WO2011017296A1 - 4, 5, 6-trisubstituted pyrimidine derivatives as factor ixa inhibitors - Google Patents

4, 5, 6-trisubstituted pyrimidine derivatives as factor ixa inhibitors Download PDF

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WO2011017296A1
WO2011017296A1 PCT/US2010/044208 US2010044208W WO2011017296A1 WO 2011017296 A1 WO2011017296 A1 WO 2011017296A1 US 2010044208 W US2010044208 W US 2010044208W WO 2011017296 A1 WO2011017296 A1 WO 2011017296A1
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compound
aryl
heteroaryl
alkyl
group
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PCT/US2010/044208
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French (fr)
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Mariappan V. Chelliah
Samuel Chackalamannil
William J. Greenlee
Keith A. Eagen
Zhuyan Guo
Martin C. Clasby
Yan Xia
Charles L. Jayne
Michael Dwyer
Kartik M. Keertikar
Tin-Yau Chan
Li Wang
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Schering Corporation
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Priority to EP10744778.1A priority Critical patent/EP2462123B1/en
Priority to US13/388,628 priority patent/US8609676B2/en
Publication of WO2011017296A1 publication Critical patent/WO2011017296A1/en

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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
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/34—One oxygen atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • 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
    • 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
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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

Definitions

  • the present invention relates to heterocyclic compounds useful as serine protease inhibitors, regulators or modulators, in particular, serine protease enzymes of the coagulation cascade and/or contact activation system; for example thrombin, factor XIa, factor Xa, factor IXa, factor Vila, and/or plasma kallikrein.
  • serine protease enzymes of the coagulation cascade and/or contact activation system for example thrombin, factor XIa, factor Xa, factor IXa, factor Vila, and/or plasma kallikrein.
  • compounds that are selective factor IXa inhibitors pharmaceutical compositions comprising the compounds, and methods of treatment using the compounds and compositions to treat various
  • thromboembolic disorders such as acute coronary syndrome, atrial fibrillation, myocardial infarction, and atherosclerosis.
  • Factor IXa is a plasma serine protease involved in the regulation of blood coagulation. While blood coagulation is a necessary and important part of the regulation of an organism's homeostasis, abnormal blood coagulation can also have deleterious effects. For instance, thrombosis is the formation or presence of a blood clot inside a blood vessel or cavity of the heart. Such a blood clot can lodge in a blood vessel blocking circulation and inducing a heart attack or stroke. Thromboembolic disorders are the largest cause of mortality and disability in the industrialized world.
  • Blood coagulation involves three distinct phases: initiation, priming and propagation. 1 >2>3 Initiation involves binding of tissue factor (TF) to activated factor VII, a circulating coagulation factor. Blood, in general is not exposed to TF which is a transmembrane protein expressed on extravascular cells. Vasular injury causes the TF-bearing cells to be exposed to blood, and initiates the coagulation process. 1 The TF/Vlla complex activates factors IX and X. 1 ' 4 Factor IXa is relatively unstable in plasma and diffuses toward activated platelets. Factor Xa on the other hand, is unstable in plasma and is rapidly inhibited by TF pathway inhibitor and antithrombin III.
  • TF tissue factor
  • Factor Xa binds factor Va on the surface of TF-bearing cells. 1 7 In turn, the Xa/Va complex generates a small but sufficient amount of thrombin to cause platelet activation. 1 ' 8 ' 9
  • Thrombin activates platelets and coagulation factors in the priming phase. 1 ' 2 Thrombin binds and cleaves platelet protease-activated receptors (PAR1 and PAR4), triggering a signaling cascade that catalyzes platelet activation and release of factor V from platelet ⁇ granules. Thrombin also activates factors V, VIII, and Xl. 1
  • thrombin generation is maximized on the surface of platelets.
  • the primed, activated platelets bind the IXa/Vllla "tenase" complex. Additional IXa is generated by factor XIa on the platelet surface. 10
  • the IXa/Vllla complex in physical proximity to Va, recruits factor X to the platelet surface for activation.
  • the Xa/Va complex on the platelet surface is protected from TF pathway inhibitor and antithrombin III. 11 ' 12
  • Factor IXa therefore represents an excellent target for anticoagulant therapy. 1
  • Ahmad SS London FS, Walsh PN.
  • the lipoprotein-associated coagulation inhibitor that inhibits the factor VII- tissue factor complex also inhibits factor Xa: insight into its possible mechanism of action. Blood. 1988; 71 : 335-343.
  • Rapaport Sl The extrinsic pathway inhibitor: a regulator of tissue factor-dependent blood coagulation. Thromb Haemost. 1991 ; 66: 6-15. 7. Monkovic DD, Tracy PB. Activation of human factor V by factor Xa and thrombin. Biochemistry. 1990; 29: 1118-1128.
  • Prothrombin protects factor Xa in the prothrombinase complex from inhibition by the heparin-antithrombin complex. Blood. 2001 ; 97: 2308-2313.
  • the present invention provides a novel class of heterocyclic compounds, pharmaceutical compositions comprising one or more said compounds, and methods for using said compounds for treating or preventing a thromboembolic disorder.
  • the present invention provides compounds of Formula (I):
  • X 1 is selected from the group consisting of a covalent bond, -S- and -O-;
  • R 1 is selected from the group consisting of halo, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein when each of said cycloalkyl, heterocyclyl, aryl and heteroaryl has substitutents on adjacent carbon atoms, said substituents can optionally be taken together with the carbon atoms to which they are attached to form a first five- or six-membered cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein when said first five- or six-membered cycloalkyl, heterocyclyl, aryl or heteroaryl has substitutents on adjacent carbon atoms, said substituents can optionally be taken together with the carbon atoms to which they are attached to form a second five- or six-membered cycloalkyl, heterocyclyl, aryl or heteroaryl;
  • X 2 is selected from the group consisting of a covalent bond, and -O-;
  • R 2 is selected from the group consisting of H, halogen and alkyl, with the proviso that when X 2 is a covalent bond, R 2 is halogen;
  • X 3 is selected from the group consisting of a covalent bond, -N(R)- and
  • R is H or alkyl
  • R 3 is selected from the group consisting of halo, alkyl, cycloalkyl, aryl and heteroaryl, wherein when each of said cycloalkyl, heterocyclyl, aryl and heteroaryl has substitutents on adjacent carbon atoms, said substituents can optionally be taken together with the carbon atoms to which they are attached to form a first five- or six-membered cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein when said first five- or six-membered cycloalkyl, heterocyclyl, aryl or heteroaryl has substitutents on adjacent carbon atoms, said substituents can optionally be taken together with the carbon atoms to which they are attached to form a second five- or six-membered cycloalkyl, heterocyclyl, aryl or heteroaryl; and
  • R 4 is selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; with the proviso that when X 1 and X 3 are both -O-, then -X 2 -R 2 is other than -halo.
  • the compounds of Formula I, or a pharmaceutically acceptable salt, solvate or ester thereof can be useful for treating or preventing a disorder or disease mediated by factor IXa, or a thromboembolic disorder (each disorder being a "Condition").
  • the present invention provides pharmaceutical compositions comprising at least one compound of Formula I or a
  • compositions can be useful for treating or preventing a Condition.
  • the present invention provides methods for treating a Condition, the method comprising administering to a patient an effective amount of at least one compound of Formula I, or a pharmaceutically acceptable salt, solvate or ester thereof.
  • the present invention provides at least one compound of Formula I or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof.
  • the compounds of formula I can be useful for treating or preventing a Condition in a patient.
  • Patient includes both human and animals.
  • “Mammal” means humans and other mammalian animals.
  • Alkyl means an aliphatic hydrocarbon group which may be straight or branched and comprising about 1 to about 20 carbon atoms in the chain.
  • Preferred alkyl groups contain about 1 to about 12 carbon atoms in the chain. More preferred alkyl groups contain about 1 to about 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkyl chain. "Lower alkyl” means a group having about 1 to about 6 carbon atoms in the chain which may be straight or branched.
  • Alkyl may be unsubstituted or optionally substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of halo, alkyl, aryl, cycloalkyl, heteroaryl, cyano, hydroxy, alkoxy, alkylthio, amino, -NH(alkyl), -NH(cycloalkyl), - N(alkyl) 2) -O-C(O)-alkyl, -O-C(O)-aryl, -O-C(O)-cycloalkyl, carboxy and -C(O)O- alkyl.
  • suitable alkyl groups include methyl, ethyl, n- propyl, isopropyl and t-butyl.
  • Alkenyl means an aliphatic hydrocarbon group containing at least one carbon-carbon double bond and which may be straight or branched and comprising about 2 to about 15 carbon atoms in the chain.
  • Preferred alkenyl groups have about 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 6 carbon atoms in the chain.
  • Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkenyl chain.
  • “Lower alkenyl” means about 2 to about 6 carbon atoms in the chain which may be straight or branched.
  • Alkenyl may be unsubstituted or optionally substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of halo, alkyl, aryl, cycloalkyl, heteroaryl, cyano, alkoxy and -S(alkyl).
  • substituents include ethenyl, propenyl, n-butenyl, 3- methylbut-2-enyl, n-pentenyl, octenyl and decenyl.
  • Alkylene means a difunctional group obtained by removal of a hydrogen atom from an alkyl group that is defined above.
  • alkylene include methylene, ethylene and propylene.
  • Alkynyl means an aliphatic hydrocarbon group containing at least one carbon-carbon triple bond and which may be straight or branched and comprising about 2 to about 15 carbon atoms in the chain.
  • Preferred alkynyl groups have about 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 4 carbon atoms in the chain.
  • Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkynyl chain.
  • “Lower alkynyl” means about 2 to about 6 carbon atoms in the chain which may be straight or branched.
  • alkynyl groups include ethynyl, propynyl, 2-butynyl and 3-methylbutynyl.
  • Alkynyl may be unsubstituted or optionally substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of alkyl, aryl and cycloalkyl.
  • Aryl means an aromatic monocyclic or multicyclic ring system comprising about 6 to about 14 carbon atoms, preferably about 6 to about 10 carbon atoms.
  • the aryl group can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined herein.
  • suitable aryl groups include phenyl and naphthyl.
  • Heteroaryl means an aromatic monocyclic or multicyclic ring system comprising about 5 to about 14 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the ring atoms is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. Preferred heteroaryls contain about 5 to about 6 ring atoms.
  • the "heteroaryl” can be optionally substituted by one or more "ring system substituents" which may be the same or different, and are as defined herein.
  • the prefix aza, oxa or thia before the heteroaryl root name means that at least a nitrogen, oxygen or sulfur atom respectively, is present as a ring atom.
  • heteroaryl may also include a heteroaryl as defined above fused to an aryl as defined above.
  • suitable heteroaryls include pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, pyridone (including N-substituted pyridones), isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl, 1 ,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, oxindolyl, imidazo[1 ,2-a]pyridinyl, imidazo[2,1 -b]thiazolyl,
  • Aralkyl or “arylalkyl” means an aryl-alkyl- group in which the aryl and alkyl are as previously described. Preferred aralkyls comprise a lower alkyl group. Non-limiting examples of suitable aralkyl groups include benzyl, 2- phenethyl and naphthalenylmethyl. The bond to the parent moiety is through the alkyl.
  • Alkylaryl means an alkyl-aryl- group in which the alkyl and aryl are as previously described. Preferred alkylaryls comprise a lower alkyl group. Non- limiting example of a suitable alkylaryl group is tolyl. The bond to the parent moiety is through the aryl.
  • Cycloalkyl means a non-aromatic mono- or multicyclic ring system comprising about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms. Preferred cycloalkyl rings contain about 5 to about 7 ring atoms.
  • the cycloalkyl can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined above.
  • suitable monocyclic cycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.
  • suitable multicyclic cycloalkyls include 1 -decalinyl, norbornyl, adamantyl and the like.
  • Cycloalkylalkyl means a cycloalkyl moiety as defined above linked via an alkyl moiety (defined above) to a parent core.
  • suitable cycloalkylalkyls include cyclohexylmethyl, adamantylmethyl and the like.
  • Cycloalkenyl means a non-aromatic mono or multicyclic ring system comprising about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms which contains at least one carbon-carbon double bond. Preferred cycloalkenyl rings contain about 5 to about 7 ring atoms.
  • the cycloalkenyl can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined above.
  • suitable monocyclic cycloalkenyls include cyclopentenyl, cyclohexenyl,
  • cyclohepta-1 ,3-dienyl and the like.
  • a suitable multicyclic cycloalkenyl is norbornylenyl.
  • Cycloalkenylalkyl means a cycloalkenyl moiety as defined above linked via an alkyl moiety (defined above) to a parent core.
  • suitable cycloalkenylalkyls include cyclopentenylmethyl, cyclohexenylmethyl and the like.
  • Halogen means fluorine, chlorine, bromine, or iodine. Preferred are fluorine, chlorine and bromine.
  • Ring system substituent means a substituent attached to an aromatic or non-aromatic ring system which, for example, replaces an available hydrogen on the ring system.
  • Ring system substituents may be the same or different, each being independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, alkylaryl, heteroaralkyl, heteroarylalkenyl,
  • YiY 2 NSO 2 - and -SO 2 NYiY 2 wherein Yi and Y 2 can be the same or different and are independently selected from the group consisting of hydrogen, alkyl, aryl, cycloalkyl, and aralkyl.
  • Ring system substituent may also mean a single moiety which simultaneously replaces two available hydrogens on two adjacent carbon atoms (one H on each carbon) on a ring system. Examples of such moiety are methylene dioxy, ethylenedioxy, -C(CHs) 2 - and the like which form moieties such as, for example: and "Heteroarylalkyl” means a heteroaryl moiety as defined above linked via an alkyl moiety (defined above) to a parent core. Non-limiting examples of suitable heteroaryls include 2-pyridinylmethyl, quinolinylmethyl and the like.
  • Heterocyclyl means a non-aromatic saturated monocyclic or multicyclic ring system comprising about 3 to about 10 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. There are no adjacent oxygen and/or sulfur atoms present in the ring system.
  • Preferred heterocyclyls contain about 5 to about 6 ring atoms.
  • the prefix aza, oxa or thia before the heterocyclyl root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom.
  • Any -NH in a heterocyclyl ring may exist protected such as, for example, as an -N(Boc), - N(CBz), -N(Tos) group and the like; such protections are also considered part of this invention.
  • the heterocyclyl can be optionally substituted by one or more "ring system substituents" which may be the same or different, and are as defined herein.
  • the nitrogen or sulfur atom of the heterocyclyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide.
  • heterocyclyl rings include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1 ,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, lactam, lactone, and the like.
  • Heterocyclyl may also mean a single moiety (e.g., carbonyl) which simultaneously replaces two available hydrogens on the same carbon atom on a ring system. Example of such moiety is pyrrolidone:
  • Heterocyclylalkyl means a heterocyclyl moiety as defined above linked via an alkyl moiety (defined above) to a parent core.
  • suitable heterocyclylalkyls include piperidinylmethyl, piperazinylmethyl and the like.
  • Heterocyclenyl means a non-aromatic monocyclic or multicyclic ring system comprising about 3 to about 10 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is an element other than carbon, for example nitrogen, oxygen or sulfur atom, alone or in combination, and which contains at least one carbon-carbon double bond or carbon-nitrogen double bond. There are no adjacent oxygen and/or sulfur atoms present in the ring system.
  • Preferred heterocyclenyl rings contain about 5 to about 6 ring atoms.
  • the prefix aza, oxa or thia before the heterocyclenyl root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom.
  • the heterocyclenyl can be optionally substituted by one or more ring system substituents, wherein "ring system substituent" is as defined above.
  • the nitrogen or sulfur atom of the heterocyclenyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S.S-dioxide.
  • heterocyclenyl groups include 1 ,2,3,4- tetrahydropyridinyl, 1 ,2-dihydropyridinyl, 1 ,4-dihydropyridinyl, 1 ,2,3,6-tetrahydropyridinyl, 1 ,4,5,6- tetrahydropyrimidinyl, 2-pyrrolinyl, 3-pyrrolinyl, 2-imidazolinyl, 2-pyrazolinyl, dihydroimidazolyl, dihydrooxazolyl, dihydrooxadiazolyl, dihydrothiazolyl, 3,4- dihydro-2H-pyranyl, dihydrofuranyl, fluorodihydrofuranyl, 7- oxabicyclo[2.2.1]heptenyl, dihydrothiophenyl, dihydrothiopyranyl, and the like.
  • Heterocyclenyl may also mean a single moiety (e.
  • Heterocyclenylalkyl means a heterocyclenyl moiety as defined above linked via an alkyl moiety (defined above) to a parent core.
  • hetero-atom containing ring systems of this invention there are no hydroxyl groups on carbon atoms adjacent to a N, O or S, as well as there are no N or S groups on carbon adjacent to another heteroatom.
  • N, O or S there are no hydroxyl groups on carbon atoms adjacent to a N, O or S, as well as there are no N or S groups on carbon adjacent to another heteroatom.
  • Alkynylalkyl means an alkynyl-alkyl- group in which the alkynyl and alkyl are as previously described. Preferred alkynylalkyls contain a lower alkynyl and a lower alkyl group. The bond to the parent moiety is through the alkyl. Non-limiting examples of suitable alkynylalkyl groups include propargylmethyl.
  • Heteroaralkyl means a heteroaryl-alkyl- group in which the heteroaryl and alkyl are as previously described. Preferred heteroaralkyls contain a lower alkyl group. Non-limiting examples of suitable aralkyl groups include
  • Hydroxyalkyl means a HO-alkyl- group in which alkyl is as previously defined. Preferred hydroxyalkyls contain lower alkyl. Non-limiting examples of suitable hydroxyalkyl groups include hydroxymethyl and 2-hydroxyethyl.
  • acyl means an H-C(O)-, alkyl-C(O)- or cycloalkyl-C(O)-, group in which the various groups are as previously described.
  • the bond to the parent moiety is through the carbonyl.
  • Preferred acyls contain a lower alkyl.
  • suitable acyl groups include formyl, acetyl and propanoyl.
  • Aroyl means an aryl-C(O)- group in which the aryl group is as previously described. The bond to the parent moiety is through the carbonyl.
  • suitable groups include benzoyl and 1- naphthoyl.
  • Alkoxy means an alkyl-O- group in which the alkyl group is as previously described.
  • suitable alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy.
  • the bond to the parent moiety is through the ether oxygen.
  • Aryloxy means an aryl-O- group in which the aryl group is as previously described.
  • suitable aryloxy groups include phenoxy and naphthoxy.
  • the bond to the parent moiety is through the ether oxygen.
  • Alkyloxy means an aralkyl-O- group in which the aralkyl group is as previously described.
  • suitable aralkyloxy groups include benzyloxy and 1 - or 2-naphthalenemethoxy.
  • the bond to the parent moiety is through the ether oxygen.
  • Alkylthio means an alkyl-S- group in which the alkyl group is as previously described.
  • suitable alkylthio groups include methylthio and ethylthio.
  • the bond to the parent moiety is through the sulfur.
  • Arylthio means an aryl-S- group in which the aryl group is as previously described.
  • suitable arylthio groups include phenylthio and naphthylthio.
  • the bond to the parent moiety is through the sulfur.
  • Alkylthio means an aralkyl-S- group in which the aralkyl group is as previously described. Non-limiting example of a suitable aralkylthio group is benzylthio. The bond to the parent moiety is through the sulfur.
  • Alkoxycarbonyl means an alkyl-0-CO- group. Non-limiting examples of suitable alkoxycarbonyl groups include methoxycarbonyl and ethoxycarbonyl. The bond to the parent moiety is through the carbonyl.
  • Aryloxycarbonyl means an aryl-O-C(O)- group.
  • suitable aryloxycarbonyl groups include phenoxycarbonyl and
  • Alkoxycarbonyl means an aralkyl-O-C(O)- group.
  • a suitable aralkoxycarbonyl group is benzyloxycarbonyl.
  • the bond to the parent moiety is through the carbonyl.
  • Alkylsulfonyl means an alkyl-S(O 2 )- group. Preferred groups are those in which the alkyl group is lower alkyl. The bond to the parent moiety is through the sulfonyl.
  • Arylsulfonyl means an aryl-S(O 2 )- group. The bond to the parent moiety is through the sulfonyl.
  • substituted means that one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency under the existing circumstances is not exceeded, and that the substitution results in a stable compound.
  • stable compound' or stable structure is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
  • purified refers to the physical state of said compound after being isolated from a synthetic process (e.g. from a reaction mixture), or natural source or combination thereof.
  • purified refers to the physical state of said compound after being obtained from a purification process or processes described herein or well known to the skilled artisan (e.g., chromatography, recrystallization and the like) , in sufficient purity to be characterizable by standard analytical techniques described herein or well known to the skilled artisan.
  • such purity means at least 95% pure, in another embodiment at lest 90% pure, in another embodiment at least 80% pure, in another embodiment at least 70% pure, and in another embodiment at least 60% pure.
  • protecting groups When a functional group in a compound is termed "protected", this means that the group is in modified form to preclude undesired side reactions at the protected site when the compound is subjected to a reaction. Suitable protecting groups will be recognized by those with ordinary skill in the art as well as by reference to standard textbooks such as, for example, T. W. Greene etal, Protective Groups in organic Synthesis, 4 th edition (2007), Wiley, New York.
  • variable e.g., aryl, heterocycle, R 2 , etc.
  • its definition on each occurrence is independent of its definition at every other occurrence.
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • Prodrugs and solvates of the compounds of the invention are also contemplated herein.
  • a discussion of prodrugs is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems (1987) 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, (1987) Edward B. Roche, ed., American Pharmaceutical Association and Pergamon Press.
  • the term "prodrug” means a compound (e.g, a drug precursor) that is transformed in vivo to yield a compound of Formula (I) or a pharmaceutically acceptable salt, hydrate or solvate of the compound. The transformation may occur by various
  • a prodrug can comprise an ester formed by the replacement of the hydrogen atom of the acid group with a group such as, for example, (C 1 - C 8 )alkyl, (C 2 -Ci 2 )alkanoyioxymethyl, 1 -(alkanoyloxy)ethyl having from 4 to 9 carbon atoms, 1-methyl-1 -(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1 -
  • a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as, for example, (Ci-C 6 )alkanoyloxymethyl, 1 - ((Ci-C 6 )alkanoyloxy)ethyl, 1 -methyl-1 -((Ci-C 6 )alkanoyloxy)ethyl, (d- C 6 )alkoxycarbonyloxymethyl, N-(Ci -C 6 )alkoxycarbonylaminomethyl, succinoyl, (C r C 6 )alkanoyl, ⁇ -amino(C r C 4 )alkanyl, arylacyl and ⁇ -aminoacyl, or ⁇ - aminoacyl- ⁇ -aminoacyl, where each ⁇ -aminoacyl group is independently selected from the naturally occurring L-amino acids, P(O)(OH)
  • a prodrug can be formed by the replacement of a hydrogen atom in the amine group with a group such as, for example, R-carbonyl, RO-carbonyl, NRR'- carbonyl where R and R' are each independently (Ci-Cio)alkyl, (C 3 -C7) cycloalkyl, benzyl, or R-carbonyl is a natural ⁇ -aminoacyl or natural ⁇ -aminoacyl, -C(OH)C(O)OY 1 wherein Y 1 is H, (C r C 6 )alkyl or benzyl,— C(OY 2 )Y 3 wherein Y 2 is (CrC 4 ) alkyl and Y 3 is (C r C 6 )alkyl, carboxy (Ci-C 6 )alkyl, amino(Ci-C 4 )alkyl or mono-N— or di-N,N-
  • R-carbonyl RO-carbonyl
  • One or more compounds of the invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the invention embrace both solvated and unsolvated forms.
  • “Solvate” means a physical association of a compound of this invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. "Solvate” encompasses both solution-phase and isolatable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like.
  • “Hydrate” is a solvate wherein the solvent molecule is H 2 O.
  • One or more compounds of the invention may optionally be converted to a solvate.
  • Preparation of solvates is generally known.
  • M. Caira et al, J. Pharmaceutical ScL, 93(3), 601 -611 (2004) describe the preparation of the solvates of the antifungal fluconazole in ethyl acetate as well as from water.
