SK15852001A3 - Substituted polycyclic aryl and heteroaryl pyrimidinones useful as anticoagulants - Google Patents

Abstract

The invention relates to substituted polycyclic aryl and heteroaryl pyrimidinone compounds useful as inhibitors of serine proteases of the coagulation cascade and compounds, compositions and methods for anticoagulant therapy for the treatment and prevention of a variety of thrombotic conditions including coronary artery and cerebrovascular diseases.

Description

Substituted polycyclic aryl and heteroaryl pyrimidinones useful as anticoagulants

Technical field

The invention relates to the field of anticoagulant therapy, and more particularly to compounds, compositions and methods for preventing and treating thrombotic conditions such as coronary artery disease and cerebrovascular diseases. More preferably, the invention relates to substituted polycyclic aryl and heteroaryl pyrimidinone compounds that inhibit serine proteases of the coagulation cascade.

BACKGROUND OF THE INVENTION

Physiological systems control blood flow in mammals (Majerus, PW et al .: Anticoagulant, Thrombolytic and Antipatelet Drugs. In Hardman, JG and Limbird, LE, editors: Goodman & Gilman ' s Pharmacological Basis of Therapeutics, ninth edition. New York, McGraw-Hill Book Co., 1996, pp. 1341-1343). Blood must remain fluid within the vascular system and be able to undergo rapid haemostasis, stopping blood loss from damaged vessels. Hemostasis or clotting begins when platelets first adhere to macromolecules in the subendothelial region of injured or damaged vessels. These platelets form aggregates to form primary hemostatic bays (primary thrombus) and stimulate local activation of plasma coagulation factors, resulting in the formation of a fibrin clot that forms a platelet aggregate reinforcement.

Plasma coagulation factors include factors II, V, VII, VIII, IX, X, XI, and XII, these factors are also called protease zymogens. These coagulation factors or protease zymogens are activated by serine proteases, leading to coagulation in the so-called. "Coagulation cascade" or chain reaction (Handin, RI: Bleeding and Thrombosis. In Wilson, J., et al., Editors: Harrizon's Principles of Intemal Medicine. 12th Edition, New York, McGraw-Hill Book Co., 1991 , p.35O). Coagulation or clotting occurs in two ways in two different pathways. The internal or even the pathway leads from the conversion of XII to XHa to Xla to IXa to the conversion of X to Xa. Factor Va Xa converts prothrombin (II) to thrombin (IIa), leading to the conversion of fibrinogen to fibrin. Polymerization of fibrin leads to the formation of a fibrin clot. The outward path is initiated by the conversion of coagulation factor VII to Fairy factor Xa. The presence of tissue factor and factor VIIa accelerates Xa formation in the presence of calcium ions and phospholipids. The formation of factor Xa leads to the formation of thrombin, fibrin and a fibrin clot as described above. The presence of one or more of this variety of different

-2 coagulation factors and two different clotting pathways allow for efficient and selective control and a better understanding of part of the coagulation or clotting process.

Although clotting as a result of the reaction to clotting of the vascular system is an important physiological process for mammals such as man, clotting can also lead to disease states. A pathological process called thrombosis occurs when platelet aggregates and / or fibrin clots block (close) the bloodstream. Arterial thromboses may result in ischemic necrosis of the tissues that are supplied by the artery. If thrombosis occurs in the coronary artery, it may result in a myocardial infarction or sudden heart failure. Thrombosis that occurs in the venous system may cause edema and subsequently inflammation in the tissue that is drained by the vein. Thromboses that develop in the deep venous system may be complicated by pulmonary embolism. Prevention of fibrin formation by inhibiting thrombus formation, inhibiting embolism may be therapeutically useful as well as for the treatment or prevention of unstable angina pectoris, recurrent angina pectoris, myocardial infarction, transient ischemic attacks, atrial fibrillation, thrombotization, embolism, deep thrombosis thrombosis coagulopathy (DIK), ischemic retinopathy, and obstruction or restenosis of recanalized vessels.

To date, there are reports of non-peptide and peptide pyrimidinone compounds that act as inhibitors of the coagulation factors present in the coagulation cascade or clotting process. Van Boeckel et al. in PCT Patent Application WO 98/47876 discloses peptide 6-alkylpyridones and 2-alkylpyrimidinones as antithrombotic agents. In PCT Patent Application WO 98/16547, Zhu and Scarborough disclose 3- (Nheterocyclylamino) -4,5,6 substituted pyridonylacetamides and 2,4-substituted 5- (Nheterocyclylamino) -pyrimidinonyl acetamides containing amide substituents having mammalian activity Xa factor. Tamura et al. U.S. Patent 5,656,645 discloses 4,5,6-substituted 3-aminopyridonyl acetamides, 1,6-substituted 5-aminouracinylacetamides, and 2,4-substituted 5-aminopyrimidinonyl acetamides containing an amide substituent having a formyl function and activity toward thrombin. Again, Tamura et al. U.S. Patent 5,658,830 discloses 4,5,6 substituted-3-aminopyridonylacetamides, 1,6 substituted-5-aminouracinylacetamides, and 2,4 substituted-5-aminopyrimidinonyl acetamides containing an amide substituent having a form function and thrombin activity. Tamura et al. in addition, PCT Patent Applications 96/18644 and 97/46207 disclose 4,5,6 substituted-3-aminopyridonyl acetamides, 1,6 substituted-5-aminouracinylacetamides and 2,4-substituted 5-aminopyrimidinonylacetamides containing an amide substituent with formyl function and activity towards

-3trombínu. In PCT Patent Application WO 98/09949 Suzuki et al. discloses 2-heterocyclylacetamide derivatives of 1,2-diketones and demonstrates that they inhibit proteases, especially chymase inhibitors.

SUMMARY OF THE INVENTION

The invention provides compounds which are useful in anticoagulant therapy and which have the structure of Formula I:

ABOUT

The invention further relates to a method for the prevention and treatment of thrombotic conditions such as coronary artery disease, cerebrovascular disease and other disorders associated with coagulation. These thrombotic conditions can be prevented or 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 invention will be apparent from the following description of the invention.

The invention relates to a class of substances consisting of substituted polycyclic aryl and heteroaryl pirimidines useful in anticoagulant therapy in the treatment and prevention of various thrombotic conditions, such as coronary artery disease and cerebrovascular disease, characterized according to formula I

or a pharmaceutically acceptable salt thereof, wherein:

J is selected from the group consisting of O and S,

J is optionally selected from the group consisting of CH-R ⁶ and NR ⁶ , wherein R ⁶ is a linear substituent forming a hanger that contains a chain of 1 to 4 atoms bonded

-4 to the binding site of substituents selected from the group consisting of R ^4j , R ^4b , R ³⁹ , R ⁴⁰ , R ⁵ , R ¹⁴ and R ¹⁵ to form a heterocyclic ring containing 5 to 8 members.

J is optionally selected from the group consisting of CH-R ⁶ and NR ⁶ , wherein R ⁶ is a hanger-forming substituent having a chain length of 1 to 4 atoms, attached to the binding sites of both R ^4a and R ^4b to form a heterocyclic ring containing 5 to 8 members.

J is optionally selected from the group consisting of CH-R ⁶ and NR ⁶ , wherein R ⁶ is a hanger-forming substituent containing a chain of 1-4 atoms, attached to the binding sites of both R ³⁹ and R ⁴⁰ to form a heterocyclic ring containing 5 to 8 members.

B is a group of formula V, (V),

D ^x

wherein D ¹ , D ² , J ¹ , J ² and K ¹ are independently selected from the group consisting of C, N, O, S and a covalent bond, with the proviso that the covalent bond may be selected only once, at most one of D ¹ , D ² , J ¹ , J ² and K ¹ is O, at most one of D ¹ , D ² , J ¹ , J ² , and K ¹ is S, one of D ¹ , D ² , J ¹ , J ² and K ¹ must be a covalent bond if two of D ¹ , D ² , J ¹ , J ² and K ¹ are O and S and at most four of D ¹ , D ² , J ¹ , J ² and K ¹ are N, that R ³² , R ³³ , R ³⁴ , R ³⁵ and R ³⁶ are each independently selected to maintain carbon tetravalence, nitrogen trivalent, sulfur bivalent and oxygen bivalent.

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 the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, dialkylsulfonium, trialkylphosphonium, dialkylsulfoniumalkyl, carboxy, heteroaralkylthio, heteroaralkoxy, cycloalkylamino, acylalkyl, acylalkoxy, aryloxylalkoxy, aryloxylalkoxy, heterocyclyalkyl, aralkylaryl, aralkylaryl, halocycloalkyl, halocycloalkenyl, cycloalkylsulfinyl, cycloalkylsulfinylalkyl, cycloalkylsulfonyl, cycloalkylsulfonylalkyl, heteroarylamino, N-heteroarylamino, N-alkylamino, heteroarylaminoalkyl, haloalkylthio, alkanoyloxy, alkoxy, alkoxyalkyl.

- 3 -alkoxyalkyl, heteroaralkoxy, cycloalkoxy, cycloalkenyloxy, cycloalkoxyalkyl, cycloalkylalkoxy, cycloalkenyloxyalkyl, cycloalkylenedioxy, halogéncykloalkoxy, halogéncykloalkoxyalkyl, halogéncykloalkenyloxy, halogéncykloalkenyloxyalkyl, hydroxy, amino, alkoxyamino, thio, nitro, lower alkylamino, alkylthio, alkylthioalkyl, arylamino, aralkylamino, arylthio, arylthioalkyl , heteroaralkyloxyalkyl, alkylsulfinyl, alkylsulfinylalkyl, arylsulfinylalkyl, arylsulfonylalkyl, heteroarylsulfinylalkyl, Heteroarylsulfonylalkyl, alkylsulfonyl, alkylsulfonylalkyl, halogénalkylsulfinylalkyl, halogénalkylsulfonylalkyl, alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl, monoarylamidosulfonyl, arylsulfonamido, diarylamidosulfonyl, monoalkyl, monoarylamidosulfonyl, arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, heterocyclylsulfonyl, heterocyclylthio, alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl, heteroara alkanoyl, haloalkanoyl, alkyl, alkenyl, alkynyl, alkenyloxy, alkenyloxyalkyl, alkylenedioxy, haloalkylenedioxy, cycloalkyl, cycloalkylalkanoyl, cycloalkenyl, lower cycloalkylalkyl, lower cycloalkenylalkyl, halo, haloalkyl, hydroxy, haloalkoxy, haloalkenyl, hydroxy, haloalkenyl, aryl, aralkyl, aryloxy, aralkoxy, aryloxyalkyl, saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl, heteroaryloxy, heteroaryloxyalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, heterorylalkenyl, carboxyalkyl, carboalkoxy, alkoxycarboxamido, carboxyalkoxy, carboxyalkoxy, carboxyalkoxy, carboxyalkoxy, carboalkoxy, , carboxamidoalkyl, cyano, carbohaloalkoxy, phosphono, phosphonoalkyl, diaralkoxyphosphono and diaralkoxyphosphonoalkyl.

R ¹⁶ , R ¹⁹ , R ³² , R ³³ , R ³⁴ , R ³⁵ and R ³⁶ are independent, possibly Q ^b with the proviso that at most one of R ¹⁶ and R ¹⁹ is Q ^b at the same time, and that Q ^b is Q ^be .

R ³² and R ³³ , R ³³ and R ³⁴ , R ³⁴ and R ³⁵ , R ³⁵ and R ³⁶ are independent, optionally selected to form a pair of arms, wherein the pair of arms together form a linear substituent containing 3 to 6 adjacent atoms linking the bonding atoms the sites of said members of a pair of arms to form a ring selected from the group consisting of a 5 to 8 membered cycloalkenyl ring, a partially saturated 5 to 8 membered heterocyclic ring, a 5 to 6 membered heteroaryl ring, and aryl, provided that at most ³² and R ³³ , R ³³ and R ³⁴ , R ³⁴ and R ³⁵ and R ³⁵ and R ³⁶ 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 pair of arms, wherein the pair of arms together form a linear substituent containing 3 to 6 adjacent atoms linking linking sites mentioned members of the pair

-6-a ring to form a ring selected from the group consisting of a 5 to 8 membered cycloalkenyl ring, a partially saturated 5 to 8 membered heterocyclic ring, a 5 to 6 membered heteroaryl ring, and aryl, provided that at most one of pairs 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 a group of formula VI:

(VI),

E ³² - _D 3

3, wherein D ³ , D ⁴ , J ³ and J ⁴ are independently selected from the group consisting of C, N, O and S, at most one of D ³ , D ⁴ , J ³ and J ⁴ is O, at most one of D ³ , D ⁴ , J ³ and 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 independently selected to comply with the natural state of tetravalent carbon, trivalent nitrogen, bivalent sulfur and bivalent oxygen,

B is optionally selected from the group consisting of hydrido, trialkylsilyl, C 2 -C 8 alkyl, C 3 -C 8 alkenyl, C 3 -C 8 alkylenyl, C 3 -C 8 alkynyl, C 2 -C 8 haloalkyl and C 3 -C 8 haloalkenyl wherein each member of group B is optionally substituted on any carbon atom up to and including 6 atoms from the B to A binding site by one or more substituents from the group consisting of R ³² , R ³³ , R ³⁴ , R ³⁵ and R ³⁶ .

B is optionally selected from the group consisting of C3-C15 cycloalkyl, C5-C10 cycloalkenyl, C4-C12 saturated heterocycle and C4-C9 partially saturated heterocycle wherein each of the ring carbons is optionally substituted with R ³³ , a ring carbon atom other than a carbon atom in the ring at the point of attachment of B to A is optionally substituted by an oxo group such that at most one ring carbon atom is substituted by the oxo group at the same time, the ring carbon atom and the nitrogen adjacent to the carbon atom at the point of attachment are optionally substituted by R ⁹ or R ¹³ , a ring carbon atom or a nitrogen atom adjacent to the R ⁹ position and two atoms away from the point of attachment is optionally substituted by R ¹⁰ , a ring carbon atom or a nitrogen atom adjacent to the R ¹³ position and two atoms away from the point of attachment is optionally substituted by R ¹² , a ring carbon atom or a nitrogen atom three atoms away from the point of attachment adjacent to the R ¹⁰ position is optionally e substituted with R ¹¹ , a ring carbon atom or a nitrogen atom three atoms away from the point of attachment adjacent to the R ¹² position is optionally substituted with R ³³ and a ring carbon atom or a nitrogen atom distant

The -7 atoms from the point of attachment adjacent to the R ¹¹ and R ³³ positions are optionally substituted with R ³⁴ .

A is selected from a single covalent bond, (W ⁷⁾ rr. (CH ^(R15)) pa and (CH (R ^{L 5))} pa. (W ⁷⁾ R wherein rrje an integer of 0-1, solder an integer selected from 0 to 6 and W ⁷ is selected from the group consisting of O, S, C (O), C (S), C (O) S, C (S) O, C (O) N (R ⁷ ) , C (S) N ^{(R7), (R7)} NC (O), ^(R7) 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 ), provided that not more than one member of the group consisting of rr and p is O at the same time.

R and R are independently selected from the group consisting of hydrido, hydroxy, alkyl, alkenyl, aryl, aralkyl, aryloxy, alkoxy, alkenyloxy, alkylthio, alkylamino, arylthio, arylamino, arylthio, arylamino, acyl, aroyl, heteroaroyl, aralkoxyalkyl, heteroaralkoxyalkyl, aryloxyalkyl , alkoxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, aralkoxyalkyl, heteroaralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, heteroaryl, heteroaryloxy, heteroarylamino, heteroaralkyl, heteroaralkyloxy, heteroaralkylamino and heteroaryloxyalkyl.

R ¹⁴ , R ¹⁵ , R ³⁷ , R ³⁸ , R ³⁹ , R ⁴⁰ , R ⁴¹ and R ⁴² are independently selected from the group consisting of amidino, hydroxyamino, hydrido, halogen, cyano, aryloxy, amino, alkylamino, dialkylamino, aminoalkyl, acyl , aroyl, heteroaroyl, heteroaralkoxyalkyl, sulfhydryl, acylamido, alkoxy, alkylthio, arylthio, alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, aralkoxyalkylalkoxy, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkythioalkyl, alkyl, heteroaralkoxythioalkyl, heteroaralkoxthio, , cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl, halogéncykloalkenyl, haloalkoxy, haloalkoxyalkyl, halogénalkenyloxyalkyl, halogéncykloalkoxy, halogéncykloalkoxyalkyl, halogéncykloalkenyloxyalkyl, saturated heterocyclic, partially saturated heterocyclic, heteroaryl, heteroarylalkyl, heteroarylthioalkyl, heteroaralkyltioalkyl, monocyanoalkyl, dikyanoalkyl, carbo alkoxykyanoalkyl, alkylsulfinyl, alkylsulfonyl, haloalkylsulfinyl, haloalkylsulfonyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, arylsulfonylalkyl, aralkylsulfinyl, aralkylsulfonyl, cycloalkylsulfinyl, cycloalkylsulfonyl, Cycloalkylsulfinylalkyl, Cycloalkylsulfonylalkyl, Heteroarylsulfonylalkyl, heteroarylsulfmyl, heteroarylsulfonyl, heteroarylsulfinylalkyl, Aralkylsulfinylalkyl, Aralkylsulfonylalkyl, carboxy, carboxyalkyl, carboalkoxy, carboxamide, carboxamidoalkyl, carboaralkoxy, trialkylsilyl, dialkoxyphosphono, diaralkoxyphosphono, dialkoxyphosphonoalkyl and

-8-diaralkoxyphosphonoalkyl with the proviso that R ³⁷ and R ³⁸ are independently selected from substituents other than forms 1 and 2-oxoacyl.

R ¹⁴ and R ¹⁴ , when attached to different carbons, are optionally joined to form a group selected from the group consisting of a covalent bond, alkylene, haloalkylene, and a linear arm selected to form a ring selected from the group consisting of 5 to 8 membered cycloalkyl ring, a cycloalkenyl ring of 5 to 8 members and a heterocycle of 5 to 8 members.

R ¹⁴ and R ¹⁵ , when attached to different carbons, are optionally joined to form a group selected from the group consisting of a covalent bond, alkylene, haloalkylene, and a linear arm selected to form a ring selected from the group consisting of 5 to 8 membered cycloalkyl ring, a cycloalkenyl ring of 5 to 8 members and a heterocycle of 5 to 8 members.

R ¹⁵ and R ^15, when attached to different carbons, are optionally joined to form a group selected from the group consisting of a covalent bond, alkylene, haloalkylene, and a linear arm selected to form a ring selected from the group consisting of 5 to 8 membered cycloalkyl ring, cycloalkenyl a ring of 5 to 8 members and a heterocycle of 5 to 8 members.

Ψ is selected from the group consisting of 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 ⁵ is selected from the group consisting of hydrido, hydroxy, amino, alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxy, aralkoxy, alkenyloxy, alkylthio, arylthio, aralkoxyalkyl, heteroaralkoxyalkyl, aryloxyalkyl, alkoxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, aralkoxyalkyl, heteroaralkyloxyalkyl, alkylsulfmylalkyl, alkylsulfonylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl, halogéncykloalkenyl, haloalkoxyalkyl, halogénalkenyloxyalkyl, halogéncykloalkoxyalkyl, halogéncykloalkenyloxyalkyl, heteroaryl, heteroarylalkyl, monocarboalkoxyalkyl, monokarboalkoxy, dicarboalkoxyalkyl, monocarboxamide, monocyanoalkyl, dikyanoalkyl, carboalkoxycyanoalkyl, acyl, aroyl, heteroaroyl, heteroaryloxyalkyl and dialkoxyphosphonoalkyl.

R ³⁹ and R ⁴⁰ , when attached to the same carbon, are optionally joined to form a group selected from oxo, thiono, R ⁵ -N, alkylene, haloalkylene, and a linear arm of 2 to 7 atoms to form a ring selected from the group consisting of a cycloalkyl ring of 3 to 8 members, a cycloalkenyl ring of 3 to 8 members and a heterocycle of 3 to 8 members.

-9M is selected from the group consisting of N and R‘-C.

R ² and R 4 are independently selected from the group consisting of Z 0 -Q, hydrido, alkyl, alkenyl and halogen.

R ¹ is optionally selected from the group consisting of amino, aminoalkyl, alkylamino, amidino, guanidino, hydroxy, hydroxyamino, alkoxy, hydroxyalkyl, alkoxyamino, thiol, alkylthio, dialkylsulfonium, trialkylphosphonium, dialkylsulfoniumalkyl, heteroarylamino, nitro, arylamino, aralkylamino, alkanoyl, alkanoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, haloalkanoyl, hydroxyhaloalkyl, cyano and phosphono.

R ² is optionally selected from the group consisting of amidino, guanidino, dialkylsulfonium, trialkylphosphonium, dialkylsulfoniumalkyl, heteroarylamino, amino, nitro, alkylamino, arylamino, aralkylamino, alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, heteroaralkanoyl, heteroaralkanoyl, heteroaralkanoyl, heteroaralkanoyl, heteroaralkanoyl,

R ² and R ^{4 a,} R ^2, and R ^4b, R ² and R ^I4, and R ² and R ¹⁵ are independently optionally selected to give the pair of shoulder straps, wherein the pair of shoulder straps together form a linear substituent containing 2-5 atoms connecting the binding sites of the members of a pair of arms to form a heterocyclic ring of 5 to 8 members, with the proviso that at most one pair of the group of arm pairs consisting of R ² and R ^4a , R ² and R ^4b , R ² and R ¹⁴ and R ² and R ¹⁵ is used at the same.

R ² is optionally independently selected to form a linear substituent containing 2 to 5 atoms linked to the binding sites of both R ^4a and R ^4b to form a heterocyclic ring containing 5 to 8 members.

Z 0 is selected from the group consisting of a covalent single bond, (CR ⁴¹ R ⁴² ) q wherein q is an integer selected from 1 to 6 and (CH (R ⁴¹ ) g W ° - (CH (R ⁴² )) _P where the gap is integers selected from 0 to 3 and W ° is selected from the group consisting of 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 (R), C (S) N (R ⁴¹ ), R ( ⁴¹ ) NC (S), OC (O) N (R ⁴¹⁾ ), (R ⁴¹⁾ C (O) O, OC (S) N (R ⁴¹⁾ (R ⁴⁾ C (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 ) N (R) N (R ⁴² ), S (O), S (O) 2, S (O) 2 N (R ⁴¹ ), N (R ⁴¹ ) Se (O) ₂ , Se (O) ₂ , Se (O) ₂ , Se (O) _2, N (R ⁴¹ ), N (R ⁴¹ ), Se (O) 2, P (O) (R ⁴¹ ), N (R ⁷ ) P (O) (R ^S ), P (O) (R ⁸ ) N (R ⁷ ), N (R ⁴¹ ), ON (R ⁴¹ ) and SiR ²⁸ R ²⁹ and (CH (R ⁴¹ ) eW ²² - (CH (R ⁴² )) h. Where eah are integers selected from 0 to 2 and W ²² is selected from the group consisting of CR ⁴¹ = CR ⁴² , CR ^4, R ⁴² = C (vinylidene), ethinylidene (C = C; 1,2-ethynyl), 1,2-cyclopropyl, 1,2-cyclobutyl, 1,3-cyclohexyl, 1,2-cyclopentyl, 1,3cyclopentyl, 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,

- 101,3-pyrrolidinyl, 2,3-pyrrolidinyl, 2,4-pyrrolidinyl, 2,5-pyrrolidinyl, 3,4-pyrrolidinyl, 2,3-tetrahydrofuranyl, 2,4-tetrahydrofuranyl, 2,5-tetrahydrofuranyl, 3,4 -tetrahydrofuranyl with the proviso that R ⁴¹ and R ⁴² are selected from substituents other than halogen and cyano when directly bound to N and Z 0 is directly bound to the pyrimidinone ring.

R ²⁸ and R ²⁹ are independently selected from the group consisting of hydrido, hydroxyalkyl, alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, acyl, aroyl, aralkanoyl, heteroaroyl, aralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkythioalkyl, heteroaralkythioalkyl, alkoxyalkyl, heteroaryalkyl, , alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl, halogéncykloalkenyl, haloalkoxyalkyl, halogénalkenylalkoxyalkyl, halogéncykloalkoxy, halogéncykloalkoxyalkyl, halogéncykloalkenyloxyalkyl, perhalogénaryl, perhalogénaralkyl, perhalogénaryloxyalkyl, heteroaryl, heteroarylalkyl, heteroarylthioalkyl, heteroaralkyltioalkyl, cyanoalkyl, dikyanoalkyl , carboxamidoalkyl, dicarboxamidoalkyl, cyanocarboalkoxyalkyl, carboalkoxyalkyl, dicarboalkoxyalkyl, cyanocycloalkyl, dicyanocycloalkyl, carboxamidocycloalkyl, dicarboxamidocycloalkyl, carboalkoxykyanocycloalkyl, carboalkoxycycloalkyl, dicarboalkoxycycloalkyl, formylalkyl, acylalkyl, arylsulfmylalkyl, arylsulfonylalkyl, aralkylsulfmyl, cycloalkylsulfonylalkyl, cycloalkylsulfonylalkyl, heteroarylsulfonylalkyl, heteroarylsulfinylalkyl, dialkylphenyl, aralkylsulfinylalkyl, aralkylsulfinylalkyl, aralkylsulfinylalkyl, aralkylsulfinylalkyl, aralkylsulfinylalkyl, aralkylsulfinylalkyl, aralkylsulfinylalkyl, aralkylsulfinylalkyl; 28 29

R and R are optionally joined to form a linear arm of 2 to 7 atoms and forming a ring selected from the group consisting of a cycloalkyl ring of 3 to 8 atoms, a cycloalkenyl ring of 3 to 8 atoms and a heterocyclic ring of 3 to 8 atoms.

- 11 Q is a group of formula II:

> 11 7 and 1 \ ¹² °

T. j-1 (II), wherein D ¹ , D ² , J ¹ , J ² and K ¹ are independently selected from the group consisting of C, N, O, S and covalent bonds, with the proviso that the covalent bond may only be selected once, at most one of D ¹ , D ² , J ¹ , J ² and K ¹ is O, at most one of D ¹ , D ² , J ¹ , J ² , and K * is S, one of D ¹ , D ² , J ¹ , J ² and K ¹ must be a covalent bond if two of D ¹ , D ² , J ¹ , J ² and K ¹ are O and S and at most four of D ¹ , D ² , J ¹ , J ² and K ¹ are N with the proviso that R ⁹ , R ¹⁰ , R ¹¹ , R ¹² and R ¹³ are each independently selected to maintain carbon tetravalence, nitrogen trivalent, sulfur bivalent and oxygen bivalent.

Q is a group optionally selected according to the general formula ΙΠ:

_R 10

(III), wherein D ³ , D ⁴ , J ³ and J ⁴ are independently selected from the group consisting of C, N, O and S, provided that at most one of D ³ , D ⁴ , J ³ and J ⁴ is O, at most one of D ³ , D ⁴ , J ³ and J ⁴ is S and at most three of D ³ , D ⁴ , J ³ and J ⁴ are N, provided that R ⁹ , R ¹⁰ , R ¹¹ and R ¹² are each independently selected to maintain carbon tetravalence, nitrogen trivalent, sulfur bivalent and oxygen bivalent.

Q is optionally selected from the group consisting of hydrido, alkyl, alkoxy, alkylamino, alkylthio, haloalkylthio, alkenyl, alkynyl, saturated heterocyclyl, partially saturated heterocyclyl, acyl, aroyl, heteroaroyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, haloalkylalkyl, haloalkyl haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxyalkyl and halocycloalkenyloxyalkyl, provided that Z 0 is not a single covalent bond when Q is hydrido.

K is (CR ^4a R ^4b ) _n where n is an integer selected from 1 to 4.

- 12R ^4a and R ^4b , when attached to the same carbon atom, are optionally joined to form a substituent selected from the group consisting of oxo, thiono and a linear arm having 2 to 7 atoms joined to form a ring selected from the group consisting of a cycloalkyl ring of 3 C 5 -C 8 cycloalkenyl and C 5 -C 8 heterocyclic ring with the proviso that R ^4a and R ^{4b taken} together are not oxo or thiono when the incoming carbon atom is directly bound to the pyrimidinone nitrogen.

E 0 is E ¹ when K is (CR ^4a R ^4b ) _n wherein E ¹ is selected from the group consisting of a single covalent bond, O, S, C (O), C (S), C (O) O, C ( S) O, C (O) S, C (S) S, C (O) N ^{(R7), (R7)} NC (O), C (S) N ^{(R7), (R7)} NC (S), OC (O) N ^{(R7), (R7)} NC (O) O, SC (S) N ^{(R7), (R7)} 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 ^{(R7), (R7)} NC (S) N (R ⁸⁾ S (O), S (O) 2, S (O) 2 N (R ^7), N ^(R7) S (O) 2, S (O) ₂ N (R ⁷⁾ C (O), C (O) N ^(R7) S (O) 2, Se, Se (O), Se ( O) 2, Se (O) 2 N (R ^7), N ^(R7) Se (O) 2, P (O) ^(R8), -N (R ⁷⁾ P (O) ^(R8), P ( O) (R ⁸ ) N (R ⁷ ), N (R ⁷ ), ON (R ⁷ ) and SiR ²⁸ R ²⁹ CR ^4a = CR ^4b , ethinylidene (C = C; 1,2-ethynyl) and C = CR ^4a R ^4b .

K is optionally selected such that (CH (R ¹⁴ )) j T wherein j is an integer selected from 0 to 3 and T is selected from the group consisting of a single covalent bond, O, S and N (R) ⁷ , that R ¹⁴ is not hydroxy, cyano, halogen, amino, alkylamino, dialkylamino and sulfhydryl when j is 1 and (CH (R ¹⁴ )) j is attached to the pyrimidinone ring.

E 0 is optionally E ² when K is (CH (R ¹⁴ )) j T wherein E ² is selected from the group consisting of a single covalent bond C (O), C (S), C (O) O, C (S) O , C (O) S, C (S) S, C (O) N ^{(R7), (R7)} NC (O), C (S) N ^{(R7), (R7)} NC (S) , ^(R7) NC (O) H, ^(R7) NC (S) S, ^(R7) NC (O) S, ^(R7) NC (S) O, N (R ⁸⁾ C (O) N ^{(R7), (R7)} NC (O) N (R ^8), -N (R ⁸⁾ C (S) N ^{(R7), (R7)} NC (S) N (R ^8), R (O), S (O) ₂ ,

S (O) ₂ N (R ^7), N ^(R7) 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 ^(R7) Se (O) 2, P (O) ^(R8), -N (R ⁷⁾ P (O) ( R ⁸ ), P (O) (R ⁸ ) N (R ⁷ ) and N (R ⁷ ).

K is optionally selected to be G- (CH (R ^{, 5} )) k where k is an integer from 1 to 3 and G is selected from the group consisting of O, S and N (R) ⁷ , provided that R is ¹⁵ is not hydroxy, cyano, halogen, amino, alkylamino, dialkylamino and sulfhydryl when k is 1.

E 0 is optionally E ³ when K is G- (CH (R ¹⁵ )) k wherein E ³ is selected from the group consisting of a single covalent bond, O, S, C (O), C (S), C (O) O, C (S), C (O), C (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) N, SC (S) N (R ⁷ ), (R ⁷ ) NC (S) S, SC ( O) N ^{(R7), (R7)} NC (O) S, OC (S) N ^{(R7), (R7)} NC (S) O, N (R ⁸⁾ C (O) N (R ^{7), (R7)} NC (O) N (R ^8), -N (R ⁸⁾ C (S) N ^{(R7), (R7)} 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) ₂ , Se (O) ₂ N (R ⁷⁾ ), N ^(R7) Se (O) _2, P (O) ^(R8), -N (R ⁷⁾ P (O) ^(R8), P (O) (R ⁸⁾ N (R ^7), N (R ⁷ ), ON (R ⁷ ) and Si (R ²⁸ ) R ²⁹ CR ^4a = CR ^4b , ethinylidene (C = C; 1,2-ethynyl) and C = CR ^4a R ^4b .

- 13 Y ° is a group of formula IV:

wherein D ⁵ , D ⁶ , J ⁵ and J ⁶ are independently selected from the group consisting of C, N, O, S and covalent bonds, with the proviso that at most one is a covalent bond, K is independently selected from the group consisting of C and N ⁺ , at most one of D ⁵ , D ⁶ , J ⁵ and J ⁶ is O, at most one of D ⁵ , D ⁶ , J ⁵ and J ⁶ is S, one of D ⁵ , D ⁶ , J ⁵ and J ⁶ must be covalent bond when two of ^{D5, D6, J5,} and ^J6 are O and S, and no more than three of ^{D5, D6, J5,} and ^J6 is N when a is N ^+, and no more than four of ^D5, D ⁶ , J ⁵ and J ⁶ are N when K ² is carbon, provided that R ¹⁶ , R ¹⁷ , R ¹⁸ and R ¹⁹ are each independently selected to maintain carbon tetravalence, nitrogen trivalent, sulfur bivalent and bivalent oxygen.

R ^I6 and ^R17 are optionally independently taken together to form a linear moiety spacer having from 3 to 6 atoms connected to form a ring selected from the group consisting of a cycloalkenyl ring having 5 through 8 contiguous members, a partially saturated heterocyclic ring containing from 5 to 8 atoms and the heteroaryl having 5 to 6 atoms and aryl.

R ¹⁸ and R ¹⁹ are optionally independently joined to form a linear chain of 3 to 6 atoms joined to form a ring selected from the group consisting of a cycloalkenyl ring of 5 to 8 atoms, a partially saturated heterocyclic ring of 5 to 8 atoms and heteroaryl containing 5 to 8 atoms 6 atoms and aryl.

Q ^b is selected from the group consisting of NR ²⁰ R ²¹ , ⁺ NR ²⁰ R ²¹ R ²² , oxy, alkyl, aminoalkenyl, alkylamino, dialkylamino, dialkylsulfonium alkyl, acylamino and Q ^be , wherein Q ^be is hydrido and R ²⁰ , R ²¹ and R 20 ²² are independently selected from the group consisting of hydrido, amino, alkyl, hydroxy, alkoxy, aminoalkenyl, alkylamino, dialkylamino and hydroxyalkyl, with the proviso that at most one of R ²⁰ , R ²¹ and R ²² is hydroxy, alkoxy, alkylamino, amino and dialkylamino simultaneously and that R ²⁰ , R ²¹ and R ²² must not be hydroxy, alkoxy, alkylamino, amino and dialkylamino when K ² is N ⁺ .

R ²⁰ and R ²¹ , R ²⁰ and R ²² and R ²¹ and R ²² are optionally independently selected to form a pair of arms, wherein the pair of arms together form a linear substituent containing 4 to 7 atoms linking the linking sites of said members of the pair of arms to form a heterocyclic a ring containing from 5 to 8 atoms, provided that at most one pair of arms of the group of arm pairs R ²⁰ and R ²¹ , R ²⁰ and R ²² and R ²¹ and R ²² are used simultaneously.

- 14Q, ^B is selected from N (R ²⁶⁾ S (O) ₂ N (R ²³⁾ (R ^24), N (R ²⁶⁾ C (O) OR \ N (R ²⁶⁾ C (O) SR ⁵ , N (R ²⁶ ) C (S) OR ⁵ and N (R ²⁶ ) C (S) SR ⁵ , provided that at most one of R ²³ , R ²⁴ and R ²⁶ may be hydroxy, alkoxy, alkyleneamino, alkylamino, amino or dialkylamino when two of the group consisting of R ²³ , R ²⁴ and R ²⁶ bind to the same atom.

Q ^b is optionally selected from the group consisting of 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 ), (R ²⁶ ) C (S) N (R ²³ ) (R ²⁴ ), CN (R 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 ² ) 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 (NR ²⁵ ) N (R ²³ ) (R ²⁴ ), C (NR ²⁵ ) SR ⁵ and C (O) NR ²³ R ²⁴ with the proviso that at most one of R ²³ , R ²⁴ and R ²⁶ may be hydroxy, alkoxy, alkylamino, amino or dialkylamino, provided that any two members of the group consisting of R ²³ , R ²⁴ and R ²⁶ bind to the same atom and the Q ^b group is directly attached to a carbon atom .

R ²³ , R ²⁴ , R ²⁵ and R ²⁶ are independently selected from the group consisting of hydrido, alkyl, hydroxy, alkoxy, alkyleneamino, amino, alkylamino, dialkylamino and hydroxyalkyl.

R ²³ and R ²⁴ are optionally joined together to form a linear arm of 4 to 7 atoms joining the linking sites to form a heterocyclic ring containing 5 to 8 atoms.

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 optionally independently selected to form a pair of arms which are joined together at the binding sites of the members of the pair of arms form a LUV group wherein L, U and V are independently selected from the group consisting of O, S, C (O), C (S), C (JH) 2 S (O), S (O) 2, OP (OR ³¹ ) R ³⁰ , P (O) R ³⁰ , P (S) R ³⁰ , C (R ³⁰ ) R ³¹ , C = C (R ³⁰ ) R ³¹ , (O) 2POP (O) _2i 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 ^{3 °)} = C (R ³¹⁾ S (O) C (R ³⁰⁾ = C (R ³¹⁾ S (O) ₂ C (R ³⁰ ) = C (R ³¹ ), P (R 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 ^{3 R),} DC ^(R30) (R ³ ') H, OP ( OR ³¹⁾ R ^30, P (O) R ^30,

P (S) R ³⁰ , Si (R ²⁸ ) R ²⁹ and N (R ³⁰ ) and a covalent bond, with the proviso that at most any two of L, U and V are both a covalent bond and the heterocyclyl formed by L, U and V from 5 to 10 atoms.

D is selected from the group consisting of O, C = O, C = S, S (O) _m wherein m is an integer selected from 0 to 2.

J h is independently selected from the group consisting of OR ²⁷ , SR ²⁷ and N (R ²⁰ ) R ²¹ .

R ²⁷ is selected from the group consisting of hydrido, alkyl, alkenyl, alkynyl, aralkyl, aryloxyalkyl, aralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkythioalkyl, heteroaralkythioalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl,

- 15aryltioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl, halogéncykloalkenyl, haloalkoxyalkyl, halogénalkenylalkoxyalkyl, halogéncykloalkoxyalkyl, halogéncykloalkenyloxyalkyl, perhalogénaryloxyalkyl, heteroaryl, heteroarylalkyl, heteroarylthioalkyl, heteroaralkyltioalkyl, arylsulfinylalkyl, arylsulfonylalkyl, Cycloalkylsulfinylalkyl, Cycloalkylsulfonylalkyl, Heteroarylsulfonylalkyl, heteroarylsulfinylalkyl , aralkylsulfinylalkyl, aralkylsulfonylalkyl.

R ³⁰ and R ³¹ are independently selected from the group consisting of hydrido, hydroxy, thiol, aryloxy, amino, alkylamino, dialkylamino, hydroxyalkyl, heteroaryloxyalkyl, alkoxy, alkylthio, arylthio, alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, aralkoxyalkyl, alkylsulfinylalkyl , alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkyloxytioalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halogénaralkylsulfinylalkyl, Aralkylsulfonylalkyl, cyanoalkyl, dikyanoalkyl, carboxamidoalkyl, dikarboxamidoalkyl, kyanokarboalkoxyalkyl, carboalkoxyalkyl, dicarboalkoxyalkyl, kyanocykloalkyl , dicyanocycloalkyl, carboxamidocycloalkyl, dicarboxamidocycloalkyl, carboalkoxycyanocycloalkyl, carboalkoxycycloalkyl, dicarboalkoxycycloalkyl, formylalkyl, acylalkyl,. dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, phosphonoalkyl, dialkoxyfosfonoalkoxy, diaralkoxyfosfonoalkoxy, fosfonoalkoxy, dialkoxyfosfonoalkylamino, diaralkoxyfosfonoalkylamino, fosfonoalkylamino, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, sulfonylalkyl, alkoxysulfonylalkyl, aralkoxysulfonylalkyl, alkoxysulfonylalkoxy, aralkoxysulfonylalkoxy, sulfonylalkoxy, alkoxysulfonylalkylamino, aralkoxysulfonylalkylamino and sulfonylalkylamino.

R ³⁰ and R ³¹ are optionally joined together to form a linear chain of 2 to 7 atoms to form a ring selected from the group consisting of a cycloalkyl ring of 3 to 8 atoms, a cycloalkenyl ring of 5 to 8 atoms and heteroaryl of 3 to 8 atoms and a heterocycle containing 3 to 8 atoms.

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 optionally independently selected so as to form a pair of arms which are joined together at the binding sites of the pair of arms forming a LUV group wherein L, U and V are independently selected from the group of 1,2disubstituted radicals containing cycloalkyl radicals and cycloalkenyl radicals wherein the cycloalkyl and cycloalkenyl radicals are substituted with one or more »31 groups selected from R ³⁰ and R ³¹ , an aryl radical, heteroaryl a radical, a saturated heterocyclic radical and a partially saturated heterocyclic radical, wherein said 1,2-162332 substituents are independently selected from the group consisting of C = O, C = S, C (R) R, S (O), S (O) ₂ , OP (OR ³ ') 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 optionally independently selected to form a pair of straps which are joined together at the binding sites of said pair of straps to form LUV, wherein L, U and V are independently selected from the group consisting of 1,2-disubstituted alkylene radicals and 1,2-disubstituted alkenyl radicals, wherein said 1,2-substituents are independently selected from the group consisting of C = O, C = S, C (R ²⁸ ) R ²⁹ , S (O) ₂ , OP (OR ³¹ ) R ³⁰ , P (O) R ³⁰ , P (S) R ³⁰ and Si (R ²⁸ ) R ²⁹ and said alkylene and alkenyl radicals are substituted with one or more R ³⁰ or R ³¹ substituents.

Q ^s is optionally selected from the group consisting of a single covalent bond a (CR ³⁷ R ³⁸ ) b W 0) a ₂ wherein z is an integer selected from 0 to, b is an integer selected from 1 to 4, and W 0 is selected from O, S, C (O), C (O), C (O) O, C (O) O, C (O) O, C (O) S, C (O) O (R ¹⁴ ), (R) ^I4) NC (O), C (S) N ^{(R14), (R14)} NC (S), OC (O) N (R ^14),

SC (S) N (R ^14), C (O) N (R ^14), OC (S) N (R ^14), N (R ¹⁵⁾ C (O) N ^{(R14), (R14)} NC (O) N (R ¹⁵ ),

N (R ¹⁵ ) C (S) N (R ¹⁴ ), (R ¹⁴ ) N (R) 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 , (CHfR '- - W'-CCHtR ¹⁵ )), wherein c and d are integers independently selected from 1 to 4 and W ¹ is selected from the group consisting of O, S, C (O), C (S), C ( O) O, C (O) S, C (O) S, C (O) S, C (O) N (R ¹⁴ ), (R ¹⁴ ) NC (O), C (S) N (R ¹⁴ ) , (R ^I4) NC (S), OC (O) N ^{(R14), (R14)} NC (O) O, SC (S) N (R ⁴⁾ (R ¹⁴⁾ C (S) S SC (O) N (R ¹⁴ ), (R ¹⁴ ) NC (O) S, OC (S) N (R ¹⁴ ), (R ¹⁴ ) NC (S) O, N (R ' ⁵ ) C (O) ) N (R ' ⁴ ), (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 ⁷⁴ ), 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 ), Sulfur ²⁸ R ²⁹ and (CH (R ¹⁴ )) t -W ²² (CH (R)) h where eah are integers independently selected from the interval 0 to 2 and W is selected from the group consisting of CR ⁴¹ = CR ⁴² , CR ⁴¹ R ⁴² = C (vinylidene), ethinylidene (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, 3,4-tetrahydroururanyl with the proviso that R ¹⁴ and R ¹⁵ are selected from substituents other than halogen and cyano when they are directly bound to N and when (CR ³⁷ R ³⁸ ) b, (CH (R ¹⁴ )) c and (CH (R ¹⁴ )) e bind to E °.

- 173V 37

R and R, when attached to different carbons, are optionally joined to form a linear arm of 1 to 7 atoms joined to form a ring selected from the group consisting of a cycloalkyl ring of 3 to 8 atoms, a cycloalkenyl ring of 3 to 8 atoms and a heterocyclic ring a ring of 3 to 8 atoms and a heteroaryl of 5 to 6 atoms and an aryl.

R and R, when attached to different carbons, are joined to form a linear arm of 1 to 7 atoms joined to form a ring selected from the group consisting of a cycloalkyl ring of 3 to 8 atoms, a cycloalkenyl ring of 3 to 8 atoms and a heterocyclic ring containing 3 to 8 atoms and heteroaryl containing 5 to 6 atoms and aryl.

R and R, when attached to different carbons, are joined to form a linear arm of 1 to 7 atoms joined to form a ring selected from the group consisting of a cycloalkyl ring of 3 to 8 atoms, a cycloalkenyl ring of 3 to 8 atoms and a heterocyclic ring containing 3 to 8 atoms and heteroaryl containing 5 to 6 atoms and aryl.

R ³⁷ and R ³⁸ , when attached to the same carbon atom, are joined to form a substituent selected from the group consisting of oxo, thiono, alkylene, haloalkylene, and a linear 2- to 7-membered ring to form a ring selected from the cycloalkyl ring containing from 3 to 7 8 atoms, a cycloalkenyl ring of 3 to 8 atoms and a heterocyclic ring of 3 to 8 atoms and heteroaryl of 5 to 6 atoms and aryl.

Y ⁰ is optionally Q ^b -Q ^ss , wherein Q ⁵⁵ is selected from the group consisting of (CR ³⁷ R ³⁸ ) f, where f is an integer selected from 1 to 6, (CH (R ¹⁴ )) cW ¹ - (CH (R ¹⁵ )) d wherein c and d are integers independently selected from 1 to 4 and W ¹ is selected from the group consisting of O, S, C (O), C (S), C (O) O, C (S) O, C (O), C (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 ^I4) NC (O) O, SC (S) N (R ¹⁴⁾ (R ^I4) NC (S) S, SC (O) N (R ¹⁴ ), (R ^I4) NC (O) S, OC (S) N (R ¹⁴⁾ (R ¹⁴⁾ C (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) ₂ , Se (O) ₂ N (R ¹⁴ ), N (R ¹⁴⁾ ) Se (O) 2, P (O) ^(R8), -N (R ⁷⁾ P (O) ^(R8), P (O) ^(R8) N ^(R7), N (R ^14), ON (R ¹⁴ ), Si (R ²⁸ R ²⁹ ) and (CH (R ¹⁴ )) eW ² - (CH (R ¹⁵ )) h, where eah are integers independently selected from 0 to 2 and W ² is selected from the group consisting of CR ^4a = CR ^4b , ethinylidene (OC, 1,2-ethynyl) and C = CR ^4a R ^4b , provided that R ¹⁴ a R ¹⁵ are not halogen and cyano when directly bound to N and that (CR ³⁷ R ³⁸ ) f, (CH (R ¹⁵ )),. and (CH (R ¹⁵ )) e bind to E 0 and Q ^b is not N (R ²⁶ ) N (R ²⁶ ) CN (R ²⁶ ) N (R ²³ ) (R ²⁴ ) or ON (R ²⁶ ) C (NR ²⁵ ) N (R ²³ ) (R ²⁴ ) when Q ^ss is (CR ³⁷ R ³⁸ ) r, where f is an integer other than 1.

Y 0 is optionally Q ^b -Q ^sss wherein Q ^sss is (CH (R ³⁸ )) _r -W ³ , where r is an integer selected from 1 to 3 and W ³ is selected from the group consisting of 1,1-cyclopropyl, 1,2-cyclopropyl, 1,1-cyclobutyl, 1,2-cyclobutyl, 1,2-cyclohexyl, 1,3-cyclohexyl, 1,4-cyclohexyl, 1,2-cyclopentyl,

181.3-cyclopentyl, 2,3-morpholinyl, 2,4-morpholinyl, 2,6-morpholinyl, 3,4-morpholinyl, 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-pyran-2-one-3,4-yl, 2H-pyran-2-one-4,5-yl, 4H-pyran-4-one-2,3-yl,

2,3-tetrahydrofuranyl, 2,4-tetrahydrofuranyl, 2,5-tetrahydrofuranyl, 3,4-tetrahydrofuranyl,

2,3-tetrahydropyranyl, 2,4-tetrahydropyranyl, 2,5-tetrahydropyranyl, 2,6-tetrahydropyranyl,

3,4-tetrahydropyranyl, 3,5-tetrahydropyranyl and all nitrogen atoms in the ring W ³ with carbon and hydride substituents other than at the binding site are optionally substituted by one or more substituents from R ⁹ , R ¹⁰ , R ¹¹ and R ¹² , that (CH (R ³⁸ )) _r binds to E ° and Q ^b binds to the position with the lowest serial number for each W ³ .

Y 0 is optionally Q ^b -Q ^ssr , wherein Q 4 is (CH (R ³⁸ )) _r -W ⁴ where r is an integer selected from 1 to 3 and W ⁴ is selected from the group consisting of 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-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-pyran-2-one-3,4-yl, 2H-pyran-2-one-4,5-yl, 4H-pyran-4- on-2,3-yl, 2,3-tetrahydrofuranosyl, 2,4-tetrahydrofuranosyl, 2,5-tetrahydrofuranosyl, 3,4-tetrahydrofuranosyl, 2,3-tetrahydropyranyl, 2,4tetrahydropyranyl, 2,5-tetrahydropyranyl, 2,6- tetrahydropyranyl, 3,4-tetrahydropyranyl, 3,5tetrahydropyranyl and all nitrogen atoms in the W ⁴ ring with carbon and hydride substituents other than at the binding site are optionally substituted with one or more substituents from R ⁹ , R ¹⁰ , R ¹¹ and R ¹² with the proviso that (CH (R ³⁸ )) _r binds to E ° and Q ^b binds to the position with the highest serial number for each W ⁴ .

Y 0 is optionally Q ^b -Q ^ssss , wherein Q ⁵⁵⁵⁵ is (CH (R ³⁸ )) _r -W ⁵ where r is an integer selected from 1 to 3 and W ⁵ is selected from the group consisting of 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, 3,5indenyl, 3,6-indenyl, 3,7-indenyl, 2,4-benzofuranyl, 2,5-benzofuranosyl, 2,6-benzofuranosyl, 2,7-benzofuranosyl, 3,4-benzofuranosyl, 3,5-benzofuranosyl, 3,6- benzofuranyl, 3,7-benzofuranyl, 2,4-19benzothiophenyl, 2,5-benzothiophenyl, 2,6-benzothiophenyl, 2,7-benzothiophenyl, 3,4-benzothiophenyl,

3,5-benzothiophenyl, 3,6-benzothiophenyl, 3,7-benzothiophenyl, 2,4-imidazo (1,2-a) pyridinyl, 2,5-imidazo (1,2-a) pyridinyl, 2,6-imidazo (1,2) -a) pyridinyl, 2,7-imidazo (1,2-a) pyridinyl, 3,4-imidazo (1,2-a) pyridinyl, 3,5-imidazo (1,2-a) pyridinyl, 3,6-imidazo (1,2-a) pyridinyl, 3,7-imidazo (1,2-a) pyridinyl, 2,4-indonyl, 2,5-indonyl, 2,6-indonyl, 2,7-indonyl, 3,4-indonyl , 3,5-indonyl, 3,6-indonyl, 3,7-indonyl, 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, 3,5indazolyl, 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, 2,8-quinolinyl, 3,4-quinolinyl, 3,5-quinolinyl, 3,6-quinolinyl, 3,7-quinolinyl, 3,8-quinoline yl, 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-cinolinyl, 3,5-cinolinyl, 3,6-cinolinyl, 3,7-cinolinyl, 3,8-cinolinyl, 4,5-cinolinyl, 4,6-cinolinyl, 4,7-cinolinyl, 4,8-cinolinyl and all nitrogen atoms in the W ⁵ ring with carbon and hydride substituents other than at the binding site are optionally substituted with one or more substituents from R ⁹ , R ¹⁰ , R ¹¹ and R ¹² , provided that (CH (R ³⁸ )) _r binds to E 0 and Q ^b binds to the position with the lowest order number for each W ⁵ .

Y is optionally Q ^b _Q ^ssss characterized wherein Q ^"55" is (CH ^(R38)) _r-W ⁶ wherein r is an integer selected from 1 through 3, and W ⁶ is selected from the group consisting of 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, 3,5indenyl , 3,6-indenyl, 3,7-indenyl, 2,4-benzofuranosyl, 2,5-benzofuranosyl, 2,6-benzofuranosyl, 2,7-benzofuranosyl, 3,4-benzofuranosyl, 3,5-benzofuranosyl, 3, 6-benzofuranosyl, 3,7-benzofuranosyl, 2,4-benzothiophenyl, 2,5-benzothiophenyl, 2,6-benzothiophenyl, 2,7-benzothiophenyl, 3,4-benzothiophenyl,

3,5-benzothiophenyl, 3,6-benzothiophenyl, 3,7-benzothiophenyl, 2,4-imidazo (1,2-a) pyridinyl, 2,5-imidazo (1,2-a) pyridinyl, 2,6-imidazo ( 1,2-a) pyridinyl, 2,7-imidazo (1,2-a) pyridinyl, 3,4-imidazo (1,2-a) pyridinyl, 3,5-imidazo (1,2-a) pyridinyl, 3, 6-imidazo (1,2-a) pyridinyl, 3,7-imidazo (1,2-a) pyridinyl, 2,4-indonyl, 2,5-indonyl, 2,6-indonyl, 2,7-indonyl, 3, 4-indonyl, 3,5-indonyl, 3,6-indonyl, 3,7-indonyl, 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, 2,6-20-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, 2,8-quinolinyl, 3,4-quinolinyl, 3, 5-quinolinyl, 3,6-quinolinyl, 3,7-quinolinyl, 3,8-quinolinyl, 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-cinolinyl, 3,5-cinolinyl, 3,6-cinolinyl, 3,7-cinolinyl, 3,8-cinolinyl, 4,5-cinolinyl, 4,6-cinolinyl, 4,7-cinolinyl, 4,8-cinolinyl and all nitrogen atoms in the ring W ⁶ with carbon and hydride substituents other than at the binding site are optionally substituted by one or more substituents from R ⁹ , R ¹⁰ , R ¹¹ and R ¹² , provided that (CH (R ³⁸ )) _r binds to E ° and Q ^b binds to the position with the highest serial number for each W ⁶ .

In a preferred embodiment, the invention encompasses compounds of Formula I or pharmaceutically acceptable salts thereof wherein:

J is selected from the group consisting of O and S,

J is optionally selected from the group consisting of CH-R ⁶ and NR ⁶ , wherein R ⁶ is a linear arm of 1 to 4 atoms attached to the substituent binding site selected from the group consisting of R ^4a , R ^4b , R ³⁹ , R ⁴⁰ , R ⁵ , R ¹⁴ and R ^1? to form a heterocyclic ring of 5 to 8 atoms.

B is a group of formula (V).

wherein D ¹ , D ² , J ¹ , J ² and K ¹ are independently selected from the group consisting of C, N, O, S and a covalent bond, with the proviso that the covalent bond may be selected only once, at most one of D ¹ , D ² , J ¹ , J ² and K ¹ is O, at most one of D ¹ , D ² , J ¹ , J ² , and K ¹ is S, one of D ¹ , D ² , J ¹ , J ² and K ¹ must be a covalent bond as long as two of D ¹ , D ² , J ¹ , J ² and K ¹ are O and S and at most four of D ¹ , D ² , J ¹ , J ² and K ¹ are N, provided that R ³² , R ³³ , R ³⁴ , R ³⁵ and R ³⁶ are each independently selected to maintain carbon tetravalence, nitrogen trivalent, sulfur bivalent and oxygen bivalent.

-21, 11n 13

R \ R ^10, R ', R ^u, R ^IJ, R .16

R ¹⁷ R ¹⁸

R ¹⁹ , R ³² , R ³³

R ³⁵ and R ³⁶ are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, dialkylsulfonium, trialkylphosphonium, dialkylsulfoniumalkyl, carboxy, heteroaralkylthio, heteroaralkoxy, cycloalkylamino, acylalkyl, aralkylalkoxy, aralkyloxy, aryloxy, aryloxy, aryloxy , heterocyclyl, perhalogénaralkyl, aralkyl, Aralkylsulfonylalkyl, aralkylsulfinyl, Aralkylsulfinylalkyl, halocycloalkyl, halogéncykloalkenyl, cycloalkylsulfinyl, Cycloalkylsulfinylalkyl, cycloalkylsulfonyl, Cycloalkylsulfonylalkyl, heteroarylamino, N-heteroarylamino, N-alkylamino, heteroarylaminoalkyl, haloalkylthio, alkanoyloxy, alkoxy, alkoxyalkyl, haloalkoxyalkyl, heteroaralkoxy, cycloalkoxy , cycloalkenyloxy, cycloalkoxyalkyl, cycloalkylalkoxy, cycloalkenyloxyalkyl, cycloalkylenedioxy, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxy, halocycloalkenyloxyalkyl, hydroxy, amino, alkoxyamino, thio, nitro, n ižší alkylamino, alkylthio, alkylthioalkyl, arylamino, aralkylamino, arylthio, arylthioalkyl, heteroaralkyloxyalkyl, alkylsulfinyl, alkylsulfmylalkyl, arylsulfinylalkyl, arylsulfonylalkyl, heteroarylsulfmylalkyl, Heteroarylsulfonylalkyl, alkylsulfonyl, alkylsulfonylalkyl, halogénalkylsulfinylalkyl, halogénalkylsulfonylalkyl, alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkyl, dialkyl, monoarylamidosulfonyl, arylsulfonamido , diarylamidosulfonyl, monoalkyl, monoarylamidosulfonyl, arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, heterocyclylsulfonyl, heterocyclylthio, alkanoyl, alkenoyl alkyl, aroyl, heteroaroyl alkyl, aralkanoyloxy, alkyl, haloalkanoyl, , cycloalkylalkanoyl, cycloalkenyl, lower cycloalkylalkyl, lower cycloalkenylalkyl, halogen, haloalkyl, haloalkenyl, haloalkoxy, hydroxyhaloalkyl , hydroxyaralkyl, hydroxyalkyl, alkylenylamino, hydroxyheteroralkyl, haloalkoxyalkyl, aryl, aralkyl, aryloxy, aralkoxy, aryloxyalkyl, saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl, heteroaryloxy, heteroaryloxyalkyl, arylalkyl, heteroarylalkyl, alkoxyalkyl, arylalkenyl, carboxylalkoxy, carboxylalkoxy, carboxylalkoxy, carboxylalkoxy, arylamidocarbonylamido, carboalkoxyalkyl, carboalkoxyalkenyl, carboxy, carboaralkoxy, carboxamido, carboxamidoalkyl, cyano, carbohaloalkoxy, phosphono, phosphonoalkyl, diaralkoxyphosphono and diaralkoxyphosphonoalkyl.

R ¹⁶ , R ¹⁹ , R ³² , R ³³ , R ³⁴ , R ³⁵ and R ³⁶ are optionally independently Q ^b with the proviso that at most one of R ¹⁶ and R ¹⁹ is Q ^b at the same time and that Q ^b is Q ^bc .

-22 R ³² and R ³³ , R ³³ and R ³⁴ , R ³⁴ and R ³⁵ and R ³⁵ and R ³⁶ are optionally independently selected to form a pair of arms, wherein the pair of arms together form a linear substituent of 3 to 6 atoms linking the bonding the sites of said members of a pair of arms to form a ring selected from the group consisting of a cycloalkenyl ring of 5 to 8 atoms, a partially saturated heterocyclic ring of 5 to 8 members, a heteroaryl ring of 5 to 6 atoms, and aryl; consisting of R ³² and R ³³ , R ³³ and R ³⁴ , R ³⁴ and R ³⁵ and R ³⁵ and R ³⁶ shall be used simultaneously.

R ⁹ and R ¹⁰ , R ¹⁰ and R ¹¹ , R ¹¹ and R ¹² and R ¹² and R ¹³ are optionally independently selected to form a pair of arms, wherein the pair of arms together form a linear substituent of 3 to 6 atoms linking the bonding sites said members of a pair of arms to form a ring selected from the group consisting of a cycloalkenyl ring of 5 to 8 atoms, a partially saturated heterocyclic ring of 5 to 8 members, a heteroaryl ring of 5 to 6 atoms, and aryl; of R ⁹ and R ¹⁰ , K and R, R and R and R and R are used simultaneously.

B is optionally selected from the group consisting of hydrido, trialkylsilyl, C 2 -C 8 alkyl, C 3 -C 8 alkylenyl, C 3 -C 8 alkenyl, C 3 -C 8 alkynyl, C 2 -C 8 haloalkyl and C 3 -C 8 haloalkenyl, wherein each member of group B may be optionally substituted on any a carbon atom of up to 6 atoms including from the B to A bonding site with one or more substituents from R ³² , R ³³ , R ³⁴ , R ³⁵ and R ³⁶ .

B is optionally selected from the group consisting of C 3 -C 15 cycloalkyl, C 5 -C 10 cycloalkylenyl, C 4 -C 12 saturated heterocycle and C 4 -C 9 partially saturated heterocycle wherein each ring carbon atom is optionally substituted with R ³³ , a ring carbon atom other than the carbon atom at B to A is optionally substituted by an oxo group so that at most one ring carbon atom is substituted by the oxo group at the same time, the carbon atom and the nitrogen atom adjacent to the carbon at B to A are optionally substituted by R ⁹ or R ¹³ , a carbon or nitrogen atom adjacent to the R ⁹ position and two atoms remote from the point of attachment are optionally substituted with R ¹⁰ , a carbon or nitrogen atom adjacent to the R ¹³ position and two atoms distant from the point of attachment are optionally substituted with R, carbon atom or a nitrogen atom three atoms away from the point of attachment and adjacent to the R ¹⁰ position are optionally substituted with R ¹¹ , a carbon atom and or a nitrogen atom three atoms from the point of attachment and adjacent to the R ¹² position is optionally substituted with R ³³ and a carbon atom or nitrogen atom four atoms from the point of attachment and adjacent to the R ¹¹ and R ³³ position is optionally substituted with R ³⁴ .

