CN1157380C

CN1157380C - Substituted polycyclic aryl and heteroaryl pyrymidinones useful as anticoagulants agents

Info

Publication number: CN1157380C
Application number: CNB008077479A
Authority: CN
Inventors: Ms; M·S·索斯; A·T·翰米二世; W·纽曼; D·E·琼斯; 3; M·L·鲁佩尔
Original assignee: Pharmacia LLC
Current assignee: Pharmacia LLC
Priority date: 1999-05-19
Filing date: 2000-05-17
Publication date: 2004-07-14
Anticipated expiration: 2020-05-17
Also published as: MXPA01011804A; PE20010229A1; EA200101214A1; EA004867B1; CA2373614A1; JP2002544262A; TWI222445B; IL146243A0; CZ20014116A3; NZ514874A; BR0010758A; AU4973400A; ZA200400448B; KR20010114271A; CN1351593A; AU2004202375A1; HUP0201242A3; NO20015604L; PL352827A1; WO2000069832A1

Abstract

The invention relates to substituted polycyclic aryl and heteroaryl pyrimidinone 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

The polyaromatic and the heteroaryl pyrimidine ketone that can be used as the replacement of anti-coagulant

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 pyrimidine ketone 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, pp.1341-1343].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, p.350].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 multiple 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 (that is, 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 unsettled angina, intractable angina, 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 peptides, they serve as the inhibitor that is present in the thrombin in coagulation cascade or the process of setting.Van Boeckel etc. has described peptide in PCT patent application WO 98/47876 6-alkyl pyridine ketone and 2-alkyl pyrimidone are antithrombotic compounds.Zhu and Scarborough have described 3-(N-heterocyclic radical amino)-4 in PCT patent application WO98/16547,5,6-replaces-pyriconyl ethanamide and 2,4-replaces-5-(N-heterocyclic radical amino) pyrimidone yl acetamide, they contain amide substituents, have the activity of resisting mammal Xa factor.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-the amino uracinyl ethanamide and 2 of 5-; 4-replaces-5-aminopyrimidinone yl acetamide; they contain amide substituents, have formyl radical official energy, have the activity of 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-the amino uracinyl ethanamide and 2 of 5-; 4-replaces-5-aminopyrimidinone yl acetamide; they contain amide substituents, have formyl radical official energy, have the activity of antithrombin.Tamura etc. have further described 4 in PCT patent application WO 96/18644 and 97/46207; 5; 6-replaces-3-aminopyridine ketone group ethanamide, 1; 6-replaces-the amino uracinyl ethanamide and 2 of 5-; 4-replaces-5-aminopyrimidinone yl acetamide; they contain amide substituents, have formyl radical official energy, have the activity of antithrombin.Suzuki etc. have described 1 in PCT patent application WO 98/09949, the 2-heterocyclic radical kharophen derivative of 2-diketone has been reported their arrestin enzyme, especially inhibitors of chymase.

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):

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 become apparent by following explanation to invention.

The explanation of invention

The present invention relates to a class and comprise the polyaromatic of replacement and the compound of heteroaryl pyrimidine ketone, 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 is selected from O and S;

J randomly is selected from CH-R ⁶And N-R ⁶, R wherein ⁶Be straight chain spacer part, and be selected from R with 1 to 4 atom chain length ^4a, R ^4b, R ³⁹, R ⁴⁰, R ⁵, R ¹⁴And R ¹⁵Substituent bonding point connect and compose heterocyclic ring with 5 to 8 continuous members;

J randomly is selected from CH-R ⁶And N-R ⁶, R wherein ⁶Be straight chain spacer part, with R with 1 to 4 atom chain length ^4aAnd R ^4bBonding point connect and compose heterocyclic ring with 5 to 8 continuous members;

J randomly is selected from CH-R ⁶And N-R ⁶, R wherein ⁶Be straight chain spacer part, with R with 1 to 4 atom chain length ³⁹And R ⁴⁰Bonding point 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, work as D ¹, D ², J ¹, J ²And K ¹In two when being O and S, 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, alkoxy carbonyl, 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, the carboxy arene alkoxyl group, carboxamido, the carboxamido alkyl, cyano group, the carboxyl halogenated alkoxy, 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, and 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 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;

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; carboxamide groups; the carboxamido alkyl; the carboxy arene alkoxyl group; 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 and 2-oxo acyl group;

R ¹⁴And R ¹⁴When with different bond with carbon, randomly constitute together and be selected from down the group of organizing: 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 ¹⁵When with different bond with carbon, randomly constitute together and be selected from down the group of organizing: 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 ¹⁵When with different bond with carbon, randomly constitute together and be selected from down the group of organizing: 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 ⁴⁰When with identical bond with carbon, randomly constitute together and be selected from down the group of organizing: oxo, thiocarbonyl group, R ⁵-N, alkylidene group, halo alkylidene group, with linear fraction spacer, constitute and to be selected from down the ring of organizing with 2 to 7 atoms that link to each other: 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 to constitute spacer independently, and wherein spacer is connected with the bonding point of described spacer to the member constituting the linear fraction with 2 to 5 continuous atoms together, constitutes 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 randomly to select to constitute linear fraction independently, with R with 2 to 5 continuous atoms ^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 ⁴²When direct and N bonding, be selected from the group except that halo and cyano group, Z ⁰Direct and pyrimidone 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, constitute 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, work as D ¹, D ², J ¹, J ²And K ¹In two when being O and S, 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 when Q is hydrogen, 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 when existing simultaneously with different bond with carbon, R ^4aAnd R ^4bWhen with the bond with carbon that is bonded directly on the pyrimidone nitrogen is not hydroxyl or cyano group;

R ^4aAnd R ^4bWhen with identical bond with carbon, randomly constitute together and be selected from down the group of organizing: oxo, thiocarbonyl group and have the straight chain spacer part of 2 to 7 atoms that link to each other, 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 when shared carbon directly and during pyrimidone nitrogen bonding, R ^4aAnd R ^4bNot oxo or thiocarbonyl group together;

When K is (CR ^4aR ^4b) _nThe time, E 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 when j is 1, R ¹⁴Not hydroxyl, cyano group, halogen, amino, alkylamino, dialkyl amido and sulfydryl, and (CH (R ¹⁴)) _jClose with the pyrimidone ring key;

When K is (CH (R ¹⁴)) _jDuring-T, 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 when k is 1, R ¹⁵Not hydroxyl, cyano group, halogen, amino, alkylamino, dialkyl amido and sulfydryl;

When K is G-(CH (R ¹⁵)) _kThe time, E 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 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, work as D ⁵, D ⁶, J ⁵And J ⁶In two when being O and S, D then ⁵, D ⁶, J ⁵And J ⁶One of must be covalent linkage, work as K ²Be N ⁺The time, D ⁵, D ⁶, J ⁵And J ⁶At the most three be N, work as K ²When being carbon, 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 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, 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, work as K ²Be N ⁺The time, R ²⁰, R ²¹And R ²²Must not 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, its condition is to work as R ²³, R ²⁴And R ²⁶In two during with identical atomic linkage, 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, its condition is to work as R ²³, R ²⁴And R ²⁶In any two during with identical atomic linkage, R ²³, R ²⁴And R ²⁶At the most one can be hydroxyl, alkoxyl group, alkylamino, amino or dialkyl amido, and 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) ₂, S (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 its valence link 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, the sulfo-hydroxyl, 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, constitute 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, the dibasic group of 2-, it is made up of group of naphthene base, cycloalkenyl groups, aromatic yl group, heteroaryl groups, saturated heterocyclic group and the heterocyclic group of fractional saturation, and wherein cycloalkyl and cycloalkenyl groups 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 that the dibasic alkenylene group 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 group 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 ¹⁵When direct and N bonding, be selected from the group except that halogen and cyano group, and (CR ³⁷R ³⁸) _b, (CH (R ¹⁴)) _c, (CH (R ¹⁴)) _eDirectly and E ⁰Bonding;

R ³⁷And R ³⁷When with different bond with carbon, randomly constitute linear fraction spacer together, constitute 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 ³⁸When with different bond with carbon, constitute linear fraction spacer together, constitute 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 ³⁸When with different bond with carbon, constitute linear fraction spacer together, constitute 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 ³⁸Constitute the group that is selected from down group when with identical bond with carbon together: oxygen base, thiocarbonyl group, alkylidene group, halo alkylidene group and have the linear fraction spacer of 2 to 7 atoms that link to each other constitute 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 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, 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 ¹⁵When directly with ^NBe selected from the group except that halogen and cyano group during bonding, and (CR ³⁷R ³⁸) _f, (CH (R ¹⁵)) _c(CH (R ¹⁵)) _eWith E ⁰Bonding is worked as Q ^SsBe (CR ³⁷R ³⁸) _f, when wherein f is not integer 1, 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 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 R ⁹, 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, 2,4-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 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, 3,6 benzothienyls, 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 ⁶Ring 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 a kind of embodiment of formula I compound or its pharmacy acceptable salt,

J is selected from O and S;

B is a formula V:

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, sulfenyl, 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 sulfenyl, 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, the carboxy arene alkoxyl group, carboxamido, the carboxamido alkyl, cyano group, the carboxyl halogenated alkoxy, 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 Qb simultaneously, 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, 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;

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, 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, carboxamide groups 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 and 2-oxo acyl group;

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, carboxamide groups and carboxamido alkyl;

M is selected from ^NAnd R ¹-C;

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 ⁴²When direct and N bonding, be selected from the group except that halogen and cyano group, Z ⁰Direct and pyrimidone 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, work as D ¹, D ², J ¹, J ²And K ¹In two when being O and S, 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):

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;

When K is (CR ^4aR ^4b) _nThe time, E 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 be selected to (CH ( 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 pyrimidone ring key;

When K is (CH (R ¹⁴)) _jDuring-T, 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 selected to 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 when k is 1, R ¹⁵Not hydroxyl, cyano group, halogen, amino, alkylamino, dialkyl amido and sulfydryl;

When K is G-(CH (R ¹⁵)) _kThe time, E 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, work as D ⁵, D ⁶, J ⁵And J ⁶In two when being O and S, D ⁵, D ⁶, J ⁵And J ⁶One of must be covalent linkage, work as K ²Be N ⁺The time, D ², D ⁶, J ⁵And J ⁶At the most three be N, work as K ²When being 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, 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, and work as K ²Be N ⁺The time, R ²⁰, R ²¹And R ²²Must not hydroxyl, alkoxyl group, alkylamino, amino and dialkyl amido;

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, its condition is to work as R ²³, R ²⁴And R ²⁶In two during with identical atomic linkage, 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, its condition is to work as R ²³, R ²⁴And R ²⁶In two during with identical atomic linkage, R ²³, R ²⁴And R ²⁶At the most one can be hydroxyl, alkoxyl group, alkylamino, amino or dialkyl amido, and 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;

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 ¹⁵When direct and N bonding, be selected from the group except that halogen 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 ¹⁵When direct and N bonding, be selected from the group except that halogen and cyano group, (CR ³⁷R ³⁸) _f, (CH (R ¹⁵)) _c(CH (R ¹⁵)) _eWith E ⁰Bonding;

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, 3,6 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 ⁶Ring 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 kind of embodiment of formula I compound or its pharmacy acceptable salt,

J is 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, work as D ¹, D ², J ¹, J ²And K ¹In two when being O and S, 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 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 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 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;

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 (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-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), 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 pyrimidone 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):

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, work as D ⁵, D ⁶, J ⁵And J ⁶In two when being O and S, D ⁵, D ⁶, J ⁵And J ⁶One of must be covalent linkage, work as K ²When being carbon, 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;

Q ^bBe selected from NR ²²R 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 ²⁵) (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), its condition is to work as R ²³, R ²⁴And R ²⁶In two during with identical atomic linkage, R ²³, 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 ¹⁵When direct and N bonding, be 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 ( 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 ¹⁵When direct and N bonding, be selected from the group except that halogen 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 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 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 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 ¹²The group of forming 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 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, 3,6 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 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, 3,6 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 ⁶Ring 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 embodiment of preferred formula I compound or its pharmacy acceptable salt,

J is O;

B is a following formula:

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, 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 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;

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 C4-heterocyclic radical, 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 can randomly be 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 that is positioned at tie point and nitrogen-atoms can be randomly by R ⁹Or R ¹³Replace, with R ⁹The position is adjacent and can be by R apart from the ring carbon or the nitrogen-atoms of two atoms of tie point ¹⁰Replace, with R ¹³The position is adjacent and can be by R apart from the ring carbon or the nitrogen-atoms of two atoms of tie point ¹²Replace, apart from three atoms of tie point and and R ¹⁰Adjacent ring carbon or the nitrogen-atoms in position can be by R ¹¹Replace, apart from three atoms of tie point and and R ¹²Adjacent ring carbon or the nitrogen-atoms in position can be by R ³³Replace, apart from four atoms of tie point and and R ¹¹And R ³³Adjacent ring carbon or the nitrogen-atoms in position can be 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, 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 pyrimidone ring key closes;

K is (CR ^4aR ^4b) _n, wherein n is selected from 1 to 2 integer;

When K is (CR ^4aR ^4b) _nThe time, E 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, work as D ⁵, D ⁶, J ⁵And J ⁶In two when being O and S, 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 ¹⁴When direct and N bonding, be 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, 3,6 benzothienyls, 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 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.

