CN1152023C - Substituted polycyclic aryl and heteroaryl uracils as anticoagulative agents - Google Patents

Abstract

This invention relates to substituted polycyclic and heteroaryl uracil compounds that can be used as inhibitors of serine proteases in the coagulation cascade, and also to compounds, compositions, and methods for anticoagulation therapy for the treatment and prevention of various thrombotic diseases, including coronary and cerebrovascular diseases.

Description

Substituted polycyclic aryl and heteroaryl uracils as anticoagulants

field of invention

The present invention belongs to the field of anticoagulant therapy, and in particular relates to compounds, compositions and methods for preventing and treating thrombotic diseases, such as coronary artery and cerebrovascular diseases. More specifically, the present invention relates to substituted polycyclic aryl and heteroaryl uracil compounds which inhibit serine proteases of the coagulation cascade.

Background of the invention

Physiological systems control the fluidity of blood in mammals [Majerus, P.W. et al. "Anticoagulant, Thrombolytic, and Antiplatelet Drugs." Hardman, J.G. and Limbird, L.E. eds. Goodman & Gilman's Goodman & Gilman's The Pharmacological Basis of Therapeutics. 9th Ed., New York, McGraw-Hill Book Co., 1996, pp. 1341-1343]. Blood must remain flowing within the vasculature and also be able to undergo rapid hemostasis, the cessation of blood loss from damaged blood vessels. Hemostasis or coagulation begins when platelets first adhere to macromolecules in the subendothelial region of injured and/or compromised blood vessels. These platelets aggregate to form a primary hemostatic plug that stimulates the local activation of plasma coagulation factors, causing a fibrin clot that strengthens the aggregated platelets.

Plasma coagulation factors include factors II, V, VII, VIII, IX, X, XI, and XII; they are also called protease zymogens. These coagulation factors or protease zymogens are activated by serine proteases, causing coagulation in the so-called "coagulation cascade" or chain reaction [Handin, R.I. "Bleeding and Thrombosis". Wilson, J. et al. eds. Harrison's Internal Medicine Harrison's Principles of Internal Medicine. 12th Ed., New York, McGraw-Hill Book Co., 1991, p. 350]. Coagulation, or coagulation, occurs in two ways and the pathways are different. The intrinsic or contact pathway results in the conversion of XII to XIIa to XIa to IXa and X to Xa. Factors Xa and Va convert prothrombin (II) to thrombin (IIa), causing the conversion of fibrinogen to fibrin. Polymerization of fibrin causes a fibrin clot. The extrinsic pathway is initiated by the conversion of VII to VIIa by coagulation factor Xa. The presence of tissue factor and VIIa accelerates the production of Xa in the presence of calcium ions and phospholipids. Generation of Xa causes thrombin, fibrin and fibrin clots, as described above. The presence of one or more of these different coagulation factors and two different coagulation pathways allows for effective selective control and better understanding of various parts of the coagulation or coagulation process.

Although coagulation as a consequence of vascular injury is a key physiological process in mammals such as humans, coagulation can also cause disease states. When platelet aggregation and/or fibrin clots block (ie occlude) blood vessels, a pathological process called thrombosis results. Arterial thrombosis can lead to ischemic necrosis of the tissue supplied by the artery.

When a blood clot forms in a coronary artery, it can lead to a myocardial infarction or heart attack. Thrombosis that occurs in a vein can cause edema and inflammation in the tissues that the vein flows through. Deep vein thrombosis can be complicated by pulmonary embolism. By inhibiting the formation of platelet aggregates, inhibiting the formation of fibrin, inhibiting the formation of thrombus, and inhibiting the formation of emboli, it can prevent or treat blood clots, and can be used therapeutically to treat or prevent unstable angina, refractory angina Angina, myocardial infarction, transient ischemic attack, atrial fibrillation, thrombotic stroke, embolic stroke, deep vein thrombosis, disseminated intravascular coagulation, ocular fibrin occlusion and reocclusion of reperforated vessels or restenosis.

There have been several reports of non-peptidic and peptidic uracil compounds acting as inhibitors of coagulation factors present in the coagulation cascade or coagulation process. Tamura et al. describe 4,5,6-substituted-3-aminopyridonylacetamides, 1,6-substituted-5-aminouracilyl (uracinyl)acetamides and 2,4- Substituted-5-aminopyrimidinylacetamides, in which both amide substituents have formyl groups, are reported to have antithrombin activity. 4,5,6-substituted-3-aminopyridinylacetamides, 1,6-substituted-5-aminouracilylacetamides and 2,4-substituted -5-aminopyrimidinylacetamide, in which both amide substituents have formyl groups, is reported to have antithrombin activity. Tamura et al. further describe 4,5,6-substituted-3-aminopyridinylacetamides, 1,6-substituted-5-aminouracilylacetamides in PCT patent applications 96/18644 and 97/46207 and 2,4-substituted-5-aminopyrimidinylacetamides, in which both amide substituents have formyl groups, are reported to have antithrombin activity.

Summary of the invention

The object of the present invention is to provide a compound useful for anticoagulant therapy and having the general structure of formula (I):

Another object of the present invention is to provide methods for the prevention and treatment of thrombotic diseases, such as coronary artery disease, cerebrovascular disease and other coagulation-related disorders. These thrombotic diseases are prevented and treated by administering to a patient in need thereof an effective amount of a compound of formula (I).

Various other objects and advantages of the present invention will become apparent from the following description of the invention.

description of the invention

The present invention relates to a class of compounds comprising substituted polycyclic aryl and heteroaryl uracils, which are beneficial in the treatment and prevention of various thrombotic diseases, including coronary artery and cerebrovascular diseases, in anticoagulant therapy, such as formula (I) as shown:

or a pharmaceutically acceptable salt thereof, wherein:

J ^a and J ^b are independently selected from O and S;

J ^{a is} optionally selected from CH-R ⁶ and NR ⁶ , wherein R ⁶ is a linear spacer moiety having 1 to 4 attached atoms, and is selected from R ^4a , R ^4b , R ¹⁴ , R ¹⁵ , R ³⁹ , the bonding points of substituents of R ⁴⁰ and R ⁵ are connected to form a heterocyclyl ring with 5 to 8 connected members;

J ^b is optionally selected from CH-R ⁶ and NR ⁶ , wherein R ⁶ is a linear spacer moiety having 1 to 4 attached atoms, and is selected from R ₁ , R ^4a , R ^4b , R ¹⁴ and R ¹⁵ The bonding points of the substituents are connected to form a heterocyclyl ring having 5 to 8 connected members;

J ^a and J ^b are optionally independently selected from CH-R ⁶ and NR ⁶ , wherein R ⁶ is a linear spacer moiety having 1 to 4 connected atoms, linked to both the bonding points of R ^4a and R ^4b to form a heterocyclyl ring having 5 to 8 connected members;

J ^{a is} optionally selected from CH-R ⁶ and NR ⁶ , wherein R ⁶ is a linear spacer moiety having 1 to 4 attached atoms, bonded to both R ³⁹ and R ⁴⁰ to form a chain having 5 to 8 atoms heterocyclyl rings of linked members;

B is formula (V):

wherein D ¹ , D ² , J ¹ , J ² and K ¹ are independently selected from C, N, O, S and covalent bonds, with the proviso that at most one can be a covalent bond, D ¹ , D ² , J ¹ , at most one of J ² and K ¹ is O, at most one of D ¹ , D ² , J ¹ , J ² and K ¹ is S, if two of D ¹ , D ² , J ¹ , J ² and K ¹ are O and S, then one of D ¹ , D ² , J ¹ , J ² and K ¹ must be a covalent bond, and at most four of D ¹ , D ² , J ¹ , J ² and K ¹ are N, the condition is R ³² , R ³³ , R ³⁴ , R ³⁵ and R ³⁶ are each independently selected to maintain the tetravalent nature of carbon, the trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature 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 ³⁵ and R ³⁶ are independently selected from hydrogen, acetamido, halogen Acetylamino, amidino, guanidino, dialkylsulfonium, trialkylphosphonium, dialkylsulfoniumalkyl, carboxyl, heteroaralkylthio, heteroaralkoxy, cycloalkylamino, acylalkyl, Acylalkoxy, aroylalkoxy, heterocyclyl, aralkylaryl, aralkyl, aralkenyl, aralkynyl, heterocyclyl, perhalogenated aralkyl, aralkylsulfonyl , Aralkylsulfonylalkyl, Aralkylsulfinyl, Aralkylsulfinylalkyl, Halocycloalkyl, Halocycloalkenyl, Cycloalkylsulfinyl, Cycloalkylsulfinyl Alkyl, cycloalkylsulfonyl, cycloalkylsulfonylalkyl, heteroarylamino, N-heteroarylamino-N-alkylamino, heteroarylaminoalkyl, haloalkylthio, alkanoyloxy , Alkoxy, Alkoxyalkyl, Haloalkoxyalkyl, Heteroaralkoxy, Cycloalkoxy, Cycloalkenyloxy, Cycloalkoxyalkyl, Cycloalkylalkoxy, Cycloalkenyloxy ylalkyl, cycloalkenedioxy, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxy, halocycloalkenyloxyalkyl, hydroxy, amino, alkoxy Amino, thio, nitro, lower alkylamino, alkylthio, alkylthioalkyl, arylamino, aralkylamino, arylthio, arylthioalkyl, heteroaralkoxyalkyl, Alkylsulfinyl, Alkylsulfinylalkyl, Arylsulfinylalkyl, Arylsulfonylalkyl, Heteroarylsulfinylalkyl, Heteroarylsulfonylalkyl, Alkylsulfonyl , Alkylsulfonylalkyl, Haloalkylsulfinylalkyl, Haloalkylsulfonylalkyl, Alkylsulfonylamino, Alkylaminosulfonyl, Amidosulfonyl, Alkylamidosulfonyl, Dioxane Alkyl amidosulfonyl, a aryl amido sulfonyl, aryl sulfonyl amino, diaryl amido sulfonyl, an alkyl-aryl amido sulfonyl, aryl sulfinyl, aryl sulfonyl, Heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, heterocyclylsulfonyl, heterocyclylthio, alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkyl Acyl, haloalkanoyl, alkyl, alkenyl, alkynyl, alkenyloxy, alkenyloxyalkyl, alkylenedioxy, haloalkanedioxy, cycloalkyl, cycloalkylalkanoyl, cycloalkene group, lower cycloalkylalkyl, lower cycloalkenylalkyl, halogen, haloalkyl, haloalkenyl, haloalkoxy, hydroxyhaloalkyl, hydroxyaralkyl, hydroxyalkyl, alkenylamino, hydroxyheteroaryl Alkyl, haloalkoxyalkyl, aryl, aralkyl, aryloxy, aralkoxy, aryloxyalkyl, saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl, heteroaryl Oxy, heteroaryloxyalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, carboxyalkyl, alkoxycarbonyl, alkoxycarboxamido, alkylacyl Aminocarbonylamido, arylamidocarbonylamido, alkoxycarbonylalkyl, alkoxycarbonylalkenyl, carboxyl, aralkoxycarbonyl, carboxamido, carboxamidoalkyl, cyano, haloalkoxycarbonyl, phosphine Acyl, phosphonoalkyl, diaralkoxyphosphono and diaralkoxyphosphonoalkyl;

R ¹⁶ , R ¹⁹ , R ³² , R ³³ , R ³⁴ , R ³⁵ and R ³⁶ are independently optionally Q ^b with the proviso that at most one of R ¹⁶ and R ¹⁹ is simultaneously Q ^b and Q ^b is Q ^be ;

R ³² and R ³³ , R ³³ and R ³⁴ , R ³⁴ and R ³⁵ , and R ³⁵ and R ³⁶ are independently optionally selected to form spacer pairs, wherein the spacer pairs together form a linear chain having 3 to 6 connected atoms moiety, connected to the bonding point of the spacer pair members to form a ring selected from the group consisting of a cycloalkenyl ring having 5 to 8 connected members, a partially saturated heterocyclyl ring having 5 to 8 connected members, Heteroaryl rings and aryl groups having 5 to 6 connected members, with the proviso that at most one spacer pair of R ³² and R ³³ , R ³³ and R ³⁴ , R ³⁴ and R ³⁵ and R ³⁵ and R ³⁶ is used at the same time;

R ⁹ and R ¹⁰ , R ¹⁰ and R ¹¹ , R ¹¹ and R ¹² , and R ¹² and R ¹³ are independently optionally selected to form spacer pairs, wherein the spacer pairs together form a linear chain having 3 to 6 connected atoms moiety, connected to the bonding point of the spacer pair members to form a ring selected from the group consisting of a cycloalkenyl ring having 5 to 8 connected members, a partially saturated heterocyclyl ring having 5 to 8 connected members, Heteroaryl rings and aryl groups having 5 to 6 connected members with the proviso that at most one spacer pair of R ⁹ and R ¹⁰ , R ¹⁰ and R ¹¹ , R ¹¹ and R ¹² and R ¹² and R ¹³ is used at the same time;

B is optionally formula (VI):

wherein D ³ , D ⁴ , J ³ and J ⁴ are independently selected from C, N, O and S ^, at most one of D ³ , D 4 , J ³ and J ⁴ is O, D ³ , D ⁴ , J ³ and At most one of J ⁴ is S and at most three of D ¹ , D ² , J ¹ and J ² are N, provided that R ³² , R ³³ , R ³⁴ and R ³⁵ are each independently selected to maintain The tetravalent nature of carbon, the trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen;

B is optionally selected from hydrogen, trialkylsilyl, C2-C8 alkyl, C3-C8 alkenyl, C3-C8 alkylene, C3-C8 alkynyl, C2-C8 haloalkyl and C3-C8 halo Alkenyl, wherein each member of group B is optionally replaced by one or more groups R ³² , R ³³ , R ³⁴ , R on any carbon up to and including 6 atoms from the point of attachment of B to A ³⁵ and R ³⁶ are substituted;

B is optionally selected from C3-C15 cycloalkyl, C5-C10 cycloalkenyl, C4-C12 saturated heterocyclyl and C4-C9 partially saturated heterocyclyl, wherein each ring carbon is optionally replaced by ^R33 Substituted, ring carbons other than the ring carbon at the point of attachment of B and A are optionally substituted with oxo, provided that at most one ring carbon is simultaneously substituted with oxo, the ring carbon adjacent to the ring carbon at the point of attachment is substituted with The nitrogen atom is optionally substituted by ^R9 or ^R13 , and the ring carbon or nitrogen atom adjacent to the ^R9 position and two atoms away from the point of attachment is optionally substituted by ^R10 , adjacent to the ^R13 position and two atoms away from the point of attachment Two atoms of the ring carbon or nitrogen atom are optionally substituted by R ¹² , three atoms from the point of attachment and the ring carbon or nitrogen atom adjacent to the ¹⁰ position of R is optionally substituted by R ¹¹ , three atoms from the point of attachment And the ring carbon or nitrogen atom adjacent to the R ¹² position is optionally substituted by R ³³ , and the ring carbon or nitrogen atom adjacent to the R ¹¹ and R ³³ positions four atoms away from the connection point is optionally substituted by R ³⁴ ;

A is selected from covalent single bonds, (W ⁷ ) _rr -(CH(R ¹⁵ )) _pa and (CH(R ¹⁵ )) _pa -(W ⁷ ) _rr , where rr is an integer selected from 0 to 1, pa is an integer selected from 0 to 6, W ⁷ is 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) ₂ N(R ⁷ ), ( R ⁷ )NS(O) ₂ , Se(O), Se(O) ₂ , Se(O) ₂ N(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 ⁷ and N(R ⁷ ), with the proviso that at most one of rr and pa is 0 at the same time;

R and ^R are independently selected from hydrogen, ^hydroxyl , alkyl, alkenyl, aryl, aralkyl, aryloxy, alkoxy, alkenyloxy, alkylthio, alkylamino, arylthio, Arylamino, acyl, aroyl, heteroaroyl, aralkoxyalkyl, heteroaralkoxyalkyl, aryloxyalkyl, alkoxyalkyl, alkenyloxyalkyl, alkylthioalkane radical, arylthioalkyl, aralkoxyalkyl, heteroaralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, heteroaryl, heteroaryloxy, heteroaryl Amino, heteroaralkyl, heteroaralkoxy, heteroaralkylamino and heteroaryloxyalkyl;

R ¹⁴ , R ¹⁵ , R ³⁷ , R ³⁸ , R ³⁹ , R ⁴⁰ , R ⁴¹ and R ⁴² are independently selected from amidino, hydroxyamino, hydrogen, hydroxy, halogen, cyano, aryloxy, amino, alkyl Amino, dialkylamino, hydroxyalkyl, aminoalkyl, acyl, aroyl, heteroaroyl, heteroaryloxyalkyl, mercapto, acylamido, alkoxy, alkylthio, arylthio, alkyl radical, alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, aralkoxyalkylalkoxy, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkylthio Alkyl, heteroaralkoxythioalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkane alkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxy, haloalkoxyalkyl, Haloalkenyloxyalkyl, Halocycloalkoxy, Halocycloalkoxyalkyl, Halocycloalkenyloxyalkyl, Saturated Heterocyclyl, Partially Saturated Heterocyclyl, Heteroaryl, Heteroarylalkyl, heteroarylthioalkyl, heteroaralkylthioalkyl, monoalkoxycarbonylalkyl, dialkoxycarbonylalkyl, monocyanoalkyl, dicyanoalkyl, alkoxycarbonyl Cyanoalkyl, alkylsulfinyl, alkylsulfonyl, haloalkylsulfinyl, haloalkylsulfonyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, arylsulfonyl Alkyl, Aralkylsulfinyl, Aralkylsulfonyl, Cycloalkylsulfinyl, Cycloalkylsulfonyl, Cycloalkylsulfinylalkyl, Cycloalkylsulfonylalkyl, Heteroarylsulfonyl Acylalkyl, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylsulfinylalkyl, aralkylsulfinylalkyl, aralkylsulfonylalkyl, carboxy, carboxyalkyl, alkane Oxycarbonyl, carboxamide, carboxamidoalkyl, aralkoxycarbonyl, trialkylsilyl, dialkoxyphosphono, diaralkoxyphosphono, dialkoxyphosphonoalkyl and diaryl Alkoxyphosphonoalkyl, with the proviso that R ^{and R} are independently selected from groups other than formyl;

R ¹⁴ and R ¹⁴ , if bonded to different carbons, optionally together form a group selected from the group consisting of a covalent bond, an alkylene group, a haloalkylene group, and a linear partial spacer, the spacer Selecting to form a ring selected from the group consisting of a cycloalkyl ring having 5 to 8 connected members, a cycloalkenyl ring having 5 to 8 connected members, and a heterocyclyl ring having 5 to 8 connected members;

R ¹⁴ and R ¹⁵ , if bonded to different carbons, optionally together form a group selected from the group consisting of a covalent bond, an alkylene group, a haloalkylene group, and a linear partial spacer, the spacer Selecting to form a ring selected from the group consisting of a cycloalkyl ring having 5 to 8 connected members, a cycloalkenyl ring having 5 to 8 connected members, and a heterocyclyl ring having 5 to 8 connected members;

R ¹⁵ and R ¹⁵ , if bonded to different carbons, optionally together form a group selected from the group consisting of a covalent bond, an alkylene group, a haloalkylene group, and a linear partial spacer, the spacer Selecting to form a ring selected from the group consisting of a cycloalkyl ring having 5 to 8 connected members, a cycloalkenyl ring having 5 to 8 connected members, and a heterocyclyl ring having 5 to 8 connected members;

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 ³⁹ R ⁴⁰ ;

^R is selected from hydrogen, hydroxyl, amino, alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxy, aralkoxy, alkoxy, alkenyloxy, alkylthio, arylthio , aralkoxyalkyl, heteroaralkoxyalkyl, aryloxyalkyl, alkoxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, aralkoxy Alkyl, heteroaralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkane radical, haloalkyl, haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxyalkyl, halocycloalkenyloxy Alkylalkyl, heteroaryl, heteroarylalkyl, monoalkoxycarbonylalkyl, monoalkoxycarbonyl, dialkoxycarbonylalkyl, monocarboxamido, monocyanoalkyl, dicyanoalkyl, Alkoxycarbonylcyanoalkyl, acyl, aroyl, heteroaroyl, heteroaryloxyalkyl and dialkoxyphosphonoalkyl;

R ³⁹ and ⁴⁰ , if bonded to the same carbon, are optionally taken together to form a group selected from the group consisting of oxo, thio(carbonyl), R ⁵ -N, alkylene, haloalkylene, and A linear partial spacer of 2 to 7 connected atoms forming a ring selected from the group consisting of cycloalkyl rings having 3 to 8 connected members, cycloalkenyl rings having 3 to 8 connected members and cycloalkenyl rings having 3 to 8 connected members to a heterocyclyl ring of 8 connected members;

M is selected from N and R ¹ -C;

R ² and R ¹ are independently selected from Z ⁰ -Q, hydrogen, alkyl, alkenyl and halogen;

^{R is} optionally selected from amino, aminoalkyl, alkylamino, amidino, guanidino, hydroxy, hydroxyamino, alkoxy, hydroxyalkyl, alkoxyamino, thiohydroxy, alkylthio, di Alkylsulfonium, trialkylphosphonium, dialkylsulfoniumalkyl, heteroarylamino, nitro, arylamino, aralkylamino, alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl, Heteroaralkanoyl, haloalkanoyl, hydroxyhaloalkyl, cyano and phosphono;

R ^{is optionally} selected from amidino, guanidino, dialkylsulfonium, trialkylphosphonium, dialkylsulfoniumalkyl, heteroarylamino, amino, nitro, alkylamino, arylamino, aralkyl ylamino, alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, haloalkanoyl, hydroxyhaloalkyl, cyano and phosphono;

R ² and R ^4a , R ² and R ^4b , R ² and R ¹⁴ , and R ² and R ¹⁵ are optionally independently selected to form spacer pairs, wherein the spacer pairs together form a straight chain having 2 to 5 connected atoms chain moiety, linked to the bonding points of said spacer pair members to form a heterocyclyl ring having 5 to 8 linked members, provided that R ² and R ^4a , R ² and R ^4b , R ² and R ¹⁴ and At most one spacer pair of R ² and R ¹⁵ is used simultaneously;

R is optionally independently selected to form a linear moiety having 2 to 5 connected atoms, connected to the bonding point of R ^and R ^4b , forming ^a heterocyclyl ring having 5 to 8 connected members;

Z ⁰ is selected from covalent single bonds, (CR ⁴¹ R ⁴² ) _q , (CH(R ⁴¹ )) _g -W ⁰ -(CH(R ⁴² )) _p and (CH(R ⁴¹ )) _e -W ²² - (CH(R ⁴² )) _h , wherein q is an integer selected from 1 to 6, g and p are integers independently selected from 0 to 3, W ⁰ is 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) ₂ N(R ⁴¹ ), N(R ⁴¹ )S(O) ₂ , Se, Se(O), Se(O) ₂ , Se( O) ₂ N(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 ²⁸ R ²⁹ , e and h are integers independently selected from 0 to 2, W ²² is selected from CR ⁴¹ =CR ⁴² , CR ⁴¹ R ⁴² =C, vinylene), ethynylene (C≡C; 1,2-ethynyl), 1,2-cyclopropyl, 1,2-cyclobutyl, 1,2-cyclohexyl, 1 , 3-cyclohexyl, 1,2-cyclopentyl, 1,3-cyclopentyl, 2,3-morpholinyl, 2,4-morpholinyl, 2,6-morpholinyl, 3,4- Morpholinyl, 3,5-morpholinyl, 1,2-piperazinyl, 1,3-piperazinyl, 2,3-piperazinyl, 2,6-piperazinyl, 1,2-piperidine Base, 1,3-piperidinyl, 2,3-piperidinyl, 2,4-piperidinyl, 2,6-piperidinyl, 3,4-piperidinyl, 1,2-pyrrolidinyl, 1,3-pyrrolidinyl, 2,3-pyrrolidinyl, 2,4-pyrrolidinyl, 2,5-pyrrolidinyl, 3,4-pyrrolidinyl, 2,3-tetrahydrofuryl, 2,4 -tetrahydrofuryl, 2,5-tetrahydrofuryl and 3,4-tetrahydrofuryl, with the proviso that R ^and R are selected from groups other than halo and ^cyano if directly bonded to N, and ^Z is directly bonded to N uracil ring bonding;

R and ^R are independently selected from hydrogen, hydroxyalkyl, alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, ^acyl , aroyl, aralkanoyl, heteroaroyl, Aralkyloxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkylthioalkyl, alkoxyalkyl, heteroaryloxyalkyl, Alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkene radical, halocycloalkyl, halocycloalkenyl, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxy Alkyl, perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl, heteroarylalkyl, heteroarylthioalkyl, heteroaralkylthioalkyl, Cyanoalkyl, dicyanoalkyl, carboxamidoalkyl, dicarboxamidoalkyl, cyanoalkoxycarbonylalkyl, alkoxycarbonylalkyl, dialkoxycarbonylalkyl, cyanocycloalkyl , dicyanocycloalkyl, carboxamidocycloalkyl, dicarboxamidocycloalkyl, alkoxycarbonylcyanocycloalkyl, alkoxycarbonylcycloalkyl, dialkoxycarbonylcycloalkyl, formyl alkane radical, acylalkyl, arylsulfinylalkyl, arylsulfonylalkyl, aralkylsulfinyl, cycloalkylsulfinylalkyl, cycloalkylsulfonylalkyl, heteroarylsulfonyl Alkyl, heteroarylsulfinylalkyl, aralkylsulfinylalkyl, aralkylsulfonylalkyl, carboxyl, dialkoxyphosphono, diaralkoxyphosphono, dialkoxy Phosphonoalkyl and diaralkoxyphosphonoalkyl;

R ²⁸ and R ²⁹ optionally together form a linear partial spacer having 2 to 7 connected atoms and form a ring selected from the group consisting of cycloalkyl rings having 3 to 8 connected members, cycloalkyl rings having 3 to 8 connected members cycloalkenyl rings with 3 to 8 connected members and heterocyclyl rings with 3 to 8 connected members;

Q is formula (II):

wherein D ¹ , D ² , J ¹ , J ² and K ¹ are independently selected from C, N, O, S and covalent bonds, with the proviso that at most one can be a covalent bond, D ¹ , D ² , J ¹ , at most one of J ² and K ¹ can be O, at most one of D ¹ , D ² , J ¹ , J ² and K ¹ can be S, if D ¹ , D ² , J ¹ , J ² and K ¹ The second is O and S, then one of D ¹ , D ² , J ¹ , J ² and K ¹ must be a covalent bond, and at most four of D ¹ , D ² , J ¹ , J ² and K ¹ can be N , with the proviso that R ⁹ , R ¹⁰ , R ¹¹ , R ¹² and R ¹³ are each independently selected to maintain the tetravalent nature of carbon, the trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen nature;

Q is optionally selected from formula (III):

wherein D ³ , D ⁴ , J ³ and J ⁴ are independently selected from C, N, O and S ^, at most one of D ³ , D 4 , J ³ and J ⁴ is O, D ³ , D ⁴ , J ³ and At most one of J ⁴ is S and at most three of D ¹ , D ² , J ¹ and J ² are N, provided that R ⁹ , R ¹⁰ , R ¹¹ and R ¹² are each independently selected to maintain The tetravalent nature of carbon, the trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen;

Q is optionally selected from hydrogen, alkyl, alkoxy, alkylamino, alkylthio, haloalkylthio, alkenyl, alkynyl, saturated heterocyclyl, partially saturated heterocyclyl, acyl, aroyl , heteroaroyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkylalkenyl, haloalkyl, haloalkoxy, haloalkenyl, halocycloalkyl, halo Halocycloalkenyl, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxyalkyl and halocycloalkenyloxyalkyl, with the proviso that if Q is hydrogen, ^Z is selected from Groups other than covalent single bonds;

K is (CR ^4a R ^4b ) _n , wherein n is an integer selected from 1 to 4;

R ^4a and R ^4b are independently selected from halogen, hydrogen, hydroxy, cyano, hydroxyalkyl, alkyl, alkenyl, aryl, aralkyl, aralkoxyalkyl, aryloxyalkyl, alkoxy arylalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, aralkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, halo Alkenyl, Heteroaryl, Heteroarylalkyl, Heteroarylthioalkyl, Heteroaralkylthioalkyl, Cyanoalkyl, Alkylsulfinylalkyl, Alkylsulfonylalkyl, Haloalkane Alkylsulfinyl, arylsulfinylalkyl, arylsulfonylalkyl, heteroarylsulfonylalkyl, heteroarylsulfinylalkyl, aralkylsulfinylalkyl and aralkylsulfonyl Acylalkyl with the proviso that the halogen, hydroxy and cyano groups, if present simultaneously, are bonded to different carbons, and ^R4a and ^R4b cannot be hydroxy or cyano if bonded to the carbon directly bonded to the nitrogen of uracil ;

R ^4a and R ^4b , if bonded to the same carbon, optionally together form a group selected from the group consisting of oxo, thio, and a linear spacer moiety having 2 to 7 connected atoms, linking to form a group selected from Rings of the following groups: cycloalkyl rings having 3 to 8 connected members, cycloalkenyl rings having 5 to 8 connected members and heterocyclyl rings having 5 to 8 connected members, provided that, if shared carbon is directly bonded to the uracil nitrogen, then R ^4a and R ^4b together cannot be oxo or thio;

If K is (CR ^4a R ^4b ) _n , then E ⁰ is E ¹ , wherein E ¹ is 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) ₂ N(R ⁷ ), N(R ⁷ )S(O) ₂ , S(O) ₂ N(R ⁷ )C(O), C(O)N(R ⁷ )S (O) ₂ , Se, Se(O), Se(O) ₂ , Se(O) ₂ N(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 ²⁸ R ²⁹ , CR ^4a =CR ^4b , Ethynylene (C≡C; 1,2-ethynyl) and C=CR ^4a R ^4b ;

K is optionally selected as (CH(R ¹⁴ )) _j -T, wherein j is selected from integers from 0 to 3, and T is selected from covalent single bonds, O, S and N(R ⁷ ), provided that if j is 1, then R ¹⁴ cannot be hydroxyl, cyano, halogen, amino, alkylamino, dialkylamino and mercapto, (CH(R ¹⁴ )) _j is bonded to the uracil ring;

If K is (CH(R ¹⁴ )) _j -T, then E ⁰ is optionally E ² , wherein E ² is selected from covalent single bonds, 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) ₂ N(R ⁷ ), N(R ⁷ )S(O) ₂ , S(O) ₂ N(H)C(O) , C(O)N(H)S(O) ₂ , Se(O), Se(O) ₂ , Se(O) ₂ N(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 is optionally selected as G-(CH(R ¹⁵ )) _k , where k is selected from integers from 1 to 3, and G is selected from O, S and N(R ⁷ ), with the proviso that if k is 1, then R ¹⁵ cannot be hydroxyl, cyano, halogen, amino, alkylamino, dialkylamino and mercapto;

If K is G-(CH(R ¹⁵ )) _k , then E ⁰ is optionally E ³ , wherein E ³ is 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) ₂ N(R ⁷ ), N(R ⁷ )S(O) ₂ , Se, Se(O), Se(O) ₂ , Se(O) ₂ N (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 ²⁶ R ²⁹ , CR ^4a =CR ^4b , ethynylene (C≡C; 1,2-ethynyl) and C=CR ^4a R ^4b ;

Y ⁰ is formula (IV):

wherein D ⁵ , D ⁶ , J ⁵ and J ⁶ are independently selected from C, N, O, S and covalent bonds, with the proviso that at most one is a covalent bond, K ² is independently selected from C and N ⁺ , D ⁵ , at most one of D ⁶ , J ⁵ and J ⁶ is O, at most one of D ⁵ , D ⁶ , J ⁵ and J ⁶ is S, if two of D ⁵ , D ⁶ , J ⁵ and J ⁶ are O and S, then one of D ⁵ , D ⁶ , J ⁵ and J ⁶ must be a covalent bond, if K ² is N ⁺ , then at most three of D ⁵ , D ⁶ , J ⁵ and J ⁶ are N, if K ² is carbon, then at most four of D ⁵ , D ⁶ , J ⁵ and J ⁶ are N, provided that R ¹⁶ , R ¹⁷ , R ¹⁸ and R ¹⁹ are each independently selected to maintain four of the carbons. valency, nitrogen trivalent, sulfur divalent and oxygen divalent;

R ¹⁶ and R ¹⁷ independently optionally together form a linear partial spacer having 3 to 6 connected atoms, connected to form a ring selected from the group consisting of cycloalkenyl rings having 5 to 8 connected members, cycloalkenyl rings having 5 to 8 connected members, Partially saturated heterocyclyl rings with up to 8 connected members, heteroaryls with 5 to 6 connected members, and aryls;

R ¹⁸ and R ¹⁹ independently optionally together form a linear partial spacer having 3 to 6 connected atoms, connected to form a ring selected from the group consisting of cycloalkenyl rings having 5 to 8 connected members, cycloalkenyl rings having 5 to 8 connected members, Partially saturated heterocyclyl rings with up to 8 connected members, heteroaryls with 5 to 6 connected members, and aryls;

Q ^b is selected from NR ²⁰ R ²¹ , ⁺ NR ²⁰ R ²¹ R ²² , oxy, alkyl, aminoalkylene, alkylamino, dialkylamino, dialkylsulfoniumalkyl, acylamino and Q ^be , wherein ^Qbe is hydrogen and ^R20 , ^R21 and ^R22 are independently selected from hydrogen, amino, alkyl, hydroxy, alkoxy, aminoalkylene, alkylamino, dialkylamino and hydroxyalkyl, which The proviso is that at most one of R ²⁰ , R ²¹ and R ²² is simultaneously hydroxyl, alkoxy, alkylamino, amino and dialkylamino, and if K ² is N ⁺ , then R ²⁰ , R ²¹ and R ²² cannot be Hydroxy, alkoxy, alkylamino, amino and dialkylamino;

R ²⁰ and R ²¹ , R ²⁰ and R ²² , and R ²¹ and R ²² are independently optionally selected to form a spacer pair, wherein the spacer pair together forms a linear moiety having 4 to 7 connected atoms, and the spacer The bonding points of the base pair members are joined to form a heterocyclyl ring having 5 to 8 linked members, with the proviso that at most one spacer pair of ^R20 and ^R21 , ^R20 and ^R22 , and ^R21 and ^R22 is used at the same time;

Q ^b is optionally selected from N(R ²⁶ )SO ₂ N(R ²³ )(R ²⁴ ), N(R ²⁶ )C(O)OR ⁵ , N(R ²⁶ )C(O)SR ⁵ , N( R ²⁶ )C(S)OR ⁵ and N(R ²⁶ )C(S)SR ⁵ , with the proviso that if two of R ²³ , R ²⁴ and R ²⁶ are bonded to the same atom, then R ²³ , R ²⁴ and At most one of ^R can be hydroxy, alkoxy, alkyleneamino, alkylamino, amino or dialkylamino;

Q ^b is optionally selected from dialkylsulfonium, trialkylphosphonium, C(NR ²⁵ )NR ²³ R 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 ₂ N( R ²³ )(R ²⁴ ), C(NR ²⁵ )SR ⁵ , C(O)NR ²³ R ²⁴ and C(O)NR ²³ R ²⁴ , with the proviso that if any two of R ²³ , R ²⁴ and R ^{26 and} The same atom is bonded, then at most one of R ²³ , R ²⁴ and R ²⁶ can be hydroxyl, alkoxy, alkylamino, amino or dialkylamino, and the Q ^b group is directly bonded to a carbon atom;

R ²³ , R ²⁴ , R ²⁵ and R ²⁶ are independently selected from hydrogen, alkyl, hydroxy, alkoxy, alkyleneamino, amino, alkylamino, dialkylamino and hydroxyalkyl;

R ²³ and R ²⁴ optionally together form a linear spacer moiety having 4 to 7 linked atoms joined to the point of bonding to form a heterocyclyl ring having 5 to 8 linked members;

R ²³ and R ²⁵ , R ²⁴ and R ²⁵ , R ²⁵ and R ²⁶ , R ²⁴ and R ²⁶ , and R ²³ and R ²⁶ are independently optionally selected to form a spacer pair, wherein the spacer pair and the selected spacer The bonding points of the members together form the group LUV, 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) ₂ POP(O) ₂ , R ³⁰ (O)POP(O)R ³⁰ , Si(R ²⁹ )R ²⁸ , Si(R ²⁹ )R ²⁸ Si(R ²⁹ )R ²⁸ , Si(R ²⁹ )R ²⁸ OSi(R ²⁹ )R ²⁸ , ( R ²⁸ )R ²⁹ COC(R ²⁸ )R ²⁹ , (R ²⁸ )R ²⁹ CSC(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 ₂ C(R ³⁰ )=C(R ³¹ ), PR ³⁰ C(R ³⁰ )=C(R ³¹ ), P(O)R ³⁰ C(R ³⁰ )=C(R ³¹ ), P(S)R ³⁰ C(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 bonds, provided that L, U and V are at most Any two are covalently bonded at the same time, and the heterocyclyl ring consisting of L, U and V has 5 to 10 connected members;

D is selected from oxygen, C=O, C=S, S(O) _m , wherein m is an integer selected from 0 to 2;

J _H is independently selected from OR ²⁷ , SR ²⁷ and N(R ²⁰ )R ²¹ ;

^R is selected from hydrogen, alkyl, alkenyl, alkynyl, aralkyl, aryloxyalkyl, aralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkylthio arylalkyl, heteroaralkylthioalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkyl Alkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxyalkyl, haloalkenyloxy Alkyl, halocycloalkoxyalkyl, halocycloalkenyloxyalkyl, perhaloaryloxyalkyl, heteroaryl, heteroarylalkyl, heteroarylthioalkyl, heteroarylalkyl Thioalkyl, Arylsulfinylalkyl, Arylsulfonylalkyl, Cycloalkylsulfinylalkyl, Cycloalkylsulfonylalkyl, Heteroarylsulfonylalkyl, Heteroarylsulfinyl Acylalkyl, aralkylsulfinylalkyl and aralkylsulfonylalkyl;

R and ^R are independently selected from hydrogen, ^hydroxy , mercapto, aryloxy, amino, alkylamino, dialkylamino, hydroxyalkyl, heteroaryloxyalkyl, alkoxy, alkylthio, aryl Thio, alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, aralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkylthio arylalkyl, heteroaralkoxythioalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, cyclo Alkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, haloaralkylsulfinylalkyl, aralkylsulfonylalkyl, cyano Alkyl, dicyanoalkyl, carboxamidoalkyl, dicarboxamidoalkyl, cyanoalkoxycarbonylalkyl, alkoxycarbonylalkyl, dialkoxycarbonylalkyl, cyanocycloalkyl, di Cyanocycloalkyl, carboxamidocycloalkyl, dicarboxamidocycloalkyl, alkoxycarbonylcyanocycloalkyl, alkoxycarbonylcycloalkyl, dialkoxycarbonylcycloalkyl, formylalkyl, Acylalkyl, Dialkoxyphosphonoalkyl, Diaralkoxyphosphonoalkyl, Phosphonoalkyl, Dialkoxyphosphonoalkoxy, Diaralkoxyphosphonoalkoxy, Phosphine Acylalkoxy, dialkoxyphosphonoalkylamino, diaralkoxyphosphonoalkylamino, phosphonoalkylamino, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl , sulfonylalkyl, alkoxysulfonylalkyl, aralkoxysulfonylalkyl, alkoxysulfonylalkoxy, aralkoxysulfonylalkoxy, sulfonylalkoxy, alkoxy Sulfonylalkylamino, aralkoxysulfonylalkylamino and sulfonylalkylamino;

R and R ^{are optionally} taken together to form a linear partial spacer having 2 to 7 connected atoms forming a ring selected from the group consisting of cycloalkyl rings having 3 to 8 connected members, cycloalkyl rings having 3 to 8 connected members Cycloalkenyl rings with linked members and heterocyclyl rings with 3 to 8 linked members;

R ²³ and R ²⁵ , R ²⁴ and R ²⁵ , R ²⁵ and R ²⁶ , R ²⁴ and R ²⁶ , and R ²³ and R ²⁶ are independently optionally selected to form a spacer pair, wherein the spacer pair and the selected spacer The points of bonding of the members together form the group LUV, wherein L, U and V are independently selected from the group consisting of cycloalkyl, cycloalkenyl, aryl, heteroaryl, saturated heterocycle and partially saturated heterocyclyl A 1,2-disubstituted group, wherein the cycloalkyl and cycloalkenyl are substituted by one or more groups selected from R ³⁰ and R ³¹ , wherein the 1,2-substituents are 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 ³⁰ , and Si( R ²⁸ ) R ²⁹ ;

