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1. WO2001077079 - PYRIDONES POLYCYCLIQUES 4-ARYL ET HETEROARYL SUBSTITUEES UTILES POUR L'INHIBITION SELECTIVE DE LA CASCADE DE COAGULATION

Note: Texte fondé sur des processus automatiques de reconnaissance optique de caractères. Seule la version PDF a une valeur juridique

[ EN ]

Polycyclic Aryl and Heteroaryl Substituted 4-Pyridones Useful for Selective Inhibition of the Coagulation Cascade

Field of the Invention

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 polycyclic aryl and heteroaryl substituted 4-pyridone compounds that inhibit serine proteases of the coagulation cascade.

Background of the Invention

Physiological systems control the fluidity of blood in mammals

[Majerus, P. W. et al: Anticoagulant, Thrombolytic, and Antiplatelet Drugs. 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 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, and XII; these are also called protease zymogens. These coagulation factors or protease zymogens are activated by serine proteases leading to coagulation in a so called "coagulation cascade" or chain reaction [Handin, R. I.: Bleeding and Thrombosis. In Wilson, J., et al. editors: Harrison's Principles of Internal

Medicine. 12th Edition, New York, McGraw-Hill Book Co., 1991,p.350]. Coagulation or clotting occurs in two ways through different pathways. An intrinsic or contact pathway leads from XII to Xlla 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 of coagulation factor VII to Vila by Xa. The presence of Tissue Factor and Vila accelerates formation of Xa in the presence of calcium ion and

phospholipids. Formation of Xa leads to thrombin, fibrin, and a fibrin clot as described above. The presence of one or more of these many different coagulation factors and two distinct pathways of clotting could enable the 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 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 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 attacks, atriai 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 2-pyridone compounds that act as an inhibitor of a coagulation factor present in the coagulation cascade or clotting process. In US Patent 5,668,289, Sanderson et al. describe 6-alkyl, 6-cycloalkyl, and 6-trifluoromethyl 2-pyridones unsubstituted at the 4 and 5 positions and reported to inhibit thrombin. In PCT Patent Application WO 97/01338, Sanderson et al. describe 6-alkyl, 6-cycloalkyl, and 6-trifIuoromethyl 2-pyridones unsubstituted at the 4 and 5 positions and reported to inhibit thrombin. In US Patent 5,792,779, Sanderson et al. describe substituted 4,6-alkyl, 4,6-cycloalkyl, and 4,6-trifluoromethyl 2-pyridones having utility as thrombin inhibitors. In PCT Patent Application WO 97/30708, Sanderson et al. describe additional substituted 4,6-alkyl, 4,6-cycloalkyl, and 4,6-trifluoromethyl 2-pyridones having utility as thrombin inhibitors. In US Patent 5,869,487, Coburn et al. describe pyrido[3,4-

Bjpyrazines containing a fused 6-methyl-2-pyridone functionality and having utility as thrombin inhibitors. In PCT Patent Application WO 98/47876, Van Boeckel et al. describe 6-alkyl-2-pyridones as anti-thrombotic compounds. In PCT Patent Application WO 98/16547, Zhu and Scarborough describe 4,5,6-substituted-3-amino-2-pyridonylacetamides containing amide substituents having a heteroaroyl functions and having activity against mammalian factor Xa. In US Patent 5,656,645, Tamura et al. describe 4,5,6-substituted-3-amino-2-pyridonyl-acetamides containing amide substituents having a formyl function and having activity against thrombin. In US Patent 5,658,930, Tamura et al. again describe 4,5,6-substituted-3-amino-2-pyridonyl-acetamides containing amide substituents having a formyl function and having activity against thrombin. In PCT Patent Applications 96/18644, Tamura et al. further describe 4,5,6-substituted-3-amino-2-pyridonylacetamides containing amide substituents having a formyl function and having activity against thrombin. In PCT Patent Application WO 98/31670, Sanderson et al. describe additional 4-substituted 6-alkyl, 6-cycloalkyl, and 6-trifluoromethyl pyridones having utility as thrombin inhibitors. In PCT Patent Application WO 98/17274, Coburn et al. disclose substituted 3,4-diamino-6-methyl-2-pyridones having utility as human thrombin inhibitors. In PCT Patent Application WO 98/42342, Isaacs et al. describe additional 6-alkyl, cycloalkyl, and trifluoromethyl substituted 2-pyridones reported to inhibit human thrombin. In PCT Patent Applications WO 00/039102, Wexler et al. describe certain 4,6-disubstituted-2-pyridonylacetamides that are further substituted at the 3-position by several groups including several substituted aminos and that are reported to be inhibitors of trysin-like serine protease enzymes, especially factor Xa and thrombin.

In contrast to the disclosures that some 2-pyridone derivatives may function as thrombin inhibitors, 4-pyridonyl compounds, compositions thereof, their use for preventing and treating thrombotic conditions such as coronary artery and cerebrovascular disease, and their ability to inhibit serine proteases of the coagulation cascade have not been previously disclosed.

SUMMARY OF THE INVENTION

It is an object of the present invention to provide novel compounds that are beneficial in anticoagulant therapy and that have a general structure:


It is another object of the present invention to provide 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).

Various other obj ects 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 Polycyclic Aryl and Heteroaryl Substituted 4-pyridones, 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):


or a pharmaceutically acceptable salt thereof, wherein;

B is formula (V):


wherein D1, D2, J1, J2 and K1 are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more than one can be a covalent bond, no more than one of D1, D2, J1, J2 and K1

can be O, no more than one of D1, D2 ,J1, J2 andK1 can be S, one of D1,D2,

J1,J2 andK1 must be a covalent bond when two of D1,D2,J1,J2 andK1 are

O and S, and no more than four of D1,D2,J1,J2 and K1 can be N with the

proviso that R32,R33,R34,R35 ,andR36 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;

R32,R33,R34,R35, and R36 can independently be Qb;

R9, R1,0 R 11 , R12, R13, R16 , R17, R1,8R19 , R32, R33, R3,4R35, and

36

R are independently selected from the group consisting of hydrido, amidino, guanidino, dialkylsulfonium, trialkylphosphonium, dialkylsulfoniumalkyl, carboxy, heteroaralkylthio, heteroaralkoxy, cycloalkylamino, acylalkyl, acylalkoxy, aryloylalkoxy, heterocyclyloxy, aralkylaryl, aralkyl, aralkenyl, aralkynyl, heterocyclyl, perhaloaralkyl, aralkylsulfonyl, aralkylsulfonylalkyl, aralkylsulfinyl, aralkylsulfinylalkyl, halocycloalkyl, halocycloalkenyl, cycloalkylsulfinyl, cycloalkylsulfinylalkyl, cycloalkylsulfonyl,

cycloalkylsulfonylalkyl, heteroarylamino, N-heteroarylamino-N-alkylamino, heteroarylaminoalkyl, haloalkylthio, alkanoyloxy, alkoxy, alkoxyalkyl, haloalkoxylalkyl, heteroaralkoxy, cycloalkoxy, cycloalkenyloxy,

cycloalkoxyalkyl, cycloalkylalkoxy, cycloalkenyloxyalkyl, cycloalkylenedioxy, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxy,

halocycloalkenyloxyalkyl, hydroxy, amino, alkoxyamino, thio, nitro, lower alkylamino, alkylthio, alkylthioalkyl, arylamino, aralkylamino, arylthio, arylthioalkyl, heteroaralkoxyalkyl, alkylsulfinyl, alkylsulfinylalkyl,

arylsulfinylalkyl, arylsulfonylalkyl, heteroarylsulfmylalkyl,

heteroarylsulfonylalkyl, alkylsulfonyl, alkylsulfonylalkyl,

haloalkylsulfinylalkyl, haloalkylsulfonylalkyl, alkylsulfonamido,

alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, monoarylamidosulfonyl, arylsulfonamido, diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl, 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 cycloalkenylalkyl, halo, haloalkyl, haloalkenyl, haloalkoxy, hydroxyhaloalkyl, hydroxyaralkyl, hydroxyalkyl, aminoalkyl, hydoxyheteroaralkyl, haloalkoxyalkyl, aryl, aralkyl, aryloxy, aralkoxy, aiyloxyalkyl, saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl, heteroaryloxy, heteroaryloxyalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, carboxyalkyl, carboalkoxy, alkoxycarboxamido, alkylamidocarbonylamido, arylamidocarbonylamido, carboalkoxyalkyl, carboalkoxy alkenyl, carboaralkoxy, carboxamido, carboxamidoalkyl, cyano,

carbohaloalkoxy, phosphono, phosphonoalkyl, diaralkoxyphosphono, and diaralkoxyphosphonoalkyl ;

R32 and R33, R33 and R34, R34 and R35 , and R35 and R36 can be independently 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 8 contiguous members, a heteroaryl ring having 5 through 6 contiguous members, and an aryl with the proviso that no more than one of the group consisting of spacer pairs R32 and R33 , R33 and R34, R34 and R35 , and R35

and R36 can be used at the same time;

R9 and R10 , R 10 and R 1 1, R11 and R12, and R12 and R 13 can be independently 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 8 contiguous members, a heteroaryl ring having 5 through 6 contiguous members, and an aryl with the proviso that no more than one of the group consisting of spacer pairs R9 and R10, R 10 and R 11, R 11 and R12, and R 12

and R13 can be used at the same time;

B can be formula (VI):


wherein D3, D4, J3, and J4 are independently selected from the group consisting of

C, N, O, and S, no more than one of D3, D4, J3, and J4 can be O, no more than one

of D3, D4, J3, and J4 can be S, and no more than three of D 1, D2, J 1, and J2 can

be N with the proviso that R32 , R33, R34, and R35 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;

B can be selected from the group consisting of C3-C8 alkyl, C3-C8 alkenyl, C3-C8 alkynyl, C3-C8 haloalkyl, and C3-C8 haloalkenyl wherein each member of group B may be optionally substituted at any carbon up to and including 6 atoms from the point of attachment of B to A with one or more of the group consisting of R32, R33, R34, R35, and R36,

B can be selected from the group consisting of C3-C10 cycloalkyl, C5-C10 cycloalkenyl, C4-C9 saturated heterocyclyl, and C4-C9 partially saturated heterocyclyl, wherein each ring carbon may be optionally substituted with R33, a ring carbon other than the ring carbon at the point of attachment of B to A may be optionally substituted with oxo provided that no more than one ring carbon is substituted by oxo at the same time, ring carbon and nitrogen atoms adjacent to the carbon atom at the point of attachment may be optionally substituted with R9 or R13, a ring carbon or nitrogen atom adjacent to the R9 position and two atoms from the point of attachment may be substituted with

R10, a ring carbon or nitrogen atom adjacent to the R13 position and two atoms

from the point of attachment may be substituted with R12, a ring carbon or

nitrogen atom three atoms from the point of attachment and adjacent to the R10

position may be substituted with R11, a ring carbon or nitrogen atom three

atoms from the point of attachment and adj acent to the R12 position may be

substituted with R33, and a ring carbon or nitrogen atom four atoms from the

point of attachment and adjacent to the R11 and R33 positions may be

substituted with R34;

A is selected from the group consisting of single covalent bond, (W7 )rr-

(CH(R15 ))pa and (CH(R15 ))pa-(W7 )rr wherein rr is an integer selected from

0 through 1, pa is an integer selected from 0 through 6, and W7 is selected

from the group consisting of O, S, C(O), C(S), C(O)S, C(S)O, C(O)N(R7),

C(S)N(R7), (R7)NC(O), (R7)NC(S), S(O), S(O)2, S(O)2N(R7),

(R7)NS(O)2, Se(O), Se(O)2, Se(O)2N(R7), (R7)NSe(O)2, P(O)(R8),

N(R7)P(O)(R8), P(O)(R8)N(R7), C(NR7)N(R7), (R7)NC(NR7), and N(R7);

R7 and R8 are independently selected from the group consisting of hydrido, hydroxy, alkyl, alkenyl, aryl, aralkyl, aryloxy, alkoxy, alkenyloxy, alkylthio, alkylamino, arylthio, arylamino, acyl, aroyl, heteroaroyl, aralkoxyalkyl, heteroaralkoxyalkyl, , aiyloxyalkyl, alkoxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, aralkoxyalkyl, heteroaralkoxyalkyl, alkylsulfinylalkyl,

alkylsulfonylalkyl, heteroaryl, heteroaryloxy, heteroarylamino, heteroaralkyl, heteroaralkyloxy, heteroaralkylamino, and heteroaryloxyalkyl;

R14, R15, R37, R38, R39, R40 , R41 and R42 are independently selected from the group consisting of hydrido, hydroxy, halo, cyano, aryloxy, amino, alkylamino, dialkylamino, hydroxyalkyl, aminoalkyl, acyl, aroyl, heteroaroyl, heteroaryloxyalkyl, sulfhydryl, acylamido, alkoxy, alkylthio, arylthio, alkyl, alkenyl, alkynyl, aryl, aralkyl, aiyloxyalkyl, aralkoxyalkylalkoxy, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkoxythioalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxyalkyl, saturated heterocyclyl, partially saturated

heterocyclyl, heteroaryl, heteroarylalkyl, heteroarylthioalkyl,

heteroaralkylthioalkyl, monocarboalkoxyalkyl, dicarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl, carboalkoxycyanoalkyl, alkylsulfinyl, alkylsulfonyl, haloalkylsulfinyl, haloalkylsulfonyl, arylsulfinyl,

arylsulfϊnylalkyl, arylsulfonyl, arylsulfonylalkyl, aralkylsulfinyl,

aralkylsulfonyl, cycloalkylsulfinyl, cycloalkylsulfonyl, cycloalkylsulfinylalkyl, cycloalkylsufonylalkyl, heteroarylsulfonylalkyl, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylsulfinylalkyl, aralkylsulfinylalkyl,

aralkylsulfonylalkyl, carboxy, carboxyalkyl, carboalkoxy, carboxamide, carboxamidoalkyl, carboaralkoxy, trialkylsilyl, dialkoxyphosphono, diaralkoxyphosphono, dialkoxyphosphonoalkyl, and

diaralkoxyphosphonoalkyl ;

R14 and R14, when bonded to different carbons, can be 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 members, and a heterocyclyl having from 5 through 8 contiguous members;

R14 and R15, when bonded to different carbons, can be 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 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;

R15 and R 15, when bonded to different carbons, can be 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 members, and a heterocyclyl having from 5 through 8 contiguous members;

Ψ is selected from the group consisting of NR5 , O, C(O), C(S), S,

S(O), S(O)2, ON(R5 ), P(O)(R8 ), and CR39 R40 ;

R5 is selected from the group consisting of hydrido, alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxy, alkoxy, alkenyloxy, alkylthio, arylthio, aralkoxyalkyl, heteroaralkoxyalkyl, aiyloxyalkyl, alkoxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, aralkoxyalkyl, heteroaralkoxyalkyl,

alkylsulfinylalkyl, alkylsulfonylalkyl, cycloalkyl, cycloalkylalkyl,

cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxyalkyl, halocycloalkenyloxyalkyl, heteroaryl, heteroarylalkyl, monocarboalkoxyalkyl, monocarboalkoxy, dicarboalkoxyalkyl,

monocarboxamido, monocyanoalkyl, dicyanoalkyl, carboalkoxycyanoalkyl, acyl, aroyl, heteroaroyl, heteroaryloxyalkyl, and dialkoxyphosphonoalkyl;

R39 and R40, when bonded to the same carbon, can be taken together to

form a group selected from a group consisting of oxo, thiono, R5 -N, alkylene, haloalkylene, and a linear moiety spacer having from 2 through 7 contiguous atoms to form a ring selected from the group consisting of a cycloalkyl ring having from 3 through 8 contiguous members, a cycloalkenyl ring having from 3 through 8 contiguous members, and a heterocyclyl ring having from 3 through 8 contiguous members;

R1 is selected from the group consisting of hydrido, alkyl, alkenyl, haloalkyl, and alkoxyalkyl;

X0 and R2 are independently selected from the group consisting of Z0 - Q, hydrido, alkyl, alkenyl, and halo;

X0 and R2 can be independently selected from the group consisting of amidino, guanidino, dialkylsulfonium, trialkylphosphonium,

dialkylsulfoniumalkyl, heteroarylamino, amino, nitro, alkylamino, arylamino, aralkylamino, alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl,

heteroaralkanoyl, haloalkanoyl, hydroxyhaloalkyl, cyano, and phosphono;

X0 and R1 can be taken together to form a spacer pair wherein the spacer pair forms a linear moiety having from 3 through 6 contiguous atoms connecting the points of bonding of said spacer pair members to form a heterocyclyl ring having from 5 through 8 contiguous members with the

proviso that no more than one of the group consisting of spacer pair X0 and R1

and spacer pair R 2 and R1 can be used at the same time;

R 2 and R1 can be taken together to form a spacer pair wherein the spacer pair forms a linear moiety having from 3 through 6 contiguous atoms connecting the points of bonding of said spacer pair members to form a heterocyclyl ring having from 5 through 8 contiguous members with the proviso that no more than one of the group consisting of spacer pair X0 and R1

and spacer pair R2 and R 1 can be used at the same time ;

X0 and R5 can be taken together to form a spacer pair wherein the spacer pair forms a linear spacer moiety having from 2 through 5 contiguous atoms connecting the points of bonding of said spacer pair members to form a heterocyclyl ring having from 5 through 8 contiguous members;

X0 and R39 can be taken together to form a spacer pair wherein the spacer pair forms a linear spacer moiety having from 2 through 5 contiguous atoms connecting the points of bonding of said spacer pair members to form a heterocyclyl ring having from 5 through 8 contiguous members;

X0 and R40 can be taken together to form a spacer pair wherein the spacer pair forms a linear spacer moiety having from 2 through 5 contiguous atoms connecting the points of bonding of said spacer pair members to form a heterocyclyl ring having from 5 through 8 contiguous members;

X0 can be independently selected to form a linear moiety having from 2 through 5 contiguous atoms linked to the points of bonding of both R39 and R40 to form a heterocyclyl ring having from 5 through 8 contiguous members;

R2 and R4a, R2 and R4b, R2 and R14, and R2 and R15 can be 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 heterocyclyl ring having from 5 through 8 contiguous members with the proviso that no more than one of the group of spacer pairs consisting of R2 and R4a, R2 and R4b, R2 and R1 4, and R2 and R 15 can be used at the same time;

R2 can be independently selected to form a linear moiety having from 2 through 5 contiguous atoms linked to the points of bonding of both R4a and R4b to form a heterocyclyl ring having from 5 through 8 contiguous members;

Z0 is selected from the group consisting of covalent single bond, (CR41 R42)q wherein q is an integer selected from 1 through 6, (CH(R41))g-

W0-(CH(R42 ))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), C(S),

C(O)O, C(S)O, C(O)S, C(S)S, C(O)N(R41), (R41)NC(O), C(S)N(R41),

(R41 )NC(S), OC(O)N(R41), (R41)NC(O)O, SC(S)N(R41), (R41)NC(S)S,

SC(O)N(R41), (R41)NC(O)S, OC(S)N(R41), (R41)NC(S)O,

N(R42)C(O)N(R41), (R41)NC(O)N(R42), N(R42)C(S)N(R41),

(R41)NC(S)N(R42), S(O), S(O)2, S(O)2N(R41), N(R41)S(O)2, Se, Se(O),

Se(O)2, Se(O)2N(R41), N(R41)Se(O)2, P(O)(R8), N(R7)P(O)(R8),

P(O)(R8)N(R7), N(R41), ON(R41), and SiR28 R29 , and (CH(R41 ))e-W2-

(CH(R42 ))h wherein e and h are integers independently selected from 0

through 2 and W2 is selected from the group consisting of CR41 =CR42,

CR41 R42 =C; vinylidene), and ethynylidene (C≡C; 1,2-ethynyl), with the

proviso that R41 and R42 are selected from other than halo and cyano when directly bonded to N and Z0 is directly bonded to the pyridone ring;

Q is formula (II):


wherein D1, D2, J1, J2 and K1 are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more than one can be a covalent bond, no more than one of D 1, D2, J1, J2and K1

can be O, no more than one of D 1, D2, J 1, J 2 and K1 can be S, one of D1, D2,

J 1, J2 and K1 must be a covalent bond when two of D1, D2, J1, J2 and K1 are

O and S, and no more than four of D1, D2, J 1, J2 and K1 can be N, with the

proviso that R9 , R10, R1 1, R12, and R13 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 can be formula (III):


wherein D3, D4, J3, and J4 are independently selected from the group

consisting of C, N, O, and S, no more than one of D3 , D4, J3, and J4 can be O,

no more than one of D3, D4, J3, and J4 can be S, and no more than three of D1,

D2, J 1, and J2 can be N with the proviso that R9, R10, R1 1, and R 12 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 can be selected from the group consisting of alkyl, alkoxy, alkylamino, alkylthio, haloalkylthio, alkenyl, alkynyl, saturated heterocyclyl, partially saturated heterocyclyl, acyl, aroyl, heteroaroyl, cycloalkyl,

cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkylalkenyl, haloalkyl, haloalkoxy, haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxyalkyl, and halocycloalkenyloxyalkyl;

K is (CR4a R4b )n wherein n is an integer selected from 1 through 4;

R4a and R4b are independently selected from the group consisting of halo, hydrido, hydroxy, cyano, hydroxyalkyl, alkyl, alkenyl, aryl, aralkyl, aralkoxyalkyl, aryloxyalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, aralkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, haloalkenyl, heteroaryl, heteroarylalkyl, heteroarylthioalkyl, heteroaralkylthioalkyl, cyanoalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, haloalkylsulfinyl, arylsulfinylalkyl, arylsulfonylalkyl, heteroarylsulfonylalkyl, heteroarylsulfinylalkyl, aralkylsulfinylalkyl, and aralkylsulfonylalkyl;

R4a and R4b, when bonded to the same carbon, can be 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 contiguous members, and a heterocyclyl ring having 5 through 8 contiguous members;

E0 is E 1, when Kis (CR4a R4b )n, wherein E1 is selected from the group consisting of a covalent single bond, O, S, C(O), C(S), C(O)O, C(S)O, C(O)S,

C(S)S, C(O)N(R7), (R7)NC(O), C(S)N(R7), (R7)NC(S), OC(O)N(R7),

(R7)NC(O)O, SC(S)N(R7), (R7)NC(S)S, SC(O)N(R7), (R7)NC(O)S,

OC(S)N(R7), (R7)NC(S)O, N(R8)C(O)N(R7), (R7)NC(O)N(R8),

N(R8)C(S)N(R7), (R7)NC(S)N(R8), S(O), S(O)2, S(O)2N(R7), N(R7)S(O)2,

S(O)2N(R7)C(O), C(O)N(R7)S(O)2, Se, Se(O), Se(O)2, Se(O)2N(R7),

N(R7)Se(O)2, P(O)(R8), N(R7)P(O)(R8), P(O)(R8)N(R7), N(R7), ON(R7),

SiR28R29, CR4a=CR4b, ethynylidene (C≡C; 1,2-ethynyl), and C=CR4aR4b;

R28 and R29. 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, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxyalkyl, haloalkenyloxyalkyl,

halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxyalkyl, perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl, heteroarylalkyl, heteroarylthioalkyl, heteroaralkylthioalkyl, cyanoalkyl, dicyanoalkyl, carboxamidoalkyl,

dicarboxamidoalkyl, cyanocarboalkoxyalkyl, carboalkoxyalkyl, dicarboalkoxyalkyl, cyanocycloalkyl, dicyanocycloalkyl, carboxamidocycloalkyl,

dicarboxamidocycloalkyl, carboalkoxycyanocycloalkyl, carboalkoxycycloalkyl, dicarboalkoxycycloalkyl, formylalkyl, acylalkyl, arylsulfinylalkyl, arylsulfonylalkyl, aralkylsulfinyl, cycloalkylsulfinylalkyl, cycloalkylsufonylalkyl,

heteroarylsulfonylalkyl, heteroarylsulfinylalkyl, aralkylsulfinylalkyl,

aralkylsulfonylalkyl, carboxy, dialkoxyphosphono, diaralkoxyphosphono, dialkoxyphosphonoalkyl and diaralkoxyphosphonoalkyl;

R28 and R29 can be taken together to form a linear moiety spacer having from 2 through 7 contiguous atoms and forming a ring selected from the group consisting of a cycloalkyl ring having from 3 through 8 contiguous members, a cycloalkenyl ring having from 3 through 8 contiguous members, and a heterocyclyl ring having from 3 through 8 contiguous members;

K can be (CH(R14))j-T wherein j is selected from a integer from 0 through 3 and T is selected from the group consisting of single covalent bond,

O, S, and N(R7) with the proviso that (CH(R14))j is bonded to the pyridone ring;

E0 is E2, when K is (CH(R14 ))j-T, wherein E2 is selected from the group consisting of a covalent single bond, C(O), C(S), C(O)O, C(S)O, C(O)S,

C(S)S, C(O)N(R7), (R7)NC(O), C(S)N(R7), (R7)NC(S), (R7)NC(0)O,

(R7)NC(S)S, (R7)NC(O)S, (R7)NC(S)O, N(R8)C(O)N(R7),

(R7)NC(O)N(R8), N(R8)C(S)N(R7), (R7)NC(S)N(R8), S(O), S(O)2,

S(O)2N(R7), N(R7)S(O)2, S(O)2N(H)C(O), C(O)N(H)S(O)2, Se(O),

Se(O)2, Se(O)2N(R7), N(R7)Se(O)2, P(O)(R8), N(R7)P(O)(R8),

P(O)(R8)N(R7), and N(R7);

K can be G-(CH(R15 ))k wherein k is selected from an integer from 1

through 3 and G is selected from the group consisting of O, S, and N(R7 ) with

the proviso that R15 is other than hydroxy, cyano, halo, amino, alkylamino, dialkylamino, and sulfhydryl when k is 1;

E0 is E3 when K is G-(CH(R 15))k wherein E3 is selected from the group consisting of a covalent single bond, O, S, C(O), C(S), C(O)O, C(S)O, C(O)S, C(S)S, C(O)N(R7), (R7)NC(O), C(S)N(R7), (R7)NC(S),

OC(O)N(R7), (R7)NC(O)O, SC(S)N(R7), (R7)NC(S)S, SC(O)N(R7),

(R7)NC(O)S, OC(S)N(R7), (R7)NC(S)0, N(R8)C(O)N(R7),

(R7)NC(O)N(R8), N(R8)C(S)N(R7), (R7)NC(S)N(R8), S(O), S(O)2,

S(O)2N(R7), N(R7)S(O)2, Se, Se(O), Se(O)2, Se(O)2N(R7), N(R7)Se(O)2,

P(O)(R8), N(R7)P(O)(R8), P(O)(R8 )N(R7), N(R7), ON(R7), SiR28 R29,

CR4a =CR4b, ethynylidene (C≡C; 1,2-ethynyl), and C=CR4a R4b ;

Y0 is formula (IV):


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 can be a covalent bond, K2 is independently selected from the group

consisting of C, and N+ , no more than one of D5, D6, J5, and J6 can be O, no

more than one of D5, D6, J5, and J6 can be 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, no more than

three of D5, D6, J5, and J6 can be N when K2 is N+, and no more than four of

D5, D6, J5, and J6 can be N when K2 is carbon with the provisos that R16,

R17, R18, and R 19 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;

R16 and R 17 can be 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 having from 5 through 8 contiguous members, a heteroaryl having from 5 through 6 contiguous members, and an aryl;

R18 and R19 can be 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 having from 5 through 8 contiguous members, a heteroaryl having from 5 through 6 contiguous members, and an aryl;

Qb is selected from the group consisting of NR20 R21,+ NR20 R21 R22, oxy, alkyl, alkylaminoalkyl, aminoalkyl, dialkylsulfoniumalkyl, and acylamino wherein R20, R21, and R22 are independently selected from the group consisting of hydrido, alkyl, hydroxy, alkoxy, alkylamino, dialkylamino, aminoalkyl, and hydroxyalkyl with the provisos that no more than one of R20,

R21, and R22 can be hydroxy, alkoxy, alkylamino, amino, and dialkylamino

and that R20, R21, and R22 must be other than be hydroxy, alkoxy,

alkylamino, ammo, and dialkylamino when K2 is N+ ;

R20 and R21, R20 and R22 , and R21 and R22 can be independently 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 one of the group consisting of spacer pairs R20 and R21, R20 and R22, and R21 and R22

can be used at the same time;

Q can be selected from the group consisting of

N(R26)SO2N(R23)(R24), N(R26)C(O)OR5, N(R26)C(O)SR5,

N(R26)C(S)OR5 and N(R26)C(S)SR5 with the proviso that no more than one

of R23, R24, and R26 can be hydroxy, alkoxy, alkylamino, ammo, or

dialkylamino when two of the group consisting of R32 , R24, and R26 are bonded to the same atom;

Qb can be selected from the group consisting of dialkylsulfonium,

trialkylphosphonium, C(NR25)NR23 R24, N(R26)C(NR25 )N(R23)(R24),

N(R26)C(O)N(R23)(R24), N(R26)C(S)N(R23)(R24), C(NR25)OR5

C(O)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), N(R26)N(R26)SO2N(R23)(R24),

C(NR25 )SR5, C(O)NR23 R24, and C(O)NR23 R24 with the provisos that no

more than one of R23, R24, and R26 can be hydroxy, alkoxy, alkylamino,

amino, or dialkylamino when two of the group consisting of R23, R24, and R26

are bonded to the same atom and that said Qb group is bonded directly to a carbon atom;

R23, R24, R25, and R26 are independently selected from the group consisting of hydrido, alkyl, hydroxy, alkoxy, alkylamino, dialkylamino, aminoalkyl, and hydroxyalkyl;

R23 and R24 can be 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;

R23 and R25, R24 and R25, R25 and R26, R24 and R26 , and R23 and R26

can be independently selected to form a spacer pair wherein a spacer pair is taken together from the points of bonding of selected spacer pair members to form the group L-U-V wherein L, U, and V are independently selected from the group consisting of O, S, C(O), C(S), C(JH)2 S(O), SO2, OP(OR31)R30, P(O)R30,

P(S)R30, C(R30 )R3 1, C=C(R30 )R31, (O)2POP(O)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), SO2C(R30)=C(R31),

PR30C(R30)=C(R31), P(O)R30C(R30)=C(R31), P(S)R3°C(R3°)=C(R31),

DC(R30)(R31)D, OP(OR31)R30, P(O)R30, P(S)R30, Si(R28)R29 and N(R30), and a covalent bond with the proviso that no more than any two of L, U and V are simultaneously covalent bonds and the heterocyclyl comprised of by L, U, and V has from 5 through 10 contiguous member;

D is selected from the group consisting of oxygen, C=O, C=S, S(O)m wherein m is an integer selected from 0 through 2;

JH is independently selected from the group consisting of OR27, SR27 and

N(R20)R21;

R27 is selected from the group consisting of hydrido, alkyl, alkenyl, alkynyl, aralkyl, aryloxyalkyl, aralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkylthioalkyl, alkoxyalkyl, heteroaryloxyalkyl,

alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxyalkyl, haloalkenyloxyalkyl,

halocycloalkoxyalkyl, halocycloalkenyloxyalkyl, perhaloaryloxyalkyl, heteroaryl, heteroarylalkyl, heteroarylthioalkyl, heteroaralkylthioalkyl, arylsulfinylalkyl, arylsulfonylalkyl, cycloalkylsulfinylalkyl, cycloalkylsufonylalkyl,

heteroarylsulfonylalkyl, heteroarylsulfinylalkyl, aralkylsulfinylalkyl and

aralkylsulfonylalkyl;

R30 and R31 are independently selected from hydrido, hydroxy, thiol, aryloxy, amino, alkylamino, dialkylamino, hydroxyalkyl, heteroaryloxyalkyl, alkoxy, alkylthio, arylthio, alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, aralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkoxythioalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, haloaralkylsulfinylalkyl, aralkylsulfonylalkyl, cyanoalkyl, dicyanoalkyl, carboxamidoalkyl, dicarboxamidoalkyl, cyanocarboalkoxyalkyl, carboalkoxyalkyl, dicarboalkoxyalkyl, cyanocycloalkyl, dicyanocycloalkyl, carboxamidocycloalkyl, dicarboxamidocycloalkyl, carboalkoxycyanocycloalkyl, carboalkoxycycloalkyl, dicarboalkoxycycloalkyl, formylalkyl, acylalkyl,

dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, phosphonoalkyl,

dialkoxyphosphonoalkoxy, diaralkoxyphosphonoalkoxy, phosphonoalkoxy, dialkoxyphosphonoalkylamino, diaralkoxyphosphonoalkylamino,

phosphonoalkylamino, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, sulfonylalkyl, alkoxysulfonylalkyl, aralkoxysulfonylalkyl, alkoxysulfonylalkoxy, aralkoxysulfonylalkoxy, sulfonylalkoxy, alkoxysulfonylalkylamino,

aralkoxysulfonylalkylamino, and sulfonylalkylamino;

R30 and R31 can be 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 heterocyclyl ring having from 3 through 8 contiguous members;

R23 and R25, R24 and R25, R25 and R26, R24 and R26, and R23 and R26

can be independently selected to form a spacer pair wherein a spacer pair is taken together from the points of bonding of selected spacer pair members to form the group L-U-V wherein L, U, and V are independently selected from the group of 1,2-disubstituted radicals consisting of a cycloalkyl radical, a cycloalkenyl radical wherein cycloalkyl and cycloalkenyl radicals are substituted with one or more groups selected from R30 and R31, an aryl radical, an heteroaryl radical, a saturated heterocyclic radical and a partially saturated heterocyclic radical wherein said 1,2-substitutents are independently selected from C=O, C=S, C(R28 )R32, S(O), S(O)2, OP(OR31)R30, P(O)R30, P(S)R30 and Si(R28 )R29;

R23 and R52, R24 and R25, R25 and R26, R24 and R26, and R23 and R26

can be independently selected to form a spacer pair wherein a spacer pair is taken together from the points of bonding of selected spacer pair members to form the group L-U-V wherein L, U, and V are independently selected from the group of radicals consisting of 1 ,2-disubstituted alkylene radicals and 1 ,2-disubstituted alkenylene radical wherein said 1,2-substitutents are independently selected from

C=O, C=S, C(R28)R29, S(O), S(O)2, OP(OR31)R30, P(O)R30, P(S)R30, and Si(R28 )R29 and said alkylene and alkenylene radical are substituted with one or more R30 or R31 substituents;

Qs is selected from the group consisting of a single covalent bond,

(CR37 R38 )b-(W0 )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(O)O, C(S)O, C(O)S, C(S)S, C(O)N(R14),

(R14)NC(O), C(S)N(R14), (R 14)NC(S), OC(0)N(R 14), SC(S)N(R14),

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

N(R15)C(S)N(R 14), (R14)NC(S)N(R15), S(O), S(O)2, S(O)2N(R14),

N(R14)S(O)2, Se, Se(O), Se(O)2, Se(O)2N(R17), N(R14)Se(O)2, P(O)(R8),

N(R7)P(O)(R8), P(O)(R8)N(R7), N(R14), ON(R14), and SiR28 R29,

(CH(R 14))C-W1 -(CH(R15)) d 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(O)O, C(S)O, C(O)S, C(S)S, C(O)N(R14), (R14)NC(O),

C(S)N(R14), (R14)NC(S), OC(O)N(R14), (R14)NC(O)O, SC(S)N(R14),

(R 14)NC(S)S, SC(O)N(R14), (R 14)NC(O)S, OC(S)N(R14), (R14)NC(S)O,

N(R 15)C(O)N(R14), (R14)NC(O)N(R 15), N(R15)C(S)N(R 14),

(R 14)NC(S)N(R15), S(O), S(O)2, S(O)2N(R14), N(R14)S(O)2, Se, Se(O),

Se(O)2, Se(O)2N(R14), N(R14)Se(O)2, P(O)(R80), N(R7)P(O)(R8),

P(O)(R8 )N(R7), N(R14), ON(R14), SiR28 R29 , and (CH(R14))e- W2 -

(CH(R15 ))n wherein e and h are integers independently selected from 0

through 2 and W2 is selected from the group consisting of CR4a =CR4b ,

ethynylidene (C≡C; 1,2-ethynyl), and C=CR4a R4b with the provisos that R

and R15 are selected from other than halo and cyano when directly bonded to

N and that (CR37 R38)b, (CH(R14))C, (CH(R14))e and are bonded to E°;

R37 and R37, when bonded to different carbons, can be taken together to form a linear moiety spacer having from 1 through 7 contiguous atoms to form a ring selected from the group consisting of a cycloalkyl ring having from 3 through 8 contiguous members, a cycloalkenyl ring having from 3 through 8 contiguous members, and a heterocyclyl ring having from 3 through 8 contiguous members;

R37 and R38, when bonded to different carbons, can be taken together to form a linear moiety spacer having from 1 through 7 contiguous atoms to form a ring selected from the group consisting of a cycloalkyl ring having from 3 through 8 contiguous members, a cycloalkenyl ring having from 3 through 8 contiguous members, and a heterocyclyl ring having from 3 through 8 contiguous members;

R38 and R38 , when bonded to different carbons, can be taken together to form a linear moiety spacer having from 1 through 7 contiguous atoms to form a ring selected from the group consisting of a cycloalkyl ring having from 3 through 8 contiguous members, a cycloalkenyl ring having from 3 through 8 contiguous members, and a heterocyclyl ring having from 3 through 8 contiguous members;

R37 and R38, when bonded to the same carbon, can be taken together to form a group selected from a group consisting of oxo, thiono, alkylene, haloalkylene, and a linear moiety spacer having from 2 through 7 contiguous atoms to form a ring selected from the group consisting of a cycloalkyl ring 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;

Y0 can be Qb -Qss wherein Qss is selected from the group consisting of

(CR37 R38 )f wherein f is an integer selected from 1 through 6, (CH(R14))c-

W1-(CH(R15)) d wherein c and d are integers independently selected from 1

through 4, and W1 is selected from the group consisting of W1 is selected from the group consisting of O, S, C(O), C(S), C(O)O, C(S)O, C(O)S, C(S)S,

C(O)N(R14), (R14)NC(O), C(S)N(R14), (RM)NC(S), OC(0)N(R14),

(R14 )NC(O)O, SC(S)N(R14), (R14 )NC(S)S, SC(O)N(R14), (R1 4)NC(O)S,

OC(S)N(R14 ), (R14 )NC(S)O, N(R1 5)C(O)N(R14 ), (R14)NC(O)N(R15 ),

N(R15)C(S)N(R14), (R14)NC(S)N(R15), S(O), S(O)2, S(O)2N(R 14),

N(R14)S(O)2, Se, Se(O), Se(O)2, Se(O)2N(R14), N(R14)Se(O)2, P(O)(R8),

N(R7 )P(O)(R8), P(O)(R8)N(R7), N(R14), ON(R14), SiR28 R29, and

(CH(R14))e-W2 -(CH(R15))n wherein e and h are integers independently

selected from 0 through 2 and W2 is selected from the group consisting of

CR4a=CR4b, ethynylidene (C≡C; 1,2-ethynyl), and C=CR4aR4b with the

provisos that R14 and R15 are selected from other than halo and cyano when

directly bonded to N and that (CR37 R38)f, (CH(R15))c, and (CH(R15))e are bonded to E ;

Y0 can be Qb -Qsss wherein Qsss is (CH(R38))r-W3 , r is an integer

selected from 1 through 3, and W 3 is selected from the group consisting of 1,1-cyclopropyl, 1,2-cyclopropyl, 1,1-cyclobutyl, 1,2-cyclobutyl, 1,2-cyclohexyl, 13-cyclohexyl, 1,4-cyclohexyl, 1,2-cyclopentyl, 1,3-cyclopentyl, 2,3-morpholinyl, 2,4-morpholinyl, 2,5-morpholinyl, 2,6-morpholinyl, 3,4-morpholinyl, 3,5-morpholinyl, 1,2-piperazinyl, 1,3-piperazinyl, 1,4-piperazinyl, 2,3-piperazinyl, 2,5-piperazinyl, 2,6-piperazinyl, 1,2-piperidinyl, 1,3-piperidinyl, 1,4-piperidinyl, 23-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-ρyrrolidinyl, 2,4-pyrrolidinyl, 2,5-pyrrolidinyl, 3,4-pyrrolidinyl, 2H-2,3-pyranyl, 2H-2,4-pyranyl, 2H-2,5-pyranyl, 4H-2,3-ρyranyl, 4H-2,4-pyranyl, 4H-2,5-pyranyl, 2H-pyran-2-one-3,4-yl, 2H-pyran-2-one-4,5-yl, 4H-pyran-4-one-2,3-yl, 2,3-tetrahydrofuranyl, 2,4-tetrahydrofuranyl, 2,5-tetrahydrofuranyl, 3,4-tetrahydrofuranyl, 2,3-tetrahydropyranyl, 2,4-tetrahydropyranyl, 2,5-tetrahydropyranyl, 2,6-tetrahydropyranyl, 3,4-tetrahydropyranyl, and 3,5-tetrahydropyranyl with the proviso that (CH(R38 ))r

is bonded to E0 and Qb is bonded to lowest numbered substituent position of

each W3;

Y0 can be Qb -Qsssr wherein Qsssr is (CH(R38))r-W4 , r is an integer

selected from 1 through 3, and W4 is selected from the group consisting of 1.2-cyclobutyl, 1,2-cyclohexyl, 1,3-cyclohexyl, 1,4-cyclohexyl, 1,2-cyclopentyl, 1,3-cyclopentyl, 2,3-morpholinyl, 2,4-morpholinyl, 2,5-morpholinyl, 2,6-morpholinyl, 3,4-morpholinyl, 3,5-morpholinyl, 1,2-piperazinyl, 1,3-piperazinyl, 1,4-piperazinyl, 2,3-piperazinyl, 2,5-piperazinyl, 2,6-piperazinyl, 1,2-piperidinyl, 1,3-piperidinyl, 1,4-piperidinyl, 2,3-piperidinyl, 2,4-piperidinyl, 2,5-piperidinyl, 2,6-piperidinyl, 3,4-piperidinyl, 3,5-piperidinyl, 3,6-ρiperidinyl, 1,2-pyrrolidinyl, 1,3 -pyrrolidinyl, 2,3-pyrrolidinyl, 2,4-pyrrolidinyl, 2,5-pyrrolidinyl, 3,4-pyrrolidinyl, 2H-2,3-pyranyl, 2H-2,4-pyranyl, 2H-2,5-pyranyl, 4H-2,3-pyranyl, 4H-2,4-pyranyl, 4H-2,5-pyranyl, 2H-pyran-2-one-3,4-yl, 2H-pyran-2-one-4,5-yl, 4H-ρyran-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 with the provisos that (CH(R38))r

is bonded to E0 and Qb is bonded to highest number substituent position of

each W4 ;

Y0 can be Qb -Qssss wherein Qssss is (CH(R38 ))r-W5 , r5 is an integer

selected from 1 through 3, and 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, 3,4-benzofuranyl, 3,5-benzofuranyl, 3,6-benzofuranyl, 3,7-benzofuranyl, 2,4-benzothiophenyl, 2,5-benzothiophenyl, 2,6-benzothiophenyl, 2,7-benzothiophenyl, 3,4-benzothiophenyl, 3,5-benzothiophenyl, 3,6-benzothiophenyl, 3,7-benzothiophenyl, 2,4-indolyl, 2,5-indolyl, 2,6-indolyl, 2,7-indoly1,3,4-indolyl, 3,5-indolyl, 3,6-indolyl, 3,7-indolyl, 1,4-isoindolyl, 1,5-isoindolyl, 1,6-isoindolyl, 2,4-isoindolyl, 2,5-isoindolyl, 2,6-isoindolyl, 2,7-isoindolyl, 1,3-isoindolyl, 3,4-indazolyl, 3,5-indazolyl, 3,6-indazolyl, 3,7-indazolyl, 2,4-benzoxazolyl, 2,Sbenzoxazolyl, 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-quinohnyl, 2,8-quinolinyl, 3,4-quinolinyl, 3,5-quinolinyl, 3,6-quinolinyl, 3,7-quinolinyl, 3,8-quinolinyl, 4,5-quinolinyl, 4,6-quinolinyl, 4,7-quinolinyl, 4,8-quinolinyl, 1,4-isoquinolinyl, 1,5-isoquinolinyl, 1,6-isoquinolinyl, 1,7-isoquinolinyl, 1,8-isoquinolinyl, 3,4-isoquinolinyl, 3,5-isoquinolinyl, 3,6-isoquinolinyl, 3,7-isoquinolinyl, 3,8-isoquinolinyl, 4,5-isoquinolinyl, 4,6-isoquinolinyl, 4,7-isoquinolinyl, 4,8-isoquinolinyl, 3,4-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 with the proviso that Q is bonded to lowest number substituent position of each

W5 and that (CH(R38))r is bonded to E°;

Y0 can be Qb -Qssssr wherein Qssssr is (CH(R38))r-W6 , 6 r is an integer

selected from 1 through 3, and 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, 3,4-benzofuranyl, 3,5-benzofuranyl, 3,6-benzofuranyl, 3,7-benzofuranyl, 2,4-benzothiophenyl, 2,5-benzothiophenyl, 2,6-benzothiophenyl, 2,7-benzothiophenyl, 3,4-benzothiophenyl, 3,5-benzothiophenyl, 3,6-benzothiophenyl, 3,7-benzothiophenyl, 2,4-indolyl, 2,5-indolyl, 2,6-indolyl, 2,7-indolyl, 3,4-indolyl, 3,5-indolyl, 3,6-indolyl, 3,7-indolyl, 1,4-isoindolyl, 1,5-isoindolyl, 1,6-isoindolyl, 2,4-isoindolyl, 2,5-isoindolyl, 2,6-isoindolyl, 2,7-isoindolyl, 1,3-isoindolyl, 3,4-indazolyl, 3,5-indazolyl, 3,6-indazolyl, 3,7-indazolyl, 2,4-benzoxazolyl, 2,5-benzoxazolyl, 2,6-benzoxazolyl, 2,7-benzoxazolyl, 3,4-benzisoxazolyl, 3,5-benzisoxazolyl, 3,6-benzisoxazolyl, 3,7-benzisoxazolyl, 1,4-naphthyl, 1,5-naphthyl, 1,6-naphthyl, 1,7-naphthyl, 1,8-naphthyl, 2,4-naphthyl, 2,5-naphthyl, 2,6-naphthyl, 2,7-naphthyl, 2,8-naphthyl, 2,4-quinolinyl, 2,5-quinolinyl, 2,6-quinolinyl, 2,7-quinoUnyl, 2,8-quinolinyl, 3,4-quinolinyl, 3,5-quinolinyl, 3,6-quinolinyl, 3,7-quinolinyl, 3,8-quinolinyl, 4,S quinolinyl, 4,6-quinolinyl, 4,7-quinolinyl, 4,8-quinohnyl, 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-isoquinohnyl, 3,4-cinnohnyl, 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 with the proviso that Qb is bonded to highest number substituent position of each

W6 and that (CH(R38))r is bonded to E°.

