AU4973400A - Substituted polycyclic aryl and heteroaryl pyrymidinones useful as anticoagulants - Google Patents

Description

WO 00/69832 PCT/USOO/09806 SUBSTITUTED POLYCYCLIC ARYL AND HETEROARYL PYRYMIDINONES USEFUL AS ANTICOAGULANTS Field of the Invention 5 This invention is in the field of anticoagulant therapy, and specifically relates to compounds, compositions and methods for preventing and treating thrombotic conditions such as coronary artery and cerebrovascular disease. More particularly, the invention relates to substituted polycyclic aryl and heteroaryl pyrimidinone compounds that inhibit serine proteases of the 10 coagulation cascade. Background of the Invention Physiological systems control the fluidity of blood in mammals [Majerus, P. W. et al: Anticoagulant, Thrombolytic, and Antipiplatelet Drugs. 15 In Hardman, J. G. and Limbird, L. E., editors: Goodman & Gilman's The Pharmacological Basis of Therapeutics. 9th edition. New York, McGraw-Hill Book Co., 1996, pp. 1341-13431. Blood must remain fluid within the vascular systems and yet be able to undergo hemostasis, cessation of blood loss from a damaged vessel, quickly. Hemostasis or clotting begins when 20 platelets first adhere to macromolecules in subendothelian regions of an injured and/or damaged vessels. These platelets aggregate to form the primary hemostatic plug and stimulate local activation of plasma coagulation factors leading to generation of a fibrin clot that reinforces the aggregated platelets. Plasma coagulation factors include factors II, V, VII, VIII, IX, X, XI, 25 and XII; these are also called protease zymogens. These coagulation factors or protease zymogens are activated by serine proteases leading to coagulation in a so called "coagulation cascade" or chain reaction [Handin, R. I.: Bleeding and Thrombosis. In Wilson, J., et al. editors: Harrison's Principles of Internal Medicine. 12th Edition, New York, McGraw-Hill Book Co., 1991,p.350]. 30 Coagulation or clotting occurs in two ways through different pathways. An intrinsic or contact pathway leads from XII to XIIa to XIa to IXa and to the conversion of X to Xa. Xa with factor Va converts prothrombin (II) to thrombin (Ila) leading to conversion of fibrinogen to fibrin. Polymerization of fibrin leads to a fibrin clot. An extrinsic pathway is initiated by the conversion 35 of coagulation factor VII to VIIa by Xa. The presence of Tissue Factor and 1 WO 00/69832 PCT/USOO/09806 VIIa accelerates formation of Xa in the presence of calcium ion and phospholipids. Formation of Xa leads to thrombin, fibrin, and a fibrin clot as described above. The presence of one or more of these many different coagulation factors and two distinct pathways of clotting could enable the 5 efficacious, selective control and better understanding of parts of the coagulation or clotting process. While clotting as a result of an injury to a blood vessel is a critical physiological process for mammals such as man, clotting can also lead to disease states. A pathological process called thrombosis results when platelet 10 aggregation and/or a fibrin clot blocks (i.e., occludes) a blood vessel. Arterial thrombosis may result in ischemic necrosis of the tissue supplied by the artery. When the thrombosis occurs in a coronary artery, a myocardial infarction or heart attack can result. A thrombosis occurring in a vein may cause tissues drained by the vein to become edematous and inflamed. Thrombosis of a deep 15 vein may be complicated by a pulmonary embolism. Preventing or treating clots in a blood vessel may be therapeutically useful by inhibiting formation of blood platelet aggregates, inhibiting formation of fibrin, inhibiting thrombus formation, inhibiting embolus formation, and for treating or preventing unstable angina, refractory angina, myocardial infarction, transient ischemic 20 attacks, atrial fibrillation, thrombotic stroke, embolic stroke, deep vein thrombosis, disseminated intravascular coagulation, ocular build up of fibrin, and reocclusion or restenosis of recanalized vessels. There have been several reports of non-peptidic and peptidic pyrimidinone compounds that act as an inhibitor of a coagulation factor present 25 in the coagulation cascade or clotting process. In PCT Patent Application WO 98/47876, Van Boeckel et al. describe peptidic 6-alkylpyridones and 2 alkylpyrimidinones as anti-thrombotic compounds. In PCT Patent Application WO 98/16547, Zhu and Scarborough describe 3-(N-heterocyclylamino)4,5,6 substituted-pyridonylacetamides and 2

,

4 -substituted-5-(N-heterocyclylamino) 30 pyrimidinonyl-acetamides containing aide substituents and having activity against mammalian factor Xa. In US Patent 5,656,645, Tamura et al. describe 4 ,5, 6 -substituted-3-aminopyridonyl-acetamides, 1,6-substituted-5 aminouracinylacetamides, and 2 ,4-substituted-5-aminopyrimidinonyl acetamides containing amide substituents having a formyl function and having 35 activity against thrombin. In US Patent 5,658,930, Tamura et al. again 2 WO 00/69832 PCT/USOO/09806 describe 4

,

5

,

6 -substituted-3-aminopyridonyl-acetarnides, 1,6-substituted-5 aminouracinylacetamides, and 2

,

4 -substituted-5-aminopyrimidinonyl acetamides containing amide substituents having a formyl function and having activity against thrombin. In PCT Patent Applications 96/18644 and 97/46207, 5 Tamura et al. further describe 4

,

5

,

6 -substituted-3-aminopyridonylacetamides, 1, 6 -substituted-5-aminouracinyl-acetamides, and 2,4-substituted-5-amino pyrimidinonylacetamides containing amide substituents having a formyl function and having activity against thrombin. In PCT Patent Application WO 98/09949, Suzuki et al. describe 2-heterocyclylacetamido derivatives of 1,2 10 diketones and report that they inhibit proteases, especially chymase inhibitors. SUMMARY OF THE INVENTION 15 It is an object of the present invention to provide compounds that are beneficial in anticoagulant therapy and that have a general structure: N2 I N R B IIIPN K YO J Formula (I). It is another object of the present invention to provide methods for 20 preventing and treating thrombotic conditions, such as coronary artery disease, cerebrovascular disease, and other coagulation related disorders. Such thrombotic conditions are prevented and treated by administering to a patient in need thereof an effective amount of compounds of Formula (I). Various other objects and advantages of the present invention will 25 become apparent from the following description of the invention. DESCRIPTION OF THE INVENTION The present invention relates to a class of compounds comprising Substituted Polycyclic Aryl and Heteroaryl pyrimidinones, which are beneficial in anticoagulant therapy for the treatment and prevention of a variety of 3 WO 00/69832 PCT/USOO/09806 thrombotic conditions including coronary artery and cerebrovascular disease, as given in Formula (I): N R2 B IT) K Y J (I) or a pharmaceutically acceptable salt thereof, wherein; 5 J is selected from the group consisting of 0 and S; J is optionally selected from the group consisting of CH-R and N-R6 wherein R6 is a linear spacer moiety having a chain length of 1 to 4 atoms linked to the point of bonding of a substituent selected from the group 4a, 4b, 39, 40, 5, 14, 15 tf a heterocyclyl consistinyofR ,R ,R ,R ,R ,R and R to formhtrccy 10 ring having 5 through 8 contiguous members; J is optionally selected from the group consisting of CH-R6 and N-R6 wherein R is a linear spacer moiety having a chain length of 1 to 4 atoms linked to the points of bonding of both R and R4b to form a heterocyclyl ring having 5 through 8 contiguous members; 15 J is optionally selected from the group consisting of CH-R6 and N-R6 wherein R6 is a linear spacer moiety having a chain length of 1 to 4 atoms linked to the points of bonding of both R39 and R to form a heterocyclyl ring having 5 through 8 contiguous members; B is formula (V): 4 WO 00/69832 PCT/USOO/09806

R

3 4

R

3 3 1 1 R 3 5 R32 DD 3 (V) 1212 11K wherein D , D , , J and K are independently selected from the group consisting of C, N, 0, S and a covalent bond with the provisos that no more than one can be a covalent bond, no more than one of D , D , J , J and K is 1 21 2 1 1 2 12 5 0, no more than one of D, D , , J and K is S, one of D , D , ,J and 1 1 2 12 1 K must be a covalent bond when two of D , D , 2 , and K are 0 and S, 1 2 12 1 and no more than four of D , D , , J and K are N with the proviso that 32 33 34 35 36 R , R , R , R , and R are each independently selected to maintain the tetravalent nature of carbon, trivalent nature of nitrogen, the divalent nature of 10 sulfur, and the divalent nature of oxygen; 9 10 11 12 13 16 17 18 19 32 33 34 R , R10, R 1, R12, R13, R 1, R , R 1, R 1, R32, R33 R3 35, 36 t fhdio R3, and R are independently selected from the group consisting of hydride, acetamido, haloacetamido, amidino, guanidino, dialkylsulfonium, trialkylphosphonium, dialkylsulfoniumalkyl, carboxy, heteroaralkylthio, 15 heteroaralkoxy, cycloalkylamino, acylalkyl, acylalkoxy, aryloylalkoxy, heterocyclyloxy, aralkylaryl, aralkyl, aralkenyl, aralkynyl, heterocyclyl, perhaloaralkyl, aralkylsulfonyl, aralkylsulfonylalkyl, aralkylsulfinyl, aralkylsulfinylalkyl, halocycloalkyl, halocycloalkenyl, cycloalkylsulfinyl, cycloalkylsulfinylalkyl, cycloalkylsulfonyl, cycloalkylsulfonylalkyl, 20 heteroarylamino, N-heteroarylamino-N-alkylamino, heteroarylaminoalkyl, haloalkylthio, alkanoyloxy, alkoxy, alkoxyalkyl, haloalkoxylalkyl, heteroaralkoxy, cycloalkoxy, cycloalkenyloxy, cycloalkoxyalkyl, cycloalkylalkoxy, cycloalkenyloxyalkyl, cycloalkylenedioxy, halocycloalkoxy, 5 WO 00/69832 PCT/USOO/09806 halocycloalkoxyalkyl, halocycloalkenyloxy, halocycloalkenyloxyalkyl, hydroxy, amino, alkoxyamino, thio, nitro, lower alkylamino, alkylthio, alkylthioalkyl, arylamino, aralkylamino, arylthio, arylthioalkyl, heteroaralkoxyalkyl, alkylsulfinyl, alkylsulfinylalkyl, arylsulfinylalkyl, 5 arylsulfonylalkyl, heteroarylsulfinylalkyl, heteroarylsulfonylalkyl, alkylsulfonyl, alkylsulfonylalkyl, haloalkylsulfinylalkyl, haloalkylsulfonylalkyl, alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, monoarylamidosulfonyl, arylsulfonamido, diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl, 10 arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, heterocyclylsulfonyl, heterocyclylthio, alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, haloalkanoyl, alkyl, alkenyl, alkynyl, alkenyloxy, alkenyloxyalky, alkylenedioxy, haloalkylenedioxy, cycloalkyl, cycloalkylalkanoyl, cycloalkenyl, lower cycloalkylalkyl, lower 15 cycloalkenylalkyl, halo, haloalkyl, haloalkenyl, haloalkoxy, hydroxyhaloalkyl, hydroxyaralkyl, hydroxyalkyl, alkylenylamino, hydoxyheteroaralkyl, haloalkoxyalkyl, aryl, aralkyl, aryloxy, aralkoxy, aryloxyalkyl, saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl, heteroaryloxy, heteroaryloxyalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, 20 carboxyalkyl, carboalkoxy, alkoxycarboxamido, alkylamidocarbonylamido, arylamidocarbonylamido, carboalkoxyalkyl, carboalkoxyalkenyl, carboxy, carboaralkoxy, carboxamido, carboxamidoalkyl, cyano, carbohaloalkoxy, phosphono, phosphonoalkyl, diaralkoxyphosphono, and diaralkoxyphosphonoalkyl; 16 19 32 33 34 35 36 25 R , R , R R3, R , R , and R are independently optionally Qb with the proviso that no more than one of R16 and R19 is Qb at the same time and that Qb is Qbe 32 33 33 34 34 35 35 36 R and R 33 and R3, R and R and R and R are independently optionally selected to form a spacer pair wherein a spacer pair is 30 taken together to form a linear moiety having from 3 through 6 contiguous atoms connecting the points of bonding of said spacer pair members to form a ring selected from the group consisting of a cycloalkenyl ring having 5 through 8 contiguous members, a partially saturated heterocyclyl ring having 5 through 6 WO 00/69832 PCT/USOO/09806 8 contiguous members, a heteroaryl ring having 5 through 6 contiguous members, and an aryl with the proviso that no more than one of the group consisting of spacer pairs R32 and R 3 3 , R 3 3 and R 3 4 , R 3 4 and R 3 5 , and R and R36 are used at the same time; 9 10 10 11 11 12 12 13 5 R and R , R and R , R and R and R and R are independently optionally selected to form a spacer pair wherein a spacer pair is taken together to form a linear moiety having from 3 through 6 contiguous atoms connecting the points of bonding of said spacer pair members to form a ring selected from the group consisting of a cycloalkenyl ring having 5 through 10 8 contiguous members, a partially saturated heterocyclyl ring having 5 through 8 contiguous members, a heteroaryl ring having 5 through 6 contiguous members, and an aryl with the proviso that no more than one of the group consisting of spacer pairs R 9 and R , R and R 1 1 , R1 and R and R and R13 are used at the same time; 15 B is optionally formula (VI):

R

3 3

R

3 4 J3 4 R3RD3 N'--D4 R3 5 (VI) wherein D , D , J , and J are independently selected from the group consisting of C, N, 0, and S, no more than one of D 3, D 4, J 3, and J4 is 0, no 3 43 4 1 2 more than one of D3, D , J3, and J is S, and no more than three of D , D 1 2 32 33 34 35 20 J , and J are N with the proviso that R , R3, R3, and R are each independently selected to maintain the tetravalent nature of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen; 7 WO 00/69832 PCT/USOO/09806 B is optionally selected from the group consisting of hydrido, trialkylsilyl, C2-C8 alkyl, C3-C8 alkenyl, C3-C8 alkylenyl, C3-C8 alkynyl, C2-C8 haloalkyl, and C3-C8 haloalkenyl wherein each member of group B is optionally substituted at any carbon up to and including 6 atoms from the point 5 of attachment of B to A with one or more of the group consisting of R 3 2 , R 3 3 R 3 4 , R 3 5 , and R36; B is optionally selected from the group consisting of C3-C15 cycloalkyl, C5-C1O cycloalkenyl, C4-C12 saturated heterocyclyl, and C4-C9 partially saturated heterocyclyl, wherein each ring carbon is optionally 33 10 substituted with R , a ring carbon other than the ring carbon at the point of attachment of B to A is optionally substituted with oxo provided that no more than one ring carbon is substituted by oxo at the same time, ring carbon and nitrogen atoms adjacent to the carbon atom at the point of attachment is optionally substituted with R9 or R 13, a ring carbon or nitrogen atom adjacent 15 to the R9 position and two atoms from the point of attachment is optionally 10 13 substituted with R , a ring carbon or nitrogen atom adjacent to the R position and two atoms from the point of attachment is optionally substituted with R12, a ring carbon or nitrogen atom three atoms from the point of 10 1 attachment and adjacent to the R position is optionally substituted with R 20 a ring carbon or nitrogen atom three atoms from the point of attachment and 12 33 adjacent to the R position is optionally substituted with R , and a ring carbon or nitrogen atom four atoms from the point of attachment and adjacent to the R and R33 positions is optionally substituted with R34 A is selected from the group consisting of single covalent bond, 25 (W )rr-(CH(R15)pa and (CH(R15 )pa(W )rr wherein rr is an integer selected from 0 through 1, pa is an integer selected from 0 through 6, and W is selected from the group consisting of 0, S, C(0), C(S), C(O)S, C(S)O, 8 WO 00/69832 PCT/USOO/09806 C(O)N(R ), C(S)N(R ), (R 7)NC(O), (R )NC(S), S(O), S(O) 2 ,

S(O)

2 N(R ), (R )NS(O) 2 , Se(O), Se(O) 2 , Se(O) 2 N(R ), (R )NSe(O) 2 , P(O)(R 8), N(R )P(O)(R8), P(O)(R 8)N(R ), C(NR )N(R ), (R 7)NC(NR ), (R )NC(NR )NR , and N(R ) with the proviso that no more than one of the 5 group consisting of rr and pa is 0 at the same time; R and R8 are independently selected from the group consisting of hydrido, hydroxy, alkyl, alkenyl, aryl, aralkyl, aryloxy, alkoxy, alkenyloxy, alkylthio, alkylamino, arylthio, arylamino, acyl, aroyl, heteroaroyl, aralkoxyalkyl, heteroaralkoxyalkyl, , aryloxyalkyl, alkoxyalkyl, 10 alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, aralkoxyalkyl, heteroaralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, heteroaryl, heteroaryloxy, heteroarylamino, heteroaralkyl, heteroaralkyloxy, heteroaralkylamino, and heteroaryloxyalkyl; 14 15 37 38 39 40 41 42 R , R , R ,R ,R , R , R andR are independently 15 selected from the group consisting of amidino, hydroxyamino, hydrido, hydroxy, halo, cyano, aryloxy, amino, alkylamino, dialkylamino, hydroxyalkyl, aminoalkyl, acyl, aroyl, heteroaroyl, heteroaryloxyalkyl, sulfhydryl, acylamido, alkoxy, alkylthio, arylthio, alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, aralkoxyalkylalkoxy, alkylsulfinylalkyl, 20 alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkoxythioalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxy, halocycloalkoxyalkyl, 25 halocycloalkenyloxyalkyl, saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl, heteroarylalkyl, heteroarylthioalkyl, heteroaralkylthioalkyl, monocarboalkoxyalkyl, dicarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl, carboalkoxycyanoalkyl, alkylsulfinyl, alkylsulfonyl, haloalkylsulfinyl, haloalkylsulfonyl, arylsulfinyl, 30 arylsulfinylalkyl, arylsulfonyl, arylsulfonylalkyl, aralkylsulfinyl, aralkylsulfonyl, cycloalkylsulfinyl, cycloalkylsulfonyl, cycloalkylsulfinylalkyl, 9 WO 00/69832 PCT/USOO/09806 cycloalkylsufonylalkyl, heteroarylsulfonylalkyl, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylsulfinylalkyl, aralkylsulfinylalkyl, aralkylsulfonylalkyl, carboxy, carboxyalkyl, carboalkoxy, carboxamide, carboxamidoalkyl, carboaralkoxy, trialkylsilyl, dialkoxyphosphono, 5 diaralkoxyphosphono, dialkoxyphosphonoalkyl, and diaralkoxyphosphonoalkyl with the proviso that R37 and R 38are independently selected from other than formyl and 2-oxoacyl; 14 14 R and R , when bonded to different carbons, are optionally taken together to form a group selected from the group consisting of covalent bond, 10 alkylene, haloalkylene, and a linear moiety spacer selected to form a ring selected from the group consisting of cycloalkyl ring having from 5 through 8 contiguous members, cycloalkenyl ring having from 5 through 8 contiguous members, and a heterocyclyl having from 5 through 8 contiguous members; 14 15 R and R , when bonded to different carbons, are optionally taken 15 together to form a group selected from the group consisting of covalent bond, alkylene, haloalkylene, and a linear moiety spacer selected to form a ring selected from the group consisting of a cycloalkyl ring having from 5 through 8 contiguous members, a cycloalkenyl ring having from 5 through 8 contiguous members, and a heterocyclyl having from 5 through 8 contiguous members; 15 15 20 R and R , when bonded to different carbons, are optionally taken together to form a group selected from the group consisting of covalent bond, alkylene, haloalkylene, and a linear moiety spacer selected to form a ring selected from the group consisting of cycloalkyl ring having from 5 through 8 contiguous members, cycloalkenyl ring having from 5 through 8 contiguous 25 members, and a heterocyclyl having from 5 through 8 contiguous members; 5 'P is selected from the group consisting of NR , 0, C(O), C(S), S, S(O), S(0)2, ON(R 5), P(O)(R 8), and CR39R R5 is selected from the group consisting of hydrido, hydroxy, amino, alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxy, aralkoxy, alkoxy, alkenyloxy, 30 alkylthio, arylthio, aralkoxyalkyl, heteroaralkoxyalkyl, aryloxyalkyl, alkoxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, aralkoxyalkyl, 10 WO 00/69832 PCT/USOO/09806 heteroaralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxyalkyl, halocycloalkenyloxyalkyl, 5 heteroaryl, heteroarylalkyl, monocarboalkoxyalkyl, monocarboalkoxy, dicarboalkoxyalkyl, monocarboxamido, monocyanoalkyl, dicyanoalkyl, carboalkoxycyanoalkyl, acyl, aroyl, heteroaroyl, heteroaryloxyalkyl, and dialkoxyphosphonoalkyl; R39 and R , when bonded to the same carbon, are optionally taken 5 10 together to form a group selected from a group consisting of oxo, thiono, R5 N, alkylene, haloalkylene, and a linear moiety spacer having from 2 through 7 contiguous atoms to form a ring selected from the group consisting of a cycloalkyl ring having from 3 through 8 contiguous members, a cycloalkenyl ring having from 3 through 8 contiguous members, and a heterocyclyl ring 15 having from 3 through 8 contiguous members; M is selected from the group consisting of N and R I-C; R2 and R are independently selected from the group consisting of Z Q, hydrido, alkyl, alkenyl, and halo; R is optionally selected from the group consisting of amino, 20 aminoalkyl, alkylamino, amidino, guanidino, hydroxy, hydroxyamino, alkoxy, hydroxyalkyl, alkoxyamino, thiol, alkylthio, dialkylsulfonium, trialkylphosphonium, dialkylsulfoniumalkyl, heteroarylamino, nitro, arylamino, aralkylamino, alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, haloalkanoyl, hydroxyhaloalkyl, cyano, and phosphono; 25 R2 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, haloalkanoyl, hydroxyhaloalkyl, cyano, and phosphono; 30 R 2 and R 4 a, R2 and R 4 b, R 2 and R 4 , and R2 and R 15 are optionally independently selected to form spacer pairs wherein a spacer pair is taken together to form a linear moiety having from 2 through 5 contiguous atoms 11 WO 00/69832 PCT/USOO/09806 connecting the points of bonding of said spacer pair members to form a heterocyclyl ring having from 5 through 8 contiguous members with the proviso that no more than one of the group of spacer pairs consisting of R2 and

R

4 a, R 2and R 4 b, R2 and R 4, and R 2 and R 15 is used at the same time; 5 R 2 is optionally independently selected to form a linear moiety having from 2 through 5 contiguous atoms linked to the points of bonding of both R 4 a and R4b to form a heterocyclyl ring having from 5 through 8 contiguous members; Z is selected from the group consisting of covalent single bond, 10 (CR 41R 42)q wherein q is an integer selected from 1 through 6, (CH(R 41 W'-(CH(R 42)) wherein g and p are integers independently selected from 0 through 3 and WO is selected from the group consisting of 0, S, C(O), C(S), C(0)0, C(S)O, C(O)S, C(S)S, C(O)N(R 41), (R 41)NC(O), C(S)N(R )1 (R 41)NC(S), OC(O)N(R 41), (R 41)NC(0)0, SC(S)N(R 41), (R 41)NC(S)S, 15 SC(O)N(R 41), (R 41)NC(O)S, OC(S)N(R 41), (R 41)NC(S)O, N(R 42)C(O)N(R 41), (R 41)NC(O)N(R 42), N(R 42)C(S)N(R 41), (R 41)NC(S)N(R 42), S(O), S(0) 2 , S(0) 2 N(R 41), N(R 41)S(0)2, Se, Se(O), Se(O) 2 , Se(0) 2 N(R 41), N(R 41)Se(0) 2 , P(O)(R 8), N(R 7)P(O)(R8 ),

P(O)(R

8 )N(R 7 ), N(R 4 1 ), ON(R 4 1 ), and SiR 2 8

R

2 9 , and (CH(R 4 1 )) W 22 20 (CH(R 42)h wherein e and h are integers independently selected from 0 through 2 and 2is selected from the group consisting of CR 41=CR42 41 42 CR 41R 42=C; vinylidene), ethynylidene (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 12 WO 00/69832 PCT/USOO/09806 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 5 pyrrolidinyl, 2,3-tetrahydrofuranyl, 2,4-tetrahydrofuranyl, 2,5 tetrahydrofuranyl, and 3,4-tetrahydrofuranyl, with the provisos that R4 and R42 are selected from other than halo and cyano when directly bonded to N and Z is directly bonded to the pyrimidinone ring: R28 and R29 are independently selected from the group consisting of 10 hydrido, hydroxyalkyl, alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, acyl, aroyl, aralkanoyl, heteroaroyl, aralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkylthioalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, 15 haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxyalkyl, perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl, heteroarylalkyl, heteroarylthioalkyl, heteroaralkylthioalkyl, cyanoalkyl, dicyanoalkyl, carboxamidoalkyl, dicarboxamidoalkyl, cyanocarboalkoxyalkyl, 20 carboalkoxyalkyl, dicarboalkoxyalkyl, cyanocycloalkyl, dicyanocycloalkyl, carboxamidocycloalkyl, dicarboxamidocycloalkyl, carboalkoxycyanocycloalkyl, carboalkoxycycloalkyl, dicarboalkoxycycloalkyl, formylalkyl, acylalkyl, arylsulfinylalkyl, arylsulfonylalkyl, aralkylsulfinyl, cycloalkylsulfinylalkyl, cycloalkylsufonylalkyl, heteroarylsulfonylalkyl, heteroarylsulfinylalkyl, 25 aralkylsulfinylalkyl, aralkylsulfonylalkyl, carboxy, dialkoxyphosphono, diaralkoxyphosphono, dialkoxyphosphonoalkyl and diaralkoxyphosphonoalkyl; R28 and R29 are optionally taken together to form a linear moiety spacer having from 2 through 7 contiguous atoms and forming a ring selected from the group consisting of a cycloalkyl ring having from 3 through 8 contiguous 30 members, a cycloalkenyl ring having from 3 through 8 contiguous members, and a heterocyclyl ring having from 3 through 8 contiguous members; Q is formula (II): 13 WO 00/69832 PCT/USOO/09806 R R10 i 12 12 R1 D D R13 (II) wherein D 1, D2 , J , J and K1 are independently selected from the group consisting of C, N, 0, S and a covalent bond with the provisos that no more than one can be a covalent bond, no more than one of D , D , , J and K 122 1 1 5 can be 0, no more than one of D, D , , J and K can be S, one of D 2 12 1 1 21 2 D J , J and K must be a covalent bond when two of D , D , , J and 1 12 12 1 K are O and S, and no more than four of D, D , , J and K can be N, with the proviso that R 9, R 10, R II, R 12, and R13 are each independently selected to maintain the tetravalent nature of carbon, trivalent nature of 10 nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen; Q is optionally selected from formula (III): R 10 3 4 wherein D 3, D 4, J 3, and J4 are independently selected from the group consisting of C, N, 0, and S, no more than one of D 3, D 4, J 3, and J4 is 0, no 15 more than one of D3, D 4, J3, and J is S, and no more than three of DI, D2 14 WO 00/69832 PCT/US00/09806 1 2 9 10 11 12 J ,and J are N with the proviso that R , R , R , and R are each independently selected to maintain the tetravalent nature of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen; 5 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, cycloalkylalkenyl, haloalkyl, haloalkoxy, haloalkenyl, halocycloalkyl, halocycloalkenyl, 10 haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxyalkyl, and halocycloalkenyloxyalkyl with the proviso that ZO is selected from other than a single covalent bond when Q is hydrido; K is (CR R 4)n wherein n is an integer selected from I through 4; R and R4b are independently selected from the group consisting of 15 halo, hydrido, hydroxy, cyano, hydroxyalkyl, alkyl, alkenyl, aryl, aralkyl, aralkoxyalkyl, aryloxyalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, aralkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, haloalkenyl, heteroaryl, heteroarylalkyl, heteroarylthioalkyl, heteroaralkylthioalkyl, cyanoalkyl, alkylsulfinylalkyl, 20 alkylsulfonylalkyl, haloalkylsulfinyl, arylsulfinylalkyl, arylsulfonylalkyl, heteroarylsulfonylalkyl, heteroarylsulfinylalkyl, aralkylsulfinylalkyl, and aralkylsulfonylalkyl with the provisos that halo, hydroxy, and cyano are bonded to different carbons when simultaneously present and that R and R4b are other than hydroxy or cyano when bonded to the carbon directly bonded to 25 the pyrimidinone nitrogen; 4a 4b R and R , when bonded to the same carbon, are optionally taken together to form a group selected from the group consisting of oxo, thiono, and a linear spacer moiety having from 2 through 7 contiguous atoms connected to form a ring selected from the group consisting of a cycloalkyl ring having 3 30 through 8 contiguous members, a cycloalkenyl ring having 5 through 8 contiguous members, and a heterocyclyl ring having 5 through 8 contiguous 15 WO 00/69832 PCT/USOO/09806 members with the proviso that R and R4b taken together is other than oxo or thiono when the common carbon is directly bonded to the pyrimidinone nitrogen; 0 1 4a 4b1 E is E , when K is (CR R )n, wherein E is selected from the 5 group consisting of a covalent single bond, 0, S, C(O), C(S), C(0)0, C(S)O, C(O)S, C(S)S, C(O)N(R ), (R )NC(O), C(S)N(R ), (R 7)NC(S), OC(O)N(R ), (R )NC(0)0, SC(S)N(R ), (R )NC(S)S, SC(O)N(R ), (R )NC(O)S, OC(S)N(R ), (R )NC(S)O, N(R 8)C(O)N(R ), (R )NC(O)N(R 8), N(R 8)C(S)N(R ), (R )NC(S)N(R 8), S(O), S(0)2, 10 S(O) 2 N(R ), N(R 7)S(0)2, S(0) 2 N(R )C(O), C(O)N(R )S(0) 2 , Se, Se(O), Se(0) 2 , Se(O) 2 N(R ), N(R )Se(0) 2 , P(O)(R 8), N(R )P(O)(R8 ), P(O)(R 8)N(R ), N(R ), ON(R ), SiR R 29, CR =CR 4b, ethynylidene (C-C; 1,2-ethynyl), and C=CR R4b K is optionally selected to be (CH(R 4))--T whereinj is selected from a 15 integer from 0 through 3 and T is selected from the group consisting of single covalent bond, 0, S, and N(R ) with the provisos that R14 is other than hydroxy, cyano, halo, amino, alkylamino, dialkylamino, and sulfhydryl when j is 1 and that (CH(R 14))j is bonded to the pyrimidinone ring; E is optionally E 2, when K is (CH(R14))j-T, wherein E2 is selected 20 from the group consisting of a covalent single bond, C(0), C(S), C(0)0, C(S)O, C(O)S, C(S)S, C(0)N(R ), (R )NC(O), C(S)N(R ), (R )NC(S), (R )NC(0)0, (R )NC(S)S, (R )NC(O)S, (R )NC(S)O, N(R 8)C(O)N(R ), (R )NC(O)N(R 8), N(R 8)C(S)N(R ), (R )NC(S)N(R 8), S(O), S(0) 2 , 16 WO 00/69832 PCT/US00/09806 S(0) 2 N(R ), N(R 7)S(O) 2 , S(O) 2 N(H)C(O), C(O)N(H)S(O) 2 , Se(O), Se(O) 2 , Se(O) 2 N(R ), N(R )Se(O) 2 , P(O)(R8), N(R 7)P(O)(R8), P(O)(R 8)N(R 7), and N(R ); K is optionally selected to be G-(CH(R 15))k wherein k is selected from 5 an integer from 1 through 3 and G is selected from the group consisting of 0, S, and N(R ) with the proviso that R15 is other than hydroxy, cyano, halo, amino, alkylamino, dialkylamino, and sulfhydryl when k is 1; E is optionally E3 when K is G-(CH(R 15)k wherein E3 is selected from the group consisting of a covalent single bond, 0, S, C(O), C(S), 10 C(0)0, C(S)O, C(O)S, C(S)S, C(O)N(R ), (R )NC(O), C(S)N(R ), (R 7)NC(S), OC(O)N(R ), (R )NC(0)0, SC(S)N(R ), (R )NC(S)S, SC(O)N(R ), (R )NC(O)S, OC(S)N(R ), (R )NC(S)O, N(R 8)C(O)N(R ), (R )NC(O)N(R8), N(R 8)C(S)N(R ), (R )NC(S)N(R 8), S(O), S(0) 2 , S(0) 2 N(R ), N(R 7)S(0)2, Se, Se(O), Se(0) 2 , Se(0) 2 N(R ), N(R )Se(O) 2 , 15 P(O)(R 8), N(R )P(O)(R 8), P(O)(R8)N(R ), N(R ), ON(R ), SiR R29 CR =CR 4b, ethynylidene (C=C; 1,2-ethynyl), and C=CR 4 aR 4 b YO is formula (IV): S R17 R18 R'R 5 6 R16 K2 R 19 1b Qb (IV) 17 WO 00/69832 PCT/USOO/09806 5 65 6 wherein D , D , 5 , and J are independently selected from the group consisting of C, N, 0, S and a covalent bond with the provisos that no more than one is a covalent bond, K2 is independently selected from the group consisting of C and N+, no more than one of D 5 , D 6 5, and J6 s 0, no more 5 65 6. 5 65 6 5 than one of D5, D , ,and J is S, one of D , D ,and J must be a 5 65 6 covalent bond when two of D , D , 5 , and J are 0 and S, no more than three of D5, D6 , J 5, and J6 are N when K2 s N +, and no more than four of 5 65 6 2 16 17 D , D , J , and J are N when K is carbon with the provisos that R , R , 18 19 R , and R are each independently selected to maintain the tetravalent nature 10 of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen; R16 and R 7 are independently optionally taken together to form a linear moiety spacer having from 3 through 6 contiguous atoms connected to form a ring selected from the group consisting of a cycloalkenyl ring having 15 from 5 through 8 contiguous members, a partially saturated heterocyclyl ring having from 5 through 8 contiguous members, a heteroaryl having from 5 through 6 contiguous members, and an aryl; R18 and R19 are independently optionally taken together to form a linear moiety spacer having from 3 through 6 contiguous atoms connected to 20 form a ring selected from the group consisting of a cycloalkenyl ring having from 5 through 8 contiguous members, a partially saturated heterocyclyl ring having from 5 through 8 contiguous members, a heteroaryl having from 5 through 6 contiguous members, and an aryl; b. 20 21 Q is selected from the group consisting of NR R , + 20 21 22 25 *NR R R , oxy, alkyl, aminoalkylenyl, alkylamino, dialkylamino, be be 20 dialkylsulfoniumalkyl, acylamino and Q wherein Q is hydrido and R 18 WO 00/69832 PCT/USOO/09806 21 22 R21, and R are independently selected from the group consisting of hydride, amino, alkyl, hydroxy, alkoxy, aminoalkylenyl,alkylamino, dialkylamino, and 20 21 22 hydroxyalkyl with the provisos that no more than one of R , R and R is hydroxy, alkoxy, alkylamino, amino, and dialkylamino at the same time and 20 21 22 5 that R , R , and R must be other than be hydroxy, alkoxy, alkylamino, amino, and dialkylamino when K2 is N+ 20 21 20 22 21 22 R and R , R and R , and R and R are independently optionally selected to form a spacer pair wherein a spacer pair is taken together to form a linear moiety having from 4 through 7 contiguous atoms connecting 10 the points of bonding of said spacer pair members to form a heterocyclyl ring having 5 through 8 contiguous members with the proviso that no more than 20 21 20 22 one of the group consisting of spacer pairs R and R , R and R , and R21 and R22 is used at the same time; Qb is optionally selected from the group consisting of 15 N(R 26)SO 2 N(R )(R 24), N(R 26)C(O)OR5, N(R 26)C(O)SR5 N(R 26)C(S)OR5 and N(R 26)C(S)SR5 with the proviso that no more than one of R , R 24, and R26 can be hydroxy, alkoxy, alkyleneamino, alkylamino, amino, or dialkylamino when two of the group consisting of R , R 24, and R26 are bonded to the same atom; 20 Qb is optionally selected from the group consisting of 25 23 24 dialkylsulfonium, trialkylphosphonium, C(NR )NR R N(R 26)C(NR 25)N(R )(R24), N(R 26)C(O)N(R )(R 24 N(R 26)C(S)N(R )(R 24), C(NR 25)OR5 19 WO 00/69832 PCT/USOO/09806 26 25 23 24 26 25 23 24 C(O)N(R )C(NR )N(R )(R ), C(S)N(R )C(NR )N(R )(R24 N(R 26)N(R 26)C(NR 25)N(R )(R ), ON(R 26)C(NR 25)N(R )(R 24 N(R 26)N(R 26)SO 2 N(R )(R24), C(NR 25)SR5, C(O)NR R 24, and 23 24 23 24 26 C(O)NR R with the provisos that no more than one of R , R , and R 5 can be hydroxy, alkoxy, alkylamino, amino, or dialkylamino when any two of 23 24 26 the group consisting of R , R , and R are bonded to the same atom and that said Qb group is bonded directly to a carbon atom; 23 24 25 26 R , R , R , and R are independently selected from the group consisting of hydrido, alkyl, hydroxy, alkoxy, alkylenylamino, amino, 10 alkylamino, dialkylamino, and hydroxyalkyl: R and R24 are optionally taken together to form a linear spacer moiety having from 4 through 7 contiguous atoms connecting the points of bonding to form a heterocyclyl ring having 5 through 8 contiguous members; 23 25 24 25 25 26 24 26 23 R and R 24 and R2, R and R26 R and R2, and R and 15 R26 are independently optionally selected to form a spacer pair wherein a spacer pair is taken together from the points of bonding of selected spacer pair members to form the group L-U-V wherein L, U, and V are independently selected from the group consisting of 0, S, C(O), C(S), C(JH) 2 S(O), S02, OP(OR 31)R30 P(O)R30, P(S)R 0, C(R 30)R31, C=C(R 30)R 31 (O) 2 POP(0) 2 , 30 30 29 28 29 28 29 28 20 R (O)POP(O)R0, Si(R )R , Si(R 9)R Si(R )R28 Si(R 29)R 280Si(R29 )R 28, (R 28)R 29COC(R 28)R 29, (R 28)R 29CSC(R 28)R29, C(O)C(R 30)=C(R 31), C(S)C(R 30)=C(R3 1), S(O)C(R 30)=C(R ),

SO

2 C(R30)=C(R31), PR 30C(R 30)=C(R ), P(O)R 30C(R 30)=C(R 31), P(S)R 0C(R30)=C(R3 ), DC(R30)(R3)D, OP(OR )R 0, P(O)R30, P(S)R 3, 20 WO 00/69832 PCT/USOO/09806 Si(R 28)R29 and N(R 30), and a covalent bond with the proviso that no more than any two of L, U and V are simultaneously covalent bonds and the heterocyclyl comprised of by L, U, and V has from 5 through 10 contiguous member; D is selected from the group consisting of oxygen, C=O, C=S, S(O)m 5 wherein m is an integer selected from 0 through 2; JH is independently selected from the group consisting of OR 27, SR27 and N(R20)R21 R27 is selected from the group consisting of hydrido, alkyl, alkenyl, alkynyl, aralkyl, aryloxyalkyl, aralkoxyalkyl, alkylsulfinylalkyl, 10 alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkylthioalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxyalkyl, halocycloalkenyloxyalkyl, 15 perhaloaryloxyalkyl, heteroaryl, heteroarylalkyl, heteroarylthioalkyl, heteroaralkylthioalkyl, arylsulfinylalkyl, arylsulfonylalkyl, cycloalkylsulfinylalkyl, cycloalkylsufonylalkyl, heteroarylsulfonylalkyl, heteroarylsulfinylalkyl, aralkylsulfinylalkyl and aralkylsulfonylalkyl; R30 and R are independently selected from the group consisting of 20 hydrido, hydroxy, thiol, aryloxy, amino, alkylamino, dialkylamino, hydroxyalkyl, heteroaryloxyalkyl, alkoxy, alkylthio, arylthio, alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, aralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkoxythioalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, 25 cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, haloaralkylsulfinylalkyl, aralkylsulfonylalkyl, cyanoalkyl, dicyanoalkyl, carboxamidoalkyl, dicarboxamidoalkyl, cyanocarboalkoxyalkyl, carboalkoxyalkyl, dicarboalkoxyalkyl, cyanocycloalkyl, dicyanocycloalkyl, carboxamidocycloalkyl, dicarboxamidocycloalkyl, carboalkoxycyanocycloalkyl, carboalkoxycycloalkyl, 30 dicarboalkoxycycloalkyl, formylalkyl, acylalkyl, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, phosphonoalkyl, dialkoxyphosphonoalkoxy, diaralkoxyphosphonoalkoxy, phosphonoalkoxy, dialkoxyphosphonoalkylamino, 21 WO 00/69832 PCT/USOO/09806 diaralkoxyphosphonoalkylanino, phosphonoalkylamino, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, sulfonylalkyl, alkoxysulfonylalkyl, aralkoxysulfonylalkyl, alkoxysulfonylalkoxy, aralkoxysulfonylalkoxy, sulfonylalkoxy, alkoxysulfonylalkylamino, 5 aralkoxysulfonylalkylamino, and sulfonylalkylanino; R30 and R31 are optionally taken to form a linear moiety spacer group having from 2 through 7 contiguous atoms to form a ring selected from the group consisting of a cycloalkyl ring having from 3 through 8 contiguous members, a cycloalkenyl ring having from 3 through 8 contiguous members, and a 10 heterocyclyl ring having from 3 through 8 contiguous members; 23 25 24 25 25 26 24 26 23 R and R , R and R , R and R , R and R , and R and R26 are independently optionally selected to form a spacer pair wherein a spacer pair is taken together from the points of bonding of selected spacer pair members to form the group L-U-V wherein L, U, and V are independently selected from the 15 group of 1,2-disubstituted radicals consisting of a cycloalkyl radical, a cycloalkenyl radical wherein cycloalkyl and cycloalkenyl radicals are substituted with one or 30 31 more groups selected from R and R , an aryl radical, an heteroaryl radical, a saturated heterocyclic radical and a partially saturated heterocyclic radical wherein 28 32 said 1,2-substitutents are independently selected from C=O, C=S, C(R )R 20 S(O), S(O)2, OP(OR31)R 0, P(O)R 30, P(S)R30 and Si(R 28)R29 23 25 24 25 25 26 24 26 23 R andR , R andR ,R andR ,R andR ,andR and R26 are independently optionally selected to form a spacer pair wherein a spacer pair is taken together from the points of bonding of selected spacer pair members to form the group L-U-V wherein L, U, and V are independently selected from the 25 group of radicals consisting of 1,2-disubstituted alkylene radicals and 1,2 disubstituted alkenylene radical wherein said 1,2-substitutents are independently selected from C=O, C=S, C(R 28)R 29, S(O), S(O) 2 , OP(OR 31)R 0, P(O)R30 22 WO 00/69832 PCT/USOO/09806 P(S)R 30, and Si(R2 )R29 and said alkylene and alkenylene radical are substituted with one or more R30 or R31 substituents; QS is selected from the group consisting of a single covalent bond, (CR3 R 3)b-(W)az wherein az is an integer selected from 0 through 1, b is 5 an integer selected from 1 through 4, and WO is selected from the group consisting of 0, S, C(O), C(S), C(0)0, C(S)O, C(O)S. C(S)S, C(O)N(R 14 (R 4)NC(O), C(S)N(R 14), (R 14)NC(S), OC(0)N(R 14), SC(S)N(R 14), SC(O)N(R 4), OC(S)N(R 4), 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(0)2, S(0) 2 N(R 4), 10 N(R 14)S(0)2, Se, Se(O), Se(O) 2 , Se(0) 2 N(R 17), N(R 14)Se(O) 2 , P(O)(R 8 N(R )P(O)(R 8), P(O)(R 8)N(R ), N(R14 ), ON(R 14), and SiR R29 (CH(R 4))c-W -(CH(R 15))d wherein c and d are integers independently selected from 1 through 4, and W is selected from the group consisting of 0, S, C(O), C(S), C(0)0, C(S)O, C(O)S, C(S)S, C(O)N(R 4), (R 14)NC(O), 15 C(S)N(R 14), (R 4)NC(S), OC(O)N(R14 ), (R 4)NC(0)0, SC(S)N(R 14), (R 14)NC(S)S, SC(O)N(R 14), (R 14)NC(O)S, OC(S)N(R 14), (R 14)NC(S)O, N(R15 )C(O)N(R 14), (R 14)NC(O)N(R 15), N(R 15)C(S)N(R 4), (R 14)NC(S)N(R15 ), S(O), S(0) 2 , S(0) 2 N(R 4), N(R 14)S(0)2, Se, Se(O), Se(0) 2 , Se(0) 2 N(R 14), N(R 14)Se(0) 2 , P(O)(R 8), N(R )P(O)(R8 ), 20 P(O)(R 8

)N(R

7 ), N(R 14 ), ON(R 14 ), SiR 2 8

R

2 9 , and (CH(R14 2 (CH(R 15))h wherein e and h are integers independently selected from 0 23 WO 00/69832 PCT/USOO/09806 through 2 and 2 s selected from the 4 =CR42 CR 41R 42=C; vinylidene), ethynylidene (CmC; 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 5 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 14 10 tetrahydrofuranyl, and 3,4-tetrahydrofuranyl, with the provisos that R and R15 are selected from other than halo and cyano when directly bonded to N and that (CR 37R 38)b, (CH(R 14))c, (CH(R 4))e and are bonded to E0; R37 and R 37, when bonded to different carbons, are optionally taken together to form a linear moiety spacer having from 1 through 7 contiguous 15 atoms to form a ring selected from the group consisting of a cycloalkyl ring having from 3 through 8 contiguous members, a cycloalkenyl ring having from 3 through 8 contiguous members, and a heterocyclyl ring having from 3 through 8 contiguous members; R37 and R 38, when bonded to different carbons, are taken together to 20 form a linear moiety spacer having from 1 through 7 contiguous atoms to form a ring selected from the group consisting of a cycloalkyl ring having from 3 through 8 contiguous members, a cycloalkenyl ring having from 3 through 8 contiguous members, and a heterocyclyl ring having from 3 through 8 contiguous members; 25 R38 and R38 , when bonded to different carbons, are taken together to form a linear moiety spacer having from 1 through 7 contiguous atoms to form a ring selected from the group consisting of a cycloalkyl ring having from 3 through 8 contiguous members, a cycloalkenyl ring having from 3 through 8 contiguous members, and a heterocyclyl ring having from 3 through 8 30 contiguous members; 24 WO 00/69832 PCT/USOO/09806 R37 and R 38, when bonded to the same carbon, are taken together to form a group selected from a group consisting of oxo, thiono, alkylene, haloalkylene, and a linear moiety spacer having from 2 through 7 contiguous atoms to form a ring selected from the group consisting of a cycloalkyl ring 5 having from 3 through 8 contiguous members, a cycloalkenyl ring having from 3 through 8 contiguous members, and a heterocyclyl ring having from 3 through 8 contiguous members; Y is optionally QbQss wherein Qss is selected from the group consisting of (CR 3 7

R

3 8 )f wherein f is an integer selected from 1 through 6, 14 1 15 10 (CH(R ))c-W -(CH(R15)d wherein c and d are integers independently selected from 1 through 4, and W is selected from the group consisting of WI is selected from the group consisting of 0, S, C(O), C(S), C(0)0, C(S)O, C(O)S, C(S)S, C(O)N(R 14), (R 4)NC(O), C(S)N(R 4), (R 4)NC(S), OC(O)N(R 4), (R 14)NC(O)0, SC(S)N(R 14), (R 14)NC(S)S, SC(O)N(R 4), 15 (R 14)NC(0)S, OC(S)N(R 14), (R 14)NC(S)O, N(R 15)C(O)N(R 14 (R 14)NC(O)N(R 5), N(R 15)C(S)N(R14 ), (R 14)NC(S)N(R 15), S(O), S(0)2, S(0) 2 N(R 14), N(R 14)S(0) 2 , Se, Se(O), Se(0) 2 , Se(O) 2 N(R 14 N(R 14)Se(0)2, P(O)(R 8), N(R )P(O)(R 8), P(O)(R 8)N(R ), N(R 14), ON(R14), SiR 28R29, and (CH(R 14 ))e-W-(CH(R 15 ))h wherein e and h are 20 integers independently selected from 0 through 2 and W is selected from the group consisting of CR =CR 4b, ethynylidene (C=C; 1,2-ethynyl), and C=CR R4b with the provisos that R 4 and R15 are selected from other than halo and cyano when directly bonded to N, that (CR37 R 38)f, (CH(R15))c' and (CH(R 15))e are bonded to E0, and Qb is selected from other than 25 WO 00/69832 PCT/USOO/09806 N(R 26)N(R 26)C(NR 25)N(R )(R 24) or ON(R 26)C(NR 25)N(R )(R 24 when Qss is (CR37 R 38)f wherein f is other than the integer 1;

Y

0 is optionally Qb_ sss wherein Qsss is (CH(R 3 8 ))r-W 3 r is an integer selected from 1 through 3, W is selected from the group consisting of 5 1,1-cyclopropyl, 1,2-cyclopropyl, 1,1-cyclobutyl, 1,2-cyclobutyl, 1,2 cyclohexyl, 1,3-cyclohexyl, 1,4-cyclohexyl, 1, 2 -cyclopentyl, 1,3-cyclopentyl, 2,3-morpholinyl, 2,4-morpholinyl, 2,5-morpholinyl, 2,6-morpholinyl, 3,4 morpholinyl, 3,5-morpholinyl, 1,2-piperazinyl, 1, 3 -piperazinyl, 1,4 piperazinyl, 2,3-piperazinyl, 2,5-piperazinyl, 2,6-piperazinyl, 1,2-piperidinyl, 10 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 15 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, and 3,5 tetrahydropyranyl, and each carbon and hyrido containing nitrogen member of 20 the ring of the W other than the points of attachment is optionally substituted 9 10 11 12 with one or more of the group consisting of R , R , R , and R , with the proviso that (CH(R 38))r is bonded to E and Q is bonded to lowest numbered substituent position of each W Y is optionally Qb_ sssr wherein Qsssr is (CH(R 3 8 3r-W4, r is an 25 integer selected from 1 through 3, W 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, 26 WO 00/69832 PCT/USOO/09806 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 5 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 10 tetrahydropyranyl, and 3,5-tetrahydropyranyl, and each carbon and hydrido 4 containing nitrogen member of the ring of the W other than the points of attachment is optionally substituted with one or more of the group consisting of 9 10 11 12 38 0 R , R , R , and R , with the provisos that (CH(R ))r is bonded to E b 4 and Q is bonded to highest number substituent position of each W 15 YO is optionally Qb ssss wherein Q ssss is (CH(R 38))r-W , r is an integer selected from 1 through 3, W 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, 20 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, 2,4-imidazo(1,2-a)pyridinyl, 2,5 imidazo(1,2-a)pyridinyl, 2,6-imidazo(1,2-a)pyridinyl, 2,7-imidazo(1,2 25 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-indolyl, 2,5 indolyl, 2,6-indolyl, 2,7-indolyl, 3,4-indolyl, 3,5-indolyl, 3,6-indolyl, 3,7 indolyl, 1,4-isoindolyl, 1,5-isoindolyl, 1,6-isoindolyl, 2,4-isoindolyl, 2,5 isoindolyl, 2,6-isoindolyl, 2,7-isoindolyl, 1,3-isoindolyl, 3,4-indazolyl, 3,5 30 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 27 WO 00/69832 PCT/USOO/09806 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 5 quinolinyl, 4 ,8-quinolinyl, 1, 4 -isoquinolinyl, 1,5-isoquinolinyl, 1,6 isoquinolinyl, 1, 7 -isoquinolinyl, 1,8-isoquinolinyl, 3,4-isoquinolinyl, 3,5 isoquinolinyl, 3,6-isoquinolinyl, 3, 7 -isoquinolinyl, 3,8-isoquinolinyl, 4,5 isoquinolinyl, 4

,

6 -isoquinolinyl, 4

,

7 -isoquinolinyl, 4 ,8-isoquinolinyl, 3,4 cinnolinyl, 3,5-cinnolinyl, 3,6-cinnolinyl, 3, 7 -cinnolinyl, 3,8-cinnolinyl, 4,5 10 cinnolinyl, 4,6-cinnolinyl, 4,7-cinnolinyl, and 4,8-cinnolinyl, and each carbon and hydrido containing nitrogen member of the ring of the W other than the points of attachment is optionally substituted with one or more of the group 9 10 11 12 b consisting of R , R , R , and R , with the proviso that Q is bonded to lowest number substituent position of each W5 and that (CH(R 38))r is bonded 15 to EO;

Y

0 is optionally Qb_Q ssssr wherein Qssssr is (CH(R 3 8 )r-W6, r is an 6 integer selected from 1 through 3, W 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, 20 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, 2,4-imidazo(1,2-a)pyridinyl, 2,5 25 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-indolyl, 2,5 indolyl, 2,6-indolyl, 2,7-indolyl, 3,4-indolyl, 3,5-indolyl, 3,6-indolyl, 3,7 indolyl, 1,4-isoindolyl, 1,5-isoindolyl, 1, 6 -isoindolyl, 2,4-isoindolyl, 2,5 30 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, 28 WO 00/69832 PCT/USOO/09806 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 5 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 10 cinnolinyl, 3,5-cinnolinyl, 3,6-cinnolinyl, 3,7-cinnolinyl, 3,8-cinnolinyl, 4,5 cinnolinyl, 4 ,6-cinnolinyl, 4

,

7 -cinnolinyl, and 4,8-cinnolinyl, and each carbon and hydrido containing nitrogen member of the ring of the W6 other than the othe thn h points of attachment is optionally substituted with one or more of the group 9 10 11 12 b consisting of R , R , R , and R , with the proviso that Q is bonded to 15 highest number substituent position of each W6 and that (CH(R 38)r is bonded to E. In an embodiment of compounds of Formula I or a pharmaceutically acceptable salt thereof, J is selected from the group consisting of 0 and S; 20 J is optionally selected from the group consisting of CH-R6 and N-R6 wherein R6 is a linear spacer moiety having a chain length of 1 to 4 atoms linked to the point of bonding of a substituent selected from the group 4a 4b 3 9 40 5 14 15 consisting of R , Rb, R3, R , R5, R , and R to form a heterocyclyl ring having 5 through 8 contiguous members; 25 B is formula (V): 29 WO 00/69832 PCT/USOO/09806

