NZ514877A

NZ514877A - Substituted polycyclic aryl and heteroaryl uracils as anticoagulative agents

Info

Publication number: NZ514877A
Application number: NZ514877A
Authority: NZ
Inventors: Michael S South; Darin E Jones; Melvin L Rueppel
Original assignee: Pharmacia Corp
Priority date: 1999-05-19
Filing date: 2000-05-18
Publication date: 2004-10-29
Also published as: CN1152023C; AR043677A1; AU771740B2; UY26157A1; CN1351594A; MXPA01011806A; EP1178971A1; WO2000069833A1; ZA200109338B; AU4972400A; CA2373610A1; PE20010217A1; ZA200400450B; BR0011273A; KR20010113969A; JP2002544263A

Abstract

Substituted polycyclic aryl and heteroaryl uracil compounds useful as inhibitors of serine proteases of the coagulation cascade and compounds, compositions and methods for anticoagulant therapy for the treatment and prevention of a variety of thrombotic conditions including coronary artery and cerebrovascular diseases are disclosed.

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number 514877 K //n (0 WO 00/69833 (J H' ^ U U PCT/US00/08226 substituted polycyclic aryl and heteroaryl uracils as anticoagulative agents 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 uracil compounds that inhibit serine proteases of the coagulation 10 cascade. Background of the Invention Physiological systems control the fluidity of blood in mammals [Majerus, P. W. et al: Anticoagulant, Thrombolytic, and Antiplatelet 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. 1341-1343]. 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,p350]. 30 Coagulation or clotting occurs in two ways through different pathways. An intrinsic or contact pathway leads from XII to XHa 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 Vila by Xa. The presence of Tissue Factor and 1 WO 00/69833 PCT/US00/08226 Vila accelerates formation of Xa in the presence of calcium ion and phospholipids. Foimation 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 2 0 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 uracil compounds that act as an inhibitor of a coagulation factor present in the 25 coagulation cascade or clotting process. 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 in which the amide substituents all have a formyl group and which reportedly have activity against thrombin. In US Patent 5,658,930, Tamura et 30 al. again describe 4,5,6-substituted-3-aminopyridonyl-acetamides, 1,6-substituted-5-aminouracinylacetamides, and 2,4-substituted-5-amino-pyrimidinonylacetamides in which the amide substituents all have a formyl group and which reportedly have activity against thrombin. In PCT Patent Applications 96/18644 and 97/46207, Tamura et al. further describe 4,5,6- 3 5 substituted-3-aminopyridonylacetamides, 1,6-substituted-5-aminouracinyl- 2 WO 00/69833 PCT/US00/O8226 acetamides, and 2,4-substituted-5-amino-pyrimidinonylacetamides in which the amide substituents all have a formyl group and which reportedly have activity against thrombin. SUMMARY OF THE INVENTION It is an object of the present invention to provide compounds that are beneficial in anticoagulant therapy and that have a general structure: ,2 K ' Y Formula (I). In particular, in one aspect, the subject of this specification, the present invention provides a compound having the Formula: or a pharmaceutical acceptable salt thereof, wherein; B is selected from the group consisting of aryl and heteroaryl where: (a) a ring carbon in a first alpha position relative to the ring carbon at the point of attachment is optionally substituted by R32, (b) a ring carbon in a second alpha position relative to the ring carbon at the point of attachment is optionally substituted by R38, (c) a ring carbon, in a first beta position relative to the ring carbon at the point of attachment and in an alpha position relative to the ring atom optionally substituted by R32, is optionally substituted by R33, (d) a ring carbon, in a second beta position relative to the ring carbon at the point of attachment and in an alpha position relative to the ring atom optionally substituted by R36, is optionally substituted by R35, and (e) a ring carbon, if present, in the gamma position relative to the ring carbon at the point of attachment and in an alpha position relative to each of the ring atoms optionally substituted by R33 and R35, respectively, is optionally substituted by R34; where R32, R33, R34, R35, and R38 are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkoxy, hydroxy, amino, (followed by pages 3a-3b) INTELLECTUAL PROPERTY OFFICE OF N.Z. 0 7 iam inn/. alkoxyamino, lower alkylamino, alkylthio, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboalkoxy, carboxy, carboxamido, cyano, and Qb; A is selected from the group consisting of single covalent bond and (CH(R15))pa-(W7)^ where rr is an integer selected from 0 through 1; pa is an integer selected from 0 through 3; W7 is selected from the group consisting of (R7)NC(0) and N(R7); where R7 is selected from the group consisting of hydrido, hydroxy and alkyl; and 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; where R1 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; where Z° is selected from the group consisting of a covalent single bond, O, S, NH, and CH2; and Q is selected from the group consisting of aryl and heteroaryl where; (a) a ring carbon in a first alpha position relative to the ring carbon at the point of attachment is optionally substituted by R9, (b) a ring carbon in a second alpha position relative to the ring carbon at the point of attachment is optionally substituted by R13, (c) a ring carbon, in a first beta position relative to the ring carbon at the point of attachment and in an alpha position relative to the ring atom optionally substituted by R9, is optionally substituted by R10, (d) a ring carbon, in a second beta position relative to the ring carbon at the point of attachment and in an alpha position relative to the ring atom optionally substituted by R13, is optionally substituted by R12, and (e) a ring carbon, if present, in the gamma position relative to the ring carbon at the point of attachment and in an alpha position relative to each of the ring atoms optionally substituted by R10 and R12, respectively, is optionally substituted by R11; where R9, R11, and R13 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; and 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, amidocarbonyl, halo, haloalkyl, and cyano; and Y° is formula (IV): 3a INTELLECTUAL PROPERTY OFFICE OF N.7. 2 3 JAN 2004 'rNQ* (IV) where D5, D6, J5, and J6 are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more than one is a covalent bond, no more than one of D5, D6, J5, and J6 is O, no more than one of D5, D6, J5, and J8 is S, one of D5, D8, J5, and J8 must be a covalent bond when two of Ds, D8, J5, and J8 are O and S, and no more than four of D5, D6, J5, and J8 are N; R16, R17, R18, and R19 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; Qb is selected from the group consisting of NR20R21, hydrido, and C(NR25)NR23R24, with the provisos that no more than one of R20 and R21 is hydroxy and that no more than one of R23 and R24 is hydroxy; where R20, R21, R23, R24, and R25 are independently selected from the group consisting of hydrido, alkyl, and hydroxy; and Qs is selected from the group consisting of a single covalent bond, CH2, and CH2CH2. In another particular aspect, the present invention provides the use of a compound of the present invention, or a pharmaceutical^ acceptable salt thereof, in the manufacture of a medicament: for inhibiting thrombotic conditions in blood; for inhibiting formation of blood platelet aggregates in blood; for inhibiting thrombus formation in blood; for treating or preventing venuous thromboembolism and pulmonary embolism in a mammal in need thereof; for treating or preventing deep vein thrombosis in a mammal in need thereof; for treating or preventing cardiogenic thromboembolism in a mammal in need thereof; (followed by page 3c) 3b for treating or preventing thromboembolic stroke in a mammal in need thereof; for treating or preventing thrombosis associated with cancer and cancer chemotherapy in a mammal in need thereof; for treating or preventing unstable angina in a mammal in need thereof; and for inhibiting thrombus formation, treating thrombus formation, or preventing thrombus formation in a mammal in need thereof. In another aspect, the present invention provides methods for 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). Other aspects of the invention are the subject of New Zealand Patent Specification No. 530652 Various other objects and advantages of the present invention will become apparent from the following description of the invention. DESCRIPTION OF THE INVENTION The present invention relates to a class of compounds comprising Substituted Polycyclic Aryl and Heteroaryl uracils, which are beneficial in anticoagulant therapy for the treatment and prevention of a variety of thrombotic conditions including coronary artery and cerebrovascular disease, as given in Formula (I): 3c INTELLECTUAL PROPERTY OFFICE OF N.Z. 1 0 SEP 2004 RECEIVED WO 00/69833 PCT/US00/08226 or a pharmaceutically acceptable salt thereof, wherein; ci b J and J are independently selected from the group consisting of O and S; 5 J3 is optionally selected from the group consisting of CH-R*' and N-R^ wherein R^ is a linear spacer moiety having from 1 through 4 contiguous atoms linked to the point of bonding of a substituent selected from the group 4a 4b 14 15 39 40 5 consisting ofR , R ,R ,R ,R ,R , and R to form a heterocyclyl ring having 5 through 8 contiguous members; 10 is optionally selected from the group consisting of CH-R^ and N-R^ wherein R^ is a linear spacer moiety having from 1 through 4 contiguous atoms linked to the point of bonding of a substituent selected from the group 4a 4b 14 15 consisting of Rj, R , R , R and R to foirn a heterocyclyl ring having 5 through 8 contiguous members; 3 b 15 J and J are optionally independently selected from the group 4a consisting of CH-R^ and N-R^ wherein R^ is a linear spacer moiety having from 1 through 4 contiguous atoms linked to the points of bonding of both R 4b and R to form a heterocyclyl nng having 5 through 8 contiguous members; Ja is optionally selected from the group consisting of CH-R^ and N-R^ 20 wherein R is a linear spacer moiety having from 1 through 4 contiguous atoms 4 WO 00/69833 PCT/US00/08226 39 40 linked to the points of bonding of both R and R to form a heterocyclyl ring having 5 through 8 contiguous members; B is formula (V): R34 R33\ 1/K^2/R35 Jl J. R 32/D\^°2\r3 6 (V) , . 1 2 T1 ,2 1 . J , , 5 wherein D , D , J , J and K are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more , ^ ¥1 ,2 1 . than one can be a covalent bond, no more than one of D , D , J , J and K is 12 12 1 12 12 O, no more than one of D , D , J , J and K is S, one of D , D , J , J and K1 must be a covalent bond when two of D1, D2, J1, J2 and K1 areOand S, 12 12 1 10 and no more than four of D ,D ,J ,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 sulfur, and the divalent nature of oxygen; 9 10 11 12 13 16 17 18 19 32 33 34 R,R ,R ,R ,R ,R ,R ,R ,R ,R ,R ,R , 35 36 15 R , and R are independently selected from the group consisting of hydndo, acetamido, haloacetamido, amidino, guanidino, dialkylsulfonium, trialkylphosphonium, dialkylsulfoniumalkyl, carboxy, heteroaralkylthio, heteroaralkoxy, cycloalkylamino, acylalkyl, acylalkoxy, aryloylalkoxy, heterocyclyloxy, aralkylaiyl, aralkyl, aralkenyl, aralkynyl, heterocyclyl, 2 0 perhaloaralkyl, aralkylsulfonyl, aralkylsulfonylalkyl, aralkylsulfmyl, aralkylsulfinylalkyl, halocycloalkyl, halocycloalkenyl, cycloalkylsulfinyl, cycloalkylsulfinylalkyl, cycloalkylsulfonyl, cycloalkylsulfonylalkyl, 5 WO 00/69833 PCT/US00/08226 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, arylamino, aralkylamino, arylthio, arylthioalkyl, heteroaralkoxyalkyl, alkylsulfinyl, alkylsulfinylalkyl, arylsulfmylalkyl, arylsulfonylalkyl, heteroarylsulfmylalkyl, 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, haloalkoxy alkyl, aryl, aralkyl, aryloxy, aralkoxy, aryloxyalkyl, saturated lieterocyclyl, 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 di aralkoxyphosphonoalky 1; 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 R^ and R^ is Q*5 at the same time and that Q*5 is Q^e; 32 33 33 34 34 35 35 36 R andR ,R andR ,R and R , and R andR are independently optionally selected to form a spacer pair wherein a spacer pair is WO 00/69833 PCT/US00/08226 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 5 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 36 and R are used at the same time; 9 10 10 11 11 12 12 13 R and R , R and R , R and R , and R and R are 10 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 8 contiguous members, a partially saturated heterocyclyl ring having 5 through 15 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 R , and R 13 , and R are used at the same time; B is optionally formula (VI): ,34 R33 ^3 R32—D3 e \ I P X35 20 ' (VI) 3 4 3 4 wherein D , D , J , and J are independently selected from the group 3 4 3 4 consisting of C, N, O, and S, no more than one of D , D , J , and J is O, no 3434 12 more than one of D , D , J , and J is S, and no more than three of D , D , 7 WO 00/69833 PCT/U S00/08226 1 2 32 33 34 35 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 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 of attachment of B to A with one or more of the group consisting of R32* R33, 10 R34, r35, and R36; B is optionally selected from the group consisting of C3-C15 cycloalkyl, C5-C10 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 15 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 nitrogen adjacent to the carbon atom at the point of attachment are optionally 9 13 R9 substituted with R or R , a ring carbon or nitrogen adjacent to the position and two atoms from the point of attachment is optionally substituted 2 0 with R , a ring carbon or nitrogen adjacent to the R_ position and two atoms 12 from the point of attachment is optionally substituted with R , a ring carbon or nitrogen three atoms from the point of attachment and adjacent to the R^ position is optionally substituted with R^, a ring carbon or nitrogen atom 12 three atoms from the point of attachment and adjacent to the R position is 33 25 optionally substituted with R , and a ring carbon or nitrogen four atoms from 11 33 the point of attachment and adjacent to the R and R positions is optionally substituted with R ; 8 WO 00/69833 PCT/US00/08226 A is selected from the group consisting of single covalent bond, (W^)rr-(CH(R*5))pa and (CH(R^))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 is selected from the group consisting of O, S, C(O), C(S), C(0)S, C(S)0, 5 C(0)N(R?), C(S)N(R7), (R?)NC(0), (R?)NC(S), S(O), S(0)2, S(0)2N(R7), (R7)NS(0)2, Se(O), Se(0)2, Se(0)2N(R7), (R7)NSe(0)2, P(0)(R8), N(R7)P(0)(R8), P(0)(R8)N(R7), C(NR7)N(R7), (R7)NC(NR7), 7 7 7 7 (R )NC(NR )NR , 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; 7 8 10 R and R are independently selected from the group consisting of hydrido, hydroxy, alkyl, alkenyl, aryl, aralkyl, aiyloxy, alkoxy, alkenyloxy, alkylthio, alkylamino, arylthio, arylamino, acyl, aroyl, heteroaroyl, aralkoxyalkyl, heteroaralkoxyalkyl,, aryloxyalkyl, alkoxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, aralkoxyalkyl, 15 heteroaralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, heteroaryl, heteroaryloxy, heteroarylamino, heteroaralkyl, heteroaralkyloxy, heteroaralkylamino, and heteroaryloxyalkyl; 14 15 Jil 38 39 40 41. 42 R ,R ,R ,R ,R ,R , R and R are independently selected from the group consisting of amidino, hydroxyamino, hydrido, 20 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, alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkoxythioalkyl, alkoxyalkyl, 25 heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxyalkyl, saturated heterocyclyl, partially saturated 30 heterocyclyl, heteroaryl, heteroarylalkyl, heteroarylthioalkyl, 9 WO 00/69833 PCT/US00/08226 heteroaralkylthioalkyl, monocarboalkoxyalkyl, dicarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl, carboalkoxycyanoalkyl, alkylsulfinyl, alkylsulfonyl, haloalkylsulfinyl, haloalkylsulfonyl, arylsulfinyl, arylsulfmylalkyl, arylsulfonyl, arylsulfonylalkyl, aralkylsulfinyl, 5 aralkylsulfonyl, cycloalkylsulfinyl, cycloalkylsulfonyl, cycloalkylsulfmylalkyl, cycloalkylsufonylalkyl, heteroarylsulfonylalkyl, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylsulfinylalkyl, aralkylsulfinylalkyl, aralkylsulfonylalkyl, carboxy, carboxyalkyl, carboalkoxy, carboxamide, carboxamidoalkyl, carboaralkoxy, trialkylsilyl, dialkoxypbosphono, 10 diaralkoxyphosphono, dialkoxypbosphonoalkyl, and 37 38 diaralkoxyphosphonoalkyl with the proviso that R and R are independently selected from other than formyl; 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, 15 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 2 0 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 25 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 30 members, and a heterocyclyl having from 5 through 8 contiguous members; 10 WO 00/69833 PCT/US00/08226 V is selected from the group consisting of NR^, O, C(O), C(S), S, 5 8 39 40 S(O), S(0)2, ON(R ), P(0)(R ), and CR R ; 5 R is selected from the group consisting of hydrido, hydroxy, amino, alkyl, alkenyl, alkynyl, aryl, aralkyl, aiyloxy, aralkoxy, alkoxy, alkenyloxy, 5 alkylthio, arylthio, aralkoxyalkyl, heteroaralkoxyalkyl, aryloxyalkyl, alkoxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, aralkoxyalkyl, heteroaralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxyalkyl, 10 haloalkenyloxyalkyl, halocycloalkoxyalkyl, halocycloalkenyloxyalkyl, heteroaryl, heteroarylalkyl, monocarboalkoxyalkyl, monocarboalkoxy, dicarboalkoxyalkyl, monocarboxamido, monocyanoalkyl, dicyanoalkyl, carboalkoxycyanoalkyl, acyl, aroyl, heteroaroyl, heteroaiyloxyalkyl, and dialkoxyphosphonoalkyl; 39 40 15 R and R , when bonded to the same carbon, are optionally taken together to form a group selected from a group consisting of oxo, thiono, R^- 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 2 0 ring having from 3 through 8 contiguous members, and a heterocyclyl ring having from 3 through 8 contiguous members; M is selected from the group consisting of N and R^-C; 2 1. o R and R are independently selected from the group consisting of Z - Q, hydrido, alkyl, alkenyl, and halo; 25 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, arylamino, aralkylamino, alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl, 3 0 heteroaralkanoyl, haloalkanoyl, hydroxyhaloalkyl, cyano, and phosphono; 11 WO 00/69833 PCT/US00/08226 0 R 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, 5 hydroxyhaloalkyl, cyano, and phosphono; R^ and R4a, R^ and R4^, R^ and R14, and R^ and R^ 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 connecting the points of bonding of said spacer pair members to form a 10 heterocyclyl ring having from 5 through 8 contiguous members with the 2 proviso that no more than one of the group of spacer pairs consisting of R and 43 9 4b o 14 0 15 R , R andR , R and R , and R andR is used at the same time; 2 R is optionally independently selected to form a linear moiety having 4a from 2 through 5 contiguous atoms linked to the points of bonding of both R 4b 15 and R to form a heterocyclyl ring having from 5 through 8 contiguous members; Z° is selected from the group consisting of covalent single bond, 41 42 41 (CR R )a wherein q is an integer selected from 1 through 6, (CH(R ))„- 4 & jo 42 W-(CH(R ))p wherein g and p are integers independently selected from 0 20 through 3 and W° is selected from the group consisting of O, S, C(O), C(S), C(0)0, C(S)0, C(0)S, C(S)S, C(0)N(R41), (R41)NC(0), C(S)N(R41), (R41)NC(S), 0C(0)N(R41), (R41)NC(0)0, SC(S)N(R41), (R41)NC(S)S, SC(0)N(R41), (R41)NC(0)S, OC(S)N(R41), (R41)NC(S)0, 42 41 41 42 42 41 N(R )C(0)N(R ), (R )NC(0)N(R ), N(R )C(S)N(R ), 25 (R41)NC(S)N(R42), S(O), S(0)2, S(0)2N(R41), N(R41)S(0)2, Se, Se(0), Se(0)2, Se(0)2N(R41), N(R41)Se(0)2, P(0)(R8), N(R?)P(0)(R8), 12 WO 00/69833 PCT/US00/08226 8 7 41 41 28 29 41 22 P(0)(R )N(R ), N(R ), ON(R ), and SiR R , and (CH(R ))e-\V" - 42 (CH(R ))jj wherein e and h are integers independently selected from 0 22 41 42 through 2 and w* is selected from the group consisting of CR =CR , 41 42 CR R =C; vinylidene), ethynyhdene (CsC; 1,2-ethynyl), 1,2-cyclopropyl, 5 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, 13-piperidinyl, 2,3-piperidinyl, 2,4-piperidinyl, 2,6-piperidinyl, 3,4-piperidiiiyl, 1,2-pyrrolidinyl, 1,3-10 pyrrolidinyl, 23-pyrrolidinyl, 2,4-pyrrolidinyl, 2,5-pyrrolidinyl, 3,4-pyrrolidinyl, 23-tetrahydrofuranyl, 2,4-tetrahydrofuranyl, 2,5- 41 tetrahydrofuranyl, and 3,4-tetrahydrofuranyl, with the provisos that R and 42 R are selected from other than halo and cyano when directly bonded to N and Z° is directly bonded to the uracil ring; 28 29 15 R and R are independently selected from the group consisting of hydrido, hydroxyalkyl, alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, acyl, aroyl, aralkanoyl, heteroaroyl, aralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkylthioalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, 20 cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxyalkyl, haloalkenyloxy alkyl, halocycloalkoxy, halocycloalkoxy alkyl, halocycloalkenyloxyalkyl, perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl, heteroaryl alkyl, heteroarylthioalkyl, heteroaralkylthioalkyl, cyanoalkyl, 25 dicyanoalkyl, carboxamidoalkyl, dicarboxamidoalkyl, cyanocarboalkoxyalkyl, carboalkoxyalkyl, dicarboalkoxyalkyl, cyanocycloalkyl, dicyanocycloalkyl, carboxamidocycloalkyl, dicarboxamidocycloalkyl, carboalkoxy cyanocycloalkyl, carboalkoxycycloalkyl, dicarboalkoxycycloalkyl, formylalkyl, acylalkyl, arylsulfinylalkyl, arylsulfonylalkyl, aralkylsulfmyl, cycloalkylsulfinylalkyl, 30 cycloalkylsufonylalkyl, heteroarylsulfonylalkyl, heteroaiylsulfinylalkyl, 13 WO 00/69833 PCT/US00/08226 aralkylsulfinylalkyl, aralkylsulfonylalkyl, carboxy, dialkoxyphosphono, diaralkoxyphosphono, dialkoxyphosphonoalkyl and diaralkoxyphosphonoalkyl; 28 29 R and R are optionally taken together to form a linear moiety spacer having from 2 through 7 contiguous atoms and forming a ring selected from the 5 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; Q is formula (II): f11 r10\ ,/k1^ 2/r12 J- Jp r9/D\^D\r13 (II) 12 12 1 10 wherein D ,D ,J ,J andK are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more 12 12 1 than one can be a covalent bond, no more than one of D , D , J , J and K 12 12 1 1 can be O, no more than one of D ,D ,J ,J andK can be S, one of D , 2 12 1 12 12 D , J ,J andK must be a covalent bond when two of D ,D ,J ,J and 1 12 12 1 15 K are O and S, and no more than four of D , D , J , J and K can be N, 9 10 11 12 13 with the proviso that 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): 14 WO 00/69833 PCT/US00/08226 R10 \3 /r11 J a' R D\ I m^d v f \r12 ' (HI) 3 4 3 4 wherein D , D , J , and J are independently selected from the group 3 4 3 4. consisting of C, N, O, and S, no more than one of D , D , J , and J is O, no 3 4 3 4 1 2 more than one of D , D , J , and J is S, and no more than three of D , D , 12 9 10 11 12 5 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; Q is optionally selected from the group consisting of hydrido, alkyl, 10 alkoxy, alkylamino, alkylthio, haloalkylthio, alkenyl, alkynyl, saturated heterocyclyl, partially saturated heterocyclyl, acyl, aroyl, heteroaroyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkylalkenyl, haloalkyl, haloalkoxy, haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxyalkyl, and 15 halocycloalkenyloxyalkyl with the proviso that Z° is selected from other than a single covalent bond when Q is hydrido; 4a 4b K is (CR R )n wherein n is an integer selected from 1 through 4; 4a 4b . R and R are independently selected from the group consisting of halo, hydrido, hydroxy, cyano, hydroxyalkyl, alkyl, alkenyl, aryl, aralkyl, 20 aralkoxyalkyl, aiyloxyalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, aralkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, haloalkenyl, heteroaryl, heteroaryl alkyl, heteroaiylthioalkyl, heteroaralkylthioalkyl, cyanoalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, haloalkylsulfinyl, arylsulfinylalkyl, aiylsulfonylalkyl, 25 heteroaiylsulfonylalkyl, heteroarylsulfmylalkyl, aralkylsulfinylalkyl, and 15 WO 00/69833 PCT/US00/08226 aralkylsulfonylalkyl with the provisos that halo, hydroxy, and cyano are 4b bonded to different carbons when simultaneously present and that R and R are other than hydroxy or cyano when bonded to the carbon directly bonded to the uracil nitrogen; 4a 4b 5 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 through 8 contiguous members, a cycloalkenyl ring having 5 through 8 10 contiguous members, and a heterocyclyl ring having 5 through 8 contiguous 4a 4b members with the proviso that R and R taken together is other than oxo or thiono when the common carbon is direcdy bonded to the uracil nitrogen; _o. _1 , Tjr . , 4a 4b . 1 E is E , when K is (CR R )n, wherein E is selected from the group consisting of a covalent single bond, O, S. C(O), C(S), C(0)0, C(S)0, 15 C(0)S, C(S)S, C(0)N(R7), (R7)NC(0), C(S)N(R?), (R?)NC(S), 0C(0)N(R7), (R?)NC(0)0, SC(S)N(R?), (R?)NC(S)S, SC(0)N(R?), (R?)NC(0)S, OC(S)N(R7), (R?)NC(S)0, N(R8)C(0)N(R?), (R7)NC(0)N(R8), N(R8)C(S)N(R7), (R7)NC(S)N(R8>, S(O), S(0)2, S(0)2N(R7), N(R/)S(0)2, S(0)2N(R7)C(0), C(0)N(R7)S(0)2, Se, Se(O), 20 Se(0)2, Se(0)2N(R?), N(R7)Se(0)2, P(0)(R8), N(R7)P(0)(R8), P(0)(R8)N(R7), N(R7), ON(R?), SiR^R29, CR4a=CR4b, ethynylidene /| j /IK (C=C; 1,2-ethynyl), and C=CR R ; 14 K is optionally selected to be (CH(R ))j-T wherein j is selected from a integer from 0 through 3 and T is selected from the group consisting of single 7 14 25 covalent bond, O, S, and N(R ) with the provisos that R is other than 16 WO 00/69833 PCT/USO0/08226 hydroxy, cyano, halo, amino, alkylamino, dialkylamino, and sulfhydryl when 14 j is 1 and that (CH(R ))j is bonded to the uracil ring; E° is optionally E^, when K is (CH(R^))j-T, wherein E^ is selected from the group consisting of a covalent single bond, C(O), C(S), C(0)0, 5 C(S)0, C(0)S, C(S)S, C(0)N(R?), (R7)NC(0), C(S)N(R?), (R?)NC(S), (R7)NC(0)0, (R7)NC(S)S, (R?)NC(0)S, (R?)NC(S)0, N(R8)C(0)N(R7), (R7)NC(0)N(R8), N(R8)C(S)N(R7), (R7)NC(S)N(R8), S(O), S(0)2, S(G)2N(R7), N(R7)S(0)2, S(0)2N(H)C(0), C(0)N(H)S(0)2, Se(0), Se(0)2, Se(0)2N(R?), N(R?)Se(0)2, P(0)(R8), N(R7)P(0)(R8),- 10 P(0)(R8)N(R7), and N(R?); K is optionally selected to be G-(CH(R^))^ wherein k is selected from an integer from 1 through 3 and G is selected from the group consisting of O, 7 15 S, and N(R ) with the proviso that R is other than hydroxy, cyano, halo, amino, alkylamino, dialkylamino, and sulfhydryl when k is 1; o ^ 15 3 15 E is optionally E when K is G-(CH(R ))^ wherein E is selected from the group consisting of a covalent single bond, O, S, C(O), C(S), C(0)0, C(S)0, C(0)S, C(S)S, C(0)N(R?), (R7)NC(0), C(S)N(R?), (R?)NC(S), 0C(0)N(R7), (R?)NC(0)0, SC(S)N(R?), (R7)NC(S)S, SC(0)N(R?), (R?)NC(0)S, OC(S)N(R?), (R?)NC(S)0, N(R8)C(0)N(R7), 20 (R7)NC(0)N(R8), N(R8)C(S)N(R7), (R7)NC(S)N(R8), S(O), S(0)2, S(0)2N(R7), N(R7)S(0)2, Se, Se(0), Se(0)2, Se(0)2N(R?), N(R7)Se(0)2, 8 7 8 8 7 7 7 /ZR 29 P(0)(R ), N(R )P(0)(R ), P(0)(R )N(R ), N(R ), ON(R ), SiR R , CR4a=CR4^, ethynylidene (C=C; 1,2-ethynyl), and ocrv; 17 WO 00/69833 PCT/US00/08226 Y° is formula (IV): 0s 117 1 ^5 j n/1 ^ O R K2 u R18 16/DX,2^D^r19 (IV) 5 6 5 6 wherein D , D , J , and J are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more 2 5 than one is a covalent bond, K is independently selected from the group consisting of C and N+, no more than one of D^, J~*, and is O, no more 565 6 565 6 than one of D , D , J , and J is S, one of D , D , J , and J must be a 5 6 5 6 covalent bond when two of D , D , J , and J are O and S, no more than 5 6 5 6 2 + three of D , D ,J , and J are N when K is N , and no more than four of 5 6 5 6 2. 16 17 10 D ,D ,J ,andJ are N when K is carbon with the provisos that R ,R , ^18 Jr,19 L' , , . . L R , and R are eachandependently 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 R and R are independently optionally taken together to form a 15 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 having from 5 through 8 contiguous members, a heteroaryl having from 5 through 6 contiguous members, and an aryl; 18 19 20 R and R are independently optionally taken together to form a linear moiety spacer having from 3 through 6 contiguous atoms connected to 18 WO 00/69833 PCT/US00/08226 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 5 Q is selected from the group consisting of NR R , + 20 21 22 NR R R , oxy, alkyl, aminoalkylenyl, alkylamino, dialkylamino, dialkylsulfoniumalkyl, acylamino and Q^e wherein Q^e is hydrido and R2^, 21 22 R , and R are independently selected from the group consisting of hydrido, amino, alkyl, hydroxy, alkoxy, aminoalkylenyl,alkylamino, dialkylamino, and 20 21 22. 10 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 K is N ; 20 21 20 22 21 22 R and R , R and R , and R and R are independently 15 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 one of the group consisting of spacer pairs R andR ,R andR , and 21 22 20 R andR is used at the same time; Q is optionally selected from the group consisting of N(R26)S02N(R23)(R24), N(R26)C(0)0R5 N(R26)C(0)SR5, 26 5 26 5 N(R )C(S)OR and N(R )C(S)SR with the proviso that no more than one 23 24 26 of R , R , and R can be hydroxy, alkoxy, alkyleneamino, alkylamino, 19 WO 00/69833 PCT/US00/08226 23 24 amino, or dialkylamino when two of the group consisting of R , R , and 26 R are bonded to the same atom; is optionally selected from the group consisting of 25 23 24 dialkylsulfonium, tiialkylphosphonium, C(NR )NR R , 5 NCR^CCNR25)!^23)^24), N(R26)C(0)N(R23)(R24), N(R26)C(S)N(R23)(R24), C(NR25)OR5, C(0)N(R26)C(NR25)N(R23)(R24), C(S)N(R26)C(NR25)N(R23)(R24), N(R26)N(R26)C(NR25)N(R23)(R24), ON(R26)C(NR25)N(R23XR24), C no <*y A N(R )N(R )S02N(R )(R ),C(NR )SR , C(0)NR R , and 23 24 23 24 26 10 C(0)NR R with the provisos that no more than one of R ,R ,andR 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 b that said Q group is bonded directly to a carbon atom; 23 24 25 26 R , R , R , and R are independently selected from the group 15 consisting of hydrido, alkyl, hydroxy, alkoxy, alkylenylamino, amino, alkylamino, dialkylamino, and hydroxyalkyl; 23 24 R and R 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 20 R andR ,R andR ,R andR ,R andR , and R and 26 R 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 t form the group L-U-V wherein L, U, and V are independently selected from the group consisting of O, S, C(O), C(S), C(JH)2 S(O), S02, OP(OR31)R3°, 20 WO 00/69833 PCT/US00/08226 P(0)R30, P(S)R30, C(R30)R31, C=C(R30)R31, (0)2P0P(0)2, R30(O)POP(O)R30, Si(R29)R28, Si(R29)R28Si(R29)R28, Si(R29)R28OSi(R29)R28, (R28)R29COC(R28)R29, (R28)R29CSC(R28)R29, C(O)C(R30)=C(R31), C(S)C(R30)=C(R31), S(O)C(R30)=C(R31), 30 31 30 30 31 30 30 31 5 S02C(R )=C(R ), PR C(R )=C(R ), P(0)R C(R )=C(R ), 30 30 31 30 31 31 30 30 30 P(S)R C(R )=C(R ), DC(R )(R )D, OP(OR )R , P(0)R , P(S)R , 28 29 30 Si(R )R and N(R ), 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; 10 D is selected from the group consisting of oxygen, C=0, C=S, S(0)m wherein m is an integer selected from 0 through 2; 27 27 JH is independently selected from the group consisting of OR , SR and N(R2°)R21; 27 R is selected from the group consisting of hydrido, alkyl, alkenyl, 15 alkynyl, aralkyl, aryloxyalkyl, aralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkylthioalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxyalkyl, 20 haloalkenyloxyalkyl, halocycloalkoxyalkyl,halocycloalkenyloxyalkyl, perhaloaryloxyalkyl, heteroaryl, heteroaiylalkyl, heteroarylthioalkyl, heteroaralkylthioalkyl, arylsulfinylalkyl, arylsulfonylalkyl, cycloalkylsulfinylalkyl, cy cloalkylsufonylalkyl, heteroary lsulfonylalkyl, heteroarylsulfinylalkyl, aralkylsulfinylalkyl and aralkylsulfonylalkyl; 30 31 25 R andR are independently selected from the group consisting of hydrido, hydroxy, thiol, aryloxy, amino, alkylamino, dialkylamino, hydroxyalkyl, heteroaryloxyalkyl, alkoxy, alkylthio, arylthio, alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, aralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, 21 WO 00/69833 PCT/US00/08226 aralkylthioalkyl, heteroaralkoxythioalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, haloaralkylsulflnylalkyl, aralkylsulfonylalkyl, cyanoalkyl, dicyanoalkyl, 5 carboxamidoalkyl, dicarboxamidoalkyl, cyanocarboalkoxyalkyl, carboalkoxy alkyl, dicarboalkoxyalkyl, cyanocycloalkyl, dicyanocycloalkyl, carboxamidocycloalkyl, dicarboxamidocycloalkyl, carboalkoxycyanocycloalkyl, carboalkoxycycloalkyl, dicarboalkoxycycloalkyl, formylalkyl, acylalkyl, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, phosphonoalkyl, dialkoxyphosphonoalkoxy, 10 diaralkoxyphosphonoalkoxy, phosphonoalkoxy, dialkoxyphosphonoalkylamino, diaralkoxyphosphonoalkylamino, phosphonoalkylamino, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, sulfonylalkyl, alkoxysulfonylalkyl, aralkoxysulfonylalkyl, alkoxysulfonylalkoxy, aralkoxysulfonylalkoxy, sulfonylalkoxy, alkoxysulfonylalkylamino, 15 aralkoxysulfonylalkylamino, and sulfonylalkylamino; 30 31 R and R 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 2 0 heterocyclyl ring having from 3 through 8 contiguous members; 23 25 24 25 25 26 24 26 23 R andR ,R andR ,R andR ,R andR , and R and 26 R 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 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=0, C=S, C(R )R , 30 S(O), S(0)2, OP(OR3 V30, P(0)R3°, P(S)R30 and Si(R28)R29; 22 WO 00/69833 PCT/USOO/08226 _,23 n25 _ 24 j 25 25 , 26 24 , 26 , ^23 J R and R , R and R , R and R , R and R , and R and 26 R 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 5 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=0, OS, C(R28)R29, S(O), S(0)2, OP(OR31)R3°, P(0)R30, 30 28 29 P(S)R , and Si(R )R and said alkylene and alkenylene radical are substituted 30 31 with one or more R or R substituents; s . 10 Q is selected from the group consisting of a single covalent bond, 37 38 n (CR R )^-(W )az wherein az is an integer selected from 0 through 1, b is an integer selected from 1 through 4, and W° is selected from the group consisting of O, S, C(O), C(S), C(0)0, C(S)0, C(0)S, C(S)S, C(0)N(R14), (R14)NC(0), C(S)N(R14), (R14)NC(S), 0C(0)N(R14), SC(S)N(R14), 15 SC(0)N(R14), OC(S)N(R14), N(R15)C(0)N(R14), (RM)NC(0)N(R15), N(R15)C(S)N(R14), (R14)NC(S)N(R15), S(O), S(0)2, S(0)2N(R14), N(R14)S(0)2, Se, Se(0), Se(0)2, Se(0)2N(R17), N(R14)Se(0)2, P(0)(R8), N(R7)P(0)(R8), P(0)(R8)N(R7), N(R14), ON(R14), and SiR^R29, (CH(R^4))c-W^-(CH(R^))cj wherein c and d are integers independently 20 selected from 1 through 4, and W* is selected from the group consisting of O, S, C(O), C(S), C(0)0, C(S)0, C(0)S, C(S)S, C(0)N(R14), (R14)NC(0), C(S)N(R14), (R14)NC(S), 0C(0)N(R14), (R14)NC(0)0, SC(S)N(R14), (R14)NC(S)S, SC(0)N(R14), (R14)NC(0)S, OC(S)N(R14), (R14)NC(S)0, 23 WO 00/69833 PCT/US00/08226 N(R15)C(0)N(R14), (R14)NC(0)N(R15), N(R15)C(S)N(R14), (R14)NC(S)N(R1:>), S(O), S(0)2, S(0)2N(R14), N(R14)S(0)2, Se, Se(0), Se(0)2, Se(0)2N(R14), N(R14)Se(0)2, P(0)(R8), N(R7)P(0)(R8), 8 7 14 14 28 29 14 P(0)(R )N(R ), N(R ), ON(R ), SiR R , and (CH(R )), i-w22- 5 (CH(R^»jj wherein e and h are integers independently selected from 0 22 41 42 through 2 and \V is selected from the group consisting of CR =CR , 41 42 CR R =C; vinylidene), ethynylidene (CsC; 1,2-ethynyl), 1,2-cyclopropyl, 1,2-cyclobutyl, 1,2-cyclohexyl, 1,3-cyclohexyl, 1,2-cyclopentyl, 13-cyclopentyl, 2,3-morpholinyl, 2,4-morpholinyl, 2,6-moipholinyl, 3,4-10 morpholinyl, 3,5-morpholinyl, 1,2-piperazinyl, 1,3-piperazinyl, 2,3- piperazinyl, 2,6-piperazinyl, 1,2-piperidinyl, 13-piperidinyl, 2,3-piperidinyl, 2,4-piperidinyl, 2,6-piperidinyl, 3,4-piperidinyl, 1,2-pyrrolidinyl, 13-pyrrolidinyl, 2,3-pynrolidinyl, 2,4-pyrrolidinyl, 2,5-pyrrolidinyl, 3,4-pyrrolidinyl, 23-tetrahydrofuranyl, 2,4-tetrahydrofuranyl, 2,5- 14 15 tetrahydrofuranyl, and 3,4-tetrahydrofuranyl, with the provisos that R and 15 R are selected from other than halo and cyano when directly bonded to N and that (CR37R38)b, (CH(R14))c, (CH(R14))e and are bonded to E°; 37 37 R and R , when bonded to different carbons, are optionally taken together to form a linear moiety spacer having from 1 through 7 contiguous 2 0 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; 37 38 R and R , when bonded to different carbons, are taken together to 2 5 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 24 WO 00/69833 PCT/US00/08226 contiguous members, and a heterocyclyl ring having from 3 through 8 contiguous members; 38 38 R and R , when bonded to different carbons, are taken together to form a linear moiety spacer having from 1 through 7 contiguous atoms to form 5 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; 37 38 R and R , when bonded to the same carbon, are taken together to 10 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 having from 3 through 8 contiguous members, a cycloalkenyl ring having from 3 through 8 contiguous members, and a heterocyclyl ring having from 3 15 through 8 contiguous members; 0 b ss ss Y is optionally Q -Q wherein Q is selected from the group 37 38 consisting of (CR R )f wherein f is an integer selected from 1 through 6, (CH(R^))c-W^-(CH(R^))cj wherein c and d are integers independently selected from 1 through 4, and W* is selected from the group consisting of W* 20 is selected from the group-consisting of O, S, C(O), C(S), C(0)0, C(S)0, C(0)S, C(S)S, C(0)N(R14), (R14)NC(0), C(S)N(R14), (R14)NC(S), 0C(0)N(R14), (R14)NC(0)0, SC(S)N(R14), (R14)NC(S)S, SC(0)N(R14), (R14)NC(0)S, OC(S)N(R14), (R14)NC(S)0, N(R15)C(0)N(R14), (R14)NC(0)N(R15), N(R15)C(S)N(R14), (R14)NC(S)N(R15), S(O), 25 S(0)2, S(0)2N(R14), N(R14)S(0)2, Se, Se(0), Se(0)2, Se(0)2N(R14), N(R14)Se(0)2, P(0)(R8), N(R?)P(0)(R8), P(0)(R8)N(R?), N(R14), 14 28 29 14 2 15 ON(R ), SiR R , and (CH(R ))e-W-(CH(R ))h wherein e and h are 25 WO 00/69833 PCT/USO0/08226 integers independently selected from 0 through 2 and W2 is selected from the 4a 4b group consisting of CR =CR , ethynylidene (C^C; 1,2-ethynyl), and 4a 4b 14 15 C=CR R with the provisos that R and R are selected from other than 37 38 15 halo and cyano when directly bonded to N, that (CR R )f, (CH(R ))c, 5 and (CH(R^))e are bonded to E°, and is selected from other than N(R26)N(R26)C(NR25)N(R23)(R24) or ON(R26)C(NR25)N(R23)(R24) ss 37 38 when Q is (CR R )f wherein f is other than the integer 1; Y° is optionally Q^-Qsss wherein QSSS is (CH(R38))r-W^, r is an integer selected from 1 through 3, 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-piperazinyI, 2,5-piperazinyl, 2,6-piperazinyl, 1,2-piperidinyl, 15 13-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, 13-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 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 26 WO 00/69833 PCT/US00/08226 proviso that (CH(R^8))r is bonded to E° and Qb is bonded to lowest numbered substituent position of each ; Y° is optionally Qb-Qsssr wherein Qsssr is (CH(R38))r-W , r is an 4 integer selected from 1 through 3, W 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-morphoIinyl, 3,5-morpholinyl, 1,2-piperaziriyl, 1,3-piperazinyl, 1,4-piperazinyl, 2,3-piperazinyl, 2,5-piperazinyl, 2,6-piperazinyl, 1,2-piperidinyl, 1,3-piperidinyl, 1,4-piperidinyl, 23-10 piperidinyl, 2,4-piperidinyl, 2,5-piperidinyl, 2,6-piperidinyl, 3,4-piperidinyl, 3,5-piperidinyl, 3,6-piperidinyl, 1,2-pyrroIidinyl, 1,3-pyrrolidinyl, 23-pyrrolidinyl, 2,4-pyrrolidinyl, 2,5-pyrrolidinyl, 3,4-pyrrolidinyl, 2H-2,3-pyranyl, 2H-2,4-pyranyl, 2H-2,5-pyranyl, 4H-23-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-15 4-one-2,3-yl, 2,3-tetrahydrofuranyl, 2,4-tetrahydrofuranyl, 2,5- tetrahydrofuranyl, 3,4-tetrahydrofuranyl, 23-tetrahydropyranyl, 2,4-tetrahydropyranyl, 2,5-tetrahydropyranyl, 2,6-tetrahydropyranyl, 3,4-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 20 attachment is optionally substituted with one or more of the group consisting of R9, R^, R1 \ and R^, with the provisos that (CH(R^8))r is bonded to E° and Qb is bonded to highest number substituent position of each W^; Y° is optionally Qb-QSSSS wherein Qssss is (CH(R"^))r-W^, r is an integer selected from 1 through 3, w5 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- 27 WO 00/69833 PCT/US00/08226 benzothiophenyl, 3,4-benzothiophenyl, 3,5-benzothiophenyl, 3,6-benzothiophenyl, 3,7-benzothiophenyl, 2,4-imidazo(l,2-a)pyridinyI, 2,5-imidazo(l,2-a)pyridinyl, 2,6-imidazo(l,2-a)pyridinyl, 2,7-imidazo(l,2-a)pyridinyl, 3,4-imidazo(l,2-a)pyridinyl, 3,5-imidazo(l,2-a)pyridinyl, 3,6-5 imidazo(l,2-a)pyridinyl, 3,7-imidazo(l,2-a)pyridinyl, 2,4-indolyI, 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-isoindoIyl, 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, 10 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, 2,5r-quinolinyl, 2,6-quinolinyl, 2,7-quinolinyl, 2,8-quinolinyl, 3,4-quinolinyl, 3,5-quinolinyl, 3,6-15 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, 3,4-2 0 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 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 25 lowest number substituent position of each arid that (CH(R38))r is bonded to E°; Y° is optionally Qb-Qssssr wherein Qssssr is (CH(R38))r-W^, r is an integer selected from 1 through 3, 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, 30 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, 28 WO 00/69833 PCT/USOO/Q8226 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(l,2-a)pyridinyl, 2,5-imidazo( 1 r2-a)pyridinyl, 2,6-imidazo(l,2-a)pyridinyl, 2,7-imidazo(l,2-5 a)pyridinyl, 3,4-imidazo(l,2-a)pyridinyl, 3,5-imidazo(l,2-a)pyridinyl, 3,6-imidazo(l,2-a)pyridinyl, 3,7-imidazo(l,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, 13-isoindolyl, 3,4-indazolyI, 3,5-10 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-benzisoxazolyI, 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, 2,6-15 quinolinyl, 2,7-quinolinyl, 2,8-quinolinyl, 3,4-quinolinyl, 3,5-quinolinyl, 3,6-quinolinyl, 3,7-quinolinyl, 3,8-quinolinyl, 4,5-quinolinyl, 4,6-quinolinyl, 4,7-quinolinyl, 4,8-quinolinyl, 1,4-isoquinolinyl, 1,5-isoquinolinyl, 1,6-isoquinolinyl, 1,7-isoquinolinyl, 1,8-isoquinolinyl, 3,4-isoquinolinyl, 3,5-isoquinolinyl, 3,6-isoquinolinyl, 3,7-isoquinolinyl, 3,8-isoquinolinyl, 4,5-20 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 6 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 25 consisting of R^, R^, R^, and R^, with the proviso that Qb is bonded to 6 38 highest number substituent position of each W and that (CH(R ))r is bonded „ co toE . In an embodiment of compounds of Formula I or a pharmaceutically acceptable salt thereof, 3 b 30 J and J are independently selected from the group consisting of O and S; 29 WO 00/69833 PCT/USOO/08226 B is formula (V): R34 R\1/k1^2/R35 J1 JT R 32/D"\^D2\R3 6 (v) wherein D*, D2, J1, J2 and K* are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more 12 12 1 . 