexylidene or phenylene: A, OA, Cl, F, COOCH 3, COOH, phenoxy group or aminocarboxyl.
Het is for example 2-or 3-furyl, 2-or 3-thienyl, 1-, 2-or 3-pyrryl; 1-, 2-, 4-or 5-imidazolyl; 1-, 3-, 4-or 5-pyrazolyl; 2-, 4-or 5-oxazolyl; 3-, 4-or 5-isoxazolyl; 2-, 4-or 5-thiazolyl, 3-, 4-or 5-isothiazolyl; 2-, 3-or 4-pyridyl; 2-, 4-, 5-or 6-pyrimidyl, preferred in addition 1,2,3-triazoles-1-,-4-or-the 5-base; 1,2,4-triazole-1-,-3-or-the 5-base; 1-or 5-tetrazyl, 1,2,3-oxadiazole-4-or-the 5-base; 1,2,4-oxadiazole-3-or-the 5-base; 1,3,4-thiadiazoles-2-or-the 5-base; 1,2,4-thiadiazoles-3-or-the 5-base; 1,2,3-thiadiazoles-4-or-the 5-base; 3-or 4-pyridazinyl, pyrazinyl, 1-, 2-, 3-, 4-, 5-, 6-or 7-indyl; 4-or 5-pseudoindoyl; 1-, 2-, 4-or 5-benzimidazolyl-; 1-, 3-, 4-, 5-, 6-or 7-benzopyrazoles base; 2-, 4-, 5-, 6-or 7-benzoxazolyl; 3-, 4-, 5-, 6-or 7-benzoisoxazole base; 2-, 4-, 5-, 6-or 7-benzothiazolyl; 2-, 4-, 5-, 6-or 7-benzisothiazole base; 4-, 5-, 6-or 7-benzo-2,1,3-oxadiazole base; 2-, 3-, 4-, 5-, 6-, 7-or 8-quinolyl; 1-, 3-, 4-, 5-, 6-, 7-or 8-isoquinolyl; 3-, 4-, 5-, 6-, 7-or 8-cinnolinyl; 2-, 4-, 5-, 6-, 7-or 8-quinazolyl; 5-or 6-quinoxalinyl; 2-, 3-, 5-, 6-, 7-or 8-2H-phendioxin, the 4-oxazinyl; Preferred in addition 1,3-benzodioxole-5-base, 1,4-benzodioxan-6-base, 2,1,3-diazosulfide-4-or-5-base or 2,1,3-Ben Bing oxadiazole-5-base.
Heterocyclic radical is partially or completely hydrogenation also.Therefore, Het for example also can be 2,3-dihydro-2-,-3-,-4-or-the 5-furyl; 2,5-dihydro-2-,-3-,-4-or-the 5-furyl; Tetrahydrochysene-2-or-3-furyl, 1,3-dioxolane-4-base, tetrahydrochysene-2-or-3-thienyl, 2,3-dihydro-1-,-2-,-3-,-4-or-the 5-pyrryl; 2,5-dihydro-1-,-2-,-3-,-4-or-the 5-pyrryl; 1-, 2-or 3-pyrrolidyl; Tetrahydrochysene-1-,-2-or-the 4-imidazolyl; 2,3-dihydro-1-,-2-,-3-,-4-or-the 5-pyrazolyl; Tetrahydrochysene-1-,-3-or-the 4-pyrazolyl; 1,4-dihydro-1-,-2-,-3-or-the 4-pyridyl; 1,2,3,4-tetrahydrochysene-1-,-2 ,-3-,-4-,-5-or-the 6-pyridyl; 1-, 2-, 3-or 4-piperidyl; 2-, 3-or 4-morpholinyl; Tetrahydrochysene-2-,-3-or-the 4-pyranyl; 1,4-alkyl dioxin, 1,3-diox-2-,-4-or-the 5-base; Six hydrogen-1-,-3-or-the 4-pyridazinyl; Six hydrogen-1-,-2-,-4-or-the 5-pyrimidyl; 1-, 2-or 3-piperazinyl; 1,2,3,4-tetrahydrochysene-1-,-2 ,-3-,-4-,-5-,-6-,-7-or-the 8-quinolyl; 1,2,3,4-tetrahydrochysene-1-,-2 ,-3-,-4-,-5-,-6-,-7-or-the 8-isoquinolyl; 2,3-, 5-, 6-, 7-or 8-3,4-dihydro-2H-phendioxin, the 4-oxazinyl, preferred in addition 2,3-methylenedioxyphenyl, 3,4-methylenedioxyphenyl, 2,3-ethylenedioxy phenyl, 3,4-ethylenedioxy phenyl, 3,4-(difluoro methylene-dioxy) phenyl, 2,3-Dihydrobenzofuranes-5-or-6-base, 2,3-(2-oxo methylene-dioxy) phenyl or 3,4-dihydro-2H-1,5-benzo two oxa-English in heptan (benzodioxepin)-6-or-the 7-base, preferred in addition 2,3-dihydro benzo furyl or 2,3-dihydro-2-oxo-furyl.
Preferred Het ' is for example 2-or 3-furyl, 2-or 3-thienyl, 1-, 2-or 3-pyrryl, 1-, 2-, 4-or 5-imidazolyl, 1-, 3-, 4-or 5-pyrazolyl, 2-, 4-or 5-oxazolyl; 3-, 4-or 5-isoxazolyl; 2-, 4-or 5-thiazolyl, 3-, 4-or 5-isothiazolyl; 2-, 3-or 4-pyridyl; 2-, 4-, 5-or 6-pyrimidyl, preferred in addition 1,2,3-triazoles-1-,-4-or-the 5-base; 1,2,4-triazole-1-,-3-or-the 5-base; 1-or 5-tetrazyl, 1,2,3-oxadiazole-4-or-the 5-base; 1,2,4-oxadiazole-3-or-the 5-base; 1,3,4-thiadiazoles-2-or-the 5-base; 1,2,4-thiadiazoles-3-or-the 5-base; 1,2,3-thiadiazoles-4-or-the 5-base; 3-or 4-pyridazinyl, pyrazinyl, 1-, 2-, 3-, 4-, 5-, 6-or 7-indyl; 4-or 5-pseudoindoyl; 1-, 2-, 4-or 5-benzimidazolyl-; 1-, 3-, 4-, 5-, 6-or 7-benzopyrazoles base; 2-, 4-, 5-, 6-or 7-benzoxazolyl; 3-, 4-, 5-, 6-or 7-benzoisoxazole base; 2-, 4-, 5-, 6-or 7-benzothiazolyl; 2-, 4-, 5-, 6-or 7-benzisothiazole base; 4-, 5-, 6-or 7-benzo-2,1,3-oxadiazole base; 2-, 3-, 4-, 5-, 6-, 7-or 8-quinolyl; 1-, 3-, 4-, 5-, 6-, 7-or 8-isoquinolyl; 3-, 4-, 5-, 6-, 7-or 8-cinnolinyl; 2-, 4-, 5-, 6-, 7-or 8-quinazolyl; 5-or 6-quinoxalinyl; 2-, 3-, 5-, 6-, 7-or 8-2H-phendioxin, the 4-oxazinyl; Preferred in addition 1,3-benzodioxole-5-base, 1,4-benzodioxan-6-base, 2,1,3-diazosulfide-4-or-5-base or 2,1,3-Ben Bing oxadiazole-5-base.
Heterocyclic radical is partially or completely hydrogenation also.Therefore, Het ' for example also can be 2,3-dihydro-2-,-3-,-4-or-the 5-furyl; 2,5-dihydro-2-,-3-,-4-or-the 5-furyl; Tetrahydrochysene-2-or-3-furyl, 1,3-dioxolane-4-base, tetrahydrochysene-2-or-3-thienyl, 2,3-dihydro-1-,-2-,-3-,-4-or-the 5-pyrryl; 2,5-dihydro-1-,-2-,-3-,-4-or-the 5-pyrryl; 1-, 2-or 3-pyrrolidyl; Tetrahydrochysene-1-,-2-or-the 4-imidazolyl; 2,3-dihydro-1-,-2-,-3-,-4-or-the 5-pyrazolyl; Tetrahydrochysene-1-,-3-or-the 4-pyrazolyl; 1,4-dihydro-1-,-2-,-3-or-the 4-pyridyl; 1,2,3,4-tetrahydrochysene-1-,-2 ,-3-,-4-,-5-or-the 6-pyridyl; 1-, 2-, 3-or 4-piperidyl; 2-, 3-or 4-morpholinyl; Tetrahydrochysene-2-,-3-or-the 4-pyranyl; 1,4-alkyl dioxin, 1,3-diox-2-,-4-or-the 5-base; Six hydrogen-1-,-3-or-the 4-pyridazinyl; Six hydrogen-1-,-2-,-4-or-the 5-pyrimidyl; 1-, 2-or 3-piperazinyl; 1,2,3,4-tetrahydrochysene-1-,-2 ,-3-,-4-,-5-,-6-,-7-or-the 8-quinolyl; 1,2,3,4-tetrahydrochysene-1-,-2 ,-3-,-4-,-5-,-6-,-7-or-the 8-isoquinolyl; 2-, 3-, 5-, 6-, 7-or 8-3,4-dihydro-2H-phendioxin, the 4-oxazinyl, preferred in addition 2,3-methylenedioxyphenyl, 3,4-methylenedioxyphenyl, 2,3-ethylenedioxy phenyl, 3,4-ethylenedioxy phenyl, 3,4-(difluoro methylene-dioxy) phenyl, 2,3-Dihydrobenzofuranes-5-or-6-base, 2,3-(2-oxo methylene-dioxy) phenyl or 3,4-dihydro-2H-1,5-benzo two oxa-English-6-in heptan or-the 7-base, preferred in addition 2,3-dihydro benzo furyl or 2,3-dihydro-2-oxo-furyl.
Preferred T has the monocycle of 1-2 N and/or O atom or dicyclo, saturated or unsaturated heterocycle, replaced by following group list or two replacement :=O ,=S ,=NR 2,=N-CN ,=N-O 2,=NOR 2,=NCOR 2,=NCOOR 2Or=NOCOCR 2, also can be replaced in addition by Hal, A or the single replacement of OA or two.
In a further embodiment, preferred T is for example 2-imino-piperidines-1-base, 2-lminopyrrolidine-1-base, 2-imino--1H-pyridine-1-base, 3-imino-morpholine-4-base, 4-imino--1H-pyridine-1-base, 2,6-diimino piperidines-1-base, 2-imino-piperazine-1-base, 2,6-diimino piperazine-1-base, 2,5-diimino tetramethyleneimine-1-base, 2-imino--1,3-oxazolidine-3-base, 3-imino--2H-pyridazine-2-base, 2-imino-azepine ring-1-in heptan base, 2-hydroxyl-6-imino-piperazine-1-base or 2-methoxyl group-6-imino-piperazine-1-base.
T is in particular the saturated or unsaturated heterocycle of monocycle with 1-2 N and/or O atom, quilt=O ,=S or=NH is single to be replaced or two replaces, can be replaced or two replace by Hal, A and/or OA are single in addition.
Preferred especially T is piperidines-1-base, tetramethyleneimine-1-base, pyridine-1-base, morpholine-4-base, piperazine-1-base, 1,3-oxazolidine-3-base, pyridazine-2-base, pyrazine-1-base, azepine ring-1-in heptan base, 2-azabicyclic [2.2.2] octane-2-base, imidazolidyl, thiazolyl or 1,4-oxa-azepine cyclic group in heptan, they separately by=O or=NH is single to be replaced or two replaces, and wherein each group also can be replaced or two replace by Hal, A and/or OA are single; 3-oxo morpholine-4-base very particularly preferably.Preferred in addition T is 2-oxo-3-methoxyl group-1H-pyridine-1-base.
Preferred D is phenyl, thienyl, pyridyl, furyl, thiazolyl, pyrryl or imidazolyl, they are replaced by the single replacement of Hal or two separately, preferred especially phenyl, pyridyl, thienyl, furyl or imidazolyl, they are replaced by the single replacement of Hal or two separately.
Preferred group Be tetramethyleneimine-1,2-two bases, piperidines-1,2-two bases, piperidines-1,3-two Ji, oxazolidines-3,4-or-3,5-two bases, thiazolidine-3,4-two bases, 2,5-dihydro-1H-pyrroles-1,5-two bases, 1,3-dioxolane-4,5-two bases, 1, oneself encircles-3 3-oxa-azepine, 4-two bases, piperazine-1,4-two bases, tetrahydrofuran (THF)-3,4-two bases or azetidine-1,2-two bases.
Formula I compound can have one or more chiral centres, therefore can have various stereoisomeric forms in any ratio.Formula I is contained all these forms.
Therefore, specifically, the present invention relates to the formula I compound that has one of preferred above-mentioned implication at least one described group wherein.Compound and pharmaceutically acceptable derivates thereof, solvate, salt and comprise that some preferred groups of the steric isomer of its various ratio miscellanys can represent by following inferior formula Ia to Iw, these inferior formulas meet formula I and wherein more not detailed indicated group suc as formula defining among the I, but wherein:
In Ia
D is monocycle or dicyclo aromatic carbon ring or the heterocycle with 0-4 N, O and/or S atom, replaces or is replaced by the single replacement of Hal or two;
In Ib
D is phenyl, pyridyl, thienyl, furyl or imidazolyl, and they are replaced by the single replacement of Hal or two separately;
In Ic
R 1, R 2Independently of one another, respectively do for oneself H ,=O, COOR 3, OH, OA, NH 2, have alkyl, a N of 1,2,3,4,5 or 6 carbon atom 3, ethynyl, vinyl, allyloxy, NHCOA, NHSO 2A, OCH 2COOA or OCH 2COOH;
In Id
G is (CH 2) n, (CH 2) nNH-,-CH=CH-or-CH=CH-CH=CH-;
In Ie
X is-[C (R 4) 2] nCONR 3[C (R 4) 2] n-;
In If
X is-CONH-or-CON (CH 2COOA)-;
In Ig
Y is cycloalkylidene, Het-two bases or Ar-two bases;
In Ih
Y is not for replacing or replaced by following group list or Disubstituted pyridine two bases, piperidines two bases, cyclohexylidene or 1,4-phenylene: A, OA, Cl, F, COOCH 3, COOH, phenoxy group or aminocarboxyl;
In Ii
T is the monocycle with 1-2 N and/or O atom, saturated or unsaturated heterocycle, quilt=O ,=S or=NH is single to be replaced or two replaces, and can be replaced or two replace by Hal, A and/or OA are single;
In Ij
T is piperidines-1-base, tetramethyleneimine-1-base, pyridine-1-base, morpholine-4-base, piperazine-1-base, 1,3-oxazolidine-3-base, pyridazine-2-base, pyrazine-1-base, azepine ring-1-in heptan base, 2-azabicyclic [2.2.2] octane-2-base, imidazolidyl, thiazolyl or 1,4-oxa-azepine cyclic group in heptan, they separately by=O or=NH is single to be replaced or two replaces, and wherein each group also can be replaced or two replace by Hal, A and/or OA are single;
In Ik
Ar is not for replacing or replaced by following group list or dibasic phenyl: Hal, A, OA, SO 2A, COOR 3, SO 2NH 2, CN, COOA, COOH or phenoxy group;
In Il
D is monocycle or dicyclo, aromatic carbon ring or the heterocycle with 0-4 N, O and/or S atom, replaces or replaced by the single replacement of Hal or two,
R 1, R 2Independently of one another, respectively do for oneself H ,=O, COOR 3, OH, OA, NH 2, have alkyl, a N of 1,2,3,4,5 or 6 carbon atom 3, ethynyl, vinyl, allyloxy, NHCOA, NHSO 2A, OCH 2COOA or OCH 2COOH,
Perhaps, R 1And R 2Be the first carbocyclic ring of the 3-6 of volution connection together,
R 3Be H, A, phenyl, benzyl or [C (R 4) 2] nCOOA,
R 4Be H or A,
W is N, CR 3Or sp 2-hydridization carbon atom,
E is first saturated carbon ring of the 3-7 with 0-3 N, a 0-2 O and/or 0-2 S atom or heterocycle with W,
It can contain two keys,
G is (CH 2) n, (CH 2) nNH-,-CH=CH-or-CH=CH-CH=CH-,
X is-[C (R 4) 2] nCONR 3[C (R 4) 2] n-,
Y is cycloalkylidene, Het-two bases or Ar-two bases,
Ar is not for replacing or replaced by following group list or dibasic phenyl: Hal, A, OA, SO 2A, COOR 2, SO 2NH 2, CN, COOA, COOH or phenoxy group,
T is the monocycle with 1-2 N and/or O atom, saturated or unsaturated heterocycle, quilt=O ,=S or=NH is single to be replaced or two replaces, and can be replaced or two replace by Hal, A and/or OA are single,
A is non-side chain or the branched-chain alkyl with 1-10 carbon atom, and wherein 1-7 H atom can be replaced by F,
Hal is F, Cl, Br or I,
N is 0,1 or 2;
In Im
D is phenyl, pyridyl, thienyl, furyl or imidazolyl, and they are replaced by the single replacement of Hal or two separately;
R 1, R 2Independently of one another, respectively do for oneself H ,=O, COOR 3, OH, OA, NH 2, have alkyl, a N of 1,2,3,4,5 or 6 carbon atom 3, ethynyl, vinyl, allyloxy, NHCOA, NHSO 2A, OCH 2COOA or OCH 2COOH,
Perhaps, R 1And R 2Be the first carbocyclic ring of the 3-6 of volution connection together,
R 3Be H, A or CH 2COOA,
R 4Be H or A,
W is N, CR 3Or sp 2-hydridization carbon atom,
E is first saturated carbon ring of the 3-7 with 0-3 N, a 0-2 O and/or 0-2 S atom or heterocycle with W,
It can contain two keys,
G is (CH 2) n, (CH 2) nNH-,-CH=CH-or-CH=CH-CH=CH-,
X is-CONH-or-CON (CH 2COOA)-,
Y is not for replacing or replaced by following group list or Disubstituted pyridine two bases, piperidines two bases, cyclohexylidene or phenylene: A, OA, Cl, F, COOCH 3, COOH, phenoxy group or aminocarboxyl,
T is piperidines-1-base, tetramethyleneimine-1-base, pyridine-1-base, morpholine-4-base, piperazine-1-base, 1,3-oxazolidine-3-base, pyridazine-2-base, pyrazine-1-base, azepine ring-1-in heptan base, 2-azabicyclic [2.2.2] octane-2-base, imidazolidyl, thiazolyl or 1,4-oxa-azepine cyclic group in heptan, they separately by=O or=NH is single to be replaced or two replaces, and wherein each group also can be replaced or two replace by Hal, A and/or OA are single
A is non-side chain or the branched-chain alkyl with 1-10 carbon atom, and wherein 1-7 H atom can be replaced by F,
Hal is F, Cl, Br or I,
N is 0,1 or 2;
In In
D is phenyl, pyridyl or thienyl, and they are replaced by the single replacement of Hal or two separately,
R 1For H ,=O, COOR 3, OH, OA, NH 2, have alkyl, a N of 1,2,3,4,5 or 6 carbon atom 3, ethynyl, vinyl, allyloxy ,-OCOR 3, NHCOA or NHSO 2A,
R 2For H ,=O, OH, OA or have the alkyl of 1,2,3,4,5 or 6 carbon atom,
Perhaps, R 1And R 2Be the first carbocyclic ring of the 3-6 of volution connection together,
R 3Be H or A,
R 4Be H or A,
Be tetramethyleneimine-1,2-two bases, piperidines-1,2-two Ji, oxazolidines-3,4-or 3,5-two bases, thiazolidine-3,4-two bases, 2,5-dihydro-1H-pyrroles-1,5-two bases, 1,3-dioxolane-4,5-two bases, 1, oneself encircles-3 3-oxa-azepine, 4-two bases, piperazine-1,4-two bases, tetrahydrofuran (THF)-3,4-two bases or azetidine-1,2-two bases
G is (CH 2) nOr (CH 2) nNH-,
X is CONH,
Y is for replacing or replaced by following group list or dibasic 1,3-or 1, and the 4-phenylene: methyl, trifluoromethyl, ethyl, propyl group, Cl or F,
T is piperidines-1-base, tetramethyleneimine-1-base, 1H-pyridine-1-base, morpholine-4-base, piperazine-1-base, 1,3-oxazolidine-3-base, 2H-pyridazine-2-base, pyrazine-1-base, azepine ring-1-in heptan base or 2-azabicyclic [2.2.2] octane-2-base, they are replaced or two replacements by the ketonic oxygen list separately
A is non-side chain or the branched-chain alkyl with 1-10 carbon atom, and wherein 1-7 H atom can be replaced by F,
Hal is F, Cl, Br or I,
N is 0,1 or 2;
In Io
D is phenyl, pyridyl or thienyl, and they are replaced by the single replacement of Hal or two separately,
R 1For H ,=O, COOR 3, OH, OA, NH 2, have alkyl, a N of 1,2,3,4,5 or 6 carbon atom 3, ethynyl, vinyl, allyloxy ,-OCOR 3, NHCOA or NHSO 2A,
R 2For H ,=O, OH, OA or have the alkyl of 1,2,3,4,5 or 6 carbon atom,
Perhaps, R 1And R 2Be the first carbocyclic ring of the 3-6 of volution connection together,
R 3Be H or A,
R 4Be H or A,
Figure A20048000935400581
Be tetramethyleneimine-1,2-two bases, piperidines-1,2-two Ji, oxazolidines-3,4-or 3,5-two bases, thiazolidine-3,4-two bases, 2,5-dihydro-1H-pyrroles-1,5-two bases, 1,3-dioxolane-4,5-two bases, 1, oneself encircles-3 3-oxa-azepine, 4-two bases, piperazine-1,4-two bases, tetrahydrofuran (THF)-3,4-two bases or azetidine-1,2-two bases
G is (CH 2) nOr (CH 2) nNH-,
X is CONH,
Y is for replacing or replaced by following group list or dibasic 1,3-or 1, and the 4-phenylene: methyl, trifluoromethyl, ethyl, propyl group, Cl or F,
T is for to be replaced or dibasic morpholine-4-base by the ketonic oxygen list,
A is non-side chain or the branched-chain alkyl with 1-10 carbon atom, and wherein 1-7 H atom can be replaced by F,
Hal is F, Cl, Br or I,
N is 0,1 or 2,
In Ip
X is-[C (R 4) 2] nCONR 3[C (R 4) 2] n-or-[C (R 4) 2] nCO[C (R 4) 2] n-;
In Iq
X is CONH or COCH 2,
In Ir
D is phenyl, pyridyl or thienyl, and they are replaced by the single replacement of Hal or two separately,
R 1For H ,=O, COOR 3, OH, OA, NH 2, have alkyl, a N of 1,2,3,4,5 or 6 carbon atom 3, ethynyl, vinyl, allyloxy ,-OCOR 3, NHCOA or NHSO 2A,
R 2For H ,=O, OH, OA or have the alkyl of 1,2,3,4,5 or 6 carbon atom,
Perhaps, R 1And R 2Be the first carbocyclic ring of the 3-6 of volution connection together,
R 3Be H or A,
R 4Be H or A,
Be tetramethyleneimine-1,2-two bases, piperidines-1,2-two Ji, oxazolidines-3,4-or 3,5-two bases, thiazolidine-3,4-two bases, 2,5-dihydro-1H-pyrroles-1,5-two bases, 1,3-dioxolane-4,5-two bases, 1, oneself encircles-3 3-oxa-azepine, 4-two bases, piperazine-1,4-two bases, tetrahydrofuran (THF)-3,4-two bases or azetidine-1,2-two bases
G is (CH 2) nOr (CH 2) nNH-,
X is CONH or COCH 2,
Y is for replacing or replaced by following group list or dibasic 1,3-or 1, and the 4-phenylene: methyl, trifluoromethyl, ethyl, propyl group, Cl or F,
T is for to be replaced or dibasic morpholine-4-base by the ketonic oxygen list,
A is non-side chain or the branched-chain alkyl with 1-10 carbon atom, and wherein 1-7 H atom can be replaced by F,
Hal is F, Cl, Br or I,
N is 0,1 or 2,
In Is
D is monocycle or dicyclo, aromatic carbon ring or the heterocycle with 0-4 N, O and/or S atom, replaces or replaced by the single replacement of Hal or two,
R 1, R 2Independently of one another, respectively do for oneself H ,=O, COOR 3, OH, OA, NH 2, have alkyl, a N of 1,2,3,4,5 or 6 carbon atom 3, ethynyl, vinyl, allyloxy ,-OCOR 3, NHCOA or NHSO 2A,
Perhaps, R 1And R 2Be the first carbocyclic ring of the 3-6 of volution connection together,
R 3Be H or A,
R 4Be H or A,
W is N, CR 3Or sp 2-hydridization carbon atom,
E is first saturated carbon ring of the 3-7 with 0-3 N, a 0-2 O and/or 0-2 S atom or heterocycle with W,
It can contain two keys,
G is (CH 2) nOr (CH 2) nNH-,
X is-[C (R 4) 2] nCONR 3[C (R 4) 2] n-or-[C (R 4) 2] nCO[C (R 4) 2] n-,
Y be Ar-two bases,
Ar is not for replacing or replaced by following group list or dibasic phenyl: Hal, A, OA, SO 2A, COOR 2, SO 2NH 2Or CN,
T is for to be replaced or dibasic morpholine-4-base by the ketonic oxygen list,
A is non-side chain or the branched-chain alkyl with 1-10 carbon atom, and wherein 1-7 H atom can be replaced by F,
Hal is F, Cl, Br or I,
N is 0,1 or 2,
In It
D is phenyl, pyridyl or thienyl, and they are replaced by the single replacement of Hal or two separately,
R 1For H ,=O, COOR 3, OH, OA, NH 2, have alkyl, a N of 1,2,3,4,5 or 6 carbon atom 3, ethynyl, vinyl, allyloxy ,-OCOR 3, NHCOA, NHSO 2A, CH 3-C ≡ C-CH 2-O-,-O-CH 2-CH (OH)-CH 2OH ,-O-CH 2-CH (OH)-CH 2NH 2Or-O-CH 2-CH (OH)-CH 2Het ',
R 2For H ,=O, OH, OA or have the alkyl of 1,2,3,4,5 or 6 carbon atom,
Perhaps, R 1And R 2Be the first carbocyclic ring of the 3-6 of volution connection together,
R 3Be H or A,
R 4Be H or A,
Figure A20048000935400611
Be tetramethyleneimine-1,2-two bases, piperidines-1,2-two Ji, oxazolidines-3,4-or 3,5-two bases, thiazolidine-3,4-two bases, 2,5-dihydro-1H-pyrroles-1,5-two bases, 1,3-dioxolane-4,5-two bases, 1, oneself encircles-3 3-oxa-azepine, 4-two bases, piperazine-1,4-two bases, tetrahydrofuran (THF)-3,4-two bases or azetidine-1,2-two bases
G is (CH 2) nOr (CH 2) nNH-,
X is CONH or COCH 2,
Y is for replacing or replaced by following group list or dibasic 1,3-or 1, and the 4-phenylene: methyl, trifluoromethyl, ethyl, propyl group, Cl or F,
T is for to be replaced or dibasic morpholine-4-base by the ketonic oxygen list,
Het ' can not replace or replaced or two replacements by following group list: ketonic oxygen, Hal, A, OH, NH for the first heterocycle of the saturated 3-6 with 1-3 N and/or O atom 2, NO 2, CN, COOA or CONH 2,
A is non-side chain or the branched-chain alkyl with 1-10 carbon atom, and wherein 1-7 H atom can be replaced by F,
Hal is F, Cl, Br or I,
N is 0,1 or 2,
In Iu
D is phenyl, pyridyl or thienyl, and they are replaced by the single replacement of Hal or two separately,
R 1For H ,=O, COOR 3, OH, OA, NH 2, have alkyl, a N of 1,2,3,4,5 or 6 carbon atom 3, ethynyl, vinyl, allyloxy ,-OCOR 3, NHCOA, NHSO 2A, H-C ≡ C-CH 2-, CH 3-C ≡ C-CH 2-O-,-O-CH 2-CH (OH)-CH 2OH ,-O-CH 2-CH (OH)-CH 2NH 2Or-O-CH 2-CH (OH)-CH 2Het ',
R 2For H ,=O, OH, OA or have the alkyl of 1,2,3,4,5 or 6 carbon atom,
Perhaps, R 1And R 2Be the first carbocyclic ring of the 3-6 of volution connection together,
R 3Be H or A,
R 4Be H or A,
Figure A20048000935400621
Be tetramethyleneimine-1,2-two bases, piperidines-1,2-two Ji, oxazolidines-3,4-or 3,5-two bases, thiazolidine-3,4-two bases, 2,5-dihydro-1H-pyrroles-1,5-two bases, 1,3-dioxolane-4,5-two bases, 1, oneself encircles-3 3-oxa-azepine, 4-two bases, piperazine-1,4-two bases, tetrahydrofuran (THF)-3,4-two bases or azetidine-1,2-two bases
G is (CH 2) nOr (CH 2) nNH-,
X is CONH, COCH 2, CO or COO,
Y is for replacing or replaced by following group list or dibasic 1,3-or 1, and the 4-phenylene: methyl, trifluoromethyl, ethyl, propyl group, Cl or F,
T is for to be replaced or dibasic morpholine-4-base by the ketonic oxygen list,
Het ' can not replace or replaced or two replacements by following group list: ketonic oxygen, Hal, A, OH, NH for the first heterocycle of the saturated 3-6 with 1-3 N and/or O atom 2, NO 2, CN, COOA or CONH 2,
A is non-side chain or the branched-chain alkyl with 1-10 carbon atom, and wherein 1-7 H atom can be replaced by F,
Hal is F, Cl, Br or I,
N is 0,1 or 2;
In Iv
D is phenyl, pyridyl or thienyl, and they are replaced by the single replacement of Hal or two separately,
R 1Be ethynyl, vinyl, allyloxy, CH 3-C ≡ C-CH 2-O-,-O-CH 2-CH (OH)-CH 2OH ,-O-CH 2-CH (OH)-CH 2NH 2Or-O-CH 2-CH (OH)-CH 2Het ',
R 2Be H or OH,
Perhaps, R 1And R 2Be the first carbocyclic ring of the 3-6 of volution connection together,
R 3Be H or A,
R 4Be H or A,
Be tetramethyleneimine-1,2-two bases, piperidines-1,2-two Ji, oxazolidines-3,4-or 3,5-two bases, thiazolidine-3,4-two bases, 2,5-dihydro-1H-pyrroles-1,5-two bases, 1,3-dioxolane-4,5-two bases, 1, oneself encircles-3 3-oxa-azepine, 4-two bases, piperazine-1,4-two bases, tetrahydrofuran (THF)-3,4-two bases or azetidine-1,2-two bases
G is (CH 2) nOr (CH 2) nNH-,
X is CONH, CO, COO or COCH 2,
Y is for replacing or replaced by following group list or dibasic 1,3-or 1, and the 4-phenylene: methyl, trifluoromethyl, ethyl, propyl group, Cl or F,
T is piperidines-1-base, tetramethyleneimine-1-base, 1H-pyridine-1-base, morpholine-4-base, piperazine-1-base, 1,3-oxazolidine-3-base, 2H-pyridazine-2-base, pyrazine-1-base, azepine ring-1-in heptan base or 2-azabicyclic [2.2.2] octane-2-base, they are replaced by ketonic oxygen or the single replacement of OA or two separately
Het ' can not replace or replaced or two replacements by following group list: ketonic oxygen, Hal, A, OH, NH for the first heterocycle of the saturated 3-6 with 1-3 N and/or O atom 2, NO 2, CN, COOA or CONH 2,
A is non-side chain or the branched-chain alkyl with 1-10 carbon atom, and wherein 1-7 H atom can be replaced by F,
Hal is F, Cl, Br or I,
N is 0,1 or 2;
In Iw
D is phenyl, pyridyl, thienyl, furyl or imidazolyl, and they are replaced by the single replacement of Hal or two separately,
R 1For H ,=O, COOR 3, OH, OA, NH 2, have alkyl, a N of 1,2,3,4,5 or 6 carbon atom 3, ethynyl, vinyl, allyloxy, NHCOA, NHSO 2A, OCH 2COOA or OCH 2COOH,
R 2For H ,=O, OH, OA or have the alkyl of 1,2,3,4,5 or 6 carbon atom,
Perhaps, R 1And R 2Be the first carbocyclic ring of the 3-6 of volution connection together,
R 3Be H or A,
R 4Be H or A,
Figure A20048000935400641
Be tetramethyleneimine-1,2-two bases, piperidines-1,2-two Ji, oxazolidines-3,4-or 3,5-two bases, thiazolidine-3,4-two bases, 2,5-dihydro-1H-pyrroles-1,5-two bases, 1,3-dioxolane-4,5-two bases, 1, oneself encircles-3 3-oxa-azepine, 4-two bases, piperazine-1,4-two bases, tetrahydrofuran (THF)-3,4-two bases or azetidine-1,2-two bases
G is (CH 2) n, (CH 2) nNH-,-CH=CH-or-CH=CH-CH=CH-,
X is CONH, CONH 2Or-CON (CH 2COOA)-,
Y is not for replacing or replaced by following group list or Disubstituted pyridine two bases, piperidines two bases, cyclohexylidene or phenylene: A, OA, Cl, F, COOCH 3, COOH, phenoxy group or aminocarboxyl,
T is for to be replaced or dibasic morpholine-4-base by the ketonic oxygen list,
A is non-side chain or the branched-chain alkyl with 1-10 carbon atom, and wherein 1-7 H atom can be replaced by F,
Hal is F, Cl, Br or I,
N is 0,1 or 2.