R

3 4 33 i 35 R K 2 1,R 1 2 R32~ D DR3 (V) wherein D , D , , J and K are independently selected from the group consisting of C, N, 0, S and a covalent bond with the provisos that no more 1 2 12 1 than one is a covalent bond, no more than one of D , D , , 2 and K is O, 1 2 12 1 1 21 2 5 no more than one of D, D ,1 ,J and K is S, one of D , D2 , J and 1 1 21 2 1 K must be a covalent bond when two of D , D , , J and K are O and S, 1 2 12 1 and no more than four of D , D , , J and K are N with the proviso that 32 33 34 35 36 R3, R3, R , R , and R are each independently selected to maintain the tetravalent nature of carbon, trivalent nature of nitrogen, the divalent nature of 10 sulfur, and the divalent nature of oxygen; 9 10 11 12 13 16 17 18 19 32 33 34 R , R , R , R , R 3, R , R , R1, R , R3, R3, R R 35, and R36 are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, dialkylsulfonium, trialkylphosphonium, dialkylsulfoniumalkyl, carboxy, heteroaralkylthio, 15 heteroaralkoxy, cycloalkylamino, acylalkyl, acylalkoxy, aryloylalkoxy, heterocyclyloxy, aralkylaryl, aralkyl, aralkenyl, aralkynyl, heterocyclyl, perhaloaralkyl, aralkylsulfonyl, aralkylsulfonylalkyl, aralkylsulfinyl, aralkylsulfinylalkyl, halocycloalkyl, halocycloalkenyl, cycloalkylsulfinyl, cycloalkylsulfinylalkyl, cycloalkylsulfonyl, cycloalkylsulfonylalkyl, 20 heteroarylamino, N-heteroarylamino-N-alkylamino, heteroarylaminoalkyl, haloalkylthio, alkanoyloxy, alkoxy, alkoxyalkyl, haloalkoxylalkyl, heteroaralkoxy, cycloalkoxy, cycloalkenyloxy, cycloalkoxyalkyl, cycloalkylalkoxy, cycloalkenyloxyalkyl, cycloalkylenedioxy, halocycloalkoxy, 30 WO 00/69832 PCT/USOO/09806 halocycloalkoxyalkyl, halocycloalkenyloxy, halocycloalkenyloxyalkyl, hydroxy, amino, alkoxyamino, thio, nitro, lower alkylamino, alkylthio, alkylthioalkyl, arylamino, aralkylamino, arylthio, arylthioalkyl, heteroaralkoxyalkyl, alkylsulfinyl, alkylsulfinylalkyl, arylsulfinylalkyl, 5 arylsulfonylalkyl, heteroarylsulfinylalkyl, heteroarylsulfonylalkyl, alkylsulfonyl, alkylsulfonylalkyl, haloalkylsulfinylalkyl, haloalkylsulfonylalkyl, alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, monoarylamidosulfonyl, arylsulfonamido, diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl, 10 arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, heterocyclylsulfonyl, heterocyclylthio, alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, haloalkanoyl, alkyl, alkenyl, alkynyl, alkenyloxy, alkenyloxyalky, alkylenedioxy, haloalkylenedioxy, cycloalkyl, cycloalkylalkanoyl, cycloalkenyl, lower cycloalkylalkyl, lower 15 cycloalkenylalkyl, halo, haloalkyl, haloalkenyl, haloalkoxy, hydroxyhaloalkyl, hydroxyaralkyl, hydroxyalkyl, alkylenylamino, hydoxyheteroaralkyl, haloalkoxyalkyl, aryl, aralkyl, aryloxy, aralkoxy, aryloxyalkyl, saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl, heteroaryloxy, heteroaryloxyalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, 20 carboxyalkyl, carboalkoxy, alkoxycarboxamido, alkylamidocarbonylamido, arylarnidocarbonylamido, carboalkoxyalkyl, carboalkoxyalkenyl, carboxy, carboaralkoxy, carboxamido, carboxamidoalkyl, cyano, carbohaloalkoxy, phosphono, phosphonoalkyl, diaralkoxyphosphono, and diaralkoxyphosphonoalkyl; 16 19 32 33 34 35 36 25 R , R , R , R , R , R3, and R are independently optionally b 16 19 b Q with the proviso that no more than one of R and R is Q at the same time and that Qb be 32 33 33 34 34 35 35 36 R and R3, R and R3, R and R and R andR are independently optionally selected to form a spacer pair wherein a spacer pair is 30 taken together to form a linear moiety having from 3 through 6 contiguous atoms connecting the points of bonding of said spacer pair members to form a ring selected from the group consisting of a cycloalkenyl ring having 5 through 8 contiguous members, a partially saturated heterocyclyl ring having 5 through 31 WO 00/69832 PCT/USOO/09806 8 contiguous members, a heteroaryl ring having 5 through 6 contiguous members, and an aryl with the proviso that no more than one of the group 32 33 33 34 34 35 35 consisting of spacer pairs R and R , R and R , R and R , and R and R36 can be used at the same time; 9 10 10 11 11 12 12 13 5 R and R1, R and R , R and R and R and R are independently optionally selected to form a spacer pair wherein a spacer pair is taken together to form a linear moiety having from 3 through 6 contiguous atoms connecting the points of bonding of said spacer pair members to form a ring selected from the group consisting of a cycloalkenyl ring having 5 through 10 8 contiguous members, a partially saturated heterocyclyl ring having 5 through 8 contiguous members, a heteroaryl ring having 5 through 6 contiguous members, and an aryl with the proviso that no more than one of the group 9 10 10 11 11 12 12 consisting of spacer pairs R and R , R and R , R and R1, and R and R13 can be used at the same time; 15 B is optionally selected from the group consisting of hydrido, trialkylsilyl, C2-C8 alkyl, C3-C8 alkylenyl, C3-C8 alkenyl, C3-C8 alkynyl, C2-C8 haloalkyl, and C3-C8 haloalkenyl wherein each member of group B may be optionally substituted at any carbon up to and including 6 atoms from the point of attachment of B to A with one or more of the group consisting of 32 33 34 35 36 20 R R R3, R3, and R B is optionally selected from the group consisting of C3-C15 cycloalkyl, C5-C1O cycloalkenyl, C4-C12 saturated heterocyclyl, and C4-C9 partially saturated heterocyclyl, wherein each ring carbon is optionally 33 substituted with R , a ring carbon other than the ring carbon at the point of 25 attachment of B to A is optionally substituted with oxo provided that no more than one ring carbon is substituted by oxo at the same time, ring carbon and nitrogen atoms adjacent to the carbon atom at the point of attachment is 9 13 optionally substituted with R or R , a ring carbon or nitrogen atom adjacent to the R9 position and two atoms from the point of attachment is optionally 32 WO 00/69832 PCT/USOO/09806 10 13 substituted with R , a ring carbon or nitrogen atom adjacent to the R position and two atoms from the point of attachment is optionally substituted 12 with R , a ring carbon or nitrogen atom three atoms from the point of 10 1 attachment and adjacent to the R position is optionally substituted with R 5 a ring carbon or nitrogen atom three atoms from the point of attachment and 12 33 adjacent to the R position is optionally substituted with R , and a ring carbon or nitrogen atom four atoms from the point of attachment and adjacent to the R and R33 positions is optionally substituted with R34 A is selected from the group consisting of single covalent bond, 10 (W )rr-(CH(R 15))pa and (CH(R 15))pa-(W )rr wherein rr is an integer selected from 0 through 1, pa is an integer selected from 0 through 6, and W is selected from the group consisting of 0, S, C(O), C(S), C(O)S, C(S)O, C(O)N(R ), C(S)N(R ), (R )NC(O), (R )NC(S), S(O), S(0) 2 , S(0) 2 N(R ), (R )NS(O) 2 , P(O)(R 8), N(R )P(O)(R 8), P(O)(R 8)N(R ), 15 C(NR )N(R ), (R 7)NC(NR ), (R )NC(NR )NR , and N(R ) with the proviso that no more than one of the group consisting of rr and pa can be 0 at the same time; R and R8 are independently selected from the group consisting of hydrido, hydroxy, alkyl, acyl, aroyl, heteroaroyl, and alkoxyalkyl; 14 15 37 38 20 R , R , R , and R are independently selected from the group consisting of hydrido, hydroxy, halo, cyano, hydroxyalkyl, alkoxy, alkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxyalkyl, carboxy, 25 carboxyalkyl, carboalkoxy, carboxamide, and carboxamidoalkyl; 33 WO 00/69832 PCT/US00/09806 R14 and R38 can be independently selected from the group consisting of acyl, aroyl, and heteroaroyl with the proviso that acyl is selected from other than formyl and 2-oxoacyl; 5 TP is selected from the group consisting of NR , 0, C(O), C(S), S, 5 S(O), S(0) 2 , ON(R 5), P(O)(R 8), and CR39R ; R5 is selected from the group consisting of hydrido, hydroxy, amino, alkyl, alkoxy, alkoxyalkyl, haloalkyl, acyl, aroyl, and heteroaroyl; 39 40 R and R are independently selected from the group consisting of hydrido, hydroxy, halo, cyano, hydroxyalkyl, acyl, aroyl, heteroaroyl, 10 acylamido, alkoxy, alkyl, alkoxyalkyl, haloalkyl, haloalkoxy, haloalkoxyalkyl, alkylsulfonyl, haloalkylsulfonyl, carboxy, carboxyalkyl, carboalkoxy, carboxamide, and carboxamidoalkyl; M is selected from the group consisting of N and R -C; R2 and R 1 are independently selected from the group consisting of Z 0 15 Q, hydrido, alkyl, alkenyl, and halo; R 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, 20 arylamino, aralkylamino, alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, haloalkanoyl, hydroxyhaloalkyl, cyano, and phosphono; Z is selected from the group consisting of covalent single bond, 41 42 4 (CR R )q wherein q is an integer selected from 1 through 6, (CH(R W'-(CH(R 42)), wherein g and p are integers independently selected from 0 25 through 3 and WO is selected from the group consisting of 0, S, C(O), C(S), C(0)0, C(S)O, C(O)S, C(S)S, C(O)N(R 41), (R 41)NC(0), C(S)N(R 41), (R 41)NC(S), OC(O)N(R 41), (R 41)NC(0)0, SC(S)N(R 41), (R 41)NC(S)S, 34 WO 00/69832 PCT/USOO/09806 SC(O)N(R 41), (R 41)NC(O)S, OC(S)N(R 41), (R 41)NC(S)O, N(R42)C(O)N(R 41), (R 41)NC(O)N(R42), N(R42)C(S)N(R 41), (R 41)NC(S)N(R 42), S(O), S(O) 2 , S(O) 2 N(R41), N(R 41)S(O) 2 , Se, Se(O), Se(O) 2 , Se(O) 2 N(R41), N(R 41)Se(O) 2 , P(O)(R8), N(R )P(O)(R8), 5 P(O)(R 8 )N(R 7 ), N(R 4 1 ), ON(R 4 1 ), and SiR 2 8

R

2 9 , and (CH(R 4 1 ))e-W 2 2 (CH(R 42)h wherein e and h are integers independently selected from 0 through 2 and 2 s selected from the group consisting of CR 41=CR42 CR 41R 42=C; vinylidene), ethynylidene (C=C; 1,2-ethynyl), 1,2-cyclopropyl, 1,2-cyclobutyl, 1,2-cyclohexyl, 1,3-cyclohexyl, 1,2-cyclopentyl, 1,3 10 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 15 pyrrolidinyl, 2

,

3 -tetrahydrofuranyl, 2,4-tetrahydrofuranyl, 2,5 tetrahydrofuranyl, and 3,4-tetrahydrofuranyl, with the provisos that R4 and R42 are selected from other than halo and cyano when directly bonded to N and Z is directly bonded to the pyrimidinone ring; 41 42 R and R are independently selected from the group consisting of 20 amidino, hydroxyamino, hydrido, hydroxy, amino, halo, cyano, aryloxy, hydroxyalkyl, acyl, aroyl, heteroaroyl, heteroaryloxyalkyl, alkoxy, alkyl, aryl, aralkyl, aryloxyalkyl, aralkoxyalkylalkoxy, alkoxyalkyl, heteroaryloxyalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxy, 25 haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxyalkyl, saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl, heteroaralkyl, heteroarylthioalkyl, heteroaralkylthioalkyl, alkylsulfonyl, haloalkylsulfonyl, arylsulfonyl, 35 WO 00/69832 PCT/USOO/09806 arylsulfonylalkyl, aralkylsulfonyl, cycloalkylsulfonyl, cycloalkylsufonylalkyl, heteroarylsulfonylalkyl, heteroarylsulfonyl, and aralkylsulfonylalkyl; Q is formula (II): 10 Ri 1 Ri K 2 R1 1." 2 R1. Di 10 D2 R13 (II) 1 2 12 1 5 wherein D , D , , J and K are independently selected from the group consisting of C, N, 0, S and a covalent bond with the provisos that no more 1 2 12 1 than one is a covalent bond, no more than one of D , D , , J and K isO, 1 2 12 1 1 21 2 no more than one of D , D , , J and K is S, one of D , D2 , J and 1 1 21 21 K must be a covalent bond when two of D, D , , J and K are O and S, 1 2 12 1 10 and no more than four of D, D ,1 ,J and K are N, with the proviso that 9 10 11 12 13 R , R , R , R , and R are each independently selected to maintain the tetravalent nature of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen; Q is optionally selected from formula (III): RiR RD---D 34 4

.---

D ""l R2 15(11 wherein D 3, D 4, J 3, and J4 are independently selected from the group consisting of C, N, 0, and S, no more than one of D , D , J , and J is 0, no 36 WO 00/69832 PCT/US00/09806 more than one of D 3, D 4, J 3, and J4 is S, and no more than three of D , D2 1 2 9 10 11 12 J , and J are N with the proviso that R , R1, R , and R are each independently selected to maintain the tetravalent nature of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of 5 oxygen; 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, cycloalkylalkenyl, 10 haloalkyl, haloalkoxy, haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxyalkyl, and halocycloalkenyloxyalkyl with the proviso that Z is selected from other than a single covalent bond when Q is hydrido; K is (CR R n4b wherein n is an integer selected from 1 through 2; 15 R and R4b are independently selected from the group consisting of halo, hydrido, hydroxy, cyano, hydroxyalkyl, alkyl, alkenyl, alkoxyalkyl, aralkyl, heteroaralkyl, alkylthioalkyl, haloalkyl, haloalkenyl, and cyanoalkyl; E 1 ~ 4a 4b I is E, when K is (CR R )n, wherein E is selected from the group consisting of a covalent single bond, 0, S, C(O), C(S), C(0)0, C(S)O, 20 C(O)S, C(S)S, C(O)N(R ), (R )NC(O), C(S)N(R ), (R )NC(S), OC(O)N(R ), (R )NC(0)0, SC(S)N(R ), (R )NC(S)S, SC(O)N(R ), (R )NC(O)S, OC(S)N(R ), (R )NC(S)O, N(R 8)C(O)N(R ), (R )NC(O)N(R 8), N(R 8)C(S)N(R ), (R )NC(S)N(R 8), S(O), S(0) 2 , S(0) 2 N(R ), N(R )S(0) 2 , S(0) 2 N(R )C(O), C(O)N(R )S(0) 2 , P(O)(R 8 25 N(R )P(O)(R 8), P(O)(R8)N(R ), N(R ), ON(R ), CR =CR4b ethynylidene (CaC; 1,2-ethynyl), and C=CRaR 4 b; 37 WO 00/69832 PCT/USOO/09806 K is optionally (CH(R14))J-T wherein j is selected from a integer from 0 through 2 and T is selected from the group consisting of single covalent bond, 0, S, and N(R ) with the proviso that (CH(R 1)) is bonded to the pyrimidinone ring; 5 EO is optionally E2, when K is (CH(R 4)),-T, wherein E2 is selected from the group consisting of a covalent single bond, C(O), C(S), C(O)0. C(S)O, C(O)S, C(S)S, C(O)N(R ), (R )NC(O), C(S)N(R ), (R )NC(S), (R )NC(0)0, (R )NC(S)S, (R )NC(O)S, (R )NC(S)O, N(R 8)C(O)N(R ), (R )NC(O)N(R 8), N(R 8)C(S)N(R ), (R )NC(S)N(R8), S(O), S(0)2, 10 S(O) 2 N(R ), N(R )S(0)2, S(0) 2 N(H)C(O), C(O)N(H)S(0) 2 , P(O)(R 8 N(R )P(0)(R 8), P(O)(R 8)N(R ), and N(R ); K is optionally G-(CH(R 15)k wherein k is selected from an integer from 1 through 2 and G is selected from the group consisting of 0, S, and N(R ) with the proviso that R15 is other than hydroxy, cyano, halo, amino, 15 alkylamino, dialkylamino, and sulfhydryl when k is 1; E is optionally E when K is G-(CH(R 15))k, wherein E3 is selected from the group consisting of a covalent single bond, 0, S, C(O), C(S), C(O)0, C(S)O, C(O)S, C(S)S, C(O)N(R ), (R 7)NC(O), C(S)N(R ), (R )NC(S), OC(0)N(R ), (R )NC(0)0, SC(S)N(R ), (R )NC(S)S, 20 SC(O)N(R 7), (R )NC(O)S, OC(S)N(R ), (R )NC(S)O, N(R 8)C(O)N(R ), (R )NC(O)N(R 8), N(R 8)C(S)N(R ), (R )NC(S)N(R 8), S(O), S(0) 2 , S(0) 2 N(R ), N(R )S(0)2, P(O)(R8), N(R )P(O)(R 8), P(O)(R8)N(R ), 38 WO 00/69832 PCT/USOO/09806 N(R ), ON(R ), CR =CR 4b, ethynylidene (CmC; 1,2-ethynyl), and C=CR R4b YO is formula (IV): S R1 7 R18 R160 K2 R19 lb Q (IV) 5 65 6 5 wherein D , D , J , and J are independently selected from the group consisting of C, N, 0, S and a covalent bond with the provisos that no more than one is a covalent bond, K2 is independently selected from the group + 5 65 6 consisting of C and N+, no more than one of D , D , J ,and J is 0, no more 5 65 6 5 65 6 than one of D5, D , J and J is S, one of D5, D , J ,and 6 must be a 5 65 6 10 covalent bond when two of D , D , J , and J are 0 and S, no more than 5 65 6 2 + three of D D , J ,and J is N when K is N+, and no more than four of 5 65 6 2 16 17 D , D , J , and J are N when K is carbon with the provisos that R , R , 18 19 R , and R are each independently selected to maintain the tetravalent nature of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the 15 divalent nature of oxygen; R16 and R17 are optionally independently taken together to form a linear moiety spacer having from 3 through 6 contiguous atoms connected to form a ring selected from the group consisting of a cycloalkenyl ring having from 5 through 8 contiguous members, a partially saturated heterocyclyl ring 20 having from 5 through 8 contiguous members, a heteroaryl having from 5 through 6 contiguous members, and an aryl; 39 WO 00/69832 PCT/USOO/09806 b. 20 21 Q is selected from the group consisting of NR R NR0R R , oxy, alkyl, aminoalkylenyl, alkylamino, dialkylamino, be be 20 dialkylsulfoniumalkyl, acylamino and Q , wherein Q is hydrido and R 21 22 R1, and R are independently selected from the group consisting of hydrido, 5 amino, alkyl, hydroxy, alkoxy, aminoalkylenyl,alkylamino, dialkylamino, and 20 21 22 hydroxyalkyl with the provisos that no more than one of R , R , and R is hydroxy, alkoxy, alkylamino, amino, and dialkylamino at the same time and 20 21 22 that R , R , and R must be other than be hydroxy, alkoxy, alkylamino, amino, and dialkylamino when K2 is N+ 20 21 20 22 21 22 10 R and R2, R and R2, and R and R are independently optionally selected to form a spacer pair wherein a spacer pair is taken together to form a linear moiety having from 4 through 7 contiguous atoms connecting the points of bonding of said spacer pair members to form a heterocyclyl ring having 5 through 8 contiguous members with the proviso that no more than 20 21 20 22 15 one of the group consisting of spacer pairs R and R , R and R , and R21 and R22 is used at the same time; Qb is optionally selected from the group consisting of 26 23 2 265 26 5 N(R )SO 2 N(R )(R ), N(R26)C(O)OR , N(R )C(O)SR5 N(R 26)C(S)OR5 and N(R 26)C(S)SR5 with the proviso that no more than one 23 24 26 20 of R , R , and R is hydroxy, alkoxy, alkylamino, amino, and 23 24 26 dialkylamino when two of the group consisting of R , R , and R are bonded to the same atom; Qb is optionally selected from the group consisting of 25 224 dialkylsulfonium, trialkylphosphonium, C(NR )N23R 40 WO 00/69832 PCT/USOO/09806 N(R 26)C(NR 25)N(R )(R 24), N(R 26)C(O)N(R )(R24), 26 23 24 25 5 N(R )C(S)N(R )(R ), C(NR )OR5 C(O)N(R )C(NR 25)N(R )(R 24), C(S)N(R 26)C(NR 25)N(R )(R 24 N(R 26)N(R 26)C(NR 25)N(R )(R 24), ON(R 26)C(NR 25)N(R )(R ), 26 26 23 24 25 5 23 24 5 N(R )N(R )SO 2 N(R )(R ), C(NR )SR , C(O)NR R , and 224 23 24 26 C(O)NR R with the provisos that no more than one of R , R , and R can be hydroxy, alkoxy, alkylaminol, amino, or dialkylamino when two of the 23 24 26 group consisting of R , R , and R are bonded to the same atom and that said Qb group is bonded directly to a carbon atom; 23 24 25 26 10 R , R , R , and R are independently selected from the group consisting of hydrido, alkyl, hydroxy, alkoxy, aminoalkylenyl, alkylamino, dialkylamino, amino, and hydroxyalkyl; R and R24 are optionally taken together to form a linear spacer moiety having from 4 through 7 contiguous atoms connecting the points of bonding to 15 form a heterocyclyl ring having 5 through 8 contiguous members; Q is selected from the group consisting of a single covalent bond, (R37 R38 o (CR3 R )b-(W )az wherein az is an integer selected from 0 through 1, b is an integer selected from 1 through 4, and Wo is selected from the group consisting of 0, S, C(O), C(S), C(O)0, C(S)O, C(O)S, C(S)S, C(O)N(R 4), 20 (R 14)NC(O), C(S)N(R 4), (R 14)NC(S), OC(O)N(R 14), SC(S)N(R 14 SC(O)N(R 14), OC(S)N(R 14), N(R 15)C(O)N(R 14), (R 14)NC(O)N(R 15 N(R 15)C(S)N(R 14), (R 4)NC(S)N(R 15), S(O), S(O) 2 , S(O) 2 N(R 4 N(R 14)S(0)2, P(O)(R 8), N(R )P(O)(R8), P(O)(R8)N(R ), N(R 14 41 WO 00/69832 PCT/USOO/09806 ON(R 14), (CH(R 14))c-W -(CH(R 15)d wherein c and d are integers independently selected from 1 through 4, and W1 is selected from the group consisting of 0, S, C(O), C(S), C(0)0, C(S)O, C(O)S, C(S)S, C(O)N(R 14), (R 4)NC(O), C(S)N(R 14), (R 14)NC(S), OC(O)N(R 14), (R 14)NC(0)0, 5 SC(S)N(R 14), (R 14)NC(S)S, SC(O)N(R 14), (R 14)NC(O)S, OC(S)N(R 14), (R 14)NC(S)O, N(R15 )C(O)N(R 14), (R 14)NC(O)N(R 15), N(R15)C(S)N(R 14), (R14 )NC(S)N(R15 S(O), S()2, S()2N(R14 N(R 14)S(0)2, P(O)(R 8), N(R )P(O)(R 8), P(O)(R 8)N(R ), N(R 4), ON(R 14), and (CH(R1 4 )) W 22

(CH(R

15 ))h wherein e and h are integers 10 independently selected from 0 through 2 and 2is selected from the group consisting of CR4 =CR42, CR1R 42=C; vinylidene), ethynylidene (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 15 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 20 provisos that R14 and R15 are selected from other than halo and cyano when directly bonded to N and that (CR 37R 38)b, (CH(R 14))c, (CH(R 4))e and are bonded to 0 ; YO is optionally Qb Qss wherein Qss is selected from the group consisting of (CR37 R 38)f wherein f is an integer selected from 1 through 6, 42 WO 00/69832 PCT/USOO/09806 (CH(R 14))c-W -(CH(R 15)d wherein c and d are integers independently selected from 1 through 4, and W is selected from the group consisting of W is selected from the group consisting of 0, 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), 5 OC(O)N(R 14), (R 14)NC(O)0, SC(S)N(R 14), (R 14)NC(S)S, SC(O)N(R 14), (R 14)NC(O)S, OC(S)N(R 14), (R 14)NC(S)O, N(R 15)C(O)N(R 14), (R 14)NC(O)N(R 15), N(R 15)C(S)N(R 14), (R 14)NC(S)N(R 15), S(O), S(0) 2 , S(0) 2 N(R 14), N(R 14)S(0)2, P(O)(R 8), N(R )P(O)(R8 ), P(O)(R 8)N(R ), N(R 4), ON(R 14), and (CH(R 14))e-W2-(CH(R15))h 10 wherein e and h are integers independently selected from 0 through 2 and W 4a 4b is selected from the group consisting of CR =CR , ethynylidene (CiC; 1,2 An4b 14 15 ethynyl), and C=CR R4b with the provisos that R and R are selected from other than halo and cyano when directly bonded to N and that (CR37 R 38)f, (CH(R 14))c, and (CH(R 14))e are bonded to E; 15 YO is optionally Qb_Q ss wherein Qsss is (CH(R 38))r-W , r is an integer selected from 1 through 3, W 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, 1,3-cyclopentyl, 2,3-morpholinyl, 2,4-morpholinyl, 2,5-morpholinyl, 2,6-morpholinyl, 3,4 20 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 25 pyrrolidinyl, 3,4-pyrrolidinyl, 2H-2,3-pyranyl, 2H-2,4-pyranyl, 2H-2,5 43 WO 00/69832 PCT/USOO/09806 pyranyl, 4H-2,3-pyranyl, 4H-2,4-pyranyl, 4 H-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 5 tetrahydropyranyl, 2,6-tetrahydropyranyl, 3

,

4 -tetrahydropyranyl, and 3,5 tetrahydropyranyl, and each carbon and hyrido containing nitrogen member of the ring of the W 3 other than the points of attachment is optionally substituted 9 10 11 12 with one or more of the group consisting of R , R1, R , and R1, with the proviso that (CH(R 38))r is bonded to E and Qb is bonded to lowest numbered 10 substituent position of each W 3 ; Y is optionally Qb_ sssr wherein Qsssr is (CH(R 38))r-W 4, r is an 4 integer selected from 1 through 3, W 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 15 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, 3,5piperidinyl, 3,6-piperidinyl, 1,2-pyrrolidinyl, 1,3-pyrrolidinyl, 2,3 20 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 25 tetrahydropyranyl, 2,5-tetrahydropyranyl, 2,6-tetrahydropyranyl, 3,4 tetrahydropyranyl, and 3,5-tetrahydropyranyl, and each carbon and hydrido containing nitrogen member of the ring of the W4 other than the points of attachment is optionally substituted with one or more of the group consisting of 44 WO 00/69832 PCT/USOO/09806 9 10 11 12 38 0 R , R , R , and R , with the provisos that (CH(R ))r is bonded to E and Qb is bonded to highest number substituent position of each W YO is optionally Qb Qssss wherein Qssss is (CH(R38 )r-W5, r is an integer selected from 1 through 3, W is selected from the group consisting of 5 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-benzofuranyl, 3,5-benzofuranyl, 3,6-benzofuranyl, 3,7-benzofuranyl, 2,4-benzothiophenyl, 2,5-benzothiophenyl, 2,6-benzothiophenyl, 2,7 10 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)pyridinyl, 3,6-imidazo(1,2 a)pyridinyl, 3,7-imidazo(1,2-a)pyridinyl, 2,4-indolyl, 2,5-indolyl, 2,6 indolyl, 2,7-indolyl, 3,4-indolyl, 3,5-indolyl, 3,6-indolyl, 3,7-indolyl, 1,4 15 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, 20 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 25 isoquinolinyl, 1,8-isoquinolinyl, 3,4-isoquinolinyl, 3,5-isoquinolinyl, 3,6 isoquinolinyl, 3, 7 -isoquinolinyl, 3,8-isoquinolinyl, 4 ,5-isoquinolinyl, 4,6 isoquinolinyl, 4

,

7 -isoquinolinyl, 4

,

8 -isoquinolinyl, 3,4-cinnolinyl, 3,5 cinnolinyl, 3,6-cinnolinyl, 3,7-cinnolinyl, 3,8-cinnolinyl, 4,5-cinnolinyl, 4,6 cinnolinyl, 4,7-cinnolinyl, and 4,8-cinnolinyl, and each carbon and hydrido 30 containing nitrogen member of the ring of the W other than the points of attachment is optionally substituted with one or more of the group consisting of 45 WO 00/69832 PCT/USOO/09806 9 10 11 12 b R , R , R , and R , with the proviso that Q is bonded to lowest number substituent position of each W and that (CH(R38)r is bonded to E; YO is optionally QbQssssr wherein Qssssr is (CH(R 3 8 ))r-W 6 , r is an integer selected from 1 through 3, W is selected from the group consisting of 5 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-benzofuranyl, 3,5-benzofuranyl, 3,6-benzofuranyl, 3,7-benzofuranyl, 2,4-benzothiophenyl, 2,5-benzothiophenyl, 2,6-benzothiophenyl, 2,7 10 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)pyridinyl, 3,6-imidazo(1,2 a)pyridinyl, 3,7-imidazo(1,2-a)pyridinyl, 2,4-indolyl, 2,5-indolyl, 2,6 indolyl, 2,7-indolyl, 3,4-indolyl, 3,5-indolyl, 3,6-indolyl, 3,7-indolyl, 1,4 15 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, 20 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 25 isoquinolinyl, 1,8-isoquinolinyl, 3,4-isoquinolinyl, 3,5-isoquinolinyl, 3,6 isoquinolinyl, 3,7-isoquinolinyl, 3,8-isoquinolinyl, 4,5-isoquinolinyl, 4,6 isoquinolinyl, 4

,

7 -isoquinolinyl, 4 ,8-isoquinolinyl, 3,4-cinnolinyl, 3,5 cinnolinyl, 3,6-cinnolinyl, 3,7-cinnolinyl, 3,8-cinnolinyl, 4,5-cinnolinyl, 4,6 cinnolinyl, 4,7-cinnolinyl, and 4,8-cinnolinyl, and each carbon and hydrido 30 containing nitrogen member of the ring of the W6 other than the points of attachment is optionally substituted with one or more of the group consisting of 46 WO 00/69832 PCT/USOO/09806 9 10 11 12 b R, R10, R , and R , with the proviso that Q is bonded to highest number 6 38 0 substituent position of each W and that (CH(R ))r is bonded to E In another embodiment of compounds of Formula I or a pharmaceutically acceptable salt thereof, 5 J is selected from the group consisting of 0 and S; B is formula (V):

R

3 4 33 1i 35 R 1."K 2 I'lR 1i 2 R32 D D R36 (V) wherein D , D2 , J 2 and K are independently selected from the group consisting of C, N, 0, S and a covalent bond with the provisos that no more 1 2 12 1 10 than one is a covalent bond, no more than one of D , D , , J and K is 0, 1 2 12 1 1 21 2 no more than one of D , D , , and K is S, one of D, D2 ,1 J and 1 1 2 12 1 K must be a covalent bond when two of D, D , , J and K are 0 and S, 1 2 12 1 and no more than four of D, D , , J and K are N;

R

9 , R 10 , R 1 1

R

12

R

13

R

16

R

17

R

18

R

19

R

3 2

R

3 3

R

3 4 15 R 35, and R36 are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, dialkylsulfonium, trialkylphosphonium, dialkylsulfoniumalkyl, carboxy, heteroaralkylthio, heteroaralkoxy, cycloalkylamino, acylalkyl, acylalkoxy, aryloylalkoxy, heterocyclyloxy, aralkylaryl, aralkyl, aralkenyl, aralkynyl, heterocyclyl, 20 perhaloaralkyl, aralkylsulfonyl, aralkylsulfonylalkyl, aralkylsulfinyl, aralkylsulfinylalkyl, halocycloalkyl, halocycloalkenyl, cycloalkylsulfinyl, cycloalkylsulfinylalkyl, cycloalkylsulfonyl, cycloalkylsulfonylalkyl, 47 WO 00/69832 PCT/USOO/09806 heteroarylamino, N-heteroarylamino-N-alkylamino, heteroarylaminoalkyl, haloalkylthio, alkanoyloxy, alkoxy, alkoxyalkyl, haloalkoxylalkyl, heteroaralkoxy, cycloalkoxy, cycloalkenyloxy, cycloalkoxyalkyl, cycloalkylalkoxy, cycloalkenyloxyalkyl, cycloalkylenedioxy, halocycloalkoxy, 5 halocycloalkoxyalkyl, halocycloalkenyloxy, halocycloalkenyloxyalkyl, hydroxy, amino, alkoxyamino, thio, nitro, lower alkylamino, alkylthio, alkylthioalkyl, arylanino, aralkylamino, arylthio, arylthioalkyl, heteroaralkoxyalkyl, alkylsulfinyl, alkylsulfinylalkyl, arylsulfinylalkyl, arylsulfonylalkyl, heteroarylsulfinylalkyl, heteroarylsulfonylalkyl, 10 alkylsulfonyl, alkylsulfonylalkyl, haloalkylsulfinylalkyl, haloalkylsulfonylalkyl, alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, monoarylamidosulfonyl, arylsulfonamido, diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl, arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl, 15 heteroarylsulfonyl, heterocyclylsulfonyl, heterocyclylthio, alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, haloalkanoyl, alkyl, alkenyl, alkynyl, alkenyloxy, alkenyloxyalky, alkylenedioxy, haloalkylenedioxy, cycloalkyl, cycloalkylalkanoyl, cycloalkenyl, lower cycloalkylalkyl, lower cycloalkenylalkyl, halo, haloalkyl, haloalkenyl, haloalkoxy, hydroxyhaloalkyl, 20 hydroxyaralkyl, hydroxyalkyl, alkylenylamino, hydoxyheteroaralkyl, haloalkoxyalkyl, aryl, aralkyl, aryloxy, aralkoxy, aryloxyalkyl, saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl, heteroaryloxy, heteroaryloxyalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, carboxyalkyl, carboalkoxy, alkoxycarboxamido, alkylamidocarbonylamido, 25 arylamidocarbonylamido, carboalkoxyalkyl, carboalkoxyalkenyl, carboxy, carboaralkoxy, carboxamido, carboxamidoalkyl, cyano, carbohaloalkoxy, phosphono, phosphonoalkyl, diaralkoxyphosphono, and diaralkoxyphosphonoalkyl; 16 19 32 33 34 35 36 R , R , R , R , R , R , and R are independently optionally 30 Qb with the proviso that no more than one of R16 and R19 is Qb at the same time and that Qb be B is optionally selected from the group consisting of hydrido, trialkylsilyl, C2-C8 alkyl, C3-C8 alkylenyl, C3-C8 alkenyl, C3-C8 alkynyl, 48 WO 00/69832 PCT/USOO/09806 C2-C8 haloalkyl, and C3-C8 haloalkenyl wherein each member of group B is optionally substituted at any carbon up to and including 6 atoms from the point of attachment of B to A with one or more of the group consisting of R 32, R33 R34, R35, and R36 5 B is optionally selected from the group consisting of C3-C12 cycloalkyl, C5-C10 cycloalkenyl, and C4-C9 saturated heterocyclyl, wherein 33 each ring carbon is optionally substituted with R , a ring carbon other than the ring carbon at the point of attachment of B to A is optionally substituted with oxo provided that no more than one ring carbon is substituted by oxo at 10 the same time, ring carbon and nitrogen atoms adjacent to the carbon atom at 9 13 the point of attachment is optionally substituted with R or R1, a ring carbon or nitrogen atom adjacent to the R9 position and two atoms from the point of 10 attachment is optionally substituted with R , a ring carbon or nitrogen atom adjacent to the R13 position and two atoms from the point of attachment is 12 15 optionally substituted with R , a ring carbon or nitrogen atom three atoms from the point of attachment and adjacent to the R10 position is optionally substituted with R , a ring carbon or nitrogen atom three atoms from the point of attachment and adjacent to the R12 position is optionally substituted 33 with R , and a ring carbon or nitrogen atom four atoms from the point of 20 attachment and adjacent to the R and R33 positions is optionally substituted with R34 A is selected from the group consisting of single covalent bond, (W )rr-(CH(R 15))pa and (CH(R 15))pa-(W )rr wherein rr is an integer 7 selected from 0 through 1, pa is an integer selected from 0 through 6, and W 49 WO 00/69832 PCT/USOO/09806 is selected from the group consisting of 0, S, C(O), C(O)N(R ), C(S)N(R ), (R )NC(O), (R )NC(S), and N(R ) with the proviso that no more than one of the group consisting of rr and pa can be 0 at the same time; R and R8 are independently selected from the group consisting of 5 hydrido, hydroxy, alkyl, and alkoxyalkyl; 14 15 37 38 R , R , R3, and R are independently selected from the group consisting of hydrido, hydroxy, halo, alkyl, alkoxyalkyl, haloalkyl, haloalkoxy, and haloalkoxyalkyl; R14 and R38 can be independently selected from the group consisting 10 of aroyl and heteroaroyl; 55 W is selected from the group consisting of NR5, C(O), and S(O)2; R5 is selected from the group consisting of hydrido, hydroxy, alkyl, and alkoxy; R39 and R are independently selected from the group consisting of 15 hydrido, hydroxy, halo, hydroxyalkyl, alkyl, alkoxyalkyl, haloalkyl, haloalkoxy, and haloalkoxyalkyl; M is selected from the group consisting of N and R -C; R is selected from the group consisting of hydrido, alkyl, alkenyl, cyano, halo, haloalkyl, haloalkoxy, haloalkylthio, amino, aminoalkyl, 20 alkylamino, amidino, guanidino, hydroxy, hydroxyamino, alkoxy, hydroxyalkyl, alkoxyamino, thiol, alkylthio, and phosphono; R2 is OQ Z is selected from the group consisting of covalent single bond, (CR 41R 42) wherein q is an integer selected from 1 through 3, (CH(R 41g 25 W-(CH(R 42)) wherein g and p are integers independently selected from 0 through 3 and W 0 is selected from the group consisting of O, S, C(O), S(O), 50 WO 00/69832 PCT/USOO/09806

S(O)

2 , N(R 41), and ON(R 41), and (CH(R 4 1 ))e-W 2 2 -(CH(R 42))h wherein e and h are integers independently selected from 0 through 2 and 2 is selected from the group consisting of CR 41=CR 42 .

2 -cyclopropyl, 1,2-cyclobutyl, 1,2-cyclohexyl, 1,3-cyclohexyl, 1,2-cyclopentyl, 1,3-cyclopentyl, 2,3 5 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 10 tetrahydrofuranyl, 2,4-tetrahydrofuranyl, 2,5-tetrahydrofuranyl, and 3,4 tetrahydrofuranyl, with the proviso that ZO is directly bonded to the pyrimidinone ring; R and R42 are independently selected from the group consisting of amidino, hydroxyamino, hydrido, hydroxy, amino, and alkyl; 15 Q is selected from the group consisting of hydrido, with the proviso that ZO is other than a covalent single bond, the formula (II): R10 K 2 R12 11 z 1 10 1 ~2 (II) 1 2 12 1 wherein D , D , 2 , and K are independently selected from the group consisting of C, N, 0, S and a covalent bond with the provisos that no more 1 2 12 1 20 than one is a covalent bond, no more than one of D , D , , 2 and K is 0, 1 2 12 1 1 2 12 no more than one of D, D ,1 ,J and K is S, one of D, D ,1 ,2 and 1 12 12 1 K must be a covalent bond when two of D , D , i , 2 and K are O and S, 51 WO 00/69832 PCT/USOO/09806 and no more than four of D , D , , J and K is N, with the proviso that 9 10 11 12 13 R , R , R , R , and R are each independently selected to maintain the tetravalent nature of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen; An4b 5 K is (CR aR )n wherein n is an integer selected from 1 through 2; R and R4b are independently selected from the group consisting of halo, hydrido, hydroxyalkyl, alkyl, alkoxyalkyl, alkylthioalkyl, and haloalkyl; O E is selected from the group consisting of a covalent single bond, C(O), C(S), C(O)N(R ), (R )NC(O), S(0)2, (R )NS(0) 2 , and S(0) 2 N(R ); 10 Y is formula (IV): S R17 * 6101 8 R' R' 5 6 R 1 6,D K2. D R1 9 lb Q (IV) wherein D 5, D6 , J and J6 are independently selected from the group consisting of C, N, 0, S and a covalent bond with the provisos that no more 2 5 65 6 than one is a covalent bond, K is C, no more than one of D D , and J 5 65 6 5 65 6 15 is O, no more than one of D5, D , ,and J is S, one of D D , and J 5 65 6 must be a covalent bond when two of D , D , 5 , and J are 0 and S, and no 5 65 6 2 more than four of D , D , J and J are N when K is carbon with the 16 17 18 19 provisos that R , R , R1, and R are each independently selected to maintain the tetravalent nature of carbon, trivalent nature of nitrogen, the 20 divalent nature of sulfur, and the divalent nature of oxygen; 52 WO 00/69832 PCT/USOO/09806 Qb is selected from the group consisting of NR 20R21 NR 20R 21R22, aminoalkylenyl, and Q be, wherein Qbe is hydrido and R20 21 22 R21, and R are independently selected from the group consisting of hydride, alkyl, hydroxy, amino, aminoalkylenyl, dialkylamino, alkylanino, and 5 hydroxyalkyl with the proviso that no more than one of R20 and R21 is hydroxy, amino, alkylamino, or dialkylamino at the same time; Qb is optionally selected from the group consisting of C(NR25 )N23R24, N(R 26)C(NR 25)N(R )(R24), C(O)N(R 26)C(NR 25)N(R )(R 24), N(R 26)N(R 26)C(NR 25)N(R )(R 24), 10 and ON(R 26)C(NR 25)N(R )(R24) with the provisos that no more than one 23 24 26 of R , R , and R is hydroxy, alkylamino, amino, or dialkylamino when 23 24 26 two of the group consisting of R , R , and R are bonded to the same atom; 23 24 25 26 R , R , R , and R are independently selected from the group 15 consisting of hydrido, alkyl, hydroxy, amino, alkylenylarnino, dialkylamino, alkylamino, and hydroxyalkyl; QS is selected from the group consisting of a single covalent bond,

(CR

3 7

R

3 8 )b-(W )az wherein az is an integer selected from 0 through 1, b is an integer selected from 1 through 5, and WO is selected from the group 20 consisting of 0, C(O), S(O), S(0) 2 , S(O) 2 N(R 14), N(R 14)S(0)2, and 14) 14))c 1l 15)) N(R ), (CH(R ))cW -(CH(R 1)d wherein c and d are integers independently selected from 1 through 4 and W is selected from the group consisting of 0, S, C(O), C(S), C(0)0, C(S)O, C(O)S, C(S)S, C(O)N(R 14 53 WO 00/69832 PCT/USOO/09806 (R 14)NC(O), C(S)N(R 14), (R 14)NC(S), OC(O)N(R 4), (R 14)NC(O)O, SC(S)N(R 14), (R 14)NC(S)S, SC(O)N(R 14), (R 14)NC(O)S, OC(S)N(R 14), (R 14)NC(S)O, N(R15 )C(O)N(R 14), (R 14)NC(O)N(R 15), N(R 15)C(S)N(R 14), (R 4)NC(S)N(R 15), S(O), S(O) 2 , S(O) 2 N(R 14 5 N(R 14)S(O) 2 , P(O)(R 8), N(R )P(O)(R 8), P(O)(R8)N(R ), N(R 14), ON(R 14), and (CH(R 14 )) W 22

(CH(R

15 ) wherein e and h are integers ON(R- )), answer independently selected from 0 through 2 and 2 s selected from the group 41 42 44 consisting of CR =CR2, CR R=C; vinylidene), ethynylidene (C=C; 1,2-ethynyl), 1,2-cyclopropyl, 1,2-cyclobutyl, 1,2-cyclohexyl, 1,3 10 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 15 pyrrolidinyl, 2,5-pyrrolidinyl, 3,4-pyrrolidinyl, 2,3-tetrahydrofuranyl, 2,4 tetrahydrofuranyl, 2,5-tetrahydrofuranyl, and 3,4-tetrahydrofuranyl, with the provisos that R14 and R15 are selected from other than halo and cyano when directly bonded to N and that (CR 37R 38)b, (CH(R 14))c, and (CH(R 14))e are bonded to E 0 ; 20 Y is optionally Qb_ ss wherein Qss is selected from the group consisting of (CR37 R 38)f wherein f is an integer selected from I through 4, (CH(R 14))C-W 1-(CH(R1 5))d wherein c and d are integers independently selected from 1 through 2, and W is selected from the group consisting of WI is selected from the group consisting of 0, S, C(O), C(O)N(R 14 54 WO 00/69832 PCT/USOO/09806 (R 4)NC(O), N(R15 )C(O)N(R 14), (R 14)NC(O)N(R 15), N(R 14), ON(R 14), and (CH(R 14))e-W -(CH(R 15)h wherein e and h are integers independently selected from 0 through 2 and W is selected from the group consisting of CR 4a=CR 4b, ethynylidene (C=C; 1,2-ethynyl), and C=CR4aR4b with the 5 provisos that R14 and R15 are selected from other than halo when directly bonded to N and that (CR37 R 38)f, (CH(R 14))c, and (CH(R 14))e are bonded to E 0 ; Y is optionally Qb_ sss wherein Qss is (CH(R 3 8 ))r-W 3 , r is an integer selected from 1 through 2, W is selected from the group consisting of 10 1,1-cyclopropyl, 1,2-cyclopropyl, 1,1-cyclobutyl, 1,2-cyclobutyl, 1,2 cyclohexyl, 1,3-cyclohexyl, 1,4-cyclohexyl, 1,2-cyclopentyl, 1,3-cyclopentyl, 2,3-morpholinyl, 2,4-morpholinyl, 2,5-morpholinyl, 2,6-morpholinyl, 3,4 morpholinyl, 3,5-morpholinyl, 1,2-piperazinyl, 1,3-piperazinyl, 1,4 piperazinyl, 2,3-piperazinyl, 2,5-piperazinyl, 2,6-piperazinyl, 1,2-piperidinyl, 15 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 20 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, and 3,5 tetrahydropyranyl, and each carbon and hyrido containing nitrogen member of 25 the ring of the W other than the points of attachment is optionally substituted 9 10 11 12 with one or more of the group consisting of R , R , R , and R , with the 55 WO 00/69832 PCT/USOO/09806 proviso that (CH(R 38)r is bonded to E and Qb is bonded to lowest numbered substituent position of each W 3 ; Y is optionally Qb Qsssr wherein Qsssr is (CH(R 3 8 ))r-W, r is an integer selected from 1 through 2, W4 is selected from the group consisting of 5 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 10 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, 4 H-2,5-pyranyl, 2H-pyran-2-one-3,4-yl, 2 H-pyran-2-one-4,5-yl, 4H-pyran 15 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, and 3 ,5-tetrahydropyranyl, and each carbon and hyrido containing nitrogen member of the ring of the W4 other than the points of 20 attachment is optionally substituted with one or more of the group consisting of 9 10 11 12 38o R , R , R , and R , with the provisos that (CH(R ))r is bonded to E and Qb is bonded to highest number substituent position of each W Y is optionally Qb_ ssss wherein QSSSS is (CH(R 3 8 ))rW5, r is an integer selected from 1 through 2, W is selected from the group consisting of 25 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-benzofuranyl, 3,5-benzofuranyl, 3,6-benzofuranyl, 3,7-benzofuranyl, 2,4-benzothiophenyl, 2,5-benzothiophenyl, 2 ,6-benzothiophenyl, 2,7 56 WO 00/69832 PCT/USOO/09806 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)pyridinyl, 3,6-imidazo(1,2 a)pyridinyl, 3,7-imidazo(1,2-a)pyridinyl, 2,4-indolyl, 2,5-indolyl, 2,6 5 indolyl, 2,7-indolyl, 3,4-indolyl, 3,5-indolyl, 3,6-indolyl, 3,7-indolyl, 1,4 isoindolyl, 1,5-isoindolyl, 1,6-isoindolyl, 2,4-isoindolyl, 2,5-isoindolyl, 2,6 isoindolyl, 2,7-isoindolyl, 1,3-isoindolyl, 3,4-indazolyl, 3,5-indazolyl, 3,6 indazolyl, 3,7-indazolyl, 2,4-benzoxazolyl, 2,5-benzoxazolyl, 2,6 benzoxazolyl, 2,7-benzoxazolyl, 3,4-benzisoxazolyl, 3 ,5-benzisoxazolyl, 3,6 10 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 15 quinolinyl, 1,4-isoquinolinyl, 1,5-isoquinolinyl, 1, 6 -isoquinolinyl, 1,7 isoquinolinyl, 1,8-isoquinolinyl, 3,4-isoquinolinyl, 3,5-isoquinolinyl, 3,6 isoquinolinyl, 3, 7 -isoquinolinyl, 3,8-isoquinolinyl, 4 ,5-isoquinolinyl, 4,6 isoquinolinyl, 4

,

7 -isoquinolinyl, 4,8-isoquinolinyl, 3,4-cinnolinyl, 3,5 cinnolinyl, 3,6-cinnolinyl, 3, 7 -cinnolinyl, 3,8-cinnolinyl, 4 ,5-cinnolinyl, 4,6 20 cinnolinyl, 4

,

7 -cinnolinyl, and 4 ,8-cinnolinyl, and each carbon and hyrido containing nitrogen member of the ring of the W other than the points of attachment is optionally substituted with one or more of the group consisting of 9 10 11 12 b R , R 1, R , and R , with the proviso that Q is bonded to lowest number substituent position of each W and that (CH(R 38))r is bonded to EO; 25 YO is optionally Qb_Qssssr wherein Qssssr is (CH(R 38))rW , r is an integer selected from 1 through 2, W6 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, 30 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 57 WO 00/69832 PCT/USOO/09806 benzothiophenyl, 3,7-benzothiophenyl, 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-indolyl, 2,5-indolyl, 2,6 indolyl, 2,7-indolyl, 3,4-indolyl, 3,5-indolyl, 3,6-indolyl, 3,7-indolyl, 1,4 5 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, 10 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 15 isoquinolinyl, 1,8-isoquinolinyl, 3,4-isoquinolinyl, 3,5-isoquinolinyl, 3,6 isoquinolinyl, 3,7-isoquinolinyl, 3,8-isoquinolinyl, 4,5-isoquinolinyl, 4,6 isoquinolinyl, 4,7-isoquinolinyl, 4,8-isoquinolinyl, 3,4-cinnolinyl, 3,5 cinnolinyl, 3,6-cinnolinyl, 3, 7 -cinnolinyl, 3,8-cinnolinyl, 4 ,5-cinnolinyl, 4,6 cinnolinyl, 4, 7 -cinnolinyl, and 4,8-cinnolinyl, and each carbon and hyrido 20 containing nitrogen member of the ring of the W6 other than the points of attachment is optionally substituted with one or more of the group consisting of 9 10 11 12 b R , R , R , and R , with the proviso that Q is bonded to highest number substituent position of each W6 and that (CH(R 38))r is bonded to E. In a preferred embodiment of compounds of Formula I or a 25 pharmaceutically acceptable salt thereof, J is 0; B is the Formula: 58 WO 00/69832 PCT/USOO/09806 R

R

3 2 36 R 1#R 9 10 11 12 13 32 33 34 35 36 R ,R ,R ,R ,R , R , R , R ,R ,andR are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkylenedioxy, haloalkylthio, 5 alkanoyloxy, alkoxy, alkoxyalkyl, haloalkoxylalkyl, hydroxy, amino, alkoxyamino, nitro, lower alkylamino, alkylthio, alkylthioalkyl, alkylsulfinyl, alkylsulfonyl, alkylsulfonylalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, alkanoyl, haloalkanoyl, alkyl, alkenyl, 10 halo, haloalkyl, haloalkenyl, haloalkoxy, hydroxyhaloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxyalkyl, carboxyalkyl, carboalkoxy, carboxy, carboxamido, carboxamidoalkyl, and cyano; 9 10 11 12 13 R , R , R , R , and R are optionally selected from the group 9 10 11 consisting of heteroaryl and heterocyclyl with the proviso that R , R , R 12 13 15 R , and R are substitutents for other than B; 16 19 32 33 34 35 36 R , R , R , R , R , R , and R are independently optionally Qb with the proviso that no more than one of R16 and R 9 is Qb at the same time and that Qb be B is optionally selected from the group consisting of hydrido, 20 trialkylsilyl, C2-C8 alkyl, C3-C8 alkylenyl, C3-C8 alkenyl, C3-C8 alkynyl, and C2-C8 haloalkyl, wherein each member of group B may be optionally substituted at any carbon up to and including 6 atoms from the point of 59 WO 00/69832 PCT/USOO/09806 attachment of B to A with one or more of the group consisting of R 3 2 , R33 34 35 36 R3, R3, and R B is selected from the group consisting of C3-C12 cycloalkyl and C4 heterocyclyl, wherein each ring carbon may be optionally substituted with R33 5 a ring carbon other than the ring carbon at the point of attachment of B to A may be optionally substituted with oxo provided that no more than one ring carbon is substituted by oxo at the same time, ring carbons and a nitrogen adjacent to the carbon at the point of attachment may be optionally substituted 9 13 9 with R or R , a ring carbon or nitrogen adjacent to the R position and two 10 10 atoms from the point of attachment may be substituted with R , a ring carbon or nitrogen adjacent to the R13 position and two atoms from the point of 12, e he tm attachment may be substituted with R1, a ring carbon or nitrogen three atoms from the point of attachment and adjacent to the R10 position may be 11 substituted with R , a ring carbon or nitrogen three atoms from the point of 15 attachment and adjacent to the R12 position may be substituted with R 33, and a ring carbon or nitrogen four atoms from the point of attachment and adjacent to the R and R33 positions may be substituted with R34 A is selected from the group consisting of single covalent bond, (W )rr-(CH(R 15))pa and (CH(R 15))pa-(W )rr wherein rr is an integer 20 selected from 0 through 1, pa is an integer selected from 0 through 6, and W is selected from the group consisting of 0, S, C(O), (R )NC(O), (R )NC(S), and N(R ) with the proviso that no more than one of the group consisting of rr and pa is 0 at the same time; R is selected from the group consisting of hydrido, hydroxy, and 25 alkyl; 60 WO 00/69832 PCT/USOO/09806 R15 is selected from the group consisting of hydrido, hydroxy, halo, alkyl, and haloalkyl; 'W is selected from the group consisting of NH and NOH; M is selected from the group consisting of N and R -C; 5 Ri is selected from the group consisting of hydrido, alkyl, alkenyl, cyano, halo, haloalkyl, haloalkoxy, haloalkylthio, amino, aminoalkyl, alkylamino, amidino, hydroxy, hydroxyamino, alkoxy, hydroxyalkyl, alkoxyamino, thiol, and alkylthio;

R

2 is Z 0 -Q; 10 Z is selected from the group consisting of covalent single bond, (CR 41R 42) wherein q is an integer selected from 1 through 3, (CH(R 41 q Ct W'-(CH(R 42)) wherein g and p are integers independently selected from 0 through 3 and W is selected from the group consisting of 0, S, C(O), S(O), 41 41 41 ~22 42 N(R ), and ON(R ), and (CH(R ))e-W -(CH(R ))h wherein e and h 15 are integers independently selected from 0 through I and 2is 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 20 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 ZO is directly bonded to the 25 pyrimidinone ring; 41 42 R and R are independently selected from the group consisting of amidino, hydroxyamino, hydrido, hydroxy, amino, and alkyl; 61 WO 00/69832 PCT/USOO/09806 Q is selected from the group consisting of hydrido, with the proviso that ZO is other than a covalent single bond, and the formula (II): R11R 1 1 0 K 2 R1 2 J12 R9 D D R 13 (II) 1 2 12 1 wherein D , D , , J and K are independently selected from the group 5 consisting of C, N, 0, S and a covalent bond with the provisos that no more 1 2 12 1 than one is a covalent bond, no more than one of D , D , J and K is 0, 1 2 12 1 1 21 2 no more than one of D, D ,1 ,J and K is S, one of D D ,1 ,J and 1 1 2 12 1 K must be a covalent bond when two of D , D , , J and K are 0 and S, 1 2 12 1 and no more than four of D , D , , J and K are N, with the proviso that 9 10 11 12 13 10 R , R , R , R , and R are each independently selected to maintain the tetravalent nature of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen; 4a 4b K is (CRaR bn wherein n is an integer selected from 1 through 2; R and R4b are independently selected from the group consisting of 15 halo, hydrido, hydroxyalkyl, alkyl, alkoxyalkyl, alkylthioalkyl, and haloalkyl; o 1 4a 4b I isE , when K is (CR R )n, wherein E is selected from the group consisting of a covalent single bond, C(O), C(S), C(O)N(R ), (R )NC(O), S(0) 2 , (R )NS(0) 2 , and S(0) 2 N(R ); Y is formula (IV): 62 WO 00/69832 PCT/USOO/09806 S 17 1 8 R 16," K2 R 1 9 lb Q (IV) 5 65 6 wherein D , D , J, and J are independently selected from the group consisting of C, N, 0, S and a covalent bond with the provisos that no more 2 5 65 6 than one is a covalent bond, K is C, no more than one of D D , and J 5 65 6 5 65 6 5 is 0, no more than one of D5, D , ,and J is S, one of D D , and J 5 65 6 must be a covalent bond when two of D , D , J , and J are 0 and S, and no 5 65 6 16 17 more than four of D5, D , ,and J are N with the proviso that R1, R 18 19 R , and R are each independently selected to maintain the tetravalent nature of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the 10 divalent nature of oxygen; 16 17 18 19 R , R , R , and R 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, halo, 15 haloalkyl, haloalkoxy, hydroxyalkyl, alkylenylamino, haloalkoxyalkyl, carboalkoxy, and cyano; b .20 21 Q is selected from the group consisting of NR2R2, aminoalkylenyl, Qbe wherein Qbe is hydrido, N(R 26)C(NR 25)N(R )(R 24), and 25 224 20 21 C(NR )NR R , with the provisos that no more than one of R and R 20 is hydroxy, amino, alkylamino, or dialkylamino at the same time and that no 63 WO 00/69832 PCT/USOO/09806 more than one of R and R24 is hydroxy, amino, alkylamino, or dialkylamino at the same time; 20 21 23 24 25 26 R2, R2, R , R , R , and R are independently selected from the group consisting of hydrido, alkyl, hydroxy, aminoalkylenyl, amino, 5 dialkylamino, alkylamino, and hydroxyalkyl; Qs is selected from the group consisting of a single covalent bond, 37 38 (CR3R3)b wherein b is an integer selected from 1 through 4, and 14 1 15 (CH(R ))c-W -(CH(R ))d wherein c and d are integers independently selected from 1 through 3 and W is selected from the group consisting of 10 C(O)N(R 4), (R 4)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 provisos that R14 is selected from other than halo when directly bonded to N and that (CR 37R 38)b, and (CH(R 14))c are bonded to E; R14 is selected from the group consisting of hydrido, halo, alkyl, and haloalkyl; 15 R37 and R38 are independently selected from the group consisting of hydrido, alkyl, and haloalkyl; R38 is optionally selected from the group consisting of aroyl and heteroaroyl; Y is optionally Qb Qss wherein Qss is (CH(R14))e-W 2

