AU771740B2 - Substituted polycyclic aryl and heteroaryl uracils as anticoagulative agents - Google Patents

Substituted polycyclic aryl and heteroaryl uracils as anticoagulative agents Download PDF

Info

Publication number
AU771740B2
AU771740B2 AU49724/00A AU4972400A AU771740B2 AU 771740 B2 AU771740 B2 AU 771740B2 AU 49724/00 A AU49724/00 A AU 49724/00A AU 4972400 A AU4972400 A AU 4972400A AU 771740 B2 AU771740 B2 AU 771740B2
Authority
AU
Australia
Prior art keywords
group
ring carbon
optionally substituted
hydrido
amidinobenzyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
AU49724/00A
Other versions
AU4972400A (en
Inventor
Darin E. Jones
Melvin L. Rueppel
Michael S. South
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Pharmacia LLC
Original Assignee
Pharmacia LLC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Pharmacia LLC filed Critical Pharmacia LLC
Publication of AU4972400A publication Critical patent/AU4972400A/en
Application granted granted Critical
Publication of AU771740B2 publication Critical patent/AU771740B2/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/52—Two oxygen atoms
    • C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
    • C07D239/545—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D253/00—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00
    • C07D253/02—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00 not condensed with other rings
    • C07D253/06—1,2,4-Triazines
    • C07D253/065—1,2,4-Triazines having three double bonds between ring members or between ring members and non-ring members
    • C07D253/07—1,2,4-Triazines having three double bonds between ring members or between ring members and non-ring members 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
    • C07D253/075—Two hetero atoms, in positions 3 and 5
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Engineering & Computer Science (AREA)
  • Public Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Description

