AU2001249870A1 - Polycyclic aryl and heteroaryl substituted 4-pyrones useful for selective inhibition of the coagulation cascade - Google Patents

Polycyclic aryl and heteroaryl substituted 4-pyrones useful for selective inhibition of the coagulation cascade

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Publication number
AU2001249870A1
AU2001249870A1 AU2001249870A AU4987001A AU2001249870A1 AU 2001249870 A1 AU2001249870 A1 AU 2001249870A1 AU 2001249870 A AU2001249870 A AU 2001249870A AU 4987001 A AU4987001 A AU 4987001A AU 2001249870 A1 AU2001249870 A1 AU 2001249870A1
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group
carbon
amino
hydrido
hydroxy
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AU2001249870A
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Kevin J. Koeller
Chun C. Ma
William L Neumann
Hayat K. Rahman
Michael S. South
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Pharmacia LLC
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Pharmacia LLC
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/34—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D309/36—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms
    • C07D309/38—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms one oxygen atom in position 2 or 4, e.g. pyrones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/34—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D309/36—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms
    • C07D309/40—Oxygen atoms attached in positions 3 and 4, e.g. maltol

Abstract

The invention relates to polycyclic aryl and heteroaryl substituted 4-pyrone compounds useful as inhibitors of serine proteases of the coagulation cascade and compounds, compositions and methods for anticoagulant therapy for the treatment and prevention of a variety of thrombotic conditions including coronary artery and cerebrovascular diseases.

Description

Polycyclic Aryl and Heteroaryl Substituted 4-Pyrones 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-pyrone 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, atrial fibrillation, thrombotic stroke, embolic stroke, deep vein thrombosis, disseminated intravascular coagulation, ocular build up of fibrin, and reocclusion or restenosis of recanalized vessels.
There have been several reports of non-peptidic and peptidic 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-trifluoromethyl 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-trifluorornethyl 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 etal. 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 contrast to the disclosures that some 2-pyridone derivatives may function as thrombin inhibitors, 4-pyrone 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:
, Formula (I). 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 objects and advantages of the present invention will become apparent from the following description of the invention.
DESCRIPTION OF THE INVENTION
The present invention relates to a class of compounds comprising Polycyclic Aryl and Heteroaryl Substituted 4-pyrones, 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):
1 2 1 2 1 wherein D , D , J , J and K are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more
1 2 1 1 than one can be a covalent bond, no more than one of D , D , J , J and K 1 2 1 1 1 2 can be O, no more than one of D , D , J , J and K can be S, one of D , D ,
1 X2 1 1 2 1 1
J , J and K must be a covalent bond when two of D , D , J , J and K are
1 2 1 2 1
O and S, and no more than four of D , D , J , J and K can be N with the
32 33 34 35 36 proviso that R , R , R , R , and R are each independently selected to maintain the tetravalent nature of carbon, bivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen;
^32 „33 34 35 , 36 . , , , , ^b R , R , R , R , and R can independently be Q ;
„9 „10 1 1 12 13 π16 17 18 19 32 33 34 35 Δ R , R , R , R , R , R , R , R , R , R , R , R , R , 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, 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 ; τ,32 Λ „33 33 Λ 34 34 , 35 , 35 , 6
R and R , R and R , R and R , and R and R 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
32 33 33 34 34 35 35 consisting of spacer pairs R and R , R and R , R and R , and R
36 and R can be used at the same time; π9 10 10 11 11 - 12 12 13
R and R , R and R , R and R , andR and R 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
9 10 10 11 11 12 12 consisting of spacer pairs R and R , R and R , R and R , andR
13 and R can be used at the same time; B can be formula (VI):
3 4 3 4 wherein D , D , J , and J are independently selected from the group consisting of
3 4 3 4
C, N, O, and S, no more than one of D , D , J , and J can be O, no more than one
3 4 3 4 1 2 1 2 of D , D , J , and J can be S, and no more than three of D , D , J , and J can
32 33 34 35 be N with the proviso that R , R , R , and R are each independently selected to maintain the tetravalent nature of carbon, bivalent 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- CIO 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
RJQ, a ring carbon or nitrogen atom adjacent to the R| position and two atoms
from the point of attachment may be substituted with R^, a ring carbon or nitrogen atom three atoms from the point of attachment and adjacent to the RJQ
position may be substituted with Rj j, a ring carbon or nitrogen atom three
atoms from the point of attachment and adjacent to the R^2 position may be
substituted with R33, and a ring carbon or nitrogen atom four atoms from the
point of attachment and adjacent to the Rj j and R33 positions may be
substituted with R34;
7 A is selected from the group consisting of single covalent bond, (W )rr-
15 15 7
(CH(R ))pa and (CH(R )) a-(W )rr wherein rr is an integer selected from
7 0 through 1, pa is an integer selected from 0 through 6, and W is selected
7 from the group consisting of O, S, C(O), C(S), C(O)S, C(S)O, C(O)N(R ),
C(S)N(R7), (R7)NC(O), (R?)NC(S), S(O), S(O)2, S(O)2N(R7),
(R7)NS(O)2, Se(O), Se(O)2, Se(O)2N(R?), (R?)NSe(O)2, P(O)(R8),
N(R7)P(O)(R8), P(O)(R8)N(R7), C(NR?)N(R7), (R7)NC(NR?), and N(R?).
7 8
R and R are independently selected from the group consisting of hydrido, hydroxy, alkyl, alkenyl, aryl, aralkyl, aryloxy, alkoxy, alkenyloxy, alkylthio, alkylamino, arylthio, arylamino, acyl, aroyl, heteroaroyl, aralkoxyalkyl, heteroaralkoxyalkyl, , aryloxyalkyl, alkoxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, aralkoxyalkyl, heteroaralkoxyalkyl, alkylsulfmylalkyl, alkylsulfonylalkyl, heteroaryl, heteroaryloxy, heteroarylamino, heteroaralkyl, heteroaralkyloxy, heteroaralkylamino, and heteroaryloxyalkyl; n14 n15 37 38 39 n 0 41 J n42 . J J R , R , R , R , R ,R , R and R 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, aryloxyalkyl, aralkoxyalkylalkoxy, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkoxythioalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxy, haloalkoxy alkyl, haloalkenyloxyalkyl, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxyalkyl, satorated heterocyclyl, partially saturated heterocyclyl, heteroaryl, heteroarylalkyl, heteroarylthioalkyl, heteroaralkylthioalkyl, monocarboalkoxyalkyl, dicarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl, carboalkoxycyanoalkyl, alkylsulfinyl, alkylsulfonyl, haloalkylsulfinyl, haloalkylsulfonyl, arylsulfmyl, arylsulfinylalkyl, arylsulfonyl, arylsulfonylalkyl, aralkylsulfinyl, aralkylsulfonyl, cycloalkylsulfmyl, cycloalkylsulfonyl, cycloalkylsulfinylalkyl, cycloalkylsufonylalkyl, heteroarylsulfonylalkyl, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylsulfinylalkyl, aralkylsulfinylalkyl, aralkylsulfonylalkyl, carboxy, carboxyalkyl, carboalkoxy, carboxamide, carboxamidoalkyl, carboaralkoxy, trialkylsilyl, dialkoxyphosphono, diaralkoxyphosphono, dialkoxyphosphonoalkyl, and diaralkoxyphosphonoalkyl ;
14 14
R and R , 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;
14 15
R and R , 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;
15 15 R and R , 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;
5 Ψ is selected from the group consisting of NR , O, C(O), C(S), S,
5 8 39 40
S(O), S(O)2, ON(R ), P(O)(R ), and CR R ;
5 R is selected from the group consisting of hydrido, alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxy, alkoxy, alkenyloxy, alkylthio, arylthio, aralkoxyalkyl, heteroaralkoxyalkyl, aryloxyalkyl, alkoxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, aralkoxyalkyl, heteroaralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxy alkyl, haloalkenyloxyalkyl, halocycloalkoxyalkyl, halocycloalkenyloxyalkyl, heteroaryl, heteroaiylalkyl, monocarboalkoxyalkyl, monocarboalkoxy, dicarboalkoxy alkyl, monocarboxamido, monocyanoalkyl, dicyanoalkyl, carboalkoxycyanoalkyl, acyl, aroyl, heteroaroyl, heteroaryloxyalkyl, and dialkoxyphosphonoalkyl;
39 40
R and R , when bonded to the same carbon, can be taken together to
form a group selected from a group consisting of oxo, thiono, R -N, alkylene, haloalkylene, and a linear moiety spacer having from 2 through 7 contiguous atoms to form a ring selected from the group consisting of a cycloalkyl ring having from 3 through 8 contiguous members, a cycloalkenyl ring having from 3 through 8 contiguous members, and a heterocyclyl ring having from 3 through 8 contiguous members;
X and R are independently selected from the group consisting of Z -
Q, hydrido, alkyl, alkenyl, and halo;
0 X and R 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; o 5 X and R 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; o 39
X and R 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; o 40
X and R 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;
X can be independently selected to form a linear moiety having from 2
39 through 5 contiguous atoms linked to the points of bonding of both R and
40 R 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 R and
4a 4b 9 14 ? 15 R , R and R , R and R , and R and R can be used at the same time;
R can be independently selected to form a linear moiety having from 2
4a through 5 contiguous atoms linked to the points of bonding of both R and
4b R to form a heterocyclyl ring having from 5 through 8 contiguous members;
Z is selected from the group consisting of covalent single bond,
41 42 41 (CR R )q wherein q is an integer selected from 1 through 6, (CH(R ))g- o 42
W -(CH(R ))„ 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), 41 41 41 41 41
(R )NC(S),OC(O)N(R ),(R )NC(O)O, SC(S)N(R ),(R )NC(S)S,
41 41 41 41
SC(O)N(R ),(R )NC(O)S,OC(S)N(R ),(R )NC(S)O,
42 41 41 42 42 41
N(R )C(O)N(R ),(R )NC(O)N(R ),N(R )C(S)N(R ),
41 42 41 41
(R )NC(S)N(R ), S(O), S(O)2, S(O)2N(R ),N(R )S(O)2, Se, Se(O),
41 41 8 7 8 Se(O)2,Se(O)2N(R ),N(R )Se(O)2, P(O)(R ), N(R )P(O)(R ),
8 7 41 41 28 29 41 2
P(O)(R )N(R ), N(R ), ON(R ), and SiR R , and (CH(R ))e-W -
42 (CH(R ))j1 wherein e and h are integers independently selected from 0
2 41 42 through 2 and W^ is selected from the group consisting of CR =CR ,
41 42 CR R =C; vinylidene), and ethynylidene (C≡C; 1,2-ethynyl), with the
41 42 proviso that R andR are selected from other than halo and cyano when directly bonded to N and Z is directly bonded to the pyrone ring; Q is formula (II):
1 2 1 2 1 wherein D ,D ,J ,J andK are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more
1 2 1 2 1 than one can be a covalent bond, no more than one of D , D , J , J and K
1 2 1 X2 1 1 2 can be O, no more than one of D , D ,J , J andK can be S, one of D ,D ,
1 1 1 2 1 2 1
J , J andK must be a covalent bond when two of D ,D ,J ,J andK are
1 2 1 2 1
O and S, and no more than four of D , D , J , J and K can be N, with the 9 10 11 12 13 proviso that R , R , R , R , and R are each independentiy 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):
3 4 3 4 wherein D , D , J , and J are independently selected from the group
3 4 3 4 consisting of C, N, O, and S, no more than one of D , D , J , and j can be O,
3 4 4 1 no more than one of D , D , j , and J can be S, and no more than three of D ,
2 1 2 9 10 11 12
D , J , and J can be N with the proviso that R , R , R , and R are each independently selected to maintain the tetravalent nature of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen;
Q 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;
4a 4b K is (CR R )n wherein n is an integer selected from 1 through 4;
4a 4b R and R are independently selected from the group consisting of halo, hydrido, hydroxy, cyano, hydroxyalkyl, alkyl, alkenyl, aryl, aralkyl, 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;
4a 4b
R and R , 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; o 1 4a 4b 1
E is E , when K is (CR R )n, wherein E is selected from the group consisting of a covalent single bond, O, S, C(O), C(S), C(O)O, C(S)O, C(O)S,
C(S)S, C(O)N(R7), (R7)NC(O), C(S)N(R7), (R?)NC(S), OC(O)N(R7),
(R7)NC(O)O, SC(S)N(R7), (R?)NC(S)S, SC(O)N(R?), (R?)NC(O)S,
OC(S)N(R7), (R?)NC(S)O, N(R8)C(O)N(R7), (R?)NC(O)N(R8),
N(R8)C(S)N(R?), (R?)NC(S)N(R8), S(O), S(O)2, S(O)2N(R7), N(R?)S(O)2,
S(O)2N(R?)C(O), C(O)N(R7)S(O)2, Se, Se(O), Se(O)2, Se(O)2N(R?),
N(R?)Se(O)2, P(O)(R8), N(R?)P(O)(R8), P(O)(R8)N(R7), N(R?), ON(R?),
28 29 4a 4b 4a 4b
SiR R , CR =CR , ethynylidene (C≡C; l,2-ethynyl), and C=CR R ;
28 29
R and R are independently selected from the group consisting of hydrido, hydroxyalkyl, alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, acyl, aroyl, aralkanoyl, heteroaroyl, aralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkylthioalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, 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, dicarboalkoxy cycloalkyl, formylalkyl, acylalkyl, arylsulfinylalkyl, arylsulfonylalkyl, aralkylsulfinyl, cycloalkylsulfinylalkyl, cycloalkylsufonylalkyl, heteroarylsulfonylalkyl, heteroarylsulfinylalkyl, aralkylsulfinylalkyl, aralkylsulfonylalkyl, carboxy, dialkoxyphosphono, diaralkoxyphosphono, dialkoxyphosphonoalkyl and diaralkoxyphosphonoalkyl;
28 29
R and R 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;
14 K can be (CH(R ))|-T wherein j is selected from a integer from 0 through 3 and T is selected from the group consisting of single covalent bond,
7 14
O, S, and N(R ) with the proviso that (CH(R )) is bonded to the pyrone ring; o 2 14 2
E is E , when K is (CH(R ));-T, wherein E 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(R?), (R7)NC(O), C(S)N(R?), (R?)NC(S), (R?)NC(O)O,
(R7)NC(S)S, (R?)NC(O)S, (R7)NC(S)O, N(R8)C(O)N(R?),
(R7)NC(O)N(R8), N(R8)C(S)N(R?), (R7)NC(S)N(R8), S(O), S(O)2,
S(O)2N(R?), N(R?)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(R?)Se(O)2, P(O)(R8), N(R7)P(O)(R8),
P(O)(R8)N(R?), and N(R?);
15 K can be G-(CH(R ) wherein k is selected from an integer from 1
7 through 3 and G is selected from the group consisting of O, S, and N(R ) with
the proviso that R is other than hydroxy, cyano, halo, amino, alkylamino, dialkylamino, and sulfhydryl when k is 1 ;
E is E when K is G-(CH(R ))^ wherein E is selected from the group consisting of a covalent single bond, O, S, C(O), C(S), C(O)O, C(S)O, C(O)S, C(S)S, C(O)N(R?), (R?)NC(O), C(S)N(R?), (R?)NC(S),
OC(O)N(R?), (R7)NC(O)O, SC(S)N(R?), (R?)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, 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(R?), N(R?), ON(R?), SiR28R29,
4a 4b 4a 4b
CR =CR , ethynylidene (C≡C; l,2-ethynyl), and C=CR R ;
Y° is formula (IV):
wherein D , D , J , and J are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more
2 than one can be a covalent bond, K is independently selected from the group
+ 5 6 5 6 consisting of C, and N , no more than one of D , D , J , and J can be O, no
5 6 5 6 _ _ 5 6 5 6 more than one of D , D , J , and J can be S, one of D , D , J , and J must
be a covalent bond when two of D , D , J , and J are O and S, no more than
5 6 5 6 2 + three of D , D , J , and J can be N when K is N , and no more than four of
5 6 5 6 2 16
D , D , J , and J can be N when K is carbon with the provisos that R ,
17 18 19 '
R , R , and R are each independently selected to maintain the tetravalent natore of carbon, trivalent natore of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen;
Λ fi 17
R and R 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;
18 19
R and R 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; b 20 21 + 20 21 22 Q is selected from the group consisting of NR R , NR R R , oxy, alkyl, alkylaminoalkyl, aminoalkyl, dialkylsulfoniumalkyl, and acylamino
20 21 22 wherein R , R , and R are independently selected from the group consisting of hydrido, alkyl, hydroxy, alkoxy, alkylamino, dialkylamino,
20 aminoalkyl, and hydroxyalkyl with the provisos that no more than one of R ,
21 22 R , and R can be hydroxy, alkoxy, alkylamino, ammo, and dialkylamino
20 21 22 and that R , R , and R must be other than be hydroxy, alkoxy,
2 + alkylamino, ammo, and dialkylamino when K is N ;
20 21 20 22 21 22
R and R , R and R , and R and R 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
20 21 20 22 21 22 group consisting of spacer pairs R and R , R and R , and R and R 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, 6 6 5
N(R )C(S)OR and N(R )C(S)SR with the proviso that no more than one
23 24 26 of R , R , andR can be hydroxy, alkoxy, alkylamino, amino, or
dialkylamino when two of the group consisting of R , R , and R are bonded to the same atom;
Q can be selected from the group consisting of dialkylsulfonium,
25 93 24 26 95 23 94 trialkylphosphonium, C(NR )NR R , N(R )C(NR )N(R )(R ),
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),
25 5 23 24 23 24
C(NR )SR , C(O)NR R , and C(O)NR R with the provisos that no
23 24 26 more than one of R , R , and R can be hydroxy, alkoxy, alkylamino,
23 24 26 amino, or dialkylamino when two of the group consisting of R , R , and R b are bonded to the same atom and that said Q group is bonded directly to a carbon atom;
23 _24 _.25 τ,26 . R , R , R , and R are independently selected from the group consisting of hydrido, alkyl, hydroxy, alkoxy, alkylamino, dialkylamino, aminoalkyl, and hydroxyalkyl;
23 24 R and R 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;
23 25 24 25 25 26 24 26 23 26
R and R , R and R , R and R , R and R , and R and R 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)R3°,
P(S)R3°, C(R30)R31, C=C(R3°)R31, (O)2POP(O)2, R3°(O)POP(O)R3°,
Si(R29)R28, Si(R29)R28Si(R2V28, Si(R29)R28OSi(R29)R28, (R28)R29COC(R28)R29, (R28)R29CSC(R28)R29, C(O)C(R30)=C(R31),
30 30 31 30 30 31 30 30 31
PR C(R )=C(R ), P(O)R C(R )=C(R ), P(S)R C(R )=C(R ),
DC(R3°)(R31)D, OP(OR31)R3°, 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;
27 27 JH is independently selected from the group consisting of OR , SR and N(R2°)R21;
27 R is selected from the group consisting of hydrido, alkyl, alkenyl, 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, heteroarylsulfmylalkyl, aralkylsulfinylalkyl and aralkylsulf onylalkyl ;
30 31
R and R 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; R and R 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;
23 25 24 25 25 26 24 26 23 26 R and R , R and R , R and R , R and R , and R and R 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
30 31 groups selected from R and R , an aryl radical, an heteroaryl radical, a saturated heterocyclic radical and a partially saturated heterocyclic radical wherein said 1,2-
28 32 substitutents are independently selected from C=O, C=S, C(R )R , S(O),
S(O)2, OP(OR31)R3°, P(O)R3°, P(S)R30 and Si(R28)R29;
23 25 24 25 25 26 24 26 23 26 R and R , R and R , R and R , R and R , and R and R 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-disubsti toted 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
28 29 Si(R )R and said alkylene and alkenylene radical are substituted with one or more R or R substituents; g
Q is selected from the group consisting of a single covalent bond,
(CR R )D-(W ^wherein az is an integer selected from 0 through 1, b is an o 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), (R14)NC(S), OC(O)N(RM), SC(S)N(R14),
SC(O)N(R14), OC(S)N(R14), N(R15)C(O)N(R14), (R14)NC(O)N(R15),
15 14 14 15 14
N(R )C(S)N(R ), (R )NC(S)N(R ), S(O), S(O)2, S(O)2N(R ),
N(R14)S(O)2, Se, Se(O), Se(O)2, Se(O)2N(R1?), N(R14)Se(O)2, P(O)(R8),
7 8 8 7 14 14 28 29
N(R )P(O)(R ), P(O)(R )N(R ), N(R ), ON(R ), and SiR R ,
14 1 15 (CH(R ))C-W -(CH(R ))j wherein c and d are integers independently
selected from 1 through 4, and W is selected from the group consisting of O,
S, C(O), C(S), C(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),
14 14 14 14 14
(R )NC(S)S, SC(O)N(R ),(R )NC(O)S, OC(S)N(R ),(R )NC(S)O,
15 14 14 15 15 14 N(R )C(O)N(R ),(R )NC(O)N(R ),N(R )C(S)N(R ),
14 15 14 14
(R )NC(S)N(R ), S(O), S(O)2, S(O)2N(R ),N(R )S(O)2, Se, Se(O),
Se(O)2, Se(O)2N(R14), N(R14)Se(O)2, P(O)(R8),N(R?)P(O)(R8),
8 7 14 14 2829 14 2 P(O)(R )N(R ), N(R ), ON(R ), SiR R , and (CH(R ))e-W - (CH(R ))^ wherein e and h are integers independentiy selected from 0
2 4a 4b through 2 and W^ is selected from the group consisting of CR =CR ,
4a 4b 14 ethynylidene (C≡C; 1,2-ethynyl), and C=CR K with the provisos that R
and R are selected from other than halo and cyano when directly bonded to
N and that (CR R )b, (CH(R ))c, (CH(R ))e and are bonded to E°;
37 37
R and R , 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;
37 38
R and R , 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;
38 38
R and R , 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;
37 38
R and R , 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; π b ss ss
Y can be Q -Q wherein Q is selected from the group consisting of
37 38 14
(CR R )f wherein f is an integer selected from 1 through 6, (CH(R ))c-
W -(CH(R ))jj wherein c and d are integers independently selected from 1
1 1 through 4, 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)O, C(O)S, C(S)S,
14 14 14 14 14
C(O)N(R ), (R )NC(O), C(S)N(R ), (R )NC(S), OC(O)N(R ),
14 14 14 14 14
(R )NC(O)O, SC(S)N(R ), (R )NC(S)S, SC(O)N(R ), (R )NC(O)S,
14 14 15 14 14 15
OC(S)N(R ), (R )NC(S)O, N(R )C(O)N(R ), (R )NC(O)N(R ),
15 14 14 15 14
N(R )C(S)N(R ), (R )NC(S)N(R ), S(O), S(O)2, S(O)2N(R ),
N(R14)S(O)2, Se, Se(O), Se(O)2, Se(O)2N(R14), N(RM)Se(O)2, P(O)(R8),
N(R7)P(O)(R8), P(O)(R8)N(R?), N(R14), ON(R14), SiR28R29, and
14 2 15
(CH(R ))e-W -(CH(R ) wherein e and h are integers independently
selected from 0 through 2 and W^ is selected from the group consisting of
4a 4b 4a 4b
CR =CR , ethynylidene (C≡C; 1,2-ethynyl), and C=CR R with the
14 15 provisos that R and R are selected from other than halo and cyano when
directly bonded to N and that (CR3? R38)f, (CH(R15))C, and (CH(R15))e are bonded to E ;
,b Λsss . . ^sss . ,~rΥ/r,38. i can be Q -Q wherein Q is (CH(R ))r-W , r is an integer
selected from 1 through 3, and W 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-piperazinyI, 2,5-piperazinyl, 2,6-piperazinyI, 1,2-piperidinyl, 1,3-piperidinyl, 1 ,4-piperidinyl, 23-piperidinyl, 2,4-piperidinyl, 2,5-piperidinyl, 2,6-piperidinyl, 3,4-piperidinyl, 3,6-piperidinyl, 1,2-pyrrolidinyl, 1,3- pyrrolidinyl, 2,3-pyrrolidinyl, 2,4-pyrrolidinyl, 2,5-pyrrolidinyl, 3,4-pyrrolidinyl, 2H-2,3-pyranyl, 2H-2,4-ρyranyl, 2H-2,5-pyranyl, 4H-23-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- -one-23-yl, 2,3-tetrahydrofuranyl, 2, tetrahydrofuranyl, 2,5- tetrahydrofuranyl, 3,4-tetrahydrofuranyl, 2,3-tetrahydropyranyl, 2,4- tetrahydropyranyl, 2,5-tetrahydropyranyl, 2,6-tetrahydropyranyl, 3,4-
38 tetrahydropyranyl, and 3,5-tetrahydropyranyl with the proviso that (CH(R ))r
is bonded to E and Q is bonded to lowest numbered substituent position of
each W ;
Y can be Q -Q wherein Q is (CH(R ))r-W , r is an integer
4 selected from 1 through 3, and W is selected from the group consisting of 1 ,2- cyclobutyl, 1,2-cyclohexyl, 1,3-cyclohexyl, 1,4-cyclohexyl, 1,2-cyclopentyl, 1,3- cyclopentyl, 2,3-moφholinyl, 2,4-morpholinyl, 2,5-moφholinyl, 2,6- moφholinyl, 3,4-moφholinyl, 3,5-moφholinyl, 1,2-piperazinyl, 1,3-piperazinyl, 1,4-piperazinyl, 2,3-piperazinyl, 2,5-piperazinyl, 2,6-piperazinyl, 1,2-piperidinyl, 1,3-piperidinyl, 1 ,4-piperidinyl, 2,3-piperidinyl, 2,4-piperidinyl, 2,5-piperidinyl, 2,6-piperidinyl, 3,4-piperidinyl, 3,5-piperidinyl, 3,6-piperidinyl, 1,2-pyrrolidinyl, 13-pyrrolidinyl, 2,3-pyrrolidinyl, 2,4-pyrrolidinyl, 2,5-pyrrolidinyl, 3,4- pyrrolidinyl, 2H-2,3-pyranyl, 2H-2,4-pyranyl, 2H-2,5-pyranyl, 4H-2,3-pyranyl, 4H-2,4-pyranyl, 4H-2,5-pyranyl, 2H-pyran-2-one-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-
38 tetrahydropyranyl, and 3,5-tetrahydropyranyl with the provisos that (CH(R ))r
is bonded to E and Q is bonded to highest number substituent position of
4 each W ;
ϊ can be Q -Q wherein Q is (CH(R ))r-W , 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-indoIyl, 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- quinohnyl, 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-cinnoIinyl, 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°;
3 . „ .6
Y can be Q -Q wherein Q is (CH(R ))r-W , 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^- 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-naρhthyl, 2,6-naphthyl, 2,7-naphthyl, 2,8-naρhthyl, 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-quinoUnyl, 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 E°.
In an embodiment of compounds of Formula I or a pharmaceutically acceptable salt thereof, B is formula (V):
1 2 1 2 1 wherein D ■ ,, DD ,, JJ ,, r J , and ' " K are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more
1 2 1 2 1 than one can be a covalent bond, no more than one of D , D , J , J and K
1 2 1 2 1 1 2 can be O, no more than one of D , D , J , J and K can be S, one of D , D ,
1 M2 1 1 2 1 2 1 J , J and K must be a covalent bond when two of D , D , J , J and K are 1 2 1 2 1
O and S, and no more than four of D , D , J , J and K can be N with the
. , ^32 33 34 35 , ^36 , . Λ , , , proviso that R , R , R , R , and R are each independently selected to maintain the tetravalent nature of carbon, trivalent natore of nitrogen, the divalent nature of sulfur, and the divalent natore of oxygen;
32 33 34 35 , 36 . J , , ^b R , R , R , R , and R can independently be Q ; 9 10 11 12 13 16 17 „18 „19 π32 33 34 35 , R , R , R , R , R , R , R , R , R , R , R , R , R , 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, alkoxy amino, thio, nitro, lower alkylamino, alkylthio, alkylthioalkyl, aryla ino, 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, 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; π32 Δ 33 33 , 34 34 Λ 35 Λ 35 Δ 36
R and R , R and R , R and R , and R and R 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
32 33 33 34 34 35 35 consisting of spacer pairs R and R , R and R , R and R , and R
and R can be used at the same time; τ,9 ^10 ^10 J ¥,ll „ll J T,12 J T,12 J T,13
R and R , R and R , R and R , andR and R 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
9 10 10 11 11 12 12 consisting of spacer pairs R and R , R and R , R and R , and R
13 and R 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 R 2, 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 substitoted 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 R ^3, a ring carbon or nitrogen atom adjacent to the R9 position and two atoms from the point of attachment may be substitoted with
RJQ, a ring carbon or nitrogen atom adjacent to the Rj^ position and two atoms
from the point of attachment may be substituted with R j2, a ring carbon or
nitrogen atom three atoms from the point of attachment and adjacent to the RJ
position may be substitoted with Rj j , a ring carbon or nitrogen atom three
atoms from the point of attachment and adjacent to the Rj 2 position may be
substitoted with R33, and a ring carbon or nitrogen atom four atoms from the
point of attachment and adjacent to the Rj j and R33 positions may be
substitoted with R34; A is selected from the group consisting of single covalent bond,
(W7)rr-(CH(R15))pa and (CH(R15))pa-(W?)rr wherein rr is an integer
7 selected from 0 through 1, pa is an integer selected from 0 through 6, and W is selected from the group consisting of O, S, C(O), C(S), C(O)S, C(S)O,
C(O)N(R7), C(S)N(R7), (R?)NC(O), (R?)NC(S), S(O), S(O)2, S(O)2N(R?), (R7)NS(O)2, P(O)(R8), N(R7)P(O)(R8), P(O)(R8)N(R7), C(NR7)N(R?),
(R7)NC(NR7), and N(R?);
7 8
R and R are independently selected from the group consisting of hydrido, hydroxy, alkyl, acyl, aroyl, heteroaroyl, and alkoxyalkyl;
„ 14 15 37 1 T 38 . , , , , R , R , R , and R are independently selected from the group consisting of hydrido, hydroxy, halo, cyano, hydroxyalkyl, alkoxy, alkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxyalkyl, carboxy, carboxyalkyl, carboalkoxy, carboxamide, and carboxamidoalkyl;
Ψ is selected from the group consisting of NR , O, C(O), C(S), S,
5 8 39 40
S(O), S(O)2, ON(R ), P(O)(R ), and CR R ;
5 R is selected from the group consisting of hydrido, alkyl, alkoxy, alkoxyalkyl, haloalkyl, acyl, aroyl, and heteroaroyl;
39 40 R and R are. independently selected from the group consisting of hydrido, hydroxy, halo, cyano, hydroxyalkyl, acyl, aroyl, heteroaroyl, acylamido, alkoxy, alkyl, alkoxyalkyl, haloalkyl, haloalkoxy, haloalkoxyalkyl, alkylsulfonyl, haloalkylsulfonyl, carboxy, carboxyalkyl, carboalkoxy, carboxamide, and carboxamidoalkyl ; X and R are independently selected from the group consisting of Z -
Q, hydrido, alkyl, alkenyl, and halo;
0 2
X and R 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;
Z is selected from the group consisting of covalent single bond,
41 42 41
(CR R )q wherein q is an integer selected from 1 through 6, (CH(R ))g- o 42
W -(CH(R ))p wherein g and p are integers independently selected from 0 through 3 and W is selected from the group consisting of O, S, C(0), 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),
41 41 41 41 41
(R )NC(S), OC(O)N(R ), (R )NC(O)O, SC(S)N(R ), (R )NC(S)S,
SC(O)N(R41), (R41)NC(O)S, OC(S)N(R41), (R41)NC(S)O,
42 41 41 42 42 41
N(R )C(O)N(R ), (R )NC(O)N(R ), N(R )C(S)N(R ),
41 42 41 41 8
(R )NC(S)N(R ), S(O), S(O)2, S(O)2N(R ), N(R )S(O)2, P(O)(R ),
7 8 R 7 41 41 41 2
N(R )P(O)(R ), P(O)(R )N(R ), N(R ), ON(R ), and (CH(R ))e-W -
42 (CH(R ))^ wherein e and h are integers independently selected from 0
2 41 42 through 2 and W is selected from the group consisting of CR =CR ,
41 42 CR R =C; vinylidene), and ethynylidene (C≡C; 1,2-ethynyl), with the
41 42 proviso that R and R are selected from other than halo and cyano when directly bonded to N and Z is directly bonded to the pyrone ring;
41 42
R and R 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):
1 1 2 wherein D~ ,,D2 D- ,,JJ' ,,r J~ and K are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more
1 2 1 2 1 than one can be a covalent bond, no more than one of D , D , J , J and K
1 2 1 2 1 1 2 can be O, no more than one of D , D , J , J and K can be S, one of D , D ,
1 2 1 1 2 1 2 1
J , J and K must be a covalent bond when two of D , D , J , JT and K are
1 2 1 2 1
O and S, and no more than four of D , D , J , J and K can be N, with the
9 10 11 12 13 proviso that R ,R ,R ,R ,andR are each independently selected to maintain the tetravalent nature of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent natore of oxygen; Q can be formula (III):
wherein DD~ , D ', JT , and - J ' are independently selected from the group
3 4 3 4 consistingof C,N,O, andS, no more than one of D ,D ,J ,andJ can be O,
3 4 3 4 1 no more than one of D , D , J , and J can be S, and no more than three of D , 2 1 2 9 10 11 12
D , J , and J can be N with the proviso that R , R , R , and R are each independently selected to maintain the tetravalent nature of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen; Q 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;
4a 4b K is (CR R )n wherein n is an integer selected from 1 through 2;
4a 4b
R and R are independently selected from the group consisting of halo, hydrido, hydroxy, cyano, hydroxyalkyl, alkyl, alkenyl, alkoxyalkyl, haloalkyl, haloalkenyl, and cyanoalkyl;
4a 4b , R and R , 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; o 1 4a 4b 1
E is E , when K is (CR R )n, wherein E is selected from the group consisting of a covalent single bond, O, S, C(O), C(S), C(O)O, C(S)O, C(O)S,
C(S)S, C(O)N(R7), (R7)NC(O), C(S)N(R7), (R?)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(R?), (R?)NC(S)O, N(R8)C(O)N(R?), (R7)NC(O)N(R8),
N(R8)C(S)N(R?), (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) 1,2-
ethynyl), and C=CR HR ;
14 K can be (CH(R ))j-T wherein j is selected from a integer from 0 through 2 and T is selected from the group consisting of single covalent bond,
7 14
O, S, and N(R ) with the proviso that (CH(R ) M): is bonded to the pyrone ring; o 2 14 2
E is E , when K is (CH(R )) -T, wherein E 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), (R?)NC(S), (R7)NC(O)O,
(R7)NC(S)S, (R7)NC(O)S, (R?)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(R?), N(R7)S(O)2, S(O)2N(H)C(O), C(O)N(H)S(O)2, P(O)(R8),
N(R?)P(O)(R8), P(O)(R8)N(R?), and N(R7);
15 K can be G-(CH(R ) wherein k is selected from an integer from 1
7 through 2 and G is selected from the group consisting of O, S, and N(R ) with
15 the proviso that R is other than hydroxy, cyano, halo, ammo, alkylamino, dialkylamino, and sulfhydryl when k is 1; 1 <C "2
E is E when K is G-(CH(R ) wherein E is selected from the group consisting of a covalent single bond, O, S, C(O), C(S), C(O)O, C(S)O, C(O)S, C(S)S, C(O)N(R7), (R?)NC(O), C(S)N(R?), (R?)NC(S),
OC(O)N(R7), (R7)NC(O)O, SC(S)N(R?), (R7)NC(S)S , SC(O)N(R?),
(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), (R?)NC(S)N(R8), S(O), S(O)2,
S(O)2N(R7), N(R?)S(O)2, P(O)(R8), N(R?)P(O)(R8), P(O)(R8)N(R?), 7 7 4a 4b
N(R ), ON(R ), CR =CR , ethynylidene (OC; 1,2-ethynyl), and
„ 4a 4b
C=CR R ;
Y° is formula (IV):
5 6 5 6 wherein D , D , J , and J are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more
2 than one can be a covalent bond, K is independently selected from the group
consisting of C, and N , no more than one of D , D , J , and J can be O, no
5 6 5 6 5 6 5 6 more than one of D , D , J , and J can be S, one of D , D , J , and J must
be a covalent bond when two of D , D , J , and J are O and S, no more than
5 6 5 6 2 + three of D , D , J , and J can be N when K is N , and no more than four of
5 6 5 6 2 16
D , D , J , and J can be N when K is carbon with the provisos that R ,
17 18 19
R , R , and R are each independently selected to maintain the tetravalent natore of carbon, trivalent nature of nitrogen, the divalent natore of sulfur, and the divalent nature of oxygen;
1 17
R and R 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; b 20 21 + 20 21 22
Q is selected from the group consisting of NR R , NR R R , oxy, alkyl, alkylaminoalkyl, aminoalkyl, dialkylsulfoniumalkyl, and acylamino
20 21 22 wherein R , R , and R are independently selected from the group consisting of hydrido, alkyl, hydroxy, alkoxy, alkylamino, dialkylamino,
20 aminoalkyl, and hydroxyalkyl with the provisos that no more than one of R ,
21 22
R , and R can be hydroxy, alkoxy, alkylamino, ammo, and dialkylamino
20 21 22 and that R , R , and R must be other than be hydroxy, alkoxy,
2 + alkylamino, ammo, and dialkylamino when K is N ;
20 21 20 22 21 22
R and R , R and R , and R and R 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
20 21 20 22 21 22 group consisting of spacer pairs R and R , R and R , and R and R 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(R )C(S)OR and N(R )C(S)SR with the proviso that no more than one
23 24 26 of R , R , and R can be hydroxy, alkoxy, alkylamino, amino, or
23 24 26 dialkylamino when two of the group consisting of R , R , and R are bonded to the same atom;
Q can be selected from the group consisting of dialkylsulfonium,
trialkylphosphonium, 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(NR25)OR5,
C(O)N(R26)C(NR25)N(R23)(R24), C(S)N(R26)C(NR25)N(R23)(R24), 26 26 25 23 24 26 26 23 24
N(R )N(R )C(NR )N(R )(R ), N(R )N(R )SO2N(R )(R ),
25 5 23 24 23 24
C(NR )SR , C(O)NR R , and C(O)NR R with the provisos that no
more than one of R , R , and R can be hydroxy, alkoxy, alkylamino,
23 24 26 amino, or dialkylamino when two of the group consisting of R , R , and R
are bonded to the same atom and that said Q group is bonded directly to a carbon atom;
23 24 25 26
R , R , R , and R are independently selected from the group consisting of hydrido, alkyl, hydroxy, alkoxy, alkylamino, dialkylamino, aminoalkyl, and hydroxyalkyl;
23 24 R and R 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;
S
Q is selected from the group consisting of a single covalent bond, (CR R )0-(W )az wherein az is an integer selected from 0 through 1 , b is an integer selected from 1 through 4, and W is selected from the group consisting of O, S, C(O), C(S), C(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(RM), SC(S)N(R14),
14 14 15 14 14 15 SC(O)N(R ),OC(S)N(R ),N(R )C(O)N(R ),(R )NC(O)N(R ),
15 14 14 15 14
N(R )C(S)N(R ),(R )NC(S)N(R ), S(O), S(O)2, S(O)2N(R ),
N(R14)S(O)2, P(O)(R8), N(R?)P(O)(R8), P(O)(R8)N(R?), N(R14),
14 14 1 15
ON(R ), (CH(R ))C-W -(CH(R ))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),
14 14 14 14 14
(R )NC(O), C(S)N(R ), (R )NC(S), OC(O)N(R ), (R* )NC(O)O, 14 14 14 14 14
SC(S)N(R ),(R )NC(S)S, SC(O)N(R ),(R )NC(O)S, OC(S)N(R ),
14 15 14 14 15
(R )NC(S)O,N(R )C(O)N(R ),(R )NC(O)N(R ),
15 14 14 15 14
N(R )C(S)N(R ),(R )NC(S)N(R ), S(O), S(O)2, S(O)2N(R ),
14 8 7 8 8 7 14 N(R )S(O)2,P(O)(R),N(R)P(O)(R ),P(O)(R)N(R),N(R ),
14 14 2 15 ON(R ), and (CH(R ))e-W -(CH(R ))h wherein e and h are integers
independently selected from 0 through 2 and W^ is selected from the group
4a 4b 4a 4b consisting of CR =CR , ethynylidene (C≡C; 1,2-ethynyl), and C=CR R
14 15 with the provisos that R and R are selected from other than halo and cyano
37 38 14 14 when directly bonded to N and that (CR R )b, (CH(R ))C, (CH(R ))e and are bonded to E ;
Ύ can be Q -Q wherein Q is selected from the group consisting of
37 38 14
(CR R )f wherein f is an integer selected from 1 through 6, (CH(R ))c-
W -(CH(R ))^ wherein c and d are integers independently selected from 1
through 4, and W is selected from the group consisting of W is selected from the group consisting of O, S, C(O), C(S), C(O)O, C(S)O, C(O)S, C(S)S,
14 14 14 14 14
C(O)N(R ),(R )NC(O), C(S)N(R ), (R )NC(S), OC(O)N(R ),
14 14 14 14 14
(R )NC(O)O, SC(S)N(R ),(R )NC(S)S, SC(O)N(R ),(R )NC(O)S,
14 14 15 14 14 15
OC(S)N(R ),(R )NC(S)O,N(R )C(O)N(R ),(R )NC(O)N(R ),
15 14 14 15 14 N(R )C(S)N(R ),(R )NC(S)N(R ), S(O), S(O)2, S(O)2N(R ),
14 8 7 8 8 7 14 N(R )S(O)2,P(O)(R),N(R)P(O)(R ),P(O)(R)N(R),N(R ),
14 14 2 15
ON(R ), and (CH(R ))e-W ~(CH(R ))h wherein e and h are integers
independently selected from 0 through 2 and W"^ is selected from the group 4a 4b 4a 4b consisting of CR =CR , ethynylidene (CsC; 1,2-ethynyl), and C=CR R
14 15 with the provisos that R and R are selected from other than halo and cyano
37 ^8 1 when directly bonded to N and that (CR R )f , (CH(R ))c, and
(CH(R ))e are bonded to E°;
Y° can be an integer
selected from 1 through 3, and W^ 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- moφholinyl, 2,4-moφholinyl, 2,5-moφholinyl, 2,6-moφholinyl, 3,4- moφholinyl, 3,5-moφholinyl, 1,2-piperazinyl, 1,3-piperazinyl, 1,4-piperazinyl, 23-piperazinyl, 2,5-piperazinyl, 2,6-piperazinyl, 1,2-piperidinyl, 1 -piperidinyl, 1,4-piperidinyl, 23-piperidinyl, 2,4-piperidinyl, 2,5-piperidinyl, 2,6-piperidinyl, 3 ,4-piperidinyl, 3, 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-pyranyl, 2H-2,5-pyranyl, 4H-2,3-pyranyl, 4H-2,4- pyranyl, 4H-2,5-pyranyl, 2H-pyran-2-one-3,4-yl, 2H-pyran-2-one-4,5-yl, 4H- pyran-4-one-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-
38 tetrahydropyranyl, and 3,5-tetrahydropyranyl with the proviso that (CH(R ))r
is bonded to E and Q is bonded to lowest numbered substituent position of
each W ;
Y can be Q -Q wherein Q is (CH(R ))r-W , r is an integer
4 selected from 1 through 3, and W is selected from the group consisting of 1,2- cyclobutyl, 1,2-cyclohexyl, 1,3-cyclohexyl, 1,4-cyclohexyl, 1,2-cyclopentyl, 1,3- cyclopentyl, 2,3-moφholinyl, 2,4-moφholinyl, 2,5-moφholinyl, 2,6- moφholinyl, 3,4-moφholinyl, 3, moφholinyl, 1,2-piperazinyl, 13-piperazinyl, 1,4-piperazinyl, 2,3-piperazinyl, 2,5-piperazinyl, 2,6-piperazinyl, 1,2-piperidinyl, 1,3-piperidinyl, 1,4-piperidinyl, 2,3-piperidinyl, 2,4-piperidinyl, 2,5-piperidinyl, 2,6-piperidinyl, 3,4-piperidinyl, 3,5-piperidinyl, 3,6-piperidinyl, 1,2-pyrrolidinyl, 1,3-pyrrolidinyl, 2,3-pyrrolidinyl, 2,4-pyrrolidinyl, 2,5-pyrrolidinyl, 3,4- pyrrolidinyl, 2H-2,3-pyranyl, 2H-2,4-pyranyl, 2H-2,5-pyranyl, 4H-2,3-pyranyl, 4H-2,4-pyranyl, 4H-2,5-pyranyl, 2H-pyran-2-one-3,4-yl, 2H-pyran-2-one-4,5- yl, 4H-pyran-4-one-2,3-yl, 2,3-tetrahydrofuranyl, 2,4-tetrahydrofuranyl, 2,5- tetrahydrofuranyl, 3,4-tetrahydrofuranyl, 2,3-tetrahydropyranyl, 2,4- tetrahydropyranyl, 2,5-tetrahydropyranyl, 2,6-tetrahydropyranyl, 3,4-
38 tetrahydropyranyl, and 3,5-tetrahydropyranyl with the provisos that (CH(R ))r
is bonded to E and Q is bonded to highest number substituent position of
4 each W ;
Y can be Q -Q wherein Q is (CH(R ))r-W , 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 -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-naρhthyl, 2,6-naphthyl, 2,7-naphthyl, 2,8-naρhthyl, 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, 4,5- 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
W and that (CH(R ))r is bonded to E°;
3& „6 ϊ can be Q -Q wherein Q is (CH(R ))r-W , 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-indoIyl, 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, quinolinyl, 3,6-quinolinyl, 3,7-quinolinyl, 3,8-quinolinyl, 4,5- quinolinyl, 4,6-quinolinyl, 4,7-quinolinyl, 4,8-quinoUnyl, 1,4-isoquinolinyl, 1,5- isoquinolinyl, 1,6-isoquinolinyl, 1,7-isoquinolinyl, l,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-cinnohnyl, 3,5-cimιolinyl, 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
W and that (CH(R ))r is bonded to E°. In another embodiment of compounds of Formula I or a pharmaceutically acceptable salt thereof, B is formula (V):
1 2 1 2 1 wherein D , D , J , j and K are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more
1 2 1 2 1 than one can be a covalent bond, no more than one of D , D , J , J and K
1 2 1 2 1 1 2 can be O, no more than one of D , D , J , J and K can be S, one of D , D ,
1 2 1 1 2 1 2 1
J , J and K must be a covalent bond when two of D , D , J , JT and K are
O a„d S. a„ no more t an four ofD1, D2 J1, J 2 and 1 canbe N;
32 33 34 35 36 b
R ,R ,R ,R , andR canmdependenuy be Q ;
9 10 11 12 13 16 17 18 19 32 33 34 35 R ,R ,R ,R ,R ,R ,R ,R ,R ,R ,R ,R ,R ,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, aralkylsulfmyl, 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, alkylsulfmyl, 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, 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 R3^;
B can be selected from the group consisting of C3-C10 cycloalkyl, C5- CIO cycloalkenyl, C4-C9 satorated heterocyclyl, and C4-C9 partially satorated 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 R or RJJ, a ring carbon or nitrogen atom adjacent to the R9 position and two atoms from the point of attachment may be substituted with RjO' a ring carbon or nitrogen atom adjacent to the Rj3 position and two atoms
from the point of attachment may be substituted with R 2, a ring carbon or
nitrogen atom three atoms from the point of attachment and adjacent to the RJQ
position may be substituted with R^ j , a ring carbon or nitrogen atom three
atoms from the point of attachment and adjacent to the Rj2 position may be
substituted with R33, and a ring carbon or nitrogen atom four atoms from the
point of attachment and adjacent to the Rj j and R33 positions may be
substitoted 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
7 selected from 0 through 1, pa is an integer selected from 0 through 6, and W is selected from the group consisting of O, S, C(O), C(S), C(O)S, C(S)O, C(O)N(R?), C(S)N(R7), (R?)NC(O), (R?)NC(S), S(O), S(O)2, S(O)2N(R7),
(R7)NS(O)2, C(NR7)N(R7), (R7)NC(NR7), and N(R?);
7 8
R and R are independently selected from the group consisting of hydrido, hydroxy, alkyl, and alkoxyalkyl;
14 15 37 38
R , R , R , and R are independently selected from the group consisting of hydrido, hydroxy, halo, alkyl, alkoxyalkyl, haloalkyl, haloalkoxy, and haloalkoxyalkyl;
Ψ is selected from the group consisting of NR , O, C(O), C(S), S,
39 40 S(O), S(O)2, and CR R ;
5 R is selected from the group consisting of hydrido, alkyl, and alkoxy; 39 40
R and R are independently selected from the group consisting of hydrido, hydroxy, halo, hydroxyalkyl, alkyl, alkoxyalkyl, haloalkyl, haloalkoxy, and haloalkoxyalkyl;
Λ and R are independently selected from the group consisting of Z - Q, hydrido, alkyl, alkenyl, and halo;
X 0 and R 2 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;
Z is selected from the group consisting of covalent single bond,
41 42 41 (CR R )q wherein q is an integer selected from 1 through 2, (CH(R ))„- o 42
W -(CH(R ))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),
41 41 41 41 41
(R )NC(S), OC(O)N(R ), (R )NC(O)O, SC(S)N(R ), (R )NC(S)S,
41 41 41 41
SC(O)N(R ), (R )NC(O)S, OC(S)N(R ), (R )NC(S)O,
42 41 41 42 42 41 N(R )C(O)N(R ), (R )NC(O)N(R ), N(R )C(S)N(R ),
41 42 41 41 41
(R )NC(S)N(R ), S(O), S(O)2, S(O)2N(R ), N(R )S(O)2, N(R ),
41 41 2 42 ON(R ), and (CH(R ))e-W -(CH(R ))h wherein e and h are integers
independently selected from 0 through 2 and W"^ is selected from the group
41 42 41 42 consisting of CR =CR , CR R =C; vinylidene), and ethynylidene (G≡C;
41 42
1 ,2-ethynyl), with the proviso that R and R are selected from other than halo and cyano when directly bonded to N and Z is directly bonded to the pyrone ring; 41 42
R and R 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, satorated heterocyclyl, partially saturated heterocyclyl, heteroaryl, and heteroaralkyl; Q is formula (II):
1 2 1 2 1 wherein D , D , J , J and K are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more
1 2 1 2 1 than one can be a covalent bond, no more than one of D , D , J , J and K
1 2 1 2 1 1 2 can be O, no more than one of D , D , J , J and K can be S, one of D , D ,
1 X2 1 1 2 1 2 1
J , J and K must be a covalent bond when two of D , D , J , J and K are
O and S, and no more than four of D1, B*. J2 and K1 can be N, with the
9 10 11 12 13 proviso that R , R , R , R , and R are each independently selected to maintain the tetravalent nature of carbon, trivalent natore 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, satorated heterocyclyl, alkyl, partially saturated heterocyclyl, acyl, aroyl, heteroaroyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkylalkenyl, haloalkyl, haloalkoxy, haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxyalkyl, and halocycloalkenyloxyalkyl;
4a 4b K is (CR R )n wherein n is the integer 1;
4a 4b
R and R are independently selected from the group consisting of halo, hydrido, hydroxy, hydroxyalkyl, alkyl, alkoxyalkyl, and haloalkyl; o 1 4a 4b 1
E is E , when K is (CR R )n, wherein E is selected from the group consisting of a covalent single bond, O, S, C(O), C(S), C(O)O, C(S)O, C(O)S,
C(S)S, C(O)N(R?), (R?)NC(O), C(S)N(R?), (R7)NC(S), OC(O)N(R?),
(R7)NC(O)O, SC(S)N(R?), (R7)NC(S)S, SC(O)N(R?), (R?)NC(O)S,
OC(S)N(R?), (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(R?), N(R?)S(O)2,
S(O)2N(R?)C(O), C(O)N(R?)S(O)2, N(R?), ON(R?), CR^CR41",
4a 4b ethynylidene (C≡C; 1,2-ethynyl), and C=CR R ;
14 K can be (CH(R ));-T wherein j is selected from a integer from 0 through 1 and T is selected from the group consisting of single covalent bond,
7 14
O, S, and N(R ) with the proviso that (CH(R )): is bonded to the pyrone πng; o 2 14 2
E is E , when K is (CH(R ));-T, wherein E 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(R?), (R?)NC(S), (R7)NC(O)O,
(R7)NC(S)S, (R?)NC(O)S, (R?)NC(S)O, N(R8)C(O)N(R?),
(R7)NC(O)N(R8), N(R8)C(S)N(R7), (R?)NC(S)N(R8), S(O), S(O)2,
S(O)2N(R?), N(R?)S(O)2, S(O)2N(H)C(O), C(O)N(H)S(O)2, and N(R?);
K can be G-(CH(R ) wherein k is the integer 1 and G is selected
7 from the group consisting of O, S, and N(R ); E is E when K is G-(CH(R ) wherein E is selected from the group consisting of a covalent single bond, O, S, C(O), C(S), C(O)O, C(S)O, C(O)S, C(S)S, C(O)N(R7), (R7)NC(O), C(S)N(R?), (R?)NC(S),
OC(O)N(R?), (R7)NC(O)O, SC(S)N(R?), (R?)NC(S)S, SC(O)N(R?),
(R7)NC(O)S, OC(S)N(R?), (R?)NC(S)O, N(R8)C(O)N(R?),
(R7)NC(O)N(R8), N(R8)C(S)N(R?), (R?)NC(S)N(R8), S(O), S(O)2,
S(O)2N(R ), N(R )S(O)2, N(R ), ON(R ), CR a=CR , ethynylidene (C≡ ,
Aa 4b 1,2-ethynyl), and C=CR R ;
Y° is formula (IV):
5 6 5 6 . wherein D , D , J , and J are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more
2 than one can be a covalent bond, K is independently selected from the group
consisting of C, and N , no more than one of , and can be O, no
5 6 5 6 5 6 5 6 more than one of D , D , J , and J can be S, one of D , D , J , and J must
5 f 5 6 be a covalent bond when two of D , D , J , and J are O and S, no more than
5 6 5 6 2 + three of D , D , J , and J can be N when K is N , and no more than four of
5 6 5 6 2 16
D , D , J , and J can be N when K is carbon with the provisos that R ,
17 18 19
R , R , and R are each independently selected to maintain the tetravalent nature of carbon, trivalent nature of nitrogen, the divalent natore of sulfur, and the divalent nature of oxygen; b 20 21 + 20 21 22
Q is selected irom the group consisting of NR R , NR R R , oxy, alkyl, alkylaminoalkyl, aminoalkyl, dialkylsulfoniumalkyl, and acylamino
20 21 22 wherein R , R , and R are independently selected from the group consisting of hydrido, alkyl, hydroxy, alkoxy, alkylamino, dialkylamino,
20 aminoalkyl, and hydroxyalkyl with the provisos that no more than one of R ,
21 22
R , and R can be hydroxy, alkoxy, alkylamino, amino, and dialkylamino
20 21 22 and that R , R , and R must be other than be hydroxy, alkoxy,
2 + alkylamino, am o, and dialkylamino when K is N ;
Q can be selected from the group consisting of
N(R26)SO2N(R23)(R24), N(R26)C(O)OR5, N(R26)C(O)SR5,
Nd αSJOR5 and N(R26)C(S)SR5 with the pπwiso that no more than one
23 24 26 of R , R , and R can be hydroxy, alkoxy, alkylamino, ammo, or
23 24 26 dialkylamino when two of the group consisting of R , R , and R are bonded to the same atom; ι_
Q can be selected from the group consisting of dialkylsulfonium,
trialkylphosphonium, C(NR )NR R , N(R )C(NR )N(R )(R ),
N(R26)C(O)N(R23)(R24), N(R26)C(S)N(R23)(R24), C(NR25)OR5, f)£i f) C ^) OΛ r) Z. ^. ^ OΛ C(O)N(R )C(NR )N(R )(R ), C(S)N(R )C(NR )N(R )(R ),
26 26 25 23 24 26 26 23 24
N(R )N(R )C(NR )N(R )(R ), N(R )N(R )SO2N(R )(R ),
25 5 23 24 23 24
C(NR )SR , C(O)NR R , and C(O)NR R with the provisos that no
23 24 26 more than one of R , R , and R can be hydroxy, alkoxy, alkylamino,
23 24 26 ammo, or dialkylamino when two of the group consisting of R , R , and R are bonded to the same atom and that said Q group is bonded directly to a carbon atom;
23 24 25 26
R , R , R , and R are independently selected from the group consisting of hydrido, alkyl, hydroxy, alkoxy, alkylamino, dialkylamino, aminoalkyl, and hydroxyalkyl; g
Q is selected from the group consisting of a single covalent bond, (CR R )b-(W )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),
14 14 14 14 14 (R )NC(O), C(S)N(R ), (R )NC(S), OC(O)N(R ), SC(S)N(R ),
14 14 15 14 14 15
SC(O)N(R ), OC(S)N(R ), N(R )C(O)N(R ), (R )NC(O)N(R ),
N(R15)C(S)N(R14), (R14)NC(S)N(R15), S(O), S(O)2, S(O)2N(R14),
14 14 14 14 1 15
N(R )S(O)2, N(R ), ON(R ), and (CH(R ))C-W -(CH(R ))d wherein
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(O)O, C(S)O, C(O)S,
14 14 14 14 14
C(S)S, C(O)N(R ), (R )NC(O), C(S)N(R ), (R )NC(S), OC(O)N(R ),
(R14)NC(O)O, SC(S)N(R14), (R14)NC(S)S, SC(O)N(R14), (R14)NC(O)S,
14 14 15 14 14 15
OC(S)N(R ), (R )NC(S)O, N(R )C(O)N(R ), (R )NC(O)N(R ),
15 14 14 15 14 N(R )C(S)N(R ), (R )NC(S)N(R ), S(O), S(O)2, S(O)2N(R ),
14 14 14 14 2 15 N(R )S(O)2, N(R ), ON(R ), and (CH(R ))e-W -(CH(R ))h wherein
e and h are integers independently selected from 0 through 2 and W^ is
4a 4b selected from the group consisting of CR =CR , ethynylidene (C≡C; 1,2-
4a 4b 14 15 ethynyl), and C=CR R with the provisos that R and R are selected from other than halo and cyano when directly bonded to N and that (CR3?R38)b, (CH(R14))C, (CH(R14))e and are bonded to E°; π b ss ss i can be Q -Q wherein Q is selected from the group consisting of
37 38 14
(CR R )f wherein f is an integer selected from 1 through 4, (CH(R ))c-
1 15 W -(CH(R ))(j wherein c and d are integers independently selected from 1
through 2, and W is selected from the group consisting of 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),
14 14 14 14 14
(R )NC(O)O, SC(S)N(R ), (R )NC(S)S, SC(O)N(R ), (R )NC(O)S,
14 14 15 14 14 15 OC(S)N(R ), (R )NC(S)O, N(R )C(O)N(R ), (R )NC(O)N(R ),
15 14 14 15 14
N(R )C(S)N(R ), (R )NC(S)N(R ), S(O), S(O)2, S(O)2N(R ),
14 14 14 14 2 15
N(R )S(O)2, N(R ), ON(R ), and (CH(R ))e-W -(CH(R ))h wherein
e and h are integers independentiy selected from 0 through 2 and W^ is
4a 4b selected from the group consisting of CR =CR , ethynylidene (C≡C; 1,2-
4a 4b 14 15 ethynyl), and C=CR with the provisos that R and R are selected
37 38 from other than halo when directly bonded to N and that (CR R )f ,
(CH(R ))c, and (CH(R ))e are bonded to E°; o y sss sss o 3 i can be Q -Q wherein Q is (CH(R ))r-W , r is an integer
selected from 1 through 2, and W 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, 23- moφholinyl, 2,4-moφholinyl, 2,5-moφholinyl, 2,6-moφholinyl, 3,4- moφholinyl, 3, moφholinyl, 1,2-piperazinyl, 1,3-piperazinyl, 1,4-piperazinyl, 23-piperazinyl, 2,5-piperazinyl, 2,6-piperazinyl, 1,2-piperidinyl, 13-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-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-ρyranyl, 4H-2,4- pyranyl, 4H-2,5-ρyranyl, 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-
38 tetrahydropyranyl, and 3,5-tetrahydropyranyl with the proviso that (CH(R ))r
is bonded to E and Q is bonded to lowest numbered substituent position of
each ;
Y can be Q -Q wherein Q is (CH(R ))r-W , r is an integer
4 selected from 1 through 2, and W is selected from the group consisting of 1,2- cyclobutyl, 1,2-cyclohexyl, 1,3-cyclohexyl, 1,4-cyclohexyl, 1,2-cyclopentyl, 1,3- cyclopentyl, 23-moφholinyl, 2,4-moφholinyl, 2,5-moφholinyl, 2,6- moφholinyl, 3,4-moφholinyl, 3,5-moφholinyl, 1,2-piperazinyl, 13-piperazinyl, 1,4-piperazinyl, 23-piperazinyl, 2,5-piperazinyl, 2,6-piperazinyl, 1,2-piperidinyl, 13-piperidinyl, 1,4-piperidinyl, 2,3-piperidinyl, 2,4-piperidinyl, 2,5-piperidinyl, 2,6-piperidinyl, 3,4-piperidinyl, 3,5-piperidinyl, 3,6-piperidinyl, 1,2-pyrrolidinyl, 1 -pyrrolidinyl, 23-pyrrolidinyl, 2,4-pyrrolidinyl, 2, pyrrolidinyl, 3,4- pyrrolidinyl, 2H-23-pyranyl, 2H-2,4-pyranyl, 2H-2,5-pyranyl, 4H-2,3-pyranyl, 4H-2,4-pyranyl, 4H-2,5-pyranyl, 2H-pyran-2-one-3,4-yl, 2H-pyran-2-one-4,5- yl, 4H-ρyran-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-
38 tetrahydropyranyl, and 3,5-tetrahydropyranyl with the provisos that (CH(R ))r
is bonded to E and Q is bonded to highest number substituent position of
4 each W ;
Ϊ can be Q -Q wherein Q is (CH(R ))r-W , 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-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, 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 W and that (CH(R ))r is bonded to E ;
can be Q -Q wherein Q is (CH(R ))r-W , 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, 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-benzisoxazolyI, 3,7- benzisoxazolyl, 1,4-naphthyl, 1,5-naphthyl, 1,6-naphthyl, 1,7-naphthyl, 1,8- naphthyl, 2,4-naphthyl, 2,5-naphthyl, 2,6-naphthyl, 2,7-naphthyl, 2,8-naphthyl, 2,4-quinolinyl, 2,5-quinolinyl, 2,6-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- 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
W and that (CH(R ))r is bonded to E°.
