AU4797300A - Substituted polycyclic aryl and heteroaryl pyridones useful for selective inhibition of the coagulation cascade - Google Patents

Substituted polycyclic aryl and heteroaryl pyridones useful for selective inhibition of the coagulation cascade Download PDF

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AU4797300A
AU4797300A AU47973/00A AU4797300A AU4797300A AU 4797300 A AU4797300 A AU 4797300A AU 47973/00 A AU47973/00 A AU 47973/00A AU 4797300 A AU4797300 A AU 4797300A AU 4797300 A AU4797300 A AU 4797300A
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hydrido
amino
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hydroxy
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Ashton T. Ii Hamme
John J. Parlow
Melvin L. Rueppel
Michael S. South
Qingpeng Zeng
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Pharmacia LLC
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Monsanto Co
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
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    • 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
    • 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
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/76—Nitrogen atoms to which a second hetero atom is attached
    • C07D213/77—Hydrazine radicals
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    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/38—Nitrogen atoms
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    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pyridine Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
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Description

WO 00/69826 PCT/US00/08220 Substituted Polycyclic Aryl and Heteroaryl Pyridones Useful for Selective Inhibition of the Coagulation Cascade Field of the Invention 5 This invention is in the field of anticoagulant therapy, and specifically relates to compounds, compositions and methods for preventing and treating thrombotic conditions such as coronary artery and cerebrovascular disease. More particularly, the invention relates to substituted polycyclic aryl and heteroaryl pyridone compounds that inhibit serine proteases of the coagulation 10 cascade. Background of the Invention Physiological systems control the fluidity of blood in mammals [Majerus, P. W. et al: Anticoagulant, Thrombolytic, and Antiplplatelet Drugs. 15 In Hardman, J. G. and Limbird, L. E., editors: Goodman & Gilman's The Pharmacological Basis of Therapeutics. 9th edition. New York, McGraw-Hill Book Co., 1996, pp. 1341-1343]. Blood must remain fluid within the vascular systems and yet be able to undergo hemostasis, cessation of blood loss from a damaged vessel, quickly. Hemostasis or clotting begins when 20 platelets first adhere to macromolecules in subendothelian regions of an injured and/or damaged vessels. These platelets aggregate to form the primary hemostatic plug and stimulate local activation of plasma coagulation factors leading to generation of a fibrin clot that reinforces the aggregated platelets. Plasma coagulation factors include factors II, V, VII, VIII, IX, X, XI, 25 and XII; these are also called protease zymogens. These coagulation factors or protease zymogens are activated by serine proteases leading to coagulation in a so called "coagulation cascade" or chain reaction [Handin, R. I.: Bleeding and Thrombosis. In Wilson, J., et al. editors: Harrison's Principles of Internal Medicine. 12th Edition, New York, McGraw-Hill Book Co., 1 9 9 1,p.
3 5 0]. 30 Coagulation or clotting occurs in two ways through different pathways. An intrinsic or contact pathway leads from XII to XIIa to XIa to IXa and to the conversion of X to Xa. Xa with factor Va converts prothrombin (II) to thrombin (IIa) leading to conversion of fibrinogen to fibrin. Polymerization of fibrin leads to a fibrin clot. An extrinsic pathway is initiated by the conversion 35 of coagulation factor VII to VIIa by Xa. The presence of Tissue Factor and WO 00/69826 PCT/US00/08220 VIIa accelerates formation of Xa in the presence of calcium ion and phospholipids. Formation of Xa leads to thrombin, fibrin, and a fibrin clot as described above. The presence of one or more of these many different coagulation factors and two distinct pathways of clotting could enable the 5 efficacious, selective control and better understanding of parts of the coagulation or clotting process. While clotting as a result of an injury to a blood vessel is a critical physiological process for mammals such as man, clotting can also lead to disease states. A pathological process called thrombosis results when platelet 10 aggregation and/or a fibrin clot blocks (i.e., occludes) a blood vessel. Arterial thrombosis may result in ischemic necrosis of the tissue supplied by the artery. When the thrombosis occurs in a coronary artery, a myocardial infarction or heart attack can result. A thrombosis occurring in a vein may cause tissues drained by the vein to become edematous and inflamed. Thrombosis of a deep 15 vein may be complicated by a pulmonary embolism. Preventing or treating clots in a blood vessel may be therapeutically useful by inhibiting formation of blood platelet aggregates, inhibiting formation of fibrin, inhibiting thrombus formation, inhibiting embolus formation, and for treating or preventing unstable angina, refractory angina, myocardial infarction, transient ischemic 20 attacks, atrial fibrillation, thrombotic stroke, embolic stroke, deep vein thrombosis, disseminated intravascular coagulation, ocular build up of fibrin, and reocclusion or restenosis of recanalized vessels. There have been several reports of non-peptidic and peptidic pyridone compounds that act as an inhibitor of a coagulation factor present in the 25 coagulation cascade or clotting process. In PCT Patent Application WO 98/47876, Van Boeckel et al. describe peptidic 6-alkylpyridones and 2 alkylpyrimidinones as anti-thrombotic compounds. In PCT Patent Application WO 98/16547, Zhu and Scarborough describe 3-(N-heterocyclylamino)-4,5,6 substituted-pyridonylacetamides and 2,4-substituted-5-(N-heterocyclylamino) 30 pyrimidinonyl-acetamides containing amide substituents and having activity against mammalian factor Xa. In US Patent 5,656,645, Tamura et al. describe 4,5,6-substituted-3-aminopyridonyl-acetamides, 1,6-substituted-5 aminouracinylacetamides, and 2,4-substituted-5-aminopyrimidinonyl acetamides containing amide substituents having a formyl function and having 35 activity against thrombin. In US Patent 5,658,930, Tamura et al. again 2 WO 00/69826 PCT/US00/08220 describe 4 ,5, 6 -substituted-3-aminopyridonyl-acetamides, 1,6-substituted-5 aminouracinylacetamides, and 2,4-substituted-5-aminopyrimidinonyl acetamides containing amide substituents having a formyl function and having activity against thrombin. In PCT Patent Applications 96/18644 and 97/46207, 5 Tamura et al. further describe 4,5,6-substituted-3-aminopyridonylacetamides, 1,6-substituted-5-aminouracinyl-acetamides, and 2,4-substituted-5-amino pyrimidinonylacetamides containing amide substituents having a formyl function and having activity against thrombin. In PCT Patent Application WO 98/09949, Suzuki et al. describe 2-heterocyclylacetamido derivatives of 1,2 10 diketones and report that they inhibit proteases, especially chymase inhibitors. In US Patent 5,668,289, Sanderson et al. describe 6-alkyl, 6-cycloalkyl, and 6-trifluoromethyl 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 pyridones unsubstituted at 15 the 4 and 5 positions and reported to inhibit thrombin. In US Patent 5,792,779, Sanderson et al. describe substituted 4,6-alkyl, 4,6-cycloalkyl, and 4,6-trifluoromethyl 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 pyridones having 20 utility as thrombin inhibitors. In US Patent 5,869,487, Coburn et al. describe pyrido[3,4-B]pyrazines containing a fused 6-methylpyridone functionality and having utility as thrombin inhibitors. 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 25 Application WO 98/17274, Coburn et al. disclose substituted 3,4-diamino-6 methylpyridones having utility as human thrombin inhibitors. In PCT Patent Application WO 98/42342, Isaacs et al. describe additional 6-alkyl, cycloalkyl, and trifluoromethyl substituted pyridones and pyrazinones reported to inhibit human thrombin. 30 Summary of the Invention It is an object of the present invention to provide compounds that are beneficial in anticoagulant therapy and that have a general structure: 3 WO 00/69826 PCT/US00/08220 R
X
o
R
2 BA eN K E°y J Formula (I). It is another object of the present invention to provide methods for preventing and treating thrombotic conditions, such as coronary artery disease, 5 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. 10 Description of the Invention The present invention relates to a class of compounds comprising Substituted Polycyclic Aryl and Heteroaryl Pyridones, which are beneficial in anticoagulant therapy for the treatment and prevention of a variety of 15 thrombotic conditions including coronary artery and cerebrovascular disease, as given in Formula (I): R X0 R2 B N K E o J (I) or a pharmaceutically acceptable salt thereof, wherein; J is selected from the group consisting of 0 and S; 4 WO 00/69826 PCT/US00/08220 J is optionally selected from the group consisting of CH-R 6 and N-R 60 wherein R is a linear spacer moiety having a chain length of 1 to 4 atoms linked to the point of bonding of a substituent selected from the group 4a 4b 39 40 5 14 15 consisting of R , R , R , R , R , R , and R to form a heterocyclyl 5 ring having 5 through 8 contiguous members; B is formula (V):
R
3 4
R
3 3 K 1
R-
3 5 12 R 32 D 1 D R 3 6 (V) 1 2 1 2 1 wherein D , D , , 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 12 1 10 than one is a covalent bond, no more than one of D , D 2 , j, J 2 and K is O, 1 2 12 1 1 21 2 no more than one of D, D 2 , , J2 and K is S, one of D D2 ,1 ,2 and 1 12 1 2 1 K must be a covalent bond when two of D ,D , D 2 , J and K are O and S, 1 2 12 1 and no more than four of D 1 , D 2 , J1 , J and K are N with the proviso that 32 33 34 35 36 R , R , R , R , and R are each independently selected to maintain the 15 tetravalent nature of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen; 9 10 11 12 13 16 17 18 19 32 33 34
R
9 ,
RIO
,
R
11,
R
12 ,
R
13 ,
R
16 ,
RI
7 ,
R
18 ,
R
19 ,
R
3 2 ,
R
3 3 ,
R
3 4
R
3 5 , and R 36 are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, dialkylsulfonium, 20 trialkylphosphonium, dialkylsulfoniumalkyl, carboxy, heteroaralkylthio, heteroaralkoxy, cycloalkylamino, acylalkyl, acylalkoxy, aryloylalkoxy, 5 WO 00/69826 PCT/US00/08220 heterocyclyloxy, aralkylaryl, aralkyl, aralkenyl, aralkynyl, heterocyclyl, perhaloaralkyl, aralkylsulfonyl, aralkylsulfonylalkyl, aralkylsulfinyl, aralkylsulfinylalkyl, halocycloalkyl, halocycloalkenyl, cycloalkylsulfinyl, cycloalkylsulfinylalkyl, cycloalkylsulfonyl, cycloalkylsulfonylalkyl, 5 heteroarylamino, N-heteroarylamino-N-alkylamino, heteroarylaminoalkyl, haloalkylthio, alkanoyloxy, alkoxy, alkoxyalkyl, haloalkoxylalkyl, heteroaralkoxy, cycloalkoxy, cycloalkenyloxy, cycloalkoxyalkyl, cycloalkylalkoxy, cycloalkenyloxyalkyl, cycloalkylenedioxy, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxy, halocycloalkenyloxyalkyl, 10 hydroxy, amino, alkoxyamino, thio, nitro, lower alkylamino, alkylthio, alkylthioalkyl, arylamino, aralkylamino, arylthio, arylthioalkyl, heteroaralkoxyalkyl, alkylsulfinyl, alkylsulfinylalkyl, arylsulfinylalkyl, arylsulfonylalkyl, heteroarylsulfinylalkyl, heteroarylsulfonylalkyl, alkylsulfonyl, alkylsulfonylalkyl, haloalkylsulfinylalkyl, 15 haloalkylsulfonylalkyl, alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, monoarylamidosulfonyl, arylsulfonamido, diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl, arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, heterocyclylsulfonyl, heterocyclylthio, alkanoyl, alkenoyl, 20 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, alkylenylamino, hydoxyheteroaralkyl, 25 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, carboxy, 30 carboaralkoxy, carboxamido, carboxamidoalkyl, cyano, carbohaloalkoxy, phosphono, phosphonoalkyl, diaralkoxyphosphono, and diaralkoxyphosphonoalkyl; 6 WO 00/69826 PCT/US00/08220 16 19 32 33 34 35 36
R
16 , R 19 , R 3 2 , R 3 3 , R 3 4 , R 3 5 , and R 3 6 are independently optionally Qb with the proviso that no more than one of R 16 and R 19 is Qb at the same time and that Qb is Qbe R32 and R 3 3 , R 3 3 and R 3 4 ,
R
34 and R 3 5 , and R 3 5 and R36 are 5 independently optionally selected to form a spacer pair wherein a spacer pair is taken together to form a linear moiety having from 3 through 6 contiguous atoms connecting the points of bonding of said spacer pair members to form a ring selected from the group consisting of a cycloalkenyl ring having 5 through 8 contiguous members, a partially saturated heterocyclyl ring having 5 through 10 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 3 consisting of spacer pairs R32 and R 3 3 , R 3 3 and R 34 , R 34 and R35, and R 3 5 and R 3 6 can be used at the same time; 9 10 10 11 11 12 12 13 R and R 10 , R 10 and R 11 , R and R 12 , and R 2 and R 3 are 15 independently optionally selected to form a spacer pair wherein a spacer pair is taken together to form a linear moiety having from 3 through 6 contiguous atoms connecting the points of bonding of said spacer pair members to form a ring selected from the group consisting of a cycloalkenyl ring having 5 through 8 contiguous members, a partially saturated heterocyclyl ring having 5 through 20 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 , R10 and R 11, R and R 2, and R 12 and R 13 can be used at the same time; B is optionally selected from the group consisting of hydrido, 25 trialkylsilyl, C2-C8 alkyl, C3-C8 alkylenyl, C3-C8 alkenyl, C3-C8 alkynyl, C2-C8 haloalkyl, and C3-C8 haloalkenyl wherein each member of group B is optionally substituted at any carbon up to and including 6 atoms from the point 7 WO 00/69826 PCT/US00/08220 of attachment of B to A with one or more of the group consisting of R 32,
R
33 34 35 36 R34, R35, and R36; B is optionally selected from the group consisting of C3-C15 cycloalkyl, C5-C10 cycloalkenyl, C4-C12 saturated heterocyclyl, and C4-C9 5 partially saturated heterocyclyl, wherein each ring carbon is optionally substituted with R 33 , a ring carbon other than the ring carbon at the point of attachment of B to A is optionally substituted with oxo provided that no more than one ring carbon is substituted by oxo at the same time, ring carbons and a nitrogen adjacent to the carbon atom at the point of attachment are optionally 10 substituted with R 9 or R 13 , a ring carbon or nitrogen adjacent to the R 9 position and two atoms from the point of attachment is optionally substituted with R 10 , a ring carbon or nitrogen adjacent to the R 13 position and two atoms 12 from the point of attachment is optionally substituted with R 12 , a ring carbon or nitrogen three atoms from the point of attachment and adjacent to the R10 11 15 position is optionally substituted with R 11 , a ring carbon or nitrogen three atoms from the point of attachment and adjacent to the R 12 position is optionally substituted with R 33 , and a ring carbon or nitrogen four atoms from the point of attachment and adjacent to the R 11 and R 33 positions is optionally substituted with R34 20 A is selected from the group consisting of single covalent bond, (W 7)rr-(CH(R15))pa and (CH(R15 ))pa-(W 7)rr wherein rr is an integer selected from 0 through 1, pa is an integer selected from 0 through 6, and W 7 is selected from the group consisting of O, S, C(0), C(S), C(0)S, C(S)O, C(0)N(R7), C(S)N(R7), (R7)NC(0), (R7)NC(S), S(0), S(0) 2 , 25 S(0) 2 N(R7), (R7)NS(0) 2 , P(0)(R ), N(R7)P(0)(R ), P(0)(R )N(R7), 8 WO 00/69826 PCT/US00/08220 C(NR7)N(R7), (R )NC(NR7), (R )NC(NR7)NR 7 , and N(R 7 ) with the proviso that no more than one of the group consisting of rr and pa can be 0 at the same time; R7and R are independently selected from the group consisting of 5 hydrido, hydroxy, alkyl, acyl, aroyl, heteroaroyl, and alkoxyalkyl; 14 15 37 38
R
14 , R 15 , R 3 7 , and R 3 8 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, 10 halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxyalkyl, carboxy, carboxyalkyl, carboalkoxy, carboxamide, and carboxamidoalkyl; R14 and R 3 8 can be independently selected from the group consisting of acyl, aroyl, and heteroaroyl with the proviso that acyl is selected from other than formyl and 2-oxoacyl; 15 T is selected from the group consisting of NR 5 , O, C(0), C(S), S, S(0), S(0) 2 , ON(R 5), P(0)(R ), and CR39R 40; R is selected from the group consisting of hydrido, hydroxy, amino, alkyl, alkoxy, alkoxyalkyl, haloalkyl, acyl, aroyl, and heteroaroyl; 39 40 R and R 4 0 are independently selected from the group consisting of 20 hydrido, hydroxy, halo, cyano, hydroxyalkyl, acyl, aroyl, heteroaroyl, acylamido, alkoxy, alkyl, alkoxyalkyl, haloalkyl, haloalkoxy, haloalkoxyalkyl, alkylsulfonyl, haloalkylsulfonyl, carboxy, carboxyalkyl, carboalkoxy, carboxamide, and carboxamidoalkyl;
R
1 , R 2 and Xo are independently selected from the group consisting of 25 Zo-Q, hydrido, alkyl, alkenyl, and halo;
R
1 and Xo are independently optionally selected from the group consisting of amino, aminoalkyl, alkylamino, amidino, guanidino, hydroxy, hydroxyamino, alkoxy, hydroxyalkyl, alkoxyamino, thiol, alkylthio, dialkylsulfonium, trialkylphosphonium, dialkylsulfoniumalkyl, 9 WO 00/69826 PCT/US00/08220 heteroarylamino, nitro, arylamino, aralkylamino, alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, haloalkanoyl, hydroxyhaloalkyl, cyano, and phosphono; Xo and R 1 and R 1 and R 2 , with the proviso that no more than one of 5 the group consisting of spacer pair X 0 and R 1 and spacer pair R and R 2 is be used at the same time, are optionally selected to be -W=X-Y=Z- wherein W=X-Y=Z- forms a ring selected from the group consisting of a heteroaryl ring having from 5 through 6 contiguous members and an aryl; W, X, Y, and Z are independently selected from the group consisting 10 of C(R9), C(R10), C(R 1 1 ), C(R 12), N, N(R10), O, S and a covalent bond with the provisos that W, X, Y, and Z can be independently selected to be a covalent bond when one of W, X, Y, and Z is selected from the group consisting of N, N(R10), O, and S, no more than one of W, X, Y, and Z can be selected from the group consisting of O and S, and no more than three of 15 W, X, Y, and Z can be selected from the group consisting of N and N(R10); Xo and R 1 and RI and R 2 spacer pairs are independently optionally selected to be taken together to form a spacer pair wherein the spacer pair forms a linear moiety having from 3 through 6 contiguous atoms connecting the points of bonding of said spacer pair members to form a ring selected from the 20 group consisting of a cycloalkenyl ring having from 5 through 8 contiguous members and a partially saturated heterocyclyl ring having from 5 through 8 contiguous members, wherein said spacer pair is optionally substituted with one or more of the group consisting of R9 , R10, R11, R 2, and R13 and with the proviso that no more than one of the group consisting of spacer pair X 0 and 25 R 1 and spacer pair RI and R 2 is present at the same time; Zo is selected from the group consisting of covalent single bond, (CR41 R 42)q wherein q is an integer selected from 1 through 6, (CH(R41)) o q 0 0 Wo-(CH(R 42)) wherein g and p are integers independently selected from 0 10 WO 00/69826 PCT/US00/08220 through 3 and Wo is selected from the group consisting of O, S, C(O), C(S), 41 41 41 C(0)O, C(S)O, C(0)S, C(S)S, C(0)N(R 41), (R 41)NC(0), C(S)N(R 41), 41 41 41 41 41 (R 41)NC(S), OC(O)N(R 41), (R 41)NC(0)O, SC(S)N(R 41), (R 41)NC(S)S, 41 41 41 41 SC(O)N(R ), (R 4)NC(0)S, OC(S)N(R 1), (R 41)NC(S)O, 42 41 41 42 42 41 5 N(R 2)C(0)N(R 4), (R )NC(0)N(R ), N(R )C(S)N(R ), 41 42 41 41 (R )NC(S)N(R 4), S(0), S(0)2, S(0) 2 N(R ), N(R 41)S(0)2, Se, Se(0), Se(0) 2 , Se(0) 2 N(R41), N(R41)Se(0) 2 , P(0)(R ), N(R7)P(O)(R ),
P(O)(R
8
)N(R
7 ), N(R 4 1 ), ON(R 4 1 ), and SiR 2 8
R
2 9 , and (CH(R41))e-W22 (CH(R42))h wherein e and h are integers independently selected from 0 10 through 2 and 2 2 is selected from the group consisting of CR 4 1
=CR
4 2 41 42 CR4 R =C; vinylidene), ethynylidene (C-C; 1,2-ethynyl), 1,2-cyclopropyl, 1,2-cyclobutyl, 1,2-cyclohexyl, 1,3-cyclohexyl, 1,2-cyclopentyl, 1,3 cyclopentyl, 2,3-morpholinyl, 2,4-morpholinyl, 2,6-morpholinyl, 3,4 morpholinyl, 3,5-morpholinyl, 1,2-piperazinyl, 1,3-piperazinyl, 2,3 15 piperazinyl, 2,6-piperazinyl, 1,2-piperidinyl, 1,3-piperidinyl, 2,3-piperidinyl, 2,4-piperidinyl, 2,6-piperidinyl, 3,4-piperidinyl, 1,2-pyrrolidinyl, 1,3 pyrrolidinyl, 2,3-pyrrolidinyl, 2,4-pyrrolidinyl, 2,5-pyrrolidinyl, 3,4 pyrrolidinyl, 2,3-tetrahydrofuranyl, 2,4-tetrahydrofuranyl, 2,5 41 tetrahydrofuranyl, and 3,4-tetrahydrofuranyl, with the provisos that R and 42 20 R 4 2 are selected from other than halo and cyano when directly bonded to N and Zo is directly bonded to the pyridone ring; 41 42 R and R 4 2 are independently selected from the group consisting of amidino, hydroxyamino, hydrido, hydroxy, amino, halo, cyano, aryloxy, hydroxyalkyl, acyl, aroyl, heteroaroyl, heteroaryloxyalkyl, alkoxy, alkyl, aryl, 25 aralkyl, aryloxyalkyl, aralkoxyalkylalkoxy, alkoxyalkyl, heteroaryloxyalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, 11 WO 00/69826 PCT/US00/08220 haloalkyl, haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxyalkyl, saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl, heteroaralkyl, heteroarylthioalkyl, 5 heteroaralkylthioalkyl, alkylsulfonyl, haloalkylsulfonyl, arylsulfonyl, arylsulfonylalkyl, aralkylsulfonyl, cycloalkylsulfonyl, cycloalkylsufonylalkyl, heteroarylsulfonylalkyl, heteroarylsulfonyl, and aralkylsulfonylalkyl; Q is formula (II):
R
1 1 R1 K 2 R R9, D D R13 R' R3 (II) 1 2 12 1 10 wherein D , D 2 , j , J2 and K are independently selected from the group consisting of C, N, 0, S and a covalent bond with the provisos that no more 1 2 12 1 than one is a covalent bond, no more than one of D , D 2 , J1, J2 and K is O, 1 21 2 1 1 2 12 no more than one of D, D 2 , 1, J2 and K is S, one of D D , 1, J2 and 1 1 2 12 1 K must be a covalent bond when two of D , D 2 , J , J2 and K are O and S, 1 2 12 1 15 and no more than four of D , D 2 , J , J2 and K are N, with the proviso that 9 10 11 12 13
R
9 , R10, R 1 1 , R12, and R 13 are each independently selected to maintain the tetravalent nature of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen; Q is optionally selected from formula (III): 12 WO 00/69826 PCT/US00/08220 10 R11 34 R 9- D3 J 0% AR I D R1 2 (III) wherein D 3 , D 4 , J3, and J are independently selected from the group consisting of C, N, O, and S, no more than one of D 3 , D 4 , J 3, and J4 is 0, no 3 43 4 1 2 more than one of D 3 , D 4 , and J is S, and no more than three of D , D 1 2 9 10 11 12 5 J, and J are N with the proviso that R 9 , R 10 , R 1 , and R 12 are each independently selected to maintain the tetravalent nature of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen; Q is optionally selected from the group consisting of hydrido, alkyl, 10 alkoxy, alkylamino, alkylthio, haloalkylthio, alkenyl, alkynyl, saturated heterocyclyl, partially saturated heterocyclyl, acyl, aroyl, heteroaroyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkylalkenyl, haloalkyl, haloalkoxy, haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxyalkyl, and 15 halocycloalkenyloxyalkyl with the proviso that Z is selected from other than a single covalent bond when Q is hydrido; K is (CR4a R4b)n wherein n is an integer selected from 1 through 2; 4a 4b R and R 4 b are independently selected from the group consisting of halo, hydrido, hydroxy, cyano, hydroxyalkyl, alkyl, alkenyl, alkoxyalkyl, 20 aralkyl, heteroaralkyl, alkylthioalkyl, haloalkyl, haloalkenyl, and cyanoalkyl; Sis E l , when K is (CR4aR4b)n, wherein E is selected from the group consisting of a covalent single bond, O, S, C(0), C(S), C(0)O, C(S)O, C(0)S, C(S)S, C(0)N(R7), (R7)NC(0), C(S)N(R7), (R7)NC(S), 13 WO 00/69826 PCT/US00/08220 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 ), (R7)NC(S)O, N(R )C(O)N(R7), (R7)NC(O)N(R ), N(R )C(S)N(R7), (R7)NC(S)N(R ), S(0), S(0)2, S(0)2N(R7), N(R7)S(0)2 , S(0)2N(R7)C(O), C(O)N(R7)S(0)2 , P(O)(R 8), 5 N(R7)P(0)(R ), P(0)(R )N(R7), N(R7), ON(R7), CR =CR 4 b 4a 4b ethynylidene (C-C; 1,2-ethynyl), and C=CRa R4b; K is optionally (CH(R14))j-T whereinj is selected from a integer from 0 through 2 and T is selected from the group consisting of single covalent bond, O, S, and N(R 7 ) with the proviso that (CH(R 14)) is bonded to the 10 pyridone ring; E is optionally E 2 , when K is (CH(R14))j-T, wherein E 2 is selected from the group consisting of a covalent single bond, C(0), C(S), C(0)O, C(S)O, C(0)S, C(S)S, C(0)N(R7), (R7)NC(0), C(S)N(R7), (R7)NC(S), (R7)NC(0)O, (R7)NC(S)S, (R7)NC(0)S, (R7)NC(S)O, N(R )C(O)N(R7), 15 (R7)NC(0)N(R ), N(R )C(S)N(R7), (R7)NC(S)N(R ), S(0), S(0) 2 , S(0) 2 N(R7), N(R7)S(O)2, S(0) 2 N(H)C(0), C(0)N(H)S(0) 2 , P(0)(R ), N(R7)P(0)(R ), P(0)(R )N(R7), and N(R7); K is optionally G-(CH(R15 ))k wherein k is selected from an integer from 1 through 2 and G is selected from the group consisting of O, S, and 20 N(R 7 ) with the proviso that R 15 is other than hydroxy, cyano, halo, amino, alkylamino, dialkylamino, and sulfhydryl when k is 1;
E
0 is optionally E 3 when K is G-(CH(R15))k, wherein E 3 is selected from the group consisting of a covalent single bond, O, S, C(O), C(S), 14 WO 00/69826 PCT/US00/08220 C(O)O, C(S)O, C(O)S, C(S)S, C(O)N(R7), (R7)NC(O), C(S)N(R7), (R7)NC(S), OC(O)N(R7), (R7)NC(O)O, SC(S)N(R7), (R7)NC(S)S, SC(O)N(R7), (R7)NC(O)S, OC(S)N(R ), (R7)NC(S)O, N(R )C(O)N(R7), (R7)NC(O)N(R ), N(R )C(S)N(R7), (R7)NC(S)N(R ), S(O), S(O) 2 , 5 S(O) 2 N(R7), N(R7)S(O) 2 , P(O)(R ), N(R7)P(O)(R ), P(O)(R )N(R7), N(R7), ON(R ), CR =CR4b, ethynylidene (CaC; 1,2-ethynyl), and C=CR aR4b; YO is formula (IV): S R1 7 s 1 8 R 6R Qb Qb (IV) 10 wherein D 5 , D 6 , J 5, and J6 are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more than one is a covalent bond, K 2 is independently selected from the group N+ m e~oe 5 6 5 6 consisting of C and N, no more than one of DS, D , J, and J is O, no more 5 65 6 5 65 6 than one of DS, D , J and J6 is S, one of D , D 6 , and J must be a 15 covalent bond when two of D , D 6 , J5, and J are O and S, no more than 5 65 6 2 + three of D , D 6 , and J is N when K is N , and no more than four of 5 65 6 2 16 17 D, D 5, and J6 are N when K 2 is carbon with the provisos that R 16 , R 17 18 19
R
18 , and R19 are each independently selected to maintain the tetravalent nature 15 WO 00/69826 PCT/US00/08220 of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen;
R
16 and R 17 are optionally independently taken together to form a linear moiety spacer having from 3 through 6 contiguous atoms connected to 5 form a ring selected from the group consisting of a cycloalkenyl ring having from 5 through 8 contiguous members, a partially saturated heterocyclyl ring having from 5 through 8 contiguous members, a heteroaryl having from 5 through 6 contiguous members, and an aryl; Qb is selected from the group consisting of NR20R21 10 NR20R21R22, oxy, alkyl, aminoalkylenyl, alkylamino, dialkylamino, be be 20 dialkylsulfoniumalkyl, acylamino and Qbe, wherein Qbe is hydrido and R 2 0 21 22
R
2 1 , and R 22 are independently selected from the group consisting of hydrido, amino, alkyl, hydroxy, alkoxy, aminoalkylenyl,alkylamino, dialkylamino, and 20 21 22. hydroxyalkyl with the provisos that no more than one of R 2 0 , R 2 1 , and R 2 2 is 15 hydroxy, alkoxy, alkylamino, amino, and dialkylamino at the same time and that R 2 0 , R 2 1 , and R 2 2 must be other than be hydroxy, alkoxy, alkylamino, amino, and dialkylamino when K 2 is N ; 20 21 20 22 21 22
R
2 0 and R 2 1 , R 20 and R 2 2 , and R 2 1 and R 2 2 are independently optionally selected to form a spacer pair wherein a spacer pair is taken together 20 to form a linear moiety having from 4 through 7 contiguous atoms connecting the points of bonding of said spacer pair members to form a heterocyclyl ring having 5 through 8 contiguous members with the proviso that no more than 20 21 20 22 one of the group consisting of spacer pairs R 2 0 and R 2 1 , R 2 0 and R 2 2 , and
R
2 1 and R 22 is used at the same time; 25 Qb is optionally selected from the group consisting of N(R26)SO 2 N(R 23)(R24), N(R26)C(O)OR5 , N(R26)C(O)SR5 16 WO 00/69826 PCT/US00/08220 N(R26)C(S)OR5 and N(R26)C(S)SR5 with the proviso that no more than one 23 24 26 of R , R 2 4 , and R 26 is hydroxy, alkoxy, alkylamino, amino, and dialkylamino when two of the group consisting of R , R 2 4 , and R 2 6 are bonded to the same atom; 5 Qb is optionally selected from the group consisting of dialkylsulfonium, trialkylphosphonium, C(NR25)NR23R24 N(R26)C(NR25)N(R 23)(R24), N(R26)C(O)N(R 23)(R24), N(R26)C(S)N(R23)(R24), C(NR25)OR 5 , C(O)N(R26)C(NR25)N(R 23)(R24), C(S)N(R26)C(NR25)N(R23)(R24), 10 N(R26)N(R26)C(NR 25)N(R 23)(R24), ON(R26)C(NR 25)N(R 2)(R24), N(R26)N(R26)SO 2 N(R 23)(R24), C(NR25)SR5, C(O)NR R23R 24 , and 23 24 23 24 26 C(O)NR R 24 with the provisos that no more than one of R , R 2 4 , and R 26 can be hydroxy, alkoxy, alkylaminol, amino, or dialkylamino when two of the group consisting of R 2 3 , R 24 , and R 2 6 are bonded to the same atom and that 15 said Q group is bonded directly to a carbon atom; 23 24 25 26 R , R , R 2 5 , and R 26 are independently selected from the group consisting of hydrido, alkyl, hydroxy, alkoxy, aminoalkylenyl, alkylamino, dialkylamino, amino, and hydroxyalkyl; R23 and R 24 are optionally taken together to form a linear spacer moiety 20 having from 4 through 7 contiguous atoms connecting the points of bonding to form a heterocyclyl ring having 5 through 8 contiguous members; QS is selected from the group consisting of a single covalent bond, (CR37 R 38)b-(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 17 WO 00/69826 PCT/US00/08220 consisting of O, S, C(O), C(S), C(O)O, C(S)O, C(0)S, C(S)S, C(O)N(R 14 ), (R 14)NC(0), C(S)N(R 14), (R14)NC(S), OC(0)N(R14), SC(S)N(R 14), SC(0)N(R14), OC(S)N(RI4), N(R15)C(0)N(R14), (R14)NC(O)N(R5), N(R15)C(S)N(R14), (R 14)NC(S)N(R15), S(O), S(0) 2 , S(0) 2 N(R14), 5 N(R 14)S(0) 2 , P(O)(R ), N(R7)P(0)(R 8), P(O)(R )N(R7), N(R 14), ON(R14), (CH(R14))c- 1-(CH(R 15))d wherein c and d are integers independently selected from 1 through 4, and W 1 is selected from the group consisting of O, S, C(0), C(S), C(0)O, C(S)O, C(0)S, C(S)S, C(0)N(R14), (R14)NC(0), C(S)N(R14), (R14)NC(S), OC(0)N(R14), (R14)NC(0)O, 10 SC(S)N(R 14), (R14)NC(S)S, SC(0)N(R14), (R 14)NC(0)S, OC(S)N(R 14), (R14)NC(S)O, N(R15)C(0)N(R14), (R14)NC(0)N(R15), N(R15)C(S)N(R14), (R14)NC(S)N(R15), S(0), S(0)2, S(0) 2 N(R14), N(R 14)S(0)2, P(0)(R ), N(R7)P(0)(R ), P(0)(R )N(R7), N(R14),
ON(R
14 ), and (CH(R 14 ))e W2-(CH(R 15 ))h wherein e and h are integers 15 independently selected from 0 through 2 and W 2 2 is selected from the group 41 42 41 42 consisting of CR =CR , CR4 R 42=C; vinylidene), ethynylidene (CEC; 1,2-ethynyl), 1, 2 -cyclopropyl, 1,2-cyclobutyl, 1,2-cyclohexyl, 1,3 cyclohexyl, 1,2-cyclopentyl, 1,3-cyclopentyl, 2,3-morpholinyl, 2,4 morpholinyl, 2
,
6 -morpholinyl, 3,4-morpholinyl, 3,5-morpholinyl, 1,2 20 piperazinyl, 1, 3 -piperazinyl, 2,3-piperazinyl, 2,6-piperazinyl, 1,2-piperidinyl, 1,3-piperidinyl, 2
,
3 -piperidinyl, 2,4-piperidinyl, 2,6-piperidinyl, 3,4 piperidinyl, 1,2-pyrrolidinyl, 1,3-pyrrolidinyl, 2,3-pyrrolidinyl, 2,4 pyrrolidinyl, 2 ,5-pyrrolidinyl, 3,4-pyrrolidinyl, 2,3-tetrahydrofuranyl, 2,4 tetrahydrofuranyl, 2 ,5-tetrahydrofuranyl, and 3,4-tetrahydrofuranyl, with the 18 WO 00/69826 PCT/US00/08220 provisos that R 14 and R 15 are selected from other than halo and cyano when directly bonded to N and that (CR37 R 38)b , (CH(R14))c, (CH(R 14))e and are bonded to E; YO is optionally QbQSS wherein QSS is selected from the group 3738 5 consisting of (CR 3 7 R38 )f wherein f is an integer selected from I through 6, (CH(R14))cWl-(CH(R15))d wherein c and d are integers independently selected from 1 through 4, and W 1 is selected from the group consisting of W is selected from the group consisting of O, S, C(0), C(S), C(O)O, C(S)O, C(0)S, C(S)S, C(0)N(R14), (R14)NC(0), C(S)N(R14), (R14)NC(S), 10 OC(0)N(R14), (R14)NC(0)O, SC(S)N(R 14), (R 14)NC(S)S, SC(0)N(R14), (R 14)NC(0)S, OC(S)N(R 14), (R 14)NC(S)O, N(R15)C(0)N(R 14), (R 14)NC(0)N(R15), N(R15)C(S)N(R 14), (R14)NC(S)N(R15), S(0),
S(O)
2 , S(0) 2 N(R14), N(R14)S(O) 2 , P(0)(R ), N(R7)P(0)(R ), P(O)(R )N(R7), N(R 14 ), ON(R 14 ), and (CH(R 14))e-W2-(CH(R15))h 15 wherein e and h are integers independently selected from 0 through 2 and W 2 is selected from the group consisting of CR4a=CR4b, ethynylidene (C-C; 1,2 ethynyl), and C=CR4aR4b with the provisos that R14 and R 15 are selected from other than halo and cyano when directly bonded to N and that (CR37 R38)f, (CH(R14)) c, and (CH(R 14))e are bonded to E; 20 YO is optiionally QbQsss wherein QSSS is (CH(R 3 8 ))r-W 3 , r is an integer selected from 1 through 3, W 3 is selected from the group consisting of 1,1-cyclopropyl, 1, 2 -cyclopropyl, 1,1-cyclobutyl, 1,2-cyclobutyl, 1,2 19 WO 00/69826 PCT/US00/08220 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, 13-piperazinyl, 1,4 piperazinyl, 2 ,3-piperazinyl, 2,5-piperazinyl, 2,6-piperazinyl, 1,2-piperidinyl, 5 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 10 3,4-yl, 2H-pyran-2-one-4,5-yl, 4H-pyran-4-one-2,3-yl, 2,3 tetrahydrofuranyl, 2,4-tetrahydrofuranyl, 2,5-tetrahydrofuranyl, 3,4 tetrahydrofuranyl, 2,3-tetrahydropyranyl, 2,4-tetrahydropyranyl, 2,5 tetrahydropyranyl, 2,6-tetrahydropyranyl, 3,4-tetrahydropyranyl, and 3,5 tetrahydropyranyl, and each carbon and hyrido containing nitrogen member of 15 the ring of the W 3 other than the points of attachment is optionally substituted with one or more of the group consisting of R , R10, R 1 1 , and R 12 , with the proviso that (CH(R38))r is bonded to E and Qb is bonded to lowest numbered substituent position of each W 3 ; Y is optionally QbQ sssr wherein Qsssr is (CH(R 3 8 )).-W4, r is an 4 20 integer selected from 1 through 3, W is selected from the group consisting of 1,2-cyclobutyl, 1,2-cyclohexyl, 1,3-cyclohexyl, 1,4-cyclohexyl, 1,2 cyclopentyl, 1,3-cyclopentyl, 2,3-morpholinyl, 2,4-morpholinyl, 2,5 morpholinyl, 2,6-morpholinyl, 3,4-morpholinyl, 3,5-morpholinyl, 1,2 piperazinyl, 1,3-piperazinyl, 1,4-piperazinyl, 2,3-piperazinyl, 2,5-piperazinyl, 25 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, 30 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 20 WO 00/69826 PCT/US00/08220 tetrahydrofuranyl, 3,4-tetrahydrofuranyl, 2,3-tetrahydropyranyl, 2,4 tetrahydropyranyl, 2,5-tetrahydropyranyl, 2,6-tetrahydropyranyl, 3,4 tetrahydropyranyl, and 3 ,5-tetrahydropyranyl, and each carbon and hydrido 4 containing nitrogen member of the ring of the W other than the points of 5 attachment is optionally substituted with one or more of the group consisting of 9 10 11 12 38 0
R
9 , R 10 , Rl, and R 12 , with the provisos that (CH(R38))r is bonded to E and Qb is bonded to highest number substituent position of each W Yo is optionally Qb -Qssss wherein Qssss is (CH(R 3 8 ))r-W 5 , r is an integer selected from 1 through 3, W 5 is selected from the group consisting of 10 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 15 benzothiophenyl, 3,4-benzothiophenyl, 3,5-benzothiophenyl, 3,6 benzothiophenyl, 3, 7 -benzothiophenyl, 2,7-imidazo(1,2-a)pyridinyl, 3,4 imidazo(1,2-a)pyridinyl, 3,5-imidazo(1,2-a)pyridinyl, 3,6-imidazo(1,2 a)pyridinyl, 3,7-imidazo(1,2-a)pyridinyl, 2,4-indolyl, 2,5-indolyl, 2,6 indolyl, 2,7-indolyl, 3,4-indolyl, 3,5-indolyl, 3,6-indolyl, 3,7-indolyl, 1,4 20 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, 25 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 30 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 21 WO 00/69826 PCT/US00/08220 cinnolinyl, 3,6-cinnolinyl, 3,7-cinnolinyl, 3,8-cinnolinyl, 4,5-cinnolinyl, 4,6 cinnolinyl, 4,7-cinnolinyl, and 4,8-cinnolinyl, and each carbon and hydrido containing nitrogen member of the ring of the other than the points of attachment is optionally substituted with one or more of the group consisting of 9 10 11 12 b 5 R 9 , R10, R , and R 12 , with the proviso that Q is bonded to lowest number substituent position of each and that (CH(R38))r is bonded to E; Yo is optionally Qb Qssssr wherein Qssssr is (CH(R 3 8 ))r-W6, r is an integer selected from 1 through 3, W 6 is selected from the group consisting of 1,4-indenyl, 1,5-indenyl, 1,6-indenyl, 1,7-indenyl, 2,7-indenyl, 2,6-indenyl, 10 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 15 benzothiophenyl, 3,7-benzothiophenyl, 2,7-imidazo(1,2-a)pyridinyl, 3,4 imidazo(1,2-a)pyridinyl, 3,5-imidazo(1,2-a)pyridinyl, 3,6-imidazo(1,2 a)pyridinyl, 3,7-imidazo(1,2-a)pyridinyl, 2,4-indolyl, 2,5-indolyl, 2,6 indolyl, 2,7-indolyl, 3,4-indolyl, 3,5-indolyl, 3,6-indolyl, 3,7-indolyl, 1,4 isoindolyl, 1,5-isoindolyl, 1,6-isoindolyl, 2,4-isoindolyl, 2,5-isoindolyl, 2,6 20 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 25 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 30 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 22 WO 00/69826 PCT/US00/08220 cinnolinyl, 4, 7 -cinnolinyl, and 4,8-cinnolinyl, and each carbon and hydrido containing nitrogen member of the ring of the W 6 other than the points of attachment is optionally substituted with one or more of the group consisting of 9 10 11 12 b R9, R10, Rll, and R 2 , with the proviso that Q is bonded to highest number 6 38 0 5 substituent position of each W and that (CH(R38 ))r is bonded to E In another embodiment of compounds of Formula I or a pharmaceutically acceptable salt thereof, J is selected from the group consisting of O andS; B is formula (V):
R
3 4 3 3 K R 3 5 12 R32/D D" 3 G 10 (v) 1 2 12 1 wherein D
I
, D 2 , 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 12 1 than one is a covalent bond, no more than one of D
I
, D 2 , J 2 and K is O, 1 2 12 1 1 21 2 no more than one of D
I
, D 2 , ,2 and K is S, one of D D , , J2 and 1 1 2 12 1 15 K must be a covalent bond when two of D , D , J , J and K are O and S, 1 21 2 1 and no more than four ofD D , D 2 , J 2 and K are N; 9 10 11 12 13 16 17 18 19 32 33 34
R
9,R I , R1, R 2 R1, R , R , R , R9, R32, R33, R34 35 36
R
35 , and R 36 are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, dialkylsulfonium, 20 trialkylphosphonium, dialkylsulfoniumalkyl, carboxy, heteroaralkylthio, heteroaralkoxy, cycloalkylamino, acylalkyl, acylalkoxy, aryloylalkoxy, heterocyclyloxy, aralkylaryl, aralkyl, aralkenyl, aralkynyl, heterocyclyl, 23 WO 00/69826 PCT/US00/08220 perhaloaralkyl, aralkylsulfonyl, aralkylsulfonylalkyl, aralkylsulfinyl, aralkylsulfinylalkyl, halocycloalkyl, halocycloalkenyl, cycloalkylsulfinyl, cycloalkylsulfinylalkyl, cycloalkylsulfonyl, cycloalkylsulfonylalkyl, heteroarylamino, N-heteroarylamino-N-alkylamino, heteroarylaminoalkyl, 5 haloalkylthio, alkanoyloxy, alkoxy, alkoxyalkyl, haloalkoxylalkyl, heteroaralkoxy, cycloalkoxy, cycloalkenyloxy, cycloalkoxyalkyl, cycloalkylalkoxy, cycloalkenyloxyalkyl, cycloalkylenedioxy, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxy, halocycloalkenyloxyalkyl, hydroxy, amino, alkoxyamino, thio, nitro, lower alkylamino, alkylthio, 10 alkylthioalkyl, arylamino, aralkylamino, arylthio, arylthioalkyl, heteroaralkoxyalkyl, alkylsulfinyl, alkylsulfinylalkyl, arylsulfinylalkyl, arylsulfonylalkyl, heteroarylsulfinylalkyl, heteroarylsulfonylalkyl, alkylsulfonyl, alkylsulfonylalkyl, haloalkylsulfinylalkyl, haloalkylsulfonylalkyl, alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, 15 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, 20 alkynyl, alkenyloxy, alkenyloxyalky, alkylenedioxy, haloalkylenedioxy, cycloalkyl, cycloalkylalkanoyl, cycloalkenyl, lower cycloalkylalkyl, lower cycloalkenylalkyl, halo, haloalkyl, haloalkenyl, haloalkoxy, hydroxyhaloalkyl, hydroxyaralkyl, hydroxyalkyl, alkylenylamino, hydoxyheteroaralkyl, haloalkoxyalkyl, aryl, aralkyl, aryloxy, aralkoxy, aryloxyalkyl, saturated 25 heterocyclyl, partially saturated heterocyclyl, heteroaryl, heteroaryloxy, heteroaryloxyalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, carboxyalkyl, carboalkoxy, alkoxycarboxamido, alkylamidocarbonylamido, arylamidocarbonylamido, carboalkoxyalkyl, carboalkoxyalkenyl, carboxy, carboaralkoxy, carboxamido, carboxamidoalkyl, cyano, carbohaloalkoxy, 30 phosphono, phosphonoalkyl, diaralkoxyphosphono, and diaralkoxyphosphonoalkyl; 24 WO 00/69826 PCT/US00/08220 16 19 32 33 34 35 36 R 6 , R 19 , R 3 2 , R 3 3 , R 3 4 , R 3 5 , and R 3 6 are independently optionally Qb with the proviso that no more than one of R 16 and R 19 is Qb at the same time and that Qb is Qbe B is optionally selected from the group consisting of hydrido, 5 trialkylsilyl, C2-C8 alkyl, C3-C8 alkylenyl, C3-C8 alkenyl, C3-C8 alkynyl, C2-C8 haloalkyl, and C3-C8 haloalkenyl wherein each member of group B is optionally substituted at any carbon up to and including 6 atoms from the point of attachment of B to A with one or more of the group consisting of R 3 2 , R 3 3 R34 , R35 , and R36 10 B is optionally selected from the group consisting of C3-C12 cycloalkyl, C5-C 10 cycloalkenyl, and C4-C9 saturated heterocyclyl, wherein 33 each ring carbon is optionally substituted with R 33 , a ring carbon other than the ring carbon at the point of attachment of B to A is optionally substituted with oxo provided that no more than one ring carbon is substituted by oxo at 15 the same time, ring carbons and nitrogen adjacent to the carbon atom at the point of attachment are optionally substituted with R or R 13 , a ring carbon or 9 nitrogen adjacent to the R position and two atoms from the point of attachment 10 is optionally substituted with R 10 , a ring carbon or nitrogen adjacent to the
R
13 position and two atoms from the point of attachment is optionally 12 20 substituted with R 2 , a ring carbon or nitrogen three atoms from the point of 10 1 attaclunent and adjacent to the RI position is optionally substituted with R 11 a ring carbon or nitrogen three atoms from the point of attachment and adjacent to the R 12 position is optionally substituted with R 3 3 , and a ring carbon or nitrogen four atoms from the point of attachment and adjacent to the R 11 and 25 R 33 positions is optionally substituted with R34 25 WO 00/69826 PCT/US00/08220 A is selected from the group consisting of single covalent bond, (W 7)rr-(CH(R 15))pa and (CH(R 15))pa-(W 7)r r wherein rr is an integer selected from 0 through 1, pa is an integer selected from 0 through 6, and W 7 is selected from the group consisting of O, S, C(O), C(0)N(R ), C(S)N(R7), 5 (R7)NC(0), (R7)NC(S), and N(R 7 ) with the proviso that no more than one of the group consisting of rr and pa can be 0 at the same time;
R
7 and R are independently selected from the group consisting of hydrido, hydroxy, alkyl, and alkoxyalkyl; 14 15 37 38
R
14 , R 15 , R 37 , and R 3 8 are independently selected from the group 10 consisting of hydrido, hydroxy, halo, alkyl, alkoxyalkyl, haloalkyl, haloalkoxy, and haloalkoxyalkyl;
R
14 and R 3 8 can be independently selected from the group consisting of aroyl and heteroaroyl; T is selected from the group consisting of NR 5 , C(O), and S(0)2 15 R 5 is selected from the group consisting of hydrido, hydroxy, alkyl, and alkoxy;
R
3 9 and R 4 0 are independently selected from the group consisting of hydrido, hydroxy, halo, hydroxyalkyl, alkyl, alkoxyalkyl, haloalkyl, haloalkoxy, and haloalkoxyalkyl; 20 R 1 and X are independently selected from the group consisting of hydrido, alkyl, alkenyl, cyano, halo, haloalkyl, haloalkoxy, haloalkylthio, amino, aminoalkyl, alkylamino, amidino, guanidino, hydroxy, hydroxyamino, alkoxy, hydroxyalkyl, alkoxyamino, thiol, alkylthio, and phosphono; X and R 1 and R and R 2 , with the proviso that no more than one of 25 the group consisting of spacer pair X 0 and R 1 and spacer pair RI and R 2 is be used at the same time, are optionally selected to be -W=X-Y=Z- wherein 26 WO 00/69826 PCT/US00/08220 W=X-Y=Z- forms a ring selected from the group consisting of a heteroaryl ring having from 5 through 6 contiguous members and an aryl; W, X, Y, and Z are independently selected from the group consisting of C(R9), C(R10), C(R 1 ), C(R 12), N, N(R 10), O, S and a covalent bond 5 with the provisos that W, X, Y, and Z can be independently selected to be a covalent bond when one of W, X, Y, and Z is selected from the group consisting of N, N(R10), O, and S, no more than one of W, X, Y, and Z can be selected from the group consisting of 0 and S, and no more than three of W, X, Y, and Z can be selected from the group consisting of N and N(R10); 10 Xo and R 1 and R I and R 2 spacer pairs are independently optionally selected to be taken together to form a spacer pair wherein the spacer pair forms a linear moiety having from 3 through 6 contiguous atoms connecting the points of bonding of said spacer pair members to form a ring selected from the group consisting of a cycloalkenyl ring having from 5 through 8 contiguous 15 members and a partially saturated heterocyclyl ring having from 5 through 8 contiguous members, wherein said spacer pair is optionally substituted with one or more of the group consisting of R 9 , R , R1 , R1 2 , and R13 and with the proviso that no more than one of the group consisting of spacer pair X 0 and
R
1 and spacer pair R 1 andR 2 is present at the same time; R 2 is Zo-Q; 20 Z is selected from the group consisting of covalent single bond, 41 42 41 (CR41 R 42)q wherein q is an integer selected from 1 through 3, (CH(R )) Wo-(CH(R 42)) 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), S(0), S(0)2, N(R41), and ON(R41), and (CH(R41))e-W22-(CH(R 4 2 ))h wherein e 25 and h are integers independently selected from 0 through 2 and W 2 2 is selected from the group consisting of CR41=CR 4 2 , 1,2-cyclopropyl, 1,2-cyclobutyl, 1,2-cyclohexyl, 1,3-cyclohexyl, 1,2-cyclopentyl, 1,3-cyclopentyl, 2,3 27 WO 00/69826 PCT/US00/08220 morpholinyl, 2,4-morpholinyl, 2,6-morpholinyl, 3,4-morpholinyl, 3,5 morpholinyl, 1,2-piperazinyl, 1,3-piperazinyl, 2,3-piperazinyl, 2,6 piperazinyl, 1,2-piperidinyl, 1,3-piperidinyl, 2,3-piperidinyl, 2,4-piperidinyl, 2,6-piperidinyl, 3,4-piperidinyl, 1,2-pyrrolidinyl, 1,3-pyrrolidinyl, 2,3 5 pyrrolidinyl, 2,4-pyrrolidinyl, 2,5-pyrrolidinyl, 3,4-pyrrolidinyl, 2,3 tetrahydrofuranyl, 2,4-tetrahydrofuranyl, 2,5-tetrahydrofuranyl, and 3,4 tetrahydrofuranyl, with the proviso that Z is directly bonded to the pyridone ring; R41 and R 4 2 are independently selected from the group consisting of 10 amidino, hydroxyamino, hydrido, hydroxy, amino, and alkyl; Q is selected from the group consisting of hydrido, with the proviso that Z is other than a covalent single bond, the formula (II): 11 R 1 K 2 R R p D1 D2 R 1 3 (II) wherein D , D 2 , , J 2 and K are independently selected from the group 15 consisting of C, N, 0, S and a covalent bond with the provisos that no more than one is a covalent bond, no more than one of D , D 2 , J1, J2 and K is O, 1 2 12 1 1 21 2 no more than one of D, D 2 , 1, J2 and K is S, one of D D , 1, J2 and 1 1 2 12 1 K must be a covalent bond when two of D , D 2 , J1, J2 and K are 0 and S, 1 21 2 1 and no more than four of D , D 2 , J1, J2 and K is N, with the proviso that 9 10 11 12 13 20 R 9 , R 10, R 1, R 12 and R13 are each independently selected to maintain the tetravalent nature of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen; 28 WO 00/69826 PCT/US00/08220 K is (CR4a R4b)n wherein n is an integer selected from I through 2;
R
4 a and R 4 b are independently selected from the group consisting of halo, hydrido, hydroxyalkyl, alkyl, alkoxyalkyl, alkylthioalkyl, and haloalkyl; Eo is selected from the group consisting of a covalent single bond, 5 C(O), C(S), C(O)N(R7), (R7)NC(O), S(0)2, (R7)NS(O) 2 , and S(0) 2 N(R7); Y is formula (IV): s R17
R
1 8 R
\
R8 R6 DS K 2 ,D R19 lb Q (IV) 5 65 6 wherein D , D 6 , J5, and J are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more 2 5 65 6 10 than one is a covalent bond, K is C, no more than one of , D , J and J6 5 6 5 6 5 6 5 6 is O, no more than one of D , D , J , and J is S, one of D , D , J, and J 5 65 6 must be a covalent bond when two of D , D 6 , J5 , and J are O and S, and no 5 65 6 2 more than four of D , D 6 , J5, and J6 are N when K is carbon with the 16 17 18 19 provisos that R , R , R , and R are each independently selected to 15 maintain the tetravalent nature of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen; b. 20 21 Q is selected from the group consisting of NR20 R21 + 02 2be be 20 NR20R 2 1R 22 , aminoalkylenyl, and Qbe, wherein Qbe is hydrido and R 2 0
R
2 , and R 22 are independently selected from the group consisting of hydrido, 20 alkyl, hydroxy, amino, aminoalkylenyl, dialkylamino, alkylamino, and 29 WO 00/69826 PCT/US00/08220 hydroxyalkyl with the proviso that no more than one of R 2 0 and R 2 1 is hydroxy, amino, alkylamino, or dialkylamino at the same time; Qb is optionally selected from the group consisting of C(NR25)NR R23R24, N(R26)C(NR25)N(R 23)(R24), 5 C(O)N(R26)C(NR25)N(R23 )(R24), N(R26)N(R26)C(NR25)N(R 23)(R24), and ON(R26)C(NR25)N(R 23)(R24) with the provisos that no more than one 23 24 26 of R , R 2 4 , and R 26 is hydroxy, alkylamino, amino, or dialkylamino when 23 24 26 two of the group consisting of R , R 2 4 , and R 2 6 are bonded to the same atom; 23 24 25 26 10 R , R 24 , R 25 , and R 2 6 are independently selected from the group consisting of hydrido, alkyl, hydroxy, amino, alkylenylamnino, dialkylamino, alkylamino, and hydroxyalkyl; QS is selected from the group consisting of a single covalent bond, (CR37R38)b-( W)az wherein az is an integer selected from 0 through 1, b is 15 an integer selected from 1 through 5, and Wo is selected from the group consisting of O, C(0), S(0), S(0)2 , S(0) 2 N(R14), N(R4)S(0)2, and N(R14), (CH(R14))cW -(CH(R 15))d wherein c and d are integers independently selected from I through 4 and W 1 is selected from the group consisting of O, S, C(0), C(S), C(0)O, C(S)O, C(0)S, C(S)S, C(0)N(R14), 20 (R14)NC(0), C(S)N(R 14), (R 14)NC(S), OC(0)N(R 14), (R I4)NC(0)O, SC(S)N(R14), (R14)NC(S)S, SC(0)N(R14), (R14)NC(0)S, OC(S)N(R14), (R14)NC(S)O, N(R15)C(0)N(R14), (R14)NC(0)N(R15), N(R15)C(S)N(R 14), (R 14)NC(S)N(R15), S(0), S(0) 2 , S(O) 2 N(R 14), 30 WO 00/69826 PCT/US00/08220 N(RI4)S(0) 2 , P(O)(R ), N(R7)P(O)(R ), P(O)(R )N(R7), N(R14), ON(R1 4 ), and (CH(R 14 ))e -W2-(CH(R1 5 ))h wherein e and h are integers independently selected from 0 through 2 and W 2 is selected from the group 41 42 41 42 consisting of CR41=CR42, CR41R42=C; vinylidene), ethynylidene (C=-C; 5 1,2-ethynyl), 1, 2 -cyclopropyl, 1,2-cyclobutyl, 1,2-cyclohexyl, 1,3 cyclohexyl, 1,2-cyclopentyl, 1,3-cyclopentyl, 2,3-morpholinyl, 2,4 morpholinyl, 2,6-morpholinyl, 3,4-morpholinyl, 3,5-morpholinyl, 1,2 piperazinyl, 1,3-piperazinyl, 2,3-piperazinyl, 2,6-piperazinyl, 1,2-piperidinyl, 1,3-piperidinyl, 2,3-piperidinyl, 2,4-piperidinyl, 2,6-piperidinyl, 3,4 10 piperidinyl, 1,2-pyrrolidinyl, 1,3-pyrrolidinyl, 2,3-pyrrolidinyl, 2,4 pyrrolidinyl, 2,5-pyrrolidinyl, 3,4-pyrrolidinyl, 2,3-tetrahydrofuranyl, 2,4 tetrahydrofuranyl, 2,5-tetrahydrofuranyl, and 3,4-tetrahydrofuranyl, with the provisos that R 14 and R 15 are selected from other than halo and cyano when directly bonded to N and that (CR37 R 38)b , (CH(R 14)) c, and (CH(R 14))e are 15 bonded to E 0 ; O is optionally Qb Qss wherein QSS is selected from the group consisting of (CR 3 7 R38)f wherein f is an integer selected from 1 through 4, (CH(R14))cW -(CH(RI 5 d wherein c and d are integers independently selected from 1 through 2, and W 1 is selected from the group consisting of W 1 20 is selected from the group consisting of O, S, C(0), C(O)N(R 14), (R14)NC(0), N(R 15)C(0)N(R14), (R14)NC(0)N(R15), N(R14), ON(R 14), and (CH(R14))e-W2-(CH(R15))h wherein e and h are integers independently selected from 0 through 2 and W 2 is selected from the group consisting of CR4a=CR 4b, ethynylidene (C=-C; 1,2-ethynyl), and C=CR4aR 4 b with the 31 WO 00/69826 PCT/US00/08220 provisos that R14 and R15 are selected from other than halo when directly bonded to N and that (CR 3 7 R38)f, (CH(R14))c, and (CH(R 14))e are bonded to E; Y0 is optionally QbQSSS wherein QSSS is (CH(R 3 8 ))r-W 3 , r is an 5 integer selected from 1 through 2, W 3 is selected from the group consisting of 1,1-cyclopropyl, 1,2-cyclopropyl, 1,1-cyclobutyl, 1,2-cyclobutyl, 1,2 cyclohexyl, 1,3-cyclohexyl, 1,4-cyclohexyl, 1,2-cyclopentyl, 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 10 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 15 pyranyl, 4 H-2,3-pyranyl, 4H-2,4-pyranyl, 4H-2,5-pyranyl, 2H-pyran-2-one 3,4-yl, 2H-pyran-2-one-4,5-yl, 4H-pyran-4-one-2,3-yl, 2,3 tetrahydrofuranyl, 2,4-tetrahydrofuranyl, 2,5-tetrahydrofuranyl, 3,4 tetrahydrofuranyl, 2 ,3-tetrahydropyranyl, 2,4-tetrahydropyranyl, 2,5 tetrahydropyranyl, 2
,
6 -tetrahydropyranyl, 3,4-tetrahydropyranyl, and 3,5 20 tetrahydropyranyl, and each carbon and hyrido containing nitrogen member of the ring of the W other than the points of attachment is optionally substituted 9 10 11 12 with one or more of the group consisting of R 9 , R , R 1 1 , and R 12 , with the proviso that (CH(R38)) r is bonded to E and Qb is bonded to lowest numbered substituent position of each W 3 ; 25 YO is optionally Qb _Qsssr wherein Qsssr is (CH(R 3 8 ))r-W4 , r is an integer selected from 1 through 2, W 4 is selected from the group consisting of 1,2-cyclobutyl, 1,2-cyclohexyl, 1,3-cyclohexyl, 1,4-cyclohexyl, 1,2 cyclopentyl, 1, 3 -cyclopentyl, 2,3-morpholinyl, 2,4-morpholinyl, 2,5 32 WO 00/69826 PCT/US00/08220 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, 5 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, 2 H-2,4-pyranyl, 2 H-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 10 tetrahydrofuranyl, 3 ,4-tetrahydrofuranyl, 2,3-tetrahydropyranyl, 2,4 tetrahydropyranyl, 2 ,5-tetrahydropyranyl, 2,6-tetrahydropyranyl, 3,4 tetrahydropyranyl, and 3 ,5-tetrahydropyranyl, and each carbon and hyrido 4 containing nitrogen member of the ring of the W other than the points of attachment is optionally substituted with one or more of the group consisting of 15 R 9 , R 10, R 1 1 , and R 12 , with the provisos that (CH(R38 ))r is bonded to Eo and Qb is bonded to highest number substituent position of each W Y0 is optionally QbQss wherein Qssss is (CH(R38 ))r-W5, r is an integer selected from 1 through 2, W 5 is selected from the group consisting of 1,4-indenyl, 1,5-indenyl, 1,6-indenyl, 1,7-indenyl, 2,7-indenyl, 2,6-indenyl, 20 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 25 benzothiophenyl, 3, 7 -benzothiophenyl, 2,7-imidazo(1,2-a)pyridinyl, 3,4 imidazo(1,2-a)pyridinyl, 3,5-imidazo(1,2-a)pyridinyl, 3,6-imidazo(1,2 a)pyridinyl, 3,7-imidazo(1,2-a)pyridinyl, 2,4-indolyl, 2,5-indolyl, 2,6 indolyl, 2,7-indolyl, 3,4-indolyl, 3,5-indolyl, 3,6-indolyl, 3,7-indolyl, 1,4 isoindolyl, 1,5-isoindolyl, 1,6-isoindolyl, 2,4-isoindolyl, 2,5-isoindolyl, 2,6 30 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 33 WO 00/69826 PCT/US00/08220 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 5 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 10 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 5 other than the points of attachment is optionally substituted with one or more of the group consisting of 9 10 11 12 b
R
9 , R10, R 11 , and R 12 , with the proviso that Q is bonded to lowest number 15 substituent position of each W 5 and that (CH(R38))r is bonded to E; Yo is optionally QbQssssr wherein QSSSSr is (CH(R 3 8 ))r- 6, r is an integer selected from 1 through 2, W 6 is selected from the group consisting of 1,4-indenyl, 1,5-indenyl, 1,6-indenyl, 1,7-indenyl, 2,7-indenyl, 2,6-indenyl, 2,5-indenyl, 2,4-indenyl, 3,4-indenyl, 3,5-indenyl, 3,6-indenyl, 3,7-indenyl, 20 2,4-benzofuranyl, 2,5-benzofuranyl, 2,6-benzofuranyl, 2,7-benzofuranyl, 3,4-benzofuranyl, 3,5-benzofuranyl, 3,6-benzofuranyl, 3,7-benzofuranyl, 2,4-benzothiophenyl, 2,5-benzothiophenyl, 2,6-benzothiophenyl, 2,7 benzothiophenyl, 3,4-benzothiophenyl, 3,5-benzothiophenyl, 3,6 benzothiophenyl, 3, 7 -benzothiophenyl, 2,7-imidazo(1,2-a)pyridinyl, 3,4 25 imidazo(1,2-a)pyridinyl, 3,5-imidazo( 1,2-a)pyridinyl, 3,6-imidazo(1,2 a)pyridinyl, 3,7-imidazo(1,2-a)pyridinyl, 2,4-indolyl, 2,5-indolyl, 2,6 indolyl, 2,7-indolyl, 3,4-indolyl, 3,5-indolyl, 3,6-indolyl, 3,7-indolyl, 1,4 isoindolyl, 1,5-isoindolyl, 1,6-isoindolyl, 2,4-isoindolyl, 2,5-isoindolyl, 2,6 isoindolyl, 2,7-isoindolyl, 1,3-isoindolyl, 3,4-indazolyl, 3,5-indazolyl, 3,6 30 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, 34 WO 00/69826 PCT/US00/08220 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 5 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 10 cinnolinyl, 4
,
7 -cinnolinyl, and 4,8-cinnolinyl, and each carbon and hyrido 6 containing nitrogen member of the ring of the W other than the points of attachment is optionally substituted with one or more of the group consisting of 9 10 11 12 b
R
9 , R10, R 1 1 , and R 12 , with the proviso that Q is bonded to highest number substituent position of each W 6 and that (CH(R38))r is bonded to Eo 15 In a preferred embodiment of compounds of Formula I or a pharmaceutically acceptable salt thereof, J is O; B is the Formula:
R
3 4
R
3 3
R
3 5
R
3 2 - #R 3 6 9 10 11 12 131 32 33 34 35 36 20 R9, R10, R 11 , R 12 , R 13 ,
R
3 2 ,
R
3 3 , R 3 4 , R 3 5 , and R36 are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkylenedioxy, haloalkylthio, alkanoyloxy, alkoxy, alkoxyalkyl, haloalkoxylalkyl, hydroxy, amino, alkoxyamino, nitro, lower alkylamino, alkylthio, alkylthioalkyl, alkylsulfinyl, 25 alkylsulfonyl, alkylsulfonylalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkyl 35 WO 00/69826 PCT/US00/08220 amidosulfonyl, dialkyl amidosulfonyl, alkanoyl, haloalkanoyl, alkyl, alkenyl, halo, haloalkyl, haloalkenyl, haloalkoxy, hydroxyhaloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxyalkyl, carboxyalkyl, carboalkoxy, carboxy, carboxamido, carboxamidoalkyl, and cyano; 5 R9 , R 10 R11 R12, ad13 5 R 9, R 10, R , R12, and R13 are optionally selected from the group 9 10 11 consisting of heteroaryl and heterocyclyl with the proviso that R , R , R 12 13 R 2 , and R 13 are substitutents for other than B; 16 19 32 33 34 35 36
R
16 , R 19 , R 32 , R 3 3 , R 3 4 , R 3 5 , and R 3 6 are independently optionally b .16 19 b Q with the proviso that no more than one of R 16 and R 19 is Q at the same 10 time and that Qb is Qbe B is optionally, with the proviso that R 1 and R 2 are selected from the group consisting of a spacer pair and -W=X-Y=Z-, Formula (V):
R
3 4 R K12 R 35 2R36 R2 D 1 D2 R36 (V) 1 2 1 2 1 wherein D , D , , J and K are independently selected from the group 15 consisting of C, N, O, S and a covalent bond with the provisos that no more 1 2 12 1 than one is a covalent bond, no more than one of D , D 2 , J1 2 and K is O, 1 2 12 1 1 2 12 no more than one of D, D 2 , J1 ,2 and K is S, one of D D 2 , j1 ,2 and 1 1 2 12 1 K must be a covalent bond when two of D , D 2 , J2 and K are O and S, 1 2 12 1 and no more than four of D , D 2 , J1 , J and K are N; 36 WO 00/69826 PCT/US00/08220 B is optionally selected from the group consisting of hydrido, trialkylsilyl, C2-C8 alkyl, C3-C8 alkylenyl, C3-C8 alkenyl, C3-C8 alkynyl, and C2-C8 haloalkyl, wherein each member of group B is optionally substituted at any carbon up to and including 6 atoms from the point of 32 33 5 attachment of B to A with one or more of the group consisting of R 3 2 , R 3 3 34 35 36
R
34 , R 3 5 , and R36 B is selected from the group consisting of C3-C12 cycloalkyl and C4 heterocyclyl, wherein each ring carbon is optionally substituted with R 33 , a ring carbon other than the ring carbon at the point of attachment of B to A is 10 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 9 13 carbon at the point of attachment are optionally substituted with R or R 13 , a ring carbon or nitrogen adjacent to the R 9 position and two atoms from the 10 point of attachment is optionally substituted with R 0 , a ring carbon or 15 nitrogen adjacent to the R 13 position and two atoms from the point of 12, e he attachment is optionally substituted with R 12 , a ring carbon or nitrogen three atoms from the point of attachment and adjacent to the R1 0 position is 11, gntreaosfo optionally substituted with R 1 1 , a ring carbon or nitrogen three atoms from the point of attachment and adjacent to the R 12 position is optionally 20 substituted with R 3 3 , and a ring carbon or nitrogen four atoms from the point of attachment and adjacent to the R 1 1 and R 3 3 positions is optionally 34 substituted with R34 B is optionally, with the proviso that RI and R 2 are selected from the group consisting of a spacer pair and -W=X-Y=Z-, a C5-C9 saturated 33 25 heterocyclyl, wherein each ring carbon is optionally substituted with R 3 3 , a 37 WO 00/69826 PCT/US00/08220 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 nitrogen adjacent to the carbon atom at the point of attachment are optionally substituted with R 9 or 13 9 5 R 13 , a ring carbon or nitrogen adjacent to the R position and two atoms from 10 the point of attachment is optionally substituted with R 10 , a ring carbon or nitrogen adjacent to the R 13 position and two atoms from the point of 12 attachment is optionally substituted with R 12 , a ring carbon or nitrogen three atoms from the point of attachment and adjacent to the R 10 position is 10 optionally substituted with R 1 1 , a ring carbon or nitrogen three atoms from the point of attachment and adjacent to the R 12 position is optionally substituted with R 3 3 , and a ring carbon or nitrogen four atoms from the point of attachment and adjacent to the R 1 and R 3 3 positions is optionally substituted with R34 15 A is selected from the group consisting of single covalent bond, W7 )r(HR15 15 7 (W7)rr-(CH(RI5))pa and (CH(R15))pa-(W )r r wherein rr is an integer selected from 0 through 1, pa is an integer selected from 0 through 6, and W7 is selected from the group consisting of O, S, C(0), (R7)NC(0), (R7)NC(S), and N(R 7 ) with the proviso that no more than one of the group consisting of rr 20 and pa is 0 at the same time;