WO 00/69833 PCT/USOO/08226 SUBSTITUTED POLYCYCLIC ARYL AND HETEROARYL URACILS AS ANTICOAGULATIVE
AGENTS
Field of the Invention This invention is in the field of anticoagulant therapy, and specifically relates to compounds, compositions and methods for preventing and treating thrombotic conditions such as coronary artery and cerebrovascular disease.
More particularly, the invention relates to substituted polycyclic aryl and heteroaryl uracil compounds that inhibit serine proteases of the coagulation cascade.
Background of the Invention Physiological systems control the fluidity of blood in mammals [Majerus, P. W. et al: Anticoagulant, Thrombolytic, and Antiplplatelet Drugs.
In Hardman, J. G. and Limbird, L. editors: Goodman Gilman's The Pharmacological Basis of Therapeutics. 9th edition. New York, McGraw-Hill Book Co., 1996, pp. 1341-1343]. Blood must remain fluid within the vascular systems and yet be able to undergo hemostasis, cessation of blood loss from a damaged vessel, quickly. Hemostasis or clotting begins when platelets first adhere to macromolecules in subendothelian regions of an injured and/or damaged vessels. These platelets aggregate to form the primary hemostatic plug and stimulate local activation of plasma coagulation factors leading to generation of a fibrin clot that reinforces the aggregated platelets.
Plasma coagulation factors include factors II, V, VII, VIII, IX, X, XI, and XII; these are also called protease zymogens. These coagulation factors or protease zymogens are activated by serine proteases leading to coagulation in a so called "coagulation cascade" or chain reaction [Handin, R. Bleeding and Thrombosis. In Wilson, et al. editors: Harrison's Principles of Internal Medicine. 12th Edition, New York, McGraw-Hill Book Co., 1991,p.350].
Coagulation or clotting occurs in two ways through different pathways. An intrinsic or contact pathway leads from XII to 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 offibrinogen to fibrin. Polymerization of fibrin leads to a fibrin clot. An extrinsic pathway is initiated by the conversion of coagulation factor VII to VIla by Xa. The presence of Tissue Factor and WO 00/69833 PCT/US00/08226 VIla accelerates formation of Xa in the presence of calcium ion and phospholipids. Formation of Xa leads to thrombin, fibrin, and a fibrin clot as described above. The presence of one or more of these many different coagulation factors and two distinct pathways of clotting could enable the efficacious, selective control and better understanding of parts of the coagulation or clotting process.
While clotting as a result of an injury to a blood vessel is a critical physiological process for mammals such as man, clotting can also lead to disease states. A pathological process called thrombosis results when platelet aggregation and/or a fibrin clot blocks occludes) a blood vessel. Arterial thrombosis may result in ischemic necrosis of the tissue supplied by the artery.
When the thrombosis occurs in a coronary artery, a myocardial infarction or heart attack can result. A thrombosis occurring in a vein may cause tissues drained by the vein to become edematous and inflamed. Thrombosis of a deep vein may be complicated by a pulmonary embolism. Preventing or treating clots in a blood vessel may be therapeutically useful by inhibiting formation of blood platelet aggregates, inhibiting formation of fibrin, inhibiting thrombus formation, inhibiting embolus formation, and for treating or preventing unstable angina, refractory angina, myocardial infarction, transient ischemic attacks, atrial fibrillation, thrombotic stroke, embolic stroke, deep vein thrombosis, disseminated intravascular coagulation, ocular build up of fibrin, and reocclusion or restenosis of recanalized vessels.
There have been several reports of non-peptidic and peptidic uracil compounds that act as an inhibitor of a coagulation factor present in the coagulation cascade or clotting process. In US Patent 5,656,645, Tamura et al.
describe 4,5,6-substituted-3-aminopyridonyl-acetamides, 1,6-substituted-5aminouracinylacetamides, and 2,4-substituted-5-aminopyrimidinonylacetamides in which the amide substituents all have a formyl group and which reportedly have activity against thrombin. In US Patent 5,658,930, Tamura et al. again describe 4,5,6-substituted-3-aminopyridonyl-acetamides, 1,6and 2,4-substituted-5-aminopyrimidinonylacetamides in which the amide substituents all have a formyl group and which reportedly have activity against thrombin. In PCT Patent Applications 96/18644 and 97/46207, Tamura et al. further describe 4,5,6substituted-3-aminopyridonylacetamides, 1,6-substituted-5-aminouracinyl- WO 00/69833 PCT/US0/08226 acetamides, and 2,4-substituted-5-amino-pyrimidinonylacetamides in which the amide substituents all have a formyl group and which reportedly have activity against thrombin.
SUMMARY OF THE INVENTION It is an object of the present invention to provide compounds that are beneficial in anticoagulant therapy and that have a general structure: 2 A 1N K ja Formula It is another object of the present invention to provide methods for preventing and treating thrombotic conditions, such as coronary artery disease, cerebrovascular disease, and other coagulation related disorders. Such thrombotic conditions are prevented and treated by administering to a patient in need thereof an effective amount of compounds of Formula Various other objects and advantages of the present invention will become apparent from the following description of the invention.
DESCRIPTION OF THE INVENTION The present invention relates to a class of compounds comprising Substituted Polycyclic Aryl and Heteroaryl uracils, which are beneficial in anticoagulant therapy for the treatment and prevention of a variety of thrombotic conditions including coronary artery and cerebrovascular disease, as given in Formula WO 00/69833 PCT/USOO/08226
AI
B A N K E YO J
(I)
or a pharmaceutically acceptable salt thereof, wherein; Ja and Jb are independently selected from the group consisting of 0 and S; Ja is optionally selected from the group consisting.of CH-R 6 and N-R 6 wherein R is a linear spacer moiety having from 1 through 4 contiguous atoms linked to the point of bonding of a substituent selected from the group 4a 4b 14 15 39 40 consisting of R 4 a R R 14, R 15, R39, R and R to form a heterocyclyl ring having 5 through 8 contiguous members; Jb is optionally selected from the group consisting of CH-R 6 and N-R 6 wherein R is a linear spacer moiety having from 1 through 4 contiguous atoms linked to the point of bonding of a substituent selected from the group 4 a 4b 14 consisting of R 4
R
4 R and R to form a heterocyclyl ring having through 8 contiguous members; Ja and Jb are optionally independently selected from the group consisting of CH-R 6 and N-R wherein R is a linear spacer moiety having from 1 through 4 contiguous atoms linked to the points of bonding of both R 4 and R 4 b to form a heterocyclyl ring having 5 through 8 contiguous members; Ja is optionally selected from the group consisting of CH-R 6 and N-R 6 wherein R 6 is a linear spacer moiety having from 1 through 4 contiguous atoms WO 00/69833 WO 0069833PC/USOO/08226 linked to the points of bonding of both R 39and R 40to form a heterocyclyl ring having 5 through 8 contiguous members; B is formula R~~kN 3 R3 D 2 R" 3 6 R R V 1 2 12 1 wherein D D J 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 21 2 1 than one can be a covalent bond, no more than one of D D J J and K is 1 21 2 1 1 21 2 0, normore than one of D D ,Ji J and K is S, one of D D ,Ji J and 1 1 2 12 1 K must be acovalent bond when two of D D J J and K are 0Qand S, 1 2 12 1 and no more than four of D D ,Ji J and K are Nwith the proviso that 32 33 34 35 36 R R R R and R are each independently selected to maintain the tetravalent nature of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen; 9 10 11 12 13 16 17 18 19 32 33 34 R .R ,R ,R ,R R ,R ,R ,R ,RR ,R 36 R ,and R are independently selected from the group consisting of hydrido, acetamido, haloacetamnido, amidino, guanidino, dialkylsuifonium, trialkyiphosphonium, dialkylsulfoniumalkyl, carboxy, heteroaralkylthio, heteroaralkoxy, cycloalkylamnino, acylalkyl, acylalkoxy, aryloylalkoxy, heterocyclyloxy, aralkylaryl, aralkyl, aralkenyl, aralkynyl, heterocyclyl, perhaloaralkyl, aralkylsulfonyl, aralkylsulfonylalkyl, aralkylsulfinyl, aralkylsulfinylalkyl, balocycloalkyl, halocycloalkenyl, cycloalkylsulfinyl, cycloalkylsulfinylalkyl, cycloalkylsulfonyl, cycloalkylsulfonylalkyl, WO 00/69833 WO 0069833PCT/USOO/08226 heteroarylamino, N-heteroarylamino-N-alkylamino, heteroarylaminoalkyl, haloalkykthio, alkanoyloxy, alkoxy, alkoxyalkyl, haloalkoxylaikyl, heteroaralkoxy, cycloalkoxy, cycloalkenyloxy, cycloalkoxyalkyl, cycloalkylalkoxy, cycloalkenyloxyalkyl, cycloalkylenedioxy, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxy, halocycloalkenyloxyalkyl, hydroxy, amino, alkoxyamnino, thio, nitro, lower alkylaxnino, alkylthio, alkylthioalkyl, arylamino, aralkylamino, arylthio, arylthioalkyl, heteroaralkoxyalkyl, alkylsulfinyl, alkylsulfinylalkyl, arylsulfinylalkyl, arylsulfonylalkyl, heteroarylsulfinylalkyl, heteroarylsulfonylalkyl, alkylsulfonyl, alkylsulfonylalkyl, haloalkylsulfinylalkl, haloalkylsulfonylalkyl, alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, monoarylamidosulfonyl, arylsulfonamido, diarylam-idosulfonyl, monoalkyl monoaryl amnidosulfonyl, arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, heterocyclylsulfonyl, heterocyclylthio, alkanoyl. alkenoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, haloalkanoyl, alkyl, alkenyl, alkynyl, alkehyloxy, 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 heterocyclyl, partially saturated heterocyclyl, heteroaryl, heteroaryloxy, heteroaryloxyalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, carboxyalkyl, carboalkoxy, alkoxycarboxamido, alkylamidocarbonylamido, arylamnidocarbonylainido, carboalkoxyalkyl, carboalkoxyalkenyl, carboxy, carboaralkoxy, carboxamido, carboxamidoalkyl, cyano, carbohaloalkoxy, phosphono, phosphonoalkyl, diaralkoxyphosphono, and diaralkoxyphosphonoalkyl; 16 19 32 33 34 35 36 R R R R R ,R and R are independently optionally Q bwith the proviso that no more than one ofR 16and R 19isQ bat the same time and that Q b is be 32 33 33 34 34 35 35 36 R and R R and R R and R ,and R and R are independently optionally selected to form a spacer pair wherein a spacer pair is WO 00/69833 PCTIUSOO/08226 taken together to form a linear moiety having from 3 through 6 contiguous atoms connecting the points of bonding of said spacer pair members to form a ring selected from the group consisting of a cycloalkenyl ring having 5 through 8 contiguous members, a partially saturated heterocyclyl ring having 5 through 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 consisting of spacer pairs R and R R and R R and R and R and R 36 are used at the same time; 9 10 10. 11 11 12 12 13 R and R 1 R and R 1 R and R 1 and R andR are independently optionally selected to form a spacer pair wherein a spacer pair is taken together to form a linear moiety having from 3 through 6 contiguous atoms connecting the points of bonding of said spacer pair members to form a ring selected from the group consisting of a cycloalkenyl ring having 5 through 8 contiguous members, a partially saturated heterocyclyl ring having 5 through 8 contiguous members, a heteroaryl ring having 5 through 6 contiguous members, and an aryl with the proviso that no more than one of the group 9 10 10 11 11 12 12 consisting of spacer pairs R and R 0 R and R 11 R and R 2 and R and R 13 are used at the same time; B is optionally formula (VI): R3 DU
(VI)
3 43 4 wherein D D J and J are independently selected from the group consisting of C, N, O, and S, no more than one of D 3
D
4 J3 ,and J 4 is 0, no 3 4 3 4 1 2 more than one of D D and J is S, and no more than three of D D WO 00/69833 PCT/US00/08226 1 2 32 33 34 J1, and J are N with the proviso that R 3 2
R
3 3 R and R 3 are each independently selected to maintain the tetravalent nature of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen; B is optionally selected from the group consisting of hydrido, trialkylsilyl, C2-C8 alkyl, C3-C8 alkenyl, C3-C8 alkylenyl, C3-C8 alkynyl, C2-C8 haloalkyl, and C3-C8 haloalkenyl wherein each member of group B is optionally substituted at any carbon up to and including 6 atoms from the point of attachment of B to A with one or more of the group consisting of R 32
R
3 3
R
34
R
3 5 and R36; B is optionally selected from the group consisting of C3-C cycloalkyl, C5-C10 cycloalkenyl, C4-C12 saturated heterocyclyl, and C4-C9 partially saturated heterocyclyl, wherein each ring carbon is optionally substituted with R 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 9 13 R9 substituted with R or R 13 a ring carbon or nitrogen adjacent to the R9 position and two atoms from the point of attachment is optionally substituted 13 with R 10 a ring carbon or nitrogen adjacent to the R 1 position and two atoms 12 from the point of attachment is optionally substituted with R a ring carbon or nitrogen three atoms from the point of attachment and adjacent to the R 10 position is optionally substituted with R a ring carbon or nitrogen atom three atoms from the point of attachment and adjacent to the R2 position is optionally substituted with R 3 3 and a ring carbon or nitrogen four atoms from 11 33 the point of attachment and adjacent to the R and R 3 3 positions is optionally substituted with R34 WO 00/69833 WO 0069833PCT/EUS00108226 Ais selected from the group consisting of single covalent bond, (W 7)n;-(CH(R 15))pa 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 6, and W7 is selected from the group consisting of 0, S, C(0)S, C(S)0, C(O)N(R C(S)N(R (R 7)NC(O), (R 7)NC(S), S()2, 7 7 7. 7 S(0) 2 N(R (R )NS(0) 2 Se(0), Se(0) 2 Se(0) 2 N(R (R )NSe(0) 2 P(0)(R N(R 7)P(O)(R P(0)(R 8)N(R C(NR 7)N(R (R 7)NC(NR 7), 7 7 7 7 (R )NC(NR )NR and N(R with the proviso that no more than one of the group consisting of rr and pa is 0 at the same time; R 7and R 8are independently selected from the group consisting of hydrido, hydroxy, alkyl, alkenyl, aryl, aralkyl, aryloxy, alkoxy, alkenyloxy, alkylthio, alkylamino, arylthio, arylamino, acyl. aroyl, heteroaroyl, aralkoxyalkyl, heteroaralkoxyalkyl, aryloxyalkyl, alkoxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, aralkoxyalkyl, heteroaralkoxyalkyl, alkylsulfmylalkyl, alkylsulfonylalkyl, heteroaryl, heteroaryloxy, heteroarylarnino, heteroaralkyl, heteroaralkyloxy, heteroaralkylamino, and heteroaryloxyalkyl; 14 15 37 38 39 40 41 42 R R ,R R R R R andR are independently selected from the group consisting of amidino, hydroxyamnino, hydrido, hydroxy, halo, cyano, aryloxy, amino, alkylaniino, dialkylamino, hydroxyalkyl, aminoalkyl, acyl, aroyl, heteroaroyl, heteroaryloxyalkyl, sulihydryl, acylamido, alkoxy, alkylthio, arylthio, alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, aralkoxyalkylalkoxy, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkoxythioalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl. halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxyalkyl, saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl, heteroarylalkyl, heteroarylthioalkyl, WO 00/69833 PCTIUS00/08226 heteroaralkylthioalkyl, monocarboalkoxyalkyl, dicarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl, carboalkoxycyanoalkyl, alkylsulfinyl, alkylsulfonyl, haloalkylsulfinyl, haloalkylsulfonyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, arylsulfonylalkyl, aralkylsulfinyl, aralkylsulfonyl, cycloalkylsulfinyl, cycloalkylsulfonyl, cycloalkylsulfinylalkyl, cycloalkylsufonylalkyl, heteroarylsulfonylalkyl, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylsulfinylalkyl, aralkylsulfinylalkyl, aralkylsulfonylalkyl, carboxy, carboxyalkyl, carboalkoxy, carboxamide, carboxamidoalkyl, carboaralkoxy, trialkylsilyl, dialkoxyphosphono, diaralkoxyphosphono, dialkoxyphosphonoalkyl, and diaralkoxyphosphonoalkyl with the proviso that R 3 7 and R 3 8 are independently selected from other than formyl; 14 14 R4 and R when bonded to different carbons, are optionally taken together to form a group selected from the group consisting of covalent bond, alkylene, haloalkylene, and a linear moiety spacer selected to form a ring selected from the group consisting of cycloalkyl ring having from 5 through 8 contiguous members, cycloalkenyl ring having from 5 through 8 contiguous members, and a heterocyclyl having from 5 through 8 contiguous members; 14
R
4 and R when bonded to different carbons, are optionally taken together to form a group selected from the group consisting of covalent bond, alkylene, haloalkylene, and a linear moiety spacer selected to form a ring selected from the group consisting of a cycloalkyl ring having from 5 through 8 contiguous members, a cycloalkenyl ring having from 5 through 8 contiguous members, and a heterocyclyl having from 5 through 8 contiguous members;
R
15 and R 15 when bonded to different carbons, are optionally taken together to form a group selected from the group consisting of covalent bond, alkylene, haloalkylene, and a linear moiety spacer selected to form a ring selected from the group consisting of cycloalkyl ring having from 5 through 8 contiguous members, cycloalkenyl ring having from 5 through 8 contiguous members, and a heterocyclyl having from 5 through 8 contiguous members; WO 00/69833 WO 0069833PCTLJSOO/08226 VP is selected from the group consisting of NR 0, S,
S(O)
2 ON(R P(0)(R and CR 39R4 Ris selected from the group consisting of hydrido, hydroxy, amino, alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxy, aralkoxy, alkoxy, alkenyloxy, alkylthio, arylthio, aralkoxyalkyl, heteroaralkoxyalkyl, aryloxyalkyl, alkoxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, aralkoxyalkyl, heteroaralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxyalkyl, halocycloalkenyloxyalkyl, heteroaryl, heteroarylalkyl, monocarboalkoxyalkyl, monocarboalkoxy.
dicarboalkoxyalkyl, monocarboxamido, monocyanoalkyl, dicyanoalkyl.
carboalkoxycyanoalkyl, acyl, aroyl, heteroaroyl, heteroaryloxyalkyl. and dial koxyphosphon oalkyl; R 39and R 40, when bonded to the same carbon, are optionally taken together to form a group selected from a group consisting of oxo, thiono, R- N, alkylene, haloalkylene, and a linear moiety spacer having from 2 through 7 contiguous atoms to form a ring selected from the group consisting of a cycloalkyl ring having from 3 through 8 contiguous members, a cycloalkenyl ring having from 3 through 8 contiguous members, and a heterocyclyl ring having from 3 through 8 contiguous members; Mis selected from the group consisting of N and R -C; R2and RIare independently selected from the group consisting of Q, hydrido, alkyl, alkenyl, and halo; R 'is optionally selected from the group consisting of amino, aminoalkyl, alkylamnino, amnidino, guanidino, hydroxy, hydroxyamino, alkoxy, hydroxyalkyl, alkoxyamino, thiol, alkylthio, dialkylsulfonium, trial kylphosphonium, dialkylsulfoniumalkyl, heteroaryl amino, nitro, arylamino, aralkylamino, alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, baloalkanoyl, hydroxyhaloalkyl, cyano, and phosphono; WO 00/69833 PCTIUS00/08226
R
2 is optionally selected from the group consisting of amidino, guanidino, dialkylsulfonium, trialkylphosphonium, dialkylsulfoniumalkyl, heteroarylamino, amino, nitro, alkylamino, arylamino, aralkylamino, alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, haloalkanoyl, hydroxyhaloalkyl, cyano, and phosphono;
R
2 and R 4 a
R
2 and R 4 b, R 2 and R 14 and R 2 and R 15 are optionally independently selected to form spacer pairs wherein a spacer pair is taken together to form a linear moiety having from 2 through 5 contiguous atoms connecting the points of bonding of said spacer pair members to form a heterocyclyl ring having from 5 through 8 contiguous members with the proviso that no more than one of the group of spacer pairs consisting of R 2 and 4a 2 4b 2 14 2 15
R
4 a, R and R R 2 and R and R and R 15 is used at the same time;
R
2 is optionally independently selected to form a linear moiety having from 2 through 5 contiguous atoms linked to the points of bonding of both R 4 a 4b and R 4 b to form a heterocyclyl ring having from 5 through 8 contiguous members; 2Z is selected from the group consisting of covalent single bond, (CR41R4)q wherein q is an integer selected from 1 through 6, (CH(R41))g S42 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, C(S), 41 41 41 C(0)O, C(S)O, C(O)S, C(S)S, C(O)N(R4), (R C(S)N(R41), (R41)NC(S), OC(0)N(R41), (R41)NC(0)O, SC(S)N(R41), (R41)NC(S)S, SC(O)N(R41), (R41)NC(O)S, OC(S)N(R41), (R41)NC(S)O, N(R42)C()N(R41), (R41)NC(O)N(R42), N(R42)C(S)N(R41), (R )NC(S)N(R 42), S(0)2, S(0) 2 N(R41), N(R41)S() 2 Se, Se(O), Se(0) 2 Se(0) 2
N(R
4 1 N(R4)Se(0) 2 P(0)(R N(R WO 00/69833 WO 0069833PCT/USOOIO8226 P(O)(R 8)N(R N(R 41), ON(R 41), and SiR 28R 29, and (CH(R 41))eW22_ (CH(R wherein e and h are integers independently selected from 0 through 2 and i22s selected from the group consisting of CR41 =C42 41 42 CR 41R 42=C; vinylidene), ethynylidene 1,2-ethynyl), 1,2-cyclopropyl, 1 ,2-cyclobutyl, 1 ,2-cyclohexyl, 1,3 -cyclohexyl, 1 .2-cyclopentyl, 1,3cyclopentyl, 2,3-morpholinyl, 2,4-morpholinyl, 2,6-morpholinyl, 3,4morpholinyl, 3 ,5-morpholinyl, 1 ,2-piperazinyl, 1 ,3-piperazinyl, 2,3piperazinyl, 2,6-piperazinyl, 1 ,2-piperidinyl, 1 ,3-piperidinyl, 2,3-piperidinyl, 2,4-piperidinyl, 2,6-piperidinyl, 3,4-piperidinyl, 1 ,2-pyn-olidinyl, 1,3pyrrolidinyl, 2,3-pyrrolidinyl, 2,4-pyrrolidinyl, 2,5-pyrrolidinyl, 3,4pyrrolidinyl, 2,3-tetrahydrofuranyl, 2,4-tetrahydrofuranyl, tetrahydrofuranyl, and 3,4-tetrahydrofuranyl, with the provisos that R 41and R 42are selected from other. than halo and cyano when directly bonded to N and ZOis directly bonded to the uracil ring; R 28and R 29are independently selected from the group consisting of hydrido, hydroxyalkyl, alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, acyl, aroyl, aralkanoyl, heteroaroyl, aralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkylthioalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxyalkyl, perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl, heteroarylalkyl, heteroarylthioalkyl, heteroaralkylthioalkyl, cyanoalkyl, dicyanoalkyl, carboxamidoalkyl, dicarboxamidoalkyl, cyanocarboalkoxyalkyl, carboalkoxyalkyl, dicarboalkoxyalkyl, cyanocycloalkyl, dicyanocycloalkyl, carboxamidocycloalkyl, dicarboxamidocycloalkyl, carboalkoxycyanocycloalkyl, carboalkoxycycloalkyl, dicarboalkoxycycloalkyl, formylalkyl, acylalkyl, arylsulfinylalkyl, arylsulfonylalkyl, aralkylsulfinyl, cycloalkylsulfinylalkyl, cycloalkylsufonylalkyl, heteroaryl sulfonylalkyl, heteroarylsutfinylalkyl, WO 00/69833 PCT/US00/08226 aralkylsulfinylalkyl, aralkylsulfonylalkyl, carboxy, dialkoxyphosphono, diaralkoxyphosphono, dialkoxyphosphonoalkyl and diaralkoxyphosphonoalkyl;
R
28 and R 2 9 are optionally taken together to form a linear moiety spacer having from 2 through 7 contiguous atoms and forming a ring selected from the group consisting of a cycloalkyl ring having from 3 through 8 contiguous members, a cycloalkenyl ring having from 3 through 8 contiguous members, and a heterocyclyl ring having from 3 through 8 contiguous members; Q is formula (II): 1 R 1 2 1 1 2 R R13
(II)
1 2 1 2 1 wherein D, D 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 than one can be a covalent bond, no more than one of D D J 2 and K 1 212 1 1 can be O, no more than one of D, D J2 and K can be S, one of D 2 1 2 1 1 2 1 2
D
2 J, 2 and K must be a covalent bond when two of D D 2 1, 2 and 1 1 212 1 K are O and S, and no more than four of D D 2 1, and K can be N, 9 10 11 12 13 with the proviso that R R 10
R
1 R 12 and R are each independently selected to maintain the tetravalent nature of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen; Q is optionally selected from formula (III): WO 00/69833 WO 0069833PCT/USOO/08226 i
III)
3 43 4 wherein D D J and J are independently selected from the group 3 43 4 consisting of C, N, 0, and S, no more than one of D D J and J isO0, no 3 43 4 1 2 more than one of D D J ,and J is S, and no more than three of D D 1 2 9 10 11 -12 J and J are Nwith the proviso thatR' R R and R are each independently selected to maintain the tetravalent nature of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen; Q is optionally selected from the grou p consisting of hydrido, alkyl, alkoxy, alkylamino, alkylthio, haloalkylthio, alkenyl, alkynyl, saturated heterocyclyl, partially saturated heterocyclyl, acyl, aroyl, heteroaroyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkylalkenyl, haloalkyl, haloalkoxy, haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxyalkyl, and halocycloalkenyloxyalkyl with the proviso that Zis selected from other than a single covalent bond when Q is hydrido; Kis (CR R b)n wherein n is an integer selected from I through 4; R 4aand R 4bare independently selected from the group consisting of halo, hydrido, hydroxy, cyano, hydroxyalkyl, alkyl, alkenyl, aryl, aralkyl, aralkoxyalkyl, aryloxyalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, aralkylthoalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, haloalkenyl, heteroaryl, heteroarylalkyl, heteroarylthioalkyl, heteroaralkyltbioalkyl, cyanoalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, haloalkylsulfinyl, arylsulfinylalkyl, arylsulfonylalkyl, heteroarylsulfonylalkyl, heteroarylsulfinylalkyl, aralkylsulfinylalkyl, and WO 00/69833 PCT/US0/08226 aralkylsulfonylalkyl with the provisos that halo, hydroxy, and cyano are 4a 4b bonded to different carbons when simultaneously present and that R and R are other than hydroxy or cyano when bonded to the carbon directly bonded to the uracil nitrogen; 4a 4b R and R when bonded to the same carbon, are optionally taken together to form a group selected from the group consisting of oxo, thiono, and a linear spacer moiety having from 2 through 7 contiguous atoms connected to form a ring selected from the group consisting of a cycloalkyl ring having 3 through 8 contiguous members, a cycloalkenyl ring having 5 through 8 contiguous members, and a heterocyclyl ring having 5 through 8 contiguous 4a 4b members with the proviso that R 4 and R taken together is other than oxo or thiono when the common carbon is directly bonded to the uracil nitrogen; Eo is E l when K is (CR R4)n, wherein E is selected from the group consisting of a covalent single bond, 0, S. C(O)O, C(S)O, C(0)S, C(S)S, C(0)N(R 7 (R7)NC(O), C(S)N(R7), (R7)NC(S), OC(O)N(R7), (R )NC(0)O, SC(S)N(R 7 (R7)NC(S)S, SC(0)N(R7), OC(S)N(R7), (R7)NC(S)O, N(R8)C(O)N(R 7 (R7)NC(O)N(R N(R (R7)NC(S)N(R8 S(0)2, S(0) 2 N(R7), N(R7)S(0)2, S(0) 2 N(R7)C(O), C(0)N(R )S(0) 2 Se, Se(O), Se(0) 2 Se(0) 2 N(R7), N(R7)Se(0) 2 N(R7)P(O)(R 8 7 7 7 28 29 4a 4b P(0)(R )N(R N(R ON(R SiR R CR =CR ethynylidene 1,2-ethynyl), and C=CR 4 aR 4 b K is optionally selected to be (CH(R 4))j-T whereinj is selected from a integer from 0 through 3 and T is selected from the group consisting of single covalent bond, 0, S, and N(R7) with the provisos that R 14 is other than WO 00/69933 WO 0069833PCT/USOO/08226 hydroxy, cyano, halo, amino, alkylamino, dialkylamino, and sulfhydryl when j is I and that (CH(R is bonded to the uracil ring;
E
0 2 opinlyKi C 14 2 is opinll when K s(HR wherein E is selected from the group consisting of a covalent single bond, C(0)0, C(S)O, C(O)S, C(S)S, C(O)N(R (R 7)NC(O), C(S)N(R (R 7)NC(S), (R 7)NC(O)O, (R 7)NC(S)S, (R 7)NC(O)S, (R 7)NC(S)O, N(R 8)C(O)N(R 7), (R 7)NC(O)N(R N(R 8)C.(S)N(R (R 7)NC(S)N(R S(0) 2
S(O)
2 N(R N(R S(O) 2
C(O)N(H)S(O)
2 Se(O), 7 7 8 7 8 Se(O) 2 Se(O) 2 N(R N(R )Se(O)2, P(O)(R N(R P(O)(R 8)N(R 7) ,and N(R k); K is optionally selected to be G-(CH(R wherein k is selected from an integer from 1 through 3 and G is selected from the group consisting of 0, S, and N(R 7) with the proviso that R 15is other than .hydroxy, cyano, halo, amino, alkylamino, dialkylamidno, and sulfhydryl when k is 1; e is optionally e? when K is G-(CH(R 15))k wherein E3 is selected from the group consisting of a covalent single bond, 0, S, C(S), C(0)0, C(S)0, C(0)S, C(S)S, C(O)N(R (R 7)NC(0), C(S)N(R )7 7 7 7 7 7 (R OC(0)N(R (R )NC(0)0, SC(S)N(R (R )NC(S)S, SC(O)N(R (R )NC(0)S, OC(S)N(R (R 7)NC(S)0, N(R8)C(O)N(R (R 7)NC(0)N(R N(R 8)C(S)N(R (R 7)NC(S)N(R S(0)2, S(0) 2 N(R N(R 7)S(0)2, Se, Se(O), Se(0) 2 Se(0) 2 N(R N(R 7)Se(0) 2 P(0)(R N(R P(0)(R 8)N(R N(R 0N(R SiR' R1 CR a=CR 4b, ethynylidene (CwC; 1,2-ethynyl), and C=CR~aR 4 b, WO 00/69833 PCT/US00/08226 YO is formula (IV): R17 1 8 R16/ 2,D R19 1l DK 1 9 lb b
(IV).
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 than one is a covalent bond, K 2 is independently selected from the group consisting of C and N no more than one of D D J5, and J is O, no more than one of D D and J is S, one of D D J5, and J must be a covalent bond when two of D, D 6 J, and J6 are O and S, no more than 6 5 6 2 three of D, D, J and 6 are N when K is N and no more than four of D5, D6, J5, and 6 are N when K is carbon with the provisos that R1, R17 18 19 R and R9 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 R and R 17 are independently optionally taken together to form a linear moiety spacer having from 3 through 6 contiguous atoms connected to form a ring selected from the group consisting of a cycloalkenyl ring having from 5 through 8 contiguous members, a partially saturated heterocyclyl ring having from 5 through 8 contiguous members, a heteroaryl having from through 6 contiguous members, and an aryl; 18 19 R and R are independently optionally taken together to form a linear moiety spacer having from 3 through 6 contiguous atoms connected to WO 00/69833 PCT/US00/08226 form a ring selected from the group consisting of a cycloalkenyl ring having from 5 through 8 contiguous members, a partially saturated heterocyclyl ring having from 5 through 8 contiguous members, a heteroaryl having from through 6 contiguous members, and an aryl; Qb is selected from the group consisting of NR20R 21 NR20R21R 22 oxy, alkyl, aminoalkylenyl, alkylamino, dialkylamino, be be dialkylsulfoniumalkyl, acylamino and Qb wherein Qb is hydrido and 21 22 R21, and R 2 are independently selected from the group consisting of hydrido, amino, alkyl, hydroxy, alkoxy, aminoalkylenyl,alkylamino, dialkylamino, and 21 22.
hydroxyalkyl with the provisos that no more than one of R 20 R and R 2 is hydroxy, alkoxy, alkylamino, amino, and dialkylamino at the same time and that R R 21 and R 2 must be other than be hydroxy, alkoxy, alkylamino, amino, and dialkylamino when K 2 is N 21 20 22 21 22 R and R R and R and R and R are independently optionally selected to form a spacer pair wherein a spacer pair is taken together to form a linear moiety having from 4 through 7 contiguous atoms connecting 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 21 20 22 one of the group consisting of spacer pairs R 2 and R 2 R and R 2 and 21 22 R and R 22 is used at the same time; Q is optionally selected from the group consisting of N(R26)SO 2
N(R
2 3
)(R
2 4 N(R26)C(O)OR 5 N(R )C(O)SR, N(R2)C(S)OR and N(R26)C(S)SR with the proviso that no more than one of R23 R24 and R26 can be hydroxy, alkoxy, alkyleneamino, alkylamino, of R R and R can be hydroxy, alkoxy, alkyleneamino, alkylamino, WO 00/69833 PCT/US00/08226 amino, or dialkylamino when two of the group consisting of R 23
R
2 4 and
R
2 6 are bonded to the same atom; Qb is optionally selected from the group consisting of dialkylsulfonium, trialkylphosphonium, C(NR25)NR R24 N(R26)C(NR 25)N(R23)(R24), N(R26)C(O)N(R23)(R24), 26 23 24 25 N(R )C(S)N(R C(NR )OR C(O)N(R26)C(NR25)N(R23)(R24), C(S)N(R26)C(NR 25)N(R23 )(R24), N(R26)N(R )C(NR )N(R 2)(R ON(R26)C(NR25)N(R2)(R 26 26 23 24 25 5 23 24 N(R26)N(R )SO 2 N(R2)(R C(NR2)SR C(O)NR R 24 and C()NR2324 with the provisos that no more than one of R R 2 4 and R 2 6 can be hydroxy, alkoxy, alkylamino, amino, or dialkylamino when any two of the group consisting of R R 24 and R are bonded to the same atom and that said Qb group is bonded directly to a carbon atom; 23 24 25 26 R R R and R are independently selected from the group consisting of hydrido, alkyl, hydroxy, alkoxy, alkylenylamino, amino, alkylamino, dialkylamino, and hydroxyalkyl; R and R 24 are optionally taken together to form a linear spacer moiety having from 4 through 7 contiguous atoms connecting the points of bonding to form a heterocyclyl ring having 5 through 8 contiguous members; 23 25 24 a 25 25 26 24 26 23 R and R R and R and R and R and R and R are independently optionally selected to form a spacer pair wherein a spacer pair is taken together from the points of bonding of selected spacer pair members to form the group L-U-V wherein L, U, and V are independently selected from the group consisting of O, S, C(JH)2 SO 2
OP(OR
3 1 WO 00/69833 WO 0069833PCTIJSOO/08226 p(O)R 30, P(S)R 30, C(R3 )R C=C(R )R (O),POP(O), 30 29 28 29 28 29 28 R (O)POP(O)R3 Si(R )R Si(R 9)R S~i(R 9)R Si(R 29)R 21OSi(R2 )R 2, (R 2)R29COC(R28)R29, (R 28)R 2CSC(R 28)R29 C(O)C(R3 C(S)C(R 3)=C(R S(O)C(R 3)=C(R 31),
SO
2 C(R PR 3C(R30)=C(R3 P(O)R 3C(R30)_C(R3 P(S)R 3C(R30)=C(R 31), DC(R 30)(R OP(OR3 )R3 P(O)R3 Si(R 21)R2 and N(R3 and a covalent bond with the proviso that no more than any two of L, U and V are simultaneously covalent bonds and the heterocyclyl comprised of by L, U, and V has from 5 through 10 contiguous member; D is selected from the group consisting of oxygen, C=0, C=S, S(O)m wherein m is an integer selected from 0 through 2: JH is independently selected from the group consisting of OR 27,SR 27and )R21; R 27is selected from the group consisting of hydrido, alkyl, alkenyl, alkynyl, aralkyl, aryloxyalkyl, aralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkylthioalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, al kylthioalkyl, arylthioalkyl, cycloalkyl, cycloallcylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxyalkyl, halocycloalkenyloxyalkyl, perhaloaryloxyalkyl, heteroaryl, heteroarylalkyl, heteroarylthioalkyl, heteroaralkylthioalkyl, arylsulfinylalkyl, arylsulfonylalkyl, cycloalkylsulfinylalkyl, cycloalkylsufonylalkyl, heteroarylsulfonylalkyl, heteroarylsulfinylalkyl, aralkylsulfinylalkyl and aralkylsulfonylalkyl; R3 and R3 are independently selected from the group consisting of hydrido, hydroxy, thiol, aryloxy, amino, alkylamino, dialkylamino, hydroxyalkyl, heteroaryloxyalkyl, alkoxy, alkylthio, arylthio, alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, aralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, WO 00/69833 WO 0069833PCTIUS0OIO8226 aralkylthioalkyl, heteroaralkoxytbioalkyl, alkoxyalkyl, heteroaryloxyalkyl, al kenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalk ylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, haloaralkylsulfinylalkyl, aralkylsulfonylalkyl, cyanoalkyl. dicyanoalkyl, carboxamidoalkyl, dicarboxamidoalkyl, cyanocarboalkoxyalkyl, carboalkoxyalkyl, dicarboalkoxyalkyl, cyanocycloalkyl, dicyanocycloalkyl, carboxamidocycloalkyl, dicarboxarnidocycloalkyl, carboalkoxycyanocycloalkyl, carboalkoxycycloalkyl, dicarboalkoxycycloalkyl, formylalkyl, acylalkyl, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, phosphonoalkyl, dialkoxyphosphonoalkoxy, diaralkoxyphosphonoalkoxy, phosphonoalkoxy, dialkoxyphosphonoalkylamino, diaralkoxyphosphonoalkylamnino, phosphonoalkylamino, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, sulfonylalkyl, alkoxysulfonylalkyl, aralkoxysulfonylalkyl, alkoxysulfonylalkoxy, aralkoxysulfonylalkoxy, sulfonylalkoxy, alkoxysulfonylalkylamino, aralkoxysulfonylalkylamino, arnd sulfonylalkylamino; R 30and R 31are optionally taken to form a linear moiety spacer group having from 2 through 7 contiguous atoms to form a ring selected from the group consisting of a cycloalkyl ring having from 3 through 8 contiguous members, a cycloalkenyl ring having from 3 through 8 contiguous members, and a heterocyclyl ring having from -3 through 8 contiguous members; 23 .25 24 25 25 26 24 26 23 R and R R and R R and R R and R and R and R 26are independently optionally selected to form a spacer pair wherein a spacer pair is taken together from the points of bonding of selected spacer pair members to form the group L-U-V wherein L, U, and V are independently selected from the group of I ,2-disubstituted radicals consisting of a cycloalkyl radical, a cycloalkenyl radical wherein cycloalkyl and cycloalkenyl radicals are substituted with one or more groups selected from R 3 and R 3 1 an aryl radical, an-heteroaryl radical, a saturated heterocyclic radical and a partially saturated heterocyclic radical wherein said 1,2-substitutents are independently selected from C=S, (R 28)R 3 S(0) 2 OP(OR 31)R 30, P(O)R 30, P(S)R 30and Si(Rk2 )R29 WO 00/69833 PC/US00/08226 23 25 24 25 25 26 24 26 23 R and R25, R24 and R26 R24R and R26,R and R and 26 R26 are independently optionally selected to form a spacer pair wherein a spacer pair is taken together from the points of bonding of selected spacer pair members to form the group L-U-V wherein L, U, and V are independently selected from the group of radicals consisting of 1,2-disubstituted alkylene radicals and 1,2disubstituted alkenylene radical wherein said 1,2-substitutents are independently selected from C=O, C=S, C(R )R29, S(0)2, OP(OR31)R30, P(0)R30 and Si(R28)R29 and said alkylene and alkenylene radical are substituted 30 31 with one or more R or R31 substituents; 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 an integer selected from 1 through 4, and WO is selected from the group 14 consisting of O, S, C(0)O, C(S)O, C(O)S, C(S)S, C(O)N(R14), (R 14)NC(O), C(S)N(R 14), (R 4)NC(S), OC(0)N(R 14), SC(S)N(R 14), SC(0)N(R OC(S)N(R 14), N(R 15)C(O)N(R 14), (R 14)NC(O)N (R 14 14 15 14 N(R1 )C(S)N(R (R )NC(S)N(R S(0)2, S(0)2N(R 14), N(R 14)S(0) 2 Se, Se(0), Se(0) 2 Se(0) 2 N(R17), N(R 14)Se(0) 2 P(0)(R N(R7 P(0)(R N(R ON(R 14), and SiR28 R29 (CH(R 14))cW 1-(CH(R 15))d wherein c and d are integers independently selected from 1 through 4, and W1 is selected from the group consisting of O, 14 14 S, C(O)O, C(S)O, C(O)S, C(S)S, C(0)N(R4), (R C(S)N(R 14), (R4 OC(0)N(RI4), (R14 )NC(0)O, SC(S)N(R14), (R 14)NC(S)S, SC(0)N(R14), (R 14)NC(0)S, OC(S)N(R14), (R 14)NC(S)O, WO 00/69933 WO 0069833PCT/USOO/08226 N(R 15)C(O)N(RI (R 14)NC(O)N(R 15), N(R 15)C(S)N(R 14 (R 14)NC(S)N(R S(O) 2
S(O)
2 N(R 1) N(R 1)S(0) 2 Se, Se(O), Se(O) 2 Se(O) 2 N(R 14). N(R 1)Se(O) 2 P(O)(R N(R
P(O)(R
8 )N(R)N(R 1 4 ),ON(R14), SiR 2 8 and (CH(Rl') W2 (CH(R 15))h wherein e and h are integers independently selected from 0 through 2 and w22is selected from the group consisting of CR =CR 2 CRIR2 vinylidene), ethynylidene 1,2-ethynyl), 1,2-cyclopropyl, I ,2-cyclobutyl, 1 ,2-cyclohexyl, 1,3 -cyclohexyl, 1 ,2-cyclopentyl, 1.3cyclopentyl, 2,3-rnorpholinyl, 2,4-morpholinyl, 2,6-morpholinyl, 3,4morpholinyl, 3 ,5-morpholinyl, I ,2-piperazinyl, 1 .3-piperazinyl, 2,3piperazinyl, 2,6-piperazinyl, 1 .2-piperidinyl, I ,3-piperidinyl, 2,3-piperidinyl, 2,A-piperidinyl. 2,6-piperidinyl, 3 ,4-piperidinyl, 1 ,2-pyrrolidinyl, 1,3pyrrolidinyl, 2,3-pyrrolidinyl, 2,4-pyrrolidinyl, 2,5-pyrrolidinyl, 3,4pyrrolidinyl, 2,3-tetrahydrofuranyl, 2,4-tetrahydrofuranyl, tetrahydrofuranyl, and 3,4-tetrahydrofuranyl, with the provisos that R 14and R 15are selected from other than halo and cyano when directly bonded to N and that (CR 37R 38)b, (CH(R 14))C, (CH(R 14))e and are bonded to E0 R 37and 37 when bonded to different carbons, are optionally taken together to form a linear moiety spacer having from 1 through 7 conti guous atoms to form a ring selected from the group consisting of a cycloalkyl. ring having from 3 through 8 contiguous members,* a cycloalkenyl ring having from 3 through 8 contiguous members, and a heterocyclyl ring having from 3 through 8 contiguous members; 37 38 R. and R when bonded to different carbons, are taken together to form a linear moiety spacer having from 1 through 7 contiguous atoms to form a ring selected from the group consisting of a cycloalkyl ring having from 3 through 8 contiguous members, a cycloalkenyl ring having from 3 throu gh 8 WO 00/69833 PCTIUS00/08226 contiguous members, and a heterocyclyl ring having from 3 through 8 contiguous members; R and R when bonded to different carbons, are taken together to form a linear moiety spacer having from 1 through 7 contiguous atoms to form a ring selected from the group consisting of a cycloalkyl ring having from 3 through 8 contiguous members, a cycloalkenyl ring having from 3 through 8 contiguous members, and a heterocyclyl ring having from 3 through 8 contiguous members;
R
3 7 and R 3 8 when bonded to the same carbon, are taken together to form a group selected from a group consisting of oxo, thiono, alkylene, haloalkylene, and a linear moiety spacer having from 2 through 7 contiguous atoms to form a ring selected from the group consisting of a cycloalkyl ring having from 3 through 8 contiguous members, a cycloalkenyl ring having from 3 through 8 contiguous members, and a heterocyclyl ring having from 3 through 8 contiguous members; YO is optionally QbQ wherein QSS is selected from the group 37 38 consisting of (CR 3 R )f wherein f is an integer selected from 1 through 6, (CH(R 4))cW -(CH(R 1))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)O, C(S)O, C(0)S, C(S)S, C(0)N(R14), (R14)NC(O), C(S)N(R14), (R14)NC(S), OC(0)N(R4), (R )NC(0)O, SC(S)N(R14), (R14)NC(S)S, SC(0)N(R14), (R14)NC(O)S, OC(S)N(R14), (RI4)NC(S)O, N(R15)C(O)N(R14), (R14)NC()N(R15), N(R15)C(S)N(R14), (RI4)NC(S)N(R15), S(0), S(0)2, S(0) 2 N(R14), N(R14)S(0) 2 Se, Se(O), Se(0) 2 Se(O) 2 N(R14), N(R 4)Se(0) 2 P(0)(R N(R7)P(O)(R8), P(0)(R8)N(R N(R 14), ON(R 14), SiR R29, and (CH(R 14)e-W-(CH(R15)) h wherein e and h are WO 00/69833 WO 0069833PCTIUSOO/08226 integers in dependently selected from 0 through 2 and Wis selected from the group. consisting of CR 4a=CR 4b,ethynylidene 1 ,2-ethynyl), and C=CR 4aR 4bwith the provisos that R 14and R 15are selected from other than halo and cyano when directly bonded to N, that (CR 37R 38)f, (CH(R and (CH(R 15 e are bonded to E and Q bis selected from other than N(R 26)N(R 26)C(NR 25)N(R 23)(R 24) or ON(R 26)C(NR 25)N(R when Q sis (CR 37R 38)f wherein f is other than the integer 1; Y 0is optionally Q s wherein (P is (CH(R r is an integer selected from I through 3,.W is selected from the group consisting of 1,1 -cyclopropyl, 1 ,2-cyclopropyl, 1, 1-cyclobutyl, 1 ,2-cyclobutyl, 1,2cyclohexyl, I ,3-cyclohexyl, 1 .4-cyclohexyl, 1 .2-cyclopentyl, 1 .3-cyclopentyl.
2.3-morpholinyl, 2,4-morpholinyl, 2,5-morpholinyl, 2,6-morpholinyl, 3,4morpholinyl, 3 ,5-morpholinyl, 1 ,2-piperazinyl, 1,3 -piperazinyl, 1,4piperazinyl, 2,3-pipefazinyl, 2,5-piperazinyl, 2,6-piperazinyl, 1 .2-piperidinyl, 1,3-piperidinyl, 1,4-piperidinyl, 2,3-piperidinyl, 2,4-piperidinyl, piperidinyl, 2,6-piperidinyl, 3,4-piperidinyl, 3,5-piperidinyl, 3 ,6-piperidinyl, 1 ,2-pyffolidinyl, 1,3 -pyrrolidinyl, 2,3-pyrrolidinyl, 2A4-pyrrolidinyl, pyrrolidinyl, 3 .4-pyrrolidinyl, 2H--2,3-pyranyl, 2H-2,4-pyranyl, 2H-2,5pyranyl, 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-yi, 2,3tetrahydrofuranyl, 2,4-tetrahydrofuranyl, 2,5-tetrahydrofuranyl, 3,4tetrahydrofuranyl, 2,3-tetrahydropyranyl, 2,4-tetrahydropyranyl, tetrahydropyranyl, 2,6-tetrahydropyranyl, 3,4-tetrahydropyranyl, and tetrahydropyranyl, and each carbon and hyrido containing nitrogen member of the ring of the W3other than the points of attachment is optionally substituted 9 10 11 12 with one or more of the group consisting of R R R and R with the WO 00/69833 WO 0069833PCT/USOO/08226 proviso that (CH(R 38))r is bonded to E 0and Q bis bonded to lowest numbered substituent position of each W 3 Y0is optionally Q b -Qsssr whri Qsssr is (CH(R 3 8 Dr- r is an integer selected from 1 through 3, W 4is selected from the group consisting of 1 ,2-cyclobutyl, 1 ,2-cyclohexyl, 1 ,3-cyclohexyl, 1 ,4-cyclohexyl, 1,2cyclopentyl, 1 ,3-cyclopentyl, 2,3 -morpholinyl, 2,A-morpholinyl, morpholinyl, 2,6-morpholinyl, 3 ,4-morpholinyl, 3 ,5-morpholinyl, 1.2piperazinyl, 1 ,3-piperazinyl, 1 ,4-piperazinyl, 2,3-piperazinyl, 2,6-piperazinyl, 1 ,2-piperidinyl, 1 ,3-piperidinyl, 1 ,4-piperidinyl, 2,3piperidinyl, 2,4-piperidinyl, 2,5-piperidinyl, 2,6-piperidinyl, 3 ,4-piperidinyl, 3 ,5-piperidinyl, 3 ,6-piperidinyl, I ,2-pyfrolidinyl, 1 ,3-pyfrolidinyl, 2,3pyrrolidinyl, 2,4-pyrrolidinyl, 2,5-pyrrolidinyl, 3A4-pyrrolidinyl, 2H-2.3pyranyl, 2H-2,4-pyranyl, 2H-2,5-pyranyl, 4H-2,3-pyranyl, 4H-2.4-pyranyl, 4H-2,5-pyranyl, 2H-pyran-2-one-3,4-yl, 2H-pyran-2-one-4,5-yl, 4H-pyran- 4-one-2,3-yl, 2,3-tetrahydrofuranyl, 2,4-tetrahydrofuranyl. tetrahydrofuranyl, 3 ,4-tetrahydrofuranyl, 2,3-tetrahydropyranyl, 2,4tetrahydropyranyl, 2,5-tetrahydropyranyl, 2,6-tetrahydropyranyl, 3,4tetrahydropyranyl, and 3,5-tetrahydropyranyl, and each carbon and hydrido containing nitrogen member of the ring of the W 4other than the points of attachment is optionally substituted with one or more of the group consisting of 9 10 11 12 38 0 R ,R ,R ,and R with the provisos that (CH(R is bonded to E and Q bis bonded to highest number substituent position of eachW YOis optionally Qb_.Qssss wherein Qssss is (CH(R 38 D W sa integer selected from I through 3, W5is selected from the group consisting of .1,4-indenyl, 1 ,5-indenyl, I ,6-indenyl, 1 ,7-indenyl, 2,7-indenyl, 2,6-indenyl, 2,4-indenyl, 3 ,4-indenyl, 3,5-i ndenyl, 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- WO 00/69833 WO 0069833PCT/USOO108226 benzothiophenyl, 3 ,4-benzothiophenyl, 3 ,5-benzothiophenyl, 3,6benzothiophenyl, 3 ,7-benzothiophenyl, 2,4-imidazo( 1,2-a)pyridinyl, imidazo( 1,2-a)pyridinyl, 2,6-imidazo( 1,2-a)pyridinyl. 2,7-imidazo( 1,2a)pyridinyl, 3,4-imnidazo( 1,2-a)pyridinyl, 3 ,5-imidazo( 1,2-a)pyridinyl, 3,6imidazo( 1,2-a)pyridinyl, 3 ,7-imidazo( 1,2-a)pyridinyl, 2,4-indolyl, indolyl, 2,6-indolyl, 2,7-indolyl, 3 ,4-indolyl, 3 ,5-indolyl, 3,6-indolyl,. 3,7indolyl, 1 ,4-isoindolyl, 1 ,5-isoindolyl, 1 ,6-isoindolyl, 2,4-isoindolyl, isoindolyl, 2,6-isoindolyl, 2,7-isoindoly], 13-isoindolyl, 3,4-indazolyl, indazolyl, 3,6-indazolyl, 3 ,7-indazolyl, 2,4-benzoxazolyl, 2,6-benzoxazolyl, 2,7-benzoxazolyl, 3 ,4-benzisoxazolyl, 3 3 ,6-benzisoxazolyl, 3,7-benzisoxazolyl, I ,4-naphthyl, 1 ,5-naphthyl, 1,6naphthyl, 1,7-naphthyl, 1,8-naphthyl, 2,4-naphthyl, 2,5-naphthyl, 2,6naphthyl, 2,7-naphthyl, 2,S-naphthyl, 2,4-quinolinyl. 2,5.-quinolinyl, 2,6quinolinyl, 2,7-quinolinyl, 2,8-quinolinyl, 3,A-quinolinyl, 3,-5-quinolinyl, 3,6quinolinyl, 3,7-quinolinyl, 3 .8-quinol inyl, 4,5-quinolinyl, 4,6-quinolinyl, 4,7quinolinyl, 4,8-quinolinyl, I ,4-isoquinolinyl, 1 ,5-isoquinolinyl, 1,6isoquinolinyl, 1 ,7-isoquinolinyl, 1 ,8-isoquinolinyl, 3 ,4-isoquinolinyl, isoquinolinyl, 3,6-isoquinolinyl, 3 ,7-isoquinolinyl, 3 ,8-isoquinolinyl, isoquinolinyl, 4,6-isoquinolinyl, 4,7-isoquinolinyl, 4,8-isoquinolinyl, 3,4cinnolinyl, 3 ,5-cinnolinyl, 3 ,6-cinnolinyl, 3,7-cinnolinyl, 3,8-cinnolinyl, cinnolinyl, 4,6-cinnolinyl, 4,7-cinnolinyl, and 4,8-cinnolinyl, and each carbon and hydrido containing nitrogen member of the ring of the W 5 other than the points of attachment is optionally substituted with one or more of the group 9 10 11 12 b.
consisting of R R R and R with the proviso that Q is bonded to lowest number substituent position of each W 5 and that (CH(R 3 8 )r is bonded toe; YOis optionally QbQssssr wherein Qssssr is (CH(R 38 r sa i nteger selected from 1 through 3, W 6is selected from the group consisting of 1 ,4-indenyl, 1 ,5-indenyl, I ,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, WO 00169833 WO 0069833PCTUSOOIOS226 2,4-benzothiophenyl, 2,5-benzothiophenyl, 2,6-benzothiophenyl, 2,7benz othiophenyl, 3 ,4-benzothiophenyl, 3 ,5-benzothiophenyl, 3,6benzothiophenyl, 3 ,7-benzothiophenyl, 2,4-imidazo( 1,2-a)pyridinyl, imidazo( 1,2-a)pyridinyl, 2,6-imidazo( 1,2-a)pyridinyl, 2,7-imidazo( 1,2a)pyridinyl, 3 ,4-imidazo( 1,2-a)pyridinyl, 3 ,5-imidazo( 1,2-a)pyridinyl, 3,6imidazo( 1,2-a)pyridinyl, 3 ,7-imidazo( 1,2-a)pyridinyl, 2A4-indolyl, indolyl, 2.6-indolyl, 2,7-indolyl, 3 ,4-indolyl, 3 ,5-indolyl, 3 ,6-indoly], 3,7indolyl, 1,4-i soindolyl, 1 ,5-isoindoly], 1 ,6-isoindolyl, 2,4-isoindolyl, isoindolyl, 2,6-isoindolyl, 2,7-isoindolyl, 1,3-isoindolyl, 3,4-indazolyl, indazolyl, 3,6-indazolyl, 3,7-indazolyl, 2,4-benzoxazolyl, 2,6-benzoxazolyl, 2,7-benzoxazolyl, 3 ,4-benzisoxazolyl, 3 ,6-benzisoxazolyl, 3 ,7-benzisoxazolyl, 1 ,4-naphthyl, 1 ,5-naphthyl, 1,6naphthyl, 1,7-naphthyl, 1,8-naphthyl, 2,4-naphthyl, 2,.5-naphthyl, 2,6naphthyl, 2,7-naphthyl, 2,8-naphthyl, 2,4-quinolinyl, 2,5-quinolinyl, 2,6quinolinyl, 2,7-quinolinyl, 2,8-quinolinyl, 3,4-quinolinyl, 3 ,5-quinolinyl, 3,6quinolinyl, 3 ,7-quinolinyl, 3 ,8-quinolinyl, 4,5-quinolinyl, 4,6-quinolinyl, 4,7quinolinyl, 4,8-quinolinyl, 1,4-isoquinolinyl, 1,5-isoquinolinyl, 1,6isoquinolinyl, 1 ,7-isoquinolinyl, 1 ,8-isoquinolinyl, 3 ,4-isoquinolinyl, isoquinolinyl, 3,6-i soquinolinyl, 3,7-isoquinolinyl, 3 ,8-isoquinolinyl, isoquinolinyl, 4,6-isoquinolinyl, 4,7-isoquinolinyl, 4,8-isoquinolinyl, 3,4cinnolinyl, 3,5-cinnolinyl, 3 ,6-cinnolinyl, 3,7-cinnolinyl, 3,8-cinnolinyl, cinnolinyl, 4,6-cinnolinyl, 4,7-cinnolinyl, and 4,8-cinnolinyl, and each carbon and hydrido containing nitrogen member of the ring of the W 6other than the points of attachment is optionally substituted with one or more of the group 2 cossiG 9 10 11 12 b cnsisingofR ,R R and R with the proviso that Q is bonded to highest number substituent position of each W 6and that (CH(R 38))r is bonded to E 0 In an embodiment of compounds of Formula I or a pharmaceutically acceptable salt thereof, JaanJb are independently selected from the group consisting of 0 and S; WO 00/69833 WO 0069833PCT/USOO/08226 B is formula R 1 R 3 j32 I 3 R r R (V 1 21 2 1 wherein D D J 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 122 1 than one is acovalent bond, no more than one of D D ,J and K is 0, 1 2 12 1 1 2 12 no more than one of D D ,Ji J andK isS,oneofD ,D ,J ,J and 1 1 2 12 1 K must be acovalent bond when two of D D J J and K are 0and S, 1 2 12 1 and no more than four of D D J J and K are Nwith the proviso that 32 33 34 35 36 R ,R ,R R and R are each independently selected to maintain the tetravalent nature of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen; 9 10 11 12 13 16 17 18 19 32 33 34 R 35, and R 36are independently selected from the group consisting of hydrido, acetamnido, haloacetamido, amidino, guanidino, dial kylsulfoni um, trial kyiphosphonium, dialkylsulfoniumalkyl, carboxy, heteroaralkylithio, heteroaralkoxy, cycloalkylamnino, acylalkyl, acylalkoxy, aryloylalkoxy, heterocyclyloxy, aralkylaryl, aralkyl, aralkenyl, aralkynyl, heterocyclyl, perhaloaralkyl, aralkylsulfonyl, aralkylsulfonylalkyl, aralkylsulfinyl, aralkylsulfinylalkyl, halocycloalkyl, halocycloalkenyl, cycloalkylsulfinyl, cycloalkylsulfinylalkyl, cycloalkylsulfonyl, cycloalkylsulfonylalkyl, heteroarylamino, N-heteroarylaniino-N-alkylamino, heteroarylarninoalkyl, haloalkylthio, alkanoyloxy, alkoxy, alkoxyalkyl, haloalkoxylalkyl, heteroaralkoxy, cycloalkoxy, cycloalkenyloxy, cycloalkoxyalkyl, WO 00/69833 WO 0069833PCT/USUO108226 cycloalkylalkoxy, cycloalkenyloxyalkyl, cycloalkylenedioxy, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxy, halocycloalkenyloxyalkyl, hydroxy, amidno, alkoxyamino, thio, nitro, lower alkylamnino, alkylthio, alkylthioalkyl, arylaino, aralkylainino, aryltbio, arylthioalkyl, heteroaralkoxyalkyl, alkylsulfinyl. alkylsulfinylalkyl, arylsulfinylalkyl, arylsulfonylalkyl, heteroarylsulfinylalkyl, heteroarylsulfonylalkyl, alkylsulfonyl, alkylsulfonylalkyl, haloalkylsulfinylalkyl, haloalkylsulfonylalkyl, alkylsulfonanuido, alkylamninosuflfonyl, amidosulfonyl, monoalkyl. amidosulfonyl, dialkyl amidosulfonyl, monoarylamridosulfonyl, arylsulfonamido, diarylamidosulfonyl, inonoalkyl monoaryl amidosulfonyl, arylsulfinyl, a rylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, heterocyclyl sulfonyl, heterocyclylthio, alkanoyl. alkenoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, haloalkanoyl, alkyl, alkenyl, alkynyl, alkenyloxy, alkenyloxyalky, alkylenedioxy, haloalkylenedioxy, cycloalkyl, cycloalkylalkanoyl, cycloalkenyl, lower cycloalkylalkyl, lower cycloalkenylalkyl, halo, haloalkyl, baloalkenyl, haloalkoxy, hydroxyhaloalkyl, hydroxyaralkyl, hydroxyalkyl, alkylenylaniino, hydoxyheteroaralkyl, haloalkoxyalkyl, aryl, aralkyl, aryloxy, aralkoxy, aryloxyalkyl, saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl, heteroaryloxy, heteroaryloxyalkyl, arylalkyl, beteroarylalkyl, 'arylalkenyl, heteroarylalkenyl, carboxyalkyl,' carboalkoxy, alkoxycarboxamido, alkylamidocarbonylamido, arylamidocarbonylamnido, carboalkoxyalkyl, carboalkoxyalkenyl, carboxy, carboaralkoxy, carboxamido, carboxamidoalkyl, cyano, carbohaloalkoxy, phosphono, phosphonoalkyl, diaralkoxyphosphono, and diaralkoxyphosphonoalkyl; 16 19 32 33 34 35. 36 R R R R R R and R are independently optionally Q bwith the proviso that no more than one of R 16and R 19is Q bat the same time and that Q bisQ b 32 33 33 34 34 35 35 36 R and R R andR ,R andR ,andR andR are independently optionally selected to form a spacer pair wherein a spacer pair is taken together to form a linear moiety having from 3 through 6 contiguous atoms connecting the points of bonding of said spacer pair members to form a ring selected from the group consisting of a cycloalkenyl ring having 5 through WO 00/69833 PCT/US00/08226 8 contiguous members, a partially saturated heterocyclyl ring having 5 through 8 contiguous members, a heteroaryl ring having 5 through 6 contiguous members, and an aryl with the proviso that no more than one of the group 32 33 33 34 34 35 consisting of spacer pairs R and R R and R R and R and R 36 and R 3 6 can be used at the same time; 9 10 10 11 11 12 12 13 R and R 10 R and R and R and R 2 and R are independently optionally selected to form a spacer pair wherein a spacer pair is taken together to form a linear moiety having from 3 through 6 contiguous atoms connecting the points of bonding of said spacer pair members to form a ring selected from the group consisting of a cycloalkenyl ring having 5 through 8 contiguous members, a partially saturated heterocyclyl ring having 5 through 8 contiguous members, a heteroaryl ring having 5 through 6 contiguous members, and an aryl with the proviso that no more than one of the group consisting of spacer pairs R and R 10 R10 and R R11 and R1 2 and R 12 and R 13 can be used at the same time; B is optionally selected from the group consisting of hydrido, trialkylsilyl, C2-C8 alkyl, C3-C8 alkylenyl, C3-C8 alkenyl, C3-C8 alkynyl, C2-C8 haloalkyl, and C3-C8 haloalkenyl wherein each member of group B may be optionally substituted at any carbon up to and including 6 atoms from the point of attachment of B to A with one or more of the group consisting of 32 R33, R34 R35 36 R R R ,R ,and R B is optionally selected from the group consisting of C3-C15 cycloalkyl, C5-C 10 cycloalkenyl, C4-C12 saturated heterocyclyl, and C4-C9 partially saturated heterocyclyl, wherein each ring carbon is optionally 33 substituted with R 3 a riqg carbon other than the ring carbon at the point of attachment of B to A is optionally substituted with oxo provided that no more than one ring carbon is substituted by oxo at the same time, ring carbons and a nitrogen adjacent to the carbon atom at the point of attachment are optionally substituted with 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 WO 00/69833 PCT/US00/08226 with R a ring carbon or nitrogen adjacent to the R 1 position and two atoms 12 from the point of attachment is optionally substituted with R a ring carbon or nitrogen three atoms from the point of attachment and adjacent to the R 10 position is optionally substituted with R 1 a ring carbon or nitrogen atom three from the point of attachment and adjacent to the R 12 position is optionally 33 substituted with R and a ring carbon or nitrogen four atoms from the point 11 33 of attachment and adjacent to the R 1 and R 33 positions is optionally substituted with R34 A is selected from the group consisting of single covalent bond, (W7)r-(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)S, C(S)O, C(0)N(R7), C(S)N(R (R (R S(0)2, S(0) 2