J is O;

B is a following formula:

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; 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 is selected from C3-C12 cycloalkyl and C4-heterocyclic radical, 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 can randomly be 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 that is positioned at tie point and nitrogen-atoms can be randomly by R ⁹Or R ¹³Replace, with R ⁹The position is adjacent and can be by R apart from the ring carbon or the nitrogen-atoms of two atoms of tie point ¹⁰Replace, with R ¹³The position is adjacent and can be by R apart from the ring carbon or the nitrogen-atoms of two atoms of tie point ¹²Replace, apart from three atoms of tie point and and R ¹⁰The adjacent ring carbon atom in position can be by R ¹¹Replace, apart from three atoms of tie point and and R ¹²The adjacent ring carbon atom in position can be by R ³³Replace, apart from four atoms of tie point and and R ¹¹And R ³³The adjacent ring carbon atom in position can be 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 pyrimidone 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):

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;

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 is O;

B is a following formula:

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 be O, D ⁵, D ⁶, J ⁵And J ⁶At the most one be S, work as D ⁵, D ⁶, J ⁵And J ⁶In two when being O and S, 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;

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 is 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 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 ²Be Z ⁰-Q;

Z ⁰Be selected from covalent single bond, O, S, NH and CH ₂

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, work as D ⁵, D ⁶, J ⁵And J ⁶In two when being O and S, 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;

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

At another kind still and then in the embodiment of preferred formula I compound or its pharmacy acceptable salt,

J is O;

B is selected from C3-C7 cycloalkyl and C4-heterocyclic radical, 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 can randomly be 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 that is positioned at tie point and nitrogen-atoms can be randomly by R ⁹Or R ¹³Replace, with R ⁹The position is adjacent and can be by R apart from the ring carbon or the nitrogen-atoms of two atoms of tie point ¹⁰Replace, with R ¹³The position is adjacent and can be by R apart from the ring carbon or the nitrogen-atoms of two atoms of tie point ¹²Replace, apart from three atoms of tie point and and R ¹⁰The adjacent ring carbon atom in position can be by R ¹¹Replace, apart from three atoms of tie point and and R ¹²The adjacent ring carbon atom in position can be by R ³³Replace, apart from four atoms of tie point and and R ¹¹And R ³³The adjacent ring carbon atom in position can be by R ³⁴Replace;

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

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 ²Be Z ⁰-Q;

Z ⁰Be selected from covalent single bond, O, S, NH and CH ₂

K is CH ₂

E ⁰Be C (O) N (H);

Y ⁰Be formula (IV):

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 is O;

B is a following formula:

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 ²Be Z ⁰-Q;

Z ⁰It is covalent single bond;

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):

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 is O;

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 ²Be Z ⁰-Q;

Z ⁰It is covalent single bond;

K is CH ₂

E ⁰Be C (O) N (H);

Y ⁰Be formula (IV):

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 the still most preferred formula I compound of another kind or its pharmacy acceptable salt,

J is O;

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

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 ²Be Z ⁰-Q;

Z ⁰It is covalent single bond;

K is CH ₂

E ⁰Be C (O) N (H);

Y ⁰Be formula (IV):

Q ^sBe CH ₂

In the embodiment of preferred formula I, this compound has formula I-S:

Or its pharmacy acceptable salt, wherein:

B is a following formula:

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; ethoxy carbonyl; 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 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, 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, two ring [3.1.0] hexane-6-base, suberyl and ring octyl groups, 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 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, ethoxy carbonyl, 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, sulfo-hydroxyl, 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 1,2,3-triazine-5-base, 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 CHR ^4a, R wherein ^4aBe selected from methyl, ethyl, propyl group, sec.-propyl, methylol, 1-hydroxyethyl, methoxymethyl, trifluoromethyl, pentafluoroethyl group, 2,2,2-trifluoromethyl, 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:

With

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;

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 embodiment of preferred formula I, this compound has formula I-MPS, and wherein B is an aromatic substituent:

(I-MPS, wherein B is an aromatic substituent)

Or its pharmacy acceptable salt, wherein:

B is a following formula:

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; ethoxy carbonyl; 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

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 embodiment of the preferred formula I of another kind, this compound has formula I-MPS, and wherein B is non-cyclic substituents:

(I-MPS, wherein B is non-cyclic substituents)

Or its pharmacy acceptable salt, 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 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

The another kind of still embodiment of preferred formula I, compound has formula I-MPS, and wherein B is non-aromatics cyclic substituents:

(I-MPS, wherein B is non-aromatics cyclic substituents)

Or its pharmacy acceptable salt, 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, two ring [3.1.0] hexane-6-base and suberyl, 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; 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; ethoxy carbonyl; the amido carbonyl; N-methyl amido carbonyl; N, N-dimethyl amido carbonyl; cyano group and Q ^b

Q ^sBe selected from covalent single bond, CH ₂And CH ₂CH ₂

The embodiment of preferred The compounds of this invention (I-MPS) has following formula:

Or its pharmacy acceptable salt, 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, 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, 2 hydroxyethyls, 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 following formula:

With

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;

In the embodiment of most preferred formula I, compound has formula I-EMPS, and wherein B is an aromatic substituent:

(I-EMPS, wherein B is an aromatic substituent)

Or its pharmacy acceptable salt, wherein:

B is a following formula:

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, 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

In the embodiment of the most preferred formula I of another kind, this compound has formula I-EMPS, and wherein B is non-cyclic substituents:

(I-EMPS, wherein B is non-cyclic substituents)

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-2 butenyl, 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;

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 embodiment of another kind still most preferred formula I, compound has formula I-EMPS, and wherein B is non-aromatics cyclic substituents:

(I-EMPS, wherein B is non-aromatics cyclic substituents)

Or its pharmacy acceptable salt, wherein:

B randomly is selected from cyclopropyl, cyclobutyl, trimethylene oxide-3-base, azetidine-3-base, Thietane-3-base, cyclopentyl and cyclohexyl, 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

Q ^sBe CH ₂

The embodiment of most preferred The compounds of this invention (I-EMPS) has following formula:

Or its pharmacy acceptable salt, 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:

With

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 to participate in serine protease and II, VII, VIII, IX, X, XI or the XII factor of coagulation cascade.The compounds of this invention can be in Mammals, blood, blood products and mammalian organs the anticoagulant thing formation, suppress fibrinous generation, suppress the formation of thrombus and suppress the formation of embolus.These compounds also can be used for the treatment of or prevent the unsettled angina of Mammals, intractable angina, 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.

The present invention also has another kind of embodiment, and novel compound is selected from embodiment 1 to embodiment 19 and the listed compound of table 1.

For clarity sake, define the usage of general terms in specification sheets of compound here.

The single-letter symbol of element of standard is used to represent the concrete kind of atom, and other has outside the definite division.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 acyclic family alkyl atomic group in " haloalkyl " and " alkylthio ", is preferably 3 to about 8 carbon atoms, and more preferably 3 to about 6 carbon atoms.Described alkyl atomic group can randomly be replaced by following defined group.The example of this class atomic group 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 acyclic family hydrocarbon atomic group, and it contains at least one two key.This class thiazolinyl atomic 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 atomic group can randomly be replaced by following defined group.The example of the thiazolinyl atomic 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 acyclic family hydrocarbon atomic group, and it contains at least one three key.This class atomic 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 atomic group can randomly be replaced by following defined group.The example of the alkynyl atomic 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 atomic group etc.

Single hydrogen atom (H) represented in term " hydrogen ".This hydrogen atom group for example can be connected to form " hydroxyl " atomic group with Sauerstoffatom, and a hydrogen atom group can be connected to form " methyne " atomic group-CH=with carbon atom, and perhaps two hydrogen atom groups can be connected to form " methylene radical " (CH with carbon atom ₂-) atomic group.

Term " carbon " atomic group is represented without any covalent linkage and can be formed the carbon atom of four covalent linkage.

Term " cyano group " atomic group is represented three carbon atom groups of sharing with nitrogen-atoms in four covalent linkage.

The atomic 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 atomic group.

The atomic group that wherein one or more end alkyl carbon atoms are replaced by one or more following defined carbonyl atomic groups contained in term " alkyloyl ".Specifically contain a carbonylic alkyl and dicarbapentaborane alkyl atomic group.The example of one carbonylic alkyl atomic group comprises formyl radical, ethanoyl and pentanoyl.The example of dicarbapentaborane alkyl atomic group comprises oxalyl group, malonyl and succinyl.

Term " alkylidene group " atomic group represents to have 1 to about 10 carbon atoms and have the straight or branched atomic group of two or more covalent linkage tie points.The example of this class atomic group is methylene radical, ethylidene, methyl ethylidene and isopropylidene.

Term " alkenylene " atomic group represents to have 2 to about 10 carbon atoms, at least one two key and have the straight or branched atomic group of two or more covalent linkage tie points.The example of this class atomic group 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 atomic 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 atomic group.One haloalkyl atomic group for example can have bromine, chlorine or a fluorine atom in atomic group.The dihalo alkyl can have the combination of two or more identical halogen atoms or different halo atomic groups, and the multi-haloalkyl atomic group can have the combination of identical halogen atom more than two or different halo atomic groups.Preferred haloalkyl atomic group is to have " low-grade halogenated alkyl " atomic group to about six carbon atom.The example of this class haloalkyl atomic 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 atomic 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 ".The example of " hydroxy halogeno alkyl " atomic group comprises the hexafluoro hydroxypropyl.

Term " halo alkylidene group atomic group " expression is the alkylidene group atomic 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 halo atomic groups, and many halos alkylidene group atomic group can have the combination of identical halogen atom more than two or different halo atomic groups.Preferred halo alkylidene group atomic group is to have " lower halogenated alkylidene group " atomic group to about six carbon atom.The example of " halo alkylidene group " atomic group 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 atomic 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.Dihalo thiazolinyl atomic group can have the combination of two or more identical halogen atoms or different halo atomic groups, and many haloalkenyl groups atomic group can have the combination of identical halogen atom more than two or different halo atomic groups.

Term " alkoxyl group " and " alkoxyalkyl " are contained straight or branched and are contained oxygen atomic group, have the moieties of one to about ten carbon atom separately, for example the methoxyl group atomic group.The alkyl atomic group that is connected with one or more alkoxyl groups also contained in term " alkoxyalkyl ", just forms an alkoxyalkyl and dialkoxy alkyl atomic group.Preferred alkoxyl group is to have " lower alkoxy " atomic group to six carbon atom.The example of this class atomic group comprises methoxyl group, oxyethyl group, propoxy-, butoxy, isopropoxy and tert.-butoxy alkyl." alkoxyl group " atomic group can further be replaced by one or more halogen atoms, and for example fluorine, chlorine or bromine obtain " halogenated alkoxy " and " halogenated alkoxy alkyl " atomic group.The example of this class halogenated alkoxy atomic 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-.The example of this class halogenated alkoxy alkyl atomic group 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 oxygen atomic group that contains of straight or branched, have the alkenyl part of two to about ten carbon atoms separately, for example vinyloxy group or propenyloxy group atomic group.The thiazolinyl with one or more alkene oxygen base atomic groups that link to each other with alkyl also contained in term " alkene oxygen base alkyl ", just forms an alkene oxygen base alkyl and diene oxygen base alkyl atomic group.Preferred alkene oxygen base atomic group is to have two " rudimentary alkene oxygen base " atomic groups to six carbon atom.The example of this class atomic group comprises vinyloxy group, propenyloxy group, butenyloxy and different propenyloxy group alkyl." alkene oxygen base " atomic group can further be replaced by one or more halogen atoms, and for example fluorine, chlorine or bromine obtain " haloalkene oxygen base " atomic group.The example of this class atomic group comprises trifluoro-ethylene oxygen base, vinyl fluoride oxygen base, difluoroethylene oxygen base and fluorine propenyloxy group.

The alkyl atomic group that is connected with one or more halogenated alkoxy atomic groups also contained in term " halogenated alkoxy alkyl ", just forms a halogenated alkoxy alkyl and dihalo alcoxyl base alkyl atomic group.The oxygen atomic group that is connected with one or more haloalkene oxygen base atomic groups also contained in term " haloalkene oxygen base ", just forms a haloalkene oxygen base and dihalo alkene oxygen base atomic group.The alkyl atomic group that is connected with one or more haloalkene oxygen base atomic groups also contained in term " haloalkene oxygen base alkyl ", just forms a haloalkene oxygen base alkyl and dihalo alkene oxygen base alkyl atomic group.

Term " alkylene dioxo base " atomic group is represented the alkylidene group atomic group of at least two oxygen and single alkylidene group bonding.The example of " alkylene dioxo base " atomic group comprises the methylene-dioxy of methylene-dioxy, ethylenedioxy, alkyl replacement and the methylene-dioxy that aryl replaces.Term " halo alkylene dioxo base " atomic group is represented the halo alkylidene group atomic group of at least two oxygen bases and single haloalkyl bonding.The example of " halo alkylene dioxo base " atomic group 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 aromatic 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 generate) by shared with first ring (promptly shared) two adjacent atoms.Term " condenses " and equals term " condensation ".The aromatics atomic group contained in term " aryl ", for example phenyl, naphthyl, tetrahydro naphthyl, indane and biphenyl.

The aromatics atomic group that aryl atomic group is wherein replaced by 3 or how following defined halogen atom group, for example phenyl, naphthyl, tetrahydro naphthyl, indane and biphenyl contained in term " perhalogeno aryl ".