  • Similar preparations of solvates, hemisolvate, hydrates and the like are described by E. C. van Tonder etal, AAPS PharmSciTech., 5(11, article 12 (2004); and A. L. Bingham etal, Chem. Commun., 603-604 (2001 ).
  • a typical, non-limiting, process involves dissolving the inventive compound in desired amounts of the desired solvent (organic or water or mixtures thereof) at a higher than ambient temperature, and cooling the solution at a rate sufficient to form crystals which are then isolated by standard methods.
  • Analytical techniques such as, for example I. R. spectroscopy, show the presence of the solvent (or water) in the crystals as a solvate (or hydrate).
  • Effective amount or “therapeutically effective amount” is meant to describe an amount of compound or a composition of the present invention effective in inhibiting the above-noted diseases and thus producing the desired therapeutic, ameliorative, inhibitory or preventative effect.
  • the compounds of Formula I can form salts which are also within the scope of this invention.
  • Reference to a compound of Formula I herein is understood to include reference to salts thereof, unless otherwise indicated.
  • the term "salt(s)", as employed herein, denotes acidic salts formed with inorganic and/or organic acids, as well as basic salts formed with inorganic and/or organic bases.
  • a compound of Formula I contains both a basic moiety, such as, but not limited to a pyridine or imidazole, and an acidic moiety, such as, but not limited to a carboxylic acid, zwitterions ("inner salts”) may be formed and are included within the term “salt(s)" as used herein.
  • Salts of the compounds of Formula I may be formed, for example, by reacting a compound of Formula I with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.
  • Exemplary acid addition salts include acetates, ascorbates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, fumarates, hydrochlorides, hydrobromides, hydroiodides, lactates, maleates, methanesulfonates, naphthalenesulfonates, nitrates, oxalates, phosphates, propionates, salicylates, succinates, sulfates, tartarates, thiocyanates, toluenesulfonates (also known as tosylates,) and the like.
  • Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as dicyclohexylamines, t-butyl amines, and salts with amino acids such as arginine, lysine and the like.
  • Basic nitrogen-containing groups may be
  • agents such as lower alkyl halides (e.g. methyl, ethyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g. dimethyl, diethyl, and dibutyl sulfates), long chain halides (e.g. decyl, lauryl, and stearyl chlorides, bromides and iodides), aralkyl halides (e.g. benzyl and phenethyl bromides), and others.
  • lower alkyl halides e.g. methyl, ethyl, and butyl chlorides, bromides and iodides
  • dialkyl sulfates e.g. dimethyl, diethyl, and dibutyl sulfates
  • long chain halides e.g. decyl, lauryl, and stearyl chlorides, bromides and iodides
  • esters of the present compounds include the following groups: (1 ) carboxylic acid esters obtained by esterification of the hydroxy groups, in which the non-carbonyl moiety of the carboxylic acid portion of the ester grouping is selected from straight or branched chain alkyl (for example, acetyl, n-propyl, t-butyl, or n-butyl), alkoxyalkyl (for example, methoxymethyl), aralkyl (for example, benzyl), aryloxyalkyl (for example, phenoxymethyl), aryl (for example, phenyl optionally substituted with, for example, halogen, or amino); (2) sulfonate esters, such as alkyl- or aralkylsulfonyl (for example, methanesulfonyl); (3) amino acid esters (for example, L-valyl or L-isoleucyl); (4) phosphonate esters and (5) mono-, di-, di
  • the compounds of Formula (I) may contain asymmetric or chiral centers, and, therefore, exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of Formula (I) as well as mixtures thereof, including racemic mixtures, form part of the present invention.
  • the present invention embraces all geometric and positional isomers. For example, if a compound of Formula (I) incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the invention.
  • Diastereomeric mixtures can be separated into their individual
  • Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an
  • optically active compound e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride
  • separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers e.g., hydrolyzing
  • some of the compounds of Formula (I) may be atropisomers (e.g., substituted biaryls) and are considered as part of this invention.
  • Enantiomers can also be separated by use of chiral HPLC column. It is also possible that the compounds of Formula (I) may exist in different tautomeric forms, and all such forms are embraced within the scope of the invention. Also, for example, all keto-enol and imine-enamine forms of the compounds are included in the invention.
  • All stereoisomers for example, geometric isomers, optical isomers and the like
  • of the present compounds including those of the salts, solvates, esters and prodrugs of the compounds as well as the salts, solvates and esters of the prodrugs
  • those which may exist due to asymmetric carbons on various substituents including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated within the scope of this invention, as are positional isomers (such as, for example, 4-pyridyl and 3-pyridyl).
  • salt is intended to equally apply to the salt, solvate, ester and prodrug of enantiomers, stereoisomers, rotamers, tautomers, positional isomers, racemates or prodrugs of the inventive compounds.
  • the present invention also embraces isotopically-labelled compounds of the present invention which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine and iodine, such as 2 H, 3 H 1 11 C, 13 C, 14 C, 15 N, 18 0, 17 O, 31 P, 32 P, 35 S, 18 F, 36 CI and 123 I, respectively.
  • Certain isotopically-labelled compounds of Formula (I) are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes are particularly preferred for their ease of preparation and detectability. Certain isotopically-labelled compounds of Formula (I) can be useful for medical imaging purposes.
  • those labeled with positron-emitting isotopes like 11 C or 18 F can be useful for application in Positron Emission Tomography (PET) and those labeled with gamma ray emitting isotopes like 123 I can be useful for application in Single photon emission computed tomography (SPECT).
  • PET Positron Emission Tomography
  • SPECT Single photon emission computed tomography
  • substitution with heavier isotopes such as deuterium (i.e., 2 H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half- life or reduced dosage requirements) and hence may be preferred in some circumstances.
  • substitution with heavier isotopes such as deuterium (i.e., 2 H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage
  • lsotopically labeled compounds of Formula (I) in particular those containing isotopes with longer half lives (T1/2 >1 day), can generally be prepared by following procedures analogous to those disclosed in the Schemes and/or in the Examples herein below, by substituting an appropriate isotopically labeled reagent for a non-isotopically labeled reagent.
  • X 1 is selected from the group consisting of a covalent bond, -S- and -O-;
  • R 1 is selected from the group consisting of halo, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein when each of said cycloalkyl, heterocyclyl, aryl and heteroaryl has substitutents on adjacent carbon atoms, said substituents can optionally be taken together with the carbon atoms to which they are attached to form a first five- or six-membered cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein when said first five- or six-membered cycloalkyl, heterocyclyl, aryl or heteroaryl has substitutents on adjacent carbon atoms, said substituents can optionally be taken together with the carbon atoms to which they are attached to form a second five- or six-membered cycloalkyl, heterocyclyl, aryl or heteroaryl;
  • X 2 is selected from the group consisting of a covalent bond, and -O-;
  • R 2 is selected from the group consisting of H, halogen and alkyl, with the proviso that when X 2 is a covalent bond, R 2 is halogen;
  • X 3 is selected from the group consisting of a covalent bond, -N(R)- and — O- "
  • R is H or alkyl
  • R 3 is selected from the group consisting of halo, alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein when each of said cycloalkyl, heterocyclyl, aryl and heteroaryl has substitutents on adjacent carbon atoms, said substituents can optionally be taken together with the carbon atoms to which they are attached to form a first five- or six-membered cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein when said first five- or six-membered cycloalkyl, heterocyclyl, aryl or heteroaryl has substitutents on adjacent carbon atoms, said substituents can optionally be taken together with the carbon atoms to which they are attached to form a second five- or six-membered cycloalkyl, heterocyclyl, aryl or heteroaryl; and
  • R 4 is selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • X 2 is -O- and R 2 is H or alkyl.
  • X 2 is a covalent bond, and R 2 is halo.
  • -X 2 R 2 is selected from the group consisting of hydroxyl, methoxy, and fluoro.
  • X 1 is selected from the group consisting of a covalent bond and -O-.
  • R 1 aryl is phenyl which is
  • R 1 aryl is phenyl which is
  • X 1 is -O-
  • X 3 is NH
  • R 3 is selected from the group consisting of alkyl, cylcloalkyl, heterocyclyl, and aryl, wherein when each of said cycloalkyl, heterocyclyl, and aryl has substitutents on adjacent carbon atoms, said substituents can optionally be taken together with the carbon atoms to which they are attached to form a five- or six-membered aryl or heteroaryl.
  • X 3 is NH
  • R 3 is alkyl which is unsubstituted or substituted with a substituent selected from the group consisting of aryl, wherein when said aryl has substitutents on adjacent carbon atoms, said substituents can optionally be taken together with the carbon atoms to which they are attached to form a five- or six-membered aryl or heteroaryl
  • X 3 is NH
  • R 3 is alkyl- benzopyridyl, wherein the benzopyridyl is attached to the alkyl through the benzene ring of said benzopyridyl, wherein said benzopyridyl is unsubstituted or substituted with a ring system substitutent.
  • X 3 is NH
  • R 3 is alkyl- benzopyridyl, wherein the benzopyridyl is attached to the alkyl through the benzene ring of said benzopyridyl, wherein said benzopyridyl is unsubstituted or substituted with a ring system substitutent, wherein said ring system substituent is -NH 2 .
  • X 3 is NH
  • R 3 is cycloalkyl, wherein when said cycloalkyl has substitutents on adjacent carbon atoms, said substituents can optionally be taken together with the carbon atoms to which they are attached to form a five- or six-membered aryl or heteroaryl.
  • X 3 is NH
  • R 3 is cycloalkyl, wherein when said cycloalkyl has substitutents on adjacent carbon atoms, said substituents can optionally be taken together with the carbon atoms to which they are attached to form a five- or six-membered aryl or heteroaryl, wherein said R 3 cycloalkyl, optionally with said five- or six-membered aryl or heteroaryl is unsubstituted or substituted with at least one ring system substituent.
  • X 3 is NH
  • R 3 is cycloalkyl selected from the group consisting of cyclohexyl, and thiazolyl-fused cyclohexyl, each of which unsubstituted or substituted with a ring system substituent.
  • X 3 is NH
  • X 3 is NH
  • R 3 is heterocyclyl, wherein when said heterocyclyl has substitutents on adjacent carbon atoms, said substituents can optionally be taken together with the carbon atoms to which they are attached to form a five- or six-membered aryl or heteroaryl.
  • X 3 is NH
  • R 3 is heterocyclyl, wherein when said heterocyclyl has substitutents on adjacent carbon atoms, said substituents can optionally be taken together with the carbon atoms to which they are attached to form a five- or six-membered aryl or heteroaryl, wherein said R 3 heterocyclyl, optionally with said five- or six-membered aryl or heteroaryl is unsubstituted or substituted with at least one ring system substituent.
  • X 3 is NH
  • R 3 is piperidinyl which is unsubstituted or substituted with at least one ring system substituent.
  • X 3 is NH
  • X 3 is NH
  • R 3 is aryl, wherein when said aryl has substitutents on adjacent carbon atoms, said substituents can optionally be taken together with the carbon atoms to which they are attached to form a five- or six-membered cyclohexyl, aryl, or heteroaryl.
  • X 3 is NH
  • R 3 is aryl, wherein when said aryl has substitutents on adjacent carbon atoms, said substituents can optionally be taken together with the carbon atoms to which they are attached to form a five- or six-membered cyclohexyl, aryl, or heteroaryl, wherein said R 3 aryl, optionally with said five- or six-membered heteroaryl is unsubstituted or substituted with at least one ring system substituent,
  • X 3 is NH
  • R 3 is aryl, wherein when said aryl has substitutents on adjacent carbon atoms, said substituents can optionally be taken together with the carbon atoms to which they are attached to form a five- or six-membered cyclohexyl, aryl, or heteroaryl, wherein said R 3 aryl
  • X 3 is NH
  • X 3 is a covalent bond
  • R 3 is heteroaryl, wherein when said heteroaryl has substitutents on adjacent carbon atoms, said substituents can optionally be taken together with the carbon atoms to which they are attached to form a five- or six-membered aryl or heteroaryl.
  • X 3 is a covalent bond
  • R 3 is heteroaryl, wherein when said heteroaryl has substitutents on adjacent carbon atoms, said substituents can optionally be taken together with the carbon atoms to which they are attached to form a five- or six-membered aryl or heteroaryl, wherein said R 3 , optionally with said five- or six-membered aryl or heteroaryl, is unsubstituted or substituted with at least one ring system substituent.
  • X 3 is a covalent bond
  • R 3 is heteroaryl, wherein when said heteroaryl has substitutents on adjacent carbon atoms, said substituents can optionally be taken together with the carbon atoms to which they are attached to form a five- or six-membered aryl or heteroaryl, wherein said R 3 , optionally with said five- or six-membered aryl or heteroaryl, is unsubstituted or substituted with at least one ring system substituent, wherein said R 3 heteroaryl is benzopyrrolidinyl which is unsubstituted or substituted with at least one ring system substituent.
  • X 3 is a covalent bond
  • R 3 is heteroaryl, wherein when said heteroaryl has substitutents on adjacent carbon atoms, said substituents can optionally be taken together with the carbon atoms to which they are attached to form a five- or six-membered aryl or heteroaryl, wherein said R 3 , optionally with said five- or six-membered aryl or heteroaryl, is unsubstituted or substituted with at least one ring system substituent, wherein the ring system substituent is selected from the group consisting of cyano, alkyl, and aminoaikyk
  • X 3 is a covalent bond, and R 3 is halo.
  • X 1 and X 3 are both -O-, and R 1 and R 3 are both H or aryl.
  • R 4 is alkyl and is f-butyl.
  • R 4 is cycloalkyl and is selected from the group consisting of cyclopropyl and cyclohexyl.
  • R 4 is aryl and is phenyl.
  • the compound of Formula (I) is selected from the group consisting of:
  • Example 7 was prepared using a procedure similar to the preparation of 6.
  • N-chlorosuccinimide 400 mg, 2.99 mmol, 1 ,1 eq.
  • the solution washed 2x with water, brine, dried over MgSO 4 , filtered, concentrated and purified by flash chromatography using 40% ethyl acetate in hexanes to provide 319 mg of P21 and 288 mg of P22.
  • P24 was prepared from 3,5-dichloro-5-methoxypyrimidine and 4-(tert- butoxycarbonyl)phenylboronic acid using a procedure similar to the preparation of P15.
  • P32 A solution of 220 mg of P31 in 5 ml of 95:5 TFA-water mixture was heated in a microwave reactor at 120 0 C for 20 min. It was concentrated and diluted with aq. NaHCO 3 . The solid was filtered, washed with water, ether and dried in vacuum oven to provide 200 mg of P32.
  • step 2 The compound from step 2 (15.14g, 0.0694 mol) was dissolved in PhMe (70 ml) and Et 3 N (10.72 ml, 1.1eq) was added. The solution was heated to 80 0 C and POCI3 (13.93 ml, 2.2 eq) was added. Once the addition was complete the mixture was heated at reflux for 2 hours. After cooling to O 0 C the mixture was quenched with ice and extracted with EtOAc. The EtOAc extracts were washed with water, NaHCO 3 ( Sat ), dried (MgSO 4 ) and concentrated to give 12.78g of the title compound.
  • Example 39 (80 mg, 0.25 mmol) was dissolved in BuOH (1.67 ml), hydrazine hydrate (0.785, 100 eq) was added and the mixture heated at 120 0 C overnight. After cooling to room temperature the mixture was concentrated and purified by C18 HPLC (89.95:9.95:0.1 H 2 O:MeCN:HCO 2 H-9.95:89.95:0.1
  • Example 57 was synthesized from 55 in a similar manner to that previously described.
  • LCMS 353.0 (MH + )
  • Example 58 was synthesized from 46 in a similar manner to that previously described.
  • LCMS 353.0 (MH + )
  • Example 59 4-(4-(Aminomethyl)-3-fluorophenylamino)-6-p-tolylpyrimidin-5-ol
  • Example 39 (0.075 mg, 0.234 mmol) was dissolved in a 1 :1 mixture of EtOH/THF (3.9 ml). A solution of 30% H 2 O 2 (0.7 ml) was added followed by 3 M NaOH (0.7ml), the mixture was then stirred for 4 days. The mixture was neutralized with dilute HCI washed with EtOAc to leave an aqueous suspension. The aqueous layer was filtered and the solid dried to give 49 mg of the title
  • Step 1 2-fluoro-4-((6-p-tolyl-5-((2-(trimethylsilyl)ethoxy)methoxy)pyrimidin- 4-yl)((2-(trimethylsilyl)ethoxy)methyl)amino)benzonitrile
  • Step 2 4-(3-aminobenzo[d]isoxazol-6-ylamino)-6-p-tolylpyrimidin-5-ol
  • Acetone oxime (23.9 mg, 1.3eq) and t-BuOK (36.7 mg, 1.3 eq) were mixed together in DMF (1 ml), after stirring for 30 minutes the compound from step 1 (0.146, 0.251 mmol) in DMF (2 ml) was added and the resulting mixture stirred for 1 hour.
  • the mixture was diluted with EtOAc and washed with H2O/N H 4 CI( Sa D, dried (MgSO 4 ), and concentrated.
  • the resulting residue was dissolved in 1 :1 1 N HCI/EtOH and heated at 8O 0 C for 2.5 hours.
  • the mixture was cooled to room temperature quenched with NaHCO 3 ( Sa t) and extracted with EtOAc, the extracts were dried (MgSO 4 ) and concentrated to give 31 mg of the title compound.
  • Step i - ⁇ -( ⁇ -methoxy- ⁇ -p-tolylpyrimidin ⁇ -yObenzofdlisoxazole-S. ⁇ - diamine
  • the title compound was synthesized from 4,6-dichloro-5-methoxypyrimidine using procedures described previously.
  • Step 1 N-(5-(benzyloxy)-6-p-tolylpyrimidin-4-yl)benzo[d]oxazol-6-amine
  • P50 was prepared from P49 and m-tolylboronic acid using a procedure similar to the preparation of 1.
  • the ketone 77 was reduced in a conventional way with NaBH 4 in MeOH at room temperature to give the alcohol 78 as a yellow solid.
  • ketone 78 was treated in a conventional way with hydroxylamine hydrochloride in pyridine at room temperature to give the oxime 79 as a yellow solid.
  • R 1 Bu, cyclohexy and phenyl
  • Preparative Examples P62- P64 were prepared by coupling the appropriate pyrimidine chloride with p- tolylboronic acid.
  • Step 1 Preparation of ⁇ -hydroxy- ⁇ -p-tolylpyrimidine ⁇ -carbonitrile P69.
  • Step 2 Preparation of ⁇ -hydroxy- ⁇ -p-tolylpyrimidine ⁇ -carboxylic acid P70.
  • Step 3 Preparation of benzyl 5-(benzyloxy)-6-p-tolylpyrimidine-4-carboxylate P71.
  • Step 4 Preparation of 5-(benzyloxy)-6-p-tolylpyrimidine-4-carboxylic acid P72.
  • Step 5 Preparation of 2-(5-hydroxy-6-p-tolylpyrimidin-4-yl)-1 H- benzo[d]imidazole-5-carbonitrile P73.
  • the intermediate was purified by flash column chromatography.
  • the intermediate was dissolved in acetic acid (5 ml_) and heated in a microwave reactor at 160 0 C for 1 hour. The organic solvent was evaporated under reduced pressure. Trifluoroacetic acid (5 ml_) was added and the solution was heated in a microwave reactor at 120 0 C for 30 minutes. The organic solvent was evaporated under reduced pressure.
  • the crude product was purified by RP-HPLC to afford the desired 2-(5-hydroxy-6-p ⁇ tolylpyrimidin-4-yl)-1 H-benzo[c ⁇ imidazole-5-carbonitrile P73 (16 mg, 0.049 mmol).
  • Step 6 Preparation of 2-(5-hydroxy-6-p-tolylpyrimidin-4-yl)-1 H- benzo[d]imidazole-5-carboximidamide P74.
  • Example 107 was prepared using a procedure similar to the preparation of 106.
  • the compounds of this invention are inhibitors of factor IXa and are useful as anticoagulants for the treatment or prevention of thromboembolic disorders in mammals (i.e., factor IXa-associated disorders).
  • a thromboembolic disorder is a circulatory disease caused by blood clots (i.e., diseases involving fibrin formation, platelet activation, and/or platelet aggregation).
  • thromboembolic disorders as used herein includes arterial cardiovascular thromboembolic disorders, venous cardiovascular or
  • thromboembolic disorders also includes specific disorders selected from, but not limited to, unstable angina or other acute coronary syndromes, first or recurrent myocardial infarction, ischemic sudden death, transient ischemic attack, stroke, atherosclerosis, peripheral occlusive arterial disease, venous thrombosis, deep vein thrombosis,
  • thrombosis includes occlusion (e.g., after a bypass) and reocclusion (e.g., during or after percutaneous transluminal coronary angioplasty).
  • the thromboembolic disorders may result from conditions including but not limited to atherosclerosis, surgery or surgical complications, prolonged immobilization, arterial fibrillation, congenital thrombophilia, cancer, diabetes, effects of medications or hormones, and complications of pregnancy.
  • the anticoagulant effect of compounds of the present invention is believed to be due to inhibition of serine proteases involved in the coagulation cascade and/or contact activation system, more specifically, inhibition of the coagulation factors: factor XIa, factor Vila, factor IXa, factor Xa, plasma kallikrein or thrombin.
  • the compounds of this invention also are inhibitors of plasma kallikrein and are useful as anti-inflammatory agents for the treatment or prevention of diseases associated with an activation of the contact activation system (i.e., plasma kallikrein associated disorders).
  • a contact activation system disorder is a disease caused by activation of blood on artificial surfaces, including prosthetic valves or other implants, indwelling catheters, stents, cardiopulmonary bypass, hemodialysis, microorganism (e.g., bacteria, virus), or other procedures in which blood is exposed to an artificial surface that promotes contact activation, blood clots (i.e., diseases involving fibrin formation, platelet activation, and/or platelet aggregation).
  • systemic inflammatory response syndrome sepsis, acute respiratory dystress syndrome, hereditary angioedema or other inherited or aquired deficencies of contact activation components or their inhibitors (plasma kallikrein, factor XIIa, high molecular weight kininogen, C1 - esterase inhibitor). It may also include acute and chronic inflammations of joints, vessels, or other mammalian organs.
  • the effectiveness of compounds of the present invention as inhibitors of the coagulation factors XIa, Vila, IXa, Xa, plasma kallikrein or thrombin can be determined using a relevant purified serine protease, respectively, and an appropriate synthetic substrate.
  • the rate of hydrolysis of the chromogenic or fluorogenic substrate by the relevant serine protease was measured both in the absence and presence of compounds of the present invention.
  • Factor XIa determinations can be made in 50 mM HEPES buffer at pH 7.4 containing 145 mM NaCI, 5 mM KCI, and 0.1% PEG 8000 (polyethylene glycol; JT Baker or Fisher Scientific). Determinations can be made using purified human Factor XIa at a final concentration of 75-200 pM (Haematologic Technologies) and the synthetic substrate S-2366 (pyroGlu-Pro-Arg-pNA; Chromogenix) at a concentration of 0.0002-0.00025 M. Compounds tested in the Factor XIa assay are considered to be active if they exhibit a K, of equal to or less than 15 ⁇ M.
  • Preferred compounds of the present invention have K,'s of equal to or less than 1 ⁇ M. More preferred compounds of the present invention have K ,'s of equal to or less than 0.1 ⁇ M. Even more preferred compounds of the present invention have K 1 1 S of equal to or less than 0.01 ⁇ M.
  • Factor Vila determinations can be made in 0.005 M calcium chloride, 0.15 M sodium chloride, 0.05 M HEPES buffer containing 0.5% PEG 8000 at a pH of 7.4. Determinations can be made using purified human Factor Vila
  • H-D-lle-Pro-Arg-pNA synthetic substrate H-D-lle-Pro-Arg-pNA
  • Enzyme is diluted 1 :800 in buffer to achieve 0.0057 ug/ml working stock for use in assay. Mix by inversion.
  • Spectrozyme factor IXa Fluorogenic substrate American Diagnostica Inc.
  • the substrate (l Oumoles lyophilized) is reconstituted with 1 ml water to give a 1OmM stock.
  • the substrate is then further diluted to 300 uM in buffer for use in assay. Mix by inversion.
  • Enzyme is diluted to 0.133 ug/ml in buffer. Mix by inversion.