-23A is selected from a covalent bond, (W ⁷⁾ RT (CH ^(R15)) pa and (CH ^(R15)) pa- (W ⁷⁾ n · wherein rr is an integer from 0 to 1, pa is an integer selected from 0 to 6 and W ⁷ is selected from the group consisting of O, S, C (O), C (S), C (O) O, C (S) O, C (O) S, C (O) N (R ^7), C (S) N ^{(R7), (R7)} NC (S), ^(R7) NC (O), S (O), S (O) 2 , S (O) ₂ N (R ⁷⁾ (R ⁷⁾ S (O) _2, P (O) ^(R8), -N (R ⁷⁾ P (O) ^(R8), P (O) ( R ⁸ ) N (R ⁷ ), CN (R ⁷ ) N (R ⁷ ), (R ⁷ ) NC (NR ⁷ ), (R ⁷ ) NC (NR ⁷ ) NR ⁷ and NR ⁷ , provided that not more than one the substituent containing rr and pa may be 0 at the same time.

R and R are independently selected from the group consisting of hydrido, hydroxy, alkyl, aroyl, acyl, heteroaroyl and alkoxyalkyl.

R ¹⁴ , R ¹⁵ , R ³⁷ and R ³⁸ are independently selected from the group consisting of hydrido, hydroxy, halogen, cyano, hydroxyalkyl alkoxy, alkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkoxy, haloalkenyl, haloalkoxy, haloalkoxy, haloalkoxy haloalkenyloxyalkyl, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxyalkyl, carboxy, carboxyalkyl, carboalkoxy, carboxamide and carboxamidoalkyl.

R ¹⁴ and R ³⁸ are independently selected from the group consisting of aroyl, acyl and heteroaroyl, provided that acyl is not formyl and 2-oxoacyl.

Vybrané is selected from the group consisting of NR ⁵ , O, C (O), C (S), S, S (O), S (O) ₂ , OfN (IV), PO (R ⁸ ) and CR ³⁹ R ⁴⁰ .

R ⁵ is selected from the group consisting of hydrido, hydroxy, amino, alkyl, alkoxy, alkoxyalkyl, haloalkyl, aroyl, acyl, and heteroaroyl.

R ³⁹ and R ⁴⁰ are independently selected from the group consisting of hydrido, hydroxy, halogen, cyano, hydroxyalkyl, acyl, aroyl, heteroaroyl acylamido, alkoxy, alkyl, alkoxyalkyl, haloalkyl, haloalkoxy, haloalkoxyalkyl, alkylsulfonyl, haloalkylsulfonyl, haloalkenyloxyalkyl, carboxyalkenyloxyalkyl, carboxy carboalkoxy, carboxamide and carboxamidoalkyl.

M is selected from the group consisting of N and R * -C.

R ² and R ¹ are independently selected from the group consisting of Z 0 -Q, hydrido, alkyl, alkenyl and halogen.

R ¹ is optionally selected from the group consisting of amino, aminoalkyl, alkylamino, amidino, guanidino, hydroxy, hydroxyamino, alkoxy, hydroxyalkyl, alkoxyamino, thiol, alkylthio, dialkylsulfonium, trialkylphosphonium, dialkylsulfoniumalkyl, heteroarylamino, nitro, arylamino, aralkylamino, alkanoyl, alkanoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, haloalkanoyl, hydroxyhaloalkyl, cyano and phosphono.

-24Z ° is selected from the group consisting of a single covalent bond, (CR ¹⁵ R ⁴² ) q where q is an integer from 1 to 6, (CH (R ⁴¹ )) g W ° - (CH (R ⁴² )) where the gap is an integer numbers from 0 to 3 and W 0 is selected from the group consisting of 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 ) N (R), C (S) N (R ⁴¹ ), (R ⁴¹ ) N (R), OC (O) N (R ⁴¹ ), (R ⁴¹ ) NC (O), SC (S), N (R ⁴¹ ), (R ⁴¹ ), NC (S), SC (O), N (R ⁴¹ ), (R ^4I ), NC (O) S, OC (S) N (R ⁴¹ ), (R ⁴ ') NC (S) O, N (R ⁴² ) C (O) N (R ⁴¹ ), (R ⁴¹ ) NC (O) N (R ⁴² ), N (R ⁴² ) N (R ⁴¹ ), (R ⁴¹ ) NC (S) N (R ⁴² ), S (O) 2, S (O) ₂ N (R ⁴¹ ) N (R ⁴¹ ) S (O) 2i Se, Se (O) 2, Se (O) 2, Se (O) 2 N (R ⁴¹ ), N (R ⁴¹ ) 2 Se (O) 2, P (O) ( R ⁸ ), N (R ⁷ ) P (O) (R ⁸ ), P (O) (R ⁸ ) N (R ⁷ ), N (R ⁴ '), ON (R ⁴¹ ), Sulfur ²⁸ R ²⁹ and (CH (R ¹⁴ )) eW ²² - (CH (R ⁴² )) h where eah are integers independently selected from 0 to 2 and W ²² is selected from the group consisting of CR ⁴¹ = CR ⁴² , CR ⁴¹ R ⁴² = C (vinylidene), ethinylidene (C = C, 1,2-ethynyl), 1,2cyclopropyl, 1,2-cyclobutyl, 1,2-cyclo xyl, 1,3-cyclohexyl, 1,2-cyclopentyl, 1,3cyclopentyl, 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-tetrahydro-furanyl, 2,4-tetrahydro-furanyl, 2,5-tetrahydro-furanyl and 3,4-tetrahydro-furanyl with the proviso that R ⁴¹ and R ⁴² are not halogen and cyano substituents when they bind directly to N and Z 0 are directly bound to the pyrimidinone ring.

R and R are independently selected from the group consisting of hydrido, hydroxy, amino, halogen, cyano, aryloxy, hydroxyalkyl, acyl, aroyl, heteroaroyl heteroaroyloxyalkyl, alkoxy, alkyl, aryl, aralkyl, aryloxyalkyl, aralkoxyalkylalkoxy, alkoxyalkyl, heteroaryloxyalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl, halogéncykloalkenyl, haloalkoxy, haloalkoxyalkyl, halogénalkenyloxyalkyl, halogéncykloalkoxy, halogéncykloalkoxyalkyl, halogéncykloalkenyloxyalkyl, saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl, heteroaralkyl, heteroarylthioalkyl, heteroaralkyltioalkyl, alkylsulfonyl, haloalkylsulfonyl, arylsulfonyl, arylsulfbnylalkyl, aralkylsulfbnyl , cycloalkylsulfonyl, cycloalkylsulfonylalkyl, heteroarylsulfonylalkyl, heteroarylsulfonyl and aralkylsulfonylalkyl.

Q is a group of formula II:

25. r

V'V (II), ₉ / ^D ^ D \ _{R 3} wherein D ^1, D ^2, J ^1, J ² and K are independently selected from the group consisting of C, N, O, S and covalent bond with the provisos that the covalent bond can be selected only once, at most one of D ¹ , D ² , J ¹ , J ² and K ¹ is O, at most one of D ¹ , D ² , J ¹ , J ² , and K ¹ is S, one of D ¹ , D ² , J ¹ , J ² and K ¹ must be a covalent bond as long as two of D ¹ , D ² , J ¹ , J ² and K ¹ are O and S and at most four of D ¹ , D ² , J ¹ , J ² and K ¹ are N with the proviso that R ⁹ , R ¹⁰ , R ¹¹ , R ¹² and R ¹³ are each independently selected to maintain carbon tetravalence, nitrogen trivalent, sulfur bivalent, and oxygen bivalent.

Q is optionally a group of formula ΠΙ, 10

RV f

11 »D

T il (III),

R 12 wherein D ³ , D ⁴ , J ³ and J ⁴ are independently selected from the group consisting of C, N, O and S, provided that at most one of D ³ , D ⁴ , J ³ and J ⁴ is O, at most one of D ³ , D ⁴ , J ³ and J ⁴ is S, and at most three of D ³ , D ⁴ , J ³ and J ⁴ are N, provided that R ⁹ , R ¹⁰ , R ¹¹ and R ¹² are each independently selected such that carbon tetravalence, nitrogen trivalent, sulfur bivalent, and oxygen bivalent are maintained.

Q is optionally selected from the group consisting of hydrido, alkyl, alkoxy, alkylamino, alkylthio, haloalkylthio, alkenyl, alkynyl, saturated heterocyclyl, acyl, aroyl, heteroaroyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, haloalkylalkyl, haloalkoxy, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxyalkyl, halocycloalkenyloxyalkyl, provided that Z 0 is not a single covalent bond when Q is hydrido.

K is (CR ^4a R ^4b ) n where n is an integer from 1 to 2.

R ^4a and R ^4b are independently selected from the group consisting of hydrido, hydroxy, halogen, cyano, hydroxyalkyl, alkyl, alkenyl, alkoxyalkyl, aralkyl, heteroaralkyl, alkylthioalkyl, haloalkyl, haloalkenyl and cyanoalkyl.

-26E ° is E ¹ when K is (CR ^4a R ^4b ) _n , wherein E 'is selected from the group consisting of a single covalent bond, O, S, C (O), C (S), C (O) O, C (S) O, C (O) S, C (S) S, C (O) N ^{(R7), (R7)} NC (O), C (S) N (R ⁷⁾ (R ⁷⁾ NC (S), OC (O) N ^{(R7), (R7)} NC (O) O, SC (S) N ^{(R7), (R7)} NC (S) S, SC (O) N ^{(R7), (R7)} NC (O) S, OC (S) N ^{(R7), (R7)} NC (S) O, N (R ⁸⁾ C (O) N (R ^{7), (R7)} NC (O) N (R ^8),

N (R ⁸⁾ C (S) N ^{(R7), (R7)} NC (S) N (R ⁸⁾ S (O), S (O) 2, S (O) 2 N (R ^7), N ^(R7) S (O) 2, S (O) ₂ N (R ⁷⁾ C (O), C (O) N ^(R7) 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 , C = CR ^4a R ^4b and ethynylidene (C = C, 1,2-ethynyl).

K is optionally (CH (R ¹⁴ )) jT wherein j is an integer from 1 to 2 and T is selected from the group consisting of a single covalent bond, O, S and N (R ⁷ ) with the proviso that (CH (R ¹⁴⁾ is bonded to the pyrimidinone ring.

E 0 is optionally E ² when K is (CH (R ¹⁴ )) j T, wherein E ² is selected from the group consisting of a single covalent bond, C (O), C (S), C (O) O, C (S) O, C (O) S, C (S) S, C (O) N ^{(R7), (R7)} NC (O), C (S) N ^{(R7), (R7)} NC (S ), ^(R7) NC (O) H, ^(R7) NC (S) S, ^(R7) NC (O) S, ^(R7) 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) ^(R8), -N (R ⁷⁾ P (O) ^(R8), P (O) ^(R8) N ^(R7) and N (R ⁷ ).

K is optionally G- (CH (R ¹⁵ )) k wherein k is an integer from 1 to 2 and G is selected from the group consisting of O, S and N (R ⁷ ) with the proviso that R ¹⁵ is not hydroxy, cyano , halogen, amino, alkylamino, dialkylamino and sulfhydryl substituents when k is 1.

E 0 is optionally E ³ when K is G- (CH (R ¹⁵ )) k, wherein E ³ is selected from the group consisting of a single covalent bond, O, S, C (O), C (S), C (O) O, C (S), C (O), C (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) N, SC (S) N (R ⁷ ), (R ⁷ ) NC (S) S, SC ( O) N ^{(R7), (R7)} NC (O) S, OC (S) N ^{(R7), (R7)} NC (S) O, N (R ⁸⁾ C (O) N (R ^{7), (R7)} NC (O) N (R ^8), -N (R ⁸⁾ C (S) N ^{(R7), (R7)} NC (S) N (R ⁸⁾ S (O) , S (O) 2, S (O) 2 N (R ^7), N ^(R7) S (O) 2, P (O) ^(R8), -N (R ⁷⁾ P (O) (R ⁸⁾ , P (O) (R ⁸ ) N (R ⁷ ), N (R ⁷ ), ON (R ⁷ ), CR ^4a = CR ^4b , C = CR ^4a R ^4b and ethinylidene (OC,

1,2-ethynyl).

Y 0 is a group of formula IV:

(IV),

-27 where D ⁵ , D ⁶ , J ⁵ and J ⁶ are independently selected from the group consisting of C, N, O, S and a covalent bond, with the proviso that at most one of D ³ , D ⁶ , J ⁵ and J ⁶ is a covalent bond , K ² is independently selected from the group consisting of C and N ⁺ , at most one of D ⁵ , D ⁶ , J ⁵ and J ⁶ is O, at most one of D ⁵ , D ⁶ , J ⁵ and J ⁶ is S, one of ^{D5, D6, J5,} and ^J6 must be a covalent bond when two of ^{D3, D6, J5,} and ^J6 are O and S, and no more than three of ^{D5, D6, J5,} and ^J6 are N if K ² is N * and at most four of D ⁵ , D ⁶ , J ⁵ and J ⁶ are N if K ² is C with the proviso that R ¹⁶ , R ¹⁷ , R ¹⁸ and R ¹⁹ are each independently selected to maintain carbon tetravalence, nitrogen trivalent, sulfur bivalent and oxygen bivalent.

R ¹⁶ and R ¹⁷ are independently optionally joined to form a linear chain of 3 to 6 atoms joined to form a ring selected from the group consisting of a cycloalkenyl ring of 5 to 8 atoms and a partially saturated heterocyclic ring of 5 to 8 atoms, heteroaryl containing 5 to 8 atoms 6 atoms and aryl.

Q ^b is selected from NR ²⁰ R ^{21, +} NR ²⁰ R ^{2 I} R ^22, oxy, alkyl, aminoalkylenyl, alkylamino, dialkylamino, dialkylsulfoniumalkyl, acylamino and Q ^be wherein Q ^be is hydrido, and R ^20, R ^21, and R ²² are independently selected from the group consisting of hydrido, amino, alkyl, hydroxy, alkoxy, aminoalkenyl, alkylamino, dialkylamino and hydroxyalkyl, with the proviso that at most one of R ²⁰ , R ²¹ and R ²² is hydroxy, alkoxy, alkylamino, amino and dialkylamino simultaneously and that R ²⁰ , R ²¹ and R ²² may not be a hydroxy, alkoxy, alkylamino, amino or dialkylamino substituent when K ² is N ⁺ .

R ²⁰ and R ²¹ , R ²⁰ and R ²² and R ²¹ and R ²² are independently optionally selected to form a pair of arms, wherein the pair of arms together form a linear substituent containing 4 to 7 atoms joining the linking sites of said members of the pair of arms to form a heterocyclic a ring having 5 to 8 atoms, provided that at most one pair of a pair of arm pairs consisting of R ¹⁰ and R ²¹ , R ²⁰ and R ²² and R ²¹ and R ²² is used simultaneously.

Q ^b is optionally selected from the group consisting of N (R ²⁶ ) S (O) 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 , N (R ²⁶ ) C (S) SR ⁵ , provided that at most one of R ²³ , R ²⁴ and R ²⁶ is a hydroxy, alkoxy, alkylamino, amino and dialkylamino substituent when two of the group consisting of R ²³ , R ²⁴ and R ²⁶ bind to the same atom.

Q ^b is optionally selected from the group consisting of dialkylsulfonium, trialkylphosphonium, C (NR ²⁵ ) NR ²³ R ²⁴ , (NR ²⁶ ) C (NR ²⁵ ) N (R ²³ ) (R ²⁴ ), (NR ²⁶ ) C (O) N (R ²³ ) (R ²⁴ ), (NR 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 ), (NR ²⁶ ) (NR ²⁶ ) C (NR ²⁵ ) N (R ²³ ) (R ²⁴ ),

ON (R ²⁶ ) C (NR ²⁵ ) N (R ²³ ) (R ²⁴ ), (NR ²⁶ ) f NR ²⁶ ) SO ₂ (NR ²⁵ ) N (R ²³ ) (R ²⁴ ), C (NR ²⁵ ) SR ⁵ and

C (O) NR ²³ R ²⁴ provided that at most one of R ²³ , R ²⁴ and R ²⁶ may be hydroxy, alkoxy,

-28alkylamino, amino or dialkylamino substituent when two of R ²³ , R ²⁴ and R ²⁶ bind to the same atom and the Q ^b group is directly attached to a carbon atom.

R ²³ , R ²⁴ , R ²⁵ and R ²⁶ are independently selected from the group consisting of a hydrido, alkyl, hydroxy, alkoxy, aminoalkylenyl, alkylamino, dialkylamino, amino and hydroxyalkyl substituent.

R ²³ and R ²⁴ are optionally joined together to form a linear arm of 4 to 7 atoms, joining the linking sites of said members to a pair of arms to form a heterocyclic ring of 5 to 8 atoms.

Q ^s is selected from the group consisting of a single covalent bond a (CR ³⁷ R ³⁸ ) b (W% where az is an integer selected from 0 to 1, b is an integer selected from 1 to 4, and W ° is selected from containing O, S, C (O), C (O), C (O) O, C (O) O, C (O) O, C (O) S, C (O) N (R ¹⁴ ), ( R ^I4) NC (O), C (S) N ^{(R14), (R14)} 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⁾ C (O) N (R ^15), N (R ¹⁵⁾ C (S) N (R ¹⁴⁾ (R ^I4) NC (S) N (R ¹⁵⁾ S (O), S (O) 2, S (O) 2 N (R ^14), N (R ¹⁴⁾ S (O) 2, P (O) ^(R8), -N (R ⁷⁾ P (O) ^(R8), P (O) ^(R8) N ^(R7), N (R ¹⁴ ), ON (R ¹⁴ ), (CH (R ¹⁴ )) c-W '- (CH (R ¹⁵ )) d where c and d are integers selected from 1 to 4 and W ¹ is selected from the group consisting of O, S, C (O), C (O), C (O) O, C (O) O, C (O) O, C (S) O, 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), SC (S) N ( R ( ¹⁴ ), (R ( ¹⁴ )), NC (S), SC (O), N (R, ¹⁴ ), (R, ¹⁴ ), NC (O), OC (S), N (R, ¹⁴ ), (R, ¹⁴ ) 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 ^{, 4} ) N (R) 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 ), ON (R ¹⁴ ), (CH (R ¹⁴⁾ ) _e -W ²² - (CH (R ¹⁵ )) h where eah are integers selected from 0 to 2 and W ²² is selected from the group consisting of CR ^41I = CR ⁴² , CR ⁴¹ R ⁴² = C (vinylidene), ethynylidene (C1-C4; 1,2-ethynyl), 1,2-cycloprop yl, 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-tetrahydrofuranyl, provided that R ¹⁴ and R ¹⁵ are not halogen and cyano substituents when they are bound directly to N and that (CR ³⁷ R ³⁸ ) b, (CH (R ¹⁴ )) c and (CH (R ¹⁴ )) _e directly bind to E °

Y 0 is optionally Q ^h -Q ^ss wherein Q ^ss is selected from the group consisting of (CR ³⁷ R ³⁸ ) f wherein f is an integer from 1 to 6, (CH (R ¹⁴ )) c-W '- (CH ( R ¹⁵ )) d wherein c and d are integers independently selected from 1 to 4 and W ¹ is selected from the group consisting of 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 4)} C (O) O, SC (S) N (R ¹⁴⁾ (R ^I4) NC (S) S, SC (O) N (R ¹⁴ ), ^(R14) NC (O) S, OC (S) N (R ^14),

-29 (R ¹⁴ ) NC (S) N (R ¹⁵ ) C (O) N (R ¹⁴ ) N (R ¹⁴ ) NC (O) N (R ¹⁵ ) N (R ¹⁵ ) C (S) N (R ¹⁴ ), (R ¹⁴ ) NC (S) N (R ¹⁵ ), S (0), S (O) 2, S (O) 2 N (R ¹⁴ ), N (R ¹⁴ ) S (O) 2, P (O) ^(R8), -N (R ⁷⁾ P (O) ^(R8), P (O) ^(R8) N ^(R7), N ^(R14), ON ^(R14) and (CH (R ¹⁴ )) _e -W ² - (CH (R ¹⁵ )) h where eah are integers selected from 0 to 2 and W ² is selected from the group consisting of CR ^4a = CR ^4b , C = CR ^4a R ^4b (vinylidene) and ethinylidene (C = C;

With the proviso that R ¹⁴ and R ¹⁵ are not halogen and cyano substituents as long as they bind directly to N, and that (CR ³⁷ R ³⁸ ) f, (CH (R ¹⁴ )) ca (CH (R ¹⁴ ) e) directly bind to E °.

Y 0 is optionally Q ^b -Q ^sss wherein Q ^sss is (CH (R ³⁸ )) _r -W ³ where r is an integer independently 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, 1,2cyclopentyl, 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-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-pyran-2-one-3,4-yl, 2H-pyran-2-one-4,5-yl, 4H-pyran-4-one-2,3-yl, 2,3- tetrahydrofuranyl, 2,4-tetrahydrofuranyl, 2,5-tetrahydrofuranyl, 3,4-tetrahydropyranyl, 2,3-tetrahydropyranyl, 2,4-tetrahydropyranyl, 2,5-tetrahydropyranyl, 2,6-tetrahydropyranyl, 3,4-tetrahydropyranyl, 3,5- tetrahydropyranyl and all nitrogen atoms in ring W ³ with carbon and hydride substituents other than at the binding site are optionally substituted with one or more substituents from R ⁹ , R ¹⁰ , R ¹¹ and R ¹² , provided that (CH (R ³⁸ )) _r binds to E ° and Q ^b binds to the position with the lowest sequence number for each W ³ .

Y 0 is optionally Q ^b -Q ^sssr wherein Q ^sssr is (CH (R ³⁸ )) _r -W ⁴ where r is an integer independently selected from 1 to 3 and W ⁴ is selected from the group consisting of 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-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-pyran-2-one-3,4-yl, 2H-pyran-2-one-4,5- yl, 4H-pyran-4-one-2,3-yl, 2,3-tetrahydrofuranyl,

2,4-tetrahydrofuranyl, 2,5-tetrahydrofuranyl, 3,4-tetrahydrofuranyl, 2,3-tetrahydropyranyl,

-302.4-tetrahydropyranyl, 2,5-tetrahydropyranyl, 2,6-tetrahydropyranyl, 3,4-tetrahydropyranyl,

3,5-tetrahydropyranyl and all nitrogen atoms in ring W ⁴ with carbon and hydride substituents other than at the binding site are optionally substituted with one or more substituents from R ⁹ , R ¹⁰ , R ¹¹ and R ¹² , provided that (CH (R ³⁸⁾ 1) _r binds to E ° and Q ^b binds to the position with the highest serial number for each W ⁴ .

Y 0 is optionally Q ^b -Q ^ssss wherein Q ^ssss is (CH (R ³⁸ )) _r -W ⁵ where r is an integer independently selected from 1 to 3 and W ⁵ is selected from the group consisting of 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, 3,5indenyl, 3,6-indenyl, 3,7-indenyl, 2,4-benzofuranyl, 2,5-benzofuranyl, 2,6-benzofuranyl, 2,7-benzofuranyl, 3,4-benzofuranyl, 3,5-benzofuranyl, 3,6- benzofuranyl, 3,7-benzofuranyl, 2,4-benzothiophenyl, 2,5-benzothiophenyl, 2,6-benzothiophenyl, 2,7-benzothiophenyl, 3,4-benzothiophenyl,

3,5-benzothiophenyl, 3,6-benzothiophenyl, 3,7-benzothiophenyl, 2,7-imidazo (1,2-a) pyridinyl, 3,4imidazo (1,2-a) pyridinyl, 3,5-imidazo (1) , 2-a) pyridinyl, 3,6-imidazo (1,2-a) pyridinyl, 3,7-imidazo (1,2-a) pyridinyl, 2,4-indonyl, 2,5-indonyl, 2,6-indonyl , 2,7-indonyl, 3,4-indonyl, 3,5-indonyl, 3,6-indonyl, 3,7-indonyl, 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, 3,5indazolyl, 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, 2,8-quinolinyl, 3,4-quinolinyl, 3,5-quinolinyl, 3,6-quinolinyl, 3 , 7-quinolinyl, 3,8-quinolinyl, 4,5-quinolinyl, 4,6-quinolinyl, 4,7-quinolinyl, 4,8-quinolinyl, 1,4-isoquinol ynyl,

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-cinolinyl, 3,5-cinolinyl, 3,6-cinolinyl, 3,7-cinolinyl, 3,8-cinolinyl, 4,5-cinolinyl, 4,6-cinolinyl, 4,7-cinolinyl, 4,8-cinolinyl and all nitrogen atoms in the ring W ⁵ with carbon and hydride substituents other than at the binding site are optionally substituted with one or more substituents from R ⁹ , R ¹⁰ , R ¹¹ and R ¹² provided that (CH (R ³⁸ )) _r binds to E ° and Q ^b binds to the position with the lowest sequence number for each W \

Y 0 is optionally Q ^b -Q ^ssssr wherein Q ^ssssr is (CH (R ³⁸ jr-W ⁶ where r is an integer independently selected from 1 to 3 and W ⁶ is selected from the group consisting of 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-benzofuranyl, 2,5-benzofuranyl, 2,6-benzofuranyl, 2,7-31 benzofuranyl, 3,4-benzofuranyl, 3,5-benzofuranyl, 3,6-benzofuranyl, 3 , 7-benzofuranyl, 2,4-benzothiophenyl, 2,5-benzothiophenyl, 2,6-benzothiophenyl, 2,7-benzothiophenyl, 3,4-benzothiophenyl,

3,5-benzothiophenyl, 3,6-benzothiophenyl, 3,7-benzothiophenyl, 2,7-imidazo (1,2-a) pyridinyl, 3,4-imidazo (1,2-a) pyridinyl, 3,5-imidazo (1,2-a); 2-a) pyridinyl, 3,6-imidazo (1,2-a) pyridinyl, 3,7-imidazo (1,2-a) pyridinyl, 2,4-indonyl, 2,5-indonyl, 2,6-indonyl, 2,7-indonyl, 3,4-indonyl, 3,5-indonyl, 3,6-indonyl, 3,7-indonyl, 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, 3,5indazolyl, 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, 2,8-quinolinyl, 3,4-quinolinyl, 3, 5-quinolinyl, 3,6-quinolinyl, 3,7-quinolinyl, 3,8-quinolinyl, 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-cinolinyl, 3,5-cinolinyl, 3,6-cinolinyl, 3,7-cinolinyl, 3,8-cinolinyl, 4,5-cinolinyl, 4,6-cinolinyl, 4,7-cinolinyl, 4,8-cinolinyl and all nitrogen atoms in the W ⁶ ring with carbon and hydride substituents other than at the binding site are optionally substituted by one or more substituents from R ⁹ , R ¹⁰ , R ¹¹ and R ¹² , provided that (CH (R ³⁸ )) _r binds to E 0 and Q ^b binds to the position with the highest serial number for each W ⁶ .

A further embodiment of the invention provides a compound of formula I or a pharmaceutically acceptable salt thereof:

J is selected from the group consisting of O and S,

B is a compound of formula V

wherein D ¹ , D ² , J ¹ , J ² and K ¹ are independently selected from the group consisting of C, N, O, S and covalent bonds, with the proviso that the covalent bond may be selected only once, at most one of D ¹ , D ² ,

-32J ', J ² and K ¹ is O, at most one of D ¹ , D ² , J ¹ , J ² , and K' is S, one of D ¹ , D ² , J ¹ , J ² and K ¹ must be a covalent bond as long as two of D ¹ , D ² , J ¹ , J ² and K ¹ are O and S 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 the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, dialkylsulfonium, trialkylphosphonium, dialkylsulfoniumalkyl, carboxy, heteroaralkylthio, heteroaralkoxy, cycloalkylamino, acylalkyl, acylalkoxy, aryloxylalkoxy, heterocyclyloxy, aralkylaryl, aralkyl, aralkenyl, aralkynyl, heterocyclyl, perhalogénaralkyl, aralkyl, Aralkylsulfonylalkyl, aralkylsulfinyl, Aralkylsulfinylalkyl, halocycloalkyl, halogéncykloalkenyl, cycloalkylsulfinyl, Cycloalkylsulfinylalkyl, cycloalkylsulfonyl, Cycloalkylsulfonylalkyl, heteroarylamino, N-heteroarylamino, N-alkylamino, heteroarylaminoalkyl, haloalkylthio, alkanoyloxy, alkoxy, alkoxyalkyl, haloalkoxyalkyl, heteroaralkoxy, cycloalkoxy, cycloalkenyloxy, cycloalkoxyalkyl, cycloalkylalkoxy, cycloalkenyloxyalkyl, cycloalkylenedioxy, halogéncykloalkoxy, halogéncykloalkoxyalkyl, halogéncykloalke nyloxy, halocycloalkenyloxyalkyl, hydroxy, amino, alkoxyamino, thio, nitro, lower alkylamino, alkylthio, alkylthioalkyl, arylamino, aralkylamino, arythioalkyl, heteroaralkoxyalkyl, alkylsulfinyl, alkylsulfinylalkyl, arylsulfinylalkyl, arylsulfinylalkyl, arylsulfonylalkyl, arylsulfonylalkyl, arylsulfonylalkyl, arylsulfonylalkyl, , alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, monoarylamidosulfonyl, arylsulfonamido, · diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl, arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, heterocyclylsulfonyl, heterocyclylthio, alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, haloalkanoyl, alkyl, alkenyl, alkynyl, alkenyloxy, alkenyloxyalkyl, alkylenedioxy, haloalkylenedioxy, cycloalkyl, cycloalkylalkanoyl, cycloalkenyl, lower cycloalkylalkyl, lower cycloalke nylalkyl, halogen, haloalkyl, haloalkenyl, haloalkoxy, hydroxyhaloalkyl, hydroxyaralkyl, hydroxyalkyl, alkylenylamino, hydroxyheteroralkyl, haloalkoxyalkyl, aryl, aralkyl, aryloxy, aralkoxy, aryloxyalkyl, saturated heterocyclyl, partially heteroaryl, heteroalkyl, heteroaryl, heterocyclyl, heteroaryl, , heterorylalkenyl, carboxyalkyl, carboalkoxy, alkoxycarboxamido, alkylamidocarbonylamido, arylamidocarbonylamido, carboalkoxyalkyl, carboalkoxyalkenyl, carboxy, carboaralkoxy, carboxamidoalkyl, carboxamidoalkyl, cyano, carbohalogenoalkoxy, phosphono, phosphono, phosphono, phosphono, phosphono, phosphono.

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

B is optionally selected from the group consisting of hydrido, trialkylsilyl, C 2 -C 8 alkyl, C 3 -C 8 alkylenyl, C 3 -C 8 alkenyl, C 3 -C 8 alkynyl, C 2 -C 8 haloalkyl and C 3 -C 8 haloalkenyl, wherein each member of group B may be optionally substituted on any a carbon atom of up to 6 atoms including from the B to A bonding site with one or more substituents from R ³² , R ³³ , R ³⁴ , R ³⁵ and R ³⁶ .

B is optionally selected from the group consisting of C 3 -C 12 cycloalkyl, C 5 -C 10 cycloalkylenyl, C 4 -C 9 saturated heterocyclyl wherein each ring carbon atom is optionally substituted with R ³³ , the ring carbon atom other than the carbon atom in the B bond site at A is optionally substituted by an oxo group such that at most one carbon atom in the ring is substituted by an oxo group at the same time, the carbon atom and the nitrogen atom adjacent to the carbon at the B-bonding point A are optionally substituted by R ⁹ or R ¹³ ; to the R ⁹ position and two atoms distant from the point of attachment are optionally substituted with R ¹⁰ , a carbon or nitrogen atom adjacent to the R ¹³ position and two atoms distant from the point of attachment are optionally substituted with R, carbon or nitrogen atom three points from the point of attachment and adjacent to the R ¹⁰ position is optionally substituted with R ¹¹ , a carbon atom or a nitrogen atom three atoms away from the m The point of attachment and adjacent to the R ¹² position is optionally substituted with R ³³ and a carbon or nitrogen atom spaced four atoms from the point of attachment and adjacent to the R ¹¹ and R ³³ positions is optionally substituted with R ³⁴ .

A is selected from the group consisting of a covalent bond, (W 1, CH 2 R ¹⁵ ) ^ and (CH (R ¹⁵ )) p a - (W ⁷ ) t T where rr is an integer from 0 to 1, pa is an integer selected from 0-6 and W ⁷ is selected from the group consisting of O, S, C (O), C (O) N (R ⁷ ), C (S) N (R ⁷ ), (R ⁷ ) NC (O), ( R ⁷ ) NC (S) and NR ⁷ with the proviso that at most one substituent containing rr and pa may be 0 at the same time.

R ⁷ and R ⁸ are independently selected from the group consisting of hydrido, hydroxy, alkyl and alkoxyalkyl,

R ¹⁴ , R ¹⁵ , R ³⁷ and R ³⁸ are independently selected from the group consisting of hydrido, hydroxy, halogen, alkyl, alkoxyalkyl, haloalkyl, haloalkoxy and haloalkoxyalkyl.

R ¹⁴ and R ³⁸ are independently selected from the group consisting of aroyl and heteroaroyl.

Ψ is selected from the group consisting of NR ⁵ , C (O), S (O) 2.

R ³ is selected from the group consisting of hydrido, hydroxy, alkyl and alkoxy.

R ³⁹ and R ⁴⁰ are independently selected from the group consisting of hydrido, hydroxy, halogen, hydroxyalkyl, alkyl, alkoxyalkyl, haloalkyl, haloalkoxy, haloalkoxyalkyl.

-34M is selected from the group consisting of N and R’-C.

R ¹ is optionally selected from the group consisting of hydrido, alkyl, alkenyl, cyano, halogen, haloalkyl, haloalkoxy, haloalkylthio, amino, aminoalkyl, alkylamino, amidino, guanidino, hydroxy, hydroxyamino, alkoxy, hydroxyalkyl, alkoxyamino, thiol, alkylthio and phosphono.

R ^{2 is} Z ° -Q.

Z ° is selected from the group consisting of a single covalent bond, (CR ⁴¹ R ⁴² ) q where q is an integer from 1 to 3, (CH (R ⁴ ')) g W ° - (CH (R ⁴² )) where the gap is an integer numbers from 0 to 3 and W 0 are selected from the group consisting of O, S, C (O), S (O), S (O) 2 N (R ⁴ ') and ON (R ⁴¹ ) and (CH (R ¹⁴⁾ )) _e -W ²² - (CH (R ⁴²⁾⁾ h wherein e and h are integers independently selected from 0 to 2, and W ²² is selected from CR ⁴¹ = CR ^42, 1,2-cyclopropyl, 1,2 -cyclobutyl, 1,2cyclohexyl, 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-tetrahydrofuranyl, provided that Z 0 binds directly to the pyrimidinone ring.

R ⁴¹ and R ⁴² are independently selected from the group consisting of amidino, hydroxyamino, hydrido, hydroxy, amino and alkyl.

Q is selected from the group consisting of hydrido with the proviso that Z 0 must not be a single covalent bond, formula II.

wherein D ¹ , D ² , J ¹ , J ² and K ¹ are independently selected from the group consisting of C, N, O, S and a covalent bond, with the proviso that the covalent bond may be selected only once, at most one of D ¹ , D ² , J ¹ , J ² and K ¹ is O, at most one of D ¹ , D ² , J ¹ , J ² , and K ¹ is S, one of D ¹ , D ² , J ¹ , J ² and K ¹ must be a covalent bond as long as two of D ¹ , D ² , J ¹ , J ² and K ¹ are O and S and at most four of D ¹ , D ² , J ¹ , J ² and K ¹ are N, provided that R ⁹ , R ¹⁰ , R ¹¹ , R ¹² and R ¹³ are each independently selected to maintain carbon tetravalence, nitrogen trivalent, sulfur bivalent and oxygen bivalent.

-35K is (CR ⁴¹ R ^4b ) _n wherein n is an integer from 1 to 2. R ^4a and R ^4b are independently selected from the group consisting of alkyl, alkoxyalkyl, alkylthioalkyl, and haloalkyl.

E 0 is selected from the group consisting of single

C (O) N (R ⁷ ), (R ⁷ ) NC (O), S (O) 2, (R ⁷ ) NS (O) 2, S (O) ₂ N (R ⁷ ).

Y 0 is a group of formula (IV) halogen, hydrido, hydroxyalkyl, a C (O), C (S) covalent bond,

(IV), wherein D ⁵ , D ⁶ , J ³ and J ⁶ are independently selected from the group consisting of C, N, O, S and a covalent bond, with the proviso that at most one of D ⁵ , D ⁶ , J ⁵ and J ⁶ is a covalent bond, K ² is C, at most one of D ⁵ , D ⁶ , J ⁵ and U is O, at most one of D ⁵ , D ⁶ , J ⁵ and J ⁶ is S, one of D ⁵ , D ⁶ , J ⁵ and J ⁶ must be a covalent bond if two of D ⁵ , D ⁶ , J ⁵ and J ⁶ are O and S and at most four of D ³ , D ⁶ , J ³ and J ⁶ are N if K ² is With the proviso that R ¹⁶ , R ¹⁷ , R ¹⁸ and R ¹⁹ are each independently selected to maintain carbon tetravalence, nitrogen trivalent, sulfur bivalent and oxygen bivalent.

Q ^b is selected from the group consisting of NR ²⁰ R ²¹ , ^H NR ²⁰ R ²¹ R ²² , aminoalkylenyl and Q ^be , wherein Q ^be is hydrido and R ²⁰ , R ²¹ and R ²² are independently selected from hydrido, alkyl, hydroxy , amino, aminoalkenyl, alkylamino, dialkylamino and hydroxyalkyl, provided that at most one of R ²⁰ and R ²¹ is hydroxy, amino, alkylamino or dialkylamino simultaneously.

Q ^b is optionally selected from the group consisting of dialkylsulfonium, trialkylphosphonium, C (NR ²³ ) NR ²³ R ²⁴ , (NR ²⁶ ) C (NR ²³ ) N (R ²³ ) (R ²⁴ ), C (O) N (R ²⁶ ) C (NR ²³ ) N (R ²³ ) (R ²⁴ )

N (R ²⁶ ) N (R ²⁶ ) C (NR ²³ ) N (R ²³ ) (R ²⁴ ) and ON (R ²⁶ ) C (NR ²⁵ ) N (R ²³ ) (R ²⁴ ), provided that not more than one of R ²³ , R ²⁴ and R ²⁶ may be a hydroxy, alkylamino, amino or dialkylamino substituent as long as two of the groups R ²³ , R ²⁴ and R ²⁶ bind to the same atom.

R ²³ , R ²⁴ , R ²³ and R ²⁶ are independently selected from the group consisting of a hydrido, alkyl, hydroxy, amino, alkylenylamino, dialkylamino, alkylamino and hydroxyalkyl substituent.

Q ^s is selected from the group consisting of a single covalent bond, (CR ³⁷ R ³ 'MW ") azi where az is an integer selected from 0 to 1, b is an integer selected from 1 to 5, and W ° is selected from containing O, C (O), S (O), S (O) ₂ , S (O) ₂ N (R ¹⁴ ), N (R ¹⁴ ) S (O) ₂ and N (R ¹⁴ ),

- 36 (CH (R ¹⁴ )) _c -W '- (CH (R ¹⁵ )) and wherein c and d are integers selected from 1 to 4 and W ¹ is selected from the group consisting of O, S, C (O), C (S), C (O) O, C (O) O, C (O) O, C (S) O, C (O) O (R ¹⁴ ), (R ¹⁴ ) NC (O), C (O) S (N ¹⁴ ), (R ¹⁴ ) NC (S), OC (O) N (R ¹⁴ ), (R ¹⁴ ) NC (O) O, SC (S) N (R ¹⁴ ), (R ¹⁴⁾ ) NC (S), SC (O) N (R ¹⁴ ), (R ¹⁴ ) NC (O) S, OC (S) N (R ¹⁴ ), (R ¹⁴ ) 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) 2, 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 ), ON (R ¹⁴ ) and (CH (R ¹⁴ )) _e -W ²² (CH ( R)) h where eah are integers selected from 0 to 2 and W is selected from the group consisting of CR ⁴¹ = CR ⁴² , CR ⁴¹ R ⁴² = C (vinylidene), ethinylidene (C = C, 1,2-ethynyl) 1,2-cyclopropyl, 1,2-cyclobutyl, 1,2-cyclohexyl, 1,3-cyclohexyl, 1,2-cyclopentyl, 1,3cyclopentyl, 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-tetrahydrofuranyl; with the proviso that R ¹⁴ and R ¹⁵ are not halogen and cyano substituents when they bind directly to N, and that (CR ³⁷ R ³⁸ ) b, (CH (R ¹⁴ )) c and (CH (R ¹⁴ )) e directly bind to E °

Y 0 is optionally Q ^b -Q ^ss wherein Q ^ss is selected from the group consisting of (CR ³⁷ R ³⁸ ) f wherein f is an integer from 1 to 4, (CH (R ¹⁴ )) e -W '- (CH ( R ¹⁵⁾⁾ j wherein c and d are integers independently selected from 1 through 2, and W ¹ is selected from O, S, C (O), C (O) N ^{(R14), (R14)} NC ( O), N (R ¹⁵ ), C (O) N (R ¹⁴ ), (R ¹⁴ ) NC (O) N (R ¹⁵ ), N (R ¹⁴ ), ON (R ¹⁴ ), and (CH (R ¹⁴ ) ) eW ² (CH (R ¹⁵ )) h where eah are integers selected from 0 to 2 and W ² is selected from the group consisting of CR ^4a = CR ^4b , C = CR ^4a R ^4b (vinylidene) and ethinylidene (C = C, 1,2-ethynyl) with the proviso that R ¹⁴ and R ¹⁵ are not halogen substituents as long as they bind directly to N, and that (CR ³⁷ R ³⁸ ) f, (CH (R ¹⁴ )) ea (CH ( R ¹⁴ ) e directly bind to E 0.

Y 0 is optionally Q ^b -Q ^sss wherein Q ^sss is (CH (R ³⁸ )) _r -W ³ where r is an integer independently selected from 1 to 2 and W ³ is selected from the group consisting of 1,1-cyclopropyl, 1,2-cyclopropyl, 1,1-cyclobutyl, 1,2-cyclobutyl, 1,2-cyclohexyl, 1,3-cyclohexyl, 1,4-cyclohexyl, 1,2cyclopentyl, 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-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-pyran-2-one-3,4-yl, 2H-pyran-2-one-4,5-yl, 4H-37-pyran-4-one-2,3-yl, 2, 3-tetrahydrofuranyl, 2,4-tetrahydrofuranyl, 2,5-tetrahydrofuranyl, 3,4tetrahydrofuranyl, 2,3-tetrahydropyranyl, 2,4-tetrahydropyranyl, 2,5-tetrahydropyranyl, 2,6tetrahydropyranyl, 3,4-tetrahydropyranyl, 3, The 5-tetrahydropyranyl and all nitrogen atoms in the W ³ ring with carbon and hydride substituents other than at the binding site are optionally substituted by one or more substituents and bind to the position with the lowest sequence number for each W ³ .

Y 0 is optionally Q ^b -Q ^sssr wherein Q ^sssr is (CH (R ³⁸ )) _r -W ⁴ where r is an integer independently selected from 1 to 2 and W ⁴ is selected from the group consisting of 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-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-pyran-2-one-3,4-yl, 2H-pyran-2-one-4,5-yl, 4H-pyran-4-one-2,3-yl, 2,3- tetrahydrofuranyl, 2,4-tetrahydrofuranyl; 2,5-tetrahydrofuranyl, 3,4-tetrahydrofuranyl, 2,3-tetrahydropyranyl, 2,4-tetrahydropyranyl, 2,5-tetrahydropyranyl, 2,6-tetrahydropyranyl, 3,4-tetrahydropyranyl, 3,5-tetrahydropyranyl and all nitrogen atoms in ring W ⁴ with carbon and hydride substituents other than at the binding site are optionally substituted by one or more substituents from R ⁹ , R ¹⁰ , R ¹¹ and R ¹² , provided that (CH (R ³⁸ )) _r is bound to E ° and Q ^b is bound to the position with the highest serial number for each W ⁴ .

Y 0 is optionally Q ^b -Q ^ssss wherein Q ^ssss is (CH (R ³⁸ )) _r -W ⁵ where r is an integer independently selected from 1 to 2 and W ⁵ is selected from the group consisting of 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, 3,5indenyl, 3,6-indenyl, 3,7-indenyl, 2,4-benzofuranyl, 2,5-benzofuranyl, 2,6-benzofiiranyl, 2,7-benzofuranyl, 3,4-benzofuranyl, 3,5-benzofuranyl, 3,6 -benzofuranyl, 3,7-benzofuranyl, 2,4-benzothiophenyl, 2,5-benzothiophenyl, 2,6-benzothiophenyl, 2,7-benzothiophenyl, 3,4-benzothiophenyl,

3,5-benzothiophenyl, 3,6-benzothiophenyl, 3,7-benzothiophenyl, 2,7-imidazo (1,2-a) pyridinyl, 3,4imidazo (1,2-a) pyridinyl, 3,5-imidazo ( 1,2-a) pyridinyl, 3,6-imidazo (1,2-a) pyridinyl, 3,7-imidazo (1,2-a) pyridinyl, 2,4-indonyl, 2,5-indonyl, 2,6- indonyl, 2,7-indonyl, 3,4-indonyl, 3,5-indonyl, 3,6-indonyl, 3,7-indonyl, 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, 3,5indazolyl, 3,6-indazolyl, 3,7-indazolyl, 2, 4-benzoxazolyl, 2,5-benzoxazolyl, 2,6-38benzoxazolyl, 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, 2,8-quinolinyl, 3,4-quinolinyl, 3, 5-quinolinyl, 3,6-quinolinyl, 3,7-quinolinyl, 3,8-quinolinyl, 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-cinolinyl, 3,5-cinolinyl, 3,6-cinolinyl, 3,7-cinolinyl, 3,8-cinolinyl, 4,5-cinolinyl, 4,6-cinolinyl, 4,7-cinolinyl, 4,8-cinolinyl and all nitrogen atoms in the W ⁵ ring with carbon and hydride substituents other than at the binding site are optionally substituted with one or more substituents from R ⁹ , R ¹⁰ , R ¹¹ and R ¹² , provided that (CH (R ³⁸ )) _r binds to E 0 and Q ^b binds to the position with the lowest order number for each W ⁵ .

Y 0 is optionally Q ^{b -} Q ssssr ^k Q _e ^Ssssr is (CH (R ³⁸ jr-W ⁶ where r is an integer independently selected from interval 1 to 2 and W ⁶ is selected from the group consisting of 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-benzofuranyl, 2,5-benzofuranyl, 2,6-benzofuranyl, 2,7-benzofuranyl, 3,4-benzophiranyl, 3,5-benzofuranyl, 3,6-benzofuranyl, 3,7- benzofuranyl, 2,4-benzothiophenyl, 2,5-benzothiophenyl, 2,6-benzothiophenyl, 2,7-benzothiophenyl, 3,4-benzothiophenyl,

3,5-benzothiophenyl, 3,6-benzothiophenyl, 3,7-benzothiophenyl, 2,7-imidazo (1,2-a) pyridinyl, 3,4-imidazo (1,2-a) pyridinyl, 3,5-imidazo (1, 2-a); 2-a) pyridinyl, 3,6-imidazo (1,2-a) pyridinyl, 3,7-imidazo (1,2-a) pyridinyl, 2,4-indonyl, 2,5-indonyl, 2,6-indonyl, 2,7-indonyl, 3,4-indonyl, 3,5-indonyl, 3,6-indonyl, 3,7-indonyl, 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, 3,5indazolyl, 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, 2,8-quinolinyl, 3,4-quinolinyl, 3,5- quinolinyl, 3,6-quinolinyl, 3,7-quinolinyl, 3,8-quinolinyl, 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-cinolinyl, 3,5-cinolinyl, 3,6-cinolinyl, 3,7-cinolinyl, 3,8-cinolinyl, 4,5-cinolinyl, 4,6-cinolinyl, 4,7-cinolinyl, 4,8-cinolinyl

-39a any ring nitrogen atoms of ⁶ W and a carbon hydride substituents other than at the point are optionally substituted by one or more substituents of the group R ^9, R ^10, R ¹¹ and R ¹² with the proviso that (CH ^(R38)) _r binds to E ° and Q ^b binds to the position with the highest serial number for each W ⁶ .

A preferred embodiment of the invention includes compounds of formula I or pharmaceutically acceptable salts thereof:

J is O.

B is a group of the formula:

R ^{3 4}

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 the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkylenedioxy, haloalkylthio, alkanoyloxy , alkoxy, alkoxyalkyl, haloalkoxyalkyl, hydroxy, amino, alkoxyamino, nitro, lower alkylamino, alkylthio, alkylthioalkyl, alkylsulfonyl, alkylsulfonyl, alkylsulfonylalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, alkylsulfonamido, alkylaminosulfonyl, dialkyl aminosulfosulfonyl, amidosulfosulfonyl, amidosulfosulfonyl, amidosulfosulfonyl, amidosulfosulfonyl, amidosulfosulfonyl, , haloalkanoyl, alkyl, alkenyl, halogen, haloalkyl, haloalkenyl, haloalkoxy, hydroxyhaloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxyalkyl, carboxyalkyl, carboalkoxy, carboxy, carboxamido, carboxamidoalkyl and cyano.

R ⁹ , R ¹⁰ , R ¹¹ , R ¹² and R ¹³ are optionally selected from heteroaryl and heterocyclyl, provided that R ⁹ , R ¹⁰ , R ¹¹ , R ¹² and R ¹³ are not substituents for B.

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

B is optionally selected from the group consisting of hydrido, trialkylsilyl, C 2 -C 8 alkyl, C 3 -C 8 alkylenyl, C 3 -C 8 alkenyl, C 3 -C 8 alkynyl and C 2 -C 8 haloalkyl, wherein each member of group B can be optionally substituted on any carbon atom up to 6 atoms including from the B to A bonding site by one or more substituents from R ³² , R ³³ , R ³⁴ , R ³⁵ and R ³⁶ .

B is selected from the group consisting of C3-C12 cycloalkyl and C4-heterocyclyl wherein each ring carbon atom is optionally substituted with ^R33 , a ring carbon atom other than a carbon atom

-40 at the binding site B to A is optionally substituted with an oxo group so that at most one carbon atom in the ring is substituted by the oxo group simultaneously, the carbon atom and the nitrogen atom adjacent to the carbon at the binding site B to A are optionally substituted with R ⁹ or R ¹³ , the carbon or nitrogen atom adjacent to the R ⁹ position and two atoms away from the point of attachment is optionally substituted with R ¹⁰ , the carbon or nitrogen atom adjacent to the R ¹³ position and two atoms away from the point of attachment is optionally substituted with R ¹² , a carbon atom or a nitrogen atom three atoms away from the point of attachment and adjacent to the R ¹⁰ position is optionally substituted with R ¹¹ , a carbon atom or nitrogen atom three atoms away from the point of attachment, and adjacent to the R ¹² position is optionally substituted with R ³³ and a carbon atom or nitrogen atom four atoms from the point of attachment and adjacent to the R ¹¹ and R ³³ positions are optionally substituted with R ³⁴ .

A is selected from the group consisting of a covalent bond, (W) rr - (CH (R)) _pa and (CH (R ¹⁵ )) _pa - (W ⁷ ) n · wherein rr is an integer from 0 to 1, pa is an integer selected from 0 to 6 and W ⁷ is selected from the group consisting of O, S, C (O), (R ⁷ ) NC (0), (R ⁷ ) NC (S) and NR ⁷ , provided that at most one substituent containing rr and pa may be 0 at the same time.

R ⁷ is independently selected from the group consisting of hydrido, hydroxy and alkyl.

R ¹⁵ is independently selected from the group consisting of hydrido, hydroxy, halogen, alkyl, and haloalkyl.

Ψ is selected from the group consisting of ΝΉ and NOH.

M is selected from the group consisting of N and R * -C.

R ¹ is selected from the group consisting of hydrido, alkyl, alkenyl, cyano, halogen, haloalkyl, haloalkoxy, haloalkylthio, amino, aminoalkyl, akylamino, amidino, hydroxy, hydroxyamino, alkoxy, hydroxyalkyl, alkoxyamino, thiol, alkylthio.

R ^{2 is} Z ° -Q.

Z ° is selected from the group consisting of a single covalent bond, (CR ⁴¹ R ⁴² ) qkde q is an integer from 1 to 3, (CH (R ⁴¹ )) g W ° - (CH (R ⁴² )) pkde gap are integers from 0 to 3 and W 0 is selected from the group consisting of O, S, C (O), C (S), S (O), N (R ⁴¹ ) and 0N (R ⁴¹ ) and (CH (R ⁴¹ )) W ²² - (CH (R ⁴² )) h wherein eah are integers independently selected from 0 to 1 and W ²² is selected from the group consisting of CR ^41I = CR ⁴² , 1,2-cyclopropyl, 1,2-cyclobutyl, 1,2cyclohexyl, 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, 2,5-41 tetrahydrofuranyl and 3,4-tetrahydrofuranyl, provided that Z 0 is directly attached to the pyrimidinone ring.

42 ',

R and R are independently selected from the group consisting of amidino, hydroxyamino, hydrido, amino and alkyl.

Q is selected from the group consisting of hydrido, with the proviso that Z 0 is not a single covalent bond, and formula II

wherein D ¹ , D ² , J ¹ , J ² and K ¹ are independently selected from the group consisting of C, N, O, S and a covalent bond, with the proviso that the covalent bond may be selected only once, at most one of D ¹ , D ² , J ¹ , J ² and K ¹ is O, at most one of D ¹ , D ² , J ¹ , J ² , and K ¹ is S, one of D ¹ , D ² , J ¹ , J ² and K ¹ must be a covalent bond as long as two of D ¹ , D ² , J ¹ , J ² and K ¹ are O and S and at most four of D ¹ , D ² , J ¹ , J ² and K ¹ are N, provided that R ⁹ , R ¹⁰ , R ¹¹ , R ¹² and R ¹³ are each independently selected to maintain carbon tetravalence, nitrogen trivalent, sulfur bivalent and oxygen bivalent.

K is (CR ^4a R ^4b ) _n where n is an integer from 1 to 2.

R ^4a and R ^4b are independently selected from the group consisting of halogen, hydrido, hydroxyalkyl, alkyl, alkoxyalkyl, alkylthioalkyl, and haloalkyl.

E 0 is E ¹ when K is (CR ^4a R ^4b ) _n , wherein E ¹ is selected from the group consisting of a single covalent bond, C (O), C (S), C (O) N (R ⁷ ), (R ⁷ ), ⁷ ) NC (O), S (O) 2, (R ⁷ ) NS (O) 2, S (O) ₂ N (R ⁷ ).

Y 0 is a group of formula IV:

, 17, 1S (IV),

RR ^y wherein D ⁵ , D ⁶ , J ⁵ and J ⁶ are independently selected from the group consisting of C, N, O, S and a covalent bond, with the proviso that at most one of D ⁵ , D ⁶ , J ⁵ and J ⁶ is covalent bond. K ² is C, at most one of D ⁵ , D ⁶ , J ⁵ and J ⁶ is O, at most one of D ⁵ , D ⁶ , J ⁵ and J ⁶ is S, one of D ⁵ , D ⁶ , J ⁵ and J ⁶ must

-42 be a covalent bond when two of ^{D5, D6, J5,} and ^J6 are O and S, and no more than four of ^{D5, D6, J5,} and ^J6 are N with the proviso that R ^16, R ¹⁷ R ¹⁸ and R ¹⁹ are each independently selected to maintain carbon tetravalence, nitrogen trivalent, sulfur bivalent and oxygen bivalent.

R ¹⁶ , R ¹⁷ , R ¹⁸ and R ¹⁹ are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, haloalkylthio, alkoxy, hydroxy, amino, nitro, alkoxyamino, lower alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, alkenyl, halogen, haloalkyl, haloalkoxy, hydroxyalkyl, alkylenylamino, haloalkoxyalkyl, carboalkoxy and cyano.

Q ^b is selected from the group consisting of NR ²⁰ R ²¹ , aminoalkylenyl and Q ^be , wherein Q ^be is hydrido and N (R ²⁶ ) C (NR ²⁵ ) N (R ²³ ) (R ²⁴ ) and C (NR ²⁵ ) NR ²³ R ²⁴ with the proviso that at most one of R ²⁰ , R ²¹ and R ²² is hydroxy, amino, alkylamino or dialkylamino simultaneously, and that R ²³ and R ²⁴ may not be a hydroxy, amino, alkylamino or dialkylamino substituent at the same time.

21 23 24 2 ^ 25

R, R, R, R, R, and R are independently selected from the group consisting of a hydrido, alkyl, hydroxy, aminoalkylenyl, amino, dialkylamino, alkylamino, and hydroxyalkyl substituent.

Q ^s is selected from the group consisting of a single covalent bond, (CR ³⁷ R ³⁸ ) b, wherein b is an integer selected from 1 to 4 a (CH (R ¹⁴ )) c-W '- (CH (R ¹⁵ )) d wherein c and d are integers independently selected from 1 to 3 and W ¹ is selected from the group consisting of 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 ), provided that R ¹⁴ is not a halogen substituent as long as it directly binds to (CR ³⁷ R ³⁸ ) ba (CH (R ¹⁴ )) _c binds to E 0.

R ¹⁴ is selected from the group consisting of a hydrido, halogen, alkyl, and haloalkyl substituent.

38

R ^J 'and F are independently selected from hydrido, alkyl, and haloalkyl.

R is optionally selected from the group consisting of aroyl and heteroaroyl.

Y 0 is optionally Q ^b -Q ^ss where Q ^ss is (CH (R ¹⁴ )) eW ² - (CH (R ¹⁵ )) h where eah are integers independently selected from the interval 1 to 2 and W ² is CR ^4a = CR ^4b with the proviso that (CH (R ¹⁴ )) _e binds directly to E °.

Y 0 is optionally Q ^b -Q ^ssss and Q ^b -Q ^ssssr wherein Q ^ssss is (CH (R ³⁸ )) rW ⁵ and Q ^ssssr is (CH (R ³⁸ )) rW ⁶ and wherein r is an integer independently selected from 1 through 2, and W ⁵ and W ⁶ are independently selected from the group consisting of 1,4-indenyl, 1,5-indenyl, 1,6-indenyl, 1,7-indenyl, 2,7-indenyl, 2,6indenyl, 2,5-indenyl, 2,4-indenyl, 3,4-indenyl, 3,5-indenyl, 3,6-indenyl, 3,7-indenyl, 2,4-benzofuranyl, 2,5-benzofuranyl, 2,6- benzofuranyl, 2,7-benzofuranyl, 3,4-benzofuranyl, 3,5-benzofuranyl, 3,6-benzofuranyl, 3,7-benzofuranyl, 2,4-benzothiophenyl, 2,5-benzothiophenyl, 2,6-benzothiophenyl, 2,7- benzothiophenyl, 3,4-benzothiophenyl, 3,5-benzothiophenyl, 3,6-benzothiophenyl,

3,7-benzothiophenyl, 2,7-imidazo (1,2-a) pyridinyl, 3,4-imidazo (1,2-a) pyridinyl, 3,5-imidazo (1,2-43 ajpyridinyl, 3,6) -imidazo (1,2-a) pyridinyl, 3,7-imidazo (1,2-a) pyridinyl, 2,4-indonyl, 2,5-indonyl, 2,6-indonyl, 2,7-indonyl, 3,4 -indonyl, 3,5-indonyl, 3,6-indonyl, 3,7-indonyl, 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-benzoxazole, 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, 2,8-quinolinyl, 3,4-quinolinyl, 3,5-quinolinyl, 3,6-quinolinyl, 3,7-quinolinyl, 3,8-quinolinyl, 4,5 -quinolinyl, 4,6-quinolinyl, 4,7-quinolinyl, 4,8-quinolinyl, 1,4-isoquinolinyl, 1,5-isoquinolinyl, 1,6-isoquinoline yl, 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-cinolinyl, 3,5-cinolinyl, 3,6-cinolinyl, 3,7-cinolinyl, 3,8-cinolinyl, 4,5-cinolinyl, 4, 6-cinnolinyl,

4,7-cinolinyl, 4,8-cinolinyl and all nitrogen atoms in ring W ⁵ and ring W ⁶ with carbon and hydride substituents other than at the W ⁵ and W ⁶ bond sites are optionally substituted with one or more R ⁹ substituents, R ¹⁰ , R ¹¹ and R ¹² , provided that (CH (R ³⁸ )) _r binds to E ° and Q ^b binds to the lowest order number for each W ⁵ and Q ^b binds to the highest order position a number for each W ⁶ .

A more preferred embodiment of the invention includes compounds of Formula I or pharmaceutically acceptable salts thereof:

J is O.

B is a group of the formula:

R ³² , R ³³ , R ³⁴ , R ³⁵ and R ³⁶ are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkylenedioxy, haloalkylthio.

-44alkanoyloxy, alkoxy, hydroxy, amino, alkoxyamino, alkanoyl, haloalkanoyl, nitro, lower alkylamino, alkylthio, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, alkylsulfonamido. alkanoyl, amidosulfonyl, dialkylaminodosulfonyl, alkyl, alkenyl, halo, haloalkyl, haloalkenyl, haloalkoxy, hydroxyalkyl, alkylenylamino, carboalkoxy, carboxy, carboxamido, cyano, and Q ^b.

B is optionally selected from the group consisting of hydrido, trialkylsilyl, C 2 -C 8 alkyl, C 3 -C 8 alkylenyl, C 3 -C 8 alkenyl, C 3 -C 8 alkynyl and C 2 -C 8 haloalkyl, wherein each member of group B may be optionally substituted on any carbon atom of up to 6 atoms including from the B to A bonding site by one or more substituents from R ³² , R ³³ , R ³⁴ , R ³⁵ and R ³⁶ .

B is selected from the group consisting of C3-C12 cycloalkyl and C4-heterocyclyl wherein each ring carbon atom is optionally substituted with ^R33 , the ring carbon atom other than the carbon atom in the B-bonding site of A is optionally substituted with an oxo group, that at most one ring carbon atom is substituted with an oxo group at the same time, the carbon atom and the nitrogen atom adjacent to the carbon at the B-bonding point on A are optionally substituted with R ⁹ or R ¹³ , a carbon atom or a nitrogen atom adjacent to the R ⁹ position; from the point of attachment is optionally substituted with R ¹⁰ , a carbon or nitrogen atom adjacent to the R ¹³ position and two atoms away from the point of attachment is optionally substituted with R ¹² , a carbon or nitrogen atom three atoms from the point of attachment, and adjacent to the R ¹⁰ position is optionally substituted with R ¹¹ , carbon or nitrogen three atoms from the point of attachment and adjacent to the R ¹² position is optionally substituted a bold R ³³ and a carbon or nitrogen atom four atoms from the point of attachment and adjacent to the R ¹¹ and R ³³ positions is optionally substituted with R ³⁴ .