R ²³ and R ²⁵ , R ²⁴ and R ²⁵ , R ²⁵ and R ²⁶ , R ²⁴ and R ²⁶ , and R ²³ and R ²⁶ are independently optionally selected to form a spacer pair, wherein the spacer pair and the selected spacer The bonding points of the members together form a group LUV, wherein L, U and V are independently selected from the group consisting of 1,2-disubstituted alkylene and 1,2-disubstituted alkenylene, wherein The 1,2-substituents are 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 ³⁰ and Si(R ²⁸ )R ²⁹ , the alkylene and alkenylene groups are substituted by one or more R ³⁰ or R ³¹ substituents;

Q ^s is selected from covalent single bond, (CR ³⁷ R ³⁸ ) _b -(W ⁰ ) _az , (CH(R ¹⁴ )) _c -W ¹ -(CH(R ¹⁵ )) _d and (CH(R ¹⁴ ) ) _e -W ²² -(CH(R ¹⁵ )) _h , wherein az is an integer selected from 0 to 1, b is an integer selected from 1 to 4, W ⁰ is 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 ⁴ )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) ₂ N(R ¹⁴ ), N(R ¹⁴ )S(O) ₂ , Se, Se (O), Se(O) ₂ , Se(O) ₂ N(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 ²⁸ R ²⁹ , c and d are integers independently selected from 1 to 4, W ¹ is 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) ₂ N(R ¹⁴ ), N(R ¹⁴ )S(O) ₂ , Se, Se(O), Se(O) ₂ , Se(O) ₂ N(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 ²⁸ R ²⁹ , e and h are independently selected from 0 to An integer of 2, W ²² is selected from CR ⁴¹ =CR ⁴² , CR ⁴¹ R ⁴² =C, vinylene), ethynylene (C≡C; 1,2-ethynyl), 1,2-cyclopropyl, 1,2-cyclobutyl, 1,2-cyclohexyl, 1,3-cyclohexyl, 1,2-cyclopentyl, 1,3-cyclopentyl, 2,3-morpholinyl, 2,4- Morpholinyl, 2,6-morpholinyl, 3,4-morpholinyl, 3,5-morpholinyl, 1,2-piperazinyl, 1,3-piperazinyl, 2,3-piperazinyl Base, 2,6-piperazinyl, 1,2-piperidinyl, 1,3-piperidinyl, 2,3-piperidinyl, 2,4-piperidinyl, 2,6-piperidinyl, 3,4-piperidinyl, 1,2-pyrrolidinyl, 1,3-pyrrolidinyl, 2,3-pyrrolidinyl, 2,4-pyrrolidinyl, 2,5-pyrrolidinyl, 3, 4-pyrrolidinyl, 2,3-tetrahydrofuranyl, 2,4-tetrahydrofuryl, 2,5-tetrahydrofuryl and ^3,4 -tetrahydrofuryl, with the proviso that R ^and R are selected if they are directly bonded to N From groups other than halo and cyano, (CR ³⁷ R ³⁸ ) _b , (CH(R ¹⁴ )) _c , (CH(R ¹⁴ )) _e are directly bonded to E ⁰ ;

^R37 and ^R37 , if bonded to different carbons, are optionally taken together to form a linear partial spacer having 1 to 7 connected atoms, forming a ring selected from the group consisting of cycloalkanes having 3 to 8 connected members Cycloalkenyl rings, cycloalkenyl rings with 3 to 8 connected members, and heterocyclyl rings with 3 to 8 connected members;

^R37 and ^R38 , if bonded to different carbons, together form a linear partial spacer having 1 to 7 connected atoms, forming a ring selected from the group consisting of cycloalkyl rings having 3 to 8 connected members, Cycloalkenyl rings having 3 to 8 connected members and heterocyclyl rings having 3 to 8 connected members;

^R38 and ^R38 , if bonded to different carbons, together form a linear partial spacer having 1 to 7 connected atoms, forming a ring selected from the group consisting of cycloalkyl rings having 3 to 8 connected members, Cycloalkenyl rings having 3 to 8 connected members and heterocyclyl rings having 3 to 8 connected members;

R ³⁷ and R ³⁸ , if bonded to the same carbon, together form a group selected from the group consisting of oxo, thio, alkylene, haloalkylene, and straight chain moieties having 2 to 7 connected atoms A spacer forming a ring selected from the group consisting of a cycloalkyl ring having 3 to 8 connected members, a cycloalkenyl ring having 3 to 8 connected members, and a heterocyclyl ring having 3 to 8 connected members;

Y ⁰ is optionally Q ^b -Q ^ss , wherein Q ^ss is selected from (CR ³⁷ R ³⁸ ) _f , (CH(R ¹⁴ )) _c -W ¹ -(CH(R ¹⁵ )) _d and (CH(R 15 )) d ¹⁴ )) _e -W ² -(CH(R ¹⁵ )) _h , wherein f is an integer selected from 1 to 6, c and d are integers independently selected from 1 to 4, W ¹ is 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) ₂ N(R ¹⁴ ), N(R ¹⁴ )S(O) ₂ , Se, Se(O), Se(O) ₂ , Se(O) ₂ N(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 ²⁸ R ²⁹ , e and h are integers independently selected from 0 to 2, W ² is selected from CR ^4a =CR ^4b , ethynylene (C≡C; 1,2-ethynyl) and C=CR ^4a R ^4b with the proviso that R ¹⁴ and R ¹⁵ if directly bonded to N are selected from the group consisting of halogenated and Groups other than cyano, (CR ³⁷ R ³⁸ ) _f , (CH(R ¹⁵ )) _c and (CH(R ¹⁵ )) _e bonded to E ⁰ , if Q ^ss is (CR ³⁷ R ³⁸ ) _f , where f is not an integer 1, then Q ^b is selected from the group consisting of N(R ²⁶ )N(R ²⁶ )C(NR ²⁵ )N(R ²³ )(R ²⁴ ) or ON(R ²⁶ )C(NR ²⁵ )N(R ²³ ) groups other than (R ²⁴ );

Y ⁰ is optionally Q ^b -Q ^sss , wherein Q ^sss is (CH(R ³⁸ )) _r -W ³ , wherein r is an integer selected from 1 to 3, and W ³ is selected from 1,1-cyclopropyl , 1,2-cyclopropyl, 1,1-cyclobutyl, 1,2-cyclobutyl, 1,2-cyclohexyl, 1,3-cyclohexyl, 1,4-cyclohexyl, 1,2- Cyclopentyl, 1,3-cyclopentyl, 2,3-morpholinyl, 2,4-morpholinyl, 2,5-morpholinyl, 2,6-morpholinyl, 3,4-morpholinyl Base, 3,5-morpholinyl, 1,2-piperazinyl, 1,3-piperazinyl, 1,4-piperazinyl, 2,3-piperazinyl, 2,5-piperazinyl, 2,6-piperazinyl, 1,2-piperidinyl, 1,3-piperidinyl, 1,4-piperidinyl, 2,3-piperidinyl, 2,4-piperidinyl, 2, 5-piperidinyl, 2,6-piperidinyl, 3,4-piperidinyl, 3,5-piperidinyl, 3,6-piperidinyl, 1,2-pyrrolidinyl, 1,3- Pyrrolidinyl, 2,3-pyrrolidinyl, 2,4-pyrrolidinyl, 2,5-pyrrolidinyl, 3,4-pyrrolidinyl, 2H-2,3-pyranyl, 2H-2, 4-pyranyl, 2H-2,5-pyranyl, 4H-2,3-pyranyl, 4H-2,4-pyranyl, 4H-2,5-pyranyl, 2H-pyranyl -2-keto-3,4-yl, 2H-pyran-2-one-4,5-yl, 4H-pyran-4-one-2,3-yl, 2,3-tetrahydrofuryl, 2, 4-tetrahydrofuryl, 2,5-tetrahydrofuryl, 3,4-tetrahydrofuryl, 2,3-tetrahydropyranyl, 2,4-tetrahydropyranyl, 2,5-tetrahydropyranyl, 2 , 6-tetrahydropyranyl, 3,4-tetrahydropyranyl and 3,5-tetrahydropyranyl, each of the W ^ring nitrogen members containing carbon and hydrogen is optionally Substituted by one or more groups selected from R ⁹ , R ¹⁰ , R ¹¹ and R ¹² with the proviso that (CH(R ³⁸ )) _r is bonded to E ⁰ and Q ^b is the lowest number of each W ³ Substituent position bonding;

Y ⁰ is optionally Q ^b -Q ^sssr , wherein Q ^sssr is (CH(R ³⁸ )) _r -W ⁴ , wherein r is an integer selected from 1 to 3, and W ⁴ is selected from 1,2-cyclobutyl , 1,2-cyclohexyl, 1,3-cyclohexyl, 1,4-cyclohexyl, 1,2-cyclopentyl, 1,3-cyclopentyl, 2,3-morpholinyl, 2,4- Morpholinyl, 2,5-morpholinyl, 2,6-morpholinyl, 3,4-morpholinyl, 3,5-morpholinyl, 1,2-piperazinyl, 1,3-piperazine Base, 1,4-piperazinyl, 2,3-piperazinyl, 2,5-piperazinyl, 2,6-piperazinyl, 1,2-piperidinyl, 1,3-piperidinyl, 1,4-piperidinyl, 2,3-piperidinyl, 2,4-piperidinyl, 2,5-piperidinyl, 2,6-piperidinyl, 3,4-piperidinyl, 3, 5-piperidinyl, 3,6-piperidinyl, 1,2-pyrrolidinyl, 1,3-pyrrolidinyl, 2,3-pyrrolidinyl, 2,4-pyrrolidinyl, 2,5- Pyrrolidinyl, 3,4-pyrrolidinyl, 2H-2,3-pyranyl, 2H-2,4-pyranyl, 2H-2,5-pyranyl, 4H-2,3-pyranyl Base, 4H-2,4-pyranyl, 4H-2,5-pyranyl, 2H-pyran-2-one-3,4-yl, 2H-pyran-2-one-4,5- Base, 4H-pyran-4-one-2,3-yl, 2,3-tetrahydrofuryl, 2,4-tetrahydrofuryl, 2,5-tetrahydrofuryl, 3,4-tetrahydrofuryl, 2,3-tetrahydrofuryl Hydropyranyl, 2,4-tetrahydropyranyl, 2,5-tetrahydropyranyl, 2,6-tetrahydropyranyl, 3,4-tetrahydropyranyl and 3,5-tetrahydropyranyl Hydropyranyl, except for the point of attachment, each W ^ring nitrogen member containing carbon and hydrogen is optionally substituted with one or more groups selected from R ⁹ , R ¹⁰ , R ¹¹ and R ¹² , which provided that (CH( ^R38 )) _r is bonded to ^E0 and ^Qb is bonded to the highest numbered substituent position of each ^W4 ;

Y ⁰ is optionally Q ^b -Q ^ssss , wherein Q ^ssss is (CH(R ³⁸ )) _r -W ⁵ , wherein r is an integer selected from 1 to 3, and W ⁵ is selected from 1,4-indenyl, 1,5-indenyl, 1,6-indenyl, 1,7-indenyl, 2,7-indenyl, 2,6-indenyl, 2,5-indenyl, 2,4-indenyl, 3 , 4-indenyl, 3,5-indenyl, 3,6-indenyl, 3,7-indenyl, 2,4-benzofuryl, 2,5-benzofuryl, 2,6-benzene And furyl, 2,7-benzofuryl, 3,4-benzofuryl, 3,5-benzofuryl, 3,6-benzofuryl, 3,7-benzofuryl, 2 , 4-benzothienyl, 2,5-benzothienyl, 2,6-benzothienyl, 2,7-benzothienyl, 3,4-benzothienyl, 3,5-benzothienyl Thienyl, 3,6-benzothienyl, 3,7-benzothienyl, 2,4-imidazo(1,2-a)pyridyl, 2,5-imidazo(1,2-a) Pyridyl, 2,6-imidazo(1,2-a)pyridyl, 2,7-imidazo(1,2-a)pyridyl, 3,4-imidazo(1,2-a)pyridyl , 3,5-imidazo(1,2-a)pyridyl, 3,6-imidazo(1,2-a)pyridyl, 3,7-imidazo(1,2-a)pyridyl, 2 , 4-indolyl, 2,5-indolyl, 2,6-indolyl, 2,7-indolyl, 3,4-indolyl, 3,5-indolyl, 3,6 -indolyl, 3,7-indolyl, 1,4-isoindolyl, 1,5-isoindolyl, 1,6-isoindolyl, 2,4-isoindolyl, 2 , 5-isoindolyl, 2,6-isoindolyl, 2,7-isoindolyl, 1,3-isoindolyl, 3,4-indazolyl, 3,5-indazolyl , 3,6-indazolyl, 3,7-indazolyl, 2,4-benzoxazolyl, 2,5-benzoxazolyl, 2,6-benzoxazolyl, 2,7 -Benzoxazolyl, 3,4-benzisoxazolyl, 3,5-benzisoxazolyl, 3,6-benzisoxazolyl, 3,7-benzisoxazolyl , 1,4-naphthyl, 1,5-naphthyl, 1,6-naphthyl, 1,7-naphthyl, 1,8-naphthyl, 2,4-naphthyl, 2,5-naphthyl, 2,6-naphthyl, 2,7-naphthyl, 2,8-naphthyl, 2,4-quinolinyl, 2,5-quinolinyl, 2,6-quinolinyl, 2,7-quinolinyl Linyl, 2,8-quinolyl, 3,4-quinolyl, 3,5-quinolyl, 3,6-quinolyl, 3,7-quinolyl, 3,8-quinolyl , 4,5-quinolinyl, 4,6-quinolinyl, 4,7-quinolinyl, 4,8-quinolinyl, 1,4-isoquinolinyl, 1,5-isoquinolinyl , 1,6-isoquinolinyl, 1,7-isoquinolinyl, 1,8-isoquinolinyl, 3,4-isoquinolinyl, 3,5-isoquinolinyl, 3,6- Isoquinolinyl, 3,7-isoquinolinyl, 3,8-isoquinolinyl, 4,5-isoquinolinyl, 4,6-isoquinolinyl, 4,7-isoquinolinyl, 4,8-isoquinolinyl, 3,4-cinnolinyl, 3,5-cinnolinyl, 3,6-cinnolinyl, 3,7-cinnolinyl, 3,8-cinnolinyl, 4 , 5-cinnolinyl, 4,6-cinnolinyl, 4,7-cinnolinyl and 4,8-cinnolinyl, except for the point of attachment, each W ^ring nitrogen member containing carbon and hydrogen is any is optionally substituted with one or more groups selected from R ⁹ , R ¹⁰ , R ¹¹ and R ¹² with the proviso that Q ^b is bonded to the lowest numbered substituent position of each W ⁵ , (CH(R ³⁸ )) _r is bonded to E ⁰ ;

Y ⁰ is optionally Q ^b -Q ^ssssr , wherein Q ^ssssr is (CH(R ³⁸ )) _r -W ⁶ , wherein r is an integer selected from 1 to 3, and W ⁶ is selected from 1,4-indenyl, 1,5-indenyl, 1,6-indenyl, 1,7-indenyl, 2,7-indenyl, 2,6-indenyl, 2,5-indenyl, 2,4-indenyl, 3 , 4-indenyl, 3,5-indenyl, 3,6-indenyl, 3,7-indenyl, 2,4-benzofuryl, 2,5-benzofuryl, 2,6-benzene And furyl, 2,7-benzofuryl, 3,4-benzofuryl, 3,5-benzofuryl, 3,6-benzofuryl, 3,7-benzofuryl, 2 , 4-benzothienyl, 2,5-benzothienyl, 2,6-benzothienyl, 2,7-benzothienyl, 3,4-benzothienyl, 3,5-benzothienyl Thienyl, 3,6-benzothienyl, 3,7-benzothienyl, 2,4-imidazo(1,2-a)pyridyl, 2,5-imidazo(1,2-a) Pyridyl, 2,6-imidazo(1,2-a)pyridyl, 2,7-imidazo(1,2-a)pyridyl, 3,4-imidazo(1,2-a)pyridyl , 3,5-imidazo(1,2-a)pyridyl, 3,6-imidazo(1,2-a)pyridyl, 3,7-imidazo(1,2-a)pyridyl, 2 , 4-indolyl, 2,5-indolyl, 2,6-indolyl, 2,7-indolyl, 3,4-indolyl, 3,5-indolyl, 3,6 -indolyl, 3,7-indolyl, 1,4-isoindolyl, 1,5-isoindolyl, 1,6-isoindolyl, 2,4-isoindolyl, 2 , 5-isoindolyl, 2,6-isoindolyl, 2,7-isoindolyl, 1,3-isoindolyl, 3,4-indazolyl, 3,5-indazolyl , 3,6-indazolyl, 3,7-indazolyl, 2,4-benzoxazolyl, 2,5-benzoxazolyl, 2,6-benzoxazolyl, 2,7 -Benzoxazolyl, 3,4-benzisoxazolyl, 3,5-benzisoxazolyl, 3,6-benzisoxazolyl, 3,7-benzisoxazolyl , 1,4-naphthyl, 1,5-naphthyl, 1,6-naphthyl, 1,7-naphthyl, 1,8-naphthyl, 2,4-naphthyl, 2,5-naphthyl, 2,6-naphthyl, 2,7-naphthyl, 2,8-naphthyl, 2,4-quinolinyl, 2,5-quinolinyl, 2,6-quinolinyl, 2,7-quinolinyl Linyl, 2,8-quinolyl, 3,4-quinolyl, 3,5-quinolyl, 3,6-quinolyl, 3,7-quinolyl, 3,8-quinolyl , 4,5-quinolinyl, 4,6-quinolinyl, 4,7-quinolinyl, 4,8-quinolinyl, 1,4-isoquinolinyl, 1,5-isoquinolinyl , 1,6-isoquinolinyl, 1,7-isoquinolinyl, 1,8-isoquinolinyl, 3,4-isoquinolinyl, 3,5-isoquinolinyl, 3,6- Isoquinolinyl, 3,7-isoquinolinyl, 3,8-isoquinolinyl, 4,5-isoquinolinyl, 4,6-isoquinolinyl, 4,7-isoquinolinyl, 4,8-isoquinolinyl, 3,4-cinnolinyl, 3,5-cinnolinyl, 3,6-cinnolinyl, 3,7-cinnolinyl, 3,8-cinnolinyl, 4 , 5-cinnolinyl, 4,6-cinnolinyl, 4,7-cinnolinyl and 4,8-cinnolinyl, except for the point of attachment, each W ^ring nitrogen member containing carbon and hydrogen is any is optionally substituted with one or more groups selected from R ⁹ , R ¹⁰ , R ¹¹ and R ¹² with the proviso that Q ^b is bonded to the highest numbered substituent position of each W ⁵ , (CH(R ³⁸ ) ) _r is bonded to E ⁰ .

In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof,

J ^a and J ^b are independently selected from O and S;

B is formula (V):

wherein D ¹ , D ² , J ¹ , J ² and K ¹ are independently selected from C, N, O, S and covalent bonds, with the proviso that at most one can be a covalent bond, D ¹ , D ² , J ¹ , at most one of J ² and K ¹ is O, at most one of D ¹ , D ² , J ¹ , J ² and K ¹ is S, if two of D ¹ , D ² , J ¹ , J ² and K ¹ are O and S, then one of D ¹ , D ² , J ¹ , J ² and K ¹ must be a covalent bond, and at most four of D ¹ , D ² , J ¹ , J ² and K ¹ are N, the condition is R ³² , R ³³ , R ³⁴ , R ³⁵ and R ³⁶ are each independently selected to maintain the tetravalent nature of carbon, the trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature 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 ³⁵ and R ³⁶ are independently selected from hydrogen, acetamido, Haloacetamido, amidino, guanidino, dialkylsulfonium, trialkylphosphonium, dialkylsulfoniumalkyl, carboxyl, heteroaralkylthio, heteroaralkoxy, cycloalkylamino, acylalkyl , Acylalkoxy, Aroylalkoxy, Heterocyclyl, Aralkylaryl, Aralkyl, Aralkenyl, Aralkynyl, Heterocyclyl, Perhalogenated Aralkyl, Aralkylsulfonyl Acyl, aralkylsulfonylalkyl, aralkylsulfinyl, aralkylsulfinylalkyl, halocycloalkyl, halocycloalkenyl, cycloalkylsulfinyl, cycloalkylsulfinyl Acylalkyl, cycloalkylsulfonyl, cycloalkylsulfonylalkyl, heteroarylamino, N-heteroarylamino-N-alkylamino, heteroarylaminoalkyl, haloalkylthio, alkanoyloxy radical, alkoxy, alkoxyalkyl, haloalkoxyalkyl, heteroaralkoxy, cycloalkoxy, cycloalkenyloxy, cycloalkoxyalkyl, cycloalkylalkoxy, cycloalkene Oxyalkyl, cycloalkenedioxy, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxy, halocycloalkenyloxyalkyl, hydroxy, amino, alkoxy Amino, thio, nitro, lower alkylamino, alkylthio, alkylthioalkyl, arylamino, aralkylamino, arylthio, arylthioalkyl, heteroaralkoxyalkyl , Alkylsulfinyl, Alkylsulfinylalkyl, Arylsulfinylalkyl, Arylsulfonylalkyl, Heteroarylsulfinylalkyl, Heteroarylsulfonylalkyl, Alkylsulfonyl Acyl, alkylsulfonylalkyl, haloalkylsulfinylalkyl, haloalkylsulfonylalkyl, alkylsulfonylamino, alkylaminosulfonyl, amidosulfonyl, monoalkylamidosulfonyl, di Alkyl amidosulfonyl, one aryl amidosulfonyl, aryl sulfonyl amino, diaryl amido sulfonyl, one alkyl-aryl amido sulfonyl, aryl sulfinyl, aryl sulfonyl , heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, heterocyclylsulfonyl, heterocyclylthio, alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl, heteroaryl Alkanoyl, haloalkanoyl, alkyl, alkenyl, alkynyl, alkenyloxy, alkenyloxyalkyl, alkylenedioxy, haloalkanedioxy, cycloalkyl, cycloalkylalkanoyl, cyclo Alkenyl, lower cycloalkylalkyl, lower cycloalkenylalkyl, halogen, haloalkyl, haloalkenyl, haloalkoxy, hydroxyhaloalkyl, hydroxyaralkyl, hydroxyalkyl, alkenylamino, hydroxyhetero Aralkyl, haloalkoxyalkyl, aryl, aralkyl, aryloxy, aralkoxy, aryloxyalkyl, saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl, hetero Aryloxy, heteroaryloxyalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, carboxyalkyl, alkoxycarbonyl, alkoxycarboxamido, alkyl Amidocarbonylamido, arylamidocarbonylamido, alkoxycarbonylalkyl, alkoxycarbonylalkenyl, carboxyl, aralkoxycarbonyl, carboxamido, carboxamidoalkyl, cyano, haloalkoxycarbonyl, Phosphono, phosphonoalkyl, diaralkoxyphosphono and diaralkoxyphosphonoalkyl;

R ¹⁶ , R ¹⁹ , R ³² , R ³³ , R ³⁴ , R ³⁵ and R ³⁶ are independently optionally Q ^b with the proviso that at most one of R ¹⁶ and R ¹⁹ is simultaneously Q ^b and Q ^b is Q ^be ;

R ³² and R ³³ , R ³³ and R ³⁴ , R ³⁴ and R ³⁵ , and R ³⁵ and R ³⁶ are independently optionally selected to form a spacer pair, wherein the spacer pair together forms a linear chain having 3 to 6 connected atoms Moiety, attached to the bonding point of the spacer pair members to form a ring selected from the group consisting of a cycloalkenyl ring having 5 to 8 attached members, a partially saturated heterocyclyl ring having 5 to 8 attached members, Heteroaryl rings having 5 to 6 connected members, and aryl, with the proviso that at most one spacer pair of ^R32 and ^R33 , ^R33 and ^R34 , ^R34 and ^R35 and ^R35 and ^R36 are used simultaneously;

R ⁹ and R ¹⁰ , R ¹⁰ and R ¹¹ , R ¹¹ and R ¹² , and R ¹² and R ¹³ are independently optionally selected to form a spacer pair, wherein the spacer pair together forms a linear chain having 3 to 6 connected atoms Moiety, attached to the bonding point of the spacer pair members to form a ring selected from the group consisting of a cycloalkenyl ring having 5 to 8 attached members, a partially saturated heterocyclyl ring having 5 to 8 attached members, Heteroaryl rings having 5 to 6 connected members, and aryl, with the proviso that at most one spacer pair of R ⁹ and R ¹⁰ , R ¹⁰ and R ¹¹ , R ¹¹ and R ¹² and R ¹² and R ¹³ are used simultaneously;

B is optionally selected from hydrogen, trialkylsilyl, C2-C8 alkyl, C3-C8 alkenyl, C3-C8 alkylene, C3-C8 alkynyl, C2-C8 haloalkyl and C3-C8 halo Alkenyl, wherein each member of group B can optionally be replaced by one or more groups R ³² , R ³³ , R ³⁴ , on any carbon up to and including 6 atoms from the point of attachment of B to A. R ³⁵ and R ³⁶ are substituted;

B is optionally selected from C3-C15 cycloalkyl, C5-C10 cycloalkenyl, C4-C12 saturated heterocyclyl and C4-C9 partially saturated heterocyclyl, wherein each ring carbon is optionally replaced by ^R33 Substituted, ring carbons other than the ring carbon at the point of attachment of B and A are optionally substituted with oxo, provided that at most one ring carbon is simultaneously substituted with oxo, the ring carbon adjacent to the ring carbon at the point of attachment is substituted with The nitrogen atom is optionally substituted by ^R9 or ^R13 , and the ring carbon or nitrogen atom adjacent to the ^R9 position and two atoms away from the point of attachment is optionally substituted by ^R10 , adjacent to the ^R13 position and two atoms away from the point of attachment Two atoms of the ring carbon or nitrogen atom are optionally substituted by R ¹² , three atoms from the point of attachment and the ring carbon or nitrogen atom adjacent to the ¹⁰ position of R is optionally substituted by R ¹¹ , three atoms from the point of attachment And the ring carbon or nitrogen atom adjacent to the R ¹² position is optionally substituted by R ³³ , and the ring carbon or nitrogen atom adjacent to the R ¹¹ and R ³³ positions four atoms away from the connection point is optionally substituted by R ³⁴ ;

A is selected from covalent single bonds, (W ⁷ ) _rr -(CH(R ¹⁵ )) _pa and (CH(R ¹⁵ )) _pa -(W ⁷ ) _rr , where rr is an integer selected from 0 to 1, pa is an integer selected from 0 to 6, W ⁷ is 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) ₂ N(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 ⁷ and N(R ⁷ ), with the proviso that at most one of rr and pa can be 0 at the same time;

R and ^R are independently selected from hydrogen, hydroxy, alkyl, acyl, aroyl, heteroaroyl ^, and alkoxyalkyl;

R ¹⁴ , R ¹⁵ , R ³⁷ and R ³⁸ are independently selected from hydrogen, hydroxy, halogen, cyano, hydroxyalkyl, alkoxy, alkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl , cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxy, halocycloalkoxy Alkyl, halocycloalkenyloxyalkyl, carboxy, carboxyalkyl, alkoxycarbonyl, carboxamide and carboxamidoalkyl;

R and ^R may be independently selected from acyl, aroyl ^and heteroaroyl, with the proviso that the acyl group is selected from groups other than formyl;

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 ³⁹ R ⁴⁰ ;

^R is selected from hydrogen, hydroxy, amino, alkyl, alkoxy, alkoxyalkyl, haloalkyl, acyl, aroyl and heteroaroyl;

R and ^R are independently selected from hydrogen, hydroxy, halogen, cyano, hydroxyalkyl, acyl, aroyl, heteroaroyl, acylamido, alkoxy ^, alkyl, alkoxyalkyl, haloalkyl , haloalkoxy, haloalkoxyalkyl, alkylsulfonyl, haloalkylsulfonyl, carboxy, carboxyalkyl, alkoxycarbonyl, carboxamide and carboxamidoalkyl;

M is selected from N and R ¹ -C;

R ² and R ¹ are independently selected from Z ⁰ -Q, hydrogen, alkyl, alkenyl and halogen;

^R is optionally selected from amino, aminoalkyl, alkylamino, amidino, guanidino, hydroxy, hydroxyamino, alkoxy, hydroxyalkyl, alkoxyamino, thiohydroxy, alkylthio,

1-Q ^b -4-Q ^s -2-R ¹⁵ -3-R ¹⁷ -5-R ¹⁸ -6-R ¹⁹ benzene, 2-Q ^b -5-Q ^s -6-R ¹⁷ -4-R ¹⁸ -2-R ¹⁹ pyridine, 3-Q ^b -6-Q ^s -2-R ¹⁶ -5-R ¹⁸ -4-R ¹⁹ pyridine, 3-Q ^b -5-Q ^s -4-R ¹⁶ -2- R ¹⁹ thiophene and 2-Q ^b -5-Q ^s -3-R ¹⁶ -4-R ¹⁷ thiophene;

R and ^R are independently selected from hydrogen, amidino, amino, ^aminomethyl , methoxy, methylamino, hydroxyl, hydroxymethyl, fluoro, chloro and cyano;

R ¹⁶ and R ¹⁹ are optionally Q ^b with the proviso that at most one of R ¹⁶ and R ¹⁹ is Q ^b at the same time, and Q ^b is Q ^be ;

R and ^R are independently selected from hydrogen, fluorine, ^chlorine , hydroxyl, hydroxymethyl, amino, carboxyl and cyano;

^{Qb is} selected from ^Qbe and C( ^NR25 ) ^NR23R24 , wherein ^Qbe is hydrogen;

R ²³ , R ²⁴ and R ²⁵ are independently selected from hydrogen and methyl;

^Qs is _CH2 .

12. A compound of the formula according to claim 9:

or a pharmaceutically acceptable salt thereof, wherein:

B is selected from aryl and heteroaryl, wherein one carbon adjacent to the carbon at the point of attachment is ^optionally substituted with R and the other carbon adjacent to the carbon at the point of attachment is ^optionally substituted with R, the carbon adjacent to ^R32 and two atoms away from the carbon on the point of attachment is optionally substituted by ^R33 , the carbon adjacent to ^R36 and two atoms away from the carbon on the point of attachment is optionally substituted by ^R35 , Any carbon adjacent to both R ³³ and R ³⁵ is optionally substituted by R ³⁴ ;

R ³² , R ³³ , R ³⁴ , R ³⁵ and R ³⁶ are independently selected from hydrogen, acetamido, haloacetamido, amidino, guanidino, alkoxy, hydroxyl, amino, alkoxyamino, lower alkyl Amino, alkylthio, amidosulfonyl, monoalkylamidosulfonyl, dialkylamidosulfonyl, alkyl, halogen, haloalkyl, haloalkoxy, hydroxyalkyl, alkoxycarbonyl, cycloalkane Oxy, halocycloalkoxyalkyl, halocycloalkenyloxyalkyl, saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl, heteroarylalkyl, heteroarylthioalkyl, Heteroaralkylthioalkyl, Alkylsulfonyl, Haloalkylsulfonyl, Arylsulfonyl, Arylsulfonylalkyl, Aralkylsulfonyl, Cycloalkylsulfonyl, Cycloalkylsulfonylalkyl, Heteroarylsulfonylalkyl, heteroarylsulfonyl and aralkylsulfonylalkyl;

Q is formula (II):

wherein D ¹ , D ² , J ¹ , J ² and K ¹ are independently selected from C, N, O, S and covalent bonds, with the proviso that at most one can be a covalent bond, D ¹ , D ² , J ¹ , at most one of J ² and K ¹ is O, at most one of D ¹ , D ² , J ¹ , J ² and K ¹ is S, if two of D ¹ , D ² , J ¹ , J ² and K ¹ are O and S, then one of D ¹ , D ² , J ¹ , J ² and K ¹ must be a covalent bond, and at most four of D ¹ , D ² , J ¹ , J ² and K ¹ are N, the condition is R ⁹ , R ¹⁰ , R ¹¹ , R ¹² and R ¹³ are each independently selected to maintain the tetravalent nature of carbon, the trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen;

Q is optionally selected from formula (III):

wherein D ³ , D ⁴ , J ³ and J ⁴ are independently selected from C, N, O and S ^, at most one of D ³ , D 4 , J ³ and J ⁴ is O, D ³ , D ⁴ , J ³ and At most one of J ⁴ is S and at most three of D ¹ , D ² , J ¹ and J ² are N, provided that R ⁹ , R ¹⁰ , R ¹¹ and R ¹² are each independently selected to maintain The tetravalent nature of carbon, the trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen;

Q is optionally selected from hydrogen, alkyl, alkoxy, alkylamino, alkylthio, haloalkylthio, alkenyl, alkynyl, saturated heterocyclyl, partially saturated heterocyclyl, acyl, aroyl , heteroaroyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkylalkenyl, haloalkyl, haloalkoxy, haloalkenyl, halocycloalkyl, halo Halocycloalkenyl, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxyalkyl and halocycloalkenyloxyalkyl, with the proviso that if Q is hydrogen, ^Z is selected from Groups other than covalent single bonds;

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

R ^4a and R ^4b are independently selected from halogen, hydrogen, hydroxy, cyano, hydroxyalkyl, alkyl, alkenyl, alkoxyalkyl, aralkyl, heteroaralkyl, alkylthioalkyl, haloalkane group, haloalkenyl and cyanoalkyl;

If K is (CR ^4a R ^4b ) _n , then E ⁰ is E ¹ , wherein E ¹ is 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) ₂ N(R ⁷ ), N(R ⁷ )S(O) ₂ , S(O) ₂ N(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; 1,2-ethynyl) and C=CR ^4a R ^4b ;

K is optionally (CH(R ¹⁴ )) _j -T, wherein j is selected from integers from 0 to 2, and T is selected from covalent single bonds, O, S and N(R ⁷ ), with the proviso that (CH( R ¹⁴ )) _j is bonded to the uracil ring;

If K is (CH(R ¹⁴ )) _j -T, then E ⁰ is optionally E ² , wherein E ² is selected from covalent single bonds, 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) ₂ N(R ⁷ ), N(R ⁷ )S(O) ₂ , S(O) ₂ N(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 is optionally G-(CH(R ¹⁵ )) _k , where k is selected from integers from 1 to 2, and G is selected from O, S and N(R ⁷ ), with the proviso that if k is 1, then R ¹⁵ Cannot be hydroxyl, cyano, halogen, amino, alkylamino, dialkylamino and mercapto;

If K is G-(CH(R ¹⁵ )) _k , then E ⁰ is optionally E ³ , wherein E ³ is 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) ₂ N(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; 1,2-ethynyl ), and C=CR ^4a R ^4b ;

Y ⁰ is formula (IV):

wherein D ⁵ , D ⁶ , J ⁵ and J ⁶ are independently selected from C, N, O, S and covalent bonds, with the proviso that at most one is a covalent bond, K ² is independently selected from C and N ⁺ , D ⁵ , at most one of D ⁶ , J ⁵ and J ⁶ is O, at most one of D ⁵ , D ⁶ , J ⁵ and J ⁶ is S, if two of D ⁵ , D ⁶ , J ⁵ and J ⁶ are O and S, then one of D ⁵ , D ⁶ , J ⁵ and J ⁶ must be a covalent bond, if K ² is N ⁺ , then at most three of D ⁵ , D ⁶ , J ⁵ and J ⁶ are N, if K ² is carbon, then at most four of D ⁵ , D ⁶ , J ⁵ and J ⁶ are N, provided that R ¹⁶ , R ¹⁷ , R ¹⁸ and R ¹⁹ are each independently selected to maintain four of the carbons. valency, nitrogen trivalent, sulfur divalent and oxygen divalent;

R ¹⁶ and R ¹⁷ are independently optionally taken together to form a linear partial spacer having 3 to 6 connected atoms joined to form a ring selected from the group consisting of cycloalkenyl rings having 5 to 8 connected members, cycloalkenyl rings having 5 to 8 connected members, Partially saturated heterocyclyl rings with up to 8 connected members, heteroaryls with 5 to 6 connected members, and aryls;

Q ^b is selected from NR ²⁰ R ²¹ , ⁺ NR ²⁰ R ²¹ R ²² , oxy, alkyl, aminoalkylene, alkylamino, dialkylamino, dialkylsulfoniumalkyl, acylamino and Q ^be , wherein ^Qbe is hydrogen, R ²⁰ , R ²¹ and R ²² are independently selected from hydrogen, amino, alkyl, hydroxy, alkoxy, aminoalkylene, alkylamino, dialkylamino and hydroxyalkyl, which The proviso is that at most one of R ²⁰ , R ²¹ and R ²² is simultaneously hydroxyl, alkoxy, alkylamino, amino and dialkylamino, and if K ² is N ⁺ , then R ²⁰ , R ²¹ and R ²² cannot be Hydroxy, alkoxy, alkylamino, amino and dialkylamino;

R ²⁰ and R ²¹ , R ²⁰ and R ²² , and R ²¹ and R ²² are independently optionally selected to form a spacer pair, wherein the spacer pair together forms a linear moiety having 4 to 7 connected atoms, with the spacer The bonding points of the base pair members are joined to form a heterocyclyl ring having 5 to 8 linked members, with the proviso that at most one spacer pair of ^R20 and ^R21 , ^R20 and ^R22 , and ^R21 and ^R22 is used at the same time;

Q ^b is optionally selected from N(R ²⁶ )SO ₂ N(R ²³ )(R ²⁴ ), N(R ²⁶ )C(O)OR ⁵ , N(R ²⁶ )C(O)SR ⁵ , N( R ²⁶ )C(S)OR ⁵ and N(R ²⁶ )C(S)SR ⁵ , with the proviso that if two of R ²³ , R ²⁴ and R ²⁶ are bonded to the same atom, then R ²³ , R ²⁴ and At most one of ^R can be hydroxy, alkoxy, alkylamino, amino and dialkylamino;

Q ^b is optionally selected from dialkylsulfonium, trialkylphosphonium, C(NR ²⁵ )NR ²³ R 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 ₂ N( R ²³ )(R ²⁴ ), C(NR ²⁵ )SR ⁵ , C(O)NR ²³ R ²⁴ and C(O)NR ²³ R ²⁴ , with the proviso that if two of R ²³ , R ²⁴ and R ²⁶ are identical to At least one of R ²³ , R ²⁴ and R ²⁶ can be hydroxyl, alkoxy, alkylamino, amino or dialkylamino, and the Q ^b group is directly bonded to a carbon atom;

R ²³ , R ²⁴ , R ²⁵ and R ²⁶ are independently selected from hydrogen, alkyl, hydroxy, alkoxy, aminoalkylene, alkylamino, dialkylamino, amino and hydroxyalkyl;

R ²³ and R ²⁴ optionally together form a linear spacer moiety having 4 to 7 linked atoms joined to the point of bonding to form a heterocyclyl ring having 5 to 8 linked members;

Q ^s is selected from covalent single bond, (CR ³⁷ R ³⁸ ) _b -(W ⁰ ) _az , (CH(R ¹⁴ )) _c -W ¹ -(CH(R ¹⁵ )) _d and (CH(R ¹⁴ ) ) _e -W ²² -(CH(R ¹⁵ )) _h , wherein az is an integer selected from 0 to 1, b is an integer selected from 1 to 4, W ⁰ is 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) ₂ N(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 An integer independently selected from 1 to 4, W ^is 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) ₂ N(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 integers independently selected from 0 to 2, W ²² is selected from CR ⁴¹ =CR ⁴² , CR ⁴¹ R ⁴² =C, ethenylene), ethynylene ( C≡C; 1,2-ethynyl), 1,2-cyclopropyl, 1,2-cyclobutyl, 1,2-cyclohexyl, 1,3-cyclohexyl, 1,2-cyclopentyl, 1,3-cyclopentyl, 2,3-morpholinyl, 2,4-morpholinyl, 2,6-morpholinyl, 3,4-morpholinyl, 3,5-morpholinyl, 1, 2-piperazinyl, 1,3-piperazinyl, 2,3-piperazinyl, 2,6-piperazinyl, 1,2-piperidinyl, 1,3-piperidinyl, 2,3- Piperidinyl, 2,4-piperidinyl, 2,6-piperidinyl, 3,4-piperidinyl, 1,2-pyrrolidinyl, 1,3-pyrrolidinyl, 2,3-pyrrolidinyl 2,4-pyrrolidinyl, 2,5-pyrrolidinyl, 3,4-pyrrolidinyl, 2,3-tetrahydrofuranyl, 2,4-tetrahydrofuranyl, 2,5-tetrahydrofuranyl and 3,4 - Tetrahydrofuryl, with the proviso that R ¹⁴ and R ¹⁵ if directly bonded to N are selected from groups other than halo and cyano, (CR ³⁷ R ³⁸ ) _b , (CH(R ¹⁴ )) _c , ( CH(R ¹⁴ )) _e is directly bonded to E ⁰ ;