N(R
7 (R7)NS(0) 2 P(O)(R N(R7)P(O)(R8), P(O)(R )N(R 7 C(NR7)N(R 7 (R7)NC(NR7), (R7)NC(NR7)NR7, 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; 7 8 R and R are independently selected from the group consisting of hydrido, hydroxy, alkyl, acyl, aroyl, heteroaroyl, and alkoxyalkyl; R 14, R15, R and R 3 are independently selected from the group consisting of hydrido, hydroxy, halo, cyano, hydroxyalkyl, alkoxy, alkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, haloalkoxy, haloalkoxyalkyl. haloalkenyloxyalkyl, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxyalkyl, carboxy, carboxyalkyl, carboalkoxy, carboxamide, and carboxamidoalkyl; WO 00/69833 PCT/US00/08226 R14 and R38 can be independently selected from the group consisting of acyl, aroyl, and heteroaroyl with the proviso that acyl is selected from other than formyl; W is selected from the group consisting of NR O, S, S(0)2, ON(R P(0)(R and CR39R R is selected from the group consisting of hydrido, hydroxy, amino, alkyl, alkoxy, alkoxyalkyl, haloalkyl, acyl, aroyl, and heteroaroyl; 39 R and R are independently selected from the group consisting of hydrido, hydroxy, halo, cyano, hydroxyalkyl, acyl, aroyl, heteroaroyl, acylamido, alkoxy, alkyl, alkoxyalkyl, haloalkyl, haloalkoxy, haloalkoxyalkyl, alkylsulfonyl, haloalkylsulfonyl, carboxy, carboxyalkyl, carboalkoxy, carboxamide, and carboxamidoalkyl; M is selected from the group consisting of N and RI-C; R2 and R 1 are independently selected from the group consisting of Z Q, hydrido, alkyl, alkenyl, and halo; R1 is optionally selected from the group consisting of amino, aminoalkyl, alkylamino, amidino, guanidino, hydroxy, hydroxyamino, alkoxy, hydroxyalkyl, alkoxyamino, thiol, alkylthio, dialkylsulfonium, trialkylphosphonium, dialkylsulfoniumalkyl, heteroarylamino, nitro, arylamino, aralkylamino, alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, haloalkanoyl, hydroxyhaloalkyl, cyano, and phosphono; Sis selected from the group consisting of covalent single bond, 41 42 41 (CR R )q wherein q is an integer selected from 1 through 6, (CH(R ))g 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 0, S, C(S), 41 41 41 C(O)0, C(S)O, C(0)S, C(S)S, C(O)N(R4 (R4 C(S)N(R OC(O)N(R41), (R41)NC( 41 (R41)NC(S)S (R OC(0)N(R (R )NC(0)O, SC(S)N(R (R )NC(S)S, WO 00/69833 WO 0069833PCTIUSOOIO8226 SC(O)N(R 41), (R 41)NC(O)S, OC(S)N(R 41), (R 41)NC(S)O, N(R42)C(O)N(R 41), (R ')NC(O)N(R42), N(R 2)C(S)N(R41), (R ')NC(S)N(R S(O) S(O) 2
S(O)
2 N(R N(R41)S(O) 2 Se, Se(O), Se(O) 2 Se(O) 2 N(R N(R )Se(O) 2 N(R7)P(O)(R )N(R N(R 1
ON(R
1 and SiR 2
YR
9 ad (CH(R 1 ))eW (CH(R 4))h wherein e and h are integers independently selected from 0 through 2 and W2is selected from the group consisting of CR41=CR 2 CR R vinyl idene), ethyn ylidene 1 ,2-ethynyl), 1 .2-cyclopropyl, 1 ,2-cyclobutyl, 1 ,2-cyclohexyl, 1 ,3-cyclohexyl, 1 ,2-cyclopentyl, 1,3cyclopentyl, 2,3-morpholinyl, 2,4-morpholinyl, 2,6-morpholinyl, 3,4morpholinyl, 3,5-morpholinyl, 1,2-piperazinyl, I ,3-piperazinyl, 2,3piperazinyl, 2,6-piperazinyl, 1 ,2-piperidinyl, 1 ,3-piperidinyl, 2,3-piperidinyl, 2,4-piperidinyl, 2,6-piperidinyl, 3 ,4-piperidinyl, 1 ,2-pyrrolidinyl, 1,3pyrrolidinyl, 2,3-pyrrolidinyl, 2,4-pyrrolidinyl, 2,5-pyrrolidinyl, 3,4pyrrolidinyl, 2,3-tetrahydrofuranyl, 2,4-tetrahydrofuranyl, tetrahydrofuranyl, and 3A4-tetrahydrofuranyl, with the provisos that Rand R 2are selected from otherT than halo and cyano when directly bonded to N and 2is directly bonded to the uracil ring; R1 and R 42are independently selected from the group consisting of amidino, hydroxyamino, hydrido, hydroxy, amino, halo, cyano, aryloxy, hydroxyalkyl, acyl, aroyl, heteroaroyl, heteroaryloxyalkyl, alkoxy, alkyl, aryl, aralkyl, aryloxyalkyl, aralkoxyalkylalkoxy, alkoxyalkyl, heteroaryloxyalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl.
haloalkyl, haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxyalkyl, saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl, heteroaralkyl, heteroarylthioalkyl, heteroaralkylthioalkyl, alkylsulfonyl, haloalkylsulfonyl, arylsulfonyl, WO 00/69833 WO 0069833PCT/USOO/08226 arylsulfonylalkyl, aralkyl sulfonyl, cycloalkylsulfonyl, cycloalkylsufonylalkyl, heteroarylsulfonylalkyl, heteroarylsulfonyl, and aralkylsulfonylalkyl; Q is formula (11): R 1 9""Di D 2 "1 1 2 12 1 wherein D D J J and K are independently selected from the group consisting of C, N, 0, S and a covalent bond with the provisos that no more than one is acovalent bond, no more than one of D I,D 2, J I, J 2and K Iis 0, 1 21 2 1 1 21 2 no more than one of D D J J and K is S, one of D D ,Ji J and 1 1 2 12 1 K must be acovalent bond when two of D D J J and K are 0and S, 1 2 12 1 and no more than four of D D ,Ji J and K are N, with the proviso that 9 10 11 12 13 R R R R and R are each independently selected to maintain the tetravalent nature of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen; Q is optionally selected from formula (111): 343 4 weenD 3, D 4, 3 and J3 are independently selected from the group consisting of C, N, 0, and S, no more than one of D 3, D 4, 3 ,and 3 isIO, no WO 00/69833 WO 009833PCTIUSOOIO8226 3 43 4 1 2 more than one of D D J and J is S, and no more than three of D D 1 2 9 10 11 12 J and J are Nwith the proviso that R R R and R are each independently selected to maintain the tetravalent nature of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen; Q is optionally selected from the group consisting of hydrido, alkyl, alkoxy. alkylamnino, alkylthio, haloalkylthio. alkenyl, alkynyl, saturated heterocyclyl, partially saturated beterocyclyl, acyl, aroyl, heteroaroyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkylalkenyl.
haloalkyl, haloalkoxy, haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxyalkyl, and halocycloalkenyloxyalkyl with the proviso that Z is selected from other than a single covalent bond when Q is hydrido;, K is (CR 4aR 4b)n wherein n is an integer selected from 1 through 2; R 4aand R 4bare independently selected from the group consisting of halo, hydrido, hydroxy, cyano, hydroxyalkyl, alkyl, alkenyl, alkoxyalkyl, aralkyl, heteroaralkyl, alkylthioalkyl, haloalkyl, haloalkenyl, and cyanoalkyl; 1 4a 4b I E when K is (CR R wherein E is selected from the group consisting of a covalent single bond, 0, S, C(0)0, C(S)0, 7 7 7 7 C(O)S, C(S)S, C(0)N(R (R C(S)N(R (R )NC(S), OC(0)N(R (R 7)NC(0)0, SC(S)N(R (R 7)NC(S)S, SC(0)N(R (R 7)NC(O)S, OC(S)N(R (R 7)NC(S)0, N(R 8)C(O)N(R 7 8 8 7 7 8 (R )NC(0)N(R N(R )C(S)N(R )NC(S)N(R S, S(0)2, S(0) 2 N(R N(R 7)S(0)2, S(0) 2 N(RI)C(0), C(0)N(R 7)S(0)2, P(0)(R )8 N(R 7)P(0)(R P(0)(R 8)N(R N(R ON(R CR 4a=CR 4 ethynylidene 1 ,2-ethynyl), and C=CR~R~ WO 00/69933 WO 0069833PCTIUSOOIO8226 K is optionally (CH(R 14)jTwherein j is selected from a integer from 0 through 2 and T is selected from the group consisting of single covalent bond, 0, S, and N(R 7) with the proviso that (CH(R is bonded to the uracil ring; ~is optionally Ewhen K is -(CH(R 14 ))-.weenE2iselcd from the group consisting of a covalent single bond, C(0)0, C(S)0, C(0)S, C(S)S, C(0)N(R (R 7)NC(0), C(S)N(R (R 7)NC(S), (R 7)NC(0)O, (R 7)NC(S)S, (R 7)NC(O)S, (R 7)NC(S)0, N(R 8)C(0)N(R 7, (R 7)NC(0)N(R N(R )C(S)N(R (R 7)NC(S)N(R S(0) 2 9 S(0) 2 N(R N(R 7)S(0) 2 S(0) 2 C(0)N(H)S(0) 2 P(0)R N(R 7)P(0)(R P(O)(R 8)N(R 7, and N(R 7); K is optionally G-(CH(R 15 A wherein k is selected from an integer.
from 1 through 2 and G is selected from the group consisting of 0, S, and N(R 7) with the proviso that R 15is other than hydroxy, cyano, halo, amino, alkylaniino, dialkylamino, and sulfhydryl when k is 1; E is optionally Jz when K is G-(CH(R wherein E3is selected from the group consisting of a covalent single bond, 0, S, C(S), C(0)0, C(S)0, C(0)S, C(S)S, C(0)N(R (R 7)NC(0), C(S)N(R (R 0C(0)N(R (R 7)NC(0)0, SC(S)N(R (R 7)NC(S)S, SC(0)N(R (R 7)NC(0)S, OC(S)N(R (R 7)NC(S)0, N(R 8)C(0)N(R 7, S(0) 2 N(R N(R 7)S(0) 2 N(R P(0)(R 8)N(R WO 00/69833 PCT/US00/08226 7 7 4a 4b N(R ON(R CR4=CR ethynylidene (CaC; 1,2-ethynyl), and C=CR4aR 4 b; YO is formula (IV):
S
R
1 7
R
1 8 R16 5 K2
R
1 9 R16'R lb b
(IV)
wherein D D, J and J are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more than one is a covalent bond, K 2 is independently selected from the group consisting of C and N no more than one of D 5
D
6 J and J6 is O, no more 6 5 6 5 6 5 6 than one of D D J and J is S, one of D D and J must be a covalent bond when two of D 5
D
6 J and J are 0 and S, no more than three of D 5
D
6 5, and J6 is N when K 2 is N and no more than four of D D J and J are N when K is carbon with the provisos that R 6
R
7 18 19 R 18, and R9 are each independently selected to maintain the tetravalent nature of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen; R and R 17 are optionally independently taken together to form a linear moiety spacer having from 3 through 6 contiguous atoms connected to form a ring selected from the group consisting of a cycloalkenyl ring having from 5 through 8 contiguous members, a partially saturated heterocyclyl ring having from 5 through 8 contiguous members, a heteroaryl having from through 6 contiguous members, and an aryl; 39 WO 00/69833 PCT/US00/08226 Qb is selected from the group consisting of NR20R21 2 1
R
2 2 oxy, alkyl, aminoalkyleryl, alkylamino, dialkylamino, dialkylsulfoniumalkyl, acylamino and Qbe, wherein Q is hydrido and R 2 0 21 22 R and R are independently selected from the group consisting of hydrido, amino, alkyl, hydroxy, alkoxy, aminoalkylenyl,alkylamino, dialkylamino, and 20 21 22.
hydroxyalkyl with the provisos that no more than one of R 2 0
R
2 1 and R is hydroxy, alkoxy, alkylamino, amino, and dialkylamino at the same time and 21 22 that R 20
R
2 1 and R 2 must be other than be hydroxy, alkoxy, alkylamino, amino, and dialkylamino when K 2 is N 21 20 22 21 22 R and R R and R, and R and R are independently optionally selected to form a spacer pair wherein a spacer pair is taken together to form a linear moiety having from 4 through 7 contiguous atoms connecting the points of bonding of said spacer pair members to form a heterocyclyl ring having 5 through 8 contiguous members with the proviso that no more than 20 21 20 22 one of the group consisting of spacer pairs R and R 2 R and R and
R
2 1 and R 22 is used at the same time; Q is optionally selected from the group consisting of 26 23 24 26 5 26 N(R2)SO 2 N(R N(R2)C(O)OR5, N(R2)C(O)SR, 26 5 26 N(R )C(S)OR and N(R )C(S)SR with the proviso that no more than one 23 24 26 of R R and R is hydroxy, alkoxy, alkylamino, amino, and 23 24 26 dialkylamino when two of the group consisting of R R 24 and R 2 are bonded to the same atom; Qb is optionally selected from the group consisting of 25 23 24 dialkylsulfonium, trialkylphosphonium, C(NR )NR R WO 00/69833 PCT/US00108226 N(R26 )C(NR 25)N(R 24), N(R26 )C(O)N(R 24), 26 23 24 25 N(R )C(S)N(R C(NR )OR, 26 25 23 24 26 25 N(23 24 C(O)N(R26 )C(NR25 )N(R C(S)N(R 26)C(NR2)N(R )(R24), N(R26)N(R26)C(NR25)N(R ON(R26)C(NR )N(R N(R26 )N(R26 )SO 2 N(R (R R C(NR25)SR, C(O)NR R24, and 232 23 24 26 C(O)NR R with the provisos that no more than one of R R and R6 can be hydroxy, alkoxy, alkylaminol, amino, or dialkylamino when two of the 23 24 26 group consisting of R R and R26 are bonded to the same atom and that said Qb group is bonded directly to a carbon atom; 23 24 25 26 R R24 R25 and R26 are independently selected from the group consisting of hydrido, alkyl, hydroxy, alkoxy, aminoalkylenyl, alkylamino, dialkylamino, amino, and hydroxyalkyl; 23 24 R and R24 are optionally taken together to form a linear spacer moiety having from 4 through 7 contiguous atoms connecting the points of bonding to form a heterocyclyl ring having 5 through 8 contiguous members; QS is selected from the group consisting of a single covalent bond,
(CR
3 7
R
3 8)bo(W)az wherein az is an integer selected from 0 through 1, b is an integer selected from 1 through 4, and WO is selected from the group consisting of 0, S, C(O)0, C(S)O, C(0)S, C(S)S, C(0)N(R14 14 14 14 14 1 (R 14)NC(0), C(S)N(R 14), (R 14)NC(S), OC(0)N(R 14), SC(S)N(R 14), 14 14 15 14 14 1 SC(0)N(R OC(S)N(R 14), N(R 5)C(0)N(R (R 4)NC(O)N(R S, 14 14 15 1 N(R (R14 )NC(S)N(R 15), S(0)2, S(0)2,N(R 4 N(R14 N(R7 P(0)(R )N(R N(R14 WO 00/69833 WO 0069833PCTIUSOOIO8226 ON(R 14), (CH(R 14))CW 1-(CH(R 15))d wherein c and d are integers independently selected from 1 through 4, and W 1is selected from the group consisting of 0, S, C(0)0, C(S)O, C(O)S, C(S)S, C(O)N(R 1), (R 14)NC(0), C(S)N(R 14), (R 1)NC(S), OC(0)N(R (R 14)NC(0)Q, SC(S)N(R 14 (R 14)NC(S)S, SC(O)N(R 14), (R 14)NC(O)S, OC(S)N(R 1), 14 15 14 14 (R )NC(S)O, N(R )C(O)N(R (R )NC(O)N(R N(R 15)C(S)N(R 14), (R 14)NC(S)N(R 15), S(0)2, S(O) 2 N(R 14 NR14 802 8()R)NR) 7 14 ON(R 14), and 4D 2-(CH(R 15 N wherein e and h are integers independently selected from 0 through 2 and W2is selected from the group consisting of CR I=CR 2, CR4IR4=C; vinylidene), ethynylidene 1 ,2-ethynyl), 1 ,2-cyclopropyl, 1 ,2-cyclobutyl, 1 ,2-cyclohexyl, 1,3cyclohexyl, 1 ,2-cyclopentyl, 1 ,3-cyclopentyl, 2,3-morpholinyl, 2,4morpholinyl, 2,6-morpholinyl, 3 ,4-morpholinyl, 3,5-morpholinyl, 1,2piperazinyl, 1,3-piperazinyl, 2,3-piperazinyl, 2,6-piperazinyl, 1,2-piperidinyl, 1 ,3-piperidinyl, 2,3-piperidinyl, 2,4-piperidinyl, 2,6-piperidinyl, 3,4piperidinyl, 1 ,2-pyrrolidinyl, 1 ,3-pyrrolidinyl, 2,3-pyrrolidinyl, 2,4pyrrolidinyl, 2,5-pyrrolidinyl, 3,4-pyrrolidinyl, 2,3-tetrahydrofuranyl, 2,4tetrahydrofuranyl, 2,5-tetrahydrofuranyl, and 3,4-tetrahydrofuranyl, with the provisos that R 14and R 15are selected from other than halo and cyano when directly bonded to N and that (CR 37R 38)b, (CH(R 14))c, (CH(R 14 e and are bonded to 0 YOis optionally Qb -Q ss wherein Q SS is selected from the group consisting of (CR 37R 38)f wherein f is an integer selected from 1 through 6, WO 00/69833 WO 0069833PCT/US00108226 (CH(R 14))c-Wl-(CH(R 1))d wherein c and d are integers independently selected from 1 througrh 4, and W1is selected from the group consisting ofW1 is selected from the group consisting-of 0, S, C(0)0, C(S)0, C(O)S, C(S)S, C(O)N(R 14), (R 14)NC(O), C(S)N(R (R 14)NC(S), OC(O)N(R 14), (R 14)NC(0)0, SC(S)N(R 14), (R )4 NC(S)S, SC(O)N(R (R1 )NC(O)S, OC(S)N(R 14), (R 14)NC(S)0, N(R 15)C(O)N(R 1), (R1 )NC(0)N(R 15), N(R 15)C(S)N(R 14), (R 14)NC(S)N(R 15),8(0), S(02,S()2(R14 NR14 )S02 ()R8 (7)PO( 8) P(O)(R8)N(R N(R 14), ON(R 14), and (CH(R 14))e-W2-(CH(R wherein e and h are integers independently selected from 0 through 2 and W is selected from the group consisting of CR 4a=CR b, ethy nylidene 1,2ethynyl), and C=C R Rb with the provisos that R 14and R 15are selected from other than halo and cyano when directly bonded to N and that (CR 3 7 R 38)f, (CH(R and (CH(R 14))e are bonded to E0; YOis othonall Qb-Qsss wherein Q~SS is (CH(R3 8 ))r-W 3 r is an integer selected from I through 3, W3is selected from the group consisting of 1,1 -cyclopropyl, 1 ,2-cyclopropyl, 1,1 -cyclobutyl, 1 ,2-cyclobutyl, 1,2cyclohexyl, 1 ,3-cyclohexyl, 1 ,4-cyclohexyl, 1 ,2-cyclopentyl, 1 .3-cyclopentyl, 2,3-morpholinyl, 2,4-morpholinyl, 2,5-morpholinyl, 2,6-morpholinyl, 3,4morpholinyl, 3,5-morpholinyl, 1,2-piperazinyl, 1,3-piperazinyl, 1,4piperazinyl, 2,3-piperazinyl, 2,5-piperazinyl, 2,6-piperazinyl, 1 ,2-piperidinyl, 1 ,3-piperidinyl, 1 ,4-piperidinyl, 2,3-piperidinyl, 2,4-piperidinyl, piperidinyl, 2,6-piperidinyl, 3 ,4-piperidinyl, 3 ,5-piperidinyl, 3 ,6-piperidinyl,.
1 ,2-pyrrolidinyl, 1 ,3-pyrrolidinyl, 2,3-pyrrolidinyl, 2,A-pyrrolidinyl, pyrrolidinyl, 3,A-pyrrolidinyl, 2H-2,3-pyranyl, 2H-2,4-pyranyl, 2H-2,5- WO 00/69833 WO 0069833PCTIUSOOIO8226 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-yi, 2,3tetrahydrofuranyl. 2,4-tetrahydrofuranyl, 2.5-tetrahydrofuranyl, 3,4tetrahydrofuranyl, 2,3-tetrahydropyranyl, 2,4-tetrahydropyranyl, tetrahydropyranyl, 2,6-tetrahydropyranyl. 3,4-tetrahydropyranyl. and tetrahydropyranyl, and each carbon and hyrido containing nitrogen member Of the ring of the W 3 other than the points of attachment is optionally substituted 9 10 11 12 with one or more of the group consisting of R R ,R and R with the proviso that (CH(R 38))r is bonded to E' and Q bis bonded to lowest numbered substituent position of each W Yis optionally Q b -Qsssr wherein Q sssr is (CH(R 3 8 r W sa 4 integer selected from 1 through 3, W is selected from the group consisting of I ,2-cyclobutyl, 1 ,2-cyclohexyl, 1 .3-cyclohexyl, 1 .4-cyclohexyl, 1,2cyclopentyl, 1 .3-cyclopentyl, 2,3-morpholinyl, 2,4-morpholinyl, morpholinyl, 2,6-morpholinyl, 3,4-morpholinyl, 3,5-morpholinyl, 1,2piperazinyl, 1,3-piperazinyl, I ,4-piperazinyl, 2,3-piperazinyl, 2,6-piperazinyl, 1 ,2-piperidinyl, I ,3-piperidinyl, I ,4-piperidinyl, 2,3piperidinyl, 2,4-piperidinyl, 2,5-piperidinyl, 2,6-piperidinyl, 3 ,4-piperidinyl, 3 .5-piperidinyl, 3,6-piperidinyl, 1 ,2-pyrrolidinyl, 1 ,3-pyrrolidinyl, 2,3pyrrolidinyl, 2,4-pyrrolidinyl, 2,5-pyrrolidinyl, 3,4-pyrrolidinyl, 2H-2,3pyranyl, 2H-2,4-pyranyl, 2H-2,5-pyranyl, 4H-2,3-pyranyl, 4H-2,4-pyranyl, 4H-2,5-pyranyl, 2H-pyran-2-one-3,4-yi, 2H-pyran-2'one-4,5-yl, 4H-pyran- 4-one-2,3-yl, 2,3-tetrahydrofuranyl, 2,4-tetrahydrofuranyl. tetrahydrofuranyl, 3,4-tetrahydrofuranyl, 2,3-tetrahydropyranyl, 2,4tetrabydropyranyl, 2,5-tetrahydropyranyl, 2,6-tetrahydropyranyl, 3,4tetrahydropyranyl, and 3,5-tetrahydropyranyl, and each carbon and hydrido containing nitrogen member of the zing of the W 4other than the points of attachment is optionally substituted with one or more of the group consisting of WO 00/69833 WO 0069833PCTfUSOOIO8226 9 10 11 12 38 o R ,R ,R ,and R with the provisos that (CH(R is bonded to E and Q bis bonded to highest number substituent position of eachW
Y
0 is optionally Q b-Q SSSS wherein Q SSSS is (CH(R 38 ))rW 5 r is an integer selected from 1 through 3, W 5is selected from the group consisting of 1,4-indenyl, 1,5-indenyl, 1,6-indenyl, 1,7-indenyl, 2,7-indenyl, 2,6-indenyl, 2,4-indenyl, 3 ,4-indenyl, 3 .3-indenyl, 3,6-indenyl, 3 ,7-indenyl, 2,4-benzofuranyl, 2,5-.benzofuranyl, 2,6-benzofuranyl, 2,7-benzofuranyl, 3,A-benzofuranyl, 3 ,5-benzofuranyl, 3,6-benzofuranyl, 3,7-benzofuranyl, 2A4-benzothiophenyl, 2,5-benzothiophenyl, 2,6-benzothiophenyl, 2,7benzothiophenyl, 3,4-benzothiophenyl, 3,5-benzothiophenyl, 3,6benzothiophenyl, 3 ,7-benzothiophenyl, 2,7-imidazo(1I,2-a)pyridinyl, 3,4imidazo( 1,2-a)pyridinyl, 3 ,5-imidazo(lI.2-a)pyridinyl, 3.6-imidazo( 1,2a)pyridinyl, 3 ,7-imidazo( 1,2-a)pyridinyl, 2,4-indolyl, 2,5-indolyl. 2,6indolyl, 2,7-indolyl, 3,4-indolyl, 3,5-indolyl, 3 ,6-indolyl, 3 ,7-indolyl, 1,4isoindolyl, 1 ,5-isoindolyl, 1 ,6-isoindolyl, 2A4-isoindolyl, 2,5-isoindolyl, 2,6isoindolyl, 2,7-isoindolyl, 1 ,3-isoindolyl, 3,A-indazolyl, 3,5-indazolyl, 3,6indazolyl, 3,7-indazolyl, 2,4-benzoxazolyl, 2,5-benzoxazolyl, 2,6benzoxazolyl, 2,7-benzoxazolyl, 3,4-benzisoxazolyl, 3,5-benzisoxazolyl, 3,6benzisoxazolyl, 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, 2,7naphthyl, 2,8-naphthyl, 2,4-quinolinyl, 2,5-quinolinyl, 2,6-quinolinyl, 2,7quinolinyl, 2,8-quinolinyl, 3 ,4-quinolinyl, 3,5-quinolinyl, 3 ,6-quinolinyl, 3,7quinolinyl, 3 ,8-quinolinyl, 4,5-quinolinyl, 4,6-quinolinyl, 4,7-quinolinyl, 4,8quinolinyl, 1 ,4-isoquinolinyl, 1 ,5-isoquinolinyl, 1 ,6-isoquinolinyl, 1,7isoquinolinyl, 1,8-i soquinolinyl, 3 ,4-isoquinolinyl, 3,5-isoquinolinyl, 3,6isoquinolinyl, 3,7-isoquinolinyl, 3 ,8-isoquinolinyl, 4,5-isoquinolinyl, 4,6isoquinolinyl, 4,7-isoquinolinyl, 4,8-isoquinolinyl, 3,4-cinnolinyl, cinnolinyl, 3 ,6-cinnolinyl, 3 ,7-cinnolinyl, 3,8-cinnolinyl, 4,5-cinnolinyl, 4,6cinnolinyl, 4,7-cinnolinyl, and 4,8-cinnolinyl, and each carbon and hydrido, containing nitrogen member of the ring of the W5other than the points of attachment is optionally substituted with one or more of the group consisting of WO 00/69833 WO 0069833PCTI/USOOIOS226 9 10 11 12 b R. ,R ,R ,and R with the proviso that Q is bonded to lowest number substituent position of each W' and that (CH(R 31))r is bonded to E0 YO i optionally QbQssssr wherein Qssssr is (CH(R 3 8 ))r-W6,risa 6 integer selected from 1 through 3, W is selected from the group consisting of 1 ,4-indenyl, 1 ,5-indenyl, 1 ,6-indenyl, 1 ,7-indenyl, 2 ,7-indenyl, 2,6.-indenyl, ndenyl, 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, 2,7benzothiophenyl, 3,4-benzothiophenyl, 3,5-benzothiophenyl, 3,6benzothiophenyl, 3,7-benzothiophenyl, 2,7-imidazo( 1,2-a)pyridinyl, 3,4imidazo( 1,2-a)pyridinyl, 3,5-imidazo( 1,2-a)pyridinyl, 3,6-imidazo( 12a)pyri dinyl, 3,7-imidazo( 1 2-a)pyridinyl, 2,4-indolyl, 2,5-indolyl. 2,6indolyl, 2,7-indolyl, 3,4-indolyl, 3,5-indolyl, 3,6-indolyl, 3,7-indolyl, 1,4i soindolyl, 1 ,5-isoindolyl, 1 ,6-isoindolyl, 2,4.-isoindolyl, 2,5-isoi ndolyl, 2,6isoi ndolyl, 2,7-i soindolyl, 1 ,3-isoindolyl, 3,4-i ndazolyl, 3,5-indazolyl, 3,6indazolyl, 3,7-indazolyl, 2,4-benzoxazolyl, 2,5-benzoxazolyl, 2,6benzoxazolyl, 2,7-benzoxazolyl, 3,4-benzisoxazolyl, 3,5-benzisoxazolyl, 3,6benzisoxazolyl, 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, 2,7naphthyl, 2,8-naphthyl, 2A4-quinolinyl, 2,5-quinolinyl, 2,6-quinolinyl, 2,7quinolinyl, 2,8-quinolinyl, 3,4-quinolinyl, 3,5-quinolinyl, 3,6-quinolinyl, 3,7quinolinyl, 3,8-quinolinyl, 4,5-quinolinyl, 4,6-quinolinyl, 4,7-quinolinyl, 4,8quinolinyl, 1 ,4-isoquinolinyl, I ,5-isoquinolinyl. 1 ,6-isoquinolinyl, 1,7isoquinolinyl, 1 ,8-isoquinolinyl, 3,4-isoquinolinyl, 3,5-isoquinolinyl, 3,6isoquinolinyl, 3,7-isoquinolinyl, 3,8-isoquinolinyl, 4,5-isoquinolinyl, 4,6isoquinolinyl, 4,7-isoquinolinyl, 4,8-isoquinolinyl, 3,4-cinnolinyl, cinnolinyl, 3,6-cinnolinyl, 3 ,7-cinnolinyl, 3,8-cinnolinyl, 4,5-cinnolinyl, 4,6cinnolinyl, 4,7-cinnolinyl, and 4,8-cinnolinyl, and each carbon and hydrido, containing nitrogen member of the ring of the W 6other than the points of attachment is optionally substituted with one or more of the group consisting of WO 00/69833 WO 0069833PCT/USOOIO8226 9 10 11 12 b R ,R ,R ,and R with the proviso that Q is bonded to highest number.
substituent position of each W 6and that (CH(R 38))r is bonded to E0 In another embodiment of compounds of Formula I or a pharmaceutically acceptable salt thereof, 1aadJ bare independently selected from the group consisting of 0 and S; B is formula 34
R
3 3 K R3 R32
R
3 6
(V)
1 2 12 1 wherein D D J 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 1 2 1.
than one is acovalent bond, no more than one of D D ,Ji J and K isO0, 1 2 12 1 1 2 12 no more than one of D D J J and K is S, one of D D J and 1 1 2 12 1 K must be acovalent bond when two of D D J J and K are 0and S, 1 2 12 1 and no more than four of D D ,Ji J and K are N; 9 10 11 12 13 16 17 18 19 32 33 34 R ,R ,R ,R ,R ,R ,R ,R ,R ,R ,R ,R, R 35, and R 36are, independently selected from the group consisting of hydrido, acetarnido, haloacetamido, ainidino, guanidino, dialkylsulfonium, trialkyiphosphonium, dialkylsulfoniumalkyl, carboxy, heteroaralkylthio, heteroaralkoxy, cycloalkylamnino, acylalkyl, acylalkoxy, aryloylalkoxy, heterocyclyloxy, aralkylaryl, aralkyl, aralkenyl, aralkynyl, heterocyclyl, perhaloaralkyl, aralkylsulfonyl, aralkylsulfonylalkyl, aralkylsulfinyl, aralkylsultinylalkyl, halocycloalkyl, halocycloalkenyl, cycloalkylsulfinyl, WO 00/69a33 WO 0069833PCTUSOOIO8226 cycloalkylsulfinylalkyl, cycloalkylsulfonyl, cycloalkylsulfonylalkyl, heteroarylanino, N-heteroarylaniino-N-alkyl amino, heteroarylaminoalkyl, haloalkylthio, alkanoyloxy, alkoxy, alkoxyalkyl, haloalkoxylalkyl, heteroaralkoxy, cycloalkoxy, cycloalkenyloxy, cycloalkoxyalkyl, cycloalkylalkoxy, cycloalkenyloxyalkyl, cycloalkylenedioxy, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxy, halocycloalkenyloxyalkyl, hydroxy, amino, alkoxyamino, thio, nitro, lower alkylamino, alkylthio, alkylthioalkyl, arylarnino, aralkylaniino, arylthio, arylthioalkyl, heteroaralkoxyalkyl, alkyl sulfinyl, alkylsulfinylalkyl, arylsulfinylalkyl, arylsulfonylalkyl, heteroarylsulfinylalkyl. heteroarylsulfonylalkyl, alkylsulfonyl, alkylsulfonylalkyl, haloalkylsulfinylalkyl, haloalkylsulfonylalkyl, alkylsulfonainido, alkylarninosulfonyl, arnidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, monoarylamidosulfonyl, arylsulfonamido, diary]anidosulfonyl, monoalkyl monoaryl amnidosulfonyl, arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, heterocyclylsulfonyl, heterocyclylthio, alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, h aloalkanoyl, alkyl, alkenyl, 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 heterocyclyl, partially saturated heterocyclyl, heteroaryl, heteroaryloxy, heteroaryloxyalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, carboxyalkyl, carboalkoxy, alkoxycarboxamidlo, alkylamidocarbonylamido, arylarnidocarbonylamiddo, carboalkoxyalkyl, carboalkoxyalkenyl, carboxy, carboaralkoxy, carboxanido, carboxaniidoalkyl, cyano, carbohaloalkoxy, phosphono, phosphonoalkyl, diaralkoxyphosphono, and diaralkoxyphosphonoalkyl; 19 32 33 34 35 36 R ,R R ,R R R ,and R are independently optionally b 16 19 b Q with the proviso that no more than one of R and R is Q at the same time and that Q bis Q b WO 00/69833 PCT/US00/08226 B is optionally selected from the group consisting of hydrido, trialkylsilyl, C2-C8 alkyl, C3-C8 alkylenyl, C3-C8 alkenyl, C3-C8 alkynyl, C2-C8 haloalkyl, and C3-C8 haloalkenyl wherein each member of group B is optionally substituted at any carbon up to and including 6 atoms from the point 32 33 of attachment of B to A with one or more of the group consisting of R R 3 3 34 35 36 R34, R3, and R36 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 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 9 13 point of attachment are optionally substituted with R or R a ring carbon or 9 nitrogen adjacent to the R position and two atoms from the point of attachment is optionally substituted with R a ring carbon or nitrogen adjacent to the
R
13 position and two atoms from the point of attachment is optionally substituted with R 1 a ring carbon or nitrogen three atoms from the point of attachment and adjacent to the R 0 position is optionally substituted with R 1 1 a ring carbon or nitrogen three atoms from the point of attachment and adjacent 12 33 to the R 1 position is optionally substituted with R 3 and a ring carbon or nitrogen four atoms from the point of attachment and adjacent to the R 1 1 and 33 34 R positions is optionally substituted with R A is selected from the group consisting of single covalent bond, 7 15 15 7 (W )r-(CH(R ))pa and (CH(R ))pa(W7)rr wherein rr is an integer selected from 0 through 1, pa is an integer selected from 0 through 6, and W 7 WO 00/69833 PCT/US00/08226 is selected from the group consisting of O, S, C(O)N(R C(S)N(R (R (R and N(R with the proviso that no more than one of the group consisting of rr and pa can be 0 at the same time; R and R are independently selected from the group consisting of hydrido, hydroxy, alkyl, and alkoxyalkyl; 14 15 37 38 R R 1
R
37 and R 3 are independently selected from the group consisting of hydrido, hydroxy, halo, alkyl, alkoxyalkyl, haloalkyl, haloalkoxy, and haloalkoxyalkyl; R and R 38 can be independently selected from the group consisting of aroyl and heteroaroyl; I is selected from the group consisting of NR and S(O)2; R is selected from the group consisting of hydrido, hydroxy, alkyl, and alkoxy; 39 40 R and R are independently selected from the group consisting of hydrido, hydroxy, halo, hydroxyalkyl, alkyl, alkoxyalkyl, haloalkyl, haloalkoxy, and haloalkoxyalkyl; M is selected from the group consisting of N and R -C;
R
1 is 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;
R
2 is Z-Q; Z is selected from the group consisting of covalent single bond, 41 42 41 (CR R 42)q wherein q is an integer selected from 1 through 3, (CH(R ))g 42 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, S(0), WO 00/69833 WO 0069833PCTUSOOOSZZ6 S(0) 2 NR4),and ONR4 ,and (C]H(R 4 1 ))e-W 2 2
-(CH(R
4 2 wherein e and h are integers independently sele cted from 0 through 2 and W2is selected from the group consisting of CR 41=CR 42, 1,2-cyclopropyl, 1.2-cyclobutyl, 1 ,2-cyclohexyl, 1 ,3-cyclohexyl, 1 ,2-cyclopentyl, 1 ,3-cyclopentyl, 2,3morpholinyl, 2,4-morpholinyl, 2,6-morpholinyl, 3 .4-morpholinyl, morpholinyl. 1,2-piperazinyl, 1,3-piperazinyl, 2,3-piperazinyl, 2,6piperazinyl, 1 ,2-piperidinyl, 1 ,3-piperidinyl, 2,3-piperidinyl. 2,4-piperidinyl, 2,6-piperidinyl, 3 .4-piperidinyl, 1 .2-pyrrolidinyl, 1 ,3-pyrrolidinyl, 2,3pyrrolidinyl, 2,4-pyrrolidinyl, 2,5-pyrrolidinyl, 3.4-pyrrolidinyl, 2,3tetrahydrofuranyl, 2,4-tetrahydrofuranyl, 2,5-tetrahydrofuranyl, and 3,4tetrahydrofuranyl, with the proviso that ZOis directly bonded to the uracil ring; 41 42 R and R are independently selected from the group consisting of arnidino, hydroxyamino, hydrido, hydroxy, amino, and alkyl; Q is selected from the group consisting of hydrido, with the proviso that Z 0 is other than a covalent single bond, the formula Rt 1 1 2 12 1 wherein D D J J and K are independently selected from the group consisting of C, N, 0, S and a covalent bond with the provisos that no more 1 2 12 1 than one is a covalent bond, no more than one of D D J J and K isO0, 1 2 12 1 1 21 2 no more than one of D D J J and K is S, one of D D ,Ji J and 1 1 2 12 1 K must be acovalent bond when two of D D ,J J and K are 0and S, 1 2 12 1 and no more than four of D D J J and K is N, with the proviso that WO 00/69833 PCT/US00/08226 R R R 1 R12, and R 1 are each independently selected to maintain the tetravalent nature of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen; K is (CRR4b)n wherein n is an integer selected from 1 through 2; 4a 4b
R
4a and R 4 b are independently selected from the group consisting of halo, hydrido, hydroxyalkyl, alkyl, alkoxyalkyl, alkylthioalkyl, and haloalkyl; E is selected from the group consisting of a covalent single bond, C(O)N(R (R7)NC(O), S(O) 2 (R7)NS(0) 2 and S(0) 2 N(R7); YO is formula (IV):
S
R17 6R 1 8
JJ
R 16D 1 9 Qb (IV) wherein D D J and J are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more than one is a covalent bond, K is C, no more than one of D 5 D, J5, and J is O, no more than one of D D 6 J, and J is S, one of DD, D 6 and J must be a covalent bond when two of D D, 5 and J are 0 and S, and no more than four of D D and J are N when K is carbon with the provisos that R R 7, R18 and R 1 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; WO 00/69833 PCT/US00/08226 Qb is selected from the group consisting of NR20R21 2 1 22 be be R22, aminoalkylenyl, and Qb, wherein Q is hydrido and R 21 22
R
21 and R 2 are independently selected from the group consisting of hydrido, alkyl, hydroxy, amino, aminoalkylenyl, dialkylamino, alkylamino, and 21 hydroxyalkyl with the proviso that no more than one of R and R is hydroxy, amino, alkylamino, or dialkylamino at the same time; Qb is optionally selected from the group consisting of 23 24 26 25 23 24 R24 N(R )C(NR2)N(R C(O)N(R26)C(NR25)N(R23)(R24), N(R26)N(R26)C(NR25)N(R23)(R24), 26 25 23 24 and ON(R )C(NR )N(R with the provisos that no more than one 23 24 26 of R R and R is hydroxy, alkylamino, amino, or dialkylamino when 23 24 26 two of the group consisting of R R and R 2 are bonded to the same atom; 23 24 25 26 R R 2 R and R 2 are independently selected from the group consisting of hydrido, alkyl, hydroxy, amino, alkylenylamino, dialkylamino, alkylamino, and hydroxyalkyl; Q 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 an integer selected from 1 through 5, and W is selected from the group consisting of O, S(0)2, S(0) 2
N(R
14 N(R14)S(0)2, and N(R14), (CH(R14))c-W -(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 O, S, C(0)O, C(S)O, C(0)S, C(S)S, C(0)N(RI4), WO 00/69833 WO 0069833PCTIUSOOIOS226 (R 14)NC(O), C(S)N(R 14), (R 14)NC(S), OC(O)N(R 14), (R 14)NC(O)O, SC(S)N(R (R 14)NC(S)S, SC(O)N(R 14), (R 14)NC(O)S, OC(S)N(R 14 (R 14)NC(S)O, N(R1 )C(O)N(R 14), (R 14)NC(O)N(R5 )C(S)N(R 14), (R 14)NC(S)N(R 15), S(O) 2
S(O)
2 N(R 14 N(R 14)S(0) 2 P(O)(R N(R P(O)(R )N(R N(R 4),
ON(R
14 and (CH(R 14 ))eCW 22 _(CH(R 15 wherein e and h are integers independently selected from 0 through 2 and W2is selected from the group consisting of CR =CR 2, CR 'R4=C; vinylidene), ethynylidene (C=C; 1 ,2-ethynyl), 1 .2-cyclopropyl, 1 ,2-cyclobutyl, 1 ,2-cyclohexyl, I .3cyclohexyl, 1,2-cyclopentyl, 1,3-cyclopentyl, 2,3-morpholinyl, 2,4morpholinyl, 2,6-morpholinyl, 3 ,4-morpholinyl, 3,5-morpholinyl, 1,2piperazinyl, 1 .3-piperazinyl, 2,3-piperazinyl, 2,6-piperazinyl, 1 .2-piperidinyl, 1 ,3-piperidinyl, 2,3-piperidinyl, 2,4-piperidinyl, 2,6-piperidinyl, 3,4piperidinyl, 1 ,2-pyrrolidinyl, 1 ,3-pyrrolidinyl, 2,3-pyrrolidinyl, 2,4pyrrolidinyl, 2,5-pyrrolidinyl, 3,4-pyrrolidinyl, 2,3-tetrahydrofuranyl, 2,4tetrahydrofuranyl, 2,5-tetrahydrofuranyl, and 3,4-tetrahydrofuranyl, with the provisos that R 14and R 15are selected from other than halo and cyano when directly bonded to N and that (CR 37R 38)b, (CH(R 14))c, and (CH(R 14 e are bonded to E 0 YO is optionally Qb-Qs wherein Qs is selected from the group consstig o (C 37R 38)f wherein f is an integer selected from 1 through 4, (CH(R 1))cW -(CH(R 1))d wherein c and d are integers indep endently selected from 1 through 2, and W1is selected from the group consisting ofW 1 is selected from the group consisting of 0, S, C(0)N(R 14 WO 001698.33 PTUO/S2 PCT[USOO/08226 (R 14)NC(O), N(R 15)C(O)N(R 14), (R 14)NC(O)N(R 15), N(R 14), ON(RI and (CH(R1 4 ))e-W2(CH(R 15 wherein e and h are integers independently selected from 0 througrh 2 and. W 2 is selected from the group consisting of CR 4a=CR 4b, ethynylidene (CmC; 1,2-ethynyl), and.C=CR 4aR 4bwith the 14 provisos that R and R are selected from other than halo when directly bonded to N and that (CR 37R 38)f, (CH(R 14 and (CH(R 14))e are bonded toE0 Y 0is optionally Q b-Q s wherein Q s is (CH(R 38))rf W3, r i s an integer selected from 1 through 2, W3is selected from the group consisting of 1,1 -cyclopropyl, 1 ,2-cyclopropyl, 1.1 -cyclobutyl, 1 ,2-cyclobutyl, 1,2cyclohexyl, 1 ,3-cyclohexyl, 1 ,4-cyclohexyl, 1 ,2-cyclopentyl, 1 ,3-cyclopentyl, 2,3-morpholinyl, 2,4-morpholinyl, 2,5-morpholinyl, 2,6-morpholinyl, 3,4morpholinyl, 3 .5-morpholinyl, 1 ,2-piperazinyl, 1 ,3-piperazinyl, 1,4piperazinyl, 2,3-piperazinyl, 2,5-piperazinyl, 2,6-piperazinyl, 1 ,2-piperidinyl, 1 ,3-piperidinyl, 1,A-piperidinyl, 2,3-piperidinyl, 2,4-piperidinyl. 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, pyrrolidinyl, 3,4-pyrrolidinyl, 2H-2,3-pyranyl, 2H-2,4-pyranyl, 2H-2,5pyranyl, 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, 2,3tetrahydrofuranyl, 2,4-tetrahydrofuranyl, 2,5-tetrahydrofuranyl, 3,4tetrahydrofuranyl, 2,3-tetrahydropyranyl, 2,4-tetrahydropyranyl, tetrahydropyranyl, 2,6-tetrahydropyranyl, 3,4-tetrahydropyranyl, and tetrahydropyranyl, and each carbon and hyrido containing nitrogen member of the ring of the W 3 other than the points of attachment is optionally substituted 9 10 11 12 with one or more of the group consisting of R R R and R With the WO 00/69833 WO 0069833PCT/USOO108226 proviso that (CH(R 38))r is bonded to E 0and Q bis bonded to l .owest numbered substituent position of each W 3 Yis optionally Q b -Qsssr wherein Q sssr is (CH(R 3 8 sa 4 integer selected from 1 through 2, W is selected from the group consisting of 1,2-cyclobutyl, 1,2-cyclohexyl, 1,3-cyclohexyl, 1,4-cyclohexyl, 1,2cyclopentyl, 1,3-cyclopentyl, 2,3-morpholinyl, 2,4-morpholinyl, morpholinyl, 2,6-inorpholinyl, 3,4-morpholinyl, 3-5 -morpholinyl, 1,2piperazinyl, 1,3-piperazinyl, 1 .4-piperazinyl, 2,3-piperazinyl, 2,6-piperazinyl, 1 ,2-piperidinyl, 1 ,3-piperidinyl, 1 ,4-piperidinyl, 2,3piperidinyl, 2,4-piperidinyl, 2,5-piperidinyl, 2,6-piperidinyl, 3,4-piperidinyl, 3 ,5-piperidinyl, 3,6-piperidi nyl, 1 ,2-pyrrolidinyl, 1 ,3-pyrrolidinyl, 2,3pyrrolidinyl, 2,4-pyrrolidinyl, 2,5-pyrrolidinyl, 3,4-pyrrolidinyl, 2H-2.3pyranyl, 2H-2,4-pyranyl, 2H-2,5-pyranyl, 4H-2,3-pyranyl, 4H-2,4-pyranyl, 4H-2,5-pyranyl, 2H-pyran-2-one-3 A4-yl, 2H-pyran-2-one-4,5-yl, 4H-pyran- 4-one-2,3-yi, 2,3-tetrahydrofuranyl, 2,4-tetrahydrofuranyl, tetrahydrofuranyl, 3A4-tetrahydrofuranyl, 2,3-tetrahydropyranyl, 2,4tetrahydropyranyl, 2,5-tetrahydropyranyl, 2,6-tetrahydropyranyl, 3,4tetrahydropyranyl, and 3,5i-tetrahydropyranyl, and each carbon and hyrido containing, nitrogen member of the ring of the W 4other than the points of attachment is optionally substituted with one or more of the group consisting of 9 10 11 12 38 0 *R ,R ,R ,and R with the provisos that (CH(R is bonded to E b4 and Q is bonded to highiest number substituent position of eachW Y 0is optionally Q SSwherein Qss is (CH(R 38))CW5 r is an integer selected from I through 2, W5is selected from the group consisting of 1 ,4-indenyl' 1 ,5-indenyl, 1,6-i ndenyl, 1 ,7-indenyl, 2,7-indenyl, 2,6-indenyl, 2,4-indeny 1, 3,4-indenyl, 3,5-indenyl, 3 ,6-indenyl, 3 ,7-indenyl, 2,A-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- WO 00/69833 WO 0069833PCT/USOO8226 benzothiophenyl, 3,4-benzotbiophenyl, 3.5-benzothiophenyl, 3,6benzothiophenyl, 3,7-benzothiophenyl, 2,7-ixnidazo( 1,2-a)pyridinyl, 3,4imidazo( 1,2-a)pyridinyl, 3 ,5-irnidazo( 1,2-a)pyridinyl, 3,6-imidazo( 1,2a)pyridinyl, 3 ,7-imidazo( 1,2-a)pyridinyl, 2,4-indolyl, 2,5-indolyl, 2,6indolyl, 2,7-indolyl, 3,4-indolyl, 3,5-indolyl, 3,6-indolyl, 3,7-indolyl, 1,4isoindolyl, 1 ,5-isoindolyl, 1 ,6-isoindolyl, 2A4-isoindolyl, 2.5-isoindolyl, 2,6isoindolyl, 2,7-isoindolyl, 1 ,3-isoindolyl, 3,4-indazolyl, 3,5-indazolyl, 3.6indazolyl, 3,7-indazolyl, 2,4-benzoxazolyl, 2,5-benzoxazolyl, 2,6benzoxazolyl, 2,7-benzoxazolyl, 3A4-benzisoxazolyl, 3,5-benzisoxazolyl. 3,6benzisoxazolyl, 3,7-benzisoxazolyl, 1 ,4-naphthyl, I ,5-naphthyl, 1 ,6-naphthyl, 1,7-naphthyl, 1,8-naphthyl, 2A4-naphthyl, 2,5-naphthyl, 2,6-naphthyl, 2,7naphthyl, 2,8-naphthyl, 2,4-quinolinyl, 2,5-quinolinyl, 2,6-quinolinyl, 2,7quinolinyl, 2,8-quinolinyl, 3 ,4-quinolinyl, 3 ,5-quinolinyl, 3,6-quinolinyl, 3,7quinolinyl, 3.8-quinolinyl, 4,5-quinolinyl, 4,6-quinolinyl, 4,7-quinolinyl, 4,8quinolinyl, 1 ,4-isoquinolinyl, 1 ,5-isoquinolinyl, 1 .6-isoquinolinyl, 1,7-.
isoquinolinyl, I ,8-isoquinolinyl, 3,4-isoquinolinyl, 3 ,5-isoquinolinyl, 3,6isoquinolinyl, 3 ,7-isoquinolinyl, 3,8-isoquinolinyl, 4,5-isoquinolinyl, 4,6isoquinolinyl, 4,7-isoquinolinyl, 4,8-i soquinolinyl, 3,4-cinnolinyl, cinnolinyl, 3 ,6-cinnolinyl, 3,7-cinnolinyl, 3,8-cinnolinyl, 4,5-cinnolinyl, 4,6cinnolinyl, 4,7-cinnolinyl, and 4,8-cinnolinyl, and each carbon and hyrido containing nitrogen member of the ring of the WV 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 R R and R with the proviso that Q is bonded to lowest number substituent position of each W1and ta C(38))r is bonded to E Y-i pinlyQQsi wherein Qsss is (CH(R 38))eW 6, r is an integer selected from 1 through 2, W 6is selected from the group consisting of 1 ,4-indenyl, 1 .5-indenyl, 1 ,6-indenyl, 1 ,7-indenyl, 2,7-indenyl, 2,6-indenyl, 2,4-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, 2,5i-benzothiophenyl, 2,6-benzothiophenyl, 2,7benzothiophenyl, 3 ,4-benzothiophenyl, 3 ,5-benzothiophenyl, 3,6- WO 00/69833 WO 0069833PCT/USOOIOSZ26 benzothiophenyl, 3,7-benzothiophenyl, 2,7-imidazo( 1,2-a)pyridinyl, 3,Aimidazo( 1,2-a)pyridinyl, 3,5-imidazo( 1,2-a)pyridinyl, 3,6-iniidazo( 1,2a)pyridinyl, 3,7-imnidazo( 1,2-a)pyridinyl, 2,4-indolyl, 2,5-indolyl, 2,6indol yl, 2,7-indolyl, 3.,4-indol yl, 3,5-indolyl, 3,6-indolyl, 3 ,7-indolyl, 1,4isoindolyl, 1 ,5-isoindolyl, 1 ,6-isoindolyl, 2,4-isoindolyl, 2,5-isoindolyl. 2,6isoindolyl, 2,7-isoindolyl, 1 ,3-isoi ndolyl, 3 ,4-indazolyl, 3.5-indazolyl. 3,6indazolyl, 3,7-indazolyl, 2,4-benzoxazolyl, 2,5-benzoxazolyl, 2,6benzoxazolyl, 2,7-benzoxazolyl, 3,4-benzisoxazolyi, 3,-5-benzisoxazolyl, 3,6benzisoxazolyl, 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, 2,7naphthyl, 2,8-naphthyl, 2,4-quinolinyl, 2,5-quinolinyl, 2,6-quinolinyl, 2,7quinolinyl, 2,8-quinolinyl, 3 .4-quinolinyl, 3,5-quinolinyl, 3 ,6-quinolinyl, 3,7quinolinyl, 3 ,8-quinolinyl, 4,5-quinolinyl, 4,6-quinolinyl, 4.7-quinolinyl, 4,8quinolinyl, 1 ,4-isoquinolinyl, 1 .5-isoquinolinyl, 1 ,6-isoqui nolinyl, 1,7isoquinolinyl, 1 ,8-isoquinolinyl, 3 ,4-isoquinolinyl, 3 ,5-isoquinolinyl, 3,6isoquinolinyl, 3,7-isoquinolinyl, 3 .8-isoquinolinyl, 4,5-isoquinolinyl, 4,6isoquinolinyl, 4,7-isoquinolinyl, 4,8-isoquinolinyl, 3 ,4-cinnolinyl, cinnolinyl, 3,6-cinnolinyl, 3 ,7-cinnolinyl, 3 ,8-cinnolinyl, 4,5-cinnolinyl, 4,6cinnolinyl, 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 croup consisting of R 10 11 12d ihhe proviso that Q is bonded to highest number substituent position of each W 6and that (CH(R 38))r is bonded to E In a preferred embodiment of compounds of Formula I or a pharmaceutically acceptable salt thereof, Saand J bare eachO0; B is formula WO 00/69833 WO 00/98,33PCT/USOO/08226 3 3 K~ K 1 2 1 2 1 31 21'' I D2 1 1 212 1 121 11 K uteclnbnwhereioofD D I ,J and K are idpednlndSctdfrmteru 121 21 annmrthanf oenrod,D o mor thand n afreND; ndKis0 9 1 1 1213 2 33 34 3 2 36 2 K Rmstbea ovletRonRwentw oR,D,Ri, andRK are 0adS independently selected from the group consisting of hydrido, acetamido, haloacetarnido, amidino, guanidino, alkylenedioxy, haloalkylthio, alkanoyloxy, alkoxy, alkoxyalkyl,.haloalkoxylalkyl, hydroxy, amino, alkoxyamino, nitro, lower alkylamino, alkylthio, alkylthioalkyl, alkylsulfinyl, alkylsulfonyl, alkylsulfonylalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, alkylsulfonamiddo, alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl aniidosulfonyl, alkanoyl, haloalkanoyl, alkyl, alkenyl, halo, haloalkyl, haloalkenyl, haloalkoxy, hydroxyhaloalkyl, hydroxyalkyl, amninoalkyl, haloalkoxyalkyl, carboxyalkyl, carboalkoxy, carboxy, carboxamido, carboxamudoalkyl, and cyano; 16 19 32 33 34 35 36 R tR R R R ,R and R are independently optionally b 16 19 b Q with the proviso that no more than one of R and R is Q at the same time and that Q bisQ b WO 00/69833 PCT/USOO/08226 B is optionally selected from the group consisting of hydrido, trialkylsilyl, C2-C8 alkyl, C3-C8 alkylenyl, C3-C8 alkenyl, C3-C8 alkynyl, and C2-C8 haloalkyl, wherein each member of group B is optionally substituted at any carbon up to and including 6 atoms from the point of 32 33 attachment of B to A with one or more of the group consisting of R R 34 35 36
R
3 4
R
3 and R36; B is optionally selected from the group consisting of C3-C12 cycloalkyl and C4-C9 saturated heterocyclyl, wherein each ring carbon may be 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 a nitrogen adjacent to the carbon atom at the point of attachment 9 13 may be optionally substituted with R or R a ring carbon or nitrogen 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 1 position and two atoms from the point of attachment is optionally substituted 12 with R a ring carbon or nitrogen three atoms from the point of attachment and adjacent to the R 0 position is 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 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 33 positions is optionally substituted with R34 A is selected from the group consisting of single covalent bond, (W7)rr-(CH(R15))pa and (CH(R 5))pa(W7)rr wherein rr is an integer selected from 0 through 1, pa is an integer selected from 0 through 6, and W is selected from the group consisting of O, S, (R7)NC(0), (R7)NC(S), WO 00/69833 WO 0069833PCT/USOOIO8226 7 and N(R with the proviso that no more than one of the group consisting of rr and pa is O at the same time; R is selected from the group consisting of hydrido, hydroxy, and a .lkyl; R is selected from the group consisting of hydrido, hydroxy, halo, alkyl, and haloalkyl; TI is selected from the group consisting of NH and NOH, 1 M is selected from the group consisting of N and R -C; RIis selected from the group consisting of hydrido, alkyl. alkenyl, cyano, halo, haloalkyl, haloalkoxy, haloalkylthio. amino, amninoalkyl, alkylamino, amidino, hydroxy, bydroxyamino, alkoxy, hydroxyalkyl, alkoxyamino, thiol, and alkylthio; R2is Z-Q; Z is selected from the group consisting of covalent single bond, 4142 41 (CR 2 wherein q is an integer selected from 1 through 3, (CH(R 41~ CR )q429
W
0 -(CH(R p wherein g and p are integers independently selected from 0 through 3 and W0is selected from the group consisting of 0, S, S(0), 41 4141 0 N(R 41), and ON(R 41), and (CH(R 41))e-W'(CH(R 4 2 wherein eand h are integers independently selected from 0 through 1 and W2is selected from the group consisting of CR 41=CR 42, 1,2-cyclopropyl, 1,2-cyclobutyl, 1,2cyclohexyl, 1 .3-cyclohexyl, 1 .2-cyclopentyl, 1 ,3-cyclopentyl, 2,3mhorpholinyl, 2,4-morpholinyl, 2.6-morpholinyl, 3,4-morpholinyl, morpholinyl, 1,2-piperazinyl, 1,3-piperazinyl, 2,3-piperazinyl, 2,6piperazinyl, 1 .2-piperidinyl, 1 ,3-piperidinyl, 2,3-piperidinyl, 2A4-piperidinyl, 2,6-piperidinyl, 3 .4-piperidinyl, 1 ,2-pyrrolidinyl, 1 ,3-pyrrolidinyl, 2,3pyrrolidinyl, 2A4-pyrrolidinyl, 2,5-pyrrolidinyl, 3 ,4-pyrrolidinyl, 2,3- WO 00/69833 PCT/US00/08226 tetrahydrofuranyl, 2,4-tetrahydrofuranyl, 2,5-tetrahydrofuranyl, and 3,4tetrahydrofuranyl, with the proviso that Zo is directly bonded to the uracil 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 that Zo is other than a covalent single bond, and the formula (II): 11
R
I0 1 R 12 R K 2
R
1 1 2 R OD R3
R
13
(II)
1 2 1 2 1 wherein D D J J and K are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more than one is a covalent bond, no more than one of D D, J 2 and K is O, no more than one of D D 2 J1, J and K is S, one of D D J and 1 1 22 1 2 1 K must be a covalent bond when two of D D J1 and K are 0 and S, 1 2 1 2 1 and no more than four of D D J J and K are N, with the proviso that R R1, R 1 R and R 1 are each independently selected to maintain the tetravalent nature of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen; K is (CR4a R 4b)n wherein n is an integer selected from 1 through 2; R and R 4 b are independently selected from the group consisting of halo, hydrido, hydroxyalkyl, alkyl, alkoxyalkyl, alkylthioalkyl, and haloalkyl; WO 00/69833 WO 0069833PCIUSOOO 8226 isE when K is (CR" 4 b) 6 whri is selected from the group consisting of a covalent single bond, C(O)N(R )7 7 7a (R 7)NC(O), S(0) 2 (R 7)NS(O) 2 and S(O) 2 N(R )7 YO is formula OWV)
S
R
1 6 ,_DA 2 ,,-kNR19 Q (IV) wherein D and J6 are independently selected from the group con sistinga of C, N, 0, S and a covalent bond with the prov isos that no more than one is acovalent bond,,K 2is C,no more than one of D 5,D 6, J 5, and J6 5 65 6 5 65 6 is0, no more than one of D D ,Ji andlJ is S, one of D D ,J ,.and J 5 65 6 must be acovalent bond when two of D D I and J are 0and S, and no 5 65 6 16 17 more thanfourof) ,D ,J andJ are Nwith the proviso thatR ,R 18 19 R and R are each independently selected to maintain the tetravalent nature of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen; 16 17 18 19 R R R and R are independently selected from the group consisting of hydrido, amidino, guanidin o, carboxy, haloalkylthio, alkoxy, hydroxy, amino, nitro, alkoxyarnino, lower alkylamnino. alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, alkenyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, alkylenylamino, haloalkoxyalkyl, carboalkoxy, and cyano; WO 00/69833 PCT/US00/08226 Qb is selected from the group consisting of NR20 R 21, aminoalkylenyl, Qbe wherein Qbe is hydrido, N(R26)C(NR25)N(R23)(R24), and 2324 20 21 C(NR )NR 2 R with the provisos that no more than one of R and R is hydroxy, amino, alkylamino, or dialkylamino at the same time and that no 23 24 more than one of R and R is hydroxy, amino, alkylamino, or dialkylamino at the same time; 21 23 24 25 26
R
20
R
2 1 R R R 2 and R 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, 37 38 (CR R 38)b wherein b is an integer selected from 1 through 4, and (CH(R14))cW-(CH(R15))d wherein c and d are integers independently selected from I through 3 and W 1 is selected from the group consisting of C(O)N(R 14), (R S(0) 2 S(0) 2 N(R14), N(R 14)S() 2 and 14 14 N(R with the provisos that R14 is selected from other than halo when directly bonded to N and that (CR R 38)b, and (CH(R are bonded to E; 14