In a preferred embodiment of compounds of Formula I or a pharmaceutically acceptable salt thereof, B is formula (V):
wheKin D1, D2 J1. ? and K are independent eiected fern Ute group consisting of C, N, O, S and a covalent bond with the provisos that no more
1 2 1 2 1 than one can be a covalent bond, no more than one of D , D , J , J and K
1 2 1 2 1 1 2 can be O, no more than one of D , D , J , J and K can be S, one of D , D , 1 X2 1 1 2 1 2 1
J , J and K must be a covalent bond when two of D , D , J , J and K are
1 2 1 2 1
O and S, and no more than four of D , D , J , J and K can be N; τ. 2 33 π34 35 , 36 . J J , t h R , R , R , R , and R can independently be Q ;
9 10 11 12 13 32 33 34 35 36
R , R , R , R , R , R , R , R , R , and R are independently selected from the group consisting of hydrido, 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 substitoted 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 R^;
B can be selected from the group consisting of C3-C10 cycloalkyl, C5- C10 cycloalkenyl, C4-C9 satorated heterocyclyl, and C4-C9 partially satorated heterocyclyl, wherein each ring carbon may be optionally substitoted with R33, a ring carbon other than the ring carbon at the point of attachment of B to A may be optionally substitoted with oxo provided that no more than one ring carbon is substitoted 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 Rχ , a ring carbon or nitrogen atom adjacent to the R9 position and two atoms from the point of attachment may be substituted with RJQ, a ring carbon or nitrogen atom adjacent to the R ^3 position and two atoms from the point of attachment may be substituted with Rj2, a ring carbon or
nitrogen atom three atoms from the point of attachment and adjacent to the R ø
position may be substituted with R-Q, a ring carbon or nitrogen atom three
atoms from the point of attachment and adjacent to the R 2 position may be
substituted with R33 , and a ring carbon or nitrogen atom four atoms from the
point of attachment and adjacent to the Rj j and R33 positions may be
substituted with R34;
A is selected from the group consisting of single covalent bond, (W )π.-(CH(R ))pa and (CH(R ))pa-(W )„. wherein rr is an integer
7 selected from 0 through 1, pa is an integer selected from 0 through 6, and W is selected from the group consisting of O, S, C(O), C(S), C(O)S, C(S)O,
C(O)N(R?), C(S)N(R7), (R7)NC(O), (R?)NC(S), S(O), S(O)2, S(O)2N(R7),
(R7)NS(O)2, C(NR7)N(R?), (R?)NC(NR7), and N(R?);
7 8
R and R are independently selected from the group consisting of hydrido, hydroxy, alkyl, and alkoxyalkyl;
R is selected from the group consisting of hydrido, hydroxy, halo, alkyl, and haloalkyl; Ψ is NH;
X is hydrido; R is selected from the group consisting of Z -Q, hydrido, alkyl, alkenyl, and halo;
Z is a covalent single bond; Q is formula (II):
.1 J2 .1 2 , „1 wherein D", D~, J" ,, J J~ ; and K~ are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more
1 2 1 2 1 than one can be a covalent bond, no more than one of D , D , J , J and K
1 2 1 2 1 1 2 can be O, no more than one of D , D , J , I and K can be S, one of D , D ,
1 2 1 1 2 1 2 1
J , J and K must be a covalent bond when two of D , D , J , J and K are
1 2 1 2 1
O and S, and no more than four of D , D , J , J and K can be N, with the
9 10 11 12 13 proviso that R , R , R , R , and R are each independently selected to maintain the tetravalent nature of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent natore of oxygen; r. • ^4a 4b K is CR R ;
4a 4b
R and R are independently selected from the group consisting of halo, hydrido, hydroxy, alkyl, and haloalkyl;
0 1 4a 4b 1 E is E , when K is CR K. , 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;
14 K can be (CH(R )):-T wherein j is selected from an integer from 0 through 1 and T is selected from the group consisting of single covalent bond
7 14 and N(R ) with the proviso that (CH(R )); is bonded to the pyrone ring; 0 2 14 2
E is E , when K is (CH(R )) -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;
14 R is selected from the group consisting of hydrido, halo, alkyl, and haloalkyl;
Y° is formula (IV):
wherein D , D , J , and J are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more
2 than one can be a covalent bond, K is independently selected from the group
C (1 f consisting of C, and N , no more than one of D , D , J , and J can be O, no
5 6 5 6 ,-τ^5 6 τ5 6 more than one of D , D , J , and J can be S, one of D , D , J , and J must
be a covalent bond when two of D , are O and S, no more than
three of is N , and no more than four of
17 18 19
R , R , and R are each independently selected to maintain the tetravalent natore of carbon, trivalent natore of nitrogen, the divalent natore of sulfur, and the divalent natore of oxygen;
16 17 18 19
R , R , R , and R are independently selected from the group consisting of hydrido, amidino, guanidino, dialkylsulfonium, carboxy, haloalkylthio, alkoxy, hydroxy, amino, thio, nitro, lower alkylamino, alkylthio, alkylsulfmyl, alkylsulfonyl, alkanoyl, alkenoyl, haloalkanoyl, alkyl, alkenyl, halo, haloalkyl, haloalkenyl, haloalkoxy, hydroxyalkyl, aminoalkyl, haloalkoxyalkyl, carboalkoxy, carboalkoxyalkyl, and cyano; b 20 21 + 20 21 22 Q is selected from the group consisting of NR R , NR R R , oxy, alkyl, alkylaminoalkyl, aminoalkyl, dialkylsulfoniumalkyl, and acylamino
20 21 22 wherein R , R , and R are independently selected from the group consisting of hydrido, alkyl, hydroxy, alkoxy, alkylamino, dialkylamino,
20 aminoalkyl, and hydroxyalkyl with the provisos that no more than one of R ,
21 22 R , and R can be hydroxy, alkoxy, alkylamino, ammo, and dialkylamino
20 21 22 and that R , R , and R must be other than be hydroxy, alkoxy,
2 + alkylamino, amino, and dialkylamino when K is N ;
Q can be N(R )SO2N(R )(R ) with the proviso that no more than
23 24 26 one of R , R , and R can be hydroxy, alkoxy, alkylamino, amino, or
23 24 26 dialkylamino when two of the group consisting of R , R , and R are bonded to the same atom;
Q can be selected from the group consisting of dialkylsulfonium, trialkylphosphonium, 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),
26 26 25 23 24 26 26 23 24
N(R )N(R )C(NR )N(R )(R ), N(R )N(R )SO2N(R )(R ),
23 24 23 24
C(O)NR R , and C(O)NR R with the provisos that no more than one of
23 24 26
R , R , and R can be hydroxy, alkoxy, alkylamino, amino, or
23 24 26 dialkylamino when two of the group consisting of R , R , and R are bonded to the same atom and that said Q group is bonded directly to a carbon atom;
23 24 25 26
R , R , R , and R are independently selected from the group consisting of hydrido, alkyl, hydroxy, alkoxy, alkylamino, dialkylamino, aminoalkyl, and hydroxyalkyl; g
Q is selected from the group consisting of a single covalent bond and
(CR R )b-(W )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
14 14 14 of O, S, C(O), S(O)2, N(R ), and ON(R ) with the proviso that R is
37 38 selected from other than halo when directly bonded to N and that (CR R )^ is bonded to E ;
R and R are independently selected from the group consisting of hydrido, halo, alkyl, and haloalkyl;
Y can be Q -Q wherein Q is (CH(R ))r-W , 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, 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-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
W and that (CH(R ))r is bonded to E°;
Y can be Q -Q wherein Q is (CH(R ))r-W , 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-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-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
W and that (CH(R ))r is bonded to E°.
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 adjacent to the carbon at the point of attachment may be substituted by
32 R , the other carbon adjacent to the carbon at the point of attachment may be
substituted by R , a carbon adjacent to R and two atoms from the carbon at
33 36 the point of attachment may be substituted by R , a carbon adjacent to R and two atoms from the carbon at the point of attachment may be substituted by
35 33 35 34
R , and any carbon adjacent to both R and R may be substituted by R ;
32 33 34 35 36
R , R , R , R , and R are independently selected from the group consisting of hydrido, amidino, guanidino, 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;
32 33 34 35 36 b
R , R , R , R , andR can independently be Q ; 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 R3g; B can be selected from the group consisting of C3-C10 cycloalkyl, C5-
C10 cycloalkenyl, C4-C9 saturated heterocyclyl, and C4-C9 partially satorated 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 R or R 3, a ring carbon or nitrogen atom adjacent to the R9 position and two atoms from the point of attachment may be substituted with R ø, a ring carbon or nitrogen atom adjacent to the Rχ3 position and two atoms
from the point of attachment may be substituted with Rχ2, a ring carbon or
nitrogen atom three atoms from the point of attachment and adjacent to the Rχø
position may be substituted with Rj j , a ring carbon or nitrogen atom three
atoms from the point of attachment and adjacent to the Rj2 position may be
substitoted with R33, and a ring carbon or nitrogen atom four atoms from the
point of attachment and adjacent to the Rj γ and R33 positions may be
substitoted with R34;
9 10 11 12 13
R , R , R , R , and R 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,
7 15 15 7
(W ^-(CH R ))pa and (CH(R ))pa-(W )π wherein π is an integer
7 selected from 0 through 1, pa is an integer selected from 0 through 6, and W is selected from the group consisting of O, S, and C(O);
15 R is selected from the group consisting of hydrido, hydroxy, halo, alkyl, and haloalkyl; Ψ is NH; X is hydrido;
R 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 9 may be substituted by R , the other carbon adjacent to the carbon at the point of
13 9 attachment may be substituted by R , a carbon adjacent to R and two atoms
from the carbon at the point of attachment may be substitoted by R , a carbon
13 adjacent to R and two atoms from the carbon at the point of attachment may
12 10 12 be substituted by R , and any carbon adjacent to both R and R may be
substitoted by R ;
4a 4b 4a 4b
K is CR R wherein R and R are independently selected from the group consisting of halo and hydrido; o 1 4a 4b 1
E is E , when K is CR R , wherem 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;
14 K can be (CH(R )):-T wherein j is selected from an integer from 0 through 1 and T is selected from the group consisting of single covalent bond
7 14 and N(R ) with the proviso that (CH(R )): is bonded to the pyrone ring;
7 R is selected from the group consisting of hydrido, hydroxy, alkyl, and alkoxyalkyl;
14 R is selected from the group consisting of hydrido and halo;
O Λ. O
E is E , when K is (CH(R )) -T, 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 formula (IV):
wherein D , D , J , and J are independentiy selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more
2 5 than one can be a covalent bond, K is independently selected from the group
consisting of C, and N , no more than one of D , D , J , and J is O, no more
5 6 5 6 . 5 6 _5 6 than one of D , D , J , and j is S, one of D , D , J , and J must be a ι , , , * ^5 6 5 J 6 Λ , 0 , covalent bond when two of D , D , J , and J are O and S, no more than three
5 6 5 6 2 + 5 of D , D , J , and J can be N when K is N , and no more than four of D ,
- Λ τ^6 τ 5 J T6 ,_ τ ,_ TM2 . L . t , . , „16 „17
10 D , J , and J can be N when K is carbon with the provisos that R , R ,
18 19
R , and R are each independently selected to maintain the tetravalent natore of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen;
16 17 18 19
R , R , R , and R are independently selected from the group
15 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; b 20 21 + 20 21 22
20 Q is selected from the group consisting of NR R , NR R R , oxy, alkyl, alkylaminoalkyl, aminoalkyl, dialkylsulfoniumalkyl, and acylamino 20 21 22 wherein R , R , and R are independently selected from the group consisting of hydrido, alkyl, hydroxy, alkoxy, alkylamino, dialkylamino,
20 aminoalkyl, and hydroxyalkyl with the provisos that no more than one of R ,
21 22
R , and R can be hydroxy, alkoxy, alkylamino, ammo, and dialkylamino
20 21 22 and that R , R , and R must be other than be hydroxy, alkoxy,
2 + alkylamino, amino, and dialkylamino when K is N ;
Q can be selected from the group consisting of dialkylsulfonium,
trialkylphosphonium, C 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)NR23R24, and C(O)NR23R24 with
23 24 26 the provisos that no more than one of R , R , and R can be hydroxy, alkoxy, alkylamino, amino, or dialkylamino when two of the group consisting
23 24 26 b of R , R , and R are bonded to the same atom and that said Q group is bonded directly to a carbon atom;
23 „24 25 , „26 . , , , R , R , R , and R are independently selected from the group consisting of hydrido, alkyl, hydroxy, alkoxy, alkylamino, dialkylamino, aminoalkyl, and hydroxyalkyl; g
Q is selected from the group consisting of a single covalent bond and (CR R )D-(W )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 (CR R )^ is bonded to E ;
37 38
R and R 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-pyrazolyl, l,2,4-triazol-3-yl, l,2,4-triazol-5-yl, l,2,4-oxadiazol-3-yl, 1,2,4- oxadiazol-5-yl, l,3,4-oxadiazol-3-yl, l,3,4-oxadiazol-5-yl, 3-isothiazolyl, 5- isothiazolyl, 2-oxazolyl, 2-thiazolyl, 3-isoxazolyl, 5-isoxazolyl, 2-pyridyl, 3- pyridyl, 4-pyridyl, 2-pyrazinyl, 2-ρyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3- pyridazinyl, 4-pyridazinyl, l,3,5-triazin-2-yl, l,2,4-triazin-3-yl, l,2,4-triazin-5-yl, l,2,4-triazin-6-yl, and l,2,3-triazin-4-yI, wherein a carbon adjacent to the carbon
32 at the point of attachment may be substituted by R , the other carbon adjacent
36 to the carbon at the point of attachment may be substitoted by R , a carbon
32 adjacent to R and two atoms from the carbon at the point of attachment may
be substituted by R , a carbon adjacent to R and two atoms from the carbon
35 at the point of attachment may be substituted by R , and any carbon adjacent
33 35 34 to both R and R may be substituted by R ;
32 33 34 35 36
R , R , R , R , and R are independently selected from the group consisting of hydrido, amidino, guanidino, 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, methylsulfmyl, ethylsulfmyl, methylsulfonyl, ethylsulfonyl, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, 2,2,3,33- 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-l-hydroxy ethyl, 2,2,2-trifluoro-l- trifluoromethyl-1 -hydroxy ethyl, 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-pentyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-pentynyl, 3- pentynyl, 2-pentyl, l-methyl-2-butenyl, l-methyl-3-butenyl, l-methyl-2- butynyl, 3-ρentyl, l-ethyl-2-propenyl, 2-methylbutyl, 2-methyl-2-butenyl, 2- methyl-3-butenyl, 2-methyl-3-butynyl, 3-methylbutyl, 3-methyl-2-butenyl, 3- methyI-3-butenyl, 1-hexyl, 2-hexenyl, 3-hexenyl, 4~hexenyl, 5-hexenyl, 2- hexynyl, 3-hexynyl, 4-hexynyl, 2-hexyl, l-methyl-2-pentenyl, l-methyl-3- pentenyl, l-methyl-4-pentenyl, l-methyl-2-pentynyl, l-methyl-3-pentynyl, 3- hexyl, l-ethyl-2-butenyl, l-ethyl-3-butenyl, l-propyl-2-propenyl, l-ethyl-2- butynyl, 1-heptyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl, 2- heptynyl, 3-heptynyl, 4-heptynyl, 5-heptynyl, 2-heptyl, l-methyl-2-hexenyl, 1- methyl-3-hexenyl, l-methyl-4-hexenyl, l-methyl-5-hexenyl, l-methyl-2- hexynyl, l-methyl-3-hexynyl, l-methyl-4-hexynyl, 3-heptyl, l-ethyl-2-pentenyl, l-ethyl-3-pentenyl, l-ethyl-4-pentenyl, l-butyl-2-propenyl, l-ethyl-2-pentynyl, l-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, l-methyl-3-heptenyl, l-methyl-4-heptenyl, l-methyl-5- heptenyl, l-methyl-6-heρtenyl, l-methyl-2-heρtynyl, l-methyl-3-heptynyl, 1- methyl-4-heptenyl, l-methyl-5-heptenyl, l-methyl-6-heptenyl, l-methyl-2- heptenyl, l-methyl-3-heptynyl, l-methyl-4-heptynyl, l-methyl-5-heptynyl, 3- octyl, l-ethyl-2-hexenyl, l-ethyl-3-hexenyl, l-ethyl-4-hexenyl, l-ethyl-2- hexynyl, l-ethyl-3-hexynyl, l-ethyl-4-hexynyl, l-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-difluoroρropyl, 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 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, 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, norbornyl, 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-moφholinyl, 3- moφholinyl, 4-moφholinyl, 1-piperazinyl, 2-piperazinyl, 1-piperidinyl, 2- piperidinyl, 3-piperidinyl, 4-piperidinyl, 1-pyrrolidinyl, 2-pyπolidinyl, 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 Rχ , a ring carbon or
nitrogen atom adjacent to the R9 position and two atoms from the point of
attachment may be substituted with RJQ, and a ring carbon or nitrogen atom
adjacent to the RJ position and two atoms from the point of attachment may
be substitoted with Rj2ϊ
9 10 11 12 13
R , R , R , R , and R 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- dimethylamino, N-methylamino, N-ethylamino, methylsulfinyl, ethylsulfinyl, methylsulfonyl, ethylsulfonyl, amidosulfonyl, N-methylamidosulfonyl, N,N- dimethylamidosulfonyl, acetyl, propanoyl, butanoyl, trifluoroacetyl, pentafluoropropanoyl, hydroxymethyl, 1 -hydroxy ethyl, 2-hydroxyethyl, 2,2,2- trifluoro-1-hydroxyethyl, 2,2,2-trifluoro-l-trifluoromethyl-l-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;
2
R 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-triazoI-5-yI, 1 ,2,4-oxadiazol-3-yl, 1 ,2,4- oxadiazol-5-yl, l,3,4-oxadiazol-3-yl, l,3,4-oxadiazol-5-yl, 3-isothiazolyl, 5- isothiazolyl, 2-oxazolyl, 2-thiazolyl, 3-isoxazolyl, 5-isoxazolyl, 2-pyridyl, 3- pyridyl, 4-pyridyl, 2-pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3- pyridazinyl, 4-pyridazinyl, l,3,5-triazin-2-yl, l,2,4~triazin-3-yl, l,2,4-triazin-5-yl, l,2,4-triazin-6-yl, and l,2,3-triazin-4-yl, wherein a carbon adjacent to the carbon
9 at the point of attachment may be substituted by R , the other carbon adjacent
13 to the carbon at the point of attachment may be substituted by R , a carbon
9 adjacent to R and two atoms from the carbon at the point of attachment may be
10 13 substituted by R , a carbon adjacent to R and two atoms from the carbon at
12 the point of attachment may be substituted by R , and any carbon adjacent to
, , ^10 , 12 , . 11 both R and R may be substituted by R ;
4a 4b 4a 4b
K is CR R wherein R and R are independently selected from the group consisting of chloro, fluoro, and hydrido; r-0 ■ τ-T , tr ■ ,4a 4b , . 1 . b is E , when K is CR R , 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); o 2 2
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;
Ϊ is selected from the group of formulas consisting of:
16 17 18 19 R , R , R , and R 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- methyla ino, dimethylamino, N-efhylamino, 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, 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- dimethylarnidocarbonyl, and cyano; Q is selected, when bonded to a carbon, from the group consisting of
20 21 + 20 21 22 NR R , NR R R , dimethylsulfonium, methylethylsulfonium,
25 23 24 diethylsulfonium, trimethylphosphonium, C(NR )NR R ,
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),
23 24 23 24
C(O)NR R , and C(O)NR R with the provisos that no more than one of
20 21 22
R , R , andR can be hydroxy, methoxy, ethoxy, N-methylammo, N,N- dimethylamino, and N,N,N-trimethylamino, and amino and that no more than
23 24 26 one of R , R , and R can be hydroxy, methoxy, ethoxy, N-methylarmno, N,N-dimethylamino, N,N,N-trimethylamino, or amino when two of the group consisting o , R , and R are on e to t e same atom and that sa Q group is bonded directly to a carbon atom;
20 21 22 23 24 25 26
R , R , R , R , R , R , and R are independentiy 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, N,N-dimethylamino, N,N- diethylamino, and N,N,N-trimethylamino; Q 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; g Q 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 s 0 proviso that Q is bonded to E 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-pyπolyl, 3-pyrrolyl, 2-imidazolyl, 4-imidazolyl, 3-pyrazolyl, 4-pyrazolyl, 2-thiazolyl, 3-isoxazolyl, 5-isoxazolyl, 2-pyridyl, 3-pyridyl, 4- pyridyl, 2-pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, and l,3,5-triazin-2-yl, wherein a carbon adjacent to the carbon at
32 the point of attachment may be substituted by R , the other carbon adjacent to
the carbon at the point of attachment may be substituted by R , a carbon
32 adjacent to R and two atoms from the carbon at the point of attachment may
be substituted by R , a carbon adjacent to R and two atoms from the carbon
35 at the point of attachment may be substitoted by R , and any carbon adjacent
33 35 34 to both R and R may be substituted by R ;
32 33 34 35 36
R , R , R , R , and R are independently selected from the group consisting of hydrido, amidino, guanidino, 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, trifluoromefhylthio, methylsulfinyl, ethylsulfinyl, methylsulfonyl, ethylsulfonyl, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, 2,2,3,3,3- pentafluoropropyl, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro, bromo, amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, acetyl, propanoyl, trifluoroacetyl, pentafluoropropanoyl, hydroxyraethyl, 1- hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro- 1-hydroxyethyl, 2,2,2-trifluoro- 1- rrifluoromethyl- 1-hydroxyethyl, carboxy methyl, methoxycarbonyl, ethoxy carbonyl, 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, sec-butyl, isobutyl, 2-methylpropenyl, 1- pentyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-pentyl, l-methyl-2-butenyl, 1- methyl-3-butenyl, 3-pentyl, l-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-3,3,3-trifluoropropyl, 1,1,1,2,2,2- hexafluoropropyl, 3,3,3-trifluoroprop-l-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 R^6',
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 Rj , a ring carbon or
nitrogen atom adjacent to the R9 position and two atoms from the point of
attachment may be substitoted with RJQ, and a ring carbon or nitrogen atom
adjacent to the Rχ3 position and two atoms from the point of attachment may
be substituted with Rχ2;
9 10 11 12 13
R , R , R , R , and R 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, methoxycarbonyi, 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;
R is selected from the group consisting of phenyl, 2-thienyl, 3-thienyl,
2-furyl, 3-furyl, 2-pyπolyl, 3-pyrrolyl, 2-imidazolyl, 4-imidazolyl, 3-pyrazolyl, 4-pyrazolyl, 2-thiazolyl, 3-isoxazolyl, 5-isoxazolyl, 2-pyridyl, 3-pyridyl, 4- pyridyl, 2-pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, and l,3,5-triazin-2-yl, wherein a carbon adjacent to the carbon at
9 the point of attachment may be substitoted by R , the other carbon adjacent to
13 the carbon at the point of attachment may be substituted by R , a carbon
9 adjacent to R and two atoms from the carbon at the point of attachment may be
10 13 substituted by R , a carbon adjacent to R and two atoms from the carbon at
12 the point of attachment may be substituted by R , and any carbon adjacent to
10 12 11 both R and R may be substituted by R ;
4a 4b 4a 4b
K is CR R wherein R and R are independently selected from the group consisting of chloro, fluoro, and hydrido;
E is E , when K is CR R , 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); n
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:
16 17 18 19 . , , ,
R , R , R , and R are independently selected from the group consisting of hydrido, amidino, guanidino, methoxy, ethoxy, isopropoxy, methylthio, ethylthio, trifluoromethylthio, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, 2,2,333-pentafluoropropyl, trifluoromethoxy, 1,1,2,2- tetrafluoroethoxy, fluoro, chloro, bromo, acetyl, propanoyl, trifluoroacetyl, pentafluoropropanoyl, methoxy carbonyl, ethoxy carbonyl, and cyano; Q is selected, when bonded to a carbon, from the group consisting of
20 21 4- 20 21 22 NR R , NR R R , dimethylsulfonium, methylethylsulfonium,
25 23 24 diethylsulfonium, trimethylphosphonium, C(NR )NR R ,
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),
23 24 23 24 C(O)NR R , and C(O)NR R with the provisos that no more than one of
20 21 22
R , R , and R can be hydroxy, methoxy, ethoxy, N-methylamino, N,N- dimethylamino, N,N,N-trimethylamino, or amino and that no more than one of
23 24 26
R , R , and R can be hydroxy, methoxy, ethoxy, N-methylamino, N,N- dimethylamino, N,N,N-trimethylamino, or amino when two of the group . . „ 23 24 1 T 26 , , , , . b consisting of R , R , and R are bonded to the same atom and that said Q group is bonded directly to a carbon atom;
^20 21 22 23 24 25 26
R , R , R , R , R , R , and R are independently selected from the group consisting of hydrido, methyl, ethyl, hydroxy, methoxy, ethoxy, 2- aminoethyl, 2-(N-methylamino)ethyl, 2-(N,N-dimethyIamino)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;
Q 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- melhylainino, N,N-dimethylamino, and N,N,N-trimethylamino; g
Q 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 s o proviso that Q is bonded to E 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-pyrazolyl, 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 32 be substituted by R , the other carbon adjacent to the carbon at the point of
attachment may be substituted by R , a carbon adjacent to R and two atoms
33 from the carbon at the point of attachment may be substitoted by R , a carbon
adjacent to R and two atoms from the carbon at the point of attachment may
be substituted by R , and any carbon adjacent to both R and R may be
34 substitoted by R ;
32 33 34 35 , 36 . , , , , R , R , R , R , and R 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, 2,2,3,33-pentafluoropropyl, fluoro, chloro, bromo, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro- 1- hydroxyethyl, 2,2,2-trifluoro-l-trifluoromethyl-l-hydroxyethyl, methoxycarbonyl, ethoxycarbonyl, cyano, and Q ; B can be selected from the group consisting of propyl, isopropyl, butyl, sec-butyl, isobutyl, 1-pentyl, 2-ρentyl, 3-ρentyl, 2-methylbutyl, 3-methylbutyl, 2,2-difluoropropyl, 2-trifluoromethyl-3,3,3-trifluoropropyl, 1,1,1,2,2,2- hexafluoropropyl, 3,33-trifluoroprop-l-yl, and 3,33-trifluoroprop-2-yl, wherein each member of group B may be optionally substitoted 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 R^g,
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 substitoted 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 R 3, a ring carbon or
nitrogen atom adjacent to the R9 position and two atoms from the point of
attachment may be substitoted with RJQ, and a ring carbon or nitrogen atom adjacent to the R 3 position and two atoms from the point of attachment may
be substituted with Rj2;
9 10 11 12 13
R , R , R , R , and R 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, 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, CH2C(O), and (O)CCH2;
2 R 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-ρyrazolyl,
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-ρyridazinyl, and l,3,5-triazin-2-yl, wherein a carbon adjacent to the carbon at
9 the point of attachment may be substituted by R , the other carbon adjacent to
13 the carbon at the point of attachment may be substitoted by R , a carbon
9 adjacent to R and two atoms from the carbon at the point of attachment may be
10 13 substitoted by R , a carbon adjacent to R and two atoms from the carbon at
•he point of ttach may b suit d by R* and an, carbon adjacen, .0
10 12 11 both R and R may be substituted by R ;
4a 4b 4a 4b
K is CR R wherein R and R are independently selected from the group consisting of chloro, fluoro, and hydrido; o 1 4a„4b 1 E is E , when K is CR JR. , 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);
0 2 2
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; i is selected from the group of formulas consisting of:
R , R , R , and R are independently selected from the group consisting of hydrido, methoxy, ethoxy, trifluoromethyl, pentafluoroethyl, 2,2,2- trifluoroethyl, trifluoromethoxy, fluoro, chloro, bromo, acetyl, trifluoroaceryl, methoxycarbonyl, ethoxycarbonyl, and cyano; b 20 21 + 20 21 22
Q is selected from the group consisting of NR R , NR R R , dimethylsulfonium, methylethylsulfonium, diethylsulfonium,
25 23 24 26 25 23 24 trimethylphosphonium, C(NR )NR R , N(R )C(NR )N(R )(R ),
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)NR23R24, and C(O)NR23R24 with
20 21 22 the provisos that no more than one of R , R , andR can be hydroxy, methoxy, ethoxy, N-methylamino, N,N-dimethylamino, N,N,N-trimethylamino,
23 24 26 or amino and that no more than one of R , R , and R can be hydroxy, methoxy, ethoxy, N-methylamino, N,N-dimethylamino, N,N,N-trimethylamino,
23 24 26 or amino when two of the group consisting of R , R , and R are bonded
to the same atom and that said Q group is bonded directly to a carbon atom; 20 21 22 23 24 25 26
R , R , R , R , R , R , and R 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)a ino, N,N-bis-(2-hydroxyethyl)amino, N-(2-hydroxyethyl)-N-(2-aιrιinoethyl)amino, N-methylamino, N,N-dimethylamino, and N,N,N-trimethylamino; g
Q 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 substitoted by
32 R , a nitrogen with a removable hydrogen or a carbon at the other position
3f adjacent to the point of attachment is optionally substitoted by R , a nitrogen
32 with a removable hydrogen or a carbon adjacent to R and two atoms from the
33 point of attachment is optionally substituted by R , a nitrogen with a
36 removable hydrogen or a carbon adjacent to R and two atoms from the point
35 of attachment is optionally substituted by R , and a nitrogen with a removable 33 35 hydrogen or a carbon adjacent to both R and R is optionally substitoted by
R9 R10 Rπ R12, R13,R32,R 33, R34.R33, aMR3 « 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, cycloalkylsulfmyl, 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;
R , R , R , R , and R are independently optionally 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
32 33 34 35 36 with one or more of the group consisting of R , R , R , R , and R ; B is optionally a C3-C12 cycloalkyl or C4-C9 saturated heterocyclyl,
33 wherein each ring carbon is optionally substitoted with R , a ring carbon other than the ring carbon at the point of attachment of B to A is optionally substituted with oxo provided that no more than one ring carbon is substituted by oxo at the same time, ring carbons and a nitrogen adjacent to the carbon
9 13 atom at the point of attachment are optionally substituted with R or R , a ring
9 carbon or nitrogen atom adjacent to the R position and two atoms from the point of attachment is optionally substitoted with R , a ring carbon or nitrogen
13 adjacent to the R position and two atoms from the point of attachment is
12 optionally substituted with R , a ring carbon or nitrogen three atoms from the
point of attachment and adjacent to the R position is optionally substituted
11 with R , a ring carbon or nitrogen three atoms from the point of attachment
12 33 and adjacent to the R position is optionally substituted with R , and a ring carbon or nitrogen four atoms from the point of attachment and adjacent to the
11 33 34
R and R positions is optionally substituted with R ;
A is selected from the group consisting of a bond, (W7)rr-(CH(R15))pa, and (CH(R15))pa-(W?)rr wherein rr is 0 or 1 , pa is an
7 integer selected from 0 through 6, and W is selected from the group
consisting of O, S, C(O), (R?)NC(O), (R?)NC(S), and N(R?) with the proviso that no more than one of the group consisting of rr and pa is 0 at the same time;
7 R is selected from the group consisting of hydrido, hydroxy, and alkyl;
15 R is selected from the group consisting of hydrido, hydroxy, halo, alkyl, and haloalkyl;
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;
R2 is Z°-Q; o 41 42
Z is selected from the group consisting of a bond, (CR R )q
41 o wherein q is an integer selected from 1 through 3, and (CH(R ))„- W - 42 (CH(R ))p wherein g and p are integers independently selected from 0 through 3 and W is selected from the group consisting of O, S, C(O), S(O),
41 41
N(R ), and ON(R );
Z° 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
41 42 CR =CR , 1,2-cyclopropyl, 1,2-cyclobutyl, 1,2-cyclohexyl, 13-cyclohexyl,
1,2-cyclopentyl, 13-cyclopentyl, 2,3-moφholinyl, 2,4-moφholinyl, 2,6-moφholinyl, 3,4-moφholinyl,3,5-moφholinyl, 1,2-piperazinyl, 13-piperazinyl, 23-piperazinyl, 2,6-piperazinyl, 1,2-piperidinyl, 13-piperidinyl, 2,3-piperidinyl, 2,4-piperidinyl, 2,6-piperidinyl, 3,4-piperidinyl, 1,2-pyrrolidinyl, 1,3-pyrrolidinyl, 23-pyπolidinyl, 2,4-pyrrolidinyl, 2,5-pyπolidinyl, 3,4-pyπolidinyl, 2,3-tetrahydrofuranyl, 2,4-tetrahydrofuranyl,
2,5-tetrahydrofuranyl, and 3,4-tetrahydrofuranyl, wherein Z is directly bonded to the 4-pyrone ring and W^ is optionally substituted with one or more
9 10 11 12 13 substituents selected from the group consisting of R , R , R , R , and R ;
41 42
R and R 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
9
R , a nitrogen with a removable hydrogen or a carbon at the other position
13 adjacent to the point of attachment is optionally substituted by R , a nitrogen
9 with a removable hydrogen or a carbon adjacent to R and two atoms from the
10 point of attachment is optionally substituted by R , a nitrogen with a
13 removable hydrogen or a carbon adjacent to R and two atoms from the point
12 of attachment is optionally substituted by R , and a nitrogen with a removable hydrogen or a carbon adjacent to both R and R is optionally substitoted by
11
R
Q is optionally hydrido with the proviso that Z is selected from other than a bond;
4a 4b K is CR R ;
4a 4b
R and R are independently selected from the group consisting of halo, hydrido, hydroxyalkyl, alkyl, alkoxyalkyl, alkylthioalkyl, and haloalkyl; o 4a 4b 1 1
E , with the proviso that K is CR R , is E wherein E 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;
14 K is optionally (CH(R ))j-T wherein j is 0 or 1 and T is a bond or
7 14
N(R ) with the proviso that (CH(R )): is bonded to the phenyl ring;
14 R is selected from the group consisting of hydrido, halo, alkyl, and haloalkyl; o 14 2 2
E , with the proviso that K is (CH(R ))j-T, is E 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;
Y is phenyl or a heteroaryl of 5 or 6 ring members, wherein one carbon of said phenyl or said heteroaryl is substituted by Q , a carbon two or three
contiguous atoms from the point of attachment of Q to said phenyl or said
heteroaryl to said phenyl or said heteroaryl is substituted by Q , a carbon s 17 adjacent to the point of attachment of Q is optionally substituted by R ,
another carbon adjacent to the point of attachment of Q is optionally substituted by R , a carbon adjacent to Q is optionally substituted by R , b 19 and another carbon adjacent to Q is optionally substituted by R ;
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 or R is optionally selected from the group consisting of
20 21 26 25 23 24 25 23 24
NR R , N(R )C(NR )N(R )(R ), and C(NR )NR R , with the
16 19 b proviso that R , R , and Q are not simultaneously hydrido; b 20 21
Q is selected from the group consisting of NR R , aminoalkyl,
26 25 23 24 25 23 24 hydrido, N(R )C(NR )N(R )(R ), and C(NR )NR R , with the
20 21 proviso that no more than one of R and R is selected from the group consisting of hydroxy, amino, alkylamino, and dialkylamino at the same time,
23 24 with the further proviso that no more than one of R and R is selected from the group consisting of hydroxy, amino, alkylamino, and dialkylamino at the same time;
20 21 23 24 25 26
R , R , R , R , R , and R are independendy selected from the group consisting of hydrido, alkyl, hydroxy, aminoalkyl, amino, dialkylamino, alkylamino, and hydroxyalkyl;
^s 37 38
Q is selected from the group consisting of a bond, (CR R
14 1 wherein b is an integer selected from 1 through 4, and (CH(R ))c- W -
(CH(R ))^ wherein c and d are integers independently selected from 1
1 14 through 3 and W is selected from the group consisting of C(O)N(R ),
(R14)NC(O), S(O), S(O)2, S(O)2N(R14), N(R14)S(O)2, and N(R14), with the 14 proviso that R is selected from other than halo when directly bonded to N,
37 38 14 and with the additional proviso that (CR R and (CH(R ))c are bonded to E"
37 38
R and R are independently selected from the group consisting of hydrido, alkyl, and haloalkyl;
38 38
R is optionally aroyl or heteroaroyl, wherein R is optionally substitoted with one or more substituents selected from the group consisting of
„16 „17 „ 18 19
R , R , R , and R ;
x is optionally Y wherein Y is Q -Q ; Y° is optionally Qb-QSS wherein QSS is (CH(R14))e- W2-(CH(R15))h,
9 4a 4b wherein e and h are independently 1 or 2 and W^ is CR =CR , with the
14 o proviso that (CH(R ))e is bonded to E ;
IS optionally Q -Q or Q -Q wherein Q is (CH(R ))r-
W , Q is (CH(R ))r-W , r is 1 or 2, W and W 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-benzothiophenyl, 3,4-benzothiophenyl, 3,5-benzothiophenyl, 3,6-benzothiophenyl, 3,7-benzothiophenyl, 2,7-imidazo( 1 ,2-a)pyridinyl, 3 ,4-imidazo( 1 ,2-a)pyridinyl, 3 ,5-imidazo( 1 ,2-a)pyridinyl , 3 ,6-imidazo( 1 ,2-a)pyridinyl , 3,7-imidazo(l,2-a)pyridinyl, 2,4-indolyl, 2,5-indolyl, 2,6-indolyl, 2,7-indolyl, 3,4-indolyl, 3,5-indolyl, 3,6-indolyl, 3,7-indolyl, 1,4-isoindolyl, 1,5-isoindolyl, 1,6-isoindolyl, 2,4-isoindolyl, 2,5-isoindolyl, 2,6-isoindolyl, 2,7-isoindolyl, 13-isoindolyl, 3,4-indazolyl, 3,5-indazolyl, 3,6-indazolyl, 3,7-indazolyl, 2,4-benzoxazolyl, 2,5-benzoxazolyl, 2,6-benzoxazolyl, 2,7-benzoxazolyl, ,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-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, and each carbon and hyrido containing nitrogen member of the ring of the an o t e ng o t e other than the points of attachment of w5 and W , is optionally substitoted with one or more of the group consisting of
R , R , R , and R , with the proviso that Q is bonded to lowest number b . substituent position of each . W5^,, with the further proviso that Q is bonded to
highest number substituent position of each W , and with the additional
proviso that (CH(R ))r is bonded to E .
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
32 ring to A is optionally substituted by R , the other carbon adjacent to the £" carbon at the point of attachment is optionally substituted by R , a carbon
32 adjacent to R and two atoms from the carbon at the point of attachment is
33 36 optionally substituted by R , a carbon adjacent to R and two atoms from the
35 carbon at the point of attachment is optionally substituted by R , and any
33 35 34 carbon adjacent to both R and R is optionally substituted by R ;
32 33 34 35 36
R , R ,R , R , and R are independenuy 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, tiialkylsilyl, 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
32 33 34 35 36 with one or more of the group consisting of R , R , R , R , and R ;
B is optionally a C3-C12 cycloalkyl or a C4-C9 saturated heterocyclyl,
33 wherein each ring carbon is optionally substituted with R , a ring carbon other than the ring carbon at the point of attachment of B to A is optionally substituted with oxo provided that no more than one ring carbon is substituted by oxo at the same time, ring carbons and a nitrogen adjacent to the carbon
9 13 atom at the point of attachment are optionally substituted with R or R , a ring
9 carbon or nitrogen atom adjacent to the R position and two atoms from the
10 point of attachment is optionally substitoted with R , a ring carbon or nitrogen
13 atom adjacent to the R position and two atoms from the point of attachment is optionaiiy snbsututed with R12 a ring carbon or nitrogen atom three atoms
from the point of attachment and adjacent to the R position is optionally
substituted with R , a ring carbon or nitrogen atom three atoms from the
12 point of attachment and adjacent to the R position is optionally substitoted
33 with R , and a ring carbon or nitrogen atom four atoms from the point of
11 33 attachment and adjacent to the R and R positions is optionally substituted
34 withR ;
9 10 11 12 13
R , R , R , R , and R are independently selected from the group consisting of hydrido, acetamido, haloacetamido, alkoxyamino, alkanoyl, haloalkanoyl, amidino, guanidino, alkylenedioxy, haloalkylthio, 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;
15 7
A is bond or (CH(R )) a-(W )π wherein rr is 0 or 1, pa is an integer
7 selected from 0 through 3, and W is selected from the group consisting of O,
S, C(O), (R7)NC(O), (R7)NC(S), and N(R7), with the proviso that W? is bonded to the N(H) on the 4-pyrone ring;
7 R is selected from the group consisting of hydrido, hydroxy and alkyl ;
15 R is selected from the group consisting of hydrido, hydroxy, halo, alkyl, and haloalkyl; X is selected from the group consisting of hydrido, alkyl, cyano, halo, haloalkyl, haloalkoxy, amino, aminoalkyl, alkylamino, amidino, hydroxy, hydr xyamino, alkoxy, hydroxyalkyl, alkoxyamino, thiol, and alkylthio;
R2 is Z°-Q; o 41 42
Z is selected from the group consisting of a bond, (CR R )q
41 o 42 wherein q is 1 or 2, and (CH(R ))g-W -(CH(R ))p wherein g and p are integers independently selected from 0 through 3 and W is selected from the group consisting of O, S, C(O), S(O), N(R41), and ON(R41);
Z° is optionally (CH(R41))e-W22-(CH(R42))h wherein e and h are
independently 0 or 1 and '.wW^2 is selected from the group consisting of
41 42 CR =CR , 1,2-cyclopropyl, 1,2-cyclobutyl, 1,2-cyclohexyl, 13-cyclohexyl,
1,2-cyclopentyl, 13-cyclopentyl, 2,3-moφholinyl, 2,4-moφholinyl, 2,6-moφholinyl, 3,4-moφholinyl, 3,5-moφholinyl, 1,2-piperazinyl, 13-piperazinyl, 2,3-piperazinyl, 2,6-piperazinyl, 1,2-piperidinyl, 1,3-piperidinyl, 2,3-piperidinyl, 2,4-piperidinyl, 2,6-piperidinyl, 3 ,4-piperidinyl,
1 ,2-pyrrolidinyl, 1 ,3-pyrrolidinyl, 2,3-pyrrolidinyl, 2,4-pyrrolidinyl, 2,5-pyπolidinyl, 3,4-pyrrolidinyl, 2,3-tetrahydrofuranyl, 2,4-tetrahydrofuranyl,
2,5-tetrahydrofuranyl, and 3,4-tetrahydrofuranyl, wherein Z is directly bonded to the 4-pyrone ring and Vf is optionally substituted with one or more
9 10 11 12 13 substituents selected from the group consisting of R , R , R , R , and R ;
41 42
R and R 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 o 9 ring to Z is optionally substituted by R , the other carbon adjacent to the
13 carbon at the point of attachment is optionally substitoted by R , a carbon
9 adjacent to R and two atoms from the carbon at the point of attachment is optionally substituted by R , a carbon adjacent to R and two atoms from the
12 carbon at the point of attachment is optionally substitoted by R , and any
10 12 11 carbon adjacent to both R and R is optionally substituted by R ;
Q is optionally hydrido with the proviso that Z is other than a bond;
4a 4b K is CR R ;
4a 4b
R and R are independently selected from the group consisting of hydrido, hydroxyalkyl, alkyl, alkoxyalkyl, alkylthioalkyl, and haloalkyl; o 4a 4b 1 1
E , with the proviso that K is CR R , 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;
14 K is optionally (CH(R )):-T wherein j is 0 or 1 and T is a bond or
7 14
N(R ) with the proviso that (CH(R )): is bonded to the phenyl ring;
14 R is hydrido or halo; o 14 2 2
E , with the proviso that K is (CH(R ))j-T, is E 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; x is phenyl or a heteroaryl of 5 or 6 ring members, wherein one carbon of said phenyl or said heteroaryl is substituted by Q , a carbon two or three
atoms from the point of attachment of Q to said phenyl or said heteroaryl is b s substituted by Q , a carbon adjacent to the point of attachment of Q is
17 optionally substituted by R , another carbon adjacent to the point of
attachment of Q is optionally substitoted by R , a carbon adjacent to Q is optionally substituted by R , and another carbon adjacent to is optionally
19 substitoted by R ;
16 17 18 19
R , R , R , and R are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, haloalkylthio, alkoxy, hydroxy, amino, alkoxyamino, alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, and cyano;
R or R is optionally selected from the group consisting of
proviso that R , R , and Q are not simultaneously hydrido; b 20 21
Q is selected from the group consisting of NR R , hydrido,
26 25 23 24 25 23 24
N(R )C(NR )N(R )(R ), and C(NR )NR R , with the proviso that no
20 21 more than one of R and R is selected from the group consisting of hydroxy, amino, alkylamino, and dialkylamino at the same time, with the further proviso that
23 24 no more than one of R and R is selected from the group consisting of hydroxy, amino, alkylamino, and dialkylamino at the same time;
20 21 23 24 25 26
R , R , R , R , R , and R are independently selected from the group consisting of hydrido, alkyl, hydroxy, amino, alkylamino and dialkylamino;
Q is selected from the group consisting of a bond, (CR R
14 1 wherein b is an integer selected from 1 through 4, and (CH(R ))C-W -
15 (CH(R ))(j wherein c and d are integers independently selected from 1
1 14 through 3 and W is selected from the group consisting of C(O)N(R ),
(R14)NC(O), S(O), S(O)2, S(O)2N(R14), N(R14)S(O)2, and N(R14), with the
14 proviso that R is selected from other than halo when directly bonded to N, 37 38 37 38 and with the additional proviso that (CR R and (CR R , and
(CH(R14))C are bonded to E°;
37 38
R and R are independently selected from the group consisting of hydrido, alkyl, and haloalkyl;
38 38
R is optionally aroyl or heteroaroyl, wherein R is optionally substituted with one or more substitoents selected from the group consisting of ϊ is optionally Y wherein Y is Q -Q ;
D h ss ς 14 2 15 is optionally Q -Q wherein Q is (CH(R ))e-W -(CH(R ))h,
.4a „ 4b wherein e and h are independently 1 or 2 and w W2^: is CR =CR with the
14 o proviso that (CH(R ))e is bonded to E .
In an even more prefeπed 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
32 ring to A is optionally substitoted by R , the other carbon adjacent to the
36 carbon at the point of attachment is optionally substituted by R , a carbon
32 adjacent to R and two atoms from the carbon at the point of attachment is
optionally substituted by R , a carbon adjacent to R and two atoms from the 35 carbon at the point of attachment is optionally substitoted by R , and any
33 35 34 carbon adjacent to both R and R is optionally substituted by R ;
32 33 34 35 36
R , R , R , R , and R are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkoxy, hydroxy, amino, alkoxyamino, alkylamino, alkylthio, amidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, hydroxyhaloalkyl, carboalkoxy, carboxy, carboxamido, cyano, and Q ;
15 7
A is a bond or (CH(R ))pa-(W )rr wherein rr is 0 or 1, pa is an
7 7 7 integer selected from 0 through 3, and W is (R )NC(O) or N(R );
7 R is selected from the group consisting of hydrido, hydroxy and alkyl;
15 R is selected from the group consisting of hydrido, halo, alkyl, and haloalkyl;
X is selected from the group consisting of hydrido, amino, alkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, hydroxy, alkoxy, hydroxyalkyl, and alkylthio;
R2 is Z°-Q;
Z is selected from the group consisting of a bond, CH2, CH2CH2, -
42 o
(CH(R ))p wherein p is 0 or 1 and W is selected from the group consisting
of O, S, and N(R41);
41 42
R and R 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
0 . . 9 ring to Z is optionally substituted by R , the other carbon adjacent to the
13 carbon at the point of attachment is optionally substitoted by R , a carbon
9 adjacent to R and two atoms from the carbon at the point of attachment is optionally substituted by R , a carbon adjacent to R and two atoms from the
12 carbon at the point of attachment is optionally substituted by R , and any
10 12 11 carbon adjacent to both R and R is optionally substituted by R ;
9 11 13
R , R , and R are independently selected from the group consisting of hydrido, hydroxy, amino, amidino, guanidino, alkylamino, alkylthio, alkylsulfonamido, alkylsulfinyl, alkylsulfonyl, amidosulfonyl, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, hydroxyalkyl, hydroxyhaloalkyl, carboxy, carboxamido, and cyano;
10 12
R and R 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; i is phenyl or a heteroaryl of 5 or 6 ring members, wherein one carbon g of said phenyl or said heteroaryl is substituted by Q , a carbon two or three
atoms from the point of attachment of Q to said phenyl or said heteroaryl is b s substituted by Q , a carbon adjacent to the point of attachment of Q is
17 optionally substituted by R , another carbon adjacent to the point of s . 18 b . attachment of Q is optionally substituted by R , a carbon adjacent to Q is
optionally substituted by R , and another carbon adjacent to Q is optionally
19 substituted by R ; i ■t 'η 10 i n
R , R , R , and R 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; .16 19 . . „ 20 21 ΛΛm25„Lm23„24 . , , R or R is optionally NR R or C(NR )NR R , with the
proviso that R , R , and Q are not simultaneously hydrido; b 20 21
Q is selected from the group consisting of NR R , hydndo, and
25 23 24 20 21
C(NR )NR R , with the proviso that no more than one of R and R is
23 hydroxy at the same time and with the further proviso that no more than one of R
24 and R is hydroxy at the same time;
20 21 23 24 25
R , R , R , R , and R are independently selected from the group consisting of hydrido, alkyl, and hydroxy;
S
Q 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 32 point of attachment of B to A with one or more of the group consisting of R ,
„33 „34 35 , 36 R , R , R , and R ;
32 33 34 35 36
R , R , R , R , andR 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 Q ;
15 7
A is a bond or (CH(R ))pa-(W )rr wherein rr is 0 or 1, pa is an
7 7 7 integer selected from 0 through 3, and W is (R )NC(O) or N(R );
7 R is selected from the group consisting of hydrido, hydroxy and alkyl;
R is selected from the group consisting of hydrido, halo, alkyl, and haloalkyl;
X is selected from the group consisting of hydrido, amino, alkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, hydroxy, alkoxy, hydroxyalkyl, and alkylthio;
R2 is Z°-Q;
Z is selected from the group consisting of a bond, CH2, CH2CH2, w -
42 o
(CH(R ))_ wherein p is 0 or 1 and W is selected from the group consisting
of O, S, and N(R41);
41 42 R and R 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 attacliment of said phenyl or heteroaryl o 9 ring to Z is optionally substituted by R , the other carbon adjacent to the
13 carbon at the point of attachment is optionally substituted by R , a carbon
9 adjacent to R and two atoms from the carbon at the point of attachment is optionally substitoted by R , a carbon adjacent to R and two atoms from the
12 carbon at the point of attachment is optionally substituted by R , and any
10 12 11 carbon adjacent to both R and R is optionally substituted by R ;
9 11 13
R , R , and R are independently selected from the group consisting of hydrido, hydroxy, amino, amidino, guanidino, alkylamino, alkylthio, alkylsulfonamido, alkylsulfinyl, alkylsulfonyl, amidosulfonyl, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, hydroxyalkyl, hydroxyhaloalkyl, carboxy, carboxamido, and cyano;
R and R are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkyl, aiyl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, alkoxy, cycloalkoxy, cycloalkylalkoxy, aralkoxy, aryloxy, heteroaryloxy, heteroaralkoxy .heterocyclyloxy, heterocyclylalkoxy, hydroxy, amino, alkoxyamino, alkylamino, aiylamino, 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; i is phenyl or a heteroaryl of 5 or 6 ring members, wherein one carbon g of said phenyl or said heteroaryl is substituted by Q , a carbon two or three
atoms from the point of attachment of Q to said phenyl or said heteroaryl is b s substituted by Q , a carbon adjacent to the point of attachment of Q is
17 optionally substituted by R , another carbon adjacent to the point of
attachment of Q is optionally substituted by R , a carbon adjacent to Q is
optionally substituted by is optionally
substituted by R ; 16 17 18 19
R , R , R , andR 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 or R is optionally selected from the group consisting of
20 21 26 25 23 24 25 23 24
NR R , N(R )C(NR )N(R )(R ), and C(NR )NR R , with the
proviso that R , R , and Q are not simultaneously hydrido; b 20 21
Q is selected from the group consisting of NR R , hydrido, r e? ' OΛ 0 ^i O^ OΛ C(NR )NR R , and N(R )C(NR )N(R )(R ), with the proviso that
20 21 no more than one of R and R is hydroxy at the same time and with the
23 24 further proviso that no more than one of R and R is hydroxy at the same time;
20 21 23 24 25 26
R , R , R , R , R , and R are independently selected from the group consisting of hydrido, alkyl, and hydroxy;
Q is selected from the group consisting of a bond, CH2, and
CH2CH .
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
33 each ring carbon is optionally substituted with R , a ring carbon other than the ring carbon at the point of attachment of B to A is optionally substitoted 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 -
9 13 of attachment are optionally substitoted with R or R , a ring carbon or
9 nitrogen adjacent to the R position and two atoms from the point of attachment
10 13 is optionally substitoted with R , a ring carbon or nitrogen adjacent to the R position and two atoms from the point of attachment is optionally substituted
12 with R , a ring carbon or nitrogen three atoms from the point of attachment
10 11 and adjacent to the R position is optionally substitoted with R , a ring carbon or nitrogen three atoms from the point of attachment and adjacent to the
12 33
R position is optionally substituted with R , and a ring carbon or nitrogen
11 33 four atoms from the point of attachment and adjacent to the R and R
34 positions is optionally substituted with R ;
9 11 13
R , R , and R 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;
R and R 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, aralkylarnino, 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;
33 34
R and R 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;
33 b
R is optionally Q ;
15 7
A is a bond or (CH(R )) a-(W )rr wherein rr is 0 or 1, pa is an
7 7 7 integer selected from 0 through 3, and W is (R )NC(O) or N(R );
7 R is selected from the group consisting of hydrido, hydroxy and alkyl;
15 R is selected from the group consisting of hydrido, halo, alkyl, and haloalkyl;
X is selected from the group consisting of hydrido, amino, alkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, hydroxy, alkoxy, hydroxyalkyl, and alkylthio;
R2 is Z°-Q;
Z is selected from the group consisting of a bond, CH2, CH2CH2, o 42 o
W -(CH(R ))_ wherein p is 0 or 1 and W is selected from the group
41 consisting of O, S, and N(R );
41 42
R and R 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 o 9 ring to Z is optionally substituted by R , the other carbon adjacent to the
13 carbon at the point of attachment is optionally substituted by R , a carbon
9 adjacent to R and two atoms from the carbon at the point of attachment is 10 13 optionally substituted by R , a carbon adjacent to R and two atoms from the
12 carbon at the point of attachment is optionally substituted by R , and any
10 12 11 carbon adjacent to both R and R is optionally substituted by R ; ϊ is phenyl or a heteroaryl of 5 or 6 ring members, wherein one carbon g of said phenyl or said heteroaryl is substituted by Q , a carbon two or three
atoms from the point of attachment of Q to said phenyl or said heteroaryl is b s substituted by Q , a carbon adjacent to the point of attachment of Q is
17 optionally substitoted by R , another carbon adjacent to the point of
attachment of Q is optionally substituted by R , a carbon adjacent to Q is
optionally substituted by is optionally
su ib-sti •tuted . , by R π 19 ;
R , R , R , and R 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; π 16 19 . . „ , 20 21 Λ m25 τ 23 24 . , ,
R or R is optionally NR R or and C(NR )NR R , with the
16 19 h proviso that R , R , and Q are not simultaneously hydrido; b 20 21
Q is selected from the group consisting of NR R , hydrido, and
25 23 24 20 21 C(NR )NR R , with the proviso that no more than one of R and R is
23 hydroxy at the same time and with the further proviso that no more than one of R
24 and R is hydroxy at the same time;
20 21 23 24 25
R , R , R , R , and R are independently selected from the group consisting of hydrido, alkyl, and hydroxy; Q is selected from the group consisting of a bond, CH , and
CH CH .