5 than one is a covalent bond, no more than one of D , D , J , J and K is O, 12 12 1 12 12 no more than one of D , D , J , J and K is S, one of D , D , J , J and 1 12 12 1 K must be a covalent bond when two of D , D , J , J and K are O and S, , , «1 ^2 T1 T2 1 „ t and no more than four of D , D , J , J and K are N with the proviso that 32 33 34 35 _36 t . J J , , . . , R , R , R , R , and R are each independently selected to maintain the 10 tetravalent nature of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen; 9 10 11 12 13 16 17 18 19 32 33 34 R,R , R , R ,R ,R ,R ,R ,R ,R ,R ,R , 35 36 R , and R are independently selected from the group consisting of hydrido, acetamido; haloacetamido, amidino, guanidino, dialkylsulfonium, 15 trialkylphosphonium, dialkylsulfoniumalkyl, carboxy, heteroaralkylthio, heteroaralkoxy, cycloalkylamino, acylalkyl, acylalkoxy, aryloylalkoxy, heterocyclyloxy, aralkylaryl, aralkyl, aralkenyl, aralkynyl, heterocyclyl, perhaloaralkyl, aralkylsulfonyl, aralkylsulfonylalkyl, aralkylsulfinyl, aralkylsulfinylalkyl, halocycloalkyl, halocycloalkenyl, cycloalkylsulfinyl, 20 cycloalkylsulfinylalkyl, cycloalkylsulfonyl, cycloalkylsulfonylalkyl, heteroarylamino, N-heteroarylamino-N-alkylamino, heteroarylaminoalkyl, haloalkylthio, alkanoyloxy, alkoxy, alkoxyalkyl, haloalkoxylalkyl, heteroaralkoxy, cycloalkoxy, cycloalkenyloxy, cycloalkoxyalkyl, 30 WO 00/69833 PCT/US00/08226 cycloalkylalkoxy, cycloalkenyloxyalkyl, cycloalkylenedioxy, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxy, halocycloalkenyloxyalkyl, hydroxy, amino, alkoxyamino, thio, nitro, lower alkylamino, alkylthio, alkylthioalkyl, arylamino, aralkylamino, arylthio, arylthioalkyl, 5 heteroaralkoxyalkyl, alkylsulfinyl, alkylsulfinylalkyl, arylsulfinylalkyl, arylsulfonylalkyl, heteroarylsulfiriylalkyl, heteroaiylsulfonylalkyl, alkylsulfonyl, alkylsulfonylalkyl, haloalkylsulfinylalkyl, haloalkylsulfonylalkyl, alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, monoarylamidosulfonyl, 10 arylsulfonamido, diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl, arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, heterocyclylsulfonyl, heterocyclylthio, alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, haloalkanoyl, alkyl, alkenyl, alkynyl, alkenyloxy, alkenyloxyalky, alkylenedioxy, haloalkylenedioxy, 15 cycloalkyl, cycloalkylalkanoyl, cycloalkenyl, lower cycloalkylalkyl, lower cycloalkenylalkyl, halo, haloalkyl, haloalkenyl, haloalkoxy, hydroxyhaloalkyl, hydroxyaralkyl, hydroxyalkyl, alkylenylamino, hydoxyheteroaralkyl, haloalkoxyalkyl, aryl, aralkyl, aryloxy, aralkoxy, aryloxyalkyl, saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl, heteroaryloxy, 2 0 heteroaryloxyalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, carboxyalkyl, carboalkoxy, alkoxycarboxamido, alkylamidocarbonylamido, arylamidocarbonylamido, carboalkoxyalkyl, carboalkoxyalkenyl, carboxy, carboaralkoxy, carboxamido, carboxamidoalkyl, cyano, carbohaloalkoxy, phosphono, phosphonoalkyl, diaralkoxyphosphono, and 25 diaralkoxyphosphonoalkyl; 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 R^ and R*9 is Qb at the same time and that Qb is Qbe; 32 33 33 34 34 35 35 36 R andR ,R andR ,R andR , and R andR are 3 0 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 31 WO 00/69833 PCT/US00/08226 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 32 33 33 34 34 35 „35 consisting of spacer pairs R andR ,R andR ,R andR , and R 36 5 and R can be used at the same time; 9 10 10 11 11 12 12 13 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 10 ring selected from the group consisting of a cycloalkenyl ring having 5 through 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 ... • ^ _10 10 11 11 12 12 consisting of spacer pairs R and R , R and R , R and R , and R 13 15 and R can be used at the same time; 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 20 the point of attachment of B to A with one or more of the group consisting of 32 33 34 35 36 R , R , R , R , and R ; B is optionally selected from the group consisting of C3-C15 cycloalkyl, C5-C10 cycloalkenyl, C4-C12 saturated heterocyclyl, and C4-C9 partially saturated heterocyclyl, wherein each ring carbon is optionally 33 25 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 carbons and a nitrogen adjacent to the carbon atom at the point of attachment are optionally 9 13 9 substituted with R or R , a ring carbon or nitrogen adjacent to the R 30 position and two atoms from the point of attachment is optionally substituted 32 WO 00/69833 PCT/US00/08226 with R^, a ring carbon or nitrogen adjacent to the R position and two atoms 12 from the point of attachment is optionally substituted with R , a ring carbon 10 or nitrogen three atoms from the point of attachment and adjacent to the R position is optionally substituted with R^, a ring carbon or nitrogen atom 12 5 three from the point of attachment and adjacent to the R position is optionally 33 . substituted with R , and a ring carbon or nitrogen four atoms from the point 11 33 of attachment and adjacent to the R and R positions is optionally ,.,■^34 substituted with R ; A is selected from the group consisting of single covalent bond, 10 (W7)rr-(CH(R^))pa and (CH(R''"~'))pa-(W7)rr wherein rr is an integer 7 selected from 0 through 1, pa is an integer selected from 0 through 6, and W is selected from the group consisting of O, S, C(O), C(S), C(0)S, C(S)0, C(0)N(R7), C(S)N(R7), (R?)NC(0), (R?)NC(S), S(O), S(0)2, S(0)2N(R7), (R7)NS(0)2, P(0)(R8), N(R7)P(0)(R8), P(0)(R8)N(R7), 15 C(NR7)N(R7), (R7)NC(NR7), (R7)NC(NR7)NR7, 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; 7 8 R and R 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 00/69833 PCT/US00/08226 14 , _38 , . , , R and R can be independently selected from the group consisting of acyl, aroyl, and heteroaroyl with the proviso that acyl is selected from other than formyl; W is selected from the group consisting of NR^, O, C(O), C(S), S, 5 8 39 40 5 S(O), S(0)2, ON(R ), P(0)(R ), and CR R ; R^ 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, haloalkoxy alkyl, alkylsulfonyl, haloalkylsulfonyl, carboxy, carboxyalkyl, carboalkoxy, carboxamide, and carboxamidoalkyl; M is selected from the group consisting of N and R^-C; 2 1 0 R and R are independently selected from the group consisting of Z - 15 Q, hydrido, alkyl, alkenyl, and halo; R1 is optionally selected from the group consisting of amino, aminoalkyl, alkylamino, amidino, guanidino, hydroxy, hydroxyamino, alkoxy, hydroxyalkyl, alkoxyamino, thiol, alkylthio, dialkylsulfonium, tiialkylphosphonium, dialkylsulfoniumalkyl, heteroarylamino, nitro, 20 arylamino, aralkylamino, alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, haloalkanoyl, hydroxy haloalkyl, cyano, and phosphono; Z° is selected from the group consisting of covalent single bond, 41 42 41 (CR R )q wherein q is an integer selected from 1 through 6, (CH(R ))g- J) 42 \r-(CH(R ))p wherein g and p are integers independently selected from 0 25 through 3 and W° is selected from the group consisting of O, S, C(O), C(S), C(0)0, C(S)0, C(0)S, C(S)S, C(0)N(R41), (R41)NC(0), C(S)N(R41), (R41)NC(S), OC(Q)N(R41), (R41)NC(0)0, SC(S)N(R41), (R41)NC(S)S, 34 WO 00/69833 PCT/US00/08226 SC(0)N(R41), (R41)NC(0)S, OC(S)N(R41), (R41)NC(S)0, 42 41 41 42 42 41 N(R )C(0)N(R ), (R )NC(0)N(R ), N(R )C(S)N(R ), (R41)NC(S)N(R42), S(O), S(0)2, S(0)2N(R41), N(R41)S(0)2, Se, Se(0), Se(0)2, Se(0)2N(R41), N(R41)Se(0)2, P(0)(R8), N(R7)P(0)(R8), 8 7 41 41 28 29 41 ,22 5 P(0)(R )N(R ), N(R ), ON(R ), and SiR R , and (CH(R ))e-W - 42 (CH(R ))j1 wherein e and h are integers independently selected from 0 22 41 42 through 2 and is selected from the group consisting of CR =CR , 41 42 CR R =C; vinylidene), ethynyhdene (CsC; 1,2-ethynyl), 1,2-cyclopropyl, 1,2-cyclobutyl, 1,2-cyclohexyl, 13-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, 13-piperazinyl, 23-piperazinyl, 2,6-piperazinyl, 1,2-piperidinyl, 13-piperidinyl, 2,3-piperidinyl, 2,4-piperidinyl, 2,6-piperidinyl, 3,4-piperidinyl, 1,2-pyrrolidinyl, 1,3-pyrrolidinyl, 23-pyrrolidinyl, 2,4-pyrrolidinyl, 2,5-pyrrolidinyl, 3,4-15 pyrrolidinyl, 2,3-tetrahydrofuranyl, 2,4-tetrahydrofuranyl, 2,5- 41 tetrahydrofuranyl, and 3,4-tetrahydrofuranyl, with the provisos that R and 42 R are selected from other than halo and cyano when directly bonded to N and Z° is directly bonded to the uracil ring; 41 42 R and R are independently selected from the group consisting of 2 0 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, 2 5 haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxyalkyl, saturated heterocyclyl, partially saturated heterocyclyl, heteroaiyl, heteroaralkyl, heteroarylthioalkyl, heteroaralkylthioalkyl, alkylsulfonyl, haloalkylsulfonyl, arylsulfonyl, 35 WO 00/69833 PCT/US00/08226 arylsulfonylalkyl, aralkylsulfonyl, cycloalkylsulfonyl, cycloalkylsufonylalkyl, heteroarylsulfonylalkyl, heteroarylsulfonyl, and araikylsulfonylalkyl; Q is formula (II): R11 RlV 2/Rl2 Jr Jj R9/D^D\R13 (II) 12 12 1 5 wherein D , D , J , J and K are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more 12 12 ] than one is a covalent bond, no more than one of D , D , J , J and K is O, 12 12 1 12 12 no more than one of D , D , J , J and K is S, one of D , D , J , J and 1 12 12 1 K must be a covalent bond when two of D , D , J , J and K are O and S, 12 12 1 10 and no more than four of D , D , J , 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): R10 \3 /R11 / ""V R9 /* XR12 15 ' (HI) 3 4 3 4 wherein D , D , J , and J are independently selected from the group 3 4 3 4 consisting of C, N, O, and S, no more than one of D , D , J , and J is O, no 36 WO 00/69833 PCT/US00/08226 3 4 3 4 12 more than one of D , D , J , and J is S, and no more than three of D , D , 12 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 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; 4a 4b K is (CR R )n wherein n is an integer selected from 1 through 2; 4a 4b 15 R and R are independently selected from the group consisting of halo, hydrido, hydroxy, cyano, hydroxyalkyl, alkyl, alkenyl, alkoxyalkyl, aralkyl, heteroaralkyl, alkylthioalkyl, haloalkyl, haloalkenyl, and cyanoalkyl; o 1 4a 4b 1 E is E , when K is (CR R )n, wherein E is selected from the group consisting of a covalent single bond, O, S, C(O), C(S), C(0)0, C(S)0, 20 C(0)S, C(S:)S,-C(0.)N(R7), (R?)NC(0), C(S)N(R?), (R?)NC(S), 0C(0)N(R7), (R7)NC(0)0, SC(S)N(R?), (R?)NC(S)S, SC(0)N(R?), (R?)NC(0)S, OC(S)N(R7), (R7)NC(S)0, N(R8)C(0)N(R7), (R7)NC(0)N(R8), N(R8)C(S)N(R7), (R7)NC(S)N(R8), S(O), S(0)2, S(0)2N(R7), N(R7)S(0)2, S(0)2N(R7)C(0), C(0)N(R7)S(0)2, P(0)(R8), 7 8 8 7 7 7 4a 4b 25 N(R )P(0)(R ), P(0)(R )N(R ), N(R ), ON(R ), CR =CR , 43. 4b ethynylidene (C=C; 1,2-ethynyl), and C=CR R ; 37 WO 00/69833 PCT/US00/08226 14 K is optionally (CH(R ))j-T wherein j is selected from a integer from 0 through 2 and T is selected from the group consisting of single covalent 7 14 bond, O, S, and N(R ) with the proviso that (CH(R ))j is bonded to the uracil ring; 5 E° is optionally E^, when K is (CH(R^))j-T, wherein E^ is selected from the group consisting of a covalent single bond, C(O), C(S), C(0)0, C(S)0, C(0)S, C(S)S, C(0)N(R?), (R?)NC(0), C(S)N(R?), (R?)NC(S), (R?)NC(0)0, (R?)NC(S)S, (R?)NC(0)S, (R7)NC(S)0, N(R8)C(0)N(R7), (R7)NC(0)N(R8), N(R8)C(S)N(R7), (R7)NC(S)N(R8), S(O), S(0)2, 10 S(0)2N(R7), N(R7)S(0)2, S(0)2N(H)C(0), C(0)N(H)S(0)2, P(0)(R8), N(R7)P(0)(R8), P(0)(R8)N(R7), and N(R7); K is optionally G-(CH(R^))j[ wherein k is selected from an integer from 1 through 2 and G is selected from the group consisting of O, S, and 7 15 N(R ) with the proviso that R is other than hydroxy, cyano, halo, amino, 15 alkylamino, dialkylamino, and sulfhydryl when k is 1; E° is optionally ET* when K is G-(CH(R1^))jc, wherein E^ is selected from the group consisting of a covalent single bond, O, S, C(O), C(S), C(0)0, C(S)0, C(0)S, C(S)S, C(0)N(R7), (R?)NC(0), C(S)N(R?), (R?)NC(S), 0C(0)N(R?), (R7)NC(0)0, SC(S)N(R?), (R?)NC(S)S, 20 SC(0)N(R?), (R?)NC(0)S, OC(S)N(R?), (R?)NC(S)0, N(R8)C(0)N(R7), (R7)NC(0)N(R8), N(R8)C(S)N(R7), (R?)NC(S)N(R8), S(O), S(0)2, S(0)2N(R7), N(R7)S(0)2, P(0)(R8), N(R7)P(0)(R8), P(0)(R8)N(R7), 38 WO 00/69833 PCT/US0O/08226 7 7 4a 4b N(R ), ON(R ), CR =CR , ethynylidene (C=C; 1,2-ethynyl), and C=CR4aR4b; Y° is formula (IV): 0s R17- Jl a Ri6/D\2^DVRl9 ib Q (iv) 5 6 5 6 5 wherein D , D , J , and J are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more 2 than one is a covalent bond, K is independently selected from the group consisting of C and N+, no more than one of D~*, D^, J^, and is O, no more , . 5 6 5 ,6 5 6 5 ,6 than one of D , D , J , and J is S, one of D , D , J , and J must be a 5 6 5 6 10 covalent bond when two of D , D , J , and J are O and S, no more than three of D^, D^, J~\ and is N when is N+, and no more than four of 5 6 5 6 2 16 17 D ,D ,J ,andJ 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; 16 17 R and R 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 2 0 having from 5 through 8 contiguous members, a heteroaryl having from 5 through 6 contiguous members, and an aryl; 39 WO 00/69833 PCT/USOQ/08226 b 20 21 Q is selected from the group consisting of NR R , + 20 21 22 NR R R , oxy, alkyl, aminoalkylenyl, alkylamino, dialkylamino, be be 20 dialkylsulfoniumalkyl, acylamino and Q , wherein Q is hydrido and R , 21 22 R , and R are independently selected from the group consisting of hydndo, 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, 2 + amino, and dialkylamino when K is N ; 20 21 20 22 21 22 10 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 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 21 22 R and R is used at the same time; Qb is optionally selected from the group consisting of N(R26)S02N(R23)(R24), N(R26)C(0)0R5, N(R26)C(0)SR5, 26 5 26 5 N(R )C(S)OR and N(R )C(S)SR with the proviso that no more than one 23 24 26 20 ofR ,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 23 24 dialkylsulfonium, trialkylphosphonium, C(NR )NR R , 40 WO 00/69833 PCT/US00/08226 26 25 23 24 26 23 24 N(R )C(NR )N(R )(R ), N(R )C(0)N(R )(R ), N(R26)C(S)N(R23)(R24), C(NR25)OR5 26 25 23 24 26 25 23 24 C(0)N(R )C(NR )N(R )(R ), C(S)N(R )C(NR )N(R )(R ), N(R26)N(R26)C(NR25)N(R23)(R24), ON(R26)C(NR25)N(R23)(R24), 5 N(R26)N(R26)S02N(R23)(R24), C(NR25)SR5 C(0)NR23R24, and 23 24 23 24 26 C(0)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 b said Q 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; 23 24 R and R 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; s Q is selected from the group consisting of a single covalent bond, 37 38 o (CR R )[3-(W )az wherein az is an integer selected from 0 through 1, b is an integer selected from 1 through 4, and W° is selected from the group consisting of O, S, C(O), C(S), C(0)0, C(S)0, C(0)S, C(S)S, C(0)N(R14), 20 (R14)NC(0), C(S)N(R14), (R14)NC(S), 0C(0)N(R14), SC(S)N(R14), SC(0)N(R14), OC(S)N(R14), N(R15)C(0)N(R14), (R14)NC(0)N(R1;>), N(R15)C(S)N(R14), (R14)NC(S)N(R15), S(O), S(0)2, S(0)2N(R14), N(R14)S(0)2, P(0)(R8), N(R7)P(0)(R8), P(0)(R8)N(R7), N(R14), 41 WO 00/69833 PCT/US00/08226 ON(R*4), (CH(R^4))c-W^-(CH(R15))d wherein c and d are integers independently selected from 1 through 4, and is selected from the group consisting of O, S, C(O), C(S), C(0)0, C(S)0, C(0)S, C(S)S, C(0)N(R14), (R14)NC(0), C(S)N(R14), (R14)NC(S), 0C(0)N(R14), (R14)NC(0)0, 5 SC(S)N(R14), (R14)NC(S)S, SC(0)N(R14), (R14)NC(0)S, OC(S)N(R14), (R14)NC(S)0, N(R15)C(0)N(R14), (R14)NC(0)N(R15), N(R15)C(S)N(R14), (R14)NC(S)N(R15), S(O), S(0)2, S(0)2N(R14), N(R14)S(0)2, P(0)(R8), N(R7)P(0)(R8), P(0)(R8)N(R7), N(R14), ON(R14), and (CH(R14))e- W^^-CCHCR^))^ wherein e and h are integers 10 independently selected from 0 through 2 and is selected from the group 41 42 41 42 consisting of CR =CR , CR R =C; vinylidene), ethynylidene (CeC; 1.2-ethynyl), 1,2-cyclopropyl, 1,2-cyclobutyl, 1,2-cyclohexyl, 13-cyclohexyl, 1,2-cyclopentyl, 13-cyclopentyl, 23-morpholinyl, 2,4-morpholinyl, 2,6-morphoIinyI, 3,4-morphoIinyI, 3,5-morpholinyl, 1,2- 15 piperazinyl, 13-piperazinyl, 2,3-piperazinyl, 2,6-piperazinyl, 1,2-piperidinyl, 1.3-piperidinyl, 23-piperidinyl, 2,4-piperidinyl, 2,6-piperidinyl, 3,4-piperidinyl, 1,2-pyrrolidinyl, 13-pyrrolidinyl, 2,3-pyrrolidinyl, 2,4-pyrrolidinyl, 2,5-pyrrolidinyl, 3,4-pyrrolidinyl, 23-tetrahydrofuranyl, 2,4-tetrahydrofuranyl, 2,5-tetrahydrofuranyl, and 3,4-tetrahydrofuranyl, with the 14 15 20 provisos that R and R are selected from other than halo and cyano when 3*7 38 directly bonded to N and that (CR R )b, (CH(R ))c, (CH(R ))e and are bonded to E°; 0 b ss ss Y is optionally Q -Q wherein Q is selected from the group 37 38 consisting of (CR R )f wherein f is an integer selected from 1 through 6, 42 WO 00/69833 PCT/U S00/08226 (CH(R* ))c-W^-(CH(R^))cj wherein c and d are integers independently selected from 1 through 4, and W is selected from the group consisting of is selected from the group consisting of O, S, C(O), C(S), C(0)0, C(S)0, C(0)S, C(S)S, C(0)N(R14), (R14)NC(0), C(S)N(R14), (R14)NC(S), 0C(0)N(R14), (R14)NC(0)0, SC(S)N(R14), (R14)NC(S)S, SC(0)N(R14), (R14)NC(0)S, OC(S)N(R14), (R14)NC(S)0, N(R15)C(0)N(R14), (R14)NC(0)N(R15), N(R15)C(S)N(R14), (R14)NC(S)N(R15), S(O), S(0)2, S(0)2N(R14), N(RI4)S(0)2, P(0)(R8), N(R7)P(0)(R8), P(0)(R8)N(R7), N(R14), ON(R14), and (CH(R14))e-W2-(CH(R15))h 10 wherein e and h are integers independently selected from 0 through 2 and w2 4-fc is selected from the group consisting of CR =CR , ethynylidene (CsC; 1,2- 4a 4b 14 15 ethynyl), and C=CR R with the provisos that R and R are selected 37 from other than halo and cyano when directly bonded to N and that (CR R38)f, (CH(R14))c, and (CH(R14))e are bonded to E°; 15 Y° is optiionally Qb-Qsss wherein QSSS is (CFKR38))^^, r is an integer selected from 1 through 3, W3 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, 13-cyclopentyl, 23-morpholinyl, 2,4-morpholinyl, 2,5-morpholinyl, 2,6-morphoIinyl, 3,4- 20 morpholinyl, 3,5-morpholinyl, 1,2-piperazinyl, 1,3-piperazinyl, 1,4- piperazinyl, 23-piperazinyl, 2,5-piperazinyl, 2,6-piperazinyl, 1,2-piperidinyl, 1,3-piperidinyl, 1,4-piperidinyl, 23-piperidinyl, 2,4-piperidinyl, 2,5-piperidinyl, 2,6-piperidinyl, 3,4-piperidinyl, 3,5-piperidinyl, 3,6-piperidinyl, 1.2-pyrrolidinyl, 13-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 00/69833 PCT/US00/08226 pyranyl, 4H-23-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-23-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 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 38 . o b proviso that (CH(R ))r is bonded to E and Q is bonded to lowest numbered 10 substituent position of each W3; Y° is optionally Qb-Qsssr wherein Qsssr js (CH(R^))r-W4, 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, 13-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, 23-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, 23-20 pyrrolidinyl, 2,4-pyrroIidinyl, 2,5-pyrrolidinyl, 3,4-pyrrolidinyr,~2H-2,3- pyranyl, 2H-2,4-pyranyl, 2H-2,5-pyranyl, 4H-2,3-pyranyl, 4H-2,4-pyranyl, 4H-2,5-pyranyI, 2H-pyran-2-one-3,4-yl, 2H-pyran=2-one-4,5-yl, 4H-pyran-4-one-23-yl, 2,3-tetrahydrofuranyl, 2,4-tetrahydrofuranyl, 2,5-tetrahydrofuranyl, 3,4-tetrahydrofuranyl, 2,3-tetrahydropyranyl, 2,4-2 5 tetrahydropyranyl, 2,5-tetrahydropyranyl, 2,6-tetrahydropyranyl, 3,4- tetrahydropyranyl, and 3,5-tetrahydropyranyl, and each carbon and hydrido 4 containing nitrogen member of the nng of the W other than the points of attachment is optionally substituted with one or more of the group consisting of 44 WO 00/69833 PCT/USO0/08226 R9, 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 ; Y° is optionally Qb-Qssss wherein Qssss js (CH(R^8))r-W^, r is an integer selected from 1 through 3, 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-benzothiophenyI, 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( l,2-a)pyridinyl, 3,4-imidazo(l,2-a)pyridinyl, 3,5-imidazo(l,2-a)pyridinyl, 3,6-imidazo(l,2-a)pyridinyl, 3,7-imidazo(l,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-quinoIinyl, 4,5-quinolinyI, 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-isoquinoIinyl, 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 3 0 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 00/69833 PCT/US00/08226 9 10 11 12 ... . , _b . , , , , , R , R , R , and R , with the proviso that Q is bonded to lowest number substituent position of each and that (CH(R^8))r is bonded to E°; Y° is optionally Qb-Qssssr wherein Qssssr is (CH(R^8))r-W^, r is an 6. 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(l,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(l ,2-a)pyridinyl, 2,4-indolyl, 2,5-indolyl, 2,6-indolyl, 2,7-indolyl, 3,4-indoIyl, 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-indazolyI, 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 6 3 0 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 46 WO 00/69833 PCT/US00/08226 R9, R^, R*\ and R*2, with the proviso that Qb is bonded to highest number 6 38 o 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, b. b J and J are independently selected from the group consisting of O and S; B is formula (V): ' R34 r33\ j/KW2^R35 Jl R32/D^D\R36 (V) 12 12 1 wherein D , D , J , J and K are independently selected from the group 10 consisting of C, N, O, S and a covalent bond with the provisos that no more 12 12 1 than one is a covalent bond, no more than one of D , D , J , J and K is O, 12 12 1 12 12 no more than one of D ,D ,J , J andK is S, one of D , D , J , J and 1 1212 1 K must be a covalent bond when two of D , D , J , J and K are O and S, 12 12 1 and no more than four of D , D ,J ,J andK are N; R9 R10 R11, R12,R13, R16 R17, R18 R19 R32, R33. R34, 35 36 R , and R are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, dialkylsulfonium, tiialkylphosphonium, dialkylsulfoniumalkyl, carboxy, heteroaralkylthio, heteroaralkoxy, cycloalkylamino, acylalkyl, acylalkoxy, aryloylalkoxy, 20 heterocyclyloxy, aralkylaryl, aralkyl, aralkenyl, aralkynyl, heterocyclyl, perhaloaralkyl, aralkylsulfonyl, aralkylsulfonylalkyl, aralkylsulfinyl, aralkylsulfinylalkyl, halocycloalkyl, halocycloalkenyl, cycloalkylsulfinyl, 47 WO 00/69833 PCT/US00/08226 cycloalkylsulfinylalkyl, cycloalkylsulfonyl, cycloalkylsulfonylalkyl, heteroarylamino, N-heteroarylamino-N-alkylamino, heteroarylaminoalkyl, haloalkylthio, alkanoyloxy, alkoxy, alkoxyalkyl, haloalkoxylalkyl, heteroaralkoxy, cycloalkoxy, cycloalkenyloxy, cycloalkoxyalkyl, 5 cycloalkylalkoxy, cycloalkenyloxyalkyl, cycloalkyleaedioxy, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxy, halocycloalkenyloxyalkyl, hydroxy, amino, alkoxyamino, thio, nitro, lower alkylamino, alkylthio, alkylthioalkyl, arylamino, aralkylamino, arylthio, arylthioalkyl, heteroaralkoxyalkyl, alkylsulfinyl, alkylsulfinylalkyl, arylsulfinylalkyl, 10 arylsulfonylalkyl, heteroaiylsulfinylalkyl, heteroarylsulfonylalkyl, alkylsulfonyl, alkylsulfonylalkyl, haloalkylsulfinylalkyl, haloalkylsulfonylalkyl, alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, monoarylamidosulfonyl, arylsulfonamido, diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl, 15 arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfmyl, heteroarylsulfonyl, heterocyclylsulfonyl, heterocyclylthio, alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, haloalkanoyl, alkyl, alkenyl, alkynyl, alkenyloxy, alkenyloxyalky, alkylenedioxy, haloalkylenedioxy, cycloalkyl, cycloalkylalkanoyl, cycloalkenyl, lower cycloalkylalkyl, lower 2 0 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, aiylalkenyl, heteroaryl alkenyl, 25 carboxyalkyl, carboalkoxy, alkoxycarboxamido, alkylamidocarbonylamido, arylaxnidocarbonylamido, carboalkoxyalkyl, carboalkoxyalkenyl, carboxy, carboaralkoxy, carboxamido, carboxamidoalkyl, cyano, carbohaloalkoxy, phosphono, phosphonoalkyl, diaralkoxyphosphono, and diaralkoxyphosphonoalkyl; 16 19 32 33 34 35 36 30 R,R,R,R,R,R , and R are independently optionally Qb with the proviso that no more than one of R^ and is Qb at the same time and that Qb is Qbe; 48 WO 00/69833 PCT/US00/08226 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 is optionally substituted at any carbon up to and including 6 atoms from the point 32 33 5 of attachment of B to A with one or more of the group consisting of R , R , 34 35 36 R , R , and R ; 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 10 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 9 13 point of attachment are optionally substituted with R or R , a ring carbon or 9 nitrogen adjacent to the R position and two atoms from the point of attachment 15 is optionally substituted with R^, a ring carbon or nitrogen adjacent to the 13 R position and two atoms from the point of attachment is optionally 12 substituted with R , a ring carbon or nitrogen three atoms from the point of 10 11 attachment and adjacent to the R position is optionally substituted with R , a ring carbon or nitrogen three atoms from the point-of attachment and adjacent 12 33 20 to the R position is optionally substituted with R , and a ring carbon or nitrogen four atoms from the point of attachment and adjacent to the R^ and 33 34 R positions is optionally substituted with R ; A is selected from the group consisting of single covalent bond, (W7)rr-(CH(R^^))pa and (CH(R^))pa-(W7)rr wherein rr is an integer 7 25 selected from 0 through 1, pa is an integer selected from 0 through 6, and W 49 WO 00/69833 PCT/US00/08226 7 7 is selected from the group consisting of O, S, C(O), C(0)N(R ), C(S)N(R ), 7 7 7 (R )NC(0), (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; 7 8 R and R are independently selected from the group consisting of 5 hydrido, hydroxy, alkyl, and alkoxyalkyl; 14 15 37 38 R , R , R , and R are independently selected from the group consisting of hydrido, hydroxy, halo, alkyl, alkoxyalkyl, haloalkyl, haloalkoxy, and haloalkoxyalkyl; 14 38 R and R can be independently selected from the group consisting 10 of aroyl and heteroaroyl; ¥ is selected from the group consisting of NR~\ C(O), and S(0)2; R^ is selected from the group consisting of hydrido, hydroxy, alkyl, and alkoxy; 39 40 R 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 Z°-Q; Z° is selected from the group consisting of covalent single bond, 41 42 41 (CR R )q wherein q is an integer selected from 1 through 3, (CH(R ))g- jo 42 25 W -(CH(R ))p wherein g and p are integers independently selected from 0 through 3 and W° is selected from the group consisting of O, S, C(O), S(O), 50 WO 00/69833 PCT/USO0/08226 41 41 41 22 42 S(0)2, N(R ), and ON(R ), and (CH(R ))e-"W -(CH(R ))^ wherein e and h are integers independently selected from 0 through 2 and is selected 41 42 from the group consisting of CR =CR , 1,2-cyclopropyl, 1,2-cyclobutyl, 1,2-cyclohexyl, 13-cyclohexyl, 1,2-cyclopentyl, 1,3-cyclopentyl, 23-5 morpholinyl, 2,4-morpholinyl, 2,6-morpholinyl, 3,4-morpholinyl, 3,5-morpholinyl, 1,2-piperazinyl, 13-piperazinyl, 2,3-piperazinyl, 2,6-piperazinyl, 1,2-piperidinyl, 13-piperidinyl, 23-piperidinyl, 2,4-piperidinyl, 2,6-piperidinyl, 3,4-piperidinyl, 1,2-pyrrolidinyl, 1,3-pyrrolidinyl, 23-pyrrolidinyl, 2,4-pyrrolidinyl, 2,5-pyrrolidinyl, 3,4-pyrrolidinyl, 23-10 tetrahydrofuranyl, 2,4-tetrahydrofuranyl, 2,5-tetrahydrofuranyl, and 3,4- tetrahydrofuranyl, with the proviso that Z° is directly bonded to the uracil ring; 41 42 R and R are independently selected from the group consisting of amidino, hydroxyamino, hydrido, hydroxy, amino, and alkyl; Q is selected from the group consisting of hydrido, with the proviso 15 that Z° is other than a covalent single bond, the formula (II): R11 »10 rA R12 J. R 9/d1"^D\r13 (II) 12 12 1 wherein D , D , J , J and K are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more 12 12 1 than one is a covalent bond, no more than one of D , D , J , J and K is O, 1212 1 1212 20 no more than one of D ,D ,J ,J andK is S, one of D ,D ,J ,J and 1 12 12 1 K must be a covalent bond when two of D , D , J , J and K are O and S, 12 12 1 and no more than four of D , D , J , J and K is N, with the proviso that 51 WO 00/69833 PCT/US00/08226 9 10 11 12 13 . . . . , , J . . . 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; 4b K is (CR R )n wherein n is an integer selected from 1 through 2; 4a 4b 5 R and R are independently selected from the group consisting of halo, hydrido, hydroxyalkyl, alkyl, alkoxyalkyl, alkylthioalkyl, and haloalkyl; E° is selected from the group consisting of a covalent single bond, C(O), C(S), C(0)N(R7), (R?)NC(0), S(0)2, (R7)NS(0)2, and S(0)2N(R7); Y° is formula (IV): Qs R 17 r18 J J ■ D5\ ^D6- R16/ ^R19 rP io Q (iv) 5 6 5 6 wherein D , D , J , and J are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more than one is a covalent bond, is C, no more than one of D^, D^, and 5 6 5 6 5 6 5 6 is O, no more than one of D , D ,J ,andJ is S, one of D , D ,J ,andJ 5 6 5 6 15 must be a covalent bond when two of D , D , J , and J are O and S, and no more than four of D*\ J^, and are N when is carbon with the . _ 16 17 18 J „19 , . , , , provisos 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; 52 WO 00/69833 PCT/US00/08226 b 20 21 Q is selected from the group consisting of NR R , + 20 21 22 be be 20 NR R R , aminoalkylenyl, and Q , wherein Q is hydrido and R , 21 22 R , and R are independently selected from the group consisting of hydrido, alkyl, hydroxy, amino, aminoalkylenyl, dialkylamino, alkylamino, 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)NR23R24, N(R26)C(NR25)N(R23)(R24), C(0)N(R26)C(NR25)N(R23)(R24), N(R26)N(R26)C(NR25)N(R23)(R24), 26 25 23 24 10 and ON(R )C(NR )N(R )(R ) 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, alkylenylamino, dialkylamino, alkylamino, and hydroxyalkyl; s Q is selected from the group consisting of a single covalent bond, 37 38 jo (CR R )b-(W )az wherein az is an integer selected from 0 through 1, b is an integer selected from 1 through 5, and W° is selected from the group 20 consisting of O, C(O), S(O), S(0)2, S(0)2N(R14), N(R14)S(0)2, and N(R ), (CH(R ))C-W -(CH(R* ))£j wherein c and d are integers independently selected from 1 through 4 and W* is selected from the group consisting of O, S, C(O), C(S), C(0)0, C(S)0, C(0)S, C(S)S, C(0)N(R14), 53 WO 00/69833 PCT/US00/08226 (R14)NC(0), C(S)N(R14), (R14)NC(S), 0C(0)N(R14), (R14)NC(0)0, SC(S)N(R14), (R14)NC(S)S, SC(0)N(R14), (R14)NC(0)S, OC(S)N(R14), (R14)NC(S)0, N(R15)C(0)N(R14), (R14)NC(0)N(R15), N(R15)C(S)N(R14), (R14)NC(S)N(R15), S(O), S(0)2, S(0)2N(R14), 5 N(R14)S(0)2, P(0)(R8), N(R7)P(0)(R8), P(0)(R8)N(R7), N(R14), ON(R^4), and (CH(R^4))e-W22-(CH(R^))j1 wherein e and h are integers independently selected from 0 through 2 and is selected from the group 41 42 41 42 consisting of CR =CR , CR R =C; vinylidene), ethynylidene (CsC; 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, 13-piperazinyl, 2,3-piperazinyl, 2,6-piperazinyl, 1,2-piperidinyl, 1.3-piperidinyl, 23-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, 23-tetrahydrofuranyl, 2,4-tetrahydrofuranyl, 2,5-tetrahydrofuranyl, and 3,4-tetrahydrofuranyl, with the 14 15 provisos that R andR are selected from other than halo and cyano when direcdy bonded to N and that (CR3?R38)5, (CH(R14))c, and (CH(R14))e are bonded to E°; 0 b ss ss 20 Y is optionally Q -Q wherein Q is selected from the group 37 38 consisting of (CR R )f wherein f is an integer selected from 1 through 4, (CH(R^4))c-W^-(CH(R^))(j wherein c and d are integers independently selected from 1 through 2, and W* is selected from the group consisting of 14 is selected from the group consisting of O, S, C(O), C(0)N(R ), 54 WO 00/69833 PCT/US00/08226 (R14)NC(0), N(R15)C(0)N(R14), (R14)NC(0)N(R15), N(R14), ON(R14), and (CH(R^4))e-W2-(CHCR^))^ wherein e and h are integers independently selected from 0 through 2 and is selected from the group consisting of 43 4b 4q 4b CR =CR , ethynylidene (CsC; 1,2-ethynyl), and C=CR R with the 14 15 provisos that R and R are selected from other than halo when directly bonded to N and that (CR37 R3^)f, (CH(R*4))c, and (CH(R*4))e are bonded to E°; Y° is optionally Qb-Qsss wherein QSSS is (CH(R38))r-W3, r is an integer selected from 1 through 2, W3 is selected from the group consisting of 10 1,1-cyclopropyl, 1,2-cyclopropyl, 1,1-cyclobutyl, 1,2-cyclobutyl, 1,2- cyclohexyl, 13-cyclohexyl, 1,4-cyclohexyl, 1,2-cyclopentyl, 13-cyclopentyl, 2,3-morpholinyI, 2,4-morpholinyl, 2,5-morpholinyl, 2,6-moipholinyl, 3,4-morpholinyl, 3,5-morpholinyl, 1,2-piperazinyl, 13-piperazinyl, 1,4-piperazinyl, 2,3-piperazinyl, 2,5-piperazinyl, 2,6-piperazinyl, 1,2-piperidinyl, 15 13-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, 23-pyrrolidinyI, 2,4-pyrrolidinyl, 2,5-pyrrolidinyl, 3,4-pyrrolidinyl, 2H-2,3-pyranyl, 2H-2,4-pyranyl, 2H-2,5-pyranyl, 4H-23-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, 23-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 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 00/69833 PCT/USO0/08226 38 o b proviso that (CH(R ))r is bonded to E and Q is bonded to lowest numbered substituent position of each W3; Y° is optionally Qb-Qsssr wherein Qsssr is (CH(R38))r-W4, r is an 4 integer selected from 1 through 2, W 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, 23-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-23-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-15 4-one-23-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, and3,5-tetrahydropyranyl, and each carbon and hyrido 4 containing nitrogen member of the ring of the W other than the points of 20 attachment is optionally substituted with one or more of the group consisting of 9 10 11 12 38 o 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 W4; Y° is optionally Qb-Qssss wherein Qssss js (CH(R38))r-W~*, r is an integer selected from 1 through 2, 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 00/69833 PCT/USOO/08226 benzothiophenyl, 3,4-benzothiophenyl, 3,5-benzothiophenyl, 3,6-benzothiophenyl, 3,7-benzothiophenyl, 2,7-imidazo(l,2-a)pyridinyl, 3,4-imidazo( 1 ,2-a)pyridinyl, 3,5-imidazo(l,2-a)pyridinyl, 3,6-imidazo(l,2-a)pyridinyl, 3,7-imidazo(l,2-a)pyridinyl, 2,4-indolyl, 2,5-indolyl, 2,6-5 indolyl, 2,7-indolyl, 3,4-indolyI, 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-indazolyI,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-isoquinoIinyl, 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 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 lowest number _5 38 o substituent position of each W and that (CH(R ))r is bonded to E ; • ii ^.ssssr . . „ssssr. ,^.^38^^ ,„6 25 Y is optionally Q -Q wherein Q is(CH(R ))r-W ,risan 6 integer selected from 1 through 2, 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, 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 00/69833 PCT/US00/08226 benzothiophenyl, 3,7-benzothiophenyl, 2,7-imidazo(l,2-a)pyridinyI, 3,4-imidazo( 1,2-a)pyridinyl, 3,5-imidazo(l,2-a)pyridinyl, 3,6-imidazo(l,2-a)pyridinyl, 3,7-imidazo(l,2-a)pyridinyl, 2,4-indolyl, 2,5-indolyl, 2,6-indolyl, 2,7-indolyl, 3,4-indolyl, 3,5-indolyI, 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-quinolinyI, 3,4-quinolinyl, 3,5-quinoIinyl, 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-isoquinoiinyl, 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 6 2 0 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 R9, R^, R^\ and R*2, with the proviso that Qb is bonded to highest number 6 38 o substituent position of each W and that (CH(R ))r is bonded to E . In a preferred embodiment of compounds of Formula I or a 25 pharmaceutically acceptable salt thereof, 3- b J and J are each O; B is formula (V): 58 WO 00/69833 PCT/US00/08226 r3 4 r33\ Jl J. R32/D^DVR36 (V) 12 12 1 wherein D , D , J , J and K are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more 12 12 1 than one is a covalent bond, no more than one of D , D , J , J and K is O, 12 12 1 12 12 5 no more than one of D , D , J , J and K is S, one of D , D , J , J and 1 12 12 1 K must be a covalent bond when two of D , D , J , J and K are O and S, 12 12 1 and no more than four of D , D , J , J and K are N; 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, 10 haloacetamido, amidino, guanidino, alkylenedioxy, haloalkylthio, alkanoyloxy, alkoxy, alkoxyalkyl, haloalkoxylalkyl, hydroxy, amino, alkoxyamino, nitro, lower alkylamino, alkylthio, alkylthioalkyl, alkylsulfinyl, alkylsulfonyl, alkylsulfonylalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaiyl, heterocyclyl, alkylsulfonamido, alkylaminosulfonyl, 15 amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, alkanoyl, haloalkanoyl, alkyl, alkenyl, halo, haloalkyl, haloalkenyl, haloalkoxy, hydroxyhaloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxyalkyl, carboxyalkyl, carboalkoxy, carboxy, carboxamido, carboxamidoalkyl, and cyano; _ 16 19 32 33 34 35 J 36 . , , . R ,R ,R ,R ,R T R , and R are independently optionally 20 Qb with the proviso that no more than one of and R^ is Qb at the same b be time and that Q is Q ; 59 WO 00/69833 PCT/U S00/08226 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 32 33 5 attachment of B to A with one or more of the group consisting of R , R , 34 35 , 36 R , R , and R ; B is optionally selected from the group consisting of C3-C12 cycloalkyl and C4-C9 saturated heterocyclyl, wherein each ring carbon may be 33 optionally substituted with R , a ring carbon other than the ring carbon at the 10 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 9 13 may be optionally substituted with R or R , a ring carbon or nitrogen 9 adjacent to the R position and two atoms from the point of attachment is 10 13 15 optionally substituted with R , a ring carbon or nitrogen adjacent to the R position and two atoms from the point of attachment is optionally substituted 12 with R , a ring caibon or nitrogen three atoms from the point of attachment 10 11 and adjacent to the R position is optionally substituted with R , a ring carbon or nitrogen three atoms from the point of attachment and adjacent to the 12 33 20 R position is optionally substituted with R , and a ring carbon or nitrogen 11 33 four atoms from the point of attachment and adjacent to the R and R 34 positions is optionally substituted with R ; A is selected from the group consisting of single covalent bond, (W ^-(CHCR ))pa and (CH(R^))pa-(W )rr wherein rr is an integer 7 25 selected from 0 through 1, pa is an integer selected from 0 through 6, and W 7 7 is selected from the group consisting of O, S, C(O), (R )NC(0), (R )NC(S), 60 WO 00/69833 PCT/US00/08226 7 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; alkyl; 7 R is selected from the group consisting of hydrido, hydroxy, and 15 5 R 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; R^ is selected from the group consisting of hydrido, alkyl, alkenyl, 10 cyano, halo, haloalkyl, haloalkoxy, haloalkylthio, amino, aminoalkyl, alkylamino, amidino, hydroxy, hydroxyamino, alkoxy, hydroxyalkyl, alkoxyamino, thiol, and alkylthio; R2 is Z°-Q; Z° is selected from the group consisting of covalent single bond, 41 42 41 15 (CR R )a wherein q is an integer selected from 1 through 3, (CH(R ))„- M b o 42 W -(CH(R ))p wherein g and p are integers independently selected from 0 through 3 and W° is selected from the group consisting of O, S, C(O), S(O), 41 41 41 22 42 N(R ), and ON(R ), and (CH(R ))e-\V -(CH(R ))^ wherein e and h are integers independently selected from 0 through 1 and is selected from 41 42 20 the group consisting of CR =CR , 1,2-cyclopropyI, 1,2-cyclobutyl, 1,2- cyclohexyl, 13-cyclohexyl, 1,2-cyclopentyl, 13-cyclopentyl, 23-morpholinyl, 2,4-morpholinyl, 2,6-morpholinyl, 3,4-morpholinyl, 3,5-morpholinyl, 1,2-piperaz.inyl, 13-piperazinyl, 2,3-piperazinyl, 2,6-piperazinyl, 1,2-piperidinyl, 13-piperidinyl, 23-piperidinyl, 2,4-piperidinyl, 25 2,6-piperidinyl, 3,4-piperidinyl, 1,2-pyrrolidinyl, 1,3-pyrrolidinyl, 23-pyrrolidinyl, 2,4-pyrrolidmyl, 2,5-pyrrolidinyl, 3,4-pyrrolidinyl, 23- 61 WO 00/69833 PCT/USO0/08226 tetrahydrofuranyl, 2,4-tetrahydrofuranyl, 2,5-tetrahydrofuranyl, and 3,4-tetrahydrofuranyl, with the proviso that Z° is directly bonded to the uracil ring; 41 42 R and R are independently selected from the group consisting of amidino, hydroxyamino, hydrido, hydroxy, amino, and alkyl; Q is selected from the group consisting of hydrido, with the proviso that Z° is other than a covalent single bond, and the formula (II): R11 Rl0\ 2/Rl2 Jl J (II) 12 12 1 wherein D , D , J , J and K are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more 12 12 1 10 than one is a covalent bond, no more than one of D , D , J , J and K is O, 12 12 1 12 12 no more than one of D , D , J , J and K is S, one of D , D , J , J and 1 12 12 1 K must be a covalent bond when two of D ,D , J ,J andK are O and S, 12 12 1 and no more than four of D , D , J , J and K are N, with the proviso that 9 10 11 12 ■ 13 , . J , , , , . . L R , R , R , R , and R are each independently selected to maintain the 15 tetravalent nature of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen; 4a 4b K is (CR R )n wherein n is an integer selected from 1 through 2; 4a 4b R and R are independently selected from the group consisting of halo, hydrido, hydroxyalkyl, alkyl, alkoxyalkyl, alkylthioalkyl, and haloalkyl; 62 WO 00/69833 PCT/US00/08226 E° is e\ when K is (CR4^ )n, wherein E^ is selected from the 7 group consisting of a covalent single bond, C(O), C(S), C(0)N(R ), (R?)NC(0), S(0)2, (R7)NS(0)2, and S(0)2N(R7); Y° is formula (IV): 0s RlVs^S^RJ •D5-^ *c- R16/-^K2^"^R19 n° 5 Q (IV) 5 6 5 6 wherein D , D , J , and J are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more 21 5 6 5 6 than one is a covalent bond, K is C, no more than one of D , D , J , and J is O, no more than one of D^, J^, and is S, one of D^, D^, J^, and 10 must be a covalent bond when two of D^, D*\ and are O and S, and no 5 6 5 6 16 17 more than four of D , D , J , and J are N with the proviso that R , R , 18 19 R ,andR 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 . , ■ • , 15 R ,R ,R , andR 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, haloalkyl, haloalkoxy, hydroxyalkyl, alkylenylamino, haloalkoxyalkyl, 20 carboalkoxy, and cyano; 63 WO 00/69833 PCT/US00/08226 b 20 21 Q is selected from the group consisting of NR R , aminoalkylenyl, Q e wherein Q e is hydrido, N(R )C(NR )N(R )(R ), and 25 23 24 . 