CN1351594A - Substituted polycyclic aryl and heteroaryl uracils as anticoagulative agents - Google Patents
Substituted polycyclic aryl and heteroaryl uracils as anticoagulative agents Download PDFInfo
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- CN1351594A CN1351594A CN00807753A CN00807753A CN1351594A CN 1351594 A CN1351594 A CN 1351594A CN 00807753 A CN00807753 A CN 00807753A CN 00807753 A CN00807753 A CN 00807753A CN 1351594 A CN1351594 A CN 1351594A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/52—Two oxygen atoms
- C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
- C07D239/545—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D253/00—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00
- C07D253/02—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00 not condensed with other rings
- C07D253/06—1,2,4-Triazines
- C07D253/065—1,2,4-Triazines having three double bonds between ring members or between ring members and non-ring members
- C07D253/07—1,2,4-Triazines having three double bonds between ring members or between ring members and non-ring members with hetero atoms, or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D253/075—Two hetero atoms, in positions 3 and 5
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
The invention relates to substituted polycyclic aryl and heteroaryl uracil compounds useful as inhibitors of serine proteases of the coagulation cascade and compounds, compositions and methods for anticoagulant therapy for the treatment and prevention of a variety of thrombotic conditions including coronary artery and cerebrovascular diseases.
Description
Invention field
The invention belongs to the anticoagulant therapy field, be specifically related to be used to prevent and treat compound, composition and the method for thrombosis disease, for example coronary artery and cerebrovascular disease.Or rather, polyaromatic that the present invention relates to replace and heteroaryl uracils compound, the serine protease of their inhibition of coagulation cascade.
Background of invention
Flowability [the Majerus of physiological system control mammalian, " anticoagulant, thrombolysis medicine and antiplatelet drug " (Anticoagulant, Thrombolytic, andAntiplplatelet Drugs) .Hardman such as P.W., J.G. and Limbird, L.E. compiles " Goodman ﹠amp; The therapeutic pharmacological basis of GilmanShi " (Goodman; Gilman ' sThe Pharmacological Basis of Therapeutics). the 9th edition, New York, McGraw-Hill Book Co., 1996,1341-1343 page or leaf].Blood must keep mobile in vascular system, can also experience rapid hemostasis, and promptly blood stops to run off from injured blood vessel.Hemostasis or solidify and start from thrombocyte and at first be adhered in the macromole in damaged and/or the injured blood vessel endothelium lower area.These platelet aggregations form primary tampon, stimulate the local activation of plasma coagulation factors, cause the generation of fibrin clot, and then strengthen institute's accumulative thrombocyte.
Plasma coagulation factors comprises II, V, VII, VIII, IX, X, XI and the XII factor; They are also referred to as the proteolytic enzyme proenzyme.These thrombin or proteolytic enzyme proenzyme are activated by serine protease, cause the blood coagulation [Handin in what is called " coagulation cascade " or the chain reaction, R.I. " hemorrhage with hemostasis " (Bleeding and Thrombosis) .Wilson, J. wait volume " HarrisonShi internal medicine principle " (Harrison ' s Principles of InternalMedicine). the 12nd edition, New York, McGraw-Hill Book Co., 1991,350 pages].Blood coagulation or solidify dual mode arranged, the approach of the two is different.Inherence or route of exposure cause from XII to XIIa to XIa to IXa and X to the conversion of Xa.The Xa and the Va factor are converted into zymoplasm (IIa) with thrombogen (II), cause that Fibrinogen is to fibrinous conversion.Fibrinous polymerization causes fibrin clot.External approach is converted into VIIa by factor Xa with VII and causes.In the presence of calcium ion and phosphatide, the generation of Xa is quickened in the existence of tissue factor and VIIa.The generation of Xa causes zymoplasm, scleroproein and fibrin clot, as mentioned above.The existence that one or more these different thrombin are different with two kinds to solidify approach is selective control and understand each several part blood coagulation or process of setting better effectively.
Although as the blood vessel injury consequence to solidify Mammals, for example people be crucial physiological process, supersolidification can not cause morbid state yet.When platelet aggregation effect and/or fibrin clot occluding vascular (promptly making it inaccessible), cause being called thrombotic pathologic process.Artery thrombosis can cause the ischemic necrosis by the tissue of this artery supply.
When thrombosis occurs in the coronary artery, can cause myocardial infarction or heart attack.Tissue edema and inflammation that venous thrombosis can cause this Venous flow warp take place.The thrombosis of dark vein can concurrent pulmonary infarction.Formation by the anticoagulant thing, suppress fibrinous generation, suppress thrombus formation, suppress the formation of embolus, can prevent or treat the grumeleuse in the blood vessel, on therapeutics, can be used for treating or preventing unstable angina pectoris, intractable angina pectoris, myocardial infarction, transient ischemic attack, auricular fibrillation, thrombus apoplexy, embolus apoplexy, venous thrombosis, disseminated inravascular coagulation, eye scleroproein to stop up and the obturation again or the restenosis of break-through blood vessel again.
Had some reports of non-peptide class and peptide class uracil compound, they serve as the inhibitor that is present in the thrombin in coagulation cascade or the process of setting.Tamura etc. are at United States Patent (USP) 5; 656; described 4 in 645; 5; 6-replaces-3-aminopyridine ketone group ethanamide, 1, and 6-replaces-5-amino uracil base (uracinyl) ethanamide and 2, and 4-replaces-5-aminopyrimidinone yl acetamide; wherein amide substituents all has formyl radical, it is reported the activity with antithrombin.Tamura etc. are at United States Patent (USP) 5; 658; described 4 once more in 930; 5; 6-replaces-3-aminopyridine ketone group ethanamide, 1, and 6-replaces-5-amino uracil yl acetamide and 2, and 4-replaces-5-aminopyrimidinone yl acetamide; wherein amide substituents all has formyl radical, it is reported the activity with antithrombin.Tamura etc. have further described 4 in PCT patent application 96/18644 and 97/46207; 5; 6-replaces-3-aminopyridine ketone group ethanamide, 1; 6-replaces-5-amino uracil yl acetamide and 2; 4-replaces-5-aminopyrimidinone yl acetamide; wherein amide substituents all has formyl radical, it is reported the activity with antithrombin.
Summary of the invention
The purpose of this invention is to provide the compound that is of value to anticoagulant therapy and has the general structure of formula (I):
Another object of the present invention provides the method for prevention and treatment thrombosis disease, for example coronary artery disease, cerebrovascular disease and other illnesss relevant with blood coagulation.Patient's administration by formula (I) compound of significant quantity is received treatment to needs prevents and treats these thrombosis diseases.
Various other purposes of the present invention and advantage will be by hereinafter becoming apparent the explanation of inventing.
The description of invention
The present invention relates to a class and comprise the polyaromatic of replacement and the compound of heteroaryl uracils, they are of value to treatment and prevent various thrombosis diseases in anticoagulant therapy, comprise coronary artery and cerebrovascular disease, shown in (I):
Or its pharmacy acceptable salt, wherein:
J
aAnd J
bBe independently selected from O and S;
J
aRandomly be selected from CH-R
6And N-R
6, R wherein
6Be straight chain spacer part, and be selected from R with 1 to 4 continuous atom
4a, R
4b, R
14, R
15, R
39, R
40And R
5Substituent bonding point connect and compose heterocyclic ring with 5 to 8 continuous members;
J
bRandomly be selected from CH-R
6And N-R
6, R wherein
6Be straight chain spacer part, and be selected from R with 1 to 4 continuous atom
1, R
4a, R
4b, R
14And R
15Substituent bonding point connect and compose heterocyclic ring with 5 to 8 continuous members;
J
aAnd J
bRandomly be independently selected from CH-R
6And N-R
6, R wherein
6Be straight chain spacer part, with R with 1 to 4 continuous atom
4aAnd R
4bBonding point all connect and compose heterocyclic ring with 5 to 8 continuous members;
Appoint J
aBe selected to choosing CH-R
6And N-R
6, R wherein
6Be straight chain spacer part, with R with 1 to 4 continuous atom
39And R
40Bonding point all connect and compose heterocyclic ring with 5 to 8 continuous members;
B is a formula V:
D wherein
1, D
2, J
1, J
2And K
1Be independently selected from C, N, O, S and covalent linkage, its condition be at the most one can be covalent linkage, D
1, D
2, J
1, J
2And K
1At the most one be O, D
1, D
2, J
1, J
2And K
1At the most one be S, if D
1, D
2, J
1, J
2And K
1Two be O and S, then D
1, D
2, J
1, J
2And K
1One of must be covalent linkage, D
1, D
2, J
1, J
2And K
1At the most four be N, its condition is R
32, R
33, R
34, R
35And R
36Selected independently of one another, with the tetravalence character of keeping carbon, the trivalent character of nitrogen, the divalence character of sulphur and the divalence character of oxygen;
R
9, R
10, R
11, R
12, R
13, R
16, R
17, R
18, R
19, R
32, R
33, R
34, R
35And R
36Be independently selected from hydrogen, kharophen, the halo kharophen, amidino groups, guanidine radicals, dialkyl matte, San Wan Ji Phosphonium, the dialkyl matte alkyl, carboxyl, assorted aromatic alkylthio, assorted aralkoxy, cycloalkyl amino, the acyl group alkyl, the acyl group alkoxyl group, the aroyl alkoxyl group, heterocyclic oxy group, the aralkyl aryl, aralkyl, arylalkenyl, sweet-smelling alkynyl, heterocyclic radical, the perhalogeno aralkyl, the aralkyl alkylsulfonyl, aralkyl sulphonyl alkyl, aralkyl sulfinyl, aralkyl sulfinyl alkyl, halogenated cycloalkyl, the halo cycloalkenyl group, the cycloalkyl sulfinyl, cycloalkyl sulfinyl alkyl, the naphthene sulfamide base, the naphthene sulfamide alkyl, heteroaryl amino, N-heteroaryl amino-N-alkylamino, the heteroaryl amino alkyl, halogenated alkylthio, alkanoyloxy, alkoxyl group, alkoxyalkyl, halogenated alkoxy alkyl, assorted aralkoxy, cycloalkyloxy, cyclenes oxygen base, the cycloalkyloxy alkyl, cycloalkyl alkoxy, cyclenes oxygen base alkyl, inferior cycloalkanes dioxy base, the halo cycloalkyloxy, halo cycloalkyloxy alkyl, halo cyclenes oxygen base, halo cyclenes oxygen base alkyl, hydroxyl, amino, alkoxy amino, sulfo-, nitro, low-grade alkyl amino, alkylthio, alkylthio alkyl, arylamino, aryl alkyl amino, arylthio, arylthio alkyl, assorted sweet-smelling alkoxy alkyl, alkyl sulphinyl, the alkyl sulfenyl alkyl, aryl sulfinyl alkyl, the arylsulfonyl alkyl, heteroaryl sulfinyl alkyl, heteroaryl sulphonyl alkyl, alkyl sulphonyl, the alkyl sulfonyl alkyl, haloalkyl sulfinyl alkyl, haloalkyl sulphonyl alkyl, alkyl sulfonyl amino, alkyl amino sulfonyl, the amido alkylsulfonyl, one alkyl amido alkylsulfonyl, dialkyl group amido alkylsulfonyl, one aryl amido alkylsulfonyl, Arenesulfonyl amino, diaryl amido alkylsulfonyl, one alkyl, one aryl amido alkylsulfonyl, aryl sulfonyl kia, aryl sulfonyl, heteroarylthio, the heteroaryl sulfinyl, heteroarylsulfonyl, the heterocyclic radical alkylsulfonyl, the heterocyclic radical sulfo-, alkyloyl, enoyl-, aroyl, 4-hetaroylpyrazol, aralkanoyl, assorted aralkanoyl, the haloalkane acyl group, alkyl, thiazolinyl, alkynyl, alkene oxygen base, alkene oxygen base alkyl, alkylene dioxo base, the halo alkylene dioxo base, cycloalkyl, the cycloalkyl alkyloyl, cycloalkenyl group, the low-grade cycloalkyl alkyl, the lower alkenyl ring alkyl, halogen, haloalkyl, haloalkenyl group, halogenated alkoxy, the hydroxy halogeno alkyl, hydroxyl aralkyl, hydroxyalkyl, alkenyl amino, the hydroxyl heteroaralkyl, halogenated alkoxy alkyl, aryl, aralkyl, aryloxy, aralkoxy, aryloxy alkyl, saturated heterocyclic radical, the heterocyclic radical of fractional saturation, heteroaryl, heteroaryloxy, the heteroaryloxy alkyl, arylalkyl, heteroarylalkyl, aryl alkenyl, the heteroaryl thiazolinyl, carboxyalkyl, carbalkoxy, the alkoxyl group carboxamido, alkyl amido carbonyl amido, aryl amido carbonyl amido, alkoxycarbonyl alkyl, the carbalkoxy thiazolinyl, carboxyl, aralkoxycarbonyl, carboxamido, the carboxamido alkyl, cyano group, the haloalkoxy carbonyl, phosphono, the phosphono alkyl, alkoxy diaryl phosphono and alkoxy diaryl phosphono alkyl;
R
16, R
19, R
32, R
33, R
34, R
35And R
36Randomly be Q independently
b, its condition is R
16And R
19At the most one be Q simultaneously
b, Q
bBe Q
Be
R
32With R
33, R
33With R
34, R
34With R
35And R
35With R
36It is right randomly to select to constitute spacer independently, wherein spacer is to constituting the linear fraction with 3 to 6 continuous atoms together, member's bonding point is connected and composed the ring that is selected from down group with described spacer: have 5 to 8 members that link to each other the cyclenes basic ring, have 5 to 8 continuous members' fractional saturation heterocyclic ring, have 5 to 6 continuous members' heteroaryl ring and aryl, its condition is R
32With R
33, R
33With R
34, R
34With R
35And R
35With R
36A pair of at the most spacer to using simultaneously;
R
9With R
10, R
10With R
11, R
11With R
12And R
12With R
13It is right randomly to select to constitute spacer independently, wherein spacer is to constituting the linear fraction with 3 to 6 continuous atoms together, member's bonding point is connected and composed the ring that is selected from down group with described spacer: have 5 to 8 members that link to each other the cyclenes basic ring, have 5 to 8 continuous members' fractional saturation heterocyclic ring, have 5 to 6 continuous members' heteroaryl ring and aryl, its condition is R
9With R
10, R
10With R
11, R
11With R
12And R
12With R
13A pair of at the most spacer to using simultaneously;
B randomly is formula (VI):
D wherein
3, D
4, J
3And J
4Be independently selected from C, N, O and S, D
3, D
4, J
3And J
4At the most one be O, D
3, D
4, J
3And J
4At the most one be S, D
1, D
2, J
1And J
2At the most three be N, its condition is R
32, R
33, R
34And R
35Selected independently of one another, with the tetravalence character of keeping carbon, the trivalent character of nitrogen, the divalence character of sulphur and the divalence character of oxygen;
B randomly is selected from hydrogen, trialkylsilkl, C2-C8 alkyl, C3-C8 thiazolinyl, C3-C8 alkylidene group, C3-C8 alkynyl, C2-C8 haloalkyl and C3-C8 haloalkenyl group, and wherein each member of group B randomly at distance B and A tie point nearly and comprise on any carbon of 6 atoms by one or more radicals R
32, R
33, R
34, R
35And R
36Replace;
B randomly is selected from the saturated heterocyclic radical of C3-C15 cycloalkyl, C5-C10 cycloalkenyl group, C4-C12 and the heterocyclic radical of C4-C9 fractional saturation, and wherein each ring carbon is randomly by R
33Replace, the ring carbon except that the ring carbon that is positioned at B and A tie point is randomly replaced by oxo, and its condition is that a ring carbon is replaced by oxo simultaneously at the most, and ring carbon adjacent with the ring carbon that is positioned at tie point and nitrogen-atoms are randomly by R
9Or R
13Replace, with R
9The position adjacent and apart from the ring carbon of two atoms of tie point or nitrogen-atoms randomly by R
10Replace, with R
13The position adjacent and apart from the ring carbon of two atoms of tie point or nitrogen-atoms randomly by R
12Replace, apart from three atoms of tie point and and R
10Ring carbon that the position is adjacent or nitrogen-atoms are randomly by R
11Replace, apart from three atoms of tie point and and R
12Ring carbon that the position is adjacent or nitrogen-atoms are randomly by R
33Replace, apart from four atoms of tie point and and R
11And R
33Ring carbon that the position is adjacent or nitrogen-atoms are randomly by R
34Replace;
A is selected from covalent single bond, (W
7)
Rr-(CH (R
15))
Pa(CH (R
15))
Pa-(W
7)
Rr, wherein rr is selected from 0 to 1 integer, and pa is selected from 0 to 6 integer, W
7Be selected from O, S, C (O), C (S), C (O) S, C (S) O, C (O) N (R
7), C (S) N (R
7), (R
7) NC (O), (R
7) NC (S), S (O), S (O)
2, S (O)
2N (R
7), (R
7) NS (O)
2, Se (O), Se (O)
2, Se (O)
2N (R
7), (R
7) NSe (O)
2, P (O) (R
8), N (R
7) P (O) (R
8), P (O) (R
8) N (R
7), C (NR
7) N (R
7), (R
7) NC (NR
7), (R
7) NC (NR
7) NR
7And N (R
7), its condition be rr and pa at the most one be 0 simultaneously;
R
7And R
8Be independently selected from hydrogen, hydroxyl, alkyl, thiazolinyl, aryl, aralkyl, aryloxy, alkoxyl group, alkene oxygen base, alkylthio, alkylamino, arylthio, arylamino, acyl group, aroyl, 4-hetaroylpyrazol, sweet-smelling alkoxy alkyl, assorted sweet-smelling alkoxy alkyl, aryloxy alkyl, alkoxyalkyl, alkene oxygen base alkyl, alkylthio alkyl, arylthio alkyl, sweet-smelling alkoxy alkyl, assorted sweet-smelling alkoxy alkyl, the alkyl sulfenyl alkyl, the alkyl sulfonyl alkyl, heteroaryl, heteroaryloxy, heteroaryl amino, heteroaralkyl, assorted aralkoxy, amino and the heteroaryloxy alkyl of heteroaralkyl;
R
14, R
15, R
37, R
38, R
39, R
40, R
41And R
42Be independently selected from amidino groups; hydroxyl amino; hydrogen; hydroxyl; halogen; cyano group; aryloxy; amino; alkylamino; dialkyl amido; hydroxyalkyl; aminoalkyl group; acyl group; aroyl; 4-hetaroylpyrazol; the heteroaryloxy alkyl; sulfydryl; the acyl group amido; alkoxyl group; alkylthio; arylthio; alkyl; thiazolinyl; alkynyl; aryl; aralkyl; aryloxy alkyl; the sweet-smelling alkoxy alkyl alkoxyl group; the alkyl sulfenyl alkyl; the alkyl sulfonyl alkyl; alkylthio-alkyl aryl; assorted aralkoxy alkylthio; alkoxyalkyl; the heteroaryloxy alkyl; alkene oxygen base alkyl; alkylthio alkyl; arylthio alkyl; cycloalkyl; cycloalkylalkyl; the cycloalkyl thiazolinyl; cycloalkenyl group; cycloalkenyl alkyl; haloalkyl; haloalkenyl group; halogenated cycloalkyl; the halo cycloalkenyl group; halogenated alkoxy; halogenated alkoxy alkyl; haloalkene oxygen base alkyl; the halo cycloalkyloxy; halo cycloalkyloxy alkyl; halo cyclenes oxygen base alkyl; saturated heterocyclic radical; the heterocyclic radical of fractional saturation; heteroaryl; heteroarylalkyl; the heteroarylthio alkyl; assorted alkylthio-alkyl aryl; one alkoxycarbonyl alkyl; the dialkoxy carbonylic alkyl; one cyano group alkyl; the dicyano alkyl; carbalkoxy cyano group alkyl; alkyl sulphinyl; alkyl sulphonyl; the haloalkyl sulfinyl; halogenated alkyl sulfonyl; aryl sulfonyl kia; aryl sulfinyl alkyl; aryl sulfonyl; the arylsulfonyl alkyl; aralkyl sulfinyl; the aralkyl alkylsulfonyl; the cycloalkyl sulfinyl; the naphthene sulfamide base; cycloalkyl sulfinyl alkyl; the naphthene sulfamide alkyl; heteroaryl sulphonyl alkyl; the heteroaryl sulfinyl; heteroarylsulfonyl; heteroaryl sulfinyl alkyl; aralkyl sulfinyl alkyl; aralkyl sulphonyl alkyl; carboxyl; carboxyalkyl; carbalkoxy; carboxylic acid amides; the carboxamido alkyl; aralkoxycarbonyl; trialkylsilkl; the dialkoxy phosphono; the alkoxy diaryl phosphono; dialkoxy phosphono alkyl and alkoxy diaryl phosphono alkyl, its condition is R
37And R
38Be independently selected from the group except that formyl radical;
R
14And R
14If then randomly constitute the group that is selected from down group together with different bond with carbon: covalent linkage, alkylidene group, halo alkylidene group, with the linear fraction spacer, this spacer is selected to constitute and is selected from down the ring of organizing: have 5 to 8 continuous members cycloalkyl ring, have 5 to 8 continuous members' cyclenes basic ring and heterocyclic radical with 5 to 8 members that link to each other;
R
14And R
15If then randomly constitute the group that is selected from down group together with different bond with carbon: covalent linkage, alkylidene group, halo alkylidene group, with the linear fraction spacer, this spacer is selected to constitute and is selected from down the ring of organizing: have 5 to 8 continuous members cycloalkyl ring, have 5 to 8 continuous members' cyclenes basic ring and heterocyclic radical with 5 to 8 members that link to each other;
R
15And R
15If then randomly constitute the group that is selected from down group together with different bond with carbon: covalent linkage, alkylidene group, halo alkylidene group, with the linear fraction spacer, this spacer is selected to constitute and is selected from down the ring of organizing: have 5 to 8 continuous members cycloalkyl ring, have 5 to 8 continuous members' cyclenes basic ring and heterocyclic radical with 5 to 8 members that link to each other;
Ψ is selected from NR
5, O, C (O), C (S), S, S (O), S (O)
2, ON (R
5), P (O) (R
8) and CR
39R
40
R
5Be selected from hydrogen, hydroxyl, amino, alkyl, thiazolinyl, alkynyl, aryl, aralkyl, aryloxy, aralkoxy, alkoxyl group, alkene oxygen base, alkylthio, arylthio, sweet-smelling alkoxy alkyl, assorted sweet-smelling alkoxy alkyl, aryloxy alkyl, alkoxyalkyl, alkene oxygen base alkyl, alkylthio alkyl, arylthio alkyl, sweet-smelling alkoxy alkyl, assorted sweet-smelling alkoxy alkyl, the alkyl sulfenyl alkyl, the alkyl sulfonyl alkyl, cycloalkyl, cycloalkylalkyl, the cycloalkyl thiazolinyl, cycloalkenyl group, cycloalkenyl alkyl, haloalkyl, haloalkenyl group, halogenated cycloalkyl, the halo cycloalkenyl group, halogenated alkoxy alkyl, haloalkene oxygen base alkyl, halo cycloalkyloxy alkyl, halo cyclenes oxygen base alkyl, heteroaryl, heteroarylalkyl, one alkoxycarbonyl alkyl, one carbalkoxy, the dialkoxy carbonylic alkyl, one carboxamido, one cyano group alkyl, the dicyano alkyl, carbalkoxy cyano group alkyl, acyl group, aroyl, 4-hetaroylpyrazol, heteroaryloxy alkyl and dialkoxy phosphono alkyl;
R
39And R
40If then randomly form the group that is selected from down group together with identical bond with carbon: oxo, sulfo-(carbonyl), R
5-N, alkylidene group, halo alkylidene group and have the linear fraction spacer of 2 to 7 atoms that link to each other are selected from down the ring of organizing thereby form: have 3 to 8 continuous members cycloalkyl ring, have 3 to 8 continuous members' cyclenes basic ring and heterocyclic ring with 3 to 8 members that link to each other;
M is selected from N and R
1-C;
R
2And R
1Be independently selected from Z
0-Q, hydrogen, alkyl, thiazolinyl and halogen;
R
1Randomly be selected from amino, aminoalkyl group, alkylamino, amidino groups, guanidine radicals, hydroxyl, hydroxyl amino, alkoxyl group, hydroxyalkyl, alkoxy amino, sulfo-hydroxyl, alkylthio, dialkyl matte, three alkane base Phosphonium, dialkyl matte alkyl, heteroaryl amino, nitro, arylamino, aryl alkyl amino, alkyloyl, enoyl-, aroyl, 4-hetaroylpyrazol, aralkanoyl, assorted aralkanoyl, haloalkane acyl group, hydroxy halogeno alkyl, cyano group and phosphono;
R
2Randomly be selected from amidino groups, guanidine radicals, dialkyl matte, San Wan Ji Phosphonium, dialkyl matte alkyl, heteroaryl amino, amino, nitro, alkylamino, arylamino, aryl alkyl amino, alkyloyl, enoyl-, aroyl, 4-hetaroylpyrazol, aralkanoyl, assorted aralkanoyl, haloalkane acyl group, hydroxy halogeno alkyl, cyano group and phosphono;
R
2With R
4a, R
2With R
4b, R
2With R
14And R
2With R
15It is right randomly to select independently to form spacer, and wherein spacer is connected with the bonding point of described spacer to the member forming the linear fraction with 2 to 5 continuous atoms together, forms the heterocyclic ring with 5 to 8 continuous members, and its condition is R
2With R
4a, R
2With R
4b, R
2With R
14And R
2With R
15A pair of at the most spacer to using simultaneously;
R
2Be the linear fraction of randomly selecting to have 2 to 5 continuous atoms independently, with R with formation
4aAnd R
4bBonding point connect, constitute heterocyclic ring with 5 to 8 continuous members;
Z
0Be selected from covalent single bond, (CR
41R
42)
q, (CH (R
41))
g-W
0-(CH (R
42))
p(CH (R
41))
e-W
22-(CH (R
42))
h, wherein q is selected from 1 to 6 integer, and g and p are independently selected from 0 to 3 integer, W
0Be selected from O, S, C (O), C (S), C (O) O, C (S) O, C (O) S, C (S) S, C (O) N (R
41), (R
41) NC (O), C (S) N (R
41), (R
41) NC (S), OC (O) N (R
41), (R
41) NC (O) O, SC (S) N (R
41), (R
41) NC (S) S, SC (O) N (R
41), (R
41) NC (O) S, OC (S) N (R
41), (R
41) NC (S) O, N (R
42) C (O) N (R
41), (R
41) NC (O) N (R
42), N (R
42) C (S) N (R
41), (R
41) NC (S) N (R
42), S (O), S (O)
2, S (O)
2N (R
41), N (R
41) S (O)
2, Se, Se (O), Se (O)
2, Se (O)
2N (R
41), N (R
41) Se (O)
2, P (O) (R
8), N (R
7) P (O) (R
8), P (O) (R
8) N (R
7), N (R
41), ON (R
41) and SiR
28R
29, e and h are independently selected from 0 to 2 integer, W
22Be selected from CR
41=CR
42, CR
41R
42=C, vinylidene), ethynylene (C ≡ C; Ethynylene), 1, the 2-cyclopropyl, 1, the 2-cyclobutyl, 1, the 2-cyclohexyl, 1, the 3-cyclohexyl, 1, the 2-cyclopentyl, 1, the 3-cyclopentyl, 2, morpholinyl, 2, the 4-morpholinyl, 2, the 6-morpholinyl, 3, the 4-morpholinyl, 3, the 5-morpholinyl, 1, the 2-piperazinyl, 1, the 3-piperazinyl, 2, the 3-piperazinyl, 2, the 6-piperazinyl, 1, the 2-piperidyl, 1, the 3-piperidyl, 2, the 3-piperidyl, 2, the 4-piperidyl, 2, the 6-piperidyl, 3, the 4-piperidyl, 1, the 2-pyrrolidyl, 1, the 3-pyrrolidyl, 2, the 3-pyrrolidyl, 2, the 4-pyrrolidyl, 2, the 5-pyrrolidyl, 3, the 4-pyrrolidyl, 2, the 3-tetrahydrofuran base, 2, the 4-tetrahydrofuran base, 2,5-tetrahydrofuran base and 3, the 4-tetrahydrofuran base, its condition is R
41And R
42If direct and N bonding then is selected from the group except that halo and cyano group, Z
0Direct and uridylic ring key closes;
R
28And R
29Be independently selected from hydrogen, hydroxyalkyl, alkyl, thiazolinyl, alkynyl, aryl, aralkyl, aryloxy alkyl, acyl group, aroyl, aralkanoyl, 4-hetaroylpyrazol, sweet-smelling alkoxy alkyl, the alkyl sulfenyl alkyl, the alkyl sulfonyl alkyl, alkylthio-alkyl aryl, assorted alkylthio-alkyl aryl, alkoxyalkyl, the heteroaryloxy alkyl, alkene oxygen base alkyl, alkylthio alkyl, arylthio alkyl, cycloalkyl, cycloalkylalkyl, the cycloalkyl thiazolinyl, cycloalkenyl group, cycloalkenyl alkyl, haloalkyl, haloalkenyl group, halogenated cycloalkyl, the halo cycloalkenyl group, halogenated alkoxy alkyl, haloalkene oxygen base alkyl, the halo cycloalkyloxy, halo cycloalkyloxy alkyl, halo cyclenes oxygen base alkyl, the perhalogeno aryl, the perhalogeno aralkyl, the perhalogeno aryloxy alkyl, heteroaryl, heteroarylalkyl, the heteroarylthio alkyl, assorted alkylthio-alkyl aryl, the cyano group alkyl, the dicyano alkyl, the carboxamido alkyl, the dicarboxylic dihydrazides aminoalkyl group, the cyano group alkoxycarbonyl alkyl, alkoxycarbonyl alkyl, the dialkoxy carbonylic alkyl, the cyano group cycloalkyl, the dicyano cycloalkyl, the carboxamido cycloalkyl, the amino cycloalkyl of dicarboxylic dihydrazides, carbalkoxy cyano group cycloalkyl, the carbalkoxy cycloalkyl, dialkoxy carbonyl cycloalkyl, the formyl radical alkyl, the acyl group alkyl, aryl sulfinyl alkyl, the arylsulfonyl alkyl, aralkyl sulfinyl, cycloalkyl sulfinyl alkyl, the naphthene sulfamide alkyl, heteroaryl sulphonyl alkyl, heteroaryl sulfinyl alkyl, aralkyl sulfinyl alkyl, aralkyl sulphonyl alkyl, carboxyl, the dialkoxy phosphono, the alkoxy diaryl phosphono, dialkoxy phosphono alkyl and alkoxy diaryl phosphono alkyl;
R
28And R
29Randomly constitute linear fraction spacer together, and form and be selected from down the ring of organizing with 2 to 7 continuous atoms: have 3 to 8 continuous members cycloalkyl ring, have 3 to 8 continuous members' cyclenes basic ring and heterocyclic ring with 3 to 8 members that link to each other;
Q is formula (II):
D wherein
1, D
2, J
1, J
2And K
1Be independently selected from C, N, O, S and covalent linkage, its condition be at the most one can be covalent linkage, D
1, D
2, J
1, J
2And K
1At the most one can be O, D
1, D
2, J
1, J
2And K
1At the most one can be S, if D
1, D
2, J
1, J
2And K
1Two be O and S, then D
1, D
2, J
1, J
2And K
1One of must be covalent linkage, D
1, D
2, J
1, J
2And K
1At the most four can be N, its condition is R
9, R
10, R
11, R
12And R
13Selected independently of one another, with the tetravalence character of keeping carbon, the trivalent character of nitrogen, the divalence character of sulphur and the divalence character of oxygen;
Q randomly is selected from formula (III):
D wherein
3, D
4, J
3And J
4Be independently selected from C, N, O and S, D
3, D
4, J
3And J
4At the most one be O, D
3, D
4, J
3And J
4At the most one be S, D
1, D
2, J
1And J
2At the most three be N, its condition is R
9, R
10, R
11And R
12Selected independently of one another, with the tetravalence character of keeping carbon, the trivalent character of nitrogen, the divalence character of sulphur and the divalence character of oxygen;
Q randomly is selected from hydrogen, alkyl, alkoxyl group, alkylamino, alkylthio, halogenated alkylthio, thiazolinyl, alkynyl, saturated heterocyclic radical, heterocyclic radical, acyl group, aroyl, 4-hetaroylpyrazol, cycloalkyl, cycloalkylalkyl, cycloalkenyl group, cycloalkenyl alkyl, cycloalkyl thiazolinyl, haloalkyl, halogenated alkoxy, haloalkenyl group, halogenated cycloalkyl, halo cycloalkenyl group, halogenated alkoxy alkyl, haloalkene oxygen base alkyl, halo cycloalkyloxy alkyl and the halo cyclenes oxygen base alkyl of fractional saturation; its condition is if Q is a hydrogen, then Z
0Be selected from the group except that covalent single bond;
K is (CR
4aR
4b)
n, wherein n is selected from 1 to 4 integer;
R
4aAnd R
4bBe independently selected from halogen; hydrogen; hydroxyl; cyano group; hydroxyalkyl; alkyl; thiazolinyl; aryl; aralkyl; sweet-smelling alkoxy alkyl; aryloxy alkyl; alkoxyalkyl; the heteroaryloxy alkyl; alkene oxygen base alkyl; alkylthio alkyl; alkylthio-alkyl aryl; arylthio alkyl; cycloalkyl; cycloalkylalkyl; haloalkyl; haloalkenyl group; heteroaryl; heteroarylalkyl; the heteroarylthio alkyl; assorted alkylthio-alkyl aryl; the cyano group alkyl; the alkyl sulfenyl alkyl; the alkyl sulfonyl alkyl; the haloalkyl sulfinyl; aryl sulfinyl alkyl; the arylsulfonyl alkyl; heteroaryl sulphonyl alkyl; heteroaryl sulfinyl alkyl; aralkyl sulfinyl alkyl and aralkyl sulphonyl alkyl; its condition is a halogen; hydroxyl and cyano group are if exist simultaneously then and different bond with carbon, R
4aAnd R
4bIf with the bond with carbon that is bonded directly on the uridylic nitrogen then can not be hydroxyl or cyano group;
R
4aAnd R
4bBe selected from down the group of organizing if then randomly constitute together: oxo, sulfo-and have the straight chain spacer part of 2 to 7 atoms that link to each other with identical bond with carbon, connect and compose the ring that is selected from down group: have 3 to 8 continuous members cycloalkyl ring, have 5 to 8 continuous members' cyclenes basic ring and heterocyclic ring with 5 to 8 members that link to each other, its condition is if shared carbon is direct and uridylic nitrogen bonding, then R
4aAnd R
4bCan not be oxo or sulfo-together;
If K is (CR
4aR
4b)
n, E then
0Be E
1, E wherein
1Be selected from covalent single bond, O, S, C (O), C (S), C (O) O, C (S) O, C (O) S, C (S) S, C (O) N (R
7), (R
7) NC (O), C (S) N (R
7), (R
7) NC (S), OC (O) N (R
7), (R
7) NC (O) O, SC (S) N (R
7), (R
7) NC (S) S, SC (O) N (R
7), (R
7) NC (O) S, OC (S) N (R
7), (R
7) NC (S) O, N (R
8) C (O) N (R
7), (R
7) NC (O) N (R
8), N (R
8) C (S) N (R
7), (R
7) NC (S) N (R
8), S (O), S (O)
2, S (O)
2N (R
7), N (R
7) S (O)
2, S (O)
2N (R
7) C (O), C (O) N (R
7) S (O)
2, Se, Se (O), Se (O)
2, Se (O)
2N (R
7), N (R
7) Se (O)
2, P (O) (R
8), N (R
7) P (O) (R
8), P (O) (R
8) N (R
7), N (R
7), ON (R
7), SiR
28R
29, CR
4a=CR
4b, ethynylene (C ≡ C; Ethynylene) and C=CR
4aR
4b
K randomly is selected to (CH (R
14))
j-T, wherein j is selected from 0 to 3 integer, and T is selected from covalent single bond, O, S and N (R
7), its condition is if j is 1, then R
14Can not be hydroxyl, cyano group, halogen, amino, alkylamino, dialkyl amido and sulfydryl, (CH (R
14))
jClose with the uridylic ring key;
If K is (CH (R
14))
j-T, then E
0Randomly be E
2, E wherein
2Be selected from covalent single bond, C (O), C (S), C (O) O, C (S) O, C (O) S, C (S) S, C (O) N (R
7), (R
7) NC (O), C (S) N (R
7), (R
7) NC (S), (R
7) NC (O) O, (R
7) NC (S) S, (R
7) NC (O) S, (R
7) NC (S) O, N (R
8) C (O) N (R
7), (R
7) NC (O) N (R
8), N (R
8) C (S) N (R
7), (R
7) NC (S) N (R
8), S (O), S (O)
2, S (O)
2N (R
7), N (R
7) S (O)
2, S (O)
2N (H) C (O), C (O) N (H) S (O)
2, Se (O), Se (O)
2, Se (O)
2N (R
7), N (R
7) Se (O)
2, P (O) (R
8), N (R
7) P (O) (R
8), P (O) (R
8) N (R
7) and N (R
7);
K randomly is selected to G-(CH (R
15))
k, wherein k is selected from 1 to 3 integer, and G is selected from O, S and N (R
7), its condition is if k is 1, then R
15Can not be hydroxyl, cyano group, halogen, amino, alkylamino, dialkyl amido and sulfydryl;
If K is G-(CH (R
15))
k, E then
0Randomly be E
3, E wherein
3Be selected from covalent single bond, O, S, C (O), C (S), C (O) O, C (S) O, C (O) S, C (S) S, C (O) N (R
7), (R
7) NC (O), C (S) N (R
7), (R
7) NC (S), OC (O) N (R
7), (R
7) NC (O) O, SC (S) N (R
7), (R
7) NC (S) S, SC (O) N (R
7), (R
7) NC (O) S, OC (S) N (R
7), (R
7) NC (S) O, N (R
8) C (O) N (R
7), (R
7) NC (O) N (R
8), N (R
8) C (S) N (R
7), (R
7) NC (S) N (R
8), S (O), S (O)
2, S (O)
2N (R
7), N (R
7) S (O)
2, Se, Se (O), Se (O)
2, Se (O)
2N (R
7), N (R
7) Se (O)
2, P (O) (R
8), N (R
7) P (O) (R
8), P (O) (R
8) N (R
7), N (R
7), ON (R
7), SiR
28R
29, CR
4a=CR
4b, ethynylene (C ≡ C; Ethynylene) and C=CR
4aR
4b
Y
0Be formula (IV):
D wherein
5, D
6, J
5And J
6Be independently selected from C, N, O, S and covalent linkage, its condition be at the most one be covalent linkage, K
2Be independently selected from
CAnd N
+, D
5, D
6, J
5And J
6At the most one be O, D
5, D
6, J
5And J
6At the most one be S, if D
5, D
6, J
5And J
6Two be O and S, then D
5, D
6, J
5And J
6One of must be covalent linkage, if K
2Be N
+, D then
5, D
6, J
5And J
6At the most three be N, if K
2Be carbon, D then
5, D
6, J
5And J
6At the most four be N, its condition is R
16, R
17, R
18And R
19Selected independently of one another, with the tetravalence character of keeping carbon, the trivalent character of nitrogen, the divalence character of sulphur and the divalence character of oxygen;
R
16And R
17Randomly constitute linear fraction spacer independently together, connect and compose and be selected from down the ring of organizing with 3 to 6 continuous atoms: have 5 to 8 continuous members the cyclenes basic ring, have 5 to 8 continuous members' fractional saturation heterocyclic ring, have 5 to 6 continuous members' heteroaryl and aryl;
R
18And R
19Randomly constitute linear fraction spacer independently together, connect and compose and be selected from down the ring of organizing with 3 to 6 continuous atoms: have 5 to 8 continuous members the cyclenes basic ring, have 5 to 8 continuous members' fractional saturation heterocyclic ring, have 5 to 6 continuous members' heteroaryl and aryl;
Q
bBe selected from NR
20R
21,
+NR
20R
21R
22, oxygen base, alkyl, amino alkylidenyl, alkylamino, dialkyl amido, dialkyl matte alkyl, acyl amino and Q
Be, Q wherein
BeBe hydrogen and R
20, R
21And R
22Be independently selected from hydrogen, amino, alkyl, hydroxyl, alkoxyl group, amino alkylidenyl, alkylamino, dialkyl amido and hydroxyalkyl, its condition is R
20, R
21And R
22At the most one be hydroxyl, alkoxyl group, alkylamino, amino and dialkyl amido simultaneously, if K
2Be N
+, R then
20, R
21And R
22Can not be hydroxyl, alkoxyl group, alkylamino, amino and dialkyl amido;
R
20With R
21, R
20With R
22And R
21With R
22It is right randomly to select to constitute spacer independently, and wherein spacer is connected with the bonding point of described spacer to the member constituting the linear fraction with 4 to 7 continuous atoms together, constitutes the heterocyclic ring with 5 to 8 continuous members, and its condition is R
20With R
21, R
20With R
22And R
21With R
22A pair of at the most spacer to using simultaneously;
Q
bRandomly be selected from N (R
26) SO
2N (R
23) (R
24), N (R
26) C (O) OR
5, N (R
26) C (O) SR
5, N (R
26) C (S) OR
5And N (R
26) C (S) SR
5, if its condition is R
23, R
24And R
26Two with identical atomic linkage, then R
23, R
24And R
26At the most one can be hydroxyl, alkoxyl group, alkylidene amino, alkylamino, amino or dialkyl amido;
Q
bRandomly be selected from dialkyl matte, San Wan Ji Phosphonium, C (NR
25) NR
23R
24, N (R
26) C (NR
25) N (R
23) (R
24), N (R
26) C (O) N (R
23) (R
24), N (R
26) C (S) N (R
23) (R
24), C (NR
25) OR
5, C (O) N (R
26) C (NR
25) N (R
23) (R
24), C (S) N (R
26) C (NR
25) N (R
23) (R
24), N (R
26) N (R
26) C (NR
25) N (R
23) (R
24), ON (R
26) C (NR
25) N (R
23) (R
24), N (R
26) N (R
26) SO
2N (R
23) (R
24), C (NR
25) SR
5, C (O) NR
23R
24And C (O) NR
23R
24, if its condition is any R
23, R
24And R
26Two with identical atomic linkage, then R
23, R
24And R
26At the most one can be hydroxyl, alkoxyl group, alkylamino, amino or dialkyl amido, described Q
bDirect and the carbon atom bonding of group;
R
23, R
24, R
25And R
26Be independently selected from hydrogen, alkyl, hydroxyl, alkoxyl group, alkylidene amino, amino, alkylamino, dialkyl amido and hydroxyalkyl;
R
23And R
24Randomly formation has the straight chain spacer part of 4 to 7 continuous atoms together, connects and composes the heterocyclic ring with 5 to 8 members that link to each other with bonding point;
R
23With R
25, R
24With R
25, R
25With R
26, R
24With R
26And R
23With R
26It is right randomly select to constitute spacer independently, and wherein spacer pair constitutes group L-U-V with selected spacer to member's bonding point, and wherein L, U and V are independently selected from O, S, C (O), C (S), C (J
H)
2S (O), SO
2, OP (OR
31) R
30, P (O) R
30, P (S) R
30, C (R
30) R
31, C=C (R
30) R
31, (O)
2POP (O)
2, R
30(O) POP (O) R
30, Si (R
29) R
28, Si (R
29) R
28Si (R
29) R
28, Si (R
29) R
28OSi (R
29) R
28, (R
28) R
29COC (R
28) R
29, (R
28) R
29CSC (R
28) R
29, C (O) C (R
30)=C (R
31), C (S) C (R
30)=C (R
31), S (O) C (R
30)=C (R
31), SO
2C (R
30)=C (R
31), PR
30C (R
30)=C (R
31), P (O) R
30C (R
30)=C (R
31), P (S) R
30C (R
30)=C (R
31), DC (R
30) (R
31) D, OP (OR
31) R
30, P (O) R
30, P (S) R
30, Si (R
28) R
29, N (R
30) and covalent linkage, its condition is that L, U and V any at the most two are covalent linkage simultaneously, the heterocyclic ring of being made up of L, U and V has 5 to 10 members that link to each other;
D is selected from oxygen, C=O, C=S, S (O)
m, wherein m is selected from 0 to 2 integer;
J
HBe independently selected from OR
27, SR
27And N (R
20) R
21
R
27Be selected from hydrogen, alkyl, thiazolinyl, alkynyl, aralkyl, aryloxy alkyl, sweet-smelling alkoxy alkyl, the alkyl sulfenyl alkyl, the alkyl sulfonyl alkyl, alkylthio-alkyl aryl, assorted alkylthio-alkyl aryl, alkoxyalkyl, the heteroaryloxy alkyl, alkene oxygen base alkyl, alkylthio alkyl, arylthio alkyl, cycloalkyl, cycloalkylalkyl, the cycloalkyl thiazolinyl, cycloalkenyl group, cycloalkenyl alkyl, haloalkyl, haloalkenyl group, halogenated cycloalkyl, the halo cycloalkenyl group, halogenated alkoxy alkyl, haloalkene oxygen base alkyl, halo cycloalkyloxy alkyl, halo cyclenes oxygen base alkyl, the perhalogeno aryloxy alkyl, heteroaryl, heteroarylalkyl, the heteroarylthio alkyl, assorted alkylthio-alkyl aryl, aryl sulfinyl alkyl, the arylsulfonyl alkyl, cycloalkyl sulfinyl alkyl, the naphthene sulfamide alkyl, heteroaryl sulphonyl alkyl, heteroaryl sulfinyl alkyl, aralkyl sulfinyl alkyl and aralkyl sulphonyl alkyl;
R
30And R
31Be independently selected from hydrogen, hydroxyl, sulfydryl, aryloxy, amino, alkylamino, dialkyl amido, hydroxyalkyl, the heteroaryloxy alkyl, alkoxyl group, alkylthio, arylthio, alkyl, thiazolinyl, alkynyl, aryl, aralkyl, aryloxy alkyl, sweet-smelling alkoxy alkyl, the alkyl sulfenyl alkyl, the alkyl sulfonyl alkyl, alkylthio-alkyl aryl, assorted aralkoxy alkylthio, alkoxyalkyl, the heteroaryloxy alkyl, alkene oxygen base alkyl, alkylthio alkyl, arylthio alkyl, cycloalkyl, cycloalkylalkyl, the cycloalkyl thiazolinyl, cycloalkenyl group, cycloalkenyl alkyl, haloalkyl, haloalkenyl group, halo aralkyl sulfinyl alkyl, aralkyl sulphonyl alkyl, the cyano group alkyl, the dicyano alkyl, the carboxamido alkyl, the dicarboxylic dihydrazides aminoalkyl group, the cyano group alkoxycarbonyl alkyl, alkoxycarbonyl alkyl, the dialkoxy carbonylic alkyl, the cyano group cycloalkyl, the dicyano cycloalkyl, the carboxamido cycloalkyl, the amino cycloalkyl of dicarboxylic dihydrazides, carbalkoxy cyano group cycloalkyl, the carbalkoxy cycloalkyl, dialkoxy carbonyl cycloalkyl, the formyl radical alkyl, the acyl group alkyl, dialkoxy phosphono alkyl, alkoxy diaryl phosphono alkyl, the phosphono alkyl, dialkoxy phosphono alkoxyl group, alkoxy diaryl phosphono alkoxyl group, the phosphono alkoxyl group, dialkoxy phosphono alkylamino, alkoxy diaryl phosphono alkylamino, the phosphono alkylamino, dialkoxy phosphono alkyl, alkoxy diaryl phosphono alkyl, the sulphonyl alkyl, alkoxyl group sulphonyl alkyl, aralkoxy sulphonyl alkyl, alkoxyl group sulphonyl alkoxyl group, aralkoxy sulphonyl alkoxyl group, the sulphonyl alkoxyl group, alkoxyl group sulphonyl alkylamino, aralkoxy sulphonyl alkylamino and sulphonyl alkylamino;
R
30And R
31Randomly constitute linear fraction spacer together, form and be selected from down the ring of organizing with 2 to 7 continuous atoms: have 3 to 8 continuous members cycloalkyl ring, have 3 to 8 continuous members' cyclenes basic ring and heterocyclic ring with 3 to 8 members that link to each other;
R
23With R
25, R
24With R
25, R
25With R
26, R
24With R
26And R
23With R
26It is right randomly to select to constitute spacer independently, wherein spacer pair constitutes group L-U-V with selected spacer to member's bonding point, wherein L, U and V are independently selected from 1 of the group be made up of the heterocyclic radical of cycloalkyl, cycloalkenyl group, aryl, heteroaryl, saturated heterocycle and fractional saturation, the dibasic group of 2-, wherein cycloalkyl and cycloalkenyl group are by one or more R that are selected from
30And R
31Group replace, wherein said 1, the 2-substituting group is independently selected from C=O, C=S, C (R
28) R
32, S (O), S (O)
2, OP (OR
31) R
30, P (O) R
30, P (S) R
30And Si (R
28) R
29
R
23With R
25, R
24With R
25, R
25With R
26, R
24With R
26And R
23With R
26It is right randomly to select to constitute spacer independently, wherein spacer pair constitutes group L-U-V with selected spacer to member's bonding point, wherein L, U and V are independently selected from 1, the dibasic alkylidene group of 2-and 1, the group of the group that the dibasic alkenylene of 2-is formed, wherein said 1, the 2-substituting group is independently selected from C=O, C=S, C (R
28) R
29, S (O), S (O)
2, OP (OR
31) R
30, P (O) R
30, P (S) R
30And Si (R
28) R
29, described alkylidene group and alkenylene are by one or more R
30Or R
31Substituting group replaces;
Q
sBe selected from covalent single bond, (CR
37R
38)
b-(W
0)
Az, (CH (R
14))
c-W
1-(CH (R
15))
d(CH (R
14))
e-W
22-(CH (R
15))
h, wherein az is selected from 0 to 1 integer, and b is selected from 1 to 4 integer, W
0Be selected from O, S, C (O), C (S), C (O) O, C (S) O, C (O) S, C (S) S, C (O) N (R
14), (R
14) NC (O), C (S) N (R
14), (R
14) NC (S), OC (O) N (R
14), SC (S) N (R
14), SC (O) N (R
14), OC (S) N (R
14), N (R
15) C (O) N (R
14), (R
14) NC (O) N (R
15), N (R
15) C (S) N (R
14), (R
14) NC (S) N (R
15), S (O), S (O)
2, S (O)
2N (R
14), N (R
14) S (O)
2, Se, Se (O), Se (O)
2, Se (O)
2N (R
17), N (R
14) Se (O)
2, P (O) (R
8), N (R
7) P (O) (R
8), P (O) (R
8) N (R
7), N (R
14), ON (R
14) and SiR
28R
29, c and d are independently selected from 1 to 4 integer, W
1Be selected from O, S, C (O), C (S), C (O) O, C (S) O, C (O) S, C (S) S, C (O) N (R
14), (R
14) NC (O), C (S) N (R
14), (R
14) NC (S), OC (O) N (R
14), (R
14) NC (O) O, SC (S) N (R
14), (R
14) NC (S) S, SC (O) N (R
14), (R
14) NC (O) S, OC (S) N (R
14), (R
14) NC (S) O, N (R
15) C (O) N (R
14), (R
14) NC (O) N (R
15), N (R
15) C (S) N (R
14), (R
14) NC (S) N (R
15), S (O), S (O)
2, S (O)
2N (R
14), N (R
14) S (O)
2, Se, Se (O), Se (O)
2, Se (O)
2N (R
14), N (R
14) Se (O)
2, P (O) (R
8), N (R
7) P (O) (R
8), P (O) (R
8) N (R
7), N (R
14), ON (R
14) and SiR
28R
29, e and h are independently selected from 0 to 2 integer, W
22Be selected from CR
41=CR
42, CR
41R
42=C, vinylidene), ethynylene (C ≡ C; Ethynylene), 1, the 2-cyclopropyl, 1, the 2-cyclobutyl, 1, the 2-cyclohexyl, 1, the 3-cyclohexyl, 1, the 2-cyclopentyl, 1, the 3-cyclopentyl, 2, morpholinyl, 2, the 4-morpholinyl, 2, the 6-morpholinyl, 3, the 4-morpholinyl, 3, the 5-morpholinyl, 1, the 2-piperazinyl, 1, the 3-piperazinyl, 2, the 3-piperazinyl, 2, the 6-piperazinyl, 1, the 2-piperidyl, 1, the 3-piperidyl, 2, the 3-piperidyl, 2, the 4-piperidyl, 2, the 6-piperidyl, 3, the 4-piperidyl, 1, the 2-pyrrolidyl, 1, the 3-pyrrolidyl, 2, the 3-pyrrolidyl, 2, the 4-pyrrolidyl, 2, the 5-pyrrolidyl, 3, the 4-pyrrolidyl, 2, the 3-tetrahydrofuran base, 2, the 4-tetrahydrofuran base, 2,5-tetrahydrofuran base and 3, the 4-tetrahydrofuran base, its condition is R
14And R
15If direct and N bonding then is selected from the group except that halo and cyano group, (CR
37R
38)
b, (CH (R
14))
c, (CH (R
14))
eDirectly and E
0Bonding;
R
37And R
37If then randomly form linear fraction spacer together with different bond with carbon, form and be selected from down the ring of organizing with 1 to 7 continuous atom: have 3 to 8 continuous members cycloalkyl ring, have 3 to 8 continuous members' cyclenes basic ring and heterocyclic ring with 3 to 8 members that link to each other;
R
37And R
38If then form linear fraction spacer together with different bond with carbon, form and be selected from down the ring of organizing with 1 to 7 continuous atom: have 3 to 8 continuous members cycloalkyl ring, have 3 to 8 continuous members' cyclenes basic ring and heterocyclic ring with 3 to 8 members that link to each other;
R
38And R
38If then form linear fraction spacer together with different bond with carbon, form and be selected from down the ring of organizing with 1 to 7 continuous atom: have 3 to 8 continuous members cycloalkyl ring, have 3 to 8 continuous members' cyclenes basic ring and heterocyclic ring with 3 to 8 members that link to each other;
R
37And R
38If then form the group that is selected from down group together with identical bond with carbon: oxo, sulfo-, alkylidene group, halo alkylidene group and have the linear fraction spacer of 2 to 7 atoms that link to each other form and are selected from down the ring of organizing: have 3 to 8 continuous members cycloalkyl ring, have 3 to 8 continuous members' cyclenes basic ring and heterocyclic ring with 3 to 8 members that link to each other;
Y
0Randomly be Q
b-Q
Ss, Q wherein
SsBe selected from (CR
37R
38)
f, (CH (R
14))
c-W
1-(CH (R
15))
d(CH (R
14))
e-W
2-(CH (R
18))
h, wherein f is selected from 1 to 6 integer, and c and d are independently selected from 1 to 4 integer, W
1Be selected from O, S, C (O), C (S), C (O) O, C (S) O, C (O) S, C (S) S, C (O) N (R
14), (R
14) NC (O), C (S) N (R
14), (R
14) NC (S), OC (O) N (R
14), (R
14) NC (O) O, SC (S) N (R
14), (R
14) NC (S) S, SC (O) N (R
14), (R
14) NC (O) S, OC (S) N (R
14), (R
14) NC (S) O, N (R
15) C (O) N (R
14), (R
14) NC (O) N (R
15), N (R
15) C (S) N (R
14), (R
14) NC (S) N (R
15), S (O), S (O)
2, S (O)
2N (R
14), N (R
14) S (O)
2, Se, Se (O), Se (O)
2, Se (O)
2N (R
14), N (R
14) Se (O)
2, P (O) (R
8), N (R
7) P (O) (R
8), P (O) (R
8) N (R
7), N (R
14), ON (R
14) and SiR
28R
29, e and h are independently selected from 0 to 2 integer, W
2Be selected from CR
4a=CR
4b, ethynylene (C ≡ C; Ethynylene) and C=CR
4aR
4b, its condition is R
14And R
15If direct and N bonding then is selected from the group except that halo and cyano group, (CR
37R
38)
f, (CH (R
15))
c(CH (R
15))
eWith E
0If bonding is Q
SsBe (CR
37R
38)
f, wherein f is not integer 1, then Q
bBe selected from and remove N (R
26) N (R
26) C (NR
25) N (R
23) (R
24) or ON (R
26) C (NR
25) N (R
23) (R
24) in addition group;
Y
0Randomly be Q
b-Q
Sss, Q wherein
SssBe (CH (R
38))
r-W
3, wherein r is selected from 1 to 3 integer, W
3Be selected from 1, the 1-cyclopropyl, 1, the 2-cyclopropyl, 1, the 1-cyclobutyl, 1, the 2-cyclobutyl, 1, the 2-cyclohexyl, 1, the 3-cyclohexyl, 1, the 4-cyclohexyl, 1, the 2-cyclopentyl, 1, the 3-cyclopentyl, 2, morpholinyl, 2, the 4-morpholinyl, 2, the 5-morpholinyl, 2, the 6-morpholinyl, 3, the 4-morpholinyl, 3, the 5-morpholinyl, 1, the 2-piperazinyl, 1, the 3-piperazinyl, 1, the 4-piperazinyl, 2, the 3-piperazinyl, 2, the 5-piperazinyl, 2, the 6-piperazinyl, 1, the 2-piperidyl, 1, the 3-piperidyl, 1, the 4-piperidyl, 2, the 3-piperidyl, 2, the 4-piperidyl, 2, the 5-piperidyl, 2, the 6-piperidyl, 3, the 4-piperidyl, 3, the 5-piperidyl, 3, the 6-piperidyl, 1, the 2-pyrrolidyl, 1, the 3-pyrrolidyl, 2, the 3-pyrrolidyl, 2, the 4-pyrrolidyl, 2, the 5-pyrrolidyl, 3, the 4-pyrrolidyl, 2H-2, the 3-pyranyl, 2H-2, the 4-pyranyl, 2H-2, the 5-pyranyl, 4H-2, the 3-pyranyl, 4H-2, the 4-pyranyl, 4H-2, the 5-pyranyl, 2H-pyran-2-one-3, the 4-base, 2H-pyran-2-one-4, the 5-base, 4H-pyrans-4-ketone-2, the 3-base, 2, the 3-tetrahydrofuran base, 2, the 4-tetrahydrofuran base, 2, the 5-tetrahydrofuran base, 3, the 4-tetrahydrofuran base, 2, the 3-THP trtrahydropyranyl, 2, the 4-THP trtrahydropyranyl, 2, the 5-THP trtrahydropyranyl, 2, the 6-THP trtrahydropyranyl, 3,4-THP trtrahydropyranyl and 3,5-THP trtrahydropyranyl, except that tie point, each contains the W of carbon and hydrogen
3Ring nitrogen member is randomly by one or more R that are selected from
9, R
10, R
11And R
12Group replace, its condition is (CH (R
38))
rWith E
0Bonding, Q
bWith each W
3Lowest number substituting group position bonding;
Y
0Randomly be Q
b-Q
Sssr, Q wherein
SssrBe (CH (R
38))
r-W
4, wherein r is selected from 1 to 3 integer, W
4Be selected from 1, the 2-cyclobutyl, 1, the 2-cyclohexyl, 1, the 3-cyclohexyl, 1, the 4-cyclohexyl, 1, the 2-cyclopentyl, 1, the 3-cyclopentyl, 2, morpholinyl, 2, the 4-morpholinyl, 2, the 5-morpholinyl, 2, the 6-morpholinyl, 3, the 4-morpholinyl, 3, the 5-morpholinyl, 1, the 2-piperazinyl, 1, the 3-piperazinyl, 1, the 4-piperazinyl, 2, the 3-piperazinyl, 2, the 5-piperazinyl, 2, the 6-piperazinyl, 1, the 2-piperidyl, 1, the 3-piperidyl, 1, the 4-piperidyl, 2, the 3-piperidyl, 2, the 4-piperidyl, 2, the 5-piperidyl, 2, the 6-piperidyl, 3, the 4-piperidyl, 3, the 5-piperidyl, 3, the 6-piperidyl, 1, the 2-pyrrolidyl, 1, the 3-pyrrolidyl, 2, the 3-pyrrolidyl, 2, the 4-pyrrolidyl, 2, the 5-pyrrolidyl, 3, the 4-pyrrolidyl, 2H-2, the 3-pyranyl, 2H-2, the 4-pyranyl, 2H-2, the 5-pyranyl, 4H-2, the 3-pyranyl, 4H-2, the 4-pyranyl, 4H-2, the 5-pyranyl, 2H-pyran-2-one-3, the 4-base, 2H-pyran-2-one-4, the 5-base, 4H-pyrans-4-ketone-2, the 3-base, 2, the 3-tetrahydrofuran base, 2, the 4-tetrahydrofuran base, 2, the 5-tetrahydrofuran base, 3, the 4-tetrahydrofuran base, 2, the 3-THP trtrahydropyranyl, 2, the 4-THP trtrahydropyranyl, 2, the 5-THP trtrahydropyranyl, 2, the 6-THP trtrahydropyranyl, 3,4-THP trtrahydropyranyl and 3, the 5-THP trtrahydropyranyl, except that tie point, each contains the W of carbon and hydrogen
4Ring nitrogen member is randomly by one or more R that are selected from
9, R
10, R
11And R
12Group replace, its condition is (CH (R
38))
rWith E
0Bonding, Q
bWith each W
4The highest numbering substituting group position bonding;
Y
0Randomly be Q
b-Q
Ssss, Q wherein
SsssBe (CH (R
38))
r-W
5, wherein r is selected from 1 to 3 integer, W
5Be selected from 1, the 4-indenyl, 1, the 5-indenyl, 1, the 6-indenyl, 1, the 7-indenyl, 2, the 7-indenyl, 2, the 6-indenyl, 2, the 5-indenyl, 2, the 4-indenyl, 3, the 4-indenyl, 3, the 5-indenyl, 3, the 6-indenyl, 3, the 7-indenyl, 2, the 4-benzofuryl, 2, the 5-benzofuryl, 2, the 6-benzofuryl, 2, the 7-benzofuryl, 3, the 4-benzofuryl, 3, the 5-benzofuryl, 3, the 6-benzofuryl, 3, the 7-benzofuryl, 2, the 4-benzothienyl, 2, the 5-benzothienyl, 2, the 6-benzothienyl, 2, the 7-benzothienyl, 3, the 4-benzothienyl, 3, the 5-benzothienyl, 3, the 6-benzothienyl, 3, the 7-benzothienyl, 2,4-imidazo (1,2-a) pyridyl, 2, the 5-imidazo (1,2-a) pyridyl, 2,6-imidazo (1,2-a) pyridyl, 2, the 7-imidazo (1,2-a) pyridyl, 3,4-imidazo (1,2-a) pyridyl, 3, the 5-imidazo (1,2-a) pyridyl, 3,6-imidazo (1,2-a) pyridyl, 3, the 7-imidazo (1,2-a) pyridyl, 2, the 4-indyl, 2, the 5-indyl, 2, the 6-indyl, 2, the 7-indyl, 3, the 4-indyl, 3, the 5-indyl, 3, the 6-indyl, 3, the 7-indyl, 1, the 4-pseudoindoyl, 1, the 5-pseudoindoyl, 1, the 6-pseudoindoyl, 2, the 4-pseudoindoyl, 2, the 5-pseudoindoyl, 2, the 6-pseudoindoyl, 2, the 7-pseudoindoyl, 1, the 3-pseudoindoyl, 3, the 4-indazolyl, 3, the 5-indazolyl, 3, the 6-indazolyl, 3, the 7-indazolyl, 2, the 4-benzoxazolyl, 2, the 5-benzoxazolyl, 2, the 6-benzoxazolyl, 2, the 7-benzoxazolyl, 3,4-benzoisoxazole base, 3,5-benzoisoxazole base, 3,6-benzoisoxazole base, 3,7-benzoisoxazole base, 1, the 4-naphthyl, 1, the 5-naphthyl, 1, the 6-naphthyl, 1, the 7-naphthyl, 1, the 8-naphthyl, 2, the 4-naphthyl, 2, the 5-naphthyl, 2, the 6-naphthyl, 2, the 7-naphthyl, 2, the 8-naphthyl, 2, the 4-quinolyl, 2, the 5-quinolyl, 2, the 6-quinolyl, 2, the 7-quinolyl, 2, the 8-quinolyl, 3, the 4-quinolyl, 3, the 5-quinolyl, 3, the 6-quinolyl, 3, the 7-quinolyl, 3, the 8-quinolyl, 4, the 5-quinolyl, 4, the 6-quinolyl, 4, the 7-quinolyl, 4, the 8-quinolyl, 1, the 4-isoquinolyl, 1, the 5-isoquinolyl, 1, the 6-isoquinolyl, 1, the 7-isoquinolyl, 1, the 8-isoquinolyl, 3, the 4-isoquinolyl, 3, the 5-isoquinolyl, 3, the 6-isoquinolyl, 3, the 7-isoquinolyl, 3, the 8-isoquinolyl, 4, the 5-isoquinolyl, 4, the 6-isoquinolyl, 4, the 7-isoquinolyl, 4, the 8-isoquinolyl, 3,4-cinnolines base, 3,5-cinnolines base, 3,6-cinnolines base, 3,7-cinnolines base, 3,8-cinnolines base, 4,5-cinnolines base, 4,6-cinnolines base, 4,7-cinnolines base and 4,8-cinnolines base, except that tie point, each contains the W of carbon and hydrogen
4Ring nitrogen member is randomly by one or more R that are selected from
9, R
10, R
11And R
12Group replace, its condition is Q
bWith each W
5Lowest number substituting group position bonding, (CH (R
38))
rWith E
0Bonding;
Y
0Randomly be Q
b-Q
Ssssr, Q wherein
SsssrBe (CH (R
38))
r-W
6, wherein r is selected from 1 to 3 integer, W
6Be selected from 1, the 4-indenyl, 1, the 5-indenyl, 1, the 6-indenyl, 1, the 7-indenyl, 2, the 7-indenyl, 2, the 6-indenyl, 2, the 5-indenyl, 2, the 4-indenyl, 3, the 4-indenyl, 3, the 5-indenyl, 3, the 6-indenyl, 3, the 7-indenyl, 2, the 4-benzofuryl, 2, the 5-benzofuryl, 2, the 6-benzofuryl, 2, the 7-benzofuryl, 3, the 4-benzofuryl, 3, the 5-benzofuryl, 3, the 6-benzofuryl, 3, the 7-benzofuryl, 2, the 4-benzothienyl, 2, the 5-benzothienyl, 2, the 6-benzothienyl, 2, the 7-benzothienyl, 3, the 4-benzothienyl, 3, the 5-benzothienyl, 3, the 6-benzothienyl, 3, the 7-benzothienyl, 2,4-imidazo (1,2-a) pyridyl, 2, the 5-imidazo (1,2-a) pyridyl, 2,6-imidazo (1,2-a) pyridyl, 2, the 7-imidazo (1,2-a) pyridyl, 3,4-imidazo (1,2-a) pyridyl, 3, the 5-imidazo (1,2-a) pyridyl, 3,6-imidazo (1,2-a) pyridyl, 3, the 7-imidazo (1,2-a) pyridyl, 2, the 4-indyl, 2, the 5-indyl, 2, the 6-indyl, 2, the 7-indyl, 3, the 4-indyl, 3, the 5-indyl, 3, the 6-indyl, 3, the 7-indyl, 1, the 4-pseudoindoyl, 1, the 5-pseudoindoyl, 1, the 6-pseudoindoyl, 2, the 4-pseudoindoyl, 2, the 5-pseudoindoyl, 2, the 6-pseudoindoyl, 2, the 7-pseudoindoyl, 1, the 3-pseudoindoyl, 3, the 4-indazolyl, 3, the 5-indazolyl, 3, the 6-indazolyl, 3, the 7-indazolyl, 2, the 4-benzoxazolyl, 2, the 5-benzoxazolyl, 2, the 6-benzoxazolyl, 2, the 7-benzoxazolyl, 3,4-benzoisoxazole base, 3,5-benzoisoxazole base, 3,6-benzoisoxazole base, 3,7-benzoisoxazole base, 1, the 4-naphthyl, 1, the 5-naphthyl, 1, the 6-naphthyl, 1, the 7-naphthyl, 1, the 8-naphthyl, 2, the 4-naphthyl, 2, the 5-naphthyl, 2, the 6-naphthyl, 2, the 7-naphthyl, 2, the 8-naphthyl, 2, the 4-quinolyl, 2, the 5-quinolyl, 2, the 6-quinolyl, 2, the 7-quinolyl, 2, the 8-quinolyl, 3, the 4-quinolyl, 3, the 5-quinolyl, 3, the 6-quinolyl, 3, the 7-quinolyl, 3, the 8-quinolyl, 4, the 5-quinolyl, 4, the 6-quinolyl, 4, the 7-quinolyl, 4, the 8-quinolyl, 1, the 4-isoquinolyl, 1, the 5-isoquinolyl, 1, the 6-isoquinolyl, 1, the 7-isoquinolyl, 1, the 8-isoquinolyl, 3, the 4-isoquinolyl, 3, the 5-isoquinolyl, 3, the 6-isoquinolyl, 3, the 7-isoquinolyl, 3, the 8-isoquinolyl, 4, the 5-isoquinolyl, 4, the 6-isoquinolyl, 4, the 7-isoquinolyl, 4, the 8-isoquinolyl, 3,4-cinnolines base, 3,5-cinnolines base, 3,6-cinnolines base, 3,7-cinnolines base, 3,8-cinnolines base, 4,5-cinnolines base, 4,6-cinnolines base, 4,7-cinnolines base and 4,8-cinnolines base, except that tie point, each contains the W of carbon and hydrogen
4Ring nitrogen member is randomly by one or more R that are selected from
9, R
10, R
11And R
12Group replace, its condition is Q
bWith each W
5The highest numbering substituting group position bonding, (CH (R
38))
rWith E
0Bonding.