R
7 is selected from the group consisting of hydrido, hydroxy, and alkyl;
R
15 is selected from the group consisting of hydrido, hydroxy, halo, alkyl, and haloalkyl; 38 WO 00/69826 PCT/US00/08220 T is selected from the group consisting of NH and NOH;
R
1 and X 0 are independently selected from the group consisting of hydrido, alkyl, alkenyl, cyano, halo, haloalkyl, haloalkoxy, haloalkylthio, amino, aminoalkyl, alkylamino, amidino, hydroxy, hydroxyamino, alkoxy, 5 hydroxyalkyl, alkoxyamino, thiol, and alkylthio; X and R 1 and R 1 and R 2 , with the proviso that no more than one of the group consisting of spacer pair X 0 and R 1 and spacer pair RI and R 2 is be used at the same time, are optionally selected to be -W=X-Y=Z- wherein W=X-Y=Z- forms a ring selected from the group consisting of a heteroaryl 10 ring having from 5 through 6 contiguous members and an aryl; W, X, Y, and Z are independently selected from the group consisting of C(R9), C(R10), C(R 11), C(R12), N, N(R 10), O, S and a covalent bond with the provisos that W, X, Y, and Z can be independently selected to be a covalent bond when one of W, X, Y, and Z is selected from the group 15 consisting of N, N(R10), O, and S, no more than one of W, X, Y, and Z can be selected from the group consisting of O and S, and no more than three of W, X, Y, and Z can be selected from the group consisting of N and N(R 10); Xo and R 1 and RI and R 2 spacer pairs are independently optionally selected to be taken together to form a spacer pair wherein the spacer pair forms 20 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 from 5 through 8 contiguous members and a partially saturated heterocyclyl ring having from 5 through 8 contiguous members, wherein said spacer pair is optionally substituted with 25 one or more of the group consisting of R9 , R10, R11, R 2, and R13 and with the proviso that no more than one of the group consisting of spacer pair X 0 and
R
1 and spacer pair RI and R 2 is present at the same time;
R
2 is Zo-Q; 39 WO 00/69826 PCT/US00/08220 Z is selected from the group consisting of covalent single bond, (CR41 R 42)q wherein q is an integer selected from 1 through 3, (CH(R41)) o W-(CH(R42))p wherein g and p are integers independently selected from 0 through 3 and Wo is selected from the group consisting of O, S, C(O), S(0), 5 N(R41), and ON(R41), and (CH(R4 1 ))e W 2 2 -(CH(R42))h wherein e and h are integers independently selected from 0 through 1 and W 2 is selected from the group consisting of CR41=CR42, 1,2-cyclopropyl, 1,2-cyclobutyl, 1,2 cyclohexyl, 1,3-cyclohexyl, 1,2-cyclopentyl, 1,3-cyclopentyl, 2,3 morpholinyl, 2,4-morpholinyl, 2,6-morpholinyl, 3,4-morpholinyl, 3,5 10 morpholinyl, 1,2-piperazinyl, 1,3-piperazinyl, 2,3-piperazinyl, 2,6 piperazinyl, 1,2-piperidinyl, 1,3-piperidinyl, 2,3-piperidinyl, 2,4-piperidinyl, 2,6-piperidinyl, 3,4-piperidinyl, 1,2-pyrrolidinyl, 1,3-pyrrolidinyl, 2,3 pyrrolidinyl, 2,4-pyrrolidinyl, 2,5-pyrrolidinyl, 3,4-pyrrolidinyl, 2,3 tetrahydrofuranyl, 2,4-tetrahydrofuranyl, 2,5-tetrahydrofuranyl, and 3,4 15 tetrahydrofuranyl, with the proviso that Z is directly bonded to the pyridone ring; 41 42 R and R 4 2 are independently selected from the group consisting of amidino, hydroxyamino, hydrido, hydroxy, amino, and alkyl; Q is selected from the group consisting of hydrido, with the proviso 20 that Z is other than a covalent single bond, and the formula (II):
R
1 10 K 1 1 2 R K 2R 9 D -1 D2 13 R NT"I R a (II) 40 WO 00/69826 PCT/US00/08220 wherein D, D 2 , J, J2 and K 1 are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more 1 2 12 1 than one is a covalent bond, no more than one of D , D 2 , J1, J2 and K is O, 1 2 12 1 1 2 12 no more than one of D, D 2 , 1, J2 and K is S, one of D, D 2 , 1, J2 and 1 1 2 12 1 5 K must be a covalent bond when two of D
I
, D 2 , J1 , J and K are O and S, 1 21 2 1 and no more than four of D , D 2 , J1 , J and K are N, with the proviso that 9 10 11 12 13 R , R , R , R , and R are each independently selected to maintain the tetravalent nature of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen; 10 K is (CR 4 aR 4 b)n wherein n is an integer selected from 1 through 2; 4a 4b R and R 4 b are independently selected from the group consisting of halo, hydrido, hydroxyalkyl, alkyl, alkoxyalkyl, alkylthioalkyl, and haloalkyl; Eo is E1 , when K is (CR4a R4b)n, wherein E is selected from the group consisting of a covalent single bond, C(O), C(S), C(O)N(R), 15 (R7)NC(O), S(O) 2 , (R7)NS(O) 2 , and S(O) 2 N(R7); Yo is formula (IV): S
R
1 7 " R 1 8 R R 5 6 R 16 D " K2 DN 19 lb Q (IV) .5 65 6 wherein D , D , J , and J are independently selected from the group consisting of C, N, 0, S and a covalent bond with the provisos that no more 41 WO 00/69826 PCT/US00/08220 2 5 65 6 than one is a covalent bond, K is C, no more than one of D 5 , D , J and J 5 65 6 5 65 6 is O, no more than one of D , D 6 , and J is S, one of DS, D , J and J 5 65 6 must be a covalent bond when two of D , D , J, and J are O and S, and no 5 65 6 16 17 more than four of DS, D , , and J6 are N with the proviso that R 16 , R 17 18 19 5 R 18 , and R 19 are each independently selected to maintain the tetravalent nature of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen; 16 17 18 19
R
16 , R 17 , R 18 , and R 19 are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, haloalkylthio, alkoxy, 10 hydroxy, amino, nitro, alkoxyamino, lower alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, alkenyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, alkylenylamino, haloalkoxyalkyl, carboalkoxy, and cyano; Qb is selected from the group consisting of NR20 R 21, aminoalkylenyl, 15 Qbe wherein Qbe is hydrido, N(R26)C(NR25)N(R 23)(R24), and 25 23 24 20 21 C(NR )NR23R , with the provisos that no more than one of R 2 0 and R 2 1 is hydroxy, amino, alkylamino, or dialkylamino at the same time and that no more than one of R 23 and R 24 is hydroxy, amino, alkylamino, or dialkylamino at the same time; 20 20 21 23 24 25 26 20 R20, R21, R , R24, R25, and R 2 6 are independently selected from the group consisting of hydrido, alkyl, hydroxy, aminoalkylenyl, amino, dialkylamino, alkylamino, and hydroxyalkyl; Qs is selected from the group consisting of a single covalent bond, (CR37R38)b wherein b is an integer selected from 1 through 4, and 25 (CH(R14))c-W 1-(CH(R15))d wherein c and d are integers independently 42 WO 00/69826 PCT/US00/08220 selected from 1 through 3 and W 1 is selected from the group consisting of C(O)N(R 14), (R14)NC(O), S(O), S(O) 2 , S(O) 2 N(R14), N(R 14)S(O) 2 , and N(R 14), with the provisos that R 14 is selected from other than halo when directly bonded to N and that (CR37 R 38)b , and (CH(R14)) c are bonded to Eo 5 R 14 is selected from the group consisting of hydrido, halo, alkyl, and haloalkyl; 37 38 R and R 3 8 are independently selected from the group consisting of hydrido, alkyl, and haloalkyl;
R
3 8 is optionally selected from the group consisting of aroyl and 10 heteroaroyl; YO is optionally Qb ss wherein Qss is (CH(R 14 ))e-W2-(CH(R5))h, wherein e and h are integers independently selected from 1 through 2 and W 2 4a 4b 14 is CR4a =CR with the proviso that (CH(R 14))e is bonded to Eo; Y0 is optionally selected from the group consisting of Q b - ssss and Qb 15 Qsssr wherein Qssss is (CH(R38 ))r-W5 and QssSr is (CH(R38 ))r-W6, r is an integer selected from 1 through 2, and W 5 and W 6 are independently selected from the group consisting of 1,4-indenyl, 1,5-indenyl, 1,6-indenyl, 1,7 indenyl, 2,7-indenyl, 2,6-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 20 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 25 a)pyridinyl, 3,6-imidazo(1,2-a)pyridinyl, 3,7-imidazo(1,2-a)pyridinyl, 2,4 indolyl, 2,5-indolyl, 2,6-indolyl, 2,7-indolyl, 3,4-indolyl, 3,5-indolyl, 3,6 indolyl, 3,7-indolyl, 1,4-isoindolyl, 1,5-isoindolyl, 1,6-isoindolyl, 2,4 43 WO 00/69826 PCT/US00/08220 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 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 10 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 15 cinnolinyl, and each carbon and hyrido containing nitrogen member of the ring of the W 5 and of the ring of the W 6 , other than the points of attachment of W and W 6 , is optionally substituted with one or more of the group consisting of 9 10 11 12 b
R
9 , R 10 ,
R
1 1 , and R 12 , with the provisos that Q is bonded to lowest number substituent position of each W 5 , Qb is bonded to highest number 20 substituent position of each W 6 , and (CH(R38))r is bonded to Eo In a more preferred embodiment of compounds of Formula I or a pharmaceutically acceptable salt thereof, J is O; B is the Formula: R3 4
R
3 3 R3 5
SR
3 2 R3 6 25 44 WO 00/69826 PCT/US00/08220 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, alkanoyl, haloalkanoyl, nitro, lower alkylamino, alkylthio, aryl, 5 aralkyl, cycloalkyl, cycloalkylalkyl, alkylsulfonamido, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, alkyl, alkenyl, halo, haloalkyl, haloalkenyl, haloalkoxy, hydroxyalkyl, alkylenylamino, carboalkoxy, carboxy, carboxamido, cyano, and Qb B is optionally, with the proviso that RI and R 2 are selected from the 10 group consisting of a spacer pair and -W=X-Y=Z-, Formula (V):
R
3 4
R
3 3 1 R 3 5 12 R3 2.,00 D D R (V) 1 2 12 1 wherein D , D 2 , J , J2 and K are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more 1 2 12 1 than one is a covalent bond, no more than one of D , D 2 , J, J2 and K is O, 1 2 12 1 1 2 12 15 no more than one of D, D2, J1 ,2 and K is S, oneof D D2, J ,J and 1 1 2 12 1
K
1 must be a covalent bond when two of D , D 2 , J2 and K are and S, 1 2 12 1 and no more than four of D , D 2 , J1 and K are N; B is optionally selected from the group consisting of hydrido, trialkylsilyl, C2-C8 alkyl, C3-C8 alkylenyl, C3-C8 alkenyl, C3-C8 alkynyl, 20 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 45 WO 00/69826 PCT/US00/08220 attachment of B to A with one or more of the group consisting of R 3 2 , R 3 3 R34 , R35 , and R36 B is selected from the group consisting of C3-C12 cycloalkyl and C4 33 heterocyclyl, wherein each ring carbon is optionally substituted with R 3 3 , a 5 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 at the point of attachment are optionally substituted with R or R 13, a 9 , a ring carbon or nitrogen adjacent to the R position and two atoms from the 10 10 point of attachment is optinally substituted with R 0, a ring carbon or nitrogen adjacent to the R 13 position and two atoms from the point of attachment are 12 optionally substituted with R 12 , a ring carbon three atoms from the point of 10 1 attachment and adjacent to the R 10 position is optionally substituted with R 1 a ring carbon three atoms from the point of attachment and adjacent to the R 12 15 position is optionally substituted with R 3 3 , and a ring carbon four atoms from the point of attachment and adjacent to the R11 and R 3 3 positions is optionally 34 substituted with R34; B is optionally, with the proviso that R I and R 2 are selected from the group consisting of a spacer pair and -W=X-Y=Z-, a C5-C9 saturated 33 20 heterocyclyl, wherein each ring carbon is optionally substituted with R 3 3 , 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 nitrogen adjacent to the carbon atom at the point of attachment are optionally substituted with R 9 or 46 WO 00/69826 PCT/US00/08220
R
13 , a ring carbon or nitrogen adjacent to the R position and two atoms from the point of attachment is optionally substituted with R 10 , a ring carbon or nitrogen adjacent to the R 13 position and two atoms from the point of 12 attachment is optionally substituted with R 12 , a ring carbon or nitrogen three 5 atoms from the point of attachment and adjacent to the R 10 position is optionally substituted with R 11 , a ring carbon or nitrogen three atoms from the point of attachment and adjacent to the R 12 position is optionally substituted with R 33 , and a ring carbon or nitrogen four atoms from the point of attachment and adjacent to the R 11 and R 3 3 positions is optionally 10 substituted with R34 9 10 11 12 13
R
9 , R 10 , R 1 1 , R 12 , and R 3 are independently selected from the group consisting of hydrido, acetamido, haloacetamido, alkoxyamino, alkanoyl, haloalkanoyl, amidino, guanidino, alkylenedioxy, haloalkylthio, alkoxy, hydroxy, amino, lower alkylamino, alkylthio, alkylsulfinyl, 15 alkylsulfonyl, alkylsulfonamido, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, carboalkoxy, carboxyalkyl, carboxy, carboxamido, and cyano; 9 10 11 12 13 R, R , R , R , and R are optionally selected from the group 9 10 11 consisting of heteroaryl and heterocyclyl with the proviso that R , R 10, R11 12 13 20 R12, and R3 are substitutents for other than B; A is selected from the group consisting of single covalent bond and (CH(R15))pa-(W 7)rr wherein rr is an integer selected from 0 through 1, pa is an integer selected from 0 through 3, and W 7 is selected from the group consisting of O, S, C(0), (R 7)NC(0), (R 7)NC(S), and N(R ); 47 WO 00/69826 PCT/US00/08220 7is selected from the group consisting of hydride, hydroxy and alkyl; R is selected from the group consisting of hydrido, hydroxy and alokyl; R5 is selected from the group consisting of hydrido, hydroxy, halo, alkyl, and haloalkyl; W is NH; 5 R 1 and X are independently selected from the group consisting of hydrido, alkyl, cyano, halo, haloalkyl, haloalkoxy, amino, aminoalkyl, alkylamino, amidino, hydroxy, hydroxyamino, alkoxy, hydroxyalkyl, alkoxyamino, thiol, and alkylthio; RI and R 2 is optionally selected to be -W=X-Y=Z- wherein -W=X 10 Y=Z- forms a ring selected from the group consisting of a heteroaryl ring having from 5 through 6 contiguous members and an aryl; W, X, Y, and Z are independently selected from the group consisting of C(R ), C(R10), C(R 1 1 ), C(R 12), N, N(R 10), O, S and a covalent bond with the provisos that W, X, Y, and Z can be independently selected to be a 15 covalent bond when one of W, X, Y, and Z is selected from the group consisting of N, N(R10), O, and S, no more than one of W, X, Y, and Z can be selected from the group consisting of O and S, and no more than three of W, X, Y, and Z can be selected from the group consisting of N and N(R10); RI and R 2 spacer pairs are independently optionally selected to be 20 taken together to form a spacer pair wherein the spacer pair forms a linear moiety having from 3 through 6 contiguous atoms connecting the points of bonding of said spacer pair members to form a ring selected from the group consisting of a cycloalkenyl ring having from 5 through 8 contiguous members and a partially saturated heterocyclyl ring having from 5 through 8 contiguous 25 members, wherein said spacer pair is optionally substituted with one or more of the group consisting of R 9 , R 10 , R 1 1 , R12, and R13
R
2 is Z-Q; 48 WO 00/69826 PCT/US00/08220 Z is selected from the group consisting of covalent single bond and (CR41 R 42)q wherein q is an integer selected from 1 through 2, (CH(R41)) W-(CH(R42)) wherein g and p are integers independently selected from 0 through 3 and Wo is selected from the group consisting of O, S, and N(R41 5 and (CH(R 4 1 )) W 22
-(CH(R
4 2 ))h wherein e and h are integers independently selected from 0 through 1 and W 2 2 is selected from the group consisting of 41 42 CR 41=CR 42, 1,2-cyclopropyl, 1,2-cyclobutyl, 1,2-cyclohexyl, 1,3 cyclohexyl, 1,2-cyclopentyl, 1,3-cyclopentyl, 2,3-morpholinyl, 2,4 morpholinyl, 2,6-morpholinyl, 3,4-morpholinyl, 3,5-morpholinyl, 1,2 10 piperazinyl, 1,3-piperazinyl, 2,3-piperazinyl, 2,6-piperazinyl, 1,2-piperidinyl, 1,3-piperidinyl, 2,3-piperidinyl, 2,4-piperidinyl, 2,6-piperidinyl, 3,4 piperidinyl, 1,2-pyrrolidinyl, 1,3-pyrrolidinyl, 2,3-pyrrolidinyl, 2,4 pyrrolidinyl, 2,5-pyrrolidinyl, 3,4-pyrrolidinyl, 2,3-tetrahydrofuranyl, 2,4 tetrahydrofuranyl, 2,5-tetrahydrofuranyl, and 3,4-tetrahydrofuranyl, with the 15 proviso that Zo is directly bonded to the pyridone ring;
R
4 1 and R 4 2 are independently selected from the group consisting of hydrido, hydroxy, and amino; Q is selected from the group consisting of hydrido, with the proviso that Z is other than a covalent single bond, aryl, and heteroaryl, wherein a 20 carbon 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 13 9 optionally substituted by R 3 , a carbon adjacent to R and two atoms from the 10 carbon at the point of attachment is optionally substituted by R 10 , a carbon adjacent to R 13 and two atoms from the carbon at the point of attachment is 12 10 12 25 optionally substituted by R 2 , and any carbon adjacent to both RI and R 2 is optionally substituted by Rl 49 WO 00/69826 PCT/US00/08220 4a 4a K is CHR 4a wherein R 4a is selected from the group consisting of hydrido, hydroxyalkyl, alkyl, alkoxyalkyl, alkylthioalkyl, and haloalkyl; E is selected from the group consisting of a covalent single bond, C(O)N(H), (H)NC(O), (R7)NS(O) 2 , and S(O) 2 N(R7); 5 Y0 is formula (IV): s R17 R1 8 R RD
D
5 R16
/
D NK 2 D R 1 9 lb Q (IV) wherein D 5 , D 6 , J 5, and J6 are independently selected from the group consisting of C, N, 0, S and a covalent bond with the provisos that no more than one is a covalent bond, K 2 is C, no more than one of D 5 , D6 , J5, and J6 5 65 6 5 65 6 10 is O, no more than one of D D , , and J6 is S, one of D , D 6 , and J 5 65 6 must be a covalent bond when two of D 5 , D 6 , and J6 are 0 and S, and no 5 65 6 16 17 more than four of DS, D , , and J are N, with the provisos that R 16 , R 17 18 19
R
18 , and R 19 are each independently selected to maintain the tetravalent nature of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the 15 divalent nature of oxygen; 16 17 18 19
R
16 , R 17 , R 18 , and R 19 are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, haloalkylthio, alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, halo, haloalkyl, haloalkoxy, 20 hydroxyalkyl, aminoalkyl, and cyano; 50 WO 00/69826 PCT/US00/08220
R
16 and R 19 are optionally Qb with the proviso that no more than one 16 19, b b be of R 16 and R 19 is Q at the same time and that Q is Qbe Qb is selected from the group consisting of NR20R21, Qbe wherein Qbe is 26 25 23 24 25 23 24 hydrido, N(R26)C(NR25)N(R )(R24), and C(NR25)NR R24, with the 5 provisos that no more than one of R 20 and R 21 is hydroxy, amino, alkylamino, or dialkylamino at the same time and that no more than one of R 23 and R 24 is hydroxy, amino, alkylamino, or dialkylamino at the same time; 20 21 23 24 25 26 R20, R 21 , R , R24, R25, and R 26 are independently selected from the group consisting of hydrido, alkyl, hydroxy, amino, alkylamino and dialkylamino; 10 QS is selected from the group consisting of a single covalent bond, (CR37 R 38)b wherein b is an integer selected from 1 through 4, and (CH(R 14))c-W I-(CH(R15))d wherein c and d are integers independently selected from 1 through 3 and W 1 is selected from the group consisting of C(O)N(R14), (R14)NC(O), S(O), S(O) 2 , S(O) 2 N(R14), N(R14)S(O) 2 , and 15 N(R14), with the provisos that R 14 is selected from other than halo when directly bonded to N and that (CR37 R 38)b , and (CH(R14))c are bonded to Eo
R
14 is selected from the group consisting of hydrido, halo, alkyl, and haloalkyl;
R
37 and R 38 are independently selected from the group consisting of 20 hydrido, alkyl, and haloalkyl;
R
38 is optionally selected from the group consisting of aroyl and heteroaroyl; 51 WO 00/69826 PCT/US00/08220 O is optionally QbQ ss wherein QSS is (CH(R 14))e-W2-(CH(R5))h, wherein e and h are integers independently selected from 1 through 2 and W 2 is CR4a=CH with the proviso that (CH(R14))e is bonded to E . In an even more preferred embodiment of compounds of Formula I or a 5 pharmaceutically acceptable salt thereof, J is O; B is the Formula:
R
3 4
R
3 3
R
3 5 K
R
3 2
R
3 6 I 32 33 34 35 36
R
3 2 , R 33 ,
R
3 4 , R 3 5 , and R 3 6 are independently selected from the 10 group consisting of hydrido, acetamindo, haloacetamido, anmidino, guanidino, alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, alkylthio, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboalkoxy, carboxy, carboxamido, cyano, and Qb 15 A is selected from the group consisting of single covalent bond and (CH(R15))pa-(W 7)rr wherein rr is an integer selected from 0 through 1, pa is an integer selected from 0 through 3, and W 7 is selected from the group consisting of (R 7)NC(O) and N(R 7); R7 is selected from the group consisting of hydrido, hydroxy and alkyl; 20 R 15 is selected from the group consisting of hydrido, halo, alkyl, and haloalkyl; 52 WO 00/69826 PCT/US00/08220 W is NH;
R
1 and X are independently selected from the group consisting of hydrido, hydroxy, hydroxyamino, amidino, amino, cyano, hydroxyalkyl, alkoxy, alkyl, alkylamino, aminoalkyl, alkylthio, alkoxyamino, haloalkyl, 5 haloalkoxy, and halo;
R
2 is Zo-Q; Z is selected from the group consisting of a covalent single bond, O, S, NH, and CH 2 ; Q is selected from the group consisting of aryl and heteroaryl wherein a 10 carbon adjacent to the carbon at the point of attachment is optionally substituted 9 by R 9 , the other carbon adjacent to the carbon at the point of attachment is 13 9 optionally substituted by R 13 , a carbon adjacent to R and two atoms from the 10 carbon at the point of attachment is optionally substituted by R , a carbon adjacent to R 13 and two atoms from the carbon at the point of attachment is 12 10 12. 15 optionally substituted by R 12 , and any carbon adjacent to both R 10 and R 2 is optionally substituted by Rl 9 11 13
R
9 , R 1 1 , and R 13 are independently selected from the group consisting of hydrido, hydroxy, amino, amidino, guanidino, lower alkylamino, alkylthio, alkylsulfonamido, alkylsulfinyl, alkylsulfonyl, 20 amidosulfonyl, monoalkyl amnidosulfonyl, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboxy, carboxamido, and cyano;
R
10 and R 12 are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkyl, alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, alkylsulfonamido, 25 amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, hydroxyalkyl, aminoalkyl, carboalkoxy, carboxy, carboxyalkyl, amidocarbonyl, halo, haloalkyl, and cyano; 53 WO 00/69826 PCT/US00/08220 K is CH 2 ; Eo is C(O)N(H); YO is formula (IV): S
R
1 7 R1 8 Qb 5 R16-" D DR1 9 (IV) 5 65 6 5 wherein D , D , J , and J are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more 2 5 65 6 than one is a covalent bond, K is C, no more than one of D 5 , D 6 , J , and J6 5 65 6 is optionally O, no more than one of D , D 6 , J5, and J is optionally S, one of 5 65 6 5 65 6
D
5 , D , J ,and J6 must be a covalent bond when two of D , D 6 , and J 10 areOandS, andnomorethanfourofD5, D6 J5 and J6 areN; 16 17 18 19
R
16 , R 17 , R 18 , and R 19 are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, haloalkylthio, alkoxy, hydroxy, amino, lower alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, 15 aminoalkyl, and cyano;
R
16 and R 19 are optionally Qb with the proviso that no more than one of
R
16 and R 19 is Qb at the same time and that Qb is Qbe Qb is selected from the group consisting of NR20R21, Qbe wherein Qbe is 25 23 24 2 hydrido, and C(NR25)NR R24, with the provisos that no more than one of R 20 54 WO 00/69826 PCT/US00/08220 and R 21 is hydroxy at the same time and that no more than one of R 23 and R 24 is hydroxy at the same time; 20 21 23 24 25 R20, R21, R , R24, and R are independently selected from the group consisting of hydrido, alkyl, and hydroxy; 5 is selected from the group consisting of a single covalent bond,
CH
2 , and CH 2
CH
2 . In another even more preferred embodiment of compounds of Formula I or a pharmaceutically acceptable salt thereof, J is O; 10 B is optionally selected from the group consisting of hydrido, C2-C8 alkyl, C3-C8 alkenyl, C3-C8 alkynyl, and C2-C8 haloalkyl, wherein each member of group B is optionally substituted at any carbon up to and including 6 atoms from the point of attachment of B to A with one or more of the group 32 33 34 35 36 consisting of R32 , R , R , R , and R36 32 33 34 35 36 15 R , R , R , R , and R are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, alkylthio, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboalkoxy, carboxy, carboxamido, 20 cyano, and Qb A is selected from the group consisting of single covalent bond and
(CH(R
15 ))pa-(W 7)rr wherein rr is an integer selected from 0 through 1, pa is 7 an integer selected from 0 through 3, and W is selected from the group consisting of (R 7)NC(O) and N(R7); 25 R 7 is selected from the group consisting of hydrido, hydroxy and alkyl;
R
15 is selected from the group consisting of hydrido, halo, alkyl, and haloalkyl; 55 WO 00/69826 PCT/US00/08220 W is NH;
R
1 and X are independently selected from the group consisting of hydrido, hydroxy, hydroxyamino, amidino, amino, cyano, hydroxyalkyl, alkoxy, alkyl, alkylamino, aminoalkyl, alkylthio, alkoxyamino, haloalkyl, 5 haloalkoxy, and halo;
R
2 is Zo-Q; Zo is selected from the group consisting of covalent single bond, O, S, NH, and CH 2 ; Q is selected from the group consisting of aryl and heteroaryl wherein a 10 carbon adjacent to the carbon at the point of attachment is optionally substituted 9 by R 9 , the other carbon adjacent to the carbon at the point of attachment is 13 9 optionally substituted by R 1 , a carbon adjacent to R and two atoms from the 10 carbon at the point of attachment is optionally substituted by R 10 , a carbon adjacent to R 13 and two atoms from the carbon at the point of attachment is 12 10 12. 15 optionally substituted by R 12 , and any carbon adjacent to both R 0 and R 12 is optionally substituted by R 1 1 9 11 13 R , R 1 1 , and R 13 are independently selected from the group consisting of hydrido, hydroxy, amino, amidino, guanidino, lower alkylamino, alkylthio, alkylsulfonamido, alkylsulfinyl, alkylsulfonyl, 20 amidosulfonyl, monoalkyl amidosulfonyl, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboxy, carboxamido, and cyano; R10 and R 12 are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkyl, alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, alkylsulfonamido, 25 amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, hydroxyalkyl, alkylenylamino, carboalkoxy, carboxy, carboxyalkyl, amidocarbonyl, halo, haloalkyl, and cyano; 56 WO 00/69826 PCT/US00/08220 K is CH 2 ;
E
0 is C(O)N(H); Y is formula (IV): s R17 R18 R16 D5 2 D R19 Qb (IV) 5 65 6 5 wherein D , D 6 , J5 , and J are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more than one is a covalent bond, K 2 is C, no more than one of DS, D 6 J5, and J6 5 65 6 5 65 6 is O, no more than one of DS, D , , and J is S, one of D D 5, and J 5 65 6 must be a covalent bond when two of D , D 6 , and J are O and S, and no 5 65 6 16 17 10 more than four of DS, D , J, and J are N, with the provisos that R 16 , R 17 18 19
R
18 , and R 19 are each independently selected to maintain the tetravalent nature of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen; 16 17 18 19
R
16 , R 17 , R 18 , and R 19 are independently selected from the group 15 consisting of hydrido, amidino, guanidino, carboxy, haloalkylthio, alkoxy, hydroxy, amino, lower alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, alkylenylamino, and cyano; 16 19 b
R
6 and R 9 are optionally Q with the proviso that no more than one 20 of RI6 and R19 is Qb at the same time and that Qb is Qbe 57 WO 00/69826 PCT/US00/08220 Qb is selected from the group consisting of NR20R 2 1 Qbe wherein be .25 23 24 26 25 23 24 Q is hydrido, C(NR 25)NR23 R 24, and N(R 26)C(NR 25)N(R 23)(R 24), with the provisos that no more than one of R20 and R21 is hydroxy at the same time and that no more than one of R 23 and R 24 is hydroxy at the same time; 20 21 23 24 25 26 5 R20, R 2 1 , R , R24, R , and R 26 are independently selected from the group consisting of hydrido, alkyl, and hydroxy; Qs is selected from the group consisting of a single covalent bond,
CH
2 , and CH 2
CH
2 . In still another even more preferred embodiment of compounds of 10 Formula I or a pharmaceutically acceptable salt thereof, J is O; B is selected from the group consisting of C3-C7 cycloalkyl and C4 heterocyclyl, wherein each ring carbon is optionally substituted with R 3 3 , a ring carbon other than the ring carbon at the point of attachment of B to A is 15 optionally substituted with oxo provided that no more than one ring carbon is substituted by oxo at the same time, ring carbons and a nitrogen adjacent to the carbon at the point of attachment are optionally substituted with R or R 13 , a ring carbon or nitrogen adjacent to the R 9 position and two atoms from the 10 point of attachment is optionally substituted with R 0 , a ring carbon or 20 nitrogen adjacent to the R 13 position and two atoms from the point of 12 attachment is optionally substituted with R 12 , a ring carbon three atoms from the point of attachment and adjacent to the R1 0 position is optionally 11 substituted with R 1 1 , a ring carbon three atoms from the point of attachment and adjacent to the R 12 position is optionally substituted with R 33 , and a ring 58 WO 00/69826 PCT/US00/08220 carbon four atoms from the point of attachment and adjacent to the R 1 1 and 33 34 R positions is optionally substituted with R34 9 11 13 R, R, and R are independently selected from the group consisting of hydrido, hydroxy, amino, amidino, guanidino, lower 5 alkylamino, alkylthio, alkylsulfonamido, alkylsulfinyl, alkylsulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboxy, carboxamido, and cyano;
R
10 and R 12 are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkyl, alkoxy, 10 hydroxy, amino, alkoxyamino, lower alkylamino, alkylsulfonamido, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, hydroxyalkyl, alkylenylamino, carboalkoxy, carboxy, carboxyalkyl, amidocarbonyl, halo, haloalkyl, and cyano; 33 34 R and R 3 4 are independently selected from the group consisting of 15 hydrido, acetamido, haloacetamido, amidino, guanidino, alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, alkylthio, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboalkoxy, carboxy, carboxamido, cyano, and Qb A is selected from the group consisting of single covalent bond and 20 (CH(R15 ))pa-(W 7)rr wherein rr is an integer selected from 0 through 1, pa is 7 an integer selected from 0 through 3, and W is selected from the group consisting of (R 7)NC(O) and N(R7); 7 is selected from the roup consisting of hydride, hydroxy and alkyl;
R
15 is selected from the group consisting of hydrido, hydroxy andlo, alkyl, and R5 is selected from the group consisting of hydrido, halo, alkyl, and 25 haloalkyl; W is NH; 59 WO 00/69826 PCT/US00/08220
R
1 and X are independently selected from the group consisting of hydrido, hydroxy, hydroxyamino, amidino, amino, cyano, hydroxyalkyl, alkoxy, alkyl, alkylamino, aminoalkyl, alkylthio, alkoxyamino, haloalkyl, haloalkoxy, and halo; 5 R 2 is Zo-Q; is selected from the group consisting of covalent single bond, O, S, NH, and CH 2 ; Q is selected from the group consisting of aryl and heteroaryl wherein a carbon adjacent to the carbon at the point of attachment is optionally substituted 10 by R , the other carbon adjacent to the carbon at the point of attachment is 13 9 optionally substituted by R 13 , a carbon adjacent to R and two atoms from the 10 carbon at the point of attachment is optionally substituted by R , a carbon 13 adjacent to R and two atoms from the carbon at the point of attachment is 12 10 12 optionally substituted by R 12 , and any carbon adjacent to both RI and R 12 is 15 optionally substituted by R 1 1 K is CH 2 ;
E
0 is C(0)N(H); Y is formula (IV): S R17 1R 8 R , R
D
5 6 K R16'D5 K24D6 R 1 9 lb Q (IV) 60 WO 00/69826 PCT/US00/08220 wherein D 5 , D 6 , J 5, and J6 are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more 2 5 65 6 than one is a covalent bond, K is C, no more than one of DS, D 6 , J5, and J6 5 65 6 5 65 6 is O, no more than one of DS, D , , and J is S, one ofD D , D 6 , and J 5 65 6 5 must be a covalent bond when two of D 5 , D 6 , J5, and J are O and S, and no 5 65 6 16 17 more than four of DS, D , , and J are N, with the provisos that R 16 , R 17 18 19
R
18 , and R 19 are each independently selected to maintain the tetravalent nature of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen; 10 17 18 19 10 R 16 ,
R
17 , R 18 , and R 19 are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, haloalkylthio, alkoxy, hydroxy, amino, lower alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, alkylenylamino, and cyano; 15 R 16 and R 19 are optionally Qb with the proviso that no more than one of 16 19 b b be R and R 19 is Q at the same time and that Q is Qbe Qb is selected from the group consisting of NR20R21, Qbe wherein Qbe is 25 23 24 2 hydrido, and C(NR25)NR R , with the provisos that no more than one of R 2 0 21 .23 24 and R 2 1 is hydroxy at the same time and that no more than one of R 2 3 and R 2 4 is 20 hydroxy at the same time; 20 21 23 24 25
R
2 0 , R 2 1 , R , R 2 4 , and R are independently selected from the group consisting of hydrido, alkyl, and hydroxy; QS is selected from the group consisting of a single covalent bond,
CH
2 , and CH 2
CH
2 . 61 WO 00/69826 PCT/US00/08220 In a further even more preferred embodiment of compounds of Formula I or a pharmaceutically acceptable salt thereof, J is O; B is the Formula (V):
R
3 4 R 3 K__, 1 R 3 5 Rn,, K lk, 2 R3 II 1%2 R32,D D D R 3 6 5 (V) 1 212 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 12 1 than one is a covalent bond, no more than one of D , D 2 , J1, J2 and K is O, 1 2 12 1 1 21 2 no more than one of D, D 2 , , J2 and K is S, one of D D , 1, J2 and 1 1 2 12 1 10 K must be a covalent bond when two of D, D 2 , 1, J2 and K are O and S, 1 2 12 1 and no more than four of D , D 2 , J1, J2 and K are N; 32 33 34 35 36 R , R , R , R , and R are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, alkylthio, 15 amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboalkoxy, carboxy, carboxamido, cyano, and Qb B is optionally selected from the group consisting of hydrido, C2-C8 alkyl, C3-C8 alkenyl, C3-C8 alkynyl, and C2-C8 haloalkyl, wherein each 20 member of group B is optionally substituted at any carbon up to and including 6 atoms from the point of attachment of B to A with one or more of the group 32 33 34 35 36 consisting of R , R , R , R , and R ; 62 WO 00/69826 PCT/US00/08220 B is selected from the group consisting of C3-C7 cycloalkyl and C4-C6 saturated heterocyclyl, wherein each ring carbon is optionally substituted with 33
R
33 , a ring carbon other than the ring carbon at the point of attachment of B to A is optionally substituted with oxo provided that no more than one ring carbon 5 is substituted by oxo at the same time, ring carbons and nitrogen adjacent to the carbon atom at the point of attachment are optionally substituted with R or 13 9 .
R
13 , a ring carbon or nitrogen adjacent to the R position and two atoms from 10 the point of attachment is optionally substituted with R 10 , a ring carbon or nitrogen adjacent to the R 13 position and two atoms from the point of 12, e he 10 attachment is optionally substituted with R 12 , a ring carbon or nitrogen three atoms from the point of attachment and adjacent to the R 10 position is 11 optionally substituted with R 11 , a ring carbon or nitrogen three atoms from the point of attachment and adjacent to the R 12 position is optionally 33 substituted with R 3 3 , and a ring carbon or nitrogen four atoms from the point 11 33 15 of attachment and adjacent to the R 1 1 and R 3 3 positions is optionally 34 substituted with R34; 9 10 11 12 13
R
9 , R10, R 1 1 , R12, and R 13 are independently selected from the group consisting of hydrido, acetamido, haloacetamido, alkoxyamino, alkanoyl, haloalkanoyl, amidino, guanidino, alkylenedioxy, haloalkylthio, 20 heteroaryl, heterocyclyl, alkoxy, hydroxy, amino, lower alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylsulfonamido, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, carboalkoxy, carboxyalkyl, carboxy, carboxamido, and cyano; 25 A is selected from the group consisting of single covalent bond and (CH(R 15))pa(W )rr wherein rr is an integer selected from 0 through 1, pa is 63 WO 00/69826 PCT/US00/08220 an integer selected from 0 through 3, and W 7 is selected from the group consisting of (R 7)NC(O) and N(R7); R7is selected from the group consisting of hydride, hydroxy and alkyl;
R
15 is selected from the group consisting of hydrido, hdralo, alkylxy and alkyl; R 15is selected from the group consisting of hydrido, halo, alkyl, and 5 haloalkyl; ' is NH; Xo 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; 10 R1 and R 2 are taken together to be -W=X-Y=Z- wherein -W=X-Y=Z forms a ring selected from the group consisting of a heteroaryl ring having from 5 through 6 contiguous members and an aryl; W, X, Y, and Z are independently selected from the group consisting of C(R ), C(R10), C(R 1 1 ), C(R12), N, N(R10), O, S and a covalent bond 15 with the provisos that W, X, Y, and Z can be independently selected to be a covalent bond when one of W, X, Y, and Z is selected from the group consisting of N, N(R10), 0, and S, no more than one of W, X, Y, and Z is optionally selected from the group consisting of O and S, and no more than three of W, X, Y, and Z can be selected from the group consisting of N and 20 N(R10); RI and R 2 spacer pair is optionally selected to be taken together to form a spacer pair wherein the spacer pair forms a linear moiety having from 3 through 6 contiguous atoms connecting the points of bonding of said spacer pair members to form a ring selected from the group consisting of a 25 cycloalkenyl ring having from 5 through 8 contiguous members and a partially saturated heterocyclyl ring having from 5 through 8 contiguous members, wherein said spacer pair is optionally substituted with one or more of the group consisting of R 9 , R 10 , R 1 1 , R 12 , and R13 64 WO 00/69826 PCT/US00/08220 K is CH 2 ; 0 E is C(O)N(H); O is formula (IV): S 17 8 R18
R
1 6 R16 Dk 2,D 6 1 9 b (IV) 5 wherein D , D 6 , J5 , and J are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more 2 5 65 6 than one is a covalent bond, K is C, no more than one of D 5 ,
D
6 , J5, and J6 5 65 6 5 65 6 is O, no more than one of DS, D , , and J is S, one of D D , J and J 5 65 6 must be a covalent bond when two of D , D 6 , and J6 are 0 and S, and no 5 65 6 16 17 10 more than four of DS, D , , and J6 are N, with the provisos that R 16 , R 17 18 19 R 8 , and R 19 are each independently selected to maintain the tetravalent nature of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen; 16 17 18 19
R
16 , R 7 , R 8 , and R 9 are independently selected from the group 15 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;
R
16 and R 19 are optionally Qb with the proviso that no more than one 16 19 b b .be 20 of R 6 and R 9 is Q at the same time and that Q is Qbe 65 WO 00/69826 PCT/US00/08220 Qb is selected from the group consisting of NR20R21 Qbe wherein Qbe is 26 25 23 24 25 23 24 hydrido, N(R26)C(NR25)N(R )(R24), and C(NR )NR R24, with the provisos that no more than one of R 2 0 and R 2 1 is hydroxy, amino, alkylamino, or dialkylamino at the same time and that no more than one of R 2 3 and R 2 4 is 5 hydroxy, amino, alkylamino, or dialkylamino at the same time; 20 21 23 24 25 26
R
2 0 , R 2 1 , R , R 2 4 , R , and R 26 are independently selected from the group consisting of hydrido, alkyl, hydroxy, amino, alkylamino and dialkylamino; Q is selected from the group consisting of a single covalent bond,
CH
2 , and CH 2
CH
2 . 10 In a most preferred embodiment of compounds of Formula I or a pharmaceutically acceptable salt thereof, J is O; B is the Formula:
R
3 4
R
3 3
R
3 5
R
3 2
R
3 6 32 33 34 35 36 15 R , R , R , R , and R are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, alkylthio, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboalkoxy, carboxy, carboxamido, 20 cyano,and Qb 66 WO 00/69826 PCT/US00/08220 A is selected from the group consisting of single covalent bond and (CH(R 15))pa-(W 7)rr wherein rr is an integer selected from 0 through 1, pa is an integer selected from 0 through 3, and W 7 is N(R7);
R
7 is selected from the group consisting of hydride and alkyl; ~5 R 15 is selected from the group consisting of hydrido, halod alkyl, and 5 R 15is selected from the group consisting of hydrido, halo, alkyl, and haloalkyl; tI is NH;
R
1 and X are independently selected from the group consisting of hydrido, hydroxy, hydroxyamino, amidino, amino, cyano, hydroxyalkyl, 10 alkoxy, alkyl, alkylamino, aminoalkyl, alkylthio, alkoxyamino, haloalkyl, haloalkoxy, and halo;
R
2 is Zo-Q; Z is a covalent single bond; Q is selected from the group consisting of aryl and heteroaryl wherein a 15 carbon 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 13 9 optionally substituted by R 13 , a carbon adjacent to R and two atoms from the 10 carbon at the point of attachment is optionally substituted by R 10 , a carbon adjacent to R 13 and two atoms from the carbon at the point of attachment is 12 10 12. 20 optionally substituted by R 12 , and any carbon adjacent to both R 0 and R 12 is optionally substituted by R 9 11 13 R , R 1 , and R 13 are independently selected from the group consisting of hydrido, hydroxy, amino, amidino, guanidino, lower alkylamino, alkylthio, alkoxy, alkylsulfinyl, alkylsulfonyl, amidosulfonyl, 25 monoalkyl amidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboxy, carboxamido, and cyano; 67 WO 00/69826 PCT/US00/08220
R
10 and R 12 are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkyl, alkoxy, alkoxyamino, aminoalkyl, hydroxy, amino, lower alkylamino, alkylsulfonamido, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl 5 amidosulfonyl, hydroxyalkyl, aminoalkyl, halo, haloalkyl, carboalkoxy, carboxy, carboxyalkyl, carboxyamido, and cyano; K is CH 2 ;
E
0 is C(O)N(H); YO is formula (IV): S R17 ' * 18 R R 1
R
1 6 / D 2 D R 1 9 10 Qb (IV) 5 65 6 wherein D , D 6 , J5 , and J are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more 2 5 65 6 than one is a covalent bond, K is C, no more than one of D , D 6 , J5, and J 5 65 6 5 65 6 is O, no more than one of DS, D , , and J is S, one of DS, D , ,and J6 5 65 6 15 must be a covalent bond when two of D 5 , D 6 , and J are 0 and S, and no 5 65 6 more than four of D , D 6 , and J are N; 16 17 18 19
R
16 , R 17 , R 18 , and R 19 are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, haloalkylthio, alkoxy, hydroxy, amino, lower alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, 20 alkanoyl, haloalkanoyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, and cyano; 68 WO 00/69826 PCT/US00/08220 16 19 b
R
16 and R 19 are optionally Q with the proviso that no more than one of
R
16 and R 19 is Qb at the same time and that Qb is Qbe Qbis selected from the group consisting of NR20R21, Qbe wherein Qbe is 25 23 24 hydrido, and C(NR )NR. R ; 20 21 23 24 25 5 R20, R21, R , R24, and R are independently selected from the group consisting of hydrido and alkyl; Qs is CH 2 . In another most preferred embodiment of compounds of Formula I or a pharmaceutically acceptable salt thereof, 10 J is O; B is optionally selected from the group consisting of hydrido, C2-C8 alkyl, C3-C8 alkenyl, C3-C8 alkynyl, and C2-C8 haloalkyl, wherein each member of group B is optionally substituted at any carbon up to and including 6 atoms from the point of attachment of B to A with one or more of the group 32 33 34 35 36 15 consisting of R 32 , R 33,
R
34 , R 35, and R36 32 33 34 35 36 R , R , R , R , and R are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, alkylthio, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, alkyl, halo, 20 haloalkyl, haloalkoxy, hydroxyalkyl, carboalkoxy, carboxy, carboxamido, cyano, and Qb A is selected from the group consisting of single covalent bond and
(CH(R
15 ))pa-(W 7)rr wherein rr is an integer selected from 0 through 1, pa is an integer selected from 0 through 3, and W 7 is N(R 7); 25 R 7 is selected from the group consisting of hydride and alkyl;
R
15 is selected from the group consisting of hydrido, halod alkyl, and R 15is selected from the group consisting of hydrido, halo, alkyl, and haloalkyl; 69 WO 00/69826 PCT/US00/08220 Sis NH;
R
1 and Xo are independently selected from the group consisting of hydrido, hydroxy, hydroxyamino, amidino, amino, cyano, hydroxyalkyl, alkoxy, alkyl, alkylamino, aminoalkyl, alkylthio, alkoxyamino, haloalkyl, 5 haloalkoxy, and halo;
R
2 is Zo-Q;
S
is a covalent single bond; Q is selected from the group consisting of aryl and heteroaryl wherein a carbon adjacent to the carbon at the point of attachment is optionally substituted 9 10 by R , the other carbon adjacent to the carbon at the point of attachment is 13 9 optionally substituted by R 13 , a carbon adjacent to R and two atoms from the 10 carbon at the point of attachment is optionally substituted by R 0 , a carbon adjacent to R 13 and two atoms from the carbon at the point of attachment is 12 10 12 optionally substituted by R 12 , and any carbon adjacent to both R 0 and R 12 is 15 optionally substituted by R 1 1
R
9 , R 11 , and R 13 are independently selected from the group consisting of hydrido, hydroxy, amino, amidino, guanidino, lower alkylamino, alkylthio, alkoxy, alkylsulfinyl, alkylsulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, 20 carboxy, carboxamido, and cyano; R1 0 and R 12 are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkyl, alkoxy, alkoxyamino, aminoalkyl, hydroxy, amino, lower alkylamino, alkylsulfonamido, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl 25 amidosulfonyl, hydroxyalkyl, aminoalkyl, halo, haloalkyl, carboalkoxy, carboxy, carboxyalkyl, carboxyamido, and cyano; K is CH 2 ; 70 WO 00/69826 PCT/US00/08220 E is C(O)N(H); YO is formula (IV): s R17 R1 8 R 16/D K2pD R 1 9 lb b (IV) 5 65 6 wherein D , D 6 , J5, and J are independently selected from the group 5 consisting of C, N, O, S and a covalent bond with the provisos that no more than one is a covalent bond, K 2 is C, no more than one of D 5 , D 6 , J 5, and J6 5 65 6 5 65 6 is O, no more than one of D 5 , D , , and J is S, one of DS, D 6 , , and J 5 65 6 must be a covalent bond when two of D , D 6 , and J are O and S, and no 5 65 6 16 17 more than four of DS, D , J, and J are N, with the provisos that R 16 , R 17 18 19 10 R 18 , and R 19 are each independently selected to maintain the tetravalent nature of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen; 16 17 18 19
R
16 , R 17 , R 18 , and R 19 are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, haloalkylthio, alkoxy, 15 hydroxy, amino, lower alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, and cyano;
R
16 and R 19 are optionally Qb with the proviso that no more than one of
R
16 and R 19 is Qb at the same time and that Qb is Qbe 71 WO 00/69826 PCT/US00/08220 b 20 21 be be. Qb is selected from the group consisting of NR20R 2 1 , be wherein Qbe is 26 25 23 24 25 23 24 hydrido, N(R26)C(NR )N(R )(R ), and C(NR25)NR R 24 20 21 23 24 25 26
R
2 0 , R 2 1 , R , R 24 ,
R
2 5 , and R 26 are independently selected from the group consisting of hydrido and alkyl; 5 Q is CH 2 In still another most preferred embodiment of compounds of Formula I or a pharmaceutically acceptable salt thereof, J is O; B is selected from the group consisting of C3-C7 cycloalkyl and C4 33 10 heterocyclyl, 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 nitrogens adjacent to the carbon at the point of attachment are optionally substituted with R or R 13 , a 9 15 ring carbon or nitrogen adjacent to the R position and two atoms from the 10 point of attachment is optionally substituted with R 10 , a ring carbon or 13 nitrogen adjacent to the R 3 position and two atoms from the point of 12 attachment is optionally substituted with R 2 , a ring carbon three atoms from the point of attachment and adjacent to the R1 0 position is optionally 20 substituted with R 11, a ring carbon three atoms from the point of attachment 12 33 and adjacent to the R 12 position is optionally substituted with R 3 3 , and a ring carbon four atoms from the point of attachment and adjacent to the R 11 and 33 34
R
3 3 positions is optionally substituted with R34 9 11 13 R , R , and R are independently selected from the group 25 consisting of hydrido, hydroxy, amino, amidino, guanidino, lower 72 WO 00/69826 PCT/US00/08220 alkylamino, alkylthio, alkoxy, alkylsulfinyl, alkylsulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboxy, carboxamido, and cyano;
R
10 and R 12 are independently selected from the group consisting of 5 hydrido, acetamido, haloacetamido, amidino, guanidino, alkyl, alkoxy, alkoxyamino, aminoalkyl, hydroxy, amino, lower alkylamino, alkylsulfonamido, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, hydroxyalkyl, aminoalkyl, halo, haloalkyl, carboalkoxy, carboxy, carboxyalkyl, carboxyamido, and cyano; 10 R 33 and R 3 4 are independently selected from the group consisting of hydrido, amidino, guanidino, alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, alkylthio, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboalkoxy, carboxy, carboxamido, and cyano; 33 b 15 R 33 is optionally Q ; A is selected from the group consisting of single covalent bond and (CH(R 15))pa-(W 7)rr wherein rr is an integer selected from 0 through 1, pa is an integer selected from 0 through 3, and W 7 is N(R7);
R
7 is selected from the group consisting of hydrido, hydroxy and alkyl; 20 R 15 is selected from the group consisting of hydrido, halo, alkyl, and haloalkyl; IF is NH;
R
1 and Xo are independently selected from the group consisting of hydrido, hydroxy, hydroxyamino, amidino, amino, cyano, hydroxyalkyl, 25 alkoxy, alkyl, alkylamino, aminoalkyl, alkylthio, alkoxyamino, haloalkyl, haloalkoxy, and halo;
R
2 is Zo-Q; Z is a covalent single bond; 73 WO 00/69826 PCT/US00/08220 Q is selected from the group consisting of aryl and heteroaryl wherein a carbon adjacent to the carbon at the point of attachment is optionally substituted 9 by R 9 , the other carbon adjacent to the carbon at the point of attachment is 13 9 optionally substituted by R 13 , a carbon adjacent to R and two atoms from the 10 5 carbon at the point of attachment is optionally substituted by R 10 , a carbon adjacent to R 13 and two atoms from the carbon at the point of attachment is 12 10 12. optionally substituted by R 12 , and any carbon adjacent to both R I and R 12 is optionally substituted by R11 K is CH 2 ; 10 E is C(O)N(H); Yo is formula (IV): S R17 R18 R 16,0,,D5N, K2 p D R19 lb Q (IV) 5 65 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 15 than one is a covalent bond, K 2 is C, no more than one of D 5 ,
D
6 5, and J6 5 6 5 6 5 6 5 6 is O, no more than one of D , D , J , and J is S, one of D D ,J ,and J 5 65 6 must be a covalent bond when two of D 5 , D 6 , J , and J are 0 and S, and no 5 65 6 16 17 more than four of D , D 6 , J , and J6 are N, with the provisos that R 16 , R 7 18 19 R , and R are each independently selected to maintain the tetravalent nature 74 WO 00/69826 PCT/US00/08220 of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen; 16 17 18 19
R
16 , R 17 , R 18 , and R 19 are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, haloalkylthio, alkoxy, 5 hydroxy, amino, lower alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, alkylenylamino, and cyano;
R
16 and R 19 are optionally Qb with the proviso that no more than one of
R
16 and R 19 is Qb at the same time and that Qb is Qbe b 20 21 be be. 10 Q is selected from the group consisting of NR20R21, be wherein Qbe is hydrido, and C(NR25 )NR23R24; 20 21 23 24 25
R
2 0 , R 2 1 , R , R 2 4 , and R 2 5 are independently selected from the group consisting of hydrido and alkyl; Qs isCH 2 . 15 In a further most preferred embodiment of compounds of Formula I or a pharmaceutically acceptable salt thereof, J is O; B is the Formula (V): 34 33 1 35
R
3 3 - Ki R K 2R R32 D 1 D2 R36 (V) 20 wherein D , D 2 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 12 1 than one is a covalent bond, no more than one of D , D 2 , J1, J2 and K is O, 75 WO 00/69826 PCT/US00/08220 no more than one of D, D2, 1, J2 and K 1 is S, one of D 1 , D2, 1, J2 and 1 1 2 12 1 K must be a covalent bond when two of D , D 2 , J , J2 and K are O and S, 1 2 12 1 and no more than four of D , J D 2 , J2 and K are N; 32 33 34 35 36 R , R , R , R , and R are independently selected from the 5 group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, alkylthio, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboalkoxy, carboxy, carboxamido, cyano,and Qb 10 B is optionally selected from the group consisting of hydrido, C2-C8 alkyl, C3-C8 alkenyl, C3-C8 alkynyl, and C2-C8 haloalkyl, wherein each member of group B is optionally substituted at any carbon up to and including 6 atoms from the point of attachment of B to A with one or more of the group 32 33 34 35 36 consisting of R 3 2 , R 3 3 , R 3 4 ,
R
3 5 , and R36 15 B is selected from the group consisting of C3-C7 cycloalkyl and C4-C6 saturated heterocyclyl, wherein each ring carbon is optionally substituted with 33 R , a ring carbon other than the ring carbon at the point of attachment of B to A is optionally substituted with oxo provided that no more than one ring carbon is substituted by oxo at the same time, ring carbons and nitrogen adjacent to the 20 carbon atom at the point of attachment are optionally substituted with R or
R
13 , a ring carbon or nitrogen adjacent to the R position and two atoms from the point of attachment is optionally substituted with R , a ring carbon or nitrogen adjacent to the R 13 position and two atoms from the point of 12 attachment is optionally substituted with R 2 , a ring carbon or nitrogen three 25 atoms from the point of attachment and adjacent to the R1 0 position is optionally substituted with R 1 1 , a ring carbon or nitrogen three atoms from 76 WO 00/69826 PCT/US00/08220 the point of attachment and adjacent to the R 12 position is optionally substituted with R 3 3 , and a ring carbon or nitrogen four atoms from the point of attachment and adjacent to the Rl and R 3 3 positions is optionally substituted with R34 9 11 13 5 R , R , and R 13 are independently selected from the group consisting of hydrido, hydroxy, amino, amidino, guanidino, lower alkylamino, alkylthio, alkoxy, alkylsulfinyl, alkylsulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboxy, carboxamido, and cyano; 10 R1 0 and R 12 are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkyl, alkoxy, alkoxyamino, aminoalkyl, hydroxy, amino, lower alkylamino, alkylsulfonamido, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, hydroxyalkyl, aminoalkyl, halo, haloalkyl, carboalkoxy, 15 carboxy, carboxyalkyl, carboxyamido, and cyano; A is selected from the group consisting of single covalent bond and (CH(R15 ))pa7(W )rr wherein rr is an integer selected from 0 through 1, pa is an integer selected from 0 through 3, and W 7 is N(R7);
R
7 is selected from the oup consisting of hydride, hydroxy and alkyl; 20 R 15 is selected from the group consisting of hydrido, hdralo, alkylxy and alkyl; 20 R 15is selected from the group consisting of hydrido, halo, alkyl, and haloalkyl; W is NH; Xo is selected from the group consisting of hydrido, alkyl, cyano, halo, haloalkyl, haloalkoxy, amino, aminoalkyl, alkylamino, amidino, hydroxy, 25 hydroxyamino, alkoxy, hydroxyalkyl, alkoxyamino, thiol, and alkylthio; 77 WO 00/69826 PCT/US00/08220 RI and R 2 are taken together to be -W=X-Y=Z- wherein -W=X-Y=Z forms a ring selected from the group consisting of a heteroaryl ring having 6 contiguous members and an aryl; W, X, Y, and Z are independently selected from the group consisting 5 of C(R9), C(R10), C(R 1 1 ), C(R12), and N; K is CH 2 ; E is C(O)N(H); YO is formula (IV): S R1 7 ' s R1 8 R| R R 16,1'D5N, 2 D R 19 Qb (IV) 10 wherein D , D 6 , J5 , and J are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more than one is a covalent bond, K 2 is C, no more than one of D 5 , D6 , J5 and J6 5 65 6 5 65 6 is O, no more than one of D . D, J 5, and J is S, one of D 5 , D 6 , and J6 5 65 6 must be a covalent bond when two of D , D 6 , J5 , and J are 0 and S, and no 5 65 6 16 17 15 more than four of D , D , J ,and J are N, with the provisos that R 16 , R 17 18 19 R 8 , and R 9 are each independently selected to maintain the tetravalent nature of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen; 16 17 1s 19 R 6 , R 17 , R 18 , and R 9 are independently selected from the group 20 consisting of hydrido, amidino, guanidino, carboxy, haloalkylthio, alkoxy, hydroxy, amino, lower alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, 78 WO 00/69826 PCT/US00/08220 alkanoyl, haloalkanoyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, and cyano;
R
16 and R 19 are optionally Qb with the proviso that no more than one of R 16 and R 19 is Qb at the same time and that Qb is Qbe 5 Qb is selected from the group consisting of NR20R 2 1 Qbe wherein Qbe is hydrido, N(R26)C(NR25)N(R 23)(R24), and C(NR25 )NR23R24 20 21 23 24 25 26
R
20 , R 2 1 , R , R 2 4 , R 25 , and R 2 6 are independently selected from the group consisting of hydrido and alkyl; Qs is CH 2 . 10 In a preferred specific embodiment of Formula I, compounds have the Formula I-S:
R
1 X0 R 2 B PI N E O H H 4a 0 R (I-S) or a pharmaceutically acceptable salt thereof, wherein; B is the Formula:
R
3 4
R
3 3
R
3 5
R
3 2 15 32 33 34 35 36 R , R , R , R , and R are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, methyl, ethyl, 79 WO 00/69826 PCT/US00/08220 isopropyl, propyl, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, methoxyamino, ethoxyamino, acetamido, trifluoroacetamido, nitro, aminomethyl, 1-aminoethyl, 2-aminoethyl, N-methylamino, dimethylamino, N-ethylamino, methylthio, ethylthio, isopropylthio, trifluoromethylthio, 5 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, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 10 2,2,2-trifluoro- 1-hydroxyethyl, 2,2,2-trifluoro- 1-trifluoromethyl- 1 hydroxyethyl, carboxymethyl, methoxycarbonyl, ethoxycarbonyl, amidocarbonyl, N-methylamidocarbonyl, N,N-dimethylamidocarbonyl, cyano, and Qb; B is selected from the group consisting of hydrido, trimethylsilyl, 15 ethyl, 2-propenyl, 2-propynyl, propyl, isopropyl, butyl, 2-butenyl, 3-butenyl, 2-butynyl, sec-butyl, tert-butyl, isobutyl, 2-methylpropenyl, 1-pentyl, 2 pentenyl, 3-pentenyl, 4-pentenyl, 2-pentynyl, 3-pentynyl, 2-pentyl, 1-methyl 2-butenyl, 1-methyl-3-butenyl, 1-methyl-2-butynyl, 3-pentyl, 1-ethyl-2 propenyl, 2-methylbutyl, 2-methyl-2-butenyl, 2-methyl-3-butenyl, 2-methyl-3 20 butynyl, 3-methylbutyl, 3-methyl-2-butenyl, 3-methyl-3-butenyl, 1-hexyl, 2 hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 2-hexyl, 1-methyl-2-pentenyl, 1-methyl-3-pentenyl, 1-methyl-4-pentenyl, 1 methyl-2-pentynyl, 1-methyl-3-pentynyl, 3-hexyl, 1-ethyl-2-butenyl, 1-ethyl 3-butenyl, 1-propyl-2-propenyl, 1-ethyl-2-butynyl, 1-heptyl, 2-heptenyl, 3 25 heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl, 2-heptynyl, 3-heptynyl, 4 heptynyl, 5-heptynyl, 2-heptyl, 1-methyl-2-hexenyl, 1-methyl-3-hexenyl, 1 methyl-4-hexenyl, 1-methyl-5-hexenyl, 1-methyl-2-hexynyl, 1-methyl-3 hexynyl, 1-methyl-4-hexynyl, 3-heptyl, 1-ethyl-2-pentenyl, 1-ethyl-3 pentenyl, 1-ethyl-4-pentenyl, 1-butyl-2-propenyl, 1-ethyl-2-pentynyl, 1-ethyl 30 3-pentynyl, 1-octyl, 2-octenyl, 3-octenyl, 4-octenyl, 5-octenyl, 6-octenyl, 7 octenyl, 2-octynyl, 3-octynyl, 4-octynyl, 5-octynyl, 6-octynyl, 2-octyl, 1 methyl-2-heptenyl, 1-methyl-3-heptenyl, 1-methyl-4-heptenyl, 1-methyl-5 heptenyl, 1-methyl-6-heptenyl, 1-methyl-2-heptynyl, 1-methyl-3-heptynyl, 1 methyl-4-heptenyl, 1-methyl-5-heptenyl, 1-methyl-6-heptenyl, 1-methyl-2 35 heptenyl, 1-methyl-3-heptynyl, 1-methyl-4-heptynyl, 1-methyl-5-heptynyl, 3 80 WO 00/69826 PCT/US00/08220 octyl, 1-ethyl-2-hexenyl, I-ethyl-3-hexenyl, 1-ethyl-4-hexenyl, 1-ethyl-2 hexynyl, 1-ethyl-3-hexynyl, 1-ethyl-4-hexynyl, 1-ethyl-5-hexenyl, 1-pentyl-2 propenyl, 4-octyl, 1-propyl-2-pentenyl, 1-propyl-3-pentenyl, 1-propyl-4 pentenyl, 1-butyl-2-butenyl, 1-propyl-2-pentynyl, 1-propyl-3-pentynyl, 1 5 butyl-2-butynyl, 1-butyl-3-butenyl, 2,2.2-trifluoroethyl, 2,2-difluoropropyl, 4-trifluoromethyl-5,5,5-trifluoropentyl, 4-trifluoromethylpentyl, 5,5,6,6,6 pentafluorohexyl, and 3,3,3-trifluoropropyl, wherein each member of group B is optionally substituted at any carbon up to and including 5 atoms from the 32 point of attachment of B to A with one or more of the group consisting of R 3 2 33 34 35 36 10 R 3 3 ,
R
3 4 ,
R