In addition, formula I compound and prepare they raw material can by as in the document (for example at classic such as Houben-Weyl, Methoden der organischen Chemie[Methods ofOrganic Chemistry], Georg-Thieme-Verlag, Stuttgart) own the known method preparation of describing is said exactly under known and the reaction conditions that is applicable to described reaction and is carried out.Here also can use itself the known but more not detailed here variation of mentioning.
If desired, but also original position forms raw material, so that needn't separate them from reaction mixture, but will immediately they further be converted into formula I compound.
The starting compound of formula II, III, IV, V and VI is generally known.If they are new, but they can be by known method preparation itself.
Preferably by making formula II compound and formula III compound reaction acquisition formula I compound.
Usually be reflected in the inert solvent, in the presence of acid binding agent, carry out, the another kind of salt of weak acid of the preferred potassium of acid binding agent preferred bases or alkaline earth metal hydroxides, carbonate or supercarbonate or alkali or alkaline-earth metal, sodium, calcium or caesium.For example the alkyl derivative of triethylamine, xylidene(s), pyridine or quinoline or excessive formula II phenol composition or formula III also may be favourable to add organic bases.Reaction times is several minutes to 14 day, and temperature of reaction is about 0 ℃ to 150 ℃, is generally 20 ℃ to 130 ℃, and this depends on used condition.
The example of suitable inert solvents is for example hexane, sherwood oil, benzene, toluene or a dimethylbenzene of hydrocarbon; Hydrochloric ether is trieline, 1 for example, 2-ethylene dichloride, tetrachloromethane, chloroform or methylene dichloride; Alcohol is methyl alcohol, ethanol, Virahol, n-propyl alcohol, propyl carbinol or the trimethyl carbinol for example; Ether is ether, isopropyl ether, tetrahydrofuran (THF) (THF) Huo diox for example; Glycol ethers is ethylene glycol monomethyl ether or single ether or glycol dimethyl ether (diglyme) for example; Ketone is acetone or butanone for example; Acid amides is ethanamide, N,N-DIMETHYLACETAMIDE or dimethyl formamide (DMF) for example; Nitrile is acetonitrile for example; Sulfoxide is methyl-sulphoxide (DMSO) for example; Dithiocarbonic anhydride; Carboxylic acid is formic acid or acetate for example; Nitro-compound is Nitromethane 99Min. or oil of mirbane for example; Ester is ethyl acetate for example, or the mixture of described solvent.
In addition can be preferably by making the reaction of formula IV compound and formula V compound obtain formula I compound.Common this is reflected at the inert solvent neutralization to carry out under these conditions.In formula V compound, preferred L is the OH group of Cl, Br, I or free or activity modifying, for example Acibenzolar, imidazoles thing (imidazolide) or have the alkylsulfonyloxy (preferable methyl sulfonyloxy or trifluoromethyl sulfonyloxy) of 1-6 carbon atom or have the aryl-sulfonyl oxygen (preferably phenyl or p-methylphenyl sulfonyloxy) of 6-10 carbon atom.In typical acylation reaction, be used to activate this group of carbonyl in the literature (for example at classic such as Houben-Weyl, Methoden derorganischen Chemie[Methods of Organic Chemistry], Georg-Thieme-Verlag, Stuttgart; ) description arranged.Preferably for example form Acibenzolar in position by adding HOBt or N-hydroxy-succinamide.
Usually be reflected in the inert solvent,, or carry out under the existence of excessive formula V carboxyl composition at the preferred organic bases of acid binding agent for example DIPEA, triethylamine, xylidene(s), pyridine or quinoline.The another kind of salt of weak acid that adds alkali or alkaline earth metal hydroxides, carbonate or supercarbonate or alkali or the preferred potassium of alkaline-earth metal, sodium, calcium or caesium also may be favourable.Reaction times is several minutes to 14 day, and temperature of reaction is generally-10 ℃ to 90 ℃ for-30 ℃ to 140 ℃ approximately, and particularly about 0 ℃ to about 70 ℃, this depends on used condition.Suitable inert solvent is above-mentioned those inert solvents.
In addition can be preferably by making the reaction of formula II compound and formula VI compound obtain formula I compound.Common this is reflected at the inert solvent neutralization to carry out under these conditions.In formula VI compound, preferred L is the OH group of Cl, Br, I or free or activity modifying, for example Acibenzolar, imidazoles thing or have the alkylsulfonyloxy (preferable methyl sulfonyloxy or trifluoromethyl sulfonyloxy) of 1-6 carbon atom or have the aryl-sulfonyl oxygen (preferably phenyl or p-methylphenyl sulfonyloxy) of 6-10 carbon atom.
In addition can be preferably by making wherein D definition with the formula D-NH of claim 1 2Compound and the chloroformate derivative for example reaction of chloroformic acid 4-nitrophenyl ester generate carbamate intermediate, make the reaction of this intermediate and formula II compound subsequently, obtain formula I compound.This reaction is carried out under these conditions.
In addition can be by with solvolysis reagent or hydrogenolysis agent treated, separate type I compound from their one of functional derivatives obtains formula I compound.
The raw material that preferably is used for solvolysis and hydrogenolysis is those raw materials that meet formula I; but contain corresponding protection amino and/or hydroxyl and replace one or more free amine groups and/or hydroxyl; those raw materials that preferably have replacement of amido protecting group and N atomic linkage H atom; specifically R ' is those raw materials of R '-N group replacement HN group of amido protecting group in order to have wherein; and/or have those raw materials that hydroxy-protective group replaces hydroxyl H atom, for example those meet formula I but have wherein R " for hydroxy-protective group-COOR " raw material of group replacement-COOH group.
Also may in raw molecule, there be multiple identical or different protection amino and/or hydroxyl.If the blocking group that exists differs from one another, alternative is dissociated them under many circumstances.
Term " amido protecting group " is known in general term, and relates to and be applicable to the amino group that can remove easily behind the chemical reaction of needs of carrying out to prevent chemical reaction but in other position of molecule of protection (sealing).Typical this group is specially acyl group, aryl, aralkoxy methyl or the aralkyl that does not replace or replace.Because after the reaction (or reaction sequence) of needs, remove the amido protecting group, so their kind and size recede into the background; But preferably have 1-20, particularly those blocking groups of 1-8 carbon atom.Term " acyl group " will be understood by relevant with existing method wide significance.It comprises derived from following acyl group: aliphatic acid, araliphatic acid, aromatic acid or heterocyclic carboxylic acid or sulfonic acid specifically are alkoxy carbonyl, aryloxycarbonyl and particularly aromatic alkoxy carbonyl.The example of this acyl group is for example ethanoyl, propionyl and a butyryl radicals of alkyloyl; Aralkanoyl is phenyl acetyl for example; Aroyl is benzoyl and tolyl (tolyl) for example; The aryloxy group alkyl acyl group is POA for example; Alkoxy carbonyl is methoxycarbonyl, ethoxy carbonyl, 2,2 for example, 2-trichlorine ethoxy carbonyl, BOC (tert-butoxycarbonyl) and 2-iodine ethoxy carbonyl; Aromatic alkoxy carbonyl is CBZ (" carbobenzoxy "), 4-methoxyl group benzyloxy base carbonyl and FMOC for example; And aryl sulfonyl Mtr for example.Preferred amido protecting group has BOC and Mtr, and CBZ, Fmoc, benzyl and ethanoyl are arranged in addition.
Term " hydroxy-protective group " is known in general term equally, and relates to and be applicable to that the protection hydroxyl carries out the group that can remove easily behind the chemical reaction of needs to prevent chemical reaction but in other position of molecule.Typical this group is above-mentioned aryl, aralkyl or the acyl group that does not replace or replace, and also has alkyl in addition.The character of hydroxy-protective group and size are inessential, because they are removed again after the chemical reaction of needs or reaction sequence; Preferably have 1-20, the particularly group of 1-10 carbon atom.Wherein the example of hydroxy-protective group is benzyl, 4-methoxy-benzyl, right-nitro benzoyl, ptoluene-sulfonyl, the tertiary butyl and ethanoyl, the wherein preferred especially benzyl and the tertiary butyl.
Formula I compound separates from their functional derivatives-and this depends on and preferably uses used blocking group-for example use strong acid TFA or perchloric acid, but also can use other strong inorganic acid for example hydrochloric acid or sulfuric acid; Strong organic carboxyl acid is trichoroacetic acid(TCA) for example, or sulfonic acid for example benzene or tosic acid.Other inert solvent can exist, but always not necessary.Preferred suitable inert solvent is for example carboxylic acid such as an acetate of organic solvent; Ether is tetrahydrofuran (THF) Huo diox for example; Acid amides is DMF for example; Halohydrocarbon is methylene dichloride for example, also has alcohol for example methyl alcohol, ethanol or Virahol and water in addition.The mixture of above-mentioned solvent is suitable in addition.The preferred excessive use of TFA and do not add other solvent is preferably with acetate and the 70% perchloric acid form of mixtures use perchloric acid by 9: 1 ratios.Dissociated temperature of reaction is preferably about 0 to about 50 ℃, preferred 15 to 30 ℃ (room temperature).
Preferably for example under 15-30 ℃, dissociate with about 3 to 5N HCl with TFA or in diox in methylene dichloride, the FMOC group can dissociate under 15-30 ℃ with the DMF solution of about 5% to 50% dimethylamine, diethylamine or piperidines for BOC, OBut and Mtr group.
For example by in the presence of catalyzer (for example being preferably in for example palladium for example of the noble metal catalyst on the carbon of carrier), handling with hydrogen, but the blocking group that the hydrogenolysis of can dissociating is removed (for example isolating amidino groups of Qi oxadiazole derivative of CBZ, benzyl or Cong).Here suitable solvent is above-mentioned those solvents, specifically for example alcohol as methyl alcohol or ethanol, or acid amides DMF for example.Hydrogenolysis is carried out under the pressure of about 0 to 100 ℃ temperature and about 1 to 200 crust usually, preferred 20-30 ℃ and 1-10 crust.For example under 20-30 ℃, in 5% to 10%Pd/C methanol solution or use methyl alcohol/DMF solution of ammonium formiate (replacement hydrogen)-Pd/C, can complete successfully CBZ group hydrogenolysis.
The example of suitable inert solvents is for example hexane, sherwood oil, benzene, toluene or a dimethylbenzene of hydrocarbon; Hydrochloric ether is trieline, 1 for example, 2-ethylene dichloride, tetrachloromethane, trifluoromethylbenzene, chloroform or methylene dichloride; Alcohol is methyl alcohol, ethanol, Virahol, n-propyl alcohol, propyl carbinol or the trimethyl carbinol for example; Ether is ether, isopropyl ether, tetrahydrofuran (THF) (THF) Huo diox for example; Glycol ethers is ethylene glycol monomethyl ether or single ether or glycol dimethyl ether (diglyme) for example; Ketone is acetone or butanone for example; Acid amides is ethanamide, N,N-DIMETHYLACETAMIDE, N-methyl-pyrrolidone (NMP) or dimethyl formamide (DMF) for example; Nitrile is acetonitrile for example; Sulfoxide is methyl-sulphoxide (DMSO) for example; Dithiocarbonic anhydride; Carboxylic acid is formic acid or acetate for example; Nitro-compound is Nitromethane 99Min. or oil of mirbane for example; Ester is ethyl acetate for example, or the mixture of described solvent.
For example with acetate or with water, water/THF or the water/dioxane solution of NaOH or KOH, at 0 to 100 ℃ of following sponifiable ester.
In addition can be according to a conventional method; be preferably in inert solvent for example among methylene dichloride or the THF and/or alkali for example triethylamine or pyridine in the presence of; under-60 ℃ to+30 ℃, make the free amine group acidylate with acyl chlorides or acid anhydrides, or with the alkyl halide or and the CH that do not replace or replace 3-C (=NH)-OEt reaction makes the free amine group alkylation.
Usable acid is converted into relevant acid salt with the alkali of formula I, for example for example reacts evaporation subsequently in the ethanol at inert solvent by the alkali and the acid that make the equivalent amount.The acid that is specially adapted to this reaction is for providing those acid of acceptable salt on the physiology.Therefore, can use for example sulfuric acid of mineral acid, nitric acid, haloid acid is hydrochloric acid or Hydrogen bromide for example, phosphoric acid is ortho-phosphoric acid or thionamic acid for example, organic acid aliphatic acid particularly in addition, alicyclic acid, araliphatic acid, aromatic acid or heterocycle monobasic or polycarboxylic acid, sulfonic acid or sulfuric acid, for example formic acid, acetate, propionic acid, PIVALIC ACID CRUDE (25), diethylacetic acid, propanedioic acid, succsinic acid, pimelic acid, fumaric acid, toxilic acid, lactic acid, tartrate, oxysuccinic acid, citric acid, glyconic acid, xitix, nicotinic acid, Yi Yansuan, methylsulfonic acid or ethyl sulfonic acid, ethionic acid, the 2-ethylenehydrinsulfonic acid, Phenylsulfonic acid, right-toluenesulphonic acids, naphthalene list sulfonic acid and naphthalene disulfonic acid and dodecyl sulphate.On the physiology salt of unacceptable acid for example picrate can be used for separating and/or purifying formula I compound.
On the other hand, formula I compound can be converted into corresponding metal salt, particularly basic metal or alkaline earth salt with alkali (for example sodium hydroxide, potassium hydroxide, yellow soda ash or salt of wormwood), or be converted into corresponding ammonium salt.Also can use for example thanomin of physiologically-acceptable organic alkali.
The invention still further relates to formula I-1 midbody compound and isomer thereof and salt
Figure A20048000935400691
Wherein
D is phenyl, pyridyl, thienyl, furyl or imidazolyl, and they are replaced by the single replacement of Hal or two separately,
R 1Be H, OH, OA, alkyl or ethynyl with 1,2,3,4,5 or 6 carbon atom,
R 2For H, OH, OA or have the alkyl of 1,2,3,4,5 or 6 carbon atom,
Figure A20048000935400692
Be tetramethyleneimine-1,2-two bases, piperidines-1,2-two Ji, oxazolidines-3,4-or 3,5-two bases,
G is (CH 2) n, (CH 2) nNH-,-CH=CH-or-CH=CH-CH=CH-;
X is COOH,
A is the alkyl with 1,2,3,4,5 or 6 carbon atom,
Hal is F, Cl, Br or I,
N is 0,1 or 2.
Be preferably selected from following compound and isomer thereof and salt especially:
3-(4-chloro-phenyl-formamyl) oxazolidine-4-formic acid,
3-(5-chlorothiophene-2-carbonyl) oxazolidine-5-formic acid.
These compounds are described in embodiment 2.
The present invention relates to following compound and isomer thereof and salt in addition:
(2R, 4S)-BOC-4-ethynyl-4-hydroxyl pyrrolidine-2-formic acid,
(2R, 4R)-BOC-4-ethynyl-4-hydroxyl pyrrolidine-2-formic acid,
(2R, 4S)-BOC-4-ethynyl-4-hydroxyl pyrrolidine-2-alkyl formate,
(2R, 4R)-BOC-4-ethynyl-4-hydroxyl pyrrolidine-2-alkyl formate,
Wherein alkyl has 1,2,3,4,5 or 6 carbon atom.
The preparation method describes in embodiment 8a.
The present invention relates to formula I-2 midbody compound and isomer thereof and salt in addition:
Wherein
R 1For H ,=O, COOR 3, OH, OA, NH 2, have alkyl, a N of 1,2,3,4,5 or 6 carbon atom 3, ethynyl, vinyl, allyloxy, NHCOA, NHSO 2A, OCH 2COOA or OCH 2COOH,
R 2For H, OH, OA or have the alkyl of 1,2,3,4,5 or 6 carbon atom,
Perhaps, R 1And R 2Be the first carbocyclic ring of the 3-6 of volution connection together,
R 3Be H or A,
Figure A20048000935400711
Be tetramethyleneimine-1,2-two bases, piperidines-1,2-two Ji, oxazolidines-3,4-or 3,5-two bases,
X is CONH,
Y is for replacing or replaced by following group list or dibasic 1,3-or 1, and the 4-phenylene: methyl, trifluoromethyl, ethyl, propyl group, Cl or F,
T is piperidines-1-base, tetramethyleneimine-1-base, 1H-pyridine-1-base, morpholine-4-base, piperazine-1-base, 1,3-oxazolidine-3-base, 2H-pyridazine-2-base, pyrazine-1-base, azepine ring-1-in heptan base or 2-azabicyclic [2.2.2] octane-2-base, they are replaced or two replacements by the ketonic oxygen list separately
A is the alkyl with 1,2,3,4,5 or 6 carbon atom,
Hal is F, Cl, Br or I,
N is 0,1 or 2.
The present invention be more particularly directed to formula I-2a midbody compound and isomer thereof and salt in addition:
Figure A20048000935400712
Wherein
R 1For H ,=O, COOR 3, OH, OA, NH 2, have alkyl, a N of 1,2,3,4,5 or 6 carbon atom 3, ethynyl, vinyl, allyloxy, NHCOA, NHSO 2A, OCH 2COOA or OCH 2COOH,
R 2For H, OH, OA or have the alkyl of 1,2,3,4,5 or 6 carbon atom,
R 3Be H or A,
Be tetramethyleneimine-1,2-two bases,
X is CONH,
Y is for replacing or replaced by following group list or dibasic 1,3-or 1, and the 4-phenylene: methyl, trifluoromethyl, ethyl, propyl group, Cl or F,
T is piperidines-1-base, tetramethyleneimine-1-base, 1H-pyridine-1-base, morpholine-4-base, piperazine-1-base, 1,3-oxazolidine-3-base, 2H-pyridazine-2-base, pyrazine-1-base, azepine ring-1-in heptan base or 2-azabicyclic [2.2.2] octane-2-base, they are replaced or two replacements by the ketonic oxygen list separately
A is the alkyl with 1,2,3,4,5 or 6 carbon atom,
Hal is F, Cl, Br or I,
N is 0,1 or 2.
Be preferably selected from following compound and isomer thereof and salt especially:
1) N-[4-(3-oxo morpholine-4-yl) phenyl]-(S)-tetramethyleneimine-2-methane amide,
2) N-[4-(3-oxo morpholine-4-yl) phenyl]-(R)-tetramethyleneimine-2-methane amide,
3) N-[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-4-hydroxyl pyrrolidine-2-methane amide,
4) N-[4-(3-oxo morpholine-4-yl) phenyl]-4-hydroxyl pyrrolidine-2-methane amide,
5) N-[4-(3-oxo morpholine-4-yl) phenyl]-(R)-4,4-dimethoxy tetramethyleneimine-2-methane amide,
6) N-[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-4-methoxyl group tetramethyleneimine-2-methane amide.
The preparation method is for example describing among the embodiment 1 and 7.
Because the cause of their molecular structures, the compound of formula I compound of the present invention and claim 24 and 25 may be chipal compounds, therefore can have various enantiomeric forms.Therefore they can exist racemic form or optically-active form.
Because the racemic modification of The compounds of this invention or the pharmaceutical activity of steric isomer may be different, therefore may need to use enantiomorph.In these situations, by chemistry well known by persons skilled in the art or physical method can with end product or even intermediate be separated into enantiomeric compounds, or even in synthetic, can so use.
In the situation of racemic amines,, from mixture, form diastereomer by reacting with the opticity resolving agent.Suitable resolving agent example is for example following acid of R and S form of opticity acid: tartrate, diacetyl tartrate, dibenzoyl tartaric acid, amygdalic acid, oxysuccinic acid, lactic acid, the suitably amino acid (for example N-benzoyl proline(Pro) or N-benzenesulfonyl proline(Pro)) or the various opticity camphorsulfonic acid of N-protected.Also favourable with the chromatography fractionation enantiomorph that opticity resolving agent (for example methacrylate polymers of the derivative of solidified dinitrobenzoyl phenylglycine, cellulose triacetate or other carbohydrate or chirality derivatize on silica gel) helps.The suitable eluent that is used for this purpose be water-based or alcohol solvent mixture for example ratio be hexane/isopropyl alcohol/acetonitrile of 82: 15: 3.
The present invention relates to the compound and/or the purposes of its physiologically acceptable salt in preparation medicine (pharmaceutical preparation) of formula I compound and claim 24 and 25 in addition, specifically by method preparation non-chemically.Here, they and at least a solid, liquid and/or semiliquid vehicle or auxiliary agent mixing can be converted into dosage forms, can make up with one or more other activeconstituentss if desired.
The present invention relates to medicine in addition, described medicine comprises compound and/or its pharmaceutically spendable derivative, solvate, the salt of at least a formula I compound or claim 24 and 25 and comprises the steric isomer of its various mixed things, if desired and vehicle and/or auxiliary agent.
These preparations can be used as human or veterinary drug uses.Suitable vehicle for be applicable to intestines (for example per os), parenteral or topical and not with the organic or inorganic material of new compound reaction, for example for example lactose or starch, Magnesium Stearate, talcum powder or Vaseline of water, vegetables oil, phenylcarbinol, alkane glycol, polyoxyethylene glycol, triacetin, gelatin, carbohydrate.The formulation that is applicable to oral administration specifically is tablet, pill, coated tablet, capsule, powder, granule, syrup, juice agent or drops; The formulation that is applicable to rectal administration is a suppository; The formulation that is applicable to administered parenterally is a solution, and preferred oil-based or aqueous solution agent have suspensoid, emulsion or implant in addition; The formulation that is applicable to local application is ointment, ointment or powder or also can be used as nasal spray.But also freeze-drying and for example prepare injection formulations of new compound with the lyophilized products that obtains.Auxiliary agent can be sterilized and/or comprise to described preparation, for example salt, buffer substance, tinting material and the seasonings of lubricant, sanitas, stablizer and/or wetting agent, emulsifying agent, adjusting osmotic pressure and/or multiple other activeconstituents one or more VITAMIN for example.
The compound of formula I compound and claim 24 and 25 and its physiologically acceptable salt can be used for anti-and for example thrombosis, myocardial infarction, arteriosclerosis, inflammation, apoplexy, stenocardia, postangioplasty restenosis, intermittent claudication, migraine, tumour, tumor disease and/or tumor metastasis of prevention of thromboembolic disorders.
Generally speaking, preferred material of the present invention is by the dosed administration of every dose unit about 1-500mg, particularly 5-100mg.Preferred per daily dose is about 0.02 to 10mg/kg body weight.But, the concrete dosage that gives every patient depends on a variety of factors, for example the severity of the disease specific of the usefulness of the particular compound of Shi Yonging, age, body weight, general health situation, sex, diet, administration time and method, excretion rate, medication combined and administering therapeutic.The preferred oral administration.
The present invention relates to medicine in addition, described medicine comprises compound and/or its pharmaceutically spendable derivative, solvate, the salt of at least a formula I compound or claim 24 and 25 and comprises the steric isomer and at least a other medicines activeconstituents of its various mixed things.
The present invention also relates to the packed medicament (kit) formed by following each independent packaging:
(a) compound of the formula I compound of significant quantity or claim 24 and 25 and/or its pharmaceutically spendable derivative, solvate, salt and comprise the steric isomer of its various mixed things,
With
(b) the other medicines activeconstituents of significant quantity.
This packed medicament comprise suitable containers for example box, independently the bottle, the bag or ampoule.This packed medicament can for example comprise independently ampoule, each ampoule contains a kind of and/or its pharmaceutically spendable derivative, the solvate in the compound of the formula I compound of significant quantity or claim 24 and 25 and comprises the steric isomer of its various mixed things and the other medicines activeconstituents of significant quantity with dissolving or lyophilized form.
The present invention relates to compound and/or its pharmaceutically spendable derivative of formula I compound and claim 24 and 25 in addition, solvate, the purposes for preparing in the medicine that is used for the treatment of following disease that is combined in of salt and the steric isomer that comprises its various mixed things and at least a other medicines activeconstituents: thrombosis, myocardial infarction, arteriosclerosis, inflammation, apoplexy, stenocardia, postangioplasty restenosis, intermittent claudication, migraine, tumour, tumor disease and/or tumor metastasis.
The present invention relates to medicine in addition, this medicine contains the 1-N-[(4-chloro-phenyl-)]-2-N-{[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-and 4-hydroxyl pyrrolidine-1, the pharmaceutically spendable derivative of 2-diformamide and/or its, solvate, salt and comprise the steric isomer and the acetylsalicylic acid of its various mixed things.
The present invention relates to the 1-N-[(4-chloro-phenyl-in addition)]-2-N-{[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-and 4-hydroxyl pyrrolidine-1, the pharmaceutically spendable derivative of 2-diformamide and/or its, solvate, the purposes for preparing in the medicine that is used for the treatment of following disease that is combined in of salt and the steric isomer that comprises its various mixed things and acetylsalicylic acid: thrombosis, myocardial infarction, arteriosclerosis, inflammation, apoplexy, stenocardia, postangioplasty restenosis, intermittent claudication, migraine, tumour, tumor disease and/or tumor metastasis.
