CN1771237A - 1-(phenylcarbamoyl)-2-(4-(3-oxo-morpholin-4-yl)-phenylcarbamoyl) as an inhibitor of coagulation factor XA in the treatment of thromboembolic diseases Pyrrolidine derivatives and related compounds - Google Patents

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

1-(Phenylcarbamoyl)-2-(4-(3-oxo-morpholin-4-yl)-phenylcarbamoyl) as an inhibitor of coagulation factor XA in the treatment of thromboembolic diseases Pyrrolidine derivatives and related compounds

The present invention relates to a compound of formula I and its pharmaceutically usable derivatives, solvates, salts and stereoisomers including mixtures thereof in various proportions:

in

R ¹ and R ² are independent of each other and each is 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 ³ COA or NR ³ SO ₂ A,

Alternatively, R ^{and R} together are a bicyclic or spiro-linked 3-7 membered carbocyclic or heterocyclic ring with 0-3 N, O and/or S atoms,

R ³ is H, A, HC≡C-CH ₂ -, CH ₃ -C≡C-CH ₂ -, -CH ₂ -CH(OH)-CH ₂ OH, -CH ₂ -CH(OH)-CH ₂ NH ₂ , -CH ₂ -CH(OH)-CH ₂ Het', -[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 ] _n N(R ⁴ ) ₂ ,

^R4 is H or A,

W is N, CR ³ or sp ² -hybridized carbon atom,

E together with W is a 3-7 membered saturated carbocyclic or heterocyclic ring with 0-3 N, 0-2 O and/or 0-2 S atoms,

It may contain double bonds,

D is a monocyclic or bicyclic aromatic carbocyclic or heterocyclic ring with 0-4 N, O and/or S atoms, which is unsubstituted or monosubstituted or polysubstituted by the following groups: Hal, A, OR ³ , N( R ³ ) ₂ , NO ₂ , CN, COOR ³ or CON(R ³ ) ₂ ,

G is -[C(R ⁴ ) ₂ ] _n -, -[C(R ⁴ ) ₂ ] _n NR ³ -, -[C(R ⁴ ) ₂ ] _n O-, -[C(R ⁴ ) ₂ ] _n S-or-[C(R ⁴ )=C(R ⁴ )] _n- ,

X is -[C(R ⁴ ) ₂ ] _n CONR ³ [C(R ⁴ ) ₂ ] _n -, -[C(R ⁴ ) ₂ ] _n NR ³ CO[C(R ⁴ ) ₂ ] _n -, - [C(R ⁴ ) ₂ ] _n NR ³ [C(R ⁴ ) ₂ ] _n -, -[C(R ⁴ ) ₂ ] _n O[C(R ⁴ ) ₂ ] _n -, -[C(R ⁴ ) ₂ ] _n CO[C(R ⁴ ) ₂ ] _n -or-[C(R ⁴ ) ₂ ] _n COO[C(R ⁴ ) ₂ ] _n -,

Y is alkylene, cycloalkylene, Het-diradical or Ar-diradical,

T is a monocyclic or bicyclic, saturated or unsaturated carbocyclic or heterocyclic ring having 0-4 N, O and/or S atoms, which is monosubstituted or disubstituted by the following groups: =O, =S, =NR ³ , =N-CN, =N-NO ₂ , =NOR ³ , =NCOR ³ , =NCOOR ³ or =NOCOR ³ , and may be further monosubstituted, disubstituted or trisubstituted by the following groups: 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 , NO ₂ , CN, COOR ³ , CON(R ³ ) ₂ , NR ³ COA, NR ³ CON(R ³ ) ₂ , NR ³ SO ₂ A, COR ³ , SO ₂ NR ³ and/or S(O ) _n A,

A is an unbranched or _branched chain alkyl group having 1-10 carbon atoms, wherein one or two CH groups may be replaced by O or S atoms and/or -CH=CH- groups, and/or additionally 1-7 H atoms can be replaced by F,

Ar is phenyl, naphthyl or biphenyl, each of which is unsubstituted or monosubstituted, disubstituted or trisubstituted by the following groups: Hal, A, OR ³ , N(R ³ ) ₂ , NO ₂ , CN, COOR ³ , CON(R ³ ) ₂ , NR ³ COA, NR ³ CON(R ³ ) ₂ , NR ³ SO ₂ A, COR ³ , SO ₂ N(R ³ ) ₂ , S(O) _n A, -[C (R ⁴ ) ₂ ] _n -COOR ³ or -O[C(R ⁴ ) ₂ ] _o -COOR ³ ,

Ar' is phenyl, naphthyl or biphenyl, each of which is unsubstituted or monosubstituted, disubstituted or trisubstituted by the following groups: Hal, A, OR ⁴ , N(R ⁴ ) ₂ , NO ₂ , CN, COOR ⁴ , CON(R ⁴ ) ₂ , NR ⁴ COA, NR ⁴ CON(R ⁴ ) ₂ , NR ⁴ SO ₂ A, COR ⁴ , SO ₂ N(R ⁴ ) ₂ , S(O) _n A, -[ C(R ⁴ ) ₂ ] _n -COOR ⁴ or -O[C(R ⁴ ) ₂ ] _o -COOR ⁴ ,

Het is a monocyclic or bicyclic, saturated, unsaturated or aromatic heterocyclic ring having 1 to 4 N, O and/or S atoms, which may be unsubstituted or monosubstituted, disubstituted or trisubstituted by: 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 ³ CON(R ³ ) ₂ , NO ₂ , CN, -[C(R ⁴ ) ₂ ] _n -COOR ³ , -[C(R ⁴ ) ₂ ] _n -CON(R ³ ) ₂ , NR ³ COA, NR ³ SO ₂ A, COR ³ , SO ₂ NR ³ , S(O) _m A and/or carbonyl oxygen,

Het' is a monocyclic or bicyclic, saturated, unsaturated or aromatic heterocyclic ring having 1 to 4 N, O and/or S atoms, which may be unsubstituted or monosubstituted or disubstituted by: carbonyl oxygen, =S, =N(R ⁴ ) ₂ , Hal, A, OR ⁴ , N(R ⁴ ) ₂ , NO ₂ , CN, COOR ⁴ , CON(R ⁴ ) ₂ , NR ⁴ COA, NR ⁴ CON(R ⁴ ) ₂ , NR ⁴ SO ₂ A, COR ⁴ , SO ₂ NR ⁴ and/or S(O) _n A,

Hal is F, Cl, Br or I,

n is 0, 1 or 2,

o is 1, 2 or 3.

The object of the present invention was to discover new compounds with valuable properties, in particular those compounds which can be used for the preparation of medicaments.

It has been found that the compounds of formula I and their salts have very valuable pharmacological properties and are well tolerated. In particular, they exhibit the property of inhibiting factor Xa and are therefore useful in the anti- and prevention of thromboembolic diseases such as thrombosis, myocardial infarction, arteriosclerosis, inflammation, stroke, angina pectoris, restenosis after angioplasty and intermittent claudication ( claudicatiointermittens).

The compounds of the formula I according to the invention may also be inhibitors of coagulation factor VIIa, factor IXa and thrombin in the blood coagulation cascade.

Arylamidine derivatives with antithrombotic effect are disclosed, for example, in the following patents: 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. Cyclic guanidines for use in the treatment of thromboembolic diseases are disclosed, for example, in WO97/08165. Aromatic heterocyclic compounds having factor Xa inhibitory activity are disclosed, for example, in WO96/10022. Substituted N-[(aminoiminomethyl)phenylalkyl]azaheterocyclic amides as Factor Xa inhibitors are described in WO 96/40679. Other carboxamide derivatives are disclosed in WO 02/48099 and WO 02/57236 and other pyrrolidine derivatives are described in WO 02/100830.

Further heterocyclic derivatives are disclosed in WO 03/045912.

The antithrombotic and anticoagulant effects of the compounds of the invention are due to the inhibition of the activation of the coagulation protease named Factor Xa, or of other activated serine proteases such as Factor VIIa, Factor IXa or thrombin.

Factor Xa is a protease involved in the complex blood clotting process. Factor Xa catalyzes the conversion of prothrombin to thrombin. Thrombin dissociates fibrinogen into fibrin monomers, and after cross-linking, fibrin monomers become the basis of thrombus formation. Activation of thrombin can lead to the development of thromboembolic disease, but inhibition of thrombin can inhibit the formation of fibrin involved in thrombus formation. Inhibition of thrombin can be measured, for example, by the method of G.F. Cousins et al. in Circulation 1996, 94, 1705-1712.

Inhibition of factor Xa thus prevents thrombin formation.

The compounds of formula I and their salts of the present invention participate in the blood coagulation process by inhibiting factor Xa, thus inhibiting thrombus formation.

The compounds of the present invention inhibit factor Xa and measure the anticoagulant and antithrombotic activity by conventional in vitro or in vivo methods. Suitable methods are eg described by J. Hauptmann et al. in Thrombosis and Haemostasis 1990, 63, 220-223.

Inhibition of factor Xa can be measured, for example, by the method described by T. Hara et al. in Thromb. Haemostas 1994, 71, 314-319.

Binding of factor VIIa and tissue factor initiates the exogenous part of the coagulation cascade, leading to activation of factor X and release of factor Xa. Inhibition of factor VIIa thus prevents the formation of factor Xa and subsequent thrombin formation. The compounds of the present invention inhibit factor VIIa and measure anticoagulant and antithrombotic activity by conventional in vitro or in vivo methods. For example H.F. Ronning et al. in Thrombosis Research 1996, 84, 73-81 describe a conventional method for measuring inhibition of Factor VIIa.

Coagulation factor IXa is produced in the endogenous coagulation cascade, which also involves the activation of factor X and the release of factor Xa. Inhibition of Factor IXa thus prevents Factor Xa formation in a different pathway. Measurement of the inhibition of Factor IXa and the anticoagulant and antithrombotic activity of the compounds of the invention can be determined by conventional in vitro or in vivo methods. For example a suitable method is described by J. Chang et al. in Journal of Biological Chemistry 1998, 273, 12089-12094.

The compounds of the invention are also useful in the treatment of tumors, neoplastic diseases and/or tumor metastases. T.Taniguchi and N.R.Lemoine in Biomed.Health Res.(2000) 41 (Molecular Pathogenesis of Pancreatic Cancer (molecular pathology of pancreatic cancer)), 57-59 have pointed out the relationship between tissue factor TF/VIIa factor and the occurrence of various cancers mutual relationship. The following publications describe the antitumor effects of TF-VII and factor Xa inhibitors on various tumors:

K. M. Donnelly et al. Thromb. Haemost. 1998; 79: 1041-1047;

E.G. Fischer et al. J. Clin. Invest. 104:1213-1221 (1999);

B.M. Mueller et al. J. Clin. Invest. 101:1372-1378 (1998);

M.E. Bromberg et al. Thromb. Haemost. 1999;82:88-92.

The compounds of formula I can be used as pharmaceutically active ingredients in human and veterinary medicine, especially for the treatment and prevention of thromboembolic diseases such as thrombosis, myocardial infarction, arteriosclerosis, inflammation, stroke, angina pectoris, restenosis after angioplasty, intermittent claudication , venous thrombosis, pulmonary embolism, arterial thrombosis, myocardial ischemia, unstable angina, and thrombosis-based stroke. The compounds of the invention are also useful in the treatment or prophylaxis of atherosclerotic diseases such as coronary artery disease, cerebral arterial disease or peripheral arterial disease. Said compound can also be used in combination with other thrombolytic drugs in myocardial infarction, and can also prevent reocclusion after thrombolysis, percutaneous transluminal angioplasty (PTCA) and coronary artery bypass surgery.

The compounds of the invention are also useful in the prevention of rethrombosis in microsurgery; and as anticoagulants in combination with artificial organs or hemodialysis. The compounds are also useful for cleaning catheters and medical aids in patients, or as anticoagulants for the extracorporeal preservation of blood, plasma and other blood products. The compounds of the invention are also useful in diseases in which blood coagulation is an important factor in the disease process, or represents a secondary etiology, eg in cancers including metastasis, inflammatory diseases including arthritis and diabetes.

The compounds of the invention are also useful in the treatment of migraine (F. Morales-Asin et al., Headache, 40, 2000, 45-47).

In the treatment of said diseases, the compounds according to the invention can also be used in combination with other thrombolytically active drugs, for example with "tissue plasminogen activator" t-PA, modified t-PA, streptokinase or urokinase. The compounds of the invention may be administered simultaneously with said other substances or before or after the other substances. Concomitant administration with aspirin is particularly preferred to prevent recurrence of clot formation. The compounds of the present invention may also be used in combination with platelet glycoprotein receptor (IIb/IIIa) antagonists which inhibit platelet aggregation.

The present invention relates to compounds of formula I and salts thereof and to methods for preparing compounds of formula I of claims 1-16 and pharmaceutically usable derivatives, solvates, salts and stereoisomers thereof, characterized in that:

a) for the preparation of compounds of the following formula I, wherein

W is N, and

G is NH,

Compound of formula II

in

R ¹ , R ² , E, X, Y and T are as defined in claim 1,

and W is N,

Reaction with compound of formula III

D-N＝C＝O III

in

D is as defined in claim 1,

or

b) for the preparation of compounds of the following formula I, wherein

X is -[C(R ⁴ ) ₂ ] _n CONR ³ [C(R ⁴ ) ₂ ] _n -,

Make formula IV compound

HNR ³ -[C(R ⁴ ) ₂ ] _n -YT IV

Wherein R ³ , n, Y and T are as defined in claim 1,

Reaction with the compound of formula V

in

L is Cl, Br, I or a free or active functional group modified OH group, and

R ¹ , R ² , R ⁴ , D, E, G, W and n are as defined in claim 1,

or

c) for the preparation of compounds of formula I wherein W is N,

Compound of formula II

in

R ¹ , R ² , E, X, Y and T are as defined in claim 1,

and W is N,

Reaction with formula VI compound

D-G-CO-L VI

wherein D and G are as defined in claim 1, and

L is Cl, Br, I or OH groups modified by free or active functional groups,

and / or

A base or acid of formula I is converted into one of its salts.

The invention also relates to the optical forms (stereoisomers), enantiomers, racemates, diastereomers, hydrates and solvates of these compounds. The term "solvate of a compound" denotes the formation of an adduct of an inert solvent molecule with a compound due to their mutual attraction. Solvates are, for example, mono- or dihydrates or alcoholates.

The term "pharmaceutically acceptable derivatives" denotes, for example, salts of the compounds of the invention and so-called prodrug compounds. The term "prodrug derivative" means a compound of formula I modified with, for example, an alkyl or acyl group, sugar or oligopeptide, which dissociates rapidly in an organism to form the active compound of the present invention. These compounds also include biodegradable polymer derivatives of the compounds of the invention, as described, for example, in Int. J. Pharm. 115, 61-67 (1995).

According to the invention, the invention also relates to mixtures of compounds of formula I, for example mixtures of two diastereomers, for example in the ratio 1:1, 1:2, 1:3, 1:4, 1:5, 1:10 , 1:100 or 1:1000 mixtures. It is particularly preferred that these mixtures are mixtures of stereoisomeric compounds.

The present invention also relates to pyrrolidine carboxylic acid derivatives and their pharmaceutically usable derivatives, solvates, salts, and stereoisomers including mixtures thereof in various proportions selected from the group consisting of:

1) 1-N-[(4-chlorophenyl)]-2-N-[(1'-methyl-[1,4']bipiperidin-4-yl)]-(2R,4R)- 4-hydroxypyrrolidine-1,2-dicarboxamide,

2) 1-N-[(4-chlorophenyl)]-2-N-[(3,4,5,6-tetrahydro-2H-[1,4']bipyridin-4-yl)]- (2R,4R)-4-hydroxypyrrolidine-1,2-dicarboxamide,

3) 1-N-[(4-chlorophenyl)]-2-N-[(3,4,5,6-tetrahydro-2H-[1,4']bipyridin-4-yl)-( 2R, 4R)-4-ethoxypyrrolidine-1,2-dicarboxamide,

4) N-(4-chlorophenyl)-(2R,4R)-4-hydroxyl-2-(4-pyridin-4-ylpiperazine-1-carbonyl)pyrrolidine-1-carboxamide,

5) N-(4-chlorophenyl)-(2R,4R)-4-hydroxy-2-[4-(2-methoxyphenyl)-piperazine-1-carbonyl]pyrrolidine-1-methan amides,

6) N-(4-chlorophenyl)-(2R,4R)-2-[4-(4-fluorophenyl)piperazine-1-carbonyl]-4-hydroxypyrrolidine-1-carboxamide,

7) N-(4-chlorophenyl)-(2R,4R)-4-hydroxyl-2-[4-hydroxyl-4-(4-methoxyphenyl)piperidine-1-carbonyl]pyrrolidine- 1-formamide,

8) N-(4-chlorophenyl)-(2R,4R)-4-hydroxyl-2-(4-pyridin-2-ylpiperazine-1-carbonyl)pyrrolidine-1-carboxamide,

9) N-(4-chlorophenyl)-(2R,4R)-2-[4-(4-ethylpiperazin-1-yl)piperidine-1-carbonyl]-4-hydroxypyrrolidine-1 - Formamide,

10) N-(4-chlorophenyl)-(2R,4R)-2-[4-(4,6-dimethylpyrimidin-2-yl)piperazine-1-carbonyl]-4-hydroxypyrrolidine -1-formamide,

11) N-(4-chlorophenyl)-(2R,4R)-4-hydroxy-2-[4-(1-methylpiperidin-4-yl)piperazine-1-carbonyl]pyrrolidine-1 - Formamide;

12) 1-N-[(4-chlorophenyl)]-2-N-{[2-(2-dimethylaminoethoxy)-4-morpholin-4-ylphenyl]}-(2R , 4R)-4-hydroxypyrrolidine-1,2-dicarboxamide,

13) 1-N-[(4-chlorophenyl)]-2-N-[(2-ethoxy-4-morpholin-4-ylphenyl)]-(2R,4R)-4-hydroxy Pyrrolidine-1,2-dicarboxamide,

14) 1-N-[(4-chlorophenyl)]-2-N-[(4-morpholin-4-yl-2-propoxyphenyl)]-(2R,4R)-4-hydroxy Pyrrolidine-1,2-dicarboxamide.

The present invention also relates to cyclopentanecarboxylic acid derivatives and pharmaceutically usable derivatives, solvates, salts, and stereoisomers including mixtures thereof in various proportions selected from the group consisting of:

N-[4-(3-oxomorpholin-4-yl)phenyl]-(rac)-2-[3-(4-chlorophenyl)ureido]cyclopentanecarboxamide,

N-[3-methyl-4-(3-oxomorpholin-4-yl)phenyl]-(rac)-2-[3-(4-chlorophenyl)-ureido]cyclopentane amides.

For all radicals such as A which occur more than once, their meanings are independent of one another.

Above and below, unless otherwise stated, the groups or parameters D, E, G, W, X, Y, T, ^R1 and ^R2 are as defined under formula I.

A is an unbranched (linear) or branched alkyl group having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. Preferably A is methyl, additionally ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, additionally also pentyl; 1-, 2- or 3-methylbutyl 1,1-, 1,2- or 2,2-dimethylpropyl; 1-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl; 1,1 -, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl; 1- or 2-ethylbutyl; 1-ethyl-1-methyl propyl, 1-ethyl-2-methylpropyl, 1,1,2- or 1,2,2-trimethylpropyl; furthermore preferably trifluoromethyl, for example. Very particularly preferably A is an alkyl group having 1, 2, 3, 4, 5 or 6 carbon atoms, preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert Butyl, pentyl, hexyl, trifluoromethyl, pentafluoroethyl or 1,1,1-trifluoroethyl.

Preferably cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. Preferred alkylene groups are methylene, ethylene, propylene, butylene, pentylene or hexylene, furthermore branched chain alkylene groups.

R ¹ and R ² , independently of each other, are each preferably, for example, H, =O, COOR ³ , OH, OA, NH ₂ , alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, N ₃ , acetylene radical, vinyl, allyloxy, NHCOA, _NHSO2A , _OCH2COOA or _OCH2COOH .

Preferably R ¹ is H, =O, COOR ³ such as COOA, OH, OA, NH ₂ , alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, N ₃ , ethynyl, vinyl, alkenyl Propoxy, -OCOR ³ such as methylcarbonyloxy, NHCOA such as acetamido or NHSO ₂ A such as methylsulfonylamino; OCH ₂ COOA such as OCH ₂ COOCH ₃ ; or OCH ₂ COOH. Preferably ^R2 is H, =0, OH, OA such as methoxy, or alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms.

In a further preferred embodiment,

R ¹ is H, =O, COOR ³ , OH, OA, NH ₂ , alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, N ₃ , ethynyl, vinyl, allyloxy , -OCOR ³ , NHCOA, NHSO ₂ A, HC≡C-CH ₂ -, CH ₃ -C≡C-CH ₂ -O-, -O-CH ₂ -CH(OH)-CH ₂ OH, -O- _CH2 - _CH (OH _{) -CH2NH2} , -O- _CH2 -CH(OH) _-CH2Het ', _OCH2COOCH3 or _OCH2COOH ;

R ^is H, =0, OH, OA or an alkyl group with 1, 2, 3, 4, 5 or 6 carbon atoms;

Het' is a saturated 3-6 membered heterocyclic ring with 1-3 N and/or O atoms, which may be unsubstituted or mono- or di-substituted by the following groups: carbonyl oxygen, Hal, A, OH, NH ₂ , NO _2. CN, COOA or _CONH2 .

In another preferred embodiment,

R ¹ is ethynyl, vinyl, allyloxy, CH ₃ -C≡C-CH ₂ -O-, -O-CH ₂ CH(OH)-CH ₂ OH, -O-CH ₂ -CH(OH )-CH ₂ NH ₂ , -O-CH ₂ -CH(OH)-CH ₂ Het', OCH ₂ COOCH ₃ or OCH ₂ COOH,

R ² is H, A or OH,

Het' is a saturated 3-6 membered heterocyclic ring with 1-3 N and/or O atoms, which may be unsubstituted or mono- or di-substituted by the following groups: carbonyl oxygen, Hal, A, OH, NH ₂ , NO _2. CN, COOA or _CONH2 .

In a further preferred embodiment,

R ¹ is ethynyl, vinyl, allyloxy, CH ₃ -C≡C-CH ₂ -O-, -O-CH ₂ -CH(OH)-CH ₂ OH, -O-CH ₂ -CH( OH)-CH ₂ NH ₂ , -O-CH ₂ -CH(OH)-CH ₂ Het', OCH ₂ COOCH ₃ or OCH ₂ COOH,

R ² is H, A or OH,

Het' is a saturated 3-6 membered heterocyclic ring having 1-3 N and/or O atoms, which may be unsubstituted or mono- or di-substituted by carbonyl oxygen.

In this linkage it is very particularly preferred that Het' is pyrrolidine, piperidine or oxazolidine, each of which is unsubstituted or monosubstituted by carbonyl oxygen.

环系统上。Alternatively, ^R and R together are a 3-6 membered carbocyclic or ^heterocyclic ring having 0-3 N, O and/or S atoms, which are spiro or bicyclic connected (fused) to

ring system.