R ⁹ , R ¹⁰ , R ¹² , R ¹² and R ¹³ are independently selected from the group consisting of hydrido, acetamido, haloacetamido, alkoxyamino, alkanoyl, haloalkanoyl, amidino, guanidino, alkylenedioxy, haloalkylthio, alkoxy, hydroxy, amino, lower alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylsulfonamido, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl aminodosulfonyl, alkyl, halogen, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, carboalkoxy, carboxyalkyl, carboxy, carboxamido and cyano.

R ⁹ , R ¹⁰ , R ¹¹ , R ¹² and R ¹³ are optionally selected from heteroaryl and heterocyclyl, provided that R ⁹ , R ¹⁰ , R ¹¹ , R ¹² and R ¹³ are not substituents for B.

A is selected from a single covalent bond, (CH (R ^l3)) pa- (W ⁷⁾ rr wherein rr is an integer from 0 or 1, pa is an integer selected from 0 through 3, and W ⁷ is selected from the group consisting of O, S, C (O), (R ⁷ ) NC (O), (R ⁷ ) NC (S) and N (R ⁷ ).

R ⁷ is independently selected from the group consisting of hydrido, hydroxy and alkyl.

-45 R ¹⁵ is independently selected from the group consisting of hydrido, hydroxy, halogen, alkyl, and haloalkyl.

'FjeNH.

M is selected from the group consisting of N and R’-C.

R ¹ is selected from the group consisting of hydrido, alkyl, cyano, halogen, haloalkyl, haloalkoxy, amino, aminoalkyl, alkylamino, amidino, hydroxy, hydroxyamino, alkoxy, hydroxyalkyl, alkoxyamino, thiol, and alkylthio.

R ² is Z ° -Q.

Z 0 is selected from the group consisting of a single covalent bond and (CR ⁴¹ R ⁴² ) q wherein q is an integer from 1 to 2, (CH (R ⁴¹ )) g W ° - (CH (R ⁴² )) p where the gap is integers from 0 to 3 and W ° are selected from the group consisting of O, S and N (R ⁴¹ ) and (CH (R ⁴¹ )) e W ²² - (CH (R ⁴² )) h where eah are integers independently selected from 0 to 1 and W is selected from the group consisting of 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, 2,3-tetrahydrofuranyl, 2,4-tetrahydrofuran, 2,5-tetrahydro furanyl and 3,4-tetrahydrofuranyl, provided that Z 0 is directly bound to pyrimidinone ring.

R ⁴¹ and R ⁴² are independently selected from the group consisting of hydrido, hydroxy and amino.

Q is selected from the group consisting of hydrido with the proviso that Z 0 is not a single covalent bond, aryl and heteroaryl, wherein the carbon atom adjacent to the carbon at the binding site is optionally substituted with R ⁹ , another carbon atom adjacent to the carbon at the binding site is optionally substituted R ¹³ and the carbon atom adjacent to the R ⁹ position and two atoms away from the point of attachment is optionally substituted with R ¹⁰ , the carbon atom adjacent to the R ¹³ position and two atoms from the point of attachment is optionally substituted with R ¹² and any carbon atom adjacent to the R ¹⁰ position if R ¹² position is optionally substituted with R ¹¹ .

K is CHR ^4a wherein R ^4a is selected from the group consisting of hydrido, hydroxyalkyl, alkyl, alkoxyalkyl, alkylthioalkyl and haloalkyl.

E 0 is selected from the group consisting of a single covalent bond, C (O) N (H), (H) NC (O), (R ⁷ ) NS (O) _2, and S (O) ₂ N (R ⁷ ).

Y 0 is a group of formula IV

wherein D ⁵ , D ⁶ , J ⁵ and J ⁶ are independently selected from the group consisting of C, N, O, S and a covalent bond, with the proviso that at most one of D ⁵ , D ⁶ , J ⁵ and J ⁶ is a covalent bond, K ² is C, at most one of D ⁵ , D ⁶ , J ⁵ and J ⁶ is O, at most one of D ⁵ , D ⁶ , J ⁵ and J ⁶ is S, one of D ⁵ , D ⁶ , J ⁵ and J ⁶ must be a covalent bond when two of D ⁵ , D ⁶ , J ⁵ and J ⁶ are O and S and 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 carbon tetravalence, nitrogen trivalent, sulfur bivalent and oxygen bivalent.

R ¹⁶ , R ¹⁷ , R ¹⁸ and R ¹⁹ are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, haloalkylthio, alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, halo, haloalkyl, haloalkoxy, halohydroxyalkyl, 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 are simultaneously Q ^b and that Qh is Q ¹ *

Q ^b is selected from the group consisting of NR ²⁰ R ²¹ , Q ^be , wherein Q ^be is hydrido, N (R ²⁶ ) C (NR ²⁵ ) N (R ²³ ) (R ²⁴ ) and C (NR ²⁵ ) NR ²³ R ²⁴ with the proviso that at most one of R ²⁰ and R ²¹ is hydroxy, amino, alkylamino or dialkylamino simultaneously, and that at most one of R ²³ and R ²⁴ is hydroxy, amino, alkylamino or dialkylamino simultaneously.

R ²⁰ , R ²¹ , R ²³ , R ²⁴ , R ²⁵ and R ²⁶ are independently selected from the group consisting of hydrido, alkyl, hydroxy, amino, alkylamino and dialkylamino.

Q ^s is selected from the group consisting of a single covalent bond, (CR ³⁷ R ³⁸ ) b, wherein b is an integer selected from 1 to 4 a (CH (R ¹⁴ )) c-W '- (CH (R ¹⁵ )) j wherein c and d are integers selected from 1 to 3 and W ¹ is selected from the group consisting of 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 not a halogen substituent when it is bound directly to N, and that (CR ³⁷ R ^38b and (CH (R ¹⁴ )) c directly bind to E °.

R ¹⁴ is selected from the group consisting of hydrido, halogen, alkyl, and haloalkyl.

R ³⁷ and R ³⁸ are independently selected from the group consisting of hydrido, alkyl and haloalkyl.

R ³⁸ is optionally selected from the group consisting of aroyl and heteroaroyl.

-47 Y ° is optionally Q ^b -Q ^ss where Q ^ss is (CH (R ¹⁴ )) eW ² - (CH (R ¹⁵ )) h where eah are integers independently selected from the interval 1 to 2 and W ² is CR ^4a = CH with the proviso that (CH (R ¹⁴ )) _e binds directly to E °.

An even more preferred embodiment of the invention comprises a compound of formula Ϊ or a pharmaceutically acceptable salt thereof:

J is O.

B is a group of the formula:

R ³² , R ³³ , R ³⁴ , R ³⁵ and R ³⁶ are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, alkylthio, amidosulfonyl, monoalkyl amidosulfonyl, dialkylamidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboalkoxy, carboxy, carboxamido, cyano, and Q ^b.

A is selected from the group consisting of a single covalent bond, (CH (R ¹⁵ )) pa '(W ⁷ ) rr where rr is an integer from 0 to 1, pa is an integer selected from 0 to 3, and W ⁷ is selected from the group consisting of (R ⁷ ) NC (O) and N (R ⁷ ).

R ⁷ is independently selected from the group consisting of hydrido, hydroxy and alkyl.

R ¹⁵ is independently selected from the group consisting of hydrido, hydroxy, halogen, alkyl, and haloalkyl.

TjeNH.

M is selected from the group consisting of N and R’-C.

R ¹ is selected from the group consisting of hydrido, hydroxy, hydroxyamino, amidino, amino, cyano, hydroxyalkyl, alkoxy, alkyl, alkylamino, alkylthio, alkoxyamino, haloalkyl, haloalkoxy and halogen.

R ^{2 is} Z ° -Q.

Z 0 is selected from the group consisting of a single covalent bond, O, S, NH 2 and CH 2.

Q is selected from the group consisting of aryl and heteroaryl, wherein the carbon atom adjacent to the carbon at the binding site is optionally substituted with R ⁹ , another carbon atom adjacent

The -48k carbon at the binding site is optionally substituted with R ¹³ and the carbon atom adjacent to the R ⁹ position and two atoms away from the point of attachment is optionally substituted with R ¹⁰ , the carbon atom adjacent to the R ¹³ position and two atoms from the point of attachment is optionally substituted with R ^12, and any carbon adjacent to R ¹⁰ when R ¹² position is optionally substituted with R ^11th

R ⁹ , R ¹¹ and R ¹³ are independently selected from the group consisting of hydrido, hydroxy, amino, amidino, guanidino, lower alkylamino, alkylthio, alkylsulfonamido, alkylsulfinyl, alkylsulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxyalkyl, carboxy, carboxamido and cyano.

R ¹⁰ and R ¹² are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkyl, alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, alkylsulfonamido, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, hydroxyalkyl, aminoalkyl, carboalkoxy, carboxy, carboxyalkyl, amidocarbonyl, halogen, haloalkyl and cyano.

KjeCH ₂ .

E 0 is C (O) N (H).

Y ⁰ is a group of formula IV

wherein D ⁵ , D ⁶ , J ⁵ and J ⁶ are independently selected from the group consisting of C, N, O, S and a covalent bond, with the proviso that at most one of D ⁵ , D ⁶ , P and J ⁶ is a covalent bond, K ² is C, no more than one of ^{D5, D6, J5,} and L is optionally O, no more than one of ^{D5, D6, J5,} and W is optionally S, one of ^{D5, D6, J5,} and P must be a covalent bond when two of ^{D5, D6, J5,} and the P and S, and no more than four of ^{D5, D6,} P and L are N.

R ¹⁶ , R ¹⁷ , R ¹⁸ and R ¹⁹ are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, haloalkylthio, alkoxy, hydroxy, amino, lower alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, halogen, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl and cyano.

^R16 and ^R19 are optionally Q ^b with the proviso that no more than one of R ¹⁶ and R ¹⁹ are the same time, Q ^b, Q ^b, and the ^p s jeQ

-49Q ^b is selected from the group consisting of NR ²⁰ R ²¹ , and Q ¹ *, wherein hydrido and C (NR ²⁵ ) NR ²³ R ²⁴ are provided that at most one of R ²⁰ and R ^{21 is a} hydroxy substituent at the same time, and that at most one of R ²³ and R ²⁴ is a hydroxy substituent simultaneously.

R ²⁰ , R ²¹ , R ²³ , R ²⁴ and R ²⁶ are independently selected from the group consisting of hydrido, alkyl and hydroxy.

Q ^s is selected from the group consisting of a single covalent bond, CH 2 and CH 2 CH 2.

Another even more preferred embodiment of the invention comprises a compound of formula I or a pharmaceutically acceptable salt thereof:

J is O.

B is optionally selected from the group consisting of hydrido, C 2 -C 8 alkyl, C 3 -C 8 alkenyl, C 3 -C 8 alkynyl and C 2 -C 8 haloalkyl, wherein each member of group B may be optionally substituted on any carbon atom up to 6 atoms including from the bond site B to A with one or more R ³² , R ³³ , R ³⁴ , R ³⁵ and R ³⁶ substituents.

R ³² , R ³³ , R ³⁴ , R ³⁵ and R ³⁶ are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, alkylthio, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl aminodosulfonyl , alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboalkoxy, carboxy, carboxamido, cyano, and Q ^b

A is selected from the group consisting of a single covalent bond and (CH (R ¹⁵ )) _pa - (W ⁷ ) n · where rr is an integer from 0 to 1, pa is an integer selected from 0 to 3 and W ⁷ is selected from the group consisting of (R) NC (O) and N (R).

R ⁷ is independently selected from the group consisting of hydrido, hydroxy and alkyl.

R ¹⁵ is independently selected from the group consisting of hydrido, hydroxy, halogen, alkyl, and haloalkyl.

T is NH.

M is selected from the group consisting of N and R ^C.

R ¹ is selected from the group consisting of hydrido, hydroxy, hydroxyamino, amidino, amino, cyano, hydroxyalkyl, alkoxy, alkyl, alkylamino, aminoalkyl, alkylthio, alkoxyamino, haloalkyl, haloalkoxy and halogen.

R ² is Z ° -Q.

Z 0 is selected from the group consisting of a single covalent bond, O, S, ΝΉ 2 and CH 2.

Q is selected from the group consisting of aryl and heteroaryl, wherein the carbon atom adjacent to the carbon at the binding site is optionally substituted by R ⁹ , another carbon atom adjacent to the carbon at the binding site is optionally substituted by R ¹³ , the carbon atom adjacent to R ⁹

-50 position and two atoms away from the point of attachment is optionally substituted with R ¹⁰ , the carbon atom adjacent to the R ¹³ position and two atoms away from the point of attachment is optionally substituted with R ¹² and any carbon atom adjacent to the R ¹⁰ and R ¹² position optionally substituted with R ¹¹ .

R ⁹ , R ¹¹ and R ¹³ are independently selected from the group consisting of hydrido, hydroxy, amino, amidino, guanidino, lower alkylamino, alkylthio, alkylsulfonamido, alkylsulfonyl, alkylsulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxyalkyl, carboxy, carboxamido and cyano.

R ¹⁰ and R ¹² are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkyl, alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, alkylsulfonamido, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, hydroxyalkyl, alkylenylamino, carboalkoxy carboxy, carboxyalkyl, amidocarbonyl, halogen, haloalkyl and cyano.

KjeCH ₂ .

E 0 is C (O) N (H).

Y 0 is a group of formula IV

wherein D ³ , D ⁶ , J ⁵ and J ⁶ are independently selected from the group consisting of C, N, O, S and a covalent bond, with the proviso that at most one of D ⁵ , D ⁶ , J ⁵ and J ⁶ is a covalent bond, K ² is C, at most one of D ⁵ , D ⁶ , J ⁵ and J ⁶ is O, at most one of D ⁵ , D ⁶ , J ⁵ and J ⁶ is optionally S, one of D ⁵ , D ⁶ , J ⁵ and J ⁶ must be a covalent bond if two of D ⁵ , D ⁶ , J ⁵ and J ⁶ are O and S and 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 carbon tetravalence, nitrogen trivalent, sulfur bivalent and oxygen bivalent.

R ¹⁶ , R ¹⁷ , R ¹⁸ and R ¹⁹ are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, haloalkylthio, alkoxy, hydroxy, amino, lower alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, halogen, haloalkyl, haloalkoxy, hydroxyalkyl, alkylenylamino and cyano.

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

-51 Q ^b is selected from the group consisting of NR ²⁰ R ²¹ , Q 6, wherein Q ^be is hydrido, C (NR ²⁵ ) NR ²³ R ²⁴ and (NR ²⁶ ) C (NR ²⁵ ) N (R ²³ ) (R ²⁴ with the proviso that at most one of R ²⁰ and R ²¹ is a hydroxy substituent at the same time, and that at most one of R ²³ and R ²⁴ is a hydroxy substituent at the same time.

R ²⁰ , R ²¹ , R ²³ , R ²⁴ , R ²⁵ and R ²⁶ are independently selected from the group consisting of hydrido, alkyl and hydroxy.

Q ^s is selected from the group consisting of a single covalent bond, CH ₂ and CH ₂ CH ₂ .

A further more preferred embodiment of the invention comprises a compound of formula I or a pharmaceutically acceptable salt thereof:

J is O.

B is optionally selected from the group consisting of C3-C7 cycloalkyl and C4-heterocyclyl, wherein each ring carbon atom is optionally substituted with ^R33 , the ring carbon atom other than the carbon atom in the B bond site at A is optionally substituted with an oxo group that at most one ring carbon atom is substituted with an oxo group at the same time, the carbon atom and the nitrogen atom adjacent to the carbon at the B-bonding point at A are optionally substituted with R ⁹ or R ¹³ , a carbon atom or nitrogen adjacent the R ⁹ position and two atoms from the point of attachment are optionally substituted with R ¹⁰ , a carbon or nitrogen atom adjacent to R ^{13 of} the '12' position and two atoms from the point of attachment is optionally substituted with R, carbon or nitrogen three atoms from the point of attachment and adjacent to R ^{The 10} position is optionally substituted with R ¹¹ , a carbon or nitrogen atom three atoms from the point of attachment, and adjacent to the R ¹² position is optionally substituted with R ³³ and a carbon or nitrogen atom four atoms from the point of attachment and adjacent to the R ^11a -R ³³ position is optionally substituted with R ³⁴ .

R ⁹ , R ¹¹ and R ¹³ are independently selected from the group consisting of hydrido, hydroxy, amidino, guanidino, lower alkylamino, alkylthio, alkylsulfonamido, alkylsulfinyl, alkylsulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxyalkyl, carboxy, carboxamido and cyano.

R ¹⁰ and R ¹² are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, hydroxy, amidino, guanidino, alkyl, alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, alkylsulfonamido, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, hydroxyalkyl, alkylenylamino, carboalkoxy, carboxy, carboxyalkyl, amidocarbonyl, halogen, haloalkyl and cyano.

R ³³ and R ³⁴ are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, alkylthio, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, alkyl,

-52 halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboalkoxy, carboxy, carboxamido, cyano, and Q ^b.

A is selected from the group consisting of a single covalent bond and (CH (R ¹⁵ )) p _and - (W ⁷ ) n where rr is an integer from 0 to 1, pa is an integer selected from 0 to 3 and W ⁷ is selected from the group consisting of (R ⁷ ) NC (O) and N (R ⁷ ).

R ⁷ is independently selected from the group consisting of hydrido, hydroxy and alkyl.

R ¹⁵ is independently selected from the group consisting of hydrido, hydroxy, halogen, alkyl, and haloalkyl.

TjeNH.

M is selected from the group consisting of N and R ¹ -C.

R ¹ is selected from the group consisting of hydrido, hydroxy, hydroxyamino, amidino, amino, cyano, hydroxyalkyl, alkoxy, alkyl, alkylamino, aminoalkyl, alkylthio, alkoxyamino, haloalkyl, haloalkoxy and halogen.

R ^{2 is} Z ° -Q.

Z 0 is selected from the group consisting of a single covalent bond, O, S, NH and CH 2.

Q is selected from the group consisting of aryl and heteroaryl, wherein the carbon atom adjacent to the carbon at the binding site is optionally substituted with R ⁹ , another carbon atom adjacent to the carbon at the binding site is optionally substituted with R ¹³ , a carbon atom adjacent to the R ⁹ position and two the atoms from the point of attachment are optionally substituted with R ¹⁰ , the carbon atom adjacent to the R ¹³ position and two atoms from the point of attachment is optionally substituted with R ^12, and any carbon atom adjacent to the R ¹⁰ and to the R ¹² position is optionally substituted with R ¹¹ .

KjeCH ₂ .

E 0 is C (O) N (H).

Y 0 is a group of formula IV

Q ^s

R (IV), 19 wherein D ⁵ , D ⁶ , J ⁵ and J ⁶ are independently selected from the group consisting of C, N, O, S and a covalent bond, with the proviso that at most one of D ⁵ , D ⁶ , J ⁵ and J ⁶ is a covalent bond, K ² is C, at most one of D ⁵ , D ⁶ , J ⁵ and J ⁶ is O, at most one of D ⁵ , D ⁶ , J ⁵ and J ⁶ is optionally S, one of ^{D5, D6, J5,} and

-53J ⁶ must be a covalent bond if two of D ⁵ , D ⁶ , J ⁵ and J ⁶ are O and S and 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 carbon tetravalence, nitrogen trivalent, sulfur bivalent and oxygen bivalent.

R ¹⁶ , R ¹⁷ , R ¹⁸ and R ¹⁹ are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, haloalkylthio, alkoxy, hydroxy, amino, lower alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, halogen, haloalkyl, haloalkoxy, hydroxyalkyl, alkylenylamino and cyano.

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

Q ^b is selected from the group consisting of NR ²⁰ R ²¹ , and Q ¹ *, wherein Q ^be is hydrido and C (NR ²⁵ ) NR ²³ R ²⁴ , provided that at most one of R ²⁰ and R ²¹ are hydroxy substituents simultaneously, and that at most one of R and R are hydroxy substituents simultaneously.

R ²⁰ , R ²¹ , R ²³ , R ²⁴ and R ²⁵ are independently selected from the group consisting of hydrido, alkyl and hydroxy.

Q ^s is selected from the group consisting of a single covalent bond, CH ₂ and CH ₂ CH ₂ .

The best embodiment of the invention comprises a compound of formula I or a pharmaceutically acceptable salt thereof:

J is O.

B is the formula:

R ³² , R ³³ , R ³⁴ , R ³⁵ and R ³⁶ are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, alkylthio, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl , alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboalkoxy, carboxy, carboxamido, cyano, and Q ^b.

A is selected from a single covalent bond, (CH / R jjpa-lw ^7): wherein r is an integer from 0-1, solder integer selected from 0 through 3, and W ⁷ is N (R ⁷⁾ .

R ⁷ is independently selected from the group consisting of hydrido and alkyl.

-54R ¹⁵ is independently selected from hydrido, halo, alkyl, and haloalkyl.

TjeNH.

M is selected from the group consisting of N and R’-C.

R ¹ is selected from the group consisting of hydrido, hydroxy, hydroxyamino, amidino, amino, cyano, hydroxyalkyl, alkoxy, alkyl, alkylamino, aminoalkyl, alkylthio, alkoxyamino, haloalkyl, haloalkoxy and halogen.

R ^{2 is} Z ° -Q.

Z 0 is a single covalent bond.

Q is selected from the group consisting of aryl and heteroaryl wherein the carbon atom adjacent to the carbon at the binding site is optionally substituted with R ⁹ , another carbon atom adjacent to the carbon at the binding site is optionally substituted with R ¹³ and a carbon atom adjacent to the R ⁹ position and two atoms from the point of attachment are optionally substituted with R ¹⁰ , a carbon atom adjacent to the R ¹³ position and two atoms from the point of attachment is optionally substituted with R ¹² and any carbon atom adjacent to R ¹⁰ and if the R ¹² position is optionally substituted with R ¹¹ .

R ⁹ , R ¹¹ and R ¹³ are independently selected from the group consisting of hydrido, hydroxy, amino, amidino, guanidino, lower alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, amidosulfonyl, alkyl, halogen, haloalkyl, haloalkoxy, hydroxyalkyl, carboxy, carboxamido and cyano .

R ¹⁰ and R ¹² are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkyl, alkoxy, alkoxyamino, aminoalkyl, hydroxy, amino, lower alkylamino, alkylsulfonamido, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, hydroxyalkyl, aminoalkyl, carboalkoxy, carboxy, carboxyalkyl, carboxamido and cyano.

A is CH _second

E 0 is C (O) N (H).

Y ⁴ 'is a group of formula IV

(IV),

- 35 wherein D ⁵ , D ⁶ , J ⁵ and J ⁶ are independently selected from the group consisting of C, N, O, S and a covalent bond, with the proviso that at most one of D ³ , D ⁶ , J ⁵ and J ⁶ is covalent a bond, K ² is C, at most one of D ⁵ , D ⁶ , J ⁵ and J ⁶ is O, at most one of D ⁵ , D ⁶ , J ⁵ and J ⁶ is S, one of D ⁵ , D ⁶ , J ⁵ and ⁶ J must be a covalent bond when two of ^{D5, D6, J5,} and ^J6 are O and S, and no more than four of ^{D5, D6, J5,} and ^J6 are N

R ¹⁶ , R ¹⁷ , R ¹⁸ and R ¹⁹ are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, haloalkylthio, alkoxy, hydroxy, amino, lower alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, halogen, 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 simultaneously Q ^b and that Qh is Q ¹ *

Q ^b is selected from the group consisting of NR ²⁰ R ²¹ , Q ¹ *, wherein Q ⁶ * is hydrido and C (NR ² R) NR ²³ R ²⁴

R ²⁰ , R ²¹ , R ²³ , R ²⁴ and R ²⁶ are independently selected from the group consisting of hydrido and alkyl.

Q ^is CH ₂ .

A further preferred embodiment of the invention comprises a compound of formula I or a pharmaceutically acceptable salt thereof:

J is O.

B is optionally selected from the group consisting of hydrido, C 2 -C 8 alkyl, C 3 -C 8 alkenyl, C 3 -C 8 alkynyl and C 2 -C 8 haloalkyl, wherein each member of group B may be optionally substituted on any carbon atom up to 6 atoms including from the bond site B to A with one or more R ³² , R ³³ , R ³⁴ , R ³⁵ and R ³⁶ substituents.

R ³² , R ³³ , R ³⁴ , R ³⁵ and R ³⁶ are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, alkylthio, amidosulfonyl, monoalkyl amidosulfonyl, dialkylamidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboalkoxy, carboxy, carboxamido, cyano, and Q ^b.

A is selected from the group consisting of a single covalent bond and (CH (R ¹⁵ )) _pa - (W ⁷ ) n where rr is an integer from 0 to 1, having an integer selected from 0 to 3 and W ⁷ is N (R) ⁷ ).

R ⁷ is independently selected from the group consisting of hydrido and alkyl.

R ¹⁵ is independently selected from the group consisting of hydrido, hydroxy, halogen, alkyl, and haloalkyl.

TjeNH.

M is selected from the group consisting of N and R’-C.

- 56 R ¹ is selected from hydrido, hydroxy, hydroxyamino, amidino, amino, cyano, hydroxy, alkoxy, alkyl, alkylamino, aminoalkyl, alkylthio, alkoxyamino, haloalkyl, haloalkoxy, and halo.

R ^{2 is} Z ° -Q.

Z 0 is a single covalent bond.

Q is selected from the group consisting of aryl and heteroaryl, wherein the carbon atom adjacent to the carbon at the binding site is optionally substituted by R ⁹ , another carbon atom adjacent to the carbon at the binding site is optionally substituted by R ¹³ , the carbon atom adjacent to the R ⁹ position and two the atoms from the point of attachment are optionally substituted with R ¹⁰ , the carbon atom adjacent to the R ¹³ position and two atoms from the point of attachment is optionally substituted with R ^12, and any carbon atom adjacent to the R ¹⁰ and to the R ¹² position is optionally substituted with R ¹¹ .

R ⁹ , R ¹¹ and R ¹³ are independently selected from the group consisting of hydrido, hydroxy, amino, amidino, guanidino, lower alkylamino, alkylthio, alkoxy, alkylsulfinyl, alkylsulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, alkyl, halogen, haloalkyl, haloalkoxy, hydroxyalkyl, carboxy, carboxamido and cyano.

R ¹⁰ and R ¹² are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkyl, alkoxy, alkoxyamino, aminoalkyl, hydroxy amino, lower alkylamino, alkylsulfonamido, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, hydroxyalkyl, aminoalkyl, halogen , haloalkyl, carboalkoxy, carboxy, carboxyalkyl, carboxamido and cyano.

K is CH 2. .

E 0 is C (O) N (H).

Y 0 is a group of formula IV

wherein D ³ , D ⁶ , J ⁵ and J ⁶ are independently selected from the group consisting of C, N, O, S and a covalent bond, with the proviso that at most one of D ⁵ , D ⁶ , J ⁵ and J ⁶ is a covalent bond, K ² is C, at most one of D ⁵ , D ⁶ , J ³ and J ⁶ is O, at most one of D ⁵ , D ⁶ , J ⁵ and J ⁶ is optionally S, one of D ³ , D ⁶ , J ⁵ and J ⁶ must be a covalent bond if two of D ⁵ , D ⁶ , J ⁵ and J ⁶ are O and S and at most four of D ³ , D ⁶ , J ⁵

-57a ^J6 are N with the proviso that R ^16, R ^17, R ¹⁸ and R ¹⁹ are each independently selected to maintain the tetravalentnosť carbon trivalentnosť 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 the group consisting of hydrido, amidino, guanidino, carboxy, haloalkylthio, alkoxy, hydroxy, amino, lower alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, halogen, 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 are simultaneously Q ^b , and that Q ^b is Q *.

Q ^b is selected from the group consisting of NR ²⁰ R ²¹ , Q ^be , wherein Q ^bc is hydrido, (NR ²⁶ ) C (NR ²⁵ ) NR ²³ R ²⁴ and C (NR ²⁵ ) NR ²³ R ²⁴ .

R ²⁰ , R ²¹ , R ²³ , R ²⁴ , R ²⁵ and R ²⁶ are independently selected from the group consisting of hydrido and alkyl.

Q ^is CH ₂ .

Another preferred embodiment of the invention comprises a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein:

J is O.

B is selected from the group consisting of C3-C7 cycloalkyl and C4-heterocyclyl wherein each ring carbon atom is optionally substituted with ^R33 , the ring carbon atom other than the carbon atom in the B-bonding site of A is optionally substituted with an oxo group, that at most one ring carbon atom is substituted by an oxo group at the same time, the carbon atom and the nitrogen atom adjacent to the carbon, at the B-bonding point A are optionally substituted by R ⁹ or R ¹³ , the carbon atom or the nitrogen atom adjacent to the R ⁹ position and two atoms from the point of attachment is optionally substituted by ^R10, a carbon or nitrogen adjacent to the R ¹³ position and two atoms from the point of attachment is optionally substituted by ^R12, a carbon or nitrogen atom three atoms from the point of attachment and adjacent to the ^R10 position is optionally substituted with R ¹¹ , a carbon atom or a nitrogen atom three atoms from the point of attachment and adjacent to the R ¹² position is optionally substituted R ³³ and the carbon or nitrogen atom four atoms from the point of attachment and adjacent to the R ¹¹ and R ³³ positions are optionally substituted with R ³⁴ .

R ⁹ , R ¹¹ and R ¹³ are independently selected from the group consisting of hydrido, hydroxy, amino, amidino, guanidino, lower alkylamino, alkylthio, alkoxy, alkylsulfinyl, alkylsulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, alkyl, halogen, haloalkyl, haloalkoxy, hydroxyalkyl, carboxy, carboxamido and cyano.

R ¹⁰ and R ¹² are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkyl, alkoxy, alkoxyamino, aminoalkyl, hydroxy,

-58amino, lower alkylamino, alkylsulfonamido, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, hydroxyalkyl, aminoalkyl, halogen, haloalkyl, carboalkoxy, carboxy, carboxyalkyl, carboxamido and cyano.

R ³³ and R ³⁴ are independently selected from the group consisting of hydrido, amidino, guanidino, alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, alkylthio, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, alkyl, halogen, haloalkyl, haloalkoxy, hydroxyalkyl, carboalkoxy, carboxy, carboxamido and cyano.

R ³³ is optionally Q ^b .

A is selected from a single covalent bond and (CH / R jjpa-LW ^7): wherein rrje an integer from 0-1, solder integer selected from 0 through 3, and W ⁷ is N (R ^7).

R ⁷ is independently selected from the group consisting of hydrido, hydroxy and alkyl.

R ¹⁵ is independently selected from the group consisting of hydrido, hydroxy, halogen, alkyl, and haloalkyl.

Ί ^ εΝΗ.

M is selected from the group consisting of N and R ¹ -C.

R ¹ is selected from the group consisting of hydrido, hydroxy, hydroxyamino, amidino, amino, cyano, hydroxyalkyl, alkoxy, alkyl, alkylamino, aminoalkyl, alkylthio, alkoxyamino, haloalkyl, haloalkoxy and halogen.

R ^{2 is} Z ° -Q.

Z 0 is a single covalent bond.

Q is selected from the group consisting of aryl and heteroaryl, wherein the carbon atom adjacent to the carbon at the binding site is optionally substituted with R ⁹ , another carbon atom adjacent to the carbon at the binding site is optionally substituted with R ¹³ , a carbon atom adjacent to the R ⁹ position and two the atoms from the point of attachment are optionally substituted with R ¹⁰ , the carbon atom adjacent to the R ¹³ position and two atoms from the point of attachment is optionally substituted with R ^12, and any carbon atom adjacent to the R ¹⁰ and R ¹² position is optionally substituted with R ¹¹ .

KjeCH ₂ .

E 0 is C (O) N (H).

Y ⁴¹ is a group of formula IV

wherein D ⁵ , D ⁶ , J ⁵ and J ⁶ are independently selected from the group consisting of C, N, O, S and a covalent bond, with the proviso that at most one of D ⁵ , D ⁶ , J ⁵ and J ⁶ is a covalent bond, K ² is C, at most one of D ⁵ , D ⁶ , J ⁵ and J ⁶ is O, at most one of D ⁵ , D ⁶ , J ⁵ and J ⁶ is optionally S, one of D ⁵ , D ⁶ , J ⁵ and J ⁶ must be a covalent bond if two of D ⁵ , D ⁶ , J ⁵ and J ⁶ are O and S and 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 carbon tetravalence, nitrogen trivalent, sulfur bivalent and oxygen bivalent.

R ¹⁶ , R ¹⁷ , R ¹⁸ and R ¹⁹ are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, haloalkylthio, alkoxy, hydroxy, amino, lower alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, halogen, haloalkyl, haloalkoxy, hydroxyalkyl, alkylenylamino and cyano.

R ¹⁶ and R ¹⁹ are optionally Q ^b with the proviso that at most one of R ¹⁶ and R ¹⁹ are simultaneously Q ^b and that Qh is Q ¹ *

Q ^b is selected from the group consisting of NR ²⁰ R ²¹ , Q ^be , wherein Q ^be is hydrido and C (NR ²⁵ ) NR ²³ R ²⁴ .

R ²⁰ , R ²¹ , R ²³ , R ²⁴ and R ²⁵ are independently selected from the group consisting of hydrido and alkyl.

Q ^s isH ₂ .

A preferred embodiment of the invention comprises compounds of formula I, compounds of formula I-S:

(I-S), or a pharmaceutically acceptable salt thereof, wherein: B is a group of the formula:

-6,033

R ³² , R ³³ , R ³⁴ , R ³⁵ and R ³⁶ are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, 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, 3,3pentafluoropropyl, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro, bromo, amidosulfonyl, N-methylamidosulfonyl, Ν, Ν-dimethylamidosulfonyl, acetyl, propanoyl, trifluoroacetyl, pentafluoropropanoyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2-hydroxyethyl 2,2-trifluoro-1 hydroxyethyl, 2,2,2-trifluoro-1-trifluoromethyl-1-hydroxyethyl, carboxymethyl, methoxycarbonyl, ethoxycarbonyl, amidocarbonyl, N-methylamidocarbonyl, Ν, dim-dimethylamidocarbonyl, cyano and

B is selected from the group consisting of hydrido, trimethylsilyl, ethyl, 2-propenyl, 2-propynyl, propyl, isopropyl, butyl, 2-butenyl, 3-butenyl, 2-butynyl, 5-butyl, tert-butyl, isobutyl, 2 -methylpropenyl, 1-pentyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-pentynyl, 3-pentynyl, 2-pentynyl,

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-hexinyl, 4-hexinyl, 2-hexyl, 1-methyl-2-pentenyl, 1-methyl-3-pentenyl, 1-methyl-4-pentenyl, 1-methyl-2-pentynyl, 1-methyl-2-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-heptinyl, 3-heptinyl, 4-heptinyl, 5-heptinyl, 6-heptinyl, 2-heptyl, 1-methyl-2-hexenyl, 1-methyl-3-hexenyl, 1-methyl-4 -hexenyl, 1-methyl-5-hexenyl, 1-methyl-2-hexinyl, 1-methyl-3-hexinyl, 1-methyl-4-hexinyl, 3-heptyl, 1-ethyl-2-pentenyl, 1-ethyl-3 -pentenyl, 1-ethyl-4pentenyl, 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-octynyl, 3-octynyl, 4-octynyl, 5-octynyl, 6-octynyl, 2-octyl, 1-methyl-2-heptenyl, 1-methyl-3-heptenyl, 1 methyl-4-heptenyl, 1-methyl-5-heptenyl, 1-methyl-6-heptenyl, 1-methyl-2-heptinyl, 1-methyl-3-heptinyl, 1-methyl-4-heptinyl, 1-61 methyl- 5-heptinyl, 3-octyl, 1-ethyl-2-hexenyl, 1-ethyl-3-hexenyl, 1-ethyl-4-hexenyl, 1-ethyl- 5-hexenyl, 1-ethyl-2-hexinyl, 1-ethyl-3-hexinyl, 1-ethyl-4-hexinyl, 1-pentyl-2-propenyl, 4-octyl, 1-propyl-2-pentenyl, 1-propyl-3- pentenyl, 1-propyl-4-pentenyl, 1-butyl-2-butenyl, 1-propyl-2pentinyl, 1-propyl-3pentinyl, 1-butyl-2-butinyl, 1-butyl-3-butenyl, 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 substituted on any carbon up to 5 atoms including from the B to A bond site by one or more substituents from R ³² , R ³³ , R ³⁴ , R ³⁵ and R ³⁶ .

B is optionally selected from the group consisting of cyclopropyl, cyclobutyl, oxetan-2-yl, oxetan-3-yl, azetidin-2-yl, azetidin-3-yl, thiaetan-2-yl, thiaetan-3-yl, cyclopentyl, cyclohexyl , adamantyl, norbomyl, 3-trifluoromethylnorbomyl, bicyclo [3.1.0] hexan-yl, cycloheptyl and cyclooctyl, wherein each ring carbon atom is optionally substituted with R ³³ , the carbon or nitrogen atom adjacent to the carbon at the binding site is optionally substituted with R or R, a carbon or nitrogen atom adjacent to the R ⁹ position and two atoms away from the point of attachment is optionally substituted with R ¹⁰ , a carbon or nitrogen atom adjacent to the R ¹³ position and two atoms from the point of attachment is optionally substituted with R ¹² .

R ⁹ , R ¹⁰ , R ¹¹ , R ¹² and R ¹³ are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, carboxymethyl, methyl, ethyl, isopropyl, propyl, methoxy, ethoxy, isopropoxy, 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, methanesulfonamido, amidosulfonyl, N-methylamidosulfonyl, N, N-dimethylamidosulfonyl, acetyl, propanoyl, trifluoroacetyl, pentafluoropropanoyl, hydroxy, 1-hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro-1-hydroxyethyl, 2,2,2-trifluoro-1-trifluoromethyl-1-hydroxyethyl, methoxycarbonyl, ethoxycarbonyl, amidocarbonyl, N-methylamidocarbonyl, N, N-dimethylamidocarbonyl and cyano.

A is selected from the group consisting of a single covalent bond. O, S, NH, N (CH ₃ ), N (OH), C (O), CH ₂ , CH ₃ CH, CF ₃ CH, NHC (O), N (CH ₃ ) 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) c ₂ , ch _{2 CH2, CH2 CH2 CH2, CH3} CH CH _2, CF ₃ CH CH _2, C H 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 .

-62A is optionally selected from the group consisting of CH ₂ N (CH 3), CH ₂ N (CH ₂ CH 3), CH ₂ CH ₂ N (CH 3) and CH ₂ CH ₂ N (CH ₂ CH ₃ ) with the proviso that B is hydrido.

M is selected from the group consisting of N and R * -C.

R ¹ is selected from the group consisting of hydrido, hydroxy, amino, thiol, amidino, hydroxyamino, aminomethyl, 1-aminoethyl, 2-aminoethyl, methylamino, dimethylamino, cyano, methyl, ethyl, isopropyl, propyl, trifluoromethyl, pentafluoroethyl, 2,2 , 2-trifluoroethyl, 2,2,3,3,3pentafluoropropyl, methoxy, ethoxy, propoxy, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, methoxyamino, ethoxyamino, methylthio, ethylthio, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy , fluoro, chloro and bromo.

R ² is Z ° -Q.

Z 0 is selected from the group consisting of a single covalent 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) CH ₂ and CH (NH ₂ ) CH ₂ .

Q is selected from the group consisting of phenyl, 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl, 4-imidazolyl, 3-pyrazolyl, 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-isothiazolyl, 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, 1,2,3-triazin-5-yl, wherein the carbon atom adjacent to the carbon optionally, R ⁹ in the binding site, another carbon atom adjacent to the carbon at the binding site is optionally substituted with R ¹³ , the carbon atom adjacent to the R ⁹ position, and two atoms away from the point of attachment optionally substituted with R ¹⁰ , a carbon atom adjacent to R ¹³ positions and two atoms away from the site of the attachment is optionally substituted with R ¹² and any carbon atom adjacent to R ¹⁰ and R ¹² is optionally substituted with R ¹¹ .

K is CHR ^4a wherein R ^4a is selected from the group consisting of methyl, ethyl, propyl, isopropyl, hydroxymethyl, 1-hydroxyethyl, methoxymethyl, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoromethyl, methylthiomethyl and hydrido.

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

Y 0 is selected from the group consisting of:

R ¹⁶ , R ¹⁷ , R ¹⁸ and R ¹⁹ are independently selected from the group consisting of hydrido, methyl, ethyl. isopropyl, propyl, amidino, guanidino, carboxy, methoxy, ethoxy, isopropoxy, propoxy.

-65hydroxy, amino, methoxyamino, ethoxyamino, aminomethyl, 1-aminoethyl, 2-aminoethyl, N-methylamino, dimethylamino, N-ethylamino, methylthio, ethylthio, isopropylthio, trifluoromethylthio, methylsulfinyl, ethylsulfinyl, methylsulfonyl, ethylsulfonyl, trifluoromethyl, trifluoromethyl, trifluoromethyl , 2-trifluoroethyl, 2,2,3,3,3-pentafluoropropyl, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro, bromo, amidosulfonyl, N-methylamidosulfonyl, Ν, Ν-dimethylamidosulfonyl, acetyl, propanoyl, trifluoroacetyl, pentafluoropropanoyl , 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 are Q ^b at the same time and that Q ^b

Q ^b is selected from the group consisting of NR ²⁰ R ²¹ , Q ¹ *, wherein Q ^be is hydrido. C (NR ²⁵ ) NR ²³ R ²⁴ and NR ²⁶ C (NR ²⁵ ) NR ²³ R ²⁴ with the proviso that not more than one of R ²⁰ and R ²¹ are hydroxy,

N-methylamino and Ν, Ν-dimethylamino simultaneously, and that at most one of R and R are hydroxy, N-methylamino and Ν, Ν-dimethylamino simultaneously.

R ²⁰ , R ²¹ , R ²³ , R ²⁴ , R ²⁵ and R ²⁶ are independently selected from the group consisting of hydrido, methyl, ethyl, propyl, butyl, isopropyl, hydroxy, 2-aminoethyl, 2- (N-methylamino) ethyl, and 2- (N, N-dimethylamino) ethyl.

Q ^s is selected from the group consisting of a single covalent 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 1 -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, ch ₂ ch = ch ₂ , CH ₂ CF = CHCH ₂ , CH ₂ C (CH ₃ ) = CHCH ₂ , ch ₂ ch = ch ₂ ch ₂ , CH ₂ CF = CHCH ₂ CH ₂ and CH ₂ C (CH ₃ ) = CHCH ₂ CH ₂ .

A more preferred embodiment of the invention includes compounds of formula I having the formula I-MPS wherein B is aromatic:

(I-MPS), or a pharmaceutically acceptable salt thereof, wherein B is a group of the formula:

R ³² , R ³³ , R ³⁴ , R ³⁵ and R ³⁶ are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, methoxyamino, ethoxyamino, acetamido, trifluoroacetamido, N- methylamino, dimethylamino, N-ethylamino, methylthio, ethylthio, isopropylthio, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, 2,2,3,3,3pentafluoropropyl, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro, bromo, amidosulfonyl, N-methylamidosulfonyl, Ν, Ν-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro-1-hydroxyethyl, methoxycarbonyl, ethoxycarbonyl, amidocarbonyl, N-methylamidocarbonyl, Ν, Ν -dimetylamidokarbonyl, cyano, and Q ^b

A is optionally selected from the group consisting of a single covalent bond, NH, N (CH ₃ ), N (OH), CH ₂ , CH ₃ CH CF ₃ CH, NHC (O), N (CH ₃ ) 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 ^{2 O} R ^21, Q ¹ *, wherein Q ¹ is hydrido and C (NR ^{2 R)} NR ²³ R ²⁴ with the proviso that no more than one of R ²⁰ and R ²¹ is hydroxy at the same time, and wherein at most one of R ²³ and R ²⁴ are hydroxy substituents simultaneously.

R ²⁰ , R ²¹ , R ²³ , R ²⁴ and R ²⁵ are independently selected from the group consisting of hydrido, methyl, ethyl, propyl, butyl, isopropyl and hydroxy.

Q ^s is selected from the group consisting of a single covalent bond, CH ₂ and CH ₂ CH ₂ .

Another more preferred embodiment of the invention includes compounds of formula I having the formula I-MPS wherein B is a non-cyclic substituent:

(1-MPS), hydrido, ethyl, 2-propenyl, 2-propynyl, propyl.

or a pharmaceutically acceptable salt thereof, wherein:

B is selected from the group consisting of isopropyl, butyl, 2-butenyl, 3-butenyl, 2-butynyl, sec-butyl, tert-butyl, isobutyl, 2-67methylpropenyl, 1-pentyl, 2-pentenyl, 3-pentenyl, 4- pentenyl, 2-pentynyl, 3-pentynyl, 2-pentynyl,

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-hexinyl, 4-hexinyl, 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-heptinyl, 3-heptinyl, 4-heptinyl, 5-heptinyl, 2-heptyl, 1-methyl-2-hexenyl, 1-methyl-3-hexenyl, 1-methyl-4-hexenyl, 1- methyl-5-hexenyl, 1-methyl-2-hexinyl, 1-methyl-3-hexinyl, 1-methyl-4-hexinyl, 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, 2,2,2-trifluoroethyl, 4-trifluoromethyl-5,5,5-trifluoropentyl, 4-trifluoromethylpentyl, 5,5,6,6,6-pentafluoroohexyl and 3,3,3-trifluoropropyl wherein each member of group B is optionally substituted on any carbon up to 5 atoms including from the B to A bond site by one or more substituents from group 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 the group consisting of hydrido, amidino, guanidino, carboxy, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, methoxyamino, ethoxyamino, acetamido, trifluoroacetamido, N- methylamino, dimethylamino, N-ethylamino, methylthio, ethylthio, isopropylthio, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, 2,2,3,3,3pentafluoropropyl, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro, bromo, amidosulfonyl, ⁷ N-methylamidosulfonyl, Ν, Ν-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro-1-hydroxyethyl, methoxycarbonyl, ethoxycarbonyl, amidocarbonyl, N-methylamidocarbonyl, Ν, -dimetylamidokarbonyl, cyano, and Q ^b

A is selected from the group consisting of a single covalent bond, NH, N (CH ₃ ), N (OH), CH ₂ , CH ₃ CH, CF ₃ CH, NHC (O), N (CH ₃ ) C (O), C (O) NH, C (O) N _{(CH3), CH2 CH2,} CH ₂ CH ₂ CH _2, CH ₃ CHCH ₂ and CF ₃ CH CH _second

A is optionally selected from the group consisting of CH ₂ N (CH ₃ ), CH ₂ N (CH ₂ CH ₃ ), CH ₂ CH ₂ N (CH ₃ ) and CH ₂ CH ₂ N (CH ₂ CH ₃ ), provided that: B is hydrido.

Q ^b is selected from NR ²⁰ R ^21, Q ¹ *, wherein Q ^be is hydrido, C (NR ^{2 R)} NR ²³ R ²⁴ and NR ²⁶ C (NR ²⁵⁾ NR ²³ R ²⁴ with the proviso that no more than one of the R ²⁰ and R ²¹ are hydroxy substituents simultaneously, and that at most one of R ²³ and R ²⁴ are hydroxy substituents simultaneously.

R ²⁰ , R ²¹ , R ²³ , R ²⁴ , R ²⁵ and R ²⁶ are independently selected from the group consisting of hydrido, methyl, ethyl, propyl, butyl, isopropyl and hydroxy.

Q ^s is selected from the group consisting of a single covalent bond, CH ₂ and CH ₂ CH ₂ .

Yet another preferred embodiment of the invention includes compounds of formula I, wherein the compounds have the formula I-MPS, wherein B is a non-aromatic cyclic substituent:

B '

(I-MPS), or a pharmaceutically acceptable salt thereof, wherein:

B is optionally selected from the group consisting of cyclopropyl, cyclobutyl, oxetan-3-yl, azetidin-1-yl, azetidin-2-yl, azetidin-3-yl, thiaethan-3-yl, cyclopentyl, cyclohexyl, norbomyl, bicyclo [3.1] .0] hexan-yl and cycloheptyl, wherein each ring carbon atom is optionally substituted with R ³³ , a carbon or nitrogen atom adjacent to the carbon at the binding site is optionally substituted with R ⁹ or R ¹³ , a carbon or nitrogen atom adjacent to the R ⁹ position, and two atoms away from the point of attachment is optionally substituted with R ¹⁰ , a carbon or nitrogen atom adjacent to the R ¹³ position and two atoms away from the point of attachment is optionally substituted with R ¹² .

A is selected from the group consisting of a single covalent bond, NH, N (CH ₃ ), N (OH), CH ₂ , CH ₃ CH, CF ₃ CH, NHC (O), N (CH ₃ ) C (O), C (0) NH, C (O) N _{(CH3), CH2 CH2,} CH ₂ CH ₂ CH _2, CH ₃ CHCH ₂ and CF ₃ CH CH _second

R is selected from the group consisting of hydrido, amidino, guanidino, carboxy, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, methoxyamino, ethoxyamino, acetamido, trifluoroacetamido, N-methylamino, dimethylamino, N-ethylamino, methylthio, ethylthio, isopropylthio, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, 2,2,3,3,3-pentafluoropropyl, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro, bromo, amidosulfonyl, N-methylamidosulfonyl, Ν, Ν- dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro-1-hydroxyethyl, methoxycarbonyl, ethoxycarbonyl, amidocarbonyl, Nmethylamidocarbonyl, Ν, Ν-dimethylamidocarbonyl, cyano, and Q ^b.

Q ^b is selected from the group consisting of NR ²⁰ R ²¹ , Q ^be , wherein Q ^be is hydrido and C (NR ²⁵ ) NR ²³ R ^24, with the proviso that at most one of R ²⁰ and R ²¹ are hydroxy substituents simultaneously and that at most one of R ²³ and R ²⁴ are hydroxy substituents simultaneously.

R, R, R, R, and R are independently selected from the group consisting of hydrido, methyl, ethyl, propyl, butyl, isopropyl and hydroxy.

Q ^s is selected from the group consisting of a single covalent bond, CH ₂ and CH ₂ CH ₂ .

The best embodiment of the invention is compounds of formula I-MPS:

> (I-MPS), or a pharmaceutically acceptable salt thereof, containing conventional structural units, wherein:

M is selected from the group consisting of N and R’-C.

R ¹ is selected from the group consisting of hydrido, hydroxy, amino, amidino, hydroxyamino, aminomethyl, 1-aminoethyl, methylamino, dimethylamino, cyano, methyl, ethyl, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, methoxy, hydroxymethyl; hydroxyethyl, 2-hydroxyethyl, methoxyamino, methylthio, ethylthio, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro and bromo.

R ^{2 is} Z ° -Q.

Z 0 is selected from the group consisting of a single covalent bond, O, S, NH and CH 2.

Q is selected from the group consisting of phenyl, 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl, 4-imidazolyl, 3-pyrazolyl, 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, 1,3,5-triazine-2- yl wherein the carbon atom adjacent to the carbon at the binding site is optionally substituted with R ⁹ , another carbon atom adjacent to the carbon at the binding site is optionally substituted with R ¹³ , the carbon atom adjacent to the R ⁹ position and two atoms away from the point of attachment is optionally substituted with R 9 ¹⁰ , the carbon atom adjacent to the R ¹³ position and two atoms apart from the point of attachment is optionally substituted with R ^12, and any carbon atom adjacent to R ¹⁰ and R ¹² is optionally substituted with R ¹¹ .

R ⁹ , R ⁹ and R ¹³ are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, N-methylamino, Ν, dim-dimethylamino , N-ethylamino, methylthio, ethylthio, isopropylthio, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, 2,2,3,3,3-pentafluoropropyl, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro , bromo, methanesulfonamido, amidosulfonyl, N-methylamidosulfonyl, N, N-dimethylamidosulfonyl, hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro-1-hydroxyethyl, N-methylamidocarbonyl, Ν, dim-dimethylamidocarbonyl and cyano.

hydroxymethyl, 1-amidocarbonyl,

-70R ¹⁰ and R ¹² are independently selected from hydrido, amidino, guanidino, carboxy, carboxy methyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, methoxy, ethoxy, acetamido, trifluoroacetamido , aminomethyl, 1-aminoethyl, 2-aminoethyl, N-methylamino, dimethylamino, N-ethylamino, methanesulfonamido, amidosulfonyl, N-methylamidosulfonyl, Ν, dim-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro-1 -hydroxyethyl, methoxycarbonyl, ethoxycarbonyl, amidocarbonyl, N-methylamidocarbonyl, Ν, Ν-dimethylamidocarbonyl, fluoro, chloro, bromo and cyano.

Y 0 is selected from the group consisting of:

R ¹⁶ , R ¹⁷ , R ¹⁸ and R ¹⁹ are independently selected from the group consisting of hydrido, methyl, ethyl. isopropyl, propyl, carboxy, amidino, guanidino, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, aminomethyl, 1-aminoethyl, 2-aminoethyl, N-methylamino, dimethylamino, N-72ethylamino, methylthio, ethylthio, isopropylthio, trifluoromethylthio, methylsulfinyl, ethylsulfinyl, methylsulfonyl, ethylsulfonyl, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, 2,2,3,3,3pentafluoropropyl, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro, bromo, amidosulfonyl, N-methylamidosulfonyl, Ν, Ν-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 are Q ^b at the same time, and that Q ^b is Q ^be .

The best embodiment of the invention includes the compounds of formula I which they have

formula I-EMPS where B is aromatic: N. .R ² / γ i vC (I-EMPS). A . Λ J X M H clay · 0 H

or a pharmaceutically acceptable salt thereof, wherein B is a group of the formula:

R ³² , R ³³ , R ³⁴ , R ³⁵ and R ³⁶ are independently selected from the group consisting of hydrido, amidino, guanidino, methyl, ethyl, methoxy, ethoxy, hydroxy, amino, N-methylamino, dimethylamino, methylthio, ethylthio, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, fluoro, chloro, bromo, amidosulfonyl, Nmethylamidosulfonyl, hydroxymethyl, amidocarbonyl, carboxy, cyano, and Q ^b.

A is selected from the group consisting of a single covalent bond, NH, N (CH 3), CH ₂ , CH ₃ CH, and CH ₂ CH ₂ .

Q ^b is selected from the group consisting of NR ²⁰ R ²¹ and C (NR ²⁵ ) NR ²³ R ²⁴ , provided that Q ^b is directly attached to a carbon atom.

R ²⁰ , R ²¹ , R ²³ , R ²⁴ and R ²⁵ are independently selected from the group consisting of hydrido, methyl and ethyl.

Q ^is CH ₂ .

Another best embodiment of the invention is a compound of formula I having the specific formula I-EMPS wherein B is a non-cyclic substituent:

B

?, γΟ (I-EMPS), or a pharmaceutically acceptable salt thereof, wherein:

B is selected from the group consisting of hydrido, ethyl, 2-propenyl, 2-propynyl, propyl, isopropyl, butyl, 2-butenyl, 2-butynyl, n-butyl, tert-butyl, isobutyl, 2-methylpropenyl, 1pentyl , 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-hexinyl, 3-hexinyl, 4-hexinyl, 2-hexyl, 1-methyl-2-pentenyl, 1-methyl-3-pentenyl, 1-methyl-2pentinyl , 1-methyl-3-pentynyl, 3-hexyl, 1-ethyl-2-butenyl, 1-heptyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 2-heptinyl, 3-heptinyl, 4-heptinyl 5-heptinyl, 2-heptyl, 1-methyl-2-hexenyl, 1-methyl-3-hexenyl, 1-methyl-4-hexenyl, 1-methyl-2-hexinyl, 1-methyl-3-hexinyl, 1-methyl-4 -hexinyl, 3-heptyl, 1-ethyl-2-pentenyl, 1-ethyl-3-pentenyl, 1-ethyl-2-pentynyl, 1-ethyl-3pentinyl, 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, each member of the groups Y is optionally substituted on any carbon of up to 5 atoms including from the B to A binding site by one or more R ³² , R ³³ , R ³⁴ , R ³⁵ and R ³⁶ substituents.

R ³² , R ³³ , R ³⁴ , R ³⁵ and R ³⁶ are independently selected from the group consisting of hydrido, amidino, guanidino, methyl, ethyl, methoxy, ethoxy, hydroxy, amino, N-methylamino, dimethylamino, methylthio, ethylthio, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, fluoro, chloro, bromo, amidosulfonyl, Nmethylamidosulfonyl, hydroxymethyl, amidocarbonyl, carboxy, cyano, and Q ^b:

A is selected from the group consisting of a single covalent bond, NH, N (CH 3), CH ₂ , CH ₃ CH, and CH ₂ CH ₂ .

A is optionally selected from the group consisting of CH ₂ N (CH ₃ ), CH ₂ N (CH ₂ CH ₃ ), CH ₂ CH ₂ N (CH ₃ ) and CH ₂ CH ₂ N (CH ₂ CH ₃ ), provided that: B is hydrido.

Q ^b is selected from the group consisting of NR ²⁰ R ²¹ , C (NR ¹⁵ ) NR ²³ R ^24, and NR ²⁶ C (NR ²⁵ ) NR ²³ R ²⁴ , provided that Q ^b is attached directly to a carbon atom.

R ²⁰ , R ²¹ , R ²³ , R ²⁴ , R ²⁵ and R ²⁶ are independently selected from the group consisting of hydrido, methyl and ethyl.

-74Q ^with CH ₂

Yet another most preferred specific embodiment of the invention includes compounds of formula I having the specific formula I-EMPS, wherein B is a non-aromatic cyclic substituent:

(I-EMPS), or a pharmaceutically acceptable salt thereof, wherein.

B is optionally selected from the group consisting of cyclopropyl, cyclobutyl, oxethan-3-yl, azetidin-3-yl, thiaethan-3-yl, cyclopentyl and cyclohexyl, wherein each ring carbon atom is optionally substituted with R ³³ , a carbon or nitrogen atom in the ring the ring adjacent to the carbon in the binding site is optionally substituted with R ⁹ or R ¹³ , a carbon or nitrogen atom adjacent to the R ⁹ position and two atoms away from the point of attachment is optionally substituted with R ¹⁰ , a carbon or nitrogen atom adjacent to R ¹³ position and two atoms from the point of attachment are optionally substituted with R ¹² .

R ³³ is independently selected from the group consisting of hydrido, amidino, guanidino, methyl, ethyl, methoxy, ethoxy, hydroxy, carboxy, amino, N-methylamino, dimethylamino, methylthio, ethylthio, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, fluoro, chloro, bromo, amidosulfonyl, Nmethylamidosulfonyl, hydroxymethyl, amidocarbonyl, cyano, and Q ^b.

A is selected from the group consisting of a single covalent bond, ΝΉ, N (CH 3), CH ₂ , CH ₃ CH, and CH ₂ CH ₂ .

Q ^b is selected from the group consisting of NR ²⁰ R ²¹ and C (NR ²⁵ ) NR ²³ R ²⁴ , provided that Q ^b is directly attached to a carbon atom.

R ²⁰ , R ²¹ , R ²³ , R ²⁴ and R ²⁵ are independently selected from the group consisting of hydrido, methyl and

Q ^is CH ₂ .

The best specific embodiment of the invention comprises compounds of formula IEMPS:

(I-EMPS), or a pharmaceutically acceptable salt thereof, containing conventional structural units, wherein:

M is selected from the group consisting of N and R * -C.

R ¹ is selected from the group consisting of hydrido, hydroxy, amino, amidino, hydroxyamino, aminomethyl, methylamino, cyano, methyl, trifluoromethyl, methoxy, hydroxymethyl, methoxyamino, methylthio, trifluoromethoxy, fluoro and chloro.

R ^{2 is} Z ° -Q.

Z 0 is a single covalent bond.

Q is selected from the group consisting of phenyl, 2-thienyl, 2-furyl, 2-pyrrolyl, 2-imidazolyl, 2-thiazolyl, 3-isoxazolyl, 2-pyridyl and 3-pyridyl, wherein the carbon atom adjacent to the carbon at the binding site is optionally substituted with R ⁹ , another carbon atom adjacent to the carbon at the binding site is optionally substituted with R ¹³ , a carbon atom adjacent to the R ⁹ position and two atoms away from the point of attachment is optionally substituted with R ¹⁰ , a carbon atom adjacent to R ¹³ position and two the atoms from the point of attachment are optionally substituted with R ¹² and any carbon atom adjacent to R ¹⁰ and R ¹² is optionally substituted with R ¹¹ .

R ⁹ , R ¹¹ and R ¹³ are independently selected from the group consisting of hydrido, methyl, ethyl, methoxy, ethoxy, hydroxy; amino, N-methylamino, Ν, Ν-dimethylamino, methylthio, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, fluoro, chloro, bromo, amidosulfonyl, N-methylamidosulfonyl, Ν, dim-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, amidocarbonyl, N-methylamidocarbonyl, carboxy and cyano.

R ¹⁰ and R ¹² are independently selected from the group consisting of hydrido, amidino, amidocarbonyl, N-methylamidocarbonyl, guanidino, methyl, ethyl, methoxy, ethoxy, hydroxy, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, carboxy, carboxymethyl, amino, acetamido trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, trifluoroacetamido, aminomethyl, N-methylamino, dimethylamino, amidosulfonyl, N-methylamidosulfonyl, Ν, im-dimethylamidosulfonyl, methoxycarbonyl, fluoro, chloro, bromo and cyano.

Y 0 is selected from the group consisting of:

amidino, guanidino, methoxy, hydroxy, amino, aminomethyl, 1-aminoethyl, 2-aminoethyl, 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 invention may be used in anticoagulant therapy in the treatment and prevention of various thrombotic conditions such as coronary artery disease and cerebrovascular disease.

The compounds of the invention can be used to inhibit the serine proteases associated with the coagulation cascade and Factors II, VII, VHI, ΓΧ, X, XI or XII. The compounds of the invention may inhibit platelet aggregation, inhibit fibrin formation, inhibit thrombus formation, and inhibit embolism in mammals, blood, blood products, and mammalian organs. The compounds may also be used for the treatment and / or prevention of unstable angina pectoris, recurrent angina pectoris, myocardial infarction, transient ischemic attacks, atrial fibrillation, thrombotization, embolism, deep vein thrombosis, disseminated intravascular coagulopathy, or retinal coagulopathy (D) recanalized vessels in mammals. The compounds may also be used in preventive action in subjects at risk of developing these diseases. The compounds may also be used to reduce the risk of arteriosclerosis. The compounds of formula I could also be used in the prevention of stroke.

