WO2001087851A1 - Aryle polycyclique substitue et pyrimidinones d'heteroaryle utiles a l'inhibition selective de la coagulation - Google Patents

Aryle polycyclique substitue et pyrimidinones d'heteroaryle utiles a l'inhibition selective de la coagulation Download PDF

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Publication number
WO2001087851A1
WO2001087851A1 PCT/US2000/031901 US0031901W WO0187851A1 WO 2001087851 A1 WO2001087851 A1 WO 2001087851A1 US 0031901 W US0031901 W US 0031901W WO 0187851 A1 WO0187851 A1 WO 0187851A1
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Prior art keywords
amino
group
phenyl
carbon
hydrido
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PCT/US2000/031901
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English (en)
Inventor
Michael S. South
Ashton T. Ii Hamme
William L. Neumann
Darin E. Jones
Melvin L. Ruppel
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Pharmacia Corporation
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Priority claimed from US09/574,739 external-priority patent/US6750342B1/en
Application filed by Pharmacia Corporation filed Critical Pharmacia Corporation
Priority to AU2001222501A priority Critical patent/AU2001222501A1/en
Priority to US10/275,856 priority patent/US7015223B1/en
Publication of WO2001087851A1 publication Critical patent/WO2001087851A1/fr

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    • 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
    • C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • 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 pyrimidinone compounds that inhibit serine proteases of the coa *gou*-lation cascade.
  • Hemostasis or ( clotting begins when platelets first adhere to macromolecules in subendothelian regions of an injured and/or damaged vessels. These platelets aggregate to form the primary hemostatic plug and stimulate local activation of plasma coagulation factors leading to generation of a fibrin clot that reinforces the aggregated platelets.
  • Plasma coagulation factors include factors II, V, VII, VIII, IX, X, XI, and XII; these are also called protease zymogens. These coagulation factors or protease zymogens are activated by serine proteases leading to coagulation in a so called “coagulation cascade” or chain reaction [Handin, R. I.: Bleeding and Thrombosis. In Wilson, J., et al. editors: Harrison's Principles of Internal Medicine. 12th Edition, New York, McGraw-Hill Book Co., 1991,p.350]. Coagulation or clotting occurs in two ways through different pathways.
  • An intrinsic or contact pathway leads from XII to Xlla to XIa to IXa and to the conversion of X to Xa.
  • Xa with factor Va converts prothrombin (II) to thrombin (Ila) leading to conversion of fibrinogen to fibrin. Polymerization of fibrin leads to a fibrin clot.
  • An extrinsic pathway is initiated by the conversion of coagulation factor VII to Vila by Xa. The presence of Tissue Factor and Vila accelerates formation of Xa in the presence of calcium ion and phospholipids. Formation of Xa leads to thrombin, fibrin, and a fibrin clot as described above. The presence of one or more of these many different coagulation factors and two distinct pathways of clotting could enable the efficacious, selective control and better understanding of parts of the coagulation or clotting process.
  • thrombosis results when platelet aggregation and/or a fibrin clot blocks (i.e., occludes) a blood vessel.
  • Arterial thrombosis may result in ischemic necrosis of the tissue supplied by the artery.
  • 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, irihibiting thrombus formation, inhibiting embolus formation, and for treating or preventing unstable angina, refractory angina, myocardial infarction, transient ischemic attacks, ati ⁇ al fibrillation, thrombotic stroke, embolic stroke, deep vein thrombosis, disseminated intravascular coagulation, ocular build up of fibrin, and reocclusion or restenosis of recanalized vessels.
  • the present invention relates to a class of compounds comprising Substituted Polycyclic Aryl and Heteroaryl pyrimidinones, which are beneficial in anticoagulant therapy for the treatment and prevention of a variety of thrombotic conditions including coronary artery and cerebro vascular disease, as given in Formula (I):
  • J is selected from the group consisting of O and S;
  • J is optionally selected from the group consisting of CH-R and N-R wherein R is a linear spacer moiety having a chain length of 1 to 4 atoms linked to the point of bonding of a substituent selected from the group
  • J is optionally selected from the group consisting of CH-R and N-R wherein R is a linear spacer moiety having a chain length of 1 to 4 atoms
  • J is optionally selected from the group consisting of CH-R and N-R wherein R is a linear spacer moiety having a chain length of 1 to 4 atoms
  • 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
  • K 1 must -acova.e ⁇ ..odwhentwoofD'.D 2 j'./ ⁇ dK 1 ax OandS.
  • D , D , J , J and K are selected to maintain an aromatic ring system and that
  • R ,R ,R ,R ,andR are each independently selected to maintain the tetravalent nature of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen;
  • heterocyclylalkoxy N-all-yl-N-arylamino, heterocyclylamino, heterocyclylalkylamino, hydrido, acetamido, haloacetamido, amidino, guanidino, dialkylsulfonium, trialkylphosphonium, dialkylsulfoniumalkyl, carboxy, heteroaralkylthio, haloalkylthio, alkanoyloxy, alkoxy, alkoxyalkyl, haloalkoxylalkyl, heteroaralkoxy, cycloalkylamino, acylalkyl, acylalkoxy,
  • R , R , R , R , R , and R are independently optionally
  • R and R , R and R , R and R , and R and R are independently optionally selected to form a spacer pair wherein a spacer pair is taken together to form a linear moiety having from 3 through 6 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 members, a partially saturated heterocyclyl ring having 5 through 8 members, a heteroaryl ring having 5 through 6 members, and an aryl with the proviso that
  • R and R , R and R , R and R , and R and R are independently optionally selected to form a spacer pair wherein a spacer pair is taken together to form a linear moiety having from 3 through 6 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 members, a partially saturated heterocyclyl ring having 5 through 8 members, a heteroaryl ring having 5 through 6 members, and an aryl with the proviso that
  • 3 4 3 4 consisting of C, N, O, and S, no more than one of D , D , J , and J is O, no
  • B is optionally selected from the group consisting of hydrido, trialkylsilyl, C2-C8 alkyl, C3-C8 alkenyl, C3-C8 alkylenyl, C3-C8 alkynyl, C2-C8 haloalkyl, and C3-C8 haloalkenyl wherein each member of group B is optionally substituted at any carbon up to and including 6 atoms from the point of attachment of B to A with one or more of the group consisting of R32, R33 ,
  • B is optionally selected from the group consisting of C3-C15 cycloalkyl, C5-C10 cycloalkenyl, C4-C12 saturated heterocyclyl, and C4-C9 partially saturated heterocyclyl, wherein each ring carbon is optionally
  • a ring carbon other than the ring carbon at the point of attachment of B to A is optionally substituted with oxo provided that no more than one ring carbon is substituted by oxo at the same time, ring carbon and nitrogen atoms adjacent to the carbon atom at the point of attachment is
  • R9 to the position and two atoms from the point of attachment is optionally
  • attachment and adjacent to the R position is optionally substituted with R , a ring carbon or nitrogen atom three atoms from the point of attachment and
  • R 12 33 adjacent to the R position is optionally substituted with R , and a ring carbon or nitrogen atom four atoms from the point of attachment and adjacent
  • A is selected from the group consisting of single covalent bond, ( W ⁇ ) rr --((OCHK(RR 1155 )))) ⁇ Da aanndd ((CCHH((RR 11::>> )))) pDaa --((WW 77 )) rr ⁇ r - wherein rr is an integer
  • W is selected from the group consisting of O, S, C(O), C(S), C(O)S, C(S)O, C(0)N(R ? ), C(S)N(R ? ), (R ? )NC(0), (R ? )NC(S), S(O), S(O) 2 , S(O) 2 N(R ? ),
  • R and R are independently selected from the group consisting of hydrido, hydroxy, alkyl, alkenyl, aryl, aralkyl, aryloxy, alkoxy, alkenyloxy, alkylthio, alkylamino, arylthio, arylamino, acyl, aroyl, heteroaroyl, aralkoxyalkyl, heteroaralkoxyalkyl, , aryloxyalkyl, alkoxyalkyl, alkenyloxyalkyl, aikylthioalkyl, arylthioalkyl, aralkoxyalkyl, heteroaralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, heteroaryl, heteroaryloxy, heteroarylarnino, heteroaralkyl, heteroaralkylarmno, and heteroaryloxy alkyl; n 14 15 37 38 39
  • R , R , R , R , R , R , R and R are independently selected from the group consisting of amidino, hydroxyamino, hydrido, hydroxy, halo, cyano, aryloxy, amino, alkylamino, dialkylamino, hydroxyalkyl, aminoalkyl, acyl, aroyl, heteroaroyl, heteroaryloxyalkyl, sulfhydryl, acylamido, alkoxy, alkylthio, arylthio, alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, aralkoxyalkylalkoxy, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkoxythioalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalky
  • R and R are independently selected from other than formyl and 2-oxoacyl;
  • R and R when bonded to different carbons, are optionally taken together to form a group selected from the group consisting of covalent bond, alkylene, haloalkylene, and a linear moiety spacer selected to form a ring selected from the group consisting of cycloaikyl ring having from 5 through 8 members, cycloalkenyl ring having from 5 through 8 members, and a heterocyclyl having from 5 through 8 members;