3 5 , and R36 B is optionally selected from the group consisting of cyclopropyl, cyclobutyl, oxetan-2-yl, oxetan-3-yl, azetidin-1-yl, azetidin-2-yl, azetidin-3-yl, thiaetan-2-yl, thiaetan-3-yl, cyclopentyl, cyclohexyl, adamantyl, norbornyl, 3 trifluoromethylnorbornyl, bicyclo[3.1.0]hexan-6-yl, cycloheptyl, and 33 15 cyclooctyl, wherein each ring carbon is optionally substituted with R , ring carbons or a nitrogen adjacent to the carbon atom at the point of attachment are optonll sbsttuedwih 9 R13 optionally substituted with R9 or R13, a ring carbon or a nitrogen adjacent to 9. the R position and two atoms from the point of attachment is optionally 10 1 substituted with R 10 , and a ring carbon or a nitrogen adjacent to the R 13 20 position and two atoms from the point of attachment is optionally substituted with R12 9 10 11 12 13 R , R , R , R , and R are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, carboxymethyl, methyl, ethyl, isopropyl, propyl, methoxy, ethoxy, isopropoxy, propoxy, 25 hydroxy, amino, methoxyamino, ethoxyamino, acetamido, trifluoroacetamido, nitro, aminomethyl, 1-aminoethyl, 2-aminoethyl, N-methylamino, dimethylamino, N-ethylamino, methylthio, ethylthio, isopropylthio, trifluoromethylthio, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, 2,2,3,3,3-pentafluoropropyl, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, 30 fluoro, chloro, bromo, methanesulfonamido, amidosulfonyl, N 81 WO 00/69826 PCT/US00/08220 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, 5 ethoxycarbonyl, amidocarbonyl, N-methylamidocarbonyl,
N,N
dimethylamidocarbonyl, and cyano; A is selected from the group consisting of single covalent bond, O, S, NH, N(CH 3 ), N(OH), C(0), CH 2 , CH 3 CH, CF 3 CH, NHC(0),
N(CH
3 )C(0), C(0)NH, C(0)N(CH 3 ), CF 3 CC(0), C(O)CCH 3 , C(0)CCF 3 ' 10 CH 2 C(0), (0)CCH 2 , CH 2
CH
2 , CH 2
CH
2
CH
2 , CH 3
CHCH
2 , CF 3
CHCH
2 ,
CH
3 CC(0)CH 2 , CF 3 CC(0)CH 2 , CH 2 C(0)CCH 3 , CH 2 C(0)CCF 3 ,
CH
2
CH
2 C(0), and CH 2 (0)CCH 2 ; A is optionally selected from the group consisting of CH 2
N(CH
3 ),
CH
2
N(CH
2
CH
3 ), CH 2
CH
2
N(CH
3 ), and CH 2
CH
2
N(CH
2
CH
3 ) with the 15 proviso that B is hydrido;
R
1 and X 0 are independently selected from the group consisting of hydrido, hydroxy, amino, thiol, amidino, hydroxyamino, aminomethyl, 1 aminoethyl, 2-aminoethyl, methylamino, dimethylamino, cyano, methyl, ethyl, isopropyl, propyl, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, 20 2
,
2
,
3
,
3 ,3-pentafluoropropyl, methoxy, ethoxy, propoxy, hydroxymethyl, 1 hydroxyethyl, 2-hydroxyethyl, methoxyamino, ethoxyamino, methylthio, ethylthio, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro, and bromo;
R
2 is Zo-Q; 25 is selected from the group consisting of covalent single bond, O, S, NH, CH 2 , CH 2
CH
2 , CH(OH), CH(NH 2 ), CH 2 CH(OH), CH 2
CHNH
2 ,
CH(OH)CH
2 , and CH(NH 2
)CH
2 ; 82 WO 00/69826 PCT/US00/08220 Q is selected from the group consisting of phenyl, 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl, 4-imidazolyl, 3 pyrazolyl, 4-pyrazolyl, 1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl, 1,2,4-oxadiazol 3-yl, 1,2,4-oxadiazol-5-yl, 1,3,4-oxadiazol-3-yl, 1,3,4-oxadiazol-5-yl, 3 5 isothiazolyl, 5-isothiazolyl, 2-oxazolyl, 2-thiazolyl, 3-isoxazolyl, 5-isoxazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5 pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 1,3,5-triazin-2-yl, 1,2,4-triazin-3 yl, 1,2,4-triazin-5-yl, 1,2,4-triazin-6-yl, 1,2,3-triazin-4-yl, and 1,2,3-triazin 5-yl, wherein a carbon adjacent to the carbon at the point of attachment is 10 optionally substituted by R 9 , the other carbon adjacent to the carbon at the 13 9 point of attachment is optionally substituted by R 13 , a carbon adjacent to R and two atoms from the carbon at the point of attachment is optionally 10 13 substituted by R 10 , a carbon adjacent to R 13 and two atoms from the carbon at 12 the point of attachment is optionally substituted by R 12 , and any carbon 15 adjacent to both RI 0 and R 12 is optionally substituted by R 11 4a 4a K is CHR 4 a wherein R 4 a is selected from the group consisting of methyl, ethyl, propyl, isopropyl, hydroxymethyl, 1-hydroxyethyl, methoxymethyl, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoromethyl, methylthiomethyl, and hydrido; 20 E is a covalent single bond, C(O)N(H), (H)NC(O), and S(O) 2 N(H); Yo is selected from the group of formulas consisting of: S
R
1 7
R
1 8
R
1 6 R19 Qb 83 WO 00/69826 PCT/US00/08220 s s R17 Y
R
1 8
R
1 8 N
R
1 9 R16 R19 Qb Qb s s
R
1 8 R18 N
R
1 6 R19 Qb Qb S S
R
1 7
R
1 8 N N
R
1 6
R
1 9 Qb Qb Qs S s
R
1 9 Qb R16 )R17 Qb Qb R 1 6 84 WO 00/69826 PCT/US00/08220 Q S Q
R
1 9 Qb
R
1 6 17
R
1 Qb R 1 6 Q SH SH N H Qsbs R1 9 -Qb
R
1 6 1 7
R
1 R bQ Qb R 1 6 Q H S H N QN sR19 s > - b
R
1 7 N Qb QS Q b QS H O\ N
R
1 6
R
1 6
R
1 6 Qb QS b Q S S Q S si R9 -\s b and R17N 5 O 16 17 18 19 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 10 N-methylamino, dimethylamino, N-ethylamino, methylthio, ethylthio, 85 WO 00/69826 PCT/US00/08220 isopropylthio, trifluoromethylthio, methylsulfinyl, ethylsulfinyl, methylsulfonyl, ethylsulfonyl, trifluoromethyl, pentafluoroethyl, 2,2,2 trifluoroethyl, 2,2,3,3,3-pentafluoropropyl, trifluoromethoxy, 1,1,2,2 tetrafluoroethoxy, fluoro, chloro, bromo, amidosulfonyl, N 5 methylamidosulfonyl, N,N-dimethylamidosulfonyl, acetyl, propanoyl, trifluoroacetyl, pentafluoropropanoyl, hydroxymethyl, 1-hydroxyethyl, 2 hydroxyethyl, 2,2,2-trifluoro-1-hydroxyethyl, and cyano; R16 an 19 Qb R16 and R9 are optionally Qb with the proviso that no more than one of R 16 and R 19 is Qb at the same time and that Qb is Qbe b 20 21 be 10 Q is selected from the group consisting of NR20R21, Qbe wherein be .25 23 24 26 25 23 24 Q is hydrido, C(NR 25)NR 23R and N(R 26)C(NR 25)N(R 23)(R 24), with the proviso that no more than one of R 2 0 and R 2 1 is hydroxy, N methylamino, and N,N-dimethylamino at the same time and that no more than one of R 2 3 and R 24 is hydroxy, N-methylamino, and N,N-dimethylamino at 15 the same time; 20 21 23 24 25 26
R
2 0 , R 2 1 , R , R 24 , R , and R 2 6 are independently selected from the group consisting of hydrido, methyl, ethyl, propyl, butyl, isopropyl, hydroxy, 2 aminoethyl, 2-(N-methylamino)ethyl, and 2-(N,N-dimethylamino)ethyl; Qs is selected from the group consisting of a single covalent bond, 20 CH 2 , CH 2
CH
2 , CH 3 CH, CF 3 CH, CH 3
CHCH
2 '
CF
3
CHCH
2 '
CH
2
(CH
3 )CH, CH=CH, CF=CH, C(CH 3 )=CH, CH=CHCH 2 , CF=CHCH 2 ,
C(CH
3
)=CHCH
2 , CH 2 CH=CH, CH 2 CF=CH, CHC(CH 3 )=CH,
CH
2
CH=CHCH
2 , CH 2
CF=CHCH
2 , CH 2
C(CH
3
)=CHCH
2 ,
CH
2
CH=CHCH
2
CH
2 , CH2CF=CHCH 2
CH
2 , and 25 CH 2
C(CH
3
)=CHCH
2
CH
2 . In a more preferred specific embodiment of Formula I, compounds have the Formula I-MPS wherein B is an aromatic: 86 WO 00/69826 PCT/US00/08220
R
1 Xoo N Y B N NN 7 H H 0 (I-MPS wherein B is aromatic) or a pharmaceutically acceptable salt thereof, wherein; B is the Formula:
R
3 4
R
3 3
R
35
R
3 2
R
3 6 5 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, 10 methylthio, ethylthio, isopropylthio, trifluoromethyl, pentafluoroethyl, 2,2,2 trifluoroethyl, 2,2,3,3,3-pentafluoropropyl, trifluoromethoxy, 1,1,2,2 tetrafluoroethoxy, fluoro, chloro, bromo, amidosulfonyl, N methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl, 1 hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro-1-hydroxyethyl, 15 methoxycarbonyl, ethoxycarbonyl, amrnidocarbonyl, N-methylamidocarbonyl, N,N-dimethylamidocarbonyl, cyano, and Qb A is selected from the group consisting of single covalent bond, NH,
N(CH
3 ), N(OH), CH 2 , CH 3 CH, CF 3 CH, NHC(O), N(CH 3 )C(O), 87 WO 00/69826 PCT/US00/08220 C(O)NH, C(O)N(CH 3 ), CH 2
CH
2 , CH 2
CH
2
CH
2 , CH 3
CHCH
2 , and
CF
3
CHCH
2 ;
R
1 and X 0 are independently selected from the group consisting of hydrido, hydroxy, amino, amidino, hydroxyamino, aminomethyl, 1 5 aminoethyl, methylamino, dimethylamino, cyano, methyl, ethyl, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, methoxy, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, methoxyamino, methylthio, ethylthio, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro, and bromo; 10 R 2 is Zo-Q; Z is selected from the group consisting of covalent single bond, O, S, NH, and CH 2 ; Q is selected from the group consisting of phenyl, 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl, 4-imidazolyl, 3 15 pyrazolyl, 4-pyrazolyl, 2-thiazolyl, 3-isoxazolyl, 5-isoxazolyl, 2-pyridyl, 3 pyridyl, 4-pyridyl, 2-pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, and 1,3,5-triazin-2-yl, wherein a carbon adjacent to the carbon at the point of attachment is optionally substituted by R , the other carbon adjacent to the carbon at the point of attachment is optionally 13 9 20 substituted by R 13, a carbon adjacent to R and two atoms from the carbon at 10 the point of attachment is optionally substituted by R 10 , a carbon adjacent to
R
13 and two atoms from the carbon at the point of attachment is optionally 12 10 12 substituted by R 2 , and any carbon adjacent to both R 10 and R 12 is optionally substituted by R 1 1 9 11 13 25 R 9 , R l , and R 3 are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, N-methylamino, 88 WO 00/69826 PCT/US00/08220 N,N-dimethylamino, N-ethylamino, methylthio, ethylthio, isopropylthio, trifluoromethyl, pentafluoroethyl, 2 ,2,2-trifluoroethyl, 2,2,3,33 pentafluoropropyl, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro, bromo, methanesulfonamido, amidosulfonyl, N-methylamidosulfonyl, 5 N,N-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, 2 hydroxyethyl, 2,2,2-trifluoro-l1-hydroxyethyl, amidocarbonyl,
N
methylamidocarbonyl, N,N-dimethylamidocarbonyl, and cyano;
R
10 and R 12 are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, carboxymethyl, methyl, ethyl, propyl, 10 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, 15 2,2,2-trifluoro-1-hydroxyethyl, methoxycarbonyl, ethoxycarbonyl, amidocarbonyl, N-methylamidocarbonyl, N,N-dimethylamidocarbonyl, fluoro, chloro, bromo, and cyano; Qb is selected from the group consisting of NR 20R21, Qbe wherein Qbe is 25 224 2 hydrido, and C(NR )NR23R 4, with the provisos that no more than one of R 2 0 20 and R 2 1 is hydroxy at the same time and that no more than one of R 2 3 and R 24 is hydroxy at the same time; 20 21 23 24 25
R
2 0 , R 2 1 , R , R 24 , and R are independently selected from the group consisting of hydrido, methyl, ethyl, propyl, butyl, isopropyl, and hydroxy; Q is selected from the group consisting of a single covalent bond, 25 CH 2 , and CH 2
CH
2 . In another more preferred specific embodiment of Formula I, compounds have the Formula I-MPS wherein B is a non-cyclic substituent: 89 WO 00/69826 PCT/US00/08220
R
1 XR2 RlR NyO B N N H H 0 (I-MPS wherein B is a non-cyclic substituent) or a pharmaceutically acceptable salt thereof, wherein; B is selected from the group consisting of hydrido, ethyl, 2-propenyl, 5 2-propynyl, propyl, isopropyl, butyl, 2-butenyl, 3-butenyl, 2-butynyl, sec butyl, tenrt-butyl, isobutyl, 2-methylpropenyl, 1-pentyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-pentynyl, 3-pentynyl, 2-pentyl, 1-methyl-2-butenyl, 1-methyl-3 butenyl, 1-methyl-2-butynyl, 3-pentyl, 1-ethyl-2-propenyl, 2-methylbutyl, 2 methyl-2-butenyl, 2-methyl-3-butenyl, 2-methyl-3-butynyl, 3-methylbutyl, 3 10 methyl-2-butenyl, 3-methyl-3-butenyl, 1-hexyl, 2-hexenyl, 3-hexenyl, 4 hexenyl, 5-hexenyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 2-hexyl, 1-methyl-2 pentenyl, 1-methyl-3-pentenyl, 1-methyl-4-pentenyl, 1-methyl-2-pentynyl, 1 methyl-3-pentynyl, 3-hexyl, 1-ethyl-2-butenyl, 1-ethyl-3-butenyl, 1-propyl-2 propenyl, 1-ethyl-2-butynyl, 1 -heptyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5 15 heptenyl, 6-heptenyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 5-heptynyl, 2 heptyl, 1-methyl-2-hexenyl, 1-methyl-3-hexenyl, 1-methyl-4-hexenyl, 1 methyl-5-hexenyl, 1-methyl-2-hexynyl, 1-methyl-3-hexynyl, 1-methyl-4 hexynyl, 3-heptyl, 1-ethyl-2-pentenyl, 1-ethyl-3-pentenyl, 1-ethyl-4-pentenyl, 1-butyl-2-propenyl, 1-ethyl-2-pentynyl, 1-ethyl-3-pentynyl, 2,2,2 20 trifluoroethyl, 2,2-difluoropropyl, 4 -trifluoromethyl-5,5,5-trifluoropentyl, 4 trifluoromethylpentyl, 5,5,6,6,6-pentafluorohexyl, and 3,3,3-trifluoropropyl, wherein each member of group B is optionally substituted at any carbon up to and including 5 atoms from the point of attachment of B to A with one or more 32 33 34 35 36 of the group consisting of R 3 2 , R 3 3 , R 3 4 ,
R
3 5 , and R36 32 33 34 35 36 25 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, 90 WO 00/69826 PCT/US00/08220 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 5 methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl, 1 hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro-1-hydroxyethyl, methoxycarbonyl, ethoxycarbonyl, amidocarbonyl, N-methylamidocarbonyl, N,N-dimethylamidocarbonyl, cyano, and Qb A is selected from the group consisting of single covalent bond, NH, 10 N(CH 3 ), N(OH), CH 2 , CH 3 CH, CF 3 CH, NHC(O), N(CH 3 )C(O), C(O)NH, C(O)N(CH 3 ), CH 2
CH
2 , CH 2
CH
2
CH
2 , CH 3
CHCH
2 , and
CF
3
CHCH
2 ; A is optionally selected from the group consisting of CH 2
N(CH
3 ),
CH
2
N(CH
2
CH
3 ), CH 2
CH
2
N(CH
3 ), and CH 2
CH
2
N(CH
2
CH
3 ) with the 15 proviso that B is hydrido;
R
1 and X 0 are independently selected from the group consisting of hydrido, hydroxy, amino, amidino, hydroxyamino, aminomethyl, 1 aminoethyl, methylarmino, dimethylamino, cyano, methyl, ethyl, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, methoxy, 20 hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, methoxyamino, methylthio, ethylthio, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro, and bromo;
R
2 is Zo-Q; Zo is selected from the group consisting of covalent single bond, O, S, 25 NH, and CH2; Q is selected from the group consisting of phenyl, 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl, 4-imidazolyl, 3 pyrazolyl, 4-pyrazolyl, 2-thiazolyl, 3-isoxazolyl, 5-isoxazolyl, 2-pyridyl, 3 pyridyl, 4-pyridyl, 2-pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 91 WO 00/69826 PCT/US00/08220 3-pyridazinyl, 4-pyridazinyl, and 1,3,5-triazin-2-yl, wherein a carbon adjacent to the carbon at the point of attachment is optionally substituted by R , the other carbon adjacent to the carbon at the point of attachment is optionally 13 9 substituted by R , a carbon adjacent to R and two atoms from the carbon at 10 5 the point of attachment is optionally substituted by R 10 , a carbon adjacent to
R
13 and two atoms from the carbon at the point of attachment is optionally 12 10 12 substituted by R 2 , and any carbon adjacent to both R 10 and R 12 is optionally substituted by Rl 9 11 13 R , R , and R 13 are independently selected from the group consisting 10 of hydrido, amidino, guanidino, carboxy, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, N-methylamino, N,N-dimethylamino, N-ethylamino, methylthio, ethylthio, isopropylthio, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, 2,2,3,3,3 pentafluoropropyl, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, 15 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
10 and R 12 are independently selected from the group consisting of 20 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 25 dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2,2,2 trifluoro-1-hydroxyethyl, methoxycarbonyl, ethoxycarbonyl, amidocarbonyl, N methylamidocarbonyl, N,N-dimethylamidocarbonyl, fluoro, chloro, bromo, and cyano; 92 WO 00/69826 PCT/US00/08220 b 20 21 be b Qb is selected from the group consisting of NR20R21, Qbe, wherein Qbe is hydrido, C(NR25 )N23R24, and N(R26)C(NR25)N(R 23)(R24), with the provisos that no more than one of R20 and R21 is hydroxy at the same time and that no more than one of R 2 3 and R 24 is hydroxy at the same time; 20 21 23 24 25 26 5 R20, R 2 1 , R , R24, R25, and R 2 6 are independently selected from the group consisting of hydrido, methyl, ethyl, propyl, butyl, isopropyl, and hydroxy; Qs is selected from the group consisting of a single covalent bond, CH,, and CH 2
CH
2 . In still another more preferred specific embodiment of Formula I, 10 compounds have the Formula I-MPS wherein B is a non-aromatic cyclic substituent:
R
1 Xo R 2 0 r2 0 B N Y H H 0 (I-MPS wherein B is a non-aromatic cyclic substituent) or a pharmaceutically acceptable salt thereof, wherein; 15 B is optionally selected from the group consisting of cyclopropyl, cyclobutyl, oxetan-3-yl, azetidin-1-yl, azetidin-2-yl, azetidin-3-yl, thiaetan-3 yl, cyclopentyl, cyclohexyl, norbornyl, bicyclo[3.1.Ol]hexan-6-yl, and cycloheptyl , wherein each ring carbon is optionally substituted with R 33 , ring carbons or a nitrogen adjacent to the carbon atom at the point of attachment is 9 13 20 optionally substituted with R or R 3, a ring carbon or nitrogen adjacent to the
R
9 position and two atoms from the point of attachment is optionally 93 WO 00/69826 PCT/US00/08220 substituted with R 10 , and a ring carbon or nitrogen adjacent to the R 13 position and two atoms from the point of attachment is optionally substituted with R12 9 11 13
R
9 , R l, and R 13 are independently selected from the group consisting 5 of hydrido, amidino, guanidino, carboxy, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, N-methylamino, N,N-dimethylamino, N-ethylamino, methylthio, ethylthio, isopropylthio, trifluoromethyl, pentafluoroethyl, 2 ,2,2-trifluoroethyl, 2,2,3,3,3 pentafluoropropyl, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, 10 chloro, bromo, 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
10 and R 12 are independently selected from the group consisting of 15 hydrido, amidino, guanidino, carboxy, carboxymethyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, methoxyamino, ethoxyamino, acetamido, trifluoroacetamido, aminomethyl, 1 aminoethyl, 2-aminoethyl, N-methylamino, dimethylamino, N-ethylamino, methanesulfonamido, amidosulfonyl, N-methylamidosulfonyl,
N,N
20 dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2,2,2 trifluoro-1-hydroxyethyl, methoxycarbonyl, ethoxycarbonyl, amidocarbonyl, N methylamidocarbonyl, N,N-dimethylamidocarbonyl, fluoro, chloro, bromo, and cyano; R33 are independently selected from the group consisting of hydrido, 25 amidino, guanidino, carboxy, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, methoxyamino, ethoxyamino, acetamido, trifluoroacetamido, N-methylamino, dimethylamino, N-ethylamino, methylthio, ethylthio, isopropylthio, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, 2,2,3,3,3-pentafluoropropyl, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, 30 fluoro, chloro, bromo, amidosulfonyl, N-methylamidosulfonyl,
N,N
dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro- 1-hydroxyethyl, methoxycarbonyl, ethoxycarbonyl, 94 WO 00/69826 PCT/US00/08220 amidocarbonyl, N-methylamidocarbonyl, N,N-dimethylamidocarbonyl, cyano, and Qb; A is selected from the group consisting of single covalent bond, NH,
N(CH
3 ), N(OH), CH 2 , CH 3 CH, CF 3 CH, NHC(O), N(CH 3 )C(O), 5 C(O)NH, C(O)N(CH 3 ), CH 2
CH
2 , CH 2
CH
2
CH
2 , CH 3
CHCH
2 , and
CF
3
CHCH
2 ;
R
1 and X 0 are independently selected from the group consisting of hydrido, hydroxy, amino, amidino, hydroxyamino, aminomethyl, 1 aminoethyl, methylamino, dimethylamino, cyano, methyl, ethyl, 10 trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, methoxy, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, methoxyamino, methylthio, ethylthio, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro, and bromo;
R
2 is Zo-Q; 15 is selected from the group consisting of covalent single bond, O, S, NH, and CH 2 ; Q is selected from the group consisting of phenyl, 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyrrolyl, 3 -pyrrolyl, 2-imidazolyl, 4-imidazolyl, 3 pyrazolyl, 4-pyrazolyl, 2-thiazolyl, 3-isoxazolyl, 5-isoxazolyl, 2-pyridyl, 3 20 pyridyl, 4-pyridyl, 2-pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, and 1,3,5-triazin-2-yl, wherein a carbon adjacent 9 to the carbon at the point of attachment is optionally substituted by R , the other carbon adjacent to the carbon at the point of attachment is optionally 13 9 substituted by R 13 , a carbon adjacent to R and two atoms from the carbon at 10 25 the point of attachment is optionally substituted by R 10 , a carbon adjacent to
R
13 and two atoms from the carbon at the point of attachment is optionally 95 WO 00/69826 PCT/US00/08220 substituted by R 12 , and any carbon adjacent to both R1 0 and R 12 is optionally substituted by R 11 b 20 21 be be Qb is selected from the group consisting of NR20R21, Qbe wherein Qbe is 25 23 24 2 hydrido, and C(NR25)NR R24, with the provisos that no more than one of R 20 5 and R 2 1 is hydroxy at the same time and that no more than one of R 23 and R 24 is hydroxy at the same time; 20 21 23 24 25
R
2 0 , R 2 1 , R , R 24 , and R 25 are independently selected from the group consisting of hydrido, methyl, ethyl, propyl, butyl, isopropyl, and hydroxy;
Q
s is selected from the group consisting of a single covalent bond, 10 CH 2 , and CH 2
CH
2 . In a further even more preferred embodiment of compounds of Formula I, compounds have the Formula I-FARMPS wherein there are two fused aromatic rings: Y x o 0 B 1 N N N Y H H 0 (I-FARMPS) 15 or a pharmaceutically acceptable salt thereof, wherein; B is selected from the group consisting of phenyl, 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl, 4-imidazolyl, 3 pyrazolyl, 4-pyrazolyl, 2-thiazolyl, 3-isoxazolyl, 5-isoxazolyl, 2-pyridyl, 3 pyridyl, 4-pyridyl, 2-pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 20 3-pyridazinyl, 4-pyridazinyl, and 1,3,5-triazin-2-yl, wherein a carbon adjacent to the carbon at the point of attachment is optionally substituted by R 3 2 , the other carbon adjacent to the carbon at the point of attachment is optionally 96 WO 00/69826 PCT/US00/08220 36 32 substituted by R 3 6 , a carbon adjacent to R 3 2 and two atoms from the carbon at the point of attachment is optionally substituted by R 3 3 , a carbon adjacent to
R
3 6 and two atoms from the carbon at the point of attachment is optionally 35 33 35 substituted by R , and any carbon adjacent to both R 3 3 and R 3 5 is optionally 34 5 substituted by R34 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, 10 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-1-hydroxyethyl, 15 methoxycarbonyl, ethoxycarbonyl, amidocarbonyl, N-methylamidocarbonyl, N,N-dimethylamidocarbonyl, cyano, and Qb B is selected from the group consisting of hydrido, ethyl, 2-propenyl, 2-propynyl, propyl, isopropyl, butyl, 2-butenyl, 3-butenyl, 2-butynyl, sec butyl, tenrt-butyl, isobutyl, 2-methylpropenyl, 1-pentyl, 2-pentenyl, 3-pentenyl, 20 4-pentenyl, 2-pentynyl, 3-pentynyl, 2-pentyl, l-methyl-2-butenyl, 1-methyl-3 butenyl, 1-methyl-2-butynyl, 3-pentyl, 1-ethyl-2-propenyl, 2-methylbutyl, 2 methyl-2-butenyl, 2-methyl-3-butenyl, 2-methyl-3-butynyl, 3-methylbutyl, 3 methyl-2-butenyl, 3-methyl-3-butenyl, 1-hexyl, 2-hexenyl, 3-hexenyl, 4 hexenyl, 5-hexenyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 2-hexyl, 1-methyl-2 25 pentenyl, 1-methyl-3-pentenyl, 1-methyl-4-pentenyl, 1-methyl-2-pentynyl, 1 methyl-3-pentynyl, 3-hexyl, 1-ethyl-2-butenyl, 1-ethyl-3-butenyl, 1-propyl-2 propenyl, 1-ethyl-2-butynyl, 1-heptyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5 heptenyl, 6-heptenyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 5-heptynyl, 2 heptyl, 1-methyl-2-hexenyl, 1-methyl-3-hexenyl, 1-methyl-4-hexenyl, 1 30 methyl-5-hexenyl, 1-methyl-2-hexynyl, 1-methyl-3-hexynyl, 1-methyl-4 hexynyl, 3-heptyl, 1-ethyl-2-pentenyl, 1 -ethyl-3-pentenyl, 1-ethyl-4-pentenyl, 97 WO 00/69826 PCT/US00/08220 1-butyl-2-propenyl, 1-ethyl-2-pentynyl, 1-ethyl-3-pentynyl, 2,2,2 trifluoroethyl, 2,2-difluoropropyl, 4-trifluoromethyl-5,5,5-trifluoropentyl, 4 trifluoromethylpentyl, 5,5, 6 ,6,6-pentafluorohexyl, and 3,3,3-trifluoropropyl, wherein each member of group B is optionally substituted at any carbon up to 5 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 3 2 ,
R
3 3 , R 34 , R 3 5 , and R36 B is optionally selected from the group consisting of cyclopropyl, cyclobutyl, oxetan-3-yl, azetidin-1-yl, azetidin-2-yl, azetidin-3-yl, thiaetan-3 yl, cyclopentyl, cyclohexyl, norbornyl, 7-oxabicyclo[2.2.1]heptan-2-yl, 10 bicyclo[3.1.0]hexan-6-yl, cycloheptyl, 2-morpholinyl, 3-morpholinyl, 4 morpholinyl, 1-piperazinyl, 2-piperazinyl, 1-piperidinyl, 2-piperidinyl, 3 piperidinyl, 4-piperidinyl, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2 dioxanyl, 4H-2-pyranyl, 4H-3-pyranyl, 4H-4-pyranyl, 4H-pyran-4-one-2-yl, 4H-pyran-4-one-3-yl, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2 15 tetrahydropyranyl, 3-tetrahydropyranyl, 4-tetrahydropyranyl, 2 tetrahydrothienyl, and 3-tetrahydrothienyl, wherein each ring carbon is 33 optionally substituted with R , a ring carbon and nitrogen atoms adjacent to 9 the carbon atom at the point of attachment is optionally substituted with R or 13 9
R
13 , a ring carbon or nitrogen atom adjacent to the R position and two atoms 10 20 from the point of attachment is optionally substituted with R 10 , and a ring 13 carbon or nitrogen atom adjacent to the R13 position and two atoms from the point of attachment is optionally substituted with R12 R and R 1 1 are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, methyl, ethyl, propyl, isopropyl, 25 methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, N-methylamino, N,N-dimethylamino, N-ethylamino, methylthio, ethylthio, isopropylthio, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, 2,2,3,3,3 pentafluoropropyl, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro, bromo, methanesulfonamido, amidosulfonyl, N-methylamidosulfonyl, 30 N,N-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, 2 98 WO 00/69826 PCT/US00/08220 hydroxyethyl, 2,2,2-trifluoro-1-hydroxyethyl, amidocarbonyl, N methylamidocarbonyl, N,N-dimethylamidocarbonyl, and cyano;
R
10 and R 12 are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, carboxymethyl, methyl, ethyl, propyl, 5 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, 10 2,2,2-trifluoro-1-hydroxyethyl, methoxycarbonyl, ethoxycarbonyl, amidocarbonyl, N-methylamidocarbonyl, N,N-dimethylamidocarbonyl, fluoro, chloro, bromo, and cyano; A is selected from the group consisting of single covalent bond, NH,
N(CH
3 ), N(OH), CH 2 , CH 3 CH, CF 3 CH, NHC(O), N(CH 3 )C(O), 15 C(O)NH, C(O)N(CH 3 ), CH 2
CH
2 , CH 2
CH
2
CH
2 , CH 3
CHCH
2 , and
CF
3
CHCH
2 ; A is optionally selected from the group consisting of CH 2
N(CH
3 ),
CH
2
N(CH
2
CH
3 ), CH 2
CH
2
N(CH
3 ), and CH 2
CH
2
N(CH
2
CH
3 ) with the proviso that B is hydrido; 20 X 0 is selected from the group consisting of hydrido, hydroxy, amino, amidino, hydroxyamino, aminomethyl, 1-aminoethyl, methylamino, dimethylamino, cyano, methyl, ethyl, trifluoromethyl, pentafluoroethyl, 2,2,2 trifluoroethyl, methoxy, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, methoxyamino, methylthio, ethylthio, trifluoromethoxy, 1,1,2,2 25 tetrafluoroethoxy, fluoro, chloro, and bromo; W, X, Y, and Z are independently selected from the group consisting of CH, N, CF, CC1, C-CN, C-CH 3 , C-CH 2
CH
3 , C-NH 2 , C-CHNH 2 , C-CH2NHCH 3 , C-NHCH 3 , C-N(CH 3
)
2 , C-CH(NH 2
)CH
3 ,
C-CHCH
2
NH
2 , C-NHOCH 3 , C-NHOCH 2
CH
3 , C-C(NH)NH 2 , 30 C-C(NOH)NH 2 , C-OH, C-CH20H, C-CH 2 CH2OH, C-CH(OH)CH 3 , 99 WO 00/69826 PCT/US00/08220
C-OCH
3 , C-OCH 2
CH
3 , C-CO 2 H, C-CO 2
CH
3 , C-C(O)NH,.
C-C(O)NHCH
3 , C-C(O)NH(CH 3
)
2 , C-CH 2
CO
2 H, C-SO 2
NH
2 ,
C-SO
2
NHCH
3 , C-NH(O)CCH 3 , and C-NH(O)CCF 3 ; Qbis selected from the group consisting of NR20R21 Qbe, wherein Qbe 25 23 24 26 25 23 24 5 is hydrido, C(NR )NR R , and N(R )C(NR )N(R )(R ), with the provisos that no more than one of R20 and R21 is hydroxy at the same time and that no more than one of R 23 and R 24 is hydroxy at the same time; 20 21 23 24 25 26 R20, R 2 1 , R , R24, R25, and R 26 are independently selected from the group consisting of hydrido, methyl, ethyl, propyl, butyl, isopropyl, and hydroxy; 10 QS is selected from the group consisting of a single covalent bond,
CH
2 , and CH 2
CH
2 . The more preferred specific embodiment (I-MPS) and (I-FARMPS) compounds of the present invention having the Formula:
R
1 Xo R2 0 B N N Y H H 0 (I-MPS) and ZX Xo W 0 BA -N NN O H H 15 0 (I-FARMPS) 100 WO 00/69826 PCT/US00/08220 or a pharmaceutically acceptable salt thereof, have common structural units, wherein; Y is selected from the group of formulas consisting of: S
R
1 7
R
1 8 1/
R
1 6 R19 Qb S s
R
1 7
R
1 8
R
1 8 Ni R9 R 16 R 19 5 Qb Qb s s
R
1 8
R
1 8 1 6 19
R
1 R NNN " R 19 Qb bQ S S R1 7 18 N 1 6 R19 Qb Q 101 WO 00/69826 PCT/US00/08220 QS s S I jR19 b R16 )iR1 7, bR Qb R 1 6 Qs R16R19 1 Qb R16/ bR17/ R b Qb
R
1 6 Q H 9H N QN R19 bQ b R16117 Qb
R
1 6 Qs H N Q H N R19 Qb
R
1 7 N Qb Q s C) b Qs H 0\ N\ R16 R16 R16Z QS b S 5 Qb Qs Qb 102 WO 00/69826 PCT/US00/08220 QS SQSS / R1 9 Qb and
R
1 7 N Qb 16 17 18 19 R , R , R , and R are independently selected from the group consisting of hydrido, methyl, ethyl, isopropyl, propyl, carboxy, amidino, guanidino, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, 5 aminomethyl, 1-aminoethyl, 2-aminoethyl, N-methylamino, dimethylamino, N-ethylamino, methylthio, ethylthio, isopropylthio, trifluoromethylthio, methylsulfinyl, ethylsulfinyl, methylsulfonyl, ethylsulfonyl, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, 2,2,3,3,3-pentafluoropropyl, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro, bromo, 10 amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro- 1 hydroxyethyl, and cyano;
R
16 and R 19 are optionally Qb with the proviso that no more than one 16 19 b b be of R 6 and R 19 is Q at the same time and that Q is Qbe 15 In a most preferred specific embodiment of Formula I, compounds have the Formula I-EMPS wherein B is an aromatic:
R
1 Xo R2 0 B N N H H 0 (I-EMPS wherein B is aromatic) or a pharmaceutically acceptable salt thereof, wherein; 20 B is the Formula: 103 WO 00/69826 PCT/US00/08220
R
3 4
R
3 3
R
3 5
R
3 2
R
3 6 I 32 33 34 35 36
R
32 , R 33 , R 34 , R 35 , and R 36 are independently selected from the group consisting of hydrido, amidino, guanidino, methyl, ethyl, methoxy, ethoxy, hydroxy, amino, N-methylamino, dimethylamino, methylthio, 5 ethylthio, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, fluoro, chloro, bromo, amidosulfonyl, N-methylamidosulfonyl, hydroxymethyl, amidocarbonyl, carboxy, cyano, and Qb; A is selected from the group consisting of single covalent bond, NH,
N(CH
3 ), CH 2 , CH 3 CH, and CH 2
CH
2 ; 10 X 0 is selected from the group consisting of hydrido, hydroxy, amino, amidino, amninomethyl, cyano, methyl, trifluoromethyl, hydroxymethyl, and fluoro;
R
1 is selected from the group consisting of hydrido, hydroxy, amino, aminomethyl, methylamino, cyano, methyl, trifluoromethyl, methoxy, 15 methylthio, trifluoromethoxy, fluoro, and chloro;
R
2 is Zo-Q; Z is a covalent single bond; Q is selected from the group consisting of phenyl, 2-thienyl, 2-furyl, 2 pyrrolyl, 2-imidazolyl, 2-thiazolyl, 3-isoxazolyl, 2-pyridyl, and 3-pyridyl, 20 wherein a carbon adjacent to the carbon at the point of attachment is optionally 9 substituted by R 9 , the other carbon adjacent to the carbon at the point of 13 9 attachment is optionally substituted by R 13 , a carbon adjacent to R and two atoms from the carbon at the point of attachment is optionally substituted by 104 WO 00/69826 PCT/US00/08220 10 13 R , a carbon adjacent to R 13 and two atoms from the carbon at the point of 12 attachment is optionally substituted by R 2 , and any carbon adjacent to both
R
10 and R 12 is optionally substituted by R 1 1 R9 , 11 an 13 R , R 11, and R13 are independently selected from the group consisting 5 of hydrido, methyl, ethyl, methoxy, ethoxy, hydroxy, amino, N-methylamino, N,N-dimethylamino, methylthio, trifluoromethyl, pentafluoroethyl, 2,2,2 trifluoroethyl, fluoro, chloro, bromo, amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, amidocarbonyl, N-methylamidocarbonyl. carboxy, and cyano; 10 R 10 and R 12 are independently selected from the group consisting of hydrido, amidino, amidocarbonyl, N-methylamidocarbonyl, guanidino, methyl, ethyl, methoxy, ethoxy, hydroxy, hydroxymethyl, 1-hydroxyethyl, 2 hydroxyethyl, carboxy, carboxymethyl, amino, acetamido, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, trifluoroacetamido, aminomethyl, N 15 methylamino, dimethylamino, amidosulfonyl, N-methylamidosulfonyl,
N,N
dimethylamidosulfonyl, methoxycarbonyl, fluoro, chloro, bromo, and cyano; b 20 21 Q is selected from the group consisting of NR20 R and C(NR25)NR R24, with the proviso that said Qb group is bonded directly to a carbon atom; 20 21 23 24 25 20 R , R , R . R , and R are independently selected from the group consisting of hydrido, methyl, and ethyl; QS is CH 2 . In another most preferred specific embodiment of Formula I, compounds have the Formula I-EMPS wherein B is a non-cyclic substituent: 105 WO 00/69826 PCT/US00/08220
R
1 R2 XoR2 x 0' 0 NN B N N-N 70 H H 0 (I-EMPS wherein B is a non-cyclic substituent) or a pharmaceutically acceptable salt thereof, wherein; B is selected from the group consisting of hydrido, ethyl, 2-propenyl, 5 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, 1-methyl-2-pentenyl, 1-methyl-3 10 pentenyl, 1-methyl-2-pentynyl, 1-methyl-3-pentynyl, 3-hexyl, 1-ethyl-2 butenyl, 1-heptyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 5-heptynyl, 2-heptyl, 1-methyl-2-hexenyl, 1-methyl 3-hexenyl, 1-methyl-4-hexenyl, 1-methyl-2-hexynyl, 1-methyl-3-hexynyl, 1 methyl-4-hexynyl, 3-heptyl, 1-ethyl-2-pentenyl, 1-ethyl-3-pentenyl, 1-ethyl-2 15 pentynyl, 1-ethyl-3-pentynyl, 2,2,2-trifluoroethyl, 2,2-difluoropropyl, 4 trifluoromethyl-5,5,5-trifluoropentyl, 4-trifluoromethylpentyl, 5,5,6,6,6 pentafluorohexyl, and 3,3,3-trifluoropropyl, wherein each member of group B is optionally substituted at any carbon up to and including 5 atoms from the 32 point of attachment of B to A with one or more of the group consisting of R 3 2 33 34 35 36 20 R 33 ,
R
34 , R 3 5 , and R36 32 33 34 35 36
R
3 2 , R 33 , R 34 , R 3 5 , and R 3 6 are independently selected from the group consisting of hydrido, amidino, guanidino, methyl, ethyl, methoxy, ethoxy, hydroxy, amino, N-methylamino, dimethylamino, methylthio, ethylthio, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, fluoro, 25 chloro, bromo, amidosulfonyl, N-methylamidosulfonyl, hydroxymethyl, amidocarbonyl, carboxy, cyano, and Qb 106 WO 00/69826 PCT/US00/08220 A is selected from the group consisting of single covalent bond, NH,
N(CH
3 ), CH 2 , CH 3 CH, and CH 2
CH
2 ; A is optionally selected from the group consisting of CH 2
N(CH
3 ),
CH
2
N(CH
2
CH
3 ), CH 2
CH
2
N(CH
3 ), and CH 2
CH
2
N(CH
2
CH
3 ) with the 5 proviso that B is hydrido;
X
0 is selected from the group consisting of hydrido, hydroxy, amino, amidino, aminomethyl, cyano, methyl, trifluoromethyl, hydroxymethyl, and fluoro;
R
1 is selected from the group consisting of hydrido, hydroxy, amino, 10 aminomethyl, methylamino, cyano, methyl, trifluoromethyl, methoxy, methylthio, trifluoromethoxy, fluoro, and chloro;
R
2 is Zo-Q; Z is a covalent single bond; Q is selected from the group consisting of phenyl, 2-thienyl, 2-furyl, 2 15 pyrrolyl, 2-imidazolyl, 2-thiazolyl, 3-isoxazolyl, 2-pyridyl, and 3-pyridyl, wherein a carbon adjacent to the carbon at the point of attachment is optionally substituted by R , the other carbon adjacent to the carbon at the point of 13 9 attachment is optionally substituted by R 3 , a carbon adjacent to R and two atoms from the carbon at the point of attachment is optionally substituted by 10 13 20 R 10, a carbon adjacent to R13 and two atoms from the carbon at the point of 12 attachment is optionally substituted by RI 2 , and any carbon adjacent to both
R
10 and R 12 is optionally substituted by R 11 9 11 13
R
9 , R , and R 3 are independently selected from the group consisting of hydrido, methyl, ethyl, methoxy, ethoxy, hydroxy, amino, N-methylamino, 25 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; 107 WO 00/69826 PCT/US00/08220
R
10 and R 12 are independently selected from the group consisting of hydrido, amidino, amidocarbonyl, N-methylamidocarbonyl, guanidino, methyl, ethyl, methoxy, ethoxy, hydroxy, hydroxymethyl, 1-hydroxyethyl, 2 hydroxyethyl, carboxy, carboxymethyl, amino, acetamido, trifluoromethyl, 5 pentafluoroethyl, 2,2,2-trifluoroethyl, trifluoroacetamido, aminomethyl, N methylamino, dimethylamino, amidosulfonyl, N-methylamidosulfonyl, N,N dimethylamidosulfonyl, methoxycarbonyl, fluoro, chloro, bromo, and cyano; Qb is selected from the group consisting of NR20R 2 1 25 23 24 26 25 23 24 C(NR )NR R24, and N(R26)C(NR25)N(R )(R24), with the proviso that 10 said Qb group is bonded directly to a carbon atom; 20 21 23 24 25 26
R
20 , R 2 1 , R , R 2 4 ,
R
25 , and R 2 6 are independently selected from the group consisting of hydrido, methyl, and ethyl; Q is CH 2 . In still another most preferred specific embodiment of Formula I, 15 compounds have the Formula I-EMPS wherein B is a non-aromatic cyclic substituent: R1 Xo R 2 X°0 R 0 N NY B N N N Y H H 0 (I-EMPS wherein B is a non-aromatic cyclic substituent) or a pharmaceutically acceptable salt thereof, wherein; 20 B is optionally selected from the group consisting of cyclopropyl, cyclobutyl, oxetan-3-yl, azetidin-3-yl, thiaetan-3-yl, cyclopentyl, and 33 cyclohexyl, wherein each ring carbon is optionally substituted with R , ring carbons or a nitrogen adjacent to the carbon atom at the point of attachment is 108 WO 00/69826 PCT/US00/08220 optionally substituted with R9 or R , a ring carbon or nitrogen adjacent to the
R
9 position and two atoms from the point of attachment is optionally substituted with R 10 , and a ring carbon or nitrogen adjacent to the R 13 position and two atoms from the point of attachment is optionally substituted 5 with R12
R
3 3 are independently selected from the group consisting of hydrido, amidino, guanidino, methyl, ethyl, methoxy, ethoxy, hydroxy, carboxy, amino, N-methylamino, dimethylamino, methylthio, ethylthio, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, fluoro, chloro, bromo, amidosulfonyl, 10 N-methylamidosulfonyl, hydroxymethyl, amidocarbonyl, cyano, and Qb A is selected from the group consisting of single covalent bond, NH,
N(CH
3 ), CH 2 , CH 3 CH, and CH 2
CH
2 ;
X
0 is selected from the group consisting of hydrido, hydroxy, amino, amidino, aminomethyl, cyano, methyl, trifluoromethyl, hydroxymethyl, and 15 fluoro;
R
1 is selected from the group consisting of hydrido, hydroxy, amino, aminomethyl, methylamino, cyano, methyl, trifluoromethyl, methoxy, methylthio, trifluoromethoxy, fluoro, and chloro;
R
2 is Zo-Q; 20 Z is a covalent single bond; Q is selected from the group consisting of phenyl, 2-thienyl, 2-furyl, 2 pyrrolyl, 2-imidazolyl, 2-thiazolyl, 3-isoxazolyl, 2-pyridyl, and 3-pyridyl, wherein a carbon adjacent to the carbon at the point of attachment is optionally 9 substituted by R , the other carbon adjacent to the carbon at the point of 13 9 25 attachment is optionally substituted by R 3 , 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 109 WO 00/69826 PCT/US00/08220 attachment is optionally substituted by R 12 , and any carbon adjacent to both
R
10 and R 12 is optionally substituted by R 1 1 R , R 11, and R 13 are independently selected from the group consisting of hydrido, methyl, ethyl, methoxy, ethoxy, hydroxy, amino, N-methylamino, 5 N,N-dimethylamino, methylthio, trifluoromethyl, pentafluoroethyl, 2,2,2 trifluoroethyl, fluoro, chloro, bromo, amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, amidocarbonyl, N-methylamidocarbonyl, carboxy, and cyano; R10 and R12 are independently selected from the group consisting of 10 hydrido, amidino, amidocarbonyl, N-methylamidocarbonyl, guanidino, methyl, ethyl, methoxy, ethoxy, hydroxy, hydroxymethyl, 1-hydroxyethyl, 2 hydroxyethyl, carboxy, carboxymethyl, amino, acetamido, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, trifluoroacetamido, aminomethyl, N methylamino, dimethylamino, amidosulfonyl, N-methylamidosulfonyl, N,N 15 dimethylamidosulfonyl, methoxycarbonyl, fluoro, chloro, bromo, and cyano; b. 20 21 Q is selected from the group consisting of NR20 R and C(NR25)NR23R24, with the proviso that said Qb group is bonded directly to a carbon atom; 20 21 23 24 25
R
2 0 , R 2 1 , R , R 2 4 , and R 2 5 are independently selected from the group 20 consisting of hydrido, methyl, and ethyl; QS is CH 2 . In a further most preferred embodiment of compounds of Formula 1, compounds have the Formula I-FARMPS wherein there are two fused aromatic rings: 110 WO 00/69826 PCT/US00/08220 z Y x Xo B-' N NN H H 0 (I-FARMPS) 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 5 pyrazolyl, 4-pyrazolyl, 2-thiazolyl, 3-isoxazolyl, and 5-isoxazolyl, wherein a carbon adjacent to the carbon at the point of attachment is optionally substituted by R 3 2 , the other carbon adjacent to the carbon at the point of attachment is 36 32 optionally substituted by R 3 6 , a carbon adjacent to R 3 2 and two atoms from the carbon at the point of attachment is optionally substituted by R 3 3 , a carbon 36 10 adjacent to R 3 6 and two atoms from the carbon at the point of attachment is 35 33 35 optionally substituted by R , and any carbon adjacent to both R 3 3 and R 3 5 is optionally substituted by R34 32 33 34 35 36
R
3 2 , R 33 ,
R
3 4 , R 3 5 , and R 3 6 are independently selected from the group consisting of hydrido, amidino, guanidino, methyl, ethyl, methoxy, 15 ethoxy, hydroxy, amino, N-methylamino, dimethylamino, methylthio, ethylthio, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, fluoro, chloro, bromo, amidosulfonyl, N-methylamidosulfonyl, hydroxymethyl, amidocarbonyl, carboxy, cyano, and Qb B is selected from the group consisting of hydrido, ethyl, 2-propenyl, 20 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, 111 WO 00/69826 PCT/US00/08220 3-methylbutyl, 3-methyl-2-butenyl, 1-hexyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 2-hexyl, 1-methyl-2-pentenyl, 1-methyl-3 pentenyl, 1-methyl-2-pentynyl, 1-methyl-3-pentynyl, 3-hexyl, 1-ethyl-2 butenyl, 1-heptyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 2-heptynyl, 5 3-heptynyl, 4-heptynyl, 5-heptynyl, 2-heptyl, 1-methyl-2-hexenyl, 1-methyl 3-hexenyl, 1-methyl-4-hexenyl, 1-methyl-2-hexynyl, 1-methyl-3-hexynyl, 1 methyl-4-hexynyl, 3-heptyl, 1-ethyl-2-pentenyl, 1-ethyl-3-pentenyl, 1-ethyl-2 pentynyl, 1-ethyl-3-pentynyl, 2,2,2-trifluoroethyl, 2,2-difluoropropyl, 4 trifluoromethyl-5,5,5-trifluoropentyl, 4-trifluoromethylpentyl, 5,5,6,6,6 10 pentafluorohexyl, and 3,3,3-trifluoropropyl, wherein each member of group B is optionally substituted at any carbon up to and including 5 atoms from the 32 point of attachment of B to A with one or more of the group consisting of R 3 2 33 34 35 36
R
3 3 ,
R
34 ,
R
3 5 , and R36 B is optionally selected from the group consisting of cyclopropyl, 15 cyclobutyl, oxetan-3-yl, azetidin-3-yl, thiaetan-3-yl, cyclopentyl, cyclohexyl, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-tetrahydrofuranyl, 3 tetrahydrofuranyl, 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 20 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 10 , and a ring carbon or nitrogen atom adjacent to the R 13 position and 12 two atoms from the point of attachment is optionally substituted with R 2 9 11 13 R , R , and R are independently selected from the group consisting 25 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; 112 WO 00/69826 PCT/US00/08220 R1 0 and R 12 are independently selected from the group consisting of hydrido, amidino, amidocarbonyl, N-methylamidocarbonyl, guanidino, methyl, ethyl, methoxy, ethoxy, hydroxy, hydroxymethyl, 1-hydroxyethyl, 2 hydroxyethyl, carboxy, carboxymethyl, amino, acetamido, trifluoromethyl, 5 pentafluoroethyl, 2,2,2-trifluoroethyl, trifluoroacetamido, aminomethyl, N methylamrino, dimethylamino, amidosulfonyl, N-methylamidosulfonyl,
N,N
dimethylamidosulfonyl, methoxycarbonyl, fluoro, chloro, bromo, and cyano; A is selected from the group consisting of single covalent bond, NH,
N(CH
3 ), CH 2 , CH 3 CH, and CH 2
CH
2 ; 10 A is optionally selected from the group consisting of CH 2
N(CH
3 )
CH
2
N(CH
2
CH
3 ), CH 2
CH
2
N(CH
3 ), and CH 2
CH
2
N(CH
2
CH
3 ) with the proviso that B is hydrido;
X
0 is selected from the group consisting of hydrido, hydroxy, amino, amidino, aminomethyl, cyano, methyl, trifluoromethyl, hydroxymethyl, and 15 fluoro; W and Z are independently selected from the group consisting of CH, N, CF, CCI, C-CN, C-NH 2 , C-CH 2
NH
2 , C-NHCH 3 , C-OH, C-CH 2 0H, C
CO
2 H, and C-C(O)NH 2 ; X and Y are independently selected from the group consisting of CH, 20 N, CF, C-CN, C-CH 3 , C-NH 2 , C-CH 2
NH
2 , C-CH 2
NHCH
3 , C-NHCH 3 ,
C-CH(NH
2
)CH
3 , C-CH 2
CHNH
2 , C-NHOCH 3 , C-C(NH)NH 2 ,
C-C(NOH)NH
2 , C-OH, C-CH 2 0H, C-CH 2
CH
2 0H, C-CH(OH)CH 3 ,
C-OCH
3 , C-CO2H, C-C(O)NH 2 , C-C(O)NHCH 3 , C-CH2COH, and
C-SO
2
NH
2 ; b 20 21 25 Q is selected from the group consisting of NR20R21 C(NR25)NR23 R24, and N(R26)C(NR25)N(R 23)(R24), with the proviso that said Qb group is bonded directly to a carbon atom; 113 WO 00/69826 PCT/US00/08220 20 21 23 24 25 26 R20, R , R , R24, R25, and R 26 are independently selected from the group consisting of hydrido, methyl, and ethyl; Qs is CH,. 5 The most preferred specific embodiment (I-EMPS) compounds of the present invention having the Formula:
R
1 Xo R2 N N H H 0 (I-MPS) and ZX xo0 Xo B A N N N 0 H H 0 (I-FARMPS) or a pharmaceutically acceptable salt thereof, have common structural units, 10 wherein; YO is selected from the group of formulas consisting of: S R1 7 R1 8
R
1 6 R 19 Qb 114 WO 00/69826 PCTIUSOO/08220 Q b Q b Q S Q s I/ K9 b R 1 6 R1 7 Z Q s H Q s H N N 6
R
1 7 ) and R 1 7 ) N 115 WO 00/69826 PCT/US00/08220 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, 5 methylsulfonyl, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, trifluoromethoxy, fluoro, chloro, amidosulfonyl, N-methylamidosulfonyl, hydroxymethyl, carboxy, and cyano. The compounds of this invention can be used in anticoagulant therapy for the treatment and prevention of a variety of thrombotic conditions including 10 coronary artery and cerebrovascular disease. The compounds of this invention can be used to inhibit serine protease associated with the coagulation cascade and factors II, VII, VIII, IX, X, XI, or XII. The compounds of the invention can inhibit the formation of blood platelet aggregates, inhibit the formation of fibrin, inhibit thrombus formation, and inhibiting embolus formation in a 15 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 20 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. 25 Besides being useful for human treatment, these compounds are also useful for veterinary treatment of companion animals, exotic animals and farm animals, including mammals, rodents, and the like. More preferred animals include horses, dogs, and cats. In yet another embodiment of the present invention, the novel 30 compounds are selected from the compounds set forth in Examples 1 through Example 28 and Example Table 1. The use of generic terms in the description of the compounds are herein defined for clarity. Standard single letter elemental symbols are used to represent specific types 35 of atoms unless otherwise defined. The symbol "C" represents a carbon atom. 116 WO 00/69826 PCT/US00/08220 The symbol "O" represents an oxygen atom. The symbol "N" represents a nitrogen atom. The symbol "P" represents a phosphorus atom. The symbol "S" represents a sulfur atom. The symbol "H" represents a hydrido atom. Double letter elemental symbols are used as defined for the elements of the periodical table 5 (i.e., Cl represents chlorine, Se represents selenium, etc.). As utilized herein, the term "alkyl", either alone or within other terms such as "haloalkyl" and "alkylthio", means an acyclic alkyl radical containing from 1 to about 10, preferably from 3 to about 8 carbon atoms and more preferably 3 to about 6 carbon atoms. Said alkyl radicals may be optionally substituted with 10 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 15 so much as it contains at least one double bond. Such alkenyl radicals contain from about 2 to about 10 carbon atoms, preferably from about 3 to about 8 carbon atoms and more preferably 3 to about 6 carbon atoms. Said alkenyl radicals may be optionally substituted with groups as defined below. Examples of suitable alkenyl radicals include propenyl, 2-chloropropenyl, buten-1-yl, isobutenyl, penten-l-yl, 2 20 2-methylbuten-1-yl, 3-methylbuten-1-yl, hexen-1-yl, 3-hydroxyhexen-1-yl, hepten-1-yl, and octen-1-yl, and the like. The term "alkynyl" refers to an unsaturated, acyclic hydrocarbon radical in so much as it contains one or more triple bonds, such radicals containing about 2 to about 10 carbon atoms, preferably having from about 3 to about 8 25 carbon atoms and more preferably having 3 to about 6 carbon atoms. Said alkynyl radicals may be optionally substituted with groups as defined below. Examples of suitable alkynyl radicals include ethynyl, propynyl, hydroxypropynyl, butyn-1-yl, butyn-2-yl, pentyn-1-yl, pentyn-2-yl, 4 methoxypentyn-2-yl, 3-methylbutyn-1-yl, hexyn-1-yl, hexyn-2-yl, hexyn-3 30 yl, 3,3-dimethylbutyn-1-yl radicals and the like. The term "hydrido" denotes a single hydrogen atom (H). This hydrido radical may be attached, for example, to an oxygen atom to form a "hydroxyl" radical, one hydrido radical may be attached to a carbon atom to form a "methine" radical -CH=, or two hydrido radicals may be attached to a carbon 35 atom to form a "methylene" (-CH 2 -) radical. 117 WO 00/69826 PCT/US00/08220 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. 5 The term "hydroxyalkyl" embraces radicals wherein any one or more of the alkyl carbon atoms is substituted with a hydroxyl as defined above. Specifically embraced are monohydroxyalkyl, dihydroxyalkyl and polyhydroxyalkyl radicals. The term "alkanoyl" embraces radicals wherein one or more of the 210 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. 15 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 20 having from 2 to about 10 carbon atoms, at least one double bond, and having attachment points for two or more covalent bonds. Examples of such radicals are 1,1-vinylidene (CH 2 =C), 1,2-vinylidene (-CH=CH-), and 1,4-butadienyl (-CH=CH-CH=CH-). The term "halo" means halogens such as fluorine, chlorine, bromine or 25 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 30 fluoro atom within the radical. Dihalo radicals may have two or more of the same halo atoms or a combination of different halo radicals and polyhaloalkyl radicals may have more than two of the same halo atoms or a combination of different halo radicals. More preferred haloalkyl radicals are "lower haloalkyl" radicals having one to about six carbon atoms. Examples of such haloalkyl 35 radicals include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, 118 WO 00/69826 PCT/US00/08220 dichloromethyl, trichloromethyl, trifluoroethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl. The term "hydroxyhaloalkyl" embraces radicals wherein any one or 5 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 10 above. Dihalo alkylene radicals may have two or more of the same halo atoms or a combination of different halo radicals and polyhaloalkylene radicals may have more than two of the same halo atoms or a combination of different halo radicals. More preferred haloalkylene radicals are "lower haloalkylene" radicals having one to about six carbon atoms. Examples of "haloalkylene" 15 radicals include difluoromethylene, tetrafluoroethylene, tetrachloroethylene, alkyl substituted monofluoromethylene, and aryl substituted trifluoromethylene. The term "haloalkenyl" denotes linear or branched radicals having from 1 to about 10 carbon atoms and having one or more double bonds wherein any 20 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. 25 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 30 radicals are "lower alkoxy" radicals having one to six carbon atoms. Examples of such radicals include methoxy, ethoxy, propoxy, butoxy, isopropoxy and tert-butoxy alkyls. The "alkoxy" radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide "haloalkoxy" and "haloalkoxyalkyl" radicals. Examples of such haloalkoxy radicals include 35 fluoromethoxy, chloromethoxy, trifluoromethoxy, difluoromethoxy, 119 WO 00/69826 PCT/US00/08220 trifluoroethoxy, fluoroethoxy, tetrafluoroethoxy, pentafluoroethoxy, and fluoropropoxy. Examples of such haloalkoxyalkyl radicals include fluoromethoxymethyl, chloromethoxyethyl, trifluoromethoxymethyl, difluoromethoxyethyl, and trifluoroethoxymethyl. 5 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 10 monoalkenyloxyalkyl and dialkenyloxyalkyl radicals. More preferred alkenyloxy radicals are "lower alkenyloxy" radicals having two to six carbon atoms. Examples of such radicals include ethenyloxy, propenyloxy, butenyloxy, and isopropenyloxy alkyls. The "alkenyloxy" radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or 15 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 20 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 25 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, 30 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 35 monofluoromethylenedioxy, and arylsubstituted monofluoromethylenedioxy. 120 WO 00/69826 PCT/US00/08220 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 5 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 10 substituted with 3 or more halo radicals as defined below. The term "heterocyclyl" embraces saturated and partially saturated heteroatom-containing ring-shaped radicals having from 4 through 15 ring members, herein referred to as "C4-C15 heterocyclyl" selected from carbon, nitrogen, sulfur and oxygen, wherein at least one ring atom is a heteroatom. 15 Heterocyclyl radicals may contain one, two or three rings wherein such rings may be attached in a pendant manner or may be fused. Examples of saturated heterocyclic radicals include saturated 3 to 6-membered heteromonocylic group containing 1 to 4 nitrogen atoms[e.g. pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl, etc.]; saturated 3 to 6-membered heteromonocyclic group 20 containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g. morpholinyl, etc.]; saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., thiazolidinyl, etc.]. Examples of partially saturated heterocyclyl radicals include dihydrothiophene, dihydropyran, dihydrofuran and dihydrothiazole. Non-limiting examples of 25 heterocyclic radicals include 2-pyrrolinyl, 3-pyrrolinyl, pyrrolindinyl, 1,3 dioxolanyl, 2H-pyranyl, 4H-pyranyl, piperidinyl, 1,4-dioxanyl, morpholinyl, 1,4-dithianyl, thiomorpholinyl, and the like. The term "heteroaryl" embraces fully unsaturated heteroatom-containing ring-shaped aromatic radicals having from 5 through 15 ring members selected 30 from carbon, nitrogen, sulfur and oxygen, wherein at least one ring atom is a heteroatom. Heteroaryl radicals may contain one, two or three rings wherein such rings may be attached in a pendant manner or may be fused. Examples of "heteroaryl" radicals, include unsaturated 5 to 6 membered heteromonocyclyl group containing 1 to 4 nitrogen atoms, for example, pyrrolyl, pyrrolinyl, 35 imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl, 121 WO 00/69826 PCT/US00/08220 pyridazinyl, triazolyl [e.g., 4H-1, 2 ,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3 triazolyl, etc.] tetrazolyl [e.g. IH-tetrazolyl, 2H-tetrazolyl, etc.], etc.; unsaturated condensed heterocyclic group containing 1 to 5 nitrogen atoms, for example, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, 5 isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl [e.g., tetrazolo [1,5-bjpyridazinyl, 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 10 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 15 heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl, thiadiazolyl [e.g., 1,2,4- thiadiazolyl, 1,3,4 thiadiazolyl, 1,2,5-thiadiazolyl, etc.] etc.; unsaturated condensed heterocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., benzothiazolyl, benzothiadiazolyl, etc.] and the like. The term also embraces 20 radicals where heterocyclic radicals are fused with aryl radicals. Examples of such fused bicyclic radicals include benzofuran, benzothiophene, and the like. Said "heterocyclyl" group may have 1 to 3 substituents as defined below. Preferred heterocyclic radicals include five to twelve membered fused or unfused radicals. Non-limiting examples of heteroaryl radicals include 25 pyrrolyl, pyridinyl, pyridyloxy, pyrazolyl, triazolyl, pyrimidinyl, pyridazinyl, oxazolyl, thiazolyl, imidazolyl, indolyl, thiophenyl, furanyl, tetrazolyl, 2 imidazolinyl, imidazolidinyl, 2-pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,3-triazolyl, 1,3,4-thiadiazolyl, pyrazinyl, piperazinyl, 1,3,5-triazinyl, 1,3,5-trithianyl, benzo(b)thiophenyl, 30 benzimidazoyl, quinolinyl, tetraazolyl, and the like. The term "sulfonyl", whether used alone or linked to other terms such as alkylsulfonyl, denotes respectively divalent radicals -SO 2 -. "Alkylsulfonyl", embraces alkyl radicals attached to a sulfonyl radical, where alkyl is defined as above. "Alkylsulfonylalkyl", embraces alkylsulfonyl radicals attached to an 35 alkyl radical, where alkyl is defined as above. "Haloalkylsulfonyl", embraces 122 WO 00/69826 PCT/US00/08220 haloalkyl radicals attached to a sulfonyl radical, where haloalkyl is defined as above. "Haloalkylsulfonylalkyl", embraces haloalkylsulfonyl radicals attached to an alkyl radical, where alkyl is defined as above. The term "aminosulfonyl" denotes an amino radical attached to a sulfonyl radical. 5 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 10 haloalkyl radicals attached to a sulfinyl radical, where haloalkyl is defined as above. "Haloalkylsulfinylalkyl", embraces haloalkylsulfinyl radicals attached to an alkyl radical, where alkyl is defined as above. The term "aralkyl" embraces aryl-substituted alkyl radicals. Preferable aralkyl radicals are "lower aralkyl" radicals having aryl radicals attached to 15 alkyl radicals having one to six carbon atoms. Examples of such radicals include benzyl, diphenylmethyl, triphenylmethyl, phenylethyl and diphenylethyl. The terms benzyl and phenylmethyl are interchangeable. The term "heteroaralkyl" embraces heteroaryl-substituted alkyl radicals wherein the heteroaralkyl radical may be additionally substituted with three or 20 more substituents as defined above for aralkyl radicals. The term "perhaloaralkyl" embraces aryl-substituted alkyl radicals wherein the aralkyl radical is substituted with three or more halo radicals as defined above. The term "aralkylsulfinyl", embraces aralkyl radicals attached to a sulfinyl radical, where aralkyl is defined as above. "Aralkylsulfinylalkyl", 25 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 30 defined as above. The term "cycloalkyl" embraces radicals having three to 15 carbon atoms. More preferred cycloalkyl radicals are "lower cycloalkyl" radicals having three to seven carbon atoms. Examples include radicals such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. The term 35 cycloalkyl embraces radicals having seven to 15 carbon atoms and having two 123 WO 00/69826 PCT/US00/08220 to four rings. Examples incude radicals such as norbornyl (i.e., bicyclo[2.2.1]heptyl) and adamantyl. The term "cycloalkylalkyl" embraces cycloalkyl-substituted alkyl radicals. Preferable cycloalkylalkyl radicals are "lower cycloalkylalkyl" radicals having cycloalkyl radicals attached to alkyl 5 radicals having one to six carbon atoms. Examples of such radicals include cyclohexylhexyl. The term "cycloalkenyl" embraces radicals having three to ten carbon atoms and one or more carbon-carbon double bonds. Preferred cycloalkenyl radicals are "lower cycloalkenyl" radicals having three to seven carbon atoms. Examples include radicals such as cyclobutenyl, cyclopentenyl, 10 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 15 within the radical. Dihalo radicals may have two or more of the same halo atoms or a combination of different halo radicals and polyhalocycloalkyl radicals may have more than two of the same halo atoms or a combination of different halo radicals. More preferred halocycloalkyl radicals are "lower halocycloalkyl" radicals having three to about eight carbon atoms. Examples of 20 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 25 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 30 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. 124 WO 00/69826 PCT/US00/08220 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 5 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 10 "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 15 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", 20 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 25 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. 30 The term "alkylthio" embraces radicals containing a linear or branched alkyl radical, of one to ten carbon atoms, attached to a divalent sulfur atom. More preferred alkylthio radicals are "lower alkylthio" radicals having one to six carbon atoms. An example of "lower alkylthio" is methylthio (CH 3 -S-). The "alkylthio" radicals may be further substituted with one or more halo 35 atoms, such as fluoro, chloro or bromo, to provide "haloalkylthio" radicals. 125 WO 00/69826 PCT/US00/08220 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 5 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 terms alkylamino denotes "monoalkylamino" and "dialkylamino" containing one or two alkyl radicals, respectively, attached to an amino radical. 10 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 15 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 20 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 25 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 30 "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 35 to an oxygen atom. Examples of such radicals include phenoxy, 4-chloro-3 126 WO 00/69826 PCT/US00/08220 ethylphenoxy, 4 -chloro-3-methylphenoxy, 3-chloro-4-ethylphenoxy, 3,4 dichlorophenoxy, 4-methylphenoxy, 3-trifluoromethoxyphenoxy, 3 trifluoromethylphenoxy, 4-fluorophenoxy, 3,4-dimethylphenoxy, 5-bromo-2 fluorophenoxy, 4 -bromo-3-fluorophenoxy, 4-fluoro-3-methylphenoxy, 5 5