In a kind of embodiment of formula I compound or its pharmacy acceptable salt,
J
aAnd J
bBe independently selected from O and S;
B is a formula V:
D wherein
1, D
2, J
1, J
2And K
1Be independently selected from C, N, O, S and covalent linkage, its condition be at the most one can be covalent linkage, D
1, D
2, J
1, J
2And K
1At the most one be O, D
1, D
2, J
1, J
2And K
1At the most one be S, if D
1, D
2, J
1, J
2And K
1Two be O and S, then D
1, D
2, J
1, J
2And K
1One of must be covalent linkage, D
1, D
2, J
1, J
2And K
1At the most four be N, its condition is R
32, R
33, R
34, R
35And R
36Selected independently of one another, with the tetravalence character of keeping carbon, the trivalent character of nitrogen, the divalence character of sulphur and the divalence character of oxygen;
R
9, R
10, R
11, R
12, R
13, R
16, R
17, R
18, R
19, R
32, R
33, R
34, R
35And R
36Be independently selected from hydrogen, kharophen, the halo kharophen, amidino groups, guanidine radicals, dialkyl matte, San Wan Ji Phosphonium, the dialkyl matte alkyl, carboxyl, assorted aromatic alkylthio, assorted aralkoxy, cycloalkyl amino, the acyl group alkyl, the acyl group alkoxyl group, the aroyl alkoxyl group, heterocyclic oxy group, the aralkyl aryl, aralkyl, arylalkenyl, sweet-smelling alkynyl, heterocyclic radical, the perhalogeno aralkyl, the aralkyl alkylsulfonyl, aralkyl sulphonyl alkyl, aralkyl sulfinyl, aralkyl sulfinyl alkyl, halogenated cycloalkyl, the halo cycloalkenyl group, the cycloalkyl sulfinyl, cycloalkyl sulfinyl alkyl, the naphthene sulfamide base, the naphthene sulfamide alkyl, heteroaryl amino, N-heteroaryl amino-N-alkylamino, the heteroaryl amino alkyl, halogenated alkylthio, alkanoyloxy, alkoxyl group, alkoxyalkyl, halogenated alkoxy alkyl, assorted aralkoxy, cycloalkyloxy, cyclenes oxygen base, the cycloalkyloxy alkyl, cycloalkyl alkoxy, cyclenes oxygen base alkyl, inferior cycloalkanes dioxy base, the halo cycloalkyloxy, halo cycloalkyloxy alkyl, halo cyclenes oxygen base, halo cyclenes oxygen base alkyl, hydroxyl, amino, alkoxy amino, sulfo-, nitro, low-grade alkyl amino, alkylthio, alkylthio alkyl, arylamino, aryl alkyl amino, arylthio, arylthio alkyl, assorted sweet-smelling alkoxy alkyl, alkyl sulphinyl, the alkyl sulfenyl alkyl, aryl sulfinyl alkyl, the arylsulfonyl alkyl, heteroaryl sulfinyl alkyl, heteroaryl sulphonyl alkyl, alkyl sulphonyl, the alkyl sulfonyl alkyl, haloalkyl sulfinyl alkyl, haloalkyl sulphonyl alkyl, alkyl sulfonyl amino, alkyl amino sulfonyl, the amido alkylsulfonyl, one alkyl amido alkylsulfonyl, dialkyl group amido alkylsulfonyl, one aryl amido alkylsulfonyl, Arenesulfonyl amino, diaryl amido alkylsulfonyl, one alkyl, one aryl amido alkylsulfonyl, aryl sulfonyl kia, aryl sulfonyl, heteroarylthio, the heteroaryl sulfinyl, heteroarylsulfonyl, the heterocyclic radical alkylsulfonyl, the heterocyclic radical sulfo-, alkyloyl, enoyl-, aroyl, 4-hetaroylpyrazol, aralkanoyl, assorted aralkanoyl, the haloalkane acyl group, alkyl, thiazolinyl, alkynyl, alkene oxygen base, alkene oxygen base alkyl, alkylene dioxo base, the halo alkylene dioxo base, cycloalkyl, the cycloalkyl alkyloyl, cycloalkenyl group, the low-grade cycloalkyl alkyl, the lower alkenyl ring alkyl, halogen, haloalkyl, haloalkenyl group, halogenated alkoxy, the hydroxy halogeno alkyl, hydroxyl aralkyl, hydroxyalkyl, alkenyl amino, the hydroxyl heteroaralkyl, halogenated alkoxy alkyl, aryl, aralkyl, aryloxy, aralkoxy, aryloxy alkyl, saturated heterocyclic radical, the heterocyclic radical of fractional saturation, heteroaryl, heteroaryloxy, the heteroaryloxy alkyl, arylalkyl, heteroarylalkyl, aryl alkenyl, the heteroaryl thiazolinyl, carboxyalkyl, carbalkoxy, the alkoxyl group carboxamido, alkyl amido carbonyl amido, aryl amido carbonyl amido, alkoxycarbonyl alkyl, the carbalkoxy thiazolinyl, carboxyl, aralkoxycarbonyl, carboxamido, the carboxamido alkyl, cyano group, the haloalkoxy carbonyl, phosphono, the phosphono alkyl, alkoxy diaryl phosphono and alkoxy diaryl phosphono alkyl;
R
16, R
19, R
32, R
33, R
34, R
35And R
36Randomly be Q independently
b, its condition is R
16And R
19At the most one be Q simultaneously
b, Q
bBe Q
Be
R
32With R
33, R
33With R
34, R
34With R
35And R
35With R
36It is right randomly to select to form spacer independently, wherein spacer is to forming the linear fraction with 3 to 6 continuous atoms together, member's bonding point is connected to form the ring that is selected from down group with described spacer: have 5 to 8 members that link to each other the cyclenes basic ring, have 5 to 8 continuous members' fractional saturation heterocyclic ring, have 5 to 6 continuous members' heteroaryl ring and aryl, its condition is R
32With R
33, R
33With R
34, R
34With R
35And R
35With R
36A pair of at the most spacer to using simultaneously;
R
9With R
10, R
10With R
11, R
11With R
12And R
12With R
13It is right randomly to select to form spacer independently, wherein spacer is to forming the linear fraction with 3 to 6 continuous atoms together, member's bonding point is connected to form the ring that is selected from down group with described spacer: have 5 to 8 members that link to each other the cyclenes basic ring, have 5 to 8 continuous members' fractional saturation heterocyclic ring, have 5 to 6 continuous members' heteroaryl ring and aryl, its condition is R
9With R
10, R
10With R
11, R
11With R
12And R
12With R
13A pair of at the most spacer to using simultaneously;
B randomly is selected from hydrogen, trialkylsilkl, C2-C8 alkyl, C3-C8 thiazolinyl, C3-C8 alkylidene group, C3-C8 alkynyl, C2-C8 haloalkyl and C3-C8 haloalkenyl group, wherein each member of group B can be randomly at distance B and A tie point nearly and comprise on any carbon of 6 atoms by one or more radicals R
32, R
33, R
34, R
35And R
36Replace;
B randomly is selected from the saturated heterocyclic radical of C3-C15 cycloalkyl, C5-C10 cycloalkenyl group, C4-C12 and the heterocyclic radical of C4-C9 fractional saturation, and wherein each ring carbon is randomly by R
33Replace, the ring carbon except that the ring carbon that is positioned at B and A tie point is randomly replaced by oxo, and its condition is that a ring carbon is replaced by oxo simultaneously at the most, and ring carbon adjacent with the ring carbon that is positioned at tie point and nitrogen-atoms are randomly by R
9Or R
13Replace, with R
9The position adjacent and apart from the ring carbon of two atoms of tie point or nitrogen-atoms randomly by R
10Replace, with R
13The position adjacent and apart from the ring carbon of two atoms of tie point or nitrogen-atoms randomly by R
12Replace, apart from three atoms of tie point and and R
10Ring carbon that the position is adjacent or nitrogen-atoms are randomly by R
11Replace, apart from three atoms of tie point and and R
12Ring carbon that the position is adjacent or nitrogen-atoms are randomly by R
33Replace, apart from four atoms of tie point and and R
11And R
33Ring carbon that the position is adjacent or nitrogen-atoms are randomly by R
34Replace;
A is selected from covalent single bond, (W
7)
Rr-(CH (R
16))
Pa(CH (R
15))
Pa-(W
7)
Rr, wherein rr is selected from 0 to 1 integer, and pa is selected from 0 to 6 integer, W
7Be selected from O, S, C (O), C (S), C (O) S, C (S) O, C (O) N (R
7), C (S) N (R
7), (R
7) NC (O), (R
7) NC (S), S (O), S (O)
2, S (O)
2N (R
7), (R
7) NS (O)
2, P (O) (R
8), N (R
7) P (O) (R
8), P (O) (R
8) N (R
7), C (NR
7) N (R
7), (R
7) NC (NR
7), (R
7) NC (NR
7) NR
7And N (R
7), its condition be rr and pa at the most one can be 0 simultaneously;
R
7And R
8Be independently selected from hydrogen, hydroxyl, alkyl, acyl group, aroyl, 4-hetaroylpyrazol and alkoxyalkyl;
R
14, R
15, R
37And R
38Be independently selected from hydrogen, hydroxyl, halogen, cyano group, hydroxyalkyl, alkoxyl group, alkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl group, cycloalkenyl alkyl, haloalkyl, haloalkenyl group, halogenated alkoxy, halogenated alkoxy alkyl, haloalkene oxygen base alkyl, halo cycloalkyloxy, halo cycloalkyloxy alkyl, halo cyclenes oxygen base alkyl, carboxyl, carboxyalkyl, carbalkoxy, carboxylic acid amides and carboxamido alkyl;
R
14And R
38Can be independently selected from acyl group, aroyl and 4-hetaroylpyrazol, its condition is that acyl group is selected from the group except that formyl radical;
Ψ is selected from NR
5, O, C (O), C (S), S, S (O), S (O)
2, ON (R
5), P (O) (R
8) and CR
39R
40
R
5Be selected from hydrogen, hydroxyl, amino, alkyl, alkoxyl group, alkoxyalkyl, haloalkyl, acyl group, aroyl and 4-hetaroylpyrazol;
R
39And R
40Be independently selected from hydrogen, hydroxyl, halogen, cyano group, hydroxyalkyl, acyl group, aroyl, 4-hetaroylpyrazol, acyl group amido, alkoxyl group, alkyl, alkoxyalkyl, haloalkyl, halogenated alkoxy, halogenated alkoxy alkyl, alkyl sulphonyl, halogenated alkyl sulfonyl, carboxyl, carboxyalkyl, carbalkoxy, carboxylic acid amides and carboxamido alkyl;
M is selected from N and R
1-C;
R
2And R
1Be independently selected from Z
0-Q, hydrogen, alkyl, thiazolinyl and halogen;
R
1Randomly be selected from amino, aminoalkyl group, alkylamino, amidino groups, guanidine radicals, hydroxyl, hydroxyl amino, alkoxyl group, hydroxyalkyl, alkoxy amino, sulfo-hydroxyl, alkylthio, dialkyl matte, three alkane base Phosphonium, dialkyl matte alkyl, heteroaryl amino, nitro, arylamino, aryl alkyl amino, alkyloyl, enoyl-, aroyl, 4-hetaroylpyrazol, aralkanoyl, assorted aralkanoyl, haloalkane acyl group, hydroxy halogeno alkyl, cyano group and phosphono;
Z
0Be selected from covalent single bond, (CR
41R
42)
q, (CH (R
41))
g-W
0-(CH (R
42))
p(CH (R
41))
e-W
22-(CH (R
42))
h, wherein q is selected from 1 to 6 integer, and g and p are independently selected from 0 to 3 integer, W
0Be selected from O, S, C (O), C (S), C (O) O, C (S) O, C (O) S, C (S) S, C (O) N (R
41), (R
41) NC (O), C (S) N (R
41), (R
41) NC (S), OC (O) N (R
41), (R
41) NC (O) O, SC (S) N (R
41), (R
41) NC (S) S, SC (O) N (R
41), (R
41) NC (O) S, OC (S) N (R
41), (R
41) NC (S) O, N (R
42) C (O) N (R
41), (R
41) NC (O) N (R
42), N (R
42) C (S) N (R
41), (R
41) NC (S) N (R
42), S (O), S (O)
2, S (O)
2N (R
41), N (R
41) S (O)
2, Se, Se (O), Se (O)
2, Se (O)
2N (R
41), N (R
41) Se (O)
2, P (O) (R
8), N (R
7) P (O) (R
8), P (O) (R
8) N (R
7), N (R
41), ON (R
41) and SiR
28R
29, e and h are independently selected from 0 to 2 integer, W
22Be selected from CR
41=CR
42, CR
41R
42=C, vinylidene), ethynylene (C ≡ C; Ethynylene), 1, the 2-cyclopropyl, 1, the 2-cyclobutyl, 1, the 2-cyclohexyl, 1, the 3-cyclohexyl, 1, the 2-cyclopentyl, 1, the 3-cyclopentyl, 2, morpholinyl, 2, the 4-morpholinyl, 2, the 6-morpholinyl, 3, the 4-morpholinyl, 3, the 5-morpholinyl, 1, the 2-piperazinyl, 1, the 3-piperazinyl, 2, the 3-piperazinyl, 2, the 6-piperazinyl, 1, the 2-piperidyl, 1, the 3-piperidyl, 2, the 3-piperidyl, 2, the 4-piperidyl, 2, the 6-piperidyl, 3, the 4-piperidyl, 1, the 2-pyrrolidyl, 1, the 3-pyrrolidyl, 2, the 3-pyrrolidyl, 2, the 4-pyrrolidyl, 2, the 5-pyrrolidyl, 3, the 4-pyrrolidyl, 2, the 3-tetrahydrofuran base, 2, the 4-tetrahydrofuran base, 2,5-tetrahydrofuran base and 3, the 4-tetrahydrofuran base, its condition is R
41And R
42If direct and N bonding then is selected from the group except that halogen and cyano group, Z
0Direct and uridylic ring key closes;
R
41And R
42Be independently selected from amidino groups, hydroxyl amino, hydrogen, hydroxyl, amino, halogen, cyano group, aryloxy, hydroxyalkyl, acyl group, aroyl, 4-hetaroylpyrazol, the heteroaryloxy alkyl, alkoxyl group, alkyl, aryl, aralkyl, aryloxy alkyl, the sweet-smelling alkoxy alkyl alkoxyl group, alkoxyalkyl, the heteroaryloxy alkyl, cycloalkyl, cycloalkylalkyl, the cycloalkyl thiazolinyl, cycloalkenyl group, cycloalkenyl alkyl, haloalkyl, haloalkenyl group, halogenated cycloalkyl, the halo cycloalkenyl group, halogenated alkoxy, halogenated alkoxy alkyl, haloalkene oxygen base alkyl, the halo cycloalkyloxy, halo cycloalkyloxy alkyl, halo cyclenes oxygen base alkyl, saturated heterocyclic radical, the heterocyclic radical of fractional saturation, heteroaryl, heteroaralkyl, the heteroarylthio alkyl, assorted alkylthio-alkyl aryl, alkyl sulphonyl, halogenated alkyl sulfonyl, aryl sulfonyl, the arylsulfonyl alkyl, the aralkyl alkylsulfonyl, the naphthene sulfamide base, the naphthene sulfamide alkyl, heteroaryl sulphonyl alkyl, heteroarylsulfonyl and aralkyl sulphonyl alkyl;
Q is formula (II):
D wherein
1, D
2, J
1, J
2And K
1Be independently selected from C, N, O, S and covalent linkage, its condition be at the most one can be covalent linkage, D
1, D
2, J
1, J
2And K
1At the most one be O, D
1, D
2, J
1, J
2And K
1At the most one be S, if D
1, D
2, J
1, J
2And K
1Two be O and S, then D
1, D
2, J
1, J
2And K
1One of must be covalent linkage, D
1, D
2, J
1, J
2And K
1At the most four be N, its condition is R
9, R
10, R
11, R
12And R
13Selected independently of one another, with the tetravalence character of keeping carbon, the trivalent character of nitrogen, the divalence character of sulphur and the divalence character of oxygen;
Q randomly is selected from formula (III):
D wherein
3, D
4, J
3And J
4Be independently selected from C, N, O and S, D
3, D
4, J
3And J
4At the most one be O, D
3, D
4, J
3And J
4At the most one be S, D
1, D
2, J
1And J
2At the most three be N, its condition is R
9, R
10, R
11And R
12Selected independently of one another, with the tetravalence character of keeping carbon, the trivalent character of nitrogen, the divalence character of sulphur and the divalence character of oxygen;
Q randomly is selected from hydrogen, alkyl, alkoxyl group, alkylamino, alkylthio, halogenated alkylthio, thiazolinyl, alkynyl, saturated heterocyclic radical, heterocyclic radical, acyl group, aroyl, 4-hetaroylpyrazol, cycloalkyl, cycloalkylalkyl, cycloalkenyl group, cycloalkenyl alkyl, cycloalkyl thiazolinyl, haloalkyl, halogenated alkoxy, haloalkenyl group, halogenated cycloalkyl, halo cycloalkenyl group, halogenated alkoxy alkyl, haloalkene oxygen base alkyl, halo cycloalkyloxy alkyl and the halo cyclenes oxygen base alkyl of fractional saturation; its condition is if Q is a hydrogen, then Z
0Be selected from the group except that covalent single bond;
K is (CR
4aR
4b)
n, wherein n is selected from 1 to 2 integer;
R
4aAnd R
4bBe independently selected from halogen, hydrogen, hydroxyl, cyano group, hydroxyalkyl, alkyl, thiazolinyl, alkoxyalkyl, aralkyl, heteroaralkyl, alkylthio alkyl, haloalkyl, haloalkenyl group and cyano group alkyl;
If K is (CR
4aR
4b)
n, E then
0Be E
1, E wherein
1Be selected from covalent single bond, O, S, C (O), C (S), C (O) O, C (S) O, C (O) S, C (S) S, C (O) N (R
7), (R
7) NC (O), C (S) N (R
7), (R
7) NC (S), OC (O) N (R
7), (R
7) NC (O) O, SC (S) N (R
7), (R
7) NC (S) S, SC (O) N (R
7), (R
7) NC (O) S, OC (S) N (R
7), (R
7) NC (S) O, N (R
8) C (O) N (R
7), (R
7) NC (O) N (R
8), N (R
8) C (S) N (R
7), (R
7) NC (S) N (R
8), S (O), S (O)
2, S (O)
2N (R
7), N (R
7) S (O)
2, S (O)
2N (R
7) C (O), C (O) N (R
7) S (O)
2, P (O) (R
8), N (R
7) P (O) (R
8), P (O) (R
8) N (R
7), N (R
7), ON (R
7), CR
4a=CR
4b, ethynylene (C ≡ C; Ethynylene) and C=CR
4aR
4b
K randomly is (CH (R
14))
j-T, wherein j is selected from 0 to 2 integer, and T is selected from covalent single bond, O, S and N (R
7), its condition is (CH (R
14))
jClose with the uridylic ring key;
If K is (CH (R
14))
j-T, then E
0Randomly be E
2, E wherein
2Be selected from covalent single bond, C (O), C (S), C (O) O, C (S) O, C (O) S, C (S) S, C (O) N (R
7), (R
7) NC (O), C (S) N (R
7), (R
7) NC (S), (R
7) NC (O) O, (R
7) NC (S) S, (R
7) NC (O) S, (R
7) NC (S) O, N (R
8) C (O) N (R
7), (R
7) NC (O) N (R
8), N (R
8) C (S) N (R
7), (R
7) NC (S) N (R
8), S (O), S (O)
2, S (O)
2N (R
7), N (R
7) S (O)
2, S (O)
2N (H) C (O), C (O) N (H) S (O)
2, P (O) (R
8), N (R
7) P (O) (R
8), P (O) (R
8) N (R
7) and N (R
7);
K randomly is G-(CH (R
15))
k, wherein k is selected from 1 to 2 integer, and G is selected from O, S and N (R
7), its condition is if k is 1, then R
15Can not be hydroxyl, cyano group, halogen, amino, alkylamino, dialkyl amido and sulfydryl;
If K is G-(CH (R
15))
k, E then
0Randomly be E
3, E wherein
3Be selected from covalent single bond, O, S, C (O), C (S), C (O) O, C (S) O, C (O) S, C (S) S, C (O) N (R
7), (R
7) NC (O), C (S) N (R
7), (R
7) NC (S), OC (O) N (R
7), (R
7) NC (O) O, SC (S) N (R
7), (R
7) NC (S) S, SC (O) N (R
7), (R
7) NC (O) S, OC (S) N (R
7), (R
7) NC (S) O, N (R
8) C (O) N (R
7), (R
7) NC (O) N (R
8), N (R
8) C (S) N (R
7), (R
7) NC (S) N (R
8), S (O), S (O)
2, S (O)
2N (R
7), N (R
7) S (O)
2, P (O) (R
8), N (R
7) P (O) (R
8), P (O) (R
8) N (R
7), N (R
7), ON (R
7), CR
4a=CR
4b, ethynylene (C ≡ C; Ethynylene) and C=CR
4aR
4b
Y
0Be formula (IV):
D wherein
5, D
6, J
5And J
6Be independently selected from C, N, O, S and covalent linkage, its condition be at the most one be covalent linkage, K
2Be independently selected from C and N
+, D
5, D
6, J
5And J
6At the most one be O, D
5, D
6, J
5And J
6At the most one be S, if D
5, D
6, J
5And J
6Two be O and S, then D
5, D
6, J
5And J
6One of must be covalent linkage, if K
2Be N
+, D then
5, D
6, J
5And J
6At the most three be N, if K
2Be carbon, D then
5, D
6, J
5And J
6At the most four be N, its condition is R
16, R
17, R
18And R
19Selected independently of one another, with the tetravalence character of keeping carbon, the trivalent character of nitrogen, the divalence character of sulphur and the divalence character of oxygen;
R
16And R
17Randomly form linear fraction spacer independently together, be connected to form and be selected from down the ring of organizing with 3 to 6 continuous atoms: have 5 to 8 continuous members the cyclenes basic ring, have 5 to 8 continuous members' fractional saturation heterocyclic ring, have 5 to 6 continuous members' heteroaryl and aryl;
Q
bBe selected from NR
20R
21,
+NR
20R
21R
22, oxygen base, alkyl, amino alkylidenyl, alkylamino, dialkyl amido, dialkyl matte alkyl, acyl amino and Q
Be, Q wherein
BeBe hydrogen, R
20, R
21And R
22Be independently selected from hydrogen, amino, alkyl, hydroxyl, alkoxyl group, amino alkylidenyl, alkylamino, dialkyl amido and hydroxyalkyl, its condition is R
20, R
21And R
22At the most one be hydroxyl, alkoxyl group, alkylamino, amino and dialkyl amido simultaneously, if K
2Be N
+, R then
20, R
21And R
22Can not be hydroxyl, alkoxyl group, alkylamino, amino and dialkyl amido;
R
20With R
21, R
20With R
22And R
21With R
22It is right randomly to select to form spacer independently, and wherein spacer is connected with the bonding point of described spacer to the member forming the linear fraction with 4 to 7 continuous atoms together, forms the heterocyclic ring with 5 to 8 continuous members, and its condition is R
20With R
21, R
20With R
22And R
21With R
22A pair of at the most spacer to using simultaneously;
Q
bRandomly be selected from N (R
26) SO
2N (R
23) (R
24), N (R
26) C (O) OR
5, N (R
26) C (O) SR
5, N (R
26) C (S) OR
5And N (R
26) C (S) SR
5, if its condition is R
23, R
24And R
26Two with identical atomic linkage, then R
23, R
24And R
26At the most one can be hydroxyl, alkoxyl group, alkylamino, amino and dialkyl amido;
Q
bRandomly be selected from dialkyl matte, San Wan Ji Phosphonium, C (NR
25) NR
23R
24, N (R
26) C (NR
25) N (R
23) (R
24), N (R
26) C (O) N (R
23) (R
24), N (R
26) C (S) N (R
23) (R
24), C (NR
25) OR
5, C (O) N (R
26) C (NR
25) N (R
23) (R
24), C (S) N (R
26) C (NR
25) N (R
23) (R
24), N (R
26) N (R
26) C (NR
25) N (R
23) (R
24), ON (R
26) C (NR
25) N (R
23) (R
24), N (R
26) N (R
26) SO
2N (R
23) (R
24), C (NR
25) SR
5, C (O) NR
23R
24And C (O) NR
23R
24, if its condition is R
23, R
24And R
26Two with identical atomic linkage, then R
23, R
24And R
26At the most one can be hydroxyl, alkoxyl group, alkylamino, amino or dialkyl amido, described Q
bDirect and the carbon atom bonding of group;
R
23, R
24, R
25And R
26Be independently selected from hydrogen, alkyl, hydroxyl, alkoxyl group, amino alkylidenyl, alkylamino, dialkyl amido, amino and hydroxyalkyl;
R
23And R
24Randomly formation has the straight chain spacer part of 4 to 7 continuous atoms together, is connected to form the heterocyclic ring with 5 to 8 members that link to each other with bonding point;
Q
sBe selected from covalent single bond, (CR
37R
38)
b-(W
0)
Az, (CH (R
14))
c-W
1-(CH (R
15))
d(CH (R
14))
e-W
22-(CH (R
15))
h, wherein az is selected from 0 to 1 integer, and b is selected from 1 to 4 integer, W
0Be selected from O, S, C (O), C (S), C (O) O, C (S) O, C (O) S, C (S) S, C (O) N (R
14), (R
14) NC (O), C (S) N (R
14), (R
14) NC (S), OC (O) N (R
14), SC (S) N (R
14), SC (O) N (R
14), OC (S) N (R
14), N (R
15) C (O) N (R
14), (R
14) NC (O) N (R
15), N (R
15) C (S) N (R
14), (R
14) NC (S) N (R
15), S (O), S (O)
2, S (O)
2N (R
14), N (R
14) S (O)
2, P (O) (R
8), N (R
7) P (O) (R
8), P (O) (R
8) N (R
7), N (R
14) and ON (R
14), c and d are independently selected from 1 to 4 integer, W
1Be selected from O, S, C (O), C (S), C (O) O, C (S) O, C (O) S, C (S) S, C (O) N (R
14), (R
14) NC (O), C (S) N (R
14), (R
14) NC (S), OC (O) N (R
14), (R
14) NC (O) O, SC (S) N (R
14), (R
14) NC (S) S, SC (O) N (R
14), (R
14) NC (O) S, OC (S) N (R
14), (R
14) NC (S) O, N (R
15) C (O) N (R
14), (R
14) NC (O) N (R
15), N (R
15) C (S) N (R
14), (R
14) NC (S) N (R
15), S (O), S (O)
2, S (O)
2N (R
14), N (R
14) S (O)
2, P (O) (R
8), N (R
7) P (O) (R
8), P (O) (R
8) N (R
7), N (R
14) and ON (R
14), e and h are independently selected from 0 to 2 integer, W
22Be selected from CR
41=CR
42, CR
41R
42=C, vinylidene), ethynylene (C ≡ C; Ethynylene), 1, the 2-cyclopropyl, 1, the 2-cyclobutyl, 1, the 2-cyclohexyl, 1, the 3-cyclohexyl, 1, the 2-cyclopentyl, 1, the 3-cyclopentyl, 2, morpholinyl, 2, the 4-morpholinyl, 2, the 6-morpholinyl, 3, the 4-morpholinyl, 3, the 5-morpholinyl, 1, the 2-piperazinyl, 1, the 3-piperazinyl, 2, the 3-piperazinyl, 2, the 6-piperazinyl, 1, the 2-piperidyl, 1, the 3-piperidyl, 2, the 3-piperidyl, 2, the 4-piperidyl, 2, the 6-piperidyl, 3, the 4-piperidyl, 1, the 2-pyrrolidyl, 1, the 3-pyrrolidyl, 2, the 3-pyrrolidyl, 2, the 4-pyrrolidyl, 2, the 5-pyrrolidyl, 3, the 4-pyrrolidyl, 2, the 3-tetrahydrofuran base, 2, the 4-tetrahydrofuran base, 2,5-tetrahydrofuran base and 3, the 4-tetrahydrofuran base, its condition is R
14And R
15If direct and N bonding then is selected from the group except that halo and cyano group, (CR
37R
38)
b, (CH (R
14))
c, (CH (R
14))
eDirectly and E
0Bonding;
Y
0Randomly be Q
b-Q
Ss, Q wherein
SsBe selected from (CR
37R
38)
f, (CH (R
14))
c-W
1-(CH (R
15))
d(CH (R
14))
e-W
2-(CH (R
15))
h, wherein f is selected from 1 to 6 integer, and c and d are independently selected from 1 to 4 integer, W
1Be selected from O, S, C (O), C (S), C (O) O, C (S) O, C (O) S, C (S) S, C (O) N (R
14), (R
14) NC (O), C (S) N (R
14), (R
14) NC (S), OC (O) N (R
14), (R
14) NC (O) O, SC (S) N (R
14), (R
14) NC (S) S, SC (O) N (R
14), (R
14) NC (O) S, OC (S) N (R
14), (R
14) NC (S) O, N (R
15) C (O) N (R
14), (R
14) NC (O) N (R
15), N (R
15) C (S) N (R
14), (R
14) NC (S) N (R
15), S (O), S (O)
2, S (O)
2N (R
14), N (R
14) S (O)
2, P (O) (R
8), N (R
7) P (O) (R
8), P (O) (R
8) N (R
7), N (R
14) and ON (R
14), e and h are independently selected from 0 to 2 integer, W
2Be selected from CR
4a=CR
4b, ethynylene (C ≡ C; Ethynylene) and C=CR
4aR
4b, its condition is R
14And R
15If direct and N bonding then is selected from the group except that halo and cyano group, (CR
37R
38)
f, (CH (R
15))
c(CH (R
15))
eWith E
0Bonding;
Y
0Randomly be Q
b-Q
Sss, Q wherein
SssBe (CH (R
38))
r-W
3, wherein r is selected from 1 to 3 integer, W
3Be selected from 1, the 1-cyclopropyl, 1, the 2-cyclopropyl, 1, the 1-cyclobutyl, 1, the 2-cyclobutyl, 1, the 2-cyclohexyl, 1, the 3-cyclohexyl, 1, the 4-cyclohexyl, 1, the 2-cyclopentyl, 1, the 3-cyclopentyl, 2, morpholinyl, 2, the 4-morpholinyl, 2, the 5-morpholinyl, 2, the 6-morpholinyl, 3, the 4-morpholinyl, 3, the 5-morpholinyl, 1, the 2-piperazinyl, 1, the 3-piperazinyl, 1, the 4-piperazinyl, 2, the 3-piperazinyl, 2, the 5-piperazinyl, 2, the 6-piperazinyl, 1, the 2-piperidyl, 1, the 3-piperidyl, 1, the 4-piperidyl, 2, the 3-piperidyl, 2, the 4-piperidyl, 2, the 5-piperidyl, 2, the 6-piperidyl, 3, the 4-piperidyl, 3, the 5-piperidyl, 3, the 6-piperidyl, 1, the 2-pyrrolidyl, 1, the 3-pyrrolidyl, 2, the 3-pyrrolidyl, 2, the 4-pyrrolidyl, 2, the 5-pyrrolidyl, 3, the 4-pyrrolidyl, 2H-2, the 3-pyranyl, 2H-2, the 4-pyranyl, 2H-2, the 5-pyranyl, 4H-2, the 3-pyranyl, 4H-2, the 4-pyranyl, 4H-2, the 5-pyranyl, 2H-pyran-2-one-3, the 4-base, 2H-pyran-2-one-4, the 5-base, 4H-pyrans-4-ketone-2, the 3-base, 2, the 3-tetrahydrofuran base, 2, the 4-tetrahydrofuran base, 2, the 5-tetrahydrofuran base, 3, the 4-tetrahydrofuran base, 2, the 3-THP trtrahydropyranyl, 2, the 4-THP trtrahydropyranyl, 2, the 5-THP trtrahydropyranyl, 2, the 6-THP trtrahydropyranyl, 3,4-THP trtrahydropyranyl and 3,5-THP trtrahydropyranyl, except that tie point, each contains the W of carbon and hydrogen
3Ring nitrogen member is randomly by one or more R
9, R
10, R
11And R
12Group replaces, and its condition is (CH (R
38))
rWith E
0Bonding, Q
bWith each W
3Lowest number substituting group position bonding;
Y
0Randomly be Q
b-Q
Sssr, Q wherein
SssrBe (CH (R
38))
r-W
4, wherein r is selected from 1 to 3 integer, W
4Be selected from 1, the 2-cyclobutyl, 1, the 2-cyclohexyl, 1, the 3-cyclohexyl, 1, the 4-cyclohexyl, 1, the 2-cyclopentyl, 1, the 3-cyclopentyl, 2, morpholinyl, 2, the 4-morpholinyl, 2, the 5-morpholinyl, 2, the 6-morpholinyl, 3, the 4-morpholinyl, 3, the 5-morpholinyl, 1, the 2-piperazinyl, 1, the 3-piperazinyl, 1, the 4-piperazinyl, 2, the 3-piperazinyl, 2, the 5-piperazinyl, 2, the 6-piperazinyl, 1, the 2-piperidyl, 1, the 3-piperidyl, 1, the 4-piperidyl, 2, the 3-piperidyl, 2, the 4-piperidyl, 2, the 5-piperidyl, 2, the 6-piperidyl, 3, the 4-piperidyl, 3, the 5-piperidyl, 3, the 6-piperidyl, 1, the 2-pyrrolidyl, 1, the 3-pyrrolidyl, 2, the 3-pyrrolidyl, 2, the 4-pyrrolidyl, 2, the 5-pyrrolidyl, 3, the 4-pyrrolidyl, 2H-2, the 3-pyranyl, 2H-2, the 4-pyranyl, 2H-2, the 5-pyranyl, 4H-2, the 3-pyranyl, 4H-2, the 4-pyranyl, 4H-2, the 5-pyranyl, 2H-pyran-2-one-3, the 4-base, 2H-pyran-2-one-4, the 5-base, 4H-pyrans-4-ketone-2, the 3-base, 2, the 3-tetrahydrofuran base, 2, the 4-tetrahydrofuran base, 2, the 5-tetrahydrofuran base, 3, the 4-tetrahydrofuran base, 2, the 3-THP trtrahydropyranyl, 2, the 4-THP trtrahydropyranyl, 2, the 5-THP trtrahydropyranyl, 2, the 6-THP trtrahydropyranyl, 3,4-THP trtrahydropyranyl and 3, the 5-THP trtrahydropyranyl, except that tie point, each contains the W of carbon and hydrogen
4Ring nitrogen member is randomly by one or more 9
R, R
10, R
11And R
12Group replaces, and its condition is (CH (R
38))
rWith E
0Bonding, Q
bWith each W
4The highest numbering substituting group position bonding;
Y
0Randomly be Q
b-Q
Ssss, Q wherein
SsssBe (CH (R
38))
r-W
5, wherein r is selected from 1 to 3 integer, W
5Be selected from 1, the 4-indenyl, 1, the 5-indenyl, 1, the 6-indenyl, 1, the 7-indenyl, 2, the 7-indenyl, 2, the 6-indenyl, 2, the 5-indenyl, 2, the 4-indenyl, 3, the 4-indenyl, 3, the 5-indenyl, 3, the 6-indenyl, 3, the 7-indenyl, 2, the 4-benzofuryl, 2, the 5-benzofuryl, 2, the 6-benzofuryl, 2, the 7-benzofuryl, 3, the 4-benzofuryl, 3, the 5-benzofuryl, 3, the 6-benzofuryl, 3, the 7-benzofuryl, 2, the 4-benzothienyl, 2, the 5-benzothienyl, 2, the 6-benzothienyl, 2, the 7-benzothienyl, 3, the 4-benzothienyl, 3, the 5-benzothienyl, 3,6 benzothienyls, 3, the 7-benzothienyl, 2, the 7-imidazo (1,2-a) pyridyl, 3,4-imidazo (1,2-a) pyridyl, 3, the 5-imidazo (1,2-a) pyridyl, 3,6-imidazo (1,2-a) pyridyl, 3, the 7-imidazo (1,2-a) pyridyl, 2, the 4-indyl, 2, the 5-indyl, 2, the 6-indyl, 2, the 7-indyl, 3, the 4-indyl, 3, the 5-indyl, 3, the 6-indyl, 3, the 7-indyl, 1, the 4-pseudoindoyl, 1, the 5-pseudoindoyl, 1, the 6-pseudoindoyl, 2, the 4-pseudoindoyl, 2, the 5-pseudoindoyl, 2, the 6-pseudoindoyl, 2, the 7-pseudoindoyl, 1, the 3-pseudoindoyl, 3, the 4-indazolyl, 3, the 5-indazolyl, 3, the 6-indazolyl, 3, the 7-indazolyl, 2, the 4-benzoxazolyl, 2, the 5-benzoxazolyl, 2, the 6-benzoxazolyl, 2, the 7-benzoxazolyl, 3,4-benzoisoxazole base, 3,5-benzoisoxazole base, 3,6-benzoisoxazole base, 3,7-benzoisoxazole base, 1, the 4-naphthyl, 1, the 5-naphthyl, 1, the 6-naphthyl, 1, the 7-naphthyl, 1, the 8-naphthyl, 2, the 4-naphthyl, 2, the 5-naphthyl, 2, the 6-naphthyl, 2, the 7-naphthyl, 2, the 8-naphthyl, 2, the 4-quinolyl, 2, the 5-quinolyl, 2, the 6-quinolyl, 2, the 7-quinolyl, 2, the 8-quinolyl, 3, the 4-quinolyl, 3, the 5-quinolyl, 3, the 6-quinolyl, 3, the 7-quinolyl, 3, the 8-quinolyl, 4, the 5-quinolyl, 4, the 6-quinolyl, 4, the 7-quinolyl, 4, the 8-quinolyl, 1, the 4-isoquinolyl, 1, the 5-isoquinolyl, 1, the 6-isoquinolyl, 1, the 7-isoquinolyl, 1, the 8-isoquinolyl, 3, the 4-isoquinolyl, 3, the 5-isoquinolyl, 3, the 6-isoquinolyl, 3, the 7-isoquinolyl, 3, the 8-isoquinolyl, 4, the 5-isoquinolyl, 4, the 6-isoquinolyl, 4, the 7-isoquinolyl, 4, the 8-isoquinolyl, 3,4-cinnolines base, 3,5-cinnolines base, 3,6-cinnolines base, 3,7-cinnolines base, 3,8-cinnolines base, 4,5-cinnolines base, 4,6-cinnolines base, 4,7-cinnolines base and 4,8-cinnolines base, except that tie point, each contains the W of carbon and hydrogen
5Ring nitrogen member is randomly by one or more R
9, R
10, R
11And R
12Group replaces, and its condition is Q
bWith each W
5Lowest number substituting group position bonding, (CH (R
38))
rWith E
0Bonding;
Y
0Randomly be Q
b-Q
Ssssr, Q wherein
SsssrBe (CH (R
38))
r-W
6, wherein r is selected from 1 to 3 integer, W
6Be selected from 1, the 4-indenyl, 1, the 5-indenyl, 1, the 6-indenyl, 1, the 7-indenyl, 2, the 7-indenyl, 2, the 6-indenyl, 2, the 5-indenyl, 2, the 4-indenyl, 3, the 4-indenyl, 3, the 5-indenyl, 3, the 6-indenyl, 3, the 7-indenyl, 2, the 4-benzofuryl, 2, the 5-benzofuryl, 2, the 6-benzofuryl, 2, the 7-benzofuryl, 3, the 4-benzofuryl, 3, the 5-benzofuryl, 3, the 6-benzofuryl, 3, the 7-benzofuryl, 2, the 4-benzothienyl, 2, the 5-benzothienyl, 2, the 6-benzothienyl, 2, the 7-benzothienyl, 3, the 4-benzothienyl, 3, the 5-benzothienyl, 3, the 6-benzothienyl, 3, the 7-benzothienyl, 2, the 7-imidazo (1,2-a) pyridyl, 3,4-imidazo (1,2-a) pyridyl, 3, the 5-imidazo (1,2-a) pyridyl, 3,6-imidazo (1,2-a) pyridyl, 3, the 7-imidazo (1,2-a) pyridyl, 2, the 4-indyl, 2, the 5-indyl, 2, the 6-indyl, 2, the 7-indyl, 3, the 4-indyl, 3, the 5-indyl, 3, the 6-indyl, 3, the 7-indyl, 1, the 4-pseudoindoyl, 1, the 5-pseudoindoyl, 1, the 6-pseudoindoyl, 2, the 4-pseudoindoyl, 2, the 5-pseudoindoyl, 2, the 6-pseudoindoyl, 2, the 7-pseudoindoyl, 1, the 3-pseudoindoyl, 3, the 4-indazolyl, 3, the 5-indazolyl, 3, the 6-indazolyl, 3, the 7-indazolyl, 2, the 4-benzoxazolyl, 2, the 5-benzoxazolyl, 2, the 6-benzoxazolyl, 2, the 7-benzoxazolyl, 3,4-benzoisoxazole base, 3,5-benzoisoxazole base, 3,6-benzoisoxazole base, 3,7-benzoisoxazole base, 1, the 4-naphthyl, 1, the 5-naphthyl, 1, the 6-naphthyl, 1, the 7-naphthyl, 1, the 8-naphthyl, 2, the 4-naphthyl, 2, the 5-naphthyl, 2, the 6-naphthyl, 2, the 7-naphthyl, 2, the 8-naphthyl, 2, the 4-quinolyl, 2, the 5-quinolyl, 2, the 6-quinolyl, 2, the 7-quinolyl, 2, the 8-quinolyl, 3, the 4-quinolyl, 3, the 5-quinolyl, 3, the 6-quinolyl, 3, the 7-quinolyl, 3, the 8-quinolyl, 4, the 5-quinolyl, 4, the 6-quinolyl, 4, the 7-quinolyl, 4, the 8-quinolyl, 1, the 4-isoquinolyl, 1, the 5-isoquinolyl, 1, the 6-isoquinolyl, 1, the 7-isoquinolyl, 1, the 8-isoquinolyl, 3, the 4-isoquinolyl, 3, the 5-isoquinolyl, 3, the 6-isoquinolyl, 3, the 7-isoquinolyl, 3, the 8-isoquinolyl, 4, the 5-isoquinolyl, 4, the 6-isoquinolyl, 4, the 7-isoquinolyl, 4, the 8-isoquinolyl, 3,4-cinnolines base, 3,5-cinnolines base, 3,6-cinnolines base, 3,7-cinnolines base, 3,8-cinnolines base, 4,5-cinnolines base, 4,6-cinnolines base, 4,7-cinnolines base and 4,8-cinnolines base, except that tie point, each contains the W of carbon and hydrogen
5Ring nitrogen member is randomly by one or more R
9, R
10, R
11And R
12Group replaces, and its condition is Q
bWith each W
6The highest numbering substituting group position bonding, (CH (R
38))
rWith E
0Bonding.
In the another embodiment of formula I compound or its pharmacy acceptable salt,
J
aAnd J
bBe independently selected from O and S;
B is a formula V:
D wherein
1, D
2, J
1, J
2And K
1Be independently selected from C, N, O, S and covalent linkage, its condition be at the most one can be covalent linkage, D
1, D
2, J
1, J
2And K
1At the most one be O, D
1, D
2, J
1, J
2And K
1At the most one be S, if D
1, D
2, J
1, J
2And K
1Two be O and S, then D
1, D
2, J
1, J
2And K
1One of must be covalent linkage, D
1, D
2, J
1, J
2And K
1At the most four be N;
R
9, R
10, R
11, R
12, R
13, R
16, R
17, R
18, R
19, R
32, R
33, R
34, R
35And R
36Be independently selected from hydrogen, kharophen, the halo kharophen, amidino groups, guanidine radicals, dialkyl matte, San Wan Ji Phosphonium, the dialkyl matte alkyl, carboxyl, assorted aromatic alkylthio, assorted aralkoxy, cycloalkyl amino, the acyl group alkyl, the acyl group alkoxyl group, the aroyl alkoxyl group, heterocyclic oxy group, the aralkyl aryl, aralkyl, arylalkenyl, sweet-smelling alkynyl, heterocyclic radical, the perhalogeno aralkyl, the aralkyl alkylsulfonyl, aralkyl sulphonyl alkyl, aralkyl sulfinyl, aralkyl sulfinyl alkyl, halogenated cycloalkyl, the halo cycloalkenyl group, the cycloalkyl sulfinyl, cycloalkyl sulfinyl alkyl, the naphthene sulfamide base, the naphthene sulfamide alkyl, heteroaryl amino, N-heteroaryl amino-N-alkylamino, the heteroaryl amino alkyl, halogenated alkylthio, alkanoyloxy, alkoxyl group, alkoxyalkyl, halogenated alkoxy alkyl, assorted aralkoxy, cycloalkyloxy, cyclenes oxygen base, the cycloalkyloxy alkyl, cycloalkyl alkoxy, cyclenes oxygen base alkyl, inferior cycloalkanes dioxy base, the halo cycloalkyloxy, halo cycloalkyloxy alkyl, halo cyclenes oxygen base, halo cyclenes oxygen base alkyl, hydroxyl, amino, alkoxy amino, sulfo-, nitro, low-grade alkyl amino, alkylthio, alkylthio alkyl, arylamino, aryl alkyl amino, arylthio, arylthio alkyl, assorted sweet-smelling alkoxy alkyl, alkyl sulphinyl, the alkyl sulfenyl alkyl, aryl sulfinyl alkyl, the arylsulfonyl alkyl, heteroaryl sulfinyl alkyl, heteroaryl sulphonyl alkyl, alkyl sulphonyl, the alkyl sulfonyl alkyl, haloalkyl sulfinyl alkyl, haloalkyl sulphonyl alkyl, alkyl sulfonyl amino, alkyl amino sulfonyl, the amido alkylsulfonyl, one alkyl amido alkylsulfonyl, dialkyl group amido alkylsulfonyl, one aryl amido alkylsulfonyl, Arenesulfonyl amino, diaryl amido alkylsulfonyl, one alkyl, one aryl amido alkylsulfonyl, aryl sulfonyl kia, aryl sulfonyl, heteroarylthio, the heteroaryl sulfinyl, heteroarylsulfonyl, the heterocyclic radical alkylsulfonyl, the heterocyclic radical sulfo-, alkyloyl, enoyl-, aroyl, 4-hetaroylpyrazol, aralkanoyl, assorted aralkanoyl, the haloalkane acyl group, alkyl, thiazolinyl, alkynyl, alkene oxygen base, alkene oxygen base alkyl, alkylene dioxo base, the halo alkylene dioxo base, cycloalkyl, the cycloalkyl alkyloyl, cycloalkenyl group, the low-grade cycloalkyl alkyl, the lower alkenyl ring alkyl, halogen, haloalkyl, haloalkenyl group, halogenated alkoxy, the hydroxy halogeno alkyl, hydroxyl aralkyl, hydroxyalkyl, alkenyl amino, the hydroxyl heteroaralkyl, halogenated alkoxy alkyl, aryl, aralkyl, aryloxy, aralkoxy, aryloxy alkyl, saturated heterocyclic radical, the heterocyclic radical of fractional saturation, heteroaryl, heteroaryloxy, the heteroaryloxy alkyl, arylalkyl, heteroarylalkyl, aryl alkenyl, the heteroaryl thiazolinyl, carboxyalkyl, carbalkoxy, the alkoxyl group carboxamido, alkyl amido carbonyl amido, aryl amido carbonyl amido, alkoxycarbonyl alkyl, the carbalkoxy thiazolinyl, carboxyl, aralkoxycarbonyl, carboxamido, the carboxamido alkyl, cyano group, the haloalkoxy carbonyl, phosphono, the phosphono alkyl, alkoxy diaryl phosphono and alkoxy diaryl phosphono alkyl;
R
16, R
19, R
32, R
33, R
34, R
35And R
36Randomly be Q independently
b, its condition is R
16And R
19At the most one be Q simultaneously
b, Q
bBe Q
Be
B randomly is selected from hydrogen, trialkylsilkl, C2-C8 alkyl, C3-C8 thiazolinyl, C3-C8 alkylidene group, C3-C8 alkynyl, C2-C8 haloalkyl and C3-C8 haloalkenyl group, and wherein each member of group B randomly at distance B and A tie point nearly and comprise on any carbon of 6 atoms by one or more radicals R
32, R
33, R
34, R
35And R
36Replace;
B randomly is selected from C3-C12 cycloalkyl, C5-C10 cycloalkenyl group and the saturated heterocyclic radical of C4-C9, and wherein each ring carbon is randomly by R
33Replace, the ring carbon except that the ring carbon that is positioned at B and A tie point is randomly replaced by oxo, and its condition is that a ring carbon is replaced by oxo simultaneously at the most, and ring carbon adjacent with the ring carbon that is positioned at tie point and nitrogen-atoms are randomly by R
9Or R
13Replace, with R
9The position adjacent and apart from the ring carbon of two atoms of tie point or nitrogen-atoms randomly by R
10Replace, with R
13The position adjacent and apart from the ring carbon of two atoms of tie point or nitrogen-atoms randomly by R
12Replace, apart from three atoms of tie point and and R
10Ring carbon that the position is adjacent or nitrogen-atoms are randomly by R
11Replace, apart from three atoms of tie point and and R
12Ring carbon that the position is adjacent or nitrogen-atoms are randomly by R
33Replace, apart from four atoms of tie point and and R
11And R
33Ring carbon that the position is adjacent or nitrogen-atoms are randomly by R
34Replace;
A is selected from covalent single bond, (W
7)
Rr-(CH (R
16))
Pa(CH (R
16))
Pa-(W
7)
Rr, wherein rr is selected from 0 to 1 integer, and pa is selected from 0 to 6 integer, W
7Be selected from O, S, C (O), C (O) N (R
7), C (S) N (R
7), (R
7) NC (O), (R
7) NC (S) and N (R
7), its condition be rr and pa at the most one can be 0 simultaneously;
R
7And R
8Be independently selected from hydrogen, hydroxyl, alkyl and alkoxyalkyl;
R
14, R
15, R
37And R
38Be independently selected from hydrogen, hydroxyl, halogen, alkyl, alkoxyalkyl, haloalkyl, halogenated alkoxy and halogenated alkoxy alkyl;
R
14And R
38Can be independently selected from aroyl and 4-hetaroylpyrazol;
Ψ is selected from NR
5, C (O) and S (O)
2
R
5Be selected from hydrogen, hydroxyl, alkyl and alkoxyl group;
R
39And R
40Be independently selected from hydrogen, hydroxyl, halogen, hydroxyalkyl, alkyl, alkoxyalkyl, haloalkyl, halogenated alkoxy and halogenated alkoxy alkyl;
M is selected from N and R
1-C;
R
1Be selected from hydrogen, alkyl, thiazolinyl, cyano group, halogen, haloalkyl, halogenated alkoxy, halogenated alkylthio, amino, aminoalkyl group, alkylamino, amidino groups, guanidine radicals, hydroxyl, hydroxyl amino, alkoxyl group, hydroxyalkyl, alkoxy amino, sulfo-hydroxyl, alkylthio and phosphono;
R
2Be Z
0-Q;
Z
0Be selected from covalent single bond, (CR
41R
42)
q, (CH (R
41))
g-W0-(CH (R
42))
p(CH (R
41))
e-W
22-(CH (R
42))
h, wherein q is selected from 1 to 3 integer, and g and p are independently selected from 0 to 3 integer, W
0Be selected from O, S, C (O), S (O), S (O)
2, N (R
41) and ON (R
41), e and h are independently selected from 0 to 2 integer, W
22Be selected from CR
41=CR
421, the 2-cyclopropyl, 1, the 2-cyclobutyl, 1, the 2-cyclohexyl, 1, the 3-cyclohexyl, 1, the 2-cyclopentyl, 1, the 3-cyclopentyl, 2, morpholinyl, 2, the 4-morpholinyl, 2, the 6-morpholinyl, 3, the 4-morpholinyl, 3, the 5-morpholinyl, 1, the 2-piperazinyl, 1, the 3-piperazinyl, 2, the 3-piperazinyl, 2, the 6-piperazinyl, 1, the 2-piperidyl, 1, the 3-piperidyl, 2, the 3-piperidyl, 2, the 4-piperidyl, 2, the 6-piperidyl, 3, the 4-piperidyl, 1, the 2-pyrrolidyl, 1, the 3-pyrrolidyl, 2, the 3-pyrrolidyl, 2, the 4-pyrrolidyl, 2, the 5-pyrrolidyl, 3, the 4-pyrrolidyl, 2, the 3-tetrahydrofuran base, 2, the 4-tetrahydrofuran base, 2,5-tetrahydrofuran base and 3, the 4-tetrahydrofuran base, its condition is Z
0Direct and uridylic ring key closes;
R
41And R
42Be independently selected from amidino groups, hydroxyl amino, hydrogen, hydroxyl, amino and alkyl;
Q is selected from hydrogen, and its condition is Z
0It can not be covalent single bond; And formula (II):
D wherein
1, D
2, J
1, J
2And K
1Be independently selected from C, N, O, S and covalent linkage, its condition be at the most one can be covalent linkage, D
1, D
2, J
1, J
2And K
1At the most one be O, D
1, D
2, J
1, J
2And K
1At the most one be S, if D
1, D
2, J
1, J
2And K
1Two be O and S, then D
1, D
2, J
1, J
2And K
1One of must be covalent linkage, D
1, D
2, J
1, J
2And K
1At the most four be N, its condition is R
9, R
10, R
11, R
12And R
13Selected independently of one another, with the tetravalence character of keeping carbon, the trivalent character of nitrogen, the divalence character of sulphur and the divalence character of oxygen;
K is (CR
4aR
4b)
n, wherein n is selected from 1 to 2 integer;
R
4aAnd R
4bBe independently selected from halogen, hydrogen, hydroxyalkyl, alkyl, alkoxyalkyl, alkylthio alkyl and haloalkyl;
E
0Be selected from covalent single bond, C (O), C (S), C (O) N (R
7), (R
7) NC (O), S (O)
2, (R
7) NS (O)
2And S (O)
2N (R
7);
Y
0Be formula (IV):
D wherein
5, D
6, J
5And J
6Be independently selected from C, N, O, S and covalent linkage, its condition be at the most one be covalent linkage, K
2Be C, D
5, D
6, J
5And J
6At the most one be O, D
5, D
6, J
5And J
6At the most one be S, if D
5, D
6, J
5And J
6Two be O and S, then D
5, D
6, J
5And J
6One of must be covalent linkage, if K
2Be carbon, D then
5, D
6, J
5And J
6At the most four be N, its condition is R
16, R
17, R
18And R
19Selected independently of one another, with the tetravalence character of keeping carbon, the trivalent character of nitrogen, the divalence character of sulphur and the divalence character of oxygen;
Q
bBe selected from NR
20R
21,
+NR
20R
21R
22, amino alkylidenyl and Q
Be, Q wherein
BeBe hydrogen, R
20, R
21And R
22Be independently selected from hydrogen, alkyl, hydroxyl, amino, amino alkylidenyl, dialkyl amido, alkylamino and hydroxyalkyl, its condition is R
20And R
21At the most one be hydroxyl, amino, alkylamino or dialkyl amido simultaneously;
Q
bRandomly be selected from C (NR
25) NR
23R
24, N (R
26) C (NR
25) N (R
23) (R
24), C (O) N (R
26) C (NR
25) N (R
23) (R
24), N (R
26) N (R
26) C (NR
25) N (R
23) (R
24) and ON (R
26) C (NR
25) N (R
23) (R
24), if its condition is R
23, R
24And R
26Two with identical atomic linkage, then R
32, R
24And R
26At the most one be hydroxyl, alkylamino, amino or dialkyl amido;
R
23, R
24, R
25And R
26Be independently selected from hydrogen, alkyl, hydroxyl, amino, alkylidene amino, dialkyl amido, alkylamino and hydroxyalkyl;
Q
sBe selected from covalent single bond, (CR
37R
38)
b-(W
0)
Az, (CH (R
14))
c-W
1-(CH (R
15))
d(CH (R
14))
e-W
22-(CH (R
15))
h, wherein az is selected from 0 to 1 integer, and b is selected from 1 to 5 integer, W
0Be selected from O, C (O), S (O), S (O)
2, S (O)
2N (R
14), N (R
14) S (O)
2And ON (R
14), c and d are independently selected from 1 to 4 integer, W
1Be selected from O, S, C (O), C (S), C (O) O, C (S) O, C (O) S, C (S) S, C (O) N (R
14), (R
14) NC (O), C (S) N (R
14), (R
14) NC (S), OC (O) N (R
14), (R
14) NC (O) O, SC (S) N (R
14), (R
14) NC (S) S, SC (O) N (R
14), (R
14) NC (O) S, OC (S) N (R
14), (R
14) NC (S) O, N (R
15) C (O) N (R
14), (R
14) NC (O) N (R
15), N (R
15) C (S) N (R
14), (R
14) NC (S) N (R
15), S (O), S (O)
2, S (O)
2N (R
14), N (R
14) S (O)
2, P (O) (R
8), N (R
7) P (O) (R
8), P (O) (R
8) N (R
7), N (R
14) and ON (R
14), e and h are independently selected from 0 to 2 integer, W
22Be selected from CR
41=CR
42, CR
41R
42=C; Vinylidene), ethynylene (C ≡ C; Ethynylene), 1, the 2-cyclopropyl, 1, the 2-cyclobutyl, 1, the 2-cyclohexyl, 1, the 3-cyclohexyl, 1, the 2-cyclopentyl, 1, the 3-cyclopentyl, 2, morpholinyl, 2, the 4-morpholinyl, 2, the 6-morpholinyl, 3, the 4-morpholinyl, 3, the 5-morpholinyl, 1, the 2-piperazinyl, 1, the 3-piperazinyl, 2, the 3-piperazinyl, 2, the 6-piperazinyl, 1, the 2-piperidyl, 1, the 3-piperidyl, 2, the 3-piperidyl, 2, the 4-piperidyl, 2, the 6-piperidyl, 3, the 4-piperidyl, 1, the 2-pyrrolidyl, 1, the 3-pyrrolidyl, 2, the 3-pyrrolidyl, 2, the 4-pyrrolidyl, 2, the 5-pyrrolidyl, 3, the 4-pyrrolidyl, 2, the 3-tetrahydrofuran base, 2, the 4-tetrahydrofuran base, 2,5-tetrahydrofuran base and 3, the 4-tetrahydrofuran base, its condition is R
14And R
15If direct and N bonding then is selected from the group except that halogen and cyano group, (CR
37R
38)
b, (CH (R
14))
c, (CH (R
14))
eWith E
0Bonding;
Y
0Randomly be Q
b-Q
Ss, Q wherein
SsBe selected from (CR
37R
38)
f, (CH (R
14))
c-W
1-(CH (R
15))
d(CH (R
14))
e-W
2-(CH (R
15))
h, wherein f is selected from 1 to 4 integer, and c and d are independently selected from 1 to 2 integer, W
1Be selected from O, S, C (O), C (O) N (R
14), (R
14) NC (O), N (R
15) C (O) N (R
14), (R
14) NC (O) N (R
15), N (R
14) and ON (R
14), e and h are independently selected from 0 to 2 integer, W
2Be selected from CR
4a=CR
4b, ethynylene (C ≡ C; Ethynylene) and C=CR
4aR
4b, its condition is R
14And R
15If direct and N bonding then is selected from the group except that halogen, (CR
37R
38)
f, (CH (R
14))
c(CH (R
14))
eWith E
0Bonding;
Y
0Randomly be Q
b-Q
Sss, Q wherein
SssBe (CH (R
38))
r-W
3, wherein r is selected from 1 to 2 integer, W
3Be selected from 1, the 1-cyclopropyl, 1, the 2-cyclopropyl, 1, the 1-cyclobutyl, 1, the 2-cyclobutyl, 1, the 2-cyclohexyl, 1, the 3-cyclohexyl, 1, the 4-cyclohexyl, 1, the 2-cyclopentyl, 1, the 3-cyclopentyl, 2, morpholinyl, 2, the 4-morpholinyl, 2, the 5-morpholinyl, 2, the 6-morpholinyl, 3, the 4-morpholinyl, 3, the 5-morpholinyl, 1, the 2-piperazinyl, 1, the 3-piperazinyl, 1, the 4-piperazinyl, 2, the 3-piperazinyl, 2, the 5-piperazinyl, 2, the 6-piperazinyl, 1, the 2-piperidyl, 1, the 3-piperidyl, 1, the 4-piperidyl, 2, the 3-piperidyl, 2, the 4-piperidyl, 2, the 5-piperidyl, 2, the 6-piperidyl, 3, the 4-piperidyl, 3, the 5-piperidyl, 3, the 6-piperidyl, 1, the 2-pyrrolidyl, 1, the 3-pyrrolidyl, 2, the 3-pyrrolidyl, 2, the 4-pyrrolidyl, 2, the 5-pyrrolidyl, 3, the 4-pyrrolidyl, 2H-2, the 3-pyranyl, 2H-2, the 4-pyranyl, 2H-2, the 5-pyranyl, 4H-2, the 3-pyranyl, 4H-2, the 4-pyranyl, 4H-2, the 5-pyranyl, 2H-pyran-2-one-3, the 4-base, 2H-pyran-2-one-4, the 5-base, 4H-pyrans-4-ketone-2, the 3-base, 2, the 3-tetrahydrofuran base, 2, the 4-tetrahydrofuran base, 2, the 5-tetrahydrofuran base, 3, the 4-tetrahydrofuran base, 2, the 3-THP trtrahydropyranyl, 2, the 4-THP trtrahydropyranyl, 2, the 5-THP trtrahydropyranyl, 2, the 6-THP trtrahydropyranyl, 3,4-THP trtrahydropyranyl and 3,5-THP trtrahydropyranyl, except that tie point, each contains the W of carbon and hydrogen
3Ring nitrogen member is randomly by one or more R
9, R
10, R
11And R
12Group replace, its condition is (CH (R
38))
rWith E
0Bonding, Q
bWith each W
3Lowest number substituting group position bonding;
Y
0Randomly be Q
b-Q
Sssr, Q wherein
SssrBe (CH (R
38))
r-W
4, wherein r is selected from 1 to 2 integer, W
4Be selected from 1, the 2-cyclobutyl, 1, the 2-cyclohexyl, 1, the 3-cyclohexyl, 1, the 4-cyclohexyl, 1, the 2-cyclopentyl, 1, the 3-cyclopentyl, 2, morpholinyl, 2, the 4-morpholinyl, 2, the 5-morpholinyl, 2, the 6-morpholinyl, 3, the 4-morpholinyl, 3, the 5-morpholinyl, 1, the 2-piperazinyl, 1, the 3-piperazinyl, 1, the 4-piperazinyl, 2, the 3-piperazinyl, 2, the 5-piperazinyl, 2, the 6-piperazinyl, 1, the 2-piperidyl, 1, the 3-piperidyl, 1, the 4-piperidyl, 2, the 3-piperidyl, 2, the 4-piperidyl, 2, the 5-piperidyl, 2, the 6-piperidyl, 3, the 4-piperidyl, 3, the 5-piperidyl, 3, the 6-piperidyl, 1, the 2-pyrrolidyl, 1, the 3-pyrrolidyl, 2, the 3-pyrrolidyl, 2, the 4-pyrrolidyl, 2, the 5-pyrrolidyl, 3, the 4-pyrrolidyl, 2H-2, the 3-pyranyl, 2H-2, the 4-pyranyl, 2H-2, the 5-pyranyl, 4H-2, the 3-pyranyl, 4H-2, the 4-pyranyl, 4H-2, the 5-pyranyl, 2H-pyran-2-one-3, the 4-base, 2H-pyran-2-one-4, the 5-base, 4H-pyrans-4-ketone-2, the 3-base, 2, the 3-tetrahydrofuran base, 2, the 4-tetrahydrofuran base, 2, the 5-tetrahydrofuran base, 3, the 4-tetrahydrofuran base, 2, the 3-THP trtrahydropyranyl, 2, the 4-THP trtrahydropyranyl, 2, the 5-THP trtrahydropyranyl, 2, the 6-THP trtrahydropyranyl, 3,4-THP trtrahydropyranyl and 3, the 5-THP trtrahydropyranyl, except that tie point, each contains the W of carbon and hydrogen
4Ring nitrogen member is randomly by one or more R
9, R
10, R
11And R
12Group replace, its condition is (CH (R
38))
rWith E
0Bonding, Q
bWith each W
4The highest numbering substituting group position bonding;
Y
0Randomly be Q
b-Q
Ssss, Q wherein
SsssBe (CH (R
38))
r-W
5, wherein r is selected from 1 to 2 integer, W
5Be selected from 1, the 4-indenyl, 1, the 5-indenyl, 1, the 6-indenyl, 1, the 7-indenyl, 2, the 7-indenyl, 2, the 6-indenyl, 2, the 5-indenyl, 2, the 4-indenyl, 3, the 4-indenyl, 3, the 5-indenyl, 3, the 6-indenyl, 3, the 7-indenyl, 2, the 4-benzofuryl, 2, the 5-benzofuryl, 2, the 6-benzofuryl, 2, the 7-benzofuryl, 3, the 4-benzofuryl, 3, the 5-benzofuryl, 3, the 6-benzofuryl, 3, the 7-benzofuryl, 2, the 4-benzothienyl, 2, the 5-benzothienyl, 2, the 6-benzothienyl, 2, the 7-benzothienyl, 3, the 4-benzothienyl, 3, the 5-benzothienyl, 3, the 6-benzothienyl, 3, the 7-benzothienyl, 2, the 7-imidazo (1,2-a) pyridyl, 3,4-imidazo (1,2-a) pyridyl, 3, the 5-imidazo (1,2-a) pyridyl, 3,6-imidazo (1,2-a) pyridyl, 3, the 7-imidazo (1,2-a) pyridyl, 2, the 4-indyl, 2, the 5-indyl, 2, the 6-indyl, 2, the 7-indyl, 3, the 4-indyl, 3, the 5-indyl, 3, the 6-indyl, 3, the 7-indyl, 1, the 4-pseudoindoyl, 1, the 5-pseudoindoyl, 1, the 6-pseudoindoyl, 2, the 4-pseudoindoyl, 2, the 5-pseudoindoyl, 2, the 6-pseudoindoyl, 2, the 7-pseudoindoyl, 1, the 3-pseudoindoyl, 3, the 4-indazolyl, 3, the 5-indazolyl, 3, the 6-indazolyl, 3, the 7-indazolyl, 2, the 4-benzoxazolyl, 2, the 5-benzoxazolyl, 2, the 6-benzoxazolyl, 2, the 7-benzoxazolyl, 3,4-benzoisoxazole base, 3,5-benzoisoxazole base, 3,6-benzoisoxazole base, 3,7-benzoisoxazole base, 1, the 4-naphthyl, 1, the 5-naphthyl, 1, the 6-naphthyl, 1, the 7-naphthyl, 1, the 8-naphthyl, 2, the 4-naphthyl, 2, the 5-naphthyl, 2, the 6-naphthyl, 2, the 7-naphthyl, 2, the 8-naphthyl, 2, the 4-quinolyl, 2, the 5-quinolyl, 2, the 6-quinolyl, 2, the 7-quinolyl, 2, the 8-quinolyl, 3, the 4-quinolyl, 3, the 5-quinolyl, 3, the 6-quinolyl, 3, the 7-quinolyl, 3, the 8-quinolyl, 4, the 5-quinolyl, 4, the 6-quinolyl, 4, the 7-quinolyl, 4, the 8-quinolyl, 1, the 4-isoquinolyl, 1, the 5-isoquinolyl, 1, the 6-isoquinolyl, 1, the 7-isoquinolyl, 1, the 8-isoquinolyl, 3, the 4-isoquinolyl, 3, the 5-isoquinolyl, 3, the 6-isoquinolyl, 3, the 7-isoquinolyl, 3, the 8-isoquinolyl, 4, the 5-isoquinolyl, 4, the 6-isoquinolyl, 4, the 7-isoquinolyl, 4, the 8-isoquinolyl, 3,4-cinnolines base, 3,5-cinnolines base, 3,6-cinnolines base, 3,7-cinnolines base, 3,8-cinnolines base, 4,5-cinnolines base, 4,6-cinnolines base, 4,7-cinnolines base and 4,8-cinnolines base, except that tie point, each contains the W of carbon and hydrogen
5Ring nitrogen member is randomly by one or more R
9, R
10, R
11And R
12Group replace, its condition is Q
bWith each W
5Lowest number substituting group position bonding, (CH (R
38))
rWith E
0Bonding;
Y
0Randomly be Q
b-Q
Ssssr, Q wherein
SsssrBe (CH (R
38))
r-W
6, wherein r is selected from 1 to 2 integer, W
6Be selected from 1, the 4-indenyl, 1, the 5-indenyl, 1, the 6-indenyl, 1, the 7-indenyl, 2, the 7-indenyl, 2, the 6-indenyl, 2, the 5-indenyl, 2, the 4-indenyl, 3, the 4-indenyl, 3, the 5-indenyl, 3, the 6-indenyl, 3, the 7-indenyl, 2, the 4-benzofuryl, 2, the 5-benzofuryl, 2, the 6-benzofuryl, 2, the 7-benzofuryl, 3, the 4-benzofuryl, 3, the 5-benzofuryl, 3, the 6-benzofuryl, 3, the 7-benzofuryl, 2, the 4-benzothienyl, 2, the 5-benzothienyl, 2, the 6-benzothienyl, 2, the 7-benzothienyl, 3, the 4-benzothienyl, 3, the 5-benzothienyl, 3, the 6-benzothienyl, 3, the 7-benzothienyl, 2, the 7-imidazo (1,2-a) pyridyl, 3,4-imidazo (1,2-a) pyridyl, 3, the 5-imidazo (1,2-a) pyridyl, 3,6-imidazo (1,2-a) pyridyl, 3, the 7-imidazo (1,2-a) pyridyl, 2, the 4-indyl, 2, the 5-indyl, 2, the 6-indyl, 2, the 7-indyl, 3, the 4-indyl, 3, the 5-indyl, 3, the 6-indyl, 3, the 7-indyl, 1, the 4-pseudoindoyl, 1, the 5-pseudoindoyl, 1, the 6-pseudoindoyl, 2, the 4-pseudoindoyl, 2, the 5-pseudoindoyl, 2, the 6-pseudoindoyl, 2, the 7-pseudoindoyl, 1, the 3-pseudoindoyl, 3, the 4-indazolyl, 3, the 5-indazolyl, 3, the 6-indazolyl, 3, the 7-indazolyl, 2, the 4-benzoxazolyl, 2, the 5-benzoxazolyl, 2, the 6-benzoxazolyl, 2, the 7-benzoxazolyl, 3,4-benzoisoxazole base, 3,5-benzoisoxazole base, 3,6-benzoisoxazole base, 3,7-benzoisoxazole base, 1, the 4-naphthyl, 1, the 5-naphthyl, 1, the 6-naphthyl, 1, the 7-naphthyl, 1, the 8-naphthyl, 2, the 4-naphthyl, 2, the 5-naphthyl, 2, the 6-naphthyl, 2, the 7-naphthyl, 2, the 8-naphthyl, 2, the 4-quinolyl, 2, the 5-quinolyl, 2, the 6-quinolyl, 2, the 7-quinolyl, 2, the 8-quinolyl, 3, the 4-quinolyl, 3, the 5-quinolyl, 3, the 6-quinolyl, 3, the 7-quinolyl, 3, the 8-quinolyl, 4, the 5-quinolyl, 4, the 6-quinolyl, 4, the 7-quinolyl, 4, the 8-quinolyl, 1, the 4-isoquinolyl, 1, the 5-isoquinolyl, 1, the 6-isoquinolyl, 1, the 7-isoquinolyl, 1, the 8-isoquinolyl, 3, the 4-isoquinolyl, 3, the 5-isoquinolyl, 3, the 6-isoquinolyl, 3, the 7-isoquinolyl, 3, the 8-isoquinolyl, 4, the 5-isoquinolyl, 4, the 6-isoquinolyl, 4, the 7-isoquinolyl, 4, the 8-isoquinolyl, 3,4-cinnolines base, 3,5-cinnolines base, 3,6-cinnolines base, 3,7-cinnolines base, 3,8-cinnolines base, 4,5-cinnolines base, 4,6-cinnolines base, 4,7-cinnolines base and 4,8-cinnolines base, except that tie point, each contains the W of carbon and hydrogen
6Ring nitrogen member is randomly by one or more R
9, R
10, R
11And R
12Group replace, its condition is Q
bWith each W
6The highest numbering substituting group position bonding, (CH (R
38))
rWith E
0Bonding.