In upper and lower literary composition, used temperature is all ℃ to provide.In following examples, ' conventional aftertreatment ' refers to: add entry if desired, if desired with pH regulator to 2-10, this depends on the formation of end product, mixture separates each phase with ethyl acetate or dichloromethane extraction, and organic phase is through dried over sodium sulfate, evaporation and product are through the silica gel column chromatography purifying and/or through crystallization purifying.Rf value on the silica gel; Eluent: ethyl acetate/methanol 9: 1.
Mass spectrum (MS): EI (Electron Impactionization) M +
FAB (fast atom bombardment) (M+H) +
ESI (electron spray ionisation) (M+H) +(unless otherwise indicated)
Embodiment 1
The 1-N-[(4-chloro-phenyl-)]-2-N-{[4-(3-oxo morpholine-4-yl) phenyl]-(R)-and tetramethyleneimine-1,2-diformamide (" A1 ") prepares by the similar approach of following flow process:
1.1 0.8g (5.2mmol) I-hydroxybenzotriazole hydrate, 1.12g (5.2mmol) D-Boc-proline(Pro), 2g (10.4mmol) N-(3-dimethylamino-propyl)-N '-ethyl-carbodiimide hydrochloride (DAPECl) and 1.26ml N-methylmorpholine are added in dimethyl formamide (25ml) solution of 1.0g (5.2mmol) 4-(4-aminophenyl) morpholine-3-ketone successively, at room temperature stirred the solution obtain then 12 hours.The reduction vaporization reaction soln makes resistates be dissolved in 5% sodium hydrogen carbonate solution (10ml) to doing subsequently, then with this sodium hydrogen carbonate solution twice of ethyl acetate extraction, and each 10ml.The organic phase that merges is removed and is desolvated after dried over sodium sulfate, and solid residue grinds with the 20ml ether, obtains 1.4g 2-[4-(3-oxo morpholine-4-yl) phenyl-formamyl] tetramethyleneimine-1-formic acid tertiary butyl ester white powder; ESI 390.
1.2 4N hydrochloric acid/diox (40ml) is added 1.4g (3.60mmol) 2-[4-(3-oxo morpholine-4-yl) phenyl-formamyl] in tetramethyleneimine-1-formic acid tertiary butyl ester De diox (20ml) solution, at room temperature stirred this mixture then 12 hours.Leach precipitation with filtering subsequently, with 10ml diox and the washing of 10ml ether, drying under reduced pressure obtains 1.1g N-[4-(3-oxo morpholine-4-yl) phenyl then successively] tetramethyleneimine-2-carboxamide hydrochloride white powder; ESI 290.
1.3 95mg (0.61mmol) isocyanic acid 4-chloro-phenyl-ester is added 200mg (0.61mmol) N-[4-(3-oxo morpholine-4-yl) phenyl] in methylene dichloride (5ml) solution of tetramethyleneimine-2-carboxamide hydrochloride and 1ml triethylamine, stirring reaction solution 2 hours at room temperature then.Reaction soln is used 5ml 1N hydrochloric acid and 5ml water washing successively, and this dichloromethane solution is through dried over sodium sulfate then.After the removal of solvent under reduced pressure,, obtain the white powder of 120mg title compound (" A1 ") with ethanol/ether recrystallization crude product; ESI 443; M.p.227.6 ℃.
Obtain following compound similarly:
1) 1-N-[(4-chloro-phenyl-)]-2-N-{[3-methyl-4-(3-oxo morpholine-4-yl) phenyl]-(R)-and tetramethyleneimine-1, the 2-diformamide, ESI 457, m.p.147 ℃ (decomposition);
2) 1-N-[(4-chloro-phenyl-)]-2-N-{[3-fluoro-4-(3-oxo morpholine-4-yl) phenyl]-(R)-and tetramethyleneimine-1, the 2-diformamide, ESI 461, m.p.155 ℃;
3) 1-N-[(4-chloro-phenyl-)]-2-N-{[2-fluoro-4-(3-oxo morpholine-4-yl) phenyl]-(R)-and tetramethyleneimine-1, the 2-diformamide, ESI 461;
4) 1-N-[(4-chloro-phenyl-)]-2-N-{[3-trifluoromethyl-4-(3-oxo morpholine-4-yl) phenyl]-(R)-and tetramethyleneimine-1, the 2-diformamide, ESI 511, m.p.147 ℃;
5) 1-N-[(4-chloro-phenyl-)]-2-N-{[3-methyl-4-(3-oxo morpholine-4-yl) phenyl]-(R)-and piperidines-1, the 2-diformamide, ESI 471, m.p.140 ℃;
6) 1-N-[(4-chloro-phenyl-)]-2-N-{[4-(2-oxo-2H-pyridine-1-yl) phenyl]-(R)-and tetramethyleneimine-1,2-diformamide, m.p.221 ℃;
7) 1-N-[(4-chloro-phenyl-)]-2-N-{[4-(2-oxo-2H-pyrazine-1-yl) phenyl]-(R)-and tetramethyleneimine-1, the 2-diformamide, ESI 438, m.p.227 ℃;
8) 1-N-[(4-chloro-phenyl-)]-2-N-{[3-methyl-4-(3-oxo morpholine-4-yl) phenyl]-(S)-and tetramethyleneimine-1, the 2-diformamide, ESI 457; M.p.174 ℃;
9) 1-N-[(4-chloro-phenyl-)]-2-N-{[4-(2-oxo-2H-pyridine-1-yl) phenyl]-4,4-two fluoro-(R)-tetramethyleneimine-1, the 2-diformamide, ESI 473;
10) 1-N-[(4-chloro-phenyl-)]-2-N-{[2-fluoro-4-(2-oxo-2H-pyridine-1-yl) phenyl]-(R)-and tetramethyleneimine-1, the 2-diformamide, ESI 455;
11) 1-N-[(4-chloro-phenyl-)]-2-N-{[4-(2-oxo-3-methoxyl group-2H-pyridine-1-yl) phenyl]-(R)-and tetramethyleneimine-1, the 2-diformamide, ESI 467.
Embodiment 1a
N-[4-(3-oxo morpholine-4-yl) phenyl]-(R)-1-(5-chlorothiophene-2-carbonyl) tetramethyleneimine-2-first Acid amides(" AB1 ")
0.71g (4.66mmol) I-hydroxybenzotriazole hydrate, 0.76g (4.66mmol) 5-chlorothiophene formic acid, 1.79g (9.33mmol) N-(3-dimethylamino-propyl)-N '-ethyl-carbodiimide hydrochloride (DAPECl) and 1.13ml N-methylmorpholine are added 1.35g (4.66mmol) N-[4-(3-oxo morpholine-4-yl) phenyl successively] in dimethyl formamide (30ml) solution of tetramethyleneimine-2-methane amide, at room temperature stirred the solution that obtains then 12 hours.The reduction vaporization reaction soln makes resistates be dissolved in 5% sodium hydrogen carbonate solution (10ml) to doing subsequently, then with this sodium hydrogen carbonate solution twice of ethyl acetate extraction, and each 10ml.The organic phase that merges is removed and is desolvated after dried over sodium sulfate, and solid residue grinds with the 20ml ether, obtains 1.2g (59.4%) (" AB1 "), ESI434; M.p.195 ℃.
Obtain compound N-[3-methyl-4-(3-oxo morpholine-4-yl) phenyl]-(R)-1-(5-chlorothiophene-2-carbonyl) tetramethyleneimine-2-methane amide similarly, ESI 448; M.p.113 ℃ (decomposition).
Embodiment 1b
The 1-N-[(4-chloro-phenyl-)]-2-N-([4-(3-oxo morpholine-4-yl) phenyl] }-(R)-2, and 5-pyrrolin-1, the 2-diformamide is prepared as follows:
A) with 0.19g (5.1mmol) sodium borohydride (NaBH 4) under nitrogen, add in the trimethyl carbinol (12ml) suspension of 0.82g (2.63mmol) diphenyl disenenide ether (diphenyl diselenide), reaction mixture refluxed was become colorless until yellow reaction solution in about 1 hour.Under this temperature, be added dropwise to 1.99g (4.11mmol) (2R subsequently; 4R)-and 4-methylsulfonyl oxygen base-2-[4-(3-oxo morpholine-4-yl) phenyl amino formyl radical] trimethyl carbinol (12ml) solution of tetramethyleneimine-1-formic acid tertiary butyl ester (seeing embodiment 9.1), make this reaction mixture refluxed 12 hours under stirring then.After the reaction mixture cooling, removal of solvent under reduced pressure makes resistates be dissolved in the 20ml ethyl acetate, the solution that obtains 20ml water washing.Ethyl acetate is removed and to be desolvated after dried over sodium sulfate, obtain 1.82g (81.3%) (1R, 4R)-2-[4-(3-oxo morpholine-4-yl) phenyl amino formyl radical]-4-phenyl selenium alkyl (selanyl) tetramethyleneimine-1-formic acid tertiary butyl ester, ESI 545.
B) under 0 ℃, to a) dripping 1ml 30% hydrogen peroxide (H in methylene dichloride (25ml) solution of 1.72g (3.16mmol) selenium compound of preparation and 0.4ml pyridine down 2O 2).Made reaction mixture to room temperature in 2 hours subsequently, add 10ml 5% potassium hydrogen sulfate solution then, separate each phase, organic phase is washed with the 10ml saturated sodium bicarbonate solution.Organic phase is removed and to be desolvated after dried over sodium sulfate, the resistates silica gel column chromatography, obtain 0.73g (59.7%) (R)-2-[4-(3-oxo morpholine-4-yl) phenyl amino formyl radical]-2,5-pyrrolin-1-formic acid tertiary butyl ester, ESI388.
Further carry out reaction similar to Example 7, obtain the 1-N-[(4-chloro-phenyl-)]-2-N-{[4-(3-oxo morpholine-4-yl) phenyl]-(R)-2,5-pyrrolin-1,2-diformamide, ESI441, m.p.245 ℃.
Obtain following compound similarly:
1) 1-N-[(4-chloro-phenyl-)]-2-N-{[4-(2-oxo-1H-pyrazine-1-yl) phenyl]-(R)-2, and 5-pyrrolin-1, the 2-diformamide,
2) 1-N-[(4-chloro-phenyl-)]-2-N-{[4-(2-oxo-1H-pyridine-1-yl) phenyl]-(R)-2, and 5-pyrrolin-1, the 2-diformamide,
3) 1-N-[(4-chloro-phenyl-)]-2-N-{[3-fluoro-4-(3-oxo morpholine-4-yl) phenyl]-(R)-2, and 5-pyrrolin-1, the 2-diformamide,
4) 1-N-[(4-chloro-phenyl-)]-2-N-{[2-fluoro-4-(3-oxo morpholine-4-yl) phenyl]-(R)-2,5-pyrrolin-1,2-diformamide.
Embodiment 2
Similar approach by following flow process prepares the 3-N-[(4-chloro-phenyl-)]-4-N-{[4-(3-oxo morpholine-4-yl) phenyl]-(R)-oxazolidines-3,4-diformamide (" A2 "):
2.1 1.49ml (20.0mmol) 37% formalin is added in the solution of 1N aqueous sodium hydroxide solution (10ml) of 2.10g (20.0mmol) D-Serine.The solution that obtains was placed 18 hours down at 5 ℃.Heated solution to 80 ℃ adds 6.14g (40mmol) isocyanic acid 4-chloro-phenyl-ester, stirs this mixture 1 hour then under this temperature.Make the mixture cooling, leach the precipitation of formation then.Filtrate is used 1N HCl acidifying, leaches the precipitation and the drying of formation then, obtains (R)-3-(4-chloro-phenyl-formamyl) oxazolidine-4-formic acid colorless solid; ESI271.
2.2 to 541mg (2.00mmol) (R)-(dimethyl formamide (DMF) of 4-chloro-phenyl-formamyl) oxazolidine-4-formic acid and 384mg (2.00mmol) 4-(4-aminophenyl) morpholine-3-ketone (4ml) adds 498mg (2.60mmol) N-(3-dimethylamino-propyl)-N '-ethyl-carbodiimide hydrochloride (DAPECl) in the solution to 3-, at room temperature stirs this mixture then 18 hours.Reaction mixture is added in the saturated sodium bicarbonate solution, leaches the precipitation of formation then, obtain the 3-N-[(4-chloro-phenyl-)]-4-N-{[4-(3-oxo morpholine-4-yl) phenyl]-(R)-oxazolidines-3,4-diformamide (" A2 ") colorless solid; ESI 461.
Obtain following compound similarly:
1) 3-N-[(4-chloro-phenyl-)]-4-N-{[3-methyl-4-(3-oxo morpholine-4-yl) phenyl]-(R)-oxazolidines-3, the 4-diformamide, ESI 459;
2) 3-N-[(4-chloro-phenyl-)]-4-N-([4-(3-oxo morpholine-4-yl) phenyl] }-(4R, 5S)-5-Jia Ji oxazolidine-3, the 4-diformamide, ESI 459;
3) 3-N-[(4-chloro-phenyl-)-4-N-{[3-methyl-4-(3-oxo morpholine-4-yl) phenyl]-(4R, 5S)-5-Jia Ji oxazolidine-3, the 4-diformamide, ESI 473;
4) 3-N-[(4-chloro-phenyl-)]-4-N-{[4-(2-oxo-2H-pyridine-1-yl) phenyl]-(R)-oxazolidines-3, the 4-diformamide, ESI 439;
5) 3-N-[(4-chloro-phenyl-)]-4-N-{[4-(2-oxo-2H-pyridine-1-yl) phenyl]-(4R, 5S)-5-Jia Ji oxazolidine-3, the 4-diformamide, ESI 453;
6) 3-N-[(4-chloro-phenyl-)]-4-N-{[3-fluoro-4-(3-oxo morpholine-4-yl) phenyl]-(4R, 5S)-5-Jia Ji oxazolidine-3, the 4-diformamide, ESI 477;
7) 3-N-[(4-chloro-phenyl-)]-4-N-{[3-chloro-4-(3-oxo morpholine-4-yl) phenyl]-(4R, 5S)-5-Jia Ji oxazolidine-3, the 4-diformamide, ESI 477;
8) 3-N-[(4-chloro-phenyl-)]-4-N-{[3-methyl-4-(3-oxo morpholine-4-yl) phenyl]-(4R, 5R)-5-Jia Ji oxazolidine-3, the 4-diformamide, ESI 473;
9) 3-N-[(4-chloro-phenyl-)]-4-N-{[4-(2-oxo-2H-pyrazine-1-yl) phenyl]-(4R, 5S)-5-Jia Ji oxazolidine-3, the 4-diformamide, ESI 454;
10) 3-N-[(4-chloro-phenyl-)]-4-N-{[4-(2-oxo-2H-pyrazine-1-yl) phenyl]-(R)-oxazolidines-3, the 4-diformamide, ESI 440;
11) 3-N-[(4-chloro-phenyl-)]-4-N-{[3-chloro-4-(2-oxo-2H-pyridine-1-yl) phenyl]-(R)-oxazolidines-3, the 4-diformamide, ESI 473;
Embodiment 2a
Similar with the method for embodiment 2, be raw material with (R)-cleonine
Obtain following compound:
The 6-N-[(4-chloro-phenyl-)]-7-N-{[4-(3-oxo morpholine-4-yl) phenyl]-4-oxa--6-azaspiro [2.4] heptane-6, the 7-diformamide
Embodiment 3
Similar approach by following flow process prepares the 3-N-[(4-chloro-phenyl-)]-4-N-{[4-(3-oxo morpholine-4-yl) phenyl]-(S)-thiazolidine-3,4-diformamide (" A3 ") and 3-N-[(4-chloro-phenyl-)]-4-N-{[4-(3-oxo morpholine-4-yl) phenyl]-(S)-1,1-dioxo-1 λ 6-thiazolidine-3,4-diformamide (" A4 "):
Figure A20048000935400831
3.1 water (50ml) solution to 80 of heating 4.54g (54.0mmol) sodium bicarbonate and 3.60g (27.0mmol) 2-(S)-thiazolidine-4-formic acid ℃ adds 8.46g (54.0mmol) isocyanic acid 4-chloro-phenyl-ester then.Stirred reaction mixture is 1 hour under this temperature.Make the mixture cooling, leach the precipitation of formation then.Filtrate is used 1N HCl acidifying, leaches the precipitation and the drying of formation then, obtains (S)-3-(4-chloro-phenyl-formamyl) thiazolidine-4-formic acid colorless solid; ESI287.
3.2 to 573mg (2.00mmol) (S)-dimethyl formamide (DMF) of 3-(4-chloro-phenyl-formamyl) thiazolidine-4-formic acid and 384mg (2.00mmol) 4-(4-aminophenyl) morpholine-3-ketone (4ml) adds 498mg (2.60mmol) N-(3-dimethylamino-propyl)-N '-ethyl-carbodiimide hydrochloride (DAPECl) in the solution, at room temperature stirred this mixture then 18 hours.Reaction mixture is added in the saturated sodium bicarbonate solution, leaches the precipitation of formation then, obtain the 3-N-[(4-chloro-phenyl-)]-4-N-{[4-(3-oxo morpholine-4-yl) phenyl]-(S)-and thiazolidine-3,4-diformamide (" A3 ") colorless solid; ESI 461.
3.3 in methyl alcohol (50ml) suspension of 450mg (0.976mmol) " A3 ", add the water 30ml solution of 1.9g oxone, at room temperature stirred this reaction mixture then 24 hours.Reaction mixture is added in the entry, leaches the precipitation and the drying of formation then, obtain the 3-N-[(4-chloro-phenyl-)]-4-N-{[4-(3-oxo morpholine-4-yl) phenyl]-(S)-1,1-dioxo-1 λ 6-thiazolidine-3,4-diformamide (" A4 ") colorless solid; ESI 493.
Obtain following compound similarly:
1) 3-N-[(4-chloro-phenyl-)]-4-N-{[3-methyl-4-(3-oxo morpholine-4-yl) phenyl]-(S)-and thiazolidine-3, the 4-diformamide, ESI 475;
2) 3-N-[(4-chloro-phenyl-)]-4-N-{[3-methyl-4-(3-oxo morpholine-4-yl) phenyl]-(S)-1,1-dioxo-1 λ 6-thiazolidine-3, the 4-diformamide, ESI 507;
3) 3-N-[(4-chloro-phenyl-)]-4-N-{[4-(2-oxo-2H-pyridine-1-yl) phenyl]-(R)-and thiazolidine-3, the 4-diformamide, ESI 455.
Embodiment 4
Similar approach by following flow process prepares N-[4-(3-oxo morpholine-4-yl) phenyl]-3-(5-chlorothiophene-2-carbonyl) oxazolidine-5-methane amide (" A5 "):
Figure A20048000935400841
4.1 1.48ml (19.9mmol) 37% formalin is added in the solution of 1N aqueous sodium hydroxide solution (10ml) of 2.00g (19.0mmol) DL-isoserine.The solution that obtains was placed 18 hours down at 5 ℃.Under internal temperature 0-5 ℃, in this solution, drip acetone (10ml) solution of 3.46g (19.1mmol) 5-chlorothiophene carbonyl chloride.In the dropping process, the pH value is remained on more than 7 by adding solid sodium bicarbonate.Add when finishing, make this mixture be warming up to room temperature, add entry, mixture extracts with t-butyl methyl ether.Water extracts with t-butyl methyl ether then with 1N HCl acidifying.Organic phase is through dried over sodium sulfate, and evaporation obtains 3-(5-chlorothiophene-2-carbonyl) oxazolidine-5-formic acid colorless solid then; ESI 262.
(dimethyl formamide (DMF) of 5-chlorothiophene-2-carbonyl) oxazolidine-5-formic acid and 367mg (1.91mmol) 4-(4-aminophenyl) morpholine-3-ketone (5ml) adds 479mg (2.50mmol) N-(3-dimethylamino-propyl)-N '-ethyl-carbodiimide hydrochloride (DAPECl) in the solution, at room temperature stirs this mixture then 18 hours 4.2 to 500mg (1.91mmol) 3-.Reaction mixture is added in the saturated sodium bicarbonate solution, leaches the precipitation of formation then, obtain N-[4-(3-oxo morpholine-4-yl) phenyl]-3-(5-chlorothiophene-2-carbonyl) oxazolidine-5-methane amide (" A5 ") colorless solid; ESI 436.
Obtain following compound similarly:
N-[3-methyl-4-(3-oxo morpholine-4-yl) phenyl]-3-(5-chlorothiophene-2-carbonyl) oxazolidine-5-methane amide, ESI 450;
N-[4-(2-oxo-2H-pyridine-1-yl) phenyl]-(5-chlorothiophene-2-carbonyl) oxazolidine-5-methane amide, ESI 430 for 3-.
Embodiment 5
Similar approach by following flow process prepares 1-N-[(5-chloropyridine-2-yl)]-2-N-{[4-(2-oxo-2H-pyridine-1-yl) phenyl]-(2R, 4R)-4-hydroxyl pyrrolidine-1,2-diformamide (" A6 "):
In methylene dichloride (50ml) solution of 570mg (4.43mmol) 2-amino-5-chloropyridine and 0.73ml (9.0mmol) pyridine, add 894mg (4.43mmol) chloroformic acid 4-nitrophenyl ester, at room temperature stirred this mixture then 1 hour.With 1.49g (4.43mmol) chlorination (2R; 4R)-and 4-hydroxyl-2-[4-(2-oxo-2H-pyridine-1-yl) phenyl amino formyl radical] tetramethyleneimine and 1.5ml (9.0mmol) N-ethyl diisopropyl amine add in the suspension that obtains, stirred reaction mixture 18 hours at room temperature then.Evaporation reaction mixture, make resistates chromatography on silicagel column then, with methylene chloride 95: 5 as elutriant, obtain 1-N-[(5-chloropyridine-2-yl)]-2-N-{[4-(2-oxo-2H-pyridine-1-yl) phenyl]-(2R, 4R)-4-hydroxyl pyrrolidine-1,2-diformamide (" A6 ") colorless solid, ESI 454.
Obtain following compound similarly:
1) 1-N-[(5-chloropyridine-2-yl)]-2-N-{[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-4-hydroxyl pyrrolidine-1, the 2-diformamide, ESI 460;
2) 1-N-[(5-chloropyridine-2-yl)]-2-N-{[4-(2-oxo-2H-pyrazine-1-yl) phenyl]-(2R, 4R)-4-hydroxyl pyrrolidine-1, the 2-diformamide, ESI 455;
3) 1-N-[(5-chloropyridine-2-yl)]-2-N-{[3-fluoro-4-(2-oxo-2H-pyridine-1-yl) phenyl]-(2R, 4R)-4-hydroxyl pyrrolidine-1, the 2-diformamide, ESI 472;
4) 1-N-[(5-chloropyridine-2-yl)]-2-N-{[4-(2-oxo-2H-pyridine-1-yl) phenyl]-(R)-4, and 4-dimethoxy tetramethyleneimine-1, the 2-diformamide, ESI 498;
5) 1-N-[(5-chloropyridine-2-yl)]-2-N-{[4-(3-oxo morpholine-4-yl) phenyl]-(R)-4, and 4-dimethoxy tetramethyleneimine-1, the 2-diformamide, ESI 504;
6) 1-N-[(6-chloropyridine-3-yl)]-2-N-{[4-(2-oxo-2H-pyridine-1-yl) phenyl]-(2R, 4R)-4-hydroxyl pyrrolidine-1, the 2-diformamide, ESI 454;
7) 1-N-[(6-chloropyridine-3-yl)]-2-N-{[4-(2-oxo-2H-pyrazine-1-yl) phenyl]-(2R, 4R)-4-hydroxyl pyrrolidine-1, the 2-diformamide, ESI 455.
Embodiment 6
Similar approach by following flow process prepares the 1-N-[(4-chloro-phenyl-)]-2-N-{[4-(2-oxo-2H-pyridine-1-yl) phenyl]-(R)-4, and 4-dimethoxy tetramethyleneimine-1,2-diformamide (" A7 "):
Figure A20048000935400871
6.1 under 0 ℃, 12.2g (122mmol) chromic oxide (VI) is added in the mixture of 22ml pyridine and 50ml methylene dichloride, then this mixture was similarly being stirred 30 minutes under the temperature.Make solution be warming up to room temperature, methylene dichloride (80ml) solution of Dropwise 5 .00g cis in 5 minutes-Boc-4-hydroxyl-D-proline(Pro).After at room temperature stirring 1 hour, filter this solution, evaporated filtrate.Resistates is distributed between 1N HCl and t-butyl methyl ether.Organic phase is evaporated through dried over sodium sulfate, and recrystallization in ether/sherwood oil obtains Boc-4-ketone-D-proline(Pro) colorless solid then; ESI 130.
6.2 in toluene (25ml) suspension of 459mg (2.00mmol) Boc-4-ketone-D-proline(Pro) and 372mg (2.00mmol) 1-(4-aminophenyl)-1H-pyridin-2-ones, add 742mg (3.00mmol) 2-oxyethyl group-1,2-dihydroquinoline-1-ethyl formate (EEDQ) at room temperature stirred this mixture 18 hours then.Add the 200ml t-butyl methyl ether, leach the precipitation of formation then.In filtrate, add the 200ml sherwood oil, filter the precipitation that obtains then, obtain (R)-4-oxo-2-[4-(2-oxo-2H-pyridine-1-yl) phenyl amino formyl radical] tetramethyleneimine-1-formic acid tertiary butyl ester brown solid; ESI 398.
6.3 to 400mg (1.01mmol) (R)-4-oxo-2-[4-(2-oxo-2H-pyridine-1-yl) phenyl amino formyl radical] add 10ml methyl alcohol in the suspension of 4N HCl De dioxane solution (5ml) of tetramethyleneimine-1-formic acid tertiary butyl ester, at room temperature stirred this mixture then 1 hour.Evaporation reaction mixture obtains chlorination (R)-4,4-dimethoxy-2-[4-(2-oxo-2H-pyridine-1-yl) phenyl amino formyl radical] the tetramethyleneimine brown solid; ESI 344.
6.4,4-dimethoxy-2-[4-(2-oxo-2H-pyridine-1-yl) phenyl amino formyl radical to 250mg (0.658mmol) chlorination (R)-4] add 0.12ml triethylamine and 127mg (0.830mmol) isocyanic acid 4-chloro-phenyl-ester in methylene dichloride (10ml) solution of tetramethyleneimine.After at room temperature stirring 1 hour, evaporation reaction mixture, make resistates chromatography on silicagel column then, with methylene chloride 95: 5 as elutriant, obtain the 1-N-[(4-chloro-phenyl-)]-2-N-{[4-(2-oxo-2H-pyridine-1-yl) phenyl]-(R)-4,4-dimethoxy tetramethyleneimine-1,2-diformamide (" A7 ") colorless solid; ESI 497.
Embodiment 7
Similar approach by following flow process prepares the 1-N-[(4-chloro-phenyl-)]-2-N-{[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-4-hydroxyl pyrrolidine-1,2-diformamide (" A8 "):
Figure A20048000935400891
7.1 (add 16g (12.86mmol) 2-oxyethyl group-1 in toluene (250ml) suspension of 64.86mmol 1-(4-aminophenyl)-1H-pyridin-2-ones to 15g (64.86mmol) cis-N '-BOC-4-hydroxyl-D-proline(Pro) and 12.47g, 2-dihydroquinoline-1-ethyl formate (EEDQ) at room temperature stirred this mixture 18 hours then.The subsequent filtration precipitated product; successively with 50ml toluene and the washing of 50ml ether; dry in moisture eliminator then, obtain (2R, 4R)-4-hydroxyl-2-[4-(3-oxo morpholine-4-yl) phenyl amino formyl radical] tetramethyleneimine-1-formic acid tertiary butyl ester pale powder 24.5g (93.2%).ESI 406。
7.2 4N hydrochloric acid De dioxane solution (300ml) is added 15g (37mmol) (2R; 4R)-and 4-hydroxyl-2-[4-(3-oxo morpholine-4-yl) phenyl amino formyl radical] in tetramethyleneimine-1-formic acid tertiary butyl ester De diox (200ml) solution, at room temperature stirred this mixture then 12 hours.The subsequent filtration precipitation, dry in moisture eliminator then with 50ml diox and the washing of 50ml ether, obtain 12.64g (100%) hydrochloric acid N-[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-4-hydroxyl pyrrolidine-2-methane amide white powder.ESI 306。
7.3 with 12.64g (36.98mmol) hydrochloric acid N-[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-4-hydroxyl pyrrolidine-2-methane amide is suspended in the 1200ml methylene dichloride, adds the 5.4ml triethylamine then under the ice bath cooling.Subsequently under 2 ℃, in 1.5 hours to methylene dichloride (100ml) solution of this mixture Dropwise 5 .96g (38.83mmol) isocyanic acid 4-chloro-phenyl-ester, then ice-cooled down with reaction soln restir 30 minutes.This dichloromethane solution is used 100ml 1N hydrochloric acid and 100ml water washing successively, then through dried over sodium sulfate.After leaching siccative, with Rotary Evaporators dichloromethane solution is evaporated to 1/3 of original volume, the filtering-depositing product, use the 50ml petroleum ether, dry in moisture eliminator then, obtain 14.6g (86%) 1-N-[(4-chloro-phenyl-)]-2-N-{[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-4-hydroxyl pyrrolidine-1,2-diformamide (" A8 ") white powder, ESI 459; M.p.216 ℃.