Here, the 3-6 membered carbocyclic or heterocyclic ring is, for example, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyridyl, imidazolyl, piperidyl or 1,3-dioxolanyl .

环系统上。R ^{and R} together are in particular a 3-6 membered carbocycle whose spiro ring is connected to

ring system.

Here, the 3-6 membered carbocyclic ring is preferably cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

R ³ is preferably H or A, but also phenyl, benzyl or [C(R ⁴ ) ₂ ] _n COOA, for example CH ₂ COOCH ₃ .

Preferably ^R4 is H or A, very particularly preferably H. ^COR2 , ^COR3 and ^COR4 are eg CHO or -COA. Preferably -COA(acyl) is acetyl, propionyl, furthermore butyryl, valeryl, hexanoyl or, for example, benzoyl.

Preferably Hal is F, Cl or Br, or is I.

Ar is for example phenyl, o-, m- or p-methylphenyl; o-, m- or p-ethylphenyl; o-, m- or p-propylphenyl; o-, m- or p-isopropylphenyl; o-, m-, or p-tert-butylphenyl; o-, m-, or p-hydroxyphenyl; o-, m-, or p-nitrophenyl; o- , m- or p-aminophenyl; o-, m- or p-(N-methylamino)phenyl; o-, m- or p-(N-methylaminocarbonyl)phenyl; o-, m- or p-acetamidophenyl; o-, m- or p-methoxyphenyl; o-, m- or p-ethoxyphenyl; o-, m- or p-ethoxycarbonyl Phenyl; o-, m- or p-(N,N-dimethylamino)phenyl; o-, m- or p-(N,N-dimethylaminocarbonyl)phenyl; o-, m- or p-(N-ethylamino)phenyl; o-, m-, or p-(N,N-diethylamino)phenyl; o-, m-, or p-fluorophenyl; o-, m- or p-bromophenyl; o-, m-, or p-chlorophenyl; o-, m-, or p-(methylsulfonylamino)phenyl; o-, m-, or p-(methylsulfonyl)benzene ortho-, m- or p-phenoxyphenyl; more preferably 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-difluorobenzene 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-dibromophenyl; 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-chlorophenyl; 2-nitro-4-N, N-dimethylamino- or 3-nitro-4-N, N-dimethylaminophenyl; 2,3-diaminophenyl ; 2,3,4-, 2,3,5-, 2,3,6-, 2,4,6- or 3,4,5-trichlorophenyl; 2,4,6-trimethoxybenzene Base, 2-hydroxy-3,5-dichlorophenyl, p-iodophenyl, 3,6-dichloro-4-aminophenyl, 4-fluoro-3-chlorophenyl, 2-fluoro-4- Bromophenyl, 2,5-difluoro-4-bromophenyl, 3-bromo-6-methoxyphenyl, 3-chloro-6-methoxyphenyl, 3-chloro-4-acetamidobenzene 3-fluoro-4-methoxyphenyl, 3-amino-6-methylphenyl, 3-chloro-4-acetamidophenyl or 2,5-dimethyl-4-chlorophenyl.

Ar is preferably phenyl, for example unsubstituted or mono-, di- or trisubstituted by Hal, A, OR ² , OR ³ , SO ₂ A, COOR ² or CN. Ar is particularly preferably phenyl, for example unsubstituted or mono- or disubstituted by Hal, A, OA, phenoxy, SO ₂ A, SO ₂ NH ₂ , COOR ² or CN, for example phenyl, 2 -Methanesulfonylphenyl, 2-aminosulfonylphenyl, phenoxyphenyl, 2-, 3- or 4-chlorophenyl; 3,4-dichlorophenyl, 4-methylphenyl, 4 -Bromophenyl, 3-fluoro-4-methoxyphenyl, 4-trifluoromethoxyphenyl, 4-ethoxyphenyl, 2-methoxyphenyl, 3-cyano-phenyl , 4-ethoxycarbonylphenyl, methoxycarbonylphenyl, carboxyphenyl or aminocarbonylphenyl. Very particularly preferably Ar is unsubstituted phenyl, 4-chlorophenyl or 2-methanesulfonylphenyl.

Particularly preferably G is (CH ₂ ) _n , (CH ₂ ) _n NH—, —CH═CH— or —CH═CH—CH═CH—.

Particularly preferably X is -CONH- or -CON(CH ₂ COOA)-.

Preferably Y is a cycloalkylene, Het-diradical or Ar-diradical which is unsubstituted or monosubstituted or disubstituted by the following groups, particularly preferably 1,4-phenylene: A, OA, Cl, F, COOCH ₃ , COOH, phenoxy or aminocarbonyl, also pyridinediyl, preferably pyridine-2,5-diyl, piperidinediyl or cyclohexylene. Y is in particular pyridinediyl, piperidinediyl, cyclohexylene or phenylene which is unsubstituted or monosubstituted or disubstituted by: A, OA, Cl, F, COOCH ₃ , COOH, phenoxy or aminocarbonyl.

Het is for example 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl; 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-pyrimidinyl, in addition preferably 1,2,3-triazole-1-, -4- or -5-yl; 1,2,4-triazol-1-, -3- or -5-yl; 1- or 5-tetrazolyl, 1,2,3-oxadiazole-4- or -5 - Base; 1,2,4-oxadiazol-3-or-5-yl; 1,3,4-thiadiazol-2-or-5-yl; 1,2,4-thiadiazol-3 - or -5-yl; 1,2,3-thiadiazol-4- or -5-yl; 3- or 4-pyridazinyl, pyrazinyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl; 4- or 5-isoindolyl; 1-, 2-, 4- or 5-benzimidazolyl; 1-, 3-, 4-, 5-, 6- or 7-benzopyrazolyl; 2-, 4-, 5-, 6- or 7-benzoxazolyl; 3-, 4-, 5-, 6- or 7-benzoisoxazole 2-, 4-, 5-, 6- or 7-benzothiazolyl; 2-, 4-, 5-, 6- or 7-benzisothiazolyl; 4-, 5-, 6-or 7-Benzo-2,1,3-oxadiazolyl; 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolinyl; 1-, 3-, 4-, 5 -, 6-, 7- or 8-isoquinolinyl; 3-, 4-, 5-, 6-, 7- or 8-cinnolinyl; 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl; 5- or 6-quinoxalinyl; 2-, 3-, 5-, 6-, 7- or 8-2H-benzo-1,4-oxazinyl; in addition preferably 1,3-Benzodioxol-5-yl, 1,4-benzodioxol-6-yl, 2,1,3-benzothiadiazol-4-or-5-yl or 2,1,3-benzoxadiazol-5-yl.

Heterocyclyl groups can also be partially or fully hydrogenated. Thus, Het can also be, for example, 2,3-dihydro-2-, -3-, -4- or -5-furyl; 2,5-dihydro-2-, -3-, -4- or - 5-furyl; tetrahydro-2- or -3-furyl, 1,3-dioxolan-4-yl, tetrahydro-2- or -3-thienyl, 2,3-dihydro-1 -, -2-, -3-, -4- or -5-pyrrolyl; 2,5-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl; 1- , 2- or 3-pyrrolidinyl; tetrahydro-1-, -2- or -4-imidazolyl; 2,3-dihydro-1-, -2-, -3-, -4- or -5 -pyrazolyl; tetrahydro-1-, -3- or -4-pyrazolyl; 1,4-dihydro-1-, -2-, -3- or -4-pyridyl; 1,2, 3,4-tetrahydro-1-, -2, -3-, -4-, -5- or -6-pyridyl; 1-, 2-, 3- or 4-piperidinyl; 2-, 3 - or 4-morpholinyl; tetrahydro-2-, -3- or -4-pyranyl; 1,4-dioxanyl, 1,3-dioxane-2-, -4- or - 5-yl; Hexahydro-1-, -3- or -4-pyridazinyl; Hexahydro-1-, -2-, -4- or -5-pyrimidinyl; 1-, 2- or 3-piperidinyl Azinyl; 1,2,3,4-tetrahydro-1-, -2, -3-, -4-, -5-, -6-, -7- or -8-quinolinyl; 1,2 , 3,4-tetrahydro-1-, -2, -3-, -4-, -5-, -6-, -7- or -8-isoquinolinyl; 2, 3-, 5-, 6-, 7- or 8-3,4-dihydro-2H-benzo-1,4-oxazinyl, furthermore preferably 2,3-methylenedioxyphenyl, 3,4-methylenedioxy phenyl, 2,3-ethylenedioxyphenyl, 3,4-ethylenedioxyphenyl, 3,4-(difluoromethylenedioxy)phenyl, 2,3-dihydro Benzofuran-5-or-6-yl, 2,3-(2-oxomethylenedioxy)phenyl or 3,4-dihydro-2H-1,5-benzodioxepin (benzodioxepin)-6- or -7-yl, furthermore preferably 2,3-dihydrobenzofuryl or 2,3-dihydro-2-oxofuryl.

Preferably Het' is, for example, 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 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-pyrimidinyl, furthermore preferably 1,2,3-triazole-1-, -4 - or -5-yl; 1,2,4-triazol-1-, -3- or -5-yl; 1- or 5-tetrazolyl, 1,2,3-oxadiazole-4- or -5-yl; 1,2,4-oxadiazol-3-or-5-yl; 1,3,4-thiadiazol-2-or-5-yl; 1,2,4-thiadiazole -3- or -5-yl; 1,2,3-thiadiazol-4- or -5-yl; 3- or 4-pyridazinyl, pyrazinyl, 1-, 2-, 3-, 4 -, 5-, 6- or 7-indolyl; 4- or 5-isoindolyl; 1-, 2-, 4- or 5-benzimidazolyl; 1-, 3-, 4-, 5 -, 6-, or 7-benzopyrazolyl; 2-, 4-, 5-, 6-, or 7-benzoxazolyl; 3-, 4-, 5-, 6-, or 7-benzoiso Oxazolyl; 2-, 4-, 5-, 6-, or 7-benzothiazolyl; 2-, 4-, 5-, 6-, or 7-benzisothiazolyl; 4-, 5-, 6 - or 7-benzo-2,1,3-oxadiazolyl; 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolinyl; 1-, 3-, 4- , 5-, 6-, 7- or 8-isoquinolinyl; 3-, 4-, 5-, 6-, 7- or 8-cinnolinyl; 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl; 5- or 6-quinoxalinyl; 2-, 3-, 5-, 6-, 7- or 8-2H-benzo-1,4-oxazinyl; Further preferred are 1,3-benzodioxol-5-yl, 1,4-benzodioxol-6-yl, 2,1,3-benzothiadiazole-4- or -5 -yl or 2,1,3-benzoxadiazol-5-yl.

Heterocyclyl groups can also be partially or fully hydrogenated. Thus, Het' can also be, for example, 2,3-dihydro-2-, -3-, -4- or -5-furyl; 2,5-dihydro-2-, -3-, -4- or -5-furyl; tetrahydro-2- or -3-furyl, 1,3-dioxolan-4-yl, tetrahydro-2- or -3-thienyl, 2,3-dihydro- 1-, -2-, -3-, -4- or -5-pyrrolyl; 2,5-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl; 1 -, 2- or 3-pyrrolidinyl; tetrahydro-1-, -2- or -4-imidazolyl; 2,3-dihydro-1-, -2-, -3-, -4- or - 5-pyrazolyl; Tetrahydro-1-, -3- or -4-pyrazolyl; 1,4-dihydro-1-, -2-, -3- or -4-pyridyl; 1,2 , 3,4-tetrahydro-1-, -2, -3-, -4-, -5- or -6-pyridyl; 1-, 2-, 3- or 4-piperidyl; 2-, 3- or 4-morpholinyl; Tetrahydro-2-, -3- or -4-pyranyl; 1,4-dioxanyl, 1,3-dioxane-2-, -4- or -5-yl; Hexahydro-1-, -3- or -4-pyridazinyl; Hexahydro-1-, -2-, -4- or -5-pyrimidinyl; 1-, 2- or 3- Piperazinyl; 1,2,3,4-tetrahydro-1-, -2, -3-, -4-, -5-, -6-, -7- or -8-quinolinyl; 1, 2,3,4-Tetrahydro-1-, -2, -3-, -4-, -5-, -6-, -7- or -8-isoquinolinyl; 2-, 3-, 5 -, 6-, 7- or 8-3,4-dihydro-2H-benzo-1,4-oxazinyl, furthermore preferably 2,3-methylenedioxyphenyl, 3,4-methylene Dioxyphenyl, 2,3-ethylenedioxyphenyl, 3,4-ethylenedioxyphenyl, 3,4-(difluoromethylenedioxy)phenyl, 2,3- Dihydrobenzofuran-5-or-6-yl, 2,3-(2-oxomethylenedioxy)phenyl or 3,4-dihydro-2H-1,5-benzodioxa Heptin-6- or -7-yl, furthermore preferably 2,3-dihydrobenzofuryl or 2,3-dihydro-2-oxofuryl.

Preferably T is a monocyclic or bicyclic, saturated or unsaturated heterocyclic ring with 1-2 N and/or O atoms, monosubstituted or disubstituted by: =O, =S, =NR ² , =N- CN, =NO ₂ , =NOR ² , =NCOR ² , =NCOOR ² or =NOCOCR ² may also be mono- or di-substituted by Hal, A or OA.

In yet another embodiment, it is preferred that T is, for example, 2-iminopiperidin-1-yl, 2-iminopyrrolidin-1-yl, 2-imino-1H-pyridin-1-yl, 3-imino Morpholine-4-yl, 4-imino-1H-pyridin-1-yl, 2,6-diiminopiperidin-1-yl, 2-iminopiperazin-1-yl, 2,6-di Iminopiperazin-1-yl, 2,5-diiminopyrrolidin-1-yl, 2-imino-1,3-oxazolidin-3-yl, 3-imino-2H-pyridazine- 2-yl, 2-iminoazepan-1-yl, 2-hydroxy-6-iminopiperazin-1-yl or 2-methoxy-6-iminopiperazin-1-yl.

T is in particular a monocyclic saturated or unsaturated heterocyclic ring with 1-2 N and/or O atoms, mono- or di-substituted by =O, =S or =NH, additionally monosubstituted by Hal, A and/or OA substitution or substitution.

Particularly preferred T is piperidin-1-yl, pyrrolidin-1-yl, pyridin-1-yl, morpholin-4-yl, piperazin-1-yl, 1,3-oxazolidin-3-yl, Pyridazin-2-yl, pyrazin-1-yl, azepan-1-yl, 2-azabicyclo[2.2.2]octan-2-yl, imidazolidinyl, thiazolyl or 1, 4-Oxazepanyl, each of which is monosubstituted or disubstituted by =O or =NH, and wherein each group may also be monosubstituted or disubstituted by Hal, A and/or OA; very particularly preferably 3- Oxomorpholin-4-yl. It is also preferred that T is 2-oxo-3-methoxy-1H-pyridin-1-yl.

Preferably D is phenyl, thienyl, pyridyl, furyl, thiazolyl, pyrrolyl or imidazolyl, each of which is monosubstituted or disubstituted by Hal, particularly preferably phenyl, pyridyl, thienyl, furyl or imidazolyl , each of which is monosubstituted or disubstituted by Hal.

preferred group For pyrrolidine-1,2-diyl, piperidine-1,2-diyl, piperidine-1,3-diyl, oxazolidine-3,4-or -3,5-diyl, thiazolidine -3,4-diyl, 2,5-dihydro-1H-pyrrole-1,5-diyl, 1,3-dioxolane-4,5-diyl, 1,3-oxaazepine Hexacyclo-3,4-diyl, piperazine-1,4-diyl, tetrahydrofuran-3,4-diyl or azetidine-1,2-diyl.

Compounds of formula I may possess one or more chiral centers and thus exist in various stereoisomeric forms. Formula I encompasses all such forms.

In particular, therefore, the invention relates to compounds of the formula I in which at least one of the radicals mentioned has one of the meanings preferably indicated above. Some preferred groups of the compounds and their pharmaceutically acceptable derivatives, solvates, salts and stereoisomers including mixtures thereof in various proportions can be represented by the following subformulas Ia to Iw, which The radicals which correspond to formula I and which are not specified in more detail are as defined in formula I, but in which:

in Ia

D is a monocyclic or bicyclic aromatic carbocyclic or heterocyclic ring with 0-4 N, O and/or S atoms, unsubstituted or monosubstituted or disubstituted by Hal;

in Ib

D is phenyl, pyridyl, thienyl, furyl or imidazolyl, each of which is monosubstituted or disubstituted by Hal;

in Ic

R ¹ , R ² , independently of each other, are each H, =O, COOR ³ , OH, OA, NH ₂ , alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, N ₃ , ethynyl, Vinyl, Allyloxy, NHCOA, NHSO ₂ A, OCH ₂ COOA or OCH ₂ COOH;

in Id

G is (CH ₂ ) _n , (CH ₂ ) _n NH-, -CH=CH- or -CH=CH-CH=CH-;

in Ie

X is -[C(R ⁴ ) ₂ ] _n CONR ³ [C(R ⁴ ) ₂ ] _n -;

in if

X is -CONH- or -CON(CH ₂ COOA)-;

in Ig

Y is cycloalkylene, Het-diradical or Ar-diradical;

in Ih

Y is pyridine diyl, piperidine diyl, cyclohexylene, or 1,4-phenylene unsubstituted or monosubstituted or disubstituted by the following groups: A, OA, Cl, F, COOCH ₃ , COOH, Phenoxy or aminocarbonyl;

in Ii

T is a monocyclic, saturated or unsaturated heterocyclic ring with 1-2 N and/or O atoms, monosubstituted or disubstituted by =O, =S or =NH, and may be monosubstituted by Hal, A and/or OA substitution or secondary substitution;

in Ij

T is piperidin-1-yl, pyrrolidin-1-yl, pyridin-1-yl, morpholin-4-yl, piperazin-1-yl, 1,3-oxazolidin-3-yl, pyridazine -2-yl, pyrazin-1-yl, azepan-1-yl, 2-azabicyclo[2.2.2]octane-2-yl, imidazolidinyl, thiazolyl or 1,4- Oxazepanyl, each of which is monosubstituted or disubstituted by =O or =NH, and wherein each group may also be monosubstituted or disubstituted by Hal, A and/or OA;

in Ik

Ar is phenyl that is unsubstituted or monosubstituted or disubstituted by the following groups: Hal, A, OA, SO ₂ A, COOR ³ , SO ₂ NH ₂ , CN, COOA, COOH or phenoxy;

in Il

D is a monocyclic or bicyclic, aromatic carbocyclic or heterocyclic ring with 0-4 N, O and/or S atoms, unsubstituted or monosubstituted or disubstituted by Hal,

R ¹ , R ² , independently of each other, are each H, =O, COOR ³ , OH, OA, NH ₂ , alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, N ₃ , ethynyl, Vinyl, Allyloxy, NHCOA, NHSO ₂ A, OCH ₂ COOA or OCH ₂ COOH,

Alternatively, R ¹ and R ² are together a 3-6 membered carbocyclic ring connected by a spiro ring,

R ³ is H, A, phenyl, benzyl or [C(R ⁴ ) ₂ ] _n COOA,

^R4 is H or A,

W is N, CR ³ or sp ² -hybridized carbon atom,

E together with W is a 3-7 membered saturated carbocyclic or heterocyclic ring with 0-3 N, 0-2 O and/or 0-2 S atoms,

It may contain double bonds,

G is (CH ₂ ) _n , (CH ₂ ) _n NH-, -CH=CH- or -CH=CH-CH=CH-,

X is -[C(R ⁴ ) ₂ ] _n CONR ³ [C(R ⁴ ) ₂ ] _n -,

Y is cycloalkylene, Het-diradical or Ar-diradical,

Ar is phenyl which is unsubstituted or monosubstituted or disubstituted by Hal, A, OA, SO ₂ A, COOR ² , SO ₂ NH ₂ , CN, COOA, COOH or phenoxy,

T is a monocyclic, saturated or unsaturated heterocyclic ring with 1-2 N and/or O atoms, monosubstituted or disubstituted by =O, =S or =NH, and may be monosubstituted by Hal, A and/or OA substituted or disubstituted,

A is a non-branched or branched chain alkyl group with 1-10 carbon atoms, and wherein 1-7 H atoms 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, each of which is monosubstituted or disubstituted by Hal;

R ¹ , R ² , independently of each other, are each H, =O, COOR ³ , OH, OA, NH ₂ , alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, N ₃ , ethynyl, Vinyl, Allyloxy, NHCOA, NHSO ₂ A, OCH ₂ COOA or OCH ₂ COOH,

Alternatively, R ¹ and R ² are together a 3-6 membered carbocyclic ring connected by a spiro ring,

R ³ is H, A or CH ₂ COOA,

^R4 is H or A,

W is N, CR ³ or sp ² -hybridized carbon atom,

E together with W is a 3-7 membered saturated carbocyclic or heterocyclic ring with 0-3 N, 0-2 O and/or 0-2 S atoms,

It may contain double bonds,

G is (CH ₂ ) _n , (CH ₂ ) _n NH-, -CH=CH- or -CH=CH-CH=CH-,

X is -CONH- or -CON( _CH2COOA )-,

Y is pyridinediyl, piperidinediyl, cyclohexylene, or phenylene unsubstituted or monosubstituted or disubstituted by the following groups: A, OA, Cl, F, COOCH ₃ , COOH, phenoxy or aminocarbonyl,

T is piperidin-1-yl, pyrrolidin-1-yl, pyridin-1-yl, morpholin-4-yl, piperazin-1-yl, 1,3-oxazolidin-3-yl, pyridazine -2-yl, pyrazin-1-yl, azepan-1-yl, 2-azabicyclo[2.2.2]octane-2-yl, imidazolidinyl, thiazolyl or 1,4- Oxazepanyl, each of which is monosubstituted or disubstituted by =O or =NH, and wherein each group may also be monosubstituted or disubstituted by Hal, A and/or OA

A is a non-branched or branched chain alkyl group with 1-10 carbon atoms, and wherein 1-7 H atoms can be replaced by F,

Hal is F, Cl, Br or I,

n is 0, 1 or 2;

in

D is phenyl, pyridyl or thienyl, each of which is monosubstituted or disubstituted by Hal,

R ¹ is H, =O, COOR ³ , OH, OA, NH ₂ , alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, N ₃ , ethynyl, vinyl, allyloxy , -OCOR ³ , NHCOA or NHSO ₂ A,

^R is H, =O, OH, OA or alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms,

Alternatively, R ¹ and R ² are together a 3-6 membered carbocyclic ring connected by a spiro ring,

^R3 is H or A,

^R4 is H or A,

For pyrrolidine-1,2-diyl, piperidine-1,2-diyl, oxazolidine-3,4- or 3,5-diyl, thiazolidine-3,4-diyl, 2,5 -Dihydro-1H-pyrrole-1,5-diyl, 1,3-dioxolane-4,5-diyl, 1,3-oxazepine-3,4-diyl, piperidine Oxyzine-1,4-diyl, tetrahydrofuran-3,4-diyl or azetidine-1,2-diyl,