The heteroatomic ring-type atomic group that contains saturated and fractional saturation contained in term " heterocyclic radical ", 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 atomic 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 atomic 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 example of the heterocyclic radical atomic group of fractional saturation comprises dihydro-thiophene, dihydropyrane, dihydrofuran and thiazoline.The limiting examples of heterocyclic atom 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 aromatics atomic 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.The heteroaryl atomic group can contain one, two or three ring, and wherein these rings can or can be condensed by the hang connection.The example of " heteroaryl " atomic group 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, 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 atom group and aryl atomic group condensed atomic group also contained in this term.The example of this class fused bicyclic atomic group comprises cumarone, thionaphthene etc.Described " heterocyclic radical " can have 1 to 3 following defined substituting group.Preferred heterocyclic atom group comprises that five to ten binary condense or the atomic group of non-condensed.The limiting examples of heteroaryl atomic group 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 bivalent atom group-SO respectively ₂-." alkyl sulphonyl " contains the alkyl atomic group that is connected with the alkylsulfonyl atomic group, and wherein alkyl is as defined above." alkyl sulfonyl alkyl " contains the alkyl sulphonyl atomic group that is connected with the alkyl atomic group, and wherein alkyl is as defined above." halogenated alkyl sulfonyl " contains the haloalkyl atomic group that is connected with the alkylsulfonyl atomic group, and wherein haloalkyl is as defined above." haloalkyl sulphonyl alkyl " contains the halogenated alkyl sulfonyl atomic group that is connected with the alkyl atomic group, and wherein alkyl is as defined above.The amino atomic group that term " amino-sulfonyl " expression is connected with the alkylsulfonyl atomic group.

No matter single term " sulfinyl " with still and other term couplings, alkyl sulphinyl for example, all represent respectively bivalent atom group-S (O)-." alkyl sulphinyl " contains the alkyl atomic group that is connected with the sulfinyl atomic group, and wherein alkyl is as defined above." alkyl sulfenyl alkyl " contains the alkyl sulphinyl atomic group that is connected with the alkyl atomic group, and wherein alkyl is as defined above." haloalkyl sulfinyl " contains the haloalkyl atomic group that is connected with the sulfinyl atomic group, and wherein haloalkyl is as defined above." haloalkyl sulfinyl alkyl " contains the haloalkyl sulfinyl atomic group that is connected with the alkyl atomic group, and wherein alkyl is as defined above.

The alkyl atomic group of term " aralkyl " encompass aryl-replacement.Preferred aralkyl atomic group is " rudimentary aralkyl " atomic group, has and has an aryl atomic group that is connected to the alkyl atomic group of six carbon atom.The example of this class atomic group comprises benzyl, diphenyl methyl, trityl group, styroyl and diphenyl-ethyl.Term benzyl and phenyl methyl are interchangeable.

The alkyl atomic group of heteroaryl-replacement contained in term " heteroaralkyl ", and wherein the heteroaralkyl atomic group can as above be replaced about the defined substituting group of aralkyl atomic group by three or more in addition.The alkyl atomic group that term " perhalogeno aralkyl " encompass aryl replaces, wherein the aralkyl atomic group is replaced by the three or more atomic groups of halo as defined above.

The aralkyl atomic group that is connected with the sulfinyl atomic group contained in term " aralkyl sulfinyl ", and wherein aralkyl is as defined above." aralkyl sulfinyl alkyl " contains the aralkyl sulfinyl atomic group that is connected with the alkyl atomic group, and wherein alkyl is as defined above.

The aralkyl atomic group that is connected with the alkylsulfonyl atomic group contained in term " aralkyl alkylsulfonyl ", and wherein aralkyl is as defined above." aralkyl sulphonyl alkyl " contains the aralkyl alkylsulfonyl atomic group that is connected with the alkyl atomic group, and wherein alkyl is as defined above.

The atomic group with 3 to 15 carbon atoms contained in term " cycloalkyl ".Preferred cycloalkyl atomic group is " low-grade cycloalkyl " atomic group with three to seven carbon atoms.Example comprises such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and suberyl.The term cycloalkyl contains the atomic group that has 7 to 15 carbon atoms and have two to four rings.Example comprises such as norcamphyl (i.e. two ring [2.2.1] heptyl) and adamantyl.The alkyl atomic group of cycloalkyl-replacement contained in term " cycloalkylalkyl ".Preferred cycloalkylalkyl atomic group is " low-grade cycloalkyl alkyl " atomic group, cycloalkyl atomic group wherein with have an alkyl atomic group to six carbon atom and be connected.The example of this class atomic group comprises the cyclohexyl hexyl.The atomic group with three to ten carbon atoms and one or more carbon-to-carbon double bonds contained in term " cycloalkenyl group ".Preferred cycloalkenyl group atomic group is " lower alkenyl ring " atomic group with three to seven carbon atoms.Example comprises such as cyclobutene base, cyclopentenyl, cyclohexenyl and cycloheptenyl.The atomic 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 atomic group.One halogenated cycloalkyl for example can have bromine, chlorine or a fluorine atom in atomic group.The dihalo atomic group can have the combination of two or more identical halogen atoms or different halo atomic groups, and many halos atomic group can have the combination of identical halogen atom more than two or different halo atomic groups.Preferred halogenated cycloalkyl atomic group is to have three " lower halogenated cycloalkyl " atomic groups to about eight carbon atoms.The example of this class halogen cycloalkyl atomic group comprises fluorine cyclopropyl, difluoro cyclobutyl, trifluoro cyclopentyl, ptfe ring hexyl and dichloro cyclopropyl.The atomic 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 group atomic group.

The cycloalkyl atomic group that is connected with oxygen base atomic group contained in term " cycloalkyloxy ".The example of this class atomic group comprises cyclohexyloxy and cyclopentyloxy.The alkyl atomic group that is connected with one or more cycloalkyloxy atomic groups also contained in term " cycloalkyloxy alkyl ", just forms a cycloalkyloxy alkyl and two cycloalkyloxy alkyl atomic groups.The example of this class atomic group comprises the cyclohexyloxy ethyl." cycloalkyloxy " atomic 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 " atomic group.

The cycloalkyl atomic group that is connected with alkoxyl group contained in term " cycloalkyl alkoxy ".The example of this class atomic group comprises cyclohexyl methoxyl group and cyclopentyl methoxyl group.

The cycloalkenyl group atomic group that is connected with oxygen base atomic group contained in term " cyclenes oxygen base ".The example of this class atomic group comprises tetrahydrobenzene oxygen base and cyclopentenes oxygen base.The alkyl atomic group that is connected with one or more cyclenes oxygen base atomic groups also contained in term " cyclenes oxygen base alkyl ", just forms a cyclenes oxygen base alkyl and two cyclenes oxygen base alkyl atomic groups.The example of this class atomic group comprises tetrahydrobenzene oxygen base ethyl." cyclenes oxygen base " atomic 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 " atomic group.

Term " ring alkylene dioxo base " atomic group is represented the ring alkylidene group atomic group of at least two oxygen and single ring alkylidene group bonding.The example of " ring alkylene dioxo base " atomic group comprises 1,2-dioxy cyclohexylene.

The cycloalkyl atomic group that is connected with the sulfinyl atomic group contained in term " cycloalkyl sulfinyl ", and wherein cycloalkyl is as defined above." cycloalkyl sulfinyl alkyl " contains the alkyl atomic group that is connected with cycloalkyl sulfinyl atomic group, and wherein cycloalkyl is as defined above.The alkylsulfonyl atomic group that is connected with the cycloalkyl atomic group contained in term " naphthene sulfamide base ", and wherein cycloalkyl is as defined above." naphthene sulfamide alkyl " contains the naphthene sulfamide base atomic group that is connected with the alkyl atomic group, and wherein alkyl is as defined above.

The atomic group that wherein one or more cycloalkyl carbon atoms are replaced by carbonyl atomic group one or more as that give a definition contained in term " cycloalkyl alkyloyl ".Specifically contain a carbonyl cycloalkyl and dicarbapentaborane cycloalkyl atomic group.The example of one carbonyl cycloalkyl atomic group comprises cyclohexyl-carbonyl, cyclohexyl ethanoyl and cyclopentylcarbonyl.The example of dicarbapentaborane cycloalkyl atomic group comprises 1,2 one dicarbapentaborane hexanaphthene.

The atomic group that contains straight or branched alkyl atomic group that be connected with bivalent sulfur atom, one to ten carbon atom contained in term " alkylthio ".Preferred alkylthio atomic group is to have " lower alkylthio " atomic group to six carbon atom.The example of " lower alkylthio " is methylthio group (CH ₃-S-)." alkylthio " atomic group can further be replaced by one or more halogen atoms, and for example fluorine, chlorine or bromine obtain " halogenated alkylthio " atomic group.The example of this class atomic group comprises fluorine methylthio group, chloromethane sulfenyl, trifluoromethylthio, difluoro methylthio group, trifluoro ethylmercapto group, fluorine ethylmercapto group, tetrafluoro ethylmercapto group, five fluorine ethylmercapto groups and fluorine rosickyite base.

The straight or branched alkyl atomic group that contains one to ten carbon atom and the atomic group of an aryl atomic group contained in term " alkyl aryl amino ", and the two all is connected with amino atomic 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 atomic group that one or two is connected with amino atomic group respectively.

The amino expression of term aryl " arylamino " and " ammonia diaryl base " contains the aryl atomic group that one or two is connected with amino atomic group respectively.The example of this class atomic group comprises N-phenyl amino and N-naphthyl amino.

The aralkyl atomic group that is connected with amino atomic 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 aralkyl atomic group that one or two is connected with amino atomic group respectively.The amino further expression " aralkyl one alkylamino " of term aralkyl contains an aralkyl atomic group and an alkyl atomic group of being connected with amino atomic group.

Term " aryl sulfonyl kia " contain contain be connected with divalence S (O) atom, the atomic group of aryl atomic group as defined above.The aryl sulfonyl kia atomic group that term " aryl sulfinyl alkyl " expression is connected with the straight or branched alkyl atomic group of one to ten carbon atom.

The aryl atomic group that is connected with the alkylsulfonyl atomic group contained in term " aryl sulfonyl ", and wherein aryl is as defined above." arylsulfonyl alkyl " contains the aryl sulfonyl atomic group that is connected with the alkyl atomic group, and wherein alkyl is as defined above.Term " heteroaryl sulfinyl " contain contain be connected with divalence S (O) atom, the atomic group of heteroaryl atomic group as defined above.The heteroaryl sulfinyl atomic group that term " heteroaryl sulfinyl alkyl " expression is connected with the straight or branched alkyl atomic group of one to ten carbon atom.The heteroaryl atomic group that is connected with the alkylsulfonyl atomic group contained in term " heteroarylsulfonyl ", and wherein heteroaryl is as defined above." heteroaryl sulphonyl alkyl " contains the heteroarylsulfonyl atomic group that is connected with the alkyl atomic group, and wherein alkyl is as defined above.

Term " aryloxy " contain be connected with Sauerstoffatom, aryl atomic group as defined above.The example of this class atomic group 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 atomic group as defined above, aryl atomic group as defined above.The example of this class atomic group comprises benzoyl and toluyl.

Term " aralkanoyl " contain be connected with carbonyl atomic group as defined above, aralkyl atomic group as defined above.The example of this class atomic group for example comprises phenylacetyl.

Term " aralkoxy " is contained by what Sauerstoffatom was connected with other atomic groups and is contained oxygen aralkyl atomic group.Preferred aralkoxy atomic group is " rudimentary aralkoxy " atomic group of being connected with above-mentioned lower alkoxy atomic group of phenyl atomic group wherein.The example of this class atomic group 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 atomic group as defined above.The example of this class atomic group comprises phenoxymethyl.

Aryloxy alkyl as defined above contained in term " halo aryloxy alkyl ", and wherein one to five halo atomic group is connected with aryloxy.

Term " 4-hetaroylpyrazol " contain be connected with carbonyl atomic group as defined above, heteroaryl atomic group as defined above.The example of this class atomic group comprises furoyl base and nicotinoyl.

Term " assorted aralkanoyl " contain be connected with carbonyl atomic group as defined above, heteroaralkyl atomic group as defined above.The example of this class atomic group for example comprises pyridine ethanoyl and furans butyryl radicals.

Term " assorted aralkoxy " is contained by what Sauerstoffatom was connected with other atomic groups and is contained the oxa-aralkyl.Preferred assorted aralkoxy atomic group is " rudimentary assorted aralkoxy " atomic group of being connected with above-mentioned lower alkoxy atomic group of heteroaryl atomic group wherein.

Heteroaryloxy alkyl atomic group as defined above contained in term " halo heteroaryloxy alkyl ", and wherein one to four halo atomic group is connected with heteroaryloxy.

Term " heteroaryl amino " is contained and amino be connected, heterocyclic radical atomic group as defined above.The example of this class atomic group comprises pyridinylamino.

Term " heteroaryl amino alkyl " contain be connected with alkyl, heteroaryl amino atomic group as defined above.The example of this class atomic group comprises pyridylmethyl amino.

Term " heteroaryloxy " contain be connected with the oxygen base, heterocyclic radical atomic group as defined above.The example of this class atomic group comprises 2-thiophene oxy, 2-2-pyrimidinyl oxy, 2-pyridyloxy, 3-pyridyloxy and 4-pyridyloxy.