In the embodiment of preferred formula I compound or its pharmacy acceptable salt,
J
aAnd J
bEach is O naturally;
B is a formula V:
D wherein
1, D
2, J
1, J
2And K
1Be independently selected from C, N, O, S and covalent linkage, its condition be at the most one can be covalent linkage, D
1, D
2, J
1, J
2And K
1At the most one be O, D
1, D
2, J
1, J
2And K
1At the most one be S, if D
1, D
2, J
1, J
2And K
1Two be O and S, then D
1, D
2, J
1, J
2And K
1One of must be covalent linkage, D
1, D
2, J
1, J
2And K
1At the most four be N;
R
9, R
10, R
11, R
12, R
13, R
32, R
33, R
34, R
35And R
36Be independently selected from hydrogen, kharophen, the halo kharophen, amidino groups, guanidine radicals, alkylene dioxo base, halogenated alkylthio, alkanoyloxy, alkoxyl group, alkoxyalkyl, halogenated alkoxy alkyl, hydroxyl, amino, alkoxy amino, nitro, low-grade alkyl amino, alkylthio, alkylthio alkyl, alkyl sulphinyl, alkyl sulphonyl, the alkyl sulfonyl alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclic radical, alkyl sulfonyl amino, alkyl amino sulfonyl, the amido alkylsulfonyl, one alkyl amido alkylsulfonyl, dialkyl group amido alkylsulfonyl, alkyloyl, the haloalkane acyl group, alkyl, thiazolinyl, halogen, haloalkyl, haloalkenyl group, halogenated alkoxy, the hydroxy halogeno alkyl, hydroxyalkyl, aminoalkyl group, halogenated alkoxy alkyl, carboxyalkyl, carbalkoxy, carboxyl, carboxamido, carboxamido alkyl and cyano group;
R
16, R
19, R
32, R
33, R
34, R
35And R
36Randomly be Q independently
b, its condition is R
16And R
19At the most one be Q simultaneously
b, Q
bBe Q
Be
B randomly is selected from hydrogen, trialkylsilkl, C2-C8 alkyl, C3-C8 thiazolinyl, C3-C8 alkylidene group, C3-C8 alkynyl and C2-C8 haloalkyl, wherein each member of group B can be randomly at distance B and A tie point nearly and comprise on any carbon of 6 atoms by one or more radicals R
32, R
33, R
34, R
35And R
36Replace;
B randomly is selected from C3-C12 cycloalkyl and the saturated heterocyclic radical of C4-C9, and wherein each ring carbon can be randomly by R
33Replace, the ring carbon except that the ring carbon that is positioned at B and A tie point is randomly replaced by oxo, and its condition is that a ring carbon is replaced by oxo simultaneously at the most, and ring carbon and the nitrogen-atoms adjacent with the ring carbon that is positioned at tie point can be randomly by R
9Or R
13Replace, with R
9The position adjacent and apart from the ring carbon of two atoms of tie point or nitrogen-atoms randomly by R
10Replace, with R
13The position adjacent and apart from the ring carbon of two atoms of tie point or nitrogen-atoms randomly by R
12Replace, apart from three atoms of tie point and and R
10Ring carbon that the position is adjacent or nitrogen-atoms are randomly by R
11Replace, apart from three atoms of tie point and and R
12Ring carbon that the position is adjacent or nitrogen-atoms are randomly by R
33Replace, apart from four atoms of tie point and and R
11And R
33Ring carbon that the position is adjacent or nitrogen-atoms are randomly by R
34Replace;
A is selected from covalent single bond, (W
7)
Rr-(CH (R
15))
Pa(CH (R
15))
Pa-(W
7)
Rr, wherein rr is selected from 0 to 1 integer, and pa is selected from 0 to 6 integer, W
7Be selected from O, S, C (O), (R
7) NC (O), (R
7) NC (S) and N (R
7), its condition be rr and pa at the most one be O simultaneously;
R
7Be selected from hydrogen, hydroxyl and alkyl;
R
15Be selected from hydrogen, hydroxyl, halogen, alkyl and haloalkyl;
Ψ is selected from NH and NOH;
M is selected from N and R
1-C;
R
1Be selected from hydrogen, alkyl, thiazolinyl, cyano group, halogen, haloalkyl, halogenated alkoxy, halogenated alkylthio, amino, aminoalkyl group, alkylamino, amidino groups, hydroxyl, hydroxyl amino, alkoxyl group, hydroxyalkyl, alkoxy amino, sulfo-hydroxyl and alkylthio;
R
2Be Z
0-Q;
Z
0Be selected from covalent single bond, (CR
41R
42)
q, (CH (R
41))
g-W
0-(CH (R
42))
p(CH (R
41))
e-W
22-(CH (R
42))
h, wherein q is selected from 1 to 3 integer, and g and p are independently selected from 0 to 3 integer, W
0Be selected from O, S, C (O), S (O), N (R
41) and ON (R
41), e and h are independently selected from 0 to 1 integer, W
22Be selected from CR
41=CR
421, the 2-cyclopropyl, 1, the 2-cyclobutyl, 1, the 2-cyclohexyl, 1, the 3-cyclohexyl, 1, the 2-cyclopentyl, 1, the 3-cyclopentyl, 2, morpholinyl, 2, the 4-morpholinyl, 2, the 6-morpholinyl, 3, the 4-morpholinyl, 3, the 5-morpholinyl, 1, the 2-piperazinyl, 1, the 3-piperazinyl, 2, the 3-piperazinyl, 2, the 6-piperazinyl, 1, the 2-piperidyl, 1, the 3-piperidyl, 2, the 3-piperidyl, 2, the 4-piperidyl, 2, the 6-piperidyl, 3, the 4-piperidyl, 1, the 2-pyrrolidyl, 1, the 3-pyrrolidyl, 2, the 3-pyrrolidyl, 2, the 4-pyrrolidyl, 2, the 5-pyrrolidyl, 3, the 4-pyrrolidyl, 2, the 3-tetrahydrofuran base, 2, the 4-tetrahydrofuran base, 2,5-tetrahydrofuran base and 3, the 4-tetrahydrofuran base, its condition is Z
0Direct and uridylic ring key closes;
R
41And R
42Be independently selected from amidino groups, hydroxyl amino, hydrogen, hydroxyl, amino and alkyl;
Q is selected from hydrogen, and its condition is Z
0It can not be covalent single bond; And formula (II):
D wherein
1, D
2, J
1, J
2And K
1Be independently selected from C, N, O, S and covalent linkage, its condition be at the most one can be covalent linkage, D
1, D
2, J
1, J
2And K
1At the most one be O, D
1, D
2, J
1, J
2And K
1At the most one be S, if D
1, D
2, J
1, J
2And K
1Two be O and S, then D
1, D
2, J
1, J
2And K
1One of must be covalent linkage, D
1, D
2, J
1, J
2And K
1At the most four be N, its condition is R
9, R
10, R
11, R
12And R
13Selected independently of one another, with the tetravalence character of keeping carbon, the trivalent character of nitrogen, the divalence character of sulphur and the divalence character of oxygen;
K is (CR
4aR
4b)
n, wherein n is selected from 1 to 2 integer;
R
4aAnd R
4bBe independently selected from halogen, hydrogen, hydroxyalkyl, alkyl, alkoxyalkyl, alkylthio alkyl and haloalkyl;
If K is (CR
4aR
4b)
n, E then
0Be E
1, E wherein
1Be selected from covalent single bond, C (O), C (S), C (O) N (R
7), (R
7) NC (O), S (O)
2, (R
7) NS (O)
2And S (O)
2N (R
7);
Y
0Be formula (IV):
D wherein
5, D
6, J
5And J
6Be independently selected from C, N, O, S and covalent linkage, its condition be at the most one be covalent linkage, K
2Be C, D
5, D
6, J
5And J
6At the most one be O, D
5, D
6, J
5And J
6At the most one be S, if D
5, D
6, J
5And J
6Two be O and S, then D
5, D
6, J
5And J
6One of must be covalent linkage, D
5, D
6, J
5And J
6At the most four be N, its condition is R
16, R
17, R
18And R
19Selected independently of one another, with the tetravalence character of keeping carbon, the trivalent character of nitrogen, the divalence character of sulphur and the divalence character of oxygen;
R
16, R
17, R
18And R
19Be independently selected from hydrogen, amidino groups, guanidine radicals, carboxyl, halogenated alkylthio, alkoxyl group, hydroxyl, amino, nitro, alkoxy amino, low-grade alkyl amino, alkylthio, alkyl sulphinyl, alkyl sulphonyl, alkyloyl, haloalkane acyl group, alkyl, thiazolinyl, halogen, haloalkyl, halogenated alkoxy, hydroxyalkyl, alkylidene amino, halogenated alkoxy alkyl, carbalkoxy and cyano group;
Q
bBe selected from NR
20R
21, amino alkylidenyl, Q
Be, N (R
26) C (NR
25) N (R
23) (R
24) and C (NR
25) NR
23R
24, Q wherein
BeBe hydrogen, its condition is R
20And R
21At the most one be hydroxyl, amino, alkylamino or dialkyl amido simultaneously, R
23And R
24At the most one be hydroxyl, amino, alkylamino or dialkyl amido simultaneously;
R
20, R
21, R
23, R
24, R
25And R
26Be independently selected from hydrogen, alkyl, hydroxyl, amino alkylidenyl, amino, dialkyl amido, alkylamino and hydroxyalkyl;
Q
sBe selected from covalent single bond, (CR
37R
38)
b(CH (R
14))
c-W
1-(CH (R
15))
d, wherein b is selected from 1 to 4 integer, and c and d are independently selected from 1 to 3 integer, W
1Be selected from C (O) N (R
14), (R
14) NC (O), S (O), S (O)
2, S (O)
2N (R
14), N (R
14) S (O)
2And N (R
14), its condition is R
14If direct and N bonding then is selected from the group except that halogen, (CR
37R
38)
b(CH (R
14))
cWith E
0Bonding;
R
14Be selected from hydrogen, halogen, alkyl and haloalkyl;
R
37And R
38Be independently selected from hydrogen, alkyl and haloalkyl;
R
38Randomly be selected from aroyl and 4-hetaroylpyrazol;
Y
0Randomly be Q
b-Q
Ss, Q wherein
SsBe (CH (R
14))
e-W
2-(CH (R
15))
h, wherein e and h are independently selected from 1 to 2 integer, W
2Be CR
4a=CR
4b, its condition is (CH (R
15))
eWith E
0Bonding;
Y
0Randomly be selected from Q
b-Q
SsssAnd Q
b-Q
Ssssr, Q wherein
SsssBe (CH (R
38))
r-W
5, Q
SsssrBe (CH (R
38))
r-W
6, r is selected from 1 to 2 integer, W
5And W
6Be independently selected from 1, the 4-indenyl, 1, the 5-indenyl, 1, the 6-indenyl, 1, the 7-indenyl, 2, the 7-indenyl, 2, the 6-indenyl, 2, the 5-indenyl, 2, the 4-indenyl, 3, the 4-indenyl, 3, the 5-indenyl, 3, the 6-indenyl, 3, the 7-indenyl, 2, the 4-benzofuryl, 2, the 5-benzofuryl, 2, the 6-benzofuryl, 2, the 7-benzofuryl, 3, the 4-benzofuryl, 3, the 5-benzofuryl, 3, the 6-benzofuryl, 3, the 7-benzofuryl, 2, the 4-benzothienyl, 2, the 5-benzothienyl, 2, the 6-benzothienyl, 2, the 7-benzothienyl, 3, the 4-benzothienyl, 3, the 5-benzothienyl, 3, the 6-benzothienyl, 3, the 7-benzothienyl, 2, and the 7-imidazo (1,2-a) pyridyl, 3,4-imidazo (1,2-a) pyridyl, 3, and the 5-imidazo (1,2-a) pyridyl, 3,6-imidazo (1,2-a) pyridyl, 3, and the 7-imidazo (1,2-a) pyridyl, 2, the 4-indyl, 2, the 5-indyl, 2, the 6-indyl, 2, the 7-indyl, 3, the 4-indyl, 3, the 5-indyl, 3, the 6-indyl, 3, the 7-indyl, 1, the 4-pseudoindoyl, 1, the 5-pseudoindoyl, 1, the 6-pseudoindoyl, 2, the 4-pseudoindoyl, 2, the 5-pseudoindoyl, 2, the 6-pseudoindoyl, 2, the 7-pseudoindoyl, 1, the 3-pseudoindoyl, 3, the 4-indazolyl, 3, the 5-indazolyl, 3, the 6-indazolyl, 3, the 7-indazolyl, 2, the 4-benzoxazolyl, 2, the 5-benzoxazolyl, 2, the 6-benzoxazolyl, 2, the 7-benzoxazolyl, 3,4-benzoisoxazole base, 3,5-benzoisoxazole base, 3,6-benzoisoxazole base, 3,7-benzoisoxazole base, 1, the 4-naphthyl, 1, the 5-naphthyl, 1, the 6-naphthyl, 1, the 7-naphthyl, 1, the 8-naphthyl, 2, the 4-naphthyl, 2, the 5-naphthyl, 2, the 6-naphthyl, 2, the 7-naphthyl, 2, the 8-naphthyl, 2, the 4-quinolyl, 2, the 5-quinolyl, 2, the 6-quinolyl, 2, the 7-quinolyl, 2, the 8-quinolyl, 3, the 4-quinolyl, 3, the 5-quinolyl, 3, the 6-quinolyl, 3, the 7-quinolyl, 3, the 8-quinolyl, 4, the 5-quinolyl, 4, the 6-quinolyl, 4, the 7-quinolyl, 4, the 8-quinolyl, 1, the 4-isoquinolyl, 1, the 5-isoquinolyl, 1, the 6-isoquinolyl, 1, the 7-isoquinolyl, 1, the 8-isoquinolyl, 3, the 4-isoquinolyl, 3, the 5-isoquinolyl, 3, the 6-isoquinolyl, 3, the 7-isoquinolyl, 3, the 8-isoquinolyl, 4, the 5-isoquinolyl, 4, the 6-isoquinolyl, 4, the 7-isoquinolyl, 4, the 8-isoquinolyl, 3,4-cinnolines base, 3,5-cinnolines base, 3,6-cinnolines base, 3,7-cinnolines base, 3,8-cinnolines base, 4,5-cinnolines base, 4,6-cinnolines base, 4,7-cinnolines base and 4,8-cinnolines base removes W
5And W
6Tie point beyond, each contains the W of carbon and hydrogen
5And W
6Ring nitrogen member is randomly by one or more R
9, R
10, R
11And R
12Group replace, its condition is Q
bWith each W
5Lowest number substituting group position bonding, Q
bWith each W
6The highest numbering substituting group position bonding, (CH (R
38))
rWith E
0Bonding.
In the embodiment of preferred formula I compound or its pharmacy acceptable salt,
J
aAnd J
bEach is O naturally;
B is selected from aryl and heteroaryl, and the adjacent carbon of the carbon on one of them and the tie point is randomly by R
32Replace, the adjacent carbon of the carbon on another and the tie point is randomly by R
36Replace, with R
32Adjacent and apart from the carbon of two atoms of the carbon on the tie point randomly by R
33Replace, with R
36Adjacent and apart from the carbon of two atoms of the carbon on the tie point randomly by R
35Replace any and R
33And R
35All adjacent carbon is randomly by R
34Replace;
R
32, R
33, R
34, R
35And R
36Be independently selected from hydrogen; kharophen; the halo kharophen; amidino groups; guanidine radicals; alkylene dioxo base; halogenated alkylthio; alkanoyloxy; alkoxyl group; hydroxyl; amino; alkoxy amino; alkyloyl; the haloalkane acyl group; nitro; low-grade alkyl amino; alkylthio; aryl; aralkyl; cycloalkyl; cycloalkylalkyl; heteroaryl; heterocyclic radical; alkyl sulfonyl amino; the amido alkylsulfonyl; one alkyl amido alkylsulfonyl; dialkyl group amido alkylsulfonyl; alkyl; thiazolinyl; halogen; haloalkyl; haloalkenyl group; halogenated alkoxy; hydroxyalkyl; alkylidene amino; carbalkoxy; carboxyl; carboxamido; cyano group and Q
b
B randomly is selected from hydrogen, trialkylsilkl, C2-C8 alkyl, C3-C8 alkylidene group, C3-C8 thiazolinyl, C3-C8 alkynyl and C2-C8 haloalkyl, wherein each member of group B can be randomly at distance B and A tie point nearly and comprise on any carbon of 6 atoms by one or more radicals R
32, R
33, R
34, R
35And R
36Replace;
B randomly is selected from C3-C12 cycloalkyl and the saturated heterocyclic radical of C4-C9, and wherein each ring carbon is randomly by R
33Replace, the ring carbon except that the ring carbon that is positioned at B and A tie point is randomly replaced by oxo, and its condition is that a ring carbon is replaced by oxo simultaneously at the most, and ring carbon adjacent with the ring carbon that is positioned at tie point and nitrogen-atoms are randomly by R
9Or R
13Replace, with R
9The position adjacent and apart from the ring carbon of two atoms of tie point or nitrogen-atoms randomly by R
10Replace, with R
13The position adjacent and apart from the ring carbon of two atoms of tie point or nitrogen-atoms randomly by R
12Replace, apart from three atoms of tie point and and R
10Ring carbon that the position is adjacent or nitrogen-atoms are randomly by R
11Replace, apart from three atoms of tie point and and R
12Ring carbon that the position is adjacent or nitrogen-atoms are randomly by R
33Replace, apart from four atoms of tie point and and R
11And R
33Ring carbon that the position is adjacent or nitrogen-atoms are randomly by R
34Replace;
R
9, R
10, R
11, R
12And R
13Be independently selected from hydrogen, kharophen, the halo kharophen, alkoxy amino, alkyloyl, the haloalkane acyl group, amidino groups, guanidine radicals, alkylene dioxo base, halogenated alkylthio, alkoxyl group, hydroxyl, amino, low-grade alkyl amino, alkylthio, alkyl sulphinyl, alkyl sulphonyl, alkyl sulfonyl amino, the amido alkylsulfonyl, one alkyl amido alkylsulfonyl, dialkyl group amido alkylsulfonyl, alkyl, halogen, haloalkyl, halogenated alkoxy, hydroxyalkyl, aminoalkyl group, carbalkoxy, carboxyalkyl, carboxyl, carboxamido and cyano group;
A is selected from covalent single bond and (CH (R
15))
Pa-(W
7)
Rr, wherein rr is selected from 0 to 1 integer, and pa is selected from 0 to 3 integer, W
7Be selected from O, S, C (O), (R
7) NC (O), (R
7) NC (S) and N (R
7);
R
7Be selected from hydrogen, hydroxyl and alkyl;
R
15Be selected from hydrogen, hydroxyl, halogen, alkyl and haloalkyl;
Ψ is NH;
M is selected from N and R
1-C;
R
1Be selected from hydrogen, alkyl, cyano group, halogen, haloalkyl, halogenated alkoxy, amino, aminoalkyl group, alkylamino, amidino groups, hydroxyl, hydroxyl amino, alkoxyl group, hydroxyalkyl, alkoxy amino, sulfo-hydroxyl and alkylthio;
R
2Be Z
0-Q;
Z
0Be selected from covalent single bond, (CR
41R
42)
q, (CH (R
41))
g-W
0-(CH (R
42))
p(CH (R
41))
e-W
22-(CH (R
42))
h, wherein q is selected from 1 to 2 integer, and g and p are independently selected from 0 to 3 integer, W
0Be selected from O, S and N (R
41), e and h are independently selected from 0 to 1 integer, W
22Be selected from CR
41=CR
421, the 2-cyclopropyl, 1, the 2-cyclobutyl, 1, the 2-cyclohexyl, 1, the 3-cyclohexyl, 1, the 2-cyclopentyl, 1, the 3-cyclopentyl, 2, morpholinyl, 2, the 4-morpholinyl, 2, the 6-morpholinyl, 3, the 4-morpholinyl, 3, the 5-morpholinyl, 1, the 2-piperazinyl, 1, the 3-piperazinyl, 2, the 3-piperazinyl, 2, the 6-piperazinyl, 1, the 2-piperidyl, 1, the 3-piperidyl, 2, the 3-piperidyl, 2, the 4-piperidyl, 2, the 6-piperidyl, 3, the 4-piperidyl, 1, the 2-pyrrolidyl, 1, the 3-pyrrolidyl, 2, the 3-pyrrolidyl, 2, the 4-pyrrolidyl, 2, the 5-pyrrolidyl, 3, the 4-pyrrolidyl, 2, the 3-tetrahydrofuran base, 2, the 4-tetrahydrofuran base, 2,5-tetrahydrofuran base and 3, the 4-tetrahydrofuran base, its condition is Z
0Direct and uridylic ring key closes;
R
41And R
42Be independently selected from hydrogen, hydroxyl and amino;
Q is selected from hydrogen, and its condition is Z
0It can not be covalent single bond; The adjacent carbon of carbon on aryl and the heteroaryl, one of them and tie point is randomly by R
9Replace, the adjacent carbon of the carbon on another and the tie point is randomly by R
13Replace, with R
9Adjacent and apart from the carbon of two atoms of the carbon on the tie point randomly by R
10Replace, with R
13Adjacent and apart from the carbon of two atoms of the carbon on the tie point randomly by R
12Replace any and R
10And R
12All adjacent carbon is randomly by R
11Replace;
K is CHR
4a, R wherein
4aBe selected from hydrogen, hydroxyalkyl, alkyl, alkoxyalkyl, alkylthio alkyl and haloalkyl;
E
0Be selected from covalent single bond, C (O) N (H), (H) NC (O), (R
7) NS (O)
2And S (O)
2N (R
7);
Y
0Be formula (IV):
D wherein
5, D
6, J
5And J
6Be independently selected from C, N, O, S and covalent linkage, its condition be at the most one be covalent linkage, K
2Be C, D
5, D
6, J
5And J
6At the most one be O, D
5, D
6, J
5And J
6At the most one be S, if D
5, D
6, J
5And J
6Two be O and S, then D
5, D
6, J
5And J
6One of must be covalent linkage, D
5, D
6, J
5And J
6At the most four be N, its condition is R
16, R
17, R
18And R
19Selected independently of one another, with the tetravalence character of keeping carbon, the trivalent character of nitrogen, the divalence character of sulphur and the divalence character of oxygen;
R
16, R
17, R
18And R
19Be independently selected from hydrogen, amidino groups, guanidine radicals, carboxyl, halogenated alkylthio, alkoxyl group, hydroxyl, amino, alkoxy amino, low-grade alkyl amino, alkylthio, alkyl sulphinyl, alkyl sulphonyl, alkyloyl, haloalkane acyl group, alkyl, halogen, haloalkyl, halogenated alkoxy, hydroxyalkyl, aminoalkyl group and cyano group;
R
16And R
19Randomly be Q
b, its condition is R
15And R
19At the most one be Q simultaneously
b, Q
bBe Q
Be
Q
bBe selected from NR
20R
21, Q
Be, N (R
26) C (NR
25) N (R
23) (R
24) and C (NR
25) NR
23R
24, Q wherein
BeBe hydrogen, its condition is R
20And R
21At the most one be hydroxyl, amino, alkylamino or dialkyl amido simultaneously, R
23And R
24At the most one be hydroxyl, amino, alkylamino or dialkyl amido simultaneously;
R
20, R
21, R
23, R
24, R
25And R
26Be independently selected from hydrogen, alkyl, hydroxyl, amino, alkylamino and dialkyl amido;
Q
sBe selected from covalent single bond, (CR
37R
38)
b(CH (R
14))
c-W
1-(CH (R
15))
d, wherein b is selected from 1 to 4 integer, and c and d are independently selected from 1 to 3 integer, W
1Be selected from C (O) N (R
14), (R
14) NC (O), S (O), S (O)
2, S (O)
2N (R
14), N (R
14) S (O)
2And N (R
14), its condition is R
14If direct and N bonding then is selected from the group except that halogen, (CR
37R
38)
b(CH (R
14))
cWith E
0Bonding;
R
14Be selected from hydrogen, halogen, alkyl and haloalkyl;
R
37And R
38Be independently selected from hydrogen, alkyl and haloalkyl;
R
38Randomly be selected from aroyl and 4-hetaroylpyrazol;
Y
0Randomly be Q
b-Q
Ss, Q wherein
SsBe (CH (R
14))
e-W
2-(CH (R
15))
h, wherein e and h are independently selected from 1 to 2 integer, W
2Be CR
4a=CH, its condition is (CH (R
14))
eWith E
0Bonding.
So the embodiment of preferred formula I compound or its pharmacy acceptable salt in,
J
aAnd J
bEach is O naturally;
B is selected from aryl and heteroaryl, and the adjacent carbon of the carbon on one of them and the tie point is randomly by R
32Replace, the adjacent carbon of the carbon on another and the tie point is randomly by R
36Replace, with R
32Adjacent and apart from the carbon of two atoms of the carbon on the tie point randomly by R
33Replace, with R
36Adjacent and apart from the carbon of two atoms of the carbon on the tie point randomly by R
35Replace any and R
33And R
35All adjacent carbon is randomly by R
34Replace;
R
32, R
33, R
34, R
35And R
36Be independently selected from hydrogen, kharophen, halo kharophen, amidino groups, guanidine radicals, alkoxyl group, hydroxyl, amino, alkoxy amino, low-grade alkyl amino, alkylthio, amido alkylsulfonyl, an alkyl amido alkylsulfonyl, dialkyl group amido alkylsulfonyl, alkyl, halogen, haloalkyl, halogenated alkoxy, hydroxyalkyl, carbalkoxy, carboxyl, carboxamido, cyano group and Q
b
A is selected from covalent single bond and (CH (R
15))
Pa-(W
7)
Rr, wherein rr is selected from 0 to 1 integer, and pa is selected from 0 to 3 integer, W
7Be selected from (R
7) NC (O) and N (R
7);
R
7Be selected from hydrogen, hydroxyl and alkyl;
R
15Be selected from hydrogen, halogen, alkyl and haloalkyl;
Ψ is NH;
M is selected from N and R
1-C;
R
1Be selected from hydrogen, hydroxyl, hydroxyl amino, amidino groups, amino, cyano group, hydroxyalkyl, alkoxyl group, alkyl, alkylamino, aminoalkyl group, alkylthio, alkoxy amino, haloalkyl, halogenated alkoxy and halogen;
R
2Be Z
0-Q;
Z
0Be selected from covalent single bond, O, S, NH and CH
2
Q is selected from aryl and heteroaryl, and the adjacent carbon of the carbon on one of them and the tie point is randomly by R
9Replace, the adjacent carbon of the carbon on another and the tie point is randomly by R
13Replace, with R
9Adjacent and apart from the carbon of two atoms of the carbon on the tie point randomly by R
10Replace, with R
13Adjacent and apart from the carbon of two atoms of the carbon on the tie point randomly by R
12Replace any and R
10And R
12All adjacent carbon is randomly by R
11Replace;
R
9, R
11And R
13Be independently selected from hydrogen, hydroxyl, amino, amidino groups, guanidine radicals, low-grade alkyl amino, alkylthio, alkyl sulfonyl amino, alkyl sulphinyl, alkyl sulphonyl, amido alkylsulfonyl, an alkyl amido alkylsulfonyl, alkyl, alkoxyl group, halogen, haloalkyl, halogenated alkoxy, hydroxyalkyl, carboxyl, carboxamido and cyano group;
R
10And R
12Be independently selected from hydrogen, kharophen, halo kharophen, amidino groups, guanidine radicals, alkyl, alkoxyl group, hydroxyl, amino, alkoxy amino, low-grade alkyl amino, alkyl sulfonyl amino, amido alkylsulfonyl, an alkyl amido alkylsulfonyl, dialkyl group amido alkylsulfonyl, hydroxyalkyl, aminoalkyl group, carbalkoxy, carboxyl, carboxyalkyl, amido carbonyl, halogen, haloalkyl and cyano group;
K is CH
2
E
0Be C (O) N (H);
Y
0Be formula (IV):
D wherein
5, D
6, J
5And J
6Be independently selected from C, N, O, S and covalent linkage, its condition be at the most one be covalent linkage, K
2Be C, D
5, D
6, J
5And J
6At the most one optional be O, D
5, D
6, J
5And J
6At the most one optional be S, if D
5, D
6, J
5And J
6Two be O and S, then D
5, D
6, J
5And J
6One of must be covalent linkage, D
5, D
6, J
5And J
6At the most four be N;
R
16, R
17, R
18And R
19Be independently selected from hydrogen, amidino groups, guanidine radicals, carboxyl, halogenated alkylthio, alkoxyl group, hydroxyl, amino, low-grade alkyl amino, alkylthio, alkyl sulphinyl, alkyl sulphonyl, alkyloyl, haloalkane acyl group, alkyl, halogen, haloalkyl, halogenated alkoxy, hydroxyalkyl, aminoalkyl group and cyano group;
R
16And R
19Randomly be Q
b, its condition is R
16And R
19At the most one be Q simultaneously
b, Q
bBe Q
Be
Q
bBe selected from NR
20R
21, Q
BeAnd C (NR
25) NR
23R
24, Q wherein
BeBe hydrogen, its condition is R
20And R
21At the most one be hydroxyl simultaneously, R
23And R
24At the most one be hydroxyl simultaneously;
R
20, R
21, R
23, R
24And R
25Be independently selected from hydrogen, alkyl and hydroxyl;
Q
sBe selected from covalent single bond, CH
2And CH
2CH
2
In the embodiment of another kind of and then preferred formula I compound or its pharmacy acceptable salt,
J
aAnd J
bEach is O naturally;
B randomly is selected from hydrogen, C2-C8 alkyl, C3-C8 thiazolinyl, C3-C8 alkynyl and C2-C8 haloalkyl, and wherein each member of group B randomly at distance B and A tie point nearly and comprise on any carbon of 6 atoms by one or more radicals R
32, R
33, R
34, R
35And R
36Replace;
R
32, R
33, R
34, R
35And R
36Be independently selected from hydrogen, kharophen, halo kharophen, amidino groups, guanidine radicals, alkoxyl group, hydroxyl, amino, alkoxy amino, low-grade alkyl amino, alkylthio, amido alkylsulfonyl, an alkyl amido alkylsulfonyl, dialkyl group amido alkylsulfonyl, alkyl, halogen, haloalkyl, halogenated alkoxy, hydroxyalkyl, carbalkoxy, carboxyl, carboxamido, cyano group and Q
b
A is selected from covalent single bond and (CH (R
15))
Pa-(W
7)
Rr, wherein rr is selected from 0 to 1 integer, and pa is selected from 0 to 3 integer, W
7Be selected from (R
7) NC (O) and N (R
7);
R
7Be selected from hydrogen, hydroxyl and alkyl;
R
15Be selected from hydrogen, halogen, alkyl and haloalkyl;
Ψ is NH;
M is selected from N and R
1-C;
R
1Be selected from hydrogen, hydroxyl, hydroxyl amino, amidino groups, amino, cyano group, hydroxyalkyl, alkoxyl group, alkyl, alkylamino, aminoalkyl group, alkylthio, alkoxy amino, haloalkyl, halogenated alkoxy and halogen;
R
2Be Z
0-Q;
Z
0Be selected from covalent single bond, O, S, NH and CH
2
Q is selected from aryl and heteroaryl, and the adjacent carbon of the carbon on one of them and the tie point is randomly by R
9Replace, the adjacent carbon of the carbon on another and the tie point is randomly by R
13Replace, with R
9Adjacent and apart from the carbon of two atoms of the carbon on the tie point randomly by R
10Replace, with R
13Adjacent and apart from the carbon of two atoms of the carbon on the tie point randomly by R
12Replace any and R
10And R
12All adjacent carbon is randomly by R
11Replace;
R
9, R
11And R
13Be independently selected from hydrogen, hydroxyl, amino, amidino groups, guanidine radicals, low-grade alkyl amino, alkylthio, alkyl sulfonyl amino, alkyl sulphinyl, alkyl sulphonyl, amido alkylsulfonyl, an alkyl amido alkylsulfonyl, alkyl, alkoxyl group, halogen, haloalkyl, halogenated alkoxy, hydroxyalkyl, carboxyl, carboxamido and cyano group;
R
10And R
12Be independently selected from hydrogen, kharophen, halo kharophen, amidino groups, guanidine radicals, alkyl, alkoxyl group, hydroxyl, amino, alkoxy amino, low-grade alkyl amino, alkyl sulfonyl amino, amido alkylsulfonyl, an alkyl amido alkylsulfonyl, dialkyl group amido alkylsulfonyl, hydroxyalkyl, alkylidene amino, carbalkoxy, carboxyl, carboxyalkyl, amido carbonyl, halogen, haloalkyl and cyano group;
K is CH
2
E
0Be C (O) N (H);
Y
0Be formula (IV):
D wherein
5, D
6, J
5And J
6Be independently selected from C, N, O, S and covalent linkage, its condition be at the most one be covalent linkage, K
2Be C, D
5, D
6, J
5And J
6At the most one be O, D
5, D
6, J
5And J
6At the most one be S, if D
5, D
6, J
5And J
6Two be O and S, then D
5, D
6, J
5And J
6One of must be covalent linkage, D
5, D
6, J
5And J
6At the most four be N, its condition is R
16, R
17, R
18And R
19Selected independently of one another, with the tetravalence character of keeping carbon, the trivalent character of nitrogen, the divalence character of sulphur and the divalence character of oxygen;
R
16, R
17, R
18And R
19Be independently selected from hydrogen, amidino groups, guanidine radicals, carboxyl, halogenated alkylthio, alkoxyl group, hydroxyl, amino, low-grade alkyl amino, alkylthio, alkyl sulphinyl, alkyl sulphonyl, alkyloyl, haloalkane acyl group, alkyl, halogen, haloalkyl, halogenated alkoxy, hydroxyalkyl, alkylidene amino and cyano group;
R
16And R
19Randomly be Q
b, its condition is R
16And R
19At the most one be Q simultaneously
b, Q
bBe Q
Be
Q
bBe selected from NR
20R
21, Q
Be, C (NR
25) NR
23R
24And N (R
26) C (NR
25) NR
23R
24, Q wherein
BeBe hydrogen, its condition is R
20And R
21At the most one be hydroxyl simultaneously, R
23And R
24At the most one be hydroxyl simultaneously;
R
20, R
21, R
23, R
24, R
25And R
26Be independently selected from hydrogen, alkyl and hydroxyl;
Q
sBe selected from covalent single bond, CH
2And CH
2CH
2
At another kind still and then in the embodiment of preferred formula I compound or its pharmacy acceptable salt,
J
aAnd J
bEach is O naturally;
B randomly is selected from C3-C7 cycloalkyl and the saturated heterocyclic radical of C4-C6, and wherein each ring carbon is randomly by R
33Replace, the ring carbon except that the ring carbon that is positioned at B and A tie point is randomly replaced by oxo, and its condition is that a ring carbon is replaced by oxo simultaneously at the most, and ring carbon adjacent with the ring carbon that is positioned at tie point and nitrogen-atoms are randomly by R
9Or R
13Replace, with R
9The position adjacent and apart from the ring carbon of two atoms of tie point or nitrogen-atoms randomly by R
10Replace, with R
13The position adjacent and apart from the ring carbon of two atoms of tie point or nitrogen-atoms randomly by R
12Replace, apart from three atoms of tie point and and R
10Ring carbon that the position is adjacent or nitrogen-atoms are randomly by R
11Replace, apart from three atoms of tie point and and R
12Ring carbon that the position is adjacent or nitrogen-atoms are randomly by R
33Replace, apart from four atoms of tie point and and R
11And R
33Ring carbon that the position is adjacent or nitrogen-atoms are randomly by R
34Replace;
R
9, R
11And R
13Be independently selected from hydrogen, hydroxyl, amino, amidino groups, guanidine radicals, low-grade alkyl amino, alkylthio, alkyl sulfonyl amino, alkyl sulphinyl, alkyl sulphonyl, amido alkylsulfonyl, an alkyl amido alkylsulfonyl, alkyl, alkoxyl group, halogen, haloalkyl, halogenated alkoxy, hydroxyalkyl, carboxyl, carboxamido and cyano group;
R
10And R
12Be independently selected from hydrogen, kharophen, halo kharophen, amidino groups, guanidine radicals, alkyl, alkoxyl group, hydroxyl, amino, alkoxy amino, low-grade alkyl amino, alkyl sulfonyl amino, amido alkylsulfonyl, an alkyl amido alkylsulfonyl, dialkyl group amido alkylsulfonyl, hydroxyalkyl, alkylidene amino, carbalkoxy, carboxyl, carboxyalkyl, amido carbonyl, halogen, haloalkyl and cyano group;
R
33And R
34Be independently selected from hydrogen, kharophen, halo kharophen, amidino groups, guanidine radicals, alkoxyl group, hydroxyl, amino, alkoxy amino, low-grade alkyl amino, alkylthio, amido alkylsulfonyl, an alkyl amido alkylsulfonyl, dialkyl group amido alkylsulfonyl, alkyl, halogen, haloalkyl, halogenated alkoxy, hydroxyalkyl, carbalkoxy, carboxyl, carboxamido, cyano group and Q
b
A is selected from covalent single bond and (CH (R
15))
Pa-(W
7)
Rr, wherein rr is selected from 0 to 1 integer, and pa is selected from 0 to 3 integer, W
7Be selected from (R
7) NC (O) and N (R
7);
R
7Be selected from hydrogen, hydroxyl and alkyl;
R
15Be selected from hydrogen, halogen, alkyl and haloalkyl;
Ψ is NH;
M is selected from N and R
1-C;
R
1Be selected from hydrogen, hydroxyl, hydroxyl amino, amidino groups, amino, cyano group, hydroxyalkyl, alkoxyl group, alkyl, alkylamino, aminoalkyl group, alkylthio, alkoxy amino, haloalkyl, halogenated alkoxy and halogen;
R
2Be Z
0-Q;
Z
0Be selected from covalent single bond, O, S, NH and CH
2
Q is selected from aryl and heteroaryl, and the adjacent carbon of the carbon on one of them and the tie point is randomly by R
9Replace, the adjacent carbon of the carbon on another and the tie point is randomly by R
13Replace, with R
9Adjacent and apart from the carbon of two atoms of the carbon on the tie point randomly by R
10Replace, with R
13Adjacent and apart from the carbon of two atoms of the carbon on the tie point randomly by R
12Replace any and R
10And R
12All adjacent carbon is randomly by R
11Replace;
K is CH
2
E
0Be C (O) N (H);
Y
0Be formula (IV):
D wherein
5, D
6, J
5And J
6Be independently selected from C, N, O, S and covalent linkage, its condition be at the most one be covalent linkage, K
2Be C, D
5, D
6, J
5And J
6At the most one be O, D
5, D
6, J
5And J
6At the most one be S, if D
5, D
6, J
5And J
6Two be O and S, then D
5, D
6, J
5And J
6One of must be covalent linkage, D
5, D
6, J
5And J
6At the most four be N, its condition is R
16, R
17, R
18And R
19Selected independently of one another, with the tetravalence character of keeping carbon, the trivalent character of nitrogen, the divalence character of sulphur and the divalence character of oxygen;
R
16, R
17, R
18And R
19Be independently selected from hydrogen, amidino groups, guanidine radicals, carboxyl, halogenated alkylthio, alkoxyl group, hydroxyl, amino, low-grade alkyl amino, alkylthio, alkyl sulphinyl, alkyl sulphonyl, alkyloyl, haloalkane acyl group, alkyl, halogen, haloalkyl, halogenated alkoxy, hydroxyalkyl, alkylidene amino and cyano group;
R
16And R
19Randomly be Q
b, its condition is R
16And R
19At the most one be Q simultaneously
b, Q
bBe Q
Be
Q
bBe selected from NR
20R
21, Q
BeAnd C (NR
25) NR
23R
24, Q wherein
BeBe hydrogen, its condition is R
20And R
21At the most one be hydroxyl simultaneously, R
23And R
24At the most one be hydroxyl simultaneously;
R
20, R
21, R
23, R
24And R
25Be independently selected from hydrogen, alkyl and hydroxyl;
Q
sBe selected from covalent single bond, CH
2And CH
2CH
2
In the embodiment of most preferred formula I compound or its pharmacy acceptable salt,
J
aAnd J
bEach is O naturally;
B is selected from aryl and heteroaryl, and the adjacent carbon of the carbon on one of them and the tie point is randomly by R
32Replace, the adjacent carbon of the carbon on another and the tie point is randomly by R
36Replace, with R
32Adjacent and apart from the carbon of two atoms of the carbon on the tie point randomly by R
33Replace, with R
36Adjacent and apart from the carbon of two atoms of the carbon on the tie point randomly by R
35Replace any and R
33And R
35All adjacent carbon is randomly by R
34Replace;
R
32, R
33, R
34, R
35And R
36Be independently selected from hydrogen, kharophen, halo kharophen, amidino groups, guanidine radicals, alkoxyl group, hydroxyl, amino, alkoxy amino, low-grade alkyl amino, alkylthio, amido alkylsulfonyl, an alkyl amido alkylsulfonyl, dialkyl group amido alkylsulfonyl, alkyl, halogen, haloalkyl, halogenated alkoxy, hydroxyalkyl, carbalkoxy, carboxyl, carboxamido, cyano group and Q
b
A is selected from covalent single bond and (CH (R
15))
Pa-(W
7)
Rr, wherein rr is selected from 0 to 1 integer, and pa is selected from 0 to 3 integer, W
7Be N (R
7);
R
7Be selected from hydrogen and alkyl;
R
15Be selected from hydrogen, halogen, alkyl and haloalkyl;
Ψ is NH;
M is selected from N and R
1-C;
R
1Be selected from hydrogen, hydroxyl, hydroxyl amino, amidino groups, amino, cyano group, hydroxyalkyl, alkoxyl group, alkyl, alkylamino, aminoalkyl group, alkylthio, alkoxy amino, haloalkyl, halogenated alkoxy and halogen;
R
2Be Z
0-Q;
Z
0It is covalent single bond;
Q is selected from aryl and heteroaryl, and the adjacent carbon of the carbon on one of them and the tie point is randomly by R
9Replace, the adjacent carbon of the carbon on another and the tie point is randomly by R
13Replace, with R
9Adjacent and apart from the carbon of two atoms of the carbon on the tie point randomly by R
10Replace, with R
13Adjacent and apart from the carbon of two atoms of the carbon on the tie point randomly by R
12Replace any and R
10And R
12All adjacent carbon is randomly by R
11Replace;
R
9, R
11And R
13Be independently selected from hydrogen, hydroxyl, amino, amidino groups, guanidine radicals, low-grade alkyl amino, alkylthio, alkoxyl group, alkyl sulphinyl, alkyl sulphonyl, amido alkylsulfonyl, an alkyl amido alkylsulfonyl, alkyl, halogen, haloalkyl, halogenated alkoxy, hydroxyalkyl, carboxyl, carboxamido and cyano group;
R
10And R
12Be independently selected from hydrogen, kharophen, halo kharophen, amidino groups, guanidine radicals, alkyl, alkoxyl group, alkoxy amino, aminoalkyl group, hydroxyl, amino, low-grade alkyl amino, alkyl sulfonyl amino, amido alkylsulfonyl, an alkyl amido alkylsulfonyl, dialkyl group amido alkylsulfonyl, hydroxyalkyl, aminoalkyl group, halogen, haloalkyl, carbalkoxy, carboxyl, carboxyalkyl, carboxamido and cyano group;
K is CH
2
E
0Be C (O) N (H);
Y
0Be formula (IV):
D wherein
5, D
6, J
5And J
6Be independently selected from C, N, O, S and covalent linkage, its condition be at the most one be covalent linkage, K
2Be C, D
5, D
6, J
5And J
6At the most one be O, D
5, D
6, J
5And J
6At the most one be S, if D
5, D
6, J
5And J
6Two be O and S, then D
5, D
6, J
5And J
6One of must be covalent linkage, D
5, D
6, J
5And J
6At the most four be N;
R
16, R
17, R
18And R
19Be independently selected from hydrogen, amidino groups, guanidine radicals, carboxyl, halogenated alkylthio, alkoxyl group, hydroxyl, amino, low-grade alkyl amino, alkylthio, alkyl sulphinyl, alkyl sulphonyl, alkyloyl, haloalkane acyl group, alkyl, halogen, haloalkyl, halogenated alkoxy, hydroxyalkyl, aminoalkyl group and cyano group;
R
16And R
19Randomly be Q
b, its condition is R
16And R
19At the most one be Q simultaneously
b, Q
bBe Q
Be
Q
bBe selected from NR
20R
21, Q
BeAnd C (NR
25) NR
23R
24, Q wherein
BeBe hydrogen;
R
20, R
21, R
23, R
24And R
25Be independently selected from hydrogen and alkyl;
Q
sBe CH
2
In the embodiment of the most preferred formula I compound of another kind or its pharmacy acceptable salt,
J
aAnd J
bBe O;
B randomly is selected from hydrogen, C2-C8 alkyl, C3-C8 thiazolinyl, C3-C8 alkynyl and C2-C8 haloalkyl, and wherein each member of group B randomly at distance B and A tie point nearly and comprise on any carbon of 6 atoms by one or more radicals R
32, R
33, R
34, R
35And R
36Replace;
R
32, R
34, R
35, R
35And R
36Be independently selected from hydrogen, kharophen, halo kharophen, amidino groups, guanidine radicals, alkoxyl group, hydroxyl, amino, alkoxy amino, low-grade alkyl amino, alkylthio, amido alkylsulfonyl, an alkyl amido alkylsulfonyl, dialkyl group amido alkylsulfonyl, alkyl, halogen, haloalkyl, halogenated alkoxy, hydroxyalkyl, carbalkoxy, carboxyl, carboxamido, cyano group and Q
b
A is selected from covalent single bond and (CH (R
15))
Pa-(W
7)
Rr, wherein rr is selected from 0 to 1 integer, and pa is selected from 0 to 3 integer, W
7Be N (R
7);
R
7Be selected from hydrogen and alkyl;
R
15Be selected from hydrogen, halogen, alkyl and haloalkyl;
Ψ is NH;
M is selected from N and R
1-C;
R
1Be selected from hydrogen, hydroxyl, hydroxyl amino, amidino groups, amino, cyano group, hydroxyalkyl, alkoxyl group, alkyl, alkylamino, aminoalkyl group, alkylthio, alkoxy amino, haloalkyl, halogenated alkoxy and halogen;
R
2Be Z
0-Q;
Z
0It is covalent single bond;
Q is selected from aryl and heteroaryl, and the adjacent carbon of the carbon on one of them and the tie point is randomly by R
9Replace, the adjacent carbon of the carbon on another and the tie point is randomly by R
13Replace, with R
9Adjacent and apart from the carbon of two atoms of the carbon on the tie point randomly by R
10Replace, with R
13Adjacent and apart from the carbon of two atoms of the carbon on the tie point randomly by R
12Replace any and R
10And R
12All adjacent carbon is randomly by R
11Replace;
R
9, R
11And R
13Be independently selected from hydrogen, hydroxyl, amino, amidino groups, guanidine radicals, low-grade alkyl amino, alkylthio, alkoxyl group, alkyl sulphinyl, alkyl sulphonyl, amido alkylsulfonyl, an alkyl amido alkylsulfonyl, alkyl, halogen, haloalkyl, halogenated alkoxy, hydroxyalkyl, carboxyl, carboxamido and cyano group;
R
10And R
12Be independently selected from hydrogen, kharophen, halo kharophen, amidino groups, guanidine radicals, alkyl, alkoxyl group, alkoxy amino, aminoalkyl group, hydroxyl, amino, low-grade alkyl amino, alkyl sulfonyl amino, amido alkylsulfonyl, an alkyl amido alkylsulfonyl, dialkyl group amido alkylsulfonyl, hydroxyalkyl, aminoalkyl group, halogen, haloalkyl, carbalkoxy, carboxyl, carboxyalkyl, carboxyl amido and cyano group;
K is CH
2
E
0Be C (O) N (H);
Y
0Be formula (IV):
D wherein
5, D
6, J
5And J
6Be independently selected from C, N, O, S and covalent linkage, its condition be at the most one be covalent linkage, K
2Be C, D
5, D
6, J
5And J
6At the most one be O, D
5, D
6, J
5And J
6At the most one be S, if D
5, D
6, J
5And J
6Two be O and S, then D
5, D
6, J
5And J
6One of must be covalent linkage, D
5, D
6, J
5And J
6At the most four be N, its condition is R
16, R
17, R
18And R
19Selected independently of one another, with the tetravalence character of keeping carbon, the trivalent character of nitrogen, the divalence character of sulphur and the divalence character of oxygen;
R
16, R
17, R
18And R
19Be independently selected from hydrogen, amidino groups, guanidine radicals, carboxyl, halogenated alkylthio, alkoxyl group, hydroxyl, amino, low-grade alkyl amino, alkylthio, alkyl sulphinyl, alkyl sulphonyl, alkyloyl, haloalkane acyl group, alkyl, halogen, haloalkyl, halogenated alkoxy, hydroxyalkyl, aminoalkyl group and cyano group;
R
16And R
19Randomly be Q
b, its condition is R
16And R
19At the most one be Q simultaneously
b, Q
bBe Q
Be
Q
bBe selected from NR
20R
21, Q
Be, N (R
26) C (NR
25) N (R
23) (R
24) and C (NR
25) NR
23R
24, Q wherein
BeBe hydrogen;
R
20, R
21, R
23, R
24, R
25And R
26Be independently selected from hydrogen and alkyl;
Q
sBe CH
2
In the embodiment of another most preferred formula I compound or its pharmacy acceptable salt,
J
aAnd J
bEach is O naturally;
B randomly is selected from C3-C7 cycloalkyl and the saturated heterocyclic radical of C4-C6, and wherein each ring carbon is randomly by R
33Replace, the ring carbon except that the ring carbon that is positioned at B and A tie point is randomly replaced by oxo, and its condition is that a ring carbon is replaced by oxo simultaneously at the most, and ring carbon adjacent with the carbon atom that is positioned at tie point and nitrogen-atoms are randomly by R
9Or R
13Replace, with R
9The position adjacent and apart from the ring carbon of two atoms of tie point or nitrogen-atoms randomly by R
10Replace, with R
13The position adjacent and apart from the ring carbon of two atoms of tie point or nitrogen-atoms randomly by R
12Replace, apart from three atoms of tie point and and R
10Ring carbon that the position is adjacent or nitrogen-atoms are randomly by R
11Replace, apart from three atoms of tie point and and R
12Ring carbon that the position is adjacent or nitrogen-atoms are randomly by R
33Replace, apart from four atoms of tie point and and R
11And R
33Ring carbon that the position is adjacent or nitrogen-atoms are randomly by R
34Replace;
R
9, R
11And R
13Be independently selected from hydrogen, hydroxyl, amino, amidino groups, guanidine radicals, low-grade alkyl amino, alkylthio, alkoxyl group, alkyl sulphinyl, alkyl sulphonyl, amido alkylsulfonyl, an alkyl amido alkylsulfonyl, alkyl, halogen, haloalkyl, halogenated alkoxy, hydroxyalkyl, carboxyl, carboxamido and cyano group;
R
10And R
12Be independently selected from hydrogen, kharophen, halo kharophen, amidino groups, guanidine radicals, alkyl, alkoxyl group, alkoxy amino, aminoalkyl group, hydroxyl, amino, low-grade alkyl amino, alkyl sulfonyl amino, amido alkylsulfonyl, an alkyl amido alkylsulfonyl, dialkyl group amido alkylsulfonyl, hydroxyalkyl, aminoalkyl group, halogen, haloalkyl, carbalkoxy, carboxyl, carboxyalkyl, carboxyl amido and cyano group;
R
33And R
34Be independently selected from hydrogen, amidino groups, guanidine radicals, alkoxyl group, hydroxyl, amino, alkoxy amino, low-grade alkyl amino, alkylthio, amido alkylsulfonyl, an alkyl amido alkylsulfonyl, dialkyl group amido alkylsulfonyl, alkyl, halogen, haloalkyl, halogenated alkoxy, hydroxyalkyl, carbalkoxy, carboxyl, carboxamido and cyano group;
R
33Randomly be Q
b
A is selected from covalent single bond and (CH (R
15))
Pa-(W
7)
Rr, wherein rr is selected from 0 to 1 integer, and pa is selected from 0 to 3 integer, W
7Be N (R
7);
R
7Be selected from hydrogen, hydroxyl and alkyl;
R
15Be selected from hydrogen, halogen, alkyl and haloalkyl;
Ψ is NH;
M is selected from N and R
1-C;
R
1Be selected from hydrogen, hydroxyl, hydroxyl amino, amidino groups, amino, cyano group, hydroxyalkyl, alkoxyl group, alkyl, alkylamino, aminoalkyl group, alkylthio, alkoxy amino, haloalkyl, halogenated alkoxy and halogen;
R
2Be Z
0-Q;
Z
0It is covalent single bond;
Q is selected from aryl and heteroaryl, and the adjacent carbon of the carbon on one of them and the tie point is randomly by R
9Replace, the adjacent carbon of the carbon on another and the tie point is randomly by R
13Replace, with R
9Adjacent and apart from the carbon of two atoms of the carbon on the tie point randomly by R
10Replace, adjacent with R13 and apart from the carbon of two atoms of the carbon on the tie point randomly by R
12Replace any and R10 and R
12All adjacent carbon is randomly by R
11Replace;
K is CH
2
E
0Be C (O) N (H);
Y
0Be formula (IV):
D wherein
5, D
6, J
5And J
6Be independently selected from C, N, O, S and covalent linkage, its condition be at the most one be covalent linkage, K
2Be C, D
5, D
6, J
5And J
6At the most one be O, D
5, D
6, J
5And J
6At the most one be S, if D
5, D
6, J
5And J
6Two be O and S, then D
5, D
6, J
5And J
6One of must be covalent linkage, D
5, D
6, J
5And J
6At the most four be N, its condition is R
16, R
17, R
18And R
19Selected independently of one another, with the tetravalence character of keeping carbon, the trivalent character of nitrogen, the divalence character of sulphur and the divalence character of oxygen;
R
16, R
17, R
18And R
19Be independently selected from hydrogen, amidino groups, guanidine radicals, carboxyl, halogenated alkylthio, alkoxyl group, hydroxyl, amino, low-grade alkyl amino, alkylthio, alkyl sulphinyl, alkyl sulphonyl, alkyloyl, haloalkane acyl group, alkyl, halogen, haloalkyl, halogenated alkoxy, hydroxyalkyl, alkylidene amino and cyano group;
R
16And R
19Randomly be Q
b, its condition is R
16And R
19At the most one be Q simultaneously
b, Q
bBe Q
Be
Q
bBe selected from NR
20R
21, Q
BeAnd C (NR
25) NR
23R
24, Q wherein
BeBe hydrogen;
R
20, R
21, R
23, R
24And R
25Be independently selected from hydrogen and alkyl;
Q
sBe CH
2
In the specific embodiments of preferred formula I compound or its pharmacy acceptable salt, described compound has formula I-S structure:
Wherein:
B is selected from phenyl, the 2-thienyl, the 3-thienyl, the 2-furyl, the 3-furyl, the 2-pyrryl, the 3-pyrryl, the 2-imidazolyl, the 4-imidazolyl, the 3-pyrazolyl, the 4-pyrazolyl, 1,2,4-triazole-3-base, 1,2,4-triazole-5-base, 1,2,4-oxadiazole-3-base, 1,2,4-oxadiazole-5-base, 1,3,4-oxadiazole-3-base, 1,3,4-oxadiazole-5-base, the 3-isothiazolyl, the 5-isothiazolyl, the 2-oxazolyl, the 2-thiazolyl, the 3-isoxazolyl, the 5-isoxazolyl, the 2-pyridyl, the 3-pyridyl, the 4-pyridyl, the 2-pyrazinyl, the 2-pyrimidyl, the 4-pyrimidyl, the 5-pyrimidyl, the 3-pyridazinyl, the 4-pyridazinyl, 1,3,5-triazine-2-base, 1,2,4-triazine-3-base, 1,2,4-triazine-5-base, 1,2,4-triazine-6-base, 1,2,3-triazine-4-base and 1,2, the adjacent carbon of the carbon on the 3-triazine 5-base, one of them and tie point is randomly by R
32Replace, the adjacent carbon of the carbon on another and the tie point is randomly by R
36Replace, with R
32Adjacent and apart from the carbon of two atoms of the carbon on the tie point randomly by R
33Replace, with R
36Adjacent and apart from the carbon of two atoms of the carbon on the tie point randomly by R
35Replace any and R
33And R
35All adjacent carbon is randomly by R
34Replace;
R
32, R
33, R
34, R
35And R
36Be independently selected from hydrogen; amidino groups; guanidine radicals; carboxyl; methyl; ethyl; sec.-propyl; propyl group; methoxyl group; oxyethyl group; isopropoxy; propoxy-; hydroxyl; amino; methoxyl group amino; oxyethyl group amino; kharophen; trifluoroacetamido; nitro; amino methyl; the 1-amino-ethyl; the 2-amino-ethyl; the N-methylamino; dimethylamino; the N-ethylamino; methylthio group; ethylmercapto group; the iprotiazem base; trifluoromethylthio; trifluoromethyl; pentafluoroethyl group; 2; 2; the 2-trifluoroethyl; 2; 2; 3; 3; 3-five fluoropropyls; trifluoromethoxy; 1; 1; 2; 2-tetrafluoro oxyethyl group; fluorine; chlorine; bromine; the amido alkylsulfonyl; N-methyl amido alkylsulfonyl; N; N-dimethyl amido alkylsulfonyl; ethanoyl; propionyl; trifluoroacetyl group; five fluorine propionyls; methylol; the 1-hydroxyethyl; the 2-hydroxyethyl; 2; 2; 2-three fluoro-1-hydroxyethyls; 2; 2; 2-three fluoro-1-Trifluoromethyl-1-hydroxyethyls; carboxymethyl; methoxycarbonyl; ethoxycarbonyl; the amido carbonyl; N-methyl amido carbonyl; N, N-dimethyl amido carbonyl; cyano group and Q
b
B is selected from hydrogen, trimethyl silyl, ethyl, the 2-propenyl, 2-propynyl, propyl group, sec.-propyl, butyl, crotyl, the 3-butenyl, the 2-butyne base, sec-butyl, the tertiary butyl, isobutyl-, the 2-methylpropenyl, the 1-amyl group, pentenyl, the 3-pentenyl, the 4-pentenyl, the valerylene base, the 3-pentynyl, the 2-amyl group, 1-methyl-2-butene base, 1-methyl-3-butenyl, 1-methyl-2-butyne base, the 3-amyl group, 1-ethyl-2-propenyl, the 2-methyl butyl, 2-methyl-2-butene base, 2-methyl-3-butenyl, 2-methyl-3-butynyl, the 3-methyl butyl, 3-methyl-2-butene base, 3-methyl-3-butenyl, the 1-hexyl, the 2-hexenyl, the 3-hexenyl, the 4-hexenyl, the 5-hexenyl, 2-hexin base, 3-hexin base, 4-hexin base, the 2-hexyl, 1-methyl-pentenyl, 1-methyl-3-pentenyl, 1-methyl-4-pentenyl, 1-methyl-valerylene base, 1-methyl-3-pentynyl, the 3-hexyl, 1-ethyl-crotyl, 1-ethyl-3-butenyl, 1-propyl group-2-propenyl, 1-ethyl-2-butyne base, the 1-heptyl, the 2-heptenyl, the 3-heptenyl, the 4-heptenyl, the 5-heptenyl, the 6-heptenyl, 2-heptyne base, 3-heptyne base, 4-heptyne base, 5-heptyne base, the 2-heptyl, 1-methyl-2-hexenyl, 1-methyl-3-hexenyl, 1-methyl-4-hexenyl, 1-methyl-5-hexenyl, 1-methyl-2-hexin base, 1-methyl-3-hexin base, 1-methyl-4-hexin base, the 3-heptyl, 1-ethyl-pentenyl, 1-ethyl-3-pentenyl, 1-ethyl-4-pentenyl, 1-butyl-2-propenyl, 1-ethyl-valerylene base, 1-ethyl-3-pentynyl, the 1-octyl group, the 2-octenyl, the 3-octenyl, the 4-octenyl, the 5-octenyl, the 6-octenyl, the 7-octenyl, 2-octyne base, 3-octyne base, 4-octyne base, 5-octyne base, 6-octyne base, the 2-octyl group, 1-methyl-2-heptenyl, 1-methyl-3-heptenyl, 1-methyl-4-heptenyl, 1-methyl-5-heptenyl, 1-methyl-6-heptenyl, 1-methyl-2-heptyne base, 1-methyl-3-heptyne base, 1-methyl-4-heptyne base, 1-methyl-5-heptyne base, the 3-octyl group, 1-ethyl-2-hexenyl, 1-ethyl-3-hexenyl, 1-ethyl-4-hexenyl, 1-ethyl-2-hexin base, 1-ethyl-3-hexin base, 1-ethyl-4-hexin base, 1-ethyl-5-hexenyl, 1-amyl group-2-propenyl, the 4-octyl group, 1-propyl group-pentenyl, 1-propyl group-3-pentenyl, 1-propyl group-4-pentenyl, 1-butyl-crotyl, 1-propyl group-valerylene base, 1-propyl group-3-pentynyl, 1-butyl-2-butyne base, 1-butyl-3-butenyl, 2,2, the 2-trifluoroethyl, 2,2-two fluoropropyls, 4-trifluoromethyl-5,5,5-trifluoro amyl group, 4-trifluoromethyl amyl group, 5,5,6,6,6-five fluorine hexyls and 3,3, the 3-trifluoro propyl, wherein each member of group B randomly at distance B and A tie point nearly and comprise quilt-individual or a plurality of radicals R on any carbon of 5 atoms
32, R
33, R
34, R
35And R
36Replace;
B randomly is selected from cyclopropyl, cyclobutyl, trimethylene oxide-2-base, trimethylene oxide-3-base, azetidine-1-base, azetidine-2-base, azetidine-3-base, Thietane-2-base, Thietane-3-base, cyclopentyl, cyclohexyl, adamantyl, norcamphyl, 3-trifluoromethyl norcamphyl, 7-oxabicyclo [2.2.1] heptane-2-base, two ring [3.1.0] hexane-6-bases, suberyl, the ring octyl group, the 2-morpholinyl, morpholinyl, the 4-morpholinyl, the 1-piperazinyl, the 2-piperazinyl, piperidino, the 2-piperidyl, the 3-piperidyl, the 4-piperidyl, the 1-pyrrolidyl, the 2-pyrrolidyl, the 3-pyrrolidyl, the 2-alkyl dioxin, the 4H-2-pyranyl, the 4H-3-pyranyl, the 4H-4-pyranyl, 4H-pyrans-4-ketone-2-base, 4H-pyrans-4-ketone-3-base, the 2-tetrahydrofuran base, the 3-tetrahydrofuran base, the 2-THP trtrahydropyranyl, the 3-THP trtrahydropyranyl, the 4-THP trtrahydropyranyl, 2-tetrahydro-thienyl and 3-tetrahydro-thienyl, wherein each ring carbon is randomly by R
33Replace, ring carbon adjacent with carbon atom on the tie point and nitrogen-atoms are randomly by R
9Or R
13Replace, with R
9The position adjacent and apart from the ring carbon of two atoms of tie point or nitrogen-atoms randomly by R
10Replace, with R
13The position adjacent and apart from the ring carbon of two atoms of tie point or nitrogen-atoms randomly by R
12Replace;
R
9, R
10, R
11, R
12And R
13Be independently selected from hydrogen, amidino groups, guanidine radicals, carboxyl, carboxymethyl, methyl, ethyl, sec.-propyl, propyl group, methoxyl group, oxyethyl group, isopropoxy, propoxy-, hydroxyl, amino, methoxyl group amino, oxyethyl group amino, kharophen, trifluoroacetamido, nitro, amino methyl, the 1-amino-ethyl, the 2-amino-ethyl, the N-methylamino, dimethylamino, the N-ethylamino, methylthio group, ethylmercapto group, the iprotiazem base, trifluoromethylthio, trifluoromethyl, pentafluoroethyl group, 2,2, the 2-trifluoroethyl, 2,2,3,3,3-five fluoropropyls, trifluoromethoxy, 1,1,2,2-tetrafluoro oxyethyl group, fluorine, chlorine, bromine, methanesulfonamido, the amido alkylsulfonyl, N-methyl amido alkylsulfonyl, N, N-dimethyl amido alkylsulfonyl, ethanoyl, propionyl, trifluoroacetyl group, five fluorine propionyls, methylol, the 1-hydroxyethyl, the 2-hydroxyethyl, 2,2,2-three fluoro-1-hydroxyethyls, 2,2,2-three fluoro-1-Trifluoromethyl-1-hydroxyethyls, carboxymethyl, methoxycarbonyl, ethoxycarbonyl, the amido carbonyl, N-methyl amido carbonyl, N, N dimethyl amido carbonyl and cyano group;
A is selected from covalent single bond, O, S, NH, N (CH
3), N (OH), C (O), CH
2, CH
3CH, CF
3CH, NHC (O), N (CH
3) C (O), C (O) NH, C (O) N (CH
3), CF
3CC (O), C (O) CCH
3, C (O) CCF
3, CH
2C (O), (O) CCH
2, CH
2CH
2, CH
2CH
2CH
2, CH
3CHCH
2, CF
3CHCH
2, CH
3CC (O) CH
2, CF
3CC (O) CH
2, CH
2C (O) CCH
3, CH
2C (O) CCF
3, CH
2CH
2C (O) and CH
2(O) CCH
2
A randomly is selected from CH
2N (CH
3), CH
2N (CH
2CH
3), CH
2CH
2N (CH
3) and CH
2CH
2N (CH
2CH
3), its condition is that B is a hydrogen;
M is selected from N and R
1-C;
R
1Be selected from hydrogen, hydroxyl, amino, sulfydryl, amidino groups, hydroxyl amino, amino methyl, 1-amino-ethyl, 2-amino-ethyl, methylamino, dimethylamino, cyano group, methyl, ethyl, sec.-propyl, propyl group, trifluoromethyl, pentafluoroethyl group, 2,2,2-trifluoroethyl, 2,2,3,3,3-five fluoropropyls, methoxyl group, oxyethyl group, propoxy-, methylol, 1-hydroxyethyl, 2-hydroxyethyl, methoxyl group amino, oxyethyl group amino, methylthio group, ethylmercapto group, trifluoromethoxy, 1,1,2,2-tetrafluoro oxyethyl group, fluorine, chlorine and bromine;
R
2Be Z
0-Q;
Z
0Be selected from covalent single bond, O, S, NH, CH
2, CH
2CH
2, CH (OH), CH (NH
2), CH
2CH (OH), CH
2CHNH
2, CH (OH) CH
2And CH (NH
2) CH
2
Q is selected from phenyl, the 2-thienyl, the 3-thienyl, the 2-furyl, the 3-furyl, the 2-pyrryl, the 3-pyrryl, the 2-imidazolyl, the 4-imidazolyl, the 3-pyrazolyl, the 4-pyrazolyl, 1,2,4-triazole-3-base, 1,2,4-triazole-5-base, 1,2,4-oxadiazole-3-base, 1,2,4-oxadiazole-5-base, 1,3,4-oxadiazole-3-base, 1,3,4-oxadiazole-5-base, the 3-isothiazolyl, the 5-isothiazolyl, the 2-oxazolyl, the 2-thiazolyl, the 3-isoxazolyl, the 5-isoxazolyl, the 2-pyridyl, the 3-pyridyl, the 4-pyridyl, the 2-pyrazinyl, the 2-pyrimidyl, the 4-pyrimidyl, the 5-pyrimidyl, the 3-pyridazinyl, the 4-pyridazinyl, 1,3,5-triazine-2-base, 1,2,4-triazine-3-base, 1,2,4-triazine-5-base, 1,2,4-triazine-6-base, 1,2,3-triazine-4-base and 1,2, the adjacent carbon of the carbon on the 3-triazine 5-base, one of them and tie point is randomly by R
9Replace, the adjacent carbon of the carbon on another and the tie point is randomly by R
13Replace, with R
9Adjacent and apart from the carbon of two atoms of the carbon on the tie point randomly by R
10Replace, with R
13Adjacent and apart from the carbon of two atoms of the carbon on the tie point randomly by R
12Replace any and R
10And R
12All adjacent carbon is randomly by R
11Replace;
K is CHR
4a, R wherein
4aBe selected from methyl, ethyl, propyl group, sec.-propyl, methylol, 1-hydroxyethyl, methoxymethyl, trifluoromethyl, pentafluoroethyl group, 2,2,2-trifluoroethyl, methylthiomethyl and hydrogen;
E
0Be covalent single bond, C (O) N (H), (H) NC (O) and S (O)
2N (H);
Y
0Be selected from following formula:
R
16, R
17, R
18And R
19Be independently selected from hydrogen, methyl, ethyl, sec.-propyl, propyl group, amidino groups, guanidine radicals, carboxyl, methoxyl group, oxyethyl group, isopropoxy, propoxy-, hydroxyl, amino, methoxyl group amino, oxyethyl group amino, amino methyl, the 1-amino-ethyl, the 2-amino-ethyl, the N-methylamino, dimethylamino, the N-ethylamino, methylthio group, ethylmercapto group, the iprotiazem base, trifluoromethylthio, methylsulfinyl, the ethyl sulfinyl, methylsulfonyl, ethylsulfonyl, trifluoromethyl, pentafluoroethyl group, 2,2, the 2-trifluoroethyl, 2,2,3,3,3-five fluoropropyls, trifluoromethoxy, 1,1,2,2-tetrafluoro oxyethyl group, fluorine, chlorine, bromine, the amido alkylsulfonyl, N-methyl amido alkylsulfonyl, N, N-dimethyl amido alkylsulfonyl, ethanoyl, propionyl, trifluoroacetyl group, five fluorine propionyls, methylol, the 1-hydroxyethyl, the 2-hydroxyethyl, 2,2,2-three fluoro-1-hydroxyethyl and cyano group;
R
16And R
19Randomly be Q
b, its condition is R
16And R
19At the most one be Q simultaneously
b, Q
bBe Q
Be
Q
bBe selected from NR
20R
21, Q
Be, C (NR
25) NR
23R
24And N (R
26) C (NR
25) N (R
23) (R
24), Q wherein
BeBe hydrogen, its condition is R
20And R
21At the most one be hydroxyl, N-methylamino and N simultaneously, N-dimethylamino, R
23And R
24At the most one be hydroxyl, N-methylamino and N simultaneously, the N-dimethylamino;
R
20, R
21, R
23, R
24, R
25And R
26Be independently selected from hydrogen, methyl, ethyl, propyl group, butyl, sec.-propyl, hydroxyl, 2-amino-ethyl, 2-(N-methylamino) ethyl and 2-(N, N-dimethylamino) ethyl;
Q
sBe selected from covalent single bond, CH
2, CH
2CH
2, CH
3CH, CF
3CH, CH
3CHCH
2, CF
3CHCH
2, CH
2(CH
3) CH, CH=CH, CF=CH, C (CH
3)=CH, CH=CHCH
2, CF=CHCH
2, C (CH
3)=CHCH
2, CH
2CH=CH, CH
2CF=CH, CH
2C (CH
3)=CH, CH
2CH=CHCH
2, CH
2CF=CHCH
2, CH
2C (CH
3)=CHCH
2, CH
2CH=CHCH
2CH
2, CH
2CF=CHCH
2CH
2And CH
2C (CH
3)=CHCH
2CH
2
In the specific embodiments of preferred formula I compound or its pharmacy acceptable salt, described compound has formula I-MPS structure, and wherein B is an aromatic substituent:
Wherein:
B is selected from phenyl, 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyrryl, 3-pyrryl, 2-imidazolyl, 4-imidazolyl, 3-pyrazolyl, 4-pyrazolyl, 2-thiazolyl, 3-isoxazolyl, 5-isoxazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrazinyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, 3-pyridazinyl, 4-pyridazinyl and 1,3, the adjacent carbon of carbon on the 5-triazine-2-base, one of them and tie point is randomly by R
32Replace, the adjacent carbon of the carbon on another and the tie point is randomly by R
36Replace, with R
32Adjacent and apart from the carbon of two atoms of the carbon on the tie point randomly by R
33Replace, with R
36Adjacent and apart from the carbon of two atoms of the carbon on the tie point randomly by R
35Replace any and R
33And R
35All adjacent carbon is randomly by R
34Replace;
R
32, R
33, R
34, R
35And R
36Be independently selected from hydrogen; amidino groups; guanidine radicals; carboxyl; methoxyl group; oxyethyl group; isopropoxy; propoxy-; hydroxyl; amino; methoxyl group amino; oxyethyl group amino; kharophen; trifluoroacetamido; the N-methylamino; dimethylamino; the N-ethylamino; methylthio group; ethylmercapto group; the iprotiazem base; trifluoromethyl; pentafluoroethyl group; 2; 2; the 2-trifluoroethyl; 2; 2; 3; 3; 3-five fluoropropyls; trifluoromethoxy; 1; 1; 2; 2-tetrafluoro oxyethyl group; fluorine; chlorine; bromine; the amido alkylsulfonyl; N-methyl amido alkylsulfonyl; N; N-dimethyl amido alkylsulfonyl; methylol; the 1-hydroxyethyl; the 2-hydroxyethyl; 2; 2,2-three fluoro-1-hydroxyethyls; methoxycarbonyl; ethoxycarbonyl; the amido carbonyl; N-methyl amido carbonyl; N, N-dimethyl amido carbonyl; cyano group and Q
b
A is selected from covalent single bond, NH, N (CH
3), N (OH), CH
2, CH
3CH, CF
3CH, NHC (O), N (CH
3) C (O), C (O) NH, C (O) N (CH
3), CH
2CH
2, CH
2CH
2CH
2, CH
3CHCH
2And CF
3CHCH
2
Q
bBe selected from NR
20R
21, Q
BeAnd C (NR
25) NR
23R
24, Q wherein
BeBe hydrogen, its condition is R
20And R
21At the most one be hydroxyl simultaneously, R
23And R
24At the most one be hydroxyl simultaneously;
R
20, R
21, R
23, R
24And R
25Be independently selected from hydrogen, methyl, ethyl, propyl group, butyl, sec.-propyl and hydroxyl;
Q
sBe selected from covalent single bond, CH
2And CH
2CH
2
In the specific embodiments of the preferred formula I compound of another kind or its pharmacy acceptable salt, described compound has formula I-MPS structure, and wherein B is an acyclic family substituting group:
Wherein:
B is selected from hydrogen, ethyl, the 2-propenyl, 2-propynyl, propyl group, sec.-propyl, butyl, crotyl, the 3-butenyl, the 2-butyne base, sec-butyl, the tertiary butyl, isobutyl-, the 2-methylpropenyl, the 1-amyl group, pentenyl, the 3-pentenyl, the 4-pentenyl, the valerylene base, the 3-pentynyl, the 2-amyl group, 1-methyl-2-butene base, 1-methyl-3-butenyl, 1-methyl-2-butyne base, the 3-amyl group, 1-ethyl-2-propenyl, the 2-methyl butyl, 2-methyl-2-butene base, 2-methyl-3-butenyl, 2-methyl-3-butynyl, the 3-methyl butyl, 3-methyl-2-butene base, 3-methyl-3-butenyl, the 1-hexyl, the 2-hexenyl, the 3-hexenyl, the 4-hexenyl, the 5-hexenyl, 2-hexin base, 3-hexin base, 4-hexin base, the 2-hexyl, 1-methyl-pentenyl, 1-methyl-3-pentenyl, 1-methyl-4-pentenyl, 1-methyl-valerylene base, 1-methyl-3-pentynyl, the 3-hexyl, 1-ethyl-crotyl, 1-ethyl-3-butenyl, 1-propyl group-2-propenyl, 1-ethyl-2-butyne base, the 1-heptyl, the 2-heptenyl, the 3-heptenyl, the 4-heptenyl, the 5-heptenyl, the 6-heptenyl, 2-heptyne base, 3-heptyne base, 4-heptyne base, 5-heptyne base, the 2-heptyl, 1-methyl-2-hexenyl, 1-methyl-3-hexenyl, 1-methyl-4-hexenyl, 1-methyl-5-hexenyl, 1-methyl-2-hexin base, 1-methyl-3-hexin base, 1-methyl-4-hexin base, the 3-heptyl, 1-ethyl-pentenyl, 1-ethyl-3-pentenyl, 1-ethyl-4 pentenyl, 1-butyl-2-propenyl, 1-ethyl-valerylene base, 1-ethyl-3-pentynyl, 2,2, the 2-trifluoroethyl, 2,2-two fluoropropyls, 4-trifluoromethyl-5,5,5-trifluoro amyl group, 4-trifluoromethyl amyl group, 5,5,6,6,6-five fluorine hexyls and 3,3, the 3-trifluoro propyl, wherein each member of group B randomly at distance B and A tie point nearly and comprise on any carbon of 5 atoms by one or more radicals R
32, R
33, R
34, R
35And R
36Replace;
R
32, R
33, R
34, R
35And R
36Be independently selected from hydrogen; amidino groups; guanidine radicals; carboxyl; methoxyl group; oxyethyl group; isopropoxy; propoxy-; hydroxyl; amino; methoxyl group amino; oxyethyl group amino; kharophen; trifluoroacetamido; the N-methylamino; dimethylamino; the N-ethylamino; methylthio group; ethylmercapto group; the iprotiazem base; trifluoromethyl; pentafluoroethyl group; 2; 2; the 2-trifluoroethyl; 2; 2; 3; 3; 3-five fluoropropyls; trifluoromethoxy; 1; 1; 2; 2-tetrafluoro oxyethyl group; fluorine; chlorine; bromine; the amido alkylsulfonyl; N-methyl amido alkylsulfonyl; N; N-dimethyl amido alkylsulfonyl; methylol; the 1-hydroxyethyl; the 2-hydroxyethyl; 2; 2,2-three fluoro-1-hydroxyethyls; methoxycarbonyl; ethoxycarbonyl; the amido carbonyl; N-methyl amido carbonyl; N, N-dimethyl amido carbonyl; cyano group and Q