R
4 is selected from the group consisting of hydrido, halo, alkyl, and haloalkyl; 37 38 R and R are independently selected from the group consisting of hydrido, alkyl, and haloalkyl; 38.
R
3 8 is optionally selected from the group consisting of aroyl and heteroaroyl; WO 00/69933 WO 0069833PCFIUSOO/08226 YO' is optionally Q b-Q ssweenQS s(HR 14))eCW2(CH(R wherein e and h are integers independently selected from I through 2 and W is CR 4a=CR 4bwith the proviso that (CH(R 14 e is bonded to E0 YO is optionally selected from the group consisting of QbQ SSSS and Qb_ Qss weenQss is (CH(R 3 and Q~s, is (CH(R 3 ))r-W6 r is an inteaer selected from 1 through 2, and W 5 adW 6 aeidpnetyslce from the group consisting of 1,4-indenyl, 1,5-indenyl, 1,6-indenyl, 1,7indenyl, 2,7-indenyl, 2,6-indenyl, 2,5-indenyl, 2,4-indenyl, 3,4-indenyl, indenyl, 3,6-indenyl, 3,7-indenyl, 2,4-benzofuranyl, 2,5.-benzofuranyl, 2,6benzofuranyl, 2,7-benzofuranyl, 3A4-benzofuranyl, 3,5-benzofuranyl. 3.6benzofuranyl, 3 ,7-benzofuranyl, 2,4-benzothiophenyl, 2,6-benzotbiophenyl, 2,7-benzothiophenyl, 3,4-benzothiophenyl, benzothiophenyl, 3,6-benzothiophenyl, 3 ,7-benzothiophenyl, 2,7im-idazo( 1,2-a)pyridinyl, 3,4-imidazo 1 ,2-a)pyridinyl, 3 ,5-imidazo( 1,2a)pyridinyl, 3,6-imidazo( 1,2-a)pyridinyl, 3 ,7-imidazo( 1,2-a)pyridinyl, 2,4indolyl, 2,5-indolyl, 2,6-indolyl, 2,7-indolyl, 3,4-indolyl, 3,5-indolyl, 3,6indolyl, 3 ,7-indolyl, 1 ,4-isoindolyl, 1 ,5-isoindolyl, I .6-isoindolyl, 2,4isoindolyl, 2,5-isoindolyl, 2,6-isoindolyl, 2,7-isoindolyl, 1,3-isoindolyl, 3,4indazolyl, 3,5-indazolyl, 3,6-indazolyl, 3,7-indazolyl, 2,4-benzoxazolyl, benzoxazolyl, 2,6-benzoxazolyl, 2,7-benzoxazolyl, 3,4-benzisoxazolyl, benzisoxazolyl, 3.6-benzisoxazolyl, 3,7-benzisoxazolyl, I ,4-naphthyl, naphthyl, 1,6-naphthyl, I.7-naphthyl, 1,8-naphthyl, 2,4-naphthyl, naphthyl, 2,6-naphthyl, 2,7-naphthyl, 2,8-naphthyl, 2,4-quinolinyl, quinolinyl, 2,6-quinolinyl, 2,7-quinolinyl, 2,8-quinolinyl, 3,4-quinolinyl, quinolinyl, 3,6-quinolinyl, 3,7-quinolinyl, 3,8-quinolinyl, 4,5-quinolinyl, 4,6quinolinyl, 4,7-quinolinyl, 4,8-quinolinyl, 1 ,4-isoquinolinyl, isoquinolinyl, 1 ,6-isoquinolinyl, 1 7 -isoquinolinyl, I ,8-isoquinolinyl, 3,Aisoquinolinyl, 3,5-isoquinolinyl, 3 ,6-isoquinolinyl, 3 ,7-isoquinolinyl, 3,8isoquinolinyl, 4,5-isoquinolinyl, 4,6-isoquinolinyl, 4,7-isoquinolinyl, 4,8isoquinolinyl, 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- WO 00/69833 PCT/US00/08226 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 6 and W is optionally substituted with one or more of the group consisting of R R 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 substituent position of each W 6 and (CH(R38))r is bonded to E°.
In a more preferred embodiment of compounds of Formula I or a pharmaceutically acceptable salt thereof, a and Jb are each O; B is selected from the group consisting of aryl and heteroaryl wherein a carbon adjacent to the carbon at the point of attachment is optionally substituted 32 by R 3 2 the other carbon adjacent to the carbon at the point of attachment is 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 adjacent to R 36 and two atoms from the carbon at the point of attachment is 33 optionally substituted by R5 and any carbon adjacent to both R and R is 34 optionally substituted by R;
R
3 2
R
3 3
R
3 4
R
3 5 and R 3 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, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, alkylsulfonamido, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, alkyl, alkenyl, halo, haloalkyl, haloalkenyl, haloalkoxy, hydroxyalkyl, alkylenylamino, carboalkoxy, carboxy, carboxamido, cyano, and Qb; WO 00/69833 PCT/US00/08226 B is optionally selected from the group consisting of hydrido, trialkylsilyl, C2-C8 alkyl, C3-C8 alkylenyl, C3-C8 alkenyl, C3-C8 alkynyl, and C2-C8 haloalkyl, wherein each member of group B is optionally substituted at any carbon up to and including 6 atoms from the point of 32 33 attachment of B to A with one or more of the group consisting of R R 3 3 34 35 36
R
3 4
R
3 and R 3 6 B is optionally selected from the group consisting of C3-C12 cycloalkyl and C4-C9 saturated heterocyclyl, wherein each ring carbon is 33 optionally optionally substituted with R 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 9 13 attachment are optionally substituted with R or R a ring carbon or nitrogen 9 adjacent to the R position and two atoms from the point of attachment is optionally substituted with R 10 a ring carbon or nitrogen adjacent to the R 1 position and two atoms from the point of attachment is optionally substituted 12 with R a ring carbon or nitrogen three atoms from the point of attachment and adjacent to the R 0 position is optionally substituted with R 1 1 a ring carbon or nitrogen three atoms from the point of attachment and adjacent to the 12 33
R
1 position is optionally substituted with R33,and a ring carbon or nitrogen 11 33 four atoms from the point of attachment and adjacent to the R and R 3 positions is optionally substituted with R34 9 10 11 12 13 R R R R 12, and R 1 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, alkylsulfonyl, alkylsulfonamido, amidosulfonyl, monoalkyl amidosulfonyl, WO 00/69833 PCTIUS0008226 dialkyl amidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, carboalkoxy, carboxyalkyl, carboxy, carboxamido, and cyano; A is selected from the group consisting of single covalent bond and (CH(R ))pa(W 7)rr wherein rr is an integer selected from 0 through 1, pa is an integer selected from 0 through 3, and W7 is selected from the group consisting of O, S, (R7)NC(0), (R7)NC(S), and N(R7); R7 is selected from the group consisting of hydrido, hydroxy and alkyl; R is selected from the group consisting of hydrido, hydroxy, halo, alkyl, and haloalkyl; IF is NH; M is selected from the group consisting of N and RI-C;
R
1 is selected from the group consisting of hydrido, alkyl, cyano, halo, haloalkyl, haloalkoxy, amino, aminoalkyl, alkylamino, amidino, hydroxy, hydroxyamino, alkoxy, hydroxyalkyl, alkoxyamino, thiol, and alkylthio; R2 is ZO-Q; Sis selected from the group consisting of covalent single bond and (CR41 R42)q wherein q is an integer selected from I through 2, (CH(R41))g Wo-(CH(R42))p wherein g and p are integers independently selected from 0 through 3 and Wo is selected from the group consisting of 0, S, and N(R41 and (CH(R41 2-(CH(R 42))h wherein e and h are integers independently selected from 0 through 1 and 2 is selected from the group consisting of 41 42 CR1 =CR 1,2-cyclopropyl, 1,2-cyclobutyl, 1,2-cyclohexyl, 1,3cyclohexyl, 1,2-cyclopentyl, 1,3-cyclopentyl, 2,3-morpholinyl, 2,4morpholinyl, 2,6-morpholinyl, 3,4-morpholinyl, 3,5-morpholinyl, 1,2piperazinyl, 1,3-piperazinyl, 2,3-piperazinyl, 2,6-piperazinyl, 1,2-piperidinyl, WO 00/69833 PCT/US00/08226 1,3-piperidinyl, 2,3-piperidinyl, 2,4-piperidinyl, 2,6-piperidinyl, 3,4piperidinyl, 1,2-pyrrolidinyl, 1,3-pyrrolidinyl, 23-pyrrolidinyl, 2,4pyrrolidinyl, 2,5-pyrrolidinyl, 3,4-pyrrolidinyl, 2,3-tetrahydrofuranyl, 2,4tetrahydrofuranyl, 2,5-tetrahydrofuranyl, and 3,4-tetrahydrofuranyl, with the proviso that Zo is directly bonded to the uracil ring; 41 42 R and R are independently selected from the group consisting of hydrido, hydroxy, and amino; Q is selected from the group consisting of hydrido, with the proviso that Z is other than a covalent single bond, aryl, and heteroaryl, wherein a carbon adjacent to the carbon at the point of attachment is optionally substituted 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 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 and any carbon adjacent to both R and R is optionally substituted by R 1 1 K is CHR wherein R is selected from the group consisting of hydrido, hydroxyalkyl, alkyl, alkoxyalkyl, alkylthioalkyl, and haloalkyl; E is selected from the group consisting of a covalent single bond, (R7)NS(0) 2 and S(O) 2 N(R7); Yo is formula (IV): WO 00/69833 PCT/USOO/08226 17 R 1 8 R16/ 2 R19 b
Q
3
(IV)
wherein D D J and J are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more than one is a covalent bond, K is C, no more than one of D J and J is O, no more than one of D 5 D and J is S, one of D, D J ,and must be a covalent bond when two of D 5
D
6 J, and J are O and S, and no more than four of D D 6 J5, and J6 are N, with the provisos that R 6
R
17 18 19 R and R19 are each independently selected to maintain the tetravalent nature of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen; 16 17 18 19 R R R R and R are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, haloalkylthio, alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, and cyano;
R
16 and R 19 are optionally Qb with the proviso that no more than one of R 6 and R 9 is Qb at the same time and that Qb is Qbe Q is selected from the group consisting of NR20R21 Q wherein Qbe is 26 25 23 24 25 23 24 hydrido, N(R )C(NR )N(R and C(NR )NR R with the provisos that no more than one of R 20 and R 2 1 is hydroxy, amino, alkylamino, or WO 00/69833 PCT/US00/08226 dialkylamino at the same time and that no more than one of R 23 and R 2 is hydroxy, amino, alkylamino, or dialkylamino at the same time; 21 23 24 25 26
R
20
R
2 1 R R 24 R and R 2 are independently selected from the group consisting of hydrido, alkyl, hydroxy, amino, alkylamino and dialkylamino; QS is selected from the group consisting of a single covalent bond, 37 38 (CR R 38)b wherein b is an integer selected from 1 through 4, and (CH(R 14))cW 1-(CH(R 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) 2 S(0) 2 N(R14); N(R14)S() 2 and 14 14 N(R with the provisos that R14 is selected from other than halo when 37 104 o A directly bonded to N and that (CR R38)b, and (CH(R are bonded to E; 14 R 14 is selected from the group consisting of hydrido, halo, alkyl, and haloalkyl; 37 38 R and R are independently selected from the group consisting of hydrido, alkyl, and haloalkyl; 38.
R
3 8 is optionally selected from the group consisting of aroyl and heteroaroyl; y 0 is optionally Qb s wherein QSS is (CH(R 14 )e-W2CH(R 15)) h wherein e and h are integers independently selected from 1 through 2 and W2 is CR4a=CH with the proviso that (CH(R 14 is bonded to E.
In an even more preferred embodiment of compounds of Formula I or a pharmaceutically acceptable salt thereof, Ja and Jb are each O; B is selected from the group consisting of aryl and heteroaryl wherein a carbon adjacent to the carbon at the point of attachment is optionally substituted WO 00/69833 PCT/US00/08226 by R 3 2 the other carbon adjacent to the carbon at the point of attachment is optionally substituted by R 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 35 33 optionally substituted by R and any carbon adjacent to both R and R is 34 optionally substituted by R34 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, haloalkyl, haloalkoxy, hydroxyalkyl, carboalkoxy, carboxy, carboxamido, cyano, and Qb; A is selected from the group consisting of single covalent bond and (CH(R )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(O) and N(R7);
R
7 is selected from the group consisting of hydrido, hydroxy and alkyl; R 5 is selected from the group consisting of hydrido, halo, alkyl, and haloalkyl; IP isNH; M is selected from the group consisting of N and R1-C;
R
1 is selected from the group consisting of hydrido, hydroxy, hydroxyamino, amidino, amino, cyano, hydroxyalkyl, alkoxy, alkyl, alkylamino, aminoalkyl, alkylthio, alkoxyamino, haloalkyl, haloalkoxy, and halo; WO 00/69833 PCT/US00/08226
R
2 is Z-Q; Zo is selected from the group consisting of a covalent single bond, 0, S, NH, and CH2; Q is selected from the group consisting of aryl and heteroaryl wherein a carbon adjacent to the carbon at the point of attachment is optionally substituted 9 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 1 and any carbon adjacent to both R and R is optionally substituted by R11 R R and R 13 are independently selected from the group consisting of hydrido, hydroxy, amino, amidino, guanidino, lower alkylamino, alkylthio, alkylsulfonamido, alkylsulfinyl, alkylsulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboxy, carboxamido, and cyano; R and R 2 are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkyl, alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, alkylsulfonamido, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, hydroxyalkyl, aminoalkyl, carboalkoxy, carboxy, carboxyalkyl, amidocarbonyl, halo, haloalkyl, and cyano; K is CH 2 E° is C(O)N(H); YO is formula (IV): WO 00/69833 PCT/US00/08226 1 R16/D 2D 1 9 Qb
(IV)
wherein D 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 C, no more than one of D, D and J6 5 6 5 6is optionally O, no more than one of D D J and J is optionally S, one of D D 6 5, and J6 must be a covalent bond when two of D 5
D
6 J, and J6 are O and S, and no more than four of D, D and 6 are N; R R R 18, and R19 are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, haloalkylthio, alkoxy, hydroxy, amino, lower alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, and cyano; 16 19 b R and R 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 Qb is selected from the group consisting of NR20 R 21, Qbe wherein Qbe is hydrido, and C(N25 R 23R 24 with the provisos that no more than one of R 2 and R 2 1 is hydroxy at the same time and that no more than one of R and R 2 is hydroxy at the same time; 21 23 24
R
20
R
2 1 R R 24 and R 2 are independently selected from the group consisting of hydrido, alkyl, and hydroxy; WO 00/69833 PCT/US00/08226 QS is selected from the group consisting of a single covalent bond,
CH
2 and CH 2
CH
2 In another even more preferred embodiment of compounds of Formula I or a pharmaceutically acceptable salt thereof, J and Jb are each O; B is optionally selected from the group consisting of hydrido, C2-C8 alkyl, C3-C8 alkenyl, C3-C8 alkynyl, and C2-C8 haloalkyl, wherein each member of group B is optionally substituted at any carbon up to and including 6 atoms from the point of attachment of B to A with one or more of the group 32 33 34 35 36 consisting of R 2
R
3 R R and R 32 33 34 35 36
R
3 2
R
33
R
34
R
3 and R 3 are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, alkylthio, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboalkoxy, carboxy, carboxamido, cyano, and Qb A is selected from the group consisting of single covalent bond and 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(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; tP is NH; M is selected from the group consisting of N and R -C;
R
1 is selected from the group consisting of hydrido, hydroxy, hydroxyamino, amidino, amino, cyano, hydroxyalkyl, alkoxy, alkyl, WO 00/69833 PCTIUS00/08226 alkylamino, aminoalkyl, alkylthio, alkoxyamino, haloalkyl, haloalkoxy, and halo; R2 is ZO-Q; Zo is selected from the group consisting of a covalent single bond, 0, S, NH, and CH 2 Q is selected from the group consisting of aryl and heteroaryl wherein a carbon adjacent to the carbon at the point of attachment is optionally substituted 9' by R the other carbon adjacent to the carbon at the point of attachment is 13 9 optionally substituted by R 3, 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 R13 and two atoms from the carbon at the point of attachment is 12 10 12.
optionally substituted by R12, and any carbon adjacent to both RIO and R2 is optionally substituted by R11 9 11 13 R9 R and R13 are independently selected from the group consisting of hydrido, hydroxy, amino, amidino, guanidino, lower alkylamino, alkylthio, alkylsulfonamido, alkylsulfinyl, alkylsulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboxy, carboxamido, and cyano; and R12 are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkyl, alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, alkylsulfonamido, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, hydroxyalkyl, alkylenylamino, carboalkoxy, carboxy, carboxyalkyl, amidocarbonyl, halo, haloalkyl, and cyano; KisCH 2 0 E is C(O)N(H); Y is formula (IV): WO 00/69833 WO 0069833PCT/USOO/08226 R 1 7 "1 R1 8 R 16 D N K2: D ~R19 lb Q (IV) wherein D 5, D 6, J 5, and J 6are inde pendently selected from the group consistingy of C, N, 0, S and a covalent bond with the provisos that no more 2. 5 65 6 than one is acovalent bond, K is C,no more than one of D D J and J 65 6 65 6 is0, no morethan one ofD D ,i andJ is S,one ofD D and J 65 6 must be acovalent bond when two of D D ,Ji and J are 0and S, and no 65 6 16 17 more than four of D D ,Ji and J are N, with the provisos that R R 18 19 R and R are each independently selected to maintain the tetravalent nature of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen; 16 17 18 19' R R R and R are independently selected from the group consisting of hydrido, amidi no, guanidino, carboxy, haloalkylthio, alkoxy, hydroxy, amino, lower alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, alkylenylarnino, and cyano; R 16and R 19are optionally Q bwith the proviso that no more than one of R 16andR 19is Q batthe same time and that Q bisQ b is selected from the group consisting of NR 20R 21, Q bewherein is hyrdCN 2 5 232Z4 26 25 23 24 Q i hyrid, Q R.)NR R and N(R )C(NR )N(R with WO 00/69833 PCT/US00/08226 the provisos that no more than one of R20 and R21 is hydroxy at the same time and that no more than one of R and R is hydroxy at the same time; 21 23 24 25 26
R
20
R
2 R R R and R are independently selected from the group consisting of hydrido, alkyl, and hydroxy; QS is selected from the group consisting of a single covalent bond,
CH
2 and CH 2
CH
2 In still another even more preferred embodiment of compounds of Formula I or a pharmaceutically acceptable salt thereof, Ja and Jb are each O; B is optionally selected from the group consisting of C3-C7 cycloalkyl and C4-C6 saturated heterocyclyl, wherein each ring carbon is optionally 33 substituted with R a ring carbon other than the ring carbon at the point of attachment of B to A is optionally substituted with oxo provided that no more than one ring carbon is substituted by oxo at the same time, ring carbons and a nitrogen adjacent to the carbon atom at the point of attachment are optionally 9 13 9 substituted with R or R a ring carbon or nitrogen adjacent to the R position and two atoms from the point of attachment is optionally substituted with R 10 a ring carbon or nitrogen adjacent to the R 1 position and two atoms from the point of attachment is optionally substituted with R 12 a ring carbon or nitrogen three atoms from the point of attachment and adjacent to the position is 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 substituted with R33, and a ring carbon or nitrogen four atoms from 11 33 the point of attachment and adjacent to the R 1 and R33 positions is optionally 5 substituted with R34 substituted with R WO 00/69833 WO 0069833PCTIUSOOIO8226 9 11 13 R R and R are independently selected from the group consisting of hydrido, hydroxy, amino, amidino, guanidino, lower alkylarnino, alkylthio, alkylsulfonamido, alkylsulfinyl, alkylsulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboxy. carboxamido, and cyano; R 10and R 12are independe ntly selected from the group'consisting of hydrido, acetamido, haloacetamnido, amidino, guanidino, alkyl, alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, alkylsulfonamido.
amiddosulfontyl, monoalk~yl amidosulfonyl, dialkyl amidosulfonyl, hydroxyalkyl, alkylenylamino, carboalkoxy, carboxy. carboxyalkyl, amidocarbonyl, halo, haloalkyl, and cyano; R 33and R 34are independently selected from the .group consisting of hydrido, acetarnido, haloacetamido, amridino, 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 7 (CH(R )rr wherein rr is an integer selected from 0 through 1, pa is an integer selected from 0 through 3, and W 7is selected from the group consisting of (R 7)NC(O) and N(R )7 7 R is selected from the group consisting of hydrido, hydroxy and alkyl; R isis selected from the group consisting of hydrido, halo, alkyl, and haloalkyl; WJ is NH; M is selected from the group consisting of N and R -C; Riis selected from the group consisting of hydrido, hydroxy, hydroxyamino, ainidino, amino, cyano, hydroxyalkyl, alkoxy, alkyl.
WO 00/69833 PCT/US00/08226 alkylamino, aminoalkyl, alkylthio, alkoxyamino. haloalkyl. haloalkoxy, and halo;
R
2 is Z-Q; Z is selected from the group consisting of a covalent single bond, 0, S, NH, and CH 2 Q is selected from the group consisting of aryl and heteroaryl wherein a carbon adjacent to the carbon at the point of attachment is optionally substituted 9 by R the other carbon adjacent to the carbon at the point of attachment is 13 9 optionally substituted by R a carbon adjacent to R and two atoms from the carbon at the point of attachment is optionally substituted by R a carbon 13 adjacent to R 1 and two atoms from the carbon at the point of attachment is 12 10 12.
optionally substituted by R and any carbon adjacent to both R and R is optionally substituted by R 11 K is CH 2 E° is C(0)N(H); YO is formula (IV): 1 7
JR
1 8 R I R16 K 2 R 9 lb Q
(IV)
wherein D 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 is C, no more than one of D D and J WO 00/69833 PCT/US00/08226 is O, no more than one of D D J and J is S, one of D D J and J must be a covalent bond when two of D D J and J are O and S, and no more than four of D D J, and J are N, with the provisos that R 6
R
17 18 19 R 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; R R R and R are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, haloalkylthio, alkoxy, hydroxy, amino, lower alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, alkylenylamino, and cyano; R 6 and R 9 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 Q is Qbe b 20d 21 be be Qb is selected from the group consisting of NR20 R 21 Qbe wherein Qbe is hydrido, and C(NR )NR R 2 with the provisos that no more than one of R 2 21 23 24 and R 21 is hydroxy at the same time and that no more than one of R and R is hydroxy at the same time; 21 23 24 R R 21 R R 24 and R 2 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 In a most preferred embodiment of compounds of Formula I or a pharmaceutically acceptable salt thereof, Ja and Jb are each 0; B is selected from the group consisting of aryl and heteroaryl wherein a carbon adjacent to the carbon at the point of attachment is optionally substituted WO 00/69833 PCT/US00/08226 32 by R 32 the other carbon adjacent to the carbon at the point of attachment is optionally substituted by R 36 a carbon adjacent to R 32 and two atoms from the carbon at the point of attachment is optionally substituted by R 33 a carbon adjacent to R 36 and two atoms from the carbon at the point of attachment is 33 optionally substituted by R 35 and any carbon adjacent to both R 3 and R 3 is 34 optionally substituted by R34 32 33 34 35 36
R
32
R
33
R
34
R
35 and R 3 are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, alkylthio, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboalkoxy, carboxy, carboxamido, cyano, and Qb; A is selected from the group consisting of single covalent bond and (CH(R )rr wherein rr is an integer selected from 0 through 1, pa is 7 7 an integer selected from 0 through 3, and W is N(R7);
R
7 is selected from the group consisting of hydrido and alkyl;
R
15 is selected from the group consisting of hydrido, halo, alkyl, and haloalkyl: 'q is NH; M is selected from the group consisting of N and R1-C; R1 is selected from the group consisting of hydrido, hydroxy, hydroxyamino, amidino, amino, cyano, hydroxyalkyl, alkoxy, alkyl, alkylamino, aminoalkyl, alkylthio, alkoxyamino, haloalkyl, haloalkoxy, and halo;
R
2 is Z
O
-Q;
WO 00/69833 PCTIUS00/08226 Z is a covalent single bond; Q is selected fom the group consisting of aryl and heteroaryl wherein a carbon adjacent to the carbon at the point of attachment is optionally substituted 9 by R the other carbon adjacent to the carbon at the point of attachment is 13 9 optionally substituted by R 1 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 optionally substituted by R 2 and any carbon adjacent to both R l O and R 12 is optionally substituted by Rl R 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, carboxy, carboxamido, and cyano; 12 R and R are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkyl, alkoxy, alkoxyamino, aminoalkyl, hydroxy, amino, lower alkylamino, alkylsulfonamido, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, hydroxyalkyl, aminoalkyl, halo, haloalkyl, carboalkoxy, carboxy, carboxyalkyl, carboxyamido, and cyano; K is CH 2 E is C(O)N(H); Sis formula (IV): 83 WO 00/69833 WO 0069833PCT/USOOIOS226 R 1 ~DK ~DKi 9 Qb (IV) 65 6 wherein D ,D J and J are independently selected from the group consisting of C, N, 0, S and a covalent bond with the provisos that no more than one is a covalent bond, K 2is C, no more than one of D 5, D 6, J 5, and J6 65 6 '5 65 6 is 0,no more than one ofD ,D J andJ is S,oneofD D ,Ji ,and J 65 6 must be acovalent bond when two of D D J and J are 0and S, and no more than four of D 5,D 6, J 5and J 6are N; 16 17 18 19 R R R and R are independently selected. from the group consisting of hydrido, amidino, guanidino, carboxy, haloalkylthio, alkoxy, hydroxy, amino, lower alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, aniinoalkyl, and cyano;, R 16and R 19are optionally Q bwith the proviso tha .t no more than one of R 16and R 19isQb at the same time and that Q bisQ b Q bis selected from the group consisting of NR 20R 21, Q bewherein Q beis hydrido, and C(NR 25)NR 23R2 21 23 24 R R R R and R are independently selected from the group consisting of hydrido and alkyl; Q'is
CH
2 WO 00/69833 PCT/USOO/08226 In another most preferred embodiment of compounds of Formula I or a pharmaceutically acceptable salt thereof, Ja and Jb are each O; B is optionally selected from the group consisting of hydrido, C2-C8 alkyl, C3-C8 alkenyl, C3-C8 alkynyl, and C2-C8 haloalkyl, wherein each member of group B is optionally substituted at any carbon up to and including 6 atoms from the point of attachment of B to A with one or more of the group 32 33 34 35 36 consisting of R R R R and R
R
3 2
R
3 3
R
34
R
3 5 and R 3 are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, alkylthio, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboalkoxy, carboxy, carboxamido, cyano, and Qb; A is selected from the group consisting of single covalent bond and wherein rr is an integer selected from 0 through 1, pa is an integer selected from 0 through 3, and W is N(R); R is selected from the group consisting of hydrido and alkyl; R is selected from the group consisting of hydrido, halo, alkyl, and haloalkyl; Wp isNH; M is selected from the group consisting of N and R -C;
R
1 is selected from the group consisting of hydrido, hydroxy, hydroxyamino, amidino, amino, cyano, hydroxyalkyl, alkoxy, alkyl, alkylamino, aminoalkyl, alkylthio, alkoxyamino, haloalkyl, haloalkoxy, and halo;
R
2 is Z-Q; ZD is a covalent single bond; WO 00/69833 PCT/US00/08226 Q is selected from the group consisting of aryl and heteroaryl wherein a carbon adjacent to the carbon at the point of attachment is optionally substituted by R 9 the other carbon adjacent to the carbon at the point of attachment is 13 9 optionally substituted by R a carbon adjacent to R and two atoms from the carbon at the point of attachment is optionally substituted by R a carbon adjacent to R 13 and two atoms from the carbon at the point of attachment is 12 10 12.
optionally substituted by R and any carbon adjacent to both R and R is optionally substituted by R1; 9 11 13 R R and R 1 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; 12 R 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, carboxy, carboxyalkyl, carboxyamido, and cyano; K is CH 2
E
0 is C(O)N(H); YO is formula (IV): WO 00/69833 WO 0069833PCT/USO/08226 R 1 7~F~
R
1 8 R166 Q b (IV) 65 6 wherein D D J and J are independently selected from the group consisting of C, N, 0, S and a covalent bond with the provisos that no more 2 5 65 6 than one is acovalent bond, K is C,no more than one of D D J and J 65 6 5 65 6 is0, no morethan one ofD D ,i andJ is S,oneOf D D I andJ must be acovalent bond when two of D 5,D 6, J 5, and J 6are 0a ndS, and no 65 6 16 17 more than four of D D ,Ji and J are N, with the provisos that R R 18 19 R and R are each independently selected to maintain the tetravalent nature of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen; 16 17 18 19 R R R and R are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, haloalkylthio, alkoxy, hydroxy, amino, lower aikylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, amninoalkyl, and cyano; R 16and R 19are optionally Q bwith the proviso that no more than one of R 16andR 19is Q batthe same time and that Q bis Q b is selected from the group consisting of NR 20R 21, Q bewherein Q beis hydrido, N(R 26C( NR 25)N(R 23)(R 24), and C(NR 25)NR 23R2 WO 00/69833 PCT/US00/08226 21 23 24 25 26
R
20
R
21 R R 24 R 25 and R 2 are independently selected from the group consisting of hydrido and alkyl; QS is CH 2 In still another most preferred embodiment of compounds of Formula I or a pharmaceutically acceptable salt thereof, Ja and Jb are each O; B is optionally selected from the group consisting of C3-C7 cycloalkyl and C4-C6 saturated heterocyclyl, wherein each ring carbon is optionally 33 substituted with R a ring carbon other than the ring carbon at the point of attachment of B to A is optionally substituted with oxo provided that no more than one ring carbon is substituted by oxo at the same time, ring carbons and a nitrogen adjacent to the carbon atom at the point of attachment are optionally 9 13 9 substituted with R or R a ring carbon or nitrogen adjacent to the R 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 a ring carbon or nitrogen three atoms from the point of attachment and adjacent to the position is optionally substituted with R 1 a ring carbon or nitrogen three 12 atoms from the point of attachment and adjacent to the R 1 position is 33 optionally substituted with R and a ring carbon or nitrogen four atoms from 11 33 the point of attachment and adjacent to the R 1 and R 33 positions is optionally 34 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, WO 00/69833 WO 0069833PCT/USOOIO8226 monoalkyl arnidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboxy, carboxamiddo, and cyano; R 10and R 12are independently selected from the group consisting of hydrido. acetamido, haloacetamido, amidino, guanidino, alkyl, alkoxy, alkoxyamino, aniinoalkyl, hydroxy, amino, lower alkylamino, alkylsulfonamido, amidosulfonyl, monoalkyl amnidosulfonyl, dialkyl amidosulfonyl, hydroxyalkyl, amninoalkyl, halo, haloalkyl, carboalkoxy, carboxy, carboxyalkyl, carboxyamido, and cyano; 33 34 R and R are independently selected from the group consisting of hydrido, amidino, guanidino, alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, alkylthio, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amiddosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboalkoxy, carboxy, carboxamido, and cyano; R 33isoptionally Qb A is selected from the group consisting of single covalent bond and 7 (CH(R )rr wherein rr is an integer selected from 0 through 1, pa is an integer selected from 0 through 3, and W 7is N(R 7); R 7is selected from the group consisting of bydrido, hydroxy and alkyl; 150 R 15is selected from the group consisting of hydrido, halo, alkyl, and haloalkyl; IF is NH; M is selected from the group consisting of N and R I-C; Riis selected from the group consisting of hydrido, hydroxy, hydroxyarnino, amidino, amino, cyano, hydroxyalkyl, alkoxy,'alkyl, alkylainino, amninoalkyl, alkylthio, alkoxyamino, haloalkyl, haloalkoxy, and halo;
R
2 is ZO-Q; is a covalent single bond; WO 00/69833 PCT/US00/08226 Q is selected from the group consisting of aryl and heteroaryl wherein a carbon adjacent to the carbon at the point of attachment is optionally substituted 9 by R 9 the other carbon adjacent to the carbon at the point of attachment is 13 9 optionally substituted by R a carbon adjacent to R and two atoms from the carbon at the point of attachment is optionally substituted by R a carbon adjacent to R 13 and two atoms from the carbon at the point of attachment is optionally substituted by R and any carbon adjacent to both R 1 and R 2 is optionally substituted by R11 K is CH 2 E is C(O)N(H); Y is formula (IV): R17 6 R 1 8 R16 K 2
R
1 9 lb Q
(IV)
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 2 5 6 5 6 than one is a covalent bond, K is C, no more than one of D J and J 6 5 6 5 6 5 6 is O, no more than one of D, D and J is S, one of DD and J 65 6 must be a covalent bond when two of D, D and J are 0 and S, and no 6 5 6 16 17 more than four of D 5 D ,and J are N, with the provisos that R R 18 and R19 are each independently selected to maintain the tetravalent nature R and R are each independently selected to maintain the tetravalent nature WO 00/69833 WO 0069833PCr[USOOIO8226 of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen; 16 17 18 19 R ,R ,R and R are independently selected from the group consisting of hydrido, amnidino, guanidino, carboxy, haloalkylthio, alkoxy, hydroxy, amino, lower alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, alkylenylamino, and cyano; R 16and R 19are optionally Q bwith the proviso that no more than one of R 16andR 19is Q bat the same time and that Q bisQ b b 20 21 be be Q is selected from the group consisting of NR R Q wherein Q is hydrido, and C(NR 25)NR 23R2 21 23 24 R ,R ,R R and R are independently selected from the group consisting of hydrido and alkyl; QS is CH 2 In a preferred specific embodiment of Formula I, compounds have the Formula I-S: 2 A NyE B N Y
H
0 4a-S or a pharmaceutically acceptable salt thereof, wherein; B is selected from the group consisting of phenyl, 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl, 4-imidazolyl, 3pyrazolyl, 4-pyrazolyl, 1 ,2,4-triazol-3-yl, 1 ,2,4-triazol-5-yl, I ,2,4-oxadiazol- 3-yl, 1 ,2,4-oxadiazol-5-yl, 1,3 ,4-oxadiazol-3-yl, 1,3 ,4-oxadiazol-5-yl, 3isothiazolyl, 5-isothiazolyl, 2-oxazolyl, 2-thiazolyl, 3-isoxazolyl, WO 00/69933 WO 0069833PCT/USOO/08226 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl, pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 1,3 ,5-triazin-2-yI, 1 ,2,4-triazin-3yI, 1 ,2,4-triazin-5-yl, 1 ,2,4-triazin-6-yl, 1,2,3 -triazin-4-yl, and 1 ,2,3-triazin- S-yI,, wherein a carbon adjacent to the carbon at the point of attachment is 'optionally substituted by R 32, the other carbon adjacent to the carbon at the 36 3 point of attachment is optionally substituted by R a carbon adjacent toR and two atoms from the carbon at the point of attachment is optionally subtittedby 33, acarbon adjacent to R 36and two atoms from the carbon at the point of attachment is optionally substituted by R 35, and any carbon adjacent to both R 33and R 35is optionally substituted by R 3 32 33 34 35 36 R -9 R R R and R are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, methyl, ethyl, isopropyl, propyl, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, methoxyamino, ethoxyaxnino, acetainido, trifluoroacetamido, nitro, aininomethyl, 1 -aminoerthyl, 2-aminoethyl, N-methylamino, dimethylamino, N-ethylainino, methylthio, ethylthio, isopropylthio, trifluoromethylthio, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, 2,2,3,3,3pentafluoropropyl, trifluoromethoxy, 1.1 ,2,2-tetrafluoroethoxy, fluoro, chloro, bromo, amidosulfonyl, N-methylamidosulfonyl, N,Ndimethylamidosulfonyl, acetyl, propanoyl, trifluoroacetyl, pentafluoropropanoyl, hydroxymethyl, 1 -hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro-l1-hydroxyethyl, 2,2,2-trifluoro-l1-trifluoromethyl- 1hydroxyethyl, carboxymethyl, methoxycarbonyl, ethoxycarbonyl, amidocarbonyl, N-methylamidocarbonyl, N,N-dimethylamidocarbonyl, cyano, andQ;b B is selected from the group consisting of hydrido, trimethylsily], ethyl, 2-propenyl, 2-propynyl, propyl, isopropyl, butyl, 2-butenyl, 3-butenyl, 2-butynyl, sec-butyl, ten-butyl, isobutyl, 2-methyipropenyl, 1-pentyl, 2pentenyl, 3-pentenyl, 4-pentenyl, 2-pentynyl, 3-pentynyl, 2-pentyl, 1-methyl- 2-butenyl, 1 -methyl-3-butenyl, 1-methyl-2-butynyl, 3-pentyl, I -ethyl-2propenyl, 2-methylbutyl, 2-methyl-2-butenyl, 2-methyl-3-butenyl, 2-methyl-3- WO 00/69833 WO 0069833PCTIUSOOM0226 butynyl, 3-methylbutyl, 3-methyl-2-butenyl, 3-methyl-3-butenyl, 1-hexyl, 2hexenyl, 3-hexenyl, 4-hexenyl,5-hexenyl,-2-hexyny-l-,3-hexy-nyl, 4-hexynyl, 2-hexyl, 1 -methyl-2-pentenyl, I -methyl-3-pentenyl, 1 -methyl-4-pentenyl, 1methyl-2-pentynyl, 1 -methyl-3-pentynyl, 3-hexyl, 1 -ethyl-2-butenyl, 1 -ethyl- 3-butenyl, l-propyl-2-propenyl, I1-ethyl -2-butynyl, 1-beptyl, 2-heptenyl, 3heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl, 2-heptynyl, 3-heptynyl, 4heptynyl, 5-heptynyl, 2-heptyl, 1-methyl-2-hexenyl, 1-methyl-3-hexenyl, Imethyl4-hexenyl, 1 -methyl-5-hexenyl, 1-methyl-2-hexynyl, 1 -methyl-3hexynyl, 1-methyl4hexynyl, 3-heptyl, 1-ethyl-2-pentenyl, 1-ethyl-3pentenyl, 1 -ethyl -pentenyl, 1 -butyl-2-propenyl, 1 -ethyl-2-pentynyl, 1 -ethyl- 3-pentynyl, 1 -octyl, 2-octenyl, 3 -octenyl, 4-octenyl, 5-octenyl, 6-octenyl, 7octenyl, 2-octynyl, 3-octynyl, 4-octynyl, 5-octynyl, 6-octynyl, 2-octyl, Imethyl-2-heptenyl, I -methyl-3-heptenyl, 1-methy[-4-heptenyl, heptenyl, 1-methyl-6-heptenyl, 1-methyl-2-heptynyl, 1 -methyl-3-heptynyl, Imethyl-4-heptenyl. 1 -methyl-5-heptenyl, 1 -methyl-6-heptepnyl, 1 -methyl-2heptenyl, 1 -methyl-3-heptynyl, 1-rnethyl-4-heptynyl, 1 -methyl-5-heptynyl, 3octyl, 1-ethyl-2-hexenyl, 1-ethyl-3-hexenyl, 1 -ethyl-4-bexenyl, 1-ethyl-2hexynyl, 1-ethyl-3-hexynyl, 1-ethyl-4-hexynyl, 1 -ethyl-5-hexenyl, I -pentyl-2propenyl, 4-octyl,* 1-propyl-2-pentenyl, 1 -propyl-3-pentenyl, 1-propyl-4pentenyl, 1-butyl-2-butenyl, 1-propyl-2-pentynyl, 1-propyl-3-pentynyl, 1butyl-2-butynyl, I -butyl-3-butenyl, 2,2,2-trifluoroethyl, 2,2-difluoropropyl, 4-trifluoromethyl-5,5,5-trifluoropentyl, 4-trifluoromethylpentyl, 5,5,6,6,6pentafluorohexyl, 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 33 34 35 36 R R R and R B is optionally selected from the group consisting of cyclopropyl, cyclobutyl, oxetan-2-yl, oxetan-3-yi, azetidin-1-I*, azetidin-2-yI, azetidin-3-yl, thiaetan-2-yl, thiaetan-3-yI, cyclopentyl, cyclohexyl, adamantyl, norbornyl, 3trifluoromethylnorbornyl, 7-oxabicyclo[2.2. 1 lheptan-2-yl, bicyclo[3.1 .0]hexan-6-yI, cycloheptyl, cyclooctyl, 2-morpholinyl, 3morpholinyl, 4-morpholinyl, 1-piperazinyl, 2-piperazinyl, 1-piperidinyl, 2piperidinyl, 3-piperidinyl, 4-piperidinyl, 1-pyrrolidinyl, 2-pyrrolidinyl, 3pyrrolidinyl, 2-dioxanyl, 4H-2-pyranyl, 4H-3-pyranyl, 4H-4-pyranyl, 41-- WO 00/69933 WO 0069833PCTIUSOOIO8226 pyran-4-one-2-yl, 4H-pyran-4-one-3-yl, 2-tetrahydrofuranyl, 3tetrahydrofuranyl, 2-tetrahydropyranyl, 3-tetrahydropyranyl, 4tetrahydropyranyl, 2-tetrahydrothienyl, and 3-tetrahydrothienyl, wherein each ring carbon is optionally substituted with R 33, ring carbons and a nitrogen adjacent to the carbon atom at the point of attachment is optionally substituted 9 13 9 with R or R a ring carbon or nitrogen adjacent to the R position and two atoms from the point of attachment is optionally substituted with R ,and a ring carbon or nitrogen adjacent to the R positdon and two atoms from the point ofatcmn soptionally substituted with R 1 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, hydroxy, amidno, 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, fluoro, chioro, bromo, methanesulfonamido, amidosulfonyl, Nmethylamidosulfonyl, NN-dimethylamnidosulfonyl, acetyl, propanoyl, trifluoroacetyl, pentafluoropropanoyl, hydroxymethyl, 1-hydroxyethyl, 2hydroxyethyl, 2,2,2-trifluoro-l1-hydroxyethyl, 2,2,2-trifluoro- 1trifluoromnethyl-l1-hydroxyethyl, carboxymethyl, methoxycarbonyl, ethoxycarbonyl, amidocarbonyl, N-methylamidocarbonyl, N,Ndimethylamidocarbonyl, and cyano; A is selected from the group consisting of single covalent bond, 0, S, NH, N(CH 3
CH
2
CH
3 CH, CF 3 CH, NHC(0),
N(CH
3 C(0)NH, C(O)N(CH 3
CF
3 CC(O), C(0)CCH 3 C(0)CCF 3
CH
2 (0)CCH 2
CH
2
CH
2
CH
2
CH
2
CH
2
CH
3
CHCH
2
CF
3
CHCH
2 WO 00/69833 WO 0069833PCr/USOO/08226
CH
3
CC(O)CH
2
CF
3
CC(O)CH
2
CH
2
C(O)CCH
3
CH
2
C(O)CCF
3
CH
2
CH
2 and CH 2
(O)CCH
2 Ais optionally selected from the group consisting of CH- 2
(H)
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; Mis selected from the group, consisting of N andRI C RIis selected from the group consisting of hydrido, hydroxy, amino, thiol, am-idino, hydroxyarnino, am-inomethyl, 1-aminoethyl, 2-aminoethyl, methylamino, dimethylamino, cyano, methyl, ethyl, isopropyl, propyl, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, 2,2,33,3pentafluoropropyl, methoxy, ethoxy, propoxy, hydroxymethyl, Ihydroxyethyl, 2-hydroxyethyl, methoxyamino, ethoxyamino, methylthio, ethylthio, trifluoromethoxy, 1, 1,2,2-tetrafluoroethoxy, fluoro, chioro, and bromo;
R
2 is ZO-Q; is selected from the group consisting of covalent single bond, 0, 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 Q is selected from the group consisting of phenyl, 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyrrolyl, 3-pyr-rolyl, 2-imidazolyl, 4-imidazolyl, 3pyrazolyl, 4-pyrazolyl, 1 ,2,4-triazol-3-yl, 1 ,2A4-triazol-5-yl, 1 ,2,A-oxadiazol- 3-yl, I ,2,4-oxadiazol-5-yl, I ,3A-oxadiazol-3-yl, 1,3 ,4-oxadiazol-5-yl, 3isothiazolyl, 5-isothiazolyl, 2-oxazolyl, 2-thiazolyl, 3-isoxazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl, pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 1 ,3,5-triazin-2-yl, 1 ,2,4-triazin-3yl, 1 ,2,A-triazin-5-yi, 1 ,2,A-triazin-6-yl, 1 ,2,3-triazin-4-yl, and 1 .2,3-triazinwherein 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 WO 00/69833 PCT/US00/08226 13 9 point of attachment is optionally substituted by R a carbon adjacent to R and two atoms from the carbon at the point of attachment is optionally substituted by R a carbon adjacent to R 3 and two atoms from the carbon at 12 the point of attachment is optionally substituted by R and any carbon adjacent to both R 0 and R 2 is optionally substituted by R 1 1 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; E is a covalent single bond, and S(0) 2
N(H);
Yo is selected from the group of formulas consisting of:
S
R17 R 1 8
R
1 6
R
1 9 Qb S S
R
1 7
R
1 8
R
1 8 R19 R16 R 19 t y R R
R^^
WO 00/69833 PCT/USOO/08226 S S
R
1 6 RN N9~ Q b Q b S
S
NN 1 6 1 Qb b R QS s Q R 9 I b R 1 6 qb R 1 7
R
QS
Q
R
19 I b
Q
1 Qb R 1
R
1 6 QH s N Q H R19 K Qb
R
1 6 QbR 1 7
R
1 6 WO 00/69833 WO 0069833PCT/USOO/08226
-/R
1 9 R 17
N
Qb QS Q b QS H
N
K)
R
1 6
R
1 6
R
1 6 Qb QS Q s Q Q Q b Qb R 9Q '16 17 18 19 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, methoxyamnino, ethoxyamino, aminomethyl, 1-aminoethyl, 2-aniinoethyl, N- N-methylamino, dirnethylamidno, N-ethylamino, methylthio, ethylthio, isopropylthio, trifluoromethylthio, methylsulfinyl, ethylsulfinyl, methylsulfonyl, ethylsulfonyl, trifluoromethyl, pentafluoroethyl, 2,2,2trifluoroethyl, 2,2,3,3 ,3-pentafluoropropyl, trifluoromethoxy, 1, 1,2,2tetrafluoroethoxy, fluoro, chioro, bromo, amidosulfonyl, N-* methylamidosulfonyl, N,N-dimethylaxnidosulfonyl, acetyl, propanoyl, trifluoroacetyl, pentafluoropropanoyl, hydroxymethyl, 1-hydroxyethyl, 2hydroxyethyl, 2,2,2-trifl uoro-1I-hydroxyethyl, and cyano; R 16and R 19are optionally Q bwith the proviso that no more than one ofR 16andR 19is Q batthe same time and that Q bis Q b WO 00/69833 WO 0069833PCT/USOO/08226 Q bis selected from the group consisting of NR 20R 21 Q bewherein Q beis hydrido. C(NR 25)NR23R2 and N(R 26)C(NR25)N(R 23)(R 24), with the proviso that no more than one of R 20and R 21is hydroxy, Nmethylamino, and N,N-dimethylarnino at the same time and that no more than one of R 23and R 24is hydroxy, N-methylamino, and N,N-dimethylamino at the same time; 20 21 23 24 25 26 R *R ,R R R and R are independently selected from the group consisting of hydrido, methyl, ethyl, propyl, butyl, isopropyl, hydroxy, 2aminoethyl, 2-(N-methylamino)ethyl, and 2-(N,N-dimethylamnino)ethyl; Qs is selected from the group consisting of a single covalent bond,
CR
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=CHCH
2
CF=CHCH
2
C(CH
3
)=CHCH
2 CH.,CH=CH, CH 2 CF=CH, CH 2
C(CH
3
)=CH,
CH-,CH=CHCH
2
CH
2
CF=CHCH
2
CH,C(CH
3
)=CHCH
2
CH
2
CH=CHCH
2
CH
2
CH
2
CF=CHCH
2
CH
2 and
CH
2
C(CH
3
)=CHCH
2
CH
2 In a more preferred specific embodiment of Formula 1, compounds have the Formula I-NIPS wherein B is an aromatic: 72 A
N
H H 0 (I-MPS wherein B is aromatic) or a pharmaceutically acceptable salt thereof, wherein; WO 00/69833 WO 0069833PCT/USOO/08226 B is selected from the group consisting of phenyl, 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl, 4-imidazolyl, 3pyrazolyl, 4-pyrazolyl, 2-thiazolyl, 3-isoxazolyl, 5-isoxazolyl, 2-pyridyl. 3pyridyl, '1-pyridyl, 2-pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 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 32, the other carbon adjacent to the carbon at the point of attachment is optionally 36 32 substituted by R a carbon adjacent to R and two atoms from the carbon at the point of attachment is optionally substituted by R 33, a carbon adjacent to 36 R and two atoms from the carbon at the point of attachment is optionally 33 substituted by R ,and any carbon adjacent to both R and R is optionally substituted byR 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, trifluoroacetaiido, N-methylamino, dimethylamino, N-ethylamino, methylthio, ethylthio, isopropylthio, trifi uoromethyl, pentafluoroethyl, 2,2,2trifluoroethyl, 2,2,3,3,3-pentafluoropropyl, trifluoromethoxy, 1, 1,2,2tetrafluoroethoxy, fluoro, chloro, bromo, amidosulfonyl, Nmethylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl, 1hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro- 1 -hydroxyethyl,' methoxycarbonyl, ethoxycarbonyl, aniidocarbonyl, N-methylamidocarbonyl, N,N-dimethylamidocarbonyl, cyano, and Q b.
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)NH, C(O)N(CH 3
CH
2
CH
2
CH
2
CI-
2
CH
2
CH
3
CHCH
2 and
CF
3
CHCH
2 100 WO 00/69933 WO 0069833PCT/USOOIO8226 Q bis selected from the group consisting of NR 20R 2, Qb wherein Q beis hydrido, and C(NR 25)NR23R 24, with the provisos that no more than one of R2 and R 21is hydr .oxy at the same'time and that no more than one of R 23and R 24is hydroxy at the same time;/ 20 21 23 24 25 R R R R and R are independently selected from the group consisting of hydrido, methyl, ethyl, propyl, butyl, isopropyl, and hydroxy,, Q is selected from the group consisting of a single covalent bond,
CH
2 and CH 2
CH
2 In another more preferred specific embodiment of Formula 1, compounds have the Formula I-MPS wherein B is a non-c yclic substituent: 72 A N
Y
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, 2-propynyl, propyl, isopropyl, butyl, 2-butenyl, 3-butenyl, 2-butynyl, secbutyl, tent-butyl, isobutyl, 2-methylpropenyl, 1-pentyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-pentynyl, 3-pentynyl. 2-pentyl, 1 -methyl-2-butenyl, 1 -methyl-3butenyl, 1 -methyl-2-butynyl, 3-pentyl, 1 -ethyl-2-propenyl, 2-methylbutyl, 2methyl-2-butenyl, 2-methyl-3 -butenyl, 2-methyl-3-butynyl, 3-methylbutyl, 3methyl-2-butenyl, 3-methyl-3-butenyl, 1-hexyl, 2-hexenyl, 3-hexenyl, 4hexenyl, 5-hexenyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 2-hexyl, l-methyl-2pentenyl, 1 -methyl.-3-pentenyl, I -methyl-4-pentenyl, 1 -methyl-2-pentynyl, 1methyl-3-pentynyl, 3-hexyl, 1 -ethyl-2-butenyl, 1 -ethyl-3-butenyl, 1-propyl-2propenyl, 1-ethyl-2-butynyl, 1-heptyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, WO 00/69833 WO 0069833PCT/USOO/08226 heptenyl, 6-heptenyl, 2-heptynyl. 3-heptynyl, 4-heptynyl. 5-heptynyl, 2heptyl, 1 -methyl-2-hexenyl, 1-methyl-3-hexenyl, 1-methyl-4-hexenyl, 1- 1-methyl-2-hexynyl, l-methyl-3-hexynyl, 1-methyl-4hexynyl, 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, 2,2,2trifluoroethyl, 2,2-difluoropropyl, 4-trifluoromethyl-5,5,5-trifluoropentyl, 4trifluoromethylpentyl, 5,5,6,6,6-pentafluorohexyl, and 3 ,3,3-trifluoropropyl, wherein each member of group B is optionally substituted at any carbon up to and including 5 atoms from the point of attachment of B to A with one or more 32 33 34 35 36 of the group consisting of R R R R and R 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, trifluor-oacetamido, N-methylamino, dimethylaniino, N-ethylainino, methylthio, ethylthio, isopropylthio, trifluoromethyl, pentafluoroethyl, 2,2,2trifluoroethyl, 2,2,3,3 ,3-pentafluoropropyl, trifluoromethoxy, 1, 1,2,2tetrafluoroethoxy, fluoro, chioro, bromo. amidosulfonyl, Nmethylamidosulfonyl, N.N-dimethylamidosulfonyl, hydroxymetbyl, 1hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro-1I-hydroxyethyl, methoxycarbonyl, ethoxycarbonyl, ainidocarbonyl, N-methylamiddocarbonyl, N,N-dimethylamidocarbonyl, cyano, and Qb Ais 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)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; 102 WO 00/69833 WO 0069833PCTJUS00108226 Q bis selected from the group consisting of NR 20R 21 Q be, wherein Q b 23 24 26 25 23 24 is hydrido, C(NR )NR R and N(R )C(NR )N(R with the 20 21 provisos that no more than one of R and R is hydroxy at the same time and that no more .than one of R 23and R 24is hydroxy at the same time-, 20 21 23 24 25 26 R ,R ,R R R and R are independently selected from the group consisting of hydrido, methyl, ethyl, propyl, butyl, isopropyl, and hydroxy;
S
Q is selected from the group consisting of a single covalent bond,
CH
2 and CH 2
CH
2 In still another more preferred specific embodiment of Formula 1, compounds have the Formula l-MPS wherein B is a non-aromatic cyclic substituent: 2 A N0 H H 0
(I-MPS
wherein B is a non-aromatic cyclic substituent) or a pharmaceutically acceptable salt thereof, wherein; B is optionally selected from the group consisting of cyclopropyl, cyclobutyl, oxetan-3-yl, azetidin- 1-yl, azetidin-2-yl, azetidin-3-yl, thiaetan-3yl, cyclopentyl, cyclohexyl, norbornyl, 7-oxabicyclo[2.2. 1]heptan-2-yl, bicyclo[3. 1 .0]hexan-6-yl, cycloheptyl, 2-morpholinyl, 3-morpholinyl, 4morpholinyl, 1-piperazinyl, 2-piperazinyl, 1 -piperidinyl, 2-piperidinyl, 3piperidinyl, 4-piperidinyl, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2dioxanyl, 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, 2tetrahydropyranyl, 3-tetrahydropyranyl, 4-tetraliydropyranyl, 2tetrahydrothienyl, and 3-tetrahydrothienyl, wherein each ring carbon is 103 WO 00/69833 WO 0069833PCT/USOO/08226 optionally substituted with R 33, a ring carbon and a nitrogen adjace .nt to the carbon atom at the point of attachment are optionally substituted with R 9or 13 9 R ,a ring carbon or nitrogen adjacent to the R position and two atoms from the point of attachment is optionally substituted with R and a ring carbon or 13 nitrogen adjacent to the R position and two atoms from the point of attachment is optionally substituted with R 1 Ais selected from the group consisting'of single covalent bond, NH,
N(CH
3 N(QH), CH 2
CH
3 CH, CF 3 CH, NHC(O), N(CH 3 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 R3 is selected from the group consisting of hydrido, amidino, guanidino, carboxy, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, methoxyamino, ethoxyamino, acetamido, trifluoroacetanido, N-methylamino, dimethylamino, N-ethylarnino, methylthio, ethylthio, isopropylthio, trifluorornethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, 2,2,3,3,3pentafluoropropyl, trifluoromethoxy, 1,1 ,2,2-tetrafluoroethoxy, fluoro, chioro, bromo, amidosulfonyl, N-methylamiddosulfonyl, N,Ndimethylamidosulfonyl, hydroxymethyl, 1 -hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro- 1 -hydroxyethyl, methoxycarbonyl, ethoxycarbonyl, amidocarbonyl, N-methylamidocarbonyl, N,N-dimethylamidocarbonyl, cyano, andQ b; Q bis selected from the group consisting of NR 20R 21, Q bewherein Q beis hydrido, and C(NR )NR R 2, with the provisos that no more than one of R2 and R 21is'hydroxy at the same time and that no more than one of R 23and R 24is hydroxy at the same time; 104 WO 00/69833 WO 0069833PCT/USOO/08226 20 21 23 24 25 R ,R ,R R and R are independently selected from the group consisting of hydrido, methyl, ethyl, propyl, butyl, isopropyl, and hydroxy; Qs is selected from the group consisting of a single covalent bond,