In an embodiment of compounds of Formula I or a pharmaceutically acceptable salt thereof,

B is formula (V):


wherein D1, D2, J1, J2 and K1 are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more than one can be a covalent bond, no more than one of D1 , D2, J1, J2 and K1

can be O, no more than one of D1 , D2, J1, J2 and K1 can be S, one of D1 ,D2 ,

J1 , J2 and K1 must be a covalent bond when two of D1 , D2 , J1 , J2 and K1 are

O and S, and no more than four of D1 , D2 , J1 , J2 and K1 can be N with the

proviso that R32 ,R33 ,R34 ,R35 ,andR36 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;

R32 ,R33 ,R34 ,R35 ,andR36 can independently be Qb ;

R9, R10, R11, R12, R13, R16, R147, R18, R19, R32, R33, R34, R35,and

R36 are independently selected from the group consisting of hydrido, amidino, guanidino, dialkylsulfonium, trialkylphosphonium, dialkylsulfoniumalkyl, carboxy, heteroaralkylthio, heteroaralkoxy, cycloalkylamino, acylalkyl,

acylalkoxy, aryloylalkoxy, heterocyclyloxy, aralkylaryl, aralkyl, aralkenyl, aralkynyl, heterocyclyl, perhaloaralkyl, aralkylsulfonyl, aralkylsulfonylalkyl, aralkylsulfinyl, aralkylsulfinylalkyl, halocycloalkyl, halocycloalkenyl, cycloalkylsulfinyl, cycloalkylsulfinylalkyl, cycloalkylsulfonyl,

cycloalkylsulfonylalkyl, heteroarylammo, N-heteroarylamino-N-alkylamino, heteroarylaminoalkyl, haloalkylthio, alkanoyloxy, alkoxy, alkoxyalkyl, haloalkoxylalkyl, heteroaralkoxy, cycloalkoxy, cycloalkenyloxy,

cycloalkoxyalkyl, cycloalkylalkoxy, cycloalkenyloxyalkyl, cycloalkylenedioxy, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxy,

halocycloalkenyloxyalkyl, hydroxy, amino, alkoxyamino, thio, nitro, lower alkylamino, alkylthio, alkylthioalkyl, arylamino, aralkylamino, arylthio, arylthioalkyl, heteroaralkoxyalkyl, alkylsulfinyl, alkylsulfinylalkyl,

arylsulfmylalkyl, arylsulfonylalkyl, heteroarylsulfinylalkyl,

heteroarylsulfonylalkyl, alkylsulfonyl, alkylsulfonylalkyl,

haloalkylsulfmylalkyl, haloalkylsulfonylalkyl, alkylsulfonamido,

alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, monoarylamidosulfonyl, arylsulfonamido, diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl, arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, heterocyclylsulfonyl, heterocyclylthio, alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, haloalkanoyl, alkyl, alkenyl, alkynyl, alkenyloxy, alkenyloxyalky,

alkylenedioxy, haloalkylenedioxy, cycloalkyl, cycloalkylalkanoyl,

cycloalkenyl, lower cycloalkylalkyl, lower cycloalkenylalkyl, halo, haloalkyl, haloalkenyl, haloalkoxy, hydroxyhaloalkyl, hydroxyaralkyl, hydroxyalkyl, aminoalkyl, hydoxyheteroaralkyl, haloalkoxyalkyl, aryl, aralkyl, aryloxy, aralkoxy, aryloxyalkyl, saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl, heteroaryloxy, heteroaryloxyalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, carboxyalkyl, carboalkoxy, alkoxycarboxamido, alkylamidocarbonylamido, arylamidocarbonylamido, carboalkoxyalkyl, carboalkoxyalkenyl, carboaralkoxy, carboxamido, carboxamidoalkyl, cyano, carbohaloalkoxy, phosphono, phosphonoalkyl, diaralkoxyphosphono, and diaralkoxyphosphonoalkyl;

R32 and R33 , R33 and R34, R34 and R35, and R35 and R36 can be independently 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 8 contiguous members, a heteroaryl ring having 5 through 6 contiguous members, and an aryl with the proviso that no more than one of the group consisting of spacer pairs R32 and R33 , R33 and R34, R34 and R35, and R35

and R36 can be used at the same time;

R9 and R10 , R10 and R1 1, R1 1 and R12, and R12. and R13 can be independently 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 8 contiguous members, a heteroaryl ring having 5 through 6 contiguous members, and an aryl with the proviso that no more than one of the group consisting of spacer pairs R9 and R10, R10 and R1 1, R11 and R12, andR12

and R13 can be used at the same time;

B can be selected from the group consisting of C3-C8 alkyl, C3-C8 alkenyl, C3-C8 alkynyl, C3-C8 haloalkyl, and C3-C8 haloalkenyl wherein each member of group B may be optionally substituted at any carbon up to and including 6 atoms from the point of attachment of B to A with one or more of the group consisting of R32, R33, R34, R35, and R36,

B can be selected from the group consisting of C3-C10 cycloalkyl, C5-C10 cycloalkenyl, C4-C9 saturated heterocyclyl, and C4-C9 partially saturated heterocyclyl, wherein each ring carbon may be optionally substituted with R33, a ring carbon other than the ring carbon at the point of attachment of B to A may be optionally substituted with oxo provided that no more than one ring carbon is substituted by oxo at the same time, ring carbon and nitrogen atoms adjacent to the carbon atom at the point of attachment may be optionally substituted with R9 or R13, a ring carbon or nitrogen atom adjacent to the R9 position and two atoms from the point of attachment may be substituted with R10, a ring carbon or nitrogen atom adjacent to the R13 position and two atoms

from the point of attachment may be substituted with R12, a ring carbon or

nitrogen atom three atoms from the point of attachment and adjacent to the R10

position may be substituted with R11, a ring carbon or nitrogen atom three

atoms from the point of attachment and adjacent to the R12 position may be

substituted with R33, and a ring carbon or nitrogen atom four atoms from the

point of attachment and adjacent to the R11 and R33 positions may be

substituted with R34;

A is selected from the group consisting of single covalent bond, (W7)rr-(CH(R15))pa and (CH(R15))pa-(W7)rr wherein rr is an integer

selected from 0 through 1, pa is an integer selected from 0 through 6, and W7

is selected from the group consisting of O, S, C(O), C(S), C(O)S, C(S)O,

C(O)N(R7), C(S)N(R7), (R7)NC(O), (R7)NC(S), S(O), S(O)2, S(O)2N(R7),

(R7)NS(O)2, P(O)(R8), N(R7)P(O)(R8), P(O)(R8)N(R7), C(NR7)N(R7),

(R7)NC(NR7), and N(R7);

R7 and R8 are independently selected from the group consisting of hydrido, hydroxy, alkyl, acyl, aroyl, heteroaroyl, and alkoxyalkyl;

R14, R15, R37, and R38 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, carboxyalkyl, carboalkoxy, carboxamide, and carboxamidoalkyl;

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

S(O), S(O)2, ON(R5 ), P(O)(R8 ), and CR39 R40 ;

R5 is selected from the group consisting of hydrido, alkyl, alkoxy, alkoxyalkyl, haloalkyl, acyl, aroyl, and heteroaroyl;

R39 and R40 are independently selected from the group consisting of hydrido, hydroxy, halo, cyano, hydroxyalkyl, acyl, aroyl, heteroaroyl, acylamido, alkoxy, alkyl, alkoxyalkyl, haloalkyl, haloalkoxy, haloalkoxyalkyl, alkylsulfonyl, haloalkylsulfonyl, carboxy, carboxyalkyl, carboalkoxy, carboxamide, and carboxamidoalkyl;

R1 is selected from the group consisting of hydrido, alkyl, alkenyl, haloalkyl, and alkoxyalkyl;

X0 and R2 are independently selected from the group consisting of Z0 - Q, hydrido, alkyl, alkenyl, and halo;

X0 and R2 can be independently selected from the group consisting of amidino, guanidino, dialkylsulfonium, trialkylphosphonium,

dialkylsulfoniumalkyl, heteroarylamino, amino, nitro, alkylamino, arylamino, aralkylamino, alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl,

heteroaralkanoyl, haloalkanoyl, hydroxyhaloalkyl, cyano, and phosphono;

X0 and R1 can be taken together to form a spacer pair wherein the spacer pair forms a linear moiety having from 3 through 6 contiguous atoms connecting the points of bonding of said spacer pair members to form a heterocyclyl ring having from 5 through 8 contiguous members with the proviso that no more than one of the group consisting of spacer pair X0 and R 1

and spacer pair R 7 and R1 can be used at the same time;

R2 and R1 can be taken together to form a spacer pair wherein the spacer pair forms a linear moiety having from 3 through 6 contiguous atoms connecting the points of bonding of said spacer pair members to form a heterocyclyl ring having from 5 through 8 contiguous members with the proviso that no more than one of the group consisting of spacer pair X0 and R1

and spacer pair R 2 and R1 can be used at the same time;

Z0 is selected from the group consisting of covalent single bond, (CR41 R42)q wherein q is an integer selected from 1 through 6, (CH(R41))g-

W0 -(CH(R42 ))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), C(S),

C(O)O, C(S)O, C(O)S, C(S)S, C(O)N(R41), (R41)NC(O), C(S)N(R41),

(R41)NC(S), OC(O)N(R41), (R41)NC(O)O, SC(S)N(R41), (R41)NC(S)S,

SC(O)N(R41), (R41)NC(O)S, OC(S)N(R41), (R41)NC(S)O,

N(R42)C(O)N(R41), (R41)NC(0)N(R42), N(R42)C(S)N(R41 ),

(R41)NC(S)N(R42), S(O), S(O)2, S(O)2N(R41), N(R41)S(O)2, P(O)(R8),

N(R7)P(O)(R8), P(O)(R8)N(R7), N(R41), ON(R41), and (CH(R41))e-W2 -

(CH(R42))n wherein e and h are integers independently selected from 0

through 2 and W2 is selected from the group consisting of CR41 =CR42,

CR41 R42 =C; vinylidene), and ethynylidene (C≡C; 1,2-ethynyl), with the

proviso that R41 and R42 are selected from other than halo and cyano when directly bonded to N and Z0 is directly bonded to the pyridone ring;

R41 and R42 are independently selected from the group consisting of hydrido, hydroxy, 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, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxy, halocycloalkoxyalkyl,

halocycloalkenyloxyalkyl, saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl, heteroaralkyl, heteroarylthioalkyl,

heteroaralkylthioalkyl, alkylsulfonyl, haloalkylsulfonyl, arylsulfonyl, arylsulfonylalkyl, aralkylsulfonyl, cycloalkylsulfonyl, cycloalkylsufonylalkyl, heteroarylsulfonylalkyl, heteroarylsulfonyl, and aralkylsulfonylalkyl;

Q is formula (II):


wherein D1, D2, J 1 , J2 and K1 are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more than one can be a covalent bond, no more than one of D1 , D2 , J 1 , J2 and K 1

can be O, no more than one of D1 , D2 , J 1 , J2 and K 1 can be S, one of D1, D2,

J1, J2 and K1 must be a covalent bond when two of D1 , D2 , J 1 , J2 and K 1 are

O and S, and no more than four of D1 , D2 , J 1 , J2 and K 1 can be N, with the

proviso that R9 , R10, R1 1, R12, and R13 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 can be formula (III) :


wherein D3, D4, J3, and J4 are independently selected from the group

consisting of C, N, O, and S, no more than one of D3, D4, J3, and J4 can be O,

no more than one of D3, D4, J3, and J4 can be S, and no more than three of D1 ,

D2, J1, and J2 can be N with the proviso that R9, R10, R1 1, and R12 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 can be selected from the group consisting of alkyl, alkoxy, alkylamino, alkylthio, haloalkylthio, alkenyl, alkynyl, saturated heterocyclyl, partially saturated heterocyclyl, acyl, aroyl, heteroaroyl, cycloalkyl,

cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkylalkenyl, haloalkyl, haloalkoxy, haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxyalkyl, and halocycloalkenyloxyalkyl;

K is (CR4a R4b )n wherein n is an integer selected from 1 through 2;

R4a and R4b are independently selected from the group consisting of halo, hydrido, hydroxy, cyano, hydroxyalkyl, alkyl, alkenyl, alkoxyalkyl, haloalkyl, haloalkenyl, and cyanoalkyl;

R4a and R4b , when bonded to the same carbon, can be taken together to form a group selected from the group consisting of oxo, 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 contiguous members, and a heterocyclyl ring having 5 through 8 contiguous members;

E0 is E1 , when K is (CR4a R4b )n, wherein E is selected from the group consisting of a covalent single bond, O, S, C(O), C(S), C(O)O, C(S)O, C(O)S,

C(S)S, C(O)N(R ), (R7)NC(O), C(S)N(R7), (R7)NC(S), OC(O)N(R7),

(R7 )NC(O)O, SC(S)N(R7), (R7)NC(S)S, SC(O)N(R7), (R7)NC(O)S,

OC(S)N(R7), (R7)NC(S)O, N(R8)C(O)N(R7), (R7)NC(O)N(RR),

N(R8)C(S)N(R7), (R7)NC(S)N(R8), S(O), S(O)2, S(O)2N(R7), N(R7)S(O)2,

S(O)2N(R7)C(O), C(O)N(R7)S(O)2, P(O)(R8), N(R7)P(O)(R8),

P(O)(R8)N(R7), N(R7), ON(R7), CR4a a=CR4b , ethynylidene {C≡O, 1,2-

ethynyl), and C=CR4a R4b

K can be (CH(R14))j-T wherein j is selected from a integer from 0 through 2 and T is selected from the group consisting of single covalent bond,

O, S, and N(R7) with the proviso that (CH(R14))j is bonded to the pyridone ring;

E0 is E2 , when K is (CH(R14 ))j-T, wherein E2 is selected from the group consisting of a covalent single bond, C(O), C(S), C(O)O, C(S)O, C(O)S, C(S)S, C(O)N(R7), (R7)NC(O), C(S)N(R7), (R7)NC(S), (R7)NC(O)O,

(R7)NC(S)S, (R7)NC(O)S, (R7)NC(S)O, N(R8)C(O)N(R7),

(R7)NC(O)N(R8), N(R8)C(S)N(R7), (R7)NC(S)N(R8), S(O), S(O)2,

S(O)2N(R7), N(R7)S(O)2, S(O)2N(H)C(O), C(O)N(H)S(O)2, P(O)(R8),

N(R7)P(O)(R8), P(O)(R8)N(R7), and N(R7);

K can be G-(CH(R15)) k wherein k is selected from an integer from 1

through 2 and G is selected from the group consisting of O, S, and N(R7) with

the proviso that R is other than hydroxy, cyano, halo, amino, alkylamino, dialkylamino, and sulfhydryl when k is 1;

E0 is E3 when K is G-(CH(R15))k wherein E3 is selected from the group consisting of a covalent single bond, O, S, C(O), C(S), C(O)O, C(S)O, C(O)S, C(S)S, C(0)N(R7), (R7)NC(O), C(S)N(R7), (R7)NC(S),

OC(0)N(R7), (R7)NC(O)O, SC(S)N(R7), (R7)NC(S)S, SC(O)N(R7),

(R7)NC(O)S, OC(S)N(R7), (R7)NC(S)O, N(R8)C(O)N(R7),

(R7)NC(O)N(R8), N(R8)C(S)N(R7), (R7)NC(S)N(R8), S(O), S(O)2,

S(O)2N(R7), N(R7)S(O)2, P(O)(R8), N(R7)P(O)(R8), P(O)(R8)N(R7),

N(R7), ON(R7), CR4a=CR4b, ethynylidene (C≡C; 1,2-ethynyl), and

C=CR4a R4b;

Y° is formula (IV):


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 can be a covalent bond, K2 is independently selected from the group

+

consisting of C, and N , no more than one of D5, D6, J5, and J6 can be O, no

more than one of D5, D6, J5, and J6 can be 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, no more than

three of D5, D6, J5, and J6 can be N when K2 is N+ , and no more than four of

D5 , D6, J5, and J6 can be N when K2 is carbon with the provisos that R16,

R 17, R18 , a,nd R19 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;

R16 and R17 can be 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 having from 5 through 8 contiguous members, a heteroaryl having from 5 through 6 contiguous members, and an aryl;

Qb is selected from the group consisting of NR20 R21, + NR20 R21 R22, oxy, alkyl, alkylaminoalkyl, aminoalkyl, dialkylsulfoniumalkyl, and acylamino wherein R20 , R21, and R22 are independently selected from the group consisting of hydrido, alkyl, hydroxy, alkoxy, alkylamino, dialkylamino, aminoalkyl, and hydroxyalkyl with the provisos that no more than one of R20,

R21, and R22 can be hydroxy, alkoxy, alkylamino, amino, and dialkylamino

and that R20, R21, and R22 must be other than be hydroxy, alkoxy,

alkylamino, ammo, and dialkylamino when K2 is N+ ;

R20 and R2 , R20 and R22, and R21 and R22 can be independently 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 one of the group consisting of spacer pairs R20 and R21, R20 and R22, and R21 and R22

can be used at the same time;

Q can be selected from the group consisting of

N(R26)SO2N(R23)(R24), N(R26)C(O)OR5, N(R26)C(O)SR5,

N(R26 )C(S)OR5 and N(R26 )C(S)SR5 with the proviso that no more than one

of R23, R24, and R26 can be hydroxy, alkoxy, alkylamino, amino, or

dialkylamino when two of the group consisting of R23 , R24 , and R26 are bonded to the same atom;

Q can be selected from the group consisting of dialkylsulfonium,

trialkylphosphonium, C(NR25)NR23 R24 , N(R26)C(NR25)N(R23)(R24),

N(R26)C(O)N(R23)(R24), N(R26)C(S)N(R23)(R24), C(NR25)OR5,

C(O)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), N(R26 )N(R26)SO2N(R23)(R24),

C(NR25 )SR5, C(O)NR23 R24, and C(O)NR23 R24 with the provisos that no

more than one of R23, R24, and R26 can be hydroxy, alkoxy, alkylamino,

amino, or dialkylamino when two of the group consisting of R23, R24, and R26

are bonded to the same atom and that said Qb group is bonded directly to a carbon atom;

R23 , R24, R25, and R26 are independently selected from the group consisting of hydrido, alkyl, hydroxy, alkoxy, alkylamino, dialkylamino, aminoalkyl, and hydroxyalkyl;

R23 and R24 can be 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;

Qs is selected from the group consisting of a single covalent bond,

(CR37 R38 )b-(W0 )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 ofO, S, C(O), C(S), C(O)O, C(S)O, C(O)S, C(S)S, C(O)N(R14),

(R14)NC(O), C(S)N(R14),(R14)NC(S), OC(O)N(R14), SC(S)N(R14), SC(O)N(R14),OC(S)N(R14),N(R15)C(O)N(R14),(R14)NC(O)N(R15),

N(R15)C(S)N(R14), (R14)NC(S)N(R15), S(O), S(O)2, S(O)2N(R14),

N(R14)S(O)2,P(O)(R8),N(R7)P(O)(R8),P(O)(R8)N(R7),N(R14),

ON(R14), (CH(R14))C-W1 -(CH(R15))d 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(O)O, C(S)O, C(O)S, C(S)S, C(O)N(R14),

(R14)NC(O), C(S)N(R14), (R14)NC(S), OC(O)N(R14), (R14)NC(O)O,

SC(S)N(R14),(R14)NC(S)S, SC(O)N(R14),(R14)NC(O)S, OC(S)N(R14),

(R14)NC(S)O,N(R15)C(O)N(R14),(R14)NC(O)N(R15),

N(R15)C(S)N(R14),(R14)NC(S)N(R15), S(O), S(O)2, S(O)2N(R14),

N(R14)S(O)2,P(O)(R8),N(R7)P(O)(R8),P(O)(R8)N(R7),N(R14),

ON(R14), and (CH(R14))e-W2 -(CH(R14))h wherein e and h are integers independently selected from 0 through 2 and W^ is selected from the group

consisting of CR4a =CR4b , ethynylidene (G≡C; 1,2-ethynyl), and C=CR4a R4b

with the provisos that R14 and R15 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 ;

Y0 can be Qb-Qss wherein Qss is selected from the group consisting of

(CR37 R38)f wherein f is an integer selected from 1 through 6, (CH(R14))c-

W1 -(CH(R15))d wherein c and d are integers independently selected from 1 through 4, and W 1 is selected from the group consisting of W1 is selected from the group consisting of O, S, C(O), C(S), C(O)O, C(S)O, C(O)S, C(S)S, C(O)N(R14),(R14)NC(O), C(S)N(R14),(R14)NC(S), OC(O)N(R14),

(R14)NC(O)O,SC(S)N(R14),(R14)NC(S)S, SC(O)N(R14),(R14)NC(O)S,

OC(S)N(R14),(R14)NC(S)O,N(R15)C(O)N(R14),(R14)NC(O)N(R15),

N(R 15)C(S)N(R14), (R14 )NC(S)N(R15), S(O), S(O)2, S(O)2N(R14),

N(R14)S(O)2, P(O)(R8), N(R7)P(O)(R8), P(O)(R8 )N(R7), N(R14),

ON(R14), and (CH(R14))e-W2 -(CH(R15))h wherein e and h are integers

independently selected from 0 through 2 and W2 is selected from the group

consisting of CR4a =CR4b , ethynylidene (C≡C; 1,2-ethynyl), and C=CR4a R4b

with the provisos that R 14 and R15 are selected from other than halo and cyano

when directly bonded to N and that (CR37 R38)f , (CH(R15))c, and

(CH(R15))e are bonded to E°;

Y 0 can be Qb -Qsss wherein Qsss is (CH(R38 ))r-W3 , r is an integer

selected from 1 through 3, and W 3 is selected from the group consisting of 1,1-cyclopropyl, 1,2-cyclopropyl, 1,1-cyclobutyl, 1,2-cyclobutyl, 1,2-cyclohexyl, 13-cyclohexyl, 1,4-cyclohexyl, 1,2-cyclopentyl, 13-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, 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, 2,3-pyrrolidinyl, 2,4-pyrrolidinyl, 2,5-pyrrolidinyl, 3,4-pyrrolidinyl, 2H-23-pyranyl, 2H-2,4-ρyranyl, 2H-2,5-pyranyl, 4H-2,3-pyranyl, 4H-2,4-pyranyl, 4H-2,5-pyranyl, 2H-pyran-2-one-3,4-yl, 2H-pyran-2-one-4,5-yl, 4H-pyran-4-one-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 with the proviso that (CH(R38))r

is bonded to E0 and Qb is bonded to lowest numbered substituent position of

each W3;

Y can be Q -QS wherein QSSSr is (CH(R38 ))r-W4 , r is an integer

selected from 1 through 3, and W4 is selected from the group consisting of 1,2-cyclobutyl, 1,2-cyclohexyl, 1,3-cyclohexyl, 1,4-cyclohexyl, 1,2-cyclopentyl, 1,3-cyclopentyl, 2,3-morpholinyl, 2,4-morpholinyl, 2,5-morpholinyl, 2,6-morpholinyl, 3,4-morpholinyl, 3,5-morpholinyl, 1,2-piperazinyl, 1,3-piperazinyl, 1,4-piperazinyl, 2,3-piperazinyl, 2,5-piperazinyl, 2,6-piperazinyl, 1,2-piperidinyl, 1,3-piperidinyl, 1,4-piρeridinyl, 2,3-piperidinyl, 2,4-ρiρeridinyl, 2,5-piρeridinyl, 2,6-piperidinyl, 3,4-piperidinyl, 3,5-piperidinyl, 3,6-piperidinyl, 1,2-pyrrolidinyl, 1,3-pyrrolidinyl, 2,3-pyrrolidinyl, 2,4-pyrrolidinyl, 2,5-pyrrolidinyl, 3,4-pyrrolidinyl, 2H-2,3-ρyranyl, 2H-2,4-ρyranyl, 2H-2,5-ρyranyl, 4H-2,3-pyranyl, 4H-2,4-pyranyl, 4H-2,5-pyranyl, 2H-pyran-2-one-3,4-yl, 2H-pyran-2-one-4,5-yl, 4H-pyran-4-one-2,3-yl, 2,3-tetrahydrofuranyl, 2,4-tetrahydrofuranyl, 2,5-tetrahydrofuranyl, 3,4-tetrahydrofuranyl, 2,3-tetrahydropyranyl, 2,4-tetrahydropyranyl, 2,5-tetrahydropyranyl, 2,6-tetrahydropyranyl, 3,4-tetrahydropyranyl, and 3,5-tetrahydropyranyl with the provisos that (CH(R38 ))r

is bonded to E0 and Qb is bonded to highest number substituent position of

each W4

Y0 can be Qb -Qssss wherein Qssss is (CH(R38 ))r-W5 , r is an integer

selected from 1 through 3, and 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, 3,4-benzofuranyl, 3,5-benzofuranyl, 3,6-benzofuranyl, 3,7-benzofuranyl, 2,4-benzothiophenyl, 2,5-benzothiophenyl, 2,6-benzothiophenyl, 2,7-benzothiophenyl, 3,4-benzothiophenyl, 3,5-benzothiophenyl, 3,6-benzothiophenyl, 3,7-benzothiophenyl, 2,4-indolyl, 2,5-indolyl, 2,6-indolyl, 2,7-indolyl, 3,4-indolyl, 3,Sindolyl, 3,6-indolyl, 3,7-indolyl, 1,4-isoindolyl, 1,5-isoindolyl, 1,6-isoindolyl, 2,4-isoindolyl, 2,Sisoindolyl, 2,6-isoindolyl, 2,7-isoindolyl, 1,3-isoindolyl, 3,4-indazolyl, 3,5-indazolyl, 3,6-indazolyl, 3,7-indazolyl, 2,4-benzoxazolyl, 2,5-benzoxazolyl, 2,6-benzoxazolyl, 2,7-benzoxazolyl, 3,4-benzisoxazolyl, 3,5-benzisoxazolyl, 3,6-benzisoxazolyl, 3,7-benzisoxazolyl, 1,4-naphthyl, 1,5-naphthyl, 1,6-naphthyl, 1,7-naphthyl, 1,8-

naphthyl, 2,4-naphthyl, 2,5-naphthyl, 2,6-naphthyl, 2,7-naphthyl, 2,8-naphthyl, 2,4-quinolinyl, 2,5-quinolinyl, 2,6-quinolinyl, 2,7-quinoHnyl, 2,8-quinolinyl, 3,4-quinolinyl, 3,5-quinolinyl, 3,6-quinolinyl, 3,7-quinolinyl, 3,8-quinolinyl, 4,5-quinolinyl, 4,6-quinolinyl, 4,7-quinolinyl, 4,8-quinolinyl, 1,4-isoquinolinyl, 1,5-isoquinolinyl, 1,6-isoquinolinyl, 1,7-isoquinolinyl, 1,8-isoquinolinyl, 3,4-isoquinolinyl, 3,5-isoquinolinyl, 3,6-isoquinolinyl, 3,7-isoquinolinyl, 3,8-isoquinolinyl, 4,5-isoquinolinyl, 4,6-isoquinolinyl, 4,7-isoquinolinyl, 4,8-isoquinolinyl, 3,4-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 with the proviso that Q is bonded to lowest number substituent position of each

W5 and that (CH(R3 8 ))r is bonded to E0;

Y0 can be Qb -Qssssr wherein Qssssr is (CH(R38 ))r-W6 , r is an integer

selected from 1 through 3, and 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, 3,4-benzofuranyl, 3,5-benzofuranyl, 3,6-benzofuranyl, 3,7-benzofuranyl, 2,4-benzothiophenyl, 2,5-benzothiophenyl, 2,6-benzothiophenyl, 2,7-benzothiophenyl, 3,4-benzothiophenyl, 3,5-benzothiophenyl, 3,6-benzothiophenyl, 3 ,7-benzothiophenyl, 2,4-indolyl, 2r5-indolyl, 2,6-indolyl, 2,7-indolyl, 3,4-indolyl, 3,5-indolyl, 3,6-indolyl, 3,7-indolyl, 1,4-isoindolyl, 1,5-isoindolyl, 1,6-isoindolyl, 2,4-isoindolyl, 2,5-isoindolyl, 2,6-isoindolyl, 2,7-isoindolyl, 1,3-isoindolyl, 3,4-indazolyl, 3,5-indazolyl, 3,6-indazolyl, 3,7-indazolyl, 2,4-benzoxazolyl, 2,5-benzoxazolyl, 2,6-benzoxazolyl, 2,7-benzoxazolyl, 3,4-benzisoxazolyl, 3,5-benzisoxazolyl, 3,6-benzisoxazolyl, 3,7-benzisoxazolyl, 1,4-naphthyl, 1,5-naphthyl, 1,6-naphthyl, 1,7-naphthyl, 1,8-naphthyl, 2,4-naphthyl, 2,5-naphthyl, 2,6-naphthyl, 2,7-naphthyl, 2,8-naphthyl, 2,4-quinolinyl, 2,5-quinolinyl, 2,6-quinolinyl, 2,7-quinolinyl, 2,8-quinolinyl, 3,4-quinolinyl, 3,Squinolinyl, 3,6-quinolinyl, 3,7-quinolinyl, 3,8-quinolinyl, 4,5-quinolinyl, 4,6-quinolinyl, 4,7-quinolinyl, 4,8-quinoHnyl, 1 ,4-isoquinolinyl, 1,5-isoquinolinyl, 1,6-isoquinolinyl, 1,7-isoquinolinyl, 1,8-isoquinolinyl, 3,4-isoquinolinyl, 3,5-isoquinolinyl, 3,6-isoquinolinyl, 3,7-isoquinolinyl, 3,8-isoquinolinyl, 4,5-isoquinolinyl, 4,6-isoquinolinyl, 4,7-isoquinolinyl, 4,8-isoquinolinyl, 3,4-cinnolinyl, 3,5-cinnolinyl, 3,6-cinnolinyl, 3,7-cinnolinyl, 3,8- cinnolinyl, 4,5-cinnolinyl, 4,6-cinnolinyl, 4,7-cinnolinyl, and 4,8-cinnolinyl with the proviso that Q is bonded to highest number substituent position of each

W6 and that (CH(R38))r is bonded to E0.

In another embodiment of compounds of Formula I or a

pharmaceutically acceptable salt thereof,

B is formula (V):


wherein D1 , D2 , J 1 , J2 and K 1 are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more than one can be a covalent bond, no more than one of D1 , D2 , J 1 , J2 and K 1

can be O, no more than one of D1 , D2 , J 1 , J2 and K 1 can be S, one of D 1, D2,

J1, J2 and K 1 must be a covalent bond when two of D1 , D2 , J 1 , J2 and K 1 are

O and S, and no more than four of D1 , D2 , J 1 , J2 and K 1 can be N;

R32, R33, R34, R35, and R36 can independently be Qb;

R9, R10, R1 1, R12, R 13, R 16, R17, R18, R19, R32, R33, R34, R35, and

R are independently selected from the group consisting of hydrido, amidino, guanidino, dialkylsulfonium, trialkylphosphonium, dialkylsulfoniumalkyl, carboxy, heteroaralkylthio, heteroaralkoxy, cycloalkylamino, acylalkyl, acylalkoxy, aryloylalkoxy, heterocyclyloxy, aralkylaryl, aralkyl, aralkenyl, aralkynyl, heterocyclyl, perhaloaralkyl, aralkylsulfonyl, aralkylsulfonylalkyl, aralkylsulfinyl, aralkylsulfinylalkyl, halocycloalkyl, halocycloalkenyl, cycloalkylsulfinyl, cycloalkylsulfinylalkyl, cycloalkylsulfonyl,

cycloalkylsulfonylalkyl, heteroarylammo, N-heteroarylamino-N-alkylamino,

heteroarylaminoalkyl, haloalkylthio, alkanoyloxy, alkoxy, alkoxyalkyl, haloalkoxylalkyl, heteroaralkoxy, cycloalkoxy, cycloalkenyloxy,

cycloalkoxyalkyl, cycloalkylalkoxy, cycloalkenyloxyalkyl, cycloalkylenedioxy, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxy,

halocycloalkenyloxyalkyl, hydroxy, amino, alkoxyamino, thio, nitro, lower alkylamino, alkylthio, alkylthioalkyl, arylamino, aralkylamino, arylthio, arylthioalkyl, heteroaralkoxyalkyl, alkylsulfinyl, alkylsulfinylalkyl,

arylsulfinylalkyl, arylsulfonylalkyl, heteroarylsulfinylalkyl,

heteroarylsulfonylalkyl, alkylsulfonyl, alkylsulfonylalkyl,

haloalkylsulfmylalkyl, haloalkylsulfonylalkyl, alkylsulfonamido,

alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, monoarylamidosulfonyl, arylsulfonamido, diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl, arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, heterocyclylsulfonyl, heterocyclylthio, alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, haloalkanoyl, alkyl, alkenyl, alkynyl, alkenyloxy, alkenyloxyalky,

alkylenedioxy, haloalkylenedioxy, cycloalkyl, cycloalkylalkanoyl,

cycloalkenyl, lower cycloalkylalkyl, lower cycloalkenylalkyl, halo, haloalkyl, haloalkenyl, haloalkoxy, hydroxyhaloalkyl, hydroxyaralkyl, hydroxyalkyl, aminoalkyl, hydoxyheteroaralkyl, haloalkoxyalkyl, aryl, aralkyl, aryloxy, aralkoxy, aryloxyalkyl, saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl, heteroaryloxy, heteroaryloxyalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, carboxyalkyl, carboalkoxy, alkoxycarboxamido, alkylamidocarbonylamido, arylamidocarbonylamido, carboalkoxyalkyl, carboalkoxyalkenyl, carboaralkoxy, carboxamido, carboxamidoalkyl, cyano, carbohaloalkoxy, phosphono, phosphonoalkyl, diaralkoxyphosphono, and diaralkoxyphosphonoalkyl ;

B can be selected from the group consisting of C3-C8 alkyl, C3-C8 alkenyl, C3-C8 alkynyl, C3-C8 haloalkyl, and C3-C8 haloalkenyl wherein each member of group B may be optionally substituted at any carbon up to and including 6 atoms from the point of attachment of B to A with one or more of the group consisting of R32, R33, R34, R35, and R36,

B can be selected from the group consisting of C3-C10 cycloalkyl, C5-C10 cycloalkenyl, C4-C9 saturated heterocyclyl, and C4-C9 partially saturated heterocyclyl , wherein each ring carbon may be optionally substituted with R33, a ring carbon other than the ring carbon at the point of attachment of B to A may be optionally substituted with oxo provided that no more than one ring carbon is substituted by oxo at the same time, ring carbon and mtrogen atoms adjacent to the carbon atom at the point of attachment may be optionally substituted with R9 or R13, a ring carbon or nitrogen atom adjacent to the R9 position and two atoms from the point of attachment may be substituted with

R10, a ring carbon or nitrogen atom adjacent to the R13 position and two atoms

from the point of attachment may be substituted with R12, a ring carbon or

nitrogen atom three atoms from the point of attachment and adjacent to the R10

position may be substituted with R11 , a ring carbon or nitrogen atom three

atoms from the point of attachment and adjacent to the R12 position may be

substituted with R33, and a ring carbon or nitrogen atom four atoms from the

point of attachment and adjacent to the R11 and R33 positions may be

substituted with R34;

A is selected from the group consisting of single covalent bond,

(W7)rr-(CHCR15))pa and (CH(R15))pa-(W7)rr wherein rr is an integer

selected from 0 through 1, pa is an integer selected from 0 through 6, and W7

is selected from the group consisting of O, S, C(O), C(S), C(O)S, C(S)O,

C(O)N(R7), C(S)N(R7), (R7)NC(O), (R7)NC(S), S(O), S(O)2, S(O)2N(R7),

(R7)NS(O)2, C(NR7)N(R7), (R7)NC(NR7), and N(R7);

R7 and R8 are independently selected from the group consisting of hydrido, hydroxy, alkyl, and alkoxyalkyl;

R 14, R 15, R37, and R38 are independently selected from the group consisting of hydrido, hydroxy, halo, alkyl, alkoxyalkyl, haloalkyl, haloalkoxy, and haloalkoxyalkyl;

ψ is selected from the group consisting of NR5 , O, C(O), C(S), S,

S(O), S(O)2, and CR39 R40 ;

R5 is selected from the group consisting of hydrido, alkyl, and alkoxy;

R39 and R40 are independently selected from the group consisting of hydrido, hydroxy, halo, hydroxyalkyl, alkyl, alkoxyalkyl, haloalkyl, haloalkoxy, and haloalkoxyalkyl;

R1 is selected from the group consisting of hydrido, alkyl, alkenyl, haloalkyl, and alkoxyalkyl;

X0 and R2 are independently selected from the group consisting of Z0 -Q, hydrido, alkyl, alkenyl, and halo;