  • Spectrozyme factor IXa Fluorogenic substrate (American Diagnostica Inc.) Reconstitute with 1 ml water to give a 1OmM stock. The substrate is then further diluted to 30OuM in buffer for use in assay. Mix by inversion.
  • the compounds of the present invention have factor IXa IC 50 (nM; nanomolar) values ranging from about 10 nM to greater than 25,000 nM.
  • the values range from about 10 nM to about 20,000 nM, and in another embodiment from about 20 nM to about 10,000 nM, and in another embodiment from about 20 nM to about 1000 M, and in another embodiment from about 20 nM to about 500 nM, and in another embodiment from about 20 nM to about 100 nM, and in another embodiment from about 5 nM to about 100 nM.
  • some of the compounds of the present invention are selective factor IXa inhibitors, i.e., selective for factor IXa over other coagulation factors, such as factor Xa.
  • Selectivity for Factor IXa activity over Factor Xa activity can be determined by the following calculation.: (IC50 Factor Xa) / (IC50 Factor IXa). Similar calculations can be made for selectivity of compounds for Factor IX compared to other coagulation factors.
  • Plasma kallikrein determinations can be made in 0.1 M sodium phosphate buffer at a pH of 7.4 containing 0.2 M sodium chloride and 0.5% PEG 8000.
  • Determinations can be made using purified human kallikrein (Enzyme Research Laboratories) at a final assay concentration of 200 pM and the synthetic substrate S-2302 (H-(D)-Pro-Phe-Arg-pNA; Chromogenix) at a concentration of 0.00008-0.0004 M.
  • the Km value useful for calculation of K is 0.00005 to
  • Thrombin determinations can be made in 0.1 M sodium phosphate buffer at a pH of 7.4 containing 0.2 M sodium chloride and 0.5% PEG 8000.
  • Determinations are made using purified human alpha thrombin (Haematologic Technologies or Enzyme Research Laboratories) at a final assay concentration of 200-250 ⁇ M and the synthetic substrate S-2366 (pyroGlu-Pro-Arg-pNA;
  • Chromogenix at a concentration of 0.0002 M.
  • Compounds tested in the thrombin assay are considered to be active if they exhibit a K, of equal to or less than 15 ⁇ M.
  • Compounds of the present invention are useful as effective inhibitors of the coagulation cascade and/or contact activation system, and useful as anticoagulants for the prevention or treatment of thromboembolic disorders in mammals and/or as anti-inflammatory agents for the prevention or treatment of inflammatory disorders in mammals.
  • o V 0 is the velocity of the control in the absence of inhibitor
  • o v s is the velocity in the presence of inhibitor
  • o B is the maximum activity remaining (usually locked at 1.0) ;
  • o n is the Hill coefficient, a measure of the number and cooperativity of potential inhibitor binding sites
  • o IC 50 is the concentration of inhibitor that produces 50% inhibition under the assay conditions
  • 0 Ki is the dissociation constant of the enzyme:inhibitor complex
  • 0 S is the concentration of substrate
  • 0 K m is the Michaelis constant for the substrate.
  • the effectiveness of compounds of the present invention as inhibitors of the coagulation factors XIa 1 Vila, IXa, Xa 1 or thrombin, can be determined using relevant in vivo thrombosis models, including In Vivo Electrically-induced Carotid Artery Thrombosis Models and In Vivo Rabbit Arterio-venous Shunt Thrombosis Models.
  • In Vivo Electrically-induced Carotid Artery Thrombosis Model The
  • ECAT electrically-induced carotid artery thrombosis
  • rabbits are anesthetized with a mixture of ketamine (50 mg/kg i.m.) and xylazine (10 mg/kg i.m.).
  • a femoral vein and a femoral artery are isolated and catheterized.
  • the carotid artery is also isolated such that its blood flow can be measured with a calibrated flow probe that is linked to a flowmeter.
  • a stainless steel bipolar hook electrode is placed on the carotid artery and positioned caudally in relationship to the flow probe as a means of applying electrical stimulus. In order to protect the surrounding tissue, a piece of Parafilm is placed under the electrode.
  • Test compounds are considered to be effective as anticoagulants based on their ability to maintain blood flow in the carotid artery following the induction of thrombosis by an electrical stimulus.
  • a test compound or vehicle is given as continuous intravenous infusion via the femoral vein, starting 1 hour before electrical stimulation and continuing to the end of the test.
  • Thrombosis is induced by applying a direct electrical current of 4 mA for 3 min to the external arterial surface, using a constant current unit and a d.c. stimulator.
  • the carotid blood flow is monitored and the time to occlusion (decrease of blood flow to zero following induction of thrombosis) in minutes is noted.
  • the change in observed blood flow is calculated as a percentage of the blood flow prior to induction of thrombosis and provides a measure of the effect of a test compound when compared to the case where no compound is administered. This information is used to estimate the ED 50 value, the dose that increases blood flow to 50% of the control (blood flow prior to induction of thrombosis) and is accomplished by nonlinear least square regression.
  • AV arterio-venous
  • rabbits weighing 2-3 kg anesthetized with a mixture of xylazine (10 mg/kg i.m.) and ketamine (50 mg/kg i.m.) are used.
  • a saline-filled AV shunt device is connected between the femoral arterial and the femoral venous cannulae.
  • the AV shunt device consists of a piece of 6-cm tygon tubing that contains a piece of silk thread. Blood will flow from the femoral artery via the AV-shunt into the femoral vein.
  • the exposure of flowing blood to a silk thread will induce the formation of a significant thrombus.
  • the shunt is disconnected and the silk thread covered with thrombus is weighed.
  • Test agents or vehicle will be given (i.v., i.p., s. c, or orally) prior to the opening of the AV shunt.
  • the percentage inhibition of thrombus formation is determined for each treatment group.
  • the ID 5O values dose which produces 50% inhibition of thrombus formation) are estimated by linear regression.
  • mice are dosed with a compound of the present invention, Evans Blue is injected via the tail vein, and extravasation of the blue dye is determined by spectrophotometric means from tissue extracts.
  • the ability of the compounds of the current invention to reduce or prevent the systemic inflammatory response syndrome can be tested in in vitro perfusion systems, or by on-pump surgical procedures in larger mammals, including dogs and baboons.
  • Read-outs to assess the benefit of the compounds of the present invention include for example reduced platelet loss, reduced platelet/white blood cell complexes, reduced neutrophil elastase levels in plasma, reduced activation of complement factors, and reduced activation and/or consumption of contact activation proteins (plasma kallikrein, factor XII, factor Xl, high molecular weight kininogen, C1 -esterase inhibitors).
  • the utility of the compounds of the current invention to reduce or prevent the morbidity and/or mortality of sepsis can be assessed by injecting a mammalian host with bacteria or viruses or extracts there of and compounds of the present invention.
  • Typical read-outs of the efficacy include changes in the LD50 and blood pressure preservation.
  • the compounds of the present invention may also be useful as inhibitors of additional serine proteases, notably human thrombin, human plasma kallikrein and human plasmin. Because of their inhibitory action, these compounds are indicated for use in the prevention or treatment of physiological reactions, including blood coagulation, fibrinolysis, blood pressure regulation and inflammation, and wound healing catalyzed by the aforesaid class of enzymes. Specifically, the compounds have utility as drugs for the treatment of diseases arising from elevated thrombin activity of the aforementioned serine proteases, such as myocardial infarction, and as reagents used as anticoagulants in the processing of blood to plasma for diagnostic and other commercial purposes.
  • the compounds of the present invention can be administered alone or in combination with one or more additional therapeutic agents. These include other anti-coagulant or coagulation inhibitory agents, anti-platelet or platelet inhibitory agents, anti-inflammatory agents, thrombin inhibitors, or thrombolytic or fibrinolytic agents.
  • the compounds are administered to a mammal in a therapeutically effective amount.
  • therapeutically effective amount it is meant an amount of a compound of the present invention that, when administered alone or in combination with an additional therapeutic agent to a mammal, is effective to treat (i.e. prevent, inhibit or ameliorate) the thromboembolic and/or inflammatory disease condition or treat the progression of the disease in a host.
  • the compounds of the invention are preferably administered alone to a mammal in a therapeutically effective amount.
  • the compounds of the invention can also be administered in combination with an additional therapeutic agent, as define below, to a mammal in a therapeutically effective amount.
  • the combination of compounds is preferably, but not necessarily, a synergistic combination. Synergy, as described for example by Chou and Talalay, Adv. Enzyme Regui 1984, 22, 27-55, occurs when the effect (in this case, inhibition of the desired target) of the compounds when
  • administered in combination is greater than the additive effect of the compounds when administered alone as a single agent.
  • a synergistic effect is most clearly demonstrated at suboptimal concentrations of the compounds.
  • Synergy can be in terms of lower cytotoxicity, increased anticoagulant effect, or some other beneficial effect of the combination compared with the individual components.
  • administered in combination or “combination therapy” it is meant that the compound of the present invention and one or more additional therapeutic agents are administered concurrently to the mammal being treated.
  • each component may be administered at the same time or sequentially in any order at different points in time.
  • component may be administered separately but sufficiently closely in time so as to provide the desired therapeutic effect.
  • anticoagulants anti-thrombin agents, anti-platelet agents, fibrinolytics, and
  • hypolipidemic agents antihypertensive agents, and anti-ischemic agents.
  • anticoagulant agents or coagulation inhibitory agents
  • warfarin heparin (either unfractionated heparin or any commercially available low molecular weight heparin, for example LOVANOX®)
  • heparin either unfractionated heparin or any commercially available low molecular weight heparin, for example LOVANOX®
  • aprotinin synthetic pentasaccharide
  • direct acting thrombin inhibitors including hirudin and
  • Factor IXa inhibitors different from the compounds of Formulae l-lll include monoclonal antibodies, synthetic active-site blocked competitive inhibitors, oral inhibitors and RNA aptamers. These are described in the previously cited Howard et al. reference (Howard, EL, Becker KC, Rusconi, CP, Becker RC. Factor IXa Inhibitors as Novel Anticoagulents. Arterioscler Thmmb Vase Biol. 2007; 27: 722-727.)
  • anti-platelet agents denotes agents that inhibit platelet function, for example, by inhibiting the aggregation, adhesion or granular secretion of platelets.
  • agents include, but are not limited to, the various known non-steroidal anti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, sulindac, indomethacin, mefenamate, droxicam, diclofenac, sulfinpyrazone, and piroxicam, including pharmaceutically acceptable salts or prodrugs thereof.
  • NSAIDS non-steroidal anti-inflammatory drugs
  • aspirin acetylsalicylic acid or ASA
  • piroxicam are preferred.
  • Suitable platelet inhibitory agents include llb/llla antagonists (e.g., tirofiban, eptifibatide, and abciximab), thromboxane-A2-receptor antagonists (e.g., ifetroban), thromboxane- A2-synthetase inhibitors, phosphodiesterase-lll (PDE-III) inhibitors (e.g., dipyridamole, cilostazol), and PDE V inhibitors (such as sildenafil), and
  • anti-platelet agents is also intended to include ADP (adenosine diphosphate) receptor antagonists, preferably antagonists of the purinergic receptors P2Y 1 and P 2 Y12, with P 2 Y1 2 being even more preferred.
  • Preferred P 2 Y1 2 receptor antagonists include ticlopidine and clopidogrel, including pharmaceutically acceptable salts or prodrugs thereof.
  • Clopidogrel is an even more preferred agent.
  • Ticlopidine and clopidogrel are also preferred compounds since they are known to be gentle on the gastro-intestinal tract in use.
  • the compounds of the present invention may also be dosed in combination with aprotinin.
  • thrombin inhibitors denotes inhibitors of the serine protease thrombin.
  • various thrombin-mediated processes such as thrombin-mediated platelet activation (that is, for example, the aggregation of platelets, and/or the granular secretion of plasminogen activator inhibitor-l and/or serotonin), endothelial cell activation, inflammatory reactions, and/or fibrin formation are disrupted.
  • thrombin inhibitors are known to one of skill in the art and these inhibitors are contemplated to be used in combination with the present compounds.
  • Such inhibitors include, but are not limited to, boroarginine derivatives, boropeptides, heparins, hirudin and argatroban, including pharmaceutically acceptable salts and prodrugs thereof.
  • Boroarginine derivatives and boropeptides include N-acetyl and peptide derivatives of boronic acid, such as C-terminal alpha-aminoboronic acid derivatives of lysine, ornithine, arginine, homoarginine and corresponding isothiouronium analogs thereof.
  • hirudin includes suitable derivatives or analogs of hirudin, referred to herein as hirulogs, such as disulfatohirudin.
  • thrombin receptor antagonists also known as protease activated receptor (PAR) antagonists or PAR-1 antagonists, are useful in the treatment of thrombotic, inflammatory, atherosclerotic and fibroproliferative disorders, as well as other disorders in which thrombin and its receptor play a pathological role.
  • PAR-1 antagonists protease activated receptor
  • Thrombin receptor antagonist peptides have been identified based on structure-activity studies involving substitutions of amino acids on thrombin receptors. In Bernatowicz et al, J. Med. Chem., vol. 39, pp. 4879-4887 (1996), tetra-and pentapeptides are disclosed as being potent thrombin receptor antagonists, for example N-trans-cinnamoyl-p-fluoroPhe-p-guanidinoPhe-Leu- Arg-NH 2 and N-trans-cinnamoyl-p-fluoroPhe-p-guanidinoPhe-Leu-Arg-Arg-NHa. Peptide thrombin receptor antagonists are also disclosed in WO 94/03479, published Feb. 17, 1994.
  • Substituted tricyclic thrombin receptor antagonists are disclosed in U.S. Pat. Nos. 6,063,847, 6,326,380 and WO 01/96330 and 10/271 ,715.
  • thrombin receptor antagonists include those disclosed in U.S. Pat. Nos. 7,304,078; 7,235,567; 7,037920; 6,645,987; and EP Patent Nos.
  • thrombolytic agents denotes agents that lyse blood clots (thrombi).
  • agents include tissue plasminogen activator (TPA, natural or recombinant) and modified forms thereof, anistreplase, urokinase, streptokinase, tenecteplase (TNK), lanoteplase (nPA), factor Vila inhibitors, PAI-I inhibitors (i.e., inactivators of tissue plasminogen activator inhibitors), alpha-2-antiplasmin inhibitors, and anisoylated plasminogen streptokinase activator complex, including pharmaceutically acceptable salts or prodrugs thereof.
  • TPA tissue plasminogen activator
  • TNK tenecteplase
  • nPA lanoteplase
  • PAI-I inhibitors i.e., inactivators of tissue plasminogen activator inhibitors
  • alpha-2-antiplasmin inhibitors alpha-2-antiplasmin inhibitors
  • anistreplase refers to anisoylated plasminogen streptokinase activator complex, as described, for example, in European Patent Application No. 028,489, the disclosure of which is hereby incorporated herein by reference herein.
  • urokinase as used herein, is intended to denote both dual and single chain urokinase, the latter also being referred to herein as prourokinase.
  • Suitable anti-arrythmic agents for use in combination with the present compounds include: Class I agents (such as propafenone); Class Il agents (such as carvadiol and propranolol); Class III agents (such as sotalol, dofetilide, amiodarone, azimilide and ibutilide); Class IV agents (such as ditiazem and verapamil); K + channel openers such as U c h inhibitors, and l ⁇ Ur inhibitors (e.g., compounds such as those disclosed in WO01/40231).
  • Class I agents such as propafenone
  • Class Il agents such as carvadiol and propranolol
  • Class III agents such as sotalol, dofetilide, amiodarone, azimilide and ibutilide
  • Class IV agents such as ditiazem and verapamil
  • K + channel openers such as U c h inhibitors, and l ⁇ Ur inhibitors (e.g.,
  • antihypertensive agents include: alpha adrenergic blockers; beta adrenergic blockers; calcium channel blockers (e.g., diltiazem, verapamili nifedipine, amlodipine and mybefradil); diruetics (e.g., chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide,
  • bendroflumethiazide methylchlorothiazide, trichloromethiazide, polythiazide, benzthiazide, ethacrynic acid tricrynafen, chlorthalidone, furosemide, musolimine, bumetanide, triamtrenene, amiloride, spironolactone); renin inhibitors;
  • angiotensin-converting enzyme (ACE) inhibitors e.g., captopril, lisinopril, fosinopril, enalapril, ceranopril, cilazopril, delapril, pentopril, quinapril, ramipril, lisinopril
  • angiotensin-ll receptor antagonists e.g., irbestatin, losartan
  • ET receptor antagonists e.g., sitaxsentan, atrsentan and compounds disclosed in U.S. Pat. Nos. 5,612,359 and 6,043,265
  • Dual ET/AII antagonist e.g., compounds disclosed in WO 00/01389
  • neutral endopeptidase (NEP) inhibitors e.g., neutral endopeptidase (NEP) inhibitors
  • vasopepsidase inhibitors dual ACE/NEP inhibitors, e.g., omapatrilat, gemopatrilat, nitrates
  • ⁇ -blockers e.g., propanolol, nadolo, or carvedilol.
  • suitable cardiac glycosides for use in combination with the compounds of the present invention include digitalis and ouabain.
  • Suitable cholesterol/lipid lowering agents and lipid profile therapies for use in combination with the compounds of the present invention include: HMG-CoA reductase inhibitors (e.g., pravastatin, lovastatin, atorvastatin, simvastatin, fluvastatin, NK-104 (a.k.a. itavastatin, or nisvastatin or nisbastatin) and ZD-4522 (a.k.a.
  • HMG-CoA reductase inhibitors e.g., pravastatin, lovastatin, atorvastatin, simvastatin, fluvastatin, NK-104 (a.k.a. itavastatin, or nisvastatin or nisbastatin)
  • ZD-4522 a.k.a.
  • rosuvastatin, or atavastatin or visastatin rosuvastatin, or atavastatin or visastatin
  • squalene synthetase inhibitors include fibrates; bile acid sequestrants (such as questran); ACAT inhibitors; MTP inhibitors; lipooxygenase inhibitors; choesterol absorption inhibitors; and cholesterol ester transfer protein inhibitors (e.g., CP-529414).
  • anti-diabetic agents for use in combination with the compounds of the present invention include: biguanides (e.g., metformin);
  • glucosidase inhibitors e.g., acarbose
  • insulins including insulin secretagogues or insulin sensitizers
  • meglitinides e.g., repaglinide
  • sulfonylureas e.g., glimepiride, glyburide and glipizide
  • biguanide/glyburide combinations e.g., glucovance
  • thiozolidinediones e.g., troglitazone, rosiglitazone and
  • PPAR-alpha agonists PPAR-gamma agonists
  • PPAR-gamma agonists PPAR-alpha agonists
  • PPAR-gamma agonists PPAR-gamma agonists
  • alpha/gamma dual agonists SGLT2 inhibitors, inhibitors of fatty acid binding protein (aP2) such as those disclosed in WO00/59506, glucagon-like peptide-1 (GLP-1 ), and dipeptidyl peptidase IV (DP4) inhibitors.
  • aP2 fatty acid binding protein
  • GLP-1 glucagon-like peptide-1
  • DP4 dipeptidyl peptidase IV
  • Suitable anti-depressant agents for use in combination with the compounds of the present invention include nefazodone and sertraline.
  • Suitable anti-inflammatory agents for use in combination with the compounds of the present invention include: prednisone; dexamethasone; enbrel; protein tyrosine kinase (PTK) inhibitors; cyclooxygenase inhibitors (including NSAIDs, and COX-1 and/or COX-2 inhibitors); aspirin; indomethacin; ibuprofen; prioxicam; naproxen; celecoxib; and/or rofecoxib.
  • PTK protein tyrosine kinase
  • cyclooxygenase inhibitors including NSAIDs, and COX-1 and/or COX-2 inhibitors
  • aspirin indomethacin
  • ibuprofen prioxicam
  • naproxen naproxen
  • celecoxib celecoxib
  • rofecoxib examples include: aspirin; indomethacin; ibuprofen; prioxicam; naproxen; cele
  • Suitable anti-osteoporosis agents for use in combination with the compounds of the present invention include alendronate and raloxifene.
  • suitable hormone replacement therapies for use in combination with the compounds of the present invention include estrogen (e.g., congugated estrogens) and estradiol.
  • Suitable anti-obesity agents for use in combination with the compounds of the present invention include orlistat and aP2 inhibitors (such as those disclosed in WO00/59506).
  • suitable anti-anxiety agents for use in combination with the compounds of the present invention include diazepam, lorazepam, buspirone, and hydroxyzine pamoate.
  • suitable anti-anxiety agents for use in combination with the compounds of the present invention include diazepam, lorazepam, buspirone, and hydroxyzine pamoate.
  • Suitable anti-proliferative agents for use in combination with the compounds of the present invention include cyclosporin A, paclitaxel, adriamycin; epithilones, cisplatin, and carboplatin.
  • Suitable anti-ulcer and gastroesophageal reflux disease agents for use in combination with the compounds of the present invention include famotidine, ranitidine, and omeprazole.
  • Administration of the compounds of the present invention i. e., a first therapeutic agent in combination with at least one additional therapeutic agent (i.e., a second therapeutic agent), preferably affords an efficacy advantage over the compounds and agents alone, preferably while permitting the use of lower doses of each.
  • a lower dosage minimizes the potential of side effects, thereby providing an increased margin of safety.
  • at least one of the therapeutic agents is administered in a sub-therapeutic dose. It is even more preferred that all of the therapeutic agents be administered in sub-therapeutic doses.
  • Sub-therapeutic is intended to mean an amount of a therapeutic agent that by itself does not give the desired therapeutic effect for the condition or disease being treated. Synergistic combination is intended to mean that the observed effect of the combination is greater than the sum of the individual agents administered alone.
  • the compounds of the present invention are also useful as standard or reference compounds, for example as a quality standard or control, in tests or assays involving the inhibition of thrombin, Factor Vila, IXa, Xa, XIa, and/or plasma kallikrein.
  • Such compounds may be provided in a commercial kit, for example, for use in pharmaceutical research involving thrombin, Factor Vila, IXa, Xa, XIa, and/or plasma kallikrein.
  • XIa for example, a compound of the present invention could be used as a reference in an assay to compare its known activity to a compound with an unknown activity. This would ensure the experimentor that the assay was being performed properly and provide a basis for comparison, especially if the test compound was a derivative of the reference compound.
  • compounds according to the present invention could be used to test their effectiveness.
  • the compounds of the present invention may also be used in diagnostic assays involving thrombin, Factor Vila, IXa, Xa, XIa, and/or plasma kallikrein.
  • thrombin, Factor Vila, IXa, Xa, XIa, and/or plasma kallikrein in an unknown sample could be determined by addition of the relevant chromogenic substrate, for example S2366 for Factor XIa, to a series of solutions containing test sample and optionally one of the compounds of the present invention. If production of pNA is observed in the solutions containing test sample, but not in the presence of a compound of the present invention, then one would conclude Factor XIa was present.
  • Extremely potent and selective compounds of the present invention those having K 1 values less than or equal to 0.001 ⁇ M against the target protease and greater than or equal to 0.1 ⁇ M against the other proteases, may also be used in diagnostic assays involving the quantitation of thrombin, Factor Vila, IXa, Xa, XIa, and/or plasma kallikrein in serum samples.
  • the amount of Factor IXa in serum samples could be determined by careful titration of protease activity in the presence of the relevant chromogenic substrate, S2366, with a potent and selective Factor IXa inhibitor of the present invention.
  • the present invention also encompasses an article of manufacture.
  • article of manufacture is intended to include, but not be limited to, kits and packages.
  • the article of manufacture of the present invention comprises: (a) a first container; (b) a pharmaceutical composition located within the first container, wherein the composition, comprises: a first therapeutic agent, comprising: a compound of the present invention or a pharmaceutically acceptable salt form thereof; and, (c) a package insert stating that the
  • the package insert states that the pharmaceutical composition can be used in combination (as defined previously) with a second therapeutic agent to treat a thromboembolic and/or inflammatory disorder.
  • the article of manufacture can further comprise: (d) a second container, wherein components (a) and (b) are located within the second container and component (c) is located within or outside of the second container. Located within the first and second containers means that the respective container holds the item within its boundaries.
  • the first container is a receptacle used to hold a pharmaceutical composition. This container can be for manufacturing, storing, shipping, and/or individual/bulk selling.