Term " heteroaryloxy alkyl " contain be connected with alkyl, heteroaryloxy atomic group as defined above.The example of this class atomic group comprises 2-pyridyloxy methyl, 3-pyridyloxy ethyl and 4-pyridyloxy methyl.

Term " arylthio " contain be connected with sulphur atom, aryl atomic group as defined above.The example of this class atomic group comprises thiophenyl.

Term " arylthio alkyl " contain be connected with alkyl, arylthio atomic group as defined above.The example of this class atomic group comprises the thiophenyl methyl.

Term " alkylthio alkyl " contain be connected with alkyl, alkylthio atomic group as defined above.The example of this class atomic group comprises methylthiomethyl.Term " alkoxyalkyl " contain be connected with alkyl, alkoxyl group as defined above.The example of this class atomic group comprises methoxymethyl.

Two carbon atom groups of sharing in four covalent linkage of term " carbonyl " expression with Sauerstoffatom.Term " carboxyl " contain with carbonyl in two share one of key is connected, hydroxyl atomic 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 atomic group that one of key is connected.Term " carboxamido alkyl " contain be connected with alkyl, carboxylic acid amides atomic group as defined above.Term " carboxyalkyl " contain be connected with alkyl, carboxyl atomic group as defined above.Term " carbalkoxy " contain with carbonyl in two share one of key is connected, alkoxyl group as defined above.Term " carboxylic aralkoxy " contain with carbonyl in two share one of key is connected, aralkoxy atomic group as defined above.Term " alkoxycarbonyl alkyl " contain be connected with alkyl, carbalkoxy atomic group as defined above.Term " dialkoxy carbonylic alkyl " contain be connected with alkylidene group, two carbalkoxy atomic groups as defined above.Term " a cyano group alkyl " contain be connected with alkyl, cyano group atomic group as defined above.Term " dicyano alkylidene group " contain be connected with alkyl, two cyano group atomic groups as defined above.Term " carbalkoxy cyano group alkyl " contain be connected with alkoxycarbonyl alkyl, cyano group atomic group as defined above.

Independent or the expression and the carbonyl or the thiocarbonyl that for example are selected from following atomic group bonding in combination of term " acyl group ": hydrogen; alkyl; thiazolinyl; alkynyl; haloalkyl; alkoxyl group; alkoxyalkyl; halogenated alkoxy; aryl; heterocyclic radical; heteroaryl; the alkyl sulfenyl alkyl; the 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 atomic group as defined above, halo atomic groups as defined above contained in term " haloalkane acyl group ".The example of this class atomic group for example comprises chloracetyl, trifluoroacetyl group, bromine propionyl and seven fluorine butyryl radicalies.

The pentavalent phosphorus that is connected with oxygen atomic group by two covalent linkage contained in term " phosphono ".That term " dialkoxy phosphono " expression is connected with the phosphono atomic group by two covalent linkage, two alkoxyl groups as defined above.That term " alkoxy diaryl phosphono " is represented to be connected with the phosphono atomic group with two covalent linkage, two aralkoxy atomic groups as defined above.That term " dialkoxy phosphine acyl-alkyl " expression is connected with the alkyl atomic group, dialkoxy phosphono atomic group as defined above.That term " alkoxy diaryl phosphine acyl-alkyl " expression is connected with the alkyl atomic group, alkoxy diaryl phosphono atomic 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 single atom of bonding, for example carbon.The example of the amino atomic group of this class 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 single atom of bonding, for example carbon.The example of this class imino-atomic group for example comprises=NH ,=NCH ₃,=NOH and=NOCH ₃Two carbon atom groups of sharing in four covalent linkage positions of term " imino-carbonyl " expression with imino-.The example of this class imino-carbonyl atomic 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 atomic group keys bonding, replacement or unsubstituted amino.The example of this class amidino groups atomic group 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 guanidine radicals atomic 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 class 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.The example of this class dialkyl matte atomic group for example comprises (CH ₃) ₂S ⁺-.Term " dialkyl matte alkyl " expression dialkyl matte base, wherein said group and one is alkylene base key bonding as defined above.The example of this class dialkyl matte alkyl atomic 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 class 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.The example of this class San Wan Ji Phosphonium atomic group 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 "; " ring alkylene dioxo base "; " halo cycloalkyloxy "; " halo cycloalkyloxy alkyl "; " halo cyclenes oxygen base "; " halo cyclenes oxygen base alkyl "; " alkylthio "; " halogenated alkylthio "; " alkyl sulphinyl "; " amino "; " oxygen base "; " sulfo-"; " 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; the ring alkylene dioxo base; the halo cycloalkyloxy; halo cycloalkyloxy alkyl; halo cyclenes oxygen base; halo cyclenes oxygen base alkyl; hydroxyl; amino; sulfenyl; 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; the carboxylic aralkoxy; carboxamido; the carboxamido alkyl; cyano group; the carboxylic halogenated alkoxy; 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 atomic 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 atomic 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 atomic 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; the ring alkylene dioxo base; the halo cycloalkyloxy; halo cycloalkyloxy alkyl; halo cyclenes oxygen base; halo cyclenes oxygen base alkyl; hydroxyl; amino; sulfenyl; 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; the carboxylic aralkoxy; carboxamido; the carboxamido alkyl; cyano group; the carboxylic halogenated alkoxy; 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 type isomer and R and S type for each three-dimensional center.

Some compound described herein can contain one or more ketone carbonyls or aldehyde carbonyl or its separately or as the combination of a heterocycle ring system part.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.

Some compound described herein can contain one or more amidocarbonylations or its separately or as the combination of a heterocycle ring system part.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 the unsettled angina of Mammals, intractable angina, 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, glucoronic acid, 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 one or more nontoxic pharmaceutically acceptable carriers and/or thinner and/or auxiliary agent (this paper is referred to as " carrier " material), also comprises 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 about 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 granular substance 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, for example silicon rubber, silicon 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 polyethylene oxide-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 lactone, 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 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.

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 dimethyl sulfoxide (DMSO) and relevant analogue.The compounds of this invention also can pass through the administration of transdermal medical instrument.Preferably, utilization is stocked with the patch of porous-film type or solid substrate kind and 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, the different hexadecyl ester of stearic acid, coconut fatty acid.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 is 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 unsettled angina 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 is not interpreted as restriction.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 embodiment 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 manipulation 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, elementary composition and similar operations 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 that other has except the indication.

Following general synthetic order can be used for implementing the present invention.Used abbreviation comprises in route 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; " Boc " represents tert-butoxycarbonyl; " BOP " represents benzotriazole-1-base oxygen base three (dimethylaminos); " bu " represents butyl; dba " represent dibenzalacetone; " DCC " represents 1; the 3-dicyclohexylcarbodiimide; " DCM " represents methylene dichloride or METHYLENE CHLORIDE; " DIBAH " or " DIBAL " represents diisobutyl aluminium hydride; " DMF " represents dimethyl formamide; " DMSO " represents dimethyl sulfoxide (DMSO); " 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 9-fluorenyl methoxy carbonyl; " 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 benzyloxycarbonyl, and " PTC " represents phase-transfer catalyst; " py " represents pyridine, " RNH ₂" represent organic primary amine; on behalf of 2-(trimethyl silyl) oxyethyl group-methyl chloride, " p-TsOH ", " SEM " represent tosic acid; " TBAF " represents tetrabutyl ammonium fluoride; " TBTU " represents 2-(1H-benzotriazole-1-yl)-1; 1; 3,3-tetramethyl-urea a tetrafluoro borate, " TEA " represents triethylamine, " TFA " represents trifluoroacetic acid, and " THF " represents tetrahydrofuran (THF), and " TMS " represents trimethyl silyl, " TMSCN " represents trimethyl silyl cyanogen, and " Cbz " or " Z " represents benzyloxycarbonyl.

General synthetic operation and specific embodiment

The compounds of this invention for example can be synthesized according to following operation and the route that hereinafter provides.

Multiple R ²The following route 1 of universal synthesis method of the pyrimidone of-replacement is to shown in the route 5.The methanol solution of benzenecarboximidic acid carbethoxy hydrochloride is handled the benzamidine that obtains replacing with the aminoacetaldehyde dimethyl-acetal.The cyclic action of benzamidine and methoxyl group methylene radical dimethyl malonate generates the pyrimidone heteronucleus, has the required functional group of further processing.Ester lithium iodide demethylation, gained acid carry out curtius' rearrangement again, with protected carboxylamine ester-formin conclusive nitrogen are installed on C-5.The hydrolysis of dimethyl-acetal and the Textone oxidation of gained aldehyde obtain glycine unit on N-3.The acid protection for tertiary butyl ester, is carried out the provide protection of going of carbamate again by hydrogenization, on C-5, obtain free amine.This amine is handled under the reductive amination condition with SULPHURYL CHLORIDE or aldehyde, obtains sulphonamide or secondary amine respectively.Protected acid is deshielded with HCl then.These acid then under the peptide coupling condition of standard with various amine couplings.These amine are normally polyfunctional, use its some protected form.Remove these blocking groups, obtain the compound that is used to estimate.These synthetic routes and operation illustration are as follows.

Route 1: general pyrimidone synthesizes-I

Route 2: general pyrimidone synthesizes-I (continuing)

Route 3: general pyrimidone synthesizes-I (continuing)

Route 4: general pyrimidone synthesizes-I (having continued)

Route 5: general pyrimidone synthesizes-I (having continued)

The following example illustration synthetic route 1 to route 5.

Embodiment 1

(EX-1A) with benzenecarboximidic acid carbethoxy hydrochloride (92.25g, 496.9mmol) 300.0ml absolute methanol solution (1.68M) be cooled to about 0 ℃, drip aminoacetaldehyde dimethyl-acetal (73.10ml with a kind of like this speed, 670.9mmol) absolute methanol solution (75.0ml, 9.0M), temperature is remained on below 5 ℃.Gained solution stirring 3 days remains on temperature below 5 ℃.Reaction mixture under reduced pressure concentrates then, obtains xanchromatic oil.Resistates is dissolved in 1N NaOH (750ml), with dichloromethane extraction (4 * 250ml).Organic solution merges, dry (MgSO ₄), concentrate, obtain the thick N-of 108.13g (2, the 2-dimethoxy-ethyl) benzamidine, be xanchromatic oil.At room temperature, to thick N-(2, the 2-dimethoxy-ethyl) benzamidine (108.13g, absolute methanol solution 519.2mmol) (125.0ml, 4.2M) in disposable adding methoxyl group methylene radical dimethyl malonate (94.13g, 540.5mmol).The gained mixture heating up is gone through slowly to distill to remove in two hours and is desolvated to about 100 ℃.Make gained dark-brown solution be cooled to room temperature, with ethyl acetate (1L) dilution.The saturated NH of organic solution ₄Cl (2 * 500ml) and salt solution (1 * 500ml) washing.Organic solution drying (MgSO ₄), filter, concentrate.Crude product is through MPLC purifying (25% ethyl acetate/hexane), obtain pure 1-(2,2-dimethoxy-ethyl-2-phenyl pyrimidine-6 (1H)-ketone-5-carboxylate methyl ester (EX-1A), yield 73% is the oil of brown:

¹H NMR (300MHz, CDCl ₃) δ 8.73 (s, 1H), 7.59-7.49 (m, 5H), 4.86 (t, J=5.5Hz, 1H), 4.16 (d, J=5.4Hz, 2H), 3.95 (s, 3H), 3.32 (s, 6H); ¹³C NMR (75MHz, CDCl ₃) δ 165.9,164.6,159.3,158.2,134.6,130.9,128.93,128.78,114.9,101.4,56.0,55.1,52.7,49.1; HRMS (ES) calculated value C ₁₆H ₁₉N ₂O ₅319.1294, actual measurement 319.1288.

(EX-1B) in room temperature with under stirring, to 1-(2,2-dimethoxy-ethyl-2-phenyl pyrimidine-6 (1H)-ketone-5-carboxylate methyl ester (93.00g, disposable adding lithium iodide (98.00ml in the 420.0ml anhydrous pyridine solution (0.70M) 292.2mmol), 732.2mmol), heat release takes place immediately.Gained light brown suspension is heated to and refluxed 2 hours.Make the dark-brown reactant be cooled to room temperature, under reduced pressure remove volatile matter.The oil of gained dilutes with 1N HCl (500ml).The aqueous solution with methylene chloride extraction (4: 1,4 * 250ml).The 6N HCl washing of organic solution after the merging (2 * 250ml), dry (MgSO ₄), filter, concentrate.Crude product is through crystallization (ethyl acetate/hexane) purifying, obtain pure 1-(2,2-dimethoxy-ethyl-2-phenyl pyrimidine-6 (1H)-ketone-5-carboxylicesters (EX-1B), yield 63% is white solid:

¹H NMR (300MHz, CDCl ₃) δ 12.99 (s, 1H), 8.97 (s, 1H), 7.63-7.51 (m, 5H), 4.78 (dd, J=4.3,5.5Hz, 1H), 4.28 (d, J=5.4Hz, 2H), 3.30 (s, 6H); ¹³CNMR (75MHz, CDCl ₃) δ 165.8,165.1,164.1,159.1,133.6,131.5,129.1,129.0,112.6,101.0,55.8,49.2; HRMS (ES) calculated value C ₁₅H ₁₇N ₂O ₅305.1137, actual measurement 305.1113.