X0 and R2 can be independently selected from the group consisting of amidino, guanidino, dialkylsulfonium, trialkylphosphonium,

dialkylsulfoniumalkyl, heteroarylammo, amino, nitro, alkylamino, arylamino, aralkylamino, alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl,

heteroaralkanoyl, haloalkanoyl, hydroxyhaloalkyl, cyano, and phosphono;

Z0 is selected from the group consisting of covalent single bond, (CR41 R42)q wherein q is an integer selected from 1 through 2, (CH(R41))g-

W0 -(CH(R42))p wherein g and p are integers independently selected from 0 through 2 and W is selected from the group consisting of O, S, C(O), C(S), C(O)O, C(S)O, C(O)S, C(S)S, C(O)N(R41), (R41)NC(O), C(S)N(R41),

(R41)NC(S), OC(O)N(R41), (R41)NC(O)O, SC(S)N(R41), (R41)NC(S)S,

SC(O)N(R41), (R41)NC(O)S, OC(S)N(R41), (R41)NC(S)O,

N(R42)C(O)N(R41), (R41)NC(O)N(R42), N(R42)C(S)N(R41),

(R 41)NC(S)N(R42), S(O), S(O)2, S(O)2N(R41), N(R41)S(O)2, N(R41),

ON(R41), and (CH(R41))e- W2 -(CH(R44))h wherein e and h are integers

independently selected from 0 through 2 and W2 is selected from the group

consisting of CR41 =CR42, CR41 R42 =C; vinylidene), and ethynylidene (C≡C;

1 ,2-ethynyl), with the proviso that R41 and R42 are selected from other than halo and cyano when directly bonded to N and Z0 is directly bonded to the pyridone ring;

R41 and R42 are independently selected from the group consisting of hydrido, hydroxy, 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, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxy, halocycloalkoxyalkyl,

halocycloalkenyloxyalkyl, saturated heterocyclyl, partially saturated

heterocyclyl, heteroaryl, and heteroaralkyl;

Q is formula (II):


consisting of C, N, O, S and a covalent bond with the provisos that no more than one can be a covalent bond, no more than one of D1 , D2 , J 1 , J2 and K 1

can be O, no more than one of D1 , D2 , J 1 , J2 and K 1 can be S, one of D , D ,

J1 , J2 and K1 mustbe a covalentbond when two of D1 , D2 , J 1 , J2 and K 1 are

O and S, and no more than four of D1 , D2 , J 1 , J2 and K 1 can be N, with the

proviso that R9 , R10 , R1 1 , R12 , and R13 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 can be selected from the group consisting of alkyl, alkoxy, alkylamino, alkylthio, haloalkylthio, saturated heterocyclyl, alkyl, partially saturated heterocyclyl, acyl, aroyl, heteroaroyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkylalkenyl, haloalkyl, haloalkoxy, haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxyalkyl,

haloalkenyloxyalkyl, halocycloalkoxyalkyl, and halocycloalkenyloxyalkyl;

K is (CR4a R4b )n wherein n is the integer 1 ;

R4a and R4b are independently selected from the group consisting of halo, hydrido, hydroxy, hydroxyalkyl, alkyl, alkoxyalkyl, and haloalkyl;

E0 is E1 , when K is (CR4a R4b)n, wherein E is selected from the group consisting of a covalent single bond, O, S, C(O), C(S), C(O)O, C(S)O, C(O)S,

C(S)S, C(O)N(R7), (R7)NC(O), C(S)N(R7), (R7)NC(S), OC(O)N(R7),

(R7)NC(0)0, SC(S)N(R7), (R7)NC(S)S, SC(O)N(R7), (R7)NC(O)S,

OC(S)N(R7), (R7)NC(S)O, N(R8)C(O)N(R7), (R7)NC(O)N(R8),

N(R8)C(S)N(R7), (R7)NC(S)N(R8), S(O), S(O)2, S(O)2N(R7), N(R7)S(O)2,

S(O)2N(R7)C(O), C(O)N(R7)S(O)2, N(R7), ON(R7), CR4a =CR4b ,

ethynylidene (C≡C; 1,2-ethynyl), and C=CR4a R4b ;

K can be (CH(R14 )) :-T wherein j is selected from a integer from 0 through 1 and T is selected from the group consisting of single covalent bond,

O, S, and N(R7) with the proviso that (CH(R 14)); is bonded to the pyridone ring;

E0 is E2 , when K is (CH(R14 ))j-T, wherein E2 is selected from the group consisting of a covalent single bond, C(O), C(S), C(O)O, C(S)O, C(O)S,

C(S)S, C(O)N(R7), (R7)NC(O), C(S)N(R7), (R7)NC(S), (R7)NC(O)O,

(R7)NC(S)S, (R7)NC(O)S, (R7)NC(S)O, N(R8)C(O)N(R7),

(R7)NC(O)N(R8), N(R8)C(S)N(R7), (R7)NC(S)N(R8), S(O), S(0)2,

S(O)2N(R7), N(R7)S(O)2, S(O)2N(H)C(O), C(O)N(H)S(O)2, and N(R7);

K can be G-(CH(R 15 )) k wherein k is the integer 1 and G is selected

from the group consisting of O, S, and N(R7 );

E is E when K is G-(CH(R 15 )) k wherein E is selected from the group consisting of a covalent single bond, O, S, C(O), C(S), C(O)O, C(S)O, C(O)S, C(S)S, C(O)N(R7), (R7)NC(O), C(S)N(R7), (R7)NC(S),

OC(O)N(R7), (R7)NC(O)O, SC(S)N(R7), (R7)NC(S)S, SC(O)N(R7),

(R7)NC(O)S, OC(S)N(R7), (R7)NC(S)O, N(R8)C(O)N(R7),

(R7)NC(O)N(R8), N(R8)C(S)N(R7), (R7)NC(S)N(R8), S(O), S(O)2,

S(O)2N(R7), N(R7)S(O)2, N(R7), ON(R7), CR4a=CR4b, ethynylidene (C≡C;

1,2-ethynyl), and C=CR4a R4b;

Y° is formula (IV):


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 can be a covalent bond, K2 is independently selected from the group

consisting of C, and N , no more than one of D5 , D6 , J5 , and J6 can be O, no

more than one oi D5, D6, J5, and J6 can be 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, no more than

three of D5 , D6 , J5 , and J6 can be N when K2 is N+ , and no more than four of

D5, D6, J5, and J6 can be N when K is carbon with the provisos that R ,

R 17, R18, and R 19 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;

Qb is selected from the group consisting of NR20 R21, + NR20 R21 R22, oxy, alkyl, alkylaminoalkyl, aminoalkyl, dialkylsulfoniumalkyl, and acylamino wherein R20 , R21 , and R22 are independently selected from the group consisting of hydrido, alkyl, hydroxy, alkoxy, alkylamino, dialkylamino, aminoalkyl, and hydroxyalkyl with the provisos that no more than one of R20,

R 21 , and R22 can be hydroxy, alkoxy, alkylamino, amino, and dialkylamino

and that R20 , R21 , and R22 must be other than be hydroxy, alkoxy,

alkylamino, amino, and dialkylamino when K2 is N+ ;

Qb can be selected from the group consisting of

N(R26)SO2N(R23)(R24), N(R26)C(O)OR5, N(R26)C(O)SR5,

N(R26)C(S)OR5 and N(R26)C(S)SR5 with the proviso that no more than one

of R23, R24, andR26 can be hydroxy, alkoxy, alkylamino, amino, or

dialkylamino when two of the group consisting of R23, R24, and R26 are bonded to the same atom;

Qb can be selected from the group consisting of dialkylsulfonium,

trialkylphosphonium, C(NR25)NR23 R24 , N(R26)C(NR25)N(R23)(R24),

N(R26)C(O)N(R23)(R24), N(R26)C(S)N(R23)(R24), C(NR25)OR5,

C(O)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), N(R26)N(R26)SO2N(R23)(R24),

C(NR25 )SR5 , C(O)NR23 R24 , and C(0)NR23 R24 with the provisos that no

more than one of R23 , R24 , and R26 can be hydroxy, alkoxy, alkylamino,

amino, or dialkylamino when two of the group consisting of R23 , R24 , and R26

are bonded to the same atom and that said Q group is bonded directly to a carbon atom;

R23 , R24 , R25 , and R26 are independently selected from the group consisting of hydrido, alkyl, hydroxy, alkoxy, alkylamino, dialkylamino, aminoalkyl, and hydroxyalkyl;

Qs is selected from the group consisting of a single covalent bond,

(CR37 R38 )b -(W0 )az wherein az is an integer selected from 0 through 1 , b is an integer selected from 1 through 2, and W is selected from the group consisting of O, S, C(O), C(S), C(O)O, C(S)O, C(O)S, C(S)S, C(O)N(R14),

(R14)NC(0), C(S)N(R14), (R14)NC(S), OC(O)N(R14), SC(S)N(R14),

SC(O)N(R14), OC(S)N(R14), N(R15)C(O)N(R14), (R14)NC(O)N(R15),

N(R15)C(S)N(R14), (R14)NC(S)N(R15), S(O), S(O)2, S(O)2N(R14),

N(R14)S(O)2, N(R 14), ON(R14), and (CH(R14))C-W 1 -(CH(R15))d wherein

1 c and d are integers independently selected from 1 through 2, and W is selected from the group consisting of O, S, C(O), C(S), C(0)O, C(S)O, C(O)S, C(S)S, C(O)N(R14),(R14)NC(O), C(S)N(R14),(R14)NC(S), OC(O)N(R14),

(R14)NC(0)O, SC(S)N(R14),(R14)NC(S)S, SC(O)N(R14), (R14)NC(O)S,

OC(S)N(R14),(R14)NC(S)O,N(R15)C(O)N(R14),(R14)NC(0)N(R15), N(R15)C(S)N(R14),(R14)NC(S)N(R15), S(O), S(O)2, S(0)2N(R14), .

N(R 14)S(O)2, N(R14), ON(R14), and (CH(R14))e-W2 -(CH(R15))h wherein

e and h are integers independently selected from 0 through 2 and W^ is

selected from the group consisting of CR4a =CR4b , ethynylidene (C≡C; 1,2-

ethynyl), and C=CR4a R4b with the provisos that R and R are selected from other than halo and cyano when directly bonded to N and that

(CR37 R38 )b, (CH(R14 ))C, (CH(R14 ))e and are bonded to E0;

Y0 can be Qb -Qss wherein Qss . is selected from the group consisting of

(CR37 R38)f wherein f is an integer selected from 1 through 4, (CH(R14))c-

W1-(CH(R15))d wherein c and d are integers independently selected from 1

through 2, and W is selected from the group consisting of W is selected from the group consisting of O, S, C(O), C(S), C(O)O, C(S)0, C(O)S, C(S)S, C(O)N(R14), (R14)NC(O), C(S)N(R14), (R14)NC(S), OC(0)N(R14),

(R14)NC(O)O, SC(S)N(R14), (R14)NC(S)S, SC(O)N(R14), (R14)NC(O)S,

OC(S)N(R14), (R14)NC(S)O, N(R15)C(O)N(R 14), (R14)NC(O)N(R15),

N(R15)C(S)N(R 14), (R14)NC(S)N(R15), S(O), S(O)2, S(O)2N(R14),

N(R14)S(O)2, N(R14), ON(R14), and (CH(R 14))e-W2-(CH(R15))h wherein

e and h are integers independently selected from 0 through 2 and W^ is selected from the group consisting of CR4a =CR4b , ethynylidene (C≡C; 1,2-

ethynyl), and C=CR4a R4b with the provisos that R14 and R15 are selected

from other than halo when directly bonded to N and that (CR37 R38)f,

(CH(R 15))c, af nd (CH(R15))e are bonded to E0;

Y0 can be Qb -Qsss wherein Qsss is (CH(R38))r-W3 , r is an integer

selected from 1 through 2, and W3 is selected from the group consisting of 1,1-cyclopropyl, 1,2-cyclopropyl, 1,1-cyclobutyl, 1,2-cyclobutyl, 1,2-cyclohexyl, 13-cyclohexyl, 1,4-cyclohexyl, 1,2-cyclopentyl, 13-cycloρentyl, 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, 23-piperazinyl, 2,5-piperazinyl, 2,6-piperazinyl, 1,2-ρiperidinyl, 1,3-ρiperidinyl, 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, 1,3-pyrrolidinyl, 2,3-pyrrolidinyl, 2,4-pyrrolidinyl, 2,5-ρyrrolidinyl, 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,Syl, 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 with the proviso that (CH(R38))r

is bonded to E0 and Qb is bonded to lowest numbered substituent position of

each W3;

Y0 can be Qb -Qsssr wherein Qsssr is (CH(R38 ))r-W4 , r is an integer

selected from 1 through 2, and W4 is selected from the group consisting of 1 ,2-cyclobutyl, 1,2-cyclohexyl, 1,3-cyclohexyl, 1,4-cyclohexyl, 1,2-cyclopentyl, 1,3-cyclopentyl, 23-morpholinyl, 2,4-morpholinyl, 2,5-morpholinyl, 2,6-morpholinyl, 3,4-morpholinyl, 3,5-morpholinyl, 1,2-piperazinyl, 13-piperazinyl, 1,4-ρiperazinyl, 23-piperazinyl, 2,5-piperazinyl, 2,6-piperazinyl, 1,2-piperidinyl, 13-piρeridinyl, 1,4-piperidinyl, 2,3-piperidinyl, 2,4-piperidinyl, 2,5-piperidinyl,

2,6-piperidinyl, 3,4-piperidinyl, 3,5-piperidinyl, 3,6-piperidinyl, 1,2-pyrrolidinyl, 1,3-pyrrolidinyl, 2,3-pyrrolidinyl, 2,4-pyrrolidinyl, 2,5-pyrrolidinyl, 3,4-pyrrolidinyl, 2H-2,3-ρyranyl, 2H-2,4-ρyranyl, 2H-2,5-ρyranyl, 4H-2,3-ρyranyl, 4H-2,4-ρyranyl, 4H-2,5-ρyranyl, 2H-pyran-2-one-3,4-yl, 2H-ρyran-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 with the provisos that (CH(R38))r

is bonded to E0 and Qb is bonded to highest number substituent position of

each W4 ;

Y0 can be Qb -Qssss wherein Qssss is (CH(R38 ))r-W5 , r is an integer

selected from 1 through 2, and W5 is selected from the group consisting of 1,4-indenyl, 1,5-indenyl, 1,6-indenyl, 1,7-indenyl, 2,7-indenyl, 2,6-indenyl, 2,5-indenyl, 2,4-indenyl, 3,4-indenyl, 3,5-indenyl, 3,6-indenyl, 3,7-indenyl, 2,4-benzofuranyl, 2,5-benzofuranyl, 2,6-benzofuranyl, 2,7-benzofuranyl, 3,4-benzofuranyl, 3,5-benzofuranyl, 3,6-benzofuranyl, 3,7-benzofuranyl, 2,4-benzothiophenyl, 2,5-benzothiophenyl, 2,6-benzothiophenyl, 2,7-benzothiophenyl, 3,4-benzothiophenyl, 3,5-benzothiophenyl, 3,6-benzothiophenyl, 3,7-benzothiophenyl, 2,4-indolyl, 2,5-indolyl, 2,6-indolyl, 2,7-indolyl, 3,4-indolyl, 3,5-indolyl, 3,6-indolyl, 3,7-indolyl, 1,4-isoindolyl, 1,5-isoindolyl, 1,6-isoindolyl, 2,4-isoindolyl, 2,5-isoindolyl, 2,6-isoindolyl, 2,7-isoindolyl, 1,3-isoindolyl, 3,4-indazolyl, 3,5-indazolyl, 3,6-indazolyl, 3,7-indazolyl, 2,4-benzoxazolyl, 2,5-benzoxazolyl, 2,6-benzoxazolyl, 2,7-benzoxazolyl, 3,4-benzisoxazolyl, 3,5-benzisoxazolyl, 3,6-benzisoxazolyl, 3,7-benzisoxazolyl, 1,4-naphthyl, 1,5-naphthyl, 1,6-naphthyl, 1,7-naphthyl, 1,8-naphthyl, 2,4-naphthyl, 2,5-naphthyl, 2,6-naphthyl, 2,7-naphthyl, 2,8-naphthyl, 2,4-quinolinyl, 2,5-quinolinyl, 2,6-quinolinyl, 2,7-quinolinyl, 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,Sisoquinolinyl, 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 with the proviso that Q is bonded to lowest number substituent position of each

W5 and that (CH(R38))r is bonded to E0;

Y0 can be Qb -Qssssr wherein Qssssr is (CH(R38 ))r-W6 , r is an integer

selected from 1 through 2, and 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, 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-benzotbiophenyl, 3,5-benzothiophenyl, 3,6-benzothiophenyl, 3,7-benzothiophenyl, 2,4-indolyl, 2,5-indolyI, 2,6-indolyl, 2,7-indolyl, 3,4-indolyl, 3,5-indolyl, 3,6-indolyl, 3,7-indolyl, 1,4-isoindolyl, 1,5-isoindolyl, 1,6-isoindolyl, 2,4-isoindolyl, 2,5-isoindolyl, 2,6-isoindolyl, 2,7-isoindolyl, 1,3-isoindolyl, 3,4-indazolyl, 3,5-indazolyl, 3,6-indazolyl, 3,7-indazolyl, 2,4-benzoxazolyl, 2,5-benzoxazolyl, 2,6-benzoxazolyl, 2,7-benzoxazolyl, 3,4-benzisoxazolyl, 3,5-benzisoxazolyl, 3,6-benzisoxazolyl, 3,7-benzisoxazolyl, 1,4-naphthyl, 1,5-naphthyl, 1,6-naphthyl, 1,7-naphthyl, 1,8-naphthyl, 2,4-naphthyl, 2,5-naphthyl, 2,6-naphthyl, 2,7-naphthyl, 2,8-naphthyl, 2,4-quinolinyl, 2,Squinolinyl, 2,6-quinolinyl, 2,7-quinolinyl, 2,8-quinolinyl, 3,4-quinolinyl, 3,Squinolinyl, 3,6-quinolinyl, 3,7-quinolinyl, 3,8-quinolinyl, 4,5-quinolinyl, 4,6-quinolinyl, 4,7-quinolinyl, 4,8-quinolinyl, 1,4-isoquinolinyl, 1,5-isoquinolinyl, 1,6-isoquinolinyl, 1,7-isoquinolinyl, 1,8-isoquinolinyl, 3,4-isoquinolinyl, 3,5-isoquinolinyl, 3,6-isoquinolinyl, 3,7-isoquinolinyl, 3,8-isoquinolinyl, 4,5-isoquinolinyl, 4,6-isoquinolinyl, 4,7-isoquinolinyl, 4,8-isoquinoUnyl, 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 with the proviso that Q is bonded to highest number substituent position of each

W6 and that (CH(R38))r is bonded to E°.

In a preferred embodiment of compounds of Formula I or a

pharmaceutically acceptable salt thereof,

B is formula (V):


wherein D1, D2, J 1, J2 and K 1 are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more than one can be a covalent bond, no more than one of D1, D2, J 1, J2 and K 1

can be O, no more than one of D1 , D2 , J 1 , J2 and K 1 can be S, one of D1, D2,

J1, J2 and K1 must be a covalent bond when two of D1, D2, J 1, J2 and K 1 are

O and S, and no more than four of D1, D2, J 1, J2 and K 1 can be N;

R32 , R33 , R34 , R35 , and R36 can independently be Qb ;

R9, R10, R1 1, R12, R13, R32, R33, R34, R35, and R36 are

independently selected from the group consisting of hydrido, amidino, guanidino, dialkylsulfonium, carboxy, haloalkylthio, alkanoyloxy, alkoxy, alkoxyalkyl, haloalkoxylalkyl, hydroxy, amino, alkoxyamino, thio, nitro, lower alkylamino, alkylthio, alkylthioalkyl, alkylsulfinyl, alkylsulfinylalkyl, alkylsulfonyl, alkylsulfonylalkyl, haloalkylsulfinylalkyl, haloalkylsulfonylalkyl, alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkyl

amidosulfonyl, dialkyl amidosulfonyl, alkanoyl, alkenoyl, haloalkanoyl, alkyl, alkenyl, alkenyloxy, alkenyloxyalky, halo, haloalkyl, haloalkenyl, haloalkoxy, hydroxyhaloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxyalkyl, carboxyalkyl, carboalkoxy, alkoxycarboxamido, alkylamidocarbonylamido, carboalkoxyalkyl, carboalkoxyalkenyl, carboxamido, carboxamidoalkyl, and cyano;

B can be selected from the group consisting of C3-C8 alkyl, C3-C8 alkenyl, C3-C8 alkynyl, C3-C8 haloalkyl, and C3-C8 haloalkenyl wherein each member of group B may be optionally substituted at any carbon up to and

including 6 atoms from the point of attachment of B to A with one or more of the group consisting of R 32, R33, R34, R35, and R36;

B can be selected from the group consisting of C3-C10 cycloalkyl, C5-C10 cycloalkenyl, C4-C9 saturated heterocyclyl, and C4-C9 partially saturated heterocyclyl, wherein each ring carbon may be optionally substituted with R33, a ring carbon other than the ring carbon at the point of attachment of B to A may be optionally substituted with oxo provided that no more than one ring carbon is substituted by oxo at the same time, ring carbon and nitrogen atoms adjacent to the carbon atom at the point of attachment may be optionally substituted with R9 or R13, a ring carbon or nitrogen atom adjacent to the R9 position and two atoms from the point of attachment may be substituted with

R10, a ring carbon or nitrogen atom adjacent to the R13 position and two atoms

from the point of attachment may be substituted with R12, a ring carbon or

nitrogen atom three atoms from the point of attachment and adjacent to the R10

position may be substituted with R11 , a ring carbon or nitrogen atom three

atoms from the point of attachment and adjacent to the R12 position may be

substituted with R33, and a ring carbon or nitrogen atom four atoms from the

point of attachment and adjacent to the R11 and R33 positions may be

substituted with R34;

A is selected from the group consisting of single covalent bond,

(W7)rr-(CHCR 15 ))pa and (CH(R15))pa-(W7)„ wherein rr is an integer

selected from 0 through 1, pa is an integer selected from 0 through 6, and W7

is selected from the group consisting of O, S, C(O), C(S), C(O)S, C(S)O,

C(O)N(R7), C(S)N(R7), (R7)NC(O), (R7)NC(S), S(O), S(O)2, S(O)2N(R7),

(R7)NS(O)2, C(NR7)N(R7), (R7)NC(NR7), and N(R7);

R7 and R8 are independently selected from the group consisting of hydrido, hydroxy, alkyl, and alkoxyalkyl;

R 15 is selected from the group consisting of hydrido, hydroxy, halo, alkyl, and haloalkyl;

Ψ is NH;

X0 is hydrido;

R 1 is selected from the group consisting of hydrido, alkyl, and haloalkyl;

R2 is selected from the group consisting of Z0 -Q, hydrido, alkyl, alkenyl, and halo;

Z0 is a covalent single bond;

Q is formula (II):


wherein D1, D2, J 1, J2 and K 1 are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more than one can be a covalent bond, no more than one of D1, D2, J 1, J2 and K 1

can be O, no more than one of D1, D2, J 1, J2 and K 1 can be S, one of D1, D2,

J 1, J2 and K 1 must be a covalent bond when two of D1, D2, J 1, J2 and K 1 are

O and S, and no more than four of D1, D2, J 1, J2 and K 1 can be N, with the

proviso that R9, R10, R 1 1, R12, and R13 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;

K is CR4a R4b ;

R4a and R4b are independently selected from the group consisting of halo, hydrido, hydroxy, alkyl, and haloalkyl;

E0 is E1 , when K is CR4a R4b , wherein E is selected from the group consisting of a covalent single bond, (O)N(H), (H)NC(O), C(S)N(H),

(H)NC(S), S(O)2N(H), N(H)S(O)2, S(O)2N(H)C(O), and C(O)N(H)S(O)2;

K can be (CH(R 14))j-T wherein j is selected from an integer from 0 through 1 and T is selected from the group consisting of single covalent bond and N(R7 ) with the proviso that (CH(R14))j is bonded to the pyridone ring;

E0 is E2 , when K is (CH(R14))j-T, wherein E is selected from the

group consisting of C(O)N(H), (H)NC(O), C(S)N(H), (H)NC(S), S(O)2N(H),

N(H)S(O)2, S(O)2N(H)C(O), and C(O)N(H)S(O)2;

R 14 is selected from the group consisting of hydrido, halo, alkyl, and haloalkyl;

Y0 is formula (IV):


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 can be a covalent bond, K2 is independently selected from the group

consisting of C, and N , no more than one of D5, D6, J5, and J6 can 6e O, no more than one of D5, D6, J5, and J6 can be 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, no more than

three of D5, D6, J5, and J6 can be N when K is N , and no more than four of

D5, D6, J5, and J6 can be N when K is carbon with the provisos that R16 ,

R 16 , R17 , R18 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;

R 16 , R17 , R18 , and R19 are independently selected from the group consisting of hydrido, amidino, guanidino, dialkylsulfonium, carboxy, haloalkylthio, alkoxy, hydroxy, amino, thio, nitro, lower alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoyl, alkenoyl, haloalkanoyl, alkyl, alkenyl, halo, haloalkyl, haloalkenyl, haloalkoxy, hydroxyalkyl, aminoalkyl,

haloalkoxyalkyl, carboalkoxy, carboalkoxyalkyl, and cyano;

Qb is selected from the group consisting of NR20 R21 ,+ NR20 R21 R22, oxy, alkyl, alkylaminoalkyl, aminoalkyl, dialkylsulfoniumalkyl, and acylamino wherein R20, R21 , and R22 are independently selected from the group consisting of hydrido, alkyl, hydroxy, alkoxy, alkylamino, dialkylamino, aminoalkyl, and hydroxyalkyl with the provisos that no more than one of R20,

R21, and R22 can be hydroxy, alkoxy, alkylamino, amino, and dialkylamino

and that R23 , R21 , and R22 must be other than be hydroxy, alkoxy,

alkylamino, ammo, and dialkylamino when K2 is N+;

Qb can be N(R26 )SO2N(R23 )(R24 ) with the proviso that no more than

one of R23 , R24 , and R26 can be hydroxy, alkoxy, alkylamino, amino, or

dialkylamino when two of the group consisting of R23 , R24 , and R26 are bonded to the same atom;

Qb can be selected from the group consisting of dialkylsulfonium,

trialkyl phosphonium, C(NR25)NR23R24, N(R26)C(NR25)N(R23)(R24),

N(R26)C(O)N(R23)(R24), N(R26)C(S)N(R23)(R24),

C(O)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), N(R26)N(R26)SO2N(R23)(R24),

C(O)NR23 R24 , and C(O)NR23 R24 with the provisos that no more than one of

R23 , R24 , and R26 can be hydroxy, alkoxy, alkylamino, ammo, or

dialkylamino when two of the group consisting of R23 , R24 , and R26 are

bonded to the same atom and that said Qb group is bonded directly to a carbon atom;

R23 , R24 , R25 , and R26 are independently selected from the group consisting of hydrido, alkyl, hydroxy, alkoxy, alkylamino, dialkylamino, aminoalkyl, and hydroxyalkyl;

Qs is selected from the group consisting of a single covalent bond and

(CR37 R38 )b -(W0 )az wherein az is an integer selected from 0 through 1 , b is an integer selected from 1 through 2, and W0 is selected from the group consisting of O, S, C(O), S(O)2, N(R14), and ON(R14) with the proviso that R14 is

selected from other than halo when directly bonded to N and that (CR37 R38)b is bonded to E0 ;

R37 and R38 are independently selected from the group consisting of hydrido, halo, alkyl, and haloalkyl;

Y0 can be Qb -Qssss wherein Qssss is (CH(R38 ))r-W5 , r is an integer

selected from 1 through 2, and 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, 3,4-benzofuranyl, 3 ,5-benzofuranyl, 3 ,6-benzofuranyl, 3 ,7-benzofuranyl, 2,4-benzothiophenyl, 2,5-benzothiophenyl, 2,6-benzothiophenyl, 2,7-benzothiophenyl, 3,4-benzothiophenyl, 3,5-benzothiophenyl, 3,6-benzothiophenyl, 3,7-benzothiophenyl, 2,4-indolyl, 2,5-indolyl, 2,6-indolyl, 2,7-indolyl, 3,4-indolyl, 3,5-indolyl, 3,6-indolyl, 3,7-indolyl, 1,4-isoindolyl, 1,5-isoindolyl, 1,6-isoindolyl, 2,4-isoindolyl, 2,5-isoindolyl, 2,6-isoindolyl, 2,7-isoindolyl, 1,3-isoindolyl, 3,4-indazolyl, 3,5-indazolyl, 3,6-indazolyl, 3,7-indazolyl, 2,4-benzoxazolyl, 2,5-benzoxazolyl, 2,6-benzoxazolyl, 2,7-benzoxazolyl, 3,4-benzisoxazolyl, 3,5-benzisoxazolyl, 3,6-benzisoxazolyl, 3,7-benzisoxazolyl, 1,4-naphthyl, 1,5-naphthyl, 1,6-naphthyl, 1,7-naphthyl, 1,8-naphthyl, 2,4-naphthyl, 2,5-naphthyl, 2,6-naphthyl, 2,7-naphthyl, 2,8-naphthyl, 2,4-quinolinyl, 2,5-quinolinyl, 2,6-quinolinyl, 2,7-quinolinyl, 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-quinohnyl, 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-isoquinoUnyl, 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 with the proviso that Q is bonded to lowest number substituent position of each

W5 and that (CH(R38))r is bonded to E°;

Y0 can be Qb -Qssssr wherein Qssssr is (CH(R38 ))r-W6 , r is an integer

selected from 1 through 2, and 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^-indenyl, 2,4-indenyl, 3,4-indenyl, 3,5-indenyl, 3,6-indenyl, 3,7-indenyl, 2,4-benzofuranyl, 2,5-benzofuranyl, 2,6-benzofuranyl, 2,7-benzofuranyl, 3,4-benzofuranyl, 3,5-benzofuranyl, 3,6-benzofuranyl, 3,7-benzofuranyl, 2,4-benzothiophenyl, 2,5-benzothiophenyl, 2,6-benzothiophenyl, 2,7-benzothiophenyl, 3,4-benzothiophenyl, 3,5-benzothiophenyl, 3,6-benzothiophenyl, 3,7-benzothiophenyl, 2,4-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-indazolyl, 3,5-indazolyl, 3,6-indazolyl, 3,7-indazolyl, 2,4-benzoxazolyl, 2,5-benzoxazolyl, 2,6-benzoxazolyl, 2,7-benzoxazolyl, 3,4-benzisoxazolyl, 3,5-benzisoxazolyl, 3,6-benzisoxazolyl, 3,7-benzisoxazolyl, 1,4-naphthyl, 1,5-naphthyl, 1,6-naphthyl, 1,7-naphthyl, 1,8-naphthyl, 2,4-naphthyl, 2,5-naphthyl, 2,6-naphthyl, 2,7-naphthyl, 2,8-naphthyl, 2,4-quinolinyl, 2,5-quinolinyl, 2,6-quinolinyl, 2,7-quinolinyl, 2,8-quinolinyl, 3,4-quinolinyl, 3,5-quinolinyl, 3,6-quinolinyl, 3,7-quinolinyl, 3,8-quinolinyl, 4,5-quinolinyl, 4,6-quinolinyl, 4,7-quinolinyl, 4,8-quinoHnyl, 1,4-isoquinolinyl, 1,5-isoquinolinyl, 1,6-isoquinolinyl, 1,7-isoquinolinyl, 1,8-isoquinolinyl, 3,4-isoquinoUnyl, 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-cinnoUnyl, 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 with the proviso that Q is bonded to highest number substituent position of each

W6 and that (CH(R38))r is bonded to E0.

In a more preferred embodiment of compounds of Formula I or a pharmaceutically acceptable salt thereof,

B is selected from the group consisting of aryl and heteroaryl wherein a carbon adj acent to the carbon at the point of attachment may be substituted by R32, the other carbon adjacent to the carbon at the point of attachment may be

substituted by R36, a carbon adjacent to R32 and two atoms from the carbon at

the point of attachment may be substituted by R33, a carbon adjacent to R36

and two atoms from the carbon at the point of attachment may be substituted by R35, and any carbon adjacent to both R33 and R35 may be substituted by R34 ;

R32 , R33 , R34 , R35 , and R33 are independently selected from the group consisting of hydrido, amidino, guanidino, dialkylsulfonium, carboxy, haloalkylthio, alkoxy, hydroxy, amino, alkoxyamino, thio, nitro, lower alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, amidosulfonyl, alkanoyl, haloalkanoyl, alkyl, halo, haloalkyl, haloalkenyl, haloalkoxy, hydroxyhaloalkyl, hydroxyalkyl, aminoalkyl, carboxyalkyl, carboalkoxy, carboxamido, and cyano;

R32, R33, R34, R35, and R36 can independently be Qb ;

B can be selected from the group consisting of C3-C8 alkyl, C3-C8 alkenyl, C3-C8 haloalkyl, and C3-C8 haloalkenyl wherein each member of group B may be optionally substituted at any carbon up to and including 6 atoms from the point of attachment of B to A with one or more of the group consisting of R32, R33, R34, R35, and R36,

B can be selected from the group consisting of C3-C10 cycloalkyl, C5-C10 cycloalkenyl, C4-C9 saturated heterocyclyl, and C4-C9 partially saturated heterocyclyl, wherein each ring carbon may be optionally substituted with R33, a ring carbon other than the ring carbon at the point of attachment of B to A may be optionally substituted with oxo provided that no more than one ring carbon is substituted by oxo at the same time, ring carbon and nitrogen atoms adjacent to the carbon atom at the point of attachment may be optionally substituted with R9 or R13, a ring carbon or nitrogen atom adjacent to the Rg position and two atoms from the point of attachment may be substituted with

R10, a ring carbon or nitrogen atom adjacent to the R13 position and two atoms

from the point of attachment may be substituted with R12, a ring carbon or

nitrogen atom three atoms from the point of attachment and adjacent to the R10

position may be substituted with R11, a ring carbon or nitrogen atom three

atoms from the point of attachment and adjacent to the R12 position may be

substituted with R33, and a ring carbon or nitrogen atom four atoms from the

point of attachment and adjacent to the R11 and R33 positions may be

substituted with R34;

R9 , R10 , R1 1 , R12 , and R13 are independently selected from the group consisting of hydrido, amidino, guanidino, dialkylsulfonium, carboxy, haloalkylthio, alkoxy, hydroxy, amino, alkoxyamino, thio, nitro, lower alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, amidosulfonyl, alkanoyl, haloalkanoyl, alkyl, halo, haloalkyl, haloalkenyl, haloalkoxy, hydroxyhaloalkyl, hydroxyalkyl, aminoalkyl, carboxyalkyl, carboalkoxy, carboxamido, and cyano;

A is selected from the group consisting of single covalent bond,

(W7)rr-(CH(R15))pa and (CH(R15))pa-(W7)rr wherein rr is an integer

selected from 0 through 1, pa is an integer selected from 0 through 6, and W7

is selected from the group consisting of O, S, and C(O);

R15 is selected from the group consisting of hydrido, hydroxy, halo, alkyl, and haloalkyl;

Ψ is NH;

X0 is hydrido;

R1 is selected from the group consisting of hydrido, alkyl, and haloalkyl;

R2 is Q, wherein Q is selected from the group consisting of aryl and heteroaryl wherein a carbon adjacent to the carbon at the point of attachment may be substituted by R9 , the other carbon adjacent to the carbon at the point of

attachment may be substituted by R13 , a carbon adjacent to R9 and two atoms

from the carbon at the point of attachment may be substituted by R 10, a carbon

adjacent to R 13 and two atoms from the carbon at the point of attachment may

be substituted by R12 , and any carbon adjacent to both R110 and R12 may be

substituted by R11;

K is CR4a R4b wherein R4a and R4b are independently selected from the group consisting of halo and hydrido;

E0 IS E1 , when K ιs CR4a R4b , wherein E is selected from the group

consisting of a covalent single bond, (O)N(H), (H)NC(O), S(O)2N(H),

N(H)S(O)2, S(O)2N(H)C(O), and C(O)N(H)S(O)2;

K can be (CH(R 14 ))j-T wherein j is selected from an integer from 0 through 1 and T is selected from the group consisting of single covalent bond and N(R7) with the proviso that (CH(R14))j is bonded to the pyridone ring;

R7 is selected from the group consisting of hydrido, hydroxy, alkyl, and alkoxyalkyl;

R14 is selected from the group consisting of hydrido and halo;

E0 is E2 , when K is (CH(R14 ))j-T, wherein E2 is selected from the

group consisting of C(O)N(H), (H)NC(O), S(O)2N(H), N(H)S(O)2,

S(O)2N(H)C(O), and C(O)N(H)S(O)2;

Y0 is formula (IV):


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 can be a covalent bond, K2 is independently selected from the group

consisting of C, and N+ , 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, no more than three

of D5, D6, J5, and J6 can be N when K2 is N+ , and no more than four of D5 ,

D6, J5, and J6 can be N when K2 is carbon with the provisos that R16 , R17, R18, and R19 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;

R16 , R17 , R18 , and R19 are independently selected from the group consisting of hydrido, amidino, guanidino, dialkylsulfonium, carboxy, haloalkylthio, alkoxy, hydroxy, amino, thio, nitro, lower alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoyl, alkenoyl, haloalkanoyl, alkyl, alkenyl, halo, haloalkyl, haloalkenyl, haloalkoxy, hydroxyalkyl, aminoalkyl,

haloalkoxyalkyl, carboalkoxy, carboalkoxyalkyl, and cyano;

Qb is selected from the group consisting of NR20 R21 ,+ NR20 R21 R22 , oxy, alkyl, alkylaminoalkyl, aminoalkyl, dialkylsulfoniumalkyl, and acylamino wherein R20 , R21 , and R22 are independently selected from the group consisting of hydrido, alkyl, hydroxy, alkoxy, alkylamino, dialkylamino, aminoalkyl, and hydroxyalkyl with the provisos that no more than one of R20,

R21 , and R22 can be hydroxy, alkoxy, alkylamino, amino, and dialkylamino

and that R20, R21 , and R22 must be other than be hydroxy, alkoxy,

alkylamino, ammo, and dialkylamino when K2 is N+ ;

Qb can be selected from the group consisting of dialkylsulfonium,

trialkylphosphonium, C(NR25 )NR23 R24, N(R26)C(NR25)N(R23 )(R24),

C(O)N(R26)C(NR25)N(R23)(R24), N(R26)N(R26)C(NR25)N(R23)(R24),

N(R26)N(R26)SO2N(R23)(R24), C(O)NR23 R24, and C, (O)NR23 R24 with

the provisos that no more than one of R23, R24, and R26 can be hydroxy, alkoxy, alkylamino, amino, or dialkylamino when two of the group consisting of R23, R24, and R26are bonded to the same atom and that said Q group is bonded directly to a carbon atom;

R23 , R24 , R25 , and R26 are independently selected from the group consisting of hydrido, alkyl, hydroxy, alkoxy, alkylamino, dialkylamino, aminoalkyl, and hydroxyalkyl;

Qs is selected from the group consisting of a single covalent bond and

(CR37 R38 )b-(W0 )az wherein az is an integer selected from 0 through 1, b is the integer 1, and W is selected from the group consisting of O, S, and C(O) with the proviso that (CR37 R38 )b is bonded to E ;

R37 and R38 are independently selected from the group consisting of hydrido, halo, alkyl, and haloalkyl.