,
6
,
7 ,8-tetrahydronaphthyloxy, 3 -isopropylphenoxy, 3-cyclopropylphenoxy, 3-ethylphenoxy, 3 -pentafluoroethylphenoxy, 3-(1,1,2,2-tetrafluoroethoxy) phenoxy, and 4-tert -butylphenoxy. The term "aroyl" embraces aryl radicals, as defined above, attached to an carbonyl radical as defined above. Examples of such radicals include 10 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 15 through an oxygen atom to other radicals. More preferred aralkoxy radicals are "lower aralkoxy" radicals having phenyl radicals attached to lower alkoxy radical as described above. Examples of such radicals include benzyloxy, 1 phenylethoxy, 3-trifluoromethoxybenzyloxy, 3-trifluoromethylbenzyloxy, 3,5 difluorobenyloxy, 3-bromobenzyloxy, 4-propylbenzyloxy, 2-fluoro-3 20 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. 25 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 30 radicals include, for example, pyridylacetyl and furylbutyryl. The term "heteroaralkoxy" embraces oxy-containing heteroaralkyl radicals attached through an oxygen atom to other radicals. More preferred heteroaralkoxy radicals are "lower heteroaralkoxy" radicals having heteroaryl radicals attached to lower alkoxy radical as described above. 127 WO 00/69826 PCT/US00/08220 The term "haloheteroaryloxyalkyl" embraces heteroaryloxyalkyl radicals, as defined above, wherein one to four halo radicals are attached to an heteroaryloxy group. The term "heteroarylamino" embraces heterocyclyl radicals, as defined 5 above, attached to an amino group. Examples of such radicals include pyridylamino. The term "heteroarylaminoalkyl" embraces heteroarylamino radicals, as defined above, attached to an alkyl group. Examples of such radicals include pyridylmethylamino. 10 The term "heteroaryloxy" embraces heterocyclyl radicals, as defined above, attached to an oxy group. Examples of such radicals include 2 thiophenyloxy, 2-pyrimidyloxy, 2-pyridyloxy, 3-pyridyloxy, and 4 pyridyloxy. The term "heteroaryloxyalkyl" embraces heteroaryloxy radicals, as 15 defined above, attached to an alkyl group. Examples of such radicals include 2-pyridyloxymethyl, 3-pyridyloxyethyl, and 4-pyridyloxymethyl. The term "arylthio" embraces aryl radicals, as defined above, attached to an sulfur atom. Examples of such radicals include phenylthio. The term "arylthioalkyl" embraces arylthio radicals, as defined above, 20 attached to an alkyl group. Examples of such radicals include phenylthiomethyl. The term "alkylthioalkyl" embraces alkylthio radicals, as defined above, attached to an alkyl group. Examples of such radicals include methylthiomethyl. The term "alkoxyalkyl" embraces alkoxy radicals, as defined 25 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 30 carbonyl group. The term "carboxamide" embraces amino, monoalkylamino, dialkylamino, monocycloalkylamino, alkylcycloalkylamino, and dicycloalkylamino radicals, attached to one of two unshared bonds in a carbonyl group. The term "carboxamidoalkyl" embraces carboxamride radicals, as defined above, attached to an alkyl group. The term "carboxyalkyl" embraces a carboxy radical, as defined 35 above, attached to an alkyl group. The term "carboalkoxy" embraces alkoxy 128 WO 00/69826 PCT/US00/08220 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, 5 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 10 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, 15 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 20 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 25 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. 30 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, -NH 2 , -NHCH 3 , -NHOH, and -NHOCH 3 . The term "imino" denotes a nitrogen atom containing one substituent such as hydrido, hydroxy or alkyl and 35 having two covalent bonds available for bonding to a single atom such as carbon. 129 WO 00/69826 PCT/US00/08220 Examples of such imino radicals include, for example, =NH, =NCH 3 , =NOH, and =NOCH 3 . The term "imino carbonyl" denotes a carbon radical having two of the four covalent bond sites shared with an imino group. Examples of such imino carbonyl radicals include, for example, C=NH, C=NCH 3 , C=NOH, and 5 C=NOCH 3 . The term "amidino" embraces a substituted or unsubstituted amino group bonded to one of two available bonds of an iminocarbonyl radical. Examples of such amidino radicals include, for example, NH 2 -C=NH, NH 2
-C=NCH
3 ,
NH
2
-C=NOCH
3 and CH 3 NH-C=NOH. The term "guanidino" denotes an amidino group bonded to an amino group as defined above where said amino 10 group can be bonded to a third group. Examples of such guanidino radicals include, for example, NH 2 -C(NH)-NH-, NH 2
-C(NCH
3 )-NH-, NH 2 C(NOCH 3 )-NH-, and CH 3 NH-C(NOH)-NH-. The term "sulfonium" denotes a positively charged trivalent sulfur atom where said sulfur is substituted with three carbon based groups such as alkyl, 15 alkenyl, aralkyl, or aryl. The term "dialkyl sulfonium" denotes a sulfonium group where said sulfur is substituted with two alkyl groups. Examples of such dialkylsulfonium radicals include, for example, (CH 3
)
2 S -. The term "dialkyl 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 20 dialkylsulfoniumalkyl radicals include (CH 3
)
2
S+-CH
2
CH
2 -. 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 25 alkyl groups. Examples of such trialkylphosphonium radicals include, for example,
(CH
3
)
3
P
+
. Said "alkyl", "alkenyl", "alkynyl", "alkanoyl", "alkylene", "alkenylene", "hydroxyalkyl", "haloalkyl", "haloalkylene", "haloalkenyl", "alkoxy", "alkenyloxy", "alkenyloxyalkyl", "alkoxyalkyl", "aryl", "perhaloaryl", 130 WO 00/69826 PCT/US00/08220 "haloalkoxy", "haloalkoxyalkyl", "haloalkenyloxy", "haloalkenyloxyalkyl", "alkylenedioxy", "haloalkylenedioxy", "heterocyclyl", "heteroaryl", "hydroxyhaloalkyl", "alkylsulfonyl", "haloalkylsulfonyl", "alkylsulfonylalkyl", "haloalkylsulfonylalkyl", "alkylsulfinyl", "alkylsulfinylalkyl", 5 "haloalkylsulfinylalkyl", "aralkyl", "heteroaralkyl", "perhaloaralkyl", "aralkylsulfonyl", "aralkylsulfonylalkyl", "aralkylsulfinyl", "aralkylsulfinylalkyl", "cycloalkyl", "cycloalkylalkanoyl", "cycloalkylalkyl", "cycloalkenyl", "halocycloalkyl", "halocycloalkenyl", "cycloalkylsulfinyl", "cycloalkylsulfinylalkyl", "cycloalkylsulfonyl", "cycloalkylsulfonylalkyl", 10 "cycloalkoxy", "cycloalkoxyalkyl", "cycloalkylalkoxy", "cycloalkenyloxy", "cycloalkenyloxyalkyl", "cycloalkylenedioxy", "halocycloalkoxy", "halocycloalkoxyalkyl", "halocycloalkenyloxy", "halocycloalkenyloxyalkyl", "alkylthio", "haloalkylthio", "alkylsulfinyl", "amino", "oxy", "thio", "alkylamino", "arylamino", "aralkylamino", "arylsulfinyl", "arylsulfinylalkyl", "arylsulfonyl", 15 "arylsulfonylalkyl", "heteroarylsulfinyl", "heteroarylsulfinylalkyl", "heteroarylsulfonyl", "heteroarylsulfonylalkyl", "heteroarylamino", "heteroarylaminoalkyl", "heteroaryloxy", "heteroaryloxylalkyl", "aryloxy", "aroyl", "aralkanoyl", "aralkoxy", "aryloxyalkyl", "haloaryloxyalkyl", "heteroaroyl", "heteroaralkanoyl", "heteroaralkoxy", "heteroaralkoxyalkyl", 20 "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, 25 aralkylsulfinyl, aralkylsulfinylalkyl, halocycloalkyl, halocycloalkenyl, cycloalkylsulfinyl, cycloalkylsulfinylalkyl, cycloalkylsulfonyl, cycloalkylsulfonylalkyl, heteroarylamino, N-heteroarylamino-N-alkylamino, heteroarylaminoalkyl, heteroaryloxy, heteroaryloxylalkyl, haloalkylthio, alkanoyloxy, alkoxy, alkoxyalkyl, haloalkoxylalkyl, heteroaralkoxy, cycloalkoxy, 30 cycloalkenyloxy, cycloalkoxyalkyl, cycloalkylalkoxy, cycloalkenyloxyalkyl, cycloalkylenedioxy, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxy, halocycloalkenyloxyalkyl, hydroxy, amino, thio, nitro, lower alkylamino, alkylthio, alkylthioalkyl, arylamino, aralkylamino, arylthio, arylthioalkyl, heteroaralkoxyalkyl, alkylsulfinyl, alkylsulfinylalkyl, arylsulfinylalkyl, 35 arylsulfonylalkyl, heteroarylsulfinylalkyl, heteroarylsulfonylalkyl, alkylsulfonyl, 131 WO 00/69826 PCT/US00/08220 alkylsulfonylalkyl, haloalkylsulfinylalkyl, haloalkylsulfonylalkyl, alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, monoarylamidosulfonyl, arylsulfonamido, diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl, arylsulfinyl, 5 arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, 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, 10 hydroxyaralkyl, hydroxyalkyl, aminoalkyl, hydoxyheteroaralkyl, haloalkoxyalkyl, aryl, aralkyl, aryloxy, aralkoxy, aryloxyalkyl, saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl, heteroaryloxy, heteroaryloxyalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, carboxyalkyl, carboalkoxy, alkoxycarbonyl, carboaralkoxy, carboxamido, carboxamidoalkyl, cyano, 15 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 20 by a radical selected from -- C(H)-, =C(R 2a)-, -0-, -S-, -S(O)-, -S(O) 2 -, -NH-, -N(R 2a)-, -N=, -CH(OH)-, =C(OH)-, -CH(OR 2a)-, =C(OR2a)-, and -C(0)- wherein R 2a is selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, aryloxyalkyl, alkoxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkoxyalkyl, perhaloaralkyl, 25 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: lower alkylene, lower alkenyl, -0-, -O-CH 2 -, -S-CH 2 -, -CH 2
CH
2 -, ethenyl, 30 -CH=CH(OH)-,
-OCH
2 0-, -O(CH 2
)
2 0-, -NHCH 2 -, -OCH(R2a )0-,
-O(CH
2 CHR2a )0-, -OCF 2 0-, -O(CF 2
)
2 0-, -S-, -S(0)-, -S(0) 2 -, -N(H)-, 132 WO 00/69826 PCT/US00/08220 2a 2a 2a -N(H)O-, -N(R )O-, -N(R )-, -C(O)-, -C(O)NH-, -C(O)NR -, -N=,
-OCH
2 -, -SCH 2 -, S(O)CH 2 -, -CH 2 C(O)-, -CH(OH)-, =C(OH)-, -CH(OR2a)-, 2a 2a =C(OR )-, S(O) 2
CH
2 -, and -NR CH 2 - and many other radicals defined above or generally known or ascertained by one of skill-in-the art. Side chains may 5 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, 10 heteroarylamino, N-heteroarylamino-N-alkylamino, heteroarylaminoalkyl, heteroaryloxy, heteroaryloxylalkyl, haloalkylthio, alkanoyloxy, alkoxy, alkoxyalkyl, haloalkoxylalkyl, heteroaralkoxy, cycloalkoxy, cycloalkenyloxy, cycloalkoxyalkyl, cycloalkylalkoxy, cycloalkenyloxyalkyl, cycloalkylenedioxy, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxy, 15 halocycloalkenyloxyalkyl, hydroxy, amino, thio, nitro, lower alkylamino, alkylthio, alkylthioalkyl, arylamnino, aralkylamino, arylthio, arylthioalkyl, heteroaralkoxyalkyl, alkylsulfinyl, alkylsulfinylalkyl, arylsulfinylalkyl, arylsulfonylalkyl, heteroarylsulfinylalkyl, heteroarylsulfonylalkyl, alkylsulfonyl, alkylsulfonylalkyl, haloalkylsulfinylalkyl, haloalkylsulfonylalkyl, 20 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, 25 alkenyl, alkynyl, alkenyloxy, alkenyloxyalky, alkylenedioxy, haloalkylenedioxy, cycloalkyl, cycloalkenyl, lower cycloalkylalkyl, lower cycloalkenylalkyl, halo, haloalkyl, haloalkenyl, haloalkoxy, hydroxyhaloalkyl, hydroxyaralkyl, hydroxyalkyl, aminoalkyl, hydoxyheteroaralkyl, haloalkoxyalkyl, aryl, aralkyl, aryloxy, aralkoxy, aryloxyalkyl, saturated heterocyclyl, partially saturated 30 heterocyclyl, heteroaryl, heteroaryloxy, heteroaryloxyalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, carboxyalkyl, carboalkoxy, carboaralkoxy, carboxamido, carboxamidoalkyl, cyano, carbohaloalkoxy, 133 WO 00/69826 PCT/US00/08220 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, 5 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. 10 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 15 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 20 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 25 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 30 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 35 part or principally in the "imine" form and in part or principally as one or more 134 WO 00/69826 PCT/US00/08220 "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 5 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): R
X
0 R2 B AN K E yO J (I) 10 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 15 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 20 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 25 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 extracorporeal circulation systems. 135 WO 00/69826 PCT/US00/08220 Compounds of Formula (I) are capable of inhibiting activity of serine proteases related to the coagulation cascade, and thus could be used in the manufacture of a medicament, a method for the prophylactic or therapeutic treatment of diseases mediated by coagulation cascade serine proteases, such as 5 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 10 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 15 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 20 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, 25 carbonic, sulfuric and phosphoric acid. Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, examples of which are formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucoronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, 30 anthranilic, mesylic, salicylic, p-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethylsulfonic, benzenesulfonic, sulfanilic, stearic, cyclohexylaminosulfonic, algenic, galacturonic acid. Suitable pharmaceutically-acceptable base addition salts of compounds of Formula (I) include metallic salts made from aluminum, calcium, lithium, magnesium, 35 potassium, sodium and zinc or organic salts made from N,N' 136 WO 00/69826 PCT/US00/08220 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 5 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 10 active compounds of Formula (I) in association with one or more non-toxic, pharmaceutically-acceptable carriers and/or diluents and/or adjuvants (collectively referred to herein as "carrier" materials) and, if desired, other active ingredients. The active compounds of the present invention may be administered by any suitable route, preferably in the form of a pharmaceutical 15 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, 20 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 25 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 30 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. 35 The compounds may also be coupled with soluble polymers as targetable drug 137 WO 00/69826 PCT/US00/08220 carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxy-propyl-methacrylamide-phenol, polyhydroxyethyl-aspartamide phenol, or ployethyleneoxide-polylysine substituted with palmitoyl residues. Furthermore, the compounds may be coupled to a class of biodegradable 5 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. 10 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 15 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 20 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. 25 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. 30 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. 138 WO 00/69826 PCT/US00/08220 Alternatively, the active ingredients may be formulated in a cream with an oil-in-water cream base. If desired, the aqueous phase of the cream base may include, for example at least 30% w/w of a polyhydric alcohol such as propylene glycol, butane-1,3-diol, mannitol, sorbitol, glycerol, polyethylene 5 glycol and mixtures thereof. The topical formulation may desirably include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethylsulfoxide and related analogs. The compounds of this invention can also be administered by a transdermal device. Preferably 10 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 15 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 20 merely an emulsifier, it may comprise a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabilizer. It is also preferred to include both an oil and a fat. Together, the emulsifier(s) with or without stabilizer(s) make-up the so-called emulsifying wax, and the wax 25 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. 30 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 35 from tubes or other containers. Straight or branched chain, mono- or dibasic 139 WO 00/69826 PCT/US00/08220 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 5 properties required. Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils can be used. For therapeutic purposes, the active compounds of the present invention are ordinarily combined with one or more adjuvants appropriate to the indicated route of administration. If administered per os, the compounds 10 may be admixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted or encapsulated for convenient administration. Such 15 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 20 granules having one or more of the carriers or diluents mentioned for use in the formulations for oral administration. The compounds may be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, and/or various buffers. Other adjuvants and modes of administration are well and widely 25 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 30 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 35 restenosis), anti-coagulants such as aspirin, warfarin or heparins, thrombolytic 140 WO 00/69826 PCT/US00/08220 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 5 synthatase inhibitors, etc.), anti-diabetic drugs, or other cardiovascular agents (loop diuretics, thiazide type diuretics, nitrates, aldosterone antagonistics (i.e., spironolactone and epoxymexlerenone), angiotensin converting enzyme (e.g. ACE) inhibitors, angiotensin II receptor antagonists, beta-blockers, antiarrythmics, anti-hypertension agents, and calcium channel blockers) to treat 10 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 15 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 20 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 25 patient's therapeutic needs. All mentioned references are incorporated by reference as if here written. Although this invention has been described with respect to specific embodiments, the details of these embodiments are not to be construed as 30 limitations. The following examples are provided to illustrate the present invention and are not intended to limit the scope thereof. Without further elaboration, it is believed that one skilled in the art can, using the preceding descriptions, utilize the present invention to its fullest extent. Therefore the following preferred specific embodiments are to be construed as merely 35 illustrative and not limitative of the remainder of the disclosure in any way 141 WO 00/69826 PCT/US00/08220 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 5 procedures can be used to prepare these compounds. One skilled in the art may use these generic methods to prepare the following specific examples, which have been or may be properly characterized by 'H NMR, mass spectrometry, elemental composition, and similar procedures. These compounds also may be formed in vivo. 10 The following examples contain detailed descriptions of the methods of preparation of compounds of Formula (I). These detailed descriptions fall within the scope and are presented for illustrative purposes only and are not intended as a restriction on the scope of the invention. All parts are by weight and temperatures are Degrees centigrade unless otherwise indicated. 15 The following general synthetic sequences are useful in making the present invention. Abbreviations used in the schemes and tables include: "AA" represents amino acids, "AcCN" represents acetonitrile, "AcOH" represents acetic acid, "BINAP" represents 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, "BnOITH" represents benzyl alcohol, "BnCHO" represents 2-phenylethanal," 20 BnSO 2 CI" represents benzylsulfonyl chloride, "Boc" represents tert butyloxycarbonyl, "BOP" represents benzotriazol- 1 -yl-oxy-tris (dimethylamino), "bu" represents butyl, "dba" represents dibenzylidene acetone, "DCC" represents 1,3-dicyclohexylcarbodiimide, "DCM" represents dichloromethane or methylene chloride, "DIBAH" or "DIBAL" represents 25 diisobutylaluminum hydride, "DMF" represents dimethylformamide, "DMSO" represents dimethylsulfoxide, "DPPA" represents diphenylphosphoryl azide", "EDC" represents 1-[ 3 -(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride, "Ex. No." represents Example Number, "Fmoc" represents 9 fluorenylmethoxycarbonyl, "HOBt" represents hydroxybenzoltriazole", "LDA" 30 represents lithium diisopropylamrnide, "MW" represents molecular weight, "NMM" represents N-methylmorpholine, "Ph" represents phenyl or aryl, "PHTH" represents a phthaloyl group, "pnZ" represents 4-nitrobenzyloxy carbonyl, "PTC" represents a phase transfer catalyst , "py" represents pyridine,
"RNH
2 " represents a primary organic amine, "SEM" represents 2 35 (trimethylsilyl)ethoxy-methyl chloride, "p-TsOH" represents 142 WO 00/69826 PCT/US00/08220 paratoluenesulfonic acid, "TBAF' represents tetrabutylammonium fluoride, "TBTU" represents 2-(1H-benzotriozole- 1-yl)- 1,1,3,3-tetramethyl uronium tetrafluoroborate, "TEA" represents triethylamine, "TFA" represents trifluoroacetic acid, "THF' represents tetrahydrofuran, "TMS" represents 5 trimethylsilyl, "TMSCN" represents trimethylsilyl cyanide, and "Cbz" or "Z" represents benzyloxycarbonyl. GENERAL SYNTHETIC PROCEDURES AND SPECIFIC EXAMPLES 10 The pyridone compounds of the present invention can be synthesized, for example, according to the following procedures and Schemes given below. A pyridone having a fused aryl or heteroaryl group can be considered to be a quinolone. A generic quinolinone analogous structure to the basic pyridone ring type is shown in Figure 1. W, X, Y and Z are optionally selected from CH, Xo W B ""k N N N 0 H H 15 0 Figure 1. Quinolinone Analogues of Pyridones N, CF, CCI, C-CN, C-CH 3 , C-CH 2
CH
3 , C-NH 2 , C-CH 2
NH
2 ,
C-CH
2
NHCH
3 , C-NHCH 3 , C-N(CH 3
)
2 , C-CH(NH 2
)CH
3 , 20 C-CH 2
CH
2 NH,, C-NHOCH 3 , C-NHOCH 2
CH
3 , C-C(NH)NH 2 '
C-C(NOH)NH
2 , C-OH, C-CH2OH, C-CH 2
CH
2 OH, C-CH(OH)CH 3 ,
C-OCH
3 , C-OCH 2
CH
3 , C-CO 2 H, C-CO 2
CH
3 , C-C(O)NH 2 ,
C-C(O)NHCH
3 , C-C(O)NH(CH 3
)
2 , C-CH 2
CO
2 H, C-SO 2
NH
2 ,
C-SO
2
NHCH
3 , C-NH(O)CCH 3 , and C-NH(O)CCF 3 . Quinolones in which W of 25 W-X=Y-Z is attached to the four and five positions of the pyridone instead of the 143 WO 00/69826 PCT/US00/08220 five and six positions can be prepared by comparable procedures. A general procedure for the preparation a wide variety of quinolone type 2-pyridones is summarized in Scheme 1 and Scheme 2. These procedures can accommodate the introduction of a wide range of substituents into the fused ring either as such, 5 precursors groups for desired groups (for example, a nitro for subsequent conversion to an amino, an acetoxymethyl for subsequent hydrolysis to an hydroxymethyl or oxidation to an aldehyde or carboxylic acid, and the like) or using protected groups. The preparation of specific quinolinone analogues of a pyridone of this invention are exemplified as in Example 1 through Example 10 16. 144 WO 00/69826 PCT/US00/08220 Scheme 1: General Quinolone Synthesis-I Z CHO 0 2O
S~NH
2 0N w NH2 I piperidine W toluene NHo 0 2 N 0 NaH/DMFN Methyl bromoacetate O 2 N O
H
2 Z #~ X vPd/C 11 B=O / S NaBH(OAc) 3 Z HNN H H 2 N / O Z X B -A=O0O B Ao S NaBH(OAc) 3 W ZB-A-C(O)CI 0 TEA HNN O A-B 0 B-A-C(0)- N NO Nl ° H4 0 145 WO 00/69826 PCT/US00/08220 Scheme 2: General Quinolone Synthesis-1 (Concluded) EDC HOBT, ZX Cbz-Yo-NH, NaOH Pd/C, H 2 Z PZ X BN N H N N-N N 1, H H EDC 0 HOBT, Na Cbz-Yo-NH 2 XN Pd/C,
H
2 HN N A-B 0 Yo Z HN N IA-B 0 NW B-A,-Cg0) Nx I0 HN NaOH 0 EDC B-A-C(O),, N o HOBT, N N Cbz-Yo-NH 2 H H Pd/C, H 2 O 146 WO 00/69826 PCT/US00/08220 Example 1 0 0 S H Ph~~-N N N -, N NH2 11 H H O TFA NH 5 EX-IA) 3-Nitro-lH-Quinolin-2-One (2.35 g, 12.37 mmole) in 50 ml anhydrous DMF was mixed with NaH 60% in mineral oil (0.59 g, 14.87 g), and the mixture was stirred for five minutes. To this mixture, 2-methyl-2-bromoacetate (2.27g, 14.84 mmole) was added dropwise. After stirring the reaction mixture for 2 hours at 20 oC, DMF was removed via vacuum rotary evaporation to lead to a 10 yellow oil residue. The residue was triturated in water to yield a yellow solid that was washed with water and hexane. The yellow solid was re-crystallized in ethylacetate to yield a yellow needle crystal solid (138 g) as the expected product, methyl-(3-nitro-2-oxo-2H-quinolin- 1-yl)acetate. More product (1.20 g) was obtained from the mother liquor via silica gel flash chromatography to separate it 15 from the O-alkylated side product (0.334 g). The desired product (EX- 1 A) yield was 80%. HPLC-MS (0 to 95% AcCN / 6 min @ 1.0 mL / Min @ 254 nn @ 50 oC): retention time 2.48 min, M+H' = 263.2 for formula C 12 HioN 2 0 5 . H NMR (400 MHz, CDCl 3 ): 6 3.80 (s, 3H), 5.17 (s, 2H), 7.19 (d, J = 8.4 Hz, 1H), 7.40 (t, J = 7.6 Hz, 1H), 7.76 (t, J = 7.6 Hz, 1H), 7.78 (d, J = 8.4 Hz, 1H), 8.61 (s, 20 1H). 13C NMR (101 MHz, CDCl 3 ): 6 44.2, 52.9, 114.2, 117.1, 124.0, 131.7, 134.8, 137.9, 140.6, 154.0, 167.6. EX-1B) Compound EX-1A (2.51 g, 9.58 mmole) was mixed with 10% Pd on activated carbon (0.51 g, 0.48 mmole) in 150 ml methanol. The mixture was stirred under IH, that was introduced through a rubber balloon for 2 hours. 25 The reaction mixture was filtered, and the methanol was removed to yield a white crystalline solid (2.06 g, y = 93%) as methyl-(3-amino-2-oxo-2H-quinolin-1 yl)acetate (3). HPLC-MS (0 to 95% AcCN / 6 min @ 1.0 mL / Min @ 254 nm @ 50 oC): retention time 2.12 min, M+H* = 233.1 for formula C 12
H
12
N
2 0 3 . 147 WO 00/69826 PCT/US00/08220 Compound 3 (2.04 g, 8.79 mmole) and pyridine (3.55 ml, 43.95 mmole) were dissolved in 200 ml acetonitrile. This mixture was cooled down to -10 oC with a water-acetone-dry ice mixture bath. To this mixture, a-tolunesulfonyl chloride (4.19 g, 21.98 mmole) dissolved in 10 ml acetonitrile was added dropwise 5 quickly. The reaction mixture was stirred for 2.5 hours from -10 oC to 0 oC. During the reaction, the product as a white solid precipitated from the solution. The pure product, methyl-(3-benzylsulfonylamido-2-oxo-2H-quinolin-1-yl)acetate (EX-1B) (2.92 g) was obtained by filtration and washing it with acetonitrile. More product (0.34 g) was obtained by working up the filtrate and subjecting it to a 10 Biotage-40 silica gel column chromatography using 25% ethylacetate in hexane as the elute. HPLC-MS (0 to 95% AcCN / 6 min @ 1.0 mL / Min @ 254 nm @ 50 oC): retention time 3.52 min, M+Na' = 408.9 for formula C 19
H
18
N
2 0 5 SNa. IH NMR (400 MHz, CDCl 3 ): 6 3.81 (s, 3H), 4.42 (s, 2H), 5.14 (s, 2H), 7.09 (d, J = 8.8 Hz, 1H), 7.27 (m, 5H), 7.48 (t, J = 7.6 Hz, 2H), 7.61 (d, J = 10 Hz, 1H), 15 8.61 (s, 1H). 1 3 C NMR (101 MHz, CDCl 3 ): 6 44.5, 52.8, 58.5, 113.3, 119.5, 120.4, 123.5, 127.2, 127.8, 128.7, 128.8, 129.0, 129.2, 130.8, 135.2, 157.3, 167.9. EX-1C) Compound EX-1B (3.19 g, 8.26 mmole) was dissolved in 50 ml THF, 30 ml MeOH and 50 ml 1 M LiOH. The mixture was stirred at 20 oC for 20 one hour. The mixture was concentrated to remove the organic solvents. The remaining aqueous solution was acidified to pH = 1 with IM HC1, and a solid precipitated from the solution. The solid was purified by filtration, washing with IM HCI and water, and drying via vacuum to give a white solid as the pure product
(
3 -benzylsulfonylamino-2-oxo-2H-quinolin-1-yl)acetic acid (EX-1C) (2.98 g, 25 yield of 97%). HPLC-MS (0 to 95% AcCN / 6 min @ 1.0 mL/ Min @ 254 nm @ 50 oC): retention time 3.09 min, M+Na' = 395.2 for formula C 18
HI
6
N
2 OsSNa. 1 H NMR (400 MHz, CDCl 3 ): 6 4.54 (s, 2H), 5.13 (s, 2H), 7.15 (t, J = 87.2 Hz, 1H), 7.23 (m, 3H), 7.33 (m, 3H), 7.50 (t, J = 7.6 Hz, 2H), 7.59 (s, 1H). EX-1D) Compound EX-1C (0.209 g, 0.56 mmol), EDC (0.140 g, 0.73 30 mmol) and HOBt (0.112 g, 0.73 mmol) were mixed in 1.5 ml DMF, and the mixture was stirred at 20 oC for 10 minutes. To this mixture was added the premixed solution of (4S)-(9C1)-N-[[[4-amino-5-hydroxy-5-(2 thiazolyl)pentyl]amino]iminomethyl ]-4-methoxy-2,3,6 148 WO 00/69826 PCT/US00/08220 trimethylbenzenesulfonamide HCI salt (0.387 g, 0.73 mmol), diisopropylethylamine (0.65 ml, 3.93 mmol) in 1.5 ml DMF. The combined reaction mixture was stirred for 45 minutes at 20 oC. The reaction mixture was partitioned between ethylacetate and saturated ammonium chloride aqueous 5 solution. The organic phase was washed with saturated aqueous potassium carbonate and ammonium chloride solution, dried over Na 2
SO
4 After removing the ethylacetate, the residue was subjected to a Biotage silica gel column chromatography to yield a white solid as the product N-[2(S)-1(R,S)-2-[1 hydroxy- 1-(2-thiazolyl)]-5-[[(4-methoxy-2,3,6-trimethyl)sulfonylamino] 10 iminomethyl]aminopentyl]-[3-benzylsulfonylamino-2-oxo-2H-quinolin-1 yl)acetamide (EX- ID) (0.347 g, y = 76%). HPLC-MS (0 to 95% AcCN / 6 min @ 1.0 mL / Min @ 254 nm @ 50 oC): retention time 3.75 min, M+H* = 810.3 for formula C 37
H
43
N
7 0 8
S
3 . Since the compound is a mixture of two diastereomers, the 1H NMR and 1 3 C NMR was complex. 15 EX-1E) Compound EX-1D (0.32 g, 0.395 mmol) was mixed with 1,3 dihydro- 1-hydroxy-3,3-bis(trifluoromethyl)-1-oxide- 1,2-benziodoxole (0.238 g, 0.593 mmole) in 5 ml acetonitrile. The mixture was stirred at 20 C for 2 hours. It was then mixed with 30 ml 1M NaHSO 3 aqueous solution. The combined solution was extracted with ethylacetate, and the organic phase was washed with saturated 20 NaHCO 3 aqueous solution and dried over NaSO 4 . After removing the ethylacetate, the remaining residue was subjected to a silica gel flash column chromatography using 30% ethylacetate in hexane as elute to yield a white solid as the product N-[[2(S)- 2-[ 1-Oxo- 1-( 2 -thiazolyl)]-5-[[[(4-methoxy-2,3,6 trimethyl)sulfonylamrino]iminomethyl]amino]pentyl]-(3-benzylsulfonylamino-2 25 oxo-2H-quinolin-1-yl)acetamide (EX-1E) (0.296 g, 93%). HPLC-MS (0 to 95% AcCN / 6 min @ 1.0 mL / Min @ 254 nm @ 50 oC): retention time 4.07 min, M+H* = 808.2 for formula C 3 7
H
4 1
N
7 0 8 S 3 . H NMR (400 MHz, acetone-d 6 ): 6 1.71 (b, 4H), 2.07 (s, 3H), 2.59 (s, 3H), 2.64 (s, 3H), 3.24 (m, 2H), 3.80 (s, 3H), 4.62 (s, 2H), 5.17 (d, J = -16.4 Hz, 1H), 5.22(d, J = 16.4Hz, 1H), 5.62 30 (m, 1H), 6.47 (b, 2H), 6.64(s, IH), 7.24 (m, 4H), 7.36 (m, 3H), 7.44 (m, 2H), 7.59 (t, J = 7.2 Hz, 2H), 7.95 (b, 1H), 8.08 (m, 3H). 13C NMR (101 MHz,
CDCI
3 ): 6 12.0, 15.6, 18.6, 24.2, 41.1, 46.6, 55.8, 55.9, 58.5, 66.1, 112.3, 120.3, 121.2, 123.8, 124.8, 128.5, 129.1, 129.2, 129.3, 129.6, 129.7, 129.9, 149 WO 00/69826 PCT/US00/08220 123.0, 131.9, 135.8, 136.7, 137.0, 139.0, 146.1, 157.4, 158.0, 158.8, 165.6, 167.7, 192.0. Compound EX-1 E (0.240 g, 0.296 mmol) was treated with thioanisole (0.220 g, 1.78 rmmol) and 8 ml trifluoroacetic acid for 5 hours. After removing 5 the TFA, the residue was triturated in diethylether twice and ethylacetate once to give a white amorphous solid as the product N-[[2(S)- 2-[1-Oxo-1-(2-thiazolyl)]-5 [(amino)iminomethyl)amino] pentyl]-(3-benzylsulfonylamino-2-oxo-2H-quinolin 1-yl)acetamide trifluoroacetic acid salt (0.183 g, yield of 87%). HPLC-MS (0 to 95% AcCN / 6 min @ 1.0 mL / Min @ 254 nm @ 50 C): retention time 3.07 min, 10 M+H' = 596.2 for formula C 27
H
29
N
7 0 5
S
2 . IH NMR (400 MHz, DMSO-d 6 ): 6 1.58 (bm, 2H), 1.67 (bm, 1H), 1.90 (b, 1H), 3.10 (bm, 2H), 4.60 (s, 2H), 3.80 (s, 3H), 4.62 (s, 2H), 5.01 (d, J = -17.2 Hz, 1H), 5.11 (d, J = -17.2 Hz, 1H), 5.38 (m, 1H), 6.80-7.70 (m, 15H), 8.14(s, 1H), 8.23 (s, 1H), 8.88 (b, 1H), 9.99 (d, J = 8.0 Hz, 1H). 13C NMR (101 MHz, DMSO-d 6 ): 6 25.3, 28.0, 44.9, 15 48.6, 54.4, 58.0, 114.2, 119.7, 121.9, 124.8, 126.1, 128.2, 128.3, 128.7, 131.0, 135.9, 137.1, 138.7, 144.7, 145.4, 156.6, 157.4, 164.4, 166.8, 191.4. Example 2 0 3 H Ph S N \ H H I NH 2 PhOS N / NH2/-,, NH 20 EX-2A) 3 -Benzylsulfonylamino-2-oxo-2H-quinolin-1-yl)acetic acid was coupled with benzyl-[[( 4 -aminomethylphenyl)iminomethyl] amino]carbamnate hydrogen chloride salt using EDC, HOBt as coupling agents in the presence of DIEA in DMF. Work up procedure gave a white amorphous solid as the product, N-[[4-[(benzylcarbonyl-amino)iminomethyl]phenyl]methyl]-(3 25 benzylsulfonylamino-2-oxo-2H-quinolin-1-yl)acetamide. HPLC-MS (0 to 95% AcCN / 6 min @ 1.0 mL / Min @ 254 nm @ 50 oC): retention time 3.38 min, M+H = 638.3 for formula C 34
H
3 1
N
5 0 6 S. H NMR (400 MHz, CDCl 3 ): 64.38 150 WO 00/69826 PCT/US00/08220 (s, 2H), 4.50 (d, J = 6.0 Hz, 2H), 4.92 (s, 2H), 5.14 (s, 2H), 7.06 (t, J = 7.2 Hz, 1H), 7.13 (t, J = 7.6 Hz, 2H), 7.15-7.24 (m, 6H), 7.30-7.40 (m, 6H), 7.45 (m, 3H), 7.52 (m, 1H), 7.57 (d, J = 8.4 Hz, 2H), 8.65(b, 1H), 9.09 (b, 1H). Compound EX-2A (0.118 g, 0.185 mmol), p-toluenesulfonic acid mono 5 hydrate (0.035 g, 0.185 mmol) and 10% Pd on activated carbon (0.029 g, 0.018 mmol) were mixed with 5 ml methanol. The mixture was stirred for 2 hours under an atmosphere of hydrogen that was introduced through a rubber balloon. After filtering off the catalyst and removing the methanol, the remaining residue was recrystallized in a solvent of 2:1 ether to methanol to yield a white amorphous solid 10 as the product, N-[[ 4 -[(amino)iminomethyl]phenyl]methyl]-(3-benzylsulfonyl amino-2-oxo-2H-quinolin-1-yl)acetamide p-toluenesulfonic acid salt, (0.080 g, yield = 64%). HPLC-MS (0 to 95% AcCN / 6 min @ 1.0 mL / Min @ 254 nm @ 50 oC): retention time 2.81 min, M+H' = 504.5 for formula C 26
H
25
N
5 0 4 S. IH NMR (400 MHz, CD 3 OD): 6 2.36 (s, 3H), 4.52 (s, 2H), 4.57 (s, 2H), 5.15 (s, 15 2H), 7.18-7.32 (m, 7H), 7.36 (t, J = 7.2 Hz, 2H), 7.48-7.55 (m, 4H), 7.59 (s, 1H), 7.70 (d, J = 8.0 Hz, 2H), 7.74 (d, J = 8.4 Hz, 2H). Example 3 I N N N H H
NH
2 p-MePhSO 3 H NH EX-3A) Methyl 2
-[
3 -amino-2-oxo-2H-quinolin-l-yl]acetate, (9.1 g, 39.2 20 mmol) was mixed with Boc anhydride (9.41 g, 43.1 mmol), triethylamine (6 ml, 43.1 mmol) and DMAP (50 mg, 0.4 mmol) in 200 ml DCM. The reaction mixture was stirred at 20 oC for 14 hours. The reaction solution was washed with IM citric acid solution twice, saturated sodium bicarbonate solution three times, saturated ammonium chloride once and it was dried over anhydrous MgSO 4 . After filtration 25 and removing the solvent, the residue was treated with methanol. A white solid was precipitated. Filtration and washing with methanol, the pure product, EX 3A, was obtained as a white powder (9.90 g, 87%). HPLC-MS (0 to 95% AcCN / 6 min @ 1.0 mL / Min @ 254 nm @ 50 oC): retention time 2.85 min, M+H' = 151 WO 00/69826 PCT/US00/08220 291.1 for formula C,4H,5N,05. 1H NMR (400 MHz, Methanol-d 4 ): d 3.76 (s, 3H), 3.82 (s, 3H), 5.15 (s, 2H), 7.09 (d, J = 8.4 Hz, 1H), 7.26 (t, J = 7.6 Hz, 1H), 7.43 (t, J = 7.6 Hz, 2H), 7.61 (d, J = 7.6 Hz, 1H), 7.96 (s, 1H), 8.39 (s, 1H). 3C NMR (101 MHz, Methanol-d 4 ): d (ppm) 44.4, 52.5, 52.6, 113.1, 5 118.9, 121.0, 123.3, 127.4, 128.4, 128.5, 134.5, 153.9, 157.6, 168.1. EX-3B) Compound EX-3A (1.09 g, 3.75 mmol) was mixed with KOH (5.2 g, 92.8 mmol) in 30 ml water and 30 ml methanol. After refluxing for three hours, the reaction solution was concentrated to 10 ml and acidified with concentrated HCI to pH = 2. After cooling down to 0 oC, the product was filtered 10 out, washed with water and dried via vacuum. A yellow powder acid was obtained as the pure product (0.733 g, y = 90%). HPLC-MS (0 to 95% AcCN / 6 min @ 1.0 mL/ Min @ 254 nm @ 50 C): retention time 1.60 min, M+H + = 219.1 for formula C 11H 1 1
N
2 0 3 . EX-3C) Compound EX-3B (0.296 g, 1.16 mmol) was treated with 15 phenylacetaldehyde (0.21 g, 1.74 mmol) in 15 ml methanol for 10 minutes. To this mixture was added sodium cyanoborohydride (0.08 g, 1.28 mmol). After two hours, the reaction was completed. Methanol was removed under reduced pressure and the residue was mixed with water. The product 2-[3-(2-phenylethylamino)-2 oxo-2H-quinolin-1-yl]acetic acid (EX-3C) was obtained after filtration and 20 washed with water as a white powder (0.225 g, 60%). HPLC-MS (0 to 95% AcCN / 6 min @ 1.0 mL / Min @ 254 nm @ 50 oC): retention time 3.55 min, M+H = 323.2 for formula C 1 9 Hi 9
N
2 0 3 . H NMR (400 MHz, Methanol-d 4 ): d 2.97 (t, J = 7.2 Hz, 2H), 3.45 (t, J = 7.2 Hz, 2H), 5.02 (s, 2H), 6.65 (s, 1H), 7.13-7.29 (m, 8H), 7.46 (d, J = 8.0 Hz, 1H). 13C NMR (101 MHz, Methanol 25 d 4 ): d (ppm) 35.9, 45.5, 46.6, 105.7, 115.1, 123.9, 124.5, 125.9, 127.0, 127.4, 129.6, 129.8, 133.9, 137.8, 140.8, 159.9, 173.1. EX-3D) Compound EX-3D was synthesized in same way as described for compound EX-2A. It is a white powder. HPLC-MS (0 to 95% AcCN / 6 min @ 1.0 mL / Min @ 254 nm @ 50 oC): retention time 3.65 min, M+H* = 588.6 for 30 formula C 35
H
34
N
5 0 4 . H NMR (400 MHz, Methanol-d 4 ): d 2.95 (t, J = 7.2 Hz, 2H), 3.43 (t, J = 7.2 Hz, 2H), 4.46 (s, 2H), 5.09 (s, 2H), 5.37 (s, 2H), 6.64 (s, 1H), 7.13-7.29 (m, 9H), 7.38-7.41 (m, 3H), 7.47 (m, 4H), 7.70 (d, J = 8.4 Hz, 2H). 13C NMR (101 MHz, Methanol-d 4 ): d (ppm) 35.8, 43.7, 45.4, 46.9, 70.6, 152 WO 00/69826 PCT/US00/08220 105.8, 114.9, 124.2, 124.6, 126.0, 127.2, 127.4, 129.1, 129.6, 129.7, 129.8, 129.9, 130.0, 133.8, 137.8, 140.7, 160.2, 170.3. The product of Example 3 was synthesized in same way as described for compound of Example 2 as a p-toluenesulfonic acid salt and an amorphous solid. 5 HPLC-MS (0 to 95% AcCN / 6 min @ 1.0 mL / Min @ 254 nm @ 50 C): retention time 3.18 min, M+H' = 454.1 for formula C 27
H
28
N
5 0 2 . IH NMR (400 MHz, Methanol-d 4 ): d 2.32 (s, 3H), 3.03 (t, J = 7.2 Hz, 2H), 3.56 (t, J = 7.2 Hz, 2H), 4.48 (s, 2H), 5.14 (s, 2H), 7.19 (d, J = 8.0 Hz, 4H), 7.26-7.34 (m, 6H), 7.48 (d, J = 8.0 Hz, 2H), 7.55 (s, 1H), 7.64 (d, J = 7.6 Hz, 1H), 7.69 (t, J = 8 10 Hz, 4H), 8.72 (s, 2H), 9.18 (s, 2H). 13C NMR (101 MHz, Methanol-d 4 ): d (ppm) 21.3, 34.3, 43.7, 46.8, 59.6, 115.4, 122.0, 124.6, 126.9, 127.8, 128.2, 128.3, 129.0, 129.2, 129.5, 129.7, 129.8, 129.9, 130.3, 131.4, 137.4, 138.9, 141.8, 146.7, 159.5, 168.2, 168.3, 169.7. 15 Example 4 0I" " y " PV hS 'N N N H H NH 2 O \ - NH 2 p-MePhSO 3 H NH EX-4A) 2
-[
3 -Amino-2-oxo-2H-quinolin- 1-yl]acetic acid, (0.206 g, 0.81 mmol) was treated with benzenesulfonyl chloride (0.172 g, 0.97 mmol) in pyridine for one hour. After removing the pyridine, the residue was recrystallized in 20 acetone to yield a white crystal solid as the product, 2-[3-benzenesulfonylamino-2 oxo-2H-quinolin-1-yl]acetic acid, (EX-4A)(0.117 g, y = 41% ). HPLC-MS (0 to 95% AcCN / 6 min @ 1.0 mL / Min @ 254 nm @ 50 oC): retention time 2.85 min, M+H = 359.2 for formula C 17
H
1 5 sNO 2 S. H NMR (400 MHz, Acetone-d 6 ): d 5.12 (s, 2H), 7.28 (t, J = 7.2 Hz, 1H), 7.36 (d, J = 8.8 Hz, 1H), 7.48-7.63 (m, 25 4H), 7.75 (dd, J = 8, 1.6 Hz, 1H), 7.74 (s, 1H), 8.00-8.03 (m, 2H). 13C NMR (101 MHz, Acetone-d6): d (ppm) 44.8, 115.0, 120.8, 120.9, 123.9, 127.8, 128.1, 129.4, 129.9, 130.1, 134.2, 136.7, 140.4, 158.2, 169.1. 153 WO 00/69826 PCT/US00/08220 EX-4B) Compound EX-4A was synthesized in same way as described for compound EX-2A giving a white powder. HPLC-MS (0 to 95% AcCN / 6 min @ 1.0 mL / Min @ 254 nm @ 50 oC): retention time 3.23 min, M+H' = 624.2 for formula C 33
H
30
N
5 0 6 S. H NMR (400 MHz, Methanol-d 4 ): d 4.45 (s, 2H), 5 5.06 (s, 2H), 5.38 (s, 2H), 7.24-7.60 (m, 14H), 7.71 (d, J = 8.0 Hz, 2H), 7.84 (s, IH), 7.94 (d, J = 7.2 Hz, 2H). 13C NMR (101 MHz, Methanol-d 4 ): d (ppm) 43.7, 47.0, 70.7, 115.3, 121.7, 122.5, 124.5, 127.3, 128.4, 129.1, 129.6, 129.7, 129.9, 130.0, 130.1, 130.2, 130.3, 134.4, 135.8, 137.2, 140.8, 147.7, 154.6, 159.3, 167.9, 169.8. 10 Compound of this example was synthesized in same way as described for compound Example 2. It is an amorphous off-white solid and ap toluenesulfonic acid salt. HPLC-MS (5 to 95% AcCN / 6 min @ 1.0 mL / Min @ 254 nm @ 50 oC): retention time 2.02 min, M+H' = 490.1 for formula
C
25
H
24
N
5 0 4 S. 1H NMR (400 MHz, Methanol-d): d 2.34 (s, 3H), 4.46 (s, 2H), 15 5.06 (s, 2H), 7.20 (d, J = 8.0 Hz, 1H), 7.24-7.29 (m, 2H), 7.46-7.51 (m, 6H), 7.55 (d, J = 7.2 Hz, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.71 (m, 4H), 7.86 (s, 1H), 7.95 (d, J = 8.0 Hz, 2H). " 3 C NMR (101 MHz, Methanol-d 4 ): d (ppm) 21.3, 43.6, 46.9, 115.1, 121.6, 122.4, 124.4, 126.8, 127.9, 128.2, 128.9, 129.0, 129.5, 129.7, 130.1, 130.2, 134.3, 137.0, 140.6, 146.6, 159.2, 169.5, 184.2. 20 Example 5 N 0 HCI HN NNH Ph HCI
H
2 N EX-SA) A solution of 2-amino pyridine (20.42 g, 217.0 mmol) in dichloromethane 500 mL was cooled to 0 0 C and treated with triethyl amine (36.29 25 mL, 260.4 mmol) and pivaloyl chloride (28.06 mL, 227.8 mmol). After 15 154 WO 00/69826 PCT/US00/08220 minutes, the reaction mixture was allowed to warm to room temperature and stir overnight. The reaction mixture was poured onto ice, and the organic layer was washed with saturated NaHCO 3 (aq), and dried over Na 2
SO
4 . The volatile components were removed, and a brown oil was isolated. Crystallization with 5 hexanes afforded 31 g of N-(pyrid-2-yl)-2,2-dimethylacetamide (EX-5A)as white crystals in 80% yield. Reference: Turner, J. A. J. Org. Chem. 1983, 48, 3401. EX-5B) A solution of EX-5A (2.00 g, 11.23 mmol) in THF (115 mL) at -78 OC was treated with n-BuLi (14.1 mL, 28.10 mmol of a 2.0 M solution in hexanes). The reaction mixture was allowed to warm to 0 oC and stir for 2h. The 10 reaction mixture was again cooled to -78 oC, and the mixture was quenched with DMF (2.18 mL, 28.10 mmol). The reaction mixture was allowed to warm to room temperature and to stir overnight. The reaction mixture was poured into a slurry of ice and 6N HC1, and the acidified mixture was stirred for 15 minutes. The organic layer was separated (discard), and the aqueous layer was neutralized with K 2
C
3 15 and extracted with ether (3 x 100 mL). The combined organic layers were washed with water, brine and dried over MgSO 4 . After filtration and evaporation of the volatiles, a yellow oil was isolated which solidified upon standing. 1.23 g (53%) of EX-5B product was isolated. Reference: Turner, J. A. J. Org. Chem. 1990, 55, 4744. 20 EX-SC) A mixture of EX-SB (0.62 g, 3.01 mmol) and 3N HCI (30 mL) was refluxed overnight. After the reaction mixture was allowed to cool to room temperature, it was washed with ether (2 x 50 mL). The organic layer was discarded. The aqueous layer was neutralized with K 2
CO
3 , and extracted with ether (4 x 50 mL). The combined ether layers were dried over K 2
CO
3 , filtered, 25 and concentrated to afford 2 -aminopyridinecarboxaldehyde (EX-5C) as a yellow oil (036 g) which solidified upon standing. The crude material was used with any further purification. Reference: Moormann, A. E.; Yen, C. H.; Yu, S. Syn. Commun. 1987, 17, 1695. EX-SD) A mixture of hippuric acid (0.54 g, 3.01 mmol) and acetic 30 anhydride (30 mL) was heated to 80 oC. After 2h, the reaction mixture was homogeneous. The hot reaction mixture was treated with a solution of EX-SC (037 g, 3.01 mmol) in acetic anhydride. After stirring the reaction mixture for an 155 WO 00/69826 PCT/US00/08220 additional 16 h, the reaction mixture became heterogeneous. The volatile components were removed in vacuo, and the precipitate was filtered. The filter cake was washed with ether (3 x 30 mL), and 0.36 g of 3-benzamido-2-oxo-2H 1,8-naphthyridine (EX-5D) was isolated as tan colored powder in 45% yield: H 5 NMR (300 MHz, d-DMSO) d 12.77 (s, 1H), 9.47 (s, 1H), 8.72 (s, 1H), 8.45 (d, J= 3.42 Hz, 1H), 8.21-8.18 (m, 1H), 7.95 (d, J= 7.6 Hz, 2H), 7.66-7.54 (m, 3H), 7.28 (dd, J, = 4.6 Hz, J 2 = 4.8 Hz, 1H); 13C NMR (75 MHz, CDCI 3 ) d 165.8, 159.4, 149.2, 146.6, 136.6, 134.3, 133.0, 130.3, 129.61 (2C), 129.58, 127.9, 120.2, 119.8, 115.7; HFIRMS (EI) calcd for C 15
H
1 1
N
3 0 2 266.0930, found 10 266.0939. EX-SE) A solution of EX-SD (0.072 g, 0.271 mmol) in DMF (5 mL) was cooled to 0 oC, and NaHi (60% dispersion in mineral oil, 0.013 g, 0.325 mmol) was slowly added. After five minutes, methyl bromoacetate was added dropwise via syringe. The reaction mixture was allowed to warm to room 15 temperature, and it was stirred until no starting material remained by TLC. DMF was removed in vacuo which afforded a yellow residue. The residue was triturated in water and washed with water and hexanes to afford 0.062g of methyl 2-[3 benzamido-2-oxo-2H-1,8-naphthyridin-1-yl]acetate (EX-S5E) in 68% yield: H NMR (400 MHz, CDCI 3 ) d 9.30 (s, 1H), 8.88 (s, 1H), 8.45 (d, J = 4.6 Hz, 1H), 20 7.95-7.91 (min, 3H), 7.56-7.46 (m, 3H), 7.23-7.20 (min, 1H), 5.37 (s, 2H), 3.74 (s, 3H); 1 3 C NMR (100 MHz, CDCI 3 ) d 168.8, 166.1, 159.0, 148.0, 145.5, 136.5, 134.0, 132.6, 129.12, 129.11, 129.08, 128.8, 127.4, 119.8, 119.0, 116.7, 52.7, 43.2; HRMS (EI) calcd for C 18 Hs 15
N
3 0 4 338.1156, found 338.1141. 25 EX-SF) A solution of EX-5E (0.053 g, 0.157 mmol) in THF and methanol (3:2, 5mL) was treated with 1.0 M LiOH (aq). The reaction mixture was stirred over night. The mixture was concentrated to remove the volatile components. The resulting aqueous solution was acidified with iN HCI, and a solid precipitated from the solution. After filtration, the filter cake was washed 30 with IN HCI and water to afford 0.038 g of 2-[3-benzamido-2-oxo-2H-1,8 naphthyridin-l-yl]acetcc acid (EX-SF) as white solid in 74% yield: H NMR (400 MHz, d-DMSO) d 13.10 (br s, IH), 9.53 (s, 1H), 8.78 (s, 1H), 8.51-8.50 156 WO 00/69826 PCT/US00/08220 (m, 1H), 8.26 (d, J= 7.8 Hz, 1H), 7.93 (d, J= 8.1 Hz, 2H), 7.62-7.51 (m, 3H), 7.36-7.32 (m, 1H), 5.14 (s, 2H); 13 C NMR (100 MHz, d-DMSO) d 169.9, 166.0, 158.7, 148.8, 145.9, 137.5, 134.2, 133.0, 129.5 (2C), 128.8, 128.0 (2C), 120.4, 120.2, 116.2, 43.5; HRMS (EI) calcd for C 17
HI
3
N
3 0 4 324.1004, 5 found 324.098. EX-SG) A solution of EX-SF (0.099g, 0.30 mmol) in 3 mL of DMF was treated with N-hydroxybenzotriazole (0.054 g, 0.40 mmol), and 1-[3 (dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.076 g, 0.40 mmol), and N,N-diisopropylethylamine (0.37 mL, 2,14 mmol). The resulting mixture 10 was allowed to stir for 15 minutes at room temperature. The reaction mixture was then treated with 4-(N-Cbz-amidino)benzylamine (0.127 g, 0.40 mmol) as a solution in DMF (3 mL). The resulting reaction mixture was allowed to stir for 18 hours. The reaction mixture was partitioned between ethyl acetate and a saturated
NH
4 Cl(aq) solution. The separated organic layer was washed with saturated 15 K 2
CO
3 (aq), saturated NH 4 CI (aq), and brine. The organic solution was dried (Na 2
SO
4 ), filtered and concentrated. (EX-SG) was isolated as a white solid, and the crude product was used in the next step without further purification: HRMS (El) calcd for C 33
H
28
N
6 0 5 589.2178, found 589.2199. A solution of Cbz-amidine (EX-SG) (0.090 g, 0.15 mmol) in 6 mL of 20 methanol, and 1 mL of 4 N HCI in dioxane was treated with 25 mg of 10% Pd/C in one portion. The resulting reactin mixture was stirred under hydrogen gas (25 psi) for 18 hours. After filtration of the reaction mixture through a pad of Celite, the solvent was removed under reduced pressure. Slow addition of 1 M HCI precipitated pure product of the invention as a white solid: H NMR (400 MHz, d 25 DMSO) d 9.52 (s, 1H), 9.24 (s, 2H), 8.91-8.83 (min, 2H), 8.77 (s, 1H), 8.53 8.52 (m, 1H), 8.27 (d, J= 7.5 Hz, 1H), 7.93 (d, J= 7.5 Hz, 2H), 7.73 (d, J= 8.3 Hz, 2H), 7.63-7.61 (m, 1H), 7.56-7.52 (m, 2H), 7.43 (d, J= 8.1 Hz, 2H), 7.37-7.34 (m, 1H), 5.17 (s, 2H), 4.35 (d, J= 5.9 Hz, 2H); 13C NMR (100 MHz, d-DMSO) d 167.7, 166.0, 165.9, 159.0, 148.6, 146.4, 146.2, 137.4, 134.2, 30 133.1, 129.6, 128.9, 128.8, 127.93 (2C), 127.88 (2C), 127.0, 120.21, 120.16, 116.5, 72.9, 60.9, 44.8, 42.4; HRMS (El) calcd for C 25
H
22 N60 3 455.1832, found 455.1840. 157 WO 00/69826 PCT/US00/08220 Additional substituted N-[Substituted]-(3-benzylsulfonylamino-2-oxo-2H quinolin-1-yl)acetamides can be prepared by one skilled in the art using methods similar to those above. These acetamides as shown in Example Table 1. 5 Example Table 1. N-[Substituted]-(3-benzylsulfonylamino-2-oxo-2H quinolin- 1 -yl)acetamides. o0 OV NN qpYo Ex.No. yo 6 2-[4-Aminophenyl]ethyl 7 4-aminobutyl 8 5-aminopentyl 9 6-(N,N-dimethylamino)hexyl 10 4-Aminomethylbenzyl 11 3-Aminomethylbenzyl 12 3-[Imidazo-1-yl]propyl 13 2-[Imidazo-5-yl]ethyl 14 2-[Pyrid-3-yl]ethyl 15 3-[N-Methylpiperidin-4-yl]propyl 16 4-Aminobenzyl 10 158 WO 00/69826 PCT/US00/08220 The pyridone analogs of the present invention have the general structure as shown in Figure 2. R1 N N N H H 0 O Y 5 Figure 2. General Structure of Pyridone Analogues The general synthetic route is illustrated in Scheme 3 wherein substituents are as defined herein. These compounds are exemplified in Examples 17 through 23. 159 WO 00/69826 PCT/US00/08220 Scheme 3: General Synthesis of Pyridones 1 1
(CH
3 0) 2 CHN(CH 3
)
2 2 R 22-Cyanoacetamide N NC H HBr R AcOH Reflux 1
R
2 12 hrs I R 2 1. DPPAfTEA/Dioxane R N 2. t-BuOH, reflux N Boc-HN* Y " H N O 1. NaH HOOC H 1 2. BrCH 2 -EO YLL 0 R2 TFA B-A=0 E NaBH(OAc) 3 ' N E Boc-HN YLL 1 Removal of R B N %OH 1 H 0 2
NH
2
-Y
0 -Cbz, R then
H
2 , Pd/C A N E B N YO H J 160 WO 00/69826 PCT/US00/08220 Example 17 Ph S STFA 0 0 N H O N O
NH
2 & N , N NH O H NH N-[[2(S)- 2-[1-hydroxy- 1-(2-thiazolyl)]-5-[[[(4-methoxy-2,3,6 trimethyl)sulfonylamino] iminomethyl]aminol]pentyl]-6-(2-phenylethyl)-2-oxo-3 5 [[(phenylmethyl) sulfonyl]amino]-1(2H)-pyridineacetanmide (0.084 g, 0.098 mmol) was treated with 1,3-dihydro- 1-hydroxy-3,3-bis(trifluoromethyl)- 1-oxide- 1,2 benziodoxole (0.0588 g, 0.147 mmole) in 1 ml acetonitrile. Similar work-up procedure as in preparing EX-1 E was used to yield the oxidation product. The oxidation product was treated with thioanisole (0.073 g, 0.59 mmol) and 3 ml 10 trifluoroacetic acid for 6 hours. After removing the TFA, the residue was triturated in ether. It was purified by a preparative C-18 reverse HPLC column using a gradient that proceed from 5% to 95% acetonitrile in H2 in the presence of 0.1% TFA in 30 minutes to yield the product, N-[[2(S)- 2-[1-Oxo-l-(2-thiazolyl)]-5 [[[(amino)iminomethyl]amino] pentyl]-6-(2-phenylethyl)-2-oxo-3 15 [[(phenylmethyl)sulfonyl]amino]-1(2H)-pyridineacetamide trifluoroacetic acid salt, as a white amorphous solid (0.0232 g, y = 31 %). HPLC-MS (0 to 95% AcCN / 6 min @ 1.0 mL / Min @ 254 nm @ 50 oC): retention time 3.43 min, M+H* = 650.2 for formula C 3 1
H
35
N
7 0 5
S
2 . 20 Example 18 0 TFA 0 0 N H H H NH This compound, N-[[2(S)- 2-[1-Oxo- 1-(2-thiazolyl)]-5 [(amino)iminomethyl)-amino] pentyl ]-6-methyl-2-oxo-3 [[(phenylmethyl)sulfonyl]amino]- 1(2H)-pyridineacetamide trifluoroacetic acid salt, 25 was prepared in a similar fashion as for Example 1. HPLC-MS (0 to 95% AcCN 161 WO 00/69826 PCT/US00/08220 / 6 min @ 1.0 mL / Min @ 254 nm @ 50 oC): retention time 2.69 min, M+H = 560.3 for formula C 24
H
29
N
7 0 5
S
2 . Example 19 Ph
SO
3 H N N N C 100 Hj
NH
2 5 NH The compound, N-[[ 4 -(amino)iminomethyl]phenyl]methyl]- 6-(2 phenylethyl)-2-oxo-3-[[(phenylmethyl)sulfonyl]amino]- 1(2H)-pyridineacetamide p-toluenesulfonic acid salt, was synthesized in a similar fashion as for Example 2 using 6
-(
2 -phenylethyl)-2-oxo-3-[[(phenylmethyl) sulfonyl]amino]- 1 (2H) 10 pyridineacetic acid as starting material. HPLC-MS (0 to 95% AcCN / 6 min @ 1.0 mL / Min @ 254 nm @ 50 oC): retention time 3.23 min, M+H' = 558.5 for formula C 30
H
3 1
N
5 0 4 S. H NMR (400 MHz, CD 3 OD): 6 2.36 (s, 3H), 2.92 (bin, 4H), 4.43 (s, 2H), 4.54 (s, 2H), 4.87 9s, 2H), 6.10 (d, J = 8.0 Hz, 1H), 7.21 (m, SH), 7.26-7.31 (m, 8H), 7.55 (d, J = 8.4 Hz, 2H), 7.69 (d, J = 8.0 Hz, 15 2H), 7.71 (d, J = 8.0 Hz, 2H). Example 20 03H O O O / NH2 NH This compound, N-[[ 4 [-(amino)iminomethyl]phenyl]methyl]- 6-methyl-2 oxo-3-[[(phenylmethyl)sulfonyl]amino]- 1(2H)-pyridineacetamide p 20 toluenesulfonic acid salt, was synthesized in a similar fashion as for Example 2 using 6 -methyl-2-oxo-3-[[(phenylmethyl)sulfonyl] amino]l- 1(2H)-pyridineacetic acid as starting material. HPLC-MS (0 to 95% AcCN / 6 min @ 1.0 mL / Min @ 254 nm @ 50 oC): retention time 2.41 min, M+H' = 468.1 for formula C23H 25 N50 4 S. iH NMR (400 MHz, CD 3 0D): 6 2.34 (s, 3H), 2.36 (s, 3H), 25 4.43 (s, 2H), 4.53 (s, 2H), 4.87 (s, 2H), 6.15 (d, J = 7.6 Hz, 1H), 7.21-7.31 162 WO 00/69826 PCT/US00/08220 (m, 8H), 7.56 (d, J = 8.4 Hz, 2H), 7.69 (d, J = 8.0 Hz, 2H), 7.72 (d, J = 8.0 Hz, 2H), 8.70 (b, 1H), 9.19 (b, 1H). Example 21 Ph Ph 'AN N )N O H 0 P H H N
NH
2 5 HCI NH This compound was synthesized in a similar fashion as for Example 2 using 6
-(
2 -phenylethyl)-2-oxo-3-[[(phenylmethyl)sulfonyl] amino]- l(2H) pyridineacetic acid as starting material and coupling it with 4-[ 1-(N,N-bis-Boc amidino)piperidinyl]methylamine The coupling product was treated with 4N HCI 10 in dioxane to generate the product. The compounds were purified by reverse phase C-18 HPLC to generate the final pure products. HPLC-MS (0 to 95% AcCN / 6 min @ 1.0 mL / Min @ 254 nm @ 50 oC): retention time 3.10 min, M+H* = 565.6 for formula C 29
H
37
N
6 0 4 S. 15 Example 22 0 o Ph N N O N NH 2 NH This compound was synthesized in a similar fashion as for Example 2 using 6 -methyl-2-oxo-3-[[(phenylmethyl)sulfonyl] amino]- l(2H)-pyridineacetic 20 acid as starting material and coupling it with 4-[1-(N,N-bis-Boc amidino)piperidinyl]methylamine The coupling product was treated with 4N HCI in dioxane to generate the product. The compounds were purified by reverse phase C-18 HPLC to generate the final pure products. HPLC-MS (0 to 95% AcCN / 6 163 WO 00/69826 PCT/US00/08220 min @ 1.0 mL / Min @ 254 nm @ 50 oC): retention time 2.42 min, M+H' = 475.3 for formula C 22
H
3 1
N
6 0 4 S. One subclass of pyridone analogs have a heteroaryl group substituting the pyridone ring at the 5 or 6 position. Scheme 4 illustrates a process to prepare 5 heteroaryl substituted pyridones. The preparation procedure is exemplified in Example 23 for the preparation of a 6-substituted pyridyl group although it will be readily recognized that a wide variety of substituted pyridines and other 5 and 6 membered heteroaryl groups can be introduced using the procedure described below. 10 164 WO 00/69826 PCT/US00/08220 Scheme 4: Preparation of Heteroaryl Pyridones N (CH30)2CHN(CH3)2 2-Cyanoacetamide Sub NC H 3Sub HBr/AcOH I O Reflux, 12 hrs Hub N 1. DPPA/TEA/Dioxane ' 2. t-BuOH, reflux Boc-HN Sub 1. NaH O HOOC H 2. BrCH2-CO2CH Sub 1. TFA 2. B-CHO y N CO2CH 3. NaBH(OAc)u Boc-H SSub OO B-A AN OH H LNH -Cbz 0 N EDC/HOBt/DIEA BASub H2, Pd/C, HCI B- N N ONH IfNH H 3 HCI O NH2 165 WO 00/69826 PCT/US00/08220 Example 23 NN Ph
N
N ' HH 0 H NH 2 3 HCI H EX-23A) One equivalent of commercially available 4-acetylpyridine is treated with three equivalents N, N-dimethylformamide dimethyl acetal in refluxing 5 acetonitrile for 12 hours. After removing the solvent and excess amount of N, N dimethylformamide dimethyl acetal, the resulting yellow solid is dissolved in DMF. To this solution is added one equivalent cyanoacetamide and two equivalents of sodium methoxide. The resulting mixture is heated at 100 oC for 5 hours. After cooling down, the reaction mixture is mixed with water and acidified with HCI to 10 pH 5. The resulting yellow precipitate is filtered, washed with water and dried via vacuum to give the product EX-23A as a yellow solid. EX-23B) Compound EX-23A is heated to reflux in one portion of 48% aqueous HBr and two portions of acetic acid for 12 hours. After the mixture is cooled down, mixed with water and adjusted the pH to 5, a light yellow precipitate 15 is formed. The light yellow precipitate is filtered and washed with 1N HC1 and water, dried via vacuum to give the product EX-23B as an off-white solid. EX-23C) Compound EX-23B is treated with 1.1 equivalent of DPPA, 1 equivalent triethylamine in dioxane at refluxing temperature for two hours. Five equivalents t-butanol is added into the mixture, and the mixture is then refluxed 20 overnight. After removing the solvent, the remaining residue is worked up by standard aqueous work-up procedure. The residue is then purified by silica gel column chromatography to yield Compound EX-23C. EX-23D) Compound EX-23C is mixed with one equivalent sodium hydride in DMF and one equivalent methyl bromoacetate subsequently. After 25 stirring at ambient temperature for 12 hours, the reaction is worked up by standard procedure. The product EX-23D is purified by silica gel column chromatography. 166 WO 00/69826 PCT/US00/08220 EX-23E) Compound EX-23D is treated with 50% TFA in dichloromethane for 1 hour. After removing the solvent and TFA, the residue is redissolved in THF with one equivalent of triethylamine. To this solution is added one equivalent phenylacetaldehyde and two equivalents sodium 5 triacetoxyborohydride. After stirring for 12 hours, the reaction is quenched with addition of aqueous ammonium chloride. Standard aqueous work-up and silica gel column chromatography yields the desired product EX-23E. EX-23F) Compound EX-23E is treated with IM LiOH in 1: 1: 1 ratio of THF, methanol and water for half hour. After it is acidified with IN HC1, the 10 organic solvent is removed and a precipitate will form. The precipitate is filtered, washed with water and dried by vacuum to give the desired product EX-23F. Compound EX-23F is treated with one equivalent EDC and HOBt in the presence of three equivalents diisopropylethylamine in DMF for 10 minutes. One equivalent of 4 -aminomethylbenzamidine, which is protected with Cbz at the amidine, is then 15 added into the reaction mixture. After stirring at ambient temperature for four hours, the reaction mixture is worked up by standard procedure and the product EX-23G is purified by silica gel column chromatography. Compound EX-23G is dissolved in methanol in the presence of 5 equivalents of HQC and 5% equivalent of 10% Pd /C. The mixture is stirred under 20 an atmosphere of hydrogen (ambient pressure) for five hours. After filtration and removing the solvent, Compound 23 is obtained as the pure product. In a related procedure, 5-substituted pyridones can be prepared as illustrated in Examples 24 and 25. 25 30 35 167 WO 00/69826 PCT/US00/08220 Example 24
NH
2 N N N NH H H 0 EX-24A) 3-Nitro-2-hydroxylpyridine (49.5 g, 0.35 mol) and 10% Pd/C (4.21 g, 4 mmol) in 500 ml ethanol was stirred under an atmosphere of hydrogen 5 introduced via a balloon for 24 hours. After filtering through a pad of Celite 545 and removing the ethanol, a brown solid was obtained as the pure product, 3 aminopyrid-2-one, (38 g, 97%). HPLC-MS (0 to 30% AcCN / 6 min @ 1.0 mL / Min @ 254 nm @ 50 oC): retention time 0.097 min, M+H* = 111.1 for formula
C
5
H
7
N
2 0. 10 EX-24B) Compound EX-24A (27.25 g, 0.248 mol) was treated with Boc anhydride (59.47 g, 0.272 mol), triethylamine (52 ml, 0372 mol) and DMAP (1.5 g, 12.4 mmol) in 500 ml DCM for 4 hours. After an aqueous work-up and removing the solvent, the residue was passed through a short silica gel plug using 40% ethylacetate in hexane as eluent to yield the crude product (28 g, 56%0. Pure 15 product, 3-(N-Boc-amino)pyrid-2-one, was obtained by recrystallization in acetone as a needle-like white crystalline solid. HPLC-MS (0 to 95% AcCN / 6 min @ 1.0 mL / Min @ 254 nm @ 50 C): retention time 239 min, M-Boc + H' = 111.1 for formula CsH 7
N
2 0. H NMR (400 MHz, CDCl 3 ): d 1.52 (s, 9H), 6.32 (t, J = 7.2 Hz, 1H), 7.00 (dd, J = 6.4, 1.6 Hz, 1H), 7.55 (s, 1H), 8.10 (d, J = 6.4 Hz, 20 1H), 12.86(b, 1H). 13C NMR (101 MHz, CDCl 3 ): d 28.2, 80.8, 107.7, 121.8, 125.2, 129.7, 152.7, 158.8. EX-24C) Compound EX-24B (13.58 g, 64.6 mmol) and N iodosuccinimide (21.8 g, 97 mmol) in 250 ml dichloromethane was stirred at room temperature for 18 hours. After filtration to remove the by-product succinimide, 168 WO 00/69826 PCT/US00/08220 the solvent was removed under reduced pressure. The remaining residue was subjected to a silica gel flash chromatography to yield a brown solid as the product, 3-(N-Boc-amino)-5-iodopyrid-2-one, (17.3g, 80%). HPLC-MS (0 to 95% AcCN / 6 min @ 1.0 mL / Min @ 254 nm @ 50 oC): retention time 3.22 min, 5 M + Na' = 359.0 for formula CloH 13
IN
2 3 Na. EX-24D) Compound EX-24C (9.62 g, 28.6 mmol) was treated with sodium hydride (1.71 g, 42.9 mmol) 60% in mineral oil in 200 ml THF for 10 minutes. To this mixture was added methyl bromoacetate (4.33 ml, 45.8 mmol). The resulting structure was stirred at room temperature for 1 hour. After removing 10 the THF, the residue was washed with hexanes to remove the mineral oil. It was then partitioned between ethylacetate and saturated aqueous ammonium chloride. The organic layer was washed with saturated aqueous ammonium chloride three times and dried over anhydrous MgSO 4 . After removing the solvent, a yellow amorphous solid was obtained as the product, methyl 2-[3-(N-Boc-amino)-5-iodo 15 2-oxopyrid-2-yl]acetate, (11.1 g, 95%). EX-24E) 3-Pyridyl boronic acid (2.0 g, 4.93 mmol) was suspended in 80 ml toluene and the mixture was degassed by bubbling nitrogen through for 10 minutes. Tetrakis-(triphenyl)phosphine Palladium (0.54 g, 0.46 mmol) was dissolved in a pre-degassed mixture of 20 ml toluene and 50 ml methanol. The 20 catalyst solution was added to the boronic acid solution under nitrogen. To this resulting mixture was added compound EX-24D (3.80 g, 9.31 mmol) in 25 ml methanol followed with 22 ml 2M Na.CO 3 solution. The reaction solution was heated to reflux for 2.5 hours. After it was cooled down to room temperature, it was mixed with 10 ml 2.5N NaOH and was stirred for an half hour. After 25 removing all the solvent, the remaining residue was re-dissolved in methanol and the pH of the solution was adjusted to 6 with 1 N HC. After removing all the solvent, the residue was absorbed on silica gel and subjected to silica gel flash chromatography using 5% methanol in DCM as the eluate. The pure product, methyl 2