Obtain following compound similarly:
1) 1-N-[(4-chloro-phenyl-)]-2-N-{[3-methyl-4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-4-hydroxyl pyrrolidine-1, the 2-diformamide, ESI 473; M.p.250 ℃;
2) 1-N-[(4-chloro-phenyl-)]-2-N-{[4-(2-oxo-2H-pyridine-1-yl) phenyl]-(2R, 4R)-4-hydroxyl pyrrolidine-1, the 2-diformamide, ESI 453; M.p.160 ℃;
3) 1-N-[(4-chloro-phenyl-)]-2-N-{[2-fluoro-4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-4-hydroxyl pyrrolidine-1, the 2-diformamide, ESI 477; M.p.235 ℃;
4) 1-N-[(4-chloro-phenyl-)]-2-N-{[4-(2-Oxopyrazine-1-yl) phenyl]-(2R, 4R)-4-hydroxyl pyrrolidine-1, the 2-diformamide, ESI 454;
5) 1-N-[(4-chloro-phenyl-)]-2-N-{[2-fluoro-4-(2-oxo-2H-pyridine-1-yl) phenyl]-(2R, 4R)-4-hydroxyl pyrrolidine-1, the 2-diformamide, ESI 471;
6) 1-N-[(4-chloro-phenyl-)]-2-N-{[3-fluoro-4-(3-oxo morpholine-4-yl) phenyl]-(2R, 3R)-3-hydroxyl pyrrolidine-1, the 2-diformamide,
7) 1-N-[(4-chloro-phenyl-)]-2-N-{[3-fluoro-4-(3-oxo morpholine-4-yl) phenyl]-(2R, 3S)-3-hydroxyl pyrrolidine-1, the 2-diformamide,
8) 1-N-[(4-chloro-phenyl-)]-2-N-{[3-fluoro-4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-4-hydroxyl pyrrolidine-1, the 2-diformamide,
9) 1-N-[(4-chloro-phenyl-)]-2-N-{[4-(2-oxo-3-methoxyl group-2H-pyridine-1-yl) phenyl]-(2R, 4R)-4-hydroxyl pyrrolidine-1, the 2-diformamide, ESI 483,
10) 1-N-[(4-chloro-phenyl-)]-2-N-{[4-(3-oxo morpholine-4-yl) phenyl]-(2S, 3S)-3-hydroxyl pyrrolidine-1, the 2-diformamide, ESI 459;
11) 1-N-[(4-chloro-phenyl-)]-2-N-{[4-(3-oxo morpholine-4-yl) phenyl]-(2S, 4S)-4-hydroxyl pyrrolidine-1, the 2-diformamide, ESI 459
Figure A20048000935400911
12) 1-N-[(4-chloro-phenyl-)]-2-N-{[2-methoxycarbonyl-4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-3-hydroxyl pyrrolidine-1, the 2-diformamide, ESI 517, m.p.119; And thus by hydrolysis
13) 1-N-[(4-chloro-phenyl-)]-2-N-{[2-carboxyl-4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-3-hydroxyl pyrrolidine-1, the 2-diformamide, ESI 503, and m.p.145 ℃,
14) 1-N-[(4-chloro-phenyl-)]-2-N-{[2-methoxycarbonyl-4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-4-hydroxyl pyrrolidine-1, the 2-diformamide, and thus by hydrolysis
15) 1-N-[(4-chloro-phenyl-)]-2-N-{[2-carboxyl-4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-4-hydroxyl pyrrolidine-1, the 2-diformamide.
Embodiment 8
Similar approach by following flow process prepares the 1-N-[(4-chloro-phenyl-)]-2-N-{[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4S)-4-hydroxyl pyrrolidine-1, the 2-diformamide:
Figure A20048000935400921
8.1 under 0 ℃, nitrogen; to 7.0g (7.26mmol) (2R, 4R)-4-hydroxyl-2-[4-(3-oxo morpholine-4-yl) phenyl amino formyl radical] tetramethyleneimine-1-formic acid tertiary butyl ester, 5.77g (34.5mmol) be right-be added dropwise to 5.51ml (35mmol) diethyl azodiformate (DEAD) in tetrahydrofuran (THF) (350ml) solution of nitrobenzoic acid and 9.18g (35mmol) triphenylphosphine.At room temperature stirred this reaction mixture subsequently 12 hours, reduction vaporization adds the 20ml methylene dichloride to doing to resistates then, and this dichloromethane solution is used 10ml saturated nacl aqueous solution and 10ml water washing then successively, then through dried over sodium sulfate.After leaching siccative; remove with Rotary Evaporators and to desolvate; resistates grinds with the 30ml ether; obtain 8.5g (88.8%) (2R; 4S)-and 4-(4-nitro benzoyl oxygen base)-2-[4-(3-oxo morpholine-4-yl) phenyl amino formyl radical] tetramethyleneimine-little yellow crystal of 1-formic acid tertiary butyl ester, ESI 555.
8.2 it is similar to Example 7; (2R; 4S)-and 4-(4-nitro benzoyl oxygen base)-2-[4-(3-oxo morpholine-4-yl) phenyl amino formyl radical] the reacting generating compound 4-nitrobenzoic acid (3S of tetramethyleneimine-1-formic acid tertiary butyl ester; 5R)-and 1-(4-chloro-phenyl-formamyl)-5-[4-(3-oxo morpholine-4-yl) phenyl amino formyl radical] tetramethyleneimine-little yellow crystal of 3-base ester, ESI 608.
8.3 under ice-cooled; 0.075ml 1N sodium hydroxide solution is added 50mg (0.082mmol) 4-nitrobenzoic acid (3S; 5R)-and 1-(4-chloro-phenyl-formamyl)-5-[4-(3-oxo morpholine-4-yl) phenyl amino formyl radical] in methyl alcohol (2ml) solution of tetramethyleneimine-3-base ester, stirred this reaction mixture then 15 minutes.Filtering-depositing is used the 2ml methanol wash, drying then, obtain 35mg (93%) 1-N-[(4-chloro-phenyl-)]-2-N-{[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4S)-4-hydroxyl pyrrolidine-1,2-diformamide colourless crystallization, ESI 459, m.p.243 ℃ (decomposition).
Similar approach obtains following compound:
The 1-N-[(4-chloro-phenyl-)]-2-N-{[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 3S, 4R)-3, and 4-dihydroxy pyrrolidine-1, the 2-diformamide, ESI 475, m.p.247;
The 1-N-[(4-chloro-phenyl-)]-2-N-{[4-(3-oxo morpholine-4-yl) phenyl]-(2S, 4R)-4-hydroxyl pyrrolidine-1, the 2-diformamide, ESI 459; M.p.253 ℃;
The 1-N-[(4-chloro-phenyl-)]-2-N-{[4-(3-oxo morpholine-4-yl) phenyl]-3,4-dihydroxy pyrrolidine-1,2-diformamide.
Embodiment 8a
Similar approach by following flow process prepares the 1-N-[(4-chloro-phenyl-)]-2-N-{[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4S)-4-ethynyl-4-hydroxyl pyrrolidine-1, the 2-diformamide, ESI483:
Figure A20048000935400941
Obtain following compound similarly:
The 1-N-[(4-chloro-phenyl-)]-2-N-{[4-(2-oxo-1H-pyridine-1-yl) phenyl]-(2R, 4S)-4-ethynyl-4-hydroxyl pyrrolidine-1, the 2-diformamide, ESI 477;
The 1-N-[(4-chloro-phenyl-)]-2-N-{[4-(2-oxo-2H-pyrazine-1-yl) phenyl]-(2R, 4S)-4-ethynyl-4-hydroxyl pyrrolidine-1, the 2-diformamide, ESI 478.
Embodiment 9
Similar approach by following flow process prepares the 1-N-[(4-chloro-phenyl-)] 2-N-{[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4S)-4-azido-tetramethyleneimine-1,2-diformamide (" A9 ") and 1-N-[(4-chloro-phenyl-)]-2-N-{[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4S)-and 4-amino-pyrrolidine-1,2-diformamide (" A10 "):
Figure A20048000935400951
9.1 under ice-cooled; to 4.5g (11.1mmol) (2R; 4R)-and 4-hydroxyl-2-[4-(3-oxo morpholine-4-yl) phenyl amino formyl radical] drip 1.3ml (16.65mmol) methylsulfonyl chloride in the pyridine 20ml solution of tetramethyleneimine-1-formic acid tertiary butyl ester, at room temperature stirred this reaction soln then 12 hours.Pyridine is removed in decompression subsequently, adds the saturated citric acid solution of 10ml to resistates, then this acidic solution dichloromethane extraction twice, 10ml at every turn.The organic phase that merges is then with the washing of 10ml saturated nacl aqueous solution, then through dried over sodium sulfate.Siccative is gone out in filtration, removes then and desolvates, obtain yellow oily 5.4g (100%) (2R, 4R)-4-methylsulfonyl oxygen base-2-[4-(3-oxo morpholine-4-yl) phenyl amino formyl radical] tetramethyleneimine-1-formic acid tertiary butyl ester, ESI484.
9.2 under 60 ℃; stir 5.4g (11.7mmol) (2R, 4R)-4-methylsulfonyl oxygen base-2-[4-(3-oxo morpholine-4-yl) phenyl amino formyl radical] tetramethyleneimine-1-formic acid tertiary butyl ester and 3.69g (56.8mmol) sodiumazide be in the mixture of dimethyl formamide (DMF) in (50ml) 12 hours.Elimination insolubles subsequently, reduction vaporization filtrate is to doing then.Then resistates is dissolved in 20ml water, then this aqueous solution dichloromethane extraction twice, 10ml at every turn.The dichloromethane extraction liquid that merges washs once with the 10ml saturated nacl aqueous solution at last, then through dried over sodium sulfate.Siccative is gone out in filtration, removes then and desolvates, obtain 4.8g (100%) (2R, 4S)-4-azido--2-[4-(3-oxo morpholine-4-yl) phenyl amino formyl radical] tetramethyleneimine-little yellow crystal of 1-formic acid tertiary butyl ester, ESI 431.
9.3 it is similar to Example 7; (2R; 4S)-and 4-azido--2-[4-(3-oxo morpholine-4-yl) phenyl amino formyl radical] the reacting generating compound 1-N-[(4-chloro-phenyl-of tetramethyleneimine-1-formic acid tertiary butyl ester)]-2-N-{[4-(3-oxo morpholine-4-yl) phenyl]-(2R; 4S)-4-azido-tetramethyleneimine-1; 2-diformamide (" A9 ") white powder; ESI 459, m.p.145 ℃.
9.4 at room temperature, the tetrahydrofuran (THF) (0.5ml) of stirring 25mg (0.052mmol) " A9 " and 20.46mg (0.08mmol) triphenylphosphine and water (0.5ml) mixture solution are 12 hours.Leach the triphenylphosphine oxide post precipitation, evaporated filtrate is to doing, resistates is with preparing HPLC (acetonitrile/water/0.1% trifluoroacetic acid) purifying then, obtain 12mg (40%) 1-N-[(4-chloro-phenyl-)]-2-N-{[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4S)-4-amino-pyrrolidine-1,2-diformamide (" 10 ") colourless crystallization, ESI 458.
Similar approach obtains following compound:
The 1-N-[(4-chloro-phenyl-)]-2-N-{[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-4-azido-tetramethyleneimine-1, the 2-diformamide, ESI 484, m.p.125 ℃;
The 1-N-[(4-chloro-phenyl-)]-2-N-{[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-4-amino-pyrrolidine-1, the 2-diformamide, ESI 458, m.p.110 ℃;
The 1-N-[(4-chloro-phenyl-)]-2-N-{[3-methyl-4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4S)-4-amino-pyrrolidine-1, the 2-diformamide, ESI 472, m.p.218 ℃.
With the 4-aminocompound is raw material,
A) and excess acetyl chloride, obtain following compound:
The 1-N-[(4-chloro-phenyl-)]-2-N-{[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4S)-4-kharophen tetramethyleneimine-1, the 2-diformamide,
The 1-N-[(4-chloro-phenyl-)]-2-N-{[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-4-kharophen tetramethyleneimine-1, the 2-diformamide, ESI 458;
And obtain similarly
The 1-N-[(4-chloro-phenyl-)]-2-N-{[3-methyl-4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4S)-4-kharophen tetramethyleneimine-1, the 2-diformamide, ESI 514, m.p.170 ℃;
B) with the methylsulfonyl chloride reaction, obtain following compound:
The 1-N-[(4-chloro-phenyl-)]-2-N-{[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4S)-4-methylsulfonyl amino-pyrrolidine-1, the 2-diformamide and
The 1-N-[(4-chloro-phenyl-)]-2-N-{[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-4-methylsulfonyl amino-pyrrolidine-1, the 2-diformamide;
C) with the reaction of fourth SULPHURYL CHLORIDE, obtain following compound:
The 1-N-[(4-chloro-phenyl-)]-2-N-{[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-4-fourth sulfuryl amino tetramethyleneimine-1, the 2-diformamide,
The 1-N-[(4-chloro-phenyl-)]-2-N-{[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4S)-4-fourth sulfuryl amino tetramethyleneimine-1, the 2-diformamide, ESI 592;
D) with the isobutyryl chloride reaction, obtain compound:
The 1-N-[(4-chloro-phenyl-)]-2-N-{[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4S)-4-(2-methylpropionyl amino) tetramethyleneimine-1, the 2-diformamide, ESI 542; M.p.169.
Embodiment 10
Similar approach by following flow process prepares the 1-N-[(4-chloro-phenyl-)]-2-N-{[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-4-methoxyl group tetramethyleneimine-1,2-diformamide (" A11 "):
10.1 under nitrogen, in the mixture of acetone (15ml), add 0.94ml (15.1mmol) methyl-iodide to 1g (4.32mmol) cis-N '-BOC-4-hydroxyl-D-proline(Pro) and 3.31g (14.27mmol) silver suboxide, then stirred reaction mixture 48 hours at room temperature.Leach precipitation subsequently, reduction vaporization filtrate obtains colorless oil 1g (89.2%) cis-N '-BOC-4-methoxyl group-D-proline(Pro) methyl ester to doing, and this product need not to be further purified and can further react ESI260.
10.2 (75ml) add 25ml methyl alcohol, 25ml water and 0.28g (11.57mmol) lithium hydroxide in the solution to the tetrahydrofuran (THF) (THF) of 1g (3.85mmol) cis-N '-BOC-4-methoxyl group-D-proline(Pro) methyl ester, then stirring reaction solution 5 hours at room temperature.Remove methyl alcohol and TFH with Rotary Evaporators subsequently, use the 10ml methylene dichloride shaking out aqueous solution then once, be acidified to pH2 with saturated citric acid solution then, this acidic solution dichloromethane extraction twice, each 10ml.The organic phase that merges is removed then and is desolvated through dried over sodium sulfate, obtains 0.5g (53%) light color oily cis-N '-BOC-4-methoxyl group-D-proline(Pro), and it is crystallization gradually, and ESI 246.
10.3 it is similar to Example 7, the reacting generating compound 1-N-[(4-chloro-phenyl-of cis-N '-BOC-4-methoxyl group-D-proline(Pro))]-2-N-{[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-4-methoxyl group tetramethyleneimine-1,2-diformamide (" A11 ") white powder, ESI 473, m.p.133 ℃.
Obtain following compound similarly:
1) 1-N-[(4-chloro-phenyl-)]-2-N-{[2-fluoro-4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-4-allyloxy tetramethyleneimine-1, the 2-diformamide, ESI 517, m.p.106 ℃
Figure A20048000935400991
2) 1-N-[(4-chloro-phenyl-)]-2-N-{[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-4-oxyethyl group tetramethyleneimine-1, the 2-diformamide, ESI 487, m.p.136 ℃;
3) 1-N-[(4-chloro-phenyl-)]-2-N-{[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-4-propoxy-tetramethyleneimine-1, the 2-diformamide, ESI 501, m.p.106;
4) 1-N-[(4-chloro-phenyl-)]-2-N-{[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-4-allyloxy tetramethyleneimine-1, the 2-diformamide, ESI 499, m.p.100 ℃ and as by product
5) 2-N-{ allyl group-[4-(3-oxo morpholine-4-yl) phenyl] }-the 1-N-[(4-chloro-phenyl-)]-4-hydroxyl pyrrolidine-1, the 2-diformamide, ESI 499;
6) 1-N-[(4-chloro-phenyl-)]-2-N-{[3-methyl-4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-4-methoxyl group tetramethyleneimine-1, the 2-diformamide, ESI 487, m.p.140 ℃;
7) 1-N-[(4-chloro-phenyl-)]-2-N-{[4-(2-oxo-2H-pyridine-1-yl) phenyl]-(2R, 4R)-4-methoxyl group tetramethyleneimine-1, the 2-diformamide, ESI 467, m.p.133 ℃;
8) 1-N-[(4-chloro-phenyl-)]-2-N-{[2-fluoro-4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-4-methoxyl group tetramethyleneimine-1, the 2-diformamide, ESI 491, m.p.109 ℃;
9) 1-N-[(4-chloro-phenyl-)]-2-N-{[4-(2-oxo-2H-pyrazine-1-yl) phenyl]-(2R, 4R)-4-methoxyl group tetramethyleneimine-1, the 2-diformamide, ESI 468, m.p.127 ℃;
10) 1-N-[(4-chloro-phenyl-)]-2-N-{[3-fluoro-4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-4-methoxyl group tetramethyleneimine-1, the 2-diformamide, ESI 491, m.p.99 ℃;
11) 1-N-[(4-chloro-phenyl-)]-2-N-{[2-fluoro-4-(2-oxo-2H-pyridine-1-yl) phenyl]-(2R, 4R)-4-methoxyl group tetramethyleneimine-1, the 2-diformamide, ESI 485;
12) 1-N-[(4-chloro-phenyl-)]-2-N-{[4-(2-oxo-2H-pyrazine-1-yl) phenyl]-(2R, 4R)-4-oxyethyl group tetramethyleneimine-1, the 2-diformamide, ESI 482, m.p.132 ℃;
13) 1-N-[(4-chloro-phenyl-)]-2-N-{[3-fluoro-4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-4-oxyethyl group tetramethyleneimine-1, the 2-diformamide, ESI 505, m.p.131 ℃;
14) 1-N-[(4-chloro-phenyl-)]-2-N-{[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-4-(Propargyl oxygen base) tetramethyleneimine-1, the 2-diformamide, ESI 497, m.p.120 ℃;
15) 1-N-[(4-chloro-phenyl-)]-2-N-{[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-4-(fourth-2-alkynyloxy base) tetramethyleneimine-1, the 2-diformamide,
16) 1-N-[(4-chloro-phenyl-)]-2-N-{[2-fluoro-4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-4-(Propargyl oxygen base) tetramethyleneimine-1, the 2-diformamide, ESI 515, m.p.108 ℃;
17) 1-N-[(4-chloro-phenyl-)]-2-N-{[2-fluoro-4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4S)-4-(Propargyl oxygen base) tetramethyleneimine-1, the 2-diformamide, ESI 515, m.p.92 ℃;
18) 1-N-[(4-chloro-phenyl-)]-2-N-{[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-4-(methoxycarbonyl methoxyl group) tetramethyleneimine-1, the 2-diformamide, ESI 531, m.p.106 ℃; Thus by hydrolysis
19) 1-N-[(4-chloro-phenyl-)]-2-N-{[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-4-(carboxyl methoxyl group) tetramethyleneimine-1, the 2-diformamide, ESI 517, m.p.134 ℃;
20) 1-N-[(4-bromophenyl)]-2-N-{[2-fluoro-4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-4-methoxyl group tetramethyleneimine-1, the 2-diformamide, ESI 536, m.p.103 ℃.
Embodiment 11
By the similar approach of following flow process prepare isopropylformic acid (3R, 5R)-1-(4-chloro-phenyl-formamyl)-5-[4-(3-oxo morpholine-4-yl) phenyl amino formyl radical] tetramethyleneimine-3-base ester (" A12 "):
Figure A20048000935401011
At room temperature stir pyridine (1ml) solution 12 hours of the isobutyric anhydride (0.146ml) of 0.2g (0.44mmol) " A8 ".Add the 10ml ethyl acetate subsequently in this reaction mixture, ethyl acetate solution is successively with 1N hydrochloric acid 5ml and the washing of 5ml saturated nacl aqueous solution, then through dried over sodium sulfate then.Siccative is gone out in filtration; remove then and desolvate, obtain 183mg (79.3%) isopropylformic acid (3R, 5R)-1-(4-chloro-phenyl-formamyl)-5-[4-(3-oxo morpholine-4-yl) phenyl amino formyl radical] tetramethyleneimine-3-base ester (" A12 ") white crystals; ESI 529, m.p.129 ℃.
Obtain following compound similarly:
Propionic acid (3R, 5R)-1-(4-chloro-phenyl-formamyl)-5-[4-(3-oxo morpholine-4-yl) phenyl amino formyl radical] tetramethyleneimine-3-base ester, ESI 515;
Acetate (3R, 5R)-1-(4-chloro-phenyl-formamyl)-5-[4-(3-oxo morpholine-4-yl) phenyl amino formyl radical] tetramethyleneimine-3-base ester, ESI 501, m.p.148 ℃.
Embodiment 12
Similar approach by following flow process prepares the 4-N-[(4-chloro-phenyl-)]-5-N-{[4-(3-oxo morpholine-4-yl) phenyl]-1,3-dioxolane-4, the 5-diformamide:
Figure A20048000935401021
Obtain following compound similarly:
1) 4-N-[(4-chloro-phenyl-)]-5-N-{[3-methyl-4-(3-oxo morpholine-4-yl) phenyl]-1,3-dioxolane-4, the 5-diformamide,
2) 4-N-[(4-chloro-phenyl-)]-5-N-{[4-(2-oxo-2H-pyridine-1-yl) phenyl]-1,3-dioxolane-4, the 5-diformamide, ESI 440;
3) 4-N-[(4-chloro-phenyl-)]-5-N-{[4-(3-oxo morpholine-4-yl) phenyl]-1,3-dioxolane-2,2-dimethyl-4, the 5-diformamide, ESI 474;
4) 4-N-[(4-chloro-phenyl-)]-5-N-{[3-methyl-4-(3-oxo morpholine-4-yl) phenyl]-1,3-dioxolane-2,2-dimethyl-4, the 5-diformamide, ESI 488;
5) 4-N-[(4-chloro-phenyl-)]-5-N-{[4-(2-oxo-1H-pyridine-1-yl) phenyl]-1,3-dioxolane-2,2-dimethyl-4, the 5-diformamide, ESI 468.
Embodiment 13
Similar to Example 7, N-[4-(3-oxo morpholine-4-yl) phenyl]-1-BOC-piperazine-2-methane amide and isocyanic acid 4-chloro-phenyl-ester reacting generating compound:
The 1-N-[4-chloro-phenyl-)]-2-N-{[4-(3-oxo morpholine-4-yl) phenyl]-1-BOC-piperazine-1, the 2-diformamide
Remove the BOC group, obtain
The 1-N-[4-chloro-phenyl-)]-2-N-{[4-(3-oxo morpholine-4-yl) phenyl]-piperazine-1, the 2-diformamide.
Similarly, isocyanic acid 4-chloro-phenyl-ester and N-[4-(3-oxo morpholine-4-yl) phenyl]-1, the own ring-4-formamide of 3-oxa-azepine generates compound
The 1-N-[4-chloro-phenyl-]-2-N-{[4-(3-oxo morpholine-4-yl) phenyl]-1, oneself encircles-3 3-oxa-azepine, the 4-diformamide.
Embodiment 13-1
Similar approach by following flow process prepares the 1-N-[(4-chloro-phenyl-)]-2-N-{[4-(3-oxo morpholine-4-yl) phenyl]-(R)-and 4-oxo-pyrrolidine-1, the 2-diformamide:
Figure A20048000935401032
To 0.3g (0.65mmol) 1-N-[(4-chloro-phenyl-)]-2-N-{[4-(3-oxo morpholine-4-yl) phenyl]-(1R, 4R)-4-hydroxyl pyrrolidine-1, add 0.21g (0.98mmol) pyridinium chlorochromate (PCC) in methylene dichloride (15ml) solution of 2-diformamide (embodiment 7), then stirred reaction mixture 48 hours at room temperature.Leach precipitation subsequently, the filtrate water washing is 3 times then, and each 20ml is then through dried over sodium sulfate.Except that after desolvating, resistates obtains 140mg (47%) 1-N-[(4-chloro-phenyl-with preparation HPLC purifying)]-2-N-{[4-(3-oxo morpholine-4-yl) phenyl]-(R)-and 4-oxo-pyrrolidine-1,2-diformamide white powder, ESI 457, m.p.154 ℃.
Embodiment 13-2
Similar approach by following flow process prepares N-[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-1-[2-(4-chloro-phenyl-) ethanoyl]-4-hydroxyl pyrrolidine-2-methane amide:
Figure A20048000935401041
At room temperature, to 0.5g (1.46mmol) N-[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-add 0.25g (1.46mmol) 4-chlorobenzene acetic acid and 0.36g (1.46mmol) 2-oxyethyl group-1 successively, 2-dihydroquinoline-1-ethyl formate (EEDQ) in toluene (20ml) solution of 4-hydroxyl pyrrolidine-2-methane amide (embodiment 7.2) and 0.2ml triethylamine.The reaction mixture that stirring at room temperature subsequently obtains 12 hours, successively with 10ml 1N hydrochloric acid and the washing of 10ml saturated sodium bicarbonate solution, organic phase is through dried over sodium sulfate then then.Except that after desolvating; crude product obtains 0.31g (46.4%) N-[4-(3-oxo morpholine-4-yl) phenyl with preparation HPLC purifying]-(2R, 4R)-1-[2-(4-chloro-phenyl-) ethanoyl]-4-hydroxyl pyrrolidine-2-methane amide white powder; ESI 458, m.p.141 ℃.
Obtain following compound similarly:
1) N-[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-1-(4-chlorobenzene formacyl)-4-hydroxyl pyrrolidine-2-methane amide, ESI 444, m.p.216 ℃;
2) N-[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-1-(1-1H-indol-3-yl-formyl radical)-4-hydroxyl pyrrolidine-2-methane amide, ESI 449, m.p.283 ℃;
3) N-[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-1-(1-1H-indoles-6-base-formyl radical)-4-hydroxyl pyrrolidine-2-methane amide, ESI 449, m.p.148 ℃.
Embodiment 13-3
Similar approach by following flow process prepares the 1-N-[(4-chloro-phenyl-)]-2-N-{[3-methyl-4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-4-oxyethyl group tetramethyleneimine-1, the 2-diformamide:
Figure A20048000935401051
With the tetrahydrofuran (THF) (THF) of 5g (21.62mmol) cis-N '-Boc-4-hydroxyl-D-proline(Pro) and 8.66g (43.24mmol) 4-toluenesulphonic acids ethyl ester (5ml) suspension add with 2.94g (73.5mmol) sodium hydroxide water (5ml) solution.Stir this reaction mixture 12 hours down at 40 ℃ then, with the Rotary Evaporators evaporation, then resistates is dissolved in 10ml water subsequently.The aqueous solution is used washed with dichloromethane twice then, and each 10ml uses the 2N hcl acidifying then.The acidic solution that obtains dichloromethane extraction three times, each 20ml.The dichloromethane extraction liquid that merges removes and desolvates through dried over sodium sulfate, obtains 4.87g (86.9%) colorless oil cis-N '-Boc-4-oxyethyl group-D-proline(Pro).ESI 232。
Similar to Example 7, the reacting generating compound of cis-N '-Boc-4-oxyethyl group-D-proline(Pro):
The 1-N-[(4-chloro-phenyl-)]-2-N-{[3-methyl-4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-4-oxyethyl group tetramethyleneimine-1, the 2-diformamide, ESI 501, m.p.117 ℃.
Obtain following compound similarly:
The 1-N-[(4-chloro-phenyl-)]-2-N-{[4-(2-oxo-1H-pyridine-1-yl) phenyl]-(2R, 4R)-4-oxyethyl group tetramethyleneimine-1, the 2-diformamide, ESI 481, m.p.209 ℃;
The 1-N-[(4-chloro-phenyl-)]-2-N-{[2-fluoro-4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-4-oxyethyl group tetramethyleneimine-1, the 2-diformamide, ESI 505, m.p.187 ℃.