In addition to their use in human medicine, these compounds may be suitable for veterinary use in the treatment of domestic animals, exotic animals and breeding animals, including mammals, rodents, and others. More preferred is application to horses, dogs and cats.

Another embodiment of the invention includes novel compounds which are selected from the compounds listed in Examples 1 to 19 and Table 1.

Here, for clarity, the following definition of the generic terms used in the description of the invention.

Standard one-letter elementary symbols are used to represent a specific type of atom without further definition. 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 elemental symbols are used as defined by the elements in the Periodic Table of the Elements (for example, Cl represents chlorine, Se represents selenium, etc.).

As used herein, the term "alkyl" either alone or in other terms such as "haloalkyl" and "alkylthio" means an acyclic alkyl radical containing 1 to 10, preferably 3 to 8, and more preferably 3 to 6 carbon atoms. These alkyl radicals may be optionally substituted with the substituents listed below. Examples of these radicals include methyl, ethyl, chloroethyl, hydroxyethyl, n-propyl, oxopropyl, isopropyl, n-butyl, cyanobutyl, isobutyl, secbutyl, tert-butyl, pentyl, aminoethyl, isoamyl, hexyl, octyl and the like.

The term "alkenyl" refers to an unsaturated, acyclic hydrocarbon radical having at least one double bond. The alkenyl radical contains 2 to 10, preferably 3 to 8 and more preferably 3 to 6 carbon atoms. These alkyl radicals may be optionally substituted with the substituents listed below. These radicals may be optionally substituted with the substituents listed below. Examples of suitable alkenyl radicals include propenyl, 2-chloropropenyl, buten-1-yl, isobutenyl, penten-1-yl, 2-methylbuten-1-yl, 3-methylbuten-1-yl, hexen-1-yl, 3-hydroxyhexen-1-yl , hepten-1-yl and octen-1-yl and the like.

The term "alkynyl" refers to an unsaturated, acyclic hydrocarbon radical having at least one triple bond containing 2 to 10, preferably 3 to 8, and more preferably 3 to 6 carbon atoms. These alkyl radicals may be optionally substituted with the substituents listed below. These radicals may be optionally substituted with the substituents listed below. Examples of suitable alkynyl radicals include ethynyl, propynyl, hydroxypropinyl, butin-1-yl, butin-2-yl, pentin-1-yl, pentin-2-yl, 4-methoxypentin-2-yl, 3-methylbutin-1-yl, hexin 1-yl, hexin-2-yl, hexin-3-yl, 3,3-dimethylbutin-1-yl and the like.

The term "hydrido" means a separate hydrogen atom (H). This hydride radical may be attached, for example, to an oxygen atom to form a "hydroxyl" radical, one hydride radical may be attached to a carbon atom to form a "meth" radical CH = or two hydride radicals may be attached to a carbon atom to form a "methylene" radical (-CH ₂ -).

The term "carbon" radical means a carbon atom without any covalent bond and capable of forming four covalent bonds.

The term "cyano" radical means a carbon radical with three of the four covalent bonds shared with a nitrogen atom.

The term "hydroxyalkyl" refers to radicals wherein any one or more of the carbon atoms of the alkyl is substituted with hydroxyl as defined above. Specifically, the monohydroxyalkyl, dihydroxyalkyl and polyhydroxyalkyl radicals are designated.

The term "alkanoyl" refers to radicals wherein any one or more of the terminal carbon atoms of the alkyl are substituted with one or more of the carbonyl radicals listed below. Specifically, it refers to a monocarbonylalkyl and dicarbonylalkyl radical. Examples of monocarbonylalkyl radicals include formyl, acetyl and pentanoyl. Examples of dicarbonylalkyl radicals include oxalyl, malonyl and succinyl.

The term "alkylene" radical means a linear or branched radical having 2 to 10 carbon atoms, at least one double bond, and having binding sites for two or more covalent bonds. Examples of such radicals include 1,1-vinylidene (CH 2 = C), 1,2-vinylidene (-CH = CH-) and 1,4-butadienyl (-CH = CH-CH = CH-).

The term "halogen" means halogens such as fluorine, chlorine, bromine or iodine atoms.

The term "haloalkyl" refers to radicals wherein any one or more carbon atoms are substituted with halogen as defined above. Specifically, it refers to a monohaloalkyl, dihaloalkyl and polyhaloalkyl radical. The monohaloalkyl radical may contain, for example, either a bromine, chlorine or fluorine atom in the radical structure. The dihaloalkyl radicals may have two identical halogen atoms or a combination of different halogen radical atoms and the polyhaloalkyl radical may contain more than two identical halogen atoms or a combination of different halogen radicals. The most preferred haloalkyl radicals are "lower haloalkyl" radicals having 1 to 6 carbon atoms. Examples of such haloalkyl radicals include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, trifluoroethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl.

The term "hydroxyahaloalkyl" refers to radicals wherein any one or more of the haloalkyl carbon atoms are substituted with a hydroxy group as defined above. Examples of "hydroxyhaloalkyl" radicals include hexafluorohydroxypropyl.

The term "haloalkylene radical" refers to alkylene radicals wherein any one or more carbon atoms of the alkylene are substituted with halogen as defined

-80vyššie. The dihaloalkylene radicals may have two identical halogen atoms or a combination of different halogen radical atoms and the polyhaloalkyl radical may contain more than two identical halogen atoms or a combination of different halogen radicals. More preferred haloalkylene radicals are "lower haloalkylene" radicals having 1 to 6 carbon atoms. Examples of such haloalkylene radicals include difluoromethylene, tetrafluoroethylene, tetrachlorethylene, alkyl substituted monofluoromethylene and aryl substituted trifluoromethylene.

The term "haloalkenyl" means linear or branched radicals having 1 to 10 carbon atoms and having one or more double bonds, wherein one or more carbon atoms of the alkenyl are substituted with halogens as defined above. The dihaloalkyl radicals may have two identical halogen atoms or a combination of different halogen radical atoms and the polyhaloalkyl radical may contain more than two identical halogen atoms or a combination of different halogen radicals.

The terms " alkoxy " and " alkoxyalkyl " linear or branched oxygen-containing radicals having 1 to 10 carbon atoms in the alkyl moiety. The term "alkoxyalkyl" also refers to alkyl radicals having one or more alkoxy radicals attached to an alkyl radical, i.e., they form monoalkoxyalkyl and dialkoxyalkyl radicals. More preferred alkoxy radicals are "lower alkoxy radicals of one to six carbon atoms". Examples of such radicals include methoxy, ethoxy, propoxy, butoxy, isopropoxy and tert-butoxy alkyls. The "alkoxy" radicals may be further substituted by one or more halogen atoms such as fluorine, chlorine or bromine to form "haloalkoxy" and "haloalkoxyalkyl" radicals. Examples of such haloalkoxy radicals include fluoromethoxy, chloromethoxy, trifluoromethoxy, difluoromethoxy, trifluoroethoxy, fluoroethoxy, tetrafluoroethoxy, pentafluoroethoxy and fluoropropoxy. Examples of such haloalkoxyalkyl radicals include fluoromethoxymethyl, chloromethoxyethyl, trifluoromethoxymethyl, difluoromethoxyethyl and trifluoroethoxymethyl.

The terms "alkenyloxy" and "alkenyloxyalkyl" represent linear or branched oxygen-containing radicals having an alkenyl moiety of from 2 to 10 carbon atoms, such as an ethyleneoxy or propyleneoxy radical. The term "alkenyloxyalkyl" also refers to alkenyl radicals having one or more alkenyloxy radicals attached to an alkyl radical, i.e., a monoalkenyloxyalkyl and a dialkenyloxyalkyl radical are formed. More preferred alkenyloxy radicals are "lower alkenyloxy" radicals having 2 to 6 carbon atoms. Examples of such radicals include ethyleneoxy, propylenoxy, butenyloxy and isopropenyloxy alkyl. The "alkenyloxy" radicals may be further substituted with one

-81 or two halogen atoms such as fluorine, chlorine or bromine to form "haloalkenyloxy" radicals. Examples of such radicals include trifluoroetenyloxy, fluoroetenyloxy, difluoroetenyloxy and fluoropropenyloxy.

The term "haloalkoxyalkyl" also refers to alkyl radicals having one or more haloalkoxy radicals bonded to an alkyl radical, i.e., a monohaloalkoxyalkyl and dihaloalkoxyalkyl radical are formed.

The term "haloalkenyloxy" includes oxygen radicals with one or more haloalkenyloxy radicals attached to an oxygen radical, i.e., a monohaloalkenyloxy and dihaloalkenyloxy radicals are formed. The term "haloalkenyloxyalkyl" also refers to alkyl radicals with one or more haloalkenyloxy radicals attached to an alkyl radical, i.e., a monohaloalkenyloxy and dihaloalkenyloxy radical are formed.

The term "alkylenedioxy" means an alkylene radical with at least two oxygen atoms bound to one alkylene group. Examples of "alkylenedioxy" radicals include methylenedioxy, ethylenedioxy, alkyl substituted methylenedioxy and aryl substituted methylenedioxy. The term "haloalkylledioxyl" radical refers to haloalkylene radicals having at least two oxy groups bonded to one haloalkyl group. Examples of "haloalkylenedioxy" radicals include. difluoromethylenedioxy, tetrafluoroethylenedioxy, tetrachloroethylenedioxy, alkyl substituted monofluoromethylenedioxy and aryl substituted monofluoromethylenedioxy.

The term "aryl" alone or in combination means a carbocyclic aromatic system containing one, two or three rings, wherein the rings may be joined together "serially" in succession or fused. The term "fused" means that the second ring shares two adjacent atoms with the first ring. The term "fused" is equivalent to the term "condensed". The term "aryl" refers to aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, indane, and biphenyl.

The term "perhalogenaryl" represents aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, indane and biphenyl, wherein the aryl radical is substituted with 3 or more halogen radicals as defined above.

The term "heterocyclyl" refers to saturated and partially saturated ring radicals having a heteroatom of 4 to 15 ring atoms, referred to herein as C4 to 05 heterocyclyl, selected from carbon, nitrogen, sulfur and oxygen, wherein at least one ring atom is a heteroatom. Heterocyclic radicals may contain one, two or three rings, where the rings may be "serially" joined in series or fused. Examples of saturated heterocyclic

-82 radicals include a saturated 3 to 6 membered heteromonocyclic group containing 1 to 4 nitrogen atoms (e.g. pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl etc.), a saturated 3 to 6 membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms (eg morpholinyl, etc.), a saturated 3 to 6 membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms (e.g., thiazolidinyl, etc.). Examples of partially saturated heterocyclic radicals include dihydrothiophene, dihydropyran, dihydrofuran and dihydrothiazole. Non-exhaustive examples of heterocyclic derivatives include 2-pyrrolinyl, 3-pyrrolinyl, pyrolinidyl, 1,3-dioxolanyl, 2H-pyranyl, 4H-pyranyl, piperidinyl,

1,4-dioxanyl, morpholinyl, 1,4-dithianyl, thiomorpholinyl and the like.

The term "heteroaryl" represents a fully unsaturated ring aromatic heteroatom containing 5 to 15 ring atoms radicals selected from carbon, nitrogen, sulfur and oxygen, wherein at least one ring atom is a heteroatom. Heteroaryl radicals may contain one, two or three rings, where these rings may be "serially" joined in series or fused. Examples of "heteroaryl" radicals include an unsaturated 5-6 membered heteromonocyclic group containing 1 to 4 nitrogen atoms, for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, 2-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (e.g. 4H-1) , 2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl), tetrazolyl (e.g. ΙΗ-tetrazolyl, 2H-tetrazolyl, etc.), etc., an unsaturated condensed heterocyclic group containing 1 up to 5 nitrogen atoms such as indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl (e.g. tetrazolo [1,5-b] pyridazinyl etc.), etc., unsaturated 3-6 membered heterocyclic group containing such as pyranyl, 2-furyl, 3-furyl, etc., an unsaturated 5-6 membered sulfur-containing heteromonocyclic group, e.g. 2-thienyl, 3-thienyl, etc., an unsaturated 5-6 membered heteromonocyclic group containing having 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example oxazolyl, isoxazolyl, oxadiazolyl (e.g.

1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.), etc., an unsaturated condensed heterocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms (e.g. benzoxazolyl, benzoxadiazolyl, etc.). ), an unsaturated 5-6 membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms such as thiazolyl, thiadiazolyl (e.g.

1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, etc.), etc., an unsaturated condensed heterocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms (e.g. benzothiazolyl, benzothiadiazolyl, etc.). ) and so on. The term also includes radicals in which heterocyclic radicals are fused to aryl radicals. Examples of such fused bicyclic radicals include benzofuran, benzothiophene and the like. "Heterocyclyl"

The radicals may have 1 to 3 substituents as defined below. Preferred heterocyclic radicals include 5-12 membered fused or unfused radicals. Non-limiting examples of heteroaryl radicals include pyrrolyl, pyridinyl, pyridyloxy, pyrazolyl, triazolyl, pyrimidinyl, pyridazinyl, oxazolyl, thiazolyl, imidazolyl, indolyl, thiophenyl, furanyl, tetrazolyl, 2-imidazolinyl, imidazolidinyl, 2-pyrazololinyl, 1-pyrazololinyl, 1-pyrazololinyl, 1-pyrazololyl, pyrazolol, , 2,3-oxadiazolyl, 1,2,3-triazolyl, 1,3,4-thiadiazolyl, pyrazinyl, piperazinyl, 1,3,5-triazinyl, 1,3,5-triazianyl, benzo (b) thiophenyl, benzimidazolyl, quinolinyl, tetrazolyl and so on.

The term "sulfonyl" when used alone or in conjunction with other terms such as alkylsulfonyl means respectively the divalent radical -SO 2 -. "Alkylsulfonyl" refers to an alkyl radical attached to a sulfonyl radical, wherein alkyl is as defined above. "Alkylsulfonylalkyl" includes alkylsulfonyl radicals attached to alkyl radicals, where alkyl is as defined above. "Haloalkylsulfonyl" means a haloalkyl radical attached to a sulfonyl radical, wherein haloalkyl is as defined above. Haloalkylsulfonylalkyl "refers to a haloalkylsulfonyl radical attached to an alkyl radical where alkyl is as defined above. The term "aminosulfonyl" means an amino radical attached to a sulfonyl radical.

The term "sulfinyl" when used alone or in conjunction with other terms such as alkylsulfinyl means respectively the divalent radical -S (O) -. "Alkylsulfinyl" refers to an alkyl radical attached to a sulfinyl radical, wherein alkyl is as defined above. "Alkylsulfinylalkyl" includes alkylsulfinyl radicals attached to alkyl radicals, where alkyl is as defined above. "Haloalkylsulfinyl" means a haloalkyl radical attached to a sulfinyl radical, wherein haloalkyl is as defined above. Haloalkylsulfinylalkyl "refers to a haloalkylsulfinyl radical attached to an alkyl radical where alkyl is as defined above.

The term "aralkyl" refers to an aryl-substituted alkyl radical. Preferred aralkyl radicals are "lower aralkyl" radicals with an aryl radical attached to an alkyl radical of one or six carbon atoms. Examples of such radicals include benzyl, diphenylmethyl, triphenylmethyl, phenylethyl and diphenylethyl. The terms benzyl and phenylmethyl are interchangeable.

The term "heteroaralkyl" refers to a heteroaryl substituted alkyl radical, wherein the heteroaralkyl radical may be further substituted with one or more substituents as defined above for aralkyl radicals. The term "perhaloaralkyl" includes an aryl-substituted alkyl radical, wherein the aralkyl radical is substituted with three or more halogen radicals as defined above.

The term "aralkylsulfinyl" represents aralkyl radicals attached to the sulfinyl radical, wherein aralkyl is as defined above. "Aralkylsulfinylalkyl" refers to aralkylsulfinyl radicals attached to alkyl radicals, wherein alkyl is as defined above.

The term "aralkylsulfonyl" represents aralkyl radicals attached to a sulfonyl radical, wherein aralkyl is as defined above. "Aralkylsulfonylalkyl" refers to aralkylsulfonyl radicals attached to alkyl radicals, wherein alkyl is as defined above.

The term "cycloalkyl" refers to radicals of 3 to 15 carbon atoms. More preferred cycloalkyl radicals are "lower cycloalkyl" radicals having 3 to 7 carbon atoms. Examples include radicals such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. The term cycloalkyl includes radicals of 7 to 15 atoms and two to four rings. Examples include radicals such as norbomyl (i.e., bicyclo [2.2.1] heptyl) and adamantyl. The term "cycloalkylalkyl" refers to cycloalkyl-substituted alkyl radicals. Preferred cycloalkylalkyl radicals are "lower cycloalkylalkyl" radicals containing a cycloalkyl radical attached to an alkyl radical of 1 to 6 carbon atoms. Examples of such radicals include cyclohexylhexyl. The term "cycloalkenyl" represents radicals containing 3 to 10 carbon atoms and one or more carbon-carbon double bonds. Preferred cycloalkenyl radicals are "lower cycloalkenyl" radicals with three to seven carbon atoms. Examples include radicals such as cyclobutenyl, cyclopentenyl, cyclohexenyl and cycloheptenyl. The term "halocycloalkyl" refers to radicals wherein one or more cycloalkyl carbon atoms are substituted with halo as defined above. Specifically, it denotes monohalocycloalkyl, dihalocycloalkyl and polyhalocycloalkyl radicals. For example, the monohalocycloalkyl radical may contain either a bromine, chlorine or fluorine atom in the radical structure. The dihalogen radicals may contain two identical halogen atoms or a combination of different halogen radicals and the polyhalocycloalkyl radicals may contain more than two identical halogen atoms or a combination of different halogen radicals. More preferred halocycloalkyl radicals are "lower halocycloalkyl" radicals having 3 to 8 carbon atoms. Examples of such halocycloalkyl radicals include fluorocyclopropyl, difluorocyclobutyl, trifluorocyclopentyl, tetrafluorocyclohexyl and dichlorocyclopropyl. The term "halocycloalkenyl" refers to radicals wherein one or more cycloalkenyl carbon atoms are substituted with halogen as defined above. Specifically, it refers to monohalocycloalkenyl, dihalocycloalkenyl and polyhalocycloalkenyl radicals.

-85The term cycloalkoxy represents cycloalkyl radicals attached to an oxy radical. Examples of such radicals include cyclohexoxy and cyclopentoxy. The term "cycloalkoxyalkyl" also means an alkyl radical having one or more cycloalkoxy radicals attached to an alkyl radical, i.e., a monocycloalkoxyalkyl and dicycloalkoxyalkyl radical are formed. Examples of such radicals include cyclohexoxyethyl. "Cycloalkoxy" radicals may be further substituted with one or more halogen atoms such as fluorine, chlorine or bromine to form "halocycloalkoxy" radicals and "halocycloalkoxyalkyl" radicals.

The term "cycloalkyloxy" refers to a cycloalkyl radical attached to an alkoxy radical. Examples of such radicals include cyclohexylmethoxy and cyclopentyl methoxy.

The term "cycloalkenyloxy" denotes cycloalkenyl radicals attached to an oxy radical. Examples of such radicals include cyclohexenyloxy and cyclopentenyloxy. The term "cycloalkenyloxyalkyl" also refers to an alkyl radical having one or more cycloalkenyloxy radicals attached to an alkyl radical, i.e., a monocycloalkenyloxyalkyl and a dicycloalkenyloxyalkyl radical are formed. Examples of such radicals include cyclohexenyloxyethyl. "Cycloalkenyloxy" radicals may be further substituted with one or more halogen atoms such as fluorine, chlorine or bromine to form "halocycloalkenyloxyalkyl" and "halocycloalkenyloxyalkyl" radicals.

The term "cycloalkylenedioxyl" radical means a cycloalkylene radical with at least two oxygen attached to one cycloalkylene group. Examples of "alkylenedioxy" radicals include 1,2-dioxycyclohexylene.

The term "cycloalkylsulfinyl" refers to cycloalkyl radicals attached to a sulfinyl radical, where cycloalkyl is as defined above. "Cycloalkylsulfmylalkyl" refers to a cycloalkylsulfinyl radical attached to an alkyl radical where alkyl is as defined above. The term "cycloalkylsulfonyl" refers to cycloalkyl radicals attached to a sulfonyl radical, where cycloalkyl is as defined above. "Cycloalkylsulfonylalkyl" refers to a cycloalkylsulfonyl radical attached to an alkyl radical where alkyl is as defined above.

The term "cycloalkylalkanoy" refers to radicals wherein one or more of the cycloalkyl carbon atoms are substituted with one or more carbonyl radicals as defined below. Specifically, monocarbonylcycloalkyl and dicarbonylcycloalkyl radicals are designated. Examples of monocarbonylcycloalkyl radicals include cyclohexylcarbonyl, cyclohexylacetyl and cyclopentylcarbonyl. Examples of dicarbonylcycloalkyl radicals include 1,2-dicarbonylcyclohexane.

The term "alkylthio" includes radicals containing a linear or branched alkyl radical of one to ten carbon atoms attached to a divalent sulfur atom. More preferred alkylthiol radicals are "lower alkylthiol" radicals having one to six carbon atoms. An example of a "lower alkylthiol" is methylthio (CH 3 -S-). The "alkylthio" radicals may be further substituted with one or more halogen atoms, such as fluorine, chlorine or bromine, to form "haloalkylthio" radicals. Examples of such radicals include fluoromethylthio, chloromethylthio, trifluoromethylthio, difluoromethylthio, trifluoroethylthio, fluoroethylthio, tetrafluoroethylthio, pentafluoroethylthio and fluoropropylthio.

The term "alkylarylamino" refers to radicals containing a linear or branched alkyl radical of 1 to 10 carbon atoms attached together with one aryl radical to an amino radical. Examples include N-methyl-4-methoxyaniline, N-ethyl-4-methoxyaniline and N-methyl-4-trifluoromethoxyaniline.

The term akylamino means "monoalkylamino" and "dialkylamino" - one or two alkyl radicals respectively linked to the amino radical.

The term arylamino means "monoarylamino" and "diarylamino" - one or two aryl radicals respectively linked to an amino radical. Examples of such radicals include N-phenylamino and N-naphthylamino.

The term "aralkylamino" refers to aralkyl radicals attached to an amino radical, wherein aralkyl is as defined above. The term aralkylamino means "monoaralkylamino" and "diaralkylamino" - one or two aralkyl radicals respectively linked to the amino radical. The term aralkylamino further means "monoaralkyl monoalkylamino" - one aralkyl and one alkyl radical attached to an amino radical.

The term "arylsulfinyl" refers to radicals containing an aryl radical, as defined above, attached to a divalent sulfur atom S (O). The term "arylsulfinylalkyl" means an arylsulfinyl radical attached to a linear or branched alkyl radical of 1 to 10 carbon atoms.

The term "arylsulfonyl" refers to aryl radicals attached to a sulfonyl radical, wherein aryl is as defined above. The term "arylsulfonylalkyl" means an arylsulfonyl radical attached to, wherein alkyl is as defined above.

The term "heteroarylsulfinyl" refers to radicals containing a heteroaryl radical, as defined above, attached to a divalent sulfur atom S (O). The term "heteroarylsulfinylalkyl" means a heteroarylsulfinyl radical attached to a linear or branched alkyl radical of 1 to 10 carbon atoms. The term "heteroarylsulfonyl" refers to heteroaryl radicals attached to a sulfonyl radical, wherein the heteroaryl is as defined above. Term

-87 "heteroarylsulfonylalkyl" means an arylsulfonyl radical bonded to, wherein alkyl is as defined above.

The term "aryloxy" refers to aryl radicals, as defined above, attached to an oxygen atom. Examples of such radicals 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-dimethylphenoxy, 5-bromo-2-fluorophenoxy,

4-bromo-3-fluorophenoxy, 4-fluoro-3-methylphenoxy, 5,6,7,8-tetrahydronaphthyloxy, 3-isopropylphenoxy, 3-cyclopropylphenoxy, 3-ethylphenoxy, 3-pentafluoroethylphenoxy, 3- (1,1,2,2) , 2-tetrafluoroethoxy) phenoxy and 4-tert-butylphenoxy.

The term "aralkanoyl" refers to aralkyl radicals, as defined above, attached to a carbonyl radical, as defined above. Examples of such radicals include, for example, phenylacetyl.

The term "aralkoxy" refers to aralkyl radicals containing an oxy group bonded via an oxygen atom to other radicals. More preferred aralkoxy radicals are "lower aralkoxy" radicals containing a phenyl radical bonded to lower alkoxy radicals as described above. Examples of such radicals include benzyloxy, 1-phenylethoxy, 3-trifluoromethoxybenzyloxy, 3-trifluoromethylbenzyloxy, 3,5-difluorobenzyloxy, 3-bromobidvenzyloxy, 4-propylbenzyloxy, 2-fluoro-3-trifluoromethylbenzyloxy and 2-phenylethoxy.

The term "aryloxyalkyl" refers to aryloxy radicals, as defined above, attached to an alkyl group. Examples of such radicals include phenoxymethyl.

The term "haloaryloxyalkyl" represents an aryloxyalkyl radical as defined above wherein 1 to 5 halogen radicals are attached to an aryloxy group.

The term "heteroaroyl" refers to a heteroaryl radical, as defined above, attached to a carbonyl radical, as defined above. Examples of such radicals include furoyl and nicotinyl. ¹ ,

The term "heteroaralkanoyl" refers to a heteroaralkyl radical, as defined above, attached to a carbonyl radical, as defined above. Examples of such radicals include, for example, pyridylacetyl and furylbutyryl.

The term "heteroaralkoxy" represents a heteroaralkyl radical containing an oxy group bonded via an oxygen atom to another radical. More preferred heteroaralkoxy radicals are "lower heteroaralkoxy" radicals containing a heteroaryl radical bonded to a lower alkoxy radical as described above.

The term "halo heteroaryloxy alkoxy" refers to a heteroaryloxyalkyl radical as defined above, wherein 1 to 4 halogen radicals are attached to a heteroaryloxy radical.

The term "heteroarylamino" represents a heterocyclic radical, as defined above, attached to an amino group. Examples of such radicals include pyridylamino.

The term "heteroarylaminoalkyl" represents a heteroarylamino radical, as defined above, attached to an alkyl radical. Examples of such radicals include pyridylmethylamino.

The term "heteroaryloxy" refers to a heterocyclic radical, as defined above, attached to an oxy group. Examples of such radicals include 2-thiophenyloxy, 2-pyrimidyloxy, 2-pyridyloxy, 3-pyridyloxy and 4-pyridyloxy.

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

The term "arylthio" refers to an aryl radical, as defined above, attached by a sulfur atom. Examples of such radicals include phenylthio.

The term "arylthioalkyl" refers to an arylthiol radical, as defined above, attached to an alkyl radical. Examples of such radicals include phenylthiomethyl.

The term "alkylthioalkyl" refers to an alkylthiol radical, as defined above, attached to an alkyl radical. Examples of such radicals include methylthiomethyl.

The term "alkoxyalkyl" refers to alkoxy radicals, as defined above, attached to an alkyl radical. Examples of such radicals include methoxymethyl.

The term "carbonyl" means a carbon radical containing 2 to 4 covalent bonds shared with an oxygen atom. The term "carboxy" refers to a hydroxyl radical, as defined above, attached to one of two non-shared bonds in the carbonyl group. The term "carboxamide" means amino, monoalkylamino, dialkylamino, monocycloalkylamino, alkylcycloalkylamino and dicycloalkylamino radicals which bind to one of two non-shared bonds in the carbonyl group. The term "carboxamidoalkyl" means a carboxamide radical, as defined above, attached to an alkyl radical. The term "carboxyalkyl" means a carboxyl radical, as defined above, attached to an alkyl radical. The term "carboalkoxy" represents an alkoxy radical, as defined above, attached to one of two non-shared bonds in the carbonyl group. The term "carboalkoxy" represents an aralkoxy radical, as defined above, attached to one of two non-shared bonds in the carbonyl group. The term "monocarboalkoxyalkyl" refers to a single carboalkoxy radical, as defined above, attached to an alkyl radical. The term "dicarboalkoxyalkyl" refers to two carboalkoxy radicals, as defined above, attached to an alkylene radical. The term "monocyananoalkyl" refers to one

-89 cyano radical, as defined above, attached to an alkyl radical. The term "dicyanoalkylene" refers to two cyano radicals, as defined above, attached to an alkyl radical. The term "carboalkoxycyanoalkyl" means a cyano radical, as defined above, attached to a carboalkoxyalkyl radical.

The term "acyl" alone or in combination means a carbonyl or thionocarbonyl radical attached to a radical selected from, for example, hydrido, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkoxyalkyl, haloalkoxy, aryl, heterocyclyl, heteroaryl, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkyl, cycloalkylakyl, cycloalkenyl, alkylthio, arylthio, amino, alkylamino, dialkylamino, aralkoxy, arylthio and alkylthioalkyl. Examples of "acyls" are formyl, acetyl, benzoyl, trifluoroacetyl, phthaloyl, maloyl, nicotinyl and the like. The term "haloalkanoyl" refers to one or more halogen radicals, as defined above, attached to an alkanoyl radical, as defined above. Examples of such radicals include, for example, chloroacetyl, trifluoroacetyl, bromopropanoyl and heptafluorobutanoyl.

The term "phosphono" means pentavalent phosphorus bound by two covalent bonds to an oxygen radical. The term "dialkoxyphosphono" means two alkoxy radicals, as defined above, attached to the phosphone radical by two covalent bonds. The term "diaralkoxyphosphono" means two aralkoxy radicals, as defined above, attached to the phosphone radical by two covalent bonds. The term "dialkoxyphosphonoalkyl" means a dialkoxyphosphone radical, as defined above, attached to an alkyl radical. The term "diaralkoxyphosphonoalkyl" means a diaralkoxyphosphone radical, as defined above, attached to an alkyl radical.

The term "amino" means a nitrogen atom with two substituents such as hydrido, hydroxy or alkyl and with one covalent bond capable of bonding to one atom, such as a carbon atom. Examples of such amino radicals include, for example, -NH ₂ , -NHCH ₃ , -ΝΉΟΗ and -NHOCH ₃ . The term "imino" means a nitrogen atom with one substituent such as hydrido, hydroxy or alkyl and with two covalent bonds capable of bonding to one atom, such as a carbon atom. Examples of such imino radicals include, for example, = NH, = NCH ₃ , = NOH, and = NOCH ₃ . The term "imino carbonyl" represents a carbon radical with two of the four covalent bonds shared with the imino group. Examples of such imino carbonyl radicals include, for example, C = NH, C = NCH ₃ , C = NOH, and C = NOCH ₃ . The term "amidino" refers to a substituted or unsubstituted amino group attached by one of two available bonds to the iminocarbonyl radical. Examples of such amidine radicals include, for example, NH ₂ -C = NH, NH ₂ -C = NCH ₃ , NH ₂ -C = NOH and CH ₃ NH-C = NOH.

The term "guanidino" refers to an amidine group bonded to an amino group as defined above, wherein said amino group may be bonded to a third group. Examples of such guanidine radicals include, for example, NH ₂ -C (NH) -NH-, NH ₂ -C (NCH ₃ ) -NH-, NH ₂ -C (NOCH ₃ ) -NH- and CH ₃ NH-C (NOH) -NH- .

The term "sulfonium" means a positively charged trivalent sulfur atom, wherein the sulfur is substituted with three carbon-based substituents such as alkyl, alkenyl, aralkyl or aryl. The term "dialkyl sulfonium" means a sulfonium group wherein the sulfur is substituted with two alkyl substituents. Examples of such dialkylsulfonium radicals include, for example, (CH ₃ ) 2 S ⁺ -. The term "dialkyl sulfonium alkyl" means a dialkylsulfonium group which is bound by one bond to an alkylene group as defined above. Examples of such dialkylsulfonium alkyl radicals include (CHASCH ₂ CH ₂ -.

The term "phosphonium" refers to a positively charged tetravalent phosphorus atom, wherein phosphorus is substituted with four carbon substituents such as alkyl, alkenyl, aralkyl or aryl. The term "trialkylphosphonium" refers to a phosphonium group wherein the phosphorus is substituted with three alkyl groups. Examples of such trialkylphosphonium radicals include, for example, (CH ₃ ) ₃ P 1.

The previously defined groups "alkyl", "alkenyl", "alkynyl", "alkanoyl", "alkylene", "alkenylene", "hydroxyalkyl", "haloalkyl", "haloalkylene", "haloalkenyl", "alkoxy", "alkenyloxy" , "Alkenyloxyalkyl", "alkoxyalkyl", "aryl", "perhalogenaryl", "haloalkoxy", "haloalkoxyalkyl", "haloalkenyloxy", "haloalkenyloxyalkyl", "alkylenedioxy", "haloalkylenedioxy", "heterocyclyl", "heteroaryl", "heteroaryl" "Alkylsulfonyl", "haloalkylsulfonyl", "alkylsulfonylalkyl", "haloalkylsulfonylalkyl", "alkylsulfinyl," alkylsulfinylalkyl "," haloalkylsulfinylalkyl "," aralkyl "," heteroaralkyl "," perhaloaralkyl "," aralkylsulfinyl "," aralkylsulfonyl "," aralkylsulfonyl " "Aralkylsulfinylalkyl", "cycloalkyl", "cycloalkylalkanoyl", "cycloalkylalkyl", "cycloalkenyl", "halocycloalkyl", "ha logocycloalkenyl "," cycloalkylsulfinyl, "cycloalkylsulfinylalkyl", "cycloalkylsulfonyl", "cycloalkylsulfonylalkyl," cycloalkoxy "," cyclaalkoxyalkyl "," cycloalkylalkoxy "," cycloalkenyloxy "," cycloalkenyloxyalkyl, "" cycloalkenyloxyalkyl, "" cycloalkenyloxyalkyl, "" halocycloalkenyloxy "," halocycloalkenyloxyalkyl "," alkylthio "," haloalkylthio "," amino "," oxy "," thio "," alkylamino "," arylamino "," aralkylamino "," arylsulfinyl "," arylsulfinylalkyl "," arylsulfonyl " , "Arylsulfonylalkyl", "heteroarylarylsulfinyl", "heteroarylsulfinylalkyl", "heteroarylsulfonyl", "heteroarylsulfonylalkyl," heteroarylamino "," heteroarylaminoalkyl ".

-91 "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-hydrido substituents such as amidino, guanidino , dialkylsulfonium, trialkylphosphonium, dialkylsulfoniumalkyl, perhalogénaralkyl, aralkyl, Aralkylsulfonylalkyl, aralkylsulfmyl, Aralkylsulfinylalkyl, halocycloalkyl, halogéncykloalkenyl, cykloalkylsulfmyl, Cycloalkylsulfinylalkyl, cycloalkylsulfonyl, Cycloalkylsulfonylalkyl, heteroarylamino, N-heteroarylamino, N-alkylamino, heteroarylaminoalkyl, heteroaryloxy, heteroaryloxyalkyl, haloalkylthio, alkanoyloxy, alkoxy , alkoxyalkyl, haloalkoxyalk yl, heteroaralkoxy, cycloalkoxy, cycloalkenyloxy, cycloalkoxyalkyl, cycloalkylalkoxy, cycloalkenyloxyalkyl, cycloalkylenedioxy, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxy, halocycloalkenyalkylalkyl, alkyl, aryl, lower alkyl, thio, lower alkyl , alkylsulfinylalkyl, arylsulfinylalkyl, arylsulfonylalkyl, heteroarylsulfinylalkyl, Heteroarylsulfonylalkyl, alkylsulfonyl, alkylsulfonylalkyl, halogénalkylsulfmylalkyl, halogénalkylsulfonylalkyl, alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, monoarylamidosulfonyl, arylsulfonamido, diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl, arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl , alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, haloalkanoyl, alkyl, alkenyl, alkynyl, alkenyloxy, alkenyloxy alkyl, alkylenedioxy, haloalkylenedioxy, cycloalkyl, cycloalkylalkanoyl, cycloalkenyl, low cycloalkylalkyl, lower cycloalkenylalkyl, halo, haloalkyl, haloalkenyl, haloalkoxy, hydroxyhaloalkyl, hydroxyaralkyl, hydroxyalkylalkyl, alkyl, hydroxyalkyl, aminoalkyl, hydroxyhetero, , partially saturated heterocyclyl, heteroaryl, heteroaryloxy, heteroaryloxyalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, heterorylalkenyl, carboxyalkyl, carboalkoxy, alkoxycarbonyl, carboaralkoxy, carboxamido, carboxamidoalkyl, cyano, carbohalogenoalkoxy, phosphonoarphonoalonoxy, phosphono, phosphono, phosphono, phosphono, phosphono, phosphono, phosphono.

The term "hanger" may include a covalent bond and a linear backbone substituent of from 1 to 7 atoms in length. The arm may have from 1 to 7 atoms in the univalent or multivalent chain. The divalent chain may be formed by radicals selected from = C (H) -,

-92 = C (R ^2a ) -, -Ο-, -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 ² 'is selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, aryloxyalkyl, alkoxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkoxyalkyl, perhaloaralkyl, heteroarylalkyl, heteroaryloxyalkyl, heteroarythioalkyl and heteroarylalkenyl. Multivalent chains may be formed by a straight chain of 1 to 7 atoms or a straight chain of 1 to 6 side chain atoms. The chain may be formed by one or more radicals selected from the group of lower alkylene, lower alkenyl, -O-, -O-CH 2 -, -S-CH ₂ -, -CH ₂ CH ₂ -, ethenyl, CH = CH (OH) - , -OCH ₂ O-, -O (CH ₂ ) ₂ O-, -NHCH ₂ -, -OCH (R ^2a ) 0-, -O (CH ² CHR ^2a ) O -, - OCF ² O -, - O (CF ₂ ) ₂ O-, -S, -S (0) -, -S (0) _2, -N (H) -, -N (H) 0-, -N (R ²⁾ 0-, -N (R ² ) -, -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 -N (R ^2a ) CH ₂ - a many other radicals as defined above or generally known or ascertainable by those skilled in the art. The side chains may be substituted with one or more substituents other than hydrido such as amidino, guanidino, dialkylsulfonium, trialkylphosphonium, dialkylsulfoniumalkyl, perhaloaralkyl, aralkylsulfonyl, aralkylsulfonylalkyl, cycloalkylsulfinyl, cycloalkylsulfinyl, haloalkylsulfinylalkyl, haloalkylsulfinylalkyl, haloalkylsulfinylalkyl, haloalkylsulfinylalkyl, haloalkylsulfinyl; N-heteroarylamino, N-alkylamino, heteroarylaminoalkyl, heteroaryloxy, heteroaryloxyalkyl, haloalkylthio, alkanoyloxy, alkoxy, alkoxyalkyl, haloalkoxyalkyl, heteroaralkoxy, cycloalkoxy, cycloalkenyloxy, cycloalkoxyalkyl, cycloalkylalkoxy, haloalkoxyenyloxy, cycloalkenyloxyloxy, cycloalkyleneoxy, cycloalkoxyenyloxyalkyl, cycloalkyleneoxy thio, nitro, lower alkylamino, alkylthio, alkylthioalkyl, arylamino, aralkylamino, arylthio, arylthioalkyl, heteroaralkoxyalkyl, alkylsulfinyl, alkylsulfinyla lkyl, arylsulfinylalkyl, arylsulfonylalkyl, heteroarylsulfinylalkyl, Heteroarylsulfonylalkyl, alkylsulfonyl, alkylsulfonylalkyl, halogénalkylsulfinylalkyl, halogénalkylsulfonylalkyl, alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, monoarylamidosulfonyl, arylsulfonamido, diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl, arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfmyl, heteroarylsulfonyl, alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, haloalkanoyl, alkyl, alkenyl, alkynyl, alkenyloxy, alkenyloxyalkyl, alkylenedioxy, haloalkylenedioxy, cycloalkyl, cycloalkylalkanoyl, alkyl, cycloalkenyl, low-lower cycloalkylalenyl, hydroxyaralkyl, hydroxyalkyl.

-93 aminoalkyl, hydroxyheteroralkyl, haloalkoxyalkyl, aryl, aralkyl, aryloxy, aralkoxy, aryloxyalkyl, saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl, heteroaryloxy, heteroaryloxyalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, carboxyalkyl, carboxyalkyl, carboxyalkyl, carboxyalkyl, carboxyalkyl, carboxyalkyl, carboxyalkyl, carboxyalkyl, carboxyalkyl , carbohaloalkoxy, phosphono, phosphonoalkyl, diaralkoxyphosphono and diaralkoxyphosphonoalkyl.

The compounds of the invention may exist in tautomeric, geometric or stereoisomeric forms. The invention contemplates that all of these compounds, including cis- and fra / z- geometric isomers, E- and Z-geometric isomers, R- and S-enantiomers, diastereomers, d-isomers, 1-isomers, racemic mixtures thereof, and other mixtures thereof are the subject of the invention. Pharmaceutically acceptable salts of these tautomeric, geometric or stereoisomeric forms are also within the scope of the invention.

The terms "c / 5" and "trans" mean geometric isoforms in which two carbon atoms linked by a double bond will have each hydrogen atom on the same side of the double bond ("c / 's") or on opposite sides' of the double bond ("/ ra 's').

Some of the disclosed compounds contain an alkenyl group and are intended to include both cis and trans or "E" and "Z" geometric forms.

Some of the disclosed compounds contain one or more stereocenters and are intended to include the R, S form, and mixtures of the R and S forms of all stereocenters present.

Some of the compounds described herein may contain one or more ketone or aldehyde carbonyl groups or combinations thereof alone or as part of a heterocyclic ring system. These carbonyl groups may exist partially or substantially in the "keto" form and partially or substantially in the "enol" form for each aldehyde or ketone group present. Compounds of the invention containing an aldehyde or ketone carbonyl group are intended to include both the "keto" and "enol" tautomeric forms.

Some of the compounds described herein may contain one or more amido carbonyl groups or combinations thereof alone or as part of a heterocyclic ring system. These carbonyl groups may exist partially or substantially in the "keto" form and partially or substantially in the "enol" form for each amide group present. Compounds of the invention containing an amide carbonyl group are intended to include both the "keto" and "enol" tautomeric forms. These amidocarbonyl groups can be both oxo (C = O) and thiono (C = S).

Some of the compounds described herein may contain one or more imine or enamine groups, or a combination thereof. These groups may exist partially or substantially in the "imino" form and partly or substantially in the "enamino" form for each group present. Compounds of the invention containing an imine or enamine group are contemplated to include both an "imino" and an "enamino" tautomeric form.

The invention encompasses the therapeutic and preventive use of anticoagulant therapy for the treatment and prevention of many thrombotic conditions in subjects such as coronary artery disease and cerebrovascular disease, comprising administering to a subject exhibiting such diseases a therapeutically effective amount of a compound of Formula I

vO (I), or a pharmaceutically acceptable salt thereof.

A further embodiment of the invention includes the compounds of formula I or pharmaceutically acceptable salts thereof as defined above. The invention encompasses the treatment and prevention of coronary artery disease and cerebrovascular disease and other disorders associated with the coagulation cascade, comprising administering to a subject having such diseases a therapeutically effective amount of a compound of Formula I.

The compounds of the invention of formula I, or pharmaceutically acceptable salts thereof, can also be used wherever inhibition of blood coagulation is desired, such as preventing coagulation in whole blood storage and preventing coagulation in other biological samples for testing or storage. These coagulation inhibitors of the invention may be added to or in contact with whole blood, may be part of any medium containing or predicted to contain plasma coagulation factors, and may be used in cases where coagulation inhibition is desirable, for example when mammalian blood is in contact with material selected from the group consisting of vascular graft, stents, orthopedic prostheses, cardiac prostheses and extracorporeal circulatory systems

The compounds of the formula I are capable of inhibiting the activity of the serine proteases in relation to the coagulation cascade, and thus can be used in the manufacture of medicaments, methods of prevention or treatment of diseases mediated by the serine proteases of the coagulation cascade. , thrombus formation, and inhibition of embolism in mammals, blood, blood products and the like

-95 in mammalian organs. The compounds may also be used to treat or prevent unstable angina pectoris, recurrent angina pectoris, myocardial infarction, transitory ischemic attacks, atrial fibrillation, thrombotization, embolism, deep vein thrombosis, disseminated intravascular coagulopathy or retinal restenosis (DIK), retinal restenosis (DIK), blood vessels in mammals. The compounds can also be used to study the mechanism of action of the serine proteases of the coagulation cascade and allow the design of more potent inhibitors and the development of better assay methods. Compounds of formula I may also be useful in preventing cerebral vascular accident (CVA) or stroke

Also included in the family of compounds of Formula I are their pharmaceutically acceptable salts. The term "pharmaceutically acceptable salts" includes salts commonly used to form alkali metal salts and to form additional salts of free acids and free bases. The origin of the salt is not critical as long as it is ensured that it is pharmaceutically acceptable. Suitable pharmaceutically acceptable acid addition salts of the 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 those belonging to the classes of aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic acids. Examples of such acids include formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleanoic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, anthranilic. -hydroxybenzoic, phenylacetic, almond, embon, palm, methanesulfonic, ethylsulfonic, benzenesulfonic, sulfanil, stearic, cyclohexylaminosulfonic, alginic, galacturonic. Suitable pharmaceutically acceptable base addition salts of the compounds of formula I include metal salts prepared from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc salts, or include organic salts formed from N, N'-dibenzylethylenediamine, choline, chloroprocaine, diethanolamine, diethanolamine. , meglumine (N-methylglucamine) and procaine. All of these salts can be prepared by conventional procedures from the corresponding compounds of formula I, for example by reaction of a suitable acid or base with a compound of formula I.

The invention also relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I in association with at least one pharmaceutically acceptable carrier, adjuvant or diluent. The pharmaceutical compositions of the invention may contain the active compounds of the formula I, they may contain the active compounds

Of Formula I in conjunction with one or more non-toxic pharmaceutically acceptable carriers and / or diluents and / or adjuvants (collectively referred to herein as "carrier" materials) and, if appropriate, other active ingredients. The active compounds of the invention may be administered by any suitable route, preferably in the form of a pharmaceutical composition adapted for that route and at a dose effective for the intended treatment.

The active compounds and compositions can be administered, for example, orally, intravascularly, intraperitoneally, subcutaneously, intramuscularly, via the eye or topically. For the treatment of ischemic retinopathy, the compounds may be administered intraocularly or topically as well as orally or parenterally.

The compounds may be administered in depot injections or implanted preparations, which may be prepared in such a way as to ensure continuous release of the active ingredient. The active ingredient may be compressed into pellets or small cylinders and implanted subcutaneously or intramuscularly as a depot injection or implants. The implants may contain inert materials such as biodegradable polymers or synthetic silicones, for example Silastic, silicone rubber or other silicone-containing polymers.

The compounds may also be administered in the form of liposome delivery systems, such as small single-lamellar vesicles, large single-lamellar vesicles, and multilamellar vesicles. Liposomes can be prepared from a variety of different phospholipids, such as cholesterol, sterylamine or phosphatidylcholines.

The compounds may also be delivered using monoclonal antibodies, as individual carriers to which the compound molecules are bound. The compounds can also be coupled to soluble polymers as drug carriers that can be precisely targeted. These polymers may include a copolymer of polyvinylpyrrolidone and pyran, polyhydroxypropylmethacrylamide phenol, polyhydroxyethylaspartamidephenol or polyethylene oxide polylysine substituted with palmitic acid residues. The compounds of the invention may further be coupled to a class of biodegradable polymers suitable for achieving controlled release of the drug, e.g. or an amphipathic block of copolymers of hydrogels.

For oral administration, the pharmaceutical compositions may be in the form of tablets, capsules (each including sustained release or time-release formulations), pills, powders, granules, elixirs, elixirs, suspensions, liquids comprising

Syrups and emulsions. The pharmaceutical composition is preferably prepared in the form of a dosage unit containing a specific amount of the active ingredient. Examples of such dosage units are tablets or capsules. The active ingredients may also be administered by injection as a composition wherein, for example, saline, dextrose or water may be used as a suitable carrier.

The amount of the therapeutically active compounds to be administered and the dosage regimen for treating the disease with the compounds and / or compositions of the invention depends on a number of factors such as the subject's age, weight, sex and health, severity of the disease, route and frequency of administration, so it can vary widely.

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

The formulation of the compounds may be an ointment or cream for topical application, or also as a suppository containing the active ingredients in an amount of, for example, 0.075 to 30 wt. %, preferably 0.2 to 20 wt. % and most preferably 0.4 to 15 wt. %. When an ointment formulation is chosen, the active ingredient may be used with a paraffinic or water-miscible ointment base.

Alternatively, the active ingredient may be in an oil-water cream base formulation. If desired, the aqueous phase of the cream may contain, for example, at least 30 wt. % of an alcohol such as propylene glycol, butane-1,3-diol, mannitol, sorbitol, glycerol, polyethylene glycol and mixtures thereof. The topical formulation may suitably contain a compound that facilitates absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethylsulfoxide and related analogs. The compounds of the invention may also be administered using a transdermal device. Advantageously, topical administration can be improved by using a patch of either porous membrane reservoir type and / or solid matrix variants. In both cases, the active agent is delivered continuously from the reservoir or microcapsules through the membrane to the adhesive permeable to the active agent which is in contact with the skin or mucosa of the recipient. When the active substance is absorbed through the skin, the active substance is administered to the recipient by a controlled and predetermined flow. In the case of microcapsules, the encapsulant may also have a membrane function.

The oily phase of the emulsion of the invention may be formed by known ingredients in a known manner. If the phase may comprise only an emulsifier, the mixture may comprise at least one emulsifier with a fat or an oil, or both with a fat and an oil. Preferably, it is hydrophilic

The emulsifier is included together with a lipophilic emulsifier which acts as a stabilizer. It is also preferred to include both oil and fat. Altogether, the emulsifier (s) with and / or without stabilizer (s) forms the so-called emulsifying wax and the wax together with the oil and fat forms the so-called emulsifying base of the ointment which forms the oil dispersion phase of the cream formulation. Emulsifiers and emulsion stabilizers suitable for use in the invention include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate, sodium lauryl sulfate and many others.

The choice of suitable oils or fats is based on obtaining the desired cosmetic properties since the solubility of the active ingredient in most oils that can be used for the emulsion pharmaceutical composition is very low. The cream should preferably be a non-greasy, non-color and water-soluble product with a suitable consistency to prevent leakage from tubes or other containers. Straight or branched chains of mono- or dibasic alkyl esters such as diisoadipate, isocetyl stearate, propylene glycol, coconut fatty acid diester, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or branched chain esters may be used.

For therapeutic purposes, the active compounds of the invention are usually combined with one or more adjuvants. suitable for the intended mode of administration. When administered orally, the compounds may be mixed with lactose, sucrose, starch powder, cellulose esters of alkane acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acid, gelatin, arabic, arabic, gelatin, , sodium alginate, polyvinylpyrrolidone and / or polyvinyl alcohol and then compressed into tablets or coated for convenient administration. These capsules or tablets may contain a controlled release formulation as well as the active ingredient in hydroxypropylmethylcellulose. Formulations for parenteral administration may be in the form of aqueous or non-aqueous isotonic sterile injectable solutions or suspensions. These solutions and suspensions may be prepared from sterile powder or granules containing one or more of the carriers or diluents generally used in the formulations for oral administration. The compounds may 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 routes of administration are well and detailed in pharmacy.

In practicing the methods of the invention for treating and preventing various thrombotic conditions, such as coronary artery disease and cerebrovascular disease, the compounds and pharmaceutical compositions of the invention are administered alone or in combination with a

-99 another compound or in combination with other therapeutic or in vivo diagnostic agents. The coagulation cascade inhibitors of the invention may also be co-administered with a suitable agent having an antiplatelet effect for platelets, including (but not limited to) ticlopidine or clopidorgel, fibrin receptor antagonists (e.g., in the treatment or prevention of unstable angina or for reocclusion of angioplasty and restenosis) agents such as acylpirine, warfarin or heparin, thrombolytic agents such as plasminogen activators or streptokinases to achieve a synergistic effect in the treatment of various pathological conditions, including lipid lowering agents including antihypercholesterolemics (e.g. HMG CoA reductase inhibitors, lovastastine, mastatin) and fluvastatin, HMG CoA synthetase inhibitors, etc.), antidiabetic drugs or other cardiovascular agents (loop diuretics, thiazide-type diuretics, nitrates, aldoste antagonists) angiotensin converting enzyme inhibitors (e.g. ACE), angiotensin II receptor antagonists, beta-blockers, antiarrhythmic agents, antihypertensive agents and calcium channel blockers) for the treatment or prevention of arteriosclerosis. For example, for patients suffering from coronary artery disease and patients undergoing angioplasty, it may be advantageous to administer them together with fibrinogen receptor antagonists and coagulation cascade inhibitors of the invention. Coagulation cascade inhibitors may also increase the efficacy of tissue plasminogen activator-mediated thrombolytic reperfusion.

Typical dosages of the coagulation cascade inhibitors of the invention with other suitable agents having antiplatelet activity for platelets, anticoagulants, cardiovascular therapeutics or thrombolytic agents may be the same as dosages of coagulation cascade inhibitors administered without coadministration of antiplatelet agents; therapeutic agents or thrombolytic agents, or may be significantly lower than the dosage of the coagulation cascade inhibitors administered without co-administration of platelet antiplatelet agents, anticoagulants, cardiovascular therapeutics, or thrombolytic agents, depending on the therapeutic requirements of the patient.

All references are incorporated herein by reference.

Although the invention has been described with respect to specific embodiments, the details of these embodiments are not intended to be exhaustive. The following examples are selected to describe the invention and are not intended to be exhaustive of the invention. No more

It is believed that one skilled in the art can, using the above descriptions, utilize the invention to its fullest extent. Accordingly, the following preferred specific embodiments are set forth to be fully illustrative and not limiting of the scope of the invention. Also included are compounds containing multiple variations of the structural modifications shown in the schemes of the following examples. It will be readily apparent to those skilled in the art that known changes in conditions and processes in the following preparative protocols may be used to prepare these compounds.

One of ordinary skill in the art can use general methods to prepare the following specific examples which have been or can be accurately characterized by 1 H NMR, mass spectrometry, elemental composition determination, and similar procedures. The compounds may also be formed in vivo. The following examples contain a detailed description of methods for preparing compounds of Formula I. This detailed description is within the scope of the invention and is provided for illustrative purposes only and is not intended to limit the scope of the invention. All components are by weight and temperatures are in degrees Celsius unless otherwise indicated.

The following general synthetic sequences are useful in the preparation of the invention. Abbreviations used in the Schemes and Tables include: "AA" represents amino acid, "AcCN" represents acetoneitrile, "AcOH" represents acetic acid, "BnNAP" represents 2,2'bis (diphenylphosphino) -1,1'-binaphthyl, "BnOH" represents benzyl alcohol, "BnCHO" represents 2-phenylethanal, BnSO ₂ Cl "represents benzylsulfonyl chloride," Boe "represents tert-butyloxycarbonyl," BOP "represents benzotriazol-1-yl-oxy-tris- (dimethylamino)," bu "represents butyl," DBA ""Representsdibenzylideneacetone," DCC "represents 1,3dicyclohexylcarbodiimide," DICHLORMETHANE "represents dichloromethane or methylene chloride," DIBAH "or" DIBBAL "represents diisobutylaluminium hydride," DMF "represents dimethylformamide," DMSO "represents dimethylsulfoxide," dimethylsulfoxide ", EDC 'represents 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride, "Ex. No "" is an example number, "Fmoc" is 9fluorenylmethoxycarbonyl, "HOBt" is hydroxybenzoltriazole, "LDA" is lithium diisopropylamide, "MW" is molecular weight, "NMM" is Nmethylmorpholine, "Ph" is phenyl or aryl, "PHT" is phthaloyl, "pnZ" represents 4-nitrobenzyloxycarbonyl, "PTC" represents phase transfer catalyst, "py" represents pyridine, "RNH ₂ " represents primary organic amine, "SEM" represents 2- (trimethylsilyl) ethoxymethylchloride, "P-TsOH" represents paratoluenesulfonic acid, "TBAF" represents tetrabutylammonium fluoride, "TBTU"

- 101 represents 2- (1H-benzotriazolo-1-yl) -1,1,3,3-tetramethyl uronium tetrafluoroborate, "TEA" represents triethylamine, "TFA" represents trifluoroacetic acid, "TF" represents tetrahydrofuran, "TMS" represents trimethylsilyl , "TMSCN" represents trimethylsilyl cyanide and "Cbz" or "Z" represents benzyloxycarbonyl.

General synthetic procedures and specific examples

The compounds of the invention can be synthesized, for example, according to the following procedures and schemes below.

A general synthetic approach for a wide range of R ² -substituted pyrimidinones is shown in Schemes 1-5 below. Incubation of a solution of ethylbenzimidate hydrochloride in methanol with aminoacetaldehyde dimethyl acetal gives the substituted benzamidine. Cyclization of benzamidine with dimethylmethoxymethyl malonate results in the formation of a pyrimidinone heterocyclic core with the desired functional group for further manipulations. Demethylation of the ester with lithium iodide followed by the "Curtiz" rearrangement of the resulting acid places the necessary nitrogen on the C-5 carbon protected as the carbamate. Hydrolysis of dimethylacetal and oxidation of the resulting aldehyde with sodium chlorite gives a glycine residue at the N-3 position. Protection of the acid as t-butyl ester followed by deprotection of the carbamate by hydrogenation affords the free amine on carbon C5. Incubation of this amine with a sulfonyl chloride or with an aldehyde under conditions of reductive deamination gives rise to a sulfonamide or secondary amine, respectively. The protected acids are then deprotected with HCl. These acids are then coupled under standard conditions to bind peptides to various amines. These amines are usually multifunctional and are used in certain protected forms. Removal of these protecting groups produces a compound that can be evaluated. These synthetic schemes and procedures are set forth below.

Scheme 1: General Synthesis of Pyrimidinones

R

- 103-

- 104 I continued

Scheme 3:

General synthesis of pyrimidinones

ABOUT

- 105 B-HN '

Scheme 4 'General Synthesis of Pyrimidinones - I

0-HN

B-H

-N,

Pd / C, H ₂

EDC

HOBT

Cbz-Y ° -NH ₂ BC (O) -HN

Pd / C, H ₂

X -R X o

Y °

4b ‘N

H

NV .R ² X ^ X o

BC (O) -H

O zi

Y °

- 106 -

Synthesis schemes 1 to 5 are exemplified in the following examples.

IT

107 Examples of embodiments of the invention

(Pr.-IA)

A solution of ethylbenzimidate hydrochloride (92.25 g, 496.9 mmol) in 300.0 mL dry ethanol (1.68) M was allowed to cool to 0 ° C and a solution of aminoacetaldehyde dimethylacetal (73.10 mL, 670.9 mmol) was added. ) in dry methanol (75.0 mL, 9.0 M) dropwise at a rate such that the temperature was maintained below 5 ° C. The reaction mixture was concentrated under vacuum to give a yellow oil. The reaction residue was dissolved in 1M NaOH (750ml) and extracted with dichloromethane (4 x 250ml). The organic solutions were combined, dried (Mg SO ₄₎ and concentrated to give 108.13 g of gross N- (2,2-dimethoxyethyl) benzamidine as a yellow oil. Crude N- (2,2-dimethoxyethyl) benzamidine (108.13 g, 519.2 mmol) in dry methanol (125.0 mL, 4.2 M) was added in one portion to dimethyl methoxymethylenemalonate (94.13 g, 540, 5 mmol) at room temperature. The resulting mixture was heated to approximately 100 ° C where the solution was slowly distilled off for about two hours. The dark brown solution so formed was allowed to cool to room temperature and diluted with ethyl acetate (1 liter). The organic solution was washed with saturated NH 4 Cl (2 x 500 mL) and brine (1 x 500 mL). The organic solution was dried (Mg SO _4), filtered and concentrated. Purification of the crude by MPLC (25% ethyl acetate / hexane) gave pure methyl (1- (2,2-dimethoxyethyl-2-phenylpyrimidin-6 (1H) -one-5-carboxylate)) (Pr.-IA) with Yield 73% as a light brown oil: 1 H NMR (300 MHz, CDCl 3) δ 8.73 (s, 1H), 7.59-7.49 (m, 5H), 4.86 (t, J = 5, 5 Hz, 1H), 4.16 (d, J = 5.4 Hz, 2H), 3.95 (s, 3H), 3.32 (s, 6H), ¹³ C NMR (75 MHz, CDCl 3) δ 165.9, 164.6, 159.3, 158.2, 134.6, 130.9, 128.93, 128.78,

114.9, 101.4, 56.0, 55.1, 52.7, 49.1; HRMS (ES) theoretical for C ₁₆ H ₁₉ N ₂ O ₅ 319.1294, experimentally found 319.1288.

(Pr.-IB)

A solution of methyl 1- (2,2-dimethoxyethyl-2-phenylpyrimidin-6 (1H) -one-5-carboxylate (93.0 g, 393.3 mmol) in 420 mL dry pyridine (0.70 M) was added in one portion. to lithium iodide (98,00 ml,

108.732.2 mmol) with stirring and at room temperature, upon addition, the heat of the exothermic reaction was released. The resulting light brown suspension was heated at reflux for 2 hours. The dark brown reaction mixture was allowed to cool to room temperature and the volatiles were removed under vacuum. The remaining oil was diluted with 1M HCl (500 mL). The aqueous solution was extracted with dichloromethane / methanol (4: 1, 4 x 250 mL). The combined organic fractions were washed with 6 N HCl (2 x 250 mL), dried (MgSO 4), filtered and concentrated. The crude product was purified by crystallization (ethyl acetate / hexane) to give pure 1- (2,2-dimethoxyethyl-2-phenylpyrimidine-6 (1H) -one-5-carboxylate) (Pr.-IB) in 63% yield as a white solid. 1 H NMR (300 MHz, CDCl ₃ ) δ 12.99 (s, 1H), 8.97 (s, 1H), 7.63-7.51 (m, 5H), 4.78 (dd, J) = 4.3, 5.5Hz, 1H), 4.28 (d, J = 5.4Hz, 2H), 3.30 (s, 6H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 165.8, 165.1, 164.1, 159.1, 133.6, 131.5, 129.1, 129.0, 112.6, 101.0 , 55.8, 49.2; HRMS (ES) theoretical for C 15 H 17 N 2 O 5 305.1137, experimentally found 305.1113.