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 23 24 5 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, aminoalkylenyl, amino, dialkylamino, alkylamino, and hydroxyalkyl; g 10 Q is selected from the group consisting of a single covalent bond, 37 38 (CR R )£, wherein b is an integer selected from 1 through 4, and (CH(R^4))c-W^-(CH(R^))cj wherein c and d are integers independently selected from 1 through 3 and is selected from the group consisting of C(0)N(R14), (R14)NC(0), S(O), S(0)2, S(0)2N(R14), N(R14)S(0)2, and 14 14 15 N(R ), with the provisos that R is selected from other than halo when 37 38 14 directly bonded to N and that (CR R )^, and (CH(R ))c are bonded_to E°; 14 R is selected from the group consisting of hydrido, halo, alkyl, and haloalkyl; R: 20 hydrido, alkyl, and haloalkyl; R38 heteroaroyl; 37 38 R and R are independently selected from the group consisting of 38. R is optionally selected from the group consisting of aroyl and 64 WO 00/69833 PCT/US00/08226 * Y° is optionally Qb-QSS wherein QSS is (CH(R^ ))e-W2-(CH(R ))j,, wherein e and h are integers independently selected from 1 through 2 and 4a 4b 14 . o is CR =CR with the proviso that (CH(R ))e is bonded to E ; 0 b ssss b Y is optionally selected from the group consisting of Q -Q and Q - ^ssssr , . ^ssss. ,, ^5 jnssssr. , 38_ „.6 Q wherein Q is (CH(R ))r-W and Q ' is (CH(R ))r-W , r is an integer selected from 1 through 2, and and are independently selected fromthe 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( l,2-a)pyridinyl, 2,4-indolyl, 2,5-indolyl, 2,6-indolyI, 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-indazolyI, 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-isoquinoiinyl, 1,5-isoquinolinyl, 1,6-isoquinoIinyl, 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, 4,8-3 0 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- 65 WO 00/69833 PCT/US00/08226 cinnolinyl, and each carbon and hyrido containing nitrogen member of the ring ,5 6 5 of the \v and of the ring of the W , other than the points of attachment of W and W^, is optionally substituted with one or more of the group consisting of R9, R^, R^, and R*2, with the provisos that Q*5 is bonded to lowest 5 number substituent position of each W^, Qb is bonded to highest number 6 38 o substituent position of each W , and (CH(R ))r is bonded to E . In a more preferred embodiment of compounds of Formula I or a pharmaceutically acceptable salt thereof, a b J and J are each O; 10 B 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 32 by R , the other carbon adjacent to the carbon at the point of attachment is 36 32 optionally substituted by R , a carbon adjacent to R and two atoms from 33 the carbon at the point of attachment is optionally substituted by R , a carbon 36 15 adjacent to R and two atoms from the carbon at the point of attachment is 35 33 35 optionally substituted by R , and any carbon adjacent to both R and R is • j i n34 optionally substituted by 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, 20 alkylenedioxy, haloalkylthio, alkanoyloxy, alkoxy, hydroxy, amino, alkoxyamino, alkanoyl, haloalkanoyl, nitro, lower alkylamino, alkylthio, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, alkylsulfonamido, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, alkyl, alkenyl, halo, haloalkyl, haloalkenyl, haloalkoxy, 25 hydroxyalkyl, alkylenylamino, carboalkoxy, carboxy, carboxamido, cyano, and Qb; 66 WO 00/69833 PCT/US00/08226 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 32 33 5 attachment of B to A with one or more of the group consisting of R , R , 34 35 J 36 R , R , and R ; B is optionally selected from the group consisting of C3-C12 cycloalkyl and C4-C9 saturated heterocyclyl, wherein each ring carbon is 33 optionally optionally substituted with R , a ring carbon other than the ring 10 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 9 13 attachment are optionally substituted with R or R , a ring carbon or nitrogen 9 adjacent to the R position and two atoms from the point of attachment is 10 . 13 15 optionally substituted with R , a ring carbon or nitrogen adjacent to the R position and two atoms from the point of attachment is optionally substituted 12 with R , a nng carbon or nitrogen three atoms from the point of attachment L T.10 . . . ' . „ . j . . t „11 and adjacent to the R position is optionally substituted with R , a nng carbon or nitrogen three atoms from the point of attachment and adjacent to the 12 33 20 R position is optionally substituted with R , and a ring carbon or nitrogen 11 33 four atoms from the point of attachment and adjacent to the R and R 34 positions is optionally substituted with R ; 9 10 11 12 13 R , R , R , R , and R are independently selected from the group consisting of hydrido, acetamido, haloacetamido, alkoxyamino, 25 alkanoyl, haloalkanoyl, amidino, guanidino, alkylenedioxy, haloalkylthio, alkoxy, hydroxy, amino, lower alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylsulfonamido, amidosulfonyl, monoalkyl amidosulfonyl, 67 WO 00/69833 PCT/US00/08226 dialkyl amidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, carboalkoxy, carboxyalkyl, carboxy, carboxamido, and cyano; 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 5 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?); 7 R is selected from the group consisting of hydrido, hydroxy and alkyl; 15 R is selected from the group consisting of hydrido, hydroxy, halo, alkyl, and haloalkyl; 10 W is NH; M is selected from the group consisting of N and R^-C; R1 is selected from the group consisting of hydrido, alkyl, cyano, halo, haloalkyl, haloalkoxy, amino, aminoalkyl, alkylamino, amidino, hydroxy, hydroxyamino, alkoxy, hydroxyalkyl, alkoxyamino, thiol, and 15 alkylthio; R2 is Z°-Q; Z° is selected from the group consisting of covalent single bond and 41 42 41 (CR R )q wherein q is an integer selected from 1 through 2, (CH(R ))g- J) 42 W -(CH(R ))p wherein g and p are integers independently selected from 0 o 41 20 through 3 and W is selected from the group consisting of 0, S, and N(R ), 41 22 42 and (CH(R ))e-\V -(CH(R ))}j wherein e and h are integers independently selected from 0 through 1 and is 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, 13-cyclopentyl, 2,3-morpholinyl, 2,4-25 morpholinyl, 2,6-morpholinyl, 3,4-morpholinyl, 3,5-morpholinyl, 1,2- piperazinyl, 13-piperazinyl, 2,3-piperazinyl, 2,6-piperazinyl, 1,2-piperidinyl, 68 WO 00/69833 PCT/US00/08226 13-piperidinyl, 2,3-piperidinyl, 2,4-piperidinyl, 2,6-piperidinyl, 3,4-piperidinyl, 1,2-pyrrolidinyl, 13-pyrrolidinyl, 23-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 5 proviso that Z° is directly bonded to the uracil ring; 41 42 R and R are independently selected from the group consisting of hydrido, hydroxy, and amino; Q is selected from the group consisting of hydrido, with the proviso thatZ° is other than a covalent single bond, 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 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 13 adjacent to R and two atoms from the carbon at the point of attachment is 12 10 12 15 optionally substituted by R , and any carbon adjacent to both R and R is optionally substituted by R^; 4a 4a 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, 2 0 C(0)N(H), (H)NC(O), (R7)NS(0)2, and S(0)2N(R?); Y° is formula (IV): 69 WO 00/69833 PCT/US00/08226 0s R17- Jll J. D5^ V, 16/ ^,2 R1 9 (IV) R K R ib 5 6 5 6 wherein D , D , J , and J are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more than one is a covalent bond, is C, no more than one of D^, D^, J^, and 565 6 565 6 5 is O, no more than one of D , D , J , and J is S, one of D , D , J , and J must be a covalent bond when two of D^, D^, J^, and are O and S, and no 5 6 5 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 of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the 10 divalent nature of oxygen; ^16 „17 _18 19 . J , , 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, alkylsulfmyl, alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, halo, haloalkyl, haloalkoxy, 15 hydroxyalkyl, aminoalkyl, and cyano; R^ and R^ 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 is Q ; b 20 21 b b Q is selected from the group consisting of NR R , Q wherein Q oq oa. tc oa hydrido, N(R )C(NR )N(R )(R ), and C(NR )NR R , with the 20 21 20 provisos that no more than one of R and R is hydroxy, amino, alkylamino, 70 WO 00/69833 PCT/US00/08226 23 24 dialkylamino at the same time and that no more than one of R andR 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; § 5 Q is selected from the group consisting of a single covalent bond, 37 38 (CR R )fc wherein b is an integer selected from 1 through 4, and (CH(R^))c-W^-(CH(R^))cj wherein c and d are integers independently selected from 1 through 3 and is selected from the group consisting of C(0)N(R14), (R14)NC(0), S(O), S(0)2, S(0)2N(R14); N(R14)S(0)2, and 14 14 10 N(R ), with the provisos that R is selected from other than halo when 3*7 38 directly bonded to N and that (CR R )b, and (CH(R ))c are bonded to E°; 14 R is selected from the group consisting of hydrido, halo, alkyl, and haloalkyl; 37 38 R and R are independently selected from the group consisting of 15 hydrido, alkyl, and haloalkyl; 38 R is optionally selected from the group consisting of aroyl and heteroaroyl; Y° is optionally Qb-QSS wherein QSS is (CH(R14))e-W2-(CH(R15))h, wherein e and h are integers independently selected from 1 through 2 and 20 is CR4a=CH with the proviso that (CH(R*4))e is bonded to E°. w2 In an even more preferred embodiment of compounds of Formula I or a pharmaceutically acceptable salt thereof, a b J and J are each O; B is selected from the group consisting of aryl and heteroaryl wherein a 2 5 carbon adjacent to the carbon at the point of attachment is optionally substituted 71 WO 00/69833 PCT/USOQ/08226 32 by R , the other carbon adjacent to the carbon at the point of attachment is 36 32 optionally substituted by R , a carbon adjacent to R and two atoms from 33 the carbon at the point of attachment is optionally substituted by R , a carbon 36 adjacent to R and two atoms from the carbon at the point of attachment is 35 33 35 5 optionally substituted by R , and any carbon adjacent to both R and R is 34 optionally substituted by 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, 10 amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, alkyl, halo, 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 15 an integer selected from 0 through 3, and W is selected from the group 7 7 consisting of (R )NC(0) and N(R ); 7~ R is selected from the group consisting of hydrido, hydroxy and alkyl; 15 R is selected from the group consisting of hydrido, halo, alkyl, and haloalkyl; 20 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, alkylamino, aminoalkyl, alkylthio, alkoxyamino, haloalkyl, haloalkoxy, and 25 halo; 72 WO 00/69833 PCT/US00/08226 R2 is Z°-Q; Z° is selected from the group consisting of a covalent single bond, O, S, NH, and CH2; Q is selected from the group consisting of aryl and heteroaryl wherein a 5 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 carbon at the point of attachment is optionally substituted by R^, a carbon 13 adjacent to R and two atoms from the carbon at the point of attachment is 12 10 12 10 optionally substituted by R , and any carbon adjacent to both R andR 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 alkylamino, alkylthio, alkylsulfonamido, alkylsulfinyl, alkylsulfonyl, 15 amidosulfonyl, monoalkyl amidosulfonyl, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboxy, carboxamido, and cyano; 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, 20 amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, hydroxyalkyl, aminoalkyl, carboalkoxy, carboxy, carboxyalkyl, amidocarbonyl, halo, haloalkyl, and cyano; K is CH2; E° is C(0)N(H); 25 Y° is formula (IV): 73 WO 00/69833 PCT/US00/08226 Qs ji? a6 R11 R16/D\2^D^R19 nb Q JIV) wherein D^, D^, J , and J are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more than one is a covalent bond, is C, no more than one of D^, D^, J^, and 5 6 5 6 5 is optionally O, no more than one of D , D , J , and J is optionally S, one of 5656 5656 D , D , J , and J must be a covalent bond when two of D , D , J , and J 5 6 5 6 are O and S, and no more than four of D , D , J , and J are N; R^, r'7, R^8, and R^9 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; R^ and R^ are optionally Qb with the proviso that no more than one of R^ and R*^ is Qb at the same time and that is Q^C; b 20 21 be be 15 Q is selected from the group consisting of NR R ,Q wherein Q is 25 23 24 20 hydrido, and C(NR )NR R , with the provisos that no more than one of R 21 23 24 and R 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 R , R , R , F 20 consisting of hydrido, alkyl, and hydroxy; 20 21 23 24 25 R , R , R , R , and R are independently selected from the group 74 WO 00/69833 PCT/US00/08226 s • Q is selected from the group consisting of a single covalent bond, CH2, andCH2CH2. In another even more preferred embodiment of compounds of Formula I or a pharmaceutically acceptable salt thereof, a b 5 J and J are each O; 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 10 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, 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(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 7 7 20 consisting of (R )NC(0) and N(R ); 7 R is selected from the group consisting of hydrido, hydroxy and alkyl; R^ is selected from the group consisting of hydrido, halo, alkyl, and haloalkyl; is NH; 25 Mis selected from the group consisting of N and R^-C; R1 is selected from the group consisting of hydrido, hydroxy, hydroxyamino, amidino, amino, cyano, hydroxyalkyl, alkoxy, alkyl, 75 WO 00/69833 PCT/US00/08226 alkylamino, aminoalkyl, alkylthio, alkoxyamino, haloalkyl, haloalkoxy, and halo; R2 is Z°-Q; Z° is selected from the group consisting of a covalent single bond, O, 5 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 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 13 adjacent to R and two atoms from the carbon at the point of attachment is 12 10 12 optionally substituted by R , 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 15 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 R and R are independently selected from the group consisting of 2 0 hydrido, acetamido, haloacetamido, amidiiio, guanidino, alkyl, alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, alkylsulfonamido, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, hydroxyalkyl, alkylenylamino, carboalkoxy, carboxy, carboxyalkyl, amidocarbonyl, halo, haloalkyl, and cyano; 25 K is CH2; E° is C(0)N(H); Y° is formula (IV): 76 WO 00/69833 PCT/USOO/08226 Qs i?17 ^ R R11 Jl J ,5 R16/D%2^D^-R19 Jb (IV) 5 6 5 6 wherein D , D , J , and J are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more than one is a covalent bond, is C, no more than one of D^, J~*, and 565 6 565 6 5 is O, no more than one of D , D , J , and J is S, one of D , D , J , and J must be a covalent bond when two of D^, D^, and are O and S, and no 5 6 5 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 of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the 10 divalent nature of oxygen; _16 17 18 19 . J ■ , , ' 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, 15 alkylenylamino, and cyano; R^ and R^9 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 is Q ; b 20 21 be Q is selected from the group consisting of NR R , Q wherein 1 ac no *ya nz nc no Q is hydrido, C(NR )NR R , and N(R )C(NR )N(R )(R ), with 77 WO 00/69833 PCT/US00/08226 20 21 . the provisos that no more than one of R and R is hydroxy at the same time 23 24 and that no more than one of R and R is hydroxy at the same time; 20 21 23 „24 25 J 26 . R , R , R , R , R , and R are independently selected from the group consisting of hydrido, alkyl, and hydroxy; s 5 Q is selected from the group consisting of a single covalent bond, CH2, andCH2CH2. In still another even more preferred embodiment of compounds of Formula I or a phaimaceutically acceptable salt thereof, a b J and J are each O; 10 B is optionally selected from the group consisting of C3-C7 cycloalkyl and C4-C6 saturated heterocyclyl, wherein each ring carbon is optionally 33 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 carbons and a 15 nitrogen adjacent to the carbon atom at the point of attachment are optionally 9 13 9 substituted with R or R , a ring carbon or nitrogen adjacent to the R position and two atoms from the point of attachment is optionally substituted • t«10 ■ ^ • j- ^ _ 13 with R , a nng carbon or nitrogen adjacent to the R position and two atoms 12 from the point of attachment is optionally substituted with R , a ring carbon 20 or nitrogen three atoms from the point of attachment and adjacent to the R^ position is optionally substituted with R^, a ring carbon or nitrogen three 12 atoms from the point of attachment and adjacent to the R position is 33 optionally substituted with R , and a ring carbon or nitrogen four atoms from 11 33 the point of attachment and adjacent to the R and R positions is optionally 34 25 substituted with R ; 78 WO 00/69833 PCT/US00/08226 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; R^ and R*2 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, alkylenylamino, carboalkoxy, carboxy, carboxyalkyl, amidocarbonyl, halo, haloalkyl, and cyano; 33 34 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 15 amidosulfonyl, dialkyl amidosulfonyl, alkyl, halo, 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 an integer selected from 0 through 3, and W is selected from the group 7 7 20 consisting of (R )NC(0)andN(R ); 7 R is selected from the group consisting of hydrido, hydroxy and alkyl; 15 R is selected from the group consisting of hydrido, halo, alkyl, and haloalkyl; ^ is NH; 25 Mis selected from the group consisting of N and R* -C; R1 is selected from the group consisting of hydrido, hydroxy, hydroxyamino, amidino, amino, cyano, hydroxyalkyl, alkoxy, alkyl, 79 WO 00/69833 PCT/US00/08226 alkylamino, aminoalkyl, alkylthio, alkoxyamino, haloalkyl, haloalkoxy, and halo; R2 is Z°-Q; Z° is selected from the group consisting of a covalent single bond, O, 5 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 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 13 adjacent to R and two atoms from the carbon at the point of attachment is 12 10 12 optionally substituted by R , and any carbon adjacent to both R and R is optionally substituted by R**; K is CH2; 15 E° is C(0)N(H); Y° is formula (IV): 0s R17- R16/D\2^D\R19 nb Q (iv) 5 6 5 6 wherein D , D , J , and J are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more 2 0 than one is a covalent bond, is C, no more than one of J~*, and 80 WO 00/69833 PCT/US00/08226 is O, no more than one of D"\ J , andJ is S, one of D , D ,J ,andJ must be a covalent bond when two of D^, D^, J ,andJ are O and S, and no more than four of D6, J^, and J6 are N, with the provisos that R1^, R17, 18 19 R , 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; R^, R^7, R*8, and R*9 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; R^ and R*9 are optionally Qb with the proviso that no more than one of 16 19, b . _ b. _be R and R is Q at the same time and that Q is Q ; b 20 21 be be Q is selected from the group consisting of NR R , Q wherein Q is 25 23 24 20 15 hydrido, and C(NR )NR R , with the provisos that no more than one of R 21 23 24 and R 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 R ,R ,R ,R ,andR are independently selected fromthe group consisting of hydrido, alkyl, and hydroxy; s 20 Q is selected from the group consisting of a single covalent bond, CH2, and CH2CH2. In a most preferred embodiment of compounds of Formula I or a phannaceutically acceptable salt thereof, J3 and Jb are each O; 25 B 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 81 WO 00/69833 PCT/US00/08226 32 by R , the other carbon adjacent to the carbon at the point of attachment is 36 32 optionally substituted by R , a carbon adjacent to R and two atoms from 33 the carbon at the point of attachment is optionally substituted by R , a carbon 36 adjacent to R and two atoms from the carbon at the point of attachment is 35 33 35 5 optionally substituted by R , and any carbon adjacent to both R and R is 34 optionally substituted by 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, 10 amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, alkyl, halo, 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 15 an integer selected from 0 through 3, and W is N(R ); 7 R is selected from the group consisting of hydrido and alkyl; 15 R is selected from the group consisting of hydrido, halo, alkyl, and haloalkyl; ^ is NH; 20 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; 25 R2 is Z°-Q; 82 WO 00/69833 PCT/US00/08226 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 9 by R , the other carbon adjacent to the carbon at the point of attachment is 13 9 5 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 13 adjacent to R and two atoms from the carbon at the point of attachment is 12 10 12 optionally substituted by R , and any carbon adjacent to both R and R is optionally substituted by R^; 9 11 13 10 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 12 15 R and R 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, 2 0 carboxy, carboxy al ky 1, carboxy amido, and cyano; K is CH2; E° is C(0)N(H); Y° is formula (IV): 83 WO 00/69833 PCT/US00/08226 Qs R17^ ^ R11 lb Q (iv) 5 6 5 6 wherein D , D , J , and J are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more than one is a covalent bond, is C, no more than one of D^, J^, and 5 is O, no more than one of D~*, D*\ J~*, and is S, one of D^, D*\ J^, and must be a covalent bond when two of D~*, D^, J^, and 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 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, alkylsulflnyl, alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, and cyano; R^ and R^ are optionally Q*5 with the proviso that no more than one of R^ and R*9 is Qb at the same time and that is Qbe; _b. , ,, . . . -__20_21 _be , . „be . 15 Q is selected from the group consisting of NR R ,Q wherein Q is 25 23 24 hydrido, and C(NR )NR R ; 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. 84 WO 00/69833 PCT/US00/08226 In another most preferred embodiment of compounds of Formula I or a pharmaceutical^ acceptable salt thereof, a b J and J are each O; B is optionally selected from the group consisting of hydrido, C2-C8 5 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 consisting of R , R , R , R , and R ; 32 33 34 35 36 R , R , R , R , and R are independently selected from the 10 group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, alkylthio, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboalkoxy, carboxy, carboxamido, cyano, and Qb; 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 7 an integer selected from 0 through 3, and W is N(R ); 7 R is selected from the group consisting of hydrido and alkyl; 15 R is selected from the group consisting of hydrido, halo, alkyl, and 20 haloalkyl; W is NH; M is selected from the group consisting of N and R1 -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; R2 is Z°-Q; Z° is a covalent single bond; 85 WO 00/69833 PCT/US00/08226 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 5 carbon at the point of attachment is optionally substituted by R' a carbon 13 adjacent to R and two atoms from the carbon at the point of attachment is optionally substituted by R^, 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, alkylsulflnyl, alkylsulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboxy, carboxamido, and cyano; R^ and R^ 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, carboxyalkyl, carboxyamido, and cyano; 20 K is CH2; E° is C(0)N(H); Y° is formula (IV): 86 WO 00/69833 PCT/US00/08226 Qs R17 \A/ Ji • D5- R16/"^K2^R19 Qb (iv) 5 6 5 6 wherein D , D , J , and J are independently selected from the group consisting of C, N, O, 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^, D^, J^, and 5 is O, no more than one of D^, J~*, and is S, one of D^, D^, J^, and 5 6 5 6 must be a covalent bond when two of D , D , J , and J are O and S, and no 5 6 5 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 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, lower alkylamino, alkylthio, alkylsulflnyl, alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, 15 aminoalkyl, and cyano; R^ and R*9 are optionally with the proviso that no more than one of R^ and R*9 is Qb at the same time and that Qb is Qbe; b 20 21 be b Q is selected from the group consisting of NR R , Q wherein Q hydrido, N(R26)C(NR25)N(R23)(R24), and C(NR25)NR23R24; 87 WO 00/69833 PCT/USOQ/08226 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 CH2. In still another most preferred embodiment of compounds of Formula I 5 or a pharmaceutical^ acceptable salt thereof, a b J and J are each O; B is optionally selected from the group consisting of C3-C7 cycloalkyl and C4-C6 saturated heterocyclyl, wherein each ring carbon is optionally 33 substituted with R , a ring carbon other than the nng carbon at the point of 10 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 are optionally 9 13 9 substituted with R or R , a ring carbon or nitrogen adjacent to the R position and two atoms from the point of attachment is optionally substituted ., „10 . j. , 13 . . 15 with R , a nng carbon or nitrogen adjacent to the R position and two atoms 12 from the point of attachment is optionally substituted with R , a ring carbon or nitrogen three atoms from the point of attachment and adjacent to the R^ position is optionally substituted with R* \ a ring carbon or nitrogen three 12 atoms from the point of attachment and adjacent to the R position is 33 2 0 optionally substituted with R , and a ring carbon or nitrogen four atoms from 11 33 the point of attachment and adjacent to the R and R positions is optionally 34 substituted with 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, alkylsulflnyl, alkylsulfonyl, amidosulfonyl, 88 WO 00/69833 PCT/US00/08226 monoalkyl amidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboxy, carboxamido, and cyano; and R*2 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, aminoalkyl, halo, haloalkyl, carboalkoxy, carboxy, carboxyalkyl, carboxyamido, and cyano; 33 34 R and R are independently selected from the group consisting of 10 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; 33 b R is optionally Q ; 15 A is selected from the group consisting of single covalent bond and 15 7 (CH(R ))pa-(W )„. wherein rr is an integer selected from 0 through 1, pa is 7 7 an integer selected from 0 through 3, and W isN(R ); 7 R is selected from the group consisting of hydrido, hydroxy and alkyl; 15 R is selected from the group consisting of hydrido, halo, alkyl, and 20 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, hydroxyamino, amidino, amino, cyano, hydroxyalkyl, alkoxy, alkyl, 25 alkylamino, aminoalkyl, alkylthio, alkoxyamino, haloalkyl, haloalkoxy, and halo; R2 is Z°-Q; Z° is a covalent single bond; 89 WO 00/69833 PCT/US00/08226 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 13 adjacent to R and two atoms from the carbon at the point of attachment is 12 10 12 optionally substituted by R , and any carbon adjacent to both R and R is optionally substituted by R^; K is CH2; 10 E° is C(0)N(H); Y° is formula (IV): (IV) 5 6 5 6 wherein D , D , J , and J are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more 2 5 6 5 6 15 than one is a covalent bond, K is C, no more than one of D , D , J , and J is O, no more than one of D~*, D , and is S, one of D~", D^, J^, and 5 6 5 6 must be a covalent bond when two of D , D , J , and J are O and S, and no more than four of D^, D^, and are N, with the provisos that R^, R*7, R*8, and R^ are each independently selected to maintain the tetravalent nature 90 WO 00/69833 PCT/US00/08226 10 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, alkylsulflnyl, alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, alkylenylamino, and cyano; R^ and R^9 are optionally Qb with the proviso that no more than one of R^ and R^ is Qb at the same time and that Qb is Q^e; Qb is selected from the group consisting of NR^R^\ Qbe wherein Qbe is 25 23 24 hydrido, and C(NR )NR R ; 20 21 23 24 25 R , R , R , R , and R are independently selected from the group consisting of hydrido and alkyl; QSisCH2. In a preferred specific embodiment of Formula 1, compounds have the Formula I-S: o m (i-s) or a pharmaceutical^ acceptable salt thereof, wherein; B 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, l,2,4-triazol-3-yl, l,2,4-triazol-5-yl, 1,2,4-oxadiazol-3-yl, l,2,4-oxadiazol-5-yl, 13,4-oxadiazol-3-yl, l,3,4-oxadiazol-5-yl, 3-isothiazolyl, 5-isothiazolyl, 2-oxazolyl, 2-thiazolyl, 3-isoxazolyl, 5-isoxazolyl, 91 WO 00/69833 PCT/US00/08226 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyI, 13,5-triazin-2-yl, l,2,4-triazin-3-yl, l,2,4-triazin-5-yl, l,2,4-triazin-6-yl, l,23-triazin-4-yl, and 1,23-triazin-5-yl„ wherein a carbon adjacent to the carbon at the point of attachment is 32 5 optionally substituted by R , the other carbon adjacent to the carbon at the 36 32 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 33 36 substituted by R , a carbon adjacent to R and two atoms from the carbon at 35 the point of attachment is optionally substituted by R , and any carbon 33 35 34 10 adjacent to both R and R is optionally substituted by R ; 32 33 _34 35 36 R , 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, 15 aminomethyl, 1-aminoethyl, 2-aminoethyl, N-methylamino, dimethylamino, N-ethylamino, methylthio, ethylthio, isopropylthio, trifluoromethylthio, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, 2,2333-pentafluoropropyl, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro, bromo, amidosulfonyl, N-methylamidosulfonyl, N,N-20 dimethylamidosulfonyl, acetyl, propanoyl, trifluoroacetyl, 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, 25 and Qb; B is selected from the group consisting of hydrido, trimethylsilyl, ethyl, 2-propenyl, 2-propynyl, propyl, isopropyl, butyl, 2-butenyl, 3-butenyl, 2-butynyl, sec-butyl, /ert-butyl, isobutyl, 2-methylpropenyl, l-pentyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-pentynyl, 3-pentynyl, 2-pentyl, 1-methyl-30 2-butenyl, l-methyl-3-butenyl, l-methyl-2-butynyl, 3-pentyl, l-ethyl-2- propenyl, 2-methylbutyl, 2-methyl-2-butenyl, 2-methyl-3-butenyl, 2-methyl-3- 92 WO 00/69833 PCT/US00/08226 butynyl, 3-methylbutyl, 3-methyl-2-butenyl, 3-methyl-3-butenyl, l-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, l-methyl-4-pentenyl, 1-methyl-2-pentynyl, l-methyl-3-pentynyl, 3-hexyl, l-ethyl-2-butenyl, 1-ethyl- 5 3-butenyl, l-propyl-2-propenyl, l-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, l-methyl-3-hexenyl, 1-methyl-4-hexenyl, l-methyl-5-hexenyl, l-methyl-2-hexynyl, l-methyl-3-hexynyl, l-methyl-4-hexynyl, 3-heptyl, l-ethyl-2-pentenyl, l-ethyI-3-10 pentenyl, l-ethyl-4-pentenyl, l-butyl-2-propenyl, l-ethyl-2-pentynyl, 1-ethyl- 3-pentynyl, 1-octyl, 2-octenyl, 3-octenyl, 4-octenyl, 5-octenyl, 6-octenyl, 7-octenyl, 2-octynyl, 3-octynyl, 4-octynyl, 5-octynyl, 6-octynyl, 2-octyl, 1-methyl-2-heptenyl, 1-methyl-3-heptenyl, l-methyl-4-heptenyl, l-methyl-5-heptenyl, l-methyl-6-heptenyl, l-methyl-2-heptynyl, l-methyl-3-heptynyl, 1- 15 methyl-4-heptenyl, 1-methyl-5-heptenyl, l-methyl-6-heptenyl, l-methyl-2-heptenyl, 1-methyl-3-heptynyl, l-methyl-4-heptynyI, 1-methyl-5-heptynyl, 3-octyl, l-ethyl-2-hexenyl, l-ethyl-3-hexenyl, l-ethyl-4-hexenyl, l-ethyl-2-hexynyl, l-ethyl-3-hexynyI, l-ethyl-4-hexynyl, 1-ethyl-5-hexenyl, l-pentyl-2-propenyl, 4-octyl, l-propyl-2-pentenyl, l-propyl-3-pentenyI, l-propyl-4-20 pentenyl, l-butyl-2-butenyl, l-propyl-2-pentynyl, l-propyl-3-pentynyl, 1-butyl-2-butynyl, l-butyl-3-butenyl, 2,2,2-trifIuoroethyl, 2,2-difluoropropyl, 4-trifluoromethyl-5,5,5-trifluoropentyl, 4-trifluoromethylpentyl, 5,5,6,6,6-pentafluorohexyl, and 33,3-trifluoropropyl, wherein each member of group B is optionally substituted at any carbon up to and including 5 atoms from the 32 2 5 point of attachment of B to A with one or more of the group consisting of R , 33 34 35 36 R , R , R , and R ; B is optionally selected from the group consisting of cyclopropyl, cyclobutyl, oxetan-2-yl, oxetan-3-yl, azetidin-l-yl, azetidin-2-yl, azetidin-3-yI, thiaetan-2-yl, thiaetan-3-yl, cyclopentyl, cyclohexyl, adamantyl, norbornyl, 3-30 trifluoromethylnorbornyl, 7-oxabicyclo[2.2.1]heptan-2-yl, bicyclo[3.1.0]hexan-6-yl, cycloheptyl, cyclooctyl, 2-morpholinyl, 3-morpholinyl, 4-morpholinyl, 1-piperazinyl, 2-piperazinyl, 1-piperidinyI, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 1-pyrrolidinyl, 2-pyrroIidinyl, 3-pyrrolidinyl, 2-dioxanyl, 4H-2-pyranyl, 4H-3-pyranyl, 4H-4-pyranyl, 4H- 93 WO 00/69833 PCT/US00/08226 pyran-4-one-2-yl, 4H-pyran-4-one-3-yl, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydropyranyl, 3-tetrahydropyranyl, 4-tetrahydropyranyl, 2-tetrahydrothienyl, and 3-tetrahydrothienyl, wherein each , 33 ring carbon is optionally substituted with R , ring carbons and a nitrogen 5 10 group consisting of hydrido, amidino, guanidino, carboxy, carboxymethyl, methyl, ethyl, isopropyl, propyl, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, methoxyamino, ethoxyamino, acetamido, trifluoroacetamido, nitro, aminomethyl, 1-aminoethyl, 2-aminoethyl, N-methylamino, 15 dimethylamino, N-ethylamino, methylthio, ethylthio, isopropylthio, trifluoromethylthio, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyI, 2,2333-pentafluoropropyl, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro, bromo, methanesulfonamido, amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, acetyl, propanoyl, 2 0 trifluoroacetyl, pentafiuoropropanoyl, hydroxy methyl, 1 -hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro-l-hydroxyethyl, 2,2,2-trifluoro-l-trifluoromethyl-l-hydroxyethyl, carboxymethyl, methoxycarbonyl, ethoxycarbonyl, amidocarbonyl, N-methylamidocarbonyl, N,N-dimethylamidocarbonyl, and cyano; 25 A is selected from the group consisting of single covalent bond, O, S, nh, n(ch3), n(oh), c(o), ch2, ch3ch, cf3ch, nhc(o), n(ch3)c(0), c(0)nh, c(0)n(ch3), cf3cc(0), c(0)cch3, c(0)ccf3, ch2c(0), (0)cch2, ch2ch2, ch2ch2ch2, ch3chch2, cf3chch2, adjacent to the carbon atom at the point of attachment is optionally substituted 9 13 9 with R orR , a ring carbon or nitrogen adjacent to the R position and two 10 atoms from the point of attachment is optionally substituted with R , and a 13 ring carbon or nitrogen adjacent to the R position and two atoms from the 12 point of attachment is optionally substituted with R ; 9 10 11 12 13 R , R , R , R , and R are independently selected from the 94 WO 00/69833 PCT/US00/08226 CH3CC(0)CH2, CF3CC(0)CH2, CH2C(0)CCH3, CH2C(0)CCF3, CH2CH2C(0), and CH2(0)CCH2; A is optionally selected from the group consisting of CH2N(CH3), CH2N(CH2CH3), CH2CH2N(CH3), and CH2CH2N(CH2CH3) with the 5 proviso that B is hydrido; M is selected from the group consisting of N and R^-C; 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, 10 trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, 2,2,333-pentafluoropropyl, methoxy, ethoxy, propoxy, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, methoxyamino, ethoxyamino, methylthio, ethylthio, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro, and bromo; 15 R2isZ°-Q; Z° is selected from the group consisting of covalent single bond, O, S, NH, CH2, CH2CH2, CH(OH), CH(NH2), CH2CH(OH), CH2CHNH2, CH(OH)CH2, and CH(NH2)CH2; Q is selected from the group consisting of phenyl, 2-thienyl, 3-thienyl, 2 0 2-furyl, 3-furyl, 2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl, 4-imidazolyl, 3- pyrazolyl, 4-pyrazolyl, l,2,4-triazol-3-yl, l,2.4-triazol-5-yl, 1,2,4-oxadiazol-3-yl, l,2,4-oxadiazol-5-yl, 13,4-oxadiazol-3-yl, l,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, 5-25 pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 13,5-triazin-2-yl, l,2,4-triazin-3-yl, l,2,4-triazin-5-yl, l,2,4-triazin-6-y1, l,23-triazin-4-yl, and 1,2,3-triazin-5-yl, wherein a carbon adjacent to the carbon at the point of attachment is 9 optionally substituted by R , the other carbon adjacent to the carbon at the 95 WO 00/69833 PCT/US00/08226 10 13 9 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 R , a carbon adjacent to R and two atoms from the carbon at 12 the point of attachment is optionally substituted by R , and any carbon , , 10 . _11 adjacent to both R and R is optionally substituted by R ; 4a 4a K is CHR wherein R is selected from the group consisting of methyl, ethyl, propyl, isopropyl, hydroxymethyl, 1-hydroxyethyl, methoxymethyl, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoromethyl, methylthiomethyl, and hydrido; E° is a covalent single bond, C(0)N(H), (H)NC(O), and S(0)2N(H); Y° is selected from the group of formulas consisting of: 96 WO 00/69833 PCT/US00/08226 97 WO 00/69833 PCT/US00/08226 5 consisting of hydrido, methyl, ethyl, isopropyl, propyl, amidino, guanidino, 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, 10 methylsulfonyl, ethylsulfonyl, trifluoromethyl, pentafluoroethyl, 2,2,2- trifluoroethyl, 2,2,333-pentafluoropropyl, trifluoromethoxy, 1,1,2,2- tetrafluoroethoxy, fluoro, chloro, bromo, amidosulfonyl, N- methylamidosulfonyl, N,N-dimethylamidosulfonyl, acetyl, propanoyl, trifluoroacetyl, pentafluoropropanoyl, hydroxymethyl, 1-hydroxyethyl, 2- 15 hydroxyethyl, 2,2,2-trifluoro- 1-hydroxyethyl, and cyano; R16 and R*9 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 is Q ; 98 WO 00/69833 PCT/US00/08226 b 20 21 be Q is selected from the group consisting of NR R , Q wherein K 'JA. Ofi 0^ 94 Q is hydrido, c(NR )NR R andN(R )c(NR )N(R )(R ), with 20 21 the proviso that no more than one of R and R is hydroxy, N- methylamino, and N,N-dimethylamino at the same time and that no more than 23 24 5 one of R and R is hydroxy, N-methylamino, and N,N-dimethylamino 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, hydroxy, 2-aminoethyl, 2-(N-methylamino)ethyl, and 2-(N,N-dimethylamino)ethyl; g 10 Q is selected from the group consisting of a single covalent bond, ch2, ch2ch2, ch3ch, cf3ch, ch3chch2, cf3chch2, CH2(CH3)CH, CH=CH, CF=CH, C(CH3)=CH, CH=CHCH2, CF=CHCH2, C(GH3)=CHCH2, CH2CH=GH, CH2CF=CH, CH2C(CH3)=CH, CH2CH=CHCH2, CH2CF=CHCH2, CH2C(CH3)=CHCH2, 15 CH2CH=CHCH2CH2, CH2CF=CHCH2CH2, and CH2C(CH3)=CHCH2CH2. In a more preferred specific embodiment of Formula I, compounds have the Formula I-MPS wherein B is an aromatic: 20 (I-MPS wherein B is aromatic) or a pharmaceutical^ acceptable salt thereof, wherein; 99 V WO 00/69833 PCT/USOO/08226 B 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, 5 3-pyridazinyl, 4-pyridazinyl, and 13,5-triazin-2-yl, wherein a carbon adjacent 32 to the carbon at the point of attachment is optionally substituted by R , the 10 15 20 25 N(CH3), N(OH), CH2, CH3CH, CF3CH, NHC(O), N(CH3)C(0), C(0)NH, C(0)N(CH3), CH2CH2, CH2CH2CH2, CH3CHCH2, and CF3CHCH2; 100 other carbon adjacent to the carbon at the point of attachment is optionally 36 32 substituted by R , a carbon adjacent to R and two atoms from the carbon at 33 the point of attachment is optionally substituted by R , a carbon adjacent to 36 R and two atoms from the carbon at the point of attachment is optionally 35 33 35 substituted by R , and any carbon adjacent to both R and R is optionally 34 substituted by 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, acetamido, trifluoroacetamido, N-methylamino, dimethylamino, N-ethylamino, methylthio, ethylthio, isopropylthio, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, 2,2,333-pentafluoropropyl, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro, bromo, amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxy ethyl, 2,2,2-trifluoro-1-hydroxyethyl, methoxycarbonyl, ethoxycarbonyl, amidocarbonyl, N-methylamidocarbonyl, N,N-dimethylamidocarbonyl, cyano, and Qb; A is selected from the group consisting of single covalent bond, NH, WO 00/69833 PCT/US00/O8226 b 20 21 be be Q is selected from the group consisting of NR R , Q wherein Q is 25 23 24 20 hydrido, and C(NR )NR R , with the provisos that no more than one of R 21 23 24 and R 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 5 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, CH2, and CH2CH2. In another more preferred specific embodiment of Formula I, 10 compounds have the Formula I-MPS wherein B is a non-cyclic substituent: (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, 15 2-propynyl, propyl, isopropyl, butyl, 2-butenyl, 3-butenyl, 2-butynyl, sec- butyl, /m-butyl, isobutyl, 2-methylpropenyl, 1-pentyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-pentynyl, 3-pentynyl, 2-pentyl, l-methyl-2-butenyl, l-methyl-3-butenyl, l-methyl-2-butynyl, 3-pentyl, l-ethyl-2-propenyl, 2-methylbutyl, 2-methyl-2-butenyl, 2-methyl-3-butenyl, 2-methyl-3-butynyl, 3-methylbutyl, 3-2 0 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, l-methyl-2-pentenyl, 1-methyl-3-pentenyl, 1 -methyl-4-pentenyl, l-methyl-2-pentynyl, 1-methyl-3-pentynyl, 3-hexyl, l-ethyl-2-butenyl, l-ethyl-3-butenyl, l-propyl-2-propenyl, l-ethyl-2-butynyl, 1-heptyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5- 101 WO 00/69833 PCT/US00/08226 heptenyl, 6-heptenyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 5-heptynyl, 2-heptyl, l-methyl-2-hexenyl, l-methyl-3-hexenyl, l-methyl-4-hexenyl, 1-methyl-5-hexenyl, l-methyl-2-hexynyl, l-methyl-3-hexynyl, l-methyl-4-hexynyl, 3-heptyl, l-ethyl-2-pentenyl, l-ethyl-3-pentenyl, 1-ethyl-4-pentenyl, 5 l-butyl-2-propenyl, 1-ethyl-2-pentynyl, l-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 3,33-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 Jn36 10 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, amidino, guanidino, carboxy, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, methoxyamino, ethoxyamino, acetamido, trifluoroacetamido, N-methylamino, dimethylamino, N-ethylamino, 15 methylthio, ethylthio, isopropylthio, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, 2,2,3,3,3-pentafluoropropy 1, 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, 20 methoxycarbonyl, ethoxycarbonyl, amidocarbonyl, N-methylamidocarbonyl, N,N-dimethylamidocarbonyl, cyano, and Q ; A is selected from the group consisting of single covalent bond, NH, N(CH3), N(OH), CH2, CH3CH, CF3CH, NHC(O), N(CH3)C(0), C(0)NH, C(0)N(CH3), CH2CH2, CH2CH2CH2, CH3CHCH2, and 