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, tiialkylsilyl, 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
32 33 34 of the group consisting of R , R , and R ;
32 33 34
R , R , and R 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;
15 7
A is (CH(R ))pa-N(R ) wherein pa is an integer selected from 0
7 through 2 and R is hydrido or alkyl;
R 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;
R2 isZ°-Q;
Z is a bond or CH ; 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 o 9 ring to Z is optionally substituted by R , the other carbon adjacent to the
13 carbon at the point of attachment is optionally substituted by R , a carbon
9 adjacent to R and two atoms from the carbon at the point of attachment is
10 13 optionally substitoted by R , a carbon adjacent to R and two atoms from the
12 carbon at the point of attachment is optionally substituted by R , and any
10 12 11 carbon adjacent to both R and R is optionally substituted by R ;
9 11 13
R , R , and R are independently selected from the group consisting of hydrido, hydroxy, amino, amidino, guanidino, alkylamino, alkylthio, alkylsulfonamido, alkylsulfinyl, alkylsulfonyl, amidosulfonyl, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, hydroxyalkyl, hydroxyhaloalkyl, carboxy, carboxamido, and cyano;
10 12
R and R 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, heterocyclylalkylammo, alkylsulfonamido, amidosulfonyl, arylsulfinyl, aralkylsulfinyl, cycloalkylsulfinyl, heteroarylsulfinyl, arylsulfonyl, aralkylsulfonyl, cycloalkylsulfonyl, heteroarylsulfonyl, hydroxyalkyl, hydroxyhaloalkyl, aminoalkyl, carboalkoxy, carboxy, carboxyalkyl, carboxamido, halo, haloalkyl, and cyano; Ϊ is phenyl or a heteroaryl of 5 or 6 ring members, wherein one carbon g of said phenyl or said heteroaryl is substituted by Q , a carbon two or three
§ atoms from the point of attachment of Q to said phenyl or said heteroaryl is b s substitoted by Q , a carbon adjacent to the point of attachment of Q is 17 optionally substitoted by R , another carbon adjacent to the point of
attachment of Q is optionally substituted by R , a carbon adjacent to Q is
16 b optionally substituted by R , and another carbon adjacent to Q is optionally
substituted by R ;
16 17 1 R 19 R , R , R , and R 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 or R is optionally selected from the group consisting of
XTT 20 21 ^26^ 25^^23^24, J m25 23 24 . , t NR R ,N(R )C(NR )N(R )(R ), and C(NR )NR R , with the
16 19 b proviso that R , R , and Q are not simultaneously hydrido; b 20 21
Q is selected from the group consisting of NR R , hydrido,
25 23 24 26 25 23 24
C(NR )NR R , and N(R )C(NR )N(R )(R ), with the proviso that
20 21 no more than one of R and R is hydroxy at the same time and with the
23 24 further proviso that no more than one of R and R is hydroxy at the same time;
20 21 23 24 25 26
R , R , R , R , R , and R are independently selected from the group consisting of hydrido, alkyl, and hydroxy; g Q is selected from the group consisting of a bond, CH2, and
CH2CH2.
In a fifth even more prefeπed 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
32 ring to A is optionally substituted by R , the other carbon adjacent to the 6 carbon at the point of attachment is optionally substituted by R , a carbon
32 adjacent to R and two atoms from the carbon at the point of attachment is
33 36 optionally substitoted by R , a carbon adjacent to R and two atoms from the
35 carbon at the point of attachment is optionally substituted by R , and any
33 35 34 carbon adjacent to both R and R is optionally substituted by R ;
32 33 34 35 36
R , R , R , R , andR are independenuy 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, tiialkylsilyl, 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
32 33 34 35 36 with one or more of the group consisting of R , R , R , R , and R ;
B is optionally a C3-C12 cycloalkyl or a C4-C9 satorated heterocyclyl,
33 wherein each ring carbon is optionally substituted with R , a ring carbon other than the ring carbon at the point of attachment of B to A is optionally substituted with oxo provided that no more than one ring carbon is substituted by oxo at the same time, ring carbons and a nitrogen adjacent to the carbon
9 13 atom at the point of attachment are optionally substituted with R or R , a ring
9 carbon or mtrogen adjacent to the R position and two atoms from the point of
attachment is optionally substituted with R , a ring carbon or nitrogen adjacent
13 to the R position and two atoms from the point of attachment is optionally
12 substitoted with R , a ring carbon or nitrogen three atoms from the point of
10 . 11 attachment and adjacent to the R position is optionally substitoted with R , a ring carbon or nitrogen three atoms from the point of attachment and adjacent
12 33 to the R position is optionally substitoted with R , and a ring carbon or
11 nitrogen four atoms from the point of attachment and adjacent to the R and
33 34
R positions is optionally substituted with R ;
9 10 11 12 13
R , R , R , R , and R are independendy 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, heterocyclyldkylamino, alkylthio, alkylsulfinyl, arylsulfmyl, 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; 15 7
A is a bond or (CH(R ))pa-(W )rr wherein rr is 0 or 1, pa is an
7 . integer selected from 0 through 3, and W is selected from the group
consisting of O, S, C(O), (R?)NC(O), (R?)NC(S), and N(R?);
7 R is selected from the group consisting of hydrido, hydroxy and alkyl;
R is selected from the group consisting of hydrido, hydroxy, halo, alkyl, and haloalkyl;
X is selected from the group consisting of hydrido, amino, alkyl, cyano, halo, haloalkyl, haloalkoxy, aminoalkyl, hydroxy, alkoxy, hydroxyalkyl, and alkylthio; R2 is Z°-Q; o 41 42
Z is selected from the group consisting of a bond, (CR R )q
41 o 42 wherein q is 1 or 2, and (CH(R ))g-W -(CH(R ))p wherein g and p are integers independently selected from 0 through 3 and w is selected from the group consisting of O, S, C(O), S(O), N(R41), and ON(R41);
Z° 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
41 42 CR =CR , 1,2-cyclopropyl, 1,2-cyclobutyl, 1,2-cyclohexyl, 13-cyclohexyl,
1,2-cyclopentyl, 13-cyclopentyl, 2,3-moφholinyl, 2,4-moφholinyl, 2,6-moφholinyl, 3,4-moφholinyl, 3,Smoφholinyl, 1,2-piperazinyl, 13-piperazinyl, 2,3-piperazinyl, 2,6-piperazinyl, 1 ,2-piperidinyl, 1 ,3-piperidinyl, 2,3-piperidinyl, 2,4-piperidinyl, 2,6-piperidinyl, 3,4-piperidinyl, l,2-pyrrolidinyl,13-pyrrolidinyl, 2,3-pyrrolidinyl, 2,4-pyπolidinyl, 2,5-pyπolidinyl, 3,4-pyπolidinyl, 2,3-tetrahydrofuranyl, 2,4-tetrahydrofuranyl,
2,5-tetrahydrofuranyl, and 3,4-tetrahydrofuranyl, wherein Z is directly bonded to the 4-pyrone ring and '^ is optionally substituted with one or more
9 10 11 12 13 substituents selected from the group consisting of R , R , R , R , and R ; 41 42
R and R 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 o 9 ring to Z is optionally substituted by R , the other carbon adjacent to the
13 carbon at the point of attachment is optionally substituted by R , a carbon
9 adjacent to R and two atoms from the carbon at the point of attachment is
10 13 optionally substitoted by R , a carbon adjacent to R and two atoms from the
12 carbon at the point of attachment is optionally substituted by R , and any
10 12 11 carbon adjacent to both R and R is optionally substituted by R , with the proviso that Q is other than a phenyl when Z is a bond;
Q is optionally hydrido with the proviso that Z is selected from other than a bond;
4a 4a
K is CHR wherein R is selected from the group consisting of hydrido, hydroxyalkyl, alkyl, alkoxyalkyl, alkylthioalkyl, and haloalkyl; E is selected from the group consisting of a bond, C(O)N(H),
(H)NC(O), (R7)NS(O)2, and S(O)2N(R7);
Y is Qh-QS;
37 38 Q is (CR R )b wherein b is an integer selected from 1 through 4,
37 R is selected from the group consisting of hydrido, alkyl, and haloalkyl, and O
R 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
37 38 is bonded to (CR R )jj at the same time, with the still further proviso that said aroyl and said heteroaroyl are optionally substituted with one or more , • • ^ 16 _ 17 ^18 , 19 substituents selected from the group consisting of R , R , R , and R , with another further proviso that said aroyl and said heteroaroyl are bonded to the CR R that is directly bonded to E , with still another further proviso
37 38 that no more than one alkyl or one haloalkyl is bonded to a CR R 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;
R 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;
16 19 R or R is optionally selected from the group consisting of
proviso that R , R , and Q are not simultaneously hydrido; b 20 21 Q is selected from the group consisting of NR R , hydrido,
N(R26)C(NR25)N(R23)(R24), and QNR^NR^R24, with the proviso that
20 21 no more than one of R and R is selected from the group consisting of hydroxy, amino, alkylamino, and dialkylamino at the same time and with the
23 24 further proviso that no more than one of R and R is selected from the group consisting of hydroxy, amino, alkylamino, and dialkylamino at the same time;
20 21 23 24 25 26
R , R , R , R , R , and R are independently selected from the group consisting of hydrido, alkyl, hydroxy, amino, alkylamino and (halkylarnino. 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
32 ring to A is optionally substitoted by R , the other carbon adjacent to the
36 carbon at the point of attachment is optionally substituted by R , a carbon
32 adjacent to R and two atoms from the carbon at the point of attachment is
optionally substituted by R , a carbon adjacent to R and two atoms from the
35 carbon at the point of attachment is optionally substitoted by R , and any
33 35 34 carbon adjacent to both R and R is optionally substituted by R ;
32 33 34 35 36
R , R , R , R , and R are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkoxy, hydroxy, amino, alkoxyamino, alkylamino, alkylthio, amidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboalkoxy, carboxy, carboxamido, cyano, and Q ;
15 7
A is a bond or (CH(R ))pa-(W )π wherein rr is 0 or 1, pa is an
7 7 integer selected from 0 through 3, and W is N(R );
7 R is hydrido or alkyl;
R is selected from the group consisting of hydrido, halo, alkyl, and haloalkyl; X is selected from the group consisting of hydrido, alkyl, halo, haloalkyl, aminoalkyl, and hydroxyalkyl; R2 is Z°-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 o 9 ring to Z is optionally substituted by R , the other carbon adjacent to the
13 carbon at the point of attachment is optionally substitoted by R , a carbon
9 adjacent to R and two atoms from the carbon at the point of attachment is
10 13 optionally substituted by R , a carbon adjacent to R and two atoms from the
carbon a, the point of a«actaen, is optionaiiy substituted by R12, and any
10 12 11 carbon adjacent to both R and R is optionally substituted by R ;
9 11 13
R , R , and R are independentiy 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;
10 12
R and R 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;
Y is phenyl or a heteroaryl of 5 or 6 ring members, wherein one carbon of said phenyl or said heteroaryl is substituted by Q , a carbon two or three g atoms from the point of attachment of Q to said phenyl or said heteroaryl is b s substitoted by Q , a carbon adjacent to the point of attachment of Q is
17 optionally substituted by R , another carbon adjacent to the point of 10 1_ attachment of Q is optionally substituted by R , a carbon adjacent to Q is
16 b optionally substituted by R , and another carbon adjacent to Q is optionally
19 substitoted by R ;
„16 17 „18 19 . , , , ,
R , R , R , and R are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, haloalkylthio, alkoxy, hydroxy, amino, alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, and cyano;
R or R is optionally NR R or C(NR )NR R , with the
proviso that R , R , and Q are not simultaneously hydrido; b 20 21
Q is selected from the group consisting of NR R , hydrido, and
25 23 24 C(NR )NR R ;
20 91 93 24 25
R , R ,R , R , and R are independently hydrido or alkyl;
QS is CH2. In a further most prefeπed 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 32 point of attachment of B to A with one or more of the group consisting of R ,
33 34 35 , 36 R , R , R , and R ;
32 33 34 35 36
R , R , R , R , and R are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkoxy, hydroxy, amino, alkoxyamino, alkylamino, alkylthio, amidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboalkoxy, carboxy, carboxamido, cyano, and Q ;
15 7
A is a bond or (CH(R ))pa-(W )rr wherein rr is 0 or 1, pa is an
7 7 integer selected from 0 through 3, and W is N(R );
7 R is hydrido or alkyl;
R is selected from the group consisting of hydrido, halo, alkyl, and haloalkyl;
Λ is selected from the group consisting of hydrido, alkyl, halo, haloalkyl, aminoalkyl, and hydroxyalkyl; R2 is Z°-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 o 9 ring to Z is optionally substituted by R , the other carbon adjacent to the
13 carbon at the point of attachment is optionally substitoted by R , a carbon
9 adjacent to R and two atoms from the carbon at the point of attachment is
optionally substituted by R , a carbon adjacent to R and two atoms from the
carbon at *e point of attachment is optional substituted by R12 and any
10 12 11 carbon adjacent to both R and R is optionally substituted by R ; 9 11 13
R , R , and R are independentiy 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;
10 12 R and R 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; Y is phenyl or a heteroaryl of 5 or 6 ring members, wherein one carbon s of said phenyl or said heteroaryl is substituted by Q , a carbon two or three s atoms from the point of attachment of Q to said phenyl or said heteroaryl is b s substituted by Q , a carbon adjacent to the point of attachment of Q is
17 optionally substitoted by R , another carbon adjacent to the point of
attachment of Q is optionally substituted by R , a carbon adjacent to Q is
16 b optionally substitoted by R , and another carbon adjacent to Q is optionally
19 substitoted by R ;
16 17 18 19 . , , , ,
R , R , R , and R are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, haloalkylthio, alkoxy, hydroxy, amino, alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, and cyano;
R or R is optionally selected from the group consisting of
20 21 26 25 23 24 25 23 24
NR R ,N(R )C(NR )N(R )(R ), and C(NR )NR R , with the
proviso that R , R , and Q are not simultaneously hydrido; b 20 21
Q is selected from the group consisting of NR R , hydrido,
26 25 23 24 25 23 24
N(R )C(NR )N(R )(R ), and C(NR )NR R ;
20 21 23 24 25 26
R , R , R , R , R , and R 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
33 each ring carbon is optionally substituted with R , a ring carbon other than the ring carbon at the point of attachment of B to A is optionally substitoted 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
9 13 of attachment are optionally substituted with R or R , a ring carbon or
nitrogen adjacent to the R position and two atoms from the point of attachment
10 13 is optionally substituted with R , a ring carbon or nitrogen adjacent to the R position and two atoms from the point of attachment is optionally substituted
12 with R , a ring carbon or nitrogen three atoms from the point of attachment
and adjacent to the R position is optionally substitoted with R , a ring carbon or nitrogen three atoms from the point of attachment and adjacent to the
12 33
R position is optionally substitoted with R , and a ring carbon or nitrogen 11 33 four atoms from the point of attachment and adjacent to the R and R
34 positions is optionally substituted with R ;
9 11 13
R , R , and R 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;
R and R 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;
33 34
R and R 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;
33 b
R is optionally Q ;
15 7
A is a bond or (CH(R ))pa-(W )rr wherein π is 0 or 1, pa is an
7 7 integer selected from 0 through 3, and W is N(R );
7 R is hydrido or alkyl;
R is selected from the group consisting of hydrido, halo, alkyl, and haloalkyl;
X is selected from the group consisting of hydrido, alkyl, halo, haloalkyl, aminoalkyl, and hydroxyalkyl;
R2 is Z°-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 o 9 ring to Z is optionally substituted by R , the other carbon adjacent to the 13 carbon at the point of attachment is optionally substitoted by R , a carbon
9 adjacent to R and two atoms from the carbon at the point of attachment is
10 13 optionally substituted by R , a carbon adjacent to R and two atoms from the
12 carbon at the point of attachment is optionally substituted by R , and any
carbon adjacent to both R and R is optionally substituted by R ;
Y is phenyl or a heteroaryl of 5 or 6 ring members, wherein one carbon of said phenyl or said heteroaryl is substituted by Q , a carbon two or three
atoms from the point of attachment of Q to said phenyl or said heteroaryl is b s substituted by Q , a carbon adjacent to the point of attachment of Q is
17 optionally substitoted by R , another carbon adjacent to the point of
attachment of Q is optionally substituted by R , a carbon adjacent to Q is
optionally substituted by R , and another carbon adjacent to Q is optionally
19 substituted by R ;
„16 17 18 19 . , , , ,
R , R , R , and R are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, haloalkylthio, alkoxy, hydroxy, amino, alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, and cyano;
T, 16 „ 19 . • „ m20 21 m25xxm23 24 . , , R or R is optionally NR R or C(NR )NR R , with the
16 19 b proviso that R , R , and Q are not simultaneously hydrido;
Q is selected from the group consisting of NR R , hydrido, and
25 23 24 C(NRZ )NR^R ;
20 21 23 24 25
R , R , R , R , and R are independently hydrido or alkyl; Q 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-ρyπolyl, 2-imidazolyl, 4-imidazolyl, 3-pyrazolyI, 4-pyrazolyl, l,2,4-triazol-3-yl, l,2,4-triazol-5-yl, l,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-Syl, l,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, l,3,5-triazin-2-yl, l,2,4-triazin-3-yl, l,2,4-triazin-5-yl, l,2,4-triazin-6-yl, l,2,3-triazin-4-yl, and l,23-triazin-5-yl,, wherein a carbon adjacent to the carbon at the point of attachment is optionally
32 substitoted by R , the other carbon adjacent to the carbon at the point of
36 32 attachment is optionally substituted by R , a carbon adjacent to R and two atoms from the carbon at the point of attachment is optionally substituted by
33 36
R , a carbon adjacent to R and two atoms from the carbon at the point of
35 attachment is optionally substituted by R , and any carbon adjacent to both
33 35 34
R and R is optionally substituted by R ;
32 33 34 35 36
R , R , R , R , andR are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, methyl, ethyl, isopropyl, propyi, 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,
2,23 3-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-l-trifluoromethyl-l-hydroxyethyl, carboxymethyl, methoxycarbonyl, ethoxycarbonyl, amidocarbonyl, N-methylamidocarbonyl, N,N-dimethylamidocarbonyl, cyano, and Q ;
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, l-methyl-2-butenyl, l-methyl-3-butenyl, l-methyl-2-butynyl, 3-pentyl, l-ethyl-2-propenyl, 2-methylbutyl, 2-methyl-2-butenyl, 2-methyl-3-butenyl, 2-methyl-3-butynyl, 3-methylbutyl, 3-methyl-2-butenyl, 3-methyl-3-butenyl, 1-hexyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 2-hexyl, l-methyl-2-pentenyl, l-methyl-3-pentenyl, l-methyl-4-pentenyl, l-methyl-2-pentynyl, l-methyl-3-pentynyl, 3-hexyl, l-ethyl-2-butenyl, l-ethyl-3-butenyl, l-propyl-2-propenyl, l-ethyl-2-butynyl, 1-heptyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 5-heptynyl, 2-heptyl, l-methyl-2-hexenyl, l-methyl-3-hexenyl, 1-methyl^l-hexenyl, l-methyl-5-hexenyl, l-methyl-2-hexynyl, l-methyl-3-hexynyl, l-methyl-4-hexynyl, 3-heptyl, l-ethyl-2-pentenyl, l-ethyl-3-pentenyl, l-ethyl-4-pentenyl, l-butyl-2-ρropenyl, l-ethyl-2-pentynyl, l-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, l-methyl-2-heptenyl, l-methyl-3-heptenyl, l-methyl-4-heptenyl, l-methyl-5-heptenyl, l-methyl-6-heptenyl, l-methyl-2-heptynyl, l-methyl-3-heptynyl, l-methyl-4-heptenyl, l-methyl-5-heptenyl, l-methyl-6-heptenyl, l-methyl-2-heptenyl, l-methyl-3-heptynyl, l-methyl-4-heptynyl, l-methyl-5-heptynyl, 3-octyl, l-ethyl-2-hexenyl, l-ethyl-3-hexenyl, l-ethyl-4-hexenyl, l-ethyl-2-hexynyl, l-ethyl-3-hexynyl, l-ethyl-4-hexynyl, l-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, l-butyl-2-butynyl, l-butyl-3-butenyl, 2,2,2-trifluoroethyl, 2,2-difluoropropyl, 4-trifluoromethyl-5,5, trifluoropentyl, 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
„ 32 33 π34 35 , 36 consisting of R , R , R , R , and R ;
B is optionally selected from the group consisting of cyclopropyl, cyclobutyl, oxetan-2-yl, oxetan-3-yl, azetidin-1-yl, azetidin-2-yl, azetidin-3-yl, thiaetan-2-yl, thiaetan-3-yl, cyclopentyl, cyclohexyl, adamantyl, norbomyl, 3-trifluoromethylnorbornyl, 7-oxabicyclo[2.2. l]heptan-2-yl, bicyclo[3.1.0]hexan-6-yl, cycloheptyl, cyclooctyl, 2-moφholinyl, 3-moφholinyl, 4-moφholinyl, 1-piperazinyl, 2-piperazinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 1-pyπolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-dioxanyl, 4H-2-ρyranyl, 4H-3-pyranyl, 4H-4-ρyranyl, 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
33 ring carbon is optionally substituted with R , a ring carbon and nitrogen atoms adjacent to the carbon atom at the point of attachment is optionally
9 13 9 substituted with R or R , a ring carbon or nitrogen atom adjacent to the R position and two atoms from the point of attachment is optionally substituted
10 13 with R , and a ring carbon or nitrogen atom adjacent to the R position and
12 two atoms from the point of attachment is optionally substituted with R ;
9 10 11 12 13 R , R , R , R , and R are independentiy 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-l-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-(l-methyl- l-phenylethyl)amidocarbonyl, N-benzyl ami dosulf onyl , N-(2-chl orobenzyl)ami dosulf onyl , N-ethylamidocarbonyl, N-isopropylamidocarbonyl, N-propylamidocarbonyl, N-isobutylamidocarbonyl, N-(2-butyl)amidocarbonyl, N-cy clobutylamidocarbonyl , 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-trifluoromethoxybenzyloxy, 4-trifluoromethoxybenzyloxy, 3-trifluoromethoxyphenoxy, 4-trifluoromethoxyphenoxy, 3-trifluoromethylbenzyloxy, 4-trifluoromethylbenzyloxy, 2,4-bis-trifluoromethylbenzyloxy, 3-trifluoromethylbenzyl, ,5-bis-trifluoromethylbenzyloxy, 4-trifluoromethylphenoxy, 3-trifluoromethylphenoxy, 3-trifluoromethylthiobenzyIoxy, 4-trifluoromethyltlήobenzyloxy, 2,3,4-trifluorophenoxy, 2,3,5-trifluorophenoxy, 3-pentafluoroethylphenoxy, 3-(l,l,2,2-tetrafIuoroethoxy)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), (O)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-aminopropyl, methylamino, dimethylamino, cyano, methyl, ethyl, isopropyl, propyl, butyl, trifluoromethyl, pentafluoroethyl, 2,2,2- trifluoroethyl, 3,33-trifluoroρroρyl, 2,2 3 -pentafluoropropyl, methoxy, ethoxy, propoxy, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 3- hydroxypropyl, 2,3-dihydroxypropyl, methoxyamino, ethoxyamino, methylthio, ethylthio, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro, and bromo;
R2 is Z°-Q;
Z is selected from the group consisting of a bond, CH2, CH2CH , 0,
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-ρyrrolyl, 3-pyrrolyl, 2-imidazolyl, 4-imidazolyl, 3-pyrazolyl, 4-pyrazolyl, l,2,4-triazol-3-yl, 1,2,4-triazol-Syl, l,2;4-oxadiazol-3-yl, 1,2,4- oxadiazol-Syl, l,3,4-oxadiazol-3-yl, 1,3,4-oxadiazol-Syl, 3-isothiazolyl, 5- isothiazolyl, 2-oxazolyl, 2-thiazolyl, 3-isoxazolyl, 5-isoxazolyl, 2-pyridyl, 3- pyridyl, 4-pyridyl, 2-pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl, Spyrimidinyl, 3- pyridazinyl, 4-pyridazinyl, l,3,Striazin-2-yl, l,2,4-triazin-3-yl, 1,2,4-triazin-Syl, l,2,4-triazin-6-yl, l,2,3-triazin-4-yl, and 1,2,3-triazin-Syl, wherein a carbon
9 adjacent to the carbon at the point of attachment is optionally substituted by R , the other carbon adjacent to the carbon at the point of attachment is optionally
13 9 substituted by R , a carbon adjacent to R and two atoms from the carbon at
the point of attachment is optionally substituted by R , a carbon adjacent to
13 R and two atoms from the carbon at the point of attachment is optionally
12 . 10 12 substituted by R , and any carbon adjacent to both R and R is optionally
11 substituted by R
.4a ,4b
K is CR 11 wherein R "~ and R ' " 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;
E° is a bond, C(O)N(H), (H)NC(O), and S(O)2N(H); Ϊ is selected from the group of formulas consisting of:
, b . s Λ 16 „ 17 e 18 „ „19,
1-Q -4-Q -2-R -3-R -5-R -6-R benzene,
18 19
3-Qb-6-QS-2-R16-S R -4-R pyridine,
„ Xo „ Λs „ „ 16 „ „ 18
2-Q -5-Q -3-R -6-R pyrazme,
^ «18 ,π19 .Λ .
.Q -6-QS-2-R185-R -4-R pyπdazme,
-Qb-5-QS-4-R17-6-R18pyrimidine,
b s 16 19 -Q -2-Q -4-R -6-R pyrimidine,
b s 16 19 _Q _5_Q _4_RX _ .R thiophene, -Q -5-QS-3-R16-4-R17thiophene,
b s 16 19 -Q -5-Q -4-R -2-R furan,
2-Qb-5-QS-3-R16-4-R17furan,
,-. ^ D ,- ^ s Λ ^. 6 „ ^19
3-Q -5-Q -4-R -2-R pyrrole,
,, ^b „ Λs „ „16 „ 17
2-Q -5-Q -3-R -4-R pyπole,
b s 19 4-Q -2-Q -5-R imidazole,
2-Q -4-QS-5-R imidazole,
-Q -5-Q -4-R isoxazole,
2-Q -5-QS-4-R pyrazole,
b s 19 4-Q -2-Q -5-R thiazole, and
2-Q -5-Q -4-R thiazole;
1 1 *7 i Q 1 Q
R , R , R , and R 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; b 20 21
Q is selected from the group consisting of NR R , hydrido,
C(NR25)NR23R24 and N(R26)C(NR25)N(R23)(R24), with the proviso that
20 21 no more than one of R and R is hydroxy, N-methylamino, and N,N-
23 24 dimethylamino at the same time and that no more than one of R and R is hydroxy, N-methylamino, and N,N-dimethylamino at the same time;
20 21 23 24 25 26
R , R , R , R , R , and R are independently selected from the group consisting of hydrido, methyl, ethyl, propyl, butyl, isopropyl, hydroxy, 2- aminoethyl, 2-(N-methylamino)ethyl, and 2-(N,N-dimethylamino)ethyl;
Q is 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 prefeπed 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-pyπolyl, 3-pyrrolyl, 2-imidazolyl, 4-imidazolyl, 3-ρyrazolyl, 4-pyrazolyl, 2-thiazolyl, 3-isoxazolyl, Sisoxazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl, Spyrimidinyl, 3-pyridazinyI, 4-pyridazinyl, and l,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
32 optionally substitoted by R , the other carbon adjacent to the carbon at the ^r o^ point of attachment is optionally substituted by R , a carbon adjacent to R and two atoms from the carbon at the point of attachment is optionally substituted by , a car on a acent to and two atoms from the carbon at
35 the point of attachment is optionally substituted by R , and any carbon
33 35 34 adjacent to both R and R is optionally substituted by R ;
32 33 34 35 36
R , R , R , R , and R are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, 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-l-hydroxyethyl, methoxycarbonyl, ethoxycarbonyl, 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;
R are independently selected from the group consisting of hydrido, methyl, ethyl, isopropyl, propyl, carboxy, amidino, guanidino, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, aminomethyl, 1-aminoethyl, 2-aminoethyl, N-methylamino, dimethylamino, N-ethylamino, methylthio, ethylthio, isopropylthio, trifluoromethylthio, methylsulfinyl, ethylsulfinyl, methylsulfonyl, ethylsulfonyl, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, 2,2333-pentafluoropropyl, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro, bromo, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, and cyano;
„16 19 . . „ ^TT.25N1 23 24 . , , . , 16
R or R is optionally C(NR )NR R with the proviso that R ,
19 b
R , and Q are not simultaneously hydrido; Γ 2 OΛ.
Q is C(NR )NR R or hydrido, with the proviso that no more than
23 24 one of R and R is hydroxy at the same time;
23 24 25 R , R , and R 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 formula:
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, l-methyl-2-butenyl, l-methyl-3-butenyl, l-methyl-2-butynyl, 3-pentyl, l-ethyl-2-propenyl, 2-methylbutyl, 2-methyl-2-butenyl, 2-methyl-3-butenyl, 2-methyl-3-butynyl, 3-methylbutyl, 3-methyl-2-butenyl, 3-methyl-3-butenyl, 1-hexyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 2-hexyl, l-methyl-2-pentenyl, l-methyl-3-pentenyl, l-methyl-4-pentenyl, l-methyl-2-pentynyl, l-methyl-3-pentynyl, 3-hexyl, l-ethyl-2-butenyl, l-ethyl-3-butenyl, l-propyl-2-propenyl, l-ethyl-2-butynyl, 1-heptyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, Sheptenyl, 6-heptenyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 5-heptynyl, 2-heptyl, l-methyl-2-hexenyl, l-methyl-3-hexenyl, 1 -methyl -4-hexenyl, 1-methyl-Shexenyl, l-methyl-2-hexynyl, l-methyl-3-hexynyl, l-methyl-4-hexynyl, 3-heptyl, l-ethyl-2-pentenyl, l-ethyl-3-pentenyl, l-ethyl-4-pentenyl, l-butyl-2-propenyl, l-ethyl-2-pentynyl, l-ethyl-3-pentynyl, 2,2,2-trifluoroethyl, 2,2-difluoropropyl, 4-trifluoromethyl- 5,5,5-trifluoropentyl, 4-trifluoromethylpentyl, 5,5,6,6,6-pentafluorohexyl, 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
32 33 34 35 36 A with one or more of the group consisting of R , R , R , R , and R ;
32 33 34 35 36
R , R , R , R , and R are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, methoxyamino, ethoxyamino, acetamido, trifluoroacetamido, N-methylamino, dimethylamino, N-ethylamino, methylthio, ethylthio, isopropylthio, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, 2,2,333-pentafluoropropyl, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro, bromo, amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro-l-hydroxyethyl, methoxycarbonyl, ethoxycarbonyl, amidocarbonyl, N-methylamidocarbonyl,
N,N-dimethylamidocarbonyl, cyano, and Q ;
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;
„16 17 „18 19 . , , , ,
R , R , R , and R are independently selected from the group consisting of hydrido, methyl, ethyl, isopropyl, propyl, carboxy, amidino, guanidino, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, aminomethyl, 1-aminoethyi, 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;
R or R is optionally selected from the group consisting of NR R ,
C(NR25)NR23R24, and N(R26)C(NR25)N(R23)(R24), with the proviso that R16,
19 b
R , and Q are not simultaneously hydrido; b 20 21
Q is selected from the group consisting of NR R , hydrido, m25 23 24 T/T,26 ^/ T 25 τ 23 24, C(NR )NR R , and N(R )C(NR )N(R )(R ), with the proviso that no
20 21 more than one of R and R is hydroxy at the same time and with the further
23 24 proviso that no more than one of R and R is hydroxy at the same time; 20 21 23 24 25 26
R , R , R , R , R , and R are independently selected from the group consisting of hydrido, methyl, ethyl, propyl, butyl, isopropyl, and hydroxy.
In still another more prefeπed 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-moφholinyl, 3-moφholinyl, 4-moφholinyl, 1-piperazinyl, 2-piperazinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-ρiperidinyl, 1 -pyrrolidinyl, 2-pyπolidinyl, 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-tetrahydroρyranyl, 4-tetrahydropyranyl, 2-tetrahydrothienyl, and 3-tetrahydrothienyl, wherein each ring carbon is
33 optionally substituted with R , ring carbons and a nitrogen adjacent to the
9 carbon atom at the point of attachment are optionally substituted with R or
13 9 R , a ring carbon or nitrogen adj acent to the R position and two atoms from
the point of attachment is optionally substituted with R , and a ring carbon or
13 nitrogen adjacent to the R position and two atoms from the point of
12 attachment is optionally substitoted with R ;
33 R is selected from the group consisting of hydrido, amidino, guanidino, carboxy, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, methoxyamino, ethoxyamino, acetamido, tiifluoroacetamido, N-methylamino, dimethylamino, N-ethylamino, methylthio, ethylthio, isopropylthio, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl,
2,2333-pentafluoropropyl, trifluoromethoxy, 1,1,2,2-tefrafluoroethoxy, fluoro, chloro, bromo, amidosulfonyl, N-methylamidosulfonyl,
N,N-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro-l-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;
„ 16 17 „18 , 19 . , , , ,
R , R , R , and R are independently selected from the group consisting of hydrido, methyl, ethyl, isopropyl, propyl, carboxy, amidino, guanidino, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, aminomethyl, 1-aminoethyl, 2-aminoethyl, N-methylamino, dimethylamino, N-ethylamino, methylthio, ethylthio, isopropylthio, trifluoromethylthio, methylsulfinyl, ethylsulfinyl, methylsulfonyl, ethylsulfonyl, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, 2,2,333-pentafluoropropyl, trifluoromethoxy, 1 , 1 ,2,2-tetrafluoroethoxy , fluoro, chloro, bromo, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, and cyano;
16 19 25 23 24 16
R or R is optionally C(NR )NR R with the proviso that R ,
R , and Q are not simultaneously hydrido;
• C O
Q is C(NR )NR R or hydrido, with the proviso that no more than
23 24 one of R and R is hydroxy at the same time;
23 24 25
R , R , and R are 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;
X° 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;
R2 is Z°-Q;
Z is selected from the group consisting of a bond, CH2, CH2CH2, 0,
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, Sisoxazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl, Spyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, and l,3,Striazin-2-yl, wherein a carbon adjacent to the carbon at the point of attachment of said phenyl or heteroaryl ring to Z is
9 optionally substituted by R , the other carbon adjacent to the carbon at the point
13 9 of attachment is optionally substituted by R , a carbon adjacent to R and two atoms from the carbon at the point of attachment is optionally substituted by
10 13
R , a carbon adjacent to R and two atoms from the carbon at the point of
attache is optional substito,ed by R» and any carbon adjacent to bo*
R and R is optionally substituted by R ; 9 11 13
R , R , and R are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, methyl, ethyl, propyl, isopropyl, 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-hydroxyethyl, 2,2,2-trifluoro- 1-hydroxyethyl, amidocarbonyl, N-methylamidocarbonyl, N,N-dimethylamidocarbonyl, and cyano;
R and R are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, carboxymethyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, methoxyamino, ethoxyamino, acetamido, tiifluoroacetamido, aminomethyl, 1-aminoethyl, 2-aminoethyl, N-methylamino, dimethylamino, N-ethylamino, methanesulfonamido, amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro- 1-hydroxyethyl, methoxycarbonyl, ethoxy carbonyl, amidocarbonyl, N-methylamidocarbonyl, N,N-dimethylamidocarbonyl, N-benzylamidocarbonyl, N-(2-chlorobenzyl)amidocarbonyl,
N-(3-fluorobenzyl)amidocarbonyl, N-(2-trifluoromethylbenzyl)amidocarbonyl, N-( 1 -phenylethyl)amidocarbonyl, N-( 1 -methyl- 1 -phenylethyl)amidocarbonyl, N-benzylamidosulfonyl, N-(2-chlorobenzyl)amidosulfonyl, N-ethylamidocarbonyl, N-isopropylamidocarbonyl, N-propylamidocarbonyl, N-isobutylamidocarbonyl, N-(2-buxyl)amidocarbonyl,
N-cyclobutylamidocarbonyl, N-cyclopentylamidocarbonyl, N-cyclohexylamidocarbonyl, fluoro, chloro, bromo, cyano, cyclobutoxy, cyclohexoxy, cyclohexylmethoxy, 4-trifluoromethycyclohexylmethoxy, cyclopentoxy, benzyl, benzyloxy, 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 ,Sdifluorobenzyloxy, 4-difluoromethoxybenzyloxy, 23-difluorophenoxy, 2,4-difluorophenoxy, 2,5-difluorophenoxy, ,5-dimethylphenoxy, 3,4-dimethylphenoxy, 3,4-dimethylbenzyloxy, 3,Sdimethylbenzyloxy, 4-ethoxyphenoxy, 4-ethylbenzyloxy, 3-ethylphenoxy, 4-ethylaminophenoxy, 3-ethyl-Smethylphenoxy, 4-fluorobenzyloxy, 2-fluoro-3-trifluoromethylbenzyloxy, 3-fluoro-Strifluoromethylbenzyloxy, 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-ρhenylethylamino, phenylsulfonyl-, 3-trifluoromethoxybenzyloxy, 4-trifluoromethoxybenzyloxy, 3-trifluoromethoxyphenoxy, 4-trifluoromethoxyphenoxy, 3-trifluoromethylbenzyloxy, 4-trifluoromethylbenzyloxy, 2,4-bis-trifluoromethylbenzyloxy, 3-trifluoromethylbenzyl, 3 ,5-bis-trifluoromethylbenzyloxy , 4-trifluoromethylphenoxy , 3-trifluoromethylphenoxy, 3-trifluoromethylthiobenzyloxy,
4-trifluoromethylthiobenzyloxy, 23,4-trifluorophenoxy, 2,3,5-trifluorophenoxy, 3-pentafluoroethylphenoxy, 3-(l,l,2,2-tetrafluoroethoxy)phenoxy, and 3-trifluoromethylthiophenoxy;
Y^ is selected from the group of formulas consisting of:
, 3 Λ s „ ^16 „ „17 e „ 18 ,. 19L
1-Q -4-Q -2-R -3-R -5-R -6-R benzene,
-Qb-5-QS-6-R17-4-R18-3-R19pyridine,
> , ^s, 16 ^ 18 λ 19 .,. -Q -6-Q -2-R -5-R -4-R pyridine,
-Qb-5-QS-3-R16-6-R18pyr£izrne,
-Qb-6-QS-2-R18-5-R18-4-R1 pyridazine,
b s 17 18 -Q -5-Q -4-R -6-R pyrimidine,
-Q -2-QS-4-R -6-R pyrimidine,
Λt ,- ^ s Λ ^16 „ „19 , . , -Q -5-Q -4-R -2-R thiophene,
,16 ^17 ,. L
2-Qb-5-QS-3- R -4-R thiophene,
b s 16 19 3-Q -5-Q -4-R -2-R furan,
2-Qb-5-QS-3-R16-4-R17furan,
„ > , s Λ ^16 ,, 19
3-Q -5-Q -4-R -2-R pyπole,
■1 -j £~ I T -Q -5-QS-3-R -4-R pyrrole,
b s 19 -Q -2-Q -5-R imidazole,
_Q _4-Q -5_R imidazole,
„ Λb _ , s , 16.
3-Q -5-Q -4-R isoxazole,
5-Q -3-Q -4-R isoxazole,
_ Λb „ Λs „ 16 ,
2-Q -5-Q -4-R pyrazole,
b s 19 4-Q -2-Q -5-R thiazole, and
2-Q -5-Q -4-R thiazole;
Q 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-pyπolyl, 3-ρyπolyI, 2-imidazolyl, 4-imidazolyl, 3-pyrazolyl, 4-pyrazolyl, 2-thiazolyl, 3-isoxazolyl, and Sisoxazolyl, wherein a carbon adjacent to the carbon at the point of attachment of said phenyl or heteroaryl
32 ring to A is optionally substituted by R , the other carbon adjacent to the
36 carbon at the point of attachment is optionally substitoted by R , a carbon
32 adjacent to R and two atoms from the carbon at the point of attachment is
33 36 optionally substitoted by R , a carbon adjacent to R and two atoms from the
35 carbon at the point of attachment is optionally substitoted by R , and any
33 35 34 carbon adjacent to both R and R is optionally substituted by R ;
R , 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 Q ;
A is selected from the group consisting of a bond, NH, N(CH3), CH2,
CH3CH, and CH2CH2;
^b . .TD20 21 TD25. ™23_24 Q is NR R or C(NR )NR R ; 20 21 23 24 25
R , R , R , R , and R are 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-pentynyl, 2-ρentyl, 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, l-methyl-2-pentenyl, l-methyl-3-pentenyl, l-methyl-2-pentynyl, l-methyl-3-pentynyl, 3-hexyl, l-ethyl-2-butenyl, 1-heptyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, Sheptenyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 5-heptynyl, 2-heptyI, l-methyl-2-hexenyl, l-methyl-3-hexenyl, l-methyl-4-hexenyl, l-methyl-2-hexynyl, l-methyl-3-hexynyl, l-methyl-4-hexynyl, 3-heptyl, l-ethyl-2-pentenyl, l-ethyl-3-pentenyl, l-ethyl-2-pentynyl, l-ethyl-3-pentynyl, 2,2,2-trifluoroethyl, 2,2-difluoropropyl , 4-trifluoromethyl-5,5,5-trifluoropentyl,
4-trifluoromethylpentyl, 5,5,6,6,6-pentafluorohexyl, and 3,3,3-trifluoropropyl, wherein each member of group B is optionally substitoted at any carbon up to and including 5 atoms from the point of attachment of B to A with one or more
32 33 34 35 36 of the group consisting of R , R , R , R , and R ;
32 33 34 35 36 R , R , R , R , and R are independently selected from the group consisting of hydrido, amidino, guanidino, methyl, ethyl, methoxy, ethoxy, hydroxy, amino, N-methylamino, dimethylamino, methoxyamino, methylthio, ethylthio, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, fluoro, chloro, bromo, amidosulfonyl, N-methylamidosulfonyl, hydroxymethyl, amidocarbonyl, carboxy, cyano, and Q ;
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(CH ),
CH2N(CH2CH3), CH2CH2N(CH3), and C^C^^CT^C^) with the proviso that B is hydrido; b 20 21
Q is selected from the group consisting of NR R ,
25 23 24 26 25 23 24
C(NR )NR R , and N(R )C(NR )N(R )(R ); τ,20 21 23 24 „25 , 26 . , , , ,
R , R , R , R , R , and R are independently selected from the group consisting of hydrido, methyl, and ethyl.
In still another most prefeπed 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-moφholinyl, 3-moφholinyl, 4-moφholinyl, 1-piperazinyl, 2-piperazinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 1-pyπolidinyl, 2-pyπolidinyl, 3-pyπolidinyl, 2-dioxanyl, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydropyranyl, 3 -tetrahydropyranyl, 4-tetrahydropyranyl, 2-tetrahydrothienyl, and 3-tetrahydrothienyl, wherein each
33 ring carbon is optionally substituted with R , ring carbons and a nitrogen adjacent to the carbon atom at the point of attachment are optionally substituted 9 13 . 9 with R or R , a ring carbon or nitrogen adjacent to the R position and two
atoms from the point of attachment are optionally substituted with R , and a
13 ring carbon or nitrogen atom adjacent to the R position and two atoms from
12 the point of attachment is optionally substituted with R ;
33 R 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;
^b . .m20 21 „^m25^^23J2 Q is NR R or C(NR )NR R ;
20 21 23 24 25
R , R , R , R , and R 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 structoral units, wherein;
X° is selected from the group consisting of hydrido, aminomethyl, methyl, ethyl, trifluoromethyl, 2,2,2-trifluoroethyl, hydroxymethyl, 2-hydroxyethyl, chloro, and fluoro; R is selected from the group consisting of phenyl, 2-thienyl, 2-furyl, 2-pyπolyl, 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
9 phenyl or heteroaryl ring to the 4-pyrone ring is optionally substituted by R , the other carbon adjacent to the carbon at the point of attachment is optionally
13 . 9 substitoted by R , a carbon adjacent to R and two atoms from the carbon at
the point of attachment is optionally substituted by R , a carbon adjacent to
13 R and two atoms from the carbon at the point of attachment is optionally
12 10 12 substituted by R , and any carbon adjacent to both R and R is optionally
11 substitoted by R ;
9 11 13
R , R , and R are independently selected from the group consisting of hydrido, methyl, ethyl, methoxy, ethoxy, hydroxy, amino, N-methylamino, N,N-dimethylamino, methylthio, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, fluoro, chloro, bromo, amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl,
1-hydroxyethyl, amidocarbonyl, N-methylamidocarbonyl, carboxy, and cyano;
10 12
R and R 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-(l-methyl-l-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; x is selected from the group of formulas consisting of:
l_Qb- QS.2-R16_3-R17-5_R18-6-R19benzene,
. > * Λs -„1 Λ „18^ „19 .,. 2-Q -SQ -6-R -4-R -3-R pyπdine,
-Qb-6-QS-2-R16-5-R18-4-R19pyridine,
„ Λb „ Λs Λ ^16 ,, 19 , . , 3-Q -5-Q -4-R -2-R thiophene,
2-Q -5-QS-3-R -4-R thiophene,
3-Qb-5-QS-4-R16-2-R19furan,
b s 16 Λ 17, 2-Q -5-Q -3- R -4-R furan, b s 16 19 3-Q -5-Q -4-R -2- R pyrrole,
2-Qb-5-QS-3-R16-4-R17pyπole,
b s 19 4-Q -2-Q -5-R thiazole, and
2-Q -5-QS-4-R thiazole;
16 17 „18 , 19 . , , , R , R , R , and R are independently selected from the group consisting of hydrido, methyl, ethyl, 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, Nil, NIII, 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, atrial fibrillation, thrombotic stroke, embolic stroke, deep vein thrombosis, disseminated intravascular coagulation, ocular build up of fibrin, and reocclusion or restenosis of recanalized vessels in a mammal. The compounds 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 "Ν" 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 substitoted 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 substitoted 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-l-yl, hexen-1-yl, 3-hydroxyhexen-l-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- methoxyρentyn-2-yl, 3-methylbutyn-l-yl, hexyn-1-yl, hexyn-2-yl, hexyn-3-yl, 3,3-dimethylbutyn-l-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 l,l-vinylidene (CH2=C), l,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 prefeπed haloalkyl radicals are " haloalkyl" radicals having one to about six carbon atoms. Examples of such haloalkyl radicals include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, trifiuoroethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, 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 prefeπed haloalkylene radicals are " haloalkylene" radicals having one to about six carbon atoms. Examples of "haloalkylene" radicals include difluoromethylene, tetrafluoroethylene, tetrachloroethylene, alkyl substituted monofϊuoromethylene, 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 trifluoroethoxymethyl. The terms "alkenyloxy" and "alkenyloxyalkyl" embrace linear or branched oxy-containing radicals each having alkenyl portions of two to about ten carbon atoms, such as ethenyloxy or propenyloxy radical. The term "alkenyloxyalkyl" also embraces alkenyl radicals having one or more 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 substitoted 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 refeπed 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. pyπolidinyl, 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. moφholinyl, etc.]; saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., thiazoHdinyl, etc.]. Examples of partially saturated heterocyclyl radicals include dihydrothiophene, dihydropyran, dihydrofuran and dihydrothiazole. Non-limiting examples of heterocyclic radicals include 2-pyπolinyl, 3-pyπolinyl, pyπolindinyl, 1,3- dioxolanyl, 2H-pyranyl, 4H-ρyranyl, piperidinyl, 1,4-dioxanyl, moφholinyl, 1,4-dithianyl, thiomoφholinyl, 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, pyπolinyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl [e.g., 4H-l,2,4-triazolyl, lH-l,23-triazolyl, 2H- 1,2,3-triazolyl, etc.] tetrazolyl [e.g. lH-tetrazolyl, 2H-tetrazolyl, etc.], etc.; unsaturated condensed heterocyclic group containing 1 to 5 nitrogen atoms, for example, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl [e.g., tetrazolo [l,5-b]pyridazinyl, etc.], etc.; unsaturated 3 to 6-membered heteromonocyclic group containing an oxygen atom, for example, pyranyl, 2-furyl, 3-furyl, etc.; unsaturated 5 to 6- membered heteromonocyclic group containing a sulfur atom, for example, 2- thienyl, 3-thienyl, etc.; unsaturated 5- to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl [e.g., 1,2,4-oxadiazolyl, 13,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.] etc.; unsaturated condensed heterocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [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, xhiadiazolyl [e.g., 1,2,4- thiadiazolyl, 1,3,4-thiadiazolyl, l,2,Sthiadiazolyl, 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. Prefeπed 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-pyπoIyl, 3-pyπolyl, 2-imidazolyl, 4- imidazolyl, 3-pyrazolyl, 4-pyrazolyl, l,2,4-triazol-3-yl, 1,2,4-tiiazol-Syl, 1,2,4- oxadiazol-3-yl, l,2,4-oxadiazol-5-yl, l,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, 13,Striazin-2-yl, l,2,4-triazin-3-yl, 1,2,4-triazin-Syl, l,2,4-triazin-6-yl, l,2,3-triazin-4-yI, and l,23-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-substitated 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-substitoted 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-substitoted 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 norbomyl (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 prefeπed 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 cyclohexenyloxyethyl. 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 "monoarylamino" and "diarylamino" containing one or two aryl radicals, respectively, attached to an amino radical. Examples of such radicals include N-phenylamino and N-naphthylamino.
The term "aralkylamino", embraces aralkyl radicals attached to an amino radical, where aralkyl is defined as above. The term aralkylamino 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 "heteroarylsulfinylalkyl" denotes heteroarylsulfinyl radicals attached to a linear or branched alkyl radical, of one to ten carbon atoms. The term "Heteroarylsulfonyl", embraces heteroaryl radicals attached to a sulfonyl radical, where heteroaryl is defined as above. "Heteroarylsulfonylalkyl", 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, fluoro-3-methylphenoxy, 5,6,7,8- tetrahydronaphthyloxy, 3-isopropylphenoxy, 3-cyclopropylphenoxy, 3- ethylphenoxy, 3-pentafluoroethylphenoxy, 3-(l,l,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,S 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 "heteroaralkyl amino" embraces heteroaralkyl radicals, as defined above, attached to an amino group. Examples of such radicals include pyridylmethylamino. The term "heterocyclylalkylammo" 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 mexhylthiomethyl. 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, =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 substitoted with two alkyl groups. Examples of such dialkylsulfonium radicals include, for example, (CH3)2S -. The term "dialkyl sulfonium alkyl" denotes a dialkyl sulfonium group where said group is bonded to one bond of an alkylene group as defined above. Examples of such dialkylsulfoniumalkyl radicals include (CH )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", "haloalkenyloxyalkyl", "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", "halocycloalkoxyalkyl", "halocycloalkenyloxy", "halocycloalkenyloxyalkyl", "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", "haloaryloxyalkyl", "heteroaroyl", "heteroaralkanoyl", "heteroaralkoxy", "heteroaralkoxyalkyl", "arylthio", "arylthioalkyl", "alkoxyalkyl", "acyl", "amidino", "guanidino", "dialkylsulfonium", "trialkylphosphonium", and "dialkylsulfoniumalkyl" groups defined above may optionally have 1 or more non-hydrido substituents such as 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, satorated 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
2a by a radical selected from =C(H)-, =C(R )-, -O-, -S-, -S(O)-, -S(O)2-,
2a 2a 2a
-NH-, -N(R )-, -N=, -CH(OH)-, =C(OH)-, -CH(OR )-, =C(OR )-, and
2a -C(O)- wherein R is selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, aryloxyalkyl, alkoxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkoxyalkyl, perhaloaralkyl, heteroarylalkyl, heteroaryloxyalkyl, heteroarylthioalkyl, and heteroarylalkenyl. 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 CH^HR^O-, -OCF2O-, -O(CF2)2O-, -S-, -S(O)-, -S(O)2-, -N(H)-,
2a 2a 2a -N(H)O-, -N(R )O-, -N(R )-, -C(O)-, -C(O)NH-, -C(O)NR -, -N=,
-OCH2-, -SCH2-, S(O)CH2-, -CH2C(O)-, -CH(OH)-, =C(OH)-, -CH(OR2a)-,
2a 2a
=C(OR )-, S(O) CH2-, and -NR 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, satorated heterocyclyl, partially saturated heterocyclyl, heteroaryl, heteroaryloxy, heteroaryloxyalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, carboxyall yl, 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 ketonic or aldehydic carbonyl groups or combinations thereof alone or as part of a heterocyclic ring system. Such carbonyl groups may exist in part or principally in the "keto" form and in part or principally as one or more
"enol" forms of each aldehyde and ketone group present. Compounds of the present 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 imine or enamine groups or combinations thereof. Such groups may exist in part or principally in the "imine" form and in part or principally as one or more "enamine" forms of each group present. Compounds of the present invention having said imine or enamine groups are meant to include both
"imine" and "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 manufactore 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, atrial fibrillation, thrombotic stroke, embolic stroke, deep vein thrombosis, disseminated intravascular coagulation, ocular build up of fibrin, and reocclusion or restenosis of recanalized vessels in a mammal. The compounds also can be used to study the mechanism of action of coagulation cascade serine 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, succmic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucoronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, salicylic, p-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), mexhanesulfonic, 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 refeπed 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 polyvinylpyπolidone, pyran copolymer, polyhydroxy-propyl-methacrylamide-phenol, polyhydroxy ethyl -aspartamide- phenol, or ployethyleneoxide-polylysine substitoted 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 administered by injection as a composition wherein, for example, saline, dextrose or water may be used as a suitable carrier. The amount of therapeutically active compounds which are administered and the dosage regimen for treating a disease condition with the compounds and/or compositions of this invention depends on a variety of 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 paraffinic or a water-miscible ointment base.
Alternatively, the active ingredients may be formulated in a cream with an oil-in-water cream base. If desired, the aqueous phase of the cream base may include, for example at least 30% w/w of a polyhydric alcohol such as propylene glycol, butane-l,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 dimethylsulf oxide 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 prefeπed 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 administered er 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, polyvinylpyπolidone, 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, com 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 Mockers) 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 administered 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-NIIA 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 ΝMR, 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)-l, -binaphthyl, "BnOH" represents benzyl alcohol, "BnCHO" represents 2-phenylethanal, "
BnSO2Cl" represents benzylsulfonyl chloride, "Boc" represents tert- butyloxycarbonyl, "BOP" represents benzotriazol-1-yl-oxy-tris- (dimethylamino), "bu" represents butyl, "dba" represents dibenzylideneacetone, "DCC" represents l,3-dicyclohexylcarbodiimide, "DCM" represents dichloromethane or methylene chloride, "DIBAH" or "DIBAL" represents diisobutylaluminum hydride, "DJVIF" represents dimethylformamide, "DMSO" represents dimethylsulfoxide, "DPPA" represents diphenylphosphoryl azide", "EDC" represents l-[3- (dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride, "Fmoc" represents 9-fluorenylmethoxy carbonyl, "HOBT" represents hydroxybenzoltriazole", "LDA" represents lithium diisopropylamide, "NMM" represents N-methylmoφholine, "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-(lH-benzotriozole-l-yl)- 1,133-tetramethyl uronium tetrafluoroborate, "TEA" represents triethylamine, "TFA" represents trifluoroacetic acid, "THF" represents tetrahydrofuran, "TMS" represents trimethylsilyl, "TMSCN" represents trimethylsilyl cyanide, and "Cbz" or "Z" represents benzyloxycarbonyl. GENERAL SYNTHETIC PROCEDURES AND SPECIFIC EXAMPLES
The 4-pyrone compounds of the present invention can be synthesized, for example, according to the following procedures and Schemes given below.
SCHEME 1
SCHEME 2
SCHEME 3
SCHEME 4
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
2 ability to introduce numerous R substituents represented by Z°-Q, a wide variety of amino substituting groups represented by B-, B-CH2, B-CO, and B-SO2, and a large number of amide forming Y groups at the carboxylic acid group in which E° is C(O)NH. Example 1 below shows the preparation of a compound wherein X° is hydrido.
Example 1
EX-1A (Step A)
1
A solution of 2,2-dimethyl l,3-dioxane-4-dione (1 mol) and pyridine (2 mol) in dichloromethane at 0°C will be treated with 4-penenoyl chloride. The reaction mixture is stiπed for 1 hour at 0°C , and an additional hour at room temperatore. The volatile components is removed in vacuo, and the residue is dissolved in t-butanol. The reaction mixture is heated for 4 hours. After solvent removal, the red-brown residue is treated with 500 mL of ethyl acetate, and the insoluble material is filtered. Evaporation of the filtrate will afford a dark red oil 1.
EX- IB (Step B)
A mixture of 1 and N,N-dimethylformamide dimethyl acetal (excess) is heated to 80°C for two hours. The volatile components is removed in vacuo, and the crude residue is purified by flash chromatography which will afford a yellow oil 2. EX-1C (Step C)
A dry ice cooled solution of LHMDS (2.5 mmol) in THF is treated with 3- nitrobenzoyl chloride (1.2 mmol) and 2 (1 mmol) as a solution in THF. The dry ice bath is removed, and the reaction mixture is stirred for 5 minutes. Diethyl ether is added to the reaction mixture followed by 3 M HCI. The resulting reaction mixture is stiπed for an additional 1.5 hours. The organic layer is separated and washed with saturated aqueous NaHCO3 and brine. After drying over NajSO,^ and concentration, the crude product is purified by flash chromatography to afford a yellow oil 3.
EX- ID (Step D)
A solution of 3 in dichloromethane is treated with trifluoroacetic acid. After stirring the reaction mixture for 1 hour, the mixture is concentrated in vacuo. The residue is dissolved in 4N HCI in dioxane, and the volatile components is removed to afford a yellow solid 4.
EX- IE (Step E)
A mixture of 4 (1 mmol), dry t-butanol, diphenyl phosphoryl azide (DPPA) (1 mmol), and triethyl amine is heated to reflux temperature for 48 hours. Removal of the volatiles gives a residue which is purified by column chromatography to afford a yellow oil 5.
EX- IF (Step F)
A solution of 5 is treated with a solution of 4N HCI in dioxane. The reaction mixture is stiπed at room temperature for 2 hours. After evaporation of the solvent, the desired compound 6 is isolated.
EX-1G (Step G)
A solution of acetone (1.5 mmol) in THF (lmL) is added to a solution of 6
(1 mmol) in THF (4 mL). This mixtore is treated with sodium triacetoxyborohydride (1.5 mmol). The reaction mixtore is quenched with NH4C1, and extracted with ether. The combined organic layers is dried over MgSO4, filtered, and concentrated. The residue is purified via column chromatography affording the desired compound 7.
EX-1H (Step H)
A solution of 7 (2 mmol) in acetone (10 mL) is treated with 0.25 mL (2 mol %) of a 4 wt % solution of OsO4 in water and 2.6 mL (6.9 mmol of Cr^) of Jones reagent. After stirring the mixture for 20 hours at room temperature, 1 mL of 2- propanol is added followed by 0.3 g of NaHSO3. After diluting the mixtore with 10 mL of water, the mixture is stiπed until a dark green, homogeneous solution is produced. This solution is diluted with 20 mL of water and extracted with six 10 mL portions of ethyl acetate. The organic extracts is combined and dried over MgSO4. After concentration of the organic components, the product 8 is isolated by recrystallization.