In a specific embodiment of Formula I, compounds have the Formula

I-S:


or a pharmaceutically acceptable salt thereof, wherein;

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-ρyrazolyl, 1,2,4-triazol-3-yl, 1,2,4-triazol-Syl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,3,4-oxadiazol-3-yl, 1,3,4-oxadiazol-5-yl, 3-isothiazolyl, 5-isothiazolyl, 2-oxazolyl, 2-thiazolyl, 3-isoxazolyl, 5-isoxazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 13,5-triazin-2-yl, 1,2,4-triazin-3-yl, 1,2,4-triazin-5-yl, 1,2,4-triazin-6-yl, and 1,2,3-triazin-4-yl, wherein a carbon adjacent to the carbon at the point of attachment may be substituted by R32 , the other carbon adjacent

to the carbon at the point of attachment may be substituted by R36 , a carbon

adjacent to R32 and two atoms from the carbon at the point of attachment may

be substituted by R33, a carbon adjacent to R36 and two atoms from the carbon

at the point of attachment may be substituted by R35, and any carbon adjacent

to both R33 and R35 may be substituted by R34 ;

R32 , R33 , R34 , R35 , and R36 are independently selected from the group consisting of hydrido, amidino, guanidino, dimethylsulfonium, carboxy, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, methoxyamino, ethoxyamino, thio, nitro, aminomethyl, 1-aminoethyl, 2-aminoethyl, N-N-methylamino, dimethylamino, N-ethylamino, methylthio, ethylthio,

isopropylthio, trifluoromethylthio, methylsulfinyl, ethylsulfmyl, 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-hydroxyethyl, 2,2,2-trifluoro-1-hydroxyethyl, 2,2,2-trifluoro-1-trifluoromethyl-1-hydroxyethyl, carboxymethyl, methoxycarbonyl,

ethoxycarbonyl, amidocarbonyl, N-methylamidocarbonyl, N,N-dimethylamidocarbonyl, cyano, and Q ;

B can be selected from the group consisting of 1-propenyl, propyl, isopropyl, butyl, 2-butenyl, 3-butenyl, 2-butynyl, sec-butyl, isobutyl, 2-methylpropenyl, 1-ρentyl, 2-ρentenyl, 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, l-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-ρentenyl, 1-ethyl-3-pentenyl, 1-ethyl-4-pentenyl, l-butyl-2-propenyl, 1-ethyl-2-pentynyl, 1-ethyl-3-pentynyl, 1-octyl, 2-octenyl, 3-octenyl, 4-octenyl, 5-octenyl, 6-octenyl, 7-octenyl, 2-octynyl, 3-octynyl, 4-octynyl, 5-octynyl, 6-octynyl, 2-octyl, 1-methyl-2-heptenyl, 1-methyl-3-heptenyl, 1-methyl-4-heptenyl, 1-methyl-5-heptenyl, 1-methyl-6-heptenyl, 1-methyl-2-heptynyl, 1-methyl-3-heptynyl, 1-methyl-4-heptenyl, 1-methyl-5-heptenyl, 1-methyl-6-heptenyl, 1-methyl-2-heptenyl, 1-methyl-3-heptynyl, 1-methyl-4-heptynyl, 1-methyl-5-heptynyl, 3-octyl, 1-ethyl-2-hexenyl, 1-ethyl-3-hexenyl, 1-ethyl-4-hexenyl, 1-ethyl-2-hexynyl, 1-ethyl-3-hexynyl, 1-ethyl-4-hexynyl, 1-ethyl-5-hexenyl, l-pentyl-2-propenyl, 4-octyl, l-propyl-2-pentenyl, l-propyl-3-pentenyl, l-propyl-4-pentenyl, l-butyl-2-butenyl, l-propyl-2-pentynyl, l-propyl-3-pentynyl, 1-butyl-2-butynyl, l-butyl-3-butenyl, 2,2-difiuoropropyl, 4-trifluoromethyl-5,5,5-trifluoropentyl, 4-trifluoromethylpentyl, 5,5,6,6,6-pentafluorohexyl, and 3,3,3-trifluoropropyl, wherein each member of group B may be 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 R36l

B can be selected from the group consisting of cyclopropyl, cyclobutyl, oxetan-2-yl, oxetan-3-yl, azetidin-1-yl, azetidin-2-yl, azetidin-3-yl, thiaetan-2-yl, thiaetan-3-yl, cyclopentyl, cyclopent-2-enyl, cyclopent-3-enyl, cyclohexyl, 4-methylcyclohexyl, 4-chloro-3-ethylphenoxycyclohexyl, 3-trifluoromethoxyphenoxycyclohexyl, 3-trifluoromethylcyclohexyl, 4-trifluoromethylcyclohexyl, 3,5-bis-trifluoromethylcyclohexyl, adamantyl, 3-trifluoromethyladamantyl, norbomyl, 3-trifluoromethylnorbornyl, norbornenyl, 7-oxabicyclo[2.2.1]heptan-2-yl, bicyclo[3.1.0]hexan-6-yl, cyclohex-2-enyl, cyclohex-3-enyl, cycloheptyl, cyclohept-2-enyl, cyclohept-3-enyl, cyclooctyl, cyclooct-2-enyl, cyclooct-3-enyl, cyclooct-4-enyl, 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, 2H-2-pyranyl, 2H-3-pyranyl, 2H-4-pyranyl, 4H-2-pyranyl, 4H-3-pyranyl, 4H-4-pyranyl, 2H-pyran-2-one-3-yl, 2H-pyran-2-one- 4-yl, 2H-pyran-2-one-5-yl, 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 may be optionally substituted with R33 , a ring carbon and nitrogen atoms adjacent to the carbon atom at the point of attachment may be optionally substituted with R9 or R13, a ring carbon or

nitrogen atom adjacent to the R9 position and two atoms from the point of

attachment may be substituted with R10, and a ring carbon or nitrogen atom

adjacent to the R13 position and two atoms from the point of attachment may

be substituted with R12;

R9 , R10 , R1 1 , R12 , and R13 are independently selected from the group consisting of amidino, guanidino, dimethylsulfonium, methylethylsulfonium, carboxy, methoxy, ethoxy, isopropoxy, propoxy, butoxy, hydroxy, amino, methoxyamino, ethoxyamino, aminomethyl, 1-aminoethyl, 2-aminoethyl, N-N-dimemylamino, N-methylamino, N-ethylamino, methylsulfinyl, ethylsulfinyl, methylsulfonyl, ethylsulfonyl, amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, acetyl, propanoyl, butanoyl, trifluoroacetyl,

pentafluoropropanoyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro-1-hydroxyethyl, 2,2,2-trifluoro-1-trifluoromethyl-1-hydroxyethyl, carboxymethyl, 2-carboxy ethyl, methoxycarbonyl, ethoxycarbonyl,

amidocarbonyl, N-methylamidocarbonyl, N,N-dimethylamidocarbonyl, and cyano;

A is selected from the group consisting of single covalent bond, O,

C(O), CH2, CH3CH, CF3CH, CH3CC(O), CF3CC(O), C(O)CCH3,

C(O)CCF3, CH2C(O), (O)CCH2, CH2CH2, CH2CH2CH2, CH3CCH2,

CF3CCH2, CH3CC(O)CH2, CF3CC(O)CH2, CH2C(O)CCH3,

CH2C(O)CCF3, CH2CH2C(O), and CH2(O)CCH2;

R 1 is selected from the group consisting of hydrido, methyl, ethyl, propyl, butyl, 2,2,2-trifluoroethyl, and 2,2,333-pentafluoropropyl;

R2 is selected from the group consisting of phenyl, 2-thienyl, 3-thienyl,

2-furyl, 3-furyl, 2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl, 4-imidazolyl, 3-pyrazolyl, 4-pyrazolyl, 1,2,4-triazol-3-yl, 1,2,4-triazol-Syl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,3,4-oxadiazol-3-yl, 13,4-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-ρyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 1,3,5-triazin-2-yI, 1,2,4-triazin-3-yl, 1,2,4-triazin-Syl, 1,2,4-triazin-6-yl, and 1,2,3-triazin-4-yl, wherein a carbon adjacent to the carbon at the point of attachment may be substituted by R9 , the other carbon adjacent

to the carbon at the point of attachment may be substituted by R13 , a carbon

adjacent to R9 and two atoms from the carbon at the point of attachment may be

substituted by R 10 , a carbon adjacent to R13 and two atoms from the carbon at

the point of attachment may be substituted by R 12 , and any carbon adjacent to

both R 10 and R12 may be substituted by R1 1;

K is CR4a R4b wherein R4a and R4b are independently selected from the group consisting of chloro, fluoro, and hydrido;

E0 is E 1 , when K is CR4a R4b , wherein E is selected from the group

consisting of a covalent single bond, C(O)N(H), (H)NC(O), S(O)2N(H),

N(H)S(O)2, S(O)2N(H)C(O), and C(O)N(H)S(O)2;

K can be N(H) and CH2N(H);

E0 is E2 , when K is N(H) and CH2N(H), wherein E2 is selected from

the group consisting of C(O)N(H), (H)NC(O), S(O)2N(H), N(H)S(O)2,

S(O)2N(H)C(O), and C(O)N(H)S(O)2;

Y0 is selected from the group of formulas consisting of:


R16, R17, R18, and R19 are independently selected from the group consisting of hydrido, amidino, guanidino, dimethylsulfonium, carboxy, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, methoxyamino, ethoxyamino, thio, nitro, aminomethyl, 1-aminoethyl, 2-aminoethyl, N-N-methylamino, dimethylamino, N-ethylamino, methylthio, ethylthio,

isopropylthio, trifluoromethylthio, methylsulfinyl, ethylsulfinyl, methylsulfonyl, ethylsulfonyl, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, 2,2333-pentafluoropropyl, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro, bromo, amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, acetyl, propanoyl, trifluoroacetyl, pentafluoropropanoyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro-1-hydroxyethyl, 2,2,2-trifluoro-1- trifluoromethyl-1-hydroxyethyl, carboxymethyl, methoxycarbonyl,

ethoxy carbonyl, amidocarbonyl, N-methylamidocarbonyl, N,N-dimethylamidocarbonyl, and cyano;

Qb is selected, when bonded to a carbon, from the group consisting of

NR20 R21 , + NR20 R21 R22 , dimethylsulfonium, methylethylsulfonium,

diethylsulfonium, trimethylphosphonium, C(NR25 )NR23 R24 ,

N(R26)C(NR25)N(R23)(R24), C(O)N(R26)C(NR25)N(R23)(R24),

N(R26)N(R26)C(NR25)N(R23)(R24), N(R26)N(R26)SO2N(R23)(R24),

C(O)NR23 R24 , and C(O)NR23 R24 with the provisos that no more than one of

R20 , R21 , and R22 can be hydroxy, methoxy, ethoxy, N-methylamino, N,N-dimethylamino, and N,N,N-trimethylamino, and amino and that no more than one of R23 , R24 , and R26 can be hydroxy, methoxy, ethoxy, N-methylamino,

N,N-dimethylamino, N,N,N-trimethylamino, or amino when two of the group consisting of R23 , R24 , and R26 are bonded to the same atom and that said Qb group is bonded directly to a carbon atom;

R20 , R21 , R22 , R23 , R24 , R25 , and R26 are independently selected from the group consisting of hydrido, methyl, ethyl, propyl, butyl, isopropyl, hydroxy, methoxy, ethoxy, isopropoxy, propoxy, 2-aminoethyl, 2-(N-methylamino)ethyl, 2-(N,N-dimethylamino)ethyl, 2-(N,N,N-trimethylamino)ethyl, N-(2-hydroxyethyl)amino, N,N-bis-(2-hydroxyethyl)amino, N-(2-hydroxyethyl)-N-(2-aminoethyl)amino, N-methylamino, N-ethylamino, NJN-dimethylamino, N,N-diethylamino, and N,N,N-trimemylamino;

Qb is selected, when bonded to a nitrogen, from the group consisting of oxy, methyl, ethyl, 2-aminoethyl, 2-(N-methylamino)ethyl, 2-(N,N- dimethylamino)ethyl, 2-(N,N,N-trimethylamino)ethyl, N-(2-hydroxyethyl)amino, N,N-bis-(2-hydroxyethyl)amino, amino, hydroxylamino, N-methoxyamino, N- methylamino, N,N-dimethylamino, and N,N,N-trimethylamino;

Qs is selected from the group consisting of a single covalent bond, CH2, CH3CH, CF2, CF3CH, CH2O, CH3C(H)O, CF3C(H)O, CH2S, CH3C(H)S,

CF3C(H)S, CH2C(O), CH3C(H)C(0), CF3C(H)C(O), and CF2C(O) with the proviso that Qs is bonded to E0 through a carbon atom.

In a more preferred specific embodiment of Formula I, compounds have the Formula I-MPS:


or a pharmaceutically acceptable salt thereof, wherein;

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-ρyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, and 13,5-triazin-2-yl, wherein a carbon adjacent to the carbon at the point of attachment may be substituted by R32, the other carbon adjacent to

the carbon at the point of attachment may be substituted by R36, a carbon

adjacent to R32 and two atoms from the carbon at the point of attachment may

be substituted by R33 , a carbon adjacent to R36 and two atoms from the carbon at the point of attachment may be substituted by R35, and any carbon adjacent

to both R33 and R35 may be substituted by R ;

R32 , R33, R34, R35, and R36 are independently selected from the group consisting of hydrido, amidino, guanidino, dimethylsulfonium, carboxy, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, methoxyamino, ethoxyamino, thio, nitro, aminomethyl, 1-aminoethyl, 2-aminoethyl, N-N-methylamino, dimethylamino, N-ethylamino, methylthio, ethylthio,

trifluoromethylthio, methylsulfinyl, ethylsulfinyl, 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-hydroxy ethyl, 2,2,2-trifluoro-1-hydroxyethyl, 2,2,2-trifluoro-1-trifluoromethyl-1-hydroxyethyl, carboxymethyl, methoxycarbonyl,

ethoxycarbonyl, amidocarbonyl, N-methylamidocarbonyl, N,N-dimethylamidocarbonyl, cyano, and Qb ;

B can be selected from the group consisting of 1-propenyl, propyl, isopropyl, butyl, 2-butenyl, 3-butenyl, sec-butyl, isobutyl, 2-methylpropenyl, 1-pentyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-pentyl, 1-methyl-2-butenyl, 1-methyl-3-butenyl, 3-pentyl, 1-ethyl-2-propenyl, 2-methylbutyl, 2-methyl-2-butenyl, 2-methyl-3-butenyl, 3-methylbutyl, 3-methyl-2-butenyl, 3-methyl-3-butenyl, 2,2-difluoropropyl, 2-trifluoromethyl-333-trifluoropropyl, 1,1,1,2,2,2-hexafluoropropyl, 3,33-trifluoroprop-1-yl, and 3,33-trifluoroρrop-2-yl, wherein each member of group B may be 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 R35;

B can be selected from the group consisting of cyclopropyl, cyclobutyl, oxetan-2-yl, oxetan-3-yl, azetidin-1-yl, azetidin-2-yl, azetidin-3-yl, thiaetan-2-yl, thiaetan-3-yl, wherein each ring carbon may be optionally substituted with R33, a ring carbon and nitrogen atoms adjacent to the carbon atom at the point of attachment may be optionally substituted with R9 or RJ3, a ring carbon or

nitrogen atom adjacent to the R9 position and two atoms from the point of

attachment may be substituted with R10, and a ring carbon or nitrogen atom

adjacent to the R13 position and two atoms from the point of attachment may

be substituted with R12;

R9 , R10 , R1 1 , R12 , and R 13 are independently selected from the group consisting of amidino, guanidino, dimethylsulfonium, carboxy, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, methoxyamino, ethoxyamino, aminomethyl, 1-aminoethyl, 2-aminoethyl, N-N-methylamino, dimethylamino, N-ethylamino, methylsulfinyl, ethylsulfinyl, methylsulfonyl, ethylsulfonyl, amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, acetyl, propanoyl, trifluoroacetyl, pentafluoropropanoyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro-1-hydroxyethyl, 2,2,2-trifluoro-1-trifluoromethyl-1-hydroxyethyl, carboxymethyl, methoxycarbonyl,

ethoxycarbonyl, amidocarbonyl, N-methylamidocarbonyl, N,N-dimethylamidocarbonyl, and cyano;

A is selected from the group consisting of single covalent bond, O,

C(O), CH2, CH3CH, CF3CH, CH3CC(O), CF3CC(O), C

C(O)CCH3, C(O)CCF3, CH2C(O), and (O)CCH2;

R1 is selected from the group consisting of hydrido, methyl, ethyl, and 2,2,2-trifluoroethyl;

R2 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-ρyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, and 13,5-triazin-2-yl, wherein a carbon adjacent to the carbon at the point of attachment may be substituted by R9 , the other carbon adjacent to

the carbon at the point of attachment may be substituted by R13, a carbon

adjacent to R9 and two atoms from the carbon at the point of attachment may be substituted by R10 , a carbon adjacent to R 13 and two atoms from the carbon at

the point of attachment may be substituted by R12 , and any carbon adjacent to

both R 10 and R12 may be substituted by R 11 ;

K is CR4a R4b wherein R4a and R4b are independently selected from the group consisting of chloro, fluoro, and hydrido;

E0 is E1 , when K is CR4a R4b , wherein E 1 is selected from the group

consisting of a covalent single bond, C(O)N(H), (H)NC(O), S(O)2N(H),

N(H)S(O)2, S(O)2N(H)C(O), and C(O)N(H)S(O)2;

K can be N(H) and CH2N(H);

E is E , when K is N(H) and CH2N(H), wherein E is selected from

the group consisting of C(O)N(H), (H)NC(O), S(O)2N(H), N(H)S(O)2,

S(O)2N(H)C(O), and C(O)N(H)S(O)2;

Y is selected from the group of formulas consisting of:

R16, R17, R18, and R19 are independently selected from the group consisting of hydrido, amidino, guanidino, methoxy, ethoxy, isopropoxy, methylthio, ethylthio, trifluoromethylthio, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, 2,2333-pentafluoropropyl, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro, bromo, acetyl, propanoyl, trifluoroacetyl, pentafluoropropanoyl, methoxycarbonyl, ethoxy carbonyl, and cyano;

Qb is selected, when bonded to a carbon, from the group consisting of

NR20 R21, + NR20 R21 R22, dimethylsulfonium, methylethylsulfonium,

diethylsulfonium, trimethylphosphonium, C(NR25 )NR23 R24 ,

N(R26)C(NR25)N(R23 )(R24), C(O)N(R26)C(NR25)N(R23)(R24),

N(R26)N(R26)C(NR25)N(R23)(R24), N(R26)N(R26)SO2N(R23)(R24),

C(O)NR23 R24 , and C(O)NR23 R24 with the provisos that no more than one of R20 , R21 , and R22 can be hydroxy, methoxy, ethoxy, N-methylamino, N,N-dimethylamino, N,N,N-trimethylamino, or amino and that no more than one of

R23 , R24 , and R26 can be hydroxy, methoxy, ethoxy, N-methylammo, N,N-dimethylamino, N,N,N-trimethylamino, or amino when two of the group consisting of R23 , R24 , and R26 are bonded to the same atom and that said Qb

group is bonded directly to a carbon atom;

R20 , R21 , R22 , R23 , R24 , R25 , and R26 are independently selected from the group consisting of hydrido, methyl, ethyl, hydroxy, methoxy, ethoxy, 2-aminoethyl, 2-(N-methylamino)ethyl, 2-(N,N-dimethylamino)ethyl, 2-(N,N,N-trimethylamino)ethyl, N-(2-hydroxy ethyl )amino, N,N-bis-(2-hy droxy ethyl )amino, N-(2-hydroxyethyl)-N-(2-aminoethyl)amino, N-methylamino, N,N-dimethylamino, and N,N,N-trimethylamino;

Qb is selected, when bonded to a nitrogen, from the group consisting of oxy, methyl, ethyl, 2-aminoethyl, 2-(N-methylamino)ethyl, 2-(N,N-dimethylamino)ethyl, 2-(N,N,N-trimethylamino)ethyl, N-(2-hydroxyethyl)amino, N,N-bis-(2-hydroxyethyl)amino, amino, hydroxylamino, N-methoxyamino, N-methylamino, NJSf-dimethylamino, and N,N,N-trimethylamino;

Qs is selected from the group consisting of a single covalent bond, CH2,

CH3CH, CF2, CF3CH, CH2O, CH3C(H)O, CF3C(H)O, CH2S, CH3C(H)S, CF3C(H)S , CH2C(O), CH3C(H)C(O), CF3C(H)C(O), and CF2C(O) with the proviso that Qs is bonded to E0 through a carbon atom.

In an even more preferred specific embodiment of compounds of

Formula I, compounds have the Formula I-EMPS:


or a pharmaceutically acceptable salt thereof, wherein;

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-ρyrazolyl, 2-thiazolyl, 3-isoxazolyl, 5-isoxazolyl, 2-pyridyl, 3-pyridyl, and 4-pyridyl, wherein a carbon adjacent to the carbon at the point of attachment may be substituted by R32, the other carbon adjacent to the carbon at the point of

attachment may be substituted by R36, a carbon adjacent to R32 and two atoms

from the carbon at the point of attachment may be substituted by R33 , a carbon

adjacent to R36 and two atoms from the carbon at the point of attachment may

be substituted by R35 , and any carbon adjacent to both R33 and R35 may be

substituted by R34

R32 , R33 , R34 , R35 , and R36 are independently selected from the group consisting of hydrido, amidino, guanidino, methoxy, ethoxy, hydroxy, amino, methoxyamino, ethoxyamino, aminomethyl, 1-aminoethyl, 2-aminoethyl, N-N-methylamino, dimethylamino, N-ethylamino, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, 2,2333-pentafluoropropyl, fluoro, chloro, bromo, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro-1-hy droxy ethyl , 2,2,2-trifluoro-1-trifluoromethyl-1-hydroxyethyl,

methoxycarbonyl, ethoxycarbonyl, cyano, and Qb;

B can be selected from the group consisting of propyl, isopropyl, butyl, sec-butyl, isobutyl, 1-pentyl, 2-pentyl, 3-pentyl, 2-methylbutyl, 3-methylbutyl, 2,2-difluoropropyl, 2-trifluoromethyl-333-trifluoropropyl, 1,1,1,2,2,2-hexafluoropropyl, 3,33-trifluoroprop-1-yl, and 3,3,3-trifluoroprop-2-yl, wherein each member of group B may be 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,

B can be selected from the group consisting of cyclopropyl, cyclobutyl, oxetan-2-yl, oxetan-3-yl, azetidin-1-yl, azetidin-2-yl, azetidin-3-yl, thiaetan-2-yl, thiaetan-3-yl, wherein each ring carbon may be optionally substituted with R33, a ring carbon and nitrogen atoms adjacent to the carbon atom at the point of attachment may be optionally substituted with R9 or R13, a ring carbon or

nitrogen atom adjacent to the R9 position and two atoms from the point of

attachment may be substituted with R10, and a ring carbon or nitrogen atom

adjacent to the R13 position and two atoms from the point of attachment may

be substituted with R12;

R9, R10, R1 1, R12, and R13 are independently selected from the group consisting of amidino, guanidino, carboxy, methoxy, ethoxy, hydroxy, amino, methoxyamino, ethoxyamino, aminomethyl, 1-aminoethyl, 2-aminoethyl, N-N-methylamino, dimethylamino, N-ethylamino, acetyl, propanoyl, trifluoroacetyl, pentafluoropropanoyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, carboxy methyl, methoxycarbonyl, ethoxycarbonyl, amidocarbonyl, N-methylamidocarbonyl, N,N-dimethylamidocarbonyl, and cyano;

A is selected from the group consisting of single covalent bond, O,

C(O), CH2, CH2C(O), and (O)CCH2;

R1 is selected from the group consisting of hydrido and methyl;

R2 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-ρyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, and 1,3,5-triazin-2-yl, wherein a carbon adjacent to the carbon at the point of attachment may be substituted by R9 , the other carbon adjacent to the carbon at the point of attachment may be substituted by R13, a carbon

adjacent to R9 and two atoms from the carbon at the point of attachment may be

substituted by R10 , a carbon adjacent to R13 and two atoms from the carbon at

the point of attachment may be substituted by R12, and any carbon adjacent to

both R 10 and R12 may be substituted by R 1 1;

K is CR4a R4b wherein R4a and R4b are independently selected from the group consisting of chloro, fluoro, and hydrido;

E0 is E1 , when K is CR4a R4b, wherein E1 is selected from the group

consisting of a covalent single bond, C(O)N(H), (H)NC(O), S(O)2N(H),

N(H)S(O)2, S(O)2N(H)C(O), and C(O)N(H)S(O)2;

K can be N(H) and CH2N(H);

E0 is E2 , when K is N(H) and CH2N(H), wherein E2 is selected from

the group consisting of C(O)N(H), (H)NC(O), S(O)2N(H), N(H)S(O)2,

S(O)2N(H)C(O), and C(O)N(H)S(O)2;

Y is selected from the group of formulas consisting of:


R16, R17 , R18 , and R19 are independently selected from the group consisting of hydrido, methoxy, ethoxy, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, trifluoromethoxy, fluoro, chloro, bromo, acetyl, trifluoroacetyl, methoxycarbonyl, ethoxy carbonyl, and cyano;

Qb is selected from the group consisting of NR20 R21 ,+ NR20 R21 R22 , dimethylsulfonium, methylethylsulfonium, diethylsulfonium,

trimethylphosphonium, C(NR25)NR23R24, N(R26)C(NR25)N(R23)(R24),

C(O)N(R26 )C(NR25 )N(R23 )(R24 ), N(R26 )N(R26 )C(NR25 )N(R23 )(R24 ),

N(R26 )N(R26 )SO2N(R23 )(R24 ), C(O)NR23 R24 , and C(O)NR23 R24 with

the provisos that no more than one of R20 , R21 , and R22 can be hydroxy, methoxy, ethoxy, N-methylamino, N,N-dimethylamino, N,N,N-trimethylamino, or amino and that no more than one of R23 , R24 , and R26 can be hydroxy, methoxy, ethoxy, N-methylamino, N,N-dimethylamino, N,N,N-trimethylamino, or amino when two of the group consisting of R23 , R24 , and R26 are bonded

to the same atom and that said Q group is bonded directly to a carbon atom;

R20 , R21 , R22 , R23 , R24 , R25 , and R26 are independently selected from the group consisting of hydrido, methyl, ethyl, hydroxy, methoxy, ethoxy, 2-aminoethyl, 2-(N-methylamino)ethyl, 2-(N,N-dimethylamino)ethyl, 2-(N,N,N-trimethylamino)ethyl, N-(2-hydroxyethyl)amino, N,N-bis-(2-hydroxyethyl)amino, N-(2-hydroxyethyl)-N-(2-aminoethyl)amino, N-methylamino, N,N-dimethylamino, and N,N,N-trimethylamino;

Qs is selected from the group consisting of a single covalent bond, CH2, CH3CH, CF2, CF3CH, CH2O, CH3C(H)O, CF3C(H)O, CH2C(O),

CH3C(H)C(O), CF3C(H)C(O), and CF2C(O) with the proviso that QS is bonded to E through a carbon atom.

In a preferred embodiment of a compound of Formula I, said compound is the formula:


or a pharmaceutically acceptable salt thereof, wherein;

B is phenyl or a heteroaryl of 5 or 6 ring members, wherein a nitrogen with a removable hydrogen or a carbon adjacent to the carbon at the point of attachment of said phenyl or heteroaryl ring to A is optionally substituted by R32, a nitrogen with a removable hydrogen or a carbon at the other position

adjacent to the point of attachment is optionally substituted by R36, a nitrogen

with a removable hydrogen or a carbon adjacent to R32 and two atoms from the

point of attachment is optionally substituted by R33, a mtrogen with a

removable hydrogen or a carbon adjacent to R36 and two atoms from the point

of attachment is optionally substituted by R35, and a nitrogen with a removable

hydrogen or a carbon adjacent to both R33 and R35 is optionally substituted by

R34

R9 , R10 , R1 1 , R12 , R13 , R32 , R33 , R34 , R35 , and R36 are

independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkylenedioxy, haloalkylthio, alkanoyloxy, alkoxy, cycloalkoxy, cycloalkylalkoxy, aralkoxy, aryloxy, heteroaryloxy, heteroaralkoxy ,heterocyclyloxy, heterocyclylalkoxy, alkoxyalkyl,

haloalkoxylalkyl, hydroxy, amino, alkoxyamino, nitro, alkylamino,

N-alkyl-N-arylamino, arylamino, aralkylamino, heteroarylamino,

heteroaralkylamino, heterocyclylamino, heterocyclylalkylamino, alkylthio, alkylthioalkyl, alkylsulfinyl, arylsulfinyl, aralkylsulfinyl, cycloalkylsulfinyl, heteroarylsulfinyl, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl,

cycloalkylsulfonyl, heteroarylsulfonyl, alkylsulfonylalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, alkylsulfonamido, amidosulfonyl, alkanoyl, haloalkanoyl, alkyl, alkenyl, halo, haloalkyl, haloalkenyl, haloalkoxy, hydroxyhaloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxyalkyl, carboxyalkyl, carboalkoxy, carboxy, carboxamido, carboxamidoalkyl, and cyano;

R32 , R33 , R34 , R35 , and R36 are independently optionally Qb ;

B is optionally selected from the group consisting of hydrido, trialkylsilyl, C2-C8 alkyl, C3-C8 alkylenyl, C3-C8 alkenyl, C3-C8 alkynyl, and C2-C8 haloalkyl, wherein each member of group B is optionally substituted at any carbon up to and including 6 atoms from the point of attachment of B to A with one or more of the group consisting of R32, R33, R34, R35, and R36;

B is optionally a C3-C12 cycloalkyl or C4-C9 saturated heterocyclyl, wherein each ring carbon is optionally substituted with R33 , 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 substituted with R9 or R13 , a ring

carbon or nitrogen atom adjacent to the R9 position and two atoms from the

point of attachment is optionally substituted with R 10, a ring carbon or nitrogen

adjacent to the R13 position and two atoms from the point of attachment is

optionally substituted with R12 , a ring carbon or mtrogen three atoms from the

point of attachment and adjacent to the R 10 position is optionally substituted

with R1 1 , a ring carbon or nitrogen three atoms from the point of attachment

and adjacent to the R 12 position is optionally substituted with R33, and a ring carbon or nitrogen four atoms from the point of attachment and adjacent to the

R1 1 and R33 positions is optionally substituted with R34 ;

A is selected from the group consisting of a bond,

( W7 )rr-(CH(R15 ))pa, and (CH(R15 ))pa-( W7 )rr wherein rr is 0 or 1 , pa is an

integer selected from 0 through 6, and W7 is selected from the group

consisting of O, S, C(O), (R7)NC(O), (R7)NC(S), and N(R7) with the proviso that no more than one of the group consisting of rr and pa is 0 at the same time;

R7 is selected from the group consisting of hydrido, hydroxy, and alkyl;

R15 is selected from the group consisting of hydrido, hydroxy, halo, alkyl, and haloalkyl;

Ψ is NH or NOH;

X is selected from the group consisting of hydrido, alkyl, alkenyl, cyano, halo, haloalkyl, haloalkoxy, haloalkylthio, amino, aminoalkyl, alkylamino, amidino, hydroxy, hydroxyamino, alkoxy, hydroxyalkyl, alkoxyamino, thiol, and alkylthio;

R1 is selected from the group consisting of hydrido, alkyl, alkenyl, haloalkyl, amino, aminoalkyl, alkylamino, hydroxy, and hydroxyalkyl;

X0 and R1 or R1 and R2 is optionally bonded together to form a partially saturated C5-C8 heterocyclyl ring, wherein said heterocyclyl ring is optionally substituted with one or more of the group consisting of R9 , R10 ,

R11 , R12 , and R13;

R2 is Z0-Q;

Z0 is selected from the group consisting of a bond, (CR41R42)q

wherein q is an integer selected from 1 through 3, and (CH(R41 ))g-W0 -

(CH(R42))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),

N(R41 ), and ON(R41);

Z0 is optionally (CH(R41 ))e-W22 -(CH(R42 ))h wherein e and h are

independently 0 or 1 and W22 is selected from the group consisting of

CR41 =CR42, 1,2-cyclopropyl, 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-piperazinyl,

13-piρerazinyl, 23-piperazinyl, 2,6-piperazinyl, 1,2-piperidinyl, 1,3-piperidinyl, 2,3-piperidinyl, 2,4-piperidinyl, 2,6-piperidinyl, 3,4-piperidinyl, 1,2-pyrrolidinyl, 1,3-pyrrolidinyl, 2,3-pyrrolidinyl, 2,4-pyrrolidinyl, 2,5-pyrrolidinyl,

3,4-pyrrolidinyl, 23-tetrahydrofuranyl, 2,4-tetrahydrofuranyl,

2,5-tetrahydrofuranyl, and 3,4-tetrahydrofuranyl, wherein Z is directly bonded to the 4-pyridone ring and W22 is optionally substituted with one or more

substituents selected from the group consisting of R9 , R10 , R1 1 , R12 , and R13 ;

R41 and R42 are independently selected from the group consisting of amidino, hydroxyamino, hydrido, hydroxy, amino, and alkyl;

Q is phenyl or a heteroaryl of 5 or 6 ring members, wherein a nitrogen with a removable hydrogen or a carbon adjacent to the carbon at the point of attachment of said phenyl or heteroaryl ring to Z is optionally substituted by R9, a nitrogen with a removable hydrogen or a carbon at the other position

adjacent to the point of attachment is optionally substituted by R 13, a nitrogen

with a removable hydrogen or a carbon adjacent to R9 and two atoms from the

point of attachment is optionally substituted by R10, a nitrogen with a

removable hydrogen or a carbon adjacent to R13 and two atoms from the point

of attachment is optionally substituted by R 12 , and a nitrogen with a removable

hydrogen or a carbon adjacent to both R 10 and R12 is optionally substituted by

Q is optionally hydrido with the proviso that Z0 is selected from other than a bond;

K is CR4a R4b ;

R4a and R4b are independently selected from the group consisting of halo, hydrido, hydroxyalkyl, alkyl, alkoxyalkyl, alkylthioalkyl, and haloalkyl;

E0 , with the proviso that K is CR4a R4b , is E1 wherein E 1 is selected from the group consisting of a covalent single bond, C(O)N(H), (H)NC(O),

C(S)N(H), (H)NC(S), S(O)2N(H), N(H)S(O)2, S(O)2N(H)C(O), and

C(O)N(H)S(O)2;

K is optionally (CH(R14 ))j-T wherein j is 0 or 1 and T is a bond or

N(R7) with the proviso that (CH(R14))j is bonded to the phenyl ring;

R14 is selected from the group consisting of hydrido, halo, alkyl, and haloalkyl;

E0 , with the proviso that K is (CH(R 14 ))j-T, is E2 wherein E is selected from the group consisting of C(O)N(H), (H)NC(O), C(S)N(H),

(H)NC(S), S(O)2N(H), N(H)S(O)2, S(O)2N(H)C(O), and C(O)N(H)S(O)2;

Y0 is phenyl or a heteroaryl of 5 or 6 ring members, wherein one carbon of said phenyl or said heteroaryl is substituted by Qs , a carbon two or three

contiguous atoms from the point of attachment of Qs to said phenyl or said

heteroaryl to said phenyl or said heteroaryl is substituted by Qb , a carbon

adjacent to the point of attachment of Qs is optionally substituted by R17,

another carbon adjacent to the point of attachment of Qs is optionally.

substituted by R 18 , a carbon adjacent to Qb is optionally substituted by

and another carbon adjacent to Qb is optionally substituted by R19 ;

R16, R17, R18, and R19 are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, haloalkylthio, alkoxy, hydroxy, amino, nitro, alkoxyamino, alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, alkenyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, haloalkoxyalkyl, carboalkoxy, and cyano;

R 16 or R19 is optionally selected from the group consisting of

NR20 R21 , N(R26 )C(NR25 )N(R23 )(R24 ), and C(NR25 )NR23 R24 , with the

proviso that R16 , R19 , and Qb are not simultaneously hydrido;

Qb is selected from the group consisting of NR20 R21 , aminoalkyl,

hydrido, N(R26)C(NR25)N(R23)(R24), and C(NR25)NR23R24, with the

proviso that no more than one of R20 and R21 is selected from the group consisting of hydroxy, amino, alkylamino, and dialkylamino at the same time, with the further proviso that no more than one of R23 and R24 is selected from the group consisting of hydroxy, amino, alkylamino, and dialkylamino at the same time;

R20 , R21 , R23 , R24 , R25 , and R26 are independently selected from the group consisting of hydrido, alkyl, hydroxy, aminoalkyl, amino, dialkylamino, alkylamino, and hydroxyalkyl;

Qs is selected from the group consisting of a bond, (CR37 R38)b

wherein b is an integer selected from 1 through 4, and (CH(R14 ))C-W 1 -

(CH(R15 ))j wherein c and d are integers independently selected from 1

through 3 and W 1 is selected from the group consisting of C(O)N(R14 ),

(R14)NC(O), S(O), S(O)2, S(O)2N(R14), N(R14)S(O)2, and N(R14), with the

proviso that R14 is selected from other than halo when directly bonded to N,

and with the additional proviso that (CR37 R38 )j, and (CH(R14))c are bonded to E0

R37 and R38 are independently selected from the group consisting of hydrido, alkyl, and haloalkyl;

R38 is optionally aroyl or heteroaroyl, wherein R38 is optionally substituted with one or more substituents selected from the group consisting of

R16 , R17 , R18 , and R19 ;

Y0 is optionally YAT wherein Y AT is Qb -Qs ;

Y0 is optionally Qb-Qss wherein Qss is (CH(R14 ))e-W2 -(CH(R 15 ))h,

wherein e and h are independently 1 or 2 and W2 is CR4a =CR4b, with the

proviso that (CH(R14 ))e is bonded to E0 ;

Y° is optionally Qb-Qssss or Qb-Qssssr wherein QSSSS is (CH(R38))r-

W5 , Qssssr is (CH(R38 ))r-W6 , r is 1 or 2, W5 and W6 are independently selected from the group consisting of 1,4-indenyl, 1,5-indenyl, 1,6-indenyl, 1,7-indenyl, 2,7-indenyl, 2,6-indenyl, 2,5-indenyl, 2,4-indenyl, 3,4-indenyl, 3,5-indenyl, 3,6-indenyl, 3,7-indenyl, 2,4-benzofuranyl, 2,5-benzofuranyl, 2,6-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-benzotbiophenyl, 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,Simidazo(1,2-a)pyridinyl, 3,6-imidazo(1,2-a)pyridinyl,

3,7-imidazo(1,2-a)pyridinyl, 2,4-indolyl, 2,5-indolyl, 2,6-indolyl, 2,7-indolyl, 3,4-indolyl, 3 ,5-indolyl, 3 ,6-indolyl, 3 ,7-indolyl, 1,4-isoindolyl, 1,5-isoindolyl, 1,6-isoindolyl, 2,4-isoindolyl, 2,5-isoindolyl, 2,6-isoindolyl, 2,7-isoindolyl, 13-isoindolyl, 3,4-indazolyl, 3,5-indazolyl, 3,6-indazolyl, 3,7-indazolyl, 2,4-benzoxazolyl, 2,5-benzoxazolyl, 2,6-benzoxazolyl, 2,7-benzoxazolyl, 3,4-benzisoxazolyl, 3,5-benzisoxazolyl, 3,6-benzisoxazolyl, 3,7-benzisoxazolyl, 1,4-naphthyl, 1,5-naphthyl, 1,6-naphthyl, 1,7-naphthyl, 1,8-naphthyl,

2,4-naphthyl, 2,5-naphthyl, 2,6-naphthyl, 2,7-naphthyl, 2,8-naphthyl,

2,4-quinolinyl, 2,5-quinolinyl, 2,6-quinolinyl, 2,7-quinolinyl, 2,8-quinolinyl, 3,4-quinolinyl, 3,5-quinoUnyl, 3,6-quinolinyl, 3,7-quinolinyl, 3,8-quinolinyl, 4,5-quinolinyl, 4,6-quinolinyl, 4,7-quinolinyl, 4,8-quinolinyl, 1,4-isoquinoUnyl, 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-isoquiήolinyl, 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 containing nitrogen member of the ring of the W5 and of the ring of the W , other than the points of attachment of W5

and W6 , is optionally substituted with one or more of the group consisting of

R9, R10, R1 1, and R12, with the proviso that Qb is bonded to lowest number

substituent position of each W5 , with the further proviso that Qb is bonded to

highest number substituent position of each W6 , and with the additional

proviso that (CH(R38 ))r is bonded to E0.