b
A is selected from covalent single bond, NH, N (CH
3), N (OH), CH
2, CH
3CH, CF
3CH, NHC (O), N (CH
3) C (O), C (O) NH, C (O) N (CH
3), CH
2CH
2, CH
2CH
2CH
2, CH
3CHCH
2And CF
3CHCH
2
A randomly is selected from CH
2N (CH
3), CH
2N (CH
2CH
3), CH
2CH
2N (CH
3) and CH
2CH
2N (CH
2CH
3), its condition is that B is a hydrogen;
Q
bBe selected from NR
20R
21, Q
Be, C (NR
25) NR
23R
24And N (R
26) C (NR
25) N (R
23) (R
24), Q wherein
BeBe hydrogen, its condition is R
20And R
21At the most one be hydroxyl simultaneously, R
23And R
24At the most one be hydroxyl simultaneously;
R
20, R
21, R
23, R
24, R
25And R
26Be independently selected from hydrogen, methyl, ethyl, propyl group, butyl, sec.-propyl and hydroxyl;
Q
sBe selected from covalent single bond, CH
2And CH
2CH
2
In the specific embodiments of the still preferred formula I compound of another kind or its pharmacy acceptable salt, described compound has formula I-MPS structure, and wherein B is non-aromatics cyclic substituents:
Wherein:
B randomly is selected from cyclopropyl, cyclobutyl, trimethylene oxide-3-base, azetidine-1-base, azetidine-2-base, azetidine-3-base, Thietane-3-base, cyclopentyl, cyclohexyl, norcamphyl, 7-oxabicyclo [2.2.1] heptane-2-base, two ring [3.1.0] hexane-6-bases, suberyl, the 2-morpholinyl, morpholinyl, the 4-morpholinyl, the 1-piperazinyl, the 2-piperazinyl, piperidino, the 2-piperidyl, the 3-piperidyl, the 4-piperidyl, the 1-pyrrolidyl, the 2-pyrrolidyl, the 3-pyrrolidyl, the 2-alkyl dioxin, the 4H-2-pyranyl, the 4H-3-pyranyl, the 4H-4-pyranyl, 4H-pyrans-4-ketone-2-base, 4H-pyrans-4-ketone-3-base, the 2-tetrahydrofuran base, the 3-tetrahydrofuran base, the 2-THP trtrahydropyranyl, the 3-THP trtrahydropyranyl, the 4-THP trtrahydropyranyl, 2-tetrahydro-thienyl and 3-tetrahydro-thienyl, wherein each ring carbon is randomly by R
33Replace, ring carbon adjacent with carbon atom on the tie point and nitrogen-atoms are randomly by R
9Or R
13Replace, with R
9The position adjacent and apart from the ring carbon of two atoms of tie point or nitrogen-atoms randomly by R
10Replace, with R
13The position adjacent and apart from the ring carbon of two atoms of tie point or nitrogen-atoms randomly by R
12Replace;
A is selected from covalent single bond, NH, N (CH
3), N (OH), CH
2, CH
3CH, CF
3CH, NHC (O), N (CH
3) C (O), C (O) NH, C (O) N (CH
3), CH
2CH
2, CH
2CH
2CH
2, CH
3CHCH
2And CF
3CHCH
2
R
33Be selected from hydrogen; amidino groups; guanidine radicals; carboxyl; methoxyl group; oxyethyl group; isopropoxy; propoxy-; hydroxyl; amino; methoxyl group amino; oxyethyl group amino; kharophen; trifluoroacetamido; the N-methylamino; dimethylamino; the N-ethylamino; methylthio group; ethylmercapto group; the iprotiazem base; trifluoromethyl; pentafluoroethyl group; 2; 2; the 2-trifluoroethyl; 2; 2; 3; 3; 3-five fluoropropyls; trifluoromethoxy; 1; 1; 2; 2-tetrafluoro oxyethyl group; fluorine; chlorine; bromine; the amido alkylsulfonyl; N-methyl amido alkylsulfonyl; N; N-dimethyl amido alkylsulfonyl; methylol; the 1-hydroxyethyl; the 2-hydroxyethyl; 2; 2,2-three fluoro-1-hydroxyethyls; methoxycarbonyl; ethoxycarbonyl; the amido carbonyl; N-methyl amido carbonyl; N, N-dimethyl amido carbonyl; cyano group and Q
b
Q
bBe selected from NR
20R
21, Q
BeAnd C (NR
25) NR
23R
24, Q wherein
BeBe hydrogen, its condition is R
20And R
21At the most one be hydroxyl simultaneously, R
23And R
24At the most one be hydroxyl simultaneously;
R
20, R
21, R
23, R
24And R
25Be independently selected from hydrogen, methyl, ethyl, propyl group, butyl, sec.-propyl and hydroxyl;
Q
sBe selected from covalent single bond, CH
2And CH
2CH
2
The specific embodiments of preferred The compounds of this invention or its pharmacy acceptable salt (I-MPS) has the following formula structure:
They have the common structural unit, wherein:
M is selected from N and R
1-C;
R
1Be selected from hydrogen, hydroxyl, amino, amidino groups, hydroxyl amino, amino methyl, 1-amino-ethyl, methylamino, dimethylamino, cyano group, methyl, ethyl, trifluoromethyl, pentafluoroethyl group, 2,2,2-trifluoroethyl, methoxyl group, methylol, 1-hydroxyethyl, 2-hydroxyethyl, methoxyl group amino, methylthio group, ethylmercapto group, trifluoromethoxy, 1,1,2,2-tetrafluoro oxyethyl group, fluorine, chlorine and bromine;
R
2Be Z
0-Q;
Z
0Be selected from covalent single bond, O, S, NH and CH
2
Q is selected from phenyl, 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyrryl, 3-pyrryl, 2-imidazolyl, 4-imidazolyl, 3-pyrazolyl, 4-pyrazolyl, 2-thiazolyl, 3-isoxazolyl, 5-isoxazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrazinyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, 3-pyridazinyl, 4-pyridazinyl and 1,3, carbon that carbon on the 5-triazine-2-base, one of them and tie point is adjacent or nitrogen are randomly by R
9Replace, carbon that the carbon on another and the tie point is adjacent or nitrogen are randomly by R
13Replace, with R
9Adjacent and apart from the carbon of two atoms of the carbon on the tie point or nitrogen randomly by R
10Replace, with R
13Adjacent and apart from the carbon of two atoms of the carbon on the tie point randomly by R
12Replace any and R
10And R
12All adjacent carbon is randomly by R
11Replace;
R
9, R
11And R
13Be independently selected from hydrogen, amidino groups, guanidine radicals, carboxyl, methyl, ethyl, propyl group, sec.-propyl, methoxyl group, oxyethyl group, isopropoxy, propoxy-, hydroxyl, amino, the N-methylamino, N, the N-dimethylamino, the N-ethylamino, methylthio group, ethylmercapto group, the iprotiazem base, trifluoromethyl, pentafluoroethyl group, 2,2, the 2-trifluoroethyl, 2,2,3,3,3-five fluoropropyls, trifluoromethoxy, 1,1,2,2-tetrafluoro oxyethyl group, fluorine, chlorine, bromine, methanesulfonamido, the amido alkylsulfonyl, N-methyl amido alkylsulfonyl, N, N-dimethyl amido alkylsulfonyl, methylol, the 1-hydroxyethyl, the 2-hydroxyethyl, 2,2,2-three fluoro-1-hydroxyethyls, the amido carbonyl, N-methyl amido carbonyl, N, N-dimethyl amido carbonyl and cyano group;
R
10And R
12Be independently selected from hydrogen, amidino groups, guanidine radicals, carboxyl, carboxymethyl, methyl, ethyl, propyl group, sec.-propyl, methoxyl group, oxyethyl group, isopropoxy, propoxy-, hydroxyl, amino, methoxyl group amino, oxyethyl group amino, kharophen, trifluoroacetamido, amino methyl, the 1-amino-ethyl, the 2-amino-ethyl, the N-methylamino, dimethylamino, the N-ethylamino, methanesulfonamido, the amido alkylsulfonyl, N-methyl amido alkylsulfonyl, N, N-dimethyl amido alkylsulfonyl, methylol, the 1-hydroxyethyl, the 2-hydroxyethyl, 2,2,2-three fluoro-1-hydroxyethyls, methoxycarbonyl, ethoxycarbonyl, the amido carbonyl, N-methyl amido carbonyl, N, N-dimethyl amido carbonyl, fluorine, chlorine, bromine and cyano group;
Y
0Be selected from following formula:
R
16, R
17, R
18And R
19Be independently selected from hydrogen, methyl, ethyl, sec.-propyl, propyl group, carboxyl, amidino groups, guanidine radicals, methoxyl group, oxyethyl group, isopropoxy, propoxy-, hydroxyl, amino, amino methyl, the 1-amino-ethyl, the 2-amino-ethyl, the N-methylamino, dimethylamino, the N-ethylamino, methylthio group, ethylmercapto group, the iprotiazem base, trifluoromethylthio, methylsulfinyl, the ethyl sulfinyl, methylsulfonyl, ethylsulfonyl, trifluoromethyl, pentafluoroethyl group, 2,2, the 2-trifluoroethyl, 2,2,3,3,3-five fluoropropyls, trifluoromethoxy, 1,1,2,2-tetrafluoro oxyethyl group, fluorine, chlorine, bromine, the amido alkylsulfonyl, N-methyl amido alkylsulfonyl, N, N-dimethyl amido alkylsulfonyl, methylol, the 1-hydroxyethyl, the 2-hydroxyethyl, 2,2,2-three fluoro-1-hydroxyethyl and cyano group;
R
16And R
19Randomly be Q
b, its condition is R
16And R
19At the most one be Q simultaneously
b, Q
bBe Q
Be
In the specific embodiments of most preferred formula I compound or its pharmacy acceptable salt, described compound has formula I-EMPS structure, and wherein B is an aromatic substituent:
Wherein:
B is selected from phenyl, 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyrryl, 3-pyrryl, 2-imidazolyl, 4-imidazolyl, 3-pyrazolyl, 4-pyrazolyl, 2-thiazolyl, 3-isoxazolyl and 5-isoxazolyl, and the adjacent carbon of the carbon on one of them and the tie point is randomly by R
32Replace, the adjacent carbon of the carbon on another and the tie point is randomly by R
36Replace, with R
32Adjacent and apart from the carbon of two atoms of the carbon on the tie point randomly by R
33Replace, with R
36Adjacent and apart from the carbon of two atoms of the carbon on the tie point randomly by R
35Replace any and R
33And R
35All adjacent carbon is randomly by R
34Replace;
R
32, R
33, R
34, R
35And R
36Be independently selected from hydrogen, amidino groups, guanidine radicals, methyl, ethyl, methoxyl group, oxyethyl group, hydroxyl, amino, N-methylamino, dimethylamino, methylthio group, ethylmercapto group, trifluoromethyl, pentafluoroethyl group, 2; 2,2-trifluoroethyl, fluorine, chlorine, bromine, amido alkylsulfonyl, N-methyl amido alkylsulfonyl, methylol, amido carbonyl, carboxyl, cyano group and Q
b
A is selected from covalent single bond, NH, N (CH
3), CH
2, CH
3CH and CH
2CH
2
Q
bBe selected from NR
20R
21And C (NR
25) NR
23R
24, condition is described Q
bDirect and the carbon atom bonding of group;
R
20, R
21, R
23, R
24And R
25Be independently selected from hydrogen, methyl and ethyl;
Q
sBe CH
2
In the specific embodiments of the most preferred formula I compound of another kind or its pharmacy acceptable salt, described compound has formula I-EMPS structure, and wherein B is non-cyclic substituents:
Wherein:
B is selected from hydrogen, ethyl, the 2-propenyl, 2-propynyl, propyl group, sec.-propyl, butyl, crotyl, the 2-butyne base, sec-butyl, the tertiary butyl, isobutyl-, the 2-methylpropenyl, the 1-amyl group, pentenyl, the 3-pentenyl, the valerylene base, the 3-pentynyl, the 2-amyl group, the 3-amyl group, the 2-methyl butyl, 2-methyl-2-butene base, the 3-methyl butyl, 3-methyl-2-butene base, the 1-hexyl, the 2-hexenyl, the 3-hexenyl, the 4-hexenyl, 2-hexin base, 3-hexin base, 4-hexin base, the 2-hexyl, 1-methyl-pentenyl, 1-methyl-3-pentenyl, 1-methyl-valerylene base, 1-methyl-3-pentynyl, the 3-hexyl, 1-ethyl-crotyl, the 1-heptyl, the 2-heptenyl, the 3-heptenyl, the 4-heptenyl, the 5-heptenyl, 2-heptyne base, 3-heptyne base, 4-heptyne base, 5-heptyne base, the 2-heptyl, 1-methyl-2-hexenyl, 1-methyl-3-hexenyl, 1-methyl-4-hexenyl, 1-methyl-2-hexin base, 1-methyl-3-hexin base, 1-methyl-4-hexin base, the 3-heptyl, 1-ethyl-pentenyl, 1-ethyl-3-pentenyl, 1-ethyl-valerylene base, 1-ethyl-3-pentynyl, 2,2, the 2-trifluoroethyl, 2,2-two fluoropropyls, 4-trifluoromethyl-5,5,5-trifluoro amyl group, 4-trifluoromethyl amyl group, 5,5,6,6,6-five fluorine hexyls and 3,3, the 3-trifluoro propyl, wherein each member of group B randomly at distance B and A tie point nearly and comprise on any carbon of 5 atoms by one or more radicals R
32, R
33, R
34, R
35And R
36Replace;
R
32, R
33, R
34, R
35And R
36Be independently selected from hydrogen, amidino groups, guanidine radicals, methyl, ethyl, methoxyl group, oxyethyl group, hydroxyl, amino, N-methylamino, dimethylamino, methylthio group, ethylmercapto group, trifluoromethyl, pentafluoroethyl group, 2; 2,2-trifluoroethyl, fluorine, chlorine, bromine, amido alkylsulfonyl, N-methyl amido alkylsulfonyl, methylol, amido carbonyl, carboxyl, cyano group and Q
b
A is selected from covalent single bond, NH, N (CH
3), CH
2, CH
3CH and CH
2CH
2
A randomly is selected from CH
2N (CH
3), CH
2N (CH
2CH
3), CH
2CH
2N (CH
3) and CH
2CH
2N (CH
2CH
3), its condition is that B is a hydrogen;
Q
bBe selected from NR
20R
21, C (NR
25) NR
23R
24And N (R
26) C (NR
25) N (R
23) (R
24), its condition is described Q
bDirect and the carbon atom bonding of group;
R
20, R
21, R
23, R
24, R
25And R
26Be independently selected from hydrogen, methyl and ethyl;
Q
sBe CH
2
In the specific embodiments of the still most preferred formula I compound of another kind or its pharmacy acceptable salt, described compound has formula I-EMPS structure, wherein the aromatic ring-shaped substituting group of B right and wrong:
Wherein:
B randomly is selected from cyclopropyl, cyclobutyl, trimethylene oxide-3-base, azetidine-3-base, Thietane-3-base, cyclopentyl, cyclohexyl, 1-pyrrolidyl, 2-pyrrolidyl, 3-pyrrolidyl, 2-tetrahydrofuran base, 3-tetrahydrofuran base, 2-tetrahydro-thienyl and 3-tetrahydro-thienyl, and wherein each ring carbon is randomly by R
33Replace, ring carbon adjacent with carbon atom on the tie point and nitrogen-atoms are randomly by R
9Or R
13Replace, with R
9The position adjacent and apart from the ring carbon of two atoms of tie point or nitrogen-atoms randomly by R
10Replace, with R
13The position adjacent and apart from the ring carbon of two atoms of tie point or nitrogen-atoms randomly by R
12Replace;
R
33Be independently selected from hydrogen, amidino groups, guanidine radicals, methyl, ethyl, methoxyl group, oxyethyl group, hydroxyl, carboxyl, amino, N-methylamino, dimethylamino, methylthio group, ethylmercapto group, trifluoromethyl, pentafluoroethyl group, 2; 2,2-trifluoroethyl, fluorine, chlorine, bromine, amido alkylsulfonyl, N-methyl amido alkylsulfonyl, methylol, amido carbonyl, cyano group and Q
b
A is selected from covalent single bond, NH, N (CH
3), CH
2, CH
3CH and CH
2CH
2
Q
bBe selected from NR
20R
21And C (NR
25) NR
23R
24, its condition is described Q
bDirect and the carbon atom bonding of group;
R
20, R
21, R
23, R
24And R
25Be independently selected from hydrogen, methyl and ethyl;
Q
sBe CH
2
The specific embodiments of most preferred The compounds of this invention or its pharmacy acceptable salt (I-EMPS) has the following formula structure:
They have the common structural unit, wherein:
M is selected from N and R
1-C;
R
1Be selected from hydrogen, hydroxyl, amino, amidino groups, hydroxyl amino, amino methyl, methylamino, cyano group, methyl, trifluoromethyl, methoxyl group, methylol, methoxyl group amino, methylthio group, trifluoromethoxy, fluorine and chlorine;
R
2Be Z
0-Q;
Z
0It is covalent single bond;
Q is selected from phenyl, 2-thienyl, 2-furyl, 2-pyrryl, 2-imidazolyl, 2-thiazolyl, 3-isoxazolyl, 2-pyridyl and 3-pyridyl, and the adjacent carbon of the carbon on one of them and the tie point is randomly by R
9Replace, the adjacent carbon of the carbon on another and the tie point is randomly by R
13Replace, with R
9Adjacent and apart from the carbon of two atoms of the carbon on the tie point randomly by R
10Replace, with R
13Adjacent and apart from the carbon of two atoms of the carbon on the tie point randomly by R
12Replace any and R
10And R
12All adjacent carbon is randomly by R
11Replace;
R
9, R
11And R
13Be independently selected from hydrogen, methyl, ethyl, methoxyl group, oxyethyl group, hydroxyl, amino, N-methylamino, N, N-dimethylamino, methylthio group, trifluoromethyl, pentafluoroethyl group, 2,2,2-trifluoroethyl, fluorine, chlorine, bromine, amido alkylsulfonyl, N-methyl amido alkylsulfonyl, N, N-dimethyl amido alkylsulfonyl, methylol, 1-hydroxyethyl, amido carbonyl, N-methyl amido carbonyl, carboxyl and cyano group;
R
10And R
12Be independently selected from hydrogen, amidino groups, amido carbonyl, N-methyl amido carbonyl, guanidine radicals, methyl, ethyl, methoxyl group, oxyethyl group, hydroxyl, methylol, 1-hydroxyethyl, 2-hydroxyethyl, carboxyl, carboxymethyl, amino, kharophen, trifluoromethyl, pentafluoroethyl group, 2,2,2-trifluoroethyl, trifluoroacetamido, amino methyl, N-methylamino, dimethylamino, amido alkylsulfonyl, N-methyl amido alkylsulfonyl, N, N-dimethyl amido alkylsulfonyl, methoxycarbonyl, fluorine, chlorine, bromine and cyano group;
Y
0Be selected from following formula:
R
16, R
17, R
18And R
19Be independently selected from hydrogen, methyl, ethyl, amidino groups, guanidine radicals, methoxyl group, hydroxyl, amino, amino methyl, 1-amino-ethyl, 2-amino-ethyl, N-methylamino, dimethylamino, methylthio group, ethylmercapto group, trifluoromethylthio, methylsulfinyl, methylsulfonyl, trifluoromethyl, pentafluoroethyl group, 2; 2,2-trifluoroethyl, trifluoromethoxy, fluorine, chlorine, amido alkylsulfonyl, N-methyl amido alkylsulfonyl, methylol, carboxyl and cyano group.
The compounds of this invention can be used for anticoagulant therapy, is used for the treatment and the prevention of various thrombosis diseases, comprises coronary artery and cerebrovascular disease.The compounds of this invention can be used to suppress and coagulation cascade and the factor-related serine protease of II, VII, VIII, IX, X, XI or XII.The compounds of this invention can be in Mammals, blood, blood products and mammalian organs the anticoagulant thing formation, suppress fibrinous formation, suppress the formation of thrombus and suppress the formation of embolus.These compounds also can be used for the treatment of or prevent Mammals unstable angina pectoris, intractable angina pectoris, myocardial infarction, transient ischemic attack, auricular fibrillation, thrombus apoplexy, embolus apoplexy, venous thrombosis, disseminated inravascular coagulation, eye scleroproein to stop up and the obturation again or the restenosis of break-through blood vessel again.These compounds also can be used to face the curee's who develops into these illness danger preventative processing.These compounds can be used to reduce atherosclerotic danger.Formula (I) compound also will be useful in the prevention of cerebrovascular accident (CVA) or apoplexy.
Except the treatment that can be used for the people, these compounds also can be used for the veterinary treatment of pet, external animal and livestock, comprise Mammals, rodent etc.Preferred animal comprises horse, dog and cat.
Again in the embodiment, the compound of described novelty is selected from embodiment 1 to embodiment 7 described compound in the present invention.
For clarity sake, define the usage of general terms in specification sheets of compound here.
Except as otherwise noted, the single-letter symbol of element of standard is used to represent the concrete kind of atom.Symbol " C " is represented carbon atom.Symbol " O " represention oxygen atom.Symbol " N " is represented nitrogen-atoms.Symbol " P " phosphor atom.Symbol " S " is represented sulphur atom.Symbol " H " is represented hydrogen atom.The biliteral symbol of element is used for the element (that is, Cl represents chlorine, and Se represents selenium etc.) of delimiting period table.
Terminology used here " alkyl " contains 1 to about 10 carbon atoms separately or at other terms, for example represent the non-annularity alkyl group in " haloalkyl " and " alkylthio ", is preferably 3 to about 8 carbon atoms, and more preferably 3 to about 6 carbon atoms.Described alkyl can randomly be replaced by following defined group.This class examples of groups comprises methyl, ethyl, chloroethyl, hydroxyethyl, n-propyl, oxopropyl, sec.-propyl, normal-butyl, cyano group butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, amino amyl group, isopentyl, hexyl, octyl group etc.
Term " thiazolinyl " refers to undersaturated non-annularity alkyl, and it contains at least one two key.This class alkenyl group contains has an appointment 2 to about 10 carbon atoms, is preferably about 3 to about 8 carbon atoms, and more preferably 3 to about 6 carbon atoms.Described thiazolinyl can randomly be replaced by following defined group.The example of the alkenyl group that is fit to comprises propenyl, 2-Chloroallyl, butene-1-Ji, isobutenyl, amylene-1-base, 2-methyl butene-1-base, 3-methyl butene-1-base, hexene-1-base, 3-hydroxyl hexene-1-base, heptene-1-base and octene-1-Ji etc.
Term " alkynyl " refers to undersaturated non-annularity alkyl, and it contains at least one three key.This class group contains has an appointment 2 to about 10 carbon atoms, is preferably about 3 to about 8 carbon atoms, and more preferably 3 to about 6 carbon atoms.Described alkynyl can randomly be replaced by following defined group.The example of the alkynyl group that is fit to comprises ethynyl, proyl, hydroxypropyn base, butine-1-base, crotonylene-Ji, pentyne-1-base, pentyne-2-base, 4-methoxyl group pentyne-2-base, 3-methyl butine-1-base, hexin-1-base, hexin-2-base, hexin-3-base, 3,3-dimethyl butine-1-base group etc.
Single hydrogen atom (H) represented in term " hydrogen ".This hydrogen atom for example can be connected to form " hydroxyl " with Sauerstoffatom, and a hydrogen atom can be connected to form " methyne "-CH=with carbon atom, and perhaps two hydrogen groups can be connected to form " methylene radical " (CH with carbon atom
2-).
Term " carbon " group is represented without any covalent linkage and can be formed the carbon atom of four covalent linkage.
Three carbon-based groups of sharing with nitrogen-atoms in four covalent linkage of term " cyano group " expression.
The group that any one or a plurality of alkyl carbon atoms are replaced by hydroxyl as defined above contained in term " hydroxyalkyl ".Specifically contain monohydroxy alkyl, dihydroxyl alkyl and polyhydroxy alkyl group.
Term " alkyloyl " is contained wherein one or more end alkyl carbon atoms by the group of one or more following defined carbonyl substituted.Specifically contain a carbonylic alkyl and dicarbapentaborane alkyl.The example of one carbonylic alkyl comprises formyl radical, ethanoyl and pentanoyl.The example of dicarbapentaborane alkyl comprises oxalyl group, malonyl and succinyl.
Term " alkylidene group " expression has 1 to about 10 carbon atoms and have the straight or branched group of two or more covalent linkage tie points.This class examples of groups is methylene radical, ethylidene, methyl ethylidene and isopropylidene.
Term " alkenylene " expression has 2 to about 10 carbon atoms, at least one two key and have the straight or branched group of two or more covalent linkage tie points.This class examples of groups is 1,1-vinylidene (CH
2=C), (CH=CH-) and 1, the 4-butadienyl is (CH=CH-CH=CH-) for vinylene.
Term " halogen " expression halogen atom, for example fluorine, chlorine, bromine or iodine atom.
The group that any one or a plurality of alkyl carbon atoms are replaced by halogen as defined above contained wherein in term " haloalkyl ".Specifically contain a haloalkyl, dihalo alkyl and multi-haloalkyl group.One halogenated alkyl group for example can have bromine, chlorine or a fluorine atom in group.The dihalo alkyl can have the combination of two or more identical halogen atoms or different halogen groups, and the multi-haloalkyl group can have the combination of identical halogen atom more than two or different halogen groups.Preferred halogenated alkyl group is to have " low-grade halogenated alkyl " group to about six carbon atom.The example of this class halogenated alkyl group comprises methyl fluoride, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, trifluoroethyl, pentafluoroethyl group, seven fluoropropyls, difluoro chloromethyl, dichlorofluoromethyl, two fluoro ethyls, two fluoropropyls, Dichloroethyl and two chloropropyls.
The group that any one or a plurality of haloalkyl carbon atom are replaced by hydroxyl as defined above contained wherein in term " hydroxy halogeno alkyl "." hydroxy halogeno alkyl " examples of groups comprises the hexafluoro hydroxypropyl.
Term " halo alkylidene group " expression is the alkylidene group that replaced by halogen as defined above of any one or a plurality of alkylidene group carbon atom wherein.The dihalo alkylidene group can have the combination of two or more identical halogen atoms or different halogen groups, and many halos alkylidene group can have the combination of identical halogen atom more than two or different halogen groups.Preferred halo alkylidene group is to have " lower halogenated alkylidene group " group to about six carbon atom." halo alkylidene group " examples of groups comprises a fluorine methylene radical of difluoro methylene, tetrafluoro ethylidene, tetrachloro ethylidene, alkyl replacement and the trifluoro methylene radical that aryl replaces.
Term " haloalkenyl group " expression has 1 to about 10 carbon atoms and have the straight or branched group of one or more pairs of keys, and wherein any one or a plurality of thiazolinyl carbon atom are replaced by halogen as defined above.The dihalo alkenyl group can have the combination of two or more identical halogen atoms or different halogen groups, and many haloalkenyl groups group can have the combination of identical halogen atom more than two or different halogen groups.
Term " alkoxyl group " and " alkoxyalkyl " are contained the straight or branched oxy radical, have the moieties of one to about ten carbon atom separately, for example methoxy group.The alkyl group that is connected with one or more alkoxy bases also contained in term " alkoxyalkyl ", just forms an alkoxyalkyl and dialkoxy alkyl group.Preferred alkoxy base is to have " lower alkoxy " group to six carbon atom.This class examples of groups comprises methoxyl group, oxyethyl group, propoxy-, butoxy, isopropoxy and tert.-butoxy." alkoxyl group " group can further be replaced by one or more halogen atoms, and for example fluorine, chlorine or bromine form " halogenated alkoxy " and " halogenated alkoxy alkyl " group.The example of this class halo alkoxy group comprises fluorine methoxyl group, chlorine methoxyl group, trifluoromethoxy, difluoro-methoxy, trifluoro ethoxy, fluorine oxyethyl group, tetrafluoro oxyethyl group, five fluorine oxyethyl groups and fluorine propoxy-.This class halogenated alkoxy alkyl examples of groups comprises fluorine methoxymethyl, chlorine methoxy ethyl, trifluoromethoxy methyl, difluoro-methoxy ethyl and trifluoro ethoxy methyl.
Term " alkene oxygen base " and " alkene oxygen base alkyl " are contained the straight or branched oxy radical, have the alkenyl part of two to about ten carbon atoms separately, for example vinyloxy group or propenyloxy group group.The alkyl group that is connected with one or more alkene oxygen base groups also contained in term " alkene oxygen base alkyl ", just forms an alkene oxygen base alkyl and diene oxygen base alkyl group.Preferred alkene oxygen base group is to have two " rudimentary alkene oxygen base " groups to six carbon atom.This class examples of groups comprises vinyloxy group, propenyloxy group, butenyloxy and different propenyloxy group alkyl." alkene oxygen base " group can further be replaced by one or more halogen atoms, and for example fluorine, chlorine or bromine obtain " haloalkene oxygen base " group.This class examples of groups comprises trifluoro-ethylene oxygen base, vinyl fluoride oxygen base, difluoroethylene oxygen base and fluorine propenyloxy group.
The alkyl group that is connected with one or more halo alkoxy groups also contained in term " halogenated alkoxy alkyl ", just forms a halogenated alkoxy alkyl and dihalo alcoxyl base alkyl group.The oxygen groups that is connected with one or more haloalkene oxygen base groups also contained in term " haloalkene oxygen base ", just forms a haloalkene oxygen base and dihalo alkene oxygen base group.The alkyl group that is connected with one or more haloalkene oxygen base groups also contained in term " haloalkene oxygen base alkyl ", just forms a haloalkene oxygen base alkyl and dihalo alkene oxygen base alkyl group.
Term " alkylene dioxo base " group is represented the alkylidene group of at least two oxygen and single alkylidene group bonding." alkylene dioxo base " examples of groups comprises the methylene-dioxy of methylene-dioxy, ethylenedioxy, alkyl replacement and the methylene-dioxy that aryl replaces.Term " halo alkylene dioxo base " group is represented the halo alkylidene group of at least two oxygen bases and single halo alkylidene group bonding." halo alkylene dioxo base " examples of groups comprises a fluorine methylene-dioxy of difluoro methylene-dioxy, tetrafluoro ethylenedioxy, tetrachloro ethylenedioxy, alkyl replacement and the fluorine methylene-dioxy that aryl replaces.
Term " aryl " expression separately or in combination contains the carbocyclic ring aroma system of one, two or three ring, and wherein these rings can link together or can be condensed by hang.Term " condenses " second ring of expression and has (promptly be connected or form) by shared with first ring (promptly shared) two adjacent atoms.Term " condenses " and equals term " condensed ring ".Aromatic group contained in term " aryl ", for example phenyl, naphthyl, tetralyl, indane and biphenyl.
The aromatic group that aromatic yl group is wherein replaced by 3 or a plurality of following defined halogen group, for example phenyl, naphthyl, tetralyl, indane and biphenyl contained in term " perhalogeno aryl ".
What saturated and fractional saturation contained in term " heterocyclic radical " contains heteroatoms ring-type group, has 4 to 15 ring memberses that are selected from carbon, nitrogen, sulphur and oxygen, is referred to as " C4-C15 heterocyclic radical " here, and wherein at least one annular atoms is a heteroatoms.The heterocyclic radical group can contain one, two or three ring, and wherein these rings can or can be condensed by the hang connection.The example of saturated heterocyclic group comprises saturated 3 to the 6 yuan of monocyclic heterocyclic groups (for example pyrrolidyl, imidazolidyl, piperidino-(1-position only), piperazinyl etc.) that contain 1 to 4 nitrogen-atoms; Saturated 3 to the 6 yuan of monocyclic heterocyclic groups (for example morpholinyl etc.) that contain 1 to 2 Sauerstoffatom and 1 to 3 nitrogen-atoms; Saturated 3 to the 6 yuan of monocyclic heterocyclic groups (for example thiazolidyl etc.) that contain 1 to 2 sulphur atom and 1 to 3 nitrogen-atoms.The heterocyclic radical examples of groups of fractional saturation comprises dihydro-thiophene, dihydropyrane, dihydrofuran and thiazoline.The limiting examples of heterocyclic group comprises 2-pyrrolinyl, 3-pyrrolinyl, pyrrolidyl, 1,3-dioxolanyl, 2H-pyranyl, 4H-pyranyl, piperidyl, 1,4-alkyl dioxin, morpholinyl, 1,4-dithiane base, thio-morpholinyl etc.
The undersaturated heteroatoms ring-type aromatic group that contains fully contained in term " heteroaryl ", has 5 to 15 ring memberses that are selected from carbon, nitrogen, sulphur and oxygen, and wherein at least one annular atoms is a heteroatoms.Heteroaryl groups can contain one, two or three ring, and wherein these rings can or can be condensed by the hang connection." heteroaryl " examples of groups comprises unsaturated 5 to the 6 yuan of monocyclic heterocyclic groups that contain 1 to 4 nitrogen-atoms, pyrryl, pyrrolinyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (4H-1 for example for example, 2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl etc.), tetrazyl (for example 1H-tetrazyl, 2H-tetrazyl etc.) etc.; The unsaturated annelated heterocycles group that contains 1 to 5 nitrogen-atoms, for example indyl, pseudoindoyl, indolizine base (indolizinyl), benzimidazolyl-, quinolyl, isoquinolyl, indazolyl, benzotriazole base, tetrazolo pyridazinyl (for example tetrazolo [1,5-b] pyridazinyl etc.) etc.; Unsaturated 3 to the 6 yuan of monocyclic heterocyclic groups that contain Sauerstoffatom, for example pyranyl, 2-furyl, 3-furyl etc.; Unsaturated 5 to 6 yuan of monocyclic heterocyclic groups, for example 2-thienyl, the 3-thienyls etc. that contain sulphur atom; Unsaturated 5 to the 6 yuan of monocyclic heterocyclic groups that contain 1 to 2 Sauerstoffatom and 1 to 3 nitrogen-atoms, Li such as oxazolyl, isoxazolyl, oxadiazole base (for example 1,2,4-oxadiazole base, 1,3,4-oxadiazole base, 1,2,5-oxadiazole base etc.) etc.; The unsaturated annelated heterocycles group (for example benzoxazolyl, Ben Bing oxadiazole base etc.) that contains 1 to 2 Sauerstoffatom and 1 to 3 nitrogen-atoms; Unsaturated 5 to the 6 yuan of monocyclic heterocyclic groups that contain 1 to 2 sulphur atom and 1 to 3 nitrogen-atoms, for example thiazolyl, thiadiazolyl group (for example 1,2,4-thiadiazolyl group, 1,3,4-thiadiazolyl group, 1,2,5-thiadiazolyl group etc.) etc.; Contain the unsaturated annelated heterocycles group (for example benzothiazolyl, diazosulfide base etc.) of 1 to 2 sulphur atom and 1 to 3 nitrogen-atoms etc.Wherein heterocyclic group and aromatic yl group condensed group also contained in this term.This class fused bicyclic examples of groups comprises cumarone, thionaphthene etc.Described " heterocyclic radical " can have 1 to 3 following defined substituting group.Preferred heterocyclic group comprises that five to ten binary condense or the group of non-condensed.The limiting examples of heteroaryl groups comprises pyrryl, pyridyl, pyridyloxy, pyrazolyl, triazolyl, pyrimidyl, pyridazinyl oxazolyl, thiazolyl, imidazolyl, indyl, thienyl, furyl, tetrazyl, the 2-imidazolinyl, imidazolidyl, the 2-pyrazolinyl, pyrazolidyl isoxazolyl, isothiazolyl, 1,2,3-oxadiazole base, 1,2, the 3-triazolyl, 1,3, the 4-thiadiazolyl group, pyrazinyl, piperazinyl, 1,3, the 5-triazinyl, 1,3,5-trithian base, benzo (b) thienyl, benzimidazolyl-, quinolyl, tetrazyl etc.
No matter term " alkylsulfonyl " is singly used still and other term couplings, and for example alkyl sulphonyl is all represented divalent group-SO respectively
2-." alkyl sulphonyl " contains the alkyl group that is connected with the alkylsulfonyl group, and wherein alkyl is as defined above." alkyl sulfonyl alkyl " contains the alkyl sulphonyl group that is connected with alkyl group, and wherein alkyl is as defined above." halogenated alkyl sulfonyl " contains the halogenated alkyl group that is connected with the alkylsulfonyl group, and wherein haloalkyl is as defined above." haloalkyl sulphonyl alkyl " contains the halogenated alkyl sulfonyl group that is connected with alkyl group, and wherein alkyl is as defined above.The amino group that term " amino-sulfonyl " expression is connected with the alkylsulfonyl group.
No matter single term " sulfinyl " with still and other term couplings, alkyl sulphinyl for example, all represent respectively divalent group-S (O)-." alkyl sulphinyl " contains the alkyl group that is connected with the sulfinyl group, and wherein alkyl is as defined above." alkyl sulfenyl alkyl " contains the alkyl sulphinyl group that is connected with alkyl group, and wherein alkyl is as defined above." haloalkyl sulfinyl " contains the halogenated alkyl group that is connected with the sulfinyl group, and wherein haloalkyl is as defined above." haloalkyl sulfinyl alkyl " contains the haloalkyl sulfinyl group that is connected with alkyl group, and wherein alkyl is as defined above.
The alkyl group of term " aralkyl " encompass aryl-replacement.Preferred aromatic alkyl group is " rudimentary aralkyl " group, aromatic yl group wherein with have an alkyl group to six carbon atom and be connected.This class examples of groups comprises benzyl, diphenyl-methyl, trityl, styroyl and two styroyls.Term benzyl and phenmethyl are interchangeable.
The alkyl group of heteroaryl-replacement contained in term " heteroaralkyl ", and wherein the heteroaralkyl group can as above be replaced about the defined substituting group of aromatic alkyl group by three or more in addition.The alkyl group that term " perhalogeno aralkyl " encompass aryl replaces, wherein aromatic alkyl group is replaced by three or more halogen groups as defined above.
The aromatic alkyl group that is connected with the sulfinyl group contained in term " aralkyl sulfinyl ", and wherein aralkyl is as defined above." aralkyl sulfinyl alkyl " contains the aralkyl sulfinyl group that is connected with alkyl group, and wherein alkyl is as defined above.
The aromatic alkyl group that is connected with the alkylsulfonyl group contained in term " aralkyl alkylsulfonyl ", and wherein aralkyl is as defined above." aralkyl sulphonyl alkyl " contains the aralkyl alkylsulfonyl group that is connected with alkyl group, and wherein alkyl is as defined above.
The group with 3 to 15 carbon atoms contained in term " cycloalkyl ".Preferred group of naphthene base is " low-grade cycloalkyl " group with three to seven carbon atoms.Example comprises such as groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and suberyl.The term cycloalkyl contains the group that has 7 to 15 carbon atoms and have two to four rings.Example comprises such as groups such as norcamphyl (i.e. two ring [2.2.1] heptyl) and adamantyls.The alkyl group of cycloalkyl-replacement contained in term " cycloalkylalkyl ".Preferred cycloalkylalkyl group is " low-grade cycloalkyl alkyl " group, group of naphthene base wherein with have an alkyl group to six carbon atom and be connected.This class examples of groups comprises the cyclohexyl hexyl.The group with three to ten carbon atoms and one or more carbon-to-carbon double bonds contained in term " cycloalkenyl group ".Preferred cycloalkenyl groups is " lower alkenyl ring " group with three to seven carbon atoms.Example comprises such as groups such as cyclobutene base, cyclopentenyl, cyclohexenyl and cycloheptenyl.The group that any one or a plurality of cycloalkyl carbon atom are replaced by halogen as defined above contained wherein in term " halogenated cycloalkyl ".Specifically contain a halogenated cycloalkyl, dihalo cycloalkyl and many halogenated cycloalkyls group.One halogenated cycloalkyl for example can have bromine, chlorine or a fluorine atom in group.The dihalo group can have the combination of two or more identical halogen atoms or different halo groups, and many halos group can have the combination of identical halogen atom more than two or different halogen groups.Preferred halogenated cycloalkyl group is to have three " lower halogenated cycloalkyl " groups to about eight carbon atoms.This class halogenated cycloalkyl examples of groups comprises fluoro cyclopropyl, difluoro cyclobutyl, trifluoro cyclopentyl, ptfe ring hexyl and dichloro cyclopropyl.The group that any one or a plurality of cycloalkenyl group carbon atom are replaced by halogen as defined above contained wherein in term " halo cycloalkenyl group ".Specifically contain a halo cycloalkenyl group, dihalo cycloalkenyl group and many halos cycloalkenyl groups.
The group of naphthene base that is connected with oxygen base group contained in term " cycloalkyloxy ".This class examples of groups comprises cyclohexyloxy and cyclopentyloxy.The alkyl group that is connected with one or more cycloalkyloxy groups also contained in term " cycloalkyloxy alkyl ", just forms a cycloalkyloxy alkyl and two cycloalkyloxy alkyl groups.This class examples of groups comprises the cyclohexyloxy ethyl." cycloalkyloxy " group can further be replaced by one or more halogen atoms, and for example fluorine, chlorine or bromine obtain " halo cycloalkyloxy " and " halo cycloalkyloxy alkyl " group.
The group of naphthene base that is connected with alkoxy base contained in term " cycloalkyl alkoxy ".This class examples of groups comprises cyclohexyl methoxyl group and cyclopentyl methoxyl group.
The cycloalkenyl groups that is connected with oxygen base group contained in term " cyclenes oxygen base ".This class examples of groups comprises tetrahydrobenzene oxygen base and cyclopentenes oxygen base.The alkyl group that is connected with one or more cyclenes oxygen base groups also contained in term " cyclenes oxygen base alkyl ", just forms a cyclenes oxygen base alkyl and two cyclenes oxygen base alkyl groups.This class examples of groups comprises tetrahydrobenzene oxygen base ethyl." cyclenes oxygen base " group can further be replaced by one or more halogen atoms, and for example fluorine, chlorine or bromine obtain " halo cyclenes oxygen base " and " halo cyclenes oxygen base alkyl " group.
Term " inferior cycloalkanes dioxy base " group is represented the cycloalkylidene group of at least two oxygen and single cycloalkylidene bonding." inferior cycloalkanes dioxy base " examples of groups comprises 1,2-dioxy cyclohexylidene.
The group of naphthene base that is connected with the sulfinyl group contained in term " cycloalkyl sulfinyl ", and wherein cycloalkyl is as defined above." cycloalkyl sulfinyl alkyl " contains the cycloalkyl sulfinyl group that is connected with alkyl group, and wherein alkyl is as defined above.The group of naphthene base that is connected with the alkylsulfonyl group contained in term " naphthene sulfamide base ", and wherein cycloalkyl is as defined above." naphthene sulfamide alkyl " contains the naphthene base sulfonyl group that is connected with alkyl group, and wherein alkyl is as defined above.
The group that wherein one or more cycloalkyl carbon atoms are replaced by carbonyl group one or more as that give a definition contained in term " cycloalkyl alkyloyl ".Specifically contain a carbonyl cycloalkyl and dicarbapentaborane group of naphthene base.The example of one carbonyl group of naphthene base comprises cyclohexyl-carbonyl, cyclohexyl ethanoyl and cyclopentylcarbonyl.The example of dicarbapentaborane group of naphthene base comprises 1,2-dicarbapentaborane hexanaphthene.
The group that contains straight or branched alkyl group that be connected with bivalent sulfur atom, one to ten carbon atom contained in term " alkylthio ".Preferred alkylthio group is to have " lower alkylthio " group to six carbon atom.The example of " lower alkylthio " is methylthio group (CH
3-S-)." alkylthio " group can further be replaced by one or more halogen atoms, and for example fluorine, chlorine or bromine obtain " halogenated alkylthio " group.This class examples of groups comprises fluoro methylthio group, chloro methylthio group, trifluoromethylthio, difluoro methylthio group, trifluoro ethylmercapto group, fluoro ethylmercapto group, tetrafluoro ethylmercapto group, five fluorine ethylmercapto groups and fluoro rosickyite base.
The straight or branched alkyl group that contains one to ten carbon atom and the group of an aromatic yl group contained in term " alkyl aryl amino ", and the two all is connected with amino group.Example comprises N-methyl-4-anisidine, N-ethyl-4-anisidine and N-methyl-4-trifluoro-methoxyaniline.
The term alkylamino is represented " alkylamino " and " dialkyl amido ", contains the alkyl group that one or two is connected with amino group respectively.
The amino expression of term aryl " arylamino " and " ammonia diaryl base " contains the aromatic yl group that one or two is connected with amino group respectively.This class examples of groups comprises N-phenyl amino and N-naphthyl amino.
The aromatic alkyl group that is connected with amino group contained in term " aryl alkyl amino ", and wherein aralkyl is as defined above.The amino expression of term aralkyl " aryl alkyl amino " and " two aryl alkyl aminos " contains the aromatic alkyl group that one or two is connected with amino group respectively.The amino further expression " aralkyl one alkylamino " of term aralkyl contains an aromatic alkyl group and an alkyl group of being connected with amino group.
Term " aryl sulfonyl kia " contain contain be connected with divalence S (O) atom, the group of aromatic yl group as defined above.The aryl sulfonyl kia group that term " aryl sulfinyl alkyl " expression is connected with the straight or branched alkyl group of one to ten carbon atom.
The aromatic yl group that is connected with the alkylsulfonyl group contained in term " aryl sulfonyl ", and wherein aryl is as defined above." arylsulfonyl alkyl " contains the aryl sulfonyl group that is connected with alkyl group, and wherein alkyl is as defined above.
Term " heteroaryl sulfinyl " contain contain be connected with divalence S (O) atom, the group of heteroaryl groups as defined above.The heteroaryl sulfinyl group that term " heteroaryl sulfinyl alkyl " expression is connected with the straight or branched alkyl group of one to ten carbon atom.
The heteroaryl groups that is connected with the alkylsulfonyl group contained in term " heteroarylsulfonyl ", and wherein heteroaryl is as defined above." heteroaryl sulphonyl alkyl " contains the heteroarylsulfonyl group that is connected with alkyl group, and wherein alkyl is as defined above.
Term " aryloxy " contain be connected with Sauerstoffatom, aromatic yl group as defined above.This class examples of groups comprises phenoxy group, 4-chloro-3-ethyl phenoxy group, 4-chloro-3-methylphenoxy, 3-chloro-4-ethyl phenoxy group, 3, the 4-dichlorophenoxy, the 4-methylphenoxy, 3-Trifluoromethyl phenyl ether oxygen base, the 3-4-trifluoromethylphenopendant, the 4-fluorophenoxy, 3, the 4-dimethyl phenoxy, 5-bromo-2-fluorophenoxy, 4-bromo-3-fluorophenoxy, 4-fluoro-3-methylphenoxy, 5,6,7,8-tetrahydrochysene naphthyloxy, 3-sec.-propyl phenoxy group, 3-cyclopropyl phenoxy group, 3-ethyl phenoxy group, 3-pentafluoroethyl group phenoxy group, 3-(1,1,2,2-tetrafluoro oxyethyl group)-phenoxy group and 4-tertiary butyl phenoxy group.
Term " aroyl " contain be connected with carbonyl group as defined above, aromatic yl group as defined above.This class examples of groups comprises benzoyl and toluyl.
Term " aralkanoyl " contain be connected with carbonyl group as defined above, aromatic alkyl group as defined above.This class examples of groups for example comprises phenylacetyl.
Term " aralkoxy " is contained by what Sauerstoffatom was connected with other groups and is contained the oxygen aromatic alkyl group.Preferred aralkoxy group is that phenyl group is connected " rudimentary aralkoxy " group with above-mentioned lower alkoxy groups.This class examples of groups comprises benzyloxy, 1-phenyl ethoxy, 3-trifluoromethoxy benzyloxy, 3-trifluoromethyl benzyloxy, 3,5-difluoro benzyloxy, 3-bromo-benzyloxy-, 4-propyl group benzyloxy, 2-fluoro-3-trifluoromethyl benzyloxy and 2-phenyl ethoxy.
Term " aryloxy alkyl " contain be connected with alkyl, aryloxy group as defined above.This class examples of groups comprises phenoxymethyl.
Aryloxy alkyl as defined above contained in term " halo aryloxy alkyl ", and wherein one to five halogen group is connected with aryloxy.
Term " 4-hetaroylpyrazol " contain be connected with carbonyl group as defined above, heteroaryl groups as defined above.This class examples of groups comprises furoyl base and nicotinoyl.
Term " assorted aralkanoyl " contain be connected with carbonyl group as defined above, heteroaralkyl group as defined above.This class examples of groups for example comprises pyridine ethanoyl and furans butyryl radicals.
Term " assorted aralkoxy " is contained by what Sauerstoffatom was connected with other groups and is contained the oxa-aralkyl.Preferred assorted aralkoxy group is that heteroaryl groups is connected " rudimentary assorted aralkoxy " group with above-mentioned lower alkoxy groups.
Heteroaryloxy alkyl group as defined above contained in term " halo heteroaryloxy alkyl ", and wherein one to four halogen group is connected with heteroaryloxy.
Term " heteroaryl amino " is contained and amino be connected, heterocyclic radical group as defined above.This class examples of groups comprises pyridine amino.
Term " heteroaryl amino alkyl " contain be connected with alkyl, heteroaryl amino group as defined above.This class examples of groups comprises picolyl amino.
Term " heteroaryloxy " contain be connected with the oxygen base, heterocyclic radical group as defined above.This class examples of groups comprises 2-thiophene oxy, 2-2-pyrimidinyl oxy, 2-pyridyloxy, 3-pyridyloxy and 4-pyridyloxy.
Term " heteroaryloxy alkyl " contain be connected with alkyl, heteroaryloxy group as defined above.This class examples of groups comprises 2-pyridyloxy methyl, 3-pyridyloxy ethyl and 4-pyridyloxy methyl.
Term " arylthio " contain be connected with sulphur atom, aromatic yl group as defined above.This class examples of groups comprises thiophenyl.
Term " arylthio alkyl " contain be connected with alkyl, arylthio group as defined above.This class examples of groups comprises the thiophenyl methyl.
Term " alkylthio alkyl " contain be connected with alkyl, alkylthio group as defined above.This class examples of groups comprises methylthiomethyl.Term " alkoxyalkyl " contain be connected with alkyl, alkoxy base as defined above.This class examples of groups comprises methoxymethyl.
The carbon-based group that two and Sauerstoffatom of four covalent linkage of term " carbonyl " expression shared.Term " carboxyl " contain with carbonyl in two share one of key is connected, oh group as defined above.Term " carboxylic acid amides " contain with carbonyl in two share amino, an alkylamino, dialkyl amido, a cycloalkyl amino, alkyl-cycloalkyl amino and the bicyclic alkyl amino group that one of key is connected.Term " carboxamido alkyl " contain be connected with alkyl, carboxylacyl amine group as defined above.Term " carboxyalkyl " contain be connected with alkyl, carboxylic group as defined above.Term " carbalkoxy " contain with carbonyl in two share one of key is connected, alkoxy base as defined above.Term " aralkoxycarbonyl " contain with carbonyl in two share one of key is connected, aralkoxy group as defined above.Term " alkoxycarbonyl alkyl " contain be connected with alkyl, alkoxycarbonyl group as defined above.Term " dialkoxy carbonylic alkyl " contain be connected with alkylidene group, two alkoxycarbonyl groups as defined above.Term " a cyano group alkyl " contain be connected with alkyl, cyano group as defined above.Term " dicyano alkylidene group " contain be connected with alkyl, two cyano groups as defined above.Term " carbalkoxy cyano group alkyl " contain be connected with alkoxycarbonyl alkyl, cyano group as defined above.
Independent or the expression and the carbonyl or the thiocarbonyl group that for example are selected from following group bonding in combination of term " acyl group ": hydrogen, alkyl, thiazolinyl, alkynyl, haloalkyl, alkoxyl group, alkoxyalkyl, halogenated alkoxy, aryl, heterocyclic radical, heteroaryl, alkyl sulfenyl alkyl, alkyl sulfonyl alkyl, aralkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl group, alkylthio, arylthio, amino, alkylamino, dialkyl amido, aralkoxy, arylthio and alkylthio alkyl.The example of " acyl group " is formyl radical, ethanoyl, benzoyl, trifluoroacetyl group, phthaloyl, malonyl, nicotinoyl etc.
One or more be connected with alkyloyl group as defined above, halogen groups as defined above contained in term " haloalkane acyl group ".This class examples of groups for example comprises chloracetyl, trifluoroacetyl group, bromine propionyl and seven fluorine butyryl radicalies.
The pentavalent phosphorus that two covalent linkage are connected with oxygen groups contained in term " phosphono ".That term " dialkoxy phosphono " expression is connected with two covalent linkage of phosphono group, two alkoxy bases as defined above.That term " alkoxy diaryl phosphono " expression is connected with two covalent linkage of phosphono group, two aralkoxy groups as defined above.That term " dialkoxy phosphine acyl-alkyl " expression is connected with alkyl group, dialkoxy phosphono group as defined above.That term " alkoxy diaryl phosphine acyl-alkyl " expression is connected with alkyl group, alkoxy diaryl phosphono group as defined above.
The nitrogen-atoms that term " amino " expression is such contains two substituting groups, for example hydrogen, hydroxyl or alkyl, and have a covalent linkage, be used for the one atom of bonding, for example carbon.The example of this class amino group for example comprises-NH
2,-NHCH
3,-NHOH and-NHOCH
3The nitrogen-atoms that term " imino-" expression is such contains a substituting group, for example hydrogen, hydroxyl or alkyl, and have two covalent linkage, be used for the one atom of bonding, for example carbon.The example of this class imino group for example comprises=NH ,=NCH
3,=NOH and=NOCH
3The carbon-based group that two and imino-of four covalent linkage positions of term " imino-carbonyl " expression shared.The example of this class imino-carbonyl group for example comprises C=NH, C=NCH
3, C=NOH and C=NOCH
3Term " amidino groups " contain with one of two available imino-carbonyl group keys bonding, replacement or unsubstituted amino.This class amidino groups examples of groups for example comprises NH
2-C=NH, NH
2-C=NCH
3, NH
2-C=NOCH
3And CH
3NH-C=NOH.Term " guanidine radicals " expression and the amidino groups of amino bonded as defined above, wherein said amino can with the 3rd group bonding.The example of this class guanidino group for example comprises NH
2-C (NH)-NH-, NH
2-C (NCH
3)-NH-, NH
2-C (NOCH
3)-NH-and CH
3NH-C (NOH)-NH-.
The trivalent sulphur atom of term " sulfonium " expression positively charged, wherein said sulphur is replaced by three carbon back groups, for example alkyl, thiazolinyl, aralkyl or aryl.The sulfonium base that the wherein said sulphur of term " dialkyl matte " expression is replaced by two alkyl.This class dialkyl matte examples of groups for example comprises (CH
3)
2S
+-.Term " dialkyl matte alkyl " expression dialkyl matte base, wherein said group and a key bonding of alkylidene group as defined above.The example of this class dialkyl matte alkyl group comprises (CH
3)
2S
+-CH
2CH
2-.
Shu Yu “ Phosphonium " expression positively charged the tetravalence phosphorus atom, wherein said phosphorus is replaced by four carbon back groups, for example alkyl, thiazolinyl, aralkyl or aryl.The wherein said phosphorus of term " San Wan Ji Phosphonium " expression is replaced De Phosphonium base by three alkyl.This class San Wan Ji Phosphonium examples of groups for example comprises (CH
3)
3P
+-.
Described as defined above " alkyl "; " thiazolinyl "; " alkynyl "; " alkyloyl "; " alkylidene group "; " alkenylene "; " hydroxyalkyl "; " haloalkyl "; " halo alkylidene group "; " haloalkenyl group "; " alkoxyl group "; " alkene oxygen base "; " alkene oxygen base alkyl "; " alkoxyalkyl "; " aryl "; " perhalogeno aryl "; " halogenated alkoxy "; " halogenated alkoxy alkyl "; " haloalkene oxygen base "; " haloalkene oxygen base alkyl "; " alkylene dioxo base "; " halo alkylene dioxo base "; " heterocyclic radical "; " heteroaryl "; " hydroxy halogeno alkyl "; " alkyl sulphonyl "; " halogenated alkyl sulfonyl "; " alkyl sulfonyl alkyl "; " haloalkyl sulphonyl alkyl "; " alkyl sulphinyl "; " alkyl sulfenyl alkyl "; " haloalkyl sulfinyl alkyl "; " aralkyl "; " heteroaralkyl "; " perhalogeno aralkyl "; " aralkyl alkylsulfonyl "; " aralkyl sulphonyl alkyl "; " aralkyl sulfinyl "; " aralkyl sulfinyl alkyl "; " cycloalkyl "; " cycloalkyl alkyloyl "; " cycloalkylalkyl "; " cycloalkenyl group "; " halogenated cycloalkyl "; " halo cycloalkenyl group "; " cycloalkyl sulfinyl "; " cycloalkyl sulfinyl alkyl "; " naphthene sulfamide base "; " naphthene sulfamide alkyl "; " cycloalkyloxy "; " cycloalkyloxy alkyl "; " cycloalkyl alkoxy "; " cyclenes oxygen base "; " cyclenes oxygen base alkyl "; " inferior cycloalkanes dioxy base "; " halo cycloalkyloxy "; " halo cycloalkyloxy alkyl "; " halo cyclenes oxygen base "; " halo cyclenes oxygen base alkyl "; " alkylthio "; " halogenated alkylthio "; " alkyl sulphinyl "; " amino "; " oxygen base "; " sulphur "; " alkylamino "; " arylamino "; " aryl alkyl amino "; " aryl sulfonyl kia "; " aryl sulfinyl alkyl "; " aryl sulfonyl "; " arylsulfonyl alkyl "; " heteroaryl sulfinyl "; " heteroaryl sulfinyl alkyl "; " heteroarylsulfonyl "; " heteroaryl sulphonyl alkyl "; " heteroaryl amino "; " heteroaryl amino alkyl "; " heteroaryloxy "; " heteroaryloxy alkyl "; " aryloxy "; " aroyl "; " aralkanoyl "; " aralkoxy "; " aryloxy alkyl "; " halo aryloxy alkyl "; " 4-hetaroylpyrazol "; " assorted aralkanoyl "; " assorted aralkoxy "; " assorted sweet-smelling alkoxy alkyl "; " arylthio "; " arylthio alkyl "; " alkoxyalkyl "; " acyl group "; " amidino groups "; " guanidine radicals "; " dialkyl matte "; " San Wan Ji Phosphonium " and " dialkyl matte alkyl " can randomly have one or more non-hydrogen substituting groups, for example amidino groups; guanidine radicals; dialkyl matte; San Wan Ji Phosphonium; the dialkyl matte alkyl; the perhalogeno aralkyl; the aralkyl alkylsulfonyl; aralkyl sulphonyl alkyl; aralkyl sulfinyl; aralkyl sulfinyl alkyl; halogenated cycloalkyl; the halo cycloalkenyl group; the cycloalkyl sulfinyl; cycloalkyl sulfinyl alkyl; the naphthene sulfamide base; the naphthene sulfamide alkyl; heteroaryl amino; N-heteroaryl amino-N-alkylamino; the heteroaryl amino alkyl; heteroaryloxy; the heteroaryloxy alkyl; halogenated alkylthio; alkanoyloxy; alkoxyl group; alkoxyalkyl; halogenated alkoxy alkyl; assorted aralkoxy; cycloalkyloxy; cyclenes oxygen base; the cycloalkyloxy alkyl; cycloalkyl alkoxy; cyclenes oxygen base alkyl; inferior cycloalkanes dioxy base; the halo cycloalkyloxy; halo cycloalkyloxy alkyl; halo cyclenes oxygen base; halo cyclenes oxygen base alkyl; hydroxyl; amino; sulfo-; nitro; low-grade alkyl amino; alkylthio; alkylthio alkyl; arylamino; aryl alkyl amino; arylthio; arylthio alkyl; assorted sweet-smelling alkoxy alkyl; alkyl sulphinyl; the alkyl sulfenyl alkyl; aryl sulfinyl alkyl; the arylsulfonyl alkyl; heteroaryl sulfinyl alkyl; heteroaryl sulphonyl alkyl; alkyl sulphonyl; the alkyl sulfonyl alkyl; haloalkyl sulfinyl alkyl; haloalkyl sulphonyl alkyl; alkyl sulfonyl amino; alkyl amino sulfonyl; the amido alkylsulfonyl; one alkyl amido alkylsulfonyl; dialkyl group amido alkylsulfonyl; one aryl amido alkylsulfonyl; Arenesulfonyl amino; diaryl amido alkylsulfonyl; one alkyl, one aryl amido alkylsulfonyl; aryl sulfonyl kia; aryl sulfonyl; heteroarylthio; the heteroaryl sulfinyl; heteroarylsulfonyl; alkyloyl; enoyl-; aroyl; 4-hetaroylpyrazol; aralkanoyl; assorted aralkanoyl; the haloalkane acyl group; alkyl; thiazolinyl; alkynyl; alkene oxygen base; alkene oxygen base alkyl; alkylene dioxo base; the halo alkylene dioxo base; cycloalkyl; the cycloalkyl alkyloyl; cycloalkenyl group; the low-grade cycloalkyl alkyl; the lower alkenyl ring alkyl; halogen; haloalkyl; haloalkenyl group; halogenated alkoxy; the hydroxy halogeno alkyl; hydroxyl aralkyl; hydroxyalkyl; aminoalkyl group; the hydroxyl heteroaralkyl; halogenated alkoxy alkyl; aryl; aralkyl; aryloxy; aralkoxy; aryloxy alkyl; saturated heterocyclic radical; the heterocyclic radical of fractional saturation; heteroaryl; heteroaryloxy; the heteroaryloxy alkyl; arylalkyl; heteroarylalkyl; aryl alkenyl; the heteroaryl thiazolinyl; carboxyalkyl; carbalkoxy; alkoxy carbonyl; aralkoxycarbonyl; carboxamido; the carboxamido alkyl; cyano group; the haloalkoxy carbonyl; phosphono; phosphine acyl-alkyl; alkoxy diaryl phosphono and alkoxy diaryl phosphine acyl-alkyl.
Term " spacer " can comprise the linear fraction of covalent linkage and the main chain with 1 to 7 atom that links to each other.Spacer can have the monovalence or the multivalence chain of 1 to 7 atom.The monovalence chain can constitute by being selected from following group :=C (H)-,=C (R
2a)-,-O-,-S-,-S (O)-,-S (O)
2-,-NH-,-N (R
2a)-,-N=,-CH (OH)-,=C (OH)-,-CH (OR
2a)-,=C (OR
2a)-and-C (O)-, R wherein
2aBe selected from alkyl, thiazolinyl, alkynyl, aryl, heteroaryl, aralkyl, aryloxy alkyl, alkoxyalkyl, alkylthio alkyl, arylthio alkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, haloalkenyl group, halogenated alkoxy alkyl, perhalogeno aralkyl, heteroarylalkyl, heteroaryloxy alkyl, heteroarylthio alkyl and heteroaryl thiazolinyl.The multivalence chain can be made up of 1 or 2 or 3 or 4 or 5 or 6 or 7 atom straight chains or 1 or 2 or 3 or 4 or the 5 or 6 atom straight chains that have a side chain.Chain can be selected from following group and be constituted by one or more: low-grade alkylidene, low-grade alkenyl ,-O-,-O-CH
2-,-S-CH
2-,-CH
2CH
2-, vinyl ,-CH=CH (OH)-,-OCH
2O-,-O (CH
2)
2O-,-NHCH
2-,-OCH (R
2a) O-,-O (CH
2CHR
2a) O-,-OCF
2O-,-O (CF
2)
2O-,-S-,-S (O)-,-S (O)
2-,-N (H)-,-N (H) O-,-N (R
2a) O-,-N (R
2a)-,-C (O)-,-C (O) NH-,-C (O) NR
2a-,-N=,-OCH
2-,-SCH
2-, S (O) CH
2-,-CH
2C (O)-,-CH (OH)-,=C (OH)-,-CH (OR
2a)-,=C (OR
2a)-, S (O)
2CH
2-and-NR
2aCH
2-, and as defined above or as well known to those skilled in the art or definite a lot of other groups.Side chain can comprise one or more non-hydrogen substituting groups, for example amidino groups; guanidine radicals; dialkyl matte; San Wan Ji Phosphonium; the dialkyl matte alkyl; the perhalogeno aralkyl; the aralkyl alkylsulfonyl; aralkyl sulphonyl alkyl; aralkyl sulfinyl; aralkyl sulfinyl alkyl; halogenated cycloalkyl; the halo cycloalkenyl group; the cycloalkyl sulfinyl; cycloalkyl sulfinyl alkyl; the naphthene sulfamide base; the naphthene sulfamide alkyl; heteroaryl amino; N-heteroaryl amino-N-alkylamino; the heteroaryl amino alkyl; heteroaryloxy; the heteroaryloxy alkyl; halogenated alkylthio; alkanoyloxy; alkoxyl group; alkoxyalkyl; halogenated alkoxy alkyl; assorted aralkoxy; cycloalkyloxy; cyclenes oxygen base; the cycloalkyloxy alkyl; cycloalkyl alkoxy; cyclenes oxygen base alkyl; inferior cycloalkanes dioxy base; the halo cycloalkyloxy; halo cycloalkyloxy alkyl; halo cyclenes oxygen base; halo cyclenes oxygen base alkyl; hydroxyl; amino; sulfo-; nitro; low-grade alkyl amino; alkylthio; alkylthio alkyl; arylamino; aryl alkyl amino; arylthio; arylthio alkyl; assorted sweet-smelling alkoxy alkyl; alkyl sulphinyl; the alkyl sulfenyl alkyl; aryl sulfinyl alkyl; the arylsulfonyl alkyl; heteroaryl sulfinyl alkyl; heteroaryl sulphonyl alkyl; alkyl sulphonyl; the alkyl sulfonyl alkyl; haloalkyl sulfinyl alkyl; haloalkyl sulphonyl alkyl; alkyl sulfonyl amino; alkyl amino sulfonyl; the amido alkylsulfonyl; one alkyl amido alkylsulfonyl; dialkyl group amido alkylsulfonyl; one aryl amido alkylsulfonyl; Arenesulfonyl amino; diaryl amido alkylsulfonyl; one alkyl, one aryl amido alkylsulfonyl; aryl sulfonyl kia; aryl sulfonyl; heteroarylthio; the heteroaryl sulfinyl; heteroarylsulfonyl; alkyloyl; enoyl-; aroyl; 4-hetaroylpyrazol; aralkanoyl; assorted aralkanoyl; the haloalkane acyl group; alkyl; thiazolinyl; alkynyl; alkene oxygen base; alkene oxygen base alkyl; alkylene dioxo base; the halo alkylene dioxo base; cycloalkyl; cycloalkenyl group; the low-grade cycloalkyl alkyl; the lower alkenyl ring alkyl; halogen; haloalkyl; haloalkenyl group; halogenated alkoxy; the hydroxy halogeno alkyl; hydroxyl aralkyl; hydroxyalkyl; aminoalkyl group; the hydroxyl heteroaralkyl; halogenated alkoxy alkyl; aryl; aralkyl; aryloxy; aralkoxy; aryloxy alkyl; saturated heterocyclic radical; the heterocyclic radical of fractional saturation; heteroaryl; heteroaryloxy; the heteroaryloxy alkyl; arylalkyl; heteroarylalkyl; aryl alkenyl; the heteroaryl thiazolinyl; carboxyalkyl; carbalkoxy; aralkoxycarbonyl; carboxamido; the carboxamido alkyl; cyano group; the haloalkoxy carbonyl; phosphono; phosphine acyl-alkyl; alkoxy diaryl phosphono and aralkoxy phosphine acyl-alkyl.
The compounds of this invention can exist with tautomerism, rotamerism or stereoisomeric forms in any ratio.The intent of the present invention is the compound that all are such, comprise cis and trans geometrical isomer, E and Z geometrical isomer, R and S enantiomorph, diastereomer, d-isomer, 1-isomer, their racemic mixture and other mixtures, these all within the scope of the present invention.The pharmacy acceptable salt of these tautomerisms, rotamerism or stereoisomeric forms in any ratio is also included within the present invention.
The form of term " cis " and " trans " expression geometric isomerism wherein will each have a hydrogen atom at the homonymy (" cis ") of two keys or the offside (" trans ") of two keys by doubly linked two carbon atoms.
Described some compound contains thiazolinyl, this means to comprise cis and trans or " E " and " Z " rotamerism form.
Described some compound contains one or more three-dimensional centers, this means the mixture that comprises R, S isomer and R and S type for each three-dimensional center.