EX- II (Step I)
Compound 8 (1 mmol), EDC (1.3 mmol), and HOBt (1.3 mmol) is mixed in DMF, and the mixture is stirred at 20 °C for 15 minutes. To this mixture is added a solution of benzyl-[[(4-aminomethylphenyl)irninomethyl]amino]carbamate hydrogen chloride salt (1.3 mmol) and diisopropyl ethyl amine (1.3 mmol) in DMF. Typical aqueous work-up followed by chromatographic purification provides the desired product 9.
EX-1J (Step J)
Compound 9 (1 mmol), ^-toluene sulfonic acid mono hydrate (1 mmol) and 10% Pd on activated carbon (0.1 mmol) is mixed with methanol. The mixture is stirred for 2 h under hydrogen atmosphere which is introduced and maintained through a rubber balloon. After filtering off the catalyst and removing the methanol, the desired product of Example 1 is isolated as the TFA salt after reverse phase chromatography. 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 coπesponding 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 coπesponding acid chloride and similar reagents. Compounds of Formula (I) that have at least one thiol group present can be converted to the coπesponding 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 coπesponding 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 coπesponding 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 coπesponding 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 incoφorated 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 coπesponding 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-buxyl 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 concuπently. Tertiary amines can be prepared from the coπesponding 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 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. 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 incoφorated herein by reference.
The biological activity of the compounds of Example 1 and Schemes 1, 2, 3, and 4 is evaluated using 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 temperatore 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 OD^^ 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 OD^^ 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-nitiOanilide (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 temperatore 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 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.

Claims (1)

  1. What we claim is:
    1. A compound having the Formula (I):
    or a pharmaceutically acceptable salt thereof, wherein; B is formula (V):
    1 2 1 2 1 wherein D , D , J , J and K are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more
    1 2 1 2 1 than one is a covalent bond, no more than one of D , D , J , J and K is O,
    1 2 1 2 1 1 2 1 ,2 1 no more than one of D , D , J , J and K is S, one of D , D , J , J and K
    1 2 1 2 1 must be a covalent bond when two of D , D ,J , J andK are O and S, and
    1 2 1 2 1 32 no more than four of D , D ,J ,J andK are N with the proviso that R ,
    33 34 35 J „36 , . , J , , . . ,
    R ,R ,R ,an R are each independently selected to maintain the tetravalent natore of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent natore of oxygen;
    „32 „33 34 35 , 36 . Λ Λ , , , , «b R ,R ,R ,R ,andR are independently selected to be Q ;
    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, heteroarylsulfinylalkyl, heteroarylsulfonylalkyl, alkylsulfonyl, alkylsulfonylalkyl, haloalkylsulfinylalkyl, 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 satorated 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 ;
    32 33 33 34 34 35 „35 36
    R and R , R and R , R and R , and R and R substituent pairs are 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
    32 33 33 34 34 one of the group consisting of spacer pairs R and R , R and R , R
    35 35 36 and R , and R and R are used at the same time;
    B is formula (VI):
    3 4 ,3 4 wherein D , D , J , and J are independently selected from the group
    3 4 3 4 consisting of C, N, O, and S, no more than one of D , D , J , and J is O, no
    3 4 3 4 1 2 1 more than one of D , D ,J , and J is S, and no more than three of D , D , J ,
    2 32 33 34 35 and J are N with the proviso that R , R , R , and R are each independently selected to maintain the tetravalent natore of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen;
    B is 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 2, R33 , R34, R35, and R^;
    B is selected from the group consisting of C3-C10 cycloalkyl, C5-C10 cycloalkenyl, C4-C9 saturated heterocyclyl, and C4-C9 partially satorated heterocyclyl, wherein each ring carbon may be optionally substitoted 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 R^, a ring carbon or nitrogen atom adjacent to the R9 position and two atoms from the point of attachment may be substituted with
    RJQ, a ring carbon or nitrogen atom adjacent to the Rj3 position and two atoms
    from the point of attachment may be substitoted with R^2> a ring carbon or
    nitrogen atom three atoms from the point of attachment and adjacent to the RJQ
    position may be substitoted with RJ J, a ring carbon or nitrogen atom three
    atoms from the point of attachment and adjacent to the R^ position may be
    substitoted with R33, and a ring carbon or nitrogen atom four atoms from the
    point of attachment and adjacent to the R j j and R33 positions may be
    substituted with R34;
    9 10 10 11 11 12 12 13 R and R , R and R , R and R , and R and R spacer pairs are 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 • • • „9 1 T 0 10 11 _ 11 12 , 12 consisting of spacer pairs R and R , R and R , R and R , and R
    and R is used at the same time;
    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
    7 selected from 0 through 1, pa is an integer selected from 0 through 6, and W is selected from the group consisting of O, S, C(O), C(S), C(O)S, C(S)O,
    C(O)N(R7), C(S)N(R?), (R?)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(R?);
    7 8 R and R are independently selected from the group consisting of hydrido, hydroxy, alkyl, alkenyl, aryl, aralkyl, aryloxy, alkoxy, alkenyloxy, alkylthio, alkylamino, arylthio, arylamino, acyl, aroyl, heteroaroyl, aralkoxyalkyl, heteroaralkoxyalkyl, , aryloxyalkyl, alkoxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, aralkoxyalkyl, heteroaralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, heteroaryl, heteroaryloxy, heteroarylamino, heteroaralkyl, heteroaralkyloxy, heteroaralkylamino, and heteroaryloxyalkyl; π14 n15 n37 38 39 π40 41 42 . J
    R , R , R , R , R ,R , R and R 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, aryloxyalkyl, 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, satorated heterocyclyl, partially saturated heterocyclyl, heteroaryl, heteroarylalkyl, heteroarylthioalkyl, heteroaralkylthioalkyl, monocarboalkoxyalkyl, dicarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl, carboalkoxycyanoalkyl, alkylsulfinyl, alkylsulfonyl, haloalkylsulfinyl, haloalkylsulfonyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, arylsulfonylalkyl, aralkylsulfinyl, aralkylsulfonyl, cycloalkylsulfinyl, cycloalkylsulfonyl, cycloalkylsulfinylalkyl, cycloalkylsufonylalkyl, heteroarylsulfonylalkyl, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylsulfinylalkyl, aralkylsulfinylalkyl, aralkylsulfonylalkyl, carboxy, carboxyalkyl, carboalkoxy, carboxamide, carboxamidoalkyl, carboaralkoxy, tiialkylsilyl, dialkoxyphosphono, diaralkoxyphosphono, dialkoxyphosphonoalkyl, and diaralkoxyphosphonoalkyl ;
    14 14
    R and R , when bonded to different carbons, are 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;
    14 15
    R and R , when bonded to different carbons, are 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;
    R and R , when bonded to different carbons, are 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;
    14 15
    R and R , when bonded to the same carbon, are taken together to form a group selected from a group consisting of oxo, thiono, alkylene, haloalkylene, and a linear moiety spacer 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 NR , O, C(O), C(S), S,
    5 8 39 40
    S(O), S(O)2, ON(R ), P(O)(R ), and CR R ;
    R is selected from the group consisting of hydrido, alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxy, alkoxy, alkenyloxy, alkylthio, arylthio, aralkoxyalkyl, heteroaralkoxyalkyl, aryloxyalkyl, 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;
    X and R are independently selected from the group consisting of Z -
    Q, hydrido, alkyl, alkenyl, and halo;
    Λ and R are 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; and R are 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;
    A 39
    Λ and R are 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; X and R are 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; X is selected to form a linear moiety having from 2 through 5
    39 40 contiguous atoms linked to the points of bonding of both R and R to form a heterocyclyl ring having from 5 through 8 contiguous members;
    9 4a ? 4b 14 ? 15
    R and R , R and R , R and R , and R and R spacer pairs are independently selected to form spacer pairs wherein a spacer pair is taken together to form a Unear 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
    2 proviso that no more than one of the group of spacer pairs consisting of R and
    4a 9 4b 14 9 15
    R , R and R , R and R , and R and R is used at the same time; RΛ is independendy selected to form a linear moiety having from 2
    4a through 5 contiguous atoms linked to the points of bonding of both R and
    4b R to form a heterocyclyl ring having from 5 through 8 contiguous members;
    Z is selected from the group consisting of covalent single bond,
    41 42 41 (CR R )Q wherein q is an integer selected from 1 through 6, (CH(R ))„- o 42 W -(CH(R ))p wherein g and p are integers independently selected from 0 through 3 and W is selected from the group consisting of O, S, C(O), C(S),
    41 41 41
    C(O)O, C(S)O, C(O)S, C(S)S, C(O)N(R ), (R )NC(O), C(S)N(R ),
    (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,
    42 41 41 42 42 41 N(R )C(O)N(R ), (R )NC(O)N(R ), N(R )C(S)N(R ),
    41 42 41 41
    (R )NC(S)N(R ), S(O), S(O)2, S(O)2N(R ), N(R )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),
    8 7 41 41 28 29 41 2
    P(O)(R )N(R ), N(R ), ON(R ), and SiR R , and (CH(R ))e-W -
    42 (CH(R ))n wherein e and h are integers independently selected from 0
    2 41 42 through 2 and W^ is selected from the group consisting of CR =CR ,
    41 42 CR R =C; vinylidene), and ethynylidene (GsC; 1,2-ethynyl), with the
    41 42 provisos that R and R are selected from other than halo and cyano when directly bonded to N and Z is directly bonded to the pyrone ring; Q is formula (II):
    1 2 1 M2 1 wherein D , D , J , J and K are independenfly selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more
    1 2 1 2 1 than one is a covalent bond, no more than one of D , D , J , and K is O,
    1 2 1 2 1 1 2 1 2 1 no more than one of D , D , J , J and K is S, one of D , D , J , J and K
    1 2 1 2 1 must be a covalent bond when two of D , D , J , J and K are O and S, and
    1 2 1 2 1 9 no more than four of D , D , J , J and K are N, with the proviso that R ,
    10 11 12 13
    R , R , R , and R are each independently selected to maintain the tetravalent nature of carbon, trivalent natore of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen; Q is formula (III): wherein D -V, D ', J~, and - J4 ' are independently selected from the group
    consisting of C, N, O, and S, no more than one of D , D Λ , J , and - J4 i-s O, no
    3 4 3 4 1 2 1 more than one of D , D , JN and J is S, and no more than three of D , D , J ,
    2 9 10 11 12 and J are N with the proviso that R , R , R , and R are each independently selected to maintain the tetravalent nature of carbon, trivalent nature of nitrogen, the divalent natore of sulfur, and the divalent nature of oxygen;
    Q is 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 (CR JR )n wherein n is an integer selected from 1 through 4;
    4a 4b
    R and R are independently selected from the group consisting of halo, hydrido, hydroxy, cyano, hydroxyalkyl, alkyl, alkenyl, aryl, aralkyl, 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;
    4a 4b
    R and R , when bonded to the same carbon, are 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; o 1 4a 4b 1 E is E , when K is (CR R )n, wherein E is selected from the group consisting of a covalent single bond, O, S, C(O), C(S), C(O)O, C(S)O, C(O)S,
    C(S)S, C(O)N(R7), (R7)NC(O), C(S)N(R?), (R?)NC(S), OC(O)N(R7),
    (R7)NC(O)O, SC(S)N(R?), (R?)NC(S)S, SC(O)N(R7), (R?)NC(O)S,
    OC(S)N(R7), (R?)NC(S)O, N(R8)C(O)N(R7), (R7)NC(O)N(R8),
    N(R8)C(S)N(R?), (R7)NC(S)N(R8), S(O), S(O)2, S(O)2N(R?), N(R7)S(O)2,
    S(O)2N(R7)C(O), C(O)N(R?)S(O)2, Se, Se(O), Se(O)2, Se(O)2N(R7),
    N(R?)Se(O)2, P(O)(R8), N(R?)P(O)(R8), P(O)(R8)N(R?), N(R?), ON(R7),
    28 29 4a 4b 4a 4b
    SiR R , CR =CR , ethynylidene (C≡C; 1,2-ethynyl), and C=CR R ;
    14 K is (CH(R ))j-T wherein j is selected from a integer from 0 through 3 and T is selected from the group consisting of single covalent bond, O, S, and
    7 14
    N(R ) with the proviso that (CH(R ))j is bonded to the pyrone ring;
    ,4) . J2 , τ„ . ^ττ/πH, m . 2. ,
    E IS E , when K is (CH(R ));-T, wherem E 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), (R?)NC(O), C(S)N(R7), (R?)NC(S), (R7)NC(O)O,
    (R?)NC(S)S, (R7)NC(O)S, (R?)NC(S)O, N(R8)C(O)N(R?),
    (R7)NC(O)N(R8), N(R8)C(S)N(R?), (R7)NC(S)N(R8), S(O), S(O)2,
    S(O)2N(R7), N(R?)S(O)2, S(O)2N(H)C(O), C(O)N(H)S(O)2, Se(O),
    Se(O)2, Se(O)2N(R?), N(R?)Se(O)2, P(O)(R8), N(R7)P(O)(R8),
    P(O)(R8)N(R?), and N(R7); 15 K is G-(CH(R ))]- wherein k is selected from an integer from 1
    7 through 3 and G is selected from the group consisting of O, S, and N(R ) with
    the proviso that R is other than hydroxy, cyano, halo, amino, alkylamino, dialkylamino, and sulfhydryl when k is 1; o 3 15 3 E is E , when K is G-(CH(R ))^, wherein E is selected from the group consisting of a covalent single bond, O, S, C(O), C(S), C(O)O, C(S)O,
    C(O)S, C(S)S, C(O)N(R7), (R?)NC(O), C(S)N(R7), (R7)NC(S),
    OC(O)N(R?), (R?)NC(O)O, SC(S)N(R7), (R?)NC(S)S, SC(O)N(R?),
    (R7)NC(O)S, OC(S)N(R7), (R?)NC(S)O, N(R8)C(O)N(R?),
    (R7)NC(O)N(R8), N(R8)C(S)N(R7), (R?)NC(S)N(R8), S(O), S(O)2,
    S(O)2N(R?), N(R7)S(O)2, Se, Se(O), Se(O)2, Se(O)2N(R?), N(R?)Se(O)2,
    8 7 8 8 7 7 7 28 29
    P(O)(R ), N(R )P(O)(R ), P(O)(R )N(R ), N(R ), ON(R ), SiR R ,
    CR4a=CR4b, ethynylidene (OC; 1,2-ethynyl), and C=CR4aR4b;
    Y° is formula (IV):
    wherein D , D , J , and J are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more
    2 than one is a covalent bond, K is independently selected from the group
    consisting of C, and N , no more than one of D , D , J , and J is O, no more , -,5 _6 5 , β . _ „ 5 6 τ5 6 than one of D , D , J , and J is S, one of D , D , J , and j must be a
    covalent bond when two of D , D , J , and J are O and S, no more than three
    5 6 5 6 2 + 5 6 of D , D , J , and J are N when K is N , and no more than four of D , D ,
    J , and
    19 R are each independently selected to maintain the tetravalent natore of carbon, trivalent natore of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen; are 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;
    18 19
    R and R are independendy 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; b 20 21 + 20 21 22 Q is selected from the group consisting of NR R , NR R R , oxy, alkyl, alkylaminoalkyl, aminoalkyl, dialkylsulfoniumalkyl, and acylamino
    20 21 22 wherein R , R , and R are independently selected from the group consisting of hydrido, alkyl, hydroxy, alkoxy, alkylamino, dialkylamino,
    20 aminoalkyl, and hydroxyalkyl with the provisos that no more than one of R ,
    21 22 R , andR is hydroxy, alkoxy, alkylamino, amino, and dialkylamino and that
    20 21 22
    R , R , and R must be other than be hydroxy, alkoxy, alkylamino, amino,
    2 + and dialkylamino when K is N ; 20 21 20 22 21 22
    R and R , R and R , and R and R pairs are 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
    20 21 20 22 21 22 group consisting of spacer pairs R and R , R and R , and R and R is used at the same time;
    , -^ OA
    Q is selected from the group consisting of N(R )SO2N(R )(R ),
    N(R26)C(O)OR5, N(R26)C(O)SR5, N(R26)C(S)OR5 and N(R26)C(S)SR5
    23 24 26 with the proviso that no more than one of R , R , and R are hydroxy, alkoxy, alkylamino, amino, or dialkylamino when two of the group consisting
    23 24 26 of R , R , and R are bonded to the same atom;
    Q is selected from the group consisting of dialkylsulfonium, trialkylphosphonium,
    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),
    25 5 23 24 23 24
    C(NR )SR , C(O)NR R , and C(O)NR R with the provisos that no
    23 24 26 more than one of R , R , and R is hydroxy, alkoxy, alkylamino, ammo, or
    23 24 26 dialkylamino when two of the group consisting of R , R , andR are b bonded to the same atom and that said Q group is bonded directly to a carbon atom;
    23 24 25 26
    R , R , R , and R are independently selected from the group consisting of hydrido, alkyl, hydroxy, alkoxy, alkylamino, dialkylamino, aminoalkyl, and hydroxyalkyl; 23 24
    R and R are taken together to form a linear spacer moiety having from 4 through 7 contiguous atoms connecting the points of bonding to form a heterocyclyl ring having 5 through 8 contiguous members;
    23 25 24 25 25 26 24 26 23
    R and R , R and R , R and R , R and R , and R
    26 and R pairs are 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-disubstitated radicals consisting of a cycloalkyl radical, a cycloalkenyl radical wherein cycloalkyl and cycloalkenyl radicals are substituted with one or
    30 31 more groups selected from R and R , an aryl radical, an heteroaryl radical, a satorated heterocyclic radical and a partially saturated heterocyclic radical wherein
    28 32 said 1,2-substitotents are independently selected from C=O, C=S, C(R )R ,
    S(O), S(O)2, OP(OR31)R3°, P(O)R3°, P(S)R30 and Si(R28)R29;
    23 25 24 25 25 26 24 26 23 26
    R and R , R and R , R and R , R and R , and R and R pairs are 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-disubstitated alkylene radicals and 1,2-disubstitated 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)R3°, P(O)R30, P(S)R30, and
    28 29 Si(R )R and said alkylene and alkenylene radical are substituted with one or
    30 31 more R or R substituents;
    23 25 24 25 25 26 24 26 23 26
    R and R , R and R , R and R , R and R , and R and R pairs are 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)R3°, P(O)R30, P(S)R3°, C(R3°)R31, C=C(R3°)R31, (O)2POP(O)2, R3°(O)POP(O)R30, Si(R29)R28, Si(R2V8Si(R29)R28, Si(R29)R28OSi(R29)R28, (R28)R29COC(R28)R29, (R28)R29CSC(R28)R29, C(O)C(R30)=C(R31), C(S)C(R3°)=C(R31), S(O)C(R30)=C(R31), SO2C(R3°)=C(R31),
    PR30C(R30)=C(R31), P(O)R30C(R3°)=C(R31), P(S)R3°C(R3°)=C(R31), DC(R3°)(R3 X)D, OP(OR3 ^R30, P(O)R3°, P(S)R3°, Si(R28)R29 and N(R3°), 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, and S(O)m wherein m is an integer selected from 0 through 2;
    27 27 JH is independently selected from the group consisting of OR , SR and
    N(R20)R21;
    27 .
    R 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 ;
    28 29
    R and R are independently selected from the group consisting of hydrido, hydroxyalkyl, alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, acyl, aroyl, aralkanoyl, heteroaroyl, aralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkylthioalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxyalkyl, perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl, heteroarylalkyl, heteroarylthioalkyl, heteroaralkylthioalkyl, cyanoalkyl, dicyanoalkyl, carboxamidoalkyl, dicarboxamidoalkyl, cyanocarboalkoxy alkyl, carboalkoxyalkyl, dicarboalkoxyalkyl, cyanocycloalkyl, dicyanocycloalkyl, carboxamidocycloalkyl, dicarboxamidocycloalkyl, carboalkoxycyanocycloalkyl, carboalkoxycycloalkyl, dicarboalkoxy cycloalkyl, formylalkyl, acylalkyl, arylsulfinylalkyl, arylsulfonylalkyl, aralkylsulfinyl, cycloalkylsulfinylalkyl, cycloalkylsufonylalkyl, heteroarylsulfonylalkyl, heteroarylsulfinylalkyl, aralkylsulfinylalkyl, aralkylsulfonylalkyl, carboxy, dialkoxyphosphono, diaralkoxyphosphono, dialkoxyphosphonoalkyl and diaralkoxyphosphonoalkyl;
    28 29
    R and R are 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;
    30 31
    R and R 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, alkoxy sulfonylalkyl, aralkoxysulfonylalkyl, alkoxysulfonylalkoxy, aralkoxysulfonylalkoxy, sulfonylalkoxy, alkoxysulfonylalkylamino, aralkoxysulfonylalkylamino, and sulfonylalkylamino; 30 31
    R and R are 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; g
    Q is selected from the group consisting of a single covalent bond,
    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), (R14)NC(S), OC(O)N(R14), SC(S)N(R14),
    14 14 15 14 14 15
    SC(O)N(R ), OC(S)N(R ), N(R )C(O)N(R ), (R )NC(O)N(R ),
    15 14 14 15 14
    N(R )C(S)N(R ), (R )NC(S)N(R ), S(O), S(O)2, S(O)2N(R ),
    N(R14)S(O)2, Se, Se(O), Se(O)2, Se(O)2N(R17), N(R14)Se(O)2, P(O)(R8),
    7 o 8 7 14 14 28 99
    N(R )P(O)(R ), P(O)(R )N(R ), N(R ), ON(R ), and SiR R ,
    (CH(R ))C-W -(CH(R ))^ wherein c and d are integers independently
    1 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),
    14 14 14 14 14
    C(S)N(R ),(R )NC(S),OC(O)N(R ),(R )NC(O)O, SC(S)N(R ),
    14 14 14 14 14
    (R )NC(S)S, SC(O)N(R ), (R )NC(O)S, OC(S)N(R ), (R )NC(S)O,
    15 14 14 15 15 14 N(R )C(O)N(R ),(R )NC(O)N(R ),N(R )C(S)N(R ),
    (R14)NC(S)N(R15), S(O), S(O)2, S(O)2N(R14),N(R14)S(O)2, Se, Se(O),
    14 14 8 7 8
    Se(O)2,Se(O)2N(R ),N(R )Se(O)2,P(O)(R ),N(R )P(O)(R ),
    8 7 14 14 2829 14 2 P(O)(R )N(R ),N(R ),ON(R ),SiR R ,and(CH(R ))e-W^- (CH(R ))jj wherein e and h are integers independently selected from 0
    2 4a 4b through 2 and W^ is selected from the group consisting of CR =CR ,
    4a 4b 14 ethynylidene (C≡C; 1,2-ethynyl), and C=CR R with the provisos that R
    and R are selected from other than halo and cyano when directly bonded to ^7 Q 1 /1 1 /1 N and that (CR R )b, (CH(R ))C, (CH(R ))e and are bonded to E°; jQ j go σc x is Q -Q wherein Q is selected from the group consisting of
    37 38 14
    (CR R )f wherein f is an integer selected from 1 through 6, (CH(R ))c-
    1 15
    W -(CH(R ))^ wherein c and d are integers independently selected from 1
    through 4, and W is selected from the group consisting of W is selected from the group consisting of O, S, C(O), C(S), C(O)O, C(S)O, C(O)S, C(S)S,
    14 14 14 14 14
    C(O)N(R ), (R )NC(O), C(S)N(R ), (R )NC(S), OC(O)N(R ),
    14 14 14 14 14
    (R )NC(O)O, SC(S)N(R ), (R )NC(S)S, SC(O)N(R ), (R )NC(O)S,
    14 14 15 14 14 15
    OC(S)N(R ), (R )NC(S)O, N(R )C(O)N(R ), (R )NC(O)N(R ),
    15 14 14 15 14
    N(R )C(S)N(R ), (R )NC(S)N(R ), S(O), S(O)2, S(O)2N(R ),
    N(R14)S(O)2, Se, Se(O), Se(O)2, Se(O)2N(R14), N(R14)Se(O)2, P(O)(R8),
    7 8 8 7 14 14 28 29
    N(R )P(O)(R ), P(O)(R )N(R ), N(R ), ON(R ), SiR R , and
    14 2 15
    (CH(R ))e-W -(CH(R ))^ wherein e and h are integers independently
    selected from 0 through 2 and W^ is selected from the group consisting of
    4a 4b 4a 4b
    CR =CR , ethynylidene (C≡C; 1,2-ethynyl), and C=CR R with the
    14 15 provisos that R and R are selected from other than halo and cyano when
    37 38 15 15 directly bonded to N and that (CR R )f, (CH(R ))c, and (CH(R ))e are bonded to E ; _ π SSS SSS J J x is Q -Q wherein Q is (CH(R ))r-W , r is an integer selected
    3 from 1 through 3, and W 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, 13-piperazinyl, 1,4-piperazinyl, 23-piperazinyl, 2,5-piperazinyl, 2,6-piperazinyl, 1,2-piperidinyl, 1 -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-pyπolidinyl, 13- pyπolidinyl, 2,3-pyrrolidinyl, 2,4-pyπolidinyl, 2,5-pyπolidinyl, 3,4-pyπolidinyl, 2H-2,3-pyranyl, 2H-2,4-pyranyl, 2H-2,5-pyranyl, 4H-2,3-pyranyl, 4H-2,4- pyranyl, 4H-2,5-pyranyl, 2H-pyran-2-one-3,4-yl, 2H-pyran-2-one-4,5-yl, 4H- pyran-4-one-2,3-yl, 2,3-tetrahydrofuranyl, 2,4-tetrahydrofuranyl, 2,5- tetrahydrofuranyl, 3,4-tetrahydrofuranyl, 23-tetrahydropyranyl, 2,4- tetrahydropyranyl, 2,5-tetrahydropyranyl, 2,6-tetrahydropyranyl, 3,4-
    38 tetrahydropyranyl, and 3,5-tetrahydropyranyl with the proviso that (CH(R ))r
    is bonded to E and Q is bonded to lowest numbered substituent position of each W ;
    ϊ is Q -Q wherein Q is (CH(R ))r-W , r is an integer
    4 selected from 1 through 3, and W is selected from the group consisting of 1,2- cyclobutyl, 1,2-cyclohexyl, 1,3-cyclohexyl, 1,4-cyclohexyl, 1,2-cyclopentyl, 1,3- cyclopentyl, 2,3-morpholinyI, 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-pyπolidinyl, 1,3-pyπolidinyl, 2,3-pyπolidinyl, 2,4-pyπolidinyl, 2,5-pyπolidinyl, 3,4- pyπolidinyl, 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-ρyran-2-one-3,4-yl, 2H-ρyran-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-
    38 tetrahydrcpyranyl, and 3,5-tetrahydropyranyl with the provisos that (CH(R ))r
    is bonded to E and Q is bonded to highest number substituent position of
    4 each W ;
    Y is Q -Q wherein Q is (CH(R ))r-W , 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- benzoxhiophenyl, 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-indazoIyl, 3,6-indazolyI, 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
    W and that (CH(R ))_ is bonded to E ; x is Q -Q wherein Q is (CH(R ))r-W , 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, 2,5-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-cinnoUnyl with the proviso that Q is bonded to highest number substituent position of each
    W and that (CH(R ))r is bonded to E°;
    37 37
    R and R , when bonded to different carbons, are taken together to form a linear moiety spacer having from 1 through 7 contiguous atoms to form a ring selected from the group consisting of a cycloalkyl ring having from 3 through 8 contiguous members, a cycloalkenyl ring having from 3 through 8 contiguous members, and a heterocyclyl ring having from 3 through 8 contiguous members; 37 38
    R and R , when bonded to different carbons, are taken together to 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;
    38 38
    R and R , when bonded to different carbons, are taken together to form a linear moiety spacer having from 1 through 7 contiguous atoms to form a ring selected from the group consisting of a cycloalkyl ring having from 3 through 8 contiguous members, a cycloalkenyl ring having from 3 through 8 contiguous members, and a heterocyclyl ring having from 3 through 8 contiguous members;
    37 38
    R and R , when bonded to the same carbon, are taken together to 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;
    39 40 R and R , when bonded to the same carbon, are taken together to
    form a group selected from a group consisting of oxo, thiono, R -N, alkylene, haloalkylene, and a linear moiety spacer having from 2 through 7 contiguous atoms to form a ring selected from the group consisting of a cycloalkyl ring having from 3 through 8 contiguous members, a cycloalkenyl ring having from 3 through 8 contiguous members, and a heterocyclyl ring having from 3 through 8 contiguous members.
    2. The compound as recited in Claim 1 or a pharmaceutically acceptable salt thereof, wherein; B is formula (V):
    1 2 1 2 1 wherein D , D , J , J and K are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more
    1 2 1 2 1 than one is a covalent bond, no more than one of D , D , J , J and K is O,
    1 2 1 2 1 1 2 1 2 1 no more than one of D , D , J , J and K is S, one of D , D , J , J and K
    1 2 1 2 1 must be a covalent bond when two of D , D , J , J and K are O and S, and
    1 2 1 2 1 32 no more than four of D , D , J , J and K are N with the proviso that R ,
    33 34 35 36
    R , R , R , and R are each independently selected to maintain the tetravalent nature of carbon, trivalent nature of nitrogen, the divalent natore of sulfur, and the divalent natore of oxygen;
    32 33 34 35 36 b
    R , R , R , R , and R are independently selected to be Q ;
    „9 ^10 11 12 13 16 17 18 19 32 33 34 35 J R , R , R , R , R , R , R , R , R , R , R , R , R , 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, heteroarylsulfinylalkyl, heteroarylsulfonylalkyl, alkylsulfonyl, alkylsulfonylalkyl, haloalkylsulfinylalkyl, 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, satorated heterocyclyl, partially satorated 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;
    32 33 33 34 34 35 35 36
    R and R , R and R , R and R , and R and R pairs are 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 • • • T, 2 , π33 π33 J 34 34 J 35 , 35 consisting of spacer pairs R and R , R and R , R and R , and R
    36 and R is used at the same time;
    B is 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 is 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 R1 , a ring carbon or nitrogen atom adjacent to the R9 position and two atoms from the point of attachment may be substituted with
    R iQ, a ring carbon or nitrogen atom adjacent to the R1 position and two atoms
    from the point of attachment may be substitoted with Rj2, a ring carbon or
    nitrogen atom three atoms from the point of attachment and adjacent to the RJQ
    position may be substituted with R^ , a ring carbon or nitrogen atom three
    atoms from the point of attachment and adjacent to the R^2 position may be
    substituted with R33, and a ring carbon or nitrogen atom four atoms from the
    point of attachment and adjacent to the Rj j and R33 positions may be
    substituted with R34;
    ^9 Λ ^K 10 l τ,ll πll , „12 J T 12 13 . R and R , R and R , R and R , and R and R pairs are 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
    9 10 10 11 11 12 12 consisting of spacer pairs R and R , R and R , R and R , and R
    13 and R is used at the same time;
    A is selected from the group consisting of single covalent bond, (W7)rr-(CH(R15))pa and (CH(R15))pa-(W7)IT wherein π is an integer
    7 selected from 0 through 1, pa is an integer selected from 0 through 6, and W is selected from the group consisting of O, S, C(O), C(S), C(O)S, C(S)O,
    C(O)N(R?), C(S)N(R7), (R?)NC(O), (R?)NC(S), S(O), S(O)2, S(O)2N(R?),
    (R7)NS(O)2, P(O)(R8), N(R7)P(O)(R8), P(O)(R8)N(R7), C(NR7)N(R7),
    (R7)NC(NR?), and N(R7);
    7 8
    R and R are independently selected from the group consisting of hydrido, hydroxy, alkyl, acyl, aroyl, heteroaroyl, and alkoxyalkyl;
    R are independentiy 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,
    5 8 39 40 S(O), S(O)2, ON(R ), P(O)(R ), and CR R ;
    R is selected from the group consisting of hydrido, alkyl, alkoxy, alkoxyalkyl, haloalkyl, acyl, aroyl, and heteroaroyl; 39 40
    R and R are independently selected from the group consisting of hydrido, hydroxy, halo, cyano, hydroxyalkyl, acyl, aroyl, heteroaroyl, acylamido, alkoxy, alkyl, alkoxyalkyl, haloalkyl, haloalkoxy, haloalkoxyalkyl, alkylsulfonyl, haloalkylsulfonyl, carboxy, carboxyalkyl, carboalkoxy, carboxamide, and carboxamidoalkyl;
    X and R are independently selected from the group consisting of Z -
    Q, hydrido, alkyl, alkenyl, and halo;
    A and R are 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;
    Z is selected from the group consisting of covalent single bond,
    41 42 41 (CR R )q wherein q is an integer selected from 1 through 6, (CH(R ))g- o 42 W -(CH(R ))„ 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,
    42 41 41 42 42 41 N(R )C(O)N(R ), (R )NC(O)N(R ), N(R )C(S)N(R ),
    41 42 41 41 8
    (R )NC(S)N(R ), S(O), S(O)2, S(O)2N(R ), N(R )S(O)2, P(O)(R ),
    7 8 8 7 41 41 41 2
    N(R )P(O)(R ), P(O)(R )N(R ), N(R ), ON(R ), and (CH(R ))e-W -
    42 (CH(R ))b wherein e and h are integers independently selected from 0
    2 41 42 through 2 and W^ is selected from the group consisting of CR =CR ,
    41 42 CR R =C; vinylidene), and ethynylidene (C≡C; 1,2-ethynyl), with the 41 42 provisos that R and R are selected from other than halo and cyano when directly bonded to N and Z is directly bonded to the pyrone ring;
    41 42
    R and R 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, satorated heterocyclyl, partially saturated heterocyclyl, heteroaryl, heteroaralkyl, heteroarylthioalkyl, heteroaralkylthioalkyl, alkylsulfonyl, haloalkylsulfonyl, arylsulfonyl, arylsulfonylalkyl, aralkylsulfonyl, cycloalkylsulfonyl, cycloalkylsufonylalkyl, heteroarylsulfonylalkyl, heteroarylsulfonyl, and aralkylsulfonylalkyl; Q is formula (II):
    1 2 1 X2 1 wherein D , D , J , J and K are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more
    1 2 1 2 1 than one is a covalent bond, no more than one of D , D , J , J and K is O,
    1 2 1 2 1 1 2 1 2 1 no more than one of D , D , J , J and K is S, one of D , D , J , J and K
    1 2 1 1 must be a covalent bond when two of D , D , J , J and K are O and S, and
    1 2 1 .2 1 9 no more than four of D , D , J , J and K are N, with the proviso that R ,
    10 „11 „12 ι π13 , . , , , , , . . ,
    R , R , R , and R are each independentiy selected to maintain the tetravalent nature of carbon, trivalent nature of nitrogen, the divalent natore of sulfur, and the divalent nature of oxygen; Q is formula (III):
    wherein DD" ,, DD ' ,, J J" ,, ; and J ' are independently selected from the group
    3 4 3 4 consisting of C, N, O, and S, no more than one of D , D , J , and J is O, no
    3 4 3 4 1 2 1 more than one of D , D , ϊ , and J is S, and no more than three of D , D , J ,
    2 9 10 11 12 and J are N with the proviso that R , R , R , and R are each independently selected to maintain the tetravalent nature of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen;
    Q is 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;
    4a 4b K is (CR R )n wherein n is an integer selected from 1 through 2;
    4a 4b
    R and R are independently selected from the group consisting of halo, hydrido, hydroxy, cyano, hydroxyalkyl, alkyl, alkenyl, alkoxyalkyl, haloalkyl, haloalkenyl, and cyanoalkyl;
    4a 4b
    R and R , when bonded to the same carbon, are 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; o 1 4a 4b 1
    E is E , when K is (CR R )n, wherein E is selected from the group consisting of a covalent single bond, O, S, C(O), C(S), C(O)O, C(S)O, C(O)S, C(S)S, C(O)N(R7), (R?)NC(O), C(S)N(R7), (R?)NC(S), OC(O)N(R7),
    (R7)NC(O)O, SC(S)N(R?), (R?)NC(S)S, SC(O)N(R?), (R?)NC(O)S,
    OC(S)N(R7), (R?)NC(S)O, N(R8)C(O)N(R?), (R?)NC(O)N(R8),
    N(R8)C(S)N(R?), (R?)NC(S)N(R8), S(O), S(O)2, S(O)2N(R?), N(R7)S(O)2,
    S(O)2N(R7)C(O), C(O)N(R7)S(O)2, P(O)(R8), N(R?)P(O)(R8),
    P(O)(R8)N(R?), N(R7), ON(R?), CR4a=CR4b, ethynylidene (C≡C; 1 ,2-
    4a 4b ethynyl), and C=CR R ;
    14 K is (CH(R )):-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
    7 14
    N(R ) with the proviso that (CH(R )); is bonded to the pyrone ring; o 2 14 2 E is E , when K is (CH(R )VT, wherein E 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), (R?)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(R?), (R?)NC(S)N(R8), S(O), S(O)2,
    S(O)2N(R?), N(R7)S(O)2, S(O)2N(H)C(O), C(O)N(H)S(O)2, P(O)(R8),
    N(R?)P(O)(R8), P(O)(R8)N(R?), and N(R7);
    15 K is G-(CH(R ))k wherein k is selected from an integer from 1
    7 through 2 and G is selected from the group consisting of O, S, and N(R ) with the proviso that R is other than hydroxy, cyano, halo, amino, alkylamino, dialkylamino, and sulfhydryl when k is 1; 1 "2
    E is E , when K is G-(CH(R ) , wherein E is selected from the group consisting of a covalent single bond, O, S, C(O), C(S), C(O)O, C(S)O, C(O)S, C(S)S, C(O)N(R7), (R?)NC(O), C(S)N(R7), (R?)NC(S),
    OC(O)N(R7), (R7)NC(O)O, SC(S)N(R7), (R?)NC(S)S, SC(O)N(R?),
    (R7)NC(O)S, OC(S)N(R?), (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(R?), N(R?)S(O)2, P(O)(R8), N(R?)P(O)(R8), P(O)(R8)N(R7),
    7 7 4a 4b N(R ), ON(R ), CR =CR , ethynylidene (C=C; 1,2-ethynyl), and
    ^ .4a 4b C=CR R ;
    Υ° is formula (IV):
    5 6 5 6 wherein D , D , J , and J are independentiy selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more
    2 than one is a covalent bond, K is independently selected from the group
    consisting of C, and N , no more than one of D , D , J , and J is O, no more
    than one of D , D , J , and J is S, one ofD , D , J , and J mustbe a
    covalent bond when two of D , D ,J , andj are O and S, no more than three of D , D , J , andj are N when K is N , and no more than four of D , D ,
    5 6 2 . . . τ-, _ 17 _ 18
    J , and J are N when K is carbon with the provisos that R , R , R , and
    19 R are each independently selected to maintain the tetravalent natare of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen; are 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; b 20 21 + 20 21 22
    Q is selected from the group consisting of NR R , NR R R , oxy, alkyl, alkylaminoalkyl, aminoalkyl, dialkylsulfoniumalkyl, and acylamino
    20 21 22 wherein R , R , and R are independently selected from the group consisting of hydrido, alkyl, hydroxy, alkoxy, alkylamino, dialkylamino,
    20 aminoalkyl, and hydroxyalkyl with the provisos that no more than one of R ,
    21 22
    R , and R is hydroxy, alkoxy, alkylamino, amino, and dialkylamino and that
    20 21 22
    R , R , and R must be other than be hydroxy, alkoxy, alkylamino, ammo,
    2 + and dialkylamino when K is N ;
    20 21 20 22 21 22 R and R , R and R , and R and R pairs are 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
    20 21 20 22 21 22 group consisting of spacer pairs R and R , R and R , and R and R is used at the same time; , fjgi α OΛ
    Q is selected from the group consisting of N(R )SO2N(R )(R ),
    N(R26)C(O)OR5, N(R26)C(O)SR5, N(R26)C(S)OR5 and N(R26)C(S)SR5
    23 24 26 with the proviso that no more than one of R , R , and R is hydroxy, alkoxy, alkylamino, amino, or dialkylamino when two of the group consisting
    23 24 26 of R , R , and R are bonded to the same atom;
    Q is selected from the group consisting of dialkylsulfonium,
    O^i OΛ O/Z -ζ OΛ trialkylphosphonium, C(NR )NR R , N(R )C(NR )N(R )(R ),
    26 23 24 26 23 24 25 5
    N(R )C(O)N(R )(R ), N(R )C(S)N(R )(R ), C(NR )OR ,
    26 25 23 24 26 25 23 24
    C(O)N(R )C(NR )N(R )(R ), C(S)N(R )C(NR )N(R )(R ),
    N(R26)N(R26)C(NR25)N(R23)(R24), N(R26)N(R26)SO2N(R23)(R24),
    25 5 23 24 23 24
    C(NR )SR , C(O)NR R , and C(O)NR R with the provisos that no
    23 24 26 more than one of R , R , and R is hydroxy, alkoxy, alkylamino, amino, or
    23 24 26 dialkylamino when two of the group consisting of R , R , and R are
    bonded to the same atom and that said Q group is bonded directly to a carbon atom;
    23 24 25 26
    R , R , R , and R are independently selected from the group consisting of hydrido, alkyl, hydroxy, alkoxy, alkylamino, dialkylamino, aminoalkyl, and hydroxyalkyl;
    23 24
    R and R are 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; s Q is selected from the group consisting of a single covalent bond,
    (CR R )tø-(W )az wherein az is an integer selected from 0 through 1, b is an integer selected from 1 through 4, and w is selected from the group consisting of O, S, C(O), C(S), C(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),
    14 14 15 14 14 15
    SC(O)N(R ), OC(S)N(R ), N(R )C(O)N(R ), (R )NC(O)N(R ),
    15 14 14 15 14
    N(R )C(S)N(R ), (R )NC(S)N(R ), S(O), S(O)2, S(O)2N(R ),
    14 8 7 8 8 7 14 N(R )S(O)2, P(O)(R ), N(R )P(O)(R ), P(O)(R )N(R ), N(R ),
    14 14 1 15
    ON(R ), (CH(R ))C-W -(CH(R ))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),
    14 14 14 14 14
    (R )NC(O), C(S)N(R ), (R )NC(S), OC(O)N(R ), (R )NC(O)O,
    14 14 14 14 14 SC(S)N(R ), (R )NC(S)S, SC(O)N(R ), (R )NC(O)S, OC(S)N(R ),
    14 15 14 14 15
    (R )NC(S)O, N(R )C(O)N(R ), (R )NC(O)N(R ),
    15 14 14 15 14 N(R )C(S)N(R ), (R )NC(S)N(R ), S(O), S(O)2, S(O)2N(R ),
    N(R14)S(O)2, P(O)(R8), N(R7)P(O)(R8), P(O)(R8)N(R?), N(R14),
    14 14 2 15
    ON(R ), and (CH(R ))e-W -(CH(R ))h wherein e and h are integers
    independently selected from 0 through 2 and W^ is selected from the group
    4a 4b 4a 4b consisting of CR =CR , ethynylidene (C≡C; 1,2-ethynyl), and C=CR R
    14 15 with the provisos that R and R are selected from other than halo and cyano
    37 38 14 14 when directly bonded to N and that (CR R ) , (CH(R ))C, (CH(R ))e and are bonded to E ;
    is selected from the group consisting of
    37 38 14
    (CR R f wherein f is an integer selected from 1 through 6, (CH(R ))c- W -(CH(R ))(j wherein c and d are integers independentiy selected from 1
    1 1 through 4, 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)O, C(O)S, C(S)S,
    14 14 14 14 14
    C(O)N(R ),(R )NC(O), C(S)N(R ),(R )NC(S), OC(O)N(R ),
    (R14)NC(O)O, SC(S)N(R14), (R14)NC(S)S, SC(O)N(R14), (R14)NC(O)S,
    14 14 15 14 14 15
    OC(S)N(R ),(R )NC(S)O,N(R )C(O)N(R ),(R )NC(O)N(R ),
    15 14 14 15 14
    N(R )C(S)N(R ),(R )NC(S)N(R ), S(O), S(O)2, S(O)2N(R ),
    14 8 7 8 8 7 14
    N(R )S(O)2,P(O)(R ),N(R)P(O)(R ),P(O)(R )N(R ),N(R ),
    14 14 2 15
    ON(R ), and (CH(R ))e-W -(CH(R ))h wherein e and h are integers
    independently selected from 0 through 2 and W^ is selected from the group
    4a 4b 4a 4b consisting of CR =CR , ethynylidene (C≡C; 1,2-ethynyl), and C=CR R
    14 15 with the provisos that R and R are selected from other than halo and cyano
    37 38 15 when directly bonded to N and that (CR R )f , (CH(R ))c , and
    1 *Z
    (CH(R ))e are bonded to E°; In sss sss Q *j Y is Q -Q , wherein Q is (CH(R ))r- W , r is an integer selected
    from 1 through 3, and W 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, 23- morpholinyl, 2,4-morpholinyl, 2,5-morpholinyl, 2,6-morpholinyl, 3,4- morpholinyl, 3,5-morpholinyl, 1,2-piperazinyl, 1,3-piperazinyl, 1,4-piperazinyl, 23-piperazinyl, 2,5-piperazinyl, 2,6-piperazinyl, 1,2-piperidinyl, 1,3-piperidinyl, 1,4-piperidinyl, 23-piperidinyl, 2,4-piperidinyl, 2,5-piperidinyl, 2,6-piperidinyl, 3,4-piperidinyl, 3,5-piperidinyl, 3,6-piperidinyl, 1,2-pyπolidinyl, 13- pyπolidinyl, 23-pyπolidinyl, 2,4-pyπolidinyl, 2,5-pyπolidinyl, 3,4-ρyπolidinyl, 2H-2,3-pyranyl, 2H-2,4-pyranyl, 2H-2,5-pyranyl, 4H-23-pyranyl, 4H-2,4- pyranyl, 4H-2,5-pyranyl, 2H-pyran-2-one-3,4-yl, 2H-pyran-2-one-4,5-yl, 4H- pyran-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-
    38 tetrahydropyranyl, and 3,5-tetrahydropyranyl with the proviso that (CH(R ))r
    is bonded to E and Q is bonded to lowest numbered substituent position of
    each W ;
    is Q -Q , wherein Q is (CH(R ))r-W , r is an integer
    4 selected from 1 through 3, and W is selected from the group consisting of 1,2- cyclobutyl, 1,2-cyclohexyl, 1,3-cyclohexyl, 1,4-cyclohexyl, 1,2-cyclopentyl, 1,3- cyclopentyl, 2,3-morpholinyl, 2,4-morpholinyl, 2,5-morpholinyl, 2,6- morpholinyl, 3,4-morρholinyl, 3,5-morpholinyl, 1,2-piperazinyl, 1,3-piperazinyl, 1,4-piperazinyl, 2,3-piperazinyl, 2,Spiperazinyl, 2,6-piperazinyl, 1,2-piperidinyl, 1,3-ρiρeridinyl, 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-pyπolidinyl, 1,3-pyπolidinyl, 2,3-pyπolidinyl, 2,4-pyπolidinyl, 2,5-pyπolidinyl, 3,4- pyπolidinyl, 2H-2,3-pyranyl, 2H-2,4-pyranyl, 2H-2,5-pyranyl, 4H-2,3-pyranyl, 4H-2,4-ρyranyl, 4H-2,5-pyranyl, 2H-ρyran-2-one-3,4-yl, 2H-pyran-2-one-4,5- yl, 4H-pyran-4-one-2,3-yl, 23-tetrahydrofuranyl, 2,4-tetrahydrofuranyl, 2,5- tetrahydrofuranyl, 3,4-tetrahydrofuranyl, 2,3-tetrahydropyranyl, 2,4- tetrahydropyranyl, 2,5-tetrahydropyranyl, 2,6-tetrahydropyranyl, 3,4-
    38 tetrahydropyranyl, and 3,5-tetrahydropyranyl with the provisos that (CH(R ))r
    is bonded to E and Q is bonded to highest number substituent position of
    4 each W ; > . ^b „.ssss , . ~ssss . /^τ τ/τ-,38 5 . . Y is Q -Q , wherein Q is (CH(R ))r-W , 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, 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-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
    W and that (CH(R ))r is bonded to E°; f\ v* ssssr SSSSI* *5O O
    Y is Q -Q , wherein Q is (CH(R ))r-W , 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-quinolinyl, 2,8-quinolinyl, 3,4- quinolinyl, 3,5-quinolinyl, 3,6-quinolinyl, 3,7-quinolinyl, 3,8-quinolinyl, 4,5- quinolinyl, 4,6-quinolinyl, 4,7-quinolinyl, 4,8-quinolinyl, 1,4-isoquinolinyl, 1,5- isoquinolinyl, 1,6-isoquinolinyl, 1,7-isoquinolinyl, 1,8-isoquinolinyl, 3,4- isoquinolinyl, 3,5-isoquinolinyl, 3,6-isoquinolinyl, 3,7-isoquinolinyl, 3,8- isoquinolinyl, 4,5-isoquinolinyl, 4,6-isoquinolinyl, 4,7-isoquinolinyl, 4,8- isoquinolinyl, 3,4-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
    .
    3. The compound as recited in Claim 1 or a pharmaceutically acceptable salt thereof, wherein;
    B is formula (V):
    wherein D -1 , D ,ΛJ , j J2 i and -K1 are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more
    1 2 1 2 1 than one is a covalent bond, no more than one of D , D , J , J and K is O,
    1 2 1 ,2 1 1 2 1 2 1 no more t 1han one of D , D , J , J and K is S, one of D , D , J , J and K 1 2 1 2 1 must be a covalent bond when two of D , D , J , J and K are O and S, and
    1 2 1 2 1 no more than four of D , D , J , j and K are N;
    „32 33 34 35 , ^36 . , , n , , , h R , R , R , R , and R are independently selected to be Q ;
    R9 R10 R1 R12, R13, R16 R17, R18 R19 R32 R33,R34 R35 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, heteroarylsulfinylalkyl, heteroarylsulfonylalkyl, alkylsulfonyl, alkylsulfonylalkyl, haloalkylsulfinylalkyl, haloalkylsulfonylalkyl, alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, monoarylamidosulfonyl, arylsulfonamido, diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl, arylsulfinyl, arylsulfonyl, heteroaryl thio, 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 is 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 substitated 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 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 substitated 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 substitated with
    R ø> a ring carbon or nitrogen atom adjacent to the Ry$ position and two atoms
    from the point of attachment may be substituted with R^2, a ring carbon or
    nitrogen atom three atoms from the point of attachment and adjacent to the RJQ
    position may be substituted with Rj j , a ring carbon or nitrogen atom three
    atoms from the point of attachment and adjacent to the R j2 position may be
    substitated with R33, and a ring carbon or nitrogen atom four atoms from the point of attachment and adjacent to the R^ γ 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 π is an integer
    7 selected from 0 through 1, pa is an integer selected from 0 through 6, and W is selected from the group consisting of O, S, C(O), C(S), C(O)S, C(S)O,
    C(O)N(R7), C(S)N(R7), (R7)NC(O), (R?)NC(S), S(O), S(O)2, S(O)2N(R?),
    (R7)NS(O)2, C(NR7)N(R7), (R7)NC(NR7), and N(R?);
    7 8
    R and R are independently selected from the group consisting of hydrido, hydroxy, alkyl, and alkoxyalkyl;
    14 15 37 38 „
    R , R , R , and R are independently selected from the group consisting of hydrido, hydroxy, halo, alkyl, alkoxyalkyl, haloalkyl, haloalkoxy, and haloalkoxyalkyl;
    5 Ψ is selected from the group consisting of NR , O, C(O), C(S), S,
    39 40 S(O), S(O)2, and CR R ;
    R is selected from the group consisting of hydrido, alkyl, and alkoxy;
    39 40
    R and R are independently selected from the group consisting of hydrido, hydroxy, halo, hydroxyalkyl, alkyl, alkoxyalkyl, haloalkyl, haloalkoxy, and haloalkoxyalkyl; X and R are independently selected from the group consisting of Z -
    Q, hydrido, alkyl, alkenyl, and halo;
    X 0 and R 2 are 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; Z is selected from the group consisting of covalent single bond,
    41 42 41 (CR R )„ wherein q is an integer selected from 1 through 2, (CH(R ))g- o 42
    W -(CH(R ))_ 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),
    41 41 41 C(O)O, C(S)O, C(O)S, C(S)S, C(O)N(R ), (R )NC(O), C(S)N(R ),
    (R41)NC(S), OC(O)N(R41), (R41)NC(O)O, SC(S)N(R41), (R41)NC(S)S,
    41 41 41 41
    SC(O)N(R ), (R )NC(O)S, OC(S)N(R ), (R )NC(S)O,
    42 41 41 42 42 41 N(R )C(O)N(R ), (R )NC(O)N(R ), N(R )C(S)N(R ),
    (R41)NC(S)N(R42), S(O), S(O)2, S(O)2N(R41), N(R41)S(O)2, N(R41),
    41 41 2 42 ON(R ), and (CH(R ))e-W -(CH(R ))h wherein e and h are integers
    independently selected from 0 through 2 and W^ is selected from the group
    41 42 41 42 consisting of CR =CR , CR R =C; vinylidene), and ethynylidene (C≡C;
    41 42
    1 ,2-ethynyl), with the provisos that R and R are selected from other than halo and cyano when directly bonded to N and Z is directly bonded to the pyrone ring;
    41 42
    R and R 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): wherein D ~ , D~~.,JJ ~ , ϊ~: and K are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more than one is a covalent bond, no more than one of D is O,
    1 2 1 2 1 1 2 1 2 1 no more than one of D , D , J , J and K is S, one of D , D , J , J and K
    1 2 1 1 must be a covalent bond when two of D ,, DD ,, JJ ,, Γ J M and * "K are O and S, and
    1 2 1 1 9 no more than four of D , D , J , J and K are N, with the proviso that R ,
    „10 1 1 12 13 , . , , t Λ t . . ,
    R , R , R , and R are each independently selected to maintain the tetravalent nature of carbon, trivalent natore of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen;
    Q is selected from the group consisting of alkyl, alkoxy, alkylamino, alkylthio, haloalkylthio, satorated 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 (CR HR )n wherein n is the integer 1 ;
    4a 4b
    R and R are independently selected from the group consisting of halo, hydrido, hydroxy, hydroxyalkyl, alkyl, alkoxyalkyl, and haloalkyl; o 1 4a 4b 1 E is E , when K is (CR R )n, wherein E is selected from the group consisting of a covalent single bond, O, S, C(O), C(S), C(O)O, C(S)O, C(O)S,
    C(S)S, C(O)N(R?), (R7)NC(O), C(S)N(R?), (R?)NC(S), OC(O)N(R7), (R )NC(O)O, SC(S)N(R7), (R7)NC(S)S, SC(O)N(R?), (R?)NC(O)S,
    OC(S)N(R7), (R7)NC(S)O, N(R8)C(O)N(R?), (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(R?), ON(R?), CR4a=CR4b,
    4 4aa_ 4 4< bD ethynylidene (C≡C; 1,2-ethynyl), and C=CR R
    14 K is (CH(R ))j-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
    7 14
    N(R ) with the proviso that (CH(R )) is bonded to the pyrone ring; o 2 14 2
    E IS E , when K is (CH(R )VT, wherein E 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(R?), (R?)NC(O), C(S)N(R?), (R?)NC(S), (R?)NC(O)O,
    (R7)NC(S)S, (R?)NC(O)S, (R?)NC(S)O, N(R8)C(O)N(R7),
    (R?)NC(O)N(R8), N(R8)C(S)N(R7), (R7)NC(S)N(R8), S(O), S(O)2,
    S(O)2N(R?), N(R?)S(O)2, S(O)2N(H)C(O), C(O)N(H)S(O)2, and N(R?);
    K is G-(CH(R ) wherein k is the integer 1 and G is selected from
    7 the group consisting of O, S, and N(R ); 1 < *2
    E is E , when K is G-(CH(R ))jc, 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(R?), (R?)NC(S),
    OC(O)N(R7), (R?)NC(O)O, SC(S)N(R7), (R7)NC(S)S, SC(O)N(R7),
    (R7)NC(O)S, OC(S)N(R7), (R?)NC(S)O, N(R8)C(O)N(R?),
    (R7)NC(O)N(R8), N(R8)C(S)N(R7), (R?)NC(S)N(R8), S(O), S(O)2, S(O)2N(R?), N(R?)S(O)2, N(R?), ON(R?), CR4a=CR4b, ethynylidene (C≡C;
    4a 4b 1,2-ethynyl), and C=CR R ;
    Y° is formula (IV):
    wherein D , are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more
    2 than one is a covalent bond, K is independently selected from the group
    consisting of C and N , no more than one of D , D , J , and J is O, no more
    , 5 6 5 τ6 . _ . _ 5 6 x5 6 than one of D , D , J , and J is S, one of D , D , J , and J must be a
    covalent bond when two of , and are O and S, no more than three
    of D , D , J , and J are N when K is N , and no more than four of D , D ,
    5 6 2 16 17 18
    J , and J are N when K is carbon with the provisos that R , R , R , and
    19 R are each independently selected to maintain the tetravalent natare of carbon, trivalent nature of nitrogen, the divalent natare of sulfur, and the divalent nature of oxygen; b 20 21 + 20 21 22
    Q is selected from the group consisting of NR R , NR R R , oxy, alkyl, alkylaminoalkyl, aminoalkyl, dialkylsulfoniumalkyl, and acylamino
    20 21 22 wherein R , R , and R are independently selected from the group consisting of hydrido, alkyl, hydroxy, alkoxy, alkylamino, dialkylamino, 20 aminoalkyl, and hydroxyalkyl with the provisos that no more than one of R ,
    21 22
    R , and R is hydroxy, alkoxy, alkylamino, amino, or dialkylamino and that
    20 21 22
    R ,R , and R must be other than be hydroxy, alkoxy, alkylamino, amino,
    2 - and dialkylamino when K is N ; Q is selected from the group consisting of N(R )SO N(R )(R ),
    N(R26)C(O)OR5, N(R26)C(O)SR5, N(R26)C(S)OR5 and N(R26)C(S)SR5
    23 24 26 with the proviso that no more than one of R , R , and R is hydroxy, alkoxy, alkylamino, amino, or dialkylamino when two of the group consisting
    P Ω J24 26 , , , , of R , R , and R are bonded to the same atom;
    Q is selected from the group consisting of dialkylsulfonium,
    Λ Γ I*\ ^iA O^ ^ OΛ trialkylphosphonium, C(NR )NR R , N(R )C(NR )N(R )(R ),
    ,
    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),
    25 5 23 24 23 24 C(NR )SR , C(O)NR R , and C(O)NR R with the provisos that no
    23 24 26 more than one of R , R , and R is hydroxy, alkoxy, alkylamino, amino, or
    23 24 26 dialkylamino when two of the group consisting of R , R , and R are
    bonded to the same atom and that said Q group is bonded directly to a carbon atom;
    23 24 25 26 R , R , R , and R are independently selected from the group consisting of hydrido, alkyl, hydroxy, alkoxy, alkylamino, dialkylamino, aminoalkyl, and hydroxyalkyl; Q is selected from the group consisting of a single covalent bond,
    (CR R )tø-(W )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(O), C(S)N(R14), (R14)NC(S), OC(O)N(R14), SC(S)N(R14),
    14 14 15 14 14 15
    SC(O)N(R ), OC(S)N(R ), N(R )C(O)N(R ), (R )NC(O)N(R ),
    15 14 14 15 14
    N(R )C(S)N(R ), (R )NC(S)N(R ), S(O), S(O)2, S(O)2N(R ),
    14 14 14 14 1 15
    N(R )S(O)2, N(R ), ON(R ), (CH(R ))C-W -(CH(R ))d wherein 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(O)O, C(S)O, C(O)S, C(S)S,
    14 14 14 14 14
    C(O)N(R ), (R )NC(O), C(S)N(R ), (R )NC(S), OC(O)N(R ),
    14 14 14 14 14
    (R )NC(O)O, SC(S)N(R ), (R )NC(S)S, SC(O)N(R ), (R )NC(O)S,
    14 14 15 14 14 15
    OC(S)N(R ), (R )NC(S)O, N(R )C(O)N(R ), (R )NC(O)N(R ),
    15 14 14 15 14 N(R )C(S)N(R ), (R )NC(S)N(R ), S(O), S(O)2, S(O)2N(R ),
    14 14 14 14 2 15 N(R )S(O)2, N(R ), ON(R ), and (CH(R ))e-W -(CH(R ))h wherein
    e and h are integers independently selected from 0 through 2 and W^ is
    4a 4b selected from the group consisting of CR =CR , ethynylidene (G≡C; 1,2-
    4a 4b 14 15 ethynyl), and C=CR R with the provisos that R and R are selected from other than halo and cyano when directly bonded to N and that
    37 38 14 14 n (CR R )b, (CH(R ))c, and (CH(R ))e are bonded to E ;
    ■D b ss ss i is Q -Q wherein Q is selected from the group consisting of
    37 38 14
    (CR R )f wherein f is an integer selected from 1 through 4, (CH(R ))c- 1 15
    W -(CH(R ))^ 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)O, C(O)S, C(S)S,
    14 14 14 14 14
    C(O)N(R ), (R )NC(O), C(S)N(R ), (R )NC(S), OC(O)N(R ),
    (R14)NC(O)O, SC(S)N(R14), (R14)NC(S)S, SC(O)N(R14), (R14)NC(O)S,
    14 14 15 14 14 15
    OC(S)N(R ), (R )NC(S)O, N(R )C(O)N(R ), (R )NC(O)N(R ),
    15 14 14 15 14
    N(R )C(S)N(R ), (R )NC(S)N(R ), S(O), S(O)2, S(O)2N(R ),
    14 14 14 14 2 15
    N(R )S(O)2, N(R ), ON(R ), and (CH(R ))e-W -(CH(R ))h wherein
    e and h are integers independently selected from 0 through 2 and W^ is
    4a 4b selected from the group consisting of CR =CR , ethynylidene (C≡C; 1,2-
    4a 4b 14 15 ethynyl), and C=CR R with the provisos that R and R are selected
    37 38 from other than halo when directly bonded to N and that (CR R )f ,
    (CH(R ))c, and (CH(R ))e are bonded to E°;
    r is an integer selected
    3 from 1 through 2, and W 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, 23- morpholinyl, 2,4-morpholinyl, 2,5-morpholinyl, 2,6-morpholinyl, 3,4- morpholinyl, 3,5-morpholinyl, 1,2-piperazinyl, 1,3-piperazinyl, 1,4-piperazinyl, 23-piperazinyl, 2,5-piperazinyl, 2,6-piperazinyl, 1,2-piperidinyl, 1,3-piperidinyl, 1,4-piperidinyl, 23-piperidinyl, 2,4-piperidinyl, 2,5-piperidinyl, 2,6-piperidinyl, 3,4-piperidinyl, 3,5-piperidinyl, 3,6-piperidinyl, 1,2-pyπolidinyl, 1,3- pyπolidinyl, 2,3-pyπolidinyl, 2,4-pyπolidinyl, 2,5-pyπolidinyl, 3,4-ρyπolidinyl, 2H-23-pyranyl, 2H-2,4-pyranyl, 2H-2,5-pyranyl, 4H-2,3-pyranyl, 4H-2,4- pyranyl, 4H-2,5-ρyranyl, 2H-ρyran-2-one-3,4-yl, 2H-pyran-2-one-4,5-yl, 4H- ρyran-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-
    38 tetrahydropyranyl, and 3,5-tetrahydropyranyl with the proviso that (CH(R ))r
    is bonded to E and Q is bonded to lowest numbered substituent position of each W3;
    38 x is Q -Q wherein Q is (CH(R ))r-W , r is an integer
    4 selected from 1 through 2, and W is selected from the group consisting of 1,2- cyclobutyl, 1,2-cyclohexyl, 1,3-cyclohexyl, 1,4-cyclohexyl, 1,2-cyclopentyl, 13- cyclopentyl, 2,3-morpholinyl, 2,4-morpholinyl, 2,5-morpholinyl, 2,6- morpholinyl, 3,4-morpholinyl, 3,5-morpholinyl, 1,2-piperazinyl, 1,3-piperazinyl, 1,4-piperazinyl, 2,3-piperazinyl, 2,5-piperazinyl, 2,6-piperazinyl, 1,2-piperidinyl, 1,3-piperidinyl, 1,4-piperidinyl, 2,3-piperidinyl, 2,4-piperidinyl, 2,5-piperidinyl, 2,6-piperidinyl, 3,4-piperidinyl, 3,5-piperidinyl, 3,6-piperidinyl, 1,2-pyπolidinyl, 1,3-pyπolidinyl, 2,3-pyπolidinyl, 2,4-pyπolidinyl, 2,5-pyπolidinyl, 3,4- pyπolidinyl, 2H-23-pyranyl, 2H-2,4-pyranyl, 2H-2,5-pyranyl, 4H-2,3-pyranyI, 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, 23-tetrahydropyranyl, 2,4- tetrahydropyranyl, 2,5-tetrahydropyranyl, 2,6-tetrahydropyranyl, 3,4-
    38 tetrahydropyranyl, and 3,5-tetrahydropyranyl with the provisos that (CH(R ))r
    is bonded to E and Q is bonded to highest number substituent position of
    4 eachW ;
    x is Q -Qssss wherein QSSSS is (CH(R ))r-W , 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-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
    W and that (CH(R ))r is bonded to E ;
    Y° is 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,S 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^-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-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-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 Q is bonded to highest number substituent position of each
    .