In a more preferred embodiment of a compound of Formula I, said compound is the Formula:


or a pharmaceutically acceptable salt thereof, wherein;

B is phenyl or a heteroaryl of 5 or 6 ring members, wherein a carbon adjacent to the carbon at the point of attachment of said phenyl or heteroaryl ring to A is optionally substituted by R32 , the other carbon adjacent to the

carbon at the point of attachment is optionally substituted by R36 , a carbon

adjacent to R32 and two atoms from the carbon at the point of attachment is

optionally substituted by R33 , a carbon adjacent to R36 and two atoms from the carbon at the point of attachment is optionally substituted by R35 , and any

carbon adjacent to both R33 and R35 is optionally substituted by R34 ;

R32, R33, R34, R35, and R36 are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkylenedioxy, haloalkylthio, alkanoyloxy, alkoxy, hydroxy, amino,

alkoxyamino, haloalkanoyl, nitro, alkylamino, alkylthio, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, alkylsulfonamido, amidosulfonyl, alkyl, alkenyl, halo, haloalkyl, haloalkenyl, haloalkoxy, hydroxyalkyl, hydroxyhaloalkyl, aminoalkyl, carboalkoxy, carboxy, carboxamido, cyano, and Qb;

B is optionally selected from the group consisting of hydrido, trialkylsilyl, C2-C8 alkyl, C3-C8 alkylenyl, C3-C8 alkenyl, C3-C8 alkynyl, and C2-C8 haloalkyl, wherein each member of group B is optionally substituted at any carbon up to and including 6 atoms from the point of attachment of B to A with one or more of the group consisting of R32 , R33 , R34 , R35 , and R36 ;

B is optionally a C3-C12 cycloalkyl or a C4-C9 saturated heterocyclyl, wherein each ring carbon is optionally substituted with R33 , 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 substituted with R9 or R13, a ring

carbon or nitrogen atom adjacent to the R9 position and two atoms from the

point of attachment is optionally substituted with R 10, a ring carbon or nitrogen

atom adjacent to the R13 position and two atoms from the point of attachment

is optionally substituted with R12, a ring carbon or nitrogen atom three atoms

from the point of attachment and adjacent to the R10 position is optionally

substituted with R11, a ring carbon or nitrogen atom three atoms from the

point of attachment and adjacent to the R12 position is optionally substituted

with R33 , and a ring carbon or nitrogen atom four atoms from the point of

attachment and adjacent to the R1 1 and R33 positions is optionally substituted

with R34;

R9 , R10 , R1 1 , R12 , and R13 are independently selected from the group consisting of hydrido, acetamido, haloacetamido, alkoxyamino, alkanoyl, haloalkanoyl, amidino, guanidino, alkylenedioxy, haloalkylthio, alkoxy, cycloalkoxy, cycloalkylalkoxy, aralkoxy, aryloxy, heteroaryloxy,

heteroaralkoxy ,heterocyclyloxy, heterocyclylalkoxy, hydroxy, amino, alkylamino, N-alkyl-N-arylamino, arylamino, aralkylamino, heteroarylammo, heteroaralkylamino, heterocyclylamino, heterocyclylalkylamino, alkylthio, alkylsulfinyl, arylsulfinyl, aralkylsulfinyl, cycloalkylsulfinyl, heteroarylsulfinyl, alkylsulfamido, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, cycloalkylsulfonyl, heteroarylsulfonyl, amidosulfonyl, alkyl, aryl, aralkyl, cycloalkyl,

cycloalkylalkyl, heteroaryl, heterocyclyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, hydroxyhaloalkyl, aminoalkyl, carboalkoxy, carboxy, carboxyalkyl, carboxamido, and cyano;

A is bond or (CH(R15))pa-(W7)rr wherein rr is 0 or 1, pa is an integer

selected from 0 through 3, and W7 is selected from the group consisting of O,

S, C(O), (R7)NC(O), (R7)NC(S), and N(R7), with the proviso that W7 is bonded to the N(H) on the 4-pyridone ring;

R7 is selected from the group consisting of hydrido, hydroxy and alkyl;

R15 is selected from the group consisting of hydrido, hydroxy, halo, alkyl, and haloalkyl;

X0 is selected from the group consisting of hydrido, alkyl, cyano, halo, haloalkyl, haloalkoxy, amino, aminoalkyl, alkylamino, amidino, hydroxy, hydroxyamino, alkoxy, hydroxyalkyl, alkoxyamino, thiol, and alkylthio;

R1 is selected from the group consisting of hydrido, alkyl, haloalkyl, amino, aminoalkyl, alkylamino, hydroxy, and hydroxyalkyl;

X0 and R1 or R 1 and R2 is optionally bonded together to form a partially saturated C5-C8 heterocyclyl ring, wherein said heterocyclyl ring is optionally substituted with one or more of the group consisting of R9 , R10 ,

R1 1, R12 , and R13 ;

R2 is Z0-Q;

Z0 is selected from the group consisting of a bond, (CR41 R42 )q

wherein q is 1 or 2, and (CH(R41 ))g-W0 -(CH(R42 ))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), N(R41), and ON(R41);

Z0 is optionally (CH(R41))e-W22-(CH(R42))h wherein e and h are

independently 0 or 1 and W^ is selected from the group consisting of

CR41 =CR42, 1,2-cyclopropyl, 1,2-cyclobutyl, 1,2-cyclohexyl, 13-cyclohexyl,

1,2-cyclopentyl, 13-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, 2,3-ρiperidinyl, 2,4-piperidinyl, 2,6-piperidinyl, 3,4-piperidinyl,

1,2-pyrrolidinyl,13-pyπOlidinyl, 2,3-pyrrolidinyl, 2,4-pyrrolidinyl,

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

2,5-tetrahydrofuranyl, and 3,4-tetrahydrofuranyl, wherein Z is directly bonded to the 4-pyridone ring and W22 is optionally substituted with one or more

substituents selected from the group consisting of R9 , R10 , R11 , R12 , and R13 ;

R41 and R42 are independently selected from the group consisting of hydrido, hydroxy, alkyl, and amino;

Q is phenyl or a heteroaryl of 5 or 6 ring members, wherein a carbon adjacent to the carbon at the point of attachment of said phenyl or heteroaryl ring to Z0 is optionally substituted by R9 , the other carbon adjacent to the

carbon at the point of attachment is optionally substituted by R13, a carbon

adjacent to R9 and two atoms from the carbon at the point of attachment is

optionally substituted by R 10, a carbon adjacent to R 13 and two atoms from the

carbon at the point of attachment is optionally substituted by R12 , and any

carbon adjacent to both R10 and R12 is optionally substituted by R1 1;

Q is optionally hydrido with the proviso that Z0 is other than a bond;

K is CR4a R4b;

R4a and R4b are independently selected from the group consisting of hydrido, hydroxyalkyl, alkyl, alkoxyalkyl, alkylthioalkyl, and haloalkyl;

E0 , with the proviso that K is CR4a R4b , is E wherein E is selected from the group consisting of a covalent single bond, C(O)N(H), (H)NC(O),

S(O)2N(H), and N(H)S(O)2;

K is optionally (CH(R14 ))j-T wherein j is 0 or 1 and T is a bond or

N(R7) with the proviso that (CH(R14))j is bonded to the phenyl ring;

R 14 is hydrido or halo;

E0 , with the proviso that K is (CH(R14))j-T, is E2 wherein E2 is selected from the group consisting of C(0)N(H), (H)NC(O), C(S)N(H),

(H)NC(S), S(O)2N(H), N(H)S(O)2, S(O)2N(H)C(O), and C(O)N(H)S(O)2;

Y0 is phenyl or a heteroaryl of 5 or 6 ring members, wherein one carbon of said phenyl or said heteroaryl is substituted by Qs , a carbon two or three

atoms from the point of attachment of Qs to said phenyl or said heteroaryl is

substituted by Qb , a carbon adjacent to the point of attachment of Qs is

optionally substituted by R17, another carbon adjacent to the point of

attachment of Qs is optionally substituted by R18, a carbon adjacent to Qb is

optionally substituted by R16, and another carbon adjacent to Qb is optionally

substituted by R19;

R16, R17, R18, and R19 are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, haloalkylthio, alkoxy, hydroxy, amino, alkoxyamino, alkylamino, alkylthio, alkylsulfinyl,

alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, and cyano;

R16 or R19 is optionally selected from the group consisting of

NR20 R21 ,N(R26 )C(NR25 )N(R23 )(R24 ), and C(NR25 )NR23 R24, with the

proviso that R16, R19, and Qb are not simultaneously hydrido;

Qb is selected from the group consisting of NR20 R21, hydrido,

N(R26 )C(NR25 )N(R23 )(R24 ), and C(NR25 )NR23 R24 , with the proviso that no

more than one of R20 and R21 is selected from the group consisting of hydroxy, amino, alkylamino, and dialkylamino at the same time, with the further proviso that no more than one of R23 and R24 is selected from the group consisting of hydroxy, amino, alkylamino, and dialkylamino at the same time;

R20 , R21 , R23 , R24 , R25 , and R26 are independently selected from the group consisting of hydrido, alkyl, hydroxy, amino, alkylamino and dialkylamino;

Qs is selected from the group consisting of a bond, (CR37 R38)b

wherein b is an integer selected from 1 through 4, and (CH(R14 ))C-W 1-

(CH(R15 ))d wherein c and d are integers independently selected from 1

through 3 and W1 is selected from the group consisting of C(O)N(R14),

(R14)NC(O), S(O), S(O)2, S(O)2N(R14), N(R14)S(O)2, and N(R14), with the

proviso that R14 is selected from other than halo when directly bonded to N,

and with the additional proviso that (CR37 R38 )b and (CR37 R38 )b, and

(CH(R14))C are bonded to E°;

R37 and R38 are independently selected from the group consisting of hydrido, alkyl, and haloalkyl;

R38 is optionally aroyl or heteroaroyl, wherein R38 is optionally substituted with one or more substituents selected from the group consisting of

R16, R17, R18, and R19;

Y0 is optionally YAT wherein YAT is Qb -Qs ;

Y° is optionally Qb-QSS wherein QSS is (CH(R14))e-W2-(CH(R15))h,

wherein e and h are independently 1 or 2 and w W2 is CR4a =CR4b with the

proviso that (CH(R14 ))e is bonded to E0.

In an even more preferred embodiment of a compound of Formula I, said compound is the formula:


or a pharmaceutically acceptable salt thereof, wherein;

B is phenyl or a heteroaryl of 5 or 6 ring members, wherein a carbon adjacent to the carbon at the point of attachment of said phenyl or heteroaryl ring to A is optionally substituted by R32, the other carbon adjacent to the

carbon at the point of attachment is optionally substituted by R36 , a carbon

adjacent to R32 and two atoms from the carbon at the point of attachment is optionally substituted by R33, a carbon adjacent to R36 and two atoms from the

carbon at the point of attachment is optionally substituted by R35, and any

carbon adjacent to both R33 and R35 is optionally substituted by R34;

R32, R33, R34, R35, and R36 are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkoxy, hydroxy, amino, alkoxyamino, alkylamino, alkylthio, amidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, hydroxyhaloalkyl, carboalkoxy, carboxy, carboxamido, cyano, and Qb;

A is a bond or (CH(R15 ))pa-(W7 )rr wherein rr is 0 or 1, pa is an

integer selected from 0 through 3, and W7 is (R7 )NC(O) or N(R7 );

R7 is selected from the group consisting of hydrido, hydroxy and alkyl;

R15 is selected from the group consisting of hydrido, halo, alkyl, and haloalkyl;

X0 is selected from the group consisting of hydrido, amino, alkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, hydroxy, alkoxy, hydroxyalkyl, and alkylthio;

R 1 is independently selected from the group consisting of hydrido, hydroxy, amino, hydroxyalkyl, alkyl, aminoalkyl, and haloalkyl;

R2 is Z0-Q;

Z0 is selected from the group consisting of a bond, CH2, CH2CH2, W - (CH(R42 ))p wherein p is 0 or 1 and W0 is selected from the group consisting

of O, S, and N(R41);

R41 and R42 are independently hydrido or alkyl;

Q is phenyl or a heteroaryl of 5 or 6 ring members, wherein a carbon adjacent to the carbon at the point of attachment of said phenyl or heteroaryl ring to Z0 is optionally substituted by R9 , the other carbon adjacent to the

carbon at the point of attachment is optionally substituted by R13, a carbon

adjacent to R9 and two atoms from the carbon at the point of attachment is

optionally substituted by R10 , a carbon adjacent to R13 and two atoms from the

carbon at the point of attachment is optionally substituted by R12 , and any

carbon adjacent to both R10 and R12 is optionally substituted by R1 1;

R9, R1 1, and R13 are independently selected from the group consisting of hydrido, hydroxy, amino, amidino, guanidino, alkylamino, alkylthio, alkylsulfonamido, alkylsulfinyl, alkylsulfonyl, amidosulfonyl, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, hydroxyalkyl, hydroxyhaloalkyl, carboxy, carboxamido, and cyano;

R10 and R12 are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, alkoxy, cycloalkoxy, cycloalkylalkoxy, aralkoxy, aryloxy, heteroaryloxy,

heteroaralkoxy ,heterocyclyloxy, heterocyclylalkoxy, hydroxy, amino, alkoxyamino, alkylamino, arylamino, aralkylamino, heteroarylamino, heteroaralkylamino, heterocyclylamino, heterocyclylalkylamino,

alkylsulfonamido, amidosulfonyl, arylsulfinyl, aralkylsulfinyl,

cycloalkylsulfinyl, heteroarylsulfinyl, arylsulfonyl, aralkylsulfonyl,

cycloalkylsulfonyl, heteroarylsulfonyl, hydroxyalkyl, hydroxyhaloalkyl, aminoalkyl, carboalkoxy, carboxy, carboxyalkyl, carboxamido, halo, haloalkyl, and cyano;

Y0 is phenyl or a heteroaryl of 5 or 6 ring members, wherein one carbon of said phenyl or said heteroaryl is substituted by Qs, a carbon two or three

atoms from the point of attachment of Qs to said phenyl or said heteroaryl is

substituted by Qb , a carbon adjacent to the point of attachment of Qs is

optionally substituted by R17, another carbon adjacent to the point of

attachment of Q is optionally substituted by R18, a carbon adjacent to Qb is

optionally substituted by R16, and another carbon adjacent to Qb is optionally

substituted by R19;

R16, R17, R18, and R19 are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, haloalkylthio, alkoxy, hydroxy, amino, alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, and cyano;

R16 or R19 is optionally NR20 R21 or C(NR25 )NR23 R24 , with the

proviso that R 16, R19 , and Qb are not simultaneously hydrido;

Qb is selected from the group consisting of NR20 R21, hydrido, and

C(NR25 )NR23 R24, with the proviso that no more than one of R20 and R21 is

hydroxy at the same time and with the further proviso that no more than one of R23

and R24 is hydroxy at the same time;

R20 , R21, R23, R24, and R25 are independently selected from the group consisting of hydrido, alkyl, and hydroxy;

Qs is selected from the group consisting of a bond, CH2, and

CH2CH2.

In another even more preferred embodiment of a compound of Formula I, said compound is the Formula:

or a pharmaceutically acceptable salt thereof, wherein;

B is selected from the group consisting of hydrido, C2-C8 alkyl, C3-C8 alkenyl, C3-C8 alkynyl, and C2-C8 haloalkyl, wherein each member of group B is optionally substituted at any carbon up to and including 6 atoms from the point of attachment of B to A with one or more of the group consisting of R32,

R33, R34, R35, and R36;

R32, R33, R34, R35, and R36 are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkoxy, hydroxy, amino, alkoxyamino, alkylamino, alkylthio, amidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, hydroxyhaloalkyl, carboalkoxy, carboxy, carboxamido, cyano, and Qb;

A is a bond or (CH(R15 ))pa-(W7 )n wherein rr is 0 or 1, pa is an

integer selected from 0 through 3, and W7 is (R7 )NC(O) or N(R7 );

R7 is selected from the group consisting of hydrido, hydroxy and alkyl;

R15 is selected from the group consisting of hydrido, halo, alkyl, and haloalkyl;

X is selected from the group consisting of hydrido, amino, alkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, hydroxy, alkoxy, hydroxyalkyl, and alkylthio;

R 1 is independently selected from the group consisting of hydrido, hydroxy, amino, hydroxyalkyl, alkyl, aminoalkyl, and haloalkyl;

R2 is Z0-Q;

Z0 is selected from the group consisting of a bond, CH2, CH2CH2, W - (CH(R42 ))p wherein p is 0 or 1 and W is selected from the group consisting

of O, S, and N(R41);

R41 and R42 are independently hydrido or alkyl;

Q is phenyl or a heteroaryl of 5 or 6 ring members, wherein a carbon adjacent to the carbon at the point of attachment of said phenyl or heteroaryl ring to Z0 is optionally substituted by R9 , the other carbon adjacent to the

carbon at the point of attachment is optionally substituted by R13, a carbon

adjacent to R9 and two atoms from the carbon at the point of attachment is

optionally substituted by R10, a carbon adjacent to R13 and two atoms from the

carbon at the point of attachment is optionally substituted by R12, and any

carbon adjacent to both R10 and R12 is optionally substituted by R11;

R9 , R1 1, and R13 are independently selected from the group consisting of hydrido, hydroxy, amino, amidino, guanidino, alkylamino, alkylthio, alkylsulfonamido, alkylsulfinyl, alkylsulfonyl, amidosulfonyl, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, hydroxyalkyl, hydroxyhaloalkyl, carboxy, carboxamido, and cyano;

R10 and R12 are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, alkoxy, cycloalkoxy, cycloalkylalkoxy, aralkoxy, aryloxy, heteroaryloxy,

heteroaralkoxy ,heterocyclyloxy, heterocyclylalkoxy, hydroxy, amino, alkoxyamino, alkylamino, arylamino, aralkylamino, heteroarylammo, heteroaralkylamino, heterocyclylamino, heterocyclylalkylamino,

alkylsulfonamido, amidosulfonyl, arylsulfinyl, aralkylsulfinyl,

cycloalkylsulfinyl, heteroarylsulfinyl, arylsulfonyl, aralkylsulfonyl,

cycloalkylsulfonyl, heteroarylsulfonyl, hydroxyalkyl, hydroxyhaloalkyl, aminoalkyl, carboalkoxy, carboxy, carboxyalkyl, carboxamido, halo, haloalkyl, and cyano;

Y0 is phenyl or a heteroaryl of 5 or 6 ring members, wherein one carbon of said phenyl or said heteroaryl is substituted by Qs , a carbon two or three

atoms from the point of attachment of Qs to said phenyl or said heteroaryl is

substituted by Qb , a carbon adjacent to the point of attachment of Qs is

optionally substituted by R17, another carbon adjacent to the point of

attachment of Qs is optionally substituted by R18, a carbon adjacent to Qb is

optionally substituted by R16 , and another carbon adjacent to Qb is optionally

substituted by R19 ;

R16, R17, R18, and R19 are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, haloalkylthio, alkoxy, hydroxy, amino, alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, and cyano;

R16 or R19 is optionally selected from the group consisting of

NR2°R21 , N(R26)C(NR25)N(R23)(R24), and C(NR25)NR23R24, with the

proviso that R16 , R19 , and Qb are not simultaneously hydrido;

Qb is selected from the group consisting of NR20 R21 , hydrido,

C(NR25 )NR23 R24 , and N(R26 )C(NR25 )N(R23 )(R24 ), with the proviso that

no more than one of R20 and R21 is hydroxy at the same time and with the

further proviso that no more than one of R23 and R24 is hydroxy at the same time;

R20 , R21 , R23 , R24 , R25 , and R26 are independently selected from the group consisting of hydrido, alkyl, and hydroxy;

Qs is selected from the group consisting of a bond, CH2, and

CH2CH2.

In still another even more preferred embodiment of a compound of Formula I, said compound is the Formula:


or a pharmaceutically acceptable salt thereof, wherein;

B is a C3-C7 cycloalkyl or a C4-C6 saturated heterocyclyl, wherein each ring carbon is optionally substituted with R33, 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 substituted with R9 or R13, a ring carbon or

nitrogen adjacent to the R9 position and two atoms from the point of attachment

is optionally substituted with R10, a ring carbon or nitrogen adjacent to the R13

position and two atoms from the point of attachment is optionally substituted with R12, a ring carbon or nitrogen three atoms from the point of attachment

and adjacent to the R position is optionally substituted with R1 1, a ring carbon or nitrogen three atoms from the point of attachment and adjacent to the

R12 position is optionally substituted with R33 , and a ring carbon or nitrogen

four atoms from the point of attachment and adjacent to the R1 1 and R33

positions is optionally substituted with R34 ;

R9 , R1 1, and R13 are independently selected from the group consisting of hydrido, hydroxy, amino, amidino, guanidino, alkylamino, alkylthio,

alkylsulfonamido, alkylsulfinyl, alkylsulfonyl, amidosulfonyl, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, hydroxyalkyl, hydroxyhaloalkyl, carboxy, carboxamido, and cyano;

R10 and R12 are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, alkoxy, cycloalkoxy, cycloalkylalkoxy, aralkoxy, aryloxy, heteroaryloxy,

heteroaralkoxy ,heterocyclyloxy, heterocyclylalkoxy, hydroxy, amino, alkoxyamino, alkylamino, arylamino, aralkylamino, heteroarylamino, heteroaralkylamino, heterocyclylamino, heterocyclylalkylamino,

alkylsulfonamido, amidosulfonyl, arylsulfinyl, aralkylsulfinyl,

cycloalkylsulfinyl, heteroarylsulfinyl, arylsulfonyl, aralkylsulfonyl,

cycloalkylsulfonyl, heteroarylsulfonyl, hydroxyalkyl, hydroxyhaloalkyl, aminoalkyl, carboalkoxy, carboxy, carboxyalkyl, carboxamido, halo, haloalkyl, and cyano;

R33 and R34 are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkoxy, hydroxy, amino, alkoxyamino, alkylamino, alkylthio, amidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, hydroxyhaloalkyl, carboalkoxy, carboxy,

carboxamido, and cyano;

R33 is optionally Qb;

A is a bond or (CH(R15))pa-(W7)rr wherein rr is 0 or 1, pa is an

integer selected from 0 through 3, and W7 is (R7 )NC(O) or N(R7 );

R7 is selected from the group consisting of hydrido, hydroxy and alkyl;

R 15 is selected from the group consisting of hydrido, halo, alkyl, and haloalkyl;

X0 is selected from the group consisting of hydrido, amino, alkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, hydroxy, alkoxy, hydroxyalkyl, and alkylthio;

R1 is independently selected from the group consisting of hydrido, hydroxy, amino, hydroxyalkyl, alkyl, aminoalkyl, and haloalkyl;

R2 is Z°-Q;

Z0 is selected from the group consisting of a bond, CH2, CH2CH2,

W0 -(CH(R42 )) wherein p is 0 or 1 and W is selected from the group

consisting of O, S, and N(R41 );

R41 and R42 are independently hydrido or alkyl;

Q is phenyl or a heteroaryl of 5 or 6 ring members, wherein a carbon adjacent to the carbon at the point of attachment of said phenyl or heteroaryl ring to Z0 is optionally substituted by R9 , the other carbon adjacent to the

carbon at the point of attachment is optionally substituted by R13 , a carbon

adjacent to R9 and two atoms from the carbon at the point of attachment is

optionally substituted by R10, a carbon adjacent to R13 and two atoms from the

carbon at the point of attachment is optionally substituted by R12 , and any

carbon adjacent to both R10 and R12 is optionally substituted by R1 1;

Y0 is phenyl or a heteroaryl of 5 or 6 ring members, wherein one carbon of said phenyl or said heteroaryl is substituted by Qs , a carbon two or three

atoms from the point of attachment of Qs to said phenyl or said heteroaryl is

substituted by Qb , a carbon adjacent to the point of attachment of Qs is

optionally substituted by R17 , another carbon adjacent to the point of

attachment of Q is optionally substituted by R18 , a carbon adjacent to Qb is

optionally substituted by R16, and another carbon adjacent to Qb is optionally

substituted by R19 ;

R 16, R17, R18, and R19 are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, haloalkylthio, alkoxy, hydroxy, amino, alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, and cyano;

R16 or R19 is optionally NR20 R21 or and C(NR25 )NR23 R24, with the

proviso that R16, R19, and Qb are not simultaneously hydrido;

Qb is selected from the group consisting of NR20 R21 , hydrido, and

C(NR25 )NR23 R24, with the proviso that no more than one of R20 and R21 is

hydroxy at the same time and with the further proviso that no more than one of R23

and R24 is hydroxy at the same time;

R20, R21, R23, R24, and R25 are independently selected from the group consisting of hydrido, alkyl, and hydroxy;

Qs is selected from the group consisting of a bond, CH2, and

CH2CH2.

In an additional even more preferred embodiment of a compound of Formula I, said compound is the Formula:


or a pharmaceutically acceptable salt thereof, wherein;

B is selected from the group consisting of hydrido, trialkylsilyl, C2-C4 alkyl, C3-C5 alkylenyl, C3-C4 alkenyl, C3-C4 alkynyl, and C2-C4 haloalkyl, wherein each member of group B is optionally substituted at any carbon up to and including 3 atoms from the point of attachment of B to A with one or more of the group consisting of R32, R33 , and R34 ;

R32, R33, and R34 are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkoxy, hydroxy, amino, alkoxyamino, alkylamino, alkylthio, amidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, hydroxyhaloalkyl, carboalkoxy, carboxy, carboxamido, and cyano;

A is (CH(R15 ))pa-N(R7 ) wherein pa is an integer selected from 0

through 2 and R7 is hydrido or alkyl;

R15 is selected from the group consisting of hydrido, halo, alkyl, and haloalkyl;

X0 is selected from the group consisting of hydrido, amino, alkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, hydroxy, alkoxy, hydroxyalkyl, and alkylthio;

R1 is selected from the group consisting of hydrido, alkyl, haloalkyl, amino, aminoalkyl, hydroxy, and hydroxyalkyl;

R2 is Z0-Q;

Z0 is a bond or CH2;

Q is phenyl or a heteroaryl of 5 or 6 ring members, wherein a carbon adjacent to the carbon at the point of attachment of said phenyl or heteroaryl ring to Z0 is optionally substituted by R9 , the other carbon adjacent to the

carbon at the point of attachment is optionally substituted by R13, a carbon

adjacent to R9 and two atoms from the carbon at the point of atta

optionally substituted by R10 , a carbon adjacent to R13 and two atoms from the

carbon at the point of attachment is optionally substituted by R12, and any

carbon adjacent to both R10 and R12 is optionally substituted by R1 1;

R9 , R11 , and R13 are independently selected from the group consisting of hydrido, hydroxy, amino, amidino, guanidino, alkylamino, alkylthio, alkylsulfonamido, alkylsulfinyl, alkylsulfonyl, amidosulfonyl, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, hydroxyalkyl, hydroxyhaloalkyl, carboxy, carboxamido, and cyano;

R10 and R12 are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, alkoxy, cycloalkoxy, cycloalkylalkoxy, aralkoxy, aryloxy, heteroaryloxy, heteroaralkoxy,

heterocyclyloxy, heterocyclylalkoxy, hydroxy, amino, alkoxyamino, alkylamino, arylamino, aralkylamino, heteroarylamino, heteroaralkylamino,

heterocyclylamino, heterocyclylalkylamino, alkylsulfonamido, amidosulfonyl, arylsulfinyl, aralkylsulfinyl, cycloalkylsulfinyl, heteroarylsulfinyl, aiylsulfonyl, aralkylsulfonyl, cycloalkylsulfonyl, heteroarylsulfonyl, hydroxyalkyl, hydroxyhaloalkyl, aminoalkyl, carboalkoxy, carboxy, carboxyalkyl,

carboxamido, halo, haloalkyl, and cyano;

i is phenyl or a heteroaryl of 5 or 6 ring members, wherein one carbon of said phenyl or said heteroaryl is substituted by Qs, a carbon two or three

atoms from the point of attachment of Qs to said phenyl or said heteroaryl is

substituted by Qb , a carbon adjacent to the point of attachment of Qs is

optionally substituted by R17, another carbon adjacent to the point of

attachment of Qs is optionally substituted by R18, a carbon adjacent to Qb is

optionally substituted by R16 , and another carbon adjacent to Qb is optionally

substituted by R19;

R16, R17, R18, and R19 are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, haloalkylthio, alkoxy, hydroxy, amino, alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, and cyano;

R16 or R19 is optionally selected from the group consisting of

NR20 R21, N(R26 )C(NR25 )N(R23 )(R24 ), and C(NR25 )NR23 R24, with the

proviso that R16 , R19 , and Qb are not simultaneously hydrido;

Qb is selected from the group consisting of NR20 R21 , hydrido,

C(NR25 )NR23 R24 , and N(R26 )C(NR25 )N(R23 )(R24 ), with the proviso that

no more than one of R20 and R21 is hydroxy at the same time and with the

further proviso that no more than one of R23 and R24 is hydroxy at the same time;

R20 , R21 , R23 , R24 , R25 , and R26 are independently selected from the group consisting of hydrido, alkyl, and hydroxy;

Qs is selected from the group consisting of a bond, CH2, and

CH2CH2.

In a fifth even more preferied embodiment of a compound of Formula I, said compound is Formula:


or a pharmaceutically acceptable salt thereof, wherein;

B is phenyl or a heteroaryl of 5 or 6 ring members, wherein a carbon adjacent to the carbon at the point of attachment of said phenyl or heteroaryl ring to A is optionally substituted by R32 , the other carbon adjacent to the

carbon at the point of attachment is optionally substituted by R36 , a carbon adjacent to R32 and two atoms from the carbon at the point of attachment is

optionally substituted by R33 , a carbon adjacent to R36 and two atoms from the

carbon at the point of attachment is optionally substituted by R35, and any

carbon adjacent to both R33 and R35 is optionally substituted by R34 ;

R32, R33, R34, R35, and R36 are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkylenedioxy, haloalkylthio, alkanoyloxy, alkoxy, hydroxy, amino,

alkoxyamino, haloalkanoyl, nitro, alkylamino, alkylthio, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, alkylsulfonamido, amidosulfonyl, alkyl, alkenyl, halo, haloalkyl, haloalkenyl, haloalkoxy, hydroxyalkyl, alkylamino, carboalkoxy, carboxy, carboxamido, cyano, and Q ;

B is optionally selected from the group consisting of hydrido, trialkylsilyl, C2-C8 alkyl, C3-C8 alkylenyl, C3-C8 alkenyl, C3-C8 alkynyl, and C2-C8 haloalkyl, wherein each member of group B is optionally substituted at any carbon up to and including 6 atoms from the point of attachment of B to A with one or more of the group consisting of R32, R33, R34, R35, and R36

B is optionally a C3-C12 cycloalkyl or a C4-C9 saturated heterocyclyl, wherein each ring carbon is optionally substituted with R33, 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 substituted with R9 or R13, a ring

carbon or nitrogen adjacent to the R9 position and two atoms from the point of

attachment is optionally substituted with R10 , a ring carbon or nitrogen adjacent

to the R13 position and two atoms from the point of attachment is optionally

substituted wift R12, a ring carbon or nitrogen three atoms from the poiut of

attachment and adjacent to the R10 position is optionally substituted with R1 1, a ring carbon or nitrogen three atoms from the point of attachment and adjacent to the R12 position is optionally substituted with R33, and a ring carbon or

nitrogen four atoms from the point of attachment and adjacent to the R and

R33 positions is optionally substituted with R34 ;

R9 , R10 , R1 1 , R12 , and R13 are independently selected from the group consisting of hydrido, acetamido, haloacetamido, alkoxyamino, alkanoyl, haloalkanoyl, amidino, guanidino, alkylenedioxy, haloalkylthio, alkoxy, cycloalkoxy, cycloalkylalkoxy, aralkoxy, aryloxy, heteroaryloxy,

heteroaralkoxy ,heterocyclyloxy, heterocyclylalkoxy, hydroxy, amino, alkylamino, N-alkyl-N-arylamino, arylamino, aralkylamino, heteroarylamino, heteroaralkylamino, heterocyclylamino, heterocyclylalkylamino, alkylthio, alkylsulfinyl, arylsulfinyl, aralkylsulfinyl, cycloalkylsulfinyl, heteroarylsulfinyl, alkylsulfamido, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, cycloalkylsulfonyl, heteroarylsulfonyl, amidosulfonyl, alkyl, aryl, aralkyl, cycloalkyl,

cycloalkylalkyl, heteroaryl, heterocyclyl, halo, haloalkyl, haloalkoxy,

hydroxyalkyl, hydroxyhaloalkyl, aminoalkyl, carboalkoxy, carboxy,

carboxyalkyl, carboxamido, and cyano;

A is a bond or (CH(R15 ))pa-(W7 )rr wherein rr is 0 or 1, pa is an

integer selected from 0 through 3, and W7 is selected from the group

consisting of O, S, C(O), (R7)NC(O), (R7)NC(S), and N(R7);

R7 is selected from the group consisting of hydrido, hydroxy and alkyl;

R 15 is selected from the group consisting of hydrido, hydroxy, halo, alkyl, and haloalkyl;

X0 is selected from the group consisting of hydrido, amino, alkyl, cyano, halo, haloalkyl, haloalkoxy, aminoalkyl, hydroxy, alkoxy, hydroxyalkyl, and alkylthio;

R1 is selected from the group consisting of hydrido, alkyl, haloalkyl, amino, aminoalkyl, alkylamino, hydroxy, and hydroxyalkyl;

R2 is Z0-Q;

Z0 is selected from the group consisting of a bond, (CR41 R 42 )q

wherein q is 1 or 2, and (CH(R41 ))g-W0 -(CH(R42 ))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), N(R41), and ON(R41);

Z0 is optionally (CH(R41))e-W22-(CH(R42))h wherein e and h are

independently 0 or 1 and W22 is selected from the group consisting of

CR41 =CR42 , 1,2-cyclopropyl, 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-piperazinyl,

13-piperazinyl, 2,3-piperazinyl, 2,6-piperazinyl, 1,2-piperidinyl, 1,3-piperidinyl, 23-piρeridinyl, 2,4-piperidinyl, 2,6-piperidinyl, 3,4-piperidinyl,

1,2-pyrrolidinyl,1,3-pyπolidinyl, 2,3-pyrrolidinyl, 2,4-pyrrolidinyl,

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

2,5-tetrahydrofuranyl, and 3,4-tetrahydrofuranyl, wherein Z is directly bonded to the 4-pyridone ring and W^ is optionally substituted with one or more

substituents selected from the group consisting of R9, R10 , R11, R12, and R13;

R41 and R42 are independently selected from the group consisting of hydrido, hydroxy, alkyl, and amino;

Q is phenyl or a heteroaryl of 5 or 6 ring members, wherein a carbon adjacent to the carbon at the point of attachment of said phenyl or heteroaryl ring to Z0 is optionally substituted by R9 , the other carbon adjacent to the

carbon at the point of attachment is optionally substituted by R13, a carbon

adjacent to R9 and two atoms from the carbon at the point of attachment is

optionally substituted by R 10, a carbon adjacent to R13 and two atoms from the

carbon at the point of attachment is optionally substituted by R12, and any

carbon adjacent to both R10 and R12 is optionally substituted by R1 1, with the proviso that Q is other than a phenyl when Z0 is a bond;

Q is optionally hydrido with the proviso that Z0 is selected from other than a bond;

K is CHR4a wherein R4a is selected from the group consisting of hydrido, hydroxyalkyl, alkyl, alkoxyalkyl, alkylthioalkyl, and haloalkyl;

E0 is selected from the group consisting of a bond, C(O)N(H),

(H)NC(O), (R7)NS(O)2, and S(O)2N(R7);

YAT is Qb -Qs ;

Qs is (CR37 R38 )tø wherein b is an integer selected from 1 through 4,

R37 is selected from the group consisting of hydrido, alkyl, and haloalkyl, and

R38 is selected from the group consisting of hydrido, alkyl, haloalkyl, aroyl, and heteroaroyl with the proviso that there is at least one aroyl or heteroaroyl substituent, with the further proviso that no more than one aroyl or heteroaroyl is bonded to (CR37 R38)b at the same time, with the still further proviso that said aroyl and said heteroaroyl are optionally substituted with one or more substituents selected irom the group consisting of R16, R17, R18, and R19, with another further proviso that said aroyl and said heteroaroyl are bonded to the CR37 R38 that is directly bonded to E0 , with still another further proviso

that no more than one alkyl or one haloalkyl is bonded to a CR37 R38 at the same time, and with the additional proviso that said alkyl and haloalkyl are bonded to a carbon other than the one bonding said aroyl or said heteroaroyl;

R16, R17, R18, and R19, are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, haloalkylthio, alkoxy, hydroxy, amino, alkoxyamino, alkylamino, alkylthio, alkylsulfinyl,

alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, and cyano;

R16 or R19 is optionally selected from the group consisting of

NR20 R21, N(R26 )C(NR25 )N(R23 )(R24 ), and C(NR25 )NR23 R24, with the

proviso that R 16, R19, and Qb are not simultaneously hydrido;

Qb is selected from the group consisting of NR20 R21 , hydrido,

N(R26 )C(NR25 )N(R23 )(R24 ), and C(NR25 )NR23 R24 , with the proviso that

no more than one of R20 and R21 is selected from the group consisting of hydroxy, amino, alkylamino, and dialkylamino at the same time and with the further proviso that no more than one of R23 and R24 is selected from the group consisting of hydroxy, amino, alkylamino, and dialkylamino at the same time;

R20, R21, R23, R24, R25, and R26 are independently selected from the group consisting of hydrido, alkyl, hydroxy, amino, alkylamino and dialkylamino.

In a most preferred embodiment of compounds of Formula I, said compound is the Formula:


or a pharmaceutically acceptable salt thereof, wherein;

B is phenyl or a heteroaryl of 5 or 6 ring members, wherein a carbon adjacent to the carbon at the point of attachment of said phenyl or heteroaryl ring to A is optionally substituted by R32, the other carbon adjacent to the

carbon at the point of attachment is optionally substituted by R36 , a carbon

adjacent to R32 and two atoms from the carbon at the point of attachment is optionally substituted by R33, a carbon adjacent to R36 and two atoms from the

carbon at the point of attachment is optionally substituted by R35, and any

carbon adjacent to both R33 and R35 is optionally substituted by R34 ;

R32, R33 , R34, R35, and R36 are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkoxy, hydroxy, amino, alkoxyamino, alkylamino, alkylthio, amidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboalkoxy, carboxy, carboxamido, cyano, and Qb;

A is a bond or (CH(R 15 ))pa-(W7 )rr wherein ri is 0 or 1, pa is an

integer selected from 0 through 3, and W7 is N(R7 );

R7 is hydrido or alkyl;

R15 is selected from the group consisting of hydrido, halo, alkyl, and haloalkyl;

X0 is selected from the group consisting of hydrido, alkyl, halo, haloalkyl, aminoalkyl, and hydroxyalkyl;

R1 is selected from the group consisting of hydrido, alkyl,

hydroxyalkyl, and haloalkyl;

R2 is Z0-Q;

Z is a bond;

Q is phenyl or a heteroaryl of 5 or 6 ring members, wherein a carbon adjacent to the carbon at the point of attachment of said phenyl or heteroaryl ring to Z0 is optionally substituted by R9 , the other carbon adjacent to the

carbon at the point of attachment is optionally substituted by R13, a carbon

adjacent to R9 and two atoms from the carbon at the point of attachment is

optionally substituted by R10 , a carbon adjacent to R13 and two atoms from the carbon at me point of attachment is option^ substMed by R12 and any

carbon adjacent to both R10 and R12 is optionally substituted by R1 1 ;

R9 , R1 1 , and R13 are independently selected from the group consisting of hydrido, hydroxy, amino, amidino, guanidino, alkylamino, alkylthio, alkoxy, alkylsulfinyl, alkylsulfonyl, 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, hydroxy, amino, alkylamino, alkylsulfonamido, amidosulfonyl, hydroxyalkyl, aminoalkyl, halo, haloalkyl, carboalkoxy, carboxy, carboxamido, carboxyalkyl, and cyano;

Y0 is phenyl or a heteroaryl of 5 or 6 ring members, wherein one carbon of said phenyl or said heteroaryl is substituted by Qs , a carbon two or three

atoms from the point of attachment of Qs to said phenyl or said heteroaryl is

substituted by Qb , a carbon adjacent to the point of attachment of Qs is

optionally substituted by R17 , another carbon adjacent to the point of

attachment of Qs is optionally substituted by R18 , a carbon adjacent to Qb is

optionally substituted by R16 , and another carbon adjacent to Qb is optionally

substituted by R19;

R16, R17, R18, and R19 a,re independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, haloalkylthio, alkoxy, hydroxy, amino, alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, and cyano;

R16 or R19 is optionally NR20 R21 or C(NR25 )NR23 R24, with the

proviso that R16 , R19 , and Qb are not simultaneously hydrido;

Qb is selected from the group consisting of NR20 R21, hydndo, and

C(NR25 )NR23 R24 ;

R20, R21, R23, R24, and R25 are independently hydrido or alkyl;

Qs is CH2.

In a further most preferred embodiment of compounds of Formula I, said compound is the Formula:


or a pharmaceutically acceptable salt thereof, wherein;

B is selected from the group consisting of hydrido, C2-C8 alkyl, C3-C8 - alkenyl, C3-C8 alkynyl, and C2-C8 haloalkyl, wherein each member of group B is optionally substituted at any carbon up to and including 6 atoms from the point of attachment of B to A with one or more of the group consisting of R32,

R33 , R34, R35, and R36;

R32, R33, R34, R35, and R36 are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkoxy, hydroxy, amino, alkoxyamino, alkylamino, alkylthio, amidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboalkoxy, carboxy, carboxamido, cyano, and Q ;

A is a bond or (CH(R15 ))pa-(W7 )rr wherein rr is 0 or 1 , pa is an

integer selected from 0 through 3, and W7 is N(R7 );

R7 is hydndo or alkyl;

R15 is selected from the group consisting of hydrido, halo, alkyl, and haloalkyl;

X0 is selected from the group consisting of hydrido, alkyl, halo, haloalkyl, aminoalkyl, and hydroxyalkyl;

R1 is selected from the group consisting of hydrido, alkyl,

hydroxyalkyl, and haloalkyl;

R2 is Z0-Q;

Z0 is a bond;

Q is phenyl or a heteroaryl of 5 or 6 ring members, wherein a carbon adjacent to the carbon at the point of attachment of said phenyl or heteroaryl ring to Z0 is optionally substituted by R9 , the other carbon adjacent to the

carbon at the point of attachment is optionally substituted by R13, a carbon

adjacent to R9 and two atoms from the carbon at the point of attachment is

optionally substituted by R10, a carbon adjacent to R13 and two atoms from the

carbon at the point of attachment is optionally substituted by R12, and any

carbon adjacent to both R 10 and R12 is optionally substituted by R1 1;

R9 , R1 1 , and R13 are independently selected from the group consisting of hydrido, hydroxy, amino, amidino, guanidino, alkylamino, alkylthio, alkoxy, alkylsulfinyl, alkylsulfonyl, 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, hydroxy, amino, alkylamino, alkylsulfonamido, amidosulfonyl, hydroxyalkyl, aminoalkyl, halo, haloalkyl, carboalkoxy, carboxy, carboxamido, carboxyalkyl, and cyano;

Y0 is phenyl or a heteroaryl of 5 or 6 ring members, wherein one carbon of said phenyl or said heteroaryl is substituted by Qs, a carbon two or three atoms from the point of attachment of Qs to said phenyl or said heteroaryl is

substituted by Qb , a carbon adjacent to the point of attachment of Qs is

optionally substituted by R 17 , another carbon adjacent to the point of

attachment of Qs is optionally substituted by R18, a carbon adjacent to Qb is

optionally substituted by R16 , and another carbon adjacent to Qb is optionally

substituted by R19 ;

R16, R17, R 18, and R19 are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, haloalkylthio, alkoxy, hydroxy, amino, alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, and cyano;

R16 or R19 is optionally selected from the group consisting of

NR20 R21 , N(R26 )C(NR25 )N(R23 )(R24 ), and C(NR25 )NR23 R24 , with the

proviso that R16 , R19 , and Qb are not simultaneously hydrido;

Qb is selected from the group consisting of NR20 R21 , hydrido,

N(R26 )C(NR25 )N(R23 )(R24 ), and C(NR25 )NR23 R24 ;

R20, R21, R23, R24, R25, and R26 are independently hydrido or alkyl;

Qs is CH2.