Y ⁰ is optionally Q ^b -Q ^ss , wherein Q ^ss is selected from (CR ³⁷ R ³⁸ ) _f , (CH(R ¹⁴ )) _c -W ¹ -(CH(R ¹⁵ )) _d and (CH(R 15 )) d ¹⁴ )) _e -W ² -(CH(R ¹⁵ )) _h , wherein f is an integer selected from 1 to 6, c and d are integers independently selected from 1 to 4, W ¹ is 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) ₂ N(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 An integer of 0 to 2, W ² is selected from CR ^4a =CR ^4b , ethynylene (C≡C; 1,2-ethynyl) and C=CR ^4a R ^4b , provided that R ¹⁴ and R ¹⁵ are directly combined with N bonding is selected from groups other than halo and cyano, (CR ³⁷ R ³⁸ ) _f , (CH(R ¹⁵ )) _c and (CH(R ¹⁵ )) _e are bonded to E ⁰ ;

Y ⁰ is optionally Q ^b -Q ^sss , wherein Q ^sss is (CH(R ³⁸ )) _r -W ³ , wherein r is an integer selected from 1 to 3, and W ³ is selected from 1,1-cyclopropyl , 1,2-cyclopropyl, 1,1-cyclobutyl, 1,2-cyclobutyl, 1,2-cyclohexyl, 1,3-cyclohexyl, 1,4-cyclohexyl, 1,2- Cyclopentyl, 1,3-cyclopentyl, 2,3-morpholinyl, 2,4-morpholinyl, 2,5-morpholinyl, 2,6-morpholinyl, 3,4-morpholinyl Base, 3,5-morpholinyl, 1,2-piperazinyl, 1,3-piperazinyl, 1,4-piperazinyl, 2,3-piperazinyl, 2,5-piperazinyl, 2,6-piperazinyl, 1,2-piperidinyl, 1,3-piperidinyl, 1,4-piperidinyl, 2,3-piperidinyl, 2,4-piperidinyl, 2, 5-piperidinyl, 2,6-piperidinyl, 3,4-piperidinyl, 3,5-piperidinyl, 3,6-piperidinyl, 1,2-pyrrolidinyl, 1,3- Pyrrolidinyl, 2,3-pyrrolidinyl, 2,4-pyrrolidinyl, 2,5-pyrrolidinyl, 3,4-pyrrolidinyl, 2H-2,3-pyranyl, 2H-2, 4-pyranyl, 2H-2,5-pyranyl, 4H-2,3-pyranyl, 4H-2,4-pyranyl, 4H-2,5-pyranyl, 2H-pyranyl -2-keto-3,4-yl, 2H-pyran-2-one-4,5-yl, 4H-pyran-4-one-2,3-yl, 2,3-tetrahydrofuryl, 2, 4-tetrahydrofuryl, 2,5-tetrahydrofuryl, 3,4-tetrahydrofuryl, 2,3-tetrahydropyranyl, 2,4-tetrahydropyranyl, 2,5-tetrahydropyranyl, 2 , 6-tetrahydropyranyl, 3,4-tetrahydropyranyl and 3,5-tetrahydropyranyl, each of the W ^ring nitrogen members containing carbon and hydrogen is optionally Substituted by one or more R ⁹ , R ¹⁰ , R ¹¹ and R ¹² groups with the proviso that (CH(R ³⁸ )) _r is bonded to E ⁰ and Q ^b is the same as the lowest numbered substituent position of each W ³ Bond;

Y ⁰ is optionally Q ^b -Q ^sssr , wherein Q ^sssr is (CH(R ³⁸ )) _r -W ⁴ , wherein r is an integer selected from 1 to 3, and W ⁴ is selected from 1,2-cyclobutyl , 1,2-cyclohexyl, 1,3-cyclohexyl, 1,4-cyclohexyl, 1,2-cyclopentyl, 1,3-cyclopentyl, 2,3-morpholinyl, 2,4- Morpholinyl, 2,5-morpholinyl, 2,6-morpholinyl, 3,4-morpholinyl, 3,5-morpholinyl, 1,2-piperazinyl, 1,3-piperazine Base, 1,4-piperazinyl, 2,3-piperazinyl, 2,5-piperazinyl, 2,6-piperazinyl, 1,2-piperidinyl, 1,3-piperidinyl, 1,4-piperidinyl, 2,3-piperidinyl, 2,4-piperidinyl, 2,5-piperidinyl, 2,6-piperidinyl, 3,4-piperidinyl, 3, 5-piperidinyl, 3,6-piperidinyl, 1,2-pyrrolidinyl, 1,3-pyrrolidinyl, 2,3-pyrrolidinyl, 2,4-pyrrolidinyl, 2,5- Pyrrolidinyl, 3,4-pyrrolidinyl, 2H-2,3-pyranyl, 2H-2,4-pyranyl, 2H-2,5-pyranyl, 4H-2,3-pyranyl Base, 4H-2,4-pyranyl, 4H-2,5-pyranyl, 2H-pyran-2-one-3,4-yl, 2H-pyran-2-one-4,5- Base, 4H-pyran-4-one-2,3-yl, 2,3-tetrahydrofuryl, 2,4-tetrahydrofuryl, 2,5-tetrahydrofuryl, 3,4-tetrahydrofuryl, 2,3-tetrahydrofuryl Hydropyranyl, 2,4-tetrahydropyranyl, 2,5-tetrahydropyranyl, 2,6-tetrahydropyranyl, 3,4-tetrahydropyranyl and 3,5-tetrahydropyranyl Hydropyranyl, except for the point of attachment, each W ^ring nitrogen member containing carbon and hydrogen is optionally substituted with one or more R ⁹ , R ¹⁰ , R ¹¹ and R ¹² groups, provided that ( CH(R ³⁸ )) _r is bonded to E ⁰ and Q ^b is bonded to the highest numbered substituent position of each W ⁴ ;

Y ⁰ is optionally Q ^b -Q ^ssss , wherein Q ^ssss is (CH(R ³⁸ )) _r -W ⁵ , wherein r is an integer selected from 1 to 3, and W ⁵ is selected from 1,4-indenyl, 1,5-indenyl, 1,6-indenyl, 1,7-indenyl, 2,7-indenyl, 2,6-indenyl, 2,5-indenyl, 2,4-indenyl, 3 , 4-indenyl, 3,5-indenyl, 3,6-indenyl, 3,7-indenyl, 2,4-benzofuryl, 2,5-benzofuryl, 2,6-benzene And furyl, 2,7-benzofuryl, 3,4-benzofuryl, 3,5-benzofuryl, 3,6-benzofuryl, 3,7-benzofuryl, 2 , 4-benzothienyl, 2,5-benzothienyl, 2,6-benzothienyl, 2,7-benzothienyl, 3,4-benzothienyl, 3,5-benzothienyl Thienyl, 3,6-benzothienyl, 3,7-benzothienyl, 2,7-imidazo(1,2-a)pyridyl, 3,4-imidazo(1,2-a)pyridine Base, 3,5-imidazo(1,2-a)pyridyl, 3,6-imidazo(1,2-a)pyridyl, 3,7-imidazo(1,2-a)pyridyl, 2,4-indolyl, 2,5-indolyl, 2,6-indolyl, 2,7-indolyl, 3,4-indolyl, 3,5-indolyl, 3, 6-indolyl, 3,7-indolyl, 1,4-isoindolyl, 1,5-isoindolyl, 1,6-isoindolyl, 2,4-isoindolyl, 2,5-isoindolyl, 2,6-isoindolyl, 2,7-isoindolyl, 1,3-isoindolyl, 3,4-indazolyl, 3,5-indazole Base, 3,6-indazolyl, 3,7-indazolyl, 2,4-benzoxazolyl, 2,5-benzoxazolyl, 2,6-benzoxazolyl, 2, 7-Benzoxazolyl, 3,4-Benzisoxazolyl, 3,5-Benzisoxazolyl, 3,6-Benzisoxazolyl, 3,7-Benzisoxazolyl Base, 1,4-naphthyl, 1,5-naphthyl, 1,6-naphthyl, 1,7-naphthyl, 1,8-naphthyl, 2,4-naphthyl, 2,5-naphthyl , 2,6-naphthyl, 2,7-naphthyl, 2,8-naphthyl, 2,4-quinolinyl, 2,5-quinolinyl, 2,6-quinolinyl, 2,7- Quinolinyl, 2,8-quinolinyl, 3,4-quinolinyl, 3,5-quinolinyl, 3,6-quinolinyl, 3,7-quinolinyl, 3,8-quinolinyl Base, 4,5-quinolinyl, 4,6-quinolinyl, 4,7-quinolinyl, 4,8-quinolinyl, 1,4-isoquinolinyl, 1,5-isoquinolinyl Base, 1,6-isoquinolinyl, 1,7-isoquinolinyl, 1,8-isoquinolinyl, 3,4-isoquinolinyl, 3,5-isoquinolinyl, 3,6 -isoquinolinyl, 3,7-isoquinolinyl, 3,8-isoquinolinyl, 4,5-isoquinolinyl, 4,6-isoquinolinyl, 4,7-isoquinolinyl , 4,8-isoquinolinyl, 3,4-cinnolinyl, 3,5-cinnolinyl, 3,6-cinnolinyl, 3,7-cinnolinyl, 3,8-cinnolinyl, 4,5-cinnolinyl, 4,6-cinnolinyl, 4,7-cinnolinyl and 4,8-cinnolinyl, except for the point of attachment, each of the W ^ring nitrogen members containing carbon and hydrogen optionally substituted with one or more R ⁹ , R ¹⁰ , R ¹¹ and R ¹² groups, with the proviso that Q ^b is bonded to the lowest numbered substituent position of each W ⁵ , (CH(R ³⁸ )) _r bonded to ^E0 ;

Y ⁰ is optionally Q ^b -Q ^ssssr , wherein Q ^ssssr is (CH(R ³⁸ )) _r -W ⁶ , wherein r is an integer selected from 1 to 3, and W ⁶ is selected from 1,4-indenyl, 1,5-indenyl, 1,6-indenyl, 1,7-indenyl, 2,7-indenyl, 2,6-indenyl, 2,5-indenyl, 2,4-indenyl, 3 , 4-indenyl, 3,5-indenyl, 3,6-indenyl, 3,7-indenyl, 2,4-benzofuryl, 2,5-benzofuryl, 2,6-benzene And furyl, 2,7-benzofuryl, 3,4-benzofuryl, 3,5-benzofuryl, 3,6-benzofuryl, 3,7-benzofuryl, 2 , 4-benzothienyl, 2,5-benzothienyl, 2,6-benzothienyl, 2,7-benzothienyl, 3,4-benzothienyl, 3,5-benzothienyl Thienyl, 3,6-benzothienyl, 3,7-benzothienyl, 2,7-imidazo(1,2-a)pyridyl, 3,4-imidazo(1,2-a) Pyridyl, 3,5-imidazo(1,2-a)pyridyl, 3,6-imidazo(1,2-a)pyridyl, 3,7-imidazo(1,2-a)pyridyl , 2,4-indolyl, 2,5-indolyl, 2,6-indolyl, 2,7-indolyl, 3,4-indolyl, 3,5-indolyl, 3 , 6-indolyl, 3,7-indolyl, 1,4-isoindolyl, 1,5-isoindolyl, 1,6-isoindolyl, 2,4-isoindolyl , 2,5-isoindolyl, 2,6-isoindolyl, 2,7-isoindolyl, 1,3-isoindolyl, 3,4-indazolyl, 3,5-indolyl Azolyl, 3,6-indazolyl, 3,7-indazolyl, 2,4-benzoxazolyl, 2,5-benzoxazolyl, 2,6-benzoxazolyl, 2 , 7-benzoxazolyl, 3,4-benzisoxazolyl, 3,5-benzisoxazolyl, 3,6-benzisoxazolyl, 3,7-benzisoxazolyl Azolyl, 1,4-naphthyl, 1,5-naphthyl, 1,6-naphthyl, 1,7-naphthyl, 1,8-naphthyl, 2,4-naphthyl, 2,5-naphthyl Base, 2,6-naphthyl, 2,7-naphthyl, 2,8-naphthyl, 2,4-quinolyl, 2,5-quinolyl, 2,6-quinolyl, 2,7 -quinolyl, 2,8-quinolyl, 3,4-quinolyl, 3,5-quinolyl, 3,6-quinolyl, 3,7-quinolyl, 3,8-quinolinyl Linyl, 4,5-quinolinyl, 4,6-quinolinyl, 4,7-quinolinyl, 4,8-quinolinyl, 1,4-isoquinolinyl, 1,5-isoquinolinyl Linyl, 1,6-isoquinolinyl, 1,7-isoquinolinyl, 1,8-isoquinolinyl, 3,4-isoquinolinyl, 3,5-isoquinolinyl, 3, 6-isoquinolinyl, 3,7-isoquinolinyl, 3,8-isoquinolinyl, 4,5-isoquinolinyl, 4,6-isoquinolinyl, 4,7-isoquinolinyl Base, 4,8-isoquinolinyl, 3,4-cinnolinyl, 3,5-cinnolinyl, 3,6-cinnolinyl, 3,7-cinnolinyl, 3,8-cinnolinyl , 4,5-cinnolinyl, 4,6-cinnolinyl, 4,7-cinnolinyl and 4,8-cinnolinyl, except for the point of attachment, each W ^ring nitrogen member containing carbon and hydrogen are all optionally substituted with one or more R ⁹ , R ¹⁰ , R ¹¹ and R ¹² groups with the proviso that Q ^b is bonded to the highest numbered substituent position of each W ⁶ , (CH(R ³⁸ )) _r is bonded to ^E0 .

In another embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof,

J ^a and J ^b are independently selected from O and S;

B is formula (V):

wherein D ¹ , D ² , J ¹ , J ² and K ¹ are independently selected from C, N, O, S and covalent bonds, with the proviso that at most one can be a covalent bond, D ¹ , D ² , J ¹ , at most one of J ² and K ¹ is O, at most one of D ¹ , D ² , J ¹ , J ² and K ¹ is S, if two of D ¹ , D ² , J ¹ , J ² and K ¹ are O and S, then one of D ¹ , D ² , J ¹ , J ² and K ¹ must be a covalent bond, and at most four of D ¹ , D ² , J ¹ , J ² and K ¹ are N;

R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ , R ³² , R ³³ , R ³⁴ , R ³⁵ and R ³⁶ are independently selected from hydrogen, acetamido, Haloacetamido, amidino, guanidino, dialkylsulfonium, trialkylphosphonium, dialkylsulfoniumalkyl, carboxyl, heteroaralkylthio, heteroaralkoxy, cycloalkylamino, acylalkyl , Acylalkoxy, Aroylalkoxy, Heterocyclyl, Aralkylaryl, Aralkyl, Aralkenyl, Aralkynyl, Heterocyclyl, Perhalogenated Aralkyl, Aralkylsulfonyl Acyl, aralkylsulfonylalkyl, aralkylsulfinyl, aralkylsulfinylalkyl, halocycloalkyl, halocycloalkenyl, cycloalkylsulfinyl, cycloalkylsulfinyl Acylalkyl, cycloalkylsulfonyl, cycloalkylsulfonylalkyl, heteroarylamino, N-heteroarylamino-N-alkylamino, heteroarylaminoalkyl, haloalkylthio, alkanoyloxy radical, alkoxy, alkoxyalkyl, haloalkoxyalkyl, heteroaralkoxy, cycloalkoxy, cycloalkenyloxy, cycloalkoxyalkyl, cycloalkylalkoxy, cycloalkene Oxyalkyl, cycloalkenedioxy, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxy, halocycloalkenyloxyalkyl, hydroxy, amino, alkoxy Amino, thio, nitro, lower alkylamino, alkylthio, alkylthioalkyl, arylamino, aralkylamino, arylthio, arylthioalkyl, heteroaralkoxyalkyl , Alkylsulfinyl, Alkylsulfinylalkyl, Arylsulfinylalkyl, Arylsulfonylalkyl, Heteroarylsulfinylalkyl, Heteroarylsulfonylalkyl, Alkylsulfonyl Acyl, alkylsulfonylalkyl, haloalkylsulfinylalkyl, haloalkylsulfonylalkyl, alkylsulfonylamino, alkylaminosulfonyl, amidosulfonyl, monoalkylamidosulfonyl, di Alkyl amidosulfonyl, one aryl amidosulfonyl, aryl sulfonyl amino, diaryl amido sulfonyl, one alkyl-aryl amido sulfonyl, aryl sulfinyl, aryl sulfonyl , heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, heterocyclylsulfonyl, heterocyclylthio, alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl, heteroaryl Alkanoyl, haloalkanoyl, alkyl, alkenyl, alkynyl, alkenyloxy, alkenyloxyalkyl, alkylenedioxy, haloalkanedioxy, cycloalkyl, cycloalkylalkanoyl, cyclo Alkenyl, lower cycloalkylalkyl, lower cycloalkenylalkyl, halogen, haloalkyl, haloalkenyl, haloalkoxy, hydroxyhaloalkyl, hydroxyaralkyl, hydroxyalkyl, alkenylamino, hydroxyhetero Aralkyl, haloalkoxyalkyl, aryl, aralkyl, aryloxy, aralkoxy, aryloxyalkyl, saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl, hetero Aryloxy, heteroaryloxyalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, carboxyalkyl, alkoxycarbonyl, alkoxycarboxamido, alkyl Amidocarbonylamido, arylamidocarbonylamido, alkoxycarbonylalkyl, alkoxycarbonylalkenyl, carboxyl, aralkoxycarbonyl, carboxamido, carboxamidoalkyl, cyano, haloalkoxycarbonyl, Phosphono, phosphonoalkyl, diaralkoxyphosphono and diaralkoxyphosphonoalkyl;

R ¹⁶ , R ¹⁹ , R ³² , R ³³ , R ³⁴ , R ³⁵ and R ³⁶ are independently optionally Q ^b with the proviso that at most one of R ¹⁶ and R ¹⁹ is simultaneously Q ^b and Q ^b is Q ^be ;

B is optionally selected from hydrogen, trialkylsilyl, C2-C8 alkyl, C3-C8 alkenyl, C3-C8 alkylene, C3-C8 alkynyl, C2-C8 haloalkyl and C3-C8 halo Alkenyl, wherein each member of group B is optionally replaced by one or more groups R ³² , R ³³ , R ³⁴ , R on any carbon up to and including 6 atoms from the point of attachment of B to A ³⁵ and R ³⁶ are substituted;

B is optionally selected from C3-C12 cycloalkyl, C5-C10 cycloalkenyl and C4-C9 saturated heterocyclyl, wherein each ring carbon is optionally substituted by R ³³ , except for the Ring carbons other than the ring carbon are optionally substituted by oxo, provided that at most one ring carbon is simultaneously substituted by oxo, ring carbons and nitrogen atoms adjacent to the ring carbon at the point of attachment are optionally replaced by R ^or R ¹³ substituted, the ring carbon or nitrogen atom adjacent to the R ⁹ position and two atoms away from the point of attachment is optionally substituted by R ¹⁰ , any ring carbon or nitrogen atom adjacent to the R ¹³ position and two atoms away from the attachment point optionally substituted by R ¹² , a ring carbon or nitrogen atom three atoms from the point of attachment and adjacent to the ¹⁰ position of R is optionally substituted by R ¹¹ , a ring carbon three atoms from the point of attachment adjacent to ^{the 12} position of R Or the nitrogen atom is optionally substituted by R ³³ , and the ring carbon or nitrogen atom which is four atoms away from the connection point and adjacent to the R ¹¹ and R ³³ positions is optionally substituted by R ³⁴ ;

A is selected from covalent single bonds, (W ⁷ ) _rr -(CH(R ¹⁵ )) _pa and (CH(R ¹⁵ )) _pa -(W ⁷ ) _rr , where rr is an integer selected from 0 to 1, pa is an integer selected from 0 to 6, W ⁷ is 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 ), with the proviso that at most one of rr and pa can be 0 at the same time;

^R7 and ^R8 are independently selected from hydrogen, hydroxyl, alkyl and alkoxyalkyl;

R ¹⁴ , R ¹⁵ , R ³⁷ and R ³⁸ are independently selected from hydrogen, hydroxy, halogen, alkyl, alkoxyalkyl, haloalkyl, haloalkoxy and haloalkoxyalkyl;

R ¹⁴ and R ³⁸ may be independently selected from aroyl and heteroaroyl;

Ψ is selected from NR ⁵ , C(O) and S(O) ₂ ;

^R is selected from hydrogen, hydroxyl, alkyl and alkoxy;

R and ^R are independently selected from hydrogen, hydroxy, halogen, hydroxyalkyl, alkyl, alkoxyalkyl, haloalkyl, haloalkoxy ^, and haloalkoxyalkyl;

M is selected from N and R ¹ -C;

^R is selected from hydrogen, alkyl, alkenyl, cyano, halogen, haloalkyl, haloalkoxy, haloalkylthio, amino, aminoalkyl, alkylamino, amidino, guanidino, hydroxy, hydroxyamino, alkane Oxy, hydroxyalkyl, alkoxyamino, thiohydroxy, alkylthio and phosphono;

R ² is Z ⁰ -Q;

Z ⁰ is selected from covalent single bonds, (CR ⁴¹ R ⁴² ) _q , (CH(R ⁴¹ )) _g -W ⁰ -(CH(R ⁴² )) _p and (CH(R ⁴¹ )) _e -W ²² - (CH(R ⁴² )) _h , wherein q is an integer selected from 1 to 3, g and p are integers independently selected from 0 to 3, W ⁰ is selected from O, S, C(O), S(O ), S(O) ₂ , N(R ⁴¹ ) and ON(R ⁴¹ ), e and h are integers independently selected from 0 to 2, W ²² is selected from CR ⁴¹ =CR ⁴² , 1,2-cyclopropane Base, 1,2-cyclobutyl, 1,2-cyclohexyl, 1,3-cyclohexyl, 1,2-cyclopentyl, 1,3-cyclopentyl, 2,3-morpholinyl, 2, 4-morpholinyl, 2,6-morpholinyl, 3,4-morpholinyl, 3,5-morpholinyl, 1,2-piperazinyl, 1,3-piperazinyl, 2,3- Piperazinyl, 2,6-piperazinyl, 1,2-piperidinyl, 1,3-piperidinyl, 2,3-piperidinyl, 2,4-piperidinyl, 2,6-piperidinyl Base, 3,4-piperidinyl, 1,2-pyrrolidinyl, 1,3-pyrrolidinyl, 2,3-pyrrolidinyl, 2,4-pyrrolidinyl, 2,5-pyrrolidinyl, 3,4-pyrrolidinyl, 2,3-tetrahydrofuryl, 2,4-tetrahydrofuryl, 2,5-tetrahydrofuryl and 3,4-tetrahydrofuryl, with the proviso that ^Z is directly bonded to the uracil ring;

R ⁴¹ and R ⁴² are independently selected from amidino, hydroxyamino, hydrogen, hydroxy, amino and alkyl;

Q is selected from hydrogen with the proviso that ^Z cannot be a covalent single bond; and formula (II):

wherein D ¹ , D ² , J ¹ , J ² and K ¹ are independently selected from C, N, O, S and covalent bonds, with the proviso that at most one can be a covalent bond, D ¹ , D ² , J ¹ , at most one of J ² and K ¹ is O, at most one of D ¹ , D ² , J ¹ , J ² and K ¹ is S, if two of D ¹ , D ² , J ¹ , J ² and K ¹ are O and S, then one of D ¹ , D ² , J ¹ , J ² and K ¹ must be a covalent bond, and at most four of D ¹ , D ² , J ¹ , J ² and K ¹ are N, the condition is R ⁹ , R ¹⁰ , R ¹¹ , R ¹² and R ¹³ are each independently selected to maintain the tetravalent nature of carbon, the trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen;

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

R ^4a and R ^4b are independently selected from halogen, hydrogen, hydroxyalkyl, alkyl, alkoxyalkyl, alkylthioalkyl and haloalkyl;

E ⁰ is 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) ₂ and S(O) ₂ N(R ⁷ );

Y ⁰ is formula (IV):

wherein D ⁵ , D ⁶ , J ⁵ and J ⁶ are independently selected from C, N, O, S and covalent bonds, provided that at most one is a covalent bond, K ² is C, D ⁵ , D ⁶ , J At most one of ⁵ and J ⁶ is O, at most one of D ⁵ , D ⁶ , J ⁵ and J ⁶ is S, if two of D ⁵ , D ⁶ , J ⁵ and J ⁶ are O and S, then D ⁵ , One of D ⁶ , J ⁵ and J ⁶ must be a covalent bond, and if K ² is carbon, then at most four of D ⁵ , D ⁶ , J ⁵ and J ⁶ are N, provided that R ¹⁶ , R ¹⁷ , R and ^R are each independently selected to maintain the tetravalent nature of carbon, ^the trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen;

Q ^b is selected from NR ²⁰ R ²¹ , ⁺ NR ²⁰ R ²¹ R ²² , aminoalkylene and Q ^be , wherein Q ^be is hydrogen, R ²⁰ , R ²¹ and R ²² are independently selected from hydrogen, alkyl, hydroxyl, Amino, aminoalkylene, dialkylamino, alkylamino and hydroxyalkyl, with the proviso that at most one of ^R and ^R is simultaneously hydroxy, amino, alkylamino or dialkylamino;

Q ^b is optionally selected from C(NR ²⁵ )NR ²³ R ²⁴ , N(R ²⁶ )C(NR ²⁵ )N(R ²³ )(R ²⁴ ), C(O)N(R ²⁶ )C(NR ²⁵ )N(R ²³ )(R ²⁴ ), N(R ²⁶ )N(R ²⁶ )C(NR ²⁵ )N(R ²³ )(R ²⁴ ) and ON(R ²⁶ )C(NR ²⁵ )N(R ²³ )(R ²⁴ ), with the proviso that if two of R ²³ , R ²⁴ and R ²⁶ are bonded to the same atom, then at most one of R ²³ , R ²⁴ and R ²⁶ is hydroxyl, alkylamino, amino or dioxane Base amino;

R ²³ , R ²⁴ , R ²⁵ and R ²⁶ are independently selected from hydrogen, alkyl, hydroxy, amino, alkyleneamino, dialkylamino, alkylamino and hydroxyalkyl;

Q ^s is selected from covalent single bond, (CR ³⁷ R ³⁸ ) _b -(W ⁰ ) _az , (CH(R ¹⁴ )) _c -W ¹ -(CH(R ¹⁵ )) _d and (CH(R ¹⁴ ) ) _e -W ²² -(CH(R ¹⁵ )) _h , wherein az is an integer selected from 0 to 1, b is an integer selected from 1 to 5, W ⁰ is selected from O, C(O), S(O ), S(O) ₂ , S(O) ₂ N(R ¹⁴ ), N(R ¹⁴ )S(O) ₂ and ON(R ¹⁴ ), c and d are integers independently selected from 1 to 4, W ¹ is 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) ₂ N(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 integers independently selected from 0 to 2, W ²² is selected from CR ⁴¹ =CR ⁴² , CR ⁴¹ R ⁴² =C; vinylidene), ethynylene (C≡C; 1,2-ethynyl ), 1,2-cyclopropyl, 1,2-cyclobutyl, 1,2-cyclohexyl, 1,3-cyclohexyl, 1,2-cyclopentyl, 1,3-cyclopentyl, 2, 3-morpholinyl, 2,4-morpholinyl, 2,6-morpholinyl, 3,4-morpholinyl, 3,5-morpholinyl, 1,2-piperazinyl, 1,3- Piperazinyl, 2,3-piperazinyl, 2,6-piperazinyl, 1,2-piperidinyl, 1,3-piperidinyl, 2,3-piperidinyl, 2,4-piperidinyl Base, 2,6-piperidinyl, 3,4-piperidinyl, 1,2-pyrrolidinyl, 1,3-pyrrolidinyl, 2,3-pyrrolidinyl, 2,4-pyrrolidinyl, 2,5-pyrrolidinyl, 3,4-pyrrolidinyl, 2,3-tetrahydrofuryl, 2,4-tetrahydrofuryl, 2,5-tetrahydrofuryl and 3,4-tetrahydrofuryl, provided that R ^and If R ¹⁵ is directly bonded to N, it is selected from groups other than halogen and cyano, (CR ³⁷ R ³⁸ ) _b , (CH(R ¹⁴ )) _c , (CH(R ¹⁴ )) _e and E ⁰ bond combine;

Y ⁰ is optionally Q ^b -Q ^ss , wherein Q ^ss is selected from (CR ³⁷ R ³⁸ ) _f , (CH(R ¹⁴ )) _c -W ¹ -(CH(R ¹⁵ )) _d and (CH(R 15 )) d ¹⁴ )) _e -W ² -(CH(R ¹⁵ )) _h , wherein f is an integer selected from 1 to 4, c and d are integers independently selected from 1 to 2, W ¹ is selected from O, S, C(O), C(O)N(R ¹⁴ ), (R ¹⁴ )NC(O), N(R ¹⁵ )C(O)N(R ^{14 ), (R 14 )} NC(O)N(R ¹⁵ ), N(R ¹⁴ ) and ON(R ¹⁴ ), e and h are integers independently selected from 0 to 2, W ² is selected from CR ^4a =CR ^4b , ethynylene (C≡C; 1,2 -ethynyl) and C=CR ^4a R ^4b with the proviso that R ¹⁴ and R ¹⁵ are selected from groups other than halogen if directly bonded to N, (CR ³⁷ R ³⁸ ) _f , (CH(R ¹⁴ ) ) _c and (CH(R ¹⁴ )) _e are bonded to E ⁰ ;

Y ⁰ is optionally Q ^b -Q ^sss , wherein Q ^sss is (CH(R ³⁸ )) _r -W ³ , wherein r is an integer selected from 1 to 2, and W ³ is selected from 1,1-cyclopropyl , 1,2-cyclopropyl, 1,1-cyclobutyl, 1,2-cyclobutyl, 1,2-cyclohexyl, 1,3-cyclohexyl, 1,4-cyclohexyl, 1,2- Cyclopentyl, 1,3-cyclopentyl, 2,3-morpholinyl, 2,4-morpholinyl, 2,5-morpholinyl, 2,6-morpholinyl, 3,4-morpholinyl Base, 3,5-morpholinyl, 1,2-piperazinyl, 1,3-piperazinyl, 1,4-piperazinyl, 2,3-piperazinyl, 2,5-piperazinyl, 2,6-piperazinyl, 1,2-piperidinyl, 1,3-piperidinyl, 1,4-piperidinyl, 2,3-piperidinyl, 2,4-piperidinyl, 2, 5-piperidinyl, 2,6-piperidinyl, 3,4-piperidinyl, 3,5-piperidinyl, 3,6-piperidinyl, 1,2-pyrrolidinyl, 1,3- Pyrrolidinyl, 2,3-pyrrolidinyl, 2,4-pyrrolidinyl, 2,5-pyrrolidinyl, 3,4-pyrrolidinyl, 2H-2,3-pyranyl, 2H-2, 4-pyranyl, 2H-2,5-pyranyl, 4H-2,3-pyranyl, 4H-2,4-pyranyl, 4H-2,5-pyranyl, 2H-pyranyl -2-keto-3,4-yl, 2H-pyran-2-one-4,5-yl, 4H-pyran-4-one-2,3-yl, 2,3-tetrahydrofuryl, 2, 4-tetrahydrofuryl, 2,5-tetrahydrofuryl, 3,4-tetrahydrofuryl, 2,3-tetrahydropyranyl, 2,4-tetrahydropyranyl, 2,5-tetrahydropyranyl, 2 , 6-tetrahydropyranyl, 3,4-tetrahydropyranyl and 3,5-tetrahydropyranyl, each of the W ^ring nitrogen members containing carbon and hydrogen is optionally Substituted by one or more groups of R ⁹ , R ¹⁰ , R ¹¹ and R ¹² with the proviso that (CH(R ³⁸ )) _r is bonded to E ⁰ and Q ^b is the lowest numbered substituent of each W ³ position bonding;

Y ⁰ is optionally Q ^b -Q ^sssr , wherein Q ^sssr is (CH(R ³⁸ )) _r -W ⁴ , wherein r is an integer selected from 1 to 2, and W ⁴ is selected from 1,2-cyclobutyl , 1,2-cyclohexyl, 1,3-cyclohexyl, 1,4-cyclohexyl, 1,2-cyclopentyl, 1,3-cyclopentyl, 2,3-morpholinyl, 2,4- Morpholinyl, 2,5-morpholinyl, 2,6-morpholinyl, 3,4-morpholinyl, 3,5-morpholinyl, 1,2-piperazinyl, 1,3-piperazine Base, 1,4-piperazinyl, 2,3-piperazinyl, 2,5-piperazinyl, 2,6-piperazinyl, 1,2-piperidinyl, 1,3-piperidinyl, 1,4-piperidinyl, 2,3-piperidinyl, 2,4-piperidinyl, 2,5-piperidinyl, 2,6-piperidinyl, 3,4-piperidinyl, 3, 5-piperidinyl, 3,6-piperidinyl, 1,2-pyrrolidinyl, 1,3-pyrrolidinyl, 2,3-pyrrolidinyl, 2,4-pyrrolidinyl, 2,5- Pyrrolidinyl, 3,4-pyrrolidinyl, 2H-2,3-pyranyl, 2H-2,4-pyranyl, 2H-2,5-pyranyl, 4H-2,3-pyranyl Base, 4H-2,4-pyranyl, 4H-2,5-pyranyl, 2H-pyran-2-one-3,4-yl, 2H-pyran-2-one-4,5- Base, 4H-pyran-4-one-2,3-yl, 2,3-tetrahydrofuryl, 2,4-tetrahydrofuryl, 2,5-tetrahydrofuryl, 3,4-tetrahydrofuryl, 2,3-tetrahydrofuryl Hydropyranyl, 2,4-tetrahydropyranyl, 2,5-tetrahydropyranyl, 2,6-tetrahydropyranyl, 3,4-tetrahydropyranyl and 3,5-tetrahydropyranyl Hydropyranyl, each of the W ^ring nitrogen members containing carbon and hydrogen, except the point of attachment, is optionally substituted by one or more of R ⁹ , R ¹⁰ , R ¹¹ and R ¹² , provided that is (CH(R ³⁸ )) _r bonded to E ⁰ and Q ^b bonded to the highest numbered substituent position of each W ⁴ ;

Y ⁰ is optionally Q ^b -Q ^ssss , wherein Q ^ssss is (CH(R ³⁸ )) _r -W ⁵ , wherein r is an integer selected from 1 to 2, and W ⁵ is selected from 1,4-indenyl, 1,5-indenyl, 1,6-indenyl, 1,7-indenyl, 2,7-indenyl, 2,6-indenyl, 2,5-indenyl, 2,4-indenyl, 3 , 4-indenyl, 3,5-indenyl, 3,6-indenyl, 3,7-indenyl, 2,4-benzofuryl, 2,5-benzofuryl, 2,6-benzene And furyl, 2,7-benzofuryl, 3,4-benzofuryl, 3,5-benzofuryl, 3,6-benzofuryl, 3,7-benzofuryl, 2 , 4-benzothienyl, 2,5-benzothienyl, 2,6-benzothienyl, 2,7-benzothienyl, 3,4-benzothienyl, 3,5-benzothienyl Thienyl, 3,6-benzothienyl, 3,7-benzothienyl, 2,7-imidazo(1,2-a)pyridyl, 3,4-imidazo(1,2-a) Pyridyl, 3,5-imidazo(1,2-a)pyridyl, 3,6-imidazo(1,2-a)pyridyl, 3,7-imidazo(1,2-a)pyridyl , 2,4-indolyl, 2,5-indolyl, 2,6-indolyl, 2,7-indolyl, 3,4-indolyl, 3,5-indolyl, 3 , 6-indolyl, 3,7-indolyl, 1,4-isoindolyl, 1,5-isoindolyl, 1,6-isoindolyl, 2,4-isoindolyl , 2,5-isoindolyl, 2,6-isoindolyl, 2,7-isoindolyl, 1,3-isoindolyl, 3,4-indazolyl, 3,5-indolyl Azolyl, 3,6-indazolyl, 3,7-indazolyl, 2,4-benzoxazolyl, 2,5-benzoxazolyl, 2,6-benzoxazolyl, 2 , 7-benzoxazolyl, 3,4-benzisoxazolyl, 3,5-benzisoxazolyl, 3,6-benzisoxazolyl, 3,7-benzisoxazolyl Azolyl, 1,4-naphthyl, 1,5-naphthyl, 1,6-naphthyl, 1,7-naphthyl, 1,8-naphthyl, 2,4-naphthyl, 2,5-naphthyl Base, 2,6-naphthyl, 2,7-naphthyl, 2,8-naphthyl, 2,4-quinolyl, 2,5-quinolyl, 2,6-quinolyl, 2,7 -quinolyl, 2,8-quinolyl, 3,4-quinolyl, 3,5-quinolyl, 3,6-quinolyl, 3,7-quinolyl, 3,8-quinolinyl Linyl, 4,5-quinolinyl, 4,6-quinolinyl, 4,7-quinolinyl, 4,8-quinolinyl, 1,4-isoquinolinyl, 1,5-isoquinolinyl Linyl, 1,6-isoquinolinyl, 1,7-isoquinolinyl, 1,8-isoquinolinyl, 3,4-isoquinolinyl, 3,5-isoquinolinyl, 3, 6-isoquinolinyl, 3,7-isoquinolinyl, 3,8-isoquinolinyl, 4,5-isoquinolinyl, 4,6-isoquinolinyl, 4,7-isoquinolinyl Base, 4,8-isoquinolinyl, 3,4-cinnolinyl, 3,5-cinnolinyl, 3,6-cinnolinyl, 3,7-cinnolinyl, 3,8-cinnolinyl , 4,5-cinnolinyl, 4,6-cinnolinyl, 4,7-cinnolinyl and 4,8-cinnolinyl, except for the point of attachment, each W ^ring nitrogen member containing carbon and hydrogen are all optionally substituted with one or more groups of R ⁹ , R ¹⁰ , R ¹¹ and R ¹² with the proviso that Q ^b is bonded to the lowest numbered substituent position of each W ⁵ , (CH(R ³⁸ ) ) _r is bonded to E ⁰ ;

Y ⁰ is optionally Q ^b -Q ^ssssr , wherein Q ^ssssr is (CH(R ³⁸ )) _r -W ⁶ , wherein r is an integer selected from 1 to 2, and W ⁶ is selected from 1,4-indenyl, 1,5-indenyl, 1,6-indenyl, 1,7-indenyl, 2,7-indenyl, 2,6-indenyl, 2,5-indenyl, 2,4-indenyl, 3 , 4-indenyl, 3,5-indenyl, 3,6-indenyl, 3,7-indenyl, 2,4-benzofuryl, 2,5-benzofuryl, 2,6-benzene And furyl, 2,7-benzofuryl, 3,4-benzofuryl, 3,5-benzofuryl, 3,6-benzofuryl, 3,7-benzofuryl, 2 , 4-benzothienyl, 2,5-benzothienyl, 2,6-benzothienyl, 2,7-benzothienyl, 3,4-benzothienyl, 3,5-benzothienyl Thienyl, 3,6-benzothienyl, 3,7-benzothienyl, 2,7-imidazo(1,2-a)pyridyl, 3,4-imidazo(1,2-a) Pyridyl, 3,5-imidazo(1,2-a)pyridyl, 3,6-imidazo(1,2-a)pyridyl, 3,7-imidazo(1,2-a)pyridyl , 2,4-indolyl, 2,5-indolyl, 2,6-indolyl, 2,7-indolyl, 3,4-indolyl, 3,5-indolyl, 3 , 6-indolyl, 3,7-indolyl, 1,4-isoindolyl, 1,5-isoindolyl, 1,6-isoindolyl, 2,4-isoindolyl , 2,5-isoindolyl, 2,6-isoindolyl, 2,7-isoindolyl, 1,3-isoindolyl, 3,4-indazolyl, 3,5-indolyl Azolyl, 3,6-indazolyl, 3,7-indazolyl, 2,4-benzoxazolyl, 2,5-benzoxazolyl, 2,6-benzoxazolyl, 2 , 7-benzoxazolyl, 3,4-benzisoxazolyl, 3,5-benzisoxazolyl, 3,6-benzisoxazolyl, 3,7-benzisoxazolyl Azolyl, 1,4-naphthyl, 1,5-naphthyl, 1,6-naphthyl, 1,7-naphthyl, 1,8-naphthyl, 2,4-naphthyl, 2,5-naphthyl Base, 2,6-naphthyl, 2,7-naphthyl, 2,8-naphthyl, 2,4-quinolyl, 2,5-quinolyl, 2,6-quinolyl, 2,7 -quinolyl, 2,8-quinolyl, 3,4-quinolyl, 3,5-quinolyl, 3,6-quinolyl, 3,7-quinolyl, 3,8-quinolinyl Linyl, 4,5-quinolinyl, 4,6-quinolinyl, 4,7-quinolinyl, 4,8-quinolinyl, 1,4-isoquinolinyl, 1,5-isoquinolinyl Linyl, 1,6-isoquinolinyl, 1,7-isoquinolinyl, 1,8-isoquinolinyl, 3,4-isoquinolinyl, 3,5-isoquinolinyl, 3, 6-isoquinolinyl, 3,7-isoquinolinyl, 3,8-isoquinolinyl, 4,5-isoquinolinyl, 4,6-isoquinolinyl, 4,7-isoquinolinyl Base, 4,8-isoquinolinyl, 3,4-cinnolinyl, 3,5-cinnolinyl, 3,6-cinnolinyl, 3,7-cinnolinyl, 3,8-cinnolinyl , 4,5-cinnolinyl, 4,6-cinnolinyl, 4,7-cinnolinyl and 4,8-cinnolinyl, except for the point of attachment, each W ^ring nitrogen member containing carbon and hydrogen are all optionally substituted with one or more groups of R ⁹ , R ¹⁰ , R ¹¹ and R ¹² with the proviso that Q ^b is bonded to the highest numbered substituent position of each W ⁶ , (CH(R ³⁸ ) ) _r is bonded to E ⁰ .