G is (CH ₂ ) _n or (CH ₂ ) _n NH-,

X is CONH,

Y is 1,3- or 1,4-phenylene which is unsubstituted or monosubstituted or disubstituted by: methyl, trifluoromethyl, ethyl, propyl, Cl or F,

T is piperidin-1-yl, pyrrolidin-1-yl, 1H-pyridin-1-yl, morpholin-4-yl, piperazin-1-yl, 1,3-oxazolidin-3-yl, 2H-pyridazin-2-yl, pyrazin-1-yl, azepan-1-yl or 2-azabicyclo[2.2.2]octan-2-yl, each monosubstituted by carbonyloxy or two substitutions,

A is a non-branched or branched chain alkyl group with 1-10 carbon atoms, and wherein 1-7 H atoms 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, each of which is monosubstituted or disubstituted by Hal,

R ¹ is H, =O, COOR ³ , OH, OA, NH ₂ , alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, N ₃ , ethynyl, vinyl, allyloxy , -OCOR ³ , NHCOA or NHSO ₂ A,

^R is H, =O, OH, OA or alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms,

Alternatively, R ¹ and R ² are together a 3-6 membered carbocyclic ring connected by a spiro ring,

^R3 is H or A,

^R4 is H or A,

为吡咯烷-1，2-二基、哌啶-1，2-二基、噁唑烷-3，4-或3，5-二基、噻唑烷-3，4-二基、2，5-二氢-1H-吡咯-1，5-二基、1，3-二氧戊环-4，5-二基、1，3-氧杂氮杂己环-3，4-二基、哌嗪-1，4-二基、四氢呋喃-3，4-二基或氮杂环丁烷-1，2-二基，

For pyrrolidine-1,2-diyl, piperidine-1,2-diyl, oxazolidine-3,4- or 3,5-diyl, thiazolidine-3,4-diyl, 2,5 -Dihydro-1H-pyrrole-1,5-diyl, 1,3-dioxolane-4,5-diyl, 1,3-oxazepine-3,4-diyl, piperidine Oxyzine-1,4-diyl, tetrahydrofuran-3,4-diyl or azetidine-1,2-diyl,

G is (CH ₂ ) _n or (CH ₂ ) _n NH-,

X is CONH,

Y is 1,3- or 1,4-phenylene which is unsubstituted or monosubstituted or disubstituted by: methyl, trifluoromethyl, ethyl, propyl, Cl or F,

T is morpholin-4-yl monosubstituted or disubstituted by carbonyl oxygen,

A is a non-branched or branched chain alkyl group with 1-10 carbon atoms, and wherein 1-7 H atoms 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 ] _n CONR ³ [C(R ⁴ ) ₂ ] _n - or -[C(R ⁴ ) ₂ ] _n CO[C(R ⁴ ) ₂ ] _n -;

in Iq

X is CONH or COCH ₂ ,

in Ir

D is phenyl, pyridyl or thienyl, each of which is monosubstituted or disubstituted by Hal,

R ¹ is H, =O, COOR ³ , OH, OA, NH ₂ , alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, N ₃ , ethynyl, vinyl, allyloxy , -OCOR ³ , NHCOA or NHSO ₂ A,

^R is H, =O, OH, OA or alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms,

Alternatively, R ¹ and R ² are together a 3-6 membered carbocyclic ring connected by a spiro ring,

^R3 is H or A,

^R4 is H or A,

For pyrrolidine-1,2-diyl, piperidine-1,2-diyl, oxazolidine-3,4- or 3,5-diyl, thiazolidine-3,4-diyl, 2,5 -Dihydro-1H-pyrrole-1,5-diyl, 1,3-dioxolane-4,5-diyl, 1,3-oxazepine-3,4-diyl, piperidine Oxyzine-1,4-diyl, tetrahydrofuran-3,4-diyl or azetidine-1,2-diyl,

G is (CH ₂ ) _n or (CH ₂ ) _n NH-,

X is CONH or COCH ₂ ,

Y is 1,3- or 1,4-phenylene which is unsubstituted or monosubstituted or disubstituted by: methyl, trifluoromethyl, ethyl, propyl, Cl or F,

T is morpholin-4-yl monosubstituted or disubstituted by carbonyl oxygen,

A is a non-branched or branched chain alkyl group with 1-10 carbon atoms, and wherein 1-7 H atoms can be replaced by F,

Hal is F, Cl, Br or I,

n is 0, 1 or 2,

in Is

D is a monocyclic or bicyclic, aromatic carbocyclic or heterocyclic ring with 0-4 N, O and/or S atoms, unsubstituted or monosubstituted or disubstituted by Hal,

R ¹ , R ² , independently of each other, are each H, =O, COOR ³ , OH, OA, NH ₂ , alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, N ₃ , ethynyl, vinyl, allyloxy, -OCOR ³ , NHCOA or NHSO ₂ A,

Alternatively, R ¹ and R ² are together a 3-6 membered carbocyclic ring connected by a spiro ring,

^R3 is H or A,

^R4 is H or A,

W is N, CR ³ or sp ² -hybridized carbon atom,

E together with W is a 3-7 membered saturated carbocyclic or heterocyclic ring with 0-3 N, 0-2 O and/or 0-2 S atoms,

It may contain double bonds,

G is (CH ₂ ) _n or (CH ₂ ) _n NH-,

X is -[C(R ⁴ ) ₂ ] _n CONR ³ [C(R ⁴ ) ₂ ] _n -or-[C(R ⁴ ) ₂ ] _n CO[C(R ⁴ ) ₂ ] _n -,

Y is Ar-diradical,

Ar is phenyl which is unsubstituted or monosubstituted or disubstituted by Hal, A, OA, SO ₂ A, COOR ² , SO ₂ NH ₂ or CN,

T is morpholin-4-yl monosubstituted or disubstituted by carbonyl oxygen,

A is a non-branched or branched chain alkyl group with 1-10 carbon atoms, and wherein 1-7 H atoms 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, each of which is monosubstituted or disubstituted by Hal,

R ¹ is H, =O, COOR ³ , OH, OA, NH ₂ , alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, N ₃ , ethynyl, vinyl, allyloxy , -OCOR ³ , NHCOA, NHSO ₂ A, CH ₃ -C≡C-CH ₂ -O-, -O-CH ₂ -CH(OH)-CH ₂ OH, -O-CH ² -CH(OH)- _CH2NH2 or _-O - _CH2 -CH(OH) _-CH2Het ',

^R is H, =O, OH, OA or alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms,

Alternatively, R ¹ and R ² are together a 3-6 membered carbocyclic ring connected by a spiro ring,

^R3 is H or A,

^R4 is H or A,

为吡咯烷-1，2-二基、哌啶-1，2-二基、噁唑烷-3，4-或3，5-二基、噻唑烷-3，4-二基、2，5-二氢-1H-吡咯-1，5-二基、1，3-二氧戊环-4，5-二基、1，3-氧杂氮杂己环-3，4-二基、哌嗪-1，4-二基、四氢呋喃-3，4-二基或氮杂环丁烷-1，2-二基，

For pyrrolidine-1,2-diyl, piperidine-1,2-diyl, oxazolidine-3,4- or 3,5-diyl, thiazolidine-3,4-diyl, 2,5 -Dihydro-1H-pyrrole-1,5-diyl, 1,3-dioxolane-4,5-diyl, 1,3-oxazepine-3,4-diyl, piperidine Oxyzine-1,4-diyl, tetrahydrofuran-3,4-diyl or azetidine-1,2-diyl,

G is (CH ₂ ) _n or (CH ₂ ) _n NH-,

X is CONH or COCH ₂ ,

Y is 1,3- or 1,4-phenylene which is unsubstituted or monosubstituted or disubstituted by: methyl, trifluoromethyl, ethyl, propyl, Cl or F,

T is morpholin-4-yl monosubstituted or disubstituted by carbonyl oxygen,

Het' is a saturated 3-6 membered heterocyclic ring with 1-3 N and/or O atoms, which may be unsubstituted or mono- or di-substituted by the following groups: carbonyl oxygen, Hal, A, OH, NH ₂ , NO ₂ , CN, COOA or CONH ₂ ,

A is a non-branched or branched chain alkyl group with 1-10 carbon atoms, and wherein 1-7 H atoms 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, each of which is monosubstituted or disubstituted by Hal,

R ¹ is H, =O, COOR ³ , OH, OA, NH ₂ , alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, N ₃ , ethynyl, vinyl, allyloxy , -OCOR ³ , NHCOA, NHSO ₂ A, HC≡C-CH ₂ -, CH ₃ -C≡C-CH ₂ -O-, -O-CH ₂ -CH(OH)-CH ₂ OH, -O- _CH2 -CH(OH) _-CH2NH2 or _-O - _CH2 -CH(OH) _-CH2Het ',

^R is H, =O, OH, OA or alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms,

Alternatively, R ¹ and R ² are together a 3-6 membered carbocyclic ring connected by a spiro ring,

^R3 is H or A,

^R4 is H or A,

为吡咯烷-1，2-二基、哌啶-1，2-二基、噁唑烷-3，4-或3，5-二基、噻唑烷-3，4-二基、2，5-二氢-1H-吡咯-1，5-二基、1，3-二氧戊环-4，5-二基、1，3-氧杂氮杂己环-3，4-二基、哌嗪-1，4-二基、四氢呋喃-3，4-二基或氮杂环丁烷-1，2-二基，

For pyrrolidine-1,2-diyl, piperidine-1,2-diyl, oxazolidine-3,4- or 3,5-diyl, thiazolidine-3,4-diyl, 2,5 -Dihydro-1H-pyrrole-1,5-diyl, 1,3-dioxolane-4,5-diyl, 1,3-oxazepine-3,4-diyl, piperidine Oxyzine-1,4-diyl, tetrahydrofuran-3,4-diyl or azetidine-1,2-diyl,

G is (CH ₂ ) _n or (CH ₂ ) _n NH-,

X is CONH, COCH ₂ , CO or COO,

Y is 1,3- or 1,4-phenylene which is unsubstituted or monosubstituted or disubstituted by: methyl, trifluoromethyl, ethyl, propyl, Cl or F,

T is morpholin-4-yl monosubstituted or disubstituted by carbonyl oxygen,

Het' is a saturated 3-6 membered heterocyclic ring with 1-3 N and/or O atoms, which may be unsubstituted or mono- or di-substituted by the following groups: carbonyl oxygen, Hal, A, OH, NH ₂ , NO ₂ , CN, COOA or CONH ₂ ,

A is a non-branched or branched chain alkyl group with 1-10 carbon atoms, and wherein 1-7 H atoms 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, each of which is monosubstituted or disubstituted by Hal,

R ¹ is ethynyl, vinyl, allyloxy, CH ₃ -C≡C-CH ₂ -O-, -O-CH ₂ -CH(OH)-CH ₂ OH, -O-CH ₂ -CH( OH)-CH ₂ NH ₂ or -O-CH ₂ -CH(OH)-CH ₂ Het',

^R2 is H or OH,

Alternatively, R ¹ and R ² are together a 3-6 membered carbocyclic ring connected by a spiro ring,

^R3 is H or A,

^R4 is H or A,

For pyrrolidine-1,2-diyl, piperidine-1,2-diyl, oxazolidine-3,4- or 3,5-diyl, thiazolidine-3,4-diyl, 2,5 -Dihydro-1H-pyrrole-1,5-diyl, 1,3-dioxolane-4,5-diyl, 1,3-oxazepine-3,4-diyl, piperidine Oxyzine-1,4-diyl, tetrahydrofuran-3,4-diyl or azetidine-1,2-diyl,

G is (CH ₂ ) _n or (CH ₂ ) _n NH-,

X is CONH, CO, COO or COCH ₂ ,

Y is 1,3- or 1,4-phenylene which is unsubstituted or monosubstituted or disubstituted by: methyl, trifluoromethyl, ethyl, propyl, Cl or F,

T is piperidin-1-yl, pyrrolidin-1-yl, 1H-pyridin-1-yl, morpholin-4-yl, piperazin-1-yl, 1,3-oxazolidin-3-yl, 2H-pyridazin-2-yl, pyrazin-1-yl, azepan-1-yl or 2-azabicyclo[2.2.2]octane-2-yl, each of which is replaced by carbonyl oxygen or OA monosubstituted or disubstituted,

Het' is a saturated 3-6 membered heterocyclic ring with 1-3 N and/or O atoms, which may be unsubstituted or mono- or di-substituted by the following groups: carbonyl oxygen, Hal, A, OH, NH ₂ , NO ₂ , CN, COOA or CONH ₂ ,

A is a non-branched or branched chain alkyl group with 1-10 carbon atoms, and wherein 1-7 H atoms 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, each of which is monosubstituted or disubstituted by Hal,

R ¹ is H, =O, COOR ³ , OH, OA, NH ₂ , alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, N ₃ , ethynyl, vinyl, allyloxy , NHCOA, NHSO ₂ A, OCH ₂ COOA or OCH ₂ COOH,

^R is H, =O, OH, OA or alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms,

Alternatively, R ¹ and R ² are together a 3-6 membered carbocyclic ring connected by a spiro ring,

^R3 is H or A,

^R4 is H or A,

为吡咯烷-1，2-二基、哌啶-1，2-二基、噁唑烷-3，4-或3，5-二基、噻唑烷-3，4-二基、2，5-二氢-1H-吡咯-1，5-二基、1，3-二氧戊环-4，5-二基、1，3-氧杂氮杂己环-3，4-二基、哌嗪-1，4-二基、四氢呋喃-3，4-二基或氮杂环丁烷-1，2-二基，

For pyrrolidine-1,2-diyl, piperidine-1,2-diyl, oxazolidine-3,4- or 3,5-diyl, thiazolidine-3,4-diyl, 2,5 -Dihydro-1H-pyrrole-1,5-diyl, 1,3-dioxolane-4,5-diyl, 1,3-oxazepine-3,4-diyl, piperidine Oxyzine-1,4-diyl, tetrahydrofuran-3,4-diyl or azetidine-1,2-diyl,

G is (CH ₂ ) _n , (CH ₂ ) _n NH-, -CH=CH- or -CH=CH-CH=CH-,

X is CONH, CONH ₂ or -CON(CH ₂ COOA)-,

Y is pyridinediyl, piperidinediyl, cyclohexylene, or phenylene unsubstituted or monosubstituted or disubstituted by the following groups: A, OA, Cl, F, COOCH ₃ , COOH, phenoxy or aminocarbonyl,

T is morpholin-4-yl monosubstituted or disubstituted by carbonyl oxygen,

A is a non-branched or branched chain alkyl group with 1-10 carbon atoms, and wherein 1-7 H atoms can be replaced by F,

Hal is F, Cl, Br or I,

n is 0, 1 or 2.

In addition, the compounds of the formula I and the starting materials for their preparation can be obtained by methods known per se as described in the literature (e.g. in standard works such as Houben-Weyl, Methoden der organischen Chemie [Methods of Organic Chemistry], Georg-Thieme-Verlag, Stuttgart) The preparation is carried out precisely under reaction conditions known and suitable for the reaction in question. It is also possible to use variants which are known per se, but which are not mentioned here in greater detail.

If desired, the starting materials can also be formed in situ, so that they do not have to be isolated from the reaction mixture, but they are further converted immediately to compounds of the formula I.

The starting compounds of the formulas II, III, IV, V and VI are generally known. If they are new, however, they can be prepared by methods known per se.

Compounds of formula I are preferably obtained by reacting compounds of formula II with compounds of formula III.

Usually the reaction is carried out in an inert solvent in the presence of an acid binder, preferably an alkali or alkaline earth metal hydroxide, carbonate or bicarbonate, or another form of an alkali or alkaline earth metal, preferably potassium, sodium, calcium or cesium. A weak salt. It may also be advantageous to add an organic base such as triethylamine, xylidine, pyridine or quinoline, or an excess of a phenolic component of formula II or an alkylated derivative of formula III. The reaction time is several minutes to 14 days, and the reaction temperature is about 0°C to 150°C, usually 20°C to 130°C, depending on the conditions used.

Examples of suitable inert solvents are hydrocarbons such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons such as trichloroethylene, 1,2-dichloroethane, tetrachloromethane, chloroform or dichloromethane; alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers such as diethyl ether, isopropyl ether, tetrahydrofuran (THF) or dioxane; glycol ethers such as ethylene glycol monomethyl ether or mono Ethyl ether or ethylene glycol dimethyl ether (diglyme); ketones such as acetone or methyl ethyl ketone; amides such as acetamide, dimethylacetamide or dimethylformamide (DMF); nitriles such as acetonitrile; sulfoxides For example dimethylsulfoxide (DMSO); carbon disulfide; carboxylic acids such as formic acid or acetic acid; nitro compounds such as nitromethane or nitrobenzene; esters such as ethyl acetate, or mixtures of said solvents.

Furthermore, compounds of formula I can preferably be obtained by reacting compounds of formula IV with compounds of formula V. Usually the reaction is carried out in an inert solvent under the above conditions. In the compound of formula V, preferably L is Cl, Br, I or a free or active modified OH group, such as activated ester, imidazolide (imidazolide) or an alkylsulfonyloxy group with 1-6 carbon atoms (preferably methylsulfonyloxy or trifluoromethylsulfonyloxy) or arylsulfonyloxy having 6 to 10 carbon atoms (preferably phenyl or p-tolylsulfonyloxy). Such groups for activation of carbonyl groups in typical acylation reactions are described in the literature (e.g. in standard works such as Houben-Weyl, Methoden derorganischen Chemie [Methods of Organic Chemistry], Georg-Thieme-Verlag, Stuttgart;). Preferably the activated ester is formed in situ, for example by addition of HOBt or N-hydroxysuccinimide.

Usually the reaction is carried out in an inert solvent in the presence of an acid binder, preferably an organic base such as DIPEA, triethylamine, xylidine, pyridine or quinoline, or an excess of the carboxyl component of formula V. It may also be advantageous to add an alkali or alkaline earth metal hydroxide, carbonate or bicarbonate, or another weak acid salt of an alkali or alkaline earth metal, preferably potassium, sodium, calcium or cesium. The reaction time is several minutes to 14 days, and the reaction temperature is about -30°C to 140°C, usually -10°C to 90°C, especially about 0°C to about 70°C, depending on the conditions used. Suitable inert solvents are those inert solvents mentioned above.

Furthermore, compounds of formula I can preferably be obtained by reacting compounds of formula II with compounds of formula VI. Usually the reaction is carried out in an inert solvent under the above conditions. In the compound of formula VI, preferably L is Cl, Br, I or a free or active modified OH group, such as an activated ester, imidazolate or an alkylsulfonyloxy group (preferably methylsulfonyl) having 1-6 carbon atoms acyloxy or trifluoromethylsulfonyloxy) or arylsulfonyloxy having 6-10 carbon atoms (preferably phenyl or p-tolylsulfonyloxy).

In addition, it is preferred to generate a carbamate intermediate by reacting a compound of the formula D-NH wherein D is defined in accordance with claim ₁ with a chloroformate derivative such as 4-nitrophenyl chloroformate, and then making the intermediate Reaction with a compound of formula II affords a compound of formula I. The reaction is carried out under the above conditions.

Alternatively, compounds of formula I can be isolated from one of their functional derivatives by treatment with a solvolytic or hydrogenolytic reagent to give a compound of formula I.

Preferred starting materials for solvolysis and hydrogenolysis are those corresponding to formula I, but containing corresponding protected amino and/or hydroxyl groups instead of one or more free amino and/or hydroxyl groups, preferably with amino protecting groups instead of Those starting materials with an N atom bonded to an H atom, specifically those bearing an R'-N group in which R' is an amino protecting group instead of an HN group, and/or bearing a hydroxyl protecting group instead of a hydroxyl Those starting materials for the H atom, for example those conforming to formula I but bearing a -COOR" group in place of a -COOH group wherein R" is a hydroxyl protecting group.

It is also possible that several identical or different protected amino and/or hydroxyl groups are present in the starting molecule. If the protecting groups present are different from each other, they can in many cases be selectively cleaved.

The term "amino-protecting group" is known in general terms and relates to a group which is suitable for protecting (blocking) an amino group against chemical reaction, but which can be easily removed after the desired chemical reaction elsewhere in the molecule. Typical of such groups are in particular unsubstituted or substituted acyl, aryl, aralkoxymethyl or aralkyl groups. Since the amino protecting groups are removed after the desired reaction (or sequence of reactions), their type and size are not critical; however, those having 1-20, especially 1-8 carbon atoms are preferred. The term "acyl" is to be understood in the broadest sense associated with existing methods. It includes acyl groups derived from aliphatic, araliphatic, aromatic or heterocyclic carboxylic or sulfonic acids, in particular alkoxycarbonyl, aryloxycarbonyl and especially aralkoxycarbonyl . Examples of such acyl groups are alkanoyl such as acetyl, propionyl and butyryl; aralkanoyl such as phenylacetyl; aroyl such as benzoyl and tolyl; aryloxyalkanoyl such as POA; ylcarbonyl such as methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, BOC (tert-butoxycarbonyl) and 2-iodoethoxycarbonyl; aralkoxycarbonyl such as CBZ ("Carbophenyl"), 4-methoxybenzyloxycarbonyl and FMOC; and arylsulfonyl such as Mtr. Preferred amino protecting groups are BOC and Mtr, furthermore CBZ, Fmoc, benzyl and acetyl.

The term "hydroxyl protecting group" is likewise known in general terms and relates to a group which is suitable for protecting a hydroxyl group against chemical reactions, but which can be easily removed after the desired chemical reaction elsewhere in the molecule. Typical of such groups are the abovementioned unsubstituted or substituted aryl, aralkyl or acyl groups, furthermore also alkyl groups. The nature and size of the hydroxy-protecting groups are unimportant since they are removed again after the desired chemical reaction or sequence of reactions; groups having 1-20, especially 1-10, carbon atoms are preferred. Among them, examples of hydroxyl protecting groups are benzyl, 4-methoxybenzyl, p-nitrobenzoyl, p-toluenesulfonyl, tert-butyl and acetyl, among which benzyl and tert-butyl are particularly preferred.

Compounds of formula I are isolated from their functional derivatives - depending on the protecting group used - for example using strong acids, preferably TFA or perchloric acid, but also other strong mineral acids such as hydrochloric acid or sulfuric acid; strong organic carboxyl Acids such as trichloroacetic acid, or sulfonic acids such as benzene or p-toluenesulfonic acid. Other inert solvents can be present but are not always necessary. Preferred suitable inert solvents are organic solvents such as carboxylic acids such as acetic acid; ethers such as tetrahydrofuran or dioxane; amides such as DMF; halogenated hydrocarbons such as dichloromethane, furthermore alcohols such as methanol, ethanol or isopropanol and water. Furthermore, mixtures of the aforementioned solvents are suitable. Preferably TFA is used in excess without addition of other solvents, preferably perchloric acid is used in the form of a 9:1 mixture of acetic acid and 70% perchloric acid. The reaction temperature for the dissociation is preferably about 0 to about 50°C, preferably 15 to 30°C (room temperature).

The BOC, OBut and Mtr groups may be preferably cleaved, for example at 15-30°C with TFA in dichloromethane or with about 3 to 5N HCl in dioxane, FMOC groups may be available with about 5% to 50% di The DMF solution of methylamine, diethylamine or piperidine dissociates at 15-30°C.

Hydrogenolytically removable protecting groups such as CBZ, benzyl or oxadiazole derivatives thereof can be cleaved, for example by treatment with hydrogen in the presence of a catalyst such as a noble metal catalyst such as palladium preferably on a support such as carbon. isolated amidine groups). Suitable solvents here are those mentioned above, in particular alcohols such as methanol or ethanol, or amides such as DMF. The hydrogenolysis is generally carried out at a temperature of about 0 to 100° C. and a pressure of about 1 to 200 bar, preferably 20-30° C. and 1-10 bar. CBZ group hydrogenolysis can be successfully accomplished eg at 20-30°C in 5% to 10% Pd/C in methanol or using ammonium formate (instead of hydrogen)-Pd/C in methanol/DMF.

Examples of suitable inert solvents are hydrocarbons such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons such as trichloroethylene, 1,2-dichloroethane, tetrachloromethane, trifluoromethylbenzene, chloroform or Dichloromethane; alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol, or t-butanol; ethers such as diethyl ether, isopropyl ether, tetrahydrofuran (THF) or dioxane; glycol ethers such as ethylene glycol Alcohol monomethyl ether or monoethyl ether or ethylene glycol dimethyl ether (diglyme); ketones such as acetone or methyl ethyl ketone; amides such as acetamide, dimethylacetamide, N-methyl-pyrrolidone (NMP) or dimethylformamide (DMF); nitriles such as acetonitrile; sulfoxides such as dimethylsulfoxide (DMSO); carbon disulfide; carboxylic acids such as formic acid or acetic acid; nitro compounds such as nitromethane or nitrobenzene; esters such as ethyl acetate esters, or mixtures of said solvents.

Esters are saponifiable at 0 to 100° C., for example with acetic acid or with NaOH or KOH in water, water/THF or water/dioxane solutions.

In addition, the free amino groups can be converted to acid chlorides or anhydrides according to conventional methods, preferably in an inert solvent such as dichloromethane or THF and/or in the presence of a base such as triethylamine or pyridine, at -60°C to +30°C. Acylation, or alkylation of the free amino group with unsubstituted or substituted alkyl halides or with CH3 _- C(=NH)-OEt.

Bases of formula I can be converted into the relevant acid addition salts with acids, for example by reacting equivalent amounts of base and acid in an inert solvent such as ethanol followed by evaporation. Acids which are particularly suitable for this reaction are those which afford physiologically acceptable salts. Thus, inorganic acids such as sulfuric acid, nitric acid, hydrohalic acids such as hydrochloric acid or hydrobromic acid, phosphoric acids such as orthophosphoric acid or sulfamic acid, furthermore organic acids, especially aliphatic acids, alicyclic acids, araliphatic acids, aromatic acids, can be used Or heterocyclic mono- or polycarboxylic acids, sulfonic acids or sulfuric acids, such as formic acid, acetic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, Lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, ascorbic acid, niacin, isonicotinic acid, methanesulfonic acid or ethanesulfonic acid, ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluene Sulfonic acid, naphthalene monosulfonic acid and naphthalene disulfonic acid and lauryl sulfuric acid. Salts of physiologically unacceptable acids, such as picrates, can be used to isolate and/or purify compounds of formula I.

On the other hand, the compounds of formula I can be converted into the corresponding metal salts, especially alkali metal or alkaline earth metal salts, or into the corresponding ammonium salts with bases such as sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate . Physiologically acceptable organic bases such as ethanolamine may also be used.

The present invention also relates to formula I-1 intermediate compound and its isomer and salt

in

D is phenyl, pyridyl, thienyl, furyl or imidazolyl, each of which is monosubstituted or disubstituted by Hal,

^R is H, OH, OA, alkyl or ethynyl having 1, 2, 3, 4, 5 or 6 carbon atoms,

R ^is H, OH, OA or an alkyl group having 1, 2, 3, 4, 5 or 6 carbon atoms,

为吡咯烷-1，2-二基、哌啶-1，2-二基、噁唑烷-3，4-或3，5-二基，

For pyrrolidine-1,2-diyl, piperidine-1,2-diyl, oxazolidine-3,4- or 3,5-diyl,

G is (CH ₂ ) _n , (CH ₂ ) _n NH-, -CH=CH- or -CH=CH-CH=CH-;

X is COOH,

A is an alkyl group having 1, 2, 3, 4, 5 or 6 carbon atoms,

Hal is F, Cl, Br or I,

n is 0, 1 or 2.

Particular preference is given to compounds and their isomers and salts selected from the group consisting of:

3-(4-Chlorophenylcarbamoyl)oxazolidine-4-carboxylic acid,

3-(5-Chlorothiophene-2-carbonyl)oxazolidine-5-carboxylic acid.

These compounds are described in Example 2.

Furthermore the present invention relates to the following compounds and their isomers and salts:

(2R,4S)-BOC-4-ethynyl-4-hydroxypyrrolidine-2-carboxylic acid,

(2R,4R)-BOC-4-ethynyl-4-hydroxypyrrolidine-2-carboxylic acid,

(2R,4S)-BOC-4-ethynyl-4-hydroxypyrrolidine-2-carboxylic acid alkyl ester,

(2R,4R)-BOC-4-ethynyl-4-hydroxypyrrolidine-2-carboxylic acid alkyl ester,

wherein the alkyl group has 1, 2, 3, 4, 5 or 6 carbon atoms.

The method of preparation is described in Example 8a.

In addition the present invention relates to formula I-2 intermediate compound and its isomer and salt:

in

R ¹ is H, =O, COOR ³ , OH, OA, NH ₂ , alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, N ₃ , ethynyl, vinyl, allyloxy , NHCOA, NHSO ₂ A, OCH ₂ COOA or OCH ₂ COOH,

R ^is H, OH, OA or an alkyl group having 1, 2, 3, 4, 5 or 6 carbon atoms,

Alternatively, R ¹ and R ² are together a 3-6 membered carbocyclic ring connected by a spiro ring,

^R3 is H or A,

为吡咯烷-1，2-二基、哌啶-1，2-二基、噁唑烷-3，4-或3，5-二基，

For pyrrolidine-1,2-diyl, piperidine-1,2-diyl, oxazolidine-3,4- or 3,5-diyl,

X is CONH,

Y is 1,3- or 1,4-phenylene which is unsubstituted or monosubstituted or disubstituted by: methyl, trifluoromethyl, ethyl, propyl, Cl or F,

T is piperidin-1-yl, pyrrolidin-1-yl, 1H-pyridin-1-yl, morpholin-4-yl, piperazin-1-yl, 1,3-oxazolidin-3-yl, 2H-pyridazin-2-yl, pyrazin-1-yl, azepan-1-yl or 2-azabicyclo[2.2.2]octan-2-yl, each monosubstituted by carbonyloxy or two substitutions,

A is an alkyl group having 1, 2, 3, 4, 5 or 6 carbon atoms,

Hal is F, Cl, Br or I,

n is 0, 1 or 2.

In addition, the present invention relates in particular to intermediate compounds of formula I-2a and their isomers and salts:

in

R ¹ is H, =O, COOR ³ , OH, OA, NH ₂ , alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, N ₃ , ethynyl, vinyl, allyloxy , NHCOA, NHSO ₂ A, OCH ₂ COOA or OCH ₂ COOH,

R ^is H, OH, OA or an alkyl group having 1, 2, 3, 4, 5 or 6 carbon atoms,

^R3 is H or A,

is pyrrolidine-1,2-diyl,

X is CONH,

Y is 1,3- or 1,4-phenylene which is unsubstituted or monosubstituted or disubstituted by: methyl, trifluoromethyl, ethyl, propyl, Cl or F,

T is piperidin-1-yl, pyrrolidin-1-yl, 1H-pyridin-1-yl, morpholin-4-yl, piperazin-1-yl, 1,3-oxazolidin-3-yl, 2H-pyridazin-2-yl, pyrazin-1-yl, azepan-1-yl or 2-azabicyclo[2.2.2]octan-2-yl, each monosubstituted by carbonyloxy or two substitutions,

A is an alkyl group having 1, 2, 3, 4, 5 or 6 carbon atoms,

Hal is F, Cl, Br or I,

n is 0, 1 or 2.

Particular preference is given to compounds and their isomers and salts selected from the group consisting of:

1) N-[4-(3-oxomorpholin-4-yl)phenyl]-(S)-pyrrolidine-2-carboxamide,

2) N-[4-(3-oxomorpholin-4-yl)phenyl]-(R)-pyrrolidine-2-carboxamide,

3) N-[4-(3-oxomorpholin-4-yl)phenyl]-(2R,4R)-4-hydroxypyrrolidine-2-carboxamide,

4) N-[4-(3-oxomorpholin-4-yl)phenyl]-4-hydroxypyrrolidine-2-carboxamide,

5) N-[4-(3-oxomorpholin-4-yl)phenyl]-(R)-4,4-dimethoxypyrrolidine-2-carboxamide,

6) N-[4-(3-oxomorpholin-4-yl)phenyl]-(2R,4R)-4-methoxypyrrolidine-2-carboxamide.

Preparation methods are described in Examples 1 and 7, for example.

Because of their molecular structure, the compounds of the formula I according to the invention and the compounds of claims 24 and 25 may be chiral compounds and thus may exist in various enantiomeric forms. They may thus exist in racemic or optically active form.

Since the pharmaceutical activity of racemates or stereoisomers of the compounds of the invention may differ, it may be desirable to use enantiomers. In these cases, the final products or even intermediates can be separated into enantiomeric compounds by chemical or physical methods known to the person skilled in the art, or can even be used as such in the synthesis.

In the case of racemic amines, the diastereomers are formed from the mixture by reaction with an optically active resolving agent. Examples of suitable resolving agents are optically active acids such as the following acids in the R and S forms: tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, suitably N-protected amino acids (e.g. N- benzoylproline or N-benzenesulfonylproline), or various optically active camphorsulfonic acids. Chromatography assisted by optically active resolving agents such as dinitrobenzoylphenylglycine, cellulose triacetate, or other carbohydrate derivatives or chirally derivatized methacrylate polymers immobilized on silica gel Resolution of enantiomers is also advantageous. Suitable eluents for this purpose are aqueous or alcoholic solvent mixtures such as hexane/isopropanol/acetonitrile in the ratio 82:15:3.

Furthermore, the present invention relates to the use of compounds of formula I and compounds of claims 24 and 25 and/or physiologically acceptable salts thereof for the preparation of medicaments (pharmaceutical preparations), in particular by non-chemical methods. Here, they can be converted into suitable dosage forms by mixing with at least one solid, liquid and/or semi-liquid excipient or auxiliary and, if desired, in combination with one or more other active ingredients.

Furthermore, the present invention relates to a medicament comprising at least one compound of formula I or a compound of claims 24 and 25 and/or pharmaceutically usable derivatives, solvates, salts and mixtures thereof in various proportions stereoisomers, if desired, and excipients and/or auxiliaries.

These preparations can be used as human or veterinary medicine. Suitable excipients are organic or inorganic substances suitable for enteral (e.g. oral), parenteral or topical administration and which do not react with the novel compound, such as water, vegetable oils, benzyl alcohol, alkanediols, polyethylene glycols, Triacetin, gelatin, carbohydrates such as lactose or starch, magnesium stearate, talc or petrolatum. The dosage form suitable for oral administration is specifically tablet, pill, coated tablet, capsule, powder, granule, syrup, juice or drops; the dosage form suitable for rectal administration is suppository; Dosage forms for parenteral administration are solutions, preferably oily or aqueous solutions, also suspensions, emulsions, or implants; formulations suitable for topical administration are creams, ointments, or powders or also as a nasal spray agent. The novel compounds can also be lyophilized and the resulting lyophilizates used, for example, for the preparation of injectable preparations. The preparations can be sterilized and/or contain auxiliaries, such as lubricants, preservatives, stabilizers and/or wetting agents, emulsifiers, salts for adjusting the osmotic pressure, buffer substances, coloring and flavoring agents and/or various Other active ingredients such as one or more vitamins.

The compounds of formula I and the compounds of claims 24 and 25 and their physiologically acceptable salts are useful for combating and preventing thromboembolic diseases such as thrombosis, myocardial infarction, arteriosclerosis, inflammation, stroke, angina pectoris, restenosis after angioplasty , intermittent claudication, migraine, tumor, neoplastic disease and/or tumor metastasis.

In general, it is preferred that the substances according to the invention are administered in a dosage of about 1-500 mg, especially 5-100 mg, per dosage unit. A preferred daily dosage is about 0.02 to 10 mg/kg body weight. However, the specific dose administered to each patient will depend on many factors, such as the potency of the particular compound used, age, body weight, general health, sex, diet, time and method of administration, rate of excretion, drug combination and duration of therapy administered. the severity of the specific disease. Oral administration is preferred.

Furthermore, the present invention relates to a medicament comprising at least one compound of formula I or a compound of claims 24 and 25 and/or pharmaceutically usable derivatives, solvates, salts and mixtures thereof in various proportions stereoisomers and at least one other pharmaceutically active ingredient.

The present invention also relates to a set of medicines (medicine kit) consisting of the following individual packages:

(a) an effective amount of the compound of formula I or the compound of claims 24 and 25 and/or its pharmaceutically usable derivatives, solvates, salts and stereoisomers including mixtures thereof in various proportions,

and

(b) an effective amount of other pharmaceutically active ingredients.

The kit comprises suitable containers such as boxes, individual bottles, bags or ampoules. The kit may, for example, comprise individual ampoules, each containing an effective amount of the compound of formula I or one of the compounds of claims 24 and 25 and/or a pharmaceutically usable derivative thereof, in dissolved or lyophilized form, Solvates and stereoisomers including mixtures thereof in various proportions, and effective amounts of other pharmaceutically active ingredients.

In addition, the present invention relates to the compounds of formula I and the compounds of claims 24 and 25 and/or pharmaceutically usable derivatives, solvates, salts and stereoisomers including mixtures thereof in various proportions with at least one Use of a combination of other pharmaceutical active ingredients for the preparation of a medicament for the treatment of: thrombosis, myocardial infarction, arteriosclerosis, inflammation, stroke, angina pectoris, restenosis after angioplasty, intermittent claudication, migraine, tumors, Neoplastic disease and/or tumor metastasis.

In addition, the present invention relates to a medicament containing 1-N-[(4-chlorophenyl)]-2-N-{[4-(3-oxomorpholin-4-yl)phenyl]}-(2R , 4R)-4-hydroxypyrrolidine-1,2-dicarboxamide and/or its pharmaceutically usable derivatives, solvates, salts and stereoisomers including mixtures thereof in various proportions and aspirin .

Furthermore the present invention relates to 1-N-[(4-chlorophenyl)]-2-N-{[4-(3-oxomorpholin-4-yl)phenyl]}-(2R,4R)-4 -Hydroxypyrrolidine-1,2-dicarboxamide and/or pharmaceutically usable derivatives, solvates, salts and stereoisomers including mixtures thereof in various proportions and aspirin are used in the preparation Use in medicine for the treatment of thrombosis, myocardial infarction, arteriosclerosis, inflammation, stroke, angina pectoris, restenosis after angioplasty, intermittent claudication, migraine, tumor, tumor disease and/or tumor metastasis.

Above and below, the temperatures used are given in °C. In the following examples, 'conventional workup' means: adding water if necessary, adjusting the pH to 2-10 if necessary, depending on the composition of the final product, extracting the mixture with ethyl acetate or dichloromethane, separating the phases , the organic phase is dried over sodium sulfate, evaporated and the product is purified by chromatography on silica gel and/or by crystallization. Rf value on silica gel; eluent: ethyl acetate/methanol 9:1.

Mass Spectrometry (MS): EI (Electron Impact Ionization) M ⁺

FAB (Fast Atomic Bombardment) (M+H) ⁺

ESI (Electrospray Ionization) (M+H) ⁺ (unless otherwise stated)

Example 1

1-N-[(4-chlorophenyl)]-2-N-{[4-(3-oxomorpholin-4-yl)phenyl]}-(R)-pyrrolidine-1,2- Diformamide ("A1") was prepared analogously to the following scheme:

1.1 Mix 0.8g (5.2mmol) 1-hydroxybenzotriazole hydrate, 1.12g (5.2mmol) D-Boc-proline, 2g (10.4mmol) N-(3-dimethylaminopropyl)-N '-Ethylcarbodiimide hydrochloride (DAPECl) and 1.26ml N-methylmorpholine were added successively to the dimethyl of 1.0g (5.2mmol) 4-(4-aminophenyl)morpholin-3-one formamide (25ml) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was then evaporated to dryness under reduced pressure, the residue was dissolved in 5% sodium bicarbonate solution (10 ml), and the sodium bicarbonate solution was extracted twice with 10 ml each of ethyl acetate. After the combined organic phases were dried over sodium sulfate, the solvent was removed and the solid residue was triturated with 20 ml of ether to give 1.4 g of 2-[4-(3-oxomorpholin-4-yl)phenyl-carbamoyl]pyrrolidine - tert-Butyl-1-carboxylate white powder; ESI 390.

1.2 Add 4N hydrochloric acid/dioxane (40ml) to 1.4g (3.60mmol) 2-[4-(3-oxomorpholin-4-yl)phenyl-carbamoyl]pyrrolidine-1-carboxylic acid tert-butyl dioxane (20ml) and the mixture was stirred at room temperature for 12 hours. Subsequently, the precipitate was filtered off by suction, washed successively with 10ml of dioxane and 10ml of ether, and then dried under reduced pressure to obtain 1.1g of N-[4-(3-oxomorpholin-4-yl)phenyl]pyrrolidin- 2-Carboxamide hydrochloride white powder; ESI 290.

1.3 Add 95mg (0.61mmol) 4-chlorophenyl isocyanate to 200mg (0.61mmol) N-[4-(3-oxomorpholin-4-yl)phenyl]pyrrolidine-2-formamide salt NaCl and 1 ml of triethylamine in dichloromethane (5 ml), and the reaction solution was stirred at room temperature for 2 hours. The reaction solution was washed successively with 5 ml of 1N hydrochloric acid and 5 ml of water, and then the dichloromethane solution was dried over sodium sulfate. After removing the solvent under reduced pressure, the crude product was recrystallized from ethanol/ether to give 120 mg of the title compound ("A1") as a white powder; ESI 443; m.p. 227.6°C.

The following compounds are similarly obtained:

1) 1-N-[(4-chlorophenyl)]-2-N-{[3-methyl-4-(3-oxomorpholin-4-yl)phenyl]}-(R)- Pyrrolidine-1,2-dicarboxamide, ESI 457, m.p.147°C (decomposition);

2) 1-N-[(4-chlorophenyl)]-2-N-{[3-fluoro-4-(3-oxomorpholin-4-yl)phenyl]}-(R)-pyrrole Alkane-1,2-dicarboxamide, ESI 461, m.p.155℃;

3) 1-N-[(4-chlorophenyl)]-2-N-{[2-fluoro-4-(3-oxomorpholin-4-yl)phenyl]}-(R)-pyrrole Alkane-1,2-dicarboxamide, ESI 461;

4) 1-N-[(4-chlorophenyl)]-2-N-{[3-trifluoromethyl-4-(3-oxomorpholin-4-yl)phenyl]}-(R )-pyrrolidine-1,2-dicarboxamide, ESI 511, m.p.147°C;

5) 1-N-[(4-chlorophenyl)]-2-N-{[3-methyl-4-(3-oxomorpholin-4-yl)phenyl]}-(R)- Piperidine-1,2-dicarboxamide, ESI 471, m.p.140℃;

6) 1-N-[(4-chlorophenyl)]-2-N-{[4-(2-oxo-2H-pyridin-1-yl)phenyl]}-(R)-pyrrolidine- 1,2-dicarboxamide, m.p.221°C;

7) 1-N-[(4-chlorophenyl)]-2-N-{[4-(2-oxo-2H-pyrazin-1-yl)phenyl]}-(R)-pyrrolidine -1,2-dicarboxamide, ESI 438, m.p.227℃;

8) 1-N-[(4-chlorophenyl)]-2-N-{[3-methyl-4-(3-oxomorpholin-4-yl)phenyl]}-(S)- Pyrrolidine-1,2-dicarboxamide, ESI 457; m.p.174°C;

9) 1-N-[(4-chlorophenyl)]-2-N-{[4-(2-oxo-2H-pyridin-1-yl)phenyl]}-4,4-difluoro- (R)-pyrrolidine-1,2-dicarboxamide, ESI 473;

10) 1-N-[(4-chlorophenyl)]-2-N-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)phenyl]}-(R) - pyrrolidine-1,2-dicarboxamide, ESI 455;

11) 1-N-[(4-chlorophenyl)]-2-N-{[4-(2-oxo-3-methoxy-2H-pyridin-1-yl)phenyl]}-( R)-pyrrolidine-1,2-dicarboxamide, ESI 467.

Example 1a

N-[4-(3-oxomorpholin-4-yl)phenyl]-(R)-1-(5-chlorothiophene-2-carbonyl)pyrrolidine-2-carboxamide ( "AB1")

0.71g (4.66mmol) 1-hydroxybenzotriazole hydrate, 0.76g (4.66mmol) 5-chlorothiophenecarboxylic acid, 1.79g (9.33mmol) N-(3-dimethylaminopropyl)-N'- Add 1.35g (4.66mmol) N-[4-(3-oxomorpholin-4-yl)phenyl]pyrrole successively with ethylcarbodiimide hydrochloride (DAPECl) and 1.13ml N-methylmorpholine alkane-2-carboxamide in dimethylformamide (30ml), and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was then evaporated to dryness under reduced pressure, the residue was dissolved in 5% sodium bicarbonate solution (10 ml), and the sodium bicarbonate solution was extracted twice with 10 ml each of ethyl acetate. After drying the combined organic phases over sodium sulfate, the solvent was removed and the solid residue was triturated with 20 ml of diethyl ether to give 1.2 g (59.4%) ("AB1"), ESI 434; m.p. 195°C.

The compound N-[3-methyl-4-(3-oxomorpholin-4-yl)phenyl]-(R)-1-(5-chlorothiophene-2-carbonyl)pyrrolidin-2 was obtained similarly - Formamide, ESI 448; m.p. 113°C (decomposition).

Example 1b

1-N-[(4-chlorophenyl)]-2-N-([4-(3-oxomorpholin-4-yl)phenyl]}-(R)-2,5-dihydropyrrole -1,2-dicarboxamide was prepared as follows:

a) 0.19 g (5.1 mmol) of sodium borohydride (NaBH ₄ ) was added under nitrogen to a suspension of 0.82 g (2.63 mmol) of diphenyl diselenide (diphenyl diselenide) in tert-butanol (12 ml), and the reaction The mixture was refluxed for about 1 hour until the yellow reaction solution became colorless. Then 1.99 g (4.11 mmol) of (2R,4R)-4-methanesulfonyloxy-2-[4-(3-oxomorpholin-4-yl)phenylcarbamoyl] were added dropwise at this temperature Pyrrolidine-1-carboxylic acid tert-butyl ester (see Example 9.1) was dissolved in tert-butanol (12 ml), and the reaction mixture was refluxed for 12 hours with stirring. After the reaction mixture was cooled, the solvent was removed under reduced pressure, the residue was dissolved in 20 ml of ethyl acetate, and the resulting solution was washed with 20 ml of water. After drying the ethyl acetate phase over sodium sulfate, the solvent was removed to give 1.82 g (81.3%) of (1R,4R)-2-[4-(3-oxomorpholin-4-yl)phenylcarbamoyl]- tert-butyl 4-phenylselanylpyrrolidine-1-carboxylate, ESI 545.

b) To a solution of 1.72 g (3.16 mmol) of the selenium compound prepared under a) and 0.4 ml of pyridine in dichloromethane (25 ml) was added dropwise 1 ml of 30% hydrogen peroxide (H ₂ O ₂ ) at 0°C. The reaction mixture is then allowed to come to room temperature within 2 hours, then 10 ml of 5% potassium hydrogensulfate solution are added, the phases are separated and the organic phase is washed with 10 ml of saturated sodium bicarbonate solution. After the organic phase was dried over sodium sulfate, the solvent was removed and the residue was chromatographed on silica gel to obtain 0.73 g (59.7%) of (R)-2-[4-(3-oxomorpholin-4-yl)phenylaminomethyl Acyl]-2,5-dihydropyrrole-1-carboxylic acid tert-butyl ester, ESI388.

Further carry out the reaction similar to Example 7 to obtain 1-N-[(4-chlorophenyl)]-2-N-{[4-(3-oxomorpholin-4-yl)phenyl]}- (R)-2,5-Dihydropyrrole-1,2-dicarboxamide, ESI441, m.p.245°C.

The following compounds are similarly obtained:

1) 1-N-[(4-chlorophenyl)]-2-N-{[4-(2-oxo-1H-pyrazin-1-yl)phenyl]}-(R)-2, 5-dihydropyrrole-1,2-dicarboxamide,

2) 1-N-[(4-chlorophenyl)]-2-N-{[4-(2-oxo-1H-pyridin-1-yl)phenyl]}-(R)-2,5 -dihydropyrrole-1,2-dicarboxamide,

3) 1-N-[(4-chlorophenyl)]-2-N-{[3-fluoro-4-(3-oxomorpholin-4-yl)phenyl]}-(R)-2 , 5-dihydropyrrole-1,2-dicarboxamide,

4) 1-N-[(4-chlorophenyl)]-2-N-{[2-fluoro-4-(3-oxomorpholin-4-yl)phenyl]}-(R)-2 , 5-dihydropyrrole-1,2-dicarboxamide.

Example 2

3-N-[(4-chlorophenyl)]-4-N-{[4-(3-oxomorpholin-4-yl)phenyl]}-(R)- Oxazolidine-3,4-dicarboxamide ("A2"):

2.1 Add 1.49ml (20.0mmol) of 37% aqueous formaldehyde to a solution of 2.10g (20.0mmol) of D-serine in 1N aqueous sodium hydroxide solution (10ml). The resulting solution was left at 5°C for 18 hours. The solution was heated to 80° C., 6.14 g (40 mmol) of 4-chlorophenyl isocyanate were added, and the mixture was stirred at this temperature for 1 hour. The mixture was allowed to cool and the formed precipitate was filtered off. The filtrate was acidified with 1N HCl, then the formed precipitate was filtered off and dried to give (R)-3-(4-chlorophenylcarbamoyl)oxazolidine-4-carboxylic acid as a colorless solid; ESI271.

2.2 To 541 mg (2.00 mmol) (R)-3-(4-chlorophenylcarbamoyl) oxazolidine-4-carboxylic acid and 384 mg (2.00 mmol) 4-(4-aminophenyl) morpholine-3- Add 498mg (2.60mmol) N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (DAPECl) in the dimethylformamide (DMF) (4ml) solution of ketone, then The mixture was stirred at room temperature for 18 hours. The reaction mixture was added to saturated sodium bicarbonate solution and the precipitate formed was filtered off to give 3-N-[(4-chlorophenyl)]-4-N-{[4-(3-oxomorpholine-4 -yl)phenyl]}-(R)-oxazolidine-3,4-dicarboxamide ("A2"), colorless solid; ESI 461.

The following compounds are similarly obtained:

1) 3-N-[(4-chlorophenyl)]-4-N-{[3-methyl-4-(3-oxomorpholin-4-yl)phenyl]}-(R)- Oxazolidine-3,4-dicarboxamide, ESI 459;

2) 3-N-[(4-chlorophenyl)]-4-N-([4-(3-oxomorpholin-4-yl)phenyl]}-(4R, 5S)-5-methyl Oxazolidine-3,4-dicarboxamide, ESI 459;

3) 3-N-[(4-chlorophenyl)-4-N-{[3-methyl-4-(3-oxomorpholin-4-yl)phenyl]}-(4R, 5S) -5-methyloxazolidine-3,4-dicarboxamide, ESI 473;

4) 3-N-[(4-chlorophenyl)]-4-N-{[4-(2-oxo-2H-pyridin-1-yl)phenyl]}-(R)-oxazolidine -3,4-dicarboxamide, ESI 439;

5) 3-N-[(4-chlorophenyl)]-4-N-{[4-(2-oxo-2H-pyridin-1-yl)phenyl]}-(4R, 5S)-5 -Methyloxazolidine-3,4-dicarboxamide, ESI 453;

6) 3-N-[(4-chlorophenyl)]-4-N-{[3-fluoro-4-(3-oxomorpholin-4-yl)phenyl]}-(4R, 5S) -5-methyloxazolidine-3,4-dicarboxamide, ESI 477;

7) 3-N-[(4-chlorophenyl)]-4-N-{[3-chloro-4-(3-oxomorpholin-4-yl)phenyl]}-(4R, 5S) -5-methyloxazolidine-3,4-dicarboxamide, ESI 477;

8) 3-N-[(4-chlorophenyl)]-4-N-{[3-methyl-4-(3-oxomorpholin-4-yl)phenyl]}-(4R, 5R )-5-methyloxazolidine-3,4-dicarboxamide, ESI 473;

9) 3-N-[(4-chlorophenyl)]-4-N-{[4-(2-oxo-2H-pyrazin-1-yl)phenyl]}-(4R, 5S)- 5-Methyloxazolidine-3,4-dicarboxamide, ESI 454;

10) 3-N-[(4-chlorophenyl)]-4-N-{[4-(2-oxo-2H-pyrazin-1-yl)phenyl]}-(R)-oxazole Alkane-3,4-dicarboxamide, ESI 440;

11) 3-N-[(4-chlorophenyl)]-4-N-{[3-chloro-4-(2-oxo-2H-pyridin-1-yl)phenyl]}-(R) -Oxazolidine-3,4-dicarboxamide, ESI 473;

Example 2a

Similar to the method of Example 2, with (R)-cleonine as raw material

The following compounds are obtained:

6-N-[(4-chlorophenyl)]-7-N-{[4-(3-oxomorpholin-4-yl)phenyl]}-4-oxa-6-azaspiro[ 2.4] Heptane-6,7-dicarboxamide

Example 3

3-N-[(4-chlorophenyl)]-4-N-{[4-(3-oxomorpholin-4-yl)phenyl]}-(S)- Thiazolidine-3,4-dicarboxamide ("A3") and 3-N-[(4-chlorophenyl)]-4-N-{[4-(3-oxomorpholin-4-yl) Phenyl]}-(S)-1,1-dioxo- ^1λ6 -thiazolidine-3,4-dicarboxamide ("A4"):

3.1 Heat 4.54g (54.0mmol) of sodium bicarbonate and 3.60g (27.0mmol) of 2-(S)-thiazolidine-4-carboxylic acid in water (50ml) to 80°C, then add 8.46g (54.0mmol) of isocyanide Acid 4-chlorophenyl ester. The reaction mixture was stirred at this temperature for 1 hour. The mixture was allowed to cool and the formed precipitate was filtered off. The filtrate was acidified with 1N HCl, then the formed precipitate was filtered off and dried to give (S)-3-(4-chlorophenylcarbamoyl)thiazolidine-4-carboxylic acid as a colorless solid; ESI287.

3.2 To 573mg (2.00mmol) (S)-3-(4-chlorophenylcarbamoyl)thiazolidine-4-carboxylic acid and 384mg (2.00mmol) 4-(4-aminophenyl)morpholin-3-one Add 498mg (2.60mmol) N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (DAPECl) in the dimethylformamide (DMF) (4ml) solution, then in The mixture was stirred at room temperature for 18 hours. The reaction mixture was added to saturated sodium bicarbonate solution and the precipitate formed was filtered off to give 3-N-[(4-chlorophenyl)]-4-N-{[4-(3-oxomorpholine-4 -yl)phenyl]}-(S)-thiazolidine-3,4-dicarboxamide ("A3"), colorless solid; ESI 461.

3.3 To a suspension of 450 mg (0.976 mmol) of "A3" in methanol (50 ml) was added a solution of 1.9 g of potassium persulfate preparation in 30 ml of water, and the reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was added to water and the precipitate formed was filtered off and dried to give 3-N-[(4-chlorophenyl)]-4-N-{[4-(3-oxomorpholin-4-yl) Phenyl]}-(S)-1,1-dioxo- ^1λ6 -thiazolidine-3,4-dicarboxamide ("A4") Colorless solid; ESI 493.

The following compounds are similarly obtained:

1) 3-N-[(4-chlorophenyl)]-4-N-{[3-methyl-4-(3-oxomorpholin-4-yl)phenyl]}-(S)- Thiazolidine-3,4-dicarboxamide, ESI 475;

2) 3-N-[(4-chlorophenyl)]-4-N-{[3-methyl-4-(3-oxomorpholin-4-yl)phenyl]}-(S)- 1,1-dioxo-1λ ⁶ -thiazolidine-3,4-dicarboxamide, ESI 507;

3) 3-N-[(4-chlorophenyl)]-4-N-{[4-(2-oxo-2H-pyridin-1-yl)phenyl]}-(R)-thiazolidine- 3,4-Dicarboxamide, ESI 455.

Example 4

N-[4-(3-oxomorpholin-4-yl)phenyl]-3-(5-chlorothiophene-2-carbonyl)oxazolidine-5-carboxamide (" A5"):

4.1 Add 1.48ml (19.9mmol) of 37% aqueous formaldehyde to a solution of 2.00g (19.0mmol) of DL-isoserine in 1N aqueous sodium hydroxide (10ml). The resulting solution was left at 5°C for 18 hours. To this solution was added dropwise a solution of 3.46 g (19.1 mmol) of 5-chlorothiophene carbonyl chloride in acetone (10 ml) at an internal temperature of 0-5°C. During the dropwise addition, the pH was maintained above 7 by adding solid sodium bicarbonate. At the end of the addition, the mixture was allowed to warm to room temperature, water was added and the mixture was extracted with tert-butyl methyl ether. The aqueous phase was acidified with 1N HCl and extracted with tert-butyl methyl ether. The organic phase was dried over sodium sulfate and evaporated to give 3-(5-chlorothiophene-2-carbonyl)oxazolidine-5-carboxylic acid as a colorless solid; ESI 262.

4.2 Add 500 mg (1.91 mmol) of 3-(5-chlorothiophene-2-carbonyl) oxazolidine-5-carboxylic acid and 367 mg (1.91 mmol) of 4-(4-aminophenyl) morpholin-3-one into dimethyl 479mg (2.50mmol) N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (DAPECl) was added to a solution of methylformamide (DMF) (5ml), then stirred at room temperature The mixture was 18 hours. The reaction mixture was added to saturated sodium bicarbonate solution, and the formed precipitate was filtered off to give N-[4-(3-oxomorpholin-4-yl)phenyl]-3-(5-chlorothiophene-2- Carbonyl)oxazolidine-5-carboxamide ("A5"), colorless solid; ESI 436.

The following compounds are similarly obtained:

N-[3-methyl-4-(3-oxomorpholin-4-yl)phenyl]-3-(5-chlorothiophene-2-carbonyl)oxazolidine-5-carboxamide, ESI 450;

N-[4-(2-oxo-2H-pyridin-1-yl)phenyl]-3-(5-chlorothiophene-2-carbonyl)oxazolidine-5-carboxamide, ESI 430.

Example 5

1-N-[(5-chloropyridin-2-yl)]-2-N-{[4-(2-oxo-2H-pyridin-1-yl)phenyl]} was prepared in a similar manner to the following scheme -(2R,4R)-4-Hydroxypyrrolidine-1,2-dicarboxamide ("A6"):

Add 894 mg (4.43 mmol) 4-nitrophenyl chloroformate to a solution of 570 mg (4.43 mmol) 2-amino-5-chloropyridine and 0.73 ml (9.0 mmol) pyridine in dichloromethane (50 ml), then at room temperature The mixture was stirred for 1 hour. 1.49g (4.43mmol) of (2R, 4R)-4-hydroxy-2-[4-(2-oxo-2H-pyridin-1-yl)phenylcarbamoyl]pyrrolidinium chloride and 1.5ml (9.0 mmol) N-ethyldiisopropylamine was added to the resulting suspension, and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was evaporated and the residue was chromatographed on silica gel using dichloromethane/methanol 95:5 as eluent to give 1-N-[(5-chloropyridin-2-yl)]-2-N -{[4-(2-Oxo-2H-pyridin-1-yl)phenyl]}-(2R,4R)-4-hydroxypyrrolidine-1,2-dicarboxamide ("A6") colorless Solid, ESI 454.

The following compounds are similarly obtained:

1) 1-N-[(5-chloropyridin-2-yl)]-2-N-{[4-(3-oxomorpholin-4-yl)phenyl]}-(2R, 4R)- 4-Hydroxypyrrolidine-1,2-dicarboxamide, ESI 460;

2) 1-N-[(5-chloropyridin-2-yl)]-2-N-{[4-(2-oxo-2H-pyrazin-1-yl)phenyl]}-(2R, 4R)-4-hydroxypyrrolidine-1,2-dicarboxamide, ESI 455;

3) 1-N-[(5-chloropyridin-2-yl)]-2-N-{[3-fluoro-4-(2-oxo-2H-pyridin-1-yl)phenyl]}- (2R,4R)-4-hydroxypyrrolidine-1,2-dicarboxamide, ESI 472;

4) 1-N-[(5-chloropyridin-2-yl)]-2-N-{[4-(2-oxo-2H-pyridin-1-yl)phenyl]}-(R)- 4,4-dimethoxypyrrolidine-1,2-dicarboxamide, ESI 498;

5) 1-N-[(5-chloropyridin-2-yl)]-2-N-{[4-(3-oxomorpholin-4-yl)phenyl]}-(R)-4, 4-dimethoxypyrrolidine-1,2-dicarboxamide, ESI 504;

6) 1-N-[(6-chloropyridin-3-yl)]-2-N-{[4-(2-oxo-2H-pyridin-1-yl)phenyl]}-(2R, 4R )-4-hydroxypyrrolidine-1,2-dicarboxamide, ESI 454;

7) 1-N-[(6-chloropyridin-3-yl)]-2-N-{[4-(2-oxo-2H-pyrazin-1-yl)phenyl]}-(2R, 4R)-4-hydroxypyrrolidine-1,2-dicarboxamide, ESI 455.

Example 6

1-N-[(4-chlorophenyl)]-2-N-{[4-(2-oxo-2H-pyridin-1-yl)phenyl]}-(R )-4,4-dimethoxypyrrolidine-1,2-dicarboxamide ("A7"):

6.1 At 0° C., 12.2 g (122 mmol) of chromium(VI) oxide were added to a mixture of 22 ml of pyridine and 50 ml of dichloromethane, and the mixture was then stirred at similar temperature for 30 minutes. The solution was allowed to warm to room temperature and a solution of 5.00 g cis-Boc-4-hydroxy-D-proline in dichloromethane (80 mL) was added dropwise over 5 minutes. After stirring at room temperature for 1 hour, the solution was filtered and the filtrate was evaporated. The residue was partitioned between 1N HCl and tert-butyl methyl ether. The organic phase was dried over sodium sulfate, evaporated and then recrystallized from ether/petroleum ether to give Boc-4-keto-D-proline as a colorless solid; ESI 130.

6.2 To a suspension of 459 mg (2.00 mmol) Boc-4-keto-D-proline and 372 mg (2.00 mmol) 1-(4-aminophenyl)-1H-pyridin-2-one in toluene (25 ml) was added 742 mg (3.00 mmol) of ethyl 2-ethoxy-1,2-dihydroquinoline-1-carboxylate (EEDQ), and the mixture was stirred at room temperature for 18 hours. 200 ml of tert-butyl methyl ether are added and the precipitate formed is filtered off. 200 ml of petroleum ether was added to the filtrate, and the resulting precipitate was filtered to obtain (R)-4-oxo-2-[4-(2-oxo-2H-pyridin-1-yl)phenylcarbamoyl]pyrrole tert-Butyl alkane-1-carboxylate brown solid; ESI 398.

6.3 To 400mg (1.01mmol) (R)-4-oxo-2-[4-(2-oxo-2H-pyridin-1-yl)phenylcarbamoyl]pyrrolidine-1-carboxylic acid tert-butyl To a suspension of the ester in 4N HCl in dioxane (5 ml) was added 10 ml of methanol, and the mixture was stirred at room temperature for 1 hour. Evaporation of the reaction mixture gave (R)-4,4-dimethoxy-2-[4-(2-oxo-2H-pyridin-1-yl)phenylcarbamoyl]pyrrolidinium chloride as a brown solid ; ESI 344.

6.4 To 250 mg (0.658 mmol) (R)-4,4-dimethoxy-2-[4-(2-oxo-2H-pyridin-1-yl)phenylcarbamoyl]pyrrolidinium chloride To a solution of dichloromethane (10ml) was added 0.12ml of triethylamine and 127mg (0.830mmol) of 4-chlorophenyl isocyanate. After stirring at room temperature for 1 hour, the reaction mixture was evaporated and the residue was chromatographed on a silica gel column using dichloromethane/methanol 95:5 as eluent to give 1-N-[(4-chlorophenyl) ]-2-N-{[4-(2-Oxo-2H-pyridin-1-yl)phenyl]}-(R)-4,4-dimethoxypyrrolidine-1,2-dimethyl Amide ("A7") Colorless solid; ESI 497.

Example 7

1-N-[(4-chlorophenyl)]-2-N-{[4-(3-oxomorpholin-4-yl)phenyl]}-(2R,4R )-4-hydroxypyrrolidine-1,2-dicarboxamide ("A8"):

7.1 Toluene ( 250ml) suspension was added 16g (12.86mmol) 2-ethoxy-1,2-dihydroquinoline-1-formic acid ethyl ester (EEDQ), then the mixture was stirred at room temperature for 18 hours.Then filtered the precipitated product, Washed successively with 50ml of toluene and 50ml of ether, and then dried in a desiccator to obtain (2R, 4R)-4-hydroxyl-2-[4-(3-oxomorpholin-4-yl)phenylcarbamoyl] tert-butyl pyrrolidine-1-carboxylate off-white powder 24.5g (93.2%).ESI 406.

7.2 Add 4N hydrochloric acid dioxane solution (300ml) to 15g (37mmol) (2R, 4R)-4-hydroxy-2-[4-(3-oxomorpholin-4-yl)phenylcarbamoyl] pyrrolidine-1-carboxylic acid tert-butyl ester in dioxane (200ml), and the mixture was stirred at room temperature for 12 hours. Then filter the precipitate, wash with 50ml dioxane and 50ml ether, then dry in a desiccator to obtain 12.64g (100%) hydrochloric acid N-[4-(3-oxomorpholin-4-yl)phenyl]- (2R,4R)-4-hydroxypyrrolidine-2-carboxamide white powder. ESI 306.

7.3 Suspend 12.64g (36.98mmol) of N-[4-(3-oxomorpholin-4-yl)phenyl]-(2R,4R)-4-hydroxypyrrolidine-2-carboxamide hydrochloride in 1200ml di Chloromethane, and then add 5.4ml of triethylamine under ice-cooling. To the mixture was then added dropwise a solution of 5.96 g (38.83 mmol) of 4-chlorophenyl isocyanate in dichloromethane (100 ml) at 2°C over 1.5 hours, and the reaction solution was stirred for a further 30 minutes under ice cooling. The dichloromethane solution was washed successively with 100 ml of 1N hydrochloric acid and 100 ml of water, and then dried over sodium sulfate. After filtering off the desiccant, the dichloromethane solution was evaporated to 1/3 of the original volume with a rotary evaporator, and the precipitated product was filtered, washed with 50 ml of petroleum ether, and then dried in a desiccator to obtain 14.6 g (86%) of 1- N-[(4-chlorophenyl)]-2-N-{[4-(3-oxomorpholin-4-yl)phenyl]}-(2R,4R)-4-hydroxypyrrolidine-1 , 2-dicarboxamide ("A8") white powder, ESI 459; m.p.216°C.

The following compounds are similarly obtained:

1) 1-N-[(4-chlorophenyl)]-2-N-{[3-methyl-4-(3-oxomorpholin-4-yl)phenyl]}-(2R, 4R )-4-hydroxypyrrolidine-1,2-dicarboxamide, ESI 473; m.p.250°C;

2) 1-N-[(4-chlorophenyl)]-2-N-{[4-(2-oxo-2H-pyridin-1-yl)phenyl]}-(2R, 4R)-4 -Hydroxypyrrolidine-1,2-dicarboxamide, ESI 453; m.p.160°C;

3) 1-N-[(4-chlorophenyl)]-2-N-{[2-fluoro-4-(3-oxomorpholin-4-yl)phenyl]}-(2R, 4R) -4-Hydroxypyrrolidine-1,2-dicarboxamide, ESI 477; m.p.235°C;

4) 1-N-[(4-chlorophenyl)]-2-N-{[4-(2-oxopyrazin-1-yl)phenyl]}-(2R,4R)-4-hydroxy Pyrrolidine-1,2-dicarboxamide, ESI 454;

5) 1-N-[(4-chlorophenyl)]-2-N-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)phenyl]}-(2R, 4R)-4-hydroxypyrrolidine-1,2-dicarboxamide, ESI 471;

6) 1-N-[(4-chlorophenyl)]-2-N-{[3-fluoro-4-(3-oxomorpholin-4-yl)phenyl]}-(2R, 3R) -3-hydroxypyrrolidine-1,2-dicarboxamide,

7) 1-N-[(4-chlorophenyl)]-2-N-{[3-fluoro-4-(3-oxomorpholin-4-yl)phenyl]}-(2R, 3S) -3-hydroxypyrrolidine-1,2-dicarboxamide,

8) 1-N-[(4-chlorophenyl)]-2-N-{[3-fluoro-4-(3-oxomorpholin-4-yl)phenyl]}-(2R, 4R) -4-hydroxypyrrolidine-1,2-dicarboxamide,

9) 1-N-[(4-chlorophenyl)]-2-N-{[4-(2-oxo-3-methoxy-2H-pyridin-1-yl)phenyl]}-( 2R,4R)-4-hydroxypyrrolidine-1,2-dicarboxamide, ESI 483,

10) 1-N-[(4-chlorophenyl)]-2-N-{[4-(3-oxomorpholin-4-yl)phenyl]}-(2S,3S)-3-hydroxy Pyrrolidine-1,2-dicarboxamide, ESI 459;

11) 1-N-[(4-chlorophenyl)]-2-N-{[4-(3-oxomorpholin-4-yl)phenyl]}-(2S,4S)-4-hydroxy Pyrrolidine-1,2-dicarboxamide, ESI 459

12) 1-N-[(4-chlorophenyl)]-2-N-{[2-methoxycarbonyl-4-(3-oxomorpholin-4-yl)phenyl]}-(2R , 4R)-3-hydroxypyrrolidine-1,2-dicarboxamide, ESI 517, m.p.119; and thus by hydrolysis

13) 1-N-[(4-chlorophenyl)]-2-N-{[2-carboxy-4-(3-oxomorpholin-4-yl)phenyl]}-(2R, 4R) -3-Hydroxypyrrolidine-1,2-dicarboxamide, ESI 503, m.p.145°C,

14) 1-N-[(4-chlorophenyl)]-2-N-{[2-methoxycarbonyl-4-(3-oxomorpholin-4-yl)phenyl]}-(2R , 4R)-4-hydroxypyrrolidine-1,2-dicarboxamide, and thus by hydrolysis

15) 1-N-[(4-chlorophenyl)]-2-N-{[2-carboxy-4-(3-oxomorpholin-4-yl)phenyl]}-(2R, 4R) -4-Hydroxypyrrolidine-1,2-dicarboxamide.

Example 8

1-N-[(4-chlorophenyl)]-2-N-{[4-(3-oxomorpholin-4-yl)phenyl]}-(2R,4S )-4-hydroxypyrrolidine-1,2-dicarboxamide:

8.1 Add 7.0 g (7.26 mmol) (2R, 4R)-4-hydroxy-2-[4-(3-oxomorpholin-4-yl)phenylcarbamoyl]pyrrolidine at 0°C under nitrogen - tert-butyl formate, 5.77g (34.5mmol) of p-nitrobenzoic acid and 9.18g (35mmol) of triphenylphosphine in tetrahydrofuran (350ml) were added dropwise to 5.51ml (35mmol) of azodicarboxylic acid di Ethyl ester (DEAD). The reaction mixture was then stirred at room temperature for 12 hours, then evaporated to dryness under reduced pressure, 20 ml of dichloromethane was added to the residue, the dichloromethane solution was then washed successively with 10 ml of saturated sodium chloride solution and 10 ml of water, and then washed over sodium sulfate dry. After the desiccant was filtered off, the solvent was removed with a rotary evaporator, and the residue was triturated with 30 ml of ether to obtain 8.5 g (88.8%) of (2R, 4S)-4-(4-nitrobenzoyloxy)-2-[ tert-Butyl 4-(3-oxomorpholin-4-yl)phenylcarbamoyl]pyrrolidine-1-carboxylate as yellowish crystals, ESI 555.

8.2 Similar to Example 7, (2R,4S)-4-(4-nitrobenzoyloxy)-2-[4-(3-oxomorpholin-4-yl)phenylcarbamoyl] The reaction of pyrrolidine-1-carboxylic acid tert-butyl ester produces the compound 4-nitrobenzoic acid (3S, 5R)-1-(4-chlorophenylcarbamoyl)-5-[4-(3-oxomorphol Phenyl-4-yl)phenylcarbamoyl]pyrrolidin-3-yl ester yellowish crystals, ESI 608.

8.3 Under ice cooling, add 0.075ml 1N sodium hydroxide solution to 50mg (0.082mmol) 4-nitrobenzoic acid (3S, 5R)-1-(4-chlorophenylcarbamoyl)-5-[4-( 3-oxomorpholin-4-yl)phenylcarbamoyl]pyrrolidin-3-yl ester in methanol (2ml) and the reaction mixture was stirred for 15 minutes. The precipitate was filtered, then washed with 2 ml of methanol, and dried to give 35 mg (93%) of 1-N-[(4-chlorophenyl)]-2-N-{[4-(3-oxomorpholin-4-yl )phenyl]}-(2R,4S)-4-hydroxypyrrolidine-1,2-dicarboxamide as colorless crystals, ESI 459, m.p.243°C (decomposition).

The following compounds were obtained in a similar manner:

1-N-[(4-chlorophenyl)]-2-N-{[4-(3-oxomorpholin-4-yl)phenyl]}-(2R,3S,4R)-3,4 -Dihydroxypyrrolidine-1,2-dicarboxamide, ESI 475, m.p.247;

1-N-[(4-chlorophenyl)]-2-N-{[4-(3-oxomorpholin-4-yl)phenyl]}-(2S,4R)-4-hydroxypyrrolidine -1,2-dicarboxamide, ESI 459; m.p.253°C;

1-N-[(4-chlorophenyl)]-2-N-{[4-(3-oxomorpholin-4-yl)phenyl]}-3,4-dihydroxypyrrolidine-1, 2-dicarboxamide.

Example 8a

1-N-[(4-chlorophenyl)]-2-N-{[4-(3-oxomorpholin-4-yl)phenyl]}-(2R,4S )-4-ethynyl-4-hydroxypyrrolidine-1,2-dicarboxamide, ESI483:

The following compounds are similarly obtained:

1-N-[(4-chlorophenyl)]-2-N-{[4-(2-oxo-1H-pyridin-1-yl)phenyl]}-(2R,4S)-4-ethyne Base-4-hydroxypyrrolidine-1,2-dicarboxamide, ESI 477;

1-N-[(4-chlorophenyl)]-2-N-{[4-(2-oxo-2H-pyrazin-1-yl)phenyl]}-(2R,4S)-4- Ethynyl-4-hydroxypyrrolidine-1,2-dicarboxamide, ESI 478.

Example 9

1-N-[(4-chlorophenyl)]2-N-{[4-(3-oxomorpholin-4-yl)phenyl]}-(2R,4S) was prepared in a similar manner to the following scheme -4-azidopyrrolidine-1,2-dicarboxamide ("A9") and 1-N-[(4-chlorophenyl)]-2-N-{[4-(3-oxomorphol Phenyl-4-yl)phenyl]}-(2R,4S)-4-aminopyrrolidine-1,2-dicarboxamide ("A10"):

9.1 Under ice cooling, add 4.5 g (11.1 mmol) (2R, 4R)-4-hydroxy-2-[4-(3-oxomorpholin-4-yl)phenylcarbamoyl]pyrrolidin-1- To a solution of t-butyl formate in 20 ml of pyridine was added dropwise 1.3 ml (16.65 mmol) of methanesulfonyl chloride, and the reaction solution was stirred at room temperature for 12 hours. Pyridine was subsequently removed under reduced pressure, 10 ml of saturated citric acid solution were added to the residue, and the acidic solution was extracted twice with 10 ml of dichloromethane. The combined organic phases are then washed with 10 ml of saturated sodium chloride solution and dried over sodium sulfate. The drying agent was filtered off and the solvent was removed to give 5.4 g (100%) of (2R,4R)-4-methanesulfonyloxy-2-[4-(3-oxomorpholin-4-yl)benzene as a yellow oil. Carbamoyl]pyrrolidine-1-carboxylic acid tert-butyl ester, ESI484.

9.2 At 60°C, stir 5.4g (11.7mmol) of (2R,4R)-4-methanesulfonyloxy-2-[4-(3-oxomorpholin-4-yl)phenylcarbamoyl] A mixture of tert-butyl pyrrolidine-1-carboxylate and 3.69 g (56.8 mmol) of sodium azide in dimethylformamide (DMF) (50 ml) for 12 hours. The insoluble matter was subsequently filtered off, and the filtrate was evaporated to dryness under reduced pressure. The residue was then dissolved in 20 ml of water, and the aqueous solution was extracted twice with 10 ml of dichloromethane each. The combined dichloromethane extracts were finally washed once with 10 ml of saturated sodium chloride solution and dried over sodium sulfate. The desiccant was removed by filtration, and then the solvent was removed to obtain 4.8 g (100%) of (2R, 4S)-4-azido-2-[4-(3-oxomorpholin-4-yl)phenylcarbamoyl ]Pyrrolidine-1-carboxylate tert-butyl yellowish crystals, ESI 431.

9.3 Similar to Example 7, (2R,4S)-4-azido-2-[4-(3-oxomorpholin-4-yl)phenylcarbamoyl]pyrrolidine-1-carboxylic acid tert-butyl The reaction of base ester produces compound 1-N-[(4-chlorophenyl)]-2-N-{[4-(3-oxomorpholin-4-yl)phenyl]}-(2R, 4S) - 4-Azidopyrrolidine-1,2-dicarboxamide ("A9") white powder, ESI 459, m.p. 145°C.

9.4 A solution of 25 mg (0.052 mmol) "A9" and 20.46 mg (0.08 mmol) triphenylphosphine in a mixture of tetrahydrofuran (0.5 ml) and water (0.5 ml) was stirred for 12 hours at room temperature. After filtering off the precipitated triphenylphosphine oxide, the filtrate was evaporated to dryness and the residue was purified by preparative HPLC (acetonitrile/water/0.1% trifluoroacetic acid) to give 12 mg (40%) of 1-N-[(4-chlorobenzene base)]-2-N-{[4-(3-oxomorpholin-4-yl)phenyl]}-(2R,4S)-4-aminopyrrolidine-1,2-dicarboxamide (" 10") colorless crystals, ESI 458.

The following compounds were obtained in a similar manner:

1-N-[(4-chlorophenyl)]-2-N-{[4-(3-oxomorpholin-4-yl)phenyl]}-(2R,4R)-4-azido Pyrrolidine-1,2-dicarboxamide, ESI 484, m.p.125℃;

1-N-[(4-chlorophenyl)]-2-N-{[4-(3-oxomorpholin-4-yl)phenyl]}-(2R,4R)-4-aminopyrrolidine -1,2-dicarboxamide, ESI 458, m.p.110℃;

1-N-[(4-chlorophenyl)]-2-N-{[3-methyl-4-(3-oxomorpholin-4-yl)phenyl]}-(2R,4S)- 4-aminopyrrolidine-1,2-dicarboxamide, ESI 472, m.p. 218°C.

With 4-amino compound as raw material,

a) react with acetyl chloride to give the following compounds:

1-N-[(4-chlorophenyl)]-2-N-{[4-(3-oxomorpholin-4-yl)phenyl]}-(2R,4S)-4-acetylaminopyrrole Alkane-1,2-dicarboxamide,

1-N-[(4-chlorophenyl)]-2-N-{[4-(3-oxomorpholin-4-yl)phenyl]}-(2R,4R)-4-acetylaminopyrrole Alkane-1,2-dicarboxamide, ESI 458;

and similarly get

1-N-[(4-chlorophenyl)]-2-N-{[3-methyl-4-(3-oxomorpholin-4-yl)phenyl]}-(2R,4S)- 4-Acetamidopyrrolidine-1,2-dicarboxamide, ESI 514, m.p.170℃;

b) Reaction with methanesulfonyl chloride gives the following compounds:

1-N-[(4-chlorophenyl)]-2-N-{[4-(3-oxomorpholin-4-yl)phenyl]}-(2R,4S)-4-methylsulfonyl Aminopyrrolidine-1,2-dicarboxamide and

1-N-[(4-chlorophenyl)]-2-N-{[4-(3-oxomorpholin-4-yl)phenyl]}-(2R,4R)-4-methylsulfonyl Aminopyrrolidine-1,2-dicarboxamide;

c) react with butanesulfonyl chloride to give the following compound:

1-N-[(4-chlorophenyl)]-2-N-{[4-(3-oxomorpholin-4-yl)phenyl]}-(2R,4R)-4-butanesulfonyl Aminopyrrolidine-1,2-dicarboxamide,

1-N-[(4-chlorophenyl)]-2-N-{[4-(3-oxomorpholin-4-yl)phenyl]}-(2R,4S)-4-butanesulfonyl Aminopyrrolidine-1,2-dicarboxamide, ESI 592;

d) react with isobutyryl chloride to give the compound:

1-N-[(4-chlorophenyl)]-2-N-{[4-(3-oxomorpholin-4-yl)phenyl]}-(2R,4S)-4-(2- Methylpropionylamino)pyrrolidine-1,2-dicarboxamide, ESI 542; m.p.169.

Example 10

1-N-[(4-chlorophenyl)]-2-N-{[4-(3-oxomorpholin-4-yl)phenyl]}-(2R,4R )-4-methoxypyrrolidine-1,2-dicarboxamide ("A11"):

10.1 To a mixture of 1 g (4.32 mmol) cis-N'-BOC-4-hydroxy-D-proline and 3.31 g (14.27 mmol) silver oxide in acetone (15 ml) was added 0.94 ml (15.1 mmol) methyl iodide, and the reaction mixture was stirred at room temperature for 48 hours. The precipitate was then filtered off, and the filtrate was evaporated to dryness under reduced pressure to give 1 g (89.2%) of cis-N'-BOC-4-methoxy-D-proline methyl ester as a colorless oil, which was available without further purification Further Reactions, ESI260.

10.2 Add 25ml of methanol, 25ml of water and 0.28g (11.57 mmol) lithium hydroxide, and then the reaction solution was stirred at room temperature for 5 hours. Methanol and TFH were then removed using a rotary evaporator, and the aqueous solution was shaken once with 10 ml of dichloromethane, then acidified to pH 2 with saturated citric acid solution, and the acidic solution was extracted twice with 10 ml of dichloromethane each. The combined organic phases were dried over sodium sulfate and the solvent was removed to give 0.5 g (53%) of cis-N'-BOC-4-methoxy-D-proline as a pale oil which gradually crystallized, ESI 246.

10.3 Similar to Example 7, the reaction of cis-N'-BOC-4-methoxy-D-proline produces the compound 1-N-[(4-chlorophenyl)]-2-N-{[ 4-(3-Oxomorpholin-4-yl)phenyl]}-(2R,4R)-4-methoxypyrrolidine-1,2-dicarboxamide (“A11”) white powder, ESI 473 , m.p. 133°C.

The following compounds are similarly obtained:

1) 1-N-[(4-chlorophenyl)]-2-N-{[2-fluoro-4-(3-oxomorpholin-4-yl)phenyl]}-(2R, 4R) -4-Allyloxypyrrolidine-1,2-dicarboxamide, ESI 517, m.p.106℃

2) 1-N-[(4-chlorophenyl)]-2-N-{[4-(3-oxomorpholin-4-yl)phenyl]}-(2R, 4R)-4-ethane Oxypyrrolidine-1,2-dicarboxamide, ESI 487, m.p.136°C;

3) 1-N-[(4-chlorophenyl)]-2-N-{[4-(3-oxomorpholin-4-yl)phenyl]}-(2R,4R)-4-propane Oxypyrrolidine-1,2-dicarboxamide, ESI 501, m.p.106;

4) 1-N-[(4-chlorophenyl)]-2-N-{[4-(3-oxomorpholin-4-yl)phenyl]}-(2R,4R)-4-ene Propoxypyrrolidine-1,2-dicarboxamide, ESI 499, m.p.100°C and as a by-product

5) 2-N-{allyl-[4-(3-oxomorpholin-4-yl)phenyl]}-1-N-[(4-chlorophenyl)]-4-hydroxypyrrolidine -1,2-dicarboxamide, ESI 499;

6) 1-N-[(4-chlorophenyl)]-2-N-{[3-methyl-4-(3-oxomorpholin-4-yl)phenyl]}-(2R, 4R )-4-methoxypyrrolidine-1,2-dicarboxamide, ESI 487, m.p.140°C;

7) 1-N-[(4-chlorophenyl)]-2-N-{[4-(2-oxo-2H-pyridin-1-yl)phenyl]}-(2R, 4R)-4 -Methoxypyrrolidine-1,2-dicarboxamide, ESI 467, m.p.133°C;

8) 1-N-[(4-chlorophenyl)]-2-N-{[2-fluoro-4-(3-oxomorpholin-4-yl)phenyl]}-(2R, 4R) -4-Methoxypyrrolidine-1,2-dicarboxamide, ESI 491, m.p.109℃;

9) 1-N-[(4-chlorophenyl)]-2-N-{[4-(2-oxo-2H-pyrazin-1-yl)phenyl]}-(2R, 4R)- 4-Methoxypyrrolidine-1,2-dicarboxamide, ESI 468, m.p.127℃;

10) 1-N-[(4-chlorophenyl)]-2-N-{[3-fluoro-4-(3-oxomorpholin-4-yl)phenyl]}-(2R, 4R) -4-Methoxypyrrolidine-1,2-dicarboxamide, ESI 491, m.p.99°C;

11) 1-N-[(4-chlorophenyl)]-2-N-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)phenyl]}-(2R, 4R)-4-methoxypyrrolidine-1,2-dicarboxamide, ESI 485;

12) 1-N-[(4-chlorophenyl)]-2-N-{[4-(2-oxo-2H-pyrazin-1-yl)phenyl]}-(2R, 4R)- 4-Ethoxypyrrolidine-1,2-dicarboxamide, ESI 482, m.p.132℃;

13) 1-N-[(4-chlorophenyl)]-2-N-{[3-fluoro-4-(3-oxomorpholin-4-yl)phenyl]}-(2R, 4R) -4-ethoxypyrrolidine-1,2-dicarboxamide, ESI 505, m.p.131°C;

14) 1-N-[(4-chlorophenyl)]-2-N-{[4-(3-oxomorpholin-4-yl)phenyl]}-(2R, 4R)-4-( Prop-2-ynyloxy)pyrrolidine-1,2-dicarboxamide, ESI 497, m.p.120°C;

15) 1-N-[(4-chlorophenyl)]-2-N-{[4-(3-oxomorpholin-4-yl)phenyl]}-(2R, 4R)-4-( But-2-ynyloxy)pyrrolidine-1,2-dicarboxamide,

16) 1-N-[(4-chlorophenyl)]-2-N-{[2-fluoro-4-(3-oxomorpholin-4-yl)phenyl]}-(2R, 4R) -4-(prop-2-ynyloxy)pyrrolidine-1,2-dicarboxamide, ESI 515, m.p.108°C;

17) 1-N-[(4-chlorophenyl)]-2-N-{[2-fluoro-4-(3-oxomorpholin-4-yl)phenyl]}-(2R, 4S) -4-(prop-2-ynyloxy)pyrrolidine-1,2-dicarboxamide, ESI 515, m.p.92°C;

18) 1-N-[(4-chlorophenyl)]-2-N-{[4-(3-oxomorpholin-4-yl)phenyl]}-(2R, 4R)-4-( Methoxycarbonylmethoxy)pyrrolidine-1,2-dicarboxamide, ESI 531, m.p.106°C; and thus by hydrolysis

19) 1-N-[(4-chlorophenyl)]-2-N-{[4-(3-oxomorpholin-4-yl)phenyl]}-(2R, 4R)-4-( Carboxymethoxy)pyrrolidine-1,2-dicarboxamide, ESI 517, m.p.134℃;

20) 1-N-[(4-bromophenyl)]-2-N-{[2-fluoro-4-(3-oxomorpholin-4-yl)phenyl]}-(2R, 4R) -4-Methoxypyrrolidine-1,2-dicarboxamide, ESI 536, m.p.103°C.

Example 11

Isobutyric acid (3R,5R)-1-(4-chlorophenylcarbamoyl)-5-[4-(3-oxomorpholin-4-yl)phenylcarbamoyl) was prepared in a similar manner to the following scheme Acyl]pyrrolidin-3-yl esters ("A12"):

A solution of 0.2 g (0.44 mmol) of "A8" in isobutyric anhydride (0.146 ml) in pyridine (1 ml) was stirred at room temperature for 12 hours. Then 10 ml of ethyl acetate was added to the reaction mixture, and the ethyl acetate solution was washed successively with 5 ml of 1N hydrochloric acid and 5 ml of saturated sodium chloride solution, and then dried over sodium sulfate. The desiccant was filtered off, and then the solvent was removed to obtain 183 mg (79.3%) of isobutyric acid (3R, 5R)-1-(4-chlorophenylcarbamoyl)-5-[4-(3-oxomorpholine- 4-yl)phenylcarbamoyl]pyrrolidin-3-yl ester ("A12") as white crystals, ESI 529, m.p.129°C.

The following compounds are similarly obtained:

Propionic acid (3R, 5R)-1-(4-chlorophenylcarbamoyl)-5-[4-(3-oxomorpholin-4-yl)phenylcarbamoyl]pyrrolidin-3-yl Esters, ESI 515;

(3R,5R)-1-(4-chlorophenylcarbamoyl)-5-[4-(3-oxomorpholin-4-yl)phenylcarbamoyl]pyrrolidin-3-yl acetate , ESI 501, m.p.148°C.

Example 12

4-N-[(4-chlorophenyl)]-5-N-{[4-(3-oxomorpholin-4-yl)phenyl]}-1,3- Dioxolane-4,5-dicarboxamide:

The following compounds are similarly obtained:

1) 4-N-[(4-chlorophenyl)]-5-N-{[3-methyl-4-(3-oxomorpholin-4-yl)phenyl]}-1,3- Dioxolane-4,5-dicarboxamide,

2) 4-N-[(4-chlorophenyl)]-5-N-{[4-(2-oxo-2H-pyridin-1-yl)phenyl]}-1,3-dioxolane Cyclo-4,5-dicarboxamide, ESI 440;

3) 4-N-[(4-chlorophenyl)]-5-N-{[4-(3-oxomorpholin-4-yl)phenyl]}-1,3-dioxolane- 2,2-Dimethyl-4,5-dicarboxamide, ESI 474;

4) 4-N-[(4-chlorophenyl)]-5-N-{[3-methyl-4-(3-oxomorpholin-4-yl)phenyl]}-1,3- Dioxolane-2,2-dimethyl-4,5-dicarboxamide, ESI 488;

5) 4-N-[(4-chlorophenyl)]-5-N-{[4-(2-oxo-1H-pyridin-1-yl)phenyl]}-1,3-dioxolane Cyclo-2,2-dimethyl-4,5-dicarboxamide, ESI 468.

Example 13

Similar to Example 7, N-[4-(3-oxomorpholin-4-yl)phenyl]-1-BOC-piperazine-2-carboxamide reacts with 4-chlorophenyl isocyanate to generate Compound:

1-N-[4-chlorophenyl)]-2-N-{[4-(3-oxomorpholin-4-yl)phenyl]}-1-BOC-piperazine-1,2-di Formamide

Removal of the BOC group yields

1-N-[4-chlorophenyl)]-2-N-{[4-(3-oxomorpholin-4-yl)phenyl]}-piperazine-1,2-dicarboxamide.

Similarly, 4-chlorophenyl isocyanate reacts with N-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazepine-4-carboxamide , forming the compound

1-N-[4-chlorophenyl]-2-N-{[4-(3-oxomorpholin-4-yl)phenyl]}-1,3-oxazepine-3, 4-dicarboxamide.

Example 13-1

1-N-[(4-chlorophenyl)]-2-N-{[4-(3-oxomorpholin-4-yl)phenyl]}-(R)- 4-oxopyrrolidine-1,2-dicarboxamide:

To 0.3g (0.65mmol) 1-N-[(4-chlorophenyl)]-2-N-{[4-(3-oxomorpholin-4-yl)phenyl]}-(1R, 4R )-4-hydroxypyrrolidine-1,2-dicarboxamide (embodiment 7) in dichloromethane (15ml) solution, add 0.21g (0.98mmol) pyridinium chlorochromate (PCC), then stir at room temperature The reaction mixture was 48 hours. The precipitate was then filtered off, and the filtrate was washed 3 times with 20 ml of water each time and dried over sodium sulfate. After removal of the solvent, the residue was purified by preparative HPLC to afford 140 mg (47%) of 1-N-[(4-chlorophenyl)]-2-N-{[4-(3-oxomorpholin-4-yl )phenyl]}-(R)-4-oxopyrrolidine-1,2-dicarboxamide white powder, ESI 457, m.p.154°C.

Example 13-2

N-[4-(3-oxomorpholin-4-yl)phenyl]-(2R,4R)-1-[2-(4-chlorophenyl)acetyl]- 4-Hydroxypyrrolidine-2-carboxamide:

At room temperature, to 0.5g (1.46mmol) N-[4-(3-oxomorpholin-4-yl)phenyl]-(2R, 4R)-4-hydroxypyrrolidine-2-formamide (implementation Example 7.2) and 0.2ml triethylamine in toluene (20ml) solution, add 0.25g (1.46mmol) 4-chlorophenylacetic acid and 0.36g (1.46mmol) 2-ethoxy-1,2-dihydroquinoline successively - Ethyl 1-carboxylate (EEDQ). The resulting reaction mixture was subsequently stirred at room temperature for 12 hours, then washed successively with 10 ml of 1N hydrochloric acid and 10 ml of saturated sodium bicarbonate solution, and the organic phase was dried over sodium sulfate. After removal of the solvent, the crude product was purified by preparative HPLC to afford 0.31 g (46.4%) of N-[4-(3-oxomorpholin-4-yl)phenyl]-(2R,4R)-1-[2- (4-Chlorophenyl)acetyl]-4-hydroxypyrrolidine-2-carboxamide white powder, ESI 458, m.p.141℃.

The following compounds are similarly obtained:

1) N-[4-(3-oxomorpholin-4-yl)phenyl]-(2R,4R)-1-(4-chlorobenzoyl)-4-hydroxypyrrolidine-2-carboxamide , ESI 444, m.p.216℃;

2) N-[4-(3-oxomorpholin-4-yl)phenyl]-(2R,4R)-1-(1-1H-indol-3-yl-formyl)-4-hydroxy Pyrrolidine-2-carboxamide, ESI 449, m.p.283°C;

3) N-[4-(3-oxomorpholin-4-yl)phenyl]-(2R,4R)-1-(1-1H-indol-6-yl-formyl)-4-hydroxy Pyrrolidine-2-carboxamide, ESI 449, m.p. 148°C.

Example 13-3

1-N-[(4-chlorophenyl)]-2-N-{[3-methyl-4-(3-oxomorpholin-4-yl)phenyl]} was prepared in a similar manner to the following scheme -(2R,4R)-4-ethoxypyrrolidine-1,2-dicarboxamide:

5g (21.62mmol) cis-N'-Boc-4-hydroxyl-D-proline and 8.66g (43.24mmol) tetrahydrofuran (THF) (5ml) suspension of ethyl 4-toluenesulfonate were mixed with 2.94g (73.5 mmol) aqueous sodium hydroxide (5 ml) solution was added together. The reaction mixture was then stirred at 40° C. for 12 hours, then evaporated on a rotary evaporator, and the residue was dissolved in 10 ml of water. The aqueous solution was then washed twice with 10 mL of dichloromethane and acidified with 2N hydrochloric acid. The resulting acidic solution was extracted three times with 20 ml of dichloromethane each time. The combined dichloromethane extracts were dried over sodium sulfate and the solvent removed to yield 4.87 g (86.9%) of cis-N'-Boc-4-ethoxy-D-proline as a colorless oil. ESI 232.

Similar to Example 7, the reaction of cis-N'-Boc-4-ethoxyl-D-proline generates the compound:

1-N-[(4-chlorophenyl)]-2-N-{[3-methyl-4-(3-oxomorpholin-4-yl)phenyl]}-(2R,4R)- 4-Ethoxypyrrolidine-1,2-dicarboxamide, ESI 501, m.p.117°C.

The following compounds are similarly obtained:

1-N-[(4-chlorophenyl)]-2-N-{[4-(2-oxo-1H-pyridin-1-yl)phenyl]}-(2R,4R)-4-ethane Oxypyrrolidine-1,2-dicarboxamide, ESI 481, m.p.209℃;

1-N-[(4-chlorophenyl)]-2-N-{[2-fluoro-4-(3-oxomorpholin-4-yl)phenyl]}-(2R,4R)-4 - Ethoxypyrrolidine-1,2-dicarboxamide, ESI 505, m.p. 187°C.

Example 13-4

2-N-[(4-chlorophenyl)]-1-N-{[4-(3-oxomorpholin-4-yl)phenyl]}-(R)- Pyrrolidine-1,2-dicarboxamide:

1.01g (5.00mmol) of 4-nitrophenyl chloroformate and 0.404ml (5.00mmol) of pyridine were added to a solution of 961mg (5.00mmol) of 4-(4-aminophenyl)morpholin-3-one in dichloromethane ( 10 ml) solution, and the mixture was stirred at room temperature for 1 hour. To this suspension were added 1.31 g (5.00 mmol) of (R)-2-(4-chlorophenylcarbamoyl)pyrrolidinium chloride and 2.55 ml (15.0 mmol) of N-ethyldiisopropylamine. The reaction mixture was stirred at room temperature for 12 hours, then evaporated and the residue was chromatographed on a silica gel column to give 2-N-[(4-chlorophenyl)]-1-N-{[4-(3-oxo Morpholin-4-yl)phenyl]}-(R)-pyrrolidine-1,2-dicarboxamide yellowish solid, ESI 443.

2-N-[(4-chlorophenyl)]-1-N-{[4-(3-oxomorpholin-4-yl)phenyl]}-(S)-pyrrolidine-1 is obtained similarly , 2-dicarboxamide, ESI 443.

Example 13-5

N-(4-Chlorophenyl)-(R)-1-{2-[4-(3-oxomorpholin-4-yl)phenyl]acetyl}pyrrolidine- 2-Formamide:

To a suspension of 2.80 g (13.0 mmol) N-Boc-D-proline and 1.66 g (13.0 mmol) 4-chloroaniline in toluene (50 ml) was added 4.82 g (19.5 mmol) 2-ethoxy-1, 2-dihydroquinoline-1-carboxylic acid ethyl ester (EEDQ), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was filtered, and petroleum ether was added to the filtrate. The formed precipitate was filtered and dried to give colorless crystals of (R)-tert-butyl 2-(4-chlorophenylcarbamoyl)pyrrolidine-1-carboxylate; ESI325.

4.00g (12.3mmol) (R)-2-(4-chlorophenylcarbamoyl)pyrrolidine-1-carboxylic acid tert-butyl ester was dissolved in 4N HCl in dioxane solution (20ml), then at room temperature Set aside for 2 hours. The reaction mixture was evaporated and dried to give (R)-2-(4-chlorophenylcarbamoyl)pyrrolidinium chloride as a brownish solid; ESI 225.

To 261mg (1.00mmol) of (R)-2-(4-chlorophenylcarbamoyl)pyrrolidinium chloride and 235mg (1.00mmol) of 4-(3-oxomorpholin-4-yl)phenylacetic acid Add 0.26ml (2.4mmol) 4-methylmorpholine and 230mg (1.2mmol) hydrochloride N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (DAPECl) to DMF (2ml) solution , and the mixture was stirred at room temperature for 18 hours. The reaction mixture was introduced into water and the precipitate formed was filtered to give N-(4-chlorophenyl)-(R)-1-{2-[4-(3-oxomorpholin-4-yl)phenyl] Acetyl}pyrrolidine-2-carboxamide slightly brown solid; ESI 442.

N-(4-Chlorophenyl)-(S)-1-{2-[4-(3-oxomorpholin-4-yl)phenyl]acetyl}pyrrolidine-2-carboxamide is obtained analogously , ESI 442.

Preparation of carboxylic acid units

14.6g (92.7mmol) (2-chloroethoxy) acetyl chloride was added to a toluene (25ml) suspension of 20.0g (92.7mmol) ethyl 4-aminophenylacetate hydrochloride, and then the mixture was boiled and heated for 24 Hour. The reaction mixture was evaporated and dried to give ethyl {4-[2-(2-chloroethoxy)acetamido]phenyl}acetate as a yellowish solid; ESI 300.

43.4g (133mmol) cesium carbonate was added in the acetonitrile (100ml) solution of 26.6g (88.8mmol) {4-[2-(2-chloroethoxy) acetamido] phenyl} ethyl acetate, then at room temperature The mixture was stirred for 18 hours. The reaction mixture was filtered and the filtrate was evaporated to give ethyl [4-(3-oxomorpholin-4-yl)phenyl]acetate as a yellowish oil; ESI 264.

20.2 g (76.8 mmol) of ethyl [4-(3-oxomorpholin-4-yl)phenyl] acetate were dissolved in 3.37 g of sodium hydroxide in ethanol (40 ml), and the reaction was stirred at room temperature solution for 18 hours. The reaction mixture was evaporated and the residue was dissolved in water and acidified to pH 3 with 1N hydrochloric acid. The mixture was extracted with ethyl acetate and the organic phase was dried over sodium sulfate and evaporated to give 4-(3-oxomorpholin-4-yl)phenylacetic acid as a yellowish solid; ESI 236.

Similar to Example 13-5, the following compounds were obtained:

1) N-(4-chlorophenyl)-(2R,4R)-1-{2-[4-(3-oxomorpholin-4-yl)phenyl]acetyl}-4-methoxy pyrrolidine-2-carboxamide,

2) N-(4-chlorophenyl)-(2R,4S)-1-{2-[4-(3-oxomorpholin-4-yl)phenyl]acetyl}-4-methoxy pyrrolidine-2-carboxamide,

3) N-(4-chlorophenyl)-(2S,4R)-1-{2-[4-(3-oxomorpholin-4-yl)phenyl]acetyl}-4-methoxy pyrrolidine-2-carboxamide,

4) N-(4-chlorophenyl)-(S)-1-{2-[4-(2-oxo-1H-pyridin-1-yl)phenyl]acetyl}-pyrrolidine-2- Formamide,

5) N-(4-chlorophenyl)-(S)-1-{2-[4-(2-oxopyrrolidin-1-yl)phenyl]acetyl}-pyrrolidine-2-carboxamide ,

6) N-(4-chlorophenyl)-(R)-1-{2-[4-(2-oxopyrrolidin-1-yl)phenyl]acetyl}-pyrrolidine-2-carboxamide ,

7) N-(4-chlorophenyl)-(R)-1-[4-(2-oxopiperidin-1-yl)benzoyl]pyrrolidine-2-carboxamide,

8) N-(4-chlorophenyl)-(R)-1-[4-(2-oxopiperidin-1-yl)phenoxycarbonyl]pyrrolidine-2-carboxamide.

Example 13-6

1-N-[(4-chlorophenyl)]-2-N-{[4-(3-oxomorpholin-4-yl)phenyl]}-(2R,4R )-4-(2,3-dihydroxypropoxy)pyrrolidine-1,2-dicarboxamide:

Under nitrogen, to 10.3g (42mmol) (2R,4R)-4-hydroxypyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester and 36.34ml (420mmol) 3-bromo-1 - To a solution of propylene in dimethylformamide (DMF) (100 ml) was added portionwise 1.55 g (38.6 mmol) of sodium hydride and the mixture was then stirred at room temperature for 15 minutes. 9.73 g (42 mmol) of silver oxide were then added in portions to the reaction mixture, and the reaction mixture was stirred for a further 12 hours at room temperature. The reaction mixture was then filtered, the filtrate was evaporated to dryness under reduced pressure, and the residue was dissolved in 20 ml of saturated citric acid solution. After the precipitate was filtered off, the filtrate was extracted twice with 20 ml of ethyl acetate. The combined organic phases were dried over sodium sulfate and the solvent was removed to give 11.6 g of (2R,4R)-4-allyloxypyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl Esters; ESI 286.

At room temperature, 5 g (17.52 mmol) (2R, 4R)-4-allyloxypyrrolidine-1,2-dicarboxylic acid 1-tert-butyl 2-methyl ester in water (60 ml), acetone ( 25 ml) and tert-butanol (10 ml) were added successively 6.16 g (52.6 mmol) of N-methylmorpholine N-oxide (NMO) and 193.7 mg of potassium osmate dihydrate, and the mixture was stirred for 48 hours. Then 6.6 g (52.6 mmol) of sodium sulfite were added to the reaction mixture, followed by stirring at room temperature for 1 hour. The reaction mixture was then evaporated under reduced pressure, the residue was dissolved in 50 ml of water, and the aqueous solution was extracted twice with 20 ml each of ethyl acetate. The combined organic phases were dried over sodium sulfate and the solvent was removed to give 4.7 g of (2R,4R)-4-(2,3-dihydroxypropoxy)pyrrolidine-1,2-dicarboxylic acid 1-tert. Butyl ester 2-methyl ester; ESI 320. 1.06 g of lithium hydroxide was added to a solution of the methyl ester (4.6 g) in tetrahydrofuran (40 ml), methanol (10 ml) and water (10 ml), and the reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was then evaporated under reduced pressure, 10 ml of saturated citric acid solution were added to the remaining aqueous solution, and the mixture was extracted three times with 20 ml each of ethyl acetate. The combined organic phases were dried over sodium sulfate and then the solvent was removed to give 4.3 g of (2R,4R)-4-(2,3-dihydroxypropoxy)pyrrolidine-1,2-dicarboxylate tert-butyl yellow powder ; ESI 306. Similar to Example 7, the acid affords the compound 1-N-[(4-chlorophenyl)]-2-N-{[4-(3-oxomorpholin-4-yl)phenyl]}-( 2R,4R)-4-(2,3-dihydroxypropoxy)pyrrolidine-1,2-dicarboxamide; ESI 533.

1-N-[(4-chlorophenyl)]-2-N-{[2-fluoro-4-(3-oxomorpholin-4-yl)phenyl]}-(2R, 4R )-4-(2,3-dihydroxypropoxy)pyrrolidine-1,2-dicarboxamide; ESI 551.

Example 13-7

The following compounds were prepared analogously to the following schemes:

1) 1-N-[(4-chlorophenyl)]-2-N-{[4-(3-oxomorpholin-4-yl)phenyl]}-(2R, 4R)-4-( 2-hydroxy-3-pyrrolidin-1-ylpropoxy)pyrrolidine-1,2-dicarboxamide,

2) 1-N-[(4-chlorophenyl)]-2-N-{[4-(3-oxomorpholin-4-yl)phenyl]}-(2R, 4R)-4-( 2-oxooxazolidin-5-ylmethoxy)pyrrolidine-1,2-dicarboxamide and

3) 1-N-[(4-chlorophenyl)]-2-N-{[4-(3-oxomorpholin-4-yl)phenyl]}-(2R, 4R)-4-( 3-amino-2-hydroxypropoxy)pyrrolidine-1,2-dicarboxamide, ESI 532, m.p.115:

Example 13-8

1-N-[(4-chlorophenyl)]-2-N-{N-methoxycarbonylmethyl-N'-[4-(3-oxomorpholine-4) was prepared in a similar manner to the following scheme -yl)phenyl]}-(2R,4R)-4-methoxypyrrolidine-1,2-dicarboxamide:

Add 61 mg (2.54 mmol) of sodium hydride to 1 g (2.31 mmol) of (2R, 4R)-4-methoxy-2-[4-(3-oxomorpholin-4-yl)phenylcarbamoyl]pyrrole A solution of tert-butyl alkane-1-carboxylate (prepared in a similar manner to Example 7.1) in dimethylformamide (20 ml) was stirred at room temperature for 30 minutes. Then 0.22 mg (2.31 mmol) of methyl bromoacetate was added to the reaction mixture, followed by stirring at room temperature for 12 hours. The reaction mixture was then evaporated under reduced pressure, the residue was dissolved in 20 ml of water, and the aqueous solution was extracted three times with 20 ml of dichloromethane each. The combined organic phases were dried over sodium sulfate and the solvent was removed to give 1.1 g of (2R,4R)-4-methoxy-2-{methoxycarbonylmethyl-[4-(3-oxomorpholine) as a yellow oil -4-yl)phenyl]carbamoyl}pyrrolidine-1-carboxylic acid tert-butyl ester; ESI (M-BOC) 392.

Removal of the BOC group affords 1-N-[(4-chlorophenyl)]-2-N-{N-methoxycarbonylmethyl-N'-[4-(3-oxomorpholine-4- Base) phenyl]}-(2R,4R)-4-methoxypyrrolidine-1,2-dicarboxamide, ESI 545, m.p.106°C.

Compound 1-N-[(4-chlorophenyl)]-2-N-{N-methoxycarbonylmethyl-N'-[2-fluoro-4-(3-oxomorpholine- 4-yl)phenyl]}-(2R,4R)-4-methoxypyrrolidine-1,2-dicarboxamide, ESI 563, m.p.100°C.

Example 13-9

1-N-[(4-chlorophenyl)]-2-N-{[4-(3-oxomorpholin-4-yl)cyclohex-1-yl]}- (2R,4R)-4-hydroxypyrrolidine-1,2-dicarboxamide:

13-9.1 Add 6.32g (40.3mmol) (2-chloroethoxy) acetyl chloride to 10g (40.3mmol) (4-aminocyclohexyl) benzyl carbamate and 6.2ml triethylamine (TEA) in tetrahydrofuran ( 300 ml) solution, and the mixture was stirred at room temperature for 20 hours. The reaction mixture was then evaporated under reduced pressure, the residue was dissolved in 20 ml of water, and the aqueous solution was extracted three times with 20 ml of ethyl acetate. After drying the combined organic phases over sodium sulfate, the solvent is removed, the residue is dissolved in 20 ml of acetonitrile, and 2.3 g of cesium carbonate are added to the resulting solution. The reaction mixture was then stirred at room temperature for 48 hours, then evaporated under reduced pressure, the residue was dissolved in 20 ml of water, and the aqueous solution was extracted four times with 20 ml of ethyl acetate. After drying the combined organic phases over sodium sulfate, the solvent was removed, the residue was dissolved in 50 ml of tetrahydrofuran, 0.3 g of 5% palladium on carbon was added to the resulting solution, and the mixture was then hydrogenated until hydrogen absorption ceased. The catalyst was subsequently filtered off and the filtrate was evaporated to dryness under reduced pressure, yielding 1.5 g of 4-(4-aminocyclohexyl)morpholin-3-one as a colorless oil; ESI 199.

13-9.2 Similar to Example 7.3, cis-N'-BOC-4-hydroxy-D-proline reacts with 4-chlorophenyl isocyanate to generate compound (2R, 4R)-1-(4- Chlorophenylcarbamoyl)-4-hydroxypyrrolidine-2-carboxylic acid; ESI 285, m.p.132°C.

13-9.3 is similar to Example 7.1, the amine of 13-9.1 reacts with the acid of 13-9.2 to generate compound 1-N-[(4-chlorophenyl)]-2-N-{[4-(3-oxo Morpholin-4-yl)cyclohex-1-yl]}-(2R,4R)-4-hydroxypyrrolidine-1,2-dicarboxamide, ESI 465; m.p.245°C.

Example 13-10

Similar to Example 7, the following compounds were obtained:

1) 1-N-[(4-chlorophenyl)]-2-N-[(1'-methyl-[1,4']bipiperidin-4-yl)]-(2R,4R)- 4-Hydroxypyrrolidine-1,2-dicarboxamide, ESI 464; m.p.78℃

2) 1-N-[(4-chlorophenyl)]-2-N-[(3,4,5,6-tetrahydro-2H-[1,4']bipyridin-4-yl)]- (2R,4R)-4-Hydroxypyrrolidine-1,2-dicarboxamide, ESI 444

3) 1-N-[(4-chlorophenyl)]-2-N-[(3,4,5,6-tetrahydro-2H-1,4'-bipyridin-4-yl)-(2R , 4R)-4-ethoxypyrrolidine-1,2-dicarboxamide, ESI 472;

4) N-(4-chlorophenyl)-(2R,4R)-4-hydroxy-2-(4-pyridin-4-ylpiperazine-1-carbonyl)pyrrolidine-1-carboxamide, ESI 430

5) N-(4-chlorophenyl)-(2R,4R)-4-hydroxy-2-[4-(2-methoxyphenyl)piperazine-1-carbonyl]pyrrolidine-1-carboxamide , ESI 459

6) N-(4-chlorophenyl)-(2R,4R)-2-[4-(4-fluorophenyl)piperazine-1-carbonyl]-4-hydroxypyrrolidine-1-carboxamide, ESI 447;

7) N-(4-chlorophenyl)-(2R,4R)-4-hydroxyl-2-[4-hydroxyl-4-(4-methoxyphenyl)piperidine-1-carbonyl]pyrrolidine- 1-formamide, ESI 456;

8) N-(4-chlorophenyl)-(2R,4R)-4-hydroxy-2-[4-pyridin-2-ylpiperazine-1-carbonyl)pyrrolidine-1-carboxamide, ESI 430;

9) N-(4-chlorophenyl)-(2R,4R)-2-[4-(4-ethylpiperazin-1-yl)piperidine-1-carbonyl]-4-hydroxypyrrolidine-1 - Formamide, ESI 465;

10) N-(4-chlorophenyl)-(2R,4R)-2-[4-(4,6-dimethylpyrimidin-2-yl)piperazine-1-carbonyl]-4-hydroxypyrrolidine -1-formamide, ESI 459;

11) N-(4-chlorophenyl)-(2R,4R)-4-hydroxy-2-[4-(1-methylpiperidin-4-yl)piperazine-1-carbonyl]pyrrolidine-1 - Formamide; ESI 450;

12) 1-N-[(4-chlorophenyl)]-2-N-{[2-(2-dimethylaminoethoxy)-4-morpholin-4-ylphenyl]}-(2R , 4R)-4-hydroxypyrrolidine-1,2-dicarboxamide, ESI 532;

13) 1-N-[(4-chlorophenyl)]-2-N-[(2-ethoxy-4-morpholin-4-ylphenyl)]-(2R,4R)-4-hydroxy Pyrrolidine-1,2-dicarboxamide, ESI 489;

14) 1-N-[(4-chlorophenyl)]-2-N-[(4-morpholin-4-yl-2-propoxyphenyl)]-(2R,4R)-4-hydroxy Pyrrolidine-1,2-dicarboxamide, ESI 504;

Examples 13-11

Similar to Example 7, the following compounds were obtained:

1) 1-N-[(4-chlorophenyl)]-2-N-{[4-(2-iminopyrrolidin-1-yl)phenyl]}-(2R,4R)-4-hydroxy Pyrrolidine-1,2-dicarboxamide, ESI 442;

2) 1-N-[(4-chlorophenyl)]-2-N-{[3-methyl-4-(2-iminopyrrolidin-1-yl)phenyl]}-(2R, 4R )-4-hydroxypyrrolidine-1,2-dicarboxamide, ESI 456;

3) 1-N-[(4-chlorophenyl)]-2-N-[4-{2-[(E)-cyanoimino] imidazolidin-1-yl)phenyl]}-(2R , 4R)-4-hydroxypyrrolidine-1,2-dicarboxamide, ESI 468;

4) 1-N-[(4-chlorophenyl)]-2-N-{[4-(2-imino-5-methylthiazol-3-yl)phenyl]}-(2R, 4R) -4-hydroxypyrrolidine-1,2-dicarboxamide, ESI 473;

5) 1-N-[(4-fluorophenyl)]-2-N-{[2-aminocarbonyl-4-(3-oxomorpholin-4-yl)phenyl]}-(2R, 4R )-4-hydroxypyrrolidine-1,2-dicarboxamide, ESI 502;

6) 1-N-[(4-chlorophenyl)]-2-N-{[4-(3-oxomorpholin-4-yl)phenyl]}-(2R,4R)-4-hydroxy -2-Methylpyrrolidine-1,2-dicarboxamide, ESI 457.

Example 13-12

Prepared in a similar manner to the following procedure

N-[4-(3-oxomorpholin-4-yl)phenyl]-(2R,4R)-1-[(E)-3-(5-chlorothiophen-2-yl)acryloyl]- 4-Hydroxypyrrolidine-2-carboxamide:

A solution of 1 g (6.62 mmol) 5-chloro-2-thiophenecarbaldehyde and 1.38 g (13.23 mmol) malonic acid in piperidine (0.07 ml) and pyridine (5 ml) was refluxed for 2 hours. The reaction solution was subsequently cooled, poured into 20 ml of water, and acidified to pH 1 with 2N hydrochloric acid. The product precipitated during this process was filtered with suction, and then dried in a drying oven at 80° C. to obtain 1.02 g of (E)-3-(5-chlorothiophen-2-yl)acrylic acid brown crystals, ESI 189. Similar to Example 7.1, the compound of Example 7.2 reacts with (E)-3-(5-chlorothiophen-2-yl)acrylic acid to generate compound N-[4-(3-oxomorpholin-4-yl)phenyl ]-(2R,4R)-1-[(E)-3-(5-Chlorothiophen-2-yl)acryloyl]-4-hydroxypyrrolidine-2-carboxamide, colorless crystals, ESI 476, m.p.151 ℃.

The following compounds are similarly obtained:

1) N-[4-(3-oxomorpholin-4-yl)phenyl]-(2R,4R)-1-[(E)-3-thiophen-3-ylacryloyl]-4-hydroxy Pyrrolidine-2-carboxamide, ESI 442, m.p.137℃;

2) N-[4-(3-oxomorpholin-4-yl)phenyl]-(2R,4R)-1-[(2E,4E)-5-phenylpenta-2,4-diene Acyl]-4-hydroxypyrrolidine-2-carboxamide, ESI 462, m.p.127℃;

3) N-[4-(3-oxomorpholin-4-yl)phenyl]-(2R,4R)-1-[(E)-3-(5-methylfuran-2-yl)propene Acyl]-4-hydroxypyrrolidine-2-carboxamide, ESI 440, m.p.133℃;

4) N-[4-(3-oxomorpholin-4-yl)phenyl]-(2R,4R)-1-[(E)-3-thiophen-2-ylacryloyl]-4-hydroxy Pyrrolidine-2-carboxamide, ESI 442;

5) N-[2-fluoro-4-(3-oxomorpholin-4-yl)phenyl]-(2R,4R)-1-[(E)-3-(5-chlorothiophene-2- Base) acryloyl] -4-methoxypyrrolidine-2-carboxamide, ESI 508;

6) N-[2-fluoro-4-(3-oxomorpholin-4-yl)phenyl]-(2R,4R)-1-[(E)-3-(5-chlorothiophene-2- Base) acryloyl] -4-hydroxypyrrolidine-2-carboxamide, ESI 494, m.p.111 ° C;

7) N-[4-(3-oxomorpholin-4-yl)phenyl]-(2R,4R)-1-[(E)-3-(4-chlorophenyl)acryloyl]-4 -Hydroxypyrrolidine-2-carboxamide, ESI 470;

8) N-[4-(3-oxomorpholin-4-yl)phenyl]-(2R,4R)-1-[(E)-3-(3,4-dichlorophenyl)acryloyl ]-4-hydroxypyrrolidine-2-carboxamide, ESI 504;

9) N-[4-(3-oxomorpholin-4-yl)phenyl]-(2R,4R)-1-[(E)-3-(4-chlorophenyl)acryloyl]-4 -Methoxypyrrolidine-2-carboxamide, ESI 484;

10) N-[4-(3-oxomorpholin-4-yl)phenyl]-(2R,4R)-1-[(E)-3-(3,4-dichlorophenyl)acryloyl ]-4-methoxypyrrolidine-2-carboxamide, ESI 518;

11) N-[4-(3-oxomorpholin-4-yl)phenyl]-(2R,4R)-1-[(E)-3-1H-imidazol-4-ylacryloyl]-4 -Hydroxypyrrolidine-2-carboxamide, ESI 426;

12) N-[4-(3-oxomorpholin-4-yl)phenyl]-(2R,4R)-1-[(E)-3-(5-chlorothiophen-2-yl)acryloyl ]-4-methoxypyrrolidine-2-carboxamide, ESI 490;

13) N-[4-(3-oxomorpholin-4-yl)phenyl]-(2R,4R)-1-[(E)-3-(5-chlorofuran-2-yl)acryloyl ]-4-hydroxypyrrolidine-2-carboxamide, ESI 460;

14) N-[4-(3-oxomorpholin-4-yl)phenyl]-(2R,4R)-1-[(E)-3-(5-chlorofuran-2-yl)acryloyl ]-4-methoxypyrrolidine-2-carboxamide, ESI 474;

15) N-[4-(3-oxomorpholin-4-yl)phenyl]-(2R,4R)-1-[(E)-3-(4-chlorophenyl)acryloyl]-4 -Ethoxypyrrolidine-2-carboxamide, ESI 498;

16) N-[4-(3-oxomorpholin-4-yl)phenyl]-(2R,4R)-1-[(E)-3-(3,4-dichlorophenyl)acryloyl ]-4-ethoxypyrrolidine-2-carboxamide, ESI 532;

17) N-[4-(3-oxomorpholin-4-yl)phenyl]-(2R,4R)-1-[(E)-3-(5-chlorofuran-2-yl)acryloyl ]-4-ethoxypyrrolidine-2-carboxamide, ESI 488;

18) N-[4-(3-oxomorpholin-4-yl)phenyl]-(2R,4R)-1-[(E)-3-(5-chlorothiophen-2-yl)acryloyl ]-4-ethoxypyrrolidine-2-carboxamide, ESI 504;

19) N-[2-fluoro-4-(3-oxomorpholin-4-yl)phenyl]-(2R,4R)-1-[(E)-3-(4-chlorophenyl)propene Acyl]-4-hydroxypyrrolidine-2-carboxamide, ESI 488;

20) N-[2-fluoro-4-(3-oxomorpholin-4-yl)phenyl]-(2R,4R)-1-[(E)-3-(3,4-dichlorobenzene Base) acryloyl] -4-hydroxypyrrolidine-2-carboxamide, ESI 522;

21) N-[2-fluoro-4-(3-oxomorpholin-4-yl)phenyl]-(2R,4R)-1-[(E)-3-(5-chlorofuran-2- Base) acryloyl] -4-hydroxypyrrolidine-2-carboxamide, ESI 478;

22) N-[2-fluoro-4-(3-oxomorpholin-4-yl)phenyl]-(2R, 4R)-1-[(E)-3-(5-chlorofuran-2- Base) acryloyl] -4-methoxypyrrolidine-2-carboxamide, ESI 492;

23) N-[2-fluoro-4-(3-oxomorpholin-4-yl)phenyl]-(2R,4R)-1-[(E)-3-(4-chlorophenyl)propene Acyl]-4-methoxypyrrolidine-2-carboxamide, ESI 502;

24) N-[2-fluoro-4-(3-oxomorpholin-4-yl)phenyl]-(2R,4R)-1-[(E)-3-(3,4-dichlorobenzene Base) acryloyl] -4-methoxypyrrolidine-2-carboxamide, ESI 536;

25) N-[2-fluoro-4-(3-oxomorpholin-4-yl)phenyl]-(2R,4R)-1-[(E)-3-(4-chlorophenyl)propene Acyl]-4-ethoxypyrrolidine-2-carboxamide, ESI 516;

26) N-[2-fluoro-4-(3-oxomorpholin-4-yl)phenyl]-(2R,4R)-1-[(E)-3-(3,4-dichlorobenzene Base) acryloyl] -4-ethoxypyrrolidine-2-carboxamide, ESI 550;

27) N-[2-fluoro-4-(3-oxomorpholin-4-yl)phenyl]-(2R, 4R)-1-[(E)-3-(5-chlorofuran-2- Base) acryloyl] -4-ethoxypyrrolidine-2-carboxamide, ESI 506;

28) N-[2-fluoro-4-(3-oxomorpholin-4-yl)phenyl]-(2R,4R)-1-[(E)-3-(5-chlorothiophene-2- Base) acryloyl] -4-ethoxypyrrolidine-2-carboxamide, ESI 522;

29) N-[4-(3-oxomorpholin-4-yl)phenyl]-(2R,4R)-1-[(E)-3-1H-imidazol-4-ylacryloyl]-4 -Ethoxypyrrolidine-2-carboxamide, ESI 454;

30) N-[2-fluoro-4-(3-oxomorpholin-4-yl)phenyl]-(2R,4R)-1-[(E)-3-1H-imidazol-4-ylpropene Acyl]-4-hydroxypyrrolidine-2-carboxamide, ESI 444;

31) N-[2-fluoro-4-(3-oxomorpholin-4-yl)phenyl]-(2R,4R)-1-[(E)-3-1H-imidazol-4-ylpropene Acyl]-4-methoxypyrrolidine-2-carboxamide, ESI 458;

32) N-[2-fluoro-4-(3-oxomorpholin-4-yl)phenyl]-(2R,4R)-1-[(E)-3-1H-imidazol-4-ylpropene Acyl]-4-ethoxypyrrolidine-2-carboxamide, ESI 472;

33) N-[2-fluoro-4-(3-oxomorpholin-4-yl)phenyl]-(2R,4R)-1-[(E)-3-pyridin-3-ylacryloyl] -4-hydroxypyrrolidine-2-carboxamide, ESI 455;

34) N-[4-(3-oxomorpholin-4-yl)phenyl]-(2R, 4R)-1-[(E)-3-pyridin-3-ylacryloyl]-4-ethane Oxypyrrolidine-2-carboxamide, ESI 465;

35) N-[2-fluoro-4-(3-oxomorpholin-4-yl)phenyl]-(2R,4R)-1-[(E)-3-pyridin-3-ylacryloyl] -4-methoxypyrrolidine-2-carboxamide, ESI 469;

36) N-[2-fluoro-4-(3-oxomorpholin-4-yl)phenyl]-(2R,4R)-1-[(E)-3-pyridin-3-ylacryloyl] -4-ethoxypyrrolidine-2-carboxamide, ESI 483;

37) N-[4-(3-oxomorpholin-4-yl)phenyl]-(2R,4R)-1-[(E)-3-pyridin-3-ylacryloyl]-4-hydroxy Pyrrolidine-2-carboxamide, ESI 437;

38) N-[4-(3-oxomorpholin-4-yl)phenyl]-(2R, 4R)-1-[(E)-3-pyridin-3-ylacryloyl]-4-methyl Oxypyrrolidine-2-carboxamide, ESI 451;

39) N-[4-(3-oxomorpholin-4-yl)phenyl]-(2R,4R)-1-[(E)-3-pyridin-4-ylacryloyl]-4-hydroxy Pyrrolidine-2-carboxamide, ESI 437;

40) N-[4-(3-oxomorpholin-4-yl)phenyl]-(2R, 4R)-1-[(E)-3-pyridin-4-ylacryloyl]-4-ethane Oxypyrrolidine-2-carboxamide, ESI 465;

41) N-[4-(3-oxomorpholin-4-yl)phenyl]-(2R,4R)-1-[(E)-3-1H-imidazol-4-ylacryloyl]-4 -Methoxypyrrolidine-2-carboxamide, ESI 440;

42) N-[4-(3-oxomorpholin-4-yl)phenyl]-(2R,4R)-1-[(E)-3-(4-bromothiophen-2-yl)acryloyl ]-4-hydroxypyrrolidine-2-carboxamide, ESI 521;

43) N-[4-(3-oxomorpholin-4-yl)phenyl]-(2R,4R)-1-[(E)-3-(4-bromothiophen-2-yl)acryloyl ]-4-ethoxypyrrolidine-2-carboxamide, ESI 549;

44) N-[4-(3-oxomorpholin-4-yl)phenyl]-(2R,4R)-1-[(E)-3-(5-bromothiophen-2-yl)acryloyl ]-4-hydroxypyrrolidine-2-carboxamide, ESI 521;

45) N-[4-(3-oxomorpholin-4-yl)phenyl]-(2R,4R)-1-[(E)-3-(5-bromothiophen-2-yl)acryloyl ]-4-ethoxypyrrolidine-2-carboxamide, ESI 549.

Example 13-13

Similar to Example 7, the following compounds were obtained:

1) N-(4-chlorophenyl)-(R)-1-[4-(2-oxopiperidin-1-yl)benzoyl]pyrrolidine-2-carboxamide, ESI 426;

2) N-(4-chlorophenyl)-(S)-1-[4-(2-oxopiperidin-1-yl)benzoyl]pyrrolidine-2-carboxamide, ESI 426;

3) 1-N-[(4-chlorophenyl)]-2-N-{[4-(5-oxo-1,4-oxazepan-4-yl)phenyl]}- (R)-pyrrolidine-1,2-dicarboxamide, ESI 457;

4) 1-N-[(4-chlorophenyl)]-2-N-{[4-(5-oxo-1,4-oxazepan-4-yl)phenyl]}- (2R,4R)-4-hydroxypyrrolidine-1,2-dicarboxamide, ESI 473;

5) 1-N-[(4-chlorophenyl)]-2-N-{[4-((S)-2-methyl-3-oxomorpholin-4-yl)phenyl]}- (2R,4R)-4-hydroxypyrrolidine-1,2-dicarboxamide, ESI 473;

6) 1-N-[(4-chlorophenyl)]-2-N-{[4-((S)-2-methyl-3-oxomorpholin-4-yl)phenyl]}- (2R)-pyrrolidine-1,2-dicarboxamide, ESI 457;

7) 1-N-[(4-chlorophenyl)]-2-N-{[4-(R)-2-methyl-3-oxomorpholin-4-yl)phenyl]}-( 2R,4R)-4-hydroxypyrrolidine-1,2-dicarboxamide, ESI 473;

8) 1-N-[(4-chlorophenyl)]-2-N-{[4-((R)-2-methyl-3-oxomorpholin-4-yl)phenyl]}- (2R)-pyrrolidine-1,2-dicarboxamide, ESI 457;

9) 1-N-[(4-chlorophenyl)]-2-N-{[4-(3-oxomorpholin-4-yl)-2-phenoxyphenyl]}-(2R) - pyrrolidine-1,2-dicarboxamide, ESI 535;

10) 1-N-[(4-chlorophenyl)]-2-N-{[2-fluoro-4-((R)-2-methyl-3-oxomorpholin-4-yl)benzene Base]}-(2R,4R)-4-hydroxypyrrolidine-1,2-dicarboxamide, ESI 491;

11) 1-N-[(4-chlorophenyl)]-3-N-{[4-(3-oxomorpholin-4-yl)phenyl]}piperidine-1,3-dicarboxamide , ESI 457;

12) 1-N-[(4-chlorophenyl)]-3-N-{[3-methyl-4-(3-oxomorpholin-4-yl)phenyl]}piperidine-1, 3-dicarboxamide, ESI 471;

13) 1-N-[(4-chlorophenyl)]-2-N-{[4-(3-oxo-1,4-oxazepan-4-yl)phenyl]}- (2R,4R)-4-hydroxypyrrolidine-1,2-dicarboxamide, ESI 473;

14) 1-N-[(4-chlorophenyl)]-2-N-{[2-methyl-4-(3-oxomorpholin-4-yl)phenyl]}-(2R, 4R )-4-hydroxypyrrolidine-1,2-dicarboxamide, ESI 473;

15) 1-N-[(4-chlorophenyl)]-2-N-{[4-(3-oxomorpholin-4-yl)phenyl]}-(2R,4R)-4-hydroxy Pyrrolidine-1,2-dicarboxamide, ESI 459;

16) 1-N-[(4-chlorophenyl)]-2-N-{[2-(3-oxomorpholin-4-yl)phenyl]}-(2R,4R)-4-hydroxy Pyrrolidine-1,2-dicarboxamide, ESI 459.

Example 13-14

Similar to Example 7, the following compounds were obtained:

N-[4-(3-oxomorpholin-4-yl)phenyl]-(rac)-2-[3-(4-chlorophenyl)ureido]cyclopentanecarboxamide, ESI 457

N-[3-methyl-4-(3-oxomorpholin-4-yl)phenyl]-(rac)-2-[3-(4-chlorophenyl)ureido]cyclopentanecarboxamide , ESI 471.

Examples 13-15

1-N-[(4-chlorophenyl)]-2-N-{[4-(3-oxomorpholin-4-yl)phenyl]}-(2R,4R) was prepared as shown below -4-(2-methoxyethoxy)pyrrolidine-1,2-dicarboxamide, ESI 517:

14. Preparation examples of intermediate compounds

14.1 All compounds of the following formula VI (wherein R=H or methyl; n=3, 4 or 5) can be synthesized according to the following scheme.

For example, to synthesize 1-(4-amino-2-methylphenyl)piperidin-2-one:

14.2 Synthesis of methyl-free phenylpiperidone units:

For example 1-(4-amino-2-methylphenyl)piperidin-2-one is prepared as follows:

14.3 1-(4-Aminophenyl)-1H-pyrazin-2-one

14.4 1-(4-amino-2,5-dimethylphenyl)piperidin-2-one

14.5 1-(4-Amino-3-methylphenyl)piperidin-2-one

14.6 1-(5-aminopyridin-2-yl)piperidin-2-one

14.7 1-(4-Aminomethylphenyl)piperidin-2-one

14.8 2-(4-Aminophenyl)-2-azabicyclo[2,2,2]oct-3-one

14.9 1-(3-Amino-6-ethylphenyl)pyrrolidin-2-one

14.10 2-(4-Amino-2-trifluoromethylphenyl)-2-azabicyclo[2,2,2]oct-3-one

14.11 1-(4-Amino-3-chlorophenyl)pyrrolidin-2-one

14.12 1-(4-Amino-2-trifluoromethylphenyl)piperidin-2-one

14.13 3-(4-Amino-2-methylphenyl)-1,3-oxazepin-2-one

14.14 4-(4-Aminophenyl)morpholin-3-one

14.15 1-(4-Aminophenyl)pyridin-2-one

14.16 1-(4-Amino-2-methylphenyl)piperidin-2-one

14.17 1-(4-Aminophenyl)-1H-pyridin-4-one

14.18 1-(4-Aminophenyl)-4-tert-butoxycarbonylpiperazin-2-one

14.19 1-(3-Aminophenyl)piperidin-2-one

14.20 1-(4-Aminophenyl)-2-caprolactam

14.21 1-(4-Amino-3-fluorophenyl)piperidin-2-one

14.22 1-(4-Amino-2-fluorophenyl)piperidin-2-one

14.23 1-(4-Amino-2-fluorophenyl)-2-caprolactam

14.24 4-(4-Amino-2-fluorophenyl)-1,4-oxazepan-5-one

14.25 4-(4-Amino-3-phenoxyphenyl)morpholin-3-one

14.26 2-[3-(4-Chlorophenyl)ureido]cyclopentanecarboxylic acid

14.27 1-(4-Chlorophenylcarbamoyl)piperidine-3-carboxylic acid

14.28 4-(4-Aminophenyl)-1,4-oxazepan-3-one

TEMPO oxidation was carried out according to the following literature method: L. DeLuca et al., J. Org. Chem. 68, 4999-5001 (2003).

pharmacological data

affinity for the receptor

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

The following examples relate to pharmaceutical preparations:

Example A: Injection Vials

A solution of 100 g of the active ingredient of formula I and 5 g of disodium hydrogen phosphate in redistilled water (3 L) was adjusted to pH 6.5 with 2N hydrochloric acid, sterile filtered, transferred to an injection vial, lyophilized under sterile conditions, and placed in Seal under sterile conditions. Each injection vial contains 5 mg of active ingredient.

Embodiment B: Suppository

A mixture of 20 g of active ingredient of formula I, 100 g of soy lecithin and 1400 g of cocoa butter was melted, poured into molds and allowed to cool. Each suppository contains 20 mg of active ingredient.

Example C: Solution

A solution was prepared by dissolving 1 g of the active ingredient of formula I, 9.38 g of NaH ₂ PO ₄ ·2H ₂ O, 28.48 g _{of Na 2} HPO ₄ ·12H ₂ O and 0.1 g of benzalkonium chloride in 940 ml of redistilled water. The pH was adjusted to 6.8, then the solution was made up to 1 L and sterilized by irradiation. The solution is available as eye drops.

Example D: Cream

Under sterile conditions, 500 mg of the active ingredient of formula I is mixed with 99.5 g of petrolatum.

Example E: Tablets

The mixture of 1kg formula I active ingredient, 4kg lactose, 1.2kg potato starch, 0.2kg talcum powder and 0.1kg magnesium stearate is compressed into tablets according to conventional method, and each tablet contains 10mg active ingredient.

Example F: Coated Tablets

Tablets were compressed in a similar manner to Example E, and then coated with a coating material of sucrose, potato starch, talc, tragacanth and dyes in a conventional manner.

Embodiment G: Capsules

2 kg of active ingredient of formula I are conventionally introduced into hard gelatin capsules, each capsule containing 20 mg of active ingredient.

Example H: Ampoule

A solution of 1 kg of the active ingredient of formula I in double distilled water (60 L) was sterile filtered, transferred into ampoules, lyophilized under aseptic conditions, and sealed under aseptic conditions. Each ampule contains 10mg of active ingredient.

Claims (41)

1. formula I compound and pharmaceutically spendable derivative thereof, solvate, salt and the steric isomer that comprises its various mixed things:

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,

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,

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,

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,

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,

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,

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

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

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

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,

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

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,

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

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.

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.