Embodiment 13-4
Similar approach by following flow process prepares the 2-N-[(4-chloro-phenyl-)]-1-N-{[4-(3-oxo morpholine-4-yl) phenyl]-(R)-and tetramethyleneimine-1, the 2-diformamide:
Figure A20048000935401061
1.01g (5.00mmol) chloroformic acid 4-nitrophenyl ester and 0.404ml (5.00mmol) pyridine are added in methylene dichloride (10ml) solution of 961mg (5.00mmol) 4-(4-aminophenyl) morpholine-3-ketone, at room temperature stirred this mixture then 1 hour.In this suspension, add 1.31g (5.00mmol) chlorination (R)-2-(4-chloro-phenyl-formamyl) tetramethyleneimine and 2.55ml (15.0mmol) N-ethyl diisopropyl amine.At room temperature stirred this reaction mixture 12 hours, evaporation makes resistates chromatography on silicagel column then, obtains the 2-N-[(4-chloro-phenyl-)]-1-N-{[4-(3-oxo morpholine-4-yl) phenyl]-(R)-tetramethyleneimine-1, the little yellow solid of 2-diformamide, ESI 443.
Obtain the 2-N-[(4-chloro-phenyl-similarly)]-1-N-{[4-(3-oxo morpholine-4-yl) phenyl]-(S)-and tetramethyleneimine-1, the 2-diformamide, ESI 443.
Embodiment 13-5
Similar approach by following flow process prepares N-(4-chloro-phenyl-)-(R)-1-{2-[4-(3-oxo morpholine-4-yl) phenyl] ethanoyl } tetramethyleneimine-2-methane amide:
Figure A20048000935401071
In toluene (50ml) suspension of 2.80g (13.0mmol) N-Boc-D-proline(Pro) and 1.66g (13.0mmol) 4-chloroaniline, add 4.82g (19.5mmol) 2-oxyethyl group-1,2-dihydroquinoline-1-ethyl formate (EEDQ) at room temperature stirred this mixture 3 hours then.Filter reaction mixture adds sherwood oil to filtrate then.Filter the precipitation that forms, dry then, obtain (R)-2-(4-chloro-phenyl-formamyl) tetramethyleneimine-1-formic acid tertiary butyl ester colourless crystallization; ESI325.
With 4.00g (12.3mmol) (R)-2-(4-chloro-phenyl-formamyl) tetramethyleneimine-1-formic acid tertiary butyl ester is dissolved in the 4N HCl De dioxane solution (20ml), at room temperature placed then 2 hours.Evaporation reaction mixture, dry then, obtain chlorination (R)-2-(4-chloro-phenyl-formamyl) little brown solid of tetramethyleneimine; ESI 225.
In DMF (2ml) solution of 261mg (1.00mmol) chlorination (R)-2-(4-chloro-phenyl-formamyl) tetramethyleneimine and 235mg (1.00mmol) 4-(3-oxo morpholine-4-yl) toluylic acid, add 0.26ml (2.4mmol) 4-methylmorpholine and 230mg (1.2mmol) hydrochloric acid N-(3-dimethylamino-propyl)-N '-ethyl carbodiimide (DAPECl), at room temperature stirred this mixture then 18 hours.Reaction mixture is introduced in the water, is filtered the precipitation that forms then, obtain N-(4-chloro-phenyl-)-(R)-1-{2-[4-(3-oxo morpholine-4-yl) phenyl] ethanoyl } tetramethyleneimine-little brown solid of 2-methane amide; ESI 442.
Obtain N-(4-chloro-phenyl-)-(S)-1-{2-[4-(3-oxo morpholine-4-yl) phenyl similarly] ethanoyl } tetramethyleneimine-2-methane amide, ESI 442.
The preparation carboxylic acid
Figure A20048000935401081
14.6g (92.7mmol) (2-chloroethoxy) Acetyl Chloride 98Min. is added in toluene (25ml) suspension of 20.0g (92.7mmol) 4-aminophenyl ethyl acetate hydrochloride, this mixture of boiling heating is 24 hours then.Evaporation reaction mixture, dry then, obtain 4-[2-(2-chloroethoxy) kharophen] phenyl the little yellow solid of ethyl acetate; ESI 300.
43.4g (133mmol) cesium carbonate is added in acetonitrile (100ml) solution of 26.6g (88.8mmol) { 4-[2-(2-chloroethoxy) kharophen] phenyl } ethyl acetate, at room temperature stirred this mixture then 18 hours.Filter reaction mixture, evaporated filtrate obtains little yellow oily [4-(3-oxo morpholine-4-yl) phenyl] ethyl acetate then; ESI 264.
20.2g (76.8mmol) [4-(3-oxo morpholine-4-yl) phenyl] ethyl acetate is dissolved in ethanol (40ml) solution of 3.37g sodium hydroxide, at room temperature stirred this reaction soln then 18 hours.Evaporation reaction mixture, then that resistates is water-soluble, use the 1N hcl acidifying to pH3 then.This mixture ethyl acetate extraction, organic phase are through dried over sodium sulfate, and evaporation obtains 4-(3-oxo morpholine-4-yl) the little yellow solid of toluylic acid then; ESI 236.
Similar with embodiment 13-5, obtain following compound:
1) N-(4-chloro-phenyl-)-(2R, 4R)-1-{2-[4-(3-oxo morpholine-4-yl) phenyl] ethanoyl-4-methoxyl group tetramethyleneimine-2-methane amide,
2) N-(4-chloro-phenyl-)-(2R, 4S)-1-{2-[4-(3-oxo morpholine-4-yl) phenyl] ethanoyl-4-methoxyl group tetramethyleneimine-2-methane amide,
3) N-(4-chloro-phenyl-)-(2S, 4R)-1-{2-[4-(3-oxo morpholine-4-yl) phenyl] ethanoyl-4-methoxyl group tetramethyleneimine-2-methane amide,
4) N-(4-chloro-phenyl-)-(S)-1-{2-[4-(2-oxo-1H-pyridine-1-yl) phenyl] ethanoyl }-tetramethyleneimine-2-methane amide,
5) N-(4-chloro-phenyl-)-(S)-1-{2-[4-(2-oxo-pyrrolidine-1-yl) phenyl] ethanoyl }-tetramethyleneimine-2-methane amide,
6) N-(4-chloro-phenyl-)-(R)-1-{2-[4-(2-oxo-pyrrolidine-1-yl) phenyl] ethanoyl }-tetramethyleneimine-2-methane amide,
7) N-(4-chloro-phenyl-)-(R)-1-[4-(2-oxo-piperidine-1-yl) benzoyl] tetramethyleneimine-2-methane amide,
8) N-(4-chloro-phenyl-)-(R)-1-[4-(2-oxo-piperidine-1-yl) phenyloxycarbonyl] tetramethyleneimine-2-methane amide.
Embodiment 13-6
Similar approach by following flow process prepares the 1-N-[(4-chloro-phenyl-)]-2-N-{[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-4-(2,3-dihydroxyl propoxy-) tetramethyleneimine-1, the 2-diformamide:
Figure A20048000935401101
Under nitrogen, to 10.3g (42mmol) (2R, 4R)-4-hydroxyl pyrrolidine-1, the dimethyl formamide (DMF) of 2-dioctyl phthalate 1-tertiary butyl ester 2-methyl ester and 36.34ml (420mmol) 3-bromo-1-propylene (100ml) adds 1.55g (38.6mmol) sodium hydride in the solution in batches, at room temperature stirs this mixture subsequently 15 minutes.Add 9.73g (42mmol) silver suboxide then in reaction mixture, at room temperature the restir reaction mixture is 12 hours in batches.Filter reaction mixture then, reduction vaporization filtrate is dissolved in resistates the saturated citric acid solution of 20ml then to doing.Leach post precipitation, filtrate is used ethyl acetate extraction twice, each 20ml.The organic phase that merges is removed then and is desolvated through dried over sodium sulfate, obtain 11.6g reddish-brown oily (2R, 4R)-4-allyloxy tetramethyleneimine-1,2-dioctyl phthalate 1-tertiary butyl ester 2-methyl ester; ESI 286.
At room temperature, to 5g (17.52mmol) (2R, 4R)-4-allyloxy tetramethyleneimine-1, add 6.16g (52.6mmol) N-methylmorpholine N-oxide compound (NMO) and 193.7mg potassium osmate dihydrate successively in water (60ml), acetone (25ml) and the trimethyl carbinol (10ml) solution of 2-dioctyl phthalate 1-tertiary butyl ester 2-methyl ester, stirred this mixture then 48 hours.In reaction mixture, add 6.6g (52.6mmol) S-WAT subsequently, at room temperature stirred again 1 hour.The reduction vaporization reaction mixture is dissolved in resistates in the 50ml water then, then this aqueous solution ethyl acetate extraction twice, 20ml at every turn.The organic phase that merges is removed then and is desolvated through dried over sodium sulfate, obtain the little yellow oily of 4.7g (2R, 4R)-4-(2,3-dihydroxyl propoxy-) tetramethyleneimine-1,2-dioctyl phthalate 1-tertiary butyl ester 2-methyl ester; ESI 320.The 1.06g lithium hydroxide is added in tetrahydrofuran (THF) (40ml), methyl alcohol (10ml) and water (10ml) solution of this methyl ester (4.6g), at room temperature stirred reaction mixture is 12 hours.The reduction vaporization reaction mixture adds the saturated citric acid solution of 10ml in the remainder water solution subsequently, this mixture ethyl acetate extraction three times then, each 20ml.The organic phase that merges is removed then and is desolvated through dried over sodium sulfate, obtain 4.3g (2R, 4R)-4-(2,3-dihydroxyl propoxy-) tetramethyleneimine-1,2-dioctyl phthalate tertiary butyl ester yellow powder; ESI 306.Similar to Example 7, this acid obtains compound 1-N-[(4-chloro-phenyl-)]-2-N-{[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-4-(2,3-dihydroxyl propoxy-) tetramethyleneimine-1, the 2-diformamide; ESI 533.
Obtain the 1-N-[(4-chloro-phenyl-similarly)]-2-N-{[2-fluoro-4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-4-(2,3-dihydroxyl propoxy-) tetramethyleneimine-1, the 2-diformamide; ESI 551.
Embodiment 13-7
The following compound of similar approach preparation by following flow process:
1) 1-N-[(4-chloro-phenyl-)]-2-N-{[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-4-(2-hydroxyl-3-tetramethyleneimine-1-base propoxy-) tetramethyleneimine-1, the 2-diformamide,
2) 1-N-[(4-chloro-phenyl-)]-2-N-{[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-4-(2-Yang Dai oxazolidine-5-ylmethoxy) tetramethyleneimine-1, the 2-diformamide and
3) 1-N-[(4-chloro-phenyl-)]-2-N-{[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-4-(3-amino-2-hydroxyl propoxy-) tetramethyleneimine-1, the 2-diformamide, ESI 532, m.p.115:
Figure A20048000935401121
Embodiment 13-8
Similar approach by following flow process prepares the 1-N-[(4-chloro-phenyl-)]-2-N-{N-methoxycarbonyl methyl-N '-[4-(3-oxo morpholine-4-yl) phenyl] }-(2R, 4R)-4-methoxyl group tetramethyleneimine-1, the 2-diformamide:
Figure A20048000935401131
61mg (2.54mmol) sodium hydride is added 1g (2.31mmol) (2R; 4R)-and 4-methoxyl group-2-[4-(3-oxo morpholine-4-yl) phenyl amino formyl radical] in dimethyl formamide (20ml) solution of tetramethyleneimine-1-formic acid tertiary butyl ester (press embodiment 7.1 similar approach preparation), at room temperature stirred this mixture 30 minutes.In reaction mixture, add 0.22mg (2.31mmol) methyl bromoacetate subsequently, at room temperature stirred then 12 hours.This reaction mixture of reduction vaporization is dissolved in resistates in the 20ml water then, this aqueous solution dichloromethane extraction three times then, each 20ml.The organic phase that merges is removed then and is desolvated through dried over sodium sulfate, obtain the 1.1g yellow oily (2R, 4R)-4-methoxyl group-2-{ methoxycarbonyl methyl-[4-(3-oxo morpholine-4-yl) phenyl] formamyl tetramethyleneimine-1-formic acid tertiary butyl ester; ESI (M-BOC) 392.
Remove the BOC group, obtain the 1-N-[(4-chloro-phenyl-)]-2-N-{N-methoxycarbonyl methyl-N '-[4-(3-oxo morpholine-4-yl) phenyl] }-(2R, 4R)-4-methoxyl group tetramethyleneimine-1, the 2-diformamide, ESI 545, m.p.106 ℃.
Obtain compound 1-N-[(4-chloro-phenyl-similarly)]-2-N-{N-methoxycarbonyl methyl-N '-[2-fluoro-4-(3-oxo morpholine-4-yl) phenyl] }-(2R, 4R)-4-methoxyl group tetramethyleneimine-1, the 2-diformamide, ESI 563, m.p.100 ℃.
Embodiment 13-9
Similar approach by following flow process prepares the 1-N-[(4-chloro-phenyl-)]-2-N-{[4-(3-oxo morpholine-4-yl) hexamethylene-1-yl]-(2R, 4R)-4-hydroxyl pyrrolidine-1, the 2-diformamide:
Figure A20048000935401141
13-9.1 6.32g (40.3mmol) (2-chloroethoxy) Acetyl Chloride 98Min. is added in tetrahydrofuran (THF) (300ml) solution of 10g (40.3mmol) (4-aminocyclohexyl) carboxylamine benzyl ester and 6.2ml triethylamine (TEA), at room temperature stirred this mixture subsequently 20 hours.The reduction vaporization reaction mixture is dissolved in resistates in the 20ml water then, this aqueous solution ethyl acetate extraction three times then, each 20ml.The organic phase that merges is removed and is desolvated after dried over sodium sulfate, and resistates is dissolved in the 20ml acetonitrile, adds the 2.3g cesium carbonate in the solution that obtains.Stirred reaction mixture 48 hours at room temperature then, reduction vaporization is dissolved in resistates in the 20ml water then, and this aqueous solution is with ethyl acetate extraction four times, each 20ml then.The organic phase that merges is removed and is desolvated after dried over sodium sulfate, and resistates is dissolved in the 50ml tetrahydrofuran (THF), adds 0.3g 5% palladium/carbon in the solution that obtains, and this mixture hydrogenation is absorbed until hydrogen to stop then.Leach catalyzer subsequently, reduction vaporization filtrate obtains 1.5g colorless oil 4-(4-aminocyclohexyl) morpholine-3-ketone to doing then; ESI 199.
13-9.2 similar with embodiment 7.3, and cis-N '-BOC-4-hydroxyl-D-proline(Pro) and isocyanic acid 4-chloro-phenyl-ester reacting generating compound (2R, 4R)-1-(4-chloro-phenyl-formamyl)-4-hydroxyl pyrrolidine-2-formic acid; ESI 285, m.p.132 ℃.
13-9.3 similar with embodiment 7.1, the amine of 13-9.1 and the acid-respons of 13-9.2 generate compound 1-N-[(4-chloro-phenyl-)]-2-N-{[4-(3-oxo morpholine-4-yl) hexamethylene-1-yl]-(2R, 4R)-4-hydroxyl pyrrolidine-1, the 2-diformamide, ESI 465; M.p.245 ℃.
Embodiment 13-10
Similar to Example 7, obtain following compound:
1) 1-N-[(4-chloro-phenyl-)]-2-N-[(1 '-methyl-[1,4 '] connection piperidin-4-yl)]-(2R, 4R)-4-hydroxyl pyrrolidine-1, the 2-diformamide, ESI 464; M.p.78 ℃
Figure A20048000935401151
2) 1-N-[(4-chloro-phenyl-)]-and 2-N-[(3,4,5,6-tetrahydrochysene-2H-[1,4 '] dipyridyl-4-yl)]-(2R, 4R)-4-hydroxyl pyrrolidine-1, the 2-diformamide, ESI 444
Figure A20048000935401152
3) 1-N-[(4-chloro-phenyl-)]-and 2-N-[(3,4,5,6-tetrahydrochysene-2H-1,4 '-dipyridyl-4-yl)-(2R, 4R)-4-oxyethyl group tetramethyleneimine-1, the 2-diformamide, ESI 472;
4) N-(4-chloro-phenyl-)-(2R, 4R)-4-hydroxyl-2-(4-pyridin-4-yl piperazine-1-carbonyl) tetramethyleneimine-1-methane amide, ESI 430
5) N-(4-chloro-phenyl-)-(2R, 4R)-4-hydroxyl-2-[4-(2-p-methoxy-phenyl) piperazine-1-carbonyl] tetramethyleneimine-1-methane amide, ESI 459
Figure A20048000935401162
6) N-(4-chloro-phenyl-)-(2R, 4R)-2-[4-(4-fluorophenyl) piperazine-1-carbonyl]-4-hydroxyl pyrrolidine-1-methane amide, ESI 447;
7) N-(4-chloro-phenyl-)-(2R, 4R)-4-hydroxyl-2-[4-hydroxyl-4-(4-p-methoxy-phenyl) piperidines-1-carbonyl] tetramethyleneimine-1-methane amide, ESI 456;
8) N-(4-chloro-phenyl-)-(2R, 4R)-4-hydroxyl-2-[4-pyridine-2-base piperazine-1-carbonyl) tetramethyleneimine-1-methane amide, ESI 430;
9) N-(4-chloro-phenyl-)-(2R, 4R)-2-[4-(4-ethyl piperazidine-1-yl) piperidines-1-carbonyl]-4-hydroxyl pyrrolidine-1-methane amide, ESI 465;
10) N-(4-chloro-phenyl-)-(2R, 4R)-2-[4-(4,6-dimethyl pyrimidine-2-yl) piperazine-1-carbonyl]-4-hydroxyl pyrrolidine-1-methane amide, ESI 459;
11) N-(4-chloro-phenyl-)-(2R, 4R)-4-hydroxyl-2-[4-(1-methyl piperidine-4-yl) piperazine-1-carbonyl] tetramethyleneimine-1-methane amide; ESI 450;
12) 1-N-[(4-chloro-phenyl-)]-2-N-{[2-(2-dimethylamino oxyethyl group)-4-morpholine-4-base phenyl]-(2R, 4R)-4-hydroxyl pyrrolidine-1, the 2-diformamide, ESI 532;
13) 1-N-[(4-chloro-phenyl-)]-2-N-[(2-oxyethyl group-4-morpholine-4-base phenyl)]-(2R, 4R)-4-hydroxyl pyrrolidine-1, the 2-diformamide, ESI 489;
14) 1-N-[(4-chloro-phenyl-)]-2-N-[(4-morpholine-4-base-2-propoxy-phenyl)]-(2R, 4R)-4-hydroxyl pyrrolidine-1, the 2-diformamide, ESI 504;
Embodiment 13-11
Similar to Example 7, obtain following compound:
1) 1-N-[(4-chloro-phenyl-)]-2-N-{[4-(2-lminopyrrolidine-1-yl) phenyl]-(2R, 4R)-4-hydroxyl pyrrolidine-1, the 2-diformamide, ESI 442;
2) 1-N-[(4-chloro-phenyl-)]-2-N-{[3-methyl-4-(2-lminopyrrolidine-1-yl) phenyl]-(2R, 4R)-4-hydroxyl pyrrolidine-1, the 2-diformamide, ESI 456;
3) 1-N-[(4-chloro-phenyl-)]-2-N-[4-{2-[(E)-and cyanoimino] imidazolidine-1-yl) phenyl]-(2R, 4R)-4-hydroxyl pyrrolidine-1, the 2-diformamide, ESI 468;
4) 1-N-[(4-chloro-phenyl-)]-2-N-{[4-(2-imino--5-methylthiazol-3-yl) phenyl]-(2R, 4R)-4-hydroxyl pyrrolidine-1, the 2-diformamide, ESI 473;
5) 1-N-[(4-fluorophenyl)]-2-N-{[2-aminocarboxyl-4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-4-hydroxyl pyrrolidine-1, the 2-diformamide, ESI 502;
6) 1-N-[(4-chloro-phenyl-)]-2-N-{[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-4-hydroxy-2-methyl tetramethyleneimine-1, the 2-diformamide, ESI 457.
Embodiment 13-12
Similar approach preparation by following flow process
N-[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-1-[(E)-3-(5-chlorothiophene-2-yl) acryl]-4-hydroxyl pyrrolidine-2-methane amide:
Figure A20048000935401171
The piperidines (0.07ml) and pyridine (5ml) solution of 1g (6.62mmol) 5-chloro-2 thiophene carboxaldehyde and 1.38g (13.23mmol) propanedioic acid were refluxed 2 hours.Make the reaction soln cooling subsequently, in the impouring 20ml water, use the 2N hcl acidifying more then to pH1.Sedimentary product then at 80 ℃ loft drier inner drying, obtains 1.02g (E)-3-(5-chlorothiophene-2-yl) brown crystallization of vinylformic acid with filtering filtration in this process, and ESI 189.Similar with embodiment 7.1; embodiment 7.2 compounds with (E)-3-(5-chlorothiophene-2-yl) vinylformic acid reacting generating compound N-[4-(3-oxo morpholine-4-yl) phenyl]-(2R; 4R)-1-[(E)-3-(5-chlorothiophene-2-yl) acryl]-4-hydroxyl pyrrolidine-2-methane amide colourless crystallization; ESI 476, m.p.151 ℃.
Obtain following compound similarly:
1) N-[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-1-[(E)-3-thiene-3-yl-acryl]-4-hydroxyl pyrrolidine-2-methane amide, ESI 442, m.p.137 ℃;
2) N-[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-1-[(2E, 4E)-5-phenyl penta-2,4-two enoyl-s]-4-hydroxyl pyrrolidine-2-methane amide, ESI 462, m.p.127 ℃;
3) N-[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-1-[(E)-3-(5-methyl furan-2-yl) acryl]-4-hydroxyl pyrrolidine-2-methane amide, ESI 440, m.p.133 ℃;
4) N-[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-1-[(E)-3-thiophene-2-base acryl]-4-hydroxyl pyrrolidine-2-methane amide, ESI 442;
5) N-[2-fluoro-4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-1-[(E)-3-(5-chlorothiophene-2-yl) acryl]-4-methoxyl group tetramethyleneimine-2-methane amide, ESI 508;
6) N-[2-fluoro-4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-1-[(E)-3-(5-chlorothiophene-2-yl) acryl]-4-hydroxyl pyrrolidine-2-methane amide, ESI 494, m.p.111 ℃;
7) N-[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-1-[(E)-3-(4-chloro-phenyl-) acryl]-4-hydroxyl pyrrolidine-2-methane amide, ESI 470;
8) N-[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-1-[(E)-3-(3, the 4-dichlorophenyl) acryl]-4-hydroxyl pyrrolidine-2-methane amide, ESI 504;
9) N-[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-1-[(E)-3-(4-chloro-phenyl-) acryl]-4-methoxyl group tetramethyleneimine-2-methane amide, ESI 484;
10) N-[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-1-[(E)-3-(3, the 4-dichlorophenyl) acryl]-4-methoxyl group tetramethyleneimine-2-methane amide, ESI 518;
11) N-[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-1-[(E)-3-1H-imidazol-4 yl acryl]-4-hydroxyl pyrrolidine-2-methane amide, ESI 426;
12) N-[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-1-[(E)-3-(5-chlorothiophene-2-yl) acryl]-4-methoxyl group tetramethyleneimine-2-methane amide, ESI 490;
13) N-[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-1-[(E)-3-(5-chlorine furans-2-yl) acryl]-4-hydroxyl pyrrolidine-2-methane amide, ESI 460;
14) N-[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-1-[(E)-3-(5-chlorine furans-2-yl) acryl]-4-methoxyl group tetramethyleneimine-2-methane amide, ESI 474;
15) N-[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-1-[(E)-3-(4-chloro-phenyl-) acryl]-4-oxyethyl group tetramethyleneimine-2-methane amide, ESI 498;
16) N-[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-1-[(E)-3-(3, the 4-dichlorophenyl) acryl]-4-oxyethyl group tetramethyleneimine-2-methane amide, ESI 532;
17) N-[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-1-[(E)-3-(5-chlorine furans-2-yl) acryl]-4-oxyethyl group tetramethyleneimine-2-methane amide, ESI 488;
18) N-[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-1-[(E)-3-(5-chlorothiophene-2-yl) acryl]-4-oxyethyl group tetramethyleneimine-2-methane amide, ESI 504;
19) N-[2-fluoro-4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-1-[(E)-3-(4-chloro-phenyl-) acryl]-4-hydroxyl pyrrolidine-2-methane amide, ESI 488;
20) N-[2-fluoro-4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-1-[(E)-3-(3, the 4-dichlorophenyl) acryl]-4-hydroxyl pyrrolidine-2-methane amide, ESI 522;
21) N-[2-fluoro-4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-1-[(E)-3-(5-chlorine furans-2-yl) acryl]-4-hydroxyl pyrrolidine-2-methane amide, ESI 478;
22) N-[2-fluoro-4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-1-[(E)-3-(5-chlorine furans-2-yl) acryl]-4-methoxyl group tetramethyleneimine-2-methane amide, ESI 492;
23) N-[2-fluoro-4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-1-[(E)-3-(4-chloro-phenyl-) acryl]-4-methoxyl group tetramethyleneimine-2-methane amide, ESI 502;
24) N-[2-fluoro-4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-1-[(E)-3-(3, the 4-dichlorophenyl) acryl]-4-methoxyl group tetramethyleneimine-2-methane amide, ESI 536;
25) N-[2-fluoro-4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-1-[(E)-3-(4-chloro-phenyl-) acryl]-4-oxyethyl group tetramethyleneimine-2-methane amide, ESI 516;
26) N-[2-fluoro-4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-1-[(E)-3-(3, the 4-dichlorophenyl) acryl]-4-oxyethyl group tetramethyleneimine-2-methane amide, ESI 550;
27) N-[2-fluoro-4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-1-[(E)-3-(5-chlorine furans-2-yl) acryl]-4-oxyethyl group tetramethyleneimine-2-methane amide, ESI 506;
28) N-[2-fluoro-4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-1-[(E)-3-(5-chlorothiophene-2-yl) acryl]-4-oxyethyl group tetramethyleneimine-2-methane amide, ESI 522;
29) N-[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-1-[(E)-3-1H-imidazol-4 yl acryl]-4-oxyethyl group tetramethyleneimine-2-methane amide, ESI 454;
30) N-[2-fluoro-4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-1-[(E)-3-1H-imidazol-4 yl acryl]-4-hydroxyl pyrrolidine-2-methane amide, ESI 444;
31) N-[2-fluoro-4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-1-[(E)-3-1H-imidazol-4 yl acryl]-4-methoxyl group tetramethyleneimine-2-methane amide, ESI 458;
32) N-[2-fluoro-4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-1-[(E)-3-1H-imidazol-4 yl acryl]-4-oxyethyl group tetramethyleneimine-2-methane amide, ESI 472;
33) N-[2-fluoro-4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-1-[(E)-3-pyridin-3-yl acryl]-4-hydroxyl pyrrolidine-2-methane amide, ESI 455;
34) N-[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-1-[(E)-3-pyridin-3-yl acryl]-4-oxyethyl group tetramethyleneimine-2-methane amide, ESI 465;
35) N-[2-fluoro-4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-1-[(E)-3-pyridin-3-yl acryl]-4-methoxyl group tetramethyleneimine-2-methane amide, ESI 469;
36) N-[2-fluoro-4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-1-[(E)-3-pyridin-3-yl acryl]-4-oxyethyl group tetramethyleneimine-2-methane amide, ESI 483;
37) N-[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-1-[(E)-3-pyridin-3-yl acryl]-4-hydroxyl pyrrolidine-2-methane amide, ESI 437;
38) N-[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-1-[(E)-3-pyridin-3-yl acryl]-4-methoxyl group tetramethyleneimine-2-methane amide, ESI 451;
39) N-[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-1-[(E)-3-pyridin-4-yl acryl]-4-hydroxyl pyrrolidine-2-methane amide, ESI 437;
40) N-[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-1-[(E)-3-pyridin-4-yl acryl]-4-oxyethyl group tetramethyleneimine-2-methane amide, ESI 465;
41) N-[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-1-[(E)-3-1H-imidazol-4 yl acryl]-4-methoxyl group tetramethyleneimine-2-methane amide, ESI 440;
42) N-[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-1-[(E)-3-(4-bromothiophene-2-yl) acryl]-4-hydroxyl pyrrolidine-2-methane amide, ESI 521;
43) N-[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-1-[(E)-3-(4-bromothiophene-2-yl) acryl]-4-oxyethyl group tetramethyleneimine-2-methane amide, ESI 549;
44) N-[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-1-[(E)-3-(5-bromothiophene-2-yl) acryl]-4-hydroxyl pyrrolidine-2-methane amide, ESI 521;
45) N-[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-1-[(E)-3-(5-bromothiophene-2-yl) acryl]-4-oxyethyl group tetramethyleneimine-2-methane amide, ESI 549.