Separately or as a heterocycle ring system part, some compound described herein can contain one or more ketone carbonyls or aldehyde carbonyl or its combination.Such carbonyl can be partly or is mainly existed and partly or mainly exist with one or more " enol " form with " ketone " form of every kind of aldehyde and ketone group.The compounds of this invention with aldehyde carbonyl or ketone carbonyl means and comprises " ketone " and " enol " tautomeric form.
Separately or as a heterocycle ring system part, some compound described herein can contain one or more amidocarbonylations or its combination.Such carbonyl can be partly or is mainly existed and partly or mainly exist with one or more " enol " form with " ketone " form of every kind of amide group.The compounds of this invention with amidocarbonylation means and comprises " ketone " and " enol " tautomeric form.Described amidocarbonylation can be carbonyl (C=O) and thiocarbonyl group (C=S) on type.
Some compound described herein can contain one or more imines or enamine group or its combination.Such group can be partly or is mainly existed and partly or mainly exist with one or more " enamine " form with " imines " form of every kind of group.The compounds of this invention with described imines or enamine group means and comprises " imines " and " enamine " tautomeric form.
The present invention is also included within treatment and the prevention in the anticoagulant therapy, be used for the treatment and the prevention of the various thrombosis diseases of curee, comprise coronary artery and cerebrovascular disease, comprise formula (I) compound of the curee who suffers from these illnesss being given significant quantity on the therapeutics:
Or its pharmacy acceptable salt.
As further embodiment, the present invention's formula (I) compound or its pharmacy acceptable salt as defined above comprises curee's coronary artery disease, cerebrovascular disease and other treatment of conditions relevant with coagulation cascade and prevention, comprises formula of the present invention (I) compound or its pharmacy acceptable salt of the curee who suffers from these illnesss being given significant quantity on the therapeutics.
Formula of the present invention (I) compound or its pharmacy acceptable salt also can be used for requirement and suppress to solidify so that prevent the whole blood of being stored in the blood coagulation, prevent that other are used to the physiology sample solidifies of testing or storing.Thereby, blood coagulation inhibitor of the present invention can join the whole blood stored and contain or suspect in the medium that contains plasma coagulation factors or contact with it with any, it is desired wherein suppressing blood coagulation, in for example ought making mammalian and the material that is selected from down group contacting: blood vessel graft, graft fixed mould, orthopaedic prosthesis, heart prosthesis and extracorporeal circulation system.
Formula (I) compound can suppress to participate in the activity of the serine protease of coagulation cascade, thereby can be used in medicine production, be used for prevention or treatment, for example formation of anticoagulant thing in Mammals, blood, blood products and mammalian organs, suppress fibrinous generation, suppress the formation of thrombus and suppress the formation of embolus by the disease of coagulation cascade serine protease mediation.Compound also can be used for the treatment of or prevent Mammals unstable angina pectoris, intractable angina pectoris, myocardial infarction, transient ischemic attack, auricular fibrillation, thrombus apoplexy, embolus apoplexy, venous thrombosis, disseminated inravascular coagulation, eye scleroproein to stop up and the obturation again or the restenosis of break-through blood vessel again.Compound also can be used to study the mechanism of action of coagulation cascade serine protease, so that design better inhibitor, develops better assay method.Formula (I) compound also will be useful in the prevention of cerebrovascular accident (CVA) or apoplexy.
Be also included within formula (I) the compound family is its pharmacy acceptable salt.The salt that generally is used to generate an alkali metal salt and generates free acid or free alkali additive salt contained in term " pharmacy acceptable salt ".The character of salt is not crucial, as long as it is pharmaceutically acceptable.The pharmaceutically-acceptable acid addition of formula (I) compound that is fit to can be from mineral acid or organic acid preparation.This class representative examples of mineral pigments is hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, nitric acid, carbonic acid, sulfuric acid and phosphoric acid.Suitable organic acid can be selected from aliphatic series, alicyclic, aromatics, araliphatic, heterocycle family, carboxylic acid and sulfonic acid class organic acid, their example is a formic acid, acetate, propionic acid, succsinic acid, oxyacetic acid, gluconic acid, lactic acid, oxysuccinic acid, tartrate, citric acid, xitix, glucuronic acid (glucoronic), toxilic acid, fumaric acid, pyruvic acid, aspartic acid, L-glutamic acid, phenylformic acid, anthranilic acid, methylsulfonic acid, Whitfield's ointment, right-hydroxy-benzoic acid, toluylic acid, amygdalic acid, pounce on acid (pamoic acid), methylsulfonic acid, ethyl sulfonic acid, Phenylsulfonic acid, sulfanilic acid, stearic acid, cyclohexylsulfamic acid, alginic acid, galacturonic acid.The pharmaceutically acceptable base addition salt of formula (I) compound that is fit to comprises from the metal-salt of aluminium, calcium, lithium, magnesium, potassium, sodium and zinc preparation, or from N, the organic salt of N '-dibenzyl-ethylenediamin, choline, chloroprocaine, diethanolamine, quadrol, meglumine (N-methylglucosamine) and PROCAINE HCL, PHARMA GRADE preparation.All these salt can for example make the reaction of suitable acid or alkali and formula (I) compound by ordinary method from corresponding formula (I) compound.
The present invention also comprises pharmaceutical composition, wherein comprises formula (I) compound and at least a pharmaceutically acceptable carrier, auxiliary agent or the thinner of significant quantity on the therapeutics.Pharmaceutical composition of the present invention can comprise active formula (I) compound and pharmaceutically acceptable carrier and/or thinner and/or auxiliary agent (this paper is referred to as " carrier " material) that one or more are nontoxic, also can comprise other activeconstituentss if necessary.Active compound of the present invention can pass through any suitable administration, preferably is suitable for a kind of like this form of pharmaceutical composition of approach, and dosage is effective for the expection treatment.
Active compound and composition for example can be oral, in the blood vessel, intraperitoneal, subcutaneous, intramuscular, eye with or topical.Stop up for treatment eye scleroproein, compound can intraocular or topical, and oral or administered parenterally.
Compound can be with the form administration of Drug Storage injection or implantation preparation, and they can be prepared by a kind of like this mode, so that allow the lasting release of activeconstituents.Activeconstituents can be compressed into pellet or small cylinder, as the Drug Storage injection or implant is subcutaneous or intramuscular is implanted.Implant can adopt inert material, biological example degradable polymer or synthesizing organo-silicon oxygen oxygen alkane, for example Silastic, silicon rubber, silicone rubber or other silicon-containing polymers.
Compound also can be with the form administration of liposome release system, for example little individual layer capsule, big individual layer capsule and multilayer capsule.Liposome can generate from various phosphatide, for example cholesterol, stearylamine or phosphatidylcholine.
Compound also can utilize monoclonal antibody to discharge as carrier independently, and compound molecule is a link coupled with it.Compound also can with the soluble polymer coupling, the latter is orientable pharmaceutical carrier.This base polymer can comprise polyvinylpyrrolidone, pyran co-polymer, poly-hydroxyl-propyl group-different acrylamide-phenol, poly-hydroxyethyl-l-asparagine-phenol or the polyoxyethylene-polylysine that is replaced by the palmityl residue.In addition, compound can be used for realizing the biodegradable polymer coupling of medicine sustained release with a class, for example crosslinked the or amphiphilic block copolymer of the multipolymer of poly(lactic acid), polyglycolic acid, poly(lactic acid) and polyglycolic acid, poly-epsilon-caprolactone, polyhydroxybutyrate, poe, polyacetal, poly-dihydropyrane, polybutylcyanoacrylate and hydrogel.
About oral administration, pharmaceutical composition for example can be tablet, capsule (comprising the preparation that continues release or regularly discharge separately), pill, pulvis, granule, elixir, tincture, suspension, the liquid that comprises syrup and emulsion.Pharmaceutical composition is preferably made the form of dose unit, wherein contains the activeconstituents of specified quantitative.The example of this class dose unit is tablet or capsule.Activeconstituents also can pass through the composition drug administration by injection, wherein for example can use salt solution, glucose or water as the carrier that is fit to.
The dosage of therapeutical active compound and utilize the dosage of The compounds of this invention and/or composition therapeuticing disease to depend on various factors, comprise curee's the approach of age, body weight, sex and physique condition, severity of disease, administration and frequency and the specific compound that is adopted, thereby can have nothing in common with each other.
Pharmaceutical composition contains the amount of activeconstituents can be in about scope of 0.1 to 2000mg, preferably in about scope of 0.5 to 500mg.About 0.01 to 100mg/kg body weight, preferably about 0.5 and about 20mg/kg body weight between dosage every day can be suitable.Every day, dosage can divide one to four administration in every day.
Compound can be mixed with topical ointments or creme or suppository, and the total amount that wherein contains activeconstituents for example is 0.075 to 30%w/w, is preferably 0.2 to 20%w/w, most preferably is 0.4 to 15%w/w.When being mixed with ointment, activeconstituents can adopt paraffin class or water-miscible ointment base preparation.
Perhaps, activeconstituents can be mixed with creme with the oil-in-water-type cream base.If necessary, the water of cream base for example can comprise 30%w/w polyvalent alcohol at least, for example propylene glycol, fourth-1,3-glycol, mannitol, Sorbitol Powder, glycerine, polyoxyethylene glycol and composition thereof.Topical formulations can preferably comprise the compound that promotes activeconstituents to absorb or penetrate into skin or other zones of action.The example of this class skin penetration promotor comprises methyl-sulphoxide and relevant analogue.The compounds of this invention also can pass through the administration of transdermal medical instrument.Preferably, utilize the patch of stocking with porous-film type or solid substrate kind to realize topical.In both cases, promoting agent discharges from Drug Storage or micro-capsule continuously, passes film and enters promoting agent permeability surgical adhesive, and the latter contacts with the person's that is subjected to the medicine skin or mucous membrane.Pass skin if promoting agent is absorbed, with control and the promoting agent of predetermined amount of flow to the person's administration that is subjected to the medicine.Under the situation of micro-capsule, encapsulation agent can play the effect of film.
The oil phase of emulsion of the present invention can and be pressed known way from principal component and constitute.Oil phase can only comprise emulsifying agent, but also can comprise at least a emulsifying agent and oily or the fatty and oily mixture of fat.Preferably, comprise hydrophilic emulsifier and the lipophilic emulsifier that serves as stablizer.Also preferably comprise oil ﹠ fat.The emulsifying agent that contains or do not contain stablizer is formed so-called emulsifying wax together, and wax is formed so-called emulsification ointment base with oil ﹠ fat, forms the oily disperse phase of creme.The emulsifying agent and the emulsion stablizer that are applicable to preparation of the present invention especially comprise polysorbate60, sorbester p17, cetostearyl alcohol, tetradecyl alcohol, monostearin and Sodium Lauryl Sulphate BP/USP.
Be applicable to the oil of preparation or fatty selection based on realizing required beauty treatment character, because active compound is low-down in the solubleness that majority is suitable in the oil of pharmaceutical emulsion.Thereby creme should preferably be non-oily, non-staining and rinsable product, has suitable denseness, to avoid seepage from pipe or other containers.Can use the monobasic or the binary alkyl ester of straight or branched, for example the adulterant of propylene glycol ester, tetradecanoic acid isopropyl esters, oleic acid decyl ester, palmitinic acid isopropyl esters, stearic acid butyl ester, palmitinic acid 2-(ethyl hexyl) ester or the branched ester of two dissidents, two acid esters, different hexadecyl stearate, fatty acid distribution of coconut oil.They can use separately, also can unite use, and this depends on required character.Perhaps, can use the high boiling point lipid, for example paraffinum molle alba and/or whiteruss or other mineral oil.
For therapeutic purpose, active compound of the present invention combines route of administration shown in these auxiliary agents are suitable for usually with one or more auxiliary agents.If oral administration, compound can mix with calcium salt, gelatin, gum arabic, sodiun alginate, polyvinylpyrrolidone and/or polyvinyl alcohol with the vitriolic sodium salt with cellulose ester, Mierocrystalline cellulose alkyl ester, talcum, stearic acid, Magnesium Stearate, magnesium oxide, the phosphoric acid of lactose, sucrose, starch, paraffinic acid, then administration for convenience and compressing tablet or seal.This class capsule or tablet can contain controlled release preparation, and this can be provided by the dispersed system of active compound in Vltra tears.The preparation that is used for administered parenterally can be water-based or non-aqueous isoosmotic aseptic injectable solution or suspension.These solution and suspension can be from sterilized powder or granules preparation, and have one or more carriers or the thinner of mentioning about oral Preparation.Can compound is water-soluble, polyoxyethylene glycol, propylene glycol, ethanol, Semen Maydis oil, Oleum Gossypii semen, peanut oil, sesame oil, phenylcarbinol, sodium-chlor and/or various buffer reagent.Other auxiliary agents and administering mode all are that pharmaceutical field is generally known.
Treatment and prevention about various thrombosis diseases, comprise coronary artery and cerebrovascular disease, when implementing method of the present invention, compound of the present invention and pharmaceutical composition be individually dosed, administration or combine administration with other treatment agent or in-vivo diagnostic agent is bonded to each other.Coagulation cascade inhibitor of the present invention also can with the following ingredients co-administered that is fit to: anti-platelet aggregation agent includes but not limited to ticlopidine or clopidrogel; Fibrinogen deceptor antagonists (for example be used for the treatment of or prevent unstable angina pectoris or be used to prevent postangioplasty obturation and restenosis again); Antithrombotics, for example acetylsalicylic acid, warfarin or heparin; Thrombolytic agent, for example plasminogen activator or streptokinase act synergistically with realization in the treatment of various pathologies; The lipid depressant comprises hypercholesterolemia agent (HMG CoA reductase inhibitor for example, for example mevastatin, lovastatin, simvastatin, Pravastatin and fluvastatin, HMG CoA synthetase inhibitors etc.); Antidiabetic drug; Or other cardiovascular agents (loop diuretic, thiazine type diuretic(s), nitric ether, aldosterone antagonists (for example spironolactone and epoxymexlerenone), angiotensin converting enzyme (for example ACE) inhibitor, angiotensin II receptor antagonists, beta-Blocking agent, anti-arrhythmic agents, hypotensive agent and calcium channel blocker), atherosis with treatment or prevention of arterial.For example, the patient who suffers from the patient of coronary artery disease and accept angioplasty will benefit from the co-administered of fibrinogen deceptor antagonists and coagulation cascade inhibitor of the present invention.And the coagulation cascade inhibitor can improve the dabbling again efficient of thrombolysis of tissue plasminogen activator-mediation.
The typical doses of anti-platelet agents, anti-coagulant, cardiovascular treatment agent or thrombolytic agents that coagulation cascade inhibitor of the present invention and other are fit to can equal the dosage of coagulation cascade inhibitor not with other anti-platelet agents, anti-coagulant, cardiovascular treatment agent or thrombolytic agent co-administered the time, perhaps can be substantially less than the dosage of coagulation cascade inhibitor the time not with other anti-platelet agents, anti-coagulant, cardiovascular treatment agent or thrombolytic agent co-administered, this depends on patient's treatment needs.
If address here, all reference of mentioning are all in conjunction with as a reference.
Although invention has been described with regard to embodiment, but the details of these embodiments should not be construed as limitation of the present invention.The following example is set forth the present invention, but is not intended to limit its scope.Need not to give unnecessary details, utilize the explanation of preamble, believe that those skilled in the art can farthest utilize the present invention.Therefore, following preferred specific embodiments is interpreted as only supplying illustration, in any case neither be to the restriction of all the other disclosures.The compound that contains the multiple structural modification variant of setting forth in flow process or the following example also is the intention place.What the person skilled in the art will easily understand is that the known change example of following preparation method's condition and process can be used to prepare these compounds.
Those skilled in the art can use these general methods to prepare following specific embodiment, and they or can pass through
1H NMR, mass spectrum, ultimate analysis and similar approach be characterized in addition.These compounds also can be to generate in the body.The following example contains the detailed description of formula (I) compounds process for production thereof.These are described in detail within the scope of invention, only supply illustration, are not intended to limit scope of invention.All umbers all by weight, temperature is degree centigrade, other have explanation except.
Following general synthetic order can be used for implementing the present invention.Used abbreviation comprises in flow process and the table: " AA " represented amino acid, and " AcCN " represents acetonitrile, and " AcOH " represents acetate, " BINAP " represents 2,2 '-two (diphenyl phosphine)-1,1 '-dinaphthalene, " BnOH " represents phenylcarbinol, and " BnCHO " represents 2-phenyl acetaldehyde, " BnSO
2Cl " represent the benzyl SULPHURYL CHLORIDE; and " Boc " represents tertbutyloxycarbonyl; " BOP " represents benzotriazole-1-base oxygen base three (dimethylaminos); " bu " represents butyl; " dba " represents dibenzalacetone; " DCC " represents 1; the 3-dicyclohexylcarbodiimide; " DCM " represents methylene dichloride or METHYLENE CHLORIDE; " DIBAH " or " DIBAL " represents diisobutylaluminium hydride; " DMF " represents dimethyl formamide; " DMSO " represents methyl-sulphoxide; " DPPA " represents diphenyl phosphoryl azide; " EDC " represents 1-[3-(dimethylamino) propyl group]-the 3-ethyl-carbodiimide hydrochloride; " Ex.No. " represents the embodiment numbering; " Fmoc " represents the 9-fluorenylmethyloxycarbonyl; " HOBt " representation hydroxy benzotriazole; " LDA " represents the diisopropylaminoethyl lithium, and " MW " represents molecular weight, and " NMM " represents N-methylmorpholine; " Ph " represents phenyl or aryl; " PHTH " represents phthaloyl, and " pnZ " represents 4-nitro carbobenzoxy-(Cbz), and " PTC " represents phase-transfer catalyst; " py " represents pyridine, " RNH
2" represent organic primary amine; " SEM " represents 2-(trimethyl silyl) oxyethyl group-methyl chloride; " p-TsOH " represents tosic acid; " TBAF " represents tetrabutylammonium; " TBTU " represents 2-(1H-benzotriazole-1-yl)-1; 1,3,3-tetramethyl-urea a tetrafluoro borate, " TEA " represents triethylamine, and " TFA " represents trifluoroacetic acid, " THF " represents tetrahydrofuran (THF), " TMS " represents trimethyl silyl, and " TMSCN " represents trimethyl silyl cyanogen, and " Cbz " or " Z " represents carbobenzoxy-(Cbz).
Universal synthesis method and specific embodiment
Shown in the following flow process 1 of universal synthesis method of the uridylic (being pyrimidine dione) that replaces.Prepared, disclose the pyrimidine dione that some N-1 replace in the past, they are the intermediates that can be used for the The compounds of this invention preparation.In the presence of salt of wormwood, stir pyrimidine dione and the solution of alpha-halogen acetic ester in dimethyl sulfoxide (DMSO) that this N-1 replaces, carry out the alkylating of N-3 nitrogen.In nitrogen atmosphere, utilize catalytic palladium-carbon to be easy to realize the reduction of nitro functions to primary amine.Primary amine then can with various raw material reactions, include but not limited to acyl chlorides, acid anhydrides, SULPHURYL CHLORIDE, alkyl and aromatic halide, aldehyde and ketone.Acetic ester can be hydrolyzed to acid with lithium hydroxide then.Acid then can be under the peptide coupling condition of standard and multiple required amine coupling, obtains acid amides.Normally polyfunctional with amine in the methods of the invention, with protected form reaction.Remove these blocking groups, obtain compound of the present invention.
Flow process 1: general uridylic method
The following example 1 and 2 illustrations this general uridylic (being pyrimidine dione) synthesis flow.
Embodiment 1
EX-1A) will be as Vampa, G. and Pecorari, P. " Boll.Chim.Farm. " 1987,126, the 1-benzyl of the described preparation of 467-469-5-nitro-2,4 (1H, 3H) pyrimidine dione (6.14g, 24.82mmol) solution be dissolved in the 100ml methyl-sulphoxide, under agitation disposable adding saleratus (3.78g, 27.34mmol).After about 10 minutes, go through 10 minutes dripping bromine methyl acetates (2.50ml, 20ml dimethyl sulfoxide solutions 26.40mmol).Reaction mixture is heated to 40 ℃ then, stirs 18 hours.Reaction mixture water (500ml) dilution.Aqueous solution ethyl acetate extraction (4 * 100ml).Organic solution water after the merging (1 * 150ml), salt solution (2 * 150ml) washing.Organic solution drying (MgSO
4), filter, concentrate, obtain a kind of oil.Thick oil is through MPLC purifying (20% ethyl acetate/hexane), obtain pure 1-benzyl-3-methoxycarbonyl methyl-5-nitro-2,4 (1H, 3H) pyrimidine dione (EX-1A) is white solid, yield 81%:
1H NMR (400MHz, CDCl
3) δ 8.73 (and s, 1H) 7.38-7.30 (m, 5H), 5.06 (s, 2H), 4.69 (s, 2H), 3.72 (s, 3H); HRMS (ES) theoretical value C
14H
13N
3O
6319.0804, actual value 319.0797.
EX-1B) with 1-benzyl-3-methoxycarbonyl methyl-5-nitro-2,4 (1H, 3H) pyrimidine dione (EX-1A; 6.30g 100.0ml methanol solution 19.74mmol) outgases with hydrogen.In solution, add 5% Pd/C (0.737g) then, under room temperature and nitrogen atmosphere, stirred 24 hours.The crude reaction thing filters by Celite 545 pads, under reduced pressure concentrates.Oily matter is through MPLC purifying (60% ethyl acetate/hexane), obtain pure 5-amino-1-benzyl-3-methoxycarbonyl methyl-2,4 (yield 63% is brown solid for 1H, 3H) pyrimidine dione (EX-1B):
1H NMR (300MHz, DMSO) δ 7.41-7.28 (m, 5H), 6.93 (s, 1H), 4.93 (s, 2H), 4.66 (s, 2H), 4.32 (s, 2H), 3.69 (s, 3H); HRMS (ES) theoretical value C
14H
16N
3O
4290.1141, actual value 290.1138.
EX-1C) at room temperature, to 5-amino-1-benzyl-3-methoxycarbonyl methyl-2,4 (1H, 3H) pyrimidine dione (EX-1B; 3.12g, 18.0ml tetrahydrofuran (THF) 10.77mmol) and dimethyl formamide (1: 1,0.62M) disposable adding N-methylmorpholine in the solution (3.60ml, 32.74mmol).The gained mixture is cooled to 0 ℃ in ice bath, stirred 15 minutes.Go through and dripped benzyl SULPHURYL CHLORIDE (2.26g, 18.0ml tetrahydrofuran solution 11.86mmol) in 30 minutes.After adding fully, reactant stirred 3 hours down at 0 ℃.Reaction mixture is with ethyl acetate (250.0ml) dilution, with 1N HCl (2 * 50ml), saturated NaHCO
3(2 * 50ml) and salt solution (2 * 50ml) washing.Organic solution drying (MgSO
4), filter, concentrate.With ethyl acetate and hexane development, obtain pure 1-benzyl-3-methoxycarbonyl methyl-5-[[(phenmethyl) alkylsulfonyl] amino-2,4 (yield 74% is white solid for 1H, 3H) pyrimidine dione (EX-1C):
1H NMR (300MHz, DMSO) δ 9.16 (s, 1H), 8.02 (s, 1H), 7.43-7.37 (m, 10H), 5.01 (s, 2H), 4.65 (s, 2H), 4.45 (s, 2H), 3.69 (s, 3H); HRMS (ES) theoretical value C
21H
22N
3O
6S 444.1229, actual value 444.1242.
EX-1D) to 1-benzyl-3-methoxycarbonyl methyl-5-[[(phenmethyl) alkylsulfonyl] amino-2,4 (1H, 3H) pyrimidine dione (EX-1C; 3.28g, 94.0ml tetrahydrofuran (THF) 7.40mmol) and methyl alcohol (1: 1, the 0.078M) aqueous solution of adding 30.0ml 0.1M lithium hydroxide in the solution.Suspension is clarified rapidly, and becomes even.Reactant stirred 1 hour, under reduced pressure removed volatile matter.Remaining aqueous solution cools off in ice bath, is acidified to pH1 with 1.0N HCl, causes the adularescent precipitation to generate.Filter and collect this precipitation, dry under vacuum with 1.0N HCl and water washing, obtain pure 1-benzyl-3-methylene radical carboxyl-5-[[(phenmethyl) alkylsulfonyl] amino]-2,4 (1H, 3H) pyrimidine dione (EX-1D), yield 99%:
1H NMR (300MHz, DMSO) δ 9.14 (br s, 1H), 7.98 (s, 1H), 7.44-7.35 (m, 10H), 5.00 (s, 2H), 4.51 (s, 2H), 4.45 (s, 2H); HRMS (ES) theoretical value C
20H
19N
3O
6S 429.0995, actual value 429.0981.
EX-1E) to 1-benzyl-3-methylene radical carboxyl-5-[[(phenmethyl) alkylsulfonyl] amino]-2,4 (1H, 3H) pyrimidine dione (EX-1D; 531.6mg, 1.238mmol) 12.4ml tetrahydrofuran (THF) and dimethyl formamide (1: 1,0.1M) add N in the solution, N-diisopropylethylamine (1.10ml, 6.315mmol), N-hydroxybenzotriazole (499.6mg, 3.697mmol) and 1-[3-(dimethylamino) propyl group]-the 3-ethyl-carbodiimide hydrochloride (717.2mg, 3.741mmol).The gained mixture stirred 30 minutes.Then in reaction mixture disposable adding amine (623.3mg, 2.500mmol).The gained mixture stirs and spends the night.Reaction mixture with ethyl acetate (50ml) dilution, with 5% citric acid (1 * 25ml), saturated NaHCO
3(1 * 25ml) and salt solution (1 * 25ml) washing.Organic solution drying (MgSO
4), filter, concentrate.Crude reaction product obtains product EX-1E through MPLC purifying (75% ethyl acetate/hexane).
1H NMR (300MHz, DMSO) δ 9.13 (br s, 1H), 8.77 (t, J=5.3Hz, 1H), 7.98 (s, 1H), 7.91 (d, J=7.9Hz, 1H), and 7.45-7.35 (m, 13H), 5.01 (s, 2H), 4.56 (s, 2H), 4.56 (s, 2H), 4.44 (s, 2H), 4.38 (d, J=5.4Hz, 2H), 1.47 (s, 9H); HRMS (ES) theoretical value C
33H
37N
6O
7S 661.2444, actual value 661.2448.
In flask, to protected pyrimidine dione (EX-1E) (238.55mg, 0.3610mmol) the middle 4.0ml 4M HCl De dioxane solution that adds.Gained solution stirring spend the night (about 18 hours).Solution concentration, crude product is developed from ether.Filter and collect the gained white solid, with the ether washing, drying obtains pure products:
1HNMR (300MHz, DMSO) δ 9.44 (s, 2H), 9.29 (s, 2H), 9.14 (s, 1H), 9.01-8.99 (m, 1H), 7.99 (s, 1H), 7.81 (d, J=7.9Hz, 1H), 7.51-7.37 (m, 14H), 5.01 (s, 2H), 4.57 (s, 2H), 4.45-4.41 (m, 2H), 3.58 (s, 2H); HRMS (ES) theoretical value C
28H
29N
6O
5S 561.1920, actual value 561.1917.
Embodiment 2
EX-2A) to 1-benzyl-3-methylene radical carboxyl-5-[[(phenmethyl) alkylsulfonyl] amino]-2; 4 (1H; 3H) pyrimidine dione (439.8mg; 1.024mmol) 10.0ml tetrahydrofuran (THF) and dimethyl formamide (1: 1; 0.1M) add N in the solution, and the N-diisopropylethylamine (1.80ml, 10.30mmol), N-hydroxybenzotriazole (169.3mg; 1.253mmol) and 1-[3-(dimethylamino) propyl group]-the 3-ethyl-carbodiimide hydrochloride (238.2mg, 1.243mmol).The gained mixture stirred 10 minutes.Then in reaction mixture disposable adding amine (648.3mg, 1.231mmol).The gained mixture stirs and spends the night.Reaction mixture with ethyl acetate (100ml) dilution, with 5% citric acid (1 * 50ml), saturated NaHCO
3(1 * 50ml) and salt solution (1 * 50ml) washing.Organic solution drying (MgSO
4), filter, concentrate.Crude reaction product obtains product EX-2A through MPLC purifying (75% ethyl acetate/hexane):
1H NMR (300MHz, DMSO) δ 9.09 (s, 1H), 8.78 (d, J=7.1Hz, 1H), 8.28 (d, J=3.0Hz, 1H), 8.19 (d, J=3.0Hz, 1H), 7.94 (s, 1H), 7.43-7.31 (m, 10H), 6.68 (s, 1H), 5.44-5.43 (m, 1H), 4.97 (s, 2H), 4.56 (d, J=4.2Hz, 2H), 4.41 (s, 2H), 3.80 (s, 3H), 3.08 (br d, J=5.4Hz, 3H), 2.91 (s, 1H), 2.75 (s, 1H), 2.59 (s, 3H), 2.52 (s, 3H), 2.06 (s, 3H), 1.92-1.80 (m, 1H), and 1.61-1.51 (m, 3H), 1.37-133 (m 1H); HRMS (EI) theoretical value C
39H
45N
8O
9S
3865.2472, actual value 865.2484.
In room temperature with under stirring, to EX-2A (281.3mg, add in the 3.0ml trifluoroacetic acid solution (0.1M) 0.3252mmol) thioanisole (0.115ml, 0.9796mmol).The gained mixture stirred 6 hours.Reaction mixture under reduced pressure concentrates.Crude product is through ether development purifying.Filter and collect buff powder,, obtain pure products 2 with the ether washing:
1H?NMR(300MHz，DMSO)δ9.07(s，1H)，8.82(d，J＝7.0Hz，1H)，8.30(d，J＝3.0Hz，1H)，8.21(d，J＝3.0Hz，1H)，7.95(s，1H)，7.55-7.20(m，10H)，5.49-5.48(m，1H)，4.97(s，2H)，4.63-4.51(m，2H)，4.42(s，2H)，3.13(br?d，J＝6.0Hz，2H)，2.49(s，3H)，1.91(br?s，1H)，1.67-1.58(m，4H)；LRMS(EI)，(MH+)653.2.
Utilize embodiment 1 and 2 and 1 illustrational method of flow process, can prepare following compounds.
Embodiment 3
According to 1 illustrational steps A of embodiment and B, and with 3-(N-Boc-amino) bromotoluene (Murakami, Y.; Hagishita, S.; Okada, T.; Kii, M.; Hashizume, H.; Yagami, T.; Fujimoto, M. " biological organic and medical chemistry " (Bioorg.Med.Chem.) 1999,7 1703-1714) replaces bromotoluene, can prepare alkylation intermediate 3-[1-[3-(N-Boc-amino) benzyl]-5-amino-2,4-dioxo pyrimidyl] methyl acetate (EX-3A).
Add 1 equivalent sodium cyanoborohydride in the tetrahydrofuran solution of 1 equivalent (eq.) ester EX-3A and 1 equivalent cyclobutanone, mixture stirs some hrs.Evaporation removes and desolvates, and obtains crude product.Crude product obtains purified 2-[3-[1-[3-(N-Boc-amino) benzyl through the silica gel chromatography purifying]-5-(N-cyclobutyl) amino-2,4-dioxo pyrimidyl]] methyl acetate (EX-3B).
According to embodiment 1 illustrated all the other steps, can obtain the compound of embodiment 3.
The DMF solution of acid amides that 1 equivalent is suitable and 1 equivalent 3-nitrophenyl isocyanic ester is heated to 100 ℃ of some hrs.Evaporation removes and desolvates, and obtains crude product.Crude product obtains purified product 1-[3-nitrophenyl through the silica gel chromatography purifying]-5-nitro-2,4-dioxo pyrimidine (EX-4A).
Under agitation, join in the 1.1 equivalent saleratus the dimethyl sulphoxide solution of 1 equivalent uridylic EX-4A is disposable.After about 10 minutes, go through the dimethyl sulfoxide solution that dripped 1.1 equivalent methyl bromoacetates in 10 minutes.Reaction mixture is heated to 40 ℃, stirs 18 hours.The reaction mixture dilute with water.Aqueous solution ethyl acetate extraction, organic solution water after the merging and salt water washing.Organic solution is through MgSO
4Drying is filtered, and concentrates, and obtains crude product.Crude product obtains purified 2-[3-[1-[3-nitrophenyl through the silica gel chromatography purifying]-5-nitro-2,4-dioxo pyrimidyl]] methyl acetate (EX-4B).
The aqueous solution that in the tetrahydrofuran (THF) of methyl ester EX-4B and methyl alcohol suspension, adds the excessive hydrogen Lithium Oxide 98min.Reactant stirred 1 hour, under reduced pressure removed volatile matter.Remaining aqueous solution cools off in ice bath, is acidified to pH1 with 1.0N HCl, causes the adularescent precipitation to generate.Filter collecting precipitation, dry under vacuum with 1.0N HCl and water washing, obtain pure sour 2-[3-[1-[3-nitrophenyl]-5-nitro-2,4-dioxo pyrimidyl]] acetate (EX-4C).
The dimethyl formamide solution (0.1M) of sour EX-4C is joined 5 equivalent N, N-diisopropylethylamine, 1 equivalent N-hydroxybenzotriazole and 1 equivalent 1-[3-(dimethylamino) propyl group]-the 3-ethyl-carbodiimide hydrochloride in.The gained mixture stirred 30 minutes.Disposable adding 1 equivalent 4-(N-Boc-amidino groups) benzylamine in reaction mixture then.The gained mixture stirs and spends the night.Reaction mixture dilutes with ethyl acetate, with 5% citric acid, saturated NaHCO
3With the salt water washing.Organic solution drying (MgSO
4), filter, concentrate.Through the MPLC purifying, obtain pure N-[4-(N-Boc-amidino benzyl)]-the 2-[3-[1-[3-nitrophenyl]-5-nitro-2,4-dioxo pyrimidyl]] ethanamide (EX-4D).
Under nitrogen atmosphere (gasbag pressure), 10% Pd/C with 5 moles of % handles with the methanol solution of two nitro-compound EX-4D.Suspension stirs and spends the night.Filter by Celite 545, remove again and desolvate, obtain pure N-[4-(N-Boc-amidino benzyl)]-the 2-[3-[1-[3-aminophenyl]-5-amino-2,4-dioxo pyrimidyl]] ethanamide (EX-4E).
With the tetrahydrofuran solution of diamine EX-4E and 1 equivalent cyclobutanone earlier with 1 equivalent sodium cyanoborohydride, use the salt acid treatment of catalytic amount again.Reaction mixture is stirred for several hour at room temperature.Add entry carefully, finish reaction.Aqueous solution ethyl acetate extraction.Organic solution water and salt water washing.Organic solution drying (MgSO
4), filter, concentrate.Through the MPLC purifying, obtain pure N-[4-(N-Boc-amidino benzyl)]-the 2-[3-[1-[3-aminophenyl]-5-(N-cyclobutyl amino-2,4-dioxo pyrimidyl]] ethanamide (EX-4F).
The methanol solution of N-Boc amidine EX-4F is handled with 3 equivalent 4M HCl De dioxane solutions.Solution stirring five hours.Under vacuum, remove and desolvate, with the ether development, obtain pure products again.
Utilize following method can prepare the methylene radical analogue of various pyrimidine diones, wherein methylene radical has replaced the carbonyl of pyrimidine dione N-2 position ethanamide.
Embodiment 5
EX-5A) the DMF solution with 1 equivalent isocyanic acid phenylester and 1 equivalent 3-oxyethyl group-2-nitro acrylamide is heated to 100 ℃ of some hrs.Evaporation removes and desolvates, and obtains crude product.Crude product obtains purified product EX-5A through the silica gel chromatography purifying.
EX-5B) under agitation, disposable adding 1.1 equivalent saleratus in the dimethyl sulphoxide solution of 1 equivalent EX-5A.After about 10 minutes, go through the dimethyl sulphoxide solution that dripped 1.1 equivalent methyl bromoacetates in 10 minutes.Reaction mixture is heated to 40 ℃, stirs 18 hours.The reaction mixture dilute with water.Aqueous solution ethyl acetate extraction, organic solution water after the merging and salt water washing.Organic solution is through MgSO
4Drying is filtered, and concentrates, and obtains crude product.Crude product obtains purified product 2-[3-[5-nitro-2,4-dioxo-1-phenyl pyrimidine base through the silica gel chromatography purifying]] methyl acetate (EX-5B).
EX-5C) diisobutylaluminium hydride (1.05 equivalent) is gone through in the tetrahydrofuran solution that joined the 1 equivalent EX-5B that is cooled to-78 ℃ in 15 minutes.After stirring 1 hour under-78 ℃, under-78 ℃, slowly finish reaction with cold methanol.Mixture slowly is poured among the ice-cold 1NHCl, the aqueous mixture ethyl acetate extraction.MgSO is used in the salt water washing of organic layer after the merging
4Drying is filtered, and under reduced pressure removes and desolvates.Crude product obtains purified aldehyde product EX-5C through the column chromatography purifying.
EX-5D) to 1.0 equivalent aldehyde 2-[3-[5-nitros-2,4-dioxo-1-phenyl pyrimidine base]] acetaldehyde (EX-5C) and 1.0 equivalent amine 4-(N-Boc-amidino groups) benzylamines add 1.2 equivalent sodium triacetoxy borohydrides in the suspension of methylene dichloride and catalytic acetate.Suspension is clarified rapidly, and becomes even.Reactant stirred for several hour.Solution cools off in ice bath, transfers to alkalescence with 1.0NNaOH.Reaction mixture dilutes with methylene dichloride, uses the salt water washing.Organic solution drying (MgSO
4), filter, concentrate, obtain crude product.Crude product obtains purified product 2-[3-2-[2-[2-(4-(N-Boc-amidino groups) benzyl) amino through the silica gel chromatography purifying] ethyl-5-nitro-2,4-dioxo-1-phenyl pyrimidine (EX-5D).
EX-5E) methanol solution with 1 equivalent EX-5D outgases with hydrogen.Add 5% Pd/C of catalytic amount in this solution, reaction mixture stirred 24 hours under room temperature and nitrogen atmosphere.The crude reaction thing filters by Celite 545 pads, under reduced pressure concentrates.Crude product obtains purified product amine 2-[3-2-[2-[2-(4-(N-Boc-amidino groups) benzyl) amino through the silica gel chromatography purifying] ethyl-5-amino-2,4-dioxo-1-phenyl pyrimidine (EX-5E).
EX-5F) in the methylene dichloride of 1.0 equivalent EX-5E and 1.0 equivalent phenylacetic aldehydes and catalytic acetate suspension, add 1.2 equivalent sodium triacetoxy borohydrides.Suspension is clarified rapidly, and becomes even.Reactant stirred for several hour.Solution cools off in ice bath, with 1.0N NaOH alkalization.Reaction mixture dilutes with methylene dichloride, uses the salt water washing.Organic solution drying (MgSO
4), filter, concentrate, obtain crude product.Crude product obtains purified 2-[3-2-[2-[2-(4-(N-Boc-amidino groups) benzyl) amino through the silica gel chromatography purifying] ethyl-5-(N-(2-phenylethyl) amino)-2,4-dioxo-1-phenyl pyrimidine (EX-5F).
In flask, in 1 equivalent EX-5F, add 4M HCl De dioxane solution.The gained solution stirring is spent the night.Solution concentration, crude product is developed from ether, obtains purified product, is dihydrochloride.
Following specific embodiment 6 is described, can prepare the alkylsulfonyl analogue of various pyrimidine diones, and wherein alkylsulfonyl has replaced the carbonyl of pyrimidine dione N-2 position ethanamide.
Embodiment 6
EX-6A) under agitation, join in the 1.1 equivalent saleratus the dimethyl sulphoxide solution of 1 equivalent EX-5A is disposable.After about 10 minutes, go through the dimethyl sulfoxide solution that dripped 1.1 equivalent brooethyl sodium sulfonates in 10 minutes.Reaction mixture is heated to 40 ℃, stirs 18 hours.The reaction mixture dilute with water.Aqueous solution ethyl acetate extraction, organic solution water after the merging and salt water washing.Organic solution is through MgSO
4Drying is filtered, and concentrates, and obtains crude product.Crude product obtains purified product 3-[5-nitro-2,4-dioxo-1-phenyl pyrimidine base through the silica gel chromatography purifying] methylsulfonic acid (EX-6A).
EX-6B) methanol solution with 1 equivalent EX-6A outgases with hydrogen.Add 5% Pd/C of catalytic amount in this solution, reaction mixture stirred 24 hours under room temperature and nitrogen atmosphere.The crude reaction thing filters by Celite 545 pads, under reduced pressure concentrates.Crude product obtains purified product 3-[5-amino-2,4-dioxo-1-phenyl pyrimidine base through the silica gel chromatography purifying] methylsulfonic acid (EX-6B).
EX-6C) add 1.2 equivalent sodium triacetoxy borohydrides in the suspension in methylene dichloride and catalytic acetate to 1.0 equivalent EX-6B and 1.0 equivalent phenylacetic aldehydes.With solution stirring a few hours.Solution cools off in ice bath, with 1.0N NaOH alkalization.Reaction mixture dilutes with methylene dichloride, uses the salt water washing.Organic solution drying (MgSO
4), filter, concentrate, obtain crude product.Crude product obtains purified product 3-[5-[N-(2-phenylethyl) amino through the silica gel chromatography purifying]-2,4-dioxo-1-phenyl pyrimidine base] methylsulfonic acid (EX-6C).
EX-6D) solution of 1 equivalent EX-6C in methylene dichloride and several dimethyl formamides is cooled to 0 ℃.Thionyl chloride (1.1 equivalent), solution slowly is warmed to room temperature.After reacting completely, under reduced pressure remove volatile constituent, use the SULPHURYL CHLORIDE product immediately.SULPHURYL CHLORIDE is dissolved in methylene dichloride, in chloride solution, adds suitable amine 4-(N-Boc-amidino groups) benzylamine and the 5 equivalent N-methylmorpholines of 1 equivalent.After reacting completely, add polyacetals and/or versamid 900 (10 equivalent), to remove all unreacted raw materials.With resin filter, with DMF/DCM (1: 1) washing, under reduced pressure remove and desolvate, obtain pure N-[4-(N-Boc-amidino groups) benzyl]-3-[5-[N-(2-phenylethyl) amino]-2,4-dioxo-1-phenyl pyrimidine base] Toluidrin (EX-6D).
In flask, in 1 equivalent EX-6D, add 4M HCl De dioxane solution.The gained solution stirring is spent the night.Concentrated solution, crude product is developed from ether, obtains the clean product of embodiment 6.
Following specific embodiment 7 is described, can prepare the triazinediones (aza analogues) of uridylic (being pyrimidine dione), and wherein nitrogen has replaced the carbon on the pyrimidine dione 5-position.
Embodiment 7
EX-7A) with aniline (1; 50mmol), dense HCl (10ml) is cooled to 5 ℃ with the mixture of water (50ml).Water (7.2ml) solution with Sodium Nitrite (50mmol) is cooled to 5 ℃ in addition, utilizes the filling tube of liquid level below to join in the anilinechloride slurries.During adding and maintained the temperature at 5 ℃ in 1 hour afterwards.This diazotization aniline (EX-7A) solution is used in next step.
EX-7B) cyano group acetyl urethane (59mmol), pyridine (656ml), ice (216g) are remained under 5 ℃ with the mixture of water (40ml), under agitation go through the slurries that added EX-67A in 15 minutes simultaneously.After one hour, filtering separation obtains orange solids N-ethoxycarbonyl-2-cyano group-2-(N-phenyl hydrazono-) ethanamide (EX-7B) at 5 ℃ of following restir.
EX-7C) EX-7B (95mmol), sodium acetate (110mmol) were refluxed 75 minutes with the mixture of acetate (140ml).The gained settled solution under reduced pressure concentrates, and filters to isolate solid, washes with water.With compound 6-cyano group-2-phenyl-3,5-dioxo-1,2,4-triazine (EX-7C) recrystallization from 95% ethanol.
EX-7D) with compd E X-7C (50mmol), 6N HCl (190ml) Yu the mixture of diox (500ml) refluxed 12 hours.Cooling institute crystalline product, filtering separation 6-(2-phenyl-3,5-dioxo-1,2,4-triazinyl) carboxylic acid (EX-7D), recrystallization from methanol-water.
EX-7E) sour EX-7D (8.4mmol) is dissolved in anhydrous tertiary butanol (127ml) and DPPA (9.3mmol), adds triethylamine (9.3mmol).Solution refluxed 24 hours then.Concentrate solution in a vacuum this moment.Just resistates is dissolved in methylene dichloride (150ml), with 0.5N citric acid (150ml), 1N NaHCO
3(150ml) and water (150mL) washing.Dry methylene chloride solution (sodium sulfate) then.Filter and concentrate, obtain the compd E X-7E of Boc protection.If necessary, this material can pass through chromatogram purification.
EX-7F) under agitation, DMF (150ml) solution of compd E X-7E (50mmol) is disposable with salt of wormwood (55mmol) processing.After about 10 minutes, DMF (100ml) solution of dripping bromine methyl acetate (50mmol).Reaction mixture is heated to 40 ℃, stirs 18 hours.Through typical water treatment and chromatogram purification, obtain pure 2-(2-phenyl-3,5-dioxo-6-(N-Boc-amino)-1,2,4-triazinyl) methyl acetate (EX-7F).
EX-7G) compd E X-7F (50mmol) is dissolved in methylene dichloride (400ml), and handles with TFA (100ml).Gained solution at room temperature stirred 4 hours then.Concentrate and develop, obtain the tfa salt (EX-7G) of 2-(2-phenyl-3,5-dioxo-6-amino-1,2,4-triazinyl) methyl acetate with ether.
EX-7H) with the tetrahydrofuran (THF) of compd E X-7G and dichloromethane solution (1: 1,0.3M) handle with 1 equivalent phenylacetic aldehyde and 0.9 equivalent triethylamine.Solution is cooled to 0 ℃, handles with 1 equivalent sodium triacetoxy borohydride.Stir after 5 minutes, remove ice bath, make reaction mixture be warmed to room temperature, stirred 2 hours.Add 1N NaOH and finish reaction, mixture stirred 5 minutes.The laggard circumstances in which people get things ready for a trip spectrum of typical water treatment purifying obtains pure products 2-(2-phenyl-3,5-dioxo-6-(N-(2-phenylethyl) amino)-1,2,4-triazinyl) methyl acetate (EX-7H).
EX-7I) THF (250ml) solution of compd E X-7H (50mmol) is handled with LiOH (50mmol).After the hydrolysis fully, under reduced pressure remove volatile matter.Remaining aqueous solution cools off in ice bath, is acidified to pH1 with 1.0N HCl.Aqueous mixture extracts with EtOAc.EtOAc solution drying (sodium sulfate) is filtered, and concentrates, and obtains pure 2-(2-phenyl-3,5-dioxo-6-(N-(2-phenylethyl) amino)-1,2,4-triazinyl) acetate (EX-7I).
EX-7J) DMF (250ml) solution of compd E X-7I (50mmol) is handled with N-hydroxybenzotriazole (60mmol) and EDC hydrochloride (60mmol).Mixture at room temperature stirred 30 minutes, and handled with 4-(N-Cbz-amidino groups) benzylamine (50mmol).The gained mixture stirs and spends the night.The laggard circumstances in which people get things ready for a trip spectrum of typical water treatment purifying obtains pure product N-(4-Cbz-amidino benzyl)-2-(2-phenyl-3,5-dioxo-6-(N-(2-phenylethyl) amino)-1,2,4-triazinyl) ethanamide (EX-7J).
The methyl alcohol (300ml) of compd E X-7J (50mmol) is outgased with hydrogen with 4M HCl-diox (100ml) solution.Add 5% Pd (C) (0.5g), solution stirred 24 hours under room temperature and nitrogen atmosphere.Reaction mixture filters by Celite 545 pads, under reduced pressure concentrates.Through the reverse-phase chromatography purifying, obtain pure embodiment 7 products.
Utilize these methods, those of ordinary skills or can prepare the The compounds of this invention of a large amount of novelties.
Formula of the present invention (I) compound with hydroxyl, sulfydryl and amine functional group can be converted into multiple derivative.Perhaps, one or more intermediates in the preparation process of at first deriving, the intermediate after further will deriving again is converted into formula (I) compound, formula (I) compound after can obtaining deriving.Alcohol or phenol type hydroxyl are easy to be converted into the ester of carboxylic acid, sulfonic acid, carboxylamine, phosphonic acids and phosphoric acid.Use the acylating agent that is fit to be easy to carry out acylation, generate carboxylicesters, acylating agent is aliphatic anhydrides or acyl chlorides for example.Also can use corresponding aryl and heteroaryl acid anhydrides and acyl chlorides.The general amine catalyst that uses of this class reaction carries out in inert solvent, and catalyzer is pyridine for example.Similarly, the reaction by hydroxyl and isocyanic ester and urea chloride can obtain carbamate (urethane).Use corresponding acyl chlorides and similar agents can prepare sulphonate, phosphonic acid ester and phosphoric acid ester.Formula (I) compound with at least one sulfydryl can be converted into corresponding thioester derivative, be similar to use with the reacting phase that carries out pure and mild phenol with reagent and suitable reaction conditions.Formula (I) compound with at least one primary amine or secondary amine group can be converted into the corresponding amide derivative.Use suitable acyl chlorides or acid anhydrides being similar to the acid amides that can prepare carboxylic acid under the used reaction conditions of pure and mild phenol.In the presence of a kind of acid scavenger, for example triethylamine or pyridine use isocyanic ester and urea chloride can directly prepare the urea of corresponding primary amines or secondary amine.In the presence of aqueous NaOH or tertiary amine, can prepare sulphonamide from corresponding SULPHURYL CHLORIDE.Being suitable for preparing the step of these derivatives and method can be referring to " House modern synthesis " (House ' s Modern SyntheticReactions) W.A.Benjamin, Inc., Shriner, Fuson, and Curtin " system of organic compound differentiates " (Systemic Identification of OrganicCompounds) the 5th edition John Wiley ﹠amp; Sons, Fieser and Fieser " organic synthesis reagent " (0rganic Synthetic Reagents) the 1st volume John Wiley ﹠amp; Sons.The plurality of reagents of hydroxyl, sulfydryl and amine of formula (I) compound of can being used to derive can obtain from commercial source or above-mentioned reference, and these documents are incorporated herein by reference.
Formula of the present invention (I) compound with hydroxyl, sulfydryl and amine functional group can turn to multiple derivative by alkyl.Perhaps, at first alkylation prepares one or more intermediates in the process, further alkylating intermediate is converted into formula (I) compound again, can obtain alkylating formula (I) compound.The hydroxyl of formula (I) compound is easy to be converted into ether.Use the alkylating agent that is fit to be easy to carry out alkylating, generate ether, alkylating agent is alkyl bromide, alkyl iodide or alkyl sulfonic ester for example.Also can use bromide, iodide and the sulphonate of corresponding aralkyl, heteroaralkyl, alkoxyalkyl, sweet-smelling alkoxy alkyl and assorted sweet-smelling alkoxy alkyl.This class reaction is general uses alcoholate generation agent to carry out, for example sodium hydride, potassium tert.-butoxide, sodium amide, lithium amide and n-Butyl Lithium, and use inert polar solvents, for example DMF, DMSO, THF and similar suitable solvent, and amine catalyst, as pyridine.Formula (I) compound with at least one sulfydryl can be converted into the sulfide derivative that is similar to pure and mild phenol accordingly, is similar to use identical reagent and suitable reaction conditions to react.Formula (I) compound with at least one primary amine, secondary amine or tertiary amine group can be converted into corresponding secondary ammonium, tertiary amine or quaternary ammonium derivative.Use is similar to pure and mild phenol used suitable bromide, iodide and sulphonate can prepare quaternary ammonium derivative.The reaction conditions of amine relates to the amine (being tertiary amine monovalent, secondary amine two equivalents, primary amine three equivalents) of heating alkylating agent and stoichiometric quantity.About primary amine and secondary amine, use the acid scavenger that is respectively two equivalents and monovalent simultaneously.Can prepare secondary amine or tertiary amine from corresponding primary amines or secondary amine.In the presence of glacial acetic acid, use aldehyde, for example formaldehyde and sodium cyanoborohydride to carry out the reduction amination effect, can the dialkyl group primary amine.At first with being easy to cracked blocking group protection amine, trifluoroacetyl group for example can an alkylation primary amine.In the presence of non-nucleophilicity alkali, Barton alkali (the 2-tertiary butyl-1,1,3,3-tetramethyl guanidine) for example, amine and alkylating agent, for example methyl-sulfate reaction obtains monomethylated protected amine.Use aqueous potassium hydroxide to remove blocking group, obtain a required alkylating amine.Other step and methods that are suitable for preparing these derivatives can be referring to " House modern synthesis " W.A.Benjamin, Inc., Shriner, Fuson, and the 5th edition John Wiley ﹠amp of Curtin " system of organic compound differentiates "; Sons, Fieser and Fieser " organic synthesis reagent " the 1st volume John Wiley ﹠amp; Sons.(J.Chem.Soc.ChemistryCommunications) can prepare perfluoroalkyl derivatives as described in 2241 (1998) as DesMarteau " Englishize association will chemical communication ".The plurality of reagents of hydroxyl, sulfydryl and amine of formula (I) compound of can being used to derive can obtain from commercial source or above-mentioned reference, and these documents are incorporated herein by reference.
Determination of biological activity
TF-VIIa measures
This joins the 100nM recombinant soluble tissue factor and the 2nM recombinant human VIIa factor in the 96 hole assay plates in measuring, and wherein contains 0.4mM substrate N-methyl sulphonyl-D-phe-gly-arg-p-Nitraniline and inhibitor or buffer reagent (5mM CaCl
2, 50mMTris-HCl, pH8.0,100mM NaCl, 0.1% BSA).Measuring final volume immediately under 405nm is the reactant of 100 μ l, to measure background absorption.With flat board constant temperature 60 minutes at room temperature, measure the hydrolysis rate of substrate this moment by the release reaction of the p-Nitraniline under the monitoring 405nm.OD from experiment and check sample
405nmValue is calculated the active restraining effect % of TF-VIIa.
Xa measures
0.3nM people's Xa factor and 0.15mM N-α-carbobenzoxy-(Cbz)-D-arginyl-L-glutamy-L-arginine-p-Nitraniline-dihydrochloride (S-2765) are joined in the 96 hole assay plates, wherein contain inhibitor or buffer reagent (50mM Tris-HCl, pH8.0,100mMNaCl, 0.1% BSA).Measuring final volume immediately under 405nm is the reactant of 100 μ l, to measure background absorption.With flat board constant temperature 60 minutes at room temperature, measure the hydrolysis rate of substrate this moment by the release reaction of the p-Nitraniline under the monitoring 405nm.OD from experiment and check sample
405nmValue is calculated the restraining effect % to xa activity.
Zymoplasm is measured
But 0.28nM human thrombin and 0.06mM H-D-phenylalanyl-L-piperazine acyl-L-arginine-p-Nitraniline-dihydrochloride are joined in the 96 hole assay plates, wherein contain inhibitor or buffer reagent (50mM Tris-HCl, pH8.0,100mM NaCl, 0.1% BSA).Measuring final volume immediately under 405nm is the reactant of 100 μ l, to measure background absorption.With flat board constant temperature 60 minutes at room temperature, measure the hydrolysis rate of substrate this moment by the release reaction of the p-Nitraniline under the monitoring 405nm.OD from experiment and check sample
405nmValue is calculated the restraining effect % to thrombin activity.
Trypsinase is measured
5 μ g/ml are joined in the 96 hole assay plates from the IX type trypsinase and the 0.375mM N-α-benzoyl-L-arginine-right-nitro anilid (L-BAPNA) of pig pancreas; wherein contain inhibitor or buffer reagent (50mM Tris-HCl; pH8.0,100mM NaCl, 0.1% BSA).Measuring final volume immediately under 405nm is the reactant of 100 μ l, to measure background absorption.With flat board constant temperature 60 minutes at room temperature, measure the hydrolysis rate of substrate this moment by the release reaction of the p-Nitraniline under the monitoring 405nm.OD from experiment and check sample
405nmValue is calculated the restraining effect % to tryptic activity.
The recombinant soluble TF that is made up of the amino acid/11-219 of mature protein sequence at e. coli expression is with single Q agarose FPLC purifying.Recombinant human VIIa is available from AmericanDiagnostica, and Greenwich CT, chromogenic substrate N-methyl sulphonyl-D-phe-gly-arg-p-Nitraniline are by American Peptide Company, Inc., Sunnyvale, the CA preparation.Xa factor is from Enzyme ResearchLaboratories, and South Bend IN obtains, and zymoplasm is from Calbiochem, La Jolla, and CA obtains, and trypsinase and L-BAPNA are from Sigma, and St.LouisMO obtains.Chromogenic substrate S-2765 and S-2238 be available from Chromogenix, Sweden.
The biologic activity of embodiment 1 to 7 compound of measuring as these bioassay methods is summarised in the table 1.
Table 1: uridylic is to the inhibition activity of Xa factor, TF-VIIa, zymoplasm II and trypsinase II
| The embodiment numbering | ???TF-VIIa ??IC50(μM) | Zymoplasm II IC50 (μ M) | Xa factor IC50 (μ M) | Trypsinase II IC50 (μ M) |
| ????1 | ????＞100 | ????13.0 | ????25.6 | ????0.4 |
| ????2 | ????12.9 | ????0.3 | ????0.2 | ????0.2 |
Claims (50)
1. the compound that has following formula:
Or its pharmacy acceptable salt, wherein: B is a formula V:
D wherein
1, D
2, J
1, J
2And K
1Be independently selected from C, N, O, S and covalent linkage, its condition be at the most one can be covalent linkage, D
1, D
2, J
1, J
2And K
1At the most one be O, D
1, D
2, J
1, J
2And K
1At the most one be S, if D
1, D
2, J
1, J
2And K
1Two be O and S, then D
1, D
2, J
1, J
2And K
1One of must be covalent linkage, D
1, D
2, J
1, J
2And K
1At the most four be N;
R
9, R
10, R
11, R
12, R
13, R
32, R
33, R
34, R
35And R
36Be independently selected from hydrogen, kharophen, the halo kharophen, amidino groups, guanidine radicals, alkylene dioxo base, halogenated alkylthio, alkanoyloxy, alkoxyl group, alkoxyalkyl, halogenated alkoxy alkyl, hydroxyl, amino, alkoxy amino, nitro, low-grade alkyl amino, alkylthio, alkylthio alkyl, alkyl sulphinyl, alkyl sulphonyl, the alkyl sulphonyl alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclic radical, alkyl sulfonyl amino, alkyl amino sulfonyl, the amido alkylsulfonyl, one alkyl amido alkylsulfonyl, dialkyl group amido alkylsulfonyl, alkyloyl, the haloalkane acyl group, alkyl, thiazolinyl, halogen, haloalkyl, haloalkenyl group, halogenated alkoxy, the hydroxy halogeno alkyl, hydroxyalkyl, aminoalkyl group, halogenated alkoxy alkyl, carboxyalkyl, the carboxylic alkoxyl group, carboxyl, carboxamido, carboxamido alkyl and cyano group;
R
16, R
19, R
32, R
33, R
34, R
35And R
36Randomly be Q independently
b, its condition is R
16And R
19At the most one be Q simultaneously
b, and Q
bBe Q
Be
B randomly is selected from hydrogen, trialkylsilkl, C2-C8 alkyl, C3-C8 thiazolinyl, C3-C8 alkylidene group, C3-C8 alkynyl and C2-C8 haloalkyl, wherein each member of group B can be randomly at distance B and A tie point nearly and comprise on any carbon of 6 atoms by one or more radicals R
32, R
33, R
34, R
35And R
36Replace;
B randomly is selected from C3-C12 cycloalkyl and the saturated heterocyclic radical of C4-C9, and wherein each ring carbon is randomly by R
33Replace, the ring carbon except that the ring carbon that is positioned at B and A tie point is randomly replaced by oxo, and its condition is that a ring carbon is replaced by oxo simultaneously at the most, and ring carbon adjacent with the ring carbon that is positioned at tie point and nitrogen-atoms are randomly by R
9Or R
13Replace, with R
9The position adjacent and apart from the ring carbon of two atoms of tie point or nitrogen-atoms randomly by R
10Replace, with R
13The position adjacent and apart from the ring carbon of two atoms of tie point or nitrogen-atoms randomly by R
12Replace, apart from three atoms of tie point and and R
10Ring carbon that the position is adjacent or nitrogen-atoms are randomly by R
11Replace, apart from three atoms of tie point and and R
12Ring carbon that the position is adjacent or nitrogen-atoms are randomly by R
33Replace, and apart from four atoms of tie point and and R
11And R
33Ring carbon that the position is adjacent or nitrogen-atoms are randomly by R
34Replace;
A is selected from covalent single bond, (W
7)
Rr-(CH (R
15))
Pa(CH (R
15))
Pa-(W
7)
Rr, wherein rr is selected from 0 to 1 integer, and pa is selected from 0 to 6 integer, W
7Be selected from O, S, C (O), (R
7) NC (O), (R
7) NC (S) and N (R
7), its condition be rr and pa at the most one be 0 simultaneously;
R
7Be selected from hydrogen, hydroxyl and alkyl;
R
15Be selected from hydrogen, hydroxyl, halogen, alkyl and haloalkyl;
Ψ is selected from NH and NOH;
M is selected from N and R
1-C;
R
1Be selected from hydrogen, alkyl, thiazolinyl, cyano group, halogen, haloalkyl, halogenated alkoxy, halogenated alkylthio, amino, aminoalkyl group, alkylamino, amidino groups, hydroxyl, hydroxyl amino, alkoxyl group, hydroxyalkyl, alkoxy amino, sulfydryl and alkylthio;
R
2Be Z
0-Q;
Z
0Be selected from covalent single bond, (CR
41R
42)
q, (CH (R
41))
g-W
0-(CH (R
42))
p(CH (R
41))
e-W
22-(CH (R
42))
h, wherein q is selected from 1 to 3 integer, and g and p are independently selected from 0 to 3 integer, W
0Be selected from O, S, C (O), S (O), N (R
41) and ON (R
41), e and h are independently selected from 0 to 1 integer, W
22Be selected from CR
41=CR
421, the 2-cyclopropyl, 1, the 2-cyclobutyl, 1, the 2-cyclohexyl, 1, the 3-cyclohexyl, 1, the 2-cyclopentyl, 1, the 3-cyclopentyl, 2, morpholinyl, 2, the 4-morpholinyl, 2, the 6-morpholinyl, 3, the 4-morpholinyl, 3, the 5-morpholinyl, 1, the 2-piperazinyl, 1, the 3-piperazinyl, 2, the 3-piperazinyl, 2, the 6-piperazinyl, 1, the 2-piperidyl, 1, the 3-piperidyl, 2, the 3-piperidyl, 2, the 4-piperidyl, 2, the 6-piperidyl, 3, the 4-piperidyl, 1, the 2-pyrrolidyl, 1, the 3-pyrrolidyl, 2, the 3-pyrrolidyl, 2, the 4-pyrrolidyl, 2, the 5-pyrrolidyl, 3, the 4-pyrrolidyl, 2, the 3-tetrahydrofuran base, 2, the 4-tetrahydrofuran base, 2,5-tetrahydrofuran base and 3, the 4-tetrahydrofuran base, its condition is Z
0Direct and pyrazine ketone ring key closes;
R
41And R
42Be independently selected from amidino groups, hydroxyl amino, hydrogen, hydroxyl, amino and alkyl;
Q is selected from hydrogen, and its condition is Z
0It or not covalent single bond; And formula (II):
D wherein
1, D
2, J
1, J
2And K
1Be independently selected from C, N, O, S and covalent linkage, its condition be at the most one be covalent linkage, D
1, D
2, J
1, J
2And K
1At the most one be O, D
1, D
2, J
1, J
2And K
1At the most one be S, if D
1, D
2, J
1, J
2And K
1Two be O and S, then D
1, D
2, J
1, J
2And K
1One of must be covalent linkage, D
1, D
2, J
1, J
2And K
1At the most four be N, its condition is R
9, R
10, R
11, R
12And R
13Selected independently of one another, with the tetravalence character of keeping carbon, the trivalent character of nitrogen, the divalence character of sulphur and the divalence character of oxygen;
K is (CR
4aR
4b)
n, wherein n is selected from 1 to 2 integer;
R
4aAnd R
4bBe independently selected from halogen, hydrogen, hydroxyalkyl, alkyl, alkoxyalkyl, alkylthio alkyl and haloalkyl;
If K is (CR
4aR
4b)
n, E then
0Be E
1, E wherein
1Be selected from covalent single bond, C (O), C (S), C (O) N (R
7), (R
7) NC (O), S (O)
2, (R
7) NS (O)
2And S (O)
2N (R
7);
Y
0Be formula (IV):
D wherein
5, D
6, J
5And J
6Be independently selected from C, N, O, S and covalent linkage, its condition be at the most one be covalent linkage, K
2Be C, D
5, D
6, J
5And J
6At the most one be O, D
5, D
6, J
5And J
6At the most one be S, if D
5, D
6, J
5And J
6Two be O and S, then D
5, D
6, J
5And J
6One of must be covalent linkage, D
5, D
6, J
5And J
6At the most four be N;
R
16, R
17, R
18And R
19Be independently selected from hydrogen, amidino groups, guanidine radicals, carboxyl, halogenated alkylthio, alkoxyl group, hydroxyl, amino, nitro, alkoxy amino, low-grade alkyl amino, alkylthio, alkyl sulphinyl, alkyl sulphonyl, alkyloyl, haloalkane acyl group, alkyl, thiazolinyl, halogen, haloalkyl, halogenated alkoxy, hydroxyalkyl, alkylamino, halogenated alkoxy alkyl, carbalkoxy and cyano group;
Q
bBe selected from NR
20R
21, aminoalkyl group thiazolinyl, Q
Be, N (R
26) C (NR
25) N (R
23) (R
24) and C (NR
25) NR
23R
24, Q wherein
BeBe hydrogen, its condition is R
20And R
21At the most one be hydroxyl, amino, alkylamino or dialkyl amido simultaneously, R
23And R
24At the most one be hydroxyl, amino, alkylamino or dialkyl amido simultaneously;
R
20, R
21, R
23, R
24, R
25And R
26Be independently selected from hydrogen, alkyl, hydroxyl, amino alkylidenyl, amino, dialkyl amido, alkylamino and hydroxyalkyl;
Q
sBe selected from covalent single bond, (CR
37R
38)
b(CH (R
14))
c-W
1-(CH (R
15))
d, wherein b is selected from 1 to 4 integer, and c and d are independently selected from 1 to 3 integer, W
1Be selected from C (O) N (R
14), (R
14) NC (O), S (O), S (O)
2, S (O)
2N (R
14), N (R
14) S (O)
2And N (R
14), its condition is R
14If direct and N bonding then is selected from the group except that halo, (CR
37R
38)
b(CH (R
14))
cWith E
0Bonding;
R
14Be selected from hydrogen, halogen, alkyl and haloalkyl;
R
37And R
38Be independently selected from hydrogen, alkyl and haloalkyl;
R
38Randomly be selected from aroyl and 4-hetaroylpyrazol;
Y
0Randomly be Q
b-Q
Ss, Q wherein
SsBe (CH (R
14)
e-W
2-(CH (R
15))
h, wherein e and h are independently selected from 1 to 2 integer, W
2Be CR
4a=CR
4b, its condition is (CH (R
15))
eWith E
0Bonding;
Y
0Randomly be selected from Q
b-Q
SsssAnd Q
b-Q
Ssssr, Q wherein
SsssBe (CH (R
38))
r-W
5, Q
SsssrBe (CH (R
38))
r-W
6, r is selected from 1 to 2 integer, W
5And W
6Be independently selected from 1, the 4-indenyl, 1, the 5-indenyl, 1, the 6-indenyl, 1, the 7-indenyl, 2, the 7-indenyl, 2, the 6-indenyl, 2, the 5-indenyl, 2, the 4-indenyl, 3, the 4-indenyl, 3, the 5-indenyl, 3, the 6-indenyl, 3, the 7-indenyl, 2, the 4-benzofuryl, 2, the 5-benzofuryl, 2, the 6-benzofuryl, 2, the 7-benzofuryl, 3, the 4-benzofuryl, 3, the 5-benzofuryl, 3, the 6-benzofuryl, 3, the 7-benzofuryl, 2, the 4-benzothienyl, 2, the 5-benzothienyl, 2, the 6-benzothienyl, 2, the 7-benzothienyl, 3, the 4-benzothienyl, 3, the 5-benzothienyl, 3, the 6-benzothienyl, 3, the 7-benzothienyl, 2, and the 7-imidazo (1,2-a) pyridyl, 3,4-imidazo (1,2-a) pyridyl, 3, and the 5-imidazo (1,2-a) pyridyl, 3,6-imidazo (1,2-a) pyridyl, 3, and the 7-imidazo (1,2-a) pyridyl, 2, the 4-indyl, 2, the 5-indyl, 2, the 6-indyl, 2, the 7-indyl, 3, the 4-indyl, 3, the 5-indyl, 3, the 6-indyl, 3, the 7-indyl, 1, the 4-pseudoindoyl, 1, the 5-pseudoindoyl, 1, the 6-pseudoindoyl, 2, the 4-pseudoindoyl, 2, the 5-pseudoindoyl, 2, the 6-pseudoindoyl, 2, the 7-pseudoindoyl, 1, the 3-pseudoindoyl, 3, the 4-indazolyl, 3, the 5-indazolyl, 3, the 6-indazolyl, 3, the 7-indazolyl, 2, the 4-benzoxazolyl, 2, the 5-benzoxazolyl, 2, the 6-benzoxazolyl, 2, the 7-benzoxazolyl, 3,4-benzoisoxazole base, 3,5-benzoisoxazole base, 3,6-benzoisoxazole base, 3,7-benzoisoxazole base, 1, the 4-naphthyl, 1, the 5-naphthyl, 1, the 6-naphthyl, 1, the 7-naphthyl, 1, the 8-naphthyl, 2, the 4-naphthyl, 2, the 5-naphthyl, 2, the 6-naphthyl, 2, the 7-naphthyl, 2, the 8-naphthyl, 2, the 4-quinolyl, 2, the 5-quinolyl, 2, the 6-quinolyl, 2, the 7-quinolyl, 2, the 8-quinolyl, 3, the 4-quinolyl, 3, the 5-quinolyl, 3, the 6-quinolyl, 3, the 7-quinolyl, 3, the 8-quinolyl, 4, the 5-quinolyl, 4, the 6-quinolyl, 4, the 7-quinolyl, 4, the 8-quinolyl, 1, the 4-isoquinolyl, 1, the 5-isoquinolyl, 1, the 6-isoquinolyl, 1, the 7-isoquinolyl, 1, the 8-isoquinolyl, 3, the 4-isoquinolyl, 3, the 5-isoquinolyl, 3, the 6-isoquinolyl, 3, the 7-isoquinolyl, 3, the 8-isoquinolyl, 4, the 5-isoquinolyl, 4, the 6-isoquinolyl, 4, the 7-isoquinolyl, 4, the 8-isoquinolyl, 3,4-cinnolines base, 3,5-cinnolines base, 3,6-cinnolines base, 3,7-cinnolines base, 3,8-cinnolines base, 4,5-cinnolines base, 4,6-cinnolines base, 4,7-cinnolines base and 4,8-cinnolines base removes W
5And W
6Tie point beyond, each contains the W of carbon and hydrogen
5And W
6Ring nitrogen member all randomly by one or more by R
9, R
10, R
11And R
12The group of the group of forming replaces, and its condition is Q
bWith each W
5Lowest number substituting group position bonding, Q
bWith each W
6The highest numbering substituting group position bonding, (CH (R
38))
rWith E
0Bonding.