  • R and R when bonded to different carbons, are optionally taken together to form a group selected from the group consisting of covalent bond, alkylene, haloalkylene, and a linear moiety spacer selected to form a ring selected from the group consisting of a cycloaikyl ring having from 5 through 8 members, a cycloalkenyl ring having from 5 through 8 members, and a heterocyclyl having from 5 through 8 members;
  • R and R when bonded to different carbons, are optionally taken together to form a group selected from the group consisting of covalent bond, alkylene, haloalkylene, and a linear moiety spacer selected to form a ring selected from the group consisting of cycloaikyl ring having from 5 through 8 members, cycloalkenyl ring having from 5 through 8 members, and a heterocyclyl having from 5 through 8 members;
  • ⁇ is selected from the group consisting of NR , O, C(O), C(S), S,
  • R is 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, aikylthioalkyl, arylthioalkyl, aralkoxyalkyl, heteroaralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, cycloaikyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalky
  • R and R when bonded to the same carbon, are optionally taken
  • M is selected from the group consisting of N and R -C;
  • R 2 and R 1 are independently selected from the group consisting of Z 0 - Q, hydrido, alkyl, alkenyl, and halo;
  • R is optionally selected from the group consisting of amino, a inoalkyl, all-yla ino, amidino, guanidino, hydroxy, hydroxyamino, alkoxy, hydroxyalkyl, alkoxyamino, thiol, alkylthio, dialkylsulfonium, trialkylphosphomum, dialkylsulfoniumalkyl, heteroarylamino, nitro, arylamino, aralkylamino, alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, haloalkanoyl, hydroxyhaloalkyl, cyano, and phosphono;
  • R is optionally selected from the group consisting of amidino, guanidino, dialkylsulfonium, trialkylphosphonium, dialkylsulfoniumalkyl, heteroarylamino, amino, nitro, alkylamino, arylamino, aralkylamino, alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, haloalkanoyl, hydroxyhaloalkyl, cyano, and phosphono;
  • R 2 and R 4a , R 2 and R 4b , 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 atoms connecting the points of bonding of said spacer pair members to form a heterocyclyl ring having from 5 through 8 members with the proviso that no more than one of the 2 4a 2 4b 2 1 group of spacer pairs consisting of R and R , R and R , R and R , and
  • R 2 and R 15 is used at the same time
  • R is optionally independently selected to form a linear moiety having
  • Z is selected from the group consisting of covalent single bond
  • W (CH(R )) p wherein g and p are integers independently selected from 0 tlirough 3 and W is selected from the group consisting of O, S, C(O), C(S), C(0)O, C(S)O, C(O)S, C(S)S, C(O)N(R 41 ), (R 41 )NC(O), C(S)N(R 41 ),
  • CR R C; vinylidene), ethynylidene (C ⁇ C; 1,2-ethynyl), 1,2-cyclopropyl, 1,2-cyclobutyl, 1,2-cyclohexyl, l -cyclohexyl, 1,2-cyclopentyl, 1,3-cyclopentyl, 23-morpholinyl, 2,4-mo holinyl, 2,6-mo ⁇ holinyl, 3,4-morpholinyl, 3,5- morpholinyl, 1,2-piperazinyl, 1,3-piperazinyl, 2,3-piperazinyl, 2,6-piperazinyl, 1,2-piperidinyl, 1,3-pi ⁇ eridinyl, 2,3-piperidinyl, 2,4-piperidinyl, 2,6-piperidinyl, 3,4-piperidinyl, 1,2-pyrrolidinyl, 1,3-pyrrolidinyl, 23- ⁇ yrrolidinyl,
  • R and R are selected from other than halo and cyano when o . , directly bonded to N, Z is directly bonded to the pyrimidinone ring, and W ⁇ is optionally substituted with one or more substituents selected from the group
  • R and R are independently selected from the group consisting of hydrido, hydroxyalkyl, alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, acyl, aroyl, aralkanoyl, heteroaroyl, aralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkylthioalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, aikylthioalkyl, arylthioalkyl, cycloaikyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl, hal
  • R and R are optionally taken together to form a linear moiety spacer having from 2 through 7 atoms and forming a ring selected from the group consisting of a cycloaikyl ring having from 3 through 8 members, a cycloalkenyl ring having from 3 through 8 members, and a heterocyclyl ring having from 3 through 8 members;
  • Q is formula (II):
  • 1 2 1 1 1 2 can be O, no more than one of D , D , J , J and K can be S, one of D , D ,
  • K are selected to maintain an aromatic ring system
  • 3 4 3 4 consisting of C, N, O, and S, no more than one of D , D , J , and J is O, no
  • 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, alkylamino, alkylthio, haloalkylthio, alkenyl, alkynyl, saturated heterocyclyl, partially saturated heterocyclyl, acyl, aroyl, heteroaroyl, cycloaikyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkylalkenyl, haloalkyl, haloalkoxy, haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxyalkyl, and halocycloalkenyloxyalkyl with the proviso that Z is selected
  • 4a 4b K is (CR R ) n wherein n is an integer selected from 1 through 4;
  • R and R are independently selected from the group consisting of halo, hydrido, hydroxy, cyano, hydroxyalkyl, alkyl, alkenyl, aryl, aralkyl, aralkoxyalkyl, aryloxyalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, aikylthioalkyl, aralkylthioalkyl, arylthioalkyl, cycloaikyl, cycloalkylalkyl, haloalkyl, haloalkenyl, heteroaryl, heteroarylalkyl, heteroarylthioalkyl, heteroaralkylthioalkyl, cyanoalkyl, alkylsulfmylalkyl, alkylsulfonylalkyl, haloalkylsulfmyl, arylsulfinylalkyl, arylsulfon
  • R and R are other than hydroxy or cyano when bonded to the carbon directly bonded to the pyrimidinone nitrogen;
  • 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 atoms connected to form a ring selected from the group consisting of a cycloaikyl ring having 3 through 8 members, a cycloalkenyl ring having 5 through 8 members, and a heterocyclyl
  • E is E , when K is (CR R ) n , wherein E is selected from the group consisting of a covalent single bond, O, S, C(0), C(S), C(O)O, C(S)O, C(O)S,
  • 14 K is optionally selected to be (CH(R )):-T wherein j is selected from a integer from 0 through 3 and T is selected from the group consisting of single
  • E is optionally E , when K is (CH(R ));-T, wherein E is selected from the group consisting of a covalent single bond, C(O), C(S), C(O)O, C(S)O, C(0)S, C(S)S, C(0)N(R ? ), (R 7 )NC(0), C(S)N(R 7 ), (R ? )NC(S),
  • Se(0) 2 Se(0) 2 N(R ? ), N(R 7 )Se(O) 2 , P(O)(R 8 ), N(R ? )P(O)(R 8 ),
  • K is optionally selected to be G-(CH(R )) jc wherein k is selected from an integer from 1 through 3 and G is selected from the group consisting of O,
  • R is other than hydroxy, cyano, halo, amino, alkylamino, dialkylamino, and sulfhydryl when k is 1;
  • E is optionally E when K is G-(CH(R )) _ wherein E is selected from the group consisting of a covalent single bond, O, S, C(O), C(S), C(O)O, C(S)0, C(O)S, C(S)S, C(O)N(R 7 ), (R ? )NC(O), C(S)N(R ? ), (R ? )NC(S),
  • Y° is formula (IV):
  • 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
  • K is independently selected from the group
  • 5 6 5 6 -2 + 5 6 of D , D , J , and J are N when K is N , and no more than four of D , D ,
  • 19 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
  • R are independently optionally taken together to form a linear moiety spacer having from 3 through 6 atoms connected to form a ring selected from the group consisting of a cycloalkenyl ring having from 5 through 8 members, a partially saturated heterocyclyl ring having from 5 through 8 members, a heteroaryl having from 5 through 6 members, and an aryl;
  • R and R are independently optionally taken together to form a linear moiety spacer having from 3 through 6 atoms connected to form a ring selected from the group consisting of a cycloalkenyl ring having from 5 through 8 members, a partially saturated heterocyclyl ring having from 5 through 8 members, a heteroaryl having from 5 through 6 members, and an aryl;
  • h 20 21 20 21 22 Q is selected from the group consisting of NR R , NR R R ; oxy, alkyl, aminoalkyl, alkylamino, dialkylamino, dialkylsulfoniumalkyl,
  • R , R , and R are independently selected" from the group consisting of hydrido, amino, alkyl, hydroxy, alkoxy, aminoalkyl, alkylamino, dialkylamino, and hydroxyalkyl with the provisos that
  • R , R , and R is hydroxy, alkoxy, alkylamino, amino
  • 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 atoms connecting the points of bonding of said spacer pair members to form a heterocyclyl ring having 5 through 8 members with the proviso that no more than one of the group
  • Q is optionally selected from the group consisting of N(R 26 )S0 2 N(R 23 )(R 24 ), N(R 26 )C(O)OR 5 , N(R 26 )C(O)SR 5
  • R 23 24 26 of R , R , and R can be hydroxy, alkoxy, alkylamino, aminoalkyl, amino,
  • Q is optionally selected from the group consisting of
  • R , R , R , and R are independently selected from the group consisting of hydrido, alkyl, hydroxy, alkoxy, aminoalkyl, amino, alkylamino, dialkylamino, and hydroxyalkyl;
  • R and R are optionally taken together to form a linear spacer moiety having from 4 through 7 atoms connecting the points of bonding to form a heterocyclyl ring having 5 through 8 members;
  • 27 R is selected from the group consisting of hydrido, alkyl, alkenyl, alkynyl, aralkyl, aryloxyalkyl, aralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkylthioalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, aikylthioalkyl, arylthioalkyl, cycloaikyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycl
  • R and R are independently selected from the group consisting of hydrido, hydroxy, thiol, aryloxy, amino, alkylamino, diall-ylamino, hydroxyalkyl, heteroaryloxyalkyl, alkoxy, alkylthio, arylthio, alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, aralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, arallsylthioalkyl, heteroaralkoxythioalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, aikylthioalkyl, arylthioalkyl, cycloaikyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkeny
  • R and R are optionally taken to form a linear moiety spacer group having from 2 through 7 atoms to form a ring selected from the group consisting of a cycloaikyl ring having from 3 through 8 members, a cycloalkenyl ring having from 3 through 8 members, and a heterocyclyl ring having from 3 through 8 members;
  • T ⁇ 23 _, T , 25 ⁇ 24 , ⁇ 25 25 , 26 24 _, 26 J 23 ⁇ 26 R and R , R and R , R and R , R and R , and R and R are independently optionally selected to form a spacer pair wherein a spacer pair is taken together from the points of bonding of selected spacer pair members to form the group L-U-V wherein L, U, and V are independently selected from the group of, 1,2-disubstituted radicals consisting of a cycloaikyl radical, a cycloalkenyl radical wherein cycloaikyl and cycloalkenyl radicals are substituted with one or more
  • R and R , R and R , R and R , R and R , R and R , andR 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 of radicals consisting of 1 ,2-disubstituted alkylene radicals and 1 ,2-disubstituted alkenylene radical wherein said 1,2-substitutents are independently selected from
  • W is selected from 1 through 4, and W is selected from the group consisting of O,
  • Se(0) 2 Se(O) 2 N(R ), N(R )Se(O) 2 , P(O)(R ), N(R )P(0)(R ),
  • CR R C; vinylidene), ethynylidene (C ⁇ C; 1,2-ethynyl), 1,2-cyclopropyl,
  • R and R when bonded to different carbons, are optionally taken together to form a linear moiety spacer having from 1 through 7 atoms to form a ring selected from the group consisting of a cycloaikyl ring having from 3 through 8 members, a cycloalkenyl ring having from 3 through 8 members, and a heterocyclyl ring having from 3 through 8 members;
  • R and R when bonded to different carbons, are taken together to form a linear moiety spacer having from 1 through 7 atoms to form a ring selected from the group consisting of a cycloaikyl ring having from 3 through 8 members, a cycloalkenyl ring having from 3 through 8 members, and a heterocyclyl ring having from 3 through 8 members;
  • R and R when bonded to different carbons, are taken together to form a linear moiety spacer having from 1 through 7 atoms to form a ring selected from the group consisting of a cycloaikyl ring having from 3 through 8 members, a cycloalkenyl ring having from 3 through 8 members, and a heterocyclyl ring having from 3 through 8 members;
  • R and R when bonded to the same carbon, are taken together to form a group selected from a group consisting of oxo, thiono, alkylene, haloalkylene, and a linear moiety spacer having from 2 through 7 atoms to form a ring selected from the group consisting of a cycloaikyl ring having from 3 through 8 members, a cycloalkenyl ring having from 3 through 8 members, and a heterocyclyl ring having from 3 through 8 members;
  • Y is optionally Y wherein Y is Q -Q S ;
  • W is selected from the group consisting of W is selected from the group consisting of O, S, C(O), C(S), C(O)0, C(S)O, C(0)S, C(S)S, C(O)N(R 14 ), (R 14 )NC(0), C(S)N(R 14 ), (R 14 )NC(S),
  • W is selected from the group consisting of
  • Y is optionally Q -Q wherein Q is (CH(R )) r -W , r is an
  • W is selected from the group consisting of 12-cyclobutyl, 1,2-cyclohexyl, 1,3-cyclohexyl, 1,4-cyclohexyl, 1,2-cyclopentyl, 1,3-cyclo ⁇ entyl, 2,3-morpholinyl, 2,4-morpholinyl, 2, morpholinyl, 2,6- morpholinyl, 3,4-morpholinyl, 3,5-morpholinyl, 1,2-piperazinyl, 1,3-piperazinyl, 1,4-piperazinyl, 23- ⁇ i ⁇ erazinyl, 2, piperazinyl, 2,6-piperazinyl, 12-piperidinyl, 1,3-piperidinyl, 1,4-piperidinyl, 2,3-piperidinyl, 2,4-piperidinyl, 2,5-piperidinyl, 2,6-piperidinyl, 3,4-piperidinyl, 3,5-piperidinyl, 3,6-piperidinyl, 3,5-piperidin
  • ⁇ is optionally Q -Q SSS wherein Q is (CH(R )) r -W , r is an
  • W is selected from the group consisting of 1,4-indenyl, 1,5-indenyl, 1,6-indenyl, 1,7-indenyl, 2,7-indenyl, 2,6-indenyl, 2,5- indenyl, 2,4-indenyl, 3,4-indenyl, 3-5-indenyl, 3,6-indenyl, 3,7-indenyl, 2,4- benzofuranyl, 2,5-benzofuranyl, 2,6-benzofuranyl, 2,7-benzofuranyl, 3,4- benzofuranyl, 3,5-benzofuranyl, 3,6-benzofuranyl, 3,7-benzofuranyl, 2,4- benzothiophenyl, 2,5-benzothiophenyl, 2,6-benzothiophenyl, 2,7- benzothiophenyl, 3,4-benzothiophenyl, 3, benzotbiophenyl, 3,6- benzothiophenyl,
  • Y is optionally Q -Q wherein Q is (CH(R )) r -W , r is an
  • W is selected from the group consisting of
  • 1,4-indenyl 1,5-indenyl, 1,6-indenyl, 1,7-indenyl, 2,7-indenyl, 2,6-indenyl, 2,5- indenyl, 2,4-indenyl, 3,4-indenyl, 3.5-indenyl, 3,6-indenyl, 3,7-indenyl, 2,4- benzofuranyl, 2,5-benzofuranyl, 2,6-benzofuranyl, 2,7-benzofuranyl, 3,4- benzofuranyl, 3,5-benzofuranyl, 3,6-benzofuranyl, 3,7-benzofuranyl, 2,4- benzothiophenyl, 2,5-benzothiophenyl, 2,6-benzothiophenyl, 2,7- benzothiophenyl, 3,4-benzothiophenyl, 3,5-benzothiophenyl, 3,6- benzothiophenyl, 3,7-benzothiophenyl, 2,4
  • J is selected from the group consisting of O and S;
  • J is optionally selected from the group consisting of CH-R and N-R wherein R is a linear spacer moiety having a chain length of 1 to 4 atoms linked to the point of bonding of a substituent selected from the group
  • D '1 , ⁇ D 2 ,,JJ 1 .,J J 2 i and - K 1 are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more
  • 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;
  • 36 R are independently selected from the group consisting of heterocyclylalkoxy, N-alkyl-N-arylarriino, heterocyclylamino, heterocyclylalkylamino, hydrido, acetamido, haloacetamido, amidino, guanidino, dialkylsulfonium, trialkylphosphonium, dialkylsulfoniumalkyl, carboxy, heteroaralkylthio, haloalkylthio, alkanoyloxy, alkoxy, alkoxyalkyl, haloalkoxylalkyl, heteroaralkoxy, cycloalkylamino, acylalkyl, acylalkoxy, aryloylalkoxy, heterocyclyloxy, aralkylaryl, aralkyl, aralkenyl, aralkynyl, heterocyclyl, perhaloaralkyl, aralkylsulfony
  • R and R , R and R , and R and R are independently optionally selected to form a spacer pair wherein a spacer pair is taken together to form a linear moiety having from 3 through 6 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 members, a partially saturated heterocyclyl ring having 5 through 8 members, a heteroaryl ring having 5 through 6 members, and an aryl with the proviso that
  • r R. 9 and -. r R, 10 , ⁇ R 10 and J n Rll , n Rll and J R T , 12 , and J T R- 12 and J T R13 are independentiy optionally selected to form a spacer pair wherein a spacer pair is taken together to form a linear moiety having from 3 through 6 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 members, a partially saturated heterocyclyl ring having 5 through 8 members, a heteroaryl ring having 5 through 6 members, and an aryl with the proviso that
  • R , R and R , and R and R can be used at the same time;
  • B is optionally selected from the group consisting of hydrido, trialkylsilyl, C2-C8 alkyl, C3-C8 alkylenyl, C3-C8 alkenyl, C3-C8 alkynyl, C2- C8 haloalkyl, and C3-C8 haloalkenyl wherein each member of group B may be optionally substituted at any carbon up to and including 6 atoms from the point
  • B is optionally selected from the group consisting of C3-C15 cycloaikyl, C5-C10 cycloalkenyl, C4-C12 saturated heterocyclyl, and C4-C9 partially saturated heterocyclyl, wherein each ring carbon is optionally
  • 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
  • R 12 from the point of attachment is optionally substituted with R , a ring carbon or
  • R 33 optionally substituted with R , and a ring carbon or nitrogen four atoms from
  • A is selected from the group consisting of single covalent bond
  • W is selected from the group consisting of O, S, C(O), C(S), C(O)S, C(S)O, C(0)N(R ? ), C(S)N(R ? ), (R 7 )NC(0), (R 7 )NC(S), S(O), S(O) 2 , S(O) 2 N(R ? ), (R 7 )NS(O) 2 , P(O)(R 8 ), N(R 7 )P(0)(R 8 ), P(O)(R 8 )N(R ? ), C(NR 7 )N(R ? ),
  • R and R are independently selected from the group consisting of hydrido, hydroxy, alkyl, acyl, aroyl, heteroaroyl, and alkoxyalkyl;
  • R , R , R , and R are independently selected from the group consisting of hydrido, hydroxy, halo, cyano, hydroxyalkyl, alkoxy, alkyl, alkoxyalkyl, cycloaikyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxyalkyl, carboxy,
  • R and R can be independently selected from the group consisting of acyl, aroyl, and heteroaroyl with the proviso that acyl is selected from other
  • ⁇ is selected from the group consisting of NR , O, C(O), C(S), S,
  • R is selected from the group consisting of hydrido, hydroxy, ammo, alkyl, alkoxy, alkoxyalkyl, haloalkyl, acyl, aroyl, and heteroaroyl;
  • 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 R -C;
  • R 2 and R 1 are independently selected from the group consisting of Z 0 -
  • R is optionally selected from the group consisting of amino, aminoalkyl, alkylamino, amidino, guanidino, hydroxy, hydroxyamino, alkoxy, hydroxyalkyl, alkoxyamino, thiol, alkylthio, dialkylsulfonium, trialkylphosphonium, dialkylsulfoniumalkyl, heteroarylamino, nitro, arylamino, aralkylamino, alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, haloalkanoyl, hydroxyhaloalkyl, cyano, and phosphono;
  • Z is selected from the group consisting of covalent single bond,
  • W (CH(R ))
  • CR R C; vinylidene), ethynylidene (C ⁇ C; 1,2-ethynyl), 1,2-cyclopropyl,
  • R and R are selected from other than halo and cyano when o 22 directly bonded to N, Z is directly bonded to the pyrimidinone ring, and W is optionally substituted with one or more substituents selected from the group