Embodiment 13-13
Similar to Example 7, obtain following compound:
1) N-(4-chloro-phenyl-)-(R)-1-[4-(2-oxo-piperidine-1-yl) benzoyl] tetramethyleneimine-2-methane amide, ESI 426;
2) N-(4-chloro-phenyl-)-(S)-1-[4-(2-oxo-piperidine-1-yl) benzoyl] tetramethyleneimine-2-methane amide, ESI 426;
3) 1-N-[(4-chloro-phenyl-)]-2-N-{[4-(5-oxo-1,4-oxa-azepine ring-4-in heptan yl) phenyl]-(R)-and tetramethyleneimine-1, the 2-diformamide, ESI 457;
4) 1-N-[(4-chloro-phenyl-)]-2-N-{[4-(5-oxo-1,4-oxa-azepine ring-4-in heptan yl) phenyl]-(2R, 4R)-4-hydroxyl pyrrolidine-1, the 2-diformamide, ESI 473;
5) 1-N-[(4-chloro-phenyl-)]-2-N-{[4-((S)-2-methyl-3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-4-hydroxyl pyrrolidine-1, the 2-diformamide, ESI 473;
6) 1-N-[(4-chloro-phenyl-)]-2-N-{[4-((S)-2-methyl-3-oxo morpholine-4-yl) phenyl]-(2R)-and tetramethyleneimine-1, the 2-diformamide, ESI 457;
7) 1-N-[(4-chloro-phenyl-)]-and 2-N-{[4-(R)-2-methyl-3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-4-hydroxyl pyrrolidine-1, the 2-diformamide, ESI 473;
8) 1-N-[(4-chloro-phenyl-)]-2-N-{[4-((R)-2-methyl-3-oxo morpholine-4-yl) phenyl]-(2R)-and tetramethyleneimine-1, the 2-diformamide, ESI 457;
9) 1-N-[(4-chloro-phenyl-)]-2-N-{[4-(3-oxo morpholine-4-yl)-2-Phenoxyphenyl]-(2R)-and tetramethyleneimine-1, the 2-diformamide, ESI 535;
10) 1-N-[(4-chloro-phenyl-)]-2-N-{[2-fluoro-4-((R)-2-methyl-3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-4-hydroxyl pyrrolidine-1, the 2-diformamide, ESI 491;
11) 1-N-[(4-chloro-phenyl-)]-3-N-{[4-(3-oxo morpholine-4-yl) phenyl] piperidines-1, the 3-diformamide, ESI 457;
12) 1-N-[(4-chloro-phenyl-)]-3-N-{[3-methyl-4-(3-oxo morpholine-4-yl) phenyl] piperidines-1, the 3-diformamide, ESI 471;
13) 1-N-[(4-chloro-phenyl-)]-2-N-{[4-(3-oxo-1,4-oxa-azepine ring-4-in heptan yl) phenyl]-(2R, 4R)-4-hydroxyl pyrrolidine-1, the 2-diformamide, ESI 473;
14) 1-N-[(4-chloro-phenyl-)]-2-N-{[2-methyl-4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-4-hydroxyl pyrrolidine-1, the 2-diformamide, ESI 473;
15) 1-N-[(4-chloro-phenyl-)]-2-N-{[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-4-hydroxyl pyrrolidine-1, the 2-diformamide, ESI 459;
16) 1-N-[(4-chloro-phenyl-)]-2-N-{[2-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-4-hydroxyl pyrrolidine-1, the 2-diformamide, ESI 459.
Embodiment 13-14
Similar to Example 7, obtain following compound:
N-[4-(3-oxo morpholine-4-yl) phenyl]-(rac)-and 2-[3-(4-chloro-phenyl-) urea groups] cyclopentane formamide, ESI 457
Figure A20048000935401231
N-[3-methyl-4-(3-oxo morpholine-4-yl) phenyl]-(rac)-and 2-[3-(4-chloro-phenyl-) urea groups] cyclopentane formamide, ESI 471.
Embodiment 13-15
Prepare the 1-N-[(4-chloro-phenyl-by method shown below)]-2-N-{[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-4-(2-methoxy ethoxy) tetramethyleneimine-1, the 2-diformamide, ESI 517:
14. midbody compound prepares embodiment
14.1 all following formula VI compounds (wherein R=H or methyl; N=3,4 or 5) all can be synthetic by following flow process.
Figure A20048000935401242
For example, synthetic 1-(4-amino-2-methyl phenyl) piperidines-2-ketone:
14.2 the Phenylpiperidine ketone unit of synthetic no methyl:
Figure A20048000935401252
For example 1-(4-amino-2-methyl phenyl) piperidines-2-ketone prepares by method as follows:
Figure A20048000935401253
14.3 1-(4-aminophenyl)-1H-pyrazine-2-ketone
Figure A20048000935401261
14.4 1-(4-amino-2,5-3,5-dimethylphenyl) piperidines-2-ketone
Figure A20048000935401262
14.5 1-(4-amino-3-aminomethyl phenyl) piperidines-2-ketone
Figure A20048000935401263
14.6 1-(5-aminopyridine-2-yl) piperidines-2-ketone
Figure A20048000935401271
14.7 1-(4-aminomethyl phenyl) piperidines-2-ketone
Figure A20048000935401272
14.8 2-(4-aminophenyl)-2-azabicyclic [2,2,2] suffering-3-ketone
14.9 1-(3-amino-6-ethylphenyl) pyrrolidin-2-one
Figure A20048000935401282
14.10 2-(4-amino-2-trifluoromethyl)-2-azabicyclic [2,2,2] suffering-3-ketone
14.11 1-(4-amino-3-chloro-phenyl-) pyrrolidin-2-one
Figure A20048000935401292
14.12 1-(4-amino-2-trifluoromethyl) piperidines-2-ketone
14.13 3-(4-amino-2-methyl phenyl)-1, the own ring-2-ketone of 3-oxa-azepine
Figure A20048000935401302
14.14 4-(4-aminophenyl) morpholine-3-ketone
Figure A20048000935401311
14.15 1-(4-aminophenyl) pyridin-2-ones
14.16 1-(4-amino-2-methyl phenyl) piperidines-2-ketone
Figure A20048000935401313
14.17 1-(4-aminophenyl)-1H-pyridine-4-ketone
Figure A20048000935401321
14.18 1-(4-aminophenyl)-4-tert-butoxycarbonyl-piperazine-2-ketone
Figure A20048000935401322
14.19 1-(3-aminophenyl) piperidines-2-ketone
Figure A20048000935401323
14.20 1-(4-aminophenyl)-2-hexanolactam
Figure A20048000935401331
14.21 1-(4-amino-3-fluorophenyl) piperidines-2-ketone
Figure A20048000935401332
14.22 1-(4-amino-2-fluorophenyl) piperidines-2-ketone
14.23 1-(4-amino-2-fluorophenyl)-2-hexanolactam
Figure A20048000935401341
14.24 4-(4-amino-2-fluorophenyl)-1,4-oxa-azepine ring-5-in heptan ketone
14.25 4-(4-amino-3-Phenoxyphenyl) morpholine-3-ketone
14.26 2-[3-(4-chloro-phenyl-) urea groups] cyclopentane-carboxylic acid
14.27 1-(4-chloro-phenyl-formamyl) piperidines-3-formic acid
Figure A20048000935401351
14.28 4-(4-aminophenyl)-1,4-oxa-azepine ring-3-in heptan ketone
Figure A20048000935401352
The TEMPO oxidation is undertaken by following literature method: L.DeLuca etc., J.Org.Chem.68,4999-5001 (2003).
Pharmacological datum
Avidity to acceptor
Table 1
Compound number F×a-IC 50[M] TF/FVIIa-IC 50[M]
″A1″ 1.8×10 -8 2.3×10 -8
″A2″ 2.7×10 -8
″AB1″ 1.8×10 -6 3.9×10 -6
″A6″ 3.7×10 -9
Following examples relate to pharmaceutical preparation:
Embodiment A: injection phial
With 2N hydrochloric acid redistilled water (3L) solution of 100g formula I activeconstituents and 5g Sodium phosphate dibasic is adjusted to pH 6.5, sterile filtration is transferred in the injection phial, freeze-drying under aseptic condition, and in sealed under aseptic conditions.Contain the 5mg activeconstituents in every injection phial.
Embodiment B: suppository
With the mixture melt of 20g formula I activeconstituents, 100g soybean lecithin and 1400g theobroma oil, in the impouring mould, cooling then.Every suppository contains the 20mg activeconstituents.
Embodiment C: solution
With 1g formula I activeconstituents, 9.38g NaH 2PO 42H 2O, 28.48gNa 2HPO 412H 2O and 0.1g benzalkonium chloride are dissolved in redistilled water 940ml and make solution.PH is transferred to 6.8, then this solution is added to 1L, pass through irradiation sterilization.This solution can be used as the eye drops form and uses.
Embodiment D: ointment
Under aseptic condition, 500mg formula I activeconstituents is mixed with 99.5g Vaseline.
Embodiment E: tablet
Mixture with 1kg formula I activeconstituents, 4kg lactose, 1.2kg yam starch, 0.2kg talcum powder and 0.1kg Magnesium Stearate is compressed into tablet according to a conventional method, and every tablet of tablet contains the 10mg activeconstituents.
Embodiment F: coated tablet
By the similar approach compressed tablets of embodiment E, use the coating material dressing of sucrose, yam starch, talcum powder, tragacanth and dyestuff subsequently according to a conventional method.
Embodiment G: capsule
2kg formula I activeconstituents is introduced in the hard gelatin capsule according to a conventional method, and every capsules contains the 20mg activeconstituents.
Embodiment H: ampoule
Make redistilled water (60L) the solution sterile filtration of 1kg formula I activeconstituents, be transferred in the ampoule, freeze-drying under aseptic condition, and in sealed under aseptic conditions.Contain the 10mg activeconstituents in every ampoule.

Claims (41)

1. formula I compound and pharmaceutically spendable derivative thereof, solvate, salt and the steric isomer that comprises its various mixed things:
Figure A2004800093540002C1
Wherein
R 1, R 2Independently of one another, respectively do for oneself H ,=O, Hal, A, ethynyl, OR 3, N (R 3) 2, NO 2, CN, N 3, COOR 3, CON (R 3) 2,-[C (R 4) 2] n-Ar ,-[C (R 4) 2] n-Het ,-[C (R 4) 2] n-cycloalkyl ,-OCOR 3,-OCON (R 3) 2, NR 3COA or NR 3SO 2A,
Perhaps, R 1With R 2Be 3-7 unit's carbocyclic ring or the heterocycle that dicyclo or volution connect together, have 0-3 N, O and/or S atom,
R 3Be H, A, H-C ≡ C-CH 2-, CH 3-C ≡ C-CH 2-,-CH 2-CH (OH)-CH 2OH ,-CH 2-CH (OH)-CH 2NH 2,-CH 2-CH (OH)-CH 2Het ' ,-[C (R 4) 2] n-Ar ' ,-[C (R 4) 2] n-Het ' ,-[C (R 4) 2] n-cycloalkyl ,-[C (R 4) 2] n-COOA or-[C (R 4) 2] nN (R 4) 2,
R 4Be H or A,
W is N, CR 3Or sp 2-hydridization carbon atom,
E is first saturated carbon ring of the 3-7 with 0-3 N, a 0-2 O and/or 0-2 S atom or heterocycle with W,
It can contain two keys,
D is monocycle or dicyclo aromatic carbon ring or the heterocycle with 0-4 N, O and/or S atom, and it does not replace or replaced by following group list or be polysubstituted: Hal, A, OR 3, N (R 3) 2, NO 2, CN, COOR 3Or CON (R 3) 2,
G is-[C (R 4) 2] n-,-[C (R 4) 2] nNR 3-,-[C (R 4) 2] nO-,-[C (R 4) 2] nS-or-[C (R 4)=C (R 4)] n-,
X is-[C (R 4) 2] nCONR 3[C (R 4) 2] n-,-[C (R 4) 2] nNR 3CO[C (R 4) 2] n-,-[C (R 4) 2] nNR 3[C (R 4) 2] n-,-[C (R 4) 2] nO[C (R 4) 2] n-,-[C (R 4) 2] nCO[C (R 4) 2] n-or-[C (R 4) 2] nCOO[C (R 4) 2] n-,
Y is alkylidene group, cycloalkylidene, Het-two bases or Ar-two bases,
T has the monocycle of 0-4 N, O and/or S atom or dicyclo, saturated or unsaturated carbocyclic or a heterocycle, and it is replaced by following group list or two replaces :=O ,=S ,=NR 3,=N-CN ,=N-NO 2,=NOR 3,=NCOR 3,=NCOOR 3Or=NOCOR 3, and can be replaced or three replacement: R by following group list replacement, two 3, Hal, A ,-[C (R 4) 2] n-Ar ,-[C (R 4) 2] n-Het ,-[C (R 4) 2] n-cycloalkyl, OR 3, N (R 3) 2, NO 2, CN, COOR 3, CON (R 3) 2, NR 3COA, NR 3CON (R 3) 2, NR 3SO 2A, COR 3, SO 2NR 3And/or S (O) nA,
A is non-side chain or the branched-chain alkyl with 1-10 carbon atom, one of them or two CH 2Group can by O or S atom and/or-the CH=CH-group is replaced, and/or 1-7 H atom can be replaced by F in addition,
Ar is phenyl, naphthyl or xenyl, and they do not replace separately or are replaced or three replacements by following group list replacement, two: Hal, A, OR 3, N (R 3) 2, NO 2, CN, COOR 3, CON (R 3) 2, NR 3COA, NR 3CON (R 3) 2, NR 3SO 2A, COR 3, SO 2N (R 3) 2, S (O) nA ,-[C (R 4) 2] n-COOR 3Or-O[C (R 4) 2] o-COOR 3,
Ar ' is phenyl, naphthyl or xenyl, and they do not replace separately or are replaced or three replacements by following group list replacement, two: Hal, A, OR 4, N (R 4) 2, NO 2, CN, COOR 4, CON (R 4) 2, NR 4COA, NR 4CON (R 4) 2, NR 4SO 2A, COR 4, SO 2N (R 4) 2, S (O) nA ,-[C (R 4) 2] n-COOR 4Or-O[C (R 4) 2] o-COOR 4,
Het has the monocycle of 1-4 N, O and/or S atom or dicyclo, saturated, a unsaturated or aromatic heterocycle, its can not replace or by following group list replace, two replace or three replacements: Hal, A ,-[C (R 4) 2] n-Ar ,-[C (R 4) 2] n-Het ' ,-[C (R 4) 2] n-cycloalkyl, OR 3, N (R 3) 2, NR 3CON (R 3) 2, NO 2, CN ,-[C (R 4) 2] n-COOR 3,-[C (R 4) 2] n-CON (R 3) 2, NR 3COA, NR 3SO 2A, COR 3, SO 2NR 3, S (O) mA and/or ketonic oxygen,
Het ' is for having the monocycle of 1-4 N, O and/or S atom or dicyclo, saturated, unsaturated or aromatic heterocycle, and it can not replace or by following group list replacement or two replacements: ketonic oxygen ,=S ,=N (R 4) 2, Hal, A, OR 4, N (R 4) 2, NO 2, CN, COOR 4, CON (R 4) 2, NR 4COA, NR 4CON (R 4) 2, NR 4SO 2A, COR 4, SO 2NR 4And/or S (O) nA,
Hal is F, Cl, Br or I,
N is 0,1 or 2,
O is 1,2 or 3.
2. the compound of claim 1 and pharmaceutically spendable derivative thereof, solvate, salt and the steric isomer that comprises its various mixed things, wherein
D is monocycle or dicyclo aromatic carbon ring or the heterocycle with 0-4 N, O and/or S atom, and it does not replace or is replaced or two replacements by the Hal list.
3. claim 1 or 2 compound and pharmaceutically spendable derivative thereof, solvate, salt and the steric isomer that comprises its various mixed things, wherein
D is phenyl, pyridyl, thienyl, furyl or imidazolyl, and they are replaced by the single replacement of Hal or two separately.
4. one or multinomial compound and pharmaceutically spendable derivative thereof, solvate, salt and the steric isomer that comprises its various mixed things among the claim 1-3, wherein
R 1, R 2Independently of one another, respectively do for oneself H ,=O, COOR 3, OH, OA, NH 2, have alkyl, a N of 1,2,3,4,5 or 6 carbon atom 3, ethynyl, vinyl, allyloxy, NHCOA, NHSO 2A, OCH 2COOA or OCH 2COOH.
5. one or multinomial compound and pharmaceutically spendable derivative thereof, solvate, salt and the steric isomer that comprises its various mixed things among the claim 1-4, wherein
G is (CH 2) n, (CH 2) nNH-,-CH=CH-or-CH=CH-CH=CH-.
6. one or multinomial compound and pharmaceutically spendable derivative thereof, solvate, salt and the steric isomer that comprises its various mixed things among the claim 1-5, wherein
X is-[C (R 4) 2] nCONR 3[C (R 4) 2] n-.
7. one or multinomial compound and pharmaceutically spendable derivative thereof, solvate, salt and the steric isomer that comprises its various mixed things among the claim 1-6, wherein
X is-CONH-or-CON (CH 2COOA)-.
8. one or multinomial compound and pharmaceutically spendable derivative thereof, solvate, salt and the steric isomer that comprises its various mixed things among the claim 1-7, wherein
Y is cycloalkylidene, Het-two bases or Ar-two bases.
9. the compound of claim 1-8 and pharmaceutically spendable derivative thereof, solvate, salt and the steric isomer that comprises its various mixed things, wherein
Y is not for replacing or replaced by following group list or Disubstituted pyridine two bases, piperidines two bases, cyclohexylidene or phenylene: A, OA, Cl, F, COOCH 3, COOH, phenoxy group or aminocarboxyl.
10. one or multinomial compound and pharmaceutically spendable derivative thereof, solvate, salt and the steric isomer that comprises its various mixed things among the claim 1-9, wherein
T is the monocycle with 1-2 N and/or O atom, saturated or unsaturated heterocycle, its quilt=O ,=S or=NH is single to be replaced or two replaces, and can be replaced or two replace by Hal, A and/or OA are single.
11. one or multinomial compound and pharmaceutically spendable derivative thereof, solvate, salt and the steric isomer that comprises its various mixed things among the claim 1-10, wherein
T is piperidines-1-base, tetramethyleneimine-1-base, pyridine-1-base, morpholine-4-base, piperazine-1-base, 1,3-oxazolidine-3-base, pyridazine-2-base, pyrazine-1-base, azepine ring-1-in heptan base, 2-azabicyclic [2.2.2] octane-2-base, imidazolidyl, thiazolyl or 1,4-oxa-azepine cyclic group in heptan, they separately by=O or=NH is single to be replaced or two replaces, and wherein each group also can be replaced or two replace by Hal, A and/or OA are single.
12. one or multinomial compound and pharmaceutically spendable derivative thereof, solvate, salt and the steric isomer that comprises its various mixed things among the claim 1-11, wherein
Ar is not for replacing or replaced by following group list or dibasic phenyl: Hal, A, OA, SO 2A, COOR 2, SO 2NH 2, CN, COOA, COOH or phenoxy group.
13. one or multinomial compound and pharmaceutically spendable derivative thereof, solvate, salt and the steric isomer that comprises its various mixed things among the claim 1-12, wherein
D is monocycle or dicyclo, aromatic carbon ring or the heterocycle with 0-4 N, O and/or S atom, and it does not replace or is replaced or two replacements by the Hal list,
R 1, R 2Independently of one another, respectively do for oneself H ,=O, COOR 3, OH, OA, NH 2, have alkyl, a N of 1,2,3,4,5 or 6 carbon atom 3, ethynyl, vinyl, allyloxy, NHCOA, NHSO 2A, OCH 2COOA or OCH 2COOH,
Perhaps, R 1And R 2Be the first carbocyclic ring of the 3-6 of volution connection together,
R 3Be H, A, phenyl, benzyl or [C (R 4) 2] nCOOA,
R 4Be H or A,
W is N, CR 3Or sp 2-hydridization carbon atom,
E is first saturated carbon ring of the 3-7 with 0-3 N, a 0-2 O and/or 0-2 S atom or heterocycle with W,
It can contain two keys,
G is (CH 2) n, (CH 2) nNH-,-CH=CH-or-CH=CH-CH=CH-,
X is-[C (R 4) 2] nCONR 3[C (R 4) 2] N-,
Y is cycloalkylidene, Het-two bases or Ar-two bases,
Ar is not for replacing or replaced by following group list or dibasic phenyl: Hal, A, OA, SO 2A, COOR 2, SO 2NH 2, CN, COOA, COOH or phenoxy group,
T is the monocycle with 1-2 N and/or O atom, saturated or unsaturated heterocycle, its quilt=O ,=S or=NH is single to be replaced or two replaces, and can be replaced or two replace by Hal, A and/or OA are single,
A is non-side chain or the branched-chain alkyl with 1-10 carbon atom, and wherein 1-7 H atom can be replaced by F,
Hal is F, Cl, Br or I,
N is 0,1 or 2.
14. one or multinomial compound and pharmaceutically spendable derivative thereof, solvate, salt and the steric isomer that comprises its various mixed things among the claim 1-13, wherein
D is phenyl, pyridyl, thienyl, furyl or imidazolyl, and they are replaced by the single replacement of Hal or two separately,
R 1, R 2Independently of one another, respectively do for oneself H ,=O, COOR 3, OH, OA, NH 2, have alkyl, a N of 1,2,3,4,5 or 6 carbon atom 3, ethynyl, vinyl, allyloxy, NHCOA, NHSO 2A, OCH 2COOA or OCH 2COOH,
Perhaps, R 1And R 2Be the first carbocyclic ring of the 3-6 of volution connection together,
R 3Be H, A or CH 2COOA,
R 4Be H or A,
W is N, CR 3Or sp 2-hydridization carbon atom,
E is first saturated carbon ring of the 3-7 with 0-3 N, a 0-2 O and/or 0-2 S atom or heterocycle with W,
It can contain two keys,
G is (CH 2) n, (CH 2) nNH-,-CH=CH-or-CH=CH-CH=CH-,
X is-CONH-or-CON (CH 2COOA)-,
Y is not for replacing or replaced by following group list or Disubstituted pyridine two bases, piperidines two bases, cyclohexylidene or phenylene: A, OA, Cl, F, COOCH 3, COOH, phenoxy group or aminocarboxyl,
T is piperidines-1-base, tetramethyleneimine-1-base, pyridine-1-base, morpholine-4-base, piperazine-1-base, 1,3-oxazolidine-3-base, pyridazine-2-base, pyrazine-1-base, azepine ring-1-in heptan base, 2-azabicyclic [2.2.2] octane-2-base, imidazolidyl, thiazolyl or 1,4-oxa-azepine cyclic group in heptan, they separately by=O or=NH is single to be replaced or two replaces, and wherein each group also can be replaced by Hal, A and/or the single replacement of OA or two
A is non-side chain or the branched-chain alkyl with 1-10 carbon atom, and wherein 1-7 H atom can be replaced by F,
Hal is F, Cl, Br or I,
N is 0,1 or 2.
15. one or multinomial compound and pharmaceutically spendable derivative thereof, solvate, salt and the steric isomer that comprises its various mixed things among the claim 1-14, wherein
D is phenyl, pyridyl or thienyl, and they are replaced by the single replacement of Hal or two separately,
R 1For H ,=O, COOR 3, OH, OA, NH 2, have alkyl, a N of 1,2,3,4,5 or 6 carbon atom 3, ethynyl, vinyl, allyloxy ,-OCOR 3, NHCOA or NHSO 2A,
R 2For H ,=O, OH, OA or have the alkyl of 1,2,3,4,5 or 6 carbon atom,
Perhaps, R 1And R 2Be the first carbocyclic ring of the 3-6 of volution connection together,
R 3Be H or A,
R 4Be H or A,
Figure A2004800093540008C1
Be tetramethyleneimine-1,2-two bases, piperidines-1,2-two Ji, oxazolidines-3,4-or 3,5-two bases, thiazolidine-3,4-two bases, 2,5-dihydro-1H-pyrroles-1,5-two bases, 1,3-dioxolane-4,5-two bases, 1, oneself encircles-3 3-oxa-azepine, 4-two bases, piperazine-1,4-two bases, tetrahydrofuran (THF)-3,4-two bases or azetidine-1,2-two bases
G is (CH 2) nOr (CH 2) nNH-,
X is CONH,
Y is for replacing or replaced by following group list or dibasic 1,3-or 1, and the 4-phenylene: methyl, trifluoromethyl, ethyl, propyl group, Cl or F,
T is piperidines-1-base, tetramethyleneimine-1-base, 1H-pyridine-1-base, morpholine-4-base, piperazine-1-base, 1,3-oxazolidine-3-base, 2H-pyridazine-2-base, pyrazine-1-base, azepine ring-1-in heptan base or 2-azabicyclic [2.2.2] octane-2-base, they are replaced or two replacements by the ketonic oxygen list separately
A is non-side chain or the branched-chain alkyl with 1-10 carbon atom, and wherein 1-7 H atom can be replaced by F,
Hal is F, Cl, Br or I,
N is 0,1 or 2.
16. one or multinomial compound and pharmaceutically spendable derivative thereof, solvate, salt and the steric isomer that comprises its various mixed things among the claim 1-15, wherein
D is phenyl, pyridyl or thienyl, and they are replaced by the single replacement of Hal or two separately,
R 1For H ,=O, COOR 3, OH, OA, NH 2, have alkyl, a N of 1,2,3,4,5 or 6 carbon atom 3, ethynyl, vinyl, allyloxy ,-OCOR 3, NHCOA or NHSO 2A,
R 2For H ,=O, OH, OA or have the alkyl of 1,2,3,4,5 or 6 carbon atom,
Perhaps, R 1And R 2Be the first carbocyclic ring of the 3-6 of volution connection together,
R 3Be H or A,
R 4Be H or A,
Figure A2004800093540009C1
Be tetramethyleneimine-1,2-two bases, piperidines-1,2-two Ji, oxazolidines-3,4-or 3,5-two bases, thiazolidine-3,4-two bases, 2,5-dihydro-1H-pyrroles-1,5-two bases, 1,3-dioxolane-4,5-two bases, 1, oneself encircles-3 3-oxa-azepine, 4-two bases, piperazine-1,4-two bases, tetrahydrofuran (THF)-3,4-two bases or azetidine-1,2-two bases
G is (CH 2) nOr (CH 2) nNH-,
X is CONH,
Y is for replacing or replaced by following group list or dibasic 1,3-or 1, and the 4-phenylene: methyl, trifluoromethyl, ethyl, propyl group, Cl or F,
T is for to be replaced or dibasic morpholine-4-base by the ketonic oxygen list,
A is non-side chain or the branched-chain alkyl with 1-10 carbon atom, and wherein 1-7 H atom can be replaced by F,
Hal is F, Cl, Br or I,
N is 0,1 or 2.
17. one or multinomial compound and pharmaceutically spendable derivative thereof, solvate, salt and the steric isomer that comprises its various mixed things among the claim 1-16, wherein
X is-[C (R 4) 2] nCONR 3[C (R 4) 2] n-or-[C (R 4) 2] nCO[C (R 4) 2] n-.
18. one or multinomial compound and pharmaceutically spendable derivative thereof, solvate, salt and the steric isomer that comprises its various mixed things among the claim 1-17, wherein
X is CONH or COCH 2
19. one or multinomial compound and pharmaceutically spendable derivative thereof, solvate, salt and the steric isomer that comprises its various mixed things among the claim 1-18, wherein
D is phenyl, pyridyl or thienyl, and they are replaced by the single replacement of Hal or two separately,
R 1For H ,=O, COOR 3, OH, OA, NH 2, have alkyl, a N of 1,2,3,4,5 or 6 carbon atom 3, ethynyl, vinyl, allyloxy ,-OCOR 3, NHCOA or NHSO 2A,
R 2For H ,=O, OH, OA or have the alkyl of 1,2,3,4,5 or 6 carbon atom,
Perhaps, R 1And R 2Be the first carbocyclic ring of the 3-6 of volution connection together,
R 3Be H or A,
R 4Be H or A,
Figure A2004800093540010C1
Be tetramethyleneimine-1,2-two bases, piperidines-1,2-two Ji, oxazolidines-3,4-or 3,5-two bases, thiazolidine-3,4--two bases, 2,5-dihydro-1H-pyrroles-1,5-two bases, 1,3-dioxolane-4,5-two bases, 1, oneself encircles-3 3-oxa-azepine, 4-two bases, piperazine-1,4-two bases, tetrahydrofuran (THF)-3,4-two bases or azetidine-1,2-two bases
G is (CH 2) nOr (CH 2) nNH-,
X is CONH or COCH 2,
Y is for replacing or replaced by following group list or dibasic 1,3-or 1, and the 4-phenylene: methyl, trifluoromethyl, ethyl, propyl group, Cl or F,
T is for to be replaced or dibasic morpholine-4-base by the ketonic oxygen list,
A is non-side chain or the branched-chain alkyl with 1-10 carbon atom, and wherein 1-7 H atom can be replaced by F,
Hal is F, Cl, Br or I,
N is 0,1 or 2.