In preferred embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof,

J ^a and J ^b are each O;

B is formula (V):

wherein D ¹ , D ² , J ¹ , J ² and K ¹ are independently selected from C, N, O, S and covalent bonds, with the proviso that at most one can be a covalent bond, D ¹ , D ² , J ¹ , at most one of J ² and K ¹ is O, at most one of D ¹ , D ² , J ¹ , J ² and K ¹ is S, if two of D ¹ , D ² , J ¹ , J ² and K ¹ are O and S, then one of D ¹ , D ² , J ¹ , J ² and K ¹ must be a covalent bond, and at most four of D ¹ , D ² , J ¹ , J ² and K ¹ are N;

R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ³² , R ³³ , R ³⁴ , R ³⁵ and R ³⁶ are independently selected from hydrogen, acetamido, haloacetamido, amidino, guanidino, Alkanedioxy, haloalkylthio, alkanoyloxy, alkoxy, alkoxyalkyl, haloalkoxyalkyl, hydroxy, amino, alkoxyamino, nitro, lower alkylamino, alkylthio , alkylthioalkyl, alkylsulfinyl, alkylsulfonyl, alkylsulfonylalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, Alkylsulfonylamino, alkylaminosulfonyl, amidosulfonyl, monoalkylamidosulfonyl, dialkylamidosulfonyl, alkanoyl, haloalkanoyl, alkyl, alkenyl, halogen, haloalkyl, Haloalkenyl, haloalkoxy, hydroxyhaloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxyalkyl, carboxyalkyl, alkoxycarbonyl, carboxy, carboxamido, carboxamidoalkyl and cyano;

R ¹⁶ , R ¹⁹ , R ³² , R ³³ , R ³⁴ , R ³⁵ and R ³⁶ are independently optionally Q ^b with the proviso that at most one of R ¹⁶ and R ¹⁹ is simultaneously Q ^b and Q ^b is Q ^be ;

B is optionally selected from hydrogen, trialkylsilyl, C2-C8 alkyl, C3-C8 alkenyl, C3-C8 alkylene, C3-C8 alkynyl and C2-C8 haloalkyl, wherein the group B Each member of may be optionally substituted with one or more groups R ³² , R ³³ , R ³⁴ , R ³⁵ and R ³⁶ on any carbon up to and including 6 atoms from the point of attachment of B to A;

B is optionally selected from C3-C12 cycloalkyl and C4-C9 saturated heterocyclyl, wherein each ring carbon can be optionally substituted by R ³³ , ring carbons other than the ring carbon at the point of connection between B and A Optionally substituted by oxo, provided that at most one ring carbon is simultaneously substituted by oxo, ring carbons and nitrogen atoms adjacent to the ring carbon at the point of attachment may optionally be substituted by ^R9 or ^R13 , with R A ring carbon or nitrogen atom adjacent to position ⁹ and two atoms from the point of attachment is optionally substituted by R ¹⁰ , and a ring carbon or nitrogen atom adjacent to position R ¹³ and two atoms from the point of attachment is optionally substituted by R ¹² Substituted, the ring carbon or nitrogen atom three atoms away from the point of attachment and adjacent to the ¹⁰ position of R is optionally substituted by R ¹¹ , the ring carbon or nitrogen atom three atoms away from the point of attachment and adjacent to the ¹² position of R is optionally is optionally substituted by R ³³ , and the ring carbon or nitrogen atom adjacent to the R ¹¹ and R ³³ positions four atoms away from the point of attachment is optionally substituted by R ³⁴ ;

A is selected from covalent single bonds, (W ⁷ ) _rr -(CH(R ¹⁵ )) _pa and (CH(R ¹⁵ )) _pa -(W ⁷ ) _rr , where rr is an integer selected from 0 to 1, pa is an integer selected from 0 to 6, W ⁷ is selected from O, S, C(O), (R ⁷ )NC(O), (R ⁷ )NC(S) and N(R ⁷ ), with the proviso that rr and at most one of pa is 0 at the same time;

^R is selected from hydrogen, hydroxyl and alkyl;

^R is selected from hydrogen, hydroxy, halogen, alkyl and haloalkyl;

Ψ is selected from NH and NOH;

M is selected from N and R ¹ -C;

^R is selected from the group consisting of hydrogen, alkyl, alkenyl, cyano, halogen, haloalkyl, haloalkoxy, haloalkylthio, amino, aminoalkyl, alkylamino, amidino, hydroxy, hydroxyamino, alkoxy, hydroxyalkyl, alkoxyamino, thiohydroxy and alkylthio;

R ² is Z ⁰ -Q;

Z ⁰ is selected from covalent single bonds, (CR ⁴¹ R ⁴² ) _q , (CH(R ⁴¹ )) _g -W ⁰ -(CH(R ⁴² )) _p and (CH(R ⁴¹ )) _e -W ²² - (CH(R ⁴² )) _h , wherein q is an integer selected from 1 to 3, g and p are integers independently selected from 0 to 3, W ⁰ is selected from O, S, C(O), S(O ), N(R ⁴¹ ) and ON(R ⁴¹ ), e and h are integers independently selected from 0 to 1, W ²² is selected from CR ⁴¹ =CR ⁴² , 1,2-cyclopropyl, 1,2- Cyclobutyl, 1,2-cyclohexyl, 1,3-cyclohexyl, 1,2-cyclopentyl, 1,3-cyclopentyl, 2,3-morpholinyl, 2,4-morpholinyl, 2,6-morpholinyl, 3,4-morpholinyl, 3,5-morpholinyl, 1,2-piperazinyl, 1,3-piperazinyl, 2,3-piperazinyl, 2, 6-piperazinyl, 1,2-piperidinyl, 1,3-piperidinyl, 2,3-piperidinyl, 2,4-piperidinyl, 2,6-piperidinyl, 3,4- Piperidinyl, 1,2-pyrrolidinyl, 1,3-pyrrolidinyl, 2,3-pyrrolidinyl, 2,4-pyrrolidinyl, 2,5-pyrrolidinyl, 3,4-pyrrolidinyl Base, 2,3-tetrahydrofuryl, 2,4-tetrahydrofuryl, 2,5-tetrahydrofuryl and 3,4-tetrahydrofuryl, provided that ^Z is directly bonded to the uracil ring;

R ⁴¹ and R ⁴² are independently selected from amidino, hydroxyamino, hydrogen, hydroxy, amino and alkyl;

Q is selected from hydrogen with the proviso that ^Z cannot be a covalent single bond; and formula (II):

wherein D ¹ , D ² , J ¹ , J ² and K ¹ are independently selected from C, N, O, S and covalent bonds, with the proviso that at most one can be a covalent bond, D ¹ , D ² , J ¹ , at most one of J ² and K ¹ is O, at most one of D ¹ , D ² , J ¹ , J ² and K ¹ is S, if two of D ¹ , D ² , J ¹ , J ² and K ¹ are O and S, then one of D ¹ , D ² , J ¹ , J ² and K ¹ must be a covalent bond, and at most four of D ¹ , D ² , J ¹ , J ² and K ¹ are N, the condition is R ⁹ , R ¹⁰ , R ¹¹ , R ¹² and R ¹³ are each independently selected to maintain the tetravalent nature of carbon, the trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen;

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

R ^4a and R ^4b are independently selected from halogen, hydrogen, hydroxyalkyl, alkyl, alkoxyalkyl, alkylthioalkyl and haloalkyl;

If K is (CR ^4a R ^4b ) _n , then E ⁰ is E ¹ , where E ¹ is selected from covalent single bonds, C(O), C(S), C(O)N(R ⁷ ), (R ⁷ ) NC(O), S(O) ₂ , (R ⁷ )NS(O) ₂ and S(O) ₂ N(R ⁷ );

Y ⁰ is formula (IV):

wherein D ⁵ , D ⁶ , J ⁵ and J ⁶ are independently selected from C, N, O, S and covalent bonds, provided that at most one is a covalent bond, K ² is C, D ⁵ , D ⁶ , J At most one of ⁵ and J ⁶ is O, at most one of D ⁵ , D ⁶ , J ⁵ and J ⁶ is S, if two of D ⁵ , D ⁶ , J ⁵ and J ⁶ are O and S, then D ⁵ , One of D ⁶ , J ⁵ and J ⁶ must be a covalent bond, and at most four of D ⁵ , D ⁶ , J ⁵ and J ⁶ are N, with the proviso that R ¹⁶ , R ¹⁷ , R ¹⁸ and R ¹⁹ are each independently selected to maintain the tetravalent nature of carbon, the trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen;

R ¹⁶ , R ¹⁷ , R ¹⁸ and R ¹⁹ are independently selected from hydrogen, amidino, guanidino, carboxyl, haloalkylthio, alkoxy, hydroxyl, amino, nitro, alkoxyamino, lower alkylamino, Alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, alkenyl, halogen, haloalkyl, haloalkoxy, hydroxyalkyl, alkyleneamino, haloalkoxyalkyl , alkoxycarbonyl and cyano;

Q ^b is selected from NR ²⁰ R ²¹ , aminoalkylene, Q ^be , N(R ²⁶ )C(NR 25 )N( ^{R 23 )} (R ²⁴ ) and C(NR ²⁵ )NR ²³ R ²⁴ , wherein Q ^be is hydrogen, with the proviso that at most one of ^R20 and ^R21 is simultaneously hydroxyl, amino, alkylamino or dialkylamino, and at most one of ^R23 and ^R24 is simultaneously hydroxyl, amino, alkylamino or dialkyl Amino;

R ²⁰ , R ²¹ , R ²³ , R ²⁴ , R ²⁵ and R ²⁶ are independently selected from hydrogen, alkyl, hydroxy, aminoalkylene, amino, dialkylamino, alkylamino and hydroxyalkyl;

Q ^s is selected from covalent single bonds, (CR ³⁷ R ³⁸ ) _b and (CH(R ¹⁴ )) _c -W ¹ -(CH(R ¹⁵ )) _d , wherein b is an integer selected from 1 to 4, c and d are integers independently selected from 1 to 3, W ¹ is selected from C(O)N(R ¹⁴ ), (R ¹⁴ )NC(O), S(O), S(O) ₂ , S(O ) ₂ N(R ¹⁴ ), N(R ¹⁴ )S(O) ₂ and N(R ¹⁴ ), with the proviso that R ¹⁴ is selected from groups other than halogen if directly bonded to N, (CR ³⁷ R ³⁸ ) _b and (CH(R ¹⁴ )) _c are bonded to E ⁰ ;

^R is selected from hydrogen, halogen, alkyl and haloalkyl;

R ³⁷ and R ³⁸ are independently selected from hydrogen, alkyl and haloalkyl;

R is ^optionally selected from aroyl and heteroaroyl;

Y ⁰ is optionally Q ^b -Q ^ss , wherein Q ^ss is (CH(R ¹⁴ )) _e -W ² -(CH(R ¹⁵ )) _h , wherein e and h are independently selected from 1 to 2 Integer, W ² is CR ^4a =CR ^4b with the proviso that (CH(R ¹⁵ )) _e is bonded to E ⁰ ;

Y ⁰ is optionally selected from Q ^b -Q ^ssss and Q ^b -Q ^ssssr , wherein Q ^ssss is (CH(R ³⁸ )) _r -W ⁵ , Q ^ssssr is (CH(R ³⁸ )) _r -W ⁶ , r is an integer selected from 1 to 2, W ^and W are ^{independently} selected from 1,4-indenyl, 1,5-indenyl, 1,6-indenyl, 1,7-indenyl, 2,7 -indenyl, 2,6-indenyl, 2,5-indenyl, 2,4-indenyl, 3,4-indenyl, 3,5-indenyl, 3,6-indenyl, 3,7- Indenyl, 2,4-benzofuryl, 2,5-benzofuryl, 2,6-benzofuryl, 2,7-benzofuryl, 3,4-benzofuryl, 3, 5-benzofuryl, 3,6-benzofuryl, 3,7-benzofuryl, 2,4-benzothienyl, 2,5-benzothienyl, 2,6-benzothiophene Base, 2,7-benzothienyl, 3,4-benzothienyl, 3,5-benzothienyl, 3,6-benzothienyl, 3,7-benzothienyl, 2,7 -imidazo(1,2-a)pyridyl, 3,4-imidazo(1,2-a)pyridyl, 3,5-imidazo(1,2-a)pyridyl, 3,6-imidazole And (1,2-a) pyridyl, 3,7-imidazo (1,2-a) pyridyl, 2,4-indolyl, 2,5-indolyl, 2,6-indolyl , 2,7-indolyl, 3,4-indolyl, 3,5-indolyl, 3,6-indolyl, 3,7-indolyl, 1,4-isoindolyl, 1,5-isoindolyl, 1,6-isoindolyl, 2,4-isoindolyl, 2,5-isoindolyl, 2,6-isoindolyl, 2,7-isoindolyl Indolyl, 1,3-isoindolyl, 3,4-indazolyl, 3,5-indazolyl, 3,6-indazolyl, 3,7-indazolyl, 2,4-benzene And oxazolyl, 2,5-benzoxazolyl, 2,6-benzoxazolyl, 2,7-benzoxazolyl, 3,4-benzisoxazolyl, 3,5- Benzisoxazolyl, 3,6-benzisoxazolyl, 3,7-benzisoxazolyl, 1,4-naphthyl, 1,5-naphthyl, 1,6-naphthyl, 1,7-naphthyl, 1,8-naphthyl, 2,4-naphthyl, 2,5-naphthyl, 2,6-naphthyl, 2,7-naphthyl, 2,8-naphthyl, 2 , 4-quinolyl, 2,5-quinolyl, 2,6-quinolyl, 2,7-quinolyl, 2,8-quinolyl, 3,4-quinolyl, 3,5 -quinolyl, 3,6-quinolyl, 3,7-quinolyl, 3,8-quinolyl, 4,5-quinolyl, 4,6-quinolyl, 4,7-quinolinyl Linyl, 4,8-quinolinyl, 1,4-isoquinolinyl, 1,5-isoquinolinyl, 1,6-isoquinolinyl, 1,7-isoquinolinyl, 1,8 -isoquinolinyl, 3,4-isoquinolinyl, 3,5-isoquinolinyl, 3,6-isoquinolinyl, 3,7-isoquinolinyl, 3,8-isoquinolinyl , 4,5-isoquinolinyl, 4,6-isoquinolinyl, 4,7-isoquinolinyl, 4,8-isoquinolinyl, 3,4-cinnolinyl, 3,5-cinnolinyl Linyl, 3,6-cinnolinyl, 3,7-cinnolinyl, 3,8-cinnolinyl, 4,5-cinnolinyl, 4,6-cinnolinyl, 4,7-cinnolinyl and 4,8-cinnolinyl, except for the point of attachment of ^W5 and ^W6 , each of the ^W5 and ^W6 ring nitrogen members containing carbon and hydrogen is optionally replaced by one or more ^R9 , ^R10 , Group substitution of ^R11 and ^R12 with the proviso that ^Qb is bonded to the lowest numbered substituent position of each ^W5 , ^Qb is bonded to the highest numbered substituent position of each ^W6 , (CH( ^R38 )) _r is bonded to E ⁰ .

In a more preferred embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof,

J ^a and J ^b are each O;

B is selected from aryl and heteroaryl, wherein one carbon adjacent to the carbon at the point of attachment is ^optionally substituted with R and the other carbon adjacent to the carbon at the point of attachment is ^optionally substituted with R, the carbon adjacent to ^R32 and two atoms away from the carbon on the point of attachment is optionally substituted by ^R33 , the carbon adjacent to ^R36 and two atoms away from the carbon on the point of attachment is optionally substituted by ^R35 , Any carbon adjacent to both R ³³ and R ³⁵ is optionally substituted by R ³⁴ ;

R ³² , R ³³ , R ³⁴ , R ³⁵ and R ³⁶ are independently selected from hydrogen, acetamido, haloacetamido, amidino, guanidino, alkylenedioxy, haloalkylthio, alkanoyloxy, alkane Oxy, hydroxy, amino, alkoxyamino, alkanoyl, haloalkanoyl, nitro, lower alkylamino, alkylthio, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl , heterocyclyl, alkylsulfonylamino, amidosulfonyl, monoalkylamidosulfonyl, dialkylamidosulfonyl, alkyl, alkenyl, halogen, haloalkyl, haloalkenyl, haloalkoxy Base, hydroxyalkyl, alkyleneamino, alkoxycarbonyl, carboxyl, carboxamido, cyano and Q ^b ;

B is optionally selected from hydrogen, trialkylsilyl, C2-C8 alkyl, C3-C8 alkylene, C3-C8 alkenyl, C3-C8 alkynyl and C2-C8 haloalkyl, wherein the group B Each member of may be optionally substituted with one or more groups R ³² , R ³³ , R ³⁴ , R ³⁵ and R ³⁶ on any carbon up to and including 6 atoms from the point of attachment of B to A;

B is optionally selected from C3-C12 cycloalkyl and C4-C9 saturated heterocyclyl, wherein each ring carbon is optionally substituted by R ³³ , and any ring carbon other than the ring carbon at the point of connection between B and A Optionally substituted by oxo, provided that at most one ring carbon is simultaneously substituted by oxo, ring carbons and nitrogen atoms adjacent to the ring carbon at the point of attachment are optionally substituted by R ⁹ or R ¹³ , and R ⁹ A ring carbon or nitrogen atom adjacent to and two atoms from the point of attachment is optionally substituted by R ¹⁰ , a ring carbon or nitrogen atom adjacent to the position of R ¹³ and two atoms from the point of attachment is optionally substituted by R ¹² , A ring carbon or nitrogen atom three atoms from the point of attachment and adjacent to the R ¹⁰ position is optionally substituted by R ¹¹ , and a ring carbon or nitrogen atom three atoms from the attachment point adjacent to the R ¹² position is optionally substituted by R ³³ is substituted, and the ring carbon or nitrogen atom adjacent to the R ¹¹ and R ³³ positions four atoms away from the connection point is optionally substituted by R ³⁴ ;

R ⁹ , R ¹⁰ , R ¹¹ , R ¹² and R ¹³ are independently selected from hydrogen, acetamido, haloacetamido, alkoxyamino, alkanoyl, haloalkanoyl, amidino, guanidino, alkylenedioxy , Haloalkylthio, Alkoxy, Hydroxy, Amino, Lower Alkylamino, Alkylthio, Alkylsulfinyl, Alkylsulfonyl, Alkylsulfonylamino, Amidosulfonyl, Alkylamidosulfonyl Acyl, dialkylamidosulfonyl, alkyl, halogen, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, alkoxycarbonyl, carboxyalkyl, carboxy, carboxamido and cyano;

A is selected from a covalent single bond and (CH(R ¹⁵ )) _pa -(W ⁷ ) _rr , wherein rr is an integer selected from 0 to 1, pa is an integer selected from 0 to 3, W ⁷ is selected from O, S, C(O), ( ^R7 )NC(O), ( ^R7 )NC(S) and N( ^R7 );

^R is selected from hydrogen, hydroxyl and alkyl;

^R is selected from hydrogen, hydroxy, halogen, alkyl and haloalkyl;

Ψ is NH;

M is selected from N and R ¹ -C;

^R is selected from hydrogen, alkyl, cyano, halogen, haloalkyl, haloalkoxy, amino, aminoalkyl, alkylamino, amidino, hydroxy, hydroxyamino, alkoxy, hydroxyalkyl, alkoxy Amino, thiohydroxyl and alkylthio;

R ² is Z ⁰ -Q;

Z ⁰ is selected from covalent single bonds, (CR ⁴¹ R ⁴² ) _q , (CH(R ⁴¹ )) _g -W ⁰ -(CH(R ⁴² )) _p and (CH(R ⁴¹ )) _e -W ²² - (CH(R ⁴² )) _h , wherein q is an integer selected from 1 to 2, g and p are integers independently selected from 0 to 3, W ⁰ is selected from O, S and N(R ⁴¹ ), e and h is an integer independently selected from 0 to 1, W ²² is selected from CR ⁴¹ =CR ⁴² , 1,2-cyclopropyl, 1,2-cyclobutyl, 1,2-cyclohexyl, 1,3-cyclo Hexyl, 1,2-cyclopentyl, 1,3-cyclopentyl, 2,3-morpholinyl, 2,4-morpholinyl, 2,6-morpholinyl, 3,4-morpholinyl, 3,5-morpholinyl, 1,2-piperazinyl, 1,3-piperazinyl, 2,3-piperazinyl, 2,6-piperazinyl, 1,2-piperidinyl, 1, 3-piperidinyl, 2,3-piperidinyl, 2,4-piperidinyl, 2,6-piperidinyl, 3,4-piperidinyl, 1,2-pyrrolidinyl, 1,3- Pyrrolidinyl, 2,3-pyrrolidinyl, 2,4-pyrrolidinyl, 2,5-pyrrolidinyl, 3,4-pyrrolidinyl, 2,3-tetrahydrofuryl, 2,4-tetrahydrofuranyl, 2,5-tetrahydrofuryl and 3,4-tetrahydrofuryl, with the proviso that ^Z is directly bonded to the uracil ring;

R ⁴¹ and R ⁴² are independently selected from hydrogen, hydroxyl and amino;

Q is selected from hydrogen, with the proviso that ^Z cannot be a covalent single bond; aryl and heteroaryl, one of the carbons adjacent to the carbon at the point of attachment is optionally substituted with R, and the other with ^{the carbon} at the point of attachment The carbon adjacent to the carbon of R is optionally substituted by R ¹³ , the carbon adjacent to R ⁹ and two atoms away from the carbon on the point of attachment is optionally substituted by R ¹⁰ , adjacent to R ¹³ and the distance from the carbon on the point of attachment is 10 The carbon of two carbon atoms is optionally substituted by R ¹² , and any carbon adjacent to both R ¹⁰ and R ¹² is optionally substituted by R ¹¹ ;

K is ^CHR4a , wherein ^R4a is selected from hydrogen, hydroxyalkyl, alkyl, alkoxyalkyl, alkylthioalkyl and haloalkyl;

^E is selected from covalent single bonds, C(O)N(H), (H)NC(O), (R ⁷ )NS(O) ₂ and S(O) ₂ N(R ⁷ );

Y ⁰ is formula (IV):

wherein D ⁵ , D ⁶ , J ⁵ and J ⁶ are independently selected from C, N, O, S and covalent bonds, provided that at most one is a covalent bond, K ² is C, D ⁵ , D ⁶ , J At most one of ⁵ and J ⁶ is O, at most one of D ⁵ , D ⁶ , J ⁵ and J ⁶ is S, if two of D ⁵ , D ⁶ , J ⁵ and J ⁶ are O and S, then D ⁵ , One of D ⁶ , J ⁵ and J ⁶ must be a covalent bond, and at most four of D ⁵ , D ⁶ , J ⁵ and J ⁶ are N, with the proviso that R ¹⁶ , R ¹⁷ , R ¹⁸ and R ¹⁹ are each independently selected to maintain the tetravalent nature of carbon, the trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen;

R ¹⁶ , R ¹⁷ , R ¹⁸ and R ¹⁹ are independently selected from hydrogen, amidino, guanidino, carboxyl, haloalkylthio, alkoxy, hydroxyl, amino, alkoxyamino, lower alkylamino, alkylthio , alkylsulfinyl, alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, and cyano;

R ¹⁶ and R ¹⁹ are optionally Q ^b with the proviso that at most one of R ¹⁶ and R ¹⁹ is Q ^b at the same time, and Q ^b is Q ^be ;

Q ^b is selected from NR ²⁰ R ²¹ , Q ^be , N(R ²⁶ )C(NR ²⁵ )N(R ²³ )(R ²⁴ ) and C(NR ²⁵ )NR ²³ R ²⁴ , wherein Q ^be is hydrogen, and the condition It is that at most one of R ²⁰ and R ²¹ is simultaneously hydroxyl, amino, alkylamino or dialkylamino, and at most one of R ²³ and R ²⁴ is simultaneously hydroxyl, amino, alkylamino or dialkylamino;

R ²⁰ , R ²¹ , R ²³ , R ²⁴ , R ²⁵ and R ²⁶ are independently selected from hydrogen, alkyl, hydroxyl, amino, alkylamino and dialkylamino;

Q ^s is selected from covalent single bonds, (CR ³⁷ R ³⁸ ) _b and (CH(R ¹⁴ )) _c -W ¹ -(CH(R ¹⁵ )) _d , wherein b is an integer selected from 1 to 4, c and d are integers independently selected from 1 to 3, W ¹ is selected from C(O)N(R ¹⁴ ), (R ¹⁴ )NC(O), S(O), S(O) ₂ , S(O ) ₂ N(R ¹⁴ ), N(R ¹⁴ )S(O) ₂ and N(R ¹⁴ ), with the proviso that R ¹⁴ is selected from groups other than halogen if directly bonded to N, (CR ³⁷ R ³⁸ ) _b and (CH(R ¹⁴ )) _c are bonded to E ⁰ ;

^R is selected from hydrogen, halogen, alkyl and haloalkyl;

R ³⁷ and R ³⁸ are independently selected from hydrogen, alkyl and haloalkyl;

R is ^optionally selected from aroyl and heteroaroyl;

Y ⁰ is optionally Q ^b -Q ^ss , wherein Q ^ss is (CH(R ¹⁴ )) _e -W ² -(CH(R ¹⁵ )) _h , wherein e and h are independently selected from 1 to 2 Integer, W ² is CR ^4a =CH with the proviso that (CH(R ¹⁴ )) _e is bonded to E ⁰ .

In yet more preferred embodiments of the compound of formula I or a pharmaceutically acceptable salt thereof,

J ^a and J ^b are each O;

B is selected from aryl and heteroaryl, wherein one carbon adjacent to the carbon at the point of attachment is ^optionally substituted with R and the other carbon adjacent to the carbon at the point of attachment is ^optionally substituted with R, the carbon adjacent to ^R32 and two atoms away from the carbon on the point of attachment is optionally substituted by ^R33 , the carbon adjacent to ^R36 and two atoms away from the carbon on the point of attachment is optionally substituted by ^R35 , Any carbon adjacent to both R ³³ and R ³⁵ is optionally substituted by R ³⁴ ;

R ³² , R ³³ , R ³⁴ , R ³⁵ and R ³⁶ are independently selected from hydrogen, acetamido, haloacetamido, amidino, guanidino, alkoxy, hydroxyl, amino, alkoxyamino, lower alkyl Amino, alkylthio, amidosulfonyl, monoalkylamidosulfonyl, dialkylamidosulfonyl, alkyl, halogen, haloalkyl, haloalkoxy, hydroxyalkyl, alkoxycarbonyl, carboxyl, carboxyl amido, cyano and ^Qb ;

A is selected from a covalent single bond and (CH(R ¹⁵ )) _pa -(W ⁷ ) _rr , where rr is an integer selected from 0 to 1, pa is an integer selected from 0 to 3, and W ⁷ is selected from (R ⁷ ) NC(O) and N(R ⁷ );

^R is selected from hydrogen, hydroxyl and alkyl;

^R is selected from hydrogen, halogen, alkyl and haloalkyl;

Ψ is NH;

M is selected from N and R ¹ -C;

^R is selected from the group consisting of hydrogen, hydroxy, hydroxyamino, amidino, amino, cyano, hydroxyalkyl, alkoxy, alkyl, alkylamino, aminoalkyl, alkylthio, alkoxyamino, haloalkyl, Haloalkoxy and halogen;

R ² is Z ⁰ -Q;

Z ⁰ is selected from covalent single bonds, O, S, NH and CH ₂ ;

Q is selected from aryl and heteroaryl, wherein one carbon adjacent to the carbon at the point of attachment is optionally substituted with ^R , and the other carbon adjacent to the carbon at the point of attachment is optionally substituted with ^R , the carbon adjacent to ^R9 and two atoms away from the carbon on the point of attachment is optionally substituted by ^R10 , the carbon adjacent to ^R13 and two atoms away from the carbon on the point of attachment is optionally substituted by ^R12 , Any carbon adjacent to both R ¹⁰ and R ¹² is optionally substituted by R ¹¹ ;

R ⁹ , R ¹¹ and R ¹³ are independently selected from hydrogen, hydroxyl, amino, amidino, guanidino, lower alkylamino, alkylthio, alkylsulfonylamino, alkylsulfinyl, alkylsulfonyl, amidosulfonyl, monoalkylamidosulfonyl, alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxyalkyl, carboxy, carboxamido and cyano;

R and ^R are independently selected from hydrogen, acetamido, haloacetamido, amidino, guanidino, alkyl, alkoxy, hydroxyl, amino, alkoxyamino, lower alkylamino ^, alkylsulfonyl Amino, amidosulfonyl, monoalkylamidosulfonyl, dialkylamidosulfonyl, hydroxyalkyl, aminoalkyl, alkoxycarbonyl, carboxy, carboxyalkyl, amidocarbonyl, halogen, haloalkyl and cyano;

K is _CH2 ;

E ⁰ is C(O)N(H);

Y ⁰ is formula (IV):

wherein D ⁵ , D ⁶ , J ⁵ and J ⁶ are independently selected from C, N, O, S and covalent bonds, provided that at most one is a covalent bond, K ² is C, D ⁵ , D ⁶ , J At most one of ⁵ and J ⁶ is optionally O, at most one of D ⁵ , D ⁶ , J ⁵ and J ⁶ is optionally S, if two of D ⁵ , D ⁶ , J ⁵ and J ⁶ are O and S, Then one of D ⁵ , D ⁶ , J ⁵ and J ⁶ must be a covalent bond, and at most four of D ⁵ , D ⁶ , J ⁵ and J ⁶ are N;

R ¹⁶ , R ¹⁷ , R ¹⁸ and R ¹⁹ are independently selected from hydrogen, amidino, guanidino, carboxyl, haloalkylthio, alkoxy, hydroxyl, amino, lower alkylamino, alkylthio, alkylsulfinyl Acyl, alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, and cyano;

R ¹⁶ and R ¹⁹ are optionally Q ^b with the proviso that at most one of R ¹⁶ and R ¹⁹ is Q ^b at the same time, and Q ^b is Q ^be ;

Q ^b is selected from NR ²⁰ R ²¹ , Q ^be and C(NR ²⁵ )NR ²³ R ²⁴ , wherein Q ^be is hydrogen, provided that at most one of R ²⁰ and R ²¹ is simultaneously a hydroxyl group, and at most of R ²³ and R ²⁴ one is also hydroxyl;

R ²⁰ , R ²¹ , R ²³ , R ²⁴ and R ²⁵ are independently selected from hydrogen, alkyl and hydroxyl;

Q ^s is selected from a covalent single bond, CH ₂ and CH ₂ CH ₂ .

In another yet more preferred embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof,

J ^a and J ^b are each O;

B is optionally selected from hydrogen, C2-C8 alkyl, C3-C8 alkenyl, C3-C8 alkynyl, and C2-C8 haloalkyl, wherein each member of group B is optionally at a distance B from the point of attachment to A Any carbon up to and including 6 atoms is substituted by one or more groups R ³² , R ³³ , R ³⁴ , R ³⁵ and R ³⁶ ;

R ³² , R ³³ , R ³⁴ , R ³⁵ and R ³⁶ are independently selected from hydrogen, acetamido, haloacetamido, amidino, guanidino, alkoxy, hydroxyl, amino, alkoxyamino, lower alkyl Amino, alkylthio, amidosulfonyl, monoalkylamidosulfonyl, dialkylamidosulfonyl, alkyl, halogen, haloalkyl, haloalkoxy, hydroxyalkyl, alkoxycarbonyl, carboxyl, carboxyl amido, cyano and ^Qb ;

A is selected from a covalent single bond and (CH(R ¹⁵ )) _pa -(W ⁷ ) _rr , where rr is an integer selected from 0 to 1, pa is an integer selected from 0 to 3, and W ⁷ is selected from (R ⁷ ) NC(O) and N(R ⁷ );

^R is selected from hydrogen, hydroxyl and alkyl;

^R is selected from hydrogen, halogen, alkyl and haloalkyl;

Ψ is NH;

M is selected from N and R ¹ -C;

^R is selected from the group consisting of hydrogen, hydroxy, hydroxyamino, amidino, amino, cyano, hydroxyalkyl, alkoxy, alkyl, alkylamino, aminoalkyl, alkylthio, alkoxyamino, haloalkyl, Haloalkoxy and halogen;

R ² is Z ⁰ -Q;

Z ⁰ is selected from covalent single bonds, O, S, NH and CH ₂ ;

Q is selected from aryl and heteroaryl, wherein one carbon adjacent to the carbon at the point of attachment is optionally substituted with ^R , and the other carbon adjacent to the carbon at the point of attachment is optionally substituted with ^R , the carbon adjacent to ^R9 and two atoms away from the carbon on the point of attachment is optionally substituted by ^R10 , the carbon adjacent to ^R13 and two atoms away from the carbon on the point of attachment is optionally substituted by ^R12 , Any carbon adjacent to both R ¹⁰ and R ¹² is optionally substituted by R ¹¹ ;

R ⁹ , R ¹¹ and R ¹³ are independently selected from hydrogen, hydroxyl, amino, amidino, guanidino, lower alkylamino, alkylthio, alkylsulfonylamino, alkylsulfinyl, alkylsulfonyl, amidosulfonyl, monoalkylamidosulfonyl, alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxyalkyl, carboxy, carboxamido and cyano;

R and ^R are independently selected from hydrogen, acetamido, haloacetamido, amidino, guanidino, alkyl, alkoxy, hydroxyl, amino, alkoxyamino, lower alkylamino ^, alkylsulfonyl Amino, amidosulfonyl, monoalkylamidosulfonyl, dialkylamidosulfonyl, hydroxyalkyl, alkyleneamino, alkoxycarbonyl, carboxyl, carboxyalkyl, amidocarbonyl, halogen, haloalkyl and cyano;

K is _CH2 ;

E ⁰ is C(O)N(H);

Y ⁰ is formula (IV):

wherein D ⁵ , D ⁶ , J ⁵ and J ⁶ are independently selected from C, N, O, S and covalent bonds, provided that at most one is a covalent bond, K ² is C, D ⁵ , D ⁶ , J At most one of ⁵ and J ⁶ is O, at most one of D ⁵ , D ⁶ , J ⁵ and J ⁶ is S, if two of D ⁵ , D ⁶ , J ⁵ and J ⁶ are O and S, then D ⁵ , One of D ⁶ , J ⁵ and J ⁶ must be a covalent bond, and at most four of D ⁵ , D ⁶ , J ⁵ and J ⁶ are N, with the proviso that R ¹⁶ , R ¹⁷ , R ¹⁸ and R ¹⁹ are each independently selected to maintain the tetravalent nature of carbon, the trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen;

R ¹⁶ , R ¹⁷ , R ¹⁸ and R ¹⁹ are independently selected from hydrogen, amidino, guanidino, carboxyl, haloalkylthio, alkoxy, hydroxyl, amino, lower alkylamino, alkylthio, alkylsulfinyl Acyl, alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, alkyleneamino, and cyano;

R ¹⁶ and R ¹⁹ are optionally Q ^b with the proviso that at most one of R ¹⁶ and R ¹⁹ is Q ^b at the same time, and Q ^b is Q ^be ;

Q ^b is selected from NR ²⁰ R ²¹ , Q ^be , C(NR ²⁵ )NR ²³ R ²⁴ and N(R ²⁶ )C(NR ²⁵ )NR ²³ R ²⁴ , wherein Q ^be is hydrogen, provided that R ²⁰ and R At most one of ²¹ is a hydroxyl group at the same time, and at most one of ^R23 and ^R24 is a hydroxyl group at the same time;

R ²⁰ , R ²¹ , R ²³ , R ²⁴ , R ²⁵ and R ²⁶ are independently selected from hydrogen, alkyl and hydroxyl;

Q ^s is selected from a covalent single bond, CH ₂ and CH ₂ CH ₂ .