(Pr.-LC)

To a suspension of 1- (2,2-dimethoxyethyl-2-phenylpyrimidin-6 (1H) -one-5-carboxylate) (65.93 g, 219.67 mmol) in 800 mL 1,4-dioxane (0.27 M) triethylamine (50.0 mL, 358.7 mmol) was added in one portion at room temperature followed by diphenylphosphoryl azide (51.40 mL, 238.5 mmol). The resulting mixture was slowly heated at reflux for 2 hours. Benzyl alcohol (45.00 mL, 434.8 mmol) was then added to the reaction mixture and reflux was maintained for approximately 14 hours. The black solution was removed to cool to room temperature and the volatiles were removed under vacuum. The resulting reaction residue was diluted with ethyl acetate (1.5 L). The organic solution was washed with saturated NH 4 G (2 x 500 mL), 1N NaOH (1 x 500 mL), and brine (1 x 500 mL). It was then dried (MgSO4), filtered and concentrated to give the crude product. Purification by MPLC (15 = - 30% ethyl acetate / hexane) gave pure [5 - [(benzyloxycarbonyl) amino] 2-phenyl-6-oxo-1,6-dihydro-1-pyrimidinyl] acetaldehyde dimethylacetal (Pr.-1C) as a light brown solid in a yield of 46%. 1 H NMR (400 MHz, CDCl 3) δ 8.72 (br s, 1H), 7.53-7.32 (m, 11H), 5.20 (s, 2H), 4.68 (t, J = 5.6 Hz, 1H), 4.12 (d, J = 5.6 Hz, 1H), 4.12 (d, J = 5.6 Hz, 2H), 3.22 (s, 6H); ¹³ C NMR (100 MHz, CDCl 3) δ 158.3, 153.7, 153.2, 135.9, 134.9,

134.7, 130.1, 129.1, 128.9, 128.8, 128.71, 128.66, 128.44, 125.1, 101.3, 67.7, 55.4, 48, 6; HRMS (ES) calculated for C22H24N3O5 410.1716, found experimentally by 410.1741.

(Pr.-ID)

To a solution of [5 - [(benzyloxycarbonyl) amino] -2-phenyl-6-oxo-1,6-dihydro-1-pyrimidinyl] acetaldehyde dimethylacetal (17.24 g, 42.11 mmol) in 103.0 mL tetrahydrofuran was added 35.0 mL 1 M HCl. The resulting biphasic mixture was heated at reflux for 12 hours.

The reaction mixture was then allowed to cool to room temperature and the volatiles were removed under vacuum. The resulting reaction residue was diluted with water (200 mL) and pH was adjusted to 7 by addition of solid NaHCO 3. The resulting suspension was extracted with dichloromethane (4 x 150 mL). The combined organic fractions were washed with water (1 x 200 mL), dried (MgSO4), filtered, and concentrated to give 15.74 g of crude [5 [(benzyloxycarbonyl) amino] -2-phenyl-6-oxo-1,6- dihydro-l-pyrimidinyl] acetaldehyde.

A solution of crude [5 - [(benzyloxycarbonyl) amino] -2-phenyl-6-oxo-1,6-dihydro-1-pyrimidinyl] acetaldehyde (15.30 g, 42.11 mmol) in 198.0 mL of tetrahydrofuran, t-butyl alcohol and 2-Methyl-2-butene (1: 1: 1.3, 0.21 M) was cooled to 0 ° C. To the solution was then slowly added a solution of sodium chlorite (29.94 g, 331.1 mmol) and sodium dihydrogen phosphate monohydrate (35.42 g, 256.7 mmol) in 102.0 mL of water (3.2 M for sodium chlorite). A biphasic gold-colored solution was formed, which was stirred for 10 minutes and then the mixture was removed from the cooling bath. The reaction mixture was further stirred at room temperature for one hour. The volatiles were removed under vacuum. The remaining solution was diluted with water (200 mL) and the pH was adjusted to 3 by addition of saturated NaHCO 3 and 1M HCl. The aqueous solution was extracted with a mixture of tetrahydrofuran and dichloromethane (1: 2, 4 x 180 mL). The combined organic fractions were dried (MgSO 4), filtered and concentrated to give the crude product. Purification by trituration with ethyl ether gave [5 - [(benzyloxycarbonyl) amino] -2-phenyl-6-oxo-1,6-dihydro-1-pyrimidinyl] acetic acid as a white solid in 88% yield. 1 H NMR (300 MHz, d-DMSO) δ 13.34 (br s, 1H), 9.03 (s, 1H), 7.57-7.34 (m, 10H), 5.23 (s, 2H), 4.56 (s, 2H); ¹³ C NMR (75 MHz, d-DMSO) δ 169.4, 158.0, 154.6, 154.3, 137.1, 134.8,

130.9, 129.4, 129.1, 128.78, 128.72, 128.50, 125.5, 67.0, 48.8; HRMS (EI) theoretical for C 20 H 18 N 3 O 5 380.1246, experimentally found 380.1246.

(Pr.-IE)

A suspension of [5 - [(benzyloxycarbonyl) amino] -2-phenyl-6-oxo-1,6-dihydro-1-pyrimidinyl] acetic acid (5.2503 g, 13.84 mmol) in 70 mL of chloroform (0.2 M) was cooled to 0 ° C in an ice bath. To the cooled suspension was then added oxalyl chloride (6.0 mL, 68.78 mmol) dropwise via syringe. Upon vigorous evolution of gases a golden homogeneous solution is formed. The reaction mixture was further stirred for 5 minutes, then removed from the ice bath and stirring was continued for 2 hours at room temperature. The solvent was then removed under reduced pressure and solvent residues were removed under high vacuum for 10 minutes. The resulting yellow solid, which was dissolved in 70 mL of chloroform (0.2 M), was added pyridine (1.70 mL, 21.02 mmol) and 2-methyl-2-propanol (3.50 mL, 36 mL). 60 mmol). Created

The 110 light brown solution was stirred for one hour at room temperature and then heated to reflux for 12 hours. The reaction mixture was then cooled to room temperature and diluted with chloroform (300 mL). The organic solution was washed with water (1 x 100 mL), saturated NaHCO ₃ (1 x 100 mL), and brine (1 x 100 mL). The organic solution was dried (MgSO4), filtered and concentrated to give the crude product. The crude product was further purified by MPLC (25% ethyl acetate / hexane) to give the product with 49% yield: 1 H NMR (300 MHz, CDCl ₃ ) δ 8.81 (br s, 1H), 7.57-7.38 (m, 11H), 5.27 (s, 2H), 4.57 (s, 2H), 1.47 (s, 9H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 166.4, 158.0, 153.2, 135.9, 135.0, 134.4, 130.6, 129.1,

128.9, 128.7, 128.5, 128.4, 125.4, 83.4, 67.7, 49.1, 28.2; HRMS (El) theory for C ₂ 4 H 6 N ₂ 0s ₃ 436.1872, found 436.1876 experimentally.

(Ex. - 1F)

To a solution of [5-amino-2-phenyl-6-oxo-1,6-dihydro-1-pyrimidinyl] -acetic acid t-butyl ester (1.8647 g, 4.282 mmol) in 21.0 mL of methanol (0.2 M) 211.3 mg of 10% Pd / C was added in one portion. The resulting mixture was stirred under a hydrogen atmosphere (balloon) and room temperature for 16 hours. The crude reaction mixture was filtered through Celite 54 and the solvent was removed under reduced pressure. The crude product was triturated in ethyl ether to give the pure product [5 amino-2-phenyl-6-oxo-1,6-dihydro-1-pyrimidinyl] -acetic acid t-butyl ester (Pr. 1F) in 99% yield. 1 H NMR (400 MHz, CDCl ₃ ) δ 7.41-7.39 (m, 6H), 4.48 (s, 2H), 4 & 6 (br s, 2H), 1.39 (s, 9H) ); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 166.8, 158.6, 149.3, 134.9, 132.9, 130.0, 128.9, 128.5, 127.7,

82.9, 48.7, 28.1; HRMS (EI) theory for Ci6H ₂ ON 0 _{3 3} 302.1505, experimental been found 302.1491.

(Ex - 1G)

To a solution of [5-amino-2-phenyl-6-oxo-1,6-dihydro-1-pyrimidininyl] -acetic acid t-butyl ester (1.0300 g, 3.418 mmol) in 5.5 mL tetrahydrofuran and 2 mL dimethylformamide (0.45 M) was added methyl morpholine (1.20 mL, 10.91 mmol) in one portion. The solution was cooled to 0 ° C in an ice bath. After stirring for 10 minutes, a solution of 718.2 mg of α-toluenesulfonyl chloride (3.777 mmol) in 5.5 mL of tetrahydrofuran (0.68 M) was added dropwise over 5 minutes. The reaction mixture was further stirred at 0 ° C for 2 hours. It was then diluted with 150 mL of ethyl acetate. The organic solution was washed with 1 M HCl (2 x 25 mL), saturated NaHCO ₃ (2 x 25 mL), and brine (1 x 50 mL). The organic solution was dried (MgSO4), filtered, and concentrated under reduced pressure. The resulting yellow solid was triturated with ethyl ether, filtered and dried in vacuo to give the pure product (Ex. 1G) as a white solid in 74% yield. 1 H NMR (400 MHz, d-DMSO) δ 9.34 (s, 1H), 7.76 (s, 1H), 7.55-7.28 (m,

111-110), 4.59 (s, 2H), 4.49 (br s, 2H), 1.32 (s, 9H);

¹³ C NMR (100 MHz, d-DMSO) δ 167.0,

158.8, 156.5, 142.1, 134.5, 131.7, 131.0, 130.1, 129.4, 129.0, 128.94, 128.58, 124.8, 83, 0, 59.6, 49.2, 28.1; HRMS (EI) theoretical for C 23 H 26 N 3 O 5 456.1593, experimentally found

456.1597.

(Ex. 1H)

A solution (Ex. - 1G) (1.0643 g, 2.366 mmol) in 9.0 mL of 4 M HCl in dioxane (0.1 M) was stirred at room temperature for 12 hours. The crude reaction mixture was concentrated under vacuum. The residue was triturated with ethyl ether to give the pure product (Ex. 1H) as a white solid in 87% yield. 1 H NMR (400 MHz, d-DMSO) δ 9.32 (s, 1H), 7.74 (s, 1H), 7.51-7.30 (m, 10H), 4.58 (s, 2H) 1.48 (s, 2H); ¹³ C NMR (100 MHz, d-DMSO) δ 169.2, 158.7, 156.6, 141.9, 134.5, 131.7, 131.0, 130.1, 129.4, 129, 0, 128.9, 128.56, 124.8, 59.6, 48.9; HRMS (EI) calculated for C19H18N3O5 400.0967, found 400.0959 experimentally.

(Ex. - II)

To a solution of the acid (Pr. 1H (406.8 mg, 1.018 mmol) in 10 mL of dimethylformamide (0.1M) was added N, N-diisopropylethylamine (0.900 mL, 5.167 mmol), N-hydroxybenzotriazole (167.7 mg, 1.241 mmol) and 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (236.1 mg, 1.232 mmol): The resulting mixture was allowed to stir at room temperature for 30 minutes and the mixture became homogeneous. then 4- (Cbz-amidino) benzylamine (324.6 mg, 1.126 mmol) was added in one portion at room temperature and the resulting mixture was allowed to stir for 18 hours before being diluted with ethyl acetate (50 mL). citric acid (1 x 25 mL), saturated NaHCO 3 (1 x 25 mL), and brine (1 x 25 mL) The organic solution was dried (MgSO 4), filtered and concentrated to give a crude reaction mixture which was purified by rubbing with ethyl ether to give pure product (Ex. II) as a white salt. 1 H NMR (300 MHz, d-DMSO) δ 9.36 - 9.18 (br m, 3H), 8.82 - 8.78 (m, 1H 7.98 (d, J = 8.3 Hz, 2H), 7.84 (s, 1H), 7.56-7.32 (m, 16H), 5.15 (s, 2H), 4.65 (s, 2H), 4, 58 (s, 2H); 4.40 (d, J = 5.4 Hz, 2H); HRMS (EI) theoretical for C35H33N6O6 665.2182, experimentally found 665.2177.

To a solution of Cbz-amidine (Pr. II) (237.7 mg, 357.6 mmol) in 3.5 mL of methanol and 4 M HCl in dioxane (4: 1, 0.1 M) was added 42.1 mg at once. 10% Pd / C. The resulting mixture was stirred under a hydrogen atmosphere (balloon) and room temperature for about 16 hours. The crude reaction mixture was filtered through Celite 545 and the solvent was removed under reduced pressure. Purification of the crude product by HPLC (gradient, 5% -95% acetonitrile / water with 0.1% trifluoroacetic acid) gave the pure product as a white solid. 'H NMR (300 MHz, d-DMSO) δ

- 1129.31-9.28 (m, 4H), 8.88 (br s, 1H), 7.81-7.77 (m, 3H), 7.60-7.54 (m, 5H), 7.43-7.37 (m, 7H), 4.65 (s, 2H), 4.58 (s, 2H), 4.42-4.41 (m, 2H), HRMS (EI) theoretical for C27H27O4S 531.1815, found 531.1794 experimentally.

Example 2

Following the method of Example 1, the compound of the formula in Example 2 was prepared. ¹ H NMR (300 MHz, d-DMSO) δ 9.40-9.33 (m, 4H), 8.86 (s, 1H), 7 82 (s, 2H), 7.72-7.37 (m, 15H), 4.65-4.59 (m, 4H), 4.41-4.40 (m, 2H); HRMS (EI) theoretical for C 27 H 27 N 6 O 4 S 531.1815, found 531.1794 experimentally.

To a solution of [5-amino-2-phenyl-6-oxo-1,6-dihydro-1-pyrimidinyl] -acetic acid t-butyl ester (Pr. 1F) (613.7 mg, 2.037 mmol) in 7.0 Acetic acid and phenylacetaldehyde (0.475 mL, 4.060 mmol) were added to tetrahydrofuran and dichloromethane (1: 1, 0.3M). The solution was cooled to 0 ° C in an ice bath, and sodium triacetoxyborohydride (1.9131 g, 9.027 mmol) was added in one portion. After stirring for 5 minutes, the ice bath was removed and the reaction mixture was left at room temperature for 2 hours. The reaction mixture was further neutralized by addition of 1 M NaOH (5 mL) and stirred for an additional 5 minutes. Then the reaction mixture was diluted with 0.5 M NaOH (100 mL) and the aqueous solution was extracted with ethyl acetate (3 x 25 mL). The combined organic fractions were washed with 0.5 M NaOH (1 x 25 mL) and brine (1 x 25 mL). The solution was dried

- 113 MgSO ₄ , filtered and concentrated under reduced pressure. Purification by MPLC (25% ethyl acetate / hexane) gave the product (Ex. 3A) as a yellow oil in 74% yield. 1 H NMR (400 MHz, CDCl ₃ ) δ 7.43-7.40 (m, 4H), 7.31-7.26 (m, 2H), 7.23-7.16 (m, 5H) 4.70 (br s, 1H), 4.49 (s, 2H), 3.38-3.34 (m, 2H), 2.69-2.92 (m, 2H), 1.40 ( s, 9H); HRMS (EI) theoretical for C ₂₄ H ₂₈ N ₃ O ₃ 406.2131, found 406.2125 experimentally.

Solution Pr. 3A (521.3 mg, 1.286 mmol) in 13.0 mL of 4 M HCl in dioxane (0.1 M) was stirred at room temperature for 12 hours. The crude reaction mixture was concentrated under reduced pressure. The reaction residue was triturated with ethyl ether to give pure product Pr. - 3B in the form of a yellow solid in quantitative yield. 1 H NMR (300 MHz, d-DMSO) δ 7.66-7.57 (m, 5H), 7.33 7.23 (m, 6H), 4.57 (s, 2H), 3.44- 3.35 (m, 2H); 2.97-2.92 (m, 2H); ¹³ C NMR (75 MHz, dDMSO) δ 168.8, 157.0, 148.0, 139.9, 135.0, 132.2, 129.69, 129.48, 129.07, 126.9, 48.8, 44.5, 34.5; HRMS (EI) theoretical for C ₂₀ H ₂₀ N ₃ O ₃ 350.1505, experimentally found 350.1520.

To the solution of Pr. - 3B (497.8 mg, 1.290 mmol) in 13 mL of dimethylformamide (0.10 M) was added N, N-diisopropylethylamine (1,800 mL, 1.33 mmol), N-hydrobenztriazole (212.8 mg, 1.575 mmol) and 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (302.5 mg, 1.578 mmol). The resulting reaction mixture was stirred at room temperature for 30 minutes to homogenize. Then 4- (Cbz-amidino) benzylamine (410.9 mg, 1.425 mmol) was added in one portion at room temperature. The mixture was allowed to stir for 18 hours and then diluted with ethyl acetate (50 mL). The organic solution was washed with 5% citric acid (1 x 25 mL), saturated NaHCO ₃ (1 x 25 mL), and brine (1 x 25 mL). The organic solution was dried over MgSO ₄ , filtered, and concentrated. The crude reaction product was purified by rubbing with ethyl ether to give pure product Pr. - 3C in the form of a white solid. 1 H NMR (400 MHz, d-DMSO) δ 9.08 (br s, 2H), 8.62 (t, J = 5.8 Hz, 1H), 7.90 (d, J = 8.3 Hz) 2H, 7.44-7.15 (m, 17H), 5.35 (t, J = 5.9 Hz, 1H), 5.07 (s, 2H), 4.44 (s, 2H) 1.29 (d, J = 5.4 Hz, 2H), 3.31-3.26 (m, 2H), 2.88-2.85 (m, 2H); HRMS (EI) theoretical for C ₃₆ H ₃₅ N ₆ O ₄ 615.2720, experimentally found 615.2688.

To the solution of Pr. - 3C (222.6 mg, 362.1 mmol) in 4.0 mL methanol and 4M HCl in dioxane (3: 1, 0.1 M) was added in one portion 53.0 mg of 10% Pd / C. The resulting reaction mixture was stirred under a hydrogen atmosphere (balloon) at room temperature for 16 hours. The crude reaction mixture was filtered through Celite 545 and the solvent was removed under reduced pressure.

Purification of the crude product by rubbing with ethyl ether gave the pure product as a yellow solid. 1 H NMR (400 MHz, d-DMSO) δ 9.62 - 9.30 (br m, 5H), 7.88 (br m, 2H), 7.58 - 1146.86 (br m, 15H), 4.59 (br s, 2H), 4.36 (br s, 2H), 3.38 (br s, 2H), 2.91 (br s, 2H); HRMS (EI) theoretical for C28H29N6O2 481.2352, experimentally found 481.2348.

Pyrimidinones which contain, for example, a directly bound 2-aryl, 2-heteroaryl or 2-heteroatom linking / bonding an organic group via a heteroatom to a pyrimidinone ring may be prepared according to Scheme 6 and Scheme 7 below. The heteroatom is usually sulfur, nitrogen, oxygen or another suitable heteroatom. The use of the general procedure in Scheme 6 to prepare specific heteroatom-substituted pyrimidinones is shown in Examples 4 and 5.

115C ^ N

Scheme 6: Preparation of 2-substituted pyrimidinones SEM, ν ^{0 0}

J step A1. K ₂ CO ₃ SEMCl N

step B 2. K ₂ CO ₃ CICH ₂ -CO ₂ CH ₃

ABOUT SEM

H ₂ N

> First PhCH ₂ CHO step D 2. NaBH (OAc) ₃ THF, CH ₂ Cl ₂ , AcOH

O ₂ CH ₃

R-ONH

R-ONH

Step E:

1. LiOH, MeOH h ₂ by step F:

2. EDC, HOBt, DIEA, DMF, R - NH ₂

Step I:

1. R-SH, R-OH, R-NH 2 dioxane, base or step J:

2. ArB (OH) ₂ , Pd (PPh ₃ ) ₄ Na ₂ CO ₃ step Q.

h ₂ , Pd / C MeOH

N., CO ₂ CH ₃

O, N

CO ₂ CH3 step G:

1.TBAF.THF step H:

CONH-R \ 2. PhNMe ₂ Step K (Remove Protection)

K @ 1 Z @ 2 --Q

-116-

(Ex. - 4A)

To a solution of 5-nitro-2,4 (1H, 3H) pyrimidinedione in dimethylsulfoxide (0.2 M) was added simultaneously with 1.1 equivalents of magnesium carbonate. After about ten minutes, one equivalent of 2- (trimethylsilyl) ethoxymethyl chloride in dimethylsulfoxide was added dropwise to the reaction mixture. The reaction mixture was then heated to 40 ° C and allowed to stir for 18 hours. Usual laboratory procedures with aqueous solutions followed by chromatographic purification gave pure product Pr. - 4A.

(Ex. - 4B)

To a solution of 5-nitro-1-SEM-2,4 (1H, 3H) pyrimidinedione (Ex. 4A) in dimethylsulfoxide (0.2 M) was added simultaneously with 1.1 equivalents of magnesium carbonate. After about ten minutes, one equivalent of methyl bromoacetate in dimethylsulfoxide was added dropwise to the reaction mixture. The reaction mixture was then heated to 40 ° C and allowed to stir for 18 hours. Usual laboratory procedures with aqueous solutions followed by chromatographic purification gave pure product Pr. - 4B.

(Ex. - 4C)

A solution of 5-nitro-1-SEM-3-methoxycarbonylmethyl (Pr. 4B) 2,4 (1H, 3H) pyrimidinedione in methanol was degassed with hydrogen gas. 5% Pd / C was then added to the reaction mixture, and the reaction mixture was allowed to stir at room temperature for an additional 24 hours under a hydrogen atmosphere. The crude reaction mixture was then filtered through Celite 545 and concentrated under reduced pressure. Purification by column chromatography gave pure 5-amino-1-SEM-3-methoxycarbonylmethyl-2,4 (1H, 3H) pyrimidinedione (Ex. 4C).

(Ex. - 4D)

To a solution of 5-amino-1-SEM-3-methoxycarbonylmethyl-2,4 (1H, 3H) pyrimidinedione (Pr. 4C) in tetrahydrofuran and dichloromethane (1: 1, 0.3 M) was added a catalytic amount of acetic acid and one equivalent of phenylacetaldehyde. The solution was cooled to 0 ° C in an ice bath and one equivalent of sodium triacetoxyborohydride was added at once. After stirring for 5 minutes, the ice bath was removed and the reaction mixture was allowed to stir at room temperature for

-117 time 2 hours. The reaction mixture was neutralized by addition of 1 M NaOH and stirred for an additional 5 minutes. Usual laboratory procedures with aqueous solutions followed by chromatographic purification gave pure product Pr. - 4D.

(Ex - 4E)

To a solution of 1-SEM-3-methoxycarbonylmethyl-5- (2-phenylethyl) amino-2,4 (1H,

3H) Pyrimidinedione (Ex. 4D) in tetrahydrofuran and methanol (1: 1, 0.2 M) was added one equivalent of lithium hydroxide in water. Upon completion of the reaction, the flowing components were removed under reduced pressure and the remaining aqueous solution was cooled in an ice bath and acidified with 1 M HCl to pH 1. Extraction with organic solvents and removal of the solvent under reduced pressure gave pure Pr.-4E.

(Ex - 4F)

To a solution of 1-SEM-3-methylenecarboxy-5- (2-phenylethyl) amino-2,4 (1H, 3H) pyrimidinedione in dimethylformamide (0.1 M) was added 5 equivalents of Ν, Ν-diisopropylethylamine, one equivalent of N- hydroxybenzotriazole and one equivalent of 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride. The resulting mixture was stirred for 30 minutes and then incubated with one equivalent of the appropriate amine and allowed to stir overnight. Usual laboratory procedures with aqueous solutions followed by chromatographic purification gave pure product Pr. - 4F.

(Ex - 4G)

To a solution of 1-SEM-3-methylenecarbamide-5- (2-phenylethyl) amino-2,4 (1H, 3H) pyrimidinedione in tetrahydrofuran (0.3 M) was added 2 equivalents of tetrabutvlammonium fluoride in tetrahydrofuran. The resulting solution was refluxed for several hours. Usual laboratory procedures with aqueous solutions followed by chromatographic purification gave pure product Pr. - 4G.

(Ex. - 4H)

To a solution of 3-methylenecarboxamide-5- (2-phenylethyl) amino-2,4 (1H, 3H) pyrimidinedione (Pr. 4G) in N, N-dimethylaniline (0.3 M) was added 1 equivalent of phosphorus oxychloride. The resulting solution was refluxed for several hours. Usual laboratory procedures with aqueous solutions followed by chromatographic purification gave pure product Pr. - 4H.

(Ex. - 41)

To a solution of 2-chloro-3-methylenecarboxamide-5- (2-phenylethyl) amino-2,4 (1H, 3H) pyrimidinedione (Pr. 4H) in dioxane (0.3 M) was added 2 equivalents of phenylthiol. The resulting solution was refluxed for several hours. Usual laboratory procedures with aqueous solutions followed by chromatographic purification gave pure product Pr. - 41.

A solution of 2-thiophenyl-3-methylenecarboxamide-5- (2-phenylethyl) amino-2,4 (1H, 3H) pyrimidinedione (Ex. - 41) in methanol and 4M HCl dioxane (3: 1, 0.1M) was degassed in a hydrogen atmosphere. 5% Pd / C was then added to the solution and the solution was allowed to stir under hydrogen atmosphere at room temperature for 24 hours. The crude reaction mixture was filtered through Celite 545 and terminated under reduced pressure. Purification of the mixture by column chromatography gave the pure product.

(Ex. - 5 A)

To a degassed solution of 2-chloro-3-methylenecarboxamide-5- (2-phenylethyl) amino-2,4 (1H, 3H) pyrimidinedione and 1 equivalent of 3-pyridineboronic acid in L-propanol (0.5 M) was added 1, 2 2 equivalents of 2M sodium carbonate and then 1 mol% tetrakis (triphenylphosphine) palladium. The resulting mixture was heated to reflux for several hours and after cooling to room temperature, pure Pr was obtained by conventional laboratory procedures with aqueous solutions followed by chromatographic purification. - 5A.

A solution of 2- (3-pyridinyl) -3-methylenecarboxamide-5- (2-phenylethyl) amino-2,4 (1H, 3H) pyrimidinedione (Ex. 5A) in methanol and 4M HCl dioxane (3: 1, 0). , 1 M) was degassed in a hydrogen atmosphere. 5% Pd / C was then added to the solution and the solution was allowed to stir under hydrogen atmosphere at room temperature for 24 hours. The crude reaction mixture was filtered through Celite 545 and concentrated under reduced pressure. Purification of the mixture by column chromatography gave the pure product.

Pyrimidinones which contain, for example, a directly bound 2-aryl, 2-heteroaryl or 2-heteroatom linking / bonding an organic group through a heteroatom to a pyrimidinone ring can be prepared according to Scheme 7 below. The heteroatom is usually sulfur, nitrogen, oxygen or another suitable heteroatom. The use of the procedures in Scheme 7 to prepare specific heteroatom-substituted pyrimidinones is shown in Examples 6 and 7.

- 119-

ο

zl

- 120 -

2-Tiouracil (66.7 g, 520.5 mmol) was dissolved in a solution of sodium hydroxide (41.6 d solid NaOH in 365 mL water). The mixture was then incubated with methyl iodide (37 mL, 583 mmol) and the resulting reaction mixture was stirred at room temperature for 16 hours. The solution was then acidified with glacial acetic acid (30 mL). The white precipitate was collected by vacuum filtration and the solid was washed several times with cold water and dried to give 74 g of Pr. - 6A in the form of a white crystalline substance in quantitative yield.

(Ex. - 6B)

Solution Pr. - 6A (74 g, 520.05 mmol) in glacial acetic acid (2275 mL) was cooled to 0 ° C in an ice bath and incubated with Br ₂ . The reaction mixture was then allowed to warm to room temperature and stirred for an additional 16 hours. A yellow precipitate formed, which was filtered and washed three times with ether. 97.2 g of Pr-6B was isolated in 62% yield.

(Ex. - 6C)

The mixture of calcium hydride in THF was cooled to 0 ° C and incubated with pure Pr. - 6B and then with pure t-butyl bromoacetate. The reaction mixture was stirred at 0 ° C for one hour, then the reaction mixture was allowed to warm to room temperature and further stirred for 2 hours. The reaction mixture was further refluxed for 16 hours and, after cooling the reaction mixture to room temperature, slowly poured into 1 liter of a slurry of water and ice. The resulting mixture was extracted with dichloromethane (3 x 500 mL). The combined organic fractions were washed with water and brine and then dried over MgSO 4 and filtered, and the volatiles were removed under vacuum. 28.81 g (90%) of Pr. - 6C as a white solid as a 9: 1 mixture of N-alkylated and Oalkylated isomers. N-alkylated isomer: 1 H NMR (300 MHz, CDCl 3) d 8.07 (s,

121 (1H), 4.75 (s, 2H), 2.57 (s, 3H), 1.47 (s, 9H); ¹³ C NMR (75 MHz, CDCl ₃ ) d 165.1, 162.7, 158.4, 152.5, 108.3, 83.7, 46.8, 28.2 (3C), 15.5; HRMS (EI) theoretical for C ₁₁ H ₁₅ BrN ₂ O ₃ S 335.0065, experimentally found 335.007.

(Ex. - 6D)

In an argon atmosphere glove chamber, a 0.35 liter Fischer-Porter vessel containing a magnetic stirrer was charged with Pr. - 6C (5.00 g, 15 mmol), Pd (OAc) ₂ (168 mg, 0.75 mmol, 5 mol%), rac-BTNAP (654 mg, 1.05 mmol, 7 mol%), Cs ₂ CO ₃ (6.84 g, 21.0 mmol) and anhydrous degassed toluene (65.0 mL). To this mixture was added isopropylamine (3.00 mL, 35.2 mmol). The vessel was sealed with a pressure cap with a pressure gauge and removed from the glove box. The sealed system was heated to 118-120 ° C and 68.9 kPa with constant stirring in an oil bath. The Fischer-Porter reaction vessel was removed from the oil bath, allowed to cool for 30 minutes and vented to the argon flow system, and a sample was removed by syringe. LCMS analyzes showed 35% product with 65% starting material. Under argon protection, the pressure was removed and the reaction mixture was incubated with Pd (OAc) ₂ (337 mg, 1.5 mmol, 10 mol%), rac-BINAP (1.00 g, 1.6 mmol, 11 mol%), Cs ₂ CO ₃ (10.0 g, 30.7 mmol) and isopropylamine (6.00 mL, 70.4 mmol). The bottle was sealed with a pressure cap and reheated to 118-120 ° C with continuous magnetic stirring for 16 hours. Again, a sample was taken and LCMS analysis showed that the reaction was complete. The reaction mixture was then allowed to cool to room temperature and filtered through a medium thick frit glass. The solid was washed thoroughly with toluene and discarded. The filtrate was concentrated and purified by flash chromatography (Merck 230-400 mesh SiO ₂ , 10% ethyl acetate in hexane) to give 3.80 g of Pr. - 6D in the form of a light brown solid with a yield of 81%. 1 H NMR (300 MHz, CDCl ₃ ) d 7.05 (s, 1H), 4.74 (s, 2H), 3.44 (septet, J = 6.3 Hz, 1H), 2.53 (s 3H), 1.47 (s, 9H), 1.21 (d, J = 6.3Hz, 6H); ¹³ C NMR (75 MHz, CDCl ₃ ) d 165.7 (s), 158.7 (s), 147.4 (s), 130.5 (s), 123.6 (d), 82.9 (s), 45.9 (t), 44.1 (d), 28.0 (q), 22.1 (q), 14.8 (q); HRMS (ESI)) Theory for Ci4H ₂₄ N ₃ SO ₃ [M + H ^T] = 314.1538, found 314.1539 experimentally.

(Ex - 6E)

In a argon atmosphere glove chamber, a 89 ml Fischer-Porter vessel containing a magnetic stirrer was charged with Pr. - 6D (1.00 g, 3.20 mmol), 3-nitrophenylboronic acid (634mg, 3.80 mmol), Cu (I) -2-thiophenecarboxylate (1.21 g, 6.37 mmol) and Pd (Pph 3) ₁₄ (100 mg, 0.86 mmol, 2.7 mol%). THF (25 mL) was added to the flask and the bottle was sealed with a pressure cap with a pressure gauge, then removed from the glove.

- 122protection chamber. The sealed system was heated in an oil bath at 70 ° C with magnetic stirring for 16 hours. The reaction mixture was then allowed to cool to room temperature, vented, and diluted with ether (200 mL). The mixture was filtered through a medium density glass frit. The green solid was washed with ether (100 mL) and discarded. The filtrate was concentrated and purified by flash chromatography (Merck 230400 mesh S102, 10% ethyl acetate in hexane to 30%) to give 961 mg of Pr. - 6E with a yield of 78% in the form of yellow foam. 1 H NMR (300 MHz, CDCl ₃ ) d 8.39 (s, 1H), 8.31 (d, J = 8.1 Hz, 1H), 7.86 (d, J = 7.8 Hz, 1H ), 7.64 (t, J = 8.1 Hz, 1H), 7.15 (bs, 1H), 4.51 (s, 2H), 3.58 (septet, J = 6.0Hz, 1H) 1.46 (s, 9H), 1.27 (d, J = 6.3 Hz, 6H); HRMS (ESI) theoretical for C 19 H 25 N 4 O 5 [M + H] = 389.1815, found 389.1825 experimentally.

(Ex. - 6F)

A 250 ml round bottom flask equipped with a magnetic stirrer was charged with Pr. - 6E (755 mg, 1.9 mmol) and trifluoroacetic acid (30 mL). The mixture was stirred at room temperature under argon flow for 30 min. and then concentrated and rotary evaporator. The residue was triturated with ether (50 mL) and evaporated together with heptane (2 x 50 mL) to give 801 mg of Pr. - 6F in the form of bright yellow glass with a yield of 95%. 1 H NMR (300 MHz, DMSO-d 6) d 8.34-8.26 (m, 2H), 7.89 (d, J = 7.8 Hz, 1H), 7.76 (t, J = 7) 9 Hz, 1H), 7.20 (s, 1H), 4.51 (s, 2H), 3.57 (septet, J = 6.6 Hz, 1H), 1.17 (d, J = 6) 1.6 Hz, 6H); HRMS (ESI) theoretical for C 15 H 17 N 4 O 5 [M + H +] - 333.1223, found 333.1199 experimentally.

Following the procedure described for the CBZ protected precursor, Pr. -6F prepared the product: ¹ H NMR (300 MHz, CDCl 3) d 9.34 (bs, 1H), 8.32 (s, 1H), 8.14 (d, j = 8.0 Hz, 1H), 7 81 (t, J = 7.8Hz, 2H), 7.53 (d, J = 7.8Hz, 2H), 7.47 (t, J = 7.8Hz, 1H), 7.39 7.25 (m, 5H), 7.08 (s, 1H), 7.00 (d, J = 7.8 Hz, 2H), 5.12 (s, 2H), 4.61 (d, J = 7.8 Hz, 1H), 4.35 (s, 2H), 4.21 (m, 1H), 3.50 (d septets, 8 lines J = 6.3 Hz, 1H), 1.22 (d, J = 6.3Hz, H); ¹³ C NMR (75 MHz, CDCl 3) d 168.5 (s), 167.4 (s), 164.0 (s), 158.6 (s), 148.2 (s), 143.8 (s) s), 142.6 (s), 136.6 (s), 136.2 (s), 135.0 (d), 133.4 (s), 133.2 (s), 129.9 (d) ), 128.7 (d), 128.3 (d), 127.8 (d), 127.5 (d), 124.4 (d), 124.1 (d), 121.8 (d) 67.4 (t), 49.9 (t), 44.1 (d), 43.2 (t), 22.4 (q); HRMS (ESI)) calculated for C 31 H 32 N 7 O 6 [M + H] = 598.2463, found experimentally 598.2414.

According to the method described for SC-81703, from Pr. - 6G prepared the product: 1 H NMR (300 MHz, CD 3 OD) d 9.25 (bs, 1H), 8.97 (m, 1H), 8.78 (s, 1H), 7.93-7.14 ( m, 9H complex, 4.77 (s, 2H), 4.51 (s, 3H), 3.66 (m, 1H), 1.30 (d, J = 6.3 Hz, 6H); HRMS (ESI)) calculated for C 23 H 28 N 7 O ₂ [M + H] + 598 without base 44.2304, experimentally found 434.2318.

- 123 -

NH (Ex. 7A)

The substance was prepared from Pr. - 6D using the same procedure for Pr. - 6E, except that CS 2 CO 3 was used as the base. Starting material Pr. -6D (213 mg, 0.68 mmol), 1,3-propanediol pyridine-3-boronic acid cyclic ester (166 mg, 1.02 mmol) and CsCCh (771 mg, 2.37 mmol) was formed by flash purification Chromatography (Merck 230-400 mesh S1O2, 2% methanol in CHCl3) 143 mg of compound Ex. -7A with a yield of 61% in the form of light yellow glass. 1 H NMR (300 MHz, CDCl ₃ ) d 8.79-8.66 (m, 2H), 7.90-7.26 (m complex, 3H), 7.16 (s, 1H), 4, 53 (s, 2H), 3.57 septet, J = 6.3 Hz, 1H), 1.44 (s, 9H), 1.27 (d, J = 6.3 Hz, 6H); HRMS (ESI)) Theory for C ₈ H 5 N ₄ O _{2 3} [M + H ^+] = 345.1927, found 345.1928 experimentally.

(Ex. - 7B)

The substance was prepared from Pr. -7A (143 mg, 0.41 mmol) by the same procedure described for Pr. - 6F to give 212 mg of Pr. - 7B with a yield of 100% in the form of yellow foam. 1 H NMR (300 MHz, CDCl ₃ ) d 8.72-8.64 (m, H), 7.95-7.89 (m, 1H), 7.62-7.52 (complex m, 2H) 7.42-7.37 (m, 1H), 7.20 (s, 1H), 4.52 (s, 2H), 3.57 (septet, J = 6.3 Hz, 1H), 1 18 (d, J = 6.3 Hz, 6H); HRMS (ESI)) calculated for C 14 H 17 N 4 O 3 [M + H] = 289.1301, experimentally found 289.1296.

(Ex - 7C)

The compound was prepared according to the same procedure described for CBZ protected precursors from Pr. 7B to form Pr. 7-C. HRMS (ESI)) calculated for C 30 H 32 N 7 O 4 [M + H] = 554.2516, found experimentally 554.2523.

- 124 Of fabric pr. The product was obtained by the same procedure as in Example 6.

Example 8

Following the procedures of Example 6, the title compound of Example 8 was prepared. HRMS (ESI) theoretical for C ₂₄ H 27 N 7 O ₂ [M + H ⁺ ] = 446.2304, found experimentally 446.2309.

The methylene analog of pyrimidinones, where methylene is present as a replacement for carbonyl acetamide at the N-3 position of the pyrimidinone, can be prepared according to Scheme 8 - general preparation of methylene pyrimidinones - if described below by specific example 9.

- 125 Sch ima 8. “All general synthesis of methylene pyrimidinone

126 Example 9

(Ex - 9A)

To a solution of [5 - [(benzyloxycarbonyl) amino] -2-phenyl-6-oxo-1,6-dihydro-1-pyrimidinyl] acetaldehyde in tetrahydrofuran and dichloromethane (1.1, 0.3 M) was added a catalytic amount of acetic acid and one equivalent of a suitable amine. The solution was cooled to 0 ° C in an ice bath and one equivalent of sodium triacetoxyborohydride was added in one portion. After stirring for 5 minutes, the ice bath was removed and the reaction was allowed to warm to room temperature with stirring for 2 hours. The reaction was neutralized by addition of 1 M NaOH and stirred for 5 minutes. Usual laboratory procedures with aqueous solutions followed by chromatographic purification gave pure product Pr. - 9A.

(Ex. - 9B)

To a solution of [5 - [(benzyloxycarbonyl) amino] -2-phenyl-6-oxo-1,6-dihydro-1-pyrimidinyl] acetamide (Ex. 9A) in methanol (0.2 M) added 10% Pd / C. The resulting mixture was stirred under a hydrogen gas balloon at room temperature for about 16 hours. The crude reaction mixture was then filtered through Celite 545 and the solvent was removed under reduced pressure. Fraction of the reaction residue with ethyl ether gave pure product Pr. - 9B (Ex. - 9C) To a solution of [5-amino-2-phenyl-6-oxo-1,6-dihydro-1-pyrimidinyl] acetamide (Ex. - 9B) in tetrahydrofuran and dichloromethane (1: 1, 0). (3 M) was added a catalytic amount of acetic acid and one equivalent of phenylacetaldehyde. The solution was cooled to 0 ° C in an ice bath and one equivalent of sodium triacetoxyborohydride was added in one portion. After stirring for 5 minutes, the ice bath was removed and the reaction was allowed to warm to room temperature with stirring for 2 hours. The reaction was neutralized by addition of 1 M NaOH and stirred for 5 minutes. Usual laboratory procedures with aqueous solutions followed by chromatographic purification gave pure product Pr. - 9C.

A solution of [5- (2-phenylethyl) amino] -2-phenyl-6-oxo-1,6-dihydro-1-pyrimidinyl] acetamide in 4 M HCl dioxane (0.2 M) was stirred for several hours. After the reaction was complete, the volatiles were removed under reduced pressure. The reaction residue was purified by trituration with ethyl ether to give pure product 5.

The sulfonyl analog of pyrimidinones wherein the sulfonyl is present as a substituent on carbonylacetamide at the N-3 position of the pyrimidinone can be prepared by the procedures generally depicted in Schemes 1-5 from the appropriate aminomethanesulfonamide by substituting N-Bocamidino protected amine instead of 1,1-dimethoxyethylamine. For example, N (4-amidinobenzyl) -2-aminomethanesulfonamide may be used. In this way, the sulfonyl analogs of Examples 10 and 11 were prepared.

Triazinone analogs of pyrimidinones wherein nitrogen is a substitute for the carbon at the 4-position of the pyrimidinone can be prepared according to Scheme 9, "General Preparation of 4-Azapyrimidinones", as described in detail in Example 12 below.

128 Scheme 9: general synthesis of 4-aza-pyrimidinones

Lawessonóv reagent

ABOUT

129 Example 12

NH

CH ₃ PhSO ₃ H (Ex. 12A)

A solution of glycine t-butyl ester hydrochloride (1 mmol) in dichloromethane was incubated with benzoyl chloride (1 mmol) and triethylamine (2 mmol). The reaction mixture was stirred at room temperature for 16 hours, then washed with water and extracted with dichloromethane. The combined organic fractions were dried over MgSO 4. After removal of the flowing components under vacuum, the pure product Pr was isolated. - 12A.

(Ex. - 12B)

A mixture of N-benzoylglycine-t-butyl ester (1 mmol, Pr. I2A), Lawesson's reagent (0.5 mmol) and toluene was heated at 80 ° C for 16 h. The reaction mixture was then concentrated under reduced pressure. Purification by column chromatography on silica gel gave pure product Pr. - 12B.

(Ex. - 12C)

A mixture of N-thiobenzoylglycine-t-butyl ester (1 mmol, Pr. 12B) in dichloromethane was incubated with trimethyloxonium tetrafluoroborate (1.1 mmol) at -78 ° C. After stirring for 2 hours, the mixture was washed with NaHCO 3 (aq) and extracted with dichloromethane. The combined organic fractions were dried over MgSO 4 and filtered. After concentration by evaporation of the organic components, the desired product Pr was isolated. - 12C.

(Pr.-12D)

A solution of N-thiomethylbenzylglycine-t-butyl ester (1 mmol, Pr. 12C) in methanol was incubated with hydrazine (1 mmol). The flowing components were removed under vacuum and the desired compound Pr was isolated without further purification. - 12D.

(Ex - 12E)

Mixture of substances Pr. 12D (1 mmol) and ethylthiooxamate (1 mmol) in methanol were heated at reflux temperature for 4 hours. Colorless crystals and crystals of the desired product Pr precipitated. The 12E were isolated by filtration under reduced pressure.

Substance solution Pr. 12E (1 mmol) and pyridine (5 mmol) in acetonitrile were incubated with a solution of α-toluenesulfonyl chloride (3 mmol) in acetonitrile. The reaction mixture was then stirred

- 130 for 3 hours at -10 ° C to 0 ° C. After the reaction was complete, a white precipitate formed. Crystals of the desired product Pr. 12F were isolated by filtration under reduced pressure.

(Ex - 12G)

Into the mixture of the substance Pr. - 12F (1 mmol) in anisole at 0 ° C was added trifluoroacetic acid. The reaction mixture was stirred at 0 ° C for 1 hour and then extracted with organic solvents. Removal of the organic solvent under reduced pressure gave a pure product of pr. - 12G.

(Ex. - 12H)

Fabric Pr. 12G (1 mmol), EDC (1.3 mmol) and HOBt (1.3 mmol) were combined in DMF and stirred at 20 ° C for 15 min. To the mixture was added a solution of benzyl - [[(4-aminomethylphenyl) iminomethyl] amino] carbamates, the chloride chloride (1.3 mmol) and DIEA (1.3 mmol) in DMF. Usual laboratory procedures with aqueous solutions followed by chromatographic purification gave pure product Pr. - 12H.

Fabric Pr. - 12H (1 mmol), p-toluenesulfonic acid monohydrate (1 mmol) and 10% Pd on activated carbon (0.1 mmol) were mixed with methanol. The mixture was stirred for 2 hours under a hydrogen atmosphere which was formed and maintained with a rubber balloon. After filtering off the catalyst and removing the methanol, the desired product was isolated.

The compounds according to the invention of the general formula I with hydroxyl, thiol and amine functional groups can be a starting material for a large number of derivatives. Alternatively, derivatized ¹ compounds of formula (I) may be obtained by first derivatizing one or more intermediates in the preparation processes and then converting the derivatized intermediate into a compound of formula (I). The hydroxyl group in the alcohol or phenol form can readily be converted to carboxylic, sulfonic, carbamic, phosphonic and phosphoric acids. Acylation to form carboxylic acid esters is generally accomplished using suitable acylating reagents such as aliphatic anhydride or acid chloride. Corresponding aryl and heteroaryl anhydrides and acid chlorides may also be used. These reactions are generally carried out using an amine catalyst such as pyridine in an inert solvent. Similarly, carbamic acid esters (urethanes) can be obtained by reacting a hydroxyl group with an isocyanate and a chloride carbamoyl. Sulfonate, phosphonate and phosphate esters can be prepared from the corresponding acid chlorides or similar reagents. Compounds of formula I having at least one thiol group contained therein can be converted to the corresponding thioester derivatives analogous to alcohols and phenols using the same reagents and comparable reaction reagents.

- 131 conditions. Compounds of formula I which contain at least one primary or secondary amine group can be converted to the corresponding amide derivatives. Carboxylic acid amides can be prepared using suitable acid chlorides or anhydrides under reaction conditions analogous to those of alcohols or phenols. The 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 triethylemine or pyridine. The sulfonamides can be prepared with the corresponding sulfonyl chlorides in the presence of aqueous sodium hydroxide or tertiary amine. Appropriate methods and procedures for preparing these derivatives can be found in the works of House's Modem Synthetic Reactions, WA Benjamin, Inc., Shriner, Fuson, and Curtin in The Systematic Identofocation of Organics Compounds, ^{5, h} Edition, John Wiley & Sons, and Fieser and Fieser in Reagents for Organics Synthesis, Volume 1, by John Wiley & Sons. A variety of reagents that can be used to derivatize hydroxyl, thiol and amines in the compounds of Formula I are available from commercial sources or the works cited above, which are incorporated herein by reference.

The hydroxyl, thiol and amine functional compounds of the formula I according to the invention can be alkylated to form a large number of derivatives. Alternatively, alkylated compounds of formula (I) may be obtained by first alkylating one or more intermediates in the preparation processes and then converting the alkylated intermediate. The hydroxyl group of the compound of formula I can be easily converted to ethers. The alkylation to form the ether is generally carried out using a suitable alkylating agent such as an alkyl bromide, an alkyl iodide or an alkyl sulfonate. Corresponding aralkyl, heteroaralkyl, alkoxyalkyl, aralkyloxyalkyl and heteroaralkyloxyalkyl bromides, iodides and sulfonates may also be used. These reactions are generally carried out using alkoxide-forming agents such as sodium hydride, potassium t-butoxide, sodium amide, lithium amide and n-butyllithium, inert polar solvents such as DMF, DMSO, THF and similar comparable solvents, amine catalysts such as pyridine in an inert solvent. Compounds of formula I which contain at least one thiol group can be converted to the corresponding thioether derivatives analogously to alcohols and phenols using the same reagents and comparable reaction conditions. Compounds of formula I which contain at least one primary, secondary or tertiary amine group can be converted to the corresponding secondary, tertiary or quaternary ammonium derivatives. Quaternary ammonium derivatives can be prepared using suitable bromides, iodides and sulfonates in analogy to alcohols

- 132 and phenol. The reaction conditions include the reaction of the amine by heating it with an alkylating agent in the amine. stoichiometric ratio with amine (i.e., one equivalent with a tertiary amine, two with a secondary amine and three with a primary amine). At the same time as the primary and secondary amines, three equivalents of acid binders are used, respectively. Secondary or tertiary amines can be prepared from the corresponding primary or secondary amines. The primary amine can be dialkylated by reductive deamination using an aldehyde such as formaldehyde and sodium cyanoborohydride in the presence of glacial acetic acid. The primary amine may be monoalkylated first by mono-protection of the amine with a well-leaving protecting group such as trifluoroacetyl. An alkylating agent such as dimethyl sulfate in the presence of a non-nucleophilic base such as Barton's base (2-tert-butyl 1,1,1,3,3-tetramethylguanidine) yields a mono-methylated protected amine. Removal of the protecting group with aqueous potassium hydroxide gives the desired monoalkylated amine. Other suitable methods and techniques for preparing these derivatives can be found in the works of House's Modem Synthetic Reactions, WA Benjamin, Inc., Shriner, Fuson, and Curtin in The Systematic Identification of Organics Compounds, ^5th Edition, John Wiley & Sons, and Fieser and Fieser in Reagents for Organics Synthesis, published by John Wiley & Sons. Perfluoroalkyl derivatives can be prepared as described in Des Marteau, J. Chem. Soc. Chem. Commun. 2241 (1988). A variety of reagents that can be used to derivatize hydroxyl, thiol and amines in the compounds of formula (I) are available from commercial sources or from the works cited above, which are incorporated herein by reference.

The above synthetic approaches for the preparation of pyrimidinones by derivatization of nucleophilic substituents that may be present at sites B, R ¹ , R ² and Y 0 are shown in Table 1 for specific examples 13 to 19. The specific examples below should be considered as illustrative examples of a wide variety of options and not as exhaustive examples to those skilled in the art.

133 Table 1: Structures of pyrimidinones prepared using general derivatization procedures

Pr. no. R ² B-A- Y ° MW (m / z + 1) 13 phenyl methoxyacetyl 4amidinobenzyl 449.47 14 phenyl 4-methylbenzoyl 4amidinobenzyl 495.54 15 phenyl 4-nitrobenzoyl 4amidinobenzyl 526.52 16 phenyl isobutyryl 4amidinobenzyl 447.50 17 phenyl 2,4,6-trimethylbenzoyl 4amidinobenzyl 523,60 18 phenyl benzoyl 4amidinobenzyl 481.52 19 phenyl acetyl 4amidinobenzyl 419.45

Biological activity tests

TF-VIIa test

In this assay, a 100 nM amount of recombinant soluble tissue factor and 2 nM amount of Factor VIIa was added to a 96-well plate with 0.4 mM substrate, N-methylsulfonyl-D-phegly-arg-p-nitroaniline, and then either inhibitor or buffer ( 5 mM CaCl 2, 50 mM Tris-HCl, pH 8.0, 100 mM NaCl, 0.1% BSA). Immediately after the addition, the absorbance of the reaction mixture was measured at a wavelength of 405 nm in a total volume of 100 μΐ to determine the background absorbance. The plate was incubated at room temperature for 60 minutes at which time the rate of substrate hydrolysis at 405 nm was measured as an increase due to p-nitroaniline release. Percent inhibition of TF-VIIa activity was calculated from the absorbance at 405 nm of the experimental and control samples.

- 134Xa test

To a 96-well plate with either inhibitor or buffer (50 mM Tris-HCl, pH 8.0, 100 mM NaCl, 0.1% BSA) was added Na-benzyloxycarbonyl-D-arginyl-L-glycyl-L-arginine- nitroaniline dihydrochloride (0.15 mM); and human factor Xa at a concentration of 0.3 nM. Immediately after the addition, the absorbance of the reaction mixture was measured at a wavelength of 405 nm in a total volume of 100 μΐ to determine the background absorbance. The plate was incubated at room temperature for 60 minutes at which time the rate of substrate hydrolysis at 405 nm was measured as an increase due to the release of p-nitroaniline. Percent inhibition of Xa activity was calculated from the absorbance at 405 nm of the experimental and control samples.

Thrombin test

To a 96-well plate with inhibitor or buffer (50 mM Tris-HCl, pH 8.0, 100 mM NaCl, 0.1% BSA) was added HD-phenylalanyl-L-pipecolyl-L-arginine-p-nitroaniline dihydrochloride ( 0.06 mM) and human thrombin at a concentration of 0.28 nM. Immediately after the addition, the absorbance of the reaction mixture was measured at a wavelength of 405 nm in a total volume of 100 μΐ to determine background absorbance. The plate was incubated at room temperature for 60 minutes at which time the rate of substrate hydrolysis at 405 nm was measured as an increase due to p-nitroaniline release. Percent inhibition of thrombin activity was calculated from the absorbance at 405 nm of the experimental and control samples.

Trypsin test

In a 96-well plate with inhibitor or buffer (50 mM Tris-HCl, pH 8.0, 100 mM NaCl, 0.1% BSA), trypsin type IX from porcine pancreas at a concentration of 5 µg / ml and N-oc- benzoyl-L-arginine-p-nitroanilide (L-BAPNA) (0.375 mM). Immediately after the addition, the absorbance of the reaction mixture was measured at a wavelength of 405 nm in a total volume of 100 μΐ to determine the background absorbance. The plate was incubated at room temperature for 60 minutes at which time the rate of substrate hydrolysis at 405 nm was measured as an increase due to p-nitroaniline release. Percent inhibition of thrombin activity was calculated from the absorbance at 405 nm of the experimental and control samples.

Recombinant soluble TF consisting of 1-219 amino acids of the original protein sequence was expressed in E. coli and purified by Mono Q

- 135 Sepharose FPLC. Recombinant human Vila was purchased from American Diagnostica, Greenwich CT and a chromogenic substrate 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 and trypsin, and L-BAPNA from Sigma, St. Louis MO. Chromatographic substrates S-2765 and S-2238 were purchased from Chromogenix, Sweden.

The biological activities of the compounds of Examples 1 to 19 were determined by the above bioassays and are summarized in Table 2.

Table 2: Inhibitory activities of pyrimidinones against factor Xa, TF-VHa, thrombin II and trypsin Π.