25 CF3CHCH2; A is optionally selected from the group consisting of CH2N(CH3), CH2N(CH2CH3), CH2CH2N(CH3), and CH2CH2N(CH2CH3) with the proviso that B is hydrido; 102 WO 00/69833 PCT/US00/08226 b 20 21 Q is selected from the group consisting of NR R , Q , wherein Q 25 23 24 26 25 23 24 is hydrido, C(NR )NR R , and N(R )C(NR )N(R )(R ), with the 20 21 provisos that no more than one of R and R is hydroxy at the same time and 23 24 that no more than one of R and R 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, methyl, ethyl, propyl, butyl, isopropyl, and hydroxy; g Q is selected from the group consisting of a single covalent bond, CH2, and CH2CH2. In still another more preferred specific embodiment of Formula I, 10 compounds have the Formula I-MPS wherein B is a non-aromatic cyclic substituent: (I-MPS wherein B is a non-aromatic cyclic substituent) or a pharmaceutical^ acceptable salt thereof, wherein; 15 B is optionally selected from the group consisting of cyclopropyl, cyclobutyl, oxetan-3-yl, azetidin-l-yl, azetidin-2-yl, azetidin-3-yl, thiaetan-3-yl, cyclopentyl, cyclohexyl, norbornyl, 7-oxabicyclo[2.2.1]heptan-2-yl, bicyclo[3.1.0]hexan-6-yl, cycloheptyl, 2-morpholinyl, 3-morpholinyl, 4-morpholinyl, 1-piperazinyl, 2-piperazinyl, 1-piperidinyl, 2-piperidinyl, 3-20 piperidinyl, 4-piperidinyl, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-dioxanyl, 4H-2-pyranyl, 4H-3-pyranyl, 4H-4-pyranyl, 4H-pyran-4-one-2-yl, 4H-pyran-4-one-3-yl, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydropyranyl, 3-tetrahydropyranyl, 4-tetrahydropyranyl, 2-tetrahydrothienyl, and 3-tetrahydrothienyl, wherein each ring carbon is 103 WO 00/69833 PCT/USOO/08226 33 optionally substituted with R , a ring carbon and a nitrogen adjacent to the 9 carbon atom at the point of attachment are optionally substituted with R or 13 9 R , a ring carbon or nitrogen adjacent to the R position and two atoms from the point of attachment is optionally substituted with R^, and a ring carbon or 13 5 nitrogen adjacent to the R position and two atoms from the point of attachment is optionally substituted with R*2; A is selected from the group consisting of single covalent bond, NH, N(CH3), N(OH), CH2, CH3GH, CF3CH, NHC(O), N(CH3)C(0), C(0)NH, C(0)N(CH3), CH2CH2, CH2CH2CH2, CH3CHCH2, and 10 CF3CHCH2; 33 R is selected from the group consisting of hydrido, amidino, guanidino, carboxy, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, methoxyamino, ethoxyamino, acetamido, trifluoroacetamido, N-methylamino, dimethylamino, N-ethylamino, methylthio, ethylthio, isopropylthio, 15 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, hydroxy methyl, 1-hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro-1-hydroxyethyl, methoxycarbonyl, ethoxycarbonyl, 20 amidocarbonyl, N-methylamidocarbonyl, N,N-dimethylamidocarbonyl, cyano, and Qb; b 20 21 be be Q is selected from the group consisting of NR R ,Q wherein Q is 25 23 24 20 hydrido, and C(NR )NR R , with the provisos that no more than one of R 21 23 24 and R is hydroxy at the same time and that no more than one of R and R is 25 hydroxy at the same time; 104 WO 00/69833 PCT/US00/08226 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; Q is selected from the group consisting of a single covalent bond, CH2, and CH2CH2. The more preferred specific embodiment (I-MPS) compounds of the present invention having the Formula: or a pharmaceutically acceptable salt thereof, have common structural units, wherein; 10 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, 15 methoxyamino, methylthio, ethylthio, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro, and bromo; R2 is Z°-Q; Z° is selected from the group consisting of a covalent single bond, O, S, NH, and CH2; 20 Q is selected from the group consisting of phenyl, 2-thienyl, 3-thienyl, 2-furyl, 3-fuiyl, 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 l,3,5-triazin-2-yl, wherein a carbon or 105 WO 00/69833 PCT/US00/08226 nitrogen adjacent to the carbon at the point of attachment is optionally 9 substituted by R , the other carbon or nitrogen adjacent to the carbon at the 13 point of attachment is optionally substituted by R , a carbon or nitrogen 9 adjacent to R and two atoms from the carbon at the point of attachment is 5 optionally substituted by R^, a carbon adjacent to R^ and two atoms from 12 the carbon at the point of attachment is optionally substituted by R , and any carbon adjacent to both R^ and R*2 is optionally substituted by R^; 9 11 13 R , R , and R are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, methyl, ethyl, propyl, isopropyl, 10 methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, N-methylamino, N,N-dimethylamino, N-ethylamino, methylthio, ethylthio, isopropylthio, trifluoromethyl, pentafluoroethyl, 2,2,2-trifIuoroethyl, 2,2,3,33- pentafluoropropyl, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro, bromo, methanesulfonamido, amidosulfonyl, N-methylamidosulfonyl, 15 N,N-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro-1-hydroxyethyl, amidocarbonyl, N-methylamidocarbonyl, N,N-dimethylamidocarbonyl, and cyano; R^ and R*2 are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, carboxymethyl, methyl, ethyl, propyl, 2 0 isopropyl, methoxy, ethoxy, i sopropoxy, 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, 25 2,2,2-trifluoro-1-hydroxyethyl, methoxycarbonyl, ethoxycarbonyl, amidocarbonyl, N-methylamidocarbonyl, N,N-dimethylamidocarbonyl, fluoro, chloro, bromo, and cyano; 106 WO 00/69833 PCT/US0O/O8226 107 WO 00/69833 PCT/USOO/08226 108 WO 00/69833 PCT/US00/08226 10 15 20 and 16 17 R , R , R , 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, N-ethylamino, methylthio, ethylthio, isopropylthio, trifluoromethylthio, methylsulfinyl, ethylsulfinyl, methylsulfonyl, ethylsulfonyl, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, 2,23,3,3-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; 16 19 b R and R are optionally Q with the proviso that no more than one of R^ and R*9 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: (I-EMPS wherein B is aromatic) or a pharmaceutical^ acceptable salt thereof, wherein; B is selected from the group consisting of phenyl, 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyrroIyl, 3-pyiTolyl, 2-imidazolyl, 4-imidazolyl, 3- 109 WO 00/69833 PCT/US00/08226 pyrazolyl, 4-pyrazolyl, 2-thiazolyl, 3-isoxazolyl, and 5-isoxazolyl, wherein a carbon adjacent to the carbon at the point of attachment is optionally substituted 32 by R , the other carbon adjacent to the carbon at the point of attachment is 36 32 optionally substituted by R , a carbon adjacent to R and two atoms from 33 5 the carbon at the point of attachment is optionally substituted by R , a carbon 36 adjacent to R and two atoms from the carbon at the point of attachment is 35 33 35 optionally substituted by R , and any carbon adjacent to both R and R is 34 optionally substituted by R ; 32 33 34 35 36 R , R , R , R , and R are independently selected from the 10 group consisting of hydrido, amidino, guanidino, methyl, ethyl, methoxy, ethoxy, hydroxy, amino, N-methylamino, dimethylamino, methylthio, ethylthio, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, fluoro, chloro, bromo, amidosulfonyl, N-methylamidosulfonyl, hydroxymethyl, amidocarbonyl, carboxy, cyano, and Qb; 15 A is selected from the group consisting of single covalent bond, NH, N(CH3), CH2, CH3CH, and CH2CH2; b 20 21 Q is selected from the group consisting of NR R and 25 23 24 b C(NR )NR R , with the proviso that said Q group is bonded directly to a carbon atom; 20 21 23 24 25 20 R ,R ,R ,R , and R are independently selected from the group consisting of hydrido, methyl, and ethyl; Qs is CH2. In another most preferred specific embodiment of Formula 1, compounds have the Formula I-EMPS wherein B is a non-cyclic substituent: 110 WO 00/69833 PCT/US00/08226 10 15 20 (I-EMPS wherein B is a non-cyclic substituent) or a pharmaceutical^ 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-pentynyl, 3-pentynyl, 2-pentyl, 3-pentyl, 2-methylbutyl, 2-methyl-2-butenyl, 3-methylbutyl, 3-methyl-2-butenyl, 1-hexyl, 2-hexenyl, 3-hexenyI, 4-hexenyl, 2-hexynyl, 3-hexynyl, 4-hexynyI, 2-hexyl, l-methyl-2-pentenyl, l-methyI-3-pentenyl, l-methyl-2-pentynyl, l-methyl-3-pentynyl,3-hexyl, l-ethyl-2-butenyl, 1-heptyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 5-heptynyl, 2-heptyl, l-methyl-2-hexenyl, 1-methyl-3-hexenyl, 1-methyl-4-hexenyl, l-methyl-2-hexynyl, l-methyl-3-hexynyl, 1-methyl-4-hexynyl, 3-heptyl, l-ethyl-2-pentenyl, l-ethyl-3-pentenyl, l-ethyl-2-pentynyl, l-ethyl-3-pentynyl, 2,2,2-trifluoroethyl, 2,2-difluoropropyl, 4-trifluoromethyl-5,5,5-trifluoropentyl, 4-trifluoromethylpentyl, 5,5,6,6,6-pentafluorohexyl, and3,33-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 R 33 34 35 36 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, methyl, ethyl, methoxy, ethoxy, hydroxy, amino, N-methylamino, dimethylamino, methylthio, ethylthio, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, fluoro, 32 111 WO 00/69833 PCT/US00/Q8226 chloro, bromo, amidosulfonyl, N-methylamidosulfonyl, hydroxymethyl. amidocarbonyl, carboxy, cyano, and Qb; A is selected from the group consisting of single covalent bond, NH, N(CH3), CH2, CH3CH, and CH2CH2; 5 A is optionally selected from the group consisting of CH2N(CH3), CH2N(CH2CH3), CH2CH2N(CH3), and CH2CH2N(CH2CH3) with the proviso that B is hydrido; b 20 21 Q is selected from the group consisting of NR R , CCNrVr24 and N(R26)C(NR2^)N(R23)(R24), with the proviso that 10 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, 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: 20 (I-EMPS 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-3-yi, thiaetan-3-yl, cyclopentyl, cyclohexyl, 112 WO 00/69833 PCT/US0O/O8226 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrroIidinyl, 2-tetrahydrofuranyI, 3-tetrahydrofuranyl, 2-tetrahydrothienyl, and 3-tetrahydrothienyl, wherein each 33 ring carbon is optionally substituted with R , ring carbons and a nitrogen adjacent to the carbon atom at the point of attachment are optionally substituted 9 13 9 5 withR orR , a ring carbon or nitrogen adjacent to the R position and two atoms from the point of attachment is optionally substituted with R^, and a 13 ring carbon or nitrogen adjacent to the R position and two atoms from the 12 point of attachment is optionally substituted with R ; 33 R are independently selected from the group consisting of hydrido, 10 amidino, guanidino, methyl, ethyl, methoxy, ethoxy, hydroxy, carboxy, 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, 15 N(CH3), CH2, CH3CH, and CH2CH2; b 20 21 Q is selected from the group consisting of NR R and 25 23 24 b C(NR )NR R , 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 20 consisting of hydrido, methyl, and ethyl; QS is CH2. The most preferred specific embodiment (I-EMPS) compounds of the present invention having the Formula: 113 WO 00/69833 PCT/US00/08226 o or a pharmaceutical^ acceptable salt thereof, have common structural units, wherein; m is selected from the group consisting of n and r'-C; 5 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; R2isZ°-Q; 10 Z° is a covalent single bond; Q is selected from the group consisting of phenyl, 2-thienyl, 2-furyl, 2-pyrrolyl, 2-imidazolyl, 2-thiazolyl, 3-isoxazolyl, 2-pyridyl, and 3-pyridyl, wherein 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 15 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 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 10 12. . „ , 11 R and R is optionally substituted by R ; 9 11 13 20 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- 114 WO 00/69833 PCT/US00/08226 10 trifluoroethyl, fluoro, chloro, bromo, amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, amidocarbonyl, N-methylamidocarbonyl, carboxy, and cyano; 10 12 R and R are independently selected from the group consisting of hydrido, amidino, amidocarbonyl, N-methylamidocarbonyl, guanidino, methyl, ethyl, methoxy, ethoxy, hydroxy, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, carboxy, carboxymethyl, amino, acetamido, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, trifluoroacetamido, aminomethyl, N-methylamino, dimethylamino, amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, methoxycarbonyl, fluoro, chloro, bromo, and cyano; Y° is selected from the group of formulas consisting of: 115 WO 00/69833 PCT/US00/08226 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. The compounds of this invention can be used in anticoagulant therapy for the treatment and prevention of a variety of thrombotic conditions including 15 coronary artery and cerebrovascular disease. The compounds of this invention 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 20 mammal, in blood, in blood products, and in mammalian organs. The 116 WO 00/69833 PCT/US00/08226 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 5 reocclusion or restenosis of recanalized vessels in a mammal. The compounds can also be used in prophylactic treatment of subjects who are at risk of 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. 10 Besides being useful for human treatment, these compounds are also 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 15 compounds are selected from the compounds set forth in Examples 1 through Example 7. 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 20 of atoms unless otherwise defined. The symbol "C" represents a carbon atom. The symbol "O" represents an oxygen atom. The symbol "N" represents a nitrogen atom. The symbol "P" represents a phosphorus atom. The symbol "S" represents a sulfur atom. The symbol "H" represents a hydrido atom. Double letter elemental symbols are used as defined for the elements of the periodical table 25 (i.e., CI represents chlorine, Se represents selenium, etc.). 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 30 groups as defined below. Examples of such radicals include methyl, ethyl, chloroethyl, hydroxyethyl, n-propyl, oxopropyl, isopropyl, n-butyl, cyanobutyl, isobutyl, sec-butyl, tert-butyl, pentyl, aminopentyl, iso-amyl, hexyl, octyl and the like. The term "alkenyl" refers to an unsaturated, acyclic hydrocarbon radical in 35 so much as it contains at least one double bond. Such alkenyl radicals contain 117 WO 00/69833 PCT/USQO/08226 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-l-yl, isobutenyl, penten-I-yl, 2-5 2-methylbuten-l-yl, 3-methyIbuten-l-yl, hexen-l-yl, 3-hydroxyhexen-l-yl, hepten-l-yl, and octen-l-yl, and the like. 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 10 carbon atoms and more preferably having 3 to about 6 carbon atoms. Said alkynyl radicals may be optionally substituted with groups as defined below. Examples of suitable alkynyl radicals include ethynyl, propynyl, hydroxypropynyl, butyn-l-yl, butyn-2-yl, pentyn-l-yl, pentyn-2-yl, 4-methoxypentyn-2-yl, 3-methylbutyn-l-yl, hexyn-l-yl, hexyn-2-yl, hexyn-3-15 yl, 3 3-dimethylbutyn-1 -yl radicals and the like. 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 2 0 atom to form a "methylene" (-CH2-) radical. 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. 2 5 The term "hydroxyalkyl" embraces radicals wherein any one or more of the alkyl carbon_atoms is substituted with a hydroxyl as defined above. Specifically embraced are monohydroxy alkyl, dihydroxyalkyl and polyhydroxyalkyl radicals. The term "alkanoyl" embraces radicals wherein one or more of the 30 terminal alkyl carbon atoms are substituted with one or more carbonyl radicals 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. 118 WO 00/69833 PCT/US00/08226 The term "alkylene" radical denotes linear or branched radicals having 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. 5 The term "alkenylene" radical denotes linear or branched radicals having from 2 to about 10 carbon atoms, at least one double bond, and having attachment points for two or more covalent bonds. Examples of such radicals are 1,1-vinylidene (CH2=C), 1,2-vinylidene (-CH=CH-), and 1,4-butadienyl (-CH=CH-CH=CH-). 10 The term "halo" means halogens such as fluorine, chlorine, bromine or 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 15 monohaloalkyl radical, for one example, may have either a bromo, chloro or a 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" 20 radicals having one to about six carbon atoms. Examples of such haloalkyl radicals include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, trifluoroethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl. 25 The term "hydroxyhaloalkyl" embraces radicals wherein any one or 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 30 one or more of the alkylene carbon atoms is substituted with halo as defined 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" 35 radicals having one to about six carbon atoms. Examples of "haloalkylene" 119 WO 00/69833 PCT/US00/08226 radicals include difluoromethylene, tetrafluoroethylene, tetrachloroethylene, alkyl substituted monofluoromethylene, and aryl substituted trifluoromethylene. The term "haloalkenyl" denotes linear or branched radicals having from 5 1 to about 10 carbon atoms and having one or more double bonds wherein any one or more of the alkenyl carbon atoms is substituted with halo as defined 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 10 radicals. 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, 15 to form monoalkoxyalkyl and dialkoxyalkyl radicals. More preferred alkoxy radicals are "lower alkoxy" radicals having one to six carbon atoms. Examples of such radicals include methoxy, ethoxy, propoxy, butoxy, isopropoxy and te/7-butoxy alkyls. The "alkoxy" radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide "haloalkoxy" 20 and "haloalkoxyalkyl" radicals. Examples of such haloalkoxy radicals include fluoromethoxy, chloromethoxy, trifluoromethoxy, difluoromethoxy, trifluoroethoxy, fluoroethoxy, tetrafluoroethoxy, pentafluoroethoxy, and fluoropropoxy. Examples of such haloalkoxyalkyl radicals include fluoromethoxymethyl, chloromethoxyethyl, trifluoromethoxymethyl, 25 difluoromethoxyethyl, and trifluoroethoxymethyl. 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 30 alkenyloxy radicals attached to the alkyl radical, that is, to form 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 35 further substituted with one or more halo atoms, such as fluoro, chloro or 120 WO 00/69833 PCT/US00/08226 bromo, to provide "haloalkenyioxy" radicals. Examples of such radicals include trifluoroethenyloxy, fluoroethenyloxy, difluoroethenyhloxy, and fluoropropenyloxy. The term "haloalkoxyalkyl" also embraces alkyl radicals having one or 5 more haloalkoxy radicals attached to the alkyl radical, that is, to form monohaloalkoxyalkyl and dihaloalkoxyalkyl radicals. The term "haloalkenyioxy" also embraces oxygen radicals having one or more haloalkenyioxy radicals attached to the oxygen radical, that is, to form monohaloalkenyloxy and dihaloalkenyloxy radicals. The term 10 "haloalkenyloxyalkyl" also embraces alkyl radicals having one or more haloalkenyioxy 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 15 "alkylenedioxy" radicals include methyl enedioxy, ethylenedioxy, 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, 20 tetrafluoroethylenedioxy, tetrachloroethylenedioxy, alkylsubstituted monofluoromethylenedioxy, and arylsubstituted monofluoromethylenedioxy. The teim "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 25 second ring is present (ie, attached or formed) by having two adjacent atoms in 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, 30 naphthyl, tetrahydronaphthyl, indane and biphenyl wherein the aiyl radical is 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, 35 nitrogen, sulfur and oxygen, wherein at least one ring atom is a heteroatom. 121 WO 00/69833 PCT/USO0/08226 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 atomsfe.g. pyrrolidinyl, imidazolidinyl, piperidino, 5 piperazinyl, etc.]; saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g. morpholinyl, 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, 10 dihydropyran, dihydrofuran and dihydrothiazole. Non-limiting examples of 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 15 ring-shaped aromatic radicals having from 5 through 15 ring members selected from carbon, nitrogen, sulfur and oxygen, wherein at least one ring atom is a heteroatom. Heteroaryl radicals may contain one, two or three rings 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 20 group containing 1 to 4 nitrogen atoms, for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl [e.g., 4H-l,2,4-triazolyl, lH-l,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.] tetrazolyl [e.g. lH-tetrazolyl, 2H-tetrazolyl, etc.], etc.; unsaturated condensed heterocyclic group containing 1 to 5 nitrogen atoms, for 25 example, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl [e.g., tetrazolo [l,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, 30 for example, 2-thienyl, 3-thienyl, etc.; unsaturated 5- to 6-membered 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, 13,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.] etc.; unsaturated condensed heterocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms 35 [e.g. benzoxazolyl, benzoxadiazolyl, etc.]; unsaturated 5 to 6-membered 122 WO 00/69833 PCT/US00/08226 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., 5 benzothiazolyl, benzothiadiazolyl, etc.] and the like. The term also embraces radicals where heterocyclic radicals are fused with aryl radicals. Examples of such fused bicyclic radicals include benzofuran, benzothiophene, and the like. Said "heterocyclyl" group may have 1 to 3 substituents as defined below. Preferred heterocyclic radicals include five to twelve membered fused or 10 unfused radicals. Non-limiting examples of heteroaryl radicals include pyrrolyl, pyridinyl, pyridyloxy, pyrazolyl, triazolyl, pyrimidinyl, pyridazinyl, oxazolyl, thiazolyl, imidazolyl, indolyl, thiophenyl, furanyl, tetrazolyl, 2-imidazolinyl, imidazolidinyl, 2-pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,3-triazolyl, 1,3,4-thiadiazolyl, pyrazinyl, 15 piperazinyl, 13,5-triazinyl, 1,3,5-trithianyl, benzo(b)thiophenyl, 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 20 above. "Alkylsulfonylalkyl", embraces alkylsulfonyl radicals attached to an 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 teim "aminosulfonyl" 25 denotes an amino radical attached to a sulfonyl radical. The term "sulfinyl", whether used alone or linked to other terms such as alkylsulflnyl, denotes respectively divalent radicals -S(O)-. "Alkylsulflnyl", embraces alkyl radicals attached to a sulfinyl radical, where alkyl is defined as above. "Alkylsulfinylalkyl", embraces alkylsulflnyl radicals attached to an alkyl 30 radical, where alkyl is defined as above. "Haloalkylsulfmyl", embraces haloalkyl radicals attached to a sulfinyl radical, where haloalkyl is defined as above. "Haloalkylsulfinylalkyl", embraces haloalkylsulfmyl radicals attached to an alkyl radical, where alkyl is defined as above. The term "aralkyl" embraces aryl-substituted alkyl radicals. Preferable 35 aralkyl radicals are "lower aralkyl" radicals having aryl radicals attached to 123 WO 00/69833 PCT/US00/08226 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 5 wherein the heteroaralkyl radical may be additionally substituted with three or more substituents as defined above for aralkyl radicals. The term "perhaloaralkyl" embraces aryl-substituted alkyl radicals wherein the aralkyl radical is substituted with three or more halo radicals as defined above. The terni "aralkylsulfinyl", embraces aralkyl radicals attached to a 10 sulfinyl radical, where aralkyl is defined as above. "Aralkylsulfinylalkyl", 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", 15 embraces aralkylsulfonyl radicals attached to an alkyl radical, where alkyl is 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 20 cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. The term 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 25 "lower cycloalkylalkyl" radicals having cycloalkyl radicals attached to alkyl 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 30 carbon atoms. Examples include radicals such as cyclobutenyl, cyclopentenyl, 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 35 radical, for one example, may have either a bromo, chloro or a fluoro atom 124 WO 00/69833 PCT/US00/08226 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 5 halocycloalkyl" radicals having three to about eight carbon atoms. Examples of such halocycloalkyl radicals include fluorocyclopropyl, difluorocyclobutyl, 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. 10 Specifically embraced are monohalocycloalkenyl, dihalocycloalkenyl and 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 15 cycloalkoxy radicals attached to the alkyl radical, that is, to form 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. 20 The term "cycloalkylalkoxy" embraces cycloalkyl radicals attached to an 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 25 cyclopentenyloxy. The term "cycloalkenyloxyalkyl" also embraces alkyl 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 30 atoms, such as fluoro, chloro or bromo, to provide "halocycloalkenyloxy" and "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. 125 WO 00/69833 PCT/US00/08226 The term "cycloalkylsulfinyl", embraces cycloalkyl radicals attached to 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", 5 embraces cycloalkyl radicals attached to a sulfonyl radical, where cycloalkyl is defined as above. "Cycloalkylsulfonylalkyl", embraces cycloalkylsulfonyl radicals attached to an alkyl radical, where alkyl is defined as above. The term "cycloalkylalkanoyl" embraces radicals wherein one or more of the cycloalkyl carbon atoms are substituted with one or more carbonyl 10 radicals as defined below. Specifically embraced are monocarbonylcycloalkyl and dicarbonylcycloalkyl radicals. Examples of monocarbonylcycloalkyl radicals include cyclohexylcarbonyl, cyclohexylacetyl, and cyclopentylcarbonyl. Examples of dicarbonylcycloalkyl radicals include 1,2-dicarbonylcyclohexane. 15 The term "alkylthio" embraces radicals containing a linear or branched alkyl radical, of one to ten carbon atoms, attached to a divalent sulfur atom. More preferred alkylthio radicals are "lower alkylthio" radicals having one to six carbon atoms. An example of "lower alkylthio" is methylthio (CH3-S-). The "alkylthio" radicals may be further substituted with one or more halo 20 atoms, such as fluoro, chloro or bromo, to provide "haloalkylthio" radicals. Examples of such radicals include fluoromethylthio, chloromethylthio, trifluoromethylthio, difluoromethylthio, trifluoroethylthio, fluoroethylthio, tetrafiuoroethylthio, pentafluoroethylthio, and fluoropropylthio. The term "alkyl aryl amino" embraces radicals containing a linear or 25 branched alkyl radical, of one to ten carbon atoms, and one aryl radical both attached to an amino radical. Examples include N-methyl-4-methoxyaniline, N-ethyl-4-methoxyaniIine, and N-methyl-4-trifluoromethoxyaniline. The terms alkylamino denotes "monoalkylamino" and "dialkylamino" containing one or two alkyl radicals, respectively, attached to an amino radical. 30 The terms aiylamino denotes "monoarylamino" and "diarylamino" containing one or two aryl radicals, respectively, attached to an amino radical. 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 35 denotes "monoaralkylamino" and "diaralkylamino" containing one or two 126 WO 00/69833 PCT/US00/08226 aralkyl radicals, respectively, attached to an amino radical. The term 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 5 defined above, attached to a divalent S(O) atom. The term "arylsulfmylalkyl" denotes arylsulfmyl radicals attached to a linear or branched alkyl radical, of one to ten carbon atoms. The term "arylsulfonyl", embraces aryl radicals attached to a sulfonyl radical, where aiyl is defined as above, "arylsulfonylalkyl", embraces 10 arylsulfonyl radicals attached to an alkyl radical, where alkyl is defined as above. The term "heteroarylsulfinyl" embraces radicals containing an heteroaryl radical, as defined above, attached to a divalent S(O) atom. The term "heteroarylsulfmylalkyl" denotes heteroarylsulfinyl radicals attached to a linear or branched alkyl radical, of one to ten carbon atoms. The term 15 "Heteroarylsulfonyl", embraces heteroaryl radicals attached to a sulfonyl radical, where heteroaryl is defined as above. "Heteroarylsulfonylalkyl", embraces heteroarylsulfonyl radicals attached to an alkyl radical, where alkyl is defined as above. The term "aiyloxy" embraces aiyl radicals, as defined above, attached 20 to an oxygen atom. Examples of such radicals include phenoxy, 4-chloro-3-ethylphenoxy, 4-chIoro-3-methylphenoxy, 3-chloro-4-ethylphenoxy, 3,4-dichlorophenoxy, 4-methylphenoxy, 3-trifluoromethoxyphenoxy, 3-trifluoromethylphenoxy, 4-fluorophenoxy, 3,4-dimethylphenoxy, 5-bromo-2-fluorophenoxy, 4-bromo-3-fluorophenoxy, 4-fluoro-3-methylphenoxy, 25 5,6,7,8-tetrahydronaphthyloxy, 3-isopropylphenoxy, 3-cyclopropylphenoxy, 3-ethylphenoxy, 3-pentafluoroethylphenoxy, 3-( 1,1,2,2-tetrafluoroethoxy)-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 30 benzoyl and toluoyl. The teim "aralkanoyl" embraces aralkyl radicals, as defined herein, attached to an carbonyl radical as defined above. Examples of such radicals include, for example, phenylacetyl. The teim "aralkoxy" embraces oxy-containing aralkyl radicals attached 35 through an oxygen atom to other radicals. More preferred aralkoxy radicals are 127 WO 00/69833 PCT/US00/08226 "lower aralkoxy" radicals having phenyl radicals attached to lower alkoxy 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-3-5 trifluoromethylbenzyloxy, and 2-phenylethoxy. The term "aryloxyalkyl" embraces aiyloxy radicals, as defined above, attached to an alkyl group. Examples of such radicals include phenoxymethyl. The term "haloaiyloxyalkyl" embraces aryloxyalkyl radicals, as defined above, wherein one to five halo radicals are attached to an aryloxy group. 10 The teim "heteroaroyl" embraces heteroaryl radicals, as defined above, attached to an carbonyl radical as defined above. Examples of such radicals include furoyl and nicotinyl. The term "heteroaralkanoyl" embraces heteroaralkyl radicals, as defined herein, attached to an carbonyl radical as defined above. Examples of such 15 radicals include, for example, pyridylacetyl and furylbutyryl. The term "heteroaralkoxy" embraces oxy-containing heteroaralkyl 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. 20 The term "haloheteroaryloxyalkyl" embraces heteroaryloxyalkyl radicals, as defined above, wherein one to four halo radicals are attached to an heteroaryloxy group. The term "heteroarylamino" embraces heterocyclyl radicals, as defined above, attached to an amino group. Examples of such radicals include 25 pyridylamino. The term "heteroarylaminoalkyl" embraces heteroarylamino radicals, as defined above, attached to an alkyl group. Examples of such radicals include pyridylmethylamino. The term "heteroaryloxy" embraces heterocyclyl radicals, as defined 30 above, attached to an oxy group. Examples of such radicals include 2-thiophenyloxy, 2-pyrimidyloxy, 2-pyridyloxy, 3-pyridyloxy, and 4-pyridyloxy. The term "heteroaiyloxyalkyl" embraces heteroaryloxy radicals, as defined above, attached to an alkyl group. Examples of such radicals include 35 2-pyridyloxymethyl, 3-pyridyloxyethyl, and 4-pyridyloxymethyl. 128 WO 00/69833 PCT/US00/08226 The term "arylthio" embraces aryl radicals, as defined above, attached 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 5 phenylthiomethyl. The term "alkylthioalkyl" embraces alkylthio radicals, as defined above, attached to an alkyl group. Examples of such radicals include methylthiomethyl. The term "alkoxyalkyl" embraces alkoxy radicals, as defined above, attached to an alkyl group. Examples of such radicals include 10 methoxymethyl. The term "carbonyl" denotes a carbon radical having two of the four 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, 15 dialkylamino, monocycloalkylamino, alkylcycloalkylamino, and dicycloalkylamino radicals, attached to one of two unshared bonds in a carbonyl group. The term "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 2 0 radicals, as defined above, attached to one of two unshared bonds in a carbonyl group. The term "carboaralkoxy" embraces aralkoxy radicals, as defined above, 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 25 carboalkoxy radicals, as defined above, attached to an alkylene group. The term "monocyanoalkyl" embraces one cyano radical, as defined above,.attached to an 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. 30 The term "acyl", alone or in combination, means a carbonyl or thionocarbonyl group bonded to a radical selected from, for example, hydrido, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkoxyalkyl, haloalkoxy, aryl, heterocyclyl, heteroaryl, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, alkylthio, arylthio, amino, alkylamino, 35 dialkylamino, aralkoxy, arylthio, and alkylthioalkyl. Examples of "acyl" are 129 WO 00/69833 PCT/US00/08226 formyl, acetyl, benzoyl, trifluoroacetyl, phthaloyl, malonyl, nicotinyl, and the like. 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, trifluoroacetyl, bromopropanoyl, and 5 heptafluorobutanoyl. The term "phosphono" embraces a pentavalent phosphorus attached with two covalent bonds to an oxygen radical. The term "dialkoxyphosphono" denotes two alkoxy radicals, as defined above, attached to a phosphono radical with two covalent bonds. The term "diaralkoxyphosphono" denotes two aralkoxy radicals, 10 as defined above, attached to a phosphono radical with two covalent bonds. The term "dialkoxyphosphonoalkyl" denotes dialkoxyphosphono radicals, as defined 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 15 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 example, -NH2, -NHCH3, -NHOH, and -nhoch3. 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. 2 0 Examples of such imino radicals include, for example, =NH, =NCH3, =NOH, and =NOCH3. The term "imino carbonyl" denotes a carbon radical having two of the four covalent bond sites shared with an imino group. Examples of such imino carbonyl radicals include, for example, C=NH, C=NCH3, C=NOH, and C=NOCH3. The term "amidino" embraces a substituted or unsubstituted amino 25 group bonded to one of two available bonds of an iminocarbonyl radical. Examples of such amidino radicals include, for example, NH2-C=NH, NH2-C=NCH3, NH2-C=NOCH3 and CH3NH-C=NOH. The term "guanidino" denotes an amidino group bonded to an amino group as defined above where said amino group can be bonded to a third group. Examples of such guanidino radicals 130 WO 00/69833 PCT/US00/08226 include, for example, NH2-C(NH)-NH-, NH2-C(NCH3)-NH-, NH2- C(NOCH3)-NH-, and CH3NH-C(NOH)-NH-. The term "sulfonium" denotes a positively charged trivalent sulfur atom where said sulfur is substituted with three carbon based groups such as alkyl, 5 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, (CH3)2S+-. The term "dialkyl 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 10 dialkylsulfoniumalkyl radicals include (CH3>2S+-CH2CH2-. The term "phosphonium" denotes a positively charged tetravalent 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 15 alkyl groups. Examples of such tiialkylphosphonium radicals include, for example, (CH3)3P+. Said "alkyl", "alkenyl", "alkynyl", "alkanoyl", "alkylene", "alkenylene", "hydroxyalkyl", "haloalkyl", "haloalkylene", "haloalkenyl", "alkoxy", "alkenyloxy", "alkenyloxyalkyl", "alkoxyalkyl", "aryl", "perhaloaryl", 20 "haloalkoxy", "haloalkoxyalkyl", "haloalkenyioxy", "haloalkenyl oxyalkyl", "alkylenedioxy", "haloalkylenedioxy", "heterocyclyl", "heteroaryl", "hydroxyhaloalkyl", "alkylsulfonyl", "haloalkylsulfonyl", "alkylsulfonylalkyl", "haloalkylsulfonylalkyl", "alkylsulfmyl", "alkylsulfinylalkyl", "haloalkyl sulfinylalkyl", "aralkyl", "heteroaralkyl", "perhaloaralkyl", 25 "aralkylsulfonyl", "aralkylsulfonylalkyl", "aralkylsulfinyl", "aralkylsulfinylalkyl", "cycloalkyl", "cycloalkylalkanoyl", "cycloalkylalkyl", "cycloalkenyl", "halocycloalkyl", "halocycloalkenyl", "cycloalkylsulfinyl", "cycloalkylsulfinylalkyl", "cycloalkylsulfonyl", "cycloalkylsulfonylalkyl", "cycloalkoxy", "cycloalkoxyalkyl", "cycloalkylalkoxy", "cycloalkenyloxy", 30 "cycloalkenyloxyalkyl", "cycloalkylenedioxy", "halocycloalkoxy", "halocycloalkoxyalkyl", "halocycloalkenyloxy", "halocycloalkenyloxyalkyl", "alkylthio", "haloalkylthio", "alkylsulfmyl", "amino", "oxy", "thio", "alkylamino", 131 WO 00/69833 PCT/US00/08226 "arylamino", "aralkylamino", "arylsulfinyl", "arylsulfinylalkyl", "arylsulfonyl", "arylsulfonylalkyl", "heteroarylsulfinyl", "heteroarylsulfinylalkyl", "heteroarylsulfonyl", "heteroarylsulfonylalkyl", "heteroarylamino", "heteroarylaminoalkyl", "heteroaryloxy", "heteroaryloxylalkyl", "aryloxy", 5 "aroyl", "aralkanoyl", "aralkoxy", "aryloxyalkyl", "haloaiyloxyalkyl", "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 10 amidino, guanidino, dialkylsulfonium, trialkylphosphonium, dialkylsulfoniumalkyl, perhaloaralkyl, aralkylsulfonyl, aralkylsulfonylalkyl, aralkylsulfinyl, aralkylsulfinylalkyl, halocycloalkyl, halocycloalkenyl, cycloalkylsulfinyl, cycloalkylsulfinylalkyl, cycloalkylsulfonyl, cycloalkylsulfonylalkyl, heteroarylamino, N-heteroarylamino-N-alkylamino, 15 heteroarylaminoalkyl, heteroaryloxy, heteroaryloxylalkyl, haloalkylthio, alkanoyloxy, alkoxy, alkoxyalkyl, haloalkoxylalkyl, heteroaralkoxy, cycloalkoxy, cycloalkenyloxy, cycloalkoxy alkyl, cycloalkylalkoxy, cycloalkenyloxyalkyl, cycloalkylenedioxy, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxy, halocycloalkenyloxyalkyl, hydroxy, amino, thio, nitro, lower alkylamino, 20 alkylthio, alkylthioalkyl, arylamino, aralkylamino, arylthio, arylthioalkyl, heteroaralkoxyalkyl, alkylsulfmyl, alkylsulfinylalkyl, arylsulfinylalkyl, arylsulfonylalkyl, heteroarylsulfinylalkyl, heteroarylsulfonylalkyl, alkylsulfonyl, alkylsulfonylalkyl, haloalkylsulfinylalkyl, haloalkylsulfonylalkyl, alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, 25 dialkyl amidosulfonyl, monoaiylamidosulfonyl, arylsulfonamido, diaiylamidosulfonylvmonoalkyl monoaryl amidosulfonyl, arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, haloalkanoyl, alkyl, alkenyl, alkynyl, alkenyloxy, alkenyloxyalky, alkylenedioxy, haloalkylenedioxy, 30 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 saturated heterocyclyl, heteroaryl, heteroaryloxy, heteroaryloxyalkyl, arylalkyl, 35 heteroarylalkyl, arylalkenyl, heteroaiylalkenyl, carboxyalkyl, carboalkoxy, 132 WO 00/69833 PCT/US00/08226 alkoxycarbonyl, carboaralkoxy, carboxamido, carboxamidoalkyl, cyano, carbohaloalkoxy, phosphono, phosphonoalkyl, diaralkoxyphosphono, and diaralkoxyphosphonoalkyl. The term "spacer" can include a covalent bond and a linear moiety 5 having a backbone of 1 to 7 contiguous atoms. The spacer may have 1 to 7 atoms of a univalent or multi-valent chain. Univalent chains may be constituted 2a by a radical selected from =C(H)-, =C(R )-, -0-, -S-, -S(O)-, -S(0)2-, -NH-, -NCR23)-, -N=, -CH(OH)-, =C(OH)-, -CHCOR23)-, =C(0R23)-, and 2a -C(O)- wherein R is selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, 10 aralkyl, aryloxyalkyl, alkoxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkoxyalkyl, perhaloaralkyl, heteroarylalkyl, heteroaryloxyalkyl, heteroarylthioalkyl, and heteroarylalkenyl. 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 15 chain. The chain may be constituted of one or more radicals selected from: lower alkylene, lower alkenyl, -0-, -O-CH2-, -S-CH2-, -CH2CH2-, ethenyl, -CH=CH(OHV. -OCH1O-. -0(CHt)'>0-, -NHCHO-. -OCHfR^O-. WO 00/69833 PCT/US00/08226 alkoxyalkyl, haloalkoxylalkyI, heteroaralkoxy, cycloalkoxy, cycloalkenyloxy, cycloalkoxyalkyl, cycloalkylalkoxy, cycloalkenyloxyalkyl, cycloalkylenedioxy, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxy, halocycloalkenyloxy alkyl, hydroxy, amino, thio, nitro, lower alkylamino, 5 alkylthio, alkylthioalkyl, arylamino, aralkylamino, arylthio, arylthioalkyl, heteroaralkoxyalkyl, alkylsulflnyl, alkylsulfinylalkyl, arylsulfinylalkyl, arylsulfonylalkyl, heteroarylsulfinylalkyl, heteroaiylsulfonylalkyl, alkylsulfonyl, alkylsulfonylalkyl, haloalkylsulfinylalkyl, haloalkylsulfonylalkyl, alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, 10 dialkyl amidosulfonyl, monoarylamidosulfonyl, arylsulfonamido, diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl, arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, haloalkanoyl, alkyl, alkenyl, alkynyl, alkenyloxy, alkenyloxyalky, alkylenedioxy, haloalkylenedioxy, 15 cycloalkyl, cycloalkenyl, lower cycloalkylalkyl, lower cycloalkenylalkyl, halo, haloalkyl, haloalkenyl, haloalkoxy, hydroxyhaloalkyl, hydroxy aralkyl, hydroxyalkyl, aminoalkyl, hydoxyheteroaralkyl, haloalkoxyalkyl, aryl, aralkyl, aryloxy, aralkoxy, aryloxyalkyl, saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl, heteroaryloxy, heteroaryloxyalkyl, arylalkyl, 2 0 heteroarylalkyl, arylalkenyl, heteroarylalkenyl, carboxyalkyl, carboalkoxy, carboaralkoxy, carboxamido, carboxamidoalkyl, cyano, carbohaloalkoxy, phosphono, phosphonoalkyl, diaralkoxyphosphono, and diaralkoxyphosphonoalkyl. Compounds ofthe present invention can exist in tautomeric, geometric or 25 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. Phaimaceutically acceptable sales of such tautomeric, geometric or stereoisomeric 30 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"). 134 00/69833 PCT/US00/08226 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 5 stereocenter present. 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" 10 forms of each aldehyde and ketone group present. Compounds of the present 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 15 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 amide carbonyl groups may be both oxo (C=0) and thiono (C=S) in type. 2 0 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 25 "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 coronaiy artery and cerebrovascular disease in a subject, comprising administering to the subject having such disorder a 3 0 therapeutically-effective amount of a compound of Formula (I): 135 WO 00/69833 PCT/US0O/O8226 .0 J (I) or a phaimaceutically-acceptable salt thereof. As a further embodiment, compounds of the present invention of Formula (I) or a pharmaceutically-acceptable salt thereof as defined above, 5 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. 