In another still more preferred embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof,

J ^a and J ^b are each O;

B is optionally selected from C3-C7 cycloalkyl and C4-C6 saturated heterocyclyl, wherein each ring carbon is optionally substituted by R ³³ , and any ring carbon other than the ring carbon at the point of connection between B and A Optionally substituted by oxo, provided that at most one ring carbon is simultaneously substituted by oxo, ring carbons and nitrogen atoms adjacent to the ring carbon at the point of attachment are optionally substituted by R ⁹ or R ¹³ , and R ⁹ A ring carbon or nitrogen atom adjacent to and two atoms from the point of attachment is optionally substituted by R ¹⁰ , a ring carbon or nitrogen atom adjacent to the position of R ¹³ and two atoms from the point of attachment is optionally substituted by R ¹² , A ring carbon or nitrogen atom three atoms from the point of attachment and adjacent to the R ¹⁰ position is optionally substituted by R ¹¹ , and a ring carbon or nitrogen atom three atoms from the attachment point adjacent to the R ¹² position is optionally substituted by R ³³ is substituted, and the ring carbon or nitrogen atom adjacent to the R ¹¹ and R ³³ positions four atoms away from the connection point is optionally substituted by R ³⁴ ;

R ⁹ , R ¹¹ and R ¹³ are independently selected from hydrogen, hydroxyl, amino, amidino, guanidino, lower alkylamino, alkylthio, alkylsulfonylamino, alkylsulfinyl, alkylsulfonyl, amidosulfonyl, monoalkylamidosulfonyl, alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxyalkyl, carboxy, carboxamido and cyano;

R and ^R are independently selected from hydrogen, acetamido, haloacetamido, amidino, guanidino, alkyl, alkoxy, hydroxyl, amino, alkoxyamino, lower alkylamino ^, alkylsulfonyl Amino, amidosulfonyl, monoalkylamidosulfonyl, dialkylamidosulfonyl, hydroxyalkyl, alkyleneamino, alkoxycarbonyl, carboxyl, carboxyalkyl, amidocarbonyl, halogen, haloalkyl and cyano;

R ³³ and R ³⁴ are independently selected from hydrogen, acetamido, haloacetamido, amidino, guanidino, alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, alkylthio, amidosulfonyl Acyl, monoalkylamidosulfonyl, dialkylamidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, alkoxycarbonyl, carboxy, carboxamido, cyano and ^Qb ;

A is selected from a covalent single bond and (CH(R ¹⁵ )) _pa -(W ⁷ ) _rr , where rr is an integer selected from 0 to 1, pa is an integer selected from 0 to 3, and W ⁷ is selected from (R ⁷ ) NC(O) and N(R ⁷ );

^R is selected from hydrogen, hydroxyl and alkyl;

^R is selected from hydrogen, halogen, alkyl and haloalkyl;

Ψ is NH;

M is selected from N and R ¹ -C;

^R is selected from the group consisting of hydrogen, hydroxy, hydroxyamino, amidino, amino, cyano, hydroxyalkyl, alkoxy, alkyl, alkylamino, aminoalkyl, alkylthio, alkoxyamino, haloalkyl, Haloalkoxy and halogen;

R ² is Z ⁰ -Q;

Z ⁰ is selected from covalent single bonds, O, S, NH and CH ₂ ;

Q is selected from aryl and heteroaryl, wherein one carbon adjacent to the carbon at the point of attachment is optionally substituted with ^R , and the other carbon adjacent to the carbon at the point of attachment is optionally substituted with ^R , the carbon adjacent to ^R9 and two atoms away from the carbon on the point of attachment is optionally substituted by ^R10 , the carbon adjacent to ^R13 and two atoms away from the carbon on the point of attachment is optionally substituted by ^R12 , Any carbon adjacent to both R ¹⁰ and R ¹² is optionally substituted by R ¹¹ ;

K is _CH2 ;

E ⁰ is C(O)N(H);

Y ⁰ is formula (IV):

wherein D ⁵ , D ⁶ , J ⁵ and J ⁶ are independently selected from C, N, O, S and covalent bonds, provided that at most one is a covalent bond, K ² is C, D ⁵ , D ⁶ , J At most one of ⁵ and J ⁶ is O, at most one of D ⁵ , D ⁶ , J ⁵ and J ⁶ is S, if two of D ⁵ , D ⁶ , J ⁵ and J ⁶ are O and S, then D ⁵ , One of D ⁶ , J ⁵ and J ⁶ must be a covalent bond, and at most four of D ⁵ , D ⁶ , J ⁵ and J ⁶ are N, with the proviso that R ¹⁶ , R ¹⁷ , R ¹⁸ and R ¹⁹ are each independently selected to maintain the tetravalent nature of carbon, the trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen;

R ¹⁶ , R ¹⁷ , R ¹⁸ and R ¹⁹ are independently selected from hydrogen, amidino, guanidino, carboxyl, haloalkylthio, alkoxy, hydroxyl, amino, lower alkylamino, alkylthio, alkylsulfinyl Acyl, alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, alkyleneamino, and cyano;

R ¹⁶ and R ¹⁹ are optionally Q ^b with the proviso that at most one of R ¹⁶ and R ¹⁹ is Q ^b at the same time, and Q ^b is Q ^be ;

Q ^b is selected from NR ²⁰ R ²¹ , Q ^be and C(NR ²⁵ )NR ²³ R ²⁴ , wherein Q ^be is hydrogen, provided that at most one of R ²⁰ and R ²¹ is simultaneously a hydroxyl group, and at most of R ²³ and R ²⁴ one is also hydroxyl;

R ²⁰ , R ²¹ , R ²³ , R ²⁴ and R ²⁵ are independently selected from hydrogen, alkyl and hydroxyl;

Q ^s is selected from a covalent single bond, CH ₂ and CH ₂ CH ₂ .

In the most preferred embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof,

J ^a and J ^b are each O;

B is selected from aryl and heteroaryl, wherein one carbon adjacent to the carbon at the point of attachment is ^optionally substituted with R and the other carbon adjacent to the carbon at the point of attachment is ^optionally substituted with R, the carbon adjacent to ^R32 and two atoms away from the carbon on the point of attachment is optionally substituted by ^R33 , the carbon adjacent to ^R36 and two atoms away from the carbon on the point of attachment is optionally substituted by ^R35 , Any carbon adjacent to both R ³³ and R ³⁵ is optionally substituted by R ³⁴ ;

R ³² , R ³³ , R ³⁴ , R ³⁵ and R ³⁶ are independently selected from hydrogen, acetamido, haloacetamido, amidino, guanidino, alkoxy, hydroxyl, amino, alkoxyamino, lower alkyl Amino, alkylthio, amidosulfonyl, monoalkylamidosulfonyl, dialkylamidosulfonyl, alkyl, halogen, haloalkyl, haloalkoxy, hydroxyalkyl, alkoxycarbonyl, carboxyl, carboxyl amido, cyano and ^Qb ;

A is selected from a covalent single bond and (CH(R ¹⁵ )) _pa -(W ⁷ ) _rr , where rr is an integer selected from 0 to 1, pa is an integer selected from 0 to 3, and W ⁷ is N(R ⁷ );

^R is selected from hydrogen and alkyl;

^R is selected from hydrogen, halogen, alkyl and haloalkyl;

Ψ is NH;

M is selected from N and R ¹ -C;

^R is selected from the group consisting of hydrogen, hydroxy, hydroxyamino, amidino, amino, cyano, hydroxyalkyl, alkoxy, alkyl, alkylamino, aminoalkyl, alkylthio, alkoxyamino, haloalkyl, Haloalkoxy and halogen;

R ² is Z ⁰ -Q;

Z ⁰ is a covalent single bond;

Q is selected from aryl and heteroaryl, wherein one carbon adjacent to the carbon at the point of attachment is optionally substituted with ^R , and the other carbon adjacent to the carbon at the point of attachment is optionally substituted with ^R , the carbon adjacent to ^R9 and two atoms away from the carbon on the point of attachment is optionally substituted by ^R10 , the carbon adjacent to ^R13 and two atoms away from the carbon on the point of attachment is optionally substituted by ^R12 , Any carbon adjacent to both R ¹⁰ and R ¹² is optionally substituted by R ¹¹ ;

R ⁹ , R ¹¹ and R ¹³ are independently selected from hydrogen, hydroxyl, amino, amidino, guanidino, lower alkylamino, alkylthio, alkoxy, alkylsulfinyl, alkylsulfonyl, amido Sulfonyl, monoalkylamidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboxy, carboxamido and cyano;

R and ^R are independently selected from hydrogen, acetamido, haloacetamido, amidino, guanidino, alkyl, alkoxy, alkoxyamino, aminoalkyl, hydroxy, amino, ^lower alkylamino, Alkylsulfonylamino, amidosulfonyl, monoalkylamidosulfonyl, dialkylamidosulfonyl, hydroxyalkyl, aminoalkyl, halogen, haloalkyl, alkoxycarbonyl, carboxyl, carboxyalkyl, Carboxamido and cyano;

K is _CH2 ;

E ⁰ is C(O)N(H);

Y ⁰ is formula (IV):

wherein D ⁵ , D ⁶ , J ⁵ and J ⁶ are independently selected from C, N, O, S and covalent bonds, provided that at most one is a covalent bond, K ² is C, D ⁵ , D ⁶ , J At most one of ⁵ and J ⁶ is O, at most one of D ⁵ , D ⁶ , J ⁵ and J ⁶ is S, if two of D ⁵ , D ⁶ , J ⁵ and J ⁶ are O and S, then D ⁵ , One of D ⁶ , J ⁵ and J ⁶ must be a covalent bond, and at most four of D ⁵ , D ⁶ J ⁵ and J ⁶ are N;

R ¹⁶ , R ¹⁷ , R ¹⁸ and R ¹⁹ are independently selected from hydrogen, amidino, guanidino, carboxyl, haloalkylthio, alkoxy, hydroxyl, amino, lower alkylamino, alkylthio, alkylsulfinyl Acyl, alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, and cyano;

R ¹⁶ and R ¹⁹ are optionally Q ^b with the proviso that at most one of R ¹⁶ and R ¹⁹ is Q ^b at the same time, and Q ^b is Q ^be ;

Q ^b is selected from NR ²⁰ R ²¹ , Q ^be and C(NR ²⁵ )NR ²³ R ²⁴ , wherein Q ^be is hydrogen;

R ²⁰ , R ²¹ , R ²³ , R ²⁴ and R ²⁵ are independently selected from hydrogen and alkyl;

^Qs is _CH2 .

In another most preferred embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof,

J ^a and J ^b are O;

B is optionally selected from hydrogen, C2-C8 alkyl, C3-C8 alkenyl, C3-C8 alkynyl, and C2-C8 haloalkyl, wherein each member of group B is optionally at a distance B from the point of attachment to A Any carbon up to and including 6 atoms is substituted by one or more groups R ³² , R ³³ , R ³⁴ , R ³⁵ and R ³⁶ ;

R ³² , R ³³ , R ³⁴ , R ³⁵ and R ³⁶ are independently selected from hydrogen, acetamido, haloacetamido, amidino, guanidino, alkoxy, hydroxyl, amino, alkoxyamino, lower alkyl Amino, alkylthio, amidosulfonyl, monoalkylamidosulfonyl, dialkylamidosulfonyl, alkyl, halogen, haloalkyl, haloalkoxy, hydroxyalkyl, alkoxycarbonyl, carboxyl, carboxyl amido, cyano and ^Qb ;

A is selected from a covalent single bond and (CH(R ¹⁵ )) _pa -(W ⁷ ) _rr , where rr is an integer selected from 0 to 1, pa is an integer selected from 0 to 3, and W ⁷ is N(R ⁷ );

^R is selected from hydrogen and alkyl;

^R is selected from hydrogen, halogen, alkyl and haloalkyl;

Ψ is NH;

M is selected from N and R ¹ -C;

^R is selected from the group consisting of hydrogen, hydroxy, hydroxyamino, amidino, amino, cyano, hydroxyalkyl, alkoxy, alkyl, alkylamino, aminoalkyl, alkylthio, alkoxyamino, haloalkyl, Haloalkoxy and halogen;

R ² is Z ⁰ -Q;

Z ⁰ is a covalent single bond;

Q is selected from aryl and heteroaryl, wherein one carbon adjacent to the carbon at the point of attachment is optionally substituted with ^R , and the other carbon adjacent to the carbon at the point of attachment is optionally substituted with ^R , the carbon adjacent to ^R9 and two atoms away from the carbon on the point of attachment is optionally substituted by ^R10 , the carbon adjacent to ^R13 and two atoms away from the carbon on the point of attachment is optionally substituted by ^R12 , Any carbon adjacent to both R ¹⁰ and R ¹² is optionally substituted by R ¹¹ ;

R ⁹ , R ¹¹ and R ¹³ are independently selected from hydrogen, hydroxyl, amino, amidino, guanidino, lower alkylamino, alkylthio, alkoxy, alkylsulfinyl, alkylsulfonyl, amido Sulfonyl, monoalkylamidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboxy, carboxamido and cyano;

R and ^R are independently selected from hydrogen, acetamido, haloacetamido, amidino, guanidino, alkyl, alkoxy, alkoxyamino, aminoalkyl, hydroxy, amino, ^lower alkylamino, Alkylsulfonylamino, amidosulfonyl, monoalkylamidosulfonyl, dialkylamidosulfonyl, hydroxyalkyl, aminoalkyl, halogen, haloalkyl, alkoxycarbonyl, carboxyl, carboxyalkyl, Carboxyamido and cyano;

K is _CH2 ;

E ⁰ is C(O)N(H);

Y ⁰ is formula (IV):

wherein D ⁵ , D ⁶ , J ⁵ and J ⁶ are independently selected from C, N, O, S and covalent bonds, provided that at most one is a covalent bond, K ² is C, D ⁵ , D ⁶ , J At most one of ⁵ and J ⁶ is O, at most one of D ⁵ , D ⁶ , J ⁵ and J ⁶ is S, if two of D ⁵ , D ⁶ , J ⁵ and J ⁶ are O and S, then D ⁵ , One of D ⁶ , J ⁵ and J ⁶ must be a covalent bond, and at most four of D ⁵ , D ⁶ , J ⁵ and J ⁶ are N, with the proviso that R ¹⁶ , R ¹⁷ , R ¹⁸ and R ¹⁹ are each independently selected to maintain the tetravalent nature of carbon, the trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen;

R ¹⁶ , R ¹⁷ , R ¹⁸ and R ¹⁹ are independently selected from hydrogen, amidino, guanidino, carboxyl, haloalkylthio, alkoxy, hydroxyl, amino, lower alkylamino, alkylthio, alkylsulfinyl Acyl, alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, and cyano;

R ¹⁶ and R ¹⁹ are optionally Q ^b with the proviso that at most one of R ¹⁶ and R ¹⁹ is Q ^b at the same time, and Q ^b is Q ^be ;

Q ^b is selected from NR ²⁰ R ²¹ , Q ^be , N(R ²⁶ )C(NR ²⁵ )N(R ²³ )(R ²⁴ ) and C(NR ²⁵ )NR ²³ R ²⁴ , wherein Q ^be is hydrogen;

R ²⁰ , R ²¹ , R ²³ , R ²⁴ , R ²⁵ and R ²⁶ are independently selected from hydrogen and alkyl;

^Qs is _CH2 .

In yet another most preferred embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof,

J ^a and J ^b are each O;

B is optionally selected from C3-C7 cycloalkyl and C4-C6 saturated heterocyclyl, wherein each ring carbon is optionally substituted by R ³³ , and any ring carbon other than the ring carbon at the point of connection between B and A Optionally substituted by oxo, provided that at most one ring carbon is simultaneously substituted by oxo, ring carbons and nitrogen atoms adjacent to the carbon atom at the point of attachment are optionally substituted by R ⁹ or R ¹³ , and R ⁹ A ring carbon or nitrogen atom adjacent to and two atoms from the point of attachment is optionally substituted by R ¹⁰ , a ring carbon or nitrogen atom adjacent to the position of R ¹³ and two atoms from the point of attachment is optionally substituted by R ¹² , A ring carbon or nitrogen atom three atoms from the point of attachment and adjacent to the R ¹⁰ position is optionally substituted by R ¹¹ , and a ring carbon or nitrogen atom three atoms from the attachment point adjacent to the R ¹² position is optionally substituted by R ³³ is substituted, and the ring carbon or nitrogen atom adjacent to the R ¹¹ and R ³³ positions four atoms away from the connection point is optionally substituted by R ³⁴ ;

R ⁹ , R ¹¹ and R ¹³ are independently selected from hydrogen, hydroxyl, amino, amidino, guanidino, lower alkylamino, alkylthio, alkoxy, alkylsulfinyl, alkylsulfonyl, amido Sulfonyl, monoalkylamidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboxy, carboxamido and cyano;

R and ^R are independently selected from hydrogen, acetamido, haloacetamido, amidino, guanidino, alkyl, alkoxy, alkoxyamino, aminoalkyl, hydroxy, amino, ^lower alkylamino, Alkylsulfonylamino, amidosulfonyl, monoalkylamidosulfonyl, dialkylamidosulfonyl, hydroxyalkyl, aminoalkyl, halogen, haloalkyl, alkoxycarbonyl, carboxyl, carboxyalkyl, Carboxyamido and cyano;

R ³³ and R ³⁴ are independently selected from hydrogen, amidino, guanidino, alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, alkylthio, amidosulfonyl, alkylamidosulfonyl Acyl, dialkylamidosulfonyl, alkyl, halogen, haloalkyl, haloalkoxy, hydroxyalkyl, alkoxycarbonyl, carboxy, carboxamido and cyano;

R ³³ is optionally Q ^b ;

A is selected from a covalent single bond and (CH(R ¹⁵ )) _pa -(W ⁷ ) _rr , where rr is an integer selected from 0 to 1, pa is an integer selected from 0 to 3, and W ⁷ is N(R ⁷ );

^R is selected from hydrogen, hydroxyl and alkyl;

^R is selected from hydrogen, halogen, alkyl and haloalkyl;

Ψ is NH;

M is selected from N and R ¹ -C;

^R is selected from the group consisting of hydrogen, hydroxy, hydroxyamino, amidino, amino, cyano, hydroxyalkyl, alkoxy, alkyl, alkylamino, aminoalkyl, alkylthio, alkoxyamino, haloalkyl, Haloalkoxy and halogen;

R ² is Z ⁰ -Q;

Z ⁰ is a covalent single bond;

Q is selected from aryl and heteroaryl, wherein one carbon adjacent to the carbon at the point of attachment is optionally substituted with ^R , and the other carbon adjacent to the carbon at the point of attachment is optionally substituted with ^R , the carbon adjacent to ^R9 and two atoms away from the carbon on the point of attachment is optionally substituted by ^R10 , the carbon adjacent to ^R13 and two atoms away from the carbon on the point of attachment is optionally substituted by ^R12 , Any carbon adjacent to both R ¹⁰ and R ¹² is optionally substituted by R ¹¹ ;

K is _CH2 ;

E ⁰ is C(O)N(H);

Y ⁰ is formula (IV):

wherein D ⁵ , D ⁶ , J ⁵ and J ⁶ are independently selected from C, N, O, S and covalent bonds, provided that at most one is a covalent bond, K ² is C, D ⁵ , D ⁶ , J At most one of ⁵ and J ⁶ is O, at most one of D ⁵ , D ⁶ , J ⁵ and J ⁶ is S, if two of D ⁵ , D ⁶ , J ⁵ and J ⁶ are O and S, then D ⁵ , One of D ⁶ , J ⁵ and J ⁶ must be a covalent bond, and at most four of D ⁵ , D ⁶ , J ⁵ and J ⁶ are N, with the proviso that R ¹⁶ , R ¹⁷ , R ¹⁸ and R ¹⁹ are each independently selected to maintain the tetravalent nature of carbon, the trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen;

R ¹⁶ , R ¹⁷ , R ¹⁸ and R ¹⁹ are independently selected from hydrogen, amidino, guanidino, carboxyl, haloalkylthio, alkoxy, hydroxyl, amino, lower alkylamino, alkylthio, alkylsulfinyl Acyl, alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, alkyleneamino, and cyano;

R ¹⁶ and R ¹⁹ are optionally Q ^b with the proviso that at most one of R ¹⁶ and R ¹⁹ is Q ^b at the same time, and Q ^b is Q ^be ;

Q ^b is selected from NR ²⁰ R ²¹ , Q ^be and C(NR ²⁵ )NR ²³ R ²⁴ , wherein Q ^be is hydrogen;

R ²⁰ , R ²¹ , R ²³ , R ²⁴ and R ²⁵ are independently selected from hydrogen and alkyl;

^Qs is _CH2 .

In a preferred specific embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, the compound has the structure of formula I-S:

in:

B is selected from phenyl, 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl, 4-imidazolyl, 3-pyrazole Base, 4-pyrazolyl, 1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl, 1,2,4-oxadiazol-3-yl, 1, 2,4-oxadiazol-5-yl, 1,3,4-oxadiazol-3-yl, 1,3,4-oxadiazol-5-yl, 3-isothiazolyl, 5-isothiazole Base, 2-oxazolyl, 2-thiazolyl, 3-isoxazolyl, 5-isoxazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrazinyl, 2- Pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 1,3,5-triazin-2-yl, 1,2,4-triazin-3-yl , 1,2,4-triazin-5-yl, 1,2,4-triazin-6-yl, 1,2,3-triazin-4-yl and 1,2,3-triazin-5- A group wherein one carbon adjacent to the carbon at the point of attachment is optionally substituted by R ³² and the other carbon adjacent to the carbon at the point of attachment is optionally substituted by R ³⁶ , adjacent to R ³² and connected at a distance A carbon two atoms from the carbon at the point is optionally substituted with R ³³ , a carbon adjacent to R ³⁶ and two atoms away from the carbon at the point of attachment is optionally substituted with R ³⁵ , any with both R ³³ and R ³⁵ Adjacent carbons are optionally substituted by R ³⁴ ;

R ³² , R ³³ , R ³⁴ , R ³⁵ and R ³⁶ are independently selected from hydrogen, amidino, guanidino, carboxyl, methyl, ethyl, isopropyl, propyl, methoxy, ethoxy, iso Propoxy, propoxy, hydroxy, amino, methoxyamino, ethoxyamino, acetamido, trifluoroacetamido, nitro, aminomethyl, 1-aminoethyl, 2-aminoethyl, N -Methylamino, dimethylamino, N-ethylamino, methylthio, ethylthio, isopropylthio, trifluoromethylthio, trifluoromethyl, pentafluoroethyl, 2,2,2 -Trifluoroethyl, 2,2,3,3,3-pentafluoropropyl, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluorine, chlorine, bromine, amidosulfa Acyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, acetyl, propionyl, trifluoroacetyl, pentafluoropropionyl, hydroxymethyl, 1-hydroxyethyl, 2 -Hydroxyethyl, 2,2,2-trifluoro-1-hydroxyethyl, 2,2,2-trifluoro-1-trifluoromethyl-1-hydroxyethyl, carboxymethyl, methoxycarbonyl, Ethoxycarbonyl, amidocarbonyl, N-methylamidocarbonyl, N,N-dimethylamidocarbonyl, cyano and ^Qb ;

B is selected from hydrogen, trimethylsilyl, ethyl, 2-propenyl, 2-propynyl, propyl, isopropyl, butyl, 2-butenyl, 3-butenyl, 2- Butynyl, sec-butyl, tert-butyl, isobutyl, 2-methylpropenyl, 1-pentyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-pentyne Base, 3-pentynyl, 2-pentyl, 1-methyl-2-butenyl, 1-methyl-3-butenyl, 1-methyl-2-butynyl, 3-pentyl , 1-ethyl-2-propenyl, 2-methylbutyl, 2-methyl-2-butenyl, 2-methyl-3-butenyl, 2-methyl-3-butynyl , 3-methylbutyl, 3-methyl-2-butenyl, 3-methyl-3-butenyl, 1-hexyl, 2-hexenyl, 3-hexenyl, 4-hexene base, 5-hexenyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 2-hexyl, 1-methyl-2-pentenyl, 1-methyl-3-pentene Base, 1-methyl-4-pentenyl, 1-methyl-2-pentynyl, 1-methyl-3-pentynyl, 3-hexyl, 1-ethyl-2-butenyl, 1-ethyl-3-butenyl, 1-propyl-2-propenyl, 1-ethyl-2-butynyl, 1-heptyl, 2-heptenyl, 3-heptenyl, 4 -Heptenyl, 5-heptenyl, 6-heptenyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 5-heptynyl, 2-heptyl, 1-methyl -2-Hexenyl, 1-Methyl-3-Hexenyl, 1-Methyl-4-Hexenyl, 1-Methyl-5-Hexenyl, 1-Methyl-2-Hexenyl , 1-methyl-3-hexynyl, 1-methyl-4-hexynyl, 3-heptyl, 1-ethyl-2-pentenyl, 1-ethyl-3-pentenyl, 1-ethyl-4-pentenyl, 1-butyl-2-propenyl, 1-ethyl-2-pentynyl, 1-ethyl-3-pentynyl, 1-octyl, 2- Octenyl, 3-octenyl, 4-octenyl, 5-octenyl, 6-octenyl, 7-octenyl, 2-octenyl, 3-octenyl, 4-octyne Base, 5-octynyl, 6-octynyl, 2-octyl, 1-methyl-2-heptenyl, 1-methyl-3-heptenyl, 1-methyl-4-heptenyl Base, 1-methyl-5-heptenyl, 1-methyl-6-heptenyl, 1-methyl-2-heptynyl, 1-methyl-3-heptynyl, 1-methyl -4-heptynyl, 1-methyl-5-heptynyl, 3-octyl, 1-ethyl-2-hexenyl, 1-ethyl-3-hexenyl, 1-ethyl- 4-hexenyl, 1-ethyl-2-hexynyl, 1-ethyl-3-hexynyl, 1-ethyl-4-hexynyl, 1-ethyl-5-hexenyl, 1-pentyl-2-propenyl, 4-octyl, 1-propyl-2-pentenyl, 1-propyl-3-pentenyl, 1-propyl-4-pentenyl, 1- Butyl-2-butenyl, 1-propyl-2-pentynyl, 1-propyl-3-pentynyl, 1-butyl-2-butynyl, 1-butyl-3-but Alkenyl, 2,2,2-trifluoroethyl, 2,2-difluoropropyl, 4-trifluoromethyl-5,5,5-trifluoropentyl, 4-trifluoromethylpentyl, 5,5,6,6,6-pentafluorohexyl and 3,3,3-trifluoropropyl, wherein each member of group B is optionally at a distance up to and including 5 atoms from the point of attachment of B to A Any carbon of is substituted by one or more groups R ³² , R ³³ , R ³⁴ , R ³⁵ and R ³⁶ ;

B is optionally selected from cyclopropyl, cyclobutyl, oxetan-2-yl, oxetan-3-yl, azetidin-1-yl, azetidin- 2-yl, azetidin-3-yl, thietan-2-yl, thietan-3-yl, cyclopentyl, cyclohexyl, adamantyl, norbornyl, 3 -Trifluoromethyl norbornyl, 7-oxabicyclo[2.2.1]heptane-2-yl, bicyclo[3.1.0]hexane-6-yl, cycloheptyl, cyclooctyl, 2 -Morpholinyl, 3-morpholinyl, 4-morpholinyl, 1-piperazinyl, 2-piperazinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl Pyridyl, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-dioxanyl, 4H-2-pyranyl, 4H-3-pyranyl, 4H-4-pyranyl Base, 4H-pyran-4-one-2-yl, 4H-pyran-4-one-3-yl, 2-tetrahydrofuryl, 3-tetrahydrofuryl, 2-tetrahydropyranyl, 3-tetrahydro Pyranyl, 4-tetrahydropyranyl, 2-tetrahydrothiophenyl and 3-tetrahydrothiophenyl, wherein each ring carbon is optionally substituted by R ³³ , the ring adjacent to the carbon atom at the point of attachment The carbon and nitrogen atoms are optionally substituted by ^R9 or ^R13 , and the ring carbon or nitrogen atom adjacent to the ^R9 position and two atoms away from the point of attachment is optionally substituted by ^R10 , adjacent to the ^R13 position and at a distance of The ring carbon or nitrogen atom connecting the two atoms is optionally substituted by R ¹² ;

R ⁹ , R ¹⁰ , R ¹¹ , R ¹² and R ¹³ are independently selected from hydrogen, amidino, guanidino, carboxyl, carboxymethyl, methyl, ethyl, isopropyl, propyl, methoxy, ethyl Oxy, isopropoxy, propoxy, hydroxy, amino, methoxyamino, ethoxyamino, acetamido, trifluoroacetamido, nitro, aminomethyl, 1-aminoethyl, 2-amino Ethyl, N-methylamino, dimethylamino, N-ethylamino, methylthio, ethylthio, isopropylthio, trifluoromethylthio, trifluoromethyl, pentafluoroethyl, 2 , 2,2-trifluoroethyl, 2,2,3,3,3-pentafluoropropyl, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluorine, chlorine, bromine , Methanesulfonylamino, amidosulfonyl, N-methylsulfonylaminosulfonyl, N,N-dimethylsulfonylamidosulfonyl, acetyl, propionyl, trifluoroacetyl, pentafluoropropionyl, methylol Base, 1-hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro-1-hydroxyethyl, 2,2,2-trifluoro-1-trifluoromethyl-1-hydroxyethyl , carboxymethyl, methoxycarbonyl, ethoxycarbonyl, amidocarbonyl, N-methylamidocarbonyl, N,N dimethylamidocarbonyl and cyano;

A is selected from covalent single bond, O, S, NH, N( _CH3 ), N(OH), C(O), _CH2 , _CH3CH , _CF3CH , NHC(O), N( _CH3 )C(O), C(O)NH, C(O)N(CH ₃ ), CF ₃ CC(O), C(O)CCH ₃ , C(O)CCF ₃ , CH ₂ C(O), (O)CCH ₂ , CH ₂ CH ₂ , CH ₂ CH ₂ CH ₂ , CH ₃ CHCH ₂ , CF ₃ CHCH ₂ , CH ₃ CC(O)CH ₂ , CF ₃ CC(O)CH ₂ , CH ₂ C( O)CCH ₃ , CH ₂ C(O)CCF ₃ , CH ₂ CH ₂ C(O) and CH ₂ (O)CCH ₂ ;

A is optionally selected from _CH2N ( _{CH3 )} , _CH2N ( _CH2CH3 ), _CH2CH2N ( _CH3 ) and _{CH2CH2N ( CH2CH3} ), with the _proviso that _B is hydrogen;

M is selected from N and R ¹ -C;

^R is selected from hydrogen, hydroxy, amino, mercapto, amidino, hydroxyamino, aminomethyl, 1-aminoethyl, 2-aminoethyl, methylamino, dimethylamino, cyano, methyl, ethyl base, isopropyl, propyl, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, 2,2,3,3,3-pentafluoropropyl, methoxy, ethyl Oxygen, Propoxy, Hydroxymethyl, 1-Hydroxyethyl, 2-Hydroxyethyl, Methoxyamino, Ethoxyamino, Methylthio, Ethylthio, Trifluoromethoxy, 1,1 , 2,2-tetrafluoroethoxy, fluorine, chlorine and bromine;

R ² is Z ⁰ -Q;

Z ⁰ is selected from covalent single bond, O, S, NH, CH ₂ , CH ₂ CH ₂ , CH(OH), CH(NH ₂ ), CH ₂ CH(OH), CH ₂ CHNH ₂ , CH(OH) _CH2 and CH( _NH2 ) _CH2 ;

Q is selected from phenyl, 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl, 4-imidazolyl, 3-pyrazole Base, 4-pyrazolyl, 1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl, 1,2,4-oxadiazol-3-yl, 1, 2,4-oxadiazol-5-yl, 1,3,4-oxadiazol-3-yl, 1,3,4-oxadiazol-5-yl, 3-isothiazolyl, 5-isothiazole Base, 2-oxazolyl, 2-thiazolyl, 3-isoxazolyl, 5-isoxazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrazinyl, 2- Pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 1,3,5-triazin-2-yl, 1,2,4-triazin-3-yl , 1,2,4-triazin-5-yl, 1,2,4-triazin-6-yl, 1,2,3-triazin-4-yl and 1,2,3-triazin-5- A group wherein one carbon adjacent to the carbon at the point of attachment is optionally substituted by R ⁹ and the other carbon adjacent to the carbon at the point of attachment is optionally substituted by R ¹³ , adjacent to R ⁹ and connected at a distance ^{A carbon two atoms from the carbon at the point is optionally substituted with R, a carbon adjacent to R 13 and} two atoms away from ^the carbon at the point of attachment is optionally substituted with R, ^any with both ^R and R Adjacent carbons are optionally substituted by R ¹¹ ;

K is ^CHR4a , wherein ^R4a is selected from methyl, ethyl, propyl, isopropyl, hydroxymethyl, 1-hydroxyethyl, methoxymethyl, trifluoromethyl, pentafluoroethyl, 2 , 2,2-trifluoroethyl, methylthiomethyl and hydrogen;

E ⁰ is a covalent single bond, C(O)N(H), (H)NC(O) and S(O) ₂ N(H);

^Y is selected from the following formula:

and

R ¹⁶ , R ¹⁷ , R ¹⁸ and R ¹⁹ are independently selected from hydrogen, methyl, ethyl, isopropyl, propyl, amidino, guanidino, carboxyl, methoxy, ethoxy, isopropoxy , Propoxy, Hydroxy, Amino, Methoxyamino, Ethoxyamino, Aminomethyl, 1-Aminoethyl, 2-Aminoethyl, N-Methylamino, Dimethylamino, N-Ethyl Amino, methylthio, ethylthio, isopropylthio, trifluoromethylthio, methylsulfinyl, ethylsulfinyl, methylsulfonyl, ethylsulfonyl, trifluoromethyl, pentafluoroethyl , 2,2,2-trifluoroethyl, 2,2,3,3,3-pentafluoropropyl, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluorine, chlorine , bromide, amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, acetyl, propionyl, trifluoroacetyl, pentafluoropropionyl, hydroxymethyl, 1 - hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro-1-hydroxyethyl and cyano;

R ¹⁶ and R ¹⁹ are optionally Q ^b with the proviso that at most one of R ¹⁶ and R ¹⁹ is Q ^b at the same time, and Q ^b is Q ^be ;

Q ^b is selected from NR ²⁰ R ²¹ , Q ^be , C(NR ²⁵ )NR ²³ R ²⁴ and N(R ²⁶ )C(NR ²⁵ )N(R ²³ )(R ²⁴ ), wherein Q ^be is hydrogen, and the condition It is that at most one of R ²⁰ and R ²¹ is simultaneously hydroxyl, N-methylamino and N,N-dimethylamino, and at most one of R ²³ and R ²⁴ is simultaneously hydroxyl, N-methylamino and N,N- Dimethylamino;

R ²⁰ , R ²¹ , R ²³ , R ²⁴ , R ²⁵ and R ²⁶ are independently selected from hydrogen, methyl, ethyl, propyl, butyl, isopropyl, hydroxyl, 2-aminoethyl, 2-( N-methylamino)ethyl and 2-(N,N-dimethylamino)ethyl;

Q ^s is selected from covalent single bond, CH ₂ , CH ₂ CH ₂ , CH 3 CH, CF ₃ CH, CH ₃ CHCH ₂ , CF ₃ CHCH 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 ₂ CH=CH, CH ₂ CF=CH, CH ₂ C(CH ₃ )=CH, _CH2CH = _CHCH2 , _CH2CF = _CHCH2 , _CH2C ( _CH3 )= _CHCH2 , _CH2CH = _{CHCH2CH2 , CH2CF} = _CHCH2CH2 and _CH2C ( _{CH3 )} = _{CHCH2CH2 .}

In a more preferred embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, said compound has the structure of formula I-MPS, wherein B is an aromatic substituent:

in:

B is selected from phenyl, 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl, 4-imidazolyl, 3-pyrazole Base, 4-pyrazolyl, 2-thiazolyl, 3-isoxazolyl, 5-isoxazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrazinyl, 2- Pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, and 1,3,5-triazin-2-yl, one of the carbons adjacent to the carbon at the point of attachment optionally substituted by R, another carbon adjacent to the carbon at the point of attachment is optionally substituted by R, and the carbon adjacent to R ³² and ^two atoms away from the carbon at the point of attachment ^is optionally replaced by R ³³ is substituted, and the carbon adjacent to R ³⁶ and two atoms away from the carbon on the point of attachment is optionally substituted by R ³⁵ , and any carbon adjacent to both R ³³ and R ³⁵ is optionally substituted by R ³⁴ ;

R ³² , R ³³ , R ³⁴ , R ³⁵ and R ³⁶ are independently selected from hydrogen, amidino, guanidino, carboxyl, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, methyl Oxyamino, Ethoxyamino, Acetylamino, Trifluoroacetylamino, N-Methylamino, Dimethylamino, N-Ethylamino, Methylthio, Ethylthio, Isopropylthio, Trifluoromethane base, pentafluoroethyl, 2,2,2-trifluoroethyl, 2,2,3,3,3-pentafluoropropyl, trifluoromethoxy, 1,1,2,2-tetrafluoroethyl Oxygen, fluorine, chlorine, bromine, amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl , 2,2,2-trifluoro-1-hydroxyethyl, methoxycarbonyl, ethoxycarbonyl, amidocarbonyl, N-methylamidocarbonyl, N,N-dimethylamidocarbonyl, cyano and Q ^b ;

A is selected from covalent single bond, NH, N( _CH3 ), N(OH), _CH2 , CH3CH, _CF3CH , NHC(O), N( _CH3 )C( _O ), C(O )NH, C(O)N(CH ₃ ), CH ₂ CH ₂ , CH ₂ CH ₂ CH ₂ , CH ₃ CHCH ₂ and CF ₃ CHCH ₂ ;

Q ^b is selected from NR ²⁰ R ²¹ , Q ^be and C(NR ²⁵ )NR ²³ R ²⁴ , wherein Q ^be is hydrogen, provided that at most one of R ²⁰ and R ²¹ is simultaneously a hydroxyl group, and at most of R ²³ and R ²⁴ one is also hydroxyl;

R ²⁰ , R ²¹ , R ²³ , R ²⁴ and R ²⁵ are independently selected from hydrogen, methyl, ethyl, propyl, butyl, isopropyl and hydroxyl;

Q ^s is selected from a covalent single bond, CH ₂ and CH ₂ CH ₂ .

In another more preferred specific embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, said compound has the structure of formula I-MPS, wherein B is an acyclic substituent:

in:

B is selected from hydrogen, ethyl, 2-propenyl, 2-propynyl, propyl, isopropyl, butyl, 2-butenyl, 3-butenyl, 2-butynyl, sec-butyl , tert-butyl, isobutyl, 2-methylpropenyl, 1-pentyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-pentynyl, 3-pentynyl , 2-pentyl, 1-methyl-2-butenyl, 1-methyl-3-butenyl, 1-methyl-2-butynyl, 3-pentyl, 1-ethyl-2 -propenyl, 2-methylbutyl, 2-methyl-2-butenyl, 2-methyl-3-butenyl, 2-methyl-3-butynyl, 3-methylbutyl , 3-methyl-2-butenyl, 3-methyl-3-butenyl, 1-hexyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl , 2-hexynyl, 3-hexynyl, 4-hexynyl, 2-hexyl, 1-methyl-2-pentenyl, 1-methyl-3-pentenyl, 1-methyl- 4-pentenyl, 1-methyl-2-pentynyl, 1-methyl-3-pentynyl, 3-hexyl, 1-ethyl-2-butenyl, 1-ethyl-3- Butenyl, 1-propyl-2-propenyl, 1-ethyl-2-butynyl, 1-heptyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5- Heptenyl, 6-heptenyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 5-heptynyl, 2-heptyl, 1-methyl-2-hexenyl, 1-methyl-3-hexenyl, 1-methyl-4-hexenyl, 1-methyl-5-hexenyl, 1-methyl-2-hexynyl, 1-methyl-3 -hexynyl, 1-methyl-4-hexynyl, 3-heptyl, 1-ethyl-2-pentenyl, 1-ethyl-3-pentenyl, 1-ethyl-4-pentenyl Alkenyl, 1-butyl-2-propenyl, 1-ethyl-2-pentynyl, 1-ethyl-3-pentynyl, 2,2,2-trifluoroethyl, 2,2- Difluoropropyl, 4-trifluoromethyl-5,5,5-trifluoropentyl, 4-trifluoromethylpentyl, 5,5,6,6,6-pentafluorohexyl and 3,3, 3-trifluoropropyl, wherein each member of group B is optionally replaced by one or more groups R ³² , R ³³ , R on any carbon up to and including 5 atoms from the point of attachment of B to A ³⁴ , R ³⁵ and R ³⁶ are substituted;

R ³² , R ³³ , R ³⁴ , R ³⁵ and R ³⁶ are independently selected from hydrogen, amidino, guanidino, carboxyl, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, methyl Oxyamino, Ethoxyamino, Acetylamino, Trifluoroacetylamino, N-Methylamino, Dimethylamino, N-Ethylamino, Methylthio, Ethylthio, Isopropylthio, Trifluoromethane base, pentafluoroethyl, 2,2,2-trifluoroethyl, 2,2,3,3,3-pentafluoropropyl, trifluoromethoxy, 1,1,2,2-tetrafluoroethyl Oxygen, fluorine, chlorine, bromine, amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl , 2,2,2-trifluoro-1-hydroxyethyl, methoxycarbonyl, ethoxycarbonyl, amidocarbonyl, N-methylamidocarbonyl, N,N-dimethylamidocarbonyl, cyano and Q ^b ;

A is selected from covalent single bond, NH, N( _CH3 ), N(OH), _CH2 , CH3CH, _CF3CH , NHC(O), N( _CH3 )C( _O ), C(O )NH, C(O)N(CH ₃ ), CH ₂ CH ₂ , CH ₂ CH ₂ CH ₂ , CH ₃ CHCH ₂ and CF ₃ CHCH ₂ ;

A is optionally selected from _CH2N ( _{CH3 )} , _CH2N ( _CH2CH3 ), _CH2CH2N ( _CH3 ) and _{CH2CH2N ( CH2CH3} ), with the _proviso that _B is hydrogen;

Q ^b is selected from NR ²⁰ R ²¹ , Q ^be , C(NR ²⁵ )NR ²³ R ²⁴ and N(R ²⁶ )C(NR ²⁵ )N(R ²³ )(R ²⁴ ), wherein Q ^be is hydrogen, and the condition is that at most one of R ²⁰ and R ²¹ is a hydroxyl group at the same time, and at most one of R ²³ and R ²⁴ is a hydroxyl group at the same time;

R ²⁰ , R ²¹ , R ²³ , R ²⁴ , R ²⁵ and R ²⁶ are independently selected from hydrogen, methyl, ethyl, propyl, butyl, isopropyl and hydroxyl;

Q ^s is selected from a covalent single bond, CH ₂ and CH ₂ CH ₂ .