2. the compound with following formula as claimed in claim 1:
Or its pharmacy acceptable salt, wherein:
B is selected from aryl and heteroaryl, and the adjacent carbon of the carbon on one of them and the tie point is randomly by R
32Replace, the adjacent carbon of the carbon on another and the tie point is randomly by R
36Replace, with R
32Adjacent and apart from the carbon of two atoms of the carbon on the tie point randomly by R
33Replace, with R
36Adjacent and apart from the carbon of two atoms of the carbon on the tie point randomly by R
35Replace any and R
33And R
35All adjacent carbon is randomly by R
34Replace;
R
32, R
33, R
34, R
35And R
36Be independently selected from hydrogen; kharophen; the halo kharophen; amidino groups; guanidine radicals; alkylene dioxo base; halogenated alkylthio; alkanoyloxy; alkoxyl group; hydroxyl; amino; alkoxy amino; the haloalkane acyl group; nitro; low-grade alkyl amino; alkylthio; aryl; aralkyl; cycloalkyl; cycloalkylalkyl; heteroaryl; heterocyclic radical; alkyl sulfonyl amino; the amido alkylsulfonyl; one alkyl amido alkylsulfonyl; dialkyl group amido alkylsulfonyl; alkyl; thiazolinyl; halogen; haloalkyl; haloalkenyl group; halogenated alkoxy; hydroxyalkyl; alkylamino; carbalkoxy; carboxyl; carboxamido; cyano group and Q
b
B randomly is selected from hydrogen, trialkylsilkl, C2-C8 alkyl, C3-C8 alkylidene group, C3-C8 thiazolinyl, C3-C8 alkynyl and C2-C8 haloalkyl, wherein each member of group B can be randomly at distance B and A tie point nearly and comprise on any carbon of 6 atoms by one or more radicals R
32, R
33, R
34, R
35And R
36Replace;
B randomly is selected from C3-C12 cycloalkyl and the saturated heterocyclic radical of C4-C9, and wherein each ring carbon is randomly by R
33Replace, the ring carbon except that the ring carbon that is positioned at B and A tie point is randomly replaced by oxo, and its condition is that a ring carbon is replaced by oxygen simultaneously at the most, and ring carbon adjacent with the carbon atom that is positioned at tie point and nitrogen-atoms are randomly by R
9Or R
13Replace, with R
9The position adjacent and apart from the ring carbon of two atoms of tie point or nitrogen-atoms randomly by R
10Replace, with R
13The position adjacent and apart from the ring carbon of two atoms of tie point or nitrogen-atoms randomly by R
12Replace, apart from three atoms of tie point and and R
10Ring carbon that the position is adjacent or nitrogen-atoms are randomly by R
11Replace, apart from three atoms of tie point and and R
12Ring carbon that the position is adjacent or nitrogen-atoms are randomly by R
33Replace, apart from four atoms of tie point and and R
11And R
33Ring carbon that the position is adjacent or nitrogen-atoms are randomly by R
34Replace;
R
9, R
10, R
11, R
12And R
13Be independently selected from hydrogen, kharophen, the halo kharophen, alkoxy amino, alkyloyl, the haloalkane acyl group, amidino groups, guanidine radicals, alkylene dioxo base, halogenated alkylthio, alkoxyl group, hydroxyl, amino, low-grade alkyl amino, alkylthio, alkyl sulphinyl, alkyl sulphonyl, alkyl sulfonyl amino, the amido alkylsulfonyl, one alkyl amido alkylsulfonyl, dialkyl group amido alkylsulfonyl, alkyl, halogen, haloalkyl, halogenated alkoxy, hydroxyalkyl, aminoalkyl group, carbalkoxy, carboxyalkyl, carboxyl, carboxamido and cyano group;
R
9, R
10, R
11, R
12And R
13Randomly be selected from heteroaryl and heterocyclic radical, its condition is R
9, R
10, R
11, R
12And R
13It is the substituting group except that B;
A is selected from covalent single bond and (CH (R
15))
Pa-(W
7)
Rr, wherein rr is selected from 0 to 1 integer, and pa is selected from 0 to 3 integer, W
7Be selected from O, S, C (O), (R
7) NC (O), (R
7) NC (S) and N (R
7);
R
7Be selected from hydrogen, hydroxyl and alkyl;
R
15Be selected from hydrogen, hydroxyl, halogen, alkyl and haloalkyl;
M is selected from N and R
1-C;
R
1Be selected from hydrogen, alkyl, cyano group, halogen, haloalkyl, halogenated alkoxy, amino, aminoalkyl group, alkylamino, amidino groups, hydroxyl, hydroxyl amino, alkoxyl group, hydroxyalkyl, alkoxy amino, sulfydryl and alkylthio;
R
2Be Z
0-Q;
Z
0Be selected from covalent single bond, (CR
41R
42)
q, (CH (R
41))
g-W
0-(CH (R
42))
p(CH (R
41))
e-W
22-(CH (R
42))
h, wherein q is selected from 1 to 2 integer, and g and p are independently selected from 0 to 3 integer, W
0Be selected from O, S and N (R
41), e and h are independently selected from 0 to 1 integer, W
22Be selected from CR
41=CR
421, the 2-cyclopropyl, 1, the 2-cyclobutyl, 1, the 2-cyclohexyl, 1, the 3-cyclohexyl, 1, the 2-cyclopentyl, 1, the 3-cyclopentyl, 2, morpholinyl, 2, the 4-morpholinyl, 2, the 6-morpholinyl, 3, the 4-morpholinyl, 3, the 5-morpholinyl, 1, the 2-piperazinyl, 1, the 3-piperazinyl, 2, the 3-piperazinyl, 2, the 6-piperazinyl, 1, the 2-piperidyl, 1, the 3-piperidyl, 2, the 3-piperidyl, 2, the 4-piperidyl, 2, the 6-piperidyl, 3, the 4-piperidyl, 1, the 2-pyrrolidyl, 1, the 3-pyrrolidyl, 2, the 3-pyrrolidyl, 2, the 4-pyrrolidyl, 2, the 5-pyrrolidyl, 3, the 4-pyrrolidyl, 2, the 3-tetrahydrofuran base, 2, the 4-tetrahydrofuran base, 2,5-tetrahydrofuran base and 3, the 4-tetrahydrofuran base, its condition is Z
0Direct and pyrazine ketone ring key closes;
R
41And R
42Be independently selected from hydrogen, hydroxyl and amino;
Q is selected from hydrogen, and its condition is Z
0It or not covalent single bond; The adjacent carbon of carbon on aryl and the heteroaryl, one of them and tie point is randomly by R
9Replace, the adjacent carbon of the carbon on another and the tie point is randomly by R
13Replace, with R
9Adjacent and apart from the carbon of two atoms of the carbon on the tie point randomly by R
10Replace, with R
13Adjacent and apart from the carbon of two atoms of the carbon on the tie point randomly by R
12Replace any and R
10And R
12All adjacent carbon is randomly by R
11Replace;
K is CHR
4a, R wherein
4aBe selected from hydrogen, hydroxyalkyl, alkyl, alkoxyalkyl, alkylthio alkyl and haloalkyl;
E
0Be selected from covalent single bond, C (O) N (H), (H) NC (O), (R
7) NS (O)
2And S (O)
2N (R
7);
Y
0Be formula (IV):
D wherein
5, D
6, J
5And J
6Be independently selected from C, N, O, S and covalent linkage, its condition be at the most one can be covalent linkage, K
2Be C, D
5, D
6, J
5And J
6At the most one can be O, D
5, D
6, J
5And J
6At the most one can be S, if D
5, D
6, J
5And J
6Two be O and S, then D
5, D
6, J
5And J
6One of must be covalent linkage, D
5, D
6, J
5And J
6At the most four can be N, its condition is R
16, R
17, R
18And R
19Selected independently of one another, with the tetravalence character of keeping carbon, the trivalent character of nitrogen, the divalence character of sulphur and the divalence character of oxygen;
R
16, R
17, R
18And R
19Be independently selected from hydrogen, amidino groups, guanidine radicals, carboxyl, halogenated alkylthio, alkoxyl group, hydroxyl, amino, alkoxy amino, low-grade alkyl amino, alkylthio, alkyl sulphinyl, alkyl sulphonyl, alkyloyl, haloalkane acyl group, alkyl, halogen, haloalkyl, halogenated alkoxy, hydroxyalkyl, aminoalkyl group and cyano group;
R
16And R
19Randomly be Q
b, its condition is R
16And R
19At the most one be Q simultaneously
b, and Q
bBe Q
Be
Q
bBe selected from NR
20R
21, Q
Be, N (R
26) C (NR
25) N (R
23) (R
24) and C (NR
25) NR
23R
24, Q wherein
BeBe hydrogen, its condition is R
20And R
21At the most one be hydroxyl, amino, alkylamino or dialkyl amido simultaneously, R
23And R
24At the most one be hydroxyl, amino, alkylamino or dialkyl amido simultaneously;
R
20, R
21, R
23, R
24, R
25And R
26Be independently selected from hydrogen, alkyl, hydroxyl, amino, alkylamino and dialkyl amido;
Q
sBe selected from covalent single bond, (CR
37R
38)
b(CH (R
14))
c-W
1-(CH (R
15))
d, wherein b is selected from 1 to 4 integer, and c and d are independently selected from 1 to 3 integer, W
1Be selected from C (O) N (R
14), (R
14) NC (O), S (O), S (O)
2, S (O)
2N (R
14), N (R
14) S (O)
2And N (R
14), its condition is R
14If direct and N bonding then is selected from the group except that halogen, (CR
37R
38)
b(CH (R
14))
cWith E
0Bonding;
R
14Be selected from hydrogen, halogen, alkyl and haloalkyl;
R
37And R
38Be independently selected from hydrogen, alkyl and haloalkyl;
R
38Randomly be selected from aroyl and 4-hetaroylpyrazol;
Y
0Randomly be Q
b-Q
Ss, Q wherein
SsBe (CH (R
14))
e-W
2-(CH (R
15))
h, wherein e and h are independently selected from 1 to 2 integer, W
2Be CR
4a=CH, its condition is (CH (R
14))
eWith E
0Bonding.
3. compound as claimed in claim 2 or its pharmacy acceptable salt, wherein:
B is selected from hydrogen, trialkylsilkl, C2-C8 alkyl, C3-C8 alkylidene group, C3-C8 thiazolinyl, C3-C8 alkynyl and C2-C8 haloalkyl, and wherein each member of group B randomly at distance B and A tie point nearly and comprise on any carbon of 6 atoms by one or more radicals R
32, R
33, R
34, R
35And R
36Replace;
R
32, R
33, R
34, R
35And R
36Be independently selected from hydrogen, kharophen, halo kharophen, amidino groups, guanidine radicals, alkoxyl group, hydroxyl, amino, alkoxy amino, low-grade alkyl amino, alkylthio, amido alkylsulfonyl, an alkyl amido alkylsulfonyl, dialkyl group amido alkylsulfonyl, alkyl, halogen, haloalkyl, halogenated alkoxy, hydroxyalkyl, carbalkoxy, carboxyl, carboxamido, cyano group and Q
b
A is (CH (R
15))
Pa-W
7, wherein pa is selected from 1 to 3 integer, W
7Be selected from O, S and N (R
7), R wherein
7Be selected from hydrogen and alkyl;
R
15Be selected from hydrogen, hydroxyl, halogen, alkyl and haloalkyl, if its condition is R
15Be positioned at and W
7On the carbon of Direct Bonding, R then
15Can not be hydroxyl and halogen;
M is selected from N and R
1-C;
R
1Be selected from hydrogen, alkyl, cyano group, halogen, haloalkyl, halogenated alkoxy, amino, aminoalkyl group, alkylamino, amidino groups, hydroxyl, hydroxyl amino, alkoxyl group, hydroxyalkyl, alkoxy amino, sulfydryl and alkylthio;
R
2Be Z
0-Q;
Z
0Be selected from covalent single bond and (CR
41R
42)
q, wherein q is selected from 1 to 2 integer;
R
41And R
42Be independently selected from hydrogen, hydroxyl and amino;
Q is selected from aryl and heteroaryl, and the adjacent carbon of the carbon on one of them and the tie point is randomly by R
9Replace, the adjacent carbon of the carbon on another and the tie point is randomly by R
13Replace, with R
9Adjacent and apart from the carbon of two atoms of the carbon on the tie point randomly by R
10Replace, with R
13Adjacent and apart from the carbon of two atoms of the carbon on the tie point randomly by R
12Replace any and R
10And R
12All adjacent carbon is randomly by R
11Replace;
R
9, R
10, R
11, R
12And R
13Be independently selected from hydrogen, kharophen, the halo kharophen, alkoxy amino, alkyloyl, the haloalkane acyl group, amidino groups, guanidine radicals, alkylene dioxo base, halogenated alkylthio, alkoxyl group, hydroxyl, amino, low-grade alkyl amino, alkylthio, alkyl sulphinyl, alkyl sulphonyl, alkyl sulfonyl amino, the amido alkylsulfonyl, one alkyl amido alkylsulfonyl, dialkyl group amido alkylsulfonyl, alkyl, halogen, haloalkyl, halogenated alkoxy, hydroxyalkyl, aminoalkyl group, carbalkoxy, carboxyalkyl, carboxyl, carboxamido and cyano group;
K is CHR
4a, R wherein
4aBe selected from hydrogen, hydroxyalkyl, alkyl, alkoxyalkyl, alkylthio alkyl and haloalkyl;
E
0Be selected from covalent single bond, C (O) N (H), (H) NC (O), (R
7) NS (O)
2And S (O)
2N (R
7);
Y
0Be formula (IV):
D wherein
5, D
6, J
5And J
6Be independently selected from C, N, O, S and covalent linkage, its condition be at the most one be covalent linkage, K
2Be C, D
5, D
6, J
5And J
6At the most one be O, D
5, D
6, J
5And J
6At the most one be S, if D
5, D
6, J
5And J
6Two be O and S, then D
5, D
6, J
5And J
6One of must be covalent linkage, D
5, D
6, J
5And J
6At the most four be N;
R
16, R
17, R
18And R
19Be independently selected from hydrogen, amidino groups, guanidine radicals, carboxyl, halogenated alkylthio, alkoxyl group, hydroxyl, amino, alkoxy amino, low-grade alkyl amino, alkylthio, alkyl sulphinyl, alkyl sulphonyl, alkyloyl, haloalkane acyl group, alkyl, halogen, haloalkyl, halogenated alkoxy, hydroxyalkyl, aminoalkyl group and cyano group;
R
16And R
19Randomly be Q
b, its condition is R
16And R
19At the most one be Q simultaneously
b, and Q
bBe Q
Be
Q
bBe selected from NR
20R
21, Q
Be, N (R
26) C (NR
25) N (R
23) (R
24) and C (NR
25) NR
23R
24, Q wherein
BeBe hydrogen, its condition is R
20And R
21At the most one be hydroxyl, amino, alkylamino or dialkyl amido simultaneously, R
23And R
24At the most one be hydroxyl, amino, alkylamino or dialkyl amido simultaneously;
R
20, R
21, R
23, R
24, R
25And R
26Be independently selected from hydrogen, alkyl, hydroxyl, amino, alkylamino and dialkyl amido;
Q
sBe selected from covalent single bond, (CR
37R
38)
b(CH (R
14))
c-W
1-(CH (R
15))
d, wherein b is selected from 1 to 3 integer, and c and d are independently selected from 1 to 2 integer, W
1Be selected from C (O) N (R
14), (R
14) NC (O), S (O), S (O)
2, S (O)
2N (R
14), N (R
14) S (O)
2And N (R
14), its condition is R
14If direct and N bonding then is selected from the group except that halogen, (CR
37R
38)
b(CH (R
14))
cWith E
0Bonding;
R
14Be selected from hydrogen, halogen, alkyl and haloalkyl;
R
37And R
38Be independently selected from hydrogen, alkyl and haloalkyl;
R
38Randomly be selected from aroyl and 4-hetaroylpyrazol;
Y
0Randomly be Q
b-Q
Ss, Q wherein
SsBe (CH (R
14))
e-W
2-(CH (R
15))
h, wherein e and h are independently selected from 1 to 2 integer, W
2Be CR
4a=CH, its condition is (CH (R
14))
eWith E
0Bonding.
4. the compound with following formula as claimed in claim 3:
Or its pharmacy acceptable salt, wherein:
B is selected from hydrogen, trialkylsilkl, C2-C4 alkyl, C3-C5 alkylidene group, C3-C4 thiazolinyl, C3-C4 alkynyl and C2-C4 haloalkyl, and wherein each member of group B randomly at distance B and A tie point nearly and comprise on any carbon of 3 atoms by one or more radicals R
32, R
33And R
34Replace;
R
32, R
33And R
34Be independently selected from hydrogen, kharophen, halo kharophen, amidino groups, guanidine radicals, alkoxyl group, hydroxyl, amino, alkoxy amino, low-grade alkyl amino, alkylthio, amido alkylsulfonyl, an alkyl amido alkylsulfonyl, dialkyl group amido alkylsulfonyl, alkyl, halogen, haloalkyl, halogenated alkoxy, hydroxyalkyl, carbalkoxy, carboxyl, carboxamido and cyano group;
A is (CH (R
15))
Pa-N (R
7), wherein pa is selected from 1 to 2 integer, R
7Be selected from hydrogen and alkyl;
R
15Be selected from hydrogen, halogen, alkyl and haloalkyl;
M is selected from N and R
1-C;
R
1Be selected from hydrogen, alkyl, cyano group, halogen, haloalkyl, halogenated alkoxy, amino, aminoalkyl group, alkylamino, amidino groups, hydroxyl, hydroxyl amino, alkoxyl group, hydroxyalkyl, alkoxy amino and alkylthio;
R
2Be Z
0-Q;
Z
0Be selected from covalent single bond and CH
2
Q is selected from aryl and heteroaryl, and the adjacent carbon of the carbon on one of them and the tie point is randomly by R
9Replace, the adjacent carbon of the carbon on another and the tie point is randomly by R
13Replace, with R
9Adjacent and apart from the carbon of two atoms of the carbon on the tie point randomly by R
10Replace, with R
13Adjacent and apart from the carbon of two atoms of the carbon on the tie point randomly by R
12Replace any and R
10And R
12All adjacent carbon is randomly by R
11Replace;
R
9, R
11And R
13Be independently selected from hydrogen, hydroxyl, amino, amidino groups, guanidine radicals, low-grade alkyl amino, alkylthio, alkyl sulfonyl amino, alkyl sulphinyl, alkyl sulphonyl, amido alkylsulfonyl, an alkyl amido alkylsulfonyl, alkyl, alkoxyl group, halogen, haloalkyl, halogenated alkoxy, hydroxyalkyl, carboxyl, carboxamido and cyano group;
R
10And R
12Be independently selected from hydrogen, kharophen, halo kharophen, amidino groups, guanidine radicals, alkyl, alkoxyl group, hydroxyl, amino, alkoxy amino, low-grade alkyl amino, alkyl sulfonyl amino, amido alkylsulfonyl, an alkyl amido alkylsulfonyl, dialkyl group amido alkylsulfonyl, hydroxyalkyl, aminoalkyl group, carbalkoxy, carboxyl, carboxyalkyl, amido carbonyl, halogen, haloalkyl and cyano group;
Y
0Be formula (IV):
D wherein
5, D
6, J
5And J
6Be independently selected from C, N, O, S and covalent linkage, its condition be at the most one be covalent linkage, K
2Be C, D
5, D
6, J
5And J
6At the most one be O, D
5, D
6, J
5And J
6At the most one be S, if D
5, D
6, J
5And J
6Two be O and S, then D
5, D
6, J
5And J
6One of must be covalent linkage, D
5, D
6, J
5And J
6At the most four be N;
R
16, R
17, R
18And R
19Be independently selected from hydrogen, amidino groups, guanidine radicals, carboxyl, halogenated alkylthio, alkoxyl group, hydroxyl, amino, low-grade alkyl amino, alkylthio, alkyl sulphinyl, alkyl sulphonyl, alkyloyl, haloalkane acyl group, alkyl, halogen, haloalkyl, halogenated alkoxy, hydroxyalkyl, aminoalkyl group and cyano group;
R
16And R
19Randomly be Q
b, its condition is R
16And R
19At the most one be Q simultaneously
b, and Q
bBe Q
Be
Q
bBe selected from NR
20R
21, Q
Be, C (NR
25) NR
23R
24And N (R
26) C (NR
25) N (R
23) (R
24), Q wherein
BeBe hydrogen, its condition is R
20And R
21At the most one be hydroxyl simultaneously, R
23And R
24At the most one be hydroxyl simultaneously;
R
20, R
21, R
23, R
24, R
25And R
26Be independently selected from hydrogen, alkyl and hydroxyl;
Q
sBe selected from covalent single bond, CH
2And CH
2CH
2
5. compound or its pharmacy acceptable salt with described chemical formula as claimed in claim 4, wherein:
B is selected from ethyl, 2-propenyl, 2-propynyl, propyl group, sec.-propyl, trimethylene, tetramethylene, butyl, crotyl, 3-butenyl, 2-butyne base, sec-butyl, the tertiary butyl, isobutyl-, 2-methylpropenyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoro propyl and 2,2-two fluoropropyls, wherein each member of group B randomly at distance B and A tie point nearly and comprise on any carbon of 3 atoms by one or more radicals R
32, R
33And R
34Replace;
R
32, R
33And R
34Be independently selected from hydrogen, amidino groups, guanidine radicals, carboxyl, methoxyl group, oxyethyl group, isopropoxy, propoxy-, hydroxyl, amino, methoxyl group amino, oxyethyl group amino, kharophen, trifluoroacetamido, the N-methylamino, dimethylamino, the N-ethylamino, methylthio group, ethylmercapto group, the iprotiazem base, trifluoromethyl, pentafluoroethyl group, 2,2, the 2-trifluoroethyl, trifluoromethoxy, 1,1,2,2-tetrafluoro oxyethyl group, fluorine, chlorine, bromine, the amido alkylsulfonyl, N-methyl amido alkylsulfonyl, N, N-dimethyl amido alkylsulfonyl, methylol, the 1-hydroxyethyl, the 2-hydroxyethyl, 2,2,2-three fluoro-1-hydroxyethyls, methoxycarbonyl, ethoxycarbonyl, the amido carbonyl, N-methyl amido carbonyl, N, N-dimethyl amido carbonyl and cyano group;
A is selected from covalent single bond, NH and N (CH
3);
M is selected from N and R
1-C;
R
1Be selected from hydrogen, hydroxyl, amino, amidino groups, hydroxyl amino, amino methyl, 1-amino-ethyl, methylamino, dimethylamino, cyano group, methyl, ethyl, trifluoromethyl, pentafluoroethyl group, 2,2,2-trifluoroethyl, methoxyl group, methylol, 1-hydroxyethyl, 2-hydroxyethyl, methoxyl group amino, methylthio group, ethylmercapto group, trifluoromethoxy, 1,1,2,2-tetrafluoro oxyethyl group, fluorine, chlorine and bromine;
R
2Be Z
0-Q;
Z
0Be selected from covalent single bond and CH
2
Q is selected from phenyl, 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyrryl, 3-pyrryl, 2-imidazolyl, 4-imidazolyl, 3-pyrazolyl, 4-pyrazolyl, 2-thiazolyl, 3-isoxazolyl, 5-isoxazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrazinyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, 3-pyridazinyl, 4-pyridazinyl and 1,3, the adjacent carbon of carbon on the 5-triazine-2-base, one of them and tie point is randomly by R
9Replace, the adjacent carbon of the carbon on another and the tie point is randomly by R
13Replace, with R
9Adjacent and apart from the carbon of two atoms of the carbon on the tie point randomly by R
10Replace, with R
13Adjacent and apart from the carbon of two atoms of the carbon on the tie point randomly by R
12Replace any and R
10And R
12All adjacent carbon is randomly by R
11Replace;
R
9, R
11And R
13Be independently selected from hydrogen, amidino groups, guanidine radicals, carboxyl, methyl, ethyl, propyl group, sec.-propyl, methoxyl group, oxyethyl group, isopropoxy, propoxy-, hydroxyl, amino, the N-methylamino, N, the N-dimethylamino, the N-ethylamino, methylthio group, ethylmercapto group, the iprotiazem base, trifluoromethyl, pentafluoroethyl group, 2,2, the 2-trifluoroethyl, 2,2,3,3,3-five fluoropropyls, trifluoromethoxy, 1,1,2,2-tetrafluoro oxyethyl group, fluorine, chlorine, bromine, methanesulfonamido, the amido alkylsulfonyl, N-methyl amido alkylsulfonyl, N, N-dimethyl amido alkylsulfonyl, methylol, the 1-hydroxyethyl, the 2-hydroxyethyl, 2,2,2-three fluoro-1-hydroxyethyls, the amido carbonyl, N-methyl amido carbonyl, N, N-dimethyl amido carbonyl and cyano group;
R
10And R
12Be independently selected from hydrogen, amidino groups, guanidine radicals, carboxyl, carboxymethyl, methyl, ethyl, propyl group, sec.-propyl, methoxyl group, oxyethyl group, isopropoxy, propoxy-, hydroxyl, amino, methoxyl group amino, oxyethyl group amino, kharophen, trifluoroacetamido, amino methyl, the 1-amino-ethyl, the 2-amino-ethyl, the N-methylamino, dimethylamino, the N-ethylamino, methanesulfonamido, the amido alkylsulfonyl, N-methyl amido alkylsulfonyl, N, N-dimethyl amido alkylsulfonyl, methylol, the 1-hydroxyethyl, the 2-hydroxyethyl, 2,2,2-three fluoro-1-hydroxyethyls, methoxycarbonyl, ethoxycarbonyl, the amido carbonyl, N-methyl amido carbonyl, N, N-dimethyl amido carbonyl, fluorine, chlorine, bromine and cyano group;
Y
0Be selected from down group:
1-Q
b-4-Q
s-2-R
16-3-R
17-5-W
18-6-R
19Benzene, 2-Q
b-5-Q
s-6-R
17-4-R
18-2-R
19Pyridine, 3-Q
b-6-Q
s-2-R
16-5-R
18-4-R
19Pyridine, 2-Q
b-4-Q
s-3-R
16-6-R
18Pyrazine, 3-Q
b-6-Q
s-2-R
18-5-R
18-4-R
19Pyridazine, 2-Q
b-5-Q
s-6-R
17-4-R
18Pyrimidine, 5-Q
b-2-Q
s-3-R
16-6-R
19Pyrimidine, 3-Q
b-5-Q
s-4-R
16-2-R
19Thiophene, 2-Q
b-5-Q
s-3-R
16-4-R
17Thiophene, 3-Q
b-5-Q
s-4-R
16-2-R
19Furans, 2-Q
b-5-Q
s-3-R
6-4-R
17Furans, 3-Q
b-5-Q
s-4-R
16-2-R
19Pyrroles, 2-Q
b-5-Q
s-3-R
16-4-R
17Pyrroles, 4-Q
b-2-Q
s-5-R
19Imidazoles, 2-Q
b-4-Q
s-5-R
17Imidazoles, 3-Q
b-5-Q
s-4-R
16Isoxazole, 5-Q
b-3-Q
s-4-R
16Isoxazole, 2-Q
b-5-Q
s-4-R
16Pyrazoles, 4-Q
b-2-Q
s-5-R
19Thiazole and 2-Q
b-5-Q
s-4-R
17Thiazole;
R
16, R
17, R
18And R
19Be independently selected from hydrogen, methyl, ethyl, sec.-propyl, propyl group, carboxyl, amidino groups, guanidine radicals, methoxyl group, oxyethyl group, isopropoxy, propoxy-, hydroxyl, amino, amino methyl, the 1-amino-ethyl, the 2-amino-ethyl, the N-methylamino, dimethylamino, the N-ethylamino, methylthio group, ethylmercapto group, the iprotiazem base, trifluoromethylthio, methylsulfinyl, the ethyl sulfinyl, methyl sulphonyl, ethylsulfonyl, trifluoromethyl, pentafluoroethyl group, 2,2, the 2-trifluoroethyl, 2,2,3,3,3-five fluoropropyls, trifluoromethoxy, 1,1,2,2-tetrafluoro oxyethyl group, fluorine, chlorine, bromine, the amido alkylsulfonyl, N-methyl amido alkylsulfonyl, N, N-dimethyl amido alkylsulfonyl, methylol, the 1-hydroxyethyl, the 2-hydroxyethyl, 2,2,2-three fluoro-1-hydroxyethyl and cyano group;
R
16And R
19Randomly be Q
b, its condition is R
16And R
19At the most one be Q simultaneously
b, and Q
bBe Q
Be
Q
bBe selected from NR
20R
21, Q
Be, C (NR
25) NR
23R
24And N (R
26) C (NR
25) N (R
23) (R
24), Q wherein
BeBe hydrogen, if its condition is any two radicals R
20, R
21, R
23And R
24With identical atomic linkage and described Q
bGroup direct and carbon atom bonding, then R
20, R
21, R
23And R
24At the most one can be hydroxyl;
R
20, R
21, R
23, R
24, R
25And R
26Be independently selected from hydrogen, methyl, ethyl, propyl group, butyl, sec.-propyl and hydroxyl;
Q
sBe selected from covalent single bond, CH
2And CH
2CH
2
6. the compound with following formula as claimed in claim 4:
Or its pharmacy acceptable salt, wherein:
A is selected from CH
2N (CH
3), CH
2N (CH
2CH
3), CH
2CH
2N (CH
3) and CH
2CH
2N (CH
2CH
3);
M is selected from N and R
1-C;
R
1Be selected from hydrogen, hydroxyl, amino, amidino groups, hydroxyl amino, amino methyl, 1-amino-ethyl, methylamino, dimethylamino, cyano group, methyl, ethyl, trifluoromethyl, pentafluoroethyl group, 2,2,2-trifluoroethyl, methoxyl group, methylol, 1-hydroxyethyl, 2-hydroxyethyl, methoxyl group amino, methylthio group, ethylmercapto group, trifluoromethoxy, 1,1,2,2-tetrafluoro oxyethyl group, fluorine, chlorine and bromine;
R
2Be Z
0-Q;
Z
0Be selected from covalent single bond and CH
2
Q is selected from phenyl, 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyrryl, 3-pyrryl, 2-imidazolyl, 4-imidazolyl, 3-pyrazolyl, 4-pyrazolyl, 2-thiazolyl, 3-isoxazolyl, 5-isoxazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrazinyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, 3-pyridazinyl, 4-pyridazinyl and 1,3, the adjacent carbon of carbon on the 5-triazine-2-base, one of them and tie point is randomly by R
9Replace, the adjacent carbon of the carbon on another and the tie point is randomly by R
13Replace, with R
9Adjacent and apart from the carbon of two atoms of the carbon on the tie point randomly by R
10Replace, with R
13Adjacent and apart from the carbon of two atoms of the carbon on the tie point randomly by R
12Replace any and R
10And R
12All adjacent carbon is randomly by R
11Replace;
R
9, R
11And R
13Be independently selected from hydrogen, amidino groups, guanidine radicals, carboxyl, methyl, ethyl, propyl group, sec.-propyl, methoxyl group, oxyethyl group, isopropoxy, propoxy-, hydroxyl, amino, the N-methylamino, N, the N-dimethylamino, the N-ethylamino, methylthio group, ethylmercapto group, the iprotiazem base, trifluoromethyl, pentafluoroethyl group, 2,2, the 2-trifluoroethyl, 2,2,3,3,3-five fluoropropyls, trifluoromethoxy, 1,1,2,2-tetrafluoro oxyethyl group, fluorine, chlorine, bromine, methanesulfonamido, the amido alkylsulfonyl, N-methyl amido alkylsulfonyl, N, N-dimethyl amido alkylsulfonyl, methylol, the 1-hydroxyethyl, the 2-hydroxyethyl, 2,2,2-three fluoro-1-hydroxyethyls, the amido carbonyl, N-methyl amido carbonyl, N, N-dimethyl amido carbonyl and cyano group;
R
10And R
12Be independently selected from hydrogen, amidino groups, guanidine radicals, carboxyl, carboxymethyl, methyl, ethyl, propyl group, sec.-propyl, methoxyl group, oxyethyl group, isopropoxy, propoxy-, hydroxyl, amino, methoxyl group amino, oxyethyl group amino, kharophen, trifluoroacetamido, amino methyl, the 1-amino-ethyl, the 2-amino-ethyl, the N-methylamino, dimethylamino, the N-ethylamino, methanesulfonamido, the amido alkylsulfonyl, N-methyl amido alkylsulfonyl, N, N-dimethyl amido alkylsulfonyl, methylol, the 1-hydroxyethyl, the 2-hydroxyethyl, 2,2,2-three fluoro-1-hydroxyethyls, methoxycarbonyl, ethoxy carbonyl, the amido carbonyl, N-methyl amido carbonyl, N, N-dimethyl amido carbonyl, fluorine, chlorine, bromine and cyano group;
Y
0Be selected from down group:
1-Q
b-4-Q
s-2-R
16-3-R
17-5-R
18-6-R
19Benzene, 2-Q
b-5-Q
s-6-R
17-4-R
18-2-R
19Pyridine, 3-Q
b-6-Q
s-2-R
16-5-R
18-4-R
19Pyridine, 2-Q
b-4-Q
s-3-R
16-6-R
18Pyrazine, 3-Q
b-6-Q
s-2-R
18-5-R
18-4-R
19Pyridazine, 2-Q
b-5-Q
s-6-R
17-4-R
18Pyrimidine, 5-Q
b-2-Q
s-3-R
16-6-R
19Pyrimidine, 3-Q
b-5-Q
s-4-R
16-2-R
19Thiophene, 2-Q
b-5-Q
s-3-R
16-4-R
17Thiophene, 3-Q
b-5-Q
s-4-R
16-2-R
19Furans, 2-Q
b-5-Q
s-3-R
16-4-R
17Furans, 3-Q
b-5-Q
s-4-R
16-2-R
19Pyrroles, 2-Q
b-5-Q
s-3-R
16-4-R
17Pyrroles, 4-Q
b-2-Q
s-5-R
19Imidazoles, 2-Q
b-4-Q
s-5-R
17Imidazoles, 3-Q
b-5-Q
s-4-R
16Isoxazole, 5-Q
b-3-Q
s-4-R
16Isoxazole, 2-Q
b-5-Q
s-4-R
16Pyrazoles, 4-Q
b-2-Q
s-5-R
19Thiazole and 2-Q
b-5-Q
s-4-R
17Thiazole;
R
16, R
17, R
18And R
19Be independently selected from hydrogen, methyl, ethyl, sec.-propyl, propyl group, amidino groups, guanidine radicals, methoxyl group, oxyethyl group, isopropoxy, propoxy-, hydroxyl, amino, amino methyl, the 1-amino-ethyl, the 2-amino-ethyl, the N-methylamino, dimethylamino, the N-ethylamino, methylthio group, ethylmercapto group, the iprotiazem base, trifluoromethylthio, methylsulfinyl, the ethyl sulfinyl, methyl sulphonyl, ethylsulfonyl, trifluoromethyl, pentafluoroethyl group, 2,2, the 2-trifluoroethyl, 2,2,3,3,3-five fluoropropyls, trifluoromethoxy, 1,1,2,2-tetrafluoro oxyethyl group, fluorine, chlorine, bromine, the amido alkylsulfonyl, N-methyl amido alkylsulfonyl, N, N-dimethyl amido alkylsulfonyl, methylol, the 1-hydroxyethyl, the 2-hydroxyethyl, 2,2,2-three fluoro-1-hydroxyethyl and cyano group;
Q
bBe selected from NR
20R
21, C (NR
25) NR
23R
24And N (R
26) C (NR
25) N (R
23) (R
24), if its condition is any two radicals R
20, R
21, R
23And R
24With identical atomic linkage and described Q
bGroup direct and carbon atom bonding, then R
20, R
21, R
23And R
24At the most one can be hydroxyl;
R
20, R
21, R
23, R
24, R
25And R
26Be independently selected from hydrogen, methyl, ethyl, propyl group, butyl, sec.-propyl and hydroxyl;
Q
sBe selected from covalent single bond, CH
2And CH
2CH
2
7. compound as claimed in claim 6 or its pharmacy acceptable salt, wherein:
A is selected from CH
2N (CH
3), CH
2N (CH
2CH
3), CH
2CH
2N (CH
3) and CH
2CH
2N (CH
2CH
3);
M is selected from N and R
1-C;
R
1Be selected from hydrogen, hydroxyl, amino, amidino groups, hydroxyl amino, amino methyl, methylamino, cyano group, methyl, trifluoromethyl, methoxyl group, methylol, methoxyl group amino, methylthio group, trifluoromethoxy, fluorine and chlorine;
R
2Be Z
0-Q;
Z
0Be selected from covalent single bond and CH
2
Q is selected from 5-amino-3-amido carbonyl phenyl, 5-amino-2-fluorophenyl, 3-amino-5-hydroxymethyl phenyl, 5-amino-3-methoxycarbonyl phenyl, 3-amidino groups phenyl, 3-amino-2-methyl phenyl, 5-amino-2-methylthio group phenyl, the 3-aminophenyl, benzyl, the 3-carboxyl phenyl, 3-carboxyl-5-hydroxy phenyl, 3-carboxyl-5-aminophenyl, the 3-chloro-phenyl-, the 2-chloro-phenyl-, the 3-cyano-phenyl, the 3-dimethylamino phenyl, the 2-fluorophenyl, the 3-fluorophenyl, the 2-hydroxy phenyl, the 3-hydroxy phenyl, 3-methanesulfonamido phenyl, the 2-p-methoxy-phenyl, the 3-p-methoxy-phenyl, 3-methoxyl group aminophenyl, 3-methoxycarbonyl phenyl, 2-methylamino phenyl, 3-methylamino phenyl, the 2-aminomethyl phenyl, the 3-aminomethyl phenyl, the 4-aminomethyl phenyl, phenyl, 3-trifluoroacetamido phenyl, the 3-trifluoromethyl, the 2-trifluoromethyl, 5-amino-2-thienyl, 5-amino-3-thienyl, 3-bromo-2-thienyl, the 3-pyridyl, the 4-pyridyl, 2-thienyl and 3-thienyl;
Y
0Be selected from down group:
1-Q
b-4-Q
s-2-R
16-3-R
17-5-R
18-6-R
19Benzene, 2-Q
b-5-Q
s-6-R
17-4-R
18-2-R
19Pyridine, 3-Q
b-6-Q
s-2-R
16-5-R
18-4-R
19Pyridine, 3-Q
b-5-Q
s-4-R
16-2-R
19Thiophene and 2-Q
b-5-Q
s-3-R
16-4-R
17Thiophene;
R
16And R
19Be independently selected from hydrogen, amidino groups, amino, amino methyl, methoxyl group, methylamino, hydroxyl, methylol, fluorine, chlorine and cyano group;
R
16And R
19Randomly be Q
b, its condition is R
16And R
19At the most one be Q simultaneously
b, Q
bBe Q
Be
R
17And R
18Be independently selected from hydrogen, fluorine, chlorine, hydroxyl, methylol, amino, carboxyl and cyano group;
Q
bBe selected from Q
BeAnd C (NR
25) NR
23R
24, Q wherein
BeBe hydrogen;
R
23, R
24And R
25Be independently selected from hydrogen and methyl;
Q
sBe CH
2
8. compound as claimed in claim 6 or its pharmacy acceptable salt, wherein said compound is selected from:
The 2-[3-[1-[3-aminophenyl]-N-[[4-iminomethyl phenyl] methyl]-5-[N, N-dimethyl diazanyl]-2,4-dioxo-2 (2H, 4H)-pyrimidyl] ethanamide;
The 2-[3-[1-[3-aminophenyl]-5-[N-ethyl-N-methyl diazanyl]-N-[[4-iminomethyl phenyl] methyl]-2,4-dioxo-2 (2H, 4H)-pyrimidyl] ethanamide;
The 2-[3-[1-[3-aminophenyl]-6-fluoro-5-[N, N-diethyl diazanyl]-N-[[4-iminomethyl phenyl] methyl]-2,4-dioxo-2 (2H, 4H)-pyrimidyl] ethanamide;
The 2-[3-[1-[3-aminophenyl]-5-[N-(azetidine-1-yl) amino]-N-[[4-iminomethyl phenyl] methyl]-2,4-dioxo-2 (2H, 4H)-pyrimidyl] ethanamide;
The 2-[4-[2-[3-aminophenyl]-N-[[4-iminomethyl phenyl] methyl]-6-[N, N-dimethyl diazanyl]-3,5-dioxo-2 (3H, 5H)-1,2, the 4-triazinyl] ethanamide;
The 2-[4-[2-[3-aminophenyl]-6-[N-ethyl-N-methyl diazanyl]-N-[[4-iminomethyl phenyl] methyl]-3,5-dioxo-2 (3H, 5H)-1,2, the 4-triazinyl] ethanamide;
The 2-[4-[2-[3-aminophenyl]-6-[N, N-diethyl diazanyl]-N-[[4-iminomethyl phenyl] methyl]-3,5-dioxo-2 (3H, 5H)-1,2, the 4-triazinyl] ethanamide;
The 2-[4-[2-[3-aminophenyl]-6-[N-(azetidine-1-yl) amino]-N-[[4-iminomethyl phenyl] methyl]-3,5-dioxo-2 (3H, 5H)-1,2, the 4-triazinyl] ethanamide.
9. the compound with following formula as claimed in claim 2:
Or its pharmacy acceptable salt, wherein:
B is selected from aryl and heteroaryl, and the adjacent carbon of the carbon on one of them and the tie point is randomly by R
32Replace, the adjacent carbon of the carbon on another and the tie point is randomly by R
36Replace, with R
32Adjacent and apart from the carbon of two atoms of the carbon on the tie point randomly by R
33Replace, with R
36Adjacent and apart from the carbon of two atoms of the carbon on the tie point randomly by R
35Replace any and R
33And R
35All adjacent carbon is randomly by R
34Replace;
R
32, R
33, R
34, R
35And R
36Be independently selected from hydrogen, kharophen, halo kharophen, amidino groups, guanidine radicals, alkoxyl group, hydroxyl, amino, alkoxy amino, low-grade alkyl amino, alkylthio, amido alkylsulfonyl, an alkyl amido alkylsulfonyl, dialkyl group amido alkylsulfonyl, alkyl, halogen, haloalkyl, halogenated alkoxy, hydroxyalkyl, carbalkoxy, carboxyl, carboxamido, cyano group and Q
b
A is selected from covalent single bond and (CH (R
15))
Pa-(W
7)
Rr, wherein rr is selected from 0 to 1 integer, and pa is selected from 0 to 3 integer, W
7Be selected from (R
7) NC (O) and N (R
7);
R
7Be selected from hydrogen, hydroxyl and alkyl;
R
15Be selected from hydrogen, halogen, alkyl and haloalkyl;
M is selected from N and R
1-C;
R
1Be selected from hydrogen, hydroxyl, hydroxyl amino, amidino groups, amino, cyano group, hydroxyalkyl, alkoxyl group, alkyl, alkylamino, aminoalkyl group, alkylthio, alkoxy amino, haloalkyl, halogenated alkoxy and halogen;
R
2Be Z
0-Q;
Z
0Be selected from covalent single bond, O, S, NH and CH
2
Q is selected from aryl and heteroaryl, and the adjacent carbon of the carbon on one of them and the tie point is randomly by R
9Replace, the adjacent carbon of the carbon on another and the tie point is randomly by R
13Replace, with R
9Adjacent and apart from the carbon of two atoms of the carbon on the tie point randomly by R
10Replace, with R
13Adjacent and apart from the carbon of two atoms of the carbon on the tie point randomly by R
12Replace any and R
10And R
12All adjacent carbon is randomly by R
11Replace;
R
9, R
11And R
13Be independently selected from hydrogen, hydroxyl, amino, amidino groups, guanidine radicals, low-grade alkyl amino, alkylthio, alkyl sulfonyl amino, alkyl sulphinyl, alkyl sulphonyl, amido alkylsulfonyl, an alkyl amido alkylsulfonyl, alkyl, alkoxyl group, halogen, haloalkyl, halogenated alkoxy, hydroxyalkyl, carboxyl, carboxamido and cyano group;
R
10And R
12Be independently selected from hydrogen, kharophen, halo kharophen, amidino groups, guanidine radicals, alkyl, alkoxyl group, hydroxyl, amino, alkoxy amino, low-grade alkyl amino, alkyl sulfonyl amino, amido alkylsulfonyl, an alkyl amido alkylsulfonyl, dialkyl group amido alkylsulfonyl, hydroxyalkyl, aminoalkyl group, carbalkoxy, carboxyl, carboxyalkyl, amido carbonyl, halogen, haloalkyl and cyano group;
Y
0Be formula (IV):
D wherein
5, D
6, J
5And J
6Be independently selected from C, N, O, S and covalent linkage, its condition be at the most one be covalent linkage, K
2Be C, D
5, D
6, J
5And J
6At the most one be O, D
5, D
6, J
5And J
6At the most one be S, if D
5, D
6, J
5And J
6Two be O and S, then D
5, D
6, J
5And J
6One of must be covalent linkage, D
5, D
6, J
5And J
6At the most four be N;
R
16, R
17, R
18And R
19Be independently selected from hydrogen, amidino groups, guanidine radicals, carboxyl, halogenated alkylthio, alkoxyl group, hydroxyl, amino, low-grade alkyl amino, alkylthio, alkyl sulphinyl, alkyl sulphonyl, alkyloyl, haloalkane acyl group, alkyl, halogen, haloalkyl, halogenated alkoxy, hydroxyalkyl, aminoalkyl group and cyano group;
R
16And R
19Randomly be Q
b, its condition is R
16And R
19At the most one be Q simultaneously
b, Q
bBe Q
Be
Q
bBe selected from NR
20R
21, Q
BeAnd C (NR
25) NR
23R
24, Q wherein
BeBe hydrogen, its condition is R
20And R
21At the most one be hydroxyl simultaneously, R
23And R
24At the most one be hydroxyl simultaneously;
R
20, R
21, R
23, R
24And R
25Be independently selected from hydrogen, alkyl and hydroxyl;
Q
sBe selected from covalent single bond, CH
2And CH
2CH
2
10. compound as claimed in claim 9 or its pharmacy acceptable salt, wherein:
B is selected from phenyl, 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyrryl, 3-pyrryl, 2-imidazolyl, 4-imidazolyl, 3-pyrazolyl, 4-pyrazolyl, 2-thiazolyl, 3-isoxazolyl, 5-isoxazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrazinyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, 3-pyridazinyl, 4-pyridazinyl and 1,3, the adjacent carbon of carbon on the 5-triazine-2-base, one of them and tie point is randomly by R
32Replace, the adjacent carbon of the carbon on another and the tie point is randomly by R
36Replace, with R
32Adjacent and apart from the carbon of two atoms of the carbon on the tie point randomly by R
33Replace, with R
36Adjacent and apart from the carbon of two atoms of the carbon on the tie point randomly by R
35Replace any and R
33And R
35All adjacent carbon is randomly by R
34Replace;
R
32, R
33, R
34, R
35And R
36Be independently selected from hydrogen; amidino groups; guanidine radicals; carboxyl; methoxyl group; oxyethyl group; isopropoxy; propoxy-; hydroxyl; amino; methoxyl group amino; oxyethyl group amino; kharophen; trifluoroacetamido; the N-methylamino; dimethylamino; the N-ethylamino; methylthio group; ethylmercapto group; the iprotiazem base; trifluoromethyl; pentafluoroethyl group; 2; 2; the 2-trifluoroethyl; 2; 2; 3; 3; 3-five fluoropropyls; trifluoromethoxy; 1; 1; 2; 2-tetrafluoro oxyethyl group; fluorine; chlorine; bromine; the amido alkylsulfonyl; N-methyl amido alkylsulfonyl; N; N-dimethyl amido alkylsulfonyl; methylol; the 1-hydroxyethyl; the 2-hydroxyethyl; 2; 2,2-three fluoro-1-hydroxyethyls; methoxycarbonyl; ethoxycarbonyl; the amido carbonyl; N-methyl amido carbonyl; N, N-dimethyl amido carbonyl; cyano group and Q
b
A is selected from covalent single bond, NH, N (CH
3), N (OH), CH
2, CH
3CH, CF
3CH, NHC (O), N (CH
3) C (O), C (O) NH, C (O) N (CH
3), CH
2CH
2, CH
2CH
2CH
2, CH
3CHCH
2And CF
3CHCH
2
M is selected from N and R
1-C;
R
1Be selected from hydrogen, hydroxyl, amino, amidino groups, hydroxyl amino, amino methyl, 1-amino-ethyl, methylamino, dimethylamino, cyano group, methyl, ethyl, trifluoromethyl, pentafluoroethyl group, 2,2,2-trifluoroethyl, methoxyl group, methylol, 1-hydroxyethyl, 2-hydroxyethyl, methoxyl group amino, methylthio group, ethylmercapto group, trifluoromethoxy, 1,1,2,2-tetrafluoro oxyethyl group, fluorine, chlorine and bromine;
R
2Be Z
0-Q;
Z
0Be selected from covalent single bond, O, S, NH and CH
2
Q is selected from phenyl, 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyrryl, 3-pyrryl, 2-imidazolyl, 4-imidazolyl, 3-pyrazolyl, 4-pyrazolyl, 2-thiazolyl, 3-isoxazolyl, 5-isoxazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrazinyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, 3-pyridazinyl, 4-pyridazinyl and 1,3, the adjacent carbon of carbon on the 5-triazine-2-base, one of them and tie point is randomly by R
9Replace, the adjacent carbon of the carbon on another and the tie point is randomly by R
13Replace, with R
9Adjacent and apart from the carbon of two atoms of the carbon on the tie point randomly by R
10Replace, with R
13Adjacent and apart from the carbon of two atoms of the carbon on the tie point randomly by R
12Replace any and R
10And R
12All adjacent carbon is randomly by R
11Replace;
R
9, R
11And R
13Be independently selected from hydrogen, amidino groups, guanidine radicals, carboxyl, methyl, ethyl, propyl group, sec.-propyl, methoxyl group, oxyethyl group, isopropoxy, propoxy-, hydroxyl, amino, the N-methylamino, N, the N-dimethylamino, the N-ethylamino, methylthio group, ethylmercapto group, the iprotiazem base, trifluoromethyl, pentafluoroethyl group, 2,2, the 2-trifluoroethyl, 2,2,3,3,3-five fluoropropyls, trifluoromethoxy, 1,1,2,2-tetrafluoro oxyethyl group, fluorine, chlorine, bromine, methanesulfonamido, the amido alkylsulfonyl, N-methyl amido alkylsulfonyl, N, N-dimethyl amido alkylsulfonyl, methylol, the 1-hydroxyethyl, the 2-hydroxyethyl, 2,2,2-three fluoro-1-hydroxyethyls, the amido carbonyl, N-methyl amido carbonyl, N, N-dimethyl amido carbonyl and cyano group;
R
10And R
12Be independently selected from hydrogen, amidino groups, guanidine radicals, carboxyl, carboxymethyl, methyl, ethyl, propyl group, sec.-propyl, methoxyl group, oxyethyl group, isopropoxy, propoxy-, hydroxyl, amino, methoxyl group amino, oxyethyl group amino, kharophen, trifluoroacetamido, amino methyl, the 1-amino-ethyl, the 2-amino-ethyl, the N-methylamino, dimethylamino, the N-ethylamino, methanesulfonamido, the amido alkylsulfonyl, N-methyl amido alkylsulfonyl, N, N-dimethyl amido alkylsulfonyl, methylol, the 1-hydroxyethyl, the 2-hydroxyethyl, 2,2,2-three fluoro-1-hydroxyethyls, methoxycarbonyl, ethoxycarbonyl, the amido carbonyl, N-methyl amido carbonyl, N, N-dimethyl amido carbonyl, fluorine, chlorine, bromine and cyano group;
Y
0Be selected from down group:
1-Q
b-4-Q
s-2-R
16-3-R
17-5-R
18-6-R
19Benzene, 2-Q
b-5-Q
s-6-R
17-R
18-2-R
19Pyridine, 3-Q
b-6-Q
s-2-R
16-5-R
18-4-R
19Pyridine, 2-Q
b-4-Q
s-3-R
16-6-R
18Pyrazine, 3-Q
b-6-Q
s-2-R
18-5-R
18-4-R
19Pyridazine, 2-Q
b-5-Q
s-6-R
17-4-R
18Pyrimidine, 5-Q
b-2-Q
s-3-R
16-6-R
19Pyrimidine, 3-Q
b-5-Q
s-4-R
16-2-R
19Thiophene, 2-Q
b-5-Q
s-3-R
16-4-R
17Thiophene, 3-Q
b-5-Q
s-4-R
16-2-R
19Furans, 2-Q
b-5-Q
s-3-R
16-4-R
17Furans, 3-Q
b-5-Q
s-4-R
16-2-R
19Pyrroles, 2-Q
b-5-Q
s-3-R
16-4-R
17Pyrroles, 4-Q
b-2-Q
s-5-R
19Imidazoles, 2-Q
b-4-Q
s-5-R
17Imidazoles, 3-Q
b-5-Q
s-4-R
16Isoxazole, 5-Q
b-3-Q
s-4-R
16Isoxazole, 2-Q
b-5-Q
s-4-R
16Pyrazoles, 4-Q
b-2-Q
s-5-R
19Thiazole and 2-Q
b-5-Q
s-4-R
17Thiazole;
R
16, R
17, R
18And R
19Be independently selected from hydrogen, methyl, ethyl, sec.-propyl, propyl group, carboxyl, amidino groups, guanidine radicals, methoxyl group, oxyethyl group, isopropoxy, propoxy-, hydroxyl, amino, amino methyl, the 1-amino-ethyl, the 2-amino-ethyl, the N-methylamino, dimethylamino, the N-ethylamino, methylthio group, ethylmercapto group, the iprotiazem base, trifluoromethylthio, methylsulfinyl, the ethyl sulfinyl, methyl sulphonyl, ethylsulfonyl, trifluoromethyl, pentafluoroethyl group, 2,2, the 2-trifluoroethyl, 2,2,3,3,3-five fluoropropyls, trifluoromethoxy, 1,1,2,2-tetrafluoro oxyethyl group, fluorine, chlorine, bromine, the amido alkylsulfonyl, N-methyl amido alkylsulfonyl, N, N-dimethyl amido alkylsulfonyl, methylol, the 1-hydroxyethyl, the 2-hydroxyethyl, 2,2,2-three fluoro-1-hydroxyethyl and cyano group;
R
16And R
19Randomly be Q
b, its condition is R
16And R
19At the most one be Q simultaneously
b, Q
bBe Q
Be
Q
bBe selected from Q
BeAnd C (NR
25) NR
23R
24, Q wherein
BeBe hydrogen, its condition is R
23And R
24At the most one be hydroxyl simultaneously;
R
23, R
24And R
25Be independently selected from hydrogen, methyl, ethyl and hydroxyl;
Q
sBe selected from covalent single bond, CH
2And CH
2CH
2
11. compound as claimed in claim 10 or its pharmacy acceptable salt, wherein:
B is selected from the 2-aminophenyl, the 3-aminophenyl, 3-amidino groups phenyl, 4-amidino groups phenyl, the 3-carboxyl phenyl, 3-carboxyl-5-hydroxy phenyl, the 3-chloro-phenyl-, the 4-chloro-phenyl-, 3, the 4-dichlorophenyl, the 2-fluorophenyl, the 3-fluorophenyl, 3, the 4-difluorophenyl, the 3-hydroxy phenyl, the 4-hydroxy phenyl, 3-methoxyl group aminophenyl, the 3-p-methoxy-phenyl, the 4-p-methoxy-phenyl, the 3-aminomethyl phenyl, the 4-aminomethyl phenyl, phenyl, the 3-trifluoromethyl, the 2-imidazolyl, the 2-pyridyl, the 3-pyridyl, 5-chloro-3-trifluoromethyl-2-pyridyl, the 4-pyridyl, the 2-thienyl, 3-thienyl and 3-trifluoromethyl-2-pyridyl;
A is selected from CH
2, CH
3CH, CF
3CH, NHC (O), CH
2CH
2And CH
2CH
2CH
2
M is selected from N and R
1-C;
R
1Be selected from hydrogen, hydroxyl, amino, amidino groups, hydroxyl amino, amino methyl, methylamino, cyano group, methyl, trifluoromethyl, methoxyl group, methylol, methoxyl group amino, methylthio group, trifluoromethoxy, fluorine and chlorine;
R
2Be Z
0-Q;
Z
0Be selected from covalent single bond, O, S, NH and CH
2
Q is selected from 5-amino-3-amido carbonyl phenyl, 5-amino-2-fluorophenyl, 3-amino-5-hydroxymethyl phenyl, 5-amino-3-methoxycarbonyl phenyl, 3-amidino groups phenyl, 3-amino-2-methyl phenyl, 5-amino-2-methylthio group phenyl, the 3-aminophenyl, benzyl, the 3-carboxyl phenyl, 3-carboxyl-5-hydroxy phenyl, 3-carboxyl-5-aminophenyl, 3-carboxymethyl-5 aminophenyl, 3-carboxymethyl-5-hydroxy phenyl, 3-carboxymethyl-phenyl, the 3-chloro-phenyl-, the 2-chloro-phenyl-, 2, the 6-dichlorophenyl, the 3-cyano-phenyl, the 3-dimethylaminophenyl, the 2-fluorophenyl, the 3-fluorophenyl, 2, the 5-difluorophenyl, the 2-hydroxy phenyl, the 3-hydroxy phenyl, 3-methanesulfonamido phenyl, the 2-p-methoxy-phenyl, the 3-p-methoxy-phenyl, 3-methoxy aminophenyl, 3-methoxycarbonyl phenyl, 2-methylamino phenyl, 3-methylamino phenyl, the 2-aminomethyl phenyl, the 3-aminomethyl phenyl, the 4-aminomethyl phenyl, phenyl, 3-trifluoroacetamido phenyl, the 3-trifluoromethyl, the 2-trifluoromethyl, 5-amino-2-thienyl, 5-amino-3-thienyl, 3-bromo-2-thienyl, the 3-pyridyl, the 4-pyridyl, 2-thienyl and 3-thienyl;
Y
0Be selected from down group:
1-Q
b-4-Q
s-2-R
16-3-R
17-5-R
18-6-R
19Benzene, 2-Q
b-5-Q
s-6-R
17-4-R
18-2-R
19Pyridine, 3-Q
b-6-Q
s-2-R
16-5-R
18-4-R
19Pyridine, 3-Q
b-5-Q
s-4-R
16-2-R
19Thiophene and 2-Q
b-5-Q
s-3-R
16-4-R
17Thiophene;
R
16And R
19Be independently selected from hydrogen, amidino groups, amino, amino methyl, methoxyl group, methylamino, hydroxyl, methylol, fluorine, chlorine and cyano group;
R
16And R
19Randomly be Q
b, its condition is R
16And R
19At the most one be Q simultaneously
b, Q
bBe Q
Be
R
17And R
18Be independently selected from hydrogen, fluorine, chlorine, hydroxyl, methylol, amino, carboxyl and cyano group;
Q
bBe selected from Q
BeAnd C (NR
25) NR
23R
24, Q wherein
BeBe hydrogen;
R
23, R
24And R
25Be independently selected from hydrogen and methyl;
Q
sBe CH
2
12. the compound with following formula as claimed in claim 9:
Or its pharmacy acceptable salt, wherein:
B is selected from aryl and heteroaryl, and the adjacent carbon of the carbon on one of them and the tie point is randomly by R
32Replace, the adjacent carbon of the carbon on another and the tie point is randomly by R
36Replace, with R
32Adjacent and apart from the carbon of two atoms of the carbon on the tie point randomly by R
33Replace, with R
36Adjacent and apart from the carbon of two atoms of the carbon on the tie point randomly by R
35Replace any and R
33And R
35All adjacent carbon is randomly by R
34Replace;
R
32, R
33, R
34, R
35And R
36Be independently selected from hydrogen, kharophen, halo kharophen, amidino groups, guanidine radicals, alkoxyl group, hydroxyl, amino, alkoxy amino, low-grade alkyl amino, alkylthio, amido alkylsulfonyl, an alkyl amido alkylsulfonyl, dialkyl group amido alkylsulfonyl, alkyl, halogen, haloalkyl, halogenated alkoxy, hydroxyalkyl, carbalkoxy, carboxyl, carboxamido, cyano group and Q
b
A is selected from covalent single bond and (CH (R
15))
Pa-(W
7)
Rr, wherein rr is selected from 0 to 1 integer, and pa is selected from 0 to 3 integer, W
7Be N (R
7);
R
7Be selected from hydrogen and alkyl;
R
15Be selected from hydrogen, halogen, alkyl and haloalkyl;
M is selected from N and R
1-C;
R
1Be selected from hydrogen, hydroxyl, hydroxyl amino, amidino groups, amino, cyano group, hydroxyalkyl, alkoxyl group, alkyl, alkylamino, aminoalkyl group, alkylthio, alkoxy amino, haloalkyl, halogenated alkoxy and halogen;
R
2Be Z
0-Q;
Z
0It is covalent single bond;
Q is selected from aryl and heteroaryl, and the adjacent carbon of the carbon on one of them and the tie point is randomly by R
9Replace, the adjacent carbon of the carbon on another and the tie point is randomly by R
13Replace, with R
9Adjacent and apart from the carbon of two atoms of the carbon on the tie point randomly by R
10Replace, with R
13Adjacent and apart from the carbon of two atoms of the carbon on the tie point randomly by R
12Replace any and R
10And R
12All adjacent carbon is randomly by R
11Replace;
R
9, R
11And R
13Be independently selected from hydrogen, hydroxyl, amino, amidino groups, guanidine radicals, low-grade alkyl amino, alkylthio, alkoxyl group, alkyl sulphinyl, alkyl sulphonyl, amido alkylsulfonyl, an alkyl amido alkylsulfonyl, alkyl, halogen, haloalkyl, halogenated alkoxy, hydroxyalkyl, carboxyl, carboxamido and cyano group;
R
10And R
12Be independently selected from hydrogen, kharophen, halo kharophen, amidino groups, guanidine radicals, alkyl, alkoxyl group, alkoxy amino, aminoalkyl group, hydroxyl, amino, low-grade alkyl amino, alkyl sulfonyl amino, amido alkylsulfonyl, an alkyl amido alkylsulfonyl, dialkyl group amido alkylsulfonyl, hydroxyalkyl, aminoalkyl group, halogen, haloalkyl, carbalkoxy, carboxyl, carboxamide groups, carboxyalkyl and cyano group;
Y
0Be formula (IV):
D wherein
5, D
6, J
5And J
6Be independently selected from C, N, O, S and covalent linkage, its condition be at the most one be covalent linkage, K
2Be C, D
5, D
6, J
5And J
6At the most one be O, D
5, D
6, J
5And J
6At the most one be S, if D
5, D
6, J
5And J
6Two be O and S, then D
5, D
6, J
5And J
6One of must be covalent linkage, D
5, D
6, J
5And J
6At the most four be N;
R
16, R
17, R
18And R
19Be independently selected from hydrogen, amidino groups, guanidine radicals, carboxyl, halogenated alkylthio, alkoxyl group, hydroxyl, amino, low-grade alkyl amino, alkylthio, alkyl sulphinyl, alkyl sulphonyl, alkyloyl, haloalkane acyl group, alkyl, halogen, haloalkyl, halogenated alkoxy, hydroxyalkyl, aminoalkyl group and cyano group;
R
16And R
19Randomly be Q
b, its condition is R
16And R
19At the most one be Q simultaneously
b, Q
bBe Q
Be
Q
bBe selected from NR
20R
21, Q
BeAnd C (NR
25) NR
23R
24, Q wherein
BeBe hydrogen;
R
20, R
21, R
23, R
24And R
25Be independently selected from hydrogen and alkyl;
Q
sBe CH
2
13. compound as claimed in claim 12 or its pharmacy acceptable salt, wherein:
B is selected from phenyl, 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyrryl, 3-pyrryl, 2-imidazolyl, 4-imidazolyl, 3-pyrazolyl, 4-pyrazolyl, 2-thiazolyl, 3-isoxazolyl and 5-isoxazolyl, and the adjacent carbon of the carbon on one of them and the tie point is randomly by R
32Replace, the adjacent carbon of the carbon on another and the tie point is randomly by R
36Replace, with R
32Adjacent and apart from the carbon of two atoms of the carbon on the tie point randomly by R
33Replace, with R
36Adjacent and apart from the carbon of two atoms of the carbon on the tie point randomly by R
35Replace any and R
33And R
35All adjacent carbon is randomly by R
34Replace;
R
32, R
33, R
34, R
35And R
36Be independently selected from hydrogen, amidino groups, guanidine radicals, methyl, ethyl, methoxyl group, oxyethyl group, hydroxyl, amino, N-methylamino, dimethylamino, methylthio group, ethylmercapto group, trifluoromethyl, pentafluoroethyl group, 2; 2,2-trifluoroethyl, fluorine, chlorine, bromine, amido alkylsulfonyl, N-methyl amido alkylsulfonyl, methylol, amido carbonyl, carboxyl, cyano group and Q
b
A is selected from covalent single bond, NH, N (CH
3), CH
2, CH
3CH and CH
2CH
2
M is selected from N and R
1-C;
R
1Be selected from hydrogen, hydroxyl, amino, amidino groups, hydroxyl amino, amino methyl, methylamino, cyano group, methyl, trifluoromethyl, methoxyl group, methylol, methoxyl group amino, methylthio group, trifluoromethoxy, fluorine and chlorine;
R
2Be selected from phenyl, 2-thienyl, 2-furyl, 2-pyrryl, 2-imidazolyl, 2-thiazolyl, 3-isoxazolyl, 2-pyridyl and 3-pyridyl, the adjacent carbon of the carbon on one of them and the tie point is randomly by R
9Replace, the adjacent carbon of the carbon on another and the tie point is randomly by R
13Replace, with R
9Adjacent and apart from the carbon of two atoms of the carbon on the tie point randomly by R
10Replace, with R
13Adjacent and apart from the carbon of two atoms of the carbon on the tie point randomly by R
12Replace any and R
10And R
12All adjacent carbon is randomly by R
11Replace;
R
9, R
11And R
13Be independently selected from hydrogen, methyl, ethyl, methoxyl group, oxyethyl group, hydroxyl, amino, N-methylamino, N, N-dimethylamino, methylthio group, trifluoromethyl, pentafluoroethyl group, 2,2,2-trifluoroethyl, fluorine, chlorine, bromine, amido alkylsulfonyl, N-methyl amido alkylsulfonyl, N, N-dimethyl amido alkylsulfonyl, methylol, 1-hydroxyethyl, amido carbonyl, N-methyl amido carbonyl, carboxyl and cyano group;
R
10And R
12Be independently selected from hydrogen, amidino groups, amido carbonyl, N-methyl amido carbonyl, guanidine radicals, methyl, ethyl, methoxyl group, oxyethyl group, hydroxyl, methylol, 1-hydroxyethyl, 2-hydroxyethyl, carboxyl, carboxyl methyl, amino, kharophen, trifluoromethyl, pentafluoroethyl group, 2,2,2-trifluoroethyl, trifluoroacetamido, amino methyl, N-methylamino, dimethylamino, amido alkylsulfonyl, N-methyl amido alkylsulfonyl, N, N-dimethyl amido alkylsulfonyl, methoxycarbonyl, fluorine, chlorine, bromine and cyano group;
Y
0Be selected from down group:
1-Q
b-4-Q
s-2-R
16-3-R
17-5-R
18-6-R
19Benzene, 2-Q
b-5-Q
s-6-R
17-4-R
18-2-R
19Pyridine, 3-Q
b-6-Q
s-2-R
16-5-R
18-4-R
19Pyridine, 3-Q
b-5-Q
s-4-R
16-2-R
19Thiophene, 2-Q
b-5-Q
s-3-R
16-4-R
17Thiophene, 3-Q
b-5-Q
s-4-R
16-2-R
19Furans, 2-Q
b-5-Q
s-3-R
16-4-R
17Furans, 3-Q
b-5-Q
s-4-R
16-2-R
19Pyrroles, 2-Q
b-5-Q
s-3-R
16-4-R
17Pyrroles, 4-Q
b-2-Q
s-5-R
19Thiazole and 2-Q
b-5-Q
s-4-R
17Thiazole;
R
16, R
17, R
18And R
19Be independently selected from hydrogen, methyl, ethyl, amidino groups, guanidine radicals, methoxyl group, hydroxyl, amino, amino methyl, 1-amino-ethyl, 2-amino-ethyl, N-methylamino, dimethylamino, methylthio group, ethylmercapto group, trifluoromethylthio, methylsulfinyl, methyl sulphonyl, trifluoromethyl, pentafluoroethyl group, 2,2,2-trifluoroethyl, trifluoromethoxy, fluorine, chlorine, amido alkylsulfonyl, N-methyl amido alkylsulfonyl, methylol, carboxyl and cyano group;
Q
bBe selected from NR
20R
21And C (NR
25) NR
23R
24, its condition is described Q
bDirect and the carbon atom bonding of group;
R
20, R
21, R
23, R
24And R
25Be independently selected from hydrogen, methyl and ethyl;
Q
sBe CH
2
14. compound as claimed in claim 13 or its pharmacy acceptable salt, wherein:
B is selected from the 2-aminophenyl, the 3-aminophenyl, 3-amidino groups phenyl, 4-amidino groups phenyl, the 3-carboxyl phenyl, 3-carboxyl-5-hydroxy phenyl, the 3-chloro-phenyl-, the 4-chloro-phenyl-, 3, the 4-dichlorophenyl, the 2-fluorophenyl, the 3-fluorophenyl, 3, the 4-difluorophenyl, the 3-hydroxy phenyl, the 4-hydroxy phenyl, 3-methoxyl group aminophenyl, the 3-p-methoxy-phenyl, the 4-p-methoxy-phenyl, the 3-aminomethyl phenyl, the 4-aminomethyl phenyl, phenyl, the 3-trifluoromethyl, the 2-imidazolyl, the 2-pyridyl, the 3-pyridyl, 5-chloro-3-trifluoromethyl-2-pyridyl, the 4-pyridyl, the 2-thienyl, 3-thienyl and 3-trifluoromethyl-2-pyridyl;
A is selected from CH
2, CH
3CH, CF
3CH, NHC (O), CH
2CH
2And CH
2CH
2CH
2
M is selected from N and R
1-C;
R
1Be selected from hydrogen, hydroxyl, amino, methyl, trifluoromethyl, fluorine and chlorine;
R
2Be selected from 5-amino-3-amido carbonyl phenyl, 5-amino-2-fluorophenyl, 3-amino-5-hydroxymethyl phenyl, 5-amino-3-methoxycarbonyl phenyl, 3-amidino groups phenyl, 3-amino-2-methyl phenyl, 5-amino-2-methylthio group phenyl, the 3-aminophenyl, benzyl, the 3-carboxyl phenyl, 3-carboxyl-5-hydroxy phenyl, 3-carboxyl-5-aminophenyl, 3-carboxymethyl-5-aminophenyl, 3-carboxymethyl-5-hydroxy phenyl, 3-carboxymethyl phenyl, the 3-chloro-phenyl-, the 2-chloro-phenyl-, the 3-cyano-phenyl, the 3-dimethylaminophenyl, the 2-fluorophenyl, the 3-fluorophenyl, 2,5 difluorophenyls, the 2-hydroxy phenyl, the 3-hydroxy phenyl, 3-methanesulfonamido phenyl, the 2-p-methoxy-phenyl, the 3-p-methoxy-phenyl, 3-methoxyl group aminophenyl, 3-methoxycarbonyl phenyl, 2-methylamino phenyl, 3-methylamino phenyl, the 2-aminomethyl phenyl, the 3-aminomethyl phenyl, the 4-aminomethyl phenyl, phenyl, 3-trifluoroacetamido phenyl, the 3-trifluoromethyl, the 2-trifluoromethyl, 5-amino-2-thienyl, 5-amino-3-thienyl, 3-bromo-2-thienyl, the 3-pyridyl, the 4-pyridyl, 2-thienyl and 3-thienyl;
Y
0Be selected from down group:
1-Q
b-4-Q
s-2-R
16-3-R
17-5-R
18-6-R
19Benzene, 2-Q
b-5-Q
s-6-R
17-4-R
18-2-R
19Pyridine, 3-Q
b-6-Q
s-2-R
16-5-R
18-4-R
19Pyridine, 3-Q
b-5-Q
s-4-R
16-2-R
19Thiophene and 2-Q
b-5-Q
s-3-R
16-4-R
17Thiophene;
R
16And R
19Be independently selected from hydrogen, amidino groups, amino, amino methyl, methoxyl group, methylamino, hydroxyl, methylol, fluorine, chlorine and cyano group;
R
16And R
19Randomly be Q
b, its condition is R
16And R
19At the most one be Q simultaneously
b, Q
bBe Q
Be
R
17And R
18Be independently selected from hydrogen, fluorine, chlorine, hydroxyl, methylol, amino, carboxyl and cyano group;
Q
bBe selected from Q
BeAnd C (NR
25) NR
23R
24, Q wherein
BeBe hydrogen;
R
23, R
24And R
25Be independently selected from hydrogen and methyl;
Q
sBe CH
2
15. compound as claimed in claim 14 or its pharmacy acceptable salt, wherein:
B is selected from 3-aminophenyl, 3-amidino groups phenyl, 4-amidino groups phenyl, 3-chloro-phenyl-, 4-chloro-phenyl-, 3,4-dichlorophenyl, 2-fluorophenyl, 4-aminomethyl phenyl, phenyl, 2-imidazolyl, 3-pyridyl, 4-pyridyl and 3-trifluoromethyl-2-pyridyl;
A is selected from CH
2, NHC (O), CH
2CH
2And CH
2CH
2CH
2
M is selected from N and R
1-C;
R
1Be selected from hydrogen, fluorine and chlorine;
R
2Be selected from 3-aminophenyl, benzyl, 3-chloro-phenyl-, 3-dimethylaminophenyl, 3-hydroxy phenyl, 3-methanesulfonamido phenyl, 3-methylamino phenyl, 2-aminomethyl phenyl, 3-aminomethyl phenyl, phenyl, 3-trifluoroacetamido phenyl, 3-bromo-2-thienyl, 2-thienyl and 3-thienyl;
Y
0Be selected from 5-amidino groups-2-thenyl, 4-amidino benzyl, 2-fluoro-4-amidino benzyl and 3-fluoro-4-amidino benzyl.