In a still further most preferred embodiment of compounds of Formula I, said compound is the Formula:


or a pharmaceutically acceptable salt thereof, wherein;

B is a C3-C7 cycloalkyl or a C4-C6 saturated heterocyclyl, wherein each ring carbon is optionally substituted with R33, 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 substituted with R9 or R 13, a ring carbon or

nitrogen adjacent to the R9 position and two atoms from the point of attachment

is optionally substituted with R10, a ring carbon or nitrogen adjacent to the R13

position and two atoms from the point of attachment is optionally substituted with R 12, a ring carbon or nitrogen three atoms from the point of attachment

and adjacent to the R10 position is optionally substituted with R1 1, a ring carbon or nitrogen three atoms from the point of attachment and adjacent to the

R 12 position is optionally substituted with R33 , and a ring carbon or nitrogen

four atoms from the point of attachment and adjacent to the R1 1 and R33

positions is optionally substituted with R34;

R9, R1 1, and R13 are independently selected from the group consisting of hydrido, hydroxy, amino, amidino, guanidino, alkylamino, alkylthio, alkoxy, alkylsulfinyl, alkylsulfonyl, 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, hydroxy, amino, alkylamino, alkylsulfonamido, amidosulfonyl, hydroxyalkyl, aminoalkyl, halo, haloalkyl, carboalkoxy, carboxy, carboxamido, carboxyalkyl, and cyano;

R33 and R34 are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkoxy, hydroxy, amino, alkoxyamino, alkylamino, alkylthio, amidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboalkoxy, carboxy, carboxamido, and cyano;

R33 is optionally Qb;

A is a bond or (CH(R15 ))pa-(W7 )rr wherein rr is 0 or 1 , pa is an

integer selected from 0 through 3, and W7 is N(R7 );

R7 is hydrido or alkyl;

R 15 is selected from the group consisting of hydrido, halo, alkyl, and haloalkyl;

X0 is selected from the group consisting of hydrido, alkyl, halo, haloalkyl, aminoalkyl, and hydroxyalkyl;

R 1 is selected from the group consisting of hydrido, alkyl,

hydroxyalkyl, and haloalkyl;

R2 is Z0-Q;

Z0 is a bond;

Q is phenyl or a heteroaryl of 5 or 6 ring members, wherein a carbon adjacent to the carbon at the point of attachment of said phenyl or heteroaryl ring to Z0 is optionally substituted by R9 , the other carbon adjacent to the

carbon at the point of attachment is optionally substituted by R13, a carbon

adjacent to R9 and two atoms from the carbon at the point of attachment is optionally substituted by R 10, a carbon adjacent to R 13 and two atoms from the

carbon at the point of attachment is optionally substituted by R12, and any

carbon adjacent to both R10 and R 12 is optionally substituted by R1 1;

Y0 is phenyl or a heteroaryl of 5 or 6 ring members, wherein one carbon of said phenyl or said heteroaryl is substituted by Qs, a carbon two or three

atoms from the point of attachment of Qs to said phenyl or said heteroaryl is

substituted by Qb , a carbon adjacent to the point of attachment of Qs is

optionally substituted by R17 , another carbon adjacent to the point of

attachment of Qs is optionally substituted by R18 , a carbon adjacent to Qb is

optionally substituted by R16 , and another carbon adjacent to Qb is optionally

substituted by R19 ;

R 16, R17, R18, and R19 are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, haloalkylthio, alkoxy, hydroxy, amino, alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, and cyano;

R 16 or R19 is optionally NR20 R21 or C(NR25 )NR23 R24 , with the

proviso that R16 , R19 , and Qb are not simultaneously hydrido;

Qb is selected from the group consisting of NR20 R21, hydrido, and

C(NR25 )NR23 R24 ;

R20 , R21 , R23 , R24 , and R25 are independently hydrido or alkyl;

Qs is CH2.

In a preferred specific embodiment of Formula I, compounds have the formula:


or a pharmaceutically acceptable salt thereof, wherein;

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, 1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl, 1,2,4-oxadiazol-3-yl,

1,2,4-oxadiazol-Syl, 1,3,4-oxadiazol-3-yl, 13,4-oxadiazol-5-yl, 3-isothiazolyl, 5-isothiazolyl, 2-oxazolyl, 2-thiazolyl, 3-isoxazolyl, 5-isoxazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 1,3,5-triazin-2-yl, 1,2,4-triazin-3-yl,

1,2,4-triazin-Syl, 1,2,4-triazin-6-yl, 1,23-triazin--4-yl, and 1,2,3-triazin-5-yl„ wherein a carbon adjacent to the carbon at the point of attachment is optionally substituted by R32 , the other carbon adjacent to the carbon at the point of

attachment is optionally substituted by R36 , a carbon adjacent to R32 and two atoms from the carbon at the point of attachment is optionally substituted by

R33 , a carbon adjacent to R36 and two atoms from the carbon at the point of

attachment is optionally substituted by R35 , and any carbon adjacent to both

R33 and R35 is optionally substituted by R34 ;

R32 , R33 , R34 , R35 , and R36 are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, methyl, ethyl, isopropyl, propyl, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, methoxyamino, ethoxyamino, acetamido, trifluoroacetamido, nitro, aminomethyl, 1-aminoethyl, 2-aminoethyl, N-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-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, ethoxy carbonyl, amidocarbonyl, N-methylamidocarbonyl, N,N-dimethylamidocarbonyl, cyano, 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, tert-butyl, isobutyl, 2-methylpropenyl, 1-pentyl,

2-pentenyl, 3-pentenyl, 4-pentenyl, 2-pentynyl, 3-pentynyl, 2-pentyl,

1-methyl-2-butenyl, 1-methyl-3-butenyl, 1-methyl-2-butynyl, 3-pentyl,

1-ethyl-2-propenyl, 2-methylbutyl, 2-methyl-2-butenyl, 2-methyl-3-butenyl, 2-methyl-3-butynyl, 3-methylbutyl, 3-methyl-2-butenyl, 3-methyl-3-butenyl, 1-hexyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 2-hexyl, 1-methyl-2-pentenyl, 1-methyl-3-pentenyl,

1-methyl-4-pentenyl, 1-methyl-2-pentynyl, 1-methyl-3-pentynyl, 3-hexyl,

1-ethyl-2-butenyl, 1-ethyl-3-butenyl, 1-propyl-2-propenyl, 1-ethyl-2-butynyl, 1-heptyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 5-heptynyl, 2-heptyl, 1-methyl-2-hexenyl,

1-methyl-3-hexenyl, 1-methyl-4-hexenyl, 1-methyl-5-hexenyl,

1-methyl-2-hexynyl, 1-methyl-3-hexynyl, 1-methyl-4-hexynyl, 3-heptyl,

1-ethyl-2-pentenyl, 1-ethyl-3-pentenyl, 1-ethyl-4-ρentenyl, 1-butyl-2-propenyl, 1-ethyl-2-pentynyl, 1-ethyl-3-pentynyl, 1-octyl, 2-octenyl, 3-octenyl, 4-octenyl, 5-octenyl, 6-octenyl, 7-octenyl, 2-octynyl, 3-octynyl, 4-octynyl, 5-octynyl, 6-octynyl, 2-octyl, 1-methyl-2-heptenyl, 1-methyl-3-heptenyl,

1-methyl-4-heptenyl, 1-methyl-5-heptenyl, 1-methyl-6-heptenyl,

1-methyl-2-heptynyl, 1-methyl-3-heptynyl, 1-methyl-4-heptenyl,

1-methyl-Sheptenyl, 1-methyl-6-heptenyl, 1-methyl-2-heptenyl,

1-methyl-3-heptynyl, 1-methyl-4-heptynyl, 1-methyl-5-heptynyl, 3-octyl, 1-ethyl-2-hexenyl, 1-ethyl-3-hexenyl, 1-ethyl-4-hexenyl, 1-ethyl-2-hexynyl, 1-ethyl-3-hexynyl, 1-ethyl-4-hexynyl, 1-ethyl-5-hexenyl, 1-pentyl-2-propenyl, 4-octyl, 1-propyl-2-pentenyl, 1-propyl-3-pentenyl, 1-propyl-4-pentenyl,

1-butyl-2-butenyl, 1-propyl-2-pentynyl, 1-propyl-3-pentynyl,

1-butyl-2-butynyl, 1-butyl-3-butenyl, 2,2,2-trifluoroethyl, 2,2-difluoropropyl,

4-trifluoromethyl-5,5,Strifluoropentyl, 4-trifluoromethylpentyl,

5,5,6,6,6-pentafluorohexyl, and 333-trifluoropropyl, wherein each member of group B is optionally substituted at any carbon up to and including 5 atoms from the point of attachment of B to A with one or more of the group consisting of R32, R33, R34, R35, and R36 ;

B is optionally selected from the group consisting of cyclopropyl, cyclobutyl, oxetan-2-yl, oxetan-3-yl, azetidin-1-yl, azetidin-2-yl, azetidin-3-yl, thiaetan-2-yl, thiaetan-3-yl, cyclopentyl, cyclohexyl, adamantyl, norbornyl, 3-trifluoromethylnorbornyl, 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-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, wherein each ring carbon is optionally substituted with R33 , a ring carbon and nitrogen atoms adjacent to the carbon atom at the point of attachment is optionally substituted with R9 or R13, a ring carbon or nitrogen atom adjacent to the R9

position and two atoms from the point of attachment is optionally substituted with R 10 , and a ring carbon or mtrogen atom adjacent to the R13 position and

two atoms from the point of attachment is optionally substituted with R12;

R9, R10, R1 1, R12, and R13 ar1 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, N-benzylamidocarbonyl, N-(2-chlorobenzyl)amidocarbonyl,

N-(3-fluorobenzyl)amidocarbonyl, N-(2-trifluoromethylbenzyl)amidocarbonyl, N-(l-phenylethyl)amidocarbonyl, N-(1-methyl-1-phenylethyl)amidocarbonyl, N-benzylamidosulfonyl, N-(2-chlorobenzyl)amidosulfonyl,

N-ethylamidocarbonyl, N-isopropylamidocarbonyl, N-propylamidocarbonyl, N-isobutylamidocarbonyl, N-(2-butyl)amidocarbonyl,

N-cyclobutylamidocarbonyl, N-cyclopentylamidocarbonyl,

N-cyclohexylamidocarbonyl, fluoro, chloro, bromo, cyano, cyclobutoxy, cyclohexoxy, cyclohexylmethoxy, 4-trifluoromethycyclohexylmethoxy, cyclopentoxy, benzyl, benzyloxy, 4-bromo-3-fluorophenoxy,

3-bromobenzyloxy, 4-bromobenzyloxy, 4-bromobenzylamino,

5-bromopyrid-2-ylmethylamino, 4-butoxyphenamino, 3-chlorobenzyl, 4-chlorophenoxy , 4-chloro-3-ethylphenoxy , 4-chloro-3-ethylbenzylamino, 4-chloro-3-ethylphenylamino, 3-chlorobenzyloxy, 4-chlorobenzyloxy, 4-chlorobenzylsulfonyl, 4-chlorophenylamino, 4-chlorophenylsulfonyl, 5-chloropyrid-3-yloxy, 2-cyanopyrid-3-yloxy, 2,3-difluorobenzyloxy,

2,4-difluorobenzyloxy, 3,4-difluorobenzyloxy, 2,5-difluorobenzyloxy,

3 ,5-difluorophenoxy , 3 ,5-difluorobenzyloxy, 4-difluoromethoxybenzyloxy , 23-difluorophenoxy, 2,4-difluorophenoxy, 2,5-difluorophenoxy,

3,5-dimethylphenoxy, 3,4-dimethylphenoxy, 3,4-dimethylbenzyloxy,

3,5-dimethylbenzyloxy, 4-ethoxyphenoxy, 4-ethylbenzyloxy, 3-ethylphenoxy, 4-ethylaminophenoxy, 3-ethyl-5-methylphenoxy, 4-fluorobenzyloxy,

2-fluoro-3-trifluoromethylbenzyloxy, 3-fluoro-5-trifluoromethylbenzyloxy ,

4-fluoro-2-trifluoromethylbenzyloxy, 4-fluoro-3-trifluoromethylbenzyloxy, 2-fluorophenoxy, 4-fluorophenoxy, 2-fluoro-3-trifluoromethylphenoxy, 2-fluorobenzyloxy, 4-fluorophenylamino, 2-fluoro-4-trifluoromethylphenoxy, 4-isopropylbenzyloxy, 3-isopropylphenoxy, 4-isopropylphenoxy,

4-isopropyl-3-methylphenoxy, 4-isopropylbenzyloxy, 3-isopropylphenoxy ,

4-isopropylphenoxy, 4-isopropyl-3-methylphenoxy, phenylamino,

1-phenylethoxy, 2-phenylethoxy, 2-phenylethyl, 2-phenylethylamino, phenylsulfonyl, 3-trifluoromethoxybenzylόxy, 4-trifluoromethoxybenzyloxy, 3-trifluoromethoxyphenoxy, 4-trifluoromethoxyphenoxy,

3-trifluoromethylbenzyloxy, 4-trifluoromethylbenzyloxy,

2,4-bis-trifluoromethylbenzyloxy, 3-trifluoromethylbenzyl,

3 ,5-bis-tiifluoromethylbenzyloxy, 4-trifluoromethylphenoxy ,

3-trifluoromethylphenoxy, 3-trifluoromethylthiobenzyloxy,

4-trifluoromethylthiobenzyloxy, 2,3 ,4-trifluorophenoxy, 2,3,5-trifluorophenoxy, 3-pentafluoroethylphenoxy, 3-(1,1,2,2-tetrafluoroethoxy)phenoxy, and

3-trifluoromethylthiophenoxy;

A is selected from the group consisting of a bond, O, S, NH, N(CH3),

N(OH), C(O), CH2, CH3CH, CF3CH, NHC(O), N(CH3)C(O), C(O)NH,

C(O)N(CH3), CF3CC(O), C(O)CCH3, C(O)CCF3, CH2C(O), (0)CCH2,

CH2CH2, CH2CH2CH2, CH3CHCH2, CF3CHCH2, CH3CC(O)CH2,

CF3CC(O)CH2, CH2C(O)CCH3, CH2C(O)CCF3, CH2CH2C(O), and

CH2(O)CCH2;

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;

X° is selected from the group consisting of hydrido, hydroxy, amino, thiol, amidino, hydroxyamino, aminomethyl, 1-aminoethyl, 2-aminoethyl, 3-aminopropyl, 2-aminoρropyl, methylamino, dimethylamino, cyano, methyl, ethyl, isopropyl, propyl, butyl, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, 333-trifluoropropyl, 2,2333-pentafluoropropyl, methoxy, ethoxy, propoxy, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 3-hydroxypropyl, 23-dihydroxypropyl, methoxyamino, ethoxyamino, methylthio, ethylthio, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro, and bromo;

R2 is Z0-Q;

Z0 is selected from the group consisting of a bond, CH2, CH2CH2, O,

S, NH, N(CH3), CH(OH), OCH2, SCH2, N(H)CH2, CH2O, CH2S,

CH2N(H), 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-furyl, 3-furyl, 2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl, 4-imidazolyl, 3-pyrazolyl, 4-pyrazolyl, 1,2,4-triazol-3-yl, 1,2,4-triazol-Syl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,3,4-oxadiazol-3-yl, 1,3,4-oxadiazol-5-yl, 3-isothiazolyl, 5-isothiazolyl, 2-oxazolyl, 2-thiazolyl, 3-isoxazolyl, 5-isoxazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 1,3,5-triazin-2-yl, 1,2,4-triazin-3-yl, 1,2,4-triazin-5-yl, 1,2,4-triazin-6-yl, 1,2,3-triazin-4-yl, and 1,2,3-triazin-5-yl, wherein a carbon adjacent to the carbon at the point of attachment is optionally substituted by R9, the other carbon adjacent to the carbon at the point of attachment is optionally substituted by R13 , a carbon adjacent to R9 and two atoms from the carbon at

the point of attachment is optionally substituted by R10, a carbon adjacent to

R13 and two atoms from the carbon at the point of attachment is optionally

substituted by R12, and any carbon adjacent to both R10 and R12 is optionally

substituted by R1 1 ;

K is CR4a R4b wherein R4a and R4b are independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, fluoro, chloro, hydroxy, hydroxymethyl, 1-hydroxyethyl, methoxymethyl, trifluoromethyl,

pentafluoroethyl, 2,2,2-trifluoromethyl, methylthiomethyl, and hydrido;

E0 is a bond, C(O)N(H), (H)NC(O), and S(O)2N(H);

i is selected from the group of formulas consisting of:


1-Qb -4-Qs -2-R16 -3-R17 -5-R18 -6-R19 benzene,

2-Qb-5-QS-6-R17-4-R18-3-R19pyridine,

3-Qb-6-QS-2-R16-5-R18-4-R19pyridine,

2-Qb -5-Qs -3-R16 -6-R18 pyrazine,

3-Qb -6-Qs -2-R18 -5-R18 -4-R19 pyridazme,


2-Qb -5-Qs -4-R17 -6-R18 pyrimidine,


5-Qb -2-Qs -4-R16 -6-R19 pyrimidine,

3-Qb-5-Qs- 4-R16 -2-R19 thiophene,

2-Q -5-Qs-3-R16-4-R17 thiophene,

3-Qb -5-Qs -4-R16 -2-R19 furan,

2-Qb-5-Qs-3- R16-4-R17ffran,

3-Qb -5-Qs -4-R16-2-R19 pyrrole,

-Qb-5-Qs-3- R16 -4-R17 pyrrole,

4-Qb -2-Qs -5-R19 imidazole,

2-Qb -4-Qs -5-R17 miidazole,


3-Qb-5-Qs-4-R16 isoxazole,

5-Qb-3-Qs-4-R16 isoxazole,


2-Qb-5-Qs-4-R16 pyrazole,


4-Qb-2-Qs-5-R19 thiazole, and


2-Qb-5-Qs-4-R17 thiazole;

R16, R17, R18, and R19, are independently selected from the group 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, methylsulfonyl, ethylsulfonyl, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl,

2,2333-pentafluoropropyl, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro, bromo, amidosulfonyl, N-methylamidosulfonyl,

N,N-dimethylamidosulfonyl, acetyl, propanoyl, trifluoroacetyl,

pentafluoropropanoyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, and cyano;

Qb is selected from the group consisting of NR20 R21 , hydrido,

C(NR25 )NR23 R24 and N(R26 )C(NR25 )N(R23 )(R24 ), with the proviso that

no more than one of R20 and R21 is hydroxy, N-methylammo, and N,N-

dimethylamino at the same time and that no more than one of R23 and R24 is hydroxy, N-methylamino, and N,N-dimethylamino at the same time;

R20, R21, R23, R24, R25, and R26 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;

Qs iss selected from the group consisting of a bond, CH2, CH2CH2, CH3CH, CF3CH, CH3CHCH2, CF3CHCH2, CH2(CH3)CH, CH=CH, CF=CH, C(CH3)=CH, CH=CHCH2, CF=CHCH2, C(CH3)=CHCH2, CH2CH=CH, CH2CF=CH, CH2C(CH3)=CH, CH2CH=CHCH2,

CH2CF-=CHCH2, CH2C(CH3)=CHCH2, CH2CH=CHCH2CH2,

CH2CF=CHCH2CH2, and CH2C(CH3)=CHCH2CH2.

In a more preferred specific embodiment of Formula I, compounds have the formula:

or a pharmaceutically acceptable salt thereof, wherein;

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,

3-pyridazinyl, 4-pyridazinyl, and 1,3,5-triazin-2-yl, wherein a carbon adjacent to the carbon at the point of attachment of said phenyl or heteroaryl ring to A is optionally substituted by R32, the other carbon adjacent to the carbon at the

point of attachment is optionally substituted by R36 , a carbon adjacent to R32 and two atoms from the carbon at the point of attachment is optionally substituted by R33, a carbon adjacent to R36 and two atoms from the carbon at

the point of attachment is optionally substituted by R35 , and any carbon

adjacent to both R33 and R35 is optionally substituted by R34 ;

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, 2,2333-pentafluoropropyl, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro, bromo, amidosulfonyl, N-methylamidosulfonyl,

N,N-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, 2-hy droxy ethyl, 2,2,2-trifluoro-1-hydroxyethyl, methoxycarbonyl, ethoxy carbonyl,

amidocarbonyl, N-methylamidocarbonyl, N,N-dimethylamidocarbonyl, cyano, and Qb;

A is selected from the group consisting of a bond, NH, N(CH3), N(OH),

CH2, CH3CH, CF3CH, NHC(O), N(CH3)C(O), C(O)NH, C(O)N(CH3),

CH2CH2, CH2CH2CH2, CH3CHCH2, and CF3CHCH2;

R16, R17, R18, and R19 a, re 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, 2,2,333-pentafluoropropyl,

trifluoromethoxy, 1,1,2,2-tetiafluoroethoxy, fluoro, chloro, bromo,

hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, and cyano;

R16 or R19 is optionally C(NR25 )NR23 R24 with the proviso that R ,

R19 , and Qb are not simultaneously hydrido;

Qb is C(NR25 )NR23 R24 or hydrido, with the proviso that no more than

one of R23 and R24 is hydroxy at the same time;

R23, R24, and R252 are independently selected from the group consisting of hydrido, methyl, ethyl, and hydroxy.

In another more preferred specific embodiment of Formula I, compounds have the f oπnula:


or a pharmaceutically 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-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 3,33-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 R32, R33, R34, R35, and R36 ;

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, 2,2333-pentafluoropropyl, trifluoromethoxy,

1,1,2,2-tetrafluoroethoxy, fluoro, chloro, bromo, amidosulfonyl,

N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, 2-hy droxy 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 bond, NH, N(CH3), N(OH),

CH2, CH3CH, CF3CH, NHC(O), N(CH3)C(O), C(O)NH, C(O)N(CH3),

CH2CH2, CH2CH2CH2, CH3CHCH2, and CF3CHCH2;

R16, R17, R18, and R19 a,re 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, 2,2,3,33-pentafluoropropyl,

trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro, bromo,

hydroxymethyl, 1 -hydroxyethyl, 2-hydroxyethyl, and cyano; '

R16 or R19 is optionally selected from the group consisting of NR20 R21 ,

C(NR25)NR23R24, and N(R26)C(NR25)N(R23)(R24), with the proviso that R16,

R19 , and Qb are not simultaneously hydrido;

Qb is selected from the group consisting of NR20 R21 , hydrido,

C(NR25)NR23R24, and N(R26)C(NR25)N(R23)(R24), with the proviso that no

more than one of R20 and R21 is hydroxy at the same time and with the further

proviso that no more than one of R23 and R24 is hydroxy at the same time;

R20, R21, R23, R24, R25, and R26 are independently selected from the group consisting of hydrido, methyl, ethyl, propyl, butyl, isopropyl, and

hydroxy.

In still another more preferred specific embodiment of Formula I, compounds have the formula:

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, norbomyl, 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-pyπolidinyl, 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 optionally substituted with R33 , ring carbons and a nitrogen adjacent to the

carbon atom at the point of attachment are optionally substituted with R9 or

R 13, a ring carbon or nitrogen adjacent to the R9 position and two atoms from

the point of attachment is optionally substituted with R10, and a ring carbon or

nitrogen adjacent to the R13 position and two atoms from the point of

attachment is optionally substituted with R12;

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,

2,2333-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 Q ;

A is selected from the group consisting of a bond, NH, N(CH3),

N(OH), CH2, CH3CH, CF3CH, NHC(O), N(CH3)C(O), C(O)NH,

C(O)N(CH3), CH2CH2, CH2CH2CH2, CH3CHCH2, and CF3CHCH2;

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, 2,2,333-pentafluoropropyl,

trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro, bromo,

hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, and cyano;

R16 or R19 is optionally C(NR25 )NR23 R24 with the proviso that R16,

R19 , and Qb are not simultaneously hydrido;

Qb is C(NR25 )NR23 R24 or hydrido, with the proviso that no more than

one of R23 and R24 is hydroxy at the same time;

R23 , R24, and R25 a2 re independently selected from the group consisting of hydrido, methyl, ethyl, and hydroxy.

The more preferred specific embodiment compounds of Formula I having the formula:

or a pharmaceutically acceptable salt thereof, have common structural units, wherein;

X0 is selected from the group consisting of hydrido, hydroxy, amino, aminomethyl, 1-aminoethyl, methyl, ethyl, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, methoxy, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, methylthio, ethylthio, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro, and bromo;

R1 is selected from the group consisting of hydrido, hydroxy, amino, methyl, ethyl, propyl, n-butyl, 2,2,2-trifluoroethyl, 3,33-trifluoropropyl,

2,2333-pentafluoropropyl, 2-aminoethyl, 3-aminopropyl, 2-hydroxyethyl, 3-hydroxypropyl, and 2,3-dihydroxypropyl;

R2 is Z0-Q;

Z is selected from the group consisting of a bond, CH2, CH2CH2, O, S, NH, N(CH3), OCH2, SCH2, N(H)CH2, and N(CH3)CH2;

Q is selected from the group consisting of phenyl, 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl, 4-imidazolyl, 3-pyrazolyl, 4-pyrazolyl, 2-thiazolyl, 3-isoxazolyl, 5-isoxazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl,

3-pyridazinyl, 4-pyridazinyl, and 13,5-triazin-2-yl, wherein a carbon adjacent to the carbon at the point of attachment of said phenyl or heteroaryl ring to Z is optionally substituted by R9 , the other carbon adjacent to the carbon at the point

of attachment is optionally substituted by R13 , a carbon adjacent to R9 and two atoms from the carbon at the point of attachment is optionally substituted by R10, a carbon adjacent to R13 and two atoms from the carbon at the point of

attachment is optionally substituted by R12, and any carbon adjacent to both

R10 and R12 is optionally substituted by R1 1 ;

R9 , R1 1 , 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,

2,2333-pentafluoropropyl, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro, bromo, methanesulfonamido, amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, 2-hy droxy ethyl, 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, ethoxycarbonyl,

amidocarbonyl, N-methylamidocarbonyl, N,N-dimethylamidocarbonyl, N-benzylamidocarbonyl, N-(2-chlorobenzyl)amidocarbonyl,

N-(3-fluorobenzyl)amidocarbonyl, N-(2-trifluoromethylbenzyl)amidocarbonyl, N-(l-phenylethyl)amidocarbonyl, N-(1-methyl-1-phenylethyl)amidocarbonyl, N-benzylamidosulfonyl, N-(2-chlorobenzyl)amidosulfonyl,

N-ethylamidocarbonyl, N-isopropylamidocarbonyl, N-propylamidocarbonyl, N-isobutylamidocarbonyl, N-(2-butyl)amidocarbonyl,

N-cyclobutylamidocarbonyl, N-cyclopentylamidocarbonyl,

N-cyclohexylamidocarbonyl, fluoro, chloro, bromo, cyano, cyclobutoxy, cyclohexoxy, cyclohexylmethoxy, 4-trifluoromethycyclohexylmethoxy, cyclopentoxy, benzyl, benzyloxy, 4-bromo-3-fluorophenoxy,

3-bromobenzyloxy, 4-bromobenzyloxy, 4-bromobenzylamino,

Sbromopyrid-2-ylmethylamino, 4-butoxyphenamino, 3-chlorobenzyl,

4-chlorophenoxy, 4-chloro-3-ethylphenoxy, 4-chloro-3-ethylbenzylamino, 4-chloro-3-ethylphenylamino, 3-chlorobenzyloxy, 4-chlorobenzyloxy,

4-chlorobenzylsulfonyl, 4-chlorophenylamino, 4-chlorophenylsulfonyl, 5-chloropyrid-3-yloxy, 2-cyanopyrid-3-yloxy, 2,3-difluorobenzyloxy,

2,4-difluorobenzyloxy, 3,4-difluorobenzyloxy, 2,5-difluorobenzyloxy,

3,5-difluorophenoxy , 3,5-difluorobenzyloxy, 4-difluoromethoxybenzyloxy , 2,3-difluorophenoxy, 2,4-difluorophenoxy, 2,5-difluorophenoxy,

,5-dimethylphenoxy, 3,4-dimethylphenoxy, 3,4-dimethylbenzyloxy,

3,5-dimethylbenzyloxy, 4-ethoxyphenoxy, 4-ethylbenzyloxy, 3-ethylphenoxy, 4-ethylaminophenoxy, 3-ethyl-5-methylphenoxy, 4-fluorobenzyloxy,

2-fluoro-3-trifluoromethylbenzyloxy, 3-fluoro-5-trifluoromethylbenzyloxy, Φfluoro-2-trifluoromethylbenzyloxy, 4-fluoro-3-trifluoromethylbenzyloxy, 2-fluorophenoxy, 4-fluorophenoxy, 2-fluoro-3-trifluoromethylphenoxy, 2-fluorobenzyloxy, 4-fluorophenylamino, 2-fluoro-4-trifluoromethylphenoxy, 4-isopropylbenzyloxy, 3-isopropylphenoxy, 4-isopropylphenoxy,

4-isopropyl-3-methylphenoxy, 4-isopropylbenzyloxy, 3-isopropylphenoxy, 4-isopropylphenoxy, 4-isopropyl-3-methylphenoxy, phenylamino,

1-phenylethoxy, 2-phenylethoxy, 2-phenylethyl, 2-phenylethylamino, phenylsulfonyl, 3-trifluoromethoxybenzyloxy, 4-trifluoromethoxybenzyloxy, 3-trifluoromethoxyphenoxy, 4-trifluoromethoxyphenoxy,

3-trifluoromethylbenzyloxy, 4-trifluoromethylbenzyloxy,

2,4-bis-trifluoromethylbenzyloxy, 3-trifluoromethylbenzyl,

3,Sbis-trifluoromethylbenzyloxy, 4-trifluoromethylphenoxy,

3-trifluoromethylphenoxy, 3-trifluoromethylthiobenzyloxy,

4-trifluoromethylthiobenzyloxy , 23 ,4-trifluorophenoxy , 2,3 ,5-trifluorophenoxy, 3-pentafluoroethylphenoxy, 3-(l,1,2,2-tetrafluoroethoxy)phenoxy, and

3-trifluoromethylthiophenoxy;

Y is selected from the group of formulas consisting of:

1-Qb-4-Qs-2-R16-3-R17-5-R18-6-R19benzene,

2-Qb -5-Qs -6-R17 -4-R18 -3-R19 pyridme,

3-Qb-6-QS-2-R16-5-R18 -4-R19 pyridme,


2-Qb -5-Qs -3-R16 -6-R18 pyrazine,

3 -Qb-6-QS-2-R18-5-R18-4-R19pyridazine,

2-Qb -5-Qs-4-R17 -6-R18 pyrimidine,

5-Qb-2-Qs-4-R16-6-R19 pyrimidine,

3-Qb-5-Qs -4-R16 -2-R19 thiophene,

2-Qb-5-Qs-3-R16-4-R17 thiophene,

3-Qb-5-Qs-4-R16-2-R19 furan,

2-Qb-5-Qs-3 -R16-4-R17furan,

3-Qb -5-Qs -4-R16 -2-R19 pyrrole,

2-Qb -5-Qs -3-R16 -4-R17 pyrrole,

4-Qb -2-Qs -5-R19 imidazole,

2-Qb-4-Qs-5-R17 imidazole,

3-Qb-5-Qs-4-R16 isoxazole,

5-Qb-3-Qs-4-R16 isoxazole,

2-Qb-5-Qs-4-R16 pyrazole,

4-Qb -2-Qs -5-R19 thiazole, and


2-Qb -5-Qs-4-R17 thiazole;

Qs is selected from the group consisting of a bond, CH2 and CH2CH2.

In a most preferred specific embodiment of Formula I, compounds have the formula:


or a pharmaceutically acceptable salt thereof, wherein;

B is selected from the group consisting of phenyl, 2-thienyl, 3-thienyl,

2-furyl, 3-furyl, 2-pyrrolyl, 3-pyπolyl, 2-imidazolyl, 4-imidazolyl, 3-pyrazolyl, 4-pyrazolyl, 2-thiazolyl, 3-isoxazolyl, and 5-isoxazolyl, wherein a carbon adjacent to the carbon at the point of attachment of said phenyl or heteroaryl ring to A is optionally substituted by R32, the other carbon adjacent to the

carbon at the point of attachment is optionally substituted by R36 , a carbon

adjacent to R32 and two atoms from the carbon at the point of attachment is optionally substituted by R33 , a carbon adjacent to R36 and two atoms from the

carbon at the point of attachment is optionally substituted by R35, and any

carbon adjacent to both R33 and R35 is optionally substituted by R34;

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, methoxyamino, 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 a bond, NH, N(CH3), CH2,

CH3CH, and CH2CH2;

Qb is NR20 R21 or C(NR25 )NR23 R24;

R20, R21, R23, R24, and R25 a2e independently selected from the group consisting of hydrido, methyl, and ethyl.

In another most preferred specific embodiment of Formula I, compounds have the formula:


or a pharmaceutically acceptable salt thereof, wherein;

B is selected from the group consisting of hydrido, ethyl, 2-propenyl, 2-propynyl, propyl, isopropyl, butyl, 2-butenyl, 2-butynyl, sec-butyl, tert-butyl, isobutyl, 2-methylpropenyl, 1-pentyl, 2-pentenyl, 3-pentenyl, 2-pentynyl, 3-ρentynyl, 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 3,33-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 R32, R33, R34, R35, and R36 ;

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, methoxyamino, 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 a bond, NH, N(CH3), CH2,

CH3CH, and CH2CH2;

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;

Qb is selected from the group consisting of NR20 R21 ,

C(NR25 )NR23 R24 , and N(R26 )C(NR25 )N(R23 )(R24 );

R20, R21 , R23 , R24, R25, and R26 are inde2endently selected from the group consisting of hydrido, methyl, and ethyl.

In still another most preferred specific embodiment of Formula I, compounds have the formula:

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, 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-pyπolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-dioxanyl, 2-tetrahydrofuranyl,

3-tetrahydrofuranyl, 2-tetrahydropyranyl, 3-tetrahydropyranyl,

4-tetrahydropyranyl, 2-tetrahydrothienyl, and 3-tetrahydrothienyl, wherein each ring carbon is optionally substituted with R33, ring carbons and a nitrogen adjacent to the carbon atom at the point of attachment are optionally substituted with R9 or R13 , a ring carbon or nitrogen adjacent to the R9 position and two

atoms from the point of attachment are optionally substituted with R10, and a

ring carbon or nitrogen atom adjacent to the R13 position and two atoms from

the point of attachment is optionally substituted with R12 ;

R33 is selected from the group consisting of hydrido, amidino, guanidino, methyl, ethyl, methoxy, ethoxy, hydroxy, carboxy, amino,

N-methylamino, dimethylamino, methoxyamino, 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 a bond, NH, N(CH3), CH2,

CH3CH, CH2CH2, and CH2CH2CH2;

Qb is NR20 R21 or C(NR25 )NR23 R24 ;

R20, R21, R23, R24, and R25 are independently selected from the group consisting of hydrido, methyl, and ethyl.

The most prefeπed specific embodiment compounds of Formula I, said compounds having the formula:


or a pharmaceutically acceptable salt thereof, have common structural units, wherein;

X0 is selected from the group consisting of hydrido, aminomethyl, methyl, ethyl, trifluoromethyl, 2,2,2-trifluoroethyl, hydroxymethyl,

2-hydroxyethyl, chloro, and fluoro;

R1 is selected from the group consisting of hydrido, methyl, ethyl, propyl, 2,2,2-trifluoroethyl, 333-trifluoropropyl, 2,2,3,33-pentafluoropropyl, and 2-hydroxyethyl;

R2 is selected from the group consisting of phenyl, 2-thienyl, 2-furyl, 2-pyrrolyl, 2-imidazolyl, 2-thiazolyl, 3-isoxazolyl, 2-pyridyl, and 3-pyridyl, wherein a carbon adjacent to the carbon at the point of attachment of said phenyl or heteroaryl ring to the 4-pyridonering is optionally substituted by R9, the other carbon adjacent to the carbon at the point of attachment is optionally substituted by R13, a carbon adjacent to R9 and two atoms from the carbon at

the point of attachment is optionally substituted by R10, a c, arbon adjacent to R13 and two atoms from the carbon at the point of attachment is optionally

substituted by R12, and any carbon adjacent to both R10 and R12 is optionally

substituted by R1 1 ;

R9 , R1 1 , 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,

N-benzylamidocarbonyl, N-(2-chlorobenzyl)amidocarbonyl,

N-(3-fluorobenzyl)amidocarbonyl, N-(2-trifluoromethylbenzyl)amidocarbonyl, N-(l-phenylethyl)amidocarbonyl, N-(1-methyl-1-phenylethyl)amidocarbonyl, N-benzylamidosulfonyl, N-(2-chlorobenzyl)amidosulfonyl,

N-ethylamidocarbonyl, N-isopropylamidocarbonyl, N-propylamidocarbonyl, N-isobutylamidocarbonyl, N-(2-butyl)amidocarbonyl,

N-cyclobutylamidocarbonyl, N-cyclopentylamidocarbonyl,

N-cyclohexylamidocarbonyl, 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, methoxyamino, amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, methanesulfonamido, methoxycarbonyl, fluoro, chloro, bromo, and cyano;

Y is selected from the group of formulas consisting of:

1 -Qb-4-Qs-2-R16-3-R17-5-R18-6-R19 benzene,

2-Qb-5-Qs-6-R17-4-R18-3-R19 pyridine,

3-Qb-6-Qs-2-R16-5-R18-4-R19 pyridine,

3-Qb-5-Qs-4-R16-2-R19 thiophene,

2-Qb-5-Qs-3-R16-4-R17 thiophene,

3-Qb-5-Qs-4-R16-2-R19furan,

2-Qb-5-Qs-3-R16-4-R17furan,

3-Qb-5-Qs-4-R16-2-R19 pyrrole,


2-Qb-5-Qs-3-R16-4-R17 pyrrole,


4-Qb-2-Qs-5-R19 thiazole, and


2-Qb-5-Qs-4-R17 thiazole;

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, hydroxymethyl, carboxy, and cyano;

Qs is CH2.

The compounds of this invention can be used in anticoagulant therapy for the treatment and prevention of a variety of thrombotic conditions including coronary artery and cerebrovascular disease. The compounds of this invention can be used to inhibit serine protease associated with the coagulation cascade and factors II, VII, VIII, IX, X, XI, or XII. The compounds of the invention can inhibit the formation of blood platelet aggregates, inhibit the formation of fibrin, inhibit thrombus formation, and inhibiting embolus formation in a mammal, in blood, in blood products, and in mammalian organs. The compounds also can be used for treating or preventing unstable angina, refractory angina, myocardial infarction, transient ischemic attacks, atriai 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 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.

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.

The use of generic terms in the description of the compounds are herein defined for clarity.

Standard single letter elemental symbols are used to represent specific types of atoms unless otherwise defined. The symbol "C" represents a carbon atom. The symbol "O" represents an oxygen atom. The symbol "N" represents a nitrogen atom. The symbol "P" represents a phosphorus atom. The symbol "S" represents a sulfur atom. The symbol "H" represents a hydrogen atom. Double letter elemental symbols are used as defined for the elements of the periodical table

(i.e., Cl 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 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 so much as it contains at least one double bond. Such alkenyl radicals contain from about 2 to about 10 carbon atoms, preferably from about 3 to about 8 carbon atoms and more preferably 3 to about 6 carbon atoms. Said alkenyl radicals may be optionally substituted with groups as defined below. Examples of suitable alkenyl radicals include propenyl, 2-chloropropenyl, buten-1-yl, isobutenyl, penten-1-yl, 2-2-methylbuten-1-yl, 3-methylbuten-1-yl, hexen-1-yl, 3-hydroxyhexen-1-yl, hepten-1-yl, and octen-1-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 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-1-yl, butyn-2-yl, pentyn-1-yl, pentyn-2-yl, 4-methoxypentyn-2-yl, 3-methylbutyn-1-yl, hexyn-1-yl, hexyn-2-yl, hexyn-3-yl, 3,3-dimethylbutyn-1-yl radicals and the like.

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

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 monohydroxyalkyl, dihydroxyalkyl and polyhydroxyalkyl radicals.

The term "alkanoyl" embraces radicals wherein one or more of the terminal alkyl carbon atoms are substituted with one or more carbonyl radicals as defined below. Specifically embraced are monocarbonylalkyl and dicarbonylalkyl radicals. Examples of monocarbonylalkyl radicals include

formyl, acetyl, and pentanoyl. Examples of dicarbonylalkyl radicals include oxalyl, malonyl, and succinyl.

The term "alkylene" radical denotes linear or branched radicals having from 1 to about 10 carbon atoms and having attachment points for two or more covalent bonds. Examples of such radicals are methylene, ethylene, methylethylene, and isopropylidene.

The term "alkenylene" radical denotes linear or branched radicals having from 2 to about 10 carbon atoms, at least one double bond, and having 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-).

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 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 " haloalkyl" 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, difluoroetiiyl, difluoropropyl, dichloroethyl and dichloropropyl.

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 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 " haloalkylene" radicals having one to about six carbon atoms. Examples of "haloalkylene" radicals include difluoromethylene, tetrafluoroethylene, tetrachloroethylene, alkyl substituted monofluoromethylene, and aryl substituted trifluoromethylene.

The term "haloalkenyl" denotes linear or branched radicals having from 1 to about 10 carbon atoms and having one or more double bonds wherein any 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 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, to form monoalkoxyalkyl and dialkoxyalkyl radicals. More preferred alkoxy radicals are " alkoxy" radicals having one to six carbon atoms. Examples of such radicals include methoxy, ethoxy, propoxy, butoxy, isopropoxy and tert-butoxy alkyls. The "alkoxy" radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide "haloalkoxy" and "haloalkoxyalkyl" radicals. Examples of such haloalkoxy radicals include fluoromethoxy, chloromethoxy, trifluoromethoxy, difluoromethoxy, trifluoroethoxy, fluoroethoxy, tetrafluoroethoxy, pentafluoroethoxy, and fluoropropoxy. Examples of such haloalkoxyalkyl radicals include fluoromethoxymethyl, chloromethoxyethyl, trifluoromethoxymethyl, difluoromethoxyethyl, and trifluoroethόxymethyl.

The terms "alkenyloxy" and "alkenyloxyalkyl" embrace linear or branched oxy-containing radicals each having alkenyl portions of two to about ten carbon atoms, such as ethenyloxy or propenyloxy radical. The term "alkenyloxyalkyl" also embraces alkenyl radicals having one or more alkenyloxy radicals attached to the alkyl radical, that is, to form monoalkenyloxyalkyl and dialkenyloxyalkyl radicals. More preferred alkenyloxy radicals are " alkenyloxy" radicals having two to six carbon atoms. Examples of such radicals include ethenyloxy, propenyloxy, butenyloxy, and isopropenyloxy alkyls. The "alkenyloxy" radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide "haloalkenyloxy" radicals. Examples of such radicals include

trifluoroethenyloxy, fluoroethenyloxy, difluoroethenyhloxy, and fluoropropenyloxy.