In another still more preferred embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, said compound has the structure of formula I-MPS, wherein B is a non-aromatic cyclic substituent:

in:

B is optionally selected from cyclopropyl, cyclobutyl, oxetane-3-yl, azetidin-1-yl, azetidin-2-yl, azetidin- 3-yl, thietan-3-yl, cyclopentyl, cyclohexyl, norbornyl, 7-oxabicyclo[2.2.1]heptane-2-yl, bicyclo[3.1.0] Hexan-6-yl, cycloheptyl, 2-morpholinyl, 3-morpholinyl, 4-morpholinyl, 1-piperazinyl, 2-piperazinyl, 1-piperidinyl, 2-piperidinyl Pyridyl, 3-piperidyl, 4-piperidyl, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-dioxanyl, 4H-2-pyranyl, 4H- 3-pyranyl, 4H-4-pyranyl, 4H-pyran-4-one-2-yl, 4H-pyran-4-one-3-yl, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydropyranyl, 3-tetrahydropyranyl, 4-tetrahydropyranyl, 2-tetrahydrothiophenyl and ³ -tetrahydrothiophenyl, wherein each ring carbon is optionally substituted by R , the ring carbon and nitrogen atoms adjacent to the carbon atom at the point of attachment are optionally substituted by ^R9 or ^R13 , and the ring carbon or nitrogen atoms adjacent to the ^R9 position and two atoms away from the point of attachment are optionally replaced by R ¹⁰ is substituted, and the ring carbon or nitrogen atom adjacent to R ¹³ and two atoms away from the connection point is optionally substituted by R ¹² ;

A is selected from covalent single bond, NH, N( _CH3 ), N(OH), _CH2 , CH3CH, _CF3CH , NHC(O), N( _CH3 )C( _O ), C(O )NH, C(O)N(CH ₃ ), CH ₂ CH ₂ , CH ₂ CH ₂ CH ₂ , CH ₃ CHCH ₂ and CF ₃ CHCH ₂ ;

^R is selected from hydrogen, amidino, guanidino, carboxyl, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, methoxyamino, ethoxyamino, acetamido, trifluoro Acetylamino, N-methylamino, dimethylamino, N-ethylamino, methylthio, ethylthio, isopropylthio, trifluoromethyl, pentafluoroethyl, 2,2,2-tri Fluoroethyl, 2,2,3,3,3-pentafluoropropyl, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluorine, chlorine, bromine, amidosulfonyl, N-methylamidosulfonyl, N, N-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro-1-hydroxyethyl Base, methoxycarbonyl, ethoxycarbonyl, amidocarbonyl, N-methylamidocarbonyl, N, N-dimethylamidocarbonyl, cyano and Q ^b ;

Q ^b is selected from NR ²⁰ R ²¹ , Q ^be and C(NR ²⁵ )NR ²³ R ²⁴ , wherein Q ^be is hydrogen, provided that at most one of R ²⁰ and R ²¹ is simultaneously a hydroxyl group, and at most of R ²³ and R ²⁴ one is also hydroxyl;

R ²⁰ , R ²¹ , R ²³ , R ²⁴ and R ²⁵ are independently selected from hydrogen, methyl, ethyl, propyl, butyl, isopropyl and hydroxyl;

Q ^s is selected from a covalent single bond, CH ₂ and CH ₂ CH ₂ .

A more preferred specific embodiment (I-MPS) of the compound of the present invention or a pharmaceutically acceptable salt thereof has the following structure:

They have common structural units, among which:

M is selected from N and R ¹ -C;

^R is selected from hydrogen, hydroxy, amino, amidino, hydroxyamino, aminomethyl, 1-aminoethyl, methylamino, dimethylamino, cyano, methyl, ethyl, trifluoromethyl, pentafluoromethyl, Fluoroethyl, 2,2,2-trifluoroethyl, methoxy, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, methoxyamino, methylthio, ethylthio, trifluoro Methoxy, 1,1,2,2-tetrafluoroethoxy, fluorine, chlorine and bromine;

R ² is Z ⁰ -Q;

Z ⁰ is selected from covalent single bonds, O, S, NH and CH ₂ ;

Q is selected from phenyl, 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl, 4-imidazolyl, 3-pyrazole Base, 4-pyrazolyl, 2-thiazolyl, 3-isoxazolyl, 5-isoxazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrazinyl, 2- Pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, and 1,3,5-triazin-2-yl, one of the carbons adjacent to the carbon at the point of attachment or nitrogen optionally substituted with ^R9 , another carbon adjacent to the carbon at the point of attachment or nitrogen optionally substituted with ^R13 , a carbon adjacent to ^R9 and two atoms from the carbon at the point of attachment or Nitrogen is optionally substituted with R ¹⁰ , a carbon adjacent to R ¹³ and two atoms away from the carbon at the point of attachment is optionally substituted with R ¹² , any carbon adjacent to both R ¹⁰ and R ¹² is optionally substituted with R ¹¹ replaces;

R ⁹ , R ¹¹ and R ¹³ are independently selected from hydrogen, amidino, guanidino, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, propoxy Hydroxyl, amino, N-methylamino, N,N-dimethylamino, N-ethylamino, methylthio, ethylthio, isopropylthio, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, 2,2,3,3,3-pentafluoropropyl, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluorine, chlorine, Bromine, methylsulfonylamino, amidosulfonyl, N-methylsulfonylaminosulfonyl, N, N-dimethylsulfonylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2 , 2,2-trifluoro-1-hydroxyethyl, amidocarbonyl, N-methylamidocarbonyl, N,N-dimethylamidocarbonyl and cyano;

R ^{and R} are independently selected from hydrogen, amidino, guanidino, carboxyl, carboxymethyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, propyl Oxygen, hydroxyl, amino, methoxyamino, ethoxyamino, acetamido, trifluoroacetamido, aminomethyl, 1-aminoethyl, 2-aminoethyl, N-methylamino, dimethyl Amino, N-ethylamino, methanesulfonylamino, amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, 2 -Hydroxyethyl, 2,2,2-trifluoro-1-hydroxyethyl, methoxycarbonyl, ethoxycarbonyl, amidocarbonyl, N-methylamidocarbonyl, N,N-dimethylamidocarbonyl , fluorine, chlorine, bromine and cyano;

^Y is selected from the following formula:

和

and

R ¹⁶ , R ¹⁷ , R ¹⁸ and R ¹⁹ are independently selected from hydrogen, methyl, ethyl, isopropyl, propyl, carboxyl, amidino, guanidino, methoxy, ethoxy, isopropoxy , propoxy, hydroxyl, amino, aminomethyl, 1-aminoethyl, 2-aminoethyl, N-methylamino, dimethylamino, N-ethylamino, methylthio, ethylthio, Isopropylthio, trifluoromethylthio, methylsulfinyl, ethylsulfinyl, methylsulfonyl, ethylsulfonyl, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl base, 2,2,3,3,3-pentafluoropropyl, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluorine, chlorine, bromine, amidosulfonyl, N- Methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro-1-hydroxyethyl and cyano;

R ¹⁶ and R ¹⁹ are optionally Q ^b with the proviso that at most one of R ¹⁶ and R ¹⁹ is Q ^b simultaneously and Q ^b is Q ^be .

In the most preferred embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, said compound has the structure of formula I-EMPS, wherein B is an aromatic substituent:

in:

B is selected from phenyl, 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl, 4-imidazolyl, 3-pyrazole Base, 4-pyrazolyl, 2-thiazolyl, 3-isoxazolyl and 5-isoxazolyl, wherein one carbon adjacent to the carbon at the point of attachment is optionally substituted by R ³² and the other is The carbon adjacent to the carbon at the point of attachment is optionally substituted with ^R36 , the carbon adjacent to ^R32 and two atoms away from the carbon at the point of attachment is optionally substituted with ^R33 , adjacent to ^R36 and at a distance from the attachment The carbon of two atoms of the point carbon is optionally substituted by R ³⁵ , and any carbon adjacent to both R ³³ and R ³⁵ is optionally substituted by R ³⁴ ;

R ³² , R ³³ , R ³⁴ , R ³⁵ and R ³⁶ are independently selected from hydrogen, amidino, guanidino, methyl, ethyl, methoxy, ethoxy, hydroxyl, amino, N-methylamino, Dimethylamino, methylthio, ethylthio, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, fluorine, chlorine, bromine, amidosulfonyl, N-methylyl Aminosulfonyl, hydroxymethyl, amidocarbonyl, carboxyl, cyano and ^Qb ;

A is selected from covalent single bonds, NH, N( _CH3 ) _{, CH2} , _CH3CH and _CH2CH2 ;

Q ^b is selected from NR ²⁰ R ²¹ and C(NR ²⁵ )NR ²³ R ²⁴ , with the proviso that said Q ^b group is directly bonded to a carbon atom;

R ²⁰ , R ²¹ , R ²³ , R ²⁴ and R ²⁵ are independently selected from hydrogen, methyl and ethyl;

^Qs is _CH2 .

In another most preferred specific embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, said compound has the structure of formula I-EMPS, wherein B is an acyclic substituent:

in:

B is selected from hydrogen, ethyl, 2-propenyl, 2-propynyl, propyl, isopropyl, butyl, 2-butenyl, 2-butynyl, sec-butyl, tert-butyl, iso Butyl, 2-methylpropenyl, 1-pentyl, 2-pentenyl, 3-pentenyl, 2-pentynyl, 3-pentynyl, 2-pentyl, 3-pentyl, 2 -Methylbutyl, 2-methyl-2-butenyl, 3-methylbutyl, 3-methyl-2-butenyl, 1-hexyl, 2-hexenyl, 3-hexenyl , 4-hexenyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 2-hexyl, 1-methyl-2-pentenyl, 1-methyl-3-pentenyl , 1-methyl-2-pentynyl, 1-methyl-3-pentynyl, 3-hexyl, 1-ethyl-2-butenyl, 1-heptyl, 2-heptenyl, 3 -Heptenyl, 4-heptenyl, 5-heptenyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 5-heptynyl, 2-heptyl, 1-methyl -2-hexenyl, 1-methyl-3-hexenyl, 1-methyl-4-hexenyl, 1-methyl-2-hexynyl, 1-methyl-3-hexynyl , 1-methyl-4-hexynyl, 3-heptyl, 1-ethyl-2-pentenyl, 1-ethyl-3-pentenyl, 1-ethyl-2-pentynyl, 1-ethyl-3-pentynyl, 2,2,2-trifluoroethyl, 2,2-difluoropropyl, 4-trifluoromethyl-5,5,5-trifluoropentyl, 4 - trifluoromethylpentyl, 5,5,6,6,6-pentafluorohexyl and 3,3,3-trifluoropropyl, wherein each member of the group B is optionally attached to A at a distance B Any carbon up to and including 5 atoms is substituted by one or more groups R ³² , R ³³ , R ³⁴ , R ³⁵ and R ³⁶ ;

R ³² , R ³³ , R ³⁴ , R ³⁵ and R ³⁶ are independently selected from hydrogen, amidino, guanidino, methyl, ethyl, methoxy, ethoxy, hydroxyl, amino, N-methylamino, Dimethylamino, methylthio, ethylthio, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, fluorine, chlorine, bromine, amidosulfonyl, N-methylyl Aminosulfonyl, hydroxymethyl, amidocarbonyl, carboxyl, cyano and ^Qb ;

A is selected from covalent single bonds, NH, N( _CH3 ) _{, CH2} , _CH3CH and _CH2CH2 ;

A is optionally selected from _CH2N ( _{CH3 )} , _CH2N ( _CH2CH3 ), _CH2CH2N ( _CH3 ) and _{CH2CH2N ( CH2CH3} ), with the _proviso that _B is hydrogen;

Q ^b is selected from NR ²⁰ R ²¹ , C(NR ²⁵ )NR ²³ R ²⁴ and N(R ²⁶ )C(NR ²⁵ )N(R ²³ )(R ²⁴ ), with the proviso that said Q ^b group is directly in contact with Carbon atom bonding;

R ²⁰ , R ²¹ , R ²³ , R ²⁴ , R ²⁵ and R ²⁶ are independently selected from hydrogen, methyl and ethyl;

^Qs is _CH2 .

In another still most preferred embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, said compound has the structure of formula I-EMPS, wherein B is a non-aromatic cyclic substituent:

in:

B is optionally selected from cyclopropyl, cyclobutyl, oxetan-3-yl, azetidin-3-yl, thietan-3-yl, cyclopentyl, cyclohexyl , 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-tetrahydrofuryl, 3-tetrahydrofuryl, 2-tetrahydrothiophenyl and 3-tetrahydrothiophenyl, wherein each ring carbon is optionally optionally substituted by R ³³ , the ring carbon and nitrogen atoms adjacent to the carbon atom at the point of attachment are optionally substituted by R ⁹ or R ¹³ , the ring carbon or nitrogen adjacent to the R ⁹ position and two atoms away from the point of attachment The atom is optionally substituted by R ¹⁰ , and the ring carbon or nitrogen atom adjacent to the R ¹³ position and two atoms away from the point of attachment is optionally substituted by R ¹² ;

R ^is independently selected from hydrogen, amidino, guanidino, methyl, ethyl, methoxy, ethoxy, hydroxyl, carboxyl, amino, N-methylamino, dimethylamino, methylthio, ethyl Thio, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, fluorine, chlorine, bromine, amidosulfonyl, N-methylamidosulfonyl, hydroxymethyl, amido carbonyl, cyano and ^Qb ;

A is selected from covalent single bonds, NH, N( _CH3 ) _{, CH2} , _CH3CH and _CH2CH2 ;

Q ^b is selected from NR ²⁰ R ²¹ and C(NR ²⁵ )NR ²³ R ²⁴ with the proviso that said Q ^b group is directly bonded to a carbon atom;

R ²⁰ , R ²¹ , R ²³ , R ²⁴ and R ²⁵ are independently selected from hydrogen, methyl and ethyl;

^Qs is _CH2 .

The most preferred embodiment (I-EMPS) of the compound of the present invention or a pharmaceutically acceptable salt thereof has the following structure:

They have common structural units, among which:

M is selected from N and R ¹ -C;

^R is selected from hydrogen, hydroxy, amino, amidino, hydroxyamino, aminomethyl, methylamino, cyano, methyl, trifluoromethyl, methoxy, hydroxymethyl, methoxyamino, methylthio radical, trifluoromethoxy, fluorine and chlorine;

R ² is Z ⁰ -Q;

Z ⁰ is a covalent single bond;

Q is selected from phenyl, 2-thienyl, 2-furyl, 2-pyrrolyl, 2-imidazolyl, 2-thiazolyl, 3-isoxazolyl, 2-pyridyl and 3-pyridyl, one of The carbon adjacent to the carbon at the point of attachment is optionally substituted with ^R , the other carbon adjacent to the carbon at the point of attachment is optionally substituted with R, and ^the carbon adjacent to ^R9 is at a distance from the carbon at the point of attachment Two atoms of carbon are optionally substituted by R ¹⁰ , carbons adjacent to R ¹³ and two atoms away from the carbon at the point of attachment are optionally substituted by R ¹² , any carbon adjacent to both R ¹⁰ and R ¹² optionally substituted by R ¹¹ ;

R ⁹ , R ¹¹ and R ¹³ are independently selected from hydrogen, methyl, ethyl, methoxy, ethoxy, hydroxyl, amino, N-methylamino, N,N-dimethylamino, methylthio , trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, fluorine, chlorine, bromine, amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylyl Aminosulfonyl, hydroxymethyl, 1-hydroxyethyl, amidocarbonyl, N-methylamidocarbonyl, carboxyl and cyano;

R and ^R are independently selected from hydrogen, amidino, amidocarbonyl, N ^- methylamidocarbonyl, guanidino, methyl, ethyl, methoxy, ethoxy, hydroxy, hydroxymethyl, 1 -Hydroxyethyl, 2-hydroxyethyl, carboxyl, carboxymethyl, amino, acetamido, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, trifluoroacetylamino, aminomethyl , N-methylamino, dimethylamino, amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, methoxycarbonyl, fluorine, chlorine, bromine and cyanide base;

^Y is selected from the following formula:

and

R ¹⁶ , R ¹⁷ , R ¹⁸ and R ¹⁹ are independently selected from hydrogen, methyl, ethyl, amidino, guanidino, methoxy, hydroxyl, amino, aminomethyl, 1-aminoethyl, 2-amino Ethyl, N-methylamino, dimethylamino, methylthio, ethylthio, trifluoromethylthio, methylsulfinyl, methylsulfonyl, trifluoromethyl, pentafluoroethyl, 2, 2,2-Trifluoroethyl, trifluoromethoxy, fluoro, chloro, amidosulfonyl, N-methylamidosulfonyl, hydroxymethyl, carboxy and cyano.

The compounds of the present invention can be used in anticoagulant therapy, and in the treatment and prevention of various thrombotic diseases, including coronary artery and cerebrovascular diseases. The compounds of the invention may be used to inhibit serine proteases involved in the coagulation cascade and factors II, VII, VIII, IX, X, XI or XII. The compounds of the present invention are capable of inhibiting the formation of platelet aggregates, inhibiting the formation of fibrin, inhibiting the formation of thrombus and inhibiting the formation of emboli in mammals, blood, blood products and mammalian organs. These compounds are also useful in the treatment or prophylaxis of unstable angina, refractory angina, myocardial infarction, transient ischemic attack, atrial fibrillation, thrombotic stroke, embolic stroke, deep vein thrombosis, Disseminated intravascular coagulation, ocular fibrin blockage and reocclusion or restenosis of reperforated vessels. These compounds may also be used in the prophylactic treatment of subjects at risk of developing these conditions. These compounds can be used to reduce the risk of atherosclerosis. Compounds of formula (I) will also be useful in the prevention of cerebrovascular accident (CVA) or stroke.

In addition to being useful in human therapy, these compounds are also useful in veterinary therapy of pets, exotic animals, and livestock, including mammals, rodents, and the like. More preferred animals include horses, dogs and cats.

In yet another embodiment of the present invention, the novel compound is selected from the compounds described in Example 1 to Example 7.

For the sake of clarity, the general terms used in the specification are defined here for the compounds.

Unless otherwise indicated, standard one-letter element symbols are used to denote specific species of atoms. The symbol "C" represents a carbon atom. The symbol "O" represents an oxygen atom. The symbol "N" represents a nitrogen atom. The symbol "P" represents a phosphorus atom. The symbol "S" represents a sulfur atom. The symbol "H" represents a hydrogen atom. Two-letter element symbols are used to define elements in the periodic table (ie, Cl for chlorine, Se for selenium, etc.).

The term "alkyl" as used herein alone or in other terms, such as "haloalkyl" and "alkylthio" means an acyclic alkyl group containing 1 to about 10 carbon atoms, preferably 3 to about 8 carbon atoms, more preferably 3 to about 6 carbon atoms. The alkyl groups may be optionally substituted with groups as defined below. Examples of such groups include methyl, ethyl, chloroethyl, hydroxyethyl, n-propyl, oxypropyl, isopropyl, n-butyl, cyanobutyl, isobutyl, sec-butyl , tert-butyl, pentyl, aminopentyl, isopentyl, hexyl, octyl, etc.

The term "alkenyl" refers to an unsaturated, acyclic hydrocarbon group containing at least one double bond. Such alkenyl groups contain from about 2 to about 10 carbon atoms, preferably from about 3 to about 8 carbon atoms, more preferably from 3 to about 6 carbon atoms. The alkenyl group may be optionally substituted with groups as defined below. Examples of suitable alkenyl groups include propenyl, 2-chloropropenyl, buten-1-yl, isobutenyl, penten-1-yl, 2-methylbuten-1-yl, 3-methyl buten-1-yl, hexen-1-yl, 3-hydroxyhexen-1-yl, hepten-1-yl, octen-1-yl and the like.

The term "alkynyl" refers to an unsaturated, acyclic hydrocarbon group containing at least one triple bond. Such groups contain from about 2 to about 10 carbon atoms, preferably from about 3 to about 8 carbon atoms, more preferably from 3 to about 6 carbon atoms. The alkynyl group may be optionally substituted with groups as defined below. Examples of suitable alkynyl groups include ethynyl, propynyl, hydroxypropynyl, butyn-1-yl, butyn-2-yl, pentyn-1-yl, pentyn-2-yl, 4 -Methoxypentyn-2-yl, 3-methylbutyn-1-yl, hexyn-1-yl, hexyn-2-yl, hexyn-3-yl, 3,3-dimethyl Butyn-1-yl groups and the like.

The term "hydrogen" refers to a single hydrogen atom (H). The hydrogen atom, for example, can be linked with an oxygen atom to form a "hydroxyl", one hydrogen atom can be linked with a carbon atom to form a "methine"-CH=, or two hydrogen groups can be linked with a carbon atom to form a "methylene" ( -CH ₂ -).

The term "carbon" group denotes a carbon atom without any covalent bonds and capable of forming four covalent bonds.

The term "cyano" denotes a carbon group that shares three of four covalent bonds with the nitrogen atom.

The term "hydroxyalkyl" encompasses any group in which one or more of the alkyl carbon atoms is replaced by a hydroxy group as defined above. Specifically contemplated are monohydroxyalkyl, dihydroxyalkyl and polyhydroxyalkyl groups.

The term "alkanoyl" encompasses groups wherein one or more terminal alkyl carbon atoms are replaced by one or more carbonyl groups as defined below. Monocarbonylalkyl and dicarbonylalkyl are specifically contemplated. Examples of monocarbonylalkyl groups include formyl, acetyl and pentanoyl. Examples of dicarbonylalkyl groups include oxalyl, malonyl and succinyl.

The term "alkylene" means a straight or branched chain group having from 1 to about 10 carbon atoms and having two or more points of attachment by covalent bonds. Examples of such groups are methylene, ethylene, methylethylene and isopropylene.

The term "alkenylene" denotes a straight or branched chain group having from 2 to about 10 carbon atoms, at least one double bond, and having two or more points of attachment by covalent bonds. Examples of such groups are 1,1-ethenylene (CH ₂ =C), 1,2-ethenylene (-CH=CH-) and 1,4-butadienyl (-CH=CH- CH=CH-).

The term "halogen" means a halogen atom such as a fluorine, chlorine, bromine or iodine atom.

The term "haloalkyl" encompasses groups wherein any one or more alkyl carbon atoms are replaced by halogen as defined above. Specifically contemplated are monohaloalkyl, dihaloalkyl and polyhaloalkyl groups. A monohaloalkyl group can, for example, have one bromine, chlorine or fluorine atom within the group. A dihaloalkyl group may have two or more identical halogen atoms or a combination of different halogen groups, and a polyhaloalkyl group may have two or more identical halogen atoms or a combination of different halogen groups. More preferred haloalkyl groups are "lower haloalkyl" groups having from one to about six carbon atoms. Examples of such haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, trifluoroethyl, pentafluoroethyl, heptafluoropropyl Difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl.

The term "hydroxyhaloalkyl" encompasses groups wherein any one or more haloalkyl carbon atoms are replaced by hydroxy as defined above. Examples of "hydroxyhaloalkyl" groups include hexafluorohydroxypropyl.

The term "haloalkylene group" means an alkylene group in which any one or more of the alkylene carbon atoms is replaced by a halogen as defined above. A dihaloalkylene group may have two or more identical halogen atoms or a combination of different halogen groups, and a polyhaloalkylene group may have two or more identical halogen atoms or a combination of different halogen groups. More preferred haloalkylene groups are "lower haloalkylene" groups having from one to about six carbon atoms. Examples of "haloalkylene" groups include difluoromethylene, tetrafluoroethylene, tetrachloroethylene, alkyl-substituted monofluoromethylene, and aryl-substituted trifluoromethylene.

The term "haloalkenyl" denotes a straight or branched chain radical having from 1 to about 10 carbon atoms and having one or more double bonds, wherein any one or more of the alkenyl carbon atoms is replaced by a halogen as defined above . A dihaloalkenyl group may have two or more identical halogen atoms or a combination of different halogen groups, and a polyhaloalkenyl group may have two or more identical halogen atoms or a combination of different halogen groups.

The terms "alkoxy" and "alkoxyalkyl" encompass straight or branched chain oxygen-containing groups, each having an alkyl moiety of one to about ten carbon atoms, such as a methoxy group. The term "alkoxyalkyl" also covers an alkyl group attached to one or more alkoxy groups, ie to form monoalkoxyalkyl and dialkoxyalkyl groups. More preferred alkoxy groups are "lower alkoxy" groups having one to six carbon atoms. Examples of such groups include methoxy, ethoxy, propoxy, butoxy, isopropoxy and t-butoxy. "Alkoxy" groups may be further substituted with one or more halogen atoms, such as fluorine, chlorine or bromine, to form "haloalkoxy" and "haloalkoxyalkyl" groups. Examples of such haloalkoxy groups include fluoromethoxy, chloromethoxy, trifluoromethoxy, difluoromethoxy, trifluoroethoxy, fluoroethoxy, tetrafluoroethoxy, pentafluoroethoxy, Fluoroethoxy and fluoropropoxy. Examples of such haloalkoxyalkyl groups include fluoromethoxymethyl, chloromethoxyethyl, trifluoromethoxymethyl, difluoromethoxyethyl and trifluoroethoxymethyl.

The terms "alkenyloxy" and "alkenyloxyalkyl" encompass straight or branched chain oxygen-containing groups, alkenyl moieties each having from two to about ten carbon atoms, such as ethyleneoxy or propyleneoxy groups. The term "alkenyloxyalkyl" also covers an alkyl group attached to one or more alkenyloxy groups, ie to form an alkenyloxyalkyl and dienyloxyalkyl group. More preferred alkenyloxy groups are "lower alkenyloxy" groups having two to six carbon atoms. Examples of such groups include ethyleneoxy, propyleneoxy, butenyloxy and isopropenyloxyalkyl. An "alkenyloxy" group can be further substituted with one or more halogen atoms, such as fluorine, chlorine or bromine, to give a "haloalkenyloxy" group. Examples of such groups include trifluoroethyleneoxy, fluoroethyleneoxy, difluoroethyleneoxy and fluoropropyleneoxy.

The term "haloalkoxyalkyl" also covers alkyl groups attached to one or more haloalkoxy groups, ie to form monohaloalkoxyalkyl and dihaloalkoxyalkyl groups. The term "haloalkenyloxy" also covers oxy groups attached to one or more haloalkenyloxy groups, ie to form monohaloalkenyloxy and dihaloalkenyloxy groups. The term "haloalkenyloxyalkyl" also covers alkyl groups attached to one or more haloalkenyloxy groups, i.e. to form monohaloalkenyloxyalkyl and dihaloalkenyloxyalkane base group.

The term "alkylenedioxy" group denotes an alkylene group in which at least two oxygens are bonded to a single alkylene group. Examples of "alkylenedioxy" groups include methylenedioxy, ethylenedioxy, alkyl-substituted methylenedioxy, and aryl-substituted methylenedioxy. The term "haloalkylenedioxy" group denotes a haloalkylene group in which at least two oxy groups are bonded to a single haloalkylene group. Examples of "haloalkylenedioxy" groups include difluoromethylenedioxy, tetrafluoroethylenedioxy, tetrachloroethylenedioxy, alkyl-substituted monofluoromethylenedioxy, and Aryl-substituted monofluoromethylenedioxy.

The term "aryl" alone or in combination denotes a carbocyclic aromatic system containing one, two or three rings, wherein the rings may be linked together in a pendant manner or may be fused. The term "fused" means that a second ring exists (ie, is attached or formed) by sharing (ie, sharing) two adjacent atoms with the first ring. The term "fused" is equivalent to the term "fused ring". The term "aryl" encompasses aromatic groups such as phenyl, naphthyl, tetrahydronaphthyl, indane and biphenyl.

The term "perhaloaryl" encompasses aromatic groups in which the aryl group is substituted by 3 or more halogen groups as defined below, such as phenyl, naphthyl, tetrahydronaphthyl, indane and biphenyl.

The term "heterocyclyl" encompasses saturated and partially saturated heteroatom-containing cyclic groups having 4 to 15 ring members selected from carbon, nitrogen, sulfur and oxygen, referred to herein as "C4-C15 heterocyclyl" , wherein at least one ring atom is a heteroatom. A heterocyclyl group may contain one, two or three rings, wherein the rings may be linked pendantly or may be fused. Examples of saturated heterocyclic groups include saturated 3 to 6 membered monoheterocyclic groups (such as pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl, etc.) containing 1 to 4 nitrogen atoms; 2 oxygen atoms and 1 to 3 nitrogen atoms saturated 3 to 6 membered monoheterocyclic group (such as morpholinyl, etc.); containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms saturated 3 to 6 membered Monoheterocyclic group (such as thiazolidinyl, etc.). Examples of partially saturated heterocyclyl groups include dihydrothiophene, dihydropyran, dihydrofuran and dihydrothiazole. Non-limiting examples of heterocyclic groups include 2-pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl, 1,3-dioxolanyl, 2H-pyranyl, 4H-pyranyl, piperidine 1,4-dioxanyl, morpholinyl, 1,4-dithianyl, thiomorpholinyl, etc.

The term "heteroaryl" encompasses fully unsaturated heteroatom-containing cyclic aromatic groups having from 5 to 15 ring members selected from carbon, nitrogen, sulfur and oxygen, wherein at least one ring atom is a heteroatom. A heteroaryl group may contain one, two or three rings, wherein the rings may be pendantly connected or may be fused. Examples of "heteroaryl" groups include unsaturated 5 to 6 membered monoheterocyclic groups containing 1 to 4 nitrogen atoms, such as pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (such as 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.), tetrazolyl (such as 1H-tetrazolyl, 2H-tetrazolyl, etc.); unsaturated fused heterocyclic groups containing 1 to 5 nitrogen atoms , such as indolyl, isoindolyl, indolizinyl (indolizinyl), benzimidazolyl, quinolinyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl (e.g. Tetrazolo[1,5-b]pyridazinyl, etc.), etc.; unsaturated 3 to 6-membered monoheterocyclic groups containing oxygen atoms, such as pyranyl, 2-furyl, 3-furyl, etc.; containing Unsaturated 5- to 6-membered monoheterocyclic groups with sulfur atoms, such as 2-thienyl, 3-thienyl, etc.; unsaturated 5- to 6-membered monoheterocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms Cyclic groups such as oxazolyl, isoxazolyl, oxadiazolyl (e.g. 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl Azolyl, etc.) etc.; unsaturated fused heterocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms (such as benzoxazolyl, benzoxadiazolyl, etc.); containing 1 to 2 unsaturated 5 to 6 membered monoheterocyclic groups with sulfur atoms and 1 to 3 nitrogen atoms, such as thiazolyl, thiadiazolyl (such as 1,2,4-thiadiazolyl, 1,3,4- thiadiazolyl, 1,2,5-thiadiazolyl, etc.); unsaturated fused heterocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms (such as benzothiazolyl, benzene and thiadiazolyl, etc.), etc. The term also covers groups in which a heterocyclic group is fused to an aryl group. Examples of such fused bicyclic groups include benzofuran, benzothiophene, and the like. The "heterocyclic group" may have 1 to 3 substituents as defined below. Preferred heterocyclic groups include five to twelve membered fused or non-fused groups. Non-limiting examples of heteroaryl groups include pyrrolyl, pyridyl, pyridyloxy, pyrazolyl, triazolyl, pyrimidinyl, pyridazinyl, oxazolyl, thiazolyl, imidazolyl, indolyl, Thienyl, furyl, tetrazolyl, 2-imidazolinyl, imidazolidinyl, 2-pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl, 1,2,3-oxadiazole Base, 1,2,3-triazolyl, 1,3,4-thiadiazolyl, pyrazinyl, piperazinyl, 1,3,5-triazinyl, 1,3,5-trithiane benzo(b)thienyl, benzimidazolyl, quinolinyl, tetrazolyl, etc.

The term "sulfonyl", whether used alone or in combination with other terms, such as alkylsulfonyl, denotes the divalent group _-SO2- , respectively. "Alkylsulfonyl" encompasses an alkyl group attached to a sulfonyl group, wherein alkyl is as defined above. "Alkylsulfonylalkyl" encompasses an alkylsulfonyl group attached to an alkyl group, wherein alkyl is as defined above. "Haloalkylsulfonyl" encompasses a haloalkyl group attached to a sulfonyl group, wherein haloalkyl is as defined above. "Haloalkylsulfonylalkyl" encompasses a haloalkylsulfonyl group attached to an alkyl group, wherein alkyl is as defined above. The term "aminosulfonyl" denotes an amino group attached to a sulfonyl group.

The term "sulfinyl", whether used alone or in combination with other terms, such as alkylsulfinyl, denotes the divalent group -S(O)-, respectively. "Alkylsulfinyl" encompasses an alkyl group attached to a sulfinyl group, wherein alkyl is as defined above. "Alkylsulfinylalkyl" encompasses an alkylsulfinyl group attached to an alkyl group, wherein alkyl is as defined above. "Haloalkylsulfinyl" encompasses a haloalkyl group attached to a sulfinyl group, wherein haloalkyl is as defined above. "Haloalkylsulfinylalkyl" encompasses a haloalkylsulfinyl group attached to an alkyl group, wherein alkyl is as defined above.

The term "aralkyl" encompasses aryl-substituted alkyl groups. Preferred aralkyl groups are "lower aralkyl" groups in which the aryl group is attached to an alkyl group having one to six carbon atoms. Examples of such groups include benzyl, benzhydryl, trityl, phenethyl and benzhydryl. The terms benzyl and benzyl are interchangeable.

The term "heteroaralkyl" encompasses heteroaryl-substituted alkyl groups wherein the heteroaralkyl group may additionally be substituted with three or more substituents as defined above for aralkyl groups. The term "perhaloaralkyl" encompasses aryl-substituted alkyl groups wherein the aralkyl group is substituted with three or more halo groups as defined above.

The term "aralkylsulfinyl" encompasses an aralkyl group attached to a sulfinyl group, wherein aralkyl is as defined above. "Aralkylsulfinylalkyl" encompasses an aralkylsulfinyl group attached to an alkyl group, wherein alkyl is as defined above.

The term "aralkylsulfonyl" encompasses an aralkyl group attached to a sulfonyl group, wherein aralkyl is as defined above. "Aralkylsulfonylalkyl" encompasses an aralkylsulfonyl group attached to an alkyl group, wherein alkyl is as defined above.

The term "cycloalkyl" encompasses groups having 3 to 15 carbon atoms. More preferred cycloalkyl groups are "lower cycloalkyl" groups having three to seven carbon atoms. Examples include groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. The term cycloalkyl encompasses groups having 7 to 15 carbon atoms and having two to four rings. Examples include groups such as norbornyl (ie, bicyclo[2.2.1]heptyl) and adamantyl. The term "cycloalkylalkyl" encompasses cycloalkyl-substituted alkyl groups. Preferred cycloalkylalkyl groups are "lower cycloalkylalkyl" groups in which the cycloalkyl group is attached to an alkyl group having one to six carbon atoms. Examples of such groups include cyclohexylhexyl. The term "cycloalkenyl" encompasses groups having three to ten carbon atoms and one or more carbon-carbon double bonds. Preferred cycloalkenyl groups are "lower cycloalkenyl" groups having three to seven carbon atoms. Examples include groups such as cyclobutenyl, cyclopentenyl, cyclohexenyl, and cycloheptenyl. The term "halocycloalkyl" encompasses groups wherein any one or more cycloalkyl carbon atoms are replaced by halogen as defined above. Specifically contemplated are monohalocycloalkyl, dihalocycloalkyl and polyhalocycloalkyl groups. A monohalocycloalkyl group may, for example, have one bromine, chlorine or fluorine atom within the group. A dihalogenated group may have two or more identical halogen atoms or a combination of different halogenated groups, and a polyhalogenated group may have two or more identical halogen atoms or a combination of different halogenated groups. More preferred halocycloalkyl groups are "lower halocycloalkyl" groups having from three to about eight carbon atoms. Examples of such halocycloalkyl groups include fluorocyclopropyl, difluorocyclobutyl, trifluorocyclopentyl, tetrafluorocyclohexyl and dichlorocyclopropyl. The term "halocycloalkenyl" encompasses groups wherein any one or more cycloalkenyl carbon atoms are replaced by halogen as defined above. Specifically contemplated are monohalocycloalkenyl, dihalocycloalkenyl and polyhalocycloalkenyl groups.

The term "cycloalkoxy" encompasses a cycloalkyl group attached to an oxy group. Examples of such groups include cyclohexyloxy and cyclopentyloxy. The term "cycloalkoxyalkyl" also encompasses alkyl groups attached to one or more cycloalkoxy groups, ie to form monocycloalkoxyalkyl and bicycloalkoxyalkyl groups. Examples of such groups include cyclohexyloxyethyl. A "cycloalkoxy" group may be further substituted with one or more halogen atoms, such as fluorine, chlorine or bromine, to give "halocycloalkoxy" and "halocycloalkoxyalkyl" groups.

The term "cycloalkylalkoxy" encompasses a cycloalkyl group attached to an alkoxy group. Examples of such groups include cyclohexylmethoxy and cyclopentylmethoxy.

The term "cycloalkenyloxy" encompasses a cycloalkenyl group attached to an oxy group. Examples of such groups include cyclohexenyloxy and cyclopentenyloxy. The term "cycloalkenyloxyalkyl" also encompasses alkyl groups attached to one or more cycloalkenyloxy groups, ie to form monocycloalkenyloxyalkyl and bicycloalkenyloxyalkyl groups. Examples of such groups include cyclohexenyloxyethyl. "Cycloalkenyloxy" groups may be further substituted with one or more halogen atoms, such as fluorine, chlorine or bromine, to give "halocycloalkenyloxy" and "halocycloalkenyloxyalkyl" groups.

The term "cycloalkanedioxy" group denotes a cycloalkylene group in which at least two oxygens are bonded to a single cycloalkylene group. Examples of "cycloalkanedioxy" groups include 1,2-dioxcyclohexylene.

The term "cycloalkylsulfinyl" encompasses a cycloalkyl group attached to a sulfinyl group, wherein cycloalkyl is as defined above. "Cycloalkylsulfinylalkyl" encompasses a cycloalkylsulfinyl group attached to an alkyl group, wherein alkyl is as defined above. The term "cycloalkylsulfonyl" encompasses a cycloalkyl group attached to a sulfonyl group, wherein cycloalkyl is as defined above. "Cycloalkylsulfonylalkyl" encompasses a cycloalkylsulfonyl group attached to an alkyl group, wherein alkyl is as defined above.

The term "cycloalkylalkanoyl" encompasses groups wherein one or more cycloalkyl carbon atoms are replaced by one or more carbonyl groups as defined below. Specifically contemplated are monocarbonylcycloalkyl and dicarbonylcycloalkyl groups. Examples of monocarbonylcycloalkyl groups include cyclohexylcarbonyl, cyclohexylacetyl and cyclopentylcarbonyl. Examples of dicarbonylcycloalkyl groups include 1,2-dicarbonylcyclohexane.

The term "alkylthio" encompasses groups containing straight or branched chain alkyl groups of one to ten carbon atoms attached to a divalent sulfur atom. More preferred alkylthio groups are "lower alkylthio" groups having one to six carbon atoms. An example of "lower alkylthio" is methylthio ( _CH3 -S-). An "alkylthio" group may be further substituted with one or more halogen atoms, such as fluorine, chlorine or bromine, to yield a "haloalkylthio" group. Examples of such groups include fluoromethylthio, chloromethylthio, trifluoromethylthio, difluoromethylthio, trifluoroethylthio, fluoroethylthio, tetrafluoroethylthio, pentafluoromethylthio, Fluoroethylthio and fluoropropylthio.

The term "alkylarylamino" encompasses a group containing a straight or branched chain alkyl group of one to ten carbon atoms and an aryl group, both attached to an amino group. Examples include N-methyl-4-methoxyaniline, N-ethyl-4-methoxyaniline and N-methyl-4-trifluoromethoxyaniline.

The term alkylamino denotes "monoalkylamino" and "dialkylamino", respectively containing one or two alkyl groups attached to an amino group.