Pr. no. TF-VIIa IC ₅₀ (μΜ) thrombin Π IC ₅₀ (μΜ) factor Xa IC ₅₀ (μΜ) trypsin II IC50 (μΜ) 1 15.4 22.4 - 0.5 2 > 30 > 30 - > 30 3 1.0 1.0 - 0.6 4 - __ - - 5 - - - - 6 0.05 43% @ 30μΜ 33% @ 30μΜ <0,04 7 0.7 11.3 33% @ 30μΜ 0.04 8 0.08 42% @ 30μΜ 15% @ 30μΜ 0.04 9 - - - - 10 - __ - - 11 - - - - 12 - - - - 13 - - - - 14 - - - - 15 - - - - 16 - - - - 17 - - - - 18 - - - - 19 - - - -

- 136-

Claims (48)

PATENT CLAIMS Substituted polycyclic aryl and heteroaryl pyrimidinones of general formula 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 the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkylenedioxy, haloalkylthio, alkanoyloxy , alkoxy, alkoxyalkyl, haloalkoxyalkyl, hydroxy, amino, alkoxyamino, nitro, lower alkylamino, alkylthio, alkylthioalkyl, alkylsulfinyl, alkylsulfonyl, alkylsulfonylalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, alkylsulfonamido, alkylaminosulfonyl, amidosulfosulfonyl, monosulfosulfonyl, monosulfosulfonyl, monosulfosulfonyl, monosulfosulfonyl, monosulfosulfonyl, , haloalkanoyl, alkyl, alkenyl, halogen, haloalkyl, haloalkenyl, haloalkoxy, hydroxyhaloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxyalkyl, carboxyalkyl, carboalkoxy, carboxy, carboxamido, carboxamidoalkyl and cyano; R ⁹ , R ¹⁰ , R ¹¹ , R ¹² and R ¹³ are optionally selected from heteroaryl and heterocyclyl, provided that the R ⁹ , R ¹⁰ , R ¹¹ , R ¹² and R ¹³ substituents are other than B; R ^16, R ^19, R ^32, R ^33, R ^34, R ³⁵ and R ³⁶ are independently optionally Q ^b with the proviso that no more than one of R ¹⁶ and R ¹⁹ is Q ^b at the same time and that Q ^b, Q is ^be; B is optionally selected from the group consisting of hydrido, trialkylsilyl, C 2 -C 8 alkyl, C 3 -C 8 alkylenyl, C 3 -C 8 alkenyl, C 3 -C 8 alkynyl and C 2 -C 8 haloalkyl, wherein each member of group B may be optionally substituted on any carbon atom up to 6 atoms including from 137 of the B to A binding site by one or more R ³² , R ³³ , R ³⁴ , R ³⁵ and R ³⁶ substituents; B is selected from the group consisting of C3-C12 cycloalkyl and C4-heterocyclyl, wherein each ring carbon atom is optionally substituted with ^R33 , the ring carbon atom other than the carbon atom in the B bond site at A is optionally substituted with an oxo group provided that at most one ring carbon atom is substituted by an oxo group simultaneously, the carbon atom and the nitrogen atom adjacent to the carbon at the B-bonding point at A are optionally substituted with R ⁹ and R ¹³ , a ring carbon or nitrogen adjacent the R ⁹ position and two atoms apart from the point of attachment is optionally substituted with R ¹⁰ , a ring carbon or nitrogen atom adjacent to the R ¹³ position and two atoms away from the point of attachment is optionally substituted with R ¹² , a ring carbon or nitrogen atom three atoms from the point of attachment and adjacent to R ¹⁰ the position optionally substituted by R ¹¹ , a ring carbon atom or a nitrogen atom three atoms away from the point of attachment and the light to R ¹² position is optionally substituted with R ³³ and the ring carbon or nitrogen atom is four atoms away from the point of attachment and adjacent to the R ¹¹ and R ³³ positions is optionally substituted with R ³⁴ ; A is selected from the group consisting of a covalent bond, (W ⁷ ) rr - (CH (R ¹⁵ )) p and (CH (R ¹⁵ )) p ₃ - (W ⁷ ) n ·, where rr is an integer from 0 to 1 , wherein the integer is selected from 0 to 6 and W ⁷ is selected from the group consisting of O, S, C (O), (R ⁷ ) NC (O), (R ⁷ ) NC (S) and NR ⁷ , that at most one substituent containing rr and pa can be 0 simultaneously; R ⁷ is independently selected from the group consisting of hydrido, hydroxy and alkyl; R ¹⁵ is independently selected from the group consisting of hydrido, hydroxy, halo, alkyl and haloalkyl; Ψ is selected from the group consisting of NH and NOH; M is selected from the group consisting of N and R * -C; R ¹ is selected from the group consisting of hydrido, alkyl, alkenyl, cyano, halogen, haloalkyl, haloalkoxy, haloalkylthio, amino, aminoalkyl, alkylamino, amidino, hydroxy, hydroxyamino, alkoxy, hydroxyalkyl, alkoxyamino, thiol, alkylthio; R ^{2 is} Z ° -Q; Z is selected from a single covalent bond, (CR R ²⁾ q, wherein q is an integer from 1 to 3, (CH (R ⁴¹⁾⁾ and - V ^H - (CH (R ⁴²⁾⁾ _p, wherein the gap is an integer from 0 to 3 and W 0 is selected from the group consisting of O, S, C (O), S (O), N (R ⁴¹ ) and ON (R ⁴ ') and (CH (R ⁴¹⁾ ) W ²² - (CH (R ⁴² )) h wherein eah are integers independently selected from 0 to 1 and W ²² is selected from the group consisting of CR ^{4I =:} CR ⁴² , 1,2-cyclopropyl, 1,2- cyclobutyl, 1,2cyclohexyl, 1,3-cyclohexyl, 1,2-cyclopentyl, 1,3-cyclopentyl, 2,3-morpholinyl, 2,4-morpholinyl, 138 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-tetrahydrofuranyl, provided that Z 0 is directly attached to the pyrimidinone ring; R ⁴¹ and R ⁴² are independently selected from the group consisting of amidino, hydroxyamino, hydrido, amino and alkyl; Q is selected from the group consisting of hydrido with the proviso that Z 0 is other than a single covalent bond, and formula II wherein D ¹ , D ² , J ¹ , J ² and K ¹ are independently selected from the group consisting of C, N, O , S and covalent bonds, provided that the covalent bond can only be selected once, at most one of D ¹ , D ² , J ¹ , J ² and K ¹ is O, at most one of D ¹ , D ² , J ¹ , J ² , and K ¹ is S, one of D ¹ , D ² , J ¹ , J ² and K ¹ must be a covalent bond if two of D ¹ , D ² , J ¹ , J ² and K ¹ are O and S and at most four of D ¹ , D ² , J ¹ , J ² and K ¹ are N, provided that R ⁹ , R ¹⁰ , R ¹¹ , R ¹² and R ¹³ are each independently selected to maintain carbon tetravalence, nitrogen trivalent, sulfur bivalent and oxygen bivalent. K is (CR ^4a R ^4b ) _n wherein n is an integer from 1 to 2; R ^4a and R ^4b are independently selected from the group consisting of halogen, hydrido, hydroxyalkyl, alkyl, alkoxyalkyl, alkylthioalkyl and haloalkyl, E 0 is E ¹ when K is (CR ^4a R ^4b ) n, wherein E ¹ is selected from the group consisting of a single covalent bond, C (O), C (S), C (O) N (R ⁷ ), ( R ⁷ ) NC (O), S (O) 2, (R ⁷ ) NS (O) ₂ , S (O) ₂ N (R ⁷ ). Y 0 is a group of formula IV - 139- wherein D ³ , D ⁶ , J ⁵ and J ⁶ are independently selected from the group consisting of C, N, O, S and a covalent bond, with the proviso that at most one of D ³ , D ⁶ , J ⁵ and J ⁶ is a covalent bond, K ² is C, at most one of D ³ , D ⁶ , J ⁵ and J ⁶ is O, at most one of D ⁵ , D ⁶ , J ⁵ and J ⁶ is S, one of D ⁵ , D ⁶ , J ⁵ and J ⁶ must be a covalent bond when two of D ⁵ , D ⁶ , J ⁵ and J ⁶ are O and S 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 the group consisting of hydrido, amidino, guanidino, carboxy, haloalkylthio, alkoxy, hydroxy, amino, nitro, alkoxyamino, lower alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, alkenyl, halogen, haloalkyl, haloalkoxy, hydroxyalkyl, alkylenylamino, haloalkoxyalkyl, carboalkoxy and cyano; Q ^b is selected from the group consisting of NR ²⁰ R ²¹ , aminoalkylenyl and Q ^be , wherein Q ^be is hydrido and N (R ²⁶ ) N (NR ²⁵ ) N (R ²³ ) (R ²⁴ ) and C (NR ²⁵ ) NR ²³ R ²⁴ with the proviso that at most one of R ²⁰ and R ²¹ is a hydroxy, amino, alkylamino or dialkylamino simultaneously, and that at most one of R ²³ and R ²⁴ is simultaneously a hydroxy, amino, alkylamino or dialkylamino substituent; R ²⁰ , R ²¹ , R ²³ , R ²⁴ , R ²⁵ and R ²⁶ are independently selected from the group consisting of hydrido, alkyl, hydroxy, aminoalkylenyl, amino, dialkylamino, alkylamino and hydroxyalkyl substituent; Q ^s is selected from the group consisting of a single covalent bond, (CR R) b, wherein b is an integer selected from 1 to 4, and (CH (R ¹⁴ )) c-W '- (CH (R ¹⁵ )) d, wherein c and d are integers independently selected from 1 to 3 and W ¹ is selected from the group consisting of 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 ), provided that R ¹⁴ is other than a halogen substituent when it is directly bound to N and that (CR ³⁷ R ³⁸ ) ba and (CH (R ¹⁴ )) c bind to E 0; R ¹⁴ is selected from the group consisting of hydrido, halogen, alkyl, and haloalkyl; R ³⁷ and R ³⁸ are independently selected from the group consisting of hydrido, alkyl and haloalkyl; R ³⁸ is optionally selected from the group consisting of aroyl and heteroaroyl; - 140Y ° is optionally Q ^b -Q ^ss where Q ^ss is (CH (R ¹⁴ )) eW ^{2 *} - (CH (R ¹⁵ )), "where eah are integers independently selected from the interval 1 to 2 and W ² is CR ^4a = CR ^4b with the proviso that (CH (R ¹⁴ )) e binds directly to E °; Y 0 is optionally selected from the group consisting of Q ^b -Q ^ssss and Q ^b _Q ^ssssr wherein Q ^ssss is (CH (R ³⁸ )) _r -W ⁵ and Q " ^ssr is (CH (R ³⁸ jr-W ⁶⁾ and wherein r is an integer independently selected from 1 to 2 and W ⁵ and W ⁶ are independently selected from the group consisting of 1,4-indenyl, 1,5-indenyl, 1,6indenyl, 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-benzofuranyl, 2,5- benzo furanyl, 2,6-benzofuranosyl, 2,7-benzofuranosyl, 3,4-benzofuranosyl, 3,5-benzofuranosyl, 3,6-benzofuranosyl, 3,7-benzofuranosyl, 2,4benzothiophenyl, 2,5-benzothiophenyl, 2,6 -benzothiophenyl, 2,7-benzothiophenyl, 3,4-benzothiophenyl, 3,5-benzothiophenyl, 3,6-benzothiophenyl, 3,7-benzothiophenyl, 2,7-imidazo (1,2-a) pyridinyl, 3,4-imidazo (1,2-a) pyridinyl, 3,5-imidazo (1,2-a); 2-a) pyridinyl, 3,6-imidazo (1,2-a) pyridinyl, 3,7-imidazo (1,2-a) pyridinyl, 2,4-indonyl, 2,5-indonyl, 2,6-indonyl, 2,7-indonyl, 3,4-indonyl, 3,5-indonyl, 3,6-indonyl, 3,7-indonyl, 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, 2,8-quinolinyl, 3,4-quinolinyl, 3, 5-quinolinyl, 3,6-quinolinyl, 3,7-quinolinyl, 3,8-quinolinyl, 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-cinolinyl, 3,5-cinolinyl, 3,6-cinolinyl, 3,7-cinolinyl, 3,8-cinolinyl, 4,5-cinolinyl, 4,6-cinolinyl, 4,7-cinolinyl, 4,8-cinolinyl, and all nitrogen atoms in ring W ⁵ and ring W ⁶ with carbon and hydride substituents other than at the W ⁵ and W 2 bond sites are optionally substituted with one or more with the substituents of R ⁹ , R ¹⁰ , R ¹¹ and R ¹² , provided that Q ^b is at the lowest order number for each W ⁵ , Q ^b is at the highest order number for each W ⁶ a (CH (R ³⁸ ) _r binds to E 0; or a pharmaceutically acceptable salt thereof. Substituted polycyclic aryl and heteroaryl pyrimidinones according to claim 1 of the general formula 141 - wherein B is a group of the general formula: n Ί i ic jz R, R, R, R and R are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkylenedioxy, haloalkylthio, alkanoyloxy, alkoxy, hydroxy, amino, alkoxyamino, haloalkanoyl, nitro, lower alkylamino, alkylthio, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, alkylsulfonamido, amidosulfonyl, monoalkyl amidosulfonyl, dialkylaminodosulfonyl, alkyl, alkenyl, halo, haloalkyl, haloalkenyl, haloalkoxy, hydroxyalkyl, alkylamino, carboalkoxy, carboxy, carboxamido, cyano, and Q ^b; B is optionally selected from the group consisting of hydrido, trialkylsilyl, C 2 -C 8 alkyl, C 3 -C 8 alkylenyl, C 3 -C 8 alkenyl, C 3 -C 8 alkynyl and C 2 -C 8 haloalkyl, wherein each member of group B may be optionally substituted on any carbon atom of up to 6 atoms including from the binding site B to A by one or more substituents from the group R 1, R, R, R and R; B is selected from the group consisting of C3-C12 cycloalkyl and C4-heterocyclyl wherein each ring carbon atom is optionally substituted with ^R33 , the ring carbon atom other than the carbon atom in the B-bonding site of A is optionally substituted with an oxo group, that at most one ring carbon atom is substituted by an oxo group simultaneously, the carbon atom and the nitrogen atom adjacent to the carbon at the binding site are optionally substituted by R and R, the carbon atom or nitrogen atom adjacent to the R ⁹ position and two atoms away substituted with R ¹⁰ , a carbon atom or a nitrogen atom adjacent to the R ¹³ position and two apart - 1421Ί, the atoms from the point of attachment are optionally substituted with R, a carbon or nitrogen atom three atoms from the point of attachment and adjacent to the R ¹⁰ position is optionally substituted with R ¹¹ , a carbon or nitrogen atom with three atoms from the point of attachment and adjacent to the R position is optionally substituted with R ³³ and a carbon or nitrogen atom four atoms from the point of attachment and adjacent to the R ¹¹ and R ³³ position is optionally substituted with R ³⁴ ; R ⁹ , R ¹⁰ , R ¹¹ , R ¹² and R ¹³ are independently selected from the group consisting of hydrido, acetamido, haloacetamido, alkoxyamino, alkanoyl, haloalkanoyl, amidino, guanidino, alkylenedioxy, haloalkylthio, alkoxy, hydroxy, amino, lower alkylamino, alkylthio , alkylsulfinyl, alkylsulfonyl, alkylsulfonamido, amidosulfonyl, monoalkylamidosulfonyl, dialkylaminodosulfonyl, alkyl, halogen, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, carboalkoxy, carboxyalkyl, carboxy, carboxamido and cyano; R ^9, R ^10, R ^11, R ^12, and R @ ³ are optionally selected from heteroaryl and heterocyclyl with the proviso that R ^9, R ^10, R ^11, R ¹² and R ¹³ substituents are other than B; A is selected from the group consisting of a single covalent bond, (CH (R ¹⁵ )) p _and - (W ⁷ ) n ·, where rr is an integer from 0 to 1, and p is an integer selected from 0 to 3 and W ⁷ is selected from the group consisting of O, S, C (O), (R ⁷ ) NC (O), (R ⁷ ) NC (S) and N (R ⁷ ); R ⁷ is independently selected from the group consisting of hydrido, hydroxy and alkyl; R ¹⁵ is independently selected from the group consisting of hydrido, hydroxy, halo, alkyl and haloalkyl; M is selected from the group consisting of N and R’-C. R ¹ is selected from the group consisting of hydrido, alkyl, cyano, halogen, haloalkyl, haloalkoxy, amino, aminoalkyl, alkylamino, amidino, hydroxy, hydroxyamino, alkoxy, hydroxyalkyl, alkoxyamino, thiol, and alkylthio; R ² is Z ° -Q, Z 0 is selected from the group consisting of a single covalent bond a (CR ⁴¹ R ⁴² ) q, wherein q is an integer from 1 to 2, (CH (R ⁴¹ )) g W ⁰ - (CH (R ⁴² )) p, wherein gap are integers from 0 to 3 and W ° is selected from the group consisting of O, S and N (R ⁴¹ ) and (CH (R ⁴ )) eW ²² - (CH (R ⁴² )) | _b wherein eah is an integer independently selected from 0 to 1 and W ²² is selected from the group consisting of 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, 143 3,4-pyrrolidinyl, 2,3-tetrahydrofuranyl, 2,4-tetrahydrofuranyl, 2,5-tetrahydrofuranyl and 3,4-tetrahydrofuranyl, provided that Z 0 is directly attached to the pyrimidinone ring; R ⁴¹ and R ⁴² are independently selected from the group consisting of hydrido, hydroxy and amino; Q is selected from the group consisting of hydrido with the proviso that Z 0 is other than a single covalent bond, aryl and heteroaryl, wherein the carbon atom adjacent to the carbon at the binding site is optionally substituted with R ⁹ , another carbon atom adjacent to the carbon at the binding site is optionally substituted with R ¹³ and carbon atom adjacent to the R ⁹ position and two atoms away from the point of attachment is optionally substituted with R ¹⁰ , carbon atom adjacent to R ¹³ position and two atoms from the point of attachment is optionally substituted with R 10, and any carbon atom adjacent to R ¹⁰ the position if the R ¹² position is optionally substituted with R ¹ '; K is CHR ^4a wherein R ^4a is selected from the group consisting of hydrido, hydroxyalkyl, alkyl, alkoxyalkyl, alkylthioalkyl and haloalkyl; E 0 is selected from the group consisting of a single covalent bond, C (O) N (H), (H) NC (O), (R ⁷ ) NS (O) _2, and S (O) ₂ N (R ⁷ ); Y 0 is a group of the formula IV wherein D 1, D ⁵ , J ⁵ and J ⁶ are independently selected from the group consisting of C, N, O, S and a covalent bond, provided that at most one of D ⁵ , D ⁶ , J ⁵ and J ⁶ is a covalent bond, K ² is C, at most one of D ⁵ , D ⁶ , J ⁵ and J ⁶ is O, at most one of D ⁵ , D ⁶ , J ⁵ and U is S, one of D ⁵ , D ⁶ , J ⁵ and J ⁶ must be a covalent bond if two of D ⁵ , D ⁶ , J ⁵ and J ⁶ are O and S and at most four of D ⁵ , D ⁶ , J ⁵ and J ⁶ are N, that R ¹⁶ , R ¹⁷ , R ¹⁸ and R ¹⁹ are each independently selected to maintain carbon tetravalence, nitrogen trivalent, sulfur bivalent and oxygen bivalent; R ¹⁶ , R ¹⁷ , R ¹⁸ and R ¹⁹ are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, haloalkylthio, alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, halo, haloalkyl, haloalkoxy, halohydroxyalkyl, aminoalkyl and cyano; 16 'o 19 ^L6 R and R 'are optionally Q ⁿ with the proviso that no more than one of R and R' ⁷ together are Q 'and that Q ^1, Q is - 144 Q ^b is selected from the group consisting of NR ²⁰ R ²¹ , Q ^be , wherein Q ^be is hydrido, N (R ²⁶ ) C (NR ²⁵ ) N (R ²³ ) (R ²⁴ ) and C (NR ²⁵ ) NR ²³ R ²⁴ with the proviso that at most one of R ²⁰ and R ^{21 is} hydroxy, amino, alkylamino or dialkylamino simultaneously, and that at most one of R ²³ and R ²⁴ is hydroxy, amino, alkylamino or dialkylamino simultaneously; R ²⁰ , R ²¹ , R ²³ , R ²⁴ , R ²⁵ and R ²⁶ are independently selected from the group consisting of hydrido, alkyl, hydroxy, amino, alkylamino and dialkylamino; Q ^s is selected from the group consisting of a single covalent bond, (CR ³⁷ R ³⁸ ) b, wherein b is an integer selected from 1 to 4 a (CH (R ¹⁴ )) _c -W '- (CH (R ¹⁵ )) and, wherein c and d are integers selected from 1 to 3 and W ¹ is selected from the group consisting of 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 ), provided that R ¹⁴ is other than halogen, when it binds directly to N and that (CR ³⁷ R ³⁸ ) b and (CH (R ¹⁴ )) _c directly bind to E °; R ¹⁴ is selected from the group consisting of hydrido, halogen, alkyl, and haloalkyl; 37 38 R and R are independently selected from the group consisting of hydrido, alkyl and haloalkyl; R is optionally selected from the group consisting of aroyl and heteroaroyl; Y * is optionally Q ^b -Q ^ss where Q ^ss is (CH (R ¹⁴ )) eW ² - (CH (R ¹⁵ )) h where eah are integers independently selected from the interval 1 to 2 and W ² is CR ^4a = CH with the proviso that (CH (R ¹⁴ )) _e binds directly to E °; or a pharmaceutical salt thereof. The substituted polycyclic aryl and heteroaryl pyrimidinones of claim 2, wherein B is selected from the group consisting of hydrido, trialkylsilyl, C 2 -C 8 alkyl, C 3 -C 8 alkylenyl, C 3 -C 8 alkenyl, C 3 -C 8 alkynyl and C 2 -C 8 haloalkyl, wherein each member of group B may be optionally substituted on any carbon atom up to 6 atoms including from the B to A bonding site by one or more substituents from 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 the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, alkylthio, amidosulfonyl, monoalkylamidosulfonyl, dialkylaminodosulfonyl, alkyl , halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboalkoxy, carboxy, carboxamido, cyano, and Q ^b; A is (CH (R ¹⁵ )) _{p and} -W ^{3 * * * 7} , wherein the integer is selected from 1 to 3 and W ⁷ is selected from the group consisting of O, S and N (R ⁷ ), wherein R ⁷ is independently selected from the group consisting of hydrido and alkyl; 145 R ¹⁵ is independently selected from the group consisting of hydrido, hydroxy, halo, alkyl and haloalkyl, provided that R ¹⁵ is not a hydroxy and halogen substituent when R ^{15 is} on carbon bonded directly to W ⁷ ; M is selected from the group consisting of N and R‘-C; R ¹ is selected from the group consisting of hydrido, alkyl, cyano, halogen, haloalkyl, haloalkoxy, amino, aminoalkyl, alkylamino, amidino, hydroxy, hydroxyamino, alkoxy, hydroxyalkyl, alkoxyamino, thiol, and alkylthio; R ^{2 is} Z ° -Q; Z 0 is selected from the group consisting of a single covalent bond and (CR ⁴¹ R ⁴² ) _q , wherein q is an integer from group 1 to 2; R ⁴¹ and R ⁴² are independently selected from the group consisting of hydrido, hydroxy and amino; Q is selected from the group consisting of aryl and heteroaryl wherein the carbon atom adjacent to the carbon at the binding site is optionally substituted with R ⁹ , another carbon atom adjacent to the carbon at the binding site is optionally substituted with R ¹³ and a carbon atom adjacent to the R ⁹ position and two atoms from the point of attachment are optionally substituted with R ¹⁰ , the carbon atom adjacent to the R ¹³ position and two atoms from the point of attachment optionally substituted with R ^12, and any carbon atom adjacent to the R ¹⁰ position if the R ¹² position is optionally substituted R ¹¹ ; R ⁹ , R ¹⁰ , R ¹¹ , R ¹² and R ¹³ are independently selected from the group consisting of hydrido, acetamido, haloacetamido, alkoxyamino, alkanoyl, haloalkanoyl, amidino, guanidino, alkylenedioxy, haloalkylthio, alkoxy, hydroxy, amino, lower alkylamino, alkylthio , alkylsulfinyl, alkylsulfonyl, alkylsulfonamido, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, alkyl, halogen, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, carboalkoxy, carboxyalkyl, carboxy, carboxamido and cyano; K is CHR ^4a wherein R ^4a is selected from the group consisting of hydrido, hydroxyalkyl, alkyl, alkoxyalkyl, alkylthioalkyl and haloalkyl; E 0 is selected from the group consisting of a single covalent bond, C (O) N (H), (H) NC (O), (R ⁷ ) NS (O) _2, and S (O) ₂ N (R ⁷ ); Y ⁰ is a group of formula IV: - 14617 9 '(IV) 16X ^J \ K ^{of X} R ¹⁹ c - wherein D ⁵ , D ⁶ , J ⁵ and J ⁶ are independently selected from the group consisting of C, N, O, S and a covalent bond, with the proviso that at most one of D ⁵ , D ⁶ , J ⁵ and J ⁶ is a covalent bond, K ² is C, at most one of D ⁵ , D ⁶ , J ⁵ and Γ is O, at most one of D ⁵ , D ⁶ , J ⁵ and J ⁶ is S, one of D ⁵ , ^{D6, J5,} and ^J6 must be a covalent bond when two of ^{D5, D6, J5,} and ^J6 are O and S, and no more than four of ^{D5, D6, J5,} and ^J6 are N; R ¹⁶ , R ¹⁷ , R ¹⁸ and R ¹⁹ are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, haloalkylthio, alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, halogen, haloalkyl, haloalkoxy, hydroxyalkyl, alkylamino and cyano; R ¹⁶ and R ¹⁹ are optionally Q ^b with the proviso that at most one of R ¹⁶ and R ¹⁹ are simultaneously Q ^b , and that Q ^{b is} Q ^be ; Q ^b is selected from the group consisting of NR ²⁰ R ²¹ , Q ¹ *, wherein Q ** is hydrido, N (R ²⁶ ) C (NR ²⁵ ) N (R ²³ ) (R ²⁴ ), and C (NR ²⁵ ) NR ²³ R ²⁴ with the proviso that at most one of R ²⁰ and R ²¹ is hydroxy, amino, alkylamino or dialkylamino simultaneously, and that at most one of R ²³ and R ²⁴ is hydroxy, amino, alkylamino or dialkylamino simultaneously; R ²⁰ , R ²¹ , R ²³ , R ²⁴ , R ²⁵ and R ²⁶ are independently selected from the group consisting of hydrido, alkyl, hydroxy, amino, alkylamino and dialkylamino; Q ^s is selected from the group consisting of a single covalent bond, (CR ³⁷ R ³⁸ ) b, wherein b is an integer selected from 1 to 3 and (CH (R ¹⁴ )) c-W '- (CH (R ¹⁵ )) d, wherein c and d are integers selected from 1 to 2 and W ¹ is selected from the group consisting of C (O) N (R ¹⁴ ), (R ¹⁴ ) NC (O), S (O), S (O) 2 , S (O) 2N (R ¹⁴ ), N (R ¹⁴ ) S (O) 2 and N (R ¹⁴ ), provided that R ¹⁴ is other than halogen when it is directly bound to N and that (CR ³⁷ R ^38b and (CH (R ¹⁴ )) _c directly bind to E °; R ¹⁴ is selected from the group consisting of hydrido, halogen, alkyl, and haloalkyl; R ³⁷ and R ³⁸ are independently selected from the group consisting of hydrido, alkyl and haloalkyl; R ³⁸ is optionally selected from the group consisting of aroyl and heteroaroyl, - 147 Y ° is optionally Q ^b -Q ^ss where Q ^ss is (CH (R ¹⁴ )) eW ² - (CH (R ¹⁵ )) h, where eah are integers independently selected from the interval 1 to 2 and W ² is CR ^4a = CH with the proviso that (CH (R ¹⁴ )) _e binds 10 directly to E; or a pharmaceutically acceptable salt thereof. Substituted polycyclic aryl and heteroaryl pyrimidinones according to claim 3 of the general formula wherein B is selected from the group consisting of hydrido, trialkylsilyl, C 2 -C 4 alkyl, C 3 -C 5 alkylenyl, C 3 -C 5 alkenyl, C 3 -C 4 alkynyl and C 2 -C 4 haloalkyl, wherein each member of group B may be optionally substituted on any carbon atom up to 3 atoms including from the B to A binding site by one or more R ³² , R ³³ and R ³⁴ substituents; R ³² , R ³³ and R ³⁴ are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, alkylthio, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, alkyl, halogen, haloalkyl , haloalkoxy, hydroxyalkyl, carboalkoxy, carboxy, carboxamido and cyano; A is (CH (R ¹⁵ )) _p -N (R ⁷ ) wherein p is an integer selected from 1 to 2 and R ⁷ is selected from hydrido and alkyl; R ¹⁵ is independently selected from the group consisting of hydrido, halo, alkyl and haloalkyl. M is selected from the group consisting of N and R ¹ -C; R ¹ is selected from the group consisting of hydrido, hydroxy, hydroxyamino, amidino, amino, cyano, hydroxyalkyl, alkoxy, alkyl, alkylamino, aminoalkyl, alkylthio, alkoxyamino, haloalkyl, haloalkoxy and halogen; R ² is Z ° -Q; Z 0 is selected from the group consisting of a single covalent bond and CH ₂ ; Q is selected from the group consisting of aryl and heteroaryl, wherein the carbon atom adjacent to the carbon at the binding site is optionally substituted with R ⁹ , another carbon atom adjacent 148 to the carbon in the binding site is optionally substituted with R ¹³ , the carbon atom adjacent to the R ⁹ position and two atoms away from the point of attachment is optionally substituted with R ¹⁰ , the carbon atom adjacent to the R ¹³ position and two atoms from the point of attachment is optionally substituted R ¹² and any carbon atom adjacent to R ¹⁰ and when the R ¹² position is optionally substituted with R ¹¹ ; R ⁹ , R ¹¹ and R ¹³ are independently selected from the group consisting of hydrido, hydroxy, amino, amidino, guanidino, lower alkylamino, alkylthio, alkylsulfonamido, alkylsulfinyl, alkylsulfonyl, amidosulfonyl, monoalkylamidosulfonyl, alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxyalkyl , carboxy, carboxamido and cyano; R ¹⁰ and R ¹² are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkyl, alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, alkylsulfonamido, amidosulfonyl, monoalkyl amidosulfonyl, dialkylamidosulfonyl, hydroxyalkyl, aminoalkyl, carboalkoxy, carboalkoxy , carboxyalkyl, amidocarbonyl, halogen, haloalkyl and cyano. Y ⁰ is a group of formula IV wherein D ⁵ , D ⁶ , J ⁵ and J ⁶ are independently selected from the group consisting of C, N, O, S and a covalent bond, with the proviso that at most one of D ⁵ , D ⁶ , J ⁵ and J ⁶ is a covalent bond, K ² is C, at most one of D ⁵ , D ⁶ , J ⁵ and J ⁶ is O, at most one of D ⁵ , D ⁶ , J ⁵ and J ⁶ is S, one of D ⁵ D ⁶ , J ⁵ and J ⁶ must be a covalent bond when two of D ⁵ , D ⁶ , J ⁵ and J ⁶ are O and S 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 the group consisting of hydrido, amidino, guanidino, carboxy, haloalkylthio, alkoxy, hydroxy, amino, lower alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, halogen, haloalkyl, haloalkoxy, hydroxyalkyl, alkylenylamino and cyano; R ¹⁶ and R ¹⁹ are optionally Q ^b with the proviso that at most one of R ¹⁶ and R ¹⁹ are simultaneously Q ^b , and that Q ^{b is} Q ¹ "; - 149Q ^b is selected from the group consisting of NR ²⁰ R ²¹ , Q **, wherein Q ¹ * is hydrido, C (NR ²⁵ ) NR ²³ R ²⁴ and (NR ²⁶ ) C (NR ²⁵ ) N (R ²³ ) (R ²³ ) ²⁴ ) with the proviso that at most one of R ²⁰ and R ²¹ is a hydroxy substituent simultaneously, and that at most one of R ²³ and R ²⁴ is a hydroxy substituent simultaneously; R ²⁰ , R ²¹ , R ²³ , R ²⁴ , R ²⁵ and R ²⁶ are independently selected from the group consisting of hydrido, alkyl and hydroxy; Q ^s is selected from the group consisting of a single covalent bond, CH ₂ and CH ₂ CH ₂ ; or a pharmaceutically acceptable salt thereof. The substituted polycyclic aryl and heteroaryl pyrimidinones of claim 4, wherein B is selected from the group consisting of ethyl, 2-propenyl, 2-propynyl, propyl, isopropyl, trimethylene, tetramethylene, butyl, 2-butenyl, 3-butenyl, 2-butynyl, sec-butyl, Z, t-butyl, isobutyl , 2-methylpropenyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl and 2,2-difluoropropyl, wherein each member of group B is optionally substituted on any carbon of up to 3 atoms including from the B to A binding site by one or more R ³² , R ³³ and R ³⁴ substituents; R ³² , R ³³ and R ³⁴ are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, methoxyamino, ethoxyamino, acetamido, trifluoroacetamido, N-methylamino, dimethylamino, N- ethylamino, methylthio, ethylthio, isopropylthio, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro, bromo, 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 and cyano; A is optionally selected from the group consisting of a single covalent bond, NH and N (CH ₃ ); M is selected from the group consisting of N and R'-C; R ¹ is selected from the group consisting of hydrido, hydroxy, amino, amidino, hydroxyamino, aminomethyl, 1-aminoethyl, methylamino, dimethylamino, cyano, methyl, ethyl, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, methoxy, hydroxymethyl; -hydroxyethyl, 2hydroxyethyl, methoxyamino, methylthio, ethylthio, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro and bromo; R ^{2 is} Z ° -Q; Z 0 is selected from the group consisting of a single covalent bond and CH ₂ ; - 150 Q is selected from the group consisting of phenyl, 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl, 4-imidazolyl, 3-pyrazolyl, 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, 1,3,5-triazin-2-yl wherein the carbon atom adjacent to the carbon at the binding site is optionally substituted with R ⁹ , another carbon atom adjacent to the carbon at the binding site optionally substituted with R ¹³ , the carbon atom adjacent to the R ⁹ position and two atoms away from the point of attachment is optionally substituted with R ¹⁰ , the carbon atom adjacent to the R ¹³ position and two atoms away from the point of attachment is optionally substituted with R ^12, and any carbon atom adjacent R ¹⁰ and R ¹² are optionally substituted with R ¹¹ ; R ⁹ , R ¹¹ and R ¹³ are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, N-methylamino, Ν, Ν- dimethylamino, N-ethylamino, methylthio, ethylthio, isopropylthio, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, 2,2,3,3,3-pentafluoropropyl, trifluoromethoxy, 1,1,2,2tetrafluoroethoxy, fluorine, chlorine, bromo, methanesulfonamido, amidosulfonyl, N-methylamidosulfonyl, Ν, Ν-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro-1-hydroxyethyl, amidocarbonyl, N-methylamidocarbonyl, Ν, Ν-dimethyl amide. R ¹⁰ and R ¹² are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, carboxymethyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, methoxyamino, ethoxyamino, acetamido, trifluoroacetamido, aminomethyl, 1-aminoethyl, 2-aminoethyl, N-methylamino, dimethylamino, N-ethylamino, methanesulfonamido, amidosulfonyl, N-methylamidosulfonyl, Ν, Ν-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoroethyl 1-hydroxyethyl, methoxycarbonyl, ethoxycarbonyl, amidocarbonyl, N-methylamidocarbonyl, Ν, Ν-dimethylamidocarbonyl, fluoro, chloro, bromo and cyano; Y 0 is selected from the group consisting of 1Q ^b -4-Q ^with -2-R ¹⁶ -3-R ¹⁷ -5-R ¹⁸ -6-R ¹⁹ benzene, 2-Q ^b -5-Q ^with -6-R ¹⁷ -4-R ¹⁸ -2-R ¹⁹ pyridine, 3-Q ^b 6-Q ^with -2-R ¹⁶ -5-R ¹⁸ -4-R ¹⁹ pyridine, 2-Q ^b -4-Q ^with -3-R ¹⁶ -6-R ¹⁸ pyrazine, 3-Q ^b -6-Q ^with -2-R ^{, 8} -5-R ^{, 8} -4-R ¹⁹ pyridazine, 2-Q ^b -5-Q ^with -6-R ¹⁷ -4-R ¹⁸ pyrimidine, 5-Q ^b -2-Q 1 -3-R ¹⁶ -6-R ¹⁹ pyrimidine, 3-Q ^b -5-Q ^with -4R ¹⁶ -2-R ¹⁹ thiophene, 2-Q ^b -5-Q ^with -3-R ¹⁶ -4-R ¹⁷ thiophene, 3-Q ^b -5-Q ^with -4-R ⁶ -2-R ¹⁹ furan, 2-Q ^b -5-Q ^s -3-R ¹⁶ 4- R ¹⁷ furan, 3-Q ^b -5-Q ^with -4-R ¹⁶ -2-R ¹⁹ pyrrole, 2-Q ^b -5-Q ^with -3-R ¹⁶ -4-R ¹⁷ pyrrole, 4-Q ^b -2-Q ^with -5-R ¹⁹ imidazole, 2-Q ^b -4-Q ^with -5-R ¹⁷ imidazole, 3-Q ^b -5-Q ^with -4-R ¹⁶ isoxazole, 5-Q ^b -3-Q ^with -4-R ¹⁶ isoxazole, 2Q ^b- 5-Q ^with -4-R ¹⁶ pyrazole, 4-Q ^b -2-Q ^with -5-R ¹⁹ thiazole and 2-Q ^{b -5-Qs -4-R17} thiazole; R ¹⁶ , R ¹⁷ , R ¹⁸ and R ¹⁹ are independently selected from the group consisting of hydrido, methyl, ethyl, isopropyl, propyl, carboxy, amidino, guanidino, methoxy, ethoxy, isopropoxy, propoxy, - 151 hydroxy, 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, 2,2,3,3,3pentafluoropropyl, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro, bromo, amidosulfonyl, N-methylamidosulfonyl, Ν, Ν-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro-1-hydroxyethyl and cyano; ^R16 and ^R19 are optionally Q ^b with the proviso that no more than one of R ¹⁶ and R ¹⁹ is Q ^b at the same time and that Q ^{b R b} jeQ; Q ^b is selected from the group consisting of NR ²⁰ R ²¹ , Q ^b wherein Q ^be is hydrido, C (NR ²⁵ ) NR ²³ R ²⁴ and NR ²⁶ C (NR ²⁵ ) N (R ²³ ) (R ²⁴ ), that at most one of R ²⁰ , R ²¹ , R ²³ and R ²⁴ are hydroxy substituents simultaneously if any two of R ²⁰ , R ²¹ , R ²³ and R ²⁴ bind to the same atom and said Q ^b directly binds to the atom alkyl; R ²⁰ , R ²¹ , R ²³ , R ²⁴ , R ²⁵ and R ²⁶ are independently selected from the group consisting of hydrido, methyl, ethyl, propyl, butyl, isopropyl and hydroxy; Q ^s is selected from the group consisting of a single covalent bond, CH ₂ and CH ₂ CH ₂ , or a pharmaceutically acceptable salt thereof. The substituted polycyclic aryl and heteroaryl pyrimidinones of claim 4 having the formula wherein A is selected from the group consisting of CH ₂ N (CH ₃ ), CH ₂ N (CH ₂ CH ₃ ), CH ₂ CH ₂ N (CH ₃ ) and CH ₂ CH ₂ N (CH ₂ CH ₃ ); M is selected from the group consisting of N and R'-C; R ¹ is selected from the group consisting of hydrido, hydroxy, amino, amidino. hydroxyamino, aminomethyl, 1-aminoethyl, methylamino, dimethylamino, cyano, methyl, ethyl, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, methoxy, hydroxymethyl, 1-hydroxyethyl, 2hydroxyethyl, methoxyamino, methylthio, ethylthio, trifluoromethoxy, 1, 1,2,2-tetrafluoroethoxy, fluoro, chloro and bromo; 152 R ^{2 is} Z ° -Q; Z 0 is selected from the group consisting of a single covalent bond and CH ₂ ; Q is selected from the group consisting of phenyl, 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl, 4-imidazolyl, 3-pyrazolyl, 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, 1,3,5-triazin-2-yl wherein the carbon atom adjacent to the carbon at the binding site is optionally substituted with R ⁹ , another carbon atom adjacent to the carbon at the binding site is optionally substituted with R ¹³ , the carbon atom adjacent to the R ⁹ position and two atoms away from the point of attachment is optionally substituted with R ¹⁰ , the carbon atom adjacent to the R ¹³ position and two atoms away from the point of attachment is optionally substituted with R ^12, and any carbon atom adjacent R ¹⁰ and R ¹² are optionally substituted with R ¹¹ ; R ⁹ , R ¹¹ and R ¹³ are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, N-methylamino, Ν, Ν- dimethylamino, N'-ethylamino, methylthio, ethylthio, isopropylthio, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, 2,2,3,3,3-pentafluoropropyl, trifluoromethoxy, 1,1,2,2tetrafluoroethoxy, fluorine, chlorine , bromo, methanesulfonamido, amidosulfonyl, N-methylamidosulfonyl, Ν, Ν-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro-1-hydroxyethyl, amidocarbonyl, N-methylamidocarbonyl, Ν, Ν-dimethylamidocarbonyl cyano; R ¹⁰ and R ¹² are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, carboxymethyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, methoxyamino, ethoxyamino, acetamido, trifluoroacetamido, aminomethyl , 1-aminoethyl, 2-aminoethyl, N-methylamino, dimethylamino, N-ethylamino, methanesulfonamido, amidosulfonyl, N-methylamidosulfonyl, Ν, Ν-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro-1-hydroxyethyl , methoxycarbonyl, ethoxycarbonyl, amidocarbonyl, N-methylamidocarbonyl, Ν, Ν-dimethylamidocarbonyl, fluoro, chloro, bromo and cyano; Y 0 is selected from the group consisting of 1Q ^b -4-Q ^with -2-R ¹⁶ -3-R ¹⁷ -5-R ¹⁸ -6-R ¹⁹ benzene, 2-Q ^b -5-Q ^with -6-R ¹⁷ -4-R ¹⁸ -2-R ¹⁹ pyridine, 3-Q ^b 6-Q ^with -2-R ¹⁶ -5-R ¹⁸ -4-R ¹⁹ pyridine, 2-Q ^b -4-Q ^with -3-R ¹⁶ -6-R ¹⁸ pyrazine, 3-Q ^b -6-Q ^with -2-R ¹⁸ -5-R ¹⁸ -4-R ¹⁹ pyridazine, 2-Q ^b -5-Q ^with -6-R ⁷ - 4-R ¹⁸ pyrimidine, 5-Q ^b -2-Q ^with -3-R ⁶ -6-R ¹⁹ pyrimidine, 3-Q ^b -5-Q ^with -4R ¹⁶ -2-R ¹⁹ thiophene, 2-Q ^b -5-Q ^with -3-R ¹⁶ -4-R ¹⁷ thiophene, 3-Q ^b -5-Q ^with -4-R ¹⁶ -2-R ¹⁹ furan, 2-Q ^b -5-Q ^with -3 -R ¹⁶ 4- R ¹⁷ furan, 3-Q ^b -5-Q ^with -4-R ¹⁶ -2-R ¹⁹ pyrrole, 2-Q ^b -5-Q ^with -3-R ¹⁶ -4-R ¹⁷ pyrrole 4-Q ^b -2-Q ^with -5- R ¹⁹ imidazole, 2-Q ^b -4-Q ^with -5-R ¹⁷ imidazole, 3-Q ^b -5-Q ^with -4-R ¹⁶ isoxazole, 5 -Q ^b -3-Q ^with -4- R ¹⁶ isoxazole, 2Q ^b _ 5-Q ^with -4-R ¹⁶ pyrazole, 4-Q ^b -2-Q ^with -5- R ¹⁹ thiazole and 2-Q ^b -5 -Q ^with -4- R ¹⁷ thiazole. - R 153, R ¹⁶ , R ¹⁷ , R ¹⁸ and R ¹⁹ are independently selected from the group consisting of hydrido, methyl, ethyl, isopropyl, propyl, amidino, guanidino, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, aminomethyl, 1-aminoethyl, 2-aminoethyl, N-N-methylamino, dimethylamino, N-ethylamino, 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, bromine, amidosulfonyl, N-methylamidosulfonyl, Ν, dim-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro- 1-hydroxyethyl and cyano; Q ^b is selected from the group consisting of NR ²⁰ R ²¹ , C (NR ²⁵ ) NR ²³ R ²⁴ a NR ²⁶ C (NR ²⁵ ) N (R ²³ ) (R ²⁴ ), with the proviso that not more than one of R ²⁰ , R ²¹ , R ²³ and R ²⁴ are hydroxy substituents simultaneously, provided that any two of R ²⁰ , R ²¹ , R ²³ and R ²⁴ bind to the same atom and said Q ^b is directly bound to a carbon atom; R ²⁰ , R ²¹ , R ²³ , R ²⁴ , R ²⁵ and R ²⁶ are independently selected from the group consisting of hydrido, methyl, ethyl, propyl, butyl, isopropyl and hydroxy; Q ^s is selected from the group consisting of a single covalent bond, CH ₂ and CH ₂ CH ₂ ; or a pharmaceutically acceptable salt thereof. The substituted polycyclic aryl and heteroaryl pyrimidinones of claim 6, wherein A is selected from the group consisting of CH ₂ N (CH ₃ ), CH ₂ N (CH ₂ CH ₃ ), CH ₂ CH ₂ N (CH ₃ ) and CH ₂ CH ₂ N (CH ₂ CH ₃ ); M is selected from the group consisting of N and R * -C; R ¹ is selected from the group consisting of hydrido, hydroxy, amino, amidino, hydroxyamino, aminomethyl, methylamino, cyano, methyl, trifluoromethyl, methoxy, hydroxymethyl, methoxyamino, methylthio, trifluoromethoxy, fluoro and chloro; R ^{2 is} Z ° -Q; Z 0 is selected from the group consisting of a single covalent bond and CH 2. Q is selected from the group consisting of 5-amino-3-amidocarbonylphenyl, 5-amino-2-fluorophenyl, 3-amino-5-hydroxymethylphenyl, 5-amino-3-methoxycarbonylphenyl, 3-amidinophenyl, 3-amino-2-methylphenyl, 5- amino-3-methylthiophenyl, 3-aminophenyl, benzyl, 3-carboxyphenyl, 3-carboxy-5-hydroxyphenyl, 3-carboxy-5-aminophenyl, 3-chlorophenyl, 2-chlorophenyl, 3-cyanophenyl, 3-dimethylaminophenyl, 2-fluorophenyl, 3-fluorophenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 3methanesulfonylaminophenyl, 2-methoxyphenyl, 3-methoxyphenyl, 3-methoxyaminophenyl, 3-methoxycarbonylphenyl, 2-methylaminophenyl, 3-methylaminophenyl, 2-methylphenyl, 3-methylphenyl, 4- 154 methylphenyl, 4- 154 methylphenyl , 3-trifluoroacetamidophenyl, 3-trifluoromethylphenyl, 2-trifluoromethylphenyl, 5 amino-2-thienyl, 5-amino-3-thienyl, 3-bromo-2-thienyl, 3-pyridyl, 4-pyridyl, 2-thienyl and 3-thienyl ; Y 0 is selected from the group consisting of 1Q ^b -4-Q ^with -2-R ¹⁶ -3-R ¹⁷ -5-R ¹⁸ -6-R ¹⁹ benzene, 2-Q ^b -5-Q ^with -6-R ¹⁷ -4-R ¹⁸ -2-R ¹⁹ pyridine, 3-Q ^b- 6-Q ^with -2-R ¹⁶ -5-R ¹⁸ -4-R ¹⁹ pyridine, 3-Q ^b- 5-Q ^with -4-R ⁶ -2-R ¹⁹ thiophene and 2-Q ^b -5-Q ^with -3-R ^{16 -6} -R ¹⁷ thiophene; R ¹⁶ and R ¹⁹ are independently selected from the group consisting of hydrido, amidino, amino, aminomethyl, methoxy, methylamino, hydroxy, 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 are Q ^b simultaneously, and that Q ^b is Q ^be ; R ¹⁷ and R ¹⁸ are independently selected from the group consisting of hydrido, fluoro, chloro, hydroxy, hydroxymethyl, amino, carboxy and cyano; Q ^b is selected from the group consisting of Q ^be , wherein Q 6 is hydrido and C (NR ²⁵ ) NR ²³ R ²⁴ ; R ²³ , R ²⁴ and R ²⁵ are independently selected from the group consisting of hydrido and methyl; Q ^is CH ₂ ; or a pharmaceutically acceptable salt thereof. The substituted polycyclic aryl and heteroaryl pyrimidinones of claim 7, wherein said compound is selected from the group consisting of: 2- [3- [2- [3-aminophenyl] -6-chloro-N - [[4-iminometylfenyl] methyl] -5- [N, N-dimethylhydrazino] -4-oxo-l (4H) pyrimidinyl]] acetamide, 2- [3- [2- [3-Aminophenyl] -6-chloro-5- [N-ethyl-N-methylhydrazino] -N - [[4-iminomethylphenyl] methyl] 4-oxo-1 (4H) pyrimidinyl] ] -acetamide, 2- [3- [2- [3-aminophenyl] -6-chloro-5- [N, N-dimethylhydrazino] -N - [[4-iminometylfenyl] methyl] -4-oxo-l (4H) pyrimidinyl]] acetamide, 2- [3- [2- [3-aminophenyl] -5- [N- (azetidin-l-yl) amino] -6-chloro-N - [[4-iminometylfenyl] methyl] -4-oxo-l (4H) pyrimidinyl]] acetamide, 2- [4- [3- [3-aminophenyl] -N - [[4-iminometylfenyl] methyl] -6- [N, N-dimethylhydrazino] -5-oxo (5H) -l, 2,4-triazinyl] ] -acetamide, 2- [4- [3- [3-Aminophenyl] -6- [N-ethyl-N-methylhydrazino] -N - [[4-iminomethylphenyl] methyl-5-oxo (5H) -1,2,4-triazinyl] ]] acetamide, 2- [4- [3- [3-aminophenyl] -6- [N, N-diethylhydrazino] -N - [[4-iminometylfenyl] methyl-5-oxo-l (5H) 1,2,4-triazinyl] ] -acetamide, - 155 2- [4- [3- [3-aminophenyl] -6- [N- (azetidin-1-yl) amino] -N - [[4-iminomethylphenyl] methyl-5-oxo (5H) -1, 2,4-triazinyl]] acetamide. Substituted polycyclic aryl and heteroaryl pyrimidinones according to claim 2 of the general formula B ‘where B is a group of the general formula: R ³² , R ³³ , R ³⁴ , R ³⁵ and R ³⁶ are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, alkylthio, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl aminodosulfonyl , alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboalkoxy, carboxy, carboxamido, cyano, and Q ^b; A is selected from the group consisting of a single covalent bond and (CHfR 1, p-fW ⁷ ) 4 wherein rr is an integer from 0 to 1, p is an integer selected from 0 to 3, and W ⁷ is selected from (R) ⁷ ) NC (O) and N (R ⁷ ); R ⁷ is independently selected from the group consisting of hydrido, hydroxy and alkyl; R ¹⁵ is independently selected from the group consisting of hydrido, halo, alkyl and haloalkyl; M is selected from the group consisting of N and R ¹ -C; R ¹ is selected from the group consisting of hydrido, hydroxy, hydroxyamino, amidino, amino, cyano, hydroxyalkyl, alkoxy, alkyl, alkylamino, aminoalkyl, alkylthio, alkoxyamino, haloalkyl, haloalkoxy and halogen; R ^{2 is} Z ° -Q; Z 0 is selected from the group consisting of a single covalent bond, O, S, NH and CH 2; - 156 Q is selected from the group consisting of aryl and heteroaryl, wherein the carbon atom adjacent to the carbon at the binding site is optionally substituted with R ⁹ , another carbon atom adjacent to the carbon at the binding site is optionally substituted with R ¹³ and a carbon atom adjacent to the R ⁹ position; two atoms away from the point of attachment is optionally substituted with R ¹⁰ , a carbon atom adjacent to the R ¹³ position and two miles away from the point of attachment is optionally substituted with R ^12, and any carbon atom adjacent to the R ¹⁰ position if the R ¹² position is optionally substituted 11th R ⁹ , R ¹¹ and R ¹³ are independently selected from the group consisting of hydrido, hydroxy, amino, amidino, guanidino, lower alkylamino, alkylthio, alkylsulfonamido, alkylsulfinyl, alkylsulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxyalkyl, carboxy, carboxamido and cyano; R ¹⁰ and R ¹² are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkyl, alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, alkylsulfonamido, amidosulfonyl, monoalkyl amidosulfonyl, dialkylamidosulfonyl, hydroxyalkyl, aminoalkyl, carboalkoxy, carboalkoxy , carboxyalkyl, amidocarbonyl, halogen, haloalkyl and cyano; Y 0 is a group of formula IV (IV) wherein D 1, D ⁵ , J ⁵ and J ⁶ are independently selected from the group consisting of C, N, O, S and a covalent bond, provided that at most one of D ⁵ , D ⁶ , J ⁵ and J ⁶ is a covalent bond, K ² is C, at most one of D ⁵ , D ⁶ , J ⁵ and J ⁶ is optionally O, at most one of D ⁵ , D ⁶ , J ⁵ and J ⁶ is optionally S , one of D ⁵ , D ⁶ , J ⁵ and J ⁶ must be a covalent bond if two of D ⁵ , D ⁶ , J ⁵ and J ⁶ are O and S 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 the group consisting of hydrido, amidino, guanidino, carboxy, haloalkylthio, alkoxy, hydroxy, amino, lower alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, halogen, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl and cyano; - 157 R ¹⁶ and R ¹⁹ are optionally Q ^b with the proviso that at most one of R ¹⁶ and R ¹⁹ is simultaneously Q ^b , and that Q ^b is Q ^be ; Q ^b is selected from the group consisting of NR ²⁰ R ²¹ , Q 23, wherein Q ¹ * is hydrido, and C (NR ²⁵ ) NR ²³ R ²⁴ , provided that at most one of R ²⁰ and R ^{21 is a} hydroxy substituent simultaneously, and that at most one of R ²³ and R ²⁴ is a hydroxy substituent simultaneously; R ²⁰ , R ²¹ , R ²³ , R ²⁴ and R ²⁶ are independently selected from the group consisting of hydrido, alkyl and hydroxy; Q ^s is selected from the group consisting of a single covalent bond, CH ₂ and CH ₂ CH ₂ ; or a pharmaceutically acceptable salt thereof. The substituted polycyclic aryl and heteroaryl pyrimidinones of claim 9, wherein: B is a group of formula R ³² , R ³³ , R ³⁴ , R ³⁵ and R ³⁶ are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, methoxyamino, ethoxyamino, acetamido, trifluoroacetamido, N- methylamino, dimethylamino, N-ethylamino, methylthio, ethylthio, isopropylthio, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, 2,2,3,3,3pentafluoropropyl, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chlorine, bromine, amidosulfonyl, N-methylamidosulfonyl, Ν, Ν-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro-1-hydroxyethyl, methoxycarbonyl, ethoxycarbonyl, amidocarbonyl, N-methylamidocarbonyl, Ν, dimethylamidocarbonyl, cyano, and Q ^b; A is selected from the group consisting of a single covalent bond, NH, N (CH ₃ ), N (OH), CH ₂ , CH ₃ CH, CF ₃ CH, NHC (O), N (CH ₃ ) C (O), C (O) NH, C (O) N _{(CH3), CH2 CH2,} CH ₂ CH ₂ CH _2, CH ₃ CHCH ₂ and CF ₃ CHCH _2; M is selected from the group consisting of N and R'-C; R ¹ is selected from the group consisting of hydrido, hydroxy, amino, amidino, hydroxyamino, aminomethyl, 1-aminoethyl, methylamino, dimethylamino, cyano, methyl, ethyl, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, methoxy, hydroxymethyl, I -hydroxyethyl, 2- 158 hydroxyethyl, methoxyamino, methylthio, ethylthio, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro and bromo; R ^{2 is} Z ° -Q; Z 0 is selected from the group consisting of a single covalent bond, O, S, NH and CH ₂ . Q is selected from the group consisting of phenyl, 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl, 4-imidazolyl, 3-pyrazolyl, 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, 1,3,5-triazin-2-yl, wherein the carbon atom adjacent to the carbon at the binding site is optionally substituted with R ⁹ , another carbon atom adjacent to the carbon at the binding site is optionally substituted by R, a carbon adjacent to the R position and two atoms from the point of attachment is optionally substituted by ^R10, a carbon adjacent to the R ¹³ position and two atoms from the point of attachment is optionally substituted by ^R12, and any carbon adjacent to R ¹⁰ and R ¹² is optionally substituted with R ¹¹ ; R ⁹ , R ¹¹ and R ¹³ are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, N-methylamino, Ν, Ν- dimethylamino, N-ethylamino, methylthio, ethylthio, isopropylthio, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, 2,2,3,3,3-pentafluoropropyl, trifluoromethoxy, 1,1,2,2tetrafluoroethoxy, fluorine, chlorine, bromo, methanesulfonamido, amidosulfonyl, N-methylamidosulfonyl, Ν, Ν-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro-1 hydroxyethyl, amidocarbonyl, N-methylamidocarbonyl, Ν, Ν-dimethylamidocarbonyl ; R ¹⁰ and R ¹² are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, carboxymethyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, methoxyamino, ethoxyamino, acetamido, trifluoroacetamido, aminomethyl , 1-aminoethyl, 2-aminoethyl, N-methylamino, dimethylamino, N-ethylamino, methanesulfonamido, amidosulfonyl, N-methylamidosulfonyl, Ν, Ν-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro-1-hydroxyethyl , methoxycarbonyl, ethoxycarbonyl, amidocarbonyl, N-methylamidocarbonyl, Ν, Ν-dimethylamidocarbonyl, fluoro, chloro, bromo and cyano; Y 0 is selected from the group consisting of 1Q ^b -4-Q ^with -2-R ¹⁶ -3-R ¹⁷ -5-R ¹⁸ -6-R ¹⁹ benzene, 2-Q ^b -5-Q ^with -6-R ¹⁷ -4-R ¹⁸ -2-R ¹⁹ pyridine, 3-Q ^b 6-Q ^with -2-R ¹⁶ -5-R ^{, 8} -4-R ¹⁹ pyridine, 2-Q ^b -4-Q ^with -3- R ¹⁶ -6-R ¹⁸ pyrazine, 3-Q ^b -6-Q ^with -2-R ¹⁸ -5-R ¹⁸ -4-R ¹⁹ pyridazine, 2-Q ^b -5-Q ^with -6-R ¹⁷ - 4-R ¹⁸ pyrimidine, 5-Q ^b -2-Q ^with -3-R ¹⁶ -6-R ¹⁹ pyrimidine, 3-Q ^b -5-Q ^with -4 R ¹⁶ -2-R ¹⁹ thiophene, 2-Q ^{b -5-Qs -3-R,} 4-R ^{6 l7} thiophene, 3-Q ^b -5-Q ^{s -4-R 6} -2-R ¹⁹ furan, 2-Q ^b -5-Q ^s - 3-R ¹⁶ 4- R ¹⁷ furan, 3-Q ^b -5-Q ^with -4-R ¹⁶ -2-R ¹⁹ pyrrole, 2-Q ^b -5-Q ^with -3-R ¹⁶ -4-R ¹⁷ pyrrole, 4-Q ^h -2-Q ^with -5-R ¹⁹ 159-imidazole, 2-Q ^b -4-Q ^with -5-R ¹⁷ imidazole, 3-Q ^b -5-Q ^with -4-R ¹⁶ isoxazole, 5-Q ^b -3-Q ^with -4-R ¹⁶ isoxazole 2Q ^b -5.Q ^S -4-R ¹⁶ pyrazole, 4-Q ^b -2-Q ^with -5-R ¹⁹ thiazole and 2-Q ^b -5-Q ^with -4-R ¹⁷ thiazole. R ¹⁶ , R ¹⁷ , R ¹⁸ and R ¹⁹ are independently selected from the group consisting of hydrido, methyl, ethyl, isopropyl, propyl, carboxy, amidino, guanidino, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, aminomethyl, 1-aminoethyl , 2-aminoethyl, N-methylamino, dimethylamino, Nethylamino, methylthio, ethylthio, isopropylthio, trifluoromethylthio, methylsulfinyl, ethylsulfinyl, methylsulfonyl, ethylsulfonyl, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, 2,2,3,3,3pentafluoropropyl , trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro, bromo, amidosulfonyl, N-methylamidosulfonyl, Ν, dim-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 are Q ^b at the same time, and that Q ^b is Q ^be ; Q ^b is selected from the group consisting of Q ^be , wherein Q ^be is hydrido, and C (NR ²⁵ ) NR ²³ R ²⁴ , provided that at most one of R ²³ and R ²⁴ are hydroxy substituents simultaneously; R ²³ , R ²⁴ and R ²⁵ are independently selected from the group consisting of hydrido, methyl, ethyl and hydroxy. Q ^s is selected from the group consisting of a single covalent bond, CH ₂ and CH ₂ CH ₂ ; and pharmaceutically acceptable salts thereof. The substituted polycyclic aryl and heteroaryl pyrimidinones of claim 10, wherein: B is selected from the group consisting of 2-aminophenyl, 3-aminophenyl, 3-amidinophenyl, 4amidinophenyl, 3-carboxyphenyl, 3-carboxy-5-hydroxyphenyl, 3-chlorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 2-fluorophenyl, 3- fluorophenyl, 3,4-difluorophenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 3-methoxyaminophenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-methylphenyl, 4-methylphenyl, phenyl and 3-fluoromethylphenyl; A is selected from the group consisting of CH ₂ , CH ₃ CH, CF ₃ CH, NHC (O), CH ₂ CH ₂ and CH ₂ CH ₂ CH ₂ ; M is selected from the group consisting of N and R * -C; R ¹ is selected from the group consisting of hydrido, hydroxy, amino, amidino, hydroxyamino, aminomethyl, methylamino, cyano, methyl, trifluoromethyl, methoxy, hydroxymethyl, methoxyamino, methylthio, trifluoromethoxy, fluoro and chloro; R ^{2 is} Z ° -Q; Z 0 is selected from the group consisting of a single covalent bond, O, S, NH and CH ₂ ; - 160 Q is selected from the group consisting of 5-amino-3-amidocarbonylphenyl, 5-amino-2-fluorophenyl, 3-amino-5-hydroxymethylphenyl, 5-amino-3-methoxycarbonylphenyl, 3-amidinophenyl, 3-amino-2-methylphenyl, 5-amino-2-methylthiophenyl, 3-aminophenyl, benzyl, 3-carboxyphenyl, 3-carboxy-5-aminophenyl, 3-carboxy-5-hydroxyphenyl, 3-carboxymethyl-5-aminophenyl, 3-carboxymethyl-5-hydroxyphenyl, 3-carboxymethylphenyl, 3-chlorophenyl, 2-chlorophenyl, 2,6-dichlorophenyl, 3-cyanophenyl, 3-dimethylaminophenyl, 2-fluorophenyl, 3-fluorophenyl, 2,5-difluoromethyl, 3-methoxyaminophenyl, 3-methoxycarbonylphenyl, 2-methylaminophenyl, 3-methylaminophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, phenyl, 3-trifluoroacetamidophenyl, 3-trifluoromethylphenyl, 2-trifluoromethylphenyl, 5-amino-2-thienyl, 5-amino-3-thienyl, 3-bromo-2-thienyl, 3- pyridyl, 4-pyridyl, 2-thienyl and 3-thienyl; Y 0 is selected from the group consisting of 1Q ^b -4-Q ^with -2-R ¹⁶ -3-R ¹⁷ -5-R ¹⁸ -6-R ¹⁹ benzene, 2-Q ^b -5-Q ^with -6-R ¹⁷ -4-R ¹⁸ -2-R ¹⁹ pyridine, 3-Q ^b 6-Q ^with -2-R ¹⁶ -5-R ¹⁸ -4-R ¹⁹ pyridine, 3-Q ^b -5-Q ^with -4-R ¹⁶ 2-R @ ^9, thiophene and 2-Q ^b -5-Q ^{s -3-R,} 4-R ^{6 17} 'thiophene; R ¹⁶ and R ¹⁹ are independently selected from the group consisting of hydrido, amidino, amino, aminomethyl, methoxy, methylamino, hydroxy, 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 are Q ^b at the same time, and that Q ^b R ¹⁷ and R ¹⁸ are independently selected from the group consisting of hydrido, fluoro, chloro, hydroxy, hydroxymethyl, amino, carboxy and cyano; Q ^b is selected from Q ^be wherein Q ** is hydrido, and C (NR ^{2 R)} NR ²³ R ^24; R ²³ , R ²⁴ and R ²⁵ are independently selected from the group consisting of hydrido and methyl; Q ^is CH ₂ ; and pharmaceutically acceptable salts thereof. 