10 Compounds of the present invention of Formula (I) 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 storage. Thus coagulation inhibitors of the present inhibition can be added to 15 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, orthopedic prothesis, cardiac prosthesis, andextracorporeal circulation 20 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 treatment of diseases mediated by coagulation cascade serine proteases, such as 25 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, 136 WO 00/69833 PCT/US00/08226 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 5 also can be used to study the mechanism of action of coagulation cascade serine proteases to enable the design of better inhibitors and development of better assay methods. The compounds of Formula (1) 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 10 pharmaceutically-acceptable salts thereof. The term "pharmaceutically- 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) 15 may be prepared from inorganic acid or from an organic acid. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, 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, 2 0 acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, 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 25 pharmaceutically-acceptable base addition salts of compounds of Formula (I) 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 30 salts may be prepared by conventional means from the corresponding 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) 35 in association with at least one pharmaceutically-acceptable carrier, adjuvant or 137 WO 00/69833 PCT/US00/08226 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 5 active ingredients. The active compounds of the present invention may be 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 10 administered orally, intravascularly, intraperitoneally, subcutaneously, 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 15 implant preparation which may be formulated in such a manner as to permit a sustained release of the active ingredient. The active ingredient can be 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, 2 0 Silastic, silicone rubber or other silicon containing polymers. 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. 25 The compounds may also be delivered by the use of monoclonal 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- 3 0 phenol, or ployethyleneoxide-polylysine substituted with palmitoyl residues. 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, 138 WO 00/69833 PCT/US0O/O8226 polyacetals, polydihydropyrans, polycyanoacrylates and cross linked or 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 5 release or timed release formulations), pills, powders, granules, elixers, tinctures, suspensions, liquids including syrups, and emulsions. The 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 10 administered by injection as a composition wherein, for example, saline, dextrose or water may be used as a suitable carrier. 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 15 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 particular compound employed, and thus may vary widely. 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 20 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 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, 25 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 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 30 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 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 35 enhancers include dimethylsulfoxide and related analogs. The compounds of 139 WO 00/69833 PCT/US00/08226 this invention can also be administered by a transdermal device. Preferably 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 5 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 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. 10 The oily phase of the emulsions of this invention may be constituted from known ingredients in a known manner. While the phase may comprise 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 15 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 together with the oil and fat make up the so-called emulsifying ointment base which forms the oily dispersed phase of the cream formulations. Emulsifiers and emulsion stabilizers suitable for use in the formulation of the present 20 invention include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate, and sodium lauryl sulfate, among others. 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 25 formulations is very low. Thus, the cream should preferably be a non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers. 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, 30 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 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 35 invention are ordinarily combined with one or more adjuvants appropriate to 140 WO 00/69833 PCT/US00/08226 the indicated route of administration. If administered per os, the compounds 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, 5 gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted or encapsulated for convenient administration. Such 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 10 aqueous or non-aqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions may be prepared from sterile powders or 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, 15 peanut oil, sesame oil, benzyl alcohol, sodium chloride, and/or various buffers. Other adjuvants and modes of administration are well and widely known in the pharmaceutical art. In practicing the methods of the present invention for the treatment and prevention of a variety of thrombotic conditions including coronary artery and 2 0 cerebrovascular disease, the compounds and pharmaceutical compositions of the present invention are administered alone or in combination with one another, or in combination with other therapeutics or in vivo diagnostic agents. The coagulation cascade inhibitors of the present invention can also be coadministered with suitable anti-platelet agreggation agents, including, but not 25 limited to ticlopidine or clopidrogel, fibrinogen receptor antagonists (e.g. to treat or prevent unstable angina or to prevent reocculsion after angioplasty and 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 30 antihypercholesterolemics (e.g. HMG CoA reductase inhibitors such as mevastatin, lovastatin, simvastatin, pravastatin, and fluvastatin, HMG CoA 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. 35 ACE) inhibitors, angiotensin II receptor antagonists, beta-blockers, 141 WO 00/69833 PCT/US00/08226 antiarrhythmics, anti-hypertension agents, and calcium channel blockers) to treat 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 5 cascade inhibitors of the present invention. Also, coagulation cascade inhibitors could enhance the efficiency of tissue plasminogen activator-mediated thrombolytic reperfusion. Typical doses of coagulation cascade inhibitors of the present invention with other suitable anti-platelet agents, anticoagulation agents, cardiovascular 10 therapeutic agents, or thrombolytic agents may be the same as those doses of coagulation cascade inhibitors administered without coadministration of 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 15 coadministration of additional anti-platelet agents, anticoagulation agents, cardiovascular therapeutic agents, or thrombolytic agents, depending on a patient's therapeutic needs. All mentioned references are incorporated by reference as if here written. 2 0 Although this invention has been described with respect to specific embodiments, the details of these embodiments are not to be construed as 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 25 descriptions, utilize the present invention to its fullest extent. Therefore the following preferred specific embodiments are to be construed as merely 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 30 contemplated. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative 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 142 WO 00/69833 PCT/US00/08226 by 'H NMR, mass spectrometry, elemental composition, and similar procedures. These compounds also may be formed in vivo. The following examples contain detailed descriptions of the methods of preparation of compounds of Formula (1). These detailed descriptions fall 5 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. The following general synthetic sequences are useful in making the present invention. Abbreviations used in the schemes and tables include: "AA" 10 represents amino acids, "AcCN" represents acetonitrile, "AcOH" represents acetic acid, "BINAF' represents 2,2'-bis(diphenylphosphino)-l,l'-binaphthyl, "BnOH" represents benzyl alcohol, "BnCHO" represents 2-phenylethanal, " BnS02Cl" represents benzylsulfonyl chloride, "Boc" represents tert-butyloxycarbonyl, "BOP" represents benzotriazol-l-yl-oxy-tris-15 (dimethylamino), "bu" represents butyl, "dba" represents dibenzylidene- acetone, "DCC" represents 13-dicyclohexylcarbodiimide, "DCM" represents dichloromethane or methylene chloride, "DIBAH" or "DIBAL" represents diisobutylaluminum hydride, "DMF" represents dimethylformamide, "DMSO" represents dimethylsulfoxide, "DPPA" represents diphenylphosphoryl azide", 20 "EDC" represents 1 -[3-(dimethylamino)propyl]-3-ethyl carbodiimide hydrochloride, "Ex. No." represents Example Number, "Fmoc" represents 9-fluorenylmethoxycarbonyl, "HOBt" represents hydroxybenzoltriazole", "LDA" represents lithium diisopropylamide, "MW" represents molecular weight, "NMM" represents N-methylmorpholine, "Ph" represents phenyl or aryl, 25 "PHTH" represents a phthaloyl group, "pnZ" represents 4-nitrobenzyloxy- carbonyl, "PTC" represents a phase transfer catalyst, "py" represents pyridine, " RNH2" represents a primary organic amine, "SEM" represents 2-(trimethylsilyl)ethoxy-methyl chloride, "p-TsOH" represents paratoluenesulfonic acid, 'TBAF' represents tetrabutylammonium fluoride, 3 0 "TBTU" represents 2-( 1 H-benzotriozole-1 -yl)-1,13,3-tetramethyl uronium tetrafluoroborate, "TEA" represents triethylamine, "TFA" represents trifluoroacetic acid, "THF" represents tetrahydrofuran, "TMS" represents trimethylsilyl, "TMSCN" represents trimethylsilyl cyanide, and "Cbz" or "Z" represents benzyloxycarbonyl. 35 143 WO 00/69833 PCT/US00/08226 GENERAL SYNTHETIC PROCEDURES AND SPECIFIC EXAMPLES The general synthetic approach to substituted uracils (i.e., pyrimidinediones) is shown in Scheme 1 below. Several N-I substituted 5 pyrimidinediones have been previously prepared, disclosed, and are useful intermediates for the preparation of the compounds of this invention. Stirring a solution of such a N-l substituted pyrimidinedione and an a-haloacetate in dimethylsulfoxide, in the presence of potassium carbonate results in alkylation of the N-3 nitrogen. Reduction of the nitro functional group to the primary amine is 10 easily accomplished with catalytic palladium on carbon in an atmosphere of hydrogen. The primary amine can then be reacted with a variety of raw materials including, but not limited to, acid chlorides, acid anhydrides, sulfonyl chlorides, alkyl and aromatic halides, aldehydes, and ketones. The acetate ester can then be hydrolyzed to the acid with lithium hydroxide. The acid can then be coupled with a 15 wide range of desired amines under standard peptide coupling conditions to give an amide. The amines used in the process of this invention are typically multifunctional and are reacted in protected form. Removal of these protecting groups provides the compounds of the present invention. 20 144 WO 00/69833 PCT/US00/08226 Scheme 1: General Uracil Procedure BA k2co3 XCHgCOgR1 NH DMSO O Step A O Step B 0*nORE H2, Pd/C MeOH •vfc R1 O n^nRE Step D u UH B-A=0, NaBH3CN, HCI Step C B-A-CI, NMM THF, DMF ■ xV or H, O ^OR1 Step E LiOH THF, MeOH, H20 f Jsl^D n-y'S Step F 1. BOC-Y°-NH2 EDC, HOBt, DIEA THF/DMF b-a \ 2. 4 M HCI OH TFA, PhSMe Step F c>2 A H O X. O N H This general uracil (i.e., pyrimidinedione) synthetic scheme is exemplified in Examples 1 and 2 below. 145 WO 00/69833 PCT/US00/08226 Example 1 °v,p ( T 2 hci EX-1A) A solution of 1-benzyl-5-nitro-2,4(lH,3H) pyrimidinedione (6.14 g, 24.82 mmol) prepared as described by Vampa, G. and Pecorari P. Boll. 5 Chim. Farm. 1987, 126,467-469 was dissolved in 100 mL dimethylsulfoxide and potassium dicarbonate ( 3.78 g, 27.34 mmol) was added in one portion with stirring. After approximately 10 minutes a solution of methyl bromoacetate (2.50 mL, 26.40 mmol) in 20 mL dimethylsulfoxide was added drop wise over a 10 minute period. The reaction mixture was then heated to 40°C and allowed to stir 10 for 18 hours. The reaction mixture was diluted with water (500 mL). The aqueous solution was extracted with ethyl acetate (4 x 100 mL). The combined organic solutions were washed with water (1 x 150 mL), brine (2 x 150 mL). The organic solution was dried (MgS04), filtered, and concentrated to give an oil. The crude oil was purified by MPLC (20% ethyl acetate/hexanes) to give pure l-Benzyl-3-15 methoxycarbonyl-methyl-5-nitro-2,4(lH3H)pyrimidinedione (EX-1A) as a white solid in 81% yield: *H NMR (400 MHz, CDC13) 6 8.73 (s, 1H) 7.38-7.30 (m, 5H), 5.06 (s, 2H), 4.69 (s, 2H), 3.72 (s, 3H); HRMS (ES) calcd for C14H13N306 319.0804, found 319.0797. EX-IB) A solution of l-Benzyl-3-methoxycarbonylmethyl-5-nitro-20 2,4(1H,3H) pyrimidinedione (EX-1A; 6.30 g, 19.74 mmol) in 100.0 mL methanol was degassed with hydrogen gas. The solution was then added 5% Pd/C (0.737 g) and allowed to stir under an atmosphere of hydrogen at room temperature for 24 hours. The crude reaction was filtered through a pad of Celite 545 and concentrated under reduced pressure. The oil was purified by MPLC (60% Ethyl 2 5 acetate/hexanes) to give pure 5-amino-1 -Benzyl-3-methoxycarbonylmethyl- 2,4(lH,3H)-pyrimidinedione (EX-IB) in 63% yield as a tan solid: *H NMR (300 146 WO 00/69833 PCT/US0O/O8226 MHz, DMSO) 6 7.41-7.28 (m, 5H), 6.93 (s, 1H), 4.93 (s, 2H), 4.66 (s, 2H), 4.32 (s, 2H), 3.69 (s, 3H); HRMS (ES) calcd for C14H16N304 290.1141, found 290.1138. EX-1C) A solution of 5-amino-l-Benzyl-3-methoxycarbonylmethyl-5 2,4(1H,3H) pyrimidinedione (EX-IB; 3.12 g, 10:77 mmol) in 18.0 mL of tetrahydrofuran and dimethylformamide (1:1, 0.62M) was added N-methyl morpholine (3.60 mL, 32.74 mmol) in one portion at room temperature. The resulting mixture was cooled to 0°C in an ice bath and was allowed to stir for 15 minutes. A solution of benzylsulfonyl chloride (2.26g, 11.86 mmol) in 18.0 mL 10 tetrahydrofuran was added drop wise over a 30 minute period. After the addition was complete the reaction was stirred for 3 hours at 0°C. The reaction mixture was diluted with ethyl acetate (250.0 mL) and washed with IN HCI ((2 x 50 mL), saturated NaHC03 (2 x 50 mL), and brine (2 x 50 mL). The organic solution was dried (MgS04), filtered and concentrated. Trituration with ethyl acetate and 15 hexanes gave pure l-Benzyl-3-methoxycarbonylmethyl-5- [[(phenylmethyl)sulfonyl]amino]-2,4(lH,3H)pyrimidinedione (EX-1C) in 74 % yield as a white solid: *H NMR (300 MHz, DMSO) 6 9.16 (s, 1H), 8.02 (s, 1H), 7.43-7.37 (m, 10H), 5.01 (s, 2H), 4.65 (s, 2H), 4.45 (s, 2H), 3.69 (s, 3H); HRMS (ES) calcd for C21H22N306S 444.1229, found 444.1242. 2 0 EX- ID) A suspension of l-benzyl-3-methoxycarbonylmethyl-5- [[(phenylmethyl) sulfonyl]amino]-2,4(lH,3H)pyrimidinedione (EX-1C; 3.28 g, 7.40 mmol) in 94.0 mL tetrahydrofuran and methanol (1:1,0.078 M) was added 30.0 mL of 0.1 M lithium hydroxide in water. The suspension quickly clears and becomes homogeneous. The reaction was stirred for 1 hour, and the volatiles were 25 removed under reduced pressure. The remaining aqueous solution was cooled in an ice bath and acidified to a pH of 1 with 1.0 N HCI which resulted in a white precipitate forming. The precipitate was collected by filtration, washed with 1.0 N HCI and water, and dried under vacuum to give pure l-BenzyI-3-methylene-carboxy-5-[[(phenylmethyl) sulfonyl]amino]-2,4(lH,3H)pyrimidinedione (EX- 30 ID) in 99 % yield: !H NMR (300 MHz, DMSO) 6 9.14 (br s, 1H), 7.98 (s, 1H), 7.44-7.35 (m, 10H), 5.00 (s, 2H), 4.51 (s, 2H), 4.45 (s, 2H); HRMS (ES) calcd for C20H19N3O6S 429.0995, found 429.0981. 147 WO 00/69833 PCT/US00/08226 EX-IE) A solution of l-Benzyl-3-methylenecarboxy-5-[[(phenylmethyl)-sulfonyl]amino]-2,4(lH3H)pyrimidinedione (EX-ID; 531.6 mg. 1.238 mmol) in 12.4 mL tetrahydrofuran and dimethylformamide (1:1,0.1 M) was added N,N-diisopropylethylamine (1.10 mL, 6.315 mmol), N-hydroxybenzotriazole (499.6 5 mg, 3.697 mmol), and l-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (717.2 mg, 3.741 mmol). The resulting mixture was allowed to stir for 30 minutes. The reaction mixture was then added amine (623.3 mg, 2.500 mmol) in one portion. The resulting mixture was allowed to stir over night. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with 5% citric 10 acid (1 x 25 mL), saturated NaHC03 (1 x 25 mL), and brine (1 x 25 mL). The organic solution was dried (MgS04), filtered and concentrated. The crude reaction was purified by MPLC (75% ethyl acetate/hexanes) to give the product EX - IE: !H NMR (300 MHz, DMSO) 6 9.13 (br s, 1H), 8.77 (t, 7= 5.3 Hz, lH),7.98(s, 1H), 7.91 (d, J= 7.9 Hz, 1H), 7.45-7.35 (m, 13H), 5.01 (s, 2H), 4.56 (s, 2H), 15 4.56 (s, 2H), 4.44 (s, 2H), 4.38 (d, J = 5.4 Hz, 2H), 1.47 (s, 9H); HRMS (ES) calcd for C^^^OyS 661.2444, found 661.2448. A flask of protected pyrimidinedione (EX- IE) (238.5 mg, 0.3610 mmol) was added 4.0 ml of 4 M HCI in dioxane. The resulting solution was allowed to stir overnight (approximately 18 hours). The solution was concentrated and the 20 crude product was triturated from ethyl ether. The resulting white solid was collected by filtration, washed with ethyl ether and dried to give pure product: 'h NMR (300 MHz, DMSO) 6 9.44 (s, 2H), 9:29 (s, 2H), 9.14 (s, 1H), 9.01-8.99 (m, 1H), 7.99 (s, 1H), 7.81 (d, 7= 7.9 Hz, 1H), 7.51-7.37 (m, 14H), 5.01 (s, 2H), 4.57 (s, 2H), 4.45-4.41 (m, 2H), 3.58 (s, 2H); HRMS (ES) calcd for 25 C28H29N605S 561.1920, found 561.1917. 30 148 WO 00/69833 PCT/US00/08226 Example 2 o 3tfa 2 10 15 20 (EX-2A) A solution of 1 -Benzyl-3-methylenecarboxy-5-[[(phenyl-methyl)sulfonyl] amino]-2,4(lH,3H)pyrimidinedione (439.8 mg, 1.024mmol) in 10.0 mL tetrahydrofuran and dimethylformamide (1:1,0.1 M) was added N,N-diisopropylethylamine (1.80 mL, 10.30 mmol), N-hydroxybenzotriazole (169.3 mg, 1.253 mmol), and l-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (238.2 mg, 1.243 mmol). The resulting mixture was allowed to stir for 10 minutes. The reaction mixture was then added amine (648.3 mg, 1.231 mmol) in one portion. The resulting mixture was allowed to stir over night. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with 5% citric acid (1 x 50 mL), saturated NaHC03 (1 x 50 mL), and brine (1 x 50 mL). The organic solution was dried (MgS04), filtered and concentrated. The crude reaction was purified by MPLC (75% ethyl acetate/hexanes) to give the product EX-2 A: 'h NMR (300 MHz, DMSO) 8 9.09 (s, 1H), 8.78 (d, J = 7.1 Hz, 1H), 8.28 (d, J = 3.0 Hz, 1H), 8.19 (d, 7 = 3.0 Hz, 1H), 7.94 (s, 1H), 7.43-7.31 (m, 10H), 6.68 (s, 1H), 5.44-5.43 (m, 1H), 4.97 (s, 2H), 4.56 (d, J= 4.2 Hz, 2H), 4.41 (s, 2H), 3.80 (s, 3H), 3.08 (br d, J = 5:4 Hz, 3H), 2.91 (s, 1H), 2.75 (s, 1H), 2.59 (s, 3H), 2.52 (s, 3H), 2.06 (s, 3H), 1.92-1.80 (m, 1H), 1.61-1.51 (m, 3H), 1.37-1.33 (m 1H); HRMS (EI) calcd for C39H45N809S3 865.2472, found 865.2484. A solution of EX-2A (281.3 mg, 0.3252 mmol) in 3.0 mL trifluoroacetic acid (0.1 M) was added thioanisole (0.115 mL, 0.9796 mmol) at room temperature with stirring. The resulting mixture was allowed to stir 6 hours. The reaction mixture was concentrated under reduced pressure. The crude product was purified 149 WO 00/69833 PCT/US00/08226 by trituration from ethyl ether. A light yellow powder was collected by filtration. washed with ethyl ether to give pure product 2: *H NMR (300 MHz, DMSO) 6 9.07 (s, 1H), 8.82 (d, J — 7.0 Hz, 1H), 8.30 (d, 7 = 3.0 Hz, 1H), 8.21 (d,7 = 3.0 Hz, 1H), 7.95 (s, 1H), 7.55-7.20 (m, 10H), 5.49-5.48 (m, 1H), 4.97 (s, 5 2H), 4.63-4.51 (m, 2H), 4.42 (s, 2H), 3.13 (br d, J = 6.0 Hz, 2H), 2.49 (s, 3H), 1.91 (br s, 1H), 1.67-1.58 (m, 4H); LRMS (EI), (MH+) 653.2. Using the procedures exemplified in Examples 1 and 2 and the attached Scheme 1, the following compounds can be prepared. 10 Example 3 H,N HCI N HCI r 1 ° NH2 Following Steps A and B exemplified in Example 1 and replacing benzyl bromide with 3-(N-Boc-amino)benzyl bromide (Murakami, Y.; Hagishita, S.; 15 Okada, T.; Kii, M.; Hashizume, H.; Yagami, T.; Fujimoto, M.; Bioorg. Med. Chem. 1999, 7, 1703-1714.), alkylated intermediate, methyl 3-[l-[3-(N-Boc-amino)benzyl]-5-amino-2,4-dioxopyrimidinyl]acetate (EX-3A) can be prepared. To a solution of 1 eq. of ester EX-3 A and 1 eq. of cyclobutanone in tetrahydrofuran is added 1 eq. of sodium cyanoborohydride, and the mixture is 20 stirred for several hours. The solvent is evaporated off to afford the crude product. The crude product is purified by silica gel chromatagraphy to afford purified methyl 2-[3-[l-[3-(N-Boc-amino)benzyl]-5-(N-cyclobutyl)amino-2,4-dioxopyrimidinyl]]-acetate (EX-3B). Following the remaining procedure exemplified in Example 1, the 25 indicated compound of Example 3 can be obtained. 150 WO 00/69833 PCT/US00/08226 Example 4 NH2 HCI HCI HCI NH2 NH A solution of 1 eq. of the appropriate amide and 1 eq. of 3-nitropnenylisocyanate in DMF is heated to 100°C for several hours. The solvent 5 evaporated off to afford the crude product. The crude product is purified by silica gel chromatagraphy to afford purified product 1 -[3-Nitrophenyl ]-5-nitro-2,4-dioxopyrimidine (EX-4A) A solution of 1 eq. of uracil EX-4A in dimethylsulfoxide is added to 1.1 eq. of potassium dicarbonate in one portion with stirring. After 10 approximately 10 minutes a solution containing 1.1 eq. of methyl bromoacetate in dimethylsulfoxide is added dropwise over a 10 minute period. The reaction mixture is heated to 40°C and allowed to stir for 18 hours. The reaction mixture is diluted with water. The aqueous solution is extracted with ethyl acetate and the combined organic solution is washed with water and brine. The 15 organic solution is dried over MgS04, filtered, and concentrated to give a crude product. The crude product is purified by silica gel chromatagraphy to afford purified methyl 2-[3- [ 1 -[3-nitrophenyl ]-5-nitro-2,4-dioxopyrimidinyl]]acetate (EX-4B). A suspension of methyl ester EX-4B in tetrahydrofuran and methanol 20 is added excess lithium hydroxide in water. The reaction is stirred for 1 hour, and 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 HQ which results in a white precipitate forming. The precipitate is collected by filtration, washed with 1.0 N HCI and water, and dried under vacuum to give 25 pure acid, 2-[3-[l-[3-nitrophenyl]-5-nitro-2,4-dioxopyrimidinyl]]acetic acid (EX-4C). 151 WO 00/69833 PCT/US00/08226 A solution of acid EX-4C in dimethylformamide ( 0.1 M) is added to 5 eq N,N-diisopropylethylamine , 1 eq N-hydroxybenzotriazole mmol), and 1 eq l-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride. The resulting mixture is allowed to stir for 30 minutes. To the reaction mixture is 5 then added 1 eq. of 4-(N-Boc-amidino)benzylamine in one portion. The resulting mixture is allowed to stir over night. The reaction mixture is diluted with ethyl acetate and washed with 5% citric acid, saturated NaHC03, and brine. The organic solution is dried (MgS04), filtered and concentrated. Purification by MPLC pure, N-[4-(N-Boc-amidinobenzyl)]-2-[3-[l-[3-10 nitrophenyl]-5-nitro-2,4-dioxopyrimidinyl]]acetamide (EX-4D). A solution of bis-nitro compound EX-4D in methanol is treated with 5 molar percent of 10% Pd/C under an atmosphere of hydrogen (balloon pressure). The suspension is allowed to stir over night. Filtration through Celite 545 followed by removal of the solvent affords pure, N-[4-(N-Boc-15 ami dinobenzyl )]-2- [3- [ 1 -[3-aminophenyl ]-5-amino-2,4-dioxopyrimidinyl]]acetamide (EX-4E). A solution of bis-amine EX-4E and 1 eq. of cyclobutanone in tetrahydrofuran is treated with 1 eq of sodium cyanoborohydride followed by a catalytic amount of hydrochloric acid. The reaction mixture is allowed to stir at 20 room temperature for several hour. The reaction is quenched with the cautious addition of water. The aqueous solution is extracted with ethyl acetate. The organic solutions are washed with water and brine. The organic solution is dried (MgS04), filtered and concentrated. Purifaction by MPLC affords pure, N-[4-(N-Boc-amidinobenzyl)]-2-[3-[ 1 -[3-aminophenyl]-5-(N-cyclobutyl-25 amino)-2,4-dioxopyrimidinyl]]acetamide (EX-4F). A solution of N-Boc amidine EX-4F in methanol is treated with 3 eq of 4 M HCI in dioxane. The solution is stirred for five hours. Removal of the solvents under vacuum followed by trituration with ethyl ether affords pure product. 30 A wide variety of methylene analogs of pyrimidinediones wherein a methylene is present as a replacement for the carbonyl of the acetamide at the N-2 position of the pyrimidinedione can be prepared using the procedure detailed below 35 152 WO 00/69833 PCT/US00/08226 Example 5 nh2 EX-5A) A solution of 1 eq. of phenyl isocyanate and 1 eq. of 3-ethoxy-2-nitro-propenamide in DMF is heated to 100°C for several hours. The solvent is 5 evaporated off to afford the crude product. The crude product is purified by silica gel chromatagraphy to afford purified product EX-5A. EX-5B) To a solution of 1 eq. of EX-5A in dimethylsulfoxide is added to 1.1 eq. of potassium dicarbonate in one portion with stirring. After approximately 10 minutes, a solution containing 1.1 eq. of methyl bromoacetate in 10 dimethylsulfoxide is added dropwise over a 10 minute period. The reaction mixture is heated to 40°C and allowed to stir for 18 hours. The reaction mixture is diluted with water. The aqueous solution is extracted with ethyl acetate and the combined organic solution is washed with water and brine. The organic solution is dried over MgS04, filtered, and concentrated to give a crude product. The crude 15 product is purified by silica gel chromatagraphy to afford purified product methyl 2-[3-[5-nitro-2,4-dixoxo-1-phenylpyrimidyl ]]acetate (E X - 5 B). EX-5C) Diisobutylaluminum hydride (1.05 equiv.) is added over a period of 15 min to a cooled solution -78 °C of 1 eq. of EX-5B in tetrahydrofuran . After stirring for 1 h at -78 °C, the reaction is slowly quenched at -78 °C with cold 20 methanol. The mixture is slowly poured into ice-cold IN HCI, and the aqueous mixture is extracted with ethyl acetate. The combined organic layers are washed with brine, dried with MgS04, filtered, and the solvents are removed under reduced pressure. The crude product is purified by column chromatography to afford purified aldehyde product EX-5C. 25 EX-5D) A suspension of 1.0 eq. of the aldehyde, 2-[3-[5-nitro-2,4- dixoxo-l-phenylpyrixnidyl]]ethanal (EX-5C) and 1.0 eq. of the amine, 4-(N-Boc- 153 WO 00/69833 PCT/US00/08226 amidino)benzylamine in dichJoromethane, and catalytic acetic acid is added 1.2 eq. of sodium triacetoxyborohydride. The suspension quickly clears and becomes homogeneous. The reaction is stirred for several hours. The solution is cooled in an ice bath and is made alkaline with 1.0 N NaOH. The reaction mixture is diluted 5 with dichloromethane and washed with brine. The organic solution is dried (MgS04), filtered and concentrated to give the crude product. The crude product is purified by silica gel chromatagraphy to afford purified product 2-[3-2-l2-[2-(4-(N-Boc-amidino)benzyl)amino]ethyl-5-nitro-2,4-dioxo-l-phenylpyrimidine (EX-5D): 10 EX-5E) A solution of 1 eq. of EX-5D in methanol is degassed with hydrogen gas. To the solution is added a catalytic amount of 5% Pd/C, and the reaction mixture is allowed to stir 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. The crude product is purified by silica 15 gel chromatagraphy to afford purified product amine, 2-[3-2-[2-[2-(4-(N-Boc-amidino)benzyl)amino]ethyl-5-amino-2,4-dioxo-1 -phenylpyrimidine (EX-5E). EX-5F) To a suspension of 1.0 eq. of EX-5E and 1.0 eq. of the phenylacetaldehyde in dichloromethane and catalytic acetic acid is added 1.2 eq. of sodium triacetoxyborohydride. The suspension quickly clears and becomes 20 homogeneous. The reaction is stirred for several hours. The solution is cooled in an ice bath and basified with 1.0 N NaOH. The reaction mixture is diluted with dichloromethane and washed with brine. The organic solution is dried (MgS04), filtered and concentrated to give the crude product. The crude product is purified by silica gel chromatagraphy to afford purified 2-[3-2-[2-[2-(4-(N-Boc-2 5 amidino)benzyI)amino jethyl-5-(N-(2-phenylethyl)amino)-2,4-dioxo-1 -phenylpyrimidine (EX-5F). To a flask of 1 eq. of EX-5F is added 4 M HCI in dioxane. The resulting solution is allowed to stir overnight. The solution is concentrated and the crude product is triturated from ethyl ether to afford purified product as the 30 dihydrochloride salt. Sulfonyl analogs of pyrimidinediones wherein a sulfonyl is present as a replacement for the carbonyl of the acetamide at the N-2 position of the pyrimidinedione can be prepared as detailed below in the specific Example 6. 35 154 WO 00/69833 PCT/US00/08226 Example 6 NH EX-6A) A solution of 1 eq. of EX-5A in dimethylsulfoxide is added to 1.1 eq. of potassium dicarbonate in one portion with stirring. After approximately 5 10 minutes, a solution containing 1.1 eq. of sodium bromomethylsulfonate in dimethylsulfoxide is added dropwise over a 10 minute period. The reaction mixture is heated to 40°C and allowed to stir for 18 hours. The reaction mixture is diluted with water. The aqueous solution is extracted with ethyl acetate. The combined organic solutions are washed with water and brine. The organic solution 10 is dried over MgS04, filtered, and concentrated to give a crude product. The crude product is purified by silica gel chromatagraphy to afford purified product, 3-[5-nitro-2,4-dixoxo-l-phenylpyrimidyl]methanesulfonic acid (EX-6A). EX-6B) A solution of 1 eq. of EX-6A in methanol is degassed with hydrogen gas. To the solution is added a catalytic amount of 5% Pd/C, and the 15 reaction mixture is allowed to stir 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. The crude product is purified by silica gel chromatagraphy to afford purified product, 3-[5-amino-2,4-dixoxo-l-phenylpyrimidyl]methanesulfonic acid (EX-6B). 20 EX-6C) To a suspension of 1.0 eq. of EX-6B and 1.0 eq. of the phenylacetaldehyde in dichloromethane and catalytic acetic acid is added 1.2 eq. of sodium triacetoxyborohydride. The reaction is stirred for several hours. The solution is cooled iii an ice bath and basified with 1.0 N NaOH. The reaction mixture is diluted with dichloromethane and washed with brine. The organic 155 WO 00/69833 PCT/US00/08226 10 15 solution is dried (MgS04), filtered and concentrated to give the crude product. The crude product is purified by silica gel chromatagraphy to afford purified product, 3-[5-fN-(2-phenylethyI )amino]-2,4-dixoxo-1 -phenylpyrimidyl Jmethanesulfonic acid (EX-6C). EX-6D) A solution of 1 eq. of EX-6C in dichloromethane with several drops of dimethylformamide is cooled to 0 °C. Thionyl chloride (1.1 equiv.) is added dropwise, and the solution is slowly warmed to room temperature. After completion of the reaction, the volatile components are removed under reduced pressure, and the sulfonyl chloride product is immediately used. The sulfonyl chloride is dissolved into dichloromethane, and 1 eq. of the appropriate amine, 4-(N-Boc-amidino)benzylamine, in DMF is added with 5 eq. of N-methylmorpholine to the sulfonyl chloride solution. After completion of the reaction, polyaldehyde and/or polyamine resin (10 equiv.) are added to remove any unreacted starting materials. The resins are filtered, rinsed with DMF/DCM (1:1), and the solvents are removed under reduced pressure to give pure N-[4-(N-Boc-amidino)benzyl]-3-[5-[N-(2-phenylethyl)amino]-2,4-dixoxo-l-phenylpyrimidyl]methanesulfonamide (EX-6D). A flask of 1 eq. of EX-6D is added to 4 M HCI in dioxane. The resulting solution is allowed to stir overnight. The solution is concentrated and the crude product was triturated from ethyl ether to afford purified product of Example 6. Triazinedione (aza analogs) of uracils (i.e.,pyrimidinones) wherein a nitrogen is present as a replacement for the carbon at the 5-position of the pyrimidinedione can be prepared as detailed below with the specific Example 7. 25 Example-7 NH NH2 156 WO 00/69833 PCT/US00/08226 EX-7A) A mixture of aniline (1; 50 mmol), concentrated HCI (10 mL), and water (50 mL) is cooled to 5 °C. Separately, a solution of sodium nitrite (50 mmol) in water (7.2 mL) is cooled to 5 °C and added to the aniline hydrochloride slurry with the addition tube beneath the liquid surface. The temperature is 5 maintained at 5 °C during the addition and for 1 hour thereafter. This solution of diazotized aniline (EX-7 A) is used in the next step. EX-7B) A mixture of cyanoacetylurethane (59 mmol), pyridine (656 mL), ice (216 g) and water (40 mL) is held at 5 °C while the slurry of EX-67 A is added over 15 min with stirring. After an additional hour of stirring at 5 °C, the orange 10 solid, N-ethoxycarbonyl-2-cyano-2-(N-phenylhydrazo)acetamide (EX-7B is isolated by filtration. EX-7C) A mixture of EX-7B (95 mmol), sodium acetate (110 mmol) and acetic acid (140 mL) is refluxed for 75 min. The. resulting clear solution is concentrated at reduced pressure, and the solid that separates is removed by 15 filtration and washed with water. Compound, 6-cyan o-2-phenyl-3,5-dioxo-1,2,4-triazine (EX-7C), is recrystallized from 95% ethanol. EX-7D) A mixture of compound EX-7C (50 mmol), 6 N HCI (190 mL) and dioxane (500 mL) is refluxed for 12 h. On cooling the ciystallized product, 6-(2-phenyi-3,5-dioxo-l,2,4-triazinyl)carboxylic acid (EX-7D) is separated by 2 0 filtration and recrystallized from methanol-water. EX-7E) The acid EX-7D (8.4 mmol) is dissolved in dry re/7-butyl alcohol (127 mL) and DPPA (9.3 mmol), and triethyl amine (9.3 mmol) is added. The solution is refluxed for 24h thereafter. At this time the solution is concentrated in vacuo. The residue is dissolved in methylene chloride (150 mL) and washed with 25 0.5 N citric acid (150 mL), 1 N NaHC03 (150 mL) and water (150 mL). The methylene chloride solution is then dried (sodium sulfate). Filtration and concentration gives the Boc-protected compound EX-7E. This material can be purified by chromatography if necessary. EX-7F) A solution of compound EX-7E (50 mmol) in DMF (150 mL) is 30 treated with potassium carbonate (55 mmol) in one portion with stirring. After approximately 10 min, a solution of methyl bromoacetate (50 mmol) in DMF (100 mL) is added dropwise. The reaction mixture is heated to 40 °C and allowed to stir for 18 h. Typical aqueous workup and chromatographic purification provides pure methyl 2-(2-phenyl-3,5-dioxo-6-(N-Boc-amino)-1,2,4-triazinyl)acetate (E X- 7 F). 157 WO 00/69833 PCT/US00/08226 EX-7G) A solution of compound EX-7F (50 mmol) is dissolved in methylene chloride (400 mL) and is treated with TFA (100 mL). The resulting solution is stirred at room temperature for 4 h thereafter. Concentration and trituration with ether affords TFA salt of methyl 2-(2-phenyl-3,5-dioxo-6-amino-5 l,2,4-triazinyl)acetate (EX-7G). EX-7H) A solution of compound EX-7G in tetrahydrofuran and methylene chloride (1:1,03 M) is treated with 1 eq. of phenylacetaldehyde and 0.9 eq. of triethyl amine. The solution will be cooled to 0 °C and treated with 1 eq. of sodium triacetoxyborohydride. After stirring for 5 minutes, the ice bath is 10 removed, and the reaction mixture is allowed to warm to room temperature and stir there for 2 h. The reaction is quenched by the addition of 1 N NaOH, and the mixture is stirred for 5 min. Typical aqueous workup is followed by chromatographic purification to provide pure product, methyl 2-(2-phenyI-3,5-dioxo-6-(N-(2-phenylethyl)amino)-l,2,4-triazinyl)acetate (EX-7H). 15 EX-7I) A solution of compound EX-7H (50 mmol) in THF (250 mL) is treated with LiOH (50 mmol). After the hydrolysis is complete, the volatiles are removed under reduced pressure. The remaining aqueous solution is cooled in an ice bath and acidified to pH 1 with 1.0 N HCI. The aqueous mixture is extracted with EtOAc. The EtOAc solution is dried (sodium sulfate), filtered and 20 concentrated to afford pure 2-(2-phenyl-3,5-dioxo-6-(N-(2-phenylethyl)amino)-1,2,4-triazinyl)acetic acid EX-71). EX-7J) A solution of compound EX-7I (50 mmol) in DMF (250 mL) is treated with N-hydroxybenzotriazole (60 mmol) and EDC hydrochloride (60 mmol). The mixture is stirred at room temperature for 30 min and treated with 4-25 (N-Cbz-amidinobenxylamine (50 mmol). The resulting mixture is allowed to stir overnight. Typical aqueous workup is followed by chromatographic purification to afford pure product, N-(4-Cbz-amidinobenzyl)-2-(2-phenyl-3,5-dioxo-6-(N-(2-phenylethyl)amino)-l,2,4-triazinyl)acetamide (EX-7J). A solution of compound EX-7J ( 50 mmol) in methanol (300 mL) and 4M 30 HCl-dioxane (100 mL) is degassed with hydrogen. 5% Pd(C) (0.5 g) is added, and the solution is stirred under an atmosphere of hydrogen at room temp for 24 h. The reaction mixture is filtered through a pad of celite 545 and concentrated under reduced pressure. Purification by reverse phase chromatography affords pure product of Example 7. 158 WO 00/69833 PCT/US00/08226 Using these methods and ordinary skill in the art of synthetic numerous novel compounds of the present invention have been or can be prepared. Formula (I) compounds of this invention possessing hydroxyl, thiol, and amine functional groups can be converted to a wide variety derivatives. 5 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 esters of carboxylic, sulfonic, carbamic, phosphonic, and phosphoric acids. 10 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 pyridine in an inert solvent. Similarly, carbamic acid esters (urethanes) can be 15 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 thioesters derivatives analogous to those of alcohols and phenols using the same 20 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 analogous to those used with alcohols and phenols. Ureas of the corresponding 25 primary or secondary amine can be prepared using isocyanates directly and carbamoyl 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 procedures and methods for preparing these derivatives can be found in House's 30 Modern 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, thiol, and amines of compounds of Formula (I) are available from commercial 35 sources or the references cited above, which are incorporated herein by reference. 159 WO 00/69833 PCT/US00/08226 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 one or more inteimediates in the processes of preparation before further 5 transfoiming 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, heteroaralkyl, alkoxyalkyl, aralkyloxyalkyl, and heteroaralkyloxyalkyl bromides, 10 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 pyridine in an inert solvent. Compounds of Formula (I) that have at least one thiol 15 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 corresponding secondary, tertiary or quaternary ammonium derivative. Quaternary 20 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 with a secondary, and three with a primary). With primary and secondary amines, 25 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 of glacial acetic acid. A primary amine can be monoalkylated by first mono-30 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-l,13,3-tetramethylguanidine), gives the monomethylated protected amine. Removal of the protecting group using aqueous potassium hydroxide gives the desired monoalkylated amine. Additional suitable 35 procedures and methods for preparing these derivatives can be found in House's 160 WO 00/69833 PCT/US00/08226 Modern 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 Wiley & Sons. Perfluoroalkyl derivatives can be prepared as described by 5 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. 10 Assays for Biological Activity TF-VIIa Assay In this assay 100 nM recombinant soluble tissue factor and 2nM recombinant human factor Vila are added to a 96-well assay plate containing 0.4 mM of the substrate, N-Methylsulfonyl-D-phe-gly-arg-p-nitroaniline and either 15 inhibitor or buffer (5 mM CaCl,,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 measured by monitoring the reaction at 405 nm for the release of p-nitroaniline. 20 Percent inhibition of TF-VIIa activity is calculated from OD^^ value from the experimental and control sample. Xa Assay 0.3 nM human factor Xa and 0.15 mM N-a-Benzyloxycarbonyl-D-arginyl- 25 L-glycyl-L-arginine-p-nitroaniline-dihydrochloride (S-2765) are added to a 96-well assay plate containing either inhibitor or buffer (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 30 the substrate is measured by monitoring the reaction at 405 nm for the release of p-nitroaniline. Percentinhibition of Xa activity is calculated from OD^^ value from the experimental and control sample. 35 161 WO 00/69833 PCT/USO0/08226 Thrombin Assay 0.28 nM human thrombin and 0.06 mM H-D-Phenylalanyl-L-pipecolyl-L-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 NaCl, 5 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 measured by monitoring the reaction at 405 nm for the release of p-nitroaniline. Percent inhibition of thrombin activity is calculated from OD405nm value from the 10 experimental and control sample. Trypsin Assay 5 ug/ml trypsin, type IX from porcine pancreas and 0.375 mM N-a- Benzoyl-L-arginine-p-nitroanilide (L-BAPNA) are added to a 96-well assay plate 15 containing either inhibitor or buffer (50 mM Tris-HCl, 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 measured by monitoring the reaction at 405 nm for the release of p-nitroaniline. 20 Percent inhibition of trypsin activity is calculated from 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 Sepharose FPLC. Recombinant human Vila was purchased from American 25 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-BAPNA from Sigma, St. Louis MO. The chromogenic substrates S-2765 and 30 S-2238 were purchased from Chromogenix, Sweden. The biological activity of the compounds of Examples 1 through 7 as determined by the bioassay procedures is summarized in the Table 1. 162 </div>