-[
3 -(N-Boc-amino)-5-(pyrid-3-yl)-2-oxopyrid-2-yl]acetate (EX-24E), 30 was obtained as a white amorphous solid (1.01 g, 57%). HPLC-MS (5 to 95% AcCN /6 min @ 1.0 mL / Min @ 254 nm @ 50 oC): retention time 1.89 min, M+H = 346.0 for formula C 17
H
19
N
3 0 5 . IH NMR (400 MHz, CDCl 3 ): d 1.53 (s, 9H), 4.82 (s, 2H), 7.62 (d, J = 2.4 Hz, 1H), 7.87 (t, J = 6.0, 1H), 8.36 (s, 1H), 8.47 (d, J = 8.4 Hz, 1H), 8.68 (d, J = 4.4 Hz, 1H), 9.05 (s, 1H). ' 3 C NMR (101 169 WO 00/69826 PCT/US00/08220 MHz, CDCl 3 ): d 28.0, 50.9, 81.6, 113.8, 117.3, 126.5, 128.9, 130.4, 136.4, 139.8, 140.4, 140.6, 152.7, 156.6, 169.0. Starting with the intermediate EX-24E, the final inhibitor compound is synthesized in a similar fashion as described in other examples by procedures 5 described above. Example 25
NH
2 N N N H H O NH2 NH EX-25A) 3 -Nitrobenzeneboronic acid (1.41 g, 8.43 mmol) was suspended in 50 ml dioxane and the mixture was degassed with nitrogen. Tetrakis 10 (triphenyl)phosphine Palladium (0.406 g, 035 mmol) dissolved in 10 ml dioxane was added to the boronic acid solution under nitrogen. To this mixture was added compound EX-24D (2.87 g, 7.03 mmol) and 7 ml 2M potassium phosphate solution. The reaction mixture was heated to reflux for 3 hours. After removing the dioxane, the remaining residue was partitioned between ethylacetate and 15 aqueous saturated ammonium chloride. The organic layer was washed with aqueous saturated ammonium chloride and dried over sodium sulfate. The pure product was isolated by a silica gel column flash chromatography to yield a yellow crystalline solid (1.13 g, 40%). The product, methyl 2-[3-(N-Boc-amino)-5-(3 nitrophenyl)-2-oxopyrid-2-yl]acetate, showed one peak on LC-MS. However, it is 20 a mixture of two isomers with a ratio of 2.8 to I based on 1 H NMR and 13C NMR. One isomer has the nitro group at the same side of the Boc amino group, the other in the opposite direction. The NMR data only lists the dominant isomer here. 170 WO 00/69826 PCT/US00/08220 HPLC-MS (5 to 95% AcCN / 6 min@ 1.0 mL / Min @ 254 nm @ 50 oC): retention time 3.74 min, M+Na + = 4263 for formula C 19
H
2 1
N
3 0 7 Na. 'H NMR (400 MHz, CDC1 3 ): d 1.50 (s, 9H), 3.82 (s, 3H), 4.80 (s, 2H), 7.20 (d, J = 2.4 Hz, 1H), 7.56 (t, J = 8.0, 1H), 7.66 (s, 1H), 7.81 (d, J = 8.0 Hz, 1H), 8.15 (d, 5 J = 8.0 Hz, 1H), 8.28 (d, J = 2.4 Hz, 1H), 8.36 (s, 1H). Starting with the intermediate EX-25A, the final inhibitor compound is synthesized in a similar fashion as described in other examples by procedures described above. Preparation of sulfonyl analogs of pyridones of the present invention in 10 which a sulfonyl replaces the carbonyl group of the N- 1 acetamide side chain can be accomplished by use of the general procedure in Scheme 3. Example 26, a specific example of a sulfonamide of the present invention, is synthesized as according to the general procedure shown in Scheme 5. 171 WO 00/69826 PCT/US00/08220 Scheme 5: Preparation of Pyridonyl Alkyl Sulfonamid
(CH
3 0) 2
CHN(CH
3
)
2 2-Cyanoacetamide ub NNC H ub HBr/AcOH ub O Reflux, 12 hrs ub 1. DPPA/TEA/Dioxane N 2. t-BuOH, reflux B o c -H N 0,H u bC 1. NaH O HOOC H oN 2. BrCH 2
-SO
3 Na I ub 1. TFA 2. B-CHO Boc-HN N SO 3 H 3. NaBH(OAc) 3 Bo-H N O I ub PCI 5 , then H2N NH NH -Cbz
H
2, Pd/C, HCI Bb ub B- N N O NH NH NN H 2 HCI 0 172 I NH 2 WO 00/69826 PCT/US00/08220 Example 26 Ph Ph N ,ON \ 0 H
NH
2 2 HCI NH (21) Compound EX-26C can be prepared using same methods as described in 5 Example 23 for compounds EX-23A, EX-23B, and EX-23C. EX-26D) Compound EX-26C is treated with 1.1 equivalent NaH and 1.5 equivalents sodium bromomethanesulfonate in DMF overnight. The reaction is quenched by dilution with water and addition of 1N HCI to adjust the reaction solution to a pH of 3 to precipitate the product. The crude product is obtained by 10 filtration and washing with water and ether. The pure product EX-26D is further purified by recrystallization in ethanol. EX-26E) Compound EX-26D is treated with 50% TFA in dichloromethane for 1 hour. After removing the solvent and TFA, the residue is redissolved in THF/Methanol with one equivalent of triethylamine. To this 15 solution is added one equivalent phenylacetaldehyde and two equivalents sodium triacetoxyborohydride. After stirring for 12 hours, the reaction is quenched with addition of aqueous ammonium chloride. Standard aqueous work-up and silica gel column chromatography yields the desired product EX-26E. EX-26F) Compound EX-26E is treated with one equivalent PCI 5 in 20 toluene for an half hour. One equivalent of 4-aminomethylbenzamidine, which is protected with Cbz at the amidine, is then added into the reaction mixture followed with the addition of five equivalents pyridine. The mixture is allowed to be stirred for 12 hours. The reaction mixture is worked up by standard procedure and the product EX-26F is purified by silica gel column chromatography. 25 Compound 26 is prepared from EX-26F using the procedure for compound 23 in Example 23. Preparation of methylene analogs of pyridones of the present invention in which a methylene replaces the carbonyl group of the N- 1 acetamide side chain can be accomplished by using the essential features of the general procedure in 173 WO 00/69826 PCT/US00/08220 Scheme 3. Example 27, a specific example of an ethyleneamine of the present invention, can be synthesized as shown specifically in Scheme 6. 174 WO 00/69826 PCT/US00/08220 Scheme 6: Preparation of Ethylene Pyridone Analogs
(CH
3 0
)
2
CHN(
C
H
3
)
2 R2 2 2-Cyanoacetamide I R 2 NC H HBr/AcOH O Reflux, 12 hrs 2 1. DPPA/TEA/Dioxane 2 N 2. t-BuOH, reflux Boc-H N HH 1. NaH HOOC H 2. BrCH 2
-CO
2
CH
3
SF
R 2 1. TFA 2. B-CHO 3. NaBH(OAc) 3 N C 2
CH
3 R. Boc-HN N ICH O B-A NI
CO
2
CH
3 N R 2 H DIBAL O B-A N CHO NNo H
H
2 N NH NaBH(OAc) 3 - NH -Cbz B-A 1. HCI, Dioxane -"N N 2.H 2 , Pd/C, HCI NH H H NH 0 ' 3 HCI
-
NH
2 175 WO 00/69826 PCT/US00/08220 Example 27
I
Ph , N N 'N H NH 3 HCI H NH NH EX-27A) To a ether solution of pyridinylacetate ester with the B-A group added, diisobutylaluminum hydride (5 eq.) is added at -78 oC. After 30 minutes 5 stirring, methanol is added to quench the reaction. The resulting mixture is poured into a saturated aqueous solution of Rochelle salt. The layers are separated, and the aqueous layer is extracted with ethyl ether. The combined extract is dried over MgSO 4 , and the solvent is evaporated to dryness. The remaining residue is subjected to a silica gel column chromatography to yield the pure product aldehyde 10 (EX-27A). EX-27B) Compound EX-27A is mixed with one equivalent of Cbz protected 4-amidinobenzylamine and two equivalents sodium triacetoxyborohydride in THF. The reaction mixture is worked up according to the standard procedure. The product EX-27B is purified by silica gel column 15 chromatography. Compound EX-27B is first treated with 4N HCI in dioxane for 4 hours. After removing the dioxane, the residue is re-dissolved in methanol in the presence of 5 equivalents of HC1 and 5% equivalent of 10 % Pd /C. The mixture is stirred under an atmosphere of hydrogen (ambient pressure) for five hours. After 20 filtration and removing the solvent, the compound is obtained as the pure product. 25 176 WO 00/69826 PCT/US00/08220 Another subclass of pyridone analogs have the general structure as shown in Figure 3. Substituents are defined as disclosed herein. Z can be heteroatoms such as S, O, N, and others. The synthesis of this subclass of pyridone analogs is exemplified as in the synthesis of Example 28 as summarized in Scheme 7. 5 0 R1 Xo Zo BNN N O H H 0 Figure 3 10 177 WO 00/69826 PCT/US00/08220 Scheme 7. Preparation of Zo-Q Analogs of Pyridones CI f-Ph cNaCO Na 2
NO
2 NO 2 ON PhZ°H
H
2 SO4 02N 2 N H _r N 0N 5 : HPh-fO
NH
2 1. NaH ZPh NH 2 2. BrCH 2
-CO
2
CH
3 ZfPh
H
2 , Pd/C
H
2 N C02CH3H 3 0 2 NN 0 1. B-A=O Z 0 Ph O 2. NaBH(OAc) 3 B-A N N CO 2
CH
3 ZPh H h H ~LiO ZP 0 0I B-A N CO 2 H
H
2 N / \NH O -NH -Cbz EDC/HOBt/DIEA ZO Ph B-A N N CONH NH O H 0 NH -Cbz FPh
-
z P
H
2 , Pd/C, HCI B-A N N CONH NH H N 2 HCI 0 kNH 2 178 WO 00/69826 PCT/US00/08220 Example 28 Ph, I SPh PhN N 0 O N H
NH
2 2 HCI NH 2H01 NH EX-28A) Commercially available compound 2-amino-3-nitro-6 5 chloropyridine is reacted with one equivalent of phenylthiol in the presence of sodium carbonate in DMF at 80 oC. After the completion of the reaction, the reaction mixture is mixed with water. Filtration yields the crude product EX-28A that can be purified by recrystallization in methanol. EX-28B) Compound EX-28A is dissolved in 12N HLSO4. and the 10 solution is treated with aqueous solution of NaNO, (3 eq.) firstly at 0 'C, then at 100 oC. Dilution with water precipitates the product. Filtration and washing with water and ether yields the crude product EX-23B that can be further purified by recrystallization in ethanol. EX-28C) Compound EX-28B is mixed with one equivalent sodium 15 hydride in DMF and one equivalent methyl bromoacetate subsequently. After stirring at ambient temperature for 12 hours, the reaction is worked up by standard procedure. The product EX-28C is purified by silica gel column chromatography. EX-28D) Compound EX-28C is dissolved in methanol in the presence 20 of 5% equivalent of 10% Pd IC. The mixture is stirred under an atmosphere of hydrogen (ambient pressure) for an half hour. After filtration and removing the solvent, Compound EX-28D is obtained as the pure product. Example compound 28 can be prepared from EX-28D in a similar fashion as described in the preparation of compounds EX-23E, EX-23F, EX 25 23G and 23. Formula (I) compounds of this invention possessing hydroxyl, thiol, and amine functional groups can be converted to a wide variety derivatives. Alternatively, derivatized Formula (I) compounds can be obtained by first derivatizing one or more intermediates in the processes of preparation before 179 WO 00/69826 PCT/US00/08220 further transforming the derivatized intermediate to comounds of Formula (I). A hydroxyl group in the form of an alcohol or phenol can be readily converted to esters of carboxylic, sulfonic, carbamic, phosphonic, and phosphoric acids. Acylation to form a carboxylic acid ester is readily effected using a suitable 5 acylating reagent such as an aliphatic acid anhydride or acid chloride. The corresponding aryl and heteroaryl acid anhydrides and acid chlorides can also be used. Such reactions are generally carried out using an amine catalyst such as pyridine in an inert solvent. Similarly, carbamic acid esters (urethanes) can be obtained by reacting a hydroxyl group with isocyanates and carbamoyl chlorides. 10 Sulfonate, phosphonate, and phosphate esters can be prepared using the corresponding acid chloride and similar reagents. Compounds of Formula (I) that have at least one thiol group present can be converted to the corresponding thioesters derivatives analogous to those of alcohols and phenols using the same reagents and comparable reaction conditions. Compounds of Formula (I) that have 15 at least one primary or secondary amine group present can be converted to the corresponding amide derivatives. Amides of carboxylic acids can be prepared using the appropriate acid chloride or anhydrides with reaction conditions analogous to those used with alcohols and phenols. Ureas of the corresponding primary or secondary amine can be prepared using isocyanates directly and 20 carbamoyl chlorides in the presence of an acid scavenger such as triethylamine or pyridine. Sulfonamides can be prepared from the corresponding sulfonyl chloride in the presence of aqueous sodium hydroxide or a tertiary amine. Suitable procedures and methods for preparing these derivatives can be found in House's Modern Synthetic Reactions, W. A. Benjamin, Inc., Shriner, Fuson, and Curtin in 25 The Systematic Identification of Organic Compounds, 5th Edition, John Wiley & Sons, and Fieser and Fieser in Reagents for Organic Synthesis, Volume 1, John Wiley & Sons. Reagents of a wide variety that can be used to derivatize hydroxyl, thiol, and amines of compounds of Formula (I) are available from commercial sources or the references cited above, which are incorporated herein by reference. 30 Formula (I) compounds of this invention possessing hydroxyl, thiol, and amine functional groups can be alkylated to a wide variety of derivatives. Alternatively, alkylated Formula (I) compounds can be obtained by first alkylating one or more intermediates in the processes of preparation before further transforming the alkylated intermediate to comounds of Formula (I). A hydroxyl 35 group of compounds of Formula (I) can be readily converted to ethers. Alkylation 180 WO 00/69826 PCT/US00/08220 to form an ether is readily effected using a suitable alkylating reagent such as an alkyl bromide, alkyl iodide or alkyl sulfonate. The corresponding aralkyl, heteroaralkyl, alkoxyalkyl, aralkyloxyalkyl, and heteroaralkyloxyalkyl bromides, iodides, and sulfonates can also be used. Such reactions are generally carried out 5 using an alkoxide forming reagent such as sodium hydride, potassium t-butoxide, sodium amide, lithium amide, and n-butyl lithium using an inert polar solvent such as DMF, DMSO, THF, and similar, comparable solvents, amine catalyst such as pyridine in an inert solvent. Compounds of Formula (I) that have at least one thiol group present can be converted to the corresponding thioether derivatives 10 analogous to those of alcohols and phenols using the same reagents and comparable reaction conditions. Compounds of Formula (I) that have at least one primary, secondary or tertiary amine group present can be converted to the corresponding secondary, tertiary or quaternary ammonium derivative. Quaternary ammonium derivatives can be prepared using the appropriate bromides, iodides, 15 and sulfonates analogous to those used with alcohols and phenols. Conditions involve reaction of the amine by warming it with the alkylating reagent with a stoichiometric amount of the amine (i.e., one equivalent with a tertiary amine, two with a secondary, and three with a primary). With primary and secondary amines, two and one equivalents, respectively, of an acid scavenger are used concurrently. 20 Secondary or tertiary amines can be prepared from the corresponding primary or secondary amine. A primary amine can be dialkylated by reductive amination using an aldehyde, such as formaldehyde, and sodium cyanoborohydride in the presence of glacial acetic acid. A primary amine can be monoalkylated by first mono protecting the amine with a ready cleaved protecting group, such as trifluoroacetyl. 25 An alkylating agent, such as dimethylsulfate, in the presence of a non-nucleophilic base, such as Barton's base ( 2 -tert-butyl-1,1,3,3-tetramethylguanidine), gives the monomethylated protected amine. Removal of the protecting group using aqueous potassium hydroxide gives the desired monoalkylated amine. Additional suitable procedures and methods for preparing these derivatives can be found in House's 30 Modern Synthetic Reactions, W. A. Benjamin, Inc., Shriner, Fuson, and Curtin in The Systematic Identification of Organic Compounds, 5th Edition, John Wiley & Sons, and Fieser and Fieser in Reagents for Organic Synthesis published by John Wiley & Sons. Perfluoroalkyl derivatives can be prepared as described by DesMarteau in J. Chem. Soc. Chem. Commun. 2241 (1998). Reagents of a wide 35 variety that can be used to derivatize hydroxyl, thiol, and amines of compounds of 181 WO 00/69826 PCT/US00/08220 Formula (I) are available from commercial sources or the references cited above, which are incorporated herein by reference. Assays for Biological Activity 5 TF-VIIa Assay In this assay 100 nM recombinant soluble tissue factor and 2nM recombinant human factor VIIa are added to a 96-well assay plate containing 0.4 mM of the substrate, N-Methylsulfonyl-D-phe-gly-arg-p-nitroaniline and either inhibitor or buffer (5 mM CaCl 2 ,50 mM Tris-HCl, pH 8.0, 100 mM NaCl, 0.1% 10 BSA). The reaction, in a final volume of 100 ul is measured immediately at 405 rnm to determine background absorbance. The plate is incubated at room temperature for 60 min, at which time the rate of hydrolysis of the substrate is measured by monitoring the reaction at 405 nm for the release of p-nitroaniline. Percent inhibition of TF-VIIa activity is calculated from OD405,m value from the 15 experimental and control sample. Xa Assay 0.3 nM human factor Xa and 0.15 mM N-a-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-HCI, pH 8.0, 100 20 mM NaC1, 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 OD4s 5 m value from 25 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 NaCI, 30 0.1% BSA). The reaction, in a final volume of 100 ul is measured immediately at 405 rnm 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 OD4snm value from the 35 experimental and control sample. 182 WO 00/69826 PCT/US00/08220 Trypsin Assay 5 ug/ml trypsin, type IX from porcine pancreas and 0.375 mM N-a Benzoyl-L-arginine-p-nitroanilide (L-BAPNA) are added to a 96-well assay plate containing either inhibitor or buffer (50 mM Tris-HC1, pH 8.0, 100 mM NaC1, 5 0.1% BSA). The reactions, in a final volume of 100 ul are measured immediately at 405 nm to determine background absorbance. The plate is incubated at room temperature for 60 min, at which time the rate of hydrolysis of the substrate is measured by monitoring the reaction at 405 rn for the release of p-nitroaniline. Percent inhibition of trypsin activity is calculated from ODo 5 nm value from the 10 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 VIIa was purchased from American Diagnostica, Greenwich CT and chromogenic substrate N-Methylsulfonyl-D 15 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. 20 The biological activity of the compounds of Examples 1 through 22 as determined by the bioassay procedures is summarized in the Table 1. 183 WO 00/69826 PCT/US00/08220 Table 1. Inhibitory Activity of Pyridones toward Factor Xa, TF-VIIA, Thrombin II, and Trypsin II. Example TF-VIIA Thrombin Factor Trpysin Number IC50 II Xa II (uM) ICSO IC50 ICSO (uM) (uM) (uM) 1 4.6 0.7 0.07 0.21 2 46 5.5 7.7 0.5 3 26.1 11,0 >30 0.86 4 >30 22.7 23.1 0.48 5 40% 40% 27% - 6 >30 >30 >30 >30 7 >30 >30 >30 >30 8 >30 >30 >30 >30 9 >30 >30 >30 >30 10 >30 >30 >30 >30 11 >30 >30 >30 >30 12 >30 >30 >30 >30 13 >30 >30 >30 >30 14 >30 >30 >30 >30 15 >30 >30 >30 >30 16 >30 >30 >30 >30 17 1.1 0.2 0.1 0.3 18 0.8 <0.04 <4.0 0.2 19 18.0 0.4 4.1 <0.1 20 23.0 0.3 5.7 0.5 21 >30 0.5 17 0.6 22 >30 <0.04 >0 11.1 184

Claims (45)

1. A compound having the Formula: R X0 R 2 B/A N[ K E .yO 0 or a pharmaceutically acceptable salt thereof, wherein; 5 B is the Formula: R 3 4 R 3 3 R 3 5 R 3 2 R 3 6 I 9 10 11 12 13 32 33 34 35 36 R,R 0 Rl R12 R3 R32 R33 R34 R35, andR 36 are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkylenedioxy, haloalkylthio, 10 alkanoyloxy, alkoxy, alkoxyalkyl, haloalkoxylalkyl, hydroxy, amino, alkoxyamino, nitro, lower alkylamino, alkylthio, alkylthioalkyl, alkylsulfinyl, alkylsulfonyl, alkylsulfonylalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, alkanoyl, haloalkanoyl, alkyl, alkenyl, 15 halo, haloalkyl, haloalkenyl, haloalkoxy, hydroxyhaloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxyalkyl, carboxyalkyl, carboalkoxy, carboxy, carboxamido, carboxamidoalkyl, and cyano; 185 WO 00/69826 PCT/US00/08220 9 10 11 12 13 R 9 , R , R , R 2, and R 13 are optionally selected from the group consisting of heteroaryl and heterocyclyl with the proviso that R , R 10, R ll 12 13 R 12 , and R 3 are substitutents for other than B; 16 19 32 33 34 35 36 R 6 , R 19 , R 3 2 , R 3 3 , R 3 4 , R 3 5 , and R 3 6 are independently optionally 5 Qb with the proviso that no more than one of R 16 and R19 is Qb at the same time and that Qb is Qbe B is optionally, with the proviso that RI and R 2 are selected from the group consisting of a spacer pair and -W=X-Y=Z-, Formula (V): R 3 4 33 1 5 R K 21R 1 2 R32/D D2 R 3 6 (V) 1 2 12 1 10 wherein D, D 2 , J, j 2 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 12 1 than one is a covalent bond, no more than one of D , D 2 , J1 2 and K is O, 1 2 12 1 1 21 2 no more than one of D, D 2 , 1, J2 and K is S, one of D D , 1, J2 and 1 1 2 12 1 K must be a covalent bond when two of D , D 2 , J1, J2 and K are O and S, 1 2 12 1 15 and no more than four of D D, J , J2 and K are N; 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 may be optionally substituted at any carbon up to and including 6 atoms from the point of 186 WO 00/69826 PCT/US00/08220 attachment of B to A with one or more of the group consisting of R32 , R33 34 35 36 R 34 , R 3 5 , and R36; B is selected from the group consisting of C3-C12 cycloalkyl and C4 heterocyclyl, wherein each ring carbon may be optionally substituted with R 3 3 5 a ring carbon other than the ring carbon at the point of attachment of B to A may be optionally substituted with oxo provided that no more than one ring carbon is substituted by oxo at the same time, ring carbons and nitrogens adjacent to the carbon at the point of attachment may be optionally substituted wtR9 oR13 9 with R or R 13, a ring carbon or nitrogen adjacent to the R position and two 10 10 atoms from the point of attachment may be substituted with R 10 , a ring carbon or nitrogen adjacent to the R 13 position and two atoms from the point of 12 attachment may be substituted with R 2 , a ring carbon three atoms from the point of attachment and adjacent to the RI 0 position may be substituted with 11 R 11, a ring carbon three atoms from the point of attachment and adjacent to 12 33 15 the R 12 position may be substituted with R 3 3 , and a ring carbon four atoms from the point of attachment and adjacent to the R 1 1 and R 3 3 positions may be 34 substituted with R34; B is optionally, with the proviso that RI and R 2 are selected from the group consisting of a spacer pair and -W=X-Y=Z-, a C5-C9 saturated 33 20 heterocyclyl, wherein each ring carbon is optionally substituted with R 3 3 , 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 nitrogen adjacent to the carbon atom at the point of attachment are optionally substituted with R or 13 9 25 R , a ring carbon or nitrogen adjacent to the R position and two atoms from 187 WO 00/69826 PCT/US00/08220 the point of attachment is optionally substituted with R , a ring carbon or 13 nitrogen adjacent to the R 13 position and two atoms from the point of 12, e he attachment is optionally substituted with R 12 , a ring carbon or nitrogen three atoms from the point of attachment and adjacent to the R 10 position is 11 5 optionally substituted with R 1 1 , a ring carbon or nitrogen three atoms from the point of attachment and adjacent to the R 12 position is optionally substituted with R 3 3 , and a ring carbon or nitrogen four atoms from the point of attachment and adjacent to the R 1 1 and R 3 3 positions is optionally 34 substituted with R34; 10 A is selected from the group consisting of single covalent bond, (W 7)rr-(CH(R 15))pa and (CH(R15 ))pa-(W7)r r wherein rr is an integer selected from 0 through 1, pa is an integer selected from 0 through 6, and W 7 is selected from the group consisting of O, S, C(0), (R 7 )NC(0), (R7)NC(S), and N(R 7 ) with the proviso that no more than one of the group consisting of rr 15 and pa is 0 at the same time; R 7 is selected from the group consisting of hydrido, hydroxy, and alkyl; R 15 is selected from the group consisting of hydrido, hydroxy, halo, alkyl, and haloalkyl; 20 W is selected from the group consisting of NH and NOH; R 1 and Xo are independently 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; 188 WO 00/69826 PCT/US00/08220 X and R 1 and R 1 and R 2 , with the proviso that no more than one of the group consisting of spacer pair Xo and R 1 and spacer pair RI and R 2 is be used at the same time, are optionally selected to be -W=X-Y=Z- wherein W=X-Y=Z- forms a ring selected from the group consisting of a heteroaryl 5 ring having from 5 through 6 contiguous members and an aryl; W, X, Y, and Z are independently selected from the group consisting of C(R ), C(R 10), C(R l), C(R12), N, N(R10), O, S and a covalent bond with the provisos that one of W, X, Y, and Z is independently selected to be a covalent bond when one of W, X, Y, and Z is selected from the group 10 consisting of N, N(R 10), O, and S, no more than one of W, X, Y, and Z is optionally selected from the group consisting of O and S, and no more than three of W, X, Y, and Z are optionally selected from the group consisting of N and N(R 10); Xo and R 1 and RI and R 2 spacer pairs are independently optionally 15 selected to be taken together to form a spacer pair wherein the spacer pair forms a linear moiety having from 3 through 6 contiguous atoms connecting the points of bonding of said spacer pair members to form a ring selected from the group consisting of a cycloalkenyl ring having from 5 through 8 contiguous members and a partially saturated heterocyclyl ring having from 5 through 8 20 contiguous members, wherein said spacer pair is optionally substituted with one or more of the group consisting of R 9 , R10 , R11 , R12, and R13 and with the proviso that no more than one of the group consisting of spacer pair Xo and R 1 and spacer pair RI and R 2 is present at the same time; R 2 is Zo-Q; 25 Z is selected from the group consisting of covalent single bond, 41 42 41 (CR R )q wherein q is an integer selected from 1 through 3, (CH(R )) Wo-(CH(R42)) wherein g and p are integers independently selected from 0 through 3 and Wo is selected from the group consisting of 0, S, C(0), S(0), 189 WO 00/69826 PCT/US00/08220 41 41 41 22 42 N(R 41), and ON(R 41 ), and (CH(R 41 ))e-W 22 -(CH(R 4 2 ))h wherein e and h are integers independently selected from 0 through 1 and W 22 is selected from the group consisting of CR41=CR42, 1,2-cyclopropyl, 1,2-cyclobutyl, 1,2 cyclohexyl, 1,3-cyclohexyl, 1,2-cyclopentyl, 1,3-cyclopentyl, 2,3 5 morpholinyl, 2,4-morpholinyl, 2,6-morpholinyl, 3,4-morpholinyl, 3,5 morpholinyl, 1,2-piperazinyl, 1,3-piperazinyl, 2,3-piperazinyl, 2,6 piperazinyl, 1,2-piperidinyl, 1,3-piperidinyl, 2,3-piperidinyl, 2,4-piperidinyl, 2,6-piperidinyl, 3,4-piperidinyl, 1,2-pyrrolidinyl, 1,3-pyrrolidinyl, 2,3 pyrrolidinyl, 2,4-pyrrolidinyl, 2,5-pyrrolidinyl, 3,4-pyrrolidinyl, 2,3 10 tetrahydrofuranyl, 2,4-tetrahydrofuranyl, 2,5-tetrahydrofuranyl, and 3,4 tetrahydrofuranyl, with the proviso that Z is directly bonded to the pyrazinone ring; R 41 and R 42 are independently selected from the group consisting of amidino, hydroxyamino, hydrido, hydroxy, amino, and alkyl; 15 Q is selected from the group consisting of hydrido, with the proviso that Z is other than a covalent single bond, and the formula (II): 11 R10 K1 R R9 D1 D2 R 1 3 (II) 1 2 1 2 1 wherein D , D , , J and K are independently selected from the group consisting of C, N, 0, S and a covalent bond with the provisos that no more 1 2 12 1 20 than one is a covalent bond, no more than one of D , D2, J1, J2 and K is O, 1 2 12 1 1 2 12 no more than one of D, D 2 , 1, J2 and K is S, one of D D , 1, J2 and 1 1 2 12 1 K must be a covalent bond when two of D , D 2 , J , J2 and K are O and S, 190 WO 00/69826 PCT/US00/08220 1 2 12 1 and no more than four of D , D 2 , J1, J2 and K are N, with the proviso that 9 10 11 12 13 R9, R10, R 1 1 , R12, and R 13 are each independently selected to maintain the tetravalent nature of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen; 5 K is (CR4a R4b)n wherein n is an integer selected from 1 through 2; 4a4b R and R 4 b are independently selected from the group consisting of halo, hydrido, hydroxyalkyl, alkyl, alkoxyalkyl, alkylthioalkyl, and haloalkyl; E is E, when K is (CR4aR4b)n, wherein E is selected from the group consisting of a covalent single bond, C(O), C(S), C(O)N(R7), 10 (R7)NC(O), S(0)2, (R 7)NS(0) 2 , and S(0) 2 N(R7); Yo is formula (IV): S R17 R18 R16 D A K2,D R19 lb Q (IV) 5 65 6 wherein D , D 6 , J5, and J6 are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more 2 5 65 6 15 than one is a covalent bond, K is C, no more than one of D 5 , D 6 , J5, and J6 5 6 5 6 5 6 5 6 is O, no more than one of D , D , J , and J is S, one of D , D , J , and J 5 65 6 must be a covalent bond when two of D , D 6 , and J6 are O and S, and no 5 65 6 more than four of D , D 6 , and J are N; 191 WO 00/69826 PCT/US00/08220 16 17 18 19 R 16 , R 17 , R 18 , and R 19 are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, haloalkylthio, alkoxy, hydroxy, amino, nitro, alkoxyamino, lower alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, alkenyl, halo, 5 haloalkyl, haloalkoxy, hydroxyalkyl, alkylamino, haloalkoxyalkyl, carboalkoxy, and cyano; Qb is selected from the group consisting of NR20 R 21, aminoalkylenyl, be be .26 25 23 24 Q wherein Qbe is hydrido, N(R 26)C(NR 25)N(R 23)(R ), and 25 23 24 20 21 C(NR )NR23R24, with the provisos that no more than one of R 2 0 and R 2 1 10 is hydroxy, amino, alkylamino, or dialkylamino at the same time and that no more than one of R 2 3 and R 2 4 is hydroxy, amino, alkylamino, or dialkylamino at the same time; 20 21 23 24 25 26 R 2 0 , R 2 1 , R , R 2 4 , R 25 , and R 26 are independently selected from the group consisting of hydrido, alkyl, hydroxy, aminoalkylenyl, amino, 15 dialkylamino, alkylamino, and hydroxyalkyl; QS is selected from the group consisting of a single covalent bond, (CR37R38)b wherein b is an integer selected from 1 through 4, and (CH(R 14))cWl-(CH(R15))d wherein c and d are integers independently selected from 1 through 3 and W I is selected from the group consisting of 20 C(O)N(R14), (R 14)NC(O), S(0), S(0)2, S(0) 2 N(R14), N(R14)S(0)2, and N(R14), with the provisos that R 14 is selected from other than halo when directly bonded to N and that (CR37 R 38)b , and (CH(R 14))c are bonded to Eo R 14 is selected from the group consisting of hydrido, halo, alkyl, and haloalkyl; 37 38 25 R 3 7 and R 3 8 are independently selected from the group consisting of hydrido, alkyl, and haloalkyl; 192 WO 00/69826 PCT/US00/08220 R 3 8 is optionally selected from the group consisting of aroyl and heteroaroyl; YO is optionally QbQss wherein Qss is (CH(R14))e-W2-(CH(R15))h, wherein e and h are integers independently selected from 1 through 2 and W 2 4a 4b 140 5 is CR4a =CR with the proviso that (CH(R 4))e is bonded to Eo; Y is optionally selected from the group consisting of Qb -Qssss and Qb_ Qssssr wherein Qssss is (CH(R38 ))r-W5 and Qssssr is (CH(R38 ))r-W 6, r is an integer selected from 1 through 2, and W 5 and W 6 are independently selected from the group consisting of 1,4-indenyl, 1,5-indenyl, 1,6-indenyl, 1,7 10 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 15 benzothiophenyl, 3,6-benzothiophenyl, 3,7-benzothiophenyl, 2,7 imidazo( 1,2-a)pyridinyl, 3,4-imidazo(1,2-a)pyridinyl, 3,5-imidazo(1,2 a)pyridinyl, 3,6-imidazo(1,2-a)pyridinyl, 3,7-imidazo(1,2-a)pyridinyl, 2,4 indolyl, 2,5-indolyl, 2,6-indolyl, 2,7-indolyl, 3,4-indolyl, 3,5-indolyl, 3,6 indolyl, 3,7-indolyl, 1,4-isoindolyl, 1,5-isoindolyl, 1,6-isoindolyl, 2,4 20 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 25 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 30 isoquinolinyl, 3,5-isoquinolinyl, 3,6-isoquinolinyl, 3,7-isoquinolinyl, 3,8 isoquinolinyl, 4 ,5-isoquinolinyl, 4,6-isoquinolinyl, 4 , 7 -isoquinolinyl, 4,8 193 WO 00/69826 PCT/US00/08220 isoquinolinyl, 3,4-cinnolinyl, 3,5-cinnolinyl, 3,6-cinnolinyl, 3.7-cinnolinyl, 3,8-cinnolinyl, 4,5-cinnolinyl, 4,6-cinnolinyl, 4,7-cinnolinyl, and 4,8 cinnolinyl, and each carbon and hyrido containing nitrogen member of the ring of the W 5 and of the ring of the W 6, other than the points of attachment of W 5 5 and W 6, is optionally substituted with one or more of the group consisting of R , R 0 , R 11 , and R 12, with the provisos that Qb is bonded to lowest number substituent position of each W 5 , Qb is bonded to highest number substituent position of each W 6 .and (CH(R 3))r is bonded to E 0 10 2. The compound as recited in Claim 1 having the Formula: R Xo R B A NCI EZ.Y or a pharmaceutically acceptable salt thereof, wherein; B is the Formula: 34 P 3 3 R 3 5 32 36 32 33 34 35 36 15 R32, R 33 R ,R ,35 and R 36 are independently selected from the group consisting of hydrido, acetamido, haloacetamnido. amidino, guanidino, alkylenedioxy, haloalkylthio, alkanoyloxy, alkoxy, hydroxy, amino, 194 WO 00/69826 PCT/US00/08220 alkoxyamino, haloalkanoyl, nitro, lower alkylamino, alkylthio, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, alkylsulfonamido, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, alkyl, alkenyl, halo, haloalkyl, haloalkenyl, haloalkoxy, hydroxyalkyl, alkylamino, 5 carboalkoxy, carboxy, carboxamido, cyano, and Qb B is optionally, with the proviso that RI and R 2 are selected from the group consisting of a spacer pair and -W=X-Y=Z-, Formula (V): 34 3 3 1 3 5 R K1 2 R 1J R32 D DN R 3 6 (V) wherein D 1 , D 2 J , J and K are independently selected from the group 10 consisting of C, N, O, S and a covalent bond with the provisos that no more 1 2 12 1 than one is a covalent bond, no more than one of D , D 2 , J1, J2 and K is O, 1 2 12 1 1 2 12 no more than one of D, D 2 , 1, J2 and K is S, one of D, D 2 , 1, J2 and 1 1 2 12 1 K must be a covalent bond when two of D , D 2 , j , J2 and K are 0 and S, 1 21 2 1 and no more than four of D , D 2 , J2 and K are N; 15 B is optionally selected from the group consisting of hydrido, trialkylsilyl, C2-C8 alkyl, C3-C8 alkylenyl, C3-C8 alkenyl, C3-C8 alkynyl, and C2-C8 haloalkyl, wherein each member of group B is optionally substituted at any carbon up to and including 6 atoms from the point of attachment of B to A with one or more of the group consisting of R 3 2 , R 3 3 20 R 3 4 , R35, and R36 B is selected from the group consisting of C3-C12 cycloalkyl and C4 heterocyclyl, wherein each ring carbon may be optionally substituted with R 3 3 195 WO 00/69826 PCT/US00/08220 a ring carbon other than the ring carbon at the point of attachment of B to A may be optionally substituted with oxo provided that no more than one ring carbon is substituted by oxo at the same time, ring carbons and nitrogens adjacent to the carbon at the point of attachment may be optionally substituted 9 13 9 R 13 5 with R or R , a ring carbon or nitrogen adjacent to the R position and two 10 atoms from the point of attachment may be substituted with R , a ring carbon or nitrogen adjacent to the R 13 position and two atoms from the point of 12 attachment may be substituted with R 12 , a ring carbon three atoms from the 10 point of attachment and adjacent to the R10 position may be substituted with 11 10 R , a ring carbon three atoms from the point of attachment and adjacent to 12 33 the R 12 position may be substituted with R 3 3 , and a ring carbon four atoms from the point of attachment and adjacent to the R 1 1 and R 3 3 positions may be substituted with R34 B is optionally, with the proviso that R 1 and R 2 are selected from the 15 group consisting of a spacer pair and -W=X-Y=Z-, a C5-C9 saturated 33 heterocyclyl, wherein each ring carbon is optionally substituted with R 3 3 , 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 nitrogen adjacent to the 09 20 carbon atom at the point of attachment are optionally substituted with R 9 or 13 9 . R 13 , a ring carbon or nitrogen adjacent to the R position and two atoms from 10 the point of attachment is optionally substituted with R , a ring carbon or nitrogen adjacent to the R 13 position and two atoms from the point of 12 attachment is optionally substituted with R 12 , a ring carbon or nitrogen three 196 WO 00/69826 PCT/US00/08220 atoms from the point of attachment and adjacent to the R 10 position is optionally substituted with R 11, a ring carbon or nitrogen three atoms from the point of attachment and adjacent to the R 12 position is optionally 33 substituted with R 33 , and a ring carbon or nitrogen four atoms from the point 5 of attachment and adjacent to the R 1 1 and R 3 3 positions is optionally substituted with R34 9 10 11 12 13 R , R , R , R , and R are independently selected from the group consisting of hydrido, acetamido, haloacetamido, alkoxyamino, alkanoyl, haloalkanoyl, amidino, guanidino, alkylenedioxy, haloalkylthio, 10 alkoxy, hydroxy, amino, lower alkylamino, alkylthio, alkylsulfinyl, alkylsulfamido, alkylsulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, carboalkoxy, carboxy, carboxyalkyl, carboxamido, and cyano; 9 10 11 12 13 R , R10, R 1 1, R12, and R 13 are optionally selected from the group 9 10 11 15 consisting of heteroaryl and heterocyclyl with the proviso that R , R 10, R11 12 13 R 12 , and R 13 are substitutents for other than B; A is selected from the group consisting of single covalent bond and 15 7 (CH(R ))pa-(W )rr wherein rr is an integer selected from 0 through 1, pa is an integer selected from 0 through 3, and W 7 is selected from the group 20 consisting of O, S, C(0), (R7)NC(0), (R7)NC(S), and N(R7); R 7 is selected from the group consisting of hydrido, hydroxy and alkyl; R 15 is selected from the group consisting of hydrido, hydroxy, halo, alkyl, and haloalkyl; R 1 and X are independently selected from the group consisting of 25 hydrido, alkyl, cyano, halo, haloalkyl, haloalkoxy, amino, aminoalkyl, 197 WO 00/69826 PCT/US00/08220 alkylamino, amidino, hydroxy, hydroxyamino, alkoxy, hydroxyalkyl, alkoxyamino, thiol, and alkylthio; RI and R 2 are optionally selected to be -W=X-Y=Z- wherein -W=X Y=Z- forms a ring selected from the group consisting of a heteroaryl ring 5 having from 5 through 6 contiguous members and an aryl; W, X, Y, and Z are independently selected from the group consisting of C(R9), C(R10), C(R 1 1 ), C(R12), N, N(R10), O, S and a covalent bond with the provisos that one of W, X, Y, and Z is independently selected to be a covalent bond when one of W, X, Y, and Z is selected from the group 10 consisting of N, N(R 10), O, and S, no more than one of W, X, Y, and Z is optionally selected from the group consisting of O and S, and no more than three of W, X, Y, and Z are optionally selected from the group consisting of N and N(R10); RI and R 2 spacer pairs are independently optionally selected to be 15 taken together to form a spacer pair wherein the spacer pair forms a linear moiety having from 3 through 6 contiguous atoms connecting the points of bonding of said spacer pair members to form a ring selected from the group consisting of a cycloalkenyl ring having from 5 through 8 contiguous members and a partially saturated heterocyclyl ring having from 5 through 8 contiguous 20 members, wherein said spacer pair is optionally substituted with one or more 9 10 11 12 13 of the group consisting of R 9 , R 10 , R 1 1 , R 12 , and R13 R 2 is ZoQ; Zo is selected from the group consisting of covalent single bond and (CR41R42)q wherein q is an integer selected from 1 through 2, (CH(R41)) a 25 W-(CH(R 42)) wherein g and p are integers independently selected from 0 through 3 and Wo is selected from the group consisting of O, S, and N(R41), and (CH(R41))e-W2-(CH(R42)) h wherein e and h are integers independently 198 WO 00/69826 PCT/US00/08220 selected from 0 through 1 and W 2 2 is selected from the group consisting of 41 42 CR 41=CR 42, 1, 2 -cyclopropyl, 1,2-cyclobutyl, 1,2-cyclohexyl, 1,3 cyclohexyl, 1,2-cyclopentyl, 1, 3 -cyclopentyl, 2,3-morpholinyl, 2,4 morpholinyl, 2,6-morpholinyl, 3,4-morpholinyl, 3,5-morpholinyl, 1,2 5 piperazinyl, 1, 3 -piperazinyl, 2 , 3 -piperazinyl, 2,6-piperazinyl, 1,2-piperidinyl, 1,3-piperidinyl, 2,3-piperidinyl, 2 ,4-piperidinyl, 2,6-piperidinyl, 3,4 piperidinyl, 1,2-pyrrolidinyl, 1,3-pyrrolidinyl, 2,3-pyrrolidinyl, 2,4 pyrrolidinyl, 2,5-pyrrolidinyl, 3,4-pyrrolidinyl, 2,3-tetrahydrofuranyl, 2,4 tetrahydrofuranyl, 2 , 5 -tetrahydrofuranyl, and 3,4-tetrahydrofuranyl, with the 10 proviso that Z is directly bonded to the pyrazinone ring; R 4 1 and R 4 2 are independently selected from the group consisting of hydrido, hydroxy, and amino; Q is selected from the group consisting of hydrido, with the proviso that Z is other than a covalent single bond, aryl, and heteroaryl, wherein a 15 carbon adjacent to the carbon at the point of attachment is optionally substituted 9 by R , the other carbon adjacent to the carbon at the point of attachment is 13 9 optionally substituted by R 13 , a carbon adjacent to R and two atoms from the 10 carbon at the point of attachment is optionally substituted by R 10, a carbon adjacent to R 13 and two atoms from the carbon at the point of attachment is 12 10 12. 20 optionally substituted by R 2 , and any carbon adjacent to both R 10 and R 12 is optionally substituted by R 1 1 K is CHR 4 a wherein R 4 a is selected from the group consisting of hydrido, hydroxyalkyl, alkyl, alkoxyalkyl, alkylthioalkyl, and haloalkyl; E is selected from the group consisting of a covalent single bond, 25 C(O)N(H), (H)NC(O), (R7)NS(O) 2 , and S(O) 2 N(R7); Y is formula (IV): 199 WO 00/69826 PCT/US00/08220 S 17D 5 D18 R16/ D K2:D R 1 9 lb Q (IV) wherein D 5 , D 6 , J 5, and J6 are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more 2 56 5 than one can be a covalent bond, K is C, no more than one of D , D 6 , J5 6 5 65 6 5 5 and J can be O, no more than one of D , D 6 , and J can be S, one of D D 6 , J5, and J6 must be a covalent bond when two of D 5 , D6 , J5, and J6 are 0 5 65 6 and S, and no more than four of D , D 6 , and J6 can be N, with the 16 17 18 19 provisos that R , R , R , and R are each independently selected to maintain the tetravalent nature of carbon, trivalent nature of nitrogen, the 10 divalent nature of sulfur, and the divalent nature of oxygen; 16 17 18 19 R 16 , R 17 , R 18 , and R 19 are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, haloalkylthio, alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, halo, haloalkyl, haloalkoxy, 15 hydroxyalkyl, aminoalkyl, and cyano; R 16 and R 19 are optionally Qb with the proviso that no more than one of R 16 and R 19 is Qb at the same time and that Qb is Qbe Qb is selected from the group consisting of NR20R 2 1, Qbe wherein Qbe is 26 25 23 24 25 23 24 hydrido, N(R26)C(NR25)N(R23)(R24), and C(NR25)NR R , with the 20 provisos that no more than one of R 2 0 and R 2 1 is hydroxy, amino, alkylamino, or 200 WO 00/69826 PCT/US00/08220 dialkylamino at the same time and that no more than one of R 2 3 and R 2 4 is hydroxy, amino, alkylamino, or dialkylamino at the same time; 20 21 23 24 25 26 R 2 0 , R 2 1, R , R 24 , R , and R 2 6 are independently selected from the group consisting of hydrido, alkyl, hydroxy, amino, alkylamino and dialkylamino; 5 QS is selected from the group consisting of a single covalent bond, (CR37 R 38)b wherein b is an integer selected from 1 through 4, and (CH(R14))c-W -(CH(R 15))d wherein c and d are integers independently selected from 1 through 3 and W 1 is selected from the group consisting of C(O)N(R14), (R 14)NC(O), S(O), S(O) 2 , S(O) 2 N(R 14), N(R 14)S(O) 2 , and 10 N(R14), with the provisos that R 14 is selected from other than halo when directly bonded to N and that (CR37 R 38)b , and (CH(R14))c are bonded to Eo R 14 is selected from the group consisting of hydrido, halo, alkyl, and haloalkyl; 37 38 R and R 3 8 are independently selected from the group consisting of 15 hydrido, alkyl, and haloalkyl; R 3 8 is optionally selected from the group consisting of aroyl and heteroaroyl; Yo is optionally QbQ ss wherein Qss is (CH(R 14 ))e-W2-(CH(R15))h wherein e and h are integers independently selected from 1 through 2 and W 2 20 is CR 4a=CH with the proviso that (CH(R14))e is bonded to Eo
3. The compound as recited in Claim 2 or a pharmaceutically acceptable salt thereof, wherein; B is selected from the group consisting of hydrido, trialkylsilyl, C2-C8 25 alkyl, C3-C8 alkylenyl, C3-C8 alkenyl, C3-C8 alkynyl, and C2-C8 haloalkyl, wherein each member of group B is optionally substituted at any carbon up to 201 WO 00/69826 PCT/US00/08220 and including 6 atoms from the point of attachment of B to A with one or more of the group consisting of R 32 , R 33, R34, R 35, and R36 32 33 34 35 36 R 32 , R 33, R 34 , R 35 , and R 36 are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, 5 alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, alkylthio, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboalkoxy, carboxy, carboxamido, cyano, and Qb A is (CH(R15))pa-W7 wherein pa is an integer selected from 1 through 77 10 3 and W is selected from the group consisting of O, S, and N(R 7 ) wherein R 7 is selected from the group consisting of hydrido and alkyl; R 15 is selected from the group consisting of hydrido, hydroxy, halo, alkyl, and haloalkyl with the proviso that R 15 is other than hydroxy and halo 15 7 when R 15 is on the carbon bonded directly to W; 15 R 1 and X are independently selected from the group consisting of hydrido, alkyl, cyano, halo, haloalkyl, haloalkoxy, amino, aminoalkyl, alkylamino, amidino, hydroxy, hydroxyamino, alkoxy, hydroxyalkyl, alkoxyamino, thiol, and alkylthio; RI and R 2 are optionally selected to be -W=X-Y=Z- wherein -W=X 20 Y=Z- forms a ring selected from the group consisting of a heteroaryl ring having from 5 through 6 contiguous members and an aryl; W, X, Y, and Z are independently selected from the group consisting of C(R ), C(R10), C(R 11 ), C(R12), N, N(R 10), O, S and a covalent bond with the provisos that one of W, X, Y, and Z is independently selected to be a 25 covalent bond when one of W, X, Y, and Z is selected from the group consisting of N, N(R10), O, and S, no more than one of W, X, Y, and Z is optionally selected from the group consisting of O and S, and no more than 202 WO 00/69826 PCT/US00/08220 three of W, X, Y, and Z are optionally selected from the group consisting of N and N(R 10); R and R 2 spacer pairs are independently optionally selected to be taken together to form a spacer pair wherein the spacer pair forms a linear 5 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 from 5 through 8 contiguous members and a partially saturated heterocyclyl ring having from 5 through 8 contiguous members, wherein said spacer pair is optionally substituted with one or more 9 10 11 12 13 10 of the group consisting of R 9 , R 10 , R 1 1 , R 2 , and R13 R 2 is Zo-Q; 0 is selected from the group consisting of covalent single bond and (CR41R42 )q wherein q is an integer selected from 1 through 2; 41 42 R and R 4 2 are independently selected from the group consisting of 15 hydrido, hydroxy, and amino; Q is selected from the group consisting of aryl and heteroaryl, wherein a carbon adjacent to the carbon at the point of attachment is optionally 9 substituted by R 9 , the other carbon adjacent to the carbon at the point of 13 9 attachment is optionally substituted by R 13 , a carbon adjacent to R and two 20 atoms from the carbon at the point of attachment is optionally substituted by 10 13 R 10 , a carbon adjacent to R 13 and two atoms from the carbon at the point of 12 attachment is optionally substituted by R 12 , and any carbon adjacent to both R 10 and R 12 is optionally substituted by R 1 1 9 10 11 12 13 R9, R10, R 1 1 , R12, and R 13 are independently selected from the 25 group consisting of hydrido, acetamido, haloacetamido, alkoxyamino, alkanoyl, haloalkanoyl, amidino, guanidino, alkylenedioxy, haloalkylthio, alkoxy, hydroxy, amino, lower alkylamino, alkylthio, alkylsulfinyl, 203 WO 00/69826 PCT/US00/08220 alkylsulfamido, alkylsulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, carboalkoxy, carboxy, carboxyalkyl, carboxamido, and cyano; . 4a 4a K is CHR 4 a wherein R 4 a is selected from the group consisting of 5 hydrido, hydroxyalkyl, alkyl, alkoxyalkyl, alkylthioalkyl, and haloalkyl; Eo is selected from the group consisting of a covalent single bond, C(O)N(H), (H)NC(0), (R 7)NS(0) 2 , and S(O) 2 N(R7); Y is formula (IV): S R17 R18 D 5 -D 6... R16 / D ,K2D R 1 9 b Q (IV) 10 wherein D 5 , D 6 , J 5, and J6 are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more 2 5 65 6 than one is a covalent bond, K is C, no more than one of DS, D 6 , J, and J6 5 65 6 5 65 6 is O, no more than one of DS, D , , and J is S, one of D D 5, and J 5 65 6 must be a covalent bond when two of D 5 , D , J, and J are O and S, and no 5 65 6 15 more than four of D 5 , D , , and J are N; 16 17 18 19 R 6 , R 17 , R 18 , and R 19 are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, haloalkylthio, alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, halo, haloalkyl, haloalkoxy, 20 hydroxyalkyl, alkylamino, and cyano; 204 WO 00/69826 PCT/US00/08220 R 16 and R 19 are optionally Qb with the proviso that no more than one of R 16 and R 19 is Qb at the same time and that Qb is Qbe Qb is selected from the group consisting of NR20R21, Qbe wherein Qbe is hydrido, N(R26)C(NR25)N(R 23)(R24), and C(NR25 )NR23 R 24, with the 5 provisos that no more than one of R 2 0 and R 2 1 is hydroxy, amino, alkylamino, or dialkylamino at the same time and that no more than one of R 23 and R 2 4 is hydroxy, amino, alkylamino, or dialkylamino at the same time; 20 21 23 24 25 26 R 20 , R 2 1 , R , R 24 , R 2 5 , and R 26 are independently selected from the group consisting of hydrido, alkyl, hydroxy, amino, alkylamino and dialkylamino; 10 Qs is selected from the group consisting of a single covalent bond, (CR37R38)b wherein b is an integer selected from 1 through 3, and (CH(R14))c-W -(CH(R15))d wherein c and d are integers independently selected from 1 through 2 and W 1 is selected from the group consisting of C(O)N(R14), (R14)NC(O), S(O), S(O) 2 , S(O) 2 N(R 14), N(RI4)S(0)2, and 15 N(R14), with the provisos that R 14 is selected from other than halo when directly bonded to N and that (CR37 R 38)b , and (CH(R 14))c are bonded to E; R 14 is selected from the group consisting of hydrido, halo, alkyl, and haloalkyl; R37 and R 3 8 are independently selected from the group consisting of 20 hydrido, alkyl, and haloalkyl; R 3 8 is optionally selected from the group consisting of aroyl and heteroaroyl; 205 WO 00/69826 PCT/US00/08220 Y is optionally QbQss wherein QSS is (CH(R14))e-W-(CH(R 1 5 ))h, wherein e and h are integers independently selected from 1 through 2 and W 2 is CR 4a=CH with the proviso that (CH(R 14))e is bonded to Eo 5 4. The compound as recited in Claim 3 having the Formula: R1 B N N N Y H H 0 or a pharmaceutically acceptable salt thereof, wherein; B is selected from the group consisting of hydrido, trialkylsilyl, C2-C4 alkyl, C3-CS alkylenyl, C3-C4 alkenyl, C3-C4 alkynyl, and C2-C4 haloalkyl, 10 wherein each member of group B is optionally substituted at any carbon up to and including 3 atoms from the point of attachment of B to A with one or more of the group consisting of R 3 2 , R 3 3 , and R34 32 33 34 R 3 2 , R 3 3 , and R 3 4 are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkoxy, 15 hydroxy, amino, alkoxyamino, lower alkylamino, alkylthio, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboalkoxy, carboxy, carboxamido, and cyano; A is (CH(R15 ))pa-N(R7) wherein pa is an integer selected from 1 through 2 and R 7 is selected from the group consisting of hydrido and alkyl; 20 R 15 is selected from the group consisting of hydrido, halo, alkyl, and haloalkyl; 206 WO 00/69826 PCT/US00/08220 R 1 and Xo are independently selected from the group consisting of hydrido, hydroxy, hydroxyamino, amidino, amino, cyano, hydroxyalkyl, alkoxy, alkyl, alkylamino, aminoalkyl, alkylthio, alkoxyamino, haloalkyl, haloalkoxy, and halo; 5 RI and R 2 are optionally selected to be -W=X-Y=Z- wherein -W=X Y=Z- forms a ring selected from the group consisting of a heteroaryl ring having from 5 through 6 contiguous members and an aryl; W, X, Y, and Z are independently selected from the group consisting of C(R ), C(R10), C(R 11), C(R12), N, N(R 10), O, S and a covalent bond 10 with the provisos that one of W, X, Y, and Z is independently selected to be a covalent bond when one of W, X, Y, and Z is selected from the group consisting of N, N(R10), 0, and S, no more than one of W, X, Y, and Z is optionally selected from the group consisting of O and S, and no more than three of W, X, Y, and Z are optionally selected from the group consisting of N 15 and N(R10); RI and R 2 spacer pairs are independently optionally selected to be taken together to form a spacer pair wherein the spacer pair forms a linear moiety having from 3 through 6 contiguous atoms connecting the points of bonding of said spacer pair members to form a ring selected from the group 20 consisting of a cycloalkenyl ring having from 5 through 8 contiguous members and a partially saturated heterocyclyl ring having from 5 through 8 contiguous members, wherein said spacer pair is optionally substituted with one or more 9 10 11 12 13 of the group consisting of R 9 , R 10 , R 1 1 , R 12 , and R3 R 2 is Zo-Q; 25 Z is selected from the group consisting of covalent single bond and CH 2 ; Qis selected from the group consisting of aryl and heteroaryl, wherein a carbon adjacent to the carbon at the point of attachment is optionally substituted by R 9 , the other carbon adjacent to the carbon at the point of 207 WO 00/69826 PCT/US00/08220 attachment is optionally substituted by R 13 , a carbon adjacent to R and two atoms from the carbon at the point of attachment is optionally substituted by 10 13 R , a carbon adjacent to R and two atoms from the carbon at the point of 12 attachment is optionally substituted by R 12 , and any carbon adjacent to both 5 R1 0 and R 12 is optionally substituted by R 1 1 9 11 13 R , R , and R are independently selected from the group consisting of hydrido, hydroxy, amino, amidino, guanidino, lower alkylamino, alkylthio, alkylsulfonamido, alkylsulfinyl, alkylsulfonyl, amrnidosulfonyl, monoalkyl amidosulfonyl, alkyl, alkoxy, halo, haloalkyl, 10 haloalkoxy, hydroxyalkyl, carboxy, carboxamido, and cyano; R10 and R 12 are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkyl, alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, alkylsulfonamido, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, 15 hydroxyalkyl, aminoalkyl, carboalkoxy, carboxy, carboxyalkyl, amidocarbonyl, halo, haloalkyl, and cyano; Y is formula (IV): s R 1 7 1 R 1 8 m 5 R16/D K2D R19 lb Q (IV) 5 65 6 wherein D , D , J and J6 are independently selected from the group 20 consisting of C, N, O, S and a covalent bond with the provisos that no more 2 5 65 6 than one is a covalent bond, K is C, no more than one of D 5 , D 6 , J, and J6 5 65 6 5 65 6 is O, no more than one of D 5 , D , J, and J is S, one of D, D 6 J and J6 208 WO 00/69826 PCT/US00/08220 5 65 6 must be a covalent bond when two of D , D , J, and J are O and S, and no 5 65 6 more than four of D 5 , D , , and J6 are N; 16 17 18 19 R 6, R 17, R 18, and R 19 are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, haloalkylthio, alkoxy, 5 hydroxy, amino, lower alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkcyl, and cyano; R 16 and R 19 are optionally Qb with the proviso that no more than one of R 16 and R 19 is Qb at the same time and that Qb is Qbe b 20 21 be 10 Q is selected from the group consisting of NR20R21, be wherein be .25 23 24 26 25 23 24 Q is hydrido, C(NR 25)NR 23R 24, and N(R 26)C(NR )N(R 23)(R 24), with the provisos that no more than one of R20 and R21 is hydroxy at the same time and that no more than one of R 23 and R 2 4 is hydroxy at the same time; 20 21 23 24 25 26 R 2 0 , R 2 1 , R , R 2 4 , R , and R 26 are independently selected from the 15 group consisting of hydrido, alkyl, and hydroxy; Qs is selected from the group consisting of a single covalent bond, CH 2 , and CH 2 CH 2 .
5. The compound as recited in Claim 4 having the Formula or a 20 pharmaceutically acceptable salt thereof, wherein; B is selected from the group consisting of ethyl, 2-propenyl, 2 propynyl, propyl, isopropyl, trimethylene, tetramethylene, butyl, 2-butenyl, 3 butenyl, 2-butynyl, sec-butyl, tert-butyl, isobutyl, 2-methylpropenyl, 2,2,2 trifluoroethyl, 3,3,3-trifluoropropyl, and 2 ,2-difluoropropyl, wherein each 25 member of group B is optionally substituted at any carbon up to and including 3 atoms from the point of attachment of B to A with one or more of the group consisting of R 32 , R 33 , and R34 209 WO 00/69826 PCT/US00/08220 32 33 34 R 3 2 , R 33 , and R 3 4 are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, methoxyamino, ethoxyamino, acetamido, trifluoroacetamido, N-methylamino, dimethylamino, N-ethylamino, 5 methylthio, ethylthio, isopropylthio, trifluoromethyl, pentafluoroethyl, 2,2,2 trifluoroethyl, 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 10 methylamidocarbonyl, N,N-dimethylamidocarbonyl, and cyano; A is selected from the group consisting of single covalent bond, NH, and N(CH 3 ); R 1 and X 0 are independently selected from the group consisting of hydrido, hydroxy, amino, amidino, hydroxyamino, aminomethyl, 1 15 aminoethyl, methylamino, dimethylamino, cyano, methyl, ethyl, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, methoxy, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, methoxyamino, methylthio, ethylthio, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro, and bromo; 20 R 2 is Zo-Q; Zo is selected from the group consisting of a covalent single bond and CH 2 ; Q is selected from the group consisting of phenyl, 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyrrolyl, 3 -pyrrolyl, 2-imidazolyl, 4-imidazolyl, 3 25 pyrazolyl, 4-pyrazolyl, 2-thiazolyl, 3-isoxazolyl, 5-isoxazolyl, 2-pyridyl, 3 pyridyl, 4-pyridyl, 2-pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, and 1,3,5-triazin-2-yl, wherein a carbon adjacent to the carbon at the point of attachment is optionally substituted by R , the other carbon adjacent to the carbon at the point of attachment is optionally 13 9 30 substituted by R , a carbon adjacent to R and two atoms from the carbon at 210 WO 00/69826 PCT/US00/08220 the point of attachment is optionally substituted by R 10 , a carbon adjacent to R 13 and two atoms from the carbon at the point of attachment is optionally 12 10 12 substituted by R 12 , and any carbon adjacent to both R 10 and R 12 is optionally substituted by R 1 1 5 R , R , 1 1 and R 13 are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, N-methylamino, N,N-dimethylamino, N-ethylamino, methylthio, ethylthio, isopropylthio, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, 2,2,3,33 10 pentafluoropropyl, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro, bromo, methanesulfonamnido, amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, 2 hydroxyethyl, 2,2,2-trifluoro-l1-hydroxyethyl, amidocarbonyl, N methylamidocarbonyl, N,N-dimethylamidocarbonyl, and cyano; 15 R1 0 and R 12 are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, carboxymethyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, methoxyamino, ethoxyamino, acetamido, trifluoroacetamido, aminomethyl, 1 aminoethyl, 2-aminoethyl, N-methylamino, dimethylamino, N-ethylamino, 20 methanesulfonamido, amidosulfonyl, N-methylamidosulfonyl, N,N dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro-1-hydroxyethyl, methoxycarbonyl, ethoxycarbonyl, amidocarbonyl, N-methylamidocarbonyl, N,N-dimethylamidocarbonyl, fluoro, chloro, bromo, and cyano; 25 Yo is selected from the group consisting of: 1-Qb -4-Qs-2-R 16_3-R 17-5-R 18-6-R 19benzene, b s 17 18 19 2-Qb_5-Q -6-R 7-4-R 18-2-R 19pyridine, 3-Qb -6-Q s-2-R 16-5-R 18-4-R 19pyridine, 2-Qb -4-Q s-3-R 16-6-R 18pyrazine, 211 WO 00/69826 PCT/US00/08220 3-Qb -6-Qs-2-R 18-5-R 18-4-R 19pyridazine, 2-Qb-5-Qs-6-R 17-4-R 18pyrimidine, 5-Qb -2-Qs -3-R 16-6-R 19pyrimidine, 3-Qb-5-Q S-4-R 16-2-R 19thiophene, 2-Qb_5-Q S-3-R 16-4-R 17thiophene, 3-Qb-5-Qs-4-R 16-2-R 19furan, 2-Qb -5-Qs-3-R 16-4-R 17furan, 5 3-Qb-5-Q -4-R 16-2-R 19pyrrole, 2-Qb -5-Qs -3-R 16-4-R 17pyrrole, 4-Qb-2-QS-5-R 19imidazole, 2-Qb 4Q -5-R 17imidazole, b s 16 b s 16 3-Q -5-Q -4-R 16isoxazole, 5-Q -3-Q -4-R 16isoxazole, 2-Qb-5-Q s 4-R 16pyrazole, 4-Qb_2-QS-5-R 19thiazole, and b s 17 2-Q -5-Q -4-R 17thiazole; 10 17 18 19 10 RI 6 , R 17 , R 8 , and R 19 are independently selected from the group consisting of hydrido, methyl, ethyl, isopropyl, propyl, carboxy, amidino, guanidino, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, aminomethyl, 1-aminoethyl, 2-aminoethyl, N-methylamino, dimethylamino, N-ethylamino, methylthio, ethylthio, isopropylthio, trifluoromethylthio, 15 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-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro- 1 20 hydroxyethyl, and cyano; R 16 and R 19 are optionally Qb with the proviso that no more than one of R 16 and R 19 is Qb at the same time and that Qb is Qbe b 20 21 Qbe Qb is selected from the group consisting of NR20 R 21, be wherein Qbe is hydrido, C(NR25 )NR23 R 24, and N(R26)C(NR25)N(R 23)(R24), with 20 21 23 24 25 the provisos that no more than one of R 2 0 , R 2 1 , R , and R 2 4 can be 212 WO 00/69826 PCT/US00/08220 20 21 23 2 hydroxy, when any two of the group consisting of R 2 0 , R 2 1 , R , and R 24 are bonded to the same atom and that said Qb group is bonded directly to a carbon atom; 20 21 23 24 25 26 R20, R 2 1 , R , R24, R25, and R 2 6 are independently selected from the 5 group consisting of hydrido, methyl, ethyl, propyl, butyl, isopropyl, and hydroxy; QS is selected from the group consisting of a single covalent bond, CH 2 , and CH 2 CH 2 .