    4. The compound as recited in Claim 3 or a pharmaceutically acceptable salt thereof, wherein;
    B is formula (V):
    1 2 1 X2 1 wherein D , D , J , J and K are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more
    1 2 1 1 than one is a covalent bond, no more than one of D , D , J , J and K is O,
    1 2 1 2 1 1 2 1 2 1 no more than one of D , D , J , J and K is S, one of D , D , J , J and K
    1 2 1 2 1 must be a covalent bond when two of D , D , J , j and K are O and S, and
    1 2 1 2 1 no more than four of D , D , J , J and K are N; R , R , R , R , and R are independently selected to be Q ; n9 n10 πll π12 π13 n32 3 34 n35 36
    R , R , R , R , R , R , R , R , R , and R 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, monoarylamidosulfonyl, 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 is 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 is 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 substitated 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 R-^, a ring carbon or nitrogen atom adjacent to the R9 position and two atoms from the point of attachment may be substituted with RJQ, a ring carbon or nitrogen atom adjacent to the R1 position and two atoms
    from the point of attachment may be substitated with Rj2, a ring carbon or nitrogen atom three atoms from the point of attachment and adjacent to the RJQ
    position may be substitated with Rj j , a ring carbon or nitrogen atom three
    atoms from the point of attachment and adjacent to the Rj2 position may be
    substitated with R33, and a ring carbon or nitrogen atom four atoms from the
    point of attachment and adjacent to the Rj j and R33 positions may be
    substitated 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
    7 selected from 0 through 1, pa is an integer selected from 0 through 6, and W is selected from the group consisting of O, S, C(O), C(S), C(O)S, C(S)O,
    C(O)N(R7), C(S)N(R7), (R?)NC(O), (R?)NC(S), S(O), S(O)2, S(O)2N(R7),
    (R7)NS(O)2, C(NR7)N(R?), (R?)NC(NR?), and N(R?) with the proviso that no more than one of the group consisting of π and pa is 0 at the same time;
    7 8
    R and R are independently selected from the group consisting of hydrido, hydroxy, alkyl, and alkoxyalkyl;
    15 R is selected from the group consisting of hydrido, hydroxy, halo, alkyl, and haloalkyl; Ψ is NH;
    X is hydrido;
    ? 0 R is selected from the group consisting of Z -Q, hydπdo, alkyl, alkenyl, and halo; Z Z iiss aa ccoo1valent single bond; Q is formula (II)
    1 2 1 2 1 wherein D , D , J , J and K are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more
    1 2 1 2 1 . than one is a covalent bond, no more than one of D , D , J , J and K is O,
    1 2 1 2 1 1 2 1 2 1 no more than one of D , D , J , J and K is S, one of D , D , J , J and K
    1 2 1 2 1 must be a covalent bond when two of D , D , J , J and K are O and S, and
    1 1 2 1 9 no more than four of D , D , J , J and K are N, with the proviso that R ,
    10 11 12 13
    R , R , R , and R are each independently selected to maintain the tetravalent natare of carbon, trivalent nature of nitrogen, the divalent natare of sulfur, and the divalent nature of oxygen;
    K is CR ^;
    4a 4b
    R and R are independently selected from the group consisting of halo, hydrido, hydroxy, alkyl, and haloalkyl;
    E is E , when K is CR R , 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;
    14 K is (CH(R ));-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
    7 14
    N(R ) with the proviso that (CH(R )); is bonded to the pyrone ring; 14 R is selected from the group consisting of hydrido, halo, alkyl, and haloalkyl; o 2 14 2
    E is E , when K is (CH(R ))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; Y° is formula (IV):
    5 6 5 6 wherein D , D , J , and J are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more
    2 than one is a covalent bond, K is independently selected from the group
    consisting of C and N , no more than one of D , D , J , and J is O, no more
    5 6 5 6 5 6 5 6 than one of D , D , j , and J is S, one of D , D , J , and J must be a
    covalent bond when two of D , are O and S, no more than three
    of D , D , i , and J are N when K is N , and no more than four of D , D ,
    J , and
    19 R are each independently selected to maintain the tetravalent natare of carbon, trivalent nature of nitrogen, the divalent natare of sulfur, and the divalent nature of oxygen; R 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; b 20 21 + 20 21 22
    Q is selected from the group consisting of NR R , NR R R , oxy, alkyl, alkylaminoalkyl, aminoalkyl, dialkylsulfoniumalkyl, and acylamino
    20 21 22 wherein R , R , and R are independently selected from the group consisting of hydrido, alkyl, hydroxy, alkoxy, alkylamino, dialkylamino,
    20 aminoalkyl, and hydroxyalkyl with the provisos that no more than one of R ,
    21 22
    R , and R is hydroxy, alkoxy, alkylamino, amino, or dialkylamino and that
    20 21 22
    R , R , and R must be other than be hydroxy, alkoxy, alkylamino, amino,
    2 + or dialkylamino when K is N ; b 26 23 24 Q is N(R )SO2N(R )(R ) with the proviso that no more than one
    23 24 26 of R , R , and R is hydroxy, alkoxy, alkylamino, ammo, or dialkylamino
    when two of the group consisting of R , R , and R are bonded to the same atom;
    23 24 25 26
    R , R , R , and R are independently selected from the group consisting of hydrido, alkyl, hydroxy, alkoxy, alkylamino, dialkylamino, aminoalkyl, and hydroxyalkyl;
    Q is selected from the group consisting of dialkylsulfonium, ry e rt ι*S Λ rtt r £~ fJ Λ trialkylphosphonium, C(NR )NR R , N(R )C(NR )N(R )(R ),
    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), 26 26 25 23 24 26 26 23 24
    N(R )N(R )C(NR )N(R )(R ), N(R )N(R )SO2N(R )(R ),
    23 24 23 24
    C(O)NR R , and C(O)NR R with the provisos that no more than one of
    R , R , and R is hydroxy, alkoxy, alkylamino, amino, or dialkylamino when
    23 24 26 two of the group consisting of R , R , and R are bonded to the same atom and
    that said Q group is bonded directly to a carbon atom; g
    Q is selected from the group consisting of a single covalent bond and
    (CR R )D-(W )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
    14 14 14 of O, S, C(O), S(O)2, N(R ), and ON(R ) with the proviso that R is
    37 38 selected from other than halo when directly bonded to N and that (CR R ){, is bonded to E ;
    37 38
    R and R are independently selected from the group consisting of hydrido, halo, alkyl, and haloalkyl; i is Q -Q wherein Q is (CH(R ))r-W , r is an integer
    selected from 1 through 2, and ^ 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, 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,Sbenzisoxazolyl, 3,6-benzisoxazolyl, 3,7- benzisoxazolyl, 1,4-naphthyl, 1,5-naphthyl, 1,6-naphthyl, 1,7-naphthyl, 1,8- naphthyl, 2,4-naphthyl, 2,5-naphthyl, 2,6-naphthyl, 2,7-naphthyl, 2,8-naphthyl, 2,4-quinolinyl, 2,5-quinolinyl, 2,6-quinolinyl, 2,7-quinolinyl, 2,8-quinolinyl, 3,4- quinolinyl, 3,5-quinolinyl, 3,6-quinolinyl, 3,7-quinolinyl, 3,8-quinolinyl, 4,5- quinolinyl, 4,6-quinolinyl, 4,7-quinolinyl, 4,8-quinolinyl, 1,4-isoquinolinyl, 1,5- isoquinolinyl, 1,6-isoquinolinyl, 1,7-isoquinolinyl, 1,8-isoquinolinyl, 3,4- isoquinolinyl, 3,5-isoquinolinyl, 3,6-isoquinolinyl, 3,7-isoquinolinyl, 3,8- isoquinolinyl, 4,5-isoquinolinyl, 4,6-isoquinolinyl, 4,7-isoquinolinyl, 4,8- isoquinohnyl, 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
    W and that (CH(R ))r is bonded to E°;
    x is Q -Q wherein Q is (CH(R ))r-W , 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-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-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
    6 38 W and that (CH(R ))_ is bonded to E
    5. The compound as recited in Claim 4 having 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-pyrazolyl, l,2,4-triazol-3-yl, l,2,4-triazol-5-yl, l,2,4-oxadiazol-3-yl, 1,2,4- oxadiazol-5-yl, l,3,4-oxadiazol-3-yl, l,3,4-oxadiazol-5-yl, 3-isothiazolyl, 5- isothiazolyl, 2-oxazolyl, 2-thiazolyl, 3-isoxazolyl, 5-isoxazolyl, 2-pyridyl, 3- pyridyl, 4-pyridyl, 2-pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3- pyridazinyl, 4-pyridazinyl, l,3,5-triazin-2-yl, l,2,4-triazin-3-yl, l,2,4-triazin-5-yl, l,2,4-triazin-6-yl, and l,23-triazin-4-yl, wherein a carbon adjacent to the carbon
    32 at the point of attachment may be substitated by R , the other carbon adjacent
    to the carbon at the point of attachment may be substitated by R , a carbon
    32 adjacent to R and two atoms from the carbon at the point of attachment may
    33 36 be substituted by R , a carbon adjacent to R and two atoms from the carbon
    35 at the point of attachment may be substitated by R , and any carbon adjacent
    33 35 34 to both R and R may be substituted by R ; o *-} l £ t3^
    R , R , R , R , and R 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, ethoxycarbonyl, amidocarbonyl, N-methylamidocarbonyl, N,N- dimethylamidocarbonyl, cyano, and Q ; B is selected from the group consisting of 1-propenyl, propyl, isopropyl, butyl, 2-butenyl, 3-butenyl, 2-butynyl, sec-butyl, isobutyl, 2- methylpropenyl, 1-pentyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-pentynyl, 3- pentynyl, 2-pentyl, l-methyl-2-butenyl, l-methyl-3-butenyl, l-mexhyl-2- butynyl, 3-pentyl, l-ethyl-2-propenyl, 2-methylbutyl, 2-methyl-2-butenyl, 2- methyl-3-butenyl, 2-methyl-3-butynyl, 3-methylbutyl, 3-methyl-2-butenyl, 3- methyl-3-butenyl, 1-hexyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2- hexynyl, 3-hexynyl, 4-hexynyl, 2-hexyl, l-methyl-2-pentenyl, l-methyl-3- pentenyl, l-methyl-4-pentenyl, l-methyl-2-pentynyl, l-methyl-3-pentynyl, 3- hexyl, l-ethyl-2-butenyl, l-ethyl-3-butenyl, l-propyl-2-proρenyl, l-ethyl-2- butynyl, 1-heptyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl, 2- heptynyl, 3-heptynyl, 4-heptynyl, 5-heptynyl, 2-heptyl, l-methyl-2-hexenyl, 1- methyl-3-hexenyl, l-methyl-4-hexenyl, l-methyl-5-hexenyl, l-methyl-2- hexynyl, l-methyl-3-hexynyl, l-methyl-4-hexynyl, 3-heptyl, l-ethyl-2-pentenyl, l-ethyl-3-ρentenyl, l-ethyl-4-ρentenyl, l-butyl-2-proρenyl, l-ethyl-2-pentynyl, l-ethyl-3-pentynyl, 1-octyl, 2-octenyl, 3-octenyl, 4-octenyl, Soctenyl, 6-octenyl,
    7-octenyl, 2-octynyl, 3-octynyl, 4-octynyl, 5-octynyl, 6-octynyl, 2-octyl, 1- methyl-2-heptenyl, l-methyl-3-heptenyl, l-methyl-4-heρtenyl, l-methyl-5- heptenyl, l-methyl-6-heptenyl, l-methyl-2-heptynyl, l-methyl-3-heρtynyl, 1- methyl-4-heptenyl, l-methyl-5-heρtenyl, l-methyl-6-heρtenyl, l-methyl-2- heptenyl, l-methyl-3-heptynyl, l-methyl-4-heptynyl, l-methyl-5-heptynyl, 3- ocxyl, l-ethyl-2-hexenyl, l-ethyl-3-hexenyl, l-ethyl-4-hexenyl, l-ethyl-2- hexynyl, l-ethyl-3-hexynyl, l-ethyl-4-hexynyl, l-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-buxynyl, l-butyl-3-butenyl, 2,2-difluoroρropyl, 4-trifluoromethyl-5,5,5- trifluoropentyl, 4-trifluoromethylpentyl, 5,5,6,6,6-pentafluorohexyl, and 333- trifluoropropyl, wherein each member of group B may be optionally substitated 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 ^ ,'
    B is 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-pyπolidinyl, 2-pyrrolidinyl, 3- pyπolidinyl, 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-ρyran-2-one-5-yl, 4H-pyran-4-one-2-yl, 4H-pyran-4-one-3-yl, 2- tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydroρyranyl, 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 R-^, a ring carbon or
    nitrogen atom adjacent to the R9 position and two atoms from the point of
    attachment may be substitated with RJQ? an a ring carbon or nitrogen atom adjacent to the R- position and two atoms from the point of attachment may
    be substitated with Rj ;
    9 10 11 12 13
    R , R , R , R , and R 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- dimethylamino, 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 is selected from the group consisting of phenyl, 2-thienyl, 3-thienyl,
    2-furyl, 3-furyl, 2-pyπolyl, 3-pyπolyl, 2-imidazolyl, 4-imidazolyl, 3-pyrazolyl, 4-pyrazolyl, l,2,4-triazol-3-yl, l,2,4-triazol-5-yl, l,2,4-oxadiazol-3-yl, 1,2,4- oxadiazol-5-yl, 13,4-oxadiazol-3-yl, l,3,4-oxadiazol-5-yl, 3-isothiazolyl, 5- isothiazolyl, 2-oxazolyl, 2-thiazolyl, 3-isoxazolyl, 5-isoxazolyl, 2-pyridyl, 3- pyridyl, 4-pyridyl, 2-pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3- pyridazinyl, 4-pyridazinyl, 13,5-triazin-2-yl, l,2,4-triazin-3-yl, l,2,4-triazin-5-yl, l,2,4-triazin-6-yl, and l,23-triazin-4-yl, wherein a carbon adjacent to the carbon
    9 at the point of attachment may be substituted by R , the other carbon adjacent
    13 to the carbon at the point of attachment may be substituted by R , a carbon adjacent to R and two atoms from the carbon at the point of attachment may be
    10 13 substituted by R , a carbon adjacent to R and two atoms from the carbon at
    12 the point of attachment may be substitated by R , and any carbon adjacent to
    10 12 11 both R and R may be substituted by R ;
    4a 4b 4a 4b
    K is CR R wherein R and R are independently selected from the group consisting of chloro, fluoro, and hydrido;
    E is E , when K is CR R , 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 is selected from the group consisting of N(H) and CH2N(H); o 2 2
    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:
    263
    „16 17 „18 19 „
    R , R , R , and R are independentiy 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, 2,2,3,33- pentafluoropropyl, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro, bromo, amidosulfonyl, N-methylamidosulfonyl, N,N-dimefhylamidosulfonyl, acetyl, propanoyl, trifluoroacetyl, pentafluoropropanoyl, hydroxymethyl, 1- hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro- 1-hydroxyethyl, 2,2,2-trifluoro-l- tiifluoromexhyl-1-hydroxyethyl, carboxymethyl, methoxycarbonyl, ethoxycarbonyl, amidocarbonyl, N-methylamidocarbonyl, N,N- dimethylamidocarbonyl, and cyano; Q is selected, when bonded to a carbon, from the group consisting of
    20 21 + 20 21 22 NR R , NR R R , dimethylsulfonium, methylethylsulfonium,
    25 23 24 diethylsulfonium, trimethylphosphonium, C(NR )NR R ,
    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),
    23 24 23 24 C(O)NR R , and C(O)NR R with the provisos that no more than one of
    20 21 22
    R , R , and R is hydroxy, methoxy, ethoxy, N-methylamino, N,N- dimethylamino, N,N,N-trimethylamino, or amino and that no more than one of
    23 24 26
    R , R , and R is hydroxy, methoxy, ethoxy, N-methylamino, N,N- dimethylamino, N,N,N-trimethylamino, or amino when two of the group consisting of R , R , and R are bonded to the same atom and that said Q group is bonded directly to a carbon atom;
    20 21 22 23 24 25 26
    R , R , R , R , R , R , and R 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, N,N-dimethylamino, N,N- diethylamino, and N,N,N-trimethylamino;
    Q 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; g
    Q 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 s 0 proviso that Q is bonded to E through a carbon atom.
    6. The compound as recited in Claim 1 or a pharmaceutically acceptable salt thereof, wherein;
    B is selected from the group consisting of aryl and heteroaryl wherein a carbon adjacent to the carbon at the point of attachment may be substitated by
    32 R , the other carbon adjacent to the carbon at the point of attøchment may be
    36 32 substitated by R , a carbon adjacent to R and two atoms from the carbon at
    the point of attachment may be substitated by R , a carbon adjacent to R and two atoms from the carbon at the point of attachment may be substitated by
    35 33 35 34
    R , and any carbon adjacent to both R and R may be substituted by R ;
    32 33 34 35 36 R , R , R , R , and R are independentiy 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, cyano, and
    Qb;
    B is 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' R3Ψ R35' aad R36'
    B is 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 substitoted 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 substitoted with R or RJ3, a ring carbon or nitrogen atom adjacent to the R9 position and two atoms from the point of attachment may be substitated with
    Rjø, a ring carbon or nitrogen atom adjacent to the Rj3 position and two atoms
    from the point of attachment may be substitated with Rχ2, a ring carbon or
    nitrogen atom three atoms from the point of attachment and adjacent to the RJ
    position may be substituted with Rj j , a ring carbon or nitrogen atom three
    atoms from the point of attachment and adjacent to the Rj2 position may be
    substitated with R33, and a ring carbon or nitrogen atom four atoms from the
    point of attachment and adjacent to the R j j and R33 positions may be
    substituted with R34;
    9 10 11 12 13 R , R , R , R , and R 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)IT wherein π is an integer
    7 selected from 0 through 1, pa is an integer selected from 0 through 6, and W is selected from the group consisting of O, S, and C(O) with the proviso that no more than one of the group consisting of rr and pa is the integer 0 at the same time; R is selected from the group consisting of hydrido, hydroxy, halo, alkyl, and haloalkyl; Ψ is NH;
    X is hydrido; R 2 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
    9 may be substituted by R , the other carbon adjacent to the carbon at the point of
    13 9 attachment may be substituted by R , a carbon adjacent to R and two atoms
    from the carbon at the point of attøchment may be substituted by R , a carbon
    13 adjacent to R and two atoms from the carbon at the point of attøchment may
    12 10 12 be substituted by R , and any carbon adjacent to both R and R may be
    substituted by R ;
    4a 4b 4a 4b
    K is CR R wherein R and R are independently selected from the group consisting of halo and hydrido; π 1 4a_ 4b 1 E is E , when K is CR R , 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;
    14 K is (CH(R ))s-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
    7 14 N(R ) with the proviso that (CH(R )) is bonded to the pyrone ring;
    7 R is selected from the group consisting of hydrido, hydroxy, alkyl, and alkoxyalkyl;
    14 R is selected from the group consisting of hydrido and halo; o 2 14 2
    E isE , when K is (CH(R )):-T, 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 formula (IV):
    - 5 ,D 6 ,r 5 wherein D , D , J , and J are independentiy selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more
    2 than one is a covalent bond, K is independently selected from the group
    + 5 6 5 6 consisting of C and N , no more than one of D , D , J , and J is O, no more
    thanoneofD ,D ,J ,andJ isS,oneofD ,D ,J ,andJ mustbea
    covalent bond when two of D , D , J , and J are O and S, no more than three
    5 6 5 6 2 + 5 6 of D , D , J , and J are N when K is N , and no more than four of D , D ,
    5 6 2. .I * • i τ-« 16 _17 _.lo
    J , and J are N when K is carbon with the provisos that R , R , R , and
    19 R are each independently selected to maintain the tetravalent natore of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen;
    16 17 18 19 . , , , ,
    R ,R ,R , andR are independentiy 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; b 20 21 + 20 21 22
    Q is selected from the group consisting of NR R , NR R R , oxy, alkyl, alkylaminoalkyl, aminoalkyl, dialkylsulfoniumalkyl, and acylamino
    20 21 22 wherein R , R , and R are independently selected from the group consisting of hydrido, alkyl, hydroxy, alkoxy, alkylamino, dialkylamino,
    20 aminoalkyl, and hydroxyalkyl with the provisos that no more than one of R ,
    21 22
    R , and R is hydroxy, alkoxy, alkylamino, amino, or dialkylamino and that
    20 21 22
    R , R , and R must be other than be hydroxy, alkoxy, alkylamino, amino,
    2 + or dialkylamino when K is N ;
    Q is selected from the group consisting of dialkylsulfonium, trialkylphosphonium, ,
    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)NR23R24, and C(O)NR23R24 with -τ,23 ^24 ι π26 . t J the provisos that no more than one of R , R , and R is hydroxy, alkoxy,
    23 alkylamino, amino, or dialkylamino when two of the group consisting of R ,
    24 26 b
    R , and R are bonded to the same atom and that said Q group is bonded directly to a carbon atom;
    23 24 25 26
    R , R , R , and R are independently selected from the group consisting of hydrido, alkyl, hydroxy, alkoxy, alkylamino, dialkylamino, aminoalkyl, and hydroxyalkyl;
    Q is selected from the group consisting of a single covalent bond and ^7 o
    (CR R )b~(W )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) ^7 Q with the proviso that (CR R )^ is bonded to E ;
    37 38
    R and R are independently selected from the group consisting of hydrido, halo, alkyl, and haloalkyl.
    7. The compound as recited in Claim 6 having 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-pyπolyl, 3-pyπolyl, 2-imidazolyl, 4-imidazolyl, 3-pyrazolyl, 4-pyrazolyl, 2-thiazolyl, 3-isoxazolyl, 5-isoxazolyl, 2-pyridyl, 3-pyridyl, 4- pyridyl, 2-pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, and l,3,5-triazin-2-yl, wherein a carbon adjacent to the carbon at
    32 the point of attøchment may be substituted by R , the other carbon adjacent to
    the carbon at the point of attøchment may be substitated by R , a carbon
    32 adjacent to R and two atoms from the carbon at the point of attøchment may
    be substituted by R , a carbon adjacent to R and two atoms from the carbon
    35 at the point of attachment may be substitated by R , and any carbon adjacent
    33 35 34 to both R and R may be substituted by R ;
    32 33 34 35 36 R , R , R , R , and R are independently selected from the group consisting of hydrido, amidino, guanidino, 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, 2,2333- 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- trifluoromefhyl- 1-hydroxyethyl, carboxymethyl, methoxycarbonyl, ethoxycarbonyl, amidocarbonyl, N-methylamidocarbonyl, N,N- dimethylamidocarbonyl, cyano, and Q ; B is 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, l-methyl-2-butenyl, 1- methyl-3-butenyl, 3-pentyl, l-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-3,3,3-trifluoropropyl, 1,1,1,2,2,2- hexafluoropropyl, 3,3,3-trifluoroprop-l-yl, and 333-trifIuoroprop-2-yl, wherein each member of group B may be optionally substitated at any carbon up to and including 5 atoms from the point of attøchment of B to A with one or more of the group consisting of R32, R33, R34, R35, and ^β; B is 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 substitated with R33, a ring carbon and nitrogen atoms adjacent to the carbon atom at the point of attachment may be optionally substitoted with R9 or Rχ3, a ring carbon or
    nitrogen atom adjacent to the R9 position and two atoms from the point of
    attøchment may be substitated with RJQ, and a ring carbon or nitrogen atom
    adjacent to the Rj3 position and two atoms from the point of attøchment may
    be substituted with Rj2;
    9 10 11 12 13
    R , R , R , R , and R 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, carboxy methyl, methoxycarbonyl, ethoxy carbonyl, 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), CC(O)CCH3,
    C(O)CCF3, CH2C(O), and (O)CCH2;
    R 2 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 l,3,5-triazin-2-yl, wherein a carbon adjacent to the carbon at
    9 the point of attachment may be substituted by R , the other carbon adjacent to
    13 the carbon at the point of attachment may be substitated by R , a carbon
    9 adjacent to R and two atoms from the carbon at the point of attøchment may be
    10 13 substituted by R , a carbon adjacent to R and two atoms from the carbon at
    12 the point of attachment may be substitoted by R , and any carbon adjacent to
    10 12 11 both R and R may be substituted by R ;
    4a 4b 4a 4b
    K is CR R wherein R and R are independently selected from the group consisting of chloro, fluoro, and hydrido; E is E , when K is CR R , 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 is selected from the group consisting of N(H) and CH2N(H); o 2 E is E , when K is selected from the group consisting of N(H) and
    2 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; ϊ is selected from the group of formulas consisting of:
    16 17 18 19 R , R , R , and R are independently selected from the group consisting of hydrido, amidino, guanidino, methoxy, ethoxy, isopropoxy, methylthio, ethylthio, trifluoromethylthio, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, 2,2,333-pentafluoropropyl, trifluoromethoxy, 1,1,2,2- tetrafluoroethoxy, fluoro, chloro, bromo, acetyl, propanoyl, trifluoroacetyl, pentafluoropropanoyl, methoxycarbonyl, ethoxy carbonyl, and cyano;
    Q is selected, when bonded to a carbon, from the group consisting of
    20 21 4- 20 21 22 NR R , NR R R , dimethylsulfonium, methylethylsulfonium,
    25 23 24 diethylsulfonium, trimethylphosphonium, C(NR )NR R ,
    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),
    23 24 23 24
    C(O)NR R , and C(O)NR R with the provisos that no more than one of 20 21 22
    R , R , andR is hydroxy, methoxy, ethoxy, N-methylamino, N,N- dimethylamino, N,N,N-trimethylamino, or amino and that no more than one of
    23 24 26
    R , R , and R is hydroxy, methoxy, ethoxy, N-methylammo, N,N- dimethylamino, N,N,N-trimethylaιrιino, or amino when two of the group
    23 24 26 ^b consisting of R , R , and R are bonded to the same atom and that said Q group is bonded directly to a carbon atom;
    20 21 22 23 24 25 26
    R , R , R , R , R , R , and R 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;
    Q 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-hydroxyexhyl)amino, N,N-bis-(2-hydroxyethyl)amino, amino, hydroxylamino, N-methoxyamino, N- mexhylamino, N,N-dimethylamino, and N,N,N-trimethylamino;
    Q 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 s 0 proviso that Q is bonded to E through a carbon atom.
    8. The compound as recited in Claim 7 having 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-pyπolyl, 3-ρyπolyl, 2-imidazolyl, 4-imidazolyl, 3-pyrazolyl, 4-pyrazolyl, 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
    32 be substituted by R , the other carbon adjacent to the carbon at the point of
    attachment may be substitoted by R , a carbon adjacent to R and two atoms
    33 from the carbon at the point of attachment may be substituted by R , a carbon
    36 adjacent to R and two atoms from the carbon at the point of attachment may r oo "^^ζ be substituted by R , and any carbon adjacent to both R and R may be
    34 substitoted by R ;
    32 33 34 35 36
    R , R , R , R , and R 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, 2,2,3,3,3-pentafluoropropyl, fluoro, chloro, bromo, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro- 1- hydroxyethyl, 2,2,2-trifluoro- 1-trifluoromethyl- 1-hydroxyethyl, methoxycarbonyl, ethoxycarbonyl, cyano, and Q ;
    B is 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, 3,3,3-trifluoroprop-l-yl, and 3,3,3-trifluoroprop-2-yl, wherein each member of group B may be optionally substitoted at any carbon up to and including 5 atoms from the point of attachment of B to A with one or more of the group consisting of R 2, R33 , R34, R35, and R^g,
    B is 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 substitoted 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 R 3, a ring carbon or
    nitrogen atom adjacent to the R9 position and two atoms from the point of
    attachment may be substitoted with RJ , and a ring carbon or nitrogen atom
    adjacent to the ^ position and two atoms from the point of attøchment may
    be substitoted with Rj2;
    9 10 11 12 13
    R , R , R , R , and R are independentiy 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;
    R is selected from the group consisting of phenyl, 2-thienyl, 3-thienyl,
    2-furyl, 3-furyl, 2-pyπolyl, 3-pyπolyl, 2-imidazolyl, 4-imidazolyl, 3-pyrazolyl, 4-pyrazolyl, 2-thiazolyl, 3-isoxazolyl, 5-isoxazolyl, 2-pyridyl, 3-pyridyl, 4- pyridyl, 2-pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, and l,3,5-triazin-2-yl, wherein a carbon adjacent to the carbon at
    9 the point of attachment may be substitoted by R , the other carbon adjacent to
    13 the carbon at the point of attøchment may be substituted by R , a carbon
    9 adjacent to R and two atoms from the carbon at the point of attachment may be
    substitoted by R , a carbon adjacent to R and two atoms from the carbon at
    12 the point of attachment may be substituted by R , and any carbon adjacent to
    10 12 11 both R and R may be substituted by R ; 4a 4b 4a 4b
    K is CR R wherein R and R are independently selected from the group consisting of chloro, fluoro, and hydrido;
    E is E , when K is CR R , 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 is selected from the group consisting of N(H) and CH2N(H);
    E is E , when K is selected from the group consisting of N(H) and
    2 CH N(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; x is selected from the group of formulas consisting of:
    16 17 , 18 19 . , , R , R , R , and R are independently selected from the group consisting of hydrido, methoxy, ethoxy, trifluoromethyl, pentafluoroethyl, 2,2,2- trifluoroethyl, trifluoromethoxy, fluoro, chloro, bromo, acetyl, trifluoroacetyl, methoxycarbonyl, ethoxycarbonyl, and cyano; b 20 21 + 20 21 22
    Q is selected from the group consisting of NR R , NR R R , 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)NR23R24, and C(O)NR23R24 with
    20 21 22 the provisos that no more than one of R , R , and R is hydroxy, methoxy, ethoxy, N-methylamino, N,N-dimethylamino, and N,N,N-trimethylamino, or
    23 24 26 am o and that no more than one of R , R , and R is hydroxy, methoxy, ethoxy, N-methylamino, N,N-dimethylamino, N,N,N-trimethylamino, or amino
    23 24 26 when two of the group consisting of R , R , and R are bonded to the same atom;
    20 21 22 23 24 25 26
    R , R , R , R , R , R , and R 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; Q 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 o bonded to E through a carbon atom.
    9. A composition for inhibiting thrombotic conditions in blood comprising a compound of any one of Claims 1 through 8 and a pharmaceutically acceptable carrier.
    10. A method for inhibiting thrombotic conditions in blood comprising adding to blood a therapeutically effective amount of a composition of Claim 9.
    11. A method for inhibiting formation of blood platelet aggregates in blood comprising adding to blood a therapeutically effective amount of a composition of Claim 9.
    12. A method for inhibiting thrombus formation in blood comprising adding to blood a therapeutically effective amount of a composition of Claim 9.
    13. A method for treating or preventing venuous thromboembolism and pulmonary embolism in a mammal comprising administering to the mammal a therapeutically effective amount of a composition of Claim 9.
    14. A method for treating or preventing deep vein thrombosis in a mammal comprising administering to the mammal a therapeutically effective amount of a composition of Claim 9.
    15. A method for treating or preventing cardiogenic thromboembolism in a mammal comprising administering to the mammal a therapeutically effective amount of a composition of Claim 9.
    16. A method for treating or preventing thromboembolic stroke in humans and other mammals comprising administering to the mammal a therapeutically effective amount of a composition of Claim 9.
    17. A method for treating or preventing thrombosis associated with cancer and cancer chemotherapy in humans and other mammals comprising administering to the mammal a therapeutically effective amount of a composition of Claim 9.
    18. A method for treating or preventing unstable angina in humans and other mammals comprising administering to the mammal a therapeutically effective amount of a composition of Claim 9.
    19. A method for inhibiting thrombus formation in blood comprising adding to blood a therapeutically effective amount of a compound of any one of Claims 1 through 8 with a therapeutically effective amount of fibrinogen receptor antagonist.
    20. The use of a compound of any one of Claims 1 through 8, or a pharmaceutically acceptable salt thereof, in the manufacture of medicament for inhibiting thrombus formation, treating thrombus formation, or preventing thrombus formation in a mammal.
    21. A compound of 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
    32 R , a nitrogen with a removable hydrogen or a carbon at the other position
    36 adjacent to the point of attøchment is optionally substituted by R , a nitrogen
    32 with a removable hydrogen or a carbon adjacent to R and two atoms from the
    33 point of attachment is optionally substitated by R , a nitrogen with a
    36 removable hydrogen or a carbon adjacent to R and two atoms from the point
    35 of attachment is optionally substituted by R , and a nitrogen with a removable
    33 35 hydrogen or a carbon adjacent to both R and R is optionally substitated by
    34
    R
    „9 „10 11 12 13 „32 33 34 35 36
    R , R , R , R , R , R , R , R , R , and R are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkylenedioxy, haloalkylthio, 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, heterocyclylalkylammo, 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;
    32 33 34 35 36 b
    R , R , R , R , and R are independently optionally Q ;
    B is optionally selected from the group consisting of hydrido, tiialkylsilyl, C2-C8 alkyl, C3-C8 alkylenyl, C3-C8 alkenyl, C3-C8 alkynyl, and C2-C8 haloalkyl, wherein each member of group B is optionally substitated at any carbon up to and including 6 atoms from the point of attachment of B to A
    • • r n32 33 π34 35 36 with one or more of the group consisting of R , R , R , R , and R ;
    B is optionally a C3-C12 cycloalkyl or C4-C9 saturated heterocyclyl,
    33 wherein each ring carbon is optionally substitated with R , a ring carbon other than the ring carbon at the point of attøchment 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
    9 13 atom at the point of attachment are optionally substitated with R or R , a ring
    9 carbon or nitrogen atom adjacent to the R position and two atoms from the
    10 point of attøchment is optionally substitated with R , a ring carbon or nitrogen
    13 adjacent to the R position and two atoms from the point of attøchment is
    12 optionally substitated with R , a ring carbon or nitrogen three atoms from the
    10 point of attachment and adjacent to the R position is optionally substituted
    11 with R , a ring carbon or nitrogen three atoms from the point of attachment
    12 33 and adjacent to the R position is optionally substituted with R , and a ring carbon or nitrogen four atoms from the point of attachment and adjacent to the
    11 33 34
    R and R positions is optionally substituted with R ; A is selected from the group consisting of a bond, (W7)rr-(CH(R15))pa, and (CH(R15))pa-(W7)rr wherein π is 0 or 1, pa is an
    7 integer selected from 0 through 6, and W is selected from the group
    7 7 7 consisting of O, S, C(O), (R )NC(O), (R )NC(S), and N(R ) with the proviso that no more than one of the group consisting of rr and pa is 0 at the same time;
    7 R is selected from the group consisting of hydrido, hydroxy, and alkyl;
    15 R is selected from the group consisting of hydrido, hydroxy, halo, alkyl, and haloalkyl; 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; R2 is Z°-Q; o 41 42
    Z is selected from the group consisting of a bond, (CR R )q
    41 o wherein q is an integer selected from 1 through 3, and (CH(R ))g-W -
    42 (CH(R ))p wherein g and p are integers independently selected from 0 through 3 and W is selected from the group consisting of O, S, C(O), S(O),
    41 41 N(R ), and ON(R );
    Z° 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
    41 42 CR =CR , 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, morpholinyl, 1,2-piperazinyl, 13-piperazinyl, 2,3-piperazinyl, 2,6-piperazinyl, 1,2-piperidinyl, 1,3-piperidinyl, 2,3-piperidinyl, 2,4-piperidinyl, 2,6-piperidinyl, 3,4-piperidinyl, 1,2-pyπolidinyl, 1,3-pyrrolidinyl, 2,3-pyrrolidinyl, 2,4-pyrrolidinyl, 2,5-pyrrolidinyl, 3,4-pyrrolidinyl, 2,3-tetrahydrofuranyl, 2,4-tetrahydrofuranyl, 2,5-tetrahydrofuranyl, and 3,4-tetrahydrofuranyl, wherein Z is directly bonded to the 4-pyrone ring and W^ is optionally substituted with one or more
    Q 10 1 1 1? 13 substituents selected from the group consisting of R , R , R , R , andR ;
    41 42
    R and R are independently selected from the group consisting of amidino, hydroxya ino, 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
    9
    R , a nitrogen with a removable hydrogen or a carbon at the other position
    13 adjacent to the point of attøchment is optionally substituted by R , a nitrogen
    9 with a removable hydrogen or a carbon adjacent to R and two atoms from the
    point of attøchment is optionally substitated by R , a nitrogen with a
    13 removable hydrogen or a carbon adjacent to R and two atoms from the point
    12 of attachment is optionally substituted by R , and a nitrogen with a removable
    10 12 hydrogen or a carbon adjacent to both R and R is optionally substituted by
    R ;
    Q is optionally hydrido with the proviso that Z is selected from other than a bond;
    „. . ^4a 4b K is CR R ;
    4a 4b
    R and R are independently selected from the group consisting of halo, hydrido, hydroxyalkyl, alkyl, alkoxyalkyl, alkylthioalkyl, and haloalkyl; 0 4a 4b 1 1
    E , with the proviso that K is CR R , is E wherein E 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;
    14 K is optionally (CH(R )):-T wherein j is 0 or 1 and T is a bond or
    7 14
    N(R ) with the proviso that (CH(R )): is bonded to the phenyl ring;
    14 R is selected from the group consisting of hydrido, halo, alkyl, and haloalkyl; o 14 2 2
    E , with the proviso that K is (CH(R )) -T, is E 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; i is phenyl or a heteroaryl of 5 or 6 ring members, wherein one carbon of said phenyl or said heteroaryl is substituted by Q , a carbon two or three
    contiguous atoms from the point of attachment of Q to said phenyl or said
    heteroaryl to said phenyl or said heteroaryl is substituted by Q , a carbon s 17 adjacent to the point of attachment of Q is optionally substituted by R , s another carbon adjacent to the point of attachment of Q is optionally
    substituted by R , a carbon adjacent to Q is optionally substituted by R , b 19 and another carbon adjacent to Q is optionally substituted by R ;
    16 17 18 19 R , R ,R , and R are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, haloalkylthio, alkoxy, hydroxy, amino, nitro, alkoxyamino, alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, alkenyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, haloalkoxyalkyl, carboalkoxy, and cyano; R or R is optionally selected from the group consisting of
    20 21 26 25 23 24 25 23 24
    NR R , N(R )C(NR )N(R )(R ), and C(NR )NR R , with the
    proviso that R , R , and Q are not simultaneously hydrido; b 20 21
    Q is selected from the group consisting of NR R , aminoalkyl,
    hydrido, N(R26)C(NR25)N(R23)(R24), and C(NR25)NR23R24, with the
    • L ._ ^ r,20 J ¥,21 . , _, „ proviso that no more than one of R and R is selected from the group consisting of hydroxy, amino, alkylamino, and dialkylamino at the same time,
    23 24 with the further proviso that no more than one of R and R is selected from the group consisting of hydroxy, amino, alkylamino, and dialkylamino at the same time;
    20 21 23 24 25 26
    R , R , R , R , R , and R are independently selected from the group consisting of hydrido, alkyl, hydroxy, aminoalkyl, amino, dialkylamino, alkylamino, and hydroxyalkyl; f oo
    Q is selected from the group consisting of a bond, (CR R )j,
    14 1 wherein b is an integer selected from 1 through 4, and (CH(R ))C-W -
    (CH(R ))(j wherein c and d are integers independently selected from 1
    1 14 through 3 and W is selected from the group consisting of C(O)N(R ),
    (R14)NC(O), S(O), S(O)2, S(O)2N(R14), N(R14)S(O)2, and N(R14), with the
    14 proviso that R is selected from other than halo when directly bonded to N,
    Λ Λ O 1 A and with the additional proviso that (CR R )j, and (CH(R ))c are bonded toE ;
    37 38
    R and R are independently selected from the group consisting of hydrido, alkyl, and haloalkyl; R is optionally aroyl or heteroaroyl, wherein R is optionally substituted with one or more substituents selected from the group consisting of
    16 17 18 1 T 19 R , R , R , and R ;
    Y is optionally Y wherein Y is Q -Q ;
    Y° is optionally Qb-QSS wherein Qss is (CH(R14))e-W2-(CH(R15))h,
    2 4a 4b wherein e and h are independently 1 or 2 and W^ is CR =CR , with the
    14 o proviso that (CH(R ))e is bonded to E ; b „ssss ~b ^ssssr , . „ssss . „~,ττ,~38.
    Y° is optionally Q -QSSSS or Qb-Qssssr wherein QSSSS is (CH(R ))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-benzothiophenyl, 3 ,4-benzothiophenyl, 3,5-benzothiophenyl, 3,6-benzothioρhenyl, 3,7-benzothiophenyl, 2,7-imidazo(l,2-a)pyridinyl, 3,4-imidazo(l,2-a)pyridinyl, 3,5-imidazo(l,2-a)pyridinyl, 3,6-imidazo(l,2-a)pyridinyl, 3,7-imidazo(l,2-a)pyridinyl, 2,4-indolyl, 2,5-indolyl, 2,6-indolyl, 2,7-indolyl, 3,4-indolyl, 3,5-indolyl, 3,6-indolyl, 3,7-indolyl, 1,4-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-quinolinyl, 1,4-isoquinolinyl, 1,5-isoquinoIinyl, 1,6-isoquinolinyl, 1,7-isoquinolinyl, 1,8-isoquinolinyl, ,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-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, and each carbon and hyrido containing nitrogen member of the ring of the W~^
    6 . 5 6 and of the ring of the W , other than the points of attachment of W W5 ; and W ,
    9 10 is optionally substitoted with one or more of the group consisting of R , R ,
    1 1 19
    R , and R , with the proviso that Q is bonded to lowest number substitoent
    5 b position of each W , with the further proviso that Q is bonded to highest
    number substituent position of each W , and with the additional proviso that
    (CH(R38))r is bonded to E°.
    22. Compound of Claim 21 of 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 attøchment of said phenyl or heteroaryl
    32 , ring to A is optionally substitoted by R , the other carbon adjacent to the
    36 carbon at the point of attøchment is optionally substituted by R , a carbon
    32 adjacent to R and two atoms from the carbon at the point of attachment is optionally substitoted by , a carbon adjacent to and two atoms from the 35 carbon at the point of attachment is optionally substitated by R , and any
    33 35 34 carbon adjacent to both R and R is optionally substituted by R ; n Q * . ^ * (
    R , R ,R , R , andR 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, tiialkylsilyl, 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
    32 33 34 35 36 with one or more of the group consisting of R , R , R , R , and R ;
    B is optionally a C3-C12 cycloalkyl or a C4-C9 saturated heterocyclyl,
    33 wherein each ring carbon is optionally substitoted with R , a ring carbon other than the ring carbon at the point of attøchment 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
    9 13 atom at the point of attachment are optionally substitoted with R or R , a ring
    9 carbon or nitrogen atom adjacent to the R position and two atoms from the
    point of attachment is optionally substituted with R , a ring carbon or nitrogen
    13 atom adjacent to the R position and two atoms from the point of attachment
    12 is optionally substitoted with R , a ring carbon or nitrogen atom three atoms
    from the point of attachment and adjacent to the R position is optionally
    11 substitoted with R , a ring carbon or nitrogen atom three atoms from the 12 pomt of attachment and adjacent to the R position is optionally substitoted
    33 with R , and a ring carbon or nitrogen atom four atoms from the point of
    11 33 attachment and adjacent to the R and R positions is optionally substituted
    34 withR ;
    9 10 1 1 12 13 R , R , R , R , and R are independently selected from the group consisting of hydrido, acetamido, haloacetamido, alkoxyamino, alkanoyl, haloalkanoyl, amidino, guanidino, alkylenedioxy, haloalkylthio, 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;
    15 7
    A is bond or (CH(R ))pa-(W )rr wherein rr is 0 or 1, pa is an integer
    7 selected from 0 through 3, and W is selected from the group consisting of O,
    S, C(O), (R7)NC(O), (R?)NC(S), and N(R?), with the proviso that W? is bonded to the N(H) on the 4-pyrone ring;
    7 R is selected from the group consisting of hydrido, hydroxy and alkyl;
    15
    R is selected from the group consisting of hydrido, hydroxy, halo, alkyl, and haloalkyl; λ 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;
    R2 is Z°-Q; o 41 42
    Z is selected from the group consisting of a bond, (CR R )q
    41 o 42 wherein q is 1 or 2, and (CH(R ))g-W -(CH(R ))p wherein g and p are integers independently selected from 0 through 3 and W is selected from the
    41 41 group consisting of O, S, C(O), S(O), N(R ), and ON(R );
    Z° 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
    41 42 CR =CR , 1,2-cyclopropyl, 1,2-cyclobutyl, 1,2-cyclohexyl, 13-cyclohexyl,
    1,2-cyclopentyl, 13-cycloρentyl, 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-piperidinyl, 2,4-piperidinyl, 2,6-piperidinyl, 3,4-piperidinyl, l,2-pyπolidinyl,l,3-pyπolidinyl, 2,3-pyπolidinyl, 2,4-pyπolidinyl, 2,5-pyπolidinyl, 3,4-pyπolidinyl, 2,3-tetrahydrofuranyl, 2,4-tetrahydrofuranyl,
    2,5-tetrahydrofuranyl, and 3,4-tetrahydrofuranyl, wherein Z is directly bonded to the 4-pyrone ring and W^ is optionally substituted with one or more
    9 10 11 12 13 substituents selected from the group consisting of R , R , R , R , and R ;
    41 42
    R and R 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 attøchment of said phenyl or heteroaryl o 9 ring to Z is optionally substituted by R , the other carbon adjacent to the
    13 carbon at the point of attachment is optionally substituted by R , a carbon
    9 adjacent to R and two atoms from the carbon at the point of attachment is
    10 13 optionally substituted by R , a carbon adjacent to R and two atoms from the 12 carbon at the point of attachment is optionally substitoted by R , and any
    10 12 11 carbon adjacent to both R and R is optionally substitoted by R ;
    Q is optionally hydrido with the proviso that Z is other than a bond;
    4a 4b K is CR R ;
    4a 4b R and R are independently selected from the group consisting of hydrido, hydroxyalkyl, alkyl, alkoxyalkyl, alkylthioalkyl, and haloalkyl;
    E , with the proviso that K is CR R , 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;
    14 K is optionally (CH(R )):-T wherein j is O or 1 and T is a bond or
    7 14
    N(R ) with the proviso that (CH(R )) is bonded to the phenyl ring;
    14 R is hydrido or halo; o 14 2 2
    E , with the proviso that K is (CH(R )):-T, is E 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;
    Y is phenyl or a heteroaryl of 5 or 6 ring members, wherein one carbon s of said phenyl or said heteroaryl is substituted by Q , a carbon two or three
    S atoms from the point of attachment of Q to said phenyl or said heteroaryl is b s substitoted by Q , a carbon adjacent to the point of attachment of Q is
    17 optionally substituted by R , another carbon adjacent to the point of
    attachment of Q is optionally substituted by R , a carbon adjacent to Q is optionally substituted by , and another carbon adjacent to is optionally
    19 substituted by R ; R , and R 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;
    R or R is optionally selected from the group consisting of
    NR R , N(R )C(NR )N(R )(R ), and C(NR )NR R , with the
    16 19 b proviso that R , R , and Q are not simultaneously hydrido; b 20 21
    Q is selected from the group consisting of NR R , hydrido,
    26 25 23 24 25 23 24 N(R )C(NR )N(R )(R ), and C(NR )NR R , with the proviso that no
    20 21 more than one of R and R is selected from the group consisting of hydroxy, amino, alkylamino, and dialkylamino at the same time, with the further proviso that
    23 24 no more than one of R and R is selected from the group consisting of hydroxy, amino, alkylamino, and dialkylamino at the same time;
    20 21 23 24 25 26 R , R , R , R , R , and R are independently selected from the group consisting of hydrido, alkyl, hydroxy, amino, alkylamino and dialkylamino;
    37 38 Q is selected from the group consisting of a bond, (CR R )j,
    14 1 wherein b is an integer selected from 1 through 4, and (CH(R ))C-W -
    (CH(R ))^ wherein c and d are integers independentiy selected from 1
    1 14 through 3 and W is selected from the group consisting of C(O)N(R ),
    (R14)NC(O), S(O), S(O)2, S(O)2N(R14), N(R14)S(O)2, and N(R14), with the
    14 proviso that R is selected from other than halo when directly bonded to N,
    37 38 37 38 and with the additional proviso that (CR R and (CR R , and
    (CH(R14))C are bonded to E°; 37 38
    R and R are independently selected from the group consisting of hydrido, alkyl, and haloalkyl;
    38 38
    R is optionally aroyl or heteroaroyl, wherein R is optionally substitated with one or more substituents selected from the group consisting of
    Λ6 17 18 19
    R , R , R , andR ;
    ϊ is optionally Y wherein Y is Q -Q ;
    Y° is optionally Qb-QSS wherein QSS is (CH(R14))e-W2-(CH(R15))h,
    2 A 4b wherein e and h are independentiy 1 or 2 and W^ is CR =CR with the
    14 o proviso that (CH(R ))e is bonded to E .
    23. Compound of Claim 22 or a pharmaceutically acceptable salt thereof, wherein;
    B is selected from the group consisting of hydrido, tiialkylsilyl, C2-C8 alkyl, C3-C8 alkylenyl, C3-C8 alkenyl, C3-C8 alkynyl, and C2-C8 haloalkyl, wherein each member of group B is optionally substitated at any carbon up to and including 6 atoms from the point of attachment of B to A with one or more
    32 33 34 35 36 of the group consisting of R , R , R , R , and R ;
    32 33 34 35 36
    R , R , R , R , and R are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkoxy, hydroxy, amino, alkoxyamino, alkylamino, alkylthio, amidosxilf onyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, hydroxyhaloalkyl, carboalkoxy, carboxy, carboxamido, cyano, and Q ;
    15 7
    A is (CH(R ))pa-W wherein pa is an integer selected from 0 through
    7 7 7
    3 and W is selected from the group consisting of O, S, and N(R ) wherein R is hydrido or alkyl ;
    15 R is selected from the group consisting of hydrido, hydroxy, halo, alkyl, and haloalkyl; X is selected from the group consisting of hydrido, amino, alkyl, cyano, halo, haloalkyl, haloalkoxy, aminoalkyl, hydroxy, alkoxy, hydroxyalkyl, and alkylthio;
    R2 is Z°-Q; o 41 42 Z is a bond or (CR R )q wherein q is 1 or 2;
    41 42
    R and R are independently selected from the group consisting of hydrido, hydroxy, 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 o 9 ring to Z is optionally substituted by R , the other carbon adjacent to the
    13 carbon at the point of attachment is optionally substitoted by R , a carbon
    9 adjacent to R and two atoms from the carbon at the point of attøchment is
    optionally substituted by R , a carbon adjacent to R and two atoms from the
    12 carbon at the point of attachment is optionally substitoted by R , and any
    10 12 11 carbon adjacent to both R and R is optionally substituted by R , with the proviso that Q is other than a phenyl when Z is a bond;
    9 10 11 12 13
    R , R , R , R , and R are independently selected from the group consisting of hydrido, acetamido, haloacetamido, alkoxyamino, alkanoyl, haloalkanoyl, amidino, guanidino, alkylenedioxy, haloalkylthio, alkoxy, cycloalkoxy, cycloalkylalkoxy, aralkoxy, aryloxy, heteroaryloxy, heteroaralkoxy Jieterocyclyloxy, 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;
    4a 4a
    K is CHR wherein R is selected from the group consisting of hydrido, hydroxyalkyl, alkyl, alkoxyalkyl, alkylthioalkyl, and haloalkyl; E is selected from the group consisting of a bond, C(O)N(H),
    (H)NC(O), (R?)NS(O)2, and S(O)2N(R?); x is phenyl or a heteroaryl of 5 or 6 ring members, wherein one carbon s of said phenyl or said heteroaryl is substituted by Q , a carbon two or three s contiguous atoms from the point of attachment of Q to the phenyl or
    heteroaryl ring is substituted by Q , a carbon adjacent to the point of s 17 attachment of Q is optionally substituted by R , another carbon adjacent to
    the point of attøchment of Q is optionally substituted by R , a carbon adjacent to s opt ona y su s tute y , and another carbon adjacent to b 19
    Q is optionally substituted by R ;
    16 17 18 1Q R , R , R , and R are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, haloalkylthio, alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, and cyano;
    16 19 R or R is optionally selected from the group consisting of
    N , with the
    16 19 h proviso that R , R , and Q are not simultaneously hydrido;
    V» 90 1
    Q is selected from the group consisting of NR R , hydrido,
    26 25 23 24 25 23 24
    N(R )C(NR )N(R )(R ), and C(NR )NR R , with the proviso that no 20 21 more than one of R and R is selected from the group consisting of hydroxy, amino, alkylamino, and dialkylamino at the same time and with the further proviso
    23 24 that no more than one of R and R is selected from the group consisting of hydroxy, amino, alkylamino, and dialkylamino at the same time;
    20 21 23 24 25 26 R , R , R , R , R , and R are independently selected from the group consisting of hydrido, alkyl, hydroxy, amino, alkylamino and dialkylamino;
    Q is selected from the group consisting of a bond, (CR R ){, wherein b is an integer selected from 1 through 3, and
    (CH(R ))C-W -(CH(R ))^ wherein c and d are independently 1 or 2 and
    1 14 14 W is selected from the group consisting of C(O)N(R ), (R )NC(O), S(O),
    S(O)2, S(O)2N(R14), N(R14)S(O)2, and N(R14), with the proviso thatR14 is selected from other than halo when directly bonded to N and with the further '"7 ^1Q 1 A proviso that (CR R )j,, and (CH(R ))c are bonded to E ;
    14 R is selected from the group consisting of hydrido, halo, alkyl, and haloalkyl;
    37 38
    R and R are independently selected from the group consisting of hydrido, alkyl, and haloalkyl;
    38 R is optionally aroyl and heteroaroyl;
    Y° is optionally Qb-QSS wherein QSS is (CH(R14))e-W2-(CH(R15))h,
    wherein e and h are integers independently selected from 1 through 2 and W^
    4a 14 o is CR =CH with the proviso that (CH(R ))e is bonded to E .