  • First container is intended to cover a bottle, jar, vial, flask, syringe, tube (e.g., for a cream preparation), or any other container used to manufacture, hold, store, or distribute a pharmaceutical product.
  • the second container is one used to hold the first container and, optionally, the package insert.
  • the second container include, but are not limited to, boxes (e.g., cardboard or plastic), crates, cartons, bags (e.g., paper or plastic bags), pouches, and sacks.
  • the package insert can be physically attached to the outside of the first container via tape, glue, staple, or another method of attachment, or it can rest inside the second container without any physical means of attachment to the first container.
  • the package insert is located on the outside of the second container. When located on the outside of the second container, it is preferable that the package insert is physically attached via tape, glue, staple, or another method of attachment.
  • it can be adjacent to or touching the outside of the second container without being physically attached.
  • the package insert is a label, tag, marker, etc. that recites information relating to the pharmaceutical composition located within the first container.
  • the information recited will usually be determined by the regulatory agency governing the area in which the article of manufacture is to be sold (e.g., the United States Food and Drug Administration).
  • the package insert specifically recites the indications for which the pharmaceutical composition has been approved.
  • the package insert may be made of any material on which a person can read information contained therein or thereon.
  • the package insert is a printable material (e.g., paper, plastic, cardboard, foil, adhesive-backed paper or plastic, etc.) on which the desired information has been formed (e.g., printed or applied).
  • the compounds of this invention can be administered in such oral dosage forms as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. They may also be administered in intravenous (bolus or infusion), intraperitoneal, subcutaneous, or intramuscular form, all using dosage forms well known to those of ordinary skill in the pharmaceutical arts. They can be administered alone, but generally will be administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.
  • the dosage regimen for the compounds of the present invention will, of course, vary depending upon known factors, such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration; the species, age, sex, health, medical condition, and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment; the frequency of treatment; the route of administration, the renal and hepatic function of the patient, and the effect desired.
  • a physician or veterinarian can determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progress of the thromboembolic disorder.
  • the daily oral dosage of each active ingredient when used for the indicated effects, will range between about 0.001 to 1000 mg/kg of body weight, preferably between about 0.01 to 100 mg/kg of body weight per day, and most preferably between about 1.0 to 20 mg/kg/day.
  • the most preferred doses will range from about 1 to about 10 mg/kg/minute during a constant rate infusion.
  • Compounds of this invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three, or four times daily.
  • Compounds of this invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using transdermal skin patches. When administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
  • the compounds are typically administered in admixture with suitable pharmaceutical diluents, excipients, or carriers (collectively referred to herein as pharmaceutical carriers) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices.
  • suitable pharmaceutical diluents, excipients, or carriers suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices.
  • the active drug component can be combined with an oral, non-toxic,
  • the oral drug components can be combined with any oral, non-toxic,
  • Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like.
  • Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like.
  • Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.
  • the compounds of the present invention 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
  • Compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers.
  • soluble polymers can include
  • the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, and crosslinked or amphipathic block copolymers of hydrogels.
  • biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, and crosslinked or amphipathic block copolymers of hydrogels.
  • Dosage forms may contain from about 1 milligram to about 100 milligrams of active ingredient per dosage unit. In these pharmaceutical compositions the active ingredient will ordinarily be present in an amount of about 0.5-95% by weight based on the total weight of the composition.
  • Gelatin capsules may contain the active ingredient and powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective
  • Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance.
  • parenteral solutions In general, water, a suitable oil, saline, aqueous dextrose (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions.
  • Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances.
  • Antioxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or combined, are suitable stabilizing agents.
  • citric acid and its salts and sodium EDTA are also used.
  • parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl-or propyl-paraben, and chlorobutanol.
  • Suitable pharmaceutical carriers are described in Remington's
  • a daily dosage may be about 0.1 to 100 milligrams of the compound of the present invention and about 1 to 7.5 milligrams of the second anticoagulant, per kilogram of patient body weight.
  • the compounds of this invention generally may be present in an amount of about 5 to 10 milligrams per dosage unit, and the second anticoagulant in an amount of about 1 to 5 milligrams per dosage unit.
  • a daily dosage may be about 0.01 to 25 milligrams of the compound of the present invention and about 50 to 150 milligrams of the anti-platelet agent, preferably about 0.1 to 1 milligrams of the compound of the present invention and about 1 to 3 milligrams of antiplatelet agents, per kilogram of patient body weight.
  • a daily dosage may be about 0.1 to 1 milligrams of the compound of the present invention, per kilogram of patient body weight and, in the case of the thrombolytic agents, the usual dosage of the thrombotic agent when administered alone may be reduced by about 70-80% when administered with a compound of the present invention.
  • the amount of each component in a typical daily dosage and typical dosage form may be reduced relative to the usual dosage of the agent when administered alone, in view of the additive or synergistic effect of the therapeutic agents when
  • one active ingredient may be enteric coated.
  • the active ingredients may also be coated with a material that affects a sustained-release throughout the gastrointestinal tract and also serves to minimize physical contact between the combined active ingredients.
  • the sustained-released component can be additionally enteric coated such that the release of this component occurs only in the intestine. Still another approach would involve the formulation of a combination product in which the one component is coated with a sustained and/or enteric release polymer, and the other component is also coated with a polymer such as a low viscosity grade of hydroxypropyl
  • HPMC methylcellulose
  • HPMC methylcellulose
  • the polymer coating serves to form an additional barrier to interaction with the other component.

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Abstract

The present invention relates to novel heterocyclic compounds of Formulae (I): (Chemical formula should be inserted here as it appears on abstract in paper form) Formula (I) as disclosed herein, or a pharmaceutically acceptable salt, solvate, ester, prodrug or stereoisomer thereof. Also disclosed are pharmaceutical compositions comprising said compounds, and methods for using said compounds for treating or preventing a thromboembolic disorder.

Description

4, 5, 6-TRISUBSTITUTED PYRIMIDINE DERIVATIVES AS FACTOR IXA
INHIBITORS
FIELD OF THE INVENTION The present invention relates to heterocyclic compounds useful as serine protease inhibitors, regulators or modulators, in particular, serine protease enzymes of the coagulation cascade and/or contact activation system; for example thrombin, factor XIa, factor Xa, factor IXa, factor Vila, and/or plasma kallikrein. In particular, it relates to compounds that are selective factor IXa inhibitors, pharmaceutical compositions comprising the compounds, and methods of treatment using the compounds and compositions to treat various
thromboembolic disorders, such as acute coronary syndrome, atrial fibrillation, myocardial infarction, and atherosclerosis. BACKGROUND OF THE INVENTION
Factor IXa is a plasma serine protease involved in the regulation of blood coagulation. While blood coagulation is a necessary and important part of the regulation of an organism's homeostasis, abnormal blood coagulation can also have deleterious effects. For instance, thrombosis is the formation or presence of a blood clot inside a blood vessel or cavity of the heart. Such a blood clot can lodge in a blood vessel blocking circulation and inducing a heart attack or stroke. Thromboembolic disorders are the largest cause of mortality and disability in the industrialized world.
Blood coagulation involves three distinct phases: initiation, priming and propagation.1 >2>3 Initiation involves binding of tissue factor (TF) to activated factor VII, a circulating coagulation factor. Blood, in general is not exposed to TF which is a transmembrane protein expressed on extravascular cells. Vasular injury causes the TF-bearing cells to be exposed to blood, and initiates the coagulation process.1 The TF/Vlla complex activates factors IX and X.1'4 Factor IXa is relatively unstable in plasma and diffuses toward activated platelets. Factor Xa on the other hand, is unstable in plasma and is rapidly inhibited by TF pathway inhibitor and antithrombin III.1'5'6 Factor Xa binds factor Va on the surface of TF-bearing cells.1 7 In turn, the Xa/Va complex generates a small but sufficient amount of thrombin to cause platelet activation.1'8'9
Thrombin activates platelets and coagulation factors in the priming phase.1'2 Thrombin binds and cleaves platelet protease-activated receptors (PAR1 and PAR4), triggering a signaling cascade that catalyzes platelet activation and release of factor V from platelet α granules. Thrombin also activates factors V, VIII, and Xl.1
It is during the propagation phase that thrombin generation is maximized on the surface of platelets. The primed, activated platelets bind the IXa/Vllla "tenase" complex. Additional IXa is generated by factor XIa on the platelet surface.10 The IXa/Vllla complex, in physical proximity to Va, recruits factor X to the platelet surface for activation. The Xa/Va complex on the platelet surface is protected from TF pathway inhibitor and antithrombin III.11'12
Enzymology studies have shown that activation of factor X by IXa/Vllla is nearly 5Ox more efficient than activation by factor Vlla/TF.13 The platelet Xa/Va complex generates a "burst" of thrombin, resulting in a stable fibrin-platelet clot.1
The cell-based model of coagulation highlights the importance of the IXa/Vllla complex in clot formation. Factor IXa therefore represents an excellent target for anticoagulant therapy.1 There is a need for effective inhibitors of factor IXa in order to treat or prevent thromboembolic disorders.
Vijaykumar et al., Biorganic & Medicinal Chemistry Letters (2006), 16 (10),
2796-2799, discloses hydroxy pyrazole based factor IXa inhibitors.
References cited:
1. Howard, EL, Becker KC, Rusconi, CP, Becker RC. Factor IXa Inhibitors as Novel Anticoagulents. Arterioscler Thromb Vase Biol. 2007; 27: 722- 2. Monroe DM, Hoffman M, Roberts HR. Platelets and thrombin generation. Arterioscler Thromb Vase Biol. 2002; 22: 1381-1389.
3. Ahmad SS, London FS, Walsh PN. The assembly of the factor X- activating complex on activated human platelets. J Thromb Haemost. 2003; 1 : 48-59.
4. Komiyama Y, Pedersen AH, Kisiel W. Proteolytic activation of human factors IX and X by recombinant human factor Vila: effects of calcium, phospholipids, and tissue factor. Biochemistry. 1990; 29: 9418-9425.
5. Broze GJ, Warren LA, Novotny WF, Higuchi DA, Girard JJ, Miletich PJ.
The lipoprotein-associated coagulation inhibitor that inhibits the factor VII- tissue factor complex also inhibits factor Xa: insight into its possible mechanism of action. Blood. 1988; 71 : 335-343.
6. Rapaport Sl. The extrinsic pathway inhibitor: a regulator of tissue factor- dependent blood coagulation. Thromb Haemost. 1991 ; 66: 6-15. 7. Monkovic DD, Tracy PB. Activation of human factor V by factor Xa and thrombin. Biochemistry. 1990; 29: 1118-1128.
8. Hoffman M, Monroe DM, Oliver JA, Roberts HR. Factors IXa and Xa play distinct roles in tissue factor-dependent initiation of coagulation. Blood. 1995; 86: 1794-1801. 9. Monroe DM, Hoffman M, Roberts HR. Transmission of a procoagulant signal from tissue factor-bearing cells to platelets. Blood Coagul
Fibrinolysis. 1996; 7: 459-464.
10. Walsh PN, Sinha D, Koshy A, Seaman FS, Bradford H. Functional
characterization of platelet-bound factor XIa: retention of factor XIa activity on the platelet surface. Blood. 1986; 68: 225-230. 11. Franssen J, Salemink I, Willems GM, Wun TC, Hemker HC, Lindhout T. Prothrombinase is protected from inactivation by tissue factor pathway inhibitor: competition between prothrombin and inhibitor. Biochem J. 1997; 323: 33-37.
12. Rezaie AR. Prothrombin protects factor Xa in the prothrombinase complex from inhibition by the heparin-antithrombin complex. Blood. 2001 ; 97: 2308-2313.
13. Lawson JH, Mann KG. Cooperative activation of human factor IX by the human extrinsic pathway of blood coagulation. J Biol Chem. 1991 ; 266: 11317-11327.
SUMMARY OF THE INVENTION
In its many embodiments, the present invention provides a novel class of heterocyclic compounds, pharmaceutical compositions comprising one or more said compounds, and methods for using said compounds for treating or preventing a thromboembolic disorder.
Accordingly, in one aspect, the present invention provides compounds of Formula (I):
Figure imgf000006_0001
Formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein:
X1 is selected from the group consisting of a covalent bond, -S- and -O-;
R1 is selected from the group consisting of halo, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein when each of said cycloalkyl, heterocyclyl, aryl and heteroaryl has substitutents on adjacent carbon atoms, said substituents can optionally be taken together with the carbon atoms to which they are attached to form a first five- or six-membered cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein when said first five- or six-membered cycloalkyl, heterocyclyl, aryl or heteroaryl has substitutents on adjacent carbon atoms, said substituents can optionally be taken together with the carbon atoms to which they are attached to form a second five- or six-membered cycloalkyl, heterocyclyl, aryl or heteroaryl;
X2 is selected from the group consisting of a covalent bond, and -O-;
R2 is selected from the group consisting of H, halogen and alkyl, with the proviso that when X2 is a covalent bond, R2 is halogen;
X3 is selected from the group consisting of a covalent bond, -N(R)- and
-O-;
R is H or alkyl;
R3 is selected from the group consisting of halo, alkyl, cycloalkyl, aryl and heteroaryl, wherein when each of said cycloalkyl, heterocyclyl, aryl and heteroaryl has substitutents on adjacent carbon atoms, said substituents can optionally be taken together with the carbon atoms to which they are attached to form a first five- or six-membered cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein when said first five- or six-membered cycloalkyl, heterocyclyl, aryl or heteroaryl has substitutents on adjacent carbon atoms, said substituents can optionally be taken together with the carbon atoms to which they are attached to form a second five- or six-membered cycloalkyl, heterocyclyl, aryl or heteroaryl; and
R4 is selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; with the proviso that when X1 and X3 are both -O-, then -X2-R2 is other than -halo.
In another aspect, the compounds of Formula I, or a pharmaceutically acceptable salt, solvate or ester thereof can be useful for treating or preventing a disorder or disease mediated by factor IXa, or a thromboembolic disorder (each disorder being a "Condition").
In another aspect, the present invention provides pharmaceutical compositions comprising at least one compound of Formula I or a
pharmaceutically acceptable salt, solvate or ester thereof, and a pharmaceutically acceptable carrier. The compositions can be useful for treating or preventing a Condition.
In still another aspect, the present invention provides methods for treating a Condition, the method comprising administering to a patient an effective amount of at least one compound of Formula I, or a pharmaceutically acceptable salt, solvate or ester thereof.
DETAILED DESCRIPTION OF THE INVENTION
In an embodiment, the present invention provides at least one compound of Formula I or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof. The compounds of formula I can be useful for treating or preventing a Condition in a patient.
As used above, and throughout this disclosure, the following terms, unless otherwise indicated, shall be understood to have the following meanings:
"Patient" includes both human and animals.
"Mammal" means humans and other mammalian animals.
"Alkyl" means an aliphatic hydrocarbon group which may be straight or branched and comprising about 1 to about 20 carbon atoms in the chain.
Preferred alkyl groups contain about 1 to about 12 carbon atoms in the chain. More preferred alkyl groups contain about 1 to about 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkyl chain. "Lower alkyl" means a group having about 1 to about 6 carbon atoms in the chain which may be straight or branched. "Alkyl" may be unsubstituted or optionally substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of halo, alkyl, aryl, cycloalkyl, heteroaryl, cyano, hydroxy, alkoxy, alkylthio, amino, -NH(alkyl), -NH(cycloalkyl), - N(alkyl)2) -O-C(O)-alkyl, -O-C(O)-aryl, -O-C(O)-cycloalkyl, carboxy and -C(O)O- alkyl. Non-limiting examples of suitable alkyl groups include methyl, ethyl, n- propyl, isopropyl and t-butyl.
"Alkenyl" means an aliphatic hydrocarbon group containing at least one carbon-carbon double bond and which may be straight or branched and comprising about 2 to about 15 carbon atoms in the chain. Preferred alkenyl groups have about 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkenyl chain. "Lower alkenyl" means about 2 to about 6 carbon atoms in the chain which may be straight or branched. "Alkenyl" may be unsubstituted or optionally substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of halo, alkyl, aryl, cycloalkyl, heteroaryl, cyano, alkoxy and -S(alkyl). Non-limiting examples of suitable alkenyl groups include ethenyl, propenyl, n-butenyl, 3- methylbut-2-enyl, n-pentenyl, octenyl and decenyl.
"Alkylene" means a difunctional group obtained by removal of a hydrogen atom from an alkyl group that is defined above. Non-limiting examples of alkylene include methylene, ethylene and propylene.
"Alkynyl" means an aliphatic hydrocarbon group containing at least one carbon-carbon triple bond and which may be straight or branched and comprising about 2 to about 15 carbon atoms in the chain. Preferred alkynyl groups have about 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 4 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkynyl chain. "Lower alkynyl" means about 2 to about 6 carbon atoms in the chain which may be straight or branched. Non-limiting examples of suitable alkynyl groups include ethynyl, propynyl, 2-butynyl and 3-methylbutynyl. "Alkynyl" may be unsubstituted or optionally substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of alkyl, aryl and cycloalkyl.
"Aryl" means an aromatic monocyclic or multicyclic ring system comprising about 6 to about 14 carbon atoms, preferably about 6 to about 10 carbon atoms. The aryl group can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined herein. Non-limiting examples of suitable aryl groups include phenyl and naphthyl.
"Heteroaryl" means an aromatic monocyclic or multicyclic ring system comprising about 5 to about 14 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the ring atoms is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. Preferred heteroaryls contain about 5 to about 6 ring atoms. The "heteroaryl" can be optionally substituted by one or more "ring system substituents" which may be the same or different, and are as defined herein. The prefix aza, oxa or thia before the heteroaryl root name means that at least a nitrogen, oxygen or sulfur atom respectively, is present as a ring atom. A nitrogen atom of a heteroaryl can be optionally oxidized to the corresponding N-oxide. "Heteroaryl" may also include a heteroaryl as defined above fused to an aryl as defined above. Non- limiting examples of suitable heteroaryls include pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, pyridone (including N-substituted pyridones), isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl, 1 ,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, oxindolyl, imidazo[1 ,2-a]pyridinyl, imidazo[2,1 -b]thiazolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl, imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl, pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl, 1 ,2,4-triazinyl, benzothiazolyi and the like. The term "heteroaryl" also refers to partially saturated heteroaryl moieties such as, for example, tetrahydroisoquinolyl, tetrahydroquinolyl and the like.
"Aralkyl" or "arylalkyl" means an aryl-alkyl- group in which the aryl and alkyl are as previously described. Preferred aralkyls comprise a lower alkyl group. Non-limiting examples of suitable aralkyl groups include benzyl, 2- phenethyl and naphthalenylmethyl. The bond to the parent moiety is through the alkyl.
"Alkylaryl" means an alkyl-aryl- group in which the alkyl and aryl are as previously described. Preferred alkylaryls comprise a lower alkyl group. Non- limiting example of a suitable alkylaryl group is tolyl. The bond to the parent moiety is through the aryl.
"Cycloalkyl" means a non-aromatic mono- or multicyclic ring system comprising about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms. Preferred cycloalkyl rings contain about 5 to about 7 ring atoms. The cycloalkyl can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined above. Non-limiting examples of suitable monocyclic cycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. Non-limiting examples of suitable multicyclic cycloalkyls include 1 -decalinyl, norbornyl, adamantyl and the like.
"Cycloalkylalkyl" means a cycloalkyl moiety as defined above linked via an alkyl moiety (defined above) to a parent core. Non-limiting examples of suitable cycloalkylalkyls include cyclohexylmethyl, adamantylmethyl and the like.
"Cycloalkenyl" means a non-aromatic mono or multicyclic ring system comprising about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms which contains at least one carbon-carbon double bond. Preferred cycloalkenyl rings contain about 5 to about 7 ring atoms. The cycloalkenyl can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined above. Non-limiting examples of suitable monocyclic cycloalkenyls include cyclopentenyl, cyclohexenyl,
cyclohepta-1 ,3-dienyl, and the like. Non-limiting example of a suitable multicyclic cycloalkenyl is norbornylenyl.
"Cycloalkenylalkyl" means a cycloalkenyl moiety as defined above linked via an alkyl moiety (defined above) to a parent core. Non-limiting examples of suitable cycloalkenylalkyls include cyclopentenylmethyl, cyclohexenylmethyl and the like.
"Halogen" means fluorine, chlorine, bromine, or iodine. Preferred are fluorine, chlorine and bromine.
"Ring system substituent" means a substituent attached to an aromatic or non-aromatic ring system which, for example, replaces an available hydrogen on the ring system. Ring system substituents may be the same or different, each being independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, alkylaryl, heteroaralkyl, heteroarylalkenyl,
heteroarylalkynyl, alkylheteroaryl, hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo, nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylthio, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio, cycloalkyl, heterocyclyl, -C(=N-CN)- NH2, -C(=NH)-NH2, -C(=NH)-NH(alkyl), YiY2N-, YiY2N-alkyl-, Y1Y2NC(O)-,
YiY2NSO2- and -SO2NYiY2, wherein Yi and Y2 can be the same or different and are independently selected from the group consisting of hydrogen, alkyl, aryl, cycloalkyl, and aralkyl. "Ring system substituent" may also mean a single moiety which simultaneously replaces two available hydrogens on two adjacent carbon atoms (one H on each carbon) on a ring system. Examples of such moiety are methylene dioxy, ethylenedioxy, -C(CHs)2- and the like which form moieties such as, for example:
Figure imgf000012_0002
and "Heteroarylalkyl" means a heteroaryl moiety as defined above linked via an alkyl moiety (defined above) to a parent core. Non-limiting examples of suitable heteroaryls include 2-pyridinylmethyl, quinolinylmethyl and the like.
"Heterocyclyl" means a non-aromatic saturated monocyclic or multicyclic ring system comprising about 3 to about 10 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. There are no adjacent oxygen and/or sulfur atoms present in the ring system. Preferred heterocyclyls contain about 5 to about 6 ring atoms. The prefix aza, oxa or thia before the heterocyclyl root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom. Any -NH in a heterocyclyl ring may exist protected such as, for example, as an -N(Boc), - N(CBz), -N(Tos) group and the like; such protections are also considered part of this invention. The heterocyclyl can be optionally substituted by one or more "ring system substituents" which may be the same or different, and are as defined herein. The nitrogen or sulfur atom of the heterocyclyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Non-limiting examples of suitable monocyclic heterocyclyl rings include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1 ,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, lactam, lactone, and the like. "Heterocyclyl" may also mean a single moiety (e.g., carbonyl) which simultaneously replaces two available hydrogens on the same carbon atom on a ring system. Example of such moiety is pyrrolidone:
Figure imgf000013_0001
. "Heterocyclylalkyl" means a heterocyclyl moiety as defined above linked via an alkyl moiety (defined above) to a parent core. Non-limiting examples of suitable heterocyclylalkyls include piperidinylmethyl, piperazinylmethyl and the like.
"Heterocyclenyl" means a non-aromatic monocyclic or multicyclic ring system comprising about 3 to about 10 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is an element other than carbon, for example nitrogen, oxygen or sulfur atom, alone or in combination, and which contains at least one carbon-carbon double bond or carbon-nitrogen double bond. There are no adjacent oxygen and/or sulfur atoms present in the ring system. Preferred heterocyclenyl rings contain about 5 to about 6 ring atoms. The prefix aza, oxa or thia before the heterocyclenyl root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom. The heterocyclenyl can be optionally substituted by one or more ring system substituents, wherein "ring system substituent" is as defined above. The nitrogen or sulfur atom of the heterocyclenyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S.S-dioxide. Non-limiting examples of suitable heterocyclenyl groups include 1 ,2,3,4- tetrahydropyridinyl, 1 ,2-dihydropyridinyl, 1 ,4-dihydropyridinyl, 1 ,2,3,6-tetrahydropyridinyl, 1 ,4,5,6- tetrahydropyrimidinyl, 2-pyrrolinyl, 3-pyrrolinyl, 2-imidazolinyl, 2-pyrazolinyl, dihydroimidazolyl, dihydrooxazolyl, dihydrooxadiazolyl, dihydrothiazolyl, 3,4- dihydro-2H-pyranyl, dihydrofuranyl, fluorodihydrofuranyl, 7- oxabicyclo[2.2.1]heptenyl, dihydrothiophenyl, dihydrothiopyranyl, and the like. "Heterocyclenyl" may also mean a single moiety (e.g., carbonyl) which
simultaneously replaces two available hydrogens on the same carbon atom on a ring system. Example of such moiety is pyrrolidinone:
Figure imgf000015_0001
"Heterocyclenylalkyl" means a heterocyclenyl moiety as defined above linked via an alkyl moiety (defined above) to a parent core.