CH
2 and CH 2
CH
2 more preferred specifi c embodiment (I-MS) compounds of the present invention having the Formula: 2 0 B N 1N 0 H H 0 or a pharmaceutically acceptable salt thereof, have common structural units, wherein; M is selected from the group consisting of N andRI C
R
1 is selected from the group consisting of hydrido, hydroxy, amino, amidino, hydroxyanuno, aminomethyl, 1 -aminoethyl, methylamino, dimethylamino, cyano, methyl, ethyl, trifluoromethyl, pentafluoroethyl, 2,2,2trifluoroethyl, methoxy, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, methoxyamino, methylthio, ethylthio, trifluoromethoxy, 1,1,2,2tetrafluoroethoxy, fluoro, chloro, and bromo;
R
2 is ZO-Q is selected from the group consisting of a covalent single bond, 0, S, NH, and CH 2 Q is selected from the group consisting of phenyl, 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl, 4-imidazolyl, 3pyrazolyl, 4-pyrazolyl, 2-thiazolyl, 3-isoxazolyl, 5-isoxazolyl, 2-pyridyl, 3pyridyl, 4-pyridyl, 2-pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, and 1,3,5-triazin-2-yi, wherein a carbon or 105 WO 00/69833 WO 0069833PCT/USOOAj8226 nitrogen adjacent to the carbon at the point of attachment is optionally 9 substituted by R the other carbon or nitrogen adjacent to the carbon at the 13 point of attachment is optionally substituted by R a carbon or nitrogen 9 adjacent to R and two atoms from the carbon at the point of attachment is 13 optionally substituted by R a carbon adjacent to R and two atoms from 12 the carbon at the point of attachment is optionally substituted by R ,and any carbon adjacent to both R 10and R 12is optionally substituted by R 9 11 13 R R and R are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, N-methylamino, N,N-dimethylamino, N-ethylamino, methylthio, ethylthio, isopropylthio, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, 2,2,3,3,3pentafluoropropyl, trifluoromethoxy, 1, 1,2,2-tetrafluoroethoxy, fluoro, chioro, bromo, methanesulfonamido, amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, 2hydroxyethyl, 2,2,2-trifluoro- 1 -hydroxyethyl, aniidocarbonyl, Nmethylamidocarbonyl, N,N-dimethylamidocarbonyl, and cyano; R 10and R 12are independently selected from the group consisting of hydrido, amnidino, guanidino, carboxy, carboxymethyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, methoxyamino, ethoxyarmno, acetamido, trifluoroacetamido, aminomethyl, 1aminoethyl, 2-aminoethyl, N-methylaniino, dimethylamino, N-ethylamnino, methanesulfonamido, amidosulfonyl, N-methylamidosulfonyl, N,Ndimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro- 1 -hydroxyethyl, methoxycarbonyl, ethoxycarbonyl, am-idocarbonyl, N-methylamidocarbonyl, N,N-dimethylamidocarbonyl, fluoro, chloro, bromo, and cyano; WO 00/69833 WO 0069833PCTIUSOOIO8226 y0is selected from the group of formulas consisting of:
.R
1 8 R1 8 R1 9
S
R
1 6 Q b ,17 f1 .RI 8 WO 00/69833 WO 0069833PCT/USO0108226 QS
QS
KR 9 Qb
Q
1 Qb R1 6 K -R19 -Qb
Q
1 QbR1
QHS
N
QH
KR
1 9 K -Qb
R
1 6 qb- R 1 7 q Qs) H QH i /i 9 Q b RN7 Qb QS Q Qb QS 6
R
1 6 Q b Q6 108 WO 00/69833 WO 0069833PC171USO0108226 I~y
R
1 9 Qb Qb and R7 1
N
16 17 18 19 R ,R ,R ,and R are independently selected from the gru consisting of hydrido, methyl, ethyl, isopropyl, propyl, carboxy, amidino, gundio intoytoy, isopropoxy, propoxy, hydroxy, amino, aminomethyl, 1-aminoethyl, 2-aminoethyl, N-rnethylamino, dimethylamino, N-ethylamino, methyithia, ethylthio, isopropylthio, trifluoromethyltbio, methylsulfinyl, ethylsulfinyl, methylsulfonyl, ethylsulfonyl, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, 2,2,3,3 ,3-pentafluoropropyl, trifluoromethoxy, 1,1,2,2-tetralluoroethoxy, fluoro, chioro, bromo, arnidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro- 1hydroxyethyl, and cyano; R 16and R 19are optionally Q bwith the proviso that no more than one of R 16and R 19isQ bat the same time and that Q bisQ b In a most preferred specific embodiment of Formula I, compounds have the Formula I-EMPS wherein B is an aromatic: 2 A N0 B N N H H 0 (I-EMPS wherein B is aromatic) 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- 109 WO 00/69833 PCT/US00/08226 pyrazolyl, 4-pyrazolyl, 2-thiazolyl, 3-isoxazolyl, and 5-isoxazolyl, wherein a carbon adjacent to the carbon at the point of attachment is optionally substituted 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 36 adjacent to R and two atoms from the carbon at the point of attachment is 33 35 optionally substituted by R and any carbon adjacent to both R 33 and R 35 is 34 optionally substituted by R34;
R
3 2
R
34
R
3 5 and R are independently selected from the group consisting of hydrido, amidino, guanidino, methyl, ethyl, methoxy, ethoxy, hydroxy, amino, N-methylamino, dimethylamino, methylthio, ethylthio, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, fluoro, chloro, bromo, amidosulfonyl, N-methylamidosulfonyl, hydroxymethyl, amidocarbonyl, carboxy, cyano, and Qb; A is selected from the group consisting of single covalent bond, NH,
N(CH
3
CH
2
CH
3 CH, and CH 2
CH
2 Qb is selected from the group consisting of NR20R 2 1 and )NR R with the proviso that said Q group is bonded directly to a carbon atom; 21 23 24
R
20
R
2 1 R R 2 4 and R 2 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: 110 WO 00/69833 WO 0069833PCTIUSOOIO8226 1 0 B I-,A*IN N N 1- H H 0 (1-EMPS wherein B is a non-cyclic substituent) or a pharmaceutically acceptable salt thereof, wherein; Bis selected from the group consisting of hydrido, ethyl, 2-propenyl, 2-propynyl, propyl, isopropyl, butyl, 2-butenyl, 2-butynyl, sec-butyl. tertbutyl, isobutyl, 2-methyipropenyl, 1-pentyl, 2-pentenyl, 3-pentenyl, 2pentynyl, 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-3pentenyl, 1-methyl-2-pentynyl, 1-methyl-3-pentynyl, 3-hexyl, 1-ethyl-2butenyl, I1-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, 1methyl-4-hexynyl, 3-heptyl, 1 -ethyl-2-pentenyl, 1 -ethyl-3-pentenyl, I -ethyl-2pentynyl, 1-ethyl-3-pentynyl, 2,2,2-trifluoroethyl, 2,2-difluoropropyl, 4trifluoromethyl-5,5,5-trifluoropentyl, 4-trifluoromethylpentyl, 5,5,6,6,6pentafluorohexyl, 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 33 34 35 36 R ,R R ,and R 32 33 34 35 36 R ,R ,R R and R are independently selected from the group consisting of hy drido, amnidino, guanidino, methyl, ethyl, methoxy, ethoxy, hydroxy, amino, N-methylamino, dimethylaxnino, methylthio, ethylthio, trifluoromethyl, pentafluoroe thyl, 2,2,2-trifluoroethyl, fluoro, ill WO 00/69833 PCT/US00/08226 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 A is optionally selected from the group consisting of CH 2
N(CH
3
CH
2
N(CH
2
CH
3
CH
2
CH
2
N(CH
3 and CH 2
CH
2
N(CH
2
CH
3 with the proviso that B is hydrido; b 20 21 Qb is selected from the group consisting of NR R21 )NR23R 24 and N(R26)C(NR )N(R with the proviso that said Qb group is bonded directly to a carbon atom; 21 23 24 25 26
R
20 R R R 2 R and R are independently selected from the group consisting of hydrido, methyl, and ethyl; QS is CH 2 In still another most preferred specific embodiment of Formula I, compounds have the Formula I-EMPS wherein B is a non-aromatic cyclic substituent: 2 /A NY N o B N N H H 0 (I-EMPS wherein B is a non-aromatic cyclic substituent) or a pharmaceutically acceptable salt thereof, wherein; B is optionally selected from the group consisting of cyclopropyl, cyclobutyl, oxetan-3-yl, azetidin-3-yl, thiaetan-3-yl, cyclopentyl, cyclohexyl, 112 WO 00/69833 PCT/US00/08226 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-tetrahydrofuranyl, 3tetrahydrofuranyl, 2-tetrahydrothienyl, and 3-tetrahydrothienyl, wherein each 33 ring carbon is optionally substituted with R ring carbons and a nitrogen adjacent to the carbon atom at the point of attachment are optionally substituted 9 13 9 with R or R a ring carbon or nitrogen adjacent to the R position and two atoms from the point of attachment is optionally substituted with R and a ring carbon or nitrogen adjacent to the R 13 position and two atoms from the 12 point of attachment is optionally substituted 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, N-methylamidosulfonyl, hydroxymethyl, amidocarbonyl, cyano, and Qb; A is selected from the group consisting of single covalent bond, NH,
N(CH
3
CH
2
CH
3 CH, and CH 2
CH
2 Qb is selected from the group consisting of NR20R 2 1 and C(NR )NR2 R with the proviso that said Q group is bonded directly to a carbon atom; 21 23 24 25
R
2
R
2 1 R R 24 and R are independently selected from the group consisting of hydrido, methyl, and ethyl; QS is CH 2 The most preferred specific embodiment (I-EMPS) compounds of the present invention having the Formula: 113 WO 00/69833 PCT/USOO/08226
A
H H
O
or a pharmaceutically acceptable salt thereof, have common structural units, wherein; M is selected from the group consisting of N and R -C;
R
1 is selected from the group consisting of hydrido, hydroxy, amino, amidino, hydroxyamino, aminomethyl, methylamino, cyano, methyl, trifluoromethyl, methoxy, hydroxymethyl, methoxyamino, methylthio, trifluoromethoxy, fluoro, and chloro;
R
2 is Z-Q; Z is a covalent single bond; Q is selected from the group consisting of phenyl, 2-thienyl, 2-furyl, 2pyrrolyl, 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 9 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 carbon at the point of attachment is optionally substituted by 13 R a carbon adjacent to R and two atoms from the carbon at the point of attachment is optionally substituted by R 12 and any carbon adjacent to both R and R 12 is optionally substituted by Rl R R 1, and R13 are independently selected from the group consisting of hydrido, methyl, ethyl, methoxy, ethoxy, hydroxy, amino, N-methylamino, N,N-dimethylamino, methylthio, trifluoromethyl, pentafluoroethyl, 2,2,2- 114 WO 00/69933 WO 0069833PCT/USOOIO8226 trifluoroethyl, fluoro, chioro, bromno, amidosulfonyl, N-methylainidosulfonyl, N,N-dimethylaniidosulfonyl, hydroxymethyl. 1 -hydroxyethyl, amidocarbonyl, N-methylamidocarbonyl, carboxy, and cyano; R 10and R 12are independently selected from the group consisting of hydrido, amidino, amidocarbonyl, N-methylamidocarbonyl, guanidino, methyl, ethyl, methoxy, ethoxy, hydroxy, hydroxymethyl, 1-hydroxyethyl, 2bydroxyetbyl, carboxy, carboxymethyl, amino, acetam-ido, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, trifluoroacetamiddo, aniinomethyl, Nmetbylamino, dimethylamino, aniidosulfonyl, N-methylaniidosulfonyl, N,Ndimethylaniidosulfonyl, niethoxycarbonyl. fluoro, chioro, bromo, and cyano; YOis selected from the group of formulas consisting of:
R
1 8
QS
I/6
)R
1 9 Q b 115 WO 00/69833 PCT/US00/08226 R16 R17 o Qb R 1 6 Q Hs H
R
19
I/
R
1 6 R17Rq Qb R1 6 S
R
1 9 Qb Sand
R
1 7 Qb b 16 17 18 19
R
6
R
7 R and R 1 are independently selected from the group consisting of hydrido, methyl, ethyl, amidino, guanidino, methoxy, hydroxy, amino, aminomethyl, 1-aminoethyl, 2-aminoethyl, N-methylamino, dimethylamino, methylthio, ethylthio, trifluoromethylthio, methylsulfinyl, methylsulfonyl, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, trifluoromethoxy, fluoro, chloro, amidosulfonyl, N-methylamidosulfonyl, hydroxymethyl, carboxy, and cyano.
The compounds of this invention can be used in anticoagulant therapy for the treatment and prevention of a variety of thrombotic conditions including coronary artery and cerebrovascular disease. The compounds of this invention can be used to inhibit serine protease associated with the coagulation cascade and factors II, VII, VIII, IX, X, XI, or XII. The compounds of the invention can inhibit the formation of blood platelet aggregates, inhibit the formation of fibrin, inhibit thrombus formation, and inhibiting embolus formation in a mammal, in blood, in blood products, and in mammalian organs. The WO 00/69833 PCTIUSOO/08226 compounds also can be used for treating or preventing unstable angina, refractory angina, myocardial infarction, transient ischemic attacks, atrial fibrillation, thrombotic stroke, embolic stroke, deep vein thrombosis, disseminated intravascular coagulation, ocular build up of fibrin, and 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 would also be useful in prevention of cerebral vascular accident (CVA) or stroke.
Besides being useful for human treatment, these compounds are also useful for veterinary treatment of companion animals, exotic animals and farm animals, including mammals, rodents, and the like. More preferred animals include horses, dogs, and cats.
In yet another embodiment of the present invention, the novel compounds are selected from the compounds set forth in Examples 1 through Example 7.
The use of generic terms in the description of the compounds are herein defined for clarity.
Standard single letter elemental symbols are used to represent specific types of atoms unless otherwise defined. The symbol represents a carbon atom.
The symbol represents an oxygen atom. The symbol represents a nitrogen atom. The symbol represents a phosphorus atom. The symbol "S" represents a sulfur atom. The symbol represents a hydrido atom. Double letter elemental symbols are used as defined for the elements of the periodical table Cl represents chlorine, Se represents selenium, etc.).
As utilized herein, the term "alkyl", either alone or within other terms such as "haloalkyl" and "alkylthio", means an acyclic alkyl radical containing from 1 to about 10, preferably from 3 to about 8 carbon atoms and more preferably 3 to about 6 carbon atoms. Said alkyl radicals may be optionally substituted with groups as defined below. Examples of such radicals include methyl, ethyl, chloroethyl, hydroxyethyl, n-propyl, oxopropyl, isopropyl, n-butyl, cyanobutyl, isobutyl, sec-butyl, tert-butyl, pentyl, aminopentyl, iso-amyl, hexyl, octyl and the like.
The term "alkenyl" refers to an unsaturated, acyclic hydrocarbon radical in so much as it contains at least one double bond. Such alkenyl radicals contain 117 WO 00/69833 PCTIUS00/08226 from about 2 to about 10 carbon atoms, preferably from about 3 to about 8 carbon atoms and more preferably 3 to about 6 carbon atoms. Said alkenyl radicals may be optionally substituted with groups as defined below. Examples of suitable alkenyl radicals include propenyl, 2-chloropropenyl, buten- -yl, isobutenyl, penten-1-yl, 2- 2-methylbuten- l-yl, 3-methylbuten- -yl, hexen-1-yl, 3-hydroxyhexen- l-yl, hepten-1-yl, and octen-1-yl, and the like.
The term "alkynyl" refers to an unsaturated, acyclic hydrocarbon radical in so much as it contains one or more triple bonds, such radicals containing about 2 to about 10 carbon atoms, preferably having from about 3 to about 8 carbon atoms and more preferably having 3 to about 6 carbon atoms. Said alkynyl radicals may be optionally substituted with groups as defined below.
Examples of suitable alkynyl radicals include ethynyl, propynyl, hydroxypropynyl, butyn-1-yl, butyn-2-yl, pentyn-1-yl, pentyn-2-yl, 4methoxypentyn-2-yl, 3-methylbutyn-l-yl, hexyn-1-yl, hexyn-2-yl, hexyn-3yl, 3,3-dimethylbutyn-1-yl radicals and the like.
The term "hydrido" denotes a single hydrogen atom 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 or two hydrido radicals may be attached to a carbon atom to form a "methylene" (-CH 2 radical.
The term "carbon" radical denotes a carbon atom without any covalent bonds and capable of forming four covalent bonds.
The term "cyano" radical denotes a carbon radical having three of four covalent bonds shared by a nitrogen atom.
The term "hydroxyalkyl" embraces radicals wherein any one or more of the alkyl carbon atoms is substituted with a hydroxyl as defined above.
Specifically embraced are monohydroxyalkyl, dihydroxyalkyl and polyhydroxyalkyl radicals.
The term "alkanoyl" embraces radicals wherein one or more of the terminal alkyl carbon atoms are substituted with one or more carbonyl radicals as defined below. Specifically embraced are monocarbonylalkyl and dicarbonylalkyl radicals. Examples of monocarbonylalkyl radicals include formyl, acetyl, and pentanoyl. Examples of dicarbonylalkyl radicals include oxalyl, malonyl, and succinyl.
WO 00/69833 PCT/USOO/08226 The term "alkylene" radical denotes linear or branched radicals having from 1 to about 10 carbon atoms and having attachment points for two or more covalent bonds. Examples of such radicals are methylene, ethylene, methylethylene, and isopropylidene.
The term "alkenylene" radical denotes linear or branched radicals having from 2 to about 10 carbon atoms, at least one double bond, and having attachment points for two or more covalent bonds. Examples of such radicals are 1,1-vinylidene 1,2-vinylidene and 1,4-butadienyl
(-CH=CH-CH=CH-).
The term "halo" means halogens such as fluorine, chlorine, bromine or iodine atoms.
The term "haloalkyl" embraces radicals wherein any one or more of the alkyl carbon atoms is substituted with halo as defined above. Specifically embraced are monohaloalkyl, dihaloalkyl and polyhaloalkyl radicals. A monohaloalkyl radical, for one example, may have either a bromo, chloro or a fluoro atom within the radical. Dihalo radicals may have two or more of the same halo atoms or a combination of different halo radicals and polyhaloalkyl radicals may have more than two of the same halo atoms or a combination of different halo radicals. More preferred haloalkyl radicals are "lower haloalkyl" radicals having one to about six carbon atoms. Examples of such haloalkyl radicals include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, trifluoroethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl.
The term "hydroxyhaloalkyl" embraces radicals wherein any one or more of the haloalkyl carbon atoms is substituted with hydroxy as defined above. Examples of "hydroxyhaloalkyl" radicals include hexafluorohydroxypropyl.
The term "haloalkylene radical" denotes alkylene radicals wherein any one or more of the alkylene carbon atoms is substituted with halo as defined above. Dihalo alkylene radicals may have two or more of the same halo atoms or a combination of different halo radicals and polyhaloalkylene radicals may have more than two of the same halo atoms or a combination of different halo radicals. More preferred haloalkylene radicals are "lower haloalkylene" radicals having one to about six carbon atoms. Examples of "haloalkylene" 119 WO 00/69833 PCT/US00/08226 radicals include difluoromethylene, tetrafluoroethylene, tetrachloroethylene, alkyl substituted monofluoromethylene, and aryl substituted trifluoromethylene.
The term "haloalkenyl" denotes linear or branched radicals having from 1 to about 10 carbon atoms and having one or more double bonds wherein any one or more of the alkenyl carbon atoms is substituted with halo as defined above. Dihaloalkenyl radicals may have two or more of the same halo atoms or a combination of different halo radicals and polyhaloalkenyl radicals may have more than two of the same halo atoms or a combination of different halo radicals.
The terms "alkoxy" and "alkoxyalkyl" embrace linear or branched oxycontaining radicals each having alkyl portions of one to about ten carbon atoms, such as methoxy radical. The term "alkoxyalkyl" also embraces alkyl radicals having one or more alkoxy radicals attached to the alkyl radical, that is, to form monoalkoxyalkyl and dialkoxyalkyl radicals. More preferred alkoxy radicals are "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 fluoromethoxy, chloromethoxy, trifluoromethoxy, difluoromethoxy, trifluoroethoxy, fluoroethoxy, tetrafluoroethoxy, pentafluoroethoxy, and fluoropropoxy. Examples of such haloalkoxyalkyl radicals include fluoromethoxymethyl, chloromethoxyethyl, trifluoromethoxymethyl, difluoromethoxyethyl, and trifluoroethoxymethyl.
The terms "alkenyloxy" and "alkenyloxyalkyl" embrace linear or branched oxy-containing radicals each having alkenyl portions of two to about ten carbon atoms, such as ethenyloxy or propenyloxy radical. The term "alkenyloxyalkyl" also embraces alkenyl radicals having one or more alkenyloxy radicals attached to the alkyl radical, that is, to form monoalkenyloxyalkyl and dialkenyloxyalkyl radicals. More preferred alkenyloxy radicals are "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 120 WO 00/69833 PCT/USOO/08226 bromo, to provide "haloalkenyloxy" radicals. Examples of such radicals include trifluoroethenyloxy, fluoroethenyloxy, difluoroethenyhloxy, and fluoropropenyloxy.
The term "haloalkoxyalkyl" also embraces alkyl radicals having one or more haloalkoxy radicals attached to the alkyl radical, that is, to form monohaloalkoxyalkyl and dihaloalkoxyalkyl radicals. The term "haloalkenyloxy" also embraces oxygen radicals having one or more haloalkenyloxy radicals attached to the oxygen radical, that is, to form monohaloalkenyloxy and dihaloalkenyloxy radicals. The term "haloalkenyloxyalkyl" also embraces alkyl radicals having one or more haloalkenyloxy radicals attached to the alkyl radical, that is, to form monohaloalkenyloxyalkyl and dihaloalkenyloxyalkyl radicals.
The term "alkylenedioxy" radicals denotes alkylene radicals having at least two oxygens bonded to a single alkylene group. Examples of "alkylenedioxy" radicals include methylenedioxy, ethylenedioxy, alkylsubstituted methylenedioxy, and arylsubstituted methylenedioxy. The term "haloalkylenedioxy" radicals denotes haloalkylene radicals having at least two oxy groups bonded to a single haloalkyl group. Examples of "haloalkylenedioxy" radicals include difluoromethylenedioxy, tetrafluoroethylenedioxy, tetrachloroethylenedioxy, alkylsubstituted monofluoromethylenedioxy, and arylsubstituted monofluoromethylenedioxy.
The term "aryl", alone or in combination, means a carbocyclic aromatic system containing one, two or three rings wherein such rings may be attached together in a pendant manner or may be fused. The term "fused" means that a second ring is present (ie, attached or formed) by having two adjacent atoms in common (ie, shared) with the first ring. The term "fused" is equivalent to the term "condensed". The term "aryl" embraces aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, indane and biphenyl.
The term "perhaloaryl" embraces aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, indane and biphenyl wherein the aryl radical is substituted with 3 or more halo radicals as defined below.
The term "heterocyclyl" embraces saturated and partially saturated heteroatom-containing ring-shaped radicals having from 4 through 15 ring members, herein referred to as "C4-C15 heterocyclyl", selected from carbon, nitrogen, sulfur and oxygen, wherein at least one ring atom is a heteroatom.
121 WO 00/69833 PCTIUSOOI8226 Heterocyclyl radicals may contain one, two or three rings wherein such rings may be attached in a pendant manner or may be fused. Examples of saturated heterocyclic radicals include saturated 3 to 6-membered heteromonocylic group containing 1 to 4 nitrogen atoms[e.g. pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl, etc.]; saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms morpholinyl, etc.]; saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms thiazolidinyl, etc.]. Examples of partially saturated heterocyclyl radicals include dihydrothiophene, dihydropyran, dihydrofuran and dihydrothiazole. Non-limiting examples of heterocyclic radicals include 2-pyrrolinyl, 3-pyrrolinyl, pyrrolindinyl, 1,3dioxolanyl, 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 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, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3triazolyl, etc.] tetrazolyl 1H-tetrazolyl, 2H-tetrazolyl, etc.], etc.; unsaturated condensed heterocyclic group containing 1 to 5 nitrogen atoms, for example, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl tetrazolo etc.], etc.; unsaturated 3 to 6-membered heteromonocyclic group containing an oxygen atom, for example, pyranyl, 2-furyl, 3-furyl, etc.; to 6-membered heteromonocyclic group containing a sulfur atom, for example, 2-thienyl, 3-thienyl, etc.; unsaturated 5- to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.] etc.; unsaturated condensed heterocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms benzoxazolyl, benzoxadiazolyl, etc.]; unsaturated 5 to 6-membered 122 WO 00/69833 PCT/US00/08226 heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl, thiadiazolyl 1,2,4- thiadiazolyl, 1,3,4thiadiazolyl, 1,2,5-thiadiazolyl, etc.] etc.; unsaturated condensed heterocyclic group containing 1 to 2 sulfur atoms and I to 3 nitrogen atoms benzothiazolyl, benzothiadiazolyl, etc.] and the like. The term also embraces radicals where heterocyclic radicals are fused with aryl radicals. Examples of such fused bicyclic radicals include benzofuran, benzothiophene. and the like.
Said "heterocyclyl" group may have 1 to 3 substituents as defined below.
Preferred heterocyclic radicals include five to twelve membered fused or unfused radicals. Non-limiting examples of heteroaryl radicals include pyrrolyl, pyridinyl, pyridyloxy, pyrazolyl, triazolyl, pyrimidinyl, pyridazinyl, oxazolyl, thiazolyl, imidazolyl, indolyl, thiophenyl, furanyl, tetrazolyl, 2imidazolinyl, imidazolidinyl, 2-pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,23-triazolyl, 1,3,4-thiadiazolyl, pyrazinyl, piperazinyl, 1,3 ,5-triazinyl, 1,3,5-trithianyl, benzo(b)thiophenyl, benzimidazoyl, quinolinyl, tetraazolyl, and the like.
The term "sulfonyl", whether used alone or linked to other terms such as alkylsulfonyl, denotes respectively divalent radicals -SO 2 "Alkylsulfonyl", embraces alkyl radicals attached to a sulfonyl radical, where alkyl is defined as above. "Alkylsulfonylalkyl", embraces alkylsulfonyl radicals attached to an alkyl radical, where alkyl is defined as above. "Haloalkylsulfonyl", embraces haloalkyl radicals attached to a sulfonyl radical, where haloalkyl is defined as above. "Haloalkylsulfonylalkyl", embraces haloalkylsulfonyl radicals attached to an alkyl radical, where alkyl is defined as above. The term "aminosulfonyl" denotes an amino radical attached to a sulfonyl radical.
The term "sulfinyl", whether used alone or linked to other terms such as alkylsulfinyl, denotes respectively divalent radicals "Alkylsulfinyl", embraces alkyl radicals attached to a sulfinyl radical, where alkyl is defined as above. "Alkylsulfinylalkyl", embraces alkylsulfinyl radicals attached to an alkyl radical, where alkyl is defined as above. "Haloalkylsulfinyl", embraces haloalkyl radicals attached to a sulfinyl radical, where haloalkyl is defined as above. "Haloalkylsulfinylalkyl", embraces haloalkylsulfinyl radicals attached to an alkyl radical, where alkyl is defined as above.
The term "aralkyl" embraces aryl-substituted alkyl radicals. Preferable aralkyl radicals are "lower aralkyl" radicals having aryl radicals attached to 123 WO 00/69833 PCT/US00/08226 alkyl radicals having one to six carbon atoms. Examples of such radicals include benzyl, diphenylmethyl, triphenylmethyl, phenylethyl and diphenylethyl. The terms benzyl and phenylmethyl are interchangeable.
The term "heteroaralkyl" embraces heteroaryl-substituted alkyl radicals wherein the heteroaralkyl radical may be additionally substituted with three or more substituents as defined above for aralkyl radicals. The term "perhaloaralkyl" embraces aryl-substituted alkyl radicals wherein the aralkyl radical is substituted with three or more halo radicals as defined above.
The term "aralkylsulfinyl", embraces aralkyl radicals attached to a sulfinyl radical, where aralkyl is defined as above. "Aralkylsulfinylalkyl", embraces aralkylsulfinyl radicals attached to an alkyl radical, where alkyl is defined as above.
The term "aralkylsulfonyl", embraces aralkyl radicals attached to a sulfonyl radical, where aralkyl is defined as above. "Aralkylsulfonylalkyl", embraces aralkylsulfonyl radicals attached to an alkyl radical, where alkyl is defined as above.
The term "cycloalkyl" embraces radicals having three to 15 carbon atoms. More preferred cycloalkyl radicals are "lower cycloalkyl" radicals having three to seven carbon atoms. Examples include radicals such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. The term cycloalkyl embraces radicals having seven to 15 carbon atoms and having two to four rings. Exmaples incude radicals such as norbornyl 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 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, 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 124 WO 00/69833 PCT/US00/08226 within the radical. Dihalo radicals may have two or more of the same halo atoms or a combination of different halo radicals and polyhalocycloalkyl radicals may have more than two of the same halo atoms or a combination of different halo radicals. More preferred halocycloalkyl radicals are "lower halocycloalkyl" radicals having three to about eight carbon atoms. Examples of such halocycloalkyl radicals include fluorocyclopropyl, difluorocyclobutyl, trifluorocyclopentyl, tetrafluorocyclohexyl, and dichlorocyclopropyl. The term "halocycloalkenyl" embraces radicals wherein any one or more of the cycloalkenyl carbon atoms is substituted with halo as defined above.
Specifically embraced are monohalocycloalkenyl, dihalocycloalkenyl and polyhalocycloalkenyl radicals.
The term "cycloalkoxy" embraces cycloalkyl radicals attached to an oxy radical. Examples of such radicals includes cyclohexoxy and cyclopentoxy.
The term "cycloalkoxyalkyl" also embraces alkyl radicals having one or more cycloalkoxy radicals attached to the alkyl radical, that is, to form monocycloalkoxyalkyl and dicycloalkoxyalkyl radicals. Examples of such radicals include cyclohexoxyethyl. The "cycloalkoxy" radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide "halocycloalkoxy" and "halocycloalkoxyalkyl" radicals.
The term "cycloalkylalkoxy" embraces cycloalkyl radicals attached to an alkoxy radical. Examples of such radicals includes cyclohexylmethoxy and cyclopentylmethoxy.
The term "cycloalkenyloxy" embraces cycloalkenyl radicals attached to an oxy radical. Examples of such radicals includes cyclohexenyloxy and cyclopentenyloxy. The term "cycloalkenyloxyalkyl" also embraces alkyl radicals having one or more cycloalkenyloxy radicals attached to the alkyl radical, that is, to form monocycloalkenyloxyalkyl and dicycloalkenyloxyalkyl radicals. Examples of such radicals include cyclohexenyloxyethyl. The "cycloalkenyloxy" radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide "halocycloalkenyloxy" and "halocycloalkenyloxyalkyl" radicals.
The term "cycloalkylenedioxy" radicals denotes cycloalkylene radicals having at least two oxygens bonded to a single cycloalkylene group. Examples of "alkylenedioxy" radicals include 1,2-dioxycyclohexylene.
125 WO 00/69833 PCTUS0008226 The term "cycloallylsulfinyl", embraces cycloalkyl radicals attached to a sulfinyl radical, where cycloalkyl is defined as above.
"Cycloalkylsulfinylalkyl", embraces cycloalkylsulfinyl radicals attached to an alkyl radical, where alkyl is defined as above. The term "Cycloalkylsulfonyl", embraces cycloalkyl radicals attached to a sulfonyl radical, where cycloalkyl is defined as above. "Cycloalkylsulfonylalkyl", embraces cycloalkylsulfonyl radicals attached to an alkyl radical, where alkyl is defined as above.
The term "cycloalkylalkanoyl" embraces radicals wherein one or more of the cycloalkyl carbon atoms are substituted with one or more carbonyl radicals as defined below. Specifically embraced are monocarbonylcycloalkyl and dicarbonylcycloalkyl radicals. Examples of monocarbonylcycloalkyl radicals include cyclohexylcarbonyl, cyclohexylacetyl, and cyclopentylcarbonyl. Examples of dicarbonylcycloalkyl radicals include 1,2dicarbonylcyclohexane.
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 The "alkylthio" radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide "haloalkylthio" radicals.
Examples of such radicals include fluoromethylthio, chloromethylthio, trifluoromethylthio, difluoromethylthio, trifluoroethylthio, fluoroethylthio, tetrafluoroethylthio, pentafluoroethylthio, and fluoropropylthio.
The term "alkyl aryl amino" embraces radicals containing a linear or branched alkyl radical, of one to ten carbon atoms, and one aryl radical both attached to an amino radical. Examples include N-methyl-4-methoxyaniline, N-ethyl-4-methoxyaniline, and N-methyl-4-trifluoromethoxyaniline.
The terms alkylamino denotes "monoalkylamino" and "dialkylamino" containing one or two alkyl radicals, respectively, attached to an amino radical.
The terms arylamino denotes "monoarylamino" and "diarylamino" containing one or two aryl radicals, respectively, attached to an amino radical.
Examples of such radicals include N-phenylamino and N-naphthylamino.
The term "aralkylamino", embraces aralkyl radicals attached to an amino radical, where aralkyl is defined as above. The term aralkylamino denotes "monoaralkylamino" and "diaralkylamino" containing one or two 126 WO 00/69833 PCTIUS00/08226 aralkyl radicals, respectively, attached to an amino radical. The term aralkylamino further denotes "monoaralkyl monoalkylamino" containing one aralkyl radical and one alkyl radical attached to an amino radical.
The term "arylsulfinyl" embraces radicals containing an aryl radical, as defined above, attached to a divalent S(O) atom. The term "arylsulfinylalkyl" denotes arylsulfinyl radicals attached to a linear or branched alkyl radical, of one to ten carbon atoms.
The term "arylsulfonyl", embraces aryl radicals attached to a sulfonyl radical, where aryl is defined as above. "arylsulfonylalkyl", embraces arylsulfonyl radicals attached to an alkyl radical, where alkyl is defined as above. The term "heteroarylsulfinyl" embraces radicals containing an heteroaryl radical, as defined above, attached to a divalent S(O) atom. The term "heteroarylsulfinylalkyl" denotes heteroarylsulfinyl radicals attached to a linear or branched alkyl radical, of one to ten carbon atoms. The term "Heteroarylsulfonyl", embraces heteroaryl radicals attached to a sulfonyl radical, where heteroaryl is defined as above. "Heteroarylsulfonylalkyl", embraces heteroarylsulfonyl radicals attached to an alkyl radical, where alkyl is defined as above.
The term "aryloxy" embraces aryl radicals, as defined above, attached to an oxygen atom. Examples of such radicals include phenoxy, 4-chloro-3ethylphenoxy, 4-chloro-3-methylphenoxy, 3-chloro-4-ethylphenoxy, 3,4dichlorophenoxy, 4-methylphenoxy, 3-trifluoromethoxyphenoxy, 3trifluoromethylphenoxy, 4fluorophenoxy, 3,4-dimethylphenoxy, 5-bromo-2fluorophenoxy, 4-bromo-3-fluorophenoxy, 4-fluoro-3-methylphenoxy, 5,6,7,8-tetrahydronaphthyloxy, 3-isopropylphenoxy, 3-cyclopropylphenoxy, 3-ethylphenoxy, 3-pentafluoroethylphenoxy, 3-(1,1,2,2-tetrafluoroethoxy)phenoxy, and 4-tert -butylphenoxy.
The term "aroyl" embraces aryl radicals, as defined above, attached to an carbonyl radical as defined above. Examples of such radicals include benzoyl and toluoyl.
The term "aralkanoyl" embraces aralkyl radicals, as defined herein, attached to an carbonyl radical as defined above. Examples of such radicals include, for example, phenylacetyl.
The term "aralkoxy" embraces oxy-containing aralkyl radicals attached through an oxygen atom to other radicals. More preferred aralkoxy radicals are WO 00/69833 PCT/US00/08226 "lower aralkoxy" radicals having phenyl radicals attached to lower alkoxy radical as described above. Examples of such radicals include benzyloxy, 1phenylethoxy, 3-trifluoromethoxybenzyloxy, 3-trifluoromethylbenzyloxy, difluorobenyloxy, 3-bromobenzyloxy, 4-propylbenzyloxy, 2-fluoro-3trifluoromethylbenzyloxy, and 2-phenylethoxy.
The term "aryloxyalkyl" embraces aryloxy radicals, as defined above, attached to an alkyl group. Examples of such radicals include phenoxymethyl.
The term "haloaryloxyalkyl" embraces aryloxyalkyl radicals, as defined above, wherein one to five halo radicals are attached to an aryloxy group.
The term "heteroaroyl" embraces heteroaryl radicals, as defined above, attached to an carbonyl radical as defined above. Examples of such radicals include furoyl and nicotinyl.
The term "heteroaralkanoyl" embraces heteroaralkyl radicals, as defined herein, attached to an carbonyl radical as defined above. Examples of such radicals include, for example, pyridylacetyl and furylbutyryl.
The term "heteroaralkoxy" embraces oxy-containing heteroaralkyl radicals attached through an oxygen atom to other radicals. More preferred heteroaralkoxy radicals are "lower heteroaralkoxy" radicals having heteroaryl radicals attached to lower alkoxy radical as described above.
The term "haloheteroaryloxyalkyl" embraces heteroaryloxyalkyl radicals, as defined above, wherein one to four halo radicals are attached to an heteroaryloxy group.
The term "heteroarylamino" embraces heterocyclyl radicals, as defined above, attached to an amino group. Examples of such radicals include pyridylamino.
The term "heteroarylaminoalkyl" embraces heteroarylamino radicals, as defined above, attached to an alkyl group. Examples of such radicals include pyridylmethylamino.
The term "heteroaryloxy" embraces heterocyclyl radicals, as defined above, attached to an oxy group. Examples of such radicals include 2thiophenyloxy, 2-pyrimidyloxy, 2-pyridyloxy, 3-pyridyloxy, and 4pyridyloxy.
The term "heteroaryloxyalkyl" embraces heteroaryloxy radicals, as defined above, attached to an alkyl group. Examples of such radicals include 2-pyridyloxymethyl, 3-pyridyloxyethyl, and 4-pyridyloxymethyl.
128 WO 00/69833 PCT/US00/08226 The term "arylthio" embraces aryl radicals, as defined above, attached to an sulfur atom. Examples of such radicals include phenylthio.
The term "arylthioalkyl" embraces arylthio radicals, as defined above, attached to an alkyl group. Examples of such radicals include phenylthiomethyl.
The term "alkylthioalkyl" embraces alkylthio radicals, as defined above, attached to an alkyl group. Examples of such radicals include methylthiomethyl. The term "alkoxyalkyl" embraces alkoxy radicals, as defined above, attached to an alkyl group. Examples of such radicals include methoxymethyl.
The term "carbonyl" denotes a carbon radical having two of the four covalent bonds shared with an oxygen atom. The term "carboxy" embraces a hydroxyl radical, as defined above, attached to one of two unshared bonds in a carbonyl group. The term "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 carboxamide radicals, as defined above, attached to an alkyl group. The term "carboxyalkyl" embraces a carboxy radical, as defined above, attached to an alkyl group. The term "carboalkoxy" embraces alkoxy radicals, as defined above, attached to one of two unshared bonds in a carbonyl group. The term "carboaralkoxy" embraces aralkoxy radicals, as defined above, attached to one of two unshared bonds in a carbonyl group. The term "monocarboalkoxyalkyl" embraces one carboalkoxy radical, as defined above, attached to an alkyl group. The term "dicarboalkoxyalkyl" embraces two carboalkoxy radicals, as defined above, attached to an alkylene group. The term "monocyanoalkyl" embraces one cyano radical, as defined above, attached to an alkyl group. The term "dicyanoalkylene" embraces two cyano radicals, as defined above, attached to an alkyl group. The term "carboalkoxycyanoalkyl" embraces one cyano radical, as defined above, attached to an carboalkoxyalkyl group.
The term "acyl", alone or in combination, means a carbonyl or thionocarbonyl group bonded to a radical selected from, for example, hydrido, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkoxyalkyl, haloalkoxy, aryl, heterocyclyl, heteroaryl, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, alkylthio, arylthio, amino, alkylamino, dialkylamino, aralkoxy, arylthio, and alkylthioalkyl. Examples of "acyl" are 129 WO 00/69833 PCT/US00/08226 formyl, acetyl, benzoyl, trifluoroacetyl, phthaloyl, malonyl, nicotinyl, and the like.
The term "haloalkanoyl" embraces one or more halo radicals, as defined herein, attached to an alkanoyl radical as defined above. Examples of such radicals include, for example, chloroacetyl, trifluoroacetyl, bromopropanoyl, and heptafluorobutanoyl.
The term "phosphono" embraces a pentavalent phosphorus attached with two covalent bonds to an oxygen radical. The term "dialkoxyphosphono" denotes two alkoxy radicals, as defined above, attached to a phosphono radical with two covalent bonds. The term "diaralkoxyphosphono" denotes two aralkoxy radicals, as defined above, attached to a phosphono radical with two covalent bonds. The term "dialkoxyphosphonoalkyl" denotes dialkoxyphosphono radicals, as defined above, attached to an alkyl radical. The term "diaralkoxyphosphonoalkyl" denotes diaralkoxyphosphono radicals, as defined above, attached to an alkyl radical.
The term "amino" denotes a nitrogen atom containing two substituents such as hydrido, hydroxy or alkyl and having one covalent bond available for bonding to a single atom such as carbon. Examples of such amino radicals include, for example, -NH 2
-NHCH
3 -NHOH, and -NHOCH 3 The term "imino" denotes a nitrogen atom containing one substituent such as hydrido, hydroxy or alkyl and having two covalent bonds available for bonding to a single atom such as carbon.
Examples of such imino radicals include, for example, =NH, =NCH 3
=NOH,
and =NOCH 3 The term "imino carbonyl" denotes a carbon radical having two of the four covalent bond sites shared with an imino group. Examples of such imino carbonyl radicals include, for example, C=NH, C=NCH 3 C=NOH, and
C=NOCH
3 The term "amidino" embraces a substituted or unsubstituted amino group bonded to one of two available bonds of an iminocarbonyl radical. Examples of such amidino radicals include, for example, NH 2 -C=NH, NH 2
-C=NCH
3
NH
2 -C=NOCH3 and CH 3 NH-C=NOH. The term "guanidino" denotes an amidino group bonded to an amino group as defined above where said amino group can be bonded to a third group. Examples of such guanidino radicals 130 WO 00/69833 WO 0069833PCTIIJSOO/OB226 include, for example, NH 2
NH
2
-C(NCH
3
NH
2
C(NOCH
3 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, 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 The term- "dialkyl sulfonium alkyl" denotes a dialkyl sulfonium group where said group is bonded to one bond of an alkylene group as defined above. Examples of such dialkylsulfoniumalkyl radicals include (CH 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 alkyl groups. Examples of such trialkyiphosphonium radicals include, for example,
(CH
3 3
P;'
Said "alkyl", "alkenyl", "alkynyl", "alkanoyl", "alkylene", "alkenylene" "hydroxyalkyl", "haloalkyl", "haloalkylene", "haloalkenyl", "alkoxy", "alkenyloxy", "a.1kenyloxyalkyl", "alkoxyalkyl", "aryl", "perhaloaryl", "haloalkoxy", "haloalkoxyalkyl", "haloalkenyloxy", "haloallkenyloxyalkyl", "6alkylenedioxy", "haloalkylenedioxy", "heterocyclyl", "heteroaryl", "hydroxyhaloalkyl", "alkylsulfonyl", "haloalkylsulfonyl", "alkylsulfonylalkyl", "haloalkylsulfonylalkyl", "alkylsulfinyl", "alkylsulfinylakyl", "haloalkylsulfinylalkyl", "aralkyl", "heteroaralkyl", "perhaloaralkyl", "aralkylsulfonyl", "aralkylsulfonylalkyl", "aralkylsulfinyl", "aralkylsulfinylalkyl", "cycloalkyl", "cycloalkylalkanoyl", "cycloalkylalkyl", "cycloalkenyl", "halocycloalkyl", "halocycloalkenyl", "cycloalkylsulfinyl", "cycloalkylsulfinylalkyl", "cycloalkylsulfonyl", "cycloalkylsulfonylalkyl" "cycloalkoxy", "cycloalkoxyalkyl "cycloalkylalkoxy", "cycloalkenyloxy", "cycloalkenyloxyalkyl "cycloalkylenedioxy", "halocycloalkoxy", "halocycloalkoxyalkyl", "halocycloalkenyloxy", "haloc ycloalkenyloxyalkyl", "alkylthio", "haloalkylthio", "alkylsulfinyl", "amnino", "6oxy"t, "thio", "alkylamino", 131 WO 00/69833 WO 0069833PCTUSOO/08226 "arylamino", "aral kylamnino", "arylsulfinyl "arylsulfinylalkyl", "arylsulfonyl", "arylsulfonylalkyl", "heteroarylsulfinyl", "heteroarylsullinylalkyl", "heteroarylsulfonyl", "heteroarylsulfonylalkyl", "heteroarylanino", "heteroarylaniinoalkyl", "heteroaryloxy", "heteroaryloxylalkyl", "aryloxy".
"aroyl", "aralkanoyl", "'aralkoxy", "aryloxyalkylI", 4"haloaryloxyalkyl", "'heteroaroyl", "heteroaralkanoyl", "heteroaralkoxy", "heteroaralkoxyalkyl", "6aryithio", "arylthioalkyl", "alkoxyalkyl", "acyl", "amidino", "guanidino'*, "dialkylsulfonium", "trialkyiphosphoniuni", and "dialkylsulfoniumalkyl" groups defined above may optionally have 1 or more non-hydrido substituents such as amidino, guanidino, dialkylsulfonium, trialkyiphosphonium, dialkylsull'oniumalkyl, perhaloaralkyl, aralkylsulfonyl, aralkylsulfonylalkyl, aralkylsulfinyl, aralkylsulfinylalkyl, halocycloalkyl, halocycloalkenyl, cycloalkylsulfinyl, cycloalkylsulfinylalkyl, cycloalkylsulfonyl, cycloalkylsulfonylalkyl, heteroarylamino, N-heteroarylanino-N-alkylamino, heteroarylaminoalkyl, heteroaryloxy, heteroaryloxylalkyl, haloalkylthio, alkanoyloxy, alkoxy, alkoxyalkyl, haloalkoxylalkyl, heteroaralkoxy, cycloalkoxy, cycloalkenyloxy, cycloalkoxyalkyl, cycloalkylalkoxy, cycloalkenyloxyalkyl, cycloalkylenedioxy, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxy, halocycloalkenyloxyal kyl, hydroxy, amino, thio, nitro, lower alkylamino, alkylthio, alkylthioalkyl, arylaniino, aralkylamrino, arylthio, arylthioalkyl, heteroaralkoxyalkyl, alkylsulfinyl, alkyl sulfinylalkyl, arylsulfinylalkyl, arylsulfonylalkyl, heteroarylsulfinylalkyl, heteroarylsulfonylalkyl, alkylsulfonyl, alkylsulfonylalkyl, haloalkylsulfinylalkyl, haloalkylsulfonylalkyl, alkylsulfonamido, alkylamninosulfonyl, amnidosulfonyl, monoalkyl amnidosulfonyl, dialkyl amidosulfonyl, monoarylamidosulfonyl, aryl sulfonamido, diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl, arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, haloalkanoyl, alkyl, alkenyl, alkynyl, alkenyloxy, alkenyloxyalky, alkylenedioxy, haloalkylenedioxy, cycloalkyl, cycloalkylalkanoyl, cycloalkenyl, lower cycloalkylalkyl, lower cycloalkenylalkyl, halo, haloalkyl, haloalkenyl, haloalkoxy, hydroxyhaloalkyl, hydroxyaralkyl, hydroxyalkyl, aminoalkyl, hydoxyheteroaralkyl, haloalkoxyalkyl, aryl, aralkyl, aryloxy, aralkoxy, aryloxyalkyl, saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl, heteroaryloxy, heteroaryloxyalkyl, arylalkyl, heteroarylalkyl, arylakenyl, heteroarylalkenyl, carboxyalkyl, carboalkoxy, WO 00/69933 WO 0069833PCTIUSOO/08226 alkoxycarbonyl, carboaralkoxy, carboxamido, carboxamidoalkyl, cyano, carbohaloalkoxy, phosphono, phosphonoalkyl, diaralkoxyphosphono, and diaralkoxyphosphonoalkyl.
The term "spacer" can include a covalent bond and a linear moiety having a backbone of 1 to 7 contiguous atoms. The spacer may have 1 to 7 atoms of a univalent or multi-valent chain. Univalent chains may be constituted 2a by a radical selected from C(R -N(R -CH(OR =C(OR and wherein R 2ais selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, aryloxyalkyl, alkoxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloaklalkyl, haloalkyl, haloalkenyl, haloalkoxyalkyl, perhaloaralkyl, heteroarylalkyl, heteroaryloxyalkyl, heteroarylthioalkyl, and heteroaryl alkenyl.
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 I 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, -O-CH 2
-S-CH
2
-CH
2
CH
2 ethenyl, 2a -CH=CH(OH)-, -OCH 2
-O(CH
2 2
-NHCH
2 -OCH(R
-O(CH
2 CHR -OCF 2
-O(CF
2 2 -S(0) 2 -N(R 2a)0-, -N(R -C(0)NRa
-OCH
2
-SCH
2
S(O)CH
2
-CH
2 -CH(OR 2a, =C(OR 2a)-I S(0) 2
CH
2 and -NR 2aCH 2 and many other radicals defined above or generally known or ascertained by one of skill-in-the art. Side chains may include substituents such as 1 or more non-hydrido substituents such as amidino,.
guanidino, dialkylsulfonium, trialkyiphosphonium, dialkylsulfoniumalkyl, perhaloaralkyl, aralkylsulfonyl, aralkylsulfonylalkyl, aralkylsulfinyl, aralkylsulfinylalkyl, halocycloalkyl, halocycloalkenyl, cycloalkylsulfinyl, cycloalkylsulfinylalkyl, cycloalkylsulfonyl, cycloalkylsulfonylalkyl, heteroarylamino, N-heteroarylamino-N-alkylamino, heteroarylaminoalkyl, heteroaryloxy, heteroaryloxylalkyl, haloalkylthio, alkanoyloxy, alkoxy, WO 00/69833 WO 0069833PCTIUSOO108226 alkoxyalkyl, hialoalkoxylalkyl., heteroaralkoxy, cycloalkoxy, cycloalkenyloxy, cycloalkoxyalkyl, cycloalkylalkoxy, cycloallcenyloxyalkyl, cycloalkylenedioxy, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxy, halocycloalkenyloxyalkyl, hydroxy, amino, thio, nitro, lower alkylamino, alkylthio, alkylthioalkyl, arylamino, aralkylamino, arylthio, arylthioalkyl, heteroaralkoxyalkyl, alkylsulfinyl, alkylsulfinylaikyl, arylsulfinylalkyl, arylsulfonylalkyl, heteroarylsullinylalkyl, heteroarylsulfonylalkyl, alkylsulfonyl, alkylsulfonylalkyl, haloalkylsulfinylalkyl, haloalkylsulfonylalkyl, alkyl sulfonamido, alkylamninosulfonyl. amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, monoarylamidosulfonyl, arylsulfonamido, diarylamidosulfonyl, rnonoalkyl monoaryl amidosulfonyl, arylsulfinyl, aiylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, haloalkanoyl, alkyl, alkenyl, alkynyl, alkenyloxy, alkenyloxyalky, alkylenedioxy, haloalkylenedioxy, cycloalkyl, cycloalkenyl, lower cycloalkylalkyl, lower cycloalkenylalkyl, halo, haloalkyl, haloalkenyl, haloalkoxy, hydroxyhaloalkyl. hydroxyaralkyl, hydroxyalkyl, amninoalkyl, hydoxyheteroaralkyl, haloalkoxyalkyl, aryl, aralkyl, aryloxy, aralkoxy, aryloxyalkyl, saturated heterocyclyl. partially saturated heterocyclyl, heteroaryl, heteroaryloxy, heteroaryloxyalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, carboxyalkyl, carboalkoxy, carboaralkoxy, carboxamido, carboxamidoalkyl, cyano, carbohaloalkoxy, phosphono, phosphonoalkyl, diaralkoxyphosphono, and diaralkoxyphosphonoalkyl.
Compounds of the present invention can exist in tautomeric, geometric or stereoisomeric forms. The present invention contemplates all such compounds,.
including cis- and trans-geometric isomers, E- and Z-geometric isomers, R- and Senantiomers, diastereomers, d-isomers, I-isomers, the racemic mixtures thereof and other mixtures thereof, as falling within the scope of the invention.
Pharmaceutically acceptable sales of such tautomeric, geometric or stereoisomeric forms are also included within the invention.
The terms "cis" and "trans" denote a form of geometric isomerism in which two carbon atoms connected by a double bond will each have a hydrogen atom on the same side of the double bond or on opposite sides of the double bond ("trans").
WO 00/69833 PCT/US00/08226 Some of the compounds described contain alkenyl groups, and are meant to include both cis and trans or and geometric forms.
Some of the compounds described contain one or more stereocenters and are meant to include R, S, and mixtures of R and S forms for each stereocenter present.
Some of the compounds described herein may contain one or more ketonic or aldehydic carbonyl groups or combinations thereof alone or as part of a heterocyclic ring system. Such carbonyl groups may exist in part or principally in the "keto" form and in part or principally as one or more "enol" forms of each aldehyde and ketone group present. Compounds of the present invention having aldehydic or ketonic carbonyl groups are meant to include both "keto" and "enol" tautomeric forms.
Some of the compounds described herein may contain one or more amide carbonyl groups or combinations thereof alone or as part of a heterocyclic ring system. Such carbonyl groups may exist in part or principally in the "keto" form and in part or principally as one or more "enol" forms of each amide group present. Compounds of the present invention having amidic carbonyl groups are meant to include both "keto" and "enol" tautomeric forms.
Said amide carbonyl groups may be both oxo and thiono in type.