-(CH(R

15 ))h, 20 wherein e and h are integers independently selected from 1 through 2 and W 4a 4b 14o is CR =CR with the proviso that (CH(R ))e is bonded to E0; Y is optionally selected from the group consisting of Q bQ ssss and Q b_ Qssssr wherein Qssss is (CH(R 38))r-W and Qsss is (CH(R 38))r-W 6, r is an 64 WO 00/69832 PCT/USOO/09806 integer selected from 1 through 2, and W 5 and W6 are independently 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 5 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 10 a)pyridinyl, 3,6-imidazo(1,2-a)pyridinyl, 3,7-imidazo(1,2-a)pyridinyl, 2,4 indolyl, 2,5-indolyl, 2,6-indolyl, 2,7-indolyl, 3,4-indolyl, 3,5-indolyl, 3,6 indolyl, 3,7-indolyl, 1,4-isoindolyl, 1,5-isoindolyl, 1,6-isoindolyl, 2,4 isoindolyl, 2,5-isoindolyl, 2,6-isoindolyl, 2,7-isoindolyl, 1,3-isoindolyl, 3,4 indazolyl, 3,5-indazolyl, 3,6-indazolyl, 3,7-indazolyl, 2,4-benzoxazolyl, 2,5 15 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 20 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 25 isoquinolinyl, 3,4-cinnolinyl, 3,5-cinnolinyl, 3,6-cinnolinyl, 3,7-cinnolinyl, 3,8-cinnolinyl, 4,5-cinnolinyl, 4,6-cinnolinyl, 4,7-cinnolinyl, and 4,8 cinnolinyl, and each carbon and hyrido containing nitrogen member of the ring of the W and of the ring of the W 6 , other than the points of attachment of W and W 6, is optionally substituted with one or more of the group consisting of 9 10 11 12 b 30 R , R , R , and R , with the provisos that Q is bonded to lowest 65 WO 00/69832 PCT/USOO/09806 number substituent position of each W 5 , Qb is bonded to highest number 6 38 0 substituent position of each W , and (CH(R 3)r is bonded to E In a more preferred embodiment of compounds of Formula I or a pharmaceutically acceptable salt thereof, 5 J is 0; B is the Formula:

R

3 4 R 33R3 5 R3 2 R3 6 R R3 32 33 34 35 36 R , R , R , R , and R are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, 10 alkylenedioxy, haloalkylthio, alkanoyloxy, alkoxy, hydroxy, amino, alkoxyamino, alkanoyl, haloalkanoyl, nitro, lower alkylamino, alkylthio, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, alkylsulfonamido, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, alkyl, alkenyl, halo, haloalkyl, haloalkenyl, haloalkoxy, hydroxyalkyl, alkylenylamino, 15 carboalkoxy, carboxy, carboxamido, cyano, and Qb B is optionally selected from the group consisting of hydrido, trialkylsilyl, C2-C8 alkyl, C3-C8 alkylenyl, C3-C8 alkenyl, C3-C8 alkynyl, and C2-C8 haloalkyl, wherein each member of group B is optionally substituted at any carbon up to and including 6 atoms from the point of 20 attachment of B to A with one or more of the group consisting of R32 , R33 R34, R35, and R36 B is selected from the group consisting of C3-C12 cycloalkyl and C4 heterocyclyl, wherein each ring carbon may be optionally substituted with R33 66 WO 00/69832 PCT/USOO/09806 a ring carbon other than the ring carbon at the point of attachment of B to A may be optionally substituted with oxo provided that no more than one ring carbon is substituted by oxo at the same time, ring carbons and a nitrogen adjacent to the carbon at the point of attachment may be optionally substituted 9 13 poito 5 with R or R , a ring carbon or nitrogen adjacent to the R position and two 10 atoms from the point of attachment may be substituted with R , a ring carbon or nitrogen adjacent to the R13 position and two atoms from the point of 12, abntreaosfo h attachment may be substituted with R1, a ring carbon three atoms from the point of attachment and adjacent to the R10 position may be substituted with 10 R , a ring carbon three atoms from the point of attachment and adjacent to the R12 position may be substituted with R 33, and a ring carbon four atoms from the point of attachment and adjacent to the R 1 and R33 positions may be substituted with R34 9 10 11 12 13 R , R , R , R , and R are independently selected from the 15 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, halo, haloalkyl, haloalkoxy, hydroxyalkyl, 20 aminoalkyl, carboalkoxy, carboxyalkyl, carboxy, carboxamido, and cyano; 9 10 11 12 13 R , R , R , R , and R are optionally selected from the group 9 10 11 consisting of heteroaryl and heterocyclyl with the proviso that R , R , R 12 13 R , and R are substitutents for other than B; A is selected from the group consisting of single covalent bond and 25 (CH(R 15))pa-(W )rr wherein rr is an integer selected from 0 through 1, pa is 67 WO 00/69832 PCT/USOO/09806 an integer selected from 0 through 3, and W is selected from the group consisting of 0, S, C(O), (R 7 )NC(O), (R 7 )NC(S), and N(R ) 7I s R is selected from the group consisting of hydrido, hydroxy and alkyl; R 15is selected from the group consisting of hydrido, hydroxy, halo, 5 alkyl, and haloalkyl; T is NH; M is selected from the group consisting of N and R R is selected from the group consisting of hydrido, alkyl, cyano, halo, haloalkyl, haloalkoxy, amino, aminoalkyl, alkylamino, amidino, 10 hydroxy, hydroxyamino, alkoxy, hydroxyalkyl, alkoxyamino, thiol, and alkylthio;

R

2 is Z 0 -Q; ZO is selected from the group consisting of covalent single bond and (CR 41R 42)q wherein q is an integer selected from 1 through 2, (CH(R 41 15 W-(CH(R42)), wherein g and p are integers independently selected from 0 through 3 and WO is selected from the group consisting of 0, S, and N(R 41 and (CH(R 4 1 )) W 2 2

-(CH(R

4 2 )h wherein e and h are integers independently selected from 0 through 1 and 2is selected from the group consisting of CR 41=CR 42, 1, 2 -cyclopropyl, 1,2-cyclobutyl, 1,2-cyclohexyl, 1,3 20 cyclohexyl, 1,2-cyclopentyl, 1,3-cyclopentyl, 2,3-morpholinyl, 2,4 morpholinyl, 2,6-morpholinyl, 3,A-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 25 pyrrolidinyl, 2,5-pyrrolidinyl, 3,4-pyrrolidinyl, 2,3-tetrahydrofuranyl, 2,4 68 WO 00/69832 PCT/USOO/09806 tetrahydrofuranyl, 2,5-tetrahydrofuranyl, and 3,4-tetrahydrofuranyl, with the proviso that Z 0 is directly bonded to the pyrimidinone ring; R41 and R42 are independently selected from the group consisting of hydrido, hydroxy, and amino; 5 Q is selected from the group consisting of hydrido, with the proviso that ZO is other than a covalent single bond, aryl, and heteroaryl, wherein a carbon adjacent to the carbon at the point of attachment is optionally substituted 9 by R , the other carbon adjacent to the carbon at the point of attachment is 13 9 optionally substituted by R , a carbon adjacent to R and two atoms from the 10 10 carbon at the point of attachment is optionally substituted by R , a carbon adjacent to R13 and two atoms from the carbon at the point of attachment is 12 10 12. optionally substituted by R1, and any carbon adjacent to both R and R is optionally substituted by R K is CHR4a wherein R is selected from the group consisting of 15 hydrido, hydroxyalkyl, alkyl, alkoxyalkyl, alkylthioalkyl, and haloalkyl; E is selected from the group consisting of a covalent single bond, C(O)N(H), (H)NC(O), (R 7)NS(O) 2 , and S(O) 2 N(R ); YO is formula (IV): S R 1 7 1 8 5 6 R16 D NK21 D R 19 lb Q (IV) 69 WO 00/69832 PCT/USOO/09806 wherein D 5, D6 , J 5, and J6 are independently selected from the group consisting of C, N, 0, S and a covalent bond with the provisos that no more 2 5 65 6 than one is a covalent bond, K is C, no more than one of D D , J ,and J 5 65 6 5 65 6 is 0, no more than one of D5, D , , and J is S, one of D D , J ,and J 5 65 6 5 must be a covalent bond when two of D , D , 5 , and J are 0 and S, and no 5 65 6 16 17 more than four of D5, D , ,and J are N, with the provisos that R1, R 18 19 R , and R are each independently selected to maintain the tetravalent nature of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen; 16 17 18 19 10 R , R , R , and R 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, hydroxyalkyl, aminoalkyl, and cyano; 15 R16 and R19 are optionally Qb with the proviso that no more than one of R16 and R19 is Qb at the same time and that Qb s Qbe b 20 21 be be Q is selected from the group consisting of NR R , Q wherein Q is hydrido, N(R 26)C(NR 25)N(R )(R 24), and C(NR )NR R , with the provisos that no more than one of R20 and R21 is hydroxy, amino, alkylamino, or 20 dialkylarnino at the same time and that no more than one of R and R24 is hydroxy, amino, alkylamino, or dialkylamino at the same time; 20 21 23 24 25 26 R , R , R , R , R , and R are independently selected from the group consisting of hydrido, alkyl, hydroxy, amino, alkylamino and dialkylamino; QS is selected from the group consisting of a single covalent bond, 37 38 25 (CR R )b wherein b is an integer selected from 1 through 4, and 70 WO 00/69832 PCT/USOO/09806 (CH(R 14))c-W -(CH(R5 ))d wherein c and d are integers independently selected from 1 through 3 and W is selected from the group consisting of C(O)N(R 14), (R 4)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 provisos that R14 is selected from other than halo when 5 directly bonded to N and that (CR 37R 38)b, and (CH(R 4))c are bonded to E0 R14 is selected from the group consisting of hydrido, halo, alkyl, and haloalkyl; R37 and R38 are independently selected from the group consisting of hydrido, alkyl, and haloalkyl; 10 R38 is optionally selected from the group consisting of aroyl and heteroaroyl; Y is optionally Qb_ ss wherein Qss is (CH(R 14 ))e-W 2 -(CH(R1 5 ))h, wherein e and h are integers independently selected from 1 through 2 and W 4a 14 0 is CR =CH with the proviso that (CH(R )), is bonded to E 15 In an even more preferred embodiment of compounds of Formula I or a pharmaceutically acceptable salt thereof, J is 0; B is the Formula: R 34 R 3R35 R32 / 36 RR 71 WO 00/69832 PCT/USOO/09806 32 33 34 35 36 R , R , R , R , and R 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, 5 haloalkyl, haloalkoxy, hydroxyalkyl, carboalkoxy, carboxy, carboxamido, cyano, and Qb. A is selected from the group consisting of single covalent bond and (CH(R15 ))pa-(W 7)rr wherein rr is an integer selected from 0 through 1, pa is an integer selected from 0 through 3, and W is selected from the group 10 consisting of (R )NC(O) and N(R ); R 7is selected from the group consisting of hydride, hydroxy and alkyl; R15 is selected from the group consisting of hydrido, halo, alkyl, and haloalkyl; P is NH; 15 M is selected from the group consisting of N and R -C; R is selected from the group consisting of hydrido, hydroxy, hydroxyamino, amidino, amino, cyano, hydroxyalkyl, alkoxy, alkyl, alkylamino, aminoalkyl, alkylthio, alkoxyamino, haloalkyl, haloalkoxy, and halo; 20 R2 is ZO-Q; Z is selected from the group consisting of a covalent single bond, 0, S, NH, and

CH

2 ; Q is selected from the group consisting of aryl and heteroaryl wherein a carbon adjacent to the carbon at the point of attachment is optionally substituted 9 25 by R , the other carbon adjacent to the carbon at the point of attachment is 13 9 optionally substituted by R , a carbon adjacent to R and two atoms from the 72 WO 00/69832 PCT/USOO/09806 carbon at the point of attachment is optionally substituted by R 10, a carbon adjacent to R13 and two atoms from the carbon at the point of attachment is 12 10 12 optionally substituted by R1, and any carbon adjacent to both R and R is optionally substituted by R 9 11 13 5 R , R , and R are independently selected from the group consisting of hydrido, hydroxy, amino, amidino, guanidino, lower alkylamino, alkylthio, alkylsulfonamido, alkylsulfinyl, alkylsulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboxy, carboxamido, and cyano; 10 R10 and R12 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, 15 amidocarbonyl, halo, haloalkyl, and cyano; K is

CH

2 ; EO is C(O)N(H); YO is formula (IV):

R

17 18 R 16/-0'D K2 D R19 lb Q (IV) 5 65 6 20 wherein D , D , J , and J are independently selected from the group consisting of C, N, 0, S and a covalent bond with the provisos that no more 2 5 65 6 than one is a covalent bond, K is C, no more than one of D , D J , and J 73 WO 00/69832 PCT/USOO/09806 is optionally 0, no more than one of D 5 , D 6 5 , and J is optionally S, one of 5 65 6 5 65 6 D5, D , J ,and J must be a covalent bond when two of D5, D , J ,and J 5 65 6 are 0 and S, and no more than four of D, D , , and i are N; 16 17 18 19 R6, R , R1, and R are independently selected from the group 5 consisting of hydrido, amidino, guanidino, carboxy, haloalkylthio, alkoxy, hydroxy, amino, lower alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, and cyano; R16 and R19 are optionally Qb with the proviso that no more than one of 10 R16 and R19 is Qb at the same time and that Qb s Qbe b .20 21 be be Q is selected from the group consisting of NR R , Q wherein Q is 25 224 20 hydrido, and C(NR )NR R , with the provisos that no more than one of R and R21 is hydroxy at the same time and that no more than one of R and R24 is hydroxy at the same time; 20 21 23 24 25 15 R , R , R , R , and R are independently selected from the group consisting of hydrido, alkyl, and hydroxy; QS is selected from the group consisting of a single covalent bond,

CH

2 , and CH 2

CH

2 . In another even more preferred embodiment of compounds of Formula 20 1 or a pharmaceutically acceptable salt thereof, J is 0; B is optionally selected from the group consisting of hydrido, C2-C8 alkyl, C3-C8 alkenyl, C3-C8 alkynyl, and C2-C8 haloalkyl, wherein each member of group B is optionally substituted at any carbon up to and including 25 6 atoms from the point of attachment of B to A with one or more of the group 32 33 34 35 36 consisting of R , R , R , R , and R ; 74 WO 00/69832 PCT/USOO/09806 32 33 34 35 36 R , R , R , R , and R 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, 5 haloalkyl, haloalkoxy, hydroxyalkyl, carboalkoxy, carboxy, carboxamido, cyano, and Qb A is selected from the group consisting of single covalent bond and (CH(R 15))pa-(W )rr wherein rr is an integer selected from 0 through 1, pa is an integer selected from 0 through 3, and W is selected from the group 10 consisting of (R )NC(O) and N(R ); 7 R is selected from the group consisting of hydrido, hydroxy and akl; R 1 is selected from the group consisting of hydrido, halo, alkyl, and haloalkyl; W is NH; 15 M is selected from the group consisting of N and R -C; R is selected from the group consisting of hydrido, hydroxy, hydroxyamino, amidino, amino, cyano, hydroxyalkyl, alkoxy, alkyl, alkylamino, aminoalkyl, alkylthio, alkoxyamino, haloalkyl, haloalkoxy, and halo; 20

R

2 isZO-Q; Z is selected from the group consisting of covalent single bond, 0, S, NH, and

CH

2 ; Q is selected from the group consisting of aryl and heteroaryl wherein a carbon adjacent to the carbon at the point of attachment is optionally substituted 9 25 by R , the other carbon adjacent to the carbon at the point of attachment is 13 9 optionally substituted by R , a carbon adjacent to R and two atoms from the 75 WO 00/69832 PCT/USOO/09806 carbon at the point of attachment is optionally substituted by R , a carbon adjacent to R13 and two atoms from the carbon at the point of attachment is 12 10 12 optionally substituted by R1, and any carbon adjacent to both R and R is optionally substituted by R 9 11 13 5 R , R , and R are independently selected from the group consisting of hydrido, hydroxy, amino, amidino, guanidino, lower alkylamino, alkylthio, alkylsulfonamido, alkylsulfinyl, alkylsulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboxy, carboxamido, and cyano; 10 12 10 R and R . 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, 15 amidocarbonyl, halo, haloalkyl, and cyano; K is CH 2 ; EO is C(O)N(H); YO is formula (IV): S

R

17 R 18 R16 D K2D R 1 9 lb Q (IV) 20 wherein D 5, D6 , J 5, and J6 are independently selected from the group consisting of C, N, 0, S and a covalent bond with the provisos that no more 2 5 65 6 than one is a covalent bond, K is C, no more than one of D , D , J ,and J 76 WO 00/69832 PCT/USOO/09806 56 5 6 5 65 6 is 0, no more than one of D5, D , J ,and J is S, one of D D , D and J 5 65 6 must be a covalent bond when two of D5, D , ,and J are O and S, and no 5 65 6 16 17 more than four of D , D 5, and J are N, with the provisos that R , R 18 19 R1, and R are each independently selected to maintain the tetravalent nature 5 of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen; 16 17 18 19 R6, R , R18, and R are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, haloalkylthio, alkoxy, hydroxy, amino, lower alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, 10 alkanoyl, haloalkanoyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, alkylenylamino, and cyano; R16 and R19 are optionally Qb with the proviso that no more than one of R16 and R19 is Qb at the same time and that Qb s Qbe Q is selected from the group consisting of NR20R21 be wherein be 25 23 24 26 25 23 24 15 Q is hydrido, C(NR )NR R , and N(R )C(NR )N(R )(R ), with the provisos that no more than one of R20 and R21 s hydroxy at the same time and that no more than one of R and R24 s hydroxy at the same time; 20 21 23 24 25 26 R , R , R , R , R , and R are independently selected from the group consisting of hydrido, alkyl, and hydroxy; 20 Qs is selected from the group consisting of a single covalent bond,

CH

2 , and

CH

2

CH

2 In still another even more preferred embodiment of compounds of Formula I or a pharmaceutically acceptable salt thereof, J is 0; 77 WO 00/69832 PCT/USOO/09806 B is selected from the group consisting of C3-C7 cycloalkyl and C4 heterocyclyl, wherein each ring carbon may be optionally substituted with R33 a ring carbon other than the ring carbon at the point of attachment of B to A may be optionally substituted with oxo provided that no more than one ring 5 carbon is substituted by oxo at the same time, ring carbons and a nitrogen adjacent to the carbon at the point of attachment may be optionally substituted 9 139 with R or R , a ring carbon or nitrogen adjacent to the R position and two 10 atoms from the point of attachment may be substituted with R , a ring carbon or nitrogen adjacent to the R13 position and two atoms from the point of 12 10 attachment may be substituted with R , a ring carbon three atoms from the point of attachment and adjacent to the R10 position may be substituted with R , a ring carbon three atoms from the point of attachment and adjacent to 12 33 the R position may be substituted with R , and a ring carbon four atoms from the point of attachment and adjacent to the R11 and R33 positions may be 15 substituted with R34 9 11 13 R , R , and R are independently selected from the group consisting of hydrido, hydroxy, amino, amidino, guanidino, lower alkylamino, alkylthio, alkylsulfonamido, alkylsulfinyl, alkylsulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, alkyl, alkoxy, halo, haloalkyl, 20 haloalkoxy, hydroxyalkyl, carboxy, carboxamido, and cyano; R10 and R12 are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkyl, alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, alkylsulfonamido, arnidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, 25 hydroxyalkyl, alkylenylamino, carboalkoxy, carboxy, carboxyalkyl, amidocarbonyl, halo, haloalkyl, and cyano; 78 WO 00/69832 PCT/USOO/09806 R33 and R34 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, b 5 hydroxyalkyl, carboalkoxy, carboxy, carboxamido, cyano, and Q A is selected from the group consisting of single covalent bond and (CH(R 15))pa-(W )rr wherein rr is an integer selected from 0 through 1, pa is an integer selected from 0 through 3, and W7 is selected from the group consisting of (R )NC(O) and N(R ); 10 R 7is selected from the group consisting of hydride, hydroxy and alkyl; R15 is selected from the group consisting of hydrido, halo, alkyl, and haloalkyl; W i s NH; M is selected from the group consisting of N and R -C; 15 R is selected from the group consisting of hydrido, hydroxy, hydroxyamino, amidino, amino, cyano, hydroxyalkyl, alkoxy, alkyl, alkylamino, aminoalkyl, alkylthio, alkoxyamino, haloalkyl, haloalkoxy, and halo; R2 is Z Q 20 ZO is selected from the group consisting of covalent single bond, 0, S, NH, and

CH

2 ; Q is selected from the group consisting of aryl and heteroaryl wherein a carbon adjacent to the carbon at the point of attachment is optionally substituted 9 by R , the other carbon adjacent to the carbon at the point of attachment is 13 9 25 optionally substituted by R , a carbon adjacent to R and two atoms from the 10 carbon at the point of attachment is optionally substituted by R , a carbon 79 WO 00/69832 PCT/USOO/09806 adjacent to R and two atoms from the carbon at the point of attachment is 12 10 12 optionally substituted by R1, and any carbon adjacent to both R and R is optionally substituted by R K is CH 2 ; 5 E 0 is C(O)N(H); Y is formula (IV): QS 17 18 5 6 R 16 D K2 D R 9 lb Q (IV) 5 65 6 wherein D , D , J , and J are independently selected from the group consisting of C, N, 0, S and a covalent bond with the provisos that no more 2 5 65 6 10 than one is a covalent bond, K s C, no more than one of D5, D , J and J 5 65 6 5 65 6 is 0, no more than one of D, D , J ,and J s S, one of D5, D , J and J 5 65 6 must be a covalent bond when two of D, D , J ,and J are O and S, and no 5 65 6 1617 more than four of D5, D , ,and J are N, with the provisos that R1, R 18 19 R , and R are each independently selected to maintain the tetravalent nature 15 of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen; 16 17 18 19 R , R , R , and R are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, haloalkylthio, alkoxy, hydroxy, amino, lower alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, 80 WO 00/69832 PCT/USOO/09806 alkanoyl, haloalkanoyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, alkylenylamino, and cyano; R16 and R19 are optionally Qb with the proviso that no more than one of R16 and R19 is Qb at the same time and that Qb is Qbe b 20 21 be be 5 Q is selected from the group consisting of NR R , Q wherein Q is 25 23 24 2 hydrido, and C(NR )NR R , with the provisos that no more than one of R and R21 is hydroxy at the same time and that no more than one of R and R24 is hydroxy at the same time; 20, 21, 23, 24, 25gru R2, R2, R , R2, and R are independently selected from the group 10 consisting of hydrido, alkyl, and hydroxy; Qs is selected from the group consisting of a single covalent bond,

CH

2 , and CH 2

CH

2 In a most preferred embodiment of compounds of Formula I or a pharmaceutically acceptable salt thereof, 15 J is O; B is the Formula: R 34 R 33 R 35 R3 2 R36 32 33 34 35 36 R , R , R , R , and R are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, 20 alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, alkylthio, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl anidosulfonyl, alkyl, halo, 81 WO 00/69832 PCT/USOO/09806 haloalkyl, haloalkoxy, hydroxyalkyl, carboalkoxy, carboxy, carboxamido, cyano, and Qb A is selected from the group consisting of single covalent bond and (CH(R 15))pa-(W )rr wherein rr is an integer selected from 0 through 1, pa is 5 an integer selected from 0 through 3, and W is N(R ); 7 t R i s selected from the group consisting of hydrido and alkyl; R 15is selected from the group consisting, of hydrido, halo, alkyl, and haloalkyl; 'P is NH; 10 M is selected from the group consisting of N and R -C; R is selected from the group consisting of hydrido, hydroxy, hydroxyamino, amidino, amino, cyano, hydroxyalkyl, alkoxy, alkyl, alkylamino, aminoalkyl, alkylthio, alkoxyamino, haloalkyl, haloalkoxy, and halo; 15

R

2 is Z-Q; Z is a covalent single bond; Q is selected from the group consisting of aryl and heteroaryl wherein a carbon adjacent to the carbon at the point of attachment is optionally substituted by R9, the other carbon adjacent to the carbon at the point of attachment is 13 9 20 optionally substituted by R , a carbon adjacent to R and two atoms from the 10 carbon at the point of attachment is optionally substituted by R , a carbon adjacent to R13 and two atoms from the carbon at the point of attachment is 12 10 12. optionally substituted by R1, and any carbon adjacent to both R and R is optionally substituted by R 82 WO 00/69832 PCT/USOO/09806 9 11 13 R , R 1, and R are independently selected from the group consisting of hydrido, hydroxy, amino, amidino, guanidino, lower alkylamino, alkylthio, alkoxy, alkylsulfinyl, alkylsulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, 5 carboxy, carboxamido, and cyano; R10 and R12 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 10 amidosulfonyl, hydroxyalkyl, aminoalkyl, halo, haloalkyl, carboalkoxy, carboxy, carboxyalkyl, carboxyamido, and cyano; K is

CH

2 ; E is C(O)N(H); Y is formula (IV): S R1 7 R18 RDK616 5 6 R1 6 K2D R 19 15 Qb (IV) 5 65 6 wherein D5, D , J and J are independently selected from the group consisting of C, N, 0, S and a covalent bond with the provisos that no more 2 5 65 6 than one is a covalent bond, K is C, no more than one of D , D , J ,and J 5 65 6 5 65 6 is O, no more than one of D5, D , ,and J is S, one of D5, D , ,and J 5 65 6 20 must be a covalent bond when two of D , D , 5 , and J are O and S, and no more than four of D 5, D6 , J ,and J6 are N; 83 WO 00/69832 PCT/USOO/09806 16 17 18 19 R6, R , R 1, and R are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, haloalkylthio, alkoxy, hydroxy, amino, lower alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, 5 aminoalkyl, and cyano; R16 and R19 are optionally Qb with the proviso that no more than one of R16 and R19 is Qb at the same time and that Qb s be b .20 21 be be Q is selected from the group consisting of NR R , Q wherein Q is hydrido, and C(NR25 )NR 23R24 20 21 23 24 25 10 R , R , R , R , and R are independently selected from the group consisting of hydrido and alkyl; Qs is

CH

2 . In another most preferred embodiment of compounds of Formula I or a pharmaceutically acceptable salt thereof, 15 J is 0; B is optionally selected from the group consisting of hydrido, C2-C8 alkyl, C3-C8 alkenyl, C3-C8 alkynyl, and C2-C8 haloalkyl, wherein each member of group B is optionally substituted at any carbon up to and including 6 atoms from the point of attachment of B to A with one or more of the group 32 33 34 35 36 20 consisting of R R ,R R , and R 32 33 34 35 36 R , R , R , R , and R 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, 25 haloalkyl, haloalkoxy, hydroxyalkyl, carboalkoxy, carboxy, carboxamido, cyano,and Qb 84 WO 00/69832 PCT/USOO/09806 A is selected from the group consisting of single covalent bond and (CH(R 15))pa-(W )rr wherein rr is an integer selected from 0 through 1, pa is an integer selected from 0 through 3, and W is N(R ); 7is selected from the group consisting of hydrido and alkyl: 5 R15 is selected from the group consisting of hydrido, halo, alkyl, and haloalkyl; W is NH; M is selected from the group consisting of N and R -C; R is selected from the group consisting of hydrido, hydroxy, 10 hydroxyamino, amidino, amino, cyano, hydroxyalkyl, alkoxy, alkyl, alkylamino, aminoalkyl, alkylthio, alkoxyamino, haloalkyl, haloalkoxy, and halo;

R

2 is Z 0 -Q; ZO is a covalent single bond; 15 Q is selected from the group consisting of aryl and heteroaryl wherein a carbon adjacent to the carbon at the point of attachment is optionally substituted 9 by R , the other carbon adjacent to the carbon at the point of attachment is 13 9 optionally substituted by R , a carbon adjacent to R and two atoms from the 10 carbon at the point of attachment is optionally substituted by R , a carbon 20 adjacent to R13 and two atoms from the carbon at the point of attachment is 12 10 12. optionally substituted by R1, and any carbon adjacent to both R and R is optionally substituted by R 9 11 13 R , R , and R are independently selected from the group consisting of hydrido, hydroxy, amino, amidino, guanidino, lower 25 alkylamino, alkylthio, alkoxy, alkylsulfinyl, alkylsulfonyl, amidosulfonyl, 85 WO 00/69832 PCT/USOO/09806 monoalkyl amidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboxy, carboxamido, and cyano; R10 and R12 are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkyl, alkoxy, 5 alkoxyamino, aminoalkyl, hydroxy, amino, lower alkylamino, alkylsulfonamido, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, hydroxyalkyl, ailnoalkyl, halo, haloalkyl, carboalkoxy, carboxy, carboxyalkyl, carboxyamido, and cyano; K is

CH

2 ; 10

E

0 is C(O)N(H); Y is formula (IV): QS R 17R18 5 R16 D K2 D 9 Ib Q (IV) wherein D , D6 , J 5, and J6 are independently selected from the group consisting of C, N, 0, S and a covalent bond with the provisos that no more 2 5 65 6 15 than one is a covalent bond, K is C, no more than one of , D , and J 5 65 6 5 65 6 is 0, no more than one of D5, D , ,and J s S, one of D D , and J 5 65 6 must be a covalent bond when two of D , D , J ,and J are 0 and S, and no 5 65 6 16 17 more than four of D , D , J , and J are N, with the provisos that R , R 18 19 R , and R are each independently selected to maintain the tetravalent nature 20 of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen; 86 WO 00/69832 PCT/USOO/09806 16 17 18 19 R , R , R , and R are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, haloalkylthio, alkoxy, hydroxy, amino, lower alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, 5 aminoalkyl, and cyano; R16 and R19 are optionally Qb with the proviso that no more than one of R16 and R 9 is Qb at the same time and that Qb s Qbe Q is selected from the group consisting of NR20R21 be wherein Q beis hydrido, N(R 26)C(NR 25)N(R )(R 24), and C(NR 25)NR R24 20 21 23 24 25 26 10 R , R , R , R , R , and R are independently selected from the group consisting of hydrido and alkyl; Qs is CH2 In still another most preferred embodiment of compounds of Formula I or a pharmaceutically acceptable salt thereof, 15 J is 0; B is selected from the group consisting of C3-C7 cycloalkyl and C4 heterocyclyl, wherein each ring carbon may be optionally substituted with R33 a ring carbon other than the ring carbon at the point of attachment of B to A may be optionally substituted with oxo provided that no more than one ring 20 carbon is substituted by oxo at the same time, ring carbons and nitrogens adjacent to the carbon at the point of attachment may be optionally substituted 9 13 9 with R or R , a ring carbon or nitrogen adjacent to the R position and two 10 atoms from the point of attachment may be substituted with R , a ring carbon or nitrogen adjacent to the R13 position and two atoms from the point of 12 25 attachment may be substituted with R , a ring carbon three atoms from the point of attachment and adjacent to the R10 position may be substituted with 87 WO 00/69832 PCT/USOO/09806 R , a ring carbon three atoms from the point of attachment and adjacent to 12 33 the R position may be substituted with R , and a ring carbon four atoms from the point of attachment and adjacent to the R and R33 positions may be substituted with R34 9 11 13 5 R , R , and R are independently selected from the group consisting of hydrido, hydroxy, amino, amidino, guanidino, lower alkylamino, alkylthio, alkoxy, alkylsulfinyl, alkylsulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboxy, carboxamido, and cyano; 10 R10 and R12 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, halo, haloalkyl, carboalkoxy, 15 carboxy, carboxyalkyl, carboxyamido, and cyano; R33 and R34 are independently selected from the group consisting of hydrido, amidino, guanidino, alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, alkylthio, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboalkoxy, 20 carboxy, carboxamido, and cyano; R33 is optionally Qb A is selected from the group consisting of single covalent bond and (CH(R 15))pa-(W )rr wherein rr is an integer selected from 0 through 1, pa is an integer selected from 0 through 3, and W is N(R ); 25 R 7is selected from the group consisting of hydride, hydroxy and alkyl; R15 is selected from the group consisting of hydrido, halo, alkyl, and haloalkyl; 88 WO 00/69832 PCT/USOO/09806 IF is NH; M is selected from the group consisting of N and R -C; R is selected from the group consisting of hydrido, hydroxy, hydroxyamino, amidino, amino, cyano, hydroxyalkyl, alkoxy, alkyl, 5 alkylamino, aminoalkyl, alkylthio, alkoxyamino, haloalkyl, haloalkoxy, and halo;

R

2 is Z-Q; ZO is a covalent single bond; Q is selected from the group consisting of aryl and heteroaryl wherein a 10 carbon adjacent to the carbon at the point of attachment is optionally substituted 9 by R , the other carbon adjacent to the carbon at the point of attachment is optionally substituted by R13 , a carbon adjacent to R9 and two atoms from the 10 carbon at the point of attachment is optionally substituted by R , a carbon adjacent to R13 and two atoms from the carbon at the point of attachment is 15 optionally substituted by R 12, and any carbon adjacent to both R10 and R12 is optionally substituted by R ; K is CH 2 ;

E

0 is C(O)N(H); Y is formula (IV): S

R

1 7 R186 17 1 8 5 6~ R 16, D K2 ,p D R1 20 Qb (IV) 89 WO 00/69832 PCT/USOO/09806 5 65 6 wherein D , D , J , and J are independently selected from the group consisting of C, N, 0, S and a covalent bond with the provisos that no more 2 5 65 6 than one is a covalent bond, K is C, no more than one of D , D , J , and J 5 65 6. 5 65 6 is 0, no more than one of D5, D , J ,and J s S, one of D5, D , ,and J 5 65 6 5 must be a covalent bond when two of D , D , 5 , and J are O and S, and no 5 65 6 16 17 more than four of D5, D , ,and J are N, with the provisos that R1, R 18 19 R , and R are each independently selected to maintain the tetravalent nature of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen; 16 17 18 19 10 R , R , R , and R are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, haloalkylthio, alkoxy, hydroxy, amino, lower alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, alkylenylamino, and cyano; 15 R16 and R19 are optionally Qb with the proviso that no more than one of R16 and R19 is Qb at the same time and that Qb s Qbe b 20 21 be be Q is selected from the group consisting of NR R , Q wherein Q is hydrido, and C(NR 2 5 2324 20, 21, 23, 24, 25gru R2, R2, R , R2, and R are independently selected from the group 20 consisting of hydrido and alkyl; Q is CH 2 In a preferred specific embodiment of Formula 1, compounds have the Formula I-S: 90 WO 00/69832 PCT/USOO/09806

R

2 B NN R YO H 0 (1-s) or a pharmaceutically acceptable salt thereof, wherein; B is the Formula: R 3 R

R

3 6 32 33 34 35 36 5 R3, R , R , R , and R are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, methyl, ethyl, isopropyl, propyl, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, methoxyamino, ethoxyamino, acetamido, trifluoroacetamido, nitro, aminomethyl, 1-aminoethyl, 2-aminoethyl, N-methylanino, dimethylanino, 10 N-ethylamino, methylthio, ethylthio, isopropylthio, trifluoromethylthio, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, 2,2,3,3,3 pentafluoropropyl, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro, bromo, amidosulfonyl, N-methylamidosulfonyl,

N,N

dimethylamidosulfonyl, acetyl, propanoyl, trifluoroacetyl, 15 pentafluoropropanoyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro-1-hydroxyethyl, 2,2,2-trifluoro-1-trifluoromethyl-1 hydroxyethyl, carboxymethyl, methoxycarbonyl, ethoxycarbonyl, amidocarbonyl, N-methylamidocarbonyl, N,N-dimethylamidocarbonyl, cyano, and Qb 20 B is selected from the group consisting of hydrido, trimethylsilyl, ethyl, 2-propenyl, 2 -propynyl, propyl, isopropyl, butyl, 2-butenyl, 3-butenyl, 91 WO 00/69832 PCT/USOO/09806 2-butynyl, sec-butyl, tert-butyl, isobutyl, 2-methylpropenyl, 1-pentyl, 2 pentenyl, 3-pentenyl, 4-pentenyl, 2-pentynyl, 3-pentynyl, 2-pentyl, 1-methyl 2-butenyl, I -methyl-3-butenyl, I -methyl-2-butynyl, 3-pentyl, 1 -ethyl-2 propenyl, 2-methylbutyl, 2-methyl-2-butenyl, 2-methyl-3-butenyl, 2-methyl-3 5 butynyl, 3-methylbutyl, 3-methyl-2-butenyl, 3-methyl-3-butenyl, 1-hexyl, 2 hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 2-hexyl, 1-methyl-2-pentenyl, 1-methyl-3-pentenyl, 1-methyl-4-pentenyl, 1 methyl-2-pentynyl, 1-methyl-3-pentynyl, 3-hexyl, 1 -ethyl-2-butenyl, 1-ethyl 3-butenyl, 1-propyl-2-propenyl, 1-ethyl-2-butynyl, 1-heptyl, 2-heptenyl, 3 10 heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl, 2-heptynyl, 3-heptynyl, 4 heptynyl, 5-heptynyl, 2-heptyl, 1-methyl-2-hexenyl, 1-methyl-3-hexenyl,

I

methyl-4-hexenyl, 1-methyl-5-hexenyl, 1-methyl-2-hexynyl, 1-methyl-3 hexynyl, 1-methyl-4-hexynyl, 3-heptyl, 1 -ethyl-2-pentenyl, 1-ethyl-3 pentenyl, 1 -ethyl-4-pentenyl, 1-butyl-2-propenyl, 1 -ethyl-2-pentynyl, 1-ethyl 15 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-heptynyl, 1-methyl-3-heptynyl, 1 methyl4-heptenyl, 1-methyl-5-heptenyl, 1-methyl-6-heptenyl, 1-methyl-2 20 heptenyl, 1 -methyl-3-heptynyl, I -methyl-4-heptynyl, 1 -methyl -5-heptynyl, 3 octyl, 1 -ethyl-2-hexenyl, 1-ethyl-3-hexenyl, 1-ethyl-4-hexenyl, 1-ethyl-2 hexynyl, 1-ethyl-3-hexynyl, 1-ethyl-4-hexynyl, 1 -ethyl-5-hexenyl, 1-pentyl-2 propenyl, 4-octyl, 1-propyl-2-pentenyl, 1-propyl-3-pentenyl, 1-propyl-4 pentenyl, 1-butyl-2-butenyl, 1-propyl-2-pentynyl, 1-propyl-3-pentynyl, 1 25 butyl-2-butynyl, 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 at any carbon up to and including 5 atoms from the I32 point of attachment of B to A with one or more of the group consisting of R32 33 34 35 36 30 R R R3, and R B is optionally selected from the group consisting of cyclopropyl, cyclobutyl, oxetan-2-yl, oxetan-3-yl, azetidin-1-yl, azetidin-2-yl, azetidin-3-yl, thiaetan-2-yl, thiaetan-3-yl, cyclopentyl, cyclohexyl, adamantyl, norbornyl, 3 trifluoromethylnorbornyl, bicyclo[3.1 .O]hexan-6-yl, cycloheptyl, and 92 WO 00/69832 PCT/USOO/09806 cyclooctyl, wherein each ring carbon is optionally substituted with R3, ring carbons or a nitrogen adjacent to the carbon atom at the point of attachment is 9 13 optionally substituted with R or R , a ring carbon or a nitrogen adjacent to the R9 position and two atoms from the point of attachment is optionally 5 substituted with R1, and a ring carbon or a nitrogen adjacent to the R 1 3 position and two atoms from the point of attachment is optionally substituted with R12 9 10 11 12 13 R , R , R , R , and R are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, carboxymethyl, 10 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, 15 2,2,3,3,3-pentafluoropropyl, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro, bromo, methanesulfonamido, amidosulfonyl, N methylamidosulfonyl, N,N-dimethylamidosulfonyl, acetyl, propanoyl, trifluoroacetyl, pentafluoropropanoyl, hydroxymethyl, 1-hydroxyethyl, 2 hydroxyethyl, 2,2,2-trifluoro-1-hydroxyethyl, 2,2,2-trifluoro-1 20 trifluoromethyl-1-hydroxyethyl, carboxymethyl, methoxycarbonyl, ethoxycarbonyl, amidocarbonyl, N-methylamidocarbonyl,

N,N

dimethylamidocarbonyl, and cyano; A is selected from the group consisting of single covalent bond, 0, S, NH, N(CH 3 ), N(OH), C(O), CH 2 , CH 3 CH, CF 3 CH, NHC(O), 25 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)CCH 2 , CH 2

CH

2 , CH 2

CH

2

CH

2 , CH 3

CHCH

2 , CF 3

CHCH

2 ,

CH

3

CC(O)CH

2 , CF 3

CC(O)CH

2 , CH 2

C(O)CCH

3 , CH 2

C(O)CCF

3 ,

CH

2

CH

2 C(O), and CH 2 (0)CCH 2 ; 93 WO 00/69832 PCT/USOO/09806 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 ) with the proviso that B is hydrido; M is selected from the group consisting of N and R -C; 5 R 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, 2,2,3,3,3 pentafluoropropyl, methoxy, ethoxy, propoxy, hydroxymethyl, 1 10 hydroxyethyl, 2-hydroxyethyl, methoxyamino, ethoxyamino, methylthio, ethylthio, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro, and bromo;

R

2 is Z 0 -Q; Z is selected from the group consisting of covalent single bond, 0, S, 15 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 20 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, and 1,2,3-triazin 25 5-yl, wherein a carbon adjacent to the carbon at the point of attachment is optionally substituted by R 9, the other carbon adjacent to the carbon at the 139 point of attachment is optionally substituted by R , a carbon adjacent to R and two atoms from the carbon at the point of attachment is optionally 10 13 substituted by R1 , a carbon adjacent to R and two atoms from the carbon at 94 WO 00/69832 PCT/USOO/09806 the point of attachment is optionally substituted by R 12 , and any carbon . 10 12 11i adjacent to both R and R is optionally substituted by R ; K is CHR wherein R is selected from the group consisting of methyl, ethyl, propyl, isopropyl, hydroxymethyl, 1-hydroxyethyl, 5 methoxymethyl, trifluoromethyl, pentafluoroethyl, 2

,

2 ,2-trifluoromethyl, methylthiomethyl, and hydrido; E is a covalent single bond, C(O)N(H), (H)NC(O), and S(O) 2 N(H); Y is selected from the group of formulas consisting of: S R 1 7

R

1 8

R

1 6

R

1 9 Qb S S R 7 R 1 8

R

1 8 N 19 R16 R19 10 Qb Qb S S R18

R

1 8 R16 NYN R 19 Qb Qb 95 WO 00/69832 PCT/USOO/09806 R 17R1 8N N N16 1 9 SR Q Qb Q S Q s R -R 17 b Q 16 67 R R R R1?6 Q R1 6 sq RRQ 5b Q

R

1 6 H Q H N N I / 19 /b Qb R 1 6 Q s H s N Q H N) R 1/ Qb

R

1 7 , N 5 Q b 96 WO 00/69832 PCT/USOO/09806 QS Qb QS H N N

R

1 6

R

1 6 R16 Qb S b s RQb j/

-R

1 9 Qb and R17N Qb 16 17 18 19 R1, R , R , and R are independently selected from the group consisting of hydrido, methyl, ethyl, isopropyl, propyl, amidino, guanidino, 5 carboxy, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, methoxyamino, ethoxyamino, aminomethyl, 1-aminoethyl, 2-aminoethyl, N N-methylamino, dimethylamino, N-ethylamino, methylthio, ethylthio, isopropylthio, trifluoromethylthio, methylsulfinyl, ethylsulfinyl, methylsulfonyl, ethylsulfonyl, trifluoromethyl, pentafluoroethyl, 2,2,2 10 trifluoroethyl, 2,2,3,3,3-pentafluoropropyl, trifluoromethoxy, 1,1,2,2 tetrafluoroethoxy, fluoro, chloro, bromo, amidosulfonyl, N methylamidosulfonyl, NN-dimethylamidosulfonyl, acetyl, propanoyl, trifluoroacetyl, pentafluoropropanoyl, hydroxymethyl, 1-hydroxyethyl, 2 hydroxyethyl, 2,2,2-trifluoro- 1 -hydroxyethyl, and cyano; 15 R16 and R19 are optionally Qb with the proviso that no more than one of R16 and R19 is Qb at the same time and that Qb s Qbe b .20 21 be Q is selected from the group consisting of NR R Q wherein Qbe is hydrido, C(NR25 )NR R and N(R 26)C(NR 25)N(R )(R 24), with the proviso that no more than one of R20 and R21 is hydroxy, N 20 methylamino, and N,N-dimethylamino at the same time and that no more than 97 WO 00/69832 PCT/USOO/09806 23 24 one of R and R is hydroxy, N-methylamino, and N,N-dimethylamino at the same time; 20 21 23 24 25 26 R2, R , R , R , R , and R are independently selected from the group consisting of hydrido, methyl, ethyl, propyl, butyl, isopropyl, hydroxy, 2 5 aminoethyl, 2-(N-methylamino)ethyl, and 2 -(N,N-dimethylamino)ethyl; Qs 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=CH, CF=CH, C(CH 3 )=CH, CH=CHCH 2 , CF=CHCH2,

C(CH

3

)=CHCH

2 , CH 2 CH=CH, CH 2 CF=CH, CH 2

C(CH

3 )=CH, 10 CHCH=CHCH 2 , CH 2

CF=CHCH

2 , CH 2

C(CH

3

)=CHCH

2 ,

CHCH=CHCH

2

CH

2 , CH 2

CF=CHCH

2

CH

2 , and

CH

2

C(CH

3

)=CHCH

2

CH

2 . In a more preferred specific embodiment of Formula I, compounds have the Formula I-MPS wherein B is an aromatic: 2 B AN N N H H 15 0 (I-MPS wherein B is aromatic) or a pharmaceutically acceptable salt thereof, wherein; B is the Formula: 98 WO 00/69832 PCT/USOO/09806 R 34

R

3 R 32 33 34 35 36 R R R , R , and R are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, methoxyamino, ethoxyamino, 5 acetamido, trifluoroacetamido, N-methylamino, dimethylarnino, N-ethylanino, 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, N,N-dimethylamidosulfonyl, hydroxymethyl, 1 10 hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro-1-hydroxvethyl, methoxycarbonyl, ethoxycarbonyl, amidocarbonyl, N-methylamidocarbonyl, N,N-dimethylamidocarbonyl, cyano, and Qb A is selected from the group consisting of single covalent bond, NH,

N(CH

3 ), N(OH), CH 2 , CH 3 CH, CF 3 CH, NHC(O), N(CH 3 )C(O), 15 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 ; b 20 21 be be Q is selected from the group consisting of NR R , Q wherein Q is 25 23 24 2 hydrido, and C(NR )NR R , with the provisos that no more than one of R and R21 is hydroxy at the same time and that no more than one of R and R is 20 hydroxy at the same time; 20 21 23 24 25 R , R , R , R , and R are independently selected from the group consisting of hydrido, methyl, ethyl, propyl, butyl, isopropyl, and hydroxy; 99 WO 00/69832 PCT/USOO/09806 QS is selected from the group consisting of a single covalent bond,

CH

2 , and CH 2

CH

2 . In another more preferred specific embodiment of Formula I, compounds have the Formula I-MPS wherein B is a non-cyclic substituent: 00 2 B A N N H H 5 0 (I-MPS wherein B is a non-cyclic substituent) 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, 3-butenyl, 2-butynyl, sec 10 butyl, ten-butyl, isobutyl, 2-methylpropenyl, 1-pentyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-pentynyl, 3-pentynyl, 2-pentyl, 1-methyl-2-butenyl, 1-methyl-3 butenyl, 1-methyl-2-butynyl, 3-pentyl, 1-ethyl-2-propenyl, 2-methylbutyl, 2 methyl-2-butenyl, 2-methyl-3-butenyl, 2-methyl-3-butynyl, 3-methylbutyl, 3 methyl-2-butenyl, 3-methyl-3-butenyl, 1 -hexyl, 2-hexenyl, 3-hexenyl, 4 15 hexenyl, 5-hexenyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 2-hexyl, 1-methyl-2 pentenyl, 1-methyl-3-pentenyl, 1-methyl-4-pentenyl, 1-methyl-2-pentynyl, 1 methyl-3-pentynyl, 3-hexyl, 1-ethyl-2-butenyl, 1-ethyl-3-butenyl, 1-propyl-2 propenyl, 1-ethyl-2-butynyl, 1-heptyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5 heptenyl, 6-heptenyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 5-heptynyl, 2 20 heptyl, 1-methyl-2-hexenyl, 1-methyl-3-hexenyl, 1-methyl-4-hexenyl, 1 methyl-5-hexenyl, 1-methyl-2-hexynyl, 1-methyl-3-hexynyl, 1-methyl-4 hexynyl, 3-heptyl, 1-ethyl-2-pentenyl, 1-ethyl-3-pentenyl, 1-ethyl-4-pentenyl, 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 25 trifluoromethylpentyl, 5,5, 6

,

6

,

6 -pentafluorohexyl, and 3,3,3-trifluoropropyl, wherein each member of group B is optionally substituted at any carbon up to and including 5 atoms from the point of attachment of B to A with one or more 32 33 34 35 36 of the group consisting of R , R3, R3, R3, and R 100 WO 00/69832 PCT/USOO/09806 32 33 34 35 36 R , R , R , R , and R 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, 5 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, N,N-dimethylamidosulfonyl, hydroxymethyl, 1 hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro-1-hydroxyethyl, 10 methoxycarbonyl, ethoxycarbonyl, amidocarbonyl, N-methylamidocarbonyl, N,N-dimethylamidocarbonyl, cyano, and Qb A is selected from the group consisting of 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 15

CF

3

CHCH

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 ) with the proviso that B is hydrido; b .20 21 be be Q is selected from the group consisting of NR R , Q , wherein Q 20 is hydrido, C(NR 25)NR R 24, and N(R 26)C(NR 25)N(R )(R 24), with the provisos that no more than one of R20 and R21 is hydroxy at the same time and that no more than one of R and R is hydroxy at the same time; 20 21 23 24 25 26 R , R , R , R , R , and R are independently selected from the group consisting of hydrido, methyl, ethyl, propyl, butyl, isopropyl, and hydroxy; 25 Qs is selected from the group consisting of a single covalent bond,

CH

2 , and CH 2

CH

2 . 101 WO 00/69832 PCT/USOO/09806 In still another more preferred specific embodiment of Formula 1, compounds have the Formula I-MPS wherein B is a non-aromatic cyclic substituent: M 0 B N N N 0 H H 0 (I-MPS 5 wherein B is a non-aromatic cyclic substituent) 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, thiaetan-3 yl, cyclopentyl, cyclohexyl, norbornyl, bicyclo[3. 1.0]hexan-6-yl, and 33 10 cycloheptyl , wherein each ring carbon is optionally substituted with R , ng carbons or a nitrogen adjacent to the carbon atom at the point of attachment is optionally substituted with R or R1, a ring carbon or nitrogen adjacent to the R9 position and two atoms from the point of attachment is optionally substituted with R 10 , and a ring carbon or nitrogen adjacent to the R 13 15 position and two atoms from the point of attachment is optionally substituted 12 with R A is selected from the group consisting of single covalent bond, NH,

N(CH

3 ), N(OH), CH 2 , CH 3 CH, CF 3 CH, NHC(O), N(CH3)C(O), C(O)NH, C(O)N(CH 3 ), CH 2

CH

2 , CH 2

CH

2

CH

2 , CH 3

CHCH

2 , and 20

CF

3

CHCH

2 ; R33 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, 102 WO 00/69832 PCT/USOO/09806 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,

N,N

dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 5 2,2,2-trifluoro-1-hydroxyethyl, methoxycarbonyl, ethoxycarbonyl, amidocarbonyl, N-methylamidocarbonyl, NN-dimethylamidocarbonyl, cyano, and Qb Q is selected from the group consisting of NR20R21 be wherein Qbe is hydrido, and C(NR 2 5

)NR

2 3 R24, with the provisos that no more than one of R 10 and R21 is hydroxy at the same time and that no more than one of R23 and R is hydroxy at the same time; 20 21 23 24 25 R , R , R , R , and R are independently selected from the group consisting of hydrido, methyl, ethyl, propyl, butyl, isopropyl, and hydroxy; Qs is selected from the group consisting of a single covalent bond, 15

CH

2 , and CH 2

CH

2 . The more preferred specific embodiment (I-MPS) compounds of the present invention having the Formula: A R 2 B N N H H 0 or a pharmaceutically acceptable salt thereof, have common structural units, 20 wherein; M is selected from the group consisting of N and R -C; R is selected from the group consisting of hydrido, hydroxy, amino, amidino, hydroxyamino, aminomethyl, 1-aminoethyl, methylamino, dimethylanino, cyano, methyl, ethyl, trifluoromethyl, pentafluoroethyl, 2,2,2 103 WO 00/69832 PCT/USOO/09806 trifluoroethyl, methoxy, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, methoxyamino, methylthio, ethylthio, trifluoromethoxy, 1,1,2,2 tetrafluoroethoxy, fluoro, chloro, and bromo;

R

2 is Z 0 -Q; 5 ZO is selected from the group consisting of covalent single bond, 0, 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 10 pyridyl, 4-pyridyl, 2-pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, and 1,3,5-triazin-2-yl, wherein a carbon adjacent 9 to the carbon at the point of attachment is optionally substituted by R , the other carbon adjacent to the carbon at the point of attachment is optionally 13 9 substituted by R , a carbon adjacent to R and two atoms from the carbon at 10 15 the point of attachment is optionally substituted by R , a carbon adjacent to R13 and two atoms from the carbon at the point of attachment is optionally 12 10 12. substituted by R1, and any carbon adjacent to both R and R is optionally substituted by R 9 11 13 R , R , and R are independently selected from the group consisting 20 of hydrido, amidino, guanidino, carboxy, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, N-methylamino, N,N-dimethylamino, N-ethylamino, methylthio, ethylthio, isopropylthio, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, 2,2,3,3,3 pentafluoropropyl, trifluoromethoxy, 1,1, 2

,

2 -tetrafluoroethoxy, fluoro, 25 chloro, bromo, methanesulfonamido, amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl, 1 -hydroxyethyl, 2 hydroxyethyl, 2,2,2-trifluoro-1-hydroxyethyl, amidocarbonyl,

N

methylamidocarbonyl, N,N-dimethylamidocarbonyl, and cyano; 104 WO 00/69832 PCT/USOO/09806 10 12 R and R 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 5 aminoethyl, 2-aminoethyl, N-methylamino, dimethylamino, N-ethylamino. methanesulfonamido, 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, 10 fluoro, chloro, bromo, and cyano; Y is selected from the group of formulas consisting of: S R 17 R 18

R

1 6 19 Qb S S

R

1 7

R

1 8 R18

NR

1 N g19 R16 R19 Qb Qb S S 1 ~R 18

R

18 RN

R

1 9 Qb b 105 WO 00/69832 PCT/USOO/09806 R 7R18 N K'N N N 16 19 R R1 b Q Qb Q S s I / 9 b

K

7 Z QbK 6 Q 16 I / K 1 9 b RK1 6 )qR 7 / Qb qK' 6 Q R R1 b N S H H0N I/K 1 9 Qb RK1 6 17Z QbR 16 Q s H s N Q H N K'1 7 CN 5 Q b 106 WO 00/69832 PCT/USOO/09806 QS Q b Qs H N N

R

1 6

R

1 6

R

1 6 Qb S b QSS QS and

R

1 7 N Qb 16 17 18 19 R , R , R , and R are independently selected from the group consisting of hydrido, methyl, ethyl, isopropyl, propyl, carboxy, amidino, 5 guanidino, methoxy, ethoxy, isopropoxy, propoxy, 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, 2,2,3,3,3-pentafluoropropyl, 10 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, and cyano; R16 and R19 are optionally Qb with the proviso that no more than one 15 of R16 and R19 is Qb at the same time and that Qb is Qbe In a most preferred specific embodiment of Formula I, compounds have the Formula I-EMPS wherein B is an aromatic: 107 WO 00/69832 PCT/USOO/09806 0 A N R 2 Y B N N H H 0 (I-EMPS wherein B is aromatic) or a pharmaceutically acceptable salt thereof, wherein; B is the Formula: R 34 R 33R3 5 K R3 2 R3 6 R R 5 32 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, 10 chloro, bromo, amidosulfonyl, N-methylamidosulfonyl, hydroxymethyl, amidocarbonyl, carboxy, cyano, and Qb A is selected from the group consisting of single covalent bond, NH,

N(CH

3 ), CH 2 , CH 3 CH, and CH 2

CH

2 ; Qb is selected from the group consisting of NR20R21 and 15 C(NR )NR 24, with the proviso that said Qb group is bonded directly to a carbon atom; 20 21 23 24 25 R , R , R , R , and R are independently selected from the group consisting of hydrido, methyl, and ethyl; 108 WO 00/69832 PCT/USOO/09806 Qs is CH2 In another most preferred specific embodiment of Formula I, compounds have the Formula I-EMPS wherein B is a non-cyclic substituent: M 0 B AN N N N H H 0 (I-EMPS 5 wherein B is a non-cyclic substituent) 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, sec-butyl, tert butyl, isobutyl, 2-methylpropenyl, 1-pentyl, 2-pentenyl, 3-pentenyl, 2 10 pentynyl, 3-pentynyl, 2-pentyl, 3-pentyl, 2-methylbutyl, 2-methyl-2-butenyl, 3-methylbutyl, 3-methyl-2-butenyl, 1-hexyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 2-hexyl, 1-methyl-2-pentenyl, 1-methyl-3 pentenyl, 1-methyl-2-pentynyl, 1-methyl-3-pentynyl, 3-hexyl, 1-ethyl-2 butenyl, 1-heptyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 2-heptynyl, 15 3-heptynyl, 4-heptynyl, 5-heptynyl, 2-heptyl, 1-methyl-2-hexenyl, 1-methyl 3-hexenyl, 1-methyl-4-hexenyl, 1-methyl-2-hexynyl, 1-methyl-3-hexynyl,

I

methyl-4-hexynyl, 3-heptyl, 1-ethyl-2-pentenyl, 1-ethyl-3-pentenyl, 1-ethyl-2 pentynyl, 1-ethyl-3-pentynyl, 2,2,2-trifluoroethyl, 2,2-difluoropropyl, 4 trifluoromethyl-5,5,5-trifluoropentyl, 4 -trifluoromethylpentyl, 5,5,6,6,6 20 pentafluorohexyl, and 3,3,3-trifluoropropyl, wherein each member of group B is optionally substituted at any carbon up to and including 5 atoms from the point of attachment of B to A with one or more of the group consisting of R32 33 34 35 36 R ,R R3, and R 32 33 34 35 36 R , R , R , R , and R are independently selected from the 25 group consisting of hydrido, amidino, guanidino, methyl, ethyl, methoxy, ethoxy, hydroxy, amino, N-methylamino, dimethylamino, methylthio, ethylthio, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, fluoro, 109 WO 00/69832 PCT/USOO/09806 chloro, bromo, amidosulfonyl, N-methylamidosulfonyl, hydroxymethyl, amidocarbonyl, carboxy, cyano. and Qb A is selected from the group consisting of single covalent bond, NH,

N(CH

3 ), CH 2 , CH 3 CH, and CH 2

CH

2 ; 5 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 ) with the proviso that B is hydrido; b- 20 21 Q is selected from the group consisting of NR R , C(NR 25)NR R 24, and N(R 26)C(NR 25)N(R )(R 24), with the proviso that 10 said Qb group is bonded directly to a carbon atom; 20 21 23 24 25 26 R2, R2, R , R , R , and R are independently selected from the group consisting of hydrido, methyl, and ethyl; Qs is CH2 In still another most preferred specific embodiment of Formula I, 15 compounds have the Formula I-EMPS wherein B is a non-aromatic cyclic substituent: 2 M O0 B N N H H 0 (I-EMPS wherein B is a non-aromatic cyclic substituent) 20 or a pharmaceutically acceptable salt thereof, wherein; B is optionally selected from the group consisting of cyclopropyl, cyclobutyl, oxetan-3-yl, azetidin-3-yl, thiaetan-3-yl. cyclopentyl, and 33 cyclohexyl, wherein each ring carbon is optionally substituted with R , ring 110 WO 00/69832 PCT/USOO/09806 carbons or a nitrogen adjacent to the carbon atom at the point of attachment is 9 13, -croorntoeadaettth optionally substituted with R or R1, a ring carbon or nitrogen adjacent to the R9 position and two atoms from the point of attachment is optionally 10 1 substituted with R1, and a ring carbon or nitrogen adjacent to the R 5 position and two atoms from the point of attachment is optionally substituted with R12 R33 are independently selected from the group consisting of hydrido, amidino, guanidino, methyl, ethyl, methoxy, ethoxy, hydroxy, carboxy, amino, N-methylamino, dimethylamino, methylthio, ethylthio, trifluoromethyl, 10 pentafluoroethyl, 2,2,2-trifluoroethyl, fluoro, chloro, bromo, amidosulfonyl, N-methylamidosulfonyl, hydroxymethyl, amidocarbonyl, cyano, and Qb A is selected from the group consisting of single covalent bond, NH,

N(CH

3 ), CH 2 , CH 3 CH, and CH 2

CH

2 ; Qb is selected from the group consisting of NR20R21 and 15 C(NR25 )NR23R , with the proviso that said Q group is bonded directly to a carbon atom; 20 21 23 24 25 R , R , R , R , and R are independently selected from the group consisting of hydrido, methyl, and ethyl; Q is CH 2 20 The most preferred specific embodiment (I-EMPS) compounds of the present invention having the Formula: R2 M 0 B N N H .