  • R and R are 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, cycloaikyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxy, haloalkenyl
  • D " , D ⁇ y J ,,! J 2" and - K 1 ⁇ are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more 1 2 1 2 1 . than one is a covalent bond, no more than one of D , D , J , J and K is O,
  • R , R , R , and R are each independently selected to maintain the tetravalent nature of carbon, trivalent nature of nitrogen, the divalent nature of
  • 3 4 3 4 consisting of C, N, O, and S, no more than one of D , D , J , and J is O, no
  • 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, alkylamino, alkylthio, haloalkylthio,. alkenyl, alkynyl, saturated heterocyclyl, partially saturated heterocyclyl, acyl, aroyl, heteroaroyl, cycloaikyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkylalkenyl, haloalkyl, haloalkoxy, haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxyalkyl, and halocycloalkenyloxyalkyl with tthhee pp
  • 4a 4b K is (CR K ) n wherein n is an integer selected from 1 through 2;
  • R and R are independently selected from the group consisting of halo, hydrido, hydroxy, cyano, hydroxyalkyl, alkyl, alkenyl, alkoxyalkyl, aralkyl, heteroaralkyl, aikylthioalkyl, haloalkyl, haloalkenyl, and cyanoalkyl; o 1 4a 4b 1
  • E is E , when K is (CR R ) n , wherein E is selected from the group consisting of a covalent single bond, O, S, C(O), C(S), C(O)O, C(S)O, C(O)S, C(S)S, C(O)N(R 7 ), (R ? )NC(O), C(S)N(R ? ), (R ? )NC(S), OC(0)N(R ? ),
  • T is selected from the group consisting of single covalent
  • E is optionally E , when K is (CH(R )):-T, wherein E is selected from the group consisting of a covalent single bond, C(O), C(S), C(O)O,
  • K is optionally G-(CH(R )) ⁇ wherein k is selected from an integer from 1 through 2 and G is selected from the group consisting of O, S, and
  • R is other than hydroxy, cyano, halo, amino, alkylamino, dialkylamino, and sulfhydryl when k is 1; o 3 15 3
  • E is optionally E when K is G-(CH(R ) , wherein E is selected from the group consisting of a covalent single bond, O, S, C(O), C(S), C(O)0, C(S)O, C(0)S, C(S)S, C(O)N(R 7 ), (R 7 )NC(O), C(S)N(R ? ), (R ? )NC(S),
  • 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
  • K is independently selected from the group
  • R , R , R , and R are N, with the provisos that R , R , R , and R are each independently selected to maintain the tetravalent nature of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of
  • R and R are optionally independently taken together to form a linear moiety spacer having from 3 through 6 atoms connected to form a ring selected from the group consisting of a cycloalkenyl ring having from 5 through 8 members, a partially saturated heterocyclyl ring having from 5 through 8 members, a heteroaryl having from 5 through 6 members, and an aryl;
  • R or R is optionally selected from the group consisting of
  • Q is selected from the group consisting of NR R , NR R R , oxy, alkyl, , alkylamino, dialkylamino, dialkylsulfoniumalkyl, acylamino and
  • R , R , and R is hydroxy, alkoxy, alkylamino, amino, and dialkylamino at
  • 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 atoms connecting the points of bonding of said spacer pair members to form a heterocyclyl ring having 5 through 8 members with the proviso that no more than one of the group
  • Q is optionally selected from the group consisting of
  • R , R , and R is hydroxy, alkoxy, alkylamino, amino, and dialkylamino
  • Q is optionally selected from the group consisting of
  • said Q group is bonded directly to a carbon atom
  • R and R are optionally taken together to form a linear spacer moiety having from 4 through 7 atoms connecting the points of bonding to form a heterocyclyl ring having 5 through 8 members;
  • Q is selected from the group consisting of a single covalent bond,
  • W is selected from the group
  • W is selected from the group
  • i is optionally Y wherein Y is Q -Q ; ⁇ h ss ss i is optionally Q -Q wherein Q is selected from the group
  • W is selected from 1 through 4, and W is selected from the group consisting of W is selected from the group consisting of O, S, C(O), C(S), C(O)O, C(S)0,
  • Y is optiionally Q -Q SSS wherein Q SSS is (CH(R )) r -W , r is an
  • W ⁇ is selected from the group consisting of
  • ⁇ is optionally Q -Q s wherein Q SS is (CH(R )) r - W , r is an
  • W is selected from the group consisting of 1,2-cyclobutyl, 1,2-cyclohexyl, 13-cyclohexyl, 1,4-cyclohexyl, 1,2-cyclopentyl, 13-cyclopentyl, 2,3-morpholinyl, 2,4-morpholinyl, 2 ⁇ -morpho inyl, 2,6- morpholinyl, 3,4-morpholinyl, 3, morpholinyl, 1,2-piperazinyl, 1,3-piperazinyl, 1,4-piperazinyl, 23-piperazinyl, 2, piperazinyl, 2,6-piperazinyl, 1,2-piperidinyl, 13-piperidinyl, 1,4-piperidinyl, 23- ⁇ iperidinyl, 2,4-piperidinyl, 2,5-piperidinyl, 2,6-piperidinyl, 3,4-piperidinyl, 3,5-piperidinyl, 3,6-piperidinyl, 1,
  • Y is optionally Q -Q ss wherein Q SSSS is (CH(R )) r -W , r is an
  • W ⁇ ⁇ is selected from the group consisting of
  • 1,4-indenyl 1,5-indenyl, 1,6-indenyl, 1,7-indenyl, 2,7-indenyl, 2,6-indenyl, 2,5- indenyl, 2,4-indenyl, 3,4-indenyl, 3,5-indenyl, 3,6-indenyl, 3,7-indenyl, 2,4- benzofuranyl, 2,5-benzofuranyl, 2,6-benzofuranyl, 2,7-benzofuranyl, 3,4- benzofuranyl , 3 ,5-benzof uranyl , 3 ,6-benzof uranyl , 3 ,7-benzof uranyl , 2,4- benzothiophenyl, 2,5-benzothiophenyl, 2,6-benzothiophenyl, 2,7- benzothiophenyl, 3,4-benzothiophenyl, 3,5-benzothiophenyl, 3,6- benzothiophenyl,
  • Y is optionally Q -Q wherein Q is (CH(R )) r -W , r is an
  • W is selected from the group consisting of
  • 1,4-indenyl 1,5-indenyl, 1,6-indenyl, 1,7-indenyl, 2,7-indenyl, 2,6-indenyl, 2,5- indenyl, 2,4-indenyl, 3,4-indenyl, 3,5-indenyl, 3,6-indenyl, 3,7-indenyl, 2,4- benzofuranyl, 2,5-benzofuranyl, 2,6-benzofuranyl, 2,7-benzofuranyl, 3,4- benzofuranyl, 3, benzof uranyl, 3,6-benzofuranyl, 3,7-benzofuranyl, 2,4- benzothiophenyl, 2,5-benzothiophenyl, 2,6-benzothiophenyl, 2,7- benzothiophenyl, 3,4-benzothiophenyl, 3,5-benzothiophenyl, 3,6- benzothiophenyl, 3,7-benzothio ⁇ henyl, 2,
  • J is selected from the group consisting of O and S ;
  • 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
  • D , J , J and K are selected to maintain an aromatic ring system and that
  • R , R , R , R , and R are each independently selected to maintain the tetravalent nature of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen;
  • 36 R are independently selected from the group consisting of heterocyclylalkoxy, N-alkyl-N-arylamino, heterocyclylamino, heterocyclylalkylamino, hydrido, acetamido, haloacetamido, amidino, guanidino, dialkylsulfonium, trialkylphosphonium, dialkylsulfoniumalkyl, carboxy, heteroaralkylthio, heteroaralkoxy, cycloalkylamino, acylalkyl, acylalkoxy, aryloylalkoxy, heterocyclyloxy, aralkylaryl, aralkyl, aralkenyl, aralkynyl, heterocyclyl, perhaloaralkyl, aralkylsulfonyl, aralkylsulfonylalkyl, aralkylsulfinyl, aralkylsulfiny
  • R , R , R , R , R , and R are independently optionally
  • Q b is optionally selected from the group consisting of hydrido, trialkylsilyl, C2-C8 alkyl, C3-C8 alkylenyl, C3-C8 alkenyl, C3-C8 alkynyl, 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 ,
  • B is optionally selected from the group consisting of C3-C12 cycloaikyl, CSC 10 cycloalkenyl, and C4-C9 saturated heterocyclyl, wherein
  • each ring carbon is optionally substituted with R
  • a ring carbon other than the ring carbon at the point of attachment of B to A is optionally substituted with oxo provided that no more than one ring carbon is substituted by oxo at the same time
  • R optionally substituted with R , a ring carbon or nitrogen adjacent to the R position and two atoms from the point of attachment is optionally substituted
  • R is optionally substituted with R , a ring carbon or nitrogen three atoms from the point of attachment and adjacent to the
  • R position is optionally substituted with R , and a ring carbon or nitrogen
  • A is selected from the group consisting of single covalent bond, (W ⁇ -(CHCR )) pa and (CH(R 15 )) pa -(W 7 ) rr wherein ir is an integer
  • pa is an integer selected from 0 through 6
  • W is an integer selected from 0 through 7
  • 7 7 is selected from the group consisting of O, S, C(O), C(0)N(R ), C(S)N(R ),
  • R and R are independently selected from the group consisting of hydrido, hydroxy, alkyl, and alkoxyalkyl;
  • R , R , R , and R are independently selected from the group consisting of hydrido, hydroxy, halo, alkyl, alkoxyalkyl, haloalkyl, haloalkoxy, and haloalkoxyalkyl;
  • R and R can be independently selected from the group consisting of
  • R is optionally substituted at from one through three of the ring carbons with a substituent selected from the group
  • ⁇ is selected from the group consisting of NR , C(O), and S(O) ;
  • R is selected from the group consisting of hydrido, hydroxy, alkyl, and alkoxy;
  • 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 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
  • W (CH(R )) p wherein g and p are integers independently selected from 0 through 3 and W is selected from the group consisting of O, S, C(O), S(O),
  • R and R are independently selected from the group consisting of amidino, hydroxyamino, hydrido, hydroxy, amino, and alkyl;
  • Q is selected from the group consisting of hydrido, with the proviso that
  • D , D , J , J and K are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more
  • 1 2 1 2 1 must be a covalent bond when two of D , D , J , J and K . are O and S, and 1 9 1 9 1 9 10 no more than four of D , D , J , J and K is N, with the proviso that R , R .