The term arylamino means "monoarylamino" and "diarylamino", containing respectively one or two aryl groups attached to an amino group. Examples of such groups include N-phenylamino and N-naphthylamino.

The term "aralkylamino" encompasses an aralkyl group attached to an amino group, wherein aralkyl is as defined above. The term aralkylamino means "monoaralkylamino" and "diaralkylamino", containing respectively one or two aralkyl groups attached to an amino group. The term aralkylamino further means "an aralkyl-alkylamino" containing an aralkyl group and an alkyl group attached to an amino group.

The term "arylsulfinyl" encompasses groups containing an aryl group as defined above attached to a divalent S(O) atom. The term "arylsulfinylalkyl" denotes an arylsulfinyl group attached to a straight or branched chain alkyl group of one to ten carbon atoms.

The term "arylsulfonyl" encompasses an aryl group attached to a sulfonyl group, wherein aryl is as defined above. "Arylsulfonylalkyl" encompasses an arylsulfonyl group attached to an alkyl group, wherein alkyl is as defined above.

The term "heteroarylsulfinyl" encompasses groups containing a heteroaryl group as defined above attached to a divalent S(O) atom. The term "heteroarylsulfinylalkyl" denotes a heteroarylsulfinyl group attached to a straight or branched chain alkyl group of one to ten carbon atoms.

The term "heteroarylsulfonyl" encompasses a heteroaryl group attached to a sulfonyl group, wherein heteroaryl is as defined above. "Heteroarylsulfonylalkyl" encompasses a heteroarylsulfonyl group attached to an alkyl group, wherein alkyl is as defined above.

The term "aryloxy" encompasses an aryl group as defined above attached to an oxygen atom. Examples of such groups include phenoxy, 4-chloro-3-ethylphenoxy, 4-chloro-3-methylphenoxy, 3-chloro-4-ethylphenoxy, 3,4 -Dichlorophenoxy, 4-methylphenoxy, 3-trifluoromethoxyphenoxy, 3-trifluoromethylphenoxy, 4-fluorophenoxy, 3,4-dimethyl Phenoxy, 5-bromo-2-fluorophenoxy, 4-bromo-3-fluorophenoxy, 4-fluoro-3-methylphenoxy, 5,6,7,8-tetralinoxy Base, 3-isopropylphenoxy, 3-cyclopropylphenoxy, 3-ethylphenoxy, 3-pentafluoroethylphenoxy, 3-(1,1,2,2-tetra fluoroethoxy)-phenoxy and 4-tert-butylphenoxy.

The term "aroyl" encompasses an aryl group as defined above linked to a carbonyl group as defined above. Examples of such groups include benzoyl and toluoyl.

The term "aralkanoyl" encompasses an aralkyl group as defined above linked to a carbonyl group as defined above. Examples of such groups include, for example, phenylacetyl.

The term "aralkoxy" encompasses oxygen-containing aralkyl groups attached to other groups through an oxygen atom. A more preferred aralkoxy group is a "lower aralkoxy" group in which a phenyl group is linked to the above-mentioned lower alkoxy group. Examples of such groups include benzyloxy, 1-phenylethoxy, 3-trifluoromethoxybenzyloxy, 3-trifluoromethylbenzyloxy, 3,5-difluorobenzyloxy, 3-bromobenzyloxy, 4-propylbenzyloxy, 2-fluoro-3-trifluoromethylbenzyloxy and 2-phenylethoxy.

The term "aryloxyalkyl" encompasses an aryloxy group as defined above attached to an alkyl group. Examples of such groups include phenoxymethyl.

The term "haloaryloxyalkyl" encompasses aryloxyalkyl groups as defined above, wherein one to five halo groups are attached to the aryloxy group.

The term "heteroaroyl" encompasses a heteroaryl group as defined above linked to a carbonyl group as defined above. Examples of such groups include furoyl and nicotinoyl.

The term "heteroaralkanoyl" encompasses a heteroaralkyl group as defined above linked to a carbonyl group as defined above. Examples of such groups include, for example, pyridineacetyl and furanobutyryl.

The term "heteroaralkoxy" encompasses oxygen-containing heteroaralkyl groups attached to other groups through an oxygen atom. A more preferred heteroaralkoxy group is a "lower heteroaralkoxy" group in which a heteroaryl group is linked to the above-mentioned lower alkoxy group.

The term "haloheteroaryloxyalkyl" encompasses heteroaryloxyalkyl groups as defined above, wherein one to four halo groups are attached to the heteroaryloxy group.

The term "heteroarylamino" encompasses a heterocyclyl group as defined above attached to an amino group. Examples of such groups include pyridylamino.

The term "heteroarylaminoalkyl" encompasses a heteroarylamino group as defined above attached to an alkyl group. Examples of such groups include picolylamino.

The term "heteroaryloxy" encompasses a heterocyclyl group as defined above attached to an oxy group. Examples of such groups include 2-thienyloxy, 2-pyrimidinyloxy, 2-pyridyloxy, 3-pyridyloxy and 4-pyridyloxy.

The term "heteroaryloxyalkyl" encompasses a heteroaryloxy group as defined above attached to an alkyl group. Examples of such groups include 2-pyridyloxymethyl, 3-pyridyloxyethyl and 4-pyridyloxymethyl.

The term "arylthio" encompasses an aryl group as defined above attached to a sulfur atom. Examples of such groups include phenylthio.

The term "arylthioalkyl" encompasses an arylthio group as defined above attached to an alkyl group. Examples of such groups include thiophenylmethyl.

The term "alkylthioalkyl" encompasses an alkylthio group as defined above attached to an alkyl group. Examples of such groups include methylthiomethyl. The term "alkoxyalkyl" encompasses an alkoxy group as defined above attached to an alkyl group. Examples of such groups include methoxymethyl.

The term "carbonyl" denotes a carbon group in which two of four covalent bonds are shared with an oxygen atom. The term "carboxy" encompasses a hydroxy group as defined above attached to one of two unshared bonds in a carbonyl group. The term "carboxamide" encompasses amino, monoalkylamino, dialkylamino, monocycloalkylamino, alkylcycloalkylamino and dicycloalkylamino groups attached to one of the two unshared bonds in a carbonyl group . The term "carboxamidoalkyl" encompasses a carboxamide group as defined above attached to an alkyl group. The term "carboxyalkyl" encompasses a carboxyl group as defined above attached to an alkyl group. The term "alkoxycarbonyl" encompasses an alkoxy group as defined above attached to one of two unshared bonds in a carbonyl group. The term "aralkoxycarbonyl" encompasses an aralkoxy group as defined above attached to one of two unshared bonds in a carbonyl group. The term "monoalkoxycarbonylalkyl" encompasses an alkoxycarbonyl group as defined above attached to an alkyl group. The term "dialkoxycarbonylalkyl" encompasses two alkoxycarbonyl groups as defined above attached to an alkylene group. The term "monocyanoalkyl" encompasses a cyano group as defined above attached to an alkyl group. The term "dicyanoalkylene" encompasses two cyano groups as defined above attached to an alkyl group. The term "alkoxycarbonylcyanoalkyl" encompasses a cyano group as defined above attached to an alkoxycarbonylalkyl group.

The term "acyl" alone or in combination denotes a carbonyl or thiocarbonyl group bonded to, for example, a group selected from hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkoxyalkyl, Haloalkoxy, aryl, heterocyclyl, heteroaryl, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, alkylthio radical, arylthio, amino, alkylamino, dialkylamino, aralkoxy, arylthio and alkylthioalkyl. Examples of "acyl" are formyl, acetyl, benzoyl, trifluoroacetyl, phthaloyl, malonyl, nicotinoyl, and the like.

The term "haloalkanoyl" encompasses one or more halo groups as defined above linked to an alkanoyl group as defined above. Examples of such groups include, for example, chloroacetyl, trifluoroacetyl, bromopropionyl and heptafluorobutyryl.

The term "phosphono" encompasses two pentavalent phosphorus covalently bonded to an oxygen group. The term "dialkoxyphosphono" denotes two alkoxy groups as defined above linked to a phosphono group by two covalent bonds. The term "diaralkoxyphosphono" denotes two aralkoxy groups as defined above linked to a phosphono group by two covalent bonds. The term "dialkoxyphosphonoalkyl" denotes a dialkoxyphosphono group as defined above attached to an alkyl group. The term "diaralkoxyphosphonoalkyl" denotes a diaralkoxyphosphono group as defined above attached to an alkyl group.

The term "amino" denotes a nitrogen atom containing two substituents, such as hydrogen, hydroxyl or alkyl, and having a covalent bond to a single atom, such as carbon. Examples of such amino groups include, for example, _-NH2 , _-NHCH3 , -NHOH and _-NHOCH3 . The term "imino" denotes a nitrogen atom that contains a substituent, such as hydrogen, hydroxyl or alkyl, and has two covalent bonds to a single atom, such as carbon. Examples of such imino groups include, for example, =NH, = _NCH3 , =NOH and = _NOCH3 . The term "iminocarbonyl" denotes a carbon group in which two of four covalent bonds are shared with an imino group. Examples of such iminocarbonyl groups include, for example, C=NH, C= _NCH3 , C=NOH and C= _NOCH3 . The term "amidino" encompasses a substituted or unsubstituted amino group bonded to one of the two available iminocarbonyl group bonds. Examples of such amidino groups include, for example, _NH2 -C=NH, _NH2 -C= _NCH3 , _NH2 -C= _NOCH3 and _CH3NH -C=NOH. The term "guanidino" denotes an amidino group bonded to an amino group as defined above, wherein said amino group may be bonded to a third group. Examples of such guanidino groups include, for example, _NH2 -C(NH)-NH-, _NH2 -C( _NCH3 )-NH-, NH2 _- C( _NOCH3 )-NH- and _CH3NH -C (NOH)-NH-.

The term "sulfonium" denotes a positively charged trivalent sulfur atom wherein the sulfur is substituted with three carbonyl groups such as alkyl, alkenyl, aralkyl or aryl. The term "dialkylsulfonium" denotes a sulfonium group wherein the sulfur is substituted by two alkyl groups. Examples of such dialkylsulfonium groups include, for example, (CH ₃ ) ₂ S ⁺ -. The term "dialkylsulfoniumalkyl" denotes a dialkylsulfonium group wherein said group is bonded to a bond of an alkylene group as defined above. Examples of such dialkylsulfoniumalkyl groups include (CH ₃ ) ₂ S ⁺ —CH ₂ CH ₂ —.

The term "phosphonium" denotes a positively charged tetravalent phosphorus atom, wherein the phosphorus is substituted with four carbonyl groups such as alkyl, alkenyl, aralkyl or aryl. The term "trialkylphosphonium" denotes a phosphonium group in which the phosphorus is substituted with three alkyl groups. Examples of such trialkylphosphonium groups include, for example, (CH ₃ ) ₃ P ⁺ −.

"Alkyl", "alkenyl", "alkynyl", "alkanoyl", "alkylene", "alkenylene", "hydroxyalkyl", "haloalkyl", "halogenyl" as defined above alkylene", "haloalkenyl", "alkoxy", "alkenyloxy", "alkenyloxyalkyl", "alkoxyalkyl", "aryl", "perhalogenated Aryl", "haloalkoxy", "haloalkoxyalkyl", "haloalkenyloxy", "haloalkenyloxyalkyl", "alkenedioxy", "haloalkenedi Oxy", "Heterocyclyl", "Heteroaryl", "Hydroxyhaloalkyl", "Alkylsulfonyl", "Haloalkylsulfonyl", "Alkylsulfonylalkyl", "Haloalkylsulfonyl Alkyl", "Alkylsulfinyl", "Alkylsulfinylalkyl", "Haloalkylsulfinylalkyl", "Aralkyl", "Heteroarylalkyl", "Perhaloaryl Alkyl", "aralkylsulfonyl", "aralkylsulfonylalkyl", "aralkylsulfinyl", "aralkylsulfinylalkyl", "cycloalkyl", "cyclo alkylalkanoyl", "cycloalkylalkyl", "cycloalkenyl", "halocycloalkyl", "halocycloalkenyl", "cycloalkylsulfinyl", "cycloalkylene Sulfonylalkyl", "cycloalkylsulfonyl", "cycloalkylsulfonylalkyl", "cycloalkoxy", "cycloalkoxyalkyl", "cycloalkylalkoxy", " Cycloalkenyloxy", "cycloalkenyloxyalkyl", "cycloalkenedioxy", "halocycloalkoxy", "halocycloalkoxyalkyl", "halocycloalkenyloxy ", "Halocycloalkenyloxyalkyl", "Alkylthio", "Haloalkylthio", "Alkylsulfinyl", "Amino", "Oxy", "Sulphur", "Alkyl Amino", "arylamino", "aralkylamino", "arylsulfinyl", "arylsulfinylalkyl", "arylsulfonyl", "arylsulfonylalkyl", "Heteroarylsulfinyl", "heteroarylsulfinylalkyl", "heteroarylsulfonyl", "heteroarylsulfonylalkyl", "heteroarylamino", "heteroarylamino Alkyl", "heteroaryloxy", "heteroaryloxyalkyl", "aryloxy", "aroyl", "aralkanoyl", "aralkoxy", "aryloxyalkyl ", "haloaryloxyalkyl", "heteroaroyl", "heteroaralkanoyl", "heteroaralkoxy", "heteroaralkoxyalkyl", "arylthio", " "Arylthioalkyl", "Alkoxyalkyl", "Acyl", "Amidino", "Guanidino", "Dialkylsulfonium", "Trialkylphosphonium" and "Dialkylsulfoniumalkyl ” may optionally have one or more non-hydrogen substituents such as amidino, guanidino, dialkylsulfonium, trialkylphosphonium, dialkylsulfoniumalkyl, perhalogenated aralkyl, aralkylsulfonium Acyl, aralkylsulfonylalkyl, aralkylsulfinyl, aralkylsulfinylalkyl, halocycloalkyl, halocycloalkenyl, cycloalkylsulfinyl, cycloalkylsulfinyl Acylalkyl, cycloalkylsulfonyl, cycloalkylsulfonylalkyl, heteroarylamino, N-heteroarylamino-N-alkylamino, heteroarylaminoalkyl, heteroaryloxy, heteroaryl Oxyalkyl, Haloalkylthio, Alkanoyloxy, Alkoxy, Alkoxyalkyl, Haloalkoxyalkyl, Heteroaralkoxy, Cycloalkoxy, Cycloalkenyloxy, Cycloalkoxy Alkyl, cycloalkylalkoxy, cycloalkenyloxyalkyl, cycloalkanedioxy, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxy, halocyclo Alkenyloxyalkyl, hydroxy, amino, thio, nitro, lower alkylamino, alkylthio, alkylthioalkyl, arylamino, aralkylamino, arylthio, arylthioalkyl, Heteroaralkoxyalkyl, Alkylsulfinyl, Alkylsulfinylalkyl, Arylsulfinylalkyl, Arylsulfonylalkyl, Heteroarylsulfinylalkyl, Heteroarylsulfonyl Acylalkyl, alkylsulfonyl, alkylsulfonylalkyl, haloalkylsulfinylalkyl, haloalkylsulfonylalkyl, alkylsulfonylamino, alkylaminosulfonyl, amidosulfonyl, alkane Alkylamidosulfonyl, dialkylamidosulfonyl, one arylamidosulfonyl, arylsulfonylamino, diarylamidosulfonyl, one alkyl-arylamidosulfonyl, aryl Sulfonyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl, heteroarylalkanoyl, haloalkanoyl , Alkyl, alkenyl, alkynyl, alkenyloxy, alkenyloxyalkyl, alkylenedioxy, haloalkylenedioxy, cycloalkyl, cycloalkylalkanoyl, cycloalkenyl, lower ring Alkylalkyl, lower cycloalkenylalkyl, halogen, haloalkyl, haloalkenyl, haloalkoxy, hydroxyhaloalkyl, hydroxyaralkyl, hydroxyalkyl, aminoalkyl, hydroxyheteroaralkyl, haloalkane Oxyalkyl, aryl, aralkyl, aryloxy, aralkoxy, aryloxyalkyl, saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl, heteroaryloxy, hetero Aryloxyalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, carboxyalkyl, alkoxycarbonyl, alkoxycarbonyl, aralkoxycarbonyl, carboxamido, Carboxamidoalkyl, cyano, haloalkoxycarbonyl, phosphono, phosphonoalkyl, diaralkoxyphosphono and diaralkoxyphosphonoalkyl.

The term "spacer" may include covalent bonds and linear moieties having a backbone of 1 to 7 connected atoms. The spacer can have a monovalent or multivalent chain of 1 to 7 atoms. The monovalent chain may consist of groups selected from the group consisting of: =C(H)-, =C( ^R2a )-, -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)-, wherein R is selected from the ^{group consisting} of alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, aryloxyalkyl, alkoxyalkyl, alkylthioalkyl, arylthio Alkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkoxyalkyl, perhaloaralkyl, heteroarylalkyl, heteroaryloxyalkyl, heteroarylthio ylalkyl and heteroarylalkenyl. The polyvalent chain may consist 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 5 or 6 atom straight chains with side chains. The chain may consist of _one or more groups selected from the group consisting of lower alkylene, lower alkenyl, -O-, -O- _CH2- , -S- _CH2- , _-CH2CH2- , ethylene radical, -CH=CH(OH)-, -OCH ₂ O-, -O(CH ₂ ) ₂ O-, -NHCH ₂ -, -OCH(R ^2a )O-, -O(CH ₂ CHR ^2a )O -, -OCF ₂ O-, -O(CF ₂ ) ₂ O-, -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 ₂ C(O)-, -CH(OH)-, =C(OH)-, -CH(OR ^2a )-, =C(OR ^2a )-, S(O) ₂ CH ₂ - and -NR ^2a CH ₂ -, and many other groups as defined above or known or determined by those skilled in the art. Side chains may include one or more non-hydrogen substituents such as amidino, guanidino, dialkylsulfonium, trialkylphosphonium, dialkylsulfoniumalkyl, perhalogenated aralkyl, aralkylsulfonyl, Aralkylsulfonyl, Aralkylsulfinyl, Aralkylsulfinyl, Halocycloalkyl, Halocycloalkenyl, Cycloalkylsulfinyl, Cycloalkylsulfinyl radical, cycloalkylsulfonyl, cycloalkylsulfonylalkyl, heteroarylamino, N-heteroarylamino-N-alkylamino, heteroarylaminoalkyl, heteroaryloxy, heteroaryloxy Alkyl, haloalkylthio, alkanoyloxy, alkoxy, alkoxyalkyl, haloalkoxyalkyl, heteroaralkoxy, cycloalkoxy, cycloalkenyloxy, cycloalkoxyalkyl , cycloalkylalkoxy, cycloalkenyloxyalkyl, cycloalkylenedioxy, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxy, halocycloalkenyloxy Alkyl, hydroxy, amino, thio, nitro, lower alkylamino, alkylthio, alkylthioalkyl, arylamino, aralkylamino, arylthio, arylthioalkyl, heteroaryl Alkoxyalkyl, Alkylsulfinyl, Alkylsulfinylalkyl, Arylsulfinylalkyl, Arylsulfonylalkyl, Heteroarylsulfinylalkyl, Heteroarylsulfonylalkyl radical, alkylsulfonyl, alkylsulfonylalkyl, haloalkylsulfinylalkyl, haloalkylsulfonylalkyl, alkylsulfonylamino, alkylaminosulfonyl, amidosulfonyl, alkylacyl Aminosulfonyl, dialkylamidosulfonyl, monoarylamidosulfonyl, arylsulfonylamino, diarylamidosulfonyl, monoalkylarylamidosulfonyl, arylsulfinyl , arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl, heteroarylalkanoyl, haloalkanoyl, alkane group, alkenyl, alkynyl, alkenyloxy, alkenyloxyalkyl, alkylenedioxy, haloalkylenedioxy, cycloalkyl, cycloalkenyl, lower cycloalkylalkyl, lower cycloalkene arylalkyl, halogen, haloalkyl, haloalkenyl, haloalkoxy, hydroxyhaloalkyl, hydroxyaralkyl, hydroxyalkyl, aminoalkyl, hydroxyheteroaralkyl, haloalkoxyalkyl, aryl, Aralkyl, aryloxy, aralkoxy, aryloxyalkyl, saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl, heteroaryloxy, heteroaryloxyalkyl, aryl Alkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, carboxyalkyl, alkoxycarbonyl, aralkoxycarbonyl, carboxamido, carboxamidoalkyl, cyano, haloalkoxycarbonyl, Phosphono, phosphonoalkyl, diaralkoxyphosphono and aralkoxyphosphonoalkyl.

The compounds of the invention can exist in tautomeric, geometric or stereoisomeric forms. The present invention intends all such compounds, including cis and trans geometric isomers, E and Z geometric isomers, R and S enantiomers, diastereomers, d-isomers, 1-isomers Conformants, their racemic mixtures and other mixtures are within the scope of the present invention. Pharmaceutically acceptable salts of these tautomeric, geometric isomeric or stereoisomeric forms are also included within the present invention.

The terms "cis" and "trans" denote forms of geometric isomerism in which two carbon atoms joined by a double bond will each have a hydrogen atom on the same side of the double bond ("cis") or on the opposite side of the double bond. Contralateral ("trans").

Some of the compounds described contain alkenyl groups, which are meant to include cis and trans or "E" and "Z" geometric isomeric forms.

Some of the compounds described contain one or more stereocenters, which means that for each stereocenter the R, S isomers and mixtures of the R and S forms are included.

Alone or as part of a heterocyclic ring system, some of the compounds described herein may contain one or more ketocarbonyl or aldehyde carbonyl groups, or combinations thereof. Such carbonyl groups may exist partly or mainly in the "ketone" form of each aldehyde and ketone group and partly or mainly in one or more "enol" forms. Compounds of the invention having an aldehyde or ketone carbonyl are meant to include "keto" and "enol" tautomeric forms.

Alone or as part of a heterocyclic ring system, some of the compounds described herein may contain one or more amide carbonyl groups, or combinations thereof. Such carbonyl groups may exist partly or mainly in the "keto" form of each amide group and partly or mainly in one or more "enol" forms. Compounds of the invention having an amide carbonyl group are meant to include "keto" and "enol" tautomeric forms. The amide carbonyl group can be in type carbonyl (C=O) and thiocarbonyl (C=S).

Some of the compounds described herein may contain one or more imine or enamine groups or combinations thereof. Such groups may exist partly or mainly in the "imine" form of each group and partly or mainly in the form of one or more "enamines". Compounds of the invention having such an imine or enamine group are meant to include "imine" and "enamine" tautomeric forms.

The invention also includes treatment and prevention in anticoagulant therapy for the treatment and prevention of various thrombotic diseases in subjects, including coronary artery and cerebrovascular diseases, including the administration of With a compound of formula (I) in a therapeutically effective amount:

or a pharmaceutically acceptable salt thereof.

As a further embodiment, the compound of formula (I) as defined above in the present invention or a pharmaceutically acceptable salt thereof includes the treatment and prevention of coronary artery disease, cerebrovascular disease and other disorders related to the blood coagulation cascade in subjects, including A therapeutically effective amount of a compound of formula (I) of the present invention, or a pharmaceutically acceptable salt thereof, is administered to a subject suffering from these conditions.

The compound of formula (I) of the present invention or its pharmaceutically acceptable salt can also be used when it is required to inhibit blood coagulation, so as to prevent coagulation of stored whole blood, and prevent coagulation of other physiological samples used for testing or storage. Thus, the coagulation inhibitors of the present invention may be added to or contacted with stored whole blood and any medium containing or suspected to contain plasma coagulation factors where inhibition of blood coagulation is desired, for example when mammalian blood is combined with selected At the time of contact materials from the following groups: vascular grafts, graft stents, orthopedic prostheses, cardiac prostheses and extracorporeal circulatory systems.

The compound of formula (I) can inhibit the activity of serine proteases involved in blood coagulation cascade, and thus can be used in the production of medicines, for the prevention or treatment of diseases mediated by blood coagulation cascade serine proteases, such as in mammals, blood, blood Inhibition of platelet aggregate formation, inhibition of fibrin production, inhibition of thrombus formation and inhibition of emboli formation in preparations and mammalian organs. The compounds are also useful in the treatment or prophylaxis of unstable angina, refractory angina, myocardial infarction, transient ischemic attack, atrial fibrillation, thrombotic stroke, embolic stroke, deep vein thrombosis, disseminated Intravascular coagulation, ocular fibrin blockage, and reocclusion or restenosis of reperforated vessels. Compounds can also be used to study the mechanism of action of serine proteases in the coagulation cascade in order to design better inhibitors and develop better assays. Compounds of formula (I) will also be useful in the prevention of cerebrovascular accident (CVA) or stroke.

Also included within the family of compounds of formula (I) are their pharmaceutically acceptable salts. The term "pharmaceutically acceptable salt" encompasses salts commonly used to form alkali metal salts and to form free acid or free base addition salts. The nature of the salt is not critical so long as it is pharmaceutically acceptable. Suitable pharmaceutically acceptable acid addition salts of compounds of formula (I) may be prepared from inorganic or organic acids. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acids. Suitable organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic organic acids, examples of which are formic acid, acetic acid, propionic acid, succinic acid, glycolic acid , gluconic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, glucoronic acid (glucoronic), maleic acid, fumaric acid, pyruvic acid, aspartic acid, glutamic acid, benzoic acid, anthranilic acid , methanesulfonic acid, salicylic acid, p-hydroxybenzoic acid, phenylacetic acid, mandelic acid, pamoic acid (pamoic acid), methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, sulfanilic acid, stearic acid, cyclic Hexamic acid, alginic acid, galacturonic acid. Suitable pharmaceutically acceptable base addition salts of compounds of formula (I) include metal salts prepared from aluminium, calcium, lithium, magnesium, potassium, sodium and zinc, or from N,N'-dibenzylethylenediamine , choline, chloroprocaine, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and the organic salt prepared by procaine. All these salts may be prepared from the corresponding compounds of formula (I) by conventional methods, eg by reacting an appropriate acid or base with a compound of formula (I).

The present invention also includes pharmaceutical compositions comprising a therapeutically effective amount of a compound of formula (I) together with at least one pharmaceutically acceptable carrier, adjuvant or diluent. The pharmaceutical composition of the present invention may comprise the active compound of formula (I) and one or more non-toxic pharmaceutically acceptable carriers and/or diluents and/or adjuvants (collectively referred to herein as "carrier" materials), if Other active ingredients may also be included if desired. The active compounds of the present invention may be administered by any suitable route, preferably in the form of a pharmaceutical composition suitable for such a route, in a dosage effective for the intended treatment.

The active compounds and compositions can be administered, for example, orally, intravascularly, intraperitoneally, subcutaneously, intramuscularly, ophthalmically or topically. For the treatment of ocular fibrin plugging, the compounds can be administered intraocularly or topically, as well as orally or parenterally.

The compounds may be administered in the form of depot injections or implants, which may be formulated in such a way as to permit sustained release of the active ingredient. The active ingredient can be compressed into pellets or small cylinders and implanted subcutaneously or intramuscularly as depot injections or implants. Implants can be made of inert materials such as biodegradable polymers or synthetic organosiloxanes such as Silastic, silicone rubber, silicone rubber or other silicon-containing polymers.

The compounds can also be administered in the form of liposomal delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be generated from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.

Compounds can also be delivered using monoclonal antibodies as separate carriers to which the compound molecules are conjugated. Compounds can also be coupled to soluble polymers, which are orientable drug carriers. Such polymers may include polyvinylpyrrolidone, pyran copolymer, polyhydroxy-propyl-isoacrylamide-phenol, polyhydroxyethyl-aspartamide-phenol, or polyoxyethylene-polyethylene substituted with palmitoyl residues. lysine. In addition, compounds can be conjugated to a class of biodegradable polymers that can be used to achieve controlled release of drugs, such as polylactic acid, polyglycolic acid, copolymers of polylactic acid and polyglycolic acid, polyε-caprolactone, polyhydroxybutyrate Cross-linked or amphiphilic block copolymers of acids, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and hydrogels.

For oral administration, the pharmaceutical composition may be, for example, tablets, capsules (each including sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, formulations including syrups, liquids, and emulsions. Pharmaceutical compositions are preferably presented in dosage unit form containing a specific amount of the active ingredient. Examples of such dosage units are tablets or capsules. The active ingredient can also be administered by injection in a composition wherein, for example, saline, dextrose or water can be used as a suitable carrier.

The amount of therapeutically active compound to be administered and the dosage regimen for treating a disease using the compounds and/or compositions of the present invention depend on various factors, including the age, body weight, sex and physical condition of the subject, the severity of the disease, the time of administration, Routes and frequencies and the specific compounds employed can thus vary.

The pharmaceutical compositions may contain the active ingredient in an amount in the range of about 0.1 to 2000 mg, preferably in the range of about 0.5 to 500 mg. A daily dosage of about 0.01 to 100 mg/kg body weight, preferably between about 0.5 and about 20 mg/kg body weight, may be suitable. The daily dose may be administered in one to four divided doses per day.

The compounds may be formulated as topical ointments or creams or suppositories containing the total amount of active ingredient, for example, from 0.075 to 30% w/w, preferably from 0.2 to 20% w/w, most preferably from 0.4 to 15% w/w . When formulated in an ointment, the active ingredient may be formulated with a paraffinic or a water-miscible ointment base.

Alternatively, the active ingredients may be formulated in a cream with an oil-in-water cream base. The aqueous phase of the cream base may, for example, comprise at least 30% w/w polyols such as propylene glycol, butane-1,3-diol, mannitol, sorbitol, glycerol, polyethylene glycol and the like, if desired. mixture. Topical formulations may desirably include compounds which facilitate absorption or penetration of the active ingredient into the skin or other area of action. Examples of such dermal penetration enhancers include dimethylsulfoxide and related analogs. The compounds of the present invention may also be administered via transdermal devices. Preferably, topical administration is achieved using patches of the depot and porous membrane type or solid substrate type. In both cases, the active agent is released continuously from the depot or microcapsule, across the membrane into the active agent permeable adhesive plaster, which comes into contact with the recipient's skin or mucous membranes. If the active agent is absorbed through the skin, a controlled and predetermined flow of the active agent is administered to the subject. In the case of microcapsules, the encapsulating agent can function as a membrane.

The oily phase of the emulsions of this invention may be constituted from known ingredients and in a known manner. The oily phase may comprise only emulsifiers, but may also comprise a mixture of at least one emulsifier with fat or oil or fat and oil. Preferably, a hydrophilic emulsifier is included as well as a lipophilic emulsifier acting as a stabilizer. It is also preferred to include oils and fats. Emulsifiers, with or without stabilizers, together make up the so-called emulsifying waxes, which together with oils and fats make up the so-called emulsifying ointment bases, which form the oily dispersed phase of the cream. Emulsifiers and emulsion stabilizers suitable for use in the formulation of the invention include Tween 60, Span 80, cetearyl alcohol, myristyl alcohol, glyceryl monostearate and sodium lauryl sulfate, among others.

The choice of oil or fat suitable for the formulation is based on achieving the desired cosmetic properties, since the solubility of the active compound in most oils suitable for pharmaceutical emulsions is very low. Thus, the cream should preferably be a non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers. Linear or branched mono- or di-alkyl esters can be used, such as diisoadipate, isocetyl stearate, propylene glycol ester of coco fatty acid, isopropyl myristate, decyl oleate Blends of alkyl esters, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or branched chain esters. They can be used alone or in combination, depending on the desired properties. Alternatively, high boiling point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils may be used.

For therapeutic purposes, the active compounds according to the invention are usually combined with one or more adjuvants suitable for the indicated routes of administration. If administered orally, the compounds may be combined with lactose, sucrose, starch, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium salts of phosphoric and sulfuric acids, and Calcium salt, gelatin, gum arabic, sodium alginate, polyvinylpyrrolidone and/or polyvinyl alcohol are mixed, and then compressed into tablets or encapsulated for convenient administration. Such capsules or tablets may contain a controlled release formulation which may be provided by a dispersion of the active compound in hydroxypropylmethylcellulose. Preparations for parenteral administration may be aqueous or non-aqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions may be prepared from sterile powders or granules with one or more of the carriers or diluents mentioned for the formulation for oral administration. The compounds can be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, and/or various buffers. Other adjuvants and modes of administration are generally known in the art of pharmacy.

With regard to the treatment and prevention of various thrombotic diseases, including coronary artery and cerebrovascular diseases, the compounds and pharmaceutical compositions of the present invention are administered alone, in combination with each other or with other therapeutic agents when practicing the methods of the present invention Or combined administration of in vivo diagnostic agents. The coagulation cascade inhibitors of the present invention may also be co-administered with suitable anti-platelet aggregation agents, including but not limited to ticlopidine or clopidrogel; fibrinogen receptor antagonists (e.g. for the treatment or prophylaxis of stable angina or to prevent reocclusion and restenosis after angioplasty); anticoagulants, such as aspirin, warfarin, or heparin; thrombolytic agents, such as plasminogen activator or streptokinase, in various lesions Synergistic effect is achieved in the treatment of lipid-lowering agents, including antihypercholesterolemic agents (such as HMG CoA reductase inhibitors, such as mevastatin, lovastatin, simvastatin, pravastatin and fluvastatin, HMG CoA synthetase inhibitors, etc.); antidiabetic agents; or other cardiovascular agents (loop diuretics, thiazide-type diuretics, nitrates, aldosterone antagonists (such as spironolactone and epoxymexlerenone), angiotensin-converting enzyme (such as ACE) inhibitors agents, angiotensin II receptor antagonists, beta-blockers, antiarrhythmics, antihypertensives, and calcium channel blockers) to treat or prevent atherosclerosis. For example, patients with coronary artery disease and patients undergoing angioplasty would benefit from the co-administration of a fibrinogen receptor antagonist and an inhibitor of the coagulation cascade of the invention. Furthermore, inhibitors of the coagulation cascade can increase the efficiency of tissue plasminogen activator-mediated thrombolytic reperfusion.

Typical doses of the coagulation cascade inhibitors of the present invention with other suitable antiplatelet, anticoagulant, cardiovascular therapeutic or thrombolytic agents may be equivalent to the coagulation cascade inhibitors in the absence of additional antiplatelet, anticoagulant, or anticoagulant agents. Blood agents, cardiovascular therapeutics, or thrombolytics are co-administered, or may be substantially less than coagulation cascade inhibitors in the absence of additional antiplatelet, anticoagulant, cardiovascular therapeutics, or thrombolytics The dose when co-administered depends on the therapeutic needs of the patient.

If mentioned herein, all cited references are incorporated by reference.

Although the invention has been described in terms of specific embodiments, the details of these embodiments should not be construed as limitations of the invention. The following examples illustrate the invention without intending to limit its scope. Without elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. Accordingly, the following preferred specific embodiments are to be construed as illustrations only, and in no way limiting the remainder of the disclosure. Compounds containing various structurally modified variants as set forth in the schemes or in the following examples are also contemplated. Those skilled in the art will readily appreciate that known variations on the conditions and procedures of the following preparative methods may be used to prepare these compounds.

These general methods can be used by one skilled in the art to prepare the following specific examples, which have been or can be characterized ^by1H NMR, mass spectrometry, elemental analysis, and the like. These compounds may also be produced in vivo. The following examples contain detailed illustrations of the preparation of compounds of formula (I). These detailed descriptions, within the scope of the invention, are for illustration only and are not intended to limit the scope of the invention. All parts are by weight and temperatures are in degrees Celsius unless otherwise indicated.

The following general synthetic sequences can be used in the practice of the present invention. Abbreviations used in schemes and tables include: "AA" for amino acid, "AcCN" for acetonitrile, "AcOH" for acetic acid, and "BINAP" for 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl , "BnOH" stands for benzyl alcohol, "BnCHO" stands for 2-phenylacetaldehyde, "BnSO ₂ Cl" stands for benzylsulfonyl chloride, "Boc" stands for tert-butoxycarbonyl, "BOP" stands for benzotriazole-1- oxytris(dimethylamino), "bu" stands for butyl, "dba" stands for dibenzylideneacetone, "DCC" stands for 1,3-dicyclohexylcarbodiimide, "DCM" stands for dichloro Methane or methylene chloride, "DIBAH" or "DIBAL" stands for diisobutylaluminum hydride, "DMF" stands for dimethylformamide, "DMSO" stands for dimethylsulfoxide, "DPPA" stands for diphenylphosphoryl Azide, "EDC" stands for 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride, "Ex.No." stands for the example number, "Fmoc" stands for 9-fluorenylmethoxycarbonyl, "HOBt" stands for hydroxybenzotriazole, "LDA" stands for lithium diisopropylamide, "MW" stands for molecular weight, "NMM" stands for N-methylmorpholine, "Ph" stands for Phenyl or aryl, "PHTH" stands for phthaloyl, "pnZ" stands for 4-nitrobenzyloxycarbonyl, "PTC" stands for phase transfer catalyst, "py" stands for pyridine, "RNH ₂ " stands for primary organic amine , "SEM" stands for 2-(trimethylsilyl)ethoxy-methyl chloride, "p-TsOH" stands for p-toluenesulfonic acid, "TBAF" stands for tetrabutylammonium fluoride, "TBTU" stands for 2 -(1H-Benzotriazol-l-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate, "TEA" stands for triethylamine, "TFA" stands for trifluoroacetic acid, "THF" stands for tetrahydrofuran, "TMS" stands for trimethylsilyl, "TMSCN" stands for trimethylsilyl cyanide, and "Cbz" or "Z" stands for benzyloxycarbonyl.

General Synthetic Methods and Specific Examples

A general synthesis of substituted uracils (ie pyrimidine diketones) is shown in Scheme 1 below. Several N-1 substituted pyrimidinediones have been previously prepared and disclosed as intermediates useful in the preparation of the compounds of the present invention. Alkylation of the N-3 nitrogen is carried out by stirring a solution of this N-1 substituted pyrimidinedione and an α-haloacetate in dimethylsulfoxide in the presence of potassium carbonate. The reduction of nitro functional groups to primary amines is readily achieved using catalytic palladium-carbon in a hydrogen atmosphere. Primary amines can then be reacted with a variety of starting materials including, but not limited to, acid chlorides, anhydrides, sulfonyl chlorides, alkyl and aromatic halides, aldehydes, and ketones. The acetate can then be hydrolyzed to the acid with lithium hydroxide. The acid can then be coupled with a variety of desired amines under standard peptide coupling conditions to give amides. The amines used in the process of the invention are generally polyfunctional and react in protected form. Removal of these protecting groups affords compounds of the invention.

Process 1: Generic Uracil Method

Examples 1 and 2 below illustrate this general uracil (ie pyrimidinedione) synthetic scheme.

Example 1

EX-1A) 1-benzyl-5-nitro-2,4(1H, 3H) A solution of pyrimidinedione (6.14 g, 24.82 mmol) was dissolved in 100 ml of dimethyl sulfoxide, and potassium bicarbonate (3.78 g, 27.34 mmol) was added in one portion with stirring. After about 10 minutes, a solution of methyl bromoacetate (2.50ml, 26.40mmol) in 20ml of dimethylsulfoxide was added dropwise over 10 minutes. The reaction mixture was then heated to 40°C and stirred for 18 hours. The reaction mixture was diluted with water (500ml). The aqueous solution was extracted with ethyl acetate (4 x 100ml). The combined organic solutions were washed with water (1 x 150ml), brine (2 x 150ml). The organic solution was dried ( _MgSO4 ), filtered and concentrated to an oil. The crude oil was purified by MPLC (20% ethyl acetate/hexanes) to give pure 1-benzyl-3-methoxycarbonylmethyl-5-nitro-2,4(1H,3H)pyrimidinedione ( EX-1A), as a white solid, yield 81%:

¹ H NMR (400MHz, CDCl ₃ ) δ8.73(s, 1H) 7.38-7.30(m, 5H), 5.06(s, 2H), 4.69(s, 2H), 3.72(s, 3H); HRMS(ES ) theoretical value C ₁₄ H ₁₃ N ₃ O ₆ 319.0804, actual value 319.0797.