    24. Compound of Claim 23 of the Formula:
    or a pharmaceutically acceptable salt thereof, wherein;
    B is selected from the group consisting of hydrido, tiialkylsilyl, C2-C4 alkyl, C3-C5 alkylenyl, C3-C4 alkenyl, C3-C4 alkynyl, and C2-C4 haloalkyl, wherein each member of group B is optionally substitoted at any carbon up to and including 3 atoms from the point of attachment of B to A with one or more
    32 33 34 of the group consisting of R , R , and R ;
    32 33 34
    R , R , and R 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;
    15 7
    A is (CH(R ))pa-N(R ) wherein pa is an integer selected from 0
    7 through 2 and R is hydrido or alkyl;
    .15
    R 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;
    R2 is Z°-Q;
    Z 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 o 9 ring to Z is optionally substituted by R , the other carbon adjacent to the 13 carbon at the point of attachment is optionally substitated by R , a carbon
    9 adjacent to R and two atoms from the carbon at the point of attachment is
    optionally substitated by R , a carbon adjacent to R and two atoms from the
    12 carbon at the point of attachment is optionally substituted by R , and any
    10 12 . 11 carbon adjacent to both R and R is optionally substituted by R ;
    9 11 13
    R , R , and R are independently selected from the group consisting of hydrido, hydroxy, amino, amidino, guanidino, alkylamino, alkylthio, alkylsulfonamido, alkylsulfinyl, alkylsulfonyl, amidosulfonyl, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, hydroxyalkyl, hydroxyhaloalkyl, carboxy, carboxamido, and cyano;
    10 12
    R and R 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, heterocyclylalkylammo, alkylsulfonamido, amidosulfonyl, arylsulfinyl, aralkylsulfinyl, cycloalkylsulfinyl, heteroarylsulfinyl, arylsulfonyl, aralkylsulfonyl, cycloalkylsulfonyl, heteroarylsulfonyl, hydroxyalkyl, hydroxyhaloalkyl, aminoalkyl, carboalkoxy, carboxy, carboxyalkyl, carboxamido, halo, haloalkyl, and cyano; ϊ is phenyl or a heteroaryl of 5 or 6 ring members, wherein one carbon s of said phenyl or said heteroaryl is substituted by Q , a carbon two or three g atoms from the point of attachment of Q to said phenyl or said heteroaryl is b s substitated by Q , a carbon adjacent to the point of attachment of Q is
    17 optionally substituted by R , another carbon adjacent to the point of s 18 b . attøchment of Q is optionally substituted by R , a carbon adjacent to Q is optionally substitated by , and another carbon adjacent to is optionally
    19 substituted by R ;
    16 17 18 19
    R , R , R , and R are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, haloalkylthio, alkoxy, hydroxy, amino, alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, and cyano;
    16 19. . „ , ^ , . . .
    R or R 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 R , R , and Q are not simultaneously hydrido; b 20 21
    Q is selected from the group consisting of NR R , hydrido,
    C(NR25)NR23R24, and N(R26)C(NR25)N(R23)(R24), with the proviso that
    20 21 no more than one of R and R is hydroxy at the same time and with the
    23 24 further proviso that no more than one of R and R is hydroxy at the same time;
    20 21 23 24 „25 J 26 . Λ J , , R , R , R , R , R , and R are independently selected from the group consisting of hydrido, alkyl, and hydroxy; g
    Q is selected from the group consisting of a bond, CH2, and CH2CH2.
    25. Compound of Claim 24 or a pharmaceutically acceptable salt thereof, wherein;
    B is selected from the group consisting of ethyl, 2-propenyl, 2- propynyl, propyl, isopropyl, -CH2CH2CH2-, -CH2CH2CH2CH2-, butyl,
    2-butenyl, 3-butenyl, 2-butynyl, sec-butyl, tert-butyl, isobutyl, 2-methylpropenyl, 2,2,2-trifluoroethyl, 3,33-trifluoropropyl, and 2,2-difluoropropyl, wherein each member of group B is optionally substitated at any carbon up to and including 3 atoms from the point of attachment of B to
    32 33 34
    A with one or more of the group consisting of R , R , and R ;
    32 33 34
    R , R , and R are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, methoxyamino, ethoxyamino, acetamido, tiifluoroacetamido, N-methylamino, dimethylamino, N-ethylamino, methylthio, ethylthio, isopropylthio, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro, bromo, amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro- 1-hydroxyethyl, methoxycarbonyl, ethoxycarbonyl, amidocarbonyl, N-methylamidocarbonyl, N,N-dimethylamidocarbonyl, and cyano; A is selected from the group consisting of a bond, NH, and N(CH3);
    X 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,l,l,2,2-tetrafluoroethoxy, fluoro, chloro, and bromo;
    R2 is Z°-Q;
    Z is a bond or CH2;
    Q is selected from the group consisting of phenyl, 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyπolyl, 3-pyπolyl, 2-imidazolyl, 4-imidazolyl, 3-pyrazolyl, 4-pyrazolyl, 2-thiazolyl, 3-isoxazolyl, 5-isoxazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, and l,3,5-triazin-2-yl, wherein a carbon adjacent to the carbon at the point of attachment of said phenyl or heteroaryl ring to Z is
    9 optionally substitated by R , the other carbon adjacent to the carbon at the point
    13 9 of attachment is optionally substituted by R , a carbon adjacent to R and two atoms from the carbon at the point of attachment is optionally substitated by
    10 13
    R , a carbon adjacent to R and two atoms from the carbon at the point of
    attache is opttonaUy ited by R*. and any carbon adjacent to both
    10 12 11
    R and R is optionally substituted by R ;
    9 1 1 13 R , R , and R are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, N-methylamino, N,N-dimethylamino, N-ethylamino, methylthio, ethylthio, isopropylthio, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, 2,233 ,3-pentafluoropropyl, trifluoromethoxy, 1 , 1 ,2,2-tetrafluoroethoxy, fluoro, chloro, bromo, methanesulfonamido, amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro-l-hydroxyethyl, amidocarbonyl, N-methylamidocarbonyl, N,N-dimethylamidocarbonyl, and cyano; R and R are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, carboxymethyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, methoxyamino, ethoxyamino, acetamido, trifluoroacetamido, aminomethyl, 1-aminoethyl, 2-aminoethyl, N-methylamino, dimethylamino, N-ethylamino, methanesulfonamido, amidosulfonyl, N-methylamidosulfonyl,
    N,N-dimethylami dosulf onyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro-l-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-ρhenylethyl)amidocarbonyl, N-( 1 -methyl- l-ρhenylethyl)amidocarbonyl, N-benzylamidosulfonyl, N-(2-chlorobenzyl)amidosulf onyl , N-isopropylamidocarbonyl , N-cyclobutylamidocarbonyl, N-cyclopentylamidocarbonyl, 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, 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, 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-fluorophenylanιino, 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-ρhenylethoxy, 2-ρhenylethyl, 2-phenylethylamino, phenylsulfonyl, 3-trifluoromethoxybenzyloxy, 4-trifluoromethoxybenzyloxy, 3-trifluoromethoxyphenoxy, 4-trifluoromethoxyphenoxy, 3-trifluoromethylbenzyloxy, 4-trifluoromethylbenzyloxy, 2,4-bis-trifluoromethylbenzyloxy, 3-trifluoromethylbenzyl, 3 ,5-bis-trifluoromethylbenzyloxy, 4-tiifluoromethylphenoxy , 3-trifluoromethylphenoxy, 3-trifluoromethylthiobenzyloxy, 4-trifluoromethylthiobenzyloxy , 2,3 ,4-trifluorophenoxy , 2,3 ,5-trifluorophenoxy, 3-pentafluoroethylphenoxy, 3-(l,l,2,2-tetrafluoroethoxy)phenoxy, and 3-trifluoromethylthiophenoxy; x is selected from the group consisting of: l_Qb-4_QS. 2-R16_3.R17.5.R18_6-R19benzene, b s 17 18 19 2-Q -5-Q -6-R -4-R -3-R pyridine,
    3-Qb-6-QS-2-R16-5-R18-4-R19pyridine, 2-Qb-5-QS-3-R16-6-R18pyrazine, 3-Qb-6-QS-2-R18-5-R18-4-R19pyridazine,
    2-Q -5-QS- R17-6-R18pyrimidine, 5-Qb-2-QS-4-R16-6-R19pyrimidine,
    3-Qb-5-QS-4-R16-2-R19thiophene, 2-Qb-5-QS-3-R16-4-R17thiophene,
    3-Qb-5-QS-4-R16-2-R19furan, 2-Qb-5-QS-3-R16-4-R17furan,
    3-Q -5-QS-4-R -2-R pyπole, 2-Q -5-QS-3-R -4-R pyrrole, b s 19 b s 17
    4-Q -2-Q -5-R imidazole, 2-Q -4-Q -5-R imidazole,
    b s 16 b s 19
    2_Q _5_Q _4_R pyrazole, 4-Q -2-Q -5-R thiazole, and
    V. c 1 *7
    2-Q -5-Q -4-R thiazole; gr I T *1 Q i n R , R , R , andR 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;
    R or R is optionally selected from the group consisting of
    20 21 26 25 23 24 25 23 24 NR R , N(R )C(NR )N(R )(R ), and C(NR )NR R , with the
    proviso that R , R , and Q are not simultaneously hydrido; b 20 21
    Q is selected from the group consisting of NR R , hydrido,
    C(NR25)NR23R24, and N(R26)C(NR25)N(R23)(R24), with the proviso that
    20 21 23 24 no more than one of R , R , R , and R can be hydroxy, when any two 20 21 23 24 of the group consisting of R , R , R , and R are bonded to the same
    atom and with the further proviso that said group is bonded directly to a carbon atom;
    20 21 23 24 25 26
    R , R , R , R , R , and R are independently selected from the group consisting of hydrido, methyl, ethyl, propyl, butyl, isopropyl, and hydroxy;
    Q is selected from the group consisting of a bond, CH2, and CH2CH2.
    26. Compound of Claim 24 of the Formula:
    or a pharmaceutically acceptable salt thereof, wherein;
    A is selected from the group consisting of CH2N(CH3),
    CH2N(CH2CH3), CH2CH2N(CH3), and CH2CH2N(CH2CH3);
    X° 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;
    R2 is Z°-Q;
    Z is a bond or CH ; Q is selected from the group consisting of phenyl, 2-thienyl, 3-thienyl,
    2-furyl, 3-furyl, 2-pyπolyl, 3-pyrrolyl, 2-imidazolyl, 4-imidazolyl, 3-pyrazolyl, 4-pyrazolyl, 2-thiazolyl, 3-isoxazolyl, 5-isoxazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, and l,3,5-triazin-2-yl, wherein a carbon adjacent to the carbon at the point of attachment of said phenyl or heteroaryl ring to Z is
    9 optionally substitoted by R , the other carbon adjacent to the carbon at the point
    13 9 of attachment is optionally substituted by R , a carbon adjacent to R and two atoms from the carbon at the point of attøchment is optionally substitated by
    10 13
    R , a carbon adjacent to R and two atoms from the carbon at the point of
    12 attachment is optionally substituted by R , and any carbon adjacent to both
    10 12 11
    R and R is optionally substituted by R ;
    9 11 13
    R , R , and R are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, methyl, ethyl, propyl, isopropyl, 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-hydroxyethyl, 2,2,2-trifluoro-l-hydroxyethyl, amidocarbonyl, N-methylamidocarbonyl, N,N-dimethylamidocarbonyl, and cyano;
    R and R are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, carboxymethyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, methoxyamino, ethoxyamino, acetamido, trifluoroacetamido, aminomethyl, 1-aminoethyl, 2-aminoethyl, N-methylamino, dimethylamino, N-ethylamino, methanesulfonamido, amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro-l-hydroxyethyl, methoxycarbonyl, ethoxycarbonyl, amidocarbonyl, N-methylamidocarbonyl, N,N-dimethylamidocarbonyl, N-benzylamidocarbonyl, N-(2-chlorobenzyl)amidocarbonyl, N-(3-fluorobenzyl)amidocarbonyl, N-(2-trifluoromefhylbenzyl)amidocarbonyl, N-(l-phenylethyl)amidocarbonyl, N-(l-methyl-l-phenylethyl)amidocarbonyl, N-benzylamidosulfonyl , N-(2-chlorobenzyl)amidosulfonyl , N-isopropylamidocarbonyl, N-cyclobutylamidocarbonyl, N-cyclopentylamidocarbonyl, fluoro, chloro, bromo, cyano, cyclobutoxy, cyclohexoxy, cyclohexylmethoxy, 4-trifluoromethycyclohexylmethoxy, cyclopentoxy, benzyl, benzyloxy, 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, 2,3-difluorophenoxy, 2,4-difluorophenoxy, 2,5-difluorophenoxy, 3,5-dimethylphenoxy, 3,4-dimethylphenoxy, 3,4-dimexhylbenzyloxy, 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, isoproρyl-3-methylphenoxy, 4-isopropylbenzyloxy, 3-isoρroρylphenoxy, 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 ,5-bis-trifluoromethylbenzyloxy, 4-trifluoromethylphenoxy , 3-trifluoromethylphenoxy, 3-trifluoromethylthiobenzyloxy, trifluoromethylthiobenzyloxy, 23,4-trifluorophenoxy, 2,3,5-trifluorophenoxy, 3-pentafluoroethylphenoxy, 3-(l,l,2,2-tetrafluoroethoxy)phenoxy, and 3-trifluoromethylthiophenoxy; ϊ is selected from the group consisting of: l_Qb_4_QS_2_R 16_3-R17-5-R18-6-R19benzene,
    2- dine,
    ^ , r „ τ, 16 C V& „ 19 . ,. Λ ^b B s „ „16 ^. 18 3-Q -6-Q -2-R -5-R -4-R pyπdme, 2-Q -5-Q -3-R -6-R pyrazme,
    3-Q -6-QS-2-R -5-R -4-R pyridazine,
    ~ b ,. s , -17 , „18 . . ,. - , > Λ _ s _ „ 16 ,. „ 19 .
    2-Q -5-Q -4-R -6-R pyπmidme, 5-Q -2-Q -4-R -6-R pyπmidme,
    „ b „ ^s „ „ 16 „ _ 19 , . , Λ Λb _ Λs „ „ 16 „ „ 17 , . , 3-Q -5-Q -4-R -2-R thiophene, 2-Q -5-Q -3-R -4-R thiophene,
    3-Qb-5-QS-4-R16-2-R19furan, 2-Qb-5-QS-3-R16-4-R17furan,
    3-Q -5-QS-4-R -2-R pyπole, 2-Q -5-QS-3-R -4-R pyπole, b s 19 b s 17
    4-Q -2-Q -5-R imidazole, 2-Q -4-Q -5-R imidazole, b s 16 b s 16
    3-Q -5-Q -4-R isoxazole, 5-Q -3-Q -4-R isoxazole,
    ^ Jo - s A „ 16 , , Λb Λ s ,. .„ 19 , .
    2-Q -5-Q -4-R pyrazole, 4-Q -2-Q -5-R thiazole, and c 1 Ό
    2-Q -5-Q -4-R thiazole;
    are independently selected from the group consisting of hydrido, methyl, ethyl, isopropyl, propyl, amidino, guanidino, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, aminomethyl, 1-aminoethyl, 2-aminoethyl, N-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; b 20 21
    Q is selected from the group consisting of NR R ,
    C(NR25)NR23R24, and N(R26)C(NR25)N(R23)(R24), with the proviso that 20 21 23 24 no more than one of R , R , R , and R can be hydroxy, when any two
    20 21 23 ^24 of the group consisting of R , R , R , and R are bonded to the same
    atom, and with the further proviso that said Q group is bonded directly to a carbon atom;
    20 21 23 24 25 26
    R , R , R , R , R , and R are independently selected from the group consisting of hydrido, methyl, ethyl, propyl, butyl, isopropyl, and hydroxy; s Q is selected from the group consisting of a bond, CH2, and CH2CH2.
    27. Compound of Claim 26 or a pharmaceutically acceptable salt thereof, wherein;
    A is selected from the group consisting of CH2N(CH3),
    CH2N(CH2CH3), CH2CH2N(CH3), and CH2CH2N(CH2CH3);
    X° is selected from the group consisting of hydrido, hydroxy,l- aminoethyl, methyl, ethyl, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, fluoro, chloro, and bromo;
    R2 is Z°-Q;
    Z is a bond or CH2;
    Q is selected from the group consisting of 3-amidocarbonyl- aminophenyl, 3-amino-5-(N-benzylamidocarbonyl)phenyl, 3-amino-5-benzylphenyl, 3-amino-5-(2-phenylethyl)phenyl, 3-amino-5-benzylaminophenyl, 3-amino-5-(2-phenylethylamino)phenyl, 3-amino-5-benzyloxyphenyl, 3-amino-5-(2-phenylethoxy)phenyl, 3-amino-5-(N-(2-chlorobenzyl)amidocarbonyl)phenyl, 3-amino-5-(N-(3-fluorobenzyl)amidocarbonyl)phenyl,
    3-arnino-5-(N-(2-trifluoromethylbenzyl)amidocarbonyl)phenyl, 3-arnino-5-(N-(l-phenylethyl)arnidocarbonyl)phenyl, 3-amino-5-(N-( 1 -methyl- 1 -ρhenylethyl)amidocarbonyl)phenyl, 3-amino-5-(N-benzylamidosulfonyl)phenyl, 3-amino- (N-(2-chlorobenzyl)amidosulfonyl)phenyl, -amino-5-(N-ethylamidocarbonyl)phenyl, -amino-5-(N-isopropylamidocarbonyl)phenyl, -amino-5-(N-propylamidocarbonyl)phenyl, -amino- (N-isobutylamidocarbonyl)phenyl, -amino-5-(N-(2-butyl)amidocarbonyl)phenyl , -amino-S(N-cyclobutylamidocarbonyl)phenyl, -amino-5-(N-cyclopentylamidocarbonyl)phenyl, -amino-5-(N-cyclohexylamidocarbonyl)phenyl, 5-amino-2-fluorophenyl, 3-amino-5-hydroxymethylphenyl, 5-amino-3-methoxycarbonylphenyl, 3-amidinophenyl,
    3-amino-2-methylphenyl, 5-amino-2-methylthiophenyl, 3-aminophenyl, 3-carboxyphenyl, 3-carboxy-Shydroxyphenyl, 3-amino-5-carboxyphenyl, -chlorophenyl, 2-chlorophenyl, 3-cyanophenyl, 3,5-diaminophenyl, -dimethylaminophenyl, 2-fluorophenyl, 3-fluorophenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 3-methanesulfonylaminophenyl, 2-methoxyphenyl, 3-methoxyphenyl, 3-methoxyaminophenyl, 3-methoxycarbonylphenyl, 2-methylaminophenyl, 3-methylaminophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, phenyl, 3-trifluoroacetamidophenyl, 3-trifluoromethylphenyl, 2-trifluoromethylphenyl, 5-amino-2-thienyl, amino-3-thienyl, 3-bromo-2-thienyl, 3-pyridyl, 4-pyridyl, 2-thienyl, and 3-thienyl;
    Y is selected from the group consisting of: o 1 »ζ 1 ^7 1 β 1 Q l-Q -4-Q -2-R -3-R -5-R -6-R benzene,
    „ Jo e ^s ^ 17 „ „18 „ 19 . ,. 2-Q -5-Q -6-R -4-R -3-R pyπdme,
    3-Qb-6-QS-2-R16-5-R18-4-R19pyridine,
    3-Qb-5-QS-4-R16-2-R19thiophene, and 2-Qb-5-QS-3-R16-4-R17thiophene;
    R and R are independently selected from the group consisting of hydrido, amidino, amino, aminomethyl, methoxy, methylamino, hydroxy, hydroxymethyl, fluoro, chloro, and cyano;
    17 18
    R and R are independently selected from the group consisting of hydrido, fluoro, chloro, hydroxy, hydroxymethyl, amino, carboxy, and cyano;
    23 24 25
    R , R , and R are independently selected from the group consisting of hydrido and methyl; QS is CH2.
    28. A compound as recited in Claim 27 or a pharmaceutically acceptable salt thereof where said compound is selected from the group consisting of:
    2-[3-[N-[[4-aminoiminomethylphenyl]methyl]-2-[3-aminophenyl]-5- [N,N-dimethylhydrazino]-4-pyronyl]]acetamide; 2-[3-[N-[[4-aminoiminomethylphenyl]methyl]-2-[3-aminophenyl]-5-
    [N-ethyl-N-methylhydrazino]-4-pyronyl]]acetarnide;
    2-[3-[N-[[4-aminoiminomethylphenyl]methyl]-2-[3-aminophenyl]-5- [N,N-dimethylhydrazino]-6-chloro-4-pyronyl]]acetamide;
    2-[3-[N-[[ aminoiminomethylphenyl]methyl]-2-[3-aminophenyl]-5- [N-ethyl-N-methylhydrazino]-6-chloro-4-pyronyl]]acetamide;
    2-[3-[N-[[4-arninoiminomethylphenyl]methyl]-2-[3,5-diaminophenyl]- 5-[N,N-dimethylhydrazino]-4-pyronyl]]acetamide;
    2-[3-[N-[[4-aminoiminomexhylphenyl]methyl]-2-[3,5-diaminophenyl]- 5-[N-ethyl-N-methylhydrazino3-4-pyronyl]]acetømide; 2-[3-[N-[[4-aminoiminomethylphenyl]methyl]-2-[3,5-diaminophenyl]-
    5-[N,N-dimethylhydrazino]-6-chloro-4-pyronyl]]acetamide;
    2-[3-[N-[[4-aminoiminomethylphenyl]methyl]-2-[3,5-diaminophenyl]- 5-[N-ethyl-N-methylhydrazino]-6-chloro-4-pyronyl]]acetamide;
    2-[3-[N-[[4-aminoiminomethylphenyl]methyl]-2-[3-amino-5- carboxyphenyl]-5-[N,N-dimethylhydrazino]-4-pyronyl]]acetamide;
    2- [3 - [N-[[4-aminoiminomethylphenyl]methyl]-2- [3-amino-5- carboxyphenyl]-5-[N-ethyl-N-methylhydrazino]-4-pyronyl]]acetamide;
    2-[3-[N-[[4-aminoiminomethylphenyl]methyl]-2-[3-amino-5- carboxyphenyl]-5-[N,N-dimethylhydrazino]-6-chloro-4-ρyronyl3]acetamide; 2-[3-[N-[[4-aminoiminomethylphenyl]methyl]-2-[3-amino- carboxyphenyl]- 5-[N-ethyl-N-methylhydrazino]-6-chloro-4- pyronyl]]acetamide; 2-[3-[N-[[4-aminoiminomethylphenyl]methyl]-2-[3-amino-5-(N- benzylamidocarbony phenyl]- 5-[N,N- dimethylhydrazino]-4- pyronyljjacetamide;
    2-[3-[N-[[4-aminoiminomethylphenyl]methyl]-2-[3-amino-5-(N- benzylamidocarbonyl)phenyl]-5-[N-ethyl-N-methylhydrazino]-4- pyronyl]]acetømide;
    2- [3 - [N-[[4-aminoiminomethylphenyl]methyl]-2- [3-amino-5-(N- benzylamidocarbonyl)phenyl]-5-[N,N-dimethylhydrazino]-6-chloro-4- pyronyl]]acetamide;
    2- [3- [N-[[4-aminoiminomethylphenyl]methyl]-2[3-amino-5-(N- benzylamidocarbonyl)phenyl]-5-[N-ethyl-N-methylhydrazino]-6-chloro-4- pyronyl]]acetamide.
    29. Compound of Claim 22 of 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 attøchment of said phenyl or heteroaryl
    32 ring to A is optionally substituted by R , the other carbon adjacent to the
    36 carbon at the point of attachment is optionally substitoted by R , a carbon
    32 adjacent to R and two atoms from the carbon at the point of attøchment is
    optionally substituted by R , a carbon adjacent to R and two atoms from the
    35 carbon at the point of attachment is optionally substitated by R , and any
    33 35 34 carbon adjacent to both R and R is optionally substituted by R ; O A '2 *5 /l ^ <C T
    R , R , R , R , and R 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 Q ;
    15 7
    A is a bond or (CH(R ))pa-(W )n wherein rr is 0 or 1, pa is an
    7 7 7 integer selected from 0 through 3, and W is (R )NC(O) or N(R );
    7 R is selected from the group consisting of hydπdo, hydroxy and alkyl;
    15 R 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;
    R2 is Z°-Q; Z is selected from the group consisting of a bond, CH2, CH2CH2, W -
    42 o
    (CH(R ))p wherein p is 0 or 1 and W is selected from the group consisting
    of O, S, and N(R41);
    41 42
    R and R 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 o 9 ring to Z is optionally substituted by R , the other carbon adjacent to the
    13 carbon at the point of attachment is optionally substitated by R , a carbon
    9 adjacent to R and two atoms from the carbon at the point of attøchment is
    10 13 optionally substitated by R , a carbon adjacent to R and two atoms from the 12 carbon at the point of attachment is optionally substituted by R , and any
    10 12 11 carbon adjacent to both R and R is optionally substituted by R ;
    9 11 13
    R , R , and R are independently selected from the group consisting of hydrido, hydroxy, amino, amidino, guanidino, alkylamino, alkylthio, alkylsulfonamido, alkylsulfinyl, alkylsulfonyl, amidosulfonyl, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, hydroxyalkyl, hydroxyhaloalkyl, carboxy, carboxamido, and cyano;
    10 12
    R and R 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, alkylarnino, arylamino, aralkylamino, heteroarylamino, heteroaralkylamino, heterocyclylamino, heterocyclylalkylammo, alkylsulfonamido, amidosulfonyl, arylsulfinyl, aralkylsulfinyl, cycloalkylsulfinyl, heteroarylsulfinyl, arylsulfonyl, aralkylsulfonyl, cycloalkylsulfonyl, heteroarylsulfonyl, hydroxyalkyl, hydroxyhaloalkyl, aminoalkyl, carboalkoxy, carboxy, carboxyalkyl, carboxamido, halo, haloalkyl, and cyano; x is phenyl or a heteroaryl of 5 or 6 ring members, wherein one carbon of said phenyl or said heteroaryl is substituted by Q , a carbon two or three g atoms from the point of attachment of Q to said phenyl or said heteroaryl is b s substituted by Q , a carbon adjacent to the point of attachment of Q is
    17 optionally substitated by R , another carbon adjacent to the point of
    attachment of Q is optionally substituted by R , a carbon adjacent to Q is optionally substituted by , and another carbon adjacent to is optionally
    19 substitated by R ; 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; .16 19 . . „ .™20 21 m25 _23 24 . , R or R is optionally NR R or C(NR )NR R , with the
    proviso that R , R , and Q are not simultaneously hydrido; b 20 21
    Q is selected from the group consisting of NR R , hydrido, and
    25 23 24 20 21
    C(NR )NR R , with the proviso that no more than one of R and R is
    23 hydroxy at the same time and with the further proviso that no more than one of R
    24 and R is hydroxy at the same time;
    20 21 23 „24 Λ J25 . J J , , R , R , R , R , and R are independently selected from the group consisting of hydrido, alkyl, and hydroxy; g
    Q is selected from the group consisting of a bond, CH , and CH2CH2.
    30. Compound of Claim 29 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-pyπolyl, 3-pyπolyl, 2-imidazolyl, 4-imidazolyl, 3-pyrazolyl, 4-pyrazolyl, 2-thiazolyl, 3-isoxazolyl, 5-isoxazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, and l,3,5-triazin-2-yl, wherein a carbon adjacent to the carbon at the point of attachment of said phenyl or heteroaryl ring to A is
    32 optionally substituted by R , the other carbon adjacent to the carbon at the
    point of attachment is optionally substitated by and two atoms from the carbon at the point of attachment is optionally oo substituted by R , a carbon adjacent to R and two atoms from the carbon at
    35 the point of attachment is optionally substituted by R , and any carbon
    33 35 34 adjacent to both R and R is optionally substituted by R ;
    ^32 ^33 34 35 , 36 . J J , ,
    R , R , R , R , and R are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, methoxyamino, ethoxyamino, acetamido, trifluoroacetamido, N-methylamino, dimethylamino, N-ethylamino, methylthio, ethylthio, isopropylthio, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, 2,2333-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-l-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;
    X° 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,l,l,2,2-tetrafluoroethoxy, fluoro, chloro, and bromo;
    R2 is Z°-Q;
    Z is selected from the group consisting of a bond, CH2, CH2CH2, 0, 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-pyπolyl, 2-imidazolyl, 4-imidazolyl, 3-ρyrazoiyl, 4-pyrazolyl, 2-thiazolyl, 3-isoxazolyl, 5-isoxazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl, pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, and l,3,5-triazin-2-yl, wherein a carbon adjacent to the carbon at the point of attøchment of said phenyl or heteroaryl ring to Z is
    9 optionally substituted by R , the other carbon adjacent to the carbon at the point
    13 9 of attachment is optionally substituted by R , a carbon adjacent to R and two atoms from the carbon at the point of attøchment is optionally substituted by
    10 13
    R , a carbon adjacent to R and two atoms from the carbon at the point of
    12 attachment is optionally substituted by R , and any carbon adjacent to both
    10 12 11
    R and R is optionally substituted by R ;
    9 11 13
    R , R , and R are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, N-methylamino, N,N-dimethylamino, N-ethylamino, methylthio, ethylthio, isopropylthio, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, 2,2333-pentøfluoropropyl, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro, bromo, methanesulfonamido, amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylarnidosulfonyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro-l-hydroxyethyl, amidocarbonyl, N-methylamidocarbonyl, N,N-dimethylamidocarbonyl, and cyano;
    10 12
    R and R are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, carboxymethyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, methoxyamino, ethoxyamino, acetamido, trifluoroacetamido, aminomethyl, 1-aminoethyl, 2-aminoethyl, N-methylamino, dimethylamino, N-ethylamino, methanesulfonamido, amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro-l-hydroxyethyl, methoxycarbonyl, ethoxycarbonyl, amidocarbonyl, N-methylamidocarbonyl, N,N-dimethylamidocarbonyl, N-benzylamidocarbonyl, N-(2-chlorobenzyl)amidocarbonyl, N-(3-fluorobenzyl)amidocarbonyl, N-(2-trifluoromefhylbenzyl)amidocarbonyl, N-(l-phenylethyl)amidocarbonyl, N-(l-methyl-l-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-chlorobenzyl sulfonyl, 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, ,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-trifluorornethylphenoxy, 2-fluorobenzyloxy, 4-fluorophenylamino, 2-fluoro-4-trifluoromethylρhenoxy,
    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-trifluoromethoxy phenoxy, 3-trifluoromethylbenzyloxy, 4-trifluoromethylbenzyloxy, 2,4-bis-trifluoromethylbenzyloxy, 3-trifluoromethylbenzyl, 3 ,5-bis-trifluoromethylbenzyloxy , 4-trifluoromethylphenoxy , 3-trifluoromethylphenoxy, 3-trifluoromethylthiobenzyloxy, 4-trifluoromethylthiobenzyloxy , 2,3 ,4-trifluorophenoxy, 2,3 ,5-trifluorophenoxy , 3-pentafluoroethylρhenoxy, 3-(l,l ,2,2-tetrafluoroethoxy )phenoxy, and 3-trifluoromethylthiophenoxy; x is selected from the group consisting of: 1 -Qb-4-QS-2-R16-3-R17-5-R18-6-R19benzene,
    „ ^ b B ^ s ^ „17 Λ „18 19 . ,. 2-Q -5-Q -6-R -4-R -3-R pyridine, o ^b ^ ^s „ x, 16 ^ τ, 18 A 19 . ,. Λ b _ s „ „ 16 , 18
    3-Q -6-Q -2-R -5-R -4-R pyπdine, 2-Q -5-Q -3-R -6-R pyrazme,
    3-Q -6-QS-2-R18-5-R18-4-R19pyridazine,
    2-Qb-5-QS-4-R17-6-R18pyrimidine, 5-Qb-2-QS-4-R16-6-R19pyrimidine,
    3-Qb-5-QS-4-R16-2-R19thiophene, 2-Qb-5-QS-3-R16-4-R17χhiophene,
    3-Qb-5-QS-4-R16-2-R19furan, 2-Qb-5-QS-3-R16-4-R17furan,
    3-Qb-5-QS-4-R16-2-R19pyπole, 2-Qb-5-QS-3-R16-4-R17pyπole, b s 19 b s 17
    4-Q -2-Q -5-R imidazole, 2-Q -4-Q -5-R imidazole,
    „ o - ^ s Λ - t . , _ _b „ ^s Λ .6.
    3-Q -5-Q -4-R isoxazole, 5-Q -3-Q -4-R isoxazole,
    2-Q -5-QS-4-R pyrazole, 4-Q -2-QS-5-R thiazole, and
    2-Q -5-Q -4-R thiazole;
    R are independently selected from the group consisting of hydrido, methyl, ethyl, isopropyl, propyl, carboxy, amidino, guanidino, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, aminomethyl, 1-aminoethyl, 2-aminoethyl, N-methylamino, dimethylamino, N-ethylamino, methylthio, ethylthio, isopropylthio, trifluoromethylthio, methylsulfinyl, ethylsulfinyl, methylsulfonyl, ethylsulfonyl, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, 2,2,333-pentafluoropropyl, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro, bromo, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, and cyano; 16 19 25 23 24 16
    R or R is optionally C(NR )NR R with the proviso that R ,
    R , and Q are not simultaneously hydrido; h 25 23 24
    Q is C(NR )NR R or hydrido, with the proviso that no more than
    23 24 one of R and R is hydroxy at the same time;
    23 24 25
    R , R , and R are independently selected from the group consisting of hydrido, methyl, ethyl, and hydroxy;
    Q is selected from the group consisting of a bond, CH2 and CH2CH2.
    31. Compound of Claim 30 or a pharmaceutically acceptable salt thereof, wherein;
    B is selected from the group consisting of 2-aminophenyl, 3-aminophenyl, 3-amidinophenyl, 4-amidinophenyl, 3-carboxyphenyl, 3-carboxy-5-hydroxyphenyl, 3-clιlorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 3,4-difluorophenyl, 3-hydroxyphenyl, 4-hydroxyρhenyl, 3-methoxyaminophenyl,
    3-methoxyphenyl, 4-methoxyphenyl, 3-methylphenyl, 4-methylphenyl, phenyl, 3-trifluoromethylphenyl, 2-imidazoyl, 2-pyridyl, 3-pyridyl, 5-chloro-3-trifluoromethyl-2-pyridyl, 4-pyridyl, 2-thienyI, 3-thienyl, and 3-trifluoromethyl-2-pyridyl ; A is selected from the group consisting of CH2, CH3CH, CF3CH,
    NHC(O), CH2CH2, and CH2CH2CH2;
    X° is selected from the group consisting of hydrido, hydroxy, 1-aminoethyl, methyl, ethyl, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, fluoro, chloro, and bromo;
    R2 is Z°-Q;
    Z is selected from the group consisting of a bond, CH2, 0, S, NH,
    N(CH3), OCH2, and SCH2;
    Q is selected from the group consisting of -amidocarbonyl- aminophenyl, 3-amino-5-(N-benzylamidocarbonyl)phenyl, -amino-5-benzylphenyl, 3-amino- (2-phenylethyl)phenyl, -amino-5-benzylaminophenyl , 3-amino-5-(2-ρhenylethylamino)phenyl, -amino-5-benzyloxyphenyl, 3-amino-5-(2-phenylethoxy)phenyl, -amino-5-(N-(2-chlorobenzyl)amidocarbonyl)phenyl, -amino-5-(N-(3-fluorobenzyl)amidocarbonyl)phenyl, -amino-5-(N-(2-trifluoromefhylbenzyl)amidocarbonyl)phenyl, -amino-5-(N-( 1 -phenyl ethyl)amidocarbonyl)phenyl, -amino-5-(N-( 1 -methyl-1 -phenylethyl)amidocarbonyl)phenyl, -amino-5-(N-benzylamidosulfonyl)phenyl, -amino-5-(N-(2-chlorobenzyl)amidosulfonyl)phenyl, -airiino-5-(N-ethylamidocarbonyl)phenyl, -amino-5-(N-isoproρylamidocarbonyl)phenyl, -amino-5-(N-propylamidocarbonyl)phenyl, -amino-5-(N-isobutylamidocarbonyl)phenyl, -amino-5-(N-(2-butyl)amidocarbonyl)phenyl, -amino-5-(N-cyclobutylamidocarbonyl)phenyl, -amino-5-(N-cyclopentylamidocarbonyl)phenyl, -amino-5-(N-cyclohexylamidocarbonyl)phenyl, 5-amino-2-fluorophenyl, 3-amino-5-hydroxymethylphenyl, 5-amino-3-methoxycarbonylphenyl, 3-amidinophenyl, 3-amino-2-methylphenyl, 5-amino-2-methylthiophenyl, 3-aminophenyl, 3-amino-5-(4-trifluoromethylbenzylamino)phenyl, 3-arnino-5-(4-trifluoromethylbenzyloxy)phenyl, 3-carboxyphenyl, 3-carboxy-5-hydroxyphenyl, 3-amino-5-carboxyphenyl, 3-chlorophenyl, 2-chlorophenyl, 3-cyanophenyl, 3 ,5-diaminoρhenyl, 3-dimethylaminophenyl,
    2-fluorophenyl, 3-fluorophenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 3-methanesulfonylaminophenyl, 2-methoxyphenyl, 3-methoxyphenyl, 3-methoxyaminophenyl, 3-methoxycarbonylphenyl, 2-methylaminophenyl, 3-methylaminophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, phenyl, 3-trifluoroacetamidophenyl, 3-trifluoromethylphenyl,
    2-trifluoromethylphenyl, 5-amino-2-thienyl, 5-amino-3-thienyl, 3-bromo-2-thienyl, 3-pyridyl, 4-pyridyl, 2-thienyl, and 3-thienyl; ϊ is selected from the group consisting of: l-Qb-4-QS-2-R16-3-R17-5-R18-6-R19benzene, 2-Qb-5-QS-6-R17-4-R18-3-R19pyridine,
    3-Qb-6-QS-2-R16-5-R18-4-R19pyridine,
    3-Q -5-QS-4-R -2-R thiophene, and 2-Q -5-QS-3-R -4-R thiophene;
    R and R are independently selected from the group consisting of hydrido, amidino, amino, aminomethyl, methoxy, methylamino, hydroxy, hydroxymethyl, fluoro, chloro, and cyano;
    R ,
    19 b
    R , and Q are not simultaneously hydrido;
    17 18
    R and R are independently selected from the group consisting of hydrido, fluoro, chloro, hydroxy, hydroxymethyl, amino, carboxy, and cyano; h 25 23 24
    Q is C(NR )NR R or hydrido;
    23 24 25
    R , R , and R are independently hydπdo or methyl;
    Qs is CH2.
    32. Compound of Claim 29 of 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
    32 ring to A is optionally substituted by R , the other carbon adjacent to the
    carbon at the point of attachment is optionally substitoted by carbon
    32 adjacent to R and two atoms from the carbon at the point of attachment is 33 36 optionally substitoted by R , a carbon adjacent to R and two atoms from the
    35 carbon at the point of attachment is optionally substitated by R , and any
    33 35 34 carbon adjacent to both R and R is optionally substituted by R ; on oo /t o c if.
    R , R , R , R , andR 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 ;
    15 7
    A is a bond or (CH(R ))pa-(W )rr wherein π is 0 or 1 , pa is an
    7 7 integer selected from 0 through 3, and W is N(R );
    7 R is hydrido or alkyl;
    15 R is selected from the group consisting of hydrido, halo, alkyl, and haloalkyl;
    X is selected from the group consisting of hydrido, alkyl, halo, haloalkyl, aminoalkyl, and hydroxyalkyl;
    R2 isZ°-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 o 9 ring to Z is optionally substituted by R , the other carbon adjacent to the
    13 carbon at the point of attachment is optionally substitated by R , a carbon
    9 adjacent to R and two atoms from the carbon at the point of attachment is
    10 . 13 optionally substituted by R , a carbon adjacent to R and two atoms from the
    12 carbon at the point of attachment is optionally substitated by R , and any
    10 12 11 carbon adjacent to both R and R is optionally substituted by R ; 9 11 13
    R , R , and R are independently selected from the group consisting of hydrido, hydroxy, amino, amidino, guanidino, alkylamino, alkylthio, alkoxy, alkylsulfinyl, alkylsulfonyl, amidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboxy, carboxamido, and cyano;
    10 12 R and R are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkyl, alkoxy, alkoxyamino, hydroxy, amino, alkylamino, alkylsulfonamido, amidosulfonyl, hydroxyalkyl, aminoalkyl, halo, haloalkyl, carboalkoxy, carboxy, carboxamido, carboxyalkyl, and cyano; Ϊ is phenyl or a heteroaryl of 5 or 6 ring members, wherein one carbon s of said phenyl or said heteroaryl is substituted by Q , a carbon two or three s atoms from the point of attachment of Q to said phenyl or said heteroaryl is b s substitated by Q , a carbon adjacent to the point of attøchment of Q is
    17 optionally substitated by R , another carbon adjacent to the point of
    attachment of Q is optionally substituted by R , a carbon adjacent to Q is
    16 b optionally substitated by R , and another carbon adjacent to Q is optionally
    19 substitated by R ;
    16 17 „18 19 . , , , ,
    R , R , R , and R are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, haloalkylthio, alkoxy, hydroxy, amino, alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, and cyano;
    R16 or R19 is optionally NR2°R21 or C(NR25)NR23R24, with the
    proviso that R , R , and Q are not simultaneously hydrido; ι 90 91 Q is selected from the group consisting of NR R , hydrido, and
    25 23 24 C(NR )NR R ; 20 21 23 24 25
    R , R , R , R , and R are independently hydπdo or alkyl;
    Q is CH2.
    33. Compound of Claim 32 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-pyπolyl, 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
    32 ring to A is optionally substitated by R , the other carbon adjacent to the
    36 carbon at the point of attachment is optionally substitoted by R , a carbon
    32 adjacent to R and two atoms from the carbon at the point of attachment is
    QO Q /T optionally substituted by R , a carbon adjacent to R and two atoms from the
    35 carbon at the point of attachment is optionally substituted by R , and any
    33 35 34 carbon adjacent to both R and R is optionally substituted by R ;
    32 33 34 35 36
    R , R , R , R , and R are independentiy 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 Q ;
    A is selected from the group consisting of a bond, NH, N(CH3), CH ,
    CH3CH, and CH2CH2;
    X° is selected from the group consisting of hydrido, aminomethyl, methyl, ethyl, trifluoromethyl, 2,2,2-trifluoroethyl, hydroxymethyl,
    2-hydroxyethyl, chloro, and fluoro; R 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
    9 phenyl or heteroaryl ring to the 4-pyrone ring is optionally substituted by R , the other carbon adjacent to the carbon at the point of attachment is optionally
    13 9 substitoted by R , a carbon adjacent to R and two atoms from the carbon at
    the point of attachment is optionally substituted by R , a carbon adjacent to
    13 R and two atoms from the carbon at the point of attachment is optionally
    12 . 10 12 substitoted by R , and any carbon adjacent to both R and R is optionally
    11 substituted by R ;
    9 11 13 R , R , and R are independentiy 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;
    R and R 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-(l-methyl-l-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 consisting of: 1-Q -4-QS-2-R16-3-R17-5-R18-6-R19benzene,
    2-Q -5-QS-6-R -4-R -3-R pyridine, 2-Q -5-Q -3-R -4-R thiophene,
    3-Qb-6-QS-2-R16-5-R18-4-R19pyridine, 3-Qb-5-QS-4-R16-2-R19thiophene,
    3-Qb-5-QS-4-R16-2-R19furan, 2-Qb-5-QS-3-R16-4-R17furan,
    3-Q -5-QS-4-R -2-R pyπole, 2-Q -5-QS-3-R -4-R pyπole, b s 19 b s 17
    4-Q -2-Q -5-R thiazole, and 2-Q -5-Q -4-R thiazole;
    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; b 20 21 25 23 24
    Q is NR R or C(NR )NR R ;
    20 21 23 24 25
    R , R , R , R , and R are independently selected from the group consisting of hydrido, methyl, and ethyl;
    ,s .
    Q is CH2.
    34. Compound of Claim 33 or a pharmaceutically acceptable salt thereof, wherein;
    B is selected from the group consisting of 2-aminophenyl, 3-aminophenyl, 3-amidinophenyl, 4-amidinophenyl, 3-carboxyphenyl, 3-carboxy-5-hydroxyphenyl, 3-chlorophenyl, 4-chlorophenyl,
    3,4-dichlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 3,4-difluorophenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 3-methoxyaminoρhenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-methylphenyl, 4-methylphenyl, phenyl, 3-trifluoromethylphenyl, 2-imidazoyl, 2-ρyridyl, 3-pyridyl, chloro-3-trifluoromethyl-2-pyridyl, 4-pyridyl, 2-thienyl, 3-thienyl, and 3-trifluoromethyl-2-pyridyl;
    A is CH2 or CH2CH2;
    X° is selected from the group consisting of hydrido, methyl, ethyl, trifluoromethyl, 2,2,2-trifluoroethyl, hydroxymethyl, 2-hydroxyethyl, chloro, and fluoro; R is selected from the group consisting of
    3-arnidocarbonyl-Saminophenyl, 3-amidocarbonyl-5-aminophenyl,
    3-amino-5-(N-benzylamidocarbonyl)phenyl, 3-amino-5-(N-(2-chlorobenzyl)amidocarbonyl)phenyl,
    3-amino-5-(N-(3-fluorobenzyl)amidocarbonyl)phenyl,
    3-amino-5-(N-(2-trifluoromethylbenzyl)amidocarbonyl)phenyl,
    3-amino- (N-(l-phenylethyl)amidocarbonyl)phenyl,
    3-amino-5-(N-(l-methyl-l-phenylethyl)amidocarbonyl)phenyl, 3-amino- (N-benzylamidosulfonyl)phenyl,
    3-amino- (N-(2-chlorobenzyl)amidosulfonyl)ρhenyl,
    3-amino-5-(N-ethylamidocarbonyl)phenyl,
    3-amino-5-(N-isopropylamidocarbonyl)phenyl,
    3-amino- (N-propylamidocarbonyl)phenyl, 3-amino-S(N-isobutylamidocarbonyl)phenyl,
    3-amino-5-(N-(2-butyl)amidocarbonyl)phenyl, 3-amino- (N-cyclobutylamidocarbonyl)phenyl, 3-amino-5-(N-cyclopentylaιnidocarbonyl)phenyl, 3-amino-5-(N-cyclohexylamidocarbonyl)phenyl, 5-amino-2-fluoroρhenyl, 3-amino- hydroxymethylphenyl, 5-amino-3-methoxycarbonylphenyl, 3-amidinophenyl, 3-amino-2-methylphenyl, amino-2-methylthiophenyl, 3-aminophenyl, 3-carboxyρhenyl, 3-carboxy- aminoρhenyl, 3-carboxy-5-hydroxyphenyl, 3-carboxymethyl-5-aminophenyl, 3-carboxymethyl-5-hydroxyphenyl, 3-carboxymethylphenyl, 3-chlorophenyl, 2-chlorophenyl, 3-cyanophenyl, 3 ,5-diaminophenyl, 3-dimethylaminophenyl,
    2-fluorophenyl, 3-fluorophenyl, 2,5-difluorophenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 3-methanesulfonylaminophenyl, 2-methoxyphenyl, 3-methoxyphenyl, 3-methoxyaminophenyl, 3-mexhoxycarbonylphenyl, 2-methylaminophenyl, 3-methylaminophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, phenyl, 3-trifluoroacetamidophenyl, 3-trifluoromethylphenyl, 2-trifluoromethylphenyl, 5-amino-2-thienyl, 5-amino-3-thienyl, 3-bromo-2-thienyl, 3-pyridyl, 4-pyridyl, 2-thienyl, and 3-thienyl; x is selected from the group consisting of: l-Qb-4-QS-2-R16-3-R17-5-R18-6-R19benzene,
    2-Qb-5-QS-6-R17-4-R18-3-R19pyridine, o Jo , ^s „ 16 _ 18 Λ 19 . ,. 3.Q _6-Q -2-R -5-R -4-R pyridine,
    3-Q -5-QS-4-R -2-R thiophene, and 2-Q -5-QS-3-R -4-R thiophene;
    16 19 R and R are independently selected from the group consisting of hydrido, amidino, amino, aminomethyl, methoxy, methylamino, hydroxy, hydroxymethyl, fluoro, chloro, and cyano;
    17 18
    R and R are independently selected from the group consisting of hydrido, fluoro, chloro, hydroxy, hydroxymethyl, amino, carboxy, and cyano; Qb is C(NR25)NR23R24;
    23 24 25
    R , R , and R are independently hydrido or methyl;
    Qs is CH2.
    35. Compound of Claim 34 or a pharmaceutically acceptable salt thereof, wherein;
    B is selected from the group consisting of 3-aminophenyl, 3-amidinophenyl, 4-amidinophenyl, 3-chlorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 2-fluorophenyl, 4-methylphenyl, phenyl, 2-imidazoyl, 3-pyridyl, 4-pyridyl, and 3-trifluorornethyl-2-pyridyl; A is CH2 or CH2CH2;
    X° is selected from the group consisting of hydrido, methyl, ethyl, trifluoromethyl, 2,2,2-trifluoroethyl, chloro, and fluoro;
    2
    R is selected from the group consisting of 3-amidocarbonyl-5-aminophenyl, 3-amino-5-(N-benzylamidocarbonyl)phenyl,
    3-amino-5-(N-(2-chlorobenzyl)amidocarbonyl)phenyl,
    3-amino- (N-(3-fluorobenzyl)amidocarbonyl)phenyl,
    3-amino-5-(N-(2-trifluoromethylbenzyl)amidocarbonyl)phenyl, 3-amino- (N-(l-phenylethyl)amidocarbonyl)phenyl,
    3-amino-5-(N-(l-methyl-l-phenylethyl)amidocarbonyl)phenyl,
    3-amino- (N-benzylamidosulfonyl)phenyl,
    3-amino-5-(N-(2-chlorobenzyl)amidosulfonyl)phenyl,
    3-amino-5-(N-ethylamidocarbonyl)phenyl, 3-amino-5-(N-isopropylamidocarbonyl)phenyl,
    3-amino-5-(N-propylamidocarbonyl)phenyl,
    3-amino-5-(N-isobutylamidocarbonyl)phenyl,
    3-amino-5-(N-(2-butyl)amidocarbonyl)ρhenyl,
    3-amino-5-(N-cyclobutylamidocarbonyl)phenyl, 3-amino-5-(N-cyclopentylamidocarbonyl)phenyl,
    3-amino-5-(N-cyclohexylarnidocarbonyl)phenyl, 3-arninophenyl,
    3-carboxy-5-aminophenyl, 3-chlorophenyl, 3,5-diaminophenyl,
    3-dimethylaminophenyl, 3-hydroxyphenyl, 3-methanesulfonylaminophenyl,
    3-methylaminophenyl, 2-methylphenyl, 3-methylphenyl, phenyl, 3-trifluoroacetamidophenyl, 3-bromo-2-thienyl, 2-thienyl, and 3-thienyl; ϊ is selected from the group consisting of 5-amidino-2-thienylmethyl,
    4-amidinobenzyl, 2-fluoro-4-amidinobenzyl, and 3-fluoro-4-amdinobenzyl.
    36. Compound of Claim 29 where said compound is selected from the group of the Formula:
    or a pharmaceutically acceptable salt thereof, wherein B, A, R , X°, and Y are selected to form a compound selected from the group consisting of; 7 0
    R is 3-aminophenyl, B is phenyl, A is CH2, Y is 4-amidinobenzyl, and X° is hydrido;
    7 0
    R is 3-aminophenyl, B is 3-chlorophenyl, A is CH2CH2, Y is 4- amidinobenzyl, and X° is methyl; o o
    R is 3-aminophenyl, B is phenyl, A is CH , Y is 4-amidinobenzyl, and
    X° is methyl;
    R 2 is 3-aminophenyl, B is 2-imidazoyl, A is CH CH CH , Y 0 is 4- amidinobenzyl, and X° is methyl;
    2
    R is 3-amidocarbonyl-5-aminophenyl, B is 3-chlorophenyl, A is CH CH2, Y is 4-amidinobenzyl, and X° is methyl;
    2
    R is 3-amino-5-(N-benzylamidocarbonyl)phenyl, B is 3-chlorophenyl, A is CH2CH2, Y is 4-amidinobenzyl, and X° is methyl;
    R is 3-amino-5-(N-(2-chlorobenzyl)amidocarbonyl)phenyl, B is 3- chlorophenyl, A is CH CH ,Y is 4-amidinobenzyl, and X° is methyl; R is 3-amino-5-(N-(2-chlorobenzyl)amidosulfonyl)phenyl, B is 3- chlorophenyl, A is CH CH2, Y is 4-amidinobenzyl, and X° is methyl;
    R is 3-amino-5-(N-(2-trifluoromethylbenzyl)amidocarbonyl)- phenyl, B is 3-chlorophenyl, A is CH CH , Y is 4-amidinobenzyl, and X° is methyl;
    9 0
    R is 3,5-diaminophenyl, B is 3-chlorophenyl, A is CH2CH2, Y is 4- amidinobenzyl, and X° is methyl;
    R 2 is 3-amino-5-carboxyphenyl, B is 3-chlorophenyl, A is CH2CH2, Y 0 is
    4-amidinobenzyl, and X° is methyl;
    2 2
    R R iiss 33--aammiiddooccaarrbboonnyyll--55--aanminophenyl, B is 3-chlorophenyl, A is CH2CH2, x is 4-amidinobenzyl, and X° is hydrido R is 3-amino-5-(N-benzylamidocarbonyl)phenyl, B is 3-chlorophenyl, A is CH2CH2, Y is 4-amidinobenzyl, and X° is hydrido;
    R is 3-amino-5-(N-(2-chlorobenzyl)amidocarbonyl)phenyl, B is 3- chlorophenyl, A is CH CH2, Y is 4-amidinobenzyl, and X° is hydrido;
    2 R is 3-amino-5-(N-(2-chlorobenzyl)amidosulfonyl)phenyl, B is 3- chlorophenyl, A is CH CH2, Y is 4-amidinobenzyl, and X° is hydrido;
    R is 3-amino-5-(N-(2-trifluoromethylbenzyl)amidocarbonyl)- phenyl, B is
    3-chlorophenyl, A is CH2CH2, Y is 4-amidinobenzyl, and X° is hydrido;
    2 0
    R is 3,5-diaminophenyl, B is 3-chlorophenyl, A is CH2CH , Y is 4- amidinobenzyl, and X° is hydrido; and
    2 0
    R is 3-amino-5-carboxyphenyl, B is 3-chlorophenyl, A is CH2CH2, Y is
    4-amidinobenzyl, and X° is hydrido.
    37. Compound of Claim 22 of 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
    32 point of attachment of B to A with one or more of the group consisting of R
    „33 34 35 J 36 R , R ,R , and R ;
    32 33 34 35 , 36 . , J , , R , R , R , R , and R 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 Q ;
    15 7
    A is a bond or (CH(R ))pa-(W )rr wherein π is 0 or 1 , pa is an
    7 7 7 integer selected from 0 through 3, and W is (R )NC(O) or N(R );
    7 R is selected from the group consisting of hydrido, hydroxy and alkyl;
    R is selected from the group consisting of hydrido, halo, alkyl, and haloalkyl;
    X is selected from the group consisting of hydrido, amino, alkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, hydroxy, alkoxy, hydroxyalkyl, and alkylthio;
    R2 is Z°-Q;
    Z is selected from the group consisting of a bond, CH2, CH2CH2, w -
    42 o
    (CH(R )) wherein p is 0 or 1 and W is selected from the group consisting
    of O, S, and N(R41);
    41 42
    R and R 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
    0 9 ring to Z is optionally substituted by R , the other carbon adjacent to the
    13 carbon at the point of attachment is optionally substitated by R , a carbon
    9 adjacent to R and two atoms from the carbon at the point of attachment is
    10 13 optionally substituted by R , a carbon adjacent to R and two atoms from the
    12 carbon at the point of attachment is optionally substituted by R , and any
    10 12 11 carbon adjacent to both R and R is optionally substituted by R ; 9 11 13
    R , R , and R are independently selected from the group consisting of hydrido, hydroxy, amino, amidino, guanidino, alkylamino, alkylthio, alkylsulfonamido, alkylsulfinyl, alkylsulfonyl, amidosulfonyl, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, hydroxyalkyl, hydroxyhaloalkyl, carboxy, carboxamido, and cyano;
    10 12
    R and R 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, heterocyclylalkylammo, alkylsulfonamido, amidosulfonyl, arylsulfinyl, aralkylsulfinyl, cycloalkylsulfinyl, heteroarylsulfinyl, arylsulfonyl, aralkylsulfonyl, cycloalkylsulfonyl, heteroarylsulfonyl, hydroxyalkyl, hydroxyhaloalkyl, aminoalkyl, carboalkoxy, carboxy, carboxyalkyl, carboxamido, halo, haloalkyl, and cyano; is phenyl or a heteroaryl of 5 or 6 ring members, wherein one carbon g of said phenyl or said heteroaryl is substituted by Q , a carbon two or three
    § atoms from the point of attachment of Q to said phenyl or said heteroaryl is b s substituted by Q , a carbon adjacent to the point of attachment of Q is
    17 optionally substituted by R , another carbon adjacent to the point of
    attachment of Q is optionally substituted by R , a carbon adjacent to Q is
    1 f. Vι optionally substituted by R , and another carbon adjacent to Q is optionally
    substitated by R ;
    R , R , R , and R 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 or R is optionally selected from the group consisting of
    with the
    proviso that R , R , and Q are not simultaneously hydrido; b 20 21
    Q is selected from the group consisting of NR R , hydrido,
    C(NR25)NR23R24, and N(R26)C(NR25)N(R23)(R24), with the proviso that
    20 21 no more than one of R and R is hydroxy at the same time and with the
    23 24 further proviso that no more than one of R and R is hydroxy at the same time;
    20 21 23 24 25 26
    R , R , R , R , R , and R are independently selected from the group consisting of hydrido, alkyl, and hydroxy; g
    Q is selected from the group consisting of a bond, CH , and CH CH .