  • R , R , and R are each independently selected to maintain the tetravalent nature of carbon, trivalent nature of nitrogen, the divalent nature of sulfur, and the divalent nature of oxygen;
  • 4a 4b K is (CR R ) n wherein n is an integer selected from 1 through 2;
  • R and R are independently selected from the group consisting of halo, hydrido, hydroxyalkyl, alkyl, alkoxyalkyl, aikylthioalkyl, and haloalkyl;
  • E is selected from the group consisting of a covalent single bond,
  • 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
  • K is C, no more than one of D , D , J , and J is
  • R , R , R , and R are each independently selected to maintain the tetravalent nature of carbon, trivalent nature of nitrogen, the divalent nature of 5 6 5 6 sulfur, and the divalent nature of oxygen and that D , D , J , and J are selected to maintain an aromatic ring system; b 20 21 + 20 21 22
  • Q is selected from the group consisting of NR R , NR R R ,
  • R , R , and R are independently selected from the group consisting of hydrido, alkyl, hydroxy, a ino, dialkylamino, alkylamino,
  • Q is optionally selected from the group consisting of
  • R 93 94 of, of R , R , and R is selected from the groujp consisting of hydroxy, amino,
  • R , R , R , and R are independently selected from the group consisting of hydrido, alkyl, hydroxy, amino, aminoalkyl, dialkylamino, alkylamino, and hydroxyalkyl; g
  • Q is selected from the group consisting of a single covalent bond
  • W is selected from 1 through 4 and W is selected from the group consisting of O, S, C(O), C(S), C(O)O, C(S)0, C(O)S, C(S)S, C(O)N(R 14 ), (R 14 )NC(O),
  • CR R C; vinylidene), ethynylidene (C ⁇ ; 1,2-ethynyl), 1,2-cyclopropyl, 1,2-cyclobutyl, 1,2-cyclohexyl, 13-cyclohexyl, 1,2-cyclopentyl, 1,3-cyclopentyl, 23-morpholinyl, 2,4-morpholinyl, 2,6-morpholinyl, 3,4-morpholinyl, 3,5- morpholinyl, 1,2-piperazinyl, 1,3-piperazinyl, 2,3-piperazinyl, 2,6-piperazinyl, 1,2-piperidinyl, 13-pi ⁇ eridinyl, 2,3-piperidinyl, 2,4-piperidinyl, 2,6-piperidinyl, 3,4-piperidinyl, 1,2-pyrrolidinyl, 13-pyrrolidinyl, 2,3-pyrrolidinyl, 2,4- pyrrolidinyl, 1,2-
  • R and R are selected from other than halo and cyano when
  • ⁇ y gg go i is optionally Q -Q wherein Q is selected from the group
  • W is selected from 1 through 2
  • W is selected from the group consisting of W 14 is selected from the group consisting of O, S, C(O), C(O)N(R ),
  • ⁇ is selected from the group consisting of
  • W ⁇ ⁇ is selected from the group consisting of
  • Y is optionally Q -Q wherein Q is (CH(R )) r -W , r is an
  • W is selected from the group consisting of 1,2-cyclobutyl, 1,2-cyclohexyl, 13-cyclohexyl, 1,4-cyclohexyl, 1,2-cyclopentyl, 1,3-cyclopentyl, 23-morpholinyl, 2,4-morpholinyl, 2 ⁇ -morpholinyl, 2,6- morpholinyl, 3,4-morpholinyl, 3,5-morpholinyl, 1,2-piperazinyl, 1,3-piperazinyl, 1,4-piperazinyl, 23-piperazinyl, 2,5-piperazinyl, 2,6-piperazinyl, 1,2-piperidinyl, 1,3-piperidinyl, 1,4-piperidinyl, 2,3-piperidinyl, 2,4-piperidinyl, 2,5-piperidinyl, 2,6-piperidinyl, 3,4-piperidinyl, 3,5-piperidinyl, 3,6-piperidinyl, 3,5-piperidin
  • ⁇ is optionally Q -Q wherein Q is (CH(R )) r - W , r is an
  • ⁇ ⁇ is selected from the group consisting of
  • 1,4-indenyl 1,5-indenyl, 1,6-indenyl, 1,7-indenyl, 2,7-indenyl, 2,6-indenyl, 2,5- indenyl, 2,4-indenyl, 3 ,4-indenyl, 3 ,5-indenyl, 3 ,6-indenyl, 3 ,7-indenyl, 2,4- benzofuranyl, 2,5-benzof uranyl, 2,6-benzofuranyl, 2,7-benzof uranyl, 3,4- benzofuranyl, 3,5-benzofuranyl, 3,6-benzofuranyl, 3,7-benzofuranyl, 2,4- benzothiophenyl, 2,5-benzothiophenyl, 2,6-benzotbiophenyl, 2,7- benzothiophenyl, 3,4-benzothiophenyl, 3,5-benzothiophenyl, 3,6- benzothiophenyl, 3,5-benz
  • each carbon and hyrido containing nitrogen member of the ring of the W other than the points of attachment is optionally substituted with one or more of the group consisting of R , R , R , and R , with the proviso that Q is
  • W is selected from the group consisting of
  • 1,4-indenyl 1,5-indenyl, 1,6-indenyl, 1,7-indenyl, 2,7-indenyl, 2,6-indenyl, 2,5- indenyl, 2,4-indenyl, 3,4-indenyl, 3,5-indenyl, 3,6-indenyl, 3,7-indenyl, 2,4- benzofuranyl, 2,5-benzofuranyl, 2,6-benzofuranyl, 2,7-benzof uranyl, 3,4- benzofuranyl, 3, 5-benzof uranyl, 3,6-benzofuranyl, 3, 7-benzof uranyl, 2,4- benzothiophenyl, 2,5-benzothiophenyl, 2,6-benzothiophenyl, 2,7- benzothiophenyl, 3,4-benzothiophenyl, 3,5- benzothiophenyl, 3,6- benzothiophenyl, 3,7-benzothiophenyl,
  • each carbon and hyrido containing nitrogen member of the ring of the W other than the points of attachment is optionally substituted with one or more of the group consisting of R , R , R , and R , with the proviso that Q is
  • J is O;
  • B is the Formula:
  • R , R , R , R , R , R , R , R , R , R , and R are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkylenedioxy, haloalkylthio, alkanoyloxy, alkoxy, alkoxyalkyl, haloalkoxylalkyl, hydroxy, amino, alkoxya ino, nitro, alkylamino, alkylthio, aikylthioalkyl, alkylsulfinyl, alkylsulfonyl, alkylsulfonylalkyl, aryl, aralkyl, cycloaikyl, cycloalkylalkyl, alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosul
  • R , R , R , R , and R are optionally selected from the group
  • R , and R are substitutents for other than B ;
  • R , R , R , R , R , and R are independently optionally
  • each member of group B is optionally selected from the group consisting of hydrido, trialkylsilyl, C2-C8 alkyl, C3-C8 alkylenyl, C3-C8 alkenyl, C3-C8 alkynyl, and C2-C8 haloalkyl, wherein each member of group B may be optionally substituted at any carbon up to and including 6 atoms from the point of
  • B is selected from the group consisting of C3-C12 cycloaikyl and C4-
  • each ring carbon may be optionally substituted with R
  • a ring carbon other than the ring carbon at the point of attachment of B to A may be optionally substituted with oxo provided that no more than one ring carbon is substituted by oxo at the same time
  • ring carbons and a nitrogen adjacent to the carbon at the point of attachment may be optionally substituted
  • atoms from the point of attachment may be substituted with R , a ring carbon
  • attachment may be substtaed with R 12 , anng carbon or nitrogen three atoms
  • R and R positions may be substituted with R ;
  • A is selected from the group consisting of single covalent bond
  • pa is an integer selected from 0 through 6
  • W is an integer selected from 0 through 7
  • 7 7 is selected from the group consisting of O, S, C(O), (R )NC(0), (R )NC(S),
  • 7 and N(R ) with the proviso that no more than one of the group consisting of rr and pa is 0 at the same time; 7 R is selected from the group consisting of hydrido, hydroxy, and alkyl;
  • R is selected from the group consisting of hydrido, hydroxy, halo, alkyl, and haloalkyl;
  • ⁇ is selected from the group consisting of NH and NOH;
  • M is selected from the group consisting of N and R -C;
  • R is selected from the group consisting of hydrido, alkyl, alkenyl, cyano, halo, haloalkyl, haloalkoxy, haloalkylthio, amino, aminoalkyl, alkylamino, amidino, hydroxy, hydroxyamino, alkoxy, hydroxyalkyl, alkoxyamino, thiol, and alkylthio;
  • R 2 is Z°-Q
  • Z is selected from the group consisting of covalent single bond
  • W (CH(R ))
  • CR CR , 1,2-cyclopropyl, 1,2-cyclobutyl, 1 - cyclohexyl, 1,3-cyclohexyl, 1,2-cyclopentyl, 1,3-cyclopentyl, 23-morpholinyl, 2,4-morpholinyl, 2,6-morpholinyl, 3,4-morpholinyl, 3,5-morpholinyl, 1,2- piperazinyl, 1,3-piperazinyl, 23-piperazinyl, 2,6-piperazinyl, 1,2-piperidinyl, 1,3- piperidinyl, 23-piperidinyl, 2,4-piperidinyl, 2,6-piperidinyl, 3,4-piperidinyl, 1,2- pyrrolidinyl, 1,3-pyrrolidinyl, 2,3-pyrrolidinyl, 2,4-pyrrolidinyl, 2,5-pyrrolidinyl, 3,4-pyrrolidinyl, 2,3-t
  • R and R are independently selected from the group consisting of amidino, hydroxyamino, hydrido, hydroxy, amino, and alkyl;