(EX-1C) at room temperature; to 1-(2; 2-dimethoxy-ethyl-2-phenyl pyrimidine-6 (1H)-ketone-5-carboxylicesters (65.93g; 216.67mmol) 800ml 1; add triethylamine (50.0ml in the 4-diox suspension (0.27M); 358.7mmol), again property adding diphenyl phosphoryl azide (51.40ml, 238.5mmol).Gained solution slowly is heated to and refluxed 2 hours.(45.00ml 434.8mmol), keeps refluxing about 14 hours to add phenylcarbinol then in reaction mixture.Make dark solution be cooled to room temperature, removing volatiles under vacuum.The gained resistates dilutes with ethyl acetate (1.5L).The saturated NH of organic solution ₄Cl (2 * 500ml), 1N NaOH (1 * 500ml) and salt solution (1 * 500ml) washing.Organic solution drying (MgSO ₄), filter, concentrate, obtain crude product.Through MPLC purifying (15%-30% ethyl acetate/hexane), obtain pure [5-[(benzyloxycarbonyl) amino]-2-phenyl-6-oxo-1,6-dihydro-1-pyrimidyl] acetaldehyde dimethyl-acetal (EX-1C), be the light brown solid, yield 46%:

¹H NMR (400MHz, CDClL ₃) δ 8.72 (br s, 1H), 7.53-7.32 (m, 11H), 5.20 (s, 2H), 4.68 (t, J=5.6Hz, 1H), 4.12 (d, J=5.6Hz, 2H), 3.22 (s, 6H); ¹³C NMR (100MHz, CDCl ₃) δ 158.3,153.7,153.2,135.9,134.9,134.7,130.1,129.1,128.9,128.8,128.71,128.66,128.4,125.1,101.3,67.7,55.4,48.6; HRMS (EI) calculated value C ₂₂H ₂₄N ₃O ₅410.1716, actual measurement 410.1741.

(EX-1D) to [5-[(benzyloxycarbonyl) amino]-2-phenyl-6-oxo-1,6-dihydro-1-pyrimidyl] (17.24g adds 35.0ml 1N HCl to the acetaldehyde dimethyl-acetal in 103.0ml tetrahydrofuran solution 42.11mmol).The gained two-phase mixture is heated to and refluxed 12 hours.Make reaction mixture be cooled to room temperature, removing volatiles under vacuum.Gained resistates water (200ml) dilution adds solid NaHCO ₃Transfer pH to 7.Gained emulsion dichloromethane extraction (4 * 150ml).Organic solution after the merging wash with water (1 * 200ml), dry (MgSO ₄), filter, concentrate, obtain 15.74g thick [5-[(benzyloxycarbonyl) amino]-2-phenyl-6-oxo-1,6-dihydro-1-pyrimidyl] acetaldehyde.

With thick [5-[(benzyloxycarbonyl) amino]-2-phenyl-6-oxo-1,6-dihydro-1-pyrimidyl] acetaldehyde (15.30g, and 198.0ml tetrahydrofuran (THF) 42.11mmol), the trimethyl carbinol and 2-methyl-2-butene solution (1: 1: 1.3,0.21M) be cooled to 0 ℃.(29.94g is 331.1mmol) with biphosphate sodium-hydrate (35.42g, 102.0ml aqueous solution 256.7mmol) (3.2M is based on Textone) slowly to add Textone then in solution.The golden two phase liquid of gained stirred 10 minutes, removed cooling bath.Reactant at room temperature stirred 1 hour.Under reduced pressure remove volatile matter.Gained solution with water (200ml) dilution adds saturated NaHCO ₃Transfer pH to 3 with 1N HCl.The aqueous solution with tetrahydrofuran (THF), dichloromethane extraction (1: 2,4 * 180ml).Organic solution drying (MgSO after the merging ₄), filter, concentrate, obtain crude product.Through ether development purifying, obtain [5-[(benzyloxycarbonyl) the amino]-2-phenyl-6-oxo-1 of 88% yield, 6-dihydro-1-pyrimidyl] acetate, be white solid:

¹H NMR (300MHz, d-DMSO) δ 13.34 (br s, 1H), 9.03 (s, 1H), 7.57-7.34 (m, 10H), 5.23 (s, 2H), 4.56 (s, 2H); ¹³C NMR (75MHz, d-DMSO) δ 169.4,158.0, and 154.6,154.3,137.1,134.8,130.9,129.4,129.1,128.78,128.72,128.50,125.5,67.0,48.8; HRMS (EI) calculated value C ₂₀H ₁₈N ₃O ₅380.1246, actual measurement 380.1246.

(EX-1E) incite somebody to action [the 5-[(benzyloxycarbonyl) amino]-2-phenyl-6-oxo-1,6-dihydro-1-pyrimidyl] (5.2503g, 70.0ml chloroformic solution (0.2M) 13.84mmol) is cooled to about 0 ℃ to acetate in ice bath.Then in cold suspension via syringe drip oxalyl chloride (6.00ml, 68.78mmol).After acutely emitting gas, obtain golden homogeneous solution.Stir after 5 minutes, remove cooling bath, solution at room temperature stirred 2 hours in addition.Under reduced pressure remove and desolvate, be placed on the high vacuum system and reach 10 minutes to remove residual solvent.The gained yellow solid is with 70.0ml chloroform dilution (0.2M), add pyridine (1.70ml, 21.02mmol) and 2-methyl-2-propyl alcohol (3.50ml, 36.60mmol).The gained brown solution at room temperature stirred 1 hour, was heated to then to reflux 12 hours.Reaction mixture is cooled to room temperature, with chloroform (300ml) dilution.The organic solution water (1 * 100ml), saturated NaHCO ₃(1 * 100ml) and salt solution (1 * 100ml) washing.Organic solution drying (MgSO ₄), filter, concentrate.Crude reaction product obtains this product, yield 49% through MPLC purifying (25% ethyl acetate/hexane): ¹H NMR (300MHz, CDCl ₃) δ 8.81 (br s, 1H), 7.57-7.38 (m, 11H), 5.27 (s, 2H), 4.57 (s, 2H), 1.47 (s, 9H); ¹³C NMR (75MHz, CDCl ₃) δ 166.4,158.0,153.2,135.9,135.0,134.4,130.6,129.1,128.9,128.7,128.5,128.4,125.4,83.4,67.7,49.1,28.2; HRMS (EI) calculated value C ₂₄H ₂₆N ₃O ₅436.1872, actual measurement 436.1876.

(EX-1F) to [5-amino-2-phenyl-6-oxo-1,6-dihydro-1-pyrimidyl] tert.-butyl acetate (1.8647g, disposable adding 211.3mg 10%Pd/C in the 21.0ml methanol solution (0.2M) 4.282mmol).The gained mixture stirred about 16 hours down in room temperature and nitrogen atmosphere (air bag).Crude product mixture is filtered by C salt 545 pads, under reduced pressure removes and desolvates.Crude product is developed from ether, obtains pure products [5-amino-2-phenyl-6-oxo-1,6-dihydro-1-pyrimidyl] tert.-butyl acetate (EX-1F), yield 99%:

¹H NMR (400MHz, CDCl ₃) δ 7.41-7.39 (m, 6H), 4.48 (s, 2H), 4.06 (brs, 2H), 1.39 (s, 9H); ¹³C NMR (100MHz, CDCl ₃) δ 166.8,158.6,149.3,134.9,132.9,130.0,128.9,128.5,127.7,82.9,48.7,28.1; HRMS (EI) calculated value C ₁₆H ₂₀N ₃O ₃302.1505, actual measurement 302.1491.

(EX-1G) to [5-amino-2-phenyl-6-oxo-1,6-dihydro-1-pyrimidyl] tert.-butyl acetate (1.0300g, 3.418mmol) the 5.5ml tetrahydrofuran (THF) and 2.0ml dimethyl formamide solution (0.45M) in disposable adding N-methylmorpholine (1.20ml, 10.91mmol).Solution is cooled to 0 ℃ in ice bath.Stir after 10 minutes, go through the 5.5ml tetrahydrofuran solution (0.68M) that dripped 718.2mg a-toluene sulfonyl chloride (3.767mmol) in 5 minutes.Reaction mixture stirred 2 hours down at 0 ℃.Reaction mixture dilutes with ethyl acetate (150ml).Organic solution with 1N HCl (2 * 25ml), saturated NaHCO ₃(2 * 25ml) and salt solution (1 * 50ml) washing.Organic solution drying (MgSO ₄), filter, under reduced pressure concentrate.The gained yellow solid is developed with ether, filters, and is dry under vacuum, obtains pure products (EX-1G), is white solid, yield 74%:

¹H NMR (400MHz, d-DMSO) δ 9.34 (s, 1H), 7.76 (s, 1H), 7.55-7.28 (m, 10H), 4.59 (s, 2H), 4.49 (s, 2H), 1.32 (s, 9H); ¹³C NMR (100MHz, d-DMSO) δ 167.0,158.8, and 156.5,142.1,134.5,131.7,131.0,130.1,129.4,129.0,128.94,128.58,124.8,83.0,59.6,49.2,28.1; HRMS (EI) calculated value C ₂₃H ₂₆N ₃O ₅S 456.1593, actual measurement 456.1597.

(EX-1H) (1.0643g, 9.0ml 4M HCl dioxane solution (0.1M) 2.336mmol) at room temperature stirred 12 hours with (EX-1G).The crude reaction thing under reduced pressure concentrates.The gained resistates is developed with ether, obtains pure products (EX-1H), and yield 87% is white solid:

¹H NMR (400MHz, d-DMSO) δ 9.32 (s, 1H), 7.74 (s, 1H), 7.51-7.30 (m, 10H), 4.58 (s, 2H), 4.48 (s, 2H); ¹³C NMR (100MHz, d-DMSO) δ 169.2,158.7, and 156.6,141.9,134.5,131.7,131.0,130.1,129.4,129.0,128.90,128.56,124.8,59.6,48.9; HRMS (EI) calculated value C ₁₉H ₁₈N ₃O ₅S 400.0967, actual measurement 400.0959.

(EX-1I) to acid (EX-1H) (406.8mg, 1.018mmol) 10.0ml dimethyl formamide solution (0.10M) in add N, N-diisopropylethylamine (0.900ml, 5.167mmol), N-hydroxybenzotriazole (167.7mg, 1.241mmol) and 1-[3-(dimethylamino) propyl group]-the 3-ethyl-carbodiimide hydrochloride (236.1mg, 1.232mmol).The gained mixture at room temperature stirred 30 minutes, and after this mixture becomes even.Then at room temperature in reaction mixture disposable adding 4-(Cbz-amidino groups) benzylamine (324.6mg, 1.126mmol).The gained mixture stirred 18 hours then.Reaction mixture dilutes with ethyl acetate (50ml).Organic solution 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 product mixture is developed purifying with ether, obtains pure products (EX-1I), is white solid:

¹H NMR (300MHz, d-DMSO) δ 9.36-9.18 (br m, 3H), 8.82-8.78 (m, 1H), 7.98 (d, J=8.3Hz, 2H), 7.84, (s, 1H), 7.56-7.32 (m, 16H), 5,15 (s, 2H), 4.65 (s, 2H), 4.58 (s, 2H), 4.40 (d, J=5.4Hz, 2H); HRMS (EI) calculated value C ₃₅H ₃₃N ₆O ₆S ₂665.2182, actual measurement 665.2177.

To Cbz-amidine (EX-1I) (237.7mg, 3.5ml methyl alcohol 357.6mmol) and 4MHCl dioxane solution (4: 1,0.1M) in disposable adding 42.1mg 10%Pd/C.The gained mixture stirred about 16 hours down in room temperature and nitrogen atmosphere (air bag).Crude product mixture is filtered by C salt 545 pads, under reduced pressure removes and desolvates.Crude product obtains pure products through MPLC purifying (gradient contains the 5%-95% acetonitrile/water of 0.1% trifluoroacetic acid), is white solid: ¹H NMR (300MHz, d-DMSO) δ 9.31-9.28 (m, 4H), 8.88 (br s, 1H), 7.81-7.77 (m, 3H), 7.60-7.54 (m, 5H), 7.43-7.37 (m, 7H), 4.65 (s, 2H), 4.58 (s, 2H), 4.42-4.41 (m, 2H); HRMS (EI) calculated value C ₂₇H ₂₇O ₄S 531.1815, actual measurement 531.1794.

Embodiment 2

According to the method for embodiment 1, the preparation target compound:

¹H NMR (300MHz, d-DMSO) δ 9.40-9.33 (m, 4H), 8.86 (s, 1H), 7.82 (s, 2H), 7.72-737 (m, 15H), 4.65-4.59 (m, 4H), 4.41-4.40 (m, 2H); HRMS (EI) calculated value C ₂₇H ₂₇N ₆O ₄S 531.1815, actual measurement 531.1794.