16. compound as claimed in claim 9, wherein said compound is selected from the group with following formula structure:
Or its pharmacy acceptable salt, wherein:
R
2Be the 3-aminophenyl, B is the 3-chloro-phenyl-, and A is CH
2CH
2, Y
0Be the 4-amidino benzyl, M is CH;
R
2Be the 3-aminophenyl, B is a phenyl, and A is CH
2, Y
0Be the 4-amidino benzyl, M is CH;
R
2Be phenyl, B is the 3-chloro-phenyl-, and A is CH
2CH
2, Y
0Be the 4-amidino benzyl, M is CH;
R
2Be the 3-aminophenyl, B is the 2-imidazolyl, and A is CH
2CH
2CH
2, Y
0Be the 4-amidino benzyl, M is CH;
R
2Be the 3-dimethylaminophenyl, B is a phenyl, and A is CH
2CH
2, Y
0Be the 4-amidino benzyl, M is CH;
R
2Be the 2-aminomethyl phenyl, B is a phenyl, and A is CH
2CH
2, Y
0Be the 4-amidino benzyl, M is CH;
R
2Be phenyl, B is the 3-aminophenyl, and A is C (O) NH, Y
0Be the 4-amidino benzyl, M is CH;
R
2Be phenyl, B is a 3-amidino groups phenyl, and A is CH
2, Y
0Be the 4-amidino benzyl, M is CH;
R
2Be 3-(N-methylamino) phenyl, B is a phenyl, and A is CH
2CH
2, Y
0Be the 4-amidino benzyl, M is CH;
R
2Be the 3-thienyl, B is a phenyl, and A is CH
2CH
2, Y
0Be the 4-amidino benzyl, M is CH;
R
2Be the amino phenyl of 3-sulfonyloxy methyl, B is a phenyl, and A is CH
2CH
2, Y
0Be the 4-amidino benzyl, M is CH;
R
2Be phenyl, B is a 4-amidino groups phenyl, and A is CH
2, Y
0Be the 4-amidino benzyl, M is CH;
R
2Be 3-methylamino phenyl, B is a phenyl, and A is CH
2CH
2, Y
0Be the 4-amidino benzyl, M is CH;
R
2Be phenyl, B is a phenyl, and A is CH
2, Y
0Be the 4-amidino benzyl, M is CH;
R
2Be phenyl, B is the 4-pyridyl, and A is CH
2CH
2, Y
0Be the 4-amidino benzyl, M is CH;
R
2Be phenyl, B is the 3-pyridyl, and A is CH
2CH
2, Y
0Be the 4-amidino benzyl, M is CH;
R
2Be the 3-chloro-phenyl-, B is the 4-pyridyl, and A is CH
2CH
2, Y
0Be the 4-amidino benzyl, M is CH;
R
2Be the 3-aminomethyl phenyl, B is the 4-phenyl, and A is CH
2CH
2, Y
0Be the 4-amidino benzyl, M is CH;
R
2Be the 3-thienyl, B is the 3-chloro-phenyl-, and A is CH
2CH
2, Y
0Be the 4-amidino benzyl, M is CH;
R
2Be the 3-aminophenyl, B is the 3-chloro-phenyl-, and A is CH
2CH
2, Y
0Be the 4-amidino benzyl, M is CF;
R
2Be the 3-aminophenyl, B is a phenyl, and A is CH
2, Y
0Be the 4-amidino benzyl, M is CF;
R
2Be phenyl, B is the 3-chloro-phenyl-, and A is CH
2CH
2, Y
0Be the 4-amidino benzyl, M is CF;
R
2Be the 3-aminophenyl, B is the 2-imidazolyl, and A is CH
2CH
2CH
2, Y
0Be the 4-amidino benzyl, M is CF;
R
2Be the 3-dimethylaminophenyl, B is a phenyl, and A is CH
2CH
2, Y
0Be the 4-amidino benzyl, M is CF;
R
2Be the 2-aminomethyl phenyl, B is a phenyl, and A is CH
2CH
2, Y
0Be the 4-amidino benzyl, M is CF;
R
2Be phenyl, B is the 3-aminophenyl, and A is C (O) NH, Y
0Be the 4-amidino benzyl, M is CF;
R
2Be phenyl, B is a 3-amidino groups phenyl, and A is CH
2, Y
0Be the 4-amidino benzyl, M is CF;
R
2Be 3-(N-methylamino) phenyl, B is a phenyl, and A is CH
2CH
2, Y
0Be the 4-amidino benzyl, M is CF;
R
2Be the 3-thienyl, B is a phenyl, and A is CH
2CH
2, Y
0Be the 4-amidino benzyl, M is CF;
R
2Be the amino phenyl of 3-sulfonyloxy methyl, B is a phenyl, and A is CH
2CH
2, Y
0Be the 4-amidino benzyl, M is CF;
R
2Be phenyl, B is a 4-amidino groups phenyl, and A is CH
2, Y
0Be the 4-amidino benzyl, M is CF;
R
2Be 3-methylamino phenyl, B is a phenyl, and A is CH
2CH
2, Y
0Be the 4-amidino benzyl, M is CF;
R
2Be phenyl, B is a phenyl, and A is CH
2, Y
0Be the 4-amidino benzyl, M is CF;
R
2Be phenyl, B is the 4-pyridyl, and A is CH
2CH
2, Y
0Be the 4-amidino benzyl, M is CF;
R
2Be phenyl, B is the 3-pyridyl, and A is CH
2CH
2, Y
0Be the 4-amidino benzyl, M is CF;
R
2Be the 3-chloro-phenyl-, B is the 4-pyridyl, and A is CH
2CH
2, Y
0Be the 4-amidino benzyl, M is CF;
R
2Be the 3-aminomethyl phenyl, B is the 4-phenyl, and A is CH
2CH
2, Y
0Be the 4-amidino benzyl, M is CF;
R
2Be the 3-thienyl, B is the 3-chloro-phenyl-, and A is CH
2CH
2, Y
0Be the 4-amidino benzyl, M is
CF
R
2Be the 3-aminophenyl, B is the 3-chloro-phenyl-, and A is CH
2CH
2, Y
0Be the 4-amidino benzyl, M is N;
R
2Be the 3-aminophenyl, B is a phenyl, and A is CH
2, Y
0Be the 4-amidino benzyl, M is N;
R
2Be phenyl, B is the 3-chloro-phenyl-, and A is CH
2CH
2, Y
0Be the 4-amidino benzyl, M is N;
R
2Be the 3-aminophenyl, B is the 2-imidazolyl, and A is CH
2CH
2CH
2, Y
0Be the 4-amidino benzyl, M is N;
R
2Be the 3-dimethylaminophenyl, B is a phenyl, and A is CH
2CH
2, Y
0Be the 4-amidino benzyl, M is N;
R
2Be the 2-aminomethyl phenyl, B is a phenyl, and A is CH
2CH
2, Y
0Be the 4-amidino benzyl, M is N;
R
2Be phenyl, B is the 3-aminophenyl, and A is C (O) NH, Y
0Be the 4-amidino benzyl, M is N;
R
2Be phenyl, B is a 3-amidino groups phenyl, and A is CH
2, Y
0Be the 4-amidino benzyl, M is
N
R
2Be 3-(N-methylamino) phenyl, B is a phenyl, and A is CH
2CH
2, Y
0Be the 4-amidino benzyl, M is N;
R
2Be the 3-thienyl, B is a phenyl, and A is CH
2CH
2, Y
0Be the 4-amidino benzyl, M is N;
R
2Be the amino phenyl of 3-sulfonyloxy methyl, B is a phenyl, and A is CH
2CH
2, Y
0Be the 4-amidino benzyl, M is N;
R
2Be phenyl, B is a 4-amidino groups phenyl, and A is CH
2, Y
0Be the 4-amidino benzyl, M is N;
R
2Be 3-methylamino phenyl, B is a phenyl, and A is CH
2CH
2, Y
0Be the 4-amidino benzyl, M is N;
R
2Be phenyl, B is a phenyl, and A is CH
2, Y
0Be the 4-amidino benzyl, M is N;
R
2Be phenyl, B is the 4-pyridyl, and A is CH
2CH
2, Y
0Be the 4-amidino benzyl, M is N;
R
2Be phenyl, B is the 3-pyridyl, and A is CH
2CH
2, Y
0Be the 4-amidino benzyl, M is N;
R
2Be the 3-chloro-phenyl-, B is the 4-pyridyl, and A is CH
2CH
2, Y
0Be the 4-amidino benzyl, M is N;
R
2Be the 3-aminomethyl phenyl, B is the 4-phenyl, and A is CH
2CH
2, Y
0Be the 4-amidino benzyl, M is N;
R
2Be the 3-thienyl, B is the 3-chloro-phenyl-, and A is CH
2CH
2, Y
0Be the 4-amidino benzyl, M is N.
17. the compound with following formula as claimed in claim 2:
Or its pharmacy acceptable salt, wherein:
B is selected from hydrogen, C2-C8 alkyl, C3-C8 thiazolinyl, C3-C8 alkynyl and C2-C8 haloalkyl, and wherein each member of group B randomly at distance B and A tie point nearly and comprise on any carbon of 6 atoms by one or more radicals R
32, R
33, R
34, R
35And R
36Replace;
R
32, R
33, R
34, R
35And R
36Be independently selected from hydrogen, kharophen, halo kharophen, amidino groups, guanidine radicals, alkoxyl group, hydroxyl, amino, alkoxy amino, low-grade alkyl amino, alkylthio, amido alkylsulfonyl, an alkyl amido alkylsulfonyl, dialkyl group amido alkylsulfonyl, alkyl, halogen, haloalkyl, halogenated alkoxy, hydroxyalkyl, carbalkoxy, carboxyl, carboxamido, cyano group and Q
b
A is selected from covalent single bond and (CH (R
15))
Pa-(W
7)
Rr, wherein rr is selected from 0 to 1 integer, and pa is selected from 0 to 3 integer, W
7Be selected from (R
7) NC (O) and N (R
7);
R
7Be selected from hydrogen, hydroxyl and alkyl;
R
15Be selected from hydrogen, halogen, alkyl and haloalkyl;
M is selected from N and R
1-C;
R
1Be selected from hydrogen, hydroxyl, hydroxyl amino, amidino groups, amino, cyano group, hydroxyalkyl, alkoxyl group, alkyl, alkylamino, aminoalkyl group, alkylthio, alkoxy amino, haloalkyl, halogenated alkoxy and halogen;
R
2Be Z
0-Q;
Z
0Be selected from covalent single bond, O, S, NH and CH
2
Q is selected from aryl and heteroaryl, and the adjacent carbon of the carbon on one of them and the tie point is randomly by R
9Replace, the adjacent carbon of the carbon on another and the tie point is randomly by R
13Replace, with R
9Adjacent and apart from the carbon of two atoms of the carbon on the tie point randomly by R
10Replace, with R
13Adjacent and apart from the carbon of two atoms of the carbon on the tie point randomly by R
12Replace any and R
10And R
12All adjacent carbon is randomly by R
11Replace;
R
9, R
11And R
13Be independently selected from hydrogen, hydroxyl, amino, amidino groups, guanidine radicals, low-grade alkyl amino, alkylthio, alkyl sulfonyl amino, alkyl sulphinyl, alkyl sulphonyl, amido alkylsulfonyl, an alkyl amido alkylsulfonyl, alkyl, alkoxyl group, halogen, haloalkyl, halogenated alkoxy, hydroxyalkyl, carboxyl, carboxamido and cyano group;
R
10And R
12Be independently selected from hydrogen, kharophen, halo kharophen, amidino groups, guanidine radicals, alkyl, alkoxyl group, hydroxyl, amino, alkoxy amino, low-grade alkyl amino, alkyl sulfonyl amino, amido alkylsulfonyl, an alkyl amido alkylsulfonyl, dialkyl group amido alkylsulfonyl, hydroxyalkyl, aminoalkyl group, carbalkoxy, carboxyl, carboxyalkyl, amido carbonyl, halogen, haloalkyl and cyano group;
Y
0Be formula (IV):
D wherein
5, D
6, J
5And J
6Be independently selected from C, N, O, S and covalent linkage, its condition be at the most one be covalent linkage, K
2Be C, D
5, D
6, J
5And J
6At the most one be O, D
5, D
6, J
5And J
6At the most one be S, if D
5, D
6, J
5And J
6Two be O and S, then D
5, D
6, J
5And J
6One of must be covalent linkage, D
5, D
6, J
5And J
6At the most four be N;
R
16, R
17, R
18And R
19Be independently selected from hydrogen, amidino groups, guanidine radicals, carboxyl, halogenated alkylthio, alkoxyl group, hydroxyl, amino, low-grade alkyl amino, alkylthio, alkyl sulphinyl, alkyl sulphonyl, alkyloyl, haloalkane acyl group, alkyl, halogen, haloalkyl, halogenated alkoxy, hydroxyalkyl, aminoalkyl group and cyano group;
R
16And R
19Randomly be Q
b, its condition is R
16And R
19At the most one be Q simultaneously
b, Q
bBe Q
Be
Q
bBe selected from NR
20R
21, Q
Be, C (NR
25) NR
23R
24And N (R
26) C (NR
25) N (R
23) (R
24), Q wherein
BeBe hydrogen, its condition is R
20And R
21At the most one be hydroxyl simultaneously, R
23And R
24At the most one be hydroxyl simultaneously;
R
20, R
21, R
23, R
24, R
25And R
26Be independently selected from hydrogen, alkyl and hydroxyl;
Q
sBe selected from covalent single bond, CH
2And CH
2CH
2
18. compound as claimed in claim 17 or its pharmacy acceptable salt, wherein:
B is selected from hydrogen, ethyl, 2-propynyl, the 2-propenyl, propyl group, sec.-propyl, butyl, crotyl, the 3-butenyl, the 2-butyne base, sec-butyl, the tertiary butyl, isobutyl-, the 2-methylpropenyl, the 1-amyl group, pentenyl, the 3-pentenyl, the 4-pentenyl, the valerylene base, the 3-pentynyl, the 2-amyl group, 1-methyl-2-butene base, 1-methyl-3-butenyl, 1-methyl-2-butyne base, the 3-amyl group, 1-ethyl-2-propenyl, the 2-methyl butyl, 2-methyl-2-butene base, 2-methyl-3-butenyl, 2-methyl-3-butynyl, the 3-methyl butyl, 3-methyl-2-butene base, 3-methyl-3-butenyl, the 1-hexyl, the 2-hexenyl, the 3-hexenyl, the 4-hexenyl, the 5-hexenyl, 2-hexin base, 3-hexin base, 4-hexin base, the 2-hexyl, 1-methyl-pentenyl, 1-methyl-3-pentenyl, 1-methyl-4-pentenyl, 1-methyl-valerylene base, 1-methyl-3-pentynyl, the 3-hexyl, 1-ethyl-crotyl, 1-ethyl-3-butenyl, 1-propyl group-2-propenyl, 1-ethyl-2-butyne base, the 1-heptyl, the 2-heptenyl, the 3-heptenyl, the 4-heptenyl, the 5-heptenyl, the 6-heptenyl, 2-heptyne base, 3-heptyne base, 4-heptyne base, 5-heptyne base, the 2-heptyl, 1-methyl-2-hexenyl, 1-methyl-3-hexenyl, 1-methyl-4-hexenyl, 1-methyl-5-hexenyl, 1-methyl-2-hexin base, 1-methyl-3-hexin base, 1-methyl-4-hexin base, the 3-heptyl, 1-ethyl-pentenyl, 1-ethyl-3-pentenyl, 1-ethyl-4-pentenyl, 1-butyl-2-propenyl, 1-ethyl-valerylene base, 1-ethyl-3-pentynyl, 2,2, the 2-trifluoroethyl, 2,2-two fluoropropyls, 4-trifluoromethyl-5,5,5-trifluoro amyl group, 4-trifluoromethyl amyl group, 5,5,6,6,6-five fluorine hexyls and 3,3, the 3-trifluoro propyl, wherein each member of group B randomly at distance B and A tie point nearly and comprise on any carbon of 5 atoms by one or more radicals R
32, R
33, R
34, R
35And R
36Replace;
R
32, R
33, R
34, R
35And R
36Be independently selected from hydrogen; amidino groups; guanidine radicals; carboxyl; methoxyl group; oxyethyl group; isopropoxy; propoxy-; hydroxyl; amino; methoxyl group amino; oxyethyl group amino; kharophen; trifluoroacetamido; the N-methylamino; dimethylamino; the N-ethylamino; methylthio group; ethylmercapto group; the iprotiazem base; trifluoromethyl; pentafluoroethyl group; 2; 2; the 2-trifluoroethyl; 2; 2; 3; 3; 3-five fluoropropyls; trifluoromethoxy; 1; 1; 2; 2-tetrafluoro oxyethyl group; fluorine; chlorine; bromine; the amido alkylsulfonyl; N-methyl amido alkylsulfonyl; N; N-dimethyl amido alkylsulfonyl; methylol; the 1-hydroxyethyl; the 2-hydroxyethyl; 2; 2,2-three fluoro-1-hydroxyethyls; methoxycarbonyl; ethoxycarbonyl; the amido carbonyl; N-methyl amido carbonyl; N, N-dimethyl amido carbonyl; cyano group and Q
b
A is selected from covalent single bond, NH, N (CH
3), N (OH), CH
2, CH
3CH, CF
3CH, NHC (O), N (CH
3) C (O), C (O) NH, C (O) N (CH
3), CH
2CH
2, CH
2CH
2CH
2, CH
3CHCH
2And CF
3CHCH
2
M is selected from N and R
1-C;
R
1Be selected from hydrogen, hydroxyl, amino, amidino groups, hydroxyl amino, amino methyl, 1-amino-ethyl, methylamino, dimethylamino, cyano group, methyl, ethyl, trifluoromethyl, pentafluoroethyl group, 2,2,2-trifluoroethyl, methoxyl group, methylol, 1-hydroxyethyl, 2-hydroxyethyl, methoxyl group amino, methylthio group, ethylmercapto group, trifluoromethoxy, 1,1,2,2-tetrafluoro oxyethyl group, fluorine, chlorine and bromine;
R
2Be Z
0-Q;
Z
0Be selected from covalent single bond, O, S, NH and CH
2
Q is selected from phenyl, 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyrryl, 3-pyrryl, 2-imidazolyl, 4-imidazolyl, 3-pyrazolyl, 4-pyrazolyl, 2-thiazolyl, 3-isoxazolyl, 5-isoxazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrazinyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, 3-pyridazinyl, 4-pyridazinyl and 1,3, the adjacent carbon of carbon on the 5-triazine-2-base, one of them and tie point is randomly by R
9Replace, the adjacent carbon of the carbon on another and the tie point is randomly by R
13Replace, with R
9Adjacent and apart from the carbon of two atoms of the carbon on the tie point randomly by R
10Replace, with R
13Adjacent and apart from the carbon of two atoms of the carbon on the tie point randomly by R
12Replace any and R
10And R
12All adjacent carbon is randomly by R
11Replace;
R
9, R
11And R
13Be independently selected from hydrogen, amidino groups, guanidine radicals, carboxyl, methyl, ethyl, propyl group, sec.-propyl, methoxyl group, oxyethyl group, isopropoxy, propoxy-, hydroxyl, amino, the N-methylamino, N, the N-dimethylamino, the N-ethylamino, methylthio group, ethylmercapto group, the iprotiazem base, trifluoromethyl, pentafluoroethyl group, 2,2, the 2-trifluoroethyl, 2,2,3,3,3-five fluoropropyls, trifluoromethoxy, 1,1,2,2-tetrafluoro oxyethyl group, fluorine, chlorine, bromine, methanesulfonamido, the amido alkylsulfonyl, N-methyl amido alkylsulfonyl, N, N-dimethyl amido alkylsulfonyl, methylol, the 1-hydroxyethyl, the 2-hydroxyethyl, 2,2,2-three fluoro-1-hydroxyethyls, the amido carbonyl, N-methyl amido carbonyl, N, N-dimethyl amido carbonyl and cyano group;
R
10And R
12Be independently selected from hydrogen, amidino groups, guanidine radicals, carboxyl, carboxymethyl, methyl, ethyl, propyl group, sec.-propyl, methoxyl group, oxyethyl group, isopropoxy, propoxy-, hydroxyl, amino, methoxyl group amino, oxyethyl group amino, kharophen, trifluoroacetamido, amino methyl, the 1-amino-ethyl, the 2-amino-ethyl, the N-methylamino, dimethylamino, the N-ethylamino, methanesulfonamido, the amido alkylsulfonyl, N-methyl amido alkylsulfonyl, N, N-dimethyl amido alkylsulfonyl, methylol, the 1-hydroxyethyl, the 2-hydroxyethyl, 2,2,2-three fluoro-1-hydroxyethyls, methoxycarbonyl, ethoxycarbonyl, the amido carbonyl, N-methyl amido carbonyl, N, N-dimethyl amido carbonyl, fluorine, chlorine, bromine and cyano group;
Y
0Be selected from down group:
1-Q
b-4-Q
s-2-R
16-3-R
17-5-R
18-6-R
19Benzene, 2-Q
b-5-Q
s-6-R
17-4-R
18-2-R
19Pyridine, 3-Q
b-6-Q
s-2-R
16-5-R
18-4-R
19Pyridine, 2-Q
b-4-Q
s-3-R
16-6-R
18Pyrazine, 3-Q
b-6-Q
s-2-R
18-5-R
18-4-R
19Pyridazine, 2-Q
b-5-Q
s-6-R
17-4-R
18Pyrimidine, 5-Q
b-2-Q
s-3-R
16-6-R
19Pyrimidine, 3-Q
b-5-Q
s-4-R
16-2-R
19Thiophene, 2-Q
b-5-Q
s-3-R
16-4-R
17Thiophene, 3-Q
b-5-Q
s-4-R
16-2-R
19Furans, 2-Q
b-5-Q
s-3-R
16-4-R
17Furans, 3-Q
b-5-Q
s-4-R
16-2-R
19Pyrroles, 2-Q
b-5-Q
s-3-R
16-4-R
17Pyrroles, 4-Q
b-2-Q
s-5-R
19Imidazoles, 2-Q
b-4-Q
s-5-R
17Imidazoles, 3-Q
b-5-Q
s-4-R
16Isoxazole, 5-Q
b-3-Q
s-4-R
16Isoxazole, 2-Q
b-5-Q
s-4-R
16Pyrazoles, 4-Q
b-2-Q
s-5-R
19Thiazole and 2-Q
b-5-Q
s-4-R
17Thiazole;
R
16, R
17, R
18And R
19Be independently selected from hydrogen, methyl, ethyl, sec.-propyl, propyl group, carboxyl, amidino groups, guanidine radicals, methoxyl group, oxyethyl group, isopropoxy, propoxy-, hydroxyl, amino, amino methyl, the 1-amino-ethyl, the 2-amino-ethyl, the N-methylamino, dimethylamino, the N-ethylamino, methylthio group, ethylmercapto group, the iprotiazem base, trifluoromethylthio, methylsulfinyl, the ethyl sulfinyl, methyl sulphonyl, ethylsulfonyl, trifluoromethyl, pentafluoroethyl group, 2,2, the 2-trifluoroethyl, 2,2,3,3,3-five fluoropropyls, trifluoromethoxy, 1,1,2,2-tetrafluoro oxyethyl group, fluorine, chlorine, bromine, the amido alkylsulfonyl, N-methyl amido alkylsulfonyl, N, N-dimethyl amido alkylsulfonyl, methylol, the 1-hydroxyethyl, the 2-hydroxyethyl, 2,2,2-three fluoro-1-hydroxyethyl and cyano group;
R
16And R
19Randomly be Q
b, its condition is R
16And R
19At the most one be Q simultaneously
b, Q
bBe Q
Be
Q
bBe selected from NR
20R
21, Q
Be, C (NR
25) NR
23R
24And N (R
26) C (NR
25) NR
23R
24, Q wherein
BeBe hydrogen, its condition is R
20And R
21At the most one be hydroxyl simultaneously, R
23And R
24At the most one be hydroxyl simultaneously;
R
20, R
21, R
23, R
24, R
25And R
26Be independently selected from hydrogen, methyl, ethyl, propyl group, butyl, sec.-propyl and hydroxyl;
Q
sBe selected from covalent single bond, CH
2And CH
2CH
2
19. compound as claimed in claim 18 or its pharmacy acceptable salt, wherein:
B is selected from hydrogen, ethyl, the 2-propenyl, 2-propynyl, propyl group, sec.-propyl, butyl, the 2-butyl, (R)-the 2-butyl, (S)-the 2-butyl, the tertiary butyl, isobutyl-, the 1-amyl group, the 3-amyl group, the 2-methyl butyl, 2,2, the 2-trifluoroethyl, 6-amido carbonyl hexyl, 4-methyl-2-amyl group, the 3-hydroxypropyl, 3-methoxyl group-2-propyl group, the 2-methoxy ethyl, 2-methyl-2-butyl, 3-methyl-2-butyl, the 2-dimethylaminopropyl, the 2-cyano ethyl, 6-hydroxyl hexyl, the 2-hydroxyethyl, 2-amidino groups ethyl, the 2-GE, 3-guanidine radicals propyl group, 4-guanidine radicals butyl, the 3-hydroxypropyl, the 4-hydroxybutyl, 6-cyano group hexyl, the 2-dimethylaminoethyl, the 3-methyl butyl, the 2-methyl butyl, (S)-the 2-methyl butyl, the 3-aminopropyl, the amino butyl of 2-hexyl and 4-;
A is selected from covalent single bond, CH
2, NHC (O), CH
2CH
2, CH
2CH
2CH
2And CH
3CHCH
2
M is selected from N and R
1-C;
R
1Be selected from hydrogen, hydroxyl, amino, amidino groups, hydroxyl amino, amino methyl, methylamino, cyano group, methyl, trifluoromethyl, methoxyl group, methylol, methoxyl group amino, methylthio group, trifluoromethoxy, fluorine and chlorine;
R
2Be Z
0-Q;
Z
0Be selected from covalent single bond, O, S, NH and CH
2
Q is selected from 5-amino-3-amido carbonyl phenyl, 5-amino-2-fluorophenyl, 3-amino-5-hydroxymethyl phenyl, 5-amino-3-methoxycarbonyl phenyl, 3-amidino groups phenyl, 3-amino-2-methyl phenyl, 5-amino-2-methylthio group phenyl, the 3-aminophenyl, benzyl, the 3-carboxyl phenyl, 3-carboxyl-5-hydroxy phenyl, 3-carboxyl-5-aminophenyl, 3-carboxymethyl-5-aminophenyl, 3-carboxymethyl-5-hydroxy phenyl, 3-carboxymethyl phenyl, the 3-chloro-phenyl-, the 2-chloro-phenyl-, 2, the 6-dichlorophenyl, the 3-cyano-phenyl, the 3-dimethylaminophenyl, the 2-fluorophenyl, the 3-fluorophenyl, 2, the 5-difluorophenyl, the 2-hydroxy phenyl, the 3-hydroxy phenyl, 3-methanesulfonamido phenyl, the 2-p-methoxy-phenyl, the 3-p-methoxy-phenyl, 3-methoxyl group aminophenyl, 3-methoxycarbonyl phenyl, 2-methylamino phenyl, 3-methylamino phenyl, the 2-aminomethyl phenyl, the 3-aminomethyl phenyl, the 4-aminomethyl phenyl, phenyl, 3-trifluoroacetamido phenyl, the 3-trifluoromethyl, the 2-trifluoromethyl, 5-amino-2-thienyl, 5-amino-3-thienyl, 3-bromo-2-thienyl, the 3-pyridyl, the 4-pyridyl, 2-thienyl and 3-thienyl;
Y
0Be selected from down group:
1-Q
b-4-Q
s-2-R
16-3-R
17-5-R
18-6-R
19Benzene, 2-Q
b-5-Q
s-6-R
17-4-R
18-2-R
19Pyridine, 3-Q
b-6-Q
s-2-R
16-5-R
18-4-R
19Pyridine, 3-Q
b-5-Q
s-4-R
16-2-R
19Thiophene and 2-Q
b-5-Q
s-3-R
16-4-R
17Thiophene;
R
16And R
19Be independently selected from hydrogen, amidino groups, amino, amino methyl, methoxyl group, methylamino, hydroxyl, methylol, fluorine, chlorine and cyano group;
R
16And R
19Randomly be Q
b, its condition is R
16And R
19At the most one be Q simultaneously
b, Q
bBe Q
Be
R
17And R
18Be independently selected from hydrogen, fluorine, chlorine, hydroxyl, methylol, amino, carboxyl and cyano group;
Q
bBe selected from Q
BeAnd C (NR
25) NR
23R
24, Q wherein
BeBe hydrogen;
R
23, R
24And R
25Be independently selected from hydrogen and methyl;
Q
sBe CH
2
20. the compound with following formula as claimed in claim 17:
Or its pharmacy acceptable salt, wherein:
B is selected from hydrogen, C2-C8 alkyl, C3-C8 thiazolinyl, C3-C8 alkynyl and C2-C8 haloalkyl, and wherein each member of group B randomly at distance B and A tie point nearly and comprise on any carbon of 6 atoms by one or more radicals R
32, R
33, R
34, R
35And R
36Replace;
R
32, R
33, R
34, R
35And R
36Be independently selected from hydrogen, kharophen, halo kharophen, amidino groups, guanidine radicals, alkoxyl group, hydroxyl, amino, alkoxy amino, low-grade alkyl amino, alkylthio, amido alkylsulfonyl, an alkyl amido alkylsulfonyl, dialkyl group amido alkylsulfonyl, alkyl, halogen, haloalkyl, halogenated alkoxy, hydroxyalkyl, carbalkoxy, carboxyl, carboxamido, cyano group and Q
b
A is selected from covalent single bond and (CH (R
15))
Pa-(W
7)
Rr, wherein rr is selected from 0 to 1 integer, and pa is selected from 0 to 3 integer, W
7Be N (R
7);
R
7Be selected from hydrogen and alkyl;
R
15Be selected from hydrogen, halogen, alkyl and haloalkyl;
M is selected from N and R
1-C;
R
1Be selected from hydrogen, hydroxyl, hydroxyl amino, amidino groups, amino, cyano group, hydroxyalkyl, alkoxyl group, alkyl, alkylamino, aminoalkyl group, alkylthio, alkoxy amino, haloalkyl, halogenated alkoxy and halogen;
R
2Be Z
0-Q;
Z
0It is covalent single bond;
Q is selected from aryl and heteroaryl, and the adjacent carbon of the carbon on one of them and the tie point is randomly by R
9Replace, the adjacent carbon of the carbon on another and the tie point is randomly by R
13Replace, with R
9Adjacent and apart from the carbon of two atoms of the carbon on the tie point randomly by R
10Replace, with R
13Adjacent and apart from the carbon of two atoms of the carbon on the tie point randomly by R
12Replace any and R
10And R
12All adjacent carbon is randomly by R
11Replace;
R
9, R
11And R
13Be independently selected from hydrogen, hydroxyl, amino, amidino groups, guanidine radicals, low-grade alkyl amino, alkylthio, alkoxyl group, alkyl sulphinyl, alkyl sulphonyl, amido alkylsulfonyl, an alkyl amido alkylsulfonyl, alkyl, halogen, haloalkyl, halogenated alkoxy, hydroxyalkyl, carboxyl, carboxamido and cyano group;
R
10And R
12Be independently selected from hydrogen, kharophen, halo kharophen, amidino groups, guanidine radicals, alkyl, alkoxyl group, alkoxy amino, aminoalkyl group, hydroxyl, amino, low-grade alkyl amino, alkyl sulfonyl amino, amido alkylsulfonyl, an alkyl amido alkylsulfonyl, dialkyl group amido alkylsulfonyl, hydroxyalkyl, aminoalkyl group, halogen, haloalkyl, carbalkoxy, carboxyl, carboxamido, carboxyalkyl and cyano group;
Y
0Be formula (IV):
D wherein
5, D
6, J
5And J
6Be independently selected from C, N, O, S and covalent linkage, its condition be at the most one be covalent linkage, K
2Be C, D
5, D
6, J
5And J
6At the most one be O, D
5, D
6, J
5And J
6At the most one be S, if D
5, D
6, J
5And J
6Two be O and S, then D
5, D
6, J
5And J
6One of must be covalent linkage, D
5, D
6, J
5And J
6At the most four be N;
R
16, R
17, R
18And R
19Be independently selected from hydrogen, amidino groups, guanidine radicals, carboxyl, halogenated alkylthio, alkoxyl group, hydroxyl, amino, low-grade alkyl amino, alkylthio, alkyl sulphinyl, alkyl sulphonyl, alkyloyl, haloalkane acyl group, alkyl, halogen, haloalkyl, halogenated alkoxy, hydroxyalkyl, aminoalkyl group and cyano group;
R
16And R
19Randomly be Q
b, its condition is R
16And R
19At the most one be Q simultaneously
b, Q
bBe Q
Be
Q
bBe selected from NR
20R
21, Q
Be, N (R
26) C (NR
25) N (R
23) (R
24) and C (NR
25) NR
23R
24, Q wherein
BeBe hydrogen;
R
20, R
21, R
23, R
24, R
25And R
26Be independently selected from hydrogen and alkyl;
Q
sBe CH
2
21. compound as claimed in claim 17 or its pharmacy acceptable salt, wherein:
B is selected from hydrogen, ethyl, the 2-propenyl, 2-propynyl, propyl group, sec.-propyl, butyl, crotyl, the 2-butyne base, sec-butyl, the tertiary butyl, isobutyl-, the 2-methylpropenyl, the 1-amyl group, pentenyl, the 3-pentenyl, the valerylene base, the 3-pentynyl, the 2-amyl group, the 3-amyl group, the 2-methyl butyl, 2-methyl-2-butene base, the 3-methyl butyl, 3-methyl-2-butene base, the 1-hexyl, the 2-hexenyl, the 3-hexenyl, the 4-hexenyl, 2-hexin base, 3-hexin base, 4-hexin base, the 2-hexyl, 1-methyl-pentenyl, 1-methyl-3-pentenyl, 1-methyl-valerylene base, 1-methyl-3-pentynyl, the 3-hexyl, 1-ethyl-crotyl, the 1-heptyl, the 2-heptenyl, the 3-heptenyl, the 4-heptenyl, the 5-heptenyl, 2-heptyne base, 3-heptyne base, 4-heptyne base, 5-heptyne base, the 2-heptyl, 1-methyl-2-hexenyl, 1-methyl-31-hexenyl, 1-methyl-4-hexenyl, 1-methyl-2-hexin base, 1-methyl-3-hexin base, 1-methyl-4-hexin base, the 3-heptyl, 1-ethyl-pentenyl, 1-ethyl-3-pentenyl, 1-ethyl-valerylene base, 1-ethyl-3-pentynyl, 2,2, the 2-trifluoroethyl, 2,2-two fluoropropyls, 4-trifluoromethyl-5,5,5-trifluoro amyl group, 4-trifluoromethyl amyl group, 5,5,6,6,6-five fluorine hexyls and 3,3, the 3-trifluoro propyl, wherein each member of group B randomly at distance B and A tie point nearly and comprise on any carbon of 5 atoms by one or more radicals R
32, R
33, R
34, R
35And R
36Replace;
R
32, R
33, R
34, R
35And R
36Be independently selected from hydrogen, amidino groups, guanidine radicals, methyl, ethyl, methoxyl group, oxyethyl group, hydroxyl, amino, N-methylamino, dimethylamino, methylthio group, ethylmercapto group, trifluoromethyl, pentafluoroethyl group, 2; 2,2-trifluoroethyl, fluorine, chlorine, bromine, amido alkylsulfonyl, N-methyl amido alkylsulfonyl, methylol, amido carbonyl, carboxyl, cyano group and Q
b
A is selected from covalent single bond, NH, N (CH
3), CH
2, CH
3CH and CH
2CH
2
A randomly is selected from CH
2N (CH
3), CH
2N (CH
2CH
3), CH
2CH
2N (CH
3) and CH
2CH
2N (CH
2CH
3), its condition is that B is a hydrogen;
M is selected from N and R
1-C;
R
1Be selected from hydrogen, hydroxyl, amino, amidino groups, hydroxyl amino, amino methyl, methylamino, cyano group, methyl, trifluoromethyl, methoxyl group, methylol, methoxyl group amino, methylthio group, trifluoromethoxy, fluorine and chlorine;
R
2Be selected from phenyl, 2-thienyl, 2-furyl, 2-pyrryl, 2-imidazolyl, 2-thiazolyl, 3-isoxazolyl, 2-pyridyl and 3-pyridyl, the adjacent carbon of the carbon on one of them and the tie point is randomly by R
9Replace, the adjacent carbon of the carbon on another and the tie point is randomly by R
13Replace, with R
9Adjacent and apart from the carbon of two atoms of the carbon on the tie point randomly by R
10Replace, with R
13Adjacent and apart from the carbon of two atoms of the carbon on the tie point randomly by R
12Replace any and R
10And R
12All adjacent carbon is randomly by R
11Replace;
R
9, R
11And R
13Be independently selected from hydrogen, methyl, ethyl, methoxyl group, oxyethyl group, hydroxyl, amino, N-methylamino, N, N-dimethylamino, methylthio group, trifluoromethyl, pentafluoroethyl group, 2,2,2-trifluoroethyl, fluorine, chlorine, bromine, amido alkylsulfonyl, N-methyl amido alkylsulfonyl, N, N-dimethyl amido alkylsulfonyl, methylol, 1-hydroxyethyl, amido carbonyl, N-methyl amido carbonyl, carboxyl and cyano group;
R
10And R
12Be independently selected from hydrogen, amidino groups, amido carbonyl, N-methyl amido carbonyl, guanidine radicals, methyl, ethyl, methoxyl group, oxyethyl group, hydroxyl, methylol, 1-hydroxyethyl, 2-hydroxyethyl, carboxyl, carboxyl methyl, amino, kharophen, trifluoromethyl, pentafluoroethyl group, 2,2,2-trifluoroethyl, trifluoroacetamido, amino methyl, N-methylamino, dimethylamino, amido alkylsulfonyl, N-methyl amido alkylsulfonyl, N, N-dimethyl amido alkylsulfonyl, methoxycarbonyl, fluorine, chlorine, bromine and cyano group;
Y
0Be selected from down group:
1-Q
b-4-Q
s-2-R
16-3-R
17-5-R
18-6-R
19Benzene, 2-Q
b-5-Q
s-6-R
17-4-R
18-2-R
19Pyridine, 3-Q
b-6-Q
s-2-R
16-5-R
18-4-R
19Pyridine, 3-Q
b-5-Q
s-4-R
16-2-R
19Thiophene, 2-Q
b-5-Q
s-3-R
16-4-R
17Thiophene, 3-Q
b-5-Q
s-4-R
16-2-R
19Furans, 2-Q
b-5-Q
s-3-R
16-4-R
17Furans, 3-Q
b-5-Q
s-4-R
16-2-R
19Pyrroles, 2-Q
b-5-Q
s-3-R
16-4-R
17Pyrroles, 4-Q
b-2-Q
s-5-R
19Thiazole and 2-Q
b-5-Q
s-4-R
17Thiazole;
R
16, R
17, R
18And R
19Be independently selected from hydrogen, methyl, ethyl, amidino groups, guanidine radicals, methoxyl group, hydroxyl, amino, amino methyl, 1-amino-ethyl, 2-amino-ethyl, N-methylamino, dimethylamino, methylthio group, ethylmercapto group, trifluoromethylthio, methylsulfinyl, methyl sulphonyl, trifluoromethyl, pentafluoroethyl group, 2,2,2-trifluoroethyl, trifluoromethoxy, fluorine, chlorine, amido alkylsulfonyl, N-methyl amido alkylsulfonyl, methylol, carboxyl and cyano group;
Q
bBe selected from NR
20R
21, C (NR
25) NR
23R
24And N (R
26) C (NR
25) N (R
23) (R
24), its condition is described Q
bDirect and the carbon atom bonding of group;
R
20, R
21, R
23, R
24, R
25And R
26Be independently selected from hydrogen, methyl and ethyl;
Q
sBe CH
2
22. compound as claimed in claim 21 or its pharmacy acceptable salt, wherein:
B is selected from hydrogen, ethyl, the 2-propenyl, 2-propynyl, propyl group, sec.-propyl, butyl, the 2-butyl, (R)-the 2-butyl, (S)-the 2-butyl, the tertiary butyl, isobutyl-, the 1-amyl group, the 3-amyl group, the 2-methyl butyl, 2,2, the 2-trifluoroethyl, 6-amido carbonyl hexyl, 4-methyl-2-amyl group, the 3-hydroxypropyl, 3-methoxyl group-2-propyl group, the 2-methoxy ethyl, 2-methyl-2-butyl, 3-methyl-2-butyl, the 2-dimethylaminopropyl, the 2-cyano ethyl, 6-hydroxyl hexyl, the 2-hydroxyethyl, 2-amidino groups ethyl, the 2-GE, 3-guanidine radicals propyl group, 4-guanidine radicals butyl, the 3-hydroxypropyl, the 4-hydroxybutyl, 6-cyano group hexyl, the 2-dimethyl aminoethyl, the 3-methyl butyl, the 2-methyl butyl, (S)-the 2-methyl butyl, the 3-aminopropyl, the amino butyl of 2-hexyl and 4-;
A is selected from covalent single bond, CH
2, CH
3CH and CH
2CH
2
M is selected from N and R
1-C;
R
1Be selected from hydrogen, hydroxyl, amino, methyl, trifluoromethyl, fluorine and chlorine;
R
2Be selected from 5-amino-3-amido carbonyl phenyl, 5-amino-2-fluorophenyl, 3-amino-5-hydroxymethyl phenyl, 5-amino-3-methoxycarbonyl phenyl, 3-amidino groups phenyl, 3-amino-2-methyl phenyl, 5-amino-2-methylthio group phenyl, the 3-aminophenyl, benzyl, the 3-carboxyl phenyl, 3-carboxyl-5-hydroxy phenyl, 3-carboxyl-5-aminophenyl, 3-carboxymethyl-5-aminophenyl, 3-carboxymethyl-5-hydroxy phenyl, 3-carboxymethyl phenyl, the 3-chloro-phenyl-, the 2-chloro-phenyl-, 2, the 6-dichlorophenyl, the 3-cyano-phenyl, the 3-dimethylaminophenyl, the 2-fluorophenyl, the 3-fluorophenyl, 2, the 5-difluorophenyl, the 2-hydroxy phenyl, the 3-hydroxy phenyl, 3-methanesulfonamido phenyl, the 2-p-methoxy-phenyl, the 3-p-methoxy-phenyl, 3-methoxyl group aminophenyl, 3-methoxycarbonyl phenyl, 2-methylamino phenyl, 3-methylamino phenyl, the 2-aminomethyl phenyl, the 3-aminomethyl phenyl, the 4-aminomethyl phenyl, phenyl, 3-trifluoroacetamido phenyl, the 3-trifluoromethyl, the 2-trifluoromethyl, 5-amino-2-thienyl, 5-amino-3-thienyl, 3-bromo-2-thienyl, the 3-pyridyl, the 4-pyridyl, 2-thienyl and 3-thienyl;
Y
0Be selected from down group:
1-Q
b-4-Q
s-2-R
16-3-R
17-5-R
18-6-R
19Benzene, 2-Q
b-5-Q
s-6-R
17-4-R
18-2-R
19Pyridine, 3-Q
b-6-Q
s-2-R
16-5-R
18-4-R
19Pyridine, 3-Q
b-5-Q
s-4-R
16-2-R
19Thiophene and 2-Q
b-5-Q
s-3-R
16-4-R
17Thiophene;
R
16And R
19Be independently selected from hydrogen, amidino groups, amino, amino methyl, methoxyl group, methylamino, hydroxyl, methylol, fluorine, chlorine and cyano group;
R
16And R
19Randomly be Q
b, its condition is R
16And R
19At the most one be Q simultaneously
b, Q
bBe Q
Be
R
17And R
18Be independently selected from hydrogen, fluorine, chlorine, hydroxyl, methylol, amino, carboxyl and cyano group;
Q
bBe selected from Q
BeAnd C (NR
25) NR
23R
24, Q wherein
BeBe hydrogen;
R
23, R
24And R
25Be independently selected from hydrogen and methyl;
Q
sBe CH
2
23. compound as claimed in claim 22 or its pharmacy acceptable salt, wherein:
B is selected from hydrogen, ethyl, the 2-propenyl, 2-propynyl, propyl group, sec.-propyl, butyl, the 2-butyl, (R)-the 2-butyl, (S)-the 2-butyl, the tertiary butyl, isobutyl-, the 1-amyl group, the 3-amyl group, the 2-methyl butyl, 2,2, the 2-trifluoroethyl, 6-amido carbonyl hexyl, 4-methyl-2-amyl group, the 3-hydroxypropyl, 3-methoxyl group-2-propyl group, the 2-methoxy ethyl, 2-methyl-2-butyl, 3-methyl-2-butyl, the 2-dimethylaminopropyl, the 2-cyano ethyl, 6-hydroxyl hexyl, the 2-hydroxyethyl, 2-amidino groups ethyl, the 2-GE, 3-guanidine radicals propyl group, 4-guanidine radicals butyl, the 3-hydroxypropyl, the 4-hydroxybutyl, 6-cyano group hexyl, the 2-dimethyl aminoethyl, the 3-methyl butyl, the 2-methyl butyl, (S)-the 2-methyl butyl, the 3-aminopropyl, the amino butyl of 2-hexyl and 4-;
A is selected from covalent single bond, CH
2, CH
3CH and CH
2CH
2
M is selected from N and R
1-C;
R
1Be selected from hydrogen, fluorine and chlorine;
R
2Be selected from 5-amino-2-fluorophenyl, 3-amino-2-methyl phenyl, 5-amino-2-methylthio group phenyl, 3-aminophenyl, 3-carboxyl phenyl, 3-cyano-phenyl, 3-methoxycarbonyl phenyl, phenyl and 3-pyridyl;
Y
0Be selected from 5-amidino groups-2-thenyl, 4-amidino benzyl, 2-fluoro-4-amidino benzyl and 3-fluoro-4-amidino benzyl.
24. compound as claimed in claim 17, wherein said compound is selected from the group with following formula structure:
Or its pharmacy acceptable salt, wherein:
R
2Be the 3-aminophenyl, B is 2,2, and 2-trifluoroethyl, A are singly-bounds, Y
0Be the 4-amidino benzyl, M is CH;
R
2Be the 3-aminophenyl, B is (S)-2-butyl, and A is a singly-bound, Y
0Be the 4-amidino benzyl, M is CH;
R
2Be 5-amino-2-fluorophenyl, B is a sec.-propyl, and A is a singly-bound, Y
0Be the 4-amidino benzyl, M is CH;
R
2Be 2-methyl-3-aminophenyl, B is a sec.-propyl, and A is a singly-bound, Y
0Be the 4-amidino benzyl, M is CH;
R
2Be the 3-aminophenyl, B is an ethyl, and A is a singly-bound, Y
0Be the 4-amidino benzyl, M is CH;
R
2Be the 3-aminophenyl, B is an ethyl, and A is a singly-bound, Y
0Be 4-amidino groups-2-luorobenzyl, M is CH;
R
2Be the 3-aminophenyl, B is the 2-propenyl, and A is a singly-bound, Y
0Be the 4-amidino benzyl, M is CH;
R
2Be the 3-aminophenyl, B is a sec.-propyl, and A is a singly-bound, Y
0Be 4-amidino groups-2-luorobenzyl, M is CH;
R
2Be the 3-aminophenyl, B is a sec.-propyl, and A is a singly-bound, Y
0Be the 4-amidino benzyl, M is CH;
R
2Be the 3-aminophenyl, B is the 2-butyl, and A is a singly-bound, Y
0Be the 4-amidino benzyl, M is CH;
R
2Be the 3-aminophenyl, B is (R)-2-butyl, and A is a singly-bound, Y
0Be the 4-amidino benzyl, M is CH;
R
2Be the 3-aminophenyl, B is a 2-propynyl, and A is a singly-bound, Y
0Be the 4-amidino benzyl, M is CH;
R
2Be the 3-aminophenyl, B is the 3-amyl group, and A is a singly-bound, Y
0Be the 4-amidino benzyl, M is CH;
R
2Be the 3-aminophenyl, B is a hydrogen, and A is CH
2, Y
0Be the 4-amidino benzyl, M is CH;
R
2Be the 3-aminophenyl, B is an ethyl, and A is CH
2, Y
0Be the 4-amidino benzyl, M is CH;
R
2Be the 3-aminophenyl, B is the 2-methyl-propyl, and A is a singly-bound, Y
0Be the 4-amidino benzyl, M is CH;
R
2Be the 3-aminophenyl, B is the 2-propyl group, and A is CH
3CH, Y
0Be the 4-amidino benzyl, M is CH;
R
2Be the 3-aminophenyl, B is a propyl group, and A is a singly-bound, Y
0Be 4-amidino groups-2-luorobenzyl, M is CH;
R
2Be the 3-aminophenyl, B is a 6-amido carbonyl hexyl, and A is a singly-bound, Y
0Be the 4-amidino benzyl, M is CH;
R
2Be the 3-aminophenyl, B is the tertiary butyl, and A is a singly-bound, Y
0Be the 4-amidino benzyl, M is CH;
R
2Be the 3-aminophenyl, B is the tertiary butyl, and A is a singly-bound, Y
0Be the 4-amidino benzyl, M is CH;
R
2Be the 3-aminophenyl, B is the 3-hydroxypropyl, and A is a singly-bound, Y
0Be the 4-amidino benzyl, M is CH;
R
2Be the 3-aminophenyl, B is the 2-methyl-propyl, and A is a singly-bound, Y
0Be 4-amidino groups-2-luorobenzyl, M is CH;
R
2Be the 3-aminophenyl, B is a butyl, and A is a singly-bound, Y
0Be the 4-amidino benzyl, M is CH;
R
2Be the 3-aminophenyl, B is 3-methoxyl group-2-propyl group, and A is a singly-bound, Y
0Be the 4-amidino benzyl, M is CH;
R
2Be the 3-aminophenyl, B is 3-methoxyl group-2-propyl group, and A is a singly-bound, Y
0Be the 4-amidino benzyl, M is CH;
R
2Be the 3-aminophenyl, B is 2-methoxyl group-2-ethyl, and A is a singly-bound, Y
0Be the 4-amidino benzyl, M is CH;
R
2Be the 3-aminophenyl, B is the 2-propyl group, and A is a singly-bound, Y
0Be 5-amidino groups-2-thenyl, M is CH;
R
2Be the 3-aminophenyl, B is the 2-propyl group, and A is a singly-bound, Y
0Be 4-amidino groups-3-luorobenzyl, M is CH;
R
2Be the 3-carboxyl phenyl, B is the 2-propyl group, and A is a singly-bound, Y
0Be the 4-amidino benzyl, M is CH;
R
2Be the 3-aminophenyl, B is the 2-propyl group, and A is a singly-bound, Y
0Be 4-amidino groups-3-luorobenzyl, M is CH;
R
2Be the 3-aminophenyl, B is 2,2, and 2-trifluoroethyl, A are singly-bounds, Y
0Be the 4-amidino benzyl, M is N;
R
2Be the 3-aminophenyl, B is (S)-2-butyl, and A is a singly-bound, Y
0Be the 4-amidino benzyl, M is N;
R
2Be 5-amino-2-fluorophenyl, B is a sec.-propyl, and A is a singly-bound, Y
0Be the 4-amidino benzyl, M is N;
R
2Be 2-methyl-3-aminophenyl, B is a sec.-propyl, and A is a singly-bound, Y
0Be the 4-amidino benzyl, M is N;
R
2Be the 3-aminophenyl, B is an ethyl, and A is a singly-bound, Y
0Be the 4-amidino benzyl, M is N;
R
2Be the 3-aminophenyl, B is an ethyl, and A is a singly-bound, Y
0Be 4-amidino groups-2-luorobenzyl, M is N;
R
2Be the 3-aminophenyl, B is the 2-propenyl, and A is a singly-bound, Y
0Be the 4-amidino benzyl, M is N;
R
2Be the 3-aminophenyl, B is a sec.-propyl, and A is a singly-bound, Y
0Be 4-amidino groups-2-luorobenzyl, M is N;
R
2Be the 3-aminophenyl, B is a sec.-propyl, and A is a singly-bound, Y
0Be the 4-amidino benzyl, M is N;
R
2Be the 3-aminophenyl, B is the 2-butyl, and A is a singly-bound, Y
0Be the 4-amidino benzyl, M is N;
R
2Be the 3-aminophenyl, B is (R)-2-butyl, and A is a singly-bound, Y
0Be the 4-amidino benzyl, M is N;
R
2Be the 3-aminophenyl, B is a 2-propynyl, and A is a singly-bound, Y
0Be the 4-amidino benzyl, M is N;
R
2Be the 3-aminophenyl, B is the 3-amyl group, and A is a singly-bound, Y
0Be the 4-amidino benzyl, M is N;
R
2Be the 3-aminophenyl, B is a hydrogen, and A is CH
2, Y
0Be the 4-amidino benzyl, M is N;
R
2Be the 3-aminophenyl, B is an ethyl, and A is CH
2, Y
0Be the 4-amidino benzyl, M is N;
R
2Be the 3-aminophenyl, B is the 2-methyl-propyl, and A is a singly-bound, Y
0Be the 4-amidino benzyl, M is N;
R
2Be the 3-aminophenyl, B is the 2-propyl group, and A is CH
3CH, Y
0Be the 4-amidino benzyl, M is N;
R
2Be the 3-aminophenyl, B is a propyl group, and A is a singly-bound, Y
0Be 4-amidino groups-2-luorobenzyl, M is N;
R
2Be the 3-aminophenyl, B is a 6-amido carbonyl hexyl, and A is a singly-bound, Y
0Be the 4-amidino benzyl, M is N;
R
2Be the 3-aminophenyl, B is the tertiary butyl, and A is a singly-bound, Y
0Be the 4-amidino benzyl, M is N;
R
2Be the 3-aminophenyl, B is the tertiary butyl, and A is a singly-bound, Y
0Be the 4-amidino benzyl, M is N;
R
2Be the 3-aminophenyl, B is the 3-hydroxypropyl, and A is a singly-bound, Y
0Be the 4-amidino benzyl, M is N;
R
2Be the 3-aminophenyl, B is the 2-methyl-propyl, and A is a singly-bound, Y
0Be 4-amidino groups-2-luorobenzyl, M is N;
R
2Be the 3-aminophenyl, B is a butyl, and A is a singly-bound, Y
0Be the 4-amidino benzyl, M is N;
R
2Be the 3-aminophenyl, B is 3-methoxyl group-2-propyl group, and A is a singly-bound, Y
0Be the 4-amidino benzyl, M is N;
R
2Be the 3-aminophenyl, B is 3-methoxyl group-2-propyl group, and A is a singly-bound, Y
0Be the 4-amidino benzyl, M is N;
R
2Be the 3-aminophenyl, B is 2-methoxyl group-2-ethyl, and A is a singly-bound, Y
0Be the 4-amidino benzyl, M is N;
R
2Be the 3-aminophenyl, B is the 2-propyl group, and A is a singly-bound, Y
0Be 5-amidino groups-2-thenyl, M is N;
R
2Be the 3-aminophenyl, B is the 2-propyl group, and A is a singly-bound, Y
0Be 4-amidino groups-3-luorobenzyl, M is N;
R
2Be the 3-carboxyl phenyl, B is the 2-propyl group, and A is a singly-bound, Y
0Be the 4-amidino benzyl, M is N;
R
2Be the 3-aminophenyl, B is the 2-propyl group, and A is a singly-bound, Y
0Be 4-amidino groups-3-luorobenzyl, M is N.