Some of the compounds described herein may contain one or more imine or enamine groups or combinations thereof. Such groups may exist in part or principally in the "imine" form and in part or principally as one or more "enamine" forms of each group present. Compounds of the present invention having said imine or enamine groups are meant to include both "imine" and "enamine" tautomeric forms.
The present invention also comprises a treatment and prophylaxis in anticoagulant therapy for the treatment and prevention of a variety of thrombotic conditions including coronary artery and cerebrovascular disease in a subject, comprising administering to the subject having such disorder a therapeutically-effective amount of a compound of Formula 135 WO 00/69833 PCT/US00/08226 I 0 A N E ja
(I)
or a pharmaceutically-acceptable salt thereof.
As a further embodiment, compounds of the present invention of Formula or a pharmaceutically-acceptable salt thereof as defined above, comprise a treatment and prophylaxis of coronary artery disease, cerebrovascular disease and other coagulation cascade related disorders in a subject, comprising administering to the subject having such disorder a therapeutically-effective amount of compounds of formula of the present invention or a pharmaceutically-acceptable salt thereof.
Compounds of the present invention of Formula or a pharmaceutically-acceptable salt thereof can also be used whenever inhibition of blood coagulation is required such as to prevent coagulation of stored whole blood and to prevent coagulation in other biological samples for testing or storage. Thus coagulation inhibitors of the present inhibition can be added to or contacted with stored whole blood and any medium containing or suspected of containing plasma coagulation factors and in which it is desired that blood coagulation be inhibited, e.g. when contacting the mammal's blood with material selected from the group consisting of vascular grafts, stents, orthopedic prothesis, cardiac prosthesis, and extracorporeal circulation systems.
Compounds of Formula are capable of inhibiting activity of serine proteases related to the coagulation cascade, and thus could be used in the manufacture of a medicament, a method for the prophylactic or therapeutic treatment of diseases mediated by coagulation cascade serine proteases, such as inhibiting the formation of blood platelet aggregates, inhibiting the formation of fibrin, inhibiting thrombus formation, and inhibiting embolus formation in a mammal, in blood, in blood products, and in mammalian organs. The compounds also can be used for treating or preventing unstable angina, 136 WO 00/69833 PCT/USOO/08226 refractory angina, myocardial infarction, transient ischemic attacks, atrial fibrillation, thrombotic stroke, embolic stroke, deep vein thrombosis.
disseminated intravascular coagulation, ocular build up of fibrin, and reocclusion or restenosis of recanalized vessels in a mammal. The compounds also can be used to study the mechanism of action of coagulation cascade serine proteases to enable the design of better inhibitors and development of better assay methods. The compounds of Formula would be also useful in prevention of cerebral vascular accident (CVA) or stroke.
Also included in the family of compounds of Formula are the pharmaceutically-acceptable salts thereof. The term "pharmaceuticallyacceptable salt" embraces salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases. The nature of the salt is not critical, provided that it is pharmaceutically acceptable. Suitable pharmaceutically-acceptable acid addition salts of compounds of Formula (I) may be prepared from inorganic acid or from an organic acid. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid. Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, examples of which are formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucoronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, salicylic, p-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethylsulfonic, benzenesulfonic, sulfanilic, stearic, cyclohexylaminosulfonic, algenic, galacturonic acid. Suitable pharmaceutically-acceptable base addition salts of compounds of Formula (I) include metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from N,N'dibenzylethyleneldiamine, choline, chloroprocaine, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procain. All of these salts may be prepared by conventional means from the corresponding compound of Formula by reacting, for example, the appropriate acid or base with the compound of Formula 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 137 WO 00/69833 PCT/USOO/08226 diluent. Pharmaceutical compositions of the present invention can comprise the active compounds of Formula in association with one or more non-toxic, pharmaceutically-acceptable carriers and/or diluents and/or adjuvants (collectively referred to herein as "carrier" materials) and, if desired, other active ingredients. The active compounds of the present invention may be administered by any suitable route, preferably in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment intended.
The active compounds and composition may, for example, be administered orally, intravascularly, intraperitoneally, subcutaneously, intramuscularly, oculary, or topically. For treating ocular build up of fibrin, the compounds may be administered intraocularly or topically as well as orally or parenterally.
The compounds can be administered in the form of a depot injection or implant preparation which may be formulated in such a manner as to permit a sustained release of the active ingredient. The active ingredient can be compressed into pellets or small cylinders and implanted subcutaneously or intramusculary as depot injections or implants. Implants may employ inert materials such as biodegradable polymers or synthetic silicones, for example, Silastic, silicone rubber or other silicon containing polymers.
The compounds can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.
The compounds may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled.
The compounds may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxy-propyl-methacrylamide-phenol, polyhydroxyethyl-aspartamidephenol, or ployethyleneoxide-polylysine substituted with palmitoyl residues.
Furthermore, the compounds may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, WO 00/69833 PCT/US00/08226 polyacetals, polydihydropyrans, polycyanoacrylates and cross linked or amphitpathic block copolymers of hydrogels.
For oral administration, the pharmaceutical composition may be in the form of, for example, tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixers, tinctures, suspensions, liquids including syrups, and emulsions. The pharmaceutical composition is preferably made in the form of a dosage unit containing a particular amount of the active ingredient. Examples of such dosage units are tablets or capsules. The active ingredient may also be administered by injection as a composition wherein, for example, saline, dextrose or water may be used as a suitable carrier.
The amount of therapeutically active compounds which are administered and the dosage regimen for treating a disease condition with the compounds and/or compositions of this invention depends on a variety of factors, including the age, weight, sex and medical condition of the subject, the severity of the disease, the route and frequency of administration, and the particular compound employed, and thus may vary widely.
The pharmaceutical compositions may contain active ingredients in the range of about 0.1 to 2000 mg, and preferably in the range of about 0.5 to 500 mg. A daily dose of about 0.01 to 100 mg/kg body weight, and preferably between about 0.5 and about 20 mg/kg body weight, may be appropriate. The daily dose can be administered in one to four doses per day.
The compounds may be formulated in topical ointment or cream, or as a suppository, containing the active ingredients in a total amount of, for example, 0.075 to 30% w/w, preferably 0.2 to 20% w/w and most preferably 0.4 to w/w. When formulated in an ointment, the active ingredients may be employed with either paraffinic or a water-miscible ointment base.
Alternatively, the active ingredients may be formulated in a cream with an oil-in-water cream base. If desired, the aqueous phase of the cream base may include, for example at least 30% w/w of a polyhydric alcohol such as propylene glycol, butane-13-diol, mannitol, sorbitol, glycerol, polyethylene glycol and mixtures thereof. The topical formulation may desirably include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethylsulfoxide and related analogs. The compounds of 139 WO 00/69833 PCT/US00/08226 this invention can also be administered by a transdermal device. Preferably topical administration will be accomplished using a patch either of the reservoir and porous membrane type or of a solid matrix variety. In either case, the active agent is delivered continuously from the reservoir or microcapsules through a membrane into the active agent permeable adhesive, which is in contact with the skin or mucosa of the recipient. If the active agent is absorbed through the skin, a controlled and predetermined flow of the active agent is administered to the recipient. In the case of microcapsules, the encapsulating agent may also function as the membrane.
The oily phase of the emulsions of this invention may be constituted from known ingredients in a known manner. While the phase may comprise merely an emulsifier, it may comprise a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabilizer. It is also preferred to include both an oil and a fat. Together, the emulsifier(s) with or without stabilizer(s) make-up the so-called emulsifying wax, and the wax together with the oil and fat make up the so-called emulsifying ointment base which forms the oily dispersed phase of the cream formulations. Emulsifiers and emulsion stabilizers suitable for use in the formulation of the present invention include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate, and sodium lauryl sulfate, among others.
The choice of suitable oils or fats for the formulation is based on achieving the desired cosmetic properties, since the solubility of the active compound in most oils likely to be used in pharmaceutical emulsion formulations is very low. Thus, the cream should preferably be a non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers. Straight or branched chain, mono- or dibasic alkyl esters such as diisoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters may be used. These may be used alone or in combination depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils can be used.
For therapeutic purposes, the active compounds of the present invention are ordinarily combined with one or more adjuvants appropriate to 140 WO 00/69833 PCT/US00/08226 the indicated route of administration. If administered per os, the compounds may be admixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted or encapsulated for convenient administration. Such capsules or tablets may contain a controlled-release formulation as may be provided in a dispersion of active compound in hydroxypropylmethyl cellulose. Formulations for parenteral administration may be in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions.
These solutions and suspensions may be prepared from sterile powders or granules having one or more of the carriers or diluents mentioned for use in the formulations for oral administration. The compounds may be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, and/or various buffers. Other adjuvants and modes of administration are well and widely known in the pharmaceutical art.
In practicing the methods of the present invention for the treatment and prevention of a variety of thrombotic conditions including coronary artery and cerebrovascular disease, the compounds and pharmaceutical compositions of the present invention are administered alone or in combination with one another, or in combination with other therapeutics or in vivo diagnostic agents.
The coagulation cascade inhibitors of the present invention can also be coadministered with suitable anti-platelet agreggation agents, including, but not limited to ticlopidine or clopidrogel, fibrinogen receptor antagonists to treat or prevent unstable angina or to prevent reocculsion after angioplasty and restenosis), anti-coagulants such as aspirin, warfarin or heparins, thrombolytic agents such as plasminogen activators or streptokinase to achieve synergistic effects in the treatment of various pathologies, lipid lowering agents including antihypercholesterolemics HMG CoA reductase inhibitors such as mevastatin, lovastatin, simvastatin, pravastatin, and fluvastatin, HMG CoA synthatase inhibitors, etc.), anti-diabetic drugs, or other cardiovascular agents (loop diuretics, thiazide type diuretics, nitrates, aldosterone antagonistics spironolactone and epoxymexlerenone), angiotensin converting enzyme (e.g.
ACE) inhibitors, angiotensin II receptor antagonists, beta-blockers, WO 00/69833 PCT/US00/08226 antiarrythmics, anti-hypertension agents, and calcium channel blockers) to treat or prevent atheriosclerosis. For example, patients suffering from coronary artery disease, and patients subjected to angioplasty procedures, would benefit from coadministration of fibrinogen receptor antagonists and coagulation cascade inhibitors of the present invention. Also, coagulation cascade inhibitors could enhance the efficiency of tissue plasminogen activatormediated thrombolytic reperfusion.
Typical doses of coagulation cascade inhibitors of the present invention with other suitable anti-platelet agents, anticoagulation agents, cardiovascular therapeutic agents, or thrombolytic agents may be the same as those doses of coagulation cascade inhibitors administered without coadministration of additional anti-platelet agents, anticoagulation agents, cardiovascular therapeutic agents, or thrombolytic agents, or may be substantially less than those doses of coagulation cascade inhibitors administered without coadministration of additional anti-platelet agents, anticoagulation agents, cardiovascular therapeutic agents, or thrombolytic agents, depending on a patient's therapeutic needs.
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 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 illustrative and not limitative of the remainder of the disclosure in any way whatsoever. Compounds containing multiple variations of the structural modifications illustrated in the schemes or the following Examples are also contemplated. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds.
One skilled in the art may use these generic methods to prepare the following specific examples, which have been or may be properly characterized WO 00/69833 PCT/USOO/08226 by 'H NMR, mass spectrometry, elemental composition, and similar procedures. These compounds also may be formed in vivo.
The following examples contain detailed descriptions of the methods of preparation of compounds of Formula 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.
The following general synthetic sequences are useful in making the present invention. Abbreviations used in the schemes and tables include: "AA" represents amino acids, "AcCN" represents acetonitrile, "AcOH" represents acetic acid, "BINAP' represents 2,2'-bis(diphenylphosphino)- 1,1'-binaphthyl, "BnOH" represents benzyl alcohol, "BnCHO" represents 2-phenylethanal," BnSO 2 C" represents benzylsulfonyl chloride, "Boc" represents tertbutyloxycarbonyl, "BOP" represents benzotriazol-1-yl-oxy-tris- (dimethylamino), "bu" represents butyl, "dba" represents dibenzylideneacetone, "DCC" represents 1,3-dicyclohexylcarbodiimide, "DCM" represents dichloromethane or methylene chloride, "DIBAH" or "DIBAL" represents diisobutylaluminum hydride, "DMF" represents dimethylformamide, "DMSO" represents dimethylsulfoxide, "DPPA" represents diphenylphosphoryl azide", "EDC" represents 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride, "Ex. No." represents Example Number, "Fmoc" represents 9fluorenylmethoxycarbonyl, "HOBt" represents hydroxybenzoltriazole", "LDA" represents lithium diisopropylamide, "MW" represents molecular weight, "NMM" represents N-methylmorpholine, "Ph" represents phenyl or aryl, "PHTH" represents a phthaloyl group, "pnZ" represents 4-nitrobenzyloxycarbonyl, "PTC" represents a phase transfer catalyst "py" represents pyridine,
"RNH
2 represents a primary organic amine, "SEM" represents 2- (trimethylsilyl)ethoxy-methyl chloride, "p-TsOH" represents paratoluenesulfonic acid, "TBAF' represents tetrabutylammonium fluoride, "TBTU" represents 2-(1H-benzotriozole-1-yl)-1,1,3,3-tetramethyl uronium tetrafluoroborate, "TEA" represents triethylamine, "TFA" represents trifluoroacetic acid, "THF' represents tetrahydrofuran, "TMS" represents trimethylsilyl, "TMSCN" represents trimethylsilyl cyanide, and "Cbz" or "Z" represents benzyloxycarbonyl.
WO 00/69833 PCT/US00/08226 GENERAL SYNTHETIC PROCEDURES AND SPECIFIC
EXAMPLES
The general synthetic approach to substituted uracils pyrimidinediones) is shown in Scheme 1 below. Several N-l substituted pyrimidinediones have been previously prepared, disclosed, and are useful intermediates for the preparation of the compounds of this invention. Stirring a solution of such a N-l substituted pyrimidinedione and an a-haloacetate in dimethylsulfoxide, in the presence of potassium carbonate results in alkylation of the N-3 nitrogen. Reduction of the nitro functional group to the primary amine is easily accomplished with catalytic palladium on carbon in an atmosphere of hydrogen. The primary amine can then be reacted with a variety of raw materials including, but not limited to, acid chlorides, acid anhydrides, sulfonyl chlorides, alkyl and aromatic halides, aldehydes, and ketones. The acetate ester can then be hydrolyzed to the acid with lithium hydroxide. The acid can then be coupled with a wide range of desired amines under standard peptide coupling conditions to give an amide. The amines used in the process of this invention are typically multifunctional and are reacted in protected form. Removal of these protecting groups provides the compounds of the present invention.
WO 00/69833 WO 0069833PCTUSOO/08226 Scheme 1: General Uracil Procedure 2
K
2 C0 3 E _f
XCH
2 00 2 R 2NAy 2N 0 Step A 0Z>OR E Step B H 2 Pd/C MeOH 2 Step C 2 B-A-Cl, NMM j B-A TH,
M
\N4N or H2NN H 0 0>-ORE Step D 0 0).OR E Step E NaBH 3
CN,
LIOH
HOI
THF,
MeOH, Step
F
H
2 0 2 1. Boc-Y 0
-NH
2 T2 EDO, HOBt, DIEAI THF/DMF
B-A
H2.4 MHCI H 0~ 0 OH or TFA, PhSMe 0 N Step F
H
This general uracil pyrimidinedione) synthetic scheme is exemplified in Examples 1 and 2 below.
145 WO 00/69833 PCT/USOO/08226 Example 1 O. 2 HCI H
H
EX-1A) A solution of 1-benzyl-5-nitro-2,4(IH,3H) pyrimidinedione (6.14 g, 24.82 mmol) prepared as described by Vampa, G. and Pecorari P. Boll.
Chim. Farm. 1987, 126,467-469 was dissolved in 100mL dimethylsulfoxide and potassium dicarbonate 3.78 g, 27.34 mmol) was added in one portion with stirring. After approximately 10 minutes a solution of methyl bromoacetate (2.50 mL, 26.40 mmol) in 20 mL dimethylsulfoxide was added drop wise over a minute period. The reaction mixture was then heated to 40°C and allowed to stir for 18 hours. The reaction mixture was diluted with water (500 mL). The aqueous solution was extracted with ethyl acetate (4 x 100 mL). The combined organic solutions were washed with water (1 x 150 mL), brine (2 x 150 mL). The organic solution was dried (MgS04), filtered, and concentrated to give an oil. The crude oil was purified by MPLC (20% ethyl acetate/hexanes) to give pure 1-Benzyl-3methoxycarbonyl-methyl-5-nitro-2,4(1 H3H)pyrimidinedione (EX-1A) as a white solid in 81% yield: 'H NMR (400 MHz, CDCI 3 6 8.73 1H) 7.38-7.30 5H), 5.06 2H), 4.69 2H), 3.72 3H); HRMS (ES) calcd for
C
4 H13N 3 0 6 319.0804, found 319.0797.
EX-1B) A solution of 2,4(1H,3H) pyrimidinedione (EX-1A; 6.30 g, 19.74 mmol) in 100.0 mL methanol was degassed with hydrogen gas. The solution was then added 5% Pd/C (0.737 g) and allowed to stir under an atmosphere of hydrogen at room temperature for 24 hours. The crude reaction was filtered through a pad of Celite 545 and concentrated under reduced pressure. The oil was purified by MPLC (60% Ethyl acetate/hexanes) to give pure 5-amino-l-Benzyl-3-methoxycarbonylmethyl- 2,4(1H,3H)-pyrimidinedione (EX- IB) in 63% yield as a tan solid: 'H NMR (300 146 WO 00/69833 PCT/US00/08226 MHz, DMSO) 6 7.41-7.28 5H), 6.93 1H), 4.93 2H), 4.66 2H), 4.32 2H), 3.69 3H); HRMS (ES) calcd for C1 4
H
1 6
N
3 0 4 290.1141, found 290.1138.
EX-1C) A solution of 5-amino-l-Benzyl-3-methoxycarbonylmethyl- 2,4(1H,3H) pyrimidinedione (EX-1B; 3.12 g, 10.77 mmol) in 18.0 mL of tetrahydrofuran and dimethylformamide O.62M) was added N-methyl morpholine (3.60 mL, 32.74 mmol) in one portion at room temperature. The resulting mixture was cooled to 0°C in an ice bath and was allowed to stir for minutes. A solution of benzylsulfonyl chloride (2.26g, 11.86 mmol) in 18.0 mL tetrahydrofuran was added drop wise over a 30 minute period. After the addition was complete the reaction was stirred for 3 hours at 0°C. The reaction mixture was diluted with ethyl acetate (250.0 mL) and washed with IN HCI x 50 mL), saturated NaHCO3 (2 x 50 mL), and brine (2 x 50 mL). The organic solution was dried (MgSO 4 filtered and concentrated. Trituration with ethyl acetate and hexanes gave pure 1-Benzyl-3-methoxycarbonylmethyl-5- [[(phenylmethyl)sulfonyl]amino]-2,4( 1H3H)pyrimidinedione (EX- 1 C) in 74 yield as a white solid: 1H NMR (300 MHz, DMSO) 6 9.16 1H), 8.02 1H), 7.43-7.37 10H), 5.01 2H), 4.65 2H), 4.45 2H), 3.69 3H); HRMS (ES) calcd for C 2 1
H
22
N
3 0 6 S 444.1229, found 444.1242.
EX-1D) A suspension of 1-benzyl-3-methoxycarbonylmethyl-5- [[(phenylmethyl) sulfonyl]amino]-2,4( 1H,3H)pyrimidinedione (EX-1C; 3.28 g, 7.40 mmol) in 94.0 mL tetrahydrofuran and methanol 0.078 M) was added 30.0 mL of 0.1 M lithium hydroxide in water. The suspension quickly clears and becomes homogeneous. The reaction was stirred for 1 hour, and the volatiles were removed under reduced pressure. The remaining aqueous solution was cooled in an ice bath and acidified to a pH of 1 with 1.0 N HCI which resulted in a white precipitate forming. The precipitate was collected by filtration, washed with 1.0 N HCI and water, and dried under vacuum to give pure l-Benzyl-3-methylenesulfonyl]amino]-2,4(1H,3H)pyrimidinedione
(EX-
ID) in 99 yield: 'H NMR (300 MHz, DMSO) 6 9.14 (br s, 1H), 7.98 1H), 7.44-7.35 10H), 5.00 2H), 4.51 2H), 4.45 2H); HRMS (ES) calcd for C 20 H9N 3 0 6 S 429.0995, found 429.0981.
147 WO 00/69933 WO 0069833PCTIUSOOIO826 EX. 1 E) A solution of 1 -Benzyl-3-methylenecarboxy-5-[[(phenylmethyl sulfonyllaxnino]-2,4 1H,3H)pyrimidinedione (EX -1D; 531.6 mg, 1.238 mmol) in 12.4 rnL tetrahydrofuran and dimethylforminide 1,0. 1 M) was added NNdiisopropylethylamine 10 mL, 6.3 15 mmol), N-hydroxybenzotriazole (499.6 mg, 3.697 mxnol), and 1 -[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (717.2 mg, 3.741 mnrol). The resulting mixture was allowed to stir for 30 minutes. The reaction mixture was then added amnine (623.3 ma, 2.500 mmol) in one portion. The resulting mixture was allowed to stir over night. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with 5% citric acid (1 x 25 mL), saturated NaHCO 3 (1 x 25 mL,and brine (I x 25 mL. The organic solution was dried (MgSO 4 filtered and concentrated. The crude reaction was purified by MPLC (75%*ethyl acetate/hexanes) to give the product EX- lE: H NMR (300 MHz, DMSO) 6 9.13 (br s, I 8.77 J 5.3 Hz, I1H), 7.98 (s, 1 7.91 J 7.9 Hz, I1H), 7.45-7.35 (in, 13H), 5.01 2H), 4.56 2H), 4.56 2H), 4.44 2H), 4.38 J 5.4 Hz, 2H), 1.47 9H); HRMS (ES) calcd for C 33
H
37
N
6 0 7 S 661.2444, found 661.2448.
A flask of protected pyrimidinedione (E X- 1lE) (238.5 mg, 0361 Oiniol) was added 4.0 ml of 4 M HCl in dioxane. The resulting solution was allowed to stir overnight (approximately 18 hours). The solution was concentrated and the crude product was triturated from ethyl ether. The resulting white solid was collected by filtration, washed with ethyl ether and dried to give pure product: 'H NMR (300 MHz, DMSO) 6 9.44 2H), 9.29 2H), 9.14 1H), 9.01-8.99 (in, I1H), 7.99 1 7.81 J =7.9 Hz, 1LH), 7.51-7.37 14H), 5.01 (s, 2H), 4.57 2H), 4.45-4.41 (in, 2H), 3.58 2H); HRMS (ES) calcd for
C
28
H
29
N
6 0 5 S 561.1920, found 561.1917.
148 WO 00/69833 WO 0069833PCT/USOO/08226 Example 2 N. HN rN H 2 NO0 NH I P 3 TFA
NN
(EX -2A) A solution of 1 methyl)sulfonyl] amino]-2,4(1H,3H)pyrimidinedione (439.8 mg, 1.O24mmol) in 10.0 m.L tetrahydrofuran and dimethylformarnide 1,0. 1 M) was added N,Ndiisopropylethylamine (1.80 mL, 10.30 mmol), N-hydroxybenzotriazole (1693 mg, 1.253B mmol), and 1- [3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (238.2 mg, 1.243 mmol). The resulting mixture was allowed to stir for 10 minutes. The reaction mixture was then added ami ne (648.3 mg, 1.231 mmol) in one portion. The resulting mixture was allowed to stir over night. The reaction mixture was diluted with ethyl acetate (100 ml-) and washed with 5% citric acid (1 x 50 mL), saturated NaHCO 3 (I x 50 mL), and brine (1 x 50 mL). The Organic solution was dried (MgSO 4 filtered and concentrated. The crude reaction was purified by MPLC (75% ethyl acetate/hexanes) to give the product EX-ZA: 'H NMR (300 MHz, DMSO) 6 9.09 IRH), 8.78 J 7.1 Hz, I1H), 8.28 J Hz, lH), 8.19 J 3.0 Hz, 7.94 7.43-7.31 (in, 101-), 6.68 I1H), 5.44-5.43 (in, 1lH), 4.97 2H), 4.56 J 4.2 Hz, 2H), 4.41 (s, 2H), 3. 80 3 3.08 (br d, J 5.4 H z, 3 2.91 I1H), 2.75 1 2.59 3H), 2.52 3H), 2.06 3H), 1.92-1.80 (in, 1H), 1.61-1.51 (in, 3H), 1.37-1.33 (m lH); HRMS (ES) calcd for C 39
H
45
N
8 0 9
S
3 865.2472, found 865.2484.
A solution of EX-2A (281.3 mng, 03252 mmol) in 3.0 mL trifluoroacetic acid 1 M) was added thioanisole 115 mL, 0.9796 minol) at room temperature with stirring. The resulting mixture was allowed to stir 6 hours. The reaction mixture was concentrated under reduced pressure. The crude product was purified WO 00/69833 WO 0069833PCTIUSOO/08226 by trituration from ethyl ether. A light yellow powder was collected by filtration.
washed with ethyl ether to give pure product 2: 1HNMR (300 MHz, DMSO) 6 9.07 I 8.82 J 7.0 Hz, I 8.30 J 3.0 Hz, 1H), 8.21 J1= Hz, 1H), 7.95 1H), 7.55-7.20 (in, 10H), 5.49-5.48 (in, 1H), 4.97 (s, 2H), 4.63-4.51 (mn, 2H), 4.42 2H), 3.13 (br d, J 6.0 Hz, 2H), 2.49 3H), 1.91 (br s, 1H), 1.67-1.58 (in, 4H); LRMS 653.2.
Using the procedures exemplified in Examples 1 and 2 and the attached Scheme 1, the following compounds can be prepared.
Example 3 N O HCI N, HCIl H
NH
2
NH
Following Steps A and B exemplified in Example 1 and replacing benzyl bromide with 3-(N-Boc-an-ino)benzyl bromide (Murakami, Hagishita, S.; Okada, Kii Hashizumne, Yagami, Fujimoto, Bioorg. Med.
Chem. 1999, 7, 1703-1714.), alkylated intermediate, methyl 3-[1-[3-(N-Bocaniino)benzyl]-5-amino-2,4-dioxopyrim-idinyl]acetate (EX-3A) can be prepared.
To a solution of 1 eq. of ester E X -3A and 1 eq. of cyclobutanone in tetrahydrofuran is added 1 eq. of sodium cyanoborohydride, and the mixture is stirred for several hours. The. solvent is evaporated off to afford the crude product.
The crude product is purified by silica gel chromnatagraphy to afford purified methyl 3-(N-Boc-anino)benzyl]--5-(N-cyclobutyl)amino-2,4-dioxopyrirniidinyl]Jacetate (EX-3B).
Following the remaining procedure exemplified in Example 1, the indicated compound of Example 3 can be obtained.
150 WO 00/69833 PCT/USOO/08226 Example 4
NNH
2
~HCI
N O HCI ii HCI O V
NNH
H NH2
NH
A solution of 1 eq. of the appropriate amide and 1 eq. of 3nitropnenylisocyanate in DMF is heated to 100"C for several hours. The solvent is evaporated off to afford the crude product. The crude product is purified by silica gel chromatagraphy to afford purified product 1-[3-Nitrophenyl]-5-nitro-2,4dioxopyrimidine (EX-4A) A solution of 1 eq. of uracil EX-4A in dimethylsulfoxide is added to 1.1 eq. of potassium dicarbonate in one portion with stirring. After approximately 10 minutes a solution containing 1.1 eq. of methyl bromoacetate in dimethylsulfoxide is added dropwise over a 10 minute period. The reaction mixture is heated to 40 0 C and allowed to stir for 18 hours. The reaction mixture is diluted with water. The aqueous solution is extracted with ethyl acetate and the combined organic solution is washed with water and brine. The organic solution is dried over MgSO 4 filtered, and concentrated to give a crude product. The crude product is purified by silica gel chromatagraphy to afford purified methyl 3 -nitrophenyl]-5-nitro-2,4-dioxopyrimidinyl]]acetate (EX-4B).
A suspension of methyl ester EX-4B in tetrahydrofuran and methanol is added excess lithium hydroxide in water. The reaction is stirred for 1 hour, and the volatiles are removed under reduced pressure. The remaining aqueous solution is cooled in an ice bath and acidified to a pH of 1 with 1.0 N HCI which results in a white precipitate forming. The precipitate is collected by filtration, washed with 1.0 N HCI and water, and dried under vacuum to give pure acid, 3 -nitrophenyl]-5-nitro-2,4-dioxopyrimidinyl]]acetic acid (EX-4C).
151 WO 00/69833 PCT/USOO/08226 A solution of acid EX-4C in dimethylformamide 0.1 M) is added to eq N,N-diisopropylethylamine 1 eq N-hydroxybenzotriazole mmol), and 1 eq 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride. The resulting mixture is allowed to stir for 30 minutes. To the reaction mixture is then added 1 eq. of 4-(N-Boc-amidino)benzylamine in one portion. The resulting mixture is allowed to stir over night. The reaction mixture is diluted with ethyl acetate and washed with 5% citric acid, saturated NaHCO 3 and brine. The organic solution is dried (MgSO 4 filtered and concentrated.
Purification by MPLC pure, N-[4-(N-Boc-amidinobenzyl)]-2-[3-[1-[3nitrophenyl]-5-nitro-2,4-dioxopyrimidinyl]]acetamide (EX-4D).
A solution of bis-nitro compound EX-4D in methanol is treated with molar percent of 10% Pd/C under an atmosphere of hydrogen (balloon pressure). The suspension is allowed to stir over night. Filtration through Celite 545 followed by removal of the solvent affords pure, N-[4-(N-Bocamidinobenzyl)]-2-[3-[ -[3-aminophenyl]-5-amino-2,4dioxopyrimidinyl]]acetamide (EX-4E).
A solution of bis-amine EX-4E and 1 eq. of cyclobutanone in tetrahydrofuran is treated with 1 eq of sodium cyanoborohydride followed by a catalytic amount of hydrochloric acid. The reaction mixture is allowed to stir at room temperature for several hour. The reaction is quenched with the cautious addition of water. The aqueous solution is extracted with ethyl acetate. The organic solutions are washed with water and brine. The organic solution is dried (MgSO,), filtered and concentrated. Purifaction by MPLC affords pure, N-[4-(N-Boc-amidinobenzyl)]-2-[3-[1-[3-aminophenyl]-5-(N-cyclobutylamino)-2,4-dioxopyrimidinyl]]acetamide (EX-4F).
A solution of N-Boc amidine EX-4F in methanol is treated with 3 eq of 4 M HCI in dioxane. The solution is stirred for five hours. Removal of the solvents under vacuum followed by trituration with ethyl ether affords pure product.
A wide variety of methylene analogs of pyrimidinediones wherein a methylene is present as a replacement for the carbonyl of the acetamide at the N-2 position of the pyrimidinedione can be prepared using the procedure detailed below WO 00/69833 PCT/US00/08226 Example NO 2 HCI H 12 H Y NH
NH
2 A solution of 1 eq. of phenyl isocyanate and 1 eq. of 3-ethoxy-2nitro-propenamide in DMF is heated to 100 0 C for several hours. The solvent is evaporated off to afford the crude product. The crude product is purified by silica gel chromatagraphy to afford purified product To a solution of 1 eq. of EX-5A in dimethylsulfoxide is added to 1.1 eq. of potassium dicarbonate in one portion with stirring. After approximately 10 minutes, a solution containing 1.1 eq. of methyl bromoacetate in dimethylsulfoxide is added dropwise over a 10 minute period. The reaction mixture is heated to 40°C and allowed to stir for 18 hours. The reaction mixture is diluted with water. The aqueous solution is extracted with ethyl acetate and the combined organic solution is washed with water and brine. The organic solution is dried over MgSO 4 filtered, and concentrated to give a crude product. The crude product is purified by silica gel chromatagraphy to afford purified product methyl 2-[3-[5-nitro-2,4-dixoxo-1-phenylpyrimidyl]acetate (EX-SB).
Diisobutylaluminum hydride (1.05 equiv.) is added over a period of 15 min to a cooled solution -78 °C of 1 eq. of EX-5B in tetrahydrofuran After stirring for 1 h at -78 the reaction is slowly quenched at -78 °C with cold methanol. The mixture is slowly poured into ice-cold IN HCI, and the aqueous mixture is extracted with ethyl acetate. The combined organic layers are washed with brine, dried with MgSO 4 filtered, and the solvents are removed under reduced pressure. The crude product is purified by column chromatography to afford purified aldehyde product EX-5D) A suspension of 1.0 eq. of the aldehyde, 2-[3-[5-nitro-2,4dixoxo-l-phenylpyrimidyl]]ethanal (EX-5C) and 1.0 eq. of the amine, 4-(N-Boc- 153 WO 00/69833 PCT/USOO/08226 amidino)benzylamine in dichloromethane, and catalytic acetic acid is added 1.2 eq.
of sodium triacetoxyborohydride. The suspension quickly clears and becomes homogeneous. The reaction is stirred for several hours. The solution is cooled in an ice bath and is made alkaline with 1.0 N NaOH. The reaction mixture is diluted with dichloromethane and washed with brine. The organic solution is dried (MgSO 4 filtered and concentrated to give the crude product. The crude product is purified by silica gel chromatagraphy to afford purified product Boc-amidino)benzyl)amino]ethyl-5-nitro-2,4-dioxo- 1-phenylpyrimidine (EX-
SD):
EX-5E) A solution of 1 eq. of EX-SD in methanol is degassed with hydrogen gas. To the solution is added a catalytic amount of 5% Pd/C, and the reaction mixture is allowed to stir under an atmosphere of hydrogen at room temperature for 24 hours. The crude reaction is filtered through a pad of Celite 545 and concentrated under reduced pressure. The crude product is purified by silica gel chromatagraphy to afford purified product amine, amidino)benzyl)amino]ethyl-5-amino-2,4-dioxo- 1-phenylpyrimidine (EX-SE).
To a suspension of 1.0 eq. of EX-SE and 1.0 eq. of the phenylacetaldehyde in dichloromethane and catalytic acetic acid is added 1.2 eq. of sodium triacetoxyborohydride. The suspension quickly clears and becomes homogeneous. The reaction is stirred for several hours. The solution is cooled in an ice bath and basified with 1.0 N NaOH. The reaction mixture is diluted with dichloromethane and washed with brine. The organic solution is dried (MgSO 4 filtered and concentrated to give the crude product. The crude product is purified by silica gel chromatagraphy to afford purified amidino)benzyl)amino]ethyl-5-(N-(2-phenylethyl)amino)-2,4-dioxo-1phenylpyrimidine To a flask of 1 eq. of EX-5F is added 4 M HCI in dioxane. The resulting solution is allowed to stir overnight. The solution is concentrated and the crude product is triturated from ethyl ether to afford purified product as the dihydrochloride salt.
Sulfonyl analogs of pyrimidinediones wherein a sulfonyl is present as a replacement for the carbonyl of the acetamide at the N-2 position of the pyrimidinedione can be prepared as detailed below in the specific Example 6.
WO 00/69833 PCT/US00/08226 Example 6 N
NO
o 0 O2NH li^ NH 2
NH
EX-6A) A solution of 1 eq. of EX-5A in dimethylsulfoxide is added to 1.1 eq. of potassium dicarbonate in one portion with stirring. After approximately 10 minutes, a solution containing 1.1 eq. of sodium bromomethylsulfonate in dimethylsulfoxide is added dropwise over a 10 minute period. The reaction mixture is heated to 40°C and allowed to stir for 18 hours. The reaction mixture is diluted with water. The aqueous solution is extracted with ethyl acetate. The combined organic solutions are washed with water and brine. The organic solution is dried over MgSO 4 filtered, and concentrated to give a crude product. The crude product is purified by silica gel chromatagraphy to afford purified product, nitro-2,4-dixoxo-l-phenylpyrimidyl]methanesulfonic acid (EX.6A).
EX-6B) A solution of 1 eq. of EX-6A in methanol is degassed with hydrogen gas. To the solution is added a catalytic amount of 5% Pd/C, and the reaction mixture is allowed to stir under an atmosphere of hydrogen at room temperature for 24 hours. The crude reaction is filtered through a pad of Celite 545 and concentrated under reduced pressure. The crude product is purified by silica gel chromatagraphy to afford purified product, 3-[5-amino-2,4-dixoxo-1phenylpyrimidyl]methanesulfonic acid (EX-6B).
EX-6C) To a suspension of 1.0 eq. of EX-6B and 1.0 eq. of the phenylacetaldehyde in dichloromethane and catalytic acetic acid is added 1.2 eq. of sodium triacetoxyborohydride. The reaction is stirred for several hours. The solution is cooled in an ice bath and basified with 1.0 N NaOH. The reaction mixture is diluted with dichloromethane and washed with brine. The organic WO 00/69833 PCT/US00/08226 solution is dried (MgSO 4 filtered and concentrated to give the crude product. The crude product is purified by silica gel chromatagraphy to afford purified product, 3- [5-[N-(2-phenylethyl)amino]-2,4-dixoxo-1 -phenylpyrimidyl]methanesulfonic acid (EX-6C).
EX-6D) A solution of 1 eq. of EX-6C in dichloromethane with several drops of dimethylformamide is cooled to 0 oC. Thionyl chloride (1.1 equiv.) is added dropwise, and the solution is slowly warmed to room temperature. After completion of the reaction, the volatile components are removed under reduced pressure, and the sulfonyl chloride product is immediately used. The sulfonyl chloride is dissolved into dichloromethane, and 1 eq. of the appropriate amine, 4- (N-Boc-amidino)benzylamine, in DMF is added with 5 eq. of N-methylmorpholine to the sulfonyl chloride solution. After completion of the reaction, polyaldehyde and/or polyamine resin (10 equiv.) are added to remove any unreacted starting materials. The resins are filtered, rinsed with DMF/DCM and the solvents are removed under reduced pressure to give pure N-[4-(N-Boc-amidino)benzyl]-3- [5-[N-(2-phenylethyl)amino]-2,4-dixoxo-l-phenylpyrimidyl]methanesulfonamide (EX-6D).
A flask of 1 eq. of EX-6D is added to 4 M HCI in dioxane. The resulting solution is allowed to stir overnight. The solution is concentrated and the crude product was triturated from ethyl ether to afford purified product of Example 6.
Triazinedione (aza analogs) of uracils (i.e.,pyrimidinones) wherein a nitrogen is present as a replacement for the carbon at the 5-position of the pyrimidinedione can be prepared as detailed below with the specific Example 7.
Example 7 N N 0H NH2 WO 00/69833 PCT/USOO/08226 EX-7A) A mixture of aniline 50 mmol), concentrated HCI (10 mL), and water (50 mL) is cooled to 5 OC. Separately, a solution of sodium nitrite mmol) in water (7.2 mL) is cooled to 5 OC and added to the aniline hydrochloride slurry with the addition tube beneath the liquid surface. The temperature is maintained at 5 °C during the addition and for 1 hour thereafter. This solution of diazotized aniline (EX-7A) is used in the next step.
EX-7B) A mixture of cyanoacetylurethane (59 mmol), pyridine (656 mL), ice (216 g) and water (40 mL) is held at 5 °C while the slurry of EX-67A is added over 15 min with stirring. After an additional hour of stirring at 5 OC, the orange solid, N-ethoxycarbonyl-2-cyano-2-(N-phenylhydrazo)acetamide (EX-7B is isolated by filtration.
EX-7C) A mixture of EX-7B (95 mmol), sodium acetate (110 mmol) and acetic acid (140 mL) is refluxed for 75 min. The. resulting clear solution is concentrated at reduced pressure, and the solid that separates is removed by filtration and washed with water. Compound, 6-cyano-2-phenyl-3,5-dioxo-1,2,4triazine (EX-7C), is recrystallized from 95% ethanol.
EX-7D) A mixture of compound EX-7C (50 mmol), 6 N HCI (190 mL) and dioxane (500 mL) is refluxed for 12 h. On cooling the crystallized product, 6- (2-phenyl-3,5-dioxo-1,2,4-triazinyl)carboxylic acid (EX-7D) is separated by filtration and recrystallized from methanol-water.
EX-7E) The acid EX-7D (8.4 mmol) is dissolved in dry tert-butyl alcohol (127 mL) and DPPA (9.3 mmol), and triethyl amine (9.3 mmol) is added. The solution is refluxed for 24h thereafter. At this time the solution is concentrated in vacuo. The residue is dissolved in methylene chloride (150 mL) and washed with 0.5 N citric acid (150 mL), 1 N NaHCO 3 (150 mL) and water (150 mL). The methylene chloride solution is then dried (sodium sulfate). Filtration and concentration gives the Boc-protected compound EX-7E. This material can be purified by chromatography if necessary.
EX-7F) A solution of compound EX-7E (50 mmol) in DMF (150 mL) is treated with potassium carbonate (55 mmol) in one portion with stirring. After approximately 10 min, a solution of methyl bromoacetate (50 mmol) in DMF (100 mL) is added dropwise. The reaction mixture is heated to 40 °C and allowed to stir for 18 h. Typical aqueous workup and chromatographic purification provides pure methyl 2-(2-phenyl-3,5-dioxo-6-(N-Boc-amino)- 1,2,4-triazinyl)acetate (EX-7F).
WO 00/69833 PCT/USOO/08226 EX-7G) A solution of compound EX-7F (50 mmol) is dissolved in methylene chloride (400 mL) and is treated with TFA (100 mL). The resulting solution is stirred at room temperature for 4 h thereafter. Concentration and trituration with ether affords TFA salt of methyl 2-(2-phenyl-3,5-dioxo-6-amino- 1,2,4-triazinyl)acetate (EX-7G).
EX-7H) A solution of compound EX-7G in tetrahydrofuran and methylene chloride 0.3 M) is treated with 1 eq. of phenylacetaldehyde and 0.9 eq. of triethyl amine. The solution will be cooled to 0 OC and treated with 1 eq. of sodium triacetoxyborohydride. After stirring for 5 minutes, the ice bath is removed, and the reaction mixture is allowed to warm to room temperature and stir there for 2 h. The reaction is quenched by the addition of I N NaOH, and the mixture is stirred for 5 min. Typical aqueous workup is followed by chromatographic purification to provide pure product, methyl 2-(2-phenyl-3,5dioxo-6-(N-(2-phenylethyl)amino)- 1,2,4-triazinyl)acetate (EX- 7H).
EX-71) A solution of compound EX-7H (50 mmol) in THF (250 mL) is treated with LOH (50 mmol). After the hydrolysis is complete, the volatiles are removed under reduced pressure. The remaining aqueous solution is cooled in an ice bath and acidified to pH 1 with 1.0 N HCI. The aqueous mixture is extracted with EtOAc. The EtOAc solution is dried (sodium sulfate), filtered and concentrated to afford pure 2-(2-phenyl-3,5-dioxo-6-(N-(2-phenylethyl)amino)- 1,2,4-triazinyl)acetic acid EX-71).
EX-7J) A solution of compound EX-71 (50 mmol) in DMF (250 mL) is treated with N-hydroxybenzotriazole (60 mmol) and EDC hydrochloride mmol). The mixture is stirred at room temperature for 30 min and treated with 4- (N-Cbz-amidinobenxylamine (50 mmol). The resulting mixture is allowed to stir overnight. Typical aqueous workup is followed by chromatographic purification to afford pure product, N-(4-Cbz-amidinobenzyl)-2-(2-phenyl-3,5-dioxo-6-(N-(2phenylethyl)amino)-1,2,4-triazinyl)acetamide (EX-7J).
A solution of compound EX-7J (50 mmol) in methanol (300 mL) and 4M HCl-dioxane (100 mL) is degassed with hydrogen. 5% Pd(C) (0.5 g) is added, and the solution is stirred under an atmosphere of hydrogen at room temp for 24 h.
The reaction mixture is filtered through a pad of celite 545 and concentrated under reduced pressure. Purification by reverse phase chromatography affords pure product of Example 7.
158 WO 00/69833 PCTIUS00/08226 Using these methods and ordinary skill in the art of synthetic numerous novel compounds of the present invention have been or can be prepared.
Formula compounds of this invention possessing hydroxyl, thiol, and amine functional groups can be converted to a wide variety derivatives.
Alternatively, derivatized Formula compounds can be obtained by first derivatizing one or more intermediates in the processes of preparation before further transforming the derivatized intermediate to comounds of Formula A hydroxyl group in the form of an alcohol or phenol can be readily converted to esters of carboxylic, sulfonic, carbamic, phosphonic, and phosphoric acids.
Acylation to form a carboxylic acid ester is readily effected using a suitable acylating reagent such as an aliphatic acid anhydride or acid chloride. The corresponding aryl and heteroaryl acid anhydrides and acid chlorides can also be used. Such reactions are generally carried out using an amine catalyst such as pyridine in an inert solvent. Similarly, carbamic acid esters (urethanes) can be obtained by reacting a hydroxyl group with isocyanates and carbamoyl chlorides.
Sulfonate, phosphonate, and phosphate esters can be prepared using the corresponding acid chloride and similar reagents. Compounds of Formula 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 that have at least one primary or secondary amine group present can be converted to the corresponding amide derivatives. Amides of carboxylic acids can be prepared using the appropriate acid chloride or anhydrides with reaction conditions analogous to those used with alcohols and phenols. Ureas of the corresponding primary or secondary amine can be prepared using isocyanates directly and carbamoyl chlorides in the presence of an acid scavenger such as triethylamine or pyridine. Sulfonamides can be prepared from the corresponding sulfonyl chloride in the presence of aqueous sodium hydroxide or a tertiary amine. Suitable procedures and methods for preparing these derivatives can be found in House's Modem Synthetic Reactions, W. A. Benjamin, Inc., Shriner, Fuson, and Curtin in The Systematic Identification of Organic Compounds, 5th Edition, John Wiley Sons, and Fieser and Fieser in Reagents for Organic Synthesis, Volume 1, John Wiley Sons. Reagents of a wide variety that can be used to derivatize hydroxyl, thiol, and amines of compounds of Formula are available from commercial sources or the references cited above, which are incorporated herein by reference.
159 WO 00/69833 PCT/USOO/08226 Formula compounds of this invention possessing hydroxyl, thiol, and amine functional groups can be alkylated to a wide variety of derivatives.
Alternatively, alkylated Formula 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 A hydroxyl group of compounds of Formula can be readily converted to ethers. Alkylation to form an ether is readily effected using a suitable alkylating reagent such as an alkyl bromide, alkyl iodide or alkyl sulfonate. The corresponding aralkyl, heteroaralkyl, alkoxyalkyl, aralkyloxyalkyl, and heteroaralkyloxyalkyl bromides, iodides, and sulfonates can also be used. Such reactions are generally carried out using an alkoxide forming reagent such as sodium hydride, potassium t-butoxide, sodium amide, lithium amide, and n-butyl lithium using an inert polar solvent such as DMF, DMSO, THF, and similar, comparable solvents, amine catalyst such as pyridine in an inert solvent. Compounds of Formula that have at least one thiol group present can be converted to the corresponding thioether derivatives analogous to those of alcohols and phenols using the same reagents and comparable reaction conditions. Compounds of Formula 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, 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 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.
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 monoprotecting the amine with a ready cleaved protecting group, such as trifluoroacetyl.
An alkylating agent, such as dimethylsulfate, in the presence of a non-nucleophilic base, such as Barton's base (2-ert-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 WO 00/69833 PCT/US00/08226 Modem Synthetic Reactions, W. A. Benjamin, Inc., Shriner, Fuson, and Curtin in The Systematic Identification of Organic Compounds, 5th Edition, John Wiley Sons, and Fieser and Fieser in Reagents for Organic Synthesis published by John Wiley Sons. Perfluoroalkyl derivatives can be prepared as described by DesMarteau in J. Chem. Soc. Chem. Commun. 2241 (1998). Reagents of a wide variety that can be used to derivatize hydroxyl, thiol, and amines of compounds of Formula are available from commercial sources or the references cited above, which are incorporated herein by reference.
Assays for Biological Activity TF-VIIa Assay In this assay 100 nM recombinant soluble tissue factor and 2nM recombinant human factor Vlla 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 CaCI,,50 mM Tris-HC1, pH 8.0, 100 mM NaCI, 0.1% BSA). The reaction, in a final volume of 100 ul is measured immediately at 405 nm to determine background absorbance. The plate is incubated at room temperature for 60 min, at which time the rate of hydrolysis of the substrate is measured by monitoring the reaction at 405 nm for the release of p-nitroaniline.
Percent inhibition of TF-VIIa activity is calculated from OD4,,, value from the 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-HC1, pH 8.0, 100 mM NaCI, 0.1% BSA). The reaction, in a final volume of 100 ul is measured immediately at 405 nm to determine background absorbance. The plate is incubated at room temperature for 60 min, at which time the rate of hydrolysis of the substrate is measured by monitoring the reaction at 405 nm for the release of pnitroaniline. Percent inhibition of Xa activity is calculated from OD4,, value from the experimental and control sample.
WO 00/69833 PCT/USOO/08226 Thrombin Assay 0.28 nM human thrombin and 0.06 mM H-D-Phenylalanyl-L-pipecolyl-Larginine-p-nitroaniline dihydrochloride are added to a 96-well assay plate containing either inhibitor or buffer (50 mM Tris-HC1, pH 8.0, 100 mM NaCI, 0.1% BSA). The reaction, in a final volume of 100 ul is measured immediately at 405 nm to determine background absorbance. The plate is incubated at room temperature for 60 min, at which time the rate of hydrolysis of the substrate is measured by monitoring the reaction at 405 nm for the release of p-nitroaniline.
Percent inhibition of thrombin activity is calculated from OD4,5n value from the experimental and control sample.
Trypsin Assay 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 NaCI, 0.1% BSA). The reactions, in a final volume of 100 ul are measured immediately at 405 nm to determine background absorbance. The plate is incubated at room temperature for 60 min, at which time the rate of hydrolysis of the substrate is measured by monitoring the reaction at 405 nm for the release of p-nitroaniline.
Percent inhibition of trypsin activity is calculated from OD4s,, value from the experimental and control sample.
Recombinant soluble TF, consisting of amino acids 1-219 of the mature protein sequence was expressed in E. coli and purified using a Mono Q Sepharose FPLC. Recombinant human Vila was purchased from American Diagnostica, Greenwich CT and chromogenic substrate N-Methylsulfonyl-Dphe-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.
The biological activity of the compounds of Examples 1 through 7 as determined by the bioassay procedures is summarized in the Table 1.
Table 1. Inhibitory Activity of Uracils toward Factor Xa, TF-VIIA, Thrombin
II,
and Trypsin II.
Example TF-VIIA Thrombin II Factor Xa Trpysin
II
Number IC50 (uM) IC50 (uM) IC50 (uM) IC50 (uM) 1 >100 13.0 25.6 0.4 2 12.9 0.3 0.2 0.2 With reference to the use of the word(s) "comprise" or "comprises" or "comprising" in the foregoing description and/or in the following claims, unless the context requires otherwise, those words are used on the basis and clear understanding that they are to be interpreted inclusively, rather than exclusively, and that each of those words is to be so interpreted in construing'the foregoing description and/or the following claims.
*o*o 163