    38. Compound of Claim 37 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, l-methyl-2-butenyl, l-methyl-3-butenyl, l-methyl-2-butynyl, 3-pentyl, l-ethyl-2-ρroρenyl, 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, l-methyl-2-ρentenyl, l-methyl-3-pentenyl, l-methyl-4-pentenyl, l-methyl-2-pentynyl, l-methyl-3-ρentynyl, 3-hexyl, l-ethyl-2-butenyl, l-ethyl-3-butenyl, l-ρroρyl-2-ρropenyl, l-ethyl-2-butynyl, 1-heptyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, Sheptenyl, 6-heptenyl, 2-heptynyl, 3-heρtynyl, 4-heptynyl, 5-heptynyl, 2-heptyl, l-methyl-2-hexenyl, l-methyl-3-hexenyl, l-methyl-4-hexenyl, l-methyl-5-hexenyl, l-methyl-2-hexynyl, l-methyl-3-hexynyl, l-methyl-4-hexynyl, 3-heptyl, l-ethyl-2-pentenyl, l-ethyl-3-pentenyl, l-ethyl-4-pentenyl, l-butyl-2-propenyl, l-ethyl-2-pentynyl, 1 -ethyl -3-ρentynyl, 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
    32 33 34 35 36
    A with one or more of the group consisting of R , R , R , R , and R ; π 32 π33 τ.34 „35 , 36 . J J , , ., . R , R , R , R , andR are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, methoxyamino, ethoxyamino, acetamido, trifluoroacetamido, N-methylamino, dimethylamino, N-ethylamino, methylthio, ethylthio, isopropylthio, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, 2,2,33 ,3-pentafluoropropyl, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro, bromo, amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro-l-hydroxyethyl, methoxycarbonyl, ethoxycarbonyl, amidocarbonyl, N-methylamidocarbonyl, N,N-dimethylamidocarbonyl, cyano, and Q ;
    A is selected from the group consisting of bond, NH, N(CH ), N(OH),
    CH2, CH3CH, CF3CH, NHC(O), N(CH3)C(O), C(O)NH, C(0)N(CH3),
    CH2CH2, CH2CH2CH2, CH3CHCH2, and CF3CHCH2;
    X° 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;
    R2 is Z°-Q; Z is selected from the group consisting of a bond, CH2, CH2CH2, 0,
    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-pyπolyl, 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 o 9 heteroaryl ring to Z is optionally substituted by R , the other carbon adjacent
    13 to the carbon at the point of attøchment is optionally substitated by R , a
    9 carbon adjacent to R and two atoms from the carbon at the point of attachment
    10 13 is optionally substituted by R , a carbon adjacent to R and two atoms from
    12 the carbon at the point of attachment is optionally substituted by R , and any
    10 12 11 carbon adjacent to both R and R is optionally substituted by R ;
    9 11 13 R , R , and R are independently selected from the group consisting of hydrido, 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-dimethylami dosulf onyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro-l-hydroxyethyl, amidocarbonyl, N-methylamidocarbonyl, N,N-dimethylamidocarbonyl, and cyano;
    10 12 R and R are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, carboxymethyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, methoxyamino, ethoxyamino, acetamido, trifluoroacetamido, aminomethyl, 1-aminoethyl, 2-aminoethyl, N-methylamino, dimethylamino, N-ethylamino, methanesulfonamido, amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro-l-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-ρhenylethyl)amidocarbonyl, N-(l-methyl-l-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-chlorobenzyIoxy,
    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,
    3,5-dimethylphenoxy, 3,4-dimethylphenoxy, 3,4-dimethylbenzyloxy, 3,5-dimethylbenzyloxy, 4-ethoxyphenoxy, 4-ethylbenzyloxy, 3-ethylphenoxy, 4-ethylaminophenoxy, 3-exhyl-5-mexhylphenoxy, 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-trifluoromethoxybenzyloxy, 4-trifluoromethoxybenzyloxy, 3-trifluoromethoxyρhenoxy, 4-trifluoromethoxyphenoxy, 3-trifluoromethylbenzyloxy, 4-trifluoromethylbenzyloxy, 2,4-bis-trifluoromethylbenzyloxy, 3-trifluoromethylbenzyl, 3 ,5-bis-trifluoromethylbenzyloxy , 4-trifluoromethylphenoxy , 3-trifluoromethylphenoxy, 3-trifluoromethylthiobenzyloxy, 4-trifluoromethylthiobenzyloxy , 2,3 ,4-trifluorophenoxy, 23 ,5-trifluorophenoxy, 3-pentafluoroethylphenoxy, 3-(l,l,2,2-tetrafluoroethoxy)phenoxy, and 3-trifluoromethylthiophenoxy; x is selected from the group consisting of: l-Qb-4-QS-2-R16-3-R17-5-R18-6-R19benzene,
    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-R18pyrazine,
    3-Qb-6-QS-2-R18-5-R18-4-R19pyridazine, o ^ b ^s 17 ^ 18 . . Δ. e Jb n Λs Λ 16 ^ 19 .
    2-Q -5-Q -4-R -6-R pynmidme, 5-Q -2-Q -4-R -6-R pyπmidine,
    3-Qb-5-QS-4-R16-2-R19thiophene, 2-Qb-5-QS-3-R16-4-R17thiophene, b s 16 19 b s 16 17
    3-Q -5-Q -4-R -2-R furan, 2-Q -5-Q -3-R -4-R furan,
    3-Qb-5-QS-4-R16-2-R19pyrrole, 2-Qb-5-QS-3-R16-4-R17pyrrole, b s 19 b s 17 4-Q -2-Q -5-R imidazole, 2-Q -4-Q -5-R imidazole,
    3-Q -5-Q -4-R isoxazole, 5-Q -3-Q -4-R isoxazole, b s 16 b s 19
    2-Q -5-Q -4-R pyrazole, 4-Q -2-Q -5-R thiazole, and
    2-Q -5-QS-4-R thiazole;
    R , R , R , and R are independently selected from the group consisting of hydrido, methyl, ethyl, isopropyl, propyl, carboxy, amidino, guanidino, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, aminomethyl, 1-aminoethyl, 2-aminoethyl, N-methylamino, dimethylamino, N-ethylamino, methylthio, ethylthio, isopropylthio, trifluoromethylthio, methylsulfinyl, ethylsulfinyl, methylsulfonyl, ethylsulfonyl, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, 2,233 ,3-pentafluoropropyl, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro, bromo, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, and cyano;
    16 19 20 21
    R or R is optionally selected from the group consisting of NR R ,
    C(NR25)NR23R24, and N(R26)C(NR25)N(R23)(R24), with the proviso that R16,
    19 h R , and Q are not simultaneously hydrido; b 20 21
    Q is selected from the group consisting of NR R , hydrido,
    C(NR25)NR23R24, and N(R26)C(NR25)N(R23)(R24), with the proviso that no
    20 21 more than one of R and R is hydroxy at the same time and with the further
    23 24 proviso that no more than one of R and R is hydroxy at the same time;
    20 21 23 24 25 26 R , R , R , R , R , and R are independently selected from the group consisting of hydrido, methyl, ethyl, propyl, butyl, isopropyl, and hydroxy; g
    Q is selected from the group consisting of a bond, CH2, and CH2CH2.
    39. Compound of Claim 38 or a pharmaceutically acceptable salt thereof, wherein;
    B is selected from the group consisting of hydrido, ethyl, 2-propenyl, 2-propynyl, propyl, isopropyl, butyl, 2-butyl, (R)-2-butyl, (S)-2-butyl, tert-butyl, isobutyl, 1-pentyl, 3-pentyl, 2-methylbutyl, 2,2,2-trifluoroethyl, 6-amidocarbonylhexyl, 4-methyl-2-pentyl, 3-hydroxypropyl, l-methoxy-2-propyl, 2-methoxyethyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 2-dimethylaminopropyl, 2-cyanoethyl, 6-hydroxyhexyl, 2-hydroxyethyl, 2-amidinoethyl, 2-guanidinoethyl, 3-guanidinopropyl, 4-guanidinobutyl, 3-hydroxyρropyl, 4-hydroxybutyl, 6-cyanohexyl, 2-dimethylaminoethyl, 3-methylbutyl, 2-methylbutyl, (S)-2-methylbutyl, 3-aminopropyl, 2-hexyl, and 4-aminobutyl; A is selected from the group consisting of a bond, CH2, NHC(O),
    CH2CH2, CH2CH2CH2, and CH3CHCH2;
    X° is selected from the group consisting of hydrido, hydroxy, 1-aminoethyl, methyl, ethyl, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, fluoro, chloro, and bromo;
    R2 is Z°-Q;
    Z is selected from the group consisting of a bond, CH2, O, S, NH,
    N(CH3), OCH2, and SCH2; Q is selected from the group consisting of
    3-amidocarbonyl-5-aminophenyl, 3-amino-5-(N-benzylamidocarbonyl)phenyl, 3-amino-5-benzylphenyl, 3-amino-5-(2-phenylethyl)phenyl, 3-amino-5-benzylaminophenyl, 3-amino-5-(2-phenylethylamino)phenyl, 3-amino-5-benzyloxyphenyl, 3-amino-5-(2-phenylethoxy)phenyl, 3-amino-5-(N-(2-chlorobenzyl)amidocarbonyl)phenyl, 3-amino-5-(N-(3-fluorobenzyl)amidocarbonyl)phenyl, 3-amino-5-(N-(2-trifluoromethylbenzyl)amidocarbonyl)phenyl, 3-amino-5-(N-(l-phenylethyl)amidocarbonyl)phenyl, 3-amino-5-(N-(l-methyl-l-phenylethyl)amidocarbonyl)phenyl, 3-amino-5-(N-benzylamidosulfonyl)phenyl,
    3-amino-5-(N-(2-chlorobenzyl)amidosulfonyl)phenyl, 3-amino-5-(N-ethylamidocarbonyl)ρhenyl, 3-amino-5-(N-isoproρylamidocarbonyl)phenyl, 3-amino- (N-ρropylamidocarbonyl)phenyl, 3-amino-5-(N-isobutylamidocarbonyl)phenyl, 3-amino-5-(N-(2-butyl)amidocarbonyl)phenyl, 3-amino-5-(N-cyclobutylamidocarbonyl)phenyl, 3-amino-5-(N-cyclopentylamidocarbonyl)phenyl, 3-amino-S(N-cyclohexylamidocarbonyl)phenyl, amino-2-fluorophenyl , 3-amino- hydroxymethylphenyl, 5-amino-3-methoxycarbonylphenyl, 3-amidinophenyl, 3-amino-2-methylphenyl, 5-amino-2-methylthiophenyl, 3-aminophenyl, 3-amino-5-(4-trifluoromethylbenzylamino)phenyl, 3-amino- (4-trifluoromethylbenzyloxy)phenyl, 3-carboxyphenyl, 3-carboxy-5-hydroxyphenyl, 3-amino-5-carboxyphenyl, 3-chlorophenyl, 2-chlorophenyl, 3-cyanophenyl, 3,5-diaminophenyl, 3-dimethylaminophenyl, 2-fluorophenyl, 3-fluorophenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 3-methanesulfonylaminophenyl, 2-methoxyphenyl, 3-methoxyphenyl, 3-methoxyaminophenyl, 3-methoxycarbonylphenyl, 2-methylaminophenyl, 3-methylaminophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, phenyl, 3-trifluoroacetamidophenyl, 3-trifluoromethylphenyl, 2-trifluoromethylphenyl, 5-amino-2-thienyl, 5-amino-3-thienyl, 3-bromo-2-thienyl, 3-pyridyl, 4-pyridyl, 2-thienyl, and 3-thienyl; i is selected from the group consisting of:
    1-Qb.4-QS.2 .R16-3_R17-5_R18_6-R19benzene,
    „ Jo r- ^ 17 Λ 18 „ 19 . ,. 2-Q -5-Q -6-R -4-R -3-R pyridine, Jo ^ ^s „ 16 _ 18 Λ 19 . ,. 3-Q _6-Q -2-R -5-R -4-R pyridine,
    3-Q -5-QS-4-R -2-R thiophene, and 2-Q -5-QS-3-R -4-R thiophene;
    16 19 R and R are independently selected from the group consisting of hydrido, amidino, amino, aminomethyl, methoxy, rnethylamino, hydroxy, hydroxymethyl, fluoro, chloro, and cyano;
    R or R is optionally C(NR )NR R with the proviso that R ,
    19 b
    R , and Q are not simultaneously hydrido;
    17 18 R and R are independently selected from the group consisting of hydrido, fluoro, chloro, hydroxy, hydroxymethyl, amino, carboxy, and cyano; Qb is C(NR25)NR23R24 or hydrido;
    23 24 25
    R , R , and R are independently hydrido or methyl;
    QS is CH2.
    40. Compound of Claim 37 of 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
    32 point of attachment of B to A with one or more of the group consisting of R ,
    33 34 35 36
    R , R , R , and R ;
    „32 33 34 35 , 36
    R , R , R , R , and R are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkoxy, hydroxy, amino, alkoxyamino, alkylamino, alkylthio, amidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboalkoxy, carboxy, carboxamido, cyano, and Q ;
    15 7
    A is a bond or (CH(R )) a-(W )rr wherein rr is 0 or 1 , pa is an
    7 7 integer selected from 0 through 3, and W is N(R );
    7 R is hydπdo or alkyl;
    R is selected from the group consisting of hydrido, halo, alkyl, and haloalkyl;
    X is selected from the group consisting of hydrido, alkyl, halo, haloalkyl, aminoalkyl, and hydroxyalkyl;
    R2 is Z°-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 o 9 nng to Z is optionally substituted by R , the other carbon adjacent to the
    13 carbon at the point of attachment is optionally substitated by R , a carbon
    9 adjacent to R and two atoms from the carbon at the point of attachment is
    optionally substitated by R , a carbon adjacent to R and two atoms from the
    12 carbon at the point of attøchment is optionally substitated by R , and any
    10 12 11 carbon adjacent to both R and R is optionally substituted by R ;
    9 11 13
    R , R , and R are independently selected from the group consisting of hydrido, hydroxy, amino, amidino, guanidino, alkylamino, alkylthio, alkoxy, alkylsulfinyl, alkylsulfonyl, amidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboxy, carboxamido, and cyano;
    R and R are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkyl, alkoxy, alkoxyamino, hydroxy, amino, alkylarnino, alkylsulfonamido, amidosulfonyl, hydroxyalkyl, aminoalkyl, halo, haloalkyl, carboalkoxy, carboxy, carboxamido, carboxyalkyl, and cyano; r is phenyl or a heteroaryl of 5 or 6 ring members, wherein one carbon of said phenyl or said heteroaryl is substituted by Q , a carbon two or three g atoms from the point of attachment of Q to said phenyl or said heteroaryl is b s substituted by Q , a carbon adjacent to the point of attachment of Q is
    17 optionally substituted by R , another carbon adjacent to the point of
    attachment of Q is optionally substituted by R , a carbon adjacent to Q is
    optionally substitoted by R , and another carbon adjacent to Q is optionally
    19 substituted by R ; 16 17 18 19
    R , R , R , and R are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, haloalkylthio, alkoxy, hydroxy, amino, alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, and cyano;
    R or R is optionally selected from the group consisting of
    20 21 96 25 23 24 25 23 24
    NR R ,N(R )C(NR )N(R )(R ), and C(NR )NR R , with the
    16 19 h proviso that R , R , and Q are not simultaneously hydrido;
    ^b . , . . ^m20 21 ,
    Q is selected from the group consisting of NR R , hydπdo,
    N(R26)C(NR25)N(R23)(R24), and C(NR25)NR23R24;
    20 21 23 24 25 26
    R , R , R , R , R , and R are independently hydrido or alkyl;
    QS is CH2.
    41. Compound of Claim 40 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-pentynyl, 2-pentyl, 3-pentyl, 2-methylbutyl, 2-methyl-2-butenyl, 3-methylbutyl, 3-methyl-2-butenyl, 1-hexyl, 2-hexenyl, 3-hexenyl, 4-hexenyl,
    2-hexynyl, 3-hexynyl, 4-hexynyl, 2-hexyl, l-methyl-2-pentenyl, l-methyl-3-pentenyl, l-methyl-2-pentynyl, l-methyl-3-pentynyl, 3-hexyl, l-ethyl-2-butenyl, 1-heptyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 5-heptynyl, 2-heptyl, l-methyl-2-hexenyl, l-methyl-3-hexenyl, l-methyl-4-hexenyl, l-methyl-2-hexynyl, l-methyl-3-hexynyl, l-methyl-4-hexynyl, 3-heptyl, l-ethyl-2-pentenyl, l-ethyl-3-pentenyl, l-ethyl-2-pentynyl, l-ethyl-3-pentynyl, 2,2,2-trifluoroethyl, 2,2-difluoropropyl, 4-trifluoromethyl-5,5,5-trifluoropentyl, 4-trifluoromethylpentyl, 5,5,6,6,6-penxafluorohexyl, and 3,33-trifluoropropyl, wherein each member of group B is optionally substitoted at any carbon up to and including 5 atoms from the point of attachment of B to A with one or more of the group consisting of R ,
    ^32 33 34 35 J 36 . J J , ,
    R , R , R , R , and R are independently selected from the group consisting of hydrido, amidino, guanidino, methyl, ethyl, methoxy, ethoxy, hydroxy, amino, N-methylamino, dimethylamino, methoxyamino, methylthio, ethylthio, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, fluoro, chloro, bromo, amidosulfonyl, N-methylamidosulfonyl, hydroxymethyl, amidocarbonyl, carboxy, cyano, and Q ;
    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;
    X° is selected from the group consisting of hydrido, aminomethyl, methyl, ethyl, trifluoromethyl, 2,2,2-trifluoroethyl, hydroxymethyl,
    2-hydroxyethyl, chloro, and fluoro;
    2
    R 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
    9 phenyl or heteroaryl ring to the 4-pyrone ring is optionally substituted by R , the other carbon adjacent to the carbon at the point of attachment is optionally
    13 9 substituted by R , a carbon adjacent to R and two atoms from the carbon at
    the point of attachment is optionally substituted by R , a carbon adjacent to
    13 R and two atoms from the carbon at the point of attachment is optionally
    12 10 12 substituted by R , and any carbon adjacent to both R and R is optionally
    11 substituted by R ; 9 11 13
    R , R , and R are independently selected from the group consisting of hydrido, methyl, ethyl, methoxy, ethoxy, hydroxy, amino, N-methylamino, N,N-dimethylamino, methylthio, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, fluoro, chloro, bromo, amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl,
    1-hydroxyethyl, amidocarbonyl, N-methylamidocarbonyl, carboxy, and cyano;
    10 12
    R and R 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-(l-methyl-l-phenylethyl)amidocarbonyl, N-benzyl amidosulfonyl , N-(2-chlorobenzyl)amidosulf onyl , 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; x is selected from the group consisting of:
    , Jo „ ^s „ „ 16 „ 17 , „18 „ _ 19,
    1-Q -4-Q -2-R -3-R -5-R -6-R benzene,
    2-Q -5-QS-6-R -4-R -3-R pyridine, 2-Q -5-QS-3-R -4-R thiophene,
    3_Qb.6-QS-2-R16-5-R18-4-R19pyridine, 3-Qb-5-QS-4-R16-2-R19thiophene,
    3_Q b _5_Q s -4-R 16 _2_R 19 furail) 2_Q b _5_Q s -3-R 1x6.4_ 17 fU]ran5
    3-Qb-5-QS-4-R16-2-R19pyrrole, 2-Qb-5-QS-3-R16-4-R17pyπole, b s 19 b s 17
    4-Q -2-Q -5-R thiazole, and 2-Q -5-Q -4-R thiazole; 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; b 20 21
    Q is selected from the group consisting of NR R ,
    C(NR25)NR23R24, and N(R26)C(NR25)N(R23)(R24);
    20 21 23 24 25 26
    R , R , R , R , R , and R are independently selected from the group consisting of hydrido, methyl, and ethyl;
    Qs is CH2.
    42. Compound of Claim 41 or a pharmaceutically acceptable salt thereof, wherein; B is selected from the group consisting of hydrido, ethyl, 2-propenyl,
    2-propynyl, propyl, isopropyl, butyl, 2-butyl, (R)-2-butyl, (S)-2-butyl, tert-butyl, isobutyl, 1-pentyl, 3-pentyl, 2-methylbutyl, 2,2,2-trifluoroethyl, 6-amidocarbonylhexyl, 4-methyl-2-pentyl, 3-hydroxypropyl, l-methoxy-2-propyl, 2-methoxyethyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 2-dimethylaminopropyl, 2-cyanoethyl, 6-hydroxyhexyl, 2-hydroxyethyl, 2-amidinoethyl, 2-guanidinoethyl, 3-guanidinopropyl, 4-guanidinobutyl, 3-hydroxypropyl, 4-hydroxybutyl, 6-cyanohexyl, 2-dimethylaminoethyl, 3-methylbutyl, 2-methylbutyl, (S)-2-methylbutyl, 3-aminopropyl, 2-hexyl, and 4-aminobutyl; A is selected from the group consisting of a bond, CH2, CH3CH, and
    CH2CH2;
    X° is selected from the group consisting of hydrido, methyl, ethyl, trifluoromethyl, 2,2,2-trifluoroethyl, hydroxymethyl, 2-hydroxyethyl, chloro, and fluoro; R is selected from the group consisting of -amidocarbonyl-5-aminophenyl, 3-amidocarbonyl-5-aminophenyl, -amino-5-(N-benzylamidocarbonyl)phenyl, -amino-5-(N-(2-chlorobenzyl)amidocarbonyl)phenyl, -amino-5-(N-(3-fluorobenzyl)amidocarbonyl)ρhenyl, -amino-5-(N-(2-trifluoromethylbenzyl)amidocarbonyl)phenyl, -amino- (N-(l-phenylethyl)amidocarbonyl)phenyl, -amino-5-(N-( 1 -methyl- 1 -phenylethyl)amidocarbonyl)phenyl , -amino-5-(N-benzylamidosulfonyl)phenyl, -amino-5-(N-(2-chlorobenzyl)amidosulfonyl)phenyl, -amino-5-(N-ethylamidocarbonyl)phenyl, -amino-5-(N-isopropylamidocarbonyl)phenyl, -amino-5-(N-propylamidocarbonyl)phenyl, -amino- (N-isobutylamidocarbonyl)phenyl, -amino-5-(N-(2-butyl)amidocarbonyl)phenyl, -amino-5-(N-cyclobutylamidocarbonyl)phenyl, -amino-5-(N-cyclopentylainidocarbonyl)phenyl, -amino-5-(N-cyclohexylamidocarbonyl)phenyl, Samino-2-fluorophenyl, -amino-5-hydroxymethylphenyl, 5-amino-3-methoxycarbonylphenyl, -amidinophenyl, 3-amino-2-methylphenyl, 5-amino-2-methylthiophenyl, -aminophenyl, 3-carboxyphenyl, 3-carboxy- aminophenyl, -carboxy-5-hydroxyphenyl, 3-carboxymethyl-5-aminophenyl, -carboxymethyl-5-hydroxyphenyl, 3-carboxymethylphenyl, 3-chlorophenyl, -chlorophenyl, 3-cyanophenyl, 3,5-diaminophenyl, 3-dimethylaminophenyl, -fluorophenyl, 3-fluorophenyl, 2,5-difluorophenyl, 2-hydroxyphenyl, -hydroxyphenyl, 3-methanesulfonylaminophenyl, 2-methoxyphenyl, -methoxyphenyl, 3-methoxyaminophenyl, 3-methoxycarbonylphenyl, -methylaminophenyl, 3-methylaminophenyl, 2-methylphenyl, 3-methylphenyl, -methylphenyl, phenyl, 3-trifluoroacetamidophenyl, 3-trifluoromethylphenyl, -trifluoromethylphenyl, 5-amino-2-thienyl, 5-amino-3-thienyl, -bromo-2-thienyl, 3-pyridyl, 4-pyridyl, 2-thienyl, and 3-thienyl; ^ is selected from the group consisting of:
    , Jo Λ ^ n „16 „ „17 e π18 „ 19,
    1-Q -4-Q -2-R -3-R -5-R -6-R benzene,
    -Qb-5-QS-6-R17-4-R18-3-R19pyridine, 3-Qb-6-QS-2-R16-5-R18-4-R19pyridine,
    3-Qb-5-QS-4-R16-2-R19thiophene, and 2-Qb-5-QS-3-R16-4-R17thiophene;
    R and R are independently selected from the group consisting of hydrido, amidino, amino, aminomethyl, methoxy, methylamino, hydroxy, hydroxymethyl, fluoro, chloro, and cyano;
    17 18
    R and R are independently selected from the group consisting of hydrido, fluoro, chloro, hydroxy, hydroxymethyl, amino, carboxy, and cyano;
    Q is C(NR )NR R ;
    23 24 25
    R , R , and R are independently hydrido or methyl;
    QS is CH2.
    43. Compound of Claim 42 or a pharmaceutically acceptable salt thereof, wherein;
    B is selected from the group consisting of hydrido, ethyl, 2-propenyl, 2-propynyl, propyl, isopropyl, butyl, 2-butyl, (R)-2-butyl, (S)-2-butyl, tert-butyl, isobutyl, 1-pentyl, 3-pentyl, 2-methylbutyl, 2,2,2-trifluoroethyl, 6-amidocarbonylhexyl, 4-methyl-2-pentyl, 3-hydroxypropyl, l-methoxy-2-propyl, 2-methoxyethyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 2-dimethylaminopropyl, 2-cyanoethyl, 6-hydroxyhexyl, 2-hydroxyethyl, 2-amidinoethyl, 2-guanidinoethyl, 3-guanidinopropyl, 4-guanidinobutyl, 3-hydroxypropyl, 4-hydroxybutyl, 6-cyanohexyl, 2-dimethylaminoethyl, 3-methylbutyl, 2-methylbutyl, (S)-2-methylbuxyl, 3-aminopropyl, 2-hexyl, and 4-aminobutyl;
    A is selected from the group consisting of a bond, CH2, CH3CH, and
    CH2CH ;
    X° is selected from the group consisting of hydrido, methyl, ethyl, trifluoromethyl, 2,2,2-trifluoroethyl, chloro, and fluoro; ,
    R is selected from the group consisting of -amidocarbonyl-5-aminophenyl, 3-amino-5-(N-benzylamidocarbonyl)phenyl, -amino-5-(N-(2-chlorobenzyl)amidocarbonyl)phenyl, -amino-5-(N-(3-fluorobenzyl)amidocarbonyl)ρhenyl, -arnino-5-(N-(2-trifluoromethylbenzyl)amidocarbonyl)phenyl, 3-amino-5-(N-(l-phenylethyl)amidocarbonyl)phenyl,
    3-amino-5-(N-( 1 -methyl- 1 -phenylethyl)amidocarbonyl)phenyl ,
    3-amino-5-(N-benzylamidosulfonyl)phenyl,
    3-amino-5-(N-(2-chlorobenzyl)amidosulfonyl)ρhenyl,
    3-amino-5-(N-ethylamidocarbonyl)phenyl, 3-amino-5-(N-isopropylamidocarbonyl)phenyl,
    3-amino-5-(N-propylamidocarbonyl)phenyl,
    3-amino-5-(N-isobutylamidocarbonyl)phenyl,
    3-amino-5-(N-(2-butyl)amidocarbonyl)phenyl,
    3-amino-5-(N-cyclobutylamidocarbonyl)phenyl, 3-amino- (N-cyclopentylamidocarbonyl)phenyl,
    3-amino-5-(N-cyclohexylamidocarbonyl)phenyl, 3-aminophenyl,
    3-carboxy-5-aminophenyl, 3-chlorophenyl, 3,5-diaminophenyl,
    3-dimethylaminophenyl, 3-hydroxyphenyl, 3-methanesulfonylaminophenyl,
    3-methylaminophenyl, 2-methylphenyl, 3-methylphenyl, phenyl, 3-trifluoroacetamidophenyl, 3-bromo-2-thienyl, 2-thienyl, and 3-thienyl; x is selected from the group consisting of 5-amidino-2-thienylmethyl,
    4-amidinobenzyl, 2-fluoro-4-amidinobenzyl, and 3-fluoro-4-amidinobenzyl.
    44. Compound of Claim 37 where said compound is selected from the group of the Formula:
    or a pharmaceutically acceptable salt thereof , wherein B,A, R ,X°, andY are selected to form a compound selected from the group consisting of; 7 0
    R is 3-aminophenyl, B is 2,2,2-trifluoroethyl, A is a bond, Y is 4- amidinobenzyl, and X° is methyl;
    R 7 is 3-aminophenyl, B is (S)-2-butyl, A is a bond, Y 0 is 4-amidinobenzyl, and X° is methyl;
    7 0 R is 5-amino-2-fluorophenyl, B is isopropyl, A is a bond, Y is 4- amidinobenzyl, and X° is is methyl;
    7 o
    R is 2-methyl-3-aminophenyl, B is isopropyl, A is a bond, Y is 4- amidinobenzyl, and X° is methyl;
    7 0
    R is 3-aminophenyl, B is ethyl, A is a bond, Y is 4-amidinobenzyl, and X° is methyl;
    R 7 is 3-aminophenyl, B is ethyl, A is a bond, Y 0 is 4-amidino-2- fluorobenzyl, and X° is methyl;
    7 0
    R is 3-aminophenyl, B is 2-propenyl, A is a bond, Y is 4-amidinobenzyl, and X° is methyl;
    7 0 R is 3-aminophenyl, B is isopropyl, A is a bond, Y is 4-amidino-2- fluorobenzyl, and X° is methyl;
    7 0
    R is 3-aminophenyl, B is isopropyl, A is a bond, Y is 4-amidinobenzyl, and X° is methyl;
    2 0
    R is 3-aminophenyl, B is 2-butyl, A is a bond, Y is 4-amidinobenzyl, and X° is methyl;
    7 0
    R is 3-aminophenyl, B is (R)-2-butyl, A is a bond, Y is 4-amidinobenzyl, and X° is methyl;
    7 0
    R is 3-aminophenyl, B is 2-propynyl, A is a bond, Y is 4-amidinobenzyl, and X° is methyl;
    7 0 R is 3-aminophenyl, B is 3-pentyl, A is a bond, Y is 4-amidinobenzyl, and
    X° is hydrido; R is 3-aminophenyl, B is hydrido, A is CH , x is 4-amidinobenzyl, and
    X° is methyl;
    R is 3-aminophenyl, B is ethyl, A is CH2, Y is 4-amidinobenzyl, and X is methyl;
    7 R is 3-aminophenyl, B is 2-methypropyl, A is a bond, Y is 4- amidinobenzyl, and X° is methyl;
    7 0
    R is 3-aminophenyl, B is 2-ρropyl, A is CH3CH, Y is 4-amidinobenzyl, and X° is methyl;
    7 0
    R is 3-aminophenyl, B is propyl, A is a bond, Y is 4-amιdino-2- fluorobenzyl, and X° is methyl;
    7 0
    R is 3-aminophenyl, B is 6-amidocarbonylhexyl, A is a bond, Y is 4- amidinobenzyl, and X° is methyl;
    7 0
    R is 3-aminophenyl, B is tert-butyl, A is a bond, Y is 4-amidinobenzyl, and X° is hydrido; o o R is 3-aminophenyl, B is tert-butyl, A is a bond, Y is 4-amidinobenzyl, and X° is methyl;
    R 7 is 3-aminophenyl, B is 3-hydroxypropyl, A is a bond, Y 0 is 4- amidinobenzyl, and X° is methyl;
    R 7 is 3-aminophenyl, B is 2-methylρropyl, A is a bond, Y 0 is 4-amidino-2- fluorobenzyl, and X° is methyl;
    2 0
    R is 3-aminophenyl, B is butyl, A is a bond, Y is 4-amidinobenzyl, and
    X° is methyl;
    7 0
    R is 3-aminophenyl, B is l-methoxy-2-proρyl, A is a bond, Y is 4- amidinobenzyl, and X° is methyl;
    2 0 R is 3-aminophenyl, B is 2-methoxyethyl, A is a bond, Y is 4- amidinobenzyl, and X° is methyl; 7 0
    R is 3-aminophenyl, B is 2-propyl, A is a bond, Y is 5-amidino-2- thienylmethyl, and X° is methyl;
    7 0
    R is 5-amino-2-methylthiophenyl, B is 2-ρropyl, A is a bond, Y is 4- amidinobenzyl, and X° is methyl;
    7 0 R" is 3-amino-5-carboxyphenyl, B is isopropyl, A is a bond, Y is 4- amidinobenzyl, and X° is methyl;
    R 7 is 3-amino-5-carbomethoxyphenyl, B is isopropyl, A is a bond, Y 0 is 4- amidinobenzyl, and X° is methyl;
    7 0
    R is 3-aminophenyl, B is isopropyl, A is a bond, Y is 4-amidinobenzyl, and X° is ethyl;
    7 0
    R is 3-amino-5-carboxamidophenyl, B is isopropyl, A is a bond, Y is 4- amidinobenzyl, and X° is methyl;
    R is 3-amino-5-(N-benzyl-N-methylamidocarbonyl)phenyl, B is isopropyl, A is a bond, Y is 4-amidinobenzyl, and X° is methyl; R is 3-amino-5-(N-(l-phenylethyl)amidocarbonyl)phenyl, B is isopropyl,
    A is a bond, Y is 4-amidinobenzyl, and X° is methyl;
    R is 3-amino-5-(N-(2-phenyl-2-propyl)amidocarbonyl)phenyl, B is isopropyl, A is a bond, Y is 4-amidinobenzyl, and X° is methyl;
    2 R is 3-amino-5-(N-(2,4-dichlorobenzyl)amidocarbonyI)phenyl, B is isopropyl, A is a bond, Y is 4-amidinobenzyl, and X° is methyl;
    R is 3-amino-5-(N-(4-bromobenzyl)amidocarbonyl)phenyl, B is isopropyl, A is a bond, Y is 4-amidinobenzyl, and X° is methyl;
    2
    R is 3-amino-5-(N-benzylamidocarbonyl)phenyl, B is isopropyl, A is a bond, Y is 4-amidinobenzyl, and X° is methyl;
    2 R is 3-amino-5-(N-(2-chlorobenzyl)amidocarbonyl)ρhenyl, B is isopropyl,
    A is a bond, Y is 4-amidinobenzyl, and X° is methyl; R is 3-amino-5-(N-(2-trifluoromethylbenzyl)amidocarbonyl)phenyl, B is isopropyl, A is a bond, Y is 4-amidinobenzyl, and X° is methyl;
    R is 3-arnino-5-(N-(3-fluorobenzyl)amidocarbonyl)phenyl, B is isopropyl, A is a bond, Y is 4-amidinobenzyl, and X° is methyl;
    R is 3-amino-5-(N-(3-trifluoromethylbenzyl)amidocarbonyl)phenyl, B is isopropyl, A is a bond, Y is 4-amidinobenzyl, and X° is methyl;
    R is 3-amino-5-(N-isobutylamidocarbonyl)phenyl, B is isopropyl, A is a bond, Y is 4-amidinobenzyl, and X° is methyl;
    2
    R is 3-amino-5-(N-cyclobutylamidocarbonyl)phenyl, B is isopropyl, A is a bond,Y is 4-amidinobenzyl, and X° is methyl;
    2
    R is 3-amino-5-(N-cyclopentylamidocarbonyl)phenyl, B is isopropyl, A is a bond, Y is 4-amidinobenzyl, and X° is methyl;
    R is 3-amino-5-(N-cycloheptylamidocarbonyl)phenyl, B is isopropyl, A is a bond, Y is 4-amidinobenzyl, and X° is methyl; R is 3-amino-5-(N-(2-pyridylmethyl)amidocarbonyl)phenyl, B is isopropyl, A is a bond, Y is 4-amidinobenzyl, and X° is methyl;
    R is 3-amino-5-(N-(3-pyridylmethyl)amidocarbonyl)phenyl, B is isopropyl, A is a bond, Y is 4-amidinobenzyl, and X° is methyl;
    R is 3-amino-5-(N-(2-(4-methoxyphenyl)ethyl)amidocarbonyl)phenyl, B is isopropyl, A is a bond, Y is 4-amidinobenzyl, and X° is methyl;
    2
    R is 3-amino-5-(N-(3-phenylpropyl)amidocarbonyl)phenyl, B is isopropyl, A is a bond, Y is 4-amidinobenzyl, and X° is methyl;
    R is 3-amino-5-(N-(2,2-diphenylethyl)arnidocarbonyl)phenyl, B is isopropyl, A is a bond, Y is 4-amidinobenzyl, and X° is methyl;
    2 R is 3-amino-5-(N-(2-naphthylmethyl)amidocarbonyl)phenyl, B is isopropyl, A is a bond, Y is 4-amidinobenzyl, and X° is methyl; R2 is 3-amino- (N-(l,2,3,4-tetrahydronaphth-2- ylmethyl)amidocarbonyl)phenyl, B is isopropyl, A is a bond, Y is 4-amidinobenzyl, and X° is methyl;
    7 0
    R is 3-aminophenyl, B is 2-propyl, A is a bond, Y is 4-amidino-3- fluorobenzyl, and X° is hydrido;
    7 0
    R is 3-carboxyphenyl, B is 2-propyl, A is a bond, Y is 4-amidinobenzyl, and X° is hydrido;
    R 7 is 3-aminophenyl, B is 2-propyl, A is a bond, Y 0 is 4-amidino-3- fluorobenzyl, and X° is methyl;
    7 0 R is 3 ,5-diaminophenyl, B is 2,2,2-trifluoroethyl, A is a bond, Y is 4- amidinobenzyl, and X° is methyl;
    7 0
    R is 3,5-diaminophenyl, B is (S)-2-butyl, A is a bond, Y is 4- amidinobenzyl, and X° is methyl;
    R 2 is 3,5-diaminophenyl, B is isopropyl, A i •s a bond, Y 0 is 4- amidinobenzyl, and X° is methyl ;
    7 0
    R is 3,5-diaminophenyl, B is isopropyl, A is a bond, Y is 4-amidιno-2- fluorobenzylbenzyl, and X° is methyl;
    2 0
    R is 3,5-diaminophenyl, B is ethyl, A is a bond, Y is 4-amidinobenzyl, and
    X° is methyl;
    7 0 R is 3,5-diaminophenyl, B is ethyl, A is a bond, Y is 4-amidmo-2- fluorobenzyl, and X° is methyl;
    7 o
    R is 3-amino-5-carboxyphenyl, B is 2,2,2-trifluoroethyl, A is a bond, Y is
    4-amidinobenzyl, and X° is methyl;
    7 0
    R is 3-amino-5-carboxyphenyl, B is (S)-2-butyl, A is a bond, Y is 4- amidinobenzyl, and X° is methyl; R 7 is 3-amino-5-carboxyphenyl, B is isopropyl, A is a bond, Y 0 is 4- amidino-2-fluorobenzylbenzyl, and X° is methyl;
    7 0
    R is 3-amino-5-carboxyphenyl, B is ethyl, A is a bond, Y is 4- amidinobenzyl, and X° is methyl;
    7 0 Rr is 3-amino-5-carboxyphenyl, B is ethyl, A is a bond, Y is 4-amidino-2- fluorobenzyl, and X° is methyl;
    2
    R is 3-amino-5-(N-benzylamidocarbonyl)phenyl, B is 2,2,2-trifluoroethyl,
    A is a bond, Y is 4-amidinobenzyl, and X° is methyl;
    2
    R is 3-amino-5-(N-benzylamidocarbonyl)phenyl, B is (S)-2-butyl, A is a bond, Y is 4-amidinobenzyl , and X° is methyl ;
    R is 3-amino-5-(N-benzylamidocarbonyl)phenyl, B is isopropyl, A is a bond, Y is 4-amidino-2-fluorobenzylbenzyl, and X° is methyl;
    R is 3-amino-5-(N-benzylamidocarbonyl)phenyl, B is ethyl, A is a bond, is 4-amidinobenzyl, and X° is methyl;
    R is 3-amino-5-(N-benzylamidocarbonyl)phenyl, B is ethyl, A is a bond, x is 4-amidino-2-fluorobenzyl, and X° is methyl; and
    7 0
    R is 3, diarninophenyl, B is isopropyl, A is a bond, Y is 4- amidinobenzylbenzyl, and R is hydrido.
    45. Compound of Claim 22 of the Formula:
    or a pharmaceutically acceptable salt thereof, wherein; B is a C3-C7 cycloalkyl or a C4-C6 saturated heterocyclyl, wherein
    33 each ring carbon is optionally substituted with R , a ring carbon other than the ring carbon at the point of attachment of B to A is optionally substitoted 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
    9 13 of attachment are optionally substitoted with R or R , a ring carbon or
    9 nitrogen adjacent to the R position and two atoms from the point of attachment
    10 13 is optionally substitoted with R , a ring carbon or nitrogen adjacent to the R position and two atoms from the point of attøchment is optionally substituted
    12 with R , a ring carbon or nitrogen three atoms from the point of attachment
    and adjacent to the R10 position is optional s bbed with R1 \ a ring carbon or nitrogen three atoms from the point of attøchment and adjacent to the
    12 33
    R position is optionally substituted with R , and a ring carbon or nitrogen
    11 33 four atoms from the point of attachment and adjacent to the R and R
    34 positions is optionally substituted with R ;
    9 11 13
    R , R , and R 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;
    10 12
    R and R 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, alfylamino, 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;
    33 34 R and R 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;
    33 b R is optionally Q ;
    15 7
    A is a bond or (CH(R )) a-(W )rr wherein rr is 0 or 1, pa is an
    7 7 7 integer selected from 0 through 3, and W is (R )NC(O) or N(R );
    7 R is selected from the group consisting of hydrido, hydroxy and alkyl;
    R is selected from the group consisting of hydrido, halo, alkyl, and haloalkyl;
    X is selected from the group consisting of hydrido, amino, alkyl, halo, haloalkyl, haloalkoxy, aminoalkyl, hydroxy, alkoxy, hydroxyalkyl, and alkylthio;
    R2 is Z°-Q; Z is selected from the group consisting of a bond, CH2, CH2CH2,
    W -(CH(R ))p wherein p is 0 or 1 and W is selected from the group
    41 consisting of O, S, and N(R );
    41 42
    R and R 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 o . . 9 ring to Z is optionally substituted by R , the other carbon adjacent to the
    13 carbon at the point of attachment is optionally substituted by R , a carbon 9 adjacent to R and two atoms from the carbon at the point of attachment is
    10 13 optionally substitoted by R , a carbon adjacent to R and two atoms from the
    12 carbon at the point of attachment is optionally substituted by R , and any
    10 12 11 carbon adjacent to both R and R is optionally substituted by R ; x is phenyl or a heteroaryl of 5 or 6 ring members, wherein one carbon of said phenyl or said heteroaryl is substituted by Q , a carbon two or three s atoms from the point of attachment of Q to said phenyl or said heteroaryl is b s substitated by Q , a carbon adjacent to the point of attachment of Q is
    17 optionally substituted by R , another carbon adjacent to the point of
    attøchment of Q is optionally substituted by R , a carbon adjacent to Q is
    optionally substituted by R , and another carbon adjacent to Q is optionally
    substitated by R ;
    _^16 _ 17 _18 , τ-,1 . , , , , , _ ,
    R , R , R , and R 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; π 16 „19 . . „ lkm20τ_21 , m25 23 ™24
    R or R is optionally NR R or and QNR )NR R , with the
    proviso that R , R , and Q are not simultaneously hydrido; b 20 21 Q is selected from the group consisting of NR R , hydrido, and
    25 23 24 20 21
    C(NR )NR R , with the proviso that no more than one of R and R is
    23 hydroxy at the same time and with the further proviso that no more than one of R
    24 and R is hydroxy at the same time; π20 21 π23 24 , 25 . , Δ , ,
    R , R ,R , R , and R are independentiy selected from the group consisting of hydrido, alkyl, and hydroxy; g
    Q is selected from the group consisting of a bond, CH2, and
    CH2CH2-
    46. Compound of Claim 45 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-ρiperidinyl, 4-piρeridinyl, 1 -pyrrolidinyl, 2-pyπolidinyl, 3-ρyπolidinyl, 2-dioxanyl, 4H-2-ρyranyl, 4H-3-pyranyl, 4H-4-pyranyl, 4H-ρyran-4-one-2-yl, 4H-pyran-4-one-3-yI, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydropyranyl, 3-tetrahydropyranyl, 4-tetrahydropyranyl, 2-tetrahydrothienyl, and 3-tetrahydrothienyl, wherein each ring carbon is
    33 optionally substituted with R , ring carbons and a nitrogen adjacent to the
    9 carbon atom at the point of attøchment are optionally substitated with R or
    13 9 R , a ring carbon or nitrogen adjacent to the R position and two atoms from
    10 the point of attachment is optionally substituted with R , and a ring carbon or
    13 nitrogen adjacent to the R position and two atoms from the point of
    12 attachment is optionally substitated with R ;
    9 11 13
    R , R , and R are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, N-methylamino, N,N-dimethylamino, N-ethylamino, methylthio, ethylthio, isopropylthio, 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-hydroxyethyl, 2,2,2-trifluoro-l-hydroxyethyl, amidocarbonyl, N-methylamidocarbonyl, N,N-dimethylamidocarbonyl, and cyano;
    10 12
    R and R are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, carboxymethyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, methoxyamino, ethoxyamino, acetamido, trifluoroacetømido, 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-l-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-(l-methyl-l-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-chlorophenyla ino, 4-chloroρhenylsulfonyl, 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, 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-phenylexhylamino, phenylsulfonyl, 3-trifluoromethoxybenzyloxy, 4-trifluoromethoxybenzyloxy, 3-trifluoromethoxyphenoxy, 4-trifluoromethoxyphenoxy, 3-trifluoromethylbenzyloxy, 4-trifluoromethylbenzyloxy, 2,4-bis-trifluoromethylbenzyloxy, 3-trifluoromethylbenzyl, 3 ,5-bis-trifluoromethyIbenzyloxy , 4-trifluoromethylphenoxy , 3-trifluoromethylphenoxy, 3-trifluoromethylthiobenzyloxy, 4-trifluoromethylthiobenzyloxy, 23 ,4-trifluorophenoxy, 2,3 ,5-trifluorophenoxy, 3-pentafluoroethylphenoxy, 3-(l,l,2,2-tetrafluoroethoxy)phenoxy, and 3-trifluoromethylthiophenoxy;
    33 R is selected from the group consisting of hydrido, amidino, guanidino, carboxy, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, methoxyamino, ethoxyamino, acetamido, trifluoroacetamido, N-methylamino, dimethylamino, N-ethylamino, methylthio, ethylthio, isopropylthio, 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-l-hydroxyethyl, methoxycarbonyl, ethoxycarbonyl, 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;
    X° 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,l,l,2,2-tetrafluoroethoxy, fluoro, chloro, and bromo;
    R2 is Z°-Q; Z is selected from the group consisting of a bond, CH2, CH2CH2, 0,
    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-thienyI, 2-furyl, 3-furyl, 2-pyπolyl, 3-pyrrolyl, 2-imidazolyl, 4-imidazolyl, 3-pyrazolyl, 4-pyrazolyl, 2-thiazolyl, 3-isoxazolyl, 5-isoxazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl,
    3-pyridazinyl, 4-pyridazinyl, and l,3,5-triazin-2-yl, wherein a carbon adjacent to the carbon at the point of attachment of said phenyl or heteroaryl ring to Z is
    9 optionally substitated by R , the other carbon adjacent to the carbon at the point
    13 9 of attachment is optionally substituted by R , a carbon adjacent to R and two atoms from the carbon at the point of attachment is optionally substitated by
    10 13
    R , a carbon adjacent to R and two atoms from the carbon at the point of
    12 attachment is optionally substituted by R , and any carbon adjacent to both
    „10 1 T 2 . . „ , . , , πll R and R is optionally substituted by R ; ϊ is selected from the group consisting of:
    , A ^ s o ^16 „ „ 17 _ . 18 ^ 19, 1-Q -4-Q -2-R -3-R -5-R -6-R benzene,
    2-Qb-5-QS-6-R17-4-R18-3-R19pyridine, -Qb-6-QS-2-R16-5-R18-4-R19pyridine, 2-Qb-5-QS-3-R16-6-R18pyrazine,
    3-Qb-6-QS-2-R18-5-R18-4-R19pyridazine,
    2-Q -5-QS-4-R -6-R pyrimidine, 5-Q -2-QS-4-R -6-R pyrimidine,
    3-Qb-5-QS-4-R16-2-R19thiophene, 2-Qb-5-QS-3-R16-4-R17thiophene,
    3-Qb-5-QS-4-R16-2-R19furan, 2-Qb-5-QS-3-R16-4-R17furan,
    3-Qb-5-QS-4-R16-2-R19pyrrole, 2-Qb-5-QS-3-R16-4-R17pyrrole, b s 19 b s 17
    4-Q -2-Q -5-R imidazole, 2-Q -4-Q -5-R imidazole,
    3-Q -5-QS-4-R isoxazole, 5-Q -3-QS-4-R isoxazole, b s 16 b s 19
    2-Q -5-Q -4-R pyrazole, 4-Q -2-Q -5-R thiazole, and o 1 "7 2-Q -5-Q -4-R thiazole;
    R are independently selected from the group consisting of hydrido, methyl, ethyl, isopropyl, propyl, carboxy, amidino, guanidino, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, aminomethyl, 1-aminoethyl, 2-aminoethyl, N-methylamino, dimethylamino, N-ethylamino, methylthio, ethylthio, isopropylthio, trifluoromethylthio, methylsulfinyl, ethylsulfinyl, methylsulfonyl, ethylsulfonyl, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, 2,2333-pentafluoropropyl, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro, bromo, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, and cyano; τ,16 „19 . . „ m25s 23 24 . , . , „16 R or R is optionally C(NR )NR R with the proviso that R ,
    19 b
    R , and Q are not simultaneously hydrido; b 25 23 24
    Q is C(NR )NR R or hydrido, with the proviso that no more than
    23 24 one of R and R is hydroxy at the same time;
    23 24 25
    R , R , and R are independently selected from the group consisting of hydrido, methyl, ethyl, and hydroxy; Q is selected from the group consisting of a bond, CH2 and CH2CH2.
    47. Compound of Claim 46 or a pharmaceutically acceptable salt thereof, wherein; B is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, oxalan-2-yl, 2-(2R)-bicyclo[2.2.1]-heptyl, 1-pyπolidinyl, 1-piperidinyl, oxetan-3-yl, azetidin-1-yl, azetidin-2-yl, azetidin-3-yl, 7-oxabicyclo[2.2.1]heptan-2-yl, bicyclo[3.1.0]hexan-6-yl, 2-morpholinyl, 3-morpholinyl, 4-mo holinyl, 1-piperazinyl, 2-piperazinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 1-pyrrolidinyl, 2-pyπolidinyl, 3-pyπolidinyl, 2-dioxanyl, 4H-2-pyranyl, 4H-3-pyranyl, 4H-4-ρyranyI, 4H-pyran-4-one-2-yl, 4H-pyran-4-one-3-yl, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydropyranyl, 3-tetrahydropyranyl, 4-tetrahydroρyranyl, 2-tetrahydrothienyl, and 3-tetrahydrothienyl; A is selected from the group consisting of a bond, CH2, NHC(O),
    CH2CH2, and CH2CH2CH2;
    X° is selected from the group consisting of hydrido, hydroxy, 1-aminoethyl, methyl, ethyl, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, fluoro, chloro, and bromo;
    R2 is Z°-Q;
    Z is selected from the group consisting of a bond, CH2, 0, S, NH,
    N(CH3), OCH2, and SCH2;
    Q is selected from the group consisting of 3-amidocarbonyl-5-aminophenyl, 3-arnino-5-(N-benzylamidocarbonyl)phenyl,
    3-amino-5-benzylphenyl, 3-amino- (2-phenylethyl)phenyl, 3-amino-5-benzylaminophenyl, 3-amino-5-(2-phenylethylamino)phenyl, 3-amino-5-benzyloxyphenyl, 3-amino-5-(2-phenylethoxy)phenyl , 3-amino-5-(N-(2-chlorobenzyl)amidocarbonyl)phenyl, 3-amino-5-(N-(3-fluorobenzyl)amidocarbonyl)phenyl,
    3-amino-5-(N-(2-trifluoromerhylbenzyl)amidocarbonyl)phenyl, 3-amino-5-(N-(l-phenylethyl)amidocarbonyl)phenyl, -amino-5-(N-(l-methyl-l-phenylethyl)amidocarbonyl)phenyl, -amino-5-(N-benzylamidosulfonyl)phenyl, -amino-5-(N-(2-chlorobenzyl)amidosulfonyl)phenyl, -amino-5-(N-ethylamidocarbonyl)phenyl, -amino-5-(N-isopropylamidocarbonyl)phenyl, -amino-5-(N-ρropylamidocarbonyl)phenyl, -amino- (N-isobutylamidocarbonyl)phenyl, 3-amino-5-(N-(2-butyl)amidocarbonyl)phenyl, -amino-5-(N-cyclobutylamidocarbonyl)phenyl, -amino-5-(N-cyclopentylamidocarbonyl)phenyl,
    3-amino- (N-cyclohexylamidocarbonyl)phenyl, 5-amino-2-fluorophenyl, -amino-5-hydroxymethylphenyl, 5-amino-3-methoxycarbonylphenyl, 3-amidinophenyl, 3-amino-2-methylphenyl, 5-amino-2-methylthiophenyl, 3-aminophenyl, 3-amino-5-(4-trifluoromethylbenzylamino)phenyl, 3-amino-5-(4-trifluoromethylbenzyloxy)phenyl, 3-carboxyphenyl,
    3-carboxy-5-hydroxyphenyl, 3-amino-5-carboxyphenyl, 3-chlorophenyl, 2-chlorophenyl, 3-cyanophenyl, 3,5-diaminophenyl, 3-dimethylaminophenyl, 2-fluorophenyl, 3-fluoroρhenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 3-methanesulfonylaminophenyl, 2-methoxyphenyl, 3-methoxyphenyl, 3-methoxyaminophenyl, 3-methoxycarbonylphenyl, 2-methylaminophenyl, 3-methylaminophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, phenyl, 3-trifluoroacetarnidophenyl, 3-trifluoromethylphenyl, 2-trifluoromethylphenyl, 5-amino-2-thienyl, 5-amino-3-thienyl, 3-bromo-2-thienyl, 3-pyridyl, 4-pyridyl, 2-thienyl, and3-thienyl; is selected from the group consisting of: l_Qb_4-QS-2-R16-3-R17-5-R18-6-R19benzene,
    2-Qb-5-QS-6-R1?-4-R18-3-R19pyridine,
    3-Qb-6-QS-2-R16-5-R18-4-R19pyridine,
    3-Qb-5-QS-4-R16-2-R19thiophene, and 2-Qb-5-QS-3-R16-4-R17thiophene;
    R and R are independently selected from the group consisting of hydrido, amidino, amino, aminomethyl, methoxy, methylamino, hydroxy, hydroxymethyl, fluoro, chloro, and cyano; ^16 „ 19 . . „ ^Λm 5 l m23„24 . , , . , 16
    R or R is optionally C(NR )NR R with the proviso that R ,
    R , and Q are not simultaneously hydrido;
    17 18
    R and R are independently selected from the group consisting of hydrido, fluoro, chloro, hydroxy, hydroxymethyl, amino, carboxy, and cyano; h 25 23 24
    Q is C(NR )NR R or hydrido;
    23 24 25
    R , R , and R are independently hydrido or methyl;
    QS is CH2.
    48. Compound of Claim 45 of the Formula:
    or a pharmaceutically acceptable salt thereof, wherein;
    B is a C3-C7 cycloalkyl or a C4-C6 saturated heterocyclyl, wherein
    33 each ring carbon is optionally substituted with R , a ring carbon other than the ring carbon at the point of attachment of B to A is optionally substitated 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
    9 13 of attachment are optionally substituted with R or R , a ring carbon or
    9 nitrogen adjacent to the R position and two atoms from the point of attøchment
    10 13 is optionally substitated with R , a ring carbon or nitrogen adjacent to the R position and two atoms from the point of attachment is optionally substituted
    12 with R , a ring carbon or nitrogen three atoms from the point of attachment
    10 11 and adjacent to the R position is optionally substitated with R , a ring carbon or nitrogen three atoms from the point of attachment and adjacent to the
    12 33
    R position is optionally substitated with R , and a ring carbon or nitrogen
    11 33 four atoms from the point of attøchment and adjacent to the R and R
    34 positions is optionally substituted with R ;
    9 11 13 R , R , and R 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;
    R and R 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;
    33 34
    R and R 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;
    33 b
    R is optionally Q ;
    15 7
    A is a bond or (CH(R )) a-(W )rr wherein π is 0 or 1, pa is an
    7 7 integer selected from 0 through 3, and W is N(R );
    7 R is hydrido or alkyl;
    R is selected from the group consisting of hydrido, halo, alkyl, and haloalkyl;
    X is selected from the group consisting of hydrido, alkyl, halo, haloalkyl, aminoalkyl, and hydroxyalkyl; R2 is Z°-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 o 9 ring to Z is optionally substituted by R , the other carbon adjacent to the
    13 carbon at the point of attachment is optionally substitated by R , a carbon
    9 adjacent to R and two atoms from the carbon at the point of attachment is
    10 13 optionally substituted by R , a carbon adjacent to R and two atoms from the
    12 carbon at the point of attachment is optionally substituted by R , and any
    10 12 11 carbon adjacent to both R and R is optionally substituted by R ; i is phenyl or a heteroaryl of 5 or 6 ring members, wherein one carbon g of said phenyl or said heteroaryl is substituted by Q , a carbon two or three g atoms from the point of attachment of Q to said phenyl or said heteroaryl is b s substitated by Q , a carbon adjacent to the point of attachment of Q is
    17 optionally substitated by R , another carbon adjacent to the point of
    attachment of Q is optionally substituted by R , a carbon adjacent to Q is
    optionally substituted by R , and another carbon adjacent to Q is optionally
    19 substitated by R ;
    R , R , R , and R are independentiy 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;
    T, 16 T, 19 - • „ *™20 21 ^Λm25, m23„24 . , , R or R is optionally NR R or C(NR )NR R , with the
    proviso that R , R , and Q are not simultaneously hydrido; b 20 21
    Q is selected from the group consisting of NR R , hydndo, and
    C(NR25)NR23R24;
    20 21 23 24 25
    R , R , R , R , and R are independently hydrido or alkyl;
    Qs is CH2.