H 0 111 WO 00/69832 PCT/USOO/09806 or a pharmaceutically acceptable salt thereof, have common structural units. wherein; M is selected from the group consisting of N and R -C; R is selected from the group consisting of hydrido. hydroxy, amino, 5 amidino, hydroxyamino, aninomethyl, methylamino, cyano, methyl, trifluoromethyl, methoxy, hydroxymethyl, methoxyamino, methylthio, trifluoromethoxy, fluoro, and chloro;

R

2 is Z-Q; ZO is a covalent single bond; 10 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 a carbon adjacent to the carbon at the point of attachment is optionally 9 substituted by R , the other carbon adjacent to the carbon at the point of 13 9 attachment is optionally substituted by R , a carbon adjacent to R and two 15 atoms from the carbon at the point of attachment is optionally substituted by 10 13 R , a carbon adjacent to R and two atoms from the carbon at the point of 12 attachment is optionally substituted by R , and any carbon adjacent to both R10 and R12 is optionally substituted by R 9 11 13 R , R , and R are independently selected from the group consisting 20 of hydrido, methyl, ethyl, methoxy, ethoxy, hydroxy, amino, N-methylamino, N,N-dimethylamino, methylthio, trifluoromethyl, pentafluoroethyl, 2,2,2 trifluoroethyl, fluoro, chloro, bromo, amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, amidocarbonyl, N-methylamidocarbonyl, carboxy, and cyano; 25 R10 and R12 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 112 WO 00/69832 PCT/USOO/09806 methylamino, dimethylamino, amidosulfonyl, N-methylamidosulfonyl,

N,N

dimethylamidosulfonyl, methoxycarbonyl, fluoro, chloro, bromo, and cyano; Y is selected from the group of formulas consisting of: S R1 7

R

1 8

R

1 6 R19 Qb S S R 1 7 R1 8

R

1 8

R

1 9 R16 19 5 Qb b QS Q R b

R

1 6

R

1 7 Qb R16 QS Q

R

1 6

R

1 7 Qb R 1 6 113 WO 00/69832 PCT/USOO/09806 QS H H N N - R 19b R16 7 Qb 1 6 S R19 0b S QS and R 1 7 N Qb 16 17 18 19 5 R , R , R , and R 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, 10 trifluoromethoxy, fluoro, chloro, amidosulfonyl, N-methylamidosulfonyl, hydroxymethyl, carboxy, and cyano. The compounds of this invention can be used in anticoagulant therapy for the treatment and prevention of a variety of thrombotic conditions including coronary artery and cerebrovascular disease. The compounds of this invention 15 can be used to inhibit serine protease associated with the coagulation cascade and factors II, VII, VIII, IX, X, XI, or XII. The compounds of the invention can inhibit the formation of blood platelet aggregates, inhibit the formation of fibrin, inhibit thrombus formation, and inhibiting embolus formation in a mammal, in blood, in blood products, and in mammalian organs. The 20 compounds also can be used for treating or preventing unstable angina, refractory angina, myocardial infarction, transient ischemic attacks, atrial fibrillation, thrombotic stroke, embolic stroke, deep vein thrombosis, disseminated intravascular coagulation, ocular build up of fibrin, and reocclusion or restenosis of recanalized vessels in a mammal. The compounds 25 can also be used in prophylactic treatment of subjects who are at risk of 114 WO 00/69832 PCT/USOO/09806 developing such disorders. The compounds can be used to lower the risk of atherosclerosis. The compounds of Formula (I) would also be useful in prevention of cerebral vascular accident (CVA) or stroke. Besides being useful for human treatment, these compounds are also 5 useful for veterinary treatment of companion animals, exotic animals and farm animals, including mammals, rodents, and the like. More preferred animals include horses, dogs, and cats. In yet another embodiment of the present invention, the novel compounds are selected from the compounds set forth in Examples 1 through 10 Example 19 and Tables 1. The use of generic terms in the description of the compounds are herein defined for clarity. Standard single letter elemental symbols are used to represent specific types of atoms unless otherwise defined. The symbol "C" represents a carbon atom. 15 The symbol "0" 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 hydrido atom. Double letter elemental symbols are used as defined for the elements of the periodical table (i.e., Cl represents chlorine, Se represents selenium, etc.). 20 As utilized herein, the term "alkyl", either alone or within other terms such as "haloalkyl" and "alkylthio", means an acyclic alkyl radical containing from 1 to about 10, preferably from 3 to about 8 carbon atoms and more preferably 3 to about 6 carbon atoms. Said alkyl radicals may be optionally substituted with groups as defined below. Examples of such radicals include methyl, ethyl, 25 chloroethyl, hydroxyethyl, n-propyl, oxopropyl, isopropyl, n-butyl, cyanobutyl, isobutyl, sec-butyl, tert-butyl, pentyl, aninopentyl, iso-amyl, hexyl, octyl and the like. The term "alkenyl" refers to an unsaturated, acyclic hydrocarbon radical in so much as it contains at least one double bond. Such alkenyl radicals contain 30 from about 2 to about 10 carbon atoms, preferably from about 3 to about 8 carbon atoms and more preferably 3 to about 6 carbon atoms. Said alkenyl radicals may be optionally substituted with groups as defined below. Examples of suitable alkenyl radicals include propenyl, 2-chloropropenyl, buten-1-yl, isobutenyl, penten-1-yl, 2 2-methylbuten-1-yl, 3-methylbuten-1-yl, hexen-1-yl, 3-hydroxyhexen-1-yl, 35 hepten-1-yl, and octen-1-yl, and the like. 115 WO 00/69832 PCT/USOO/09806 The term "alkynyl" refers to an unsaturated, acyclic hydrocarbon radical in so much as it contains one or more triple bonds, such radicals containing about 2 to about 10 carbon atoms, preferably having from about 3 to about 8 carbon atoms and more preferably having 3 to about 6 carbon atoms. Said 5 alkynyl radicals may be optionally substituted with groups as defined below. Examples of suitable alkynyl radicals include ethynyl, propynyl, hydroxypropynyl, butyn-1-yl, butyn-2-yl, pentyn-1-yl, pentyn-2-yl, 4 methoxypentyn-2-yl, 3-methylbutyn-1-yl, hexyn-1-yl, hexyn-2-yl, hexyn-3 yl, 3,3-dimethylbutyn-1-yl radicals and the like. 10 The term "hydrido" denotes a single hydrogen atom (H). This hydrido radical may be attached, for example, to an oxygen atom to form a "hydroxyl" radical, one hydrido radical may be attached to a carbon atom to form a "methine" radical -CH=, or two hydrido radicals may be attached to a carbon atom to form a "methylene" (-CH 2 -) radical. 15 The term "carbon" radical denotes a carbon atom without any covalent bonds and capable of forming four covalent bonds. The term "cyano" radical denotes a carbon radical having three of four covalent bonds shared by a nitrogen atom. The term "hydroxyalkyl" embraces radicals wherein any one or more of 20 the alkyl carbon atoms is substituted with a hydroxyl as defined above. Specifically embraced are monohydroxyalkyl, dihydroxyalkyl and polyhydroxyalkyl radicals. The term "alkanoyl" embraces radicals wherein one or more of the terminal alkyl carbon atoms are substituted with one or more carbonyl radicals 25 as defined below. Specifically embraced are monocarbonylalkyl and dicarbonylalkyl radicals. Examples of monocarbonylalkyl radicals include formyl, acetyl, and pentanoyl. Examples of dicarbonylalkyl radicals include oxalyl, malonyl, and succinyl. The term "alkylene" radical denotes linear or branched radicals having 30 from 1 to about 10 carbon atoms and having attachment points for two or more covalent bonds. Examples of such radicals are methylene, ethylene, methylethylene, and isopropylidene. The term "alkenylene" radical denotes linear or branched radicals having from 2 to about 10 carbon atoms, at least one double bond, and having 116 WO 00/69832 PCT/USOO/09806 attachment points for two or more covalent bonds. Examples of such radicals are 1,1-vinylidene (CH,=C), 1,2-vinylidene (-CH=CH-), and 1,4-butadienyl (-CH=CH-CH=CH-). The term "halo" means halogens such as fluorine, chlorine, bromine or 5 iodine atoms. The term "haloalkyl" embraces radicals wherein any one or more of the alkyl carbon atoms is substituted with halo as defined above. Specifically embraced are monohaloalkyl, dihaloalkyl and polyhaloalkyl radicals. A monohaloalkyl radical, for one example, may have either a bromo, chloro or a 10 fluoro atom within the radical. Dihalo radicals may have two or more of the same halo atoms or a combination of different halo radicals and polyhaloalkyl radicals may have more than two of the same halo atoms or a combination of different halo radicals. More preferred haloalkyl radicals are "lower haloalkyl" radicals having one to about six carbon atoms. Examples of such haloalkyl 15 radicals include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, trifluoroethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl. The term "hydroxyhaloalkyl" embraces radicals wherein any one or 20 more of the haloalkyl carbon atoms is substituted with hydroxy as defined above. Examples of "hydroxyhaloalkyl" radicals include hexafluorohydroxypropyl. The term "haloalkylene radical" denotes alkylene radicals wherein any one or more of the alkylene carbon atoms is substituted with halo as defined 25 above. Dihalo alkylene radicals may have two or more of the same halo atoms or a combination of different halo radicals and polyhaloalkylene radicals may have more than two of the same halo atoms or a combination of different halo radicals. More preferred haloalkylene radicals are "lower haloalkylene" radicals having one to about six carbon atoms. Examples of "haloalkylene" 30 radicals include difluoromethylene, tetrafluoroethylene, tetrachloroethylene, alkyl substituted monofluoromethylene, and aryl substituted trifluoromethylene. The term "haloalkenyl" denotes linear or branched radicals having from 1 to about 10 carbon atoms and having one or more double bonds wherein any 35 one or more of the alkenyl carbon atoms is substituted with halo as defined 117 WO 00/69832 PCT/USOO/09806 above. Dihaloalkenyl radicals may have two or more of the same halo atoms or a combination of different halo radicals and polyhaloalkenyl radicals may have more than two of the same halo atoms or a combination of different halo radicals. 5 The terms "alkoxy" and "alkoxyalkyl" embrace linear or branched oxy containing radicals each having alkyl portions of one to about ten carbon atoms, such as methoxy radical. The term "alkoxyalkyl" also embraces alkyl radicals having one or more alkoxy radicals attached to the alkyl radical, that is, to form monoalkoxyalkyl and dialkoxyalkyl radicals. More preferred alkoxy 10 radicals are "lower alkoxy" radicals having 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 with one or more halo atoms, such as fluoro, chloro or bromo, to provide "haloalkoxy" and "haloalkoxyalkyl" radicals. Examples of such haloalkoxy radicals include 15 fluoromethoxy, chloromethoxy, trifluoromethoxy, difluoromethoxy, trifluoroethoxy, fluoroethoxy, tetrafluoroethoxy, pentafluoroethoxy, and fluoropropoxy. Examples of such haloalkoxyalkyl radicals include fluoromethoxymethyl, chloromethoxyethyl, trifluoromethoxymethyl, difluoromethoxyethyl, and trifluoroethoxymethyl. 20 The terms "alkenyloxy" and "alkenyloxyalkyl" embrace linear or branched oxy-containing radicals each having alkenyl portions of two to about ten carbon atoms, such as ethenyloxy or propenyloxy radical. The term "alkenyloxyalkyl" also embraces alkenyl radicals having one or more alkenyloxy radicals attached to the alkyl radical, that is, to form 25 monoalkenyloxyalkyl and dialkenyloxyalkyl radicals. More preferred alkenyloxy radicals are "lower alkenyloxy" radicals having two to six carbon atoms. Examples of such radicals include ethenyloxy, propenyloxy, butenyloxy, and isopropenyloxy alkyls. The "alkenyloxy" radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or 30 bromo, to provide "haloalkenyloxy" radicals. Examples of such radicals include trifluoroethenyloxy, fluoroethenyloxy, difluoroethenyhloxy, and fluoropropenyloxy. The term "haloalkoxyalkyl" also embraces alkyl radicals having one or more haloalkoxy radicals attached to the alkyl radical, that is, to form 35 monohaloalkoxyalkyl and dihaloalkoxyalkyl radicals. The term 118 WO 00/69832 PCT/USOO/09806 "haloalkenyloxy" also embraces oxygen radicals having one or more haloalkenyloxy radicals attached to the oxygen radical, that is, to form monohaloalkenyloxy and dihaloalkenyloxy radicals. The term "haloalkenyloxyalkyl" also embraces alkyl radicals having one or more 5 haloalkenyloxy radicals attached to the alkyl radical, that is, to form monohaloalkenyloxyalkyl and dihaloalkenyloxyalkyl radicals. The term "alkylenedioxy" radicals denotes alkylene radicals having at least two oxygens bonded to a single alkylene group. Examples of "alkylenedioxy" radicals include methylenedioxy, ethylenedioxy, 10 alkylsubstituted methylenedioxy, and arylsubstituted methylenedioxy. The term "haloalkylenedioxy" radicals denotes haloalkylene radicals having at least two oxy groups bonded to a single haloalkyl group. Examples of "haloalkylenedioxy" radicals include difluoromethylenedioxy, tetrafluoroethylenedioxy, tetrachloroethylenedioxy, alkylsubstituted 15 monofluoromethylenedioxy, and arylsubstituted monofluoromethylenedioxy. The term "aryl", alone or in combination, means a carbocyclic aromatic system containing one, two or three rings wherein such rings may be attached together in a pendant manner or may be fused. The term "fused" means that a second ring is present (ie, attached or formed) by having two adjacent atoms in 20 common (ie, shared) with the first ring. The term "fused" is equivalent to the term "condensed". The term "aryl" embraces aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, indane and biphenyl. The term "perhaloaryl" embraces aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, indane and biphenyl wherein the aryl radical is 25 substituted with 3 or more halo radicals as defined below. The term "heterocyclyl" embraces saturated and partially saturated heteroatom-containing ring-shaped radicals having from 4 through 15 ring members, herein referred to as "C4-C15 heterocyclyl" selected from carbon, nitrogen, sulfur and oxygen, wherein at least one ring atom is a heteroatom. 30 Heterocyclyl radicals may contain one, two or three rings wherein such rings may be attached in a pendant manner or may be fused. Examples of saturated heterocyclic radicals include saturated 3 to 6-membered heteromonocylic group containing 1 to 4 nitrogen atoms[e.g. pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl, etc.]; saturated 3 to 6-membered heteromonocyclic group 35 containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g. morpholinyl, 119 WO 00/69832 PCT/USOO/09806 etc.]; 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 heterocyclyl radicals include dihydrothiophene, dihydropyran, dihydrofuran and dihydrothiazole. Non-limiting examples of 5 heterocyclic radicals include 2-pyrrolinyl, 3-pyrrolinyl, pyrrolindinyl, 1,3 dioxolanyl, 2H-pyranyl, 4H-pyranyl, piperidinyl, 1,4-dioxanyl, morpholinyl, 1,4-dithianyl, thiomorpholinyl, and the like. The term "heteroaryl" embraces fully unsaturated heteroatom-containing ring-shaped aromatic radicals having from 5 through 15 ring members selected 10 from carbon, nitrogen, sulfur and oxygen, wherein at least one ring atom is a heteroatom. Heteroaryl radicals may contain one, two or three rings wherein such rings may be attached in a pendant manner or may be fused. Examples of "heteroaryl" radicals, include unsaturated 5 to 6 membered heteromonocyclyl group containing 1 to 4 nitrogen atoms, for example, pyrrolyl, pyrrolinyl, 15 imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl [e.g., 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3 triazolyl, etc.] tetrazolyl [e.g. 1H-tetrazolyl, 2H-tetrazolyl, etc.], etc.; unsaturated condensed heterocyclic group containing 1 to 5 nitrogen atoms, for example, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, 20 isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl [e.g., tetrazolo [1,5-b]pyridazinyl, etc.], etc.; unsaturated 3 to 6-membered heteromonocyclic group containing an oxygen atom, for example, pyranyl, 2-furyl, 3-furyl, etc.; unsaturated 5 to 6-membered heteromonocyclic group containing a sulfur atom, for example, 2-thienyl, 3-thienyl, etc.; unsaturated 5- to 6-membered 25 heteromonocyclic group containing 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.; unsaturated condensed heterocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g. benzoxazolyl, benzoxadiazolyl, etc.]; unsaturated 5 to 6-membered 30 heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl, thiadiazolyl [e.g., 1,2,4- thiadiazolyl, 1,3,4 thiadiazolyl, 1,2,5-thiadiazolyl, etc.] etc.; unsaturated condensed heterocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., benzothiazolyl, benzothiadiazolyl, etc.] and the like. The term also embraces 35 radicals where heterocyclic radicals are fused with aryl radicals. Examples of 120 WO 00/69832 PCT/USOO/09806 such fused bicyclic radicals include benzofuran, benzothiophene, and the like. Said "heterocyclyl" group may have I to 3 substituents as defined below. Preferred heterocyclic radicals include five to twelve membered fused or unfused radicals. Non-limiting examples of heteroaryl radicals include 5 pyrrolyl, pyridinyl, pyridyloxy, pyrazolyl, triazolyl, pyrimidinyl, pyridazinyl, oxazolyl, thiazolyl, imidazolyl, indolyl, thiophenyl, furanyl, tetrazolyl, 2 imidazolinyl, imidazolidinyl, 2-pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,3-triazolyl, 1,3,4-thiadiazolyl, pyrazinyl, piperazinyl, 1,3,5-triazinyl, 1,3,5-trithianyl, benzo(b)thiophenyl, 10 benzimidazoyl, quinolinyl, tetraazolyl, and the like. The term "sulfonyl", whether used alone or linked to other terms such as alkylsulfonyl, denotes respectively divalent radicals -S02-. "Alkylsulfonyl ", embraces alkyl radicals attached to a sulfonyl radical, where alkyl is defined as above. "Alkylsulfonylalkyl", embraces alkylsulfonyl radicals attached to an 15 alkyl radical, where alkyl is defined as above. "Haloalkylsulfonyl", embraces haloalkyl radicals attached to a sulfonyl radical, where haloalkyl is defined as above. "Haloalkylsulfonylalkyl", embraces haloalkylsulfonyl radicals attached to an alkyl radical, where alkyl is defined as above. The term "aminosulfonyl" denotes an amino radical attached to a sulfonyl radical. 20 The term "sulfinyl", whether used alone or linked to other terms such as alkylsulfinyl, denotes respectively divalent radicals -S(O)-. "Alkylsulfinyl", embraces alkyl radicals attached to a sulfinyl radical, where alkyl is defined as above. "Alkylsulfinylalkyl", embraces alkylsulfinyl radicals attached to an alkyl radical, where alkyl is defined as above. "Haloalkylsulfinyl", embraces 25 haloalkyl radicals attached to a sulfinyl radical, where haloalkyl is defined as above. "Haloalkylsulfinylalkyl", embraces haloalkylsulfinyl radicals attached to an alkyl radical, where alkyl is defined as above. The term "aralkyl" embraces aryl-substituted alkyl radicals. Preferable aralkyl radicals are "lower aralkyl" radicals having aryl radicals attached to 30 alkyl radicals having one to six carbon atoms. Examples of such radicals include benzyl, diphenylmethyl, triphenylmethyl, phenylethyl and diphenylethyl. The terms benzyl and phenylmethyl are interchangeable. The term "heteroaralkyl" embraces heteroaryl-substituted alkyl radicals wherein the heteroaralkyl radical may be additionally substituted with three or 35 more substituents as defined above for aralkyl radicals. The term 121 WO 00/69832 PCT/USOO/09806 "perhaloaralkyl" embraces aryl-substituted alkyl radicals wherein the aralkyl radical is substituted with three or more halo radicals as defined above. The term "aralkylsulfinyl", embraces aralkyl radicals attached to a sulfinyl radical, where aralkyl is defined as above. "Aralkylsulfinylalkyl", 5 embraces aralkylsulfinyl radicals attached to an alkyl radical, where alkyl is defined as above. The term "aralkylsulfonyl", embraces aralkyl radicals attached to a sulfonyl radical, where aralkyl is defined as above. "Aralkylsulfonylalkyl", embraces aralkylsulfonyl radicals attached to an alkyl radical, where alkyl is 10 defined as above. The term "cycloalkyl" embraces radicals having three to 15 carbon atoms. More preferred cycloalkyl radicals are "lower cycloalkyl" radicals having three to seven carbon atoms. Examples include radicals such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. The term 15 cycloalkyl embraces radicals having seven to 15 carbon atoms and having two to four rings. Exmaples incude radicals such as norbornyl (i.e., bicyclo[2.2.1]heptyl) and adamantyl. The term "cycloalkylalkyl" embraces cycloalkyl-substituted alkyl radicals. Preferable cycloalkylalkyl radicals are "lower cycloalkylalkyl" radicals having cycloalkyl radicals attached to alkyl 20 radicals having one to six carbon atoms. Examples of such radicals include cyclohexylhexyl. The term "cycloalkenyl" embraces radicals having three to ten carbon atoms and one or more carbon-carbon double bonds. Preferred cycloalkenyl radicals are "lower cycloalkenyl" radicals having three to seven carbon atoms. Examples include radicals such as cyclobutenyl, cyclopentenyl, 25 cyclohexenyl and cycloheptenyl. The term "halocycloalkyl" embraces radicals wherein any one or more of the cycloalkyl carbon atoms is substituted with halo as defined above. Specifically embraced are monohalocycloalkyl, dihalocycloalkyl and polyhalocycloalkyl radicals. A monohalocycloalkyl radical, for one example, may have either a bromo, chloro or a fluoro atom 30 within the radical. Dihalo radicals may have two or more of the same halo atoms or a combination of different halo radicals and polyhalocycloalkyl radicals may have more than two of the same halo atoms or a combination of different halo radicals. More preferred halocycloalkyl radicals are "lower halocycloalkyl" radicals having three to about eight carbon atoms. Examples of 35 such halocycloalkyl radicals include fluorocyclopropyl, difluorocyclobutyl, 122 WO 00/69832 PCT/USOO/09806 trifluorocyclopentyl, tetrafluorocyclohexyl, and dichlorocyclopropyl. The term "halocycloalkenyl" embraces radicals wherein any one or more of the cycloalkenyl carbon atoms is substituted with halo as defined above. Specifically embraced are monohalocycloalkenyl, dihalocycloalkenyl and 5 polyhalocycloalkenyl radicals. The term "cycloalkoxy" embraces cycloalkyl radicals attached to an oxy radical. Examples of such radicals includes cyclohexoxy and cyclopentoxy. The term "cycloalkoxyalkyl" also embraces alkyl radicals having one or more cycloalkoxy radicals attached to the alkyl radical, that is, to form 10 monocycloalkoxyalkyl and dicycloalkoxyalkyl radicals. Examples of such radicals include cyclohexoxyethyl. The "cycloalkoxy" radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide "halocycloalkoxy" and "halocycloalkoxyalkyl" radicals. The term "cycloalkylalkoxy" embraces cycloalkyl radicals attached to an 15 alkoxy radical. Examples of such radicals includes cyclohexylmethoxy and cyclopentylmethoxy. The term "cycloalkenyloxy" embraces cycloalkenyl radicals attached to an oxy radical. Examples of such radicals includes cyclohexenyloxy and cyclopentenyloxy. The term "cycloalkenyloxyalkyl" also embraces alkyl 20 radicals having one or more cycloalkenyloxy radicals attached to the alkyl radical, that is, to form monocycloalkenyloxyalkyl and dicycloalkenyloxyalkyl radicals. Examples of such radicals include cyclohexenyloxyethyl. The "cycloalkenyloxy" radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide "halocycloalkenyloxy" and 25 "halocycloalkenyloxyalkyl" radicals. The term "cycloalkylenedioxy" radicals denotes cycloalkylene radicals having at least two oxygens bonded to a single cycloalkylene group. Examples of "alkylenedioxy" radicals include 1,2-dioxycyclohexylene. The term "cycloalkylsulfinyl", embraces cycloalkyl radicals attached to 30 a sulfinyl radical, where cycloalkyl is defined as above. "Cycloalkylsulfinylalkyl", embraces cycloalkylsulfinyl radicals attached to an alkyl radical, where alkyl is defined as above. The term "Cycloalkylsulfonyl", embraces cycloalkyl radicals attached to a sulfonyl radical, where cycloalkyl is defined as above. "Cycloalkylsulfonylalkyl", embraces cycloalkylsulfonyl 35 radicals attached to an alkyl radical, where alkyl is defined as above. 123 WO 00/69832 PCT/USOO/09806 The term "cycloalkylalkanoyl" embraces radicals wherein one or more of the cycloalkyl carbon atoms are substituted with one or more carbonyl radicals as defined below. Specifically embraced are monocarbonylcycloalkyl and dicarbonylcycloalkyl radicals. Examples of monocarbonylcycloalkyl 5 radicals include cyclohexylcarbonyl, cyclohexylacetyl, and cyclopentylcarbonyl. Examples of dicarbonylcycloalkyl radicals include 1.2 dicarbonylcyclohexane. The term "alkylthio" embraces radicals containing a linear or branched alkyl radical, of one to ten carbon atoms, attached to a divalent sulfur atom. 10 More preferred alkylthio radicals are "lower alkylthio" radicals having one to six carbon atoms. An example of "lower alkylthio" is methylthio (CH 3 -S-). The "alkylthio" radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide "haloalkylthio" radicals. Examples of such radicals include fluoromethylthio, chloromethylthio, 15 trifluoromethylthio, difluoromethylthio, trifluoroethylthio, fluoroethylthio, tetrafluoroethylthio, pentafluoroethylthio, and fluoropropylthio. The term "alkyl aryl amino" embraces radicals containing a linear or branched alkyl radical, of one to ten carbon atoms, and one aryl radical both attached to an amino radical. Examples include N-methyl4-methoxyaniline, 20 N-ethyl4-methoxyaniline, and N-methyl-4-trifluoromethoxyaniline. The terms alkylamino denotes "monoalkylamino" and "dialkylamino" containing one or two alkyl radicals, respectively, attached to an amino radical. The terms arylamino denotes "monoarylamino" and "diarylamino" containing one or two aryl radicals, respectively, attached to an amino radical. 25 Examples of such radicals include N-phenylamino and N-naphthylamino. The term "aralkylamino", embraces aralkyl radicals attached to an amino radical, where aralkyl is defined as above. The term aralkylamino denotes "monoaralkylanino" and "diaralkylamino" containing one or two aralkyl radicals, respectively, attached to an amino radical. The term 30 aralkylamino further denotes "monoaralkyl monoalkylamino" containing one aralkyl radical and one alkyl radical attached to an amino radical. The term "arylsulfinyl" embraces radicals containing an aryl radical, as defined above, attached to a divalent S(O) atom. The term "arylsulfinylalkyl" denotes arylsulfinyl radicals attached to a linear or branched alkyl radical, of 35 one to ten carbon atoms. 124 WO 00/69832 PCT/USOO/09806 The term "arylsulfonyl", embraces aryl radicals attached to a sulfonyl radical, where aryl is defined as above. "arylsulfonylalkyl", embraces arylsulfonyl radicals attached to an alkyl radical, where alkyl is defined as above. The term "heteroarylsulfinyl" embraces radicals containing an heteroaryl 5 radical, as defined above, attached to a divalent S(O) atom. The term "heteroarylsulfinylalkyl" denotes heteroarylsulfinyl radicals attached to a linear or branched alkyl radical, of one to ten carbon atoms. The term "Heteroarylsulfonyl", embraces heteroaryl radicals attached to a sulfonyl radical, where heteroaryl is defined as above. "Heteroarylsulfonylalkyl", 10 embraces heteroarylsulfonyl radicals attached to an alkyl radical, where alkyl is defined as above. The term "aryloxy" embraces 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 15 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-tetrafluoroethoxy) 20 phenoxy, and 4-tert -butylphenoxy. The term "aroyl" embraces aryl radicals, as defined above, attached to an carbonyl radical as defined above. Examples of such radicals include benzoyl and toluoyl. The term "aralkanoyl" embraces aralkyl radicals, as defined herein, 25 attached to an carbonyl radical as defined above. Examples of such radicals include, for example, phenylacetyl. The term "aralkoxy" embraces oxy-containing aralkyl radicals attached through an oxygen atom to other radicals. More preferred aralkoxy radicals are "lower aralkoxy" radicals having phenyl radicals attached to lower alkoxy 30 radical as described above. Examples of such radicals include benzyloxy, 1 phenylethoxy, 3-trifluoromethoxybenzyloxy, 3-trifluoromethylbenzyloxy, 3,5 difluorobenyloxy, 3-bromobenzyloxy, 4-propylbenzyloxy, 2-fluoro-3 trifluoromethylbenzyloxy, and 2-phenylethoxy. The term "aryloxyalkyl" embraces aryloxy radicals, as defined above, 35 attached to an alkyl group. Examples of such radicals include phenoxymethyl. 125 WO 00/69832 PCT/USOO/09806 The term "haloaryloxyalkyl" embraces aryloxyalkyl radicals, as defined above, wherein one to five halo radicals are attached to an aryloxy group. The term "heteroaroyl" embraces heteroaryl radicals, as defined above, attached to an carbonyl radical as defined above. Examples of such radicals 5 include furoyl and nicotinyl. The term "heteroaralkanoyl" embraces heteroaralkyl radicals, as defined herein, attached to an carbonyl radical as defined above. Examples of such radicals include, for example, pyridylacetyl and furylbutyryl. The term "heteroaralkoxy" embraces oxy-containing heteroaralkyl 10 radicals attached through an oxygen atom to other radicals. More preferred heteroaralkoxy radicals are "lower heteroaralkoxy" radicals having heteroaryl radicals attached to lower alkoxy radical as described above. The term "haloheteroaryloxyalkyl" embraces heteroaryloxyalkyl radicals, as defined above, wherein one to four halo radicals are attached to an 15 heteroaryloxy group. The term "heteroarylamino" embraces heterocyclyl radicals, as defined above, attached to an amino group. Examples of such radicals include pyridylamino. The term "heteroarylaminoalkyl" embraces heteroarylamino radicals, as 20 defined above, attached to an alkyl group. Examples of such radicals include pyridylmethylamino. The term "heteroaryloxy" embraces heterocyclyl radicals, as defined above, attached to an oxy group. Examples of such radicals include 2 thiophenyloxy, 2-pyrimidyloxy, 2-pyridyloxy, 3-pyridyloxy, and 4 25 pyridyloxy. The term "heteroaryloxyalkyl" embraces heteroaryloxy radicals, as defined above, attached to an alkyl group. Examples of such radicals include 2 -pyridyloxymethyl, 3-pyridyloxyethyl, and 4-pyridyloxymethyl. The term "arylthio" embraces aryl radicals, as defined above, attached 30 to an sulfur atom. Examples of such radicals include phenylthio. The term "arylthioalkyl" embraces arylthio radicals, as defined above, attached to an alkyl group. Examples of such radicals include phenylthiomethyl. The term "alkylthioalkyl" embraces alkylthio radicals, as defined above, 35 attached to an alkyl group. Examples of such radicals include 126 WO 00/69832 PCT/USOO/09806 C-3203 nicthylthionethyl. The term "alkoxyalkyl" embraces alkoxy radicals, as defined above, attached to an alkyl group. Examples of such radicals include methoxymethyl. The term "carbonyl" denotes a carbon radical having two of the four 5 covalent bonds shared with an oxygen atom. The term "carboxy" embraces a hydroxyl radical, as defined above, attached to one of two unshared bonds in a carbonyl group. The term "carboxamide" embraces amino, monoalkylamino. dialkylamino, monocycloalkylamino, alkylcycloalkylamino, and dicycloalkylamino radicals, attached to one of two unshared bonds in a carbonyl group. The term 10 "carboxamidoalkyl" embraces carboxamide radicals, as defined above, attached to an alkyl group. The term "carboxyalkyl" embraces a carboxy radical, as defined above, attached to an alkyl group. The term "carboalkoxy" embraces alkoxy radicals, as defined above, attached to one of two unshared bonds in a carbonyl group. The term "carboaralkoxy" embraces aralkoxy radicals, as defined above, 15 attached to one of two unshared bonds in a carbonyl group. The term monocarboalkoxyalkyl" embraces one carboalkoxy radical, as defined above, attached to an alkyl group. The term "dicarboalkoxyalkyl" embraces two carboalkoxy radicals, as defined above, attached to an alkylene group. The term "monocyanoalkyl" embraces one cyano radical, as defined above, attached to an 20 alkyl group. The term "dicyanoalkylene" embraces two cyano radicals, as defined above, attached to an alkyl group. The term "carboalkoxycyanoalkyl" embraces one cyano radical, as defined above, attached to an carboalkoxyalkyl group. The term "acyl", alone or in combination, means a carbonyl or thionocarbonyl group bonded to a radical selected from, for example, hydrido, 25 alkyl, alkenyl, alkynyl, haloalkyi, alkoxy, alkoxyalkyl, haloalkoxy, aryl, heterocyclyl, heteroaryl, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, alkylthio, arylthio, amino, alkylamino, dialkylamino, aralkoxy, aryithio, and alkylthioalkyl. Exanpls of "acyl" are formyl, acetyl, benzoyl, trifluoroacetyl, phthalayl, malonyl, nicotinyl. and the like, 30 The term "haloalkanoyl" embraces one or more halo radicals, as defined herein, attached to an alkanoyl radical as defined above. Examples of such radicals include, for example, chloroacetyl, trifluoroacctyl, bromopropanoyl, and heptafluorobutanoyl. The term "phosphono" embraces a pentavalent phosphorus attached with 35 two covalent bonds to an oxygen radical. The term "dialkoxyphosphono" denotes 127 WO 00/69832 PCT/USOO/09806 two alkoxy radicals, as defined above, attached to a phosphono radical with two covalent bonds. The term "diaralkoxyphosphono" denotes two aralkoxy radicals, as defined above, attached to a phosphono radical with two covalent bonds. The term "dialkoxyphosphonoalkyl" denotes dialkoxyphosphono radicals, as defined 5 above, attached to an alkyl radical. The term "diaralkoxyphosphonoalkyl" denotes diaralkoxyphosphono radicals, as defined above, attached to an alkyl radical. The term "amino" denotes a nitrogen atom containing two substituents such as hydrido, hydroxy or alkyl and having one covalent bond available for bonding to a single atom such as carbon. Examples of such amino radicals include, for 10 example, -NH 2 , -NHCH 3 , -NHOH, and -NHOCH 3 . The term "imino" denotes a nitrogen atom containing one substituent such as hydrido, hydroxy or alkyl and having two covalent bonds available for bonding to a single atom such as carbon. Examples of such imino radicals include, for example, =NH, =NCH 3 , =NOH, and =NOCH 3 . The term "imino carbonyl" denotes a carbon radical having two of 15 the four covalent bond sites shared with an 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" embraces a substituted or unsubstituted amino group bonded to one of two available bonds of an iminocarbonyl radical. Examples of such amidino radicals include, for example, NH 2 -C=NH, NH 2

-C=NCH

3 , 20 NH 2

-C=NOCH

3 and CH 3 NH-C=NOH. The term "guanidino" denotes an amidino group bonded to an amino group as defined above where said amino group can be bonded to a third group. Examples of such guanidino 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-. 25 The term "sulfonium" denotes a positively charged trivalent sulfur atom where said sulfur is substituted with three carbon based groups such as alkyl, alkenyl, aralkyl, or aryl. The term "dialkyl sulfonium" denotes a sulfonium group where said sulfur is substituted with two alkyl groups. Examples of such dialkylsulfonium radicals include, for example, (CH 3

)

2 S+-. The term "dialkyl 128 WO 00/69832 PCT/USOO/09806 sulfonium alkyl" denotes a dialkyl sulfonium group where said group is bonded to one bond of an alkylene group as defined above. Examples of such dialkylsulfoniumalkyl radicals include (CH3) 2

S'-CH

2

CH

2

-

The term "phosphonium" denotes a positively charged tetravalent 5 phosphorus atom where said phosphorus is substituted with four carbon based groups such as alkyl, alkenyl, aralkyl, or aryl. The term "trialkyl phosphonium" denotes a phosphonium group where said phosphorus is substituted with three alkyl groups. Examples of such trialkylphosphonium radicals include, for example,

(CH

3

)

3 P+. 10 Said "alkyl", "alkenyl", "alkynyl", "alkanoyl", "alkylene", "alkenylene", "hydroxyalkyl", "haloalkyl", "haloalkylene", "haloalkenyl", "alkoxy", "alkenyloxy", "alkenyloxyalkyl", "alkoxyalkyl", "aryl", "perhaloaryl", "haloalkoxy", "haloalkoxyalkyl", "haloalkenyloxy", "haloalkenyloxyalkyl", "alkylenedioxy", "haloalkylenedioxy", "heterocyclyl", "heteroaryl", 15 "hydroxyhaloalkyl", "alkylsulfonyl", "haloalkylsulfonyl", "alkylsulfonylalkyl", "haloalkylsulfonylalkyl", "alkylsulfinyl", "alkylsulfinylalkyl", "haloalkylsulfinylalkyl", "aralkyl", "heteroaralkyl", "perhaloaralkyl", "aralkylsulfonyl", "aralkylsulfonylalkyl", "aralkylsulfinyl", "aralkylsulfinylalkyl", "cycloalkyl", "cycloalkylalkanoyl", "cycloalkylalkyl", "cycloalkenyl", 20 "halocycloalkyl", "halocycloalkenyl", "cycloalkylsulfinyl", "cycloalkylsulfinylalkyl", "cycloalkylsulfonyl", "cycloalkylsulfonylalkyl", "cycloalkoxy", "cycloalkoxyalkyl", "cycloalkylalkoxy", "cycloalkenyloxy", "cycloalkenyloxyalkyl", "cycloalkylenedioxy", "halocycloalkoxy", "halocycloalkoxyalkyl", "halocycloalkenyloxy", "halocycloalkenyloxyalkyl", 25 "alkylthio", "haloalkylthio", "alkylsulfinyl", "amino", "oxy", "thio", "alkylamino", "arylamino", "aralkylamino", "arylsulfinyl", "arylsulfinylalkyl", "arylsulfonyl", "arylsulfonylalkyl", "heteroarylsulfinyl", "heteroarylsulfinylalkyl", "heteroarylsulfonyl", "heteroarylsulfonylalkyl", "heteroarylamino", "heteroarylaminoalkyl", "heteroaryloxy", "heteroaryloxylalkyl", "aryloxy", 30 "aroyl", "aralkanoyl", "aralkoxy", "aryloxyalkyl", "haloaryloxyalkyl", "heteroaroyl", "heteroaralkanoyl", "heteroaralkoxy", "heteroaralkoxyalkyl", "arylthio", "arylthioalkyl", "alkoxyalkyl", "acyl", "amidino", "guanidino", "dialkylsulfonium", "trialkylphosphonium", and "dialkylsulfoniumalkyl" groups defined above may optionally have 1 or more non-hydrido substituents such as 129 WO 00/69832 PCT/USOO/09806 amidino, guanidino, dialkylsulfonium. trialkylphosphonium, dialkylsulfoniumalkyl, perhaloaralkyl, aralkylsulfonyl, aralkylsulfonylalkyl, aralkylsulfinyl, aralkylsulfinylalkyl, halocycloalkyl, halocycloalkenyl, cycloalkylsulfinyl,. cycloalkylsulfinylalkyl, cycloalkylsulfonyl, 5 cycloalkylsulfonylalkyl, heteroarylamino, N-heteroarylamino-N-alkylamino, heteroarylaminoalkyl, heteroaryloxy, heteroaryloxylalkyl, haloalkylthio, alkanoyloxy, alkoxy, alkoxyalkyl. haloalkoxylalkyl, heteroaralkoxy, cycloalkoxy, cycloalkenyloxy, cycloalkoxyalkyl, cycloalkylalkoxy, cycloalkenyloxyalkyl. cycloalkylenedioxy, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxy, 10 halocycloalkenyloxyalkyl, hydroxy, amino, thio, nitro, lower alkylamino, alkylthio, alkylthioalkyl, arylamino, aralkylamino, arylthio, arylthioalkyl, heteroaralkoxyalkyl, alkylsulfinyl, alkylsulfinylalkyl, arylsulfinylalkyl, arylsulfonylalkyl, heteroarylsulfinylalkyl, heteroarylsulfonylalkyl, alkylsulfonyl, alkylsulfonylalkyl, haloalkylsulfinylalkyl, haloalkylsulfonylalkyl, 15 alkylsulfonamido, alkylarminosulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, monoarylamidosulfonyl, arylsulfonamido, diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl, arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, haloalkanoyl, alkyl, 20 alkenyl, alkynyl, alkenyloxy, alkenyloxyalky, alkylenedioxy, haloalkylenedioxy, cycloalkyl, cycloalkylalkanoyl, cycloalkenyl, lower cycloalkylalkyl, lower cycloalkenylalkyl, halo, haloalkyl, haloalkenyl, haloalkoxy, hydroxyhaloalkyl, hydroxyaralkyl, hydroxyalkyl, aminoalkyl, hydoxyheteroaralkyl, haloalkoxyalkyl. aryl, aralkyl, aryloxy, aralkoxy, aryloxyalkyl, saturated heterocyclyl, partially 25 saturated heterocyclyl, heteroaryl, heteroaryloxy, heteroaryloxyalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, carboxyalkyl, carboalkoxy, alkoxycarbonyl, carboaralkoxy, carboxamido, carboxamidoalkyl, cyano, carbohaloalkoxy, phosphono, phosphonoalkyl, diaralkoxyphosphono, and diaralkoxyphosphonoalkyl. 30 The term "spacer" can include a covalent bond and a linear moiety having a backbone of 1 to 7 contiguous atoms. The spacer may have I to 7 atoms of a univalent or multi-valent chain. Univalent chains may be constituted by a radical selected from =C(H)-, =C(R )-, -0-, -S-, -S(O)-, -S(O) 2 -, -NH-, -N(R )-, -N=, -CH(OH)-, =C(OH)-, -CH(OR )-, =C(OR )-, and 130 WO 00/69832 PCT/USOO/09806 -C(O)- wherein R is selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, aryloxyalkyl, alkoxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkoxyalkyl, perhaloaralkyl, heteroarylalkyl, heteroaryloxyalkyl, heteroarylthioalkyl, and heteroarylalkenyl. 5 Multi-valent chains may consist of a straight chain of 1 or 2 or 3 or 4 or 5 or 6 or 7 atoms or a straight chain of 1 or 2 or 3 or 4 or 5 or 6 atoms with a side chain. The chain may be constituted of one or more radicals selected from: lower alkylene, lower alkenyl, -0-, -0-CH 2 -, -S-CH 2 -, -CH 2

CH

2 -, ethenyl, -CH=CH(OH)-,

-OCH

2 0-, -O(CH 2

)

2 0-, -NHCH 2 -, -OCH(R )0-, 10 -O(CH 2 CHR )O-, -OCF 2 0-, -O(CF 2

)

2 0-, -S-, -S(0)-, -S(0)2-, -N(H)-, 2a 2a 2a -N(H)O-, -N(R )O-, -N(R )-, -C(O)-, -C(O)NH-, -C(O)NR -, -N=,

-OCH

2 -, -SCH 2 -, S(O)CH 2 -, -CH 2 C(O)-, -CH(OH)-, =C(OH)-, -CH(OR )-, =C(OR )-, S(0) 2

CH

2 -, and -NR 2aCH 2 - and many other radicals defined above or generally known or ascertained by one of skill-in-the art. Side chains may 15 include substituents such as 1 or more non-hydrido substituents such as amidino, guanidino, dialkylsulfonium, trialkylphosphonium, dialkylsulfoniumalkyl, perhaloaralkyl, aralkylsulfonyl, aralkylsulfonylalkyl, aralkylsulfinyl, aralkylsulfinylalkyl, halocycloalkyl, halocycloalkenyl, cycloalkylsulfinyl, cycloalkylsulfinylalkyl, cycloalkylsulfonyl, cycloalkylsulfonylalkyl, 20 heteroarylamino, N-heteroarylamino-N-alkylamino, heteroarylaminoalkyl, heteroaryloxy, heteroaryloxylalkyl, haloalkylthio, alkanoyloxy, alkoxy, alkoxyalkyl, haloalkoxylalkyl, heteroaralkoxy, cycloalkoxy, cycloalkenyloxy, cycloalkoxyalkyl, cycloalkylalkoxy, cycloalkenyloxyalkyl, cycloalkylenedioxy, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxy, 25 halocycloalkenyloxyalkyl, hydroxy, amino, thio, nitro, lower alkylamino, alkylthio, alkylthioalkyl, arylamino, aralkylamino, arylthio, arylthioalkyl, heteroaralkoxyalkyl, alkylsulfinyl, alkylsulfinylalkyl, arylsulfinylalkyl, arylsulfonylalkyl, heteroarylsulfinylalkyl, heteroarylsulfonylalkyl, alkylsulfonyl, alkylsulfonylalkyl, haloalkylsulfinylalkyl, haloalkylsulfonylalkyl, 30 alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, monoarylamidosulfonyl, arylsulfonamido, 131 WO 00/69832 PCT/USOO/09806 diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl, arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, alkanoyl. alkenoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, haloalkanoyl, alkyl, alkenyl, alkynyl, alkenyloxy, alkenyloxyalky, alkylenedioxy, haloalkylenedioxy, 5 cycloalkyl, cycloalkenyl, lower cycloalkylalkyl, lower cycloalkenylalkyl, halo, haloalkyl, haloalkenyl, haloalkoxy, hydroxyhaloalkyl, hydroxyaralkyl, hydroxyalkyl, aminoalkyl, hydoxyheteroaralkyl, haloalkoxyalkyl, aryl. aralkyl, aryloxy, aralkoxy, aryloxyalkyl, saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl, heteroaryloxy, heteroaryloxyalkyl, arylalkyl, 10 heteroarylalkyl, arylalkenyl, heteroarylalkenyl, carboxyalkyl, carboalkoxy, carboaralkoxy, carboxamido, carboxamidoalkyl, cyano, carbohaloalkoxy, phosphono, phosphonoalkyl, diaralkoxyphosphono, and diaralkoxyphosphonoalkyl. Compounds of the present invention can exist in tautomeric, geometric or 15 stereoisomeric forms. The present invention contemplates all such compounds, including cis- and trans-geometric isomers, E- and Z-geometric isomers, R- and S enantiomers, diastereomers, d-isomers, 1-isomers, the racemic mixtures thereof and other mixtures thereof, as falling within the scope of the invention. Pharmaceutically acceptable sales of such tautomeric, geometric or stereoisomeric 20 forms are also included within the invention. The terms "cis" and "trans" denote a form of geometric isomerism in which two carbon atoms connected by a double bond will each have a hydrogen atom on the same side of the double bond ("cis") or on opposite sides of the double bond ("trans"). 25 Some of the compounds described contain alkenyl groups, and are meant to include both cis and trans or "E" and "Z" geometric forms. Some of the compounds described contain one or more stereocenters and are meant to include R, S, and mixtures of R and S forms for each stereocenter present. 30 Some of the compounds described herein may contain one or more ketonic or aldehydic carbonyl groups or combinations thereof alone or as part of a heterocyclic ring system. Such carbonyl groups may exist in part or principally in the "keto" form and in part or principally as one or more "enol" forms of each aldehyde and ketone group present. Compounds of the present 132 WO 00/69832 PCT/USOO/09806 invention having aldehydic or ketonic carbonyl groups are meant to include both "keto" and "enol" tautomeric forms. Some of the compounds described herein may contain one or more amide carbonyl groups or combinations thereof alone or as part of a 5 heterocyclic ring system. Such carbonyl groups may exist in part or principally in the "keto" form and in part or principally as one or more "enol" forms of each amide group present. Compounds of the present invention having amidic carbonyl groups are meant to include both "keto" and "enol" tautomeric forms. Said aide carbonyl groups may be both oxo (C=O) and thiono (C=S) in type. 10 Some of the compounds described herein may contain one or more imine or enamine groups or combinations thereof. Such groups may exist in part or principally in the "imine" form and in part or principally as one or more "enamine" forms of each group present. Compounds of the present invention having said imine or enamine groups are meant to include both "imine" and 15 "enamine" tautomeric forms. The present invention also comprises a treatment and prophylaxis in anticoagulant therapy for the treatment and prevention of a variety of thrombotic conditions including coronary artery and cerebrovascular disease in a subject, comprising administering to the subject having such disorder a 20 therapeutically-effective amount of a compound of Formula (I): N 2 M N R N E 0 J(I) or a pharmaceutically-acceptable salt thereof. As a further embodiment, compounds of the present invention of Formula (I) or a pharmaceutically-acceptable salt thereof as defined above, 25 comprise a treatment and prophylaxis of coronary artery disease, cerebrovascular disease and other coagulation cascade related disorders in a subject, comprising administering to the subject having such disorder a therapeutically-effective amount of compounds of formula (I) of the present invention or a pharmaceutically-acceptable salt thereof. 133 WO 00/69832 PCT/USOO/09806 Compounds of the present invention of Formula (1) or a pharmaceutically-acceptable salt thereof can also be used whenever inhibition of blood coagulation is required such as to prevent coagulation of stored whole blood and to prevent coagulation in other biological samples for testing or 5 storage. Thus coagulation inhibitors of the present inhibition can be added to or contacted with stored whole blood and any medium containing or suspected of containing plasma coagulation factors and in which it is desired that blood coagulation be inhibited, e.g. when contacting the mammal's blood with material selected from the group consisting of vascular grafts, stents, 10 orthopedic prothesis, cardiac prosthesis, and extracorporeal circulation systems. Compounds of Formula (I) are capable of inhibiting activity of serine proteases related to the coagulation cascade, and thus could be used in the manufacture of a medicament, a method for the prophylactic or therapeutic 15 treatment of diseases mediated by coagulation cascade serine proteases, such as inhibiting the formation of blood platelet aggregates, inhibiting the formation of fibrin, inhibiting thrombus formation, and inhibiting embolus formation in a mammal, in blood, in blood products, and in mammalian organs. The compounds also can be used for treating or preventing unstable angina, 20 refractory angina, myocardial infarction, transient ischemic attacks, atrial fibrillation, thrombotic stroke, embolic stroke, deep vein thrombosis, disseminated intravascular coagulation, ocular build up of fibrin, and reocclusion or restenosis of recanalized vessels in a mammal. The compounds also can be used to study the mechanism of action of coagulation cascade serine 25 proteases to enable the design of better inhibitors and development of better assay methods. The compounds of Formula (I) would be also useful in prevention of cerebral vascular accident (CVA) or stroke. Also included in the family of compounds of Formula (I) are the pharmaceutically-acceptable salts thereof. The term "pharmaceutically 30 acceptable salt" embraces salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases. The nature of the salt is not critical, provided that it is pharmaceutically acceptable. Suitable pharmaceutically-acceptable acid addition salts of compounds of Formula (I) may be prepared from inorganic acid or from an organic acid. Examples of 35 such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, 134 WO 00/69832 PCT/USOO/09806 carbonic, sulfuric and phosphoric acid. Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, examples of which are formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, 5 ascorbic, glucoronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, salicylic, p-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethylsulfonic, benzenesulfonic, sulfanilic, stearic, cyclohexylaminosulfonic, algenic, galacturonic acid. Suitable pharmaceutically-acceptable base addition salts of compounds of Formula (I) 10 include metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from N,N' dibenzylethyleneldiamine, choline, chloroprocaine, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procain. All of these salts may be prepared by conventional means from the corresponding 15 compound of Formula (I) by reacting, for example, the appropriate acid or base with the compound of Formula (I). The present invention also comprises a pharmaceutical composition comprising a therapeutically-effective amount of a compound of Formulas (I) in association with at least one pharmaceutically-acceptable carrier, adjuvant or 20 diluent. Pharmaceutical compositions of the present invention can comprise the active compounds of Formula (I) in association with one or more non-toxic, pharmaceutically-acceptable carriers and/or diluents and/or adjuvants (collectively referred to herein as "carrier" materials) and, if desired, other active ingredients. The active compounds of the present invention may be 25 administered by any suitable route, preferably in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment intended. The active compounds and composition may, for example, be administered orally, intravascularly, intraperitoneally, subcutaneously, 30 intramuscularly, oculary, or topically. For treating ocular build up of fibrin, the compounds may be administered intraocularly or topically as well as orally or parenterally. The compounds can be administered in the form of a depot injection or implant preparation which may be formulated in such a manner as to permit a 35 sustained release of the active ingredient. The active ingredient can be 135 WO 00/69832 PCT/USOO/09806 compressed into pellets or small cylinders and implanted subcutaneously or intramusculary as depot injections or implants. Implants may employ inert materials such as biodegradable polymers or synthetic silicones, for example, Silastic, silicone rubber or other silicon containing polymers. 5 The compounds can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines. The compounds may also be delivered by the use of monoclonal 10 antibodies as individual carriers to which the compound molecules are coupled. The compounds may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxy-propyl-methacrylamide-phenol, polyhydroxyethyl-aspartamide phenol, or ployethyleneoxide-polylysine substituted with palmitoyl residues. 15 Furthermore, the compounds may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross linked or 20 amphitpathic block copolymers of hydrogels. For oral administration, the pharmaceutical composition may be in the form of, for example, tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixers, tinctures, suspensions, liquids including syrups, and emulsions. The 25 pharmaceutical composition is preferably made in the form of a dosage unit containing a particular amount of the active ingredient. Examples of such dosage units are tablets or capsules. The active ingredient may also be administered by injection as a composition wherein, for example, saline, dextrose or water may be used as a suitable carrier. 30 The amount of therapeutically active compounds which are administered and the dosage regimen for treating a disease condition with the compounds and/or compositions of this invention depends on a variety of factors, including the age, weight, sex and medical condition of the subject, the severity of the disease, the route and frequency of administration, and the 35 particular compound employed, and thus may vary widely. 136 WO 00/69832 PCT/USOO/09806 The pharmaceutical compositions may contain active ingredients in the range of about 0.1 to 2000 mg, and preferably in the range of about 0.5 to 500 mg. A daily dose of about 0.01 to 100 mg/kg body weight, and preferably between about 0.5 and about 20 mg/kg body weight, may be appropriate. The 5 daily dose can be administered in one to four doses per day. The compounds may be formulated in topical ointment or cream, or as a suppository, containing the active ingredients in a total amount of, for example, 0.075 to 30% w/w, preferably 0.2 to 20% w/w and most preferably 0.4 to 15% w/w. When formulated in an ointment, the active ingredients may be 10 employed with either paraffinic or a water-miscible ointment base. Alternatively, the active ingredients may be formulated in a cream with an oil-in-water cream base. If desired, the aqueous phase of the cream base may include, for example at least 30% w/w of a polyhydric alcohol such as propylene glycol, butane-1,3-diol, mannitol, sorbitol, glycerol, polyethylene 15 glycol and mixtures thereof. The topical formulation may desirably include a compound which enhances 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 this invention can also be administered by a transdermal device. Preferably 20 topical administration will be accomplished using a patch either of the reservoir and porous membrane type or of a solid matrix variety. In either case, the active agent is delivered continuously from the reservoir or microcapsules through a membrane into the active agent permeable adhesive, which is in contact with the skin or mucosa of the recipient. If the active agent is absorbed 25 through the skin, a controlled and predetermined flow of the active agent is administered to the recipient. In the case of microcapsules, the encapsulating agent may also function as the membrane. The oily phase of the emulsions of this invention may be constituted from known ingredients in a known manner. While the phase may comprise 30 merely an emulsifier, it may comprise a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabilizer. It is also preferred to include both an oil and a fat. Together, the emulsifier(s) with or without stabilizer(s) make-up the so-called emulsifying wax, and the wax 35 together with the oil and fat make up the so-called emulsifying ointment base 137 WO 00/69832 PCT/USOO/09806 which forms the oily dispersed phase of the cream formulations. Emulsifiers and emulsion stabilizers suitable for use in the formulation of the present invention include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate, and sodium lauryl sulfate, among others. 5 The choice of suitable oils or fats for the formulation is based on achieving the desired cosmetic properties, since the solubility of the active compound in most oils likely to be used in pharmaceutical emulsion formulations is very low. Thus, the cream should preferably be a non-greasy, non-staining and washable product with suitable consistency to avoid leakage 10 from tubes or other containers. Straight or branched chain, mono- or dibasic alkyl esters such as diisoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters may be used. These may be used alone or in combination depending on the 15 properties required. Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils can be used. For therapeutic purposes, the active compounds of the present invention are ordinarily combined with one or more adjuvants appropriate to the indicated route of administration. If administered per os, the compounds 20 may be admixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted or encapsulated for convenient administration. Such 25 capsules or tablets may contain a controlled-release formulation as may be provided in a dispersion of active compound in hydroxypropylmethyl cellulose. Formulations for parenteral administration may be in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions may be prepared from sterile powders or 30 granules having one or more of the carriers or diluents mentioned for use 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 modes of administration are well and widely 35 known in the pharmaceutical art. 138 WO 00/69832 PCT/USOO/09806 In practicing the methods of the present invention for the treatment and prevention of a variety of thrombotic conditions including coronary artery and cerebrovascular disease, the compounds and pharmaceutical compositions of the present invention are administered alone or in combination with one 5 another, or in combination with other therapeutics or in vivo diagnostic agents. The coagulation cascade inhibitors of the present invention can also be co administered with suitable anti-platelet agreggation agents, including, but not limited to ticlopidine or clopidrogel, fibrinogen receptor antagonists (e.g. to treat or prevent unstable angina or to prevent reocculsion after angioplasty and 10 restenosis), anti-coagulants such as aspirin, warfarin or heparins, thrombolytic agents such as plasminogen activators or streptokinase to achieve synergistic effects in the treatment of various pathologies, lipid lowering agents including antihypercholesterolemics (e.g. HMG CoA reductase inhibitors such as mevastatin, lovastatin, simvastatin, pravastatin, and fluvastatin, HMG CoA 15 synthatase inhibitors, etc.), anti-diabetic drugs, or other cardiovascular agents (loop diuretics, thiazide type diuretics, nitrates, aldosterone antagonistics (i.e., spironolactone and epoxymexlerenone), angiotensin converting enzyme (e.g. ACE) inhibitors, angiotensin II receptor antagonists, beta-blockers, antiarrythmics, anti-hypertension agents, and calcium channel blockers) to treat 20 or prevent atheriosclerosis. For example, patients suffering from coronary artery disease, and patients subjected to angioplasty procedures, would benefit from coadministration of fibrinogen receptor antagonists and coagulation cascade inhibitors of the present invention. Also, coagulation cascade inhibitors could enhance the efficiency of tissue plasminogen activator 25 mediated thrombolytic reperfusion. Typical doses of coagulation cascade inhibitors of the present invention with other suitable anti-platelet agents, anticoagulation agents, cardiovascular therapeutic agents, or thrombolytic agents may be the same as those doses of coagulation cascade inhibitors administered without coadministration of 30 additional anti-platelet agents, anticoagulation agents, cardiovascular therapeutic agents, or thrombolytic agents, or may be substantially less than those doses of coagulation cascade inhibitors administered without coadministration of additional anti-platelet agents, anticoagulation agents, cardiovascular therapeutic agents, or thrombolytic agents, depending on a 35 patient's therapeutic needs. 139 WO 00/69832 PCT/USOO/09806 All mentioned references are incorporated by reference as if here written. Although this invention has been described with respect to specific embodiments, the details of these embodiments are not to be construed as 5 limitations. The following examples are provided to illustrate the present invention and are not intended to limit the scope thereof. Without further elaboration, it is believed that one skilled in the art can, using the preceding descriptions, utilize the present invention to its fullest extent. Therefore the following preferred specific embodiments are to be construed as merely 10 illustrative and not limitative of the remainder of the disclosure in any way whatsoever. Compounds containing multiple variations of the structural modifications illustrated in the schemes or the following Examples are also contemplated. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative 15 procedures can be used to prepare these compounds. One skilled in the art may use these generic methods to prepare the following specific examples, which have been or may be properly characterized by 'H NMR, mass spectrometry, elemental composition, and similar procedures. These compounds also may be formed in vivo. 20 The following examples contain detailed descriptions of the methods of preparation of compounds of Formula (I). These detailed descriptions fall within the scope and are presented for illustrative purposes only and are not intended as a restriction on the scope of the invention. All parts are by weight and temperatures are Degrees centigrade unless otherwise indicated. 25 The following general synthetic sequences are useful in making the present invention. Abbreviations used in the schemes and tables include: "AA" represents amino acids, "AcCN" represents acetonitrile, "AcOH" represents acetic acid, "BINAP" represents 2