20. one or multinomial compound and pharmaceutically spendable derivative thereof, solvate, salt and the steric isomer that comprises its various mixed things among the claim 1-19, wherein
D is phenyl, pyridyl or thienyl, and they are replaced by the single replacement of Hal or two separately,
R 1For H ,=O, COOR 3, OH, OA, NH 2, have alkyl, a N of 1,2,3,4,5 or 6 carbon atom 3, ethynyl, vinyl, allyloxy ,-OCOR 3, NHCOA, NHSO 2A, H-C ≡ C-CH 2-, CH 3-C ≡ C-CH 2-O-,-O-CH 2-CH (OH)-CH 2OH ,-O-CH 2-CH (OH)-CH 2NH 2Or-O-CH 2-CH (OH)-CH 2Het ',
R 2For H ,=O, OH, OA or have the alkyl of 1,2,3,4,5 or 6 carbon atom,
Perhaps, R 1And R 2Be the first carbocyclic ring of the 3-6 of volution connection together,
R 3Be H or A,
R 4Be H or A,
Figure A2004800093540011C1
Be tetramethyleneimine-1,2-two bases, piperidines-1,2-two Ji, oxazolidines-3,4-or 3,5-two bases, thiazolidine-3,4-two bases, 2,5-dihydro-1H-pyrroles-1,5-two bases, 1,3-dioxolane-4,5-two bases, 1, oneself encircles-3 3-oxa-azepine, 4-two bases, piperazine-1,4-two bases, tetrahydrofuran (THF)-3,4-two bases or azetidine-1,2-two bases
G is (CH 2) nOr (CH 2) nNH-,
X is CONH or COCH 2,
Y is for replacing or replaced by following group list or dibasic 1,3-or 1, and the 4-phenylene: methyl, trifluoromethyl, ethyl, propyl group, Cl or F,
T is for to be replaced or dibasic morpholine-4-base by the ketonic oxygen list,
Het ' is the first heterocycle of the saturated 3-6 with 1-3 N and/or O atom, and it can not replace or is replaced or two replacements by following group list: ketonic oxygen, Hal, A, OH, NH 2, NO 2, CN, COOA or CONH 2,
A is non-side chain or the branched-chain alkyl with 1-10 carbon atom, and wherein 1-7 H atom can be replaced by F,
Hal is F, Cl, Br or I,
N is 0,1 or 2.
21. one or multinomial compound and pharmaceutically spendable derivative thereof, solvate, salt and the steric isomer that comprises its various mixed things among the claim 1-20, wherein
D is phenyl, pyridyl or thienyl, and they are replaced by the single replacement of Hal or two separately,
R 1Be ethynyl, vinyl, allyloxy, CH 3-C ≡ C-CH 2-O-,-O-CH 2-CH (OH)-CH 2OH ,-O-CH 2-CH (OH)-CH 2NH 2Or-O-CH 2-CH (OH)-CH 2Het ',
R 2Be H or OH,
Perhaps, R 1And R 2Be the first carbocyclic ring of the 3-6 of volution connection together,
R 3Be H or A,
R 4Be H or A,
Figure A2004800093540012C1
Be tetramethyleneimine-1,2-two bases, piperidines-1,2-two Ji, oxazolidines-3,4-or 3,5-two bases, thiazolidine-3,4-two bases, 2,5-dihydro-1H-pyrroles-1,5-two bases, 1,3-dioxolane-4,5-two bases, 1, oneself encircles-3 3-oxa-azepine, 4-two bases, piperazine-1,4-two bases, tetrahydrofuran (THF)-3,4-two bases or azetidine-1,2-two bases
G is (CH 2) nOr (CH 2) nNH-,
X is CONH, CO, COO or COCH 2,
Y is for replacing or replaced by following group list or dibasic 1,3-or 1, and the 4-phenylene: methyl, trifluoromethyl, ethyl, propyl group, Cl or F,
T is piperidines-1-base, tetramethyleneimine-1-base, 1H-pyridine-1-base, morpholine-4-base, piperazine-1-base, 1,3-oxazolidine-3-base, 2H-pyridazine-2-base, pyrazine-1-base, azepine ring-1-in heptan base or 2-azabicyclic [2.2.2] octane-2-base, they are replaced by ketonic oxygen or the single replacement of OA or two separately
Het ' is the first heterocycle of the saturated 3-6 with 1-3 N and/or O atom, and it can not replace or is replaced or two replacements by following group list: ketonic oxygen, Hal, A, OH, NH 2, NO 2, CN, COOA or CONH 2,
A is non-side chain or the branched-chain alkyl with 1-10 carbon atom, and wherein 1-7 H atom can be replaced by F,
Hal is F, Cl, Br or I,
N is 0,1 or 2.
22. one or multinomial compound and pharmaceutically spendable derivative thereof, solvate, salt and the steric isomer that comprises its various mixed things among the claim 1-21, wherein
D is phenyl, pyridyl, thienyl, furyl or imidazolyl, and they are replaced by the single replacement of Hal or two separately,
R 1For H ,=O, COOR 3, OH, OA, NH 2, have alkyl, a N of 1,2,3,4,5 or 6 carbon atom 3, ethynyl, vinyl, allyloxy, NHCOA, NHSO 2A, OCH 2COOA or OCH 2COOH,
R 2For H ,=O, OH, OA or have the alkyl of 1,2,3,4,5 or 6 carbon atom,
Perhaps, R 1And R 2Be the first carbocyclic ring of the 3-6 of volution connection together,
R 3Be H or A,
R 4Be H or A,
Figure A2004800093540014C1
Be tetramethyleneimine-1,2-two bases, piperidines-1,2-two Ji, oxazolidines-3,4-or 3,5-two bases, thiazolidine-3,4-two bases, 2,5-dihydro-1H-pyrroles-1,5-two bases, 1,3-dioxolane-4,5-two bases, 1, oneself encircles-3 3-oxa-azepine, 4-two bases, piperazine-1,4-two bases, tetrahydrofuran (THF)-3,4-two bases or azetidine-1,2-two bases
G is (CH 2) n, (CH 2) nNH-,-CH=CH-or-CH=CH-CH=CH-,
X is CONH, COCH 2Or-CON (CH 2COOA)-,
Y is not for replacing or replaced by following group list or Disubstituted pyridine two bases, piperidines two bases, cyclohexylidene or phenylene: A, OA, Cl, F, COOCH 3, COOH, phenoxy group or aminocarboxyl,
T is for to be replaced or dibasic morpholine-4-base by the ketonic oxygen list,
A is non-side chain or the branched-chain alkyl with 1-10 carbon atom, and wherein 1-7 H atom can be replaced by F,
Hal is F, Cl, Br or I,
N is 0,1 or 2.
23. the compound of claim 1 and pharmaceutically spendable derivative thereof, solvate, salt and the steric isomer that comprises its various mixed things, described compound is selected from:
1) 1-N-[(4-chloro-phenyl-)]-2-N-{[4-(3-oxo morpholine-4-yl) phenyl]-(R)-and tetramethyleneimine-1, the 2-diformamide,
2) 1-N-[(4-chloro-phenyl-)]-2-N-{[3-methyl-4-(3-oxo morpholine-4-yl) phenyl]-(R)-and tetramethyleneimine-1, the 2-diformamide,
3) 1-N-[(4-chloro-phenyl-)]-2-N-{[3-fluoro-4-(3-oxo morpholine-4-yl) phenyl]-(R)-and tetramethyleneimine-1, the 2-diformamide,
4) 1-N-[(4-chloro-phenyl-)]-2-N-{[2-fluoro-4-(3-oxo morpholine-4-yl) phenyl]-(R)-and tetramethyleneimine-1, the 2-diformamide,
5) 1-N-[(4-chloro-phenyl-)]-2-N-{[3-trifluoromethyl-4-(3-oxo morpholine-4-yl) phenyl]-(R)-and tetramethyleneimine-1, the 2-diformamide,
6) 1-N-[(4-chloro-phenyl-)]-2-N-{[3-methyl-4-(3-oxo morpholine-4-yl) phenyl]-(R)-and piperidines-1, the 2-diformamide,
7) 1-N-[(4-chloro-phenyl-)]-2-N-{[4-(2-oxo-2H-pyridine-1-yl) phenyl]-(R)-and tetramethyleneimine-1, the 2-diformamide,
8) 1-N-[(4-chloro-phenyl-)]-2-N-{[4-(2-oxo-2H-pyrazine-1-yl) phenyl]-(R)-and tetramethyleneimine-1, the 2-diformamide,
9) 1-N-[(4-chloro-phenyl-)]-2-N-{[4-(3-oxo morpholine-4-yl) phenyl]-(R)-2, and 5-pyrrolin-1, the 2-diformamide,
10) N-[4-(3-oxo morpholine-4-yl) phenyl]-(R)-1-(5-chlorothiophene-2-carbonyl) tetramethyleneimine-2-methane amide,
11) N-[3-methyl-4-(3-oxo morpholine-4-yl) phenyl]-(R)-1-(5-chlorothiophene-2-carbonyl) tetramethyleneimine-2-methane amide,
12) 3-N-[(4-chloro-phenyl-)]-4-N-{[4-(3-oxo morpholine-4-yl) phenyl]-(R)-oxazolidines-3, the 4-diformamide,
13) 3-N-[(4-chloro-phenyl-)]-4-N-{[3-methyl-4-(3-oxo morpholine-4-yl) phenyl]-(R)-oxazolidines-3, the 4-diformamide,
14) 3-N-[(4-chloro-phenyl-)]-4-N-{[4-(3-oxo morpholine-4-yl) phenyl]-(4R, 5S)-5-Jia Ji oxazolidine-3, the 4-diformamide,
15) 3-N-[(4-chloro-phenyl-)-4-N-{[3-methyl-4-(3-oxo morpholine-4-yl) phenyl]-(4R, 5S)-5-Jia Ji oxazolidine-3, the 4-diformamide,
16) 3-N-[(4-chloro-phenyl-)]-4-N-{[4-(2-oxo-2H-pyridine-1-yl) phenyl]-(R)-oxazolidines-3, the 4-diformamide,
17) 3-N-[(4-chloro-phenyl-)]-4-N-{[4-(2-oxo-2H-pyridine-1-yl) phenyl]-(4R, 5S)-5-Jia Ji oxazolidine-3, the 4-diformamide,
18) 3-N-[(4-chloro-phenyl-)]-4-N-{[3-fluoro-4-(3-oxo morpholine-4-yl) phenyl]-(4R, 5S)-5-Jia Ji oxazolidine-3, the 4-diformamide,
19) 3-N-[(4-chloro-phenyl-)]-4-N-{[3-chloro-4-(3-oxo morpholine-4-yl) phenyl]-(4R, 5S)-5-Jia Ji oxazolidine-3, the 4-diformamide,
20) 3-N-[(4-chloro-phenyl-)]-4-N-{[3-methyl-4-(3-oxo morpholine-4-yl) phenyl]-(4R, 5R)-5-Jia Ji oxazolidine-3, the 4-diformamide,
21) 3-N-[(4-chloro-phenyl-)]-4-N-{[4-(2-oxo-2H-pyrazine-1-yl) phenyl]-(4R, 5S)-5-Jia Ji oxazolidine-3, the 4-diformamide,
22) 3-N-[(4-chloro-phenyl-)]-4-N-{[4-(2-oxo-2H-pyrazine-1-yl) phenyl]-(R)-oxazolidines-3, the 4-diformamide,
23) 3-N-[(4-chloro-phenyl-)]-4-N-{[3-chloro-4-(2-oxo-2H-pyridine-1-yl) phenyl]-(R)-oxazolidines-3, the 4-diformamide,
24) 3-N-[(4-chloro-phenyl-)]-4-N-{[4-(3-oxo morpholine-4-yl) phenyl]-(S)-and thiazolidine-3, the 4-diformamide,
25) 3-N-[(4-chloro-phenyl-)]-4-N-{[4-(3-oxo morpholine-4-yl) phenyl]-(S)-1,1-dioxo-1 λ 6-thiazolidine-3, the 4-diformamide,
26) 3-N-[(4-chloro-phenyl-)]-4-N-{[3-methyl-4-(3-oxo morpholine-4-yl) phenyl]-(S)-and thiazolidine-3, the 4-diformamide,
27) 3-N-[(4-chloro-phenyl-)]-4-N-{[3-methyl-4-(3-oxo morpholine-4-yl) phenyl]-(S)-1,1-dioxo-1 λ 6-thiazolidine-3, the 4-diformamide,
28) 3-N-[(4-chloro-phenyl-)]-4-N-{[4-(2-oxo-2H-pyridine-1-yl) phenyl]-(R)-and thiazolidine-3, the 4-diformamide,
29) N-[4-(3-oxo morpholine-4-yl) phenyl]-3-(5-chlorothiophene-2-carbonyl) oxazolidine-5-methane amide,
30) N-[3-methyl-4-(3-oxo morpholine-4-yl) phenyl]-3-(5-chlorothiophene-2-carbonyl) oxazolidine-5-methane amide,
31) N-[4-(2-oxo-2H-pyridine-1-yl) phenyl]-3-(5-chlorothiophene-2-carbonyl) oxazolidine-5-methane amide,
32) 1-N-[(5-chloropyridine-2-yl)]-2-N-{[4-(2-oxo-2H-pyridine-1-yl) phenyl]-(2R, 4R)-4-hydroxyl pyrrolidine-1, the 2-diformamide,
33) 1-N-[(5-chloropyridine-2-yl)]-2-N-{[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-4-hydroxyl pyrrolidine-1, the 2-diformamide,
34) 1-N-[(5-chloropyridine-2-yl)]-2-N-{[4-(2-oxo-2H-pyrazine-1-yl) phenyl]-(2R, 4R)-4-hydroxyl pyrrolidine-1, the 2-diformamide,
35) 1-N-[(5-chloropyridine-2-yl)]-2-N-{[3-fluoro-4-(2-oxo-2H-pyridine-1-yl) phenyl]-(2R, 4R)-4-hydroxyl pyrrolidine-1, the 2-diformamide,
36) 1-N-[(5-chloropyridine-2-yl)]-2-N-{[4-(2-oxo-2H-pyridine-1-yl) phenyl]-(R)-4, and 4-dimethoxy tetramethyleneimine-1, the 2-diformamide,
37) 1-N-[(5-chloropyridine-2-yl)]-2-N-{[4-(3-oxo morpholine-4-yl) phenyl]-(R)-4, and 4-dimethoxy tetramethyleneimine-1, the 2-diformamide,
38) 1-N-[(4-chloro-phenyl-)]-2-N-{[4-(2-oxo-2H-pyridine-1-yl) phenyl]-(R)-4, and 4-dimethoxy tetramethyleneimine-1, the 2-diformamide,
39) 1-N-[(4-chloro-phenyl-)]-2-N-{[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-4-hydroxyl pyrrolidine-1, the 2-diformamide,
40) 1-N-[(4-chloro-phenyl-)]-2-N-{[3-methyl-4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-4-hydroxyl pyrrolidine-1, the 2-diformamide,
41) 1-N-[(4-chloro-phenyl-)]-2-N-{[4-(2-oxo-2H-pyridine-1-yl) phenyl]-(2R, 4R)-4-hydroxyl pyrrolidine-1, the 2-diformamide,
42) 1-N-[(4-chloro-phenyl-)]-2-N-{[2-fluoro-4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-4-hydroxyl pyrrolidine-1, the 2-diformamide,
43) 1-N-[(4-chloro-phenyl-)]-2-N-{[4-(2-Oxopyrazine-1-yl) phenyl]-(2R, 4R)-4-hydroxyl pyrrolidine-1, the 2-diformamide,
44) 1-N-[(4-chloro-phenyl-)]-2-N-{[3-fluoro-4-(2-oxo-2H-pyridine-1-yl) phenyl]-(2R, 4R)-4-hydroxyl pyrrolidine-1, the 2-diformamide,
45) 1-N-[(4-chloro-phenyl-)]-2-N-{[3-fluoro-4-(3-oxo morpholine-4-yl) phenyl]-(2R, 3R)-3-hydroxyl pyrrolidine-1, the 2-diformamide,
46) 1-N-[(4-chloro-phenyl-)]-2-N-{[3-fluoro-4-(3-oxo morpholine-4-yl) phenyl]-(2R, 3S)-3-hydroxyl pyrrolidine-1, the 2-diformamide,
47) 1-N-[(4-chloro-phenyl-)]-2-N-{[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4S)-4-hydroxyl pyrrolidine-1, the 2-diformamide,
48) 1-N-[(4-chloro-phenyl-)]-2-N-{[4-(3-oxo morpholine-4-yl) phenyl]-(2S, 4R)-4-hydroxyl pyrrolidine-1, the 2-diformamide,
49) 1-N-[(4-chloro-phenyl-)]-2-N-{[4-(3-oxo morpholine-4-yl) phenyl]-3,4-dihydroxy pyrrolidine-1, the 2-diformamide,
50) 1-N-[(4-chloro-phenyl-)]-2-N-{[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4S)-4-azido-tetramethyleneimine-1, the 2-diformamide,
51) 1-N-[(4-chloro-phenyl-)]-2-N-{[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4S)-4-amino-pyrrolidine-1, the 2-diformamide,
52) 1-N-[(4-chloro-phenyl-)]-2-N-{[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-4-azido-tetramethyleneimine-1, the 2-diformamide,
53) 1-N-[(4-chloro-phenyl-)]-2-N-{[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-4-amino-pyrrolidine-1, the 2-diformamide,
54) 1-N-[(4-chloro-phenyl-)]-2-N-{[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4S)-4-kharophen tetramethyleneimine-1, the 2-diformamide,
55) 1-N-[(4-chloro-phenyl-)]-2-N-{[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-4-kharophen tetramethyleneimine-1, the 2-diformamide,
56) 1-N-[(4-chloro-phenyl-)]-2-N-{[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4S)-4-methylsulfonyl amino-pyrrolidine-1, the 2-diformamide,
57) 1-N-[(4-chloro-phenyl-)]-2-N-{[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-4-methylsulfonyl amino-pyrrolidine-1, the 2-diformamide,
58) 1-N-[(4-chloro-phenyl-)]-2-N-{[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-4-methoxyl group tetramethyleneimine-1, the 2-diformamide,
59) 1-N-[(4-chloro-phenyl-)]-2-N-{[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-4-oxyethyl group tetramethyleneimine-1, the 2-diformamide,
60) 1-N-[(4-chloro-phenyl-)]-2-N-{[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-4-propoxy-tetramethyleneimine-1, the 2-diformamide,
61) 1-N-[(4-chloro-phenyl-)]-2-N-{[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-4-allyloxy tetramethyleneimine-1, the 2-diformamide,
62) isopropylformic acid (3R, 5R)-1-(4-chloro-phenyl-formamyl)-5-[4-(3-oxo morpholine-4-yl) phenyl amino formyl radical] tetramethyleneimine-3-base ester,
63) propionic acid (3R, 5R)-1-(4-chloro-phenyl-formamyl)-5-[4-(3-oxo morpholine-4-yl) phenyl amino formyl radical] tetramethyleneimine-3-base ester,
64) acetate (3R, 5R)-1-(4-chloro-phenyl-formamyl)-5-[4-(3-oxo morpholine-4-yl) phenyl amino formyl radical] tetramethyleneimine-3-base ester,
65) 4-N-[(4-chloro-phenyl-)]-5-N-{[4-(3-oxo morpholine-4-yl) phenyl]-1,3-dioxolane-4, the 5-diformamide,
66) 4-N-[(4-chloro-phenyl-)]-5-N-{[3-methyl-4-(3-oxo morpholine-4-yl) phenyl]-1,3-dioxolane-4, the 5-diformamide,
67) 4-N-[(4-chloro-phenyl-)]-5-N-{[4-(2-oxo-2H-pyridine-1-yl) phenyl]-1,3-dioxolane-4, the 5-diformamide,
68) 4-N-[(4-chloro-phenyl-)]-5-N-{[4-(3-oxo morpholine-4-yl) phenyl]-1,3-dioxolane-2,2-dimethyl-4, the 5-diformamide,
69) 4-N-[(4-chloro-phenyl-)]-5-N-{[3-methyl-4-(3-oxo morpholine-4-yl) phenyl]-1,3-dioxolane-2,2-dimethyl-4, the 5-diformamide,
70) 4-N-[(4-chloro-phenyl-)]-5-N-{[4-(2-oxo-1H-pyridine-1-yl) phenyl]-1,3-dioxolane-2,2-dimethyl-4, the 5-diformamide,
71) 1-N-[4-chloro-phenyl-)]-2-N-{[4-(3-oxo morpholine-4-yl) phenyl]-1-BOC-piperazine-1, the 2-diformamide,
72) 1-N-[4-chloro-phenyl-)]-2-N-{[4-(3-oxo morpholine-4-yl) phenyl]-piperazine-1, the 2-diformamide,
73) 1-N-[4-chloro-phenyl-)]-2-N-{[4-(3-oxo morpholine-4-yl) phenyl]-1, oneself encircles-3 3-oxa-azepine, the 4-diformamide,
74) 1-N-[(4-chloro-phenyl-)]-2-N-{[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4S)-4-ethynyl-4-hydroxyl pyrrolidine-1, the 2-diformamide,
75) 6-N-[(4-chloro-phenyl-)]-7-N-{[4-(3-oxo morpholine-4-yl) phenyl]-4-oxa--6-azaspiro [2.4] heptane-6, the 7-diformamide,
76) 1-N-[(6-chloropyridine-3-yl)]-2-N-{[4-(2-oxo-2H-pyridine-1-yl) phenyl]-(2R, 4R)-4-hydroxyl pyrrolidine-1, the 2-diformamide,
77) 1-N-[(6-chloropyridine-3-yl)]-2-N-{[4-(2-oxo-2H-pyrazine-1-yl) phenyl]-(2R, 4R)-4-hydroxyl pyrrolidine-1, the 2-diformamide,
78) 1-N-[(4-chloro-phenyl-)]-2-N-{[3-methyl-4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4S)-4-kharophen tetramethyleneimine-1, the 2-diformamide,
79) 1-N-[(4-chloro-phenyl-)]-2-N-{[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4S)-4-fourth sulfonamido tetramethyleneimine-1, the 2-diformamide,
80) 1-N-[(4-chloro-phenyl-)]-2-N-{[4-(3-oxo morpholine-4-yl) phenyl]-(R)-and 4-oxo-pyrrolidine-1, the 2-diformamide,
81) 1-N-[(4-chloro-phenyl-)]-2-N-{[3-methyl-4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4S)-4-amino-pyrrolidine-1, the 2-diformamide,
82) 1-N-[(4-chloro-phenyl-)]-2-N-{[3-methyl-4-(3-oxo morpholine-4-yl) phenyl]-(S)-and tetramethyleneimine-1, the 2-diformamide,
83) 1-N-[(4-chloro-phenyl-)]-2-N-{[2-fluoro-4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-4-hydroxyl pyrrolidine-1, the 2-diformamide,
84) N-[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-1-[2-(4-chloro-phenyl-) ethanoyl]-4-hydroxyl pyrrolidine-2-methane amide,
85) N-[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-1-(4-chlorobenzene formacyl)-4-hydroxyl pyrrolidine-2-methane amide,
86) 1-N-[(4-chloro-phenyl-)]-2-N-{[3-methyl-4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-4-methoxyl group tetramethyleneimine-1, the 2-diformamide,
87) 1-N-[(4-chloro-phenyl-)]-2-N-{[4-(2-oxo-2H-pyridine-1-yl) phenyl]-(2R, 4R)-4-methoxyl group tetramethyleneimine-1, the 2-diformamide,
88) 1-N-[(4-chloro-phenyl-)]-2-N-{[2-fluoro-4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-4-methoxyl group tetramethyleneimine-1, the 2-diformamide,
89) 1-N-[(4-chloro-phenyl-)]-2-N-{[4-(2-oxo-2H-pyrazine-1-yl) phenyl]-(2R, 4R)-4-methoxyl group tetramethyleneimine-1, the 2-diformamide,
90) 1-N-[(4-chloro-phenyl-)]-2-N-{[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4S)-4-(2-methylpropionyl amino) tetramethyleneimine-1, the 2-diformamide,
91) N-[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-1-(1-1H-indol-3-yl-formyl radical)-4-hydroxyl pyrrolidine-2-methane amide,
92) N-[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-1-(1-1H-indoles-6-base-formyl radical)-4-hydroxyl pyrrolidine-2-methane amide,
93) 1-N-[(4-chloro-phenyl-)]-2-N-{[3-methyl-4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-4-oxyethyl group tetramethyleneimine-1, the 2-diformamide,
94) 1-N-[(4-chloro-phenyl-)]-2-N-{[4-(2-oxo-1H-pyridine-1-yl) phenyl]-(2R, 4R)-4-oxyethyl group tetramethyleneimine-1, the 2-diformamide,
95) 1-N-[(4-chloro-phenyl-)]-2-N-{[2-fluoro-4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-4-oxyethyl group tetramethyleneimine-1, the 2-diformamide,
96) 1-N-[(4-chloro-phenyl-)]-2-N-{[4-(2-oxo-1H-pyridine-1-yl) phenyl]-(2R, 4S)-4-ethynyl-4-hydroxyl pyrrolidine-1, the 2-diformamide,
97) 1-N-[(4-chloro-phenyl-)]-2-N-{[4-(2-oxo-2H-pyrazine-1-yl) phenyl]-(2R, 4S)-4-ethynyl-4-hydroxyl pyrrolidine-1, the 2-diformamide,
98) 1-N-[(4-chloro-phenyl-)]-2-N-{[4-(2-oxo-2H-pyridine-1-yl) phenyl]-4,4-two fluoro-(R)-tetramethyleneimine-1, the 2-diformamide,
99) 1-N-[(4-chloro-phenyl-)]-2-N-{[2-fluoro-4-(2-oxo-2H-pyridine-1-yl) phenyl]-(2R, 4R)-4-methoxyl group tetramethyleneimine-1, the 2-diformamide,
100) 1-N-[(4-chloro-phenyl-)]-2-N-{[2-fluoro-4-(2-oxo-2H-pyridine-1-yl) phenyl]-(R)-and tetramethyleneimine-1, the 2-diformamide,
101) 1-N-[(4-chloro-phenyl-)]-2-N-{[2-fluoro-4-(2-oxo-2H-pyridine-1-yl) phenyl]-(2R, 4R)-4-hydroxyl pyrrolidine-1, the 2-diformamide,
102) 2-N-[(4-chloro-phenyl-)]-1-N-{[4-(3-oxo morpholine-4-yl) phenyl]-(R)-and tetramethyleneimine-1, the 2-diformamide,
103) 2-N-[(4-chloro-phenyl-)]-1-N-{[4-(3-oxo morpholine-4-yl) phenyl]-(S)-and tetramethyleneimine-1, the 2-diformamide,
104) 1-N-[(4-chloro-phenyl-)]-2-N-{[4-(2-oxo-3-methoxyl group-2H-pyridine-1-yl) phenyl]-(2R, 4R)-4-hydroxyl pyrrolidine-1, the 2-diformamide,
105) 1-N-[(4-chloro-phenyl-)]-2-N-{[4-(2-oxo-3-methoxyl group-2H-pyridine-1-yl) phenyl]-(R)-and tetramethyleneimine-1, the 2-diformamide,
106) N-(4-chloro-phenyl-)-(R)-1-{2-[4-(3-oxo morpholine-4-yl) phenyl] ethanoyl } tetramethyleneimine-2-methane amide,
107) N-(4-chloro-phenyl-)-(S)-1-{2-[4-(3-oxo morpholine-4-yl) phenyl] ethanoyl } tetramethyleneimine-2-methane amide,
108) N-(4-chloro-phenyl-)-(2R, 4R)-1-{2-[4-(3-oxo morpholine-4-yl) phenyl] ethanoyl-4-methoxyl group tetramethyleneimine-2-methane amide,
109) N-(4-chloro-phenyl-)-(2R, 4S)-1-{2-[4-(3-oxo morpholine-4-yl) phenyl] ethanoyl-4-methoxyl group tetramethyleneimine-2-methane amide,
110) N-(4-chloro-phenyl-)-(2S, 4R)-1-{2-[4-(3-oxo morpholine-4-yl) phenyl] ethanoyl-4-methoxyl group tetramethyleneimine-2-methane amide,
111) N-(4-chloro-phenyl-)-(S)-1-{2-[4-(2-oxo-1H-pyridine-1-yl) phenyl] ethanoyl } tetramethyleneimine-2-methane amide,
112) N-(4-chloro-phenyl-)-(S)-1-{2-[4-(2-oxo-pyrrolidine-1-yl) phenyl] ethanoyl } tetramethyleneimine-2-methane amide,
113) N-(4-chloro-phenyl-)-(R)-1-{2-[4-(2-oxo-pyrrolidine-1-yl) phenyl] ethanoyl } tetramethyleneimine-2-methane amide,
114) N-(4-chloro-phenyl-)-(R)-1-[4-(2-oxo-piperidine-1-yl) benzoyl] tetramethyleneimine-2-methane amide,
115) N-(4-chloro-phenyl-)-(R)-1-[4-(2-oxo-piperidine-1-yl) phenyloxycarbonyl] tetramethyleneimine-2-methane amide,
116) 1-N-[(4-chloro-phenyl-)]-2-N-{[4-(2-oxo-2H-pyrazine-1-yl) phenyl]-(2R, 4R)-4-oxyethyl group tetramethyleneimine-1, the 2-diformamide,
117) 1-N-[(4-chloro-phenyl-)]-2-N-{[3-fluoro-4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-4-oxyethyl group tetramethyleneimine-1, the 2-diformamide,
118) 1-N-[(4-chloro-phenyl-)]-2-N-{[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-4-(Propargyl oxygen base) tetramethyleneimine-1, the 2-diformamide,
119) 1-N-[(4-chloro-phenyl-)]-2-N-{[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-4-(fourth-2-alkynyloxy base) tetramethyleneimine-1, the 2-diformamide,
120) 1-N-[(4-chloro-phenyl-)]-2-N-{[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-4-(2,3-dihydroxyl propoxy-) tetramethyleneimine-1, the 2-diformamide,
121) 1-N-[(4-chloro-phenyl-)]-2-N-{[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-4-(2-hydroxyl-3-tetramethyleneimine-1-base propoxy-) tetramethyleneimine-1, the 2-diformamide,
122) 1-N-[(4-chloro-phenyl-)]-2-N-{[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-4-(2-Yang Dai oxazolidine-5-ylmethoxy) tetramethyleneimine-1, the 2-diformamide,
123) 1-N-[(4-chloro-phenyl-)]-2-N-{[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-4-(3-amino-2-hydroxyl propoxy-) tetramethyleneimine-1, the 2-diformamide,
124) 1-N-[(4-chloro-phenyl-)]-2-N-{[4-(2-oxo-1H-pyrazine-1-yl) phenyl]-(R)-2, and 5-pyrrolin-1, the 2-diformamide,
125) 1-N-[(4-chloro-phenyl-)]-2-N-{[4-(2-oxo-1H-pyridine-1-yl) phenyl]-(R)-2, and 5-pyrrolin-1, the 2-diformamide,
126) 1-N-[(4-chloro-phenyl-)]-2-N-{[3-fluoro-4-(3-oxo morpholine-4-yl) phenyl]-(R)-2, and 5-pyrrolin-1, the 2-diformamide,
127) 1-N-[(4-chloro-phenyl-)]-2-N-{[2-fluoro-4-(3-oxo morpholine-4-yl) phenyl]-(R)-2, and 5-pyrrolin-1, the 2-diformamide,
128) 1-N-[(4-chloro-phenyl-)]-2-N-{[4-(3-oxo morpholine-4-yl) phenyl]-(2S, 3S)-3-hydroxyl pyrrolidine-1, the 2-diformamide,
129) 1-N-[(4-chloro-phenyl-)]-2-N-{[4-(3-oxo morpholine-4-yl) phenyl]-(2S, 4S)-4-hydroxyl pyrrolidine-1, the 2-diformamide,
130) 1-N-[(4-chloro-phenyl-)]-2-N-{[2-methoxycarbonyl-4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-3-hydroxyl pyrrolidine-1, the 2-diformamide,
131) 1-N-[(4-chloro-phenyl-)]-2-N-{[2-carboxyl-4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-3-hydroxyl pyrrolidine-1, the 2-diformamide,
132) 1-N-[(4-chloro-phenyl-)]-2-N-{[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 3S, 4R)-3, and 4-dihydroxy pyrrolidine-1, the 2-diformamide,