6. The compound as recited in Claim 4 having the Formula: R 1 Xo R2 H N N H H 10 0 or a pharmaceutically acceptable salt thereof, wherein; A is selected from the group consisting of CH 2 N(CH 3 ), CH 2 N(CH 2 CH 3 ), CH 2 CH 2 N(CH 3 ), and CH 2 CH 2 N(CH 2 CH 3 ); R 1 and X 0 are independently selected from the group consisting of 15 hydrido, hydroxy, amino, amidino, hydroxyamino, aminomethyl, 1 aminoethyl, methylamino, dimethylamino, cyano, methyl, ethyl, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, methoxy, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, methoxyamino, methylthio, ethylthio, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro, and 20 bromo; R 2 is Zo-Q; 213 WO 00/69826 PCT/US00/08220 Z is selected from the group consisting of covalent single bond and CH 2 ; Q is selected from the group consisting of phenyl, 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl, 4-imidazolyl, 3 5 pyrazolyl, 4-pyrazolyl, 2-thiazolyl, 3-isoxazolyl, 5-isoxazolyl, 2-pyridyl, 3 pyridyl, 4-pyridyl, 2-pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, and 1,3,5-triazin-2-yl, wherein a carbon adjacent 9 to the carbon at the point of attachment is optionally substituted by R , the other carbon adjacent to the carbon at the point of attachment is optionally 13 9 10 substituted by R 13, a carbon adjacent to R and two atoms from the carbon at 10 the point of attachment is optionally substituted by R 10 , a carbon adjacent to R 13 and two atoms from the carbon at the point of attachment is optionally 12 10 12 substituted by R 12 , and any carbon adjacent to both R 10 and R 12 is optionally substituted by R 1 5 9 , R 11 ad13 15 R , R 11, and R3 are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, N-methylamino, N,N-dimethylamino, N-ethylamino, methylthio, ethylthio, isopropylthio, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, 2,2,3,3,3 20 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; 25 R1 0 and R 12 are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, carboxymethyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, methoxyamino, ethoxyamino, acetamido, trifluoroacetamido, aminomethyl, 1 aminoethyl, 2-aminoethyl, N-methylamino, dimethylamino, N-ethylamino, 214 WO 00/69826 PCT/US00/08220 methanesulfonamido, amidosulfonyl, N-methylamidosulfonyl, N,N dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro-l1-hydroxyethyl, methoxycarbonyl, ethoxycarbonyl, amidocarbonyl, N-methylamidocarbonyl, N,N-dimethylamidocarbonyl, 5 fluoro, chloro, bromo, and cyano; Yo is selected from the group consisting of: 1-Qb 4-QS-2-R16-3-R17-5-R18-6-R 19 benzene, 2-Qb-5-Q s -6-R 17 -4-R 18 -2-R 19 pyridine, 3-Qb -6-Qs-2-R 16-5-R 18-4-R 19pyridine, 2-Qb 4-QS-3-R 16_6-R 18pyrazine, 10 3-Qb -6-QS-2-R 18-5-R 18-4-R 19pyridazine, 2-Qb -5-Qs-6-R 17-4-R 18pyrimidine, 5-Qb_2-QS-3-R 16-6-R 19pyrimidine, b s 16 19 b s 16 17 3-Q -5-Q -4-R 16-2-R 19thiophene, 2-Qb -5-Q -3-R 16-4-R 7thiophene, b_ s 16_ 19 b "s 16 17 3-Q -5-Q -4-R 16-2-R 19furan, 2-Q -b5-Q -3-R 16-4-R17furan, 3-Qb -5-Q -4-R 16-2-R 19pyrrole, 2-Qb_5-Q s-3-R 16-4-R 17pyrrole, 15 4-Qb-2-QS-5-R 19imidazole, 2-Qb -4-QS-5-R 17imidazole, b s 16. b s 16 3-Q -5-Q -4-R 16isoxazole, 5-Q -3-Q -4-R 16isoxazole, 2-Qb-5-Q s-4-R 16pyrazole, 4-Qb-2-Qs-5-R19thiazole, and b s 17 2-Qb _5-Q -4-R 17thiazole; 16 17 18 19 R , R , R , and R are independently selected from the group 20 consisting of hydrido, methyl, ethyl, isopropyl, propyl, amidino, guanidino, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, aminomethyl, 1 aminoethyl, 2-aminoethyl, N-N-methylamino, dimethylamino, N-ethylamino, methylthio, ethylthio, isopropylthio, trifluoromethylthio, methylsulfinyl, ethylsulfinyl, methylsulfonyl, ethylsulfonyl, trifluoromethyl, pentafluoroethyl, 25 2,2,2-trifluoroethyl, 2.2,3,3,3-pentafluoropropyl, trifluoromethoxy, 1,1,2,2 tetrafluoroethoxy, fluoro, chloro, bromo, amidosulfonyl, N 215 WO 00/69826 PCT/US00/08220 methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl, 1 hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro-1-hydroxyethyl, and cyano; Qb is selected from the group consisting of NR20R21 C(NR 25)NR23 R 2 4 , and N(R26)C(NR25)N(R 23)(R24), with the provisos 20 21 23 24 5 that no more than one of R 20 , R 2 1, R , and R 24 can be hydroxy, when any 20 21 23 24 two of the group consisting of R 2 0 , R 2 1, R , and R 24 are bonded to the same atom and that said Qb group is bonded directly to a carbon atom; 20 21 23 24 25 26 R 20 , R 2 1 , R , R 2 4 , R 2 5 , and R 2 6 are independently selected from the group consisting of hydrido, methyl, ethyl, propyl, butyl, isopropyl, and 10 hydroxy; QS is selected from the group consisting of a single covalent bond, CH 2 , and CH 2 CH 2 .
7. The compound as recited in Claim 6 or a pharmaceutically acceptable salt 15 thereof, wherein; A is selected from the group consisting of CH2N(CH 3 ), CH 2 N(CH 2 CH 3 ), CH 2 CH 2 N(CH 3 ), and CH 2 CH 2 N(CH 2 CH 3 ); R 1 and X 0 are independently selected from the group consisting of hydrido, hydroxy, amino, amidino, hydroxyamino, aminomethyl, 20 methylamino, cyano, methyl, trifluoromethyl, methoxy, hydroxymethyl, methoxyamino, methylthio, trifluoromethoxy, fluoro, and chloro; R 2 is Zo-Q; Z is selected from the group consisting of covalent single bond and CH 2 ; 25 Q is selected from the group consisting of 5-amino-3 amidocarbonylphenyl, 5-amino-2-fluorophenyl, 3-amino-5 hydroxymethylphenyl, 5-amino-3-methoxycarbonylphenyl, 3-amidinophenyl, 216 WO 00/69826 PCT/US00/08220 3 -amino-2-methylphenyl, 5 -amino-2-methylthiophenyl, 3-aminophenyl, benzyl, 3-carboxyphenyl, 3 -carboxy-5-hydroxyphenyl, 3-carboxy-5 aminophenyl, 3-chlorophenyl, 2-chlorophenyl, 3-cyanophenyl, 3 dimethylaminophenyl, 2-fluorophenyl, 3-fluorophenyl, 2-hydroxyphenyl, 3 5 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 10 thienyl, 3-pyridyl, 4-pyridyl, 2-thienyl, and 3-thienyl; Yo is selected from the group consisting of: 1-Qb -4-QS-2-R16-3-R17-5-R18-6-R19benzene, b s 17 18 19 2-Q -5-Q s -6-R 17-4-R 18-2-R 19pyridine, 3-Qb -6-Q s -2-R 16 -5-R 18 -4-R 19 pyridine, 15 3-Qb -5-Qs-4-R16-2-R19thiophene, and 2-Qb-5-QS-3-R16-4-R17thiophene; R 16 and R 19 are independently selected from the group consisting of hydrido, amidino, amino, aminomethyl, methoxy, methylamino, hydroxy, hydroxymethyl, fluoro, chloro, and cyano; R 16 and R 19 are optionally Qb with the proviso that no more than one 20 of R16 and R19 is Qb at the same time and that Qb is Qbe R 17 and R 18 are independently selected from the group consisting of hydrido, fluoro, chloro, hydroxy, hydroxymethyl, amino, carboxy, and cyano; Qb is selected from the group consisting of Qbe wherein Qbe is hydrido and C(NR 25)NR R2324 23 24 25 25 R , R 2 4 , and R 25 are independently selected from the group consisting of hydrido and methyl; QS is CH 2 . 217 WO 00/69826 PCT/US00/08220
8. A compound as recited in Claim 7 or a pharmaceutically acceptable salt thereof where said compound is selected from the group consisting of: 5 2-[ 1-[6-[3-aminophenyl]-4-chloro-N- [[4-iminomethylphenyl]methyl] 3-[N,N-dimethylhydrazino]-2-oxo- 1(2H)-pyridinyl]]acetamide; 2-[ 1-[ 6 -[ 3 -aminophenyl]-4-fluoro-3-[N-ethyl-N-methylhydrazino]-N [[ 4 -iminomethylphenyl]methyl]-2-oxo- 1 (4H)-pyridinyl]]acetamide; 2-[ 1-[ 6 -[ 3 -anminophenyl]-3-[N,N-diethylhydrazino]-N-[[4 10 iminomethylphenyl]methyl]-2-oxo- 1(4H)-pyridinyl]]acetamide; 2-[ 1 -[6-[3-aminophenyl]-3-[N-(azetidin- 1 -yl)amino]-4-fluoro-N-[[4 iminomethylphenyl]methyl]-2-oxo- 1(4H)-pyridinyl]]acetamide; 2-[ 1-[6-[3-aminophenyl]-N-[[4-iminomethylphenyl]methyl]-3-[N,N dimethylhydrazino]-2-oxo- 1(2H)-pyridinyl]]acetamide; 15 2-[ 1 -[ 6 -[3-aminophenyl]-4-fluoro-N-[[4-iminomethylphenyl]methyl] 3-[N,N-dimethylhydrazino]-2-oxo- 1(2H)-pyridinyl]]acetamide;
9. The compound as recited in Claim 2 having the Formula: R 1 0 B NNN ra YO H H O 0 20 or a pharmaceutically acceptable salt thereof, wherein; B is the Formula: 218 WO 00/69826 PCT/US00/08220 R 3 4 R 3 3 R 3 5 K R32 j# R36 32 33 34 35 36 R 32 , R 33, R 34 , R 35 , and R 36 are independently selected from the group consisting of hydrido, acetamido, haloacetamido, anmidino, guanidino, alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, alkylthio, 5 amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboalkoxy, carboxy, carboxamido, cyano, and Qb A is selected from the group consisting of single covalent bond and (CH(R 5))pa-(W 7)rr wherein rr is an integer selected from 0 through 1, pa is 7 10 an integer selected from 0 through 3, and W is selected from the group consisting of (R )NC(O) and N(R 7); R7 is selected from the group consisting of hydrido, hydroxy and alkyl; R 15 is selected from the group consisting of hydrido, halo, alkyl, and haloalkyl; 15 R 1 and X 0 are independently selected from the group consisting of hydrido, hydroxy, hydroxyamino, amidino, amino, cyano, hydroxyalkyl, alkoxy, alkyl, alkylamino, aminoalkyl,alkylthio, alkoxyamino, haloalkyl, haloalkoxy, and halo; R 2 is Zo-Q; 20 Z is selected from the group consisting of a covalent single bond, O, S, NH, and CH 2 ; 219 WO 00/69826 PCT/US00/08220 Q is selected from the group consisting of aryl and heteroaryl wherein a carbon adjacent to the carbon at the point of attachment is optionally substituted by R , the other carbon adjacent to the carbon at the point of attachment is 13 9 optionally substituted by R , a carbon adjacent to R and two atoms from the 10 5 carbon at the point of attachment is optionally substituted by R , a carbon adjacent to R 13 and two atoms from the carbon at the point of attachment is 12 10 12 optionally substituted by R 12 , and any carbon adjacent to both RI and R 12 is optionally substituted by R 1 1 9 11 13 R 9 , R , and R 13 are independently selected from the group 10 consisting of hydrido, hydroxy, amino, amidino, guanidino, lower alkylamino, alkylthio, alkylsulfonamido, alkylsulfinyl, alkylsulfonyl, amidosulfonyl, monoalkyl amnidosulfonyl, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboxy, carboxamido, and cyano; R 10 and R 12 are independently selected from the group consisting of 15 hydrido, acetamido, haloacetamido, amidino, guanidino, alkyl, alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, alkylsulfonamnido, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, hydroxyalkyl, aminoalkyl, carboalkoxy, carboxy, carboxyalkyl, amidocarbonyl, halo, haloalkyl, and cyano; 20 Yo is formula (IV): S R17 R 1 8 R 6 R16/D K 2 " R19 Qb Q (IV) 220 WO 00/69826 PCT/US00/08220 wherein D 5 , D 6 , J 5, and J6 are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more 2 5 65 6 than one is a covalent bond, K is C, no more than one of D , D , J, and J 5 65 6 5 65 6 is O, no more than one of DS, D , JS, and J is S, one of DS, D , , and J6 5 65 6 5 must be a covalent bond when two of D , D 6 , J , and J are O and S, and no 5 65 6 more than four of D , D 6 , and J are N; 16 17 18 19 R 16 , R 17 , R 8 , and R 19 are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, haloalkylthio, alkoxy, hydroxy, amino, lower alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, 10 alkanoyl, haloalkanoyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, and cyano; R 16 and R 19 are optionally Qb with the proviso that no more than one of R 16 and R 19 is Qb at the same time and that Qb is Qbe Qb isslcermteg20 21 be be. Qb is selected from the group consisting of NR20R21, be wherein Qbe is 25 23 24 20 15 hydrido, and C(NR )NR R 24 , with the provisos that no more than one of R 2 0 and R 2 1 is hydroxy at the same time and that no more than one of R 2 3 and R 2 4 is hydroxy at the same time; 20, 21, 23, 24, 25gru R 2 0 , R 2 1 , R , R 24 , and R 5 are independently selected from the group consisting of hydrido, alkyl, and hydroxy; 20 Q is selected from the group consisting of a single covalent bond, CH 2 , and CH 2 CH 2 .
10. The compound as recited in Claim 9 or a pharmaceutically acceptable salt thereof, wherein; 25 B is the Formula: 221 WO 00/69826 PCT/US00/08220 R 3 4 R 3 3 R 3 5 R 3 2 R36 32 33 34 35 36 R 3 2 , R 3 3 , R 3 4 , R 3 5 , and R 3 6 are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, methoxyamino, ethoxyamino, 5 acetamido, trifluoroacetanido, N-methylamino, dimethylamino, N-ethylamino, methylthio, ethylthio, isopropylthio, trifluoromethyl, pentafluoroethyl, 2,2,2 trifluoroethyl, 2,2,3,3, 3 -pentafluoropropyl, trifluoromethoxy, 1,1,2,2 tetrafluoroethoxy, fluoro, chloro, bromo, amidosulfonyl, N methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl, 1 10 hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro- 1-hydroxyethyl, methoxycarbonyl, ethoxycarbonyl, anmidocarbonyl, N-methylamidocarbonyl, N,N-dimethylamidocarbonyl, cyano, and Qb A is selected from the group consisting of single covalent bond, NH, N(CH 3 ), N(OH), CH 2 , CH 3 CH, CF 3 CH, NHC(O), N(CH 3 )C(O), 15 C(O)NH, C(O)N(CH 3 ), CH 2 CH 2 , CH 2 CH 2 CH 2 , CH 3 CHCH 2 , and CF 3 CHCH 2 ; R 1 and X 0 are independently selected from the group consisting of hydrido, hydroxy, amino, amidino, hydroxyamino, aminomethyl, 1 aminoethyl, methylamino, dimethylamino, cyano, methyl, ethyl, 20 trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, methoxy, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, methoxyamino, methylthio, ethylthio, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro, and bromo; R 2 is Zo-Q; 222 WO 00/69826 PCT/US00/08220 Zo is selected from the group consisting of a covalent single bond, O, S, NH, and CH 2 ; Q is selected from the group consisting of phenyl, 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl, 4-imidazolyl, 3 5 pyrazolyl, 4-pyrazolyl, 2-thiazolyl, 3-isoxazolyl, 5-isoxazolyl, 2-pyridyl, 3 pyridyl, 4-pyridyl, 2-pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, and 1,3,5-triazin-2-yl, wherein a carbon adjacent 9 to the carbon at the point of attachment is optionally substituted by R , the other carbon adjacent to the carbon at the point of attachment is optionally 13 9 10 substituted by R , a carbon adjacent to R and two atoms from the carbon at 10 the point of attachment is optionally substituted by R 10 , a carbon adjacent to R 13 and two atoms from the carbon at the point of attachment is optionally substituted by R 12 , and any carbon adjacent to both R 10 and R 12 is optionally substituted by R 11 15 R , R 1 1 , and R 13 are independently selected from the group consisting of hydrido, amiditio, guanidino, carboxy, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, N-methylamino, N,N-dimethylamino, N-ethylamino, methylthio, ethylthio, isopropylthio, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, 2,2,3,3,3 20 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; 25 R1 0 and R 12 are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, carboxymethyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, methoxyamino, ethoxyamino, acetamido, trifluoroacetamido, aminomethyl, 1 aminoethyl, 2-aminoethyl, N-methylamino, dimethylamino, N-ethylamino, 223 WO 00/69826 PCT/US00/08220 methanesulfonamido, amidosulfonyl, N-methylamidosulfonyl, N,N dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro-1-hydroxyethyl, methoxycarbonyl, ethoxycarbonyl, amidocarbonyl, N-methylamidocarbonyl, N,N-dimethylamidocarbonyl, 5 fluoro, chloro, bromo, and cyano; Yo is selected from the group consisting of: b s 16 17 18 19 1-Q -4-QS-2-R16-3-R17-5-R18-6-R19benzene, 2-Qb -5-Qs -6-R17 -4-R 18_2-R 19pyridine, 3-Qb -6-Q S-2-R 16-5-R 18-4-R 19pyridine, 2-Qb -4-Qs-3-R 16_6-R 18pyrazine, 3 b s 18 18 19 10 Q -6-Q -2-R -5-R -4-R pyridazine, b s 17 18 b s 16 19 2-Q -5-Q -6-R -4-R 18pyrimidine, 5-Q -2-Q -3-R -6-R 9pyrimidine, 3-Qb -5-Qs-4-R 16-2-R 19thiophene, 2-Qb_5-Q S-3-R 16-4-R 17thiophene, 3-Qb-5-Q -4-R 16-2-R 19furan, 2-Qb -5-Qs -3-R 16-4-R 17furan, 3-Qb -5-QS -4-R 16-2-R 19pyrrole, 2-Qb -5-Q s-3-R 16-4-R17pyrrole, 15 4-Qb-2-QS-5-R 19imidazole, 2-Qb -4-Q S-5-R 17imidazole, 3-Qb 5-Q s-4-R 16isoxazole, 5-Qb-3-Qs-4-R 16isoxazole, b s 16 b s 1 2-Q -5-Qs-4-R 6pyrazole, 4-Qb-2-Qs-5-R19thiazole, and 2-Qb -5-QS-4-R 17thiazole; 16 17 18 19 R 16 , R 17 , R 18 , and R 9 are independently selected from the group 20 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, 25 pentafluoroethyl, 2 ,2,2-trifluoroethyl, 2,2,3,3 3 -pentafluoropropyl, trifluoromethoxy, 1,1,2, 2 -tetrafluoroethoxy, fluoro, chloro, bromo, 224 WO 00/69826 PCT/US00/08220 amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro-1 hydroxyethyl, and cyano; R 16 and R 19 are optionally Qb with the proviso that no more than one of 5 R 16 and R 19 is Qb at the same time and that Qb is Qbe Qb is selected from the group consisting of Qbe wherein Qbe is hydrido 25 224 23 24 and C(NR25)NR23R24, with the proviso that no more than one of R and R 24 is hydroxy at the same time; 23 24 2-5 R , R 2 4 , and R 2 5 are independently selected from the group consisting of 10 hydrido, methyl, ethyl, and hydroxy; Qs is selected from the.group consisting of a single covalent bond, CH 2 and CH 2 CH 2 .
11. The compound as recited in Claim 10 or a pharmaceutically acceptable salt 15 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 20 hydroxyphenyl, 4-hydroxyphenyl, 3-methoxyaminophenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-methylphenyl, 4-methylphenyl, phenyl, and 3 trifluoromethylphenyl; A is selected from the group consisting of CH 2 , CH 3 CH, CF 3 CH, NHC(O), CH 2 CH 2 ,and CH 2 CH 2 CH 2 ; 25 R 1 and Xo are independently selected from the group consisting of hydrido, hydroxy, amino, amidino, hydroxyamino, aminomethyl, methylamino, cyano, methyl, trifluoromethyl, methoxy, hydroxymethyl, methoxyamino, methylthio, trifluoromethoxy, fluoro, and chloro; R 2 is ZQ; 225 WO 00/69826 PCT/US00/08220 Z is selected from the group consisting of a covalent single bond, O, S, NH, and CH 2 ; Q is selected from the group consisting of 5-amino-3 amidocarbonylphenyl, 5 -amino-2-fluorophenyl, 3-amino-5 5 hydroxymethylphenyl, 5-amino-3-methoxycarbonylphenyl, 3-amidinophenyl, 3-amino-2-methylphenyl, 5 -amino-2-methylthiophenyl, 3-aminophenyl, benzyl, 3-carboxyphenyl, 3 -carboxy-5-aminophenyl, 3-carboxy-5 hydroxyphenyl, 3 -carboxymethyl-5-aminophenyl, 3-carboxymethyl-5 hydroxyphenyl, 3 -carboxymethylphenyl, 3-chlorophenyl, 2-chlorophenyl, 10 2,6-dichlorophenyl, 3-cyanophenyl, 3-dimethylaminophenyl, 2-fluorophenyl, 3-fluorophenyl, 2,5-difluorophenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 3 methanesulfonylaminophenyl, 2-methoxyphenyl, 3-methoxyphenyl, 3 methoxyaminophenyl, 3 -methoxycarbonylphenyl, 2-methylaminophenyl, 3 methylaminophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 15 phenyl, 3-trifluoroacetamidophenyl, 3-trifluoromethylphenyl, 2 trifluoromethylphenyl, 5-amino-2-thienyl, 5-amino-3-thienyl, 3-bromo-2 thienyl, 3-pyridyl, 4-pyridyl, 2-thienyl, and 3-thienyl; Yo is selected from the group consisting of: 1-Qb -4-QS-2-R16-3-R17-5-R18-6-R19benzene, b s 17 18 19 20 2-Q -5-Q -6-R17 -4-R 18-2-R 19pyridine, b s 16 18 19 3-Q -6-Q s -2-R 16 -5-R 18 -4-R 9 pyridine, 3-Qb -5-Qs-4-R16-2-R19thiophene, and 2-Qb-5-Q S-3-R16 -4-R 7thiophene; R 16 and R 19 are independently selected from the group consisting of hydrido, amidino, amino, aminomethyl, methoxy, methylamino, hydroxy, 25 hydroxymethyl, fluoro, chloro, and cyano; R 16 and R 19 are optionally Qb with the proviso that no more than one of R 16 and R 19 is Qb at the same time and that Qb is Qbe R 17 and R 18 are independently selected from the group consisting of hydrido, fluoro, chloro, hydroxy, hydroxymethyl, amino, carboxy, and cyano; 226 WO 00/69826 PCT/US00/08220 Qb is selected from the group consisting of Qbe wherein Qbe is hydrido and C(NR25 )N23R24 R 23 , R 2 4 , and R 2 5 are independently selected from the group consisting of hydrido and methyl; 5 QS is CH 2.
12. The compound as recited in Claim 9 having the Formula: R 1 Xo R2 0 B N N N H H 0 or a pharmaceutically acceptable salt thereof, wherein; 10 B is the Formula: 34 R 3 3 R35 R 3 2 R 3 6 32 33 34 35 36 R , R , R , R , and R are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, alkylthio, 15 amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboalkoxy, carboxy, carboxamido, cyano, and Qb 227 WO 00/69826 PCT/US00/08220 A is selected from the group consisting of single covalent bond and (CH(R15))pa-(W 7)rr wherein rr is an integer selected from 0 through 1, pa is an integer selected from 0 through 3, and W 7 is N(R7); R 7 is selected from the group consisting of hydride and alkyl; 5 R 15 is selected from the group consisting of hydrido, halod alkyl, and 5 R 15is selected from the group consisting of hydrido, halo, alkyl, and haloalkyl; R 1 and X 0 are independently selected from the group consisting of hydrido, hydroxy, hydroxyamino, amidino, amino, cyano, hydroxyalkyl, alkoxy, alkyl, alkylamino, aminoalkyl, alkylthio, alkoxyamino, haloalkyl, 10 haloalkoxy, and halo; R 2 is Zo-Q; Z is a covalent single bond; Q is selected from the group consisting of aryl and heteroaryl wherein a carbon adjacent to the carbon at the point of attachment is optionally substituted 15 by R , the other carbon adjacent to the carbon at the point of attachment is 13 9 optionally substituted by R 13 , a carbon adjacent to R and two atoms from the carbon at the point of attachment is optionally substituted by R , a carbon adjacent to R 13 and two atoms from the carbon at the point of attachment is 12 10 12. optionally substituted by R 12 , and any carbon adjacent to both R 0 and R 12 is 20 optionally substituted by R11 R9 , 11 an 13 R , R 11, and R13 are independently selected from the group consisting of hydrido, hydroxy, amino, amidino, guanidino, lower alkylamino, alkylthio, alkoxy, alkylsulfinyl, alkylsulfonyl, amidosulfonyl, monoalkylamidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, 25 carboxy, carboxamido, and cyano; 228 WO 00/69826 PCT/US00/08220 R 10 and R 12 are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkyl, alkoxy, alkoxyamino, aminoalkyl, hydroxy, amino, lower alkylamino, alkylsulfonamido, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl 5 amidosulfonyl, hydroxyalkyl, aminoalkyl, halo, haloalkyl, carboalkoxy, carboxy, carboxyamido, carboxyalkyl, and cyano; YO is formula (IV): S R17 o R 18 D 5 6 R16/D K2 DN R 1 9 lb Q (IV) 5 65 6 wherein D , D 6 , J5, and J6 are independently selected from the group 10 consisting of C, N, O, S and a covalent bond with the provisos that no more 2 5 65 6 than one is a covalent bond, K is C, no more than one of D D , J and J6 5 6 5 6 5 6 5 6 is O, no more than one of D , D , J , and J is S, one of D , D , J, and J 5 65 6 must be a covalent bond when two of D , D 6 , J5, and J are O and S, and no 5 65 6 more than four of D 5 , D 6 , and J are N; 16 17 18 19 15 R 16 , R 17 , R 8 , and R are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, haloalkylthio, alkoxy, hydroxy, amino, lower alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, and cyano; 20 R 16 and R 19 are optionally Qb with the proviso that no more than one of R 16 and R 19 is Qb at the same time and that Qb is Qbe 229 WO 00/69826 PCT/US00/08220 b. 20 21 be .be. Q is selected from the group consisting of NR20 R , Qbe wherein Q is hydrido, and C(NR25)NR23 R24 20 21 23 24 25 R 2 0 , R 2 1 , R , R 2 4 , and R are independently selected from the group consisting of hydrido and alkyl; 5 Q is CH 2 .
13. The compound as recited in Claim 12 or a pharmaceutically acceptable salt thereof, wherein; B is the Formula: R 34 R 3 3 R 3 5 10 10R32 # R 3 6 32 33 34 35 36 R , R , R , R , and R are independently selected from the group consisting of hydrido, amidino, guanidino, methyl, ethyl, methoxy, ethoxy, hydroxy, amino, N-methylamino, dimethylamino, methylthio, ethylthio, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, fluoro, 15 chloro, bromo, amidosulfonyl, N-methylamidosulfonyl, hydroxymethyl, amidocarbonyl, carboxy, cyano, and Qb A is selected from the group consisting of single covalent bond, NH, N(CH 3 ), CH 2 , CH 3 CH, and CH 2 CH 2 ; X 0 is selected from the group consisting of hydrido, hydroxy, amino, 20 amidino, aminomethyl, cyano, methyl, trifluoromethyl, hydroxymethyl, and fluoro; 230 WO 00/69826 PCT/US00/08220 R 1 is selected from the group consisting of hydrido, hydroxy, amino, aminomethyl, methylamino, cyano, methyl, trifluoromethyl, methoxy, methylthio, trifluoromethoxy, fluoro, and chloro; R 2 is selected from the group consisting of phenyl, 2-thienyl, 2-furyl, 5 2-pyrrolyl, 2-imidazolyl, 2-thiazolyl, 3-isoxazolyl, 2-pyridyl, and 3-pyridyl, wherein a carbon adjacent to the carbon at the point of attachment is optionally 9 substituted by R 9 , the other carbon adjacent to the carbon at the point of 13 9 attachment is optionally substituted by R 13 , a carbon adjacent to R and two atoms from the carbon at the point of attachment is optionally substituted by 10 13 10 R10, a carbon adjacent to R 13 and two atoms from the carbon at the point of 12 attachment is optionally substituted by R 12 , and any carbon adjacent to both R1 0 and R 12 is optionally substituted by R 1 1 R9 , R11 an 13 R , R 11, and R13 are independently selected from the group consisting of hydrido, methyl, ethyl, methoxy, ethoxy, hydroxy, amino, N-methylamino, 15 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; RI 0 and R 12 are independently selected from the group consisting of 20 hydrido, amidino, amidocarbonyl, N-methylamidocarbonyl, guanidino, methyl, ethyl, methoxy, ethoxy, hydroxy, hydroxymethyl, l-hydroxyethyl, 2 hydroxyethyl, carboxy, carboxymethyl, amino, acetamido, trifluoromethyl, pentafluoroethyl, 2 ,22-trifluoroethyl, trifluoroacetamido, aminomethyl, N methylamino, dimethylamino, amidosulfonyl, N-methylamidosulfonyl, N,N 25 dimethylamidosulfonyl, methoxycarbonyl, fluoro, chloro, bromo, and cyano; YO is selected from the group consisting of: b s 16 17 18 19 1-Qb 4-Q -2-R -3-R -5-R 18-6-R 19benzene, _b_ s- 17 18_ 19 b_ 16 17 2-Q -5-Q-6-R 17-4-R 182-R 9pyridine, 2-Qb 5Q-3-R 16-4-R 7thiophene, 231 WO 00/69826 PCT/US00/08220 3-Qb -6-Qs-2-R16_-5-R
18-4-R 19pyridine, 3-Qb-5-QS-4-R 16-2-R 19thiophene, 3-Qb_5-QS-4-R 16-2-R 19furan, 2-Qb -5-Q s-3-R 16-4-R 17furan, 3-Qb_5-Qs -4-R 16-2-R 19pyrrole, 2-Qb -5-Q s-3-R16 -4-R 17pyrrole, 4-Qb-2-Qs-5-R19thiazole, and 2-Qb -5-Qs-4-R17thiazole; 16 17 18 19 5 R , R , R , and R are independently selected from the group consisting of hydrido, methyl, ethyl, amidino, guanidino, methoxy, hydroxy, amino, aminomethyl, 1-aminoethyl, 2-aminoethyl, N-methylamino, dimethylamino, methylthio, ethylthio, trifluoromethylthio, methylsulfinyl, methylsulfonyl, trifluoromethyl, pentafluoroethyl, 2 , 2 ,2-trifluoroethyl, 10 trifluoromethoxy, fluoro, chloro, amidosulfonyl, N-methylamidosulfonyl, hydroxymethyl, carboxy, and cyano. Qb is selected from the group consisting of NR20R21 and 25 23 24 b C(NR 25)NR 23R 24, with the proviso that said Q group is bonded directly to a carbon atom; 15 21 23 24 25 15 R 20 , R 2 1 , R , R 24 , and R are independently selected from the group consisting of hydrido, methyl, and ethyl; QS is CH 2 . 14. The compound as recited in Claim 13 or a pharmaceutically acceptable salt 20 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 25 hydroxyphenyl, 4-hydroxyphenyl, 3 -methoxyaminophenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-methylphenyl, 4 -methylphenyl, and phenyl; A is selected from the group consisting of CH 2 , CH 3 CH, CF 3 CH, NHC(O), CH 2 CH 2 ,and CH 2 CH 2 CH 2 ; 232 WO 00/69826 PCT/US00/08220 X 0 is selected from the group consisting of hydrido, hydroxy, amino, amidino, aminomethyl, cyano, methyl, trifluoromethyl, hydroxymethyl, and fluoro; R 1 is selected from the group consisting of hydrido, hydroxy, amino, 5 aminomethyl, cyano, methyl, trifluoromethyl, and fluoro; R 2 is selected from the group consisting of 5-amino-3 amidocarbonylphenyl, 5 -amino-2-fluorophenyl, 3-amino-5 hydroxymethylphenyl, 5-amino- 3 -methoxycarbonylphenyl, 3-amidinophenyl, 3-amino-2-methylphenyl, 5 -amino-2-methylthiophenyl, 3-aminophenyl, 10 benzyl, 3-carboxyphenyl, 3 -carboxy-5-aminophenyl, 3-carboxy-5 hydroxyphenyl, 3 -carboxymethyl-5-aminophenyl, 3-carboxymethyl-5 hydroxyphenyl, 3 -carboxymethylphenyl, 3-chlorophenyl, 2-chlorophenyl, 3 cyanophenyl, 3 -dimethylaminophenyl, 2-fluorophenyl, 3-fluorophenyl, 2.5 difluorophenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 3 15 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 20 thienyl, 3-pyridyl, 4-pyridyl, 2-thienyl, and 3-thienyl; Yo is selected from the group consisting of: 1-Qb -4-Q -2-R 16-3-R 17-5-R 18_6-R 19benzene, b s 17 18 19 2-Q -_5-Q -6-R -4-R -2-R pyridine, b s 16 18 19 3-Q -6-Q -2-R 16-5-R 18-4-R 9pyridine, 25 3-Qb-5-Q s-4-R16-2-R19thiophene, and 2-Qb-5-QS-3-R16-4-R 17thiophene; R16 and R 19 are independently selected from the group consisting of hydrido, amidino, amino, aminomethyl, methoxy, methylamino, hydroxy, hydroxymethyl, fluoro, chloro, and cyano; 233 WO 00/69826 PCT/US00/08220 R 16 and R 19 are optionally Qb with the proviso that no more than one of R 16 and R 19 is Qb at the same time and that Qb is Qbe R 17 and R 18 are independently selected from the group consisting of hydrido, fluoro, chloro, hydroxy, hydroxymethyl, amino, carboxy, and cyano; 5 Qb is selected from the group consisting of Qbe wherein Qbe is hydrido and C(NR25)NR R2324 23 24 25 R , R 24 , and R 25 are independently selected from the group consisting of hydrido and methyl; Qs is CH 2 . 10 15. The compound as recited in Claim 14 or a pharmaceutically acceptable salt thereof, wherein; B is selected from the group consisting of 3-aminophenyl, 3 amidinophenyl, 4-amidinophenyl, 3-chlorophenyl, 4-chlorophenyl, 3,4 15 dichlorophenyl, 2-fluorophenyl, 4-methylphenyl, and phenyl; A is selected from the group consisting of CH 2 , NHC(O), CH 2 CH 2 ,and CH 2 CH 2 CH 2 ; X 0 is selected from the group consisting of hydrido, hydroxy, amino, amidino, aminomethyl, cyano, methyl, trifluoromethyl, hydroxymethyl, and 20 fluoro; R 1 is selected from the group consisting of hydrido, hydroxy, amino, aminomethyl, cyano, methyl, trifluoromethyl, and fluoro; R 2 is selected from the group consisting of 3-aminophenyl, benzyl, 3 chlorophenyl, 3 -dimethylaminophenyl, 3-hydroxyphenyl, 3 25 methanesulfonylaminophenyl, 3 -methylaminophenyl, 2-methylphenyl, 3 methylphenyl, phenyl, 3 -trifluoroacetamidophenyl, 3-bromo-2-thienyl, 2 thienyl, and 3-thienyl; 234 WO 00/69826 PCT/US00/08220 Yo is selected from the group consisting of 5-amidino-2-thienylmethyl, 4-amidinobenzyl, 2-fluoro-4-amidinobenzyl, and 3-fluoro-4-amdinobenzyl. 16. A compound as recited in Claim 9 where said compound is selected from 5 the group having the Formula: R 1 Xo N Y B NN N Y0 H H 0 or a pharmaceutically acceptable salt thereof, wherein: R 2 is 3-aminophenyl, B is 3-chlorophenyl, A is CH 2 CH 2 , Y 0 is 4 amidinobenzyl, R 1 is hydrido, and X 0 is hydrido; 10 R 2 is 3-aminophenyl, B is phenyl, A is CH 2 , Y 0 is 4-amidinobenzyl, R 1 is hydrido, and X 0 is hydrido; R 2 is phenyl, B is 3-chlorophenyl, A is CH 2 CH 2 , YO is 4-amidinobenzyl, R 1 is hydrido, and X 0 is hydrido; R 2 is 3-dimethylaminophenyl, B is phenyl, A is CH 2 CH 2 , Y 0 is 4 15 amidinobenzyl, R 1 is hydrido, and X 0 is hydrido; R 2 is 2-methylphenyl, B is phenyl, A is CH 2 CH 2 , Y 0 is 4-amidinobenzyl, R 1 is hydrido, and X 0 is hydrido; R 2 is phenyl, B is 3-aminophenyl, A is C(0)NH, Yo 0 is 4-amidinobenzyl, R 1 is hydrido, and X 0 is hydrido; 20 R 2 is phenyl, B is 3-amidinophenyl, A is CH2, Y 0 is 4-amidinobenzyl, R 1 is hydrido, and X 0 is hydrido; 235 WO 00/69826 PCT/US00/08220 R 2 is 3 -(N-methylamino)phenyl, B is phenyl, A is CH 2 CH 2 , Y 0 is 4 amidinobenzyl, R 1 is hydrido, and XO is hydrido; R 2 is 3 -methylsulfonamidophenyl, B is phenyl, A is CH 2 CH 2 , Y 0 is 4 amidinobenzyl, R 1 is hydrido, and Xo is hydrido; 5 R 2 is phenyl, B is 4-amidinophenyl, A is CH 2 , Y 0 is 4-amidinobenzyl, R 1 is hydrido, and Xo is hydrido; R 2 is 3-methylaminophenyl, B is phenyl, A is CH 2 CH 2 , Y 0 is 4 amidinobenzyl, R 1 is hydrido, and Xo is hydrido; R 2 is phenyl, B is phenyl, A is CH 2 , YO 0 is 4-amidinobenzyl, R 1 is 10 hydrido, and Xo is hydrido; R 2 is 3-methylphenyl, B is 4-phenyl, A is CH 2 CH 2 , Y 0 is 4 amidinobenzyl, R 1 is hydrido, and Xo is hydrido; R 2 is 3-aminophenyl, B is 3-chlorophenyl, A is CH 2 CH 2 , Y 0 is 4 amidinobenzyl, R 1 is hydrido, and Xo is hydrido; 15 R 2 is 3-aminophenyl, B is phenyl, A is CH 2 , Y 0 is 4-amidinobenzyl, R 1 is hydrido, and Xo is hydrido; R 2 is phenyl, B is 3-chlorophenyl, A is CH 2 CH 2 , Y 0 is 4-amidinobenzyl, R 1 is hydroxy, and XO is fluoro; R 2 is 3-dimethylaminophenyl, B is phenyl, A is CH 2 CH 2 , Y 0 is 4 20 amidinobenzyl, R 1 is hydroxy, and Xo is fluoro; R 2 is 2-methylphenyl, B is phenyl, A is CH 2 CH 2 , Y 0 is 4-amidinobenzyl, R 1 is hydroxy, and Xo is fluoro; R 2 is phenyl, B is 3-aminophenyl, A is C(O)NH, Y 0 is 4-amidinobenzyl, R 1 is hydroxy, and Xo is fluoro; 236 WO 00/69826 PCT/US00/08220 R 2 is phenyl, B is 3-amidinophenyl, A is CH 2 , Y 0 is 4-amidinobenzyl, R 1 is hydroxy, and X 0 is fluoro; R 2 is 3 -(N-methylamino)phenyl, B is phenyl, A is CH 2 CH 2 , Y 0 is 4 amidinobenzyl, R 1 is hydroxy, and X 0 is fluoro; 5 R 2 is 3-methylsulfonamidophenyl, B is phenyl, A is CH 2 CH 2 , Y 0 is 4 amidinobenzyl, R 1 is hydroxy, and X 0 is fluoro; R 2 is phenyl, B is 4-amidinophenyl, A is CH 2 , Y 0 is 4-amidinobenzyl, R 1 is hydroxy, and X 0 is fluoro; R 2 is 3 -methylaminophenyl, B is phenyl, A is CH 2 CH 2 , Y 0 is 4 10 amidinobenzyl, R 1 is hydroxy, and X 0 is fluoro; R 2 is phenyl, B is phenyl, A is CH 2 , Y 0 is 4-amidinobenzyl, R 1 is hydroxy, and X 0 is fluoro; R 2 is 3-methylphenyl, B is 4-phenyl, A is CH 2 CH 2 , Yo 0 is 4 amidinobenzyl, R 1 is hydroxy, and X 0 is fluoro; 15 R 2 is 3-aminophenyl, B is 3-chlorophenyl, A is CH 2 CH 2 , Y 0 is 4 amidinobenzyl, R 1 is amino, and X 0 is hydrido; R 2 is 3-aminophenyl, B is phenyl, A is CH 2 , YO 0 is 4-amidinobenzyl, R 1 is amino, and X 0 is hydrido; R 2 is phenyl, B is 3-chlorophenyl, A is CH 2 CH 2 , Y 0 is 4-amidinobenzyl, 20 R 1 is amino, and X 0 is hydrido; R 2 is 3-dimethylaminophenyl, B is phenyl, A is CH 2 CH 2 , Y 0 is 4 amidinobenzyl, R 1 is amino, and X 0 is hydrido; R 2 is 2-methylphenyl, B is phenyl, A is CH 2 CH 2 , Y 0 is 4-amidinobenzyl, R 1 is amino, and X 0 is hydrido; 237 WO 00/69826 PCT/US00/08220 R 2 is phenyl, B is 3-aminophenyl, A is C(O)NH, Y 0 is 4-amidinobenzyl, R 1 is amino, and X 0 is hydrido; R 2 is phenyl, B is 3-amidinophenyl, A is CH 2 , Yo 0 is 4-amidinobenzyl, R 1 is amino, and X 0 is hydrido; 5 R 2 is 3 -(N-methylamino)phenyl, B is phenyl, A is CH 2 CH 2 , Y 0 is 4 amidinobenzyl, R 1 is amino, and X 0 is hydrido; R 2 is 3 -methylsulfonamidophenyl, B is phenyl, A is CH 2 CH 2 , Y 0 is 4 amidinobenzyl, R 1 is amino, and X 0 is hydrido; R 2 is phenyl, B is 4-amidinophenyl, A is CH 2 , Y 0 is 4-amidinobenzyl, R 1 10 is amino, and X 0 is hydrido; R 2 is 3-methylaminophenyl, B is phenyl, A is CH 2 CH 2 , YO is 4 amidinobenzyl, R 1 is amino, and X 0 is hydrido; R 2 is phenyl, B is phenyl, A is CH 2 , Y is 4-amidinobenzyl, R 1 is amino, and X 0 is hydrido; 15 R 2 is 3-methylphenyl, B is 4-phenyl, A is CH 2 CH 2 , YO 0 is 4 amidinobenzyl, R 1 is amino, and X 0 is hydrido; R 2 is 3-amninophenyl, B is 3-chlorophenyl, A is CH 2 CH 2 , Y 0 is 4 amidinobenzyl, R 1 is aminomethyl, and X 0 is hydrido; R 2 is 3-aminophenyl, B is phenyl, A is CH 2 , Y 0 is 4-amidinobenzyl, R 1 20 is aminomethyl, and X 0 is hydrido; R 2 is phenyl, B is 3-chlorophenyl, A is CH 2 CH 2 , Y 0 is 4-amidinobenzyl, R 1 is aminomethyl, and X 0 is hydrido; R 2 is 3-dimethylaminophenyl, B is phenyl, A is CH 2 CH 2 , Y 0 is 4 amidinobenzyl, R 1 is aminomethyl, and X 0 is hydrido; 238 WO 00/69826 PCT/US00/08220 R 2 is 2-methylphenyl, B is phenyl, A is CH 2 CH 2 , Y 0 is 4-amidinobenzyl, R 1 is aminomethyl, and XO is hydrido; R 2 is phenyl, B is 3-aminophenyl, A is C(O)NH, Yo 0 is 4-amidinobenzyl, R 1 is aminomethyl, and XO is hydrido; 5 R 2 is phenyl, B is 3-amidinophenyl, A is CH 2 , Y 0 is 4-amidinobenzyl, R 1 is aminomethyl, and Xo is hydrido; R 2 is 3 -(N-methylamino)phenyl, B is phenyl, A is CH 2 CH 2 , Y 0 is 4 amidinobenzyl, R 1 is aminomethyl, and Xo is hydrido; R 2 is 3 -methylsulfonamidophenyl, B is phenyl, A is CH 2 CH 2 , Y 0 is 4 10 amidinobenzyl, R 1 is amninomethyl, and Xo is hydrido; R 2 is phenyl, B is 4-amidinophenyl, A is CH 2 , Y 0 is 4-amidinobenzyl, R 1 is aminomethyl, and Xo is hydrido; R 2 is 3-methylaminophenyl, B is phenyl, A is CH 2 CH 2 , Y is 4 amidinobenzyl, R 1 is aminomethyl, and Xo is hydrido; 15 R 2 is phenyl, B is phenyl, A is CH 2 , Y 0 is 4-amidinobenzyl, R 1 is aminomethyl, and Xo is hydrido; R 2 is 3-methylphenyl, B is 4-phenyl, A is CH 2 CH 2 , Y 0 is 4 amidinobenzyl, R 1 is aminomethyl, and Xo is hydrido. 20 25 239 WO 00/69826 PCT/US00/08220 5 17. The compound as recited in Claim 2 having the Formula: R 1 H H 0 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 10 group B is optionally substituted at any carbon up to and including 6 atoms from the point of attachment of B to A with one or more of the group 32 33 34 35 36 consisting of R 3 2 , R 3 3 , R 3 4 , R 3 5 , and R36 32 33 34 35 36 R , R , R , R , and R are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, 15 alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, alkylthio, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboalkoxy, carboxy, carboxamido, cyano, and Qb A is selected from the group consisting of single covalent bond and 20 (CH(R 15))pa-(W 7)rr wherein rr is an integer selected from 0 through 1, pa is an integer selected from 0 through 3, and W 7 is selected from the group consisting of (R7)NC(0) and N(R7); 7 R 7 is selected from the group consisting of hydrido, hydroxy and alkyl; 240 WO 00/69826 PCT/US00/08220 R 15 is selected from the group consisting of hydrido, halo, alkyl, and haloalkyl; R 1 and X 0 are independently selected from the group consisting of hydrido, hydroxy, hydroxyamino, amidino, amino, cyano, hydroxyalkyl, 5 alkoxy, alkyl, alkylamino, aminoalkyl, alkylthio, alkoxyamino, haloalkyl, haloalkoxy, and halo; R 2 is Zo-Q; Z is selected from the group consisting of a covalent single bond, O, S, NH, and CH 2 ; 10 Q is selected from the group consisting of aryl and heteroaryl wherein a carbon adjacent to the carbon at the point of attachment is optionally substituted 9 by R , the other carbon adjacent to the carbon at the point of attachment is optionally substituted by R 13 , a carbon adjacent to R and two atoms from the 10 carbon at the point of attachment is optionally substituted by R I , a carbon 15 adjacent to R 13 and two atoms from the carbon at the point of attachment is 12 10 12 optionally substituted by R 12 , and any carbon adjacent to both RI and R 2 is optionally substituted by R 1 1 R , R 1, and R 13 are independently selected from the group consisting of hydrido, hydroxy, amino, amidino, guanidino, lower 20 alkylamino, alkylthio, alkylsulfonamido, alkylsulfinyl, alkylsulfonyl, amnidosulfonyl, monoalkyl amidosulfonyl, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboxy, carboxamido, and cyano; R 10 and R 12 are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkyl, alkoxy, 25 hydroxy, amino, alkoxyamino, lower alkylamino, alkylsulfonamido, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, hydroxyalkyl, aminoalkyl, carboalkoxy, carboxy, carboxyalkyl, amidocarbonyl, halo, haloalkyl, and cyano; 241 WO 00/69826 PCT/US00/08220 YO is formula (IV): S R17 R 1 8 5 6 R16/D K 2 R 1 9 lb (IV) 5 65 6 wherein D 5 , D 6 , j5, and J are independently selected from the group consisting of C, N, 0, S and a covalent bond with the provisos that no more 2 5 65 6 5 than one is a covalent bond, K is C, no more than one of D , D 6 , J5, and J 5 65 6 5 65 6 is O, no more than one of D , D 6 , and J is S, one of D , D 6 5, and J6 5 65 6 must be a covalent bond when two of D , D 6 , J5, and J are O and S, and no 5 65 6 more than four of D , D 6 , and J6 are N; 16 17 18 19 R 16 , R 17 , R 18 , and R 19 are independently selected from the group 10 consisting of hydrido, amidino, guanidino, carboxy, haloalkylthio, alkoxy, hydroxy, amino, lower alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, and cyano; R 16 and R 19 are optionally Qb with the proviso that no more than one 15 of R 16 and R 19 is Qb at the same time and that Qb is Qbe Qb is selected from the group consisting of NR 20 R 2 1 Qbe wherein be .25 23 24 26 25 23 24 Q is hydrido, C(NR 25)NR23 R 24, and N(R 26)C(NR 25)N(R 23)(R 24), with the provisos that no more than one of R20 and R21 is hydroxy at the same time and that no more than one of R 23 and R 24 is hydroxy at the same time; 242 WO 00/69826 PCT/US00/08220 20 21 23 24 25 26 R 2 0 , R 2 1 , R , R 2 4 , R 25 , and R 2 6 are independently selected from the group consisting of hydrido, alkyl, and hydroxy; Q is selected from the group consisting of a single covalent bond, CH 2 , and CH 2 CH 2 . 5 18. The compound as recited in Claim 17 or a pharmaceutically acceptable salt thereof, wherein; B is selected from the group consisting of hydrido, ethyl, 2-propynyl, 2-propenyl, propyl, isopropyl, butyl, 2-butenyl, 3-butenyl, 2-butynyl, sec 10 butyl, tert-butyl, isobutyl, 2 -methylpropenyl, 1-pentyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-pentynyl, 3-pentynyl, 2-pentyl, 1-methyl-2-butenyl, 1-methyl-3 butenyl, 1-methyl-2-butynyl, 3-pentyl, 1-ethyl-2-propenyl, 2-methylbutyl, 2 methyl-2-butenyl, 2-methyl-3-butenyl, 2-methyl-3-butynyl, 3-methylbutyl, 3 methyl-2-butenyl, 3-methyl-3-butenyl, 1-hexyl, 2-hexenyl, 3-hexenyl, 4 15 hexenyl, 5-hexenyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 2-hexyl, 1-methyl-2 pentenyl, 1-methyl-3-pentenyl, 1-methyl-4-pentenyl, 1-methyl-2-pentynyl, 1 methyl-3-pentynyl, 3-hexyl, 1-ethyl-2-butenyl, 1-ethyl-3-butenyl, 1-propyl-2 propenyl, 1-ethyl-2-butynyl, 1-heptyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5 heptenyl, 6-heptenyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 5-heptynyl, 2 20 heptyl, 1-methyl-2-hexenyl, 1-methyl-3-hexenyl, 1-methyl-4-hexenyl, 1 methyl-5-hexenyl, 1-methyl-2-hexynyl, 1-methyl-3-hexynyl, 1-methyl-4 hexynyl, 3-heptyl, 1-ethyl-2-pentenyl, 1-ethyl-3-pentenyl, 1-ethyl-4-pentenyl, 1-butyl-2-propenyl, 1-ethyl-2-pentynyl, 1-ethyl-3-pentynyl, 2,2,2 trifluoroethyl, 2,2-difluoropropyl, 4 -trifluoromethyl-5,5,5-trifluoropentyl, 4 25 trifluoromethylpentyl, 5,5, 6 , 6 ,6-pentafluorohexyl, and 3,3,3-trifluoropropyl, wherein each member of group B is optionally substituted at any carbon up to and including 5 atoms from the point of attachment of B to A with one or more 32 33 34 35 36 of the group consisting of R 3 2 , R 3 3 , R 3 4 , R 3 5 , and R36 32 33 34 35 36 R 3 2 , R 3 3 , R 34 , R 3 5 , and R 3 6 are independently selected from the 30 group consisting of hydrido, amidino, guanidino, carboxy, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, methoxyamino, ethoxyamino, acetamido, trifluoroacetamido, N-methylamino, dimethylamino, N-ethylamino, 243 WO 00/69826 PCT/US00/08220 methylthio, ethylthio, isopropylthio, trifluoromethyl, pentafluoroethyl, 2,2,2 trifluoroethyl, 2,2,3,3,3-pentafluoropropyl, trifluoromethoxy, 1,1,2,2 tetrafluoroethoxy, fluoro, chloro, bromo, amidosulfonyl, N methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl, 1 5 hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro-1-hydroxyethyl, methoxycarbonyl, ethoxycarbonyl, amidocarbonyl, N-methylamidocarbonyl, N,N-dimethylamidocarbonyl, cyano, and Qb A is selected from the group consisting of single covalent bond, NH, N(CH 3 ), N(OH), CH 2 , CH 3 CH, CF 3 CH, NHC(O), N(CH 3 )C(O), 10 C(O)NH, C(O)N(CH 3 ), CH 2 CH 2 , CH 2 CH 2 CH 2 , CH 3 CHCH 2 , and CF 3 CHCH 2 ; R 1 and X 0 are independently selected from the group consisting of hydrido, hydroxy, amino, amidino, hydroxyamino, aminomethyl, 1 amninoethyl, methylamino, dimethylamino, cyano, methyl, ethyl, 15 trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, methoxy, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, methoxyamino, methylthio, ethylthio, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro, and bromo; R 2 is Zo-Q; 20 Z is selected from the group consisting of a covalent single bond, O, S, NH, and CH 2 ; Q is selected from the group consisting of phenyl, 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl, 4-imidazolyl, 3 pyrazolyi, 4-pyrazolyl, 2-thiazolyl, 3-isoxazolyl, 5-isoxazolyl, 2-pyridyl, 3 25 pyridyl, 4-pyridyl, 2-pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, and 1,3,5-triazin-2-yl, wherein a carbon adjacent to the carbon at the point of attachment is optionally substituted by R , 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 244 WO 00/69826 PCT/US00/08220 the point of attachment is optionally substituted by R , a carbon adjacent to R13 and two atoms from the carbon at the point of attachment is optionally 12 10 12 substituted by R 12 , and any carbon adjacent to both RI and R 12 is optionally substituted by Rl 9 11 13 5 R , R, and R are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, N-methylamino, N,N-dimethylamino, N-ethylamino, methylthio, ethylthio, isopropylthio, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, 2,2,3,3 10 pentafluoropropyl, trifluoromethoxy, 1, 1,2,2-tetrafluoroethoxy, fluoro, chloro, bromo, methanesulfonamiido, amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, 2 hydroxyethyl, 2,2,2-trifluoro-1-hydroxyethyl, amidocarbonyl, N methylamidocarbonyl, N,N-dimethylamidocarbonyl, and cyano; 15 R 10 and R 12 are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, carboxymethyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, methoxyamino, ethoxyamino, acetamido, trifluoroacetamido, aminomethyl, 1 aminoethyl, 2-aminoethyl, N-methylamino, dimethylamino, N-ethylamino, 20 methanesulfonamido, amidosulfonyl, N-methylamidosulfonyl, N,N dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro-1-hydroxyethyl, methoxycarbonyl, ethoxycarbonyl, amidocarbonyl, N-methylamidocarbonyl, N,N-dimethylamidocarbonyl, fluoro, chloro, bromo, and cyano; 25 Yo is selected from the group consisting of: 1-Qb -4-QS-2-R 16-3-R 17_5-R 18-6-R 19benzene, b s 17 18 19 2-Q -5-Q -6-R -4-R -2-R pyridine, 245 WO 00/69826 PCT/US00/08220 3-Qb -6-Q -2-R 16-5-R 18-4-R 19pyridine, 2-Q b-4-Q -3-R 16_6-R 18pyrazine, 3 b s 18 18 19 Q -6-Q -2-R 18-5-R 18-4-R 19pyridazine, 2-Qb_5-QS-6-R 17-4-R 18pyrimidine, 5-Qb_2-QS-3-R 16-6-R 19pyrimidine, 3-Qb-5-Qs-4-R 16-2-R 19thiophene, 2-Qb_5-QS -3-R 16-4-R 17thiophene, 5 3-Qb-5-Q -4-R 16-2-R 19furan, 2-Qb-5-QS-3-R 16-4-R 17furan, 3-Qb-5-Qs-4-R 16-2-R 19pyrrole, 2-Qb_5-Q S-3-R16 -4-R 17pyrrole, 4-Qb-2-QS-5-R 19imidazole, 2-Qb 4-QS-5-R 17imidazole, b s 16 b s 1 3-Q -5-Q -4-R 16isoxazole, 5-Qb-3-Qs-4-R16isoxazole, 2-Qb -5-QS -4-R16pyrazole, 4-Qb-2-QS-5-R 19thiazole, and b s 17 10 2-Q -5-Q -4-R 17thiazole; 16 17 18 19 R , R , R , and R are independently selected from the group consisting of hydrido, methyl, ethyl, isopropyl, propyl, carboxy, amidino, guanidino, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, aminomethyl, 1-aminoethyl, 2-aminoethyl, N-methylamino, dimethylamino, 15 N-ethylamino, methylthio, ethylthio, isopropylthio, trifluoromethylthio, methylsulfinyl, ethylsulfinyl, methylsulfonyl, ethylsulfonyl, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, 2,2,3,3,3-pentafluoropropyl, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro, bromo, amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, 20 hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro-1 hydroxyethyl, and cyano; R16 an 19 Qb R16 and R19 are optionally Qb with the proviso that no more than one of R 16 and R 19 is Qb at the same time and that Qb is Qbe Qb is selected from the group consisting of NR 2 0 R 2 1 , Qbe, wherein Qbe 25 23 24 26 25 23 24 25 is hydrido, C(NR )NR R , and N(R )C(NR )N(R 23)(R 24), with the 246 WO 00/69826 PCT/US00/08220 provisos that no more than one of R20 and R21 is hydroxy at the same time and that no more than one of R 23 and R 24 is hydroxy at the same time; 20 21 23 24 25 26 R 2 0 , R 2 1 , R , R 24 , R 2 5 , and R 2 6 are independently selected from the group consisting of hydrido, methyl, ethyl, propyl, butyl, isopropyl, and hydroxy; 5 QS is selected from the group consisting of a single covalent bond, CH 2 , and CH 2 CH 2 .
19. The compound as recited in Claim 18 or a pharmaceutically acceptable salt thereof, wherein; 10 B is selected from the group consisting of hydrido,ethyl, 2-propenyl, 2-propynyl, propyl, isopropyl, butyl, 2-butyl, (R)-2-butyl,(S)-2-butyl, tert butyl, isobutyl, 1-pentyl, 3-pentyl, 2-methylbutyl, 2,2,2-trifluoroethyl, 6 amidocarbonylhexyl, 4-methyl-2-pentyl, 3-hydroxypropyl, 3-methoxy-2 propyl, 2-methoxyethyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 2 15 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; 20 A is selected from the group consisting of single covalent bond,CH 2 , NHC(O), CH 2 CH 2 , CH 2 CH 2 CH 2 , and CH 3 CHCH 2 ; R 1 and X 0 are independently selected from the group consisting of hydrido, hydroxy, amino, amidino, hydroxyamino, aminomethyl, methylamino, cyano, methyl, trifluoromethyl, methoxy, hydroxymethyl, 25 methoxyamino, methylthio, trifluoromethoxy, fluoro, and chloro; R 2 is Zo-Q; Z is selected from the group consisting of a covalent single bond, O, S, NH, and CH 2 ; 247 WO 00/69826 PCT/US00/08220 Q is selected from the group consisting of 5-amino-3 amidocarbonylphenyl, 5 -amino-2-fluorophenyl, 3-amino-5 hydroxymethylphenyl, 5 -amino-3-methoxycarbonylphenyl, 3-amidinophenyl, 3-amino-2-methylphenyl, 5-amino-2-methylthiophenyl, 3-aminophenyl, 5 benzyl, 3-carboxyphenyl, 3 -carboxy-5-aminophenyl, 3-carboxy-5 hydroxyphenyl, 3 -carboxymethyl-5-aminophenyl, 3-carboxymethyl-5 hydroxyphenyl, 3 -carboxymethylphenyl, 3-chlorophenyl, 2-chlorophenyl, 2,6-dichlorophenyl, 3-cyanophenyl, 3-dimethylaminophenyl, 2-fluorophenyl, 3-fluorophenyl, 2,5-difluorophenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 3 10 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 15 thienyl, 3-pyridyl, 4-pyridyl, 2-thienyl, and 3-thienyl; Yo is selected from the group consisting of: b s 16 17 18 19 1-Q -4-Q -2-R 16-3-R 17-5-R 18-6-R 19benzene, b s 17 18 19 2-Q _5-Q -6-R 17-4-R 18-2-R 19pyridine, b s 16 18 19 3-Q -b6Q -2-R 16_5-R18 -4-R 19pyridine, b s 16 19 b s 16 17 20 3-Q 5-Q-4-R16-2-R19thiophene, and 2-Q -5-Q -3-R16-4-R17thiophene; R 16 and R 19 are independently selected from the group consisting of hydrido, amidino, amino, aminomethyl, methoxy, methylamino, hydroxy, hydroxymethyl, fluoro, chloro, and cyano; R 16 and R 19 are optionally Qb with the proviso that no more than one 25 of R 16 and R 19 is Qb at the same time and that Qb is Qbe R17 and R 18 are independently selected from the group consisting of hydrido, fluoro, chloro, hydroxy, hydroxymethyl, amino, carboxy, and cyano; Qb is selected from the group consisting of Qbe wherein Qbe is hydrido and C(NR 25)NR R2324 248 WO 00/69826 PCT/US00/08220 23 24 25 R , R 24 , and R 25 are independently selected from the group consisting of hydrido and methyl; QS is CH 2. 5 20. The compound as recited in Claim 17 having the Formula: R 1 R2 10 N B/-1 A_ N N Yo H H 0 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 10 group B is optionally substituted at any carbon up to and including 6 atoms from the point of attachment of B to A with one or more of the group 32 33 34 35 36 consisting of R , R , R , R , and R; 32 33 34 35 36 R , R , R , R , and R are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, 15 alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, alkylthio, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboalkoxy, carboxy, carboxamido, cyano, and Qb A is selected from the group consisting of single covalent bond and 20 (CH(Rl5))pa-(W 7)rr wherein rr is an integer selected from 0 through 1, pa is an integer selected from 0 through 3, and W 7 is N(R 7 ); R 7 is selected from the group consisting of hydrido and alkyl; 249 WO 00/69826 PCT/US00/08220 R15 is selected from the group consisting of hydrido, halo, alkyl, and haloalkyl; R 1 and X 0 are independently selected from the group consisting of hydrido, hydroxy, hydroxyamino, amidino, amino, cyano, hydroxyalkyl, 5 alkoxy, alkyl, alkylamino, aminoalkyl, alkylthio, alkoxyamino, haloalkyl, haloalkoxy, and halo; R 2 is Zo-Q; Z is a covalent single bond; Q is selected from the group consisting of aryl and heteroaryl wherein a 10 carbon adjacent to the carbon at the point of attachment is optionally substituted 9 by R 9 , the other carbon adjacent to the carbon at the point of attachment is 13 9 optionally substituted by R 13 , a carbon adjacent to R and two atoms from the 10 carbon at the point of attachment is optionally substituted by R , a carbon adjacent to R 13 and two atoms from the carbon at the point of attachment is 12 10 12 15 optionally substituted by R 2 , and any carbon adjacent to both R 10 and R 2 is optionally substituted by R 1 1 9 11 13 R , R 1 1 , and R 13 are independently selected from the group consisting of hydrido, hydroxy, amino, amidino, guanidino, lower alkylamino, alkylthio, alkoxy, alkylsulfinyl, alkylsulfonyl, amidosulfonyl, 20 monoalkylamidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboxy, carboxamido, and cyano; R 0 and R 12 are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkyl, alkoxy, alkoxyamino, aminoalkyl, hydroxy, amino, lower alkylamino, 25 alkylsulfonamido, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, hydroxyalkyl, aminoalkyl, halo, haloalkyl, carboalkoxy, carboxy, carboxyamido, carboxyalkyl, and cyano; Y is formula (IV): 250 WO 00/69826 PCT/US00/08220 S R 17 * R 1 8 R R 1 R16/ 7 D K2/D I R19 1b Q (IV) 5 65 6 wherein D , D 6 , J5, and J are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more 2 5 65 6 than one is a covalent bond, K is C, no more than one of D 5 , D 6 , j5, and J 5 65 6 5 65 6 5 is 0, no more than one of DS, D , , and J is S, one of DS, D , , and J 5 65 6 must be a covalent bond when two of D , D , J, and J are 0 and S, and no 5 65 6 more than four of D , D 6 , and J are N; 16 17 18 19 R 16 , R 17 , R 18 , and R 19 are independently selected from the group consisting of hydrido, amnidino, guanidino, carboxy, haloalkylthio, alkoxy, 10 hydroxy, amino, lower alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, and cyano; R 16 and R 19 are optionally Qb with the proviso that no more than one of R 16 and R 1 9 is Qb at the same time and that Qb is Qbe 15 Qb is selected from the group consisting of NR20R21, Qbe wherein Qbe is hydrido, N(R26)C(NR25)N(R 23)(R24), and C(NR25)NR23 R24 20 21 23 24 25 26 R 2 0 , R 2 1 , R , R 24 , R 2 5 , and R 2 6 are independently selected from the group consisting of hydrido and alkyl; QS is CH 2 . 20 251 WO 00/69826 PCT/US00/08220
21. The compound as recited in Claim 17 or a pharmaceutically acceptable salt thereof, wherein; B is selected from the group consisting of hydrido, ethyl, 2-propenyl, 2-propynyl, propyl, isopropyl, butyl, 2-butenyl, 2-butynyl, sec-butyl, tert 5 butyl, isobutyl, 2 -methylpropenyl, 1-pentyl, 2-pentenyl, 3-pentenyl, 2 pentynyl, 3-pentynyl, 2-pentyl, 3-pentyl, 2-methylbutyl, 2-methyl-2-butenyl, 3-methylbutyl, 3-methyl-2-butenyl, 1-hexyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 2-hexyl, 1-methyl-2-pentenyl, 1-methyl-3 pentenyl, 1-methyl-2-pentynyl, 1-methyl-3-pentynyl, 3-hexyl, 1-ethyl-2 10 butenyl, 1-heptyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 5-heptynyl, 2-heptyl, 1-methyl-2-hexenyl, 1-methyl 3-hexenyl, 1-methyl-4-hexenyl, 1-methyl-2-hexynyl, 1-methyl-3-hexynyl, 1 methyl-4-hexynyl, 3-heptyl, 1-ethyl-2-pentenyl, 1-ethyl-3-pentenyl, 1-ethyl-2 pentynyl, 1-ethyl-3-pentynyl, 2,2,2-trifluoroethyl, 2,2-difluoropropyl, 4 15 trifluoromethyl-5,5,5-trifluoropentyl, 4-trifluoromethylpentyl, 5,5,6,6,6 pentafluorohexyl, and 3 ,3,3-trifluoropropyl, wherein each member of group B is optionally substituted at any carbon up to and including 5 atoms from the point of attachment of B to A with one or more of the group consisting of R 3 2 33 34 35 36 R, R , R , and R; 20 33 34 35 36 20 R 32 , R 33 , R 34 , R 3 5 , and R 3 6 are independently selected from the group consisting of hydrido, amidino, guanidino, methyl, ethyl, methoxy, ethoxy, hydroxy, amino, N-methylamino, dimethylamino, methylthio, ethylthio, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, fluoro, chloro, bromo, amidosulfonyl, N-methylamidosulfonyl, hydroxymethyl, 25 amidocarbonyl, carboxy, cyano, and Qb A is selected from the group consisting of single covalent bond, NH, N(CH 3 ), CH 2 , CH 3 CH, and CH 2 CH 2 ; A is optionally selected from the group consisting of CH 2 N(CH 3 ), CH 2 N(CH 2 CH 3 ), CH 2 CH 2 N(CH 3 ), and CH 2 CH 2 N(CH 2 CH 3 ) with the 30 proviso that B is hydrido; 252 WO 00/69826 PCT/US00/08220 X 0 is selected from the group consisting of hydrido, hydroxy, amino, amidino, aminomethyl, cyano, methyl, trifluoromethyl, hydroxymethyl, and fluoro; R 1 is selected from the group consisting of hydrido, hydroxy, amino, 5 aminomethyl, methylamino, cyano, methyl, trifluoromethyl, methoxy, methylthio, trifluoromethoxy, fluoro, and chloro; R 2 is selected from the group consisting of phenyl, 2-thienyl, 2-furyl, 2-pyrrolyl, 2-imidazolyl, 2-thiazolyl, 3-isoxazolyl, 2-pyridyl, and 3-pyridyl, wherein a carbon adjacent to the carbon at the point of attachment is optionally 9 10 substituted by R 9 , the other carbon adjacent to the carbon at the point of 13 9 attachment is optionally substituted by R 13 , a carbon adjacent to R and two atoms from the carbon at the point of attachment is optionally substituted by 10 13 R 10 , a carbon adjacent to R 13 and two atoms from the carbon at the point of 12 attachment is optionally substituted by R 12 , and any carbon adjacent to both 15 R1 0 and R 12 is optionally substituted by R 1 1 R 9 , R 11, and R 13 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, 20 N,N-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, amidocarbonyl, N-methylamidocarbonyl, carboxy, and cyano; RI 0 and R 12 are independently selected from the group consisting of hydrido, amidino, amidocarbonyl, N-methylamidocarbonyl, guanidino, methyl, ethyl, methoxy, ethoxy, hydroxy, hydroxymethyl, 1-hydroxyethyl, 2 25 hydroxyethyl, carboxy, carboxymethyl, amino, acetamido, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, trifluoroacetamido, aminomethyl, N methylamino, dimethylamino, amidosulfonyl, N-methylamidosulfonyl, N,N dimethylamidosulfonyl, methoxycarbonyl, fluoro, chloro, bromo, and cyano; Yo is selected from the group consisting of: 253 WO 00/69826 PCT/US00/08220 1-Qb -- QS-2-R 16-3-R 17-5-R 18_6-R 19benzene, b 7 1 9b s 16 17 2-Qb -5-QS-6-R 17-4-Rl8-2-R19pyridine, 2-Q -5-Q -3-R 16-4-R 7thiophene, b 6 18 19 b s 16 19 3-Qb -6-QS-2-R16-5-R 8-4-R 19pyridine, 3-Q -5-Qs-4-R -2-R 9thiophene, 3-Qb-5-Q -4-R 16-2-R 19furan, 2-Qb -5-Qs -3-R 16-4-R 17furan, 5 3-Qb-5-Q -4-R 16-2-R 19pyrrole, 2-Qb_5-Q S-3-R 16-4-R 17pyrrole, 4-Qb-2-Qs-5-R19thiazole, and 2-Qb-5-Q S-4-R17 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, 10 dimethylamino, methylthio, ethylthio, trifluoromethylthio, methylsulfinyl, methylsulfonyl, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, trifluoromethoxy, fluoro, chloro, amidosulfonyl, N-methylamidosulfonyl, hydroxymethyl, carboxy, and cyano. Qb is selected from the group consisting of NR20R21 15 C(NR25 )N23R24, and N(R26)C(NR25)N(R 23)(R24), with the proviso that said Qb group is bonded directly to a carbon atom; 20 21 23 24 25 26 R 20 , R 2 1 , R , R 2 4 , R 2 5 , and R 26 are independently selected from the group consisting of hydrido, methyl, and ethyl; Qs is CH 2. 20
22. The compound as recited in Claim 21 or a pharmaceutically acceptable salt thereof, wherein; B is selected from the group consisting of hydrido,ethyl, 2-propenyl, 2-propynyl, propyl, isopropyl, butyl, 2-butyl, (R)-2-butyl,(S)-2-butyl, tert 25 butyl, isobutyl, 1-pentyl, 3-pentyl, 2-methylbutyl, 2,2,2-trifluoroethyl, 6 amidocarbonylhexyl, 4-methyl-2-pentyl, 3-hydroxypropyl, 3-methoxy-2 propyl, 2-methoxyethyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 2 dimethylaminopropyl, 2-cyanoethyl, 6-hydroxyhexyl, 2-hydroxyethyl, 2 254 WO 00/69826 PCT/US00/08220 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; 5 A is selected from the group consisting of single covalent bond, CH 2 , CH 3 CH, and CH 2 CH 2 ; X 0 is selected from the group consisting of hydrido, hydroxy, amino, amidino, aminomethyl, cyano, methyl, trifluoromethyl, hydroxymethyl, and fluoro; 10 R 1 is selected from the group consisting of hydrido, hydroxy, amino, aminomethyl, cyano, methyl, trifluoromethyl, and fluoro; R 2 is selected from the group consisting of 5-amino-3 amidocarbonylphenyl, 5 -amino-2-fluorophenyl, 3-amino-5 hydroxymethylphenyl, 5 -amino-3-methoxycarbonylphenyl, 3-amidinophenyl, 15 3-amino-2-methylphenyl, 5 -amino-2-methylthiophenyl, 3-aminophenyl, benzyl, 3-carboxyphenyl, 3 -carboxy-5-aminophenyl, 3-carboxy-5 hydroxyphenyl, 3 -carboxymethyl-5-aminophenyl, 3-carboxymethyl-5 hydroxyphenyl, 3-carboxymethylphenyl, 3-chlorophenyl, 2-chlorophenyl, 2,6-dichlorophenyl, 3-cyanophenyl, 3-dimethylaminophenyl, 2-fluorophenyl, 20 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 25 trifluoromethylphenyl, 5-amino-2-thienyl, 5-amino-3-thienyl, 3-bromo-2 thienyl, 3-pyridyl, 4-pyridyl, 2-thienyl, and 3-thienyl; Yo is selected from the group consisting of: b s 16 17 18 19 1-Q -4-Qs -2-R 16-3-R 17-5-R 18-6-R 19benzene, b s 17 18 19 2-Qb -5-Q -6-R 74-R 8-2-R 19pyridine, b s 16 18 19 30 3-Qb-6-Q -2-R 6-5-R 18-4-R 19pyridine, 255 WO 00/69826 PCT/US00/08220 3-Qb 5-Qs-4-R 16-2-R 19thiophene, and 2-Qb-5-Q s -3-R 16-4-R 17thiophene; R16 and R19 are independently selected from the group consisting of hydrido, amidino, amino, aminomethyl, methoxy, methylamino, hydroxy, hydroxymethyl, fluoro, chloro, and cyano; 5 R 16 and R 19 are optionally Qb with the proviso that no more than one of R 16 and R 19 is Qb at the same time and that Qb is Qbe R 17 and R 18 are independently selected from the group consisting of hydrido, fluoro, chloro, hydroxy, hydroxymethyl, amino, carboxy, and cyano; Qb is selected from the group consisting of Qbe wherein Qbe is hydrido 10 and C(NR25)NR23 R24 23 24 25 R , R 2 4 , and R 25 are independently selected from the group consisting of hydrido and methyl; QS is CH2. 15 23. The compound as recited in Claim 22 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 20 amidocarbonylhexyl, 4-methyl-2-pentyl, 3-hydroxypropyl, 3-methoxy-2 propyl, 2-methoxyethyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 2 dimethylaminopropyl, 2-cyanoethyl, 6-hydroxyhexyl, 2-hydroxyethyl, 2 amidinoethyl, 2-guanidinoethyl, 3-guanidinopropyl, 4-guanidinobutyl, 3 hydroxypropyl, 4-hydroxybutyl, 6-cyanohexyl, 2-dimethylaminoethyl, 3 25 methylbutyl, 2-methylbutyl, (S)-2-methylbutyl, 3 -aminopropyl, 2-hexyl, and 4-aminobutyl; A is selected from the group consisting of single covalent bond, CH 2 , CH 3 CH, and CH 2 CH 2 ; 256 WO 00/69826 PCT/US00/08220 X 0 is selected from the group consisting of hydrido, hydroxy, amino, amidino, aminomethyl, cyano, methyl, trifluoromethyl, hydroxymethyl, and fluoro; R 1 is selected from the group consisting of hydrido, hydroxy, amino, 5 aminomethyl, cyano, methyl, trifluoromethyl, and fluoro; R 2 is selected from the group consisting of 5 -amino-2-fluorophenyl, 3 amino-2-methylphenyl, 5 -amino-2-methylthiophenyl, 3-aminophenyl, 3 carboxyphenyl, 3-cyanophenyl, 3-methoxycarbonylphenyl, phenyl, and 3 pyridyl; 10 y0 is selected from the group consisting of 5 -amidino-2-thienylmethyl, 4-amidinobenzyl, 2 -fluoro-4-amidinobenzyl, and 3 -fluoro-4-amidinobenzyl.