Claims

<div class="application article clearfix printTableText" id="claims"> WO 00/69833 PCT/US00/08226 Table 1. Inhibitory Activity of Uracils toward Factor Xa, TF-VIIA, Thrombin II, and Trypsin II. Example TF-VIIA Thrombin II Factor Xa Trpysin II Number ICSO (uM) IC50 (uM) IC50 (uM) IC50 (uM) 1 >100 13.0 25.6 0.4 2 12.9 0.3 0.2 0.2 163 WHAT WE CLAIM IS:

1. A compound having the Formula: B N H N H O or a pharmaceutically acceptable salt thereof, wherein; B is selected from the group consisting of aryl and heteroaryl where (a) a ring carbon in a first alpha position relative to the ring carbon at the point of attachment is optionally substituted by R32, (b) a ring carbon in a second alpha position relative to the ring carbon at the point of attachment is optionally substituted by R36, (c) a ring carbon, in a first beta position relative to the ring carbon at the point of attachment and in an alpha position relative to the ring atom optionally substituted by R32, is optionally substituted by R33, (d) a ring carbon, in a second beta position relative to the ring carbon at the point of attachment and in an alpha position relative to the ring atom optionally substituted by R36, is optionally substituted by R35, and (e) a ring carbon, if present, in the gamma position relative to the ring carbon at the point of attachment and in an alpha position relative to each of the ring atoms optionally substituted by R33 and R35, respectively, is optionally substituted by R34; where R32, R33, R34, R35, and R36 are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, alkylthio, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboalkoxy, carboxy, carboxamido, cyano, and Qb; A is selected from the group consisting of single covalent bond and (CH(R15))pa-(W7)^ where rr is an integer selected from 0 through 1; pa is an integer selected from 0 through 3; W7 is selected from the group consisting of (R7)NC(0) and N(R7); where R7 is selected from the group consisting of hydrido, hydroxy and alkyl; and R15 is selected from the group consisting of hydrido, halo, alkyl, and haloalkyl; M is selected from the group consisting of N and R1-C; where intellectual property office of N.Z. 164 2 3 JAN 2004 RECEIVED R1 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; where Z° is selected from the group consisting of a covalent single bond, O, S, NH, and CH2; and Q is selected from the group consisting of aryl and heteroaryl where; (a) a ring carbon in a first alpha position relative to the ring carbon at the point of attachment is optionally substituted by R9, (b) a ring carbon in a second alpha position relative to the ring carbon at the point of attachment is optionally substituted by R13, (c) a ring carbon, in a first beta position relative to the ring carbon at the point of attachment and in an alpha position relative to the ring atom optionally substituted by R9, is optionally substituted by R10, (d) a ring carbon, in a second beta position relative to the ring carbon at the point of attachment and in an alpha position relative to the ring atom optionally substituted by R13, is optionally substituted by R12, and (e) a ring carbon, if present, in the gamma position relative to the ring carbon at the point of attachment and in an alpha position relative to each of the ring atoms optionally substituted by R10 and R12, respectively, is optionally substituted by R11; where R9, R11, and R13 are independently selected from the group consisting of hydrido, hydroxy, amino, amidino, guanidino, lower alkylamino, alkylthio, alkylsulfonamido, alkylsulflnyl, alkylsulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboxy, carboxamido, and cyano; and 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, amidocarbonyl, halo, haloalkyl, and cyano; and Y° is formula (IV): 165 intellectual property office of n.z. 2 3 JAN 2004 Dircivcn r ">QS d 17 pT8 j Jl ^19 Qb (iv) where D5, D6, J5, and J6 are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more than one is a covalent bond, no more than one of D5, D6, J5, and J6 is O, no more than one of D5, D8, J5, and J6 is S, one of D5, D6, J5, and J6 must be a covalent bond when two of D5, D6, J5, and J6 are O and S, and no more than four of D5, D6, J5, and J6 are N; R16, R17, R18, and R19 are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, haloalkylthio, alkoxy, hydroxy, amino, lower alkylamino, alkylthio, alkylsulflnyl, alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, and cyano; Qb is selected from the group consisting of NR20R21, hydrido, and C(NR25)NR23R24, with the provisos that no more than one of R20 and R21 is hydroxy and that no more than one of R23 and R24 is hydroxy; where R20, R21, R23, R24, and R25 are independently selected from the group consisting of hydrido, alkyl, and hydroxy; and Qs is selected from the group consisting of a single covalent bond, CH2, and CH2CH2.

2. The compound as recited in claim 1, or a pharmaceutical^ acceptable salt thereof, wherein; B is selected from the group consisting of phenyl and 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- 166 intellectual property office of n.z. 2 3 JAN 20M pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, and 1,3,5-triazin-2-yl heteroaryl rings, where (a) a ring carbon in a first alpha position relative to the ring carbon at the point of attachment is optionally substituted by R32, (b) a ring carbon in a second alpha position relative to the ring carbon at the point of attachment is optionally substituted by R36, (c) a ring carbon, in a first beta position relative to the ring carbon at the point of attachment and in an alpha position relative to the ring atom optionally substituted by R32, is optionally substituted by R33, (d) a ring carbon, in a second beta position relative to the ring carbon at the point of attachment and in an alpha position relative to the ring atom optionally substituted by R36, is optionally substituted by R35, and (e) a ring carbon, if present, in the gamma position relative to the ring carbon at the point of attachment and in an alpha position relative to each of the ring atoms optionally substituted by R33 and R35, respectively, is optionally substituted by R34; where R32, R33, R34, R35, and R36 are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, methoxyamino, ethoxyamino, acetamido, trifluoroacetamido, N-methylamino, dimethylamino, N-ethylamino, methylthio, ethylthio, isopropylthio, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, 2,2,3,3,3-pentafluoropropyl, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro, bromo, amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2,2,2-trif!uoro-1-hydroxyethyl, methoxycarbonyl, ethoxycarbonyl, amidocarbonyl, N-methylamidocarbonyl, N,N-dimethylamidocarbonyl, cyano, and Qb; A is selected from the group consisting of single covalent bond, NH, N(CH3), N(OH), CH2, CH3CH, CF3CH, NHC(O), N(CH3)C(0), C(0)NH, C(0)N(CH3), CH2CH2, CH2CH2CH2i CH3CHCH2, and CF3CHCH2; M is selected from the group consisting of N and R1-C; where R1 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, 167 intellectual property office of n.z. 2 3 JAN 2004 hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, methoxyamino, methylthio, ethylthio, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro, and bromo; R2 is Z°-Q; where Z° is selected from the group consisting of a covalent single bond, O, S, NH, and CH2; and Q is selected from the group consisting of phenyl and 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 heteroaryl rings, where (a) a ring carbon in a first alpha position relative to the ring carbon at the point of attachment is optionally substituted by R9, (b) a ring carbon in a second alpha position relative to the ring carbon at the point of attachment is optionally substituted by R13, (c) a ring carbon, in a first beta position relative to the ring carbon at the point of attachment and in an alpha position relative to the ring atom optionally substituted by R9, is optionally substituted by R10, (d) a ring carbon, in a second beta position relative to the ring carbon at the point of attachment and in an alpha position relative to the ring atom optionally substituted by R13, is optionally substituted by R12, and (e) a ring carbon, if present, in the gamma position relative to the ring carbon at the point of attachment and in an alpha position relative to each of the ring atoms optionally substituted by R10 and R12, respectively, is optionally substituted by R11; where R9, R11, and R13 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-pentafIuoropropyl, 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; and intellectual property office of n 7 2 3 JAN 2004 received 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-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, fluoro, chloro, bromo, and cyano; and Y° is selected from the group consisting of: 117 qs'll q" h; i R« r17 q q: :r ,18 Q .R19 r16 ,18 ,19 q° qs -h ,18 n' ,16 Q qs' 1 qs jl ,r18 r17 Q ,19 318 N^N q qS'V )18 V°' A ,19 Q" \ ,19 ,10 A Q \ Qb ,17 >16 169 intellectual property office of n.z. 23 JAN 2004 V°\ A V°\ K V\ R'6 \ qb , r16 , qb *> QS qd r 16 \ / V ,16 \ / VQ% h ,N 116 ^ Q* r> <-> > qb ^ V . N ^ / K and ,it \ /" where R16, R17, R18, and R19 are independently selected from the group consisting of hydrido, methyl, ethyl, isopropyl, propyl, carboxy, amidino, guanidino, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, aminomethyl, 1-aminoethyl, 2-aminoethyl, N-methylamino, dimethylamino, N-ethylamino, methylthio, ethylthio, isopropylthio, trifluoromethylthio, methylsulfinyl, ethylsulfinyl, methylsulfonyl, 170 intellectual property office of n.z. 23 JAN 2004 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, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro-1-hydroxyethyl, and cyano; Qb is selected from the group consisting of hydrido and C(NR25)NR23R24, with the proviso that no more than one of R23 and R24 is hydroxy; where R23, R24, and R25are independently selected from the group consisting of hydrido, methyl, ethyl, and hydroxy; and Qs is selected from the group consisting of a single covalent bond, CH2 and CH2CH2.

3. The compound as recited in Claim 2, or a pharmaceutical^ acceptable salt thereof, wherein; B is selected from the group consisting of 2-aminophenyl, 3-aminophenyl, 3-amidinophenyl, 4-amidinophenyl, 3-carboxyphenyl, 3-carboxy-5-hydroxyphenyl, 3-chlorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 3,4-difluorophenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 3-methoxyaminophenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-methylphenyl, 4-methylphenyl, phenyl, 3-trifluoromethylphenyl, 2-imidazoyl, 2-pyridyl, 3-pyridyl, 5-chloro-3-trifluoromethyl-2-pyridyl, 4-pyridyl, 2-thienyl, 3-thienyl, and 3-trifIuoromethyl-2-pyridyl; A is selected from the group consisting of CH2, CH3CH, CF3CH, NHC(O), CH2CH2,and CH2CH2CH2; M is selected from the group consisting of N and R1-C; where R1 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; R2 is Z°-Q; where Z° is selected from the group consisting of a covalent single bond, O, S, NH, and CH2; and Q is selected from the group consisting of 5-amino-3-amidocarbonylphenyl, 5-amino-2-fluorophenyl, 3-amino-5-hydroxymethylphenyl, 5-amino-3- intellectual property office of n.z. 2 3 JAN 2004 methoxycarbonylphenyl, 3-amidinophenyl, 3-amino-2-methylphenyl, 5-amino-2-methylthiophenyl, 3-aminophenyl, benzyl, 3-carboxyphenyl, 3-carboxy-5-aminophenyl, 3-carboxy-5-hydroxyphenyl, 3-carboxymethyl-5-aminophenyl, 3-carboxymethyl-5-hydroxyphenyl, 3-carboxymethylphenyl, 3-chlorophenyl, 2-chlorophenyl, 2,6-dichlorophenyl, 3-cyanophenyl, 3-dimethylaminophenyl, 2-fluorophenyl, 3-fluorophenyl, 2,5-difluorophenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 3-methanesulfonylaminophenyl, 2-methoxyphenyl, 3-methoxyphenyl, 3-methoxyaminophenyl, 3-methoxycarbonylphenyl, 2-methylaminophenyl, 3-methylaminophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, phenyl, 3-trifluoroacetamidophenyl, 3-trifluoromethylphenyl, 2-trifluoromethylphenyl, 5-amino-2-thienyl, 5-amino-3-thienyl, 3-bromo-2-thienyl, 3-pyridyl, 4-pyridyl, 2-thienyl, and 3-thienyl; and Y° is selected from the group consisting of: R16 and R19 are independently selected from the group consisting of hydrido, amidino, amino, aminomethyl, methoxy, methylamino, hydroxy, 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; 172 intellectual property office of n.z. ? 2 iam onn/. Qb is selected from the group consisting of hydrido and C(NR25)NR23R24; where R23, R24, and R25are independently selected from the group consisting of hydrido and methyl; and Q8 is CH2.