It should be noted that in hetero-atom containing ring systems of this invention, there are no hydroxyl groups on carbon atoms adjacent to a N, O or S, as well as there are no N or S groups on carbon adjacent to another heteroatom. Thus, for example, in the ring:
Figure imgf000015_0002
there is no -OH attached directly to carbons marked 2 and 5.
It should also be noted that tautomeric forms such as, for example, the moieties:
Figure imgf000015_0003
are considered equivalent in certain embodiments of this invention.
"Alkynylalkyl" means an alkynyl-alkyl- group in which the alkynyl and alkyl are as previously described. Preferred alkynylalkyls contain a lower alkynyl and a lower alkyl group. The bond to the parent moiety is through the alkyl. Non-limiting examples of suitable alkynylalkyl groups include propargylmethyl.
"Heteroaralkyl" means a heteroaryl-alkyl- group in which the heteroaryl and alkyl are as previously described. Preferred heteroaralkyls contain a lower alkyl group. Non-limiting examples of suitable aralkyl groups include
pyridylmethyl, and quinolin-3-ylmethyl. The bond to the parent moiety is through the alkyl. "Hydroxyalkyl" means a HO-alkyl- group in which alkyl is as previously defined. Preferred hydroxyalkyls contain lower alkyl. Non-limiting examples of suitable hydroxyalkyl groups include hydroxymethyl and 2-hydroxyethyl.
"Acyl" means an H-C(O)-, alkyl-C(O)- or cycloalkyl-C(O)-, group in which the various groups are as previously described. The bond to the parent moiety is through the carbonyl. Preferred acyls contain a lower alkyl. Non-limiting examples of suitable acyl groups include formyl, acetyl and propanoyl.
"Aroyl" means an aryl-C(O)- group in which the aryl group is as previously described. The bond to the parent moiety is through the carbonyl. Non-limiting examples of suitable groups include benzoyl and 1- naphthoyl.
"Alkoxy" means an alkyl-O- group in which the alkyl group is as previously described. Non-limiting examples of suitable alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. The bond to the parent moiety is through the ether oxygen.
"Aryloxy" means an aryl-O- group in which the aryl group is as previously described. Non-limiting examples of suitable aryloxy groups include phenoxy and naphthoxy. The bond to the parent moiety is through the ether oxygen.
"Aralkyloxy" means an aralkyl-O- group in which the aralkyl group is as previously described. Non-limiting examples of suitable aralkyloxy groups include benzyloxy and 1 - or 2-naphthalenemethoxy. The bond to the parent moiety is through the ether oxygen.
"Alkylthio" means an alkyl-S- group in which the alkyl group is as previously described. Non-limiting examples of suitable alkylthio groups include methylthio and ethylthio. The bond to the parent moiety is through the sulfur.
"Arylthio" means an aryl-S- group in which the aryl group is as previously described. Non-limiting examples of suitable arylthio groups include phenylthio and naphthylthio. The bond to the parent moiety is through the sulfur.
"Aralkylthio" means an aralkyl-S- group in which the aralkyl group is as previously described. Non-limiting example of a suitable aralkylthio group is benzylthio. The bond to the parent moiety is through the sulfur. "Alkoxycarbonyl" means an alkyl-0-CO- group. Non-limiting examples of suitable alkoxycarbonyl groups include methoxycarbonyl and ethoxycarbonyl. The bond to the parent moiety is through the carbonyl.
"Aryloxycarbonyl" means an aryl-O-C(O)- group. Non-limiting examples of suitable aryloxycarbonyl groups include phenoxycarbonyl and
naphthoxycarbonyl. The bond to the parent moiety is through the carbonyl.
"Aralkoxycarbonyl" means an aralkyl-O-C(O)- group. Non-limiting example of a suitable aralkoxycarbonyl group is benzyloxycarbonyl. The bond to the parent moiety is through the carbonyl.
"Alkylsulfonyl" means an alkyl-S(O2)- group. Preferred groups are those in which the alkyl group is lower alkyl. The bond to the parent moiety is through the sulfonyl.
"Arylsulfonyl" means an aryl-S(O2)- group. The bond to the parent moiety is through the sulfonyl.
The term "substituted" means that one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency under the existing circumstances is not exceeded, and that the substitution results in a stable compound.
Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. By "stable compound' or "stable structure" is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
The term "optionally substituted" means optional substitution with the specified groups, radicals or moieties.
The term "purified", "in purified form" or "in isolated and purified form" for a compound refers to the physical state of said compound after being isolated from a synthetic process (e.g. from a reaction mixture), or natural source or combination thereof. Thus, the term "purified", "in purified form" or "in isolated and purified form" for a compound refers to the physical state of said compound after being obtained from a purification process or processes described herein or well known to the skilled artisan (e.g., chromatography, recrystallization and the like) , in sufficient purity to be characterizable by standard analytical techniques described herein or well known to the skilled artisan. In one embodiment, such purity means at least 95% pure, in another embodiment at lest 90% pure, in another embodiment at least 80% pure, in another embodiment at least 70% pure, and in another embodiment at least 60% pure.
It should also be noted that any carbon as well as heteroatom with unsatisfied valences in the text, schemes, examples and Tables herein is assumed to have the sufficient number of hydrogen atom(s) to satisfy the valences.
When a functional group in a compound is termed "protected", this means that the group is in modified form to preclude undesired side reactions at the protected site when the compound is subjected to a reaction. Suitable protecting groups will be recognized by those with ordinary skill in the art as well as by reference to standard textbooks such as, for example, T. W. Greene etal, Protective Groups in organic Synthesis, 4th edition (2007), Wiley, New York.
When any variable (e.g., aryl, heterocycle, R2, etc.) occurs more than one time in any constituent or in Formula I-VI, its definition on each occurrence is independent of its definition at every other occurrence.
As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
Prodrugs and solvates of the compounds of the invention are also contemplated herein. A discussion of prodrugs is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems (1987) 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, (1987) Edward B. Roche, ed., American Pharmaceutical Association and Pergamon Press. The term "prodrug" means a compound (e.g, a drug precursor) that is transformed in vivo to yield a compound of Formula (I) or a pharmaceutically acceptable salt, hydrate or solvate of the compound. The transformation may occur by various
mechanisms (e.g., by metabolic or chemical processes), such as, for example, through hydrolysis in blood. A discussion of the use of prodrugs is provided by T. Higuchi and W. Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the A. C. S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed.
Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.
For example, if a compound of Formula (I) or a pharmaceutically
acceptable salt, hydrate or solvate of the compound contains a carboxylic acid functional group, a prodrug can comprise an ester formed by the replacement of the hydrogen atom of the acid group with a group such as, for example, (C1- C8)alkyl, (C2-Ci2)alkanoyioxymethyl, 1 -(alkanoyloxy)ethyl having from 4 to 9 carbon atoms, 1-methyl-1 -(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1 -
(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1-methyl-1- (alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N- (aikoxycarbonyl)aminomethyi having from 3 to 9 carbon atoms, 1-(N- (alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms, 3-phthalidyl, 4- crotonolactonyl, gamma-butyrolacton-4-yl, di-N,N-(CrC2)alkylamino(C2-C3)aikyl (such as β-dimethylaminoethyl), carbamoyl-(CrC2)alkyl, N,N-di (d- C2)alkylcarbamoyl-(C1 -C2)alkyl and piperidino-, pyrrolidino- or morpholino(C2- C3)alkyl, and the like.
Similarly, if a compound of Formula (I) contains an alcohol functional group, a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as, for example, (Ci-C6)alkanoyloxymethyl, 1 - ((Ci-C6)alkanoyloxy)ethyl, 1 -methyl-1 -((Ci-C6)alkanoyloxy)ethyl, (d- C6)alkoxycarbonyloxymethyl, N-(Ci -C6)alkoxycarbonylaminomethyl, succinoyl, (CrC6)alkanoyl, α-amino(CrC4)alkanyl, arylacyl and α-aminoacyl, or α- aminoacyl-α-aminoacyl, where each α-aminoacyl group is independently selected from the naturally occurring L-amino acids, P(O)(OH)2, -P(O)(O(Ci-Cβ)alkyl)2 or glycosyl (the radical resulting from the removal of a hydroxyl group of the hemiacetal form of a carbohydrate), and the like.
If a compound of Formula (I) incorporates an amine functional group, a prodrug can be formed by the replacement of a hydrogen atom in the amine group with a group such as, for example, R-carbonyl, RO-carbonyl, NRR'- carbonyl where R and R' are each independently (Ci-Cio)alkyl, (C3-C7) cycloalkyl, benzyl, or R-carbonyl is a natural α-aminoacyl or natural α-aminoacyl, -C(OH)C(O)OY1 wherein Y1 is H, (CrC6)alkyl or benzyl,— C(OY2)Y3 wherein Y2 is (CrC4) alkyl and Y3 is (CrC6)alkyl, carboxy (Ci-C6)alkyl, amino(Ci-C4)alkyl or mono-N— or di-N,N-(CrC6)alkylaminoalkyl,— C(Y4)Y5 wherein Y4 is H or methyl and Y5 is mono-N— or di-N,N-(Ci-C-6)alkylamino morpholino, piperidin-1 -yl or pyrrolidin-1-yl, and the like.
One or more compounds of the invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the invention embrace both solvated and unsolvated forms. "Solvate" means a physical association of a compound of this invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. "Solvate" encompasses both solution-phase and isolatable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like. "Hydrate" is a solvate wherein the solvent molecule is H2O.
One or more compounds of the invention may optionally be converted to a solvate. Preparation of solvates is generally known. Thus, for example, M. Caira et al, J. Pharmaceutical ScL, 93(3), 601 -611 (2004) describe the preparation of the solvates of the antifungal fluconazole in ethyl acetate as well as from water. Similar preparations of solvates, hemisolvate, hydrates and the like are described by E. C. van Tonder etal, AAPS PharmSciTech., 5(11, article 12 (2004); and A. L. Bingham etal, Chem. Commun., 603-604 (2001 ). A typical, non-limiting, process involves dissolving the inventive compound in desired amounts of the desired solvent (organic or water or mixtures thereof) at a higher than ambient temperature, and cooling the solution at a rate sufficient to form crystals which are then isolated by standard methods. Analytical techniques such as, for example I. R. spectroscopy, show the presence of the solvent (or water) in the crystals as a solvate (or hydrate).
"Effective amount" or "therapeutically effective amount" is meant to describe an amount of compound or a composition of the present invention effective in inhibiting the above-noted diseases and thus producing the desired therapeutic, ameliorative, inhibitory or preventative effect.
The compounds of Formula I can form salts which are also within the scope of this invention. Reference to a compound of Formula I herein is understood to include reference to salts thereof, unless otherwise indicated. The term "salt(s)", as employed herein, denotes acidic salts formed with inorganic and/or organic acids, as well as basic salts formed with inorganic and/or organic bases. In addition, when a compound of Formula I contains both a basic moiety, such as, but not limited to a pyridine or imidazole, and an acidic moiety, such as, but not limited to a carboxylic acid, zwitterions ("inner salts") may be formed and are included within the term "salt(s)" as used herein. Pharmaceutically
acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful. Salts of the compounds of Formula I may be formed, for example, by reacting a compound of Formula I with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.
Exemplary acid addition salts include acetates, ascorbates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, fumarates, hydrochlorides, hydrobromides, hydroiodides, lactates, maleates, methanesulfonates, naphthalenesulfonates, nitrates, oxalates, phosphates, propionates, salicylates, succinates, sulfates, tartarates, thiocyanates, toluenesulfonates (also known as tosylates,) and the like.
Additionally, acids which are generally considered suitable for the formation of pharmaceutically useful salts from basic pharmaceutical compounds are discussed, for example, by P. Stahl et al, Camille G. (eds.) Handbook of
Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich; Wiley-VCH; S. Berge et al, Journal of Pharmaceutical Sciences (1977) 66(1 ) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33 201 -217; Anderson et al, The
Practice of Medicinal Chemistry (1996), Academic Press, New York; and in The Orange Book (Food & Drug Administration, Washington, D. C. on their website). These disclosures are incorporated herein by reference thereto.
Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as dicyclohexylamines, t-butyl amines, and salts with amino acids such as arginine, lysine and the like. Basic nitrogen-containing groups may be
quartemized with agents such as lower alkyl halides (e.g. methyl, ethyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g. dimethyl, diethyl, and dibutyl sulfates), long chain halides (e.g. decyl, lauryl, and stearyl chlorides, bromides and iodides), aralkyl halides (e.g. benzyl and phenethyl bromides), and others.
All such acid salts and base salts are intended to be pharmaceutically acceptable salts within the scope of the invention and all acid and base salts are considered equivalent to the free forms of the corresponding compounds for purposes of the invention.
Pharmaceutically acceptable esters of the present compounds include the following groups: (1 ) carboxylic acid esters obtained by esterification of the hydroxy groups, in which the non-carbonyl moiety of the carboxylic acid portion of the ester grouping is selected from straight or branched chain alkyl (for example, acetyl, n-propyl, t-butyl, or n-butyl), alkoxyalkyl (for example, methoxymethyl), aralkyl (for example, benzyl), aryloxyalkyl (for example, phenoxymethyl), aryl (for example, phenyl optionally substituted with, for example, halogen,
Figure imgf000023_0001
or amino); (2) sulfonate esters, such as alkyl- or aralkylsulfonyl (for example, methanesulfonyl); (3) amino acid esters (for example, L-valyl or L-isoleucyl); (4) phosphonate esters and (5) mono-, di- or triphosphate esters. The phosphate esters may be further esterified by, for example, a C 1-20 alcohol or reactive derivative thereof, or by a 2,3-di (C-6-24)acyl glycerol.
Compounds of Formula I, and salts, solvates, esters and prodrugs thereof, may exist in their tautomeric form (for example, as an amide or imino ether). All such tautomeric forms are contemplated herein as part of the present invention.
The compounds of Formula (I) may contain asymmetric or chiral centers, and, therefore, exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of Formula (I) as well as mixtures thereof, including racemic mixtures, form part of the present invention. In addition, the present invention embraces all geometric and positional isomers. For example, if a compound of Formula (I) incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the invention.
Diastereomeric mixtures can be separated into their individual
diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as, for example, by chromatography and/or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an
appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. Also, some of the compounds of Formula (I) may be atropisomers (e.g., substituted biaryls) and are considered as part of this invention.
Enantiomers can also be separated by use of chiral HPLC column. It is also possible that the compounds of Formula (I) may exist in different tautomeric forms, and all such forms are embraced within the scope of the invention. Also, for example, all keto-enol and imine-enamine forms of the compounds are included in the invention.
All stereoisomers (for example, geometric isomers, optical isomers and the like) of the present compounds (including those of the salts, solvates, esters and prodrugs of the compounds as well as the salts, solvates and esters of the prodrugs), such as those which may exist due to asymmetric carbons on various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated within the scope of this invention, as are positional isomers (such as, for example, 4-pyridyl and 3-pyridyl). (For example, if a compound of Formula (I) incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the invention. Also, for example, all keto-enol and imine-enamine forms of the compounds are included in the invention.) Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers. The chiral centers of the present invention can have the S or R configuration as defined by the IUPAC 1974 Recommendations. The use of the terms "salt", "solvate", "ester", "prodrug" and the like, is intended to equally apply to the salt, solvate, ester and prodrug of enantiomers, stereoisomers, rotamers, tautomers, positional isomers, racemates or prodrugs of the inventive compounds.
The present invention also embraces isotopically-labelled compounds of the present invention which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine and iodine, such as 2H, 3H1 11C, 13C, 14C, 15N, 180, 17O, 31P, 32P, 35S, 18F, 36CI and 123I, respectively.
Certain isotopically-labelled compounds of Formula (I) (e.g., those labeled with 3H and 14C) are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e., 3H) and carbon-14 (i.e., 14C) isotopes are particularly preferred for their ease of preparation and detectability. Certain isotopically- labelled compounds of Formula (I) can be useful for medical imaging purposes. E.g., those labeled with positron-emitting isotopes like 11C or 18F can be useful for application in Positron Emission Tomography (PET) and those labeled with gamma ray emitting isotopes like 123I can be useful for application in Single photon emission computed tomography (SPECT). Further, substitution with heavier isotopes such as deuterium (i.e., 2H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half- life or reduced dosage requirements) and hence may be preferred in some circumstances. Further, substitution with heavier isotopes such as deuterium (i.e., 2H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage
requirements) and hence may be preferred in some circumstances. Additionally, isotopic substitution at a site where epimerization occurs may slow or reduce the epimerization process and thereby retain the more active or efficacious form of the compound for a longer period of time, lsotopically labeled compounds of Formula (I), in particular those containing isotopes with longer half lives (T1/2 >1 day), can generally be prepared by following procedures analogous to those disclosed in the Schemes and/or in the Examples herein below, by substituting an appropriate isotopically labeled reagent for a non-isotopically labeled reagent.
The physical properties of some of the deuterated analogs described here can be significantly modified by substituting hydrogen with deuterium by employing reagents containing deuterium. This can lead to compounds with improved pharmacokinetic profiles. Three representative examples of possible method of preparation of deuterium containing analogs are presented below: Intermediate 2 can be reduced with Raney nickel under deuterium gas that will provide 3-D. Using sodiumborodeutiride, intermediate 77 can be reduced to provide analog 78-D. Similarly, P51 can be first converted to its imine and subsequently reduced with sodiumcycanoborodeuteride followed by
debenzylation to give 80-D.
Figure imgf000026_0001
3-D
Figure imgf000026_0002
Figure imgf000026_0003
P51 80-D
Polymorphic forms of the compounds of Formula I, and of the salts, solvates, esters and prodrugs of the compounds of Formula I, are intended to be included in the present invention. Heterocyclic Compounds of the Invention
the present invention provides compounds of Formula (I):
Figure imgf000027_0001
Formula (I)
or a pharmaceutically acceptable salt or solvate thereof, wherein:
X1 is selected from the group consisting of a covalent bond, -S- and -O-;
R1 is selected from the group consisting of halo, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein when each of said cycloalkyl, heterocyclyl, aryl and heteroaryl has substitutents on adjacent carbon atoms, said substituents can optionally be taken together with the carbon atoms to which they are attached to form a first five- or six-membered cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein when said first five- or six-membered cycloalkyl, heterocyclyl, aryl or heteroaryl has substitutents on adjacent carbon atoms, said substituents can optionally be taken together with the carbon atoms to which they are attached to form a second five- or six-membered cycloalkyl, heterocyclyl, aryl or heteroaryl;
X2 is selected from the group consisting of a covalent bond, and -O-;
R2 is selected from the group consisting of H, halogen and alkyl, with the proviso that when X2 is a covalent bond, R2 is halogen;
X3 is selected from the group consisting of a covalent bond, -N(R)- and — O- "
R is H or alkyl; R3 is selected from the group consisting of halo, alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein when each of said cycloalkyl, heterocyclyl, aryl and heteroaryl has substitutents on adjacent carbon atoms, said substituents can optionally be taken together with the carbon atoms to which they are attached to form a first five- or six-membered cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein when said first five- or six-membered cycloalkyl, heterocyclyl, aryl or heteroaryl has substitutents on adjacent carbon atoms, said substituents can optionally be taken together with the carbon atoms to which they are attached to form a second five- or six-membered cycloalkyl, heterocyclyl, aryl or heteroaryl; and
R4 is selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
with the proviso that when X1 and X3 are both -O-, then -X2-R2 is other than -halo.
In another embodiment, in Formula (I), X2 is -O- and R2 is H or alkyl.
In another embodiment, in Formula (I), X2 is a covalent bond, and R2 is halo.
In another embodiment, in Formula (I), -X2R2 is selected from the group consisting of hydroxyl, methoxy, and fluoro.
In another embodiment, in Formula (I), X1 is selected from the group consisting of a covalent bond and -O-.
In another embodiment, in Formula (I), wherein X1 is a covalent bond, and R1 is halo.
In another embodiment, in Formula (I), R1 aryl is phenyl which is
unsubstituted or substituted with at least one ring system substituent.
In another embodiment, in Formula (I), R1 aryl is phenyl which is
unsubstituted or substituted with at least one ring system substituent, wherein the ring system substitutent is selected from the group consisting of halo, alkyl, haloalkyl, haloalkoxy, -C(=O)OH, and -C(=NH)NH2. In another embodiment, in Formula (I), X1 is -O-, and R1 is phenyl which is substituted with a ring system substituent selected from the group consisting of fluoro, chloro, trifluoromethyl, trifluoromethoxy, methyl, ethyl, and -C(=NH)NH2.
In another embodiment, in Formula (I), X3 is NH, and R3 is selected from the group consisting of alkyl, cylcloalkyl, heterocyclyl, and aryl, wherein when each of said cycloalkyl, heterocyclyl, and aryl has substitutents on adjacent carbon atoms, said substituents can optionally be taken together with the carbon atoms to which they are attached to form a five- or six-membered aryl or heteroaryl.
In another embodiment, in Formula (I), X3 is NH, and R3 is alkyl which is unsubstituted or substituted with a substituent selected from the group consisting of aryl, wherein when said aryl has substitutents on adjacent carbon atoms, said substituents can optionally be taken together with the carbon atoms to which they are attached to form a five- or six-membered aryl or heteroaryl
In another embodiment, in Formula (I), X3 is NH, and R3 is alkyl- benzopyridyl, wherein the benzopyridyl is attached to the alkyl through the benzene ring of said benzopyridyl, wherein said benzopyridyl is unsubstituted or substituted with a ring system substitutent.
In another embodiment, in Formula (I), X3 is NH, and R3 is alkyl- benzopyridyl, wherein the benzopyridyl is attached to the alkyl through the benzene ring of said benzopyridyl, wherein said benzopyridyl is unsubstituted or substituted with a ring system substitutent, wherein said ring system substituent is -NH2.
In another embodiment, in Formula (I), X3 is NH, and R3 is cycloalkyl, wherein when said cycloalkyl has substitutents on adjacent carbon atoms, said substituents can optionally be taken together with the carbon atoms to which they are attached to form a five- or six-membered aryl or heteroaryl.
In another embodiment, in Formula (I), X3 is NH, and R3 is cycloalkyl, wherein when said cycloalkyl has substitutents on adjacent carbon atoms, said substituents can optionally be taken together with the carbon atoms to which they are attached to form a five- or six-membered aryl or heteroaryl, wherein said R3 cycloalkyl, optionally with said five- or six-membered aryl or heteroaryl is unsubstituted or substituted with at least one ring system substituent.
In another embodiment, in Formula (I), X3 is NH, and R3 is cycloalkyl selected from the group consisting of cyclohexyl, and thiazolyl-fused cyclohexyl, each of which unsubstituted or substituted with a ring system substituent.
In another embodiment, in Formula (I), X3 is NH, and R3 is cycloalkyl selected from the group consisting of cyclohexyl, and thiazolyl-fused cyclohexyl, each of which unsubstituted or substituted with a ring system substituent, wherein the ring system substituent is selected from the group consisting of alkyl, -NH2, aminoalkyl-, -alkyl-NH-C(=O)O-alkyl, -NH-C(=O)O-alkyl.
In another embodiment, in Formula (I), X3 is NH, and R3 is heterocyclyl, wherein when said heterocyclyl has substitutents on adjacent carbon atoms, said substituents can optionally be taken together with the carbon atoms to which they are attached to form a five- or six-membered aryl or heteroaryl.
In another embodiment, in Formula (I), X3 is NH, and R3 is heterocyclyl, wherein when said heterocyclyl has substitutents on adjacent carbon atoms, said substituents can optionally be taken together with the carbon atoms to which they are attached to form a five- or six-membered aryl or heteroaryl, wherein said R3 heterocyclyl, optionally with said five- or six-membered aryl or heteroaryl is unsubstituted or substituted with at least one ring system substituent.