  • Q is selected from the group consisting of hydrido, with the proviso that Z is other than a covalent single bond, and the formula (II):
  • D , DD ., ⁇ J , J J 2 : and - K 1 are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more
  • 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;
  • 4a 4b K is (CR R ) n wherein n is an integer selected from 1 through 2;
  • R and R are independently selected from the group consisting of halo, hydrido, hydroxyalkyl, alkyl, alkoxyalkyl, aikylthioalkyl, and haloalkyl;
  • E is E , when K is (CR R ) n , wherein E is selected from the group
  • Y° is formula (IV): wherein D , D , J , and J are independently selected from the group consisting of C, N, O, S and a covalent bond with the provisos that no more
  • K is C, no more than one of D , D , J , and J is
  • C C ⁇ be a covalent bond when two of D , D , J , and J are O and S, and no more
  • 19 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;
  • R , R , R , and R are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, haloalkylthio, alkoxy, hydroxy, amino, nitro, alkoxyamino, alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, alkenyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, alkylenylamino, haloalkoxyalkyl, carboalkoxy, and cyano; v. 90 91
  • Q is selected from the group consisting of NR R , , Q wherein
  • Q is hydrido, N(R )C(NR )N(R )(R ), and C(NR )NR R .
  • R is hydroxy, amino, alkylamino, or dialkylamino at the same time; 20 21 23 24 25 26
  • R , R , R , R , R , and R are independently selected from the group consisting of hydrido, alkyl, hydroxy, amino, aminoalkyl, dialkylamino, alkylamino, and hydroxyalkyl; s Q is selected from the group consisting of a single covalent bond,
  • W is selected from 1 through 3 and W is selected from the group consisting of
  • R is selected from the group consisting of hydrido, halo, alkyl, and haloalkyl;
  • R and R are independently selected from the group consisting of hydrido, alkyl, and haloalkyl;
  • 38 R is optionally selected from the group consisting of aroyl and heteroaroyl;
  • Y° is optionally Q b -Q ss wherein Q SS is (CH(R 14 )) e -W 2 -(CH(R 15 )) h ,
  • e and h are integers independently selected from 1 through 2 and w 2
  • Q b -Q ssssr wherein Q SSSS is (CH(R 38 )) r -W 5 and Q Ssssr is (CH(R 38 )) r -W 6 , r is
  • W and W are independently selected from the group consisting of 1,4-indenyl, 1,5-indenyl, 1,6-indenyl, 1,7- indenyl, 2,7-indenyl, 2,6-indenyl, 2,5-indenyl, 2,4-indenyl, 3,4-indenyl, 3,5- indenyl, 3,6-indenyl, 3,7-indenyl, 2,4-benzofuranyl, 2,5-benzofuranyl, 2,6- benzofuranyl, 2,7-benzofuranyl, 3,4-benzofuranyl, 3,5-benzofuranyl, 3,6- benzofuranyl, 3, 7-benzof uranyl, 2,4-benzothiophenyl, 2,5-benzothiophenyl, 2,6- benzotbiophenyl, 2,7-benzothiophenyl, 3,4-benzothiophenyl, 3,5- benzothiophenyl, 3,6-benz
  • J is O;
  • B is phenyl or a heteroaryl of 5 or 6 ring members, wherein a nitrogen with a removable hydrogen or a carbon adjacent to the carbon at the point of
  • R 33 optionally substituted by R , a nitrogen with a removable hydrogen or a
  • R 35 optionally substituted by R , and a nitrogen with a removable hydrogen or a
  • R , R , R , R , R , R , R , R , R , R , and R are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkylenedioxy, haloalkylthio, alkanoyloxy, alkoxy, cycloalkoxy, cycloalkylalkoxy, aralkoxy, aryloxy, heteroaryloxy, heteroaralkoxy ,heterocyclyloxy, heterocyclylalkoxy, alkoxyalkyl, haloalkoxylalkyl, hydroxy, amino, alkoxya ino, nitro, alkylamino, N-alkyl-N-arylamino, arylamino, aralkylamino, heteroarylamino, heteroaralkyla ino, heterocyclylamino, heterocyclylalkylamino, al
  • R , R , R , and R are independently optionally Q ;
  • each member of group B is optionally selected from the group consisting of hydrido, trialkylsilyl, C2-C8 alkyl, C3-C8 alkylenyl, C3-C8 alkenyl, C3-C8 alkynyl, and C2-C8 haloalkyl, wherein each member of group B may be optionally substituted at any carbon up to and including 6 atoms from the point of
  • B is optionally a C3-C12 cycloaikyl or a C4-C9 heterocyclyl, wherein
  • each ring carbon may be optionally substituted with R
  • a ring carbon other than the ring carbon at the point of attachment of B to A may be optionally substituted with oxo provided that no more than one ring carbon is substituted by oxo at the same time
  • the point of attachment may be optionally substituted with R or R , a ring
  • attachment may be substituted with R , a ring carbon or nitrogen adjacent to
  • R 34 is selected from the group consisting of single covalent bond
  • W is selected from the group
  • 7 R is selected from the group consisting of hydrido, hydroxy, and alkyl
  • R is selected from the group consisting of hydrido, hydroxy, halo, alkyl, and haloalkyl;
  • ⁇ is selected from the group consisting of NH and NOH;
  • M is N or R X -C
  • R is selected from the group consisting of hydrido, alkyl, alkenyl, cyano, halo, haloalkyl, haloalkoxy, haloalkylthio, amino, arninoalkyl, alkylamino, amidino, hydroxy, hydroxyamino, alkoxy, hydroxyalkyl, alkoxyamino, thiol, and alkylthio;
  • R 2 is Z°-Q
  • Z is selected from the group consisting of a covalent single bond, o 42 o
  • g is an integer selected from 1 through 3 with the proviso that Z is directly bonded to the pyrimidinone ring;
  • Z is optionally W -(CH(R )) ⁇ wherein h is 0 or 1 and w is
  • CR CR , 1,2-cyclopropyl, 1,2-cyclobutyl, 1,2-cyclohexyl, 13-cyclohexyl, 1,2-cyclopentyl, 1,3-cyclopentyl, 23 -morpholinyl, 2,4-morpholinyl, 2,6-morpholinyl, 3,4-morpholinyl, 3,5-morpholinyl, 1,2-piperazinyl, 13- ⁇ i ⁇ erazinyl, 23-piperazinyl, 2,6-piperazinyl, 1,2-piperidinyl, 13- ⁇ iperidinyl, 2,3-piperidinyl, 2,4-piperidinyl, 2,6-piperidinyl, 3,4-piperidinyl, 1,2-pyrrolidinyl, 1,3-pyrrolidinyl, 23-pyrrolidinyl, 2,4-pyrrolidinyl, 2,5-pyrrolidinyl, 3,4-pyrrolidinyl,
  • R and R are independently selected from the group consisting of amidino, hydroxyamino, hydrido, hydroxy, amino, and alkyl;
  • Q is phenyl or a heteroaryl of 5 or 6 ring members, wherein a nitrogen with a removable hydrogen or a carbon adjacent to the carbon at the point of
  • R 13 optionally substituted by R , a nitrogen with a removable hydrogen or a
  • Q is optionally hydrido with the proviso that Z is other than a covalent single bond
  • 4a 4b K is (CR R ) n wherein n isl or 2;
  • R and R are independently selected from the group consisting of halo, hydrido, hydroxyalkyl, alkyl, alkoxyalkyl, aikylthioalkyl, and haloalkyl;
  • E is E , when K is (CR R ) n , wherein E is selected from the group
  • S(0) 2 , (R ? )NS(0) 2 , and S(0) 2 N(R 7 ); is phenyl or a heteroaryl of 5 or 6 ring members, wherein one carbon s of said phenyl or said heteroaryl is substituted by Q , a carbon two or three s b contiguous atoms from the point of attachment of Q is substituted by Q , a s carbon adjacent to the point of attachment of Q is optionally substituted by
  • R , R , R , and R are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, haloalkylthio, alkoxy, hydroxy, amino, nitro, alkoxyamino, lower alkylamino, alkylthio, alkylsulfmyl, alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, alkenyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, haloalkoxyalkyl, carboalkoxy, and cyano;
  • R or R is optionally selected from the group consisting of
  • Q is selected from the group consisting of NR R , aminoalkyl,
  • R and R are selected from the group consisting of hydroxy, amino, alkylamino, and dialkylamino at the same time;
  • R , R , R , R , R , and R are independently selected from the group consisting of hydrido, alkyl, hydroxy, aminoalkyl, amino, dialkylamino, alkylamino, and hydroxyalkyl; S
  • Q is selected from the group consisting of a single covalent bond
  • W is selected from 1 through 3 and W is selected from the group consisting of
  • R is selected from other than halo when ⁇ 7 OO 1 ⁇ directly bonded to N and that (CR R , and (CH(R )) c are bonded to E ;