4. The compound as recited in claim 1, or a pharmaceutical!y acceptable salt thereof, wherein; B is selected from the group consisting of aryl and heteroaryl where (a) a ring carbon in a first alpha position relative to the ring carbon at the point of attachment is optionally substituted by R32, (b) a ring carbon in a second alpha position relative to the ring carbon at the point of attachment is optionally substituted by R36, (c) a ring carbon, in a first beta position relative to the ring carbon at the point of attachment and in an alpha position relative to the ring atom optionally substituted by R32, is optionally substituted by R33, (d) a ring carbon, in a second beta position relative to the ring carbon at the point of attachment and in an alpha position relative to the ring atom optionally substituted by R36, is optionally substituted by R35, and (e) a ring carbon, if present, in the gamma position relative to the ring carbon at the point of attachment and in an alpha position relative to each of the ring atoms optionally substituted by R33 and R35, respectively, is optionally substituted by R34; where R32, R33, R34, R35, and R36 are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, alkylthio, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboalkoxy, carboxy, carboxamido, cyano, and Qb; A is selected from the group consisting of single covalent bond and (CH(R15))pa-(W7)rr where rr is an integer selected from 0 through 1; pa is an integer selected from 0 through 3; W7 is N(R7); where R7 is selected from the group consisting of hydrido and alkyl; and 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; where 173 inte!^lcsrual property OFFICE OF N.Z. 2 3 JAN 2004 ft t* t _ R1 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; where Z° is a covalent single bond; and Q is selected from the group consisting of aryl and heteroaryl where (a) a ring carbon in a first alpha position relative to the ring carbon at the point of attachment is optionally substituted by R9, (b) a ring carbon in a second alpha position relative to the ring carbon at the point of attachment is optionally substituted by R13, (c) a ring carbon, in a first beta position relative to the ring carbon at the point of attachment and in an alpha position relative to the ring atom optionally substituted by R9, is optionally substituted by R10, (d) a ring carbon, in a second beta position relative to the ring carbon at the point of attachment and in an alpha position relative to the ring atom optionally substituted by R13, is optionally substituted by R12, and (e) a ring carbon, if present, in the gamma position relative to the ring carbon at the point of attachment and in an alpha position relative to each of the ring atoms optionally substituted by R10 and R12, respectively, is optionally substituted by R11; where R9, R11, and R13 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; and 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, carboxy, carboxyamido, carboxyalkyl, and cyano; and Y° is formula (IV): INTELLECTUAL property office of n.z. 2 3 JAN 2004 p 17 I p 15 II I r]6AW6^19 Qb (IV) where D5, De, J5, and J6 are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more than one is a covalent bond, no more than one of D5, D6, J5, and J6 is O, no more than one of D5, D6, J5, and J6 is S, one of D5, D6, J5, and J6 must be a covalent bond when two of D5, D6, J5, and J6 are O and S, and no more than four of D5, D6, J5, and J6 are N; R16, R17, R18, and R19 are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, haloalkylthio, alkoxy, hydroxy, amino, lower alkylamino, alkylthio, alkylsulflnyl, alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, and cyano; Qb is selected from the group consisting of NR20R21, hydrido, and C(NR25)NR23R24; where R20, R21, R23, R24, and R25 are independently selected from the group consisting of hydrido and alkyl; and Qs is CH2.

5. The compound as recited in claim 4, or a pharmaceutical^ acceptable salt thereof, wherein; B is selected from the group consisting of phenyl and 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl, 4-imidazolyl, 3-pyrazolyl, 4-pyrazolyl, 2-thiazolyl, 3-isoxazolyl, and 5-isoxazolyl heteroaryl rings, where (a) a ring carbon in a first alpha position relative to the ring carbon at the point of attachment is optionally substituted by R32, (b) a ring carbon in a second alpha position relative to the ring carbon at the point of attachment is optionally substituted by R36, (c) a ring 175 iintincsual property j office of n.z. I 2 3 JAN 2004 carbon, in a first beta position relative to the ring carbon at the point of attachment and in an alpha position relative to the ring atom optionally substituted by R32, is optionally substituted by R33, (d) a ring carbon, in a second beta position relative to the ring carbon at the point of attachment and in an alpha position relative to the ring atom optionally substituted by R36, is optionally substituted by R35, and (e) a ring carbon, if present, in the gamma position relative to the ring carbon at the point of attachment and in an alpha position relative to each of the ring atoms optionally substituted by R33 and R35, respectively, is optionally substituted by R34; where R32, R33, R34, R35, and R36 are independently selected from the group consisting of hydrido, amidino, guanidino, methyl, ethyl, methoxy, ethoxy, hydroxy, amino, N-methylamino, dimethylamino, methylthio, ethylthio, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, fluoro, chloro, bromo, amidosulfonyl, N-methylamidosulfonyl, hydroxymethyl, amidocarbonyl, carboxy, cyano, and Qb; A is selected from the group consisting of single covalent bond, NH, N(CH3), CH2, CH3CH, and CH2CH2; M is selected from the group consisting of N and R1-C; where R1 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; R2 is selected from the group consisting of phenyl and 2-thienyl, 2-furyl, 2-pyrrolyl, 2-imidazolyl, 2-thiazolyl, 3-isoxazolyl, 2-pyridyl, and 3-pyridyl heteroaryl rings, where (a) a ring carbon in a first alpha position relative to the ring carbon at the point of attachment is optionally substituted by R9, (b) a ring carbon in a second alpha position relative to the ring carbon at the point of attachment is optionally substituted by R13, (c) a ring carbon, in a first beta position relative to the ring carbon at the point of attachment and in an alpha position relative to the ring atom optionally substituted by R9, is optionally substituted by R10, (d) a ring carbon, in a second beta position relative to the ring carbon at the point of attachment and in an alpha position relative to the ring atom optionally substituted by R13, is optionally substituted by R12, and (e) a ring carbon, if present, in the gamma position relative to the ring carbon at the point of attachment and in an alpha position relative to 176 each of the ring atoms optionally substituted by R10 and R12, respectively, is optionally substituted by R11; where R9, R11, and R13 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, N-methylamidocarbonyl, carboxy, and cyano; and 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-methylamino, dimethylamino, amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, methoxycarbonyl, fluoro, chloro, bromo, and cyano; and Y° is selected from the group consisting of: intellectual property office of n.z. 2 3 JAN 2004 V I Q\ H \ q" < r \. I Q« H \ N ^A x> R16 \ R"X \ Q" Rl« R16, R17, R18, and R19 are independently selected from the group consisting of hydrido, methyl, ethyl, amidino, guanidino, methoxy, hydroxy, amino, aminomethyl, 1-aminoethyl, 2-aminoethyl, N-methylamino, dimethylamino, methylthio, ethylthio, trifluoromethylthio, methylsulfinyl, methylsulfonyl, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, trifluoromethoxy, fluoro, chloro, amidosulfonyl, N-methylamidosulfonyl, hydroxymethyl, carboxy, and cyano. Qb is selected from the group consisting of NR20R21 and C(NR25)NR23R24, with the proviso that said Qb group is bonded directly to a carbon atom; where R20, R21, R23, R24, and R25are independently selected from the group consisting of hydrido, methyl, and ethyl; and Qs is CH2.

6. The compound as recited in claim 5, or a pharmaceutical^ acceptable salt thereof, wherein; B is selected from the group consisting of 2-aminophenyl, 3-aminophenyl, 3-amidinophenyl, 4-amidinophenyl, 3-carboxyphenyl, 3-carboxy-5-hydroxyphenyl, 3-chlorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 2-fluorophenyl, 3-fluorophenyi, 3,4-difluorophenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 3-methoxyaminophenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-methylphenyl, 4-methylphenyl, phenyl, 3- 178 'ntellectual property office of n.z. 2 3 JAN 2004 received trifluoromethylphenyl, 2-imidazoyl, 2-pyridyl, 3-pyridyl, 5-chloro-3-trifluoromethyl-2-pyridyl, 4-pyridyl, 2-thienyl, 3-thienyl, and 3-trifluoromethyl-2-pyridyl; A is selected from the group consisting of CH2, CH3CH, CF3CH, NHC(O), CH2CH2,and CH2CH2CH2; M is selected from the group consisting of N and R1-C; where R1 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-amidocarbonylphenyl, 5-amino-2-fIuorophenyl, 3-amino-5-hydroxymethylphenyl, 5-amino-3-methoxycarbonylphenyl, 3-amidinophenyl, 3-amino-2-methylphenyl, 5-amino-2-methylthiophenyl, 3-aminophenyl, benzyl, 3-carboxyphenyl, 3-carboxy-5-aminophenyl, 3-carboxy-5-hydroxyphenyl, 3-carboxymethyl-5-aminophenyl, 3-carboxymethyl-5-hydroxyphenyl, 3-carboxymethylphenyl, 3-chlorophenyl, 2-chlorophenyl, 3-cyanophenyl, 3-dimethylaminophenyl, 2-fluorophenyl, 3-fluorophenyl, 2,5-difluorophenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 3-methanesulfonylaminophenyl, 2-methoxyphenyl, 3-methoxyphenyl, 3-methoxyaminophenyl, 3-methoxycarbonylphenyl, 2-methylaminophenyl, 3-methylaminophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, phenyl, 3-trifluoroacetamidophenyl, 3-trifluoromethylphenyl, 2-trifluoromethylphenyl, 5-amino-2-thienyl, 5-amino-3-thienyl, 3-bromo-2-thienyl, 3-pyridyl, 4-pyridyl, 2-thienyl, and 3-thienyl; and Y° is selected from the group consisting of: 179 intellectual property office of n.z. 2 3 JAN 2004 xtf R ,19 , and r16 ; where Q' R16 and R19 are independently selected from the group consisting of hydrido, amidino, amino, aminomethyl, methoxy, methylamino, hydroxy, 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 selected from the group consisting of hydrido and C(NR25)NR23R24; where R23, R24, and R25are independently selected from the group consisting of hydrido and methyl; and Qs is CH2.

7. The compound as recited in claim 6, or a pharmaceutical^ acceptable salt thereof, wherein; B is selected from the group consisting of 3-aminophenyl, 3-amidinophenyl, 4-amidinophenyl, 3-chlorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 2-fluorophenyl, 4-methylphenyl, phenyl, 2-imidazoyl, 3-pyridyl, 4-pyridyl, and 3-trifluoromethyl-2-pyridyl; A is selected from the group consisting of CH2, NHC(O), CH2CH2,and CH2CH2CH2; M is selected from the group consisting of N and R1-C; where R1 is selected from the group consisting of hydrido, fluoro, and 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-thienyl, and 3-thienyl; and 180 intellectual property OFFICE OF N.Z. 2 3 JAN 2004 Y° is selected from the group consisting of 5-amidino-2-thienylmethyl, 4-amidinobenzyl, 2-fluoro-4-amidinobenzyl, and 3-fluoro-4-amdinobenzyl.

8. The compound as recited in claim 1, or a pharmaceutical^ acceptable salt thereof, wherein: R2 is 3-aminophenyl, B is 3-chlorophenyl, A is CH2CH2, Y° is 4-amidinobenzyl, and M is CH; R2 is 3-aminophenyl, B is phenyl, A is CH2, Y° is 4-amidinobenzyl, and M is CH; R2 is phenyl, B is 3-chlorophenyl, A is CH2CH2, Y° is 4-amidinobenzyl, and M is CH; R2 is 3-aminophenyl, B is 2-imidazoyl, A is CH2CH2CH2, Y° is 4-amidinobenzyl, and M is CH; R2 is 3-dimethylaminophenyl, B is phenyl, A is CH2CH2, Y° is 4-amidinobenzyl, and M is CH; R2 is 2-methylphenyl, B is phenyl, A is CH2CH2, Y° is 4-amidinobenzyl, and M is CH; R2 is phenyl, B is 3-aminophenyl, A is C(0)NH, Y° is 4-amidinobenzyl, and M is CH; R2 is phenyl, B is 3-amidinophenyl, A is CH2, Y° is 4-amidinobenzyl, and M is CH; R2 is 3-(N-methylamino)phenyl, B is phenyl, A is CH2CH2, Y° is 4-amidinobenzyl, and M is CH; R2 is 3-thienyl, B is phenyl, A is CH2CH2, Y° is 4-amidinobenzyl, and M is CH; R2 is 3-methylsulfonamidophenyl, B is phenyl, A is CH2CH2, Y° is 4-amidinobenzyl, and M is CH; R2 is phenyl, B is 4-amidinophenyl, A is CH2, Y° is 4-amidinobenzyl, and M is CH; R2 is 3-methylaminophenyl, B is phenyl, A is CH2CH2, Y° is 4-amidinobenzyl, and M is CH; R2 is phenyl, B is phenyl, A is CH2, Y° is 4-amidinobenzyl, and M is CH; R2 is phenyl, B is 4-pyridyl, A is CH2CH2, Y° is 4-amidinobenzyl, and M is CH; R2 is phenyl, B is 3-pyridyl, A is CH2CH2, Y° is 4-amidinobenzyl, and M is CH; intellectual property office of n.z. 2 3 JAN 2004 R2 is 3-chlorophenyl, B is 4-pyridyl, A is CH2CH2, Y° is 4-amidinobenzyl, and M is CH; R2 is 3-methylphenyl, B is 4-phenyl, A is CH2CH2, Y° is 4-amidinobenzyl, and M is CH; R2 is 3-thienyl, B is 3-chlorophenyl, A is CH2CH2, Y° is 4-amidinobenzyl, and M is CH; R2 is 3-aminophenyl, B is 3-chlorophenyl, A is CH2CH2, Y° is 4-amidinobenzyl, and M is CF; R2 is 3-aminophenyl, B is phenyl, A is CH2, Y° is 4-amidinobenzyl, and M is CF; R2 is phenyl, B is 3-chlorophenyl, A is CH2CH2, Y° is 4-amidinobenzyl, and M is CF; R2 is 3-aminophenyl, B is 2-imidazoyl, A is CH2CH2CH2, Y° is 4-amidinobenzyl, and M is CF; R2 is 3-dimethylaminophenyl, B is phenyl, A is CH2CH2, Y° is 4-amidinobenzyl, and M is CF; R2 is 2-methylphenyl, B is phenyl, A is CH2CH2, Y° is 4-amidinobenzyl, and M is CF; R2 is phenyl, B is 3-aminophenyl, A is C(0)NH, Y° is 4-amidinobenzyl, and M is CF; R2 is phenyl, B is 3-amidinophenyl, A is CH2, Y° is 4-amidinobenzyl, and M is CF; R2 is 3-(N-methylamino)phenyl, B is phenyl, A is CH2CH2, Y° is 4-amidinobenzyl, and M is CF; R2 is 3-thienyl, B is phenyl, A is CH2CH2, Y° is 4-amidinobenzyl, and M is CF; R2 is 3-methylsulfonamidophenyl, B is phenyl, A is CH2CH2, Y° is 4-amidinobenzyl, and M is CF; R2 is phenyl, B is 4-amidinophenyl, A is CH2, Y° is 4-amidinobenzyl, and M is CF; R2 is 3-methylaminophenyl, B is phenyl, A is CH2CH2, Y° is 4-amidinobenzyl, and M is CF; R2 is phenyl, B is phenyl, A is CH2, Y° is 4-amidinobenzyl, and M is CF; R2 is phenyl, B is 4-pyridyl, A is CH2CH2, Y° is 4-amidinobenzyl, and M is CF; R2 is phenyl, B is 3-pyridyl, A is CH2CH2, Y° is 4-amidinobenzyl, and M is CF; 182 R2 is 3-chlorophenyl, B is 4-pyridyl, A is CH2CH2, Y° is 4-amidinobenzyl, and M is CF; R2 is 3-methylphenyl, B is 4-phenyl, A is CH2CH2, Y° is 4-amidinobenzyl, and M is CF; R2 is 3-thienyl, B is 3-chlorophenyl, A is CH2CH2, Y° is 4-amidinobenzyl, and M is CF; R2 is 3-aminophenyl, B is 3-chlorophenyl, A is CH2CH2, Y° is 4-amidinobenzyl, and M is N; R2 is 3-aminophenyl, B is phenyl, A is CH2, Y° is 4-amidinobenzyl, and M is N; R2 is phenyl, B is 3-chlorophenyl, A is CH2CH2, Y° is 4-amidinobenzyl, and M is N; R2 is 3-aminophenyl, B is 2-imidazoyl, A is CH2CH2CH2, Y° is 4-amidinobenzyl, and M is N; R2 is 3-dimethylaminophenyl, B is phenyl, A is CH2CH2, Y° is 4-amidinobenzyl, and M is N; R2 is 2-methylphenyl, B is phenyl, A is CH2CH2, Y° is 4-amidinobenzyl, and M is N; R2 is phenyl, B is 3-aminophenyl, A is C(0)NH, Y° is 4-amidinobenzyl, and M is N; R2 is phenyl, B is 3-amidinophenyl, A is CH2, Y° is 4-amidinobenzyl, and M is N; R2 is 3-(N-methylamino)phenyl, B is phenyl, A is CH2CH2, Y° is 4-amidinobenzyl, and M is N; R2 is 3-thienyl, B is phenyl, A is CH2CH2, Y° is 4-amidinobenzyl, and M is N; R2 is 3-methylsulfonamidophenyl, B is phenyl, A is CH2CH2, Y° is 4-amidinobenzyl, and M is N; R2 is phenyl, B is 4-amidinophenyl, A is CH2, Y° is 4-amidinobenzyl, and M is N; R2 is 3-methylaminophenyl, B is phenyl, A is CH2CH2, Y° is 4-amidinobenzyl, and M is N; R2 is phenyl, B is phenyl, A is CH2, Y° is 4-amidinobenzyl, and M is N; R2 is phenyl, B is 4-pyridyl, A is CH2CH2, Y° is 4-amidinobenzyl, and M is N; R2 is phenyl, B is 3-pyridyl, A is CH2CH2, Y° is 4-amidinobenzyl, and M is N; 183 intellectual property office of n.z. 23 JAN 2004 RECEIVED N; N; or N. R2 is 3-chlorophenyl, B is 4-pyridyl, A is CH2CH2, Y° is 4-amidinobenzyl, and M is R2 is 3-methylphenyl, B is 4-phenyl, A is CH2CH2, Y° is 4-amidinobenzyl, and M is R2 is 3-thienyl, B is 3-chlorophenyl, A is CH2CH2, Y° is 4-amidinobenzyl, and M is

9. A compound having the Formula: a ,Y b n h "n h O or a pharmaceutical^ 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, where 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, R34, R35, and R36; where R32, R33, R34, R35, and R36 are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, alkylthio, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboalkoxy, carboxy, carboxamido, cyano, and Qb; A is selected from the group consisting of single covalent bond and (CH(R15))pa-(W7)rr where rr is an integer selected from 0 through 1; pa is an integer selected from 0 through 3; W7 is selected from the group consisting of (R7)NC(0) and N(R7); where R7 is selected from the group consisting of hydrido, hydroxy and alkyl; and intellectual PROPERTY office of n.z. 184 23 JAN 2004 RECEIVED R1S is selected from the group consisting of hydrido, halo, alkyl, and haloalkyl; M is selected from the group consisting of N and R1-C; where R1 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; where Z° is selected from the group consisting of a covalent single bond, O, S, NH, and CH2; and Q is selected from the group consisting of aryl and heteroaryl where (a) a ring carbon in a first alpha position relative to the ring carbon at the point of attachment is optionally substituted by R9, (b) a ring carbon in a second alpha position relative to the ring carbon at the point of attachment is optionally substituted by R13, (c) a ring carbon, in a first beta position relative to the ring carbon at the point of attachment and in an alpha position relative to the ring atom optionally substituted by R9, is optionally substituted by R10, (d) a ring carbon, in a second beta position relative to the ring carbon at the point of attachment and in an alpha position relative to the ring atom optionally substituted by R13, is optionally substituted by R12, and (e) a ring carbon, if present, in the gamma position relative to the ring carbon at the point of attachment and in an alpha position relative to each of the ring atoms optionally substituted by R10 and R12, respectively, is optionally substituted byR11; where R9, R11, and R13 are independently selected from the group consisting of hydrido, hydroxy, amino, amidino, guanidino, lower alkylamino, alkylthio, alkylsulfonamido, alkylsulflnyl, alkylsulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboxy, carboxamido, and cyano; and 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, amidocarbonyl, halo, haloalkyl, and cyano; and INTELLECTUAL PROPERTY OFFICE OF N.Z. 185 2 3 JAN 2004 RECEIVED Y° is formula (IV): (iv) where D5, D6, J5, and J6 are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more than one is a covalent bond, no more than one of D5, D6, J5, and J6 is O, no more than one of D5, D6, J5, and J6 is S, one of D5, D6, J5, and J6 must be a covalent bond when two of D5, D6, J5, and J6 are O and S, and no more than four of D5, D6, J5, and J6 are N; R16, R17, R18, and R19 are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, haloalkylthio, alkoxy, hydroxy, amino, lower alkylamino, alkylthio, alkylsulflnyl, alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, and cyano; Qb is selected from the group consisting of NR20R21, hydrido, C(NR25)NR23R24, and N(R26)C(NR25)N(R23)(R24), with the provisos that no more than one of R20 and R21 is hydroxy and that no more than one of R23 and R24is hydroxy; where R20, R21, R23, R24, R25, and R26are independently selected from the group consisting of hydrido, alkyl, and hydroxy; and Qs is selected from the group consisting of a single covalent bond, CH2, and CH2CH2.

10. The compound as recited in claim 9, or a pharmaceutical^ acceptable salt 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- j intellectual property 186 I OFFICE OF N.Z. 23 JAN 2004 butyl, isobutyl, 2-methylpropenyl, 1-pentyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-pentynyl, 3-pentynyl, 2-pentyl, 1-methyl-2-butenyl, 1-methyl-3-butenyl, 1-methyl-2-butynyl, 3-pentyl, 1-ethyl-2-propenyl, 2-methylbutyl, 2-methyl-2-butenyl, 2-methyl-3-butenyl, 2-methyl-3-butynyl, 3-methylbutyl, 3-methyl-2-butenyl, 3-methyl-3-butenyl, 1-hexyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 2-hexyl, 1-methyl-2-pentenyl, 1-methyl-3-pentenyl, 1-methyl-4-pentenyl, 1-methyl-2-pentynyl, 1-methyl-3-pentynyl, 3-hexyl, 1-ethyl-2-butenyl, 1-ethyl-3-butenyl, 1-propyl-2-propenyl, 1-ethyl-2-butynyl, 1-heptyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 5-heptynyl, 2-heptyl, 1-methyl-2-hexenyl, 1-methyl-3-hexenyl, 1-methyl-4-hexenyl, 1-methyl-5-hexenyl, 1-methyl-2-hexynyl, 1-methyl-3-hexynyl, 1 -methyl-4-hexynyl, 3-heptyl, 1 -ethyl-2-pentenyl, 1-ethyl-3-pentenyl, 1-ethyl-4-pentenyl, 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, where 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, R33, R34, R35, and R36; where R32, R33, R34, R35, and R36 are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, methoxyamino, ethoxyamino, acetamido, trifluoroacetamido, N-methylamino, dimethylamino, N-ethylamino, methylthio, ethylthio, isopropylthio, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, 2,2,3,3,3-pentafluoropropyl, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro, bromo, amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro-1-hydroxyethyl, methoxycarbonyl, ethoxycarbonyl, amidocarbonyl, N-methylamidocarbonyl, N,N-dimethylamidocarbonyl, cyano, and Qb; A is selected from the group consisting of single covalent bond, NH, N(CH3), N(OH), CH2, CH3CH, CF3CH, NHC(O), N(CH3)C(0), C(0)NH, C(0)N(CH3), CH2CH2, CH2CH2CH2j CH3CHCH2, and CF3CHCH2; M is selected from the group consisting of N and R1-C; where 187 INTELLECTUAL PROPERTY OFFICE OF N.Z. 23 JAN 2004 RECEIVED R1 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, methoxyamino, methylthio, ethylthio, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro, and bromo; R2 is Z°-Q; where Z° is selected from the group consisting of a covalent single bond, O, S, NH, and CH2; and Q is selected from the group consisting of phenyl and 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 heteroaryl rings, where (a) a ring carbon in a first alpha position relative to the ring carbon at the point of attachment is optionally substituted by R9, (b) a ring carbon in a second alpha position relative to the ring carbon at the point of attachment is optionally substituted by R13, (c) a ring carbon, in a first beta position relative to the ring carbon at the point of attachment and in an alpha position relative to the ring atom optionally substituted by R9, is optionally substituted by R10, (d) a ring carbon, in a second beta position relative to the ring carbon at the point of attachment and in an alpha position relative to the ring atom optionally substituted by R13, is optionally substituted by R12, and (e) a ring carbon, if present, in the gamma position relative to the ring carbon at the point of attachment and in an alpha position relative to each of the ring atoms optionally substituted by R10 and R12, respectively, is optionally substituted by R11; where R9, R11, and R13 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-pentafluoropropyl, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro, bromo, methanesulfonamido, amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, 2- 188 INTELLECTUAL PROPERTY OFFICE OF N.Z. 23 JAN 2004 hydroxyethyl, 2,2,2-trifluoro-1-hydroxyethyl, amidocarbonyl, N-methylamidocarbonyl, N,N-dimethylamidocarbonyl, and cyano; and 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-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, fluoro, chloro, bromo, and cyano; and Y° is selected from the group consisting of: Qs R18 r17 ,18 *R19 R16 Q 2 Qs " I 118 ,16 - JL A Q Qs A\ Q t Qs Jl „R18 R17 ,19 ,18 I Qs, i N N ,16 - VQS A ,19 Q ,ie > Qb D19 \ QS "A ,17- >16 189 S^Qs > i19 VQ 317. Q H -N // -Q -r ,16 Q \ / Q° J16 \ / \ \ H ,N R 16 ^ Q > Q" R16, R17, R18, and R19 are independently selected from the group consisting of hydrido, methyl, ethyl, isopropyl, propyl, carboxy, amidino, guanidino, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, aminomethyl, 1-aminoethyl, 2-aminoethyl, N-methylamino, dimethylamino, N-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, 190 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 NR20R21, hydrido, C(NR25)NR23R24, and N(R26)C(NR25)N(R23)(R24), with the provisos that no more than one of R20 and R21 is hydroxy and that no more than one of R23 and R24 is hydroxy; where R20, R21, R23, R24, R25, and R26are independently selected from the group consisting of hydrido, methyl, ethyl, propyl, butyl, isopropyl, and hydroxy; and Qs is selected from the group consisting of a single covalent bond, CH2, and CH2CH2.

11. The compound as recited in claim 10, 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, te/t-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-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,CH2, NHC(O), CH2CH2, CH2CH2CH2, and CH3CHCH2; M is selected from the group consisting of N and R1-C; where R1 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; R2 is Z°-Q; where Z° is selected from the group consisting of a covalent single bond, O, S, NH, and CH2; and intellectual property 191 office of n.z. 2 3 JAN 2004 RECEIVED Q is selected from the group consisting of 5-amino-3-amidocarbonylphenyl, 5-amino-2-fluorophenyl, 3-amino-5-hydroxymethylphenyl, 5-amino-3-methoxycarbonylphenyl, 3-amidinophenyl, 3-amino-2-methylphenyl, 5-amino-2-methylthiophenyl, 3-aminophenyl, benzyl, 3-carboxyphenyl, 3-carboxy-5-aminophenyl, 3-carboxy-5-hydroxyphenyl, 3-carboxymethyl-5-aminophenyl, 3-carboxymethyl-5-hydroxyphenyl, 3-carboxymethylphenyl, 3-chlorophenyl, 2-chlorophenyl, 2,6-dichlorophenyl, 3-cyanophenyl, 3-dimethylaminophenyl, 2-fluorophenyl, 3-fluorophenyl, 2,5-difluorophenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 3-methanesulfonylaminophenyl, 2-methoxyphenyl, 3-methoxyphenyl, 3-methoxyaminophenyl, 3-methoxycarbonylphenyl, 2-methylaminophenyl, 3-methylaminophenyi, 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; and Y° is selected from the group consisting of: QS £ ,16 X y y > , and ; where R16 and R19 are independently selected from the group consisting of hydrido, amidino, amino, aminomethyl, methoxy, methylamino, hydroxy, hydroxymethyl, fluoro, chloro, and cyano; 192 intellectual property office of n.z. 23 JAN 2004 D e n e 11< 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 hydrido and C(NR25)NR23R24; where R23, R24, and R25 are independently selected from the group consisting of hydrido and methyl; and Qs is CH2.

12. The compound as recited in claim 9, or a pharmaceutical^ 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, where 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, R34, R35, and R36; where R32, R33, R34, R35, and R36 are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, alkylthio, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboalkoxy, carboxy, carboxamido, cyano, and Qb; A is selected from the group consisting of single covalent bond and (CH(R15))pa-(W7)rr where rr is an integer selected from 0 through 1; pa is an integer selected from 0 through 3; W7 is N(R7); where R7 is selected from the group consisting of hydrido and alkyl; and R15 is selected from the group consisting of hydrido, halo, alkyl, and haloalkyl; M is selected from the group consisting of N and R1-C; where R1 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; where Z° is a covalent single bond; and ,Q J 'nteopp^al property 193 i office of n.z. 2 3 JAN 2004 RECEIvrn Q is selected from the group consisting of aryl and heteroaryl where (a) a ring carbon in a first alpha position relative to the ring carbon at the point of attachment is optionally substituted by R9, (b) a ring carbon in a second alpha position relative to the ring carbon at the point of attachment is optionally substituted by R13, (c) a ring carbon, in a first beta position relative to the ring carbon at the point of attachment and in an alpha position relative to the ring atom optionally substituted by R9, is optionally substituted by R10, (d) a ring carbon, in a second beta position relative to the ring carbon at the point of attachment and in an alpha position relative to the ring atom optionally substituted by R13, is optionally substituted by R12, and (e) a ring carbon, if present, in the gamma position relative to the ring carbon at the point of attachment and in an alpha position relative to each of the ring atoms optionally substituted by R10 and R12, respectively, is optionally substituted by R11; where R9, R11, and R13 are independently selected from the group consisting of hydrido, hydroxy, amino, amidino, guanidino, lower alkylamino, alkylthio, alkoxy, alkylsulflnyl, alkylsulfonyl, amidosulfonyl, monoalkylamidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboxy, carboxamido, and cyano; and 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, carboxy, carboxyamido, carboxyalkyl, and cyano; and Y° is formula (IV): 13 II R,a^V^,9 (IV) 194 intellectual property OFFICE OF N.Z. 2 3 JAN 2004 R EC FlVrn wherein D5, D6, J5, and J6 are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more than one is a covalent bond, no more than one of D5, D6, J5, and J6 is O, no more than one of D5, D6, J5, and J6 is S, one of D5, D6, J5, and J6 must be a covalent bond when two of D5, D6, J5, and J6 are O and S, and no more than four of D5, D6, J5, and J6 are N; R16, R17, R18, and R19 are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, haloalkylthio, alkoxy, hydroxy, amino, lower alkylamino, alkylthio, alkylsulflnyl, alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, and cyano; Qb is selected from the group consisting of NR20R21, hydrido, N(R26)C(NR25)N(R23)(R24), and C(NR25)NR23R24; where R20, R21, R23, R24, R25, and R26are independently selected from the group consisting of hydrido and alkyl; and Qs is CH2.

13. The compound as recited in claim 9, 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, fert-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-butenyl, 1-heptyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 5-heptynyl, 2-heptyl, 1-methyl-2-hexenyl, 1-methyl-3-hexenyl, 1-methyl-4-hexenyl, 1-methyl-2-hexynyl, 1-methyl-3-hexynyl, 1-methyl-4-hexynyl, 3-heptyl, 1-ethyl-2-pentenyl, 1-ethyl-3-pentenyl, 1 -ethyl-2-pentynyl, 1-ethyl-3-pentynyl, 2,2,2-trifluoroethyl, 2,2-difluoropropyl, 4-trifluoromethyl-5,5,5-trifluoropentyl, 4-trifluoromethylpentyl, 5,5,6,6,6-pentafluorohexyl, and 3,3,3-trifluoropropyl, where each member of group B is optionally substituted at any 195 intellectual property OFFICE OF N.Z. 2 3 JAN 2004 RECEIVED 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, R33, R34, R35, and R36; where R32, R33, R34, R35, and R36 are independently selected from the group consisting of hydrido, amidino, guanidino, methyl, ethyl, methoxy, ethoxy, hydroxy, amino, N-methylamino, dimethylamino, methylthio, ethylthio, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, fluoro, chloro, bromo, amidosulfonyl, N-methylamidosulfonyl, hydroxymethyl, amidocarbonyl, carboxy, cyano, and Qb; A is selected from the group consisting of: (i) a single covalent bond, NH, N(CH3), CH2, CH3CH, and CH2CH2; and (ii) CH2N(CH3), CH2N(CH2CH3), CH2CH2N(CH3), and CH2CH2N(CH2CH3) with the proviso that B is hydrido; M is selected from the group consisting of N and R1-C; where R1 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; R2 is selected from the group consisting of phenyl and 2-thienyl, 2-furyl, 2-pyrrolyl, 2-imidazolyl, 2-thiazolyl, 3-isoxazolyl, 2-pyridyl, and 3-pyridyl heteroaryl rings, where (a) a ring carbon in a first alpha position relative to the ring carbon at the point of attachment is optionally substituted by R9, (b) a ring carbon in a second alpha position relative to the ring carbon at the point of attachment is optionally substituted by R13, (c) a ring carbon, in a first beta position relative to the ring carbon at the point of attachment and in an alpha position relative to the ring atom optionally substituted by R9, is optionally substituted by R10, (d) a ring carbon, in a second beta position relative to the ring carbon at the point of attachment and in an alpha position relative to the ring atom optionally substituted by R13, is optionally substituted by R12, and (e) a ring carbon, if present, in the gamma position relative to the ring carbon at the point of attachment and in an alpha position relative to each of the ring atoms optionally substituted by R10 and R12, respectively, is optionally substituted by R11; where INTELLECTUAL PROPERTY 196 OFFICE OF N.Z. 2 3 JAN 2004 RECEIVED R9, R11, and R13 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, N-methylamidocarbonyl, carboxy, and cyano; and 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-methylamino, dimethylamino, amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, methoxycarbonyl, fluoro, chloro, bromo, and cyano; and Y° is selected from the group consisting of: Q VQ' V_R» ^ ,n/ • o \ f \. \ q! \ =16 \ / V \ = 19 V \. \. 197 INTELLECTUAL PROPERTY OFFICE OF N.Z. 2 3 JAN 2004 RECEIVED Q' ; where R16, R17, R18, and R19 are independently selected from the group consisting of hydrido, methyl, ethyl, amidino, guanidino, methoxy, hydroxy, amino, aminomethyl, 1-aminoethyl, 2-aminoethyl, N-methylamino, dimethylamino, methylthio, ethylthio, trifluoromethylthio, methylsulfinyl, methylsulfonyl, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, trifluoromethoxy, fluoro, chloro, amidosulfonyl, N-methylamidosulfonyl, hydroxymethyl, carboxy, and cyano. Qb is selected from the group consisting of NR20R21, C(NR25)NR23R24, and N(R26)C(NR25)N(R23)(R24), with the proviso that said Qb group is bonded directly to a carbon atom; where R20, RZ1, R23, R24, R25, and R26are independently selected from the group consisting of hydrido, methyl, and ethyl; and

14. The compound as recited in claim 13, or a pharmaceutical^ 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-amidocarbonylhexyl, 4-methyl-2-pentyl, 3-hydroxypropyl, 3-methoxy-2-propyl, 2-methoxyethyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 2-dimethylaminopropyl, 2-cyanoethyl, 6-hydroxyhexyl, 2-hydroxyethyl, 2-amidinoethyl, 2-guanidinoethyl, 3-guanidinopropyl, 4-guanidinobutyl, 3-hydroxypropyl, 4-hydroxybutyl, 6-cyanohexyl, 2-dimethylaminoethyl, 3-methylbutyl, 2-methylbutyl, (S)-2-methylbutyl, 3-aminopropyl, 2-hexyl, and 4-aminobutyl; Qs is CH2. 198 INTELLECTUAL PROPERTY OFFICE OF N.Z. 2 3 JAN 2004 RECEIVED A is selected from the group consisting of single covalent bond, CH2, CH3CH, and CH2CH2; M is selected from the group consisting of N and R1-C; where R1 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-amidocarbonylphenyl, 5-amino-2-fluorophenyl, 3-amino-5-hydroxymethylphenyl, 5-amino-3-methoxycarbonylphenyl, 3-amidinophenyl, 3-amino-2-methylphenyl, 5-amino-2-methylthiophenyl, 3-aminophenyl, benzyl, 3-carboxyphenyl, 3-carboxy-5-aminophenyl, 3-carboxy-5-hydroxyphenyl, 3-carboxymethyl-5-aminophenyl, 3-carboxymethyl-5-hydroxyphenyl, 3-carboxymethylphenyl, 3-chlorophenyl, 2-chlorophenyl, 2,6-dichlorophenyl, 3-cyanophenyl, 3-dimethyiaminophenyl, 2-fluorophenyl, 3-fluorophenyl, 2,5-difIuorophenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 3-methanesulfonylaminophenyl, 2-methoxyphenyl, 3-methoxyphenyl, 3-methoxyaminophenyl, 3-methoxycarbonylphenyl, 2-methylaminophenyl, 3-methylaminophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, phenyl, 3-trifluoroacetamidophenyl, 3-trifluoromethylphenyl, 2-trifluoromethylphenyl, 5-amino-2-thienyl, 5-amino-3-thienyl, 3-bromo-2-thienyl, 3-pyridyl, 4-pyridyl, 2-thienyl, and 3-thienyl; and Y° is selected from the group consisting of: T-, ^q! ■Q1 , and ; where Q1 199 INTELLECTUAL PROPERTY OFFICE OF N.Z. 2 3 JAN 2004 RECEIVED R16 and R19 are independently selected from the group consisting of hydrido, amidino, amino, aminomethyl, methoxy, methylamino, hydroxy, 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 selected from the group consisting of hydrido and C(NR25)NR23R24; where R23, R24, and R25are independently selected from the group consisting of hydrido and methyl; and Qs is CH2.