The term "haloalkoxyalkyl" also embraces alkyl radicals having one or more haloalkoxy radicals attached to the alkyl radical, that is, to form monohaloalkoxyalkyl and dihaloalkoxyalkyl radicals. The term "haloalkenyloxy" also embraces oxygen radicals having one or more haloalkenyloxy radicals attached to the oxygen radical, that is, to form monohaloalkenyloxy and dihaloalkenyloxy radicals. The term "haloalkenyloxyalkyl" also embraces alkyl radicals having one or more haloalkenyloxy radicals attached to the alkyl radical, that is, to form monohaloalkenyloxyalkyl and dihaloalkenyloxyalkyl radicals.

The term "alkylenedioxy" radicals denotes alkylene radicals having at least two oxygens bonded to a single alkylene group. Examples of "alkylenedioxy" radicals include methylenedioxy, ethylenedioxy, alkylsubstituted methylenedioxy, and arylsubstituted methylenedioxy. The term "haloalkylenedioxy" radicals denotes haloalkylene radicals having at least two oxy groups bonded to a single haloalkyl group. Examples of "haloalkylenedioxy" radicals include difluoromethylenedioxy, tetrafluoroethylenedioxy, tetrachloroethylenedioxy, alkylsubstituted monofluoromethylenedioxy, and arylsubstituted monofluoromethylenedioxy.

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

The term "perhaloaryl" embraces aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, indane and biphenyl wherein the aryl radical is substituted with 3 or more halo radicals as defined below.

The term "heterocyclyl" embraces saturated and partially saturated heteroatom-containing ring-shaped radicals having from 4 through 15 ring members, herein referred to as "C4-C15 heterocyclyl", selected from carbon, nitrogen, sulfur and oxygen, wherein at least one ring atom is a heteroatom. Heterocyclyl radicals may contain one, two or three rings wherein such rings may be attached in a pendant manner or may be fused. Examples of saturated heterocyclic radicals include saturated 3 to 6-membered heteromonocylic group containing 1 to 4 nitrogen atoms[e.g. pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl, etc.]; saturated 3 to 6-membered heteromonocyclic group 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, dihydropyran, dihydrofuran and dihydrothiazole. Non-limiting examples of heterocyclic radicals include 2-pyrrolinyl, 3-pyrrolinyl, pyπolindinyl, 1,3-dioxolanyl, 2H-pyranyl, 4H-pyranyl, piperidinyl, 1,4-dioxanyl, morpholinyl, 1,4-dithianyl, thiomorpholinyl, and the like. Said "heterocyclyl" group may be substituted as defined herein. Preferred heterocyclic radicals include five to twelve membered fused or unfused radicals.

The term "heteroaryl" embraces fully unsaturated heteroatom-containing ring-shaped aromatic radicals having from 4 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 the unsaturated heteromonocyclyl group of 5 to 6 contiguous members 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-1,2,4-triazolyl, 1H-1,23-triazolyl, 2H-1,2,3-triazolyl, etc.] tetrazolyl [e.g. 1H-tetrazolyl, 2H-tetrazolyl, etc.], etc.; unsaturated condensed heterocyclic group containing 1 to 5 nitrogen atoms, for example, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl [e.g., tetrazolo [1,5-b]pyridazinyl, etc.], etc.; unsaturated 3 to 6-membered heteromonocyclic group containing an oxygen atom, for example, pyranyl, 2-furyl, 3-furyl, etc.; unsaturated 5 to 6-membered heteromonocyclic group containing a sulfur atom, for example, 2-thienyl, 3-thienyl, etc.; unsaturated 5- to 6-membered 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 mtrogen atoms [e.g. benzoxazolyl, benzoxadiazolyl, etc.]; unsaturated 5 to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl, thiadiazolyl [e.g., 1,2,4- thiadiazolyl, 13,4-thiadiazolyl, 1,2,5-thiadiazolyl, etc.] etc.; unsaturated condensed heterocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., benzothiazolyl, benzothiadiazolyl, etc.] and the like. The term also embraces radicals where heterocyclic radicals are fused with aryl radicals. Examples of such fused bicyclic radicals include benzofuran, benzothiophene, and the like. Said "heteroaryl" group may be substituted as defined herein. Preferred heteroaryl radicals include five and six membered unfused radicals. Non-limiting examples of heteroaryl radicals include 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl, 4-imidazolyl, 3-pyrazolyl, 4-pyrazolyl, 1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,3,4-oxadiazol-3-yl, 1,3,4-oxadiazol-5-yl, 3-isothiazolyl, 5-isothiazolyl, 2-oxazolyl, 2-thiazolyl, 3-isoxazolyl, 5-isoxazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 13,5-triazin-2-yl, 1,2,4-triazin-3-yl, 1,2,4-triazin-5-yl, 1,2,4-triazin-6-yl, 1,2,3-triazin-4-yl, and 1,2,3-triazin-5-yl, and the like.

The term "sulfonyl", whether used alone or linked to other terms such as alkylsulfonyl, denotes respectively divalent radicals -SO2-. "Alkylsulfonyl", embraces alkyl radicals attached to a sulfonyl radical, where alkyl is defined as 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 term "amidosulfonyl" embraces amino, monoalkylamino, dialkylamino, monocycloalkylamino, alkyl cycloalkylamino, dicycloalkylamino, N-alkyl-N-arylamino, arylamino, aralkylamino, nitrogen containing heterocyclyl, heterocyclylamino, N-alkyl-N-heterocyclylamino, heteroarylamino, and heteroaralkylamino radicals, attached to one of two unshared bonds in a sulfonyl radical.

The term "sulfinyl", whether used alone or linked to other terms such as alkylsulfinyl, denotes respectively divalent radicals -S(O)-. "Alkylsulfinyl", embraces alkyl radicals attached to a sulfinyl radical, where alkyl is defined as above. "Alkylsulfinylalkyl", embraces alkylsulfinyl radicals attached to an alkyl radical, where alkyl is defined as above. "Haloalkylsulfinyl", embraces haloalkyl radicals attached to a sulfinyl radical, where haloalkyl is defined as

above. "Haloalkylsulfinylalkyl", embraces haloalkylsulfinyl radicals attached to an alkyl radical, where alkyl is defined as above.

The term "aralkyl" embraces aryl-substituted alkyl radicals. Preferable aralkyl radicals are " aralkyl" radicals having aryl radicals attached to alkyl radicals having one to six carbon atoms. Examples of such radicals include benzyl, diphenylmethyl, triphenylmethyl, phenylethyl and diphenylethyl. The terms benzyl and phenylmethyl are interchangeable.

The term "heteroaralkyl" embraces heteroaryl-substituted alkyl radicals wherein the heteroaralkyl radical may be additionally substituted with three or 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 term "aralkylsulfinyl", embraces aralkyl radicals attached to a 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", 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 " cycloalkyl" radicals having three to seven carbon atoms. Examples include radicals such as 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 " 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 " cycloalkenyl" radicals having three to seven 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 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 polyhalocycloalkyl radicals may have more than two of the same halo atoms or a combination of different halo radicals. More preferred halocycloalkyl radicals are " 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. 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 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.

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 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 cyclohexenyloxy ethyl. The "cycloalkenyloxy" radicals may be further substituted with one or more halo 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.

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", 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 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.

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 " alkylthio" radicals having one to six carbon atoms. An example of " alkylthio" is methylthio (CH3-S-). The

"alkylthio" radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide "haloalkylthio" radicals. Examples of such radicals include fluoromethylthio, chloromethylthio, trifluoromethylthio, difluoromethylthio, trifluoroethylthio, fluoroethylthio, tetrafluoroethylthio, pentafluoroethylthio, and fluoropropylthio.

The term "alkyl aryl amino" embraces radicals containing a linear or branched alkyl radical, of one to ten carbon atoms, and one aryl radical both attached to an amino radical. Examples include N-methyl-4-methoxyaniline, N-ethyl-4-methoxyaniline, and N-methyl-4-trifluoromethoxyaniline.

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

One or two alkyl radicals of the alkylamino may be optionally substituted with hydrogen bonding substitutents selected from the group consisting of hydroxy, amino, monoalkylamino, dialkylamino, amidino, guanidino, thiol, and alkoxy provided the alkyl radicals comprises two or more carbons.

The terms arylamino denotes "monoaryl amino" 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 denotes "monoaralkylamino" and "diaralkylamino" containing one or two 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 defined above, attached to a divalent S(O) atom. The term "arylsulfinylalkyl" denotes arylsulfinyl 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 aryl is defined as above, "arylsulfonylalkyl", embraces arylsulfonyl radicals attached to an alkyl radical, where alkyl is defined as above. The term "heteroarylsulfinyl" embraces radicals containing an heteroaryl 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 "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 "aryloxy" embraces aryl radicals, as defined above, attached to an oxygen atom. Examples of such radicals include phenoxy, 4-chloro-3-ethylphenoxy, 4-chloro-3-methylphenoxy, 3-chloro-4-ethylphenoxy, 3,4-dichlorophenoxy, 4-methylphenoxy, 3-trifluoromethoxyphenoxy, 3-trifluoromethylphenoxy, 4-fluorophenoxy, 3,4-dimethylphenoxy, 5-bromo-2-fluorophenoxy, 4-bromo-3-fluorophenoxy, 4-fluoro-3-methylphenoxy, 5,6,7,8-tetrahydronaphthyloxy, 3-isopropylphenoxy, 3-cyclopropylphenoxy, 3-ethylphenoxy, 3-pentafluoroethylphenoxy , 3-(1,1,2,2-tetrafluoroethoxy)-phenoxy, and 4-tert -butylphenoxy.

The term "aroyl" embraces aryl radicals, as defined above, attached to an carbonyl radical as defined above. Examples of such radicals include benzoyl and toluoyl.

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

The term "aralkoxy" embraces oxy-containing aralkyl radicals attached through an oxygen atom to other radicals. More preferred aralkoxy radicals are " aralkoxy" radicals having phenyl radicals attached to 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-trifluoromethylbenzyloxy, and 2-phenylethoxy.

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

The term "haloaryloxyalkyl" embraces aryloxyalkyl radicals, as defined above, wherein one to five halo radicals are attached to an aryloxy group.

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

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

The term "heteroaralkoxy" embraces oxy-containing heteroaralkyl radicals attached through an oxygen atom to other radicals. More prefeπed heteroaralkoxy radicals are " heteroaralkoxy" radicals having heteroaryl radicals attached to alkoxy radical as described above. The term

"heterocyclylalkoxy" embraces oxy-containing heterocyclylalkyl radicals attached through an oxygen atom to other radicals.

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 heteroaryl radicals, as defined above, attached to an amino group. Examples of such radicals include pyridylamino. The term "heterocyclylamino" embraces heterocyclyl radicals, as defined above, attached to an amino group.

The term "heteroaralkylamino" embraces heteroaralkyl radicals, as defined above, attached to an amino group. Examples of such radicals include pyridylmethylamino. The term "heterocyclylalkylamino" embraces heterocyclylalkyl radicals, as defined above, attached to an amino group.

The term "heteroaryloxy" embraces heteroaryl radicals, as defined above, attached to an oxy group. Examples of such radicals include 2-

thiophenyloxy, 2-pyrimidyloxy, 2-pyridyloxy, 3-pyridyloxy, and 4-pyridyloxy. The term "heterocyclyloxy" embraces heterocyclyl radicals, as defined above, attached to an oxy group.

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

"heterocyclyloxyalkyl" embraces heterocyclyloxy radicals, as defined above, attached to an alkyl group.

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 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 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 "carboxamido" embraces amino, monoalkylamino, dialkylamino, monocycloalkylamino, alkylcycloalkylamino, dicycloalkylamino, N-alkyl-N-arylamino, arylamino, aralkylamino, nitrogen containing heterocyclyl, heterocyclylamino, N-alkyl-N-heterocyclylamino, heteroarylamino, and heteroaralkylamino radicals, attached to one of two unshared bonds in a carbonyl group. The term "carboxamidoalkyl" embraces carboxamido radicals, as defined above, attached to an alkyl group. The term "carboxyalkyl" embraces a carboxy radical, as defined above, attached to an alkyl group. The term "carboalkoxy" embraces alkoxy radicals, as defined above, attached to one of two unshared bonds in a carbonyl group. The term "carboaralkoxy" embraces aralkoxy radicals, as defined above, attached to one of two unshared bonds in a carbonyl group. The term "monocarboalkoxyalkyl" embraces one carboalkoxy radical, as defined above, attached to an alkyl group. The term "dicarboalkoxyalkyl" embraces two carboalkoxy radicals, as defined above, attached to an alkylene group. The term "monocyanoalkyl" embraces one cyano radical, as defined above, attached to an alkyl group. The term "dicyanoalkylene" embraces two cyano radicals, as defined above, attached to an alkyl group. The term "carboalkoxycyanoalkyl" embraces one cyano radical, as defined above, attached to an carboalkoxyalkyl group.

The term "acyl", alone or in combination, means a carbonyl or

thionocarbonyl group bonded to a radical selected from, for example, hydrido, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkoxyalkyl, haloalkoxy, aryl, heterocyclyl, heteroaryl, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, alkylthio, arylthio, amino, alkylamino, dialkylamino, aralkoxy, arylthio, and alkylthioalkyl. Examples of "acyl" are 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 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, 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 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. 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 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 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, 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 sulfomum group where said group is bonded to one bond of an alkylene group as defined above. Examples of such

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 alkyl groups. Examples of such trialkylphosphonium radicals include, for example, (CH3)3P+-.

Said "alkyl", "alkenyl", "alkynyl", "alkanoyl", "alkylene",

"alkenylene", "hydroxyalkyl", "haloalkyl", "haloalkylene", "haloalkenyl", "alkoxy", "alkenyloxy", "alkenyloxyalkyl", "alkoxyalkyl", "aryl",

"perhaloaryl", "haloalkoxy", "haloalkoxyalkyl", "haloalkenyloxy",

"haloalkenyl oxy alkyl", "alkylenedioxy", "haloalkylenedioxy", "heterocyclyl", "heteroaryl", "hydroxyhaloalkyl", "alkylsulfonyl", "haloalkylsulfonyl", "alkylsulfonylalkyl", "haloalkylsulfonylalkyl", "alkylsulfinyl",

"alkylsulfinylalkyl", "haloalkylsulfinylalkyl", "aralkyl", "heteroaralkyl", "perhaloaralkyl", "aralkylsulfonyl", "aralkylsulfonylalkyl", "aralkylsulfinyl", "aralkylsulfinylalkyl", "cycloalkyl", "cycloalkylalkanoyl", "cycloalkylalkyl", "cycloalkenyl", "halocycloalkyl", "halocycloalkenyl", "cycloalkylsulfinyl", "cycloalkylsulfinylalkyl", "cycloalkylsulfonyl", "cycloalkylsulfonylalkyl", "cycloalkoxy", "cycloalkoxyalkyl", "cycloalkylalkoxy", "cycloalkenyloxy",

"cycloalkenyloxyalkyl", "cycloalkylenedioxy", "halocycloalkoxy",

"halocycloalkoxy alkyl", "halocycloalkenyloxy", "halocycloalkenyloxy alkyl", "alkylthio", "haloalkylthio", "alkylsulfinyl", "amino", "oxy", "thio",

"alkylamino", "arylamino", "aralkylamino", "arylsulfinyl", "arylsulfinylalkyl", "arylsulfonyl", "arylsulfonylalkyl", "heteroarylsulfinyl",

"heteroarylsulfinylalkyl", "heteroarylsulfonyl", "heteroarylsulfonylalkyl", "heteroarylamino", "heteroaralkylamino", "heteroaryloxy",

"heteroaryloxylalkyl", "aryloxy", "aroyl", "aralkanoyl", "aralkoxy",

"aryloxyalkyl", "haloaryloxy alkyl", "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 amidino, guanidino, dialkylsulfonium, trialkylphosphonium, dialkylsulfoniumalkyl, perhaloaralkyl, aralkylsulfonyl, aralkylsulfonylalkyl, aralkylsulfinyl, aralkylsulfinylalkyl, halocycloalkyl, halocycloalkenyl, cycloalkylsulfinyl, cycloalkylsulfinylalkyl, cycloalkylsulfonyl, cycloalkylsulfonylalkyl, heteroarylamino, N-heteroarylamino-N-alkylamino, heteroaralkylamino, heteroaryloxy, heteroaryloxylalkyl, haloalkylthio, alkanoyloxy, alkoxy, alkoxyalkyl, haloalkoxylalkyl, heteroaralkoxy, cycloalkoxy, cycloalkenyloxy, cycloalkoxyalkyl, cycloalkylalkoxy, cycloalkenyloxyalkyl, cycloalkylenedioxy, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxy, halocycloalkenyloxyalkyl, hydroxy, amino, thio, nitro, alkylamino, alkylthio, alkylthioalkyl, arylamino, aralkylamino, arylthio, arylthioalkyl, heteroaralkoxyalkyl, alkylsulfinyl, alkylsulfinylalkyl, arylsulfinylalkyl, arylsulfonylalkyl,

heteroarylsulfinylalkyl, heteroarylsulfonylalkyl, alkylsulfonyl, alkylsulfonylalkyl, haloalkylsulfinylalkyl, haloalkylsulfonylalkyl, alkylsulfonamido,

alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl

amidosulfonyl, monoarylamidosulfonyl, arylsulfonamido, diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl, arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, haloalkanoyl, alkyl, alkenyl, alkynyl, alkenyloxy, alkenyloxyalky, alkylenedioxy, haloalkylenedioxy, cycloalkyl, cycloalkylalkanoyl, cycloalkenyl, cycloalkylalkyl, 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, heteroaralkyl, arylalkenyl, heteroarylalkenyl, carboxyalkyl, carboalkoxy, alkoxycarbonyl, carboaralkoxy, carboxamido, carboxamidoalkyl, cyano, carbohaloalkoxy, phosphono, phosphonoalkyl, diaralkoxyphosphono, and diaralkoxyphosphonoalkyl.

The term "spacer" can include a covalent bond and a linear moiety having a backbone of 1 to 7 contiguous atoms. The spacer may have 1 to 7 atoms of a univalent or multi-valent chain. Univalent chains may be constituted by a radical selected from =C(H)-, =C(R2a )-, -O-, -S-, -S(O)-, -S(O)2-,

-NH-, -N(R2a)-, -N=, -CH(OH)-, =C(OH)-, -CH(OR2a)-, =C(OR2a)-, and

-C(O)- wherein R2a is selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, 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 chain. The chain may be constituted of one or more radicals selected from:

alkylene, alkenyl, -O-, -O-CH2-, -S-CH2-, -CH2CH2-, ethenyl,

-CH=CH(OH)-, -OCH2O-, -O(CH2)2O-, -NHCH2-, -OCH(R2a)O-,

-O(CH2CHR2a)O-, -OCF2O-, -O(CF2)2O-, -S-, -S(O)-, -S(O)2-, -N(H)-,

-N(H)O-, -N(R2a )O-, -N(R2a )-, -C(O)-, -C(O)NH-, -C(O)NR2a -, -N=,

-OCH2-, -SCH2-, S(O)CH2-, -CH2C(O)-, -CH(OH)-, =C(OH)-, -CH(OR2a)-,

=C(OR2a )-, S(O)2CH2-, and -NR2a CH2- and many other radicals defined above or generally known or ascertained by one of skill-in-the art. Side chains may include substituents such as 1 or more non-hydrido substituents such as amidino, guanidino, dialkylsulfonium, trialkylphosphonium, dialkylsulfoniumalkyl, perhaloaralkyl, aralkylsulfonyl, aralkylsulfonylalkyl, aralkylsulfinyl,

aralkylsulfinylalkyl, halocycloalkyl, halocycloalkenyl, cycloalkylsulfinyl, cycloalkylsulfinylalkyl, cycloalkylsulfonyl, cycloalkylsulfonylalkyl,

heteroarylamino, N-heteroarylamino-N-alkylamino, heteroaralkylamino, heteroaryloxy, heteroaryloxylalkyl, haloalkylthio, alkanoyloxy, alkoxy, alkoxyalkyl, haloalkoxylalkyl, heteroaralkoxy, cycloalkoxy, cycloalkenyloxy, cycloalkoxyalkyl, cycloalkylalkoxy, cycloalkenyloxyalkyl, cycloalkylenedioxy, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxy, halocycloalkenyloxyalkyl, hydroxy, amino, thio, nitro, alkylamino, alkylthio, alkylthioalkyl, arylamino, aralkylamino, arylthio, arylthioalkyl, heteroaralkoxyalkyl, alkylsulfinyl, alkylsulfinylalkyl, arylsulfinylalkyl, arylsulfonylalkyl, heteroarylsulfinylalkyl, heteroarylsulfonylalkyl, alkylsulfonyl, alkylsulfonylalkyl, haloalkylsulfinylalkyl, haloalkylsulfonylalkyl, alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, monoarylamidosulfonyl, arylsulfonamido,

diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl, arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, haloalkanoyl, alkyl, alkenyl, alkynyl, alkenyloxy, alkenyloxyalky, alkylenedioxy, haloalkylenedioxy, cycloalkyl, cycloalkenyl, cycloalkylalkyl, 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, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, carboxyalkyl, carboalkoxy, carboaralkoxy, carboxamido, carboxamidoalkyl, cyano, carbohaloalkoxy, phosphono, phosphonoalkyl, diaralkoxyphosphono, and diaralkoxyphosphonoalkyl.

Compounds of the present invention can exist in tautomeric, geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis- and trans-geometric isomers, E- and Z-geometric isomers, R- and S-enantiomers, diastereomers, d-isomers, 1-isomers, the racemic mixtures thereof and other mixtures thereof, as falling within the scope of the invention. Pharmaceutically acceptable sales of such tautomeric, geometric or stereoisomeric 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").

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

Some of the compounds described contain one or more stereocenters and are meant to include R, S, and mixtures of R and S forms for each stereocenter present.

Some of the compounds described herein may contain one or more ketomc or aldehydic carbonyl groups or combinations thereof alone or as part of a heterocyclic ring system. Such carbonyl groups may exist in part or principally in the "keto" form and in part or principally as one or more "enol" forms of each aldehyde and ketone group present. Compounds of the present 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 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=O) and thiono (C=S) in type.

Some of the compounds described herein may contain one or more ϊmine 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 "enamine" tautomeric forms.

The present invention also comprises a treatment and prophylaxis in anticoagulant therapy for the treatment and prevention of a variety of thrombotic conditions including coronary artery and cerebrovascular disease in a subject, comprising administering to the subject having such disorder a therapeutically-effective amount of a compound of Formula (I):


or a pharmaceutically-acceptable salt thereof.

As a further embodiment, compounds of the present invention of Formula (I) or a pharmaceutically-acceptable salt thereof as defined above, 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.

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 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, and extracoφoreal circulation systems.

Compounds of Formula (I) are capable of inhibiting activity of serine proteases related to the coagulation cascade, and thus could be used in the manufacture of a medicament, a method for the prophylactic or therapeutic treatment of diseases mediated by coagulation cascade serine proteases, such as inhibiting the formation of blood platelet aggregates, inhibiting the formation of fibrin, inhibiting thrombus formation, and inhibiting embolus formation in a mammal, in blood, in blood products, and in mammalian organs. The compounds also can be used for treating or preventing unstable angina, refractory angina, myocardial infarction, transient ischemic attacks, atriai fibrillation, thrombotic stroke, embolic stroke, deep vein thrombosis, disseminated intravascular coagulation, ocular build up of fibrin, and

reocclusion or restenosis of recanalized vessels in a mammal. The compounds also can be used to study the mechanism of action of coagulation cascade serine proteases to enable the design of better inhibitors and development of better assay methods. The compounds of Formula (I) would be also useful in prevention of cerebral vascular accident (CVA) or stroke.

Also included in the family of compounds of Formula (I) are the pharmaceutically-acceptable salts thereof. The term "pharmaceutically-acceptable salt" embraces salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases. The nature of the salt is not critical, provided that it is pharmaceutically acceptable. Suitable

pharmaceutically-acceptable acid addition salts of compounds of Formula (I) may be prepared from inorganic acid or from an organic acid. Examples of 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, 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 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 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) in association with at least one pharmaceutically-acceptable carrier, adjuvant or diluent. Pharmaceutical compositions of the present invention can comprise the active compounds of Formula (I) in association with one or more non-toxic,

pharmaceutically-acceptable carriers and/or diluents and/or adjuvants

(collectively referred to herein as "carrier" materials) and, if desired, other active ingredients. The active compounds of the present invention may be

administered by any suitable route, preferably in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment intended.

The active compounds and composition may, for example, be administered orally, intravascularly, intraperitoneally, subcutaneously, intramuscularly, oculary, or topically. For treating ocular build up of fibrin, the compounds may be administered intraocularly or topically as well as orally or parenterally.

The compounds can be administered in the form of a depot injection or implant preparation which may be formulated in such a manner as to permit a 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, 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.

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-propy1-methacrylamide-phenol, polyhydroxyethyl-aspartamide-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, 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 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 admimstered 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 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 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,

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 paraffmic or a water-miscible ointment base.

Alternatively, the active ingredients may be formulated in a cream with an oil-in-water cream base. If desired, the aqueous phase of the cream base may include, for example at least 30% w/w of a polyhydric alcohol such as propylene glycol, butane- 1,3-diol, mannitol, sorbitol, glycerol, polyethylene glycol and mixtures thereof. The topical formulation may desirably include a compound which enhances absoφtion or penetration of the active ingredient through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethylsulfoxide and related analogs. The compounds of this invention can also be administered by a transdermal device. Preferably topical administration will be accomplished using a patch either of the reservoir and porous membrane type or of a solid matrix variety. In either case, the active agent is delivered continuously from the reservoir or microcapsules through a membrane into the active agent permeable adhesive, which is in contact with the skin or mucosa of the recipient. If the active agent is absorbed through the skin, a controlled and predetermined flow of the active agent is administered to the recipient. In the case of microcapsules, the encapsulating agent may also function as the membrane.

The oily phase of the emulsions of this invention may be constituted from known ingredients in a known manner. While the phase may comprise merely an emulsifier, it may comprise a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabilizer. It is also preferred to include both an oil and a fat. Together, the emulsifier(s) with or without stabilizer(s) make-up the so-called emulsifying wax, and the wax 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 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 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, 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 pmposes, the active compounds of the present invention are ordinarily combined with one or more adjuvants appropriate to the indicated route of administration. If admimstered 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, gelatin, acacia gum, sodium alginate, poly vinylpyrrolidone, 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 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, 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 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 co-administered with suitable anti-platelet agreggation agents, including, but not limited to ticlopidine or clopidrogel, fibrinogen receptor antagonists (e.g. to treat or prevent unstable angina or to prevent reocculsion after angioplasty and restenosis), anti-coagulants such as aspirin, warfarin or heparins, thrombolytic agents such as plasminogen activators or streptokinase to achieve synergistic effects in the treatment of various pathologies, lipid lowering agents including antihypercholesterolemics (e.g. HMG CoA reductase inhibitors such as mevastatin, lovastatin, simvastatin, pravastatin, and fluvastatin, HMG CoA synthatase inhibitors, etc.), anti-diabetic drugs, or other cardiovascular agents (loop diuretics, thiazide type diuretics, nitrates, aldosterone antagonistics (i.e., spironolactone and epoxymexlerenone), angiotensin converting enzyme (e.g. ACE) inhibitors, angiotensin II receptor antagonists, beta-blockers,

antiarrythmics, anti-hypertension agents, and calcium channel blockers) to treat or prevent atheriosclerosis. For example, patients suffering from coronary artery disease, and patients subjected to angioplasty procedures, would benefit from coadministration of fibrinogen receptor antagonists and coagulation cascade inhibitors of the present invention. Also, coagulation cascade inhibitors could enhance the efficiency of tissue plasminogen activator-mediated thrombolytic reperfusion.

Typical doses of coagulation cascade inhibitors of the present invention with other suitable anti-platelet agents, anticoagulation agents, cardiovascular therapeutic agents, or thrombolytic agents may be the same as those doses of coagulation cascade inhibitors administered without coadministration of additional anti-platelet agents, anticoagulation agents, cardiovascular therapeutic agents, or thrombolytic agents, or may be substantially less than those doses of coagulation cascade inhibitors admimstered without coadministration of additional anti-platelet agents, anticoagulation agents, cardiovascular therapeutic agents, or thrombolytic agents, depending on a patient's therapeutic needs.

The present novel methods preferably employ compounds which selectively inhibit human TF-VIIA over the inhibition of both human Thrombin II and human factor Xa. Preferably, the compounds have a human TF-VIIA

IC50 of less than 0.5 μM and also have a selectivity ratio of TF-VIIA inhibition over both human Thrombin II and human factor Xa inhibition of at least 10, and more preferably at least 100. Even more preferably, the compounds have a human TF-VIIA IC50 of less than 0.1 μM and also have a selectivity ratio of

TF-VIIA inhibition over both human Thrombin II and human factor Xa inhibition of at least 1000, and most preferably at least 10,000.

All mentioned references are incoφorated by reference as if here written.

Although this invention has been described with respect to specific embodiments, the details of these embodiments are not to be construed as limitations. The following examples are provided to illustrate the present invention and are not intended to limit the scope thereof. Without further elaboration, it is believed that one skilled in the art can, using the preceding descriptions, utilize the present invention to its fullest extent. Therefore the following prefeπed 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 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 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 (I). These detailed descriptions fall within the scope and are presented for illustrative puφoses 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 are as follows: "AA" represents amino acids, "AcCN" represents acetonitrile, "AcOH" represents acetic acid, "BINAP" represents 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, "BnOH" represents benzyl alcohol, "BnCHO" represents 2-phenylethanal, "

BnSO2Cl" represents benzylsulfonyl chloride, "Boc" represents tert-butyloxy carbonyl, "BOP" represents benzotriazol-1-yl-oxy-tris-(dimethylamino), "bu" represents butyl, "dba" represents

dibenzylideneacetone, "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", "EDC" represents 1-[3- (dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride, "Fmoc" represents 9-fluorenylmethoxycarbonyl, "HOBT" represents

hydroxybenzoltriazole", "LDA" represents lithium diisopropylamide, "NMM" represents N-methylmorpholine, "Ph" represents phenyl or aryl, "PHTH" represents a phthaloyl group, "pnZ" represents 4-nitrobenzyloxy carbonyl, "PTC" represents a phase transfer catalyst , "py" represents pyridine, " RNH2" represents a primary organic amine, "p- TsOH" represents paratoluenesulfonic acid, "TBAF' represents

tetrabutylammonium fluoride, "TBTU" represents 2-(1H-benzotriozole-1-yl)-1,1,3,3-tetramethyl uronium tetrafluoroborate, "TEA" represents triethylamine, "TFA" represents trifluoroacetic acid, "THF" represents tetrahydrofuran, "TMS" represents trimethylsilyl, "TMSCN" represents trimethylsilyl cyanide, and "Cbz" or "Z" represents benzyloxy carbonyl.

GENERAL SYNTHETIC PROCEDURES AND SPECIFIC

EXAMPLES

The 4-pyridone compounds of the present invention can be synthesized, for example, according to the following procedures and Schemes given below.





Schemes 1, 2, 3, and 4 above summarize generic procedures that permit the preparation of a wide variety of the compounds of the present invention through the ability to introduce numerous R2 substituents represented by Z0-Q, numerous R1 substituents, a wide variety of amino substituting groups represented by B-, B-CH2, B-CO, and B-SO2, and a large number of amide forming Yo groups at the carboxylic acid group in which E° is C(O)NH. Examples 1 and 2 below describe the preparation of two representat ve compounds wherein X°is hydrido and R is methyl and propyl, respectively.


To a solution of 2,2-dimethyl-1,3-dioxane-4-dione (74.93 g, 0.52 mol) and pyridine (86.0 mL, 1.06 mol) in CH2CI2 (1.0 L) at 0 °C was added 4-pentenoyl chloride (62.5 mL, 0.57 mol) over 1.5 hrs. After an additional 40 min, the reaction mixture was allowed to warm to room temperature. After an additional 1 hour, the reaction mixture was concentrated in vacuo, and the residue was dissolved in t-BuOH (750 mL). The mixture was heated to reflux for 4 hrs, and then concentrated in vacuo. The residue was triturated with ethyl acetate (500 mL) and filtered. The filtrate was concentrated in vacuo to give a dark red oil EX-IA (64.95 g, 63%). 1H NMR (CDCI3) δ 1.43 (s, 9H), 2.31 (m,2H), 2.60 (t, J = 7.2 Hz, 2H), 3.32 (s, 2H),

4.93-5.04 (m, 2H), 5.70-5.84 (m, 1H). 13C NMR (CDCI3) δ 27.3, 27.9, 41.8, 50.6,

115.4, 136.6, 166.3, 202.4. LRMS (ESI) [M + Li]+ 205.

A mixture of EX-1A (130.0 g, 0.6557 mol) and N,N-dimethylformamide dimethyl acetal (117.2 g, 0.9836 mol) was heated to 80 °C for 2 hrs. The reaction mixture was concentrated in vacuo and purified by flash chromatography on silica gel (EtOAc/hexane) to give a yellow oil EX-1B (B140.9 g/85%). 1H NMR (CDCI3) δ 1.50 (s, 9H), 2.31-2.40 (m, 2H), 2.71 (t, J = 7.8 Hz, 2H), 3.44 (s, 6H), 4.93 (dd, J

= 9.9, 1.8 Hz, 1H), 4.97-5.05 (m, 1H), 5.77-5.90 (m, 1H), 7.53 (s, 1H). HRMS (ESI), calc'd for C14H23NO3 254.1756, found 254.1753.

A solution of EX- 1B (2.50 g, 9.87 mmol) in THF (25.0 mL) was added to LiHMDS (25.0 mL, 25.0 mmol, 1M in THF) at -70 °C. After 6 min, a solution of 3-nitrobenzoyl chloride (2.19 g, 11.80 mmol) in THF (25 mL) was added dropwise over 9 min. After 2 min. more, the cooling bath was removed, and ethyl ether (20 mL) and 3N aq. HCl (30 mL) was added. The mixture's pH = 2. After 1 hr, the layers were separated, and the organic layer was washed with saturated aqueous NaHCO3 (2 x 30 mL) and saturated aqueous NaCl (25 mL). The aqueous layer was extracted with ethyl ether (2 x 25 mL). Combined organic layers were dried (MgSO4), filtered and concentrated in vacuo to give a dark reddish brown viscous liquid. Purification by flash chromatography on silica gel eluting with

EtOAc/hexanes gave an off-white solid EX-1C (1.658 g/47%). 1H NMR (CDCI3) δ 1.59 (s, 9H), 3.24 (dd, J = 4.0, 1.6 Hz, 2H), 5.05 (dd, J = 17.2, 1.2 Hz, 1H), 5.15 (dd, J = 10.0, 1.2 Hz, 1H), 5.97-6.07 (m, 1H), 7.70 (t, J = 8.0 Hz, 1H), 7.94 (d, J = 7.6 Hz, 1H), 8.39 (dd, J = 8.0, 1.2 Hz, 1H), 8.50 (s, 2H). 13C NMR (CDCI3) δ 28.2, 29.8, 82.7, 116.5, 120.1, 123.6, 125.3, 127.4, 129.8, 133.2, 134.1, 134.5, 148.2, 158.6, 160.0, 161.7, 174.2. HRMS (ESI) calc'd for C19H19NO6

358.1254, found 358.1290.

A solution of EX-1C (5.845 g, 16.36 mmol), 40% aqueous methylamine (3.5 mL, 45.1 mmol), and acetic acid (35.0 mL) in methanol (117.0 mL) was heated to 65 °C. After 3.5 hrs, the mixture was cooled to room temperature and

concentrated in vacuo to give a dark oil EX- 1D (11.64 g/ est. 100%). 1H NMR (CDCI3) δ 1.60 (s, 9H), 2.94 (d, J = 6.0 Hz, 2H), 3.32 (s, 3H), 4.58 (dd, J = 17.1, 1.5 Hz, 1H), 4.85 (dd, J = 10.2, 0.9 Hz, 1H), 5.72-5.87 (m, 1H), 7.61 (d, J = 7.50 Hz, 1H), 7.75 (t, J = 7.8 Hz, 1H), 8.15 (s, 2H), 8.38-8.41 (m, 1H). HRMS (ES/M + H). Calc'd for C20H22N2O5: 371.1607. Found: 371.1608.

A mixture of crude EX-ID (7.147 g, 19.30 mmol) and TFA (6.50 mL, 84.4 mmol) in CH2CI2 ( 100.0 mL) was stirred at room temperature. After 2.5 hrs, the reaction mixture was concentrated in vacuo and CH3CN (30 mL) and 4N HCl in dioxane (30.0 mL, 120 mmol) was added. After two hrs, the mixture was

concentrated in vacuo to give a black oily solid. Purification by flash

chromatography on silica gel (1% MeOH in CH2CI2) gave a tan solid EX- IE

(3.420 g/56%). 1H NMR (CDCI3) δ 2.99 (m, 2H), 3.46 (s, 3H), 4.69 (dd, J =

17.2, 1.6 Hz, 1H), 4.89 (dd, J = 10.0, 1.6 Hz, 1H), 5.65-5.75 (m, 1H), 7.72 (m, 1H), 7.79 (t, J = 8.0 Hz, 1H), 8.21 (t, J = 1.6 Hz, 1H), 8.38 (m, 1H), 8.68 (s, 1H). 13C NMR (CDCI3) δ 31.3, 45.8, 114.8, 116.6, 118.3, 125.0, 126.1, 130.3, 131.7, 133.8,

135.0, 136.0, 147.6, 177.6. HRMS (ES/M + H). Calc'd for C16H14N2O5:

315.0981. Found: 315.0975.

A mixture of EX-1E (0.267 g, 0.761 mmol) and Et3N (0.210 mL, 1.51 mmol) in Ph CH3 (0.50 mL) and CH3CN (0.50 mL) were stirred at room temperature in a 10 mL round-bottom flask under N2- Note: It is important to have dry glassware, reagents and solvents for this reaction. After 10 min,

diphenylphosphorylazide (0.280 mL, 1.30 mmol) was added, and the mixture was gradually heated to 80 °C. After 5 hrs, the reaction mixture was cooled to room temperature. t-BuOH (1.00 mL, 10.4 mmol) was added, and the mixture was heated to 80 °C. After 2.5 hrs, the mixture was cooled to room temperature and diluted with CH2CI2 (50 mL). The solution was washed with saturated aqueous NaHCO3 (2 x 15 mL), dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography on silica gel eluting with 20-50% EtOAc/hexanes gave EX-IF (0.084 g/29%). 1H NMR (CDCI3) δ 1.52 (s, 9H), 2.98 (dd, J = 4.4, 1.2 Hz, 2H), 3.35 (s, 3H), 4.63 (dd, J = 17.2, 2.0 Hz, 1H), 4.87 (dd, J = 10.4, 1.6 Hz, 1H), 5.71-5.82 (m, 1H), 7.59-7.61 (m, 1H), 7.71-7.79 (m, 2H), 8.16 (t, J = 1.6 Hz, 1H),

8.38 (m, 1H), 8.47 (s, 1H). 13C NMR (CDCI3) δ 28.3, 31.2, 43.5, 80.7, 114.9, 123.5, 124.1, 124.4, 126.4, 128.8, 130.2, 134.8, 135.0, 135.3, 143.8, 148.3, 153.2, 168.5. HRMS (ES/M + H). Calc'd for C20H23N3O5: 386.1716. Found:

386.1730.

4-Methylmorpholine N-oxide (0.098 g, 0.84 mmol), aq. OsO4 (9.8 mL, 1.0 mg/mL, 0.038 mmol) and acetone (6.0 mL) were combined in a 50 mL round-bottom flask. The mixture was cooled to 2 °C, and a solution of EX- IF (0.286 g, 0.742 mmol) in acetone (8.0 mL) was added over 2 minutes. The reaction mixture was allowed to warm to room temperature. After 3.5 hrs, NaHSC3 (0.080 g, 0.77 mmol), water (60 mL) and brine (10 mL) was added. The mixture was extracted

with EtOAc (4 x 30 mL), dried (MgSO4), filtered and concentrated in vacuo to give a yellow oil EX-1G (0.305 g/98%). 1H NMR (CDCI3) δ 1.49 (s, 9H), 2.36-2.57 (m, 2H), 3.22-3.32 (m, 2H), 3.36 (s, 3H), 3.47 (m, 1H), 7.60 (m, 1H), 7.72-7.76 (m, 2H), 8.12-8.14 (m, 1H), 834-8.37 (m, 1H), 8.49 (s, 1H). HRMS (ES/M + H). Calc'd for C20H25N3O7: 420.1771. Found: 420.1767.

To a solution of EX-1G (0.342 g, 0.815 mmol) in CHCl3 (6.0 mL) was added a solution of NaIO4 (0.176 g, 0.823 mmol) in water (3.0 mL). Acetonitrile (4.0 mL) was added, and the mixture was stirred at room temperature. After 2.5 hrs, water (50 mL) and brine (5 mL) was added. The mixture was extracted with CH2CI2 (3 x 11 mL), dried (MgSO4), filtered and concentrated in vacuo to give a dark oil EX-1H (0.257 g/81%). 1H NMR (CDCI3) δ 1.48 (s, 9H), 3.30 (ABq, 2H), 3.36 (s, 3H), 7.55-7.59 (m, 1H), 7.67 (d, J = 8.4 Hz, 1H), 7.72 (d, J = 7.9 Hz,

1 H), 8.10 (t, J = 1.8 Hz, 1H), 8.32-8.36 (m, 1H), 8.49 (s, 1H), 9.57 (s, 1H). 13C NMR(CDCl3) δ 28.1, 41.7, 43.5, 80.9, 118.2, 123.7, 124.7, 126.8, 128.8, 130.6, 134.4, 134.9, 144.8, 148.4, 153.0, 168.2, 198.4. HRMS (ES/M - CH3). Calc'd for C19H21N3O6: 374.1352. Found: 374.1363.