,

2 '-bis(diphenylphosphino)-1,1'-binaphthyl, "BnOH" represents benzyl alcohol, "BnCHO" represents 2-phenylethanal," 30 BnSO 2 Cl" represents benzylsulfonyl chloride, "Boc" represents tert butyloxycarbonyl, "BOP" represents benzotriazol- 1 -yl-oxy-tris (dimethylamino), "bu" represents butyl, "dba" represents dibenzylidene acetone, "DCC" represents 1,3-dicyclohexylcarbodiimide, "DCM" represents dichloromethane or methylene chloride, "DIBAH" or "DIBAL" represents 35 diisobutylaluminum hydride, "DMF" represents dimethylformamide, "DMSO" 140 WO 00/69832 PCT/USOO/09806 represents dimethylsulfoxide, "DPPA" represents diphenylphosphoryl azide", "EDC" represents 1-[ 3 -(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride, "Ex. No." represents Example Number, "Fmoc" represents 9 fluorenylmethoxycarbonyl, "HOBt" represents hydroxybenzoltriazole", "LDA" 5 represents lithium diisopropylamide, "MW" represents molecular weight, "NMM" represents N-methylmorpholine, "Ph" represents phenyl or aryl, "PHTH" represents a phthaloyl group, "pnZ" represents 4-nitrobenzyloxy carbonyl, "PTC" represents a phase transfer catalyst, "py" represents pyridine,

"RNH

2 " represents a primary organic amine, "SEM" represents 2 10 (trimethylsilyl)ethoxy-methyl chloride, "p-TsOH" represents paratoluenesulfonic acid, "TBAF' represents tetrabutylammonium fluoride, "TBTU" represents 2-(1H-benzotriozole-1-yl)-1,1,3,3-tetramethyl uronium tetrafluoroborate, "TEA" represents triethylamine, "TFA" represents trifluoroacetic acid, "THF' represents tetrahydrofuran, "TMS" represents 15 trimethylsilyl, "TMSCN" represents trimethylsilyl cyanide, and "Cbz" or "Z" represents benzyloxycarbonyl. GENERAL SYNTHETIC PROCEDURES AND SPECIFIC EXAMPLES 20 The compounds of the present invention can be synthesized, for example, according to the following procedures and Schemes given below. A general synthetic approach to a wide variety of R 2-substituted pyrimidinones is shown in Schemes 1 through Scheme 5 below. Treatment of a solution of ethyl benzimidate hydrochloride in methanol with aminoacetaldehyde 25 dimethyl acetal provided the substituted benzamidine. Cyclization of the benzamidine with dimethyl methoxymethylene-malonate resulted in the formation of the pyrimidinone heterocyclic core with the required functional groups for further manipulation. Demethylation of the ester with lithium iodide followed by Curtius rearrangement of the resulting acid installed the crucial nitrogen at C-5 as a 30 protected carbamate. Hydrolysis of the dimethyl acetal and oxidation of the resulting aldehyde with sodium chlorite gave the glycine unit at N-3. Protection of the acid as a t-butyl ester followed by deprotection of carbamate by hydrogenation gave the free amine at C-5. Treatment of this amine with a sulfonyl chloride or with an aldehyde under reductive amination conditions gave the sulfonamide or 141 WO 00/69832 PCT/USOO/09806 secondary amine, respectively. The protected acids were then unmasked with HCl. These acids are then coupled under standard peptide coupling conditions with various amines. These amines are typically multifunctional, and are used in some protected form. Removal of these protecting groups provides the compounds for 5 evaluation. These synthetic schemes and procedures are exemplified below. 142 WO 00/69832 PCT/USOO/09806 Scheme 1: General Pyrimidinone Synthesis-I 4 b

H

3 CO 0 R

H

2 N CH 3

H

3 CO - OCH 3 NHeHCI OCH 3 2I NTM R 2 OHN

H

3 CO N

OCH

3

R

4 b N R2 LiI, Pyridine HO N OCH3 0 0 R 4 b N R DPPA

CH

3 TEA BnOH N O N OCH 3 O R4b S1. 1 N HCI, 2. NaC1O2 143 WO 00/69832 PCT/USOO/09806 Scheme 2: General Pyrimidinone Synthesis-I (Continued) N R2 0 N O HN OH O (CCO)2, t-BuOH, Pyridine NR 0 HN N fN 0 R 4 b O

H

2 , Pd/C N R2

H

2 N 0 0 R 4 b 144 WO 00/69832 PCT/USOO/09806 Scheme 3: General Pyrimidinone Synthesis-I (Continued) B=O R NaBH(OAC) 3 N

H

2 N 0 T 0

R

4 b N B-COCl B-HN 0 TEA 0 R 4 b N , R 2 0 BC(O)-HN 0 B-S0 2 01 0 Rb B-CHO TEA N NaBH(OAC) 3

BSO

2 -HN, 0" 0 4 b

BCH

2 -HN 0 0

R

4 b 145 WO 00/69832 PCT/USOO/09806 Scheme 4: General Pyrimidinone Synthesis-I (Concluded) N R N B-HN 0 N2 0 R 4 b 0 H 2I BC(O)-HN 0 N 0 R 4 b N B-HN OH N EDC I HOBT, N Cbz-Y-NH 2 BC(O)-HN - OH O R R 4 b Pd/C, H 2 EDO N'r p 2 HOBT, O Cbz-r~-NH 2 N-N Pd/C, H 2 BC(B)-HN N HH O R 4b 146 WO 00/69832 PCT/USOO/09806 Scheme 5: General Pyrimidinone Synthesis-I (Concluded) N R N

BSO

2 -HN 0 N2 HCOI

BCH

2 -H N R 4 4 b HO N

BSO

2 -HN OH N R 0 4 b 0 EDCO I HOBT, N Cbz-YO-NH 2

BCH

2 -HN OH O R 4 b Pd/C, H 2 EDC N 2 HOBT, O Cbz-Y 0

-NH

2

BSO

2 -HN N Pd/C, H 2 H 0 R 4 b N VR2 N Y

BCH

2 -HNN H O R 4 b Synthetic Scheme 1 through Scheme 5 are exemplified in the following examples. 147 WO 00/69832 PCT/USOO/09806 Example 1 N 2 TFA H O ON H 2 NH (EX-1 A) A solution of ethyl benzimidate hydrochloride (92.25 g, 496.9 mmol) in 300.0 mL dry methanol (1.68 M) was cooled to ca 0*C and added a 5 solution of aminoacetaldehyde dimethyl acetal (73.10 mL , 670.9 mmol) in dry methanol (75.0 mL, 9.0 M) drop wise at such a rate the temperature was kept below 5 0 C. The resulting solution was allowed to stir for 3 days with the temperature being maintained below 5"C. The reaction mixture was then concentrated under reduced pressure to give a yellow oil. The residue was 10 dissolved in 1 N NaOH (750 mL) and extracted with dichloromethane (4 x 250 mL). The organic solutions were combined, dried (MgSO 4 ), and concentrated to give 108.13 g crude N-(2,2-dimethoxyethyl)benzami dine as a yellow oil. The crude N-(2,2-dimethoxyethyl)benzamidine (108.13 g, 519.2 mmol) in dry methanol (125.0 mL, 4.2 M) was added dimethyl methoxymethylenemalonate 15 (94.13 g, 540.5 mmol) in one portion at room temperature. The resulting mixture was heated to approximately 100'C, where the solvent was slowly distilled off over a two hour period. The resulting dark brown solution was allowed to cool to room temperature and was diluted ethyl acetate (1 L). The organic solution was washed with saturated NH 4 CI (2 x 500 mL) and brine (1 x 500 ml). The organic 20 solution was dried (MgSO 4 ), filtered and concentrated. Purification of the crude product by MPLC (25% ethyl acetate/hexane) gave pure methyl 1-(2,2 dimethoxyethyl-2-phenylpyrimidin-6(1H)-one-5-carboxylate (EX-1 A) in 73% yield as a tan oil: 'H NMR (300 MHz, CDC 3 ) 6 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); 25 3 C NMR (75 MHz, CDCl 3 ) 6 165.9, 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) calcd for

C,

6

H

1 9

N

2 0 5 319.1294, found 319.1288. 148 WO 00/69832 PCT/USOO/09806 (E X- 1B) A solution of methyl 1-( 2

,

2 -dimethoxyethyl-2-phenylpyrimidin 6(1H)-one-5-carboxylate (93.00 g, 292.2 mmol) in 420.0 mL dry pyridine (0.70 M) was added lithium iodide (98.00 mL, 732.2 mmol) in one portion with stirring at room temperature, upon which an exotherm occurs. The resulting light brown 5 suspension was heated to reflux for 2 hours. The dark brown reaction was allowed to cool to room temperature and the volatiles were removed under reduced pressure. The resulting oil was diluted with 1 N HCI (500 mL). The aqueous solution was extracted with dichloromethane/methanol (4:1, 4 x 250 mL). The combined organic solutions were washed with 6 N HCl (2 x 250 mL), dried 10 (MgSO 4 ), filtered and concentrated. The crude product was purified by crystallization (ethyl acetate/hexane) to give pure 1-(2,2-dimethoxyethyl-2 phenylpyrimidin-6(1H)-one-5-carboxylate (EX-1B) in 63 % yield as a white solid: 'H NMR (300 MHz, CDC 3 ) 6 12.99 (s, 1H), 8.97 (s, 1H), 7.63-7.51 (m, 5H),4.78 (dd, J= 4.3, 5.5 Hz, 1H), 4.28 (d, J= 5.4 Hz, 2H), 3.30 (s, 6H); ' 3 C 15 NMR (75 MHz, CDCl 3 ) 6 165.8, 165.1, 164.1, 159.1, 133.6, 131.5, 129.1, 129.0, 112.6, 101.0, 55.8, 49.2; HRMS (ES) calcd for C15H 20 305.1137, found 305.1113. (EX- IC) A suspension of 1-(2,2-dimethoxyethyl-2-phenylpyrimidin 6 (lH)-one-5-carboxylate (65.93 g, 216.67 mmol) in 800 mL 1,4-dioxane (0.27 20 M) was added triethylamine (50.0 mL, 358.7 mmol) followed by diphenylphosphoryl azide (51.40 mL, 238.5 mmol) in one portion at room temperature. The resulting solution was slowly heated to reflux for 2 hours. The reaction mixture was then added benzyl alcohol (45.00 mL, 434.8 mmol) and refluxing was maintained for approximately 14 hours. The black solution was 25 allowed to cool to room temperature, and the volatiles were removed under vacuum. The resulting residue was diluted with ethyl acetate (1.5 L). The organic solution was washed with saturated NH 4 Cl (2 x 500 mL), 1 N NaOH (1 x 500 mL), and brine (1 x 500 ml). The organic solution was dried (MgSO4), filtered and concentrated to give the crude product. Purification by MPLC( 15%-30% 30 ethyl acetate/hexane) afforded pure [5-[(benzyloxycarbonyl)amino]-2-phenyl-& oxo-1,6-dihydro-1-pyrimidinyl]acetaldehyde dimethyl acetal (E X- 1C) as light brown solid in 46% yield: 'H NMR (400 MHz, CDCl 3 ) 68.72 (br s, 1H), 7.53 7.32 (m, 1 1H), 5.20 (s, 2H), 4.68 (t, J= 5.6 Hz, 1H), 4.12 (d, J= 5.6 Hz, 2H), 149 WO 00/69832 PCT/USOO/09806 3.22 (s, 6H); 3 C NMR (100 MHz, CDC, 3 ) 6 158.3, 153.7, 153.2, 135.9, 134.9, 134.7, 130.1, 129.1, 128.9, 128.8, 128.71, 128.66, 128.4, 125.1, 101.3, 67.7, 55.4, 48.6; HRMS (EI) calcd for C, 2

H,

4

N

3 0, 410.1716, found 410.1741. (EX-1D) A solution of [5-[(benzyloxycarbonyl)amino]-2-phenyl-6-oxo 5 1, 6 -dihydro-1-pyrimidinyllacetaldehyde dimethyl acetal ( 17 .24 g, 42.11 mmol) in 103.0 mL tetrahydrofuran was added 35.0 mL 1 N HCl. The resulting biphasic mixture was allowed to heated to reflux for 12 hours. The reaction mixture was allowed to cool to room temperature and the volatiles were removed under vacuum. The resulting residue was diluted with water (200 mL) and the pH was adjusted to 10 7 by addition of solid NaHCO3. The resulting emulsion was extracted with dichloromethane (4 x 150 mL). The combined organic solutions were washed with water (1 x 200 mL), dried (MgSO 4 ), filtered, and concentrated to give 15.74 g crude [5-[(benzyloxycarbonyl)anino-2-phenyl-6-oxo-1,6-dihydro-1 pyrimidinyl]acetaldehyde. 15 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. The solution was then slowly added a solution of sodium chlorite (29.94 g, 331.1 mmol) and sodium dihydrogenphosphate monohydrate (35.42 g, 20 256.7 mmol) in 102.0 mL of water (3.2 M based on sodium chlorite). The resulting gold colored, biphasic solution was stirred for 10 minutes and the cold bath was removed. The reaction was stirred for 1 hour at room temperature. The volatiles were removed under reduced pressure. The resulting solution was diluted with water (200 mL) and the pH was adjusted to 3 by addition of sat NaHCO3 and 25 1 N HC. The aqueous solution was extracted by tetrahydrofuran, dichloromethane (1:2, 4 x 180 mL). The combined organic solutions were dried (MgSO4), filtered, and concentrated to give the crude product. Purification by trituration with ethyl ether gave an 88% yield of [5-[(benzyloxycarbonyl)anino]-2 phenyl- 6 -oxo-1,6-dihydro-1-pyrimidinyl]acetic acid as a white solid: 'H NMR 30 (300 MHz, d-DMSO) 6 13.34 (br s, 1H), 9.03 (s, 1H), 7.57-7.34 (m, 1OH), 5.23 (s, 2H), 4.56 (s, 2H); 3 C NMR (75 MHz, d-DMSO) 6 169.4, 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) calcd for C 2 HlN 3 0, 380.1246, found 380.1246. 150 WO 00/69832 PCT/USOO/09806 (EX-1E) A suspension of [5-[(benzyloxycarbonyl)amino]-2-phenyl-6 oxo-1,6-dihydro-1-pyrimidinyl]acetic acid (5.2503 g, 13.84 mmol) in 70.0 mL chloroform (0.2 M) was cooled in an ice bath to approximately 0 0 C. The cold suspension was then added oxalyl chloride (6.00 mL, 68.78 mmol) drop wise via 5 syringe. After vigorous gas evolution, a golden homogeneous solution resulted. After stirring for 5 minutes, the cold bath was removed and the solution was stirred for an additional 2 hours at room temperature. The solvent was removed under reduced pressure and placed on the high vacuum system to remove residual solvents for 10 minutes. The resulting yellow solid was diluted with 70.0 mL 10 chloroform (0.2 M) and added pyridine (1.70 mL, 21.02 mmol) and 2-methyl-2 propanol (3.50 ml, 36.60 mmol). The resulting tan colored solution was stirred for 1 hour at room temperature, and then heated to reflux for 12 hours. The reaction mixture was cooled to room temperature and diluted with chloroform (300 mL). The organic solution was washed with water (1 x 100 mL), saturated 15 NaHCO 3 (1 x 100 mL), and brine (1 x 100 mL). The organic solution was dried (MgSO 4 ), filtered and concentrated. The crude reaction was purified by MPLC (25% ethyl acetate/hexanes) to give the product in 49% yield: 'H NMR (300 MHz,

CDC

3 ) 6 8.81 (br s, 1H), 7.57-7.38 (m, 11H), 5.27 (s, 2H), 4.57 (s, 2H), 1.47 (s, 9H); 3 C NMR (75 MHz, CDCl 3 ) 6 166.4, 158.0, 153.2, 135.9, 135.0, 134.4, 20 130.6, 129.1, 128.9, 128.7, 128.5, 128.4, 125.4, 83.4, 67.7, 49.1, 28.2; HRMS (EI) calcd for C 24 ,N30, 436.1872, found 436.1876. (EX-1F) 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 methanol (0.2 M) was added 2113 mg 10% Pd/C in one portion. The resulting mixture was 25 stirred under an atmosphere of hydrogen gas (balloon) at room temperature for approximately 16 hours. The crude reaction mixture was filtered through a pad of Celite 545 and the solvent was removed under reduced pressure. The crude product was triturated from ethyl ether to give pure product [5-amino-2-phenyl-6 oxo-1,6-dihydro-1-pyrimidinyl]acetic acid t-butyl ester (E X- 1F) in 99% yield: 30 'H NMR (400 MHz, CDCl 3 ) 6 7.41-7.39 (m, 6H), 4.48 (s, 2H), 4.06 (br s, 2H), 1.39 (s, 9H); 3 C NMR (100 MHz, CDCl 3 ) 6 166.8,158.6,149.3,134.9,132.9, 130.0, 128.9, 128.5, 127.7, 82.9, 48.7, 28.1; HRMS (EI) calcd for CI 6

H

2

N

3 0 3 302.1505, found 302.1491. 151 WO 00/69832 PCT/USOO/09806 (EX-1G) A solution of [5-amino-2-phenyl-6-oxo-1,6-dihydro-1 pyrimidinyl]acetic acid t-butyl ester (1.0300 g, 3.418 mmol) in 5.5 mL tetrahydrofuran and 2.0 mL dimethylformamide (0.45 M) was added N methylmorpholine (1.20 mL, 10.91 mmol) in one portion. The solution was 5 cooled to OC in an ice bath. After stirring for 10 minutes, a solution of 718.2 mg a-toluenesulfonyl chloride (3.767 mmol) in 5.5 mL tetrahydrofuran (0.68 M) was added drop wise over a 5 minute period. The reaction mixture was stirred for 2 hours at 0*C. The reaction mixture was diluted with ethyl acetate (150 mL). The organic solution was washed with 1 N HCI (2 x 25 mL), saturated NaHCO 3 (2 x 10 25 mL), and brine (1 x 50 mL). The organic solution was dried (MgSO 4 ), filtered and concentrated under reduced pressure. The resulting yellow solid was triturated with ethyl ether, filtered, and dried under vacuum to afford pure product (E X- 1 G) as a white solid in 74% yield: 'H NMR (400 MHz, d-DMSO) 6 9.34 (s, 1H), 7.76 (s, 1H), 7.55-7.28 (m, 1OH), 4.59 (s, 2H), 4.49 (s, 2H), 1.32 (s, 9H); 3 C NMR 15 (100 MHz, d-DMSO)6 167.0, 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) calcd for C 23 H,6N 3 0 5 S 456.1593, found 456.1597. (EX-1H) A solution of (EX-1G) (1.0643g, 2.336 mmol) in 9.OmL 4M HCI in dioxane (0.1 M) was stirred for 12 hours at room temperature. The 20 crude reaction was concentrated under reduced pressure. The resulting residue was triturated with ethyl ether to afford pure product (E X- 1 H) in 87% yield as a white solid: 'H NMR (400 MHz, d-DMSO)6 9.32 (s, 1H), 7.74 (s, 1H), 7.51-7.30 (m, 10H), 4.58 (s, 2H), 4.48 (s, 2H); "C NMR (100 MHz, d-DMSO) 6 169.2, 158.7, 156.6, 141.9, 134.5, 131.7, 131.0, 130.1, 129.4, 129.0, 128.90, 128.56, 25 124.8,59.6,48.9; HRMS (El) calcd for C, 9

H

18

N

3 0 5 S 400.0967, found 400.0959. (EX-1I) A solution of acid (EX-1H) ( 4 06.8 mg, 1.018 mmol) in 10.0 mL dimethylformamide (0.10 M) was added N,N-diisopropylethylamine (0.900 mL, 5.167 mmol), N-hydroxybenzotriazole (167.7 mg, 1.241 mmol), and 1-[3 30 (dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (236.1 mg, 1.232 mmol). The resulting mixture was allowed to stir for 30 minutes at room temperature after which the mixture had become homogeneous. The reaction mixture was then added 4-(Cbz-amidino)benzylamine (324.6 mg, 1.126 mmol) in 152 WO 00/69832 PCT/USOO/09806 one portion at room temperature. The resulting mixture was then allowed to stir for 18 hours. The reaction mixture was 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 (MgSO 4 ), 5 filtered and concentrated. The crude reaction mixture was purified trituration with ethyl ether to afford pure product (EX- 11) in as a white solid: 'H NMR (300 MHz, d-DMSO) 6 9.36-9.18 (br m, 3H), 8.82-8.78 (in, 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) calcd for C 35 H33N 6 0 6 S. 665.2182, 10 found 665.2177. A solution of Cbz-amidine (EX- 1I) (237.7 mg, 357.6 mmol) in 3.5 mL methanol and 4 M HC in dioxane (4:1, 0.1 M) was added 42.1 mg 10% Pd/C in one portion. The resulting mixture was stirred under an atmosphere of hydrogen gas (balloon) at room temperature for approximately 16 hours. The crude reaction 15 mixture was filtered through a pad of 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) afforded pure product as a white solid: 'H NMR (300 MHz, d-DMSO)6 9.31-9.28 (m, 4H), 8.88 (br s, 1H), 7.81-7.77 (m, 3H), 7.60-7.54 (m, 5H), 7.43-7.37 (in, 7H), 4.65 (s, 2H), 4.58 20 (s, 2H), 4.42-4.41 (m, 2H); HRMS (EI) calcd for C 2

,

7

H

2

,

7 0 4 S 531.1815, found 531.1794. Example 2 N NI N 2 TFA NH N N NH2 HNH 25 By following the method of Example 1, the title compound was prepared: 'H NMR (300 MHz, d-DMSO) 6 9.40-9.33 (in, 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) calcd for C,,H2 7

N

6

O

4 S 531.1815, found 531.1794. 153 WO 00/69832 PCT/USOO/09806 Example 3 N N 2 HCI H ' 'I , H. /

NH

2 NH (EX-3A) A solution of [5-amino-2-phenyl-6-oxo-1,6-dihydro-1 pyrimidinyllacetic acid t-butyl ester (E X- 1F) (613.7 mg, 2.037mmol) in 7.0 mL 5 tetrahydrofuran and dichloromethane (1:1, 03 M) was added 25.0 mL acetic acid and phenylacetaldehyde (0.475 mL, 4.060 mmol). The solution was cooled to 0"C in an ice bath and added sodium triacetoxyborohydride (1.9131 g, 9.027 mmol) in one portion. After stirring for 5 minutes, the ice bath was removed and the reaction mixture was allowed to stir at room temperature for 2 hours. The reaction was 10 quenched by the addition of I N NaOH (5 mL), and the mixture was stirred for 5 minutes. The reaction mixture was diluted 0.5 N NaOH (100 mL). The aqueous solution was extracted with ethyl acetate (3 x 25 mL). The combined organic solutions were washed with 0.5 N NaOH (1 x 25 mL) and brine (1 x 25 mL). The solution was dried (MgSO 4 ), filtered and concentrated under reduced pressure. 15 Purification by MPLC (25% ethyl acetate/hexanes) afforded EX-3A as a yellow oil in 74% yield: 'H NMR (400 MHz, CDCl 3 ) 6 7.43-7.40 (m, 4H), 7.31-7.26 (in, 2H), 7.23-7.16 (m, 5H), 4.70 (br s, 1H), 4.49 (s, 2H), 3.38-3.34 (m, 2H), 2.96-2.92 (in, 2H), 1.40 (s, 9H); HRMS (El) calcd for C 24 H2,N303 406.2131, found 406-2125. 20 A solution of EX-3A ( 5 2 1.3 mg, 1.286 mmol) in 13.0 mL 4M HCl in dioxane (0.1 M) was stirred for 12 hours at room temperature. The crude reaction was concentrated under reduced pressure. The resulting residue was triturated with ethyl ether to afford pure product EX-3B in quantitative yield as a yellow solid: 'H NMR (300 MHz, d-DMSO) 6 7.66-7.57 (m, 5H), 7.33-7.23 (in, 6H), 4.57 (s, 25 2H), 3.44-3.35 (in, 2H), 2.97-2.92 (in, 2H); 3 C NMR (75 MHz, d-DMSO) 6 168.8, 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) calcd for C20H2oN303 350.1505, found 350.1520. 154 WO 00/69832 PCT/USOO/09806 A solution of EX-3B (497.8 mg, 1.290 mmol) in 13.0 mL dimethylformamide (0.10 M) was added N,N-diisopropylethylamine (1.800 mL, 10.33 mmol), N-hydroxybenzotriazole (212.8 mg, 1.575 mmol), and 1-[3 (dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (302.5 mg, 1.578 5 mmol). The resulting mixture was allowed to stir for 30 minutes at room temperature after which the mixture had become homogeneous. The reaction mixture was then added 4 -(Cbz-aiidino)benzylamine (410.9 mg, 1.425 mmol) in one portion at room temperature. The resulting mixture was then allowed to stir for 18 hours. The reaction mixture was diluted with ethyl acetate (50 mL). The 10 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 (MgSO 4 ), filtered and concentrated. The crude reaction mixture was purified trituration with ethyl ether to afford pure product E X-3C in as a white solid: 'H NMR (400 MHz, d-DMSO) 6 9.08 (br s, 2 H), 8.62 (t, J = 5.8 Hz, 1H), 7.90 (d, J = 8.3 H z, 2H), 15 7.44-7.15 (in, 17H), 5.35 (t, J= 5.9 Hz, 1H), 5.07 (s, 2H), 4.44 (s, 2H), 4.29 (d, J = 5.4 Hz, 2H), 3.31-3.26 (m, 2H), 2.88-2.85 (in, 2H); HRMS (EI) calcd for

C

36

H

35

N

6 0 4 615.2720, found 615.2688. A solution of EX-3C (222.6 mg, 362.1 mmol) in 4.0 mL methanol and 4 M HCI in dioxane (3:1, 0.1 M) was added 5 3.0 mg 10% Pd/C in one portion. The 20 resulting mixture was stirred under an atmosphere of hydrogen gas (balloon) at room temperature for approximately 16 hours. The crude reaction mixture was filtered through a pad of Celite 545 and the solvent was removed under reduced pressure. Purification of the crude product by trituration from ethyl ether afforded pure product as a yellow solid: 'H NMR (300 MHz, d-DMSO) 6 9.62-9.30 (br m, 25 5H). 7.88 (br in, 2H), 7.58-6.86 (br m, 15H), 4.59 (br s, 2H), 4.36 (br s, 2H), 3.38 (br s, 2H), 2.91 (br s, 2H); HRMS (EI) calcd for C,,H 2 9

N

6 Q 481.2352, found 481.2348. Pyrimidinones having, for example, a directly bonded 2-aryl, 2-heteroaryl, or 2-heteroatom linking/bonding an organic group through the heteroatom to the 30 pyrimidinone ring can be prepared using Scheme 6 and Scheme 7 below. The heteroatom is typically a sulfur, nitrogen, oxygen, or another suitable heteroatom. Use of the general procedure in Scheme 6 to prepare specific heteroatom substituted pyrimidinones is disclosed in Examples 4 and 5. 155 WO 00/69832 PCT/USOO/09806 Scheme 6. Preparation of 2-Substituted Pyrimidinones NN" EM Step A 1. K 2 CO3 SEMCI 0 2 N N Step B 2. K 2 CO3

CICH

2

-CO

2

CH

3 O N CO 2

CH

3 O EM Step C N

H

2 , Pd/C MeOH H2N N CO 2

CH

3 EM 1. PhCH 2 CHO I 0 Step D 2. NaBH(OAc) 3 N

THF,CH

2 Cl 2 , AcOH Step E: Phv N N 0 2

CH

3 1. LiOH, MeOH H

H

2 0 EM O Step F: / 2. EDC, HOBt, N Step G: DIEA, DMF, 1. TBAF, THF R -NH 2 Step H: N CONH-R 2. PhNMe 2 N POCd 3 Step 1: N I 1. R-SH, R-OH, or R-NH 2 Dioxane, Base P Step J: 2. ArB(OH) 2 , Pd(PPh 3

)

4 N ZO-Q Na2 CO 3 tep K (Deprotection) N CONH-R 2 , Pd/C, HCI MeOH N ZO-Q P N CONH-R H 0 156 WO 00/69832 PCT/USOO/09806 Example 4 N SPh Ph "N 2 HCI H | H

NH

2 NH (EX-4A) A solution of 5-nitro-2,4(1H,3H) pyrimidinedione in dimethylsulfoxide (0.2 M) is added 1.1 equivalents potassium carbonate in one 5 portion with stirring. After approximately 10 minutes, a solution of I equivalent 2 (trimethylsilyl)ethoxy-methyl chloride in dimethylsulfoxide is added drop wise. The reaction mixture is then heated to 40*C and allowed to stir for 18 hours. Typical aqueous work up followed by chromatographic purification provides pure product EX-4A. 10 EX-4B) A solution of 5-nitro-1-SEM-2,4(1H,3H) pyrimidinedione (EX 4A) in dimethylsulfoxide (0.2 M) is added 1.1 equivalents potassium carbonate in one portion with stirring. After approximately 10 minutes a solution of 1 equivalent methyl bromoacetate in dimethylsulfoxide is added drop wise. The reaction mixture is then heated to 40*C and allowed to stir for 18 hours. Typical 15 aqueous work up followed by chromatographic purification provides pure product EX-4B. EX-4C) A solution of 5-nitro-I-SEM-3-methoxycarbonylmethyl

(EX

4B) 2,4(1H,3H)pyrimidinedione in methanol is degassed with hydrogen gas. To the solution is then added 5% Pd/C which is stirred under an atmosphere of 20 hydrogen at room temperature for 24 hours. The crude reaction is filtered through a pad of Celite 545 and concentrated under reduced pressure. Purification by column chromatography gives pure 5-amino-i-SEM-3-methoxycarbonylmethyl 2 ,4(1H,3H)pyrimidinedione EX-4C. EX-4D) To a solution of 5-amino-l-SEM-3-methoxycarbonylmethyl 25 2

,

4 (1H,3H)pyrimidinedione (EX-4C) in tetrahydrofuran and dichloromethane (1:1, 0.3 M) is added a catalytic amount of acetic acid and 1 equivalent phenylacetaldehyde. The solution is cooled to 0C in an ice bath and 1 equivalent sodium triacetoxyborohydride is added in one portion. After stirring for 5 minutes, the ice bath is removed, and the reaction mixture is allowed to stir at room 157 WO 00/69832 PCT/USOO/09806 temperature for 2 hours. The reaction is quenched by the addition of 1 N NaOH, and the mixture is stirred for 5 minutes. Typical aqueous work up, followed by chromatographic purification provides pure product EX-4D. EX-4E) To a solution of 1-SEM-3-methoxycarbonylmethyl-5-(2 5 phenylethyl)amino-2,4(1H,3H)pyrimidinedione (EX-4D) in tetrahydrofuran and methanol (1:1, 0.2 M) is added 1 equivalent of lithium hydroxide in water. After the reaction is complete, the volatiles are removed under reduced pressure. The remaining aqueous solution is cooled in an ice bath and acidified to a pH of 1 with 1.0 N HCL. Extraction with organic solvent and removal of the solvent under 10 reduced pressure gives pure product EX-4E. EX-4F) To a solution of 1-SEM-3-methylenecarboxy-5-(2 phenylethyl)amino-2,4(1H,3H)pyrimidinedione dimethylformamide (0.1 M) are added 5 equivalents of N,N-diisopropylethylamine, 1 equivalent of N hydroxybenzotriazole, and 1 equivalent of 1-[3-(dimethylamino)propyl]-3 15 ethylcarbodiimide hydrochloride. The resulting mixture is stirred for 30 minutes. The reaction mixture is then treated with 1 equivalent of the appropriate amine and allowed to stir over night. Typical aqueous work up followed by chromatographic purification gives pure product EX-4F. EX-4G) To a solution of 1-SEM-3-methylenecarbamide-5-(2 20 phenylethyl)amino-2,4(1H,3H)pyrimidinedione in tetrahydrofuran (0.3M) is added 2 equivalents of tetrabutylammonium fluoride in tetrahydrofuran. The resulting solution is refluxed for several hours. Typical aqueous work up is followed by chromatographic purification to give pure product EX-4G. EX-4H) To a solution of 3-methylenecarboxamide-5-(2 25 phenylethyl)amnino-2,4(1H,3H)pyrimidinedione (EX-4G) in NN-dimethylaniline (0.3M) is added I equivalent of phosphorus oxychloride. The resulting solution is refluxed for several hours. Typical aqueous work up is followed by chromatographic purification to give pure product EX-4H. EX-41) To a solution of 2 -chloro-3-methylenecarboxamide-5-(2 30 phenylethyl)amino-2,4(1H,3H)pyrimidinedione (EX-4H) in dioxane (0.3M) is added 2 equivalents of phenylthiol. The resulting solution is refluxed for several hours. Typical aqueous work up is followed by chromatographic purification to give pure product E X-41. A solution of 2 -thiophenyl-3-methylenecarboxamide-5-(2 35 phenylethyl)amino-2A(1H,3H)pyrimidinedione (EX-41) in methanol and 4M 158 WO 00/69832 PCT/USOO/09806 HCl dioxane (3:1, 0.1 M) is degassed with hydrogen gas. To the solution is then added 5% Pd/C which is stirred under an atmosphere of hydrogen at room temperature for 24 hours. The crude reaction is filtered through a pad of Celite 545 and concentrated under reduced pressure. Purification by column chromatography 5 gives pure product. Example 5

I

N, Ph N N 2 HCI HO H~ 0 | H

NH

2 NH EX-SA) To a degassed solution of 2 -chloro- 3 -methylenecarboxamide-5

(

2 -phenylethyl)amino-2,4(1H,3H)pyrimidinedione and 1 equivalent of 3 10 pyridineboronic acid in 1-propanol (0.5M) is added 1.2 equivalents of 2.0 M sodium carbonate followed by 1 mol % of tetrakis(triphenylphosphine)palladium. The resulting mixture is heated to reflux for several hours. After cooling to room temperature, typical aqueous work up is followed by chromatographic purification to give pure product EX-SA. 15 A solution of 2

-(

3 -pyridinyl)-3-methylenecarboxamide-5-(2 phenylethyl)amino-2,4(1H,3H)pyrimidinedione (E X-SA) in methanol and 4M HCl dioxane (3:1, 0.1 M) is degassed with hydrogen gas. To the solution is then added 5% Pd/C, and the solution is stirred under an atmosphere of hydrogen at room temperature for 24 hours. The crude reaction is filtered through a pad of 20 Celite 545 and concentrated under reduced pressure. Purification by column chromatography gives pure product. Pyrimidinones having, for example, a directly bonded 2-aryl, 2-heteroaryl, or 2-heteroatom linking/bonding an organic group through the heteroatom to the pyrimidinone ring can also be prepared using Scheme 7 below. In this reaction 25 scheme, the aryl is introduced by forming a carbon-carbon bond. Heteroatom suitable for forming heterolinked aryl pyrimidinones include sulfur, nitrogen, oxygen, or another suitable heteroatom. Use of the general procedure in 159 WO 00/69832 PCT/USOO/09806 Scheme7 to prepare specific heteroatom substituted pyrimidinones is disclosed in Examples 6 and 7. Scheme 7: Alternate Pyrimidinone Synthesis H N S N SCH 3 N SCH 3 Br 2 ) rcOH NH NaOH NH NH B O N SCH 3 O CaH 2 O O THE t-butyl bromoacetate NC B 0

NSCH

3

B-A-NH

2 , Pd(OAc) 2 BINAP, CsCO 3 N Toluene, heat B-A-HN 0 NO2 Pd(PPh 3

)

4 , 1.4 equiv Cu(I)-TC N m-N0 2 -Ph-B(OH) 2 NO B-A-HN 0 TFA 0NH 2 EDC N HOBT, Cbz-Y 0

-NH

2 then H 2 , Pd/C B-A-HN N H 0 5 Example 6 160 WO 00/69832 PCT/USOO/09806

NH

2 N N I NN 2 TFA A N H | NH2 NH (EX-6A) 2-Thiouracil (66.7 g, 520.5 mmol) was dissolved in a sodium hydroxide solution (41.6 g of solid NaOH in 365 mL of water). The mixture was then treated with methyl iodide (37 mL, 583 mmol), and the resulting reaction 5 mixture was allowed to stir for 16 h at room temperature. The solution was then acidified with glacial acetic acid (30 mL). The white precipitate was collected by suction filtration, and the solid was washed several times with cold water and dried to afford 74 g of EX-6A as a white crystalline solid in quantitative yield. (EX-6B) A solution of EX-6A ( 7 4.0 g, 520.5 mmol) in glacial acetic 10 acid (2275 mL) was cooled to 0 *C with an ice bath and treated with Br2. The reaction mixture was allowed to warm to room temperature, and to stir for 16 h. A yellow precipitate formed which was filtered and washed with ether three times. 97.2 g of EX-6B was isolated in 62% yield. (EX-6C) A mixture of calcium hydride in THF was cooled toO 0 C and 15 treated with neat EX-6B followed by neat t-butyl bromoacetate. The reaction mixture was allowed to stir at 0 "C for 1h. The reaction mixture was then allowed to stir for 2h after the mixture was allowed to warm to room temperature. The reaction mixture was heated to reflux temperature for 16 h. After the reaction mixture was cooled to room temperature, the mixture was slowly poured into a 1 L 20 ice water slurry. The quenched mixture was extracted with dichloromethane (3 x 500mL). The organic layers were combined and washed with water and brine. After the organic layer was dried over MgSO 4 and filtered, the volatile components were removed in vacuo to afford 28.81 g (90%) of EX-6C as an off white solid as a mixture of N-alkylated and 0-alkylated isomers (9:1). N-alkylated isomer: 1H 25 NMR (300 MHz, CDCl 3 ) d 8.07 (s, 1H), 4.75 (s, 2H), 2.57 (s, 3H), 1.47 (s, 161 WO 00/69832 PCT/USOO/09806 9H); 13C 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) calcd for C 1 I H 15 BrN 2

O

3 S 335.0065, found 335.0077. (EX-6D) In an argon-filled glove box a 12-ounce Fischer-Porter bottle 5 containing a magnetic stir bar was charged with EX-6C (5.00 g, 15.0 mmol), Pd(OAc) 2 (168 mg, 0.75 mmol, 5 mole %), rac-BINAP (654 mg, 1.05 mmol, 7 mole %), Cs 2

CO

3 (6.84 g, 21.0 mmol), and anhydrous, degassed toluene (65.0 ml). To this mixture was added isopropyl amine (3.00 ml, 35.2 mmol). The bottle was capped with a pressure head fitted with a pressure gauge and removed from 10 the glove box. The closed-system was heated in an oil bath at 118-120* C with magnetic stirring for 16 h thereafter. A head-space pressure of -10 psi was developed during the reaction. The Fischer-Porter bottle containing the reaction mixture was removed from the oil bath, allowed to cool for 30 min, vented to an argon-flow system and sampled by syringe. LCMS analysis showed 35% product 15 with 65% starting material remaining. Under a blanket of argon, the pressure head was removed and the reaction mixture was treated with Pd(OAc) 2 (337 mg, 1.5 mmol, 10 mole %), rac-BINAP (1.00 g, 1.6 mmol, 11 mole %), Cs 2

CO

3 (10.0 g, 30.7 mmol), and isopropyl amine (6.00 ml, 70.4 mmol). The bottle was capped with the pressure head and again heated to 118-120* C with magnetic stirring for 20 16 h. The sampling procedure was repeated and LCMS revealed that the reaction was complete. The reaction mixture was allowed to cool to RT and filtered through a medium frit sintered-glass funnel. The solids were washed thoroughly with toluene and discarded. The filtrate was concentrated and purified by flash chromatography (Merck 230-400 mesh SiO,, 10% ethyl acetate in hexanes) to 25 afford 3.80 g (81 % yield) of (EX-6D) as a tan solid: IH NMR (300 MHz, CDCl 3 ) d 7.05 (s, 1H), 4.74 (s, 2H), 3.44 (septet, J = 6.3 Hz, 1 H), 2.53 (s, 3H), 1.47 (s, 9H), 1.21 (d, J = 6.3 Hz, 6 H); 1C 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) calcd for C 14

H

2 4

N

3

SO

3 [M+H]= 30 314.1538, found 314.1539. (E X-6E) In an argon-filled glove box a 3-ounce Fischer-Porter bottle containing a magnetic stir bar was charged with EX-6D (1.00 g, 3.20 mmol), 3 162 WO 00/69832 PCT/USOO/09806 nitrophenyl boronic acid (634 mg, 3.80 mmol), Cu(I)-2-thiophenecarboxylate (1.21 g, 6.37 mmol), and Pd(PPh3) 4 (100 mg, 0.86 mmol, 2.7 mol %). THF (25 ml) was added and the bottle was capped with a pressure head fitted with a pressure gauge and removed from the glove box. The closed-system was heated in 5 an oil bath at 70 C with magnetic stirring for 16 h thereafter. The reaction mixture was allowed to cool to RT, vented and diluted with ether (200 ml). The mixture was filtered through a medium frit sintered glass funnel. The green solid was washed with ether (100 ml) and discarded. The filtrate was concentrated and purified by flash chromatography (Merck 230-400 mesh SiO,, 10 % ethyl acetate 10 in hexanes to 30 %) to afford 961 mg (78 % yield) of EX-6E as a yellow foam: H NMR (300 MHz, CDC1 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, 1 H), 7.15 (bs, 1H), 4.51 (s, 2 H), 3.58 (septet, J = 6.0 Hz, 1 H), 1.46 (s, 9H), 1.27 (d, J = 6.3 Hz, 6 H); HRMS (ESI) calcd for C 19

H

25

N

4 0 5 [M+H]* = 389.1815, found 389.1825. 15 (EX-6F) A 250-mL round-bottom flask fitted with a magnetic stir bar was charged with E X-6E (755 mg, 1.9 mmol) and trifluoroacetic acid (30 mL). This mixture was stirred at RT under an argon-flow atmosphere for 30 min and concentrated on a rotary evaporator. The residue was triturated with ether (50 mL) and coevaporated with heptane (2 x 50 mL) to afford 801 mg (95 % yield) of EX 20 6F as a clear yellow glass: IH NMR (300 MHz, DMSO-d 6 ) d 8.34 - 8.26 (m, 2 H), 7.89 (d, J = 7.8 Hz, 1 H), 7.76 (t, J = 7.9 Hz, 1 H), 7.20 (s, 1 H), 4.51 (s, 2 H), 3.57 (septet, J = 6.6 Hz, I H), 1.17 (d, J = 6.6 Hz, 6 H); HRMS (ESI) calcd for C 15

H

17

N

4 0 5 [M+H]* of free base = 333.1223, found 333.1199. Prepared from EX-6F according to the procedure described for the CBZ 25 protected precursor to afford the product: IH NMR (300 MHz, CDCl 3 ) d 9.34 (bs, 1 H), 8.32 (s, 1 H), 8.14 (d, J = 8.0 Hz, 1 H), 7.81 (t, J = 7.8 Hz, 2 H), 7.53 (d, J = 7.8 Hz, 2 H), 7.47 (t, J = 7.8 Hz, 1 H), 7.39-7.25 (m, 5 H), 7.08 (s, 1 H), 7.00 (d, J = 7.8 Hz, 2 H), 5.12 (s, 2 H), 4.61 (d, J = 7.8 Hz, 1 H), 4.35 (s, 2 H), 4.21 (m, 1 H), 3.50 (d of septets, 8 lines J = 6.3 Hz, 1 H), 1.22 (d, J = 6.3 30 Hz, 6 H); 1C NMR (75 MHz, CDCl 3 ) d 168.5 (s), 167.4 (s), 164.0 (s), 158.6 (s), 148.2 (s), 143.8 (s), 142.6 (s), 136.6 (s), 136.2 (s), 135.0 (d), 133.4 (s), 133.2 (s), 129.9 (d), 128.7 (d), 128.3 (d), 127.8 (d), 127.5 (d), 124.4 (d), 124.1 163 WO 00/69832 PCT/USOO/09806 (d), 121.8 (d), 67.4 (t), 49.9 (t), 44.1 (d), 43.2 (t), 22.4 (q); HRMS (ESI) calcd for C 3 1

H

32

N

7 0 6 [M + H]+: 598.2463, found 598.2414. Prepared from EX-6G according to the method described for SC-81703 to afford the product: IH NMR (300 MHz, CD 3 0D) d 9.25 (bs, 1 H), 8.97 (m, 1 H), 5 8.78 (bs, 1 H), 7.93 - 7.14 (complex m, 9 H), 4.77 (s, 2 H), 4.51 (s, 3 H), 3.66 (m, 1 H), 1.30 (d, J = 6.3 Hz, 6 H); HRMS (ESI) calcd for C 23

H

28

N

7 0 2 [M + H] = 598 of free base 434.2304, found 434.2318. Example 7 N 2 TFA N N H | / NH2 10 NH (E X-7A) Prepared from E X-6D using the same procedure described for EX-6E with the only exception that Cs 2

CO

3 base was used. As such, EX-6D (213 mg, 0.68 mmol), pyridine-3-boronic acid 1,3-propanediol cyclic ester (166 mg, 1.02 mmol) and Cs 2

CO

3 (771 mg, 2.37 mmol) afforded 143 mg of EX-7A 15 (61 % yield) after flash chromatography (Merck 230-400 mesh SiO 2 , 2 % MeOH in CHCl 3 ) as a slightly yellow glass: IH NMR (300 MHz, CDCl 3 ) d 8.79 - 8.66 (m, 2 H), 7.90 - 7.26 (complex m, 3 H), 7.16 (s, 1 H), 4.53 (s, 2 H), 3.57 (septet, J = 6.3 Hz, 1 H), 1.44 (s, 9 H), 1.27 (d, J = 6.3 Hz, 6 H); HRMS (ESI) calcd for C 18

H

25

N

4 0 3 [M+H]* = 345.1927, found 345.1928. 20 (EX-7B) Prepared from EX-7A (143 mg, 0.41 mmol) using the same procedure described for EX-6F to afford 212 mg (100 % yield) of EX-7B as a yellow foam: : IH NMR (300 MHz, CDCl 3 ) d 8.72 - 8.64 (m, 2 H), 7.95 - 7.89 (m, 1 H), 7.62 - 7.52 (complex m, 2 H), 7.42 - 7.37 (m, 1 H), 7.20 (s, 1 H), 164 WO 00/69832 PCT/USOO/09806 4.52 (s, 2 H), 3.57 (septet, J = 6.3 Hz, 1 H), 1.18 (d, J = 6.3 Hz, 6 H); HRMS (ESI) calcd for C 14 H 7

N

4 0 3 [M + H]f 289.1301, found 289.1296. (EX-7C) Prepared from EX-7B using the same procedure described for the CBZ-protected materail to afford EX-7C; HRMS (ESI) calcd for 5 C 3 0

H

32

N

7 0 4 [M+H]* = 554.2516, found 554.2523. Prepared from E X-7C using the same procedure described for Example 6 to afford the product. Example 8

NH

2 N N N 2 TFA N HH /NH2 NH 10 By following the method of Example 6, the title compound was prepared: HRMS (ESI) calcd for C 24

H

27

N

7 0 2 [M+H]- 446.2304, found 446.2309. Methylene analogs of pyrimidinones wherein a methylene is present as a replacement for the carbonyl of the acetamide at the N-3 position of the pyrimidinone can be prepared using Scheme 8 "A General Methylene 15 Pyrimidinone Preparation" as detailed below along with the specific Example 9. 165 WO 00/69832 PCT/USOO/09806 Scheme 8: General Methylene Pyrimidinone Synthesis N