In another embodiment, in Formula (I), X3 is NH, and R3 is piperidinyl which is unsubstituted or substituted with at least one ring system substituent.
In another embodiment, in Formula (I), X3 is NH, and R3 is piperidinyl which is unsubstituted or substituted with at least one ring system substituent, wherein the ring system substituent is -C(=O)-O-alkyl.
In another embodiment, in Formula (I), X3 is NH, and R3 is aryl, wherein when said aryl has substitutents on adjacent carbon atoms, said substituents can optionally be taken together with the carbon atoms to which they are attached to form a five- or six-membered cyclohexyl, aryl, or heteroaryl. In another embodiment, in Formula (I), X3 is NH, and R3 is aryl, wherein when said aryl has substitutents on adjacent carbon atoms, said substituents can optionally be taken together with the carbon atoms to which they are attached to form a five- or six-membered cyclohexyl, aryl, or heteroaryl, wherein said R3 aryl, optionally with said five- or six-membered heteroaryl is unsubstituted or substituted with at least one ring system substituent,
In another embodiment, in Formula (I), X3 is NH, and R3 is aryl, wherein when said aryl has substitutents on adjacent carbon atoms, said substituents can optionally be taken together with the carbon atoms to which they are attached to form a five- or six-membered cyclohexyl, aryl, or heteroaryl, wherein said R3 aryl
is selected from the group consisting of phenyl,
Figure imgf000031_0001
isoindolinyl, benzoimidazolyl, benzoxazolyl, benzopyrrolyl, benzopyrrazolyl,
benzopyridyl,
Figure imgf000031_0002
Figure imgf000031_0003
each of which is independently unsubstituted or substituted with at least one ring system substituent, and wherein
Figure imgf000031_0004
indicates the point of attachment of the R3 aryl. In another embodiment, in Formula (I), X3 is NH, and R3 is aryl, wherein when said aryl has substitutents on adjacent carbon atoms, said substituents can optionally be taken together with the carbon atoms to which they are attached to form a five- or six-membered cyclohexyl, aryl, or heteroaryl, wherein said R3 aryl, optionally with said five- or six-membered heteroaryl is unsubstituted or substituted with at least one ring system substituent, wherein the ring system substituent is selected from the group consisting of alkyl, aminoalkyl, -NH2, - C(=NH)NH2, cyano, halo, -C(=O)O-alkyl, alkoxy, haloalkoxy, heteroaryl, hydroxyl, and -C(=O)NH2.
In another embodiment, in Formula (I), X3 is a covalent bond, and R3 is heteroaryl, wherein when said heteroaryl has substitutents on adjacent carbon atoms, said substituents can optionally be taken together with the carbon atoms to which they are attached to form a five- or six-membered aryl or heteroaryl.
In another embodiment, in Formula (I), X3 is a covalent bond, and R3 is heteroaryl, wherein when said heteroaryl has substitutents on adjacent carbon atoms, said substituents can optionally be taken together with the carbon atoms to which they are attached to form a five- or six-membered aryl or heteroaryl, wherein said R3, optionally with said five- or six-membered aryl or heteroaryl, is unsubstituted or substituted with at least one ring system substituent.
In another embodiment, in Formula (I), X3 is a covalent bond, and R3 is heteroaryl, wherein when said heteroaryl has substitutents on adjacent carbon atoms, said substituents can optionally be taken together with the carbon atoms to which they are attached to form a five- or six-membered aryl or heteroaryl, wherein said R3, optionally with said five- or six-membered aryl or heteroaryl, is unsubstituted or substituted with at least one ring system substituent, wherein said R3 heteroaryl is benzopyrrolidinyl which is unsubstituted or substituted with at least one ring system substituent.
In another embodiment, in Formula (I), X3 is a covalent bond, and R3 is heteroaryl, wherein when said heteroaryl has substitutents on adjacent carbon atoms, said substituents can optionally be taken together with the carbon atoms to which they are attached to form a five- or six-membered aryl or heteroaryl, wherein said R3, optionally with said five- or six-membered aryl or heteroaryl, is unsubstituted or substituted with at least one ring system substituent, wherein the ring system substituent is selected from the group consisting of cyano, alkyl, and aminoaikyk
In another embodiment, in Formula (I), X3 is a covalent bond, and R3 is halo.
In another embodiment, in Formula (I), X1 and X3 are both -O-, and R1 and R3 are both H or aryl.
In another embodiment, in Formula (I), R4 is alkyl and is f-butyl.
In another embodiment, in Formula (I), R4 is cycloalkyl and is selected from the group consisting of cyclopropyl and cyclohexyl.
In another embodiment, in Formula (I), R4 is aryl and is phenyl.
In another embodiment, the compound of Formula (I) is selected from the group consisting of:
Figure imgf000033_0001
Figure imgf000034_0001
33
Figure imgf000035_0001
Figure imgf000036_0001

Figure imgf000037_0001
Figure imgf000038_0001
Methods for Making the Compounds of Present Invention
General Methods
Abbreviations used μW microwave
10% Pd(C) 10% palladium on carbon
Ac acetyl
AcOH acetic acid
Ag2CO3 silver carbonate
BBr3 borontribromide
BF3 OEt2 borontrifluoride etherate
BH3 SMe2 borane dimethylsulfide complex
n-BuOH n-butanol
t-BuOH ferf-butanol
t-BuOK potassium ferf-butoxide
CH2CI2 or DCM methylene chloride
Cs2CO3 cesium carbonate
DIPEA Λ/,Λ/-diisopropylethylamine
DME 1 ,2-dimethoxyethane
DMAP dimethylaminopyridine
DMF A/,A/-dimethylfomamide
DMSO dimethylsulfoxide
DPPA diphenylphosphonyl azide
EDCI 1 -ethyl-3-(3-dimethylaminopropyl)carbodiimide
Et ethyl
Et3N triethylamine
EtOAc ethyl acetate
EtOH ethanol
H2O water HATU 2-(1 H-7-azabenzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate
HCI hydrogen chloride
HPLC high performance liquid chromatography
hr or h hour
KOH potassium hydroxide
LiOH lithium hydroxide
Me methyl
MeCN acetonitrile
MeOH methanol
MeI iodomethane
MgSO4 magnesium sulfate
NaHCO3 sodium bicarbonate
NaH sodium hydride
NaN3 sodium azide
NaOAc sodium acetate
Na2CO3 sodium carbonate
NaOEt sodium ethoxide
NH4OAc ammonium acetate
NH3 ammonia
NH4CI ammonium chloride
Pd2(dba)3 tris(dibenzylideneacetone)dipalladium(0))
PhSNa sodium thiophenolate
PMB para-methoxybenzyl
RT or rt room temperature
SGC silca gel chromatography
TBAF tertabutylammonium fluoride
TBS te/f-butyldimethylsilyl
TFA trifluoroacetic acid
THF tetrahydrofuran TLC thin layer chromatography
Solvents, reagents, and intermediates that are commercially available were used as received. Reagents and intermediates that are not commercially available were prepared in the manner as described below. 1H NMR spectra were obtained on a Varian AS-400 (400 MHz) and are reported as ppm down field from Me4Si with number of protons, multiplicities, and coupling constants in Hz indicated parenthetically. Where LC/MS data are presented, analyses were performed using an Applied Biosystems API-100 mass spectrometer and
Shimadzu SCL-10A LC column: Altech platinum C18, 3 micron, 33mm x 7mm ID; gradient flow: 0 min - 10% CH3CN, 5 min - 95% CH3CN, 7 min - 95% CH3CN, 7.5 min - 10% CH3CN, 9 min - stop. MS data were obtained using Agilent Technologies LC/MSD SL or 1100 series LC/MSD mass spectrometer.
Experimental
Scheme A:
Figure imgf000042_0001
R1 = Me, Bn
Figure imgf000042_0002
P9
Also:
Figure imgf000042_0003
A general synthesis of compounds such as P6- P9 is described in scheme A. The synthesis starts with commercially available formamidines which on reaction with malonate P1 gave P2 which on subsequent treatment with POCb gave P3. Aminobenzonitriles P4 can be reacted with P3 to give P5 which can be subjected to a Suzuki reaction to give P6. Deprotection of the phenolic ether can be achieved either using LiI at elevated temperature (for Ri = Me) of using H2, Pd-C (for Ri = Bn). The nitrile group of P7 can be converted to benzylamine P8 and amidine P9. The intermediate P6 can also be synthesized via an alternate route as depicted in the scheme. Dichloropyrimidine intermediate P3 can be subjected to a Suzuki reaction first to give P10 which can be coupled with aniline P4 either using NaH or using palladium mediated cross coupling reaction to give P6.
Example 1
4-[[5-Methoxy-6-(4-methylphenyl)-4-pyrimidinyl]amino]benzonitrile
Stepi
Figure imgf000043_0001
P11
To 1g of 4-aminobenzonitrile in 5OmL of dry THF at O0C was added 1.34g of 60% sodium hydride in mineral oil and the mixture stirred under nitrogen for 10 minutes. 1.5 g of the 4,6-dichloro-5-methoxypyrimidine (commercially available) was then added and the mixture allowed warming to room temperature while stirring. After about 16 hours the reaction mixture was quenched with water then the mixture extracted three times with ethyl acetate. The combined extracts were washed with brine, dried with magnesium sulfate, filtered and evaporated to dryness yielding 2.73g of a tan solid. The solid was triturated with diethyl ether and filtered yielding 1.73g of the desired product. Step 2
Figure imgf000044_0001
P11
To 750 mg of P11 in 4 mL of toluene, 2mL of water and 2mL of DME was added 490mg of p-tolylboronic acid, 1.19g of potassium carbonate and 330mg of tetrakis(triphenylphosphine)palladium. After bubbling with argon for 2 minutes the reaction mixture was heated to 1000C for 16 hours in an oil bath. The reaction mixture was poured onto water and extracted three times with ethyl acetate. The combined extracts were washed with brine, dried with magnesium sulfate, filtered and evaporated to dryness. The residue was purified by flash chromatography yielding 210 mg of 1. LCMS: 317.4 (MH+)
Example 2
4-[[5-Hydroxy-6-(4-methylphenyl)-4-pyrimidinyl]amino]benzonitrile
LiI
Figure imgf000044_0002
Figure imgf000044_0003
To 200mg of 1 in 3 ml. of quinoline was added 845 mg of lithium iodide and the mixture bubbled with argon for several minutes. The reaction mixture was sealed in a pressure tube and heated to 2000C for 10 minutes using a microwave reactor. The residue, now solid at room temperature, was purified by flash chromatography yielding 232 mg of 2. LCMS: 303.2 (MH+)
Example 3 4-[[4-(Aminomethyl)phenyl]amino]-6-(4-methylphenyl)-5-pyrimidinol
Raney Ni/H2
Figure imgf000045_0001
Figure imgf000045_0002
To 110mg of 2 inδmL of 7M ammonia in methanol was added about 3ml_ of a 50% Raney nickel slurry in water and the mixture shaken under 45psi of H2 for 2 hours. The reaction mixture was filtered and evaporated to dryness.
Purification by RP-HPLC yielded 53mg of 3. LCMS: 307.2 (MH+)
Example 4
4-[[5-Hydroxy-6-(4-methylphenyl)-4-pyrimidinyl]amino]benzenecarboximidamide
Figure imgf000046_0001
To 975mg of 2 in 175mL of EtOH at -780C was bubbled HCI gas until solution became saturated. The reaction flask was then sealed with rubber septa and allowed to warm to room temperature while stirring. After 16 hours the reaction mixture was evaporated to dryness. To the residue was twice added EtOH then evaporated to dryness. To the residue was added 15OmL of 7M ammonia in methanol and the mixture stirred at room temperature in a flask sealed with rubber septa. After 16 hours, the reaction mixture was evaporated to dryness and the residue purified by RP-HPLC yielding 395 mg of 4.
LCMS: 320.2 (MH+)
Example 5
Step i
2-[5-Methoxy-6-(4-methylphenyl)-4-pyrimidinyl]-1 h-indole-6-carbonitrile
Figure imgf000046_0002
P12
To 1.44g of 4,6-dichloro-5-methoxypyrimidine in 5mL of toluene, 3 mL of water and 3 mL of DME was added 1 g of 5-cyanoindole-2-boronic acid, 2.23 g of potassium carbonate and 311 mg of tetrakis(triphenylphosphine)palladium. After bubbling with argon for 2 minutes the reaction mixture was heated to 140 0C in a pressure tube using a microwave reactor. The reaction mixture was poured onto water and extracted three times with ethyl acetate. The combined extracts were washed with brine, dried with magnesium sulfate, filtered and evaporated to dryness. The solid residue was triturated in ethyl acetate and filtered. The filtrate then evaporated to dryness and purified by flash chromatography yielding 240mg of P12. Step 2
Figure imgf000047_0001
To 240mg of P12 in 2ml_ of toluene, 1 ml_ of water and 1 mL of DME was added 4-tolylboronic acid, 350mg of potassium carbonate and 49mg of tetrakis(triphenylphosphine)palladium. After bubbling with argon for 2 minutes the reaction mixture was heated to 1000C for 16 hours in an oil bath. The reaction mixture was poured onto water and extracted three times with ethyl acetate. The combined extracts were washed with brine, dried with magnesium sulfate, filtered and evaporated to dryness. The residue was purified by flash chromatography yielding 69 mg of 5. LCMS: 341.2 (MH+)
Example 6 4-[5-(Aminomethyl)-1 h-indol-2-yl]-6-(4-methylphenyl)-5-pyrimidinol
Figure imgf000048_0001
To 200mg of 11 in 1.5mL of quinoline was added 138mg of lithium iodide and the mixture bubbled with argon for several minutes. The reaction mixture was sealed in a pressure tube and heated to 2000C for 10 minutes using a microwave reactor. The reaction mixture was evaporated to dryness and purified by flash chromatography yielding 23mg of demethylated product.
To a solution of the above product in 5 ml_ of 2M ammonia in methanol was injected into an H-Cube hydrogenation device equipped with a Raney Ni cartridge and processed with 60psi of H2 at 5O0C with a flow rate of 0.5mL/min. After four cycles through the device the effluent was evaporated to dryness and the residue purified by RP-HPLC yielding 12mg of 6. LCMS: 331.2 (MH+)
Example 7
Figure imgf000048_0002
Example 7 was prepared using a procedure similar to the preparation of 6.
LCMS: 331.2 (MH+) Example 8
1 , 1 -Dimethylethyl 1 ,3-dihydro-5-[[5-methoxy-6-(4-methylphenyl)-4- pyrimidinyl]amino]-2h-isoindole-2-carboxylate
Step 1
Figure imgf000049_0001
P13 To 390 mg of 5-nitrosoindoline in 50 ml_ of DCM at O0C was added 540 uL of triethylamine and 510 mg of di-fe/t-butyldicarbonate and the mixture stirred under nitrogen while warming to room temperature. After 16 hours the reaction mixture was poured onto water and extracted three times with DCM. The combined extracts were washed with brine, dried with magnesium sulfate, filtered and evaporated to dryness yielding 560 mg of P13.
Step 2
Figure imgf000049_0002
P13 P14
To 560mg of P13 in 20 mL of ethanol was added 56 mg of 10% Pd/C and the mixture shaken under 35 psi of hydrogen gas for 15 minutes. The mixture was filtered and evaporated to dryness yielding 516 mg of P14. Step 3
Figure imgf000050_0001
P15
To 2.5 g of 4,6-dichloro-5-methoxypyrimidine in 20 ml. of toluene, 5 ml_ of water and 5 ml_ of DME was added 1.9 g of 4-tolyl boronic acid, 5.8 g of potassium carbonate and 810 mg of tetrakis(triphenylphosphine)palladium. After bubbling with argon for 2 minutes the reaction mixture was heated to 100 0C for 16 hours in an oil bath. The reaction mixture was poured onto water and extracted three times with ethyl acetate. The combined extracts were washed with brine, dried with magnesium sulfate, filtered and evaporated to dryness. The residue was purified by flash chromatography yielding 2.17 g of P15.
Step 4
Figure imgf000050_0002
P14 P15
To 517 mg of P14 in 15 ml_ of THF at O0C was added 350 mg of 60% sodium hydride in mineral oil and the mixture stirred for 10 minutes. 570 mg of P15 was then added and the mixture warmed to room temperature. After three days the reaction mixture was quenched with water then extracted three times with ethyl acetate. The combined extracts were washed with brine, dried with magnesium sulfate, filtered and evaporated to dryness. Purification by flash chromatography yielded 450mg of 8. LCMS: 433.2 (MH+) Example 9
4-[(2,3-Dihydro-1 h-isoindol-5-yl)amino]-6-(4-methylphenyl)-5-pyπmidinol
Step 1
Figure imgf000051_0001
To 100 mg of 8 in 7 ml_ of DME was added 132 uL of TMSI and the mixture stirred under nitrogen for four hours. An additional 198 uL of TMSI was added and the mixture heated to 80 0C in a pressure tube for two days. The reaction mixture was poured onto water and extracted three times with DCM. The combined extracts were washed with brine, dried with magnesium sulfate, filtered and evaporated to dryness. Purification by RP-HPLC yielded 25mg of 9. LCMS: 319.2 (MH+)
Example 10
4,6-Bis(4-fluorophenoxy)-5-methoxypyrimidine
Figure imgf000051_0002
P16 10 To a solution of 4-fluorophβnol (630 mg, 5.61 mmol) in 20 ml THF at rt was added 1BuOK (815 mg, 7.26 mmol, 1.3 eq.) and mixture for about 10 min. and cooled to 0 0C. To this was added 4,6-dichloro-5-methoxypyrimidine (1.0 g, 5.59 mmol) in one portion and the mixture was stirred overnight while allowing to warm to rt. It was quenched with aq. NH4CI, extracted 3x with ethyl acetate, the combined organic layer was washed with brine, dried over MgSO4, filtered, concentrated and the residue purified by flash chromatography using 10% ethyl acetate in hexanes to provide 950 mg of P16 and 14 mg of 10.
LCMS for 10: 331.2 (MH+)
Example 11 4-[[6-(4-Fluorophenoxy)-5-methoxy-4-pyrimidinyl]amino]benzonitrile
Figure imgf000052_0001
To solution of P16 (520 mg, 2.04 mmol) and 4-aminobenzonitrile (265 mg, 2.24 mmol, 1.1 eq.) in 10 ml DMF at rt was added a 60% suspension of sodium hydride in mineral oil (410 mg, 10.25 mmol, 5 eq.) and the mixture was stirred for 2 hr. It was quenched with aq. NH4CI, extracted 3x with ethyl acetate, the combined organic layer washed with brine, dried over MgSO4, filtered, concentrated and the crude purified by flash chromatography using 5% ethyl acetate in dichloromethane to provide 239 mg of 11.
LCMS: 337.2 (MH+) Example 12 4-[[6-(4-FIuorophenoxy)-5-hydroxy-4-pyrimidinyl]amino]benzenecarboximidamide
Step 1
Figure imgf000053_0001
A mixture of 11 (185 mg, 0.55 rnmol), lithium iodide (740 mg, 5.53 mmol, 10 eq.) in 5 ml 2-picoline was heated in a sealed tube in a microwave reactor at 200 0C for 15 min. The mixture was diluted with ethyl acetate, washed 3x with water, brine, dried over MgSO4, filtered, concentrated and purified flash
chromatography using 40% ethyl acetate in hexanes to provide 109 mg of P17.
Step 2
Figure imgf000053_0002
To a flask containing P17 (45 mg) was added 1.4 ml of absolute ethanol. The flask was flushed with nitrogen and capped with septa. Using a copper wire the septa was tied tightly to the flask so that it can withstand the small pressure that will develop during the reaction. The solution was cooled in an ice-bath and 1.1 ml of acetyl chloride was added drop by drop over a period of few minutes. Once the addition was complete, the mixture was stirred overnight while allowing warming to rt. The solvent was evaporated to dryness and the residue was taken in 7N NH3 in MeOH and heated in a sealed tube at 60 0C for 2.5 hr. The solvent was evaporated to dryness and the residue was purified by RP-HPLC to provide 31 mg 12. LCMS: 340.2 (MH+)
Examples 13 and 14 4-[(2,3-Dihydro-1 -imino-1 h-isoindol-5-yl)amino]-6-(4-methylphenyl)-5-pyrimidinol (13)
2,3-Dihydro-1 -imino-n-[5-methoxy-6-(4-methylphenyl)-4-pyrimidinyl]-1 h-isoindol- 5-amine (14)
Step i
Figure imgf000054_0001
P18
A degassed solution of 2-methyl-4-nitrobenzonitrile (10 g, 61.7 mmol), N- bromosuccinimide (13.2 g (74.17 mmol, 1.2 eq.) and azobisisobutyronitrile (AIBN) (2.0 g, 12.18 mmol, 0.2 eq) in 300 ml CCI4 was heated at reflux for 3 days. After solvent was evaporated the residue was taken in ethyl acetate and washed 2x with aq. NaHCO3 , aq. Na2S2θ3, brine, dried over MgSO4, filtered, concentrated and purified chromatography using 15% ethyl acetate in hexane to provide 1 1.7 g of 2-bromomethyl-4-nitrobenzonitrile.
A mixture of above product, Di-ferf-butyl iminodicarboxylate (13.8 g, 63.5 mmol, 1.3 eq.), potassium carbonate (13.3 g, 97.7 mmol, 2 eq) and tetrabutylammonium iodide (1.8 g, 4.87 mmol, 0.1 eq) in 150 ml DMF was stirred overnight at rt, diluted with water and extracted 3x with ether. The combined organic layer washed with water, brine, dried over MgSO4, filtered, concentrated and purified flash chromatography using 15% ethyl acetate in hexanes to provide 14.4 g of P18.
Step 2
Figure imgf000055_0001
P18 P19
A suspension of P18 (3.3 g) and 10% Pd-C (330 mg) in 30 ml each of THF and methanol was stirred overnight under a hydrogen balloon. The catalyst was removed by filtration through a CELITE pad; the filtrate was concentrated and purified by flash chromatography using 30% ethyl acetate in hexanes to provide 2.1 g of P19.
Step 3
Figure imgf000056_0001
A mixture of P19 (300 mg, 0.795 mmol), P15 (190 mg (0.81 mmol),
tris(dibenzylideneacetone)dipalladium (23 mg, 0.04 mmol, 5 mol%), (±) BINAP (74 mg, 0.1 19 mmol, 15 mol%) and sodium fe/t-butoxide (115 mg, 1.20 mmol, 1.5 eq.) in 5 ml toluene in a sealed was bubbled with argon and heated overnight in an oil bath at 110 0C. The mixture was quenched with aq. NH4CI and extracted 3x with ethyl acetate. The combined organic layer was washed with brine, dried over MgSO4, filtered, concentrated and purified by flash chromatography using 30% ethyl acetate in hexanes to provide 132 mg of P20.
Step 4
Figure imgf000056_0002
A mixture of P20 (80 mg, 0.18 mmol) and tetrabutylammonium iodide (14 mg, 0.038 mmol, 0.2 eq.) in 2 ml of 47% aq. hydroiodic acid in a microwave reactor vessel was stirred vigorously using a vortex mixture. The vessel was capped then heated in a microwave reactor at 100 0C for 30 min. The mixture was evaporated to dryness then evaporated twice with ethanol. The residue was purified by RP-HPLC to provide 20 mg of 13 and 44 mg of 14. LCMS for 13: 333.2 (MH+); LCMS for 14: 346.2 (MH+)
Example 15
4-[(6-Chloro-2,3-dihydro-1-imino-1 h-isoindol-5-yl)amino]-6-(4-methylphenyl)-5- pyrimidinol
Step 1
Figure imgf000057_0001
P21 P22
To a solution of P19 (950 mg, 2.73 mmol) in 10 ml isopropanol at 600C was added N-chlorosuccinimide (400 mg, 2.99 mmol, 1 ,1 eq). The mixture was heated at reflux for 1.5 hr, left overnight at rt, concentrated and diluted with ethyl acetate. The solution was washed 2x with water, brine, dried over MgSO4, filtered, concentrated and purified by flash chromatography using 40% ethyl acetate in hexanes to provide 319 mg of P21 and 288 mg of P22.