Claims (31)

1. A compound having the Formula: R 2 N MN 0 A I H/A H O or a pharmaceutically acceptable salt thereof, wherein; B is selected from the group consisting of aryl and heteroaryl wherein a ring carbon in a first alpha position relative to the ring carbon at the point of attachment is optionally substituted by R 32 a ring carbon in a second alpha position relative to the ring carbon at the point of attachment is optionally substituted by R 36 a ring carbon, in a first beta position relative to the ring carbon at the point of attachment and in an alpha position relative to the ring atom optionally substituted by R 32 is optionally substituted by R 33 a ring carbon, in a second beta position relative to the ring carbon at the point of attachment and in an alpha position relative to the ring atom optionally substituted by R 36 is optionally substituted by R 3 and a ring carbon, if present, in the gamma position relative to the ring carbon at the point of attachment and in an alpha position relative to each of the ring atoms optionally substituted by R 33 and R 3 5 respectively, is optionally substituted by R 34 R 32 R 33 R 3 4 R 35 and R 3 are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, alkylthio, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboalkoxy, carboxy, carboxamido, cyano, and Qb; i A is selected from the group consisting of single covalent bond and (CH(R 5 ))pa- (W 7 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 R 7 is selected from the group consisting of hydrido, hydroxy and alkyl; R' 7 is selected from the group consisting of hydrido, halo, alkyl, and haloalkyl; S* M is selected from the group consisting of N and R'-C; *i 165 R 1 is selected from the group consisting of hydrido, hydroxy, hydroxyamino, amidino, amino, cyano, hydroxyalkyl, alkoxy, alkyl, alkylamino, aminoalkyl, alkylthio, alkoxyamino, haloalkyl, haloalkoxy, and halo; R 2 is ZOQ; Z 0 is selected from the group consisting of a covalent single bond, 0, S, NH, and CH 2 Q is selected from the group consisting of aryl and heteroaryl wherein a ring carbon in a first alpha position relative to the ring carbon at the point of attachment is optionally substituted by R 9 a ring carbon in a second alpha position relative to the ring carbon at the point of attachment is optionally substituted by R 1 3 a ring carbon, in a first beta position relative to the ring carbon at the point of attachment and in an alpha position relative to the ring atom optionally substituted by R 9 is optionally substituted by R 10 a ring carbon, in a second beta position relative to the ring carbon at the point of attachment and in an alpha position relative to the ring atom optionally substituted by R 13 is optionally substituted by R 12 and a ring carbon, if present, in the gamma position relative to the ring carbon at the point of attachment and in an alpha position relative to each of the ring atoms optionally substituted by R'O and R 1 2 respectively, is optionally substituted by R"; R 9 and R 1 3 are independently selected from the group consisting of hydrido, hydroxy, amino, amidino, guanidino, lower alkylamino, alkylthio, alkylsulfonamido, alkylsulfinyl, alkylsulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboxy, carboxamido, and cyano; R'o and R' 2 are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkyl, alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, alkylsulfonamido, amidosulfonyl, monoalkyl i amidosulfonyl, dialkyl amidosulfonyl, hydroxyalkyl, aminoalkyl, carboalkoxy, carboxy, carboxyalkyl, amidocarbonyl, halo, haloalkyl, and cyano; Yo is formula (IV): (IV) wherein D 5 D 6 J 5 and J 6 are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more than one is a covalent bond, no more than one of D 5 D 6 J 5 and J 6 is O, no more than one of D 5 D 6 J 5 and J 6 is S, one of D 5 D 6 J 5 and J 6 must be a covalent bond when two of D 5 D 6 J 5 and J 6 are O and S, and no more than four of D 5 J 5 and J 6 are N; R 1 6 R 17 R 1 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, alkanoyl, haloalkanoyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, and cyano; Qb is selected from the group consisting of NR 2 0 R 21 hydrido, and C(NR 25 )NRR 24 with the provisos that no more than one of R 20 and R 21 is hydroxy and that no more than one of R 2 3 and R 2 4 is hydroxy; R 20 R 2 1 R 23 R 24 and R 25 are independently selected from the group consisting of hydrido, alkyl, and hydroxy; and i" Q' is selected from the group consisting of a single covalent bond, CH 2 and CH 2 CH 2
2. The compound as recited in claim 1, or a pharmaceutically acceptable i* salt thereof, wherein; B is selected from the group consisting of phenyl and 2-thienyl, 3-thienyl, 2- furyl, 3-furyl, 2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl, 4-imidazolyl, 3-pyrazolyl, 4-pyrazolyl, V* 2-thiazolyl, 3-isoxazolyl, 5-isoxazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrazinyl, 2- o 167 pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, and 1,3,5- triazin-2-yl heteroaryl rings, wherein a ring carbon in a first alpha position relative to the ring carbon at the point of attachment is optionally substituted by R 32 a ring carbon in a second alpha position relative to the ring carbon at the point of attachment is optionally substituted by R 3 a ring carbon, in a first beta position relative to the ring carbon at the point of attachment and in an alpha position relative to the ring atom optionally substituted by R 32 is optionally substituted by R 33 a ring carbon, in a second beta position relative.to the ring carbon at the point of attachment and in an alpha position relative to the ring atom optionally substituted by R 3 8 is optionally substituted by R 3 5 and a ring carbon, if present, in the gamma position relative to the ring carbon at the point of attachment and in an alpha position relative to each of the ring atoms optionally substituted by R 33 and R 35 respectively, is optionally substituted by R4; R 32 R 3 R, 35 and R 3 are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, methoxyamino, ethoxyamino, acetamido, trifluoroacetamido, N-methylamino, dimethylamino, N-ethylamino, methylthio, ethylthio, isopropylthio, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, 2,2,3,3,3-pentafluoropropyl, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro, bromo, amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro-1-hydroxyethyl, methoxycarbonyl, ethoxycarbonyl, amidocarbonyl, N-methylamidocarbonyl, N,N- dimethylamidocarbonyl, cyano, and Qb; A is selected from the group consisting of single covalent bond, NH, N(CH 3 N(OH), CH 2 CH 3 CH, CF 3 CH, NHC(O), N(CH 3 C(O)NH, C(O)N(CH 3 CH 2 CH 2 CH 2 CH 2 CH 2 CH 3 CHCH 2 and CF 3 CHCH 2 M is selected from the group consisting of N and R'-C; R 1 is selected from the group consisting of hydrido, hydroxy, amino, amidino, hydroxyamino, aminomethyl, 1-aminoethyl, methylamino, dimethylamino, cyano, methyl, ethyl, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, methoxy, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, methoxyamino, methylthio, ethylthio, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro, and bromo; R 2 is ZO_Q; Z is selected from the group consisting of a covalent single bond, 0, S, NH, and CH 2 Q is selected from the group consisting of phenyl and 2-thienyl, 3-thienyl, 2- furyl, 3-furyl, 2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl, 4-imidazolyl, 3-pyrazolyl, 4-pyrazolyl, 2-thiazolyl, 3-isoxazolyl, 5-isoxazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrazinyl, 2- pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, and 1,3,5- triazin-2-yl heteroaryl rings, wherein a ring carbon in a first alpha position relative to. the ring carbon at the point of attachment is optionally substituted by R 9 a ring carbon in a second alpha position relative to the ring carbon at the point of attachment is optionally substituted by R' 3 a ring carbon, in a first beta position relative to the ring carbon at the point of attachment and in an alpha position relative to the ring atom optionally substituted by R 9 is optionally substituted by R"o, a ring carbon, in a second beta position relative to the ring carbon at the point of attachment and in an alpha position relative to the ring atom optionally substituted by R 13 is optionally substituted by and a ring carbon, if present, in the gamma position relative to the ring carbon at the point of attachment and in an alpha position relative to each of the ring atoms optionally substituted by R'O and R 12 respectively, is optionally substituted by R"; R 9 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, 2,2,3,3,3-pentafluoropropyl, trifluoromethoxy, 1,1,2,2- tetrafluoroethoxy, fluoro, chloro, bromo, methanesulfonamido, amidosulfonyl, N- methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, 2- hydroxyethyl, 2,2,2-trifluoro-1 -hydroxyethyl, amidocarbonyl, N-methylamidocarbonyl, N,N-dimethylamidocarbonyl, and cyano; 169 R" 0 and R" 2 are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, carboxymethyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, methoxyamino, ethoxyamino, acetamido, trifluoroacetamido, aminomethyl, 1-aminoethyl, 2- aminoethyl, N-methylamino, dimethylamino, N-ethylamino, methanesulfonamido, am idosulfonyl, N-methylamidosulfonyl, N, N-dimethylamidosulfonyl, hydroxymethyl, 1 -hydroxyethyl, 2-hyd roxyethyl, 2,2 ,2-trifluoro-1 -hyd roxyethyl, m ethoxyca rbonyl, ethoxycarbonyl, amidocarbonyl, N-methyiamidocarbonyl, N, N- dimethylamidocarbonyl, fluoro, chioro, bromo, and cyano; Y' is selected from the group consisting of: RQ17 R 18 R 17 R e Y118 Pig0 9 1 1 je a. a. a. a. a. a a a. a a a a *a.a a a a. QS Z RWe R 16 7 Qb z 0 R18Z R 17 H N Q. O\ 0 Qb and R 16 R' 1 7, 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, 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, chioro, bromo, amidosulfonyl, N-methylamidosulfonyl, N, N-dimethylamidosulfonyl, hydroxymethyl, 1 -hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro-1 -hydroxyethyl, and cyano; Qb is selected from the group consisting of hydrido and C(NR 25 )NR 23 R 24 with the proviso that no more than one of R 23 and R 2 4 is hydroxy; R 23 R' 4 and R 2 5 are independently selected from the group consisting of hydrido, methyl, ethyl, and hydroxy; and Q' is selected from the group consisting of a single covalent bond, OH 2 and CH 2 CH 2
3. The compound as recited in claim 2, or a pharmaceutically acceptable salt thereof, wherein; B is selected from the group consisting of 2-am inophenyl, 3-aminophenyl, 3- amidinophenyl, 4-amidinophenyl, 3-carboxyphenyl, 3-carboxy-5-hyd roxyphenyl, 3- chlorophenyl, 4-chlorophenyl, 3,4-dichloroph enyl, 2-fluorophenyl, 3-fluorophenyl, 3,4-difluorophenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 3-methoxyaminophenyl, 3- methoxyphenyl, 4-methoxyphenyl, 3-methylphenyl, 4-methylphenyl, phenyl, 3- trifluoromethylphenyl, 2-imidazoyl, 2-pyridyl, 3-pyridyl, 5-chloro-3-trifluoromethyl-2- pyridyl, 4-pyridyl, 2-thienyl, 3-thienyl, and 3-trifluoromethyl-2-pyridyl; A is selected from the group consisting of OH 2 CH 3 CH, CF 3 OH, NHC(O), CH 2 CH 2 ,and CH 2 CH 2 CH 2 M is selected from the group consisting of N and Ri-c; see: R' is selected from the group consisting of hydrido, hydroxy, amino, amidino, hydroxyamin o, am inomethyl, methylamimo, cyano, methyl, trifluoromethyl, m ethoxy, ***.hydroxymethyl, methoxyamino, methylthic, trifluoromethoxy, fluoro, and chloro; R 2 is Z 0 -Q; Z 0 is selected from the group consisting of a covalent single bond, 0, S, NH, and OH 2; Q is selected from the group consisting of 5-amino-3-amidocarbonylphenyl,
5-amino-2-fluorophenyl, 3-a min o-5-h ydroxym ethyl ph enyl, 5-amino-3- 172 methoxycarbonylphenyl, 3-amidinophenyl, 3-amino-2-methylphenyl, 5-amino-2- methylthiopheny,1, 3-aminophenyl, benzyl, 3-carboxyphenyl, aminophenyl, 3-carboxy-5-hydroxyphenyi, 3-carboxymethyl-5-aminophenyl, 3- 3-carboxymethyiphenyl, 3-chlorophenyl, 2- chiorophenyl, 2,6-dichlorophenyl, 3-cyanophenyl, 3-dimethylaminophenyl, 2- fluorophenyl, 3-fluorophenyl, 2,5-difluorophenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 3-methanesuIfonyla min oph enyl, 2-methoxyphenyl, 3-methoxyphenyl, 3- methoxyaminophenyl, 3-methoxycarbonylphenyl, 2-methylaminophenyl, 3- methylaminophenyl, 2-methyiphenyl, 3-methylphenyl, 4-methylphenyl, phenyl, 3- trifluoroacetamidophenyl, 3-trifluoromethyiphenyl, 2-trifluoromethylphenyl, 2-thienyl, 5-amino-3-thienyl, 3-bromo-2-thienyi, 3-pyridyl, 4-pyridyl, 2-thieny, and 3 thienyl; Y 0 is selected from the group consisting of: as z .s as-IIa R 1 R Is R IsN 8 I RIS 19 19 1 6 1 O~D Aba S a Aand R 16 R 1 6 and R" 9 are independently selected from the group consisting of hydrido, amidino, amino, am inomethyl, methoxy, methylamino, hydroxy, hydroxymethyl, fluoro, chloro, and cyano; R 17 and R 18 are independently selected from the group consisting of hydrido, fluoro, chioro, hydroxy, hydroxymethyl, amino, carboxy, and cyano; Qb is selected from the group consisting of hydrido and C(NR 25 )NR 23 R 2 4 R 23 R 24 and R 25 are independently selected from the group consisting of hydrido and methyl; and Q' is CH 2 4. The compound as recited in claim 1, or a pharmaceutically acceptable salt thereof, wherein; B is selected from the group consisting of aryl and heteroaryl wherein a ring carbon in a first alpha position relative to the ring carbon at the point of attachment is optionally substituted by R 3 2 a ring carbon in a second alpha position relative to the ring carbon at the point of attachment is optionally substituted by R 3 6 a ring carbon, in a first beta position relative to the ring carbon at the point of attachment and in an alpha position relative to the ring atom optionally substituted by R 32 is optionally substituted by R 33 a ring carbon, in a second beta position relative to the ring carbon at the point of attachment and in an alpha position relative to the ring atom optionally substituted by R 36 is optionally substituted by R 3 5 and a ring carbon, if present, in the gamma position relative to the ring carbon at the point of attachment and in an alpha position relative to each of the ring atoms optionally substituted by R 33 and R 3 5 respectively, is optionally substituted by R3; R 3 2 R 33 R 34 R 35 and R 3 6 are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, alkylthio, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboalkoxy, carboxy, carboxamido, cyano, and Qb; A is selected from the group consisting of single covalent bond and 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; R is is selected from the group consisting of hydrido, halo, alkyl, and haloalkyl; M is selected from the group consisting of N and R1-C; o *oee 174 R 1 is selected from the group consisting of hydrido, hydroxy, hydroxyamino, amidino, amino, cyano, hydroxyalkyl, alkoxy, alkyl, alkylamino, aminoalkyf, alkylthio, alkoxyamino, haloalkyl, haloalkoxy, and halo; R 2 is Z°-Q; Z 0 is a covalent single bond; Q is selected from the group consisting of aryl and heteroaryl wherein a ring carbon in a first alpha position relative to the ring carbon at the point of attachment is optionally substituted by R 9 a ring carbon in a second alpha position relative to the ring carbon at the point of attachment is optionally substituted by R 1 3 a ring carbon, in a first beta position relative to the ring carbon at the point of attachment and in an alpha position relative to the ring atom optionally substituted by R 9 is optionally substituted by R 10 a ring carbon, in a second beta position relative to the ring carbon at the point of attachment and in an alpha position relative to the ring atom optionally substituted by R 13 is optionally substituted by R 1 2 and a ring carbon, if present, in the gamma position relative to the ring carbon at the point of attachment and in an alpha position relative to each of the ring atoms optionally substituted by R 1 0 and R 1 2 respectively, is optionally substituted by R"; R 9 and R 1 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, carboxy, carboxamido, and cyano; R 10 and R 1 2 are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkyl, alkoxy, alkoxyamino, :aminoalkyl, hydroxy, amino, lower alkylamino, alkylsulfonamido, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, hydroxyalkyl, aminoalkyl, halo, haloalkyl, carboalkoxy, carboxy, carboxyamido, carboxyalkyl, and cyano; Y 0 is formula (IV): R 18 (IV) wherein D 5 D 6 J 5 and J 6 are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more than one is a covalent bond, no more than one of D 5 D 6 J 5 and J 6 is O, no more than one of D 5 D 6 J 5 and J 6 is S, one of D 5 D 6 J 5 and J 6 must be a covalent bond when two of D 5 D 6 J 5 and J 6 are O and S, and no more than four of D 5 D 6 J 5 and J 6 are N; R 1 6 R 1 7 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, alkanoyl, haloalkanoyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, and cyano; Qb is selected from the group consisting of NR 20 R 21 hydrido, and C(NR 25 )NR 2 R 24 R 2 0 RR RR 2 R 24 and R 25 are independently selected from the group consisting of hydrido and alkyl; and Q" is CH 2 5. The compound as recited in claim 4, or a pharmaceutically acceptable salt thereof, wherein; i B is selected from the group consisting of phenyl and 2-thienyl, 3-thienyl, 2- S: furyl, 3-furyl, 2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl, 4-imidazolyl, 3-pyrazolyl, 4-pyrazolyl, 2-thiazolyl, 3-isoxazolyl, and 5-isoxazolyl heteroaryl rings, wherein a ring carbon in a first alpha position relative to the ring carbon at the point of attachment is optionally substituted by R 32 a ring carbon in a second alpha position relative to the ring carbon at the point of attachment is optionally substituted by R 36 a ring carbon, in a first beta position relative to the ring carbon at the point of attachment and in an alpha position relative to the ring atom optionally substituted by R 32 is optionally substituted by R 3 a ring carbon, in a second beta position relative to the ring carbon at the point of attachment and in an alpha position relative to the ring atom optionally substituted by R 3 6 is optionally substituted by R 3 and a ring carbon, if present, in the gamma position relative to the ring carbon at the point of attachment and in an alpha position relative to each of the ring atoms optionally substituted by R 33 and R 3 5 respectively, is optionally substituted by R 34 R 32 R 33 R 34 R 35 and R 3 are independently selected from the group consisting of hydrido, amidino, guanidino, methyl, ethyl, methoxy, ethoxy, hydroxy, amino, N-methylamino, dimethylamino, methylthio, ethylthio, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, fluoro, chloro, bromo, amidosulfonyl, N- methylamidosulfonyl, hydroxymethyl, amidocarbonyl, carboxy, cyano, and Qb; A is selected from the group consisting of single covalent bond, NH, N(CH 3 CH 2 CH 3 CH, and CH 2 CH 2 M is selected from the group consisting of N and R'-C; R 1 is selected from the group consisting of hydrido, hydroxy, amino, amidino, hydroxyamino, aminomethyl, methylamino, cyano, methyl, trifluoromethyl, methoxy, hydroxymethyl, methoxyamino, methylthio, trifluoromethoxy, fluoro, and chloro; R 2 is selected from the group consisting of phenyl and 2-thienyl, 2-furyl, 2- pyrrolyl, 2-imidazolyl, 2-thiazolyl, 3-isoxazolyl, 2-pyridyl, and 3-pyridyl heteroaryl rings, wherein a ring carbon in a first alpha position relative to the ring carbon at the point of attachment is optionally substituted by R 9 a ring carbon in a second alpha position relative to the ring carbon at the point of attachment is optionally substituted by R 1 3 a ring carbon, in a first beta position relative to the ring carbon *at the point of attachment and in an alpha position relative to the ring atom optionally substituted by R 9 is optionally substituted by R' 1 a ring carbon, in a second beta position relative to the ring carbon at the point of attachment and in an alpha position relative to the ring atom optionally substituted by R 13 is optionally substituted by R 12 and a ring carbon, if present, in the gamma position relative to the ring carbon at the point of attachment and in an alpha position relative to °e •o each of the ring atoms optionally substituted by R" 0 and R 1 2 respectively, is optionally substituted by R 11 R" 1 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-methylamidosu Ifonyl, N, N- dimethylamidosulfonyl, hydroxymethyl, 1 -hydroxyethyl, amidocarbonyl, N- methylamidocarbonyl, carboxy, and cyano; R 10 and R 1 2 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, carboxymethyt, amino, acetamido, trifluoromethyl, pentafluoroethyl, 2,2,2- trifluoroethyl, trifluoroacetamido, aminomethyl, N-methylamino, dimethylamino, amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosuifonyl, meth oxy carbon yl, fluoro, chioro, bromo, and cyano; is selected from the group consisting of: R 1 R R toj. OS R* o10 16 R Q b b R 16 a' a H H R~17 R 16 R6 NN .and 1 R, R 17 R 1 and R 19 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, trifluoromethyith io, meth ylsulfinyl, methylsulfonyl, trifluoromethyl, pentafluoroethyl, 2,2 ,2-trifluoroethyl, trifluoromethoxy, fluoro, chioro, am idosu Ifonyl, N- methylamidosufonyl, hydroxymethyl, carboxy, and cyano. Qb is selected from the group consisting of NR 20 R 1 and C(NR 25 )NR 3 R 2 with the proviso that said Qb group is bonded directly to a carbon atom; R 20 R 21 R 23 R 24 and R 2 5 are independently selected from the group consisting of hydrido, methyl, and ethyl; and QS is CH 2 sat6. The compound as recited in claim 5, or a pharmaceutically acceptable is selected from the group consisting of 2-aminophenyl, 3-aminophenyl, 3- amidinophenyl, 4-amidinophenyl, 3-carboxyphenyl, 3-carboxy-5-hydroxyphenyl, 3- chiorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 2-fluorophenyl, 3-fluorop henyl, 3 ,4-difluorophenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 3-methoxyaminophenyl, 3- methoxyphenyl, 4-methoxyphenyl, 3-methylphenyl, 4-methylphenyl, phenyl, 3- trifl uorom ethylph en yl, 2-imidazoyl, 2-pyridyl, 3-pyridyl, 5-chloro-3-trifluoromethyl-2- pyridyl, 4-pyridyl, 2-thienyl, 3-thienyl, and 3-trifluoromethyl-2-pyridyl; A is selected from the group consisting of C2' OH 3 CF 3 OH, NHC(O), CH 2 CH 2 ,and CH 2 CH 2 CH 2 M is selected from the group consisting of N and R 1 -C; R' is selected from the group consisting of hydrido, hydroxy, amino, methyl,' trifluoromethyl, fluoro, and chioro; R 2 is selected from the group consisting of 5-amino-3-amidocarbonylphenyl, 5-amino-2-fluorophenyl, 3-amino-5-hydroxym ethyl phenyl, 5-amino-3- methoxycarbonylphenyl, 3-amidinophenyl, 3-amino-2-methylphenyl, 5-amino-2- methyithiophenyl, 3-aminophenyl, benzyl, 3-carboxyphenyl, aminophenyl, 3-carboxy-5-hydroxyphenyi, 3-carboxymethyl-5-aminophenyl, 3- 3-carboxymethylphenyl, 3-chlorophenyl, 2- chiorophenyl, 3-cyanophenyl, 3-dimethylaminophenyl, 2-fluorophenyl, 3- fluorophenyl, 2,5-difluorophenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 3- methanesulfonylaminophenyl, 2-methoxyphenyl, 3-methoxyphenyl, 3- methoxyaminophenyl, 3-methoxycarbonyl phenyl, 2-methylaminophenyl, 3- methylaminophenyl, 2-methylphenyl, 3-methylphenyl, 4-methyiphenyl, phenyl, 3- trifluoroacetamidophenyl, 3-trifluoromethylphenyl, 2-trifluoromethyiphenyl, 2-thienyl, 5-amino-3-thienyl, 3-bromo-2-th jenyl, 3-pyridyl, 4-pyridyl, 2-th ienyl, and 3- thienyl; Y 0 is selected from the group co nsisting of: I a R R Ris R R 060 N N R. 19R. 6R1 r 00 0 .Q S Z S R16 R 1 aD ,and R 6 R 16 and R' 9 are independently selected from the group consisting of hydrido, amidino, amino, aminomethyl, methoxy, methylamino, hydroxy, hydroxymethyl, fluoro, chloro, and cyano; R 17 and R" 8 are independently selected from the group consisting of hydrido, fluoro; chloro, hydroxy, hydroxymethyl, amino, carboxy, and cyano; Qb is selected from the group consisting of hydrido and C(NR 25 )NR 23 R 24 R 23 R 24 and R 25 are independently selected from the group consisting of hydrido and methyl; and Q' is CH,.
7. The compound as recited in claim 6, or a pharmaceutically acceptable salt thereof, wherein; B is selected from the group consisting of 3-aminophenyl, 3-amidinophenyl, 4-amidinophenyl, 3-chlorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 2- fluorophenyl, 4-methylphenyl, phenyl, 2-imidazoyl, 3-pyridyl, 4-pyridyl, and 3- trifluoromethyl-2-pyridyl; A is selected from the group consisting of CH 2 NHC(O), CH 2 CH 2 ,and CH 2 CH 2 CH,; i* M is selected from the group consisting of N and R'-C; is selected from the group consisting of hydrido, fluoro, and chloro; R 2 is selected from the group consisting of 3-aminophenyl, benzyl, 3- chlorophenyl, 3-dimethylaminophenyl, 3-hydroxyphenyl, 3- methanesulfonylaminophenyl, 3-methylaminophenyl, 2-methylphenyl, 3- methylphenyl, phenyl, 3-trifluoroacetamidophenyl, 3-bromo-2-thienyl, 2-thienyl, and 3-thienyl; and 181 Y' is selected from the group consisting of 5-amidino-2-thienylmethyi, 4- amidinobenzyl, 2-fluoro-4-amidinobenzyl, and 3-fluoro-4-amdinobenzyl.
8. The compound as recited in claim 1, or a pharmaceutically acceptable salt thereof, wherein: R' is 3-aminophenyl, B is 3-chlorophenyl, A is OH 2 CH 2 Y' is 4-amidinobenzyl, and M is CH; R' is 3-aminophenyl, B is phenyl, A is OH 2 Y' is 4-amidinobenzyl, and M is OH; R 2 is phenyl, B is 3-chlorophenyl, A is OH 2 2 Y' is 4-amidinobenzyl, and M is OH; R 2 is 3-aminophenyl, B is 2-imidazoyl, A is CH 2 OH 2 OH 2 Y' is 4-amidinobenzyl, and M is OH; R 2 is 3-dimethylaminophenyl, B is phenyl, A is OH 2 CH 2 I is 4-amidinobenzyl, and M is OH; R' is 2-mhethylphenyl, B is phenyl, A is C2C2' Y' is 4-amidinobenzyl, and M is OH; R 2 is phenyl, B is 3-aminophenyl, A is O(O)NH, Y' is 4-amidinobenzyl, and M is OH; R 2 is phenyl, B is 3-amidinophenyl, A is OH 2 is 4-amidinobenzyl, and M is OH; R 2 is 3-(N-methylamino)phenyl, B is phenyl, A is C2C2, Y' is 4-amidinobenzyl, and M is OH; R 2 is 3-thienyl, B is phenyl, A is C2CH. is 4-amidinobenzyl, and M is OH; R' is 3- methylsulIfon amid oph en yl, B is phenyl, A is C 2 C 2 YOis 4- 0% 0 amidinobenzyl, and M is OH; 00R 2 R 2 is phenyl, B is 4-amidinophenyl, A is OH 2 Y' is 4-amidinobenzyl, and M is OH; Ris 3-methylaminophenyl, B is phenyl, A is 0H 2 0H 2 YO is 4-amidinobenzyl, and M is OH; R 2 is phenyl, B is phenyl, A is OH 2 Y' is 4-amidinobenzyl, and M is OH; R00 0p e y ,B0s 4 p r d l A i H C 2 i s 4 a i i o e z y a d M i H R 2 is phenyl, B is 4-pyridyl, A is OH 2 OH 2 YO is 4-amidinobenzyl, and M is OH; 00*0 *Goo 0 0: 182 R' is 3-chiorophenyl, B is 4-pyridyl, A is CH 2 0H 2 YO is 4-amidinobenzyl, and M is OH; R 2 is 3-methyiphenyl, B is 4-phenyl, A is OH 2 CH 2 Yo is 4-amidinobenzyl, and M is OH; R 2 is 3-thienyl, B is 3-chiorophenyl, A is C 2 CH 2 Y' is 4-amidinobenzyl, and M is OH; R 2 is 3-aminophenyl, B is 3-chiorophenyl, A is CH 2 CH 2 r 0 is 4-amidinobenzyl, and M is OF; R 2 is 3-aminophenyl, B is phenyl, A is OH 2 Y' is 4-amidinobenzyl, and M is OF; R 2 is phenyl, B is 3-chlorophenyl, A is 0H 2 0H 2 Y' is 4-amidinobenzyl, and M is OF; R 2 is 3-aminophenyl, B is 2-imidazoyl, A is OH 2 OH 2 CH 2 Y' is 4-amidinobenzyl, and M is OF; R 2 is 3-dimethytaminophenyl, B is phenyl, A is OH 2 OH 2 Y' is 4-amidinobenzyl, and M is OF; R 2 is 2-methyiphenyl, B is phenyl, A is C22' Yo is 4-amidinobenzyl, and M is OF; R 2 is phenyl, B is 3-aminophenyl, A is O(O)NH, Ye is 4-amidinobenzyl, and M is OF; R 2 is phenyl, B is 3-amidinophenyl, A is CH, r 0 is 4-amidinobenzyl, and'M is OF; Ris 3-(N-methylamino)phenyl, B is phenyl, A is C2C2' Y 0 is 4-amidinobenzyl, and M is OF; R 2 is 3-thienyl, B is phenyl, A is CH 2 OH 2 Y' is 4-amidinobenzyl, and M is OF; R 2 is 3-methylsulfonamidophenyl, B is phenyl, A is CH C Y, is 4- 20 2* amidinobenzyl, and M is OF; R' is phenyl, B is 4-amidinophenyl, A is OH 2 Y' is 4-amidinobenzyl, and M is CF; 0 9 0 R is 3-methylaminopheny, B is phenyl, A is 0H 2 0H 2 Ye is 4-amidinobenzyl, and M isCF; R* spey, speyA sC2 oi 4aiioezladMi F R 2 is phenyt, B is 4penyl, A is OH 2 H, Y is 4-amidinobenzy, and M is F; R 2 is phenyl, B is 4-pyridyt, A is C22' Y is 4-amidinobenzyl, and M is OF; 0 00 *00*0 *0 00: 183 R' is 3-chiorophenyl, B is 4-pyridyl, A is OH 2 CH 2 Y' is 4-amidinobenzyl, and M is OF; R 2 is 3-methyiphenyl, B is 4-phenyl, A is OH 2 CH 2 Y' is 4-amidinobenzyl, and M is OF; R' is 3-thienyl, B is 3-chlorophenyl, A is C2 C2' Y 1 is 4-amidinobenzyl, and M is OF; R 2 is 3-aminophenyl, B is 3-chiorophenyl, A is C 2 OH 2 Y' is 4-amidinobenzyl, and M is N; R 2 is 3-aminophenyl, B is phenyl, A is OH 2 Y' is 4-amidinobenzyl, and M is N; R 2 is phenyl, B is 3-chiorophenyl, A is OH 2 2 Y' is 4-amidinobenzyl, and M is N; R 2 is 3-aminophenyl, B is 2-imidazoyl, A is CH 2 OH 2 OH 2 Y' is 4-amid inobenzyl, and M is N; R 2 is 3-dimethylaminophenyl, B is phenyl, A is OH 2 OH 2 Yo is 4-amidinobenzyl, and M is N; R 2 is 2-methyiphenyl, B is phenyl, A is OH 2 CH 2 Y' is 4-amidinobenzyl, and M is N; R 2 is phenyl, B is 3-aminophenyl, A is C(O)NH, Yio is 4-amidinobenzyl, and M is N; R 2 is phenyl, B is 3-amidinophenyl, A is OH 2 Y' is 4-amidinobenzyl, and M is N; R 2 is 3-(N-methylamino)phenyl, B is phenyl, A is C2C2' Yo is 4-amidinobenzyl, and M is N; R 2 is 3-thienyl, B is phenyl, A is OH 2 OH 2 r~ is 4-amidinobenzyl, and M is N; R 2 is 3-methylsulfonamidophenyl, B is phenyl, A is C2C2, Yo is 4- amidinobenzyl, and M is N; R 2 is phenyl, B is 4-amidinophenyl, A is OH 2 Yo is 4-amidinobenzyl, and M is N; R 2 is 3-methylaminophenyl, B is phenyl, A is 0H 2 0H 2 Yo is 4-amidinobenzyl, and M is N; R 2 is phenyl, B is phenyl, A is OH 2 Y' is 4-amidinobenzyt, and M is N; R 2 is phenyl, B is 4-pyridyl, A is OH 2 OH 2 is 4-amidinobenzyl, and M is N; R. :R 2 is phenyl, B is 3-pyridyl, A is C2C2' Y' is 4-amidinobenzyl, and M is N; 184 R 2 is 3-chlorophenyl, B is 4-pyridyl, A is CH 2 CH 2 Y is 4-amidinobenzyl, and M is N; R 2 is 3-methylphenyl, B is 4-phenyl, A is CH 2 CH 2 Y 0 is 4-amidinobenzyl, and M is N; or R 2 is 3-thienyl, B is 3-chlorophenyl, A is CH 2 CH 2 Y is 4-arnidinobenzyl, and M is N.
9. A compound having the Formula: R 2 A N Y 0 M 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 group B is optionally substituted at any carbon up to and including 6 atoms from the point of attachment of B to A with one or more of the group consisting of R 32 R 33 R 4 R 35 and R 3 6 R 32 R 33 R 4 R 3 5 and R 36 are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, alkylthio, amidosulfonyl, monoalkyl I* 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 ))(iW 7 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 and N(R 7 R 7 is selected from the group consisting of hydrido, hydroxy and alkyl; *e* R' 5 is selected from the group consisting of hydrido, halo, alkyl, and haloalkyl; M is selected from the group consisting of N and R 1 -C; R' is selected from the group consisting of hydrido, hydroxy, hydroxyamino, amidino, amino, cyano, hydroxyalkyl, alkoxy, alkyl, alkylamino, aminoalkyl, alkylthio, alkoxyamino, haloalkyl, haloalkoxy, and halo; R 2 is Z°-Q; Z 0 is selected from the group consisting of a covalent single bond, 0, S, NH, and CH 2 Q is selected from the group consisting of aryl and heteroaryl wherein a ring carbon in a first alpha position relative to the ring carbon at the point of attachment is optionally substituted by R 9 a ring carbon in a second alpha position relative to the ring carbon at the point of attachment is optionally substituted by R 13 a ring carbon, in a first beta position relative to the ring carbon at the point of attachment and in an alpha position relative to the ring atom optionally substituted by R 9 is optionally substituted by R 1 0 a ring carbon, in a second beta position relative to the ring carbon at the point of attachment and in an alpha position relative to the ring atom optionally substituted by R 1 3 is optionally substituted by R 1 2 and a ring carbon, if present, in the gamma position relative to the ring carbon at the point of attachment and in an alpha position relative to each of the ring atoms optionally substituted by Ro 1 and R 12 respectively, is optionally substituted by R"; R 9 R 1 and R 13 are independently selected from the group consisting of hydrido, hydroxy, amino, amidino, guanidino, lower alkylamino, alkylthio, alkylsulfonamido, alkylsulfinyl, alkylsulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboxy, carboxamido, and cyano; Ro 1 and R 1 2 are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkyl, alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, alkylsulfonamido, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, hydroxyalkyl, aminoalkyl, carboalkoxy, carboxy, carboxyalkyl, amidocarbonyl, halo, haloalkyl, and cyano; *o Yo is formula (IV): Qb (IV) wherein D 5 D 6 J 5 and J 6 are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more than one is a covalent bond, no more than one of D 5 D 6 J 5 and J 6 is 0, no more than one of D 5 D 6 J 5 and J 6 is S, one of D 5 D 6 J 5 and J 6 must be a covalent bond when two of D 5 D 6 J 5 and J 6 are O and S, and no more than four of D 5 D 6 J 5 and J 6 are N; R 1 6 R 17 R 1 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, alkanoyl, haloalkanoyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, and cyano; Qb is selected from the group consisting of NR 20 R 21 hydrido, C(NR 25 )NR 2 3 R 24 and N(R 26 )C(NR 2 5 )N(R 23 )(R 2 4 with the provisos that no more than one of R 2 0 and R 21 is hydroxy and that no more than one of R 23 and R 2 is hydroxy; R 20 R 21 R 23 R 2 4 R 2 5 and R 6 are independently selected from the group i* consisting of hydrido, alkyl, and hydroxy; and QS is selected from the group consisting of a single covalent bond, CH 2 and CH 2 CH,.
10. The compound as recited in claim 9, or a pharmaceutically acceptable salt thereof, wherein; B is selected from the group consisting of hydrido, ethyl, 2-propynyl, 2- propenyl, propyl, isopropyl, butyl, 2-butenyl, 3-butenyl, 2-butynyl, sec-butyl, tert- o *o o o ooooo o *oo oo o** oo butyl, isobutyl, 2-methyipropenyl, 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- butyriyl, 3-pentyl, 1 -ethyl-2-propenyl, 2-methylbutyl, 2-rnethyl-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-hexyll, 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, 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-pen tenyl, 1 -ethyl -4-pen te nyl, 1 -butyl-2-propenyl, 1 -ethyl-2- pentynyl 1 -ethyl-3-pentynyl, 2 .2,2-trifluoroethyl, 2 ,2-d ifluoropropyl, 4-trifluoromethyl- 5,5,5-trif! uoropentyl, 4-trifl uorom ethyl pentyl, 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" 2 R" 3 R R 35 and R 36 R 32 R 33 R 34, R 35 and R' 6 are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, methoxyamino, ethoxyamino, acetamido, trifluoroacetamido, N-methylamino, dimethylamino, N-ethylamino, methylthio, ethyith io, 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, hyd roxymethyl, 1 -hydroxyethyl, 2-hydroxyethyl, 2,2 ,2-trifluoro-l1-hyd roxyethyl, methoxycarbonyl, ethoxycarbonyl, amidocarbonyl, N-methylamidocarbon yI, N, N- dimethylamidocarbonyl, cyano, and Qb; A is selected from the group consisting of single covalent bond, NH, N(CH 3 N(OH), OH 2 CH 3 CH, CF 3 CH, NHC(O), N(CH 3 C(O)NH, C(O)N(CH 3 CH 2 CH 2 CH 2 CH 2 CH 2 CH 3 CHCH 2 and CF 3 CHCH 2 M is selected from the group consisting of N and R 1 -C; R' is selected from the group consisting of hydrido, hydroxy, amino, amidino, hydroxyamino, aminomethyl, 1-aminoethyl, methylamino, dimethylamino, cyano, methyl, ethyl, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, methoxy, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 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 a covalent single bond, 0, S, NH, and CH 2 Q is selected from the group consisting of phenyl and 2-thienyl, 3-thienyl, 2- furyl, 3-furyl, 2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl, 4-imidazolyl, 3-pyrazolyl, 4-pyrazolyl, 2-thiazolyl, 3-isoxazolyl, 5-isoxazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrazinyl, 2- pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, and 1,3,5- triazin-2-yl heteroaryl rings, wherein a ring carbon in a first alpha position relative to the ring carbon at the point of attachment is optionally substituted by R 9 a ring carbon in a second alpha position relative to the ring carbon at the point of attachment is optionally substituted by R" 3 a ring carbon, in a first beta position relative to the ring carbon at the point of attachment and in an alpha position relative to the ring atom optionally substituted by R 9 is optionally substituted by Rlo, a ring carbon, in a second beta position relative to the ring carbon at the point of attachment and in an alpha position relative to the ring atom optionally substituted by R 3 is optionally substituted by and a ring carbon, if present, in the gamma position relative to the ring carbon at the point of attachment and in an alpha position relative to each of the ring atoms optionally substituted by R' 0 and R 12 respectively, is optionally substituted by R"; R 9 and R 1 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, 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- methylamidosuffonyl, N,N-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, 2- 189 hydroxyethyl, 2,2,2-trifluoro-1 -hydroxyethyl, amidocarbonyl, N-methylamidocarbonyl, N,N-dimethylamidocarbonyl, and cyano; R" 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, methanesulfonamido, amidosu Ifonyl, N-methylamidosulfonyl, N, N-dimethylamidosuifonyl, hydroxymethyl, 1 -hydroxyethyl, 2-hyd roxyethyl, 2 ,2,2-trifluoro-1 -hydroxyethyl, methoxycarbonyl, ethoxycarbonyl, amidocarbonyl, N-methylamidocarbonyl, N, N- dimethylamidocarbonyl, fluoro, chloro, bromo, and cyano; Y 0 is selected from the group consisting of: R17 18S 17 R'sR' R1e RIO R Wej -r R 1 9 I Qb 0 b Qb QS QSA O N' R 18 R 1 7 R1 N -N Q. b Qb Q b V Q-S 17S S R16~R1 -Q b 1 1 R9 9 R 1 bR 71 9R 9.. 190 as Q 0 1 's 0zZ Q S H R--Rl \_ab/ R1)R1 7 Rio b Rio b as H H N zQ N N~~ 17 N 1 N\ R1718- PR 17 N R 0 b (z QJs Qb s 1-1 N~ N Zz R a i TI R ,an b1 Nsa R 6 ,R 1 18 ad 19 ar ideenenly elctd ro te rop onisin o ipRopythi, tRfandR1mehyahie inethydenulfy selethydsufrnym thylsrupfonisin, o ethylsulfonyl, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, 2,2,3,3,3- pentafluoropropyl, trifluoromethoxy, 1,1 ,2,2-tetrafluoroethoxy, fluoro, chioro, bromo, amidosulfonyl, N-methylamidosulfonyl, N, N-dimethylamidosulfonyl, hydroxymethyl, 1 -hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro-1 -hydroxyethyl, and cyano; Qb is selected from the group consisting of NR OR 21 hydrido, C(NR 5 )NR 3 R and N(R 26 )C(NR 25 )N(R 2 3 )(R 2 4 with the provisos that no more than one of R 20 and R 21 is hydroxy and that no more than one of R 2 and R' is hyd roxy; R 20 R 21 R 23 R 24 R 25 and R 2 6 are independentiy selected from the group consisting of hydrido, methyl, ethyl, propyl, butyl, isopropyl, and hydroxy; and Qs is selected from the group consisting of a single covalent bond, CH 2 and CH 2 CH 2
11. The compound as recited in claim 10, or a pharmaceutically acceptable salt thereof, wherein; B is selected from the group consisting of hydridoethyl, 2-propenyl, 2- propynyl, propyl, isopropyl, butyl, 2-butyl, (R)-2-butyl ,(SY)2-butyl, tert-butyl, isobutyl, 1 -pentyl, 3-pentyl, 2-methylbutyl, 2,2,2-trifluoroethyl, 6-amidocarbonylhexyl, 4- methyl-2-pentyl, 3-hydroxypropyl, 3-methoxy-2-propyl, 2-methoxyethyl, 2-methyl-2- butyl, 3-methyl-2-butyl, 2-dimethylaminopropyl, 2-cyanoethyl, 6-hydroxyhexyl, 2- hydroxyethyl, 2-amidinoethyl, 2-guanidinoethyl, 3-guanidinopropyl, 4- guanidinobutyl, 3-hydroxypropyl, 4-hydroxybutyl, 6-cyanohexyl, 2- dimethylaminoethyl, 3-methylbutyl, 2-methylbutyl, (S)-2-methylbutyl, 3-aminopropyl, 2-hexyl, and 4-aminobutyl; 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.; M is selected from the group consisting of N and Ri-c; R' is selected from the group consisting of hydrido, hydroxy, amino, amidino, hydroxyamin o, amimom ethyl, methylamimo, cyano, methyl, trifluoromethyl, m ethoxy, hydroxyrnethyl, methoxyamino, methylthio, trifluoromethoxy, fluoro, and chloro; 0 0 R 2 is Z 0 -Q; Z' is selected from the group consisting of a covalent single bond, 0, S, NH, and CH 2 192 Q is selected from the group consisting of 5-amino-3-amidocarbonylphenyl, 5-amino-2-fluorophenyl, 3-a min o-5-hydroxym ethyl ph enyl, 5-amino-3- methoxycarbonyiphenyl, 3-amidinophenyl, 3-amino-2-methylphenyl, 5-amino-2- methyith iophenyl, 3-aminophenyl, benzyl, 3-carboxyphenyl, aminophenyl, 3-carboxy-5-hydroxyphenyl, 3-carboxymethyl-5-aminophenyl, 3- 3-carboxymethylphenyl, 3-chlorophenyl, 2- chlorophenyl, 2,6-dichiorophenyl, 3-cyanophenyl, 3-dimethylaminophenyl, 2- fluorophenyl, 3-fl uorophenyl, 2 ,5-difluorophe nyl, 2-hyd roxyphenyl, 3-hydroxyphenyl, 3-methanesulfonylaminophenyl, 2-methoxyphenyl, 3-methoxyphenyl, 3- methoxyaminophenyl, 3-methoxycarbonyiphenyl, 2-methylaminophenyl, 3- methylaminopheny, 2-methyiphenyl, 3-methyiphenyl, 4-methyiphenyl, phenyl, 3-, trifluoroacetamidophenyl, 3-trifluoromethyiphenyl, 2-trifluoromethylphenyl, 2-thienyl, 5-amino-3-thienyl, 3-bromo-2-thienyl, 3-pyridyl, 4-pyridyl, 2-thienyl, and 3- thienyl; Yis selected from the group consisting of: R R is R ?R NRi NN R 19 R 9 1 R1 ,andR 1 R 16 and R 19 are independently selected from the group consisting of hydrido, amidino, amino, aminomethyl, methoxy, methylamino, hydroxy, hydroxymethyl, fluoro, chioro, and cyano; 193 R 1 7 and R 1 8 are independently selected from the group consisting of hydrido, fluoro, chloro, hydroxy, hydroxymethyl, amino, carboxy, and cyano; Qb is selected from the group consisting of hydrido and C(NR 2 5 )NR 23 R 24 R 2 3 R 24 and R 25 are independently selected from the group consisting of hydrido and methyl; and QS is CH 2
12. The compound as recited in claim 9, or a pharmaceutically acceptable salt thereof, wherein; B is selected from the group consisting of hydrido, C2-C8 alkyl, C3-C8 alkenyl, C3-C8 alkynyl, and C2-C8 haloalkyl, wherein each member of group B is optionally substituted at any carbon up to and including 6 atoms from the point of attachment of B to A with one or more of the group consisting of R 32 R 33 R 4 R 3 and R3 6 R 32 R 33 R 34 R 35 and R 36 are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, alkylthio, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboalkoxy, carboxy, carboxamido, cyano, and Qb; A is selected from the group consisting of single covalent bond and (CH(R 5 ))Pa-(W 7 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; R' 5 is selected from the group consisting of hydrido, halo, alkyl, and haloalkyl; M is selected from the group consisting of N and R'-C; R' is selected from the group consisting of hydrido, hydroxy, hydroxyamino, o: amidino, amino, cyano, hydroxyalkyl, alkoxy, alkyl, alkylamino, aminoalkyl, alkylthio, alkoxyamino, haloalkyl, haloalkoxy, and halo; R 2 is Z_-Q; Z° is a covalent single bond; Q is selected from the group consisting of aryl and heteroaryl wherein a ring carbon in a first alpha position relative to the ring carbon at the point of attachment is optionally substituted by R 9 a ring carbon in a second alpha position relative to the ring carbon at the point of attachment is optionally substituted by R 13 a ring carbon, in a first beta position relative to the ring carbon at the point of attachment and in an alpha position relative to the ring atom optionally substituted by R 9 is optionally substituted by R 10 a ring carbon, in a second beta position relative to the ring carbon at the point of attachment and in an alpha position relative to the ring atom optionally substituted by R 1 3 is optionally substituted by R 1 2 and a ring carbon, if present, in the gamma position relative to the ring carbon at the point of attachment and in an alpha position relative to each of the ring atoms optionally substituted by R O 1 and R 12 respectively, is optionally substituted by R 1 1 R 9 and R 13 are independently selected from the group consisting of hydrido, hydroxy, amino, amidino, guanidino, lower alkylamino, alkylthio, alkoxy, alkylsulfinyl, alkylsulfonyl, amidosulfonyl, monoalkylamidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboxy, carboxamido, and cyano; R1 0 and R 1 2 are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkyl, alkoxy, alkoxyamino, aminoalkyl, hydroxy, amino, lower alkylamino, alkylsulfonamido, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, hydroxyalkyl, aminoalkyl, halo, haloalkyl, carboalkoxy, carboxy, carboxyamido, carboxyalkyl, and cyano; Yo is formula (IV): a r s R IS I II I i(IV) *I wherein D 5 D J 5 and J' are independently selected from the group consisting of C, N, 0, S and a covalent bond with the provisos that no more than one is a covalent bond, no more than one of D 5 DI, j 5 and j 6 is 0, no more than one of D 5 j 5 and J' is 3, one of D 5 D 6 and J' must be a covalent bond when two of D 5 DJ', and J' are 0 and S, and no more than four of D j 5 and J 6 are N; R 1 6 R" 7 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, aminoalkyl, and cyano; Qb is selected from the group consisting of NR 20 R 21 hydrido, N(R 26 )C (N R 25 )N(R 2 1)(R 2 and C(NR 25 )NR 23 R 24 R 20 R 21 R 23 2 4 R 2 5 and R 26 are independently selected from the group consisting of hydrido and alkyl; and QS is OH 2
13. The compound as recited in claim 9, or a pharmaceutically acceptable salt thereof, wherein; B is selected from the group consisting of hydrido, ethyl, 2-propenyl, 2- propynyl, propyl, isopropyl, butyl, 2-butenyl, 2-butynyl, sec-butyl, 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-pentenyl, 1 -methyl-2-pentynyl, 1 -methyl-3-pentynyl, 3-hexyl, 1 -ethyl-2-butenyl, 1 -heptyl, 2-heptenyl, 3-heptenyl, 4-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-h exynyl, 3-heptyl, 1 -ethyl-2-pentenyl, 1 -ethyl-3-pentenyl, 1 -ethyl-2- pentynyl, 1 -ethyl-3-pentynyl, 2,2,2-trifluoroethyl, 2,2-difluorop ropyl, 4-trifluoromethyl- 5,5,5-trifluoropentyl, 4-trifluoromethylpentyl, 5,5,6,6,6-pentafluorohexyl, and 3,3,3- trifluoropropyt, 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 R 33 R 3 4 R 3 5 and R 36 R 32 R 33 R 34 R 3 and R 36 are independently selected from the group consisting of hydrido, amidino, guanidino, methyl, ethyl, methoxy, ethoxy, hydroxy, amino, N-methylamino, dimethylamino, methylthio, ethylthio, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, fluoro, chloro, bromo, amidosulfonyl, N- methylamidosulfonyl, hydroxymethyl, amidocarbonyl, carboxy, cyano, and Qb; A is selected from the group consisting of: a single covalent bond, NH, N(CH 3 CH 2 CH 3 CH, and CH 2 CH 2 and (ii) CH 2 N(CH 3 CH 2 N(CH 2 CH 3 CH 2 CH 2 N(CH 3 and CH 2 CH 2 N(CH 2 CH 3 with the proviso that B is hydrido; M is selected from the group consisting of N and R'-C; R 1 is selected from the group consisting of hydrido, hydroxy, amino, amidino, hydroxyamino, aminomethyl, methylamino, cyano, methyl, trifluoromethyl, methoxy, hydroxymethyl, methoxyamino, methylthio, trifluoromethoxy, fluoro, and chloro; R 2 is selected from the group consisting of phenyl and 2-thienyl, 2-furyl, 2- pyrrolyl, 2-imidazolyl, 2-thiazolyl, 3-isoxazolyl, 2-pyridyl, and 3-pyridyl heteroaryl rings, wherein a ring carbon in a first alpha position relative to the ring carbon at the point of attachment is optionally substituted by R 9 a ring carbon in a second alpha position relative to the ring carbon at the point of attachment is optionally substituted by R 13 a ring carbon, in a first beta position relative to the ring carbon at the point of attachment and in an alpha position relative to the ring atom optionally substituted by R 9 is optionally substituted by R' 0 a ring carbon, in a second beta position relative to the ring carbon at the point of attachment and in an alpha position relative to the ring atom optionally substituted by R' 3 is optionally substituted by R" 1 and a ring carbon, if present, in the gamma position relative to the ring carbon at the point of attachment and in an alpha position relative to each of the ring atoms optionally substituted by R 1 0 and R 1 2 respectively, is optionally substituted by R"; o R 9 R" 1 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, pentaflu oroethyl, 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 1 2 are independently selected from the group consisting of hydrido, amidino, amidocarbonyl, N-methylamidocarbonyl, guanidino, methyl, ethyl, methoxy, ethoxy, hydroxy, hydroxymethyl, 1-hydroxyethyl, 27hydroxyethyl, carboxy, carboxymnethyl, amino, acetamido, trifl uoromnethyl, pentafluoroethyl, 2,2,2- trifluoroethyl, trifluoroacetamido, aminomethyl, N-methylamino, dimethylamino, amidosulfonyl, N-methyla mid osulfonyl, N,N-dimethylamidosulfonyl, methoxycarbonyl, fluoro, chloro, bromo, and cyano; YO is selected from the group consisting of: as as R 1 7 R Is8 I Ri R5 R 1 R16 R r Ri R916 19 A"'Rig R- R z A I R 16 R1 I a H ?z 12 H 2- N R 19 X R7R16 R 1 1 6 R'SpA 1 S .andN R 1 6 1 7 R 18 and R 19 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, meth ylsulfinyl, methylsulfonyl, trifl uorom ethyl, pentafluoroethyl, 2,2 ,2-trifluoroethyl, trifluoromethoxy, fluoro, chloro, amidosu Ifonyl, N- methylamidosufonyl, hydroxymethyl, carboxy, and cyano. Qb is selected from the group consisting of NR 2 'R 21 C(NR 25 )NR 23 R 24 and N(R-6)C(NR 25 )N(R 23 24 with the proviso that said Qb group is bonded directly to a carbon atom; R 20 R 21 R 23 R 24 R" 5 and R 2 6 are independently selected from the group consisting of hydrido, methyl, and ethyl; and Qs is OH 2
14. The compound as recited in claim 13, or a pharmaceutically acceptable salt thereof, wherein; B is selected from the group consisting of hydrido,ethyl, 2-propenyl, 2- propynyl, propyl, isopropyl, butyl, 2-butyl, (R)-2-butyl,(S)-2-butyl, tert-butyl, isobutyl, 1 -pentyl, 3-pentyl, 2-methylbutyl, 2,2,2-trifluoroethyl, 6-amidocarbonylhexyl, 4- methyl-2-pentyl, 3-hydroxypropyl, 3-methoxy-2-propyl, 2-methoxyethyl, 2-methyl-2- butyl, 3-methyl-2-butyl, 2-dimethylaminopropyl, 2-cyanoethyl, 6-hydroxyhexyl, 2- hydroxyethyl, 2-amidinoethyl, 2-guanidinoethyl, 3-guanidinopropyl, 4- guanidinobutyl, 3-hydroxypropyl, 4-hydroxybutyl, 6-cyanohexyl, 2- dimethylaminoethyl, 3-methylbutyl, 2-meth ylbutyl, (S)-2-methylbutyl, 3-aminopropyl, ~.2-hexyl, and 4-aminobutyl; 199 A is selected from the group consisting of single covalent bond, CH 2 CH 3 CH, and CH 2 CH 2 M is selected from the group consisting of N and R'-C; R' is selected from the group consisting of hydrido, hydroxy, amino, methyl, trifluoromethyl, fluoro, and chloro; 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- methyithiophenyl, 3-aminophenyl, benzyl, 3-carboxyphenyl, aminophenyl, 3-carboxy-5-hydroxyphenyl, 3-carboxymethyl-5-aminophenyl, 3- 3-carboxymethylphenyl, 3-chlorophenyl, 2- chlorophenyl, 2,6-dichlorophenyl, 3-cyanophenyl, 3-dimethylaminophenyl, 2- fluorophenyl, 3-fl uorophenyl, 2 ,5-difluorophenyl, 2-hyd roxyphenyl, 3-hydroxyphenyl, 3-methanesulfonylaminophenyl, 2-methoxyphenyl, 3-methoxyphenyl, 3- methoxyaminophenyl, 3-methoxycarbonylphenyl, 2-methylaminophenyl, 3- methylaminophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, phenyl, 3- trifluoroacetarnidophenyl, 3-trifl uorom ethyl ph enyl, 2-trifluoromethylphenyl, 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 consi sting of: R R s R 8 Ris R' N 16 19 19 A t 6 1 ab* jb' a S S, R R. 1 7 ,and R 1 R" 6 and R" 9 are independently selected from the group consisting of hydrido, amidino, amino, aminomethyl, methoxy, methylamino, hydroxy, hydroxymethyl, fluoro, chioro, and cyano; SR" 7 and R" 8 are independently selected from the group consisting of hydrido, fluoro, chioro, hydroxy, hydroxymethyt, amino, carboxy, and cyano; Qb is selected from the group consisting of hydrido and C(NR 25 )NR 3 R 24 R 2 1, R" 4 and R 25 are independently selected from the group consisting of hydrido and methyl; and QS is CH 2 The compound as recited in claim 14, or a pharmaceutically acceptable salt thereof, wherein; B is selected from the group consisting of hydrido,ethyl, 2-propenyl, 2- propynyl, propyl, isopropyl, butyl, 2-butyl, (R)-2-butyl,(S)-2-butyl, tert-butyl, isobutyl, 1 -pentyl, 3-pentyl, 2-methylbutyl, 2 ,2,2-trifluoroethyl, 6-amidocarbonylhexyl, 4- methyl-2-pentyl, 3-hydroxypropyl, 3-methoxy-2-propyl, 2-methoxyethyl, 2-methyl-2- butyl, 3-methyl-2-butyl, 2-dimethylaminopropyl, 2-cyanoethyl, 6-hydroxyhexyl, 2- hydroxyethyl, 2-amidinoethyl, 2-guanidinoethyl, 3-guanidinopropyl, 4- guanidinobutyl, 3-hydroxypropyl, 4-hyd roxybutyl, 6-cyanohexyl, 2- dimethylaminoethyl, 3-methylbutyl, 2-methylbutyl, (S)-2-methylbutyl, 3-aminopropyl, 2-hexyl, and 4-aminobutyl; A is selected from the group consisting of single covalent bond, CH 2 GH 3 CH, and CH 2 CH 2 50*:M is selected from the group consisting of N and R'-C; R 1 is selected from the group consisting of hydrido, fluomo, and chloro; R* 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-methoxycarbonyl-phenyl, phenyl, and 3-pyridyl; and YO is selected from the group consisting of 5-amidino-2-thienylmethyl, 4- amidinobenzyl, 2-fluoro-4-amidinobenzyl, and 3-fluoro-4-amidinobenzyl. 201
16. The compound as recited in claim 9, or a pharmaceutically acceptable salt thereof, wherein: R 2 is 3-aminophenyl, B is 2,2,2-trifluoroethyl, A is single bond, YO is 4- amidinobenzyl, and M is CH; RI is 3-aminophenyl, B is (S)-2-butyl, A is single bond, YO is 4-amidinobenzyl, and M is OH; R 2 is 5-amino-2-fluorophenyl, B is isopropyl, A is single bond, r 0 is 4- amidinobenzyl, and M is OH; R' is 2-methyl-3-aminophenyl, B is isopropyl, A is single bond, YO is 4- amidinobenzyl, and M is CH; R' is 3-aminophenyl, B is ethyl, A is single bond, r 0 is 4-amidinobenzyl, and M is OH; R 2 is 3-aminophenyl, and M is OH;' R 2 is 3-aminophenyl, and M is OH; RI is 3-aminophenyl, fluorobenzyl, and M is OH; R' is 3-aminophenyl, M is OH; R' is 3-aminophenyl, is OH; R 2 is 3-aminophenyl, and M is CH; R' is 3-aminophenyl, and M is OH R 2 is 3-aminophenyl, B is ethyl, A is single bond, Y' is 4-amidino-2-fluorobenzyl, B is 2-propenyl, A is single bond, Ye is 4-amidinobenzyl, B is isopropyl, A is single bond, Ye is 4-amidino-2- B is isopropyl, A is single bond, Ye is 4-amidinobenzyl, and B is 2-butyl, A is single bond, Y' is 4-amidinobenzyl, and M B is (R)-2-butyl, A is single bond, Ye is 4-amidinobenzyl, B is 2-propynyl, A is single bond, Ye is 4-amidinobenzyl, B is 3-pentyl, A is single bond, Ye is 4-amidinobenzyl, and M is OH; R 2 is 3-aminophenyl, B is hydnido, A is OH 2 Ye is 4-amidinobenzyl, and M is OH; R 2 is 3-aminophenyl, B is ethyl, A is OH 2 Ye is 4-amidinobenzyl, and M is OH; 2 RI is 3-aminophenyl, B is 2-rnethypropyl, A is single bond, Y' is 4-amidinobenzy, and M is OH; R 2 is 3-aminophenyt, B is 2-propyl, A is CH 3 CH, is 4-amidinobenzyl, and M is OH; R' is 3-aminophenyl, B is propyl, A is single bond, r 0 is 4-amidino-2-fluorobenzyl, and M is OH; R 2 is 3-aminophenyl, B is 6-amidocarbonyihexyl, A is single bond, is 4- amidinobenzyl, and M is OH; R' is 3-aminophenyl, B'is tert-butyl, A is single bond, is 4-amidinobenzyl, and M is OH; R 2 is 3-aminophenyl, B is tert-butyl, A is single bond, YO' is 4-amidinobenzyl, and M is CH; R 2 is 3-aminophenyl, B is 3-hydroxypropyl, A is single bond, Y' is 4- amidinobenzyl, and M is OH; R 2 is 3-aminophenyl, B is 2-methyipropyl, A is single bond, Y' is 4-amidino-2- fluorobenzyl, and M is OH; RI is 3-aminopheny, B is butyl, A is single bond, Y' is 4-amidinobenzyl, and M is CH; R 2 is 3-aminophenyl, B is 3-methoxy-2-propyl, A is single bond, Y' is 4- amidinobenzyl, and M is OH; R' is 3-aminophenyl, B is 3-rnethoxy-2-propyl, A is single bond, Y' is 4- amidinobenzyl, and M is OH; R 2 is 3-aminophenyl, B is 2-methoxy-2-ethyl, A is single bond, Y' is 4- amidinobenzyl, and M is CH; R~ 2 is 3-aminophenyl, B is 2-propyl, A is single bond, Y' is 5-amidino-2- thienylmethyl, and M is OH; R 2 is 3-aminophenyl, B is 2-propyl, A is single bond, Y' is 4-amidino-3- fluorobenzyl, and M is CH; R' is 3-carboxyphenyl, B is 2-propyl, A is single bond, is 4-amidinobenzyl, and. M is OH; V 203 R' is 3-aminophenyl, B is 2-propyl, A is single bond, Y' is 4-amidino-3- fluorobenzyl, and M is OH; R 2 is, 3-aminophenyl, B is 2,2,2-trifluoroethyl, A is single bond, -YO is 4- amidinobenzyl, and M is N; R 2 is 3-aminophenyl, B is (S)-2-butyl, A is single bond, Y' is 4-amidinobenzyl, and M is N; R 2 is 5-amino-2-fluorophenyl, B is isopropyl, A is single bond, YO is 4- amidinobenzyl, and M is N; R 2 is 2-methyl-3-aminophenyl, B is isopropyl, A is single bond, Y' is 4- amidinobenzyl, and M is N;. R 2 is 3-aminophenyl, B N; R 2 is 3-aminophenyl, B and M is N; R 2 is 3-aminophenyl, B and M is N; R 2 is 3-aminophenyl, B fluorobenzyl, and M is N; R 2 is 3-aminophenyl, B M is N; R 2 is 3-aminophenyl, B is N; R 2 is 3-aminophenyl, B and M is N; R 2 is 3-aminophenyl, B and M is N; R 2 is 3-aminophenyl, B is ethyl, A is single bond, Y' is 4-amidinobenzyl, and M is is ethyl, A is single bond, Y' is 4-amidino-2-fluorobenzyl, is 2-propenyl, A is single bond, Y' is 4-amidinobenzyl, is isopropyl, A is single bond, Y' is 4-am idino-2- is isopropyl, A is single bond, Y' is 4-amidinobenzyl, and is 2-butyl, A is single bond, Y' is 4-amidinobenzyl, and M is (R)-2-butyl, A is single bond, Y' is 4-amidinobenzyl, is 2-propynyl, A is single bond, Ye is 4-amidinobenzyl, is 3-pentyl, A is single bond, Ye is 4-amidinobenzyl, and M is N; R 2 is 3-aminophenyl, B is hydrido, A is OH 2 Ye is 4-amidinobenzyl, and M is N; R 2 is 3-aminophenyl, B is ethyl, A is OH 2 Y' is 4-amidinobenzyl, and M is N; and N; and R 2 is 3-aminophenyl, B is 2-methypropyl, A is single bond, YO is 4-amidinobenzyl, M is N; R 2 is 3-aminophenyl, B is 2-propyl, A is CH 3 CH, Y' is 4-amidinobenzyl, and M is R 2 is 3-aminophenyl, B is propyl, A is single bond, YO is 4-amidino-2-fluorobenzyl, M is N; R 2 is 3-aminophenyl, B is 6-amidocarbonyihexyl, A is single bond, Ye is 4- amidinobenzyl, and M is N; R 2 is 3-aminophenyl, B M is N; .R 2 is 3-aminophenyl, B M is N; R 2 is 3-aminophenyl, B amidinobenzyl, and M is N; R 2 is 3-aminopheny, B fluorobenzyl, and M is N; R 2 is 3-aminophenyl, B N; R 2 is 3-aminophenyl, B amidinobenzyl, and M is N; R 2 is 3-aminophenyl, B am idinobenzyl, and M is N; R 2 is 3-aminophenyl, B is tert-butyl, A is single bond, Ye is 4-am idinobenzyl, and is tert-butyl, A is single bond, Ye is 4-amidinobenzyl, and is 3-hydroxypropyl, A is single bond, Y' is 4- is 2-methyipropyl, A is single bond, YO is 4-amidino-2- is butyl, A is single bond, YO is 4-amidinobenzyl, and M is is 3-methoxy-2-propyl, A is single bond, YO is 4- is 3-methoxy-2-propyl, A is single bond, re is 4- is 2-methoxy-2-ethyl, A is single bond, Ye is 4- amidinobenzyl, and M is N; is 3-aminophenyl, B is 2-propyl, A is single bond, Ye is 5-amidino-2- thienylmethyl. and M is N; R 2 is 3-aminophenyl, B is 2-propyl, A is single bond, Ye is 4-amidino-3- fluorobenzyl, and M is N; R' is 3-carboxyphenyl, B is 2-propyl, A is single bond, Ye is 4-amidinobenzyl, and M is N; R 2 is 3-aminophenyl, B is 2-propyl, A is single bond, Y 0 is 4-amidino-3- fluorobenzyl, and M is CH.
17. A compound having the Formula: R 2 M 0 0 BA N H H 0 or a pharmaceutically acceptable salt thereof, wherein; B is selected from the group consisting of C3-C7 cycloalkyl and C4-C6 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, is optionally substituted with oxo provided that no more than one ring carbon is substituted by oxo at the same time, a ring carbon or nitrogen in a first alpha position relative to the ring carbon at the point of attachment is optionally substituted by R 9 a ring carbon or nitrogen in a second alpha position relative to the ring carbon at the point of attachment is optionally substituted by R 13 a ring carbon or nitrogen, if present, in a first beta position relative to the ring carbon at the point of attachment and in an alpha position relative to the ring atom optionally i substituted by R 9 is optionally substituted by R 1 0 a ring carbon or nitrogen, if present, in a second beta position relative to the ring carbon at the point of attachment and in an alpha position relative to the ring atom optionally substituted by R 1 3 is optionally substituted by R 12 a ring carbon or nitrogen, if present, in a first gamma position relative to the ring carbon at the point of attachment and in an alpha position relative to the ring atom optionally substituted by R' 1 is optionally substituted by R 11 and a ring carbon or nitrogen, if present, in a second gamma *o o S o* •o position relative to the carbon at the point of attachment and in an alpha position relative to the ring atom optionally substituted by R 12 is optionally substituted by R 33 R 9 and R' 3 are independently selected from the group consisting of hydrido, hydroxy, amino, amidino, guanidino, lower alkylamino, alkylthio, alkylsulfonamido, alkylsulfinyl, alkylsulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboxy, carboxamido, and cyano; Ro 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, hydroxyalkyl, aminoalkyl, carboalkoxy, carboxy, carboxyalkyl, amidocarbonyl, halo, haloalkyl, and cyano; R 33 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, cyano, and Qb; A is selected from the group consisting of single covalent bond and (CH(R 5 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 R 7 is selected from the group consisting of hydrido, hydroxy and alkyl; R' 5 is selected from the group consisting of hydrido, halo, alkyl, and haloalkyl; M is selected from the group consisting of N and R'-C; R' is selected from the group consisting of hydrido, hydroxy, hydroxyamino, amidino, amino, cyano, hydroxyalkyl, alkoxy, alkyl, alkylamino, aminoalkyl, alkylthio, alkoxyamino, haloalkyl, haloalkoxy, and halo; R 2 is ZaQ; Zo is selected from the group consisting of a covalent single bond, 0, S, NH, and CH 2 Q is selected from the group consisting of aryl and heteroaryl wherein a ring carbon in a first alpha position relative to the ring carbon at the point of attachment is optionally substituted by R 9 a ring carbon in a second alpha position relative to the ring carbon at the point of attachment is optionally substituted by R 13 a ring carbon, in a first beta position relative to the ring carbon at the point of attachment and in an alpha position relative to the ring atom optionally substituted by R 9 is optionally substituted by R' 1 a ring carbon, in a second beta position relative to the ring carbon at the point of attachment and in an alpha position relative to the ring atom optionally substituted by R 1 3 is optionally substituted by R 12 and a ring carbon, if present, in the gamma position relative to the ring carbon at the point of attachment and in an alpha position relative to each of the ring atoms optionally substituted by R' 1 and R 12 respectively, is optionally substituted by R" 1 Yo is formula (IV): R 1 7 R 1 R 16 ""-j5 Qb (iv (IV) i" wherein D 5 D 6 J 5 and J 6 are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more than one is a covalent bond, no more than one of D 5 D 6 J 5 and J 6 is O, no more than one of D 5 D 6 J 5 and J 6 is S, one of D 5 D 8 J 5 and J 8 must be a covalent bond when two of D 5 D 6 J 5 and J 6 are O and S, and no more than four of D 5 D 6 J 5 and J 6 are N; R 1 6 R 1 7 R la and R 1 9 are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, haloalkylthio, alkoxy, hydroxy, amino, lower 4 4* 44 alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, and cyano; Qb is selected from the group consisting of NR 20 R 21 hydrido, and C(NR 25 )NR 23 R 24 with the provisos that no more than one of R 20 and R 21 is hydroxy and that no more than one of R 3 and R 24 is hydroxy; R 20 R 21 R 23 R 24 and R 25 are independently selected from the group consisting of hydrido, alkyl, and hydroxy; and Q" is selected from the group consisting of a single covalent bond, CH 2 and CH 2 CH 2
18. The compound as recited in claim 17, or a pharmaceutically acceptable salt thereof, wherein; B is selected from the group consisting of cyclopropyl, cyclobutyl, oxetan-3-yl, azetidin-1-yl, azetidin-2-yl, azetidin-3-yl, thiaetan-3-yl, cyclopentyl, cyclohexyl, norbornyl, 7-oxabicyclo[2.2.1]heptan-2-yl, bicyclo[3.1.0]hexan-6-yl, cycloheptyl, 2- morpholinyl, 3-morpholinyl, 4-morpholinyl, 1-piperazinyl, 2-piperazinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2- dioxanyl, 4H-2-pyranyl, 4H-3-pyranyl, 4H-4-pyranyl, 4H-pyran-4-one-2-yl, 4H-pyran- 4-one-3-yl, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydropyranyl, 3- tetrahydropyranyl, 4-tetrahydropyranyl, 2-tetrahydrothienyl, and 3-tetrahydrothienyl, wherein each ring carbon is optionally substituted with R 33 a ring carbon or nitrogen in a first alpha position relative to the ring carbon at the point of attachment is optionally substituted by R 9 a ring carbon or nitrogen in a second alpha i position relative to the ring carbon at the point of attachment is optionally substituted by R 1 3 a ring carbon or nitrogen, if present, in a first beta position relative to the ring carbon at the point of attachment and in an alpha position relative to the ring atom optionally substituted by R 9 is.optionally substituted by R 1 0 and a ring carbon or nitrogen, if present, in a second beta position relative to the ring carbon at the point of attachment and in an alpha position relative to the ring atom optionally substituted by R 1 3 is optionally substituted by R' 2 R 9 R" 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, triflu oromethyl, pentafluo roethyl, 2,2,2-trifluoroethyl, 2,2,3,3, 3-pentafluo ropropyl, trifluoromethoxy, 1,1 ,2,2- tetrafluoroethoxy, fluoro, chioro, bromo, methan esulfonamido, amidosulfonyl, N- methylamidosufonyl, N,N-dimethylamidosulfonyl, hydroxymethyl, 1 -hydroxyethyl, 2- hydroxyethyl, 2,2,2-trifluoro-1 -hydroxyethyl, amidocarbonyl, N-methylamidocarbonyl, N,N-dimethylamidocarbonyl, and cyano; R' 0 and R 1 2 are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, carboxymethyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, methoxyamino, ethoxyamino, acetamido, trifluoroacetamido, aminomethyl, 1-aminoethyl, 2- aminoethyl, N-methylamino, dimethylamino, N-ethylamino, methanesulfonamido, amidosu Ifonyl, N-methylamidosulfonyl, N, N-dimethylamidosulfonyl, hydroxymethyl, 1 -hydroxyethyl, 2-hyd roxyethyl, 2,2 ,2-trifluoro-1 -hyd roxyethyl, m ethoxyca rbonyl, ethoxycarbonyl, amidocarbonyl, N-methylamidocarbonyl, N, N- dimethylamidocarbonyl, fluoro, chloro, bromo, and cyano; R 33 is selected from the group consisting of hydrido, amidino, guanidino, carboxy, methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, methoxyamino, ethoxyamino, acetamido, trifluoroacetamido, N-meth ylamino, dimethylamino, ethylamino, methylthio, ethylthio, isopropylthio, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, 2,2,3,3,3-pentafluoropropyl, trifluoromethoxy, 1,1,2,2- tetrafluoroethoxy, fluoro, chloro, bromo, amidosulfonyl, N-methylamidosulfonyl, N, N- dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyeth'yl, 2,2,2- trifluoro-1 -hydroxyethyl, methoxycarbonyl, ethoxycarbonyl, amidocarbonyl, N- see:.*methylamidocarbonyl, N, N-dimethylamidocarbonyl, cyano, and Qb; A is selected from the group consisting of single covalent bond, NH, N(CH 3 N(OH), OH 2 OH 3 CF 3 CH, NHC(O), N(0H 3 C(O)NH, C(O)N(0H 3 CH 2 CH 2 CH 2 CH 2 CH 2 CH 3 CHCH 2 and CF 3 CHCH 2 M is selected from the group consisting of N and R 1 -C; 210 R 1 is selected from the group consisting of hydrido, hydroxy, amino, amidino, hydroxyamino, aminomethyl, 1-aminoethyl, methylamino, dimethylamino, cyano, methyl, ethyl, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, methoxy, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, methoxyamino, methylthio, ethylthio, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro, and bromo; R 2 is ZO-Q; Z 0 is selected from the group consisting of a covalent single bond, 0, S, NH, and CH 2 Q is selected from the group consisting of phenyl and 2-thienyl, 3-thienyl, 2- furyl, 3-furyl, 2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl, 4-imidazolyl, 3-pyrazolyl, 4-pyrazolyl, 2-thiazolyl, 3-isoxazolyl, 5-isoxazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrazinyl, 2- pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, and 1,3,5- triazin-2-yl heteroaryl rings, wherein a ring carbon in a first alpha position relative to the ring carbon at the point of attachment is optionally substituted by R 9 a ring carbon in a second alpha position relative to the ring carbon at the point of attachment is optionally substituted by R 1 3 a ring carbon, in a first beta position relative to the ring carbon at the point of attachment and in an alpha position relative to the ring atom optionally substituted by R 9 is optionally substituted by Ri 1 a ring carbon, in a second beta position relative to the ring carbon at the point of attachment and in an alpha position relative to the ring atom optionally substituted by R 1 3 is optionally substituted by R 1 2 and a ring carbon, if present, in the gamma position relative to the ring carbon at the point of attachment and in an alpha position relative to each of the ring atoms optionally substituted by RO 1 and R 1 2 respectively, is optionally substituted by R 1 Y is selected from the group consisting of: R17 R 1 8 1 7 R 18 18 R' R 1 R9 R (R b b b *oooo -g e *T. 2 Q N ZN R 1 Ri1g N N bb RP 17 H N C 000000 as c-I C) ,and R 16 R 17 R 1 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, trifi uoromethylthio, methylsu Ifinyl, ethylsulfinyl, methylsulfonyl, ethylsu Ifonyl, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, 2,2,3,3,3- pentafluoropropyll, trifluoromethoxy, 1,1 ,2,2-tetrafluoroethoxy, fluoro, chloro, bromo, amidosu Ifonyl, N-methylamidosulfonyl, N, N-dimethylamidosulfonyl, hydroxymethyl, I -hyd roxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro-1 -hydroxyethyl, and cyano; Qb is selected from the group consisting of hydrido and C(NR 2 1)NR 2 'R 2 1, with the proviso that no more than one of R" 3 and R 2 is hydroxy; R 23 R 2 1, and R 2 5 are independently selected from the group consisting of hydrido, methyl, ethyl, and hydroxy; and QS is selected from the group consisting of a single covalent bond, CH 2 and CH 2 CH 2
19. The compound as recited in claim 18, or a pharmaceutically acceptable salt thereof, wherein; B is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, oxalan-2-yl, 2-(2R)-bicyclolj2.2. 1 -heptyl, 1 -pyrrolidinyl, 1- piperidinyl, 1,1 -dioxothiolan-3-yl, oxetan-3-yl, azetidin-1 -yl, azetidin-2-yl, azetidin-3- yl, 7-oxabicyclo[2 .2.1 Iheptan-2-1, bicyclo[3. 1 .]hexan-6-yl, 2-morpholinyl, 3- morpholinyl, 4-morpholinyl, 1 -piperazinyl, 2-piperazinyl, 1 -piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 1 -pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-dioxanyl, 4H- 2-pyranyi, 4H-3-pyranyl, 4H-4-pyranyl, 4H-pyran-4-one-2-yi, 4H-pyran-4-one-3-y, 2- tetra hyd rofu ra nyl, 3-tetrahydrofuranyl, 2-tetrahydropyranyl, 3-tetrahydropyranyl, 4- tetra hyd ropyranyl, 2-tetrahydrothienyl, and 3-tetrahydrothienyl; A is selected from the group consisting of single covalent bond, OH 2 NHC(O), CH 2 CH 2 and CH 2 CH 2 CH 2 M is selected from the group consisting of N and Ri-c; R' is selected from the group consisting of hydrido, hydroxy, amino, amidino, hydroxyamino, aminomethyl, methylamino, cyano, methyl, trifluoromethyl, methoxy, hydroxymethyl, methoxyamino, methylthio, trifluoromethoxy, fluoro, and chloro; R 2 is ZO-Q; Z 0 is selected from the group consisting of a covalent single bond, 0, S, NH, and OH 2 Q is selected from the group consisting of 5-amino-3-amidocarbonylphenyl, 5-amino-2-fl uorophenyl, 3-amino-5-hydroxymethylphenyl, 5-amino-3- methoxycarbonylphenyl, 3-amidinophenyl, 3-amino-2-methylphenyl, 5-amino-2- methylth iophenyl, 3-aminophenyl, benzyl, 3-carboxyphenyl, aminophenyl, 3-carboxy-5-hydroxyphenyl, 3-carboxymethyl-5-aminophenyl, 3- 3-carboxymethylphenyl, 3-chlorophenyl, 2- chlorophenyl, 2,6-dichlorophenyl, 3-cyanophenyl, 3-dimethylaminophenyl, 2- fluorophenyl, 3-fluorophenyl, 2 ,5-difluorophenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 3-methanesulfonylaminophenyl, 2-methoxyphenyl, 3-methoxyphenyl, 3- methoxyaminophenyl, 3-methoxycarbonylphenyl, 2-methylaminophenyl, 3- methylaminophenyl, 2-methylphenyl, 3-methyiphenyl, 4-methylphenyl, phenyl, 3- trifluoroacetamidophenyl, 3-trifluoromethyiphenyl, 2-trifluoromethyiphenyl, 2-thienyl, 5-amino-3-thienyl, 3-bromo-2-thienyl, 3-pynidyl, 4-pyridyl, 2-thienyl, and 3- 00 thienyl; ooo~Y 0 is selected from the group consisting of: 0 0 214 p17 1 8 I18 R R R N R 18 i 19 9 16 9 R 16 R T and R 1 R 16 and R 1 9 are independently selected from the group consisting of hydrido, amidino, amino, aminomethyl, methoxy, methylamino, hydroxy, hydroxymethyl, fluoro, chloro, and cyano; R 1 7 and R' 8 are independently selected from the group consisting of hydrido, fluoro, chloro, hydroxy, hydroxymethyl, amino, carboxy, and cyano; Qb is selected from the group consisting of hydrido and C(NR 25 )NR 23 R 24 R 23 R 24 and R 25 are independently selected from the group consisting of hydrido and methyl; and Q" is CH 2 The compound as recited in claim 17, or a pharmaceutically acceptable salt thereof, wherein; B is selected from the group consisting of C3-C7 cycloalkyl and C4-C6 saturated heterocyclyl, wherein each ring carbon is optionally substituted with R 3 a ring carbon, other than the ring carbon at the point of attachment, is o° optionally substituted with oxo provided that no more than one ring carbon is substituted by oxo at the same time, a ring carbon or nitrogen in a first alpha position relative to the ring carbon at the point of attachment is optionally substituted by R 9 a ring carbon or nitrogen in a second alpha position relative to the ring carbon at the point of attachment is optionally substituted by R 1 3 a ring carbon or nitrogen, if present, in a first beta position relative to the ring carbon at the point of attachment and in an alpha position relative to the ring atom optionally substituted by R 9 is optionally substituted by RO 1 a ring carbon or nitrogen, if present, in a second beta position relative to the ring carbon at the point of attachment and in an alpha position relative to the ring atom optionally substituted by R 1 3 is optionally substituted by R 12 a ring carbon or nitrogen, if present, in a first gamma position relative to the ring carbon at the point of attachment and in an alpha position relative to the ring atom optionally substituted by R 10 is optionally substituted by R 1 and a ring carbon or nitrogen, if present, in a second gamma position relative to the carbon at the point of attachment and in an alpha position relative to the ring atom optionally substituted by R 12 is optionally substituted by R 3 3 R 9 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; R 1 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, carboxy, carboxyalkyl, carboxyamido, and cyano; R 3 3 and R 3 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; R 33 is optionally Qb; A is selected from the group consisting of single covalent bond and (CH(R'))pa-(W 7 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; R 1 5 is selected from the group consisting of hydrido, halo, alkyl, and haloalkyl; O* le *l M is selected from the group consisting of N and R1-C; R 1 is selected from the group consisting of hydrido, hydroxy, hydroxyamino, amidino, amino, cyano, hydroxyalkyl, alkoxy, alkyl, alkylamino, aminoalkyl, alkylthio, alkoxyamino, haloalkyl, haloalkoxy, and halo; R 2 is Zo-Q; Z 0 is a covalent single bond; Q is selected from the group consisting of aryl and heteroaryl wherein a ring carbon in a first alpha position relative to the ring carbon at the point of attachment is optionally substituted by R 9 a ring carbon in a second alpha position relative to the ring carbon at the point of attachment is optionally substituted by R 1 3 a ring carbon, in a first beta position relative to the ring carbon at the point of attachment and in an alpha position relative to the ring atom optionally substituted by R 9 is optionally substituted by R 1 0 a ring carbon, in a second beta position relative to the ring carbon at the point of attachment and in an alpha position relative to the ring atom optionally substituted by R 1 3 is optionally substituted by R 1 2 and a ring carbon, if present, in the gamma position relative to the ring carbon at the point of attachment and in an alpha position relative to each of the ring atoms optionally substituted by R 10 and R 12 respectively, is optionally substituted by R 11 R 9 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, monoalkylamidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboxy, carboxamido, and cyano; Ro 1 and R 1 2 are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkyl, alkoxy, alkoxyamino, aminoalkyl, hydroxy, amino, lower alkylamino, alkylsulfonamido, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, hydroxyalkyl, aminoalkyl, halo, **haloalkyl, carboalkoxy, carboxy, carboxyamido, carboxyalkyl, and cyano; YO is formula (IV): s Qb (IV) wherein D 5 and j 6 are independentiy 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, no more than one of D 5 D 6 j 5 and j 6 is 0, no more than one of D 5 D 6 J 5 and j 6 is S, one of D 5 D 6 and j 6 must be a covalent bond when two of D 0 6, J 5 and j 6 are 0 and S, and no more than four of D 6 J's, a nd j 6 are N; R, 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, alkanoyl, haloalkanoyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, and cyano; Qb is selected from the group consisting of NR 20 R 21 hydrido, and C(N R 25 )NR R 23 R 24 R 20 R 21 R 23 R 24 and R 2 are independently selected from the group consisting of hydrido and alkyl; and Qs is OH 2
21. The compound as recited in claim 20, or a pharmaceutically acceptable see: salt thereof, wherein; 0* B is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, oxalan-2-yl, 2-(2R)-bicyclo[2 .2.1 ]-heptyl, 1,1 -dioxothiolan-3- 0@ yl, oxetan-3-yl, azetidin-1 -yl, azetidin-2-yl, azetidin-3-yi, bicyclo[3.1 .0]hexan-6-yl, 2- see:morpholinyl, 3-morpholinyl, 4-morpholinyl, 1 -piperazinyl, 2-piperazinyl, 1 -piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 1 -pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2- dioxanyl, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydropyranyl, 3- seem tetrahydropyranyl, 4-tetrahydropyranyl, 2-tetrahydrothienyl, and 3-tetrahydrothienyl, wherein each ring carbon is optionally substituted with a ring carbon or nitrogen in a first alpha position relative to the ring carbon at the point of attachment is optionally substituted by R 9 a ring carbon or nitrogen in a second alpha position relative to the ring carbon at the point of attachment is optionally substituted by R 13 a ring carbon or nitrogen, if present, in a first beta position relative to the ring carbon at the point of attachment and in an alpha position relative to the ring atom optionally substituted by R 9 is optionally substituted by R'O, and a ring carbon or nitrogen, if present, in a second beta position relative to the ring carbon at the point of attachment and in an alpha position relative to the ring atom optionally substituted by R" 3 is optionally substituted by R' 2 R 9 R 1 and R 1 3 are independently selected from the group consisting of hydrido, methyl, ethyl, methoxy, ethoxy, hydroxy, amino, N-methylamino, N,N- dimethylamino, methylthio, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, fluoro, chloro, bromo, amidosulfonyl, N-methylamidosulfonyl, N,N- dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl, amidocarbonyl, N- methylamidocarbonyl, carboxy, and cyano; R"o and R' 2 are independently selected from the group consisting of hydrido, amidino, amidocarbonyl, N-methylamidocarbonyl, guanidino, methyl, ethyl, methoxy, ethoxy, hydroxy, hydroxymethyl,: 1-hydroxyethyl, 2-hydroxyethyl, carboxy, carboxymethyl, amino, acetamido, trifluoromethyl, pentafluoroethyl, 2,2,2- trifluoroethyl, trifluoroacetamido, aminomethyl, N-methylamino, dimethylamino, amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, methoxycarbonyl, fluoro, chloro, bromo, and cyano; R 33 is selected from the group consisting of hydrido, amidino, guanidino, methyl, ethyl, methoxy, ethoxy, hydroxy, carboxy, amino, N-methylamino, dimethylamino, methylthio, ethylthio, trifluoromethyl, pentafluoroethyl, 2,2,2- trifluoroethyl, fluoro, chloro, bromo, amidosulfonyl, N-methylamidosulfonyl, 0.*0 hydroxymethyl, amidocarbonyl, cyano, and Qb; A is selected from the group consisting of single covalent bond, NH, N(CH 3 CH,2 CHCH, CHCH, and CH 2 CH 2 CH 2 00*.. 0 0 0 M is selected from the group consisting of N and R'-C; R 1 is selected from the group consisting of hydrido, hydroxy, amino, amidino, hydroxyamino, aminomethyl, methylamino, cyano, methyl, trifluoromethyl, methoxy, hydroxymethyl, methoxyamino, methylthio, 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 ring carbon in a first alpha position relative to the ring carbon at the point of attachment is optionally substituted by R 9 a ring carbon in a second alpha position relative to the ring carbon at the point of attachment is optionally substituted by R 13 a ring carbon, in a first beta position relative to the ring carbon at the point of attachment and in an alpha position relative to the ring atom optionally substituted by R 9 is optionally substituted by R 10 a ring carbon, in a second beta position relative to the ring carbon at the point of attachment and in an alpha position relative to the ring atom optionally substituted by R 1 3 is optionally substituted by R 1 2 and a ring carbon, if present, in the gamma position relative to the ring carbon at the point of attachment and in an alpha position relative to each of the ring atoms optionally substituted by R 10 and R 12 respectively, is optionally substituted by R"; Yo is selected from the group consisting of: RI I R 0 R 1 R is s R 6b. 16 IR o 220 asa H as H 0 NT R7R 16 7 R 1 I\R16 N 1 ab and R 1 R 16 R 17 R 18 and R 19 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, meth ylsulfinyl, methylsulfonyl, trifl uorom ethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, trifluoromethoxy, fi uoro, chloro, amidosu Ifonyl, N- methylamidosuffonyl, hydroxymethyl, carboxy, and cyano. Q' is selected from the group consisting of NR 2 1R 2 1 and C(NR 2 1)NR 23 R 24 with the proviso that said Qb group is bonded directly to a carbon atom; R 20 R 21 R 23 R 24 and R 2 5 are independently selected from the group consisting of hydrido, methyl, and ethyl; and Q' is CH..
22. The compound as recited in claim 21, or a pharmaceuticall y acceptable .~:salt thereof, wherein; B is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, :-cyclohexyl, oxln2y,2-(2R)-bicyclo[2.2.1]-heptyl, 1,1 -dioxothiolan-3-yi, oxetan-3- A is selected from the group consisting of a single covalent bond, CH 2 NHC(Q), CH 2 CH 2 and CH 2 CH 2 CH 2 is selected from the group consisting of N and R 1 -C; R 1 is selected from the group consisting of hydrido, hydroxy, amino, methyl, trifluoromethyl, fluoro, and chloro; 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: Q zS R 1 ie R1 R 17 b b ,and RIe Qs R 16 and R 1 9 are independently selected from the group consisting of hydrido, amidino, amino, aminomethyl, methoxy, methylamino, hydroxy, hydroxymethyl, fluoro, chloro, and cyano; R 17 and R" 8 are independently selected from the group consisting of hydrido, fluoro, chloro, hydroxy, hydroxymethyl, amino, carboxy, and cyano; Qb is selected from the group consisting of hydrido and C(NR 2 5 )NR 23 R 24 R 23 R 24 and R 25 are independently selected from the group consisting of hydrido and methyl; and Q' is CH 2
23. The compound as recited in claim 22, or a pharmaceutically acceptable salt thereof, wherein; B is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxalan-2-yl, 2-(2R)-bicyclo(2.2.1]-heptyl, 1,1-dioxothiolan-3-yl, oxetan-3- yl, azetidin-l-yl, azetidin-2-yl, azetidin-3-yl, andl-piperidinyl; A is selected from the group consisting of a single covalent bond, CH,, CH 2 CH 2 and CHCH 2 CH,; M is selected from the group consisting of N and R'-C; R' is selected from the group consisting of hydrido, fluoro, and chloro; R 2 is selected from the group consisting of 3-aminophenyl, 2,6- dichiorophenyl, 2-hydroxyhenyl, phenyl, 5-amino-2-thienyl, and 3-thienyl; and YO is selected from the group consisting of 5-amidino-2-thienylmethyl, 4- amidinobenzyl, 2-fluoro-4-amidinobenzyl, and 3-fluoro-4-amdinobenzyl.
24. The compound as recited in claim 17, or a pharmaceutically acceptable salt thereof, wherein: R 2 is 3-am inophenyl, B is cycylopropyl, A is single bond, YO is 4-amidinobenzyl, and M is OH; .R 2 is 3-aminophenyl, B is cyclobutyl, A is single bond, Y' is 4-amidino-2- fluorobenzyl, and M is CH; R 2 is 3-aminophenyl, B is cyclobutyl, A is single bond, YO is 4-amidinobenzyl, and M is OH; R 2 is 3-aminophenyl, B is cyclopropyl, A is single bond, Y 1 is 4-am idino-2- fluorobenzyl, and M is OH; R 2 is 3-aminophenyl, B is cyclobutyl, A is single bond, Y" is 4-amidinobenzyl, and M is OH; R 2 is 3-aminophenyl, B is cyclobutyl, A is single bond, YO is 4-amidino-3- fluorobenzyl, and M is OH; R 2 is 3-aminophenyl, B is cyclopentyl, A is single bond, Y' is 4-amidinobenzyl, and M is OH; R 2 is 5-amino-2-thienyl, B is cyclobutyl, A is single bond, Y' is 4-amidinobenzyl, and M is CH; R' is 3-aminophenyl, B is cyclopropyl, A is OH 2 YO is 4-amidinobenzyl, and M is OH; R 2 is 3-aminophenyl, B is 2-(2R)-bicyclo[2.2.1]-heptyl, A is single bond, YO is 4- amidinobenzyl, and M is OH; R' is 3-aminophenyl, B is cyclopentyl, A is single bond, Y' is 4-amidino-2- fluorobenzyl, and M is OH; R' is 3-aminophenyl, B is cyclohexyl, A is 0H 2 0H 2 Y' is 4-amidinobenzyl, and M is OH; R 2 is 3-aminophenyl, B is oxalan-2-yl, A is OH., Y' is 4-amidinobenzyl, and M is OH; R' is phenyl, B is 1-pyrrolidinyl, A is OH 2 CH 2 Y. is 4-amidinobenzyl, and M is OH; R 2 is 3-aminophenyl, B is 1-piperidinyl, A is CH 2 CH 2 is 4-amidinobenzyl, and M is OH; R 2 is 3-aminophenyt, B is 1 ,1-dioxothiolan-3-yl, A is singie bond, Y' is 4- amidinobenzyl, and M is OH; R 2 is 2-hydroxyphenyl, B is cyclobutyl, A is single bond, Y' is 4-amidinobenzyl, and M is OH; R' is 3-aminophenyl, B is 1-pyrrolidinyl, A is OH 2 OH 2 OH 2 Y' is 4-amidinobenzyl, and M is OH; R 2 is phenyl, B is cyclobutyl, A is single bond, YO is 4-amidinobenzyl, and M is OH; R 2 is 3-thienyl, B is cyclobutyl, A is single bond, Y' is 4-amidinobenzyl, and M is OH; R 2 is 2,6-dichiorophenyl, B is cyclobutyl, A is single bond, Y' is 4-amid inobenzyl, and M is OH; R' is 3-aminophenyl, B is cycylopropyl, A is single bond, YO is 4-amidinobenzyl, and M is OF; R' is 3-aminophenyl, B is cyclobutyl, A is single bond, YO, is 4-amidino-2- fluorobenzyl, and M is OF; R 2 is 3-aminophenyl, B is cyclobutyl, A is single bond,,Y 0 is 4-amidinobenzyl, and M is OF; R' is 3-aminophenyi, B is cyclopropyl, A is single bond, r' is 4-amidino-2- fluorobenzyl, and M is OF; Ris 3-aminophenyl, B is cyclobutyl, A is single bond, YO' is 4-amidinobenzyl, and M is OF; R 2 is 3-aminophenyi, B is cyclobutyl, A is single bond, Y' is 4-amidino-3- ~o ~:fluorobenzyl, and M is OF; 224 R' is 3-aminophenyl, B is cyclopentyl, A is single bond, Y' is 4-amidinobenzyl, and M is OF; R' is 5-amino-2-thienyl, B is cyclobutyl, A is single bond, is 4-amidinobenzyl, and M is CE; R 2 is 3-aminophenyl, B is cyclopropyl, A is CH 2 Y' is 4-amidinobenzyl, and M is OF; R 2 is 3-aminophenyl, B is 2-(21R)-bicyclo[2.2.1]-heptyl, A is single bond, Y' is 4- amidinobenzyl, and M is OF; R 2 is 3-aminophenyl, B is cyclopentyl, A is singie bond, Y' is 4-amidino-2- fluorobenzyl, and M is OF; R' is 3-aminophenyl, B is cyclohexyl, A is C2C2, Y' is 4-amidinobenzyl, and M is OF; R 2 is 3-aminophenyl, B is oxalan-2-yI, A is OH 2 Y' is 4-amidinobenzyl, and M is OF; R 2 is phenyl, B is 1-pyrrolidinyl, A is OH 2 CH 2 YO is 4-amidinobenzyl, and M is OF; R 2 is 3-aminophenyl, B is 1-piperidinyl, A is 0H- 2 0H 2 Y 0 is 4-amidinobenzyl, and M is OF; R 2 is 3-aminophenyl, B is 1,1-dioxothiolan-3-yl, A is single bond, Y' is 4- amidinobenzyl, and M is OF; R' is 2-hydroxyphenyl, B is cyclobutyl, A is single bond, Y' is 4-amidinobenzyl, and M is OF; R' is 3-aminophenyl, B is 1-pyrrolidinyl, A is 0H 2 0H 2 CH21 YO is 4-amidinobenzyl, and M is OF; R 2 is phenyl, B is cyclobutyl, A is single bond, is 4-amidinobenzyl, and M is :CF; R 2 is 3-thienyl, B is cyclobutyl, A is single bond, YO is 4-amidinobenzyl, and M is OF; R' is 2,6-dichlorophenyl, B is cyclobutyl, A is single bond, Y' is 4-amidinobenzyl, and M is OF; R' is 3-aminophenyl, B is cycylopropyl, A is single bond, YO is 4-amidinobenzyl, and M is N; R' is 3-aminophenyl, B is cyclobutyl, A is single bond, Y' is 4-amidino-2- fluorobenzyl, and M is N; R 2 is 3-aminophenyl, B is cyclobutyl, A is single bond, Y' is 4-am idinobenzyl, and M is N; R 2 is 3-aminophenyl, B is cyclopropyl, A is single bond, Y' is 4-amidino-2- fluorobenzyl, and M is N; R 2 is 3-aminophenyl, B is cyclobutyl, A is single bond, Y 1 is 4-amidinobenzyl, and M is N; R 2 is 3-aminophenyl, B is cyclobulyl, A is single bond, YO is 4-amidino-3- fluorobenzyl, and M is N; R' is 3-aminopheny, B is cyclopentyl, A is single bond, Y' is 4-amidinobenzyl, and M is N; R 2 is 5-amino-2-thienyl, B is cyciobutyl, A is single bond, Y" is 4-amidinobenzyl, and M is N; R 2 is 3-aminophenyl, B is cyclopropyl, A is C2, Y' is 4-amidinobenzyl, and M is N; R 2 is 3-amin ophenyl, B is 2-(2R)-bicyclo[2.2.1]-heptyl, A is single bond, r 0 is 4- amidinobenzyl, and M is N; R 2 is 3-am inophenyl, B is cyclopentyl, A is single bond, Y' is 4-am idino-2- fluorobenzyl, and M is N; R 2 is 3-aminophenyl, B is cyclohexyl, A is C 2 OH 2 YO' is 4-amidinobenzyl, and M is N; R 2 is 3-aminophenyl, B is oxalan-2-yl, A is OH 2 YO is 4-amidinobenzyl, and M is N; R~ 2 is phenyl, B is 1-pyrrolidinyl, A is OH 2 CH 2 Y' is 4-amidinobenzyl, and M is N; Ris 3-aminophenyl, B is 1 -piperidinyl, A is OH.OH 2 YO is 4-amidinobenzyl, and M is N; Ris 3-aminophenyl, B is 1,1-dioxothiolan-3-yl, A is single bond, r 0 is 4- amidinobenzyl, and M is N; R 2 is 2-hydroxyphenyl, B is cyclobutyl, A is single bond, Y' is 4-amidinobenzyl, and Mis N; R 2 is 3-aminophenyl, B is 1-pyrrolidinyl, A is CH 2 CHCH, Y is 4-amidinobenzyl, and M is N; R 2 is phenyl, B is cyclobutyl, A is single bond, YO is 4-amidinobenzyl, and M is N; R 2 is 3-thienyl, B is cyclobutyl, A is single bond, YO is 4-amidinobenzyl, and M is N; or R 2 is 2,6-dichlorophenyl, B is cyclobutyl, A is single bond, Y' is 4-amidinobenzyl, and M is CH. A composition for inhibiting thrombotic conditions in blood comprising a compound of any one of claims 1 to 24 and a pharmaceutically acceptable carrier.
26. A composition for inhibiting thrombotic conditions in blood comprising a compound of any one of claims 1 to 8 and a pharmaceutically acceptable carrier.
27. A composition for inhibiting thrombotic conditions in blood comprising a compound of any one of claims 9 to 16 and a pharmaceutically acceptable carrier.
28. A composition for inhibiting thrombotic conditions in blood comprising a compound of any one of claims 17 to 24 and a pharmaceutically acceptable carrier.
29. A method for inhibiting thrombotic conditions in blood comprising adding to blood a therapeutically effective amount of a compound of any one of claims 1 to 24, or a ocomposition of any one of claims 25 to 28. o• A method for inhibiting formation of blood platelet aggregates in blood comprising adding to blood a therapeutically effective amount of a compound of any one of claims 1 to 24, or a composition of any one of claims 25 to 28.
31. A method for inhibiting thrombus formation in blood comprising adding to blood *oo a therapeutically effective amount of a compound of any one of claims 1 to 24, or a composition of any one of claims 25 to 28.
32. A method for treating or preventing venuous thromboembolism and pulmonary embolism in a mammal comprising administering to the mammal a therapeutically effective %el, 227 amount of a compound of any one of claims 1 to 24, or a composition of any one of claims to 28.
33. A method for treating or preventing deep vein thrombosis in a mammal comprising administering to the mammal a therapeutically effective amount of a compound I of any one of claims 1 to 24, or a composition of any one of claims 25 to 28.
34. A method for treating or preventing cardiogenic thromboembolism in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of any one of claims 1 to 24, or a composition of any one of claims 25 to 28. A method for treating or preventing thromboembolic stroke in humans and other mammals comprising administering to the mammal a therapeutically effective amount of a compound of any one of claims 1 to 24, or a composition of any one of claims 25 to 28.
36. A method for treating or preventing thrombosis associated with cancer and cancer chemotherapy in humans and other mammals comprising administering to the mammal a therapeutically effective amount of a compound of any one of claims 1 to 24, or a composition of any one of claims 25 to 28.
37. A method for treating or preventing unstable angina in humans and other mammals comprising administering to the mammal a therapeutically effective amount of a compound of any one of claims 1 to 24, or a composition of any one of claims 25 to 28. 0 0
38. A method for inhibiting thrombus formation in blood comprising adding to blood see a therapeutically effective amount of a compound of any one of claims 1 to 24 with a therapeutically effective amount of fibrinogen receptor antagonist. ~39. The use of a compound of any one of claims I to 24, or a pharmaceutically S0* acceptable salt thereof, in the manufacture of medicament for inhibiting thrombus formation, treating thrombus formation, or preventing thrombus formation in a mammal. 0*00 0000
AU49724/00A 1999-05-19 2000-05-18 Substituted polycyclic aryl and heteroaryl uracils as anticoagulative agents Ceased AU771740B2 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US13495799P 1999-05-19 1999-05-19
US60/134957 1999-05-19
PCT/US2000/008226 WO2000069833A1 (en) 1999-05-19 2000-05-18 Substituted polycyclic aryl and heteroaryl uracils as anticoagulative agents