EX-1B) 1-benzyl-3-methoxycarbonylmethyl-5-nitro-2,4(1H,3H)pyrimidinedione (EX-1A; 6.30g, 19.74mmol) in 100.0ml methanol solution Degas with hydrogen. Then 5% Pd/C (0.737 g) was added to the solution, and stirred at room temperature under hydrogen atmosphere for 24 hours. The crude reaction was filtered through a pad of Celite 545 and concentrated under reduced pressure. The oil was purified by MPLC (60% ethyl acetate/hexanes) to give pure 5-amino-1-benzyl-3-methoxycarbonylmethyl-2,4(1H,3H)pyrimidinedione (EX- 1B), yield 63%, as a brown solid:

¹ H NMR (300MHz, DMSO) δ7.41-7.28(m, 5H), 6.93(s, 1H), 4.93(s, 2H), 4.66(s, 2H), 4.32(s, 2H), 3.69(s , 3H); HRMS (ES) theoretical value C ₁₄ H ₁₆ N ₃ O ₄ 290.1141, actual value 290.1138.

EX-1C) To 18.0 of 5-amino-1-benzyl-3-methoxycarbonylmethyl-2,4(1H,3H)pyrimidinedione (EX-1B; 3.12g, 10.77mmol) at room temperature N-methylmorpholine (3.60ml, 32.74mmol) was added in one portion to a solution of tetrahydrofuran and dimethylformamide (1:1, 0.62M) in ml. The resulting mixture was cooled to 0°C in an ice bath and stirred for 15 minutes. A solution of benzylsulfonyl chloride (2.26 g, 11.86 mmol) in 18.0 ml tetrahydrofuran was added dropwise over 30 minutes. After the addition was complete, the reaction was stirred at 0°C for 3 hours. The reaction mixture was diluted with ethyl acetate (250.0ml), washed with 1N HCl (2x50ml), saturated _NaHCO3 (2x50ml) and brine (2x50ml). The organic solution was dried ( _MgSO4 ), filtered and concentrated. Trituration with ethyl acetate and hexanes gave pure 1-benzyl-3-methoxycarbonylmethyl-5-[[(phenylmethyl)sulfonyl]amino-2,4(1H,3H)pyrimidinedione ( EX-1C), yield 74%, is white solid:

¹ H NMR (300MHz, DMSO) 69.16(s, 1H), 8.02(s, 1H), 7.43-7.37(m, 10H), 5.01(s, 2H), 4.65(s, 2H), 4.45(s, 2H ), 3.69(s, 3H); HRMS(ES) theoretical value C ₂₁ H ₂₂ N ₃ O ₆ S444.1229, actual value 444.1242.

EX-1D) To 1-benzyl-3-methoxycarbonylmethyl-5-[[(phenylmethyl)sulfonyl]amino-2,4(1H,3H)pyrimidinedione (EX-1C; 3.28g , 7.40mmol) in 94.0ml tetrahydrofuran and methanol (1:1, 0.078M) solution was added 30.0ml 0.1M lithium hydroxide aqueous solution. The suspension quickly clarified and became homogeneous. The reaction was stirred for 1 hour and the volatiles were removed under reduced pressure. The remaining aqueous solution was cooled in an ice bath and acidified to pH 1 with 1.0N HCl, resulting in the formation of a white precipitate. The precipitate was collected by filtration, washed with 1.0N HCl and water, and dried under vacuum to give pure 1-benzyl-3-methylenecarboxy-5-[[(phenylmethyl)sulfonyl]amino]-2, 4(1H,3H)pyrimidinedione (EX-1D), yield 99%:

¹ H NMR (300MHz, DMSO) δ9.14(br s, 1H), 7.98(s, 1H), 7.44-7.35(m, 10H), 5.00(s, 2H), 4.51(s, 2H), 4.45( s, 2H); HRMS (ES) theoretical value C ₂₀ H ₁₉ N ₃ O ₆ S429.0995, actual value 429.0981.

EX-1E) To 1-benzyl-3-methylenecarboxy-5-[[(phenylmethyl)sulfonyl]amino]-2,4(1H,3H)pyrimidinedione (EX-1D; 531.6mg , 1.238mmol) in 12.4ml tetrahydrofuran and dimethylformamide (1:1, 0.1M) solution, add N,N-diisopropylethylamine (1.10ml, 6.315mmol), N-hydroxybenzotriazole (499.6 mg, 3.697 mmol) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (717.2 mg, 3.741 mmol). The resulting mixture was stirred for 30 minutes. The amine (623.3 mg, 2.500 mmol) was then added in one portion to the reaction mixture. The resulting mixture was stirred overnight. The reaction mixture was diluted with ethyl acetate (50ml), washed with 5% citric acid (1x25ml), saturated _NaHCO3 (1x25ml) and brine (1x25ml). The organic solution was dried ( _MgSO4 ), filtered and concentrated. The crude reaction product was purified by MPLC (75% ethyl acetate/hexanes) to give the product EX-1E.

¹ H NMR (300MHz, DMSO) δ9.13(br s, 1H), 8.77(t, J=5.3Hz, 1H), 7.98(s, 1H), 7.91(d, J=7.9Hz, 1H), 7.45 -7.35(m, 13H), 5.01(s, 2H), 4.56(s, 2H), 4.56(s, 2H), 4.44(s, 2H), 4.38(d, J=5.4Hz, 2H), 1.47( s, 9H); HRMS (ES) theoretical value C ₃₃ H ₃₇ N ₆ O ₇ S661.2444, actual value 661.2448.

In a flask, 4.0 ml of 4M HCl in dioxane was added to the protected pyrimidinedione (EX-1E) (238.5 mg, 0.3610 mmol). The resulting solution was stirred overnight (approximately 18 hours). The solution was concentrated and the crude product was triturated from ether. The resulting white solid was collected by filtration, washed with ether, and dried to give the pure product: ¹ HNMR (300MHz, DMSO) δ 9.44(s, 2H), 9.29(s, 2H), 9.14(s, 1H), 9.01-8.99(m , 1H), 7.99(s, 1H), 7.81(d, J=7.9Hz, 1H), 7.51-7.37(m, 14H), 5.01(s, 2H), 4.57(s, 2H), 4.454.41( m, 2H), 3.58(s, 2H); HRMS (ES) theoretical value C ₂₈ H ₂₉ N ₆ O ₅ S561.1920, actual value 561.1917.

Example 2

EX-2A) To 1-benzyl-3-methylenecarboxy-5-[[(phenylmethyl)sulfonyl]amino]-2,4(1H,3H)pyrimidinedione (439.8mg, 1.024mmol) Add N,N-diisopropylethylamine (1.80ml, 10.30mmol), N-hydroxybenzotriazole (169.3mg, 1.253mmol) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (238.2mg, 1.243mmol). The resulting mixture was stirred for 10 minutes. The amine (648.3 mg, 1.231 mmol) was then added in one portion to the reaction mixture. The resulting mixture was stirred overnight. The reaction mixture was diluted with ethyl acetate (100ml), washed with 5% citric acid (1x50ml), saturated _NaHCO3 (1x50ml) and brine (1x50ml). The organic solution was dried ( _MgSO4 ), filtered and concentrated. The crude reaction product was purified by MPLC (75% ethyl acetate/hexanes) to give the product EX-2A:

¹ H NMR (300MHz, DMSO) δ9.09(s, 1H), 8.78(d, J=7.1Hz, 1H), 8.28(d, J=3.0Hz, 1H), 8.19(d, J=3.0Hz, 1H), 7.94(s, 1H), 7.43-7.31(m, 10H), 6.68(s, 1H), 5.44-5.43(m, 1H), 4.97(s, 2H), 4.56(d, J=4.2Hz , 2H), 4.41(s, 2H), 3.80(s, 3H), 3.08(br d, J=5.4Hz, 3H), 2.91(s, 1H), 2.75(s, 1H), 2.59(s, 3H ), 2.52(s, 3H), 2.06(s, 3H), 1.92-1.80(m, 1H), 1.61-1.51(m, 3H), 137-133(m 1H); HRMS(EI) theoretical value C ₃₉ H ₄₅ N ₈ O ₉ S ₃ 865.2472, actual value 865.2484.

To a solution of EX-2A (281.3 mg, 0.3252 mmol) in 3.0 ml of trifluoroacetic acid (0.1 M) was added thioanisole (0.115 ml, 0.9796 mmol) at room temperature with stirring. The resulting mixture was stirred for 6 hours. The reaction mixture was concentrated under reduced pressure. The crude product was purified by trituration with ether. The pale yellow powder was collected by filtration and washed with ether to give pure product 2:

¹ H NMR (300MHz, DMSO) δ9.07(s, 1H), 8.82(d, J=7.0Hz, 1H), 8.30(d, J=3.0Hz, 1H), 8.21(d, J=3.0Hz, 1H), 7.95(s, 1H), 7.55-7.20(m, 10H), 5.49-5.48(m, 1H), 4.97(s, 2H), 4.63-4.51(m, 2H), 4.42(s, 2H) , 3.13 (br d, J=6.0Hz, 2H), 2.49 (s, 3H), 1.91 (br s, 1H), 1.67-1.58 (m, 4H); LRMS (EI), (MH+) 653.2.

Using the methods illustrated in Examples 1 and 2 and Scheme 1, the following compounds can be prepared.

Example 3

Following steps A and B as illustrated in Example 1, and using 3-(N-Boc-amino)benzyl bromide (Murakami, Y.; Hagishita, S.; Okada, T.; Kii, M.; Hashizume, H. .; Yagami, T.; Fujimoto, M. "Bioorganic and Medicinal Chemistry" (Bioorg.Med.Chem.) 1999,7,1703-1714) instead of benzyl bromide, can prepare the alkylation intermediate 3-[1 -Methyl [3-(N-Boc-amino)benzyl]-5-amino-2,4-dioxopyrimidinyl]acetate (EX-3A).

To a solution of 1 equivalent (eq.) of ester EX-3A and 1 equivalent of cyclobutanone in tetrahydrofuran was added 1 equivalent of sodium cyanoborohydride, and the mixture was stirred for several hours. The solvent was removed by evaporation to give the crude product. The crude product was purified by silica gel chromatography to give pure 2-[3-[1-[3-(N-Boc-amino)benzyl]-5-(N-cyclobutyl)amino-2,4-dioxo Pyrimidinyl]] methyl acetate (EX-3B).

Following the remaining steps exemplified in Example 1, the compound of Example 3 can be obtained.

Example 4

A DMF solution of 1 equivalent of the appropriate amide and 1 equivalent of 3-nitrophenylisocyanate was heated to 100°C for several hours. The solvent was removed by evaporation to give the crude product. The crude product was purified by silica gel chromatography to give the pure product 1-[3-nitrophenyl]-5-nitro-2,4-dioxopyrimidine (EX-4A).

Under stirring, add 1 equivalent of uracil EX-4A in dimethyl sulfoxide solution to 1.1 equivalent of potassium bicarbonate at one time. After approximately 10 minutes, a solution of 1.1 equivalents of methyl bromoacetate in dimethyl sulfoxide was added dropwise over 10 minutes. The reaction mixture was heated to 40°C and stirred for 18 hours. The reaction mixture was diluted with water. The aqueous solution was extracted with ethyl acetate, and the combined organic solutions were washed with water and brine. The organic solution was dried over _MgSO4 , filtered and concentrated to give crude product. The crude product was purified by silica gel chromatography to give pure methyl 2-[3-[1-[3-nitrophenyl]-5-nitro-2,4-dioxopyrimidinyl]]acetate (EX-4B ).

To a suspension of the methyl ester EX-4B in tetrahydrofuran and methanol was added an excess of lithium hydroxide in water. The reaction was stirred for 1 hour and the volatiles were removed under reduced pressure. The remaining aqueous solution was cooled in an ice bath and acidified to pH 1 with 1.0N HCl, resulting in the formation of a white precipitate. The precipitate was collected by filtration, washed with 1.0N HCl and water, and dried under vacuum to give pure acid 2-[3-[1-[3-nitrophenyl]-5-nitro-2,4-dioxo Pyrimidinyl]]acetic acid (EX-4C).

A solution of acid EX-4C in dimethylformamide (0.1M) was added to 5 equivalents of N,N-diisopropylethylamine, 1 equivalent of N-hydroxybenzotriazole and 1 equivalent of 1-[3-(di Methylamino)propyl]-3-ethylcarbodiimide hydrochloride. The resulting mixture was stirred for 30 minutes. Then 1 equivalent of 4-(N-Boc-amidino)benzylamine was added to the reaction mixture in one portion. The resulting mixture was stirred overnight. The reaction mixture was diluted with ethyl acetate, washed with 5% citric acid, saturated NaHCO ₃ and brine. The organic solution was dried ( _MgSO4 ), filtered and concentrated. After MPLC purification, pure N-[4-(N-Boc-amidinobenzyl)]-2-[3-[1-[3-nitrophenyl]-5-nitro-2,4- Dioxopyrimidinyl]]acetamide (EX-4D).

Under a hydrogen atmosphere (balloon pressure), a methanol solution of the bisnitro compound EX-4D was treated with 5 mol% of 10% Pd/C. The suspension was stirred overnight. Filtration through Celite 545 and removal of the solvent afforded pure N-[4-(N-Boc-amidinobenzyl)]-2-[3-[1-[3-aminophenyl]-5-amino-2 , 4-dioxopyrimidinyl]]acetamide (EX-4E).

The tetrahydrofuran solution of bisamine EX-4E and 1 equivalent of cyclobutanone was first treated with 1 equivalent of sodium cyanoborohydride and then with a catalytic amount of hydrochloric acid. The reaction mixture was stirred at room temperature for several hours. Water was carefully added to terminate the reaction. The aqueous solution was extracted with ethyl acetate. The organic solution was washed with water and brine. The organic solution was dried ( _MgSO4 ), filtered and concentrated. After MPLC purification, pure N-[4-(N-Boc-amidinobenzyl)]-2-[3-[1-[3-aminophenyl]-5-(N-cyclobutylamino- 2,4-dioxopyrimidinyl]]acetamide (EX-4F).

A methanolic solution of N-Boc amidine EX-4F was treated with 3 equivalents of 4M HCl in dioxane. The solution was stirred for five hours. The solvent was removed in vacuo and trituration with ether gave pure product.

Various methylene analogs of pyrimidinediones, in which a methylene group replaces the carbonyl of the acetamide at the N-2 position of the pyrimidinedione, can be prepared by the following procedure.

Example 5

EX-5A) A DMF solution of 1 equivalent of phenyl isocyanate and 1 equivalent of 3-ethoxy-2-nitroacrylamide was heated to 100° C. for several hours. The solvent was removed by evaporation to give the crude product. The crude product was purified by silica gel chromatography to obtain the pure product EX-5A.

EX-5B) Under stirring, 1.1 equivalent of potassium bicarbonate was added at one time to 1 equivalent of EX-5A in dimethyl sulfoxide solution. After approximately 10 minutes, a solution of 1.1 equivalents of methyl bromoacetate in dimethylsulfoxide was added dropwise over 10 minutes. The reaction mixture was heated to 40°C and stirred for 18 hours. The reaction mixture was diluted with water. The aqueous solution was extracted with ethyl acetate, and the combined organic solutions were washed with water and brine. The organic solution was dried over _MgSO4 , filtered and concentrated to give crude product. The crude product was purified by silica gel chromatography to give the pure product methyl 2-[3-[5-nitro-2,4-dioxo-1-phenylpyrimidinyl]]acetate (EX-5B).

EX-5C) Diisobutylaluminum hydride (1.05 equiv) was added to a solution of 1 equiv of EX-5B in tetrahydrofuran cooled to -78°C over 15 minutes. After stirring at -78°C for 1 hour, the reaction was quenched slowly with cold methanol at -78°C. The mixture was poured slowly into ice-cold 1N HCl, and the aqueous mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over _MgSO4 , filtered and the solvent was removed under reduced pressure. The crude product was purified by column chromatography to obtain the pure aldehyde product EX-5C.

EX-5D) to 1.0 equivalent aldehyde 2-[3-[5-nitro-2,4-dioxo-1-phenylpyrimidinyl]] acetaldehyde (EX-5C) and 1.0 equivalent amine 4-(N -Boc-amidino)benzylamine was added to a suspension of dichloromethane and catalytic acetic acid with 1.2 equivalents of sodium triacetoxyborohydride. The suspension quickly clarified and became homogeneous. The reaction was stirred for several hours. The solution was cooled in an ice bath and made basic with 1.0 N NaOH. The reaction mixture was diluted with dichloromethane and washed with brine. The organic solution was dried ( _MgSO4 ), filtered and concentrated to give crude product. The crude product was purified by silica gel chromatography to give the pure product 2-[3-2-[2-[2-(4-(N-Boc-amidino)benzyl)amino]ethyl-5-nitro-2, 4-dioxo-1-phenylpyrimidine (EX-5D).

EX-5E) A solution of 1 equivalent of EX-5D in methanol was degassed with hydrogen. To this solution was added a catalytic amount of 5% Pd/C, and the reaction mixture was stirred at room temperature under hydrogen atmosphere for 24 hours. The crude reaction was filtered through a pad of Celite 545 and concentrated under reduced pressure. The crude product was purified by silica gel chromatography to give the pure product amine 2-[3-2-[2-[2-(4-(N-Boc-amidino)benzyl)amino]ethyl-5-amino-2, 4-dioxo-1-phenylpyrimidine (EX-5E).

EX-5F) To a suspension of 1.0 equivalents of EX-5E and 1.0 equivalents of phenylacetaldehyde in dichloromethane and catalytic acetic acid was added 1.2 equivalents of sodium triacetoxyborohydride. The suspension quickly clarified and became homogeneous. The reaction was stirred for several hours. The solution was cooled in an ice bath and basified with 1.0N NaOH. The reaction mixture was diluted with dichloromethane and washed with brine. The organic solution was dried ( _MgSO4 ), filtered and concentrated to give crude product. The crude product was purified by silica gel chromatography to give pure 2-[3-2-[2-[2-(4-(N-Boc-amidino)benzyl)amino]ethyl-5-(N-(2- Phenylethyl)amino)-2,4-dioxo-1-phenylpyrimidine (EX-5F).

In a flask, add 4M HCl in dioxane to 1 equivalent of EX-5F. The resulting solution was stirred overnight. The solution was concentrated and the crude product was triturated from ether to give the pure product as the dihydrochloride salt.

As described in Specific Example 6 below, various sulfonyl analogs of pyrimidinedione can be prepared in which the sulfonyl group replaces the carbonyl of the acetamide at the N-2 position of the pyrimidinedione.

Example 6

EX-6A) Under stirring, add 1 equivalent of EX-5A in dimethyl sulfoxide solution to 1.1 equivalent of potassium bicarbonate at one time. After approximately 10 minutes, a solution of 1.1 equivalents of sodium bromomethanesulfonate in dimethyl sulfoxide was added dropwise over 10 minutes. The reaction mixture was heated to 40°C and stirred for 18 hours. The reaction mixture was diluted with water. The aqueous solution was extracted with ethyl acetate, and the combined organic solutions were washed with water and brine. The organic solution was dried over _MgSO4 , filtered and concentrated to give crude product. The crude product was purified by silica gel chromatography to give the pure product 3-[5-nitro-2,4-dioxo-1-phenylpyrimidinyl]methanesulfonic acid (EX-6A).

EX-6B) A solution of 1 equivalent of EX-6A in methanol was degassed with hydrogen. To this solution was added a catalytic amount of 5% Pd/C, and the reaction mixture was stirred at room temperature under hydrogen atmosphere for 24 hours. The crude reaction was filtered through a pad of Celite 545 and concentrated under reduced pressure. The crude product was purified by silica gel chromatography to give the pure product 3-[5-amino-2,4-dioxo-1-phenylpyrimidinyl]methanesulfonic acid (EX-6B).

EX-6C) To a suspension of 1.0 equivalents of EX-6B and 1.0 equivalents of phenylacetaldehyde in dichloromethane and catalytic acetic acid was added 1.2 equivalents of sodium triacetoxyborohydride. The solution was stirred for several hours. The solution was cooled in an ice bath and basified with 1.0N NaOH. The reaction mixture was diluted with dichloromethane and washed with brine. The organic solution was dried ( _MgSO4 ), filtered and concentrated to give crude product. The crude product was purified by silica gel chromatography to give the pure product 3-[5-[N-(2-phenylethyl)amino]-2,4-dioxo-1-phenylpyrimidinyl]methanesulfonic acid (EX -6C).

EX-6D) A solution of 1 equivalent of EX-6C in dichloromethane and a few drops of dimethylformamide was cooled to 0°C. Thionyl chloride (1.1 equiv) was added dropwise, and the solution was slowly warmed to room temperature. After the reaction was complete, the volatile components were removed under reduced pressure and the sulfonyl chloride product was used immediately. The sulfonyl chloride was dissolved in dichloromethane, and to the sulfonyl chloride solution were added 1 equivalent of the appropriate amine 4-(N-Boc-amidino)benzylamine and 5 equivalents of N-methylmorpholine. After the reaction is complete, polyaldehyde and/or polyamine resin (10 equivalents) is added to remove all unreacted starting material. The resin was filtered, washed with DMF/DCM (1:1), and the solvent was removed under reduced pressure to give pure N-[4-(N-Boc-amidino)benzyl]-3-[5-[N- (2-Phenylethyl)amino]-2,4-dioxo-1-phenylpyrimidinyl]methanesulfonamide (EX-6D).

In a flask, add 4M HCl in dioxane to 1 equivalent of EX-6D. The resulting solution was stirred overnight. The solution was concentrated and the crude product was triturated from ether to give the pure product of Example 6.

As described in Specific Example 7 below, triazinediones (aza analogs) of uracil (ie, pyrimidinedione) can be prepared wherein the nitrogen replaces the carbon at the 5-position of the pyrimidinedione.

Example 7

EX-7A) A mixture of aniline (1; 50 mmol), concentrated HCl (10 ml) and water (50 ml) was cooled to 5°C. Separately, a solution of sodium nitrite (50 mmol) in water (7.2 ml) was cooled to 5° C., and added to the aniline hydrochloride slurry using a feeding tube below the liquid surface. The temperature was maintained at 5°C during and 1 hour after the addition. This diazotized aniline (EX-7A) solution was used in the next step.

EX-7B) A mixture of cyanoacetylurethane (59mmol), pyridine (656ml), ice (216g) and water (40ml) was maintained at 5°C while stirring a slurry of EX-67A over 15 minutes. After stirring at 5° C. for another hour, it was separated by filtration to obtain N-ethoxycarbonyl-2-cyano-2-(N-phenylhydrazono)acetamide (EX-7B) as an orange solid.

EX-7C) A mixture of EX-7B (95 mmol), sodium acetate (110 mmol) and acetic acid (140 ml) was refluxed for 75 minutes. The resulting clear solution was concentrated under reduced pressure and the solid was isolated by filtration and washed with water. Compound 6-cyano-2-phenyl-3,5-dioxo-1,2,4-triazine (EX-7C) was recrystallized from 95% ethanol.

EX-7D) A mixture of compound EX-7C (50 mmol), 6N HCl (190 ml) and dioxane (500 ml) was refluxed for 12 hours. The crystallized product was cooled, and 6-(2-phenyl-3,5-dioxo-1,2,4-triazinyl)carboxylic acid (EX-7D) was isolated by filtration and recrystallized from methanol-water.

EX-7E) Acid EX-7D (8.4 mmol) was dissolved in anhydrous tert-butanol (127 ml) and DPPA (9.3 mmol), and triethylamine (9.3 mmol) was added. The solution was then refluxed for 24 hours. At this point the solution was concentrated in vacuo. The residue was dissolved in dichloromethane (150ml), washed with 0.5N citric acid (150ml), 1N _NaHCO3 (150ml) and water (150ml). The dichloromethane solution (sodium sulfate) was then dried. Filtration and concentration afforded Boc protected compound EX-7E. The material can be purified by chromatography if necessary.

EX-7F) A solution of compound EX-7E (50 mmol) in DMF (150 ml) was treated with potassium carbonate (55 mmol) in one portion with stirring. After about 10 minutes, a solution of methyl bromoacetate (50 mmol) in DMF (100 ml) was added dropwise. The reaction mixture was heated to 40°C and stirred for 18 hours. Typical aqueous work-up and chromatographic purification yielded pure methyl 2-(2-phenyl-3,5-dioxo-6-(N-Boc-amino)-1,2,4-triazinyl)acetate Esters (EX-7F).

EX-7G) Compound EX-7F (50mmol) was dissolved in dichloromethane (400ml) and treated with TFA (100ml). The resulting solution was then stirred at room temperature for 4 hours. Concentration and trituration with ether afforded methyl 2-(2-phenyl-3,5-dioxo-6-amino-1,2,4-triazinyl)acetate as its TFA salt (EX-7G).

EX-7H) A solution of compound EX-7G in THF and dichloromethane (1:1, 0.3M) was treated with 1 equivalent of phenylacetaldehyde and 0.9 equivalents of triethylamine. The solution was cooled to 0°C and treated with 1 equivalent of sodium triacetoxyborohydride. After stirring for 5 minutes, the ice bath was removed and the reaction mixture was allowed to warm to room temperature and stirred for 2 hours. 1N NaOH was added to quench the reaction, and the mixture was stirred for 5 minutes. Typical water work-up followed by chromatographic purification afforded the pure product 2-(2-phenyl-3,5-dioxo-6-(N-(2-phenylethyl)amino)-1,2,4- Triazinyl) methyl acetate (EX-7H).

EX-7I) A solution of compound EX-7H (50 mmol) in THF (250 ml) was treated with LiOH (50 mmol). After complete hydrolysis, the volatiles were removed under reduced pressure. The remaining aqueous solution was cooled in an ice bath and acidified to pH 1 with 1.0N HCl. The aqueous mixture was extracted with EtOAc. The EtOAc solution was dried (sodium sulfate), filtered and concentrated to give pure 2-(2-phenyl-3,5-dioxo-6-(N-(2-phenylethyl)amino)-1,2 , 4-triazinyl)acetic acid (EX-7I).

EX-7J) A solution of compound EX-7I (50 mmol) in DMF (250 ml) was treated with N-hydroxybenzotriazole (60 mmol) and EDC hydrochloride (60 mmol). The mixture was stirred at room temperature for 30 minutes and treated with 4-(N-Cbz-amidino)benzylamine (50 mmol). The resulting mixture was stirred overnight. Typical water work-up followed by chromatographic purification afforded the pure product N-(4-Cbz-amidinobenzyl)-2-(2-phenyl-3,5-dioxo-6-(N-(2- Phenylethyl)amino)-1,2,4-triazinyl)acetamide (EX-7J).

A solution of compound EX-7J (50 mmol) in methanol (300 ml) and 4M HCl-dioxane (100 ml) was degassed with hydrogen. 5% Pd(C) (0.5 g) was added and the solution was stirred at room temperature under hydrogen atmosphere for 24 hours. The reaction mixture was filtered through a pad of Celite 545 and concentrated under reduced pressure. Purification by reverse phase chromatography afforded the pure product of Example 7.

Using these methods, one of ordinary skill in the art has, or can, prepare numerous novel compounds of the invention.

Compounds of formula (I) according to the invention having hydroxyl, mercapto and amine functional groups can be converted into various derivatives. Alternatively, first derivatize one or more intermediates in the preparation process, and then further convert the derivatized intermediates into the compound of formula (I), to obtain the derivatized compound of formula (I). Alcoholic or phenolic hydroxyl groups are readily converted into esters of carboxylic, sulfonic, carbamic, phosphonic and phosphoric acids. Acylation to form the carboxylic acid ester is readily carried out using a suitable acylating agent, such as an aliphatic anhydride or acid chloride. The corresponding aryl and heteroaryl anhydrides and acid chlorides can also be used. Such reactions are generally carried out using amine catalysts, such as pyridine, in inert solvents. Similarly, carbamates (urethanes) can be obtained by reaction of hydroxyl groups with isocyanates and carbamoyl chlorides. Sulfonates, phosphonates and phosphates can be prepared using the corresponding acid chlorides and similar reagents. Compounds of formula (I) having at least one mercapto group can be converted into the corresponding thioester derivatives analogously using the same reagents and comparable reaction conditions as for the reaction of alcohols and phenols. Compounds of formula (I) having at least one primary or secondary amine group can be converted into the corresponding amide derivatives. Amides of carboxylic acids can be prepared using appropriate acid chlorides or anhydrides under reaction conditions similar to those used for alcohols and phenols. Ureas of the corresponding primary or secondary amines can be prepared directly using isocyanates and carbamoyl chlorides in the presence of an acid scavenger, such as triethylamine or pyridine. Sulfonamides can be prepared from the corresponding sulfonyl chlorides in the presence of aqueous sodium hydroxide or tertiary amines. Procedures and methods suitable for preparing these derivatives can be found in "House's Modern Synthetic Reactions" (House's Modern Synthetic Reactions) W.A. Benjamin, Inc., Shriner, Fuson, and Curtin "Systemic Identification of Organic Compounds" (Systemic Identification of Organic Compounds) No. 5 ed. John Wiley & Sons, Fieser and Fieser Organic Synthetic Reagents Vol. 1 John Wiley & Sons. A variety of reagents that can be used to derivatize the hydroxy, thiol and amine groups of compounds of formula (I) are available from commercial sources or from the above references, which are incorporated herein by reference.

Compounds of formula (I) according to the invention having hydroxyl, mercapto and amine functional groups can be alkylated into various derivatives. Alternatively, firstly, one or more intermediates in the preparation process are alkylated, and then the alkylated intermediates are further converted into compounds of formula (I), to obtain alkylated compounds of formula (I). The hydroxyl groups of compounds of formula (I) are readily converted to ethers. Alkylation to form ethers is readily carried out using a suitable alkylating agent, such as an alkyl bromide, iodide, or alkyl sulfonate. The corresponding bromides, iodides and sulfonates of aralkyl, heteroaralkyl, alkoxyalkyl, aralkoxyalkyl and heteroaralkoxyalkyl can also be used. Such reactions are generally carried out using alcoholate generating agents such as sodium hydride, potassium tert-butoxide, sodium amide, lithium amide and n-butyllithium, and using inert polar solvents such as DMF, DMSO, THF and similar equivalents. solvents, and amine catalysts such as pyridine. Compounds of formula (I) having at least one mercapto group can be converted into the corresponding alcohol- and phenol-like thioether derivatives analogously using the same reagents and comparable reaction conditions. Compounds of formula (I) having at least one primary, secondary or tertiary amine group can be converted into the corresponding secondary, tertiary or quaternary ammonium derivatives. Quaternary ammonium derivatives can be prepared using appropriate bromides, iodides and sulfonates similar to those used for alcohols and phenols. The amine reaction conditions involve heating the alkylating agent with a stoichiometric amount of amine (ie, one equivalent of tertiary amine, two equivalents of secondary amine, three equivalents of primary amine). With respect to primary and secondary amines, two equivalents and one equivalent of acid scavengers were used simultaneously, respectively. Secondary or tertiary amines can be prepared from the corresponding primary or secondary amines. Primary amines can be dialkylated by reductive amination using an aldehyde, such as formaldehyde, and sodium cyanoborohydride in the presence of glacial acetic acid. Primary amines can be monoalkylated by first protecting the amine with a readily cleavable protecting group, such as trifluoroacetyl. In the presence of a non-nucleophilic base, such as Barton's base (2-tert-butyl-1,1,3,3-tetramethylguanidine), the amine is reacted with an alkylating agent, such as dimethyl sulfate, to give monomethyl Kylated protected amines. Removal of the protecting group using aqueous potassium hydroxide affords the desired monoalkylated amine. Other steps and methods suitable for preparing these derivatives can be found in "House Modern Synthetic Reactions" W.A.Benjamin, Inc., Shriner, Fuson, and Curtin "Systematic Identification of Organic Compounds" 5th Edition John Wiley & Sons, Fieser and Fieser " Reagents for Organic Synthesis Vol. 1 John Wiley & Sons. Perfluoroalkyl derivatives can be prepared as described by DesMarteau J. Chem. Soc. Chemistry Communications 2241 (1998). A variety of reagents that can be used to derivatize the hydroxy, thiol and amine groups of compounds of formula (I) are available from commercial sources or from the above references, which are incorporated herein by reference.

             Determination of Biological Activity

                                                               

In this assay, 100 nM recombinant soluble tissue factor and 2 nM recombinant human factor VIIa are added to a 96-well assay plate containing 0.4 mM of the substrate N-methylsulfonyl-D-phe-gly-arg-p-nitroaniline and inhibitor or buffer (5 mM CaCl ₂ , 50 mM Tris-HCl, pH 8.0, 100 mM NaCl, 0.1% BSA). A final volume of 100 [mu]l of the reaction was immediately measured at 405 nm to determine the background absorbance. The plate was incubated at room temperature for 60 minutes at which time the rate of substrate hydrolysis was measured by monitoring the release of p-nitroaniline at 405 nm. The % inhibition of TF-VIIa activity was calculated from the _OD405nm values of the experimental and control samples.

Determination of Xa

0.3nM Human Factor Xa and 0.15mM N-α-Benzyloxycarbonyl-D-arginyl-L-glutamyl-L-arginine-p-nitroaniline-dihydrochloride (S-2765) Add to 96-well assay plates containing inhibitors or buffer (50 mM Tris-HCl, pH 8.0, 100 mM NaCl, 0.1% BSA). A final volume of 100 [mu]l of the reaction was immediately measured at 405 nm to determine the background absorbance. The plate was incubated at room temperature for 60 minutes at which time the rate of substrate hydrolysis was measured by monitoring the release of p-nitroaniline at 405 nm. The % inhibition of Xa activity was calculated from the _OD405nm values of the experimental and control samples.

Determination of thrombin

Add 0.28nM human thrombin and 0.06mM HD-phenylalanyl-L-pipercoyl-L-arginine-p-nitroaniline-dihydrochloride to 96-well assay plates containing inhibitors or buffer (50 mM Tris-HCl, pH 8.0, 100 mM NaCl, 0.1% BSA). A final volume of 100 [mu]l of the reaction was immediately measured at 405 nm to determine the background absorbance. The plate was incubated at room temperature for 60 minutes at which time the rate of substrate hydrolysis was measured by monitoring the release of p-nitroaniline at 405 nm. The % inhibition of thrombin activity was calculated from the _OD405nm values of the experimental and control samples.

Trypsin assay

Add 5 μg/ml type IX trypsin from porcine pancreas and 0.375 mM N-α-benzoyl-L-arginine-p-nitroanilide (L-BAPNA) to a 96-well assay plate containing Inhibitor or buffer (50 mM Tris-HCl, pH 8.0, 100 mM NaCl, 0.1% BSA). A final volume of 100 [mu]l of the reaction was immediately measured at 405 nm to determine the background absorbance. The plate was incubated at room temperature for 60 minutes at which time the rate of substrate hydrolysis was measured by monitoring the release of p-nitroaniline at 405 nm. The % inhibition of trypsin activity was calculated from the _OD405nm values of the experimental and control samples.

Recombinant soluble TF consisting of amino acids 1-219 of the mature protein sequence was expressed in E. coli and purified by Single Q Sepharose FPLC. Recombinant human VIIa was purchased from American Diagnostica, Greenwich CT, and the chromogenic substrate N-methylsulfonyl-D-phe-gly-arg-p-nitroaniline was prepared by American Peptide Company, Inc., Sunnyvale, CA. Factor Xa was obtained from Enzyme Research Laboratories, South Bend IN, thrombin was obtained from Calbiochem, La Jolla, CA, trypsin and L-BAPNA were obtained from Sigma, St. Louis MO. Chromogenic substrates S-2765 and S-2238 were purchased from Chromogenix, Sweden.

The biological activities of the compounds of Examples 1 to 7 as determined by these bioassay methods are summarized in Table 1.

Table 1: Inhibitory activity of uracil on factor Xa, TF-VIIa, thrombin II, and trypsin II Example number TF-VIIaIC50(μM) Thrombin IIIC50(μM) Factor Xa IC50(μM) Trypsin IIIC50 (μM) 1 >100 13.0 25.6 0.4 2 12.9 0.3 0.2 0.2

Claims (33)

1. A compound of the following formula or a pharmaceutically acceptable salt thereof: in: B is selected from phenyl, C ₃ -C ₇ cycloalkyl and phenyl _and C 3 -C 7 cycloalkyl substituted by C ₁ -C ₆ alkyl and _{C 1 -C 6} alkylsulfonyl; A is selected from covalent single bonds and C ₁ -C ₃ alkylene groups; M is CH or N; R ² is unsubstituted phenyl or phenyl substituted by one or more substituents selected from the group consisting of amino and C ₁ -C ₆ alkyl; K is methylene or ethylene; ^E is selected from C(O)NH, NH and SO ₂ NH; Y ⁰ is amidinobenzyl or 5-guanidino-1-oxo-1-(2-thiazolyl)-2-pentyl. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein B is benzylsulfonyl. 3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein B is phenyl. 4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein B is C ₃ -C ₇ cycloalkyl. 5. The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein B is cyclobutyl. 6. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein A is a covalent single bond. 7. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein A is C ₁ -C ₃ alkylene. 8. The compound of claim 7, or a pharmaceutically acceptable salt thereof, wherein A is ethylene. 9. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R ² is a substituted phenyl group selected from C ₁ -C ₆ alkyl and amino. 10. The compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein the substituent is _C1 - _C6 alkyl. 11. The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein the alkyl group is methyl. 12. The compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein the substituent is amino. 13. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein K is methylene. 14. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein K is ethylene. 15. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein ^E0 is NH or _SO2NH . 16. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein ^E0 is C(O)NH or _SO2NH . 17. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein E ⁰ is C(O)NH or NH. 18. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein E ⁰ is C(O)NH. 19. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein E ⁰ is NH. 20. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein ^E0 is _SO2NH . 21. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein ^Y0 is amidinobenzyl. 22. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Y ⁰ is 5-guanidino-1-oxo-1-(2-thiazolyl)-2-pentyl. 23. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein B is selected from benzylsulfonyl, cyclobutyl and phenyl. 24. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein B is benzylsulfonyl or phenyl. 25. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein B is cyclobutyl or phenyl. 26. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein B is selected from 3-methylphenyl, 4-methylphenyl and phenyl; and A is selected from C ₁ -C ₃ methylene. 27. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein B is selected from 3-methylphenyl, 4-methylphenyl and phenyl; and ^R2 is selected from benzyl, aminobenzyl and phenyl. 28. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein B is selected from 4-methylphenyl and phenyl; A is selected from C ₁ -C ₃ methylene; R ^is selected from benzyl, 3-aminobenzyl, 3-methylaminophenyl, 2-methylphenyl, 3-methylphenyl and phenyl; and Y ⁰ is 4-amidinobenzyl. 29. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein ^R2 is benzyl, B is benzylsulfonyl, A is a covalent single bond, K is _CH2 , ^E0 is C(O)NH, ^Y0 is 4-amidinobenzyl, and M is CH; R ² is benzyl, B is benzylsulfonyl, A is a covalent single bond, K is CH ₂ , E ⁰ is C(O)NH, Y ⁰ is 5-guanidino-1-oxo-1-( 2-thiazolyl)-2-pentyl, and M is CH; ^R2 is 3-aminobenzyl, B is cyclobutyl, A is a covalent single bond, K is _CH2 , ^E0 is C(O)NH, ^Y0 is 4-amidinobenzyl, and M is CH ; ^R2 is 3-aminophenyl, B is cyclobutyl, A is a covalent single bond, K is _CH2 , ^E0 is C(O)NH, ^Y0 is 4-amidinobenzyl, and M is CH ; ^R2 is phenyl _, B is phenyl _{, A is CH2CH2, K is CH2CH2 , E0} ^{is NH, Y0 is} 4-amidinobenzyl, and M is CH; ^R2 is phenyl _{, B is phenyl, A is CH2CH2, K is CH2CH2 , E0} ^is _SO2NH , ^Y0 is 4-amidinobenzyl, and M is CH; or R ² is phenyl, B is phenyl, A is CH ₂ CH ₂ , K is CH ₂ CH ₂ , E ⁰ is C(O)NH, Y ⁰ is 4-amidinobenzyl, and M is N. 30. A composition for inhibiting blood thrombotic diseases, the composition comprising the compound according to any one of claims 1-29 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 31. Use of a compound according to any one of claims 1-29 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for inhibiting, treating or preventing thrombosis in mammals. 32. Use of a compound according to any one of claims 1-29, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for inhibiting blood thrombotic diseases, platelet aggregate formation or thrombus formation. 33. Use of the compound of any one of claims 1-29 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment or prevention of the following diseases in humans or other mammals, the diseases being selected from: venous thromboembolism , pulmonary thromboembolism, deep vein thrombosis, cardiogenic thromboembolism, thromboembolic stroke, thrombosis associated with cancer and cancer chemotherapy, and unstable angina.