Embodiment 3

(EX-3A) to [5-amino-2-phenyl-6-oxo-1,6-dihydro-1-pyrimidyl] tert.-butyl acetate (EX-1F) (613.7mg, 2.037mmol) the 7.0ml tetrahydrofuran (THF) and dichloromethane solution (1: 1, add in 0.3M) 25.0ml acetate and phenylacetic aldehyde (0.475ml, 4.060mmol).Solution is cooled to 0 ℃ in ice bath, and disposable adding sodium triacetoxy borohydride (1.9131g, 9.027mmol).Stir after 5 minutes, remove ice bath, reaction mixture at room temperature stirred 2 hours.Add 1N NaOH (5ml) and finish reaction, mixture stirred 5 minutes.Reaction mixture dilutes with 0.5N NaOH (100ml).Aqueous solution ethyl acetate extraction (3 * 25ml).Organic solution after the merging with 0.5N NaOH (1 * 25ml) and salt solution (1 * 25ml) washs.Solution drying (MgSO ₄), filter, under reduced pressure concentrate.Through MPLC purifying (25% ethyl acetate/hexane), obtain EX-3A, be xanchromatic oil, yield 74%: ¹H NMR (400MHz, CDCl ₃) δ 7.43-7.40 (m, 4H), 7.31-7.26 (m, 2H), 7.23-7.16 (m, 5H), 4.70 (br s, 1H), 4.49 (s, 2H), 3.38-3.34 (m, 2H), 2.96-2.92 (m, 2H), 1.40 (s, 9H); HRMS (EI) calculated value C ₂₄H ₂₈N ₃O ₃406.2131, actual measurement 406-2125.

(521.3mg, 13.0ml 4M HCl dioxane solution (0.1M) 1.286mmol) at room temperature stirred 12 hours with EX-3A.The crude reaction thing under reduced pressure concentrates.The gained resistates is developed with ether, obtains pure products EX-3B with quantitative yield, is yellow solid:

¹H NMR (300MHz, d-DMSO) δ 7.66-7.57 (m, 5H), 7.33-7.23 (m, 6H), 4.57 (s, 2H), 3.44-3.35 (m, 2H), 2.97-2.92 (m, 2H); ¹³C NMR (75MHz, d-DMSO) δ 168.8,157.0, and 148.0,139.9,135.0,132.2,129.69,129.48,129.07,126.9,48.8,44.5,34.5; HRMS (EI) calculated value C ₂₀H ₂₀N ₃O ₃350.1505, actual measurement 350.1520.

To EX-3B (497.8mg, 1.290mmol) 13.0ml dimethyl formamide solution (0.10M) in add N, N-diisopropylethylamine (1.800ml, 10.33mmol), N-hydroxybenzotriazole (212.8mg, 1.575mmol) and 1-[3-(dimethylamino) propyl group]-the 3-ethyl-carbodiimide hydrochloride (302.5mg, 1.578mmol).The gained mixture at room temperature stirred 30 minutes, and after this mixture becomes even.Then at room temperature in reaction mixture disposable adding 4-(Cbz-amidino groups) benzylamine (410.9mg, 1.425mmol).The gained mixture stirred 18 hours then.Reaction mixture dilutes with ethyl acetate (50ml).Organic solution 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 product mixture is developed purifying with ether, obtains pure products EX-3C, is white solid:

¹H NMR (400MHz.d-DMSO) δ 9.08 (br s, 2H), 8.62 (t, J=5.8Hz, 1H), 7.90 (d, J=8.3Hz, 2H), 7.44-7.15 (m, 17H), 5.35 (t, J=5.9Hz, 1H), 5.07 (s, 2H), 4.44 (s, 2H), 4.29 (d, J=5.4Hz, 2H), 331-3.26 (m, 2H), 2.88-2.85 (m, 2H); HRMS (EI) calculated value C ₃₆H ₃₅N ₆O ₄615.2720, actual measurement 615.2688.

To EX-3C (222.6mg, 4.0ml methyl alcohol 362.1mmol) and 4M HCl dioxane solution (3: 1,0.1M) in disposable adding 53.0mg 10%Pd/C.The gained mixture stirred about 16 hours down in room temperature and nitrogen atmosphere (air bag).Crude product mixture is filtered by C salt 545 pads, under reduced pressure removes and desolvates.Crude product obtains pure products through ether development purifying, is yellow solid:

¹H NMR (300MHz, d-DMSO) δ 9.62-9.30 (br m, 5H), 7.88 (br m, 2H), 7.58-6.86 (br m, 15H), 4.59 (br s, 2H), 4.36 (br s, 2H), 3.38 (br s, 2H), 2.91 (br s, 2H); HRMS (EI) calculated value C ₂₈H ₂₉N ₆O ₂481.2352, actual measurement 481.2348.

Utilize following route 6 and route 7 can preparation example to be connected/to be bonded to pyrimidone on the pyrimidone ring by the 2-heteroatoms as 2-aryl, 2-heteroaryl or organic group with Direct Bonding.Heteroatoms is sulphur, nitrogen, oxygen or the another kind of heteroatoms that is fit to normally.Embodiment 4 and 5 discloses route 6 general operation that are used to prepare the pyrimidone that concrete heteroatoms replaces.

The preparation of the pyrimidone that route 6:2-replaces

Embodiment 4

EX-4A) under agitation, to 5-nitro-2,4 (1H, 3H) disposable adding 1.1 equivalent salt of wormwood in the dimethyl sulphoxide solution of pyrimidine dione (0.2M).After about 10 minutes, drip the dimethyl sulphoxide solution of 1 equivalent 2-(trimethyl silyl) ethoxyl methyl chlorine.Reaction mixture is heated to 40 ℃ then, stirs 18 hours.Carry out chromatogram purification after the typical water treatment, obtain pure products EX-4A.

EX-4B) under agitation, to 5-nitro-1-SEM-2,4 (1H, 3H) disposable adding 1.1 equivalent salt of wormwood in the dimethyl sulphoxide solution (0.2M) of pyrimidine dione (EX-4A).After about 10 minutes, drip the dimethyl sulphoxide solution of 1 equivalent methyl bromoacetate.Reaction mixture is heated to 40 ℃ then, stirs 18 hours.Carry out chromatogram purification after the typical water treatment, obtain pure products EX-4B.

EX-4C) (1H, 3H) methanol solution of pyrimidine dione (EX-4B) outgases with hydrogen with 5-nitro-1-SEM-3-methoxycarbonyl methyl-2,4.In solution, add 5%Pd/C then, under room temperature and nitrogen atmosphere, stirred 24 hours.The crude reaction thing filters by C salt 545 pads, under reduced pressure concentrates.Through the column chromatography purifying, obtain pure 5-amino-1-SEM-3-methoxycarbonyl methyl-2,4 (1H, 3H) pyrimidine dione EX-4C.

EX-4D) to 5-amino-1-SEM-3-methoxycarbonyl methyl-2,4 (1H, 3H) tetrahydrofuran (THF) of pyrimidine dione (EX-4C) and dichloromethane solution (1: 1, add the acetate and the 1 equivalent phenylacetic aldehyde of catalytic amount in 0.3M).Solution is cooled to 0 ℃ in ice bath, disposable adding 1 equivalent sodium triacetoxy borohydride.Stir after 5 minutes, remove ice bath, reaction mixture at room temperature stirred 2 hours.Add 1N NaOH and finish reaction, mixture stirred 5 minutes.Carry out chromatogram purification after the typical water treatment, obtain pure products EX-4D.

EX-4E) to 1-SEM-3-methoxycarbonyl methyl-5-(2-phenylethyl) amino-2,4 (1H, 3H) tetrahydrofuran (THF) of pyrimidine dione (EX-4D) and methanol solution (1: 1,0.2M) in the aqueous solution of adding 1 Equivalent Hydrogen Lithium Oxide 98min.After reacting completely, under reduced pressure remove volatile matter.Remaining aqueous solution cools off in ice bath, is acidified to pH1 with 1.0N HCl.Use organic solvent extraction, under reduced pressure remove and desolvate, obtain pure products EX-4E.

EX-4F) to 1-SEM-3-methylene radical carboxyl-5-(2-phenylethyl) amino-2,4 (1H, 3H) add 5 equivalent N, N-diisopropylethylamine, 1 equivalent N-hydroxybenzotriazole and 1 equivalent 1-[3-(dimethylamino) propyl group in the dimethyl formamide solution of pyrimidine dione (0.1M)]-the 3-ethyl-carbodiimide hydrochloride.The gained mixture stirred 30 minutes.Reaction mixture is handled with the suitable amine of 1 equivalent then, and stirring is spent the night.Carry out chromatogram purification after the typical water treatment, obtain pure products EX-4F.

EX-4G) to amino-2,4 (1H, 3H) tetrahydrofuran solutions of adding 2 equivalent tetrabutyl ammonium fluorides in the tetrahydrofuran solution of pyrimidine dione (0.3M) of 1-SEM-3-methylene urea-5-(2-phenylethyl).Gained solution backflow some hrs.Carry out chromatogram purification after the typical water treatment, obtain pure products EX-4G.

EX-4H) (1H adds 1 equivalent phosphoryl chloride among the 3H) N of pyrimidine dione (EX-4G), accelerine solution (0.3M) to 3-methylene urea-5-(2-phenylethyl) amino-2,4.Gained solution backflow some hrs.Carry out chromatogram purification after the typical water treatment, obtain pure products EX-4H.

EX-4I) (1H, 3H) pyrimidine dione (adds 2 equivalent benzenethiols in the EX-4H) De dioxane solution (0.3M) to 2-chloro-3-methylene urea-5-(2-phenylethyl) amino-2,4.Gained solution backflow some hrs.Carry out chromatogram purification after the typical water treatment, obtain pure products EX-4I.

With 2-thiophenyl-3-methylene urea-5-(2-phenylethyl) amino-2,4 (1H, 3H) methyl alcohol of pyrimidine dione (EX-4I) and 4M HCl dioxane solution (3: 1,0.1M) outgas with hydrogen.In solution, add 5%Pd/C then, under room temperature and nitrogen atmosphere, stirred 24 hours.Crude reaction product is filtered by C salt 545 pads, under reduced pressure concentrates.Through the column chromatography purifying, obtain pure products.

Embodiment 5

EX-5A) (1H 3H) adds 1.2 equivalent 2.0M yellow soda ash to the 2-chloro-3-methylene urea-5-(2-phenylethyl) after the degassing amino-2,4 in the 1-propanol solution (0.5M) of pyrimidine dione and 1 equivalent 3-pyridine boric acid, add 1mol% four (triphenyl phosphine) palladium again.The gained mixture heating up is to the some hrs that refluxes.After being cooled to room temperature, carry out chromatogram purification after the typical water treatment, obtain pure products EX-5A.

With 2-(3-pyridyl)-3-methylene urea-5-(2-phenylethyl) amino-2,4 (1H, 3H) methyl alcohol of pyrimidine dione (EX-5A) and 4M HCl dioxane solution (3: 1,0.1M) outgas with hydrogen.In solution, add 5%Pd/C then, under room temperature and nitrogen atmosphere, stirred 24 hours.Crude reaction product is filtered by C salt 545 pads, under reduced pressure concentrates.Through the column chromatography purifying, obtain pure products.

Utilize following route 7 can also preparation example to connect/be bonded to pyrimidone on the pyrimidone ring by the 2-heteroatoms as 2-aryl, 2-heteroaryl or organic group with Direct Bonding.In this reaction scheme, aryl is introduced into by generating C-C.The heteroatoms that is suitable for generating the assorted aryl-pyrimidine ketones that connects comprises sulphur, nitrogen, oxygen or the another kind of heteroatoms that is fit to.Embodiment 6 and 7 discloses route 7 general operation that are used to prepare the pyrimidone that concrete heteroatoms replaces.

Route 7: interchangeable pyrimidone is synthetic

Embodiment 6

(EX-6A) (66.7g 520.5mmol) is dissolved in sodium hydroxide solution (the 365ml water that contains 41.6g solid NaOH) with the 2-thiouracil.Mixture is used methyl-iodide then, and (37ml 583mmol) handles, and the gained reaction mixture at room temperature stirred 16 hours.Solution is used glacial acetic acid (30ml) acidifying then.Suction strainer is collected white precipitate, solid cold water washing several times, and drying obtains 74g EX-6A with quantitative yield, is the white crystalline solid.

(EX-6B) (74.0g, glacial acetic acid 520.5mmol) (2275ml) solution is cooled to 0 ℃ with ice bath, uses Br with EX-6A ₂Handle.Make reaction mixture be warmed to room temperature, stirred 16 hours.There is yellow mercury oxide to generate, filters it, with ether washing three times.Be separated to 97.2gEX-6B, yield 62%.

(EX-6C) mixture of hydrolith in THF is cooled to 0 ℃, handles, handle with clean bromo-acetic acid tert-butyl again with clean EX-6B.Reaction mixture stirred 1 hour down at 0 ℃.Make reaction mixture be warmed to room temperature then, stirred 2 hours.Reaction mixture is heated to reflux temperature and reaches 16 hours.After reaction mixture is cooled to room temperature, mixture slowly is poured in the 1L frozen water slurries.Mixture after quenching dichloromethane extraction (3 * 500ml).Merge organic layer, water and salt water washing.Organic layer is through MgSO ₄Drying is filtered, and removes volatile constituent in a vacuum, obtains 28.81g (90%) EX-6C, is incomplete white solid, is N-alkylation and O alkylation mixture of isomers (9: 1).N-alkylation isomer: ¹HNMR (300MHz, CDCl ₃) d 8.07 (s, 1H), 4.75 (s, 2H), 2.57 (s, 3H), 1.47 (s, 9H); ¹³C NMR (75MHz, CDCl ₃) d 165.1,162.7,158.4,152.5,108.3,83.7,46.8,28.2 (3C), 15.5; HRMS (EI) calculated value C ₁₁H ₁₅BrN ₂O ₃S 335.0065, actual measurement 335.0077.