133) 1-N-[(4-chloro-phenyl-)]-2-N-{[2-fluoro-4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-4-allyloxy tetramethyleneimine-1, the 2-diformamide,
134) 1-N-[(4-chloro-phenyl-)]-2-N-{[2-fluoro-4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-4-(Propargyl oxygen base) tetramethyleneimine-1, the 2-diformamide,
135) 1-N-[(4-chloro-phenyl-)]-2-N-{[2-fluoro-4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4S)-4-(Propargyl oxygen base) tetramethyleneimine-1, the 2-diformamide,
136) 1-N-[(4-chloro-phenyl-)]-2-N-{[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-4-(methoxycarbonyl methoxyl group) tetramethyleneimine-1, the 2-diformamide,
137) 1-N-[(4-chloro-phenyl-)]-2-N-{[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-4-(carboxyl methoxyl group) tetramethyleneimine-1, the 2-diformamide,
138) 1-N-[(4-bromophenyl)]-2-N-{[2-fluoro-4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-4-methoxyl group tetramethyleneimine-1, the 2-diformamide,
139) 1-N-[(4-chloro-phenyl-)]-2-N-{[2-fluoro-4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-4-(2,3-dihydroxyl propoxy-) tetramethyleneimine-1, the 2-diformamide,
140) 1-N-[(4-chloro-phenyl-)]-2-N-{N-methoxycarbonyl methyl-N '-[4-(3-oxo morpholine-4-yl) phenyl] }-(2R, 4R)-4-methoxyl group tetramethyleneimine-1, the 2-diformamide,
141) 1-N-[(4-chloro-phenyl-)]-2-N-{[4-(3-oxo morpholine-4-yl) hexamethylene-1-yl]-(2R, 4R)-4-hydroxyl pyrrolidine-1, the 2-diformamide,
142) 1-N-[(4-chloro-phenyl-)]-2-N-{[4-(2-lminopyrrolidine-1-yl) phenyl]-(2R, 4R)-4-hydroxyl pyrrolidine-1,2-diformamide, ESI442;
143) 1-N-[(4-chloro-phenyl-)]-2-N-{[3-methyl-4-(2-lminopyrrolidine-1-yl) phenyl]-(2R, 4R)-4-hydroxyl pyrrolidine-1,2-diformamide, ESI456;
144) 1-N-[(4-chloro-phenyl-)]-2-N-[4-{2-[(E)-and cyanoimino] imidazolidine-1-yl) phenyl]-(2R, 4R)-4-hydroxyl pyrrolidine-1,2-diformamide, ESI468;
145) 1-N-[(4-chloro-phenyl-)]-2-N-{[4-(2-imino--5-methylthiazol-3-yl) phenyl]-(2R, 4R)-4-hydroxyl pyrrolidine-1,2-diformamide, ESI473;
146) 1-N-[(4-chloro-phenyl-)]-2-N-{[2-aminocarboxyl-4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-4-hydroxyl pyrrolidine-1,2-diformamide, ESI502;
147) 1-N-[(4-chloro-phenyl-)]-2-N-{[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-4-hydroxy-2-methyl tetramethyleneimine-1, the 2-diformamide,
148) N-[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-1-[(E)-3-(5-chlorothiophene-2-yl) acryl]-4-hydroxyl pyrrolidine-2-methane amide,
149) N-[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-1-[(E)-3-thiene-3-yl-acryl]-4-hydroxyl pyrrolidine-2-methane amide,
150) N-[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-1-[(2E, 4E)-5-phenyl-penta-2,4-two enoyl-s]-4-hydroxyl pyrrolidine-2-methane amide,
151) N-[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-1-[(E)-3-(5-methyl furan-2-yl) acryl]-4-hydroxyl pyrrolidine-2-methane amide,
152) N-[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-1-[(E)-3-thiophene-2-base acryl]-4-hydroxyl pyrrolidine-2-methane amide,
153) N-[2-fluoro-4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-1-[(E)-3-(5-chlorothiophene-2-yl) acryl]-4-methoxyl group tetramethyleneimine-2-methane amide,
154) N-[2-fluoro-4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-1-[(E)-3-(5-chlorothiophene-2-yl) acryl]-4-hydroxyl pyrrolidine-2-methane amide,
155) N-[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-1-[(E)-3-(4-chloro-phenyl-) acryl]-4-hydroxyl pyrrolidine-2-methane amide,
156) N-[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-1-[(E)-3-(3, the 4-dichlorophenyl) acryl]-4-hydroxyl pyrrolidine-2-methane amide,
157) N-[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-1-[(E)-3-(4-chloro-phenyl-) acryl]-4-methoxyl group tetramethyleneimine-2-methane amide,
158) N-[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-1-[(E)-3-(3, the 4-dichlorophenyl) acryl]-4-methoxyl group tetramethyleneimine-2-methane amide,
159) N-[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-1-[(E)-3-1H-imidazol-4 yl acryl]-4-hydroxyl pyrrolidine-2-methane amide,
160) N-[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-1-[(E)-3-(5-chlorothiophene-2-yl) acryl]-4-methoxyl group tetramethyleneimine-2-methane amide,
161) N-[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-1-[(E)-3-(5-chlorine furans-2-yl) acryl]-4-hydroxyl pyrrolidine-2-methane amide,
162) N-[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-1-[(E)-3-(5-chlorine furans-2-yl) acryl]-4-methoxyl group tetramethyleneimine-2-methane amide,
163) N-[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-1-[(E)-3-(4-chloro-phenyl-) acryl]-4-oxyethyl group tetramethyleneimine-2-methane amide,
164) N-[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-1-[(E)-3-(3, the 4-dichlorophenyl) acryl]-4-oxyethyl group tetramethyleneimine-2-methane amide,
165) N-[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-1-[(E)-3-(5-chlorine furans-2-yl) acryl]-4-oxyethyl group tetramethyleneimine-2-methane amide,
166) N-[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-1-[(E)-3-(5-chlorothiophene-2-yl) acryl]-4-oxyethyl group tetramethyleneimine-2-methane amide,
167) N-[2-fluoro-4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-1-[(E)-3-(4-chloro-phenyl-) acryl]-4-hydroxyl pyrrolidine-2-methane amide,
168) N-[2-fluoro-4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-1-[(E)-3-(3, the 4-dichlorophenyl) acryl]-4-hydroxyl pyrrolidine-2-methane amide,
169) N-[2-fluoro-4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-1-[(E)-3-(5-chlorine furans-2-yl) acryl]-4-hydroxyl pyrrolidine-2-methane amide,
170) N-[2-fluoro-4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-1-[(E)-3-(5-chlorine furans-2-yl) acryl]-4-methoxyl group tetramethyleneimine-2-methane amide,
171) N-[2-fluoro-4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-1-[(E)-3-(4-chloro-phenyl-) acryl]-4-methoxyl group tetramethyleneimine-2-methane amide,
172) N-[2-fluoro-4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-1-[(E)-3-(3, the 4-dichlorophenyl) acryl]-4-methoxyl group tetramethyleneimine-2-methane amide,
173) N-[2-fluoro-4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-1-[(E)-3-(4-chloro-phenyl-) acryl]-4-oxyethyl group tetramethyleneimine-2-methane amide,
174) N-[2-fluoro-4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-1-[(E)-3-(3, the 4-dichlorophenyl) acryl]-4-oxyethyl group tetramethyleneimine-2-methane amide,
175) N-[2-fluoro-4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-1-[(E)-3-(5-chlorine furans-2-yl) acryl]-4-oxyethyl group tetramethyleneimine-2-methane amide,
176) N-[2-fluoro-4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-1-[(E)-3-(5-chlorothiophene-2-yl) acryl]-4-oxyethyl group tetramethyleneimine-2-methane amide,
177) N-[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-1-[(E)-3-1H-imidazol-4 yl acryl]-4-oxyethyl group tetramethyleneimine-2-methane amide,
178) N-[2-fluoro-4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-1-[(E)-3-1H-imidazol-4 yl acryl]-4-hydroxyl pyrrolidine-2-methane amide,
179) N-[2-fluoro-4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-1-[(E)-3-1H-imidazol-4 yl acryl]-4-methoxyl group tetramethyleneimine-2-methane amide,
180) N-[2-fluoro-4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-1-[(E)-3-1H-imidazol-4 yl acryl]-4-oxyethyl group tetramethyleneimine-2-methane amide,
181) N-[2-fluoro-4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-1-[(E)-3-pyridin-3-yl acryl]-4-hydroxyl pyrrolidine-2-methane amide,
182) N-[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-1-[(E)-3-pyridin-3-yl acryl]-4-oxyethyl group tetramethyleneimine-2-methane amide,
183) N-[2-fluoro-4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-1-[(E)-3-pyridin-3-yl acryl]-4-methoxyl group tetramethyleneimine-2-methane amide,
184) N-[2-fluoro-4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-1-[(E)-3-pyridin-3-yl acryl]-4-oxyethyl group tetramethyleneimine-2-methane amide,
185) N-[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-1-[(E)-3-pyridin-3-yl acryl]-4-hydroxyl pyrrolidine-2-methane amide,
186) N-[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-1-[(E)-3-pyridin-3-yl acryl]-4-methoxyl group tetramethyleneimine-2-methane amide,
187) N-[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-1-[(E)-3-pyridin-4-yl acryl]-4-hydroxyl pyrrolidine-2-methane amide,
188) N-[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-1-[(E)-3-pyridin-4-yl acryl]-4-oxyethyl group tetramethyleneimine-2-methane amide,
189) N-[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-1-[(E)-3-1H-imidazol-4 yl acryl]-4-methoxyl group tetramethyleneimine-2-methane amide,
190) N-[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-1-[(E)-3-(4-bromothiophene-2-yl) acryl]-4-hydroxyl pyrrolidine-2-methane amide,
191) N-[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-1-[(E)-3-(4-bromothiophene-2-yl) acryl]-4-oxyethyl group tetramethyleneimine-2-methane amide,
192) N-[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-1-[(E)-3-(5-bromothiophene-2-yl) acryl]-4-hydroxyl pyrrolidine-2-methane amide,
193) N-[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-1-[(E)-3-(5-bromothiophene-2-yl) acryl]-4-oxyethyl group tetramethyleneimine-2-methane amide,
194) N-(4-chloro-phenyl-)-(R)-1-[4-(2-oxo-piperidine-1-yl) benzoyl] tetramethyleneimine-2-methane amide,
195) N-(4-chloro-phenyl-)-(S)-1-[4-(2-oxo-piperidine-1-yl) benzoyl] tetramethyleneimine-2-methane amide,
196) 1-N-[(4-chloro-phenyl-)]-2-N-{[4-(5-oxo-1,4-oxa-azepine ring-4-in heptan yl) phenyl]-(R)-and tetramethyleneimine-1, the 2-diformamide,
197) 1-N-[(4-chloro-phenyl-)]-2-N-{[4-(5-oxo-1,4-oxa-azepine ring-4-in heptan yl) phenyl]-(2R, 4R)-4-hydroxyl pyrrolidine-1, the 2-diformamide,
198) 1-N-[(4-chloro-phenyl-)]-2-N-{[4-((S)-2-methyl-3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-4-hydroxyl pyrrolidine-1, the 2-diformamide,
199) 1-N-[(4-chloro-phenyl-)]-2-N-{[4-((S)-2-methyl-3-oxo morpholine-4-yl) phenyl]-(2R)-and tetramethyleneimine-1, the 2-diformamide,
200) 1-N-[(4-chloro-phenyl-)]-2-N-{[4-((R)-2-methyl-3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-4-hydroxyl pyrrolidine-1, the 2-diformamide,
201) 1-N-[(4-chloro-phenyl-)]-2-N-{[4-((R)-2-methyl-3-oxo morpholine-4-yl) phenyl]-(2R)-and tetramethyleneimine-1, the 2-diformamide,
202) 1-N-[(4-chloro-phenyl-)]-2-N-{[4-(3-oxo morpholine-4-yl)-2-Phenoxyphenyl]-(2R)-and tetramethyleneimine-1, the 2-diformamide,
203) 1-N-[(4-chloro-phenyl-)]-2-N-{[2-fluoro-4-((R)-2-methyl-3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-4-hydroxyl pyrrolidine-1, the 2-diformamide,
204) 1-N-[(4-chloro-phenyl-)]-3-N-{[4-(3-oxo morpholine-4-yl) phenyl] piperidines-1, the 3-diformamide,
205) 1-N-[(4-chloro-phenyl-)]-3-N-{[3-methyl-4-(3-oxo morpholine-4-yl) phenyl] piperidines-1, the 3-diformamide,
206) 1-N-[(4-chloro-phenyl-)]-2-N-{[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-4-(2-methoxy ethoxy) tetramethyleneimine-1, the 2-diformamide,
207) 1-N-[(4-chloro-phenyl-)]-2-N-{[4-(3-oxo-1,4-oxa-azepine ring-4-in heptan yl) phenyl]-(2R, 4R)-4-hydroxyl pyrrolidine-1, the 2-diformamide,
208) 1-N-[(4-chloro-phenyl-)]-2-N-{[2-methyl-4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-4-hydroxyl pyrrolidine-1, the 2-diformamide,
209) 1-N-[(4-chloro-phenyl-)]-2-N-{[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-4-hydroxyl pyrrolidine-1, the 2-diformamide,
210) 1-N-[(4-chloro-phenyl-)]-2-N-{[2-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-4-hydroxyl pyrrolidine-1, the 2-diformamide.
24. pyrrolidinecarboxylic acid derivative and pharmaceutically spendable derivative thereof, solvate, salt and the steric isomer that comprises its various mixed things, described derivative is selected from:
1) 1-N-[(4-chloro-phenyl-)]-2-N-([connection piperidin-4-yl 1 '-methyl-[1,4 '])]-(2R, 4R)-4-hydroxyl pyrrolidine-1, the 2-diformamide,
2) 1-N-[(4-chloro-phenyl-)]-and 2-N-[(3,4,5,6-tetrahydrochysene-2H-1,4 '-dipyridyl-4-yl)]-(2R, 4R)-4-hydroxyl pyrrolidine-1, the 2-diformamide,
3) 1-N-[(4-chloro-phenyl-)]-and 2-N-[(3,4,5,6-tetrahydrochysene-2H-1,4 '-dipyridyl-4-yl)-(2R, 4R)-4-oxyethyl group tetramethyleneimine-1, the 2-diformamide,
4) N-(4-chloro-phenyl-)-(2R, 4R)-4-hydroxyl-2-(4-pyridin-4-yl piperazine-1-carbonyl) tetramethyleneimine-1-methane amide,
5) N-(4-chloro-phenyl-)-(2R, 4R)-4-hydroxyl-2-[4-(2-p-methoxy-phenyl) piperazine-1-carbonyl] tetramethyleneimine-1-methane amide,
6) N-(4-chloro-phenyl-)-(2R, 4R)-2-[4-(4-fluorophenyl) piperazine-1-carbonyl]-4-hydroxyl pyrrolidine-1-methane amide,
7) N-(4-chloro-phenyl-)-(2R, 4R)-4-hydroxyl-2-[4-hydroxyl-4-(4-p-methoxy-phenyl) piperidines-1-carbonyl] tetramethyleneimine-1-methane amide,
8) N-(4-chloro-phenyl-)-(2R, 4R)-4-hydroxyl-2-(4-pyridine-2-base piperazine-1-carbonyl) tetramethyleneimine-1-methane amide,
9) N-(4-chloro-phenyl-)-(2R, 4R)-2-[4-(4-ethyl piperazidine-1-yl) piperidines-1-carbonyl]-4-hydroxyl pyrrolidine-1-methane amide,
10) N-(4-chloro-phenyl-)-(2R, 4R)-2-[4-(4,6-dimethyl pyrimidine-2-yl) piperazine-1-carbonyl]-4-hydroxyl pyrrolidine-1-methane amide,
11) N-(4-chloro-phenyl-)-(2R, 4R)-4-hydroxyl-2-[4-(1-methyl piperidine-4-yl) piperazine-1-carbonyl] tetramethyleneimine-1-methane amide,
12) 1-N-[(4-chloro-phenyl-)]-2-N-{[2-(2-dimethylamino oxyethyl group)-4-morpholine-4-base phenyl]-(2R, 4R)-4-hydroxyl pyrrolidine-1, the 2-diformamide,
13) 1-N-[(4-chloro-phenyl-)]-2-N-[(2-oxyethyl group-4-morpholine-4-base phenyl)]-(2R, 4R)-4-hydroxyl pyrrolidine-1, the 2-diformamide,
14) 1-N-[(4-chloro-phenyl-)]-2-N-[(4-morpholine-4-base-2-propoxy-phenyl)]-(2R, 4R)-4-hydroxyl pyrrolidine-1, the 2-diformamide.
25. cyclopentane-carboxylic acid derivative and pharmaceutically spendable derivative thereof, solvate, salt and the steric isomer that comprises its various mixed things, described derivative is selected from:
N-[4-(3-oxo morpholine-4-yl) phenyl]-(rac)-and 2-[3-(4-chloro-phenyl-) urea groups] cyclopentane formamide,
N-[3-methyl-4-(3-oxo morpholine-4-yl) phenyl]-(rac)-and 2-[3-(4-chloro-phenyl-) urea groups] cyclopentane formamide.
26. the formula I compound of preparation claim 1-23 and the method for pharmaceutically spendable derivative, solvate, salt and steric isomer thereof is characterized in that
A) for preparing with the following formula I compound, wherein
W is N, and
G is NH,
Make formula II compound
Figure A2004800093540031C1
Wherein
R 1, R 2, E, X, Y and T definition be with claim 1,
And W is N,
React with the formula III compound
D-N＝C＝O III
Wherein
D defines with claim 1,
Or
B) be preparation following formula I compound, wherein
X is-[C (R 4) 2] nCONR 3[C (R 4) 2] n-,
Make formula IV compound
HNR 3-[C(R 4) 2] n-Y-T IV
R wherein 3, n, Y and T definition is with claim 1,
React with formula V compound
Figure A2004800093540031C2
Wherein
L is Cl, Br, I or OH group free or that active function groups is modified,
And
R 1, R 2, R 4, D, E, G, W and n definition be with claim 1,
Or
C) W is the formula I compound of N in order to prepare wherein,
Make formula II compound
Wherein
R 1, R 2, E, X, Y and T definition be with claim 1,
And W is N,
React with formula VI compound
D-G-CO-L VI
Wherein D and G define with claim 1, and
L is Cl, Br, I or OH group free or that active function groups is modified,
And/or
Alkali or the acid of formula I are converted into a kind of of its salt.
27. one or the multinomial formula I compound and the compound of claim 24 and 25 among the claim 1-23, described compound is a coagulation factor xa inhibitors.
28. one or the multinomial formula I compound and the compound of claim 24 and 25 among the claim 1-23, described compound is a proconvertin a inhibitor.
29. medicine, the steric isomer that described medicine comprises among at least a claim 1-23 compound of or multinomial formula I compound or claim 24 and 25 and/or its pharmaceutically spendable derivative, solvate, salt and comprises its various mixed things is if desired with vehicle and/or auxiliary agent.
30. medicine, described medicine comprises one or multinomial formula I compound or compound and/or its pharmaceutically spendable derivative, the solvate of claim 24 and 25 and steric isomer and at least a other medicines activeconstituents that comprises its various mixed things among at least a claim 1-23.
31. the compound of or multinomial compound or claim 24 and 25 and/or its physiologically acceptable salt, salt and solvate are used for the treatment of purposes in the medicine of following disease in preparation among the claim 1-23: thrombosis, myocardial infarction, arteriosclerosis, inflammation, apoplexy, stenocardia, postangioplasty restenosis, intermittent claudication, migraine, tumour, tumor disease and/or tumor metastasis.
32. packed medicament (kit), described packed medicament (kit) is made up of following independent packaging:
(a) compound of or multinomial formula I compound or claim 24 and 25 and/or its pharmaceutically spendable derivative, solvate, salt and the steric isomer that comprises its various mixed things among the claim 1-23 of significant quantity,
With
(b) the other medicines activeconstituents of significant quantity.
33. one or the multinomial formula I compound or compound and/or its pharmaceutically spendable derivative of claim 24 and 25 among the claim 1-23, solvate, salt and comprise the steric isomer of its various mixed things and the preparation that is combined in of at least a other medicines activeconstituents is used for the treatment of purposes in the medicine of following disease: thrombosis, myocardial infarction, arteriosclerosis, inflammation, apoplexy, stenocardia, postangioplasty restenosis, intermittent claudication, migraine, tumour, tumor disease and/or tumor metastasis.
34. formula I-1 midbody compound and isomer thereof and salt
Figure A2004800093540033C1
Wherein
D is phenyl, pyridyl, thienyl, furyl or imidazolyl, and they are replaced by the single replacement of Hal or two separately,
R 1Be H, OH, OA, alkyl or ethynyl with 1,2,3,4,5 or 6 carbon atom,
R 2For H, OH, OA or have the alkyl of 1,2,3,4,5 or 6 carbon atom,
Figure A2004800093540034C1
Be tetramethyleneimine-1,2-two bases, piperidines-1,2-two Ji, oxazolidines-3,4-or 3,5-two bases,
G is (CH 2) n, (CH 2) nNH-,-CH=CH-or-CH=CH-CH=CH-;
X is COOH,
A is the alkyl with 1,2,3,4,5 or 6 carbon atom,
Hal is F, Cl, Br or I,
N is 0,1 or 2.
35. the compound of claim 34 and isomer thereof and salt, described compound is selected from:
3-(4-chloro-phenyl-formamyl) oxazolidine-4-formic acid,
3-(5-chlorothiophene-2-carbonyl) oxazolidine-5-formic acid.
36. midbody compound and isomer thereof and salt, described midbody compound is selected from:
(2R, 4S)-BOC-4-ethynyl-4-hydroxyl-tetramethyleneimine-2-formic acid,
(2R, 4R)-BOC-4-ethynyl-4-hydroxyl-tetramethyleneimine-2-formic acid,
(2R, 4S)-BOC-4-ethynyl-4-hydroxyl pyrrolidine-2-alkyl formate,
(2R, 4R)-BOC-4-ethynyl-4-hydroxyl pyrrolidine-2-alkyl formate,
Wherein alkyl has 1,2,3,4,5 or 6 carbon atom.
37. formula I-2 midbody compound and isomer thereof and salt
Figure A2004800093540034C2
Wherein
R 1For H ,=O, COOR 3, OH, OA, NH 2, have alkyl, a N of 1,2,3,4,5 or 6 carbon atom 3, ethynyl, vinyl, allyloxy, NHCOA, NHSO 2A, OCH 2COOA or OCH 2COOH,
R 2For H, OH, OA or have the alkyl of 1,2,3,4,5 or 6 carbon atom,
Perhaps, R 1And R 2Be the first carbocyclic ring of the 3-6 of volution connection together,
R 3Be H or A,
Figure A2004800093540035C1
Be tetramethyleneimine-1,2-two bases, piperidines-1,2-two Ji, oxazolidines-3,4-or 3,5-two bases,
X is CONH,
Y is for replacing or replaced by following group list or dibasic 1,3-or 1, and the 4-phenylene: methyl, trifluoromethyl, ethyl, propyl group, Cl or F,
T is piperidines-1-base, tetramethyleneimine-1-base, 1H-pyridine-1-base, morpholine-4-base, piperazine-1-base, 1,3-oxazolidine-3-base, 2H-pyridazine-2-base, pyrazine-1-base, azepine ring-1-in heptan base or 2-azabicyclic [2.2.2] octane-2-base, they are replaced or two replacements by the ketonic oxygen list separately
A is the alkyl with 1,2,3,4,5 or 6 carbon atom,
Hal is F, Cl, Br or I,
N is 0,1 or 2.
38. the formula I-2a compound of claim 37 and isomer and salt
Figure A2004800093540035C2
Wherein
R 1For H ,=O, COOR 3, OH, OA, NH 2, have alkyl, a N of 1,2,3,4,5 or 6 carbon atom 3, ethynyl, vinyl, allyloxy, NHCOA, NHSO 2A, OCH 2COOA or OCH 2COOH,
R 2For H, OH, OA or have the alkyl of 1,2,3,4,5 or 6 carbon atom,
R 3Be H or A,
Figure A2004800093540036C1
Be tetramethyleneimine-1,2-two bases,
X is CONH,
Y is for replacing or replaced by following group list or dibasic 1,3-or 1, and the 4-phenylene: methyl, trifluoromethyl, ethyl, propyl group, Cl or F,
T is piperidines-1-base, tetramethyleneimine-1-base, 1H-pyridine-1-base, morpholine-4-base, piperazine-1-base, 1,3-oxazolidine-3-base, 2H-pyridazine-2-base, pyrazine-1-base, azepine ring-1-in heptan base or 2-azabicyclic [2.2.2] octane-2-base, they are replaced or two replacements by the ketonic oxygen list separately
A is the alkyl with 1,2,3,4,5 or 6 carbon atom,
Hal is F, Cl, Br or I,
N is 0,1 or 2.
39. the compound of claim 38 and isomer thereof and salt, described compound is selected from
1) N-[4-(3-oxo morpholine-4-yl) phenyl]-(S)-tetramethyleneimine-2-methane amide,
2) N-[4-(3-oxo morpholine-4-yl) phenyl]-(R)-tetramethyleneimine-2-methane amide,
3) N-[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-4-hydroxyl pyrrolidine-2-methane amide,
4) N-[4-(3-oxo morpholine-4-yl) phenyl]-4-hydroxyl pyrrolidine-2-methane amide,
5) N-[4-(3-oxo morpholine-4-yl) phenyl]-(R)-4,4-dimethoxy tetramethyleneimine-2-methane amide,
6) N-[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-4-methoxyl group tetramethyleneimine-2-methane amide.
40. the medicine of claim 30, described medicine comprises the 1-N-[(4-chloro-phenyl-)]-2-N-{[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-and 4-hydroxyl pyrrolidine-1, the pharmaceutically spendable derivative of 2-diformamide and/or its, solvate, salt and the steric isomer and the acetylsalicylic acid that comprise its various mixed things.
41. the purposes of claim 33, described medicine comprises the 1-N-[(4-chloro-phenyl-)]-2-N-{[4-(3-oxo morpholine-4-yl) phenyl]-(2R, 4R)-and 4-hydroxyl pyrrolidine-1, the pharmaceutically spendable derivative of 2-diformamide and/or its, solvate, salt and the combination that comprises the steric isomer and the acetylsalicylic acid of its various mixed things.
CNA2004800093547A 2003-04-03 2004-03-08 Pyrazolidine-1,2-dicarboxyldiphenylamide derivatives as coagulation factor xa inhibitors for the treatment of thromboses. Pending CN1771237A (en)

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