  • R is selected from the group consisting of hydrido, halo, alkyl, and haloalkyl;
  • R and R are independently selected from the group consisting of hydrido, alkyl, and haloalkyl;
  • R is optionally aroyl or heteroaroyl, wherein R is optionally substituted at from one through three of the ring carbons with a substituent selected from the group consisting of R , R , R , and R ;
  • Y is optionally Y wherein Y is Q -Q ;
  • Y° is optionally Q b -Q SS wherein Q SS is (CH(R 14 )) e -W 2 -(CH(R 15 )) h ,
  • W and W are independently selected from the group consisting of
  • 1,4-indenyl 1,5-indenyl, 1,6-indenyl, 1,7-indenyl, 2,7-indenyl, 2,6-indenyl, 2,5- indenyl, 2,4-indenyl, 3,4-indenyl, 3-5-indenyl, 3,6-indenyl, 3,7-indenyl, 2,4- benzofuranyl, 2,5-benzof uranyl, 2,6-benzof uranyl, 2,7-benzof uranyl, 3,4- benzofuranyl, 3, 5-benzof uranyl, 3,6-benzofuranyl, 3,7-benzofuranyl, 2,4- benzothiophenyl, 2,5-benzothiophenyl, 2,6-benzothio ⁇ henyl, 2,7- benzothiophenyl, 3,4-benzothio ⁇ henyl, 3,5-benzothiophenyl, 3,6- benzothiophenyl, 3,7-benzothioph
  • J is O
  • R , R , R , R , and R are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkylenedioxy, haloalkylthio, alkanoyloxy, alkoxy, hydroxy, amino, alkoxyamino, alkanoyl, haloalkanoyl, nitro, lower all-ylamino, allcylthio, aryl, aralkyl, cycloaikyl, cycloalkylalkyl, alkylsulfonamido, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, alkyl, alkenyl, halo, haloalkyl, haloalkenyl, haloalkoxy, hydroxyalkyl, alkylenylamino, carboalkoxy, carb
  • B is selected from the group consisting of C3-C12 cycloaikyl and C4-
  • each ring carbon may be optionally substituted with R
  • a ring carbon other than the ring carbon at the point of attachment of B to A may be optionally substituted with oxo provided that no more than one ring carbon is substituted by oxo at the same time
  • ring carbons and a nitrogen adjacent to the carbon at the point of attachment may be optionally substituted
  • atoms from the point of attachment may be substituted with R , a ring carbon
  • R a ring carbon three atoms from the point of attachment and adjacent to the
  • R position may be substituted with R , and a ring carbon four atoms from
  • R , R , R , R , and R are independently selected from the group consisting of hydrido, acetamido, haloacetamido, alkoxyamino, alkanoyl, haloalkanoyl, amidino, guanidino, alkylenedioxy, haloalkylthio, alkoxy, hydroxy, amino, lower alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylsulfonamido, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, airiinoalkyl, carboalkoxy, carboxyalkyl, carboxy, carboxamido, and cyano; 1 Q i i ⁇ 1
  • R , R , R , R , and R are optionally selected from the group
  • R , and R are substitutents for other than B;
  • A is selected from the group consisting of single covalent bond and
  • W is selected from the group
  • R is selected from the group consisting of hydrido, hydroxy and alkyl
  • R is selected from the group consisting of hydrido, hydroxy, halo, alkyl, and haloalkyl; ⁇ is NH; M is selected from the group consisting of N and R -C; R 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;
  • R 2 is Z°-Q; Z is selected from the group consisting of covalent single bond and
  • 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
  • R and two atoms from the carbon at the point of attachment is optionally
  • K is CHR wherein R is selected from the group consisting of hydrido, hydroxyalkyl, alkyl, alkoxyalkyl, aikylthioalkyl, and haloalkyl;
  • E is selected from the group consisting of a covalent single bond
  • 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
  • K is C, no more than one of D , D , J , and J is
  • J , , , ⁇ 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, alkylsulfmyl, alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, and cyano;
  • R and R are optionally Q with the proviso that no more than one
  • Q is selected from the group consisting of NR R , Q wherein Q is
  • R , R , R , R , R , and R are independently selected from the group consisting of hydrido, alkyl, hydroxy, amino, alkylamino and dialkylamino;
  • g Q is selected from the group consisting of a single covalent bond,
  • W is selected from 1 through 3 and W is selected from the group consisting of
  • R is selected from the group consisting of hydrido, halo, alkyl, and haloalkyl; 37 38
  • R and R are independently selected from the group consisting of hydrido, alkyl, and haloalkyl;
  • R is optionally selected from the group consisting of aroyl and heteroaroyl;
  • Y° is optionally Q b -Q SS wherein Q SS is (CH(R 14 )) e -W 2 -(CH(R 15 )) h ,
  • e and h are integers independently selected from 1 through 2 and w 2
  • J is O
  • B is phenyl or a heteroaryl of 5 or 6 ring members, wherein a carbon adjacent to the carbon at the point of attachment is optionally substituted by
  • R optionally substituted by R , a carbon adjacent to R and two atoms from the
  • R , R , R , R , and R are independentiy selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkylenedioxy, haloalkylthio, alkanoyloxy, alkoxy, hydroxy, amino, alkoxyamino, haloalkanoyl, nitro, lower alkylamino, alkylthio, aryl, aralkyl, cycloaikyl, cycloalkylalkyl, heteroaryl, heterocyclyl, alkylsulfonamido, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, alkyl, alkenyl, halo, haloalkyl, haloalkenyl, haloalkoxy, hydroxyalkyl, hydroxyhaloalkyl, aminoalkyl,
  • B is optionally a C3-C12 cycloaikyl or C4-C9 heterocyclyl, wherein
  • each ring carbon may be optionally substituted with R
  • a ring carbon other than the ring carbon at the point of attachment of B to A may be optionally substituted with oxo provided thafr-no more than one ring carbon is substituted by oxo at the same time
  • the point of attachment may be optionally substituted with R or R , a nng
  • attachment may be substituted with R , a ring carbon or nitrogen adjacent to
  • R , R , R , R , and R are independently selected from the group consisting of hydrido, acetamido, haloacetamido, alkoxyamino, alkanoyl, haloalkanoyl, amidino, guanidino, alkylenedioxy, haloalkylthio, alkoxy, cycloalkoxy, cycloalkylalkoxy, aralkoxy, aryloxy, heteroaryloxy, heteroaralkoxy Jheterocyclyloxy, heterocyclylalkoxy, hydroxy, amino, alkylamino, N-alkyl-N-arylamino, arylamino, aralkylamino, heteroarylamino, heteroaralkylamino, heterocyclylarnino, heterocyclylalkylamino, alkylthio, alkylsulfmyl, arylsulfinyl, aralkylsul
  • A is a single covalent bond or (CH(R )) pa -(W ) ⁇ wherein rr is 0 or
  • pa is an integer selected from 0 through 3
  • W is selected from the group
  • R is selected from the group consisting of hydrido, hydroxy and alkyl
  • R is selected from the group consisting of hydrido, hydroxy, halo, alkyl, and haloalkyl; ⁇ is NH;
  • M is selected from the group consisting of N and R -C;
  • R 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;
  • R 2 is Z°-Q
  • Z is selected from the group consisting of a covalent single bond, W -(CH(R )) p wherein p is an integer selected from 0 through 3 and W is
  • Z is optionally W -(CH(R )) b wherein h is 0 or 1 and W is selected from the group consisting ofl,2-cyclopropyl, 1,2-cyclobutyl, 1,2-cyclohexyl, 1,3-cyclohexyl, 1,2-cyclopentyl, 1,3-cyclopentyl, 2,3-morpholinyl, 2,4-morpholinyl, 2,6-morpholinyl, 3,4-morpholinyl, 3-5-morpholinyl, 1,2-piperazinyl, 1,3-piperazinyl, 2,3-piperazinyl, 2,6-piperazinyl, 1,2-piperidinyl, 13-piperidinyl, 23-piperidinyl, 2,4-piperidinyl, 2,6-piperidinyl, 3,4-piperidinyl, 1,2-pyrrolidinyl, 13-py ⁇ Olidinyl, 2,3-pyrrolidinyl, 2,4-pyrrolidinyl,
  • 41 R is selected from the group consisting of hydrido, hydroxy, and alkyl
  • R is selected from the group consisting of amidino, hydroxyamino, hydrido, hydroxy, amino, and alkyl;
  • Q is phenyl or a heteroaryl of 5 or 6 ring members, wherein a carbon
  • Q is optionally hydrido with the proviso that Z is selected from other than a covalent single bond