12. Substituted polycyclic aryl and heteroaryl pyrimidinones according to claim 9 of the general formula wherein: B is a group of the formula: - 161 - R ³² , R ³³ , R ³⁴ , R ³⁵ and R ³⁶ are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, alkylthio, amidosulfonyl, monoalkyl amidosulfonyl, dialkylamidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboalkoxy, carboxy, carboxamido, cyano, and Q ^b; A is selected from the group consisting of a single covalent bond and (CH (R ¹⁵ )) _pi '(W ⁷ ) n · where rr is an integer from 0 to 1, p is an integer selected from 0 to 3 and W is N (R); R ⁷ is selected from the group consisting of hydrido and alkyl; R ¹⁵ is selected from the group consisting of hydrido, halogen, alkyl and haloalkyl; M is selected from the group consisting of N and R'-C; R ¹ is selected from the group consisting of hydrido, hydroxy, hydroxyamino, amidino, amino, cyano, hydroxyalkyl, alkoxy, alkyl, alkylamino, aminoalkyl, alkylthio, alkoxyamino, haloalkyl, haloalkoxy and halogen; R ^{2 is} Z ° -Q; Z 0 is a single covalent bond; Q is selected from the group consisting of aryl and heteroaryl, wherein the carbon atom adjacent to the carbon at the binding site is optionally substituted by R ⁹ , another carbon atom adjacent to the carbon at the binding site is optionally substituted by R ¹³ , the carbon atom adjacent to the R ⁹ position and two atoms from the point of attachment are optionally substituted with R ¹⁰ , a carbon atom adjacent to the R ¹³ position and two atoms from the point of attachment is optionally substituted with R ^12, and any carbon atom adjacent to the R ¹⁰ position and if the R ¹² position is optionally substituted R ⁹ , R ¹¹ and R ¹³ are independently selected from the group consisting of hydrido, hydroxy, amino, amidino, guanidino, lower alkylamino, alkylthio, alkoxy, alkylsulfinyl, alkylsulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, alkyl, halogen, haloalkyl, haloalkoxy, hydroxyalkyl, carboxy, carboxamido and cyano; - 162 R ¹⁰ and R ¹² are independently selected from hydrido, acetamido, amidino, guanidino, alkyl, alkoxy, alkoxyamino, aminoalkyl, hydroxy, amino, lower alkylamino, alkylsulfonamido, amidosulfonyl, monoalkyl, dialkyl amidosulfonyl, hydroxyalkyl, halo , haloalkyl, carboalkoxy, carboxy, carboxamido, carboxyalkyl and cyano; - 163 Y ° is a group of formula IV n 17 Go J ⁶ ιε (IV) _,; 16X ^D X 2 * ^D \ r] wherein D ^5, D ^6, J ^5, and J ⁶ are independently selected from the group consisting of C, N, O, S and covalent bond with the provisos that no more than one of ^{D5, D6,} J ⁵ and J ⁶ is a covalent bond, K ² is C, at most one of D ⁵ , D ⁶ , J ⁵ and J ⁶ is O, at most one of D ⁵ , D ⁶ , J ⁵ and J ⁶ is S, one of D ⁵ , D ⁶ , J ⁵ and J ⁶ must be a covalent bond when two of D ⁵ , D ⁶ , J ⁵ and J ⁶ are O and S 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 the group consisting of hydrido, amidino, guanidino, carboxy, haloalkylthio, alkoxy, hydroxy, amino, lower alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, halogen, 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 are simultaneously Q ^b , and that Q ^b is Q ^be ; Q ^b is selected from the group consisting of NR ²⁰ R ²¹ , Q ¹ * where hydrido, and C (NR ²⁵ ) NR ²³ R ²⁴ ; R ²⁰ , R ²¹ , R ²³ , R ²⁴ and R ²⁶ are independently selected from the group consisting of hydrido and alkyl; Q ^is CH ₂ ; a pharmaceutically acceptable salt thereof. The substituted polycyclic aryl and heteroaryl pyrimidinones of claim 12, wherein: B is a group of the formula: - 16432 33 34 35 36 R, R, R, R, and R are independently selected from the group consisting of hydrido, amidino. guanidino, methyl, ethyl, methoxy, ethoxy, hydroxy, amino, N-methylamino, dimethylamino, methylthio, ethylthio, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, fluoro, chloro, bromo, amidosulfonyl, N-methylamidosulfonyl, hydroxymethyl, amidocarbonyl, carboxy, cyano, and Q ^b; A is selected from the group consisting of a single covalent bond, NH, N (CH ₃ ), CH ₂ , CH ₃ CH, and CH ₂ CH ₂ ; M is selected from the group consisting of N and R ¹ -C; R ¹ is selected from the group consisting of hydrido, hydroxy, amino, amidino, hydroxyamino, aminomethyl, methylamino, cyano, methyl, trifluoromethyl, methoxy, hydroxymethyl, methoxyamino, methylthio, trifluoromethoxy, fluoro and chloro; R ² is selected from the group consisting of phenyl, 2-thienyl, 2-furyl, 2-pyrrolyl, 2-imidazolyl, 2-thiazolyl, 3-isoxazolyl, 2-pyridyl and 3-pyridyl, wherein the carbon atom adjacent to the carbon at the binding site is optionally substituted with R ⁹ , another carbon atom adjacent to the carbon in the binding site is optionally substituted with R ¹³ , a carbon atom adjacent to the R ⁹ position and two atoms away from the point of attachment optionally substituted with R ¹⁰ , a carbon atom adjacent to the R ¹³ position and two atoms apart optionally, R is from the point of attachment and any carbon atom adjacent to the R ¹⁰ position and the R ¹² position optionally substituted with R ¹¹ ; R ⁹ , R ¹¹ and R ¹³ are independently selected from the group consisting of hydrido, methyl, ethyl, methoxy, ethoxy, hydroxy, amino, N-methylamino, Ν, Ν-dimethylamino, methylthio, trifluoromethyl, pentafluoroethyl, 2,2,2- trifluoroethyl, fluoro, chloro, bromo, amidosulfonyl, N-methylamidosulfonyl, Ν, Ν-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, amidocarbonyl, N-methylamidocarbonyl, carboxy and cyano; R ¹⁰ and R ¹² are independently selected from the group consisting of hydrido, amidino, amidocarbonyl, N-methylamidocarbonyl, guanidino, methyl, ethyl, methoxy, ethoxy, hydroxy, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, carboxy, carboxymethyl, amino, acetamido trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, trifluoroacetamido, aminomethyl, N-methylamino, dimethylamino, amidosulfonyl, N-methylamidosulfonyl, Ν, dim-dimethylamidosulfonyl, methoxycarbonyl, fluoro, chloro, bromo and cyano; Y 0 is selected from the group consisting of 1Q ^b -4-Q ^with -2-R ¹⁶ -3-R ¹⁷ -5-R ¹⁸ -6-R ¹⁹ benzene, 2-Q ^b -5-Q ^with -6-R ¹⁷ -4-R ¹⁸ -2-R ¹⁹ pyridine, 2-Q ^b 5-Q ^with -3-R ¹⁶ -4-R ¹⁷ thiophene, 3-Q ^b -6-Q ^with -2-R ¹⁶ -5-R ¹⁸ -4-R ¹⁹ pyridine, 3-Q ^b -5-Q ^with -4-R ¹⁶ -2-R ¹⁹ thiophene, 3Q ^b -5-Q ^with -4-R ¹⁶ -2-R ¹⁹ furans, 2-Q ^b -5-Q ^{s -3-R-4-l6 R17} furan, 3-Q ^{b -5-Qs -4-R16 -2-R19} pyrrole, 2-Q ^b -5Q ^p - 3-R ¹⁶ -4-R ¹⁷ pyrrole, 4-Q ^b -2-Q ^with -5-R ¹⁹ thiazole and 2-Q ^b -5-Q ^with -4-R ¹⁷ thiazole; 165 R ¹⁶ , R ¹⁷ , R ¹⁸ and R ¹⁹ are independently selected from the group consisting of hydrido, methyl, ethyl, amidino, guanidino, methoxy, hydroxy, amino, aminomethyl, 1-aminoethyl, 2-aminoethyl, N-methylamino, dimethylamino, methylthio ethylthio, trifluoromethylthio, methylsulfinyl, methylsulfonyl, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, trifluoromethoxy, fluoro, chloro, bromo, amidosulfonyl, N-methylamidosulfonyl, hydroxymethyl, carboxy and cyano; Q ^b is selected from the group consisting of NR ²⁰ R ²¹ and C (NR ²⁵ ) NR ²³ R ^U, with the proviso that Q ^b is directly attached to a carbon atom; R ²⁰ , R ²¹ , R ²³ , R ²⁴ and R ²⁵ are independently selected from the group consisting of hydrido, methyl and ethyl; Q ^is CH ₂ ; and a pharmaceutically acceptable salt thereof. The substituted polycyclic aryl and heteroaryl pyrimidinones of claim 13, wherein: B is selected from the group consisting of 2-aminophenyl, 3-aminophenyl, 3-amidinophenyl, 4amidinophenyl, 3-carboxyphenyl, 3-carboxy-5-hydroxyphenyl, 3-chlorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 2-fluorophenyl, 3- fluorophenyl, 3,4-difluorophenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 3-methoxyaminophenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-methylphenyl, 4-methylphenyl and phenyl. A is selected from the group consisting of CH ₂ , CH 3 CH, CF ₃ CH, NHC (O), CH ₂ CH ₂ and CH ₂ CH ₂ CH ₂ ; M is selected from the group consisting of N and R'-C; R ¹ is selected from the group consisting of hydrido, hydroxy, amino, methyl, trifluoromethyl, fluoro, and chloro; R ² is selected from the group consisting of 5-amino-3-amidocarbonylphenyl, 5-amino-2-fluorophenyl, 3-amino-5-hydroxymethylphenyl, 5-amino-3-methoxycarbonylphenyl, 3-amidinophenyl, 3-amino-2-methylphenyl, -amino-2-methylthiophenyl, 3-aminophenyl, benzyl, 3-carboxyphenyl, 3-carboxy-5-aminophenyl, 3-carboxy-5-hydroxyphenyl, 3-carboxymethyl-5-aminophenyl, 3-carboxymethyl-5-hydroxyphenyl, 3-carboxymethylphenyl, 3-chlorophenyl, 2-chlorophenyl, 3-cyanophenyl, 3-dimethylaminophenyl, 2-fluorophenyl, 3-fluorophenyl, 2,5-difluoromethyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 3-methanesulfonylaminophenyl, 2-methoxyphenyl, 3-methoxyphenyl, 3-methoxyaminophenyl, 3-methoxyaminophenyl 3-methoxycarbonylphenyl, 2-methylaminophenyl, 3-methylaminophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, phenyl, 3-trifluoroacetamidophenyl, 3-trifluoromethylphenyl, 2-trifluoromethylphenyl, 5-amino-2-thienyl, 5-amino-3- thienyl, 3-bromo-2-thienyl, 3-pyridyl, 4-pyridyl, 2-thienyl and 3-thienyl; Y 0 is selected from the group consisting of - 1661 -Q ^b -4-Q ³ -2-R ¹⁶ -3-R ¹⁷ -5-R ¹⁸ -6-R ¹⁹ benzene, 2-Q ^b -5-Q ^with -6-R ¹⁷ -4-R ¹⁸ -2-R ¹⁹ pyridine, 3-Q ^b -6Q ^with -2-R ¹⁶ -5-R ¹⁸ -4-R ¹⁹ pyridine, 3-Q ^b -5-Q ^with -4-R ¹⁶ -6- R ¹⁹ thiophene and 2-Q ^b -5-Q ^with -3-R ¹⁶ -4-R ¹⁷ thiophene; R ¹⁶ and R ¹⁹ are independently selected from the group consisting of hydrido, amidino, amino, aminomethyl, methoxy, methylamino, hydroxy, 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 are Q ^b simultaneously, and that Q ^b is Q ^be ; R ¹⁷ and R ¹⁸ are independently selected from the group consisting of hydrido, fluoro, chloro, hydroxy, hydroxymethyl, amino, carboxy and cyano; Q ^b is selected from the group consisting of Q ^be , wherein Q 6 is hydrido, and C (NR ²⁵ ) NR ²³ R ²⁴ ; R ²³ , R ²⁴ and R ²⁵ are independently selected from the group consisting of hydrido and methyl; Q ^is CH ₂ , or a pharmaceutically acceptable salt thereof. The substituted polycyclic aryl and heteroaryl pyrimidinones of claim 14, wherein: B is selected from the group consisting of 3-aminophenyl, 3-amidinophenyl, 4-amidinophenyl, 3-chlorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 2-fluorophenyl, 4-methylphenyl and phenyl; A is selected from CH _2, NHC (O), _{CH2 CH2,} and _{CH2 CH2} CH2; M is selected from the group consisting of N and R'-C; R ¹ is selected from the group consisting of hydrido, fluoro and chloro; R ² is selected from the group consisting of 3-aminophenyl, benzyl, 3-chlorophenyl, 3dimethylaminophenyl, 3-hydroxyphenyl, 3-methanesulfonylaminophenyl, 3-methylaminophenyl, 2-methylphenyl, 3-methylphenyl, phenyl, 3-trifluoroacetamidophenyl, 3-bromo-2-thienyl , 2-thienyl and 3-thienyl; Y 0 is selected from the group consisting of 5-amidino-2-thienylmethyl, 4-amidinobenzyl, 2-fluoro-4-amidinobenzyl and 3-fluoro-4-amidinobenzyl; or a pharmaceutically acceptable salt thereof. Substituted polycyclic aryl and heteroaryl pyrimidinones according to claim 9, selected from the group of compounds of the general formula ABOUT ABOUT - 167where: ^R2 is 3-aminophenyl, B is chlorophenyl, A is CH2CH2, Y is 4-amidinobenzyl, and M is CH; ^R2 is 3-aminophenyl, B is phenyl, A is _CH2, Y is 4-amidinobenzyl, and M is CH; ^R2 is phenyl, B is 3-chlorophenyl, A is CH2CH2, Y is 4-amidinobenzyl, and M is CH; ^R2 is 3-dimethylaminophenyl, B is phenyl, A is CH2CH2, Y is 4-amidinobenzyl, and M is CH; R ² is 2-methylphenyl, B is phenyl, A is CH ₂ CH ₂ , Y 2 is 4-amidinobenzyl, and M is CH; R ² is phenyl, B is 3-aminophenyl, A is C (O) NH, Ύ ° is 4-amidinobenzyl, and M is CH; ^R2 is phenyl, B is 3-amidinophenyl, A is _CH2, Y is 4-amidinobenzyl, and M is CH; R ² is 3- (N-methylamino) phenyl, B is phenyl, A is _{CH2 CH2,} Y is 4-amidinobenzyl, and M is CH. ^R2 is 3-metylsulfonyIamidofenyl, B is phenyl, A is CH2CH2, Y is 4-amidinobenzyl, and M is CH, ^R2 is phenyl, B is 4-amidinophenyl, A is CH2, Y is 4-amidinobenzyl, and M is CH; ^R2 is 3-dimethylaminophenyl, B is phenyl, A is CH2CH2, Y is 4-amidinobenzyl, and M is CH; R ² is phenyl, B is phenyl, A is CH ₂ , Y? is 4-amidinobenzyl and M is CH; ^R2 is 3-methylphenyl, B is 4-phenyl, A is _{CH2 CH2,} Y is 4-amidinobenzyl, and M is CH; ^R2 is 3-aminophenyl, B is 3-chlorophenyl, A is _{CH2 CH2,} Y is 4-amidinobenzyl, and M is CC1; ^R2 is 3-aminophenyl, B is phenyl, A is _CH2, Y is 4-amidinobenzyl, and M is C-Cl; R ² is phenyl, B is 3-chlorophenyl, A is CH ₂ CH ₂ , Y 0 is 4-amidinobenzyl, and M is CC 1; ^R2 is 3-dimethylaminophenyl, B is phenyl, A is CH2CH2, Y is 4-amidinobenzyl, and M is CC1; R ² is 2-methylphenyl, B is phenyl, A is CH ₂ CH ₂ , Y 0 is 4-amidinobenzyl, and M is CC 1; ^R2 is phenyl, B is 3-aminophenyl, A is C (O) NH, Y is 4-amidinobenzyl, and M is CC1; ^R2 is phenyl, B is 3-amidinophenyl, A is _CH2, Y is 4-amidinobenzyl, and M is CC1. R ² is 3- (N-methylamino) phenyl, B is phenyl, A is CH 2 CH 2, Y 0 is 4-amidinobenzyl, and M is CC 1; ^R2 is 3-methylsulfonamidophenyl, B is phenyl, A is _{CH2 CH2,} Y is 4-amidinobenzyl, and M is CC1. R ² is phenyl, B is 4-amidinophenyl, A is CH ₂ , Y 0 is 4-amidinobenzyl, and M is CC 1; R ² is 3-methylaminophenyl, B is phenyl, A is CH 2 CH 2, Y 4 is 4-amidinobenzyl, and M is CC 1; ^R2 is phenyl, B is phenyl, A is _CH2, Y is 4-amidinobenzyl, and M is CC1; R ² is 3-methylphenyl, B is 4-phenyl, A is CH ₂ CH ₂ , Y 0 is 4-amidinobenzyl, and M is CC 1; ^R2 is 3-aminophenyl, B is 3-chlorophenyl, A is CH2CH2, Y is 4-amidinobenzyl, and M is CF; ^R2 is 3-aminophenyl, B is phenyl, A is _CH2, Y is 4-amidinobenzyl, and M is CF; ^R2 is phenyl, B is 3-chlorophenyl, A is CH2CH2, Y is 4-amidinobenzyl, and M is CF; ^R2 is 3-dimethylaminophenyl, B is phenyl, A is CH ₂ CH 2, Y is 4-amidinobenzyl, and M is CF; R ² is 2-methylphenyl, B is phenyl, A is _{CH2 CH2,} Y ^ is 4amidinobenzyl, and M is CF; ^R2 is phenyl, B is 3-aminophenyl, A is C (O) NH, Y is 4-amidinobenzyl, and M is CF; - 168 R J is phenyl, B is 3-amidinophenyl, A is _CH2, Y is 4-amidinobenzyl, and M is CF; R ² is 3- (N-methylamino) phenyl, B is phenyl, A is _{CH2 CH2,} Y is 4-amidinobenzyl, and M is CF; ^R2 is 3-methylsulfonamidophenyl, B is phenyl, A is CH2CH2, Y is 4-amidinobenzyl, and M is CF; ^R2 is phenyl, B is 4-amidinophenyl, A is CH2, Y is 4-amidinobenzyl, and M is CF; ^R2 is 3-dimethylaminophenyl, B is phenyl, A is _{CH2 CH2,} Y is 4-amidinobenzyl, and M is CF; ^R2 is phenyl, B is phenyl, A is _CH2, Y is 4-amidinobenzyl, and M is CF; ^R2 is 3-methylphenyl, B is 4-phenyl, A is _{CH2 CH2,} Y is 4-amidinobenzyl, and M is CF; ^R2 is 3-aminophenyl, B is 3-chlorophenyl, A is _{CH2 CH2,} Y is 4-amidinobenzyl, and M is N; ^R2 is 3-aminophenyl, B is phenyl, A is _CH2, Y is 4-amidinobenzyl, and M is N; ^R2 is phenyl, B is 3-chlorophenyl, A is _{CH2 CH2,} Y is 4-amidinobenzyl, and M is N; ^R2 is 3-dimethylaminophenyl, B is phenyl, A is _{CH2 CH2,} Y is 4-amidinobenzyl, and M is N; R ² is 2-methylphenyl, B is phenyl, A is _{CH2 CH2,} Y is 4-amidinobenzyl, and M is N; ^R2 is phenyl, B is 3-aminophenyl, A is C (O) NH, ^Y0 is 4amidinobenzyl, and M is N; ^R2 is phenyl, B is 3-amidinophenyl, A is _CH2, Y is 4-amidinobenzyl, and M is N; R ² is 3- (N-methylamino) phenyl, B is phenyl, A is _{CH2 CH2,} Y is 4-amidinobenzyl, and M is N; ^R2 is 3-methylsulfonamidophenyl, B is phenyl, A is CH2CH2, Y is 4-amidinobenzyl, and M is N; ^R2 is phenyl, B is 4-amidinophenyl, A is CH2, Y is 4-amidinobenzyl, and M is N; ^R2 is 3-dimethylaminophenyl, B is phenyl, A is _{CH2 CH2,} Y is 4-amidinobenzyl, and M is N; ^R2 is phenyl, B is phenyl, A is _CH2, Y is 4-amidinobenzyl, and M is N; ^R2 is 3-methylphenyl, B is 4-phenyl, A is CH ₂ CH _2, Y is 4-amidinobenzyl, and M is N; or a pharmaceutically acceptable salt thereof. Substituted polycyclic aryl and heteroaryl pyrimidinones according to claim 2 of the general formula B Where: B is selected from the group consisting of hydrido, C 2 -C 8 alkyl, C 3 -C 8 alkenyl, C 3 -C 8 alkynyl and C 2 -C 8 haloalkyl, wherein each member of group B may be optionally substituted on - any carbon atom of up to 6 atoms including from the B to A binding site by one or more substituents from 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 the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, alkylthio, amidosulfonyl, dialkylamidosulfonyl, alkyl, halogen , haloalkyl, haloalkoxy, hydroxyalkyl, carboalkoxy, carboxy, carboxamido, cyano, and Q ^b; A is selected from the group consisting of a single covalent bond and (CH (R ¹⁵ )) p _a - (W ⁷ ) rr where rr is an integer from 0 to 1, pa is an integer selected from 0 to 3 and W is selected from the group consisting of (R ⁷ ) NC (O) and N (R ⁷ ); R ⁷ is independently selected from the group consisting of hydrido, hydroxy and alkyl; R ¹⁵ is independently selected from the group consisting of hydrido, halo, alkyl and haloalkyl; M is selected from the group consisting of N and R * -C; R ¹ is selected from the group consisting of hydrido, hydroxy, hydroxyamino, amidino, amino, cyano, hydroxyalkyl, alkoxy, alkyl, alkylamino, aminoalkyl, alkylthio, alkoxyamino, haloalkyl, haloalkoxy and halogen; R ^{2 is} Z ° -Q; Z 0 is selected from the group consisting of a single covalent bond. O, S, NH and CH 2; Q is selected from the group consisting of aryl and heteroaryl, wherein the carbon atom adjacent to the carbon at the binding site is optionally substituted by R ⁹ , another carbon atom adjacent to the carbon at the binding site is optionally substituted by R ¹³ , the carbon atom adjacent to the R ⁹ position and two atoms from the point of attachment are optionally substituted with R ¹⁰ , the carbon atom adjacent to the R ¹³ position and two atoms away from the point of attachment is optionally substituted with R ¹² and any carbon atom adjacent to the R ¹⁰ position if the R ¹² position is optionally substituted R ⁹ , R ¹¹ and R ¹³ are independently selected from the group consisting of hydrido, hydroxy, amino, amidino, guanidino, lower alkylamino, alkylthio, alkylsulfonamido, alkylsulfinyl, alkylsulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxyalkyl, carboxy, carboxamido and cyano; R ¹⁰ and R ¹² are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkyl, alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, alkylsulfonamido, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, hydroxyalkyl, aminoalkyl, carboalkoxy, carboxy, carboxyalkyl amidocarbonyl, halogen, haloalkyl and cyano; Y 0 is the general formula IV 170 (IV), wherein D ⁵ , D ⁶ , J ⁵ and J ⁶ are independently selected from the group consisting of C, N, O, S and a covalent bond, provided that at most one of D ⁵ , D ⁶ , J ⁵ and T ⁵ is a covalent bond, K ² is C, at most one of D ⁵ , D ⁶ , J ⁵ and J ⁶ is O, at most one of D ⁵ , D ⁶ , J ⁵ and J ⁶ is S, one of D ⁵ , ^{D6, J5,} and ^J6 must be a covalent bond when two of ^{D5, D6, J5,} and ^J6 are O and S, and no more than four of ^{D5, D6, J5,} and ^J6 are N; R ¹⁶ , R ¹⁷ , R ¹⁸ and R ¹⁹ are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, haloalkylthio, alkoxy, hydroxy, amino, lower alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, halogen, 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 are simultaneously Q ^b , and that Q ^{b is} Q ^bc ; Q ^b is selected from NR ^{2 O} R ^21, Q ⁶ *, which is hydrido, C (NR ²⁵⁾ NR ²³ R ²⁴ and -N (R ²⁶⁾ C (NR ^{2 R)} N) R ²³⁾ (R ²⁴⁾ p provided that at most one of R ²⁰ and R ²¹ are hydroxy substituents simultaneously and that at most one of R ²³ and R ²⁴ are hydroxy substituents simultaneously R ²⁰ , R ²¹ , R ²³ , R ²⁴ , R ²⁵ and R ²⁶ are independently selected from the group consisting of hydrido, alkyl and hydroxy; Q ^s is selected from the group consisting of a single covalent bond, CH 2 and CH 2 CH 2. or a pharmaceutically acceptable salt thereof. The substituted polycyclic aryl and heteroaryl pyrimidinones of claim 17, wherein. B is selected from the group consisting of hydrido, ethyl, 2-propynyl, 2-propenyl, propyl, isopropyl, butyl, 2-butenyl, 3-butenyl, 2-butynyl, tert-butyl, tert-butyl, isobutyl, 2-methylpropenyl, 1-pentyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-pentynyl, 3-pentynyl, 2-pentynyl, 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-hexinyl, 4-hexinyl, 2-hexyl, 1-methyl-2-pentenyl, 1-methyl-3-pentenyl, 1-methyl-4-pentenyl, 1- 171 methyl-2-pentynyl, 1-methyl-3- pentinyl, 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-heptinyl, 3-heptinyl, 4-heptinyl, 5-heptinyl, 2-heptyl, 1-methyl-2-hexenyl, 1-methyl-3-hexenyl, 1-methyl-4-hexenyl, 1-methyl-5-hexenyl, 1-methyl-2-hexinyl, 1-methyl-3-hexinyl, 1-methyl-4-hexinyl, 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, 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 substituted on any carbon of up to 5 atoms including from the B to A binding site by one or a plurality of substituents from 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 the group consisting of hydrido, amidino, guanidino, carboxy, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, methoxyamino, ethoxyamino, acetamido, trifluoroacetamido, N- methylamino, dimethylamino, N-ethylamino, methylthio, ethylthio, isopropylthio, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, 2,2,3,3,3pentafluoropropyl, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chlorine, bromine, amidosulfonyl, N-methylamidosulfonyl, Ν, Ν-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro-1-hydroxyethyl, methoxycarbonyl, ethoxycarbonyl, amidocarbonyl, N-methylamidocarbonyl, Ν, dimethylamidocarbonyl, cyano and Q ^b , A is selected from the group consisting of a single covalent bond, NH, N (CH ₃ ), N (OH), CH ₂ , CH ₃ CH, CF ₃ CH, NHC (O), N (CH ₃ ) C (O), C (O) NH, C (O) N _{(CH3), CH2 CH2,} CH ₂ CH ₂ CH _2, CH ₃ CHCH ₂ and CF ₃ CHCH _2; M is selected from the group consisting of N and R ¹ -C; R ¹ is selected from the group consisting of hydrido, hydroxy, amino, amidino, hydroxyamino, aminomethyl, 1-aminoethyl, methylamino, dimethylamino, cyano, methyl, ethyl, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, methoxy, hydroxymethyl; -hydroxyethyl, 2hydroxyethyl, methoxyamino, methylthio, ethylthio, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro and bromo; R ^{2 is} Z ° -Q; Z 0 is selected from the group consisting of a single covalent bond. O, S, NH and CHr, Q is selected from the group consisting of phenyl, 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl, 4-imidazolyl, 3-pyrazolyl, 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, 1,3,5-triazine- 2-yl, wherein the carbon atom adjacent to the carbon at the binding site is optionally substituted with R ⁹ , another carbon atom adjacent 172 to the carbon in the binding site is optionally substituted with R ¹³ , the carbon atom adjacent to the R ⁹ position and two atoms away from the point of attachment is optionally substituted with R ¹⁰ , the carbon atom adjacent to the R ¹³ position and two atoms from the point of attachment is optionally substituted R ¹² and any carbon atom adjacent to R ¹⁰ and R ¹² is optionally substituted with R ¹¹ ; R ⁹ , R ¹¹ and R ¹³ are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, N-methylamino, Ν, Ν- dimethylamino, N-ethylamino, methylthio, ethylthio, isopropylthio, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, 2,2,3,3,3-pentafluoropropyl, trifluoromethoxy, 1,1,2,2tetrafluoroethoxy, fluorine, chlorine, bromo, methanesulfonamido, amidosulfonyl, N-methylamidosulfonyl, Ν, Ν-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro-1 hydroxyethyl, amidocarbonyl, N-methylamidocarbonyl, Ν, Ν-dimethylamidocarbonyl cyano; R ¹⁰ and R ¹² are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, carboxymethyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, methoxyamino, ethoxyamino, acetamido, trifluoroacetamido, aminomethyl , Aminoethyl, 2-aminoethyl, N-methylamino, dimethylamino, N-ethylamino, methanesulfonamido, amidosulfonyl, N-methylamidosulfonyl,,, Ν-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro-1-hydroxyethyl , methoxycarbonyl, ethoxycarbonyl, amidocarbonyl, N-methylamidocarbonyl, Ν, Ν-dimethylamidocarbonyl, fluoro, chloro, bromo and cyano; Y 0 is selected from the group consisting of 1Q ^b -4-Q ^with -2-R ¹⁶ -3-R ¹⁷ -5-R ¹⁸ -6-R ¹⁹ benzene, 2-Q ^b -5-Q ^with -6-R ^{, 7} -4-R ¹⁸ -2-R ¹⁹ pyridine, 3-Q ^b 6-Q ^with -2-R ¹⁶ -5-R ¹⁸ -4-R ¹⁹ pyridine, 2-Q ^b -4-Q ^with -3- R ¹⁶ -6-R ¹⁸ pyrazine, 3-Q ^b -6-Q ^with -2-R ¹⁸ -5-R ¹⁸ -4-R ¹⁹ pyridazine, 2-Q ^b -5-Q ^with -6-R ¹⁷ - 4-R ¹⁸ pyrimidine, 5-Q ^b -2-Q ^with -3-R ¹⁶ -6-R ¹⁹ pyrimidine, 3-Q ^b -5-Q ^with -4R ¹⁶ -2-R ¹⁹ thiophene, 2-Q ^b -5-Q ^with -3-R ¹⁶ -4-R ¹⁷ thiophene, 3-Q ^b -5-Q ^with -4-R ¹⁶ -2-R ¹⁹ furan, 2-Q ^b -5-Q ^with -3- R ¹⁶ 4-R ¹⁷ furan, 3-Q ^b -5-Q ⁵ -4-R ¹⁶ -2-R ¹⁹ pyrrole, 2-Q ^b -5-Q ^with -3-R ¹⁶ -4-R ¹⁷ pyrrole, 4-Q ^b -2-Q ^with -5R ¹⁹ imidazole, 2-Q ^b -4-Q ^with -5-R ¹⁷ imidazole, 3-Q ^b -5-Q ^with -4-R ¹⁶ isoxazole, 5-Q ^b -3-Q ^s -4-R ¹⁶ isoxazole, 2-Q ^b -5-Q ^with -4-R ¹⁶ pyrazole, 4-Q ^b -2-Q ^with -5-R ¹⁹ thiazole and 2-Q ^b -5-Q ^with -4-R ¹⁷ thiazole; R ¹⁶ , R ¹⁷ , R ¹⁸ and R ¹⁹ are independently selected from the group consisting of hydrido, methyl, ethyl, isopropyl, propyl, carboxy, amidino, guanidino, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, aminomethyl, 1-aminoethyl , 2-aminoethyl, N-methylamino, dimethylamino, Nethylamino, methylthio, ethylthio, isopropylthio, trifluoromethylthio, methylsulfinyl, ethylsulfinyl, methylsulfonyl, ethylsulfonyl, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, 2,2,3,3,3pentafluoropropyl , trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro, bromo, amidosulfonyl, 173 N-methylamidosulfonyl, Ν, Ν-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro-1-hydroxyethyl and cyano; 16 'r, 19 R ¹⁶ and R ¹⁹ are optionally Q ^b with the proviso that at most one of R ^1b and R ^iy are Q ^D simultaneously, and that Q ' QBC Q ^b is selected from the group consisting of NR ²⁰ R ²¹ , Q ^be , wherein Q ^be is hydrido, C (NR ²⁵ ) NR ²³ R ²⁴ and N (R ²⁶ ) C (NR ²⁵ ) N (R ²³ ) (R ²⁴ ) with the proviso that at most one of R ²⁰ and R ²¹ are hydroxy substituents simultaneously, and that at most one of R ²³ and R ²⁴ are hydroxy substituents simultaneously; R ²⁰ , R ^21, R ²³ , R ²⁴ , R ²⁵ and R ²⁶ are independently selected from the group consisting of hydrido, methyl, ethyl, propyl, butyl, isopropyl and hydroxy; Q ^s is selected from the group consisting of a single covalent bond, CH ₂ and CH ₂ CH ₂ ; or a pharmaceutically acceptable salt thereof. The substituted polycyclic aryl and heteroaryl pyrimidinones of claim 18, wherein. B is selected from the group consisting of hydrido, ethyl, 2-propenyl, 2-propynyl, propyl, isopropyl, butyl, 2-butyl, (R) 2-butyl, (S) 2-butyl, tert-butyl, isobutyl; -pentyl, 3-pentyl, 2-methylbutyl, 2,2,2-trifluoroethyl, 6-amidocarbonylhexyl, 4-methyl-2-pentyl, 3-hydroxypropyl, 3-methoxy-2-propyl, 2-methoxyethyl, 2-methyl-2-butyl , 3-methyl-2-butyl, 2-dimethylaminopropyl, 2-cyanoethyl, 6-hydroxyhexyl, 2-hydroxyethyl, 2-amidinoethyl, 2-guanidinoethyl, 3guanidinopropyl, 4-guanidinobutyl, 3-hydroxypropyl, 4-hydroxybutyl, 6-cyanohexyl, 2-dimethylaminoethyl 3-methylbutyl, 2-methylbutyl, (S) -2-methylbutyl, 3-aminopropyl, 2-hexyl and 4aminobutyl; A is selected from the group consisting of a single covalent bond, CH ₂ , NHC (O), CH ₂ CH ₂ , CH ₂ CH ₂ CH ₂ and CH ₃ CHCH ₂ ; M is selected from the group consisting of N and R‘-C; R ¹ is selected from the group consisting of hydrido, hydroxy, amino, amidino, hydroxyamino, aminomethyl, methylamino, cyano, methyl, trifluoromethyl, methoxy, hydroxymethyl, methoxyamino, methylthio, trifluoromethoxy, fluoro and chloro; R ^{2 is} Z ° -Q. Z 0 is selected from the group consisting of a single covalent bond. O, S, NH and CH _second Q is selected from the group consisting of 5-amino-3-amidocarbonylphenyl, 5-amino-2-fluorophenyl, 3-amino-5-hydroxymethylphenyl, 5-amino-3-methoxycarbonylphenyl, 3-amidinophenyl, 3-amino-2-methylphenyl, 5-amino-3-methylthiophenyl, 3-aminophenyl, benzyl, 3-carboxyphenyl, 3-carboxy-5-aminophenyl, 3-carboxy-5-hydroxyphenyl, 3-carboxymethyl-5-aminophenyl, 3-carboxymethyl- 5-hydroxyphenyl, 3-carboxymethylphenyl, 3-chlorophenyl, 2-chlorophenyl, 2,6-174 dichlorophenyl, 3-cyanophenyl, 3-dimethylaminophenyl, 2-fluorophenyl, 3-fluorophenyl, 2,5-difluorophenyl. 2-hydroxyphenyl, 3-hydroxyphenyl, 3-methanesulfonylaminophenyl, 2-methoxyphenyl, 3-methoxyphenyl, 3-methoxyaminophenyl, 3-methoxycarbonylphenyl, 2-methylaminophenyl, 3-methylaminophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, phenyl, 3-trifluoroacetamidophenyl, 3-trifluoromethylphenyl, 2-trifluoromethylphenyl, 5-amino-2-thienyl, amino-3-thienyl, 3-bromo-2-thienyl, 3-pyridyl, 4-pyridyl, 2-thienyl and 3-thienyl; Y 0 is selected from the group consisting of 1Q ^b -4-Q ^with -2-R ¹⁶ -3-R ¹⁷ -5-R ¹⁸ -6-R ¹⁹ benzene, 2-Q ^b -5-Q ^with -6-R ¹⁷ -4-R ¹⁸ -2-R ¹⁹ pyridine, 3-Q ^b -6Q ^with -2-R ¹⁶ -5-R ¹⁸ -4-R ¹⁹ pyridine, 3-Q ^b -5-Q ^with -4-R ¹⁶ -2-R ¹⁹ thiophene and 2-Q ^b -5-Q ^with -3-R ¹⁶ -4-R ¹⁷ thiophene; R ¹⁶ and R ¹⁹ are independently selected from the group consisting of hydrido, amidino, amino, aminomethyl, methoxy, methylamino, hydroxy, 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 that Q ^b QBE R ¹⁷ and R ¹⁸ are independently selected from the group consisting of hydrido, fluoro, chloro, hydroxy, hydroxymethyl, amino, carboxy and cyano; Q ^b is selected from the group consisting of Q ^be , wherein Q 6 is hydrido, and C (NR ²⁵ ) NR ²³ R ²⁴ , R ²³ , R ²⁴ and R ²³ are independently selected from the group consisting of hydrido and methyl; Q ^is CH ₂ ; or a pharmaceutically acceptable salt thereof. Substituted polycyclic aryl and heteroaryl pyrimidinones according to claim 17 of the general formula B 'where. B is selected from the group consisting of hydrido, C 2 -C 8 alkyl, C 3 -C 8 alkenyl, C 3 -C 8 alkynyl and C 2 -C 8 haloalkyl, wherein each member of group B may be optionally substituted on any carbon atom of up to 6 atoms including from the B bond site on A, by one or more substituents R ³² , R ³³ , R ³⁴ , R ³⁵ and R ³⁶ ; - 175R ³² , R ³³ , R ³⁴ , R ^{3 S} and R ³⁶ are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, alkylthio, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboalkoxy, carboxy, carboxamido, cyano, and Q ^b; A is selected from the group consisting of a single covalent bond and (CH (R ¹⁵ )) _pa (W ⁷ ) n -, wherein rr is an integer from 0 to 1, pa is an integer selected from 0 to 3, and W ⁷ is N (R ^7); R ⁷ is independently selected from the group consisting of hydrido and alkyl; R ¹⁵ is independently selected from the group consisting of hydrido, halo, alkyl and haloalkyl, M is selected from the group consisting of N and R * -C; R ¹ is selected from the group consisting of hydrido, hydroxy, hydroxyamino, amidino, amino, cyano, hydroxyalkyl, alkoxy, alkyl, alkylamino, aminoalkyl, alkylthio, alkoxyamino, haloalkyl, haloalkoxy and halogen; R ^{2 is} Z ° -Q; Z 0 is a single covalent bond; Q is selected from the group consisting of aryl and heteroaryl, wherein the carbon atom adjacent to the carbon at the binding site is optionally substituted with R ⁹ , another carbon atom adjacent to the carbon at the binding site is optionally substituted with R ¹³ , a carbon atom adjacent to the R ⁹ position and two atoms from the point of attachment are optionally substituted with R ¹⁰ , a carbon atom adjacent to the R ¹³ position and two atoms from the point of attachment is optionally substituted with R ^12, and any carbon atom adjacent to the R ¹⁰ position and if the R ¹² position is optionally substituted with R 12; R ⁹ , R ¹¹ and R ¹³ are independently selected from the group consisting of hydrido, hydroxy, amino, amidino, guanidino, lower alkylamino, alkylthio, alkoxy, alkylsulfinyl, alkylsulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, alkyl, halogen, haloalkyl, haloalkoxy, hydroxyalkyl, carboxy, carboxamido and cyano; R ¹⁰ and R ¹² are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkyl, alkoxy, alkoxyamino, aminoalkyl, hydroxy, amino, lower alkylamino, alkylsulfonamido, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, hydroxyalkyl, aminoalkyl, halogen, haloalkyl, carboalkoxy, carboxy, carboxyamido, carboxyalkyl and cyano; Y 0 is a group of formula IV - 176 R ', R ^7' wherein D ^5, D ^6, J ^5, and J ⁶ are independently selected from the group consisting of C, N, O, S and covalent bond with the provisos that no more than one of ^{D5, D6,} J ⁵ and J ⁶ is a covalent bond, K ² is C, at most one of D ⁵ , D ⁶ , J ⁵ and J ⁶ is O, at most one of D ⁵ , D ⁶ , J ⁵ and J ⁶ is S, one of D ⁵ , D ⁶ , J ⁵ and J ⁶ must be a covalent bond when two of D ⁵ , D ⁶ , J ⁵ and J ⁶ are O and S 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 the group consisting of hydrido, amidino, guanidino, carboxy, haloalkylthio, alkoxy, hydroxy, amino, lower alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, halogen, 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 simultaneously Q ^b , and that Q ^b QBE Q ^b is selected from the group consisting of NR ²⁰ R ²¹ , Q ¹ * wherein is hydrido, N (R ²⁶ ) C (NR ²⁵ ) N) R ²³ ) (R ²⁴ ) and C (NR ²⁵ ) NR ²³ R ²⁴ ; R ²⁰ , R ²¹ , R ²³ , R ²⁴ , R ²⁵ and R ²⁶ are independently selected from the group consisting of hydrido and alkyl; Q ^{s is} CH 2; or a pharmaceutically acceptable salt thereof. The substituted polycyclic aryl and heteroaryl pyrimidinones of claim 17, wherein: B is selected from the group consisting of hydrido, ethyl, 2-propenyl, 2-propynyl, propyl, isopropyl, butyl, 2-butenyl, 2-butynyl, xa-butyl, tert-butyl, isobutyl, 2-methylpropenyl, 1pentyl, 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-hexinyl, 3-hexinyl, 4-hexinyl, 2-hexyl, 1-methyl-2-pentenyl, 1-methyl-3-pentenyl, 1-methyl-2-pentinyl, 1-methyl-3-pentynyl, 3-hexyl, 1-ethyl-2-butenyl, 1-heptyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 2-heptinyl, 3-heptinyl, 4-heptinyl, 5-heptinyl, 2-heptyl, 1-methyl- 2-hexenyl, 1-methyl-3-hexenyl, 1-methyl-4-hexenyl, 1-methyl-2-hexinyl, 1-methyl-3-hexinyl, 1- 177 methyl-4-hexinyl, 3-heptyl, 1-ethyl -2-pentenyl, 1-ethyl-3-pentenyl, 1-ethyl-2-pentynyl, 1-ethyl-3pentinyl, 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 substituted on any carbon up to 5 atoms including from the B to A binding site by one or more 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 the group consisting of hydrido, amidino, guanidino, methyl, ethyl, methoxy, ethoxy, hydroxy, amino, N-methylamino, dimethylamino methylthio, ethylthio, trifluoromethyl, pentafluoroethyl , 2,2,2-trifluoroethyl, fluoro, chloro, bromo, amidosulfonyl, Nmethylamidosulfonyl, hydroxymethyl, amidocarbonyl, carboxy, cyano, and Q ^b; A is selected from the group consisting of a single covalent bond, NH, N (CH ₃ ), N (OH), CH ₂ , CH ₃ CH, and CH ₂ CH ₂ ; A is optionally selected from the group consisting of CH ₂ N (CH ₃ ), CH ₂ N (CH ₂ CH ₃ ), CH ₂ CH ₂ N (CH ₃ ) and CH ₂ CH ₂ N (CH ₂ CH ₃ ), provided that: B is hydrido; M is selected from the group consisting of N and R * -C; R ¹ is selected from the group consisting of hydrido, hydroxy, amino, amidino, hydroxyamino, aminomethyl, methylamino, cyano, methyl, trifluoromethyl, methoxy, hydroxymethyl, methoxyamino, methylthio, trifluoromethoxy, fluoro and chloro; R ² is selected from the group consisting of phenyl, 2-thienyl, 2-fluoryl, 2-pyrrolyl, 2-imidazolyl, 2-thiazoles 1,3-isoxazolyl, 2-pyridyl and 3-pyridyl, wherein the carbon atom adjacent to the carbon in the bonding the site is optionally substituted with R ⁹ , another carbon atom adjacent to the carbon at the binding site is optionally substituted with R ¹³ , a carbon atom adjacent to the R ⁹ position and two atoms away from the point of attachment is optionally substituted with R ¹⁰ , a carbon atom adjacent to the R ¹³ position; two atoms away from the point of attachment is optionally substituted with R 1 and any carbon atom adjacent to R ¹⁰ and R ¹² is optionally substituted with R ¹¹ ; R ⁹ , R ¹¹ and R ¹³ are independently selected from the group consisting of hydrido, methyl, ethyl, methoxy, ethoxy, hydroxy, amino, N-methylamino, Ν, Ν-dimethylamino, methylthio, trifluoromethyl, pentafluoroethyl, 2,2,2- trifluoroethyl, fluoro, chloro, bromo, amidosulfonyl, N-methylamidosulfonyl, Ν, Ν-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, amidocarbonyl, N-methylamidocarbonyl, carboxy and cyano; R ¹⁰ and R ¹² are independently selected from the group consisting of hydrido, amidino, amidocarbonyl, N-methylamidocarbonyl, guanidino, methyl, ethyl, methoxy, ethoxy, hydroxy, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, carboxy, carboxymethyl, amino, acetamido , trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, trifluoroacetamido, aminomethyl. N- 178 methylamino, dimethylamino, amidosulfonyl, N-methylamidosulfonyl, Ν, Ν-dimethylamidosulfonyl, methoxycarbonyl, fluoro, chloro, bromo and cyano; Y 0 is selected from the group consisting of 1Q ^b -4-Q ^with -2-R ¹⁶ -3-R ¹⁷ -5-R ¹⁸ -6-R ¹⁹ benzene, 2-Q ^b -5-Q ^with -6-R ¹⁷ -4-R ¹⁸ -2-R ¹⁹ pyridine, 2-Q ^b -5Q ^with -3-R ¹⁶ -4-R ¹⁷ thiophene, 3-Q ^b -6-Q ^with -2-R ¹⁶ -5-R ¹⁸ -4-R ¹⁹ pyridine, 3-Q ^b -5-Q ^with -4-R ¹⁶ -2-R ¹⁹ thiophene, 3Q ^b -5-Q ^with -4-R ¹⁶ -2-R ¹⁹ furan, 2-Q ^b -5-Q ^with -3-R ^{, 6} -4-R ¹⁷ furan, 3-Q ^b -5-Q ^with -4-R ¹⁶ -2-R ¹⁹ pyrrole, 2-Q ^b -5Q ^with -3_R ¹⁶ -4-R ¹⁷ pyrrole, 4-Q ^b -2-Q ^with -5-R ^{, 9} thiazole and 2-Q ^b -5-Q ^with -4-R ¹⁷ thiazole; R ¹⁶ , R ¹⁷ , R ¹⁸ and R ¹⁹ are independently selected from the group consisting of hydrido, methyl, ethyl, amidino, guanidino, methoxy, hydroxy, amino, aminomethyl, 1-aminoethyl, 2-aminoethyl, N-methylamino, dimethylamino, methylthio, ethylthio trifluoromethylthio, methylsulfinyl, methylsulfonyl, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, trifluoromethoxy, fluoro, chloro, bromo, amidosulfonyl, N-methylamidosulfonyl, hydroxymethyl, carboxy and cyano; Q ^b is selected from the group consisting of NR ²⁰ R ²¹ , C (NR ²⁵ ) NR ^{22 23} R ²⁴ and N (R ²⁶ ) C (NR ²⁵ ) N (R ²³ ) (R ²⁴ ) with the proviso that Q ^b group binds directly to a carbon atom; R ²⁰ , R ^21, R ²³ , R ²⁴ , R ²⁵ and R ²⁶ are independently selected from the group consisting of hydrido, methyl and ethyl; Q ^is CH ₂ ; or a pharmaceutically acceptable salt thereof. The substituted polycyclic aryl and heteroaryl pyrimidinones of claim 21, wherein: B is selected from the group consisting of hydrido, ethyl, 2-propenyl, 2-propynyl, propyl, isopropyl, butyl, 2-butyl, (R) 2-butyl, (S) 2-butyl, tert-butyl, isobutyl; -pentyl, 3-pentyl, 2-methylbutyl, 2,2,2-trifluoroethyl, 6-amidocarbonylhexyl, 4-methyl-2-pentyl, 3-hydroxypropyl, 3-methoxy-2-propyl, 2-methoxyethyl, 2-methyl-2-butyl 3-methyl-2-butyl, 2-dimethylaminopropyl, 2-cyanoethyl, 6-hydroxyhexyl, 2-hydroxyethyl, 2-amidinoethyl, 2-guanidinoethyl, 3guanidinopropyl, 4-guanidinobutyl, 3-hydroxypropyl, 4-hydroxybutyl, 6-cyanohexyl, 2-dimethylaminoethyl , 3-methylbutyl, 2-methylbutyl, (S) -2-methylbutyl, 3-aminopropyl, 2-hexyl and 4-aminobutyl; A is selected from the group consisting of a single covalent bond, CH ₂ , CH ₃ CH and CH ₂ CH ₂ ; M is selected from the group consisting of N and R ¹ -C; R ¹ is selected from the group consisting of hydrido, hydroxy, amino, methyl, trifluoromethyl, fluoro, and chloro; - 179R ⁱ is selected from the group consisting of 5-amino-3-amidocarbonylphenyl, 5-amino-2-fluorophenyl, 3-amino-5-hydroxymethylphenyl, 5-amino-3-methoxycarbonylphenyl, 3-amidinophenyl, 3-amino-2-methylphenyl, 5-amino-2-methylthiophenyl, 3-aminophenyl, benzyl, 3-carboxyphenyl, 3-carboxy-5-aminophenyl, 3-carboxy-5-hydroxyphenyl, 3-carboxymethyl-5-aminophenyl, 3-carboxymethyl- 5-hydroxyphenyl, 3-carboxymethylphenyl, 3-chlorophenyl, 2-chlorophenyl, 2,6-dichlorophenyl, 3-cyanophenyl, 3-dimethylaminophenyl, 2-fluorophenyl, 3-fluorophenyl, 2,5-difluorophenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 3-methanesulfonylaminophenyl, 2-methoxyphenyl, 3-methoxyphenyl, 3-methoxyaminophenyl, 3-methoxycarbonylphenyl, 2-methylaminophenyl, 3-methylaminophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, phenyl, 3-trifluoroacetamidophenyl, 3-trifluoromethylphenyl, 2-trifluoromethylphenyl, 5-amino-2-thienyl, 5- amino-3-thienyl, 3-bromo-2-thienyl, 3-pyridyl, 4-pyridyl, 2-thienyl and 3-thienyl; Y 0 is selected from the group consisting of 1Q ^b -4-Q ^with -2-R ¹⁶ -3-R ¹⁷ -5-R ¹⁸ -6-R ¹⁹ benzene, 2-Q ^b -5-Q ^with -6-R ¹⁷ -4-R ⁸ -2-R ¹⁹ pyridine, 3-Q ^b 6-Q ^with -2-R ¹⁶ -5-R ¹⁸ -4-R ¹⁹ pyridine, 3-Q ^b -5-Q ^with -4- R ¹⁶ -2-R ¹⁹ thiophene and 2-Q ^b -5-Q ^with -3-R ¹⁶ -4-R ¹⁷ thiophene; R ¹⁶ and R ¹⁹ are independently selected from the group consisting of hydrido, amidino, amino, aminomethyl, methoxy, methylamino, hydroxy, 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 that Q ^{b is} Q ^bc ; R ¹⁷ and R ¹⁸ are independently selected from the group consisting of hydrido, fluoro, chloro, hydroxy, hydroxymethyl, amino, carboxy and cyano; Q ^b is selected from the group consisting of Q ^bc , wherein Q ^be is hydrido, and C (NR ²⁵ ) NR ²³ R ²⁴ ; R ²³ , R ²⁴ and R ²⁵ are independently selected from the group consisting of hydrido and methyl; Q ^is CH ₂ ; or a pharmaceutically acceptable salt thereof. The substituted polycyclic aryl and heteroaryl pyrimidinones of claim 22, wherein: B is selected from the group consisting of hydrido, ethyl, 2-propenyl, 2-propynyl, propyl, isopropyl, butyl, 2-butyl, (R) 2-butyl, (S) 2-butyl, tert-butyl, isobutyl; -pentyl, 3-pentyl, 2-methylbutyl, 2,2,2-trifluoroethyl, 6-amidocarbonylhexyl, 4-methyl-2-pentyl, 3-hydroxypropyl, 3-methoxy-2-propyl, 2-methoxyethyl, 2-methyl-2-butyl , 3-methyl-2-butyl, 2-dimethylaminopropyl, 2-cyanoethyl, 6-hydroxyhexyl, 2-hydroxyethyl, 2-amidinoethyl, 2-guanidinoethyl, 3-guanidinopropyl, 4-guanidinobutyl, 3-hydroxypropyl, 4-hydroxybutyl, 6-cyanohexyl , 2-dimethylaminoethyl, 3-methylbutyl, 2-methylbutyl, (S) -2-methylbutyl, 3-aminopropyl, 2-hexyl and 4-aminobutyl; - 180 A is selected from the group consisting of a single covalent bond, CH ₂ , CH ₃ CH and CH ₂ CH ₂ , M is selected from the group consisting of N and R * -C; R ¹ is selected from the group consisting of hydrido, fluoro and chloro; R ² is selected from the group consisting of 5-amino-2-fluorophenyl, 3-amino-2-methylphenyl, 5 amino-2-methylthiophenyl, 3-aminophenyl, 3-carboxyphenyl, 3-cyanophenyl, phenyl and 3-pyridyl. Y 0 is selected from the group consisting of 5-amidino-2-thienylmethyl, 4-amidinobenzyl, 2-fluoro-4-amidinobenzyl and 3-fluoro-4-amidinobenzyl; or a pharmaceutically acceptable salt thereof. Substituted polycyclic aryl and heteroaryl pyrimidinones according to claim 17, selected from the group of compounds of formula: where: ^R2 is 3-aminophenyl, B is 2,2,2-trifluoroethyl, A is single bond, Y is 4-amidinobenzyl, and M is CH; ^R2 is 3-aminophenyl, B is (S) -2-butyl, A is single bond, Y is 4-amidinobenzyl, and M is CH; ^R2 is 5-amino-2-fluorophenyl, B is isopropyl, A is single bond, Y is 4-amidinobenzyl, and M is CH; R ² is 2-methyl-3-aminophenyl, B is isopropyl, A is single bond, Y is 4-amidinobenzyl, and M is CH; ^R2 is 3-aminophenyl, B is ethyl, A is single bond, Y is 4-amidinobenzyl, and M is CH; ^R2 is 3-aminophenyl, B is ethyl, A is single bond, Y is 4-amidino-2-fluorobenzyl, and M is CH .; ^R2 is 3-aminophenyl, B is 2-propenyl, A is single bond, Y is 4-amidinobenzyl, and M is CH; ^R2 is 3-aminophenyl, B is isopropyl, A is single bond, Y is 4-amidino-2-fluorobenzyl, and M is CH; 181 RJ is 3-aminophenyl, B is isopropyl, A is single bond, Y0 is 4-amidinobenzyl and M is CH; ^R2 is 3-aminophenyl, B is 2-butyl, A is single bond, Y is 4-amidinobenzyl, and M is CH; ^R2 is 3-aminophenyl, B is (R) -2-butyl, A is single bond, Y is 4-amidinobenzyl, and M is CH; ^R2 is 3-aminophenyl, B is 2-propynyl, A is single bond, Y is 4-amidinobenzyl, and M is CH; ^R2 is 3-aminophenyl, B is 3-pentyl, A is single bond, Y is 4-amidinobenzyl, and M is CH; ^R2 is 3-aminophenyl, B is hydrido, A is _CH2, Y is 4-amidinobenzyl, and M is CH; ^R2 is 3-aminophenyl, B is ethyl, A is _CH2, Y is 4-amidinobenzyl, and M is CH; ^R2 is 3-aminophenyl, B is 2-methylpropyl, A is single bond, Y is 4-amidinobenzyl, and M is CH; ^R2 is 3-aminophenyl, B is 2-propyl, A is _CH3 CH, Y is 4-amidinobenzyl, and M is CH; ^R2 is 3-aminophenyl, B is propyl, A is single bond, Y is 4-amidinobenzyl, and M is CH; ^R2 is 3-aminophenyl, B is tert-butyl, A is single bond, Y is 4-amidinobenzyl, and M is CH; ^R2 is 3-aminophenyl, B is 3-hydroxypropyl, A is single bond, Y is 4-amidinobenzyl, and M is CH; ^R2 is 3-aminophenyl, B is 2-methylpropyl, A is single bond, Y is 4-amidino-2-fluorobenzyl, and M is CH; ^R2 is 3-aminophenyl, B is butyl, A is single bond, Y is 4-amidinobenzyl, and M is CH; ^R2 is 3-aminophenyl, B is 3-methoxy-2-propyl, A is single bond, Y is 4-amidinobenzyl, and M is CH: ^R2 is 3-aminophenyl, B is 2-methoxy-2-ethyl, A is single bond, Y is 4-amidinobenzyl, and M is CH; ^R2 is 3-aminophenyl, B is 2-propyl, A is single bond, Y is 5-amidino-2-thienylmethyl, and M is CH; ^R2 is 3-aminophenyl, B is 2-propyl, A is single bond, Y is 4-amidino-3-fluorobenzyl, and M is CH; ^R2 is 3-carboxyphenyl, B is 2-propyl, A is single bond, Y is 4-amidino-3-fluorobenzyl, and M is CH; ^R2 is 3-aminophenyl, B is 2,2,2-trifluoroethyl, A is single bond, Y is 4-amidinobenzyl, and M is N; ^R2 is 3-aminophenyl, B is (S) -2-butyl, A is single bond, Y is 4-amidinobenzyl, and M is N; ^R2 is 5-amino-2-fluorophenyl, B is isopropyl, A is single bond, Y ^fl is 4amidinobenzyl, and M is N; R 182 is 2-methyl-3-aminophenyl, B is isopropyl, A is single bond, Y 0 is 4-amidinobenzyl and M is N; ^R2 is 3-aminophenyl, B is ethyl, A is single bond, Y is 4-amidinobenzyl, and M is N; ^R2 is 3-aminophenyl, B is ethyl, A is single bond, Y ⁽⁾ is 4-amidino-2-fluorobenzyl, and M is N; ^R2 is 3-aminophenyl, B is 2-propenyl, A is single bond, Y ⁰ is 4-amidinobenzyl, and M is N; ^R2 is 3-aminophenyl, B is isopropyl, A is single bond, Y is 4-amidino-2-fluorobenzyl, and M is N; ^R2 is 3-aminophenyl, B is isopropyl, A is single bond, Y is 4-amidinobenzyl, and M is N; ^R2 is 3-aminophenyl, B is 2-butyl, A is single bond, Y is 4-amidinobenzyl, and M is N, ^R2 is 3-aminophenyl, B is (R) -2-butyl, A is single bond, Y is 4-amidinobenzyl, and M is N; ^R2 is 3-aminophenyl, B is 2-propynyl, A is single bond, Y is 4-amidinobenzyl, and M is N; R ² is 3-aminophenyl, B is 3-pentyl, A is single bond, Y ^C is 4-amidinobenzyl and M is N; R ² is 3-aminophenyl, B is hydrido, A is CH 2, Y 0 is 4-amidinobenzyl, and M is N; ^R2 is 3-aminophenyl, B is ethyl, A is CH2, Y is 4-amidinobenzyl, and M is N; ^R2 is 3-aminophenyl, B is 2-methylpropyl, A is single bond, Y is 4-amidinobenzyl, and M is N; ^R2 is 3-aminophenyl, B is 2-propyl, A is _CH3 CH, Y is 4-amidinobenzyl, and M is N; ^R2 is 3-aminophenyl, B is propyl, A is single bond, Y is 4-amidino-2-fluorobenzyl, and M is N; ^R2 is 3-aminophenyl, B is 6-amidocarbonylhexyl, A is single bond, Y is 4-amidinobenzyl and M is N; ^R2 is 3-aminophenyl, B is tert-butyl, A is single bond, Y is 4-amidinobenzyl, and M is N; ^R2 is 3-aminophenyl, B is 3-hydroxypropyl, A is single bond, Y is 4-amidinobenzyl, and M is N; ^R2 is 3-aminophenyl, B is 2-methylpropyl, A is single bond, Y is 4-amidino-2-fluorobenzyl, and M is N; ^R2 is 3-aminophenyl, B is butyl, A is single bond, Y is 4-amidinobenzyl, and M is N; ^R2 is 3-aminophenyl, B is 3-methoxy-2-propyl, A is single bond, Y is 4-amidinobenzyl, and M is N; ^R2 is 3-aminophenyl, B is 2-methoxy-2-ethyl, A is single bond, Y is 4-amidinobenzyl, and M is N; - 183R ² is 3-aminophenyl, B is 2-propyl, A is single bond, Y is 5-amidino-2-thienylmethyl, and M is N; ^R2 is 3-aminophenyl, B is 2-propyl, A is single bond, Y is 4-amidino-3-fluorobenzyl, and M is N; ^R2 is 3-carboxyphenyl, B is 2-propyl, A is single bond, Y is 4-amidinobenzyI and M is N; ^R2 is 3-aminophenyl, B is 2-propyl, A is single bond, Y is 4-amidino-3-fluorobenzyl, and M is CH; or a pharmaceutically acceptable salt thereof. 