Step 2
Figure imgf000058_0001
Using a procedure similar to the transformation of P19 to 13, 15 was obtained from P21. LCMS: 366.2 (MH+)
Example 16 6-Chloro-2,3-dihydro-1 -imino-n-[5-methoxy-6-(4-methylphenyl)-4-pyrimidinyl]-1 h- isoindol-5-amine
Step 1
Figure imgf000058_0002
Using a procedure similar to the transformation of P19 to P20, P23 was obtained from P21.
Step 2
Figure imgf000059_0001
16
A solution of 20 mg of P23 was stirred rt with 0.5mi each of trifluoroacetic acid and dichioromethane for 2 hr. it was concentrated and purified by RP-HPLC to obtained 15 mg of 16. LCMS: 380.2 (MH+)
Example 17 4-[(4-Chioro-2,3-dihydro-1 -imino-1 h-isoindoi-5-yi)amino]-6-(4-methylphenyi)-5- pyrimidinol
Figure imgf000059_0002
Using a procedure similar to the transformation of P19 to 13, 17 was obtained from P22. LCMS: 366.2 (MH+)
Example 18
4-[6-[(2,3-Dihydro-1 -imino-1 h-isoindol-5-yl)amino]-5-hydroxy-4- pyrimidinyl]benzoic acid Step 1
Figure imgf000060_0001
P25, R = NBoC2 P26, R = NHBoc
P24 was prepared from 3,5-dichloro-5-methoxypyrimidine and 4-(tert- butoxycarbonyl)phenylboronic acid using a procedure similar to the preparation of P15.
A mixture of P19 (300 mg, 0.795 mmol), P24 (255 mg, 0.795 mmol),
tris(dibenzylideneacetone)dipalladium (23 mg, 0.04 mmol, 5 mol%), BINAP (74 mg, 0.119 mmol, 15 mol%) and sodium tert-butoxide (115 mg, 1.20 mmol, 1.5 eq.) in 5 ml toluene in a sealed was bubbled with argon and heated for about 20 hr in an oil bath at 110 0C. The mixture was quenched with aq. NH4CI and extracted 3x with ethyl acetate. The combined organic layer was washed with brine, dried over MgSO4, filtered, concentrated and purified by flash
chromatography using 30% ethyl acetate in hexanes to provide 72 mg of P25 and 151 mg of P26.
Step 2
Figure imgf000061_0001
A mixture of 100 mg of P25, 150 mg of P26 and 30 mg of tetrabutylammonium iodide in 3 ml of con. hydroiodic acid was heated in a microwave reactor at 130 0C for 30 min. The product was filtered to obtain 120 mg of solid which on analysis indicated incomplete reaction. It was once again dissolved in 2 ml of con. hydroiodic acid and heated with 20 mg of tetrabutylammonium iodide for another 30 min. at 130 0C. The solid was filtered, washed with water, ether and dried in vacuum oven to provide 52 mg of 18. as the hydroiodide salt. LCMS: 362.2 (MH+)
Example 19
5-[[5-Methoxy-6-(4-methylphenyl)-4-pyrimidinyl]amino]-2-pyridinecarbonitrile
Figure imgf000061_0002
19 To a solution of P15 (500 mg, 2.13 mmol) and 3-amino-6-cyanopyridine (330 mg, 2.77 mmol, 1.3 eq.) in 10 ml DMF at rt was added a 60% suspension of sodium hydride in mineral oil (430 mg, 10.75 mmol, 5 eq.) and stirred at rt for 2 hr. It was quenched by the addition of aq. NH4CI and extracted 3x with ethyl acetate. The combined organic layer was washed with brine, dried over MgSO4, filtered, concentrated and purified by chromatography using 20% ethyl acetate in dichloromethane to provide 510 mg of 19. LCMS: 318.2 (MH+)
Example 20
5-[[5-Hydroxy-6-(4-methylphenyl)-4-pyrimidinyl]amino]-2-pyridinecarbonitrile
Figure imgf000062_0001
20
Using a procedure similar to the transformation of 1 to 2, 19 was transformed to 20. LCMS: 304.2 (MH+) Example 21
5-[[5-Hydroxy-6-(4-methylphenyl)-4-pyrimidinyl]amino]-2- pyridinecarboximidamide
Figure imgf000063_0001
21
Using a procedure similar to the transformation of P17 to 12, 20 was transformed to 21. LCMS: 321.2 (MH+)
Examples 22-29
Using procedures similar to those described above, the following examples were prepared.
Figure imgf000063_0002
Figure imgf000064_0001
Example 30
1 - Amino-n-[5-methoxy-6-(4-methylphenyl)-4-pyrimidinyl]-6- isoquinolinemethanamine
Figure imgf000064_0002
To a solution of 50 mg of 1 in 3 ml_ of DMF was added 44 mg of 6- (aminomethyl)isoquinolin-i -amine and 59 mg of potassium carbonate and the mixture stirred under nitrogen for 16 hours then the temperature raised to 60 0C. After ten days the reaction mixture was poured onto water and extracted three times with ethyl acetate. The combined extracts were washed with brine, dried with magnesium sulfate, filtered and evaporated to dryness. The residue was purified by flash chromatography yielding 30 mg of 30. LCMS: 372.2 (MH+)
Example 31 3-Chloro-4-[[5-hydroxy-6-(4-methylphenyl)-4-pyrimidinyl]oxy]benzonitrile
Step 1
Figure imgf000065_0001
A mixture of P15 (500 mg, 2.14 mmol), 3-chloro-4-hydroxybenzonitrile (400 mg, 2.60 mmol, 1.2 eq.), tetrabutylammonium iodide (480 mg, 1.30 mmol, 0.6 eq.) and potassium carbonate (350 mg, 2.57 mmol, 1.2 eq.) in 10 ml DMSO was heated in sealed tube at 130 0C for 2 hr. It was diluted with ethyl acetate, washed 3x with water, brine, dried over MgSO4, filtered, concentrated and purified by chromatography using 15% ethyl acetate in hexanes to provide 370 mg of P27.
Step 2
Figure imgf000066_0001
Using a procedure similar to the transformation of 1 to 2, 31 was obtained from P27. LCMS: 338.2 (MH+)
Example 32
3-Chloro-4-[[5-hydroxy-6-(4-methylphenyl)-4- pyrimidinyl]oxy]benzenecarboximidamide
Figure imgf000066_0002
Using procedure similar to the transformation of P17 to 12, 32 was obtained from 31. LCMS: 355.2 (MH+)
Example 33
4-[[5-Hydroxy-6-(4-methylphenyI)-4-pyrimidinyl]oxy]benzenecarboximidamide
Step 1
Figure imgf000067_0001
P28
To a solution of 4-cynaophenol (400 mg, 3.36 mmol) in 10 ml THF at rt was added potassium-tert-butoxide (380 mg, 3.39 mmol, 1.2 eq) and stirred for 20 minutes. To this was added 4,6-dichloro-5-methoxypyrimidine (500 mg, 2.79 mmol) and stirred for 3 days at rt. It was quenched by the addition of aq. NH4CI and extracted 3x with ethyl acetate. The combined organic layer was washed with brine, dried over MgSO4, filtered, concentrated and purified by flash chromatography using 20% ethyl acetate in hexanes to provide 175 mg of P28.
Step 2
Figure imgf000067_0002
P28
33
Using procedure similar to the transformation of P11 to 4, 33 was obtained from P28. LCMS: 321.2 (MH+)
Example 34
2,3-Dihydro-5-[[5-hydroxy-6-(4-methylphenyl)-4-pyrimidinyl]amino]-1 h-isoindol-1 ' one Step 1
Figure imgf000068_0001
A degassed solution of methyl 2-methyl-4-nitrobenzoate (3.5 g, 18.19 mmol), N- bromosuccinimide (3.9 g, 21.91 mmol, 1.2 eq) and benzoyl peroxide (3.63 mmoi, 0.2eq.) in 100 ml CCWwas heated at reflux for 4 hr. it was concentrated to dryness, dissolved in ether, washed 2x with water, aq. Na2S2θ3, brine, dried over MgSO4, filtered, concentrated and purified by chromatography using 15% ethyl acetate in hexanes to provide 4.11g of methyl 2-bromomethyl-4-nitrobenzoate.
To a solution of the above product in 40 ml DMF at rt was added 2,4- dimethoxybenzyl amine (2.7 ml, 17.98 mmol, 1.2 eq.), potassium carbonate (4.1 g, 30.12 mmol, 2 eq.) and the mixture stirred overnight at rt. It was diluted with ethyl acetate, washed 2x with water, 1 N HCI, brine, dried over MgSO4, filtered, concentrated and purified by chromatography using 5% ethyl acetate in dichloromethane to provide 2.43 g of P29.
Step 2
Figure imgf000069_0001
P29 P30
A mixture of 500mg of P29 and 100 mg of 10% Pd-C in 15 ml ethanol and 10 ml THF was stirred under a hydrogen balloon for 1 hr. It was filtered through a CELITE pad and concentrated to provide 440 mg of P30.
Step 3
Figure imgf000069_0002
Using a procedure similar to the transformation of P15 to 19, P15 was converted to P31.
Step 4
Figure imgf000069_0003
P32 A solution of 220 mg of P31 in 5 ml of 95:5 TFA-water mixture was heated in a microwave reactor at 120 0C for 20 min. It was concentrated and diluted with aq. NaHCO3. The solid was filtered, washed with water, ether and dried in vacuum oven to provide 200 mg of P32.
Step 5.
Figure imgf000070_0001
Using a procedure similar to the preparation of 1 to 2, 34 was obtained from P32. LCMS: 333.2 (MH+)
Example 35
2,3-Dihydro-6-[[5-hydroxy-6-(4-methylphenyl)-4-pyrimidinyl]amino]-1 h-isoindol-1- one
Step i
Figure imgf000070_0002
Commercially available 6-amino-2,3-dihydro-isoindol-1 -one was coupled with P15 using procedure similar to the transformation of P19 to P20 to obtain P33.
Step 2
Figure imgf000071_0001
A mixture of P33 (28 mg, 0.081 mmol), tetrabutylammonium iodide (6 mg, 0.2 eq.) in 1 ml concentrated hydroiodic acid was heated in a microwave reactor at 130 0C for 30 min. The mixture was concentrated and purified by RP-HPLC to provide 11 mg of 35. LCMS: 333.2 (MH+)
Example 36
4-[(4-Ethenylphenyl)amino]-6-(4-methylphenyl)-5-pyrimidinol
Step 1
Figure imgf000071_0002
To a solution of in di-ferf-butyldicarbonate (4.9 g, 22.45 mmol, 1.5 eq.) in 30 ml THF at rt was added (R)-alpha-methyl-4-nitrobenzylamine hydrochloride (3.0 g, 14.81 mmol) followed by 30 ml of 1 N aq. NaOH solution. The mixture was stirred vigorously for 2 hr, diluted with water and extracted 3x with ether. The combined organic layer was washed with brine, dried over MgSO4, filtered and
concentrated to provide 5.50 g (S)-tert-butyl 1 -(4-nitrophenyl)ethylcarbamate.
A mixture of 2.7 g of the above product and 500 mg of 10% Pd-C in 25 ml each of THF and EtOH was stirred overnight under a hydrogen balloon. The mixture was filtered through a CELITE pad, concentrated and purified by chromatography using 30% ethyl acetate to provide 1.05 g of P34.
Step 2
Figure imgf000072_0001
Using a procedure similar to the transformation of P15 to 19, P35 was obtained from P34 and P15.
Step 3
Figure imgf000072_0002
P35
When P35 was subjected to reaction conditions similar to the transformation of 1 to 2, 36 was obtained. LCMS: 304.2 (MH+) Example 37
4-[[4-(Aminomethyl)phenyl]amino]-2-cyclopropyl-6-(4-methylphenyl)-5-pyrimidinol
Step i
Figure imgf000073_0001
P36
To 17ml_ of a 30% weight solution of sodium methoxide in methanol at O 0C was added 3.65 ml_ of dimethyl methoxymalonate and, in portions, 3.34 g of cyclopropanecarboxamidine hydrochloride. After 30 minutes the mixture was heated to reflux for 1.5 hours then cooled to room temperature. After 16 hours the mixture was cooled to O 0C and quenched with 8 ml_ of concentrated aq. HCI. The white precipitate was concentrated by vacuum filtration then dried in a vacuum oven at 50 0C overnight. 3.76g of P36 was obtained. Step 2
Figure imgf000073_0002
P36 P37 To 3.76g of P36 in 4 ml_ of toluene was added 3.2 ml_ of triethylamine and, at near refluxing, 4.2 ml_ of phosphorous oxychloride added drop wise. The mixture was then heated to reflux for 2 hours then cooled to room temperature and ice added to the mixture which was stirred until the ice had melted. The phased were separated and the aqueous phase was extracted twice with toluene. The combined organic phases were washed with aq. sodium
bicarbonate and brine, dried with magnesium sulfate, filtered and evaporated to dryness yielding 3.85 g of P37.
Step 3
Figure imgf000074_0001
P37
37
Using procedures analogous to the preparation of example 3, P37 was converted to example 37. LCMS: 347.2 (MH+)
Example 38
4-[[2-Cyclopropyl-5-hydroxy-6-(4-methylphenyl)-4- pyrimidinyl]amino]benzenecarboximidamide
Figure imgf000075_0001
P37
38
Using procedures analogous to the preparation of example 4, P37 was converted to example 38. LCMS: 360.2 (MH+)
Example 39 2-Fluoro-4-(5-hydroxy-6-p-tolylpyrimidin-4-ylamino)benzonitrile
Step 1 :- Dimethyl 2-(benzyloxy)malonate
Figure imgf000075_0002
Dimethyl 2-(benzyloxy)malonate was synthesized as reported in Tetrahedron Asymmetry; 12 (2001) p 271 -277.
Step 2:- 5-(benzyloxy)pyrimidine-4,6-diol
Figure imgf000076_0001
P38
Dimethyl 2-(benzyloxy)malonate (16.1 g, 0.0675 mol) was dissolved in MeOH (27 ml), NaOMe (42.59 ml of a 30% solution in MeOH, 3.5 eq) was added and the mixture cooled to OC. Formamidine hydrochloride (5.68g, 1.05 eq) was added and the mixture stirred at O0C for 30 minutes and then at reflux for 2 hours. After cooling to 00C concentrated HCI (21 ml) was added and the solid was collected by filtration (washing with cold water 3x20ml) to give 15.14g of the title compound. Step 3:- 5-(benzyloxy)-4,6-dichloropyrimidine
Figure imgf000076_0002
The compound from step 2 (15.14g, 0.0694 mol) was dissolved in PhMe (70 ml) and Et3N (10.72 ml, 1.1eq) was added. The solution was heated to 800C and POCI3 (13.93 ml, 2.2 eq) was added. Once the addition was complete the mixture was heated at reflux for 2 hours. After cooling to O0C the mixture was quenched with ice and extracted with EtOAc. The EtOAc extracts were washed with water, NaHCO3 (Sat), dried (MgSO4) and concentrated to give 12.78g of the title compound.
Step 4:- 5-(benzyloxy)-4-chloro-6-p-tolylpyrimidine
Figure imgf000077_0001
The compound from step 3 (12.78 g, 0.05 mol) was dissolved in (4:1 :1 )
PhMe/HaO/DME (111 ml). Pd(Ph3P)4 (2.9g, 0.05 eq), K2CO3, and p-tolylboronic acid (6.81 g, 1 eq) were added, the mixture was degassed and heated at 100°C overnight. After cooling to room temperature the organic layer was purified by silica gel chromatography (0-10% EtOAc in hexane) to give 5.5 g of the title compound. Step 5:- 4-(5-(benzyloxy)-6-p-tolylpyrimidin-4-ylamino)-2-fluorobenzonitrile
Figure imgf000077_0002
The compound from step 4 (0.3 g, 0.96 mmol) was dissolved in DMF (4.83 ml), 4-cyano-3-fluoroaniline (0.131 g, 1 eq) and NaH (0.155 g of 60% dispersion in mineral oil, 4 eq) were added. After 1 hour LCMS showed complete conversion, the reaction was quenched with NH4CI(Sat) and extracted with EtOAc. The extracts were dried concentrated and the residue purified by silica gel chromatography (0-20% EtOAc in hexane) to give 0.3 g of the title compound. LCMS MH+ = 411.
Step 6:- 2-fluoro-4-(5-hydroxy-6-p-tolylpyrimidin-4-ylamino)benzonitrile
Figure imgf000078_0001
The compound from step 5 (0.3 g, 0.73 mmol) was dissolved in (3:1 ) MeOH/THF (7.3 ml), 10% Palladium on carbon (30 mg) was added and the mixture placed under H2 (1 atm). After 1 hour LCMS showed that the reaction was complete, the catalyst was removed by filtration and the mixture concentrated to give 200 mg of the title compound. LCMS = 321.2 (MH+)
The following compounds were synthesized using analogous procedures.
Figure imgf000078_0002
Figure imgf000079_0001
Figure imgf000080_0001
Example 56: 4-(3-Amino-1H-indazol-6-ylamino)-6-p-tolylpyrimidin-5-ol
Figure imgf000081_0001
Example 39 (80 mg, 0.25 mmol) was dissolved in BuOH (1.67 ml), hydrazine hydrate (0.785, 100 eq) was added and the mixture heated at 1200C overnight. After cooling to room temperature the mixture was concentrated and purified by C18 HPLC (89.95:9.95:0.1 H2O:MeCN:HCO2H-9.95:89.95:0.1
H2O:MeCN:HCO2H) to give 52 mg of the title compound. LCMS = 333.2 (MH+)
Example 57: 4-(3-Amino-1 H-indazol-6-ylamino)-6-(4-chlorophenyl)pyrimidin-5-ol
Figure imgf000081_0002
Example 57 was synthesized from 55 in a similar manner to that previously described. LCMS = 353.0 (MH+)
Example 58: 4-(3-Amino-1 H-indazol-5-ylamino)-6-p-tolylpyrimidin-5-ol
Figure imgf000081_0003
Example 58 was synthesized from 46 in a similar manner to that previously described. LCMS = 353.0 (MH+) Example 59: 4-(4-(Aminomethyl)-3-fluorophenylamino)-6-p-tolylpyrimidin-5-ol
Figure imgf000082_0001
Example 39 (0.047 mg, 0.147 mmol) was dissolved in THF (4.9 ml) to this was added borane dimethylsulfide complex (0.367 ml of a 2M solution in THF, 5 eq) followed by boron trifluoride etherate (0.091 ml, 5 eq). The mixture was then heated at reflux for 6 hours, after cooling to room temperature 6N HCI was added and the mixture heated at reflux for an additional hour and then concentrated under reduced pressure. The residue was purified by C18 HPLC (89.95:9.95:0.1 H2O:MeCN:HCO2H-9.95:89.95:0.1 H2O:MeCN:HCO2H) to give 25 mg of the title compound. LCMS = 325.2 (MH+).
The following compounds were synthesized using analogous procedures from the appropriate starting material.
Figure imgf000082_0002
Figure imgf000083_0001
Example 63: 2-Fluoro-4-(5-hydroxy-6-p-tolylpyrimidin-4-ylamino)benzamide
Figure imgf000083_0002
Example 39 (0.075 mg, 0.234 mmol) was dissolved in a 1 :1 mixture of EtOH/THF (3.9 ml). A solution of 30% H2O2 (0.7 ml) was added followed by 3 M NaOH (0.7ml), the mixture was then stirred for 4 days. The mixture was neutralized with dilute HCI washed with EtOAc to leave an aqueous suspension. The aqueous layer was filtered and the solid dried to give 49 mg of the title
compound. LCMS = 339.2 (MH+)
Example 64: 4-(3-Aminobenzo[d]isoxazol-6-ylamino)-6-p-tolylpyrimidin-5-ol
Step 1 :- 2-fluoro-4-((6-p-tolyl-5-((2-(trimethylsilyl)ethoxy)methoxy)pyrimidin- 4-yl)((2-(trimethylsilyl)ethoxy)methyl)amino)benzonitrile
Figure imgf000083_0003
39 Example 39 (100 mg, 0.312 mmol) was dissolved in DMF, NaH (37.5 mg of a 60% dispersion in mineral oil, 3 eq) was added, 10 minutes later SEMCI (0.131 ml, 2.4 eq) was added and the mixture stirred overnight. The reaction was quenched with NH4CI(Sat) and extracted with EtOAc. The extracts were dried concentrated and the residue purified by silica gel chromatography (0-20% EtOAc in hexane) to give 0.146 g of the title compound. LCMS = 581 (MH+).
Step 2:- 4-(3-aminobenzo[d]isoxazol-6-ylamino)-6-p-tolylpyrimidin-5-ol
Figure imgf000084_0001
Acetone oxime (23.9 mg, 1.3eq) and t-BuOK (36.7 mg, 1.3 eq) were mixed together in DMF (1 ml), after stirring for 30 minutes the compound from step 1 (0.146, 0.251 mmol) in DMF (2 ml) was added and the resulting mixture stirred for 1 hour. The mixture was diluted with EtOAc and washed with H2O/N H4CI(SaD, dried (MgSO4), and concentrated. The resulting residue was dissolved in 1 :1 1 N HCI/EtOH and heated at 8O0C for 2.5 hours. The mixture was cooled to room temperature quenched with NaHCO3(Sat) and extracted with EtOAc, the extracts were dried (MgSO4) and concentrated to give 31 mg of the title compound.
LCMS = 334.2 (MH+)
Example 65: 2-Hydroxy-4-(5-hydroxy-6-p-tolylpyrimidin-4- ylamino)benzimidamide
Step i :- ^-(δ-methoxy-β-p-tolylpyrimidin^-yObenzofdlisoxazole-S.Θ- diamine
Figure imgf000085_0001
P43
The title compound was synthesized from 4,6-dichloro-5-methoxypyrimidine using procedures described previously.
Step 2:- 2-hydroxy-4-(5-hydroxy-6-p-tolylpyrimidin-4-ylamino)benzimidamide
Figure imgf000085_0002
The product from step 1 (75 mg, 0.216 mmol) was dissolved in concentrated (47%) Hl(aq) (2.16 ml), Bu4I (16 mg, 0.2 eq) was added and the mixture heated at 13O0C for 30 minutes in a microwave. The mixture was evaporated to dryness and concentrated from EtOH (x2). The residue was purified by C18 HPLC (89.95:9.95:0.1 H2O:MeCN:HCO2H-9.95:89.95:0.1 H2O:MeCN:HCO2H) to give 25 mg of the title compound. LCMS = 336.2 (MH+)
Example 66: 4-(Benzo[d]oxazol-6-ylamino)-6-p-tolylpyrimidin-5-ol
Step 1 :- N-(5-(benzyloxy)-6-p-tolylpyrimidin-4-yl)benzo[d]oxazol-6-amine
Figure imgf000086_0001
5-(benzyloxy)-4-chloro-6-p-tolylpyrimidine (50 mg, 0.161 mmol) was dissolved in PhMe, to this was added benzo[d]oxazol-6-amine (23.7 mg, 1.1 eq), Pd(dba)2 (4.6 mg, 0.05 eq), t-BuONa (31 mg, 2 eq), and (±)-BINAP (15 mg, 0.15 eq). The mixture was degassed and heated at 115°C overnight. The mixture was cooled to room temperature, diluted with EtOAc and washed with H2O. Preparative TLC gave 17 mg of the title compound.
Step 2:- 4-(benzo[d]oxazol-6-ylamino)-6-p-tolylpyrimidin-5-ol
Figure imgf000086_0002
66
The compound P44 17 mg, 0.042 mmol) was dissolved in MeOH (4 ml), 10% Palladium on carbon (5 mg) was added and the mixture placed under H2 (1 atm). After 1.5 hour LCMS showed that the reaction was complete, the catalyst was removed by filtration and the mixture concentrated to give 10 mg of the title compound. LCMS = 319.2 (MH+)
Example 67:-4-(6-chloro-1 H-benzo[d]imidazol-2-ylamino)-6-p-tolylpyrimidin-5-ol
Figure imgf000087_0001
67
Example 67 was synthesized in an analogous manner to 66 using 6-chloro-1 H- benzo[d]imidazol-2-amine. LCMS = 352.2 (MH+)
Example 68.
4-[[4-(1(S)-Aminoethyl)phenyl]amino]-6-(4-methylphenyl)-5-pyrimidinol
Step i
Figure imgf000087_0002
P34 coupled with P40 using a procedure similar to the transformation of P19 to P20.