A solution of 2-methylbut-2-ene (25 mL), t-BuOH (20 mL) and THF (20 mL) was prepared. Compound EX-1H (0.240 g, 0.620 mmol) and the 2-methylbut-2-ene solution (1 mL) were combined in a 25 mL round-bottom flask. The mixture was cooled to 0 °C, and a solution of NaClO2 (0.441 g, 4.88 mmol) and NaH2PO4-H2O (0.530 g, 3.84 mmol) in water (1.50 mL) was added. After 15 min, the mixture was allowed to warm to room temperature. After an additional 2.25 hrs, the mixture was concentrated in vacuo. Water (6.0 mL) was added, and aqueous 1N HCl was added until pH equaled 3. The mixture was extracted with 2 parts THF/1 part CH2CI2 (4 x 7 mL). Combined organic layers were dried

(MgSO4), filtered and concentrated in vacuo to give a brown foam (0.287 g).

Trituration with ethyl ether (10 mL) and filtration gave a tan solid EX- 1I (0.102 g/41%). 1H NMR (CDCI3) δ 1.54 (s, 9H), 3.27 (ABq, 2H), 3.51 (s, 3H), 7.65-7.70 (m, 2H), 7.82 (d, J = 8.1 Hz, 1H), 7.84 (d, J = 7.8 Hz, 1H), 8.17 (t, J = 1.8 Hz, 1H), 8.42-8.46 (m, 1H), 8.71 (s, 1H). 13C NMR (CDCI3) δ 28.0, 33.9, 44.0, 81.2,

119.5, 123.8, 124.9, 127.6, 128.9, 130.8, 133.8, 135.0, 144.9, 148.4, 152.9, 168.5, 172.3. HRMS (ES/M + H). Calc'd for C19H21N3O7: 404.1458. Found:

404.1464.

Compound EX- 1I (0.100 g, 0.248 mmol), N-cyclohexylcarbodiimide, N-methyl polystyrene resin (0.995 g, 1.51 mmol, 1.52 mmol/g), and HOBt (0.050 g, 0.37 mmol) were combined with CH2CI2 (15.0 mL) and DMF (2.50 mL). After 40 min, a mixture of benzyl-[[(4-aminomethylphenyl)iminomethyl]amino]-carbamate hydrogen chloride salt (0.0835 g, 0.261 mmol) and Et3N (0.50 mL, 3.6 mmol) in DMF (0.75 mL) was added. After 21 hrs, the mixture was filtered, washing with CH2Cl2, and concentrated in vacuo to give a dark solid EX-1J (0.280 g/ est. 100%). HRMS (ES/M + H). Calc'd for C35H36N6O8: 669.2673.

Found: 669.2671.

Compound EX-1J (0.153 g, 0.229 mmol) and 4N HCl in dioxane (2.50 mL) were combined in a 10 mL round-bottom flask. The mixture was sonicated for 5 min. After standing at room temperature for 1.5 hrs, a solution of NaBH(OAc)3 (0.100 g, 0.472 mmol) and acetone (0.10 mL) in THF (0.90 mL) was added. After 2 hrs more, water (10 mL) was added, and the mixture was extracted with EtOAc (2 x 6 mL). Saturated aqueous NaHCO3 was added to the aqueous layer until pH = 7, and the aqueous layer was then extracted with EtOAc (3 x 6 mL). All organic extracts were combined, dried (MgSO4) and concentrated in vacuo to give a dark oil (0.143 g). Purification by filtration through silica gel eluting with 5% MeOH/

CH2CI2 gave a tan solid EX- 1K (0.083 g/59%). 1H NMR (CDCI3) δ 1.27 (d, J = 6.3 Hz, 6H), 2.84-2.97 (m, 2H), 3.39-3.48 (m, 2H), 3.41 (s, 3H), 3.60 (m, 1H), 4.39 (m, 2H), 4.80 (d, 1H), 7.28-7.46 (m, 7H), 7.64-7.80 (m, 4H), 8.14 (s, 1H), 8.38 (m, 2H). HRMS (ES/M + H). Calc'd for C33H34N6O6: 611.2618. Found:

611.2629.

Compound EX- 1K (0.070 g, 0.11 mmol), 4N HCl (2.0 mL), MeOH (9.0 mL) and 10% Pd on C (0.057 g) were combined in a Fischer-Porter bottle. The bottle was pressurized to 20 psig H2- After 70 min, the bottle was vented, and its contents were filtered through celite washing with MeOH (100 mL). The filtrate was concentrated in vacuo to give a white solid (0.080 g). Purification by reverse phase HPLC (Gilson) eluting with CH3CN/H2O(0.1%TFA) gave the white solid product (0.029 g, 49%). 1H NMR (D2O) δ 1.25 (d, J = 6.6 Hz, 6H), 3.21 (ABq,

H), 3.38 (s, 3H), 3.69 (quin, J = 6.30 Hz, 1H), 4.22 (ABq, 2H), 7.26-7.30 (m, 4H), .50-7.62 (m, 5H), 7.63-7.83 (m, 1H), 8.15 (s, 1H). HRMS (ES/M + H). Calc'd for C25H30N6O2: 447.2508. Found: 447.2526.

Example 2


The compound was prepared as described for Example 1 with the exception that re-propylamine was substituted for methylamine in the process: 1H NMR (D2O) δ 1.20 (m, 12H), 3.08 (ABq, 2H), 3.25 (d, j=16.52 Hz, 1H), 3.68 (quin, J = 6.24 Hz, 1H), 4.08 (quin, J = 6.45 Hz, 1H), 4.24 (dd,J1 = 16.12 Hz, J2 = 24.18 Hz, 2H), 7.26-7.40 (m, 4H), 7.50-7.66 (m, 4H), 8.20 (s, 1H). LC/MS (ES/M + H): 475.2.

Using the examples and methods described herein previously, the following examples having an amidinoaralkyl or amidinoheteroaralkyl type Y group could be prepared:

2-[3-[N-[[4-aminoiminomethylphenyl]methyl]-2-[3-aminophenyl]-5-[N,N-dimethylhydrazino]-4-pyridonyl]]acetamide;

2-[3-[N-[[4-aminoiminomethylphenyl]methyl]-2-[3-aminophenyl]-5-[N-ethyl-N-methylhydrazino]-4-pyridonyl]]acetamide;

2-[3-[N-[[4-aminoiminomethylphenyl]methyl]-2-[3-aminophenyl]-5- [N,N-dimethylhydrazino]-N-methyl-4-pyridonyl]]acetamide;

2-[3-[N-[[4-aminoiminomethylphenyl]methyl]-2-[3-aminophenyl]-5-[N-ethyl-N-methylhydrazino]-N-methyl-4-pyridonyl]]acetamide;

2-[3-[N-[[4-aminoiminomethylphenyl]methyl]-2-[3,5-diaminophenyl]-5-[N,N-dimethylhydrazino]-4-pyridonyl]]acetamide;

2-[3-[N-[[4-aminoiminomethylphenyl]methyl]-2-[3,5-diaminophenyl]- 5-[N-ethyl-N-methylhydrazino]-4-pyridonyl]]acetamide;

2- [3 - [N-[[4-aminoiminomethylphenyl]methyl]-2-[3,5-diaminophenyl]-S[N,N-dimethylhydrazino]-N-methyl-4-pyridonyl]]acetamide;

2- [3 - [N-[[4-aminoiminomethylphenyl]methyl]-2-[3,5-diaminophenyl]-S[N-ethyl-N-methylhydrazino]-N-methyl-4-pyridonyl]]acetamide;

2- [3 - [N-[[4-aminoiminomethylphenyl]methyl]-2-[3-amino-5-carboxyphenyl]-5-[N,N-dimethylhydrazino]-4-pyridonyl]]acetamide;

2-[3-[N-[[4-aminoiminomethylphenyl]methyl]-2-[3-amino-5-carboxyphenyl]-5-[N-ethyl-N-methylhydrazino]-4-pyridonyl]]acetamide;

2-[3-[N-[[4-aminoiminomethylphenyl]methyl]-2-[3-amino-5-carboxyphenyl]-5-[N,N-dimethylhydrazino]-N-methyl-4-pyridonyl]]acetamide;

2-[3-[N-[[4-aminoiminomethylphenyl]methyl]-2-[3-amino-S carboxyphenyl]- 5-[N-ethyl-N-methylhydrazino]-N-methyl-4-pyridonyl]]acetamide;

2-[3-[N-[[4-aminoiminomethylphenyl]methyl]-2-[3-amino-5-(N-benzylamidocarbonyl)phenyl]- 5-[N,N- dimethylhydrazino]-4-pyridonyl]]acetamide;

2-[3-[N-[[4-aminoiminomethylphenyl]methyl]-2-[3-amino-5-(N-benzylamidocarbonyl)phenyl]-5-[N-ethyl-N-methylhydrazino]-4-pyridonyl]]acetamide;

2-[3-[N-[[4-aminoiminomethylphenyl]methyl]-2-[3-amino-5-(N-benzylamidocarbonyl)phenyl]-5-[N,N-dimethylhydrazino]-N-methyl-4-pyridonyl]]acetamide; and

2-[3-[N-[[4-aminoiminomethylphenyl]methyl]-2[3-amino-5-(N-benzylamidocarbonyl)phenyl]-5-[N-ethyl-N-methylhydrazino]-N-methyl-4-pyridonyl]]acetamide.

Using the examples and methods described herein previously, the following further examples having a amidinoaralkyl or amidinoheteroaralkyl type Y group could be prepared of the formula:


wherein B, A, R 1 , R2 , X0, and Y0 are selected to form the following compounds:

R2 is 3-aminophenyl, B is phenyl, A is CH2, Y0 is 4-amidinobenzyl, and

R is methyl;

R2 is 3-aminophenyl, B is 3-chlorophenyl, A is CH2CH2, Y0 is 4-amidmobenzyl, and R1 is methyl;

R2 is 3-aminophenyl, B is phenyl, A is CH2, Y0 is 4-amidinobenzyl, and

R1 is hydrido;

R2 is 3-aminophenyl, B is 2-imιdazoyl, A is CH2CH2CH2, Y0 is 4-amidinobenzyl, and R 1 is methyl;

R2 is 3-amidocarbonyl-5-aminophenyl, B is 3-chlorophenyl, A is CH2CH2, Y0 is 4-amidinobenzyl, and R 1 is methyl;

R2 is 3-amino-5-(N-benzylamidocarbonyl)phenyl, B is 3-chlorophenyl, A is CH2CH2,Y is 4-amidinobenzyl, and R1 is methyl;

R2 is 3-amino-5-(N-(2-chlorobenzyl)amidocarbonyl)phenyl, B is 3-chlorophenyl, A is CH2CH2,Y is 4-amidinobenzyl, and R is methyl;

R2 is 3-amino-5-(N-(2-chlorobenzyl)amidosulfonyl)phenyl, B is 3-chlorophenyl, A is CH2CH2,Y0 is 4-amidinobenzyl, and R1 is methyl;

R2 is 3-amino-5-(N-(2-trifluoromethylbenzyl)amidocarbonyl)- phenyl, B is -chlorophenyl, A is CH2CH2,Y0 is 4-amidinobenzyl, and R1 is methyl;

R2 is 3,5-diaminophenyl, B is 3-chlorophenyl, A is CH2CH2, Y0 is 4-amidinobenzyl, and R 1 is methyl;

R2 is 3-amino-5-carboxyphenyl, B is 3-chlorophenyl, A is CH2CH2, Y0 is

4-amidinobenzyl, and R 1 is methyl;

R2 is 3-amidocarbonyl-5-aminophenyl, B is 3-chlorophenyl, A is CH2CH2,

Y0 is 4-amidinobenzyl, and R 1 is hydrido;

R2 is 3-amino-5-(N-benzylamidocarbonyl)phenyl, B is 3-chlorophenyl, A is CH2CH2, 1 is 4-amidinobenzyl, and R1 is hydrido;

R2 is 3-amino-5-(N-(2-chlorobenzyl)amidocarbonyl)phenyl, B is 3-chlorophenyl, A is CH2CH2, Y0 is 4-amidinobenzyl, and R1 is hydrido;

R2 is 3-amino-5-(N-(2-chlorobenzyl)amidosulfonyl)phenyl, B is 3-chlorophenyl, A is CH2CH2, Y0 is 4-amidinobenzyl, and R1 is hydrido;

R2 is 3-amino-5-(N-(2-trifluoromethylbenzyl)amidocarbonyl)- phenyl, B is

3-chlorophenyl, A is CH2CH2, Y0 is 4-amidinobenzyl, and R1 is hydrido;

R2 is 3,5-diaminophenyl, B is 3-chlorophenyl, A is CH2CH2, Y0 is 4-amidinobenzyl, and R1 is hydrido;

R2 is 3-amino-Scarboxyphenyl, B is 3-chlorophenyl, A is CH2CH2,Y0 is 4-amidinobenzyl, and R is hydrido;

R2 is 3-aminophenyl, B is 2,2,2-trifluoroethyl, A is a bond, Y0 is 4-amidinobenzyl, and R is methyl;

R2 is 3-aminophenyl, B is (S)-2-butyl, A is a bond, Y0 is 4-amidinobenzyl, and R1 is methyl;

R 7 is 5-amino-2-fluorophenyl, B is isopropyl, A is a bond, Y0 is 4-amidinobenzyl, and R 1 is methyl;

R2 is 2-methyl-3-aminophenyl, B is isopropyl, A is a bond, Y0 is 4-amidinobenzyl, and R1 is methyl;

R2 is 3-aminophenyl, B is ethyl, A is a bond, Y0 is 4-amidinobenzyl, and

R 1 is methyl;

R 2 is 3-aminophenyl, B is ethyl, A is a bond, Y0 is 4-amιdino-2-fluorobenzyl, and R1 is methyl;

R 2 is 3-aminophenyl, B is 2-propenyl, A is a bond, Y0 is 4-amidinobenzyl, and R1 is methyl;

R 2 is 3-aminophenyl, B is isopropyl, A is a bond, Y0 is 4-amιdino-2-fluorobenzyl, and R is methyl;

R 2 is 3-aminophenyl, B is isopropyl, A is a bond, Y0 is 4-amidinobenzyl, and R1 is methyl;

R 2 is 3-aminophenyl, B is 2-butyl, A is a bond, Y0 is 4-amidinobenzyl, and R1 is methyl;

R 2 is 3-aminophenyl, B is (R)-2-butyl, A is a bond, Y0 is 4-amidinobenzyl, and R1 is methyl;

R 2 is 3-aminophenyl, B is 2-propynyl, A is a bond, Y0 is 4-amidinobenzyl, and R1 is methyl;

R 2 is 3-aminophenyl, B is 3-pentyl, A is a bond, Y0 is 4-amidinobenzyl, and R1 is hydrido;

R 2 is 3-aminophenyl, B is hydrido, A is CH2, Y0 is 4-amidinobenzyl, and

R 1 is methyl;

R 2 is 3-aminophenyl, B is ethyl, A is CH2, Y0 is 4-amidmobenzyl, and R 1 is methyl;

R 2 is 3-aminophenyl, B is 2-methypropyl, A is a bond, Y0 is 4-amidinobenzyl, and R1 is methyl;

R2 is 3-aminophenyl, B is 2-propyl, A is CH3CH, Y0 is 4-amidinobenzyl, and R1 is methyl;

R2 is 3-aminophenyl, B is propyl, A is a bond, Y0 is 4-amidino-2-fluorobenzyl, and R1 is methyl;

R2 is 3-aminophenyl, B is 6-amidocarbonylhexyl, A is a bond, Y0 is 4-amidinobenzyl, and R1 is methyl;

R2 is 3-aminophenyl, B is tert-butyl, A is a bond, Y0 is 4-amidιnobenzyl, and R is hydrido;

R2 is 3-aminophenyl, B is tert-butyl, A is a bond, Y0 is 4-amidinobenzyl, and R1 is methyl;

R2 is 3-aminophenyl, B is 3-hydroxypropyl, A is a bond, Y0 is 4-amidinobenzyl, and R1 is methyl;

R2 is 3-aminophenyl, B is 2-methylpropyl, A is a bond, Y0 is 4-amidino-2-fluorobenzyl, and R1 is methyl;

R2 is 3-aminophenyl, B is butyl, A is a bond, Y0 is 4-amidinobenzyl, and R1 is methyl;

R2 is 3-aminophenyl, B is 1-methoxy-2-propyl, A is a bond, Y0 is 4-amidinobenzyl, and R1 is methyl;

R2 is 3-aminophenyl, B is 2-methoxyethyl, A is a bond, Y0 is 4-amidinobenzyl, and R1 is methyl;

R2 is 3-aminophenyl, B is 2-propyl, A is a bond, Y0 is 5-amidino-2-thienylmethyl, and R1 is methyl;

R2 is 5-amino-2-methylthiophenyl, B is 2-propyl, A is a bond, Y0 is 4-amidinobenzyl, and R1 is methyl;

R2 is 3-amino-5-carboxyphenyl, B is isopropyl, A is a bond, Y0 is 4-amidinobenzyl, and R1 is methyl;

R2 is 3-amino-5-carbomethoxyphenyl, B is isopropyl, A is a bond, Y0 is 4-amidinobenzyl, and R1 is methyl;

R2 is 3-aminophenyl, B is isopropyl, A is a bond, Y0 is 4-amidinobenzyl, and R 1 is ethyl;

R2 is 3-amino-5-carboxamidophenyl, B is isopropyl, A is a bond, Y0 is 4-amidinobenzyl, and R 1 is methyl;

R2 is 3-amino-5-(N-benzyl-N-methylamidocarbonyl)phenyl, B is isopropyl, A is a bond, Y0 is 4-amidinobenzyl, and R1 is methyl;

R2 is 3-amino-5-(N-(1 -phenyl ethyl)amidocarbonyl)phenyl, B is isopropyl, A is a bond, Y0 is 4-amidinobenzyl, and R1 is methyl;

R2 is 3-amino-5-(N-(2-phenyl-2-propyl)amidocarbonyl)phenyl, B is isopropyl, A is a bond, Y0 is 4-amidinobenzyl, and R1 is methyl;

R2 is 3-amino-5-(N-(2,4-dichlorobenzyl)amidocarbonyl)phenyI, B is isopropyl, A is a bond, Y0 is 4-amidinobenzyl, and R1 is methyl;

R2 is 3-amino-5-(N-(4-bromobenzyl)amidocarbonyl)phenyl, B is isopropyl, A is a bond, Y0 is 4-amidinobenzyl, and R1 is methyl;

R2 is 3-amino-5-(N-benzylamidocarbonyl)phenyl, B is isopropyl, A is a bond, Y0 is 4-amidinobenzyl, and R1 is methyl;

R2 is 3-amino-5-(N-(2-chlorobenzyl)amidocarbonyl)phenyl, B is isopropyl, A is a bond, Y0 is 4-amidinobenzyl, and R1 is methyl;

R2 is 3-amino-5-(N-(2-trifluoromethylbenzyl)amidocarbonyl)phenyl, B is isopropyl, A is a bond, Y0 is 4-amidinobenzyl, and R1 is methyl;

R2 is 3-amino-5-(N-(3-fluorobenzyl)amidocarbonyl)phenyl, B is isopropyl,

A is a bond, Y0 is 4-amidinobenzyl, and R1 is methyl;

R2 is 3-amino-5-(N-(3-trifluoromethylbenzyl)amidocarbonyl)phenyl, B is isopropyl, A is a bond, Y0 is 4-amidinobenzyl, and R1 is methyl;

R2 is 3-amino-5-(N-isobutylamidocarbonyl)phenyl, B is isopropyl, A is a bond, Y0 is 4-amidmobenzyl, and R1 is methyl;

R2 is 3-amino-5-(N-cyclobutylamidocarbonyl)phenyl, B is isopropyl, A is a bond, Y0 is 4-amidinobenzyl, and R1 is methyl;

R 2 is 3-amino-5-(N-cyclopentylamidocarbonyl)phenyl, B is isopropyl, A is a bond, Y0 is 4-amidinobenzyl, and R1 is methyl;

R 2 is 3-amino-5-(N-cycloheptylamidocarbonyl)phenyl, B is isopropyl, A is a bond, Y0 is 4-amidinobenzyl, and R1 is methyl;

R2 is 3-amino-5-(N-(2-pyridylmethyl)amidocarbonyl)phenyl, B is isopropyl, A is a bond, Y0 is 4-amidinobenzyl, and R 1 is methyl;

R2 is 3-amino-5-(N-(3-pyridylmethyl)amidocarbonyl)phenyl, B is isopropyl, A is a bond, Y0 is 4-amidinobenzyl, and R1 is methyl;

R2 is 3-amino-5-(N-(2-(4-methoxyphenyl)ethyl)amidocarbonyl)phenyl, B is isopropyl, A is a bond, Y0 is 4-amidinobenzyl, and R1 is methyl;

R2 is 3-amino-5-(N-(3-phenylpropyl)amidocarbonyl)phenyl, B is isopropyl, A is a bond, Y0 is 4-amidinobenzyl, and R1 is methyl;

R2 is 3-amino-5-(N-(2,2-diphenylethyl)amidocarbonyl)phenyl, B is isopropyl, A is a bond, Y0 is 4-amidinobenzyl, and R1 is methyl;

R2 is 3-amino-5-(N-(2-naphthylmethyl)amidocarbonyl)phenyl, B is isopropyl, A is a bond, Y0 is 4-amidinobenzyl, and R1 is methyl;

R2 is 3-amino-5-(N-(1,2,3,4-tetrahydronaphth-2-ylmethyl)amidocarbonyl)phenyl, B is isopropyl, A is a bond, Y0 is 4-amidinobenzyl, and R 1 is methyl;

R 2 is 3-aminophenyl, B is 2-propyl, A is a bond, Y0 is 4-amidιno-3-fluorobenzyl, and R1 is hydrido;

R2 is 3-carboxyphenyl, B is 2-propyl, A is a bond, Y0 is 4-amidinobenzyl, and R1 is hydrido;

R2 is 3-aminophenyl, B is 2-propyl, A is a bond, Y0 is 4-amidino-3-fluorobenzyl, and R1 is methyl;

R2 is 3,5-diaminophenyl, B is 2,2,2-trifluoroethyl, A is a bond, Y0 is 4-amidinobenzyl, and R1 is methyl;

R2 is 3,5-diaminophenyl, B is (S)-2-butyl, A is a bond, Y0 is 4-amidinobenzyl, and R1 is methyl;

R2 is 3,Sdiaminophenyl, B is isopropyl, A is a bond, Y0 is 4-amidinobenzyl, and R1 is methyl;

R2 is 3,5-diaminophenyl, B is isopropyl, A is a bond, Y0 is 4-amidino-2-fluorobenzylbenzyl, and R 1 is methyl;

R2 is 3,5-diaminophenyl, B is ethyl, A is a bond, Y0 is 4-amidinobenzyl, and R1 is methyl;

R2 is 3,5-diaminophenyl, B is ethyl, A is a bond, Y0 is 4-amidino-2-fluorobenzyl, and R1 is methyl;

R2 is 3-amino-Scarboxyphenyl, B is 2,2,2-trifluoroethyl, A is a bond, Y0 is

4-amidinobenzyl, and R1 is methyl;

R2 is 3-amino-5-carboxyphenyl, B is (S)-2-butyl, A is a bond, Y0 is 4-amidinobenzyl, and R 1 is methyl;

R2 is 3-amino-5-carboxyphenyl, B is isopropyl, A is a bond, Y0 is 4-amidino-2-fluorobenzylbenzyl, and R 1 is methyl;

R2 is 3-amino-5-carboxyphenyl, B is ethyl, A is a bond, Y0 is 4-amidinobenzyl, and R 1 is methyl;

R2 is 3-amino-5-carboxyphenyl, B is ethyl, A is a bond, Y0 is 4-amidino-2-fluorobenzyl, and R1 is methyl;

R2 is 3-amino-5-(N-benzylamidocarbonyl)phenyl, B is 2,2,2-trifluoroethyl,

A is a bond, Y0 is 4-amidinobenzyl, and R 1 is methyl;

R2 is 3-amino-5-(N-benzylamidocarbonyl)phenyl, B is (S)-2-butyl, A is a bond, Y0 is 4-amidinobenzyl, and R1 is methyl;

R2 is 3-amino-5-(N-benzylamidocarbonyl)phenyl, B is isopropyl, A is a bond, Y0 is 4-amidmo-2-fluorobenzylbenzyl, and R1 is methyl;

R2 is 3-amino-5-(N-benzylamidocarbonyl)phenyl, B is ethyl, A is a bond,

Y0 is 4-amidinobenzyl, and R1 is methyl;

R2 is 3-amino-5-(N-benzylamidocarbonyl)phenyl, B is ethyl, A is a bond,

Y0 is 4-amidino-2-fluorobenzyl, and R1 is methyl;

R 2 is 3,5-diaminophenyl, B is isopropyl, A is a bond, Y0 is 4-amidinobenzylbenzyl, and R1 is hydrido;

R 2 is 3-aminophenyl, B is cyclopropyl, A is a bond, Y0 is 4-amidinobenzyl, and R1 is methyl;

R2 is 3-aminophenyl, B is cyclobutyl, A is a bond, Y0 is 4-amidino-2-fluorobenzyl, and R1 is methyl;

R2 is 3-aminophenyl, B is cyclobutyl, A is a bond, Y0 is 4-amidinobenzyl, and R1 is methyl;

R2 is 3-aminophenyl, B is cyclopropyl, A is a bond, Y0 is 4-amidino-2-fluorobenzyl, and R1 is methyl;

R 2 is 3-aminophenyl, B is cyclobutyl, A is a bond, Y0 is 4-amιdinobenzyl, and R1 is hydrido;

R2 is 3-aminophenyl, B is cyclobutyl, A is a bond, Y0 is 4-amιdino-3-fluorobenzyl, and R1 is methyl;

R2 is 3-aminophenyl, B is cyclopentyl, A is a bond, Y0 is 4-amidinobenzyl, and R1 is methyl;

R2 is 5-amino-2-thienyl, B is cyclobutyl, A is a bond, Y0 is 4- amidinobenzyl, and R1 is methyl;

R2 is 3-aminophenyl, B is cyclopropyl, A is GH2Y 0 is 4-amidinobenzyl, and R1 is methyl;

R 2 is 3-aminophenyl, B is 2-(2R)-bicyclo[2.2.1]-heptyl, A is a bond, Y0 is

4-amidinobenzyl, and R1 is methyl;

R2 is 3-aminophenyl, B is cyclopentyl, A is a bond, Y0 is 4-amidino-2-fluorobenzyl, and R1 is methyl;

R2 is 3-aminophenyl, B is cyclohexyl, A is CH2CH2,Y0 is 4-amidinobenzyl, and R1 is hydrido;

R2 is 3-aminophenyl, B is oxalan-2-yl, A is CH2, Y0 is 4-amidinobenzyl, and R1 is methyl ;

R2 is 3-aminophenyl, B is 1-piperidinyl, A is CH2CH2, Y0 is 4-amidinobenzyl, and R1 is methyl;

R2 is 3-aminophenyl, B is 1-pyrrolidinyl, A is CH2CH2CH2, Y0 is 4-amidinobenzyl, and R1 is methyl;

R 2 is 3-amino-5-carbomethoxyphenyl, B is cyclobutyl, A is a bond, Y0

is 4-amidinobenzyl, and R1 is hydrido;

R 2 is 3-amino-5-carboxyphenyl, B is cyclobutyl, A is a bond, Y0 is 4-amidinobenzyl, and R1 is hydrido;

R 2 is 3,5-diaminophenyl, B is cyclobutyl, A is a bond, Y0 is 4-amidinobenzyl, and R is hydrido;

R2 is 2-amino-6-carboxy-4-pyridyl, B is cyclobutyl, A is a bond, Y0 is

4-amidinobenzyl, and R1 is hydrido;

R2 is 3-amino-5-carbomethoxyphenyl, B is cyclobutyl, A is a bond, Y0 is 4-amidinobenzyl, and R1 is methyl;

R2 is 3-amino-5-carboxyphenyl, B is cyclobutyl, A is a bond, Y0 is 4-amidinobenzyl, and R 1 is methyl;

R2 is 3,5-diaminophenyl, B is cyclopropyl, A is a bond, Y 0 is 4-amidinobenzyl, and R is methyl;

R2 is 3,Sdiaminophenyl, B is cyclobutyl, A is a bond, Y0 is 4-amidino-2-fluorobenzyl, and R1 is methyl;

R 2 is 3,5-diaminophenyl, B is cyclopropyl, A is a bond, Y0 is 4-amidino-2-fluorobenzyl, and R1 is methyl;

R2 is 3,5-diaminophenyl, B is cyclobutyl, A is a bond, Y0 is 4-amidinobenzyl, and R1 is hydrido;

R2 is 3,Sdιaminophenyl, B is cyclobutyl, A is a bond, Y0 is 4-amιdino-3-fluorobenzyl, and R1 is methyl;

R 2 is 3,5-diaminophenyl, B is cyclopentyl, A is a bond, Y0 is 4-amidinobenzyl, and R1 is methyl;

R 2 is 3-carboxy-5-aminophenyl, B is cyclopropyl, A is a bond, Y0 is 4-amidinobenzyl, and R1 is methyl;

R2 is 3-carboxy-5-aminophenyl, B is cyclobutyl, A is a bond, Y0 is 4-amidino-2-fluorobenzyl, and R1 is methyl;

R 2 is 3-carboxy-5-aminophenyl, B is cyclopropyl, A is a bond, Y0 is 4-amidino-2-fluorobenzyl, and R1 is methyl;

R2 is 3-carboxy-5-aminophenyl, B is cyclobutyl, A is a bond, Y0 is 4-amidinobenzyl, and R 1 is hydrido;

R2 is 3-carboxy-5-aminophenyl, B is cyclobutyl, A is a bond, Y0 is 4-amidino-3-fluorobenzyl, and R1 is methyl;

R2 is 3-carboxy-5-aminophenyl, B is cyclopentyl, A is a bond, Y0 is 4-amidinobenzyl, and R1 is methyl;

R2 is 3-amino-5-(N-benzylamidocarbonyl)phenyl, B is cyclopropyl, A is a bond, Y0 is 4-amidinobenzyl, and R1 is methyl;

R2 is 3-amino-5-(N-benzylamidocarbonyl)phenyl, B is cyclobutyl, A is a bond, Y0 is 4-amidino-2-fluorobenzyl, and R 1 is methyl;

R2 is 3-amino-5-(N-benzylamidocarbonyl)phenyl, B is cyclobutyl, A is a bond, Y0 is 4-amidinobenzyl, and R 1 is methyl;

R2 is 3-amino-5-(N-benzylamidocarbonyl)phenyl, B is cyclopropyl, A is a bond, Y0 is 4-amidino-2-fluorobenzyl, and R1 is methyl;

R2 is 3-amino-5-(N-benzylamidocarbonyl)phenyl, B is cyclobutyl, A is a bond, Y0 is 4-amidinobenzyl, and R1 is hydrido;

R2 is 3-amino-5-(N-benzylamidocarbonyl)phenyl, B is cyclobutyl, A is a bond, Y0 is 4-amidino-3-fluorobenzyl, and R1 is methyl;

R2 is 3-amino-5-(N-benzylamidocarbonyl)phenyl, B is cyclopentyl, A is a bond, Y0 is 4-amidinobenzyl, and R1 is methyl;

R2 is 3-amino-5-(N-(2-chlorobenzyl)amidosulfonyl)phenyl, B is cyclopropyl, A is a bond, Y0 is 4-amidinobenzyl, and R1 is methyl;

R2 is 3-amino-5-(N-(2-chlorobenzyl)amidosulfonyl)phenyl, B is cyclobutyl, A is a bond, Y0 is 4-amidino-2-fluorobenzyl, and R1 is methyl;

R2 is 3-amino-5-(N-(2-chlorobenzyl)amidosulfonyl)phenyl, B is cyclobutyl, A is a bond, Y0 is 4-amidinobenzyl, and R1 is methyl;

R2 is 3-amino-5-(N-(2-chlorobenzyl)amidosulfonyl)phenyl, B is cyclopropyl, A is a bond, Y0 is 4-amidino-2-fluorobenzyl, and R 1 is methyl;

R2 is 3-amino-5-(N-(2-chlorobenzyl)amidosulfonyl)phenyl, B is cyclobutyl, A is a bond, Y0 is 4-amidinobenzyl, and R1 is hydrido;

R2 is 3-amino-5-(N-(2-chlorobenzyl)amidosulfonyl)phenyl, B is cyclobutyl, A is a bond, Y0 is 4-amidino-3-fluorobenzyl, and R 1 is methyl;

R2 is 3-ammo-5-(N-(2-chlorobenzyl)amidosulfonyl)phenyl, B is cyclopentyl, A is a bond, Y0 is 4-amidinobenzyl, and R1 is methyl;

R2 is 3-amino-5-(N-(2-trifluoromethylbenzyl)amidocarbonyl)-phenyl, B is cyclopropyl, A is a bond, Y0 is 4-amidinobenzyl, and R1 is methyl;

R2 is 3-amino-5-(N-(2-trifluoromethylbenzyl)amidocarbonyl)-phenyl, B is cyclobutyl, A is a bond, Y0 is 4-amidino-2-fluorobenzyl, and R1 is methyl;

R2 is 3-amino-5-(N-(2-trifluoromethylbenzyl)amidocarbonyl)-phenyl, B is cyclobutyl, A is a bond, Y0 is 4-amidinobenzyl, and R1 is methyl;

R2 is 3-amino-5-(N-(2-trifluoromethylbenzyl)amidocarbonyl)-phenyl, B is cyclopropyl, A is a bond, Y0 is 4-amidino-2-fluorobenzyl, and R 1 is methyl;

R2 is 3-amino-5-(N-(2-trifluoromethylbenzyl)amidocarbonyl)-phenyl, B is cyclobutyl, A is a bond, Y0 is 4-amidinobenzyl, and R 1 is hydrido;

R2 is 3-amino-5-(N-(2-trifluoromethylbenzyl)amidocarbonyl)-phenyl, B is cyclobutyl, A is a bond, Y0 is 4-amidino-3-fluorobenzyl, and R1 is methyl; and

R2 is 3-amino-5-(N-(2-trifluoromethylbenzyl)amidocarbonyl)-phenyl, B is cyclopentyl, A is a bond, Y0 is 4-amidinobenzyl, and R1 is methyl.

Using the examples and methods described herein previously, the following additional examples having a guanidinoalkyl type Y AT group could be prepared of formula:


wherein B, A, R1 , R2 , X0, and YAT are selected to form the following compounds:

R2 is 3-aminophenyl, B is phenyl, A is CH2CH2,YAT is 5-guanidino-1-oxo-1-(2-thiazolyl)-2-pentyl, R1 is hydrido, and X0 is hydrido;

R2 is 3,5-diaminophenyl, B is phenyl, A is CH2CH2, YAT is 5-guanidino-1-oxo-1-(2-thiazolyl)-2-pentyl, R1 is hydrido, and X0 is hydrido;

R2 is 3-carboxy-5-aminophenyl, B is phenyl, A is CH2CH2,YAT is 5-guanidino-1-oxo-1-(2-thiazolyl)-2-pentyl, R 1 is hydrido, and X0 is hydrido;

R2 is 3-amino-5-(N-benzylamidocarbonyl)phenyl, B is phenyl, A is

CH2CH2, YAT is 5-guanidino-1-oxo-1-(2-thiazolyl)-2-ρentyl, R1 is hydrido, and

X0 is hydrido;

R2 is 3,5-diaminophenyl, B is isopropyl, A is single bond, YAT is 5-guanidino-1-oxo-1-(2-thiazolyl)-2-pentyl, R 1 is hydrido, and X0 is hydrido;

R2 is 3-carboxy-Saminophenyl, B is isopropyl, A is single bond, YAT is 5-guanidino-1-oxo-1-(2-thiazolyl)-2-pentyl, R 1 is hydrido, and X0 is hydrido;

R2 is 3-amino-5-(N-benzylamidocarbonyl)phenyl, B is isopropyl, A is single bond, YAT is 5-guanidino-1-oxo-1-(2-thiazolyl)-2-pentyl, R1 is hydrido, and X0 is hydrido;

R2 is 3,5-diaminophenyl, B is cyclobutyl, A is single bond, YAT is 5-guanidino-1-oxo-1-(2-thiazolyl)-2-pentyl, R1 is hydrido, and X° is hydrido;

R2 is 3-carboxy-5-aminophenyl, B is cyclobutyl, A is single bond, Y AT is 5-guanidino-1-oxo-1-(2-thiazolyl)-2-pentyl, R1 is hydrido, and X° is hydrido;

R2 is 3-amino-5-(N-benzylamidocarbonyl)phenyl, B is cyclobutyl, A is single bond, YAT is 5-guanidino- 1-oxo- l-(2-thiazolyl)-2-pentyl, R1 is hydrido, and X0 is hydrido;

R2 is 3-aminophenyl, B is phenyl, A is CH2CH2,YAT is 5- guanidino- 1-oxo-1-(2-thiazolyl)-2-pentyl, R1 is methyl, and X0 is hydrido;

R2 is 3,5-diaminophenyl, B is phenyl, A is CH2CH2,YAT is 5-guamdino-1-oxo- 1-(2-thiazolyl)-2-pentyl, R1 is methyl, and X° is hydrido;

R2 is 3-carboxy-5-aminophenyl, B is phenyl, A is CH2CH2, YAT is 5-guanidino-1-oxo-1-(2-thiazolyl)-2-pentyl, R1 is methyl, and X0 is hydrido;

R2 is 3-amino-5-(N-benzylamidocarbonyl)phenyl, B is phenyl, A is

CH2CH2, YAT is 5-guanidino-1-oxo-1-(2-thiazolyl)-2-pentyl, R1 is methyl, and X0 is hydrido;

R2 is 3,Sdiaminophenyl, B is isopropyl, A is single bond, YAT is 5-guanidino-1-oxo-1-(2-thiazolyl)-2-pentyl, R1 is methyl, and X0 is hydrido;

R2 is 3-carboxy-Saminophenyl, B is isopropyl, A is single bond, YAT is 5-guanidino-1-oxo-1-(2-thiazolyl)-2-pentyl, R1 is methyl, and X° is hydrido;

2

R2 is 3-amιno-5-(N-benzylamidocarbonyl)phenyl, B is isopropyl, A is single bond, YAT is 5-guanidino-1-oxo-1-(2-thiazolyl)-2-pentyl, R 1 is methyl, and

X0 is hydrido;

R2 is 3,5-dιaminophenyl, B is cyclobutyl, A is single bond, YAT is 5-guanidino-1-oxo-1-(2-thiazolyl)-2-ρentyl, R1 is methyl, and X0 is hydrido;

R2 is 3-carboxy-5-aminophenyl, B is cyclobutyl, A is single bond, YAT is 5-guanidino-1-oxo-1-(2-thiazolyl)-2-pentyl, R 1 is methyl, and X0 is hydrido; and R2 is 3-amino-5-(N-benzylamidocarbonyl)phenyl, B is cyclobutyl, A is single bond, YAT is Sguanidino-1-oxo-1-(2-thiazolyl)-2-pentyl, R1 is methyl, and

X0 is hydrido.

Formula (I) compounds of this invention possessing hydroxyl, thiol, and amine functional groups can be converted to a wide variety derivatives. 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. 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 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 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 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. Suitable procedures and methods for preparing these derivatives can be found in House's 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 sources or the references cited above, which are incorporated herein by reference.

Formula (I) compounds of this invention possessing hydroxyl, thiol, and amine functional groups can be alkylated to a wide variety derivatives. 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, 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 group present can be converted to the coπesponding 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 quaternary ammonium derivatives. Quaternary 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, two and one equivalents, respectively, of an acid scavenger are used concurrently. Tertiary amines can be prepared from the corresponding primary or secondary amine by reductive alkylation with aldehydes and ketones using reduction methods. Suitable procedures and methods for preparing these derivatives can be found in House's Modem Synthetic Reactions, W. A. Benjamin, Inc., Shriner, Fuson, and Curtin in The Systematic Identification of Organic Compounds, 5th Edition, John Wiley & Sons, and Fieser and Fieser in Reagents for Organic Synthesis, Volume 1, John Wiley & Sons. Perfluoroalkyl derivatives can be prepared as described by DesMarteau in J. Chem. Soc. Chem. Commun.2241 (1998). Reagents of a wide variety that can be used to derivatize hydroxyl, thiol, and amines of compounds of Formula (I) are available from commercial sources or the references cited above, which are incorporated herein by reference.

The biological activity of the compounds of Example 1 and Example 2 were evaluated using bioassay procedures below. The biological activity of the compounds of Schemes 1, 2, 3, and 4 could also be evaluated using the same bioassay procedures below.

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 inhibitor or buffer (5 mM CaCl2,50 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. Percent

inhibition of TF-VIIa activity is calculated from OD405nm value from the experimental and control sample.

Xa Assay

0.3 nM human factor Xa and 0.15 mM N-α-Benzyloxycarbonyl-D-arginyl- 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 the substrate is measured by monitoring the reaction at 405 nm for the release of p-nitroaniline. Percent inhibition of Xa activity is calculated from OD405nm value from the experimental and control sample.

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, 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 experimental and control sample.

Trypsin Assay

5 ug/ml trypsin, type IX from porcine pancreas and 0.375 mM N-α-Benzoyl-L-arginine-p-nitroanilide (L-BAPNA) 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 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 01 11014

measured by monitoring the reaction at 405 nm for the release of p-nitroaniline. Percent inhibition of trypsin activity is calculated from OD405nm 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 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 S-2238 were purchased from Chromogenix, Sweden.

Table 1. Inhibitory Activity of 4-Pyridones toward TF-VIIA, Thrombin II,

Factor Xa, and Trypsin II.