25. Substituted polycyclic aryl and heteroaryl pyrimidinones according to claim 2 having the general formula: where: B is selected from the group consisting of C 3 -C 7 cycloalkyl and C 4 - saturated heterocyclyl wherein each ring carbon atom is optionally substituted with R ³³ , the ring carbon atom other than the carbon atom at the B-bonding site of A is optionally substituted with an oxo group; such that at most one ring carbon atom is substituted by an oxo group simultaneously, the ring carbon atom and the nitrogen atom adjacent to the carbon at the binding site are optionally substituted with R ⁹ or R ¹³ , a ring carbon atom or a nitrogen atom adjacent to the R ⁹ position and spaced two atoms from the point of attachment are optionally substituted with R ¹⁰ , a carbon or nitrogen atom adjacent to the R ¹³ position and spaced two atoms from the point of attachment is optionally substituted with R ¹² , a carbon or nitrogen atom three atoms from the point of attachment and adjacent to the R ¹⁰ position is optionally substituted with R ¹¹ , a carbon atom or a nitrogen atom three atoms from the point of attachment and adjacent to the R ¹² position is optionally substituted with R ³³ and a carbon or nitrogen atom four atoms from the point of attachment and adjacent to the R ¹¹ and R ³³ positions is optionally substituted with R ³⁴ ; R ⁹ , R ¹¹ and R ¹³ are independently selected from the group consisting of hydrido, hydroxy, amino, amidino, guanidino, lower alkylamino, alkylthio, alkylsulfonamido, alkylsulfinyl, alkylsulfonyl, amidosulfonyl, monoalkylamidosulfonyl, alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxyalkyl , carboxy, carboxamido and cyano; - 184R ¹⁰ and R ¹² are independently selected from hydrido, acetamido, amidino, guanidino, alkyl, alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, alkylsulfonamido, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, hydroxyalkyl, aminoalkyl, carboalkoxy , carboxy, carboxyalkyl, amidocarbonyl, halogen, haloalkyl and cyano; R ³³ and R ³⁴ are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, alkylthio, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, alkyl, halogen, haloalkyl, haloalkoxy hydroxyalkyl, carboalkoxy, carboxy, carboxamido, cyano, and Q ^b; A is selected from the group consisting of a single covalent bond and (CH (R ¹⁵ )) p _a - (W ⁷ ) r T where rr is an integer from 0 to 1, p is an integer selected from 0 to 3 and W ⁷ is selected from the group consisting of (R) NC (O) and N (R); R ⁷ is independently selected from the group consisting of hydrido, hydroxy and alkyl; R ¹⁵ is independently selected from the group consisting of hydrido, halo, alkyl and haloalkyl; M is selected from the group consisting of N and R'-C; R ¹ is selected from the group consisting of hydrido, hydroxy, hydroxyamino, amidino, amino, cyano, hydroxyalkyl, alkoxy, alkyl, alkylamino, aminoalkyl, alkylthio, alkoxyamino, haloalkyl, haloalkoxy and halogen; R ^{2 is} Z ° -Q; Z 0 is selected from the group consisting of a single covalent bond, O, S, NH and CH 2; Q is selected from the group consisting of aryl and heteroaryl wherein the carbon atom adjacent to the carbon at the binding site is optionally substituted with R ⁹ , another carbon atom adjacent to the carbon at the binding site is optionally substituted with R ¹³ and a carbon atom adjacent to the R ⁹ position and two atoms from the point of attachment is optionally substituted by ^R10, a carbon adjacent to the R ¹³ position and two atoms from the point of attachment is optionally substituted by ^R12, and any carbon adjacent to the R position ¹⁰ when R ¹² position is optionally substituted with R; Y 0 is a group of formula IV - 185 17 í (IV), 1 and ³ \ ZD \ □ 16 * ^ \ _n 19 R of ^the R wherein ^{D5, D6, J5,} and ^J6 are independently selected from the group consisting of C, N, O, S and covalent bond with the provisos that at most one of D ⁵ , D ⁶ , J ⁵ and J ⁶ is a covalent bond, K ² is C, at most one of D ⁵ , D ⁶ , J ⁵ and J ⁶ is optionally O, at most one of D ⁵ , D ⁶ , J ⁵ and J ⁶ is optionally S, one of D ³ , D ⁶ , J ⁵ and J ⁶ must be a covalent bond as long as two of D ⁵ , D ⁶ , J ⁵ and J ⁶ are O and S 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 the group consisting of hydrido, amidino, guanidino, carboxy, haloalkylthio, alkoxy, hydroxy, amino, lower alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, halogen, 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 are simultaneously Q ^b , and that Q ^b is Q ^be ; Q ^b is selected from the group consisting of NR ²⁰ R ²¹ , Q ^be , wherein Q ⁶ * is hydrido, and C (NR ² R) NR ²³ R ²⁴ , provided that at most one of R ²⁰ and R ^{21 is a} hydroxy substituent simultaneously, and that at most one of R ²³ and R ²⁴ is a hydroxy substituent simultaneously; R ²⁰ , R ²¹ , R ²³ , R ²⁴ and R ²⁶ are independently selected from the group consisting of hydrido, alkyl and hydroxy; Q ^s is selected from the group consisting of a single covalent bond, CH ₂ and CH ₂ CH ₂ ; or a pharmaceutically acceptable salt thereof. The substituted polycyclic aryl and heteroaryl pyrimidinones of claim 25, wherein: B is selected from the group consisting of cyclopropyl, cyclobutyl, oxetan-3-yl, azetidin-1-yl, azetidin-2-yl, azetidin-3-yl, cyclopentyl, cyclohexyl, norbomyl, bicyclo [3.1.0] hexan-6-yl and cycloheptyl wherein each ring carbon atom is optionally substituted with R ³³ , the ring carbon atom other than the carbon atom at the B-bonding point A is optionally substituted with an oxo group so that at most one ring carbon atom is substituted with an oxo group simultaneously , the ring carbon atom and the nitrogen atom adjacent to the carbon at the binding site are optionally substituted with R ⁹ or R ¹³ , a carbon atom or a nitrogen atom adjacent to the R ⁹ position, and 186 two-atom atoms away from the point of attachment is optionally substituted with R ¹⁰ , a carbon or nitrogen atom adjacent to the R ¹³ position and two-atom atoms away from the point of attachment is optionally substituted with R ¹² ; R ⁹ , R ¹¹ and R ¹³ are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, N-methylamino, Ν, Ν- dimethylamino, N-ethylamino, methylthio, ethylthio, isopropylthio, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, 2,2,3,3,3-pentafluoropropyl, trifluoromethoxy, 1,1,2,2tetrafluoroethoxy, fluorine, chlorine, bromo, methanesulfonamido, amidosulfonyl, N-methylamidosulfonyl, Ν, Ν-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro-1 hydroxyethyl, amidocarbonyl, N-methylamidocarbonyl, Ν, Ν-dimethylamidocarbonyl ; R ¹⁰ and R ¹² are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, carboxymethyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, methoxyamino, ethoxyamino, acetamido, trifluoroacetamido, aminomethyl , 1-aminoethyl, 2-aminoethyl, N-methylamino, dimethylamino, N-ethylamino, methanesulfonamido, amidosulfonyl, N-methylamidosulfonyl, Ν, Ν-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro-1-hydroxyethyl , methoxycarbonyl, ethoxycarbonyl, amidocarbonyl, N-methylamidocarbonyl, Ν, Ν-dimethylamidocarbonyl, fluoro, chloro, bromo and cyano; R ³³ and R ³⁴ are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, methoxyamino, ethoxyamino, acetamido, trifluoroacetamido, N-methylamino, 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, amidosulfonyl, N-methylamidosulfonyl , Ν, Ν-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro-l-hydroxyethyl, methoxycarbonyl, ethoxycarbonyl, amidocarbonyl, Nmethylamidocarbonyl, Ν, Ν-dimethylamidocarbonyl, cyano, and Q ^b; A is selected from the group consisting of a single covalent bond, NH, N (CH ₃ ), N (OH), CH ₂ , CH ₃ CH, CF ₃ CH, NHC (O), N (CH ₃ ) C (O), C (O) NH, C (O) N _{(CH3), CH2 CH2,} CH ₂ CH ₂ CH _2, CHCH ₃ CH _2, CF ₃ CH CH _2; M is selected from the group consisting of N and R'-C; R ¹ is selected from the group consisting of hydrido, hydroxy, amino, amidino, hydroxyamino, aminomethyl, 1-aminoethyl, methylamino, dimethylamino, cyano, methyl, ethyl, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, methoxy, hydroxymethyl; -hydroxyethyl, 2- 187 hydroxyethyl, methoxyamino, methylthio, ethylthio, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro and bromo; R ^{2 is} Z ° -Q; Z 0 is selected from the group consisting of a single covalent bond, O, S, NH and CH ₂ ; Q is selected from the group consisting of phenyl, 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl, 4-imidazolyl, 3-pyrazolyl, 4-pyrazolyl, 2-thiazolyl, 3-isoxazolyl, 5-isoxazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 1,3,5-triazin-2-yl wherein the carbon atom adjacent to the carbon at the binding site is optionally substituted with R ⁹ , another carbon atom adjacent to the carbon at the binding site optionally substituted with R ¹³ , the carbon atom adjacent to the R ⁹ position and two atoms away from the point of attachment is optionally substituted with R ¹⁰ , the carbon atom adjacent to the R ¹³ position and two atoms away from the point of attachment is optionally substituted with R ^12, and any carbon atom adjacent R ¹⁰ and R ¹² are optionally substituted with R ¹¹ ; Y 0 is selected from the group consisting of 1Q ^b -4-Q ^with -2-R ¹⁶ -3-R ¹⁷ -5-R ¹⁸ -6-R ¹⁹ benzene, 2-Q ^b -5-Q ^with -6-R ¹⁷ -4-R ¹⁸ -2-R ¹⁹ pyridine, 3-Q ^b 6-Q ^with -2-R ¹⁶ -5-R ¹⁸ -4-R ¹⁹ pyridine, 2-Q ^b -4-Q ^with -3-R ¹⁶ -6-R ¹⁸ pyrazine, 3-Q ^b -6-Q ^with -2-R ¹⁸ -5-R ¹⁸ -4-R ¹⁹ pyridazine, 2-Q ^b -5-Q ^with -6-R ¹⁷ -4 -R ¹⁸ pyrimidine, 5-Q ^b -2-Q ^with -3-R ⁶ -6-R ¹⁹ pyrimidine, 3-Q ^b -5-Q ^with -4 R ¹⁶ -2-R ¹⁹ thiophene, 2-Q ^b -5-Q ^with -3-R ¹⁶ -4-R ¹⁷ thiophene, 3-Q ^b -5-Q ^with -4-R ¹⁶ -2-R ¹⁹ furan, 2-Q ^b -5-Q ^with -3- R ¹⁶ 4- R ¹⁷ furan, 3-Q ^b -5-Q ^with -4-R ¹⁶ -2-R ¹⁹ pyrrole, 2-Q ^b -5-Q ^with -3-R ¹⁶ -4-R ¹⁷ pyrrole, 4-Q ^b -2-Q ^with -5- R ¹⁹ imidazole, 2-Q ^b -4-Q ^with -5-R ¹⁷ imidazole, 3-Q ^b -5-Q ^with -4-R ¹⁶ isoxazole, 5- Q ^b -3-Q ^with -4- R ¹⁶ isoxazole, 2Q ^b -5-Q ^with -4- R ¹⁶ pyrazole, 4-Q ^b -2-Q ^with -5-R ¹⁹ thiazole and 2-Q ^b -5 -Q ^with -4- R ^{, 7} thiazole. R ¹⁶ , R ¹⁷ , R ¹⁸ and R ¹⁹ are independently selected from the group consisting of hydrido, methyl, ethyl, isopropyl, propyl, carboxy, amidino, guanidino, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, aminomethyl, 1-aminoethyl , 2-aminoethyl, N-methylamino, dimethylamino, Nethylamino, methylthio, ethylthio, isopropylthio, trifluoromethylthio, methylsulfinyl, ethylsulfinyl, methylsulfonyl, ethylsulfonyl, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, 2,2,3,3,3pentafluoropropyl , trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro, bromo, amidosulfonyl, N-methylamidosulfonyl, Ν, Ν-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 at the same time and that Q ^b Q ^b I ^t is selected from Q ^be wherein Q is hydrido, ^C, and C (NR ²⁵⁾ NR ²³ R ²⁴ with the proviso that no more than one of R ²³ and R ²⁴ is hydroxy at the same time; - 188 R ²³ , R ²⁴ and R ²⁵ are independently selected from the group consisting of hydrido, methyl, ethyl and hydroxy, Q ^s is selected from the group consisting of a single covalent bond, CH ₂ and CH ₂ CH ₂ ; or a pharmaceutically acceptable salt thereof. The substituted polycyclic aryl and heteroaryl pyrimidinones of claim 26, wherein: B is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 2- (2R) -bicyclo [2.2.1] heptyl, oxetan-3-yl, azetidin-1-yl, azetidin-2-yl, azetidin-3yl, and bicyclo [3.1.0] hexane-6-yl; A is selected from a single covalent bond, _CH2, NHC (O) CH ₂ CH _2, CH ₂ CH ₂ CH _2; M is selected from the group consisting of N and R * -C; R ¹ is selected from the group consisting of hydrido, hydroxy, amino, amidino, hydroxyamino, aminomethyl, methylamino, cyano, methyl, trifluoromethyl, methoxy, hydroxymethyl, methoxyamino, methylthio, trifluoromethoxy, fluoro and chloro; R ^{2 is} Z ° -Q; Z 0 is selected from the group consisting of a single covalent bond, O, S, NH and CH ₂ ; Q is selected from the group consisting of 5-amino-3-amidocarbonylphenyl, 5-amino-2-fluorophenyl, 3-amino-5-hydroxymethylphenyl, 5-amino-3-methoxycarbonylphenyl, 3-amidinophenyl, 3-amino-2-methylphenyl, 5- amino-2-methylthiophenyl, 3-aminophenyl, benzyl, 3-carboxyphenyl, 3-carboxy-5-aminophenyl, 3-carboxy-5-hydroxyphenyl, 3-carboxymethyl-5-aminophenyl, 3-carboxymethyl-5-hydroxyphenyl, 3-carboxymethylphenyl, 3- chlorophenyl, 2-chlorophenyl, 2,6-dichlorophenyl, 3-cyanophenyl, 3-dimethylaminophenyl, 2-fluorophenyl, 3-fluorophenyl, 2,5-difluorophenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 3-methanesulfonylaminophenyl, 2-methoxyphenyl, 3-methoxyphenyl, 3-methoxyaminophenyl, 3-methoxycarbonylphenyl, 2-methylaminophenyl, 3-methylaminophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, phenyl, 3-trifluoroacetamidophenyl, 3-trifluoromethylphenyl, 2-trifluoromethylphenyl, 5-amino-2-thienyl, 5- amino-3-thienyl, 3-bromo-2-thienyl, 3-pyridyl, 4-pyridyl, 2-thienyl and 3-thienyl; Y 0 is selected from the group consisting of 1Q ^b -4-Q ^with -2-R ¹⁶ -3-R ¹⁷ -5-R ¹⁸ -6-R ¹⁹ benzene, 2-Q ^b -5-Q ^with -6-R ¹⁷ -4-R ¹⁸ -2-R ¹⁹ pyridine, 3-Q ^b 6 -Q'-1'-R 4 -S-R 11 -R ¹⁹ pyridine, 3-Q ^b -5-Q ^with -4-R ¹⁶ -2-R ¹⁹ thiophene and 2-Q ^b -5-Q ^with -3-R ¹⁶ -4-R ¹⁷ thiophene; R ¹⁶ and R ¹⁹ are independently selected from the group consisting of hydrido, amidino, amino, aminomethyl, methoxy, methylamino, hydroxy, hydroxymethyl, fluoro, chloro and cyano; - 189 R ¹⁶ and R ¹⁹ are optionally Q ^b with the proviso that at most one of R ¹⁶ and R ¹⁹ are Q ^b at the same time and that Q ^b is Q ^be ; R ¹⁷ and R ¹⁸ are independently selected from the group consisting of hydrido, fluoro, chloro, hydroxy, hydroxymethyl, amino, carboxy and cyano; Q ^b is selected from the group consisting of Q ^be , wherein Q 1 'is hydrido, and C (NR ²⁵ ) NR ²³ R ²⁴ ; R ²³ , R ²⁴ and R ²⁵ are independently selected from the group consisting of hydrido and methyl; Q ^is CH ₂ ; or a pharmaceutically acceptable salt thereof. Substituted polycyclic aryl and heteroaryl pyrimidinones according to claim 25 of the general formula B where: B is selected from the group consisting of C 3 -C 7 cycloalkyl and C 4 - saturated heterocyclyl wherein each ring carbon atom is optionally substituted with R ³³ , the ring carbon atom other than the carbon atom in the B-bonding site of A is optionally substituted with an oxo group that at most one ring carbon atom is substituted by an oxo group simultaneously, the ring carbon atom and the nitrogen atom adjacent to the carbon at the binding site are optionally substituted with R ⁹ or R ¹³ , a carbon atom or nitrogen atom adjacent to the R ⁹ position and two atoms apart from the point of attachment is optionally substituted with R ¹⁰ , a carbon or nitrogen atom adjacent to the R ¹³ position and two atoms away from the point of attachment is optionally substituted with R ¹² , a carbon or nitrogen atom three atoms from the point of attachment, and adjacent to the R ¹⁰ position is optionally substituted with R ¹¹ , carbon or nitrogen three atoms from the point of attachment and adjacent to the R ¹² position is optionally an optionally substituted R ³³ and a carbon or nitrogen atom four atoms from the point of attachment and adjacent to the R ¹¹ and R ³³ positions is optionally substituted with R ³⁴ ; R ⁹ , R ⁹ and R ¹³ are independently selected from the group consisting of hydrido, hydroxy, amino, amidino, guanidino, lower alkylamino, alkylthio, alkoxy, alkylsulfinyl, alkylsulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, alkyl, halogen, haloalkyl, haloalkoxy, hydroxyalkyl, carboxy , carboxamido and cyano; - R ¹⁰ and R ¹² are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkyl, alkoxy, alkoxyamino, aminoalkyl, hydroxy, amino, lower alkylamino, alkylsulfonamido, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, hydroxyalkyl, halogen, haloalkyl, carboalkoxy, carboxy, carboxyalkyl, carboxyamido and cyano; R ³³ and R ³⁴ are independently selected from the group consisting of hydrido, amidino, guanidino, alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, alkylthio, amidosulfonyl, monoalkyl amidosulfonyl, dialkylamidosulfonyl, alkyl, halogen, haloalkyl, haloalkoxy, hydroxyalkyl, carboalkoxy, carboalkoxy, carboalkoxy , carboxamido and cyano; R ³³ is optionally Q ^b ; A is selected from the group consisting of a single covalent bond and (CH (R ¹⁵ )) _pa (W ⁷ ) 4, wherein rr is an integer from 0 to 1, pa is an integer selected from 0 to 3, and W ⁷ is N (R ^7); R ⁷ is independently selected from the group consisting of hydrido and alkyl; R ¹⁵ is independently selected from the group consisting of hydrido, halo, alkyl and haloalkyl; M is selected from the group consisting of N and R'-C; R ¹ is selected from the group consisting of hydrido, hydroxy, hydroxyamino, amidino, amino, cyano, hydroxyalkyl, alkoxy, alkyl, alkylamino, aminoalkyl, alkylthio, alkoxyamino, haloalkyl, haloalkoxy and halogen; R ^{2 is} Z ° -Q; Z is its covalent bond; Q is selected from the group consisting of aryl and heteroaryl, wherein the carbon atom adjacent to the carbon at the binding site is optionally substituted with R ⁹ , another carbon atom adjacent to the carbon at the binding site is optionally substituted with R ¹³ and a carbon atom adjacent to the R ⁹ position and two atoms from the point of attachment are optionally substituted with R ¹⁰ , a carbon atom adjacent to the R ¹³ position and two atoms from the point of attachment is optionally substituted with R ^12, and any carbon atom adjacent to the R ¹⁰ position and if the R ¹² position is optionally substituted with R 12; R ⁹ , R ¹¹ and R ¹³ are independently selected from the group consisting of hydrido, hydroxy, amino, amidino, guanidino, lower alkylamino, alkylthio, alkoxy, alkylsulfinyl, alkylsulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, alkyl, halogen, haloalkyl, haloalkoxy, hydroxyalkyl, carboxy, carboxamido and cyano; R ¹⁰ and R ¹² are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkyl, alkoxy, alkoxyamino, aminoalkyl, hydroxy, 191 amino, lower alkylamino, alkylsulfonamido, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, hydroxyalkyl, halogen, haloalkyl, carboalkoxy, carboxy, carboxyamido, carboxyalkyl and cyano; Y 0 is a group of formula IV wherein D ⁵ , D ⁶ , J ⁵ and J ⁶ are independently selected from the group consisting of C, N, O, S and a covalent bond, provided that at most one of D ⁵ , D ⁶ , J ⁵ and J ⁶ is a covalent bond, K ² is C, at most one of D ⁵ , D ⁶ , J ³ and J ⁶ is optionally O, at most one of D ⁵ , D ⁶ , J ⁵ and U is optionally S, one of D ⁵ , D ⁶ , J ⁵ and J ⁶ must be a covalent bond when two of D ⁵ , D ⁶ , J ⁵ and J ⁶ are O and S 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 the group consisting of hydrido, amidino, guanidino, carboxy, haloalkylthio, alkoxy, hydroxy, amino, lower alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, halogen, 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 are simultaneously Q ^b , and that Q ^b is Q ^be ; Q ^b is selected from the group consisting of NR ²⁰ R ²¹ , Q ¹ *, wherein Q ¹ * is hydrido, and C (NR ²⁵ ) NR ²³ R ²⁴ ; R ²⁰ , R ²¹ , R ²³ , R ²⁴ and R ²⁶ are independently selected from the group consisting of hydrido and alkyl; Q ^s is CH 2; or a pharmaceutically acceptable salt thereof. The substituted polycyclic aryl and heteroaryl pyrimidinones of claim 28, wherein: B is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 2- (2R) -bicyclo [2.2.1] heptyl, oxetan-3-yl, azetidin-1-yl, azetidin-2-yl, azetidine- 3yl and bicyclo [3.1.0] hexan-6-yl, wherein each ring carbon atom is optionally substituted with R ^{29 * * 33} , a ring carbon atom other than the carbon atom in the B-bonding site of A is optionally substituted with an oxo group, and that is, at most one carbon atom in the ring is substituted Simultaneously, the ring carbon atom and the nitrogen atom adjacent to the carbon at the binding site are optionally substituted by R ⁹ or R ¹³ , the carbon atom or nitrogen atom adjacent to the R ⁹ position and two atoms away from the point of attachment is optionally substituted by R ¹⁰ the carbon atom or the nitrogen atom adjacent to the R ¹³ position and two atoms apart from the point of attachment is optionally substituted with R ¹² ; R ⁹ , R ¹¹ and R ¹³ are independently selected from the group consisting of hydrido, methyl, ethyl, methoxy, ethoxy, hydroxy, amino, N-methylamino, Ν, Ν-dimethylamino, methylthio, trifluoromethyl, pentafluoroethyl, 2,2,2- trifluoroethyl, fluoro, chloro, bromo, amidosulfonyl, N-methylamidosulfonyl, Ν, Ν-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, amidocarbonyl, N-methylamidocarbonyl, carboxy and cyano; R ¹⁰ and R ¹² are independently selected from the group consisting of hydrido, amidino, amidocarbonyl, N-methylamidocarbonyl, guanidino, methyl, ethyl, methoxy, ethoxy, hydroxy, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, carboxy, carboxymethyl, amino, acetamido trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, trifluoroacetamido, aminomethyl, N-methylamino, dimethylamino, amidosulfonyl, N-methylamidosulfonyl, Ν, Ν-dimethylamidosulfonyl, methoxycarbonyl, fluoro, chloro, bromo and cyano; R ³³ is independently selected from the group consisting of hydrido, amidino, guanidino, methyl, ethyl, methoxy, ethoxy, hydroxy, amino, N-methylamino, dimethylamino, methylthio, ethylthio, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, fluoro, chloro, bromo, amidosulfonyl, Nmetylamidosulfonyl, hydroxymethyl, amidocarbonyl, cyano, and Q ^b; A is selected from the group consisting of a single covalent bond, NH, N (CH ₃ ), CH 2, CH ₃ CH, CH 2 CH 2 and CH 2 CH 2 CH 2; M is selected from the group consisting of N and R ¹ -C; R ¹ is selected from the group consisting of hydrido, hydroxy, amino, amidino, hydroxyamino, aminomethyl, methylamino, cyano, methyl, trifluoromethyl, methoxy, hydroxymethyl, methoxyamino, methylthio, trifluoromethoxy, fluoro and chloro; R ² is selected from the group consisting of phenyl, 2-thienyl, 2-furyl, 2-pyrrolyl, 2-imidazolyl, 2-thiazolyl, 3-isoxazolyl, 2-pyridyl and 3-pyridyl, wherein the carbon atom adjacent to the carbon at the binding site is optionally substituted with R ⁹ , another carbon atom adjacent to the carbon at the binding site is optionally substituted with R ¹³ and a carbon atom adjacent to the R ⁹ position and two atoms away from the point of attachment is optionally substituted with R ¹⁰ , a carbon atom adjacent to R ¹³ position and two atoms away from the point of attachment is optionally substituted with R ¹² and any carbon atom adjacent to the R ¹⁰ position and where the R ¹² position is optionally substituted with R ¹¹ ; Y 0 is selected from the group consisting of - 193l-Q ^b -4-Q ^with -2-R ¹⁶ -3-R ¹⁷ -5-R ¹⁸ -6-R ¹⁹ benzene, 2-Q ^b -5-Q ^with -6-R ¹⁷ -4-R ¹⁸ -2-R ¹⁹ pyridine, 2-Q ^b 5-Q ^with -3-R ¹⁶ -4-R ¹⁷ thiophene, 3-Q ^b -6-Q ^with -2-R ¹⁶ -5-R ¹⁸ -4- R ¹⁹ pyridine, 3-Q ^b -5-Q ^with -4-R ¹⁶ -2-R ¹⁹ thiophene, 3Q ^b -5-Q ^with -4-R ¹⁶ -2-R ¹⁹ furan, 2-Q ^b -5 -Q ^with -3-R ¹⁶ -4-R ¹⁷ furan, 3-Q ^b -5-Q ^with -4-R ¹⁶ -2-R ¹⁹ pyrrole, 2-Q ^b -5Q ^with -3-R ¹⁶ -4 -R ¹⁷ pyrrole, 4-Q ^b -2-Q ^with -5-R ¹⁹ thiazole and 2-Q ^b -5-Q ^with -4-R ¹⁷ thiazole. R ¹⁶ , R ¹⁷ , R ¹⁸ and R ¹⁹ are independently selected from the group consisting of hydrido, methyl, ethyl, amidino, guanidino, methoxy, hydroxy, amino, aminomethyl, 1-aminoethyl, 2-aminoethyl, N-methylamino, dimethylamino, methylthio, ethylthio trifluoromethylthio, methylsulfinyl, methylsulfonyl, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, trifluoromethoxy, fluoro, chloro, amidosulfonyl, N-methylamidosulfonyl, hydroxymethyl, carboxyl and cyano; Q ^b is selected from the group consisting of NR ²⁰ R ²¹ and C (NR ²⁵ ) NR ²³ R ²⁴ , provided that Q ^b is directly attached to a carbon atom; R ²⁰ , R ²¹ , R ²³ , R ²⁴ and R ²⁵ are independently selected from the group consisting of hydrido, methyl and ethyl; Q ^is CH ₂ ; or a pharmaceutically acceptable salt thereof. The substituted polycyclic aryl and heteroaryl pyrimidinones of claim 29, wherein. B is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2- (2R) -bicyclo [2.2. 1 Heptyl, oxetan-3-yl, azetidin-1-yl, azetidin-2-yl and azetidin-3-yl; A is selected from a single covalent bond, _CH2, NHC (O), _{CH2 CH2,} and _{CH2 CH2 CH2;} M is selected from the group consisting of N and R * -C; R ¹ is selected from the group consisting of hydrido, hydroxy, amino, methyl, trifluoromethyl, fluoro, and chloro; R ² is selected from the group consisting of 3-aminophenyl, 2,6-dichlorophenyl, 2-hydroxyphenyl, 5-amino-2-thienyl and 3-thienyl; Y 0 is selected from the group consisting of 1Q ^b -4-Q ^with -2-R ¹⁶ -3-R ¹⁷ -5-R ¹⁸ -6-R ¹⁹ benzene, 3-Q ^b 5-Q ^with -4-R ¹⁶ - 2-R ¹⁹ thiophene and 2-Q ^b -5-Q ^with -3-R ¹⁶ -4-R ¹⁷ thiophene; R ¹⁶ and R ¹⁹ are independently selected from the group consisting of hydrido, amidino, amino, aminomethyl, methoxy, methylamino, hydroxy, 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 that Q ^b is Q ⁶ '; R ¹⁷ and R ¹⁸ are independently selected from the group consisting of hydrido, fluoro, chloro, hydroxy, hydroxymethyl, amino, carboxy and cyano; 194 Q ^b is selected from the group consisting of Q ^be , wherein Q ^bc is hydrido, and C (NR ²⁵ ) NR ²³ R ²⁴ ; R ²³ , R ²⁴ and R ²⁵ are independently selected from the group consisting of hydrido and methyl; Q ^is CH ₂ ; or a pharmaceutically acceptable salt thereof. The substituted polycyclic aryl and heteroaryl pyrimidinones of claim 30, wherein: B is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2- (2R) -bicyclo [2.2. 1 Heptyl, oxetan-3-yl, azetidin-1-yl, azetidin-2-yl and azetidin-3-yl; A is selected from the group consisting of a single covalent bond, CH ₂ , CH ₂ CH ₂ and CH ₂ CH ₂ CH ₂ ; M is selected from the group consisting of N and R'-C; R ¹ is selected from the group consisting of hydrido, fluoro and chloro; R ² is selected from the group consisting of 3-aminophenyl, 2,6-dichlorophenyl, 2-hydroxyphenyl, phenyl, 5-amino-2-thienyl and 3-thienyl; Y 0 is selected from the group consisting of 5-amidino-2-thienylmethyl, 4-amidinobenzyl, 2-fluoro-4-amidinobenzyl and 3-fluoro-4-amidinobenzyl; or a pharmaceutically acceptable salt thereof. Substituted polycyclic aryl and heteroaryl pyrimidinones according to claim 25, selected from the group: B where: ^R2 is 3-aminophenyl, B is cyclopropyl, A is single bond, Y is 4-amidinobenzyl, and M is CH; ^R2 is 3-aminophenyl, B is cyclobutyl, A is single bond, Y is 4-amidino-2-fluorobenzyl, and M is CH; ^R2 is 3-aminophenyl, B is cyclobutyl, A is single bond, Y is 4-amidinobenzyl, and M is CH: - 195R ² is 3-aminophenyl, B is cyclopropyl, A is single bond, Y is 4-amidino-2-fluorobenzyl, and M is CH; ^R2 is 3-aminophenyl, B is cyclobutyl, A is single bond, Y is 4-amidinobenzyl, and M is CH; ^R2 is 3-aminophenyl, B is cyclobutyl, A is single bond, Y is 4-amidino-3-fluorobenzyl, and M is CH; ^R2 is 3-aminophenyl, B is cyclopentyl, A is single bond, Y is 4-amidinobenzyl, and M is CH; ^R2 is 5-amino-2-thienyl, B is cyclobutyl, A is single bond, Y is 4-amidinobenzyl, and M is CH; ^R2 is 3-aminophenyl, B is cyclopropyl, A is _CH2, Y is 4-amidinobenzyl, and M is CH; ^R2 is 3-aminophenyl, B is 2- (2R) bicyclo [2.2 Heptyl, A is a single bond, Y0 is 4amidinobenzyl, and M is CH; ^R2 is 3-aminophenyl, B is cyclopentyl, A is single bond, Y is 4-amidino-2-fluorobenzyl, and M is CH; ^R2 is 3-aminophenyl, B is cyclohexyl, A is CH ₂ CH _2, Y is 4-amidinobenzyl, and M is CH; R ² is 2-hydroxyphenyl, B is cyclobutyl, A is single bond, Y is 4-amidinobenzyl, and M is CH; ^R2 is phenyl, B is cyclobutyl, A is single bond, Y is 4-amidinobenzyl, and M is CH; R ² is 3-thienyl, B is cyclobutyl, A is single bond, Y is 4-amidinobenzyl, and M is CH; R ² is 2,6-dichlorophenyl, B is cyclobutyl, A is single bond, Y is 4-amidinobenzyl, and M is CH; ^R2 is 3-aminophenyl, B is cyclopropyl, A is single bond, Y is 4-amidinobenzyl, and M is N; ^R2 is 3-aminophenyl, B is cyclobutyl, A is single bond, Y is 4-amidino-2-fluorobenzyl, and M is N; ^R2 is 3-aminophenyl, B is cyclobutyl, A is single bond, Y is 4-amidinobenzyl, and M is N; ^R2 is 3-aminophenyl, B is cyclopropyl, A is single bond, Y is 4-amidino-2-fluorobenzyl, and M is N; ^R2 is 3-aminophenyl, B is cyclobutyl, A is single bond, Y is 4-amidinobenzyl, and M is N; ^R2 is 3-aminophenyl, B is cyclobutyl, A is single bond, Y is 4-amidino-3-fluorobenzyl, and M is N; ^R2 is 3-aminophenyl, B is cyclopentyl, A is single bond, Y is 4-amidinobenzyl, and M is N; 196 R ² is 5-amino-2-thienyl, B is cyclobutyl, A is single bond, Y 0 is 4-amidinobenzyl and M is N; ^R2 is 3-aminophenyl, B is cyclopropyl, A is _CH2, Y is 4-amidinobenzyl, and M is N; ^R2 is 3-aminophenyl, B is 2- (2R) bicyclo [2.2.1] heptyl, A is single bond, Y ⁰ is 4-amidinobenzyl, and M is N; ^R2 is 3-aminophenyl, B is cyclopentyl, A is single bond, Y is 4-amidino-2-fluorobenzyl, and M is N; ^R2 is 3-aminophenyl, B is cyclohexyl, A is CH ₂ CH _2, Y ^<) is 4amidinobenzyl, and M is N; R ² is 2-hydroxyphenyl, B is cyclobutyl, A is single bond, Y is 4-amidinobenzyl, and M is N; ^R2 is phenyl, B is cyclobutyl, A is single bond, Y is 4-amidinobenzyl, and M is N; R ² is 3-thienyl, B is cyclobutyl, A is single bond, Y is 4-amidinobenzyi and M is N; R ² is 2,6-dichlorophenyl, B is cyclobutyl, A is single bond, Y is 4-amidinobenzyl, and M is N; ^R2 is 3-aminophenyl, B is cyclopropyl, A is single bond, Y is 4-amidinobenzyl, and M is CF; ^R2 is 3-aminophenyl, B is cyclobutyl, A is single bond, Y is 4-amidino-2-fluorobenzyl, and MjeCF; ^R2 is 3-aminophenyl, B is cyclobutyl, A is single bond, Y is 4-amidinobenzyl, and M is CF; ^R2 is 3-aminophenyl, B is cyclopropyl, A is single bond, Y is 4-amidino-2-fluorobenzyl, and M is CF; ^R2 is 3-aminophenyl, B is cyclobutyl, A is single bond, Y is 4-amidinobenzyl, and M is CF; ^R2 is 3-aminophenyl, B is cyclobutyl, A is single bond, Y is 4-amidino-3-fluorobenzyl, and MjeCF; ^R2 is 3-aminophenyl, B is cyclopentyl, A is single bond, Y is 4-amidinobenzyl, and M is CF; ^R2 is 5-amino-2-thienyl, B is cyclobutyl, A is single bond, Y is 4-amidinobenzyl, and M is CF; ^R2 is 3-aminophenyl, B is cyclopropyl, A is _CH2, Y is 4-amidinobenzyl, and M is CF; ^R2 is 3-aminophenyl, B is 2- (2R) -bicyclo [2.2 Iheptyl, A is a single bond, Y0 is 4amidinobenzyl and M is CF; 197 R ² is 3-aminophenyl, B is cyclopentyl, A is single bond, Y 0 is 4-amidino-2-fluorobenzyl and M is CF; ^R2 is 3-aminophenyl, B is cyclohexyl, A is CH2CH2, Y is 4-amidinobenzyl, and M is CF; R ² is 2-hydroxyphenyl, B is cyclobutyl, A is single bond, Y is 4-amidinobenzyl, and M is CF; ^R2 is phenyl, B is cyclobutyl, A is single bond, Y is 4-amidinobenzyl, and M is CF; R ² is 3-thienyl, B is cyclobutyl, A is single bond, Υ ^ΰ is 4-amidinobenzyl, and M is CF; R ² is 2,6-dichlorophenyl, B is cyclobutyl, A is single bond, Y is 4-amidinobenzyl, and M is CF; or a pharmaceutically acceptable salt thereof. 33. Substituted polycyclic aryl and heteroaryl pyrimidinones of general formula R ³² , R ³³ , R ³⁴ , R ^3? and R ³⁶ are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkylenedioxy, haloalkylthio, alkanoyloxy, alkoxy, hydroxy, amino, alkoxyamino, haloalkanoyl, nitro, lower alkylamino, alkylthio, aryl, aralkyl. cycloalkyl, cycloalkylalkyl, alkylsulfonamido, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl, alkyl, alkenyl, halo, haloalkyl, haloalkenyl, haloalkoxy, hydroxyalkyl, alkylamino, carboalkoxy, carboxy, carboxamido, cyano, and Q ^b; - 198 B is optionally selected from the group consisting of hydrido, trialkylsilyl, C 2 -C 8 alkyl, C 3 -C 8 alkylenyl, C 3 -C 8 alkenyl, C 3 -C 8 alkynyl and C 2 -C 8 haloalkyl, wherein each member of group B may be optionally substituted on any carbon atom up to up to 6 atoms including from the B to A binding site with one or more substituents from R ³² , R ³³ , R ³⁴ , R ³⁵ and R ³⁶ ; B is optionally selected from the group consisting of C 3 -C 12 cycloalkyl and C 4 -heterocyclyl wherein each ring carbon atom is optionally substituted with R ³³ , a ring carbon atom other than the carbon atom in the B-bonding site of A is optionally substituted with an oxo group that at most one carbon atom in the ring is substituted by an oxo group simultaneously, the carbon atom and the nitrogen atom adjacent to the carbon at the B-bonding point on A are optionally substituted with R ⁹ or R ¹³ , a carbon atom or a nitrogen atom adjacent to the R ⁹ position; atoms from the point of attachment are optionally substituted with R ¹⁰ , a carbon or nitrogen atom adjacent to the R ¹³ position and two atoms from the point of attachment optionally substituted with R ¹² , a carbon or nitrogen atom three atoms from the point of attachment, and adjacent to the R ¹⁰ position is optionally substituted with R ¹¹ , a carbon atom or a nitrogen atom three atoms from the point of attachment and adjacent to the R ¹² position is optionally e substituted with R ³³ and a carbon or nitrogen atom four atoms from the point of attachment and adjacent to the R ¹¹ and R ³³ positions is optionally substituted with R ³⁴ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² and R ¹³ are independently selected from the group consisting of hydrido, acetamido, haloacetamido, alkoxyamino, alkanoyl, haloalkanoyl, amidino, guanidino, alkylenedioxy, haloalkylthio, alkoxy, hydroxy, amino, lower alkylamino, alkylthio , alkylsulfinyl, alkylsulfonamido, alkylsulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, alkyl, halogen, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, carboalkoxy, carboxy, carboxyalkyl, carboxamido and cyano; A is selected from a single covalent bond, (CH (R ¹ 5) ^ - (W ^7): wherein r is an integer from 0 through 1, pa is an integer selected from 0 through 3, and W ⁷ is selected from the group consisting of O, S, C (O), (R ⁷ ) NC (O), (R ⁷ ) NC (S) and N (R ⁷ ); R ⁷ is independently selected from the group consisting of hydrido, hydroxy and alkyl; R ¹⁵ is independently selected from the group consisting of hydrido, hydroxy, halo, alkyl and haloalkyl; M is selected from the group consisting of N and R'-C; R ¹ is selected from the group consisting of hydrido, hydroxy, hydroxyamino, amidino, amino, cyano, hydroxyalkyl, alkoxy, alkyl, alkylamino, aminoalkyl, alkylthio, alkoxyamino, haloalkyl, haloalkoxy and halogen; R ^{2 is} Z ° -Q; - 199 Z ° is selected from the group consisting of a single covalent bond a (CR ⁴¹ R ⁴² ) q, where q is an integer from 1 to 2, (CH (R ⁴¹ )) g -W ° - (CH (R ⁴² )) ) P, where the gap is an integer from 0 to 3 and W ° is selected from the group consisting of O, S, N (R ⁴¹ ) and (CH (R ⁴¹ )) eW ²² - (CH (R ⁴² )) |, wherein eah is integers independently selected from 0 to 1 and W is selected from the group consisting of 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, 2,3-tetrahydrofuranosyl, 2,4-tetrahydrofuranosyl, 2,5-tetrahydrofuranosyl and 3,4-tetrahydrofuranosyl, provided that Z 0 is directly bound to the pyrimidinone circle; R ⁴¹ and R ⁴² are independently selected from the group consisting of hydrido, hydroxy and amino; Q is selected from the group consisting of hydrido with the proviso that Z 0 is not a single covalent bond, aryl and heteroaryl wherein the carbon atom adjacent to the carbon at the binding site is optionally substituted with R ⁹ , the other carbon atom adjacent to the carbon at the binding site is optionally substituted R ¹³ and the carbon atom adjacent to the R ⁹ position and two atoms away from the point of attachment is optionally substituted with R ¹⁰ , the carbon atom adjacent to the R ¹³ position and two atoms away from the point of attachment is optionally substituted with R ¹² and any carbon atom adjacent to R ¹⁰ the position when the R ¹² position is optionally substituted with R ¹¹ ; K is CHR ⁴ 'wherein R ^4a is selected from the group consisting of hydrido, hydroxyalkyl, alkyl, alkoxyalkyl, alkylthioalkyl and haloalkyl; E 0 is selected from the group consisting of a single covalent bond, C (O) N (H), (H) NC (O), (R ⁷ ) NS (O) _2, and S (O) ₂ N (R ⁷ ); Y ^{AT is} Q ^b -Q ^s ; Q ^s is (CR ³⁷ R ³⁸ ) b, wherein b is an integer selected from 1 to 4, R ³⁷ is selected from the group consisting of hydrido, alkyl, haloalkyl, and R is selected from the group consisting of hydrido, alkyl, haloalkyl, aroyl, and heteroaroyl provided that it contains at least one substituent that is aroyl or heteroaroyl, that at most one aroyl or heteroaroyl binds to (CR ³⁷ R ³⁸ ) b simultaneously, and that said aroyl or heteroaroyl is optionally substituted on one to three carbon atoms in ring substituents selected from the group consisting of R ¹⁶ , R ¹⁷ , R ¹⁸ and R ¹⁹ , with the proviso that the aroyl or heteroaroyl is bound to CR ³⁷ R ³⁸ that is directly bound to E, that at most one alkyl or haloalkyl binds to CR R simultaneously, and that alkyl or haloalkyl binds to a carbon other than aroyl or heteroaroyl-binding carbon; -200R ^16, R ^17, R ¹⁸ and R ¹⁹ are independently selected from hydrido, amidino, guanidino, carboxy, haloalkylthio, alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl , halogen, 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 are simultaneously Q ^b , and that Q ^{b is} Q ^be ; Q ^b is selected from the group consisting of NR ²⁰ R ²¹ , and Q ¹ *, wherein Q ^be is hydrido, and (NR ²⁶ ) C (NR ²⁵ ) N (R ²³ ) (R ²⁴ ) and C (NR ²⁵ ) NR ²³ R ²⁴ with the proviso that at most one of R ²⁰ and R ^{21 is a} hydroxy, amino, alkylamino or dialkylamino substituent simultaneously, and that at most one of R ²³ and R ²⁴ is a hydroxy, amino, alkylamino or dialkylamino substituent simultaneously; R ²⁰ , R ²¹ , R ²³ , R ²⁴ , R ²⁵ and R ²⁶ are independently selected from the group consisting of hydrido, alkyl, hydroxy, amino, alkylamino and dialkylamino; or a pharmaceutically acceptable salt thereof. 34. Substituted polycyclic aryl and heteroaryl having the general formula: pyrimidinones according to claim 33 R ³² . R ³³ , R ³⁴ , R ³⁵ and R ³⁶ are independently selected from the group consisting of hydrido, amidino, guanidino, methyl, ethyl, methoxy, ethoxy, hydroxy, amino, N-methylamino, dimethylamino, methylthio, ethylthio, trifluoromethyl, pentafluoroethyl, 2 , 2,2-trifluoroethyl, fluoro, chloro, bromo, amidosulfonyl, Nmethylamidosulfonyl, hydroxymethyl, amidocarbonyl, carboxy, cyano, and Q ^b; -201 B is selected from the group consisting of hydrido, ethyl, 2-propenyl, 2-propynyl, propyl, isopropyl, butyl, 2-butenyl, 2-butynyl, tert-butyl, tert-butyl, isobutyl, 2-methylpropenyl, 1pentyl , 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-hexinyl, 3-hexinyl, 4-hexinyl, 2-hexyl, 1-methyl-2-pentenyl, 1-methyl-3-pentenyl, 1-methyl-2-pentinyl, 1-methyl-3-pentynyl, 3-hexyl, 1-ethyl-2-butenyl, 1-heptyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 2-heptinyl, 3-heptinyl, 4-heptinyl, 5-heptinyl, 2-heptyl, 1-methyl- 2-hexenyl, 1-methyl-3-hexenyl, 1-methyl-4-hexenyl, 1-methyl-2-hexinyl, 1-methyl-3-hexinyl, 1-methyl-4-hexinyl, 3-heptyl, 1-ethyl-2- pentenyl, 1-ethyl-3-pentenyl, 1-ethyl-2-pentynyl, 1-ethyl-3pentinyl, 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 substituted on any carbon up to 5 atoms including from the B to A binding site by one or more substituents from the group R ³² , R ³³ , R ³⁴ , R ³⁵ and R ³⁶ ; B is optionally selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 2- (2R) -bicyclo [2.2.1] heptyl, oxetan-3-yl, azetidin-1-yl, azetidin-2yl, azetidin-3 -yl and bicyclo [3.1.0] hexan-6-yl, wherein each ring carbon atom is optionally substituted with R ³³ , the ring carbon atom other than the carbon atom at the B-bonding point A is optionally substituted with an oxo group, that at most one ring carbon atom is substituted by an oxo group simultaneously, the ring carbon atom and the nitrogen atom adjacent to the carbon at the binding site are optionally substituted by R ⁹ or R ¹³ , a carbon atom or nitrogen adjacent to the R ⁹ position and two atoms apart the point of attachment is optionally substituted with R ¹⁰ , a carbon atom or a nitrogen atom adjacent to the R ¹³ position and two atoms away from the point of attachment is optionally substituted with R ¹² ; R ⁹ , R ¹¹ and R ¹³ are independently selected from the group consisting of hydrido, methyl, ethyl, methoxy, ethoxy, hydroxy, amino, N-methylamino, Ν, Ν-dimethylamino, methylthio, trifluoromethyl, pentafluoroethyl, 2,2,2- trifluoroethyl, fluoro, chloro, bromo, amidosulfonyl, N-methylamidosulfonyl, Ν, Ν-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, amidocarbonyl, N-methylamidocarbonyl, carboxy and cyano; R ¹⁰ and R ¹² are independently selected from the group consisting of hydrido, amidino, amidocarbonyl, N-methylamidocarbonyl, guanidino, methyl, ethyl, methoxy, ethoxy, hydroxy, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, carboxy, carboxymethyl, amino, acetamido trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, trifluoroacetamido, aminomethyl, N-methylamino, dimethylamino, amidosulfonyl, N-methylamidosulfonyl, Ν, Ν-dimethylamidosulfonyl, methoxycarbonyl, fluoro, chloro, bromo and cyano; -202 A is selected from the group consisting of a single covalent bond, NH, N (CH ₃ ), CH ₂ , CH ₃ CH, CH ₂ CH _2, and CH ₂ CH ₂ CH ₂ ; M is selected from the group consisting of N and R ¹ -C; R ¹ is independently selected from the group consisting of hydrido, hydroxy, amino, amidino, hydroxyamino, aminomethyl, 1-aminoethyl, methylamino, dimethylamino, cyano, methyl, ethyl, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, methoxy, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, methoxyamino, methylthio, ethylthio, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro and bromo; R ² is selected from the group consisting of phenyl, 2-thienyl, 2-furyl, 2-pyrrolyl, 2-imidazolyl, 2-thiazolyl, 3-isoxazolyl, 2-pyridyl and 3-pyridyl, wherein the carbon atom adjacent to the carbon at the binding site is optionally substituted with R ⁹ , another carbon atom adjacent to the carbon at the binding site is optionally substituted with R ^13, and a carbon atom adjacent to the R ⁹ position and two atoms away from the point of attachment is optionally substituted with R ¹⁰ , a carbon atom adjacent to R ¹³ position and two the atoms from the point of attachment are optionally substituted with R ¹² and any carbon atom adjacent to the R ¹⁰ position and to the R ¹² position being optionally substituted with R ¹¹ ; Y ^AT is Q ^b -Q ^s ; Q ^s is selected from the group consisting of: C [R ³⁷ (benzoyl)] (CR ³⁷ R ³⁸ ) _b ], C [R ³⁷ (2-pyridylcarbonyl)] (CR ³⁷ R ³⁸ ) b], C ^[R37 (3-pyridylcarbonyl])] (CR ³⁷ R ³⁸⁾ _b], C [R ³⁷ (4-pyridylcarbonyl)] (CR ³⁷ R ³⁸ ) _b ], C [R ³⁷ (2-thienylcarbonyl)] (CR ³⁷ R ³⁸ ) b], C [R ³⁷ (3-thienylcarbonyl)] (CR ³⁷ R ³⁸ ) b], C [R ³⁷ (2-thiazolylcarbonyl)] (CR ³⁷ R ³⁸ ) _b ], C ^[R37 (4-thiazolylcarbonyl])] (CR ³⁷ R ³⁸⁾ _b], and C [R ³⁷ (5-thiazolylcarbonyl])] (CR ³⁷ R ³⁸ ) b], wherein b is an integer from 1 to 3, R ³⁷ and R ³⁸ are independently selected from the group consisting of hydrido, alkyl and haloalkyl, that said aroyl or heteroaroyl is optionally substituted on one to three ring carbon atoms with substituents selected from the group consisting of R ¹⁶ , R ¹⁷ , R ¹⁸ and R ¹⁹ , provided that R ¹⁷ and R ¹⁸ are optionally substituted on carbon selected from other than the meta and para carbon relative to the carbonyl of the benzoyl substituent and the heteroaroyl substituent, and that benzoyl and said heteroaroyl bind to the carbon directly bonded to the nitrogen of the amide of the 1-203- (amidocarbonylmethylene) group and provided that at most one alkyl or haloalkyl binds to CR ³⁷ R ³⁸ simultaneously; R ¹⁶ , R ¹⁷ , R ¹⁸ and R ¹⁹ are independently selected from the group consisting of hydrido, methyl, ethyl, amidino, guanidino, methoxy, hydroxy, amino, aminomethyl, 1-aminoethyl, 2-aminoethyl, N-methylamino, dimethylamino, methylthio, ethylthio trifluoromethylthio, methylsulfinyl, methylsulfonyl, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, trifluoromethoxy, fluoro, chloro, amidosulfonyl, N-methylamidosulfonyl, hydroxymethyl, carboxy and cyano; Q ^b is selected from the group consisting of NR ²⁰ R ²¹ and C (NR ²⁵ ) NR ²³ R ²⁴ , provided that Q ^b is directly attached to a carbon atom; R ²⁰ , R ²¹ , R ³ , R ²⁴ and R ²⁵ are independently selected from the group consisting of hydrido, methyl and ethyl; or a pharmaceutically acceptable salt thereof. Substituted polycyclic aryl and heteroaryl pyrimidinones according to claim 34, wherein: B is selected from the group consisting of 2-aminophenyl, 3-aminophenyl, 3-amidinophenyl, 4amidinophenyl, 3-carboxyphenyl, 3-carboxy-5-hydroxyphenyl, 3-chlorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 2-fluorophenyl, 3- fluorophenyl, 3,4-difluorophenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 3-methoxyaminophenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-methylphenyl, 4-methylphenyl, phenyl and 3-trifluoromethylphenyl; B is selected from the group consisting of hydrido, ethyl, 2-propenyl, 2-propynyl, propyl, isopropyl, butyl, 2-butyl, (R) 2-butyl, (S) 2-butyl, tert-butyl, isobutyl, 1-pentyl, 3-pentyl, 2-methylbutyl, 2,2,2-trifluoroethyl, 6-amidocarbonylhexyl, 4-methyl-2-pentyl, 3-hydroxypropyl, 3-methoxy-2-propyl, 2-methoxyethyl, 2-methyl-2- butyl, 3-methyl-2-butyl, 2-dimethylaminopropyl, 2-cyanoethyl, 6-hydroxyhexyl, 2-hydroxyethyl, 2-amidinoethyl, 2-guanidinoethyl, 3guanidinopropyl, 4-guanidinobutyl, 3-hydroxypropyl, 4-hydroxybutyl, 6-cyanohexyl, 2-dimethylaminoethyl, 3-methylbutyl, 2-methylbutyl, (S) -2-methylbutyl, 3-aminopropyl, 2-hexyl and 4-aminobutyl; B is optionally selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2- (2R) -bicyclo [2.2.1] heptyl, oxetan-3-yl, azetidin-1-yl, azetidin-2-yl and azetidin-3 yl; A is selected from the group consisting of a single covalent bond, CH ₂ , CH ₃ CH, CH ₂ CH ₂ and CH ₂ CH ₂ CH ₂ ; M is selected from the group consisting of N and R ¹ -C; -204R ¹ is independently selected from hydrido, hydroxy, amino, amidino, hydroxyamino, aminomethyl, methylamino, cyano, methyl, trifluoromethyl, methoxy, hydroxymethyl, methoxy, methylthio, trifluoromethoxy, fluoro and chloro; R ² is selected from the group consisting of 5-amino-3-amidocarbonylphenyl, 5-amino-2-fluorophenyl, 3-amino-5-hydroxymethylphenyl, 5-amino-3-methoxycarbonylphenyl, 3-amidinophenyl, 3-amino-2-methylphenyl, -amino-2-methylthiophenyl, 3-aminophenyl, benzyl, 3-carboxyphenyl, 3-carboxy-5-aminophenyl, 3-carboxy-5-hydroxyphenyl, 3-carboxymethyl-5-aminophenyl, 3-carboxymethyl-5-hydroxyphenyl, 3-carboxymethylphenyl, 3 -chlorophenyl, 2-chlorophenyl, 2,6-dichlorophenyl, 3-cyanophenyl, 3-dimethylaminophenyl, 2-fluorophenyl, 3-fluorophenyl, 2,5-difluorophenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 3-methanesulfonylaminophenyl, 2-methoxyphenyl, 3-methoxyphenyl, 3-methoxyaminophenyl, 3-methoxycarbonylphenyl, 2-methylaminophenyl, 3-methylaminophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, phenyl, 3-trifluoroacetamidophenyl, 3-trifluoromethylphenyl, 2-trifluoromethylphenyl, 5-amino-2-thienyl, 5- amino-3-thienyl, 3-bromo-2-thienyl, 3-pyridyl, 4-pyridyl, 2-thienyl and 3-thienyl; Y ^AT is Q ^b -Q ^s ; Q ^s is selected from the group consisting of: [CH (benzoyl)] (CH ₂ ) _b ], [CH (2-pyridylcarbonyl)] (CH ₂ ) _b ], [CH (3-pyridylcarbonyl)] (CH ₂ ) _b ], [CH (4-pyridylcarbonyl)] ] (CH ₂ ) b], [CH (2-thienylcarbonyl)] (CH ₂ ) b], [CH (3-thienylcarbonyl)] (CH ₂ ) b], [CH (2-thiazolylcarbonyl)] (CH ₂ ) b], [CH (4-thiazolylcarbonyl)] (CH ₂ ) b] and [CH (5-thiazolylcarbonyl)] (CH ₂ ) b], wherein b is an integer from 1 to 3, provided that the aroyl and said heteroaroyl is optionally substituted on one to three ring carbon atoms with substituents selected from the group consisting of R ¹⁶ , R ¹⁷ , R ¹⁸ and R ¹⁹ , with the proviso that R ¹⁷ and R ¹⁸ are optionally substituted on carbon other than meta and para carbon relative to the carbonyl of the benzoyl substituent and the heteroaroyl substituent, and that benzoyl and said heteroaroyl bind to the carbon directly bonded to the nitrogen of the amide of the 1-amidocarbonylmethylene group; R ¹⁶ and R ¹⁹ are independently selected from the group consisting of hydrido, fluoro, chloro, hydroxy, hydroxymethyl, amino, carboxy and cyano; 205 R ¹⁷ and R ¹⁸ are independently selected from the group consisting of hydrido, fluoro, chloro, hydroxy, hydroxymethyl, amino, carboxy and cyano; Q ^{b is} C (NR ²⁵ ) NR ²³ R ²⁴ ; R ²³ , R ²⁴ and R ²⁵ are independently selected from the group consisting of hydrido and methyl; or a pharmaceutically acceptable salt thereof. The substituted polycyclic aryl and heteroaryl pyrimidinones of claim 35, wherein: B is selected from the group consisting of 3-aminophenyl, 3-amidinophenyl, 4-amidinophenyl, 3-chlorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 2-fluorophenyl, 4-methylphenyl and phenyl; B is optionally selected from the group consisting of hydrido, ethyl, 2-propenyl, 2-propynyl, propyl, isopropyl, butyl, 2-butyl, (R) 2-butyl, (S) 2-butyl, tert-butyl, isobutyl, 1-pentyl, 3-pentyl, 2-methylbutyl, 2,2,2-trifluoroethyl, 6-amidocarbonylhexyl, 4-methyl-2-pentyl, 3-hydroxypropyl, 3-methoxy-2-propyl, 2-methoxyethyl, 2-methyl-2- butyl, 3-methyl-2-butyl, 2-dimethylaminopropyl, 2-cyanoethyl, 6-hydroxyhexyl, 2-hydroxyethyl, 2-amidinoethyl, 2guanidinoethyl, 3-guanidinopropyl, 4-guanidinobutyl, 3-hydroxypropyl, 4-hydroxybutyl, 6cyanohexyl, 2- dimethylaminoethyl, 3-methylbutyl, 2-methylbutyl, (S) -2-methylbutyl, 3-aminopropyl, 2-hexyl and 4-aminobutyl; B is optionally selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2- (2R) -bicyclo [2.2. 1 Heptyl, oxethan-3-yl, azetidin-1-yl, azetidin-2-yl and azetidin-3-yl; A is selected from the group consisting of a single covalent bond, CH 2, CH ₂ CH ₂ and CH ₂ CH ₂ CH ₂ ; M is selected from the group consisting of N and R'-C; R ¹ is independently selected from the group consisting of hydrido, hydroxy, amino, methyl, trifluoromethyl, fluoro, and chloro; R ² is selected from the group consisting of 3-aminophenyl, benzyl, 2,6-dichlorophenyl, 5-amino-2-thienyl, 5-amino-2-fluorophenyl, 3-amino-2-methylphenyl, 5-amino-2-methylthiophenyl, 3-carboxyphenyl 3-cyanophenyl, 3-chlorophenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 3-methanesulfonylaminophenyl, 3-methoxycarbonylphenyl, 3-dimethylamnophenyl, 3-methylaminophenyl, 2-methylphenyl, 3-methylphenyl, phenyl, 3-pyridyl, 3-trifluoroacetamidophenyl, 3 -bromo-2-thienyl, 2-thienyl and 3-thienyl; Υ ^ΛΓ is selected from the group consisting of 5-quanidino-1-oxo-1- (2-thiazolyl) -2-pentyl, 5-quanidino-1-oxo-1- (4-thiazolyl) -2-pentyl, 5-quanidino-1-oxo-1- (5-thiazolyl) -2-pentyl, 5-quanidino-1-oxo-1- (4-amino-2-thiazolyl) -2-pentyl and 5-quanidino-1-oxo-1 phenyl-2-pentyl; - 206 or a pharmaceutically acceptable salt thereof. The substituted polycyclic aryl and heteroaryl of the general formula pyrimidinones according to claim 33 wherein R ² is 3-aminophenyl, B is phenyl, A is CH 2, Y ^AT is 5-guanidino-1-oxo-1- (2-thiazolyl) -2-pentyl, and M is CH; R is phenyl, B is phenyl, A is CH2CH2, Y is 5-guanidino-1-oxo-1- (2-thiazolyl) -2-pentyl, and M is CH; 2 AT R is benzyl, B is phenyl, A is CH 2 CH 2, Y is 5-guanidino-1-oxo-1- (2-thiazolyl) -2-pentyl, and M is CH; R is phenyl, B is phenyl, A is CH2CH2, Y is 5-guanidino-1-oxo-1- (2-thiazolyl) -2-pentyl, and M is CH; R ² is benzyl, B is phenyl, A is CH 2 CH 2, Y ^AT is 5-guanidino-1-oxo-1- (2-thiazolyl) -2-pentyl, and M is CH; R is phenyl, B is phenyl, A is CH2CH2, Y is 5-guanidino-1-oxo-1- (2-thiazolyl) -2-pentyl, and M is CH; R ² is 3-aminophenyl, B is phenyl, A is CH 2, Y ^AT is 5-guanidino-1-oxo-1- (2-thiazolyl) -2-pentyl, and M is CF; R ² is phenyl, B is phenyl, A is CH 2 CH 2, Y ^AT is 5-guanidino-1-oxo-1- (2-thiazolyl) -2-pentyl, and M is CF; R ² is benzyl, B is phenyl, A is CH 2 CH 2, Y ^AT is 5-guanidino-1-oxo-1- (2-thiazolyl) -2-pentyl, and M is CF; R ² is phenyl, B is phenyl, A is CH 2 CH 2, Y ^AT is 5-guanidino-1-oxo-1- (2-thiazolyl) -2-pentyl, and M is CF; R ² is benzyl, B is phenyl, A is CH 2 CH 2, Y ^AT is 5-guanidino-1-oxo-1- (2-thiazolyl) -2-pentyl, and M is CF; - 207R ² is phenyl, B is phenyl, A is CH ₂ CH _2, Y ^AT is 5-guanidino-l-oxo-l- (2-thiazolyl) -2-pentyl, and M is CF; R ² is 3-aminophenyl, B is phenyl, A is CH ₂ , Y ^AT is 5-guanidino-1-oxo-1- (2-thiazolyl) -2-pentyl, and M is CC 1; R ² is phenyl, B is phenyl, A is CH ₂ CH ₂ , Y ^AT is 5-guanidino-1-oxo-1- (2-thiazolyl) -2-pentyl, and M is CC 1; R ² is benzyl, B is phenyl, A is CH ₂ CH ₂ , Y ^AT is 5-guanidino-1-oxo-1- (2-thiazolyl) -2-pentyl, and M is Cl; R ² is phenyl, B is phenyl, A is CH ₂ CH ₂ , Y ^AT is 5-guanidino-1-oxo-1- (2-thiazolyl) -2-pentyl, and M is CC 1; R ² is benzyl, B is phenyl, A is CH ₂ CH ₂ , Y ^AT is 5-guanidino-1-oxo-1- (2-thiazolyl) -2-pentyl, and M is Cl; R ² is phenyl, B is phenyl, A is CH ₂ CH ₂ , Y ^AT is 5-guanidino-1-oxo-1- (2-thiazolyl) -2-pentyl, and M is CC 1; R ² is 3-aminophenyl, B is phenyl, A is CH ₂ , Y ^AT is 5-guanidino-1-oxo-1- (2-thiazolyl) -2-pentyl, and M is N; R ² is phenyl, B is phenyl, A is CH ₂ CH ₂ , Y ^AT is 5-guanidino-1-oxo-1- (2-thiazolyl) -2-pentyl, and M is N; R ² is benzyl, B is phenyl, A is CH ₂ CH ₂ , Y ^AT is 5-guanidino-1-oxo-1- (2-thiazolyl) -2-pentyl, and M is N; R ² is phenyl, B is phenyl, A is CH ₂ CH ₂ , Y ^AT is 5-guanidino-1-oxo-1- (2-thiazolyl) -2-pentyl, and M is N; R ² is benzyl, B is phenyl, A is CH ₂ CH ₂ , Y ^AT is 5-guanidino-1-oxo-1- (2-thiazolyl) -2-pentyl, and M is N; R ² is phenyl, B is phenyl, A is CH ₂ CH ₂ , Y ^AT is 5-guanidino-1-oxo-1- (2-thiazolyl) -2-pentyl, and M is N; R ² is benzyl, B is phenyl, A is CH ₂ CH ₂ , Y ^AT is 5-guanidino-1-oxo-1- (2-thiazolyl) -2-pentyl, and M is N; R ² is phenyl, B is phenyl, A is CH ₂ CH ₂ , Y ^AT is 5-guanidino-1-oxo-1- (2-thiazolyl) -2-pentyl, and M is N; or a pharmaceutically acceptable salt thereof. -20838. A composition for inhibiting thrombotic conditions in blood comprising a compound according to any one of claims 8, 16, 24, 32 and 37 and a pharmaceutically acceptable carrier. A composition for inhibiting thrombotic conditions in blood comprising a compound according to any one of claims 1 to 7, 9 to 15, 17 to 23, 25 to 31, and claims 33 to 36, and a pharmaceutically acceptable carrier. The composition of one of claims 38 and 39 for use in inhibiting thrombotic conditions in the blood. The composition of one of claims 38 and 39 for use in inhibiting the formation of platelet aggregates in blood. The composition of one of claims 38 and 39 for use in inhibiting thrombus formation in the blood. The composition of one of claims 38 and 39 for use in treating and preventing venous thromboembolism and pulmonary embolism in mammals. The composition of one of claims 38 and 39 for use in treating and preventing thrombosis in a deep venous system in a mammal. The composition of one of claims 38 and 39 for use in treating and preventing cardiogenic thromboembolism in humans and other mammals. The composition of one of claims 38 and 39 for use in the treatment and prevention of thromboembolic stroke in humans and other mammals. The composition of one of claims 38 and 39 for use in the treatment and prevention of thrombosis associated with cancer and anticancer chemotherapy in humans and other mammals. -20948. The composition of one of claims 38 and 39 for use in treating and preventing unstable angina pectoris in humans and other mammals. The substituted polycyclic aryl and heteroaryl pyrimidinones of any one of claims 1 to 37 for use in inhibiting the formation of thrombus in blood, together with a therapeutically effective amount of a fibrinogen receptor antagonist. Use of a compound according to any one of claims 1 to 37, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting thrombus formation, for treating thrombus formation or for preventing thrombus formation in mammals.