    49. Compound of Claim 48 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-piρeridinyl, 3-piρeridinyl, 4-piperidinyl, 1-pyrrolidinyl, 2-pyπolidinyl, 3-pyπolidinyl, 2-dioxanyl, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydropyranyl, 3-tetrahydropyranyl, 4-tetrahydropyranyl, 2-tetrahydrothienyl, and 3-tetrahydrothienyl, wherein each
    33 ring carbon is optionally substitated with R , ring carbons and a nitrogen adjacent to the carbon atom at the point of attachment are optionally substitated
    9 13 9 with R or R , a ring carbon or nitrogen adjacent to the R position and two
    10 atoms from the point of attachment are optionally substitated with R , and a
    13 ring carbon or nitrogen atom adjacent to the R position and two atoms from
    12 the point of attachment is optionally substitated with R ;
    9 11 13
    R , R , and R are independently selected from the group consisting of hydrido, methyl, ethyl, methoxy, ethoxy, hydroxy, amino, N-methylamino, N,N-dimethylamino, methylthio, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, fluoro, chloro, bromo, amidosulfonyl,
    N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, amidocarbonyl, N-methylamidocarbonyl, carboxy, and cyano; R and R 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-(l-methyl- l-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;
    33 R 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 Q ;
    A is selected from the group consisting of a bond, NH, N(CH3), CH2,
    CH3CH, CH2CH2, and CH2CH2CH2;
    X° is selected from the group consisting of hydrido, aminomethyl, methyl, ethyl, trifluoromethyl, 2,2,2-trifluoroethyl, hydroxymethyl,
    2-hydroxyethyl, chloro, and fluoro;
    R is selected from the group consisting of phenyl, 2-thienyl, 2-furyl,
    2-ρyπolyl, 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
    9 phenyl or heteroaryl ring to the 4-pyrone ring is optionally substituted by R , the other carbon adjacent to the carbon at the point of attachment is optionally
    13 9 substitated by R , a carbon adjacent to R and two atoms from the carbon at
    10 the point of attachment is optionally substituted by R , a carbon adjacent to
    13 R and two atoms from the carbon at the point of attøchment is optionally
    12 10 12 substitated by R , and any carbon adjacent to both R and R is optionally
    substitated by R ; x is selected from the group consisting of: ι T 1 *7 1 ©
    1-Q -4-QS-2-R -3-R -5-R -6-R benzene,
    „ Jo , Λs „ „ 16 „ ,, 18 „ ^ 19 . ,. b „ Λs , „ 16 Λ „ 19 , . , 3-Q -6-Q -2-R -5-R -4-R pyridine, 3-Q -5-Q -4-R -2-R thiophene,
    „ Jo „ ^s „ „ 16 Λ ^19„ „ Λb „ ^s 16 Λ ^ 17„
    3-Q -5-Q -4-R -2-R furan, 2-Q -5-Q -3-R -4-R furan,
    ^ b _ _s Λ „16 „ 19 „ Λ Λb _ Λs „ 16 , ^17
    3-Q -5-Q -4-R -2-R pyπole, 2-Q -5-Q -3-R -4-R pyπole, b s 19 b s 17 '
    4-Q -2-Q -5-R thiazole, and 2-Q -5-Q -4-R thiazole;
    „ 16 „17 18 1 T 19 . , , , ,
    R , R , R , and R are independently selected from the group consisting of hydrido, methyl, ethyl, amidino, guanidino, methoxy, hydroxy, amino, aminomethyl, 1-aminoethyl, 2-aminoethyl, N-methylamino, dimethylamino, methylthio, ethylthio, trifluoromethylthio, methylsulfinyl, methylsulfonyl, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, trifluoromethoxy, fluoro, chloro, hydroxymethyl, carboxy, and cyano; b 20 21 25 23 24 Q is NR R or C(NR )NR R ;
    20 21 23 24 25
    R , R , R , R , andR are independently selected from the group consisting of hydrido, methyl, and ethyl; Qs is CH2.
    50. Compound of Claim 49 or a pharmaceutically acceptable salt thereof, wherein;
    B is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxalan-2-yl, 2-(2R)-bicyclo[2.2.1]-heptyl, oxetan-3-yl, azetidin-1-yl, azetidin-2-yl, azetidin-3-yl, 1-pyπolidinyl and 1-piperidinyl;
    A is selected from the group consisting of a bond, CH2, CH2CH and
    CH2CH2CH2;
    X° is selected from the group consisting of hydrido, methyl, ethyl, trifluoromethyl, 2,2,2-trifluoroethyl, hydroxymethyl, 2-hydroxyethyl, chloro, and fluoro;
    2
    R is selected from the group consisting of
    3-amidocarbonyl-5-aminophenyl, 3-amidocarbonyl-5-aminophenyl,
    3-amino-5-(N-benzylamidocarbonyl)phenyl,
    3-arnino-5-(N-(2-chlorobenzyl)amidocarbonyl)phenyl, 3-amino-5-(N-(3-fluorobenzyl)amidocarbonyl)phenyl,
    3-amino-5-(N-(2-trifluoromethylbenzyl)amidocarbonyl)phenyl,
    3-amino-5-(N-(l-phenylethyl)amidocarbonyl)phenyl,
    3-amino-5-(N-( 1 -methyl- 1 -phenylethyl)amidocarbonyl)phenyl,
    3-amino-5-(N-benzylarnidosulfonyl)phenyl, 3-amino-5-(N-(2-chlorobenzyl)amidosulfonyl)phenyl,
    3-amino-5-(N-ethylamidocarbonyl)ρhenyl,
    3-amino-5-(N-isoρropylamidocarbonyl)phenyl,
    3-amino-5-(N-propylamidocarbonyl)phenyl,
    3-amino-5-(N-isobutylamidocarbonyl)phenyl, 3-amino-5-(N-(2-butyl)amidocarbonyl)phenyl ,
    3-amino-5-(N-cyclobutylamidocarbonyl)phenyl, 3-arnino- (N-cyclopentylamidocarbonyl)phenyl,
    3-amino-5-(N-cyclohexylamidocarbonyl)phenyl, 5-amino-2-fluorophenyl, 3-amino-5-hydroxymethylphenyl, 5-amino-3-methoxycarbonylphenyl, 3-amidinophenyl, 3-amino-2-methylphenyl, 5-amino-2-methylthiophenyl,
    3-aminophenyl, 3-carboxyphenyl, 3-carboxy-5-aminophenyl, 3-carboxy-5-hydroxyρhenyl, 3-carboxymethyl- aminophenyl , 3-carboxymethyl- hydroxyphenyl, 3-carboxymethylphenyl, 3-chlorophenyl, 2-chlorophenyl, 3-cyanophenyl, 3,5-diaminophenyl, 3-dimethylamihophenyl, -fluorophenyl, 3-fluoroρhenyl, 2,5-difluorophenyl, 2-hydroxyρhenyl, -hydroxyphenyl, 3-methanesulfonylaminophenyl, 2-methoxyphenyl, 3-methoxyphenyl, 3-methoxyaminophenyl, 3-methoxycarbonylphenyl, 2-methylaminophenyl, 3-methylaminophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, phenyl, 3-trifluoroacetamidophenyl, 3-trifluoromethylphenyl, 2-trifluoromethylphenyl, 5-amino-2-thienyl, 5-amino-3-thienyl, 3-bromo-2-thienyl, 3-pyridyl, 4-pyridyl, 2-thienyl, and 3-thienyl;
    Y is selected from the group consisting of: 1-Q -4-QS-2-R -3-R -5-R -6-R benzene,
    2-Qb-5-QS-6-R17-4-R18-3-R19pyridine,
    3-Qb-6-QS-2-R16-5-R18-4-R19pyridine,
    3-Q -5-QS-4-R -2-R thiophene, and 2-Q -5-QS-3-R -4-R thiophene;
    R and R are independently selected from the group consisting of hydrido, amidino, amino, aminomethyl, methoxy, methylamino, hydroxy, hydroxymethyl, fluoro, chloro, and cyano;
    17 18
    R and R are independently selected from the group consisting of hydrido, fluoro, chloro, hydroxy, hydroxymethyl, amino, carboxy, and cyano;
    Q is C(NR )NR R ;
    23 24 25
    R , R , and R are independently hydrido or methyl;
    QS is CH2.
    51. Compound of Claim 50 or a pharmaceutically acceptable salt thereof, wherein;
    B is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxalan-2-yl, 2-(2R)-bicyclo[2.2.1]-heptyl, oxetan-3-yl, azetidin-1-yl, azetidin-2-yl, azetidin-3-yl, and 1-piperidinyl;
    A is selected from the group consisting of a bond, CH2, CH2CH2 and
    CH2CH2CH2; X° is selected from the group consisting of hydrido, methyl, ethyl, trifluoromethyl, 2,2,2-trifluoroethyl, chloro, and fluoro;
    2
    R is selected from the group consisting of
    3-amidocarbonyl- aminophenyl, 3-amino-5-(N-benzylamidocarbonyl)phenyl, 3-amino-5-(N-(2-chlorobenzyl)amidocarbonyl)phenyl ,
    3-amino-5-(N-(3-fluorobenzyl)amidocarbonyl)phenyl,
    3-amino-5-(N-(2-trifluoromethylbenzyl)amidocarbonyl)phenyl,
    3-amino-5-(N-( 1 -phenylethyl)amidocarbonyI)phenyI ,
    3-amino- (N-(l-methyl-l-phenylethyl)arnidocarbonyl)phenyl, 3-amino-5-(N-benzylamidosulfonyl)phenyl,
    3-amino-5-(N-(2-chlorobenzyl)amidosulfonyl)phenyl,
    3-amino-5-(N-ethylamidocarbonyl)phenyl,
    3-amino-5-(N-isopropylamidocarbonyl)phenyl,
    3-amino-5-(N-propylamidocarbonyl)phenyl, 3-amino- (N-isobutylamidocarbonyl)phenyl ,
    3-amino-5-(N-(2-butyl)amidocarbonyl)phenyl,
    3-amino-5-(N-cyclobutylamidocarbonyl)phenyl,
    3-amino-5-(N-cyclopentylamidocarbonyl)phenyl,
    3-amino-5-(N-cyclohexylamidocarbonyl)phenyl, 3-aminophenyl, 3-carboxy- aminophenyl, 3-chlorophenyl, 3,5-diaminophenyl,
    3-dimethylaminophenyl, 3-hydroxyphenyl, 3-methanesulfonylaminophenyl,
    3-methylaminophenyl, 2-methylphenyl, 3-methylphenyl, phenyl,
    3-trifluoroacetømidophenyl, 3-bromo-2-thienyl, 2-thienyl, and 3-thienyl; ϊ is selected from the group consisting of 5-amidino-2-thienylmethyl, 4-amidinobenzyl, 2-fluoro-4-amidinobenzyl, and 3-fluoro-4-amdinobenzyl.
    52. Compound of Claim 45 where said compound is selected from the group of the Formula:
    or a pharmaceutically acceptable salt thereof, wherein B, A, R , X°, and Y are selected to form a compound selected from the group consisting of;
    R 7 is 3-aminophenyl, B is cyclopropyl, A is a bond, Y 0 is 4- amidinobenzyl, and X° is methyl;
    7 0
    R is 3-aminophenyl, B is cyclobutyl, A is a bond, Y is 4-amidino-2- fluorobenzyl, and X° is methyl;
    7 0
    R is 3-aminophenyl, B is cyclobutyl, A is a bond, Y is 4-amidinobenzyl, and X° is methyl; 0
    R is 3-aminophenyl, B is cyclopropyl, A is a bond, Y is 4-amidino-2- fluorobenzyl, and X° is is methyl;
    2 0
    R is 3-aminophenyl, B is cyclobutyl, A is a bond, Y is 4-amidinobenzyl, and X° is hydrido;
    2 0
    R is 3-aminophenyl, B is cyclobutyl, A is a bond, Y is 4-amidino-3- fluorobenzyl, and X° is methyl;
    2 0 R is 3-aminophenyl, B is cyclopentyl, A is a bond, Y is 4-amidinobenzyl, and X° is methyl;
    7 0
    R is amino-2-thienyl, B is cyclobutyl, A is a bond, Y is 4- amidinobenzyl, and X° is methyl;
    2 0
    R is 3-aminophenyl, B is cyclopropyl, A is CH2, Y is 4-amidinobenzyl, and X° is methyl;
    7 0
    R is 3-aminophenyl, B is 2-(2R)-bicyclo[2.2.1]-heptyl, A is a bond, Y is
    4-amidinobenzyl, and X° is methyl;
    2 0
    R is 3-aminophenyl, B is cyclopentyl, A is a bond, Y is 4-amidino-2- fluorobenzyl, and X° is methyl;
    2 0 R is 3-aminophenyl, B is cyclohexyl, A is CH2CH2, Y is 4- amidinobenzyl, and X° is hydrido;
    2 . 0 .
    R is 3-aminophenyl, B is oxalan-2-yl, A is CH , Y is 4-amidinobenzyl, and X° is methyl;
    2 0
    R is 3-aminophenyl, B is 1-piperidinyl, A is CH CH , Y is 4- amidinobenzyl, and X° is methyl;
    7 0 R is 3-aminophenyl, B is 1 -pyrrolidinyl, A is CH2CH2CH2, Y is 4- amidinobenzyl, andX° is methyl;
    2 0
    R is 3-amino-5-carbomethoxyphenyl, B is cyclobutyl, A is a bond, Y is 4-amidinobenzyl, and X° is hydrido;
    7 0
    R is 3-amino-5-carboxyphenyl, B is cyclobutyl, A is a bond, Y is 4- amidinobenzyl, and X° is hydrido;
    7 0
    R is 3,5-diaminophenyl, B is cyclobutyl, A is a bond, Y is 4- amidinobenzyl, and X° is hydrido;
    7 0
    R is 2-amino-6-carboxy-4-pyridyl, B is cyclobutyl, A is a bond, Y is
    4-amidinobenzyl, and X° is hydrido;
    7 0 R is 3-amino-5-carbornethoxyphenyl, B is cyclobutyl, A is a bond, Y is 4-amidinobenzyl, and X° is methyl;
    2 0
    R is 3-amino-5-carboxyphenyl, B is cyclobutyl, A is a bond, Y is 4- amidinobenzyl, and X° is methyl;
    7 0
    R is 3, diaminophenyl, B is cyclopropyl, A is a bond, Y is 4- amidinobenzyl, and X° is methyl ;
    2 0
    R is 3,5-diaminophenyl, B is cyclobutyl, A is a bond, Y is 4-amidino-2- fluorobenzyl, and X° is methyl;
    7 0
    R is 3,5-diaminophenyl, B is cyclopropyl, A is a bond, Y is 4-amidino-2- fluorobenzyl, and X° is methyl;
    2 o R is 3 , diaminophenyl, B is cyclobutyl, A is a bond, Y is 4- amidinobenzyl, and X° is hydrido;
    2 . 0 .
    R is 3,Sdiaminophenyl, B is cyclobutyl, A is a bond, Y is 4-amidmo-3- fluorobenzyl, and X° is methyl;
    R 2 is 3,5-diaminophenyl, B is cyclopentyl, A is a bond, Y 0 is 4- amidinobenzyl, and X° is methyl;
    2 0 . R is 3-carboxy-5-aminophenyl, B is cyclopropyl, A is a bond, Y is 4- amidinobenzyl, and X° is methyl;
    R 2 is 3-carboxy-5-aminophenyl, B is cyclobutyl, A is a bond, Y 0 is 4- amidino-2-fluorobenzyl, and X° is methyl;
    7 0
    R is 3-carboxy-5-aminophenyl, B is cyclopropyl, A is a bond, Y is 4- amidino-2-fluorobenzyl, and X° is methyl;
    R 2 is 3-carboxy-5-aminophenyl, B is cyclobutyl, A is a bond, Y 0 is 4- amidinobenzyl, and X° is hydrido;
    2 0
    R is 3-carboxy-5-aminophenyl, B is cyclobutyl, A is a bond, Y is 4- amidino-3-fluorobenzyl, and X° is methyl; R 2 is 3-carboxy- aminophenyl, B is cyclopentyl, A is a bond, Y o is 4- amidinobenzyl, and X° is methyl;
    2
    R is 3-amino-5-(N-benzylamidocarbonyl)phenyl, B is cyclopropyl, A is a bond, Y is 4-amidinobenzyl, and X° is methyl;
    2
    R is 3-amino-5-(N-benzylamidocarbonyl)phenyl, B is cyclobutyl, A is a bond, Y is amidino-2-fluorobenzyl, and X° is methyl;
    R is 3-amino-5-(N-benzylamidocarbonyl)phenyl, B is cyclobutyl, A is a bond, Y is 4-amidinobenzyl, and X° is methyl;
    2
    R is 3-amino-5-(N-benzylamidocarbonyl)ρhenyl, B is cyclopropyl, A is a
    0 1 bond, Y is 4-amidino-2-fluorobenzyl, and R is methyl; R is 3-amino-5-(N-benzylamidocarbonyl)phenyl, B is cyclobutyl, A is a bond, Y is 4-amidinobenzyl, and X° is hydrido; 2 R is 3-amino-5-(N-benzylamidocarbonyl)phenyl, B is cyclobutyl, A is a
    0 n bond, Y is 4-amidino-3-fluorobenzyl, and X is methyl;
    2 R is 3-amino-5-(N-benzylamidocarbonyl)phenyl, B is cyclopentyl, A is a bond, Y is 4-amidinobenzyl, and X° is methyl; R is 3-amino-5-(N-(2-chlorobenzyl)amidosulfonyl)phenyl, B is cyclopropyl, A is a bond, Y is 4-amidinobenzyl, and X° is methyl;
    R is 3-amino-5-(N-(2-chlorobenzyl)amidosulfonyl)phenyl, B is cyclobutyl, A is a bond, Y is 4-amidino-2-fluorobenzyl, and X° is methyl;
    2 R is 3-amιno-5-(N-(2-chlorobenzyl)amidosulfonyl)phenyl, B is cyclobutyl, A is a bond, Y is 4-amidinobenzyl, and X° is methyl;
    2 R is 3-amino-5-(N-(2-chlorobenzyl)amidosulfonyl)phenyl, B is cyclopropyl, A is a bond, Y is 4-amidino-2-fluorobenzyl, and X° is methyl;
    2 R is 3-amino-5-(N-(2-chlorobenzyl)amidosulfonyl)ρhenyl, B is cyclobutyl, A is a bond, Y is 4-amidinobenzyl, and X° is hydrido;
    2 R is 3-amino-5-(N-(2-chlorobenzyl)ami dosulf onyl)phenyl, B is cyclobutyl, A is a bond, Y is 4-amidino-3-fluorobenzyl, and X° is methyl;
    2 R is 3-amino-5-(N-(2-chlorobenzyl)amidosulfonyl)phenyl, B is cyclopentyl, A is a bond, Y is 4-amidinobenzyl, and X° is methyl;
    2 R is 3-amino- (N-(2-trifluoromethylbenzyl)amidocarbonyl)-phenyl, B is cyclopropyl, A is a bond, Y is 4-amidinobenzyl, and X° is methyl;
    2
    R is 3-amino-5-(N-(2-trifluoromethylbenzyl)amidocarbonyl)-phenyl, B is cyclobutyl, A is a bond, Y is 4-amidino-2-fluorobenzyl, and X° is methyl;
    2 R is 3-amino-5-(N-(2-trifluoromethylbenzyl)amidocarbonyl)-ρhenyl, B is cyclobutyl, A is a bond, Y is 4-amidinobenzyl, and X° is methyl; R is 3-amino-5-(N-(2-trifluoromethylbenzyl)amidocarbonyl)-phenyl, B is cyclopropyl, A is a bond, Y is 4-amidino-2-fluorobenzyl, and X° is methyl; R X is 3-amino-5-(N-(2-trifluoromethylbenzyl)arnidocarbonyl)-phenyl, B is cyclobutyl, A is a bond, Y is 4-amidinobenzyl, and X° is hydrido;
    R is 3-amino-5-(N-(2-trifluoromethylbenzyl)amidocarbonyl)-phenyl, B is cyclobutyl, A is a bond, Y is 4-amidino-3-fluorobenzyl, and X° is methyl; and
    2
    R is 3-amino-5-(N-(2-trifluoromethylbenzyl)amidocarbonyl)-phenyl,
    B is cyclopentyl, A is a bond, Y is 4-amidinobenzyl, and X° is methyl.
    53. Compound of Claim 22 of 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
    32 ring to A is optionally substituted by R , the other carbon adjacent to the
    36 carbon at the point of attachment is optionally substitated by R , a carbon
    32 adjacent to R and two atoms from the carbon at the point of attachment is
    OO *\( optionally substituted by R , a carbon adjacent to R and two atoms from the
    35 carbon at the point of attachment is optionally substituted by R , and any
    33 35 34 carbon adjacent to both R and R is optionally substituted by R ; „32 33 „34 35 , 36 . , , ,
    R , R , R , R , and R are independently selected from the group consisting of hydrido, 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, tiialkylsilyl, C2-C8 alkyl, C3-C8 alkylenyl, C3-C8 alkenyl, C3-C8 alkynyl, and C2-C8 haloalkyl, wherein each member of group B is optionally substitated at any carbon up to and including 6 atoms from the point of attachment of B to A
    32 33 34 35 36 with one or more of the group consisting of R , R , R , R , and R ;
    B is optionally a C3-C12 cycloalkyl or a C4-C9 saturated heterocyclyl,
    33 wherein each ring carbon is optionally substitated with R , a ring carbon other than the ring carbon at the point of attachment of B to A is optionally substituted with oxo provided that no more than one ring carbon is substituted by oxo at the same time, ring carbons and a nitrogen adjacent to the carbon
    9 13 atom at the point of attachment are optionally substitated with R or R , a ring
    9 carbon or nitrogen adjacent to the R position and two atoms from the point of
    attøchment is optionally substitated with R , a ring carbon or nitrogen adjacent
    13 to the R position and two atoms from the point of attachment is optionally
    12 substituted with R , a ring carbon or nitrogen three atoms from the point of
    attøchment and adjacent to the R position is optionally substitated with R , a ring carbon or nitrogen three atoms from the point of attachment and adjacent
    12 33 to the R position is optionally substitated with R , and a ring carbon or
    11 nitrogen four atoms from the point of attachment and adjacent to the R and
    33 34
    R positions is optionally substituted with R ; 9 10 11 12 13
    R , R , R , R , and R are independently selected from the group consisting of hydrido, acetamido, haloacetamido, alkoxyamino, 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;
    15 7
    A is a bond or (CH(R )) a-(W )rr wherein π is 0 or 1 , pa is an
    7 integer selected from 0 through 3 , and W is selected from the group
    consisting of O, S, C(O), (R?)NC(O), (R7)NC(S), and N(R?);
    7 R is selected from the group consisting of hydrido, hydroxy and alkyl;
    15 R is selected from the group consisting of hydrido, hydroxy, halo, alkyl, and haloalkyl; X is selected from the group consisting of hydrido, amino, alkyl, cyano, halo, haloalkyl, haloalkoxy, aminoalkyl, hydroxy, alkoxy, hydroxyalkyl, and alkylthio;
    R2 is Z°-Q; o 41 42
    Z is selected from the group consisting of a bond, (CR R )q
    41 o 42 wherein q is 1 or 2, and (CH(R ))g-W -(CH(R ))p wherein g and p are integers independently selected from 0 through 3 and W is selected from the
    41 41 group consisting of O, S, C(O), S(O), N(R ), and ON(R ); Z° is optionally (CH(R41))e- 22-(CH(R42))h wherein e and h are
    independently 0 or 1 and W^ is selected from the group consisting of
    41 42 CR =CR , 1,2-cyclopropyl, 1,2-cyclobutyl, 1,2-cyclohexyl, 13-cyclohexyl,
    1,2-cyclopentyl, 13-cyclopenxyl, 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, 2,3-piperidinyl, 2,4-piperidinyl, 2,6-piperidinyl, 3,4-piperidinyl, 1 ,2-pyπolidinyl, 1 ,3-pyπolidinyl, 2,3-pyπolidinyl, 2,4-pyrrolidinyl, 2,5-pyrrolidinyl, 3,4-pyπolidinyl, 2,3-tetrahydrofuranyl, 2,4-tetrahydrofuranyl, 2,5-tetrahydrofuranyl, and 3,4-tetrahydrofuranyl, wherein Z is directly bonded to the 4-pyrone ring and W"^ is optionally substituted with one or more
    9 10 11 12 13 substituents selected from the group consisting of R , R , R , R , and R ;
    41 42
    R and R 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 o 9 ring to Z is optionally substituted by R , the other carbon adjacent to the
    13 carbon at the point of attachment is optionally substituted by R , a carbon
    9 adjacent to R and two atoms from the carbon at the point of attachment is
    10 13 optionally substitated by R , a carbon adjacent to R and two atoms from the
    12 carbon at the point of attachment is optionally substitated by R , and any
    10 12 11 carbon adjacent to both R and R is optionally substituted by R , with the proviso that Q is other than a phenyl when Z is a bond;
    Q is optionally hydrido with the proviso that Z is selected from other than a bond; 4a 4a
    K is CHR wherein R is selected from the group consisting of hydrido, hydroxyalkyl, alkyl, alkoxyalkyl, alkylthioalkyl, and haloalkyl; E is selected from the group consisting of a bond, C(O)N(H),
    (H)NC(O), (R?)NS(O)2, and S(O)2N(R?);
    YAT is Qb-Qs; s 37 38
    Q is (CR R )tø wherein b is an integer selected from 1 through 4,
    37 R is selected from the group consisting of hydrido, alkyl, and haloalkyl, and
    38 R 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
    37 38 is bonded to (CR R )^ at the same time, with the still further proviso that said aroyl and said heteroaroyl are optionally substituted with one or more substitoents selected from the group consisting of with another further proviso that said aroyl and said heteroaroyl are bonded to the CR R that is directly bonded to E , with still another further proviso
    37 38 that no more than one alkyl or one haloalkyl is bonded to a CR R 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;
    R are independentiy 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;
    R or R 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 R , R , and Q are not simultaneously hydrido; O \ OΛ
    Q is selected from the group consisting of NR R , hydrido,
    with the proviso that
    ^20 , 21 , , . . no more than one of R and R is selected from the group consisting of hydroxy, amino, alkylamino, and diallcylamino at the same time and with the
    23 24 further proviso that no more than one of R and R is selected from the group consisting of hydroxy, amino, alkylamino, and dialkylamino at the same time;
    20 21 23 24 25 26
    R , R , R , R , R , and R are independently selected from the group consisting of hydrido, alkyl, hydroxy, amino, alkylamino and dialkylamino.
    54. Compound of Claim 53 of 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-pyπolyl, 3-ρyπolyl, 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
    32 heteroaryl ring to A is optionally substituted by R , the other carbon adjacent
    36 to the carbon at the point of attachment is optionally substitated by R , a
    32 carbon adjacent to R and two atoms from the carbon at the point of
    33 f. attachment is optionally substituted by R , a carbon adjacent to R and two atoms from the carbon at the point of attachment is optionally substituted by R , and any carbon adjacent to both R and R is optionally substitated by
    32 33 34 35 36
    R , R , R , R , and R are independently selected from the group consisting of hydrido, amidino, guanidino, methyl, ethyl, methoxy, ethoxy, hydroxy, amino, N-methylamino, dimethylamino, methoxyamino, methylthio, ethylthio, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, fluoro, chloro, bromo, amidosulfonyl, N-methylamidosulfonyl, hydroxymethyl, amidocarbonyl, carboxy, cyano, and Q ;
    B is optionally selected from the group consisting of hydrido, ethyl, 2-propenyl, 2-propynyl, propyl, isopropyl, butyl, 2-butenyl, 2-butynyl, sec-butyl, tert-butyl, isobutyl, 2-methylpropenyl, 1-pentyl, 2-pentenyl, 3-pentenyl, 2-pentynyl, 3-pentynyl, 2-pentyl, 3-pentyl, 2-methylbutyl, 2-methyl-2-butenyl, 3-methylbutyl, 3-methyl-2-butenyl, 1-hexyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 2-hexyl, l-methyl-2-pentenyl, l-methyl-3-pentenyl, l-methyl-2-pentynyl, l-methyl-3-pentynyl, 3-hexyl, l-ethyl-2-butenyl, 1-heptyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 2-heρtynyl, 3-heptynyl, 4-heρtynyl, 5-heptynyl, 2-heptyl, l-methyl-2-hexenyl, l-methyl-3-hexenyl, l-methyl-4-hexenyl, l-methyl-2-hexynyl, l-methyl-3-hexynyl, l-methyl-4-hexynyl, 3-heptyl, l-ethyl-2-ρentenyl, l-ethyl-3-ρentenyl, l-ethyl-2-pentynyl, l-ethyl-3-pentynyl, 2,2,2-trifluoroethyl, 2,2-difluoropropyl, 4-trifluoromethyl-5,5,5-trifluoropentyl, 4-trifluoromethylρentyl, 5,5,6,6,6-ρentafluorohexyl, and333-tiifluoroproρyl, wherein each member of group B is optionally substituted at any carbon up to and including 5 atoms from the point of attøchment of B to A with one or more of the group r 32 ^33 34 35 36 consisting of R ,R , R , R , and R ;
    B is optionally 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-ρiperazinyl, 1-piperidinyl, 2-ρiperidinyl, 3-piρeridinyl, 4-ρiperidinyl, 1-pyπolidinyl, 2-ρyπolidinyl, 3-pyπolidinyl, 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
    33 R , ring carbons and a nitrogen adjacent to the carbon atom at the point of
    9 13 attachment are optionally substituted with R or R , a ring carbon or nitrogen
    9 adjacent to the R position and two atoms from the point of attachment is
    10 optionally substituted with R , and a ring carbon or nitrogen adjacent to the
    13 R position and two atoms from the point of attachment is optionally
    12 substituted with R ;
    9 11 13 R , R , and R are independentiy 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;
    10 12
    R and R 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-trifluoromethyIbenzyl)amidocarbonyl, N-(l-phenylethyl)amidocarbonyl, N-(l-methyl-l-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;
    A is selected from the group consisting of a bond, NH, N(CH3), CH ,
    CH3CH, CH2CH2, and CH2CH2CH2;
    X° 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;
    2 R is selected from the group consisting of phenyl, 2-thienyl, 2-furyl, 2- pyπolyl, 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
    9 phenyl or heteroaryl ring to the 4-pyrone ring is optionally substituted by R , the other carbon adjacent to the carbon at the point of attachment is optionally
    13 9 substitoted by R , a carbon adjacent to R and two atoms from the carbon at
    the point of attøchment is optionally substituted by R , a carbon adjacent to
    13 R and two atoms from the carbon at the point of attøchment is optionally
    12 10 12 substitoted by R , and any carbon adjacent to both R and R is optionally
    su tbsti •toted , , by π Rιι ;
    Q is selected from the group consisting of:
    C Λm[R37 (Λbenzoyl)(CR,37„ R3& )b ,],
    37 37 38
    C[R (2-pyridylcarbonyiχCR R )b],
    C[R37(3-pyridylcarbonylXCR37R38)b],
    37 37 38 C[R (4-pyridylcarbonyl)(CR R )b], 37 37 38
    C[R (2-thienylcarbonyl)(CR R )b],
    37 37 38
    C[R (3-thienylcarbonyl)(CR R )b],
    37 37 38
    C[R (2-thiazolylcarbonyl)(CR R )b],
    37 37 38
    C[R (4-thiazolylcarbonyl)(CR R )b], and
    37 37 38 C[R (5-tiiiazolylcarbonyiX (CR R )b], wherein b is an integer selected
    from 1 through 3, R and R are independently selected from the group consisting of hydrido, alkyl, and haloalkyl, with the proviso that said benzoyl and the heteroaroyls are optionally substituted with one or more substitoents
    16 17 18 19 selected from the group consisting of R , R , R , and R with the proviso
    17 18 that R and R are optionally substituted at a carbon selected from other than the meta and para carbons relative to the carbonyl of the benzoyl or heteroaroyl, with the further proviso that said benzoyl or said heteroaroyl are bonded to the carbon directly bonded to amide nitrogen of the l-(amidocarbonymethylene) group, and with the still further proviso that is no more than one alkyl or one
    37 38 haloalkyl is bonded to a CR R at the same time;
    16 17 18 , 19 . , , , R , R , R , and R are independently selected from the group consisting of hydrido, methyl, ethyl, amidino, guanidino, methoxy, hydroxy, 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; b 25 23 24 26 25 23 24
    Q is C(NR )NR R or N(R )C(NR )N(R )(R );
    23 24 25 26
    R , R , R , and R are independently selected from the group consisting of hydrido, methyl, and ethyl.
    55. Compound of Claim 54 or a pharmaceutically acceptable salt thereof, wherein; B is selected from the group consisting of 2-aminophenyl, 3-aminophenyl, 3-amidinophenyl, 4-amidinophenyl, 3-carboxyphenyl, 3-carboxy-5-hydroxyphenyl, 3-chlorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 3,4-difluorophenyl, 3-hydroxyρhenyl, 4-hydroxyphenyl, 3-methoxyaininophenyl,
    3-methoxyphenyl, 4-methoxyphenyl, 3-methylphenyl, 4-methylphenyl, phenyl, 3-trifluoromethylphenyl, 2-imidazoyl, 2-pyridyl, 3-pyridyl, 5-chloro-3-trifluoromethyl-2-pyridyl, 4-pyridyl, 2-thienyl, 3-thienyl, and 3-trifluoromethyl-2-pyridyl ; B is optionally selected from the group consisting of hydrido, ethyl,
    2-propenyl, 2-propynyl, propyl, isopropyl, butyl, 2-butyl, (R)-2-butyl, (S)-2-butyl, tert-butyl, isobutyl, 1-pentyl, 3-pentyl, 2-methylbutyl, 2,2,2-trifluoroethyl, 6-amidocarbonylhexyl, 4-methyl-2-pentyl, 3-hydroxypropyl, l-methoxy-2-propyl, 2-methoxyethyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 2-dimethylaminopropyl, 2-cyanoethyl , 6-hydroxyhexyl, 2-hydroxyethyl, 2-amidinoethyl, 2-guanidinoethyl, 3-guanidinopropyl, 4-guanidinobutyl, 3-hydroxypropyl, 4-hydroxybutyl, 6-cyanohexyl, 2-dimethylaminoethyl, 3-methylbutyl, 2-methylbutyl, (S)-2-methylbutyl, 3-aminopropyl, 2-hexyl, and 4-aminobutyl; B is optionally selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxalan-2-yl, 2-(2R)-bicyclo[2.2.1]-heptyl, oxetan-3-yl, azetidin-1-yl, azetidin-2-yl, azetidin-3-yl, 1-pyπolidinyl and 1-piperidinyl;
    A is selected from the group consisting of a bond, CH2, CH3CH,
    CH2CH2, and CH2CH2CH2;
    X° is selected from the group consisting of hydrido, hydroxy,l- aminoethyl, methyl, ethyl, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, fluoro, chloro, and bromo;
    R is selected from the group consisting of 3-amidocarbonyl-5-aminophenyl, 3-amidocarbonyl-5-aminophenyl, 3-amino-5-(N-benzylamidocarbonyl)phenyl, 3-amino-5-(N-(2-chlorobenzyl)amidocarbonyl)ρhenyl, 3-amino-5-(N-(3-fluorobenzyl)amidocarbonyl)phenyl, 3-amino-5-(N-(2-trifluoromethylbenzyl)amidocarbonyl)phenyl, -amino-5-(N-(l-phenylethyl)amidocarbonyl)ρhenyl, -amino-5-(N-(l-methyl-l-phenylethyl)amidocarbonyl)phenyl, 3-amino- (N-benzylamidosulfonyl)phenyl, 3-amino-5-(N-(2-chlorobenzyl)amidosulfonyl)phenyl, 3-amino-5-(N-ethylamidocarbonyι)phenyl, 3-amino-5-(N-isopropylamidocarbonyl)phenyl, 3-amino-5-(N-propylamidocarbonyl)phenyl, 3-amino-5-(N-isobutylamidocarbonyl)phenyl, 3-amino-5-(N-(2-butyl)amidocarbonyl)phenyl, 3-amino-5-(N-cyclobutylamidocarbonyl)phenyl, 3-amino-5-(N-cyclopentylamidocarbonyl)phenyl, 3-amino-5-(N-cyclohexylamidocarbonyl)phenyl, 5-amino-2-fluorophenyl , 3-amino-5-hydroxymethylphenyl, 5-amino-3-methoxycarbonylphenyl, 3-amidinophenyl, 3-amino-2-methylphenyl, 5-amino-2-methylthiophenyl, 3-aminophenyl, 3-carboxyphenyl, 3-carboxy-5-aminophenyl, 3-carboxy-5-hydroxyphenyl, 3-carboxymethyl-5-aminophenyl, 3-carboxymethyl-5-hydroxyphenyl, 3-carboxymethylphenyl, 3-chlorophenyl, 2-chlorophenyl, 3-cyanophenyl, ,5-diaminophenyl, 3-dimethylaminophenyl, 2-fluorophenyl, 3-fluorophenyl, 2,5-difluorophenyl, 2-hydroxyphenyl, 3-hydroxyphenyl,
    3-methanesulfonylaminophenyl, 2-methoxyphenyl, 3-methoxyphenyl, 3-methoxyaminophenyl, 3-methoxycarbonylphenyl, 2-methylaminophenyl, 3-methylaminophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, phenyl, 3-trifluoroacetamidophenyl, 3-trifluoromethylphenyl, 2-trifluoromethylphenyl, 5-amino-2-thienyl, 5-amino-3-thienyl, 3-bromo-2-thienyl, 3-pyridyl, 4-pyridyl, 2-thienyl, and 3-thienyl;
    YAT is Qb-QS; s Q is selected from the group consisting of:
    [CH(benzoyl)](CH2)b, [CH(2-pyridylcarbonyl)](CH2)b,
    [CH(3-pyridylcarbonyl)](CH2)b, [CH(4-pyridylcarbonyl)](CH2)b,
    [CH(2-thienylcarbonyl)](CH2)b,[CH(3-thienylcarbonyl)](CH2)b,
    [CH(2-thiazolylcarbonyl)](CH2) , [CH(4-thiazolylcarbonyl)](CH2)b, and [CH(5-thiazolylcarbonyl)](CH2) , wherein b is an integer selected from 1 through 3, with the proviso that said benzoyl and said heteroaroyls are optionally substituted with one or more substituents selected from the group
    • .- r 6 17 18 . 9 . , t . t „17 J T,18 consisting of R , R , R , and R with the proviso that R and R are optionally substituted at a carbon selected from other than the metø and para carbons relative to the carbonyl of the benzoyl or the heteroaroyl, and that said benzoyl or said heteroaroyl are bonded to the carbon directly bonded to amide nitrogen of the l-(amidocarbonymethylene) group;
    R and R are independently selected from the group consisting of hydrido, amidino, amino, aminomethyl, methoxy, methylamino, hydroxy, hydroxymethyl, fluoro, chloro, and cyano;
    17 18 .
    R and R are independently selected from the group consisting of hydrido, fluoro, chloro, hydroxy, hydroxymethyl, amino, carboxy, and cyano; rjf- and are independently hydrido or methyl.
    56. Compound of Claim 55 or a pharmaceutically acceptable salt thereof, wherein;
    B is selected from the group consisting of 3-aminophenyl, 3-amidinophenyl, 4-amidinophenyl, 3-chlorophenyl, 4-chlorophenyl,
    3,4-dichloroρhenyl, 2-fluorophenyl, 4-methylphenyl, phenyl, 2-imidazoyl, 3-pyridyl, 4-pyridyl, and 3-trifluoromethyl-2-pyridyl;
    B is optionally selected from the group consisting of hydrido, ethyl, 2-propenyl, 2-propynyl, propyl, isopropyl, butyl, 2-butyl, (R)-2-butyl, (S)-2-butyl, tert-butyl, isobutyl, 1-pentyl, 3-pentyl, 2-methylbutyl, 2,2,2-trifluoroethyl, 6-amidocarbonylhexyl, methyl-2-pentyl, 3-hydroxypropyl, l-methoxy-2-propyl, 2-methoxy ethyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 2-dimethylaminopropyl, 2-cyanoethyl, 6-hydroxyhexyl, 2-hydroxyethyl, 2-amidinoethyl, 2-guanidinoethyl, 3-guanidinopropyl, 4-guanidinobutyl, 3-hydroxypropyl, 4-hydroxybutyl, 6-cyanohexyl,
    2-dimethylaminoethyl, 3-methylbutyl, 2-methylbutyl, (S)-2-methylbutyl, 3-aminopropyl, 2-hexyl, and 4-aminobutyl;
    B is optionally selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxalan-2-yl, 2-(2R)-bicyclo[2.2.1]-heptyl, oxetan-3-yl, azetidin-1-yl, azetidin-2-yl, azetidin-3-yl, and 1-piperidinyl; A is selected from the group consisting of a bond, CH2, CH2CH2 and
    CH2CH2CH2;
    X° is selected from the group consisting of hydrido, aminomethyl, methyl, ethyl, trifluoromethyl, 2,2,2-trifluoroethyl, hydroxymethyl,
    2-hydroxyethyl, chloro, and fluoro; R is selected from the group consisting of
    3-amidocarbonyl-5-aminophenyl, 3-amino-5-(N-benzylamidocarbonyl)phenyl,
    3-amino-5-(N-(2-chlorobenzyl)arnidocarbonyl)phenyl,
    3-amino-5-(N-(3-fluorobenzyl)amidocarbonyl)phenyl,
    3-amino-5-(N-(2-trifluoromethylbenzyl)amidocarbonyl)phenyl, 3-amino-5-(N-( 1 -phenyl ethyl)amidocarbonyl)phenyl ,
    3-amino-5-(N-(l-methyl-l-phenylethyl)amidocarbonyl)phenyl,
    3-amino-5-(N-benzylamidosulfonyl)phenyl,
    3-amino- (N-(2-chlorobenzyl)amidosulfonyl)phenyl,
    3-amino-5-(N-ethylamidocarbonyl)phenyl, 3-amino-5-(N-isoproρylamidocarbonyl)phenyl,
    3-amino-5-(N-proρylamidocarbonyl)phenyl,
    3-amino-5-(N-isobutylamidocarbonyl)phenyl,
    3-amino-5-(N-(2-butyl)amidocarbonyl)phenyl,
    3-amino-5-(N-cyclobutylamidocarbonyl)phenyl, 3-amino- (N-cyclopentylamidocarbonyl)phenyl,
    3-amino-5-(N-cyclohexylamidocarbonyl)phenyl, 3-aminophenyl, 3-carboxy- aminophenyl, 3-chlorophenyl, 3,5-diaminophenyl, 3-dimethylaminophenyl, 3-hydroxyphenyl, 3-methanesulfonylarninophenyl, 3-methylaminophenyl, 2-methylphenyl, 3-methylphenyl, phenyl, 3-trifluoroacetamidophenyl, 3-bromo-2-thienyl, 2-thienyl, and 3-thienyl;
    Y^ is selected from the group consisting of 5-guanidino-l-oxo-l-(2- thiazolyl)-2-pentyl, 5-guanidino-l-oxo-l-(4-thiazolyl)-2-pentyl, 5-guanidino-l- oxo-l-(5-thiazolyl)-2-pentyl, 5-guanidino-l-oxo-l-(4-amino-2-thiazolyl)-2- pentyl, and 5-guanidino-l-oxo-l-phenyl-2-pentyl.
    57. A compound as recited in Claim 53 where said compound is selected from the group of the Formula:
    or a pharmaceutically acceptable salt thereof, wherein B, A, R , X°, and Y are selected to form a compound selected from the group consisting of;
    2 AT
    R is 3-aminophenyl, B is phenyl, A is CH CH , Y is 5-guanidino- 1- oxo-l-(2-thiazolyl)-2-pentyl, and X° is hydrido;
    R is 3, diaminophenyl, B is phenyl, A is CH CH , Y is 5-guanidino- 1- oxo-l-(2-thiazolyl)-2-pentyl, and X° is hydrido;
    R is 3-carboxy-5-aminophenyl, B is phenyl, A is CH2CH , Y^ is 5- guanidino-l-oxo-l-(2-thiazolyl)-2-ρentyl, and X° is hydrido;
    2 R is 3-amino-5-(N-benzylamidocarbonyl)phenyl, B is phenyl, A is
    AT o
    CH2CH2, Y is 5-guanidino-l-oxo-l-(2-thiazoIyl)-2-pentyl, and X is hydπdo; AT
    R is 3,5-diaminophenyl, B is isopropyl, A is single bond, Y is 5- guanidino-l-oxo-l-(2-thiazolyl)-2-pentyl, and X° is hydrido; AT
    R is 3-carboxy-5-aminophenyl, B is isopropyl, A is single bond, Y is 5- guanidino-l-oxo-l-(2-thiazolyl)-2-pentyl, and X° is hydrido;
    R is 3-amino-5-(N-benzylamidocarbonyl)phenyl, B is isopropyl, A is single bond, Y is 5-guanidino- 1-oxo- l-(2-thiazolyl)-2-pentyl, and X° is hydrido;
    2 AT
    R is 3,5-diaminophenyl, B is cyclobutyl, A is single bond, Y is 5- guanidino-l-oxo-l-(2-thiazolyl)-2-pentyl, and X° is hydrido; 2 AT
    R is 3-carboxy-5-aminophenyl, B is cyclobutyl, A is single bond, Y is 5- guanidino-l-oxo-l-(2-thiazolyl)-2-pentyl, and X° is hydrido;
    2
    R is 3-amino-5-(N-benzylamidocarbonyl)phenyl, B is cyclobutyl, A is single bond, Y is 5-guanidino-l-oxo-l-(2-thiazolyl)-2-pentyl, and X° is hydrido;
    2 AT RΛ is 3-aminophenyl, B is phenyl, A is CH2CH2,Y is 5-guanidino- 1- oxo-l-(2-thiazolyl)-2-pentyl, and X° is hydrido;
    2 AT
    R is 3, diaminophenyl, B is phenyl, A is CH2CH2, Y is 5-guanidino- 1- oxo-l-(2-thiazolyl)-2-ρentyl, and X° is hydrido;
    R is 3-carboxy-5-aminophenyl, B is phenyl, A is CH2CH , i is 5- guanidino- 1 -oxo- l-(2-thiazolyl)-2-pentyl, and X° is hydrido;
    2 R is 3-amino-5-(N-benzylamidocarbonyl)phenyl, B is phenyl, A is
    AT n
    CH CH2,Y is 5-guanidino-l-oxo-l-(2-thiazolyl)-2-pentyl, and X is hydrido;
    2 AT
    R is 3,5-diaminophenyl, B is isopropyl, A is single bond, Y is 5- guanidino-l-oxo-l-(2-thiazolyl)-2-pentyl, and X° is hydrido; AT ,
    R is 3-carboxy-5-aminophenyl, B is isopropyl, A is single bond, Y is 5- guanidino-l-oxo-l-(2-thiazolyl)-2-pentyl, and X° is hydrido;
    R is 3-amino-5-(N-benzylamidocarbonyl)phenyl, B is isopropyl, A is single bond, Y is 5-guanidino-l-oxo-l~(2-thiazolyl)-2-pentyl, and X° is hydrido; AT R is 3,5-diaminophenyl, B is cyclobutyl, A is single bond, Y is 5- guanidino-l-oxo-l-(2-thiazolyl)-2-pentyl, and X° is hydrido; AT
    R is 3-carboxy-5-aminoρhenyl, B is cyclobutyl, A is single bond, Y is 5- guanidino-l-oxo-l-(2-thiazolyl)-2-pentyl, and X° is hydrido; and
    R is 3-amino-5-(N-benzylamidocarbonyl)phenyl, B is cyclobutyl, A is single bond, Y is 5-guanidino- l-oxo-l-(2-thiazolyl)-2-pentyl, and X° is hydrido.
    58. A composition for inhibiting thrombotic conditions in blood comprising a compound of Claim 21 and a pharmaceutically acceptable carrier.
    59. A method for inhibiting thrombotic conditions in blood comprising adding to blood a therapeutically effective amount of a composition of Claim 58.
    60. A method for inhibiting formation of blood platelet aggregates in blood comprising adding to blood a therapeutically effective amount of a composition of Claim 58.
    61. A method for inhibiting thrombus formation in blood comprising adding to blood a therapeutically effective amount of a composition of Claim 58.
    62. A method for treating or preventing venuous thromboembolism and pulmonary embolism in a mammal comprising administering to the mammal a therapeutically effective amount of a composition of Claim 58.
    63. A method for treating or preventing deep vein thrombosis in a mammal comprising administering to the mammal a therapeutically effective amount of a composition of Claim 58.
    64. A method for treating or preventing cardiogenic thromboembolism in a mammal comprising administering to the mammal a therapeutically effective amount of a composition of Claim 58.
    65. A method for treating or preventing thromboembolic stroke in humans and other mammals comprising administering to the mammal a therapeutically effective amount of a composition of Claim 58.
    66. A method for treating or preventing thrombosis associated with cancer and cancer chemotherapy in humans and other mammals comprising administering to the mammal a therapeutically effective amount of a composition of Claim 58.
    67. A method for treating or preventing unstable angina in humans and other mammals comprising administering to the mammal a therapeutically effective amount of a composition of Claim 58.
    68. A method for inhibiting thrombus formation in blood comprising adding to blood a therapeutically effective amount of a compound of Claim 21 with a therapeutically effective amount of fibrinogen receptor antagonist.
    69. The use of a compound of Claim 21, or a pharmaceutically acceptable salt thereof, in the manufacture of medicament for inhibiting thrombus formation, treating thrombus formation, or preventing thrombus formation in a mammal.
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Families Citing this family (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2001243598A1 (en) 2000-03-13 2001-09-24 Pharmacia Corporation Polycyclic aryl and heteroaryl substituted benzenes useful for selective inhibition of the coagulation cascade
AU2001249870A1 (en) 2000-04-05 2001-10-23 Pharmacia Corporation Polycyclic aryl and heteroaryl substituted 4-pyrones useful for selective inhibition of the coagulation cascade
US7119094B1 (en) 2000-11-20 2006-10-10 Warner-Lambert Company Substituted polycyclic aryl and heteroarpyl pyrazinones useful for selective inhibition of the coagulation cascade
US7015223B1 (en) 2000-11-20 2006-03-21 Pharmacia Corporation Substituted polycyclic aryl and heteroaryl 1,2,4-triazinones useful for selective inhibition of the coagulation cascade
EP1351686A2 (en) * 2000-11-20 2003-10-15 Pharmacia Corporation Substituted polycyclic aryl and heteroaryl pyridines useful for selective inhibition of the coagulation cascade
MXPA04003163A (en) 2001-10-03 2004-07-08 Pharmacia Corp 6-membered heterocyclic compounds useful for selective inhibition of the coagulation cascade.
WO2003093242A2 (en) 2001-10-03 2003-11-13 Pharmacia Corporation Substituted 5-membered polycyclic compounds useful for selective inhibition of the coagulation cascade
US8753124B2 (en) * 2009-02-15 2014-06-17 Cheryl Lynn Evans Method and apparatus for prescribing and preparing a reproducible and customized dysphagia diet
WO2015085238A1 (en) * 2013-12-05 2015-06-11 The Regents Of The University Of California, A California Corporation Inhibitors of lpxc

Family Cites Families (63)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5910541A (en) * 1982-07-09 1984-01-20 Takeda Chem Ind Ltd Quinone compound
JPS60255749A (en) * 1984-05-31 1985-12-17 Univ Nagoya Quinone derivative
US5304658A (en) * 1984-08-01 1994-04-19 Takeda Chemical Industries, Ltd. Quinone derivatives, their production and use
IL81264A (en) * 1986-01-30 1990-11-05 Takeda Chemical Industries Ltd Quinone derivatives,their production and pharmaceutical compositions containing them
DE3826846A1 (en) 1988-08-06 1990-02-08 Goedecke Ag ALKOXY-4 (1H) -PYRIDONE DERIVATIVES, PROCESS FOR THEIR PREPARATION AND THEIR USE AS DRUGS
US5008267A (en) 1988-10-29 1991-04-16 Mitsui Toatsu Chemicals, Incorporated Pyrimidinedione compounds, method of producing the same and antiarrythmic agents containing the same
ES2079068T3 (en) * 1990-06-29 1996-01-01 Upjohn Co 2-AMINO-6-FENIL-4H-PIRAN-4-ONAS ANTIATEROSCLEROTICAS AND ANTITROMBOTICAS.
GB9216272D0 (en) 1991-08-15 1992-09-09 Ici Plc Substituted heterocycles
CA2133657A1 (en) 1992-04-16 1993-10-28 Peter R. Bernstein Substituted derivatives
US5441960A (en) * 1992-04-16 1995-08-15 Zeneca Limited 1-pyrimidinylacetamide human leukocyte elastate inhibitors
US5618792A (en) * 1994-11-21 1997-04-08 Cortech, Inc. Substituted heterocyclic compounds useful as inhibitors of (serine proteases) human neutrophil elastase
NZ298699A (en) 1994-12-13 2001-03-30 Corvas Int Inc 3-amino-1,2-dihydropyrid-1-yl(and 5-amino-1,6-dihydro-6-oxo(and 5,6-dioxo)pyrimidin-1-yl)-acetyl-argininal derivatives, useful for the treatment of blood coagulation and thrombosis
US5656645A (en) * 1994-12-13 1997-08-12 Corvas International, Inc. Aromatic heterocyclic derivatives as enzyme inhibitors
US5658930A (en) * 1994-12-13 1997-08-19 Corvas International, Inc. Aromatic heterocyclic derivatives as enzyme inhibitors
US6011158A (en) 1994-12-13 2000-01-04 Corvas International, Inc. Aromatic heterocyclic derivatives as enzyme inhibitors
WO1996033974A1 (en) 1995-04-27 1996-10-31 The Green Cross Corporation Heterocyclic amide compounds and medicinal use of the same
US5612378A (en) 1995-06-06 1997-03-18 3-Dimensional Pharmaceuticals, Inc. Bis-arylsulfonylaminobenzamide derivatives and the use thereof as factor Xa inhibitors
US5741819A (en) 1995-06-07 1998-04-21 3-Dimensional Pharmaceuticals, Inc. Arylsulfonylaminobenzene derivatives and the use thereof as factor Xa inhibitors
WO1997001338A1 (en) 1995-06-27 1997-01-16 Merck & Co., Inc. Pyridinone-thrombin inhibitors
JP2921606B2 (en) 1995-11-08 1999-07-19 ケーニツヒ ウント バウエル−アルバート アクチエンゲゼルシヤフト Folding device
AU720616B2 (en) 1996-02-22 2000-06-08 Merck & Co., Inc. Pyridinone thrombin inhibitors
DE69709727T2 (en) 1996-04-23 2002-08-08 Merck & Co Inc PARAZINON THROMBIN INHIBITORS
US5668289A (en) * 1996-06-24 1997-09-16 Merck & Co., Inc. Pyridinone thrombin inhibitors
CA2263999A1 (en) 1996-08-29 1998-03-05 Merck & Co., Inc. Integrin antagonists
WO1998009987A1 (en) 1996-09-06 1998-03-12 Biochem Pharma, Inc. Lactam inhibitors of thrombin
TW498068B (en) 1996-09-06 2002-08-11 Nippon Kayaku Kk Novel acetamide derivatives and protease inhibitors
CA2264037A1 (en) 1996-09-13 1998-03-19 Merck & Co., Inc. Thrombin inhibitors
US5872138A (en) * 1996-09-13 1999-02-16 Merck & Co., Inc. Thrombin inhibitors
JP2001502674A (en) 1996-10-11 2001-02-27 シーオーアール・セラピューティックス・インコーポレーテッド Selective factor Xa inhibitor
WO1998016547A1 (en) 1996-10-11 1998-04-23 Cor Therapeutics, Inc. SELECTIVE FACTOR Xa INHIBITORS
US5869487A (en) * 1996-10-24 1999-02-09 Merck & Co., Inc. Pyrido 3,4-B!pyrazines for use as thrombin inhibitors
DE69719775T2 (en) 1996-10-24 2004-02-05 Merck & Co., Inc. THROMBIN INHIBITORS
US6080738A (en) 1996-10-25 2000-06-27 Yoshitomi Pharmaceuticals Industries, Ltd. Heterocyclic amide compounds and medicinal uses thereof
CA2277929A1 (en) 1997-01-22 1998-07-23 Merck & Co., Inc. Thrombin inhibitors
US5792779A (en) * 1997-02-19 1998-08-11 Merck & Co., Inc. Pyridinone thrombin inhibitors
JP2001518932A (en) 1997-03-24 2001-10-16 メルク エンド カンパニー インコーポレーテッド Thrombin inhibitors
US5866573A (en) * 1997-04-21 1999-02-02 Merck & Co., Inc. Pyrazinone thrombin inhibitors
IL123986A (en) 1997-04-24 2011-10-31 Organon Nv Serine protease inhibiting antithrombotic agents and pharmaceutical compositions comprising them
ES2218827T3 (en) 1997-05-02 2004-11-16 Akzo Nobel N.V. INHIBITORS OF SERINA PROTEASA.
ES2241151T3 (en) 1997-06-26 2005-10-16 Eli Lilly And Company ANTITROMBOTIC AGENTS.
EP0999834B1 (en) 1997-06-26 2005-10-12 Eli Lilly And Company Antithrombotic agents
IL133621A0 (en) 1997-06-26 2001-04-30 Lilly Co Eli Antithrombotic agents
CA2301520A1 (en) 1997-09-05 1999-03-11 Merck & Co., Inc. Pyrazinone thrombin inhibitors
PL340560A1 (en) 1997-11-26 2001-02-12 Dimensional Pharmaceuticals 3 Heteroaryl aminoguanidines and alkoxyguanidines and their application as protease inhibitors
WO1999026920A1 (en) 1997-11-26 1999-06-03 Corvas International, Inc. Substituted 3-amino-2-hydroxyphenylacetamide derivatives as enzyme inhibitors (ii)
PT1049703E (en) 1998-01-20 2003-06-30 Warner Lambert Co N-2- (5-BENZYLOXYCARBONYLAMINO-6-OXO-2- (4-FLUOROPHENYL) -1,6-DIHYDRO-1-PYRIMIDINYL) ACETOXYL-ASPARTIC ACID AS INHIBITOR OF THE INVENTION INTERLEUCINA-1BETA IN VIVO
AU2881199A (en) 1998-02-26 1999-09-15 Neurogen Corporation Substituted 1,4-dihydro-4-oxonicotinic carboxamides: gaba brain receptor ligands
GB9806102D0 (en) 1998-03-20 1998-05-20 Merck Sharp & Dohme Therapeutic agents
JP2002515434A (en) 1998-05-19 2002-05-28 メルク エンド カムパニー インコーポレーテッド Pyrazinone thrombin inhibitors
CA2333040A1 (en) 1998-05-26 1999-12-02 Merck & Co., Inc. Imidazopyridine thrombin inhibitors
KR20010078725A (en) 1998-06-03 2001-08-21 존 더블류. 갈루치 2세 Peptoid and Nonpeptoid Containing Alpha-Keto Oxadiazoles as Serine Protease Inhibitors
DE69926884T2 (en) 1998-06-11 2006-06-14 Johnson & Johnson Pharm Res PYRAZINE PROTEASE INHIBITORS
ATE253076T1 (en) 1998-08-14 2003-11-15 Pfizer ANTITHROMBOTIC DRUGS
WO2000018762A1 (en) 1998-09-28 2000-04-06 Merck & Co., Inc. Thrombin inhibitors
CA2348734A1 (en) 1998-10-30 2000-05-11 Merck & Co., Inc. Thrombin inhibitors
AU752186B2 (en) 1998-10-30 2002-09-12 Merck & Co., Inc. Thrombin inhibitors
DE19851421A1 (en) 1998-11-07 2000-05-11 Boehringer Ingelheim Pharma New pyrimidines, their production and use
FR2786482B1 (en) 1998-11-27 2002-08-09 Synthelabo NOVEL 2-PYRIDONE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION
AU2381600A (en) 1998-12-23 2000-07-31 Du Pont Pharmaceuticals Company Thrombin or factor xa inhibitors
EP1178971A1 (en) 1999-05-19 2002-02-13 Pharmacia Corporation Substituted polycyclic aryl and heteroaryl uracils as anticoagulative agents
WO2000069826A1 (en) 1999-05-19 2000-11-23 Pharmacia Corporation Substituted polycyclic aryl and heteroaryl pyridones useful for selective inhibition of the coagulation cascade
AU771718B2 (en) 1999-05-19 2004-04-01 Pharmacia Corporation Substituted polycyclic aryl and heteroaryl pyrymidinones useful as anticoagulants
AU2001249870A1 (en) 2000-04-05 2001-10-23 Pharmacia Corporation Polycyclic aryl and heteroaryl substituted 4-pyrones useful for selective inhibition of the coagulation cascade

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