24. A compound as recited in Claim 17 where said compound is selected from the group having the Formula: R 1 Xo R2 B N-, N 1-lYO H H 15 0 or a pharmaceutically acceptable salt thereof, wherein: R 2 is 3-aminophenyl, B is 2,2,2-trifluoroethyl, A is single bond, Y0 is 4 amidinobenzyl, R 1 is hydrido, and X 0 is hydrido; R 2 is 3-aminophenyl, B is (S)-2-butyl, A is single bond, Y 0 is 4 20 amidinobenzyl, R 1 is hydrido, and X 0 is hydrido; R 2 is 5 -amino-2-fluorophenyl, B is isopropyl, A is single bond, Y0 is 4 amidinobenzyl, R 1 is hydrido, and X 0 is hydrido; R 2 is 2 -methyl-3-aminophenyl, B is isopropyl, A is single bond, Y0 is 4 amidinobenzyl, R 1 is hydrido, and X 0 is hydrido; 257 WO 00/69826 PCT/US00/08220 R 2 is 3-aminophenyl, B is ethyl, A is single bond, Y 0 is 4-amidinobenzyl, R 1 is hydrido, and X 0 is hydrido; R 2 is 3-aminophenyl, B is ethyl, A is single bond, Y 0 is 4-amidino-2 fluorobenzyl, R 1 is hydrido, and X 0 is hydrido; 5 R 2 is 3-aminophenyl, B is 2-propenyl, A is single bond, Y0 is 4 amidinobenzyl, R 1 is hydrido, and X 0 is hydrido; R 2 is 3-aminophenyl, B is isopropyl, A is single bond, YO 0 is 4-amidino-2 fluorobenzyl, R 1 is hydrido, and X 0 is hydrido; R 2 is 3 -aminophenyl, B is isopropyl, A is single bond, YO 0 is 4 10 amidinobenzyl, R 1 is hydrido, and X 0 is hydrido; R 2 is 3-aminophenyl, B is 2-butyl, A is single bond, Y 0 is 4 amidinobenzyl, R 1 is hydrido, and X 0 is hydrido; R 2 is 3-aminophenyl, B is (R)-2-butyl, A is single bond, Yo 0 is 4 amidinobenzyl, R 1 is hydrido, and X 0 is hydrido; 15 R 2 is 3-aminophenyl, B is 2-propynyl, A is single bond, Y 0 is 4 amidinobenzyl, R 1 is hydrido, and X 0 is hydrido; R 2 is 3-aminophenyl, B is 3-pentyl, A is single bond, Y 0 is 4 amidinobenzyl, R 1 is hydrido, and X 0 is hydrido; R 2 is 3-aminophenyl, B is hydrido, A is CH2, Y 0 is 4-amidinobenzyl, R 1 20 is hydrido, and X 0 is hydrido; R 2 is 3-aminophenyl, B is ethyl, A is CH 2 , Y 0 is 4-amidinobenzyl, R 1 is hydrido, and X 0 is hydrido; R 2 is 3-aminophenyl, B is 2-methypropyl, A is single bond, Y0 is 4 amidinobenzyl, R 1 is hydrido, and X 0 is hydrido; 258 WO 00/69826 PCT/US00/08220 R 2 is 3-aminophenyl, B is 2-propyl, A is CH 3 CH, Y 0 is 4-amidinobenzyl, R 1 is hydrido, and X 0 is hydrido; R 2 is 3-aminophenyl, B is propyl, A is single bond, Y0 is 4-amidino-2 fluorobenzyl, R 1 is hydrido, and X 0 is hydrido; 5 R 2 is 3-aminophenyl, B is 6-amidocarbonylhexyl, A is single bond, Y0 is 4-amidinobenzyl, R 1 is hydrido, and X 0 is hydrido; R 2 is 3-aminophenyl, B is tert-butyl, A is single bond, Y0 is 4 amidinobenzyl, R 1 is hydrido, and X 0 is hydrido; R 2 is 3-aminophenyl, B is tert-butyl, A is single bond, Y0 is 4 10 amidinobenzyl, R 1 is hydrido, and X 0 is hydrido; R 2 is 3-aminophenyl, B is 3-hydroxypropyl, A is single bond, Y0 is 4 amidinobenzyl, R 1 is hydrido, and X 0 is hydrido; R 2 is 3-aminophenyl, B is 2-methylpropyl, A is single bond, Y0 is 4 amidino-2-fluorobenzyl, R 1 is hydrido, and X 0 is hydrido; 15 R 2 is 3-aminophenyl, B is butyl, A is single bond, Y0 is 4-amidinobenzyl, R 1 is hydrido, and X 0 is hydrido; R 2 is 3-aminophenyl, B is 3 -methoxy-2-propyl, A is single bond, Y0 is 4 amidinobenzyl, R 1 is hydrido, and X 0 is hydrido; R 2 is 3-aminophenyl, B is 3-methoxy-2-propyl, A is single bond, Y0 is 4 20 amidinobenzyl, R 1 is hydrido, and X 0 is hydrido; R 2 is 3-aminophenyl, B is 2-methoxy-2-ethyl, A is single bond, Y0 is 4 amidinobenzyl, R 1 is hydrido, and X 0 is hydrido; R 2 is 3-aminophenyl, B is 2-propyl, A is single bond, Y 0 is 5-amidino-2 thienylmethyl, R 1 is hydrido, and X 0 is hydrido; 259 WO 00/69826 PCT/US00/08220 R 2 is 3-aminophenyl, B is 2-propyl, A is single bond, Y0 is 4-amidino-3 fluorobenzyl, R 1 is hydrido, and X 0 is hydrido; R 2 is 3-carboxyphenyl, B is 2-propyl, A is single bond, Y is 4 amidinobenzyl, R 1 is hydrido, and X 0 is hydrido; 5 R 2 is 3-aminophenyl, B is 2-propyl, A is single bond, Y0 is 4-amidino-3 fluorobenzyl, R 1 is hydrido, and X 0 is hydrido; R 2 is 3-aminophenyl, B is 2,2,2-trifluoroethyl, A is single bond, Y0 is 4 amidinobenzyl, R 1 is aminomethyl, and X 0 is hydrido; R 2 is 3-aminophenyl, B is (S)-2-butyl, A is single bond, Y0 is 4 10 amidinobenzyl, R 1 is aminomethyl, and X 0 is hydrido; R 2 is 5-amino-2-fluorophenyl, B is isopropyl, A is single bond, Y0 is 4 amidinobenzyl, R 1 is aminomethyl, and X 0 is hydrido; R 2 is 2-methyl-3-aminophenyl, B is isopropyl, A is single bond, Y0 is 4 amidinobenzyl, R 1 is aminomethyl, and X 0 is hydrido; 15 R 2 is 3-aminophenyl, B is ethyl, A is single bond, Y0 is 4-amidinobenzyl, R 1 is aminomethyl, and X 0 is hydrido; R 2 is 3-aminophenyl, B is ethyl, A is single bond, Y 0 is 4-amidino-2 fluorobenzyl, R 1 is aminomethyl, and X 0 is hydrido; R 2 is 3-aminophenyl, B is 2-propenyl, A is single bond, Y0 is 4 20 amidinobenzyl, R 1 is aminomethyl, and X 0 is hydrido; R 2 is 3-aminophenyl, B is isopropyl, A is single bond, Y 0 is 4-amidino-2 fluorobenzyl, R 1 is aminomethyl, and X 0 is hydrido; R 2 is 3-aminophenyl, B is isopropyl, A is single bond, Y0 is 4 amidinobenzyl, R 1 is aminomethyl, and X 0 is hydrido; 260 WO 00/69826 PCT/US00/08220 R 2 is 3-aminophenyl, B is 2-butyl, A is single bond, Y 0 is 4 amidinobenzyl, R 1 is aminomethyl, and X 0 is hydrido; R 2 is 3-aminophenyl, B is (R)-2-butyl, A is single bond, Y0 is 4 amidinobenzyl, R 1 is aminomethyl, and X 0 is hydrido; 5R 2 is 3-aminophenyl, B is 2-propynyl, A is single bond, Y0 is 4 amidinobenzyl, R 1 is aminomethyl, and X 0 is hydrido; R 2 is 3-aminophenyl, B is 3-pentyl, A is single bond, Y 0 is 4 amidinobenzyl, R 1 is amrninomethyl, and X 0 is hydrido; R 2 is 3-aminophenyl, B is hydrido, A is CH 2 , Yo 0 is 4-amidinobenzyl, R 1 10 is aminomethyl, and X 0 is hydrido; R 2 is 3-aminophenyl, B is ethyl, A is CH 2 , Y 0 is 4-amidinobenzyl, R 1 is aminomethyl, and X 0 is hydrido; R 2 is 3-aminophenyl, B is 2-methypropyl, A is single bond, Y0 is 4 amidinobenzyl, R 1 is aminomethyl, and X 0 is hydrido; 15 R 2 is 3-aminophenyl, B is 2-propyl, A is CH 3 CH, Y 0 is 4-amidinobenzyl, R 1 is aminomethyl, and X 0 is hydrido; R 2 is 3-aminophenyl, B is propyl, A is single bond, Y0 is 4-amidino-2 fluorobenzyl, R 1 is aminomethyl, and X 0 is hydrido; R 2 is 3-aminophenyl, B is 6-amidocarbonylhexyl, A is single bond, Y 0 is 20 4-amidinobenzyl, R 1 is aminomethyl, and X 0 is hydrido; R 2 is 3-aminophenyl, B is tert-butyl, A is single bond, Y 0 is 4 amidinobenzyl, R 1 is aminomethyl, and X 0 is hydrido; R 2 is 3-aminophenyl, B is tert-butyl, A is single bond, Y 0 is 4 amidinobenzyl, R 1 is aminomethyl, and X 0 is hydrido; 261 WO 00/69826 PCT/US00/08220 R 2 is 3-aminophenyl, B is 3-hydroxypropyl, A is single bond, Yo 0 is 4 amidinobenzyl, R 1 is aminomethyl, and X 0 is hydrido; R 2 is 3-aminophenyl, B is 2-methylpropyl, A is single bond, YO is 4 amidino-2-fluorobenzyl, R 1 is aminomethyl, and X 0 is hydrido; 5 R 2 is 3-aminophenyl, B is butyl, A is single bond, Y is 4-amidinobenzyl, R 1 is aminomethyl, and X 0 is hydrido; R 2 is 3-aminophenyl, B is 3-methoxy-2-propyl, A is single bond, Yo 0 is 4 amidinobenzyl, R 1 is aminomethyl, and X 0 is hydrido; R 2 is 3-aminophenyl, B is 3-methoxy-2-propyl, A is single bond, Y 0 is 4 10 amidinobenzyl, R 1 is aminomethyl, and X 0 is hydrido; R 2 is 3-aminophenyl, B is 2-methoxy-2-ethyl, A is single bond, Y 0 is 4- amidinobenzyl, R 1 is aminomethyl, and X 0 is hydrido; R 2 is 3-aminophenyl, B is 2-propyl, A is single bond, Y 0 is 5-amidino-2 thienylmethyl, R 1 is aminomethyl, and X 0 is hydrido; 15 R 2 is 3-aminophenyl, B is 2-propyl, A is single bond, Y 0 is 4-amidino-3 fluorobenzyl, R 1 is aminomethyl, and X 0 is hydrido; R 2 is 3-carboxyphenyl, B is 2-propyl, A is single bond, Y 0 is 4 amidinobenzyl, R 1 is aminomethyl, and X 0 is hydrido; R 2 is 3-aminophenyl, B is 2-propyl, A is single bond, Y0 is 4-amidino-3 20 fluorobenzyl, R 1 is aminomethyl, and X 0 is hydrido.
25. The compound as recited in Claim 2 having the Formula: 262 WO 00/69826 PCT/US00/08220 R 1 Xo R 2 B A N N NyO H H 0 or a pharmaceutically acceptable salt thereof, wherein; B is selected from the group consisting of C3-C7 cycloalkyl and C4 saturated heterocyclyl, wherein each ring carbon is optionally substituted with 5 R 33 , a ring carbon other than the ring carbon at the point of attachment of B to A is optionally substituted with oxo provided that no more than one ring carbon is substituted by oxo at the same time, ring carbon sand a nitrogen adjacent to the carbon atom at the point of attachment is optionally substituted with R 9 or 139 R 3 , a ring carbon or nitrogen adjacent to the R position and two atoms from 10 10 the point of attachment is optionally substituted with R 10, a ring carbon or nitrogen adjacent to the R 13 position and two atoms from the point of 12 attachment is optionally substituted with R 12 , a ring carbon three atoms from the point of attachment and adjacent to the RI 0 position is optionally substituted with R , a ring carbon three atoms from the point of attachment 15 and adjacent to the R 12 position is optionally substituted with R 3 3 , and a ring carbon atoms from the point of attachment and adjacent to the Rl and R 3 3 positions is optionally substituted with R34 9 11 13 R 9 , R , and R 13 are independently selected from the group consisting of hydrido, hydroxy, amino, amidino, guanidino, lower 20 alkylamino, alkylthio, alkylsulfonamido, alkylsulfinyl, alkylsulfonyl, 263 WO 00/69826 PCT/US00/08220 amidosulfonyl, monoalkyl amidosulfonyl, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboxy, carboxamido, and cyano; R 10 and R 12 are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkyl, alkoxy, 5 hydroxy, amino, alkoxyamino, lower alkylamino, alkylsulfonamido, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, hydroxyalkyl, aminoalkyl, carboalkoxy, carboxy, carboxyalkyl, amidocarbonyl, halo, haloalkyl, and cyano; 33 34 R33 and R 3 4 are independently selected from the group consisting of 10 hydrido, acetamido, haloacetamido, amidino, guanidino, alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, alkylthio, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboalkoxy, carboxy, carboxamido, cyano, and Qb A is selected from the group consisting of single covalent bond and 15 (CH(R 15))pa-(W 7)rr wherein rr is an integer selected from 0 through 1, pa is 7 an integer selected from 0 through 3, and W is selected from the group consisting of (R7)NC(O) and N(R7); R 7 is selected from the group consisting of hydride, hydroxy and alkyl; RI is selected from the group consisting of hydrido, hdralo, alkylxy and alkyl; R 15is selected from the group consisting of hydrido, halo, alkyl, and 20 haloalkyl; R 1 and X 0 are independently selected from the group consisting of hydrido, hydroxy, hydroxyamino, amidino, amino, cyano, hydroxyalkyl, alkoxy, alkyl, alkylamino, aminoalkyl, alkylthio, alkoxyamino, haloalkyl, haloalkoxy, and halo; 25 R 2 is Zo-Q; Z is selected from the group consisting of a covalent single bond, O, S, NH, and CH 2 ; 264 WO 00/69826 PCT/US00/08220 Q is selected from the group consisting of aryl and heteroaryl wherein a carbon adjacent to the carbon at the point of attachment is optionally substituted 9 by R 9 , the other carbon adjacent to the carbon at the point of attachment is 13 9 optionally substituted by R 13 , a carbon adjacent to R and two atoms from the 5 carbon at the point of attachment is optionally substituted by R , a carbon adjacent to R 13 and two atoms from the carbon at the point of attachment is optionally substituted by R 12 , and any carbon adjacent to both R1 0 and R 12 is optionally substituted by R 1 1 YO is formula (IV): S R17 * R 1 8 R 6R 1 5 R162, 2 R1 9 10 Qb IV) 5 65 6 wherein D , D 6 , J , and J are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more 2 5 65 6 than one is a covalent bond, K is C, no more than one of D 5 , D 6 , J and J6 5 65 6 5 65 6 is O, no more than one of D 5 , D 6 , and J6 is S, one of D , D 6 J and J 5 65 6 15 must be a covalent bond when two of D 5 , D 6 , J , and J6 are 0 and S, and no 5 65 6 more than four of D , D 6 , and J are N; 16, 17, 18, 19gru R 6 , R 17 , R 18 , and R 9 are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, haloalkylthio, alkoxy, hydroxy, amino, lower alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, 265 WO 00/69826 PCT/US00/08220 alkanoyl, haloalkanoyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, and cyano; R 16 and R 19 are optionally Qb with the proviso that no more than one of R 16 and R 19 is Qb at the same time and that Qb is Qbe Qb is selected from the group consisting of NR20R21, be wherein Qbe is 25 23 24 2 hydrido, and C(NR )NR R24, with the provisos that no more than one of R 2 0 and R 2 1 is hydroxy at the same time and that no more than one of R 23 and R 2 4 is hydroxy at the same time; 20 21 23 24 25 R 2 0 , R 2 1 , R , R 24 , and R are independently selected from the group 10 consisting of hydrido, alkyl, and hydroxy; QS is selected from the group consisting of a single covalent bond, CH 2 , and CH 2 CH 2 .
26. The compound as recited in Claim 25 or a pharmaceutically acceptable salt 15 thereof, wherein; B is selected from the group consisting of cyclopropyl, cyclobutyl, oxetan-3-yl, azetidin-1-yl, azetidin-2-yl, azetidin-3-yl, thiaetan-3-yl, cyclopentyl, cyclohexyl, norbornyl, bicyclo[3.1.0]hexan-6-yl, and 33 cycloheptyl, wherein each ring carbon is optionally substituted with R 33 , ring 20 carbons and a nitrogen adjacent to the carbon atom at the point of attachment is 9 13 optionally substituted with R or R 13 , a ring carbon or nitrogen adjacent to the R position and two atoms from the point of attachment is optionally substituted with R 10 , and a ring carbon or nitrogen adjacent to the R 3 position and two atoms from the point of attachment is optionally substituted 12 25 with R12 266 WO 00/69826 PCT/US00/08220 R9, 1 1 an 13 R , R, and R are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, N-methylamino, N,N-dimethylamino, N-ethylamino, methylthio, ethylthio, isopropylthio, 5 trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, 2,2,3,3,3 pentafluoropropyl, trifluoromethoxy, 1,1, 2 ,2-tetrafluoroethoxy, fluoro, chloro, bromo, methanesulfonamido, amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl, 1 -hydroxyethyl, 2 hydroxyethyl, 2,2,2-trifluoro-1-hydroxyethyl, amidocarbonyl, N 10 methylamidocarbonyl, N,N-dimethylamidocarbonyl, and cyano; R 10 and R 12 are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, carboxymethyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, methoxyamino, ethoxyamino, acetarnido, trifluoroacetamido, aminomethyl, 1 15 aminoethyl, 2-aminoethyl, N-methylamino, dimethylamino, N-ethylamino, methanesulfonamido, amidosulfonyl, N-methylamidosulfonyl, N,N dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro-1-hydroxyethyl, methoxycarbonyl, ethoxycarbonyl, amidocarbonyl, N-methylamidocarbonyl, N,N-dimethylamidocarbonyl, 20 fluoro, chloro, bromo, and cyano; 33 34 R and R 3 4 are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, methoxyamino, ethoxyamino, acetamido, trifluoroacetamido, N-methylamino, dimethylamino, N-ethylamino, 25 methylthio, ethylthio, isopropylthio, trifluoromethyl, pentafluoroethyl, 2,2,2 trifluoroethyl, 2,2,3,3 3 -pentafluoropropyl, trifluoromethoxy, 1,1,2,2 tetrafluoroethoxy, fluoro, chloro, bromo, amidosulfonyl, N methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl, 1 hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro-1-hydroxyethyl, 30 methoxycarbonyl, ethoxycarbonyl, amidocarbonyl, N-methylamidocarbonyl, N,N-dimethylamidocarbonyl, cyano, and Qb 267 WO 00/69826 PCT/US00/08220 A is selected from the group consisting of single covalent bond, NH, N(CH 3 ), N(OH), CH 2 , CH 3 CH, CF 3 CH, NHC(O), N(CH 3 )C(O), C(O)NH, C(O)N(CH 3 ), CH 2 CH 2 , CH 2 CH 2 CH 2 , CH 3 CHCH 2 , and CF 3 CHCH 2 ; 5 R 1 and X 0 are independently selected from the group consisting of hydrido, hydroxy, amino, amidino, hydroxyamino, aminomethyl, 1 aminoethyl, methylamino, dimethylamino, cyano, methyl, ethyl, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, methoxy, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, methoxyamino, methylthio, 10 ethylthio, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro, and bromo; R 2 is Zo-Q; Z is selected from the group consisting of a covalent single bond, O, S, NH, and CH 2 ; 15 Q is selected from the group consisting of phenyl, 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyrrolyl, 3 -pyrrolyl, 2-imidazolyl, 4-imidazolyl, 3 pyrazolyl, 4-pyrazolyl, 2-thiazolyl, 3-isoxazolyl, 5-isoxazolyl, 2-pyridyl, 3 pyridyl, 4-pyridyl, 2-pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, and 1, 3 ,5-triazin-2-yl, wherein a carbon adjacent 9 20 to the carbon at the point of attachment is optionally substituted by R 9 , the other carbon adjacent to the carbon at the point of attachment is optionally 13 9 substituted by R 3 , a carbon adjacent to R and two atoms from the carbon at 10 the point of attachment is optionally substituted by R 10 , a carbon adjacent to R 13 and two atoms from the carbon at the point of attachment is optionally 12 10 12 25 substituted by R 12 , and any carbon adjacent to both R 0 and R 2 is optionally substituted by Rl Yo is selected from the group consisting of: 268 WO 00/69826 PCT/US00/08220 1-Qb -4-QS-2-R16-3-R17-5-R18-6-R 19 benzene, 2-Qb-5-Qs-6-R 17-4-R 18-2-R 19pyridine, 3-Qb _6_Qs -2-R16_-5-R 18 -4-R 19pyridine, 2-Qb -4-QS-3-R 16-6-R 18pyrazine, 3 b s 18 18 19 Q-6-Q -2-R 18-5-R 18-4-R 19pyridazine, 5 2-Qb-5-Q S-6-R 17-4-R 18pyrimidine, 5-Qb_-2-QS-3-R 16-6-R 19pyrimidine, 3-Qb-5-Q s-4-R 16-2-R 19thiophene, 2-Qb_5-Qs-3-R16 -4-R 17thiophene, 3-Qb_5-Qs-4-R 16_2-R 19furan, 2-Qb -5-Q s-3-R 16-4-R 17furan, 3-Qb-5-Q S-4-R 16-2-R 19pyrrole, 2-Qb_5-Q S-3-R 16-4-R 17pyrrole, 4-Qb-2-Qs-5-R 19imidazole, 2-Qb 4QS-5-R 17imidazole, b s 16 b s 1 10 3-Q -b5-Q -4-R 16isoxazole, 5-Qb-3-Qs-4-R 16isoxazole, 2-Qb -5-Qs-4R 16pyrazole, 4-Qb-2-Qs-5-R 19thiazole, and 2-Qb 5-Q s- 4-R 17thiazole; 16 17 18 19 R 16 , R 17 , R 18 , and R 19 are independently selected from the group consisting of hydrido, methyl, ethyl, isopropyl, propyl, carboxy, amidino, 15 guanidino, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, aminomethyl, 1-aminoethyl, 2-aminoethyl, N-methylamino, dimethylamino, N-ethylamino, methylthio, ethylthio, isopropylthio, trifluoromethylthio, methylsulfinyl, ethylsulfinyl, methylsulfonyl, ethylsulfonyl, trifluoromethyl, pentafluoroethyl, 2 ,2,2-trifluoroethyl, 2,2,3,3,3-pentafluoropropyl, 20 trifluoromethoxy, 1,1, 2 , 2 -tetrafluoroethoxy, fluoro, chloro, bromo, amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro- 1 hydroxyethyl, and cyano; R16 an 19 Qb R6 and R19 are optionally Qb with the proviso that no more than one of 25 R 16 and R 19 is Qb at the same time and that Qb is Qbe 269 WO 00/69826 PCT/US00/08220 Qb is selected from the group consisting of Qbe wherein Qbe is hydride CD C wherein Q is hydrido and C(NR 25)NR23 R24, with the proviso that no more than one of R 23 and R 24 is hydroxy at the same time; 23 24 25 R , R 24 , and R are independently selected from the group consisting of 5 hydrido, methyl, ethyl, and hydroxy; QS is selected from the group consisting of a single covalent bond, CH, and CH 2 CH 2 .
27. The compound as recited in Claim 26 or a pharmaceutically acceptable salt 10 thereof, wherein; B is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 2-(2R)-bicyclo[2.2. 1]-heptyl, oxetan-3 yl, azetidin-1-yl, azetidin-2-yl, azetidin-3-yl,and bicyclo[3.1.0]hexan-6-yl; A is selected from the group consisting of single covalent bond, CH2 15 NHC(O), CH 2 CH 2 , and CH 2 CH 2 CH 2 ; R1 and X 0 are independently selected from the group consisting of hydrido, hydroxy, amino, amidino, hydroxyamino, aminomethyl, methylamino, cyano, methyl, trifluoromethyl, methoxy, hydroxymethyl, methoxyamino, methylthio, trifluoromethoxy, fluoro, and chloro; 20 R 2 is Zo-Q; S is selected from the group consisting of a covalent single bond, O, S, NH, and CH 2 ; Q'is selected from the group consisting of 5-amino-3 amidocarbonylphenyl, 5-amino-2-fluorophenyl, 3-amino-5 25 hydroxymethylphenyl, 5-amino-3-methoxycarbonylphenyl, 3-amidinophenyl, 3-amino-2-methylphenyl, 5-amino-2-methylthiophenyl, 3-aminophenyl, benzyl, 3-carboxyphenyl, 3 -carboxy-5-aminophenyl, 3-carboxy-5 hydroxyphenyl, 3 -carboxymethyl-5-aminophenyl, 3-carboxymethyl-5 hydroxyphenyl, 3 -carboxymethylphenyl, 3-chlorophenyl, 2-chlorophenyl, 270 WO 00/69826 PCT/US00/08220 2,6-dichlorophenyl, 3-cyanophenyl, 3 -dimethylaminophenyl, 2-fluorophenyl, 3-fluorophenyl, 2,5-difluorophenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 3 methanesulfonylaminophenyl, 2 -methoxyphenyl, 3-methoxyphenyl, 3 methoxyaminophenyl, 3 -methoxycarbonylphenyl, 2 -methylaminophenyl, 3 5 methylaminophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, phenyl, 3 -trifluoroacetamidophenyl, 3 -trifluoromethylphenyl, 2 trifluoromethylphenyl, 5-amino-2-thienyl, 5-amino-3-thienyl, 3-bromo-2 thienyl, 3-pyridyl, 4-pyridyl, 2-thienyl, and 3-thienyl; Yo is selected from the group consisting of: 10 1-Qb 4-QS-2-R 16-3-R 17-5-R 18-6-R 19benzene, 2-Qb -5-Q s -6-R 17 -4-R 18 -2-R 19 pyridine, b s 16 18 19 3-Q -6-Q -2-R 16-5-R 18-4-R 19pyridine, 3-Qb -5-Qs-4-R16-2-R19thiophene, and 2-Qb-5-QS-3-R16 -4-R 17thiophene; R 16 and R 19 are independently selected from the group consisting of 15 hydrido, amidino, amino, aminomethyl, methoxy, methylamino, hydroxy, hydroxymethyl, fluoro, chloro, and cyano; R16 an 19 Qb R16 and R9 are optionally Qb with the proviso that no more than one of R 16 and R 19 is Qb at the same time and that Qb is Qbe R 17 and R 18 are independently selected from the group consisting of 20 hydrido, fluoro, chloro, hydroxy, hydroxymethyl, amino, carboxy, and cyano; Qb is selected from the group consisting of Qbe wherein Qbe is hydrido and C(NR25)NR R2324 23, 24, 25 o R , R 24 , and R 2 5 are independently selected from the group consisting of hydrido and methyl; 25 Qs is CH2
28. The compound as recited in Claim 25 having the Formula: 271 WO 00/69826 PCT/US00/08220 1 R2 0 B N HIH O 0 or a pharmaceutically acceptable salt thereof, wherein; B is selected from the group consisting of C3-C7 cycloalkyl and C4 saturated heterocyclyl, wherein each ring carbon is optionally substituted with 33 5 R 3 3 , a ring carbon other than the ring carbon at the point of attachment of B to A is optionally substituted with oxo provided that no more than one ring carbon is substituted by oxo at the same time, ring carbons and a nitrogen adjacent to the carbon atom at the point of attachment is optionally substituted with R or 139 R 3 , a ring carbon or nitrogen adjacent to the R position and two atoms from 10 10 the point of attachment is optionally substituted with R 10 , a ring carbon or nitrogen adjacent to the R 13 position and two atoms from the point of 12 attachment is optionally substituted with R 12 , a ring carbon three atoms from the point of attachment and adjacent to the R1 0 position is optionally substituted with Rl, a ring carbon three atoms from the point of attachment 15 and adjacent to the R 12 position is optionally substituted with R 3 3 , and a ring carbon four atoms from the point of attachment and adjacent to the Rl and R 3 3 positions is optionally substituted with R34 9 11 13 R , R , and R are independently selected from the group consisting of hydrido, hydroxy, amino, amidino, guanidino, lower 20 alkylamino, alkylthio, alkoxy, alkylsulfinyl, alkylsulfonyl, amidosulfonyl, 272 WO 00/69826 PCT/US00/08220 monoalkyl amidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboxy, carboxamido, and cyano; R 10 and R 12 are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkyl, alkoxy, 5 alkoxyamino, aminoalkyl, hydroxy, amino, lower alkylamino, alkylsulfonamido, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, hydroxyalkyl, aminoalkyl, halo, haloalkyl, carboalkoxy, carboxy, carboxyalkyl, carboxyamido, and cyano; R 33 and R 34 are independently selected from the group consisting of 10 hydrido, amidino, guanidino, alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, alkylthio, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboalkoxy, carboxy, carboxamido, and cyano; R 33 is optionally Qb 15 A is selected from the group consisting of single covalent bond and (CH(R15 ))pa-(W 7)rr wherein rr is an integer selected from 0 through 1, pa is an integer selected from 0 through 3, and W 7 is N(R7 7 R is selected from the group consisting of hydrido and alkyl; R 15 is selected from the group consisting of hydrido, halo, alkyl, and 20 haloalkyl; R 1 and X 0 are independently selected from the group consisting of hydrido, hydroxy, hydroxyamino, amidino, amino, cyano, hydroxyalkyl, alkoxy, alkyl, alkylamino, aminoalkyl, alkylthio, alkoxyamino, haloalkyl, haloalkoxy, and halo; 25 R 2 is Zo-Q; Z is a covalent single bond; Q is selected from the group consisting of aryl and heteroaryl wherein a carbon adjacent to the carbon at the point of attachment is optionally substituted by R , the other carbon adjacent to the carbon at the point of attachment is 273 WO 00/69826 PCT/US00/08220 optionally substituted by R 13 , a carbon adjacent to R and two atoms from the 10 carbon at the point of attachment is optionally substituted by R 10 , a carbon 13 adjacent to R3 and two atoms from the carbon at the point of attachment is optionally substituted by R 12 , and any carbon adjacent to both R 10 and R 12 is 5 optionally substituted by R 1 1 9 11 13 R 9 , R 11, and R 3 are independently selected from the group consisting of hydrido, hydroxy, amino, amidino, guanidino, lower alkylamino, alkylthio, alkoxy, alkylsulfinyl, alkylsulfonyl, amidosulfonyl, monoalkylamidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, 10 carboxy, carboxamido, and cyano; R10 and R 12 are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkyl, alkoxy, alkoxyamino, aminoalkyl, hydroxy, amino, lower alkylamino, alkylsulfonamido, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl 15 amidosulfonyl, hydroxyalkyl, aminoalkyl, halo, haloalkyl, carboalkoxy, carboxy, carboxyamido, carboxyalkyl, and cyano; Yo is formula (IV): S R17 R1 8 J R 6R R 16/D 5 , K2/ D 6 ,, R19 lb Q (IV) 5 65 6 wherein D , D 6 , J , and J6 are independently selected from the group 20 consisting of C, N, O, S and a covalent bond with the provisos that no more 2 5 65 6 than one is a covalent bond, K is C, no more than one of D , D 6 , J , and J6 274 WO 00/69826 PCT/US00/08220 5 65 6 5 65 6 is O, no more than one of DS, D , j, and J is S, one of D , D 6 , and J 5 65 6 must be a covalent bond when two of D , D 6 , J , and J6 are O and S, and no 5 65 6 more than four of D , D 6 , and J are N; 16 17 18 19 R 6 , R 17 , R 18 , and R 19 are independently selected from the group 5 consisting of hydrido, amidino, guanidino, carboxy, haloalkylthio, alkoxy, hydroxy, amino, lower alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, and cyano; R 16 and R 19 are optionally Qb with the proviso that no more than one of 10 R 16 and R 19 is Qb at the same time and that Qb is Qbe Qbis selected from the group consisting of NR 20 R 2 1 , Qbe wherein Qbe is 25 224 hydrido, and C(NR )NR3R24 20 21 23 24 25 R 2 0 , R 2 1 , R , R 2 4 , and R are independently selected from the group consisting of hydrido and alkyl; 15 Q is CH2.
29. The compound as recited in Claim 28 or a pharmaceutically acceptable salt thereof, wherein; B is selected from the group consisting of cyclopropyl, cyclobutyl, 20 cyclopentyl, cyclohexyl, cycloheptyl, 2-(2R)-bicyclo[2.2.1 ]-heptyl, oxetan-3 yl, azetidin-1-yl, azetidin-2-yl, azetidin-3-yl, and bicyclo[3.1.0]hexan-6-yl, wherein each ring carbon is optionally substituted with R 3 3 , ring carbons and a nitrogen atoadjacent to the carbon atom at the point of attachment is optionally 9 139 substituted with R or R 13 , a ring carbon or nitrogen adjacent to the R 25 position and two atoms from the point of attachment is optionally substituted 275 WO 00/69826 PCT/US00/08220 10 13 with R 10 , and a ring carbon or nitrogen adjacent to the R 13 position and two atoms from the point of attachment is optionally substituted with R12 9 , R11 an 13 R 9, R , and R13 are independently selected from the group consisting of hydrido, methyl, ethyl, methoxy, ethoxy, hydroxy, amino, N-methylamino, 5 N,N-dimethylamino, methylthio, trifluoromethyl, pentafluoroethyl, 2,2,2 trifluoroethyl, fluoro, chloro, bromo, amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, amidocarbonyl, N-methylamidocarbonyl, carboxy, and cyano; R10 and R 12 are independently selected from the group consisting of 10 hydrido, amidino, amidocarbonyl, N-methylamidocarbonyl, guanidino, methyl, ethyl, methoxy, ethoxy, hydroxy, hydroxymethyl, 1-hydroxyethyl, 2 hydroxyethyl, carboxy, carboxymethyl, amino, acetamido, trifluoromethyl, pentafluoroethyl, 2 ,2,2-trifluoroethyl, trifluoroacetamido, aminomethyl, N methylamino, dimethylamino, amidosulfonyl, N-methylamidosulfonyl, N,N 15 dimethylamidosulfonyl, methoxycarbonyl, fluoro, chloro, bromo, and cyano; R 33 are independently selected from the group consisting of hydrido, amidino, guanidino, methyl, ethyl, methoxy, ethoxy, hydroxy, carboxy, amino, N-methylamino, dimethylamino, methylthio, ethylthio, trifluoromethyl, pentafluoroethyl, 2 ,2,2-trifluoroethyl, fluoro, chloro, bromo, amidosulfonyl, 20 N-methylamidosulfonyl, hydroxymethyl, amidocarbonyl, cyano, and Qb A is selected from the group consisting of single covalent bond, NH, N(CH 3 ), CH 2 , CH 3 CH, CH 2 CH 2 , and CH 2 CH 2 CH 2 ; X 0 is selected from the group consisting of hydrido, hydroxy, amino, amidino, aminomethyl, cyano, methyl, trifluoromethyl, hydroxymethyl, and 25 fluoro; R 1 is selected from the group consisting of hydrido, hydroxy, amino, aminomethyl, methylamino, cyano, methyl, trifluoromethyl, methoxy, methylthio, trifluoromethoxy, fluoro, and chloro; R 2 is selected from the group consisting of phenyl, 2-thienyl, 2-furyl, 30 2-pyrrolyl, 2-imidazolyl, 2-thiazolyl, 3-isoxazolyl, 2 -pyridyl, and 3-pyridyl, 276 WO 00/69826 PCT/US00/08220 wherein a carbon 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 13 9 attachment is optionally substituted by R 13 , a carbon adjacent to R and two atoms from the carbon at the point of attachment is optionally substituted by 5 R 10 , a carbon adjacent to R 13 and two atoms from the carbon at the point of 12 attachment is optionally substituted by R 12 , and any carbon adjacent to both R 10 and R 12 is optionally substituted by R 1 1 Yo is selected from the group consisting of: b s 16 1.7 18 19 1-Q -4-Q -2-R 6-3-R17-5-R18-6-R b enzene, b s 17 18 19 b s 16 17 10 2-Q -5-QS-6-R 17-4-R 8-2-R 19pyridine, 2-Qb _5-Q -3-R 16-4-R 17thiophene, 3-Qb -6-QS-2-R 16-5-R 18-4-R 19pyridine, 3-Qb_5-Qs -4-R 16-2-R 19thiophene, 3-Qb 5-QS-4-R 16-2-R 19furan, 2-Qb_5-Q S-3-R 16-4-R 17furan, 3-Qb -5-Q -4-R 16-2-R 19pyrrole, 2-Qb -5-Q -3-R 16-4-R 17pyrrole, b s 9b s 17 4-Qb -2-Qs-5-R19thiazole, and 2-Q -5-Q -4-R 17thiazole; 16 17 18 19 15 R 16 , R 7 , R 18 , 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, 20 trifluoromethoxy, fluoro, chloro, amidosulfonyl, N-methylamidosulfonyl, hydroxymethyl, carboxy, and cyano. b. 20 21 Q is selected from the group consisting of NR20 R and C(NR25)NRR 2 4 , with the proviso that said Qb group is bonded directly to a carbon atom; 277 WO 00/69826 PCTIUS00/08220 20 21 23 24 25 R 20 , R 2 1 , R , R 24 , and R 2 5 are independently selected from the group consisting of hydrido, methyl, and ethyl; Qs is CH 2 * 5 30. The compound as recited in Claim 29 or a pharmaceutically acceptable salt thereof, wherein; B is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2-(2R)-bicyclo[2.2.1]-heptyl, oxetan-3-yl, azetidin-1 yl, azetidin-2-yl,and azetidin-3-yl; 10 A is selected from the group consisting of a single covalent bond, CH 2 , NHC(O), CH 2 CH 2 and CH 2 CH 2 CH 2 ; X 0 is selected from the group consisting of hydrido, hydroxy, amino, amidino, aminomethyl, cyano, methyl, trifluoromethyl, hydroxymethyl, and fluoro; 15 R 1 is selected from the group consisting of hydrido, hydroxy, amino, aminomethyl, cyano, methyl, trifluoromethyl, and fluoro; R 2 is selected from the group consisting of 3-aminophenyl, 2,6 dichlorophenyl, 2-hydroxyphenyl, 5-amino-2-thienyl, and 3-thienyl; Yo is selected from the group consisting of: b s 16 17 18 19 20 1-Q -4-Q -2-R16-3-R 17-5-R 18-6-R 19benzene, b s 16 19 b s 16 17 3-Qb-5-Q -4-R16-2-R 9thiophene, and 2-Qb-5-Q -3-R16-4-R17thiophene; R 16 and R 19 are independently selected from the group consisting of hydrido, amidino, amino, aminomethyl, methoxy, methylamino, hydroxy, hydroxymethyl, fluoro, chloro, and cyano; 25 R 16 and R 19 are optionally Qb with the proviso that no more than one of R 16 and R 19 is Qb at the same time and that Qb is Qbe R 17 and R 18 are independently selected from the group consisting of hydrido, fluoro, chloro, hydroxy, hydroxymethyl, amino, carboxy, and cyano; 278 WO 00/69826 PCT/US00/08220 Qbis selected from the group consisting of Qbe wherein Qbe is hydrido and C(NR25)NR23 R24 23 24 25 R , R 24 , and R are independently selected from the group consisting of hydrido and methyl; 5 Qs is CH 2 .
31. The compound as recited in Claim 30 or a pharmaceutically acceptable salt thereof, wherein; B is selected from the group consisting of cyclopropyl, cyclobutyl, 10 cyclopentyl, cyclohexyl, 2-(2R)-bicyclo[2.2.1 ]-heptyl, oxetan-3-yl, azetidin- 1 yl, azetidin-2-yl,and azetidin-3-yl; A is selected from the group consisting of a single covalent bond, CH 2 , CH 2 CH 2 and CH 2 CH 2 CH 2 ; X 0 is selected from the group consisting of hydrido, hydroxy, amino, 15 amidino, aminomethyl, cyano, methyl, trifluoromethyl, hydroxymethyl, and fluoro; R 1 is selected from the group consisting of hydrido, hydroxy, amino, aminomethyl, cyano, methyl, trifluoromethyl, and fluoro; R 2 is selected from the group consisting of 3-aminophenyl, 2,6 20 dichlorophenyl, 2-hydroxyhenyl, phenyl, 5-amino-2-thienyl, and 3-thienyl; Yo is selected from the group consisting of 5-amidino-2-thienylmethyl, 4-amidinobenzyl, 2-fluoro-4-amidinobenzyl, and 3 -fluoro-4-amdinobenzyl.
32. A compound as recited in Claim 25 where said compound is selected from 25 the group having the Formula: 279 WO 00/69826 PCT/US00/08220 R 1 Xo R2 00 N B N N H H 0 or a pharmaceutically acceptable salt thereof, wherein: R 2 is 3-aminophenyl, B is cycylopropyl, A is single bond, Y 0 is 4 amidinobenzyl, R 1 is aminomethyl, and X 0 is hydrido; 5 R 2 is 3-aminophenyl, B is cyclobutyl, A is single bond, Yo 0 is 4-amidino-2 fluorobenzyl, R 1 is aminomethyl, and X 0 is hydrido; R 2 is 3-aminophenyl, B is cyclobutyl, A is single bond, Y 0 is 4 amidinobenzyl, R 1 is aminomethyl, and X 0 is hydrido; R 2 is 3-aminophenyl, B is cyclopropyl, A is single bond, Y 0 is 4-amidino 10 2-fluorobenzyl, R 1 is aminomethyl, and X 0 is hydrido; R 2 is 3-aminophenyl, B is cyclobutyl, A is single bond, Y 0 is 4 amidinobenzyl, R 1 is aminomethyl, and X 0 is hydrido; R 2 is 3-aminophenyl, B is cyclobutyl, A is single bond, Y 0 is 4-amidino-3 fluorobenzyl, R 1 is aminomethyl, and X 0 is hydrido; 15 R 2 is 3-aminophenyl, B is cyclopentyl, A is single bond, Y 0 is 4 amidinobenzyl, R 1 is aminomethyl, and X 0 is hydrido; R 2 is 5-amino-2-thienyl, B is cyclobutyl, A is single bond, Y 0 is 4 amidinobenzyl, R 1 is aminomethyl, and X 0 is hydrido; R 2 is 3-aminophenyl, B is cyclopropyl, A is CH 2 , YO 0 is 4-amidinobenzyl, 20 R 1 is aminomethyl, and X 0 is hydrido; 280 WO 00/69826 PCT/US00/08220 R 2 is 3-aminophenyl, B is 2-(2R)-bicyclo[2.2.1]-heptyl, A is single bond, Yo is 4-amidinobenzyl, R 1 is aminomethyl, and X 0 is hydrido; R 2 is 3-aminophenyl, B is cyclopentyl, A is single bond, Y0 is 4-amidino 2-fluorobenzyl, R 1 is aminomethyl, and X 0 is hydrido; 5 R 2 is 3-aminophenyl, B is cyclohexyl, A is CH 2 CH 2 , Y 0 is 4 amidinobenzyl, R 1 is aminomethyl, and X 0 is hydrido; R 2 is 2-hydroxyphenyl, B is cyclobutyl, A is single bond, Y0 is 4 amidinobenzyl, R 1 is aminomethyl, and X 0 is hydrido; R 2 is phenyl, B is cyclobutyl, A is single bond, Y 0 is 4-amidinobenzyl, R 1 10 is aminomethyl, and X 0 is hydrido; R 2 is 3-thienyl, B is cyclobutyl, A is single bond, Y 0 is 4 amidinobenzyl, R 1 is aminomethyl, and X 0 is hydrido; R 2 is 2,6-dichlorophenyl, B is cyclobutyl, A is single bond, Y0 is 4 amidinobenzyl, R 1 is amrninomethyl, and X 0 is hydrido; 15 R 2 is 3-aminophenyl, B is cycylopropyl, A is single bond, Y0 is 4 amidinobenzyl, R 1 is hydrido, and X 0 is hydroxymethyl; R 2 is 3-aminophenyl, B is cyclobutyl, A is single bond, Y 0 is 4-amidino-2 fluorobenzyl, R 1 is hydrido, and X 0 is hydroxymethyl; R 2 is 3-aminophenyl, B is cyclobutyl, A is single bond, YO 0 is 4 20 amidinobenzyl, R 1 is hydrido, and X 0 is hydroxymethyl; R 2 is 3-aminophenyl, B is cyclopropyl, A is single bond, Y0 is 4-amidino 2-fluorobenzyl, R 1 is hydrido, and X 0 is hydroxymethyl; R 2 is 3-aminophenyl, B is cyclobutyl, A is single bond, Y 0 is 4 amidinobenzyl, R 1 is hydrido, and X 0 is hydroxymethyl; 281 WO 00/69826 PCT/US00/08220 R 2 is 3-aminophenyl, B is cyclobutyl, A is single bond, Y is 4-amidino-3 fluorobenzyl, R 1 is hydrido, and X 0 is hydroxymethyl; R 2 is 3-aminophenyl, B is cyclopentyl, A is single bond, Y is 4 amidinobenzyl, R 1 is hydrido, and X 0 is hydroxymethyl; 5 R 2 is 5-amino-2-thienyl, B is cyclobutyl, A is single bond, Y0 is 4 amidinobenzyl, R 1 is hydrido, and Xo is hydroxymethyl; R 2 is 3-aminophenyl, B is cyclopropyl, A is CH 2 , Y 0 is 4-amidinobenzyl, R 1 is hydrido, and X 0 is hydroxymethyl; R 2 is 3-aminophenyl, B is 2-(2R)-bicyclo[2.2.1]-heptyl, A is single bond, 10 y0 is 4-amidinobenzyl, R 1 is hydrido, and X 0 is hydroxymethyl; R 2 is 3-aminophenyl, B is cyclopentyl, A is single bond, Yo 0 is 4-amidino 2-fluorobenzyl, R 1 is hydrido, and X 0 is hydroxymethyl; R 2 is 3-aminophenyl, B is cyclohexyl, A is CH 2 CH 2 , Y 0 is 4 amidinobenzyl, R 1 is hydrido, and X 0 is hydroxymethyl; 15 R 2 is 2-hydroxyphenyl, B is cyclobutyl, A is single bond, Y0 is 4 amidinobenzyl, R 1 is hydrido, and X 0 is hydroxymethyl; R 2 is phenyl, B is cyclobutyl, A is single bond, Y0 is 4-amidinobenzyl, R 1 is hydrido, and X 0 is hydroxymethyl; R 2 is 3-thienyl, B is cyclobutyl, A is single bond, Y 0 is 4 20 amidinobenzyl, R 1 is hydrido, and X 0 is hydroxymethyl; R 2 is 2,6-dichlorophenyl, B is cyclobutyl, A is single bond, Y0 is 4 amidinobenzyl, R 1 is hydrido, and X 0 is hydroxymethyl; R 2 is 3-aminophenyl, B is cycylopropyl, A is single bond, Y0 is 4 amidinobenzyl, R 1 is hydroxymethyl, and X 0 is hydrido; 282 WO 00/69826 PCT/US00/08220 R 2 is 3-aminophenyl, B is cyclobutyl, A is single bond, Y is 4-amidino-2 fluorobenzyl, R 1 is hydroxymethyl, and X 0 is hydrido; R 2 is 3-anminophenyl, B is cyclobutyl, A is single bond, Y is 4 amidinobenzyl, R 1 is hydroxymethyl, and X 0 is hydrido; 5R 2 is 3-aminophenyl, B is cyclopropyl, A is single bond, Y0 is 4-amidino 2-fluorobenzyl, R 1 is hydroxymethyl, and X 0 is hydrido; R 2 is 3-aminophenyl, B is cyclobutyl, A is single bond, Y0 is 4 amidinobenzyl, R 1 is hydroxymethyl, and X 0 is hydrido; R 2 is 3-aminophenyl, B is cyclobutyl, A is single bond, Y0 is 4-amidino-3 10 fluorobenzyl, R 1 is hydroxymethyl, and X 0 is hydrido; R 2 is 3-aminophenyl, B is cyclopentyl, A is single bond, Y0 is 4 amniidinobenzyl, R 1 is hydroxymethyl, and X 0 is hydrido; R 2 is 5-amino-2-thienyl, B is cyclobutyl, A is single bond, Y0 is 4 amidinobenzyl, R 1 is hydroxymethyl, and X 0 is hydrido; 15 R 2 is 3-aminophenyl, B is cyclopropyl, A is CH 2 , Y 0 is 4-amidinobenzyl, R 1 is hydroxymethyl, and X 0 is hydrido; R 2 is 3-aminophenyl, B is 2-(2R)-bicyclo[2.2.1]-heptyl, A is single bond, y is 4-amidinobenzyl, R 1 is hydroxymethyl, and X 0 is hydrido; R 2 is 3-aminophenyl, B is cyclopentyl, A is single bond, Y0 is 4-amidino 20 2-fluorobenzyl, R 1 is hydroxymethyl, and X 0 is hydrido; R 2 is 3-aminophenyl, B is cyclohexyl, A is CH 2 CH 2 , Y 0 is 4 amidinobenzyl, R 1 is hydroxymethyl, and X 0 is hydrido; R 2 is 2-hydroxyphenyl, B is cyclobutyl, A is single bond, Y 0 is 4 amidinobenzyl, R 1 is hydroxymethyl, and X 0 is hydrido; 25 283 WO 00/69826 PCT/US00/08220 R 2 is phenyl, B is cyclobutyl, A is single bond, Yo 0 is 4-amidinobenzyl, R 1 is hydroxymethyl, and X 0 is hydrido; R 2 is 3-thienyl, B is cyclobutyl, A is single bond, Y is 4 amidinobenzyl, R 1 is hydroxymethyl, and X 0 is hydrido; 5 R 2 is 2,6-dichlorophenyl, B is cyclobutyl, A is single bond, Y 0 is 4 amidinobenzyl, R 1 is hydroxymethyl, and X 0 is hydrido.
33. The compound as recited in Claim 2 having the Formula: Xo W 0 BNN N/Y B N NN y H H 0 10 or a pharmaceutically acceptable salt thereof, wherein; B is the Formula (V): R 3 4 R 3 3 K R 3 5 R K 2 R 12 R32/D D2" R3 (V) 1 2 12 1 wherein D , D 2 , J1, J2 and K are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more 1 2 12 1 15 than one is a covalent bond, no more than one of D , D 2 , J1, 2 and K isO, 1 2 12 1 1 2 12 no more than one of D, D 2 , 1, J2 and K is S, one of D D , 1, J2 and 284 WO 00/69826 PCT/US00/08220 K1 must be a covalent bond when two ofD 1D , J 1, J2 and K1 are O and S, 1 2 12 1 and no more than four of D , D 2 , J , J2 and K are N; 32 33 34 35 36 R , R , R , R , and R are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, 5 alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, alkylthio, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboalkoxy, carboxy, carboxamido, cyano, and Qb B is optionally selected from the group consisting of hydrido, C2-C8 10 alkyl, C3-C8 alkenyl, C3-C8 alkynyl, and C2-C8 haloalkyl, wherein each member of group B is optionally substituted at any carbon up to and including 6 atoms from the point of attachment of B to A with one or more of the group 32 33 34 35 36 consisting of R 3 2 , R 3 3 , R 3 4 , R 3 5 , and R36 B is selected from the group consisting of C3-C7 cycloalkyl and C4-C6 15 saturated heterocyclyl, wherein each ring carbon is optionally substituted with R33, a ring carbon other than the ring carbon at the point of attachment of B to A is optionally substituted with oxo provided that no more than one ring carbon is substituted by oxo at the same time, ring carbons and nitrogen adjacent to the carbon atom at the point of attachment are optionally substituted with R or 20 R 13, a ring carbon or nitrogen adjacent to the R 9 position and two atoms from the point of attachment is optionally substituted with R , a ring carbon or 13 nitrogen adjacent to the R3 position and two atoms from the point of 12 attachment is optionally substituted with R 2 , a ring carbon or nitrogen three atoms from the point of attachment and adjacent to the RI 0 position is 11 25 optionally substituted with R , a ring carbon or nitrogen three atoms from the point of attachment and adjacent to the R 12 position is optionally 285 WO 00/69826 PCT/US00/08220 substituted with R 33 , and a ring carbon or nitrogen four atoms from the point of attachment and adjacent to the R 11 and R 33 positions is optionally substituted with R 3 4 9 10 11 12 13 R , R , R , R , and R are independently selected from the 5 group consisting of hydrido, acetamido, haloacetamido, alkoxyamino, alkanoyl, haloalkanoyl, amidino, guanidino, alkylenedioxy, haloalkylthio, heteroaryl, heterocyclyl, alkoxy, hydroxy, amino, lower alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylsulfonamido, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, 10 hydroxyalkyl, aminoalkyl, carboalkoxy, carboxyalkyl, carboxy, carboxamido, and cyano; A is selected from the group consisting of single covalent bond and (CH(R15))pa-(W 7)rr wherein rr is an integer selected from 0 through 1, pa is 7 an integer selected from 0 through 3, and W is selected from the group 15 consisting of (R7)NC(O) and N(R7); R 7 is selected from the group consisting of hydrido, hydroxy and alkyl; R 15 is selected from the group consisting of hydrido, halo, alkyl, and haloalkyl; X is selected from the group consisting of hydrido, alkyl, cyano, halo, 20 haloalkyl, haloalkoxy, amino, aminoalkyl, alkylamino, amidino, hydroxy, hydroxyamino, alkoxy, hydroxyalkyl, alkoxyamino, thiol, and alkylthio; W, X, Y, and Z are independently selected from the group consisting of C(R ), C(R 10), C(R 11 ), C(R 12), N, N(R10), O, S and a covalent bond with the provisos that one of W, X, Y, and Z is independently selected to be a 25 covalent bond when one of W, X, Y, and Z is selected from the group consisting of N, N(R 10), O, and S, no more than one of W, X, Y, and Z is optionally selected from the group consisting of O and S, and no more than 286 WO 00/69826 PCT/US00/08220 three of W, X, Y, and Z are optionally selected from the group consisting of N an 10 and N(R0); Y0 is formula (IV): S R17 R! 8 R 1 6 D 5 2 D R19 Rb Q (IV) 5 65 6 5 wherein D , D 6 , J5, and J are independently selected from the group consisting of C, N, 0, S and a covalent bond with the provisos that no more 2. 5 65 6 than one is a covalent bond, K is C, no more than one of D , D 6 , J5, and J 5 6 5 6 5 6 5 6 is 0, no more than one of D , D , J , and J is S, one of D , D , J, and J 5 65 6 must be a covalent bond when two of D , D 6 , J5, and J are O and S, and no 5 65 6 16 17 10 more than four of DS, D , , and J6 are N, with the provisos that R 6, R7 18 19 R 8 , and R 9 are each independently selected to maintain the tetravalent nature of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen; 16 17 18 19 R 6 , R 17 , R 18 , and R 9 are independently selected from the group 15 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; R 16 and R 19 are optionally Qb with the proviso that no more than one 20 of R 16 and R 19 is Qb at the same time and that Qb is Qbe 287 WO 00/69826 PCT/US00/08220 b 20 21 be b Qb is selected from the group consisting of NR20R21, be wherein Qbe is 26 25 23 2425 24 hydrido, N(R26)C(NR25)N(R )(R24), and C(NR25)NR R24, with the provisos that no more than one of R 2 0 and R 2 1 is hydroxy, amino, alkylamino, or dialkylamino at the same time and that no more than one of R 23 and R 24 is 5 hydroxy, amino, alkylamino, or dialkylamino at the same time; 20 21 23 24 25 26 R20, R21, R , R24, R , and R 26 are independently selected from the group consisting of hydrido, alkyl, hydroxy, amino, alkylamino and dialkylamino; Qs is selected from the group consisting of a single covalent bond, CH 2 , and CH 2 CH 2 . 10
34. The compound as recited in Claim 33 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 15 pyrazolyl, 4-pyrazolyl, 2-thiazolyl, 3-isoxazolyl, 5-isoxazolyl, 2-pyridyl, 3 pyridyl, 4-pyridyl, 2-pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, and 1,3,5-triazin-2-yl, wherein a carbon adjacent to the carbon at the point of attachment is optionally substituted by R 3 2 , the other carbon adjacent to the carbon at the point of attachment is optionally 20 substituted by R 3 6 , a carbon adjacent to R 3 2 and two atoms from the carbon at the point of attachment is optionally substituted by R 3 3 , a carbon adjacent to R36 and two atoms from the carbon at the point of attachment is optionally substituted by R 3 5 , and any carbon adjacent to both R 33 and R 3 5 is optionally substituted by R34 25 33 34 35 36 25 R 3 2 , R 3 3 , R 34 , R 3 5 , and R 3 6 are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, methoxy, ethoxy, 288 WO 00/69826 PCT/US00/08220 isopropoxy, propoxy, hydroxy, amino, methoxyamino, ethoxyamino, acetamido, trifluoroacetamido, N-methylamino, dimethylamino, N-ethylamino, methylthio, ethylthio, isopropylthio, trifluoromethyl, pentafluoroethyl, 2,2,2 trifluoroethyl, 2,2,3,3,3-pentafluoropropyl, trifluoromethoxy, 1,1,2,2 5 tetrafluoroethoxy, fluoro, chloro, bromo, amidosulfonyl, N methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl, 1 hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro- 1 -hydroxyethyl, methoxycarbonyl, ethoxycarbonyl, amidocarbonyl, N-methylamidocarbonyl, N,N-dimethylamidocarbonyl, cyano, and Qb 10 B is optionally selected from the group consisting of hydrido, ethyl, 2 propenyl, 2-propynyl, propyl, isopropyl, butyl, 2-butenyl, 3-butenyl, 2 butynyl, sec-butyl, tenrt-butyl, isobutyl, 2 -methylpropenyl, 1-pentyl, 2 pentenyl, 3-pentenyl, 4-pentenyl, 2 -pentynyl, 3 -pentynyl, 2-pentyl, 1-methyl 2-butenyl, 1-methyl-3-butenyl, 1-methyl-2-butynyl, 3-pentyl, 1-ethyl-2 15 propenyl, 2-methylbutyl, 2 -methyl-2-butenyl, 2 -methyl-3-butenyl, 2-methyl-3 butynyl, 3-methylbutyl, 3 -methyl-2-butenyl, 3 -methyl-3-butenyl, 1-hexyl, 2 hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 2-hexyl, 1-methyl-2-pentenyl, 1-methyl-3-pentenyl, 1-methyl-4-pentenyl, 1 methyl-2-pentynyl, 1-methyl-3-pentynyl, 3-hexyl, 1-ethyl-2-butenyl, 1-ethyl 20 3-butenyl, 1-propyl-2-propenyl, 1-ethyl-2-butynyl, 1-heptyl, 2-heptenyl, 3 heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl, 2-heptynyl, 3-heptynyl, 4 heptynyl, 5-heptynyl, 2-heptyl, 1-methyl-2-hexenyl, 1-methyl-3-hexenyl, 1 methyl-4-hexenyl, 1-methyl-5-hexenyl, 1-methyl-2-hexynyl, 1-methyl-3 hexynyl, 1-methyl4-hexynyl, 3-heptyl, 1-ethyl-2-pentenyl, 1-ethyl-3 25 pentenyl, 1-ethyl-4-pentenyl, 1-butyl-2-propenyl, 1-ethyl-2-pentynyl, 1-ethyl 3-pentynyl, 2 ,2,2-trifluoroethyl, 2 ,2-difluoropropyl, 4 -trifluoromethyl-5,5,5 trifluoropentyl, 4-trifluoromethylpentyl, 5,5,6,6,6-pentafluorohexyl, and 3, 3 , 3 -trifluoropropyl, wherein each member of group B is optionally substituted at any carbon up to and including 5 atoms from the point of 30 attachment of B to A with one or more of the group consisting of R 3 2 , R 3 3 R34 , R35 , and R36 B is optionally selected from the group consisting of cyclopropyl, cyclobutyl, oxetan-3-yl, azetidin-1-yl, azetidin-2-yl, azetidin-3-yl, thiaetan-3 yl, cyclopentyl, cyclohexyl, norbornyl, 7-oxabicyclo[2.2. 1 ]heptan-2-yl, 289 WO 00/69826 PCT/US00/08220 bicyclo[3.1.0]hexan-6-yl, cycloheptyl, 2 -morpholinyl, 3-morpholinyl, 4 morpholinyl, 1-piperazinyl, 2-piperazinyl, 1-piperidinyl, 2-piperidinyl, 3 piperidinyl, 4-piperidinyl, 1-pyrrolidinyl, 2 -pyrrolidinyl, 3-pyrrolidinyl, 2 dioxanyl, 4H-2-pyranyl, 4H-3-pyranyl, 4 H-4-pyranyl, 4H-pyran-4-one-2-yl, 5 4H-pyran-4-one-3-yl, 2-tetrahydrofuranyl, 3 -tetrahydrofuranyl, 2 tetrahydropyranyl, 3 -tetrahydropyranyl, 4 -tetrahydropyranyl, 2 tetrahydrothienyl, and 3-tetrahydrothienyl, wherein each ring carbon is 33 optionally substituted with R 33 , a ring carbon and nitrogen atoms adjacent to the carbon atom at the point of attachment is optionally substituted with R or 13 9 10 R 13, a ring carbon or nitrogen atom adjacent to the R position and two atoms 10, from the point of attachment is optionally substituted with RI, and a ring carbon or nitrogen atom adjacent to the R 13 position and two atoms from the point of attachment is optionally substituted with R12 R 9 and R 1 1 are independently selected from the group consisting of 15 hydrido, amidino, guanidino, carboxy, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, N-methylamino, N,N-dimethylamino, N-ethylamino, methylthio, ethylthio, isopropylthio, trifluoromethyl, pentafluoroethyl, 2 ,2,2-trifluoroethyl, 2,2,3,3,3 pentafluoropropyl, trifluoromethoxy, 1,1,2, 2 -tetrafluoroethoxy, fluoro, 20 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 10 and R 12 are independently selected from the group consisting of 25 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 30 dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 290 WO 00/69826 PCT/US00/08220 2,2,2-trifluoro-1-hydroxyethyl, methoxycarbonyl, ethoxycarbonyl, amidocarbonyl, N-methylamrnidocarbonyl, N,N-dimethylamidocarbonyl, fluoro, chloro, bromo, and cyano; A is selected from the group consisting of single covalent bond, NH, N(CH 3 ), 5 N(OH), CH 2 , CH 3 CH, CF 3 CH, NHC(O), N(CH 3 )C(O), C(O)NH, C(O)N(CH 3 ), CH 2 CH 2 , CH 2 CH 2 CH 2 , CH 3 CHCH 2 , and CF 3 CHCH 2 ; A is optionally selected from the group consisting of CH 2 N(CH 3 ), CH 2 N(CH 2 CH 3 ), CH 2 CH 2 N(CH 3 ), and CH 2 CH 2 N(CH 2 CH 3 ) with the proviso that B is hydrido; 10 X 0 is selected from the group consisting of hydrido, hydroxy, amino, amidino, hydroxyamino, aminomethyl, 1-aminoethyl, methylamino, dimethylamino, cyano, methyl, ethyl, trifluoromethyl, pentafluoroethyl, 2,2,2 trifluoroethyl, methoxy, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, methoxyamino, methylthio, ethylthio, trifluoromethoxy, 1,1,2,2 15 tetrafluoroethoxy, fluoro, chloro, and bromo; W, X, Y, and Z are independently selected from the group consisting of CH, N, CF, CC1, C-CN, C-CH 3 , C-CH 2 CH 3 , C-NH 2 , C-CH 2 NH 2 , C-CH 2 NHCH 3 , C-NHCH 3 , C-N(CH 3 ) 2 , C-CH(NH 2 )CH 3 , C-CH 2 CH 2 NH 2 , C-NHOCH 3 , C-NHOCH 2 CH 3 , C-C(NH)NH 2 , 20 C-C(NOH)NH 2 , C-OH, C-CH 2 OH, C-CH 2 CH 2 OH, C-CH(OH)CH 3 , C-OCH 3 , C-OCH 2 CH 3 , C-CO 2 H, C-CO 2 CH 3 , C-C(O)NH 2 , C-C(O)NHCH 3 , C-C(O)NH(CH 3 ) 2 , C-CH 2 CO 2 H, C-SO 2 NH 2 , C-SO 2 NHCH 3 , C-NH(O)CCH 3 , and C-NH(O)CCF 3 ; Yo is selected from the group consisting of: b s 16 17 18 19 25 1-Q -4-Q -2-R 6-3-R 17-5-R 18-6-R 19benzene, b s 17 18 19 2-Qb-5-Q s -6-R 17-4-R 18-2-R 19pyridine, 291 WO 00/69826 PCT/US00/08220 b s 16 18 19 b s 6_ 18 3-Q -6-Q -2-R16-5-R18 -4-R19pyridine, 2-Q -4-QS-3-R 6-6-R 8pyrazine, 3 b s 18 18 19 Q-6-Q -2-R -5-R 18-4-R 9pyridazine, b s 17 18b s 16 9 2-Q -5-Qs-6-R 17-4-R 8pyrimidine, 5-Qb-2-Qs -3-R 16 -6-R19pyrimidine, b _6- 6 -R 176r9bm ne, 3-Q -5QS-4-R 16-2-R 9thiophene, 2-Qb 5Q -3-R16-4-R 7thiophene, b_ s 16_ 19 b s 16 17 5 3-Q -5QS-4-R 16-2-R 19furan, 2-Qb -5-Q -3-R 16-4-R 7furan, 3-Qb_5-Q s-4-R 16-2-R 19pyrrole, 2-Qb _5-Qs-3-R 16-4-R 17pyrrole, 4-Qb_-2-QS-5-R 19imidazole, 2-Q b 4QS-5-R 17imidazole, b s 16 b s 16 3-Q -b5-Q -4-R 6isoxazole, 5-Q -3-Q -4-R 16isoxazole, b s 16 b s 19 2-Q -5-Q -4-R 16pyrazole, 4-Q -2-Q -5-R 9thiazole, and b s 17 10 2-Qb _5-Q -4-R 17thiazole; 16 17 18 19 R 6 , R 17 , R 18 , and R 19 are independently selected from the group consisting of hydrido, methyl, ethyl, isopropyl, propyl, carboxy, amidino, guanidino, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, aminomethyl, 1-aminoethyl, 2-aminoethyl, N-methylamino, dimethylamino, 15 N-ethylamrnino, methylthio, ethylthio, isopropylthio, trifluoromethylthio, methylsulfinyl, ethylsulfinyl, methylsulfonyl, ethylsulfonyl, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, 2,2,3,3, 3 -pentafluoropropyl, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro, bromo, amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, 20 hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro- 1 hydroxyethyl, and cyano; R16 an 19 Qb R16 and R19 are optionally Qb with the proviso that no more than one of R 16 and R 19 is Qb at the same time and that Qb is Qbe Qb is selected from the group consisting of NR20R21, Qbe wherein Qbe is 25 hydrido, C(NR25)NR23R24, and N(R26)C(NR25)N(R23)(R24), with the 292 WO 00/69826 PCT/US00/08220 provisos that no more than one of R20 and R21 is hydroxy at the same time and that no more than one of R 2 3 and R 2 4 is hydroxy at the same time; 20 21 23 24 25 26 R 20 , R 2 1 , R , R 24 , R 2 5 , and R 2 6 are independently selected from the group consisting of hydrido, methyl, ethyl, propyl, butyl, isopropyl, and hydroxy; 5 QS is selected from the group consisting of a single covalent bond, CH 2 , and CH 2 CH 2 .