Step 2
Figure imgf000088_0001
A suspension of 80 mg of P45 and 12 mg of 10% Pd-C in 5 ml ethyl acetate was stirred under hydrogen balloon for 2 hr at which time additional 10 mg of the catalyst was added and stirred for another 2 hr. It was filtered through a CELITE pad and concentrated to provide 60 mg of P46.
Step 3
Figure imgf000088_0002
A solution of 60 mg of P46 in 1 ml each of TFA and DCM was stirred at 00C for 1.5 hr, concentrated then added HCI in ether to provide 58 mg of 68. LCMS: 321.2 (MH+)
Example 69
4-[[4-(1 (R)-Aminoethyl)phenyl]amino]-6-(4-methylphenyl)-5-pyrimidinol
Figure imgf000089_0001
P47 was prepared using a procedure similar to the preparation of P34 and converted to 69 using a procedure similar to the preparation of 68. LCMS: 321.2 (MH+)
Example 70 4-[[6-(Aminomethyl)-3-pyridinyl]amino]-6-(4-methylphenyl)-5-pyrimidinol
Step 1
Figure imgf000089_0002
P40 converted to P48 using a procedure similar to the preparation of 19. Step 2
Figure imgf000090_0001
A suspension of 350 mg of P48 and 60 mg of 10% Pd-C in 5 ml each of THF and MeOH was stirred under hydrogen balloon. After 3 hr, additional 50 mg of catalyst was added and the mixture stirred overnight. It was filtered through a CELITE pad, concentrated and purified by RPHPLC to provide 51 mg of 70. LCMS; 308.2 (MH+)
Example 71
^[[δ-HYDROXY-e-^-METHYLPHENYLH-PYRIMIDINYqAMINOlBENZAMIDE
Figure imgf000090_0002
A mixture of 2 (90 mg, 0.30 mmol) and KOH (85 mg, 1.52 mmol, 5 eq.) in 1 ml each of THF, MeOH and water in a sealed tube was stirred overnight at 1 10 0C. The mixture was purified by RP-HPLC to provide 18 mg of 71. LCMS: 321.2 (MH+)
Example 72
4-[[4-(Aminomethyl)phenyl]amino]-6-(3-methylphenyl)-5-pyrimidinol Step i
Figure imgf000091_0001
P39 P49
To a solution of 4-aminobenzonitrile (3.0 g, 11.76 mmol) in 30 ml DMF at rt was added a 60% suspension of sodium hydride in mineral oil and stirred for 10 min. It was cooled to 0 0C then P39 was added in one portion. The mixture was stirred at rt for 1 hr, quenched with aq. NH4CI and extracted 3x with ethyl acetate. The combined organic layer was washed with brine, dried over MgSO4, filtered, concentrated and purified flash chromatography using 1 :1 :3 ethyl acetate- dichloromethane-hexanes to provide 820 mg of P49.
Step 2
Figure imgf000091_0002
P50 was prepared from P49 and m-tolylboronic acid using a procedure similar to the preparation of 1.
Step 3
Figure imgf000092_0001
A mixture of 75 mg of P50, -75 mg of Ra-Ni and 10 mg of 10% Pd-C in 3 ml of 7N NH3 in methanol solution was stirred under a hydrogen balloon for 1 hr. It was filtered, concentrated and purified by RP-HPLC to provide 24 mg of 72.
LCMS: 307.2 (MH+)
The following examples were prepared in a similar manner.
Figure imgf000092_0002
Example 77
2,3-Dihydro-5-[[5-hydroxy-6-(4-methylphenyl)-4-pyrimidinyl]amino]-1h-inden-1 - one Step 1
Figure imgf000093_0001
Compound P40 (34 mg, 0.11 mmol), 5-amino-2,3-dihydro-1 H-inden-1 -one (29 mg, 0.20 mmol), cesium carbonate (89 mg, 0.27 mmol), Pd2(dba)3 (9 mg, 0.01 mmol), and racemic BINAP (8 mg, 0.01 mmol) were combined in toluene (1 ml_). The mixture was purged with nitrogen and stirred at 130 0C for 16 h. The mixture was filtered, washed with EtOAc, and concentrated in vacuo. The residue was separated on a silica gel cartridge (eluting with acetone in DCM (0->20%) to give compound P51 as a tan solid (26 mg, 56% yield).
Step 2
Figure imgf000093_0002
77
Compound P51 was stirred over 10% Pd/C in MeOH under a hydrogen atmosphere at room temperature for 2 h. The mixture was filtered and concentrated in vacuo to give compound 77 as a yellow solid (100%). LCMS: 332.2 (MH+). Example 78
4-[(2,3-Dihydro-1 -hydroxy-1 h-inden-5-yl)amino]-6-(4-methylphenyl)-5-pyrimidinoi
Figure imgf000094_0001
The ketone 77 was reduced in a conventional way with NaBH4 in MeOH at room temperature to give the alcohol 78 as a yellow solid. LCMS: 334.2 (MH+).
Example 79
(1 E)-2,3-Dihydro-5-[[5-hydroxy-6-(4-methylphenyl)-4-pyrimidinyl]amino]-1 h- inden-1 -one oxime
Figure imgf000094_0002
79
78 The ketone 78 was treated in a conventional way with hydroxylamine hydrochloride in pyridine at room temperature to give the oxime 79 as a yellow solid. LCMS: 347.2 (MH+).
Example 80
4-[(1 -Amino-2,3-dihydro-1 h-inden-5-yl)amino]-6-(4-methylphenyl)-5-pyrimidinol
Step i
Figure imgf000095_0001
P51 P52
Compound P51 (13 mg, 0.031 mmol) and ammonium acetate (0.10 g, 1.4 mmol) were stirred in /-PrOH (1.5 ml_) at room temperature for 1 h. Sodium cyanoborohydride (11 mg, 0.18 mmol)) was added and heated at 100 0C for 4 h. The mixture was quenched with saturated NH4CI and washed with DCM. The organic layer was dried (MgSO4) and concentrated in vacuo. The residue was separated on a preparative TLC plate (5% 2N NH^MeOH in DCM) to give compound P52 as a clear resin.
Figure imgf000095_0002
P52
80
Compound P52 was converted to compound 80 in a similar fashion as the preparation of compound 77. LCMS: 333.2 (MH+).
Example 81
4-[(1 -Amino-6-isoquinolinyl)amino]-6-(4-methylphenyl)-5-pyrimidinol Step 1
Figure imgf000096_0001
Compound P40 was converted to compound P54 in a similar fashion as preparation of compound P51 , using aniline P53 (prepared as shown in WO 2007002313).
Figure imgf000096_0002
Compound 54 was converted to compound 55 in a similar fashion as Preparation of Compound 77 from P51.
Figure imgf000096_0003
Compound P55 was deprotected with trifluoroacetic acid in DCM at room temperature. Concentration in vacuo followed by purification with reverse phase HPLC gave compound 81 formate as a yellow solid. LCMS: 344.2 (MH+).
Example 82
4-[(1-Amino-5-chloro-6-isoquinolinyl)amino]-6-(4-methylphenyl)-5-pyrimidinol Step i
Figure imgf000097_0001
Compound P53 (0.10 g, 0.26 mmol) and /V-chlorosuccinimide (0.038 g, 0.28 mmoi) were stirred in DMF (2 mL) at room temperature for 2 h. The mixture was concentrated in vacuo. The residue was separated on a silica gel cartridge (eiuting with EtOAc in hexanes (0->50%) to give compound P54 (0.06 g).
Step 2
Figure imgf000097_0002
Compound P54 was converted to compound 82 in a similar fashion as Preparation of Compound 81 from P53. LCMS: 378.2 (MH+).
Example 83
4-[(1 -AMINO-6-ISOQUINOLINYL)AMINO]-6-(4-CHLOROPHENYL)-5- PYRIMIDINOL
Figure imgf000097_0003
Using a procedure similar to the transformation of P40 to P51 , P53 was coupled with P39 to obtain P55.
Figure imgf000098_0001
Compound P55 was converted to compound P56 by a conventional Suzuki coupling method.
Figure imgf000098_0002
P56 83
Compound P55 was converted to compound 83 in a similar fashion as preparation of compound 81 from P54. LCMS: 364.2 (MH+).
The following compounds were prepared from compound P55 using the method described above and using the appropriate boronic acid:
Cpd. No. Structure LCMS (MH+)
84 398.2
Figure imgf000098_0003
Figure imgf000099_0001
Preparative example P57
Figure imgf000099_0002
P57
To a solution of dimethyl 2-(benzyloxy)malonate (7.0 g, 29 mmol) in MeOH (27 ml_) at O 0C was added NaOMe (5.5 g, 0.10 mol) portion wise over approximately 10 min. Te/t-butylcarbamidine hydrochloride (4.23 g, 31 mmol) was then added portion wise over approximately 15 min and the resulting mixture was stirred for 30 min at 0 0C. The mixture was affixed with a reflux condenser, heated to 85 0C, and was stirred for 3.5 h. The mixture was cooled to 0 0C, treated with cone. HCI (-10 ml_), and stirred for 15 min. The resultant yellow solid was filtered off thru a medium glass - sintered funnel and was washed with cold water (3 x 15 ml_). The solid was dried in a vacuum oven at 35 0C for 12h to afford 5.8 g (73% yield) of an off-white solid which was used without further purification. LC-MS: M+H = 275.2
Preparative example P58
Figure imgf000100_0001
Utilizing the procedure set forth in Preparative Example 2, dimethyl 2-
(benzyloxy)malonate (7.0 g, 29 mmol) was treated with NaOMe (5.5 g, 0.10 mol) and cyclohexylcarboxamidine hydrochloride (5.0 g, 31 mmol) to afford 7.0 g (79% yield) of a light yellow solid which was used without further purification. LC-MS:
M+H = 301.2.
Preparative example P59
Figure imgf000100_0002
P57
To a solution of P57 (5.7 g, 20.7 mmol) from in toluene (40 mL) was added Et3N (3.2 mL, 22.8 mmol). The mixture was affixed with a reflux condenser and was heated to 100 0C. POCb (4.3 mL, 46 mmol) was added drop wise over five minutes and the mixture was heated to 125 0C. The mixture was stirred for 2.5 h, cooled to 0 0C, and treated with ice (~ 20 g). The mixture was allowed to stir for 20 min while warming to rt. The layers were separated and the aqueous layer was extracted with toluene (2 x 15 ml_). The organic layers were combined and were washed sequentially with sat. aq. NaHCO3 (1 x 20 ml_) and brine (1 x 20 ml_). The organic layer was dried (Na2SO4), filtered, and concentrated to afford 5.1 g (79% yield) of an orange oil that was used without further purification. LC-MS: M+H = 311.1.
Preparative example P60
Figure imgf000101_0001
P58 P60
Utilizing the procedure set forth in Preparative Example P59, treatment of P58 (5.7 g, 19 mmol) with Et3N (2.9 ml_, 21 mmol) and POCI3 (4.0 mL, 42.0 mmol) afforded 5.0 g (78% yield) of a yellow semisolid which was used without further purification. LC-MS: M+H = 337.
Preparative example P61
Figure imgf000102_0001
P61
The title compound was prepared according to the procedure set forth in US2005/046652.
Preparative example P62
Figure imgf000102_0002
R = 1Bu, cyclohexy and phenyl
Using a procedure, similar to the preparation of P15, Preparative Examples P62- P64 were prepared by coupling the appropriate pyrimidine chloride with p- tolylboronic acid.
Table 1
Figure imgf000103_0001
Example 86
1 ,1 -Dimethylethyl 4-[[5-methoxy-6-(4-methylphenyl)-4-pyrimidinyl]amino]-1■ piperidinecarboxylate
Figure imgf000104_0001
To a solution of P15 (0.14 g, 0.60 mmol) in π-BuOH (3 ml) at rt was added Et3N (0.42 ml, 3 mmol) followed by 4-amino-1 -Bocpiperidine (0.18 g, 0.89 mmol). The mixture was affixed with a condenser and was heated to 115 0C. The mixture was stirred for 14 h whereupon an additional portion of amine (100 mg, 0.5 mmol) and stirred for 8 h. The mixture was cooled to rt, concentrated under reduced pressure, and placed under high vacuum. The crude material was purified by preparative thin-layer chromatography eluting with 30:1 CH2CI2/MeOH to afford 0.16 g (67% yield) of 86. LCMS = 399.2 (MH+)
By essentially the same procedure set forth in Example 86, only substituting the amines of Table 2 and reacting with chlorides P15 or P64.
TABLE 2
Figure imgf000104_0002
Figure imgf000105_0002
Example 90
4-(4-Methylphenyl)-6-(4-piperidinylamino)-5-pyrimidinol
Figure imgf000105_0001
86 90
To a solution of 5-methoxypyrimidine (0.13 g, 0.33 mmol) from Example 1 in CH2CI2 (1.5 ml) at 0 0C was added BBr3 (1.49 ml, 1.0 M soln in CH2CI2 ) drop wise. The mixture was allowed to warm to rt and stir for 14 h whereupon the mixture was treated with H2O (3 ml_). The mixture was stirred for 30 min and the resultant solid was filtered off and placed under high vacuum. The crude material was purified by reverse phase HPLC (C18 column: 95:5 H2O:CH3CN (w/ 0.1 % TFA) to 90:10 CH3CN:H2O) to afford 84 mg (70% yield) of light orange solid as the TFA salt. LC-MS: M+H (-TFA) = 285.2. Examples 91-99
By essentially the same procedure set forth in Preparative Example 6 only substituting the precursor adducts, the corresponding products were made in Table 3:
TABLE 3
Figure imgf000106_0001
Preparative Example P66
Figure imgf000107_0001
To a solution of 4-aminobenzonitrile (97 mg, 0.82 mmol) in THF (4.5 ml_) at 0 0C was added NaH (78 mg, 3.27 mmol) and the mixture was stirred for 15 min. P59 (0.30 g, 0.82 mmol) was added in one portion and the mixture was stirred at rt for 12 h. The mixture was cooled to 0 0C and was treated with water (3 ml_) followed by dilution with EtOAc (9 ml_). The layers were separated and the aqueous layer was extracted with EtOAc (2 x 9 mL) and the organic layers were combined. The organic layer was washed with brine (1 x 5 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography using a 50:1 mixture of CH2CI2/MeOH as eluent to afford 0.27 g (73% yield) of the title compound as a yellow solid. LC- MS: M+H = 449.2.
Preparative Example P67, P68
By essentially the same procedure set forth in Preparative Example P66 except utilizing the chloro adduct indicated, the products in Table 4 were prepared:
TABLE 4
Figure imgf000108_0001
Example 94
N-[5-Methoxy-6-(4-methylphenyl)-4-pyrimidinyl]-7-isoguinolinamine
Figure imgf000108_0002
94 Using a procedure analogous to the one outlined for P66, 7- aminoquinoline (0.15 g, 1.05 mmol) was treated with NaH (0.18 g, 4.4 mmol) in the presence of P15 (0.30 g, 1.2 mmol) to afford 0.20 g (59% yield) of an orange solid. LC-MS: M+H = 343.2.
Example 95
4-[[2-Cyclohexyl-5-hydroxy-6-(4-methylphenyl)-4-pyrimidinyl]amino]benzonitrile
Figure imgf000109_0001
To a solution of P68 (0.43 g, 0.91 mmol) in MeOH/THF (2:1 ; 25 ml total) at rt was added 10% Pd/C (40 mg). The mixture was degassed and filled with N2 followed by repeating the procedure except filling with H2. The mixture was stirred for 1 h under a H2 balloon and was filtered through a pad of CELITE. The CELITE pad was washed with the MeOH/THF (4:1 ; 100 ml total) and the resultant filtrate was concentrated under reduced pressure and placed under high vacuum to afford 0.35 g (99% yield) of a light yellow solid. LC-MS: M+H = 385.2. This material was used without further purification. Example 96
4-[[2-(1 ,1-Dimethylethyl)-5-hydroxy-6-(4-methylphenyl)-4- pyrimidinyl]amino]benzonitrile
Figure imgf000110_0001
Using the procedure outlined in example 95, P66 (0.43 g, 0.96 mmol) from was converted to 0.33 g (99% yield) of the title compound as a yellow solid which was used without further purification. LC-MS: M+H = 359.5.
Example 97
4-[[5-Hydroxy-6-(4-methylphenyl)-2-phenyl-4-pyrimidinyl]amino]benzonitrile
Figure imgf000111_0001
Treatment of P67 (0.20 g, 0.52 mmol) under the conditions listed for the preparation of example 90 yielded 80 mg (41% yield) of the title compound as a yellow solid. LC-MS: M+H = 379.2.
Example 98 4-[[4-(Aminomethyl)phenyl]amino]-2-cyclohexyl-6-(4-methylphenyl)-5-pyrimidinol
Figure imgf000111_0002
To a pressure bottle charged with 95 (0.10 g, 0.26 mmol) in 7M NH3 in
MeOH (5 ml_) at rt was added 50% Raney Ni in H2O (~ 4 ml_). The mixture was shaken under 50 psi of H2 for 3 h and purged to N2. The mixture was filtered thru a pad of CELITE which was generously washed with 7M NH3 in MeOH (50 ml_). The filtrate was concentrated under reduced pressure and was placed under high vacuum. The crude material was purified by reverse phase HPLC (C18 column: 95:5 H2O:CH3CN (w/ 0.1 % TFA) to 90:10 CH3CN:H2O) to afford 110 mg (70% yield) of light orange solid as the monohydrochloride salt after HCI treatment. LC-MS: M+H = 285.2.
By essentially the same procedure set forth in Example 98, only substituting the precursor nitriles, the compounds in Table 5 were prepared:
TABLE 5
Figure imgf000112_0001
Figure imgf000113_0002
Examples 101-102 4-[[5-Hydroxy-6-(4-methylphenyl)-2-phenyl-4-pyrimidinyl]amino]benzamide (101 )
4-[[5-Hydroxy-6-(4-methylphenyl)-2-phenyl-4- pyrimidinyl]amino]benzenecarboximidamide (102)
Figure imgf000113_0001
97 101 : X = O
102: X = NH
To a pressure tube charged with 97 (50 mg, 0.07 mmol) in MeOH (2 ml_) at O 0C was added AcCI (2 ml_) drop wise. The tube was purged to N2, capped, and stirred at rt for 12 h. The mixture was concentrated under reduced pressure and placed under high vacuum to remove trace volatiles. The crude imidate product was taken up in 7 M NH3 in MeOH (10 ml_), transferred to a pressure tube. The tube was capped and stirred for 72 h. The solution was concentrated under reduced pressure and the crude mixture was purified by reverse-phase HPLC to afford 3 mg (1 1 % yield) of amide 101 (LC-MS = M+H = 397) and 50 mg (87% yield) of annidine 102 as the monohydrochloride after HCI treatment (LC- MS = M+H (-HCI) = 396.2).
By essentially the same procedure set forth in Examples 101-102 only substituting the precursor nitrites, the compounds in Table 6 were prepared:
TABLE 6
Figure imgf000114_0001
Examples 106 4-(7-lsoquinolinylamino)-6-(4-methylphenyl)-5-pyrimidinol
Figure imgf000115_0001
Treatment of 94 (0.20 g, 0.50 mmol) under the reaction conditions outlined for the preparation of Example 90 afforded 25 mg (16% yield) of the title compound as brown solid. LC-MS: M+H = 329.2.
Example 107
2-(5-Hydroxy-6-p-tolylpyrimidin-4-yl)-1 H-benzo[c/]imidazole-5-carboximidamide
Step 1 : Preparation of δ-hydroxy-θ-p-tolylpyrimidine^-carbonitrile P69.
Figure imgf000115_0002
P15 P69
To a solution of 4-chloro-5-methoxy-6-p-tolylpyrimidine P5 (100 mg, 0.43 mmol) in DMF (2 ml_) and NMP (0.5 ml_) was added triethylenediamine (62 mg, 0.55 mmol) and potassium cyanide (55 mg, 0.85 mmol). The reaction mixture was stirred at room temperature for 18 hours. Diehloromethane and 1 N hydrochloric acid were added. The organic layer was dried over anhydrous sodium sulfate. The organic solvent was evaporated under reduced pressure. The crude product was purified by flash column chromatography to afford the desired 5-hydroxy-6- p-tolylpyrimidine-4-carbonitrile P69 (70 mg, 0.33 mmol).
Step 2: Preparation of δ-hydroxy-β-p-tolylpyrimidine^-carboxylic acid P70.
Figure imgf000116_0001
P69 P70
To 5-hydroxy-6-/>tolylpyrimidine-4-carbonitrile P69 (360 mg, 1.71 mmol) was added water (20 ml_) and concentrated sulfuric acid (20 ml_). The reaction mixture was heated under reflux for 4 hours. The reaction mixture was poured onto ice. The precipitate was filtered and washed with water. The solid product was dried under reduced pressure to afford the desired 5-hydroxy-6-p- tolylpyrimidine-4-carboxylic acid P70 (210 mg, 0.91 mmol).
Step 3: Preparation of benzyl 5-(benzyloxy)-6-p-tolylpyrimidine-4-carboxylate P71.
Figure imgf000116_0002
P71
To a solution of 5-hydroxy-6-p-tolylpyrimidine-4-carboxylic acid P70 (40 mg, 0.17 mmol) in anhydrous DMF (2 ml_) was add potassium fe/t-butoxide (39 mg, 0.35 mmol) and benzyl bromide (44 mg, 0.26 mmol). The reaction mixture was stirred at room temperature for 18 hours. Organic solvent was evaporated under reduced pressure. Ethyl acetate and 1 N hydrochloric acid were added. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The organic solvent was evaporated under reduced pressure. The crude product was purified by flash column chromatography to afford the desired benzyl 5-(benzyloxy)-6-p-tolylpyrimidine-4-carboxylate P71 (50 mg, 0.12 mmol).
Step 4: Preparation of 5-(benzyloxy)-6-p-tolylpyrimidine-4-carboxylic acid P72.
Figure imgf000117_0001
P71 P72
To a solution of benzyl 5-(benzyloxy)-6-p-tolylpyrimidine-4-carboxylate P71 (90 mg, 0.22 mmol) in methanol (5 ml_) was added lithium hydroxide monohydrate (46 mg, 1.10 mmol). The reaction mixture was heated in a microwave reactor at 900C for 10 minutes. The organic solvent was evaporated under reduced pressure. Ethyl acetate and 1 N hydrochloric acid were added. The organic layer was washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate. The organic solvent was evaporated under reduced pressure. The solid product was dried under reduced pressure to afford the desired 5-(benzyloxy)-6-p-tolylpyrimidine-4-carboxylic acid P72 (70 mg, 0.22 mmol).
Step 5: Preparation of 2-(5-hydroxy-6-p-tolylpyrimidin-4-yl)-1 H- benzo[d]imidazole-5-carbonitrile P73.
Figure imgf000118_0001
P72
To a solution of 5-(benzyloxy)-6-p-tolylpyrimidine-4-carboxylic acid P72 (80 mg, 0.25 mmol) in DMF (3 ml_) was added 3,4-diaminobenzonitrile (40 mg, 0.30 mmol), HATU (124 mg, 0.33 mmol) and diisopropylethylamine (48 mg, 0.37 mmol). The reaction mixture was stirred at room temperature for 18 hours. The organic solvent was evaporated under reduced pressure. Ethyl acetate and 1 N hydrochloric acid were added. The organic layer was washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate. The organic solvent was evaporated under reduced pressure. The intermediate was purified by flash column chromatography. The intermediate was dissolved in acetic acid (5 ml_) and heated in a microwave reactor at 160 0C for 1 hour. The organic solvent was evaporated under reduced pressure. Trifluoroacetic acid (5 ml_) was added and the solution was heated in a microwave reactor at 120 0C for 30 minutes. The organic solvent was evaporated under reduced pressure. The crude product was purified by RP-HPLC to afford the desired 2-(5-hydroxy-6-p~ tolylpyrimidin-4-yl)-1 H-benzo[c^imidazole-5-carbonitrile P73 (16 mg, 0.049 mmol). Step 6: Preparation of 2-(5-hydroxy-6-p-tolylpyrimidin-4-yl)-1 H- benzo[d]imