CN1164232A

CN1164232A - Aminoheterocyclic derivatives as antithrombotic or anticoagulant agents

Info

Publication number: CN1164232A
Application number: CN 95196337
Authority: CN
Inventors: A·W·弗尔; C·M·梅约; J·普里斯通; A·斯托克
Original assignee: Zeneca Ltd
Current assignee: Syngenta Ltd
Priority date: 1994-09-26
Filing date: 1995-09-25
Publication date: 1997-11-05

Abstract

The invention concerns compounds or a pharmaceutically-acceptable salt of formula (I), wherein each of G<1>, G<2> and G<3> is CH or N; m is 1 or 2; R<1> includes hydrogen, halogeno and (1-4C)alkyl; M<1> is a group of formula: NR<2>-L<1>-T<1>R<3>, in which R<2> and R<3> together form a (1-4C)alkylene group, L<1> includes (1-4C)alkylene, and T<1> is CH or N; A may be a direct link; M<2> is a group of the formula: (T<2>R<4>)r-L<2>-T<3>R<5> in which R is 0 or 1, each of T<2> and T<3> is CH or N, each of R<4> and R<5> is hydrogen or (1-4C)alkyl, or R<4> and R<5> together form a (1-4C)alkylene group, and L<2> includes (1-4C)alkylene; M<3> may be a direct link to X; X includes sulphonyl; and Q includes naphthyl and a heterocyclic moiety; processes for their preparation, pharmaceutical compositions containing them and their use as antithrombotic or anticoagulant agents.

Description

Amino-heterocycles derivative as antithrombotic agent or anti-coagulant

The present invention relates to a class amino-heterocycles derivative or its pharmacologically acceptable salt, they have antithrombotic and form or anticoagulation character, therefore can be used for treating in the method for human or animal body, the present invention also relates to the preparation method of described amino-heterocycles derivative, the pharmaceutical composition that contains them, and they are used to produce in preparation, and antithrombotic forms or the purposes of the medicine of blood coagulation resisting function.

The antithrombotic that The compounds of this invention produces forms or blood coagulation resisting function it is believed that it is because they are to being called factor X _aActivatory blood coagulating protein enzyme have stronger restraining effect, factor X _aBe included in the placed in-line a member of proteolytic enzyme in the complex process of hemopexis.The proteolytic enzyme that is called zymoplasm is the final proteolytic enzyme in series connection, factor X _aBe the prothrombin cracking can be produced zymoplasm at preceding proteolytic enzyme.

Known some compound has factor X _aInhibition activity, this respect be by R.B.Wallis, Current Opinion in Therapeutic Patents., 1993,1173-1179 summarizes, and known two kinds of protein (a kind of antistatin that is called, another kind are called signal anticoagulant protein matter (TAP)) are specificity factor X _aInhibitor, they have antithrombotic formation character to the various animal models of thrombotic disease.

Also known some non-peptide compound has factor X _aInhibition activity is mentioned in the low-molecular-weight inhibitor in the R.B.Wallis summary, all has strong basicity group such as amidino groups phenyl or amidino groups naphthyl.

The purpose of this invention is to provide the new medicament that does not have above-mentioned amidino groups of a class, this amidino groups it is believed that and is factor X _aThe essential feature of inhibitor.

We have been found that now the Hete rocyclic derivatives of some amino-replacement has factor X _aSuppress active, chemical compound lot of the present invention also has can be factor X optionally _aThe advantage of inhibitor that is to say, enzyme factor X _aUnder the concentration of test compound, suppressed strongly, and do not suppress or on less degree Trombin inhibiting, this zymoplasm also is a member in the blood clotting hemase series connection.

Compound of the present invention is in treatment or prevent to have activity in the various medical condition, and anticoagulation therapy is designated as here, for example, and treatment or prevention thrombotic disease such as coronary artery disease and cerebrovascular disease.Other examples of these medical condition comprise that various cardiovascular and cerebrovascular diseases such as myocardial infarction form, atherosclerotic formation, vein or artery thrombosis, the blood coagulation symptom, blood vessel injury is included in reclosing plug and the restenosis after angioplasty and the coronary artery bypass surgical operation, use vascular surgery, the synthetical heart lobe or of packing into to the thrombosis after the recirculation of blood, cerebrum block forms, big cerebral thrombosis, apoplexy, cerebral embolism, pulmonary infarction, local asphyxia and angina (comprising unsettled angina).

Compound of the present invention also can be used as the inhibitor of the hemopexis under the environment that exsomatizes, and for example, estimates to contain factor X _aAnd solidifying is the storage of deleterious whole blood or other biological sample.

One aspect of the present invention has provided amino-heterocycles derivative or its pharmacologically acceptable salt of formula I (vide infra): G wherein ¹Be CH or N; G ²Be CH or N; G ³Be CH or N; M is 1 or 2; R ¹Be hydrogen, amino, halo, cyano group, (1-4C) alkyl or (1-4C) alkoxyl group; M ¹Be the following formula group:

NR ²-L ¹-T ¹R ³R wherein ²And R ³Form (1-4C) alkylidene group or methylene radical carbonyl together, or R ³Be (2-3C) alkylidene group, it and L ¹In methylene radical be connected to form and comprise T ¹And R ³5 or 6 yuan of rings, L ¹Be (1-4C) alkylidene group, (3-6C) cycloalkyl-1,2-two base or (1-3C) alkylidene group carbonyl, and T ¹Be CH or N, and wherein at L ¹In 1 or 2 methylene radical and work as R ²And R ³Or R ³The ring that is connected to form with L is optional to have a substituting group, and this substituting group is selected from (1-4C) alkyl, the alkyl of hydroxyl-(1-4C), and (1-4C) alkyl of alkyl of alkoxyl group-(1-4C) and phenyl-(1-4C), and at M ¹In any phenyl optional have 1 or 2 substituting groups, described substituting group is selected from halo, trifluoromethyl, (1-4C) alkyl and (1-4C) alkoxyl group; A is the direct key that is connected with carbonyl, or A is (1-4C) alkylidene group; M ²Be the following formula group:

(T ²R ⁴) _r-L ²-T ³R ⁵Wherein r is 0 or 1, T ²Be CH or N, T ³Be CH or N, R ⁴Be hydrogen or (1-4C) alkyl, R ⁵Be hydrogen or (1-4C) alkyl or R ⁴And R ⁵Form (1-4C) alkylidene group, methylene radical carbonyl or carbonyl methylene radical, or R together ⁴Be (2-3C) alkylidene group, it and L ²In methylene radical be connected to form and comprise R ⁴And T ²5 or 6 yuan of rings, or R ⁵Be (2-3C) alkylidene group, it and L ²In methylene radical be connected to form and comprise R ⁵And T ³5 or 6 yuan of rings, L ²Be (1-4C) alkylidene group, (3-6C) cycloalkanes-1,2-two bases, (1-3C) alkylidene group-carbonyl or phenylene, and when r is 1, L ²Also can be the alkylidene group of carbonyl-(1-3C), and wherein at L ²In 1 or 2 methylene radical and work as R ⁴And R ⁵, R ⁴And L ²Or R ⁵And L ²The ring that is connected to form is chosen wantonly and is had a substituting group; this substituting group is selected from oxo; carboxyl; (1-4C) carbalkoxy; formamyl; N-(1-4C) alkyl-carbamoyl; N; N-two-(1-4C) alkyl-carbamoyls; tetramethyleneimine-1-base carbonyl; the piperidino-(1-position only) carbonyl; morpholino carbonyl; piperazine-1-base carbonyl; 4-(1-4C) alkylpiperazine-1-base carbonyl; N-phenyl amino formyl radical; N-(1-4C) alkyl-N-phenyl amino formyl radical; the alkyl of N-[phenyl-(1-3C)] formamyl; the alkyl of N-(1-4C) alkyl-N-[phenyl-(1-3C)] formamyl; the alkyl of N-[hydroxyl-(2-3C)] formamyl; the alkyl of N-(1-4C) alkyl-N-[hydroxyl-(2-3C)] formamyl; N-[(1-4C) alkyl of alkoxyl group-(2-3C)] formamyl; the alkyl of the alkoxyl group of N-(1-4C) alkyl-N-[(1-4C)-(2-3C)] formamyl; the alkyl of N-[carboxyl-(1-3C)] formamyl; the alkyl of N-(1-4C) alkyl-N-[carboxyl-(1-3C)] formamyl; the alkyl of N-[carboxyl-(1-3C)]-alkyl of N-[hydroxyl-(2-3C)] formamyl; the alkyl of N-[carboxyl-(1-3C)]-N-[(1-4C) alkyl of alkoxyl group-(2-3C)] formamyl; N-[(1-4C) alkyl of carbalkoxy-(1-3C)] formamyl; the alkyl of the carbalkoxy of N-(1-4C) alkyl-N-[(1-4C)-(1-3C)] formamyl; N-[(1-4C) alkyl of carbalkoxy-(1-3C)]-alkyl of N-[hydroxyl-(2-3C)] formamyl; N-[(1-4C) alkyl of carbalkoxy-(1-3C)]-N-[(1-4C) alkyl of alkoxyl group-(2-3C)] formamyl; (1-4C) alkyl; carboxyl (1-4C) alkyl; (1-4C) alkyl of carbalkoxy-(1-4C); the alkyl of formamyl-(1-4C); the alkyl of N-(1-4C) alkyl-carbamoyl-(1-4C); N; the alkyl of N-two (1-4C) alkyl-carbamoyl-(1-4C); the alkyl of tetramethyleneimine-1-base carbonyl-(1-4C); the alkyl of piperidino-(1-position only) carbonyl-(1-4C); the alkyl of morpholino carbonyl-(1-4C); the alkyl of piperazine-1-base carbonyl-(1-4C); the alkyl of 4-(1-4C) alkylpiperazine-1-base carbonyl-(1-4C); the alkyl of N-phenyl amino formyl radical-(1-4C); the alkyl of N-[phenyl-(1-3C)] alkyl of formamyl-(1-4C); the alkyl of hydroxyl-(1-4C); (1-4C) alkyl of alkyl of alkoxyl group-(1-4C) and phenyl-(1-4C); and have 1 or 2 substituting group in that described substituent any heterocyclic radical is optional; substituting group is selected from (1-4C) alkyl; (1-4C) alkoxyl group; carboxyl; (1-4C) carbalkoxy; formamyl; N-(1-4C) alkyl-carbamoyl or N; N-two (1-4C) alkyl-carbamoyl, and at M ²In any phenyl optional have 1 or 2 substituting groups, described substituting group is selected from halo, trifluoromethyl, (1-4C) alkyl and (1-4C) alkoxyl group; M ³Be the direct key that is connected with X, or M ³Be the following formula group:

L ³-(NR ⁶) _sWherein s is 0 or 1, R ⁶Be hydrogen or (1-4C) alkyl, or R ⁵And R ⁶Form (1-4C) alkylidene group, methylene radical carbonyl or carbonyl methylene radical, or R together ⁶Be (2-3C) alkylidene group, it and L ³In methylene radical be connected to form and comprise NR ⁶5 or 6 yuan of rings, L ³Be (1-4C) alkylidene group, (3-6C) cycloalkanes-1,2-two bases, carbonyl-(1-3C) alkylidene group or phenylene, and when s is 1, L ³Also can be (1-3C) alkylidene group-carbonyl, and wherein at L ³In 1 or 2 methylene radical and work as R ⁵And R ⁶Or R ⁶And L ³The ring that is connected to form is chosen wantonly and is had a substituting group; this substituting group is selected from oxo; carboxyl; (1-4C) carbalkoxy; formamyl; N-(1-4C) alkyl-carbamoyl; N; N-two-(1-4C) alkyl-carbamoyls; tetramethyleneimine-1-base carbonyl; the piperidino-(1-position only) carbonyl; morpholino carbonyl; piperazine-1-base carbonyl; 4-(1-4C) alkylpiperazine-1-base carbonyl; N-phenyl amino formyl radical; N-(1-4C) alkyl-N-phenyl amino formyl radical; the alkyl of N-[phenyl-(1-3C)] formamyl; the alkyl of N-(1-4C) alkyl-N-[phenyl-(1-3C)] formamyl; (1-4C) alkyl; the alkyl of carboxyl-(1-4C); (1-4C) alkyl of alkoxy carbonyl-(1-4C); the alkyl of formamyl-(1-4C); the alkyl of N-(1-4C) alkyl-carbamoyl-(1-4C); N; the alkyl of N-two-(1-4C) alkyl-carbamoyls-(1-4C); the alkyl of tetramethyleneimine-1-base carbonyl-(1-4C); the alkyl of piperidino-(1-position only) carbonyl-(1-4C); the alkyl of morpholino carbonyl-(1-4C); the alkyl of piperazine-1-base carbonyl-(1-4C); the alkyl of 4-(1-4C) alkylpiperazine-1-base carbonyl-(1-4C); the alkyl of N-phenyl amino formyl radical-(1-4C); the alkyl of N-[phenyl-(1-3C)] alkyl of formamyl-(1-4C); the alkyl of hydroxyl-(1-4C); (1-4C) alkyl of alkyl of alkoxyl group-(1-4C) and phenyl-(1-4C); and have 1 or 2 substituting group in that described substituent any heterocyclic radical is optional; substituting group is selected from (1-4C) alkyl; (1-4C) alkoxyl group; carboxyl; (1-4C) carbalkoxy; formamyl; N-(1-4C) alkyl-carbamoyl or N; N-two (1-4C) alkyl-carbamoyl, and at M ³In any phenyl or phenylene is optional has 1 or 2 substituting groups, described substituting group is selected from halo, trifluoromethyl, (1-4C) alkyl and (1-4C) alkoxyl group; X is oxygen, sulphur, sulfinyl, alkylsulfonyl, carbonyl, carbonyl oxygen base, carbonylamino, N-(1-4C) alkyl-carbonyl-amino, sulfuryl amino, methylene radical, (1-4C) alkyl methylene radical or two-(1-4C) alkyl methylene radical or works as T ³Be CH, M ³Be the direct key that is connected with X, X also is amino-sulfonyl or oxygen carbonyl; With Q be phenyl, naphthyl, the alkyl of phenyl-(1-4C), the alkenyl of phenyl-(2-4C), the alkynyl of phenyl-(2-4C), (5-7C) cycloalkyl or contain at the most 4 and be selected from nitrogen, the heteroatomic heterocyclic moiety of oxygen and sulphur, Q is optional to have 1,2 or 3 substituting groups, substituting group is selected from hydroxyl, amino, halo, cyano group, trifluoromethyl, nitro, carboxyl, formamyl, formyl radical, formimino, first hydroxyl oximido, (1-4C) carbalkoxy, (1-4C) alkyl, (1-4C) alkoxyl group, N-(1-4C) alkyl-carbamoyl, N, N-two-(1-4C) alkyl-carbamoyls, (1-4C) alkylamino, two-(1-4C) alkylaminos, (2-4C) alkanoyl amino, (2-4C) alkanoyl, (2-4C) alkane acylimino, (2-4C) alkanoyl hydroxyl oximido, phenyl, heteroaryl, phenoxy group, thiophenyl, the phenyl sulfinyl, phenyl sulfonyl, heteroaryl oxygen base, the heteroaryl sulfenyl, the heteroaryl sulfinyl, heteroarylsulfonyl, benzyl and benzoyl, and wherein said heteroaryl substituting group or the heteroaryl in containing the substituting group of heteroaryl comprise that containing at the most 3 is selected from nitrogen, heteroatomic 5 or 6 yuan of bicyclic heteroaryl rings of oxygen and sulphur, and described phenyl, heteroaryl, phenoxy group, thiophenyl, the phenyl sulfinyl, phenyl sulfonyl, heteroaryl oxygen base, the heteroaryl sulfenyl, the heteroaryl sulfinyl, heteroarylsulfonyl, benzyl or benzoyl substituting group are optional to have 1,2,3 or 4 substituting groups, substituting group is selected from halo, trifluoromethyl, cyano group, trifluoromethoxy, nitro, (1-4C) alkyl, (1-4C) alkoxyl group, hydroxyl, amino, carboxyl, formamyl, (1-4C) carbalkoxy, N-(1-4C) alkyl-carbamoyl, N, N-two-(1-4C) alkyl-carbamoyls, (1-4C) alkylamino, two-(1-4C) alkylaminos, (2-4C) alkanoyl amino and tetrazyl; Or its pharmacologically acceptable salt.

The chemical formula that this paper represents with Roman number is for the ease of being used for each chart hereinafter, and term " alkyl " comprises the alkyl of straight chain and side chain in this manual, only specifically refers to the straight chain variant but relate to concrete alkyl as " propyl group ".Similarly routine also can be used in other general termses.

Should be understood that some amino-heterocycles derivative of the present invention can exist with form non-solventization such as hydrated form with solvation, also should be understood that the present invention includes to have factor X _aSuppress active all such solvation forms.

Should be understood that further therefore some general formula compound defined above can exist with optically-active or racemic form owing to having one or more unsymmetrical carbons, the present invention includes to have factor X _aSuppress active all such optically-actives or racemic form.The organic chemistry ordinary method synthetic available well known in the art of optically-active form is carried out, and is for example undertaken by optically-active starting raw material or resolution of racemic form.

The present invention further provides formula I _aAmino-heterocycles derivative or its pharmacologically acceptable salt: G wherein ¹Be CH or N;

G ²Be CH or N; M is 1 or 2; R ¹Be hydrogen, amino, halo, cyano group, (1-4C) alkyl or (1-4C) alkoxyl group; M ¹Be the following formula group:

NR ²-L ¹-T ¹R ³R wherein ²And R ³Form (1-4C) alkylidene group or methylene radical carbonyl together, or R ³Be (2-3C) alkylidene group, it and L ¹In methylene radical be connected to form and comprise T ¹And R ³5 or 6 yuan of rings, L ¹Be (1-4C) alkylidene group, (3-6C) cycloalkanes-1,2-two base or (1-3C) alkylidene group carbonyl, and T ¹Be CH or N, and wherein at L ¹In 1 or 2 methylene radical and work as R ²And R ³Or R ³And L ¹The ring that is connected to form is optional to have a substituting group, and this substituting group is selected from (1-4C) alkyl, the alkyl of hydroxyl-(1-4C), and (1-4C) alkyl of alkyl of alkoxyl group-(1-4C) and phenyl-(1-4C), and at M ¹In any phenyl optional have 1 or 2 substituting groups, described substituting group is selected from halo, trifluoromethyl, (1-4C) alkyl and (1-4C) alkoxyl group; A is the direct key that is connected with carbonyl, or A is (1-4C) alkylidene group; M ²Be the following formula group:

(T ²R ⁴) _r-L ²-T ³R ⁵Wherein r is 0 or 1, T ²Be CH or N, T ³Be CH or N, R ⁴Be hydrogen or (1-4C) alkyl, R ⁵Be hydrogen or (1-4C) alkyl or R ⁴And R ⁵Form (1-4C) alkylidene group, methylene radical carbonyl or carbonyl methylene radical, or R together ⁴Be (2-3C) alkylidene group, it and L ²In methylene radical be connected to form and comprise R ⁴And T ²5 or 6 yuan of rings, or R ⁵Be (2-3C) alkylidene group, it and L ²In methylene radical be connected to form and comprise R ⁵And T ³5 or 6 yuan of rings, L ²Be (1-4C) alkylidene group, (3-6C) cycloalkanes-1,2-two bases, (1-3C) alkylidene group-carbonyl or phenylene, and when r is 1, L ²Also can be the alkylidene group of carbonyl-(1-3C), and wherein at L ²In 1 or 2 methylene radical and work as R ⁴And R ⁵, R ⁴And L ²Or R ⁵And L ²The ring that is connected to form is chosen wantonly and is had a substituting group; this substituting group is selected from carboxyl; (1-4C) carbalkoxy; formamyl; N-(1-4C) alkyl-carbamoyl; N; N-two-(1-4C) alkyl-carbamoyls; tetramethyleneimine-1-base carbonyl; the piperidino-(1-position only) carbonyl; morpholino carbonyl; piperazine-1-base carbonyl; 4-(1-4C) alkylpiperazine-1-base carbonyl; N-phenyl amino formyl radical; N-(1-4C) alkyl-N-phenyl amino formyl radical; the alkyl of N-[phenyl-(1-3C)] formamyl; the alkyl of N-(1-4C) alkyl-N-[phenyl-(1-3C)] formamyl; the alkyl of N-[hydroxyl-(2-3C)] formamyl; the alkyl of N-(1-4C) alkyl-N-[hydroxyl-(2-3C)] formamyl; N-[(1-4C) alkyl of alkoxyl group-(2-3C)] formamyl; the alkyl of the alkoxyl group of N-(1-4C) alkyl-N-[(1-4C)-(2-3C)] formamyl; the alkyl of N-[carboxyl-(1-3C)] formamyl; the alkyl of N-(1-4C) alkyl-N-[carboxyl-(1-3C)] formamyl; the alkyl of N-[carboxyl-(1-3C)]-alkyl of N-[hydroxyl-(2-3C)] formamyl; the alkyl of N-[carboxyl-(1-3C)]-N-[(1-4C) alkyl of alkoxyl group-(2-3C)] formamyl; N-[(1-4C) alkyl of carbalkoxy-(1-3C)] formamyl; the alkyl of the carbalkoxy of N-(1-4C) alkyl-N-[(1-4C)-(1-3C)] formamyl; N-[(1-4C) alkyl of carbalkoxy-(1-3C)]-alkyl of N-[hydroxyl-(2-3C)] formamyl; N-[(1-4C) alkyl of carbalkoxy-(1-3C)]-N-[(1-4C) alkyl of alkoxyl group-(2-3C)] formamyl; (1-4C) alkyl; carboxyl (1-4C) alkyl; (1-4C) alkyl of carbalkoxy-(1-4C); the alkyl of formamyl-(1-4C); the alkyl of N-(1-4C) alkyl-carbamoyl-(1-4C); N; the alkyl of N-two (1-4C) alkyl-carbamoyl-(1-4C); the alkyl of tetramethyleneimine-1-base carbonyl-(1-4C); the alkyl of piperidino-(1-position only) carbonyl-(1-4C); the alkyl of morpholino carbonyl-(1-4C); the alkyl of piperazine-1-base carbonyl-(1-4C); the alkyl of 4-(1-4C) alkylpiperazine-1-base carbonyl-(1-4C); the alkyl of N-phenyl amino formyl radical-(1-4C); the alkyl of N-[phenyl-(1-3C)] alkyl of formamyl-(1-4C); the alkyl of hydroxyl-(1-4C); (1-4C) alkyl of alkyl of alkoxyl group-(1-4C) and phenyl-(1-4C); and have 1 or 2 substituting group in that described substituent any heterocyclic radical is optional; substituting group is selected from (1-4C) alkyl; (1-4C) alkoxyl group; carboxyl; (1-4C) carbalkoxy; formamyl; N-(1-4C) alkyl-carbamoyl or N; N-two (1-4C) alkyl-carbamoyl, and at M ²In any phenyl or phenylene is optional has 1 or 2 substituting groups, described substituting group is selected from halo, trifluoromethyl, (1-4C) alkyl and (1-4C) alkoxyl group; M ³Be the direct key that is connected with X, or M ³Be the following formula group:

L ³-(NR ⁶) _sWherein s is 0 or 1, R ⁶Be hydrogen or (1-4C) alkyl, or R ⁵And R ⁶Form (1-4C) alkylidene group, methylene radical carbonyl or carbonyl methylene radical, or R together ⁶Be (2-3C) alkylidene group, it and L ³In methylene radical be connected to form and comprise NR ⁶5 or 6 yuan of rings, L ³Be (1-4C) alkylidene group, (3-6C) cycloalkanes-1,2-two bases, carbonyl-(1-3C) alkylidene group or phenylene, and when s is 1, L ³Also can be (1-3C) alkylidene group-carbonyl, and wherein at L ³In 1 or 2 methylene radical and work as R ⁵And R ⁶Or R ⁶And L ³The ring that is connected to form is chosen wantonly and is had a substituting group; this substituting group is selected from carboxyl; (1-4C) carbalkoxy; formamyl; N-(1-4C) alkyl-carbamoyl; N; N-two-(1-4C) alkyl-carbamoyls; tetramethyleneimine-1-base carbonyl; the piperidino-(1-position only) carbonyl; morpholino carbonyl; piperazine-1-base carbonyl; 4-(1-4C) alkylpiperazine-1-base carbonyl; N-phenyl amino formyl radical; N-(1-4C) alkyl-N-phenyl amino formyl radical; the alkyl of N-[phenyl-(1-3C)] formamyl; the alkyl of N-(1-4C) alkyl-N-[phenyl-(1-3C)] formamyl; (1-4C) alkyl; the alkyl of carboxyl-(1-4C); (1-4C) alkyl of alkoxy carbonyl-(1-4C); the alkyl of formamyl-(1-4C); the alkyl of N-(1-4C) alkyl-carbamoyl-(1-4C); N; the alkyl of N-two-(1-4C) alkyl-carbamoyls-(1-4C); the alkyl of tetramethyleneimine-1-base carbonyl-(1-4C); the alkyl of piperidino-(1-position only) carbonyl-(1-4C); the alkyl of morpholino carbonyl-(1-4C); the alkyl of piperazine-1-base carbonyl-(1-4C); the alkyl of 4-(1-4C) alkylpiperazine-1-base carbonyl-(1-4C); the alkyl of N-phenyl amino formyl radical-(1-4C); the alkyl of N-[phenyl-(1-3C)] alkyl of formamyl-(1-4C); the alkyl of hydroxyl-(1-4C); (1-4C) alkyl of alkyl of alkoxyl group-(1-4C) and phenyl-(1-4C); and have 1 or 2 substituting group in that described substituent any heterocyclic radical is optional; substituting group is selected from (1-4C) alkyl; (1-4C) alkoxyl group; carboxyl; (1-4C) carbalkoxy; formamyl; N-(1-4C) alkyl-carbamoyl or N; N-two (1-4C) alkyl-carbamoyl, and at M ³In any phenyl optional have 1 or 2 substituting groups, described substituting group is selected from halo, trifluoromethyl, (1-4C) alkyl and (1-4C) alkoxyl group; X is oxygen, sulphur, sulfinyl, alkylsulfonyl, carbonyl, carbonyl oxygen base, carbonylamino, N-(1-4C) alkyl-carbonyl-amino, sulfuryl amino, methylene radical, (1-4C) alkyl methylene radical or two-(1-4C) alkyl methylene radical or works as T ³Be CH, M ³Be the direct key that is connected with X, X also is amino-sulfonyl or oxygen carbonyl; With Q be phenyl, naphthyl, the alkyl of phenyl-(1-4C), the alkenyl of phenyl-(2-4C), the alkynyl of phenyl-(2-4C), (5-7C) cycloalkyl or contain at the most 4 and be selected from nitrogen, the heteroatomic heterocyclic moiety of oxygen and sulphur, Q is optional to have 1,2 or 3 substituting groups, substituting group is selected from hydroxyl, amino, halo, cyano group, trifluoromethyl, nitro, carboxyl, formamyl, formyl radical, formimino, first hydroxyl oximido, (1-4C) carbalkoxy, (1-4C) alkyl, (1-4C) alkoxyl group, N-(1-4C) alkyl-carbamoyl, N, N-two-(1-4C) alkyl-carbamoyls, (1-4C) alkylamino, two-(1-4C) alkylaminos, (2-4C) alkanoyl amino, (2-4C) alkanoyl, (2-4C) alkane acylimino, (2-4C) alkanoyl hydroxyl oximido, phenyl, heteroaryl, phenoxy group, thiophenyl, the phenyl sulfinyl, phenyl sulfonyl, heteroaryl oxygen base, the heteroaryl sulfenyl, the heteroaryl sulfinyl, heteroarylsulfonyl, benzyl and benzoyl, and wherein said heteroaryl substituting group or the heteroaryl in containing the substituting group of heteroaryl comprise that containing at the most 3 is selected from nitrogen, heteroatomic 5 or 6 yuan of bicyclic heteroaryl rings of oxygen and sulphur, and described phenyl, heteroaryl, phenoxy group, thiophenyl, the phenyl sulfinyl, phenyl sulfonyl, heteroaryl oxygen base, the heteroaryl sulfenyl, the heteroaryl sulfinyl, heteroarylsulfonyl, benzyl or benzoyl substituting group are chosen wantonly and are had 1 or 2 substituting group, substituting group is selected from halo, trifluoromethyl, (1-4C) alkyl, the alkoxyl group of (-4C), hydroxyl, amino, carboxyl, formamyl, (1-4C) carbalkoxy, N-(1-4C) alkyl-carbamoyl, N, N-two-(1-4C) alkyl-carbamoyls, (1-4C) alkylamino, two-(1-4C) alkylaminos, (2-4C) alkanoyl amino and tetrazyl; Or its pharmacologically acceptable salt.

The suitable implication of the general terms that relates to above is as described below:

When m is 2, R ¹Be selected from hydrogen, amino, halo, cyano group, (1-4C) alkyl and (1-4C) alkoxyl group independently of one another.

For R ¹Be halo group and M ¹, M ²Or M ³In the halo substituting group or for the halo substituting group among the Q, suitable implication is fluorine, chlorine, bromine or iodine.

For R ¹Be (1-4C) alkyl and M ¹, M ²Or M ³In (1-4C) alkyl substituent or for (1-4C) alkyl substituent among the Q, suitable implication is methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl or the tertiary butyl.

For R ¹Be (1-4C) alkoxyl group and M ¹, M ²Or M ³In (1-4C) alkoxy substituent or for (1-4C) alkoxy substituent among the Q, suitable implication is methoxyl group, oxyethyl group, propoxy-, isopropoxy or butoxy.

Work as R ⁴, R ⁵, R ⁶During for (1-4C) alkyl, suitable implication for example is methyl, ethyl, propyl group, sec.-propyl, butyl or sec-butyl.

R ²And R ³Together, R ⁴And R ⁵Together or R ⁵And R ⁶The suitable implication that forms (1-4C) alkylidene group together for example is methylene radical, ethylidene, trimethylene or tetramethylene.

R ³With at L ¹In methylene radical connect R ⁴With at L ²In methylene radical connect R ⁵With at L ²In methylene radical connect or R ⁶With at L ³In methylene radical connect, the suitable implication that forms (2-3C) alkylidene group for example is ethylidene or trimethylene.

Work as L ¹, L ²Or L ³For the suitable implication of (1-4C) alkylidene group for example is a methylene radical, ethylidene, trimethylene or tetramethylene; When it is (3-6C) cycloalkanes-1, during 2-two bases, suitable implication for example is a cyclopropane-1,2-two bases, tetramethylene-1,2-two bases, pentamethylene-1,2-two bases or hexanaphthene-1,2-two bases; When it was (1-3C) alkylidene group-carbonyl, suitable implication for example was the methylene radical carbonyl, ethylidene carbonyl or trimethylene carbonyl; And when it was phenylene, it was 1,3-or 1,4-phenylene.

Work as L ²And L ³During for the alkylidene group of carbonyl-(1-3C), suitable implication for example is carbonyl methylene radical, carbonyl ethylidene or carbonyl trimethylene.

At M ¹, M ²Or M ³In the substituent suitable implication that exists comprise as follows: for (1-4C) carbalkoxy: methoxycarbonyl, ethoxycarbonyl, the third oxygen carbonyl and uncle's fourth oxygen

Carbonyl; For N-(1-4C) alkyl N-methylamino formyl radical, N-ethylamino formamido group formyl radical: base and N-propyl group formamyl; For N, N-two-[(1-4C) alkyl]-formamyl: N, the N-formyl-dimethylamino,

N-ethyl-N-methylamino first

Acyl group and N, the N-diethylamino

Formyl radical; For 4-(1-4C) alkylpiperazine-1-base carbonyl: 4-methylpiperazine-1-base carbonyl and

4-ethyl piperazidine-1-base carbonyl; For N-(1-4C) alkyl-N-phenyl amino formyl radical: N-methyl-N-phenyl amino formyl

Base and N-ethyl-N-phenyl amino

Formyl radical; For the alkyl of N-[phenyl-(1-3C)]-formamyl: N-benzylamino formyl radical and N-benzene

The ethylamino formyl radical; For the alkyl of N-(1-4C) alkyl-N-[phenyl-(1-3C)] formamyl: N-benzyl-N-methylamino formyl

Base and N-methyl-N-styroyl ammonia

The base formyl radical; For the alkyl of N-[hydroxyl-(2-3C)]-the amino first of formamyl: N-(2-hydroxyethyl)

Acyl group and N-(3-hydroxypropyl)

Formamyl; For the alkyl of N-(1-4C) alkyl-N-[hydroxyl-(2-3C)] formamyl: N-(2-hydroxyethyl)-N-

Methylamino formyl radical and N-(2-

Hydroxyethyl)-N-ethyl-amino

Formyl radical; For N-[(1-4C) alkyl of alkoxyl group-(2-3C)] formamyl: N-(2-methoxy ethyl) amino

Formyl radical and N-(2-oxyethyl group second

Base) formamyl; For the alkyl of the alkoxyl group of N-(1-4C) alkyl-N-[(1-4C)-(2-3C)] formamyl: N-(2-methoxy ethyl)-N

-methylamino formyl radical and N-(2

-ethoxyethyl group)-the N-ethyl-

Formamyl; For the alkyl of N-[carboxyl-(1-3C)]-formamyl: N-(carboxyl methyl) formamyl,

The amino first of N-(1-carboxy ethyl)

Acyl group and N-(2-carboxy ethyl)

Formamyl; For the alkyl of N-(1-4C) alkyl-N-[carboxyl-(1-3C)] formamyl: N-(carboxyl methyl)-N-methyl

Formamyl, N-(1-carboxyl

Ethyl)-N-methylamino formyl radical

And N-(2-carboxy ethyl)-N

-methylamino formyl radical; For the alkyl of N-[carboxyl-(1-3C)]-alkyl of N-[hydroxyl-(2-3C)] formamyl: N-(carboxyl methyl)-N-(2

-hydroxyethyl)-formamyl; For the alkyl of N-[carboxyl-(1-3C)]-N-[(1-4C) alkyl of alkoxyl group-(2-3C)] formamyl: N-(carboxyl methyl)-N-(2

-methoxy ethyl) formamyl; For N-[(1-4C) alkyl of carbalkoxy-(1-3C)] the amino first of formamyl: N-(methoxycarbonyl methyl)

Acyl group, N-(ethoxy carbonyl first

Base) formamyl, N-(1-

The methoxycarbonyl ethyl) formamyl

And N-(2-methoxycarbonyl second

Base) formamyl; For carbalkoxy (1-3C) alkyl of N-(1-4C) alkyl-N-[(1-4C)] formamyl: N-(methoxycarbonyl methyl)-N

-methylamino formyl radical; For N-[(1-4C) alkyl of alkoxy carbonyl-(1-3C)]-alkyl of N-[hydroxyl-(2-3C)] formamyl: N-(2-hydroxyethyl)-N-

(methoxycarbonyl methyl) formamyl; For N-[(1-4C) alkyl of carbalkoxy-(1-3C)]-N-[(1-4C) alkyl of alkoxyl group-(2-3C)] formamyl: N-(methoxycarbonyl methyl)-N-

(2-methoxy ethyl) formamyl; For (1-4C) alkyl: methyl, ethyl, propyl group, sec.-propyl and

Butyl; For the alkyl of carboxyl-(1-4C): the carboxyl methyl, the 1-carboxy ethyl,

2-carboxy ethyl and 3-carboxyl propyl group; For the alkyl of (1-4C) carbalkoxy-(1-4C): the methoxycarbonyl methyl, ethoxycarbonylmethyl group,

The tert-butoxycarbonyl methyl, the 1-methoxy

Base carbonyl ethyl, the 1-ethoxy carbonyl

Ethyl, 2-methoxycarbonyl ethyl,

2-ethoxy carbonyl ethyl, the 3-first

Oxygen base carbonyl propyl group and 3-oxyethyl group carbonyl

The base propyl group; For the alkyl of formamyl-(1-4C): carbamyl ylmethyl, 1-carbamyl

The base ethyl, 2-formamyl ethyl and

3-formamyl propyl group; For the alkyl of N-(1-4C) alkyl-carbamoyl-(1-4C): N-methylamino formyl radical methyl,

N-ethylamino formyl radical methyl,

N-propyl group carbamyl ylmethyl,

1-(N-methylamino formyl radical) ethyl,

1-(N-ethylamino formyl radical) ethyl,

2-(N-methylamino formyl radical) ethyl,

2-(N-ethylamino formyl radical) ethyl,

3-(N-methylamino formyl radical) propyl group; For N, alkyl: the N of N-two-[(1-4C) alkyl]-formamyl-(1-4C), N-formyl-dimethylamino methyl,

N-ethyl-N-methylamino formyl

Ylmethyl, N, N-diethylamino

The formyl radical methyl, (N, N-two for 1-

The methylamino formyl radical) ethyl, 1-

(N, N-diethylamino formyl radical)

Ethyl, 2-(N, N-dimethylamino

The base formyl radical) ethyl, 2-(N, N

-diethylamino formyl radical) ethyl,

Or 3-(N, N-dimethylamino

Formyl radical) propyl group; For the alkyl of tetramethyleneimine-1-base carbonyl-(1-4C): tetramethyleneimine-1-base carbonyl methyl,

1-(tetramethyleneimine-1-base carbonyl)

Ethyl and 2-(tetramethyleneimine-1-base

Carbonyl) ethyl; For the alkyl of piperidino-(1-position only) carbonyl-(1-4C): piperidino-(1-position only) carbonyl methyl,

1-(piperidino-(1-position only) carbonyl) ethyl and

2-(piperidino-(1-position only) carbonyl) ethyl; For the alkyl of morpholino carbonyl-(1-4C): the morpholino carbonyl methyl,

1-(morpholino carbonyl) ethyl and

2-(morpholino carbonyl) ethyl; For the alkyl of piperazine-1-base-carbonyl-(1-4C): piperazine-1-base carbonyl methyl,

1-(piperazine-1-base carbonyl) ethyl

And 2-(piperazine-1-base carbonyl)

Ethyl; For the alkyl of 4-(1-4C) alkylpiperazine-1-base carbonyl-(1-4C): 4-methylpiperazine-1-Ji Tangjijia

Base, 4-ethyl piperazidine-1-base carbonyl

Ylmethyl, 2-(4-methylpiperazine

-1-base carbonyl)-ethyl and 2-

(4-ethyl piperazidine-1-base carbonyl)

Ethyl; For the alkyl of N-phenyl amino formyl radical-(1-4C): N-phenyl amino formyl radical methyl and

2-(N-phenyl amino formyl radical)

Ethyl; For the alkyl of N-[phenyl-(1-3C)]-alkyl of formamyl-(1-4C): N-benzylamino formyl radical methyl,

N-styroyl carbamyl ylmethyl and

2-(N-benzylamino formyl radical)

Ethyl; For the alkyl of hydroxyl-(1-4C): hydroxymethyl, the 1-hydroxyethyl,

2-hydroxyethyl and 3-hydroxypropyl; For the alkyl of (1-4C) alkoxyl group-(1-4C): methoxymethyl, ethoxyl methyl,

The 1-methoxymethyl, the 2-methoxyl group

Ethyl, 2-ethoxyethyl group and 3-

Methoxy-propyl; And for the alkyl of phenyl-(1-4C): benzyl, styroyl and 3-phenyl propyl.

At M ²Or M ³In the substituent suitable implication that exists on the heterocyclic radical in the substituting group that exists comprise as follows: for (1-4C) alkyl: methyl, ethyl, propyl group and sec.-propyl; For (1-4C) alkoxyl group: methoxyl group, oxyethyl group and propoxy-; For (1-4C) alkoxy carbonyl: methoxycarbonyl, ethoxycarbonyl, the third oxygen carbonyl;

Tertbutyloxycarbonyl; For N-(1-4C) alkyl-carbamoyl: N-methylamino formyl radical and N-

The ethylamino formyl radical; And for N, N-two-(1-4C) alkyl-formamyl: N, the N-formyl-dimethylamino,

N-ethyl-N-methylamino formyl radical and

N, N-diethylamino formyl radical.

When A was (1-4C) alkylidene group, suitable implication for example was methylene radical, ethylidene, trimethylene and tetramethylene.

Should be understood that and work as M ¹During for the following formula group,

NR ²-L ¹-T ¹R ³The order that this group exists is very important for the orientation that group connects, for example, and NR ²Group is connected as works as G with heterocyclic radical ¹And G ²When respectively doing for oneself CH, and have substituent R ¹Pyridyl connect; Also should be understood that at NR ²N atom and L in the group ¹Connect.Equally, R ²Group be connected with the N atom and not with L ¹Group connects; Similarly, at T ¹R ³In the group, T ¹Group is connected (or being connected with CO group among the formula I) and R when A is direct key with group A among the formula I ³With T ¹Group connects and is not connected with the group A of formula I.Same application of rules is in group M ²And M ³Connection and at M ²Or M ³In T ², T ³And NR ⁶Connection.

It is further to be understood that and work as R ²And R ³When forming the methylene radical carbonyl together, its methylene radical with have a R ²Nitrogen-atoms connect, its carbonyl with have R ³Group T ¹Connect.

It is further to be understood that and work as R ³Be (2-3C) alkylidene group such as ethylidene and trimethylene and L ¹Methylene radical be connected to form and comprise T ¹And R ³5-or 6-when ring unit, if T ¹Be N, formed suitable ring for example is a tetramethyleneimine-1,3-two bases, and piperidines-1,3-two base and piperidines-1, if 4-two bases are T ¹Be CH, formed suitable ring for example is a pentamethylene-1,3-two bases, hexanaphthene-1,3-two base and hexanaphthenes-1,4-two bases.For example work as R ⁴With L ²In methylene radical connect or R ⁵With L ²In methylene radical when connecting, these loop systems also are suitable.Work as R ⁶With L ³In methylene radical when connecting, loop systems such as tetramethyleneimine-1,3-two bases, piperidines-1,3-two base and piperidines-1,4-two bases also are suitable.

Puzzled for fear of coagulating, illustrate at M ²And M ³Suitable heterocyclic radical in the middle substituting group that exists for example comprises tetramethyleneimine-1-base, piperidino-(1-position only), morpholino, piperazine-1-base and 4-(1-4C) alkylpiperazine-1-base, in group, can directly connect or connect by the key group, for example, alkyl such as 2-(tetramethyleneimine-1-base carbonyl) ethyl of tetramethyleneimine-1-base carbonyl-(1-4C).

When X was N-(1-4C) alkyl-carbonyl-amino, suitable implication was N-methyl carbonylamino or N-ethyl carbonylamino; When X was (1-4C) alkyl methylene radical, suitable implication was an ethane-1,1-two bases or propane-1,1-two bases; When X was two-(1-4C) alkyl methylene radical, suitable implication for example was a propane-2,2-two bases.Should be understood that also working as X is carbonyl oxygen base, during carbonylamino or N-(1-4C) alkyl-carbonyl-amino, carbonyl wherein and M ³Connect.Equally, when X is sulfuryl amino, alkylsulfonyl wherein and M ³Connect, and when X was amino-sulfonyl, alkylsulfonyl wherein was connected with Q.

When Q was naphthyl, suitable implication for example was 1-naphthyl or 2-naphthyl; When Q was the alkyl of phenyl-(1-4C), suitable implication for example was a benzyl, styroyl and 3-phenyl propyl, and when Q was the alkenyl of phenyl-(2-4C), suitable implication for example was a styryl, cinnamyl or 3-phenyl third-2-thiazolinyl; When Q was the alkynyl of phenyl-(2-4C), suitable implication for example was a 2-phenylacetylene base, 3-phenyl Propargyl and 3-phenyl third-1-alkynyl; When Q was (5-7C) cycloalkyl, suitable implication for example was cyclopentyl, cyclohexyl and suberyl.

When Q is selected from nitrogen for containing at the most 4, during the heteroatomic heterocyclic moiety of oxygen and sulphur, suitable implication for example is a 5-or 6-unit heterocycle, it can be monocycle or with one or two benzo ring condensed rings, furyl for example, benzofuryl, tetrahydrofuran base, chromanyl, thienyl, benzothienyl, pyridyl, piperidyl, quinolyl, 1,2,3, the 4-tetrahydric quinoline group, isoquinolyl, 1,2,3, the 4-isoquinolyl, pyrazinyl, piperazinyl, pyrimidyl, pyridazinyl, quinoxalinyl, quinazolyl, the cinnolines base, pyrryl, pyrrolidyl, indyl, indolinyl, imidazolyl, benzimidazolyl-, pyrazolyl, indazolyl, Costumes azoles base, benzo Costumes azoles base, different Costumes azoles base, thiazolyl, benzothiazolyl, isothiazolyl, morpholinyl, 4H-1,4-benzo Costumes piperazine base, 4H-1,4-benzothiazine base, the 1,2,3-triazoles base, 1,2,4-triazolyl, di azoly, the furazan base, thiadiazolyl group, tetrazyl, dibenzofuran group and dibenzothiophene base, they can connect by the position of any permission, comprise for suitable X group by as carbonyl or methylene radical connect, by the nitrogen-atoms connection that allows, and can have at the most substituting group on the nitrogen-atoms that 3 substituting groups are included in any permission.

The substituent suitable implication that exists in Q for example comprises: for (1-4C) alkoxy carbonyl: methoxycarbonyl, ethoxycarbonyl and tert-butoxycarbonyl; For (1-4C) alkyl: methyl, ethyl, propyl group and sec.-propyl; For (1-4C) alkoxyl group: methoxyl group, oxyethyl group, propoxy-and isopropoxy; For N-(1-4C) alkyl-carbamoyl: N-methylamino formyl radical and N-ethylamino

Formyl radical; For N, N-two-(1-4C) alkyl-formamyl: N, the N-formyl-dimethylamino and

N, N-diethylamino formyl radical; For (1-4C) alkylamino: methylamino-, the ethylamino and third amino; For two-(1-4C) alkylaminos: dimethylamino, N-ethyl-N-methyl ammonia

Base and diethylamino; For (2-4C) alkanoyl amino: kharophen, propionamido and butyrylamino; For (2-4C) alkanoyl: ethanoyl, propionyl and butyryl radicals; For (2-4C) alkanoyl imino-: acetylimino-and propionyl imino-; And for (2-4C) alkanoyl hydroxyl oximido: acetyl hydroxyl oximido and propionyl hydroxyl oximido.

The suitable implication of heteroaryl substituting group or the heteroaryl in containing the substituting group of heteroaryl comprises and contains 3 heteroatomic 5 or 6 yuan of bicyclic heteroaryls that are selected from oxygen, nitrogen and sulphur at the most, furyl for example, thienyl, pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, pyrryl, pyrazolyl oxazolyl isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl ， oxadiazole base, furazan base and thiadiazolyl group, they can connect by the position of any permission, comprise that the nitrogen-atoms by any permission connects.

The suitable pharmacologically acceptable salt of amino-heterocycles derivative of the present invention is for example for having the acid salt of amino-heterocycles derivative of the present invention of enough alkalescence, for example with inorganic or organic acid hydrochloric acid for example, Hydrogen bromide, sulfuric acid, phosphoric acid, trifluoroacetic acid, the acid salt that citric acid and toxilic acid form.In addition, for example an alkali metal salt, for example sodium or sylvite of the suitable pharmacologically acceptable salt with enough tart amino-heterocycles derivative of the present invention, alkaline earth salt, for example calcium or magnesium salts, ammonium salt, or with the salt that can provide physiologically acceptable cationic organic bases to form, for example, with methylamine, dimethylamine, Trimethylamine 99, piperidines, the salt that morpholine or three-(2-hydroxyethyl) amine forms.

Particular compound of the present invention comprises amino-heterocycles derivative or its pharmacologically acceptable salt of formula I for example or formula Ia, wherein, except as otherwise noted, G ¹, G ², G ³, m, R ¹, M ¹, A, M ², M ³, X and Q have above or relating to any implication in the part of particular compound of the present invention: (a) G ¹, G ²And G ³CH respectively does for oneself; (b) G ¹, G ²The CH that respectively does for oneself, G ³Be N, or G ¹Be N, G ²And G ³Respectively do for oneself

CH; (c) m is 1 and R ¹Be hydrogen; (d) M ¹Be the following formula group:

NR ²-L ¹-T ¹R ³R wherein ²And R ³Form (1-4C) alkylidene group, L together ¹Be (1-4C) alkylidene group, T ¹Be CH or N, and wherein at L ¹In 1 or 2 methylene radical and work as R ²And R ³The ring that is connected to form is optional to have (1-4C) alkyl substituent, and (e) A is the direct key that is connected with carbonyl, and (f) A is (1-4C) alkylidene group; (g) M ²Be the following formula group:

(T ²R ⁴) _r-L ²-T ³R ⁵Wherein r is 1, T ²Be CH or N, T ³Be CH or N, R ⁴Be hydrogen or (1-4C) alkyl, R ⁵Be hydrogen or (1-4C) alkyl or R ⁴And R ⁵Form (1-4C) alkylidene group together, or R ⁴Be (2-3C) alkylidene group, it and L ²In methylene radical be connected to form and comprise R ⁴And T ²5 or 6 yuan of rings, L ²Be (1-4C) alkylidene group, and wherein at L ²In 1 or 2 methylene radical and work as R ⁴And R ⁵Or R ⁴And L ²The ring that is connected to form is chosen wantonly and is had a substituting group; this substituting group is selected from carboxyl, (1-4C) carbalkoxy, formamyl, N-(1-4C) alkyl-carbamoyl, N; the alkyl of N-two-(1-4C) alkyl-carbamoyls, tetramethyleneimine-1-base carbonyl, piperidino-(1-position only) carbonyl, morpholino carbonyl, piperazine-1-base carbonyl, 4-(1-4C) alkylpiperazine-1-base carbonyl, N-phenyl amino formyl radical, (1-4C) alkyl and phenyl-(1-4C); and have 1 or 2 (1-4C) alkyl substituent in that described substituent any heterocyclic radical is optional, and at M ²In any phenyl optional have 1 or 2 substituting groups, described substituting group is selected from halo, (1-4C) alkyl and (1-4C) alkoxyl group; (h) M ³Be the direct key that is connected with X, (i) M ³Be the following formula group:

L ³-(NR ⁶) _sWherein s is 1, R ⁶Be hydrogen or (1-4C) alkyl, L ³Be the alkylidene group of (1-4C) alkylidene group or carbonyl-(1-3C), and wherein at L ³In 1 or 2 methylene radical are optional has a substituting group, this substituting group is selected from the alkyl of the alkyl of (1-4C) alkyl, hydroxyl-(1-4C) and phenyl-(1-4C), and at M ³In any phenyl optional have 1 or 2 substituting groups, described substituting group is selected from halo, (1-4C) alkyl and (1-4C) alkoxyl group; (i) X is sulphur, sulfinyl or alkylsulfonyl; (k) X is an alkylsulfonyl; (l) X is that carbonyl, carbonyl oxygen base, carbonylamino or N-(1-4C) alkyl-carbonyl-amino, (m) X are sulfuryl amino or work as T ³Be CH, M ³Be the direct key that is connected with X, X also is an amino-sulfonyl; (n) X is a methylene radical, (1-4C) alkyl methylene radical or two-(1-4C) alkyl methylene radical; (o) Q is the alkyl of phenyl, naphthyl or phenyl-(1-4C), they optionally have 1,2 or 3 substituting groups, substituting group is selected from hydroxyl, halo, cyano group, trifluoromethyl, (1-4C) alkyl, (1-4C) alkoxyl group, phenyl, phenoxy group, thiophenyl, phenyl sulfinyl, phenyl sulfonyl, benzyl and benzoyl, and wherein said phenyl substituent or the phenyl in containing the substituting group of phenyl have 1 or 2 substituting group, substituting group is selected from halo, (1-4C) alkyl and (1-4C) alkoxyl group; (p) Q is a phenyl, and it has phenyl substituent and has 1 or 2 substituting group with optional, and substituting group is selected from hydroxyl, halo, cyano group, trifluoromethyl, (1-4C) alkyl and (1-4C) alkoxyl group, and wherein phenyl substituent is chosen wantonly and is had 4 substituting groups at the most, substituting group is selected from halo, trifluoromethyl, cyano group, trifluoromethoxy, (1-4C) alkyl and (1-4C) alkoxyl group; (q) Q is the alkyl of phenyl-(1-4C), the alkynyl of alkenyl of phenyl-(2-4C) or phenyl-(2-4C), and it is optional to have 1,2 or 3 substituting group, and substituting group is selected from halo, cyano group, trifluoromethyl, (1-4C) alkyl and (1-4C) alkoxyl group; (r) Q is the alkenyl of phenyl-(2-4C), and it is optional to have 1,2 or 3 substituting group, and substituting group is selected from halo, cyano group, trifluoromethyl, (1-4C) alkyl and (1-4C) alkoxyl group; (s) Q is the alkyl of phenyl or phenyl-(1-4C), it has 1 substituting group, substituting group is selected from heteroaryl, heteroaryloxy, the heteroaryl sulfenyl, heteroaryl sulfinyl and heteroarylsulfonyl, wherein heteroaryl substituting group or the heteroaryl in containing the substituting group of heteroaryl comprise and contain 3 heteroatomic 5 or 6 yuan of bicyclic heteroaryl rings that are selected from nitrogen, oxygen and sulphur at the most, and wherein said heteroaryl is chosen wantonly with the substituting group that contains heteroaryl and is had 1 or 2 substituting group, substituting group is selected from halo, (1-4C) alkyl and (1-4C) alkoxyl group; (t) Q is a phenyl, and it has 1 substituting group, and substituting group is selected from heteroaryl, heteroaryloxy, heteroaryl sulfenyl and heteroarylsulfonyl, wherein heteroaryl substituting group or the heteroaryl in containing the substituting group of heteroaryl are selected from thienyl, pyridyl, pyrimidyl, pyrazolyl oxazolyl, thiazolyl, 1,2,3-triazolyl and 1,2,4-triazolyl, and wherein said heteroaryl and contain that the substituting group of heteroaryl is optional to have 1 or 2 substituting group, substituting group are selected from halo and (1-4C) alkyl; (u) Q is a naphthyl, and it is chosen wantonly and has 1 or 2 substituting group, and substituting group is selected from hydroxyl, halo, cyano group, trifluoromethyl, (1-4C) alkyl and (1-4C) alkoxyl group; (v) Q is for containing 2 heteroatomic heterocyclic radicals at the most, and it is selected from benzofuryl, quinolyl, tetrahydric quinoline group, isoquinolyl, quinoxalinyl, quinazolyl, cinnolines base, indyl, benzimidazolyl-, indazolyl, benzoxazolyl and benzothiazolyl, Q is optional to have 1 or 2 substituting group, and substituting group is selected from halo, cyano group, trifluoromethyl, (1-4C) alkyl and (1-4C) alkoxyl group; (w) Q is for containing 2 heteroatomic heterocyclic radicals at the most, and it is selected from benzofuryl, quinolyl, tetrahydric quinoline group, isoquinolyl, quinoxalinyl, quinazolyl, the cinnolines base, indyl, benzimidazolyl-, indazolyl, benzoxazolyl, benzothiazolyl, dibenzofuran group and dibenzothiophene base, and Q is optional has 1 or 2 substituting group, and substituting group is selected from halo, cyano group, trifluoromethyl, (1-4C) alkyl and (1-4C) alkoxyl group; (x) Q is for containing 4 heteroatomic heterocyclic radicals at the most, and it is selected from furyl, thienyl, pyridyl, pyrimidyl, pyrryl, pyrrolidyl, imidazolyl, pyrazolyl ， oxazolyl isoxazolyl, thiazolyl, isothiazolyl, the 1,2,3-triazoles base, 1,2, the 4-triazolyl, di azoly, thiadiazolyl group and tetrazyl, and Q is optional has 1 or 2 substituting group, substituting group is selected from halo, cyano group, carboxyl, formamyl, (1-4C) alkoxy carbonyl, (1-4C) alkyl, (1-4C) alkoxyl group, N-(1-4C) alkyl-carbamoyl and N, N-two-(1-4C) alkyl-carbamoyls; (y) Q is for containing 2 heteroatomic heterocyclic radicals at the most, and it is selected from thienyl, pyridyl, pyrimidyl, imidazolyl, pyrazolyl oxazolyl and thiazolyl, and Q is optional has 1 or 2 substituting group, and substituting group is selected from halo, (1-4C) alkyl, (1-4C) alkoxyl group, phenyl, heteroaryl, phenoxy group, thiophenyl, phenyl sulfinyl, phenyl sulfonyl, heteroaryl oxygen base, the heteroaryl sulfenyl, the heteroaryl sulfinyl, heteroarylsulfonyl, benzyl and benzoyl, wherein heteroaryl substituting group or the heteroaryl in containing the substituting group of heteroaryl are selected from thienyl, pyridyl, pyrimidyl, pyrazolyl oxazolyl and thiazolyl, and wherein said phenyl contains phenyl, heteroaryl or contain that the substituting group of heteroaryl is optional to have 1 or 2 substituting group, substituting group is selected from halo, (1-4C) alkyl and (1-4C) alkoxyl group; Or (z) Q for containing 2 heteroatomic heterocyclic radicals at the most, it is selected from thienyl, pyridyl ， oxazolyl and thiazolyl, and Q has and is selected from phenyl, thienyl, pyridyl, the substituting group of pyrimidyl oxazolyl and thiazolyl, and substituting group is optional to have 1 or 2 substituting group, and substituting group is selected from halo, (1-4C) alkyl and (1-4C) alkoxyl group; And Q is optional to have the other halo and (1-4C) substituting group of alkyl of being selected from; Or its pharmacologically acceptable salt.

The amino-heterocycles derivative that preferred compound of the present invention is formula I or its pharmacologically acceptable salt: G wherein ¹, G ²And G ³CH or G respectively do for oneself ¹, G ²The CH that respectively does for oneself, G ³Be N, or G ¹Be N, G ²And G ³CH respectively does for oneself; M is 1 or 2, R ¹Independently be selected from hydrogen separately, amino, fluorine, chlorine, bromine, cyano group, methyl, ethyl and methoxyl group; M ¹Be the following formula group:

NR ²-L ¹-T ¹R ³R wherein ²And R ³Form ethylidene together, L ¹Be methylene radical or ethylidene, and T ¹Be CH or N, and wherein at L ¹In 1 or 2 methylene radical and work as R ²And R ³The optional substituting group that is selected from methyl and ethyl that has of the ring that is connected to form; A is the direct key that is connected with carbonyl, or A is a methylene radical; M ²Be the following formula group:

(T ²R ⁴) _r-L ²-T ³R ⁵Wherein r is 0 or 1, T ²Be CH or N, T ³Be N, R ⁴Be hydrogen, methyl or ethyl, R ⁵Be hydrogen, methyl or ethyl or R ⁴And R ⁵Form methylene radical together, ethylidene, trimethylene or methylene radical carbonyl, or R ⁴Be ethylidene, it and L ²In methylene radical be connected to form and comprise R ⁴And T ²5 or 6 yuan of rings, L ²Be methylene radical, ethylidene, trimethylene, methylene radical carbonyl or phenylene, and wherein at L ²In 1 or 2 methylene radical and work as R ⁴And R ⁵The ring that is connected to form is chosen wantonly and is had a substituting group, this substituting group is selected from oxo, carboxyl, methoxycarbonyl, ethoxycarbonyl, formamyl, N-methylamino formyl radical, N, the N-formyl-dimethylamino, tetramethyleneimine-1-base carbonyl, the piperidino-(1-position only) carbonyl, morpholino carbonyl, piperazine-1-base carbonyl, 4-methylpiperazine-1-base carbonyl, methyl, ethyl, the carboxyl methyl, the methoxycarbonyl methyl, the ethoxy carbonyl methyl, hydroxymethyl, methoxymethyl and benzyl, and tetramethyleneimine-1-base carbonyl wherein, the piperidino-(1-position only) carbonyl, morpholino carbonyl, piperazine-1-base carbonyl or 4-methylpiperazine-optional methyl or ethyl substituting group of having of 1-base carbonyl substituted base; M ³Be the direct key that is connected with X, or M ³Be the following formula group:

L ³-(NR ⁶) _sWherein s is 1, R ⁶Be hydrogen, L ³Be carbonyl methylene radical or carbonyl ethylidene; X is sulphur, sulfinyl, alkylsulfonyl, carbonyl, carbonyl oxygen base or methylene radical; Q is a phenyl, naphthyl, benzyl, styroyl, styryl, 2-phenylacetylene base, dibenzofuran group, xenyl, pyridyl phenyl or pyridyl thienyl, and Q is optional has 1,2 or 3 substituting groups, substituting group is selected from hydroxyl, amino, fluorine, chlorine, bromine, iodine, cyano group, trifluoromethyl, nitro, carboxyl, formamyl, methoxycarbonyl, ethoxy carbonyl, methyl, ethyl, methoxyl group and oxyethyl group; Or its pharmacologically acceptable salt.

The compound of present invention further optimization is the amino-heterocycles derivative of formula I: G wherein ¹, G ²And G ³CH or G respectively do for oneself ¹, G ²The CH that respectively does for oneself, G ³Be N, or G ¹Be N, G ²And G ³CH respectively does for oneself; M is 1 or 2, R ¹Independently be selected from hydrogen separately, amino, chlorine, methyl and ethyl; M ¹Be the following formula group:

NR ²-L ¹-T ¹R ³R wherein ²And R ³Form ethylidene together, L ¹Be ethylidene, and T ¹Be CH or N, A is the direct key that is connected with carbonyl, or A is a methylene radical; M ²Be the following formula group:

(T ²R ⁴) _r-L ²-T ³R ⁵Wherein r is 0 or 1, T ²Be N, T ³Be N, R ⁴Be hydrogen, R ⁵Be hydrogen or R ⁴And R ⁵Form ethylidene together, or R ⁴Be ethylidene, it and L ²In methylene radical be connected to form and comprise R ⁴And T ²5 or 6 yuan of rings, L ²Be methylene radical, ethylidene or phenylene, and wherein at L ²In 1 or 2 methylene radical and work as R ⁴And R ⁵The ring that is connected to form is chosen wantonly and is had a substituting group, this substituting group is selected from carboxyl, methoxycarbonyl, ethoxycarbonyl, tetramethyleneimine-1-base carbonyl, piperidino-(1-position only) carbonyl, morpholino carbonyl, piperazine-1-base carbonyl, 4-methylpiperazine-1-base carbonyl, methyl, ethyl and benzyl, and tetramethyleneimine-1-base carbonyl wherein, the piperidino-(1-position only) carbonyl, morpholino carbonyl, piperazine-1-base carbonyl or 4-methylpiperazine-optional methyl or ethyl substituting group of having of 1-base carbonyl substituted base; M ³Be the direct key that is connected with X, or M ³Be the following formula group:

L ³-(NR ⁶) _sWherein s is 1, R ⁶Be hydrogen, L ³Be the carbonyl methylene radical; X is an alkylsulfonyl; Q is a phenyl, naphthyl, benzyl, styroyl, styryl, 2-phenylacetylene base, dibenzofuran group, xenyl, pyridyl phenyl or pyridyl thienyl, and Q is optional has 1 or 2 substituting group, and substituting group is selected from fluorine, chlorine, bromine, iodine, methyl, ethyl, methoxyl group and oxyethyl group; Or its pharmacologically acceptable salt.

The compound of present invention further optimization is the amino-heterocycles derivative of formula Ia: G wherein ¹, G ²CH respectively does for oneself; M is 1, R ¹Be hydrogen; M ¹Be the following formula group:

NR ²-L ¹-T ¹R ³R wherein ²And R ³Form ethylidene together, L ¹Be methylene radical or ethylidene, and T ¹Be CH or N, and wherein at L ¹In 1 or 2 methylene radical and work as R ²And R ³The ring that is connected to form is optional to have the substituting group that is selected from methyl and ethyl, and A is the direct key that is connected with carbonyl, or A is a methylene radical; M ²Be the following formula group:

(T ²R ⁴) _r-L ²-T ³R ⁵Wherein r is 1, T ²Be CH or N, T ³Be N, R ⁴Be hydrogen, methyl or ethyl, R ⁵Be hydrogen, methyl or ethyl, or R ⁴And R ⁵Form ethylidene together, or R ⁴Be ethylidene, it and L ²In methylene radical be connected to form and comprise R ⁴And T ²5 or 6 yuan of rings, L ²Be methylene radical, ethylidene or trimethylene, and wherein at L ²In 1 or 2 methylene radical and work as R ⁴And R ⁵The ring that is connected to form is chosen wantonly and is had a substituting group, this substituting group is selected from carboxyl, methoxycarbonyl, ethoxycarbonyl, formamyl, N-methylamino formyl radical, N, N-formyl-dimethylamino, tetramethyleneimine-1-base carbonyl, piperidino-(1-position only) carbonyl, methyl, ethyl and benzyl, and wherein tetramethyleneimine-1-base carbonyl or optional methyl or the ethyl substituting group of having of piperidino-(1-position only) carbonyl substituted base; M ³Be the direct key that is connected with X, or M ³Be the following formula group:

L ³-(NR ⁶) _sWherein s is 1, R ⁶Be hydrogen, L ³Be carbonyl methylene radical or carbonyl ethylidene; X is an alkylsulfonyl; Q is a phenyl, 2-naphthyl or benzyl, and it is chosen wantonly and has 1 or 2 substituting group, and substituting group is selected from fluorine, chlorine, bromine and trifluoromethyl; Or its pharmacologically acceptable salt.

The compound of present invention further optimization is the amino-heterocycles derivative of formula I: G wherein ³Be CH or N, G ¹, G ²CH respectively does for oneself; M is 1, R ¹Be hydrogen; M ¹Be the following formula group:

(T ²R ⁴) _r-L ²-T ³R ⁵Wherein r is 1, T ²Be CH or N, T ³Be N, R ⁴Be hydrogen, methyl or ethyl, R ⁵Be hydrogen, methyl or ethyl, or R ⁴And R ⁵Form methylene radical together, ethylidene or trimethylene, or R ⁴Be ethylidene, it and L ²In methylene radical be connected to form and comprise R ⁴And T ²5 or 6 yuan of rings, L ²Be methylene radical, ethylidene or trimethylene, and wherein at L ²In 1 or 2 methylene radical and work as R ⁴And R ⁵The ring that is connected to form is chosen wantonly and is had a substituting group, this substituting group is selected from oxo, carboxyl, methoxycarbonyl, ethoxycarbonyl, formamyl, N-methylamino formyl radical, N, N-formyl-dimethylamino, tetramethyleneimine-1-base carbonyl, piperidino-(1-position only) carbonyl, morpholino carbonyl, methyl, ethyl and benzyl, and wherein tetramethyleneimine-1-base carbonyl or optional methyl or the ethyl substituting group of having of piperidino-(1-position only) carbonyl substituted base; M ³Be the direct key that is connected with X, or M ³Be the following formula group:

L ³-(NR ⁶) _sWherein s is 1, R ⁶Be hydrogen, L ³Be carbonyl methylene radical or carbonyl ethylidene; X is an alkylsulfonyl; Q is 3-or 4-xenyl, with ring that X is connected in optionally have 1 or 2 substituting group, substituting group is selected from hydroxyl, fluorine, chlorine, bromine, cyano group, trifluoromethyl, methyl, ethyl, methoxyl group and oxyethyl group, and optional 4 substituting groups at the most that have in the phenyl endways, substituting group is selected from fluorine, chlorine, bromine, trifluoromethyl, cyano group, trifluoromethoxy, methyl, ethyl, methoxyl group and oxyethyl group; Or its pharmacologically acceptable salt.

(T ²R ⁴) _r-L ²-T ³R ⁵Wherein r is 1, T ²Be CH or N, T ³Be N, R ⁴Be hydrogen, methyl or ethyl, R ⁵Be hydrogen, methyl or ethyl, or R ⁴And R ⁵Form ethylidene together, ethylidene or trimethylene or R ⁴Be ethylidene, it and L ²In methylene radical be connected to form and comprise R ⁴And T ²5 or 6 yuan of rings, L ²Be methylene radical, ethylidene or trimethylene, and wherein at L ²In 1 or 2 methylene radical and work as R ⁴And R ⁵The ring that is connected to form is chosen wantonly and is had a substituting group, this substituting group is selected from oxo, carboxyl, methoxycarbonyl, ethoxycarbonyl, formamyl, N-methylamino formyl radical, N, N-formyl-dimethylamino, tetramethyleneimine-1-base carbonyl, piperidino-(1-position only) carbonyl, morpholino carbonyl, methyl, ethyl and benzyl, and wherein tetramethyleneimine-1-base carbonyl or optional one or two methyl or the ethyl substituting group of having of piperidino-(1-position only) carbonyl substituted base; M ³Be the direct key that is connected with X, or M ³Be the following formula group:

L ³-(NR ⁶) _sWherein s is 1, R ⁶Be hydrogen, L ³Be carbonyl methylene radical or carbonyl ethylidene; X is an alkylsulfonyl; Q is a phenyl, styroyl, styryl or 2-phenylacetylene base, and it is chosen wantonly and has 1,2 or 3 substituting group, and substituting group is selected from fluorine, chlorine, bromine, cyano group, trifluoromethyl, methyl, ethyl, methoxyl group and oxyethyl group; Or its pharmacologically acceptable salt.

L ³-(NR ⁶) _sWherein s is 1, R ⁶Be hydrogen, L ³Be carbonyl methylene radical or carbonyl ethylidene; X is an alkylsulfonyl; Q is the 2-thienyl, and it is optional to have the substituting group that is selected from phenyl, thienyl, pyridyl and pyrimidyl, and described substituting group is optional has 1 or 2 substituting group, and substituting group is selected from fluorine, chlorine, bromine and methyl; Or its pharmacologically acceptable salt.

(T ²R ⁴) _r-L ²-T ³R ⁵Wherein r is 1, T ²Be CH or N, T ³Be N, R ⁴Be hydrogen, methyl or ethyl, R ⁵Be hydrogen, methyl or ethyl, or R ⁴And R ⁵Form ethylidene together, or R ⁴Be ethylidene, it and L ²In methylene radical be connected to form and comprise R ⁴And T ²5 or 6 yuan of rings, L ²Be methylene radical, ethylidene or trimethylene, and wherein at L ²In 1 or 2 methylene radical and work as R ⁴And R ⁵The ring that is connected to form is chosen wantonly and is had a substituting group, this substituting group is selected from carboxyl, methoxycarbonyl, ethoxycarbonyl, formamyl, N-methylamino formyl radical, N, N-formyl-dimethylamino, tetramethyleneimine-1-base carbonyl, piperidino-(1-position only) carbonyl, morpholino carbonyl, methyl, ethyl and benzyl, and wherein tetramethyleneimine-1-base carbonyl or piperidino-(1-position only) carbonyl substituted base are optional has one or two methyl or an ethyl substituting group; M ³Be the direct key that is connected with X, or M ³Be the following formula group:

L ³-(NR ⁶) _sWherein s is 1, R ⁶Be hydrogen, L ³Be carbonyl methylene radical or carbonyl ethylidene; X is an alkylsulfonyl; Q is 3-or 4-xenyl, and it is optional in the phenyl endways to have 4 substituting groups at the most, and substituting group is selected from fluorine, chlorine, bromine, trifluoromethyl, trifluoromethoxy, methyl and methoxyl group; Or its pharmacologically acceptable salt.

(T ²R ⁴) _r-L ²-T ³R ⁵Wherein r is 1, T ²Be CH or N, T ³Be N, R ⁴Be hydrogen, methyl or ethyl, R ⁵Be hydrogen, methyl or ethyl, or R ⁴And R ⁵Form ethylidene together, or R ⁴Be ethylidene, it and L ²In methylene radical be connected to form and comprise R ⁴And T ²5 or 6 yuan of rings, L ²Be methylene radical, ethylidene or trimethylene, and wherein at L ²In 1 or 2 methylene radical and work as R ⁴And R ⁵The ring that is connected to form is chosen wantonly and is had a substituting group, this substituting group is selected from carboxyl, methoxycarbonyl, ethoxycarbonyl, formamyl, N-methylamino formyl radical, N, N-formyl-dimethylamino, tetramethyleneimine-1-base carbonyl, piperidino-(1-position only) carbonyl, morpholino carbonyl, methyl, ethyl and benzyl, and wherein tetramethyleneimine-1-base carbonyl or optional methyl or the ethyl substituting group of having of piperidino-(1-position only) carbonyl substituted base; M ³Be the direct key that is connected with X, or M ³Be the following formula group:

L ³-(NR ⁶) _sWherein s is 1, R ⁶Be hydrogen, L ³Be carbonyl methylene radical or carbonyl ethylidene; X is an alkylsulfonyl; Q is styroyl, styryl or 2-phenylacetylene base, and it is chosen wantonly and has 1,2 or 3 substituting group, and substituting group is selected from fluorine, chlorine, bromine, trifluoromethyl, methyl and methoxyl group; Or its pharmacologically acceptable salt.

NR ²-L ¹-T ¹R ³R wherein ²And R ³Form ethylidene together, L ¹Be ethylidene, and T ¹Be CH or N, A is the direct key that is connected with carbonyl; M ²Be the following formula group:

(T ²R ⁴) _r-L ²-T ³R ⁵Wherein r is 1, T ²Be N, T ³Be N, R ⁴Be hydrogen, R ⁵Be hydrogen, or R ⁴And R ⁵Form ethylidene together, L ²Be ethylidene, and wherein at L ²In 1 methylene radical optional have a substituting group, this substituting group is selected from carboxyl, ethoxycarbonyl, N-methylamino formyl radical, piperidino-(1-position only) carbonyl and benzyl, M ³Be the direct key that is connected with X, or M ³Be the following formula group:

L ³-(NR ⁶) _sWherein s is 1, R ⁶Be hydrogen, L ³Be the carbonyl methylene radical; X is an alkylsulfonyl; Q is the 2-naphthyl; Or its pharmaceutically useful acid salt.

The compound of present invention further optimization is the amino-heterocycles derivative of formula Ia: G wherein ¹, G ²The CH that respectively does for oneself, G ¹Be N and G ²Be CH, or G ¹Be CH and G ²Be N; M is 1, R ¹Be hydrogen; M ¹Be the following formula group:

NR ²-L ¹-T ¹R ³R wherein ²And R ³Form ethylidene together, L ¹Be ethylidene, and T ¹Be CH or N, A is the direct key that is connected with carbonyl, M ²Be the following formula group:

(T ²R ⁴) _r-L ²-T ³R ⁵Wherein r is 1, T ²Be N, T ³Be N, R ⁴Be hydrogen, R ⁵Be hydrogen, or R ⁴And R ⁵Form ethylidene together, L ²Be ethylidene, and wherein at L ²In 1 methylene radical optional have a substituting group, this substituting group is selected from carboxyl, ethoxycarbonyl, N-methylamino formyl radical, piperidino-(1-position only) carbonyl, methyl and benzyl, M ³Be the direct key that is connected with X, or M ³Be the following formula group:

L ³-(NR ⁶) _sWherein s is 1, R ⁶Be hydrogen, L ³Be the carbonyl methylene radical; X is an alkylsulfonyl; Q is the 2-naphthyl, and it is chosen wantonly and has 1 or 2 substituting group, and substituting group is selected from fluorine, chlorine, bromine, trifluoromethyl, methyl, methoxyl group and oxyethyl group; Or its pharmaceutically useful acid salt.

The compound of present invention further optimization is the amino-heterocycles derivative of formula I: G wherein ¹, G ²And G ³CH respectively does for oneself; M is 1, R ¹Be hydrogen; M ¹Be the following formula group:

(T ²R ⁴) _r-L ²-T ³R ⁵Wherein r is 1, T ²Be CH or N, T ³Be N, R ⁴Be hydrogen, R ⁵Be hydrogen, or R ⁴And R ⁵Form ethylidene together, L ²Be ethylidene, and wherein at L ²In 1 methylene radical optional have a substituting group, this substituting group is selected from carboxyl, ethoxycarbonyl, N-methylamino formyl radical, piperidino-(1-position only) carbonyl and benzyl, M ³Be the direct key that is connected with X, or M ³Be the following formula group:

L ³-(NR ⁶) _sWherein s is 1, R ⁶Be hydrogen, L ³Be the carbonyl methylene radical; X is an alkylsulfonyl; Q is the 4-xenyl, and it has 1 or 2 substituting group in the phenyl endways, and substituting group is selected from fluorine, chlorine, bromine, trifluoromethyl and methyl; Or its pharmaceutically useful acid salt.

The compound of present invention further optimization is the amino-heterocycles derivative of formula I: G wherein ¹, G ²And G ³The CH that respectively does for oneself, G ¹Be N, G ²And G ³CH or G respectively do for oneself ³Be N, G ¹And G ²CH respectively does for oneself; M is 1, R ¹Be hydrogen; M ¹Be the following formula group:

L ³-(NR ⁶) _sWherein s is 1, R ⁶Be hydrogen, L ³Be the carbonyl methylene radical; X is an alkylsulfonyl; Q is the 4-xenyl, and it is chosen wantonly and has 1 or 2 substituting group, and substituting group is selected from fluorine, chlorine, bromine, trifluoromethyl and methyl; Or its pharmaceutically useful acid salt.

L ³-(NR ⁶) _sWherein s is 1, R ⁶Be hydrogen, L ³Be the carbonyl methylene radical; X is an alkylsulfonyl; Q is a styryl, and it is chosen wantonly and has 1 or 2 substituting group, and substituting group is selected from fluorine, chlorine, bromine, trifluoromethyl and methyl; Or its pharmaceutically useful acid salt.

The amino-heterocycles derivative that particularly preferred compound of the present invention is following formula I: 2-(2-naphthalene sulfonyl amino)-N-{1-piperidino-(1-position only) carbonyl-2-[1-(4-pyridyl)-piperidin-4-yl carbonylamino] ethyl } ethanamide, 1-(2-naphthalene sulfonyl base)-4-[1-(4-pyridyl)-piperidin-4-yl carbonyl]-piperazine, 2-(2-naphthalene sulfonyl amino)-N-(1-piperidino-(1-position only) carbonyl-2-{2-[1-(4-pyridyl)-piperidin-4-yl] kharophen } ethyl) ethanamide, 2-(2-naphthalene sulfonyl amino)-N-(1-piperidino-(1-position only) carbonyl-2-{2-[4-(4-pyridyl)-piperazine-1-yl] kharophen } ethyl) ethanamide, 2-(2-naphthalene sulfonyl amino)-3-[1-(4-pyridyl) piperidin-4-yl carbonylamino] ethyl propionate, 1-[1-(2-naphthalene sulfonyl base) piperidin-4-yl carbonyl]-4-(4-pyridyl)-piperazine, or 2-(2-naphthalene sulfonyl amino)-N-{1-phenyl-3-[1-(4-pyridyl)-piperidin-4-yl carbonylamino] third-2-yl ethanamide; Or its pharmaceutically useful acid salt.

The amino-heterocycles derivative that further particularly preferred compound of the present invention is following formula I: 4-[1-(4-pyridyl) piperidin-4-yl carbonyl]-1-[(E)-and the styryl alkylsulfonyl] piperazine, 1-[(E)-4-chloro-styrene base alkylsulfonyl]-4-[1-(4-pyridyl) piperidin-4-yl carbonyl] piperazine, 1-[(E)-4-vinyl toluene base alkylsulfonyl]-4-[1-(4-pyridyl) piperidin-4-yl carbonyl] piperazine, 4-[(E)-4-chloro-styrene base alkylsulfonyl]-2-methyl isophthalic acid-[1-(4-pyridyl) piperidin-4-yl carbonyl] piperazine, the 1-[4-biphenyl sulfonyl]-4-[1-(4-pyridyl) piperidin-4-yl carbonyl] piperazine, 1-(4 '-chloro-4-biphenyl sulfonyl)-4-[1-(4-pyridyl) piperidin-4-yl carbonyl] piperazine, or 1-[(E)-4-chloro-styrene base alkylsulfonyl]-4-[1-(4-pyrimidyl) piperidin-4-yl carbonyl] piperazine; Or its pharmaceutically useful acid salt.

The amino-heterocycles derivative that further particularly preferred compound of the present invention is following formula I: 1-(7-chloronaphthalene-2-base alkylsulfonyl)-4-[1-(4-pyridyl) piperazine-4-base carbonyl] piperazine, 2-ethoxy carbonyl-4-(2-naphthyl alkylsulfonyl)-1-[1-(4-pyridyl) piperazine-4-base carbonyl] piperazine, or 1-(2-naphthyl alkylsulfonyl)-4-[1-(4-pyrimidyl) piperazine-4-base carbonyl] piperazine; Or its pharmaceutically useful acid salt.

The amino-heterocycles derivative that further particularly preferred compound of the present invention is following formula I: 1-[(E)-4-fluorobenzene vinylsulfonyl]-4-[1-(4-pyridyl) piperidin-4-yl carbonyl] piperazine, 1-[(E)-4-bromstyrol base alkylsulfonyl]-4-[1-(4-pyridyl) piperidin-4-yl carbonyl] piperazine, 1-(4 '-bromo-4-biphenyl sulfonyl]-4-[1-(4-pyridyl) piperidin-4-yl carbonyl] piperazine; Or its pharmaceutically useful acid salt.

The amino-heterocycles derivative that further particularly preferred compound of the present invention is following formula I: 1-(6-chloronaphthalene-2-base alkylsulfonyl]-4-[1-(4-pyridyl) piperidin-4-yl carbonyl] piperazine, 1-(6-bromonaphthalene-2-base alkylsulfonyl]-4-[1-(4-pyridyl) piperidin-4-yl carbonyl] piperazine, 1-(6-chloronaphthalene-2-base alkylsulfonyl]-4-[4-(4-pyridyl) piperazine-1-base carbonyl] piperazine, 4-(2-naphthyl alkylsulfonyl]-2-piperidino-(1-position only) carbonyl-1-[1-(4-pyridyl) piperidin-4-yl carbonyl] piperazine, 4-(6-chloronaphthalene-2-base alkylsulfonyl)-2-ethoxy carbonyl-1-[1-(4-pyridyl) piperidin-4-yl carbonyl] piperazine, 2-carboxyl-4-(6-chloronaphthalene-2-base alkylsulfonyl]-1-[1-(4-pyridyl) piperidin-4-yl carbonyl] piperazine, 1-(6-chloronaphthalene-2-base alkylsulfonyl]-4-[1-(4-pyrimidyl) piperidin-4-yl carbonyl] piperazine, 4-[1-(2-aminopyrimidine-4-yl) piperidin-4-yl carbonyl]-1-(6-chloronaphthalene-2-base alkylsulfonyl] piperazine, or 1-(6-chloronaphthalene-2-base alkylsulfonyl]-4-[1-(4-pyridazinyl) piperidin-4-yl carbonyl] piperazine; Or its pharmaceutically useful acid salt.

The amino-heterocycles derivative that further particularly preferred compound of the present invention is following formula I: 4-(6-bromonaphthalene-2-base alkylsulfonyl)-2-ethoxycarbonyl-1-[1-(4-pyridyl)-piperidin-4-yl carbonyl] piperazine, 4-(6-bromonaphthalene-2-base alkylsulfonyl)-2-carboxyl-1-[1-(4-pyridyl)-piperidin-4-yl carbonyl] piperazine, 4-(6-bromonaphthalene-2-base alkylsulfonyl)-2-morpholino carbonyl-1-[1-(4-pyridyl)-piperidin-4-yl carbonyl] piperazine, 4-(6-chloronaphthalene-2-base alkylsulfonyl)-2-methoxycarbonyl-1-[1-(4-pyridyl)-piperidin-4-yl carbonyl] piperazine, or 2-carboxyl-4-(6-chloronaphthalene-2-base alkylsulfonyl)-1-[1-(4-pyridyl)-piperidin-4-yl carbonyl] piperazine; Or its pharmaceutically useful acid salt.

The amino-heterocycles derivative of formula I or formula Ia or its pharmacologically acceptable salt can be prepared with any known method of the preparation that is applicable to the compound that structure is close, these methods that provided are another feature of the present invention, and illustrate with following representational method, wherein, except as otherwise noted, G ¹, G ², G ³, m, R ¹, M ¹, A, M ², M ³, X and Q (and any group of this paper definition) have top definition, and its condition is to work as at R ¹, M ¹, M ², M ³Or Q is amino, alkylamino, and when hydroxyl or carboxyl, these groups can be with the protection of GPF (General Protection False base, and the available ordinary method of words that needs is removed.

Can make essential starting raw material with vitochemical ordinary method, the preparation of these starting raw materials can illustrate in appended examples; In addition, illustrated similar approach only available organic chemist's ordinary skill use.(a) for preparation I compound, M wherein ²Be the following formula group:

(T ²R ⁴) _r-L ²-T ³R ⁵T wherein ²For N and r are 1, suit in the presence of suitable alkali, the acid of formula II or its reactive derivative react with following formula amine:

HNR ⁴-L ²-T ³R ⁵-M ³-X-Q

The suitable reactive derivative of formula II acid for carboxylic acid halides for example as acyl chlorides by acid and inorganic acyl chlorides such as thionyl chloride reaction are generated; Mixed anhydride, for example acid anhydride by acid and chloro-formic ester such as isobutyl chlorocarbonate reaction are generated; Active ester, for example by making acid and phenol such as Pentafluorophenol reaction generate ester, ester such as trifluoroacetic acid pentafluorophenyl group ester or alcohol are as N-hydroxybenzotriazole or N-hydroxy-succinamide; Acyl azide, for example triazo-compound that forms by acid and trinitride such as diphenyl phosphoryl azide; Acyl cyanide, for example prussiate that generates by acid and prussiate such as the reaction of diethyl phosphoryl prussiate; Or acid and carbodiimide such as N, the product of N '-dicyclohexyl carbonization imines or N-(3-dimethylaminopropyl)-N '-ethyl carbodiimide reaction.

Reaction suits at suitable alkali such as alkali or alkaline earth metal carbonate, alkoxide, oxyhydroxide or hydride, for example yellow soda ash, salt of wormwood, sodium ethylate, butanols potassium, sodium hydroxide, potassium hydroxide, sodium hydride or potassium hydride KH, or organo-metallic alkali such as lithium alkylide, for example n-Butyl Lithium or lithium dialkyl amides, lithium diisopropylamine for example, or for example organic amine such as pyridine, 2, the 6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, morpholine or diazabicyclo [5.4.0] 11-7-alkene carries out under existing.Reaction is also preferably at suitable inert solvent or thinner methylene dichloride for example, chloroform, tetracol phenixin, tetrahydrofuran (THF), 1, the 2-glycol dimethyl ether, N, dinethylformamide, N, the N-N,N-DIMETHYLACETAMIDE, N-methylpyrrolidin-2-ketone for example-78 ℃ is suiting in room temperature or near carrying out under the room temperature to 150 ℃ in methyl-sulphoxide or the acetone.

The suitable protecting group of amino or alkylamino for example is an acyl group, for example alkanoyl such as ethanoyl, and alkoxy carbonyl, methoxycarbonyl for example, ethoxy carbonyl or tertiary butyl carbonyl, the aryl methoxy carbonyl is carbobenzoxy-(Cbz) for example, or aroyl, for example benzoyl.The deprotection condition of above-mentioned protecting group must change with the selection of protecting group.For example, by for example lithium hydroxide or sodium hydroxide are hydrolyzed and remove acyl group such as alkanoyl or alkoxy carbonyl or aroyl with suitable alkali such as alkali metal hydroxide.In addition; for example remove acyl group such as tert-butoxycarbonyl by handling with suitable sour example hydrochloric acid, sulfuric acid or phosphoric acid or trifluoroacetic acid, for example by with catalyzer such as palladium/hydrogenated carbon or with the Louis sour as three (trifluoroacetic acid) boron processing remove aryl methoxy carbonyl such as benzyloxycarbonyl.The suitable other protecting group of primary amino is for by with alkylamine dimethylamino propylamine or handle with hydrazine and to remove phthaloyl for example.

The suitable protecting group of hydroxyl for example is acyl group such as alkanoyl such as ethanoyl, aroyl such as benzoyl, or arylmethyl such as benzyl.The deprotection condition of above-mentioned protecting group must change with the selection of protecting group.For example, acyl group such as alkanoyl or aroyl for example can be by removing with suitable alkali such as alkali metal hydroxide such as lithium hydroxide or sodium hydrolysis.In addition, for example useful catalyst such as palladium/hydrogenated carbon are removed for arylmethyl such as benzyl.

The esterification base that the suitable protecting group of carboxyl is for example removed for available bases such as sodium hydroxide hydrolysis as methyl or ethyl, or for example is the usable acid tertiary butyl removed of organic acid such as trifluoroacetic acid for example, or the benzyl of for example removing for useful catalyst such as palladium/hydrogenated carbon.(b) for preparation I compound: M wherein ²Be the following formula group:

(T ²R ⁴) _r-L ²-T ³R ⁵T wherein ³Be N, and M wherein ³Be the direct key that is connected with X, suit in the presence of suitable alkali as defined above, make the compound reaction of formula III amine and formula Z-X-Q (wherein Z is a displaceable group).

The suitable implication of displacement group Z for example is halo or alkylsulfonyl oxygen base for example fluorine, chlorine, bromine, mesyloxy or 4-tolylsulfonyl-oxygen base.

This reaction suit in suitable inert solvent as defined above or thinner in temperature for example is 0 ℃-150 ℃ scope, to suit or near carrying out under the room temperature.(c) for preparation I compound: M wherein ¹Be the following formula group:

NR ²-L ¹-T ¹R ³T wherein ¹Be N, and wherein A is the direct key that is connected with carbonyl, suits in the presence of suitable alkali as defined above, make acid or its response derivative reaction as defined above of formula IV amine and following formula:

HO ²C-M ²-M ³-X-Q

This reaction suit in suitable inert solvent as defined above or thinner in temperature for example is 0 ℃-150 ℃ scope, to suit or near carrying out under the room temperature.(d) for preparation I compound: M wherein ²Be the following formula group:

(T ²R ⁴) _r-L ²-T ³R ⁵T wherein ³Be N, and M wherein ³Be the following formula group:

L ³-(NR ⁶) _sL wherein ³Be the carbonyl methylene radical, suit in the presence of suitable alkali as defined above, make acid or its response derivative reaction as defined above of formula III amine and following formula:

HO ₂C-CH ₂-(NR ⁶) _s-X-Q

This reaction suit in suitable inert solvent as defined above or thinner in temperature for example is 0 ℃-150 ℃ scope, to suit or near carrying out under the room temperature.(e) for preparation I compound: M wherein ²Be the following formula group:

(T ²R ⁴) _r-L ²-T ³R ⁵T wherein ³Be N, and M wherein ³Be the direct key that is connected with X, X is a carbonylamino, makes the isocyanate reaction of formula III amine and following formula:

OCN-X-Q

This reaction suit in suitable inert solvent as defined above or thinner in temperature for example is 0 ℃-60 ℃ scope, to suit or near carrying out under the room temperature.(f) suit in the presence of suitable alkali as defined above, make the amine reaction of compound (wherein Z for sub stituent) as defined above with the following formula of formula V:

HNR ²-L ¹-T ¹R ³-A-CO-M ²-M ³-X-Q

This reaction suits in suitable inert solvent as defined above or thinner to suit to carry out under 15 ℃-100 ℃ in temperature for example is 0 ℃-150 ℃ scope.(g) for preparation I compound M wherein ², M ³Or Q has carboxyl or contains the group of carboxyl, and hydrolyzing type I compound is M wherein ², M ³Or Q has (1-4C) alkoxy carbonyl.

Hydrolysis reaction is suitable for example to use acidity or basic catalyst to carry out with ordinary method.The suitable acid of acidic hydrolysis that is used for ester group for example is mineral acid example hydrochloric acid or sulfuric acid.The suitable alkali of alkaline hydrolysis that is used for ester group for example is alkali or alkaline earth metal hydroxides such as sodium hydroxide or potassium hydroxide.

Reaction suits for example suiting to carry out under 15 ℃-60 ℃ in 0 ℃-120 ℃ the scope in as methyl alcohol or ethanol as alcohol at suitable solvent.(h) for preparation I compound M wherein ², M ³Or Q has formamyl, N-alkyl-carbamoyl or N, N-dialkyl amido formyl radical, wherein M ², M ³Or Q has the compound of carboxyl or its response derivative and ammonia or suitable alkylamine or dialkylamine reaction as defined above.

This reaction suits in suitable inert solvent as defined above or thinner to suit to carry out under 15 ℃-60 ℃ in temperature for example is 0 ℃-120 ℃ scope.(i) in order to prepare the formula I compound that Q wherein has hydroxyl, wherein Q has the formula I compound dealkylation of (1-4C) alkoxyl group.

Suitable dealkylation reagent is for example for carrying out the known any many reagent of this conversion.Reaction is for example used basic metal (1-4C) alkyl sulfur compounds such as sulfur alcohol sodium or is used basic metal diaryl phosphides such as phenylbenzene phosphatization lithium to carry out.In addition, the suitable boron trihalides or aluminium such as boron tribromide of using of reaction carries out.

This dealkylation reacts and suits for example to suit to carry out under 0 ℃-50 ℃ in-80 ℃-100 ℃ the scope in temperature in suitable inert solvent as defined above or thinner.

When needing the pharmacologically acceptable salt of formula I compound, available ordinary method makes described compound and suitable acid and alkali reaction.

When needing the optically-active form of formula I compound, available a kind of aforesaid method uses the optically-active starting raw material or makes by the racemic form that splits described compound with ordinary method.

As mentioned above, formula I and formula Ia compound are the enzyme factor Xa inhibitor, and its restraining effect can prove with one or more following ordinary methods: a) measurement of factor Xa inhibition

The in vitro tests system is according to people such as Kettner, J.Biol.Chem., 1990,265, the method of 18289-18297 is carried out, the test compound of various concentration is dissolved in the damping fluid that contains 0.5% polyoxyethylene glycol of pH7.5, and (0.001 unit/ml 0.3ml) was cultivated 15 minutes at 37 ℃ of factor Xa that choose down, add chromogen substrate S-2765 (KabiVitum AB, 20 μ M), mixture was cultivated the absorption of measuring 405nm simultaneously 20 minutes at 37 ℃.Determine maximum speed of response (Vmax) and with do not contain test compound to compare the effect IC of inhibitor in the same old way ₅₀Value representation.B) measurement of zymoplasm inhibition

Repetition methods step a), just end user's zymoplasm (0.005 unit/ml) and chromogen substrate S-2238 (KabiVitum AB).C) measurement of anticoagulant active

In vitro tests is collector's venous blood, and it is directly joined sodium citrate solution (3.2g/100ml, 9 parts of blood/1 part citrate solutions).By centrifugal (1000g, 15 minutes) preparation blood plasma, and preserve down at 2-4 ℃, in the presence of the test compound of various concentration, carry out the test of conventional activatory partial thromboplastin time (APTT) and prothrombin time (PT), measure the concentration of required test compound of two times of grumeleuse times (CT2 hereinafter referred to as).In the APTT test, test compound, blood plasma and APTT reagent were cultivated 3 minutes down at 37 ℃, added calcium chloride (0.02M), measured fiber and formed and form the required time of grumeleuse.In the PT test,, just tissue thromboplastin is replaced APTT reagent according to similar method.D) isolated test of anticoagulant active

With the test compound intravenously or orally give one group of Alderley Park Wistar mouse, with the various times after the Animal Anesthesia, collect blood, by similar method recited above, carry out APTT and PT thrombotest.E) in-vivo measurement of anti-thrombosis activity

Use people such as Vogel, Throm.Research, 1989,54, the described similar approach of 399-410 is induced the formation of thrombus.Anaesthetize one group of Alderley Park Wistar mouse, undergo surgery and open venous lumen, find out two seams on every side in the internal jugular vein chamber, at a distance of 0.7cm.Vein or oral test compound, after the suitable time, (1ml/kg) applies in the jugular vein with tissue thromboplastin, after 10 seconds, tightens two seams and induces retardance in the ligation of venous lumen part.After 10 minutes, the tissue of excision ligation is isolated thrombus wherein, blots and weighs.

Although as might be expected, the pharmacological effect of formula I and Ia compound becomes with structural changes, usually, formula I and Ia compound at least a above-mentioned test a)-c) following concentration or have activity during dosage:

Test is a): IC for example ₅₀(factor Xa) scope is 0.001-25 μ M;

Test b): IC for example ₅₀(zymoplasm) is greater than 50 μ M;

Test c): for example CT2 (PT) scope is 1-50 μ M;

For example CT2 (APPT) scope is 10-100 μ M.

By example, hereinafter disclosed embodiment 1 compound is for test factor X a) _aIC ₅₀Be 0.3 μ M, for the test b) zymoplasm IC ₅₀Greater than 100 μ M, at test c) in CT2 (PT) be 14 μ M, CT2 (APTT) is 62 μ M, and shows at test d) after medium sized vein used 10mg/kg dosage, the grumeleuse time increased, and is testing e) after medium sized vein uses 5mg/kg dosage, reduced the weight of thrombus.

By other example, hereinafter disclosed embodiment 39 compounds (compound 2) are for test factor X a) _aIC ₅₀Be 0.012 μ M, for the test b) zymoplasm IC ₅₀Greater than 100 μ M, at test c) in CT2 (PT) be 1 μ M, CT2 (APTT) is 1.8 μ M, and shows at test d) after medium sized vein used 5mg/kg dosage, the grumeleuse time increased, and is testing d) after medium sized vein uses 5mg/kg dosage, reduced the weight of thrombus.

By other example, hereinafter disclosed embodiment 41 compounds (compound 3) are for test factor X a) _aIC ₅₀Be 0.01 μ M, for the test b) zymoplasm IC ₅₀Be 83 μ M.

By other example, hereinafter disclosed embodiment 40 compounds (compound 5) are for test factor X a) _aIC ₅₀Be 0.003 μ M, for the test b) zymoplasm IC ₅₀Be 34 μ M, at test c) in CT2 (PT) be 0.5 μ M, CT2 (APTT) is 1.2 μ M, and shows at test d) after medium sized vein uses 5mg/kg dosage, the increase of grumeleuse time.

By other example, the compound of hereinafter disclosed embodiment 62 is for test factor X a) _aIC ₅₀Be 0.002 μ M, for the test b) zymoplasm IC ₅₀Greater than 10 μ M, at test c) in CT2 (PT) be 0.7 μ M, and show at test d) after medium sized vein uses 5mg/kg dosage, the increase of grumeleuse time.

By other example, the compound of hereinafter disclosed embodiment 63 is for test factor X a) _aIC ₅₀Be 0.008 μ M, for the test b) zymoplasm IC ₅₀Greater than 10 μ M, at test c) in CT2 (PT) be 4.6 μ M, and show at test d) after medium sized vein used 5mg/kg dosage, the grumeleuse time increased, and is testing e) after medium sized vein uses 5mg/kg dosage, reduced the weight of thrombus.

According to a further aspect in the invention, provide pharmaceutical composition, comprised amino-heterocycles derivative or its pharmacologically acceptable salt and acceptable diluents or the carrier of formula I or Ia.

Composition can adopt the form that is fit to orally use, tablet for example, capsule, aqueous or buttery solution, suspension or emulsion; For using the part, emulsifiable paste for example, ointment, gel or aqueous or buttery solution or suspension; Use for nose, for example smell agent, nasal spray, nose drops; Use for sheath or rectum, for example suppository; For inhalation, for example fine powder agent such as dry powder agent, microcrystalline form or liquid aerosol; Use for hypogloeeis or cheek, for example tablet or capsule; Or use (comprising in intravenously, subcutaneous, intramuscular, the blood vessel or infusion), for example aseptic aqueous or buttery solution or suspension for parenteral.Usually, use conventional excipients can prepare above-mentioned composition according to a conventional method.

The amount for preparing the activeconstituents (the amino-heterocycles derivative of formula I or Ia or its pharmacologically acceptable salt) of single formulation with one or more mixed with excipients must change according to host who is treated and concrete route of administration, for example, be used for preparation to the human oral administration generally contain the 0.5mg-2g promoting agent and with it blended suitable with vehicle sufficient quantity, its amount account for total composition weight about 5 to about 98% between change, unit dosage generally contains the about 500mg activeconstituents of about 1mg-.

According to a further aspect in the invention, provide the amino-heterocycles derivative of formula I or Ia or its pharmacologically acceptable salt to be used for the treatment of in the method for human or animal body.

The present invention comprises that also these activeconstituentss are used for the purposes of the medicine aspect following in preparation:

(i) produce factor Xa restraining effect;

(ii) produce blood coagulation resisting function;

(iii) produce antithrombotic effect;

(iv) treat the disease or the medical symptom of factor Xa mediation;

(v) treat the disease or the medical symptom of thrombosis mediation;

(vi) treat the blood coagulation disease; And/or

(vii) treatment comprises the thrombosis and the embolism of the blood coagulation of factor Xa mediation.

The present invention also comprises the effect that produces above-mentioned definition or treats one or more diseases of above-mentioned definition, comprises the activeconstituents as defined above of using significant quantity to the warm-blooded animal of needs treatment like this.

According to known principle in the medical treatment, the dosage size of treatment or prevention formula I of purpose or Ia compound is generally according to the character and the severity of medical symptom, animal of being treated or patient's age and sex and route of administration and change.As mentioned above, formula I or Ia compound can be used for treating or prevent the various medical condition that are indicated as anticoagulation therapy.Use formula I compound for this purpose, general for example is the dosed administration of 0.5-500mg/kg body weight can receive per daily dose, if necessary, and can the divided dose administration.Usually, when using parenteral route, can use low dosage, for example, the dosage of intravenously administrable generally uses the 0.5-50mg/kg body weight.For preferred and particularly preferred The compounds of this invention, generally use low dosage, for example per daily dose is the 0.5-10mg/kg body weight.

Although formula I or Ia compound are mainly with acting on treatment or the preventive that warm-blooded animal comprises the people, they also can be used for needs generation blood coagulation resisting function for example has in the biological test of compound of anticoagulation character at the in vitro conservation of whole blood or in exploitation.

The present invention can the single therapy administration or they can be with other drug promoting agent such as thrombolytic agent as organizing plasminogen activator or derivatives thereof or streptokinase administration, The compounds of this invention also can with known anticoagulant (acetylsalicylic acid for example, thromboxane inhibitor or thromboxane synthase inhibitor), known lipid lowering agent or the administration together of known hypotensive agent.

The present invention will illustrate with the following example, except as otherwise noted:

(i) evaporation is to be undertaken by rotary evaporation in vacuo, and treatment step is to carry out after removing by filter remaining solid;

(ii) operation is to carry out under the atmosphere of rare gas element such as argon gas in room temperature is 18-25 ℃ temperature range;

(iii) column chromatography (fast method) and medium pressure liquid chromatography (MPLC) are that (derive from E.Merck, Darmstadt Germany) carries out at MerckKieselgel silica gel (Art.9385) or Merck Lichroprep RP-18 (Art.9303) reverse phase silica gel;

(iv) productive rate only is in order to illustrate, and needs not to be maximum available;

(v) the final product of formula I has satisfied microanalysis, and its structure can be passed through nucleus magnetic resonance (NMR) and mass-spectrometric technique conclusive evidence; Except as otherwise noted, the CDCl3 solution of formula I final product is used to measure the NMR characteristic, and chemical displacement value is pressed the δ scale and measured, and uses following abbreviation: s, and is unimodal; D, bimodal; T, triplet; M, multiplet;

(vi) intermediate does not generally have full characterization, available tlc, infrared spectra (IR) or NMR assay determination purity;

(vii) measure fusing point with automatic fusing point instrument of Mettler SP62 or oil bath device; The fusing point of the final product of formula I is generally being measured after with independent or mixed form crystallization with conventional organic solvent such as ethanol, methyl alcohol, acetone, ether or hexane; And

(viii) use following abbreviation:

DMF N, dinethylformamide;

The THF tetrahydrofuran (THF);

The DMSO methyl-sulphoxide;

DMPU 1,3-dimethyl-3,4,5,6-tetrahydrochysene-2 (1H)-pyrimidone.Embodiment 1

With N-[2-amino-1-(piperidino-(1-position only) carbonyl) ethyl]-2-(2-naphthalene sulfonyl amino) acetamide hydrochloride (2.6g) and triethylamine (3.18ml) join in methylene dichloride (20ml) solution of 1-(4-pyridyl) piperidines-4-carbonyl chlorine (1.54g) that is stirring successively, mixture at room temperature stirred 16 hours, mixture distributes between ethyl acetate and water then, wash organic phase with water, dry (sal epsom) and evaporation, resistates column chromatography purifying, ethyl acetate with 89: 10: 1, methyl alcohol and ammonia water mixture are as eluent, the product of gained is developed with ether, obtain foamed 2-(2-naphthalene sulfonyl amino)-N-{1-piperidino-(1-position only) carbonyl-2-[1-(4-pyridyl)-piperidin-4-yl carbonylamino] ethyl } ethanamide (1.9g, 55%).Nuclear-magnetism spectrum (CD ₃SOCD ₃) 1.37-1.76 (m, 10H), 3.15-3.5 (m, 10H), 3.6 (s, 2H), 4.1-4.2 (d, 2H), 4.9 (t, 1H), 7.1 (d, 2H), 7.6-8.2 (m, 10H), 8.4 (s, 1H); Ultimate analysis: C ₃₁H ₃8N ₆O ₅S0.5H ₂O measured value: C, 60.7; H, 6.5; N, 13.2; Calculated value: C, 60.5; H, 6.3; N, 13.6%.

As N-[2-amino-1-(piperidino-(1-position only) carbonyl) ethyl of starting raw material]-2-(2-naphthalene sulfonyl amino) ethanamide is prepared as follows:

N-hydroxybenzotriazole (10.16g) and N-(3-dimethylaminopropyl)-N '-ethyl carbodiimide (14.7g) are joined the N under the stirring of having cooled off successively in ice bath ²In DMF (200ml) solution of-benzyloxycarbonyl-DL-l-asparagine (20g), mixture stirred 1 hour down at 0 ℃-5 ℃, add piperidines (7.4ml), mixture was stirred 16 hours, be heated to room temperature then, evaporation concentrated mixture adds entry (500ml), isolate precipitation and dry, thereby obtain N ²-benzyloxycarbonyl-DL-l-asparagine piperidines (12g), m.p.159-162 ℃.

After the reaction repeated, the piperidines (17g) of gained is joined in the two solution of (trifluoroacetyl oxygen base) iodobenzene (33g) in the mixture of DMF (100ml) and water (100ml), mixture at room temperature stirred 20 minutes, add triethylamine (14.2ml), mixture stirred 16 hours, mixture adds the acidifying of 2N aqueous hydrochloric acid, use ethyl acetate extraction, by add 2N aqueous sodium hydroxide solution alkalization water to pH be 8, with ethyl acetate (3 * 60ml) extractions, combining extraction liquid washes with water, dry (sal epsom) and evaporation.Thereby obtain buttery 1-[3-amino-2-(benzyloxycarbonyl amino) propionyl] piperidines (8.12g).

Tert-Butyl dicarbonate (8.75g) and triethylamine (7.1ml) are joined in methylene dichloride (150ml) solution of the piperidines of the gained that is stirring successively; mixture at room temperature stirred 16 hours; mixture distributes between methylene dichloride and 1N aqueous citric acid solution then; wash organic phase with water; dry (sal epsom) and evaporation; resistates column chromatography purifying; with the mixture of 1: 1 hexane and ethyl acetate as eluent, thereby obtain buttery 1-[2-(benzyloxycarbonyl amino)-3-(tert-butoxycarbonyl amino) propionyl] piperidines (7.98g).

Product with a part (4.2g) gained; 10% Pd/carbon catalyst (0.3g) and ethanol (100ml) stirred 8 hours under nitrogen atmosphere; filtering mixt; evaporated filtrate; resistates is developed with ether; obtain 1-[2-amino-3-(tert-butoxycarbonyl amino) propionyl] piperidines (2.3g), m.p.87-90 ℃.

DMF (20ml) solution of N-(2-naphthyl alkylsulfonyl) glycine (2.93g) is joined the N-hydroxybenzotriazole (1.5g) that is stirring that had cooled off in ice bath; in the mixture of N-(3-dimethylaminopropyl)-N-ethyl carbodiimide (2.16g) and DMF (80ml); mixture stirred 1 hour; add 1-[2-amino-3-(tert-butoxycarbonyl amino) propionyl] DMF (10ml) solution of piperidines (2.98g); mixture heating up is to room temperature; stirred 16 hours; mixture distributes between methylene dichloride and water then; wash organic phase with water; dry (sal epsom) and evaporation; resistates column chromatography purifying; with ethyl acetate as eluent; thereby obtain N-[2-(tert-butoxycarbonyl amino)-1-(piperidino-(1-position only) carbonyl) ethyl]-2-(2-naphthalene sulfonyl amino) ethanamide (3.2g), m.p.95-98 ℃.

The product an of part (0.5g) gained is suspended in the ethyl acetate (25ml), and mixture cools off in ice bath, and hydrogen chloride gas was imported in the reaction mixture 20 minutes, generates clear soln, then deposits precipitation, isolates solid and drying.Thereby obtain N-[2-amino-1-(piperidino-(1-position only) carbonyl) ethyl]-2-(2-naphthalene sulfonyl amino) acetamide hydrochloride (0.34g); Nuclear-magnetism spectrum (CD ₃SOCD ₃+ CD ₃CO ₂D) 1.2-1.6 (m, 6H), 2.7-3.1 (m, 2H), 3.1-3.25 (t, 2H), 3.3-3.5 (m, 2H), 3.6 (s, 2H), 4.8-5.0 (t, 1H), 6.5-8.1 (m, 7H), 8.4 (s, 1H); Ultimate analysis: C ₂₀H ₂₆N ₄O ₄SHClH ₂O measured value: C, 50.9; H, 6.3; N, 11.8; Calculated value: C, 50.7; H, 6.1; N, 11.8%.

1-(4-pyridyl) piperidines-4-carbonyl chlorine as starting raw material is prepared as follows:

Oxalyl chloride (0.14ml) and DMF (2) are joined 1-(4-pyridyl) piperidines-4-carboxylic acid [Tetrahedron, 1988,44,7095 of stirring successively; 0.21g] methylene dichloride (20ml) solution, mixture at room temperature stirred 4 hours, evaporating mixture obtains required starting raw material, need not to be further purified.Embodiment 2

Methylene dichloride (10ml) solution of 2-naphthyl alkylsulfonyl chlorine (0.55g) is joined 1-[1-(4-pyridyl) the piperidin-4-yl carbonyl that is stirring] piperazine trihydrochloride salt (0.85g); the mixture of triethylamine (3.1ml) and methylene dichloride (80ml); the mixture of gained at room temperature stirred 18 hours; mixture distributes between methylene dichloride and water; wash organic phase with water; dry (sal epsom) and evaporation; resistates column chromatography purifying; with the mixture that increases polar methylene dichloride and methyl alcohol (100: 6 to 100: 10) as eluent, thereby obtain solid 1-(2-naphthyl alkylsulfonyl)-4-[1-(4-pyridyl) piperidines-4-carbonyl] piperazine (0.727g).Nuclear-magnetism spectrum (CD ₃SOCD ₃) 1.4-1.65 (m, 4H), 2.75-3.05 (m, 7H), 3.5-3.7 (m, 4H), 3.8-3.95 (m, 2H), 6.8 (d, 2H), 7.65-7.8 (m, 3H), 8.05-8.25 (m, 5H), 8.45 (d, 1H); Ultimate analysis: C ₂₅H ₂₈N ₄O ₃S0.5H ₂O measured value: C, 63.4; H, 6.1; N, 11.5; Calculated value: C, 63.4; H, 6.1; N, 11.8%.

As 1-[1-(4-pyridyl) the piperidin-4-yl carbonyl of starting raw material] piperazine is prepared as follows:

Thionyl chloride (1.6ml) is added dropwise in methylene dichloride (30ml) suspension of 1-(4-pyridyl) piperidines-4-carboxylic acid (2.17g) that is stirring, mixture at room temperature stirred 1 hour, evaporating mixture obtains 1-(4-pyridyl) piperidines-4-carbonyl chlorine, need not to be further purified.

The product of gained is suspended in methylene dichloride (30ml) and the triethylamine (7.8ml), methylene dichloride (10ml) solution that adds 1-tert-butoxycarbonyl piperazine (2.08g) successively, mixture at room temperature stirred 4 hours, mixture distributes between methylene dichloride and water, wash organic phase with water, dry (sal epsom) and evaporation, resistates column chromatography purifying, with the mixture that increases polar methylene dichloride and methyl alcohol (100: 5 to 100: 13) as eluent, thereby obtain 1-(tert-butoxycarbonyl)-4-[1-(4-pyridyl) piperidines-4-carbonyl] piperazine (2.38g).

The ether saturated solution (25ml) of hydrogenchloride is joined methylene dichloride (120ml) solution of the 1-tert-butoxycarbonyl piperazine of the gained that is stirring, mixture at room temperature stirred 18 hours, evaporating mixture, resistates is developed with ether, thereby obtains 1-[1-(4-pyridyl) piperidin-4-yl carbonyl] piperazine trihydrochloride salt (2.85g); Nuclear-magnetism spectrum (CD ₃SOCD ₃) 1.5-1.9 (m, 4H), 3.0-3.2 (m, 7H), 3.6-3.85 (m, 4H), 4.15-4.3 (m, 2H), 7.2 (d, 2H), 8.2 (d, 2H). embodiment 3

With 1,1 '-carbonyl dimidazoles (0.089g) and triethylamine (0.08ml) join N-[2-amino-1-(piperidino-(1-position only) carbonyl) ethyl that had cooled off successively in ice bath]-DMF (15ml) solution of 2-(2-naphthalene sulfonyl amino) acetamide hydrochloride (0.25g) in.Mixture stirred 30 minutes, add 1-(4-pyridyl) piperazine (0.089g), mixture at room temperature stirred 16 hours, mixture distributes between ethyl acetate and water, wash organic phase with water, dry (sal epsom) and evaporation, resistates column chromatography purifying, with ethyl acetate as eluent, thereby obtain foamed 2-(2-naphthalene sulfonyl amino)-N-{1-piperidino-(1-position only) carbonyl-2-[4-(4-pyridyl) piperazine-1-base carbonylamino] ethyl ethanamide (0.118g); Nuclear-magnetism spectrum (CD ₃SOCD ₃+ CD ₃CO ₂D) 1.3-1.6 (m, 6H), 3.0-3.1 (m, 1H), 3.2-3.6 (m, 15H), 4.8-4.9 (m, 1H), 7.0 (d, 2H), 7.5-7.7 (m, 2H), 7.75-7.83 (m, 1H), 7.9-8.1 (m, 3H), 8.1-8.2 (d, 2H), 8.4 (s, 1H); Ultimate analysis: C ₃₀H ₃₇N ₇O ₅S0.25EtAc measured value: C, 58.9; H, 6.4; N, 15.3; Calculated value: C, 59.1; H, 6.2; N, 15.6%.Embodiment 4

The similar approach of using embodiment 1 to describe, just with 2-[1-(4-pyridyl) piperidin-4-yl] ethanoyl villaumite hydrochlorate replacement 1-(4-pyridyl) piperidines-4-carbonyl chlorine, product high pressure liquid chromatography purifying, acetonitrile with 50: 50: 0.1, water and trifluoroacetic acid be as eluent, thereby obtain foamed 2-(2-naphthalene sulfonyl amino)-N-(1-piperidino-(1-position only) carbonyl-2-{2-[1-(4-pyridyl) piperidin-4-yl] kharophen } ethyl) ethanamide (18% productive rate); Nuclear-magnetism spectrum (CD ₃SOCD ₃+ CD ₃CO ₂D) 1.0-1.7 (m, 6H), 1.7-2.1 (m, 8H), 3.0-3.4 (m, 9H), 3.5-3.6 (s, 2H), 4.1-4.2 (d, 2H), 4.8-4.9 (m, 1H), 7.05-7.2 (d, 2H), 7.6-8.2 (m, 8H), 8.4-8.5 (s, 1H); Ultimate analysis: C ₃₂H ₄₀N ₆O ₅SCF ₃CO ₂HH ₂O measured value: C, 52.8; H, 5.4; N, 11.4; Calculated value: C, 53.0; H, 5.8; N, 10.9%.

2-[1-(4-pyridyl) piperidin-4-yl as starting raw material] acetyl chloride hydrochloride is prepared as follows:

Phosphine acyl acetic acid three ethyl (19.8ml) is added dropwise to the sodium hydride that is stirring that cooled off (50% dispersion liquid in mineral oil in ice bath; 4.8g) glycol dimethyl ether (300ml) suspension in; mixture stirred 1 hour down at 0 ℃-5 ℃; be added dropwise to 1-benzyl-4-piperidone (17.85ml); mixture at room temperature stirred 16 hours; mixture distributes between ether and water; water and salt water washing organic phase; dry (sal epsom) and evaporation; resistates column chromatography purifying; with the mixture of 3: 2 hexanes and ethyl acetate as eluent, thereby obtain 1-benzyl-4-(ethoxy carbonyl methylene radical) piperidines (5.52g).

With the product of gained, the mixture of 10% Pd/carbon catalyst (1g) and ethanol (250ml) stirred 6 hours under nitrogen atmosphere, and filtering mixt obtains buttery 2-(piperidin-4-yl) ethyl acetate (3.31g), and product need not to be further purified; Nuclear-magnetism spectrum (CDCl ₃) 1.0-1.2 (m, 2H), 1.25 (t, 3H), 1.7 (s, 2H), 1.9 (m, 1H), 2.2 (d, 2H), 2.6 (m, 2H), 3.05 (m, 2H), 4.0 (m, 2H).

Product (3.25g) with a part of gained, 4-chloropyridine hydrochloride (2.85g), the mixture stirring of triethylamine (5.28ml) and dimethylbenzene (100ml) and reflux 16 hours, mixture is cooled to room temperature, and filter, evaporated filtrate, resistates distributes between methylene dichloride and water, wash organic phase with water, dry (sal epsom) and evaporation, resistates column chromatography purifying, with 10: 1 methylene dichloride and methanol mixture as eluent, thereby obtain buttery 2-[1-(4-pyridyl) piperidin-4-yl] ethyl acetate (2.15g).

With the product of gained, the mixture of 1N aqueous hydrochloric acid (35.5ml) and dioxane (100ml) stirs, be heated to 95 ℃ 3 hours.Evaporating mixture obtains 2-[1-(4-pyridyl) piperidin-4-yl with the resistates lyophilize] acetic acid hydrochloride (2.3g), m.p.105-108 ℃.

The similar approach of use described in the part that relates to the embodiment 1 for preparing starting raw material makes the reaction of acetate and oxalyl chloride obtain 2-[1-(4-pyridyl) piperidin-4-yl of quantitative yield] acetyl chloride hydrochloride.Embodiment 5

Use embodiment 1 described similar approach, just with 2-[4-(4-pyridyl) piperazine-1-yl] Acetyl Chloride 98Min. replacement 1-(4-pyridyl) piperidines-4-carbonyl chlorine.Thereby obtain foamed 2-(2-naphthalene sulfonyl amino)-N-(1-piperidino-(1-position only) carbonyl-2-{2-[4-(4-pyridyl) piperazine-1-yl] kharophen ethanamide (6% productive rate); Nuclear-magnetism spectrum (CD ₃SOCD ₃) 1.3-1.6 (m, 6H), 2.9-3.05 (s, 2H), 3.1-3.7 (m, 14H), 4.8-5.0 (t, 1H), 7.0-7.2 (d, 2H), 7.6-8.2 (m, 9H), 8.4 (s, 1H); Ultimate analysis: C ₃₁H ₃₉N ₇O ₅S1.5H ₂O measured value: C, 57.4; H, 6.2; N, 14.5; Calculated value: C, 57.4; H, 6.5; N, 15.1%.

As 2-[4-(4-pyridyl) piperazine-1-of starting raw material] Acetyl Chloride 98Min. is prepared as follows:

With sodium hydride (50% dispersion liquid in mineral oil, 1.9g) join in the mixture of 1-(4-pyridyl) piperazine (3g) that stirring and DMF (20ml) in batches, mixture at room temperature stirred 1 hour, be added dropwise to bromoacetic acid tertiary butyl ester (6.5ml), mixture stirred 18 hours, mixture distributes between ethyl acetate and water, wash organic phase with water, dry (sal epsom) and evaporation, resistates column chromatography purifying, with 17: 3 methylene dichloride and methanol mixture as eluent, thereby obtain solid 2-[4-(4-pyridyl) piperazine-1-yl] ra-butyl acetate (2.85g).

The product of gained and the mixture of trifluoroacetic acid (7ml) were at room temperature stirred 18 hours, and evaporating mixture obtains 2-[4-(4-pyridyl) piperazine-1-yl of quantitative yield] acetate; Nuclear-magnetism spectrum (CD ₃SOCD ₃) 3.35-3.5 (m, 4H), 3.9-4.05 (m, 4H), 4.1 (s, 2H), 7.25 (d, 2H), 8.35 (d, 2H).

With the product (2.27g) of gained, oxalyl chloride (1.5ml), DMF (3) and methylene dichloride (20ml) at room temperature stirred 4 hours, evaporating mixture obtains 2-[4-(4-pyridyl) piperazine-1-yl] Acetyl Chloride 98Min., need not to be further purified.Embodiment 6

Triethylamine (0.77ml) is joined the 2-amino-3-[1-that had cooled off (4-pyridyl) the piperidin-4-yl carbonylamino that is stirring] ethyl propionate dihydrochloride (1g), in the mixture of succinimido 2-(2-naphthalene sulfonyl amino)-acetic ester (0.92g) and methylene dichloride (50ml), mixture heating up is to room temperature, and stirred 4 hours, mixture distributes between methylene dichloride and water, wash organic phase with water, dry (sal epsom) and evaporation, resistates column chromatography purifying, with 4: 1 ethyl acetate and methanol mixture as eluent, thereby obtain foamed N-{1-ethoxy carbonyl-2-[1-(4-pyridyl) piperidin-4-yl carbonylamino] ethyl-2-(2-naphthalene sulfonyl amino) ethanamide (0.203g); Nuclear-magnetism spectrum (CD ₃SOCD ₃) 1.1-1.2 (t, 3H), 1.4-1.8 (m, 4H), 2.2-2.4 (m, 1H), 2.7-3.0 (t, 2H), 3.5 (s, 2H), 3.8-4.1 (m, 4H), 4.2-4.4 (t, 1H), 6.7-6.8 (d, 2H), 7.6-8.3 (m, 11H), 8.4 (s, 1H); Ultimate analysis: C ₂₈H ₃₃N ₅O ₆S ₂H ₂O measured value: C, 55.7; H, 6.0; N, 11.1; Calculated value: C, 55.5; H, 6.1; N, 11.6%.

As 2-amino-3-[1-(4-pyridyl) piperidin-4-yl carbonylamino of starting raw material] the ethyl propionate dihydrochloride is prepared as follows:

With N ²-benzyloxycarbonyl-DL-l-asparagine (25g) joins in the two solution of (trifluoroacetyl oxygen base) iodobenzene (60.6g) in the mixture of DMF (350ml) and water (350ml) that stirring, mixture at room temperature stirred 15 minutes, add pyridine (15ml), mixture stirred 16 hours, evaporating mixture, resistates distributes between water and ether, the evaporation water layer obtains being mixed with solid oily matter, isolate solid, wash with ether, and dry, thereby obtain 3-amino-2-(benzyloxycarbonyl amino) propionic acid (6.3g).

The product (3g) of a part of gained is joined in the mixture (being cooled to-10 ℃) of the thionyl chloride (1.01ml) that stirring and ethanol (100ml), with mixture heating up to room temperature, stirred 16 hours, evaporating mixture, resistates is developed with ether, thereby obtains 3-amino-2-(benzyloxycarbonyl amino) ethyl propionate hydrochloride (3.45g); Nuclear-magnetism spectrum (CD ₃SOCD ₃) 1.1-1.25 (t, 3H), 3.0-3.2 (m, 2H), 4.05-4.2 (q, 2H), 4.3-4.5 (m, 1H), 5.1 (s, 2H), 7.3 (m, 5H), 7.8-7.9 (d, 1H), 8.3 (s, 2H).

Triethylamine (0.7ml) is joined 3-amino-2-(benzyloxycarbonyl amino) the ethyl propionate hydrochloride (0.5g) that is stirring, the mixture of 1-(4-pyridyl) piperidines-4-carbonyl chlorine (0.45g) and methylene dichloride (20ml), the mixture of gained at room temperature stirred 16 hours.Mixture distributes between methylene dichloride and water, wash organic phase with water, dry (sal epsom) and evaporation, resistates column chromatography purifying, with increasing polar ethyl acetate and methanol mixture as eluent, thus the 2-that obtains (benzyloxycarbonyl amino)-3-[1-(4-pyridyl) piperidin-4-yl carbonylamino] ethyl propionate (0.5g).

After repeating above-mentioned steps, product (2g) with gained, 10% Pd/carbon catalyst (0.2g), the mixture of 1N aqueous hydrochloric acid (8.8ml) and ethanol (50ml) stirred 6 hours under nitrogen atmosphere, filtering mixt, evaporated filtrate, thereby obtain 2-amino-3-[1-(4-pyridyl) piperidin-4-yl carbonylamino] ethyl propionate dihydrochloride (2.48g); Nuclear-magnetism spectrum (CD ₃SOCD ₃) 1.2-1.3 (t, 3H), 1.5-1.7 (m, 2H), 1.8-2.0 (m, 2H), 2.6-2.7 (m, 1H), 3.2-3.4 (t, 2H), 4.0-4.3 (m, 6H), 7.15-7.82 (d, 2H), 8.1-8.2 (d, 2H), 8.5-8.65 (t, 1H).

Succinimido 2-(2-naphthalene sulfonyl amino)-acetic ester as starting raw material is prepared as follows:

With N, ethyl acetate (50ml) solution of N '-dicyclohexyl carbodiimide (4.12g) is cooled to 0 ℃, add N-(the 2-naphthyl alkylsulfonyl) glycine (5.3g) that is stirring, in the compound of N-hydroxy-succinamide (2.3g) and ethyl acetate (being cooled to 0 ℃), mixture stirred 1 hour down at 0 ℃, be heated to room temperature, and stirred 16 hours, with mixture be cooled to again 0 ℃ 1 hour, and filter, evaporated filtrate, the resistates mixture recrystallization of hexane and ethyl acetate, thus obtain required starting raw material (6.2g); Nuclear-magnetism spectrum (CD ₃SOCD ₃) 2.8 (m, 4H), 4.25 (d, 2H), 7.6-7.75 (m, 2H), 7.8-7.9 (m, 1H), 8.0-8.2 (m, 3H), 8.45 (s, 1H), 8.6 (t, 1H). embodiment 7

Use embodiment 2 described similar approach, make 2-naphthyl alkylsulfonyl chlorine and 2-amino-3-[1-(4-pyridyl) piperidin-4-yl carbonylamino] the ethyl propionate dihydrochloride reacts and obtains foamed 2-(2-naphthalene sulfonyl amino)-3-[1-(4-pyridyl) piperidin-4-yl carbonylamino] ethyl propionate (37% productive rate); Nuclear-magnetism spectrum (CD ₃SOCD ₃) 1.1-1.2 (t, 3H), 1.3-1.7 (m, 4H), 2.1-2.3 (m, 1H), 2.7-2.9 (m, 2H), 3.1-3.9 (m, 6H), 3.9-4.1 (t, 1H), 6.7-6.8 (d, 2H), 7.6-8.2 (m, 11H), 8.35 (s, 1H); Ultimate analysis: C ₂₆H ₃₀N ₄O ₅S0.75H ₂O measured value: C, 59.8; H, 6.4; N, 10.3; Calculated value: C, 59.6; H, 6.0; N, 10.7%.Embodiment 8

With N-{1-ethoxy carbonyl-2-[1-(4-pyridyl) piperidin-4-yl carbonylamino] ethyl }-2-(2-naphthalene sulfonyl amino) ethanamide (0.1g), methylamine (33% solution in ethanol, 0.2ml) and the mixture of ethanol (5ml) at room temperature stirred 2 hours, isolate precipitation, use the column chromatography purifying, with increasing polar ethyl acetate and methanol mixture, thereby obtain N-methyl-2-[2-(2-naphthalene sulfonyl amino) kharophen as eluent]-3-[1-(4-pyridyl) piperidin-4-yl carbonylamino] propionic acid amide (0.01g); Ultimate analysis: C ₂₇H ₃₂N ₆O ₅S1.5H ₂O0.5EtOH measured value: C, 57.6; H, 6.1; N, 13.9; Calculated value: C, 57.5; H, 6.1; N, 14.3%.Embodiment 9

With N-{1-ethoxycarbonyl-2-[1-(4-pyridyl) piperidin-4-yl carbonylamino] ethyl }-2-(2-naphthalene sulfonyl amino) ethanamide (0.15g), 0.1N the mixture of aqueous sodium hydroxide solution (5.3ml) and methyl alcohol (3ml) at room temperature stirred 2 hours, by adding in the 0.1N aqueous hydrochloric acid (5.3ml) and basic solution and evaporation.Develop resistates with ether, thereby obtain 2-[2-(2-naphthalene sulfonyl amino) kharophen]-3-[1-(4-pyridyl) piperidin-4-yl carbonylamino] propionic acid (0.123g); Nuclear-magnetism spectrum (CD ₃SOCD ₃) 1.4-1.65 (m, 2H), 1.6-1.75 (m, 2H), 2.3-2.5 (m, 1H), 2.8-3.0 (t, 2H), 3.25-3.4 (m, 2H), 3.85-3.95 (d, 2H), 4.0-4.15 (m, 1H), 6.7-6.9 (s, 2H), 7 .6-8.4 (m, 10H), 8.4 (s, 1H); Ultimate analysis: C ₂₆H ₂₉N ₅O ₆S ₂NaClH ₂O measured value: C, 46.7; H, 4.5; N, 10.3; Calculated value: C, 46.3; H, 4.6; N, 10.4%.Embodiment 10

The similar approach of using embodiment 1 to describe, make 1-(4-pyridyl) piperidines-4-carbonyl chlorine and 1-[3-amino-2-(2-naphthalene sulfonyl amino) propionyl] piperidine hydrochlorate reaction obtains N-[2-(2-naphthalene sulfonyl amino)-2-(piperidino-(1-position only) carbonyl) ethyl]-1-(4-pyridyl) piperidines-4-methane amide, productive rate 17%; Ultimate analysis: C ₂₉H ₃₅N ₅O ₄SH ₂O calculated value: C, 61.4; H, 6.8; N, 12.1; Measured value: C, 61.3; H, 6.5; N, 12.3%.

As 1-[3-amino-2-(2-naphthalene sulfonyl amino) propionyl of starting raw material] piperidine hydrochlorate is prepared as follows:

Triethylamine (3.1ml) is joined the 2-naphthyl alkylsulfonyl chlorine (1.67g) that is stirring; 1-[2-amino-3-(tert-butoxycarbonyl amino) propionyl] in the mixture of piperidines (2g) and DMF (25ml); mixture at room temperature stirred 16 hours; mixture distributes between ethyl acetate and water; with salt water washing organic phase; dry (sal epsom) and evaporation; resistates column chromatography purifying; with the mixture that increases polar hexane and ethyl acetate as eluent, thereby obtain solid 1-[3-tert-butoxycarbonyl amino)-2-(2-naphthalene sulfonyl amino) propionyl] piperidines (2.6g).

The compound of gained is suspended in the ethyl acetate; mixture cools off in ice bath; hydrogen chloride gas was imported mixture 1 hour; generate settled solution; then isolate sedimentary precipitation; thereby obtain foamed 1-[3-amino-2-(2-naphthalene sulfonyl amino) propionyl] piperidine hydrochlorate (2g), need not to be further purified then and can use.Embodiment 11

The similar approach of using embodiment 1 to describe, make 1-(4-pyridyl) piperidines-4-carbonyl chlorine and N-[2-amino-2-(piperidino-(1-position only) carbonyl) ethyl]-2-(2-naphthalene sulfonyl amino) ethanamide reaction obtains 2-(2-naphthalene sulfonyl amino)-N-{2-piperidino-(1-position only) carbonyl-2-[1-(4-pyridyl) piperidin-4-yl carbonylamino] ethyl } ethanamide, productive rate 41%; M.p.200-202 ℃; Nuclear-magnetism spectrum (CD ₃SOCD ₃+ CD ₃CO ₂D) 1.1-1.8 (m, 9H), 3.0-3.6 (m, 12H), 4.0-4.2 (m, 2H), 4.8-5.0 (t, 1H), 7.0-7.2 (s, 2H), 7.6-7.8 (m, 2H), 7.8-7.9 (m, 1H), 8.0-8.3 (m, 5H), 8.4-8.5 (s, 1H); Ultimate analysis: C ₃₁H ₃₈N ₆O ₅S measured value: C, 61.1; H, 6.4; N, 13.7; Calculated value: C, 61.4; H, 6.3; N, 13.9%.

As N-[2-amino-2-(piperidino-(1-position only) carbonyl) ethyl of starting raw material]-2-(2-naphthalene sulfonyl amino) ethanamide is prepared as follows:

With 1-[3-amino-2-(benzyloxycarbonyl amino) propionyl] piperidines (2g); the mixture of succinimido 2-(2-naphthalene sulfonyl amino) acetic ester (2.4g) and ethyl acetate (25ml) at room temperature stirred 12 hours; mixture distributes between ethyl acetate and water; wash organic phase with water; dry (sal epsom) and evaporation; resistates column chromatography purifying; with ethyl acetate as eluent, thereby obtain foamed N-[2-(benzyloxycarbonyl amino)-2-(piperidino-(1-position only) carbonyl) ethyl]-2-(2-naphthalene sulfonyl amino) ethanamide (1.83g).

Product with gained, the mixture of 10% Pd/carbon catalyst (0.3g) and ethanol (40ml) stirred 8 hours under nitrogen atmosphere, filtering mixt, evaporated filtrate, resistates column chromatography purifying, with the mixture of 1: 1 hexane and ethyl acetate as eluent, thereby obtain N-[2-amino-2-(piperidino-(1-position only) carbonyl) ethyl]-2-(2-naphthalene sulfonyl amino) ethanamide (0.52g), need not to be further purified then and can use.Embodiment 12

Repeat the method for description among the embodiment 2, just replace 2-naphthyl alkylsulfonyl chlorine, thereby obtain 1-(1-naphthyl alkylsulfonyl)-4-[1-(4-pyridyl) piperidin-4-yl carbonyl with 1-naphthyl alkylsulfonyl chloro] piperazine, productive rate 52%; Nuclear-magnetism spectrum (CD ₃SOCD ₃) 1.4-1.7 (m, 4H), 2.75-2.95 (m, 3H), 3.0-3.2 (m, 4H), 3.45-3.65 (m, 4H), 3.8-3.95 (m, 2H), 6.75 (d, 2H), 7.6-7.8 (m, 3H), 8.0-8.2 (m, 4H), 8.35 (d, 1H), 8.7 (d, 1H); Ultimate analysis: C ₂₅H ₂₈N ₄O ₃SH ₂O measured value: C, 62.2; H, 6.1; N, 11.3; Calculated value: C, 62.2; H, 6.2; N, 11.6%.Embodiment 13

N-methylmorpholine (0.095g) and isobutyl chlorocarbonate (0.13g) are joined successively THF (6ml) suspension (being cooled to-10 ℃) of 1-(the 2-naphthyl alkylsulfonyl) piperidines-4-carboxylic acid (0.3g) that is stirring, mixture stirred 30 minutes down at-10 ℃, DMF (3ml) solution that adds 1-(4-pyridyl) piperazine (0.155g), mixture at room temperature stirred 18 hours, evaporating mixture, resistates column chromatography purifying, with 22: 3 methylene dichloride and methanol mixture as eluent, thereby obtain solid 1-[1-(2-naphthyl alkylsulfonyl) piperidin-4-yl carbonyl]-4-(4-pyridyl)-piperazine (0.07g); Nuclear-magnetism spectrum (CD ₃SOCD ₃) 1.5-1.75 (m, 4H), 2.3-2.45 (m, 2H), 2.5-2.65 (m, 1H), 3.5-3.75 (m, 10H), 7.05 (d, 2H), 7.6-7.75 (m, 3H), 8.0-8.2 (m, 5H), 8.35 (d, 1H).

1-(2-naphthyl alkylsulfonyl) piperidines-4-carboxylic acid as starting raw material is prepared as follows:

Methylene dichloride (5ml) solution of piperidines-4-carboxylic acid, ethyl ester (1.02ml) is joined the 2-naphthyl SULPHURYL CHLORIDE (1.5g) that is stirring; in the mixture of triethylamine (4ml) and methylene dichloride (10ml) (being cooled to 5 ℃); mixture at room temperature stirred 18 hours; evaporating mixture; resistates distributes between ethyl acetate and water; with 2N aqueous hydrochloric acid and water washing organic phase; dry (sal epsom) and evaporation, thus 1-(2-naphthyl alkylsulfonyl) piperidines-4-carboxylic acid, ethyl ester (1.95g) obtained.

Product with gained, the mixture stirring of potassium hydroxide (0.62g) and ethanol (18ml) and reflux 4 hours, evaporating mixture, resistates distributes between methylene dichloride and water, dry (sal epsom) and evaporation, thus 1-(2-naphthyl alkylsulfonyl) piperidines-4-carboxylic acid (1.35g) obtained; Nuclear-magnetism spectrum (CD ₃SOCD ₃) 1.5-1.7 (m, 2H), 1.8-1.95 (m, 2H), 2.2-2.3 (m, 1H), 2.45-2.55 (m, 2H), 3.5-3.6 (m, 2H), 7.65-7.8 (m, 3H), 8.05-8.25 (m, 3H), 8.45 (d, 1H). embodiment 14

With N, N '-dicyclohexyl carbodiimide (0.5g) joins N-(2-amino-3-phenyl propyl)-1-(4-pyridyl) piperidines-4-methane amide (1.08g) that is stirring, N-(2-naphthyl alkylsulfonyl) glycine (0.85g), N-hydroxybenzotriazole (0.34g), in the mixture of N-methylmorpholine (0.71ml) and DMF (20ml) (being cooled to 5 ℃), mixture at room temperature stirred 18 hours, evaporating mixture, resistates is by the column chromatography purifying, use the mixture that increases polar methylene dichloride and methyl alcohol (20: 1 to 20: 3) as eluent, thereby obtain solid 2-(2-naphthalene sulfonyl amino)-N-{1-phenyl-3-[1-(4-pyridyl) piperidin-4-yl carbonylamino] third-2-yl } ethanamide (0.52g); Nuclear-magnetism spectrum (CD ₃SOCD ₃) 1.5-1.7 (m, 2H), 1.75-1.9 (m, 2H), 2.4-2.65 (m, 4H), 2.9-3.4 (m, 6H), 3.85-4.0 (m, 1H), 4.0-4.15 (m, 2H), 7.0-7.2 (m, 6H), 7.55-7.65 (m, 3H), 7.75 (m, 1H), 7.9-8.1 (m, 5H), 8.35 (d, 1H).

N-(2-amino-3-phenyl propyl)-1-(4-pyridyl) piperidines-4-methane amide as starting raw material is prepared as follows:

Use J.Chem.Res. (S), 1992,391 described similar approach go on foot N through four ²-tert-butoxycarbonyl-DL-phenylalanine is converted into 1-amino-2-(tert-butoxycarbonyl amino)-3-phenyl-propane.

Use relates to the similar approach of describing in second section of embodiment 2 parts of starting raw material preparation, make 1-(4-pyridyl) piperidines-4-carbonyl chlorine and 1-amino-2-(tert-butoxycarbonyl amino)-3-phenyl-propane reaction obtain N-[2-(tert-butoxycarbonyl amino)-3-phenyl propyl]-1-(4-pyridyl) piperidines-4-methane amide, productive rate 39%.

The product (0.95g) of gained and the mixture of trifluoroacetic acid (2ml) were at room temperature stirred 18 hours, evaporating mixture, resistates is developed in ether, thereby obtain N-(2-amino-3-phenyl propyl)-1-(4-pyridyl) piperidines-4-methane amide (0.9g), need not to be further purified then and can use.Nuclear-magnetism spectrum (CD ₃SOCD ₃) 1.5-1.7 (m, 2H), 1.85-2.0 (m, 2H), 2.75-3.0 (m, 2H), 3.1-3.5 (m, 6H), 4.15-4.3 (m, 2H), 7.15-7.4 (m, 7H), 8.2-8.3 (m, 2H). embodiment 15

The similar approach of using embodiment 2 to describe, just replace methylene dichloride as reaction solvent with DMF, make 1-{2-[4-(4-pyridyl) piperazine-1-yl] ethanoyl } reaction of piperazine and 2-naphthyl SULPHURYL CHLORIDE obtains 1-(2-naphthyl alkylsulfonyl)-4-{2-[4-(4-pyridyl) piperazine-1-yl] ethanoyl } and piperazine, productive rate 22%; Nuclear-magnetism spectrum (CD ₃SOCD ₃+ CD ₃CO ₂D) 2.4-2.5 (m, 4H), 2.9-3.05 (m, 4H), 3.15 (s, 2H), 3.3-3.45 (m, 4H), 3.45-3.65 (m, 4H), 6.95 (d, 2H), 7.5-7.75 (m, 3H), 7.95-8.2 (m, 5H), 8.4 (s, 1H); Ultimate analysis: C ₂₅H ₂₉N ₅O ₃S measured value: C, 62.1; H, 6.1; N, 14.4; Calculated value: C, 62.6; H, 6.1; N, 14.6%.

As 1-{2-[4-(4-pyridyl) piperazine-1-yl of starting raw material] ethanoyl } piperazine is prepared as follows:

With N; N '-dicyclohexyl carbodiimide (0.84g) joins 2-[4-(4-pyridyl) piperazine-1-yl that is stirring] acetate (1g); 1-(tert-butoxycarbonyl) piperazine (0.67g); N-hydroxybenzotriazole (0.382g); in the mixture of N-methylmorpholine (0.79ml) and DMF (30ml) (being cooled to 5 ℃); mixture at room temperature stirred 18 hours; evaporating mixture; resistates is by the column chromatography purifying; use 17: 3 methylene dichloride and methanol mixture as eluent, thereby obtain foamed 1-(tert.-butoxy)-4-{2-[4-(4-pyridyl) piperazine-1-yl] ethanoyl } piperazine (0.87g).

With a part of product (0.75g) of gained, the mixture of trifluoroacetic acid (2ml) and methylene dichloride (5ml) at room temperature stirred 4 hours, and evaporating mixture obtains 1-{2-[4-(4-pyridyl) piperazine-1-yl with quantitative yield] ethanoyl } piperazine; Nuclear-magnetism spectrum (CD ₃SOCD ₃) 3.05-3.25 (m, 4H), 3.55-3.7 (m, 2H), 3.7-3.8 (m, 2H), 3.9-4.1 (m, 4H), 4.3 (s, 2H), 7.3 (d, 2H), 8.4 (d, 2H), 9.35 (s, 2H). embodiment 16

The similar approach of using embodiment 1 to describe, make 1-(4-pyridyl) piperidines-4-carbonyl chlorine and N-[3-amino-1-(piperidino-(1-position only) carbonyl) propyl group]-2-(2-naphthalene sulfonyl amino)-acetamide hydrochloride reaction obtains 2-(2-naphthalene sulfonyl amino)-N-{1-piperidino-(1-position only) carbonyl-3-[1-(4-pyridyl) piperidin-4-yl carbonylamino] propyl group } ethanamide, productive rate 17%; Nuclear-magnetism spectrum (CD ₃SOCD ₃) 1.3-1.8 (m, 12H), 2.3-2.5 (m, 1H), 2.7-3.1 (m, 4H), 3.2-3.45 (m, 4H), 3.5-3.6 (m, 2H), 3.8-4.0 (m, 2H), 4.6-4.7 (m, 1H), 6.7-6.85 (m, 2H), 7.6-7.8 (m, 3H), 7.8-7.9 (m, 1H), 8.0-8.35 (m, 7H), 8.4 (s, 1H); Ultimate analysis: C ₃₂H ₄₀N ₆O ₅S1.25H ₂O measured value: C, 59.6; H, 6.6; N, 13.0; Calculated value: C, 59.8; H, 6.6; N, 13.1%.

As N-[3-amino-1-(piperidino-(1-position only) carbonyl) propyl group of starting raw material]-2-(2-naphthalene sulfonyl amino)-acetamide hydrochloride is prepared as follows:

With 1,1 '-carbonyl dimidazoles (3.95g) joins the N that is stirring ²In DMF (60ml) solution of-benzyloxycarbonyl-DL-glutamine (8.47g), mixture at room temperature stirred 15 minutes, mixture is cooled to 5 ℃, is added dropwise to piperidines (4.82ml), with mixture heating up to room temperature 1 hour, mixture distributes between ethyl acetate and 2N hydrochloric acid, water and salt water washing organic phase, dry (sal epsom) and evaporation, resistates column chromatography purifying, with 9: 1 ethyl acetate and methanol mixture as eluent, thereby obtain N ²-benzyloxycarbonyl-DL-glutamine piperidines (4.78g), m.p.136-138 ℃.

Use relates to the similar approach of describing in second and third and four sections of embodiment 1 part of starting raw material preparation, and DL-glutamine piperidines is converted into 1-[2-amino-4-(tert-butoxycarbonyl amino) butyryl radicals] piperidines, productive rate 14%.

With 1; 1 '-carbonyl dimidazoles (0.31g) joins in DMF (5ml) solution of N-(the 2-naphthyl alkylsulfonyl) L-glutamic acid (0.446g) that is stirring; mixture at room temperature stirred 30 minutes; mixture is cooled to 5 ℃; add 1-[2-amino-4 (tert-butoxycarbonyl amino) butyryl radicals] piperidines (0.546g); mixture at room temperature stirred 6 hours; mixture distributes between ethyl acetate and 1M aqueous citric acid solution; water and salt water washing organic phase; dry (sal epsom) and evaporation; resistates column chromatography purifying; with the mixture of 1: 1 methylene dichloride and ethyl acetate as eluent, thereby obtain N-[3-(tert-butoxycarbonyl amino)-1-(piperidino-(1-position only) carbonyl) propyl group]-2-(2-naphthalene sulfonyl amino) ethanamide (0.607g).

The product of gained is suspended in the ethyl acetate (50ml), cool off in the mixture ice bath, hydrogen chloride gas was imported in the mixture 5 minutes, obtain settled solution, then deposit precipitation, evaporating mixture obtains N-[3-amino-1-(piperidino-(1-position only) carbonyl) propyl group]-2-(2-naphthalene sulfonyl amino) acetamide hydrochloride (0.528g), need not to be further purified then and can use.Embodiment 17

N-(3-dimethylaminopropyl)-N '-ethyl-carbodiimide hydrochloride (0.575g) is joined (3S)-3-(2-naphthalene sulfonyl amino)-3-(piperidino-(1-position only) carbonyl) propionic acid (1.17g) that is stirring, N-hydroxybenzotriazole (0.405g), in the mixture of triethylamine (0.417ml) and DMF (10ml), mixture at room temperature stirred 30 minutes, add 1-(4-pyridyl) piperazine (0.489g), mixture at room temperature stirred 16 hours, mixture distributes between ethyl acetate and water, water and salt water washing organic phase, dry (sal epsom) and evaporation, resistates column chromatography purifying, with increasing polar methylene dichloride and methanol mixture, thereby obtain solid 1-[(3S as eluent)-3-(2-naphthalene sulfonyl amino)-3-(piperidino-(1-position only) carbonyl)-propionyl]-4-(4-pyridyl) piperazine (0.407g); Nuclear-magnetism spectrum (CDCl ₃) 0.8-1.1 (m, 2H), 1.2-1.5 (m, 4H), 2.5-2.8 (m, 2H), and 3.0-3.2 (m, 1H), 3.2-3.45 (m, 7H), 3.5-3.7 (m, 3H), 3.75-3.9 (m, 1H), 4.6-4.7 (m, 1H), 6.2-6.4 (m, 1H), 6.6-6.65 (m, 2H), 7.5-8.0 (m, 6H), 8.3-8.4 (m, 2H), 8.43 (m, 1H); Ultimate analysis: C ₂₈H ₃₃N ₅O ₄S0.3CH ₂Cl ₂Measured value: C, 60.0; H, 6.0; N, 12.3; Calculated value: C, 60.4; H, 6.0; N, 12.4%.

(3S)-3-(2-naphthalene sulfonyl amino)-3-(piperidino-(1-position only) carbonyl) propionic acid as starting raw material is prepared as follows:

With N ²-(tert-butoxycarbonyl)-L-aspartic acid O ⁴-benzyl ester (16.2g) join in batches stirring 1,1 '-DMF (100ml) mixture of carbonyl dimidazoles (8.1g) in, the mixture of gained at room temperature stirred 30 minutes, mixture cools off in ice bath, is added dropwise to piperidines (6ml).Mixture stirs and was heated to room temperature 3 hours, and mixture distributes between ethyl acetate and 2N aqueous hydrochloric acid, washes organic phase with water, dry (sal epsom) and evaporation, and resistates column chromatography purifying is used ethyl acetate as eluent, thereby is obtained N ²-(tert-butoxycarbonyl)-L-L-glutamic acid 1-piperidines O ⁴-benzyl ester (17.9g).

A part (4.5g) product of gained is dissolved in the ethyl acetate (75ml), and solution cools off in ice bath, and hydrogenchloride was imported solution 20 minutes, and evaporating mixture obtains L-aspartic acid 1-piperidines O ⁴-benzyl ester hydrochloride (3.6g); Nuclear-magnetism spectrum (CDCl ₃) 1.3-1.8 (m, 6H), 3.05-3.3 (m, 2H), 3.4-3.6 (m, 4H), 4.9-5.0 (m, 1H), 5.15 (s, 2H), 7.3-7.4 (m, 5H), 8.5-8.8 (m, 3H).

The similar approach of using embodiment 2 to describe with a part of product (2.63g) and 2-naphthalic sulfonic chloride (2g) reaction of gained, thereby obtains buttery (3S)-3-(2-naphthalene sulfonyl amino)-3-(piperidino-(1-position only) carbonyl) benzyl propionate (2.96g, 82%).

Product with gained, the mixture of 10% Pd/carbon catalyst (0.2g) and ethanol (25ml) stirred 6 hours under nitrogen atmosphere, filtering mixt, evaporated filtrate, thereby obtain foamed (3S)-3-(2-naphthalene sulfonyl amino)-3-(piperidino-(1-position only) carbonyl) propionic acid (2.2g, 86%); Nuclear-magnetism spectrum (CDCl ₃) 0.8-1.1 (m, 1H), 1.1-1.5 (m, 5H), 2.4-2.7 (m, 2H), 3.0-3.4 (m, 4H), 4.7 (t, 1H), 5.3-5.7 (m, 2H), 7.5-7.7 (m, 2H), 7.75-8.0 (m, 4H), 8.45 (s, 1H). embodiment 18

With 1,1 '-carbonyl dimidazoles (0.307g) joins (3S)-3-[2-(2-naphthalene sulfonyl amino) kharophen]-DMF (10ml) solution of 3-(piperidino-(1-position only) carbonyl) propionic acid (0.85g) in, mixture at room temperature stirred 30 minutes, add 1-(4-pyridyl) piperazine (0.309g), mixture at room temperature stirred 16 hours, mixture distributes between ethyl acetate and water, water and salt water washing organic phase, dry (sal epsom) and evaporation, resistates column chromatography purifying, with increasing polar methylene dichloride and methanol mixture as eluent, the product of gained acetonitrile recrystallization, thereby obtain 2-(2-naphthalene sulfonyl amino)-N-{ (1S)-1-(piperidino-(1-position only) carbonyl)-2-[4-(4-pyridyl) piperazine-1-base carbonyl] ethyl) ethanamide (0.201g, 17%), m.p.201-203 ℃; Nuclear-magnetism spectrum (CDCl ₃+ CD ₃CO ₂D) 1.2-1.6 (m, 6H), 2.1-2.3 (m, 1H), 2.7-2.9 (m, 1H), 3.1-4.8 (m, 14H), 4.9-5.0 (m, 1H), 7.0 (d, 2H), 7.6-7.75 (m, 2H), 7.8-7.85 (m, 1H), 7.9-8.15 (m, 3H), 8.2-8.3 (m, 2H), 8.4 (s, 1H): ultimate analysis: C ₃₀H ₃₆N ₆O ₅S0.5H ₂O measured value: C, 59.9; H, 6.2; N, 14.1; Calculated value: C, 59.9; H, 6.2; N, 14.0%.

As (3S)-3-[2-(2-naphthalene sulfonyl amino) kharophen of starting raw material]-3-(piperidino-(1-position only) carbonyl) propionic acid is prepared as follows:

With 1,1 '-carbonyl dimidazoles (0.81g) joins in the mixture of N-(the 2-naphthyl alkylsulfonyl) glycine (1.33g) that stirring and DMF (10ml), and mixture at room temperature stirred 30 minutes, added L-aspartic acid 1-piperidines O successively ⁴-benzyl ester hydrochloride (1.63g) and triethylamine (0.87ml), mixture at room temperature stirred 16 hours, mixture distributes between ethyl acetate and water, water and salt water washing organic phase, dry (sal epsom) and evaporation, resistates column chromatography purifying, with the mixture of 3: 2 methylene dichloride and ethyl acetate as eluent, thereby obtain foamed (3S)-3-[2-(2-naphthalene sulfonyl amino) kharophen]-3-(piperidino-(1-position only) carbonyl) propionic acid benzyl ester (1.59g).

A part of product (1.44g) with gained, the mixture of 10% Pd/carbon catalyst (0.2g) and ethanol (30ml) stirred 6 hours under nitrogen atmosphere, filtering mixt, evaporated filtrate, resistates column chromatography purifying, with ethyl acetate as eluent, thereby obtain buttery (3S)-3-[2-(2-naphthalene sulfonyl amino) kharophen]-3-(piperidino-(1-position only) carbonyl) propionic acid (0.858g); Nuclear-magnetism spectrum (CDCl ₃) 1.4-1.7 (m, 6H), 2.4-2.8 (m, 2H), 3.4-3.6 (m, 4H), 3.6-3.8 (m, 2H), 5.1-5.35 (m, 1H), 6.5-6.6 (m, 2H), 7.5-7.7 (m, 2H), 7.8-8.0 (m, 5H), 8.4 (s, 1H). embodiment 19

The similar approach of using embodiment 1 to describe, make 1-(4-pyridyl) piperidines-4-carbonyl chlorine and 1-[3-amino-2-(benzyloxycarbonyl amino) propionyl] piperidines reaction obtains N-[2-(benzyloxycarbonyl amino)-2-(piperidino-(1-position only) carbonyl) ethyl]-1-(4-pyridyl) piperidines-4-methane amide, productive rate 44%; Nuclear-magnetism spectrum 1.5-2.0 (m, 10H), 2.2-2.4 (m, 1H), 2.8-3.0 (m, 2H), and 3.2-3.35 (m, 1H), 3.4-3.7 (m, 5H), 3.8-3.95 (m, 2H), 4.7-4.8 (m, 1H), 5.2 (s, 2H), 6.0-6.2 (m, 1H), 6.2-6.4 (m, 1H), 6.6-6.7 (m, 2H), 7.3-7.4 (m, 5H), 8.2-8.3 (m, 2H); Ultimate analysis: C ₂₇H ₃₄N ₅O ₄SH ₂O measured value: C, 63.1; H, 7.4; N, 13.3; Calculated value: C, 63.4; H, 7.2; N, 13.7%.Embodiment 20

With 3-(2-naphthalene sulfonyl amino) propionic acid [by making 2-naphthalene sulfonyl base chlorine and 3-alanine prepared in reaction; 0.163g], N-hydroxy-succinamide (0.067g), the mixture of N-(3-dimethylaminopropyl)-N '-ethyl carbodiimide (0.112g) and DMF (10ml) at room temperature stirred 30 minutes, add N-[2-amino-2-(piperidino-(1-position only) carbonyl) ethyl]-DMF (2ml) solution of 1-(4-pyridyl) piperidines-4-methane amide (0.21g), mixture at room temperature stirred 16 hours, evaporating mixture, resistates distributes between methylene dichloride and water, with 2N aqueous sodium hydroxide solution and water washing organic phase, dry (sal epsom) and evaporation, resistates column chromatography purifying, with increasing polar ethyl acetate and methanol mixture as eluent, thereby obtain 3-(2-naphthalene sulfonyl amino)-N-{1-(piperidino-(1-position only) carbonyl)-2-[1-(4-pyridyl) piperidin-4-yl carbonylamino] ethyl } propionic acid amide (0.14g), m.p.201-203 ℃; Nuclear-magnetism spectrum (CD ₃SOCD ₃) 1.2-1.6 (m, 10H), 2.1-2.3 (m, 3H), 2.6-2.8 (m, 2H), 2.9 (t, 2H), 3.0-3.1 (m, 1H), 3.3-3.5 (m, 3H), 3.7-3.9 (m, 2H), 4.7-4.8 (m, 1H), 6.6-6.7 (m, 2H), 7.5-7.7 (m, 3H), 7.7-7.8 (m, 2H), 7.9-8.2 (m, 6H), 8.35 (m, 1H); Ultimate analysis: C ₃₂H ₄₀N ₆O ₅S0.5EtAc measured value: C, 61.2; H, 6.4; N, 12.8; Calculated value: C, 61.4; H, 6.6; N, 12.7%.

As N-[2-amino-2-(piperidino-(1-position only) carbonyl) ethyl of starting raw material]-1-(4-pyridyl) piperidines-4-methane amide is prepared as follows:

With N-[2-(benzyloxycarbonyl amino)-2-(piperidino-(1-position only) carbonyl) ethyl]-1-(4-pyridyl) piperidines-4-methane amide (1.37g), 10% Pd/carbon catalyst (0.2g) and alcoholic acid mixture stirred 1 hour under nitrogen atmosphere, filtering mixt, evaporated filtrate, thereby obtain required starting raw material, productive rate 91%.Embodiment 21

Use embodiment 2 described similar approach, make N-[2-amino-2-(piperidino-(1-position only) carbonyl) ethyl]-1-(4-pyridyl) piperidines-4-methane amide and naphthalene-2-carbonyl chlorine reaction obtains N-{1-(piperidino-(1-position only) carbonyl)-2-[1-(4-pyridyl) piperidin-4-yl carbonylamino] ethyl } naphthalene-2-methane amide, productive rate 85%; Nuclear-magnetism spectrum (CDCl ₃) 1.5-2.1 (m, 10H), 2.3-2.4 (m, 1H), 2.8-3.0 (m, 2H), 3.4-4.0 (m, 8H), 5.15-5.25 (m, 1H), 6.6 (m, 1H), 6.85 (m, 1H), 7.5-7.7 (m, 2H), 7.8-8.0 (m, 5H), 8.2 (d, 2H), 8.35 (s, 1H); Ultimate analysis: C ₃₀H ₃₅N ₅O ₃H ₂O measured value: C, 67.6; H, 7.0; N, 13.0; Calculated value: C, 67.8; H, 7.0; N, 13.1%.Embodiment 22

Methylene dichloride (5ml) drips of solution of isocyanic acid 4-tolyl ester (0.133g) is added N-[2-amino-2-(piperidino-(1-position only) carbonyl) ethyl that is stirring]-methylene dichloride (10ml) solution of 1-(4-pyridyl) piperidines-4-methane amide (0.359g) in, mixture at room temperature stirred 2 hours, isolate precipitation, use the column chromatography purifying, with 9: 1 methylene dichloride and methyl alcohol as eluent, thereby obtain N-{2-piperidino-(1-position only) carbonyl-2-[3-(4-tolyl) urea groups] ethyl }-1-(4-pyridyl) piperidines-4-methane amide (0.13g), m.p.252-253 ℃; Nuclear-magnetism spectrum (CD ₃SOCD ₃) 1.4-1.8 (m, 10H), 2.2 (s, 3H), 2.25 (m, 1H), 2.7-2.9 (m, 2H), 3.05-3.25 (m, 2H), 3.35-3.5 (m, 2H), 3.5-3.6 (m, 2H), 3.75-4.0 (m, 2H), 4.8-5.0 (m, 1H), 6.3 (d, 1H), 6.7 (m, 2H), 7.0 (d, 2H), 7.25 (d, 2H), 7.95 (m, 1H), 8.05-8.15 (m, 1H), 8.7 (s, 1H); Ultimate analysis: C ₂₇H ₃₆N ₆O ₃Measured value: C, 65.8; H, 7.4; N, 16.9; Calculated value: C, 65.8; H, 7.4; N, 17.1%.Embodiment 23

Use embodiment 2 described similar approach, make 2-amino-N-{1-piperidino-(1-position only) carbonyl-2-[1-(4-pyridyl) piperidin-4-yl carbonylamino] ethyl } reaction of acetamide hydrochloride and 4-tosyl group chlorine obtains foamed N-{1-piperidino-(1-position only) carbonyl-2-[1-(4-pyridyl) piperidin-4-yl carbonylamino] ethyl }-2-(4-tolylsulfonyl amino) ethanamide, productive rate 50%; Nuclear-magnetism spectrum (CD ₃SOCD ₃) 1.3-1.8 (m, 10H), 2.2-2.4 (m, 4H), 2.7-2.9 (m, 2H), 3.0-3.2 (m, 1H), 3.3-3.6 (m, 12H), 3.8-4.0 (m, 2H), 4.8-4.95 (m, 1H), 6.7-6.8 (m, 2H), 7.35 (d, 2H), 7.6-7.7 (m, 2H), 8.05-8.2 (m, 2H), 8.25 (d, 2H).

As 2-amino-N-{1-piperidino-(1-position only) carbonyl-2-[1-(4-pyridyl) piperidin-4-yl carbonylamino of starting raw material] ethyl } acetamide hydrochloride is prepared as follows:

2-(tert-butoxycarbonyl amino) acetate N-hydroxy-succinamide ester [is obtained by make acid and N-hydroxy-succinamide reaction in the presence of dicyclohexyl carbodiimide, 0.272g] join N-[2-amino-2-(piperidino-(1-position only) carbonyl) ethyl that is stirring]-methylene dichloride (5ml) solution of 1-(4-pyridyl) piperidines-4-methane amide (0.359g) in, mixture at room temperature stirred 16 hours, mixture distributes between methylene dichloride and 2N aqueous sodium hydroxide solution, organic phase washes with water, dry (sal epsom) and evaporation, the product of gained is suspended in the methylene dichloride (25ml), hydrogen chloride gas imported solution 5 minutes, obtain clear soln, then deposit precipitation, evaporating mixture obtains required starting raw material.Embodiment 24

With 1; 1 '-carbonyl dimidazoles (0.11g) joins in DMF (2ml) solution (being cooled to 5 ℃) of 2-(the 2-naphthalene sulfonyl amino) acetate (0.182g) that is stirring; mixture stirred 30 minutes down at 5 ℃; add 1-{4-amino-4-(piperidino-(1-position only) carbonyl) butyryl radicals]-DMF (3ml) solution of 4-(4-pyridyl) piperazine (0.247g); mixture at room temperature stirred 16 hours; mixture distributes between ethyl acetate and water; wash organic phase with water; dry (sal epsom) and evaporation; resistates column chromatography purifying; ethyl acetate with 95: 5: 0.5; methyl alcohol and ammonium hydroxide aqueous solution be as eluent, thereby obtain 2-(2-naphthalene sulfonyl amino)-N-{1-piperidino-(1-position only) carbonyl-3-[4-(4-pyridyl) piperazine-1-base carbonyl] propyl group } ethanamide (0.14g).Nuclear-magnetism spectrum (CD ₃SOCD ₃) 1.4-1.7 (m, 7H), 1.8-1.95 (m, 1H), 2.1-2.4 (m, 2H), 3.2-3.6 (m, 14H), 4.65-5.75 (m, 1H), 6.8 (d, 2H), 7.6-7.75 (m, 2H), 7.8-7.9 (m, 1H), 7.9-8.2 (m, 7H), 8.45 (s, 1H).

1-[4-amino-4-(piperidino-(1-position only) carbonyl) butyryl radicals as starting raw material]-4-(4-pyridyl) piperazine is prepared as follows:

Methylene dichloride (5m1) drips of solution of piperidines (0.85g) is joined N ²-benzyloxycarbonyl-DL-L-glutamic acid acid anhydride [J.Chem.Soc., 1950,1954; 2.63g] methylene dichloride (20ml) solution (being cooled to 0 ℃) in, mixture stirred 1 hour down at 0 ℃, use the ethyl acetate extraction mixture, extraction liquid washes with water by adding the concentrated hydrochloric acid acidifying, dry (sal epsom) and evaporate.Resistates column chromatography purifying, using increases polar ethyl acetate, acetate and methanol mixture as eluent (99: 1: 0 to 99: 1: 5), thereby obtains N ²-carbobenzoxy-(Cbz)-DL-L-glutamic acid C ¹-piperidines (0.78g), m.p.92-93 ℃.

A part of product (0.7g) of gained is dissolved among the DMF (10ml); in ice bath, cool off; add 1; 1 '-carbonyl dimidazoles (0.325g); mixture stirred 30 minutes down at 5 ℃; DMF (2ml) solution that adds 1-(4-pyridyl) piperazine (0.327g); mixture at room temperature stirred 3 hours; mixture distributes between ethyl acetate and water; organic phase washes with water; dry (sal epsom) and evaporation, thereby obtain 1-[4-(benzyloxycarbonyl amino)-4-(piperidino-(1-position only) carbonyl)-butyryl radicals]-4-(4-pyridyl) piperazine (0.55g).

A part of product (0.4g) with gained, 10% Pd/carbon catalyst (0.1g) and ethanol (20ml) stirred 6 hours under nitrogen atmosphere, filtering mixt, evaporated filtrate, thereby obtain 1-[4-amino-4-(piperidino-(1-position only) carbonyl) butyryl radicals]-4-(4-pyridyl) piperazine (0.26g); Nuclear-magnetism spectrum (CDCl ₃+ CD ₃SOCD ₃) 1.4-1.7 (m, 6H), 1.9-2.1 (m, 1H), 2.3-2.6 (m, 2H), 2.7-2.8 (m, 1H), 3.2-3.8 (m, 12H), 6.65 (d, 2H), 8.3 (d, 2H). embodiment 25

The similar approach of using embodiment 1 to describe, make 2-[4-(4-pyridyl) piperazine-1-yl] Acetyl Chloride 98Min. and N-(3-aminopropyl) naphthalene-2-sulfuryl amine reaction obtain N-[3-(2-naphthalene sulfonyl amino) propyl group]-2-[4-(4-pyridyl) piperazine-1-yl] ethanamide, productive rate 34%; Nuclear-magnetism spectrum (CD ₃SOCD ₃) 1.5-1.7 (m, 2H), 2.75-2.9 (t, 2H), 2.9-3.0 (s, 2H), 3.1-3.25 (t, 2H), 3.4-3.6 (m, 8H), 7.6-7.9 (m, 6H), 8.0-8.2 (m, 4H), 8.4 (s, 1H), 8.7-8.8 (d, 2H); Ultimate analysis: C ₂₄H ₂₉N ₅O ₃S measured value: C, 61.6; H, 6.25; N, 15.0; Calculated value: C, 61.2; H, 6.2; N, 14.8%.

N-(3-aminopropyl) naphthalene-2-sulphonamide as starting raw material can be by making 2-naphthyl alkylsulfonyl chlorine (2g) and 1, and methylene dichloride (25ml) solution of 3-diaminopropanes (2.95ml) at room temperature reacts and made in 16 hours.Embodiment 26

The similar approach of using embodiment 1 to describe makes 1-(4-pyridyl) piperidines-4-carbonyl chlorine and N-(piperidin-4-yl) naphthalene-2-sulfonamide hydrochloride reaction obtain 4-(2-naphthalene sulfonyl amino)-1-[1-(4-pyridyl) piperidin-4-yl carbonyl] piperidines, productive rate 28%; Nuclear-magnetism spectrum (CD ₃SOCD ₃) 1.1-1.4 (m, 2H), 1.5-1.8 (m, 6H), 2.6-2.8 (m, 1H), 2.85-3.3 (m, 6H), 3.7-3.9 (m, 1H), 4.0-4.2 (m, 4H), 6.9-7.1 (d, 2H), 7.5-7.7 (m, 2H), 7.8-8.1 (m, 6H), 8.4 (s, 1H); Ultimate analysis: C ₂₆H ₃₀N ₄O ₃S0.5H ₂O measured value: C, 62.7; H, 6.5; N, 11.0; Calculated value: C, 64.1; H, 6.3; N, 11.4%.

N-(piperidin-4-yl) naphthalene-2-sulfonamide hydrochloride as starting raw material is prepared as follows:

With 4-amino-1-benzyl piepridine (1.8ml); 2-naphthyl alkylsulfonyl chlorine (2g); the mixture of triethylamine (3.7ml) and methylene dichloride (25ml) at room temperature stirred 16 hours; mixture distributes between ethyl acetate and water; wash organic phase with water, dry (sal epsom) and evaporation, resistates column chromatography purifying; with increasing polar ethyl acetate and methanol mixture, thereby obtain N-(1-benzyl piepridine-4-yl) naphthalene-2-sulphonamide (2.98g) as eluent.

The a part of product (0.5g) of gained and the mixture of methylene dichloride (20ml) are cooled off in ice bath, add chloroformic acid 1-chloro-ethyl ester (0.2ml), mixture at room temperature stirs and spends the night, evaporating mixture is dissolved in resistates in the methyl alcohol (5ml) vlil 3 hours, evaporating mixture, resistates column chromatography purifying is used increase polar ethyl acetate and methanol mixture as eluent, thereby is obtained N-(piperidin-4-yl) naphthalene-2-sulfonamide hydrochloride (0.2g).Nuclear-magnetism spectrum (CD ₃SOCD ₃) 1.5-1.8 (m, 4H), 2.75-2.9 (m, 2H), 3.05-3.2 (m, 2H), 3.25-3.4 (m, 1H), 7.6-7.7 (m, 2H), 7.8-7.9 (m, 1H), 7.9-8.15 (m, 3H), 8.4 (s, 1H). embodiment 27

Use embodiment 2 described similar approach, make 3-amino-1-[1-(4-pyridyl) piperidin-4-yl carbonyl] reaction of pyrrolidine hydrochloride and 2-naphthyl alkylsulfonyl chlorine obtains 3-(2-naphthalene sulfonyl amino)-1-[1-(4-pyridyl) piperidin-4-yl carbonyl] tetramethyleneimine, productive rate 37%; Nuclear-magnetism spectrum (CD ₃SOCD ₃+ CD ₃CO ₂D) 1.5-2.0 (m, 6H), 2.75-2.9 (m, 1H), 3.1-4.0 (m, 7H), 4.0-4.3 (m, 2H), 7.0-7.1 (m, 2H), 7.6-7.7 (m, 2H), 7.9-8.0 (m, 1H), 8.0-8.2 (m, 5H), 8.5 (d, 1H); Ultimate analysis: C ₂₅H ₂₈N ₄SO ₃₂H ₂O0.5CH ₂Cl ₂Measured value: C, 56.8; H, 5.5; N, 10.3; Calculated value: C, 56.4; H, 6.1; N, 10.3%.

As 3-amino-1-[1-(4-pyridyl) piperidin-4-yl carbonyl of starting raw material] pyrrolidine hydrochloride is prepared as follows:

Use embodiment 1 described similar approach, make the reaction of 1-(4-pyridyl) piperidines-4-carbonyl chlorine and 3-(tert-butoxycarbonyl amino) tetramethyleneimine obtain 3-(t-butoxycarbonyl amino)-1-[1-(4-pyridyl) piperidin-4-yl carbonyl] tetramethyleneimine, productive rate 41%.

Use relates to the disclosed similar approach of final stage of embodiment 1 part of starting raw material preparation, handles the product of gained with hydrogen chloride gas, thus quantitative yield obtain 3-amino-1-[1-(4-pyridyl) piperidin-4-yl carbonyl] pyrrolidine hydrochloride; Nuclear-magnetism spectrum (CD ₃SOCD ₃) 1.5-1.8 (m, 2H), 1.75-2.4 (m, 4H), 2.8-3.0 (m, 1H), 3.25-4.0 (m, 7H), 4.2-4.4 (d, 2H), 7.7 (d, 2H), 8.1-8.3 (d, 2H), 8.5-8.7 (m, 2H). embodiment 28

Repeat embodiment 2 described methods, only be to use 8-chloronaphthalene-2-base alkylsulfonyl chloro, thereby obtain 1-(8-chloronaphthalene-2-base alkylsulfonyl)-4-[1-(4-pyridyl) piperidin-4-yl carbonyl for 2-naphthyl alkylsulfonyl chlorine] piperazine, productive rate 74%; Nuclear-magnetism spectrum (CD ₃SOCD ₃+ CD ₃CO ₂D) 1.35-1.7 (m, 4H), 2.85-3.15 (m, 7H), 3.5-3.7 (m, 4H), 3.95-4.1 (m, 2H), 7.0 (d, 2H), 7.75 (t, 1H), 7.85-7.95 (m, 2H), 8.1-8.2 (m, 3H), 8.3 (d, 1H), 8.55 (s, 1H); Ultimate analysis: C ₂₅H ₂₇ClN ₄O ₃S0.5H ₂O measured value: C, 59.4; H, 5.5; N, 10.9; Calculated value: C, 59.1; H, 5.5; N, 11.0%.Embodiment 29

Use embodiment 2 described similar approach, make 2-naphthyl alkylsulfonyl chlorine and 3-ethoxycarbonyl-1-[1-(4-pyridyl) piperidin-4-yl carbonyl] piperazine reaction obtains 2-ethoxycarbonyl-1-(2-naphthyl alkylsulfonyl)-4-[1-(4-pyridyl) piperidin-4-yl carbonyl] piperazine, productive rate 31%; Nuclear-magnetism spectrum (CD ₃SOCD ₃, 100 ℃) 1.05 (t, 3H), 1.5-1.8 (m, 4H), 2.9-3.25 (m, 5H), 3.35-3.5 (m, 2H), 3.7-4.15 (m, 7H), 5.5-5.7 (m, 2H), 6.75-6.95 (m, 2H), 7.6-7.85 (m, 3H), 8.0-8.15 (m, 5H), 8.45 (d, 1H); Ultimate analysis: C ₂₈H ₃₂N ₄O ₅SH ₂O measured value: C, 60.4; H, 6.1; N, 10.1; Calculated value: C, 60.6; H, 6.1; N, 10.1%.

As 3-ethoxycarbonyl-1-[1-(4-pyridyl) piperidin-4-yl carbonyl of starting raw material] piperazine is prepared as follows:

Use embodiment 1 described similar approach, make 1-(4-pyridyl) piperidines-4-carbonyl chlorine and 1-benzyl diethylenediamine-2-carboxylic acid, ethyl ester (Helv.Chim Acta, 1962,45,2383) reaction obtains 1-benzyl-2-ethoxycarbonyl-4-[1-(4-pyridyl) piperidin-4-yl carbonyl] piperazine, 67%.

Product (0.667g) with gained, trifluoroacetic acid (2ml), the mixture of 10% Pd/carbon catalyst (0.15g) and methyl alcohol (20ml) stirred 48 hours under 7 hydrogen-pressure, filtering mixt, and evaporation, resistates distributes between methylene dichloride and saturated sodium bicarbonate aqueous solution, wash organic phase with water, dry (sal epsom) and evaporation, resistates is developed with ether, obtains the required starting raw material of quantitative yield; Nuclear-magnetism spectrum (CD ₃SOCD ₃) 1.2-1.4 (m, 3H), 1.8-2.0 (m, 4H), 2.7-3.55 (m, 8H), 3.6-3.85 (m, 2H), 3.9-4.05 (m, 2H), 4.15-4.3 (m, 2H), 6.75 (d, 2H), 8.3 (d, 2H). embodiment 30

Use embodiment 1 described similar approach, make 1-(4-pyridyl) piperidines-4-carbonyl villaumite hydrochlorate and N-(2-amino-ethyl)-2-(2-naphthalene sulfonyl amino) acetamide hydrochloride prepared in reaction obtain 2-(2-naphthalene sulfonyl amino)-N-{2-[1-(4-pyridyl) piperidin-4-yl carbonylamino] ethyl } ethanamide, productive rate 49%, m.p.107-109 ℃; Nuclear-magnetism spectrum (CD ₃SOCD ₃) 1.4-1.6 (m, 4H), 2.2-2.4 (m, 1H), 2.7-2.9 (m, 2H), 2.9-3.1 (m, 4H), 3.2-3.4 (m, 2H), 3.6-4.0 (m, 2H), 6.7-6.8 (d, 2H), 7.6-8.2 (m, 11H), 8.4 (s, 1H); Ultimate analysis: C ₂₅H ₂₉N ₅O ₄S0.4H ₂O measured value: C, 59.7; H, 5.9; N, 14.1; Calculated value: C, 59.7; H, 5.9; N, 13.9%.

N-(2-amino-ethyl)-2-(2-naphthalene sulfonyl amino) acetamide hydrochloride as starting raw material is prepared as follows:

With 1; 1 '-carbonyl dimidazoles (1.62g) joins in DMF (20ml) solution of N-(the 2-naphthyl alkylsulfonyl) glycine (2.65g) that is stirring; mixture at room temperature stirred 20 minutes; mixture is cooled to 5 ℃; DMF (5ml) solution that adds 2-(N-t-butoxycarbonyl amino) ethamine (1.6g); mixture at room temperature stirred 2 hours; evaporating mixture; resistates distributes between ethyl acetate and 1M aqueous citric acid solution; organic phase washes with water; dry (sal epsom) and evaporation; resistates column chromatography purifying; with the mixture that increases polar methylene dichloride and ethyl acetate as eluent, thereby obtain N-[2-(t-butoxycarbonyl amino) ethyl]-2-(2-naphthalene sulfonyl amino) ethanamide (2.3g), m.p.150-152 ℃.

A part of product (2g) of gained is suspended in the ethyl acetate, and mixture is cooled to 5 ℃, and hydrogen chloride gas was imported in the mixture 10 minutes, obtain clear soln, then deposit precipitation, isolate solid, with ether washing and dry, thereby obtain required starting raw material (1.37g); Nuclear-magnetism spectrum (CD ₃SOCD ₃) 2.7-2.9 (m, 2H), 3.15-3.3 (m, 2H), 3.4-3.5 (d, 2H), 7.6-7.9 (m, 3H), 7.9-8.3 (m, 8H), 8.45 (d, 1H). embodiment 31

Use embodiment 3 described similar approach, make N-(2-amino-ethyl)-2-(2-naphthalene sulfonyl amino) acetamide hydrochloride, 1, the reaction of 1 '-carbonyl dimidazoles and 1-(4-pyridyl) piperazine obtains 2-(2-naphthalene sulfonyl amino)-N-{2-[4-(4-pyridyl) piperazine-1-base carbonylamino] ethyl } ethanamide, productive rate 10%; Nuclear-magnetism spectrum (CD ₃SOCD ₃+ CD ₃CO ₂D) 3.1-3.2 (m, 4H), 3.4-3.6 (m, 6H), 3.6-3.7 (m, 4H), 7.1 (d, 2H), 7.6-7.75 (m, 2H), 7.8-7.9 (m, 1H), 8.0-8.05 (m, 1H), 8.1-8.2 (m, 4H), 8.4 (s, 1H); Ultimate analysis: C ₂₄H ₂₈N ₆O ₄S0.5H ₂O0.5EtAc measured value: C, 56.4; H, 5.9; N, 15.5; Calculated value: C, 56.8; H, 6.0; N, 15.3%.Embodiment 32

Triethylamine (0.686ml) is joined the 4-chloropyrimide hydrochloride (0.151g) that is stirring, 2-(2-naphthalene sulfonyl amino)-N-[2-(piperidin-4-yl carbonylamino) ethyl] in the solution of acetamide hydrochloride (0.453g) and ethanol (10ml), mixture at room temperature stirred 4 days, mixture distributes between ethyl acetate and water, wash organic phase with water, dry (sal epsom) and evaporation, resistates acetonitrile recrystallization, thereby obtain 2-(2-naphthalene sulfonyl amino)-N-{2-[1-(4-pyrimidyl) piperidin-4-yl carbonylamino] ethyl } ethanamide (0.08g), m.p.178-179 ℃; Nuclear-magnetism spectrum (CD ₃SOCD ₃) 1.3-1.6 (m, 2H), 1.65-1.85 (m, 2H), 2.3-2.45 (m, 1H), 2.8-3.05 (m, 6H), 3.4 (d, 2H), 4.3-4.5 (m, 2H), 6.8 (d, 1H), 7.3-7.8 (m, 3H), 7.8-7.95 (m, 2H), 8.0 (m, 2H), 8.1-8.2 (m, 3H), 8.4-8.5 (m, 2H); Ultimate analysis: C ₂₄H ₂₈N ₆O ₄S measured value: C, 57.6; H, 5.7; N, 16.6; Calculated value: C, 58.0; H, 5.7; N, 16.9%.

As 2-(2-naphthalene sulfonyl amino)-N-[2-(piperidin-4-yl carbonylamino) ethyl of starting raw material] ethanamide is prepared as follows:

N-hydroxybenzotriazole (0.135g) and N-(3-dimethylaminopropyl)-N '-ethyl carbodiimide (0.191g) are joined successively DMF (10ml) solution (being cooled to 0 ℃) of 1-(tertbutyloxycarbonyl) piperidines-4-carboxylic acid (0.229g) that is stirring, mixture stirred 30 minutes down at 0 ℃, DMF (5ml) solution that adds N-(2-amino-ethyl)-2-(2-naphthalene sulfonyl amino) acetamide hydrochloride (0.343g), then add triethylamine (0.101g), the mixture heating up of gained is to room temperature, stirred 3 hours, mixture distributes between ethyl acetate and water, use the 2N aqueous hydrochloric acid successively, saturated sodium bicarbonate aqueous solution and salt water washing, dry (sal epsom) and evaporation, thereby obtain N-{2-[1-(tert-butoxycarbonyl) piperidin-4-yl carbonylamino] ethyl }-2-(2-naphthalene sulfonyl amino) ethanamide (0.192g), m.p.176-178 ℃.

Use relates to the described similar approach of final stage of embodiment 30 parts of starting raw material preparation and removes tertbutyloxycarbonyl, thereby obtains 2-(2-naphthalene sulfonyl amino)-N-[2-(piperidin-4-yl carbonylamino) ethyl] acetamide hydrochloride, productive rate 96%.Embodiment 33

Repeat embodiment 32 described methods, only be to use 2-amino-4-chloropyrimide hydrochloride to replace 4-chloropyrimide hydrochloride, thereby obtain N-{2-[1-(2-aminopyrimidine-4-yl) piperidin-4-yl carbonylamino] ethyl }-2-(2-naphthalene sulfonyl amino) ethanamide, productive rate 53%, m.p.197-199 ℃; Nuclear-magnetism spectrum (CD ₃SOCD ₃) 1.3-1.55 (m, 2H), 1.6-1.8 (m, 2H), 2.2-2.4 (m, 1H), and 2.7-2.9 (m, 2H), 2.9-3.1 (m, 4H), 3.4 (s, 2H), 4.2-4.4 (m, 2H), 5.9 (s, 2H), 6.0 (d, 1H), 7.6-7.8 (m, 4H), 7.8-7.95 (m, 2H), 7.95-8.2 (m, 4H), 8.45 (s, 1H); Ultimate analysis: C ₂₄H ₂₉N ₇O ₄S measured value: C, 55.9; H, 5.6; N, 19.1; Calculated value: C, 56.3; H, 5.7; N, 19.2%.Embodiment 34

Repeat embodiment 32 described methods, only be to use 2-amino-4-chloro-6-methylpyrimidine hydrochloride to replace 4-chloropyrimide hydrochloride, with reaction mixture be heated to 80 ℃ 16 hours, thereby obtain N-{2-[1-(2-amino-6-methylpyrimidine-4-yl) piperidin-4-yl carbonylamino] ethyl }-2-(2-naphthalene sulfonyl amino) ethanamide, productive rate 38%, m.p.225-226 ℃; Nuclear-magnetism spectrum 1.3-1.5 (m, 2H), 1.6-1.8 (m, 2H), 2.05 (s, 3H), and 2.2-2.4 (m, 1H), 2.7-2.9 (m, 2H), 2.95-3.1 (m, 4H), 3.45 (s, 2H), 4.2-4.4 (m, 2H), 5.8 (s, 2H), 5.9 (s, 1H), 7.6-7.75 (m, 3H), 7.8-8.0 (m, 2H), 8.0-8.2 (m, 4H), 8.45 (s, 1H); Ultimate analysis: C ₂₅H ₃₁N ₇O ₄S measured value: C, 57.1; H, 6.0; N, 18.4; Calculated value: C, 56.9; H, 5.9; N, 18.4%.Embodiment 35

Use embodiment 18 described similar approach, make 4-[2-(2-naphthalene sulfonyl amino) kharophen] reaction of butyric acid and 1-(4-pyridyl) piperazine obtains foamed 2-(2-naphthalene sulfonyl amino)-N-{3-[4-(4-pyridyl) piperazine-1-base carbonyl] propyl group } ethanamide, productive rate 21%; Nuclear-magnetism spectrum (CD ₃SOCD ₃) 1.45-1.65 (m, 2H), 2.3 (t, 2H), 2.9-3.1 (m, 2H), 3.2-3.4 (m, 4H), 3.5-3.65 (m, 4H), 6.8 (m, 2H), 7.6-7.75 (m, 4H), 8.0-8.3 (m, 6H), 8.45 (s, 1H); Ultimate analysis: C ₂₅H ₂₉N ₅O ₄SH ₂O0.5EtAc measured value: C, 57.7; H, 6.1; N, 12.7; Calculated value: C, 58.2; H, 6.3; N, 12.6%.

As 4-[2-(the 2-naphthalene sulfonyl amino) kharophen of starting raw material] butyric acid and 1-(4-pyridyl) piperazine be prepared as follows:

Use relates to first section described similar approach of embodiment 30 parts of starting raw material preparation, makes N-(2-naphthyl alkylsulfonyl) glycine and 4-aminobutyric acid methyl esters obtain 4-[2-(2-naphthalene sulfonyl amino) kharophen) methyl-butyrate, productive rate 56%.

Use embodiment 9 described similar approach, the product of hydrolysis gained, thus obtain required starting raw material, productive rate 79%, m.p.187-189 ℃; Nuclear-magnetism spectrum (CD ₃SOCD ₃+ CD ₃CO ₂D) 1.5-1.7 (m, 2H), 2.15 (t, 2H), 3.0 (t, 2H), 3.5 (s, 2H), 7.6-7.8 (m, 2H), 7.8-7.9 (m, 1H), 7.95-8.2 (m, 3H), 8.5 (s, 1H). embodiment 36

N-(3-dimethylaminopropyl)-N '-ethyl carbodiimide (0.21g) is joined N-(2-naphthyl alkylsulfonyl) glycine (0.265g); in the mixture of 1-(4-pyridyl) piperazine (0.169g) and DMF (10ml) (being cooled to 5 ℃); mixture at room temperature stirred 3 hours; mixture distributes between ethyl acetate and water; organic phase washes with water; dry (sal epsom) and evaporation; resistates column chromatography purifying; with 19: 1 methylene dichloride and methanol mixture as eluent; thereby obtain N-[4-(4-pyridyl) piperazine-1-base carbonyl methyl] naphthalene-2-sulphonamide (0.126g), m.p.182-184 ℃.Nuclear-magnetism spectrum (CD ₃SOCD ₃) 3.1-3.6 (m, 8H), 3.8-3.9 (m, 2H), 6.7-6.8 (m, 2H), 7.6-7.75 (m, 2H), 7.75-7.9 (m, 2H), 8.0-8.2 (m, 5H), 8.45 (s, 1H); Ultimate analysis: C ₂₁H ₂₂N ₄O ₃S measured value: C, 61.0; H, 5.3; N, 13.5; Calculated value: C, 61.4; H, 5.4; N, 13.5%.Embodiment 37

Use embodiment 36 described similar approach, make the reaction of 4-(2-naphthalene sulfonyl amino) butyric acid and 1-(4-pyridyl) piperazine obtain N-{3-[4-(4-pyridyl) piperazine-1-base carbonyl] propyl group } naphthalene-2-sulphonamide, productive rate 15% is foam; Nuclear-magnetism spectrum (CD ₃SOCD ₃) 1.7-1.9 (m, 2H), 2.3-2.4 (t, 2H), 2.95-3.05 (m, 2H), 3.2-3.3 (m, 4H), 3.4-3.5 (m, 2H), 3.6-3.75 (m, 2H), 5.4-5.6 (d, 1H), 6.5-6.6 (m, 2H), 7.5-7.65 (m, 2H), 7.75-8.0 (m, 4H), 8.2-8.3 (m, 2H), 8.35 (s, 1H).

4-(2-naphthalene sulfonyl amino) butyric acid as starting raw material is prepared as follows:

Use embodiment 2 described similar approach, make the reaction of 2-naphthyl alkylsulfonyl chlorine and 4-aminobutyric acid methyl esters obtain 4-(2-naphthalene sulfonyl amino) methyl-butyrate, productive rate 94%.

Use embodiment 9 described similar approach, the product of hydrolysis gained, thus obtain required starting raw material, productive rate 88%, m.p.123-125 ℃; Nuclear-magnetism spectrum (CDCl ₃) 1.7-1.9 (m, 2H), 2.35 (t, 2H), 2.9-3.1 (m, 2H), 6.3-6.5 (m, 1H), 7.5-7.7 (m, 2H), 7.8-8.1 (m, 4H), 8.4 (s, 1H). embodiment 38

With 5-(2-pyridyl) thiophene-2-base alkylsulfonyl chlorine [Chem.Abs., 1983,98,215349; 0.162g] methylene dichloride (5ml) solution join 1-[1-(4-pyridyl) the piperidin-4-yl carbonyl that is stirring] piperazine (0.314g), in the mixture of triethylamine (0.9ml) and methylene dichloride (15ml), the mixture of gained at room temperature stirred 18 hours, mixture distributes between methylene dichloride and water, organic phase washes with water, dry (sal epsom) and evaporation, resistates column chromatography purifying, with increasing polar methylene dichloride and methanol mixture as eluent, thereby obtain 1-[1-(4-pyridyl) piperidin-4-yl carbonyl]-4-[5-(2-pyridyl) thiophene-2-base alkylsulfonyl] piperazine (0.231g, 74%); Nuclear-magnetism spectrum (CD ₃SOCD ₃) 1.4-1.7 (m, 4H), 2.8-3.1 (m, 7H), 3.55-3.75 (m, 4H), 3.85-3.95 (m, 2H), 6.8 (d, 2H), 7.35-7.45 (m, 1H), 7.65 (d, 1H), 7.9-8.0 (m, 2H), 8.05-8.15 (m, 3H), 8.55-8.6 (m, 1H); Ultimate analysis: C ₂₄H ₂₇N ₅O ₃S ₂0.25H ₂O measured value: C, 57.2; H, 5.5; N, 13.9; Calculated value: C, 57.4; H, 5.5; N, 14.0%.Embodiment 39

Use embodiment 2 described similar approach, make 1-[1-(4-pyridyl) piperidin-4-yl carbonyl] piperazine and suitable (E)-styryl alkylsulfonyl chlorine reaction, thus obtaining (E)-vinylbenzene disclosed in Table I, its structure is proved conclusively with the NMR spectrum.Except as otherwise noted, use the described similar approach of note b of Table I down, prepare suitable (E)-vinylbenzene SULPHURYL CHLORIDE by corresponding vinylbenzene.

Table I

Embodiment 39 compounds	????R	????m.p.(℃)	Productive rate (%)
Embodiment 39 compounds	????R	????m.p.(℃)	Productive rate (%)	????1 ^a????2 ^b????3 ^c????4 ^d????5 ^e????6 ^f????7 ^g????8 ^h????9 ^I????10 ^j	Hydrogen 4-chlorine 4-methyl 4-methyl 4-fluorine 2-chlorine 3-chlorine 3,4-dichloro-4,4-bromine 4-trifluoromethyl	Glue 172-173 223-226 148-149 125-126 froth foam froth foam foam	????27 ????32 ????42 ????37 ????55 ????39 ????49 ????33 ????54 ????30

Explain: a. product obtains following NMR signal (CD ₃SOCD ₃) (m, 4H), (m, 7H), (m, 4H), 4.12 (m, 2H), 7.05 (d, 2H), 7.38 (m, 5H), 7.75 (m, 2H), 8.2 (d, 2H) the .b. product obtains following NMR signal (CD to 3.5-3.75 to 2.95-3.25 to 1.45-1.8 ₃SOCD ₃) 1.4-1.65 (m, 4H), 2.8-3.0 (m, 3H), 3.12 (m, 4H), 3.65 (m, 4H), 3.92 (m, 2H), 6.8 (d, 2H), 7.4 (d, 2H), 7.5 (d, 2H), 7.8 (d, 2H), 8.15 (d, 2H).

4-chloro-styrene base SULPHURYL CHLORIDE as starting raw material is prepared as follows:

Alkylsulfonyl chlorine (1.37ml) is added drop-wise among the DMF (1.55ml) that stirs and be cooled under 0-5 ℃, mixture at room temperature stirred 30 minutes, add 4-chloro-styrene (1.2ml), stir the mixture and be heated to 90 ℃ 3.5 hours, mixture is cooled to room temperature, pours into then in the mixture (25ml) of ice and water, isolate formed precipitation, wash with water and drying, thereby obtain 4-hydrogen-β-styryl alkylsulfonyl chlorine (1.8g); Nuclear-magnetism spectrum (CD ₃SOCD ₃) 6.95 (s, 2H), 7.4 (d, 2H), 7.55 (d, 2) c. product provides following NMR signal (CD ₃SOCD ₃) (m, 4H), 2.3 (s, 3H), (m, 7H), 3.6 (m, 4H), 4.07 (m, 2H), 7.0 (m, 3H), 7.25 (m, 3H), 7.5 (d, 2H), 8.05 (d, 2H) the .d. product provides following NMR signal (CD to 2.95-3.3 to 1.4-1.85 ₃SOCD ₃) (m, 4H), 2.4 (s, 3H), (m, 7H), (m, 4H), 3.92 (m, 2H), 6.8 (d, 2H), (m, 4H), 7.68 (m, 2H), 8.15 (d, 2H) the .e. product provides following NMR signal (CD to 7.1-7.4 to 3.55-3.75 to 2.85-3.25 to 1.45-1.75 ₃SOCD ₃) (m, 4H), (m, 3H), (m, 4H), (m, 4H), 3.92 (m, 2H), 6.85 (d, 2H), (m, 4H), 7.85 (m, 2H), 8.15 (d, 2H) .f, product provide following NMR signal (CD to 7.2-7.5 to 3.5-3.75 to 3.05-3.2 to 2.85-3.0 to 1.45-1.75 ₃SOCD ₃) 1.45-1.75 (m, 4H), 2.85-2.95 (m, 3H), 3.05-3.25 (m, 4H), 3.55-3.75 (m, 4H), 3.92 (m, 2H), 6.8 (d, 2H), 7.4-7.7 (m, 5H), 8.0 (m, 1H), 8.1 (d, 2H) the .g. product provides following NMR signal (CD ₃SOCD ₃) 1.45-1.75 (m, 4H), 2.85-3.0 (m, 3H), 3.0-3.2 (m, 4H), 3.55-3.75 (m, 4H), 3.92 (m, 2H), 6.8 (d, 2H), 7.4-7.5 (m, 4H), 7.72 (m, 1H), 7.93 (m, 1H), 8.15 (d, 2H) the .h. product provides following NMR signal (CD ₃SOCD ₃+ CD ₃CO ₂D) (m, 4H), (m, 7H), (m, 4H), 4.15 (m, 2H), 7.1 (d, 2H), 7.4 (d, 2H), 7.7 (m, 2H), 8.1 (s, 1H), 8.15 (d, 2H) the .i. product provides following NMR signal (CD to 3.55-3.75 to 3.0-3.3 to 1.5-1.9 ₃SOCD ₃+ CD ₃CO ₂D) (m, 4H), (m, 7H), (m, 4H), 4.17 (m, 2H), 7.1 (d, 2H), (m, 2H), 7.65 (m, 4H), 8.15 (d, 2H) the .j. product provides following NMR signal (CD to 7.15-7.5 to 3.6-3.75 to 3.0-3.35 to 1.55-1.85 ₃SOCD ₃+ CD ₃CO ₂D) 1.5-1.85 (m, 4H), 3.0-3.3 (m, 7H), 3.55-3.75 (m, 4H), 4.15 (m, 2H), 7.1 (d, 2H), 7.5 (m, 2H), 7.8 (d, 2H), 7.95 (d, 2H), 8.15 (d, 2H). embodiment 40

Use embodiment 2 described similar approach, make 1-[1-(4-pyridyl) piperidin-4-yl carbonyl] piperazine and suitable 2-naphthalene sulfonyl base chlorine reaction, thus obtaining disclosed compound in Table II, its structure is proved conclusively with the NMR spectrum.Except as otherwise noted, use the described similar approach of note c of the following Table III of embodiment 41, prepare suitable naphthalic sulfonic chloride by corresponding naphthalene.

Table II

The compound number of embodiment 40	??????R	?m.p.(℃)	Productive rate (%)
The compound number of embodiment 40	??????R	?m.p.(℃)	Productive rate (%)	????1 ^a????2 ^b????3 ^c????4 ^d????5 ^e????6 ^f????7 ^g????8 ^h????9 ⁱ	4-chlorine 7-chlorine 7-ethyoxyl 6,7-dimethoxy 6-hydrogen 6-bromine 6-methoxyl group 7-methoxyl group 6-fluorine	199-203 glassy mass glassy mass glassy mass 115 (decomposition) 142-145 jelly glassy mass 108-111 (decomposition)	????38 ????18 ????13 ????30 ????82 ????81 ????28 ????29 ????73

Explain: a. product provides following NMR signal (CD ₃SOCD ₃) 1.35-1.65 (m, 4H), 2.75-2.9 (m, 3H), 3.0-3.15 (m, 4H), 3.6 (m, 4H), 3.85 (m, 2H), 6.75 (d, 2H), 7.9 (m, 3H), 8.1 (d, 2H), 8.35 (t, 2H), 8.5 (s, 1H) the .b. product provides following NMR signal (CD ₃SOCD ₃) (m, 4H), (m, 7H), (m, 4H), (m, 2H), 6.75 (d, 2H), 7.78 (m, 2H), 8.15 (m, 4H), 8.45 (d, 1H) the .c. product provides following NMR signal (CD to 3.8-3.9 to 3.5-3.7 to 2.8-3.05 to 1.35-1.65 ₃SOCD ₃) 1.35-1.7 (m, 4H), 1.45 (t, 3H), 2.8-3.05 (m, 7H), 3.3 (m, 2H), 3.5-3.7 (m, 4H), 3.83 (m, 2H), 4.2 (m, 2H), 6.85 (d, 2H), 7.35 (m, 1H), 7.58 (m, 2H), 7.95-8.15 (m, 4H), 8.3 (d, 1H) the .d. product provides following NMR signal (CD ₃SOCD ₃) 1.35-1.65 (m, 4H), 2.75-3.0 (m, 7H), 3.5-3.7 (m, 4H), 3.85 (m, 2H), 3.95 (s, 6H), 6.75 (d, 2H), 7.5 (s, 1H), 7.6 (m, 2H), 7.95 (d, 1H), 8.1 (m, 2H), 8.25 (s, 1H) the .e. product provides following NMR signal (CD ₃SOCD ₃+ CD ₃CO ₂D) 1.45-1.8 (m, 4H), 2.9-3.1 (m, 5H), 3.22 (m, 2H), 3.55-3.75 (m, 4H), 4.1 (m, 2H), 7.05 (d, 2H), 7.65-7.85 (m, 2H), 8.1-8.25 (m, 5H), 8.45 (s, 1H); And the following analytical data:Found C, 58.9; H, 5.3; N, 10.9; C ₂₅H ₂₇ClN ₄O ₃S0.2CH ₂Cl ₂Requires C, 58.7; H, 5.3; N, 10.9%.

6-chloro-2-naphthyl alkylsulfonyl chlorine as starting raw material is prepared as follows:

Water (5ml) solution of Sodium Nitrite (2.7g) was joined 6-amino-2-naphthene sulfonic acid (8.8g), diluted hydrochloric acid aqueous solution (2.8% weight/volume that is stirring in 2 hours, 20ml) and in the mixture of water (15ml) (being cooled to 0 ℃), mixture stirred 30 minutes down at 0 ℃, pour the diluted hydrochloric acid aqueous solution (2.8% of the cuprous chloride (3.96g) that is stirring then into, in suspension 20ml), mixture was at room temperature stored 18 hours, evaporating mixture obtains 6-chloro-2-naphthene sulfonic acid, need not to be further purified then and can use.

Product is suspended among the DMF (40ml), be cooled to 5 ℃, be added dropwise to thionyl chloride (8.6ml), mixture stirred 3 hours down at 5 ℃, and mixture is poured in the ice, used dichloromethane extraction, dry (sal epsom) organic solution and evaporation, resistates column chromatography purifying, with the mixture of 20: 1 hexanes and ethyl acetate as eluent, thereby obtain 6-chloro-2-naphthyl alkylsulfonyl chlorine (2.49g); Nuclear-magnetism spectrum (CD ₃SOCD ₃) 7.45 (m, 1H), 7.8 (m, 1H), 7.85 (d, 1H), 8.05 (m, 2H), 8.2 (s, 1H) the .f. product provides following NMR signal (CD ₃SOCD ₃) 1.35-1.65 (m, 4H), 2.75-3.05 (m, 7H), 3.5-3.7 (m, 4H), 3.87 (m, 2H), 6.8 (d, 2H), 7.85 (m, 2H), 8.05-8.25 (m, 4H), 8.4 (d, 1H), 8.5 (d, 1H).

Use the described similar approach of above-mentioned note e; just replace hydrochloric acid and cuprous chloride respectively with Hydrogen bromide and cuprous bromide; prepare 6-bromo-2-naphthyl alkylsulfonyl chlorine (productive rate 22%) as starting raw material by 6-amino-2-naphthene sulfonic acid, product provides following NMR signal (CD ₃SOCD ₃) 7.65 (m, 1H), 7.75-8.0 (m, 3H), 8.15-8.2 (m, 2H).G. product provides following NMR signal (CD ₃SOCD ₃, 100 ℃)

1.48-1.73(m，4H)，2.75-3.02(m，3H)，3.06-3.11(t，4H)，3.56(t，4H)，

3.76(t，1H)，3.81(t，1H)，3.95(s，3H)，6.7(d，2H)，7.32(m，1H)，

7.44(m，1H)，7.71(m，1H)，8.03(m，2H)，8.12(d，2H)，8.31(d，1H).

6-methoxyl group-2-naphthyl alkylsulfonyl chlorine as starting raw material is prepared as follows:

The mixture of 6-hydroxyl-2-sodium naphthasulfonate (5g) and DMSO (100ml) is joined the sodium hydride that stirring (60% dispersion liquid in mineral oil, in DMSO 1g) (20ml) suspension, mixture at room temperature stirred 30 minutes, and mixture is cooled to 10 ℃, was added dropwise to methyl-iodide (22ml), with mixture heating up to room temperature, stirred 2 hours, mixture is poured in the acetone, isolate precipitation, wash with acetone and ether successively, thereby obtain 6-methoxyl group-2-sodium naphthasulfonate (3.3g).

Sulfinyl chlorine (0.82ml) is joined in DMF (10ml) solution of a part of product (0.96g) of the gained that is stirring; mixture at room temperature stirred 2 hours; mixture is poured in the ice; isolate precipitation; and it is dry; thereby obtain 6-methoxyl group-2-naphthyl alkylsulfonyl chlorine (0.7g), need not to be further purified then and can use.H. product provides following NMR signal (CD ₃SOCD ₃)

1.4-1.65(m，4H)，2.75-3.0(m，7H)，3.5-3.7(m，4H)，3.88(m，2H)，

6.75(d，2H)，7.35-7.65(m，3H)，7.95-8.1(m，4H)，8.35(s，1H).

Use the described similar approach of above-mentioned note g, prepare 7-methoxyl group-2-naphthyl alkylsulfonyl chlorine as starting raw material by 7-hydroxyl-2-sodium naphthasulfonate.I. product provides following NMR signal (CD ₃SOCD ₃+

CD ₃CO ₂D)1.45-1.8(m，4H)，2.9-3.1(m，5H)，3.22(m，2H)，3.55-3.75

(m，4H)，4.12(m，2H)，7.1(d，2H)，7.57(m，1H)，7.75-7.9(m，2H)，

8.15(m，2H)，8.3(m，1H)，8.5(d，1H).

6-fluoro-2-naphthyl alkylsulfonyl chlorine as starting raw material is prepared as follows:

In 10 minutes, 6-amino-2-naphthene sulfonic acid (5.41g) is joined in batches in methylene dichloride (100ml) suspension (being cooled to 5 ℃) of the Tetrafluoroboric acid nitrous (3.12g) that is stirring, mixture stirred 2 hours down at 5 ℃, at room temperature stirred 18 hours, evaporating mixture, in resistates, add 1,2-dichlorobenzene (100ml), stir the mixture and be heated to 150 ℃ 2 hours, mixture is cooled to 5 ℃, add thionyl chloride (3.6ml) and DMF (10ml), mixture at room temperature stirred 18 hours, mixture distributes between methylene dichloride and water, dry (sal epsom) organic phase and evaporation, resistates column chromatography purifying, with the mixture of 9: 1 hexanes and ethyl acetate as eluent, thereby obtain 6-fluoro-2-naphthyl alkylsulfonyl chlorine (1.53g); Nuclear-magnetism spectrum (CD ₃SOCD ₃) 7.4 (m, 1H), 7.65-7.9 (m, 3H), 8.05 (m, 2H).8.2(d，1H)。Embodiment 41

Use embodiment 2 described similar approach, make 1-[1-(4-pyridyl) piperidin-4-yl carbonyl] piperazine and suitable benzenesulfonyl chlorine reaction, thus obtaining disclosed compound in Table III, its structure is proved conclusively with the NMR spectrum.

Table III

The compound number of embodiment 41	????R	?m.p.(℃)	Productive rate (%)
The compound number of embodiment 41	????R	?m.p.(℃)	Productive rate (%)	????1 ^a????2 ^b????3 ^c	4-bromine 4-phenyl 4-(4-chloro-phenyl-	Glassy mass glassy mass glassy mass	????67 ????64 ????61

Explain: a. product provides following NMR signal (CD ₃SOCD ₃) (m, 4H), (m, 7H), (m, 4H), (m, 2H), 6.75 (d, 2H), 7.65 (d, 2H), 7.85 (d, 2H), 8.12 (broad s, 2H) the .b. product provides following NMR signal (CD to 3.8-3.95 to 3.5-3.7 to 2.8-3.0 to 1.4-1.7 ₃SOCD ₃) (m, 4H), (m, 7H), (m, 4H), 3.88 (m, 2H), 6.8 (d, 2H), 7.5 (m, 3H), 7.78 (m, 4H), 7.95 (d, 2H), 8.1 (d, 2H) the .c. product provides following NMR signal (CD to 3.5-3.7 to 2.8-3.0 to 1.35-1.37 ₃SOCD ₃+ CD ₃CO ₂D) 1.55-1.8 (m, 4H), 2.8-3.05 (m, 3H), 3.15 (t, 4H), 3.6 (t, 4H), 3.85 (m, 2H), 6.75 (d, 2H), 7.55 (d, 2H), 7.75 (d, 2H), 7.9 (d, 2H), 8.15 (d, 2H).

As 4 of starting raw material '-chloro-4-biphenyl sulfonyl chlorine is prepared as follows:

Chlorsulfonic acid (9ml) is added dropwise in chloroform (200ml) solution of the 4-chlordiphenyl (21g) that is stirring, mixture at room temperature stirred 30 minutes, isolated precipitation, with chloroform (50ml) washing, thus obtain 4 '-chloro-4-xenyl sulfonic acid (26.8g).

With thionyl chloride (0.85ml) be added dropwise to stirring 4 '-DMF (120ml) solution (being cooled to 5 ℃) of chloro-4-xenyl sulfonic acid (1.7g) in; mixture at room temperature stirred 3 hours; mixture is poured in the water; isolate the precipitation of gained; be dissolved in the ether; dry (sal epsom) and evaporating solvent separate once more, thus obtain 4 '-chloro-4-biphenyl sulfonyl chlorine (0.7g), need not to be further purified then and can use.Embodiment 42

Use embodiment 2 described similar approach, make 1-[1-(4-pyridyl) piperidin-4-yl carbonyl] piperazine and diphenylene-oxide-3-alkylsulfonyl chlorine reaction obtains 1-(diphenylene-oxide-3-base alkylsulfonyl)-4-[1-(4-pyridyl) piperidin-4-yl carbonyl of vitreous solid] piperazine, productive rate 75%; Nuclear-magnetism spectrum (CD ₃SOCD ₃) 1.35-1.75 (m, 1H), 2.8-3.1 (m, 7H), 3.6-3.8 (m, 4H), 3.9-4.0 (m, 2H), 6.8 (d, 2H), 7.67 (m, 2H), 7.85-8.2 (m, 5H), 8.5 (d, 1H), 8.75 (d, 1H); Ultimate analysis: C ₂₇H ₂₈N ₄O ₄S0.5H ₂O measured value: C, 62.8; H, 5.5; N, 10.8; Calculated value: C, 63.1; H, 5.7; N, 10.9%.Embodiment 43

With 2-ethoxy carbonyl-1-(2-naphthyl alkylsulfonyl)-4-[1-(4-pyridyl) piperidin-4-yl carbonyl] piperazine, the mixture of 2N aqueous sodium hydroxide solution (0.37ml) and methyl alcohol (4ml) at room temperature stirred 3 hours, evaporating mixture, in the resistates water-soluble (4ml), by adding the Glacial acetic acid acidifying, the precipitation of gained washes with water, dry and in ether, develop, thereby obtain 1-(2-naphthyl alkylsulfonyl)-4-[1-(4-pyridyl) piperidin-4-yl carbonyl] piperazine-2-carboxylic acid (0.082g), m.p.188-193 ℃; Nuclear-magnetism spectrum (CD ₃SOCD ₃+ CD ₃CO ₂D) 1.45-1.8 (m, 4H), 2.9-3.4 (m, 5H), 3.78 (m, 1H), 4.1 (m, 2H), 4.5 (m, 2H), 7.1 (d, 2H), 7.6-7.9 (m, 3H), 8.0-8.2 (m, 5H), 8.45 (d, 1H); Ultimate analysis: C ₂₆H ₂₈N ₄O ₅S0.75H ₂O measured value: C, 59.6; H, 5.7; N, 10.3; Calculated value: C, 59.8; H, 5.7; N, 10.7%.Embodiment 44

Use embodiment 1 described similar approach, make 1-(4-pyridyl) piperidines-4-carbonyl chlorine and 1-(2-naphthyl alkylsulfonyl) piperazine-3-carboxylic acid, ethyl ester obtain 2-ethoxy carbonyl-4-(2-naphthyl alkylsulfonyl)-1-[1-(4-pyridyl) the piperidin-4-yl carbonyl of vitreous solid] piperazine, productive rate 9%; Nuclear-magnetism spectrum (CD ₃SOCD ₃) 1.3 (t, 3H), 1.65-2.1 (m, 4H), 2.5 (m, 2H), 2.78 (m, 1H), 3.05 (m, 2H), 3.6-3.95 (m, 5H), 4.2 (m, 2H), 4.4 (m, 1H), 5.07 (m, 1H), 5.3 (m, 1H), 6.65 (d, 2H), 7.7 (m, 3H), 7.98 (m, 3H), 8.2 (d, 2H), 8.35 (d, 1H); Ultimate analysis: C ₂₈H ₃₂N ₄O ₅S measured value: C, 62.3; H, 6.5; N, 10.8; Calculated value: C, 62.7; H, 6.1; N, 10.4%.

1-(2-naphthyl alkylsulfonyl) piperazine-3-carboxylic acid, ethyl ester as starting raw material is prepared as follows:

Use embodiment 2 described similar approach, make the reaction of 1-benzyl diethylenediamine-2-carboxylic acid, ethyl ester and 2-naphthyl alkylsulfonyl chlorine obtain 1-benzyl-4-(2-naphthyl alkylsulfonyl) piperazine-2-carboxylic acid's ethyl ester, productive rate 93%.

Chloroformic acid 1-chloro-ethyl ester (1.5ml) is joined 1 of 1-benzyl-4-(2-naphthyl alkylsulfonyl) piperazine-2-carboxylic acid's ethyl ester (2.44g); in the 2-ethylene dichloride (50ml); stir the mixture and reflux 48 hours; evaporating mixture; resistates is developed with hexane, and methyl alcohol (50ml) is joined in the glue of gained, and mixture heating up refluxed 2 hours; evaporating mixture, resistates distributes between methylene dichloride and water.Dry (sal epsom) organic phase and evaporation, resistates are used increase polar methylene dichloride and methanol mixture as eluent, thereby are obtained gelationus 1-(2-naphthyl alkylsulfonyl) piperazine-3-carboxylic acid, ethyl ester (1.55g) by the column chromatography purifying.Nuclear-magnetism spectrum (CDCl ₃) 1.3 (t, 3H), 2.65-3.0 (m, 3H), 3.5 (m, 2H), 3.75 (m, 1H), 4.2 (q, 2H), 7.7 (m, 3H), 7.98 (m, 3H), 8.35 (d, 1H). embodiment 45

Use embodiment 14 described similar approach, make 1-(4-pyridyl) piperazine and 1-(2-naphthyl alkylsulfonyl) piperidines-3-carboxylic acid reaction obtain foamed 1-[1-(2-naphthyl alkylsulfonyl) piperidines-3-base carbonyl]-4-(4-pyridyl) piperazine, productive rate 25%; Nuclear-magnetism spectrum (CD ₃SOCD ₃) 0.95-1.75 (m, 6H), 2.3-2.45 (m, 2H), 2.6 (m, 1H), 3.5-3.75 (m, 8H), 7.05 (d, 2H), 7.6-7.75 (m, 3H), 8.1 (m, 5H), 8.4 (s, 1H).

1-(2-naphthyl alkylsulfonyl) piperidines-3-carboxylic acid as starting raw material is prepared as follows:

Use embodiment 2 described similar approach, make the reaction of piperidines-3-carboxylic acid, ethyl ester and 2-naphthyl alkylsulfonyl chlorine obtain 1-(2-naphthyl alkylsulfonyl) piperidines-3-carboxylic acid, ethyl ester, productive rate 62%.

Product (1.33g) with gained, the mixture of potassium hydroxide (0.43g) and ethanol (17ml) stir and be heated to 80 ℃ 4 hours, evaporating mixture, in the resistates water-soluble (5ml), by adding the acidifying of 2N aqueous hydrochloric acid, isolate the precipitation of gained, wash with water, drying, thus 1-(2-naphthyl alkylsulfonyl) piperidines-3-carboxylic acid (0.81g) obtained; Nuclear-magnetism spectrum (CD ₃SOCD ₃) 1.45-1.64 (m, 2H), 1.8-1.95 (m, 2H), 2.25 (m, 1H), 2.5 (m, 2H), 3.58 (m, 2H), 7.72 (m, 3H), 8.15 (m, 3H), 8.45 (d, 1H). embodiment 46

Use embodiment 1 described similar approach, just replace methylene dichloride as reaction solvent with DMF, 1-(4-pyridyl) piperidines-4-carbonyl chlorine and 1-(2-naphthyl methyl)-2-oxo piperazine trifluoroacetic acid reactant salt obtains 1-(2-naphthyl methyl)-2-oxo-4-[1-(4-pyridyl) piperidin-4-yl carbonyl] piperazine, productive rate 18%.Nuclear-magnetism spectrum (CD ₃SOCD ₃) 1.45-1.75 (m, 4H), 2.85-3.05 (m, 3H), 3.3 (m, 2H), 3.65-4.4 (m, 6H), 4.75 (s, 2H), 6.8 (d, 2H), 7.5 (m, 3H), 7.8 (s, 1H), 7.9 (d, 2H), 8.1 (d, 2H); Ultimate analysis: C ₂₆H ₂₈N ₄O ₂0.8H ₂O measured value: C, 70.6; H, 6.7; N, 12.5; Calculated value: C, 70.5; H, 6.7; N, 12.6%.

1-(2-naphthyl methyl)-2-oxo piperazine trifluoroacetate as starting raw material is prepared as follows:

Coke acid di-t-butyl ester (7.75g) is joined in the mixture of the 2-oxo piperazine (3.23g), salt of wormwood (4.46g), the trimethyl carbinol (15ml) and the water (15ml) that are stirring in batches, mixture at room temperature stirred 2 hours, the mixture ethyl acetate extraction, dry organic phase and evaporation, the resistates re-crystallizing in ethyl acetate, thereby obtain 4-tertbutyloxycarbonyl-2-oxo piperazine (5.31g), m.p.157-159 ℃.

With the sodium hydride (dispersion liquid in 60% mineral oil, 0.145g) join in the mixture (being cooled to 5 ℃) of the 4-tertbutyloxycarbonyl-2-oxo piperazine (0.5g) that stirring and DMF (15ml) in batches, mixture at room temperature stirred 1.5 hours, be added dropwise to DMF (3ml) solution of 2-brooethyl naphthalene (0.552g), with mixture heating up to room temperature, stirred 18 hours, mixture distributes between methylene dichloride and water, dry (sal epsom) organic phase and evaporation, resistates is by the column chromatography purifying, the mixture that uses 3: 2 hexanes and ethyl acetate is as eluent, thereby obtains gelationus 4-tertbutyloxycarbonyl-1-(2-naphthyl methyl)-2-oxo piperazine (0.41g).

The mixture of product, trifluoroacetic acid (1.5ml) and the methylene dichloride (10ml) of gained was at room temperature stirred 18 hours, add entry (0.5ml), evaporating mixture, thus 1-(2-naphthyl methyl)-2-oxo piperazine trifluoroacetate (0.4g) obtained, need not to be further purified then and can use.Nuclear-magnetism spectrum (CD ₃SOCD ₃) 3.4-3.5 (m, 4H), 3.9 (s, 2H), 4.8 (s, 2H), 7.4-7.6 (m, 3H), 7.8-8.0 (m, 4H). embodiment 47

Use embodiment 20 described similar approach, make 2-[2-(2-naphthalene sulfonyl amino) kharophen]-3-[1-(4-pyridyl) piperidin-4-yl carbonylamino] reaction of propionic acid and 4-methyl piperidine obtains N-{1-(4-methyl piperidine-1-base carbonyl)-2-[1-(4-pyridyl) piperidin-4-yl carbonylamino] ethyl }-2-(2-naphthalene sulfonyl amino) ethanamide, productive rate 22%.Embodiment 48

Use embodiment 20 described similar approach, make 2-[2-(2-naphthalene sulfonyl amino) kharophen]-3-[1-(4-pyridyl) piperidin-4-yl carbonylamino] reaction of propionic acid and morpholine obtains N-{1-morpholine carbonyl-2-[1-(4-pyridyl) piperidin-4-yl carbonylamino] ethyl }-2-(2-naphthalene sulfonyl amino) ethanamide, productive rate 36%.Embodiment 49

Use embodiment 1 described similar approach; make 1-(4-pyridyl) piperidin-4-yl carbonyl chlorine and 1-(2-naphthyl alkylsulfonyl)-1; the reaction of 4-diazepine obtains 1-(2-naphthyl alkylsulfonyl)-4-[1-(4-pyridyl) piperidin-4-yl carbonyl]-1,4-diaza , productive rate 42%.Nuclear-magnetism spectrum (CD ₃SOCD ₃+ CD ₃CO ₂D) 1.5-2.0 (m, 6H), 3.15 (m, 1H), 3.3-3.6 (m, 5H), 3.65 (m, 2H), 3.75 (m, 2H), 3.85 (m, 1H), 4.28 (m, 2H), 7.25 (m, 1H), 7.75-8.0 (m, 3H), 8.15-8.4 (m, 5H), 8.6 (d, 1H); Ultimate analysis: C ₂₆H ₃₀N ₄O ₃S0.25H ₂O measured value: C, 64.5; H, 6.2; N, 11.8; Calculated value: C, 64.6; H, 6.3; N, 11.6%.

As the 1-(2-naphthyl alkylsulfonyl)-1 of starting raw material, 4-diaza is prepared as follows:

With methylene dichloride (5ml) solution of 2-naphthyl alkylsulfonyl chlorine (2.26g) join stirring 1; 4-diaza (is called high piperazine again; in methylene dichloride 5g) (50ml) solution (being cooled to 5 ℃); mixture at room temperature stirred 2 hours; mixture distributes between ethyl acetate and 2N aqueous hydrochloric acid; by adding 10N aqueous sodium hydroxide solution alkalization water layer to pH13; use ethyl acetate extraction; wash organic phase with water; dry (sal epsom); evaporation obtains required starting raw material, productive rate 96%.Nuclear-magnetism spectrum (CD ₃SOCD ₃) 1.6-1.75 (m, 2H), 2.6-2.8 (m, 4H), 3.2-3.4 (m, 4H), 7.6-7.9 (m, 3H), 8.0-8.3 (m, 3H), 8.5 (s, 1H). embodiment 50

With 1-(4-pyridyl) piperazine (0.136g), 4-(2-naphthyl alkylsulfonyl) piperazine-1-carboxylic acid 2,4, the mixture of 5-trichlorophenyl ester (0.2g) and DMF (2ml) stir and be heated to 80 ℃ 24 hours, mixture is cooled to room temperature, between ethyl acetate and water, distribute, organic phase salt water washing, dry (sal epsom) and evaporation, resistates be by the column chromatography purifying, with 19: 1 methylene dichloride and methanol mixture as eluent, the oily matter of gained is developed with ether, thereby obtain 1-(2-naphthyl alkylsulfonyl)-4-[4-(4-pyridyl) piperazine-1-base carbonyl] piperazine (0.139g, 73%), m.p.210-212 ℃; Nuclear-magnetism spectrum (CD ₃SOCD ₃) 2.9-3.05 (m, 4H), 3.1-3.4 (m, 12H), 6.7 (d, 2H), 7.7 (m, 3H), 8.1-8.3 (m, 5H), 8.45 (s, 1H); Ultimate analysis: C ₂₄H ₂₇N ₅O ₃S measured value: C, 61.4; H, 6.0; N, 14.7; Calculated value: C, 61.9; H, 5.9; N, 15.0%.

As 4-(the 2-naphthyl alkylsulfonyl) piperazine-1-carboxylic acid 2,4 of starting raw material, 5-trichlorophenyl ester is prepared as follows:

With chloroformic acid 2,4,5-trichlorophenyl ester (0.26g) is added dropwise to 1-(the 2-naphthyl alkylsulfonyl) piperazine hydrochloride (0.63g) that is stirring, in the mixture of triethylamine (0.41g) and methylene dichloride (10ml), mixture at room temperature stirred 18 hours, mixture distributes between ethyl acetate and 2N aqueous hydrochloric acid, organic phase water and salt water washing, dry (sal epsom) and evaporation, resistates column chromatography purifying, with the mixture of 1: 1 hexane and methylene dichloride as eluent, thereby obtain required starting raw material (0.32g); Nuclear-magnetism spectrum (CD ₃SOCD ₃) 3.0-3.2 (m, 4H), 3.5-3.8 (m, 4H), 7.65-7.8 (m, 4H), 7.9 (s, 1H), 8.05 (m, 1H), 8.2 (m, 2H), 8.45 (s, 1H).

1-(2-naphthyl alkylsulfonyl) piperazine hydrochloride as starting raw material is prepared as follows:

Methylene dichloride (20ml) drips of solution of 2-naphthyl alkylsulfonyl chlorine (6.12g) is added in the mixture (cooling off in ice bath) of the 1-tert-butoxycarbonyl piperazine (5g), triethylamine (5.63ml) and the methylene dichloride (50ml) that are stirring; mixture stirred 4 hours down at 5 ℃-10 ℃; mixture distributes between ethyl acetate and 1M aqueous citric acid solution; organic phase water and salt water washing; dry (sal epsom) and evaporation; thereby obtain solid 1-(tertbutyloxycarbonyl)-4-(2-naphthyl alkylsulfonyl) piperazine (4.84g), m.p.174-176 ℃.

A part of product (0.25g) of gained is suspended in the ethyl acetate (20ml), and cooling mixture in ice bath imported hydrogen chloride gas in the mixture 20 minutes, evaporating mixture, thus obtain 1-(2-naphthyl alkylsulfonyl) piperazine hydrochloride (0.21g).Nuclear-magnetism spectrum (CD ₃SOCD ₃) 3.1-3.3 (m, 8H), 7.7-7.85 (m, 3H), 8.1 (d, 1H), 8.15-8.2 (m, 2H), 8.5 (s, 1H), 9.2-9.4 (s, 1H). embodiment 51

Use embodiment 1 described similar approach, make 1-(4-pyridyl) piperidines-4-carbonyl chlorine and (2RS, 5SR)-2, the reaction of 5-dimethyl-1-(2-naphthyl alkylsulfonyl) piperazine obtains (2RS, 5SR)-2,5-dimethyl-1-(2-naphthyl alkylsulfonyl)-4-[1-(4-pyridyl) piperidin-4-yl carbonyl] piperazine, productive rate 13%; Nuclear-magnetism spectrum (CDCl ₃) 0.85-1.03 (m, 3H), 1.1-1.4 (m, 2H), 1.65-2.1 (m, 4H), 2.65 (m, 1H), 2.90 (m, 2H), 3.18 (m, 1H), 3.58 (m, 2H), 3.89 (m, 2H), 4.25 (m, 2H), 6.62 (d, 2H), 7.7 (m, 3H), 7.95 (m, 3H), 8.25 (d, 2H), 8.39 (s, 1H); Ultimate analysis: C ₂₇H ₃₂N ₄O ₃S0.9CH ₂Cl ₂Measured value: C, 58.7; H, 6.2; N, 9.5; Calculated value: C, 58.5; H, 6.0; N, 9.8%.

Use embodiment 2 described similar approach, make (2RS, 5SR)-2,5-lupetazin and the reaction of 2-naphthyl alkylsulfonyl chlorine obtain being used as starting raw material (2RS, 5SR)-2,5-dimethyl-1-(2-naphthyl alkylsulfonyl) piperazine, productive rate 50%.Embodiment 52

Use embodiment 1 described similar approach, make 1-(4-pyridyl) piperidines-4-carbonyl chlorine and 3-methyl isophthalic acid-(2-naphthyl alkylsulfonyl) piperazine reaction obtain 3-methyl isophthalic acid-(2-naphthyl alkylsulfonyl)-4-[1-(4-pyridyl) piperidin-4-yl carbonyl] piperazine, productive rate 32%; Nuclear-magnetism spectrum (CD ₃SOCD ₃, 100 ℃) 1.5-1.75 (m, 4H), 2.45-2.7 (m, 3H), 3.19 (m, 1H), 3.57 (m, 1H), 3.75 (m, 3H), 4.06 (d, 1H), 4.52 (m, 1H), 6.65 (d, 2H), 7.6-7.79 (m, 3H) 8.0-8.15 (m, 5H), 8.38 (s, 1H); Ultimate analysis: C ₂₆H ₃₀N ₄O ₃S0.25EtoAc0.15H ₂O measured value: C, 64.1; H, 6.4; N, 11.3; Calculated value: C, 64.4; H, 6.47; N, 11.1%.

Use embodiment 2 described similar approach, obtain 3-methyl isophthalic acid-(2-naphthyl alkylsulfonyl) piperazine with making 2-methylpiperazine and 2-naphthyl alkylsulfonyl chlorine reaction quantitative yield as starting raw material.Embodiment 53

Use embodiment 2 described similar approach, make the reaction of 3-methyl isophthalic acid-[1-(4-pyridyl) piperidin-4-yl carbonyl] piperazine and 2-naphthyl alkylsulfonyl chlorine, evaporation reaction mixture, resistates distributes between ethyl acetate and 2N aqueous hydrochloric acid, by adding 10N aqueous sodium hydroxide solution alkalization water layer, use ethyl acetate extraction, dry (sal epsom) organic layer and evaporation, thereby obtain 2-methyl isophthalic acid-(2-naphthyl alkylsulfonyl)-4-[1-(4-pyridyl) piperidin-4-yl carbonyl] piperazine, productive rate 96%; Nuclear-magnetism spectrum (CD ₃SOCD ₃, 100 ℃) 1.5-1.75 (m, 4H), 2.75-3.3 (m, 6H), 3.6-4.2 (m, 6H), 6.7 (d, 2H), 7.61-7.84 (m, 3H), 8.0-8.16 (m, 5H), 8.45 (s, 1H).Ultimate analysis: C ₂₆H ₃₀N ₄O ₃S0.8H ₂O measured value: C, 63.2; H, 6.5; N, 11.1; Calculated value: C, 63.2; H, 6.5; N, 11.3%.

Use embodiment 1 described similar approach, make 1-(4-pyridyl) piperidines-4-carbonyl chlorine and 2-methylpiperazine react 3-methyl isophthalic acid-[1-(4-pyridyl) piperidin-4-yl carbonyl] piperazine that obtains as starting raw material, productive rate 39%.Embodiment 54

Use embodiment 1 described similar approach, make 1-(4-pyridyl) piperidin-4-yl carbonyl chlorine and 1-[(E)-4-chloro-styrene base alkylsulfonyl]-reaction of 3-methylpiperazine, evaporation reaction mixture, resistates distributes between ethyl acetate and 2N aqueous hydrochloric acid, by adding 10N aqueous sodium hydroxide solution alkalization water layer, use ethyl acetate extraction, dry (sal epsom) organic layer and evaporation, resistates is by the column chromatography purifying, with increasing polar ethyl acetate and methanol mixture as eluent, thereby obtain 4-[(E)-4-chloro-styrene base alkylsulfonyl]-2-methyl isophthalic acid-[1-(4-pyridyl) piperidin-4-yl carbonyl] piperazine, productive rate 24%; Nuclear-magnetism spectrum (CD ₃SOCD ₃, 100 ℃) 1.24 (d, 3H), 1.6-1.8 (m, 4H), 2.7to3.05 (m, 5H), 3.22 (m, 1H), 3.45 (m, 1H), 3.62 (m, 1H), 3.84 (m, 2H), 4.12 (m, 1H), 4.6 (m, 1H), 6.71 (d, 2H), 7.14 (d, 1H), 7.42 (d, 1H), 7.4-7.7 (m, 4H), 8.15 (d, 2H); Ultimate analysis: C ₂₄H ₂₉ClN ₄O ₃0.5EtOAc0.5H ₂O measured value: C, 57.6; H, 6.2; N, 10.5; Calculated value: C, 57.6; H, 6.3; N, 10.3%.

Use embodiment 2 described similar approach, make the 2-methylpiperazine with (E)-reaction of 4-chloro-styrene base alkylsulfonyl chlorine obtains the 1-[(E as starting raw material)-4-chloro-styrene base alkylsulfonyl]-the 3-methylpiperazine.Embodiment 55

The mixture of 4-chloropyrimide hydrochloride (0.151g), 1-(2-naphthyl alkylsulfonyl)-4-(4-piperidino carbonyl) piperazine (0.387g), triethylamine (0.202g) and ethanol (5ml) stirred and reflux 1 hour, evaporating mixture, resistates is by the column chromatography purifying, with 19: 1 methylene dichloride and methanol mixture as eluent, the solid of gained acetonitrile recrystallization, thereby obtain 1-(2-naphthyl alkylsulfonyl)-4-[1-(4-pyrimidyl) piperidin-4-yl carbonyl] piperazine (0.135g, 29%), m.p.203-205 ℃; Nuclear-magnetism spectrum (CD ₃SOCD ₃) 1.38 (m, 2H), 1.63 (m, 2H), 2.8-3.1 (m, 7H), 3.5-3.8 (m, 4H), 4.3 (m, 2H), 6.75 (d, 1H), 7.7-7.85 (m, 3H), 8.05-8.3 (m, 4H), 8.45 (m, 2H); Ultimate analysis: C ₂₄H ₂₇N ₅O ₃S0.2H ₂O measured value: C, 61.4; H, 5.9; N, 15.1; Calculated value: C, 61.5; H, 5.85; N, 14.9%.

1-(2-naphthyl alkylsulfonyl)-4-(4-piperidino carbonyl) piperazine as starting raw material is prepared as follows:

Methylene dichloride (50ml) drips of solution of tert-Butyl dicarbonate (10.9g) is added in the mixture of piperidines-4-carboxylic acid, ethyl ester (7.85g), triethylamine (10.1g) and methylene dichloride (100ml), mixture is cooled to 5-10 ℃ in ice bath, mixture stirred 1 hour down at 5 ℃, evaporating mixture, resistates distributes between ether and 1M aqueous citric acid solution, water and salt water washing organic phase, dry (sal epsom) and evaporation, thus buttery 1-tertiary butyloxycarbonyl phenylpiperidines-4-carboxylic acid, ethyl ester obtained.

The mixture of the product of gained, 2N aqueous sodium hydroxide solution (50ml) and methyl alcohol (125ml) at room temperature stirred 1 hour, evaporate most of methyl alcohol enriched mixture, resistates distributes between ether and 1M aqueous citric acid solution, water and salt water washing organic phase, dry (sal epsom) and evaporation, thereby obtain 1-tertiary butyloxycarbonyl phenylpiperidines-4-carboxylic acid (10.6g, 92%).

N-(3-dimethylaminopropyl)-N '-ethyl carbodiimide (2.5g) is joined 1-(the 2-naphthyl alkylsulfonyl) piperazine [3.61g that is stirring; By corresponding piperazine hydrochloride is distributed between ether and 10N aqueous sodium hydroxide solution; dry (sal epsom) and evaporation organic phase obtain]; in the mixture (in ice bath, cooling off) of 1-tertiary butyloxycarbonyl phenylpiperidines-4-carboxylic acid (3g) and DMF (40ml); mixture at room temperature stirred 18 hours; mixture distributes between ethyl acetate and water; water and salt water washing organic phase; dry (sal epsom) and evaporation; resistates column chromatography purifying; with ethyl acetate as eluent; thereby obtain 1-(2-naphthyl alkylsulfonyl)-4-(1-tertbutyloxycarbonyl piperidin-4-yl carbonyl) piperazine (3.79g, 59%), m.p.195-197 ℃.

The a part of product (1g) of gained and the mixture of trifluoroacetic acid (5ml) were at room temperature stirred 2 hours, mixture distributes between methylene dichloride and 2N aqueous sodium hydroxide solution, wash organic phase with water, dry (sal epsom) and evaporation, thereby obtain 1-(2-naphthyl alkylsulfonyl)-4-(4-piperidino carbonyl) piperazine (0.61g, 77%); Nuclear-magnetism spectrum (CD ₃SOCD ₃) 1.2-1.5 (m, 4H), 2.4-2.7 (m, 3H), 2.8-3.1 (m, 6H), 3.5-3.7 (m, 4H), 7.6-7.8 (m, 3H), 8.0-8.3 (m, 3H), 8.4 (s, 1H). embodiment 56

The mixture of 2-amino-4-chloro-6-methylpyrimidine (0.143g), 1-(2-naphthyl alkylsulfonyl)-4-(4-piperidino carbonyl) piperazine (0.387g), triethylamine (0.101g) and ethanol (5ml) stirred and reflux 18 hours, mixture is cooled to room temperature, between ethyl acetate and water, distribute, organic phase washes with water, dry (sal epsom) and evaporation, resistates is developed with ether, thereby obtain 4-[1-(2-amino-6-methylpyrimidine-4-yl) piperidin-4-yl carbonyl]-1-(2-naphthyl alkylsulfonyl) piperazine (0.29g, 58%); Nuclear-magnetism spectrum (CD ₃SOCD ₃) 1.2-1.45 (m, 2H), 1.55 (m, 2H), 2.05 (s, 3H), 2.8 (m, 3H), 2.9-3.2 (m, 4H), 3.5-3.7 (m, 4H), 4.23 (m, 2H), 5.95 (d, 3H), 7.7-7.85 (m, 3H), 8.2 (m, 3H), 8.45 (s, 1H); Ultimate analysis: C ₂₅H ₃₀N ₆O ₃S0.3H ₂O measured value: C, 60.1; H, 6.4; N, 16.6; Calculated value: C, 60.1; H, 6.1; N, 16.8%.Embodiment 57

With succinimido 1-(4-pyrimidyl) piperidines-4-carboxylicesters (0.326g), 1-[(E)-and 4-chloro-styrene base alkylsulfonyl] mixture of piperazine (0.4g) and DMF (5ml) at room temperature stirred 16 hours, mixture distributes between ethyl acetate and water, organic phase washes with water, dry (sal epsom) and evaporation, resistates is by the column chromatography purifying, with 49: 1 methylene dichloride and methanol mixture as eluent, gained use the acetonitrile recrystallization, thereby obtain 1-[(E)-4-chloro-styrene base alkylsulfonyl]-4-[1-(4-pyrimidyl) piperidin-4-yl carbonyl] piperazine (0.133g, 22%), m.p.209-210 ℃; Nuclear-magnetism spectrum (CD ₃SOCD ₃) 1.3-1.6 (m, 2H), 1.7 (m, 2H), 2.9-3.2 (m, 7H), 3.5-3.8 (m, 4H), 4.4 (m, 2H), 6.8 (d, 1H), 7.4 (m, 4H), 7.8 (d, 2H), 8.15 (d, 1H), 8.45 (s, 1H); Ultimate analysis: C ₂₂H ₂₆ClN ₅O ₃S measured value: C, 55.2; H, 5.5; N, 14.7; Calculated value: C, 55.5; H, 5.5; N, 14.7%.

Succinimido 1-(4-pyrimidyl) piperidines-4-carboxylicesters as starting raw material is prepared as follows:

With embodiment 32 described similar approach, make 4-chloropyrimide hydrochloride and piperidines-4-carboxylic acid, ethyl ester reaction obtain 1-(4-pyrimidyl) piperidines-4-carboxylic acid, ethyl ester, productive rate 46%.

The mixture of product (0.5g), 2N aqueous hydrochloric acid (5ml) and the THF (15ml) of gained stirred and reflux 18 hours, evaporating mixture, resistates washs with ethyl acetate, thereby obtains 1-(4-pyrimidyl) piperidines-4-carboxylic acid hydrochloride (0.49g, 95%); Nuclear-magnetism spectrum (CD ₃SOCD ₃) 1.6 (m, 2H), 2.0 (m, 2H), 2.7 (m, 1H), 3.4 (m, 2H), 4.5 (broad s, 2H), 7.2 (d, 1H), 8.3 (d, 1H), 8.8 (s, 1H).

The mixture of acid, N-hydroxy-succinamide (0.29g), triethylamine (0.6 1g), N-(3-dimethylaminopropyl)-N '-ethyl carbodiimide (0.48g) and the DMSO (10ml) of gained was at room temperature stirred 5 hours, organic phase washes with water, dry (sal epsom) and evaporation, thereby obtain succinimido 1-(4-pyrimidyl) piperidines-4-carboxylicesters, need not to be further purified then and can use.

Use embodiment 2 described similar approach, make piperazine with (E)-reaction of 4-chloro-styrene base sulfinyl chlorine obtains the 1-[(E as starting raw material)-4-chloro-styrene base alkylsulfonyl] piperazine, productive rate 42%.Embodiment 58

Use embodiment 1 described similar approach, make 1-(4-pyridyl) piperidines-4-carbonyl chlorine and 1-(4 '-methyl biphenyl-4-base alkylsulfonyl) piperazine reaction obtain 1-(4 '-methyl biphenyl-4-base alkylsulfonyl)-4-[1-(4-pyridyl) piperidin-4-yl carbonyl] piperazine, productive rate 67%, m.p.213-217 ℃; Nuclear-magnetism spectrum (CD ₃SOCD ₃+ CD ₃CO ₂D) 1.6-1.85 (m, 4H), 2.35 (s, 3H), 2.98 (m, 1H), 3.05-3.3 (m, 6H), 3.55-3.65 (m, 4H), 3.95 (m, 2H), 6.95 (d, 2H), 7.3 (d, 2H), 7.55 (d.2H), 7.8 (m, 4H), 8.05 (d, 2H); Ultimate analysis: C ₂₈H ₃₂N ₄O ₃S0.66H ₂O measured value: C, 65.0; H, 6.3; N, 10.8; Calculated value: C, 65.1; H, 6.5; N, 10.8%.

Be prepared as follows as the 1-of starting raw material (4 '-methyl diphenyl-4-base alkylsulfonyl) piperazine:

Methylene dichloride (150ml) drips of solution of 4-iodophenyl alkylsulfonyl chlorine (5g) is added in methylene dichloride (50ml) solution (cooling off in ice bath) of the piperazine (7.1g) that is stirring; mixture at room temperature stirred 14 hours; mixture extracts with the 2N aqueous hydrochloric acid; the aqueous solution washs with ethyl acetate; by adding the alkalization of 2N aqueous sodium hydroxide solution; use ethyl acetate extraction; organic extract liquid washes with water; dry (sal epsom) and evaporation; thereby obtain 1-(4-iodine alkylsulfonyl) piperazine (4.6g), need not to be further purified.

With the product (0.5g) of gained, 4-tolyl boric acid (0.19g), 2N aqueous sodium carbonate (7.8ml), tetrakis triphenylphosphine palladium (O) (0.1g), the mixture of ethanol (15ml) and toluene (21ml) stirs and reflux 5 hours, mixture is cooled to room temperature, between ethyl acetate and water, distribute, organic phase washes with water, dry (sal epsom) and evaporation, thus 1-(4 '-methyl biphenyl-4-base alkylsulfonyl) piperazine (0.43g) obtained; Nuclear-magnetism spectrum (CD ₃SOCD ₃) 2.35 (s, 3H), 2.7-2.9 (m, 8H), 7.35 (d, 2H), 7.65 (d, 2H), 7.8 (d, 2H), 7.95 (d, 2H).Embodiment 59

Use embodiment 1 described similar approach; make 1-(4-pyridyl) piperidines-4-carbonyl chlorine and suitable 1-(phenyl sulfonyl) piperazine reaction; thereby obtain the compound described in the Table IV; its structure is by NMR spectrum conclusive evidence; except as otherwise noted; use relates to the described similar approach of final stage of embodiment 58 parts of starting raw material preparation, prepares suitable 1-(phenyl sulfonyl) piperazine by 1-(4-iodophenyl alkylsulfonyl) piperazine.

Table IV

The compound number of embodiment 59	??????R	??m.p.(℃)	Productive rate (%)
The compound number of embodiment 59	??????R	??m.p.(℃)	Productive rate (%)	????1 ^a????2 ^b????3 ^c????4 ^d????5 ^e????6 ^f????7 ^g????8 ^h????9 ^I????10 ^j	4-(4-bromophenyl) 4-(3; The 5-dichlorophenyl) 3-(4-chlorphenyl) 3-phenyl 4-iodine 4-(4-carbethoxyl group)-phenyl) 4-(4-cyano-phenyl) 3-(3,5-dichlorophenyl) 4-(4-nitrobenzophenone) 4-(4-chloro-2-nitro-phenyl)	203-207 jelly foam jelly glassy mass jelly jelly jelly jelly jelly	????54 ????13 ????12 ????12 ????79 ????5 ????3 ????18 ????27 ????19

Explain: a. product provides following NMR signal (CD ₃SOCD ₃+ CD ₃CO ₂D) 1.6-1.85 (m, 4H), 2.98 (m, 1H), 3.05-3.3 (m, 6H), 3.55-3.65 (m, 4H), 3.93 (m, 2H), 6.9 (d, 2H), 7.55-7.65 (m, 4H), 7.8-7.9 (m, 4H), 8.1 (d, 2H).

1-(4 '-bromo biphenyl base-4-base alkylsulfonyl) piperazine as starting raw material can be prepared by the 4-bromo biphenyl; use the described similar approach of the c that makes a bet of the Table III of embodiment 41; compound is converted into 4 '-bromo-4-biphenyl sulfonyl chlorine; use embodiment 2 described similar approach; make the product and the piperazine reaction of gained, required starting raw material provides following NMR signal (CD ₃SOCD ₃) 2.7-2.8 (m, 4H), 2.8-2.9 (m, 4H), 7.75 (d, 4H), 7.8 (d, 2H), 7.95 (d, 2H).B. product provides following NMR signal (CD ₃SOCD ₃) 1.5-1.75 (m, 4H), 2.8-3.15 (m, 7H), 3.55-3.65 (m, 4H), 3.8 (m, 2H), 6.7 (d, 2H), 7.55 (t, 1H), 7.7 (d, 2H), 7.8-7.95 (m, 4H), 8.1 (d, 2H).

Starting raw material 1-(3 ', 5 '-DCBP-4-base alkylsulfonyl) piperazine provides following NMR signal (CD ₃SOCD ₃) 2.7-2.8 (m, 4H), 2.8-2.9 (m, 4H), 7.65 (t, 1H), 7.75-7.85 (m, 4H), 8.0 (d, 2H).C. product provides following NMR signal (CD ₃SOCD ₃) 1.55-1.75 (m, 4H), 2.7-3.05 (m, 3H), 3.05-3.15 (m, 4H), 3.55-3.6 (m, 4H), 3.6-3.75 (m, 2H), 6.7 (d, 2H), 7.5 (d, 2H), 7.65-7.8 (m, 4H), 7.92 (m, 2H), 8.1 (d, 2H).

Use relates to the described similar approach of final stage of embodiment 58 parts of starting raw material preparation, by 1-(3-bromophenyl alkylsulfonyl) piperazine (reaction of piperazine and 3-bromophenyl alkylsulfonyl chlorine is obtained) and 4-chlorophenylboronic acid being reacted obtain starting raw material 1-(4 '-the basic alkylsulfonyl of chlordiphenyl-3-) piperazine.Required starting raw material provides following NMR signal (CD ₃SOCD ₃) 2.7-2.8 (m, 4H), 2.8-2.9 (m, 4H), 7.6 (d, 2H), 7.7-7.8 (m, 5H), 8.05 (m, 1H).D. product provides following NMR signal (CD ₃SOCD ₃) 1.6-1.8 (m, 4H), 2.98 (m, 1H), 3.1-3.3 (m, 6H), 3.55-3.65 (m, 4H), 3.95 (m, 2H), 6.95 (d, 2H), 7.4-7.55 (m, 3H), 3.65-3.8 (m, 4H), 7.92 (m, 2H), 8.1 (d, 2H) the .e. product provides following NMR signal (CD ₃SOCD ₃) (m, 4H), (m, 7H), (m, 4H), 3.89 (d, 2H), 6.78 (d, 2H), 7.49 (d, 2H), 8.02 (d, 2H), 8.10 (d, 2H) the .f. product provides following NMR signal (CD to 3.54-3.62 to 2.82-2.91 to 1.41-1.64 ₃SOCD ₃) 1.28-1.68 (m, 7H), 2.76-3.07 (m, 7H), 3.49-3.75 (m, 4H), 3.8-4.07 (d, 2H), 4.42-4.43 (m, 2H), 6.76 (d, 2H), 7.8-8.2 (m, 10H).

1-(4 '-ethoxy carbonyl biphenyl-4-base alkylsulfonyl) piperazine as starting raw material is prepared as follows:

With 1-(4-iodophenyl alkylsulfonyl) piperazine (5g); two (tributyl tins) (11ml); the mixture of tetrakis triphenylphosphine palladium (O) (0.1 6g) and toluene (200ml) stir and be heated to 120 ℃ 36 hours; mixture is cooled to room temperature; filter; evaporated filtrate; resistates column chromatography purifying; with increasing polar methylene dichloride and methanol mixture as eluent; the product of gained is dissolved in methylene dichloride (20ml); in the mixture of methyl alcohol (5ml) and water (0.2m1); add Potassium monofluoride (3g); mixture at room temperature stirred 1 hour; mixture distributes between methylene dichloride and water; organic phase washes with water; dry (sal epsom) and evaporation, thus [4-(piperazine-1-base alkylsulfonyl) phenyl] tributyl tin (1.5g) obtained.

With the product of gained, 4-iodo ethyl benzoate (1.6g), tetrakis triphenylphosphine palladium (O) (0.034g) and the mixture of toluene (50ml) stirs and reflux 72 hours, evaporating mixture, with 97: 3 methylene dichloride and methanol mixture washing, thereby obtain 1-(4 '-ethoxycarbonyl biphenyl-4-base alkylsulfonyl) piperazine (0.76g); Nuclear-magnetism spectrum (CD ₃SOCD ₃) (t, 3H), (d, 8H), (m, 2H), (m, 4H), (m, 4H) the .g. product provides following NMR signal (CD to 7.97-8.15 to 7.65-7.97 to 4.27-4.44 to 3.07-3.37 to 1.3-1.43 ₃SOCD ₃, 100 ℃) 1.57-1.78 (m, 4H), 2.79-3.08 (m, 3H), 3.08-3.18 (t, 4H), 3.55-3.68 (t, 4H), 3.75-3.82 (t, 1H), 3.85 (t, 1H), 6.74 (d, 2H), 7.85-8.02 (m, 8H), 8.14 (m, 2H).

Use the described similar approach of above-mentioned note f, make [4-(piperazine-1-base alkylsulfonyl) phenyl] tributyl tin and the reaction of 4-iodobenzene formonitrile HCN obtain 1-(4 '-cyanobiphenyl-4-base alkylsulfonyl) piperazine as starting raw material.H. product provides following NMR signal (CD ₃SOCD ₃, 100 ℃) and 1.53-1.8 (m, 4H), 2.65-3.08 (m, 3H), 3.08-3.20 (t, 4H), 3.54-3.65 (t, 4H), 3.84 (t, 1H), 3.90 (t, 1H), 6.75-6.85 (d, 2H), 7.58 (t, 1H), 7.7-7.9 (m, 4H), 7.95-8.08 (m, 2H), 8.08-8.18 (m, 2H).

As the 1-of starting raw material (3 ', 5 '-DCBP-3-base alkylsulfonyl) piperazine is prepared as follows:

Use relates to the described similar approach of embodiment 58 parts of starting raw material preparation, by making the reaction of piperazine and 3-bromophenyl alkylsulfonyl chlorine obtain 1-(3-bromophenyl alkylsulfonyl) piperazine, then with 3,5-dichlorophenyl acid reaction obtain 1-(3 ', 5 '-DCBP base-3-base alkylsulfonyl) piperazine, productive rate 29%; Nuclear-magnetism spectrum (CD ₃SOCD ₃, 100 ℃) and (m, 4H), (7.58 (t, 1H), (m, 4H), (m, 2H) the .i. product provides following NMR signal (CD to 7.91-8.05 to 7.68-7.85 to 2.95-3.05 to 2.7-2.85 for m, 4H ₃SOCD ₃100 ℃) and 1.5-1.75 (m, 4H), 2.75-3.04 (m, 5H), 3.05-3.17 (t, 4H), 3.53-3.65 (t, 4H), 3.75 (t, 1H), 3.81 (t, 1H), 6.69 (d, 2H), 7.88 (d, 2H), 7.93-8.04 (d, 4H), 8.1 (d, 2H), 8.3 (d, 2H).

Use the described similar approach of above-mentioned note f, make [4-(piperazine-1-base alkylsulfonyl) phenyl] tributyl tin and the reaction of 4-iodobenzene obtain 1-(4 '-nitrobiphenyl-4-base alkylsulfonyl) piperazine as starting raw material.J. product provides following NMR signal (CD ₃SOCD ₃100 ℃) 1.53-1.77 (m, 4H), 2.61-3.06 (m, 3H), 3.11 (t, 4H), 3.58 (t, 4H), 3.75 (t, 1H), 3.86 (t, 1H), 6.73 (d, 2H), 7.58 (d, 3H), 7.82 (m, 4H), 8.12 (d, 2H).

Use the described similar approach of above-mentioned note f, make [4-(piperazine-1-base alkylsulfonyl) phenyl] tributyl tin and the reaction of 2-bromo-5-chloro-1-oil of mirbane obtain as starting raw material 1-(4 '-chloro-2 '-nitrobiphenyl-4-base alkylsulfonyl) piperazine.Embodiment 60

Use embodiment 1 described similar approach, make 1-(4-pyridyl) piperidines-4-carbonyl chlorine and 1-[4-(2-pyridyl) phenyl sulfonyl] piperazine reaction obtains 1-[4-(2-pyridyl) phenyl sulfonyl]-4-[1-(4-pyridyl) piperidin-4-yl carbonyl] piperazine, productive rate 54%, m.p.224-226 ℃; Nuclear-magnetism spectrum (CD ₃SOCD ₃) 1.35-1.65 (m, 4H), 2.75-3.05 (m, 7H), 3.5-3.7 (m, 4H), 3.88 (m, 2H), 6.75 (d, 2H), 7.45 (m, 1H), 7.8-8.0 (m, 3H), 8.05-8.15 (m, 3H), 8.35 (d, 2H), 8.72 (m, 1H); Ultimate analysis: C ₂₆H ₂₉N ₅O ₃S0.5H ₂O measured value: C, 62.7; H, 5.9; N, 14.0; Calculated value: C, 62.4; H, 6.0; N, 14.0%.

As 1-[4-(2-pyridyl) phenyl sulfonyl of starting raw material] piperazine is prepared as follows:

With 1-(4-iodophenyl alkylsulfonyl) piperazine (0.48g), (2-pyridyl) tributyl tin (1.18g), tetrakis triphenylphosphine palladium (O) (0.1g) and the mixture of toluene (15ml) stirs and reflux 18 hours, evaporating mixture, resistates column chromatography purifying, with increasing polar methylene dichloride and methanol mixture, thereby obtain 1-[4-(2-pyridyl) phenyl sulfonyl as eluent] piperazine (0.439g); Nuclear-magnetism spectrum (CD ₃SOCD ₃) 2.65-2.8 (m, 4H), 2.8-2.9 (m, 4H), 7.45 (m, 1H), 7.8-8.1 (m, 3H), 8.35 (d, 2H), 8.73 (m, 1H). embodiment 61

With 2-ethoxycarbonyl-4-(2-naphthyl alkylsulfonyl)-1-[1-(4-pyridyl) piperidin-4-yl carbonyl] mixture of piperazine (0.67g), 2N aqueous sodium hydroxide solution (2.5ml) and methyl alcohol (10ml) at room temperature stirred 3 hours, evaporating mixture, in resistates water-soluble (10ml), add the acetate souring soln, isolate precipitation, dry, thereby obtain 2-carboxyl-4-(2-naphthyl alkylsulfonyl)-1-[1-(4-pyridyl) piperidin-4-yl carbonyl] piperazine (0.47g), m.p.225-228 ℃ (decomposition); Nuclear-magnetism spectrum (CD ₃SOCD ₃+ CD ₃CO ₂D, 100 ℃) 1.55-1.9 (m, 4H, 2.45-2.55 (m, 1H), 2.65-2.75 (m, 1H), 2.9-3.05 (m, 1H), 3.1-3.4 (m, 3H), 3.7 (m, 1H), 3.92 (m, 2H), 4.07 (m, 1H), 4.25 (m, 1H), 4.98 (m, 1H), 6.9 (d, 2H), 7.6-7.8 (m, 3H), 7.95-8.2 (m, 5H), 8.4 (d, 1H). ultimate analysis: C ₂₆H ₂₈N ₄O ₅S1.5H ₂O measured value: C, 58.4; H, 5.8; N, 10.3; Calculated value: C, 58.3; H, 5.8; N, 10.45%.Embodiment 62

Use embodiment 1 described similar approach, make 1-(4-pyridyl) piperidines-4-carbonyl chlorine and 1-(6-chloronaphthalene-2-base alkylsulfonyl) piperazine-3-carboxylic acid, ethyl ester reaction obtain 4-(6-chloronaphthalene-2-base alkylsulfonyl)-2-ethoxycarbonyl-1-[1-(4-pyridyl) piperidin-4-yl carbonyl] piperazine, productive rate 37%; Nuclear-magnetism spectrum (CD ₃SOCD ₃, 100 ℃) 1.2 (t, 3H), 1.5-1.8 (m, 4H), 2.6 (m, 1H), 2.8 (m, 1H), 2.85-3.05 (m, 4H), and 3.65-3.85 (m, 3H), 4.05-4.25 (m, 4H), 5.1 (m, 1H), 6.7 (d, 2H), 7.65 (m, 1H), 7.8 (m, 1H), 8.1-8.25 (m, 5H), 8.45 (d, 1H); Ultimate analysis: C ₂₈H ₃₁ClN ₄O ₅S measured value: C, 58.5; H, 5.6; N, 9.6; Calculated value: C, 58.9; H, 5.5; N, 9.8%.

Use relates to the described similar approach of embodiment 44 parts of starting raw material preparation; obtain 1-(6-chloronaphthalene-2-base alkylsulfonyl) piperazine-3-carboxylic acid, ethyl ester as starting raw material, productive rate 78% by 1-benzyl diethylenediamine-2-carboxylic acid, ethyl ester and 6-chloronaphthalene-2-base alkylsulfonyl chlorine.Embodiment 63

Use embodiment 61 described similar approach, hydrolysis 4-(6-chloronaphthalene-2-base alkylsulfonyl)-2-ethoxycarbonyl-1-[1-(4-pyridyl) piperidin-4-yl carbonyl] piperazine obtains 2-carboxyl-4-(6-chloronaphthalene-2-base alkylsulfonyl)-1-[1-(4-pyridyl) piperidin-4-yl carbonyl] piperazine, productive rate 90%, m.p.215-220 ℃ (decomposition); Nuclear-magnetism spectrum (CD ₃SOCD ₃, 100 ℃) 1.5-1.8 (m, 4H), 2.7-3.05 (m, 5H), 3.6-3.85 (m, 4H), 4.1 (m, 1H), 4.25 (m, 1H), 4.95 (m, 1H), 6.7 (d, 2H), 7.65 (m, 1H), 7.8 (m, 1H), 8.05-8.25 (m, 5H), 8.45 (d, 1H); Ultimate analysis: C ₂₆H ₂₇ClN ₄O ₅S0.5H ₂O measured value: C, 56.7; H, 5.0; N, 9.9; Calculated value: C, 56.6; H, 5.1; N, 10.15%.Embodiment 64

With 2-carboxyl-4-(2-naphthyl alkylsulfonyl)-1-[1-(4-pyridyl) piperidin-4-yl carbonyl] piperazine (0.11g); piperidines (0.064g); N-hydroxybenzotriazole (0.029g); N; N-dicyclohexyl carbodiimide (0.054g); the mixture of DMF (2ml) and DMSO (2ml) at room temperature stirred 18 hours; mixture distributes between methylene dichloride and water; with organic phase drying (sal epsom) and evaporation; resistates is by the column chromatography purifying; with increasing polar methylene dichloride and methanol mixture, thereby obtain glass 4-(2-naphthyl alkylsulfonyl)-2-piperidino-(1-position only) carbonyl-1-[1-(4-pyridyl) piperidin-4-yl carbonyl as eluent] piperazine (0.063g).Nuclear-magnetism spectrum (CD ₃SOCD ₃+ CD ₃CO ₂D, 100 ℃) 1.2-1.8 (m, 10H), 2.7-3.05 (m, 3H), 3.12 (m, 2H), 3.25-3.4 (m, 5H), 3.65 (m, 1H), 3.75-4.0 (m, 4H), 5.2 (m, 1H), 6.85 (d, 2H), 7.6-7.75 (m, 3H), 7.95-8.1 (m, 5H), 8.35 (d, 1H); Ultimate analysis: C ₃₁H ₃₇N ₅O ₄S0.5H ₂O measured value: C, 63.6; H, 7.0; N, 12.0; Calculated value: C, 63.7; H, 6.5; N, 12.0%.Embodiment 65

With 1-(2-naphthyl alkylsulfonyl)-4-[1-(4-pyridyl) piperidin-4-yl carbonyl] mixture of piperazine-2-carboxylic acid (0.121g) and thionyl chloride (0.2ml) at room temperature stirred 1 hour, evaporating mixture, successively methylene dichloride (8ml) and piperidines (0.23ml) are joined in the resistates, mixture at room temperature stirred 2 hours, mixture distributes between methylene dichloride and water, with organic phase drying (sal epsom) and evaporation, resistates column chromatography purifying, use increase polar methylene dichloride and methanol mixture as eluent, thereby obtain glass 1-(2-naphthyl alkylsulfonyl)-2-piperidino-(1-position only) carbonyl-4-[1-(4-pyridyl) piperidin-4-yl carbonyl] piperazine (0.061g); Nuclear-magnetism spectrum (CD ₃SOCD ₃+ CD ₃CO ₂D) 1.2-1.8 (m, 10H), 2.9-3.3 (m, 6H), 3.45-3.75 (m, 4H), 3.9-4.2 (m, 4H), 4.47 (m, 1H), 5.0 (m, 1H), 6.8 (d, 2H), 7.68 (m, 3H), 8.0-8.2 (m, 5H), 8.35 (d, 1H); Ultimate analysis: C ₃₁H ₃₇N ₅O ₄SH ₂O measured value: C, 62.5; H, 6.4; N, 11.7; Calculated value: C, 62.7; H, 6.6; N, 11.8%.Embodiment 66

Use embodiment 1 described similar approach, make the reaction of 1-(4-pyridyl) piperidines-4-carbonyl chlorine and 2-benzyl-1-(2-naphthyl alkylsulfonyl) piperazine obtain 2-benzyl-1-(2-naphthyl alkylsulfonyl)-4-[1-(4-pyridyl) piperidin-4-yl carbonyl] piperazine, productive rate 70%; M.p.186-188 ℃ of nuclear-magnetism spectrum (CD ₃SOCD ₃) 1.6 (m, 4H), 2.7 (m, 3H), 3.0 (m, 4H), 3.9 (m, 4H), 4.2 (d, 2H), 6.6 (d, 3H), 7.2 (d, 5H), 7.7 (m, 3H), 8.1 (m, 5H), 8.5 (s, 1H). ultimate analysis: C ₃₂H ₃₄N ₄O ₃S0.6H ₂O measured value: C, 67.9; H, 6.3; N, 9.8; Calculated value: C, 68.0; H, 6.3; N, 9.9%.

2-benzyl-1-(2-naphthyl alkylsulfonyl) piperazine as starting raw material is prepared as follows:

N-methylmorpholine (3.12ml) is joined the N-tertbutyloxycarbonyl-DL-phenylalanine (3g) that is stirring, N-n-benzylglycine ethyl ester (2.18g), in the mixture of N-hydroxybenzotriazole (1.26g) and DMF (50ml) (being cooled to 0 ℃), mixture stirred 30 minutes down at 0 ℃, at room temperature stirred 16 hours, filtering mixt, evaporated filtrate, resistates distributes between ethyl acetate and water, organic phase washes with water, dry (sal epsom) and evaporation, resistates column chromatography purifying, the mixture that uses 5: 1 hexane and ethyl acetate obtains solid (3.7g) as eluent.

The mixture of the diethyl ether solution of the product of gained and 4M hydrogenchloride was at room temperature stirred 16 hours, and evaporating mixture obtains phenyl propionamido-N-n-benzylglycine ethyl ester (2.65g); Nuclear-magnetism spectrum (CD ₃SOCD ₃) 1.2 (m, 2H), 3.1 (t, 2H), 3.6 (m, 4H), 4.1 (m, 2H), 4.6 (m, 2H), 7.2 (m, 10H), 8.4 (s, 2H).

A part of product (0.5g) with gained, the mixture stirring of the trimethyl carbinol (25ml) solution of N-methylmorpholine (0.15g) and 0.1M acetate and reflux 3 hours, evaporating mixture, resistates distributes between methylene dichloride and water, organic phase washes with water, dry (sal epsom) and evaporation, resistates is by the column chromatography purifying, use increase polar methylene dichloride and methanol mixture as eluent, thereby obtain 1,3-dibenzyl-2,5-dioxo piperazine (0.29g), m.p.173-174 ℃.

After repeating above-mentioned reaction, with 1,3-dibenzyl-2,5-dioxo piperazine (1.6g), the mixture stirring of boron trifluoride diethyl etherate title complex (0.1g) and THF (5ml) and reflux 15 minutes, mixture is cooled to room temperature, is added dropwise to borane disulphide (0.04ml), mixture at room temperature stirred 30 minutes, evaporating mixture, with resistates be heated to 100 ℃ 5 minutes, add 6N aqueous hydrochloric acid (1ml), mixture heating up refluxed 1 hour, mixture is cooled to 0 ℃, adds 6N aqueous sodium hydroxide solution (1.5ml), mixture distributes between methylene dichloride and unsaturated carbonate aqueous solutions of potassium, organic phase washes with water, dry (sal epsom) and evaporation, resistates column chromatography purifying is with increasing polar methylene dichloride and methanol mixture as eluent, thereby obtain 1,3-dibenzyl piperazine (0.29g).

The dichloromethane solution (3ml) of the product of gained is added dropwise to the 2-naphthyl alkylsulfonyl chlorine (0.257g) that is stirring, in the mixture of triethylamine (0.7ml) and methylene dichloride (5ml) (being cooled to 0 ℃), mixture at room temperature stirred 16 hours, evaporating mixture, resistates distributes between methylene dichloride and water, organic phase washes with water, dry (sal epsom) and evaporation, resistates column chromatography purifying, with increasing polar methylene dichloride and methanol mixture as eluent, thereby obtain 2,4-dibenzyl-1-(2-naphthyl alkylsulfonyl) piperazine (0.37g); Nuclear-magnetism spectrum (CD ₃SOCD ₃) 1.8 (m, 2H), 2.6 (m, 3H), 3.1 (m, 2H), 3.45 (d, 1H), 3.75 (d, 1H), 4.1 (s, 1H), 6.95 (m, 2H), 7.1 (m, 3H), 7.25 (s, 5H), 7.75 (m, 3H), 8.1 (m, 3H), 8.5 (s, 1H).

Product with gained; the mixture of 10% Pd/carbon catalyst (0.23g) and methylene dichloride (50ml) stirred 24 hours under nitrogen atmosphere; filtering mixt; evaporated filtrate; resistates is by the column chromatography purifying; with 99: 1 methylene dichloride and methanol mixture as eluent, thereby obtain 2-benzyl-1-(2-naphthyl alkylsulfonyl) piperazine (0.08g).Nuclear-magnetism spectrum (CD ₃SOCD ₃) 2.4-2.8 (m, 4H), 3.1-3.4 (m, 3H), 3.6 (d, 1H), 4.0 (t, 1H), 7.2 (m, 5H), 7.7 (m, 3H), 8.1 (m, 3H), 8.4 (s, 1H). embodiment 67

Use embodiment 2 described similar approach; make 2-amino-N-{1-piperidino-(1-position only) carbonyl-2-[1-(4-pyridyl) piperidin-4-yl carbonylamino] ethyl acetamide hydrochloride with (E)-4-chloro-styrene base alkylsulfonyl chlorine reaction obtains gelationus 2-[(E)-4-chloro-styrene ylsulfonylamino]-N-{1-piperidino-(1-position only) carbonyl-2-[1-(4-pyridyl) piperidin-4-yl carbonylamino] ethyl ethanamide (0.1g, 16%).Nuclear-magnetism spectrum (CDCl ₃) 1.4-2.1 (m, 10H), 2.45 (m, 1H), 2.6-3.1 (m, 2H), 3.4-4.0 (m, 10H), 5.1 (m, 1H), 6.7 (d, 2H), 6.85 (d, 1H), 6.95 (m, 1H), 7.2-7.55 (m, 6H), 7.65 (d, 1H), 8.22 (m, 2H). embodiment 68

Use embodiment 2 described similar approach; make 2-amino-N-{1-piperidino-(1-position only) carbonyl-2-[1-(4-pyridyl) piperidin-4-yl carbonylamino] ethyl } acetamide hydrochloride and 3; the reaction of 4-dichlorophenyl alkylsulfonyl chlorine obtains gelationus 2-(3; 4-dichlorophenyl sulfonamido)-and N-{1-piperidino-(1-position only) carbonyl-2-[1-(4-pyridyl) piperidin-4-yl carbonylamino] ethyl } ethanamide (0.17g, 27%).Nuclear-magnetism spectrum (CD ₃SOCD ₃) 1.4-1.8 (m, 10H), 2.35 (m, 1H), 2.88 (m, 2H), 3.02 (m, 1H), 3.15-3.5 (m, 8H), 3.55 (d, 1H), 3.9 (m, 2H), 4.85 (m, 1H), 6.8 (d, 2H), 7.7-7.9 (m, 3H), 8.0 (d, 1H), 8.05 (d, 1H), 8.15 (m, 3H); Ultimate analysis: C ₂₇H ₃₄Cl ₂N ₆O ₅S0.4CH ₂Cl ₂Measured value: C, 49.9; H, 5.4; N, 12.5; Calculated value: C, 49.9; H, 5.2; N, 12.7%.Embodiment 69

Use embodiment 56 described similar approach, make 4-chloropyrimide and 1-(6-chloronaphthalene-2-base alkylsulfonyl)-4-(4-piperidino carbonyl) piperazine reaction, when reaction mixture is cooled to room temperature, isolate sedimentary precipitation, use the acetonitrile recrystallization, thereby obtain 1-(6-chloronaphthalene-2-base alkylsulfonyl)-4-[1-(4-pyrimidyl) piperidin-4-yl carbonyl] piperazine, productive rate 60%, m.p.218-219 ℃; Nuclear-magnetism spectrum (CD ₃SOCD ₃) 1.25-1.5 (m, 2H), 1.62 (m, 2H), 2.8-3.1 (m, 7H), 3.5-3.75 (m, 4H), 4.32 (m, 2H), 6.75 (m, 1H), 7.7 (m, 1H), 7.85 (m, 1H), 8.15 (d, 1H), 8.2 (d, 1H), 8.28 (m, 3H), 8.45 (s, 1H), 8.5 (s, 1H); Ultimate analysis: C ₂₄H ₂₆ClN ₅O ₃S measured value: C, 57.6; H, 5.3; N, 13.9; Calculated value: C, 57.7; H, 5.2; N, 14.0%.

1-(6-chloronaphthalene-2-base alkylsulfonyl)-4-(4-piperidino carbonyl) piperazine as starting raw material is prepared as follows:

Use relates to the similar approach described in two paragraphs of embodiment 50 parts of starting raw material preparation, makes 1-tert-butoxycarbonyl-piperazine and 6-chloronaphthalene-2-base alkylsulfonyl chlorine reaction obtain 1-(the basic alkylsulfonyl of 6-chloronaphthalene-2-) piperazine hydrochloride, productive rate 58%.

Use relates to the similar approach described in the 3rd and 4 paragraphs of embodiment 55 parts of starting raw material preparation; make the product and the 1-tertiary butyloxycarbonyl phenylpiperidines-4-carboxylic acid reaction of gained; thereby obtain 1-(6-chloronaphthalene-2-base alkylsulfonyl)-4-(4-piperidino carbonyl) piperazine, productive rate 63%.Nuclear-magnetism spectrum (CDCl ₃) 1.5-1.75 (m, 4H), 2.4-2.7 (m, 3H), 3.0-3.2 (m, 6H), 3.5-3.75 (m, 4H), 7.55 (m, 1H), 7.75 (m, 1H), 7.95 (m, 3H), 8.3 (s, 1H). embodiment 70

Use embodiment 56 described similar approach, make 2-amino-4-chloropyrimide and 1-(6-chloronaphthalene-2-base alkylsulfonyl)-4-(4-piperidino carbonyl) piperazine reaction, work as reaction mixture, isolate sedimentary precipitation, with cold washing with alcohol, drying, thereby obtain 4-[1-(2-aminopyrimidine-4-yl) piperidin-4-yl carbonyl]-1-(6-chloronaphthalene-2-base alkylsulfonyl) piperazine, productive rate 73%, m.p.265-267 ℃; Nuclear-magnetism spectrum (CD ₃SOCD ₃) 1.0-1.4 (m, 4H), 2.5-2.7 (m, 3H), 2.7-2.9 (m, 4H), 3.3-3.5 (m, 4H), 4.08 (m, 2H), 5.7 (s, 2H), 5.8 (d, 1H), 7.5-7.7 (m, 3H), 7.75 (d, 1H), 8.05 (s, 1H), 8.1 (d, 1H), 8.3 (s, 1H); Ultimate analysis: C ₂₄H ₂₇ClN ₆O ₃S measured value: C, 55.9; H, 5.4; N, 15.9; Calculated value: C, 56.0; H, 5.3; N, 16.3%.Embodiment 71

Use embodiment 32 described similar approach; 3; 4; 5-trichlorine pyridazine and 1-(6-chloronaphthalene-2-base alkylsulfonyl)-4-(4-piperidino carbonyl) piperazine reaction; crude reaction product uses the mixture that increases polar methylene dichloride and ethyl acetate as eluent by the column chromatography purifying, thereby obtains 1-(6-chloronaphthalene-2-base alkylsulfonyl)-4-[1-(3; 4-dichloro-pyridazine-5-yl) piperidin-4-yl carbonyl] piperazine, productive rate 35%.Nuclear-magnetism spectrum (CD ₃SOCD ₃) 1.5-1.7 (m, 4H), 2.7-2.9 (m, 1H), 2.95-3.1 (m, 6H), 3.5-3.85 (m, 6H), 7.7 (m, 1H), 7.85 (m, 1H), 8.15 (d, 1H), 8.22 (s, 1H), 8.25 (d, 1H), 8.5 (s, 1H), 8.9 (s, 1H). embodiment 72

With 1-(6-chloronaphthalene-2-base alkylsulfonyl)-4-[1-(3,4-dichloro-pyridazine-5-yl) piperidin-4-yl carbonyl] piperazine (0.2g), the mixture of 10% Pd/carbon catalyst (0.05g) and ethanol (10ml) stirred 48 hours under nitrogen atmosphere, filtering mixt, evaporated filtrate, resistates column chromatography purifying, use increase polar methylene dichloride and methanol mixture as eluent, thereby obtain 1-(6-chloronaphthalene-2-base alkylsulfonyl)-4-[1-(4-pyridazinyl) piperidin-4-yl carbonyl] piperazine (0.045g, 25%); Nuclear-magnetism spectrum (CD ₃SOCD ₃) 1.4-1.7 (m, 4H), 2.6-3.1 (m, 7H), 3.5-3.7 (m, 4H), 3.9-4.0 (m, 2H), 6.85 (m, 1H), 7.7 (m, 1H), 7.82 (m, 1H), 8.15 (d, 1H), 8.27 (m, 2H), 8.5 (s, 1H), 8.55 (d, 1H), 8.9 (d, 1H). embodiment 73

With 1-(6-chloronaphthalene-2-base alkylsulfonyl)-4-(4-piperidino carbonyl) piperazine (0.96g), the mixture of triethylamine (0.35ml) and methylene dichloride (10ml) be added dropwise to stirring 2,4,6-three chloro-1,3, in methylene dichloride (20ml) solution (being cooled to 0 ℃) of 5-triazine (0.42g), mixture stirred 1 hour down at 5 ℃, evaporating mixture, resistates distributes between ethyl acetate and water, and organic phase washes with water, dry (sal epsom) and evaporation, resistates column chromatography purifying, use to increase polar methylene dichloride and methanol mixture as eluent, thus obtain 1-(6-chloronaphthalene-2-base alkylsulfonyl)-4-[1-(4,6-two chloro-1,3,5-triazine-2-yl) piperidin-4-yl carbonyl] piperazine (0.96g, 74%), m.p.230-233 ℃; Nuclear-magnetism spectrum (CDCl ₃) 1.7-1.9 (m, 4H), 2.7 (m, 1H), 3.0-3.2 (m, 6H), 3.55-3.85 (m, 4H), 4.73 (m, 2H), 7.6 (m, 1H), 7.75 (m, 1H), 7.95 (m, 3H), 8.3 (s, 1H); Ultimate analysis: C ₂₃H ₂₃Cl ₃N ₆O ₃S0.25CH ₂Cl ₂Measured value: C, 46.9; H, 3.9; N, 14.4; Calculated value: C, 47.3; H, 4.0; N, 14.2%.Embodiment 74

With 1-(4-pyridyl) piperazine (0.163g), DMF (5ml) mixture of 4-(6-chloronaphthalene-2-base alkylsulfonyl) piperazine-1-carboxylic acid 4-nitrophenyl ester (0.475g) stir and be heated to 100 ℃ 16 hours, evaporating mixture, resistates distributes between ethyl acetate and 2N aqueous hydrochloric acid, the aqueous sodium hydroxide solution alkalization water layer that adds dilution, the mixture ethyl acetate extraction, organic extract liquid drying (sal epsom) and evaporation, the solid of the gained mixture recrystallization of isohexane and ethyl acetate, thereby obtain 1-(6-chloronaphthalene-2-base alkylsulfonyl)-4-[4-(4-pyridyl) piperazine-1-base carbonyl] piperazine (0.34g); Nuclear-magnetism spectrum (CD ₃SOCD ₃) 2.95-3.05 (m, 4H), 3.15-3.3 (m, 12H), 6.75 (m, 2H), 7.75 (m, 1H), 7.8 (m, 1H), 8.1-8.3 (m, 5H), 8.5 (s, 1H); Ultimate analysis: C ₂₄H ₂₆ClN ₅O ₃S measured value: C, 57.5; H, 5.3; N, 13.9; Calculated value: C, 57.7; H, 5.2; N, 14.0%.

4-(6-chloronaphthalene-2-base alkylsulfonyl) piperazine-1-carboxylic acid 4-nitrophenyl ester as starting raw material is prepared as follows:

Methylene dichloride (15ml) solution of chloroformic acid 4-nitrophenyl ester (0.4g) is joined 1-(6-chloronaphthalene-2-base alkylsulfonyl) piperazine hydrochloride (0.69g) that is stirring, in the mixture of triethylamine (0.56m1) and methylene dichloride (30ml) (being cooled to 0 ℃), evaporating mixture, resistates distributes between ethyl acetate and dense sodium bicarbonate aqueous solution, organic solution 1N aqueous hydrochloric acid and water washing, dry (sal epsom) and evaporation, the solid of the gained mixture recrystallization of isohexane and ethyl acetate, thus 4-(6-chloronaphthalene-2-base alkylsulfonyl) piperazine-1-carboxylic acid 4-nitrophenyl ester (0.73g) obtained; Nuclear-magnetism spectrum (CD ₃SOCD ₃) 3.1 (m, 4H), 3.5-3.75 (m, 4H), 7.25 (m, 1H), 7.38 (d, 2H), 7.85 (m, 1H), 8.15-8.3 (m, 5H), 8.5 (s, 1H). embodiment 75

Use embodiment 1 described similar approach, make the reaction of 1-(4-pyridyl) piperidines-4-carbonyl chlorine and 4-(2-naphthyl alkylsulfonyl) piperidines obtain 4-(2-naphthyl alkylsulfonyl)-1-[1-(4-pyridyl) piperidin-4-yl carbonyl] piperidines, productive rate 33%; Nuclear-magnetism spectrum (CD ₃SOCD ₃) 1.42-1.82 (m, 6H), 1.85-2.21 (m, 2H), 2.82-3.04 (m, 4H), 3.73-3.98 (m, 5H), 4.43 (m, 1H), 6.78 (d, 2H), 7.64-7.89 (m, 3H), 8.04-8.27 (m, 5H), 8.37 (s, 1H).

4-(2-naphthyl alkylsulfonyl) piperidines as starting raw material is prepared as follows:

Triethylamine (8.8ml) is joined the 4-hydroxy piperidine-1-carboxylic acid tertiary butyl ester (European Patent Application No. 0495750 that is stirring; Chem.Abstracts; Vol.117; Abstract191869g; 6.38g); in the mixture of methylsulfonyl chlorine (3.7ml) and methylene dichloride (70ml) (being cooled to 0 ℃); mixture stirred 2 hours down at 0 ℃; evaporation then, resistates distributes between ethyl acetate and dense aqueous citric acid solution, and organic phase washes with water; dry (sal epsom) and evaporation; resistates column chromatography purifying as eluent, obtains 4-mesyloxy piperidines-1-carboxylic acid tertiary butyl ester (7.82g) with ethyl acetate.

With the mixture of a part of product (0.99g), 2-naphthalene sulfinic acid sodium (14.3g) and the DMF (70ml) of gained stir and be heated to 120 ℃ 5 hours; evaporating mixture; resistates distributes between ethyl acetate and 2N aqueous sodium hydroxide solution; organic phase drying (sal epsom) and evaporation are obtained 4-(2-naphthyl alkylsulfonyl) piperidines-1-carboxylic acid tert-butyl ester (0.64g), need not to be further purified then and can use.

The a part of product (0.56g) of gained and the mixture of trifluoroacetic acid (5ml) were at room temperature stirred 1 hour, mixture dilutes with ethyl acetate, wash with the 2N aqueous sodium hydroxide washes, organic layer drying (sal epsom) and evaporation obtain 4-(2-naphthyl alkylsulfonyl) piperidines (0.18g); Nuclear-magnetism spectrum (CD ₃SOCD ₃) 1.36-2.08 (m, 4H), 2.8-3.05 (m, 4H), 4.12-4.55 (m, 1H), 7.6-8.25 (m, 6H), 8.34 (s, 1H).

Above used 2-naphthalene sulfinic acid sodium be prepared as follows:

2-naphthalene sulfonyl base chlorine (15.9g) was joined in batches the-sulfinic acid sodium (33g) that is stirring in 2 hours; in the mixture of sodium bicarbonate (11.6g) and water (66ml) (being heated to 70 ℃); the mixture of gained stirred 1 hour down at 75 ℃; at room temperature stored 16 hours; isolate precipitation, thereby obtain 2-naphthalene sulfinic acid sodium (31g).Embodiment 76

Use embodiment 1 described similar approach, make the reaction of 1-(4-pyridyl) piperidines-4-carbonyl chlorine and 4-(2-naphthyl sulfenyl) piperidines obtain 4-(2-naphthyl sulfenyl)-1-[1-(4-pyridyl) piperidin-4-yl carbonyl] piperidines, productive rate 62%.Nuclear-magnetism spectrum (CD ₃SOCD ₃, 100 ℃) and 1.25-1.75 (m, 6H), 1.87-2.1 (broad s, 2H), 2.78-3.0 (m, 4H), 3.20 (d, 1H), 3.64 (m, 1H), 3.6-4.04 (m, 3H), 4.2 (d, 1H), 6.78 (d, 2H), 7.44-7.58 (m, 3H), 7.63-7.74 (m, 3H), 7.75 (d, 1H), 8.12 (s, 2H); Ultimate analysis: C ₂₆H ₂₉N ₃OS measured value: C, 72.2; H, 6.7; N, 9.7; Calculated value: C, 72.4; H, 6.8; N, 9.7%.

4-(naphthyl sulfenyl) piperidines as starting raw material is prepared as follows:

DMF (10ml) drips of solution of 2-naphthyl mercaptan (2.34g) is added the sodium hydride (60% that is stirring, dispersion liquid in mineral oil, 0.65g) and the mixture (being cooled to 10 ℃) of DMF (20ml) in, the mixture of gained stirred 30 minutes down at 0 ℃, be added dropwise in DMF (40ml) solution of 4-mesyloxy piperidines-1-carboxylic acid tertiary butyl ester (3.9g), mixture heating up is to room temperature, mixture distributes between ethyl acetate and water, organic phase washes with water, dry (sal epsom) and evaporation, resistates column chromatography purifying is used methylene dichloride as eluent, thereby is obtained 4-(2-naphthyl sulfenyl) piperidines-1-carboxylic acid tertiary butyl ester (0.65g).

The product of gained and the mixture of trifluoroacetic acid were at room temperature stirred 30 minutes, and mixture dilutes with ethyl acetate, washs with the 2N aqueous sodium hydroxide washes, and organic solution drying (sal epsom) and evaporation obtain 4-(2-naphthyl sulfenyl) piperidines (0.32g); Nuclear-magnetism spectrum (CD ₃SOCD ₃) 1.42 (m, 2H), 1.88 (m, 2H), 2.58 (m, 2H), 2.94 (m, 2H), 3.43 (m, 1H), 7.5 (m, 3H), 7.89 (m, 4H).Embodiment 77

Use embodiment 1 described similar approach; make the reaction of 1-(4-pyridyl) piperidines-4-carbonyl chlorine and 2-hydroxymethyl-4-(2-naphthyl alkylsulfonyl) piperazine obtain 2-hydroxymethyl-4-(2-naphthyl alkylsulfonyl)-1-[1-(4-pyridyl) piperidin-4-yl carbonyl] piperazine, productive rate 42%.Nuclear-magnetism spectrum (CD ₃SOCD ₃, 100 ℃) 1.55-1.72 (m, 2H), 1.83-1.95 (m, 2H), 2.35-3.05 (m, 8H), 3.49 (m, 2H), 3.7 (m, 2H), 4.01 (m, 2H), 6.72 (d, 2H), 7.63-7.79 (m, 3H), 8.0-8.2 (m, 5H), 8.39 (s, 1H); Ultimate analysis: C ₂₆H ₃₀N ₄O ₄S0.25EtAc0.75H ₂O measured value: C, 61.2; H, 6.2; N, 10.4; Calculated value: C, 61.2; H, 6.4; N, 10.6%.

Use embodiment 2 described similar approach, make 2-hydroxymethyl piperazine (J.Med.Chem., 1990,33,142) and 2-naphthyl alkylsulfonyl chlorine react 2-hydroxymethyl-4-(the 2-naphthyl alkylsulfonyl) piperazine that obtains as starting raw material, productive rate 49%.Nuclear-magnetism spectrum (CD ₃SOCD ₃) 1.93 (t, 1H), 2.24 (m, 2H), 2.68 (m, 2H), 2.93 (m, 1H), 3.6 (m, 2H), 4.67 (t, 1H), 7.76 (m, 3H), 8.07-8.28 (m, 3H), 8.44 (s, 1H). embodiment 78

With 1; 1 '-carbonyl dimidazoles (0.208g) joins in DMF (10ml) solution of the N-that stirring (6-chloronaphthalene-2-base alkylsulfonyl) glycine (0.39g); mixture at room temperature stirred 30 minutes; add 1-(4-pyridyl) piperazine (0.21g); mixture at room temperature stirred 18 hours; mixture distributes between ethyl acetate and water, organic phase salt water washing, dry (sal epsom) and evaporation.Resistates hexane, ethyl acetate and methanol mixture recrystallization, thereby obtain 1-[2-(6-chloronaphthalene sulfonamido) ethanoyl]-4-(4-pyridyl) piperazine (0.179g, 20%), m.p.192-193 ℃; Nuclear-magnetism spectrum (CD ₃SOCD ₃) 3.15 (m, 2H), 3.3-3.6 (m, 6H), 3.85 (m, 2H), 6.7-7.0 (m, 2H), 7.6 (m, 1H), 7.8-8.0 (m, 2H), 8.1-8.3 (m, 4H), 8.5 (s, 1H); Ultimate analysis: C ₂₁H ₂₁ClN ₄O ₃S measured value: C, 56.5; H, 4.8; N, 12.4; Calculated value: C, 56.7; H, 4.8; N, 12.6%.

N-(6-chloronaphthalene-2-base alkylsulfonyl) glycine as starting raw material is prepared as follows:

Triethylamine (0.278g) is joined in the mixture of 6-chloronaphthalene-2-base alkylsulfonyl chlorine (0.522g), glycine methyl ester hydrochloride (0.251g) and methylene dichloride (10ml); mixture at room temperature stirred 1 hour; mixture distributes between ethyl acetate and water; organic phase salt water washing; dry (sal epsom) and evaporation; the resistates recrystallizing methanol obtains N-(6-chloronaphthalene-2-base alkylsulfonyl) glycine methyl ester (0.46g).

The product of gained and the mixture of 2N aqueous sodium hydroxide solution (3ml) were at room temperature stirred 30 minutes, mixture distributes between ether and water, add 2N aqueous hydrochloric acid acidifying water, use ethyl acetate extraction, organic phase water and salt water washing, dry (sal epsom) and evaporation, thus required starting raw material (0.39g) obtained, need not to be further purified then and can use.Embodiment 79

With 1-(4 '-ethoxycarbonyl xenyl-4-base alkylsulfonyl)-4-[1-(4-pyridyl) piperidin-4-yl carbonyl] piperazine (0.08g), 2N aqueous sodium hydroxide solution (0.28ml), the mixture stirring of water (2ml) and methyl alcohol (10ml) and reflux 3 hours, mixture is poured in the water, with dichloromethane extraction filtered water suspension, once more the solid suspension that obtains in water, by adding Glacial acetic acid acidifying mixture, stirred 2 hours, isolate solid, water and ether washing, drying, thereby obtain 1-(4 '-carboxyl biphenyl-4-base alkylsulfonyl)-4-[1-(4-pyridyl) piperidin-4-yl carbonyl] piperazine (0.035g); Nuclear-magnetism spectrum (CD ₃SOCD ₃, 100 ℃) 1.6-1.86 (m, 4H), 3.0 (m, 1H), 3.15 (t, 4H), 3.32 (m, 2H), 3.63 (t, 4H), 3.97 (t, 1H), 4.03 (t, 1H), 7.01 (d, 2H), 7.24-7.96 (m, 6H), 8.09 (d, 4H). embodiment 80

With sulfur alcohol (0.15ml) be added dropwise to stirring be cooled to 3 ℃ sodium hydride (60% dispersion liquid in mineral oil; 0.083g) DMPU (3ml) suspension in; stir the mixture; be heated to room temperature 30 minutes; add 1-(6-methoxynaphthalene-2-base alkylsulfonyl)-4-[1-(4-pyridyl) piperidin-4-yl carbonyl] DMPU (2ml) solution of piperazine (0.1g); mixture stirred and is heated to 110 ℃ 90 minutes; mixture is cooled to room temperature; between methylene dichloride and water, distribute; organic phase and excessive a little 2M aqueous sodium hydroxide solution one oscillates; isolate the precipitation of gained, and dry.Thereby obtain 1-(6-hydroxyl naphthalene-2-base alkylsulfonyl)-4-[1-(4-pyridyl) piperidin-4-yl carbonyl] piperazine sodium salt (0.052g); Nuclear-magnetism spectrum (CD ₃SOCD ₃, 100 ℃) 1.5-1.73 (m, 4H), 2.72-3.23 (m, 7H), 3.55 (t, 4H), 3.68-3.88 (m, 2H), 6.72 (m, 2H), 6.8 (m, 1H), 6.96 (m, 1H), 7.45 (m, 2H), 7.69 (m, 1H), 7.99 (m, 1H), 8.11 (m, 2H); Ultimate analysis: C ₂₅H ₂₇N ₄O ₄S3H ₂ONa measured value: C, 53.8; H, 5.6; N, 10.0; Calculated value: C, 53.9; H, 5.9; N, 10.1%.Embodiment 81

Use embodiment 1 described similar approach, make 1-(4-pyridyl) piperidines-4-carbonyl chlorine and 2-[1-(2-naphthyl alkylsulfonyl) piperazine-2-yl] methyl acetate reaction obtains 2-methoxycarbonyl methyl isophthalic acid-(2-naphthyl alkylsulfonyl)-4-[1-(4-pyridyl) piperidin-4-yl carbonyl] piperazine, productive rate 90%, glassy mass; Nuclear-magnetism spectrum (CD ₃SOCD ₃+ CD ₃CO ₂D, 100 ℃) 1.6-1.85 (m, 4H), 2.4-2.65 (m, 2H), 2.85-3.35 (m, 6H), 3.55 (s, 3H), 3.78 (m, 1H), 3.9-4.1 (m, 4H), 4.45 (m, 1H), 6.95 (d, 2H), 7.68 (m, 2H), 7.8 (m, 1H), 7.95-8.15 (m, 5H), 8.45 (d, 1.H); Ultimate analysis: C ₂₈H ₃₂N ₄O ₅S0.5H ₂O measured value: C, 61.7; H, 6.3; N, 10.3; Calculated value: C, 61.65; H, 6.05; N, 10.3%.

As 2-[1-(the 2-naphthyl alkylsulfonyl) piperazine-2-yl of starting raw material] methyl acetate is prepared as follows:

Use embodiment 2 described similar approach; make 2-(1-benzyl diethylenediamine-3-yl) methyl acetate (J.Chem.Soc.Perkin I; 1992,1035) obtain 2-[4-benzyl-1-(2-naphthyl alkylsulfonyl) piperazine-2-yl with the reaction of 2-naphthyl alkylsulfonyl chlorine] methyl acetate, productive rate 90%.

Use relates to the similar approach described in second section of embodiment 44 parts of starting raw material preparation, the product of gained and chloroformic acid 1-chloroethene ester is reacted, thereby obtain 2-[1-(2-naphthyl alkylsulfonyl) piperazine-2-yl] methyl acetate, productive rate 87%.Nuclear-magnetism spectrum (CD ₃SOCD ₃) 2.55-2.7 (m, 2H), 2.9 (m, 1H), 3.05-3.45 (m, 4H), 3.55 (s, 3H), 3.9 (m, 1H), 4.6 (m, 1H), 7.65-7.9 (m, 3H), 8.12 (m, 3H), 8.55 (d, 1H), 9.3 (t, 2H). embodiment 82

Use embodiment 1 described similar approach, make 1-(4-pyridyl) piperidines-4-carbonyl chlorine and 1-(6-bromonaphthalene-2-base alkylsulfonyl) piperazine-3-carboxylic acid, ethyl ester reaction obtain 4-(6-bromonaphthalene-2-base alkylsulfonyl)-2-ethoxycarbonyl-1-[1-(4-pyridyl) piperidin-4-yl carbonyl] piperazine, productive rate 42%, m.p.117-121 ℃; Nuclear-magnetism spectrum (CD ₃SOCD ₃, 100 ℃) 1.2 (t, 3H), 1.5-1.8 (m, 4H), 2.55 (m, 1H), 2.7-3.05 (m, 5H), 3.65-3.85 (m, 3H), 4.05-4.25 (m, 4H), 5.08 (m, 1H), 6.7 (d, 2H), 7.77 (m, 2H), 8.1 (m, 4H), 8.3 (d, 1H), 8.45 (d, 1H). ultimate analysis: C ₂₈H ₃₁BrN ₄O ₅S measured value: C, 54.2; H, 5.2; N, 9.0; Calculated value: C, 54.6; H, 5.1; N, 9.1%.

Use relates to the described similar approach of embodiment 44 parts of starting raw material preparation; make the reaction of 1-benzyl diethylenediamine-2-carboxylic acid, ethyl ester and 6-bromonaphthalene-2-base alkylsulfonyl chlorine obtain 1-(6-bromonaphthalene-2-base alkylsulfonyl) piperazine-3-carboxylic acid, ethyl ester as starting raw material, productive rate 71%.Embodiment 83

Use embodiment 61 described similar approach, with 4-(6-bromonaphthalene-2-base alkylsulfonyl)-2-ethoxycarbonyl-1-[1-(4-pyridyl) piperidin-4-yl carbonyl] piperazine obtains 4-(6-bromonaphthalene-2-base alkylsulfonyl)-2-carboxyl-1-[1-(4-pyridyl) piperidin-4-yl carbonyl] piperazine, productive rate 92%, m.p.216-222 ℃ (decomposition); Nuclear-magnetism spectrum (CD ₃SOCD ₃, 100 ℃) 1.5-1.8 (m, 4H), 2.52 (m, 1H), 2.7 (m, 1H), 2.8-3.05 (m, 3H), 3.25 (m, 1H), 3.6-4.3 (m, 5H), 4.95 (m, 1H), 6.75 (d, 2H), 7.75 (m, 2H), 8.0-8.15 (m, 4H), 8.3 (d, 1H), 8.4 (d, 1H). ultimate analysis: C ₂₆H ₂₇BrN ₄O ₅S0.5H ₂O measured value: C, 52.4; H, 4.8; N, 9.3; Calculated value: C, 52.35; H, 4.7; N, 9.4%.Embodiment 84

Use embodiment 20 described similar approach, make 4-(6-bromonaphthalene-2-base alkylsulfonyl)-2-carboxyl-1-[1-(4-pyridyl) piperidin-4-yl carbonyl] piperazine obtains 4-(the basic alkylsulfonyl of 6-bromonaphthalene-2-)-2-morpholino carbonyl-1-[1-(4-pyridyl) piperidin-4-yl carbonyl with the morpholine reaction] piperazine, productive rate 60%, m.p.235-237 ℃; Nuclear-magnetism spectrum (CD ₃SOCD ₃, 100 ℃) 1.5-1.8 (m, 4H), 2.7-3.05 (m, 5H), 3.4 (m, 4H), 3.5-3.6 (m, 4H), 3.67 (m, 1H), 3.75-3.9 (m, 4H), 3.98 (m, 1H), 5.2 (m, 1H), 6.65-6.8 (m, 2H), 7.75 (m, 2H), 8.1 (m, 4H), 8.3 (d, 1H), 8.45 (d, 1H); Ultimate analysis: C ₃₀H ₃₄BrN ₅O ₅SH ₂O measured value: C, 53.7; H, 5.2; N, 10.2; Calculated value: C, 53.5; H, 5.35; N, 10.4%.Embodiment 85

With 1-(6-chloronaphthalene-2-base alkylsulfonyl)-4-[1-(4,6-two chloro-1,3,5-triazine-2-yl) piperidin-4-yl carbonyl] piperazine (0.891g), magnesium oxide (0.5g), the mixture of 10% Pd/carbon catalyst (0.2g) and DMF (15ml) stirs under nitrogen atmosphere up to the hydrogen picked-up and stops, filtering mixt, filtrate is distributed between ethyl acetate and water, with organic phase drying (sal epsom) and evaporation, thereby obtain 1-(2-naphthyl alkylsulfonyl)-4-[1-(1,3,5-triazines-2-yl) piperidin-4-yl carbonyl] piperazine (0.36g); Nuclear-magnetism spectrum (CD ₃SOCD ₃) 1.3-1.7 (m, 4H), 2.8-3.1 (m, 7H), 3.5-3.7 (m, 4H), 4.5-4.7 (m, 2H), 7.6-7.8 (m, 3H), 8.1-8.3 (m, 3H), 8.45 (s, 1H), 8.55 (s, 2H). embodiment 86

Use embodiment 56 described similar approach, make 2-amino-4-chloro-6-methylpyrimidine and 1-(6-chloronaphthalene-2-base alkylsulfonyl)-4-(4-piperidino carbonyl) piperazine reaction, the evaporation concentration reaction mixture is to half of original volume, be cooled to room temperature, isolate formed precipitation, wash with ether, dry, thereby obtain 4-[1-(2-amino-6-methylpyrimidine-4-yl) piperidin-4-yl carbonyl]-1-(6-chloronaphthalene-2-base alkylsulfonyl) piperazine, productive rate 39%, m.p.210-212 ℃; Nuclear-magnetism spectrum (CD ₃SOCD ₃) 1.2-1.6 (m, 4H), 2.0 (s, 3H), 2.8 (m, 3H), 2.9-3.1 (m, 4H), 3.5-3.7 (m, 4H), 4.2 (m, 2H), 5.82 (s, 2H), 5.86 (s, 1H), 7.7 (m, 1H), 7.8 (m, 1H), 8.2 (d, 1H), 8.25 (s, 1H), 8.3 (d, 1H), 8.5 (s, 1H); Ultimate analysis: C ₂₅H ₂₉ClN ₆O ₃S0.4H ₂O measured value: C, 56.3; H, 5.5; N, 15.3; Calculated value: C, 55.9; H, 5.6; N, 15.7%.Embodiment 87

Use embodiment 56 described similar approach, make 4-chloropyrimide and 4-(6-chloronaphthalene-2-base alkylsulfonyl)-1-(4-piperidino carbonyl) piperazine-2-carboxylic acid's methyl esters reaction, by column chromatography purification reaction product, using increases polar methylene dichloride and methanol mixture wash-out, obtain 4-(6-chloronaphthalene-2-base alkylsulfonyl)-2-methoxycarbonyl-1-[1-(4-pyridyl) piperidin-4-yl carbonyl] piperazine, productive rate 77%; Nuclear-magnetism spectrum 1.6-2.0 (m, 4H), 2.5 (m, 2H), 2.8 (m, 1H), 3.0 (m, 1H), 3.6-3.9 (m, 6H), 4.25-4.45 (m, 3H), 5.35 (m, 1H), 6.5 (d, 1H), 7.6 (m, 1H), 7.75 (m, 1H), 7.95 (m, 3H), 8.2 (d, 1H), 8.35 (s, 1H), 8.6 (s, 1H); Ultimate analysis: C ₂₆H ₂₈ClN ₅O ₅S0.2CH ₂Cl ₂Measured value: C, 54.5; H, 5.2; N, 11.8; Calculated value: C, 54.7; H, 4.9; N, 12.2%.

4-(6-chloronaphthalene-2-base alkylsulfonyl)-1-(4-piperidino carbonyl) piperazine-2-carboxylic acid's methyl esters as starting raw material is prepared as follows:

Benzyl chloroformate (8.5g) is added drop-wise to the piperidines-4-carboxylic acid, ethyl ester (7.85g) that is stirring, in the mixture of triethylamine (6.95ml) and methylene dichloride (50ml) (being cooled to 5 ℃), mixture at room temperature stirred 18 hours, mixture distributes between ethyl acetate and 2N aqueous hydrochloric acid, water and salt water washing organic phase, dry (sal epsom) and evaporation, resistates is dissolved in the methyl alcohol (100ml), add 2N aqueous sodium hydroxide solution (125ml), evaporation concentrated mixture, resistates distributes between ether and water, add concentrated hydrochloric acid acidifying water to pH be 3, the mixture ethyl acetate extraction, organic extract liquid washes with water, and dry (sal epsom) and evaporation obtain 1-carbobenzoxy-(Cbz) piperidines-4-carboxylic acid (10.1g).

Oxalyl chloride (0.429ml) and DMF (1) are joined in methylene dichloride (20ml) solution of the 1-carbobenzoxy-(Cbz) piperidines-4-carboxylic acid (0.622g) that is stirring, mixture at room temperature stirred 2 hours, evaporation then, resistates is dissolved in the methylene dichloride (10ml), be added drop-wise to 4-(6-chloronaphthalene-2-base alkylsulfonyl) piperazine-3-carboxylate methyl ester (0.93g) that is stirring then, in the mixture of triethylamine (0.7ml) and methylene dichloride (10ml) (being cooled to 0 ℃), mixture at room temperature stirred 2 hours, mixture distributes between ethyl acetate and 2N aqueous hydrochloric acid, the organic phase saturated sodium bicarbonate aqueous solution, water and salt water washing, dry (sal epsom) and evaporation, resistates column chromatography purifying, with the mixture that increases polar hexane and ethyl acetate as eluent, thereby obtain 1-(1-carbobenzoxy-(Cbz) piperidin-4-yl carbonyl)-4-(6-chloronaphthalene-2-base alkylsulfonyl) piperazine-2-carboxylic acid's methyl esters (1.21g); Nuclear-magnetism spectrum 1.4-1.9 (m, 4H), 2.3-2.7 (m, 3H), 2.85 (m, 2H), 3.5-3.9 (m, 6H), 4.15 (m, 2H), 4.35 (m, 1H), 5.1 (s, 2H), 5.3 (m, 1H), 7.2-7.4 (m, 5H), 7.6 (m, 1H), 7.75 (m, 1H), 7.75-8.0 (m, 3H), 8.3 (s, 1H).

The mixture of Glacial acetic acid (5ml) solution of a part of product (0.512g) of gained and saturated bromize hydrogen gas was at room temperature stirred 20 minutes; add ether (100ml); the vigorous stirring mixture; isolate precipitation; wash with ether; drying, thus 4-(6-chloronaphthalene-2-base alkylsulfonyl)-1-(4-piperidino carbonyl) piperazine-2-carboxylic acid's methyl esters obtained, need not to be further purified then and can use.

Use relates to the described similar approach of embodiment 44 parts of starting raw material preparation; make 1-benzyl diethylenediamine-2-carboxylate methyl ester (by being similar to Chim.Acta. at Helv; 1962; 45; the mode of the corresponding ethyl ester described in 2383 prepares) react 4-(6-chloronaphthalene-2-base alkylsulfonyl) piperazine-3-carboxylate methyl ester that obtains as above-mentioned intermediate with 6-chloronaphthalene-2-base alkylsulfonyl chlorine, embodiment 88

With 4-(6-chloronaphthalene-2-base alkylsulfonyl)-2-methoxycarbonyl-1-[1-(4-pyridyl) piperidin-4-yl carbonyl] the mixture stirring of piperazine (0.362g), 1N aqueous sodium hydroxide solution (1.3ml) and methyl alcohol (5ml) and reflux 30 minutes, mixture is by adding 2N aqueous hydrochloric acid (2ml) acidifying, evaporation, dried residue obtains 2-carboxyl-4-(6-chloronaphthalene-2-base alkylsulfonyl)-1-[1-(4-pyridyl) piperidin-4-yl carbonyl] piperazine (0.41g); Nuclear-magnetism spectrum (CD ₃SOCD ₃) 1.4-1.9 (m, 4H), 2.1-2.5 (m, 1H), 3.0-3.75 (m, 8H), 4.0-4.3 (m, 2H), 5.12 (m, 1H), 7.2 (m, 1H), 7.7 (m, 1H), 7.85 (m, 1H), 8.1-8.3 (m, 4H), 8.55 (s, 1H), 8.75 (s, 1H); Ultimate analysis: C ₂₅H ₂₆ClN ₅O ₅S2NaCl2H ₂OHCl measured value: C, 41.0; H, 4.2; N, 9.4; Calculated value: C, 40.9; H, 4.3; N, 9.6%.Embodiment 89

Methylene dichloride (2ml) solution of (E)-4-chloro-styrene base alkylsulfonyl chlorine (0.12g) is joined 4-[4-(4-pyridyl) piperazine-1-base carbonyl that is stirring] in methylene dichloride (10ml) suspension of aniline (0.141g), mixture at room temperature stirred 64 hours, isolate the solid of gained, use washed with dichloromethane, resistates column chromatography purifying, with 10: 1 methylene dichloride and methanol mixture as eluent, thereby obtain N-{4-[4-(4-pyridyl) piperazine-1-base carbonyl] phenyl }-(E)-and 4-chloro-styrene base sulphonamide (0.089g), m.p.207-209 ℃; Nuclear-magnetism spectrum (CD ₃SOCD ₃, 100 ℃) 3.43 (m, 4H), 3.6 (m, 4H), 6.8 (d, 2H), 7.15 (d, 1H), 7.27 (d, 2H), 7.3-7.5 (m, 5H), 7.63 (d, 2H), 8.16 (d, 2H); Ultimate analysis: C ₂₄H ₂₃ClN ₄O ₃S0.25H ₂O measured value: C, 59.0; H, 4.9; N, 11.3; Calculated value: C, 59.1; H, 4.9; N, 11.5%.

As 4-[4-(4-pyridyl) piperazine of starting raw material-1-base carbonyl] aniline is prepared as follows:

4-nitro benzoyl chlorine (4.64g) is joined 1-(4-pyridyl) piperazine (4.08g) that is stirring; in the mixture of triethylamine (3.48ml) and DMF (50ml) (being cooled to 4 ℃); mixture stirred 1 hour down at 4 ℃; at room temperature stirred 16 hours; mixture distributes between methylene dichloride and water; organic phase salt water washing; dry (sal epsom) and evaporation; resistates column chromatography purifying; use 10: 1 methylene dichloride and methanol mixture as eluent; thereby obtain 4-[4-(4-pyridyl) piperazine-1-base carbonyl] oil of mirbane (5.09g), m.p.158-160 ℃.

A part of product (3.74g) with gained, 10% Pd/carbon catalyst (0.3g), the mixture of 1N aqueous hydrochloric acid (24ml) and methyl alcohol (75ml) stirs under nitrogen atmosphere up to the hydrogen picked-up and stops, filtering mixt, evaporated filtrate, in the resistates water-soluble (25ml), by add the 1N aqueous sodium hydroxide solution make solution alkalize to pH be 10, isolate the precipitation of gained, wash with water, drying, thereby obtain 4-[4-(4-pyridyl) piperazine-1-base carbonyl] aniline (2.91g), m.p.254-256 ℃.Embodiment 90

Use embodiment 89 described similar approach, make 4-[4-(4-pyridyl) piperazine-1-base carbonyl] aniline and 4 '-reaction of bromo-4-biphenyl sulfonyl chlorine obtains the basic carbonyl of N-{4-[4-(4-pyridyl) piperazine-1-] phenyl }-4 '-bromo-4-biphenyl sulfonamides hydrochloride, productive rate 90%, m.p.201-205 ℃; Nuclear-magnetism spectrum (CD ₃SOCD ₃) 3.6 (m, 4H), 3.73 (m, 4H), 7.18 (m, 4H), 7.39 (m, 2H), 7.69 (s, 4H), 7.9 (s, 4H), 8.27 (d, 2H); Ultimate analysis: C ₂₈H ₂₅BrN ₄O ₃SHCl0.5H ₂O measured value: C, 54.0; H, 4.4; N, 9.0; Calculated value: C, 54.0; H, 4.4; N, 9.9%.Embodiment 91

Use embodiment 20 described similar approach, make 4-(6-bromonaphthalene-2-base alkylsulfonyl)-2-carboxyl-1-[1-(4-pyridyl) piperidin-4-yl carbonyl] piperazine obtains 4-(the basic alkylsulfonyl of 6-bromonaphthalene-2-)-2-[N-(methoxycarbonyl methyl) formamyl with the glycine methyl ester reaction]-1-[1-(4-pyridyl) piperidin-4-yl carbonyl] piperazine, productive rate 76% is glassy mass; Nuclear-magnetism spectrum (CD ₃SOCD ₃, 100 ℃) 1.55-1.8 (m, 4H), 2.55-3.1 (m, 6H), 3.4 (m, 1H), 3.65 (s, 3H), 3.7-3.95 (m, 4H), 4.15 (m, 2H), 4.95 (m, 1H), 6.75 (d, 2H), 7.7-7.9 (m, 3H), 8.05-8.15 (m, 4H), 8.3 (d, 1H), 8.4 (d, 1H); Ultimate analysis: C ₂₉H ₃₂BrN ₅O ₆S0.75H ₂O measured value: C, 51.9; H, 5.0; N, 10.2; Calculated value: C, 51.9; H, 5.0; N, 10.4%.Embodiment 92

Use embodiment 2 described similar approach, make 1-(4-piperidino carbonyl)-4-(4-pyridyl) piperazine and 6-bromonaphthalene-2-base alkylsulfonyl chlorine reaction obtain 1-[1-(6-bromonaphthalene-2-base alkylsulfonyl) piperidin-4-yl carbonyl]-4-(4-pyridyl) piperazine, productive rate 20%, m.p.229-230 ℃; Nuclear-magnetism spectrum (CD ₃SOCD ₃) 1.6 (m.4H), 2.3-2.7 (m, 3H), 3.5-3.8 (m, 10H), 6.8 (d, 2H), 7.8 (d, 2H), 8.2 (t, 4H), 8.4 (d, 1H), 8.5 (d, 1H).

1-(4-piperidino carbonyl)-4-(4-pyridyl) piperazine as starting raw material is prepared as follows:

Tert-Butyl dicarbonate (5.09g) is joined the piperidines-4-carboxylic acid (3g) that is stirring, yellow soda ash (2.48g), 1, in the mixture of 4-diox (20ml) and water (20ml) (being cooled to 0 ℃), mixture at room temperature stirred 18 hours, evaporation concentrated mixture is to 1/3rd of original volume, add saturated sodium bisulfate, the pH that makes solution is 2 to 3, the mixture ethyl acetate extraction, organic phase water and salt water washing, dry (sal epsom) and evaporation obtain 1-tertiary butyloxycarbonyl phenylpiperidines-4-carboxylic acid (4.36g), need not to be further purified then and can use.

Use embodiment 14 described similar approach, a part of product (1.41g) and the reaction of 1-(4-pyridyl) piperazine of gained obtained 1-(1-tertbutyloxycarbonyl piperidin-4-yl carbonyl)-4-(4-pyridyl) piperazine, productive rate 20%; Nuclear-magnetism spectrum (CD ₃SOCD ₃) 1.4 (s, 9H), 1.6 (m, 2H), 2.9 (m, 6H), 3.4 (s, 2H), 3.6 (d, 3H), 4.0 (m, 4H), 7.0-8.0 (m, 4H).

The mixture of product (0.45g), 4N aqueous hydrochloric acid (2ml) and the ether (15ml) of gained was at room temperature stirred 18 hours, evaporating mixture, obtain 1-(4-piperidino carbonyl)-4-(4-pyridyl) piperazine (0.31g), need not to be further purified then and can use.Embodiment 93

The following describes the representational pharmaceutical dosage form that contains formula I compound or pharmaceutically acceptable salt thereof (compounds X hereinafter referred to as), it is used for people's treatment or prophylactic applications: (a) Table I mg/ tablet

Compounds X 100

Lactose Ph.Eur 182.75

Croscarmellose sodium 12.0

Corn starch paste (5%w/v paste) 2.25

Magnesium Stearate 3.0 (b) Table II mg/ tablet

Compounds X 50

Lactose Ph.Eur 223.75

Croscarmellose sodium 6.0

W-Gum 15.0

Polyvinylpyrrolidone (5%w/v paste) 2.25

Magnesium Stearate 3.0 (c) Table III mg/ tablet

Compounds X 1.0

Lactose Ph.Eur 93.25

Croscarmellose sodium 4.0

Corn starch paste (5%w/v paste) 0.75

Magnesium Stearate 1.0 (d) capsule mg/ capsule

Compounds X 10

Lactose Ph.Eur 488.5

Magnesium Stearate 1.5 (e) injection liquid I (50mg/ml)

Compounds X 5.0%w/v

1M sodium hydroxide solution 15.0%v/v

0.1M hydrochloric acid (regulating pH to 7.6)

Poly(oxyethylene glycol) 400 4.5%w/v

Injection water to 100% (f) injection liquid II 10mg/ml

Compounds X 1.0%w/v

Sodium phosphate BP 3.6%w/v

0.1M sodium hydroxide solution 15.0%v/v

(1mg/ml is buffered to injection water to 100% (g) injection liquid III

PH is 6)

Compounds X 0.1%w/v

Sodium phosphate BP 2.26%w/v

Citric acid 0.38%w/v

Poly(oxyethylene glycol) 400 3.5%w/v

Injection water to 100% is annotated:

Above-mentioned preparation can make by the known ordinary method of pharmacy field, and the available ordinary method of tablet (a)-(c) is carried out enteric coating, and a kind of dressing of fiber acetate phthalate for example is provided.

Chemical molecular formula

Claims

1. the amino-heterocycles derivative of formula I or its pharmacologically acceptable salt:

G wherein ¹Be CH or N; G ²Be CH or N; G ³Be CH or N; M is 1 or 2; R ¹Be hydrogen, amino, halo, cyano group, (1-4C) alkyl or (1-4C) alkoxyl group; M ¹Be the following formula group:

NR ²-L ¹-T ¹R ³R wherein ²And R ³Form (1-4C) alkylidene group or methylene radical carbonyl together, or R ³Be (2-3C) alkylidene group, it and L ¹In methylene radical be connected to form and comprise T ¹And R ³5 or 6 yuan of rings, L ¹Be (1-4C) alkylidene group, (3-6C) cycloalkyl-1,2-two base or (1-3C) alkylidene group carbonyl, and T ¹Be CH or N, and wherein at L ¹In 1 or 2 methylene radical and work as R ²And R ³Or R ³And L ¹The ring that is connected to form is optional to have a substituting group, and this substituting group is selected from (1-4C) alkyl, the alkyl of hydroxyl-(1-4C), and (1-4C) alkyl of alkyl of alkoxyl group-(1-4C) and phenyl-(1-4C), and at M ¹In any phenyl optional have 1 or 2 substituting groups, described substituting group is selected from halo, trifluoromethyl, (1-4C) alkyl and (1-4C) alkoxyl group; A is the direct key that is connected with carbonyl, or A is (1-4C) alkylidene group; M ²Be the following formula group:

L ³-(NR ⁶) _sWherein s is 0 or 1, R ⁶Be hydrogen or (1-4C) alkyl, or R ⁵And R ⁶Form (1-4C) alkylidene group, methylene radical carbonyl or carbonyl methylene radical, or R together ⁶Be (2-3C) alkylidene group, it and L ³In methylene radical be connected to form and comprise NR ⁶5 or 6 yuan of rings, L ³Be (1-4C) alkylidene group, (3-6C) cycloalkanes-1,2-two bases, carbonyl-(1-3C) alkylidene group or phenylene, and when s is 1, L ³Also can be (1-3C) alkylidene group-carbonyl, and wherein at L ³In 1 or 2 methylene radical and work as R ⁵And R ⁶Or R ⁶And L ³The ring that is connected to form is chosen wantonly and is had a substituting group; this substituting group is selected from oxo; carboxyl; (1-4C) carbalkoxy; formamyl; N-(1-4C) alkyl-carbamoyl; N; N-two-(1-4C) alkyl-carbamoyls; tetramethyleneimine-1-base carbonyl; the piperidino-(1-position only) carbonyl; morpholino carbonyl; piperazine-1-base carbonyl; 4-(1-4C) alkylpiperazine-1-base carbonyl; N-phenyl amino formyl radical; N-(1-4C) alkyl-N-phenyl amino formyl radical; the alkyl of N-[phenyl-(1-3C)] formamyl; the alkyl of N-(1-4C) alkyl-N-[phenyl-(1-3C)] formamyl; (1-4C) alkyl; the alkyl of carboxyl-(1-4C); (1-4C) alkyl of alkoxy carbonyl-(1-4C); the alkyl of formamyl-(1-4C); the alkyl of N-(1-4C) alkyl-carbamoyl-(1-4C); N; the alkyl of N-two-(1-4C) alkyl-carbamoyls-(1-4C); the alkyl of tetramethyleneimine-1-base carbonyl-(1-4C); the alkyl of piperidino-(1-position only) carbonyl-(1-4C); the alkyl of morpholino carbonyl-(1-4C); the alkyl of piperazine-1-base carbonyl-(1-4C); the alkyl of 4-(1-4C) alkylpiperazine-1-base carbonyl-(1-4C); the alkyl of N-phenyl amino formyl radical-(1-4C); the alkyl of N-[phenyl-(1-3C)] alkyl of formamyl-(1-4C); the alkyl of hydroxyl-(1-4C); (1-4C) alkyl of alkyl of alkoxyl group-(1-4C) and phenyl-(1-4C); and have 1 or 2 substituting group in that described substituent any heterocyclic radical is optional; substituting group is selected from (1-4C) alkyl; (1-4C) alkoxyl group; carboxyl; (1-4C) carbalkoxy; formamyl; N-(1-4C) alkyl-carbamoyl or N; N-two (1-4C) alkyl-carbamoyl, and at M ³In any phenyl or phenylene is optional has 1 or 2 substituting groups, described substituting group is selected from halo, trifluoromethyl, (1-4C) alkyl and (1-4C) alkoxyl group; X is oxygen, sulphur, sulfinyl, alkylsulfonyl, carbonyl, carbonyl oxygen base, carbonylamino, N-(1-4C) alkyl-carbonyl-amino, sulfuryl amino, methylene radical, (1-4C) alkyl methylene radical or two-(1-4C) alkyl methylene radical or works as T ³Be CH, M ³For with direct key that X is connected the time, X also is amino-sulfonyl or oxygen carbonyl; With Q be phenyl; naphthyl; the alkyl of phenyl-(1-4C); the alkenyl of phenyl-(2-4C); the alkynyl of phenyl-(2-4C); (5-7C) cycloalkyl or contain at the most 4 and be selected from nitrogen; the heteroatomic heterocyclic moiety of oxygen and sulphur; Q is optional to have 1; 2 or 3 substituting groups; substituting group is selected from hydroxyl; amino; halo; cyano group; trifluoromethyl; nitro; carboxyl; formamyl; formyl radical; formimino; first hydroxyl oximido; (1-4C) carbalkoxy; (1-4C) alkyl; (1-4C) alkoxyl group; N-(1-4C) alkyl-carbamoyl; N; N-two-(1-4C) alkyl-carbamoyls; (1-4C) alkylamino; two-(1-4C) alkylaminos; (2-4C) alkanoyl amino; (2-4C) alkanoyl; (2-4C) alkane acylimino; (2-4C) alkanoyl hydroxyl oximido; phenyl; heteroaryl; phenoxy group; thiophenyl; the phenyl sulfinyl; phenyl sulfonyl; heteroaryl oxygen base; the heteroaryl sulfenyl; the heteroaryl sulfinyl; heteroarylsulfonyl; benzyl and benzoyl; and wherein said heteroaryl substituting group or the heteroaryl in containing the substituting group of heteroaryl comprise that containing at the most 3 is selected from nitrogen; heteroatomic 5 or 6 yuan of bicyclic heteroaryl rings of oxygen and sulphur; and described phenyl; heteroaryl; phenoxy group; thiophenyl; the phenyl sulfinyl; phenyl sulfonyl; heteroaryl oxygen base; the heteroaryl sulfenyl; the heteroaryl sulfinyl; heteroarylsulfonyl; benzyl or benzoyl substituting group are optional to have 1; 2; 3 or 4 substituting groups; substituting group is selected from halo; trifluoromethyl; cyano group; trifluoromethoxy; nitro; (1-4C) alkyl; (1-4C) alkoxyl group; hydroxyl; amino; carboxyl; formamyl; (1-4C) carbalkoxy; N-(1-4C) alkyl-carbamoyl; N, N-two-(1-4C) alkyl-carbamoyls; (1-4C) alkylamino; two-(1-4C) alkylaminos; (2-4C) alkanoyl amino and tetrazyl.

2. by amino-heterocycles derivative or its pharmacologically acceptable salt of the formula I of claim 1: G wherein ¹, G ²And G ³CH or G respectively do for oneself ¹, G ²The CH that respectively does for oneself, G ³Be N, or G ¹Be N, G ²And G ³CH respectively does for oneself; M is 1 or 2, R ¹Independently be selected from hydrogen separately, amino, fluorine, chlorine, bromine, cyano group, methyl, ethyl and methoxyl group; M ¹Be the following formula group:

(T ²R ⁴) _r-L ²-T ³R ⁵Wherein r is 0 or 1, T ²Be CH or N, T ³Be N, R ⁴Be hydrogen, methyl or ethyl, R ⁵Be hydrogen, methyl or ethyl or R ⁴And R ⁵Form methylene radical together, ethylidene, trimethylene or methylene radical carbonyl, or R ⁴Be ethylidene, it and L ²In methylene radical be connected to form and comprise R ⁴And T ²5 or 6 yuan of rings, L ²Be methylene radical, ethylidene, trimethylene, methylene radical carbonyl or phenylene, and wherein at L ²In 1 or 2 methylene radical and R ⁴And R ⁵The ring that is connected to form is chosen wantonly and is had a substituting group, this substituting group is selected from oxo, carboxyl, methoxycarbonyl, ethoxycarbonyl, formamyl, N-methylamino formyl radical, N, the N-formyl-dimethylamino, tetramethyleneimine-1-base carbonyl, the piperidino-(1-position only) carbonyl, morpholino carbonyl, piperazine-1-base carbonyl, 4-methylpiperazine-1-base carbonyl, methyl, ethyl, the carboxyl methyl, the methoxycarbonyl methyl, the ethoxy carbonyl methyl, hydroxymethyl, methoxymethyl and benzyl, and tetramethyleneimine-1-base carbonyl wherein, the piperidino-(1-position only) carbonyl, morpholino carbonyl, piperazine-1-base carbonyl or 4-methylpiperazine-optional methyl or ethyl substituting group of having of 1-base carbonyl substituted base; M ³Be the direct key that is connected with X, or M ³Be the following formula group:

L ³-(NR ⁶) _sWherein s is 1, R ⁶Be hydrogen, L ³Be carbonyl methylene radical or carbonyl ethylidene; X is sulphur, sulfinyl, alkylsulfonyl, carbonyl, carbonyl oxygen base or methylene radical; Q is a phenyl, naphthyl, benzyl, styroyl, styryl; 2-phenylacetylene base, dibenzofuran group, xenyl, pyridyl phenyl or pyridyl thienyl, and Q is optional has 1; 2 or 3 substituting groups, substituting group is selected from hydroxyl, amino, fluorine, chlorine; bromine, iodine, cyano group, trifluoromethyl; nitro, carboxyl, formamyl, methoxycarbonyl; ethoxy carbonyl, methyl, ethyl, methoxyl group and oxyethyl group.

3. by formula I amino-heterocycles derivative or its pharmacologically acceptable salt of claim 1: G wherein ¹, G ²And G ³CH or G respectively do for oneself ¹, G ²The CH that respectively does for oneself, G ³Be N, or G ¹Be N, G ²And G ³CH respectively does for oneself; M is 1 or 2, R ¹Independently be selected from hydrogen separately, amino, chlorine, methyl and ethyl; M ¹Be the following formula group:

L ³-(NR ⁶) _sWherein s is 1, R ⁶Be hydrogen, L ³Be the carbonyl methylene radical; X is an alkylsulfonyl; Q is a phenyl, naphthyl, benzyl, styroyl, styryl, 2-phenylacetylene base, dibenzofuran group, xenyl, pyridyl phenyl or pyridyl thienyl, and Q is optional has 1 or 2 substituting group, and substituting group is selected from fluorine, chlorine, bromine, iodine, methyl, ethyl, methoxyl group and oxyethyl group.

4. by amino-heterocycles derivative or its pharmacologically acceptable salt of the formula Ia of claim 1: G wherein ³Be CH or N, G ¹, G ²CH respectively does for oneself; M is 1, R ¹Be hydrogen; M ¹Be the following formula group:

L ³-(NR ⁶) _sWherein s is 1, R ⁶Be hydrogen, L ³Be carbonyl methylene radical or carbonyl ethylidene; X is an alkylsulfonyl; Q is 3-or 4-xenyl, with ring that X is connected in optionally have 1 or 2 substituting group, substituting group is selected from hydroxyl, fluorine, chlorine, bromine, cyano group, trifluoromethyl, methyl, ethyl, methoxyl group and oxyethyl group, and optional 4 substituting groups at the most that have in the phenyl endways, substituting group is selected from fluorine, chlorine, bromine, trifluoromethyl, cyano group, trifluoromethoxy, methyl, ethyl, methoxyl group and oxyethyl group.

5. by amino-heterocycles derivative or its pharmacologically acceptable salt of the formula I of claim 1: G wherein ³Be CH or N, G ¹, G ²CH respectively does for oneself; M is 1, R ¹Be hydrogen; M ¹Be the following formula group:

(T ²R ⁴) _r-L ²-T ³R ⁵Wherein r is 1, T ²Be CH or N, T ³Be N, R ⁴Be hydrogen, methyl or ethyl, R ⁵Be hydrogen, methyl or ethyl, or R ⁴And R ⁵Form ethylidene together, ethylidene or trimethylene or R ⁴Be ethylidene, it and L ²In methylene radical be connected to form and comprise R ⁴And T ²5 or 6 yuan of rings, L ²Be methylene radical, ethylidene or trimethylene, and wherein at L ²In 1 or 2 methylene radical and R ⁴And R ⁵The ring that is connected to form is chosen wantonly and is had a substituting group, this substituting group is selected from oxo, carboxyl, methoxycarbonyl, ethoxycarbonyl, formamyl, N-methylamino formyl radical, N, N-formyl-dimethylamino, tetramethyleneimine-1-base carbonyl, piperidino-(1-position only) carbonyl, morpholino carbonyl, methyl, ethyl and benzyl, and wherein tetramethyleneimine-1-base carbonyl or optional methyl or the ethyl substituting group of having of piperidino-(1-position only) carbonyl substituted base; M ³Be the direct key that is connected with X, or M ³Be the following formula group:

L ³-(NR ⁶) _sWherein s is 1, R ⁶Be hydrogen, L ³Be carbonyl methylene radical or carbonyl ethylidene; X is an alkylsulfonyl; Q is a phenyl, styroyl, styryl or 2-phenylacetylene base, and it is chosen wantonly and has 1,2 or 3 substituting group, and substituting group is selected from fluorine, chlorine, bromine, cyano group, trifluoromethyl, methyl, ethyl, methoxyl group and oxyethyl group.Or its pharmacologically acceptable salt.

6. the amino-heterocycles derivative of formula Ia:

G wherein ¹, G ²The CH that respectively does for oneself, G ¹Be N and G ²Be CH, or G ¹Be CH and G ²Be N; M is 1, R ¹Be hydrogen; M ¹Be the following formula group:

L ³-(NR ⁶) _sWherein s is 1, R ⁶Be hydrogen, L ³Be the carbonyl methylene radical; X is an alkylsulfonyl; Q is the 2-naphthyl, and it is chosen wantonly and has 1 or 2 substituting group, and substituting group is selected from fluorine, chlorine, bromine, trifluoromethyl, methyl, methoxyl group and oxyethyl group.

7. press the amino-heterocycles derivative of the formula I of claim 1; it is selected from following compounds or its pharmaceutically useful acid salt: 2-(2-naphthalene sulfonyl amino)-N-{1-piperidino-(1-position only) carbonyl-2-[1-(4-pyridyl)-piperidin-4-yl carbonylamino] ethyl } ethanamide; 1-(2-naphthalene sulfonyl base)-4-[1-(4-pyridyl)-piperidin-4-yl carbonyl]-piperazine; 2-(2-naphthalene sulfonyl amino)-N-(1-piperidino-(1-position only) carbonyl-2-{2-[1-(4-pyridyl)-piperidin-4-yl] kharophen } ethyl) ethanamide; 2-(2-naphthalene sulfonyl amino)-N-(1-piperidino-(1-position only) carbonyl-2-{2-[4-(4-pyridyl)-piperazine-1-yl] kharophen } ethyl) ethanamide; 2-(2-naphthalene sulfonyl amino)-3-[1-(4-pyridyl) piperidin-4-yl carbonylamino] ethyl propionate; 1-[1-(2-naphthalene sulfonyl base) piperidin-4-yl carbonyl]-4-(4-pyridyl)-piperazine, 2-(2-naphthalene sulfonyl amino)-N-{1-phenyl-3-[1-(4-pyridyl)-piperidin-4-yl carbonylamino] third-2-yl } ethanamide.4-[1-(4-pyridyl) piperidin-4-yl carbonyl]-1-[(E)-and the styryl alkylsulfonyl] piperazine; 1-[(E)-4-chloro-styrene base alkylsulfonyl]-4-[1-(4-pyridyl) piperidin-4-yl carbonyl] piperazine; 1-[(E)-4-vinyl toluene base alkylsulfonyl]-4-[1-(4-pyridyl) piperidin-4-yl carbonyl] piperazine; 4-[(E)-4-chloro-styrene base alkylsulfonyl]-2-methyl isophthalic acid-[1-(4-pyridyl) piperidin-4-yl carbonyl] piperazine; the 1[4-biphenyl sulfonyl]-4-[1-(4-pyridyl) piperidin-4-yl carbonyl] piperazine; 1-(4 '-chloro-4-biphenyl sulfonyl)-4-[1-(4-pyridyl) piperidin-4-yl carbonyl] piperazine; 1-[(E)-4-chloro-styrene base alkylsulfonyl]-4-[1-(4-pyrimidyl) piperidin-4-yl carbonyl] piperazine; 1-(7-chloronaphthalene-2-base alkylsulfonyl)-4-[1-(4-pyridyl) piperazine-4-base carbonyl] piperazine; 2-ethoxy carbonyl-4-(2-naphthyl alkylsulfonyl)-1-[1-[1-(4-pyridyl) piperazine-4-base carbonyl] piperazine; 1-(2-naphthyl alkylsulfonyl)-4-[1-(4-pyrimidyl) piperazine-4-base carbonyl] piperazine; 1-[(E)-4-fluorobenzene vinylsulfonyl]-4-[1-(4-pyridyl) piperidin-4-yl carbonyl] piperazine; 1-[(E)-4-bromstyrol base alkylsulfonyl]-4-[1-(4-pyridyl) piperidin-4-yl carbonyl] piperazine; 1-(4 '-bromo-4-biphenyl sulfonyl]-4-[1-(4-pyridyl) piperidin-4-yl carbonyl] piperazine; 1-(6-chloronaphthalene-2-base alkylsulfonyl]-4-[1-(4-pyridyl) piperidin-4-yl carbonyl] piperazine; 1-(6-bromonaphthalene-2-base alkylsulfonyl]-4-[1-(4-pyridyl) piperidin-4-yl carbonyl] piperazine; 1-(6-chloronaphthalene-2-base alkylsulfonyl]-4-[4-(4-pyridyl) piperazine-1-base carbonyl] piperazine; 4-(2-naphthyl alkylsulfonyl]-2-piperidino-(1-position only) carbonyl-1-[1-(4-pyridyl) piperidin-4-yl carbonyl] piperazine; 4-(6-chloronaphthalene-2-base alkylsulfonyl)-2-ethoxy carbonyl-1-[1-(4-pyridyl) piperidin-4-yl carbonyl] piperazine; 2-carboxyl-4-(6-chloronaphthalene-2-base alkylsulfonyl]-1-[1-(4-pyridyl) piperidin-4-yl carbonyl] piperazine; 1-(6-chloronaphthalene-2-base alkylsulfonyl]-4-[1-(4-pyrimidyl) piperidin-4-yl carbonyl] piperazine; 4-[1-(2-aminopyrimidine-4-yl) piperidin-4-yl carbonyl]-1-(6-chloronaphthalene-2-base alkylsulfonyl] piperazine; 1-(6-chloronaphthalene-2-base alkylsulfonyl]-4-[1-(4-pyridazinyl) piperidin-4-yl carbonyl] piperazine; 4-(6-bromonaphthalene-2-base alkylsulfonyl)-2-ethoxycarbonyl-1-[1-(4-pyridyl)-piperidin-4-yl carbonyl] piperazine; 4-(6-bromonaphthalene-2-base alkylsulfonyl)-2-carboxyl-1-[1-(4-pyridyl)-piperidin-4-yl carbonyl] piperazine; 4-(6-bromonaphthalene-2-base alkylsulfonyl)-2-morpholino carbonyl-1-[1-(4-pyridyl)-piperidin-4-yl carbonyl] piperazine; 4-(6-chloronaphthalene-2-base alkylsulfonyl)-2-methoxycarbonyl-1-[1-(4-pyridyl)-piperidin-4-yl carbonyl] piperazine and 2-carboxyl-4-(6-chloronaphthalene-2-base alkylsulfonyl)-1-[1-(4-pyridyl)-piperidin-4-yl carbonyl] piperazine.

8. the amino-heterocycles derivative of the formula I of each of claim 1-7 or Ia or the preparation method of its pharmacologically acceptable salt, this method comprises: (a) for preparation I compound, M wherein ²Be the following formula group:

(T ²R ⁴) _r-L ²-T ³R ⁵T wherein ²For N and r are 1, with acid or its reactive derivative of formula II React with following formula amine:

HNR ⁴-L ²-T ³R ⁵-M ³-X-Q (b) is for preparation I compound: M wherein ²Be the following formula group:

(T ²R ⁴) _r-L ²-T ³R ⁵T wherein ³Be N, and M wherein ³Direct key for being connected with X makes formula III amine: Compound reaction with formula Z-X-Q (wherein Z is a displaceable group).(c) for preparation I compound: M wherein ²Be the following formula group:

NR ²-L ¹-T ¹R ³T wherein ¹Be N, and wherein A is the direct key that is connected with carbonyl, makes formula IV amine:

Acid or its activity derivatives reaction with following formula:

HO ²C-M ²-M ³-X-Q (d) is for preparation I compound: M wherein ²Be the following formula group:

L ³-(NR ⁶) _sL wherein ³Be the carbonyl methylene radical, make acid or its activity derivatives reaction of formula III amine and following formula:

HO ₂C-CH ₂-(NR ⁶) _s-X-Q (e) is for preparation I compound: M wherein ²Be the following formula group:

OCN-X-Q (f) makes the compound of formula V Wherein Z is a displaceable group, and the amine of following formula reaction:

HNR ²-L ¹-T ¹R ³-A-CO-M ²-M ³-X-Q (g) is for preparation I compound M wherein ², M ³Or Q has carboxyl or contains the group of carboxyl, and hydrolyzing type I compound is M wherein ², M ³Or Q has (1-4C) alkoxy carbonyl; (h) for preparation I compound M wherein ², M ³Or Q has formamyl, N-alkyl-carbamoyl or N, N-dialkyl amido formyl radical, wherein M ², M ³Or Q has formula I compound or its reactive derivative and the ammonia or the suitable alkylamine or the dialkylamine reaction of carboxyl; (i) in order to prepare the formula I compound that Q wherein has hydroxyl, wherein Q has the formula I compound dealkylation of (1-4C) alkoxyl group;

When needing the pharmacologically acceptable salt of formula I compound, available ordinary method makes described compound and suitable acid and alkali reaction;

9. pharmaceutical composition, comprise claim 1-7 each formula I or amino-heterocycles derivative or its pharmacologically acceptable salt and acceptable diluents or the carrier of Ia.

10. the amino-heterocycles derivative of the formula I of each of claim 1-7 or Ia or its pharmacologically acceptable salt are used to produce the purposes of the medicine of anticoagulation or anti-thrombosis function in preparation.