25. the compound with following formula as claimed in claim 2:
Or its pharmacy acceptable salt, wherein:
B is selected from C3-C7 cycloalkyl and the saturated heterocyclic radical of C4-C6, and wherein each ring carbon is randomly by R
33Replace, the ring carbon except that the ring carbon that is positioned at B and A tie point is randomly replaced by oxo, and its condition is that a ring carbon is replaced by oxo simultaneously at the most, and ring carbon adjacent with the ring carbon that is positioned at tie point and nitrogen-atoms are randomly by R
9Or R
13Replace, with R
9The position adjacent and apart from the ring carbon of two atoms of tie point or nitrogen-atoms randomly by R
10Replace, with R
13The position adjacent and apart from the ring carbon of two atoms of tie point or nitrogen-atoms randomly by R
12Replace, apart from three atoms of tie point and and R
10Ring carbon that the position is adjacent or nitrogen-atoms are randomly by R
11Replace, apart from three atoms of tie point and and R
12Ring carbon that the position is adjacent or nitrogen-atoms are randomly by R
33Replace, apart from four atoms of tie point and and R
11And R
33Ring carbon that the position is adjacent or nitrogen-atoms are randomly by R
34Replace;
R
9, R
11And R
13Be independently selected from hydrogen, hydroxyl, amino, amidino groups, guanidine radicals, low-grade alkyl amino, alkylthio, alkyl sulfonyl amino, alkyl sulphinyl, alkyl sulphonyl, amido alkylsulfonyl, an alkyl amido alkylsulfonyl, alkyl, alkoxyl group, halogen, haloalkyl, halogenated alkoxy, hydroxyalkyl, carboxyl, carboxamido and cyano group;
R
10And R
12Be independently selected from hydrogen, kharophen, halo kharophen, amidino groups, guanidine radicals, alkyl, alkoxyl group, hydroxyl, amino, alkoxy amino, low-grade alkyl amino, alkyl sulfonyl amino, amido alkylsulfonyl, an alkyl amido alkylsulfonyl, dialkyl group amido alkylsulfonyl, hydroxyalkyl, aminoalkyl group, carbalkoxy, carboxyl, carboxyalkyl, amido carbonyl, halogen, haloalkyl and cyano group;
R
33And R
34Be independently selected from hydrogen, kharophen, halo kharophen, amidino groups, guanidine radicals, alkoxyl group, hydroxyl, amino, alkoxy amino, low-grade alkyl amino, alkylthio, amido alkylsulfonyl, an alkyl amido alkylsulfonyl, dialkyl group amido alkylsulfonyl, alkyl, halogen, haloalkyl, halogenated alkoxy, hydroxyalkyl, carbalkoxy, carboxyl, carboxamido, cyano group and Q
b
A is selected from covalent single bond and (CH (R
15))
Pa-(W
7)
Rr, wherein rr is selected from 0 to 1 integer, and pa is selected from 0 to 3 integer, W
7Be selected from (R
7) NC (O) and N (R
7);
R
7Be selected from hydrogen, hydroxyl and alkyl;
R
15Be selected from hydrogen, halogen, alkyl and haloalkyl;
M is selected from N and R
1-C;
R
1Be selected from hydrogen, hydroxyl, hydroxyl amino, amidino groups, amino, cyano group, hydroxyalkyl, alkoxyl group, alkyl, alkylamino, aminoalkyl group, alkylthio, alkoxy amino, haloalkyl, halogenated alkoxy and halogen;
R
2Be Z
0-Q;
Z
0Be selected from covalent single bond, O, S, NH and CH
2
Q is selected from aryl and heteroaryl, and the adjacent carbon of the carbon on one of them and the tie point is randomly by R
9Replace, the adjacent carbon of the carbon on another and the tie point is randomly by R
13Replace, with R
9Adjacent and apart from the carbon of two atoms of the carbon on the tie point randomly by R
10Replace, with R
13Adjacent and apart from the carbon of two atoms of the carbon on the tie point randomly by R
12Replace any and R
10And R
12All adjacent carbon is randomly by R
11Replace;
Y
0Be formula (IV):
D wherein
5, D
6, J
5And J
6Be independently selected from C, N, O, S and covalent linkage, its condition be at the most one be covalent linkage, K
2Be C, D
5, D
6, J
5And J
6At the most one be O, D
5, D
6, J
5And J
6At the most one be S, if D
5, D
6, J
5And J
6Two be O and S, then D
5, D
6, J
5And J
6One of must be covalent linkage, D
5, D
6, J
5And J
6At the most four be N;
R
16, R
17, R
18And R
19Be independently selected from hydrogen, amidino groups, guanidine radicals, carboxyl, halogenated alkylthio, alkoxyl group, hydroxyl, amino, low-grade alkyl amino, alkylthio, alkyl sulphinyl, alkyl sulphonyl, alkyloyl, haloalkane acyl group, alkyl, halogen, haloalkyl, halogenated alkoxy, hydroxyalkyl, aminoalkyl group and cyano group;
R
16And R
19Randomly be Q
b, its condition is R
16And R
19At the most one be Q simultaneously
b, Q
bBe Q
Be
Q
bBe selected from NR
20R
21, Q
BeAnd C (NR
25) NR
23R
24, Q wherein
BeBe hydrogen, its condition is R
20And R
21At the most one be hydroxyl simultaneously, R
23And R
24At the most one be hydroxyl simultaneously;
R
20, R
21, R
23, R
24And R
25Be independently selected from hydrogen, alkyl and hydroxyl;
Q
sBe selected from covalent single bond, CH
2And CH
2CH
2
26. compound as claimed in claim 25 or its pharmacy acceptable salt, wherein:
B is selected from cyclopropyl, cyclobutyl, trimethylene oxide-3-base, azetidine-1-base, azetidine-2-base, azetidine-3-base, Thietane-3-base, cyclopentyl, cyclohexyl, norcamphyl, 7-oxabicyclo [2.2.1] heptane-2-base, two ring [3.1.0] hexane-6-bases, suberyl, the 2-morpholinyl, morpholinyl, the 4-morpholinyl, the 1-piperazinyl, the 2-piperazinyl, piperidino, the 2-piperidyl, the 3-piperidyl, the 4-piperidyl, the 1-pyrrolidyl, the 2-pyrrolidyl, the 3-pyrrolidyl, the 2-alkyl dioxin, the 4H-2-pyranyl, the 4H-3-pyranyl, the 4H-4-pyranyl, 4H-pyrans-4-ketone-2-base, 4H-pyrans-4-ketone-3-base, the 2-tetrahydrofuran base, the 3-tetrahydrofuran base, the 2-THP trtrahydropyranyl, the 3-THP trtrahydropyranyl, the 4-THP trtrahydropyranyl, 2-tetrahydro-thienyl and 3-tetrahydro-thienyl, wherein each ring carbon is randomly by R
33Replace, ring carbon adjacent with the carbon atom that is positioned at tie point and nitrogen-atoms are randomly by R
9Or R
13Replace, with R
9The position adjacent and apart from the ring carbon of two atoms of tie point or nitrogen-atoms randomly by R
10Replace, with R
13The position adjacent and apart from the ring carbon of two atoms of tie point or nitrogen-atoms randomly by R
12Replace;
R
9, R
11And R
13Be independently selected from hydrogen, amidino groups, guanidine radicals, carboxyl, methyl, ethyl, propyl group, sec.-propyl, methoxyl group, oxyethyl group, isopropoxy, propoxy-, hydroxyl, amino, the N-methylamino, N, the N-dimethylamino, the N-ethylamino, methylthio group, ethylmercapto group, the iprotiazem base, trifluoromethyl, pentafluoroethyl group, 2,2, the 2-trifluoroethyl, 2,2,3,3,3-five fluoropropyls, trifluoromethoxy, 1,1,2,2-tetrafluoro oxyethyl group, fluorine, chlorine, bromine, methanesulfonamido, the amido alkylsulfonyl, N-methyl amido alkylsulfonyl, N, N-dimethyl amido alkylsulfonyl, methylol, the 1-hydroxyethyl, the 2-hydroxyethyl, 2,2,2-three fluoro-1-hydroxyethyls, the amido carbonyl, N-methyl amido carbonyl, N, N-dimethyl amido carbonyl and cyano group;
R
10And R
12Be independently selected from hydrogen, amidino groups, guanidine radicals, carboxyl, carboxymethyl, methyl, ethyl, propyl group, sec.-propyl, methoxyl group, oxyethyl group, isopropoxy, propoxy-, hydroxyl, amino, methoxyl group amino, oxyethyl group amino, kharophen, trifluoroacetamido, amino methyl, the 1-amino-ethyl, the 2-amino-ethyl, the N-methylamino, dimethylamino, the N-ethylamino, methanesulfonamido, the amido alkylsulfonyl, N-methyl amido alkylsulfonyl, N, N-dimethyl amido alkylsulfonyl, methylol, the 1-hydroxyethyl, the 2-hydroxyethyl, 2,2,2-three fluoro-1-hydroxyethyls, methoxycarbonyl, ethoxycarbonyl, the amido carbonyl, N-methyl amido carbonyl, N, N-dimethyl amido carbonyl, fluorine, chlorine, bromine and cyano group;
R
33Be selected from hydrogen; amidino groups; guanidine radicals; carboxyl; methoxyl group; oxyethyl group; isopropoxy; propoxy-; hydroxyl; amino; methoxyl group amino; oxyethyl group amino; kharophen; trifluoroacetamido; the N-methylamino; dimethylamino; the N-ethylamino; methylthio group; ethylmercapto group; the iprotiazem base; trifluoromethyl; pentafluoroethyl group; 2; 2; the 2-trifluoroethyl; 2; 2; 3; 3; 3-five fluoropropyls; trifluoromethoxy; 1; 1; 2; 2-tetrafluoro oxyethyl group; fluorine; chlorine; bromine; the amido alkylsulfonyl; N-methyl amido alkylsulfonyl; N; N-dimethyl amido alkylsulfonyl; methylol; the 1-hydroxyethyl; the 2-hydroxyethyl; 2; 2,2-three fluoro-1-hydroxyethyls; methoxycarbonyl; ethoxycarbonyl; the amido carbonyl; N-methyl amido carbonyl; N, N-dimethyl amido carbonyl; cyano group and Q
b
A is selected from covalent single bond, NH, N (CH
3), N (OH), CH
2, CH
3CH, CF
3CH, NHC (O), N (CH
3) C (O), C (O) NH, C (O) N (CH
3), CH
2CH
2, CH
2CH
2CH
2, CH
3CHCH
2And CF
3CHCH
2
M is selected from N and R
1-C;
R
1Be selected from hydrogen, hydroxyl, amino, amidino groups, hydroxyl amino, amino methyl, 1-amino-ethyl, methylamino, dimethylamino, cyano group, methyl, ethyl, trifluoromethyl, pentafluoroethyl group, 2,2,2-trifluoroethyl, methoxyl group, methylol, 1-hydroxyethyl, 2-hydroxyethyl, methoxyl group amino, methylthio group, ethylmercapto group, trifluoromethoxy, 1,1,2,2-tetrafluoro oxyethyl group, fluorine, chlorine and bromine;
R
2Be Z
0-Q;
Z
0Be selected from covalent single bond, O, S, NH and CH
2
Q is selected from phenyl, 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyrryl, 3-pyrryl, 2-imidazolyl, 4-imidazolyl, 3-pyrazolyl, 4-pyrazolyl, 2-thiazolyl, 3-isoxazolyl, 5-isoxazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrazinyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, 3-pyridazinyl, 4-pyridazinyl and 1,3, the adjacent carbon of carbon on the 5-triazine-2-base, one of them and tie point is randomly by R
9Replace, the adjacent carbon of the carbon on another and the tie point is randomly by R
13Replace, with R
9Adjacent and apart from the carbon of two atoms of the carbon on the tie point randomly by R
10Replace, with R
13Adjacent and apart from the carbon of two atoms of the carbon on the tie point randomly by R
12Replace any and R
10And R
12All adjacent carbon is randomly by R
11Replace;
Y
0Be selected from down group:
1-Q
b-4-Q
s-2-R
16-3-R
17-5-R
18-6-R
19Benzene, 2-Q
b-5-Q
s-6-R
17-4-R
18-2-R
19Pyridine, 3-Q
b-6-Q
s-2-R
16-5-R
18-4-R
19Pyridine, 2-Q
b-4-Q
s-3-R
16-6-R
18Pyrazine, 3-Q
b-6-Q
s-2-R
18-5-R
18-4-R
19Pyridazine, 2-Q
b-5-Q
s-6-R
17-4-R
18Pyrimidine, 5-Q
b-2-Q
s-3-R
16-6-R
19Pyrimidine, 3-Q
b-5-Q
s-4-R
16-2-R
19Thiophene, 2-Q
b-5-Q
s-3-R
16-4-R
17Thiophene, 3-Q
b-5-Q
s-4-R
16-2-R
19Furans, 2-Q
b-5-Q
s-3-R
16-4-R
17Furans, 3-Q
b-5-Q
s-4-R
16-2-R
19Pyrroles, 2-Q
b-5-Q
s-3-R
16-4-R
17Pyrroles, 4-Q
b-2-Q
s-5-R
19Imidazoles, 2-Q
b-4-Q
s-5-R
17Imidazoles, 3-Q
b-5-Q
s-4-R
16Isoxazole, 5-Q
b-3-Q
s-4-R
16Isoxazole, 2-Q
b-5-Q
s-4-R
16Pyrazoles, 4-Q
b-2-Q
s-5-R
19Thiazole and 2-Q
b-5-Q
s-4-R
17Thiazole;
R
16, R
17, R
18And R
19Be independently selected from hydrogen, methyl, ethyl, sec.-propyl, propyl group, carboxyl, amidino groups, guanidine radicals, methoxyl group, oxyethyl group, isopropoxy, propoxy-, hydroxyl, amino, amino methyl, the 1-amino-ethyl, the 2-amino-ethyl, the N-methylamino, dimethylamino, the N-ethylamino, methylthio group, ethylmercapto group, the iprotiazem base, trifluoromethylthio, methylsulfinyl, the ethyl sulfinyl, methyl sulphonyl, ethylsulfonyl, trifluoromethyl, pentafluoroethyl group, 2,2, the 2-trifluoroethyl, 2,2,3,3,3-five fluoropropyls, trifluoromethoxy, 1,1,2,2-tetrafluoro oxyethyl group, fluorine, chlorine, bromine, the amido alkylsulfonyl, N-methyl amido alkylsulfonyl, N, N-dimethyl amido alkylsulfonyl, methylol, the 1-hydroxyethyl, the 2-hydroxyethyl, 2,2,2-three fluoro-1-hydroxyethyl and cyano group;
R
16And R
19Randomly be Q
b, its condition is R
16And R
19At the most one be Q simultaneously
b, Q
bBe Q
Be
Q
bBe selected from Q
BeAnd C (NR
25) NR
23R
24, Q wherein
BeBe hydrogen, its condition is R
23And R
24At the most one be hydroxyl simultaneously;
R
23, R
24And R
25Be independently selected from hydrogen, methyl, ethyl and hydroxyl;
Q
sBe selected from covalent single bond, CH
2And CH
2CH
2
27. compound as claimed in claim 26 or its pharmacy acceptable salt, wherein:
B is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, tetrahydrofuran-2-base, 2-(2R)-two encircles [2.2.1] heptyl, the 1-pyrrolidyl, piperidino, 1,1-dioxo thiacyclopentane-3-base, trimethylene oxide-3-base, azetidine-1-base, azetidine-2-base, azetidine-3-base, 7-oxabicyclo [2.2.1] heptane-2-base, two ring [3.1.0] hexane-6-bases, the 2-morpholinyl, morpholinyl, the 4-morpholinyl, the 1-piperazinyl, the 2-piperazinyl, piperidino, the 2-piperidyl, the 3-piperidyl, the 4-piperidyl, the 1-pyrrolidyl, the 2-pyrrolidyl, the 3-pyrrolidyl, the 2-alkyl dioxin, the 4H-2-pyranyl, the 4H-3-pyranyl, the 4H-4-pyranyl, 4H-pyrans-4-ketone-2-base, 4H-pyrans-4-ketone-3-base, the 2-tetrahydrofuran base, the 3-tetrahydrofuran base, the 2-THP trtrahydropyranyl, the 3-THP trtrahydropyranyl, the 4-THP trtrahydropyranyl, 2-tetrahydro-thienyl and 3-tetrahydro-thienyl;
A is selected from covalent single bond, CH
2, NHC (O), CH
2CH
2And CH
2CH
2CH
2
M is selected from N and R
1-C;
R
1Be selected from hydrogen, hydroxyl, amino, amidino groups, hydroxyl amino, amino methyl, methylamino, cyano group, methyl, trifluoromethyl, methoxyl group, methylol, methoxyl group amino, methylthio group, trifluoromethoxy, fluorine and chlorine;
R
2Be Z
0-Q;
Z
0Be selected from covalent single bond, O, S, NH and CH
2
Q is selected from 5-amino-3-amido carbonyl phenyl, 5-amino-2-fluorophenyl, 3-amino-5-hydroxymethyl phenyl, 5-amino-3-methoxycarbonyl phenyl, 3-amidino groups phenyl, 3-amino-2-methyl phenyl, 5-amino-2-methylthio group phenyl, the 3-aminophenyl, benzyl, the 3-carboxyl phenyl, 3-carboxyl-5-hydroxy phenyl, 3-carboxyl-5-aminophenyl, 3-carboxymethyl-5-aminophenyl, 3-carboxymethyl-5-hydroxy phenyl, 3-carboxymethyl phenyl, the 3-chloro-phenyl-, the 2-chloro-phenyl-, 2, the 6-dichlorophenyl, the 3-cyano-phenyl, the 3-dimethylaminophenyl, the 2-fluorophenyl, the 3-fluorophenyl, 2, the 5-difluorophenyl, the 2-hydroxy phenyl, the 3-hydroxy phenyl, 3-methanesulfonamido phenyl, the 2-p-methoxy-phenyl, the 3-p-methoxy-phenyl, 3-methoxy aminophenyl, 3-methoxycarbonyl phenyl, 2-methylamino phenyl, 3-methylamino phenyl, the 2-aminomethyl phenyl, the 3-aminomethyl phenyl, the 4-aminomethyl phenyl, phenyl, 3-trifluoroacetamido phenyl, the 3-trifluoromethyl, the 2-trifluoromethyl, 5-amino-2-thienyl, 5-amino-3-thienyl, 3-bromo-2-thienyl, the 3-pyridyl, the 4-pyridyl, 2-thienyl and 3-thienyl;
Y
0Be selected from down group:
1-Q
b-4-Q
s-2-R
16-3-R
17-5-R
18-6-R
19Benzene, 2-Q
b-5-Q
s-6-R
17-4-R
18-2-R
19Pyridine, 3-Q
b-6-Q
s-2-R
16-5-R
18-4-R
19Pyridine, 3-Q
b-5-Q
s-4-R
16-2-R
19Thiophene and 2-Q
b-5-Q
s-3-R
16-4-R
17Thiophene;
R
16And R
19Be independently selected from hydrogen, amidino groups, amino, amino methyl, methoxyl group, methylamino, hydroxyl, methylol, fluorine, chlorine and cyano group;
R
16And R
19Randomly be Q
b, its condition is R
16And R
19At the most one be Q simultaneously
b, Q
bBe Q
Be
R
17And R
18Be independently selected from hydrogen, fluorine, chlorine, hydroxyl, methylol, amino, carboxyl and cyano group;
Q
bBe selected from Q
BeAnd C (NR
25) NR
23R
24, Q wherein
BeBe hydrogen;
R
23, R
24And R
25Be independently selected from hydrogen and methyl;
Q
sBe CH
2
28. the compound with following formula as claimed in claim 25:
Or its pharmacy acceptable salt, wherein:
B is selected from C3-C7 cycloalkyl and the saturated heterocyclic radical of C4-C6, and wherein each ring carbon is randomly by R
33Replace, the ring carbon except that the ring carbon that is positioned at B and A tie point is randomly replaced by oxo, and its condition is that a ring carbon is replaced by oxo simultaneously at the most, and ring carbon adjacent with the ring carbon that is positioned at tie point and nitrogen-atoms are randomly by R
9Or R
13Replace, with R
9The position adjacent and apart from the ring carbon of two atoms of tie point or nitrogen-atoms randomly by R
10Replace, with R
13The position adjacent and apart from the ring carbon of two atoms of tie point or nitrogen-atoms randomly by R
12Replace, apart from three atoms of tie point and and R
10Ring carbon that the position is adjacent or nitrogen-atoms are randomly by R
11Replace, apart from three atoms of tie point and and R
12Ring carbon that the position is adjacent or nitrogen-atoms are randomly by R
33Replace, apart from four atoms of tie point and and R
11And R
33Ring carbon that the position is adjacent or nitrogen-atoms are randomly by R
34Replace;
R
9, R
11And R
13Be independently selected from hydrogen, hydroxyl, amino, amidino groups, guanidine radicals, low-grade alkyl amino, alkylthio, alkoxyl group, alkyl sulphinyl, alkyl sulphonyl, amido alkylsulfonyl, an alkyl amido alkylsulfonyl, alkyl, halogen, haloalkyl, halogenated alkoxy, hydroxyalkyl, carboxyl, carboxamido and cyano group;
R
10And R
12Be independently selected from hydrogen, kharophen, halo kharophen, amidino groups, guanidine radicals, alkyl, alkoxyl group, alkoxy amino, aminoalkyl group, hydroxyl, amino, low-grade alkyl amino, alkyl sulfonyl amino, amido alkylsulfonyl, an alkyl amido alkylsulfonyl, dialkyl group amido alkylsulfonyl, hydroxyalkyl, aminoalkyl group, halogen, haloalkyl, carbalkoxy, carboxyl, carboxyalkyl, carboxyl amido and cyano group;
R
33And R
34Be independently selected from hydrogen, amidino groups, guanidine radicals, alkoxyl group, hydroxyl, amino, alkoxy amino, low-grade alkyl amino, alkylthio, amido alkylsulfonyl, an alkyl amido alkylsulfonyl, dialkyl group amido alkylsulfonyl, alkyl, halogen, haloalkyl, halogenated alkoxy, hydroxyalkyl, carbalkoxy, carboxyl, carboxamido and cyano group;
R
33Randomly be Q
b
A is selected from covalent single bond and (CH (R
15))
Pa-(W
7)
Rr, wherein rr is selected from 0 to 1 integer, and pa is selected from 0 to 3 integer, W
7Be N (R
7);
R
7Be selected from hydrogen and alkyl;
R
15Be selected from hydrogen, halogen, alkyl and haloalkyl;
M is selected from N and R
1-C;
R
1Be selected from hydrogen, hydroxyl, hydroxyl amino, amidino groups, amino, cyano group, hydroxyalkyl, alkoxyl group, alkyl, alkylamino, aminoalkyl group, alkylthio, alkoxy amino, haloalkyl, halogenated alkoxy and halogen;
R
2Be Z
0-Q;
Z
0It is covalent single bond;
Q is selected from aryl and heteroaryl, and the adjacent carbon of the carbon on one of them and the tie point is randomly by R
9Replace, the adjacent carbon of the carbon on another and the tie point is randomly by R
13Replace, with R
9Adjacent and apart from the carbon of two atoms of the carbon on the tie point randomly by R
10Replace, with R
13Adjacent and apart from the carbon of two atoms of the carbon on the tie point randomly by R
12Replace any and R
10And R
12All adjacent carbon is randomly by R
11Replace;
R
9, R
11And R
13Be independently selected from hydrogen, hydroxyl, amino, amidino groups, guanidine radicals, low-grade alkyl amino, alkylthio, alkoxyl group, alkyl sulphinyl, alkyl sulphonyl, amido alkylsulfonyl, an alkyl amido alkylsulfonyl, alkyl, halogen, haloalkyl, halogenated alkoxy, hydroxyalkyl, carboxyl, carboxamido and cyano group;
R
10And R
12Be independently selected from hydrogen, kharophen, halo kharophen, amidino groups, guanidine radicals, alkyl, alkoxyl group, alkoxy amino, aminoalkyl group, hydroxyl, amino, low-grade alkyl amino, alkyl sulfonyl amino, amido alkylsulfonyl, an alkyl amido alkylsulfonyl, dialkyl group amido alkylsulfonyl, hydroxyalkyl, aminoalkyl group, halogen, haloalkyl, carbalkoxy, carboxyl, carboxyalkyl, carboxyl amido and cyano group;
Y
0Be formula (IV):
D wherein
5, D
6, J
5And J
6Be independently selected from C, N, O, S and covalent linkage, its condition be at the most one be covalent linkage, K
2Be C, D
5, D
6, J
5And J
6At the most one be O, D
5, D
6, J
5And J
6At the most one be S, if D
5, D
6, J
5And J
6Two be O and S, then D
5, D
6, J
5And J
6One of must be covalent linkage, D
5, D
6, J
5And J
6At the most four be N;
R
16, R
17, R
18And R
19Be independently selected from hydrogen, amidino groups, guanidine radicals, carboxyl, halogenated alkylthio, alkoxyl group, hydroxyl, amino, low-grade alkyl amino, alkylthio, alkyl sulphinyl, alkyl sulphonyl, alkyloyl, haloalkane acyl group, alkyl, halogen, haloalkyl, halogenated alkoxy, hydroxyalkyl, aminoalkyl group and cyano group;
R
16And R
19Randomly be Q
b, its condition is R
16And R
19At the most one be Q simultaneously
b, Q
bBe Q
Be
Q
bBe selected from NR
20R
21, Q
BeAnd C (NR
25) NR
23R
24, Q wherein
BeBe hydrogen;
R
20, R
21, R
23, R
24And R
25Be independently selected from hydrogen and alkyl;
Q
sBe CH
2
29. compound as claimed in claim 28 or its pharmacy acceptable salt, wherein:
B is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, tetrahydrofuran-2-base, 2-(2R)-two encircles [2.2.1] heptyl, 1,1-dioxo thiacyclopentane-3-base, trimethylene oxide-3-base, azetidine-1-base, azetidine-2-base, azetidine-3-base, two ring [3.1.0] hexane-6-bases, the 2-morpholinyl, morpholinyl, the 4-morpholinyl, the 1-piperazinyl, the 2-piperazinyl, piperidino, the 2-piperidyl, the 3-piperidyl, the 4-piperidyl, the 1-pyrrolidyl, the 2-pyrrolidyl, the 3-pyrrolidyl, the 2-alkyl dioxin, the 2-tetrahydrofuran base, the 3-tetrahydrofuran base, the 2-THP trtrahydropyranyl, the 3-THP trtrahydropyranyl, the 4-THP trtrahydropyranyl, 2-tetrahydro-thienyl and 3-tetrahydro-thienyl, wherein each ring carbon is randomly by R
33Replace, ring carbon adjacent with the carbon atom that is positioned at tie point and nitrogen-atoms are randomly by R
9Or R
13Replace, with R
9The position adjacent and apart from the ring carbon of two atoms of tie point or nitrogen-atoms randomly by R
10Replace, with R
13The position adjacent and apart from the ring carbon of two atoms of tie point or nitrogen-atoms randomly by R
12Replace;
R
9, R
11And R
13Be independently selected from hydrogen, methyl, ethyl, methoxyl group, oxyethyl group, hydroxyl, amino, N-methylamino, N, N-dimethylamino, methylthio group, trifluoromethyl, pentafluoroethyl group, 2,2,2-trifluoroethyl, fluorine, chlorine, bromine, amido alkylsulfonyl, N-methyl amido alkylsulfonyl, N, N-dimethyl amido alkylsulfonyl, methylol, 1-hydroxyethyl, amido carbonyl, N-methyl amido carbonyl, carboxyl and cyano group;
R
10And R
12Be independently selected from hydrogen, amidino groups, amido carbonyl, N-methyl amido carbonyl, guanidine radicals, methyl, ethyl, methoxyl group, oxyethyl group, hydroxyl, methylol, 1-hydroxyethyl, 2-hydroxyethyl, carboxyl, carboxyl methyl, amino, kharophen, trifluoromethyl, pentafluoroethyl group, 2,2,2-trifluoroethyl, trifluoroacetamido, amino methyl, N-methylamino, dimethylamino, amido alkylsulfonyl, N-methyl amido alkylsulfonyl, N, N-dimethyl amido alkylsulfonyl, methoxycarbonyl, fluorine, chlorine, bromine and cyano group;
R
33Be selected from hydrogen, amidino groups, guanidine radicals, methyl, ethyl, methoxyl group, oxyethyl group, hydroxyl, carboxyl, amino, N-methylamino, dimethylamino, methylthio group, ethylmercapto group, trifluoromethyl, pentafluoroethyl group, 2; 2,2-trifluoroethyl, fluorine, chlorine, bromine, amido alkylsulfonyl, N-methyl amido alkylsulfonyl, methylol, amido carbonyl, cyano group and Q
b
A is selected from covalent single bond, NH, N (CH
3), CH
2, CH
3CH, CH
2CH
2And CH
2CH
2CH
2
M is selected from N and R
1-C;
R
1Be selected from hydrogen, hydroxyl, amino, amidino groups, hydroxyl amino, amino methyl, methylamino, cyano group, methyl, trifluoromethyl, methoxyl group, methylol, methoxyl group amino, methylthio group, trifluoromethoxy, fluorine and chlorine;
R
2Be selected from phenyl, 2-thienyl, 2-furyl, 2-pyrryl, 2-imidazolyl, 2-thiazolyl, 3-isoxazolyl, 2-pyridyl and 3-pyridyl, the adjacent carbon of the carbon on one of them and the tie point is randomly by R
9Replace, the adjacent carbon of the carbon on another and the tie point is randomly by R
13Replace, with R
9Adjacent and apart from the carbon of two atoms of the carbon on the tie point randomly by R
10Replace, with R
13Adjacent and apart from the carbon of two atoms of the carbon on the tie point randomly by R
12Replace any and R
10And R
12All adjacent carbon is randomly by R
11Replace;
Y
0Be selected from down group:
1-Q
b-4-Q
s-2-R
16-3-R
17-5-R
18-6-R
19Benzene, 2-Q
b-5-Q
s-6-R
17-4-R
18-2-R
19Pyridine, 3-Q
b-6-Q
s-2-R
16-5-R
18-4-R
19Pyridine, 3-Q
b-5-Q
s-4-R
16-2-R
19Thiophene, 2-Q
b-5-Q
s-3-R
16-4-R
17Thiophene, 3-Q
b-5-Q
s-4-R
16-2-R
19Furans, 2-Q
b-5-Q
s-3-R
16-4-R
17Furans, 3-Q
b-5-Q
s-4-R
16-2-R
19Pyrroles, 2-Q
b-5-Q
s-3-R
16-4-R
17Pyrroles, 4-Q
b-2-Q
s-5-R
19Thiazole and 2-Q
b-5-Q
s-4-R
17Thiazole;
R
16, R
17, R
18And R
19Be independently selected from hydrogen, methyl, ethyl, amidino groups, guanidine radicals, methoxyl group, hydroxyl, amino, amino methyl, 1-amino-ethyl, 2-amino-ethyl, N-methylamino, dimethylamino, methylthio group, ethylmercapto group, trifluoromethylthio, methylsulfinyl, methyl sulphonyl, trifluoromethyl, pentafluoroethyl group, 2,2,2-trifluoroethyl, trifluoromethoxy, fluorine, chlorine, amido alkylsulfonyl, N-methyl amido alkylsulfonyl, methylol, carboxyl and cyano group;
Q
bBe selected from NR
20R
21And C (NR
25) NR
23R
24, its condition is described Q
bDirect and the carbon atom bonding of group;
R
20, R
21, R
23, R
24And R
25Be independently selected from hydrogen, methyl and ethyl;
Q
sBe CH
2
30. compound as claimed in claim 29 or its pharmacy acceptable salt, wherein:
B is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuran-2-base, 2-(2R)-two and encircles [2.2.1] heptyl, 1,1-dioxo thiacyclopentane-3-base, trimethylene oxide-3-base, azetidine-1-base, azetidine-2-base, azetidine-3-base, 1-pyrrolidyl and piperidino;
A is selected from covalent single bond, CH
2, NHC (O), CH
2CH
2And CH
2CH
2CH
2
M is selected from N and R
1-C;
R
1Be selected from hydrogen, hydroxyl, amino, methyl, trifluoromethyl, fluorine and chlorine;
R
2Be selected from 3-aminophenyl, 2,6-dichlorophenyl, 2-hydroxy phenyl, 5-amino-2-thienyl and 3-thienyl;
Y
0Be selected from down group:
1-Q
b-4-Q
s-2-R
16-3-R
17-5-R
18-6-R
19Benzene, 3-Q
b-5-Q
s-4-R
16-2-R
19Thiophene and 2-Q
b-5-Q
s-3-R
16-4-R
17Thiophene;
R
16And R
19Be independently selected from hydrogen, amidino groups, amino, amino methyl, methoxyl group, methylamino, hydroxyl, methylol, fluorine, chlorine and cyano group;
R
16And R
19Randomly be Q
b, its condition is R
16And R
19At the most one be Q simultaneously
b, Q
bBe Q
Be
R
17And R
18Be independently selected from hydrogen, fluorine, chlorine, hydroxyl, methylol, amino, carboxyl and cyano group;
Q
bBe selected from Q
BeAnd C (NR
25) NR
23R
24, Q wherein
BeBe hydrogen;
R
23, R
24And R
25Be independently selected from hydrogen and methyl;
Q
sBe CH
2
31. compound as claimed in claim 30 or its pharmacy acceptable salt, wherein:
B is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuran-2-base, 2-(2R)-two and encircles [2.2.1] heptyl, 1,1-dioxo thiacyclopentane-3-base, trimethylene oxide-3-base, azetidine-1-base, azetidine-2-base, azetidine-3-base and piperidino;
A is selected from covalent single bond, CH
2, CH
2CH
2And CH
2CH
2CH
2
M is selected from N and R
1-C;
R
1Be selected from hydrogen, fluorine and chlorine;
R
2Be selected from 3-aminophenyl, 2,6-dichlorophenyl, 2-hydroxy phenyl, phenyl, 5-amino-2-thienyl and 3-thienyl;
Y
0Be selected from 5-amidino groups-2-thenyl, 4-amidino benzyl, 2-fluoro-4-amidino benzyl and 3-fluoro-4-amidino benzyl.
32. compound as claimed in claim 25, wherein said compound is selected from the group with following formula structure:
Or its pharmacy acceptable salt, wherein:
R
2Be the 3-aminophenyl, B is a cyclopropyl, and A is a singly-bound, Y
0Be the 4-amidino benzyl, M is CH;
R
2Be the 3-aminophenyl, B is a cyclobutyl, and A is a singly-bound, Y
0Be 4-amidino groups-2-luorobenzyl, M is CH;
R
2Be the 3-aminophenyl, B is a cyclobutyl, and A is a singly-bound, Y
0Be the 4-amidino benzyl, M is CH;
R
2Be the 3-aminophenyl, B is a cyclopropyl, and A is a singly-bound, Y
0Be 4-amidino groups-2-luorobenzyl, M is CH;
R
2Be the 3-aminophenyl, B is a cyclobutyl, and A is a singly-bound, Y
0Be the 4-amidino benzyl, M is CH;
R
2Be the 3-aminophenyl, B is a cyclobutyl, and A is a singly-bound, Y
0Be 4-amidino groups-3-luorobenzyl, M is CH;
R
2Be the 3-aminophenyl, B is a cyclopentyl, and A is a singly-bound, Y
0Be the 4-amidino benzyl, M is CH;
R
2Be 5-amino-2-thienyl, B is a cyclobutyl, and A is a singly-bound, Y
0Be the 4-amidino benzyl, M is CH;
R
2Be the 3-aminophenyl, B is a cyclopropyl, and A is CH
2, Y
0Be the 4-amidino benzyl, M is CH;
R
2Be the 3-aminophenyl, B is 2-(2R)-two ring [2.2.1] heptyl, and A is a singly-bound, Y
0Be the 4-amidino benzyl, M is CH;
R
2Be the 3-aminophenyl, B is a cyclopentyl, and A is a singly-bound, Y
0Be 4-amidino groups-2-luorobenzyl, M is CH;
R
2Be the 3-aminophenyl, B is a cyclohexyl, and A is CH
2CH
2, Y
0Be the 4-amidino benzyl, M is CH;
R
2Be the 3-aminophenyl, B is tetrahydrofuran-2-base, and A is CH
2, Y
0Be the 4-amidino benzyl, M is CH;
R
2Be phenyl, B is the 1-pyrrolidyl, and A is CH
2CH
2, Y
0Be the 4-amidino benzyl, M is CH;
R
2Be the 3-aminophenyl, B is a piperidino, and A is CH
2CH
2, Y
0Be the 4-amidino benzyl, M is CH;
R
2Be the 3-aminophenyl, B is 1,1-dioxo thiacyclopentane-3-base, and A is a singly-bound, Y
0Be the 4-amidino benzyl, M is CH;
R
2Be the 2-hydroxy phenyl, B is a cyclobutyl, and A is a singly-bound, Y
0Be the 4-amidino benzyl, M is CH;
R
2Be the 3-aminophenyl, B is the 1-pyrrolidyl, and A is CH
2CH
2CH
2, Y
0Be the 4-amidino benzyl, M is CH;
R
2Be phenyl, B is a cyclobutyl, and A is a singly-bound, Y
0Be the 4-amidino benzyl, M is CH;
R
2Be the 3-thienyl, B is a cyclobutyl, and A is a singly-bound, Y
0Be the 4-amidino benzyl, M is CH;
R
2Be 2,6-dichlorophenyl, B are cyclobutyl, and A is a singly-bound, Y
0Be the 4-amidino benzyl, M is CH;
R
2Be the 3-aminophenyl, B is a cyclopropyl, and A is a singly-bound, Y
0Be the 4-amidino benzyl, M is CF;
R
2Be the 3-aminophenyl, B is a cyclobutyl, and A is a singly-bound, Y
0Be 4-amidino groups-2-luorobenzyl, M is CF;
R
2Be the 3-aminophenyl, B is a cyclobutyl, and A is a singly-bound, Y
0Be the 4-amidino benzyl, M is CF;
R
2Be the 3-aminophenyl, B is a cyclopropyl, and A is a singly-bound, Y
0Be 4-amidino groups-2-luorobenzyl, M is CF;
R
2Be the 3-aminophenyl, B is a cyclobutyl, and A is a singly-bound, Y
0Be the 4-amidino benzyl, M is CF;
R
2Be the 3-aminophenyl, B is a cyclobutyl, and A is a singly-bound, Y
0Be 4-amidino groups-3-luorobenzyl, M is CF;
R
2Be the 3-aminophenyl, B is a cyclopentyl, and A is a singly-bound, Y
0Be the 4-amidino benzyl, M is CF;
R
2Be 5-amino-2-thienyl, B is a cyclobutyl, and A is a singly-bound, Y
0Be the 4-amidino benzyl, M is CF;
R
2Be the 3-aminophenyl, B is a cyclopropyl, and A is CH
2, Y
0Be the 4-amidino benzyl, M is CF;
R
2Be the 3-aminophenyl, B is 2-(2R)-two ring [2.2.1] heptyl, and A is a singly-bound, Y
0Be the 4-amidino benzyl, M is CF;
R
2Be the 3-aminophenyl, B is a cyclopentyl, and A is a singly-bound, Y
0Be 4-amidino groups-2-luorobenzyl, M is CF;
R
2Be the 3-aminophenyl, B is a cyclohexyl, and A is CH
2CH
2, Y
0Be the 4-amidino benzyl, M is CF;
R
2Be the 3-aminophenyl, B is tetrahydrofuran-2-base, and A is CH
2, Y
0Be the 4-amidino benzyl, M is CF;
R
2Be phenyl, B is the 1-pyrrolidyl, and A is CH
2CH
2, Y
0Be the 4-amidino benzyl, M is CF;
R
2Be the 3-aminophenyl, B is a piperidino, and A is CH
2CH
2, Y
0Be the 4-amidino benzyl, M is CF;
R
2Be the 3-aminophenyl, B is 1,1-dioxo thiacyclopentane-3-base, and A is a singly-bound, Y
0Be the 4-amidino benzyl, M is CF;
R
2Be the 2-hydroxy phenyl, B is a cyclobutyl, and A is a singly-bound, Y
0Be the 4-amidino benzyl, M is CF;
R
2Be the 3-aminophenyl, B is the 1-pyrrolidyl, and A is CH
2CH
2CH
2, Y
0Be the 4-amidino benzyl, M is CF;
R
2Be phenyl, B is a cyclobutyl, and A is a singly-bound, Y
0Be the 4-amidino benzyl, M is CF;
R
2Be the 3-thienyl, B is a cyclobutyl, and A is a singly-bound, Y
0Be the 4-amidino benzyl, M is CF;
R
2Be 2,6-dichlorophenyl, B are cyclobutyl, and A is a singly-bound, Y
0Be the 4-amidino benzyl, M is CF;
R
2Be the 3-aminophenyl, B is a cyclopropyl, and A is a singly-bound, Y
0Be the 4-amidino benzyl, M is N;
R
2Be the 3-aminophenyl, B is a cyclobutyl, and A is a singly-bound, Y
0Be 4-amidino groups-2-luorobenzyl, M is N;
R
2Be the 3-aminophenyl, B is a cyclobutyl, and A is a singly-bound, Y
0Be the 4-amidino benzyl, M is N;
R
2Be the 3-aminophenyl, B is a cyclopropyl, and A is a singly-bound, Y
0Be 4-amidino groups-2-luorobenzyl, M is N;
R
2Be the 3-aminophenyl, B is a cyclobutyl, and A is a singly-bound, Y
0Be the 4-amidino benzyl, M is N;
R
2Be the 3-aminophenyl, B is a cyclobutyl, and A is a singly-bound, Y
0Be 4-amidino groups-3-luorobenzyl, M is N;
R
2Be the 3-aminophenyl, B is a cyclopentyl, and A is a singly-bound, Y
0Be the 4-amidino benzyl, M is N;
R
2Be 5-amino-2-thienyl, B is a cyclobutyl, and A is a singly-bound, Y
0Be the 4-amidino benzyl, M is N;
R
2Be the 3-aminophenyl, B is a cyclopropyl, and A is CH
2, Y
0Be the 4-amidino benzyl, M is N;
R
2Be the 3-aminophenyl, B is 2-(2R)-two ring [2.2.1] heptyl, and A is a singly-bound, Y
0Be the 4-amidino benzyl, M is N;
R
2Be the 3-aminophenyl, B is a cyclopentyl, and A is a singly-bound, Y
0Be 4-amidino groups-2-luorobenzyl, M is N;
R
2Be the 3-aminophenyl, B is a cyclohexyl, and A is CH
2CH
2, Y
0Be the 4-amidino benzyl, M is N;
R
2Be the 3-aminophenyl, B is tetrahydrofuran-2-base, and A is CH
2, Y
0Be the 4-amidino benzyl, M is N;
R
2Be phenyl, B is the 1-pyrrolidyl, and A is CH
2CH
2, Y
0Be the 4-amidino benzyl, M is N;
R
2Be the 3-aminophenyl, B is a piperidino, and A is CH
2CH
2, Y
0Be the 4-amidino benzyl, M is N;
R
2Be the 3-aminophenyl, B is 1,1-dioxo thiacyclopentane-3-base, and A is a singly-bound, Y
0Be the 4-amidino benzyl, M is N;
R
2Be the 2-hydroxy phenyl, B is a cyclobutyl, and A is a singly-bound, Y
0Be the 4-amidino benzyl, M is N;
R
2Be the 3-aminophenyl, B is the 1-pyrrolidyl, and A is CH
2CH
2CH
2, Y
0Be the 4-amidino benzyl, M is N;
R
2Be phenyl, B is a cyclobutyl, and A is a singly-bound, Y
0Be the 4-amidino benzyl, M is N;
R
2Be the 3-thienyl, B is a cyclobutyl, and A is a singly-bound, Y
0Be the 4-amidino benzyl, M is N;
R
2Be 2,6-dichlorophenyl, B are cyclobutyl, and A is a singly-bound, Y
0Be the 4-amidino benzyl, M is N.
33. have the compound of following formula:
Or its pharmacy acceptable salt, wherein:
B is selected from aryl and heteroaryl, and the adjacent carbon of the carbon on one of them and the tie point is randomly by R
32Replace, the adjacent carbon of the carbon on another and the tie point is randomly by R
36Replace, with R
32Adjacent and apart from the carbon of two atoms of the carbon on the tie point randomly by R
33Replace, with R
36Adjacent and apart from the carbon of two atoms of the carbon on the tie point randomly by R
35Replace any and R
33And R
35All adjacent carbon is randomly by R
34Replace;
R
32, R
33, R
34, R
35And R
36Be independently selected from hydrogen; kharophen; the halo kharophen; amidino groups; guanidine radicals; alkylene dioxo base; halogenated alkylthio; alkanoyloxy; alkoxyl group; hydroxyl; amino; alkoxy amino; alkyloyl; the haloalkane acyl group; nitro; low-grade alkyl amino; alkylthio; aryl; aralkyl; cycloalkyl; cycloalkylalkyl; heteroaryl; heterocyclic radical; alkyl sulfonyl amino; the amido alkylsulfonyl; one alkyl amido alkylsulfonyl; dialkyl group amido alkylsulfonyl; alkyl; thiazolinyl; halogen; haloalkyl; haloalkenyl group; halogenated alkoxy; hydroxyalkyl; alkylamino; carbalkoxy; carboxyl; carboxamido; cyano group and Q
b
B randomly is selected from hydrogen, trialkylsilkl, C2-C8 alkyl, C3-C8 alkylidene group, C3-C8 thiazolinyl, C3-C8 alkynyl and C2-C8 haloalkyl, wherein each member of group B can be randomly at distance B and A tie point nearly and comprise on any carbon of 6 atoms by one or more radicals R
32, R
33, R
34, R
35And R
36Replace;
B randomly is selected from C3-C12 cycloalkyl and the saturated heterocyclic radical of C4-C9, and wherein each ring carbon is randomly by R
33Replace, the ring carbon except that the ring carbon that is positioned at B and A tie point is randomly replaced by oxo, and its condition is that a ring carbon is replaced by oxo simultaneously at the most, and ring carbon adjacent with the carbon atom that is positioned at tie point and nitrogen-atoms are randomly by R
9Or R
13Replace, with R
9The position adjacent and apart from the ring carbon of two atoms of tie point or nitrogen-atoms randomly by R
10Replace, with R
13The position adjacent and apart from the ring carbon of two atoms of tie point or nitrogen-atoms randomly by R
12Replace, apart from three atoms of tie point and and R
10Ring carbon that the position is adjacent or nitrogen-atoms are randomly by R
11Replace, apart from three atoms of tie point and and R
12Ring carbon that the position is adjacent or nitrogen-atoms are randomly by R
33Replace, apart from four atoms of tie point and and R
11And R
33Ring carbon that the position is adjacent or nitrogen-atoms are randomly by R
34Replace;
R
9, R
10, R
11, R
12And R
13Be independently selected from hydrogen, kharophen, the halo kharophen, alkoxy amino, alkyloyl, the haloalkane acyl group, amidino groups, guanidine radicals, alkylene dioxo base, halogenated alkylthio, alkoxyl group, hydroxyl, amino, low-grade alkyl amino, alkylthio, alkyl sulphinyl, alkyl sulfonyl amino, alkyl sulphonyl, the amido alkylsulfonyl, one alkyl amido alkylsulfonyl, dialkyl group amido alkylsulfonyl, alkyl, halogen, haloalkyl, halogenated alkoxy, hydroxyalkyl, aminoalkyl group, carbalkoxy, carboxyl, carboxyalkyl, carboxamido and cyano group;
A is selected from covalent single bond and (CH (R
15))
Pa-(W
7)
Rr, wherein rr is selected from 0 to 1 integer, and pa is selected from 0 to 3 integer, W
7Be selected from O, S, C (O), (R
7) NC (O), (R
7) NC (S) and N (R
7);
R
7Be selected from hydrogen, hydroxyl and alkyl;
R
15Be selected from hydrogen, hydroxyl, halogen, alkyl and haloalkyl;
M is selected from N and R
1-C;
R
1Be selected from hydrogen, hydroxyl, hydroxyl amino, amidino groups, amino, cyano group, hydroxyalkyl, alkoxyl group, alkyl, alkylamino, aminoalkyl group, alkylthio, alkoxy amino, haloalkyl, halogenated alkoxy and halogen;
R
2Be Z
0-Q;
Z
0Be selected from covalent single bond, (CR
41R
42)
q, (CH (R
41))
g-W
0-(CH (R
42))
p(CH (R
41))
e-W
22-(CH (R
42))
h, wherein q is selected from 1 to 2 integer, and g and p are independently selected from 0 to 3 integer, W
0Be selected from O, S and N (R
41), e and h are independently selected from 0 to 1 integer, W
22Be selected from CR
41=CR
421, the 2-cyclopropyl, 1, the 2-cyclobutyl, 1, the 2-cyclohexyl, 1, the 3-cyclohexyl, 1, the 2-cyclopentyl, 1, the 3-cyclopentyl, 2, morpholinyl, 2, the 4-morpholinyl, 2, the 6-morpholinyl, 3, the 4-morpholinyl, 3, the 5-morpholinyl, 1, the 2-piperazinyl, 1, the 3-piperazinyl, 2, the 3-piperazinyl, 2, the 6-piperazinyl, 1, the 2-piperidyl, 1, the 3-piperidyl, 2, the 3-piperidyl, 2, the 4-piperidyl, 2, the 6-piperidyl, 3, the 4-piperidyl, 1, the 2-pyrrolidyl, 1, the 3-pyrrolidyl, 2, the 3-pyrrolidyl, 2, the 4-pyrrolidyl, 2, the 5-pyrrolidyl, 3, the 4-pyrrolidyl, 2, the 3-tetrahydrofuran base, 2, the 4-tetrahydrofuran base, 2,5-tetrahydrofuran base and 3, the 4-tetrahydrofuran base, its condition is Z
0Direct and pyrazine ketone ring key closes;
R
41And R
42Be independently selected from hydrogen, hydroxyl and amino;
Q is selected from hydrogen, and its condition is Z
0It or not covalent single bond; The adjacent carbon of carbon on aryl and the heteroaryl, one of them and tie point is randomly by R
9Replace, the adjacent carbon of the carbon on another and the tie point is randomly by R
13Replace, with R
9Adjacent and apart from the carbon of two atoms of the carbon on the tie point randomly by R
10Replace, with R
13Adjacent and apart from the carbon of two atoms of the carbon on the tie point randomly by R
12Replace any and R
10And R
12All adjacent carbon is randomly by R
11Replace;
K is CHR
4a, R wherein
4aBe selected from hydrogen, hydroxyalkyl, alkyl, alkoxyalkyl, alkylthio alkyl and haloalkyl;
E
0Be selected from covalent single bond, C (O) N (H), (H) NC (O), (R
7) NS (O)
2And S (O)
2N (R
7);
Y
ATBe Q
b-Q
s
Q
sBe (CR
37R
38)
b, wherein b is selected from 1 to 4 integer, R
37Be selected from hydrogen, alkyl and haloalkyl, R
38Be selected from hydrogen, alkyl, haloalkyl, aroyl and 4-hetaroylpyrazol, its condition is to have at least one aroyl or 4-hetaroylpyrazol substituting group, and aroyl or 4-hetaroylpyrazol are simultaneously and (CR at the most
37R
38)
bBonding, described aroyl and described 4-hetaroylpyrazol randomly are selected from R on one to three ring carbon
16, R
17, R
18And R
19Substituting group replace described aroyl and described 4-hetaroylpyrazol and direct same E
0The CR of bonding
37R
38Bonding, at the most alkyl or or haloalkyl simultaneously and CR
37R
38Bonding, described alkyl and haloalkyl and the bond with carbon except that bonding aroyl or 4-hetaroylpyrazol person;
R
16, R
17, R
18And R
19Be independently selected from hydrogen, amidino groups, guanidine radicals, carboxyl, halogenated alkylthio, alkoxyl group, hydroxyl, amino, alkoxy amino, low-grade alkyl amino, alkylthio, alkyl sulphinyl, alkyl sulphonyl, alkyloyl, haloalkane acyl group, alkyl, halogen, haloalkyl, halogenated alkoxy, hydroxyalkyl, aminoalkyl group and cyano group;
R
16And R
19Randomly be Q
b, its condition is R
16And R
19At the most one be Q simultaneously
b, Q
bBe Q
Be
Q
bBe selected from NR
20R
21, Q
Be, N (R
26) C (NR
25) N (R
23) (R
24) and C (NR
25) NR
23R
24, Q wherein
BeBe hydrogen, its condition is R
20And R
21At the most one be hydroxyl, amino, alkylamino or dialkyl amido simultaneously, R
23And R
24At the most one be hydroxyl, amino, alkylamino or dialkyl amido simultaneously;
R
20, R
21, R
23, R
24, R
25And R
26Be independently selected from hydrogen, alkyl, hydroxyl, amino, alkylamino and dialkyl amido.
34. the compound with following formula as claimed in claim 33:
Or its pharmacy acceptable salt, wherein:
B is selected from phenyl, 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyrryl, 3-pyrryl, 2-imidazolyl, 4-imidazolyl, 3-pyrazolyl, 4-pyrazolyl, 2-thiazolyl, 3-isoxazolyl and 5-isoxazolyl, and the adjacent carbon of the carbon on one of them and the tie point is randomly by R
32Replace, the adjacent carbon of the carbon on another and the tie point is randomly by R
36Replace, with R
32Adjacent and apart from the carbon of two atoms of the carbon on the tie point randomly by R
33Replace, with R
36Adjacent and apart from the carbon of two atoms of the carbon on the tie point randomly by R
35Replace any and R
33And R
35All adjacent carbon is randomly by R
34Replace;
R
32, R
33, R
34, R
35And R
36Be independently selected from hydrogen, amidino groups, guanidine radicals, methyl, ethyl, methoxyl group, oxyethyl group, hydroxyl, amino, N-methylamino, dimethylamino, methylthio group, ethylmercapto group, trifluoromethyl, pentafluoroethyl group, 2; 2,2-trifluoroethyl, fluorine, chlorine, bromine, amido alkylsulfonyl, N-methyl amido alkylsulfonyl, methylol, amido carbonyl, carboxyl, cyano group and Q
b
B randomly is selected from hydrogen, ethyl, the 2-propenyl, 2-propynyl, propyl group, sec.-propyl, butyl, crotyl, the 2-butyne base, sec-butyl, the tertiary butyl, isobutyl-, the 2-methylpropenyl, the 1-amyl group, pentenyl, the 3-pentenyl, the valerylene base, the 3-pentynyl, the 2-amyl group, the 3-amyl group, the 2-methyl butyl, 2-methyl-2-butene base, the 3-methyl butyl, 3-methyl-2-butene base, the 1-hexyl, the 2-hexenyl, the 3-hexenyl, the 4-hexenyl, 2-hexin base, 3-hexin base, 4-hexin base, the 2-hexyl, 1-methyl-pentenyl, 1-methyl-3-pentenyl, 1-methyl-valerylene base, 1-methyl-3-pentynyl, the 3-hexyl, 1-ethyl-crotyl, the 1-heptyl, the 2-heptenyl, the 3-heptenyl, the 4-heptenyl, the 5-heptenyl, 2-heptyne base, 3-heptyne base, 4-heptyne base, 5-heptyne base, the 2-heptyl, 1-methyl-2-hexenyl, 1-methyl-3-hexenyl, 1-methyl-4-hexenyl, 1-methyl-2-hexin base, 1-methyl-3-hexin base, 1-methyl-4-hexin base, the 3-heptyl, 1-ethyl-pentenyl, 1-ethyl-3-pentenyl, 1-ethyl-valerylene base, 1-ethyl-3-pentynyl, 2,2, the 2-trifluoroethyl, 2,2-two fluoropropyls, 4-trifluoromethyl-5,5,5-trifluoro amyl group, 4-trifluoromethyl amyl group, 5,5,6,6,6-five fluorine hexyls and 3,3, the 3-trifluoro propyl, wherein each member of group B randomly at distance B and A tie point nearly and comprise on any carbon of 5 atoms by one or more radicals R
32, R
33, R
34, R
35And R
36Replace;
B randomly is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, tetrahydrofuran-2-base, 2-(2R)-two encircles [2.2.1] heptyl, 1,1-dioxo thiacyclopentane-3-base, trimethylene oxide-3-base, azetidine-1-base, azetidine-2-base, azetidine-3-base, two ring [3.1.0] hexane-6-bases, the 2-morpholinyl, morpholinyl, the 4-morpholinyl, the 1-piperazinyl, the 2-piperazinyl, piperidino, the 2-piperidyl, the 3-piperidyl, the 4-piperidyl, the 1-pyrrolidyl, the 2-pyrrolidyl, the 3-pyrrolidyl, the 2-alkyl dioxin, the 2-tetrahydrofuran base, the 3-tetrahydrofuran base, the 2-THP trtrahydropyranyl, the 3-THP trtrahydropyranyl, the 4-THP trtrahydropyranyl, 2-tetrahydro-thienyl and 3-tetrahydro-thienyl, wherein each ring carbon is randomly by R
33Replace, ring carbon adjacent with the carbon atom that is positioned at tie point and nitrogen-atoms are randomly by R
9Or R
13Replace, with R
9The position adjacent and apart from the ring carbon of two atoms of tie point or nitrogen-atoms randomly by R
10Replace, with R
13The position adjacent and apart from the ring carbon of two atoms of tie point or nitrogen-atoms randomly by R
12Replace;
R
9, R
11And R
13Be independently selected from hydrogen, methyl, ethyl, methoxyl group, oxyethyl group, hydroxyl, amino, N-methylamino, N, N-dimethylamino, methylthio group, trifluoromethyl, pentafluoroethyl group, 2,2,2-trifluoroethyl, fluorine, chlorine, bromine, amido alkylsulfonyl, N-methyl amido alkylsulfonyl, N, N-dimethyl amido alkylsulfonyl, methylol, 1-hydroxyethyl, amido carbonyl, N-methyl amido carbonyl, carboxyl and cyano group;
R
10And R
12Be independently selected from hydrogen, amidino groups, amido carbonyl, N-methyl amido carbonyl, guanidine radicals, methyl, ethyl, methoxyl group, oxyethyl group, hydroxyl, methylol, 1-hydroxyethyl, 2-hydroxyethyl, carboxyl, carboxyl methyl, amino, kharophen, trifluoromethyl, pentafluoroethyl group, 2,2,2-trifluoroethyl, trifluoroacetamido, amino methyl, N-methylamino, dimethylamino, amido alkylsulfonyl, N-methyl amido alkylsulfonyl, N, N-dimethyl amido alkylsulfonyl, methoxycarbonyl, fluorine, chlorine, bromine and cyano group;
A is selected from covalent single bond, NH, N (CH
3), CH
2, CH
3CH, CH
2CH
2And CH
2CH
2CH
2
M is selected from N and R
1-C;
R
1Be selected from hydrogen, hydroxyl, amino, amidino groups, hydroxyl amino, amino methyl, 1-amino-ethyl, methylamino, dimethylamino, cyano group, methyl, ethyl, trifluoromethyl, pentafluoroethyl group, 2,2,2-trifluoroethyl, methoxyl group, methylol, 1-hydroxyethyl, 2-hydroxyethyl, methoxyl group amino, methylthio group, ethylmercapto group, trifluoromethoxy, 1,1,2,2-tetrafluoro oxyethyl group, fluorine, chlorine and bromine;
R
2Be selected from phenyl, 2-thienyl, 2-furyl, 2-pyrryl, 2-imidazolyl, 2-thiazolyl, 3-isoxazolyl, 2-pyridyl and 3-pyridyl, the adjacent carbon of the carbon on one of them and the tie point is randomly by R
9Replace, the adjacent carbon of the carbon on another and the tie point is randomly by R
13Replace, with R
9Adjacent and apart from the carbon of two atoms of the carbon on the tie point randomly by R
10Replace, with R
13Adjacent and apart from the carbon of two atoms of the carbon on the tie point randomly by R
12Replace any and R
10And R
12All adjacent carbon is randomly by R
11Replace;
Y
ATBe Q
b-Q
s
Q
sBe selected from down group:
C[R
37(benzoyl)] (CR
37R
38)
b], C[R
37(2-pyridyl carbonyl)] (CR
37R
38)
b], C[R
37(3-pyridyl carbonyl)] (CR
37R
38)
b], C[R
37(4-pyridyl carbonyl)] (CR
37R
38)
b], C[R
37(2-thienyl carbonyl)] (CR
37R
38)
b], C[R
37(3-thienyl carbonyl)] (CR
37R
38)
b], C[R
37(2-thiazolyl carbonyl)] (CR
37R
38)
b], C[R
37(4-thiazolyl carbonyl)] (CR
37R
38)
b] and C[R
37(5-thiazolyl carbonyl)] (CR
37R
38)
b], wherein b is selected from 1 to 3 integer, R
37And R
38Be independently selected from hydrogen, alkyl and haloalkyl, its condition is that described aroyl and described 4-hetaroylpyrazol randomly are selected from R on one to three ring carbon
16, R
17, R
18And R
19Substituting group replace, its condition is R
17And R
18Randomly on the carbon position and the para-position carbon except that between relative benzoyl substituting group and the substituent carbonyl of 4-hetaroylpyrazol, be substituted; the bond with carbon of the amide nitrogen bonding of described benzoyl and described 4-hetaroylpyrazol and direct same 1-(amido carbonyl methylene radical), alkyl or haloalkyl are simultaneously and CR at the most
37R
38Bonding;
R
16, R
17, R
18And R
19Be independently selected from hydrogen, methyl, ethyl, amidino groups, guanidine radicals, methoxyl group, hydroxyl, amino, amino methyl, 1-amino-ethyl, 2-amino-ethyl, N-methylamino, dimethylamino, methylthio group, ethylmercapto group, trifluoromethylthio, methylsulfinyl, methyl sulphonyl, trifluoromethyl, pentafluoroethyl group, 2,2,2-trifluoroethyl, trifluoromethoxy, fluorine, chlorine, amido alkylsulfonyl, N-methyl amido alkylsulfonyl, methylol, carboxyl and cyano group;
Q
bBe selected from NR
20R
21And C (NR
25) NR
23R
24, its condition is described Q
bDirect and the carbon atom bonding of group;
R
20, R
21, R
23, R
24And R
25Be independently selected from hydrogen, methyl and ethyl.
35. compound as claimed in claim 34 or its pharmacy acceptable salt, wherein:
B is selected from the 2-aminophenyl, the 3-aminophenyl, 3-amidino groups phenyl, 4-amidino groups phenyl, the 3-carboxyl phenyl, 3-carboxyl-5-hydroxy phenyl, the 3-chloro-phenyl-, the 4-chloro-phenyl-, 3, the 4-dichlorophenyl, the 2-fluorophenyl, the 3-fluorophenyl, 3, the 4-difluorophenyl, the 3-hydroxy phenyl, the 4-hydroxy phenyl, 3-methoxyl group aminophenyl, the 3-p-methoxy-phenyl, the 4-p-methoxy-phenyl, the 3-aminomethyl phenyl, the 4-aminomethyl phenyl, phenyl, the 3-trifluoromethyl, the 2-imidazolyl, the 2-pyridyl, the 3-pyridyl, 5-chloro-3-trifluoromethyl-2-pyridyl, the 4-pyridyl, the 2-thienyl, 3-thienyl and 3-trifluoromethyl-2-pyridyl;
B randomly is selected from hydrogen, ethyl, the 2-propenyl, 2-propynyl, propyl group, sec.-propyl, butyl, the 2-butyl, (R)-the 2-butyl, (S)-the 2-butyl, the tertiary butyl, isobutyl-, the 1-amyl group, the 3-amyl group, the 2-methyl butyl, 2,2, the 2-trifluoroethyl, 6-amido carbonyl hexyl, 4-methyl-2-amyl group, the 3-hydroxypropyl, 3-methoxyl group-2-propyl group, the 2-methoxy ethyl, 2-methyl-2-butyl, 3-methyl-2-butyl, the 2-dimethylaminopropyl, the 2-cyano ethyl, 6-hydroxyl hexyl, the 2-hydroxyethyl, 2-amidino groups ethyl, the 2-GE, 3-guanidine radicals propyl group, 4-guanidine radicals butyl, the 3-hydroxypropyl, the 4-hydroxybutyl, 6-cyano group hexyl, the 2-dimethyl aminoethyl, the 3-methyl butyl, the 2-methyl butyl, (S)-the 2-methyl butyl, the 3-aminopropyl, the amino butyl of 2-hexyl and 4-;
B randomly is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuran-2-base, 2-(2R)-two and encircles [2.2.1] heptyl, 1,1-dioxo thiacyclopentane-3-base, trimethylene oxide-3-base, azetidine-1-base, azetidine-2-base, azetidine-3-base, 1-pyrrolidyl and piperidino;
A is selected from covalent single bond, CH
2, CH
3CH, CH
2CH
2And CH
2CH
2CH
2
M is selected from N and R
1-C;
R
1Be selected from hydrogen, hydroxyl, amino, amidino groups, hydroxyl amino, amino methyl, methylamino, cyano group, methyl, trifluoromethyl, methoxyl group, methylol, methoxyl group amino, methylthio group, trifluoromethoxy, fluorine and chlorine;
R
2Be selected from 5-amino-3-amido carbonyl phenyl, 5-amino-2-fluorophenyl, 3-amino-5-hydroxymethyl phenyl, 5-amino-3-methoxycarbonyl phenyl, 3-amidino groups phenyl, 3-amino-2-methyl phenyl, 5-amino-2-methylthio group phenyl, the 3-aminophenyl, benzyl, the 3-carboxyl phenyl, 3-carboxyl-5-hydroxy phenyl, 3-carboxyl-5-aminophenyl, 3-carboxymethyl-5-aminophenyl, 3-carboxymethyl-5-hydroxy phenyl, 3-carboxymethyl phenyl, the 3-chloro-phenyl-, the 2-chloro-phenyl-, 2, the 6-dichlorophenyl, the 3-cyano-phenyl, the 3-dimethylaminophenyl, the 2-fluorophenyl, the 3-fluorophenyl, 2, the 5-difluorophenyl, the 2-hydroxy phenyl, the 3-hydroxy phenyl, 3-methanesulfonamido phenyl, the 2-p-methoxy-phenyl, the 3-p-methoxy-phenyl, 3-methoxyl group aminophenyl, 3-methoxycarbonyl phenyl, 2-methylamino phenyl, 3-methylamino phenyl, the 2-aminomethyl phenyl, the 3-aminomethyl phenyl, the 4-aminomethyl phenyl, phenyl, 3-trifluoroacetamido phenyl, the 3-trifluoromethyl, the 2-trifluoromethyl, 5-amino-2-thienyl, 5-amino-3-thienyl, 3-bromo-2-thienyl, the 3-pyridyl, the 4-pyridyl, 2-thienyl and 3-thienyl;
Y
ATBe Q
b-Q
s
Q
sBe selected from down group:
[CH (benzoyl)] (CH
2)
b, [CH (2-pyridyl carbonyl)] (CH
2)
b, [CH (3-pyridyl carbonyl)] (CH
2)
b, [CH (4-pyridyl carbonyl)] (CH
2)
b, [CH (2-thienyl carbonyl)] (CH
2)
b, [CH (3-thienyl carbonyl)] (CH
2)
b, [CH (2-thiazolyl carbonyl)] (CH
2)
b, [CH (4-thiazolyl carbonyl)] (CH
2)
b[CH (5-thiazolyl carbonyl)] (CH
2)
b, wherein b is selected from 1 to 3 integer, and its condition is that described aroyl and described 4-hetaroylpyrazol randomly are selected from R on one to three ring carbon
16, R
17, R
18And R
19Substituting group replace, its condition is R
17And R
18Randomly on the carbon position and the para-position carbon except that between relative benzoyl substituting group and the substituent carbonyl of 4-hetaroylpyrazol, be substituted the bond with carbon of the amide nitrogen bonding of described benzoyl and described 4-hetaroylpyrazol substituting group and direct same 1-(amido carbonyl methylene radical);
R
16And R
19Be independently selected from hydrogen, amidino groups, amino, amino methyl, methoxyl group, methylamino, hydroxyl, methylol, fluorine, chlorine and cyano group;
R
17And R
18Be independently selected from hydrogen, fluorine, chlorine, hydroxyl, methylol, amino, carboxyl and cyano group;
Q
bBe C (NR
25) NR
23R
24
R
23, R
24And R
25Be independently selected from hydrogen and methyl.
36. compound as claimed in claim 35 or its pharmacy acceptable salt, wherein:
B is selected from 3-aminophenyl, 3-amidino groups phenyl, 4-amidino groups phenyl, 3-chloro-phenyl-, 4-chloro-phenyl-, 3,4-dichlorophenyl, 2-fluorophenyl, 4-aminomethyl phenyl, phenyl, 2-imidazolyl, 3-pyridyl, 4-pyridyl and 3-trifluoromethyl-2-pyridyl;
B randomly is selected from hydrogen, ethyl, the 2-propenyl, 2-propynyl, propyl group, sec.-propyl, butyl, the 2-butyl, (R)-the 2-butyl, (S)-the 2-butyl, the tertiary butyl, isobutyl-, the 1-amyl group, the 3-amyl group, the 2-methyl butyl, 2,2, the 2-trifluoroethyl, 6-amido carbonyl hexyl, 4-methyl-2-amyl group, the 3-hydroxypropyl, 3-methoxyl group-2-propyl group, the 2-methoxy ethyl, 2-methyl-2-butyl, 3-methyl-2-butyl, the 2-dimethylaminopropyl, the 2-cyano ethyl, 6-hydroxyl hexyl, the 2-hydroxyethyl, 2-amidino groups ethyl, the 2-GE, 3-guanidine radicals propyl group, 4-guanidine radicals butyl, the 3-hydroxypropyl, the 4-hydroxybutyl, 6-cyano group hexyl, the 2-dimethyl aminoethyl, the 3-methyl butyl, the 2-methyl butyl, (S)-the 2-methyl butyl, the 3-aminopropyl, the amino butyl of 2-hexyl and 4-;
B randomly is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuran-2-base, 2-(2R)-two and encircles [2.2.1] heptyl, 1,1-dioxo thiacyclopentane-3-base, trimethylene oxide-3-base, azetidine-1-base, azetidine-2-base, azetidine-3-base and piperidino;
A is selected from covalent single bond, CH
2, CH
2CH
2And CH
2CH
2CH
2
M is selected from N and R
1-C;
R
1Be selected from hydrogen, hydroxyl, amino, methyl, trifluoromethyl, fluorine and chlorine;
R
2Be selected from 3-aminophenyl, benzyl, 2,6-dichlorophenyl, 5-amino-2-thienyl, 5-amino-2-fluorophenyl, 3-amino-2-methyl phenyl, 5-amino-2-methylthio group phenyl, 3-carboxyl phenyl, 3-cyano-phenyl, 3-chloro-phenyl-, 2-hydroxy phenyl, 3-hydroxy phenyl, 3-methanesulfonamido phenyl, 3-methoxycarbonyl phenyl, 3-dimethylaminophenyl, 3-methylamino phenyl, 2-aminomethyl phenyl, 3-aminomethyl phenyl, phenyl, 3-pyridyl, 3-trifluoroacetamido phenyl, 3-bromo-2-thienyl, 2-thienyl and 3-thienyl;
Y
ATBe selected from 5-guanidine radicals-1-oxo-1-(2-thiazolyl)-2-amyl group, 5-guanidine radicals-1-oxo-1-(4-thiazolyl)-1-2-amyl group, 5-guanidine radicals-1-oxo-1-(5-thiazolyl)-2-amyl group, 5-guanidine radicals-1-oxo-1-(4-amino-2-thiazolyl)-2-amyl group and 5-guanidine radicals-1-oxo-1-phenyl-2-amyl group.
37. compound as claimed in claim 33, wherein said compound is selected from the group with following formula:
Or its pharmacy acceptable salt, wherein:
R
2Be the 3-aminophenyl, B is a phenyl, and A is CH
2, Y
ATBe 5-guanidine radicals-1-oxo-1-(2-thiazolyl)-2-amyl group, M is CH;
R
2Be phenyl, B is a phenyl, and A is CH
2CH
2, Y
ATBe 5-guanidine radicals-1-oxo-1-(2-thiazolyl)-2-amyl group, M is CH;
R
2Be benzyl, B is a phenyl, and A is CH
2CH
2, Y
ATBe 5-guanidine radicals-1-oxo-1-(2-thiazolyl)-2-amyl group, M is CH;
R
2Be phenyl, B is a phenyl, and A is CH
2CH
2, Y
ATBe 5-guanidine radicals-1-oxo-1-(2-thiazolyl)-2-amyl group, M is CH;
R
2Be benzyl, B is a phenyl, and A is CH
2CH
2, Y
ATBe 5-guanidine radicals-1-oxo-1-(2-thiazolyl)-2-amyl group, M is CH;
R
2Be phenyl, B is a phenyl, and A is CH
2CH
2, Y
ATBe 5-guanidine radicals-1-oxo-1-(2-thiazolyl)-2-amyl group, M is CH;
R
2Be the 3-aminophenyl, B is a phenyl, and A is CH
2, Y
ATBe 5-guanidine radicals-1-oxo-1-(2-thiazolyl)-2-amyl group, M is CF;
R
2Be phenyl, B is a phenyl, and A is CH
2CH
2, Y
ATBe 5-guanidine radicals-1-oxo-1-(2-thiazolyl)-2-amyl group, M is CF;
R
2Be benzyl, B is a phenyl, and A is CH
2CH
2, Y
ATBe 5-guanidine radicals-1-oxo-1-(2-thiazolyl)-2-amyl group, M is CF;
R
2Be phenyl, B is a phenyl, and A is CH
2CH
2, Y
ATBe 5-guanidine radicals-1-oxo-1-(2-thiazolyl)-2-amyl group, M is CF;
R
2Be benzyl, B is a phenyl, and A is CH
2CH
2, Y
ATBe 5-guanidine radicals-1-oxo-1-(2-thiazolyl)-2-amyl group, M is CF;
R
2Be phenyl, B is a phenyl, and A is CH
2CH
2, Y
ATBe 5-guanidine radicals-1-oxo-1-(2-thiazolyl)-2-amyl group, M is CF;
R
2Be the 3-aminophenyl, B is a phenyl, and A is CH
2, Y
ATBe 5-guanidine radicals-1-oxo-1-(2-thiazolyl)-2-amyl group, M is CCl;
R
2Be phenyl, B is a phenyl, and A is CH
2CH
2, Y
ATBe 5-guanidine radicals-1-oxo-1-(2-thiazolyl)-2-amyl group, M is CCl;
R
2Be benzyl, B is a phenyl, and A is CH
2CH
2, Y
ATBe 5-guanidine radicals-1-oxo-1-(2-thiazolyl)-2-amyl group, M is CCl;
R
2Be phenyl, B is a phenyl, and A is CH
2CH
2, Y
ATBe 5-guanidine radicals-1-oxo-1-(2-thiazolyl)-2-amyl group, M is CCl;
R
2Be benzyl, B is a phenyl, and A is CH
2CH
2, Y
ATBe 5-guanidine radicals-1-oxo-1-(2-thiazolyl)-2-amyl group, M is CCl;
R
2Be phenyl, B is a phenyl, and A is CH
2CH
2, Y
ATBe 5-guanidine radicals-1-oxo-1-(2-thiazolyl)-2-amyl group, M is CCl;
R
2Be the 3-aminophenyl, B is a phenyl, and A is CH
2, Y
ATBe 5-guanidine radicals-1-oxo-1-(2-thiazolyl)-2-amyl group, M is N;
R
2Be phenyl, B is a phenyl, and A is CH
2CH
2, Y
ATBe 5-guanidine radicals-1-oxo-1-(2-thiazolyl)-2-amyl group, M is N;
R
2Be benzyl, B is a phenyl, and A is CH
2CH
2, Y
ATBe 5-guanidine radicals-1-oxo-1-(2-thiazolyl)-2-amyl group, M is N;
R
2Be phenyl, B is a phenyl, and A is CH
2CH
2, Y
ATBe 5-guanidine radicals-1-oxo-1-(2-thiazolyl)-2-amyl group, M is N;
R
2Be benzyl, B is a phenyl, and A is CH
2CH
2, Y
ATBe 5-guanidine radicals-1-oxo-1-(2-thiazolyl)-2-amyl group, M is N;
R
2Be phenyl, B is a phenyl, and A is CH
2CH
2, Y
ATBe 5-guanidine radicals-1-oxo-1-(2-thiazolyl)-2-amyl group, M is N.
38. a composition that is used to suppress the blood thrombosis disease comprises claim 8,16,24,32 and 37 any one compound and pharmaceutically acceptable carriers.
39. a composition that is used to suppress the blood thrombosis disease comprises any one compound of claim 1 to 7, claim 9 to 15, claim 17 to 23, claim 25 to 31 and claim 33 to 36 and pharmaceutically acceptable carrier.
40. a method that is used to suppress the blood thrombosis disease comprises the claim 38 and 39 any one compositions that add significant quantity on the therapeutics in blood.
41. one kind is used to suppress the method that blood platelet aggregation thing forms, comprises the claim 38 and 39 any one compositions that add significant quantity on the therapeutics in blood.
42. one kind is used to suppress the thrombotic method of blood, comprises the claim 38 and 39 any one compositions that add significant quantity on the therapeutics in blood.
43. a method that is used for the treatment of or prevents Mammals venous thromboembolism and pulmonary thromboembolism comprises this Mammals drug treatment is learned claim 38 and 39 any one compositions of going up significant quantity.
44. a method that is used for the treatment of or prevents the Mammals venous thrombosis comprises this Mammals drug treatment is learned claim 38 and 39 any one compositions of going up significant quantity.
45. a method that is used for the treatment of or prevents Mammals heart source property thromboembolism comprises this Mammals drug treatment is learned claim 38 and 39 any one compositions of going up significant quantity.
46. a method that is used for the treatment of or prevents people and other Mammals thrombus embolic stroke comprises this Mammals drug treatment is learned claim 38 and 39 any one compositions of going up significant quantity.
47. one kind is used for the treatment of or prevents people's thrombotic method relevant with cancer and cancer chemotherapy with other Mammalss, comprises this Mammals drug treatment is learned claim 38 and 39 any one compositions of going up significant quantity.
48. a method that is used for the treatment of or prevents people and other Mammals unstable angina pectoriss comprises this Mammals drug treatment is learned claim 38 and 39 any one compositions of going up significant quantity.
49. one kind is used to suppress the thrombotic method of blood, comprises in blood the fibrinogen deceptor antagonists of significant quantity on compound that the claim 1 to 37 that adds significant quantity on the therapeutics is any one and the therapeutics.
50. being used to suppress the Mammals thrombus, compound that claim 1 to 37 is any or the purposes of its pharmacy acceptable salt in medication preparation, this medicine form, treat thrombosis or prevention thrombosis.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US13495799P | 1999-05-19 | 1999-05-19 | |
| US60/134,957 | 1999-05-19 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1351594A true CN1351594A (en) | 2002-05-29 |
| CN1152023C CN1152023C (en) | 2004-06-02 |
Family
ID=22465795
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB008077533A Expired - Fee Related CN1152023C (en) | 1999-05-19 | 2000-05-18 | Substituted polycyclic aryl and heteroaryl uracils as anticoagulative agents |
Country Status (14)
| Country | Link |
|---|---|
| EP (1) | EP1178971A1 (en) |
| JP (1) | JP2002544263A (en) |
| KR (1) | KR20010113969A (en) |
| CN (1) | CN1152023C (en) |
| AR (1) | AR043677A1 (en) |
| AU (1) | AU771740B2 (en) |
| BR (1) | BR0011273A (en) |
| CA (1) | CA2373610A1 (en) |
| MX (1) | MXPA01011806A (en) |
| NZ (1) | NZ514877A (en) |
| PE (1) | PE20010217A1 (en) |
| UY (1) | UY26157A1 (en) |
| WO (1) | WO2000069833A1 (en) |
| ZA (2) | ZA200109338B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2023125792A1 (en) * | 2021-12-29 | 2023-07-06 | 杭州奥默医药股份有限公司 | Multi-substituted uracil derivative and preparation method therefor and application thereof |
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| US7015230B1 (en) | 1999-05-19 | 2006-03-21 | Pharmacia Corporation | Substituted polycyclic aryl and heteroaryl uracils useful for selective inhibition of the coagulation cascade |
| US6750342B1 (en) | 1999-05-19 | 2004-06-15 | Pharmacia Corporation | Substituted polycyclic aryl and heteroaryl pyrimidinones useful for selective inhibition of the coagulation cascade |
| US6458952B1 (en) * | 1999-05-19 | 2002-10-01 | Pharmacia Corporation | Substituted polycyclic aryl and heteroaryl uracils useful for selective inhibition of the coagulation cascade |
| US6664255B1 (en) | 1999-05-19 | 2003-12-16 | Pharmacia Corporation | Substituted polycyclic aryl and heteroaryl pyrazinones useful for selective inhibition of the coagulation cascade |
| US6653316B1 (en) | 1999-05-19 | 2003-11-25 | Pharmacia Corporation | Substituted polycyclic aryl and heteroaryl pyrimidinones useful for selective inhibition of the coagulation cascade |
| US6716838B1 (en) | 1999-05-19 | 2004-04-06 | Pharmacia Corporation | Substituted polycyclic aryl and heteroaryl uracils as anticoagulative agents |
| US6608197B2 (en) * | 2000-01-25 | 2003-08-19 | Neurocrine Biosciences, Inc. | Gonadotropin-releasing hormone receptor antagonists and methods relating thereto |
| AU2004200664B2 (en) * | 2000-01-25 | 2007-08-16 | Neurocrine Biosciences, Inc. | Gonadotropin-releasing hormone receptor antagonists and methods relating thereto |
| US6852761B2 (en) | 2000-03-13 | 2005-02-08 | Pharmacia Corporation | Polycyclic aryl and heteroaryl substituted benzenes useful for selective inhibition of the coagulation cascade |
| ATE289299T1 (en) | 2000-04-05 | 2005-03-15 | Pharmacia Corp | POLYCYCLIC ARYL AND HETEROARYL SUBSTITUTED 4-PYRONES USABLE FOR SELECTIVE INHIBITION OF THE COAGULATION PROCESS |
| EP1268428A2 (en) | 2000-04-05 | 2003-01-02 | Pharmacia Corporation | Polycyclic aryl and heteroaryl substituted 4-pyridones useful for selective inhibition of the coagulation cascade |
| US6686484B2 (en) | 2000-04-17 | 2004-02-03 | Pharmacia Corporation | Polycyclic aryl and heteroaryl substituted 1,4-quinones useful for selective inhibition of the coagulation cascade |
| US6710058B2 (en) | 2000-11-06 | 2004-03-23 | Bristol-Myers Squibb Pharma Company | Monocyclic or bicyclic carbocycles and heterocycles as factor Xa inhibitors |
| EP1351686A2 (en) | 2000-11-20 | 2003-10-15 | Pharmacia Corporation | Substituted polycyclic aryl and heteroaryl pyridines useful for selective inhibition of the coagulation cascade |
| US7119094B1 (en) | 2000-11-20 | 2006-10-10 | Warner-Lambert Company | Substituted polycyclic aryl and heteroarpyl pyrazinones useful for selective inhibition of the coagulation cascade |
| US7015223B1 (en) | 2000-11-20 | 2006-03-21 | Pharmacia Corporation | Substituted polycyclic aryl and heteroaryl 1,2,4-triazinones useful for selective inhibition of the coagulation cascade |
| US7105559B2 (en) | 2001-10-03 | 2006-09-12 | Pharmacia Corporation | Substituted 5-membered polycyclic compounds useful for selective inhibition of the coagulation cascade |
| JP2005519866A (en) | 2001-10-03 | 2005-07-07 | ファルマシア・コーポレーション | 6-membered heterocyclic compounds useful for selective inhibition of the coagulation cascade |
| TW200307667A (en) | 2002-05-06 | 2003-12-16 | Bristol Myers Squibb Co | Sulfonylaminovalerolactams and derivatives thereof as factor Xa inhibitors |
| GB0622472D0 (en) * | 2006-11-10 | 2006-12-20 | Addex Pharmaceuticals Sa | Novel heterocyclic derivatives |
| RS54738B1 (en) | 2011-11-29 | 2016-10-31 | Perosphere Inc | Anticoagulant reversal agents |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1996018644A1 (en) * | 1994-12-13 | 1996-06-20 | Corvas International, Inc. | Aromatic heterocyclic derivatives as enzyme inhibitors |
| CA2373614A1 (en) * | 1999-05-19 | 2000-11-23 | Pharmacia Corporation | Substituted polycyclic aryl and heteroaryl pyrymidinones useful as anticoagulants |
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2000
- 2000-05-18 CA CA002373610A patent/CA2373610A1/en not_active Abandoned
- 2000-05-18 EP EP00931917A patent/EP1178971A1/en not_active Withdrawn
- 2000-05-18 CN CNB008077533A patent/CN1152023C/en not_active Expired - Fee Related
- 2000-05-18 BR BR0011273-9A patent/BR0011273A/en not_active IP Right Cessation
- 2000-05-18 KR KR1020017014750A patent/KR20010113969A/en not_active Application Discontinuation
- 2000-05-18 JP JP2000618250A patent/JP2002544263A/en active Pending
- 2000-05-18 WO PCT/US2000/008226 patent/WO2000069833A1/en not_active Application Discontinuation
- 2000-05-18 AU AU49724/00A patent/AU771740B2/en not_active Ceased
- 2000-05-18 MX MXPA01011806A patent/MXPA01011806A/en unknown
- 2000-05-18 NZ NZ514877A patent/NZ514877A/en unknown
- 2000-05-19 UY UY26157A patent/UY26157A1/en unknown
- 2000-05-19 AR ARP000102449A patent/AR043677A1/en unknown
- 2000-06-02 PE PE2000000543A patent/PE20010217A1/en not_active Application Discontinuation
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2001
- 2001-11-13 ZA ZA200109338A patent/ZA200109338B/en unknown
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2004
- 2004-01-21 ZA ZA200400450A patent/ZA200400450B/en unknown
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2023125792A1 (en) * | 2021-12-29 | 2023-07-06 | 杭州奥默医药股份有限公司 | Multi-substituted uracil derivative and preparation method therefor and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| KR20010113969A (en) | 2001-12-28 |
| ZA200109338B (en) | 2004-05-26 |
| AU4972400A (en) | 2000-12-05 |
| AU771740B2 (en) | 2004-04-01 |
| CA2373610A1 (en) | 2000-11-23 |
| JP2002544263A (en) | 2002-12-24 |
| AR043677A1 (en) | 2005-08-10 |
| WO2000069833A1 (en) | 2000-11-23 |
| ZA200400450B (en) | 2004-09-29 |
| NZ514877A (en) | 2004-10-29 |
| UY26157A1 (en) | 2000-12-29 |
| PE20010217A1 (en) | 2001-03-07 |
| EP1178971A1 (en) | 2002-02-13 |
| BR0011273A (en) | 2002-06-18 |
| CN1152023C (en) | 2004-06-02 |
| MXPA01011806A (en) | 2003-09-04 |
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