(EX-6D) in being full of the glove box of argon gas, and the EX-6C that in the 12-ounce Fischer-Porter bottle that contains the magnetic agitator arm, packs into (5.00g, 15.0mmol), Pd (OAc) ₂(168mg, 0.75mmol, 5mol%), rac-BINAP (654mg, 1.05mmol, 7mol%), Cs ₂CO ₃(6.84g, 21.0mmol) and the toluene (65.0ml) of no water degasification.In this mixture, add Isopropylamine (3.00ml, 35.2mmol).Cover bottle with having manometric manometric head, from glove box, take out.Closed system is heated in 118-120 ℃ of oil bath, and magnetic stirred 16 hours simultaneously.Space pressure on the liquid of formation～10psi during reaction.From oil bath, take out the Fischer-Porter bottle that contains reaction mixture, cooled off 30 minutes, be discharged in the argon streaming system, use syringe sampling.Lcms analysis shows that product accounts for 35%, and all the other 65% are raw material.Under argon shield, remove space pressure on the liquid, reaction mixture Pd (OAc) ₂(337mg, 1.5mmol, 10mol%), rac-BINAP (1.00g, 1.6mmol, 11mol%), Cs ₂CO ₃(10.0g, 30.7mmol) and Isopropylamine (6.00ml 70.4mmol) handles.Cover bottle with manometric head, be heated to 118-120 ℃ once more, magnetic stirred 16 hours simultaneously.The repeated sampling operation, it is completely that LCMS discloses reaction.Make reaction mixture be cooled to RT, filter by medium glass sintering funnel.Solid toluene thorough washing discards.Filtrate concentrates, through purification by flash chromatography (Merck 230-400 order SiO ₂, contain the hexane of 10% ethyl acetate), obtain 3.80g (yield 81%) EX-6D, be brown solid:

¹H NMR (300MHz, CDCl3) d 7.05 (s, 1H), 4.74 (s, 2H), 3.44 (septet, J=6.3Hz, 1H), 2.53 (s, 3H), 1.47 (s, 9H), 1.21 (d, J=6.3Hz, 6H); ¹³C NMR (75MHz, CDCl ₃) d165.7 (s), 158.7 (s), 147.4 (s), 130.5 (s), 123.6 (d), 82.9 (s), 45.9 (t), 44.1 (d), 28.0 (q), 22.1 (q), 14.8 (q); HRMS (ESI) calculated value C ₁₄H ₂₄N ₃SO ₃[M+H] ⁺=314.1538, actual measurement 314.1539.

(EX-6E) in being full of the glove box of argon gas, EX-6D (1.00g packs in the 3-ounce Fischer-Porter bottle that contains the magnetic agitator arm, 3.20mmol), 3-nitrophenyl boric acid (634mg, 3.80mmol), Cu (I)-2-Thiophene Carboxylic Acid salt (1.21g, 6.37mmol) and Pd (PPh ₃) ₄(100mg, 0.86mmol, 2.7mol%).Add THF (25ml), cover bottle, from glove box, take out with having manometric manometric head.Closed system is heated in 70 ℃ of oil baths, and magnetic stirred 16 hours simultaneously.Make reaction mixture be cooled to RT, discharging is with ether (200ml) dilution.Mixture filters by medium glass sintering funnel.Green solid discards with ether (100ml) washing.Filtrate concentrates, through purification by flash chromatography (Merck 230-400 order SiO ₂, contain the hexane of 10% to 30% ethyl acetate), obtain 961mg (yield 78%) EX-6E, be yellow foam:

¹H NMR (300MHz, CDCl ₃) d 8.39 (s, 1H), 8.31 (d, J=8.1Hz, 1H), 7.86 (d, J=7.8Hz, 1H), 7.64 (t, J=8.1Hz, 1H), 7.15 (bs, 1H), 4.51 (s, 2H), 3.58 (septets, J=6.0Hz, 1H), 1.46 (s, 9H), 1.27 (d, J=6.3Hz, 6H); HRMS (ESI) calculated value C ₁₉H ₂₅N ₄O ₅[M+H] ⁺=389.1815, actual measurement 389.1825.

(EX-6F) in having the 250-ml round-bottomed flask of magnetic agitator arm, pack into EX-6E (755mg, 1.9mmol) and trifluoroacetic acid (30ml).This mixture stirred 30 minutes under RT and argon gas atmosphere, concentrated on rotatory evaporator.Resistates with ether (50ml) development, with the heptane azeotropic (2 * 50ml), obtain 801mg (yield 95%) EX-6F, be clarifying yellow glass shape thing: ¹H NMR (300MHz, DMSO-d ₆) d 8.34-8.26 (m, 2H), 7.89 (d, J=7.8Hz, 1H), 7.76 (t, J=7.9Hz, 1H), 7.20 (s, 1H), 4.51 (s, 2H), 3.57 (septet, J=6.6Hz, 1H), 1.17 (d, J=6.6Hz, 6H); HRMS (ESI) calculated value C ₁₅H ₁₇N ₄O ₅[M+H] ⁺, free alkali=333.1223, actual measurement 333.1199.

The described operation of precursor according to about the CBZ-protection prepares this product from EX-6F:

¹H NMR (300MHz, CDCl ₃) d 9.34 (bs, 1H), 8.32 (s, 1H), 8.14 (d, J=8.0Hz, 1H), 7.81 (t, J=7.8Hz, 2H), 7.53 (d, J=7.8Hz, 2H), 7.47 (t, J=7.8Hz, 1H), 7.39-7.25 (m, 5H), 7.08 (s, 1H), 7.00 (d, J=7.8Hz, 2H), 5.12 (s, 2H), 4.61 (d, J=7.8Hz, 1H), 4.35 (s, 2H), 4.21 (m, 1H), 3.50 (d of septet, 8 line J=6.3Hz, 1H), 1.22 (d, J=6.3Hz, 6H); ¹³C NMR (75MHz, CDCl ₃) d 168.5 (s), 167.4 (s), 164.0 (s), 158.6 (s), 148.2 (s), 143.8 (s), 142.6 (s), 136.6 (s), 136.2 (s), 135.0 (d), 133.4 (s), 133.2 (s), 129.9 (d), 128.7 (d), 128.3 (d), 127.8 (d), 127.5 (d), 124.4 (d), 124.1 (d), 121.8 (d), 67.4 (t), 49.9 (t), 44.1 (d), 43.2 (t), 22.4 (q); HRMS (ESI) calculated value C ₃₁H ₃₂N ₇O ₆[M+H] ⁺: 598.2463, actual measurement 598.2414.

According to about the described method of SC-81703, prepare this product from EX-6G:

¹H NMR (300MHz, CD ₃OD) d 9.25 (bs, 1H), 8.97 (m, 1H), 8.78 (bs, 1H), 7.93-7.14 (compound m, 9H), 4.77 (s, 2H), 4.51 (s, 3H), 3.66 (m, 1H), 1.30 (d, J=6.3Hz, 6H); HRMS (ESI) calculated value C ₂₃H ₂₈N ₇O ₂[M+H] ⁺=598, free alkali=434.2304, actual measurement 434.2318.

Embodiment 7

(EX-7A) utilize about the described same operation of EX-6E, sole exception be to use Cs ₂CO ₃Alkali is prepared from EX-6D.So, from EX-6D (213mg, 0.68mmol), pyridine-3-boric acid 1, the ammediol cyclic ester (166mg, 1.02mmol) and Cs ₂CO ₃(771mg is 2.37mmol) through flash chromatography (Merck 230-400 order SiO ₂, contain the CHCl of 2%MeOH ₃) obtain 143mg EX-7A (yield 61%) afterwards, be little yellow glass shape thing:

¹H NMR (300MHz, CDCl ₃) d 8.79-8.66 (m, 2H), 7.90-7.26 (compound m, 3H), 7.16 (s, 1H), 4.53 (s, 2H), 3.57 (septet, J=6.3Hz, 1H), 1.44 (s, 9H), 1.27 (d, J=6.3Hz, 6H); HRMS (ESI) calculated value C ₁₈H ₂₅N ₄O ₃[M+H] ⁺=345.1927, actual measurement 345.1928.

(EX-7B) utilize about the described same operation of EX-6F, from EX-7A (143mg 0.41mmol) prepares 212mg (yield 100%) EX-7B, is yellow foam:

¹H NMR (300MHz, CDCl ₃) d 8.72-8.64 (m, 2H), 7.95-7.89 (m, 1H), 7.62-7.52 (compound m, 2H), 7.42-737 (m, 1H), 7.20 (s, 1H), 4.52 (s, 2H), 3.57 (septet, J=6.3Hz, 1H), 1.18 (d, J=6.3Hz, 6H); HRMS (ESI) calculated value C ₁₄H ₁₇N ₄O ₃[M+H] ⁺289.1301, actual measurement 289.1296.

(EX-7C) utilize the described same operation of protecting about CBZ-of raw material, prepare EX-7C from EX-7B; HRMS (ESI) is about C ₃₀H ₃₂N ₇O ₄[M+H] ⁺Calculated value 554.2516, measured value 554.2523

Utilization prepares this product about embodiment 6 described same operation from EX-7C.

Embodiment 8

According to the method for embodiment 6, preparation target compound: HRMS (ESI) is about C ₂₄H ₂₇N ₇O ₂[M+H] ⁺Calculated value 446.2304, measured value 446.2309

Utilize following route 8 " general methylene radical pyrimidone preparation " and specific embodiment 9 can prepare the methylene radical analogue of pyrimidone, wherein methylene radical has replaced the carbonyl of pyrimidone N-3 position ethanamide.

Route 8: general methylene radical pyrimidone is synthetic

Embodiment 9

EX-9A) to [5-[(benzyloxycarbonyl) amino]-2-phenyl-6-oxo-1,6-dihydro-1-pyrimidyl] and the tetrahydrofuran (THF) of acetaldehyde and dichloromethane solution (1: 1, add catalytic amount acetate and the suitable amine of 1 equivalent in 0.3M).Solution is cooled to 0 ℃ in ice bath, disposable adding 1 equivalent sodium triacetoxy borohydride.Stir after 5 minutes, remove ice bath, reaction mixture at room temperature stirred 2 hours.Add 1N NaOH and finish reaction, mixture stirred 5 minutes.Carry out chromatogram purification after the typical water treatment, obtain pure products EX-9A.

EX-9B) to [5-[(benzyloxycarbonyl) amino]-2-phenyl-6-oxo-1,6-dihydro-1-pyrimidyl] disposable adding 10%Pd/C in the methanol solution (0.2M) of ethanamide (EX-9A).The gained mixture stirred about 16 hours down in room temperature and nitrogen atmosphere (air bag).Crude product mixture is filtered by C salt 545 pads, under reduced pressure removes and desolvates.Resistates is developed from ether, obtains pure products EX-9B.

EX-9C) to the tetrahydrofuran (THF) of [5-amino-2-phenyl-6-oxo-1,6-dihydro-1-pyrimidyl] ethanamide (EX-9B) and dichloromethane solution (1: 1, add catalytic amount acetate and 1 equivalent phenylacetic aldehyde in 0.3M).Solution is cooled to 0 ℃ in ice bath, disposable adding 1 equivalent sodium triacetoxy borohydride.Stir after 5 minutes, remove ice bath, reaction mixture at room temperature stirred 2 hours.Add 1N NaOH and finish reaction, mixture stirred 5 minutes.Carry out chromatogram purification after the typical water treatment, obtain pure products EX-9C.

The 4M HCl dioxane solution (0.2M) of [5-(2-phenylethyl) amino-2-phenyl-6-oxo-1,6-dihydro-1-pyrimidyl] ethanamide is stirred some hrs.After reacting completely, under reduced pressure remove volatile matter.Resistates obtains pure products 5 through ether development purifying.

Amino Toluidrin with the amine of suitable N-Boc-amidino groups protection replaces 1; the 1-dimethoxy-ethylamine; utilize that general disclosed operation can prepare the alkylsulfonyl analogue of pyrimidone based on route 1-5, wherein alkylsulfonyl has replaced the carbonyl of pyrimidone N-3 position ethanamide.For example, can use the amino Toluidrin of N-(4-amidino benzyl)-2-.Utilize this method, can prepare the alkylsulfonyl analogue of embodiment 10 and 11.

Embodiment 10

Embodiment 11

Utilize following route 9 " general 4-aza-pyrimidine ketone preparation " and specific embodiment 12 can prepare the triazone analogue of pyrimidone, wherein nitrogen has replaced the carbon of pyrimidone 4-position.

Route 9: general 4-aza-pyrimidine ketone is synthetic

Embodiment 12

EX-12A) dichloromethane solution of glycine tert-butyl hydrochloride (1mmol) is handled with Benzoyl chloride (1mmol) and triethylamine (2mmol).Reaction mixture at room temperature stirred 16 hours.Mixture washes with water, uses dichloromethane extraction.Organic layer after the merging is through MgSO ₄Dry.After removing volatile matter in a vacuum, be separated to pure products EX-12A.

EX-12B) with the N-benzoyl-glycine tert-butyl ester (1mmol, EX-12A), the mixture heating up to 80 of Lawesson reagent (0.5mmol) and toluene ℃ reaches 16 hours.Reaction mixture under reduced pressure concentrates.Via silica gel chromatography, obtain pure products EX-12B.