35. The compound as recited in Claim 34 or a pharmaceutically acceptable salt thereof, wherein; 10 B is selected from the group consisting of 2-aminophenyl, 3 aminophenyl, 3-amidinophenyl, 4-amidinophenyl, 3-carboxyphenyl, 3 carboxy-5-hydroxyphenyl, 3-chlorophenyl, 4-chlorophenyl, 3,4 dichlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 3,4-difluorophenyl, 3 hydroxyphenyl, 4-hydroxyphenyl, 3 -methoxyaminophenyl, 3-methoxyphenyl, 15 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 20 propenyl, 2-propynyl, propyl, isopropyl, butyl, 2-butyl, (R)-2-butyl,(S)-2 butyl, tert-butyl, isobutyl, 1-pentyl, 3-pentyl, 2-methylbutyl, 2,2,2 trifluoroethyl, 6 -amidocarbonylhexyl, 4-methyl-2-pentyl, 3-hydroxypropyl, 3 methoxy-2-propyl, 2-methoxyethyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 2 dimethylaminopropyl, 2-cyanoethyl, 6-hydroxyhexyl, 2-hydroxyethyl, 2 25 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-amninobutyl; B is optionally selected from the group consisting of cyclopropyl, 30 cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, oxalan-2-yl, 2-(2R) bicyclo[2.2.1]-heptyl, 1-pyrrolidinyl, 1-piperidinyl, 1,1-dioxothiolan-3-yl, oxetan-3-yl, azetidin-1-yl, azetidin-2-yl, azetidin-3-yl, 7 oxabicyclo[2.2. I Iheptan-2-yl, bicyclo[3.1.0]hexan-6-yl, 2-morpholinyl, 3 293 WO 00/69826 PCT/US00/08220 morpholinyl, 4-morpholinyl, 1-piperazinyl, 2 -piperazinyl, 1-piperidinyl, 2 piperidinyl, 3-piperidinyl, 4-piperidinyl, 1-pyrrolidinyl, 2-pyrrolidinyl, 3 pyrrolidinyl, 2-dioxanyl, 4H-2-pyranyl, 4 H-3-pyranyl, 4H-4-pyranyl, 4H pyran-4-one-2-yl, 4H-pyran-4-one-3-yl, 2 -tetrahydrofuranyl, 3 5 tetrahydrofuranyl, 2-tetrahydropyranyl, 3 -tetrahydropyranyl, 4 tetrahydropyranyl, 2-tetrahydrothienyl, and 3-tetrahydrothienyl; A is selected from the group consisting of single covalent bond, CH 2 , NHC(O), CH 2 CH 2 , and CH 2 CH 2 CH 2 ; X 0 is selected from the group consisting of hydrido, hydroxy, amino, 10 amidino, hydroxyamino, aminomethyl, methylamino, cyano, methyl, trifluoromethyl, methoxy, hydroxymethyl, methoxyamino, methylthio, trifluoromethoxy, fluoro, and chloro; W and Z are independently selected from the group consisting of CH, N, CF, CC1, C-CN, C-NH 2 , C-CH 2 NH 2 , C-NHCH 3 , C-OH, C-CH 2 OH, C 15 CO 2 H, and C-C(O)NH 2 ; X and Y are independently selected from the group consisting of CH, N, CF, C-CN, C-CH 3 , C-NH 2 , C-CH 2 NH 2 , C-CH 2 NHCH 3 , C-NHCH 3 , C-CH(NH 2 )CH 3 , C-CH 2 CH 2 NH 2 , C-NHOCH 3 , C-C(NH)NH 2 , C-C(NOH)NH 2 , C-OH, C-CH 2 OH, C-CH 2 CH 2 OH, C-CH(OH)CH 3 , 20 C-OCH 3 , C-CO 2 H, C-C(O)NH 2 , C-C(O)NHCH 3 , C-CH 2 CO 2 H, and C-SO 2 NH 2 ; Yo is selected from the group consisting of: b s 16 17 1 8 19 l-Q -4-Q -2-R16-3-R17-5-R18 -6-R19benzene, b s 17 18 19 2-Qb-5-Q -6-R 17-4-R 18-2-R 9pyridine, b s 16 18 19 25 3-Q -6-Q -2-R 6-5-R 8-4-R 19pyridine, 3-Qb-5-Qs-4-R 16-2-R19thiophene, and 2-Qb-5-QS-3-R16 -4-R17thiophene; 294 WO 00/69826 PCT/US00/08220 R 16 and R 19 are independently selected from the group consisting of hydrido, amidino, amino, aminomethyl, methoxy, methylamino, hydroxy, hydroxymethyl, fluoro, chloro, and cyano; R 16 and R 19 are optionally Qb with the proviso that no more than one 5 of R 16 and R 19 is Qb at the same time and that Qb is Qbe R 17 and R 18 are independently selected from the group consisting of hydrido, fluoro, chloro, hydroxy, hydroxymethyl, amino, carboxy, and cyano; Qbis selected from the group consisting of Qbe wherein Qbe is hydrido and C(NR25)NR23 R24 10 R 23, R 24, and R 25 are independently selected from the group consisting of hydrido and methyl; QS is CH 2 *
36. The compound as recited in Claim 33 having the Formula: y 0 XoyW B AN N Ny H H 15 or a pharmaceutically acceptable salt thereof, wherein; B is the Formula (V): 295 WO 00/69826 PCT/US00/08220 R 3 4 R 33, K 1 R 3 5 RK 2 R R32/ D 1 -D2", R 3 (V) 1 2 12 1 wherein D , D 2 , j , J2 and K are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more 1 2 12 1 than one is a covalent bond, no more than one of D , D 2 , J, J2 and K is O, 1 2 12 1 1 21 2 5 no more than one of D, D 2 , 1, J2 and K is S, one of D D 2 , 1 , 2 and 1 1 2 12 1 K must be a covalent bond when two of D , D 2 , J2 and K are O and S, 1 2 12 1 and no more than four of D I , D 2 , J1 and K are N; 32 33 34 35 36 R 3 2 , R 3 3 , R 3 4 , R 3 5 , and R 3 6 are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, 10 alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, alkylthio, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboalkoxy, carboxy, carboxamido, cyano,and Qb B is optionally selected from the group consisting of hydrido, C2-C8 15 alkyl, C3-C8 alkenyl, C3-C8 alkynyl, and C2-C8 haloalkyl, wherein each member of group B is optionally substituted at any carbon up to and including 6 atoms from the point of attachment of B to A with one or more of the group 32 33 34 35 36 consisting of R 3 2 , R 3 3 , R 3 4 , R 35 , and R36 B is optionally selected from the group consisting of C3-C7 cycloalkyl 20 and C4-C6 saturated heterocyclyl, wherein each ring carbon is optionally 33 substituted with R 3 3 , 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 296 WO 00/69826 PCT/US00/08220 nitrogen adjacent to the carbon atom at the point of attachment are optionally substituted with R 9 or R 13 , a ring carbon or nitrogen adjacent to the R position and two atoms from the point of attachment is optionally substituted 10 13 with R 10 , a ring carbon or nitrogen adjacent to the R 13 position and two atoms 12 5 from the point of attachment is optionally substituted with R 2, a ring carbon or nitrogen three atoms from the point of attachment and adjacent to the R 10 position is optionally substituted with R 11, a ring carbon or nitrogen three atoms from the point of attachment and adjacent to the R 12 position is optionally substituted with R 33 , and a ring carbon or nitrogen four atoms from 10 the point of attachment and adjacent to the R l and R 33 positions is optionally substituted with R34 9 11 13 R , R , and R are independently selected from the group consisting of hydrido, hydroxy, amino, amidino, guanidino, lower alkylamino, alkylthio, alkoxy, alkylsulfinyl, alkylsulfonyl, amidosulfonyl, 15 monoalkyl amidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboxy, carboxamido, and cyano; R 10 and R 12 are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkyl, alkoxy, alkoxyamino, aminoalkyl, hydroxy, amino, lower alkylamino, 20 alkylsulfonamido, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, hydroxyalkyl, aminoalkyl, halo, haloalkyl, carboalkoxy, carboxy, carboxyalkyl, carboxyamido, and cyano; A is selected from the group consisting of single covalent bond and (CH(R15))pa-(W 7)rr wherein rr is an integer selected from 0 through 1, pa is 25 an integer selected from 0 through 3, and W 7 is N(R7); 7 R is selected from the group consisting of hydrido, hydroxy and alkyl; 297 WO 00/69826 PCT/US00/08220 R 15 is selected from the group consisting of hydrido, halo, alkyl, and haloalkyl; Xo is selected from the group consisting of hydrido, alkyl, cyano, halo, haloalkyl, haloalkoxy, amino, aminoalkyl, alkylamino, amidino, hydroxy, 5 hydroxyamino, alkoxy, hydroxyalkyl, alkoxyamino, thiol, and alkylthio; R and R 2 are taken together to be -W=X-Y=Z- wherein -W=X-Y=Z forms a ring selected from the group consisting of a heteroaryl ring having 6 contiguous members and an aryl; W, X, Y, and Z are independently selected from the group consisting 10 of C(R ), C(R10), C(R 11 ), C(R 12), and N; YO is formula (IV): s R17 I Ri 8 D 5 -D R16 / D K 2 D R 1 9 Qb Q (IV) wherein D 5 , D 6 , J 5, and J6 are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more 2 5 65 6 15 than one is a covalent bond, K is C, no more than one of DS, D 6 , J5, and J6 5 65 6 5 65 6 is O, no more than one of D 5 , D 6 , and J6 is S, one of D D , J and J6 must be a covalent bond when two of D 5 , D6 , J5, and J6 are 0 and S, and no 5 65 6 16 17 more than four of D , D 6 , j5 , and J6 are N, with the provisos that R 16 , R 17 18 19 R 18, and R9 are each independently selected to maintain the tetravalent nature 20 of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen; 298 WO 00/69826 PCT/US00/08220 16 17 18 19 R 16 , R 7 , R 18 , and R 9 are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, haloalkylthio, alkoxy, hydroxy, amino, lower alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, 5 aminoalkyl, and cyano; R16 an 19 Qb R16 and R19 are optionally Qb with the proviso that no more than one of R 16 and R 19 is Qb at the same time and that Qb is Qbe Q is selected from the group consisting of NR20R21, Qbe wherein Qbe is hydrido, N(R26)C(NR25)N(R23)(R24), and C(NR25)NR R2324 10 21 23 24 25 26 10 R 2 0 , R 2 1, R , R 24 , R 2 5 , and R 2 6 are independently selected from the group consisting of hydrido and alkyl; Qs is CH 2 .
37. The compound as recited in Claim 36 or a pharmaceutically acceptable salt 15 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, and 5-isoxazolyl, wherein a carbon adjacent to the carbon at the point of attachment is optionally substituted 20 by R 3 2 , the other carbon adjacent to the carbon at the point of attachment is 36 32 optionally substituted by R , a carbon adjacent to R and two atoms from the carbon at the point of attachment is optionally substituted by R 3 3 , a carbon a36 adjacent to and two atoms from the carbon at the point of attachment is optionally substituted by R 3 5 , and any carbon adjacent to both R 3 3 and R 3 5 is 25 optionally substituted by R34 299 WO 00/69826 PCT/US00/08220 32 33 34 35 36 R 3 2 , R 33 , R 3 4 , R 3 5 , and R 3 6 are independently selected from the group consisting of hydrido, amidino, guanidino, methyl, ethyl, methoxy, ethoxy, hydroxy, amino, N-methylamino, dimethylamino, methylthio, ethylthio, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, fluoro, 5 chloro, bromo, amidosulfonyl, N-methylamidosulfonyl, hydroxymethyl, amnidocarbonyl, carboxy, cyano, and Qb B is optionally selected from the group consisting of hydrido, ethyl, 2 propenyl, 2-propynyl, propyl, isopropyl, butyl, 2-butenyl, 2-butynyl, sec butyl, tert-butyl, isobutyl, 2-methylpropenyl, 1-pentyl, 2-pentenyl, 3-pentenyl, 10 2-pentynyl, 3-pentynyl, 2-pentyl, 3-pentyl, 2-methylbutyl, 2-methyl-2 butenyl, 3-methylbutyl, 3-methyl-2-butenyl, 1-hexyl, 2-hexenyl, 3-hexenyl, 4 hexenyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 2-hexyl, 1-methyl-2-pentenyl, 1 methyl-3-pentenyl, 1-methyl-2-pentynyl, 1-methyl-3-pentynyl, 3-hexyl, 1 ethyl-2-butenyl, 1-heptyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 2 15 heptynyl, 3-heptynyl, 4-heptynyl, 5-heptynyl, 2-heptyl, 1-methyl-2-hexenyl, 1-methyl-3-hexenyl, 1-methyl-4-hexenyl, 1-methyl-2-hexynyl, 1-methyl-3 hexynyl, 1-methyl4-hexynyl, 3-heptyl, 1-ethyl-2-pentenyl, 1-ethyl-3 pentenyl, 1-ethyl-2-pentynyl, 1-ethyl-3-pentynyl, 2,2,2-trifluoroethyl, 2,2 difluoropropyl, 4-trifluoromethyl-5,5,5-trifluoropentyl, 4 20 trifluoromethylpentyl, 5,5,6,6,6-pentafluorohexyl, and 3,3,3-trifluoropropyl, wherein each member of group B is optionally substituted at any carbon up to and including 5 atoms from the point of attachment of B to A with one or more 32 33 34 35 36 of the group consisting of R 3 2 , R 3 3 , R 3 4 , R 3 5 , and R36 B is optionally selected from the group consisting of cyclopropyl, 25 cyclobutyl, oxetan-3-yl, azetidin-3-yl, thiaetan-3-yl, cyclopentyl, cyclohexyl, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-tetrahydrofuranyl, 3 tetrahydrofuranyl, 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 30 substituted with R 9 or R 13 , a ring carbon or nitrogen atom adjacent to the R position and two atoms from the point of attachment is optionally substituted 300 WO 00/69826 PCT/US00/08220 with R 10 , and a ring carbon or nitrogen atom adjacent to the R 13 position and two atoms from the point of attachment is optionally substituted with R12 R 9 , R 11 , and R 13 are independently selected from the group consisting of hydrido, methyl, ethyl, methoxy, ethoxy, hydroxy, amino, N-methylamino, 5 N,N-dimethylamino, methylthio, trifluoromethyl, pentafluoroethyl, 2,2,2 trifluoroethyl, fluoro, chloro, bromo, amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, amidocarbonyl, N-methylamidocarbonyl, carboxy, and cyano; R 10 and R 12 are independently selected from the group consisting of 10 hydrido, amidino, amidocarbonyl, N-methylamidocarbonyl, guanidino, methyl, ethyl, methoxy, ethoxy, hydroxy, hydroxymethyl, 1-hydroxyethyl, 2 hydroxyethyl, carboxy, carboxymethyl, amino, acetamido, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, trifluoroacetamido, aminomethyl, N methylamino, dimethylamino, amidosulfonyl, N-methylamidosulfonyl, N,N 15 dimethylamidosulfonyl, methoxycarbonyl, fluoro, chloro, bromo, and cyano; A is selected from the group consisting of single covalent bond, NH, N(CH 3 ), CH 2 , CH 3 CH, and CH 2 CH 2 ; A is optionally selected from the group consisting of CH 2 N(CH 3 ), CH 2 N(CH 2 CH 3 ), CH 2 CH 2 N(CH 3 ), and CH 2 CH 2 N(CH 2 CH 3 ) with the 20 proviso that B is hydrido; X 0 is selected from the group consisting of hydrido, hydroxy, amino, amidino, aminomethyl, cyano, methyl, trifluoromethyl, hydroxymethyl, and fluoro; W and Z are independently selected from the group consisting of CH, 25 N, CF, CCI, C-CN, C-NH 2 , C-CH 2 NH 2 , C-NHCH 3 , C-OH, C-CH 2 OH, C CO 2 H, and C-C(O)NH 2 ; X and Y are independently selected from the group consisting of CH, N, CF, C-CN, C-CH 3 , C-NH 2 , C-CH 2 NH 2 , C-CH 2 NHCH 3 , C-NHCH 3 , C-CH(NH 2 )CH 3 , C-CH 2 CH 2 NH 2 . C-NHOCH 3 , C-C(NH)NH 2 , 301 WO 00/69826 PCT/US00/08220 C-3202 C-C(NOH)NH 2 , C-OH, C-CH 2 OH, C-CH 2 CH 2 0H, C-CH(OH)CH 3 , C-OCH 3 , C-CO 2 H, C-C(O)NH 2 , C-C(O)NHCH 3 , C-CH 2 CO 2 H, and C-SO 2 NH 2 ; Qb is selected from the group consisting of NR20R21 5 C(NR25 )N23R24, and N(R26)C(NR25)N(R 23)(R24), with the proviso that said Qb group is bonded directly to a carbon atom; 20 21 23 24 25 26 R 2 0 , R 2 1 , R , R 2 4 , R 2 5 , and R 2 6 are independently selected from the group consisting of hydrido, methyl, and ethyl; QS is CH 2 . 10
38. The compound as recited in Claim 37 or a pharmaceutically acceptable salt thereof, wherein; B is selected from the group consisting of 2-aminophenyl, 3 aminophenyl, 3-amidinophenyl, 4-amidinophenyl, 3-carboxyphenyl, 3 15 carboxy-5-hydroxyphenyl, 3-chlorophenyl, 4-chlorophenyl, 3,4 dichlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 3,4-difluorophenyl, 3 hydroxyphenyl, 4-hydroxyphenyl, 3 -methoxyaminophenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-methylphenyl, 4-methylphenyl, phenyl, 3 trifluoromethylphenyl, 2-imidazoyl, 2-pyridyl, 3-pyridyl, 5-chloro-3 20 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 25 trifluoroethyl, 6-amidocarbonylhexyl, 4 -methyl-2-pentyl, 3-hydroxypropyl, 3 methoxy-2-propyl, 2-methoxyethyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 2 dimethylaminopropyl, 2-cyanoethyl, 6-hydroxyhexyl, 2-hydroxyethyl, 2 amidinoethyl, 2-guanidinoethyl, 3-guanidinopropyl, 4-guanidinobutyl, 3 hydroxypropyl, 4-hydroxybutyl, 6-cyanohexyl, 2-dimethylaminoethyl, 3 30 methylbutyl, 2-methylbutyl, (S)-2-methylbutyl, 3-aminopropyl, 2-hexyl, and 4-aminobutyl; 302 WO 00/69826 PCT/US00/08220 B is optionally selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxalan-2-yl, 2-(2R)-bicyclo[2.2.1] heptyl, 1,1-dioxothiolan-3-yl, oxetan-3-yl, azetidin-1-yl, azetidin-2-yl, azetidin-3-yl, 1-pyrrolidinyl and 1-piperidinyl; 5 A is selected from the group consisting of single covalent bond, CH 2 , CH 3 CH, and CH 2 CH 2 ; X 0 is selected from the group consisting of hydrido, hydroxy, amino, amidino, aminomethyl, cyano, methyl, trifluoromethyl, hydroxymethyl, and fluoro; 10 W and Z are independently selected from the group consisting of CH, N, CF, CCI, C-CN, C-NH 2 , C-CH 2 NH 2 , C-OH, C-CH 2 OH, C-CO 2 H, and C-C(O)NH 2 ; X and Y are independently selected from the group consisting of CH, N, CF, C-CN, C-NH 2 , C-CH 2 NH 2 , C-CH 2 CH 2 NH 2 , C-C(NH)NH 2 , 15 C-C(NOH)NH 2 , C-OH, C-CH20H, C-CH 2 CH20H, C-CO 2 H, C-C(O)NH 2 , and C-CH 2 CO 2 H; Qb is selected from the group consisting of NR20R 2 1 C(NR25 )NR 2 3 R 2 4 , and N(R26)C(NR25)N(R 23)(R24), with the proviso that said Qb group is bonded directly to a carbon atom; 20 21 23 24 25 26 20 R 20 , R 2 1 , R , R 24 , R 2 5 , and R 2 6 are independently selected from the group consisting of hydrido, methyl, and ethyl; Qs is CH 2 .
39. The compound as recited in Claim 38 or a pharmaceutically acceptable salt 25 thereof, wherein; B is selected from the group consisting of 3-aminophenyl, 3 amidinophenyl, 4-amidinophenyl, 3-chlorophenyl, 4-chlorophenyl, 3,4 dichlorophenyl, 2-fluorophenyl, 4-methylphenyl, phenyl, 2-imidazoyl, 3 pyridyl, 4-pyridyl, and 3-trifluoromethyl-2-pyridyl; 303 WO 00/69826 PCT/US00/08220 B is optionally selected from the group consisting of hydrido,ethyl, 2 propenyl, 2-propynyl, propyl, isopropyl, butyl, 2-butyl, (R)-2-butyl,(S)-2 butyl, tert-butyl, isobutyl, 1-pentyl, 3-pentyl, 2-methylbutyl, 2,2,2 trifluoroethyl, 6-amidocarbonylhexyl, 4 -methyl-2-pentyl, 3-hydroxypropyl, 3 5 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 10 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, 1,1-dioxothiolan-3-yl, oxetan-3-yl, azetidin-1-yl, azetidin-2-yl, azetidin-3-yl, andl-piperidinyl; 15 A is selected from the group consisting of single covalent bond, CH 2 , CH 3 CH, and CH 2 CH 2 ; X 0 is selected from the group consisting of hydrido, hydroxy, amino, amidino, aminomethyl, cyano, methyl, trifluoromethyl, hydroxymethyl, and fluoro; 20 W and Z are independently selected from the group consisting of CH, N, CF, CC1, C-CN, C-NH 2 , C-CH 2 NH 2 , C-OH, C-CH 2 OH, C-CO 2 H, and C-C(O)NH 2 ; X and Y are independently selected from the group consisting of CH, N, CF, C-CN, C-NH 2 , C-CH 2 NH 2 , C-CH 2 CH 2 NH 2 , C-C(NH)NH 2 , 25 C-C(NOH)NH 2 , C-OH, C-CH 2 OH, C-CH 2 CH 2 OH, C-CO 2 H, C-C(O)NH 2 , and C-CH 2 CO 2 H; YO is selected from the group consisting of 5 -amidino-2-thienylmethyl, 4-amidinobenzyl, 2-fluoro-4-amidinobenzyl, and 3 -fluoro-4-amidinobenzyl. 30 40. A compound as recited in Claim 33 where said compound is selected from the group having the Formula: 304 WO 00/69826 PCT/US00/08220 y xIfw W 0 N0 N N N y H H O or a pharmaceutically acceptable salt thereof, wherein: B is 3-chlorophenyl, A is CH 2 CH 2 , Yo 0 is 4-amidinobenzyl, W is CH, X is C-NH 2 , Y is C-CH 2 CO 2 H, Z is CH, and X 0 is hydrido; 5 B is phenyl, A is CH 2 , Y is 4-amidinobenzyl, W is N, X is C-CH 2 NH 2 , Y is C-CO 2 H, Z is CH, and X 0 is hydrido; B is 3-chlorophenyl, A is CH 2 CH 2 , YO is 4-amidinobenzyl, W is C-OH, X is C-CH 2 CH 2 NH 2 , Y is C-OH, Z is CH, and X 0 is hydrido; B is 2-imidazoyl, A is CH 2 CH 2 CH 2 , YO is 4-amidinobenzyl, W is C 10 NH 2 , X is C-CH 2 OH, Y is C- NH 2 , Z is CH, and X 0 is hydrido; B is 2,2,2-trifluoroethyl, A is single bond, Y 0 is 4-amidinobenzyl, W is CH, X is C-NH 2 , Y is C-CHCO 2 H, Z is CH, and X 0 is hydrido; B is (S)-2-butyl, A is single bond, Y0 is 4-amidinobenzyl, W is N, X is C CH,NH 2 , Y is C-CO2H, Z is CH, and X 0 is hydrido; 15 B is isopropyl, A is single bond, Y is 4-amidinobenzyl, W is C-OH, X is C-CH2CH 2 NH 2 , Y is C-OH, Z is CH, and X 0 is hydrido; B is isopropyl, A is single bond, Y0 is 4-amidinobenzyl, W is C-NH 2 , X is C-CH 2 0H, Y is C- NH 2 , Z is CH, and X 0 is hydrido; 305 WO 00/69826 PCT/US00/08220 B is hydrido, A is CH 2 (CH 3 )N, Yo 0 is 4-amidinobenzyl, W is CH, X is C NH 2 , Y is C-CH 2 CO 2 H, Z is CH, and X 0 is hydrido; B is ethyl, A is single bond, Y is 4-amidinobenzyl, W is N, X is C CH 2 NH 2 , Y is C-CO 2 H, Z is CH, and X 0 is hydrido; 5 B is ethyl, A is single bond, Y is 4-amidino-2-fluorobenzyl, W is C-OH, X is C-CH 2 CH 2 NH 2 , Y is C-OH, Z is CH, and X 0 is hydrido; B is 2-propenyl, A is single bond, Y0 is 4-amidinobenzyl, W is C-NH 2 , X is C-CH20H, Y is C- NH 2 , Z is CH, and X 0 is hydrido; B is isopropyl, A is single bond, Y 0 is 4 -amidino-2-fluorobenzyl, W is 10 CH, X is C-NH 2 , Y is C-CH 2 CO 2 H, Z is CH, and X 0 is hydrido; B is isopropyl, A is single bond, Y is 4-amidinobenzyl, W is N, X is C CH 2 NH 2 , Y is C-CO 2 H, Z is CH, and X 0 is hydrido; B is 2-butyl, A is single bond, Y0 is 4-amidinobenzyl, W is C-OH, X is C-CH 2 CH 2 NH 2 , Y is C-OH, Z is CH, and X 0 is hydrido; 15 B is (R)-2-butyl, A is single bond, Y is 4-amidinobenzyl, W is C-NH 2 , X is C-CH 2 OH, Y is C- NH 2 , Z is CH, and X 0 is hydrido; B is 2-propynyl, A is single bond, YO 0 is 4-amidinobenzyl, W is CH, X is C-NH 2 , Y is C-CHCO 2 H, Z is CH, and X 0 is hydrido; B is hydrido, A is CH 2 , YO 0 is 4-amidinobenzyl, W is N, X is C 20 CH 2 NH 2 , Y is C-CO 2 H, Z is CH, and X 0 is hydrido; B is cycylopropyl, A is single bond, Y is 4-amidinobenzyl, W is C-OH, X is C-CH,CH 2 NH 2 , Y is C-OH, Z is CH, and X 0 is hydrido; 306 WO 00/69826 PCT/US00/08220 B is cyclobutyl, A is single bond, Yo 0 is 4-amidino-2-fluorobenzyl, W is C NH 2 , X is C-CH 2 OH, Y is C- NH 2 , Z is CH, and X 0 is hydrido; B is cyclobutyl, A is single bond, Y is 4-amidinobenzyl, W is CH, X is C-NH 2 , Y is C-CH 2 CO 2 H, Z is CH, and X 0 is hydrido; 5 B is cyclopropyl, A is single bond, YO 0 is 4-amidino-2-fluorobenzyl, W is N, X is C-CH 2 NH 2 , Y is C-CO 2 H, Z is CH, and X 0 is hydrido; B is cyclobutyl, A is single bond, Y is 4-amidinobenzyl, W is C-OH, X is C-CH 2 CH 2 NH 2 , Y is C-OH, Z is CH, and X 0 is hydrido; B is cyclobutyl, A is single bond, Y is 4-amidino-3-fluorobenzyl, W is C 10 NH 2 , X is C-CH 2 OH, Y is C- NH 2 , Z is CH, and X 0 is hydrido; B is cyclopentyl, A is single bond, Y0 is 4-amidinobenzyl, W is CH, X is C-NH 2 , Y is C-CH 2 CO 2 H, Z is CH, and X 0 is hydrido; B is cyclobutyl, A is single bond, Y is 4-amidinobenzyl, W is N, X is C CH 2 NH 2 , Y is C-CO 2 H, Z is CH, and X 0 is hydrido; 15 B is cyclopropyl, A is CH 2 , Yo is 4-amidinobenzyl, W is C-OH, X is C CH 2 CH 2 NH 2 , Y is C-OH, Z is CH, and X 0 is hydrido; B is 2-(2R)-bicyclo[2.2.1I-heptyl, A is single bond, Y 0 is 4 amidinobenzyl, W is C-NH 2 , X is C-CH 2 OH, Y is C- NH 2 , Z is CH, and X 0 is hydrido; 20 B is cyclopentyl, A is single bond, YO 0 is 4-amidino-2-fluorobenzyl, W is CH, X is C-NH 2 , Y is C-CH 2 CO 2 H, Z is CH, and X 0 is hydrido; B is cyclohexyl, A is CH 2 CH 2 , YO is 4-amidinobenzyl, W is N, X is C-CH 2 NH 2 , Y is C-CO 2 H, Z is CH, and X 0 is hydrido; 307 WO 00/69826 PCT/US00/08220 B is 3-chlorophenyl, A is CH 2 CH 2 , Y0 is 4-amidinobenzyl, W is C-OH, X is C-CH 2 CH 2 NH 2 , Y is C-OH, Z is CH, and X 0 is hydrido; B is phenyl, A is CH 2 , Y is 4-amidinobenzyl, W is C-NH 2 , X is C CH 2 OH, Y is C- NH 2 , Z is CH, and X 0 is hydrido; 5 B is 3-chlorophenyl, A is CH 2 CH 2 , YO 0 is 4-amidinobenzyl, W is CH, X is C-NH 2 , Y is C-CH 2 CO 2 H, Z is CH, and X 0 is hydrido; B is 2-imidazoyl, A is CH 2 CH 2 CH 2 , YO is 4-amidinobenzyl, W is N, X is C-CH 2 NH 2 ,Y is C-CO 2 H, Z is CH, and X 0 is hydrido; B is 2,2,2-trifluoroethyl, A is single bond, Y0 is 4-amidinobenzyl, W is C 10 OH, X is C-CH2CH 2 NH 2 , Y is C-OH, Z is CH, and X 0 is hydrido; B is (S)-2-butyl, A is single bond, Y is 4-amidinobenzyl, W is C-NH 2 , X is C-CH20H, Y is C- NH 2 , Z is CH, and X 0 is hydrido; B is isopropyl, A is single bond, Y0 is 4-amidinobenzyl, W is CH, X is C NH 2 , Y is C-CH 2 CO 2 H, Z is CH, and X 0 is hydrido; 15 B is isopropyl, A is single bond, Y0 is 4-amidinobenzyl, W is N, X is C CH 2 NH 2 , Y is C-CO 2 H, Z is CH, and X 0 is hydrido; B is hydrido, A is CH 2 (CH 3 )N, YO is 4-amidinobenzyl, W is C-OH, X is C-CH 2 CH 2 NH 2 , Y is C-OH, Z is CH, and X 0 is hydrido; B is ethyl, A is single bond, Y0 is 4 -amidinobenzyl, W is C-NH 2 , X is C 20 CH20H, Y is C- NH 2 , Z is CH, and X 0 is hydrido; B is ethyl, A is single bond, Y is 4 -amidino-2-fluorobenzyl, W is CH, X is C-NH 2 , Y is C-CH 2 CO 2 H, Z is CH, and X 0 is hydrido; 308 WO 00/69826 PCT/US00/08220 B is 2-propenyl, A is single bond, Yo 0 is 4-amidinobenzyl, W is N, X is C CH 2 NH 2 , Y is C-CO 2 H, Z is CH, and X 0 is hydrido; B is isopropyl, A is single bond, Y is 4-amidino-2-fluorobenzyl, W is C OH, X is C-CH 2 CH 2 NH 2 , Y is C-OH, Z is CH, and X 0 is hydrido; 5 B is isopropyl, A is single bond, Y0 is 4-amidinobenzyl, W is C-NH 2 , X is C-CH20H, Y is C- NH 2 , Z is CH, and X 0 is hydrido; B is 2-butyl, A is single bond, Y is 4-amidinobenzyl, W is CH, X is C NH 2 , Y is C-CH 2 CO 2 H, Z is CH, and X 0 is hydrido; B is (R)-2-butyl, A is single bond, Y is 4-amidinobenzyl, W is N, X is 10 C-CH 2 NH 2 , Y is C-CO 2 H, Z is CH, and X 0 is hydrido; B is 2-propynyl, A is single bond, Y is 4-amidinobenzyl, W is C OH, X is C-CH 2 CH 2 NH 2 , Y is C-OH, Z is CH, and X 0 is hydrido; B is hydrido, A is CH 2 , Y0 is 4-amidinobenzyl, W is C-NH 2 , X is C CH20H, Y is C- NH 2 , Z is CH, and X 0 is hydrido; 15 B is cycylopropyl, A is single bond, Y0 is 4-amidinobenzyl, W is CH, X is C-NH 2 , Y is C-CH 2 CO 2 H, Z is CH, and X 0 is hydrido; B is cyclobutyl, A is single bond, Y0 is 4-amidino-2-fluorobenzyl, W is N, X is C-CH 2 NH 2 , Y is C-CO 2 H, Z is CH, and X 0 is hydrido; B is cyclobutyl, A is single bond, Y is 4-amidinobenzyl, W is C-OH, X 20 is C-CH 2 CH 2 NH 2 , Y is C-OH, Z is CH, and X 0 is hydrido; B is cyclopropyl, A is single bond, Y is 4-amidino-2-fluorobenzyl, W is C-NH 2 , X is C-CH 2 OH, Y is C- NH 2 , Z is CH, and X 0 is hydrido; B is cyclobutyl, A is single bond, Y0 is 4-amidinobenzyl, W is CH, X is C-NH 2 , Y is C-CH 2 CO 2 H, Z is CH, and X 0 is hydrido; 309 WO 00/69826 PCT/US00/08220 B is cyclobutyl, A is single bond, Yo 0 is 4 -amidino-3-fluorobenzyl, W is N, X is C-CH 2 NH 2 , Y is C-CO 2 H, Z is CH, and X 0 is hydrido; B is cyclopentyl, A is single bond, Y is 4-amidinobenzyl, W is C-OH, X is C-CH 2 CH 2 NH 2 , Y is C-OH, Z is CH, and X 0 is hydrido; 5 B is cyclobutyl, A is single bond, Y is 4-amidinobenzyl, W is C-NH 2 , X is C-CH 2 OH, Y is C- NH 2 , Z is CH, and X 0 is hydrido; B is cyclopropyl, A is CH 2 , Y is 4-amidinobenzyl, W is CH, X is C NH 2 , Y is C-CH 2 CO 2 H, Z is CH, and X 0 is hydrido; B is 2-(2R)-bicyclo[2.2.1]-heptyl, A is single bond, Yo 0 is 4 10 amidinobenzyl, W is N, X is C-CH 2 NH 2 , Y is C-CO 2 H, Z is CH, and X 0 is hydrido; B is cyclopentyl, A is single bond, Yo 0 is 4 -amidino-2-fluorobenzyl, W is C-OH, X is C-CH 2 CH 2 NH 2 , Y is C-OH, Z is CH, and X 0 is hydrido; B is cyclohexyl, A is CH 2 CH 2 , Y is 4-amidinobenzyl, W is C-NH 2 , 15 X is C-CH 2 OH, Y is C- NH 2 , Z is CH, and X 0 is hydrido.
41. The compound having the Formula: R 1 Xo R2 B N N H H 0 or a pharmaceutically acceptable salt thereof, wherein; 20 B is the Formula: 310 WO 00/69826 PCT/US00/08220 R3 4 R 3 3 R 3 5 R 3 2 R 3 6 32 33 34 35 36 R 3 2 , R 3 3 , R 3 4 , R 3 5 , and R 3 6 are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkylenedioxy, haloalkylthio, alkanoyloxy, alkoxy, hydroxy, amino, 5 alkoxyamino, haloalkanoyl, nitro, lower alkylamino, alkylthio, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, alkylsulfonamido, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, alkyl, alkenyl, halo, haloalkyl, haloalkenyl, haloalkoxy, hydroxyalkyl, alkylamino, carboalkoxy, carboxy, carboxamido, cyano, and Qb 10 B is optionally selected from the group consisting of hydrido, trialkylsilyl, C2-C8 alkyl, C3-C8 alkylenyl, C3-C8 alkenyl, C3-C8 alkynyl, and C2-C8 haloalkyl, wherein each member of group B is optionally substituted at any carbon up to and including 6 atoms from the point of attachment of B to A with one or more of the group consisting of R 3 2 , R 3 3 15 R 3 4 , R 3 5 , and R36 B is optionally selected from the group consisting of C3-C12 cycloalkyl and C4-C saturated heterocyclyl, wherein each ring carbon is 33 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 20 no more than one ring carbon is substituted by oxo at the same time, ring carbons and a nitrogen adjacent to the carbon atom at the point of attachment 9 13 are optionally substituted with R or R , a ring carbon or nitrogen adjacent to the R 9 position and two atoms from the point of attachment is optionally 311 WO 00/69826 PCT/US00/08220 10 13 substituted with R 10 , a ring carbon or nitrogen adjacent to the R 13 position 12 and two atoms from the point of attachment is optionally substituted with R2 a ring carbon three atoms from the point of attachment and adjacent to the R 10 position is optionally substituted with R 1 1 , a ring carbon three atoms from the 5 point of attachment and adjacent to the R 12 position is optionally substituted with R 3 3 , and a ring carbon four atoms from the point of attachment and adjacent to the R 11 and R 3 3 positions is optionally substituted with R34 9 10 11 12 13 R9, R10, R11, R12, and R 13 are independently selected from the group consisting of hydrido, acetamido, haloacetamido, alkoxyamino, 10 alkanoyl, haloalkanoyl, amidino, guanidino, alkylenedioxy, haloalkylthio, alkoxy, hydroxy, amino, lower alkylamino, alkylthio, alkylsuffinyl, alkylsulfamido, alkylsulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, carboalkoxy, carboxy, carboxyalkyl, carboxamido, and cyano; 15 A is selected from the group consisting of single covalent bond and (CH(R 15))pa-(W 7)rr wherein rr is an integer selected from 0 through 1, pa is an integer selected from 0 through 3, and W 7 is selected from the group consisting of 0, S, C(0), (R 7)NC(0), (R7)NC(S), and N(R7); R 7 is selected from the group consisting of hydrido, hydroxy and alkyl; 20 R 15 is selected from the group consisting of hydrido, hydroxy. halo, alkyl, and haloalkyl; R 1 and X 0 are independently selected from the group consisting of hydrido, hydroxy, hydroxyamino, amidino, amino, cyano, hydroxyalkyl, alkoxy, alkyl, alkylamino, aminoalkyl, alkylthio, alkoxyamino, haloalkyl, 25 haloalkoxy, and halo; R 2 is Zo-Q; 312 WO 00/69826 PCT/US00/08220 Z is selected from the group consisting of covalent single bond and (CR41R42)q wherein q is an integer selected from 1 through 2, (CH(R41)) W-(CH(R42))p wherein g and p are integers independently selected from 0 through 3 and W is selected from the group consisting of O, S, and N(R41), 5 and (CH(R41))e 2-(CH(R42)h wherein e and h are integers independently selected from 0 through 1 and 2 is selected from the group consisting of CR41=CR42, 1,2-cyclopropyl, 1,2-cyclobutyl, 1,2-cyclohexyl, 1,3 cyclohexyl, 1,2-cyclopentyl, 1,3-cyclopentyl, 2 , 3 -morpholinyl, 2,4 morpholinyl, 2,6-morpholinyl, 3,4-morpholinyl, 3 ,5-morpholinyl, 1,2 10 piperazinyl, 1,3-piperazinyl, 2 ,3-piperazinyl, 2 , 6 -piperazinyl, 1,2-piperidinyl, 1,3-piperidinyl, 2,3-piperidinyl, 2,4-piperidinyl, 2 ,6-piperidinyl, 3,4 piperidinyl, 1,2-pyrrolidinyl, 1,3-pyrrolidinyl, 2 , 3 -pyrrolidinyl, 2,4 pyrrolidinyl, 2,5-pyrrolidinyl, 3,4-pyrrolidinyl, 2 , 3 -tetrahydrofuranyl, 2,4 tetrahydrofuranyl, 2,5-tetrahydrofuranyl, and 3 ,4-tetrahydrofuranyl, with the 15 proviso that Zo is directly bonded to the pyrazinone ring; R 4 1 and R 4 2 are independently selected from the group consisting of hydrido, hydroxy, and amino; Q is selected from the group consisting of hydrido with the proviso that Z is other than a covalent single bond, aryl and heteroaryl, wherein a carbon 20 adjacent to the carbon at the point of attachment is optionally substituted by R9 the other carbon adjacent to the carbon at the point of attachment is optionally 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 10 , a carbon adjacent to R 13 and two atoms from the carbon at the point of attachment is optionally 12 10 12 25 substituted by R 12 , and any carbon adjacent to both R 10 and R 2 is optionally substituted by Rl 313 WO 00/69826 PCT/US00/08220 4a 4a K is CHR 4 a wherein R 4 a is selected from the group consisting of hydrido, hydroxyalkyl, alkyl, alkoxyalkyl, alkylthioalkyl, and haloalkyl; E is selected from the group consisting of a covalent single bond, C(O)N(H), (H)NC(O), (R7)NS(O) 2 , and S(O) 2 N(R7); bT b 5 Y is QbS; Qs is (CR37R38)b wherein b is an integer selected from 1 through 4, R 3 7 is selected from the group consisting of hydrido, alkyl, and haloalkyl, and R 3 8 is selected from the group consisting of hydrido, alkyl, haloalkyl, aroyl, and heteroaroyl with the provisos that there is at least one aroyl or heteroaroyl 10 substituent, that no more than one aroyl or heteroaroyl is bonded to (CR37 R 38)b at the same time, that said aroyl and said heteroaroyl are optionally substituted at from one through three of the ring carbons with a 16 17 18 19 substituent selected from the group consisting of R 16 , R 17 , R 18 , and R 19 that said aroyl and said heteroaroyl are bonded to the CR37R38 that is directly 15 bonded to Eo, that is no more than one alkyl or one haloalkyl is bonded to a CR37R38 at the same time, and that said alkyl and haloalkyl are bonded to a carbon other than the one bonding the aroyl or heteroaroyl; 16 , 17 , 18 19 R, R , R, and R are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, haloalkylthio, alkoxy, 20 hydroxy, amino, alkoxyamino, lower alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, and cyano; R16 an 19 Qb R16 and R19 are optionally Qb with the proviso that no more than one of R 16 and R 19 is Qb at the same time and that Qb is Qbe 314 WO 00/69826 PCT/US00/08220 b 20 21 be b Q is selected from the group consisting of NR20R21, be wherein Qbe is 26 25 23 24 25 23 24 hydrido, N(R26)C(NR25)N(R )(R24), and C(NR25)NR R 2 4 , with the provisos that no more than one of R 20 and R 2 1 is hydroxy, amino, alkylamino, or dialkylamino at the same time and that no more than one of R 23 and R 24 is 5 hydroxy, amino, alkylamino, or dialkylamino at the same time; 20 21 23 24 25 26 R20, R 2 1 , R , R24, R25, and R 26 are independently selected from the group consisting of hydrido, alkyl, hydroxy, amino, alkylamino and dialkylamino. 10 42. The compound as recited in Claim 41 having the Formula: R 1 o R2 B 1** :N N A H H 0 O or a pharmaceutically acceptable salt thereof, wherein; B is the Formula: R 3 4 R 3 3 R 3 5 R 3 2 R36 32 33 34 35 36 15 R , R , R , R , and R are independently selected from the group consisting of hydrido, amidino, guanidino, methyl, ethyl, methoxy, ethoxy, hydroxy, amino, N-methylamino, dimethylamino, methylthio, 315 WO 00/69826 PCT/US00/08220 ethylthio, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, fluoro, chloro, bromo, amidosulfonyl, N-methylamidosulfonyl, hydroxymethyl, amidocarbonyl, carboxy, cyano, and Qb B is optionally selected from the group consisting of hydrido, ethyl, 2 5 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, 1-methyl-2-pentenyl, 1 10 methyl-3-pentenyl, 1-methyl-2-pentynyl, 1-methyl-3-pentynyl, 3-hexyl, 1 ethyl-2-butenyl, 1-heptyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 2 heptynyl, 3-heptynyl, 4-heptynyl, 5-heptynyl, 2-heptyl, 1-methyl-2-hexenyl, 1-methyl-3-hexenyl, 1-methyl-4-hexenyl, 1-methyl-2-hexynyl, 1-methyl-3 hexynyl, 1-methyl-4-hexynyl, 3-heptyl, 1-ethyl-2-pentenyl, 1-ethyl-3 15 pentenyl, 1-ethyl-2-pentynyl, 1-ethyl-3-pentynyl, 2,2,2-trifluoroethyl, 2,2 difluoropropyl, 4-trifluoromethyl-5,5,5-trifluoropentyl, 4 trifluoromethylpentyl, 5,5,6,6,6-pentafluorohexyl, and 3,3,3-trifluoropropyl, wherein each member of group B is optionally substituted at any carbon up to and including 5 atoms from the point of attachment of B to A with one or more 32 33 34 35 36 20 of the group consisting of R , R , R , R , and R ; B is optionally selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 2-(2R)-bicyclo[2.2.1] heptyl, oxetan-3-yl, azetidin-1-yl, azetidin-2-yl, azetidin-3-yl, and bicyclo[3.1.0]hexan-6-yl, wherein each ring carbon is optionally substituted 33 25 with R 33 , ring carbons and anitrogen adjacent to the carbon atom at the point 9 13 of attachment is optionally substituted with R or R 13 , a ring carbon or nitrogen adjacent to the R 9 position and two atoms from the point of attachment 10 is optionally substituted with R 10 , and a ring carbon or nitrogen adjacent to the R 13 position and two atoms from the point of attachment is optionally 30 substituted with R12 316 WO 00/69826 PCT/US00/08220 R , R 11 , and R 13 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, 5 N,N-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, amidocarbonyl, N-methylamidocarbonyl, carboxy, and cyano; R 10 and R 12 are independently selected from the group consisting of hydrido, amidino, amidocarbonyl, N-methylamidocarbonyl, guanidino, methyl, ethyl, methoxy, ethoxy, hydroxy, hydroxymethyl, 1-hydroxyethyl, 2 10 hydroxyethyl, carboxy, carboxymethyl, amino, acetamido, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, trifluoroacetamido, aminomethyl, N methylamino, dimethylamino, amidosulfonyl, N-methylamidosulfonyl, N,N dimethylamidosulfonyl, methoxycarbonyl, fluoro, chloro, bromo, and cyano; A is selected from the group consisting of single covalent bond, NH, 15 N(CH 3 ), CH 2 , CH 3 CH, CH 2 CH 2 , and CH 2 CH 2 CH 2 ; R 1 and X 0 are independently selected from the group consisting of hydrido, hydroxy, amino, amidino, hydroxyamino, aminomethyl, 1 aminoethyl, methylamino, dimethylamino, cyano, methyl, ethyl, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, methoxy, 20 hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, methoxyamino, methylthio, ethylthio, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro, and bromo; R 2 is selected from the group consisting of phenyl, 2-thienyl, 2-furyl, 2-pyrrolyl, 2-imidazolyl, 2-thiazolyl, 3-isoxazolyl, 2-pyridyl, and 3-pyridyl, 25 wherein a carbon adjacent to the carbon at the point of attachment is optionally 9 substituted by R 9 , the other carbon adjacent to the carbon at the point of 13 9 attachment is optionally substituted by R , a carbon adjacent to R and two atoms from the carbon at the point of attachment is optionally substituted by 10 13 R 10 , a carbon adjacent to R 13 and two atoms from the carbon at the point of 317 WO 00/69826 PCT/US00/08220 attachment is optionally substituted by R 12 , and any carbon adjacent to both RI 0 and R 12 is optionally substituted by R 1 1 YAT bb s YAT is Qb-Qs; QS is selected from the group consisting of: 5 C[R 3 7 (benzoyl)](CR 3 7 R 3 8 )b' ] , C[R37(2-pyridylcarbonyl])](CR37 R 38 )b], C[R 3 7 (3 -pyridylcarbonyl])](CR 3 7 R 3 8 )b] , C[R 3 7 (4 -pyridylcarbonyl])](CR 3 7 R 3 8 )b ] , C[R37 (2-thienylcarbonyl])](CR37R38)b], 10 C[R 3 7 (3-thienylcarbonyl])](CR 3 7 R 3 8 )b ] , C[R 37 (2-thi a zol ylcarbonyl])](CR 3 7 R 3 8 )b ], C[R 37 (4 -thi a zol ylcarbonyl])](CR37R38)b], and C[R37(5-thiazolylcarbonyl])](CR 3 7 R 3 8 )b] , wherein b is an integer selected 37 38 from 1 through 3, R 3 7 and R 3 8 are independently selected from the group 15 consisting of hydrido, alkyl, and haloalkyl, with the provisos that said aroyl and said heteroaroyl are optionally substituted at from one through three of the 16 ring carbons with a substituent selected from the group consisting of R 16 17 18 19 17 18 R 17 , R 8 , and R 9 with the proviso that R 17 and R 18 are optionally substituted at a carbon selected from other than the meta and para carbons 20 relative to the carbonyl of the benzoyl substituent and the heteroaroyl substituent, that said benzoyl and said heteroaroyl are bonded to the carbon directly bonded to amide nitrogen of the 1-(amidocarbonymethylene) group, and that is no more than one alkyl or one haloalkyl is bonded to a CR37R 3 8 at the same time; 318 WO 00/69826 PCT/US00/08220 16 17 18 19 R 16 , R 17 , R 18 , 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, 5 methylsulfonyl, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, trifluoromethoxy, fluoro, chloro, amidosulfonyl, N-methylamidosulfonyl, hydroxymethyl, carboxy, and cyano; Qb is selected from the group consisting of NR 2 0 R 2 1 and 25 224 b C(NR )NR2R 2 4 , with the proviso that said Q group is bonded directly to a 10 carbon atom; 20 21 23 24 25 R20, R 2 1 , R , R24, and R 2 5 are independently selected from the group consisting of hydrido, methyl, and ethyl.
43. The compound as recited in Claim 42 or a pharmaceutically acceptable salt 15 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 20 hydroxyphenyl, 4-hydroxyphenyl, 3 -methoxyaminophenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-methylphenyl, 4-methylphenyl, phenyl, and 3 trifluoromethylphenyl; 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 25 butyl, tert-butyl, isobutyl, 1-pentyl, 3-pentyl, 2-methylbutyl, 2,2,2 trifluoroethyl, 6-amidocarbonylhexyl, 4 -methyl-2-pentyl, 3-hydroxypropyl, 3 methoxy-2-propyl, 2-methoxyethyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 2 dimethylaminopropyl, 2-cyanoethyl, 6-hydroxyhexyl, 2-hydroxyethyl, 2 amidinoethyl, 2-guanidinoethyl, 3-guanidinopropyl, 4-guanidinobutyl, 3 30 hydroxypropyl, 4-hydroxybutyl, 6-cyanohexyl, 2-dimethylaminoethyl, 3 methylbutyl, 2-methylbutyl, (S)-2-methylbutyl, 3 -aminopropyl, 2-hexyl, and 4-aminobutyl; 319 WO 00/69826 PCT/US00/08220 B is optionally selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2-(2R)-bicyclo[2.2.1]-heptyl, oxetan-3 yl, azetidin-1-yl, azetidin-2-yl, an d azetidin-3-yl; A is selected from the group consisting of single covalent bond, CH 2 , 5 CH 3 CH, CH 2 CH 2 , and CH 2 CH 2 CH 2 ; R 1 and X 0 are independently selected from the group consisting of hydrido, hydroxy, amino, amrnidino, hydroxyamino, aminomethyl, methylamino, cyano, methyl, trifluoromethyl, methoxy, hydroxymethyl, methoxyamino, methylthio, trifluoromethoxy, fluoro, and chloro; 10 R 2 is selected from the group consisting of 5-amino-3 amidocarbonylphenyl, 5-amino-2-fluorophenyl, 3-amino-5 hydroxymethylphenyl, 5 -amino-3-methoxycarbonylphenyl, 3-amidinophenyl, 3-amino-2-methylphenyl, 5-amino-2-methylthiophenyl, 3-aminophenyl, benzyl, 3-carboxyphenyl, 3-carboxy-5-aminophenyl, 3-carboxy-5 15 hydroxyphenyl, 3 -carboxymethyl-5-aminophenyl, 3-carboxymethyl-5 hydroxyphenyl, 3-carboxymethylphenyl, 3-chlorophenyl, 2-chlorophenyl, 2,6-dichlorophenyl, 3-cyanophenyl, 3-dimethylaminophenyl, 2-fluorophenyl, 3-fluorophenyl, 2,5-difluorophenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 3 methanesulfonylaminophenyl, 2-methoxyphenyl, 3-methoxyphenyl, 3 20 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; 25 YAT is QbQ s; QS is selected from the group consisting of: [CH(benzoyl)](CH 2 ) b , [CH(2-pyridylcarbonyl)](CH 2 )b, [CH(3-pyridylcarbonyl)](CH 2 ) b , [CH(4-pyridylcarbonyl)](CH 2 )b, [CH(2-thienylcarbonyl)](CH 2 ) b , [CH(3-thienylcarbonyl)](CH 2 )b, 30 [CH(2-thiazolylcarbonyl)](CH 2 )b, [CH(4-thiazolylcarbonyl)](CH 2 )b, 320 WO 00/69826 PCT/US00/08220 and [CH(5-thiazolylcarbonyl)](CH 2 )b. wherein b is an integer selected from 1 through 3, with the provisos that said aroyl and said heteroaroyl are optionally substituted at from one through three of the ring carbons with a substituent 16 17 18 19 selected from the group consisting of R 16 , R 17 , R 18 , and R 9 with the 5 proviso that R 17 and R 18 are optionally substituted at a carbon selected from other than the meta and para carbons relative to the carbonyl of the benzoyl substituent and the heteroaroyl substituent, and that said benzoyl and said heteroaroyl substituent are bonded to the carbon directly bonded to amide nitrogen of the 1-(amidocarbonymethylene) group; 10 R 16 and R19 are independently selected from the group consisting of hydrido, amidino, amino, aminomethyl, methoxy, methylamino, hydroxy, hydroxymethyl, fluoro, chloro, and cyano; R 17 and R 18 are independently selected from the group consisting of hydrido, fluoro, chloro, hydroxy, hydroxymethyl, amino, carboxy, and cyano; 15 Qb is C(NR 25)NR23 R24 23 24 25 R , R 2 4 , and R 2 5 are independently selected from the group consisting of hydrido and methyl.
44. The compound as recited in Claim 43 or a pharmaceutically acceptable salt 20 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, and phenyl; B is optionally selected from the group consisting of hydrido,ethyl, 2 25 propenyl, 2-propynyl, propyl, isopropyl, butyl, 2-butyl, (R)-2-butyl,(S)-2 butyl, ten-butyl, isobutyl, 1-pentyl, 3-pentyl, 2-methylbutyl, 2,2,2 trifluoroethyl, 6-amidocarbonylhexyl, 4 -methyl-2-pentyl, 3-hydroxypropyl, 3 methoxy-2-propyl, 2-methoxyethyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 2 dimethylaminopropyl, 2-cyanoethyl, 6-hydroxyhexyl, 2-hydroxyethyl, 2 30 amidinoethyl, 2-guanidinoethyl, 3-guanidinopropyl, 4-guanidinobutyl, 3 hydroxypropyl, 4-hydroxybutyl, 6-cyanohexyl, 2-dimethylaminoethyl, 3 321 WO 00/69826 PCT/US00/08220 methylbutyl, 2-methylbutyl, (S)-2-methylbutyl, 3-aminopropyl, 2-hexyl, and 4-aminobutyl; B is optionally selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2-(2R)-bicyclo[2.2.1]-heptyl, oxetan-3 5 yl, azetidin-1-yl, azetidin-2-yl, and azetidin-3-yl; A is selected from the group consisting of a single covalent bond, CH 2 , CH 2 CH 2 and CH 2 CH 2 CH 2 ; X 0 is selected from the group consisting of hydrido, hydroxy, amino, amidino, aminomethyl, cyano, methyl, trifluoromethyl, hydroxymethyl, and 10 fluoro; R 1 is selected from the group consisting of hydrido, hydroxy, amino, aminomethyl, methylamino, cyano, methyl, trifluoromethyl, methoxy, methylthio, trifluoromethoxy, fluoro, and chloro; R 2 is selected from the group consisting of 3-aminophenyl, benzyl, 15 2,6-dichlorophenyl, 5-amino-2-thienyl, 5 -amino-2-fluorophenyl, 3-amino-2 methylphenyl, 5-amino-2-methylthiophenyl, 3-carboxyphenyl, 3-cyanophenyl, 3-chlorophenyl, 2-hydroxyhenyl, 3-hydroxyphenyl, 3 methanesulfonylaminophenyl, 3-methoxycarbonylphenyl, 3 dimethylaminophenyl, 3-methylaminophenyl, 2-methylphenyl, 3 20 methylphenyl, phenyl, 3-pyridyl, 3-trifluoroacetamidophenyl, 3-bromo-2 thienyl, 2-thienyl, and 3-thienyl; YAT is selected from the group consisting of 5-guanidino-1-oxo-1-(2 thiazolyl)-2-pentyl, 5-guanidino- 1-oxo- 1-(4-thiazolyl)-2-pentyl, 5-guanidino 1-oxo-1-(5-thiazolyl)-2-pentyl, 5-guanidino- 1-oxo- 1-(4-amino-2-thiazolyl)-2 25 pentyl, and 5-guanidino- 1-oxo- 1-phenyl-2-pentyl.
45. A compound as recited in Claim 41 where said compound is selected from the group having the Formula: 322 WO 00/69826 PCT/US00/08220 R 1 Xo R 2 B N N yAT H H O or a pharmaceutically acceptable salt thereof, wherein: R 2 is 3-aminophenyl, B is phenyl, A is CH 2 , YAT is 5-guanidino-1-oxo-1 (2-thiazolyl)-2-pentyl, R 1 is hydroxymethyl, and X 0 is hydrido; R 2 is phenyl, B is phenyl, A is CH 2 CH 2 , yAT is 5-guanidino-1-oxo-1-(2 thiazolyl)-2-pentyl, R 1 is hydroxymethyl, and X 0 is hydrido; R 2 is benzyl, B is phenyl, A is CH 2 CH 2 , AT is 5-guanidino-1-oxo-1-(2 thiazolyl)-2-pentyl, R 1 is hydroxymethyl, and X 0 is hydrido; R 2 is phenyl, B is phenyl, A is CH 2 CH 2 , YAT is 5-guanidino-1-oxo-1-(2 10 thiazolyl)-2-pentyl, R 1 is hydroxymethyl, and X 0 is hydrido; R 2 is benzyl, B is phenyl, A is CH 2 CH 2 , YAT is 5-guanidino-1-oxo-1-(2 thiazolyl)-2-pentyl, R 1 is hydroxymethyl, and X 0 is hydrido; R 2 is phenyl, B is phenyl, A is CH 2 CH 2 , AT is 5-guanidino-1-oxo-1-(2 thiazolyl)-2-pentyl, R 1 is hydroxymethyl, and X 0 is hydrido; 15 R 2 is 3-aminophenyl, B is phenyl, A is CH 2 , AT is 5-guanidino-1-oxo-1 (2-thiazolyl)-2-pentyl, R 1 is aminomethyl, and X 0 is fluoro; R 2 is phenyl, B is phenyl, A is CH 2 CH 2 , AT is 5-guanidino-1-oxo-1-(2 thiazolyl)-2-pentyl, R 1 is aminomethyl, and X 0 is fluoro; R 2 is benzyl, B is phenyl, A is CH 2 CH 2 , YAT is 5-guanidino-1-oxo-1-(2 20 thiazolyl)-2-pentyl, R 1 is aminomethyl, and X 0 is fluoro; 323 WO 00/69826 PCT/US00/08220 R 2 is phenyl, B is phenyl, A is CH 2 CH 2 , AT is 5-guanidino-1-oxo-1-(2 thiazolyl)-2-pentyl, R 1 is amninomethyl, and Xo is fluoro; R 2 is benzyl, B is phenyl, A is CH 2 CH 2 , AT is 5-guanidino-1-oxo-1-(2 thiazolyl)-2-pentyl, R 1 is aminomethyl, and Xo is fluoro; 5R 2 is phenyl, B is phenyl, A is CH 2 CH 2 , YAT is 5-guanidino-1-oxo-1-(2 thiazolyl)-2-pentyl, R 1 is aminomethyl, and Xo is fluoro; R 2 is 3-amrninophenyl, B is phenyl, A is CH 2 , AT is 5-guanidino-1-oxo-1 (2-thiazolyl)-2-pentyl, R 1 is fluoro, and Xo is hydroxymethyl; R 2 is phenyl, B is phenyl, A is CH 2 CH 2 , AT is 5-guanidino-1-oxo-1-(2 10 thiazolyl)-2-pentyl, R 1 is fluoro, and Xo is hydroxymethyl; R 2 is benzyl, B is phenyl, A is CH 2 CH 2 , YAT is 5-guanidino-1-oxo-1-(2 thiazolyl)-2-pentyl, R 1 is fluoro, and Xo is hydroxymethyl; R 2 is phenyl, B is phenyl, A is CH 2 CH 2 , YAT is 5-guanidino-1-oxo-1-(2 thiazolyl)-2-pentyl, R 1 is fluoro, and Xo is hydroxymethyl; 15 R 2 is benzyl, B is phenyl, A is CH 2 CH 2 , AT is 5-guanidino-1-oxo-1-(2 thiazolyl)-2-pentyl, R 1 is fluoro, and Xo is hydroxymethyl; R 2 is phenyl, B is phenyl, A is CH 2 CH 2 , yAT is 5-guanidino-1-oxo-1-(2 thiazolyl)-2-pentyl, R 1 is fluoro, and Xo is hydroxymethyl; R 2 is 3-aminophenyl, B is phenyl, A is CH 2 , AT is 5-guanidino-1-oxo-1 20 (2-thiazolyl)-2-pentyl, R 1 is methoxy, and Xo is aminomethyl; R 2 is phenyl, B is phenyl, A is CH 2 CH 2 , YAT is 5-guanidino-1-oxo-1-(2 thiazolyl)-2-pentyl, R 1 is methoxy, and Xo is aminomethyl; 2 AT. R 2 is benzyl, B is phenyl, A is CH 2 CH 2 , YT is 5-guanidino-1-oxo-1-(2 thiazolyl)-2-pentyl, R 1 is methoxy, and Xo is amninomethyl; 324 WO 00/69826 PCT/US00/08220 R 2 is phenyl, B is phenyl, A is CH 2 CH 2 , YAT is 5-guanidino-1-oxo-1-(2 thiazolyl)-2-pentyl, R 1 is methoxy, and X 0 is aminomethyl; R 2 is benzyl, B is phenyl, A is CH 2 CH 2 , YAT is 5-guanidino-1-oxo-1-(2 thiazolyl)-2-pentyl, R 1 is methoxy, and X 0 is aminomethyl; 5R 2 is phenyl, B is phenyl, A is CH 2 CH 2 , YAT is 5-guanidino-1-oxo-1-(2 thiazolyl)-2-pentyl, R 1 is methoxy, and X 0 is aminomethyl.
46. A composition for inhibiting thrombotic conditions in blood comprising a compound of any one of Claims 8, 16, 24, 32, 40, and 45 and a 10 pharmaceutically acceptable carrier.
47. A composition for inhibiting thrombotic conditions in blood comprising a compound of any one of Claims 1 through 7, Claims 9 through 15, Claims 17 through 23, Claims 25 through 31, Claims 33 through 39, and Claims 41 15 through 44 and a pharmaceutically acceptable carrier.
48. A method for inhibiting thrombotic conditions in blood comprising adding to blood a therapeutically effective amount of a composition of any one of Claims 46 and 47. 20
49. A method for inhibiting formation of blood platelet aggregates in blood comprising adding to blood a therapeutically effective amount of a composition of any one of Claims 46 and 47. 25 50. A method for inhibiting thrombus formation in blood comprising adding to blood a therapeutically effective amount of a composition of any one of Claims 46 and 47.
51. A method for treating or preventing venuous thromboembolism and 30 pulmonary embolism in a mammal comprising administering to the mammal a therapeutically effective amount of a composition of any one of Claims 46 and 47. 325 WO 00/69826 PCT/US00/08220
52. A method for treating or preventing deep vein thrombosis in a mammal comprising administering to the mammal a therapeutically effective amount of a composition of of any one of Claims 46 and 47. 5 53. A method for treating or preventing cardiogenic thromboembolism in a mammal comprising administering to the mammal a therapeutically effective amount of a composition of any one of Claims 46 and 47.
54. A method for treating or preventing thromboembolic stroke in humans and 10 other mammals comprising administering to the mammal a therapeutically effective amount of a composition of any one of Claims 46 and 47.
55. A method for treating or preventing thrombosis associated with cancer and cancer chemotherapy in humans and other mammals comprising administering 15 to the mammal a therapeutically effective amount of a composition of any one of Claims 46 and 47.
56. A method for treating or preventing unstable angina in humans and other mammals comprising administering to the mammal a therapeutically effective 20 amount of a composition of any one of Claims 46 and 47.
57. 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 45 with a therapeutically effective amount of fibrinogen receptor 25 antagonist.
58. The use of a compound of any one of Claims 1 through 45, or a pharmaceutically acceptable salt thereof, in the manufacture of medicament for inhibiting thrombus formation, treating thrombus formation, or preventing 30 thrombus formation in a mammal. 326
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