15. The compound as recited in claim 14, 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, te/t-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-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, CH2, CH3CH, and CH2CH2; M is selected from the group consisting of N and R1-C; where R1 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-carboxyphenyl, 3-cyanophenyl, 3-methoxycarbonylphenyl, phenyl, and 3-pyridyl; and Y° is selected from the group consisting of 5-amidino-2-thienylmethyl, 4-amidinobenzyl, 2-fluoro-4-amidinobenzyl, and 3-fluoro-4-amidinobenzyl. 200 INTELLECTUAL PROPERTY OFFICE OF N.Z. 2 3 JAN 2004 n r n r I ii i> >«

16. The compound as recited in claim 9, or a pharmaceutical^ acceptable salt thereof, wherein: R2 is 3-aminophenyl, B is 2,2,2-trifluoroethyl, A is single bond, Y° is 4-amidinobenzyl, and M is CH; R2 is 3-aminophenyl, B is (S)-2-butyl, A is single bond, Y° is 4-amidinobenzyl, and M is CH; R2 is 5-amino-2-fluorophenyl, B is isopropyl, A is single bond, Y° is 4-amidinobenzyl, and M is CH; R2 is 2-methyl-3-aminophenyl, B is isopropyl, A is single bond, Y° is 4-amidinobenzyl, and M is CH; R2 is 3-aminophenyl, B is ethyl, A is single bond, Y° is 4-amidinobenzyl, and M is CH; R2 is 3-aminophenyl, B is ethyl, A is single bond, Y° is 4-amidino-2-fluorobenzyl, and M is CH; R2 is 3-aminophenyl, B is 2-propenyl, A is single bond, Y° is 4-amidinobenzyl, and M is CH; R2 is 3-aminophenyl, B is isopropyl, A is single bond, Y° is 4-amidino-2-fluorobenzyl, and M is CH; R2 is 3-aminophenyl, B is isopropyl, A is single bond, Y° is 4-amidinobenzyl, and M is CH; R2 is 3-aminophenyl, B is 2-butyl, A is single bond, Y° is 4-amidinobenzyl, and M is CH; R2 is 3-aminophenyl, B is (R)-2-butyl, A is single bond, Y° is 4-amidinobenzyl, and M is CH; R2 is 3-aminophenyl, B is 2-propynyl, A is single bond, Y° is 4-amidinobenzyl, and M is CH; R2 is 3-aminophenyl, B is 3-pentyl, A is single bond, Y° is 4-amidinobenzyl, and M is CH; R2 is 3-aminophenyl, B is hydrido, A is CH2, Y° is 4-amidinobenzyl, and M is CH; R2 is 3-aminophenyl, B is ethyl, A is CH2, Y° is 4-amidinobenzyl, and M is CH; 201 INTELLECTUAL PROPERTY OFFICE OF N.Z. 2 3 JAN 2004 RECEIVED R2 is 3-aminophenyl, B is 2-methypropyl, A is single bond, Y° is 4-amidinobenzyl, and M is CH; R2 is 3-aminophenyl, B is 2-propyl, A is CH3CH, Y° is 4-amidinobenzyl, and M is CH; R2 is 3-aminophenyl, B is propyl, A is single bond, Y° is 4-amidino-2-fluorobenzyl, and M is CH; R2 is 3-aminophenyl, B is 6-amidocarbonylhexyl, A is single bond, Y° is 4-amidinobenzyl, and M is CH; R2 is 3-aminophenyl, B is tert-butyl, A is single bond, Y° is 4-amidinobenzyl, and M is CH; R2 is 3-aminophenyl, B is tert-butyl, A is single bond, Y° is 4-amidinobenzyl, and M is CH; R2 is 3-aminophenyl, B is 3-hydroxypropyl, A is single bond, Y° is 4-amidinobenzyl, and M is CH; R2 is 3-aminophenyl, B is 2-methylpropyl, A is single bond, Y° is 4-amidino-2-fluorobenzyl, and M is CH; R2 is 3-aminophenyl, B is butyl, A is single bond, Y° is 4-amidinobenzyl, and M is CH; R2 is 3-aminophenyl, B is 3-methoxy-2-propyl, A is single bond, Y° is 4-amidinobenzyl, and M is CH; R2 is 3-aminophenyl, B is 3-methoxy-2-propyl, A is single bond, Y° is 4-amidinobenzyl, and M is CH; R2 is 3-aminophenyl, B is 2-methoxy-2-ethyl, A is single bond, Y° is 4-amidinobenzyl, and M is CH; R2 is 3-aminophenyl, B is 2-propyl, A is single bond, Y° is 5-amidino-2-thienylmethyl, and M is CH; R2 is 3-aminophenyl, B is 2-propyl, A is single bond, Y° is 4-amidino-3-fluorobenzyl, and M is CH; R2 is 3-carboxyphenyl, B is 2-propyl, A is single bond, Y° is 4-amidinobenzyl, and M is CH; 202 intellectual property OFFICE OF N.Z. 23 JAN 2004 neiieiwit^ R2 is 3-aminophenyl, B is 2-propyl, A is single bond, Y° is 4-amidino-3-fluorobenzyl, and M is CH; R2 is 3-aminophenyl, B is 2,2,2-trifluoroethyl, A is single bond, Y° is 4-amidinobenzyl, and M is N; R2 is 3-aminophenyl, B is (S)-2-butyl, A is single bond, Y° is 4-amidinobenzyl, and M is N; R2 is 5-amino-2-fluorophenyl, B is isopropyl, A is single bond, Y° is 4-amidinobenzyl, and M is N; R2 is 2-methyl-3-aminophenyl, B is isopropyl, A is single bond, Y° is 4-amidinobenzyl, and M is N; R2 is 3-aminophenyl, B is ethyl, A is single bond, Y° is 4-amidinobenzyl, and M is N; R2 is 3-aminophenyl, B is ethyl, A is single bond, Y° is 4-amidino-2-fluorobenzyl, and M is N; R2 is 3-aminophenyl, B is 2-propenyl, A is single bond, Y° is 4-amidinobenzyl, and M is N; R2 is 3-aminophenyl, B is isopropyl, A is single bond, Y° is 4-amidino-2-fluorobenzyl, and M is N; R2 is 3-aminophenyl, B is isopropyl, A is single bond, Y° is 4-amidinobenzyl, and M is N; R2 is 3-aminophenyl, B is 2-butyl, A is single bond, Y° is 4-amidinobenzyl, and M is N; R2 is 3-aminophenyl, B is (R)-2-butyl, A is single bond, Y° is 4-amidinobenzyl, and M is N; R2 is 3-aminophenyl, B is 2-propynyl, A is single bond, Y° is 4-amidinobenzyl, and M is N; R2 is 3-aminophenyl, B is 3-pentyl, A is single bond, Y° is 4-amidinobenzyl, and M is N; R2 is 3-aminophenyl, B is hydrido, A is CH2, Y° is 4-amidinobenzyl, and M is N; R2 is 3-aminophenyl, B is ethyl, A is CH2, Y° is 4-amidinobenzyl, and M is N; intellectual property OFFICE OF N.Z. 2 3 JAN 2004 b e a e i ii r n R2 is 3-aminophenyl, B is 2-methypropyl, A is single bond, Y° is 4-amidinobenzyl, and M is N; R2 is 3-aminophenyl, B is 2-propyl, A is CH3CH, Y° is 4-amidinobenzyl, and M is N; R2 is 3-aminophenyl, B is propyl, A is single bond, Y° is 4-amidino-2-fluorobenzyl, and M is N; R2 is 3-aminophenyl, B is 6-amidocarbonylhexyl, A is single bond, Y° is 4-amidinobenzyl, and M is N; R2 is 3-aminophenyl, B is tert-butyl, A is single bond, Y° is 4-amidinobenzyl, and M is N; R2 is 3-aminophenyl, B is tert-butyl, A is single bond, Y° is 4-amidinobenzyl, and M is N; R2 is 3-aminophenyl, B is 3-hydroxypropyl, A is single bond, Y° is 4-amidinobenzyl, and M is N; R2 is 3-aminophenyl, B is 2-methylpropyl, A is single bond, Y° is 4-amidino-2-fluorobenzyl, and M is N; R2 is 3-aminophenyl, B is butyl, A is single bond, Y° is 4-amidinobenzyl, and M is N; R2 is 3-aminophenyl, B is 3-methoxy-2-propyl, A is single bond, Y° is 4-amidinobenzyl, and M is N; R2 is 3-aminophenyl, B is 3-methoxy-2-propyl, A is single bond, Y° is 4-amidinobenzyl, and M is N; R2 is 3-aminophenyl, B is 2-methoxy-2-ethyl, A is single bond, Y° is 4-amidinobenzyl, and M is N; 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° is 4-amidino-3-fluorobenzyl, and M is N; R2 is 3-carboxyphenyl, B is 2-propyl, A is single bond, Y° is 4-amidinobenzyl, and M is N; or 204 INTELLECTUAL PROPERTY OFFICE OF N.Z. 23 JAN 2004 «* r f* P l if r r* R2 is 3-aminophenyl, B is 2-propyl, A is single bond, Y° is 4-amidino-3-fluorobenzyl, and M is CH.

17. A compound having the Formula: 0 b n' h or a pharmaceutical^ acceptable salt thereof, wherein; B is selected from the group consisting of C3-C7 cycloalkyl and C4-C6 saturated heterocyclyl, where (a) each ring carbon is optionally substituted with R33, (b) a ring carbon, other than the ring carbon at the point of attachment, is optionally substituted with oxo provided that no more than one ring carbon is substituted by oxo at the same time, (c) a ring carbon or nitrogen in a first alpha position relative to the ring carbon at the point of attachment is optionally substituted by R9, (d) a ring carbon or nitrogen in a second alpha position relative to the ring carbon at the point of attachment is optionally substituted by R13, (e) a ring carbon or nitrogen, if present, in a first beta position relative to the ring carbon at the point of attachment and in an alpha position relative to the ring atom optionally substituted by R9, is optionally substituted by R10, (f) a ring carbon or nitrogen, if present, in a second beta position relative to the ring carbon at the point of attachment and in an alpha position relative to the ring atom optionally substituted by R13, is optionally substituted by R12, (g) a ring carbon or nitrogen, if present, in a first gamma position relative to the ring carbon at the point of attachment and in an alpha position relative to the ring atom optionally substituted by R10, is optionally substituted by R11, and (h) a ring carbon or nitrogen, if present, in a second gamma intellectual property office of n.z. 2 3 JAN 2004 RECEIVED position relative to the carbon at the point of attachment and in an alpha position relative to the ring atom optionally substituted by R12, is optionally substituted by R33; where R9, R11, and R13 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; 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, amidocarbonyl, halo, haloalkyl, and cyano; and 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, hydroxyalkyl, carboalkoxy, carboxy, carboxamido, cyano, and Qb; A is selected from the group consisting of single covalent bond and (CH(R15))pa-(W7)rr where rr is an integer selected from 0 through 1; pa is an integer selected from 0 through 3; W7 is selected from the group consisting of (R7)NC(0) and N(R7); where R7 is selected from the group consisting of hydrido, hydroxy and alkyl; and R15 is selected from the group consisting of hydrido, halo, alkyl, and haloalkyl; M is selected from the group consisting of N and R1-C; where R1 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; where Z° is selected from the group consisting of a covalent single bond, O, S, NH, and CH2; and INTELLECTUAL property 206 office of n.z. 23 JAN 2004 RECEIVED Q is selected from the group consisting of aryl and heteroaryl where (a) a ring carbon in a first alpha position relative to the ring carbon at the point of attachment is optionally substituted by R9, (b) a ring carbon in a second alpha position relative to the ring carbon at the point of attachment is optionally substituted by R13, (c) a ring carbon, in a first beta position relative to the ring carbon at the point of attachment and in an alpha position relative to the ring atom optionally substituted by R9, is optionally substituted by R10, (d) a ring carbon, in a second beta position relative to the ring carbon at the point of attachment and in an alpha position relative to the ring atom optionally substituted by R13, is optionally substituted by R12, and (e) a ring carbon, if present, in the gamma position relative to the ring carbon at the point of attachment and in an alpha position relative to each of the ring atoms optionally substituted by R10 and R12, respectively, is optionally substituted by R11; and Y° is formula (IV): qb (IV) where D5, D6, J5, and J6 are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more than one is a covalent bond, no more than one of D5, D6, J5, and J6 is O, no more than one of D5, D6, J5, and J6 is S, one of D5, D6, J5, and J6 must be a covalent bond when two of D5, D6, J5, and J6 are O and S, and no more than four of D5, D6, J5, and J6 are N; R16, R17, R18, and R19 are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, haloalkylthio, alkoxy, hydroxy, amino, lower intellectual property OFFICE OF N.Z. 2 3 JAN 2004 RECEIVED alkylamino, alkylthio, alkylsulflnyl, alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, and cyano; Qb is selected from the group consisting of NR20R21, hydrido, and C(NR25)NR23R24, with the provisos that no more than one of R20 and R21 is hydroxy and that no more than one of R23 and R24 is hydroxy; where R20, R21, R23, R24, and R25 are independently selected from the group consisting of hydrido, alkyl, and hydroxy; and Qs is selected from the group consisting of a single covalent bond, CH2, and CH2CH2.

18. The compound as recited in claim 17, or a pharmaceutically acceptable salt 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, 7-oxabicyclo[2.2.1]heptan-2-yl, bicyclo[3.1.0]hexan-6-yl, cycloheptyl, 2-morpholinyl, 3-morpholinyl, 4-morpholinyl, 1-piperazinyl, 2-piperazinyl, 1 -piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-dioxanyl, 4H-2-pyranyl, 4H-3-pyranyl, 4H-4-pyranyl, 4H-pyran-4-one-2-yl, 4H-pyran-4-one-3-yl, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydropyranyl, 3-tetrahydropyranyl, 4-tetrahydropyranyl, 2-tetrahydrothienyl, and 3-tetrahydrothienyl, where (a) each ring carbon is optionally substituted with R33, (b) a ring carbon or nitrogen in a first alpha position relative to the ring carbon at the point of attachment is optionally substituted by R9, (c) a ring carbon or nitrogen in a second alpha position relative to the ring carbon at the point of attachment is optionally substituted by R13, (d) a ring carbon or nitrogen, if present, in a first beta position relative to the ring carbon at the point of attachment and in an alpha position relative to the ring atom optionally substituted by R9, is optionally substituted by R10, and (e) a ring carbon or nitrogen, if present, in a second beta position relative to the ring carbon at the point of attachment and in an alpha position relative to the ring atom optionally substituted by R13, is optionally substituted by R12; where intellectual property OFFICE OF N.Z. 2 3 JAN 2004 RECEIVED R9, R11, and R13 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-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; 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-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, ethoxy carbonyl, amidocarbonyl, N-methylamidocarbonyl, N,N-dimethylamidocarbonyl, fluoro, chloro, bromo, and cyano; and R33 is selected from the group consisting of hydrido, amidino, guanidino, carboxy, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, methoxyamino, ethoxyamino, acetamido, trifluoroacetamido, N-methylamino, dimethylamino, N-ethylamino, methylthio, ethylthio, isopropylthio, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, 2,2,3,3,3-pentafluoropropyl, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro, bromo, amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro-1-hydroxyethyl, methoxycarbonyl, ethoxycarbonyl, amidocarbonyl, N-methylamidocarbonyl, N,N-dimethyiamidocarbonyl, cyano, and Q15; A is selected from the group consisting of single covalent bond, NH, N(CH3), N(OH), CH2, CH3CH, CF3CH, NHC(O), N(CH3)C(0), C(0)NH, C(0)N(CH3), CH2CH2, CH2CH2CH2, CH3CHCH2, and CF3CHCH2; M is selected from the group consisting of N and R1-C; where 209 R1 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, methoxyamino, methylthio, ethylthio, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro, and bromo; R2 is Z°-Q; where Z° is selected from the group consisting of a covalent single bond, O, S, NH, and CH2; and Q is selected from the group consisting of phenyl and 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 heteroaryl rings, where (a) a ring carbon in a first alpha position relative to the ring carbon at the point of attachment is optionally substituted by R9, (b) a ring carbon in a second alpha position relative to the ring carbon at the point of attachment is optionally substituted by R13, (c) a ring carbon, in a first beta position relative to the ring carbon at the point of attachment and in an alpha position relative to the ring atom optionally substituted by R9, is optionally substituted by R10, (d) a ring carbon, in a second beta position relative to the ring carbon at the point of attachment and in an alpha position relative to the ring atom optionally substituted by R13, is optionally substituted by R12, and (e) a ring carbon, if present, in the gamma position relative to the ring carbon at the point of attachment and in an alpha position relative to each of the ring atoms optionally substituted by R10 and R12, respectively, is optionally substituted by R11; and Y° is selected from the group consisting of: 210 2 3 JAN 2004 RECEIVcn 211 R16, R17, R18, and R19 are independently selected from the group consisting of hydrido, methyl, ethyl, isopropyl, propyl, carboxy, amidino, guanidino, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, aminomethyl, 1-aminoethyl, 2-aminoethyl, N-methylamino, dimethylamino, N-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, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro-1-hydroxyethyl, and cyano; Qb is selected from the group consisting of hydrido and C(NR25)NR23R24, with the proviso that no more than one of R23 and R24 is hydroxy; where R23, R24, and R25are independently selected from the group consisting of hydrido, methyl, ethyl, and hydroxy; and Qs is selected from the group consisting of a single covalent bond, CH2 and CH2CH2.

19. The compound as recited in claim 18, or a pharmaceutically acceptable salt thereof, wherein; B is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, oxalan-2-yl, 2-(2R)-bicyclo[2.2.1]-heptyl, 1-pyrrolidinyl, 1-piperidinyl, 1,1-dioxothiolan-3-yl, oxetan-3-yl, azetidin-1-yl, azetidin-2-yl, azetidin-3-yl, 7-oxabicyclo[2.2.1]heptan-2-yl, bicyclo[3.1.0]hexan-6-yl, 2-morpholinyl, 3-morpholinyl, 4-morpholinyl, 1-piperazinyl, 2-piperazinyl, 1-piperidinyl, 2-piperidinyi, 3-piperidinyl, 4-piperidinyl, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-dioxanyl, 4H- intellectual property office of n.z. 23 JAN 2004 received 2-pyranyl, 4H-3-pyrany1, 4H-4-pyranyl, 4H-pyran-4-one-2-yl, 4H-pyran-4-one-3-yl, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydropyranyl, 3-tetrahydropyranyl, 4-tetrahydropyranyl, 2-tetrahydrothienyl, and 3-tetrahydrothienyl; A is selected from the group consisting of single covalent bond, CH2, NHC(O), CH2CH2, and CH2CH2CH2; M is selected from the group consisting of N and R1-C; where R1 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; R2 is Z°-Q; where Z° is selected from the group consisting of a covalent single bond, O, S, NH, and CH2; and Q is selected from the group consisting of 5-amino-3-amidocarbonylphenyl, 5-amino-2-fluorophenyl, 3-amino-5-hydroxymethylphenyl, 5-amino-3-methoxycarbonylphenyl, 3-amidinophenyl, 3-amino-2-methylphenyl, 5-amino-2-methylthiophenyl, 3-aminophenyl, benzyl, 3-carboxyphenyl, 3-carboxy-5-aminophenyl, 3-carboxy-5-hydroxyphenyl, 3-carboxymethyl-5-aminophenyl, 3-carboxymethyl-5-hydroxyphenyl, 3-carboxymethylphenyl, 3-chlorophenyl, 2-chlorophenyl, 2,6-dichlorophenyl, 3-cyanophenyl, 3-dimethylaminophenyl, 2-fluorophenyl, 3-fluorophenyl, 2,5-difluorophenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 3-methanesulfonylaminophenyl, 2-methoxyphenyl, 3-methoxyphenyl, 3-methoxyaminophenyl, 3-methoxycarbonylphenyl, 2-methylaminophenyl, 3-methylaminophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, phenyl, 3-trifluoroacetamidophenyl, 3-trifluoromethylphenyl, 2-trifluoromethylphenyl, 5-amino-2-thienyl, 5-amino-3-thienyI, 3-bromo-2-thienyl, 3-pyridyl, 4-pyridyl, 2-thienyl, and 3-thienyl; and Y° is selected from the group consisting of: 213 INTELLECTUAL PROPERTY OFFICE OF N.Z. 23 JAN 2004 RECEIVED R16 and R19 are independently selected from the group consisting of hydrido, amidino, amino, aminomethyl, methoxy, methylamino, hydroxy, 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 selected from the group consisting of hydrido and C(NR25)NR23R24; where R23, R24, and R25 are independently selected from the group consisting of hydrido and methyl; and Qs is CH2.

20. The compound as recited in claim 17, or a pharmaceutical^ acceptable salt thereof, wherein; B is selected from the group consisting of C3-C7 cycloalkyl and C4-C6 saturated heterocyclyl, where (a) each ring carbon is optionally substituted with R33, (b) a ring carbon, other than the ring carbon at the point of attachment, is optionally substituted with oxo provided that no more than one ring carbon is substituted by oxo at the same time, (c) a ring carbon or nitrogen in a first alpha position relative to the ring carbon at the point of attachment is optionally substituted by R9, (d) a ring carbon or nitrogen in a second alpha position relative to the ring 214 intellectual property OFFICE OF N.Z. 23 JAN 2004 carbon at the point of attachment is optionally substituted by R13, (e) a ring carbon or nitrogen, if present, in a first beta position relative to the ring carbon at the point of attachment and in an alpha position relative to the ring atom optionally substituted by R9, is optionally substituted by R10, (f) a ring carbon or nitrogen, if present, in a second beta position relative to the ring carbon at the point of attachment and in an alpha position relative to the ring atom optionally substituted by R13, is optionally substituted by R12, (g) a ring carbon or nitrogen, if present, in a first gamma position relative to the ring carbon at the point of attachment and in an alpha position relative to the ring atom optionally substituted by R10, is optionally substituted by R11, and (h) a ring carbon or nitrogen, if present, in a second gamma position relative to the carbon at the point of attachment and in an alpha position relative to the ring atom optionally substituted by R12, is optionally substituted by R33; where R9, R11, and R13 are independently selected from the group consisting of hydrido, hydroxy, amino, amidino, guanidino, lower alkylamino, alkylthio, alkoxy, alkylsulflnyl, alkylsulfonyl, amidosulfonyl, 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, alkoxyamino, aminoalkyl, hydroxy, amino, lower alkylamino, alkylsulfonamido, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, hydroxyalkyl, aminoalkyl, halo, haloalkyl, carboalkoxy, carboxy, carboxyalkyl, carboxyamido, and cyano; and 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; and R33 is optionally Qb; A is selected from the group consisting of single covalent bond and (CH(R15))pa-(W7)rr where rr is an integer selected from 0 through 1; pa is an integer selected from 0 through 3; W7 is N(R7); where R7 is selected from the group consisting of hydrido and alkyl; and R15 is selected from the group consisting of hydrido, halo, alkyl, and haloalkyl; 215 INTELLECTUAL PROPERTY OFFICE OF N.Z. 2 3 JAN 2004 M is selected from the group consisting of N and R1-C; where R1 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; where Z° is a covalent single bond; and Q is selected from the group consisting of aryl and heteroaryl where (a) a ring carbon in a first alpha position relative to the ring carbon at the point of attachment is optionally substituted by R9, (b) a ring carbon in a second alpha position relative to the ring carbon at the point of attachment is optionally substituted by R13, (c) a ring carbon, in a first beta position relative to the ring carbon at the point of attachment and in an alpha position relative to the ring atom optionally substituted by R9, is optionally substituted by R10, (d) a ring carbon, in a second beta position relative to the ring carbon at the point of attachment and in an alpha position relative to the ring atom optionally substituted by R13, is optionally substituted by R12, and (e) a ring carbon, if present, in the gamma position relative to the ring carbon at the point of attachment and in an alpha position relative to each of the ring atoms optionally substituted by R10 and R12, respectively, is optionally substituted by R11; where R9, R11, and R13 are independently selected from the group consisting of hydrido, hydroxy, amino, amidino, guanidino, lower alkylamino, alkylthio, alkoxy, alkylsulflnyl, alkylsulfonyl, amidosulfonyl, monoalkylamidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboxy, carboxamido, and cyano; and 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, carboxy, carboxyamido, carboxyalkyl, and cyano; and Y° is formula (IV): INTELLECTUAL PROPERTY OFFICE OF N.Z. 216 2 3 JAN 2004 RECEIVED .r 18 II I (IV) where D5, D6, J5, and J6 are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more than one is a covalent bond, no more than one of D5, D6, j5, and J6 is O, no more than one of D5, D6, J5, and J6 is S, one of D5, D6, J5, and J6 must be a covalent bond when two of D5, D6, J5, and J6 are O and S, and no more than four of D5, D6, J5, and J6 are N; R16, R17, R18, and R19 are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, haloalkylthio, alkoxy, hydroxy, amino, lower alkylamino, alkylthio, alkylsulflnyl, alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, and cyano; Qb is selected from the group consisting of NR20R21, hydrido, and C(NR25)NR23R24; where R20, R21, R23, R24, and R25 are independently selected from the group consisting of hydrido and alkyl; and

21. The compound as recited in claim 20, or a pharmaceutically acceptable salt thereof, wherein; B is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, oxalan-2-yl, 2-(2R)-bicyclo[2.2.1]-heptyl, 1,1-dioxothiolan-3-yl, oxetan-3-yl, azetidin-1-yl, azetidin-2-yl, azetidin-3-yl, bicyclo[3.1.0]hexan-6-yl, 2-morpholinyl, 3-morpholinyl, 4-morpholinyl, 1-piperazinyl, 2-piperazinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-dioxanyl, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydropyranyl, 3- Qs is CH2. 217 intellectual property office of n.z. 2 3 JAN 2004 n r ft f I If r n tetrahydropyranyl, 4-tetrahydropyranyl, 2-tetrahydrothienyl, and 3-tetrahydrothienyl, where (a) each ring carbon is optionally substituted with R33, (b) a ring carbon or nitrogen in a first alpha position relative to the ring carbon at the point of attachment is optionally substituted by R9, (c) a ring carbon or nitrogen in a second alpha position relative to the ring carbon at the point of attachment is optionally substituted by R13, (d) a ring carbon or nitrogen, if present, in a first beta position relative to the ring carbon at the point of attachment and in an alpha position relative to the ring atom optionally substituted by R9, is optionally substituted by R10, and (e) a ring carbon or nitrogen, if present, in a second beta position relative to the ring carbon at the point of attachment and in an alpha position relative to the ring atom optionally substituted by R13, is optionally substituted by R12; where R9, R11, and R13 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, 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, pentafluoroethyl, 2,2,2-trifluoroethyl, trifluoroacetamido, aminomethyl, N-methylamino, dimethylamino, amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, methoxycarbonyl, fluoro, chloro, bromo, and cyano; and R33 is selected from the group consisting of hydrido, amidino, guanidino, methyl, ethyl, methoxy, ethoxy, hydroxy, carboxy, amino, N-methylamino, dimethylamino, methylthio, ethylthio, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, fluoro, chloro, bromo, amidosulfonyl, N-methylamidosulfonyl, hydroxymethyl, amidocarbonyl, cyano, and Qb; A is selected from the group consisting of single covalent bond, NH, N(CH3), CH2, CH3CH, CH2CH2, and CH2CH2CH2; intellectual property office of n.z. 218 2 3 JAN 2004 RECEIVED M is selected from the group consisting of N and R1-C; where R1 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; 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, where (a) a ring carbon in a first alpha position relative to the ring carbon at the point of attachment is optionally substituted by R9, (b) a ring carbon in a second alpha position relative to the ring carbon at the point of attachment is optionally substituted by R13, (c) a ring carbon, in a first beta position relative to the ring carbon at the point of attachment and in an alpha position relative to the ring atom optionally substituted by R9, is optionally substituted by R10, (d) a ring carbon, in a second beta position relative to the ring carbon at the point of attachment and in an alpha position relative to the ring atom optionally substituted by R13, is optionally substituted by R12, and (e) a ring carbon, if present, in the gamma position relative to the ring carbon at the point of attachment and in an alpha position relative to each of the ring atoms optionally substituted by R10 and R12, respectively, is optionally substituted by R11; and Y° is selected from the group consisting of: Q L Q1 Q' intellectual property OFFICE OF N.Z. 219 23 JAN 2004 RECEIVED Q1 Q' • where R16, R17, R18, and R19 are independently selected from the group consisting of hydrido, methyl, ethyl, amidino, guanidino, methoxy, hydroxy, amino, aminomethyl, 1-aminoethyl, 2-aminoethyl, N-methylamino, dimethylamino, methylthio, ethylthio, trifluoromethylthio, methylsulfinyl, methylsulfonyl, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, trifluoromethoxy, fluoro, chloro, amidosulfonyl, N-methylamidosulfonyl, hydroxymethyl, carboxy, and cyano. Qb is selected from the group consisting of NR20R21 and C(NR25)NR23R24, with the proviso that said Qb group is bonded directly to a carbon atom; where R20, R21, R23, R24, and R25are independently selected from the group consisting of hydrido, methyl, and ethyl; and

22. The compound as recited in claim 21, or a pharmaceutically acceptable salt thereof, wherein; B is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxalan-2-yl, 2-(2R)-bicyclo[2.2.1]-heptyl, 1,1-dioxothiolan-3-yl, oxetan-3-yl, azetidin-1-yl, azetidin-2-yl, azetidin-3-yl, 1-pyrrolidinyl and 1-piperidinyl; A is selected from the group consisting of a single covalent bond, CH2, NHC(O), CH2CH2 and CH2CH2CH2; M is selected from the group consisting of N and R1-C; where Qs is CH2. INTELLECTUAL PROPERTY. OFFICE OF N.Z. 220 23 JAN 2004 RECEIVED R1 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-dichlorophenyl, 2-hydroxyphenyl, 5-amino-2-thienyl, and 3-thienyl; and Y° is selected from the group consisting of: Qs "I 118 -R 19 K -.17 \ f -Q , and ,16 ; where R16 and R19 are independently selected from the group consisting of hydrido, amidino, amino, aminomethyl, methoxy, methylamino, hydroxy, 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 selected from the group consisting of hydrido and C(NR25)NR23R24; where R23, R24, and R25 are independently selected from the group consisting of hydrido and methyl; and

23. The compound as recited in claim 22, or a pharmaceutically acceptable salt thereof, wherein; B is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxalan-2-yl, 2-(2R)-bicyclo[2.2.1]-heptyl, 1,1-dioxothiolan-3-yl, oxetan-3-yl, azetidin-1-yl, azetidin-2-yl, azetidin-3-yl, and 1 -piperidinyl; A is selected from the group consisting of a single covalent bond, CH2, CH2CH2 and CH2CH2CH2; M is selected from the group consisting of N and R1-C; where 221 13 JAN 2004 R1 is selected from the group consisting of hydrido, fluoro, and chloro; R2 is selected from the group consisting of 3-aminophenyl, 2,6-dichlorophenyl, 2-hydroxyhenyl, phenyl, 5-amino-2-thienyl, and 3-thienyl; and Y° is selected from the group consisting of 5-amidino-2-thienylmethyl, 4-amidinobenzyl, 2-fluoro-4-amidinobenzyl, and 3-fluoro-4-amdinobenzyl.

24. The compound as recited in claim 17, or a pharmaceutically acceptable salt thereof, wherein: R2 is 3-aminophenyl, B is cycylopropyl, A is single bond, Y° is 4-amidinobenzyl, and M is CH; R2 is 3-aminophenyl, B is cyclobutyl, A is single bond, Y° is 4-amidino-2-fluorobenzyl, and M is CH; R2 is 3-aminophenyl, B is cyclobutyl, A is single bond, Y° is 4-amidinobenzyl, and M is CH; R2 is 3-aminophenyl, B is cyclopropyl, A is single bond, Y° is 4-amidino-2-fluorobenzyl, and M is CH; R2 is 3-aminophenyl, B is cyclobutyl, A is single bond, Y° is 4-amidinobenzyl, and M is CH; R2 is 3-aminophenyl, B is cyclobutyl, A is single bond, Y° is 4-amidino-3-fluorobenzyl, and M is CH; R2 is 3-aminophenyl, B is cyclopentyl, A is single bond, Y° is 4-amidinobenzyl, and M is CH; R2 is 5-amino-2-thienyl, B is cyclobutyl, A is single bond, Y° is 4-amidinobenzyl, and M is CH; R2 is 3-aminophenyl, B is cyclopropyl, A is CH2, Y° is 4-amidinobenzyl, and M is CH; R2 is 3-aminophenyl, B is 2-(2R)-bicyclo[2.2.1]-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° is 4-amidino-2-fluorobenzyl, and M is CH; intellectual property office of n.z. 2 3 JAN 2004 RECEIVED R2 is 3-aminophenyl, B is cyclohexyl, A is CH2CH2, Y° is 4-amidinobenzyl, and M is CH; R2 is 3-aminophenyl, B is oxalan-2-yl, A is CH2, Y° is 4-amidinobenzyl, and M is CH; R2 is phenyl, B is 1-pyrrolidinyl, A is CH2CH2, Y° is 4-amidinobenzyl, and M is CH; R2 is 3-aminophenyl, B is 1 -piperidinyl, A is CH2CH2, Y° is 4-amidinobenzyl, and M is CH; R2 is 3-aminophenyl, B is 1,1-dioxothiolan-3-yl, A is single bond, Y° is 4-amidinobenzyl, and M is CH; R2 is 2-hydroxyphenyl, B is cyclobutyl, A is single bond, Y° is 4-amidinobenzyl, and M is CH; R2 is 3-aminophenyl, B is 1-pyrrolidinyl, A is CH2CH2CH2, Y° is 4-amidinobenzyl, and M is CH; R2 is phenyl, B is cyclobutyl, A is single bond, Y° is 4-amidinobenzyl, and M is CH; R2 is 3-thienyl, B is cyclobutyl, A is single bond, Y° is 4-amidinobenzyl, and M isCH; R2 is 2,6-dichlorophenyl, B is cyclobutyl, A is single bond, Y° is 4-amidinobenzyl, and M is CH; R2 is 3-aminophenyl, B is cycylopropyl, A is single bond, Y° is 4-amidinobenzyl, and M is CF; R2 is 3-aminophenyl, B is cyclobutyl, A is single bond, Y° is 4-amidino-2-fluorobenzyl, and M is CF; R2 is 3-aminophenyl, B is cyclobutyl, A is single bond, Y° is 4-amidinobenzyl, and M is CF; R2 is 3-aminophenyl, B is cyclopropyl, A is single bond, Y° is 4-amidino-2-fluorobenzyl, and M is CF; R2 is 3-aminophenyl, B is cyclobutyl, A is single bond, Y° is 4-amidinobenzyl, and M is CF; R2 is 3-aminophenyl, B is cyclobutyl, A is single bond, Y° is 4-amidino-3-fluorobenzyl, and M is CF; 223 23 JAN 2004 received R2 is 3-aminophenyl, B is cyclopentyl, A is single bond, Y° is 4-amidinobenzyl, and M is CF; R2 is 5-amino-2-thienyl, B is cyclobutyl, A is single bond, Y° is 4-amidinobenzyl, and M is CF; R2 is 3-aminophenyl, B is cyclopropyl, A is CH2, Y° is 4-amidinobenzyl, and M is CF; R2 is 3-aminophenyl, B is 2-(2R)-bicyclo[2.2.1]-heptyl, A is single bond, Y° is 4-amidinobenzyl, and M is CF; R2 is 3-aminophenyl, B is cyclopentyl, A is single bond, Y° is 4-amidino-2-fluorobenzyl, and M is CF; R2 is 3-aminophenyl, B is cyclohexyl, A is CH2CH2, Y° is 4-amidinobenzyl, and M is CF; R2 is 3-aminophenyl, B is oxalan-2-yl, A is CH2, Y° is 4-amidinobenzyl, and M is CF; R2 is phenyl, B is 1-pyrrolidinyl, A is CH2CH2, Y° is 4-amidinobenzyl, and M is CF; R2 is 3-aminophenyl, B is 1-piperidinyl, A is CH2CH2, Y° is 4-amidinobenzyl, and M is CF; R2 is 3-aminophenyl, B is 1,1-dioxothiolan-3-yl, A is single bond, Y° is 4-amidinobenzyl, and M is CF; R2 is 2-hydroxyphenyl, B is cyclobutyl, A is single bond, Y° is 4-amidinobenzyl, and M is CF; R2 is 3-aminophenyl, B is 1-pyrrolidinyl, A is CH2CH2CH2, Y° is 4-amidinobenzyl, and M is CF; R2 is phenyl, B is cyclobutyl, A is single bond, Y° is 4-amidinobenzyl, and M is CF; 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; R2 is 3-aminophenyl, B is cycylopropyi, A is single bond, V° is 4-amidinobenzyl, and M is N; 224 intellectual property office of n.z. 23 JAN 2004 RECEIVED R2 is 3-aminophenyl, B is cyclobutyl, A is single bond, Y° is 4-amidino-2-fluorobenzyl, and M is N; R2 is 3-aminophenyl, B is cyclobutyl, A is single bond, Y° is 4-amidinobenzyl, and M is N; R2 is 3-aminophenyl, B is cyclopropyl, A is single bond, Y° is 4-amidino-2-fluorobenzyl, and M is N; R2 is 3-aminophenyl, B is cyclobutyl, A is single bond, Y° is 4-amidinobenzyl, and Mis N; R2 is 3-aminophenyl, B is cyclobutyl, A is single bond, Y° is 4-amidino-3-fluorobenzyl, and M is N; R2 is 3-aminophenyl, B is cyclopentyl, A is single bond, Y° is 4-amidinobenzyl, and M is N; R2 is 5-amino-2-thienyl, B is cyclobutyl, A is single bond, Y° is 4-amidinobenzyl, and M is N; R2 is 3-aminophenyl, N; R2 is 3-aminophenyl, amidinobenzyl, and M is N; R2 is 3-aminophenyl, fluorobenzyl, and M is N; R2 is 3-aminophenyl, is N; R2 is 3-aminophenyl, N; R2 is phenyl, B is 1-pyrrolidinyl, A is CH2CH2, Y° is 4-amidinobenzyl, and M is N; R2 is 3-aminophenyl, B is 1-piperidinyl, A is CH2CH2, Y° is 4-amidinobenzyl, and M is N; R2 is 3-aminophenyl, B is 1,1-dioxothiolan-3-yl, A is single bond, Y° is 4-amidinobenzyl, and M is N; R2 is 2-hydroxyphenyl, B is cyclobutyl, A is single bond, Y° is 4-amidinobenzyl, and M is N; intellectual property office of n.z. 23 JAN 2004 RECEIVED B is cyclopropyl, A is CH2, Y° is 4-amidinobenzyl, and M is B is 2-(2R)-bicyclo[2.2.1]-heptyl, A is single bond, Y° is 4-B is cyclopentyl, A is single bond, Y° is 4-amidino-2-B is cyclohexyl, A is CH2CH2, Y° is 4-amidinobenzyl, and M B is oxalan-2-yl, A is CH2, Y° is 4-amidinobenzyl, and M is R2 is 3-aminophenyl, B is 1-pyrrolidinyl, A is CH2CH2CH2, Y° is 4-amidinobenzyl, and M is N; R2 is phenyl, B is cyclobutyl, A is single bond, Y° is 4-amidinobenzyl, and M is N; R2 is 3-thienyl, B is cyclobutyl, A is single bond, Y° is 4-amidinobenzyl, and M is N; or R2 is 2,6-dichlorophenyl, B is cyclobutyl, A is single bond, Y° is 4-amidinobenzyl, and M is CH.

25. A composition for inhibiting thrombotic conditions in blood comprising a compound of claim 8, 16 or 24 and a pharmaceutically acceptable carrier.

26. A composition for inhibiting thrombotic conditions in blood comprising a compound of any one of claims 1 to 7, 9 to 15 and 17 to 23 and a pharmaceutically acceptable carrier.

27. Use of a compound of any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting thrombotic conditions in blood.

28. Use of a compound of any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting formation of blood platelet aggregates in blood.

29. Use of a compound of any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting thrombus formation in blood.

30. Use of a compound of any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing venuous thromboembolism and pulmonary embolism in a mammal in need thereof. P^LEfDOropmwomEl OF N.Z. 226 10 SEP 2004

31. Use of a compound of any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing deep vein thrombosis in a mammal in need thereof.

32. Use of a compound of any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing cardiogenic thromboembolism in a mammal in need thereof.

33. Use of a compound of any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing thromboembolic stroke in a mammal in need thereof.

34. Use of a compound of any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing thrombosis associated with cancer and cancer chemotherapy in a mammal in need thereof.

35. Use of a compound of any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing unstable angina in a mammal in need thereof.

36. Use of a compound of any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting thrombus formation, treating thrombus formation, or preventing thrombus formation in a mammal in need thereof. '^reLLEC^ATTO^fY- OF N.2. 227 1 0 SEP 2004 RECEIVED

37. The use as recited in any one of claims 27 to 36, substantially as herein described.

38. A composition as recited in claim 25 or 26, substantially as herein described.

39. A compound as recited in any one of claims 1 to 24, substantially as herein described. 228 </div>