EX-12C) under-78 ℃, with N-thiobenzoyl tert-butyl glycinate (1mmol; EX-12B) mixture in methylene dichloride is handled with trimethylammonium oxygen a tetrafluoro borate (1.1mmol).After stirred reaction mixture reaches 2 hours, mixture NaHCO ₃(aq) dichloromethane extraction is used in washing.Organic layer after the merging is through MgSO ₄Drying is filtered.After concentrating volatile organic constituents, be separated to required product EX-12C.

EX-12D) with N-thiomethyl benzyl tert-butyl glycinate (1mmol; EX-12C) methanol solution is handled with hydrazine (1mmol).Remove volatile matter in a vacuum, be separated to required compound EX-12D, need not to be further purified.

EX-12E) compd E X-12D (1mmol) is reached 4 hours with the mixture heating up of sulfo-ethyl oxamide (1mmol) in methyl alcohol to reflux temperature.Have colourless crystal settling to generate, suction strainer separates the crystal of required product EX-12E.

Compd E X-12E (1mmol) is handled with the acetonitrile solution of a-toluene sulfonyl chloride (3mmol) with the acetonitrile solution of pyridine (5mmol).Reaction mixture stirred 3 hours down at-10 ℃ to 0 ℃.The back adularescent precipitation that reacts completely generates.Suction strainer separates the crystal of required product EX-12F.

EX-12G) under 0 ℃, trifluoroacetic acid is joined in the mixture of compd E X-12F (1mmol) in phenylmethylether.Reaction mixture stirred 1 hour down at 0 ℃.The reaction mixture organic solvent extraction.Under reduced pressure remove and desolvate, obtain pure products EX-12G.

EX-12H) compd E X-12G (1mmol), EDC (1.3mmol) and HOBt (1.3mmol) are blended among the DMF, mixture stirred 15 minutes down at 20 ℃.The DMF solution that in this mixture, adds benzyl-[[(4-aminomethyl phenyl) iminomethyl] amino] carbamate hydrogen chloride salt (1.3mmol) and DIEA (1.3mmol).Carry out chromatogram purification after the typical water treatment, obtain required product EX-12H.

Compd E X-12H (1mmol), right-toluenesulphonic acids monohydrate (1mmol) are used methanol mixed with 10%Pd-gac (0.1mmol).Mixture stirred 2 hours under nitrogen atmosphere, and nitrogen atmosphere is introduced and kept by rubber-bag.Leach catalyzer, remove methyl alcohol, be separated to required product.

Formula of the present invention (I) compound with hydroxyl, sulfo-hydroxyl 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.This class reaction is general uses a kind of amine catalyst to carry 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 sulfo-hydroxyl can be converted into corresponding thioester derivative, is similar to use identical reagent and suitable reaction conditions to carry out the reaction of pure and mild phenol.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 a kind of tertiary amine, can prepare sulphonamide from corresponding SULPHURYL CHLORIDE.Being suitable for preparing the operation of these derivatives and method can be referring to " House modern synthesis " (House ' s ModernSynthetic Reactions) W.A.Benjamin, Inc., Shriner, Fuson and Curtin " system of organic compound differentiates " (Systemic Identification ofOrganic Compounds) the 5th edition John Wiley ﹠amp; Sons, Fieser and Fieser " organic synthesis reagent " (Organic Synthetic Reagents) the 1st volume JohnWiley ﹠amp; Sons.The plurality of reagents of hydroxyl, sulfo-hydroxyl 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, sulfo-hydroxyl 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 is reacted general and is used alkoxide 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.Amine catalyst is the pyridine in inert solvent for example.Formula (I) compound with at least one sulfo-hydroxyl can be converted into corresponding sulfide derivative, is similar to use identical reagent and suitable reaction conditions to carry out the reaction of pure and mild phenol.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 monovalent tertiary amine, two equivalent secondary amine, three equivalent primary amine) 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 a kind of aldehyde, for example formaldehyde and sodium cyanoborohydride to carry out reductive amination, can make primary amine by dialkyl groupization.At first with being easy to cracked blocking group protection amine, for example trifluoroacetyl group can make primary amine by an alkylation.In the presence of non-nucleophilicity alkali, Barton alkali (the 2-tertiary butyl-1,1,3,3-tetramethyl guanidine) for example, amine and the reaction of a kind of alkylating agent, for example methyl-sulfate obtains monomethylated protected amine.Use aqueous potassium hydroxide to remove blocking group, obtain a required alkylating amine.Other operation and methods that are suitable for preparing these derivatives can be referring to " House modern synthesis " W.A.Benjamin, Inc., Shriner, Fuson, the 5th edition John Wiley ﹠amp of and Curtin " system of organic compound differentiates "; Sons, Fieser and Fieser " organic synthesis reagent " the 1st volume John Wiley ﹠amp; Sons.As described in DesMarteau " Englishize association will chemical communication " (J.Br.Chem.Soc.Chemistry Communications) 2241 (1998), can prepare perfluoroalkyl derivatives.The plurality of reagents of hydroxyl, sulfo-hydroxyl 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.

About specific embodiment 13 to 19, table 1 has shown that the derivatization by the nucleophilic substitution base prepares the above-mentioned synthetic method result of pyrimidone, and the nucleophilic substitution base for example may reside in B, R ¹, R ²And Y ⁰In.It only is the illustration of multiple possibility and unrestricted that following specific examples should be considered as by those of ordinary skills.

Table 1: the structure of pressing the pyrimidone of general derivation operation preparation

General structure

Ex.No.	R ²	B-A-	Y ⁰	M/W(m/z+1)
Ex.No.	R ²	B-A-	Y ⁰	M/W(m/z+1)	13	Phenyl	The methoxyl group ethanoyl	The 4-amidino benzyl	449.47
14	Phenyl	The 4-methyl benzoyl	The 4-amidino benzyl	495.54	13	Phenyl	The methoxyl group ethanoyl	The 4-amidino benzyl	449.47
14	Phenyl	The 4-methyl benzoyl	The 4-amidino benzyl	495.54	15	Phenyl	The 4-nitro benzoyl	The 4-amidino benzyl	526.52
16	Phenyl	Isobutyryl	The 4-amidino benzyl	447.50	15	Phenyl	The 4-nitro benzoyl	The 4-amidino benzyl	526.52
16	Phenyl	Isobutyryl	The 4-amidino benzyl	447.50	17	Phenyl	2,4, the 6-trimethylbenzoyl	The 4-amidino benzyl	523.60
18	Phenyl	Benzoyl	The 4-amidino benzyl	481.52	17	Phenyl	2,4, the 6-trimethylbenzoyl	The 4-amidino benzyl	523.60
18	Phenyl	Benzoyl	The 4-amidino benzyl	481.52	19	Phenyl	Ethanoyl	4-amido benzyl	419.45

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-benzyloxycarbonyl-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, pH8.0,100mM 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 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, LaJolla, 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 operating embodiment 1 to 19 compound of being measured as these biological assays is summarised in the table 2.

Table 2: pyrimidone 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)
The embodiment numbering	TF-VIIa IC50(μM)	Zymoplasm II IC50 (μ M)	Xa factor IC50 (μ M)	Trypsinase II IC50 (μ M)	1	15.4	22.4	--	0.5
2	＞30	＞30	--	＞30	1	15.4	22.4	--	0.5
2	＞30	＞30	--	＞30	3	1.0	1.0	--	0.6
4	--	--	--	--	3	1.0	1.0	--	0.6
4	--	--	--	--	5	--	--	--	--
6	0.05	43％@30μM	33％@30μM	＜0.04	5	--	--	--	--
6	0.05	43％@30μM	33％@30μM	＜0.04	7	0.7	11.3	33％@30μM	0.04
8	0.08	42％@30μM	15％@30μM	0.04	7	0.7	11.3	33％@30μM	0.04
8	0.08	42％@30μM	15％@30μM	0.04	9	--	--	--	--
10	--	--	--	--	9	--	--	--	--
10	--	--	--	--	11	--	--	--	--
12	--	--	--	--	11	--	--	--	--
12	--	--	--	--	13	--	--	--	--
14	--	--	--	--	13	--	--	--	--
14	--	--	--	--	15	--	--	--	--
16	--	--	--	--	15	--	--	--	--
16	--	--	--	--	17	--	--	--	--
18	--	--	--	--	17	--	--	--	--
18	--	--	--	--	19	--	--	--	--

Claims

1. the compound or its pharmacy acceptable salt that have the following formula structure:

Wherein:

B is hydrogen, phenyl, C _1-6Alkyl, C _1-6Alkoxyl group or C _3-7Cycloalkyl, described phenyl are unsubstituted or by one or more C that are selected from _1-6The group of alkyl and nitro replaces;

A is selected from singly-bound, SO ₂,-C (O)-, C _1-6Alkylidene group and-C (O)-C _1-6Alkylidene group;

M is CH or N;

R ²Be Z ⁰-Q;

Z ⁰Be sulphur or covalent single bond;

Q is selected from the aryl of phenyl, naphthyl, tetralyl, indane and xenyl or for pyridyl, for unsubstituted or by one or more amino replacements;

Y ⁰Be benzyl unsubstituted or that replaced by amidino groups or amido.

2. the compound of claim 1 or its pharmacy acceptable salt, wherein:

B is selected from phenyl, 4-aminomethyl phenyl, 4-nitrophenyl, 2,4,6-trimethylphenyl, benzyl, methyl, methoxyl group, sec.-propyl, butyl and cyclobutyl.

3. the compound of claim 1 or its pharmacy acceptable salt, wherein:

A is selected from covalent single bond, SO ₂,-C (O)-, CH ₂CH ₂With-C (O)-CH ₂

4. the compound of claim 1 or its pharmacy acceptable salt, wherein:

R ²Be selected from phenyl, thiophenyl, 3-aminophenyl and pyridin-3-yl.

5. the compound of claim 1 or its pharmacy acceptable salt, wherein:

Y ⁰Be selected from 4-amidino benzyl, 3-amidino benzyl and 4-amido benzyl.

6. any one described compound or its pharmacy acceptable salt among the claim 1-5, wherein:

M is CH.

7. any one described compound or its pharmacy acceptable salt among the claim 1-5, wherein:

M is N.

8. the compound of claim 1 or its pharmacy acceptable salt, wherein:

B is a benzyl, and A is SO ₂, M is CH, R ²Be phenyl and Y ⁰Be the 4-amidino benzyl;

B is a benzyl, and A is SO ₂, M is CH, R ²Be phenyl and Y ⁰Be the 3-amidino benzyl;

B is a phenyl, and A is CH ₂CH ₂, M is CH, R ²Be phenyl and Y ⁰Be the 4-amidino benzyl;

B is a phenyl, and A is CH ₂CH ₂, M is CH, R ²Be thiophenyl and Y ⁰Be the 4-amidino benzyl;

B is a phenyl, and A is CH ₂CH ₂, M is CH, R ²Be pyridin-3-yl and Y ⁰Be the 4-amidino benzyl;

B is a sec.-propyl, and A is a singly-bound, and M is CH, R ²Be 3-aminophenyl and Y ⁰Be the 4-amidino benzyl;

B is a sec.-propyl, and A is a singly-bound, and M is CH, R ²Be 3-pyridin-3-yl and Y ⁰Be the 4-amidino benzyl;

B is a cyclobutyl, and A is a singly-bound, and M is CH, R ²Be 3-aminophenyl and Y ⁰Be the 4-amidino benzyl;

B is a butyl, and A is SO ₂, M is N, R ²Be phenyl and Y ⁰Be the 4-amidino benzyl;

B is a methoxyl group, and A is-CO-CH ₂, M is CH, R ²Be phenyl and Y ⁰Be the 4-amidino benzyl;

B is the 4-aminomethyl phenyl, and A is-CO-that M is CH, R ²Be phenyl and Y ⁰Be the 4-amidino benzyl;

B is the 4-nitrophenyl, and A is-CO-that M is CH, R ²Be phenyl and Y ⁰Be the 4-amidino benzyl;

B is a sec.-propyl, and A is-CO-that M is CH, R ²Be phenyl and Y ⁰Be the 4-amidino benzyl;

B is 2,4, and 6-trimethylphenyl, A are-CO-that M is CH, R ²Be phenyl and Y ⁰Be the 4-amidino benzyl;

B is a phenyl, and A is-CO-that M is CH, R ²Be phenyl and Y ⁰Be the 4-amidino benzyl; Or

B is a methyl, and A is-CO-that M is CH, R ²Be phenyl and Y ⁰Be 4-amido benzyl.

9. composition that is used to suppress the blood thrombosis disease, said composition comprise among the claim 1-8 compound or its pharmacy acceptable salt and the pharmaceutically acceptable carrier of any one.

10. the purposes that the compound of any one or its pharmacy acceptable salt are used for suppressing, treat or prevent the medicine that the Mammals thrombus forms among the claim 1-8 in preparation.

11. the compound of any one or its pharmacy acceptable salt are used for suppressing the blood thrombosis disease in preparation among the claim 1-8, the platelet aggregation thing forms or the purposes of thrombotic medicine.

12. the compound of any one or its pharmacy acceptable salt are used for the treatment of or prevent purposes in the medicine of people or the following disease of other Mammalss in preparation among the claim 1-8, described disease is selected from: venous thromboembolism, pulmonary thromboembolism, venous thrombosis, heart source property thromboembolism, thromboembolic stroke, thrombosis and the unstable angina pectoris relevant with cancer and cancer chemotherapy.