  • K is CHR wherein R is selected from the group consisting of hydrido, hydroxyalkyl, alkyl, alkoxyalkyl aikylthioalkyl, and haloalkyl; E is selected from the group consisting of a covalent single bond,
  • Y is phenyl or a heteroaryl of 5 or 6 ring members, wherein one carbon s of said phenyl or said heteroaryl is substituted by Q , a carbon two or three s b contiguous atoms from the point of attachment of Q is substituted by Q , a g carbon adjacent to the point of attachment of Q is optionally substituted by
  • R , R , R , and R are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, haloalkylthio, alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, alkylthio, alkylsulfmyl, alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, and cyano;
  • R or R is optionally selected from the group consisting of
  • Q is selected from the group consisting of NR R , Q wherein Q is
  • R and R is selected from the group consisting of hydroxy, amino, alkylamino, and dialkylamino at the same time and that no more
  • R is selected from the group consisting of hydroxy, amino, alkylamino, and dialkylamino at the same time;
  • R , R , R , R , R , and R are independently selected from the group consisting of hydrido, alkyl, hydroxy, amino, alkylamino and dialkylamino; S
  • Q is selected from the group consisting of a single covalent bond
  • W is selected from 1 through 3 and W is selected from the group consisting of
  • R is selected from the group consisting of hydrido, halo, alkyl, and haloalkyl;
  • R and R are independently selected from the group consisting of hydrido, alkyl, and haloalkyl;
  • R is optionally aroyl or heteroaroyl, wherein R is optionally substituted at from one tlirough three of the ring carbons with a substituent selected ., - f.rom th-.e group consi •sti ⁇ ng of - ⁇ R16 , R relieve1 , R -,18 , and R 19 ;
  • Y is optionally Y wherein Y is Q -Q ;
  • Y° is optionally Q b -Q ss wherein Q SS is (CH(R 14 )) e -W 2 -(CH(R 15 )) h ,
  • J is O;
  • B is the Formula:
  • 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 Q ;
  • A is selected from the group consisting of single covalent bond and
  • W is selected from the group
  • R is selected from the group consisting of hydrido, hydroxy and alkyl
  • R is selected from the group consisting of hydrido, halo, alkyl, and haloalkyl; ⁇ is NH;
  • 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 Z°-Q;
  • Z is selected from the group consisting of a covalent single bond, O, S,
  • 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
  • R , R , and R are independently selected from the group consisting of hydrido, hydroxy, amino, amidino, guanidino, lower alkylamino, alkylthio, alkylsulfonarnido, alkylsulfinyl, alkylsulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboxy, carboxamido, and cyano;
  • R and R are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkyl, alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, alkylsulfonarnido, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, hydroxyalkyl, aminoalkyl, carboalkoxy, carboxy, carboxyalkyl, amidocarbonyl, halo, haloalkyl, and cyano;
  • K is CH 2 ;
  • E° is C(0)N(H);
  • 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
  • K is C, no more than one of D , D , J , and J is
  • D , D , J , and J must be a covalent bond when two of D , D , J , and J are
  • R , R , R , and R are independently selected from the group consisting of hydrido, amidino, guanidino, carboxy, haloalkylthio, alkoxy, hydroxy, a ino, lower alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, and cyano;

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Abstract

L'invention concerne des composés d'aryle polycyclique substitué et de pyrimidinone d'hétéroaryle utilisés comme inhibiteurs de sérine protéases de la coagulation, et des composés, des compositions et des méthodes destinés à la thérapie d'anticoagulation permettant de traiter et de prévenir plusieurs affections thrombotiques, notamment des maladies cardio-vasculaires et celles liées aux artères coronariennes.
PCT/US2000/031901 2000-05-18 2000-11-20 Aryle polycyclique substitue et pyrimidinones d'heteroaryle utiles a l'inhibition selective de la coagulation WO2001087851A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
AU2001222501A AU2001222501A1 (en) 2000-05-18 2000-11-20 Substituted polycyclic aryl and heteroaryl pyrimidinones useful for selective inhibition of the coagulation cascade
US10/275,856 US7015223B1 (en) 2000-11-20 2000-11-20 Substituted polycyclic aryl and heteroaryl 1,2,4-triazinones useful for selective inhibition of the coagulation cascade

Applications Claiming Priority (2)

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US09/574,739 US6750342B1 (en) 1999-05-19 2000-05-18 Substituted polycyclic aryl and heteroaryl pyrimidinones useful for selective inhibition of the coagulation cascade
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WO2003029224A1 (fr) * 2001-10-03 2003-04-10 Pharmacia Corporation Composes heterocycliques insatures a 6 chainons utiles pour l'inhibition selective de reactions en cascade de la coagulation
WO2003029216A1 (fr) * 2001-10-03 2003-04-10 Pharmacia Corporation Composes heterocycliques a 6 chainons utiles dans l'inhibition selective de la cascade de la coagulation
US7094783B2 (en) 2002-06-26 2006-08-22 Bristol-Myers Squibb Company Bicyclic pyrimidinones as coagulation cascade inhibitors

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WO1993021214A1 (fr) * 1992-04-16 1993-10-28 Zeneca Limited Peptides d'acide alpha-aminoboronique et leur utilisation comme inhibiteurs d'elastase
US5441960A (en) * 1992-04-16 1995-08-15 Zeneca Limited 1-pyrimidinylacetamide human leukocyte elastate inhibitors
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EP0826671A1 (fr) * 1995-04-27 1998-03-04 The Green Cross Corporation Composes heterocycliques amides et leur utilisation medicinale
WO1997046207A2 (fr) * 1996-06-07 1997-12-11 Corvas International, Inc. Derives aromatiques heterocycliques utilises comme inhibiteurs enzymatiques
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EP0936216A1 (fr) * 1996-09-06 1999-08-18 Nippon Kayaku Kabushiki Kaisha Nouveaux derives d'acetamide et inhibiteurs de protease
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EP0940400A1 (fr) * 1996-10-25 1999-09-08 Yoshitomi Pharmaceutical Industries, Ltd. Nouveaux composes d'amide heterocycliques et leur utilisation a des fins medicinales
WO1998047876A1 (fr) * 1997-04-24 1998-10-29 Akzo Nobel N.V. Derives heterocycliques et leur utilisation en tant qu'agents antithrombotiques
WO1999036426A1 (fr) * 1998-01-20 1999-07-22 Warner-Lambert Company ALDEHYDE DE L'ACIDE N-[2-(5-BENZYLOXYCARBONYL-AMINO-6-OXO-2-(4-FLUOROPHENYL)-1,6-DIHYDRO-1-PYRIMIDINYL)ACETOXYL]-L-ASPARTIQUE, INHIBITEUR in vivo DE L'ENZYME DE CONVERSION DE L'INTERLEUKINE-1$g(b)
WO1999062538A1 (fr) * 1998-06-03 1999-12-09 Cortech Inc. Alpha-ceto-oxadiazoles en tant qu'inhibiteurs de la serine protease
WO2000069832A1 (fr) * 1999-05-19 2000-11-23 Pharmacia Corporation Pyrimidinones aryle et heteroaryle polycycliques substituees utilisees comme anticoagulants

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003029224A1 (fr) * 2001-10-03 2003-04-10 Pharmacia Corporation Composes heterocycliques insatures a 6 chainons utiles pour l'inhibition selective de reactions en cascade de la coagulation
WO2003029216A1 (fr) * 2001-10-03 2003-04-10 Pharmacia Corporation Composes heterocycliques a 6 chainons utiles dans l'inhibition selective de la cascade de la coagulation
US6969715B2 (en) 2001-10-03 2005-11-29 Pharmacia Corporation 6-membered heterocyclic compounds useful for selective inhibition of the coagulation cascade
US7094783B2 (en) 2002-06-26 2006-08-22 Bristol-Myers Squibb Company Bicyclic pyrimidinones as coagulation cascade inhibitors

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