Publications (2)

Publication Number Publication Date
AU4972400A AU4972400A (en) 2000-12-05
AU771740B2 true AU771740B2 (en) 2004-04-01

Family

ID=22465795

Family Applications (1)

Application Number Title Priority Date Filing Date
AU49724/00A Ceased AU771740B2 (en) 1999-05-19 2000-05-18 Substituted polycyclic aryl and heteroaryl uracils as anticoagulative agents

Country Status (14)

Country Link
EP (1) EP1178971A1 (en)
JP (1) JP2002544263A (en)
KR (1) KR20010113969A (en)
CN (1) CN1152023C (en)
AR (1) AR043677A1 (en)
AU (1) AU771740B2 (en)
BR (1) BR0011273A (en)
CA (1) CA2373610A1 (en)
MX (1) MXPA01011806A (en)
NZ (1) NZ514877A (en)
PE (1) PE20010217A1 (en)
UY (1) UY26157A1 (en)
WO (1) WO2000069833A1 (en)
ZA (2) ZA200109338B (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2004200664B2 (en) * 2000-01-25 2007-08-16 Neurocrine Biosciences, Inc. Gonadotropin-releasing hormone receptor antagonists and methods relating thereto

Families Citing this family (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6458952B1 (en) * 1999-05-19 2002-10-01 Pharmacia Corporation Substituted polycyclic aryl and heteroaryl uracils useful for selective inhibition of the coagulation cascade
US6716838B1 (en) 1999-05-19 2004-04-06 Pharmacia Corporation Substituted polycyclic aryl and heteroaryl uracils as anticoagulative agents
US6750342B1 (en) 1999-05-19 2004-06-15 Pharmacia Corporation Substituted polycyclic aryl and heteroaryl pyrimidinones useful for selective inhibition of the coagulation cascade
US6653316B1 (en) 1999-05-19 2003-11-25 Pharmacia Corporation Substituted polycyclic aryl and heteroaryl pyrimidinones useful for selective inhibition of the coagulation cascade
US6867217B1 (en) 1999-05-19 2005-03-15 Pharmacia Corporation Substituted polycyclic aryl and heteroaryl pyridones useful for selective inhibition of the coagulation cascade
US6664255B1 (en) 1999-05-19 2003-12-16 Pharmacia Corporation Substituted polycyclic aryl and heteroaryl pyrazinones useful for selective inhibition of the coagulation cascade
US7015230B1 (en) 1999-05-19 2006-03-21 Pharmacia Corporation Substituted polycyclic aryl and heteroaryl uracils useful for selective inhibition of the coagulation cascade
JP4931314B2 (en) 2000-01-25 2012-05-16 ニューロクライン バイオサイエンシーズ，インコーポレイテッド Gonadotropin releasing hormone receptor antagonist and related methods
AU2001243598A1 (en) 2000-03-13 2001-09-24 Pharmacia Corporation Polycyclic aryl and heteroaryl substituted benzenes useful for selective inhibition of the coagulation cascade
AU2001251315A1 (en) 2000-04-05 2001-10-23 Pharmacia Corporation Polycyclic aryl and heteroaryl substituted 4-pyridones useful for selective inhibition of the coagulation cascade
US6875791B2 (en) 2000-04-05 2005-04-05 Pharmacia Corporation Polycyclic aryl and heteroaryl substituted 4-pyrones useful for selective inhibition of the coagulation cascade
US20040171616A9 (en) 2000-04-17 2004-09-02 South Michael S. Polycyclic aryl and heteroaryl substituted 1,4-quinones useful for selective inhibition of the coagulation cascade
US6710058B2 (en) 2000-11-06 2004-03-23 Bristol-Myers Squibb Pharma Company Monocyclic or bicyclic carbocycles and heterocycles as factor Xa inhibitors
WO2002042272A2 (en) 2000-11-20 2002-05-30 Pharmacia Corporation Substituted polycyclic aryl and heteroaryl pyridines useful for selective inhibition of the coagulation cascade
US7015223B1 (en) 2000-11-20 2006-03-21 Pharmacia Corporation Substituted polycyclic aryl and heteroaryl 1,2,4-triazinones useful for selective inhibition of the coagulation cascade
US7119094B1 (en) 2000-11-20 2006-10-10 Warner-Lambert Company Substituted polycyclic aryl and heteroarpyl pyrazinones useful for selective inhibition of the coagulation cascade
AU2002367752A1 (en) 2001-10-03 2003-11-17 Pharmacia Corporation Substituted 5-membered polycyclic compounds useful for selective inhibition of the coagulation cascade
WO2003029216A1 (en) 2001-10-03 2003-04-10 Pharmacia Corporation 6-membered heterocyclic compounds useful for selective inhibition of the coagulation cascade
TW200307667A (en) 2002-05-06 2003-12-16 Bristol Myers Squibb Co Sulfonylaminovalerolactams and derivatives thereof as factor Xa inhibitors
GB0622472D0 (en) * 2006-11-10 2006-12-20 Addex Pharmaceuticals Sa Novel heterocyclic derivatives
JP6134731B2 (en) 2011-11-29 2017-05-24 ペロスフィア インコーポレイテッド Anticoagulant antagonist
CN116410143A (en) * 2021-12-29 2023-07-11 杭州奥默医药股份有限公司 Polysubstituted uracil derivative, preparation method and application thereof

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU4973400A (en) * 1999-05-19 2000-12-05 Pharmacia Corporation Substituted polycyclic aryl and heteroaryl pyrymidinones useful as anticoagulants

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BR9509994A (en) * 1994-12-13 1997-12-30 Corvas Int Inc Aromatic heterocyclic derivatives as enzyme inhibitors

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU4973400A (en) * 1999-05-19 2000-12-05 Pharmacia Corporation Substituted polycyclic aryl and heteroaryl pyrymidinones useful as anticoagulants

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2004200664B2 (en) * 2000-01-25 2007-08-16 Neurocrine Biosciences, Inc. Gonadotropin-releasing hormone receptor antagonists and methods relating thereto

Also Published As

Publication number Publication date
JP2002544263A (en) 2002-12-24
BR0011273A (en) 2002-06-18
PE20010217A1 (en) 2001-03-07
UY26157A1 (en) 2000-12-29
AR043677A1 (en) 2005-08-10
CN1351594A (en) 2002-05-29
KR20010113969A (en) 2001-12-28
ZA200109338B (en) 2004-05-26
NZ514877A (en) 2004-10-29
CA2373610A1 (en) 2000-11-23
EP1178971A1 (en) 2002-02-13
ZA200400450B (en) 2004-09-29
MXPA01011806A (en) 2003-09-04
AU4972400A (en) 2000-12-05
WO2000069833A1 (en) 2000-11-23
CN1152023C (en) 2004-06-02

Similar Documents

Publication Publication Date Title
AU771740B2 (en) Substituted polycyclic aryl and heteroaryl uracils as anticoagulative agents
US6624180B2 (en) Substituted polycyclic aryl and heteroaryl pyridines useful for selective inhibition of the coagulation cascade
AU771718B2 (en) Substituted polycyclic aryl and heteroaryl pyrymidinones useful as anticoagulants
AU771928B2 (en) Substituted polycyclic aryl and heteroaryl pyridones useful for selective inhibition of the coagulation cascade
AU775229B2 (en) Substituted polycyclic aryl and heteroaryl pyrazinones useful for selective inhibition of the coagulation cascade
US6664255B1 (en) Substituted polycyclic aryl and heteroaryl pyrazinones useful for selective inhibition of the coagulation cascade
US6653316B1 (en) Substituted polycyclic aryl and heteroaryl pyrimidinones useful for selective inhibition of the coagulation cascade
US6458952B1 (en) Substituted polycyclic aryl and heteroaryl uracils useful for selective inhibition of the coagulation cascade
US7015230B1 (en) Substituted polycyclic aryl and heteroaryl uracils useful for selective inhibition of the coagulation cascade
US6750342B1 (en) Substituted polycyclic aryl and heteroaryl pyrimidinones useful for selective inhibition of the coagulation cascade
US6867217B1 (en) Substituted polycyclic aryl and heteroaryl pyridones useful for selective inhibition of the coagulation cascade
US7015223B1 (en) Substituted polycyclic aryl and heteroaryl 1,2,4-triazinones useful for selective inhibition of the coagulation cascade
US6716838B1 (en) Substituted polycyclic aryl and heteroaryl uracils as anticoagulative agents
US6906068B1 (en) Substituted polycyclic aryl and heteroaryl 1,2,4 - triazinones useful as anticoagulants
US20040068113A1 (en) Substituted polycyclic aryl and heteroaryl pyridines useful for selective inhibition of the coagulation cascade
EP1586565A1 (en) Substituted polycyclic aryl and heteroaryl pyrazinones useful for selective inhibition of the coagulation cascade
AU2002226902A1 (en) Substituted polycyclic aryl and heteroaryl pyridines useful for selective inhibition of the coagulation cascade

Legal Events

Date Code Title Description
FGA Letters patent sealed or granted (standard patent)