,

2 N R H FN H Y0

R

4 b J NN 2 Boc-YO-NH 2 Boc NaBH(OAc) N O N N H 0 R 4 b N R2 Pd/C,

H

2 Boc 1.B=O SI NaBH(OAc) 3 N Yo 2. HCI

H

2 N N 2 H N R o R 4 b 0

B-SO

2 CI N TEA B-HN N 1. B-CHO 0 NaBH(OAc) 3 b 2. HCI N R 0 HCIO

BCH

2 -HN N Yo H N R 2 O R 4 b ~N. 00

BSO

2 -HN N Yo H 0

R

4 b 166 WO 00/69832 PCT/USOO/09806 Example 9 N Ph Ph HCI N

NH

2 NH EX-9A) To a solution of [[5-[(benzyloxycarbonyl)amino]-2-phenyl-6 oxo-1,6-dihydro-1-pyrimidinyllacetaldehyde in tetrahydrofuran and 5 dichloromethane (1:1, 0.3 M) is added a catalytic amount of acetic acid and 1 equivalent of the appropriate amine. The solution is cooled to 0*C in an ice bath, and 1 equivalent sodium triacetoxyborohydride is added in one portion. After stirring for 5 minutes, the ice bath is removed, and the reaction mixture is allowed to stir at room temperature for 2 hours. The reaction is quenched by the addition of 10 1 N NaOH, and the mixture is stirred for 5 minutes. Typical aqueous work up is followed by chromatographic purification to provide pure product EX-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) is added 10% Pd/C in one portion. The resulting mixture is stirred under an atmosphere of 15 hydrogen gas (balloon) at room temperature for approximately 16 hours. The crude reaction mixture is filtered through a pad of Celite 545, and the solvent is removed under reduced pressure. Trituration of the residue from ethyl ether gives pure product EX-9B. EX-9C) To a solution of [5-amino-2-phenyl-6-oxo-1,6-dihydro-1 20 pyrimidinyl]acetamide (E X-9B) in tetrahydrofuran and dichloromethane (1:1, 0.3 M) is added a catalytic amount of acetic acid and 1 equivalent phenylacetaldehyde. The solution is cooled to 0*C in an ice bath, and 1 equivalent sodium triacetoxyborohydride is added in one portion. After stirring for 5 minutes, the ice bath is removed, and the reaction mixture is allowed to stir at room temperature for 25 2 hours. The reaction is quenched by the addition of 1 N NaOH, and the mixture is stirred for 5 minutes. Typical aqueous work up is followed by chromatographic purification to provide pure product EX-9C. A solution of [5-( 2 -phenylethyl)amino-2-phenyl-6-oxo- 1,6-dihydro- 1 pyrimidinyl]acetamide in 4M HCl dioxane ( 0.2 M) is stirred for several hours. 167 WO 00/69832 PCT/USOO/09806 After the reaction is complete, the volatiles are removed under reduced pressure. The residue is purified by trituration with ethyl ether to afford pure product 5. Sulfonyl analogs of pyrimidinones wherein a sulfonyl is present as a replacement for the carbonyl of the acetamide at the N-3 position of the 5 pyrimidinone can be prepared using procedures generally based on those disclosed in Schemes 1-5 by substituting an appropriate aminomethanesulfonamide of an N-Boc-amidino-protected amine in place of the 1,1-dimethoxyethylamine. For example, the N-( 4 -amidinobenzyl)2-aminomethanesulfonamide can be used. Using this approach, sulfonyl analogs in Examples 10 and 11 can be prepared. 10 Example 10 NhHPh P~~ h- N C N H0| HN O H NH

NH

2 Example 11 N NH2 N H N H NH o \\N 0

NH

2 15 Triazinone analogs of pyrimidinones wherein a nitrogen is present as a replacement for the carbon at the 4-position of the pyrimidinone can be prepared using Scheme 9 "A General 4-Aza Pyrimidinone Preparation" as detailed below along with the specific Example 12. 168 WO 00/69832 PCT/USOO/09806 Scheme 9: General 4-AzaPyrimidinone Synthesis R 4 b -0 0 R 4b R C I H 2 N 0 C M TEA, IDCM ILawesson's Reagent

(OH

3

)

3 BF4 0

NH

2

NH

2

SCH

3 R4a 0 Ethyl Thiooxamate H2N H H4a R2 2

H

2 N O N N R0 B-A=O B-A-HN N NaBH(OAC) 3 b H O R4 b N R 2 4 Pd/C, H 2 N EDC, HOBT, B-A-HN N Cbz-YO-NH 2 0 R 4 b 169 WO 00/69832 PCT/USOO/09806 Example 12 NH H O H

NH

2 Bn\ , N NN % NP N Ph 0

CH

3 PhSO 3 H EX- 12) A solution of glycine t-butyl ester hydrochloride (1 mmol) in dichloromethane is treated with benzoyl chloride (1 mmol) and triethyl amine (2 5 mmol). The reaction mixture is allowed to stir at room temperature for 16 h. The mixture is washed with water and extracted with dichloromethane. The combined organic layers are dried over MgSO 4 . After removing the volatiles in vacuo pure product E X- 12A is isolated. EX- 12B) A mixture of N-benzoylglycine t-butyl ester (1 mmol; EX 10 12A), Lawesson's reagent (0.5 mmol) and toluene are heated to 80 *C for 16h. The reaction mixture is concentrated under reduced pressure. Purification via column chromatography on silica gel gives pure product EX- 12B. EX-12C) A mixture of N-thiobenzoylglycine t-butyl ester (1 mmol; EX12B) in dichloromethane is treated with trimethyloxonium tetrafluoroborate 15 (1.1 mmol) at - 78 *C. After stirring the reaction mixture for 2 h, the mixture is washed with NaHCO 3 (aq) and extracted with dichloromethane. The combined organic layers are dried over MgSO 4 and filtered. After concentration of the volatile organic components, the desired product EX- 12C is isolated. EX- 12D) A solution of N-thiomethylbenzylglycine t-butyl ester (1 mmol; 20 EX-12C) in methanol is treated with hydrazine (1 mmol). The volatile materials are removed in vacuo, and the desired compound EX-12D is isolated without further purification. EX-12E) A mixture of compound EX-12D (1 mmol) and ethyl thiooxamate (1 mmol) in methanol is heated to reflux temperature for 4 h. A 25 precipitation of colorless crystals occurs, and the crystals of the desired product EX- 12E are isolated by suction filtration. A solution of compound EX-12E (1 mmol) and pyridine (5 mmol) in acetonitrile is treated with a solution of a-toluenesulfonyl chloride (3 mmol) in 170 WO 00/69832 PCT/USOO/09806 acetonitrile. The reaction mixture is stirred at -10 C to 0 "C for 3 h. A white precipitate forms after the reaction is complete. The crystals of the desired product EX- 12F are isolated by suction filtration. EX-12G) Trifluoroacetic acid is added to a mixture of compound EX 5 12F (1 mmol) in anisole at 0 "C. The reaction mixture is allowed to stir at 0 "C for lh. The reaction mixture is extracted with an organic solvent. Removal of the organic solvent under reduced pressure gives pure product EX- 12G. EX-12H) Compound EX-12G (1 mmol), EDC(1.3 mmol), and HOBt (1.3 mmol) are mixed in DMF, and the mixture is stirred at 20 "C for 15 minutes. 10 To this mixture is added a solution of benzyl-[[(4 aminomethylphenyl)iminomethyl] amino]carbamate hydrogen chloride salt (1.3 mmol) and DIEA (1.3 mmol) in DMF. Typical aqueous work-up is followed by chromatographic purification to provide the desired product EX- 12H. Compound EX- 12H (1 mmol) , p-toluene sulfonic acid mono hydrate (1 15 mmol) and 10% Pd on activated carbon (0.1 mmol) are mixed with methanol. The mixture is stirred for 2 h under hydrogen atmosphere which is introduced and maintained through a rubber balloon. After filtering off the catalyst and removing the methanol, the desired product is isolated. Formula (I) compounds of this invention possessing hydroxyl, thiol, and 20 amine functional groups can be converted to a wide variety derivatives. Alternatively, derivatized Formula (I) compounds can be obtained by first derivatizing one or more intermediates in the processes of preparation before further transforming the derivatized intermediate to comounds of Formula (I). A hydroxyl group in the form of an alcohol or phenol can be readily converted to 25 esters of carboxylic, sulfonic, carbamic, phosphonic, and phosphoric acids. Acylation to form a carboxylic acid ester is readily effected using a suitable acylating reagent such as an aliphatic acid anhydride or acid chloride. The corresponding aryl and heteroaryl acid anhydrides and acid chlorides can also be used. Such reactions are generally carried out using an amine catalyst such as 30 pyridine in an inert solvent. Similarly, carbanic acid esters (urethanes) can be obtained by reacting a hydroxyl group with isocyanates and carbamoyl chlorides. Sulfonate, phosphonate, and phosphate esters can be prepared using the corresponding acid chloride and similar reagents. Compounds of Formula (I) that have at least one thiol group present can be converted to the corresponding 35 thioesters derivatives analogous to those of alcohols and phenols using the same 171 WO 00/69832 PCT/USOO/09806 reagents and comparable reaction conditions. Compounds of Formula (I) that have at least one primary or secondary amine group present can be converted to the corresponding amide derivatives. Amides of carboxylic acids can be prepared using the appropriate acid chloride or anhydrides with reaction conditions 5 analogous to those used with alcohols and phenols. Ureas of the corresponding primary or secondary amine can be prepared using isocyanates directly and carbanoyl chlorides in the presence of an acid scavenger such as triethylamine or pyridine. Sulfonamides can be prepared from the corresponding sulfonyl chloride in the presence of aqueous sodium hydroxide or a tertiary amine. Suitable 10 procedures and methods for preparing these derivatives can be found in House's Modem Synthetic Reactions, W. A. Benjamin, Inc., Shriner, Fuson, and Curtin in The Systematic Identification of Organic Compounds, 5th Edition, John Wiley & Sons, and Fieser and Fieser in Reagents for Organic Synthesis, Volume 1, John Wiley & Sons. Reagents of a wide variety that can be used to derivatize hydroxyl, 15 thiol, and amines of compounds of Formula (I) are available from commercial sources or the references cited above, which are incorporated herein by reference. Formula (I) compounds of this invention possessing hydroxyl, thiol, and amine functional groups can be alkylated to a wide variety of derivatives. Alternatively, alkylated Formula (I) compounds can be obtained by first alkylating 20 one or more intermediates in the processes of preparation before further transforming the alkylated intermediate to comounds of Formula (I). A hydroxyl group of compounds of Formula (I) can be readily converted to ethers. Alkylation to form an ether is readily effected using a suitable alkylating reagent such as an alkyl bromide, alkyl iodide or alkyl sulfonate. The corresponding aralkyl, 25 heteroaralkyl, alkoxyalkyl, aralkyloxyalkyl, and heteroaralkyloxyalkyl bromides, iodides, and sulfonates can also be used. Such reactions are generally carried out using an alkoxide forming reagent such as sodium hydride, potassium t-butoxide, sodium amide, lithium amide, and n-butyl lithium using an inert polar solvent such as DMF, DMSO, THF, and similar, comparable solvents. amine catalyst such as 30 pyridine in an inert solvent. Compounds of Formula (I) that have at least one thiol group present can be converted to the corresponding thioether derivatives analogous to those of alcohols and phenols using the same reagents and comparable reaction conditions. Compounds of Formula (I) that have at least one primary, secondary or tertiary amine group present can be converted to the 35 corresponding secondary, tertiary or quaternary ammonium derivative. Quaternary 172 WO 00/69832 PCT/USOO/09806 ammonium derivatives can be prepared using the appropriate bromides. iodides, and sulfonates analogous to those used with alcohols and phenols. Conditions involve reaction of the amine by warming it with the alkylating reagent with a stoichiometric amount of the amine (i.e., one equivalent with a tertiary amine, two 5 with a secondary, and three with a primary). With primary and secondary amines, two and one equivalents, respectively, of an acid scavenger are used concurrently. Secondary or tertiary amines can be prepared from the corresponding primary or secondary amine. A primary amine can be dialkylated by reductive amination using an aldehyde, such as formaldehyde, and sodium cyanoborohydride in the presence 10 of glacial acetic acid. A primary amine can be monoalkylated by first mono protecting the amine with a ready cleaved protecting group, such as trifluoroacetyl. An alkylating agent, such as dimethylsulfate, in the presence of a non-nucleophilic base, such as Barton's base ( 2 -tert-butyl-1,1,3,3-tetramethylguanidine), gives the monomethylated protected amine. Removal of the protecting group using aqueous 15 potassium hydroxide gives the desired monoalkylated amine. Additional suitable procedures and methods for preparing these derivatives can be found in House's Modem Synthetic Reactions, W. A. Benjamin, Inc., Shriner, Fuson, and Curtin in The Systematic Identification of Organic Compounds, 5th Edition, John Wiley & Sons, and Fieser and Fieser in Reagents for Organic Synthesis published by John 20 Wiley & Sons. Perfluoroalkyl derivatives can be prepared as described by DesMarteau in J. Chem. Soc. Chem. Commun. 2241 (1998). Reagents of a wide variety that can be used to derivatize hydroxyl, thiol, and amines of compounds of Formula (I) are available from commercial sources or the references cited above, which are incorporated herein by reference. 25 The results of the aforementioned synthetic approaches to the preparation pyrimidinones by derivatization of a nucleophilic substituent such as may be present in B, R , R 2 and Y 0 are shown in Table 1 for the specific Examples 13 through 19. The specific examples recited below should be considered a being merely illustrative of the wide variety possible and not as 30 limiting to one of ordinary skill in the art. 173 WO 00/69832 PCT/USOO/09806 Table 1. Structures of Pyrimidinones Prepared by General Derivatization Procedures N R2 B N N N H H o General Structure Ex. R 2 B-A- Yo MW No. (m/z+1) 13 phenyl methoxyacetyl 4-amidinobenzyl 449.47 14 phenyl 4-methylbenzoyl 4-amidinobenzyl 495.54 15 phenyl 4-nitrobenzoyl 4-amidinobenzyl 526.52 16 phenyl isobutyryl 4-amidinobenzyl 447.50 17 phenyl 2,4,6-trimethylbenzoyl 4-amidinobenzyl 523.60 18 phenyl benzoyl 4-amidinobenzyl 481.52 19 phenyl acetyl 4-amidobenzyl 419.45 5 Assays for Biological Activity TF-VIIa Assay In this assay 100 nM recombinant soluble tissue factor and 2nM recombinant human factor VIIa are added to a 96-well assay plate containing 0.4 10 mM of the substrate, N-Methylsulfonyl-D-phe-gly-arg-p-nitroaniline and either inhibitor or buffer (5 mM CaCl 2 ,50 mM Tris-HCl, pH 8.0, 100 mM NaCl, 0.1% BSA). The reaction, in a final volume of 100 ul is measured immediately at 405 nm to determine background absorbance. The plate is incubated at room temperature for 60 min, at which time the rate of hydrolysis of the substrate is 15 measured by monitoring the reaction at 405 nm for the release of p-nitroaniline. Percent inhibition of TF-VIla activity is calculated from OD4 5 nm value from the experimental and control sample. Xa Assay 0.3 nM human factor Xa and 0.15 mM N-a-Benzyloxycarbonyl-D-arginyl 20 L-glycyl-L-arginine-p-nitroaniline-dihydrochloride (S-2765) are added to a 96-well 174 WO 00/69832 PCT/USOO/09806 assay plate containing either inhibitor or buffer (50 mM Tris-HCI, pH 8.0, 100 mM NaCi, 0.1% BSA). The reaction, in a final volume of 100 ul is measured immediately at 405 nm to determine background absorbance. The plate is incubated at room temperature for 60 min, at which time the rate of hydrolysis of 5 the substrate is measured by monitoring the reaction at 405 rm for the release of p nitroaniline. Percent inhibition of Xa activity is calculated from OD4-, value from the experimental and control sample. Thrombin Assay 0.28 nM human thrombin and 0.06 mM H-D-Phenylalanyl-L-pipecolyl-L 10 arginine-p-nitroaniline dihydrochloride are added to a 96-well assay plate containing either inhibitor or buffer (50 mM Tris-HCl, pH 8.0, 100 mM NaCI, 0.1% BSA). The reaction, in a final volume of 100 ul is measured immediately at 405 nm to determine background absorbance. The plate is incubated at room temperature for 60 min, at which time the rate of hydrolysis of the substrate is 15 measured by monitoring the reaction at 405 nm for the release of p-nitroaniline. Percent inhibition of thrombin activity is calculated from OD 4

,

05 n value from the experimental and control sample. Trypsin Assay 5 ug/mI trypsin, type IX from porcine pancreas and 0.375 mM N-a 20 Benzoyl-L-arginine-p-nitroanilide (L-BAPNA) are added to a 96-well assay plate containing either inhibitor or buffer (50 mM Tris-HCI, pH 8.0, 100 mM NaCl, 0.1% BSA). The reactions, in a final volume of 100 ul are measured immediately at 405 nm to determine background absorbance. The plate is incubated at room temperature for 60 min, at which time the rate of hydrolysis of the substrate is 25 measured by monitoring the reaction at 405 nm for the release of p-nitroaniline. Percent inhibition of trypsin activity is calculated from OD 5 nm value from the experimental and control sample. Recombinant soluble TF, consisting of amino acids 1-219 of the mature protein sequence was expressed in E. coli and purified using a Mono Q 30 Sepharose FPLC. Recombinant human VIIa was purchased from American Diagnostica, Greenwich CT and chromogenic substrate N-Methylsulfonyl-D phe-gly-arg-p-nitroaniline was prepared by American Peptide Company, Inc., Sunnyvale, CA. Factor Xa was obtained from Enzyme Research Laboratories, South Bend IN, thrombin from Calbiochem, La Jolla, CA, and trypsin and L 175 WO 00/69832 PCT/USOO/09806 BAPNA from Sigma, St. Louis MO. The chromogenic substrates S-2765 and S-2238 were purchased from Chromogenix, Sweden. The biological activity of the compounds of Examples 1 through 19 as determined by the bioassay procedures is summarized in the Table 2. 5 Table 2. Inhibitory Activity of Pyrimidinones toward Factor Xa, TF-VIIA,. Thrombin II, and Trypsin II. Example TF-VIIA Thrombin II Factor Xa Trpysin II Number IC50 (uM) ICSO (uM) IC50 (uM) IC50 (uM) 1 15.4 22.4 - 0.5 2 >30 >30 -- >30 3 1.0 1.0 -- 0.6 4 5 - - 6 0.05 43% @ 30 uM 33% @ 30 uM <0.04 7 0.7 11.3 33% @ 30 uM 0.04 8 0.08 42% @ 30 uM 15% @ 30 uM 0.04 9 - 10 -- 11 -- - 12 13 - 14 15 -- - 16 -- 17 - 18 - - 19 - 176

Claims (31)

1. A compound having the Formula: M N R2 A N E 0 B NI -- YK Y0 0 or a pharmaceutically acceptable salt thereof, wherein; 5 B is the Formula: R 34 R 33R35 R 32# R 3 9 10 11 12 13 32 33 34 35 36 R ,R , R , R , R , R , R , R , R ,and R are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkylenedioxy, haloalkylthio, 10 alkanoyloxy, alkoxy, alkoxyalkyl, haloalkoxylalkyl, hydroxy, amino, alkoxyamino, nitro, lower alkylamino, alkylthio, alkylthioalkyl, alkylsulfinyl, alkylsulfonyl, alkylsulfonylalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, alkanoyl, haloalkanoyl, alkyl, alkenyl, 15 halo, haloalkyl, haloalkenyl, haloalkoxy, hydroxyhaloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxyalkyl, carboxyalkyl, carboalkoxy, carboxy, carboxamido, carboxamidoalkyl, and cyano; 9 10 11 12 13 R , R , R , R , and R are optionally selected from the group 9 10 11 consisting of heteroaryl and heterocyclyl with the proviso that R , R , R 12 13 20 R , and R are substitutents for other than B; 177 WO 00/69832 PCT/USOO/09806 16 19 32 33 34 35 36 R , R , R , R , R , R , and R are independently optionally Qb with the proviso that no more than one of R16 and R19 is Qb at the same time and that Qb be B is optionally selected from the group consisting of hydrido, 5 trialkylsilyl, C2-C8 alkyl, C3-C8 alkylenyl, C3-C8 alkenyl, C3-C8 alkynyl, and C2-C8 haloalkyl, wherein each member of group B may be optionally substituted at any carbon up to and including 6 atoms from the point of attachment of B to A with one or more of the group consisting of R32, R33 34 35 36 R3, R3, and R 10 B is selected from the group consisting of C3-C12 cycloalkyl and C4 heterocyclyl, wherein each ring carbon may be optionally substituted with R33 a ring carbon other than the ring carbon at the point of attachment of B to A may be optionally substituted with oxo provided that no more than one ring carbon is substituted by oxo at the same time, ring carbons and nitrogens 15 adjacent to the carbon at the point of attachment may be optionally substituted 9 139 with R or R , a ring carbon or nitrogen adjacent to the R position and two 10 atoms from the point of attachment may be substituted with R , a ring carbon or nitrogen adjacent to the R position and two atoms from the point of 12 attachment may be substituted with R , a ring carbon three atoms from the 20 point of attachment and adjacent to the R10 position may be substituted with R , a ring carbon three atoms from the point of attachment and adjacent to 12 33 the R position may be substituted with R , and a ring carbon four atoms from the point of attachment and adjacent to the R and R33 positions may be 34 substituted with R ; 178 WO 00/69832 PCT/US00/09806 A is selected from the group consisting of single covalent bond, (W )rr5-(CH(R15)pa and (CH(R 15)pa(W )rr wherein rr is an integer selected from 0 through 1, pa is an integer selected from 0 through 6, and W is selected from the group consisting of 0, S, C(O), (R )NC(O), (R )NC(S), 5 and N(R ) with the proviso that no more than one of the group consisting of rr and pa is 0 at the same time; R is selected from the group consisting of hydrido, hydroxy, and alkyl; R15 is selected from the group consisting of hydrido, hydroxy, halo, 10 alkyl, and haloalkyl; 'P is selected from the group consisting of NH and NOH; M is selected from the group consisting of N and R I-C; R is selected from the group consisting of hydrido, alkyl, alkenyl, cyano, halo, haloalkyl, haloalkoxy, haloalkylthio, amino, aminoalkyl, 15 alkylamino, amidino, hydroxy, hydroxyamino, alkoxy, hydroxyalkyl, alkoxyamino, thiol, and alkylthio; R 2 is Z 0 -Q; Z is selected from the group consisting of covalent single bond, (CR 41R 42)q wherein q is an integer selected from 1 through 3, (CH(R 41 20 WO-(CH(R 42)) wherein g and p are integers independently selected from 0 0. through 3 and W is selected from the group consisting of 0, S, C(O), S(O), N(R 41), and ON(R 41), and (CH(R4 ))e-w 2-(CH(R42)h wherein e and h are integers independently selected from 0 through l and 2 s selected from the group consisting of CR 41=CR 42, 1,2-cyclopropyl, 1,2-cyclobutyl, 1,2 25 cyclohexyl, 1,3-cyclohexyl, 1,2-cyclopentyl, 1,3-cyclopentyl, 2,3 morpholinyl, 2,4-morpholinyl, 2,6-morpholinyl, 3,4-morpholinyl, 3,5 179 WO 00/69832 PCT/USOO/09806 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 5 tetrahydrofuranyl, 2,4-tetrahydrofuranyl, 2,5-tetrahydrofuranyl, and 3,4 tetrahydrofuranyl, with the proviso that Z is directly bonded to the pyrazinone ring; R41 and R42 are independently selected from the group consisting of amidino, hydroxyamino, hydrido, hydroxy, amino, and alkyl; 10 Q is selected from the group consisting of hydrido, with the proviso that Z is other than a covalent single bond, and the formula (II): 0 112 R1- K 2 121 1 wherein D , D , , J and K are independently selected from the group consisting of C, N, 0, S and a covalent bond with the provisos that no more 1 2 12 1 15 than one is a covalent bond, no more than one of D , D , , J and K is 0, 1 2 12 1 1 21 2 no more than one of D , D , ,J and K is S, one of D, D ,1 ,J and 1 1 2 12 1 K must be a covalent bond when two of D , D , , J and K are O and S, 1 2 12 1 and no more than four of D , D , i , J and K are N, with the proviso that 9 10 11 12 13 R , R , R , R , and R are each independently selected to maintain the 20 tetravalent nature of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen; K is (CR R 4)n wherein n is an integer selected from 1 through 2; 180 WO 00/69832 PCT/USOO/09806 R and R4b are independently selected from the group consisting of halo, hydrido, hydroxyalkyl, alkyl, alkoxyalkyl, alkylthioalkyl, and haloalkyl; o 1 da 4b 1 E is E , whenKis(CRKaRb),,whereinE is selected from the group consisting of a covalent single bond, C(O), C(S), C(O)N(R ), 5 (R )NC(O), S(0)2, (R )NS(0) 2 , and S(0) 2 N(R ); Y is formula (IV): S 17 1 8 R 16,1 _ K2 D _'R 19 b (IV) wherein D 5, D6 J , and J6 are independently selected from the group consisting of C, N, 0, S and a covalent bond with the provisos that no more 2 5 65 6 10 than one is a covalent bond, K is C, no more than one of D , D 5, and J 5 65 6 5 65 6 is 0, no more than one of D5, D , ,and J is S, one of DS, D 5J, and J 5 65 6 must be a covalent bond when two of D , D , 5 , and J are 0 and S, and no more than four of D 5, D6 , J 5, and J6 are N; 16 17 18 19 R , R , R , and R are independently selected from the group 15 consisting of hydrido, amidino, guanidino, carboxy, haloalkylthio, alkoxy, hydroxy, amino, nitro, alkoxyamino, lower alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, alkenyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, alkylamino, haloalkoxyalkyl, carboalkoxy, and cyano; 181 WO 00/69832 PCT/USOO/09806 b. 20 21 Q is selected from the group consisting of NR R , aminoalkylenyl, Qbe wherein Qbe is hydrido, N(R 26)C(NR 25)N(R )(R 24), and 25 224 20 21 C(NR )NR R , with the provisos that no more than one of R and R is hydroxy, amino, alkylamino, or dialkylamino at the same time and that no 5 more than one of R and R24 is hydroxy, amino, alkylamino, or dialkylamino at the same time; 20 21 23 24 25 26 R , R , R , R , R , and R are independently selected from the group consisting of hydrido, alkyl, hydroxy, aminoalkylenyl, amino, dialkylamino, alkylamino, and hydroxyalkyl; 10 Q is selected from the group consisting of a single covalent bond, (CR 37R 38)b wherein b is an integer selected from 1 through 4, and (CH(R 14))c-W -(CH(R 15)d wherein c and d are integers independently selected from 1 through 3 and W is selected from the group consisting of C(O)N(R 4), (R 14)NC(O), S(O), S(O) 2 , S(0) 2 N(R 14), N(R 14)S(O) 2 , and 15 N(R 14), with the provisos that R14 is selected from other than halo when directly bonded to N and that (CR 37R 38)b, and (CH(R 14))c are bonded to EO; R 4 is selected from the group consisting of hydrido, halo, alkyl, and haloalkyl; R37 and R38 are independently selected from the group consisting of 20 hydrido, alkyl, and haloalkyl; R38 is optionally selected from the group consisting of aroyl and heteroaroyl; 182 WO 00/69832 PCT/USOO/09806 Y is optionally Qb_ SS wherein Qss is (CH(R 14 ))e-W-(CH(R 15))h wherein e and h are integers independently selected from 1 through 2 and W 4a 4b 14 0 is CR =CR with the proviso that (CH(R ))e is bonded to E Y is optionally selected from the group consisting of Q b_Q ssss and Q b 5 Qssssr wherein Qssss is (CH(R 38))r-W and Qssssr is (CH(R 38))rW, r is an integer selected from 1 through 2, and W and W6 are independently 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 10 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 15 a)pyridinyl, 3,6-imidazo(1,2-a)pyridinyl, 3,7-imidazo(1,2-a)pyridinyl, 2,4 indolyl, 2,5-indolyl, 2,6-indolyl, 2,7-indolyl, 3,4-indolyl, 3,5-indolyl, 3,6 indolyl, 3,7-indolyl, 1,4-isoindolyl, 1,5-isoindolyl, 1,6-isoindolyl, 2,4 isoindolyl, 2,5-isoindolyl, 2,6-isoindolyl, 2,7-isoindolyl, 1,3-isoindolyl, 3,4 indazolyl, 3,5-indazolyl, 3,6-indazolyl, 3,7-indazolyl, 2,4-benzoxazolyl, 2,5 20 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 25 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 30 isoquinolinyl, 3,4-cinnolinyl, 3,5-cinnolinyl, 3,6-cinnolinyl, 3,7-cinnolinyl, 3,8-cinnolinyl, 4 ,5-cinnolinyl, 4,6-cinnolinyl, 4,7-cinnolinyl, and 4,8 cinnolinyl, and each carbon and hyrido containing nitrogen member of the ring 183 WO 00/69832 PCT/USOO/09806 of the W 5 and of the ring of the W , other than the points of attachment of and W6, is optionally substituted with one or more of the group consisting of 9 10 11 12 b R R1, R , and R , with the provisos that Q is bonded to lowest number substituent position of each W 5 , Qb is bonded to highest number 6 38 o 5 substituent position of each W , and (CH(R ))r is bonded to E .

2. The compound as recited in Claim I having rhe formula: 2 R. 0 B K I YO H O or a pharmaceutically acceptable salt thereof, wherein; 10 B is the Formula: 34 R33 R 3 5 ~32 3 32 33 34 35 36 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, Is alkoxyamino, haloalkanoyl. nitro, lower alkylamino, alkylthio, aryl, aralkyl, cycloalky), cycJoalkylalkyl. heteroary), heterocyclyl, alkylsulfonamido, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, alkyl, alkenyl, halo, haloalkyl, haloalkenyl, haloalkoxy, hydroxyalkyl, alkylamino, carboalkoxy, carboxy, carboxamido, cyano, and Q ; 184 WO 00/69832 PCT/USOO/09806 B is optionally selected from the group consisting of hydrido, trialkylsilyl, C2-C8 alkyl, C3-C8 alkylenyl, C3-C8 alkenyl, C3-C8 alkynyl, and C2-C8 haloalkyl, wherein each member of group B is optionally substituted at any carbon up to and including 6 atoms from the point of 5 attachment of B to A with one or more of the group consisting of R32, R33 R34, R35, and R36 B is selected from the group consisting of C3-C12 cycloalkyl and C4 heterocyclyl, wherein each ring carbon may be optionally substituted with R33 a ring carbon other than the ring carbon at the point of attachment of B to A 10 may be optionally substituted with oxo provided that no more than one ring carbon is substituted by oxo at the same time, ring carbons and nitrogens adjacent to the carbon at the point of attachment may be optionally substituted 9 13 9 with R or R , a ring carbon or nitrogen adjacent to the R position and two 10 atoms from the point of attachment may be substituted with R , a ring carbon 13 15 or nitrogen adjacent to the R position and two atoms from the point of 12 attachment may be substituted with R , a ring carbon three atoms from the point of attachment and adjacent to the R10 position may be substituted with 11 R , a ring carbon three atoms from the point of attachment and adjacent to the R12 position may be substituted with R 33, and a ring carbon four atoms 20 from the point of attachment and adjacent to the R and R33 positions may be substituted with R34 R 9, R 10 R , R 12, and R13 are independently selected from the group consisting of hydrido, acetamido, haloacetamido, alkoxyamino, alkanoyl, haloalkanoyl, amidino, guanidino, alkylenedioxy, haloalkylthio, 25 alkoxy, hydroxy, amino, lower alkylamino, alkylthio, alkylsulfinyl, alkylsulfamido, alkylsulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, 185 WO 00/69832 PCT/USOO/09806 dialkyl amidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, carboalkoxy, carboxy, carboxyalkyl, carboxamido, and cyano; 9 10 11 12 13 R , R , R , R , and R are optionally selected from the group 9 10 11 consisting of heteroaryl and heterocyclyl with the proviso that R , R , R 12 13 5 R , and R are substitutents for other than B; A is selected from the group consisting of single covalent bond and (CH(R15)pa(W7)rr wherein rr is an integer selected from 0 through 1, pa is 7 an integer selected from 0 through 3, and W is selected from the group consisting of 0, S, C(O), (R 7)NC(O), (R )NC(S), and N(R ); 10 R 7is selected from the group consisting of hydride, hydroxy and alkyl; R15 is 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 is selected from the group consisting of hydrido, alkyl, cyano, 15 halo, haloalkyl, haloalkoxy, amino, aminoalkyl, alkylamino, amidino, hydroxy, hydroxyamino, alkoxy, hydroxyalkyl, alkoxyamino, thiol, and alkylthio; R 2 isZ -Q; R20 Z is selected from the group consisting of covalent single bond and 20 (CR 41R 42)q wherein q is an integer selected from 1 through 2, (CH(R 41 W'-(CH(R42)), wherein g and p are integers independently selected from 0 0 41 through 3 and W is selected from the group consisting of 0, S, and N(R 41 and (CH(R 4 1 ))e- 2 (CH(R 4 2 ))h wherein e and h are integers independently selected from 0 through 1 and 2s selected from the group consisting of 186 WO 00/69832 PCT/USOO/09806 41 42 CR =CR4, 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, 5 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 ZO is directly bonded to the pyrazinone ring; 10 R41 and R42 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 ZO is other than a covalent single bond, aryl, and heteroaryl, wherein a carbon adjacent to the carbon at the point of attachment is optionally substituted 9 15 by R , the other carbon adjacent to the carbon at the point of attachment is 13 9 optionally substituted by R , a carbon adjacent to R and two atoms from the carbon at the point of attachment is optionally substituted by R 10, a carbon adjacent to R13 and two atoms from the carbon at the point of attachment is optionally substituted by R 12, and any carbon adjacent to both R10 and R12 is 20 optionally substituted by R11 K is CHR wherein R is selected from the group consisting of hydrido, hydroxyalkyl, alkyl, alkoxyalkyl, alkylthioalkyl, and haloalkyl; E is selected from the group consisting of a covalent single bond, C(O)N(H), (H)NC(O), (R )NS(O) 2 , and S(O) 2 N(R ); 25 Y is formula (IV): 187 WO 00/69832 PCT/USOO/09806 S 17 R18 D5K 1 R 16/D1 K R1 9 lb Qb (IV) 5 65 6 wherein D , D , J, and J are independently selected from the group consisting of C, N, 0, S and a covalent bond with the provisos that no more 2 56 5 than one can be a covalent bond, K is C, no more than one of D , D ,5 6 5 65 6 5 5 and J can be 0, no more than one of D5, D , J ,and J can be S, one of D 6 5 6 5 65 6 D , J ,and J must be a covalent bond when two of DS, D , ,and J are O 5 65 6 and S, and no more than four of D , D , J ,and J can be N, with the 16 17 18 19 provisos that R , R , R , and R are each independently selected to maintain the tetravalent nature of carbon, trivalent nature of nitrogen, the 10 divalent nature of sulfur, and the divalent nature of oxygen; 16 17 18 19 R , R , R , and R 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, 15 hydroxyalkyl, aminoalkyl, and cyano; R16 and R19 are optionally Qb with the proviso that no more than one of R16 and R19 is Qb at the same time and that Qb is Qbe Q is selected from the group consisting of NR20R21 be wherein Qbe is 26 25 23 24 25 23 24 hydrido, N(R )C(NR )N(R )(R ), and C(NR )NR R , with the 20 provisos that no more than one of R20 and R21 is hydroxy, amino, alkylamino, or 188 WO 00/69832 PCT/USOO/09806 dialkylamino at the same time and that no more than one of R 2 3 and R24 s hydroxy, amino, alkylamino, or dialkylamino at the same time; 20 21 23 24 25 26 R , R , R , R , R , and R are independently selected from the group consisting of hydrido, alkyl, hydroxy, amino, alkylamino and dialkylamino; 5 QS is selected from the group consisting of a single covalent bond, (CR37 R 38)b wherein b is an integer selected from 1 through 4, and (CH(R 4))c-W 1-(CH(R 15))d wherein c and d are integers independently selected from 1 through 3 and W is selected from the group consisting of 14 14 14 14 C(O)N(R ), (R )NC(O), S(O), S(O) 2 , S(O) 2 N(R ), N(R )S(O) 2 , and 10 N(R 14), with the provisos that R14 is selected from other than halo when directly bonded to N and that (CR 37R 38)b, and (CH(R 14))c are bonded to E0 R14 is selected from the group consisting of hydrido, halo, alkyl, and haloalkyl; R37 and R38 are independently selected from the group consisting of 15 hydrido, alkyl, and haloalkyl; R38 is optionally selected from the group consisting of aroyl and heteroaroyl; YO is optionally QbQss wherein Qss is (CH(R1 4 ))e-W 2 -(CH(R 15 ))h, wherein e and h are integers independently selected from 1 through 2 and W 20 is CR =CH with the proviso that (CH(R 14))e is bonded to E0.

3. The compound as recited in Claim 2 or a pharmaceutically acceptable salt thereof, wherein; B is selected from the group consisting of hydrido, trialkylsilyl, C2-C8 25 alkyl, C3-C8 alkylenyl, C3-C8 alkenyl, C3-C8 alkynyl, and C2-C8 haloalkyl, wherein each member of group B is optionally substituted at any carbon up to 189 WO 00/69832 PCT/USOO/09806 and including 6 atoms from the point of attachment of B to A with one or more 32 33 34 35 36 of the group consisting of R , R , R , R ,and R 32 33 34 35 36 R , R , R , R , and R are independently selected from the group consisting of hydrido. acetamido, haloacetamido, amidino, guanidino, 5 alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, alkylthio, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboalkoxy, carboxy, carboxamido, cyano, and Qb A is (CH(R15)paW wherein pa is an integer selected from 1 through 10 3 and W is selected from the group consisting of 0, S, and N(R ) wherein R 7is selected from the group consisting of hydride and alyl; R15 is selected from the group consisting of hydrido, hydroxy, halo, alkyl, and haloalkyl with the proviso that R15 is other than hydroxy and halo 15 7 when R is on the carbon bonded directly to W ; 15 M is selected from the group consisting of N and R -C; R is selected from the group consisting of hydrido, alkyl, cyano, halo, haloalkyl, haloalkoxy, amino, aminoalkyl, alkylamino, amidino, hydroxy, hydroxyamino, alkoxy, hydroxyalkyl, alkoxyamino, thiol, and alkylthio; 20 R 2 is ZO-Q; Z is selected from the group consisting of covalent single bond and (CR4R 42)q wherein q is an integer selected from 1 through 2; R41 and R42 are independently selected from the group consisting of hydrido, hydroxy, and amino; 25 Q is selected from the group consisting of aryl and heteroaryl, wherein a carbon adjacent to the carbon at the point of attachment is optionally 190 WO 00/69832 PCT/US00/09806 9 substituted by R , the other carbon adjacent to the carbon at the point of 13 9 attachment is optionally substituted by R , a carbon adjacent to R and two atoms from the carbon at the point of attachment is optionally substituted by 10 13 R , a carbon adjacent to R and two atoms from the carbon at the point of 12 5 attachment is optionally substituted by R1, and any carbon adjacent to both R10 and R12 is optionally substituted by R I 9 10 11 12 13 R , R , R , R , and R are independently selected from the group consisting of hydrido, acetamido, haloacetamido, alkoxyamino, alkanoyl, haloalkanoyl, amidino, guanidino, alkylenedioxy, haloalkylthio, 10 alkoxy, hydroxy, amino, lower alkylamino, alkylthio, alkylsulfinyl, alkylsulfamido, alkylsulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, carboalkoxy, carboxy, carboxyalkyl, carboxamido, and cyano; K is CHR4a wherein R4a is selected from the group consisting of 15 hydrido, hydroxyalkyl, alkyl, alkoxyalkyl, alkylthioalkyl, and haloalkyl; E is selected from the group consisting of a covalent single bond, C(O)N(H), (H)NC(O), (R )NS(O) 2 , and S(O) 2 N(R ); YO is formula (IV): R17 *1 18 5 6 R16 D K2D NR19 lb Q (IV) 5 65 6 20 wherein D , D , J and J are independently selected from the group consisting of C, N, 0, S and a covalent bond with the provisos that no more 191 WO 00/69832 PCT/USOO/09806 2 5 65 6 than one is a covalent bond, K is C, no more than one of , D , J ,and J 5 65 6 5 65 6 is 0, no more than one of D5, D , J ,and J is S, one of D D , I ,and J 5 65 6 must be a covalent bond when two of D , D , J ,and J are O and S, and no 5 6 5 6 more than four of D , D , J , and J are N; 16 17 18 19 5 R1, R , R1, and R 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, hydroxyalkyl, alkylamino, and cyano; 10 R16 and R19 are optionally Qb with the proviso that no more than one of R16 and R19 is Qb at the same time and that Qb be b 20 21 be be Q is selected from the group consisting of NR R , Q wherein Q is hydrido, N(R 26)C(NR 25)N(R )(R 24), and C(NR 25)NR R24, with the provisos that no more than one of R20 and R21 is hydroxy, amino, alkylamino, or 15 dialkylamino at the same time and that no more than one of R and R is hydroxy, amino, alkylamino, or dialkylamino at the same time; 20 21 23 24 25 26 R , R , R , R , R , and R are independently selected from the group consisting of hydrido, alkyl, hydroxy, amino, alkylamino and dialkylamino; Qs is selected from the group consisting of a single covalent bond, 20 (CR 37R 38)b wherein b is an integer selected from 1 through 3, and (CH(R 4))c-W -(CH(R5 ))d wherein c and d are integers independently selected from 1 through 2 and W is selected from the group consisting of C(O)N(R 14), (R 4)NC(O), S(O), S(0) 2 , S(0) 2 N(R 14), N(R 14)S(0) 2 , and 192 WO 00/69832 PCT/USOO/09806 N(R 14), with the provisos that R 4 is selected from other than halo when directly bonded to N and that (CR 37R 38)b, and (CH(R 14))c are bonded to E ; R14 is selected from the group consisting of hydrido, halo, alkyl, and haloalkyl; 5 R37 and R38 are independently selected from the group consisting of hydrido, alkyl, and haloalkyl; R38 is optionally selected from the group consisting of aroyl and heteroaroyl; Y is optionally Q bQ ss wherein Qss is (CH(R 14))e-W -(CH(R1))h' 10 wherein e and h are integers independently selected from 1 through 2 and W is CR =CH with the proviso that (CH(R 14))e is bonded to E0.

4. The compound as recited in Claim 3 having the Formula: N R 2 B N N H H 0 15 or a pharmaceutically acceptable salt thereof, wherein; B is selected from the group consisting of hydrido, trialkylsilyl, C2-C4 alkyl, C3-C5 alkylenyl, C3-C4 alkenyl, C3-C4 alkynyl, and C2-C4 haloalkyl, wherein each member of group B is optionally substituted at any carbon up to and including 3 atoms from the point of attachment of B to A with one or more 20 of the group consisting of R 32, R 33, and R34 R 32, R 33, and R34 are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, alkylthio, amidosulfonyl, 193 WO 00/69832 PCT/USOO/09806 monoalkyl amidosulfonyl, dialkyl amidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboalkoxy, carboxy, carboxamido, and cyano; A is (CH(R 15))pa-N(R ) wherein pa is an integer selected from 1 7 through 2 and R is selected from the group consisting of hydrido and alkyl; 5 R15 is selected from the group consisting of hydrido, halo, alkyl, and haloalkyl; M is selected from the group consisting of N and R -C; R is selected from the group consisting of hydrido, hydroxy, hydroxyamino, amidino, amino, cyano, hydroxyalkyl, alkoxy, alkyl, 10 alkylamino, aminoalkyl, alkylthio, alkoxyamino, haloalkyl, haloalkoxy, and halo; R 2 is Z 0 -Q; ZO is selected from the group consisting of covalent single bond and CH 2 ; 15 Q is selected from the group consisting of aryl and heteroaryl, wherein a carbon adjacent to the carbon at the point of attachment is optionally 9 substituted by R , the other carbon adjacent to the carbon at the point of 13 9 attachment is optionally substituted by R , a carbon adjacent to R and two atoms from the carbon at the point of attachment is optionally substituted by 10 13 20 R , a carbon adjacent to R and two atoms from the carbon at the point of 12 attachment is optionally substituted by R1, and any carbon adjacent to both R10 and R12 is optionally substituted by R 9 11 13 R , R , and R are independently selected from the group consisting of hydrido, hydroxy, amino, amidino, guanidino, lower 25 alkylamino, alkylthio, alkylsulfonamido, alkylsulfinyl, alkylsulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboxy, carboxamido, and cyano; 194 WO 00/69832 PCT/USOO/09806 10 12 R and R 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, 5 hydroxyalkyl, aminoalkyl, carboalkoxy, carboxy, carboxyalkyl, amidocarbonyl, halo, haloalkyl, and cyano; YO is formula (IV): S 17 R 1 8 5 6 R 16 K2 R 1 9 lb Q (IV) 5 6 5 6 wherein D , D , J , and J are independently selected from the group 10 consisting of C, N, 0, S and a covalent bond with the provisos that no more 2 5 65 6 than one is a covalent bond, K is C, no more than one of D , D , J ,and J 5 65 6 5 65 6 is 0, no more than one of D5, D , i ,and J is S, one of D5, D , J ,and J 5 65 6 must be a covalent bond when two of D , D , J , and J are 0 and S, and no more than four of D, D6 , J ,and J6 are N; 16 17 18 19 15 R , R , R , and R are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, haloalkylthio, alkoxy, hydroxy, amino, lower alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, and cyano; 20 R16 and R19 are optionally Qb with the proviso that no more than one of R16 and R19 is Qb at the same time and that Qb is Qbe 195 WO 00/69832 PCT/USOO/09806 b 20 21 be Q is selected from the group consisting of NR2R be wherein bet 25 232h26 25e3i2 Qbe is hydrido, C(NR 25)NR R 24, and N(R 26)C(NR 25)N(R )(R 24), with the provisos that no more than one of R20 and R21 s hydroxy at the same time and that no more than one of R and R24 is hydroxy at the same time; 20 21 23 24 25 26 5 R , R , R , R , R , and R are independently selected from the group consisting of hydrido, alkyl, and hydroxy; Q is selected from the group consisting of a single covalent bond, CH 2 , and CH 2 CH 2 . 10 5. The compound as recited in Claim 4 having the Formula or a pharmaceutically acceptable salt thereof, 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, tert-butyl, isobutyl, 2-methylpropenyl, 2,2,2 15 trifluoroethyl, 3,3,3-trifluoropropyl, and 2,2-difluoropropyl, wherein each member of group B is optionally substituted at any carbon up to and including 3 atoms from the point of attachment of B to A with one or more of the group consisting of R 3 2 , R 33 , and R 3 4 32 33 34 R , R3, and R are independently selected from the group 20 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, 25 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; 196 WO 00/69832 PCT/USOO/09806 A is selected from the group consisting of single covalent bond, NH, and N(CH 3 ); M is selected from the group consisting of N and R -C; R is selected from the group consisting of hydrido, hydroxy, amino, 5 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; 10 R 2 isZ 0 -Q; ZO is selected from the group consisting of a covalent single 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 15 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, and 1,3,5-triazin-2-yl, wherein a carbon adjacent 9 to the carbon at the point of attachment is optionally substituted by R , the other carbon adjacent to the carbon at the point of attachment is optionally 13 9 20 substituted by R , a carbon adjacent to R and two atoms from the carbon at 10 the point of attachment is optionally substituted by R , a carbon adjacent to R13 and two atoms from the carbon at the point of attachment is optionally 12 10 12 substituted by R , and any carbon adjacent to both R and R is optionally substituted by R 9 11 13 25 R , R , and R are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, N-methylamino, N,N-dimethylamino, N-ethylamino, methylthio, ethylthio, isopropylthio, 197 WO 00/69832 PCT/USOO/09806 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, hydroxymethyl, 1 -hydroxyethyl, 2 5 hydroxyethyl, 2,2,2-trifluoro-1-hydroxyethyl, amidocarbonyl, N methylamidocarbonyl, N,N-dimethylamidocarbonyl, and cyano; R10 and R12 are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, carboxymethyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, 10 methoxyamino, ethoxyamino, acetamido, trifluoroacetamido, aminomethyl, 1 aminoethyl, 2-aminoethyl, N-methylamino, dimethylamino, N-ethylamino, methanesulfonamido, amidosulfonyl, N-methylamidosulfonyl, N,N dimethylamidosulfonyl, hydroxymethyl, I -hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro-1-hydroxyethyl, methoxycarbonyl, ethoxycarbonyl, 15 amidocarbonyl, N-methylamidocarbonyl, N,N-dimethylamidocarbonyl, fluoro, chloro, bromo, and cyano; Y is selected from the group consisting of: b s 16 17 18 19 1-Q -4-Qs-2-R -3-R -5-R -6-R benzene, b_ s 17 182 19 2-Q s-Qs-6-R -4-R -2-R pyridine, 20 3-Qb -6-Qs-2-R 16-5-R 18-4-R 19pyridine, 2-Qb s4-Q-3-R 16-6-R 18pyrazine, b s 18 18 19 3-Q -6-Q -2-R -5-R -4-R pyridazine, 2-Q b5-Q s-6-R 17-4-R 18pyrimidine, 5-Q -2-Qs-3-R 16-6-R 19pyrimidine, 3-Qb s 16-4-R -2-R 19thiophene, 2-Q -5-Q s-3-R 16-4-R 17thiophene, b s 619 b s16 17 3-Q -5-Q 4-R -2-R furan, 2-Q -5-Q s-3-R 1-4-R furan, 25 3-Q -5-Q s-4-R 16-2-R 19pyrrole, 2-Q b5-Q s-3-R 16-4-R 17pyrrole, 4-Q -2-Q s-5-R 19imidazole, 2-Qb 4-Q -5-R 17imidazole, 3-Qb -5-Q s-4-R 16isoxazole, 5-Q b-3-Q s-4-R 16isoxazole, 198 WO 00/69832 PCT/USOO/09806 b s 16 b s 19 2-Q -5-Q -4-R pyrazole, 4-Q -2-Qs-5-R thiazole, and 2-Qb-5-Q -4-R 17thiazole; 16 17 18 19 R , R , R , and R are independently selected from the group consisting of hydrido, methyl, ethyl, isopropyl, propyl, carboxy, amidino, 5 guanidino, methoxy, ethoxy, isopropoxy, propoxy, 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, 2,2,3,3,3-pentafluoropropyl, 10 trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro, bromo, amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl, 1 -hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifl uoro- 1 hydroxyethyl, and cyano; R16 and R19 are optionally Qb with the proviso that no more than one 15 of R16 and R19 isQb at the same time and that Qb isQbe b 20 21 be Q is selected from the group consisting of NR2R be wherein Qbe is hydrido, C(NR 25)NR R 24, and N(R 26)C(NR 25)N(R )(R24), with 20 21 23 24 the provisos that no more than one of R , R , R , and R can be 20 21 23 24 hydroxy, when any two of the group consisting of R , R , R , and R 20 are bonded to the same atom and that said Qb group is bonded directly to a carbon atom; 20 21 23 24 25 26 R , R , R , R , R , and R are independently selected from the group consisting of hydrido, methyl, ethyl, propyl, butyl, isopropyl, and hydroxy; QS is selected from the group consisting of a single covalent bond, 25 CH 2 , and CH 2 CH 2 . 199 WO 00/69832 PCT/USOO/09806

6. The compound as recited in Claim 4 having the Formula: 0 R 2 M N H A N N N 0 H H 0 or a pharmaceutically acceptable salt thereof, wherein; A is selected from the group consisting of CH 2 N(CH 3 ), 5 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 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 10 trifluoroethyl, methoxy, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, methoxyamino, methylthio, ethylthio, trifluoromethoxy, 1,1,2,2 tetrafluoroethoxy, fluoro, chloro, and bromo; R 2 is Z 0 -Q; Z is selected from the group consisting of covalent single bond and 15 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, 20 3-pyridazinyl, 4-pyridazinyl. and 1, 3 ,5-triazin-2-yl, wherein a carbon adjacent 9 to the carbon at the point of attachment is optionally substituted by R , the other carbon adjacent to the carbon at the point of attachment is optionally 13 9 substituted by R , a carbon adjacent to R and two atoms from the carbon at 10 the point of attachment is optionally substituted by R , a carbon adjacent to 200 WO 00/69832 PCT/USOO/09806 R13 and two atoms from the carbon at the point of attachment is optionally 12 10 12 substituted by R1, and any carbon adjacent to both R and R is optionally substituted by R 9 11 13 R , R , and R are independently selected from the group consisting 5 of hydrido, amidino, guanidino, carboxy, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, N-methylamino, N,N-dimethylamino, N-ethylamino, methylthio, ethylthio, isopropylthio, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, 2,2,3,3,3 pentafluoropropyl, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, 10 chloro, bromo, methanesulfonarnido, amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl, 1 -hydroxyethyl, 2 hydroxyethyl, 2,2,2-trifluoro-1-hydroxyethyl, amidocarbonyl, N methylamidocarbonyl, N,N-dimethylamidocarbonyl, and cyano; 10 12 R and R are independently selected from the group consisting of 15 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, N,N 20 dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro- 1 -hydroxyethyl, methoxycarbonyl, ethoxycarbonyl, amidocarbonyl, N-methylamidocarbonyl, N,N-dimethylamidocarbonyl, fluoro, chloro, bromo, and cyano; Y is selected from the group consisting of: 25 1-Qb -4-Q s-2-R 16-3-R 17-5-R 18-6-R 19benzene, b s 17 18 19 2-Q b5-Q -6-R -4-R -2-R pyridine, 3-Q b6-Q s-2-R 16-5-R 18-4-R 9pyridine, 2-Qb -4-Q -3-R 16-6-R 18pyrazine, b s R 1 8 18 19 3-Q s-2-RQ -5-R -4-R pyridazine, 201 WO 00/69832 PCT/USOO/09806 2-Q s-5-Q-6-R 7-4-R 18pyrimidine, 5-Q -2-Qs-3-R

16-6-R 19pyrimidine, 3-Q - s-4-R 16-2-R 19thiophene, 2-Q s5-Qs-3-R 16-4-R 17thiophene, b s 16 19 b s 16 17 3-Q -5-Q -4-R -2-R furan, 2-Q -5-Q s-3-R -4-R furan, 3-Q -5-Q s-4-R162-R 19pyrrole, 2-Q s5-Qs-3-R 16-4-R 7pyrrole, 5 4-Q -2-Qs-5-R 19imidazole, 2-Qb 4Qs-5-R 17imidazole, 3-Q -5-Q s-4-R 16isoxazole, 5-Q -3-Qs-4-R16 isoxazole, 2-Q b5-Q s-4-R 16pyrazole, 4-Q -2-Qs-5-R 19thiazole, and 2-Q -5-Qs-4-R thiazole; 16 17 18 19 R , R , R , and R are independently selected from the group 10 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, 15 2,2,2-trifluoroethyl, 2,2,3,3, 3 -pentafluoropropyl, 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, and cyano; Qb is selected from the group consisting of NR 20R21 20 C(NR25 )NR23 R 24, and N(R 26)C(NR 25)N(R )(R 24), with the provisos 20 21 23 24 that no more than one of R , R , R , and R can be hydroxy, when any two of the group consisting of R2, R21 R , and R24 are bonded to the same atom and that said Qb group is bonded directly to a carbon atom; 202 WO 00/69832 PCT/USOO/09806 20 21 23 24 25 26 R , R , R , R , R , and R are independently selected from the group consisting of hydrido, methyl, ethyl, propyl, butyl, isopropyl, and hydroxy; QS is selected from the group consisting of a single covalent bond, 5 CH 2 , and CH 2 CH 2 . 7. The compound as recited in Claim 6 or a pharmaceutically acceptable salt thereof, wherein; A is selected from the group consisting of CH 2 N(CH 3 ), 10 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 is selected from the group consisting of hydrido, hydroxy, amino, amidino, hydroxyamino, aminomethyl, methylamino, cyano, methyl, trifluoromethyl, methoxy, hydroxymethyl, methoxyamino, methylthio, 15 trifluoromethoxy, fluoro, and chloro; R 2 is Z-Q; ZO is selected from the group consisting of covalent single bond and CH 2 ; Q is selected from the group consisting of 5-amino-3 20 amidocarbonylphenyl, 5-ami no-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-hydroxyphenyl, 3-carboxy-5 aminophenyl, 3-chlorophenyl, 2-chlorophenyl, 3-cyanophenyl, 3 25 dimethylaminophenyl, 2-fluorophenyl, 3-fluorophenyl, 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, 203 WO 00/69832 PCT/USOO/09806 2-trifluoromethylphenyl, 5-amino-2-thienyl, 5-amino-3-thienyl, 3-bromo-2 thienyl, 3-pyridyl, 4-pyridyl, 2-thienyl, and 3-thienyl; YO is selected from the group consisting of: b s 16 17 18 19 1-Q s4-Q-2-R -3-R -5-R -6-R benzene, b s 17 18 19 5 2-Q b5-Q -6-R -4-R -2-R pyridine, b ~2 1 6 18 19 3-Q s-2-R -5-R -4-R pyridine, 3-Q b5-Q s-4-R 16-2-R 19thiophene, and 2-Qb -5-Qs-3-R 16-4-R 17thiophene; R16 and R19 are independently selected from the group consisting of hydrido, amidino, amino, aminomethyl, methoxy, methylamino, hydroxy, 10 hydroxymethyl, fluoro, chloro, and cyano; R16 and R19 are optionally Qb with the proviso that no more than one of R16 and R19 isQb at the same time and that Qb be R and R18 are independently selected from the group consisting of hydrido, fluoro, chloro, hydroxy, hydroxymethyl, amino, carboxy, and cyano; 15 Qb is selected from the group consisting of Qbe wherein Qbe is hydrido and C(NR 25)NR R24 23 24 25 R , R , and R are independently selected from the group consisting of hydrido and methyl; Qs is CH2 20 8. A compound as recited in Claim 7 or a pharmaceutically acceptable salt thereof where said compound is selected from the group consisting of: 2 -[ 3 -[ 2 -[ 3 -aminophenyl]-6-chloro-N-[[ 4 -iminomethylphenyl]methyl] 25 5-[N,N-dimethylhydrazino]-4-oxo-1( 4 H)-pyrimidinyl]]acetamide; 2 -[ 3 -[ 2 -[ 3 -aminophenyl]-6-chloro-5-[N-ethyl-N-methylhydrazino]-N [[4-iminomethylphenyllmethyl]-4-oxo-1( 4 H)-pyrimidinyl]]acetamide; 204 WO 00/69832 PCT/USOO/09806 2-[3-[2-[ 3 -aminophenyll-6-chloro-5-[N,N-diethylhydrazino]-N-[[4 iminomethylphenyl]methyl]-4-oxo- l(4H)-pyrimidinyl]]acetamide; 2 -[ 3 -[ 2 -[ 3 -aminophenyl]-5-[N-(azetidin- 1-yl)amino]-6-chloro-N- [[4 iminomethylphenyl]methyl]-4-oxo-1( 4 H)-pyrimidinyl]jacetamide; 5 2 -[4-[3-[3-aminophenyl]-N-[[ 4 -iminomethylphenylImethyl]- 6-[NN dimethylhydrazino]-5-oxo-1(5H)-1,2,4-triazinyl]]acetamide; 2 -[4-[ 3 -[ 3 -aminophenyl]-&[N-ethyl-N-methylhydrazinol-N-[[4 iminomethylphenyl]methyl]-5-oxo-1(5H)-1, 2 ,4-triazinyl]]acetamide; 2 -[ 4 -[ 3 -[ 3 -aminophenyl]-6-[N,N-diethylhydrazino]-N-[[4 10 iminomethylphenyl]methyl]-5-oxo- 1(5H)- 1, 2 ,4-triazinyl]]acetamide; 2-[4-[3-[ 3 -aminophenyl]-6-[N-(azetidin- 1-yl)amino]-N-[[4 iminomethylphenyl]methyl]-5-oxo-1(5H)-1,2,4-triazinyl]]acetamide. 9. The compound as recited in Claim 2 having the Formula: 0 B A N N H H 15 0 or a pharmaceutically acceptable salt thereof, wherein; B is the Formula: R R 33R3 5 R3 2 R3 6 32 33 34 35 36 R 33, R , R , and R are independently selected from the 20 group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, alkylthio, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, alkyl, halo, 205 WO 00/69832 PCT/USOO/09806 haloalkyl, haloalkoxy, hydroxyalkyl, carboalkoxy, carboxy, carboxamido, cyano, and Qb A is selected from the group consisting of single covalent bond and (CH(R15 ))pa-(W )rr wherein rr is an integer selected from 0 through 1, pa is 5 an integer selected from 0 through 3, and W is selected from the group consisting of (R )NC(O) and N(R ); R 7is selected from the group consisting of hydride, hydroxy and alkyl; R15 is selected from the group consisting of hydrido, halo, alkyl, and haloalkyl; 10 M is selected from the group consisting of N and R -C; R is selected from the group consisting of hydrido, hydroxy, hydroxyamino, amidino, amino, cyano, hydroxyalkyl, alkoxy, alkyl, alkylamino, aminoalkyl, alkylthio, alkoxyamino, haloalkyl, haloalkoxy, and halo; 15 R 2 isZ 0 -Q; Z is selected from the group consisting of a covalent single bond, 0, S, NH, and CH2; Q is selected from the group consisting of aryl and heteroaryl wherein a carbon adjacent to the carbon at the point of attachment is optionally substituted 9 20 by R , the other carbon adjacent to the carbon at the point of attachment is 13 9 optionally substituted by R , a carbon adjacent to R and two atoms from the 10 carbon at the point of attachment is optionally substituted by R , a carbon adjacent to R13 and two atoms from the carbon at the point of attachment is 12 10 12. optionally substituted by R1, and any carbon adjacent to both R and R is 25 optionally substituted by R 206 WO 00/69832 PCT/USOO/09806 9 11 13 R , R , and R are independently selected from the group consisting of hydrido, hydroxy, amino, amidino, guanidino, lower alkylamino, alkylthio, alkylsulfonamido, alkylsulfinyl, alkylsulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, alkyl, alkoxy, halo, haloalkyl, 5 haloalkoxy, hydroxyalkyl, carboxy, carboxamido, and cyano; R10 and R12 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, 10 hydroxyalkyl, aminoalkyl, carboalkoxy, carboxy, carboxyalkyl, amidocarbonyl, halo, haloalkyl, and cyano; Y is formula (IV): s 17 18 5 6 R16 D K2 R19 lb Q (IV) wherein D 5, D6 , J 5, and J6 are independently selected from the group 15 consisting of C, N, 0, S and a covalent bond with the provisos that no more 2 5 65 6 than one is a covalent bond, K is C, no more than one of D , D , 5 and J 5 65 6 5 65 6 is 0, no more than one of D5, D , J ,and J s S, one of D5, D , J and J 5 65 6 must be a covalent bond when two of D , D , J ,and J are O and S, and no 5 65 6 more than four of D5, D , , and J are N; 16 17 18 19 20 R , R , R , and R are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, haloalkylthio, alkoxy, hydroxy, amino, lower alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, 207 WO 00/69832 PCT/USOO/09806 alkanoyl, haloalkanoyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, and cyano; R16 and R19 are optionally Qb with the proviso that no more than one of R16 and R19 isQb at the same time and that Qb is Qbe b 20 21 be be 5 Q is selected from the group consisting of NR R , Q wherein Q is 25 23 24 2 hydrido, and C(NR )NR R , with the provisos that no more than one of R and R21 is hydroxy at the same time and that no more than one of R and R24 is hydroxy at the same time; 20 21 23 24 25 R2, R2, R , R , and R are independently selected from the group 10 consisting of hydrido, alkyl, and hydroxy; Qs is selected from the group consisting of a single covalent bond, CH 2 , and CH 2 CH 2 10. The compound as recited in Claim 9 or a pharmaceutically acceptable salt 15 thereof, wherein; B is the Formula: R34 R 33 R 35 R 3 2 36 32 33 34 35 36 R , R , R , R , and R are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, methoxy, ethoxy, 20 isopropoxy, propoxy, hydroxy, amino, methoxyamino, ethoxyamino, acetamido, trifluoroacetamido, N-methylamino, dimethylamino, N-ethylamino, methylthio, ethylthio, isopropylthio, trifluoromethyl, pentafluoroethyl, 2,2,2 208 WO 00/69832 PCT/USOO/09806 trifluoroethyl, 2 , 2 , 3 , 3 ,3-pentafluoropropyl, trifluoromethoxy, 1,1,2,2 tetrafluoroethoxy, fluoro, chloro, bromo, amidosulfonyl, N methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl, I hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro-1-hydroxyethyl, 5 methoxycarbonyl, ethoxycarbonyl, amidocarbonyl, N-methylamidocarbonyl, N,N-dimethylamidocarbonyl, cyano, and Qb. A is selected from the group consisting of 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 10 CF 3 CHCH 2 ; M is selected from the group consisting of N and R -C; R 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 15 trifluoroethyl, methoxy, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, methoxyamino, methylthio, ethylthio, trifluoromethoxy, 1,1.2,2 tetrafluoroethoxy, fluoro, chloro, and bromo; R 2 is Z 0 -Q; Z is selected from the group consisting of a covalent single bond, 0, 20 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, 25 3-pyridazinyl, 4-pyridazinyl, and 1,3,5-triazin-2-yl, wherein a carbon adjacent to the carbon at the point of attachment is optionally substituted by R 9, the other carbon adjacent to the carbon at the point of attachment is optionally 13 9 substituted by R , a carbon adjacent to R and two atoms from the carbon at 209 WO 00/69832 PCT/USOO/09806 the point of attachment is optionally substituted by R , a carbon adjacent to R13 and two atoms from the carbon at the point of attachment is optionally 12 10 12 substituted by R1, and any carbon adjacent to both R and R is optionally substituted by R 9 11 13 5 R , R , and R are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, N-methylamino. N,N-dimethylamino, N-ethylamino, methylthio, ethylthio, isopropylthio, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, 2,2,3,3,3 10 pentafluoropropyl, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro, bromo, methanesulfonamido, amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl, 1 -hydroxyethyl, 2 hydroxyethyl, 2,2,2-trifluoro-1-hydroxyethyl, amidocarbonyl, N methylamidocarbonyl, N,N-dimethylamidocarbonyl, and cyano; 15 R10 and R12 are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, carboxymethyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, methoxyamino, ethoxyanino, acetamido, trifluoroacetamido, aminomethyl, 1 aninoethyl, 2-aminoethyl, N-methylamino, dimethylamino, N-ethylamino, 20 methanesulfonamido, 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, fluoro, chloro, bromo, and cyano; 25 Yo is selected from the group consisting of: b s 16 17 18 19 1-Q -4-Q -2-R -3-R -5-R -6-R benzene, b s 17 18 19 2-Q b5-Q -6-R -4-R -2-R pyridine, 210 WO 00/69832 PCT/USOO/09806 3-Qb -6-Qs-2-R 16-5-R 18-4-R 19pyridine, 2-Qb -4-Qs-3-R 16-6-R8 pyrazine, 3 Q -6-Q -2-R18-5-R 18-4-R 9pyridazine, b_ s 17 18 b_ s- 16_ 19 2-Q Q-6-R -4-R pyrimidine, 5-Q -2-Q -3-R -6-R pyrimidine, 3-Q s5-Q 16 -2-R 19thiophene, 2-Q s5-Qs-3-R 16-4-R 17thiophene, b s 16 19 b s 16 17 5 3-Q -5-Q -4-R -2-R furan, 2-Q -5-Q -3-R -4-R furan, 3-Q -5-Qs 4-R 16-2-R 19pyrrole, 2-Q s5-Qs-3-R 16-4-R 17pyrrole, 4-Q -2-Q s-5-R 19imidazole, 2-Qb -4-Qs-5-R 7imidazole, 3-Q -5-Q s-4-R 16isoxazole, 5-Q b-3-Q s-4-R16 isoxazole, 2-Q s5-Qs-4-R16 pyrazole, 4-Q -2-Q -5-R 19thiazole, and b s 17 10 2-Q b5-Q -4-R thiazole; 16 17 18 19 R1 R , R 18, and R 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, 15 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, fluoro, chloro, bromo, amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, 20 hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro-1 hydroxyethyl, and cyano; R16 and R 9 are optionally Qb with the proviso that no more than one of R16 and R19 is Qb at the same time and that Qb be Qb is selected from the group consisting of Qbe wherein Qbe is hydrido 25 224 23 24 25 and C(NR )NR23R , with the proviso that no more than one of R and R is hydroxy at the same time; 211 WO 00/69832 PCT/USOO/09806 R , R 24, and R25 are independently selected from the group consisting of hydrido, methyl, ethyl, and hydroxy; Qs is selected from the group consisting of a single covalent bond, CH 2 and CH 2 CH 2 5 11. The compound as recited in Claim 10 or a pharmaceutically acceptable salt thereof, wherein; B is selected from the group consisting of 2-aminophenyl, 3 aminophenyl, 3-amidinophenyl, 4-amidinophenyl, 3-carboxyphenyl, 3 10 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; 15 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; Ri is selected from the group consisting of hydrido, hydroxy, amino, amidino, hydroxyamino, aminomethyl, methylamino, cyano, methyl, 20 trifluoromethyl, methoxy, hydroxymethyl, methoxyamino, methylthio, trifluoromethoxy, fluoro, and chloro; R 2 is ZO-Q; Z is selected from the group consisting of a covalent single bond, 0, S, NH, and CH 2 ; 25 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 30 hydroxyphenyl, 3 -carboxymethyl-5-aminophenyl, 3-carboxymethyl-5 212 WO 00/69832 PCT/USOO/09806 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 5 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; 10 Y is selected from the group consisting of: b s 16 17 18 19 1-Q -4-Qs-2-R -3-R -5-R -6-R benzene, b s 7 18 19 2-Q -5-Qs-6-RI-4-R -2-R pyridine, b s 16 18 19 3-Q s6-Qs-2-R -5-R -4-R pyridine, b s 16 19 b s 16 17 3-Q b5-Qs-4-R -2-R thiophene, and 2-Q -5-Q -3-R -4-R thiophene; 15 R16 and R19 are independently selected from the group consisting of hydrido, amidino, amino, aminomethyl, methoxy, methylamino, hydroxy, hydroxymethyl, fluoro, chloro, and cyano; R16 and R19 are optionally Qb with the proviso that no more than one of R16 and R19 is Qb at the same time and that Qb be 20 R17 and R18 are independently selected from the group consisting of hydrido, fluoro, chloro, hydroxy, hydroxymethyl, amino, carboxy, and cyano; Qb is selected from the group consisting of Qbe wherein Qbe is hydrido and C(NR 25)NR R ; 23 24 25 R , R , and R are independently selected from the group consisting of 25 hydrido and methyl; Qs is CH 2 213 WO 00/69832 PCT/USOO/09806 12. The compound as recited in Claim 9 having the Formula: R 2 B A N N H H 0 or a pharmaceutically acceptable salt thereof, wherein; B is the Formula: R R 33R3 5 R3 2 R3 6 5 32 33 34 35 36 R R R , R , and R 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, 10 haloalkyl, haloalkoxy, hydroxyalkyl, carboalkoxy, carboxy, carboxamido, cyano, and Qb A is selected from the group consisting of single covalent bond and 15 7 (CH(R ))pa-(W )rr wherein rr is an integer selected from 0 through 1, pa is 7 7 an integer selected from 0 through 3, and W is N(R ); 15 R is selected from the group consisting of hydrido and alkyl; R15 is selected from the group consisting of hydrido, halo, alkyl, and haloalkyl; M is selected from the group consisting of N and R -C; 214 WO 00/69832 PCT/USOO/09806 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 halo; 5 R 2 is Z 0 -Q; ZO is a covalent single bond; Q is selected from the group consisting of aryl and heteroaryl wherein a carbon adjacent to the carbon at the point of attachment is optionally substituted 9 by R , the other carbon adjacent to the carbon at the point of attachment is 10 optionally substituted by R 13, a carbon adjacent to R9 and two atoms from the carbon at the point of attachment is optionally substituted by R 10, a carbon adjacent to R13 and two atoms from the carbon at the point of attachment is 12 10 12 optionally substituted by R1, and any carbon adjacent to both R and R is optionally substituted by R 9 11 13 15 R , R , and R are independently selected from the group consisting of hydrido, hydroxy, amino, amidino, guanidino, lower alkylamino, alkylthio, alkoxy, alkylsulfinyl, alkylsulfonyl, amidosulfonyl, monoalkylamidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboxy, carboxamido, and cyano; 20 R10 and R12 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, halo, haloalkyl, carboalkoxy, 25 carboxy, carboxyamido, carboxyalkyl, and cyano; Y is formula (IV): 215 WO 00/69832 PCT/USOO/09806 S R17 * R18 J, J R16/DK2,D R 1 9 lb Q (IV) .5 65 6 wherein D , D , J , and J are independently selected from the group consisting of C, N, 0, S and a covalent bond with the provisos that no more than one is a covalent bond, K2 is C, no more than one of D 5, D6 , J ,and J6 5 65 6 5 65 6 5 is 0, no more than one of D5, D , J ,and J s S, one of D5, D , ,and J 5 65 6 must be a covalent bond when two of D , D , J , and J are O and S, and no 5 65 6 more than four of D , D , 5 , and J are N; 16 17 18 19 R , R , R , and R are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, haloalkylthio, alkoxy, 10 hydroxy, amino, lower alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, and cyano; R16 and R19 are optionally Qb with the proviso that no more than one of R16 and R19 is Qb at the same time and that Qb isQbe b -20 21 be be 15 Q is selected from the group consisting of NR R , Q wherein Q is hydrido, and C(NR 25)NR R24 20 21 23 24 25 R , R , R , R , and R are independently selected from the group consisting of hydrido and alkyl; Qs is CH2 20 216 WO 00/69832 PCT/USOO/09806 13. The compound as recited in Claim 12 or a pharmaceutically acceptable salt thereof, wherein; B is the Formula: R 34 32 33 34 35 36 5 R , R , R , R5, 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, 10 amidocarbonyl, carboxy, cyano, and Qb A is selected from the group consisting of 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 C; R is selected from the group consisting of hydrido, hydroxy, amino, 15 amidino, hydroxyamino, aminomethyl, methylamino, cyano, methyl, trifluoromethyl, methoxy, hydroxymethyl, methoxyamino, methylthio, trifluoromethoxy, fluoro, and chloro; R2 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, 20 wherein a carbon adjacent to the carbon at the point of attachment is optionally 9 substituted by R , the other carbon adjacent to the carbon at the point of 13 9 attachment is optionally substituted by R , a carbon adjacent to R and two atoms from the carbon at the point of attachment is optionally substituted by 217 WO 00/69832 PCT/USOO/09806 10 13 R , a carbon adjacent to R and two atoms from the carbon at the point of attachment is optionally substituted by R 12, and any carbon adjacent to both R10 and R12 is optionally substituted by R I 9 11 13 R , R , and R are independently selected from the group consisting 5 of hydrido, methyl, ethyl, methoxy, ethoxy, hydroxy, amino, N-methylamino, N,N-dimethylamino, methylthio, trifluoromethyl, pentafluoroethyl, 2,2,2 trifluoroethyl, fluoro, chloro, bromo, amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, amidocarbonyl, N-methylamidocarbonyl, carboxy, and cyano; 10 R10 and R12 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 15 methylamino, dimethylamino, amidosulfonyl, N-methylamidosulfonyl, N,N dimethylamidosulfonyl, methoxycarbonyl, fluoro, chloro, bromo, and cyano; YO is selected from the group consisting of: b s 16 17 18 19 1-Q -4-Q -2-R -3-R -5-R -6-R benzene, 2-Qb s5_Q-6-R 17-4-R 18-2-R 9pyridine, 2-Q s5-Qs-3-R 16-4-R thiophene, b s 16 18 19 b s 16 19 20 3-Q -6-Qs-2-R -5-R -4-R pyridine, 3-Q b5-Q -4-R -2-R thiophene, 3-Q b5-Q s-4-R 16-2-R 19furan, 2-Q b-5-Q s-3-R 16-4-R 7furan, 3-Q s5-Qs-4-R 16-2-R 19pyrrole, 2-Q b-5-Q s-3-R16 -4-R pyrrole, b s 19 b s 7 4-Q -2-Qs-5-R thiazole, and 2-Q s5-Q -4-RI thiazole; 16 17 18 19 R , R , R , and R are independently selected from the group 25 consisting of hydrido, methyl, ethyl, amidino, guanidino, methoxy, hydroxy, amino, aminomethyl, 1 -aminoethyl, 2-aninoethyl, N-methylamino, dimethylamino, methylthio, ethylthio, trifluoromethylthio, methylsulfinyl, 218 WO 00/69832 PCT/USOO/09806 methylsulfonyl, trifluoromethyl, pentafluoroethyl, 2.2,2-trifluoroethyl, trifluoromethoxy, fluoro, chloro, amidosulfonyl, N-methylamidosulfonyl, hydroxymethyl, carboxy, and cyano. b. 20 21 Q is selected from the group consisting of NR R and 25 224, b Uu sbne ietyt 5 C(NR )N23R2, with the proviso that said Q group is bonded directly to a carbon atom; 20 21 23 24 25 R , R , R , R , and R are independently selected from the group consisting of hydrido, methyl, and ethyl; Qs is CH2. 10 14. The compound as recited in Claim 13 or a pharmaceutically acceptable salt thereof, wherein; B is selected from the group consisting of 2-aminophenyl, 3 aminophenyl, 3-amidinophenyl, 4-amidinophenyl, 3-carboxyphenyl, 3 15 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, 20 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; R2 is selected from the group consisting of 5-amino-3 25 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 30 hydroxyphenyl, 3-carboxymethylphenyl, 3-chlorophenyl, 2-chlorophenyl, 3 219 WO 00/69832 PCT/USOO/09806 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 5 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 is selected from the group consisting of: b s 16 17 18 19 10 1-Q s4-Q-2-R -3-R -5-R -6-R benzene, b s 17 18 19 2-Q s5-Qs-6-R -4-R -2-R pyridine, b s 16 18 19 3-Q b6-Q -2-R -5-R -4-R pyridine, 3-Qb -4-R 16-2-R 9thiophene, and 2-Qb -5-Q s-3-R 16-4-R 17thiophene; R16 and R 9 are independently selected from the group consisting of 15 hydrido, amidino, amino, aminomethyl, methoxy, methylamino, hydroxy, hydroxymethyl, fluoro, chloro, and cyano; 16 19 b R and R - are optionally Q with the proviso that no more than one of R16 and R19 is Qb at the same time and that Qb be R17 and R18 are independently selected from the group consisting of 20 hydrido, fluoro, chloro, hydroxy, hydroxymethyl, amino, carboxy, and cyano; Qb is selected from the group consisting of Qbe wherein Qbe is hydrido and C(NR 25)NR R ; R , R 24, and R25 are independently selected from the group consisting of hydrido and methyl; 25 Qs is CH2 220 WO 00/69832 PCT/USOO/09806 15. The compound as recited in Claim 14 or a pharmaceutically acceptable salt thereof, wherein; B is selected from the group consisting of 3-aminophenyl, 3 amidinophenyl, 4-amidinophenyl, 3-chlorophenyl, 4-chlorophenyl, 3,4 5 dichlorophenyl, 2-fluorophenyl, 4-methylphenyl, and phenyl; A is selected from the group consisting of CH 2 , 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, fluoro, and 10 chloro; R2 is selected from the group consisting of 3-aminophenyl, benzyl, 3 chlorophenyl, 3-dimethylaminophenyl, 3-hydroxyphenyl, 3 methanesulfonylaminophenyl, 3 -methylaminophenyl, 2-methylphenyl, 3 methylphenyl, phenyl, 3 -trifluoroacetamidophenyl, 3-bromo-2-thienyl, 2 15 thienyl, and 3-thienyl; Y is selected from the group consisting of 5-amidino-2-thienylmethyl, 4-amidinobenzyl, 2 -fluoro-4-amidinobenzyl, and 3 -fluoro-4-amdinobenzyl. 16. A compound as recited in Claim 9 where said compound is selected from 20 the group having the Formula: R2 M 0 B N N N H H 0 or a pharmaceutically acceptable salt thereof, wherein: R2 is 3-aminophenyl, B is 3-chlorophenyl, A is CH 2 CH 2 , Y 0 is 4 amidinobenzyl, and M is CH; 25 R2 is 3-aminophenyl, B is phenyl, A is CH 2 , Y 0 is 4-amidinobenzyl, and M is CH; 221 WO 00/69832 PCT/USOO/09806 R2 is phenyl, B is 3-chlorophenyl, A is CH 2 CH 2 , Y 0 is 4-amidinobenzyl, and M is CH; R2 is 3-dimethylaminophenyl, B is phenyl, A is CH 2 CH 2 , Y 0 is 4 anidinobenzyl, and M is CH; 5 R2 is 2-methylphenyl, B is phenyl, A is CH 2 CH 2 , Y 0 is 4-amidinobenzyl, and M is CH; R2 is phenyl, B is 3-aminophenyl, A is C(O)NH, Y 0 is 4-amidinobenzyl, and M is CH; R2 is phenyl, B is 3-amidinophenyl, A is CH 2 , Yo is 4-amidinobenzyl, 10 and M is CH; R2 is 3-(N-methylamino)phenyl, B is phenyl, A is CH 2 CH 2 , Y 0 is 4 amidinobenzyl, and M is CH; R2 is 3-methylsulfonamidophenyl, B is phenyl, A is CH 2 CH 2 , Y 0 is 4 amidinobenzyl, and M is CH; 15 R2 is phenyl, B is 4-amidinophenyl, A is CH 2 , Y 0 is 4-amidinobenzyl, and M is CH; R2 is 3-methylaminophenyl, B is phenyl, A is CH 2 CH 2 , Y 0 is 4 amidinobenzyl, and M is CH; R2 is phenyl, B is phenyl, A is CH 2 , Y 0 is 4-amidinobenzyl, and M is CH; 20 R2 is 3-methylphenyl, B is 4-phenyl, A is CH 2 CH 2 , Y 0 is 4 amidinobenzyl, and M is CH; R2 is 3-aminophenyl, B is 3-chlorophenyl, A is CH 2 CH 2 , Y 0 is 4 amidinobenzyl, and M is CCI; R2 is 3-aminophenyl, B is phenyl, A is CH 2 , Y 0 is 4-amidinobenzyl, and 25 M is CCI; R2 is phenyl, B is 3-chlorophenyl, A is CH 2 CH 2 , Y 0 is 4-amidinobenzyl, and M is CCl; 222 WO 00/69832 PCT/USOO/09806 R2 is 3-dimethylaminophenyl, B is phenyl, A is CH 2 CH 2 , Y 0 is 4 amidinobenzyl, and M is CCI; R2 is 2-methylphenyl, B is phenyl, A is CH 2 CH 2 , Y 0 is 4 -amidinobenzyl, and M is CCl; 5 R2 is phenyl, B is 3-aminophenyl, A is C(O)NH, Y 0 is 4-amidinobenzyl, and M is CCl; R2 is phenyl, B is 3-amidinophenyl, A is CH 2 , Y 0 is 4-amidinobenzyl, and M is CCl; R2 is 3-(N-methylamino)phenyl, B is phenyl, A is CH 2 CH 2 , Y 0 is 4 10 amidinobenzyl, and M is CCl; R2 is 3-methylsulfonamidophenyl, B is phenyl, A is CH 2 CH 2 , Y 0 is 4 amidinobenzyl, and M is CC; R2 is phenyl, B is 4-amidinophenyl, A is CH 2 , Y is 4-amidinobenzyl, and M is CCI; 15 R2 is 3-methylaminophenyl, B is phenyl, A is CH 2 CH 2 , Y 0 is 4 amidinobenzyl, and M is CCl; R2 is phenyl, B is phenyl, A is CH 2 , Y 0 is 4-amidinobenzyl, and M is CCI; R2 is 3-methylphenyl, B is 4-phenyl, A is CH 2 CH 2 , Y 0 is 4 20 amidinobenzyl, and M is CC; R2 is 3-aminophenyl, B is 3-chlorophenyl, A is CH 2 CH 2 , Y 0 is 4 amidinobenzyl, and M is CF; R2 is 3-aminophenyl, B is phenyl, A is CH 2 , Y 0 is 4-amidinobenzyl, and M is CF; 25 R2 is phenyl, B is 3-chlorophenyl, A is CH 2 CH 2 , Y is 4-amidinobenzyl, and M is CF; 223 WO 00/69832 PCT/USOO/09806 R2 is 3-dimethylaminophenyl, B is phenyl, A is CH 2 CH2, Y 0 is 4 amidinobenzyl, and M is CF; R2 is 2-methylphenyl, B is phenyl, A is CH 2 CH 2 , Y 0 is 4-anidinobenzyl, and M is CF; 5 R2 is phenyl, B is 3-aminophenyl, A is C(O)NH, Y 0 is 4-amidinobenzyl, and M is CF; R2 is phenyl, B is 3-amidinophenyl, A is CH 2 , Y 0 is 4-amidinobenzyl, and M is CF; R2 is 3-(N-methylamino)phenyl, B is phenyl, A is CH 2 CH 2 , Yo is 4 10 amidinobenzyl, and M is CF; R2 is 3-methylsulfonamidophenyl, B is phenyl, A is CH 2 CH 2 , Y 0 is 4 amidinobenzyl, and M is CF; R2 is phenyl, B is 4-amidinophenyl, A is CH 2 , Y 0 is 4-amidinobenzyl, and M is CF; 15 R2 is 3-methylaminophenyl, B is phenyl, A is CH 2 CH 2 , Y 0 is 4 amidinobenzyl, and M is CF; R2 is phenyl, B is phenyl, A is CH 2 , Y 0 is 4-amidinobenzyl, and M is CF; R2 is 3-methylphenyl, B is 4-phenyl, A is CH 2 CH 2 , Y 0 is 4 amidinobenzyl, and M is CF; 20 R2 is 3-aminophenyl, B is 3-chlorophenyl, A is CH 2 CH 2 , Y 0 is 4 amidinobenzyl, and M is N; R2 is 3-aminophenyl, B is phenyl, A is CH 2 , Y 0 is 4-amidinobenzyl, and M is N; R2 is phenyl, B is 3-chlorophenyl, A is CH 2 CH 2 , Y 0 is 4-amidinobenzyl, 25 and M is N; R2 is 3-dimethylaminophenyl, B is phenyl, A is CH 2 CH 2 , Y 0 is 4 amidinobenzyl, and M is N; 224 WO 00/69832 PCT/USOO/09806 R2 is 2-methylphenyl, B is phenyl, A is CH 2 CH 2 , Y 0 is 4-amidinobenzyl, and M is N; R2 is phenyl, B is 3-aminophenyl, A is C(O)NH, Y 0 is 4-amidinobenzyl, and M is N; 5 R2 is phenyl, B is 3-aniidinophenyl, A is CH 2 , Y 0 is 4-amidinobenzyl, and M is N; R2 is 3-(N-methylamino)phenyl, B is phenyl, A is CH 2 CH 2 , Y 0 is 4 amidinobenzyl, and M is N; R2 is 3-methylsulfonamidophenyl, B is phenyl, A is CH 2 CH 2 . Y 0 is 4 10 amidinobenzyl, and M is N; R2 is phenyl, B is 4-amidinophenyl, A is CH 2 , Y 0 is 4-amidinobenzyl, and M is N; R2 is 3-methylaminophenyl, B is phenyl, A is CH 2 CH 2 , Y 0 is4 amidinobenzyl, and M is N; 15 R2 is phenyl, B is phenyl, A is CH 2 , Y 0 is 4-amidinobenzyl, and M is N; R2 is 3-methylphenyl, B is 4-phenyl, A is CH 2 CH 2 , Y 0 is 4 amidinobenzyl, and M is N. 20 25 30 225 WO 00/69832 PCT/USOO/09806

17. The compound as recited in Claim 2 having the Formula: R 2 M O B N B "*AN- N N N 0 H H 0 or a pharmaceutically acceptable salt thereof, wherein; 5 B is selected from the group consisting of hydrido, C2-C8 alkyl, C3 C8 alkenyl, C3-C8 alkynyl, and C2-C8 haloalkyl, wherein each member of group B is optionally substituted at any carbon up to and including 6 atoms from the point of attachment of B to A with one or more of the group consisting of R 3 2 , R , R , R , and R36 32 33 34 35 36 10 R , R , R , R , and R are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, alkylthio, aiidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboalkoxy, carboxy, carboxamido, 15 cyano,and Qb A is selected from the group consisting of single covalent bond and (CH(R 15))pa-(W )rr wherein rr is an integer selected from 0 through 1, pa is 7 an integer selected from 0 through 3, and W is selected from the group consisting of (R )NC(O) and N(R ); 20 R7 is selected from the group consisting of hydride, hydroxy and alkyl; R15 is selected from the group consisting of hydrido, halo, alkyl, and haloalkyl; M is selected from the group consisting of N and R -C; 226 WO 00/69832 PCT/USOO/09806 R is selected from the group consisting of hydrido, hydroxy, hydroxyamino, amidino, amino, cyano, hydroxyalkyl, alkoxy, alkyl, alkylamino, aminoalkyl, alkylthio, alkoxyamino, haloalkyl, haloalkoxy, and halo; 5 R 2 is Z 0 -Q; Z is selected from the group consisting of a covalent single bond, 0, S, NH, and CH 2 ; Q is selected from the group consisting of aryl and heteroaryl wherein a carbon adjacent to the carbon at the point of attachment is optionally substituted 9 10 by R , the other carbon adjacent to the carbon at the point of attachment is 13 9 optionally substituted by R , a carbon adjacent to R and two atoms from the 10 carbon at the point of attachment is optionally substituted by R , a carbon adjacent to R13 and two atoms from the carbon at the point of attachment is 12 10 12 optionally substituted by R1, and any carbon adjacent to both R and R is 15 optionally substituted by R 9 11 13 R , R , and R are independently selected from the group consisting of hydrido, hydroxy, amino, amidino, guanidino, lower alkylamino, alkylthio, alkylsulfonamido, alkylsulfinyl, alkylsulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, alkyl, alkoxy, halo, haloalkyl, 20 haloalkoxy, hydroxyalkyl, carboxy, carboxamido, and cyano; R10 and R12 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, 25 hydroxyalkyl, aminoalkyl, carboalkoxy, carboxy, carboxyalkyl, amidocarbonyl, halo, haloalkyl, and cyano; YO is formula (IV): 227 WO 00/69832 PCT/USOO/09806 QS R17 6 R18 5 DK R16 K2,, R 9 lb Q (IV) 5 6 5 6 wherein D , D , J , and J are independently selected from the group consisting of C, N, 0, S and a covalent bond with the provisos that no more 2 5 65 6 than one is a covalent bond, K is C, no more than one of D D , J and J 5 65 6 5 65 6 5 is 0, no more than one of D5, D , ,and J s S, one of D D 5, and J 5 65 6 must be a covalent bond when two of D , D , 5 , and J are 0 and S, and no 5 65 6 more than four of D , D , 5 , and J are N; 16 17 18 19 R , R , R , and R are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, haloalkylthio, alkoxy, 10 hydroxy, amino, lower alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, aiinoalkyl, and cyano; R16 and R19 are optionally Qb with the proviso that no more than one of R16 and R 9 is Qb at the same time and that Qb is Qbe b 20 21 be 15 Q is selected from the group consisting of NR R , Q wherein Qbe is hydrido, C(NR )NR 23R , and N(R 26)C(NR 25)N(R )(R 24), with the provisos that no more than one of R20 and R21 s hydroxy at the same time and that no more than one of R and R24 s hydroxy at the same time; 20 21 23 24 25 26 R , R , R , R , R , and R are independently selected from the 20 group consisting of hydrido, alkyl, and hydroxy; 228 WO 00/69832 PCT/USOO/09806 Qs is selected from the group consisting of a single covalent bond, CH 2 , and CH 2 CH 2 .

18. The compound as recited in Claim 17 or a pharmaceutically acceptable salt 5 thereof, wherein; B is selected from the group consisting of hydrido, ethyl, 2-propynyl, 2-propenyl, propyl, isopropyl, butyl, 2-butenyl, 3-butenyl, 2-butynyl, sec butyl, tert-butyl, isobutyl, 2-methylpropenyl, 1-pentyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-pentynyl, 3-pentynyl, 2-pentyl, 1-methyl-2-butenyl, 1-methyl-3 10 butenyl, 1-methyl-2-butynyl, 3-pentyl, 1-ethyl-2-propenyl, 2-methylbutyl, 2 methyl-2-butenyl, 2-methyl-3-butenyl, 2 -methyl-3-butynyl, 3-methylbutyl, 3 methyl-2-butenyl, 3-methyl-3-butenyl, 1-hexyl, 2-hexenyl, 3-hexenyl, 4 hexenyl, 5-hexenyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 2-hexyl, 1-methyl-2 pentenyl, 1-methyl-3-pentenyl, 1-methyl-4-pentenyl, 1-methyl-2-pentynyl, 1 15 methyl-3-pentynyl, 3-hexyl, 1-ethyl-2-butenyl, 1-ethyl-3-butenyl, 1-propyl-2 propenyl, 1-ethyl-2-butynyl, 1-heptyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5 heptenyl, 6-heptenyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 5-heptynyl, 2 heptyl, 1-methyl-2-hexenyl, 1-methyl-3-hexenyl, 1-methyl-4-hexenyl, 1 methyl-5-hexenyl, 1-methyl-2-hexynyl, 1-methyl-3-hexynyl, 1-methyl-4 20 hexynyl, 3-heptyl, 1-ethyl-2-pentenyl, 1-ethyl-3-pentenyl, 1-ethyl-4-pentenyl, 1-butyl-2-propenyl, 1-ethyl-2-pentynyl, 1-ethyl-3-pentynyl, 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 at any carbon up to 25 and including 5 atoms from the point of attachment of B to A with one or more . 32 33 34 35 36 of the group consistmg of R , R , R ,R , and R 32 33 34 35 36 R , R , R , R , and R are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, methoxyamino, ethoxyamino, 30 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 229 WO 00/69832 PCT/USOO/09806 methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl, 1 hydroxyethyl, 2-hydroxyethyl, 2 .2,2-trifluoro-1-hydroxyethyl, methoxycarbonyl, ethoxycarbonyl, amidocarbonyl, N-methylamidocarbonyl, N,N-dimethylamidocarbonyl, cyano, and Qb; 5 A is selected from the group consisting of 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 ; M is selected from the group consisting of N and R -C; 10 R is selected from the group consisting of hydrido, hydroxy, amino, amidino, hydroxyamino, aminomethyl, I -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 15 tetrafluoroethoxy, fluoro, chloro, and bromo; R 2 is Z -Q; R20 Z is selected from the group consisting of a covalent single bond, 0, S, NH, and CH 2 ; Q is selected from the group consisting of phenyl, 2-thienyl, 3-thienyl, 20 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, and 1, 3 ,5-triazin-2-yl, wherein a carbon adjacent to the carbon at the point of attachment is optionally substituted by R 9, the 25 other carbon adjacent to the carbon at the point of attachment is optionally 13 9 substituted by R , a carbon adjacent to R and two atoms from the carbon at 10 the point of attachment is optionally substituted by R , a carbon adjacent to R13 and two atoms from the carbon at the point of attachment is optionally 230 WO 00/69832 PCT/USOO/09806 12 10 12. substituted by R1, and any carbon adjacent to both R and R is optionally substituted by R R , R1, and R13 are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, methyl, ethyl, propyl, isopropyl, 5 methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, N-methylamino, N,N-dimethylamino, N-ethylamino, methylthio, ethylthio, isopropylthio, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, 2,2,3,3,3 pentafluoropropyl, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro, bromo, methanesulfonamido, amidosulfonyl, N-methylamidosulfonyl, 10 N,N-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, 2 hydroxyethyl, 2,2,2-trifluoro-1-hydroxyethyl, amidocarbonyl, N methylamidocarbonyl, N,N-dimethylamidocarbonyl, and cyano; R10 and R12 are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, carboxymethyl, methyl, ethyl, propyl, 15 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, N,N dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 20 2,2,2-trifluoro-1-hydroxyethyl, methoxycarbonyl, ethoxycarbonyl, amidocarbonyl, N-methylamidocarbonyl, N,N-dimethylamidocarbonyl, fluoro, chloro, bromo, and cyano; Y is selected from the group consisting of: b s 16 17 18 19 1-Q s4-Q-2-R -3-R -5-R -6-R benzene, 25 2-Q b5-Q s-6-R 174-R 18-2-R 19pyridine, 3-Q b6-Q s-2-R 16-5-R 18-4-R 19pyridine, 2-Qb s4-Q-3-R 16-6-R 18pyrazine, 3 b s 18 18 19 Q -6-Q -2-R -5-R -4-R pyridazine, 2-Q -5-s -6-R 17-4-R 18pyrimidine, 5-Q -2-Qs-3-R 16-6-R 9pyrimidine, 231 WO 00/69832 PCT/USOO/09806 3-Qb -5-Qs-4-R16-2-R 19thiophene, 2-Q -5-Qs-3-R 16-4-R 17thiophene, b_ s 6_ 19 b 5s- 16 17 3-Q s5-Q-4-R1-2-R furan, 2-Q -5-Q 3-R -4-R furan, 3-Q -5-Qs-4-R 16-2-R 9pyrrole, 2-Qb -s-Q -3-R 16-4-R17 pyrrole, 4-Q -2-Qs-5-R 19imidazole, 2-Q b s-Qs-5-R 17imidazole, 5 3-Q -5-Qs-4-R 16isoxazole, 5-Q -3-Q s-4-R 16isoxazole, 2-Q s-5-Q-4-R 16pyrazole, 4-Q -2-Qs-5-R19thiazole, and b s 17 2-Q -5-Qs-4-R thiazole; 16 17 18 19 R , R , R , and R are independently selected from the group consisting of hydrido, methyl, ethyl, isopropyl, propyl, carboxy, amidino, 10 guanidino, methoxy, ethoxy, isopropoxy, propoxy, 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, 2,2,3,3,3-pentafluoropropyl, 15 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, and cyano; R16 and R19 are optionally Qb with the proviso that no more than one of 20 R 16 and R19 is Qb at the same time and that Qb be b 20 21 be be Q is selected from the group consisting of NR R , Q , wherein Q 25 23 24 26 25 23 4 is hydrido, C(NR )NR R , and N(R )C(NR )N(R )(R ), with the provisos that no more than one of R20 and R21 is hydroxy at the same time and that no more than one of R and R24 is hydroxy at the same time; 232 WO 00/69832 PCT/USOO/09806 20 21 23 24 25 26 R2, R , R , R , R , and R are independently selected from the group consisting of hydrido. methyl, ethyl, propyl, butyl, isopropyl, and hydroxy; Q is selected from the group consisting of a single covalent bond, CH 2 , and CH 2 CH 2 5

19. The compound as recited in Claim 18 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-butyl, (R)-2-butyl,(S)-2-butyl, ter 10 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, 3-guanidinopropyl, 4-guanidinobutyl, 3 15 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 single covalent bond,CH 2 , NHC(O), CH 2 CH 2 , CH 2 CH 2 CH 2 , and CH 3 CHCH 2 ; 20 M is selected from the group consisting of N and R -C; R 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; 25 R 2 is Z-Q; 0 Z is selected from the group consisting of a covalent single bond, 0, S, NH, and CH 2 ; Q is selected from the group consisting of 5-amino-3 amidocarbonylphenyl, 5-amino-2-fluorophenyl, 3-amino-5 30 hydroxymethylphenyl, 5-amino-3-methoxycarbonylphenyl, 3-amidinophenyl, 233 WO 00/69832 PCT/USOO/09806 3-amino-2-methylphenyl, 5 -amino-2-methylthiophenyl, 3-aniinophenyl, 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, 5 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, 10 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; is selected from the group consisting of: 1-Qb s-2-R16-3-R 17-5-R 18-6-R 19benzene, b s 7 18 19 15 2-Q s5-Qs-6-RI -4-R -2-R pyridine, 3-Q s6-Q -2-R 16-5-R18 -4-R 19pyridine, 3-Qb s-4-R 16-2-R 19thiophene, and 2-Q -5-Qs-3-R 16-4-R 7thiophene; R16 and R19 are independently selected from the group consisting of hydrido, amidino, amino, aminomethyl, methoxy, methylamino, hydroxy, 20 hydroxymethyl, fluoro, chloro, and cyano; R16 and R19 are optionally Qb with the proviso that no more than one 16 19 b b be of R and R is Q at the same time and that Q isQ R17 and R18 are independently selected from the group consisting of hydrido, fluoro, chloro, hydroxy, hydroxymethyl, amino, carboxy, and cyano; 25 Qb is selected from the group consisting of Qbe wherein Qbe is hydrido and C(NR 25)NR R24 23 24 25 R , R , and R are independently selected from the group consisting of hydrido and methyl; 234 WO 00/69832 PCT/USOO/09806 Q is CH 2 .

20. The compound as recited in Claim 17 having the Formula: R2 M 0 1N 0 B N N N H H 0 5 or a pharmaceutically acceptable salt thereof, wherein; B is selected from the group consisting of hydrido, C2-C8 alkyl, C3 C8 alkenyl, C3-C8 alkynyl, and C2-C8 haloalkyl, wherein each member of group B is optionally substituted at any carbon up to and including 6 atoms from the point of attachment of B to A with one or more of the group 10 consisting of R 3 2 , R 3 3 3 4 ,R 3 5 , and R 3 6 32 33 34 35 36 R R3, R3, R3, and R 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, 15 haloalkyl, haloalkoxy, hydroxyalkyl, carboalkoxy, carboxy, carboxamido, cyano, and Qb A is selected from the group consisting of single covalent bond and 15 7 (CH(R1 ))pa-(W )rr wherein rr is an integer selected from 0 through 1, pa is an integer selected from 0 through 3, and W is N(R ); 7 s e ty 20 R is selected from the group consisting of hydrido and alkyl; R 15is selected from the group consisting of hydrido, halo, alkyl, and haloalkyl; M is selected from the group consisting of N and R -C; 235 WO 00/69832 PCT/USOO/09806 Ri is selected from the group consisting of hydrido, hydroxy, hydroxyamino, amidino, amino, cyano, hydroxyalkyl, alkoxy, alkyl, alkylamino, aminoalkyl, alkylthio, alkoxyamino, haloalkyl, haloalkoxy, and halo; 5 R2 is Z-Q; ZO is a covalent single bond; Q is selected from the group consisting of aryl and heteroaryl wherein a carbon adjacent to the carbon at the point of attachment is optionally substituted 9 by R , the other carbon adjacent to the carbon at the point of attachment is 13 9 10 optionally substituted by R , a carbon adjacent to R and two atoms from the 10 carbon at the point of attachment is optionally substituted by R1, a carbon adjacent to R13 and two atoms from the carbon at the point of attachment is 12 10 12 optionally substituted by R1, and any carbon adjacent to both R and R is optionally substituted by R 9 11 13 15 R , R , and R are independently selected from the group consisting of hydrido, hydroxy, amino, amidino, guanidino, lower alkylamino, alkylthio, alkoxy, alkylsulfinyl, alkylsulfonyl, amidosulfonyl, monoalkylamidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboxy, carboxamido, and cyano; 20 R10 and R12 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, halo, haloalkyl, carboalkoxy, 25 carboxy, carboxyamido, carboxyalkyl, and cyano; YO is formula (IV): 236 WO 00/69832 PCT/USOO/09806 S R17 R1 8 R, R R16 K2 D R 1 9 b (IV) 5 65 6 wherein D , D , 5 , and J are independently selected from the group consisting of C, N, 0, S and a covalent bond with the provisos that no more than one is a covalent bond, K2 is C, no more than one of D 5, D 6, 5, and J6 5 65 6. 5 65 6 5 is 0, no more than one of D5, D , ,and J s S, one of D5, D , ,and J 5 65 6 must be a covalent bond when two of D , D , J , and J are 0 and S. and no 5 65 6 more than four of D5, D , ,and J are N; 16 17 18 19 R , R , R , and R are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, haloalkylthio, alkoxy, 10 hydroxy, amino, lower alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, and cyano; R16 and R19 are optionally Qb with the proviso that no more than one of R16 and R19 is Qb at the same time and that Qb is Qbe b .20 21 be be 15 Q is selected from the group consisting of NR R , Q wherein Q is hydrido, N(R 26)C(NR 25)N(R )(R24), and C(NR 25)NR R24 20 21 23 24 25 26 R , R , R , R , R , and R are independently selected from the group consisting of hydrido and alkyl; Qs is CH 2 20 237 WO 00/69832 PCT/USOO/09806

21. The compound as recited in Claim 17 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, sec-butyl, terr 5 butyl, isobutyl, 2-methylpropenyl, 1-pentyl, 2-pentenyl, 3-pentenyl, 2 pentynyl, 3-pentynyl, 2-pentyl, 3-pentyl, 2-methylbutyl, 2-methyl-2-butenyl, 3-methylbutyl, 3-methyl-2-butenyl, 1-hexyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 2-hexyl, 1-methyl-2-pentenyl, 1-methyl-3 pentenyl, 1-methyl-2-pentynyl, 1-methyl-3-pentynyl, 3-hexyl, 1-ethyl-2 10 butenyl, 1-heptyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 5-heptynyl, 2-heptyl, 1-methyl-2-hexenyl, 1-methyl 3-hexenyl, 1-methyl-4-hexenyl, 1-methyl-2-hexynyl, 1-methyl-3-hexynyl, 1 methyl-4-hexynyl, 3-heptyl, 1 -ethyl-2-pentenyl, 1-ethyl-3-pentenyl, 1-ethyl-2 pentynyl, 1-ethyl-3-pentynyl, 2,2,2-trifluoroethyl, 2,2-difluoropropyl, 4 15 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 at any carbon up to and including 5 atoms from the point of attachment of B to A with one or more of the group consisting of R32 33 34 35 36 R , R3, R3, and R 32 33 34 35 36 20 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, 25 amidocarbonyl, carboxy, cyano, and Qb A is selected from the group consisting of 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 ) with the 30 proviso that B is hydrido; 238 WO 00/69832 PCT/USOO/09806 M is selected from the group consisting of N and R -C; R is selected from the group consisting of hydrido, hydroxy, amino, amidino, hydroxyamino, aminomethyl, methylamino, cyano, methyl, trifluoromethyl, methoxy, hydroxymethyl, methoxyamino, methylthio, 5 trifluoromethoxy, fluoro, and chloro; R2 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 a carbon adjacent to the carbon at the point of attachment is optionally 9 substituted by R , the other carbon adjacent to the carbon at the point of 13 9 10 attachment is optionally substituted by R , a carbon adjacent to R and two atoms from the carbon at the point of attachment is optionally substituted by 10 13 R , a carbon adjacent to R and two atoms from the carbon at the point of 12 attachment is optionally substituted by R1, and any carbon adjacent to both R10 and R12 is optionally substituted by R1 9 11 13 15 R , R , and R are independently selected from the group consisting of hydrido, methyl, ethyl, methoxy, ethoxy, hydroxy, amino, N-methylamino, N,N-dimethylamino, methylthio, trifluoromethyl, pentafluoroethyl, 2,2,2 trifluoroethyl, fluoro, chloro, bromo, amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, amidocarbonyl, 20 N-methylamidocarbonyl, carboxy, and cyano; R10 and R12 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, 25 pentafluoroethyl, 2,2,2-trifluoroethyl, trifluoroacetamido, aminomethyl, N methylamino, dimethylamino, amidosulfonyl, N-methylamidosulfonyl, N,N dimethylamidosulfonyl, methoxycarbonyl, fluoro, chloro, bromo, and cyano; YO is selected from the group consisting of: 1-Qb 4-Q -2-R 16-3-R 17-5-R 18-6-R 19benzene, 239 WO 00/69832 PCT/USOO/09806 2-Q -5-Qs-6-R 17-4-R 18-2-R 9pyridine, 2-Q s5-Q -3-R 16-4-R thiophene, 3-Qb -6-Q-2-R 16-5-R 18-4-R 9pyridine, 3-Q s5-Q -4-R 16-2-R 19thiophene, b s 16 19 b s 16 17 3--Qb_5- -4R -2-R furan, 2-Q -5-Q s-3-R -4-R furan, 3-Qb -5Qs-4-R 16-2-R 19pyrrole, 2-Q b-5-Q s-3-R 16-4-R 17pyrrole, 5 4-Q -2-Q s-5-R 19thiazole, and 2-Q b-5-Q s-4-R 17thiazole; 16 17 18 19 R , R , R , and R 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, 10 methylsulfonyl, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, trifluoromethoxy, fluoro, chloro, amidosulfonyl, N-methylamidosulfonyl, hydroxymethyl, carboxy, and cyano. Qb is selected from the group consisting of NR 20R21 C(NR 25)NR R24, and N(R 26)C(NR 25)N(R )(R 24), with the proviso that b 15 said Q group is bonded directly to a carbon atom; 20 21 23 24 25 26 R , R , R , R , R , and R are independently selected from the group consisting of hydrido, methyl, and ethyl; Qs is CH2 20 22. The compound as recited in Claim 21 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-butyl, (R)-2-butyl,(S)-2-butyl, tert butyl, isobutyl, 1-pentyl, 3-pentyl, 2-methylbutyl, 2 ,2,2-trifluoroethyl, 6 25 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, 3 240 WO 00/69832 PCT/USOO/09806 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 single covalent bond, CH 2 , 5 CH 3 CH, and CH 2 CH 2 ; M is selected from the group consisting of N and R -C: R is selected from the group consisting of hydrido, hydroxy. amino, methyl, trifluoromethyl, fluoro, and chloro; R2 is selected from the group consisting of 5-amino-3 10 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 15 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 20 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; YO is selected from the group consisting of: b s 16 17 18 19 25 1-Q b-Q -2-R -3-R -5-R -6-R benzene, b s 17 18 19 2-Q -5-Q -6-R -4-R -2-R pyridine, b s 16 18 19 3-Q -Q -2-R -5-R -4-R pyridine, b s 6 19 b s 16 17 3-Q -5-Qs-4-R1 -2-R thiophene, and 2-Q -5-Q -3-R -4-R thiophene; 241 WO 00/69832 PCT/USOO/09806 R16 and R19 are independently selected from the group consisting of hydrido, amidino, amino, aminomethyl, methoxy, methylamino, hydroxy, hydroxymethyl, fluoro, chloro, and cyano; R16 and R19 are optionally Qb with the proviso that no more than one 5 of R16 and R 9 isQb at the same time and that Qb is Qbe R and R18 are independently selected from the group consisting of hydrido, fluoro, chloro, hydroxy, hydroxymethyl, amino, carboxy, and cyano; Qb is selected from the group consisting of Qbe wherein Qbe is hydrido and C(NR25 23R24 23 24 25 10 R , R , and R are independently selected from the group consisting of hydrido and methyl; Qs is CH 2 23. The compound as recited in Claim 22 or a pharmaceutically acceptable salt 15 thereof, 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, 1-pentyl, 3-pentyl, 2-methylbutyl, 2,2,2-trifluoroethyl, 6 amidocarbonyihexyl, 4-methyl-2-pentyl, 3-hydroxypropyl, 3-methoxy-2 20 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 25 4-aminobutyl; A is selected from the group consisting of 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; 242 WO 00/69832 PCT/USOO/09806 R is selected from the group consisting of hydrido, fluoro, and chloro; R2 is selected from the group consisting of 5 -amino-2-fluorophenyl, 3 amino-2-methylphenyl, 5 -amino-2-methylthiophenyl, 3-aminophenyl, 3 5 carboxyphenyl, 3-cyanophenyl, 3 -methoxycarbonylphenyl, phenyl, and 3 pyridyl; YU is selected from the group consisting of 5 -amidino-2-thienylmethyl, 4-amidinobenzyl, 2 -fluoro-4-amidinobenzyl, and 3-fluoro-4-amidinobenzyl. 10 24. A compound as recited in Claim 17 where said compound is selected from the group having the Formula: 0 M O-1 B A N N N H H 0 or a pharmaceutically acceptable salt thereof, wherein: R2 is 3-aminophenyl, B is 2,2,2-trifluoroethyl, A is single bond, Y 0 is 4 15 amidinobenzyl, and M is CH; R2 is 3-aminophenyl, B is (S)-2-butyl, A is single bond, Y 0 is 4 amidinobenzyl, and M is CH; R2 is 5-amino-2-fluorophenyl, B is isopropyl, A is single bond, Y 0 is 4 amidinobenzyl, and M is CH; 20 R2 is 2 -methyl-3-aminophenyl, B is isopropyl, A is single bond, YO is 4 amidinobenzyl, and M is CH; R2 is 3-aminophenyl, B is ethyl, A is single bond, Y 0 is 4-amidinobenzyl, and M is CH; R2 is 3-aminophenyl, B is ethyl, A is single bond, Y 0 is 4-amidino-2 25 fluorobenzyl, and M is CH; 243 WO 00/69832 PCT/US00/09806 R2 is 3-aminophenyl, B is 2-propenyl, A is single bond, Y 0 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; 5 R2 is 3-aminophenyl, B is isopropyl, A is single bond, Y 0 is 4 amidinobenzyl, and M is CH; R 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 0 is 4 10 amidinobenzyl, and M is CH; R2 is 3-aminophenyl, B is 2-propynyl, A is single bond, Y 0 is 4 amidinobenzyl, and M is CH; R2 is 3-aminophenyl, B is 3-pentyl, A is single bond, Y 0 is 4 amidinobenzyl, and M is CH; 15 R2 is 3-aminophenyl, B is hydrido, A is CH 2 , Y 0 is 4-amidinobenzyl, and M is CH; R2 is 3-aminophenyl, B is ethyl, A is CH 2 , Y is 4-amidinobenzyl, and M is CH; R2 is 3-aminophenyl, B is 2-methypropyl, A is single bond, Y 0 is 4 20 amidinobenzyl, and M is CH; R2 is 3-aminophenyl, B is 2-propyl, A is CH 3 CH, Y 0 is 4-amidinobenzyl, and M is CH; R2 is 3-aminophenyl, B is propyl, A is single bond, Y 0 is 4-amidino-2 fluorobenzyl, and M is CH; 25 R2 is 3-aminophenyl, B is 6-amidocarbonylhexyl, A is single bond, Y 0 is 4-amidinobenzyl, and M is CH; R2 is 3-aminophenyl, B is tert-butyl, A is single bond, Y 0 is 4 amidinobenzyl, and M is CH; 244 WO 00/69832 PCT/USOO/09806 R is 3-aminophenyl, B is tert-butyl, A is single bond, YU is 4 amidinobenzyl, and M is CH; R is 3-aminophenyl, B is 3-hydroxypropyl, A is single bond, Y 0 is 4 amidinobenzyl, and M is CH; 5 R2 is 3-aminophenyl, B is 2-methylpropyl, A is single bond, Y 0 is 4 amidino-2-fluorobenzyl, and M is CH; R2 is 3-aminophenyl, B is butyl, A is single bond, Y 0 is 4-amidinobenzyl, and M is CH; R2 is 3-aminophenyl, B is 3-methoxy-2-propyl, A is single bond, Y 0 is 4 10 amidinobenzyl, and M is CH; R2 is 3-aminophenyl, B is 3-methoxy-2-propyl, A is single bond, Y 0 is 4 amidinobenzyl, and M is CH; R is 3-aminophenyl, B is 2-methoxy-2-ethyl, A is single bond, Y 0 is 4 amidinobenzyl, and M is CH; 15 R2 is 3-aminophenyl, B is 2-propyl, A is single bond, Y 0 is 5-amidino-2 thienylmethyl, and M is CH; R2 is 3-aminophenyl, B is 2-propyl, A is single bond, Y 0 is 4-amidino-3 fluorobenzyl, and M is CH; R2 is 3-carboxyphenyl, B is 2-propyl, A is single bond, Y 0 is 4 20 amidinobenzyl, and M is CH; R2 is 3-aminophenyl, B is 2-propyl, A is single bond, Y 0 is 4-amidino-3 fluorobenzyl, and M is CH; R2 is 3-aminophenyl, B is 2,2,2-trifluoroethyl, A is single bond, Y 0 is 4 amidinobenzyl, and M is N; 25 R2 is 3-aminophenyl, B is (S)-2-butyl, A is single bond, Y 0 is 4 amidinobenzyl, and M is N; R2 is 5-amino-2-fluorophenyl, B is isopropyl, A is single bond, Y is4 amidinobenzyl, and M is N; 245 WO 00/69832 PCT/USOO/09806 R2 is 2-methyl-3-aminophenyl, B is isopropyl, A is single bond, Y 0 is4 amidinobenzyl, and M is N; R2 is 3-aminophenyl, B is ethyl, A is single bond, Y is 4 -amidinobenzyl, and M is N; 5R2 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 0 is 4-amidino-2 10 fluorobenzyl, and M is N; R2 is 3-aminophenyl, B is isopropyl, A is single bond, Y 0 is 4 amidinobenzyl, and M is N; R2 is 3-aminophenyl, B is 2-butyl, A is single bond, Yis 4 amidinobenzyl, and M is N; 15 R2 is 3-aminophenyl, B is (R)-2-butyl, A is single bond, Y 0 is 4 amidinobenzyl, and M is N; R2 is 3-aminophenyl, B is 2-propynyl, A is single bond, Y 0 is 4 amidinobenzyl, and M is N; R2 is 3-aminophenyl, B is 3-pentyl, A is single bond, Y 0 is 4 20 amidinobenzyl, and M is N; R2 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 CH 2 , Y 0 is 4-amidinobenzyl, and M is N; 25 R is 3-aminophenyl, B is 2-methypropyl, A is single bond, Yis 4 amidinobenzyl, and M is N; R2 is 3-aminophenyl, B is 2-propyl, A is CH 3 CH, Y 0 is 4-amidinobenzyl, and M is N; 246 WO 00/69832 PCT/USOO/09806 R2 is 3-aminophenyl, B is propyl, A is single bond, Y 0 is 4-amidino-2 fluorobenzyl, and M is N; R2 is 3-aminophenyl, B is 6-amidocarbonylhexyl, A is single bond, Y 0 is 4-amidinobenzyl, and M is N; 5 R2 is 3-aminophenyl, B is tert-butyl, A is single bond, Y 0 is 4 amidinobenzyl, and M is N; R2 is 3-aminophenyl, B is tert-butyl, A is single bond, Y 0 is 4 amidinobenzyl, and M is N; R2 is 3-aminophenyl, B is 3-hydroxypropyl, A is single bond, Y 0 is 4 10 amidinobenzyl, and M is N; R2 is 3-aminophenyl, B is 2-methylpropyl, A is single bond, Y 0 is 4 amidino-2-fluorobenzyl, and M is N; R2 is 3-aminophenyl, B is butyl, A is single bond, Y 0 is 4-amidinobenzyl, and M is N; 15 R2 is 3-aminophenyl, B is 3-methoxy-2-propyl, A is single bond, Y 0 is 4 amidinobenzyl, and M is N; R 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 0 is 4 20 amidinobenzyl, and M is N; R2 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 0 is 4-amidino-3 fluorobenzyl, and M is N; 25 R2 is 3-carboxyphenyl, B is 2-propyl, A is single bond, Yis 4 amidinobenzyl, and M is N; R2 is 3-aminophenyl, B is 2-propyl, A is single bond, Y 0 is 4-amidino-3 fluorobenzyl, and M is CH. 247 WO 00/69832 PCT/USOO/09806

25. The compound as recited in Claim 2 having the Formula: 2 0 M O B#A N N N 0 H H 0 or a pharmaceutically acceptable salt thereof, wherein; 5 B is selected from the group consisting of C3-C7 cycloalkyl and C4 saturated heterocyclyl, wherein each ring carbon is optionally substituted with 33 R , a ring carbon other than the ring carbon at the point of attachment of B to A is optionally substituted with oxo provided that no more than one ring carbon is substituted by oxo at the same time, ring carbon sand a nitrogen adjacent to 10 the carbon atom at the point of attachment is optionally substituted with R9 or R13, a nng carbon or nitrogen adjacent to the R9 position and two atoms from 10 the point of attachment is optionally substituted with R , a ring carbon or 13 nitrogen adjacent to the R13 position and two atoms from the point of 12 attachment is optionally substituted with R , a ring carbon three atoms from 15 the point of attachment and adjacent to the R10 position is optionally 11 substituted with R , a ring carbon three atoms from the point of attachment and adjacent to the R12 position is optionally substituted with R 33, and a ring carbon atoms from the point of attachment and adjacent to the R and R33 positions is optionally substituted with R34 9 11 13 20 R , R , and R are independently selected from the group consisting of hydrido, hydroxy, amino, amidino, guanidino, lower alkylamino, alkylthio, alkylsulfonamido, alkylsulfinyl, alkylsulfonyl, 248 WO 00/69832 PCT/USOO/09806 amidosulfonyl, monoalkyl amidosulfonyl, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboxy, carboxamido, and cyano; R10 and R12 are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkyl, alkoxy, 5 hydroxy, amino, alkoxyamino, lower alkylamino, alkylsulfonamido, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, hydroxyalkyl, aminoalkyl, carboalkoxy, carboxy, carboxyalkyl, amidocarbonyl, halo, haloalkyl, and cyano; R33 and R34 are independently selected from the group consisting of 10 hydrido, acetamido, haloacetamido, amidino, guanidino, alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, alkylthio, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl armidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboalkoxy, carboxy, carboxamido, cyano, and Qb A is selected from the group consisting of single covalent bond and 15 (CH(R 15))pa-(W 7)rr wherein rr is an integer selected from 0 through 1, pa is an integer selected from 0 through 3. and W is selected from the group consisting of (R )NC(O) and N(R ); 7 R is selected from the group consisting of hydrido, hydroxy and alkyl; R15 is selected from the group consisting of hydrido, halo, alkyl, and 20 haloalkyl; M is selected from the group consisting of N and R -C; R is selected from the group consisting of hydrido, hydroxy, hydroxyamino, amidino, amino, cyano, hydroxyalkyl, alkoxy, alkyl, alkylamino, aminoalkyl, alkylthio, alkoxyamino, haloalkyl, haloalkoxy, and 25 halo; R 2 is ZO-Q; Z is selected from the group consisting of a covalent single bond, 0, S, NH, and CH 2 ; 249 WO 00/69832 PCT/USOO/09806 Q is selected from the group consisting of aryl and heteroaryl wherein a carbon adjacent to the carbon at the point of attachment is optionally substituted 9 by R , the other carbon adjacent to the carbon at the point of attachment is 13 9 optionally substituted by R , a carbon adjacent to R and two atoms from the 10 5 carbon at the point of attachment is optionally substituted by R , a carbon adjacent to R13 and two atoms from the carbon at the point of attachment is 12 10 12 optionally substituted by R1, and any carbon adjacent to both R and R is optionally substituted by R Y is formula (IV): S , 1 7 18 R R 6 5 6 R 16 K2 D R 19 lb 10 Q IV) wherein D 5, D6 , J 5, and J6 are independently selected from the group consisting of C, N, 0, S and a covalent bond with the provisos that no more 2 5 65 6 than one is a covalent bond, K is C, no more than one of D , D , J , and J 5 65 6 5 65 6 is 0, no more than one of D, D , J ,and J is S, one of D, D , J ,and J 5 65 6 15 must be a covalent bond when two of D , D , J , and J are 0 and S, and no 5 6 5 6 more than four of D , D , J , and J are N; 16 17 18 19 R1, R , R , and R are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, haloalkylthio, alkoxy, hydroxy, amino, lower alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, 250 WO 00/69832 PCT/USOO/09806 alkanoyl, haloalkanoyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, and cyano; R16 and R19 are optionally Qb with the proviso that no more than one of R16 and R19 is Qb at the same time and that Qb be 5 Qb is selected from the group consisting of NR20R21 be wherein Q beis 25 23 24 2 hydrido, and C(NR )NR R , with the provisos that no more than one of R and R21 is hydroxy at the same time and that no more than one of R and R24 is hydroxy at the same time; 20 21 23 24 25 R2, R2, R , R , and R are independently selected from the group 10 consisting of hydrido, alkyl, and hydroxy; Q is selected from the group consisting of a single covalent bond, CH 2 , and CH 2 CH 2 .

26. The compound as recited in Claim 25 or a pharmaceutically acceptable salt 15 thereof, wherein; B is selected from the group consisting of cyclopropyl, cyclobutyl, oxetan-3-yl, azetidin-1-yl, azetidin-2-yl, azetidin-3-yl, thiaetan-3-yl, cyclopentyl, cyclohexyl, norbornyl, bicyclo[3. 1.0]hexan-6-yl, and 33 cycloheptyl, wherein each ring carbon is optionally substituted with R , ring 20 carbons and a nitrogen adjacent to the carbon atom at the point of attachment is 9 13 optionally substituted with R or R , a ring carbon or nitrogen adjacent to the 9 R position and two atoms from the point of attachment is optionally substituted with R 10 , and a ring carbon or nitrogen adjacent to the R13 position and two atoms from the point of attachment is optionally substituted 25 with R12 251 WO 00/69832 PCT/USOO/09806 9 11 13 R , R , and R are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, N-methylamino, N,N-dimethylamino, N-ethylamino, methylthio, ethylthio, isopropylthio, 5 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, hydroxymethyl, I -hydroxyethyl, 2 hydroxyethyl, 2,2,2-trifluoro-1-hydroxyethyl, amidocarbonyl, N 10 methylamidocarbonyl, N,N-dimethylamidocarbonyl, and cyano; R10 and R12 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 15 aminoethyl, 2-aminoethyl, N-methylamino, dimethylamino, N-ethylamino, methanesulfonamido, 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, 20 fluoro, chloro, bromo, and cyano; 33 34 R and R 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, 25 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, N,N-dimethylamidosulfonyl, hydroxymethyl, 1 hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro- 1 -hydroxyethyl, 30 methoxycarbonyl, ethoxycarbonyl, amidocarbonyl, N-methylamidocarbonyl, N,N-dimethylamidocarbonyl, cyano, and Qb 252 WO 00/69832 PCT/USOO/09806 A is selected from the group consisting of 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 ; 5 M is selected from the group consisting of N and R -C; R 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, 2-hydroxyethyl, 10 methoxyamino, methylthio, ethylthio, trifluoromethoxy, 1,1,2,2 tetrafluoroethoxy, fluoro, chloro, and bromo; R 2 isZO-Q; Z is selected from the group consisting of a covalent single bond, 0, S, NH, and CH 2 ; 15 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, and 1,3,5-triazin-2-yl, wherein a carbon adjacent 9 20 to the carbon at the point of attachment is optionally substituted by R , the other carbon adjacent to the carbon at the point of attachment is optionally 13 9 substituted by R , a carbon adjacent to R and two atoms from the carbon at 10 the point of attachment is optionally substituted by R , a carbon adjacent to R13 and two atoms from the carbon at the point of attachment is optionally 12 10 12. 25 substituted by R1, and any carbon adjacent to both R and R is optionally substituted by R YO is selected from the group consisting of: 253 WO 00/69832 PCT/USOO/09806 1-Qb 4-Q-2-R1 -3-R 1-5-R 18-6-R 19benzene, 2-Q b5-Q s-6-R -4-R 18-2-R 9pyridine, 3-Q s6-Qs-2-R16-5-R 18-4-R 19pyridine, 2-Qb s4-Q-3-R16-6-R 18pyrazine, 3 Qb -6-Qs-2-R 18-5-R 18-4-R 19pyridazine, 5 2-Q -5-Qs-6-R 17-4-R 18pyrimidine, 5-Q -2-Qs-3-R 16-6-R 19pyrimidine, 3-Q s5-Q -4-R 16-2-R 19thiophene, 2-Q s5-Q 5 -3-R 16-4-R thiophene, b s 16 19 b s 16 17 3-Q -5-Q -4-R -2-R furan, 2-Q -5-Q s-3-R -4-R furan, 3-Q -5-Q s-4-R 16-2-R 19pyrrole, 2-Q -5-Q s-3-R 16-4-R 17pyrrole, 4-Q -2-Q s-5-R 19imidazole, 2-Qb -4-Qs-5-R 17imidazole, 10 3-Q -5-Q s-4-R 16isoxazole, 5-Q -3-Qs-4-RI6 isoxazole, 2-Q b-5-Q s-4-R 16pyrazole, 4-Q -2-Qs-5-R 9thiazole, and b s 17 2-Q b5-Q -4-R thiazole; 16 17 18 19 R , R , R , and R are independently selected from the group consisting of hydrido, methyl, ethyl, isopropyl, propyl, carboxy, amidino, 15 guanidino, methoxy, ethoxy, isopropoxy, propoxy, 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, 2,2,3,3,3-pentafluoropropyl, 20 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, and cyano; R16 and R19 are optionally Qb with the proviso that no more than one of 25 R16 and R19 isQb at the same time and that Qb is Qbe 254 WO 00/69832 PCT/USOO/09806 Qb is selected from the group consisting of Qbe wherein Q is hydride 25 232 23 24d and C(NR25 )N23R24, with the proviso that no more than one of R and R24 is hydroxy at the same time; R , R 24, and R25 are independently selected from the group consisting of 5 hydrido, methyl, ethyl, and hydroxy; Q is selected from the group consisting of a single covalent bond, CH 2 and CH 2 CH 2 .

27. The compound as recited in Claim 26 or a pharmaceutically acceptable salt 10 thereof, 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-3-yl,and bicyclo[3.1.0]hexan-6-yl; A is selected from the group consisting of single covalent bond, CH 2 , 15 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, 20 trifluoromethoxy, fluoro, and chloro; R 2 is ZO-Q; ZO is selected from the group consisting of a covalent single bond, 0, S, NH, and CH 2 ; Q is selected from the group consisting of 5-amino-3 25 amidocarbonylphenyl, 5-amino-2-fluorophenyl, 3-amino-5 hydroxymethylphenyl, 5-amino-3-methoxycarbonylphenyl, 3-amidinophenyl, 3-amino-2-methylphenyl, 5-amino-2-methylthiophenyl, 3-aiinophenyl, benzyl, 3-carboxyphenyl, 3 -carboxy-5-aminophenyl, 3-carboxy-5 hydroxyphenyl, 3 -carboxymethyl-5-aminophenyl, 3-carboxymethyl-5 255 WO 00/69832 PCT/USOO/09806 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 5 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; 10 Y is selected from the group consisting of: b s 16 17 18 19 1-Q 4-Q -2-R -3-R -5-R -6-R benzene, b s 17 18 19 2-Q b5-Q -6-R -4-R -2-R pyridine, b s2R 16 18 19 3-Q -2-R1-5--R -4-R pyridine, b s 16 19 b s 16 17 3-Q -5-Qs-4-R -2-R thiophene, and 2-Q -5-Q -3-R -4-R thiophene; 15 R16 and R19 are independently selected from the group consisting of hydrido, amidino, amino, aminomethyl, methoxy, methylamino, hydroxy, hydroxymethyl, fluoro, chloro, and cyano; R16 and R 9 are optionally Qb with the proviso that no more than one of R16 and R19 isQb at the same time and that Qb be 20 R17 and R18 are independently selected from the group consisting of hydrido, fluoro, chloro, hydroxy, hydroxymethyl, amino, carboxy, and cyano; Qb is selected from the group consisting of Qbe wherein Qbe is hydrido and C(NR25 )NR23 R 23 24 25 R , R , and R are independently selected from the group consisting of 25 hydrido and methyl; Qs is CH2. 256 WO 00/69832 PCT/USOO/09806

28. The compound as recited in Claim 25 having the Formula: R R 2 N B NN H H 0 or a pharmaceutically acceptable salt thereof, wherein; B is selected from the group consisting of C3-C7 cycloalkyl and C4 5 saturated heterocyclyl, wherein each ring carbon is optionally substituted with 33 R3, a ring carbon other than the ring carbon at the point of attachment of B to A is optionally substituted with oxo provided that no more than one ring carbon is substituted by oxo at the same time, ring carbons and a nitrogen adjacent to the carbon atom at the point of attachment is optionally substituted with R9 or 10 R13, a rng carbon or nitrogen adjacent to the R9 position and two atoms from 10 the point of attachment is optionally substituted with R , a ring carbon or 13) nitrogen adjacent to the R13 position and two atoms from the point of 12 attachment is optionally substituted with R , a ring carbon three atoms from the point of attachment and adjacent to the R10 position is optionally 11 15 substituted with R , a ring carbon three atoms from the point of attachment and adjacent to the R12 position is optionally substituted with R 33, and a ring carbon four atoms from the point of attachment and adjacent to the R and R33 positions is optionally substituted with R34 9 11 13 R , R , and R are independently selected from the group 20 consisting of hydrido, hydroxy, amino, amidino, guanidino, lower 257 WO 00/69832 PCT/USOO/09806 alkylamino, alkylthio, alkoxy, alkylsulfinyl, alkylsulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboxy, carboxamido, and cyano; R10 and R12 are independently selected from the group consisting of 5 hydrido, acetamido, haloacetamido, amidino, guanidino, alkyl, alkoxy, alkoxyamino, aminoalkyl, hydroxy, amino, lower alkylamino, alkylsulfonamido, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, hydroxyalkyl, aminoalkyl, halo, haloalkyl, carboalkoxy, carboxy, carboxyalkyl, carboxyamido, and cyano; 10 R33 and R34 are independently selected from the group consisting of hydrido, amidino, guanidino, alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, alkylthio, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboalkoxy, carboxy, carboxamido, and cyano; 15 R33 is optionally Qb A is selected from the group consisting of single covalent bond and (CH(R 15))pa-(W )rr wherein rr is an integer selected from 0 through 1, pa is an integer selected from 0 through 3, and W is N(R ); Ris selected from the group consisting of hydride and alkyl; 20 R 15 is selected from the group consisting of hydrido, halo, alkyl, and haloalkyl; M is selected from the group consisting of N and R -C; R is selected from the group consisting of hydrido, hydroxy, hydroxyamino, amidino, amino, cyano, hydroxyalkyl, alkoxy, alkyl, 25 alkylamino, arninoalkyl, alkylthio, alkoxyamino, haloalkyl, haloalkoxy, and halo; R 2 is Z-Q; ZO is a covalent single bond; 258 WO 00/69832 PCT/USOO/09806 Q is selected from the group consisting of aryl and heteroaryl wherein a carbon adjacent to the carbon at the point of attachment is optionally substituted 9 by R , the other carbon adjacent to the carbon at the point of attachment is 13 9 optionally substituted by R , a carbon adjacent to R and two atoms from the 10 5 carbon at the point of attachment is optionally substituted by R , a carbon adjacent to R13 and two atoms from the carbon at the point of attachment is 12 10 12 optionally substituted by R1, and any carbon adjacent to both R and R is optionally substituted by R 9 11 13 R , R , and R are independently selected from the group 10 consisting of hydrido, hydroxy, amino, amidino, guanidino, lower alkylamino, alkylthio, alkoxy, alkylsulfinyl, alkylsulfonyl, amidosulfonyl, monoalkylamidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboxy, carboxamido, and cyano; R10 and R12 are independently selected from the group consisting of 15 hydrido, acetamido, haloacetamido, amidino, guanidino, alkyl, alkoxy, alkoxyamino, aminoalkyl, hydroxy, amino, lower alkylamino, alkylsulfonamido, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, hydroxyalkyl, aminoalkyl, halo, haloalkyl, carboalkoxy, carboxy, carboxyamido, carboxyalkyl, and cyano; 20 YO is formula (IV): S R 1 7 R 1 8 17 1 8 R 16 D K2 R 19 lb Q (IV) 259 WO 00/69832 PCT/USOO/09806 5 65 6 wherein D , D , J , and J are independently selected from the group consisting of C, N, 0, S and a covalent bond with the provisos that no more 2. 5 65 6 than one is a covalent bond, K is C, no more than one of , D , and J 5 65 6 5 65 6 is 0, no more than one of D5, D , ,and J s S, one of D D , and J 5 65 6 5 must be a covalent bond when two of D , D , J ,and J are 0 and S, and no 5 65 6 more than four of D , D , J , and J are N; 16 17 18 19 R , R , R , and R are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, haloalkylthio, alkoxy, hydroxy, amino, lower alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, 10 alkanoyl, haloalkanoyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, and cyano; R16 and R19 are optionally Qb with the proviso that no more than one of R16 and R19 is Qb at the same time and that Qb s Qbe b 20 21 be be Q is selected from the group consisting of NR R , Q wherein Q is 25 224 15 hydrido, and C(NR )NR23R24 20 21 23 24 25 R , R , R , R , and R are independently selected from the group consisting of hydrido and alkyl; Qs is CH 2 20 29. The compound as recited in Claim 28 or a pharmaceutically acceptable salt thereof, 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-3-yl, and bicyclo[3.1.0]hexan-6-yl, 25 wherein each ring carbon is optionally substituted with R 33, ring carbons and a nitrogen atoadjacent to the carbon atom at the point of attachment is optionally 260 WO 00/69832 PCT/USOO/09806 substituted with R or R 13 , a ring carbon or nitrogen adjacent to the R position and two atoms from the point of attachment is optionally substituted 10 13 with R , and a ring carbon or nitrogen adjacent to the R13 position and two atoms from the point of attachment is optionally substituted with R12 9 11 13 5 R , R , and R are independently selected from the group consisting of hydrido, methyl, ethyl, methoxy, ethoxy, hydroxy, amino, N-methylamino, N,N-dimethylamino, methylthio, trifluoromethyl, pentafluoroethyl, 2,2,2 trifluoroethyl, fluoro, chloro, bromo, amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, amidocarbonyl, 10 N-methylamidocarbonyl, carboxy, and cyano; R10 and R12 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, 15 pentafluoroethyl, 2,2,2-trifluoroethyl, trifluoroacetamido, aminomethyl, N methylamino, dimethylamino, amidosulfonyl, N-methylamidosulfonyl, N,N dimethylamidosulfonyl, methoxycarbonyl, fluoro, chloro, bromo, and cyano; R33 are independently selected from the group consisting of hydrido, amidino, guanidino, methyl, ethyl, methoxy, ethoxy, hydroxy, carboxy, 20 amino, N-methylamino, dimethylamino, methylthio, ethylthio, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, fluoro, chloro, bromo, amidosulfonyl, N-methylamidosulfonyl, hydroxymethyl, amidocarbonyl, cyano, and Qb A is selected from the group consisting of single covalent bond, NH, N(CH 3 ), CH 2 , CH 3 CH, CH 2 CH 2 , and CH 2 CH 2 CH 2 ; 25 M is selected from the group consisting of N and R -C; R 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; 261 WO 00/69832 PCT/USOO/09806 R2 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 a carbon adjacent to the carbon at the point of attachment is optionally 9 substituted by R , the other carbon adjacent to the carbon at the point of 13 9 5 attachment is optionally substituted by R , a carbon adjacent to R and two atoms from the carbon at the point of attachment is optionally substituted by 10 13 R , a carbon adjacent to R and two atoms from the carbon at the point of 12 attachment is optionally substituted by R , and any carbon adjacent to both R 0 and R12 is optionally substituted by RI ; 10 Y is selected from the group consisting of: b s 16 17 18 19 1-Q 4-Q -2-R -3-R -5-R -6-R benzene, b s 17 18 19 b s 16 17 2-Q b5-Q -6-R -4-R -2-R pyridine, 2-Q -5-Q -3-R -4-R thiophene, b s 16 18 19 b s 16 19 3-Q -6-Q -2-R -5-R -4-R pyridine, 3-Q 5-Q -4-R -2-R thiophene, b s 16 19 b s 16 17 3-Q s5-Qs-4-R -2-R furan, 2-Q -5-Q -3-R -4-R furan, b s 16 19 b s 16 17 15 3-Q b5-Q 4-R -2-R pyrrole, 2-Q -5-Q -3-R -4-R pyrrole, 4-Q -2-Q s-5-R 19thiazole, and 2-Q s5-Q 17 thiazole; 16 17 18 19 R , R , R , and R are independently selected from the group consisting of hydrido, methyl, ethyl, amidino, guanidino, methoxy, hydroxy, amino, aminomethyl, 1-aminoethyl, 2-aminoethyl, N-methylamino, 20 dimethylamino, methylthio, ethylthio, trifluoromethylthio, methylsulfinyl, methylsulfonyl, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, trifluoromethoxy, fluoro, chloro, amidosulfonyl, N-methylamidosulfonyl, hydroxymethyl, carboxy, and cyano. 262 WO 00/69832 PCT/USOO/09806 b 20 R21 -n Q is selected from the group consisting of NR2R2and 25 23 24 b C(NR )NR R2, with the proviso that said Q group is bonded directly to a carbon atom; 20 21 23 24 25 R2, R2, R , R , and R are independently selected from the group 5 consisting of hydrido, methyl, and ethyl; Qs is CH2

30. The compound as recited in Claim 29 or a pharmaceutically acceptable salt thereof, wherein; 10 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 , NHC(O), CH 2 CH 2 and CH 2 CH 2 CH 2 ; 15 M is selected from the group consisting of N and R -C; R is selected from the group consisting of hydrido, hydroxy, amino, methyl, trifluoromethyl, fluoro, and chloro; R2 is selected from the group consisting of 3-aminophenyl, 2,6 00 dichlorophenyl, 2-hydroxyphenyl, 5-amino-2-thienyl, and 3-thienyl; 20 YO is selected from the group consisting of: 1-Qb 4-Q s-2-R 16-3-R 17-5-R 18-6-R 19benzene, b s 16 19 b s 16 17 3-Q -5-Qs-4-R -2-R thiophene, and 2-Q b5-Q -3-R -4-R thiophene; R16 and R19 are independently selected from the group consisting of hydrido, amidino, amino, aminomethyl, methoxy, methylamino, hydroxy, 25 hydroxymethyl, fluoro, chloro, and cyano; R16 and R19 are optionally Qb with the proviso that no more than one of R16 and R19 is Qb at the same time and that Qb be 263 WO 00/69832 PCT/USOO/09806 R17 and R18 are independently selected from the group consisting of hydrido, fluoro, chloro, hydroxy, hydroxymethyl, amino, carboxy, and cyano; Qb is selected from the group consisting of Qbe wherein Qbe is hydrido and C(NR25 23R24 23 24 25 5 R , R , and R are independently selected from the group consisting of hydrido and methyl; QS is CH 2 31. The compound as recited in Claim 30 or a pharmaceutically acceptable salt 10 thereof, 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, 15 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 is selected from the group consisting of hydrido, fluoro, and chloro; R2 is selected from the group consisting of 3-aminophenyl, 2,6 20 dichlorophenyl, 2-hydroxyhenyl, phenyl, 5-amino-2-thienyl, and 3-thienyl; Y is selected from the group consisting of 5-anidino-2-thienylmethyl, 4-amidinobenzyl, 2 -fluoro-4-amidinobenzyl, and 3-fluoro-4-amdinobenzyl.

32. A compound as recited in Claim 25 where said compound is selected from 25 the group having the Formula: 264 WO 00/69832 PCT/USOO/09806 R2 A NNN Y B N N H H 0 or a pharmaceutically acceptable salt thereof, wherein: R is 3-aminophenyl, B is cycylopropyl, A is single bond, Y is 4 amidinobenzyl, and M is CH; 5 R2 is 3-aminophenyl, B is cyclobutyl, A is single bond, Y 0 is 4-amidino-2 fluorobenzyl, and M is CH; R2 is 3-aminophenyl, B is cyclobutyl, A is single bond, Y 0 is 4 amidinobenzyl, and M is CH; R2 is 3 -aminophenyl, B is cyclopropyl, A is single bond, Y 0 is 4-amidino 10 2-fluorobenzyl, and M is CH; R2 is 3-aminophenyl, B is cyclobutyl, A is single bond, Y 0 is 4 amidinobenzyl, and M is CH; R2 is 3-aminophenyl, B is cyclobutyl, A is single bond, Y 0 is 4-amidino-3 fluorobenzyl, and M is CH; 15 R2 is 3-aminophenyl, B is cyclopentyl, A is single bond, Y 0 is 4 amidinobenzyl, and M is CH; R2 is 5-amino-2-thienyl, B is cyclobutyl, A is single bond, Y 0 is 4 amidinobenzyl, and M is CH; R2 is 3 -aminophenyl, B is cyclopropyl, A is CH 2 , Y 0 is 4-amidinobenzyl, 20 and M is CH; R2 is 3-aminophenyl, B is 2 -(2R)-bicyclo[2.2.1]-heptyl, A is single bond, Y is 4-amidinobenzyl, and M is CH; R2 is 3-aminophenyl, B is cyclopentyl, A is single bond, Y 0 is 4-amidino 2-fluorobenzyl, and M is CH; 265 WO 00/69832 PCT/USOO/09806 R2 is 3-aminophenyl, B is cyclohexyl, A is CH 2 CH 2 , Y 0 is 4 amidinobenzyl, and M is CH; R2 is 2-hydroxyphenyl, B is cyclobutyl, A is single bond, Yis 4 amidinobenzyl, and M is CH; 5 R is phenyl, B is cyclobutyl, A is single bond, Y is 4-amidinobenzyl, and M is CH; R2 is 3-thienyl, B is cyclobutyl, A is single bond, Y 0 is 4 amidinobenzyl, and M is CH; R2 is 2,6-dichlorophenyl, B is cyclobutyl, A is single bond, Yis 4 10 amidinobenzyl, and M is CH; R2 is 3-aminophenyl, B is cycylopropyl, A is single bond, Yis 4 amidinobenzyl, and M is N; R2 is 3-aminophenyl, B is cyclobutyl, A is single bond, Y 0 is 4-amidino-2 fluorobenzyl, and M is N; 15 R2 is 3-aminophenyl, B is cyclobutyl, A is single bond, Yis 4 amidinobenzyl, and M is N; R2 is 3-aninophenyl, 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 0 is 4 20 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 0 is 4 amidinobenzyl, and M is N; 25 R2 is 5-amino-2-thienyl, B is cyclobutyl, A is single bond, Yis 4 amidinobenzyl, and M is N; R2 is 3-aminophenyl, B is cyclopropyl, A is CH 2 , Y 0 is 4-amidinobenzyl, and M is N; 266 WO 00/69832 PCT/USOO/09806 is 3-aminophenyl, B is 2-(2R)-bicyclo[2.2.1]-heptyl, A is single bond, Y0 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; 5 R2 is 3-aminophenyl, B is cyclohexyl, A is CH 2 CH 2 , Y 0 is 4 amidinobenzyl, and M is N; R2 is 2-hydroxyphenyl, B is cyclobutyl, A is single bond, Y 0 is 4 amidinobenzyl, and M is N; R2 is phenyl, B is cyclobutyl, A is single bond, Y 0 is 4-amidinobenzyl, 10 and M is N; R2 is 3-thienyl, B is cyclobutyl, A is single bond, Y 0 is 4 amidinobenzyl, and M is N; R2 is 2,6-dichlorophenyl, B is cyclobutyl, A is single bond, Y is 4 amidinobenzyl, and M is N; 15 R2 is 3-aminophenyl, B is cycylopropyl, A is single bond, Yis 4 amidinobenzyl, and M is CF; R2 is 3-aminophenyl, B is cyclobutyl, 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, Yis 4 20 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 0 is 4 amidinobenzyl, and M is CF; 25 R2 is 3-aminophenyl, B is cyclobutyl, A is single bond, Y is 4-amidino-3 fluorobenzyl, and M is CF; R2 is 3-aminophenyl, B is cyclopentyl, A is single bond, Y 0 is 4 amidinobenzyl, and M is CF; 267 WO 00/69832 PCT/USOO/09806 0 R2 is 5-amino-2-thienyl, B is cyclobutyl, A is single bond. Y is 4 amidinobenzyl, and M is CF; R2 is 3-arminophenyl, B is cyclopropyl, A is CH 2 , Y 0 is 4-amidinobenzyl, and M is CF; 5 R2 is 3-aminophenyl, B is 2-(2R)-bicyclo[2.2.l]-heptyl, A is single bond, yo is 4-amidinobenzyl, and M is CF; R 2 is 3-aminophenyl, B is cyclopentyl. A is single bond, Y 0 is 4-amidino 2-fluorobenzyl, and M is CF; R 2 is 3-arinophenyl, B is cyclohexyl, A is CH 2 CH 2 , Y 0 is 4 10 amidinobenzyl, and M is CF; R 2 is 2-hydroxyphenyl, B is cyclobutyl, A is single bond, YO is 4 amidinobenzyl, and M is CF; R2 is phenyl, B is cyclobutyl, A is single bond. Y 0 is 4-amidinobenzyl, and M is CF; 15 R2 is 3-thienyl, B is cyclobutyl, A is single bond, Y is 4 amidinobenzyl, and M is CF; R2 is 2,6-dichlorophenyl, B is cyclobutyl, A is single bond. Y is 4 amidinobenzyl, and M is CF. 20 33. The compound having the Formula 2 0 N E AT or a pharmaccutically acceptable salt thereof, wherein; B is the Formula: 268 WO 00/69832 PCT/USOO/09806 R 3 4 RR R 33R3 5 R 32R3 32 33 34 35 36 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, 5 alkoxyamino, haloalkanoyl, nitro, lower alkylamino, alkylthio, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, alkylsulfonamido, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, alkyl, alkenyl, halo, haloalkyl, haloalkenyl, haloalkoxy, hydroxyalkyl, alkylamino, carboalkoxy, carboxy, carboxamido, cyano, and Qb; 10 B is optionally selected from the group consisting of hydrido, trialkylsilyl, C2-C8 alkyl, C3-C8 alkylenyl, C3-C8 alkenyl, C3-C8 alkynyl, and C2-C8 haloalkyl, wherein each member of group B is optionally substituted at any carbon up to and including 6 atoms from the point of attachment of B to A with one or more of the group consisting of R32, R33 34 35 36 15 R , R ,and R ; B is optionally selected from the group consisting of C3-C12 cycloalkyl and C4-C saturated heterocyclyl, wherein each ring carbon is optionally substituted with R 33, a ring carbon other than the ring carbon at the point of attachment of B to A is optionally substituted with oxo provided that 20 no more than one ring carbon is substituted by oxo at the same time, ring carbons and a nitrogen adjacent to the carbon atom at the point of attachment are optionally substituted with R9 or R 13, a ring carbon or nitrogen adjacent to the R9 position and two atoms from the point of attachment is optionally 269 WO 00/69832 PCT/USOO/09806 substituted with R 10, a ring carbon or nitrogen adjacent to the R position 12 and two atoms from the point of attachment is optionally substituted with R a ring carbon three atoms from the point of attachment and adjacent to the R10 position is optionally substituted with R , a ring carbon three atoms from the 5 point of attachment and adjacent to the R12 position is optionally substituted with R33, and a ring carbon four atoms from the point of attachment and adjacent to the R and R33 positions is optionally substituted with R34 9 10 11 12 13 R , R , R , R , and R are independently selected from the group consisting of hydrido, acetamido, haloacetamido, alkoxyamino, 10 alkanoyl, haloalkanoyl, amidino, guanidino, alkylenedioxy, haloalkylthio, alkoxy, hydroxy, amino, lower alkylamino, alkylthio, alkylsulfinyl, alkylsulfamido, alkylsulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, carboalkoxy, carboxy, carboxyalkyl, carboxamido, and cyano; 15 A is selected from the group consisting of single covalent bond and 15 7 (CH(R ))pa-(W )rr wherein rr is an integer selected from 0 through 1, pa is 7 an integer selected from 0 through 3, and W is selected from the group consisting of 0, S, C(O), (R )NC(0), (R )NC(S), and N(R ); R 7is selected from the group consisting of hydride, hydroxy and alkyl; 20 R15 is selected from the group consisting of hydrido, hydroxy, halo, alkyl, and haloalkyl; M is selected from the group consisting of N and R I-C; R is selected from the group consisting of hydrido, hydroxy, hydroxyamino, amidino, amino, cyano, hydroxyalkyl, alkoxy, alkyl, 25 alkylamino, aminoalkyl, alkylthio, alkoxyamino, haloalkyl, haloalkoxy, and halo; 270 WO 00/69832 PCT/USOO/09806 R 2 is Z 0 -Q; Z is selected from the group consisting of covalent single bond and (CR 4R 42)q wherein q is an integer selected from I through 2, (CH(R 41 W'-(CH(R 42)) wherein g and p are integers independently selected from 0 5 through 3 and WO is selected from the group consisting of 0, S, and N(R 41) and (CH(R 4 1 ))e-W 22 -(CH(R 42))h wherein e and h are integers independently selected from 0 through 1 and 2s selected from the group consisting of 41 42 CR =CR , 1,2-cyclopropyl, 1,2-cyclobutyl, 1,2-cyclohexyl, 1,3 cyclohexyl, 1,2-cyclopentyl, 1,3-cyclopentyl, 2,3-morpholinyl, 2,4 10 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 15 tetrahydrofuranyl, 2 ,5-tetrahydrofuranyl, and 3,4-tetrahydrofuranyl, with the proviso that ZU is directly bonded to the pyrazinone ring; R41 and R42 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 20 Z is other than a covalent single bond, aryl and heteroaryl, wherein a carbon adjacent to the carbon at the point of attachment is optionally substituted by R 9 the other carbon adjacent to the carbon at the point of attachment is optionally 13 9 substituted by R , a carbon adjacent to R and two atoms from the carbon at 10 the point of attachment is optionally substituted by R , a carbon adjacent to -13 25 R and two atoms from the carbon at the point of attachment is optionally 271 WO 00/69832 PCT/USOO/09806 12 10 12 substituted by R1, and any carbon adjacent to both R and R is optionally substituted by R K is CHR4a wherein R is selected from the group consisting of hydrido, hydroxyalkyl, alkyl, alkoxyalkyl, alkylthioalkyl, and haloalkyl; 5 EO is selected from the group consisting of a covalent single bond, 7 C7 C(O)N(H), (H)NC(O), (R )NS(O) 2 , and S(O) 2 N(R ); Y isQb s; Qs is (CR37 R 38)b wherein b is an integer selected from 1 through 4, R37 s selected from the group consisting of hydride, alkyl, and haloalkyl, and 10 R38 is selected from the group consisting of hydrido, alkyl, haloalkyl, aroyl, and heteroaroyl with the provisos that there is at least one aroyl or heteroaroyl substituent, that no more than one aroyl or heteroaroyl is bonded to (CR 37R 38)b at the same time, that said aroyl and said heteroaroyl are optionally substituted at from one through three of the ring carbons with a 16 17 18 19 15 substituent selected from the group consisting of R , R , R , and R that said aroyl and said heteroaroyl are bonded to the CR37R38 that is directly bonded to E0, that is no more than one alkyl or one haloalkyl is bonded to a CR37R38 at the same time, and that said alkyl and haloalkyl are bonded to a carbon other than the one bonding the aroyl or heteroaroyl; 16 17 18 19 20 R , R , R , and R 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, hydroxyalkyl, aminoalkyl, and cyano; 272 WO 00/69832 PCT/USOO/09806 R 16 and R 9 are optionally Qb with the proviso that no more than one of R16 and R19 is Qb at the same time and that Qb isQbe Qb is selected from the group consisting of NR20R21 be wherein Q beis 26 25 23 24 25 23 24 hydrido, N(R )C(NR )N(R )(R ), and C(NR )NR R , with the 5 provisos that no more than one of R20 and R21 is hydroxy, amino, alkylamino, or dialkylamino at the same time and that no more than one of R and R24 is hydroxy, amino, alkylamino, or dialkylamino at the same time; 20 21 23 24 25 26 R2, R2, R , R , R , and R are independently selected from the group consisting of hydrido, alkyl, hydroxy, amino, alkylamino and 10 dialkylamino.

34. The compound as recited in Claim 33 having the Formula: 0 'N R 2 0 y B" A N N N AT H H 0 or a pharmaceutically acceptable salt thereof, wherein; 15 B is the Formula: R R 3R35 R 3)R 3 273 WO 00/69832 PCT/USOO/09806 32 33 34 35 36 R3, 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, 5 chloro, bromo, amidosulfonyl, N-methylamidosulfonyl, hydroxymethyl, amidocarbonyl, carboxy, cyano, and Qb; B is optionally selected from the group consisting of hydrido, ethyl, 2 propenyl, 2-propynyl, propyl, isopropyl, butyl, 2-butenyl, 2-butynyl, sec butyl, tert-butyl, isobutyl, 2-methylpropenyl, 1-pentyl, 2-pentenyl, 3-pentenyl, 10 2-pentynyl, 3-pentynyl, 2-pentyl, 3-pentyl, 2-methylbutyl, 2-methyl-2 butenyl, 3-methylbutyl, 3-methyl-2-butenyl, 1-hexyl, 2-hexenyl, 3-hexenyl, 4 hexenyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 2-hexyl, 1-methyl-2-pentenyl, 1 methyl-3-pentenyl, 1-methyl-2-pentynyl, 1-methyl-3-pentynyl, 3-hexyl, 1 ethyl-2-butenyl, 1-heptyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 2 15 heptynyl, 3-heptynyl, 4-heptynyl, 5-heptynyl, 2-heptyl, 1-methyl-2-hexenyl, 1-methyl-3-hexenyl, 1-methyl-4-hexenyl, 1-methyl-2-hexynyl, 1-methyl-3 hexynyl, 1-methyl-4-hexynyl, 3-heptyl, 1-ethyl-2-pentenyl, 1-ethyl-3 pentenyl, I -ethyl-2-pentynyl, 1-ethyl-3-pentynyl, 2,2,2-trifluoroethyl, 2,2 difluoropropyl, 4 -trifluoromethyl-5,5,5-trifluoropentyl, 4 20 trifluoromethylpentyl, 5,5,6,6,6-pentafluorohexyl, and 3,3,3-trifluoropropyl, wherein each member of group B is optionally substituted at any carbon up to and including 5 atoms from the point of attachment of B to A with one or more 32 33 34 35 36 of the group consisting of R , R , R , R , and R B is optionally selected from the group consisting of cyclopropyl, 25 cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 2-(2R)-bicyclo[2.2.1] heptyl, oxetan-3-yl, azetidin-1-yl, azetidin-2-yl, azetidin-3-yl, and bicyclo[3. 1.Olhexan-6-yl, wherein each ring carbon is optionally substituted with R 33, ring carbons and anitrogen adjacent to the carbon atom at the point 9 13 of attachment is optionally substituted with R or R , a ring carbon or 30 nitrogen adjacent to the R position and two atoms from the point of attachment 10 is optionally substituted with R , and a ring carbon or nitrogen adjacent to the 274 WO 00/69832 PCT/USOO/09806 13 R position and two atoms from the point of attachment is optionally 12 substituted with R ; R 9, R , and R13 are independently selected from the group consisting of hydrido, methyl, ethyl, methoxy, ethoxy, hydroxy, amino, N-methylamino, 5 N,N-dimethylamino, methylthio, trifluoromethyl, pentafluoroethyl, 2,2.2 trifluoroethyl, fluoro, chloro, bromo, amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylanmlidosulfonyl, hydroxymethyl, 1-hydroxyethyl, amidocarbonyl, N-methylamidocarbonyl, carboxy, and cyano; R10 and R12 are independently selected from the group consisting of 10 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, N,N 15 dimethylamidosulfonyl, methoxycarbonyl, fluoro, chloro, bromo, and cyano; A is selected from the group consisting of 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 -C; R is selected from the group consisting of hydrido, hydroxy, amino, 20 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; 25 R2 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 a carbon adjacent to the carbon at the point of attachment is optionally 9 substituted by R , the other carbon adjacent to the carbon at the point of 13 9 attachment is optionally substituted by R , a carbon adjacent to R and two 30 atoms from the carbon at the point of attachment is optionally substituted by 275 WO 00/69832 PCT/USOO/09806 10 13 R , a carbon adjacent to R and two atoms from the carbon at the point of 12 attachment is optionally substituted by R1, and any carbon adjacent to both .R10 and R12 is optionally substituted by R Y is QbQ s; 5 QS is selected from the group consisting of: C[R 37(benzoyl)](CR 37R38)bl CR37 (2-pyridylcarbonyl])](CR37R38)b, C[R 37(3-pyridylcarbonyl])](CR 37R 38)bl' C[R 37(4-pyridylcarbonyl])](CR 37R38)bl 10 C[R37 (2-thienylcarbonyl])](CR37R38)bl C[R 37(3-thienylcarbonyl])](CR 37R38)b, C[R 37(2-thiazolylcarbonyl])](CR 37R38)b, C[R 37(4-thiazolylcarbonyl])](CR 37R 38)b], and C[R 37(-thiazolylcarbonyl])](CR37R38)b], wherein b is an integer selected 37 38 15 from 1 through 3, R and R are independently selected from the group consisting of hydrido, alkyl, and haloalkyl, with the provisos that said aroyl and said heteroaroyl are optionally substituted at from one through three of the 16 ring carbons with a substituent selected from the group consisting of R 17 18 19 17 18 R , R , and R with the proviso that R and R are optionally 20 substituted at a carbon selected from other than the meta and para carbons relative to the carbonyl of the benzoyl substituent and the heteroaroyl substituent, that said benzoyl and said heteroaroyl are bonded to the carbon directly bonded to amide nitrogen of the 1-(amidocarbonymethylene) group, 276 WO 00/69832 PCT/USOO/09806 and that is no more than one alkyl or one haloalkyl is bonded to a CR 37R38 at the same time; 16 17 18 19 R , R , R , and R are independently selected from the group consisting of hydrido, methyl, ethyl, amidino, guanidino, methoxy, hydroxy, 5 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; 10 Qb is selected from the group consisting of NR20R21 and 25 23 24 b C(NR )NR R2, with the proviso that said Q group is bonded directly to a carbon atom; 20 21 23 24 25 R2, R2, R , R , and R are independently selected from the group consisting of hydrido, methyl, and ethyl. 15

35. The compound as recited in Claim 34 or a pharmaceutically acceptable salt thereof, wherein; B is selected from the group consisting of 2-aminophenyl, 3 aminophenyl, 3-amidinophenyl, 4-amidinophenyl, 3-carboxyphenyl, 3 20 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; 25 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 30 dimethylaminopropyl, 2-cyanoethyl, 6-hydroxyhexyl, 2-hydroxyethyl, 2 amidinoethyl, 2-guanidinoethyl, 3 -guanidinopropyl, 4-guanidinobutyl, 3 hydroxypropyl, 4-hydroxybutyl, 6-cyanohexyl, 2-dimethylaminoethyl, 3 277 WO 00/69832 PCT/USOO/09806 methylbutyl, 2-methylbutyl, (S)-2-methylbutyl, 3-aninopropyl, 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 5 yl, azetidin-1-yl, azetidin-2-yl, an d azetidin-3-yl; A is selected from the group consisting of single covalent bond, CH 2 , CH 3 CH, CH 2 CH 2 , and CH 2 CH 2 CH 2 ; is selected from the group consisting of N and R -C; R is selected from the group consisting of hydrido, hydroxy, amino, 10 amidino, hydroxyamino, aminomethyl, methylamino, cyano, methyl, trifluoromethyl, methoxy, hydroxymethyl, methoxyamino, methylthio, trifluoromethoxy, fluoro, and chloro; R2 is selected from the group consisting of 5-amino-3 amidocarbonylphenyl, 5 -amino-2-fluorophenyl, 3-amino-5 15 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, 20 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, 25 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; yAT isQb -Qs Y" isQbQs Q is selected from the group consisting of: 30 [CH(benzoyl)](CH 2 )b, [CH(2-pyridylcarbonyl)](CH 2 )b, 278 WO 00/69832 PCT/USOO/09806 [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 selected from 1 5 through 3, with the provisos that said aroyl and said heteroaroyl are optionally substituted at from one through three of the ring carbons with a substituent 16 17 18 19 selected from the group consisting of R , R , R , and R with the proviso that R17 and R18 are optionally substituted at a carbon selected from other than the meta and para carbons relative to the carbonyl of the benzoyl 10 substituent and the heteroaroyl substituent, and that said benzoyl and said heteroaroyl substituent are bonded to the carbon directly bonded to amide nitrogen of the 1-(amidocarbonymethylene) group; R16 and R19 are independently selected from the group consisting of hydrido, amidino, amino, aminomethyl, methoxy, methylamino, hydroxy, 15 hydroxymethyl, fluoro, chloro, and cyano; R17 and R18 are independently selected from the group consisting of hydrido, fluoro, chloro, hydroxy, hydroxymethyl, amino, carboxy, and cyano; Qb is C(NR 25)NR R24 23 24 25 R , R , and R are independently selected from the group 20 consisting of hydrido and methyl.

36. The compound as recited in Claim 35 or a pharmaceutically acceptable salt thereof, wherein; B is selected from the group consisting of 3-aminophenyl, 3 25 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, ten-butyl, isobutyl, 1-pentyl, 3-pentyl, 2-methylbutyl, 2,2,2 279 WO 00/69832 PCT/USOO/09806 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 5 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 10 yl, azetidin-I-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 is selected from the group consisting of hydrido, hydroxy, amino, 15 methyl, trifluoromethyl, fluoro, and chloro; R2 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-hydroxyhenyl, 3-hydroxyphenyl, 3 20 methanesulfonylaminophenyl, 3-methoxycarbonylphenyl, 3 dimethylaminophenyl, 3-methylaminophenyl, 2-methylphenyl, 3 methylphenyl, phenyl, 3-pyridyl, 3-trifluoroacetamidophenyl, 3-bromo-2 thienyl, 2-thienyl, and 3-thienyl; Y is selected from the group consisting of 5-guanidino-1-oxo-1-(2 25 thiazolyl)-2-pentyl, 5-guanidino-1-oxo-1-(4-thiazolyl)-2-pentyl, 5-guanidino 1-oxo-1-(5-thiazolyl)-2-pentyl, 5-guanidino-1-oxo-1-(4-amino-2-thiazolyl)-2 pentyl, and 5-guanidino- 1 -oxo- 1 -phenyl-2-pentyl.

37. A compound as recited in Claim 33 where said compound is selected from 30 the group having the Formula: 280 WO 00/69832 PCT/USOO/09806 m 0 R 2 N AT B A N N N H H 0 or a pharmaceutically acceptable salt thereof, wherein: R2 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; 5R2 is phenyl, B is phenyl, A is CH 2 CH 2 , AT is 5-guanidino-1-oxo-1-(2 thiazolyl)-2-pentyl, and M is CH; R2 is benzyl, B is phenyl, A is CH 2 CH 2 , YAT is 5-guanidino-1-oxo-1-(2 thiazolyl)-2-pentyl, and M is CH; R2 is phenyl, B is phenyl, A is CH 2 CH 2 , Y AT is 5-guanidino-1-oxo-1-( 2 10 thiazolyl)-2-pentyl, and M is CH; R2 is benzyl, B is phenyl, A is CH 2 CH 2 , YAT is 5-guanidino-1-oxo-1-(2 thiazolyl)-2-pentyl, and M is CH; R2 is phenyl, B is phenyl, A is CH 2 CH 2 , is 5-guanidino-1-oxo-1-(2 thiazolyl)-2-pentyl, and M is CH; 15 R2 is 3-aminophenyl, B is phenyl, A is CH 2 AT is 5-guanidino-1-oxo-1 (2-thiazolyl)-2-pentyl, and M is CF; is phenyl, B is phenyl, A is CH 2 CH 2 , Y is 5-guanidino-1-oxo-l-(2 thiazolyl)-2-pentyl, and M is CF; R2 is benzyl, B is phenyl, A is CH 2 CH 2 , AT is 5-guanidino-1-oxo-1-(2 20 thiazolyl)-2-pentyl, and M is CF; R2 is phenyl, B is phenyl, A is CH 2 CH 2 , Y is 5-guanidino-1-oxo-1-(2 thiazolyl)-2-pentyl, and M is CF; 281 WO 00/69832 PCT/USOO/09806 R2 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 CF; R2 is phenyl, B is phenyl, A is CH 2 CH 2 , AT is 5-guanidino-1-oxo-1-(2 thiazolyl)-2-pentyl, and M is CF; 5 R2 is 3-aminophenyl, B is phenyl, A is CH 2 , Y is 5-guanidino-1-oxo-I (2-thiazolyl)-2-pentyl, and M is CCl; R2 is phenyl, B is phenyl, A is CH 2 CH 2 , Y is 5-guanidino-1-oxo-1-(2 thiazolyl)-2-pentyl, and M is CCl; R2is benzyl, B is phenyl, A is CH 2 CH 2 , Y is 5-guanidino-1-oxo-1-(2 10 thiazolyl)-2-pentyl, and M is CCI; R is phenyl, B is phenyl, A is CH 2 CH 2 , Y is 5-guanidino-I-oxo-1-(2 thiazolyl)-2-pentyl, and M is CCI; R2 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 CCI; 15 R2 is phenyl, B is phenyl, A is CH 2 CH 2 , Y is 5-guanidino-1-oxo-1-(2 thiazolyl)-2-pentyl, and M is CC1; R2 is 3-aminophenyl, B is phenyl, A is CH 2 Y is 5-guanidino-1-oxo-1 (2-thiazolyl)-2-pentyl, and M isN; R2 is phenyl, B is phenyl, A is CH 2 CH 2 , Y is 5-guanidino-1-oxo-1-(2 20 thiazolyl)-2-pentyl, and M is N; R2 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 N; 2 AT R is phenyl, B is phenyl, A is CH 2 CH 2 , Y is 5-guanidino-1-oxo-1-(2 thiazolyl)-2-pentyl, and M isN; 25 R2 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 N; 282 WO 00/69832 PCT/USOO/09806 R2 is phenyl, B is phenyl, A is CH 2 CH 2 , Y is 5-guanidino-1-oxo-1-(2 thiazolyl)-2-pentyl, and M is N.

38. A composition for inhibiting thrombotic conditions in blood comprising a 5 compound of any one of Claims 8, 16, 24, 32, and 37 and a pharmaceutically acceptable carrier.

39. A composition for inhibiting thrombotic conditions in blood comprising a compound of any one of Claims 1 through 7, Claims 9 through 15, Claims 17 10 through 23, Claims 25 through 31, and Claims 33 through 36 and a pharmaceutically acceptable carrier.

40. A method for inhibiting thrombotic conditions in blood comprising adding to blood a therapeutically effective amount of a composition of any one of 15 Claims 38 and 39.

41. A method for inhibiting formation of blood platelet aggregates in blood comprising adding to blood a therapeutically effective amount of a composition of any one of Claims 38 and 39. 20

42. A method for inhibiting thrombus formation in blood comprising adding to blood a therapeutically effective amount of a composition of any one of Claims 38 and 39. 25 43. A method for treating or preventing venuous thromboembolism and pulmonary embolism in a mammal comprising administering to the mammal a therapeutically effective amount of a composition of any one of Claims 38 and 39. 30 44. A method for treating or preventing deep vein thrombosis in a mammal comprising administering to the mammal a therapeutically effective amount of a composition of of any one of Claims 38 and 39. 283 WO 00/69832 PCT/USOO/09806

45. A method for treating or preventing cardiogenic thromboembolism in a mammal comprising administering to the mammal a therapeutically effective amount of a composition of any one of Claims 38 and 39. 5 46. A method for treating or preventing thromboembolic stroke in humans and other mammals comprising administering to the mammal a therapeutically effective amount of a composition of any one of Claims 38 and 39.

47. A method for treating or preventing thrombosis associated with cancer and 10 cancer chemotherapy in humans and other mammals comprising administering to the mammal a therapeutically effective amount of a composition of any one of Claims 38 and 39.

48. A method for treating or preventing unstable angina in humans and other 15 mammals comprising administering to the mammal a therapeutically effective amount of a composition of any one of Claims 38 and 39.

49. A method for inhibiting thrombus formation in blood comprising adding to blood a therapeutically effective amount of a compound of any one of Claims 1 20 through 37 with a therapeutically effective amount of fibrinogen receptor antagonist.

50. The use of a compound of any one of Claims 1 through 37, or a pharmaceutically acceptable salt thereof, in the manufacture of medicament for 25 inhibiting thrombus formation, treating thrombus formation, or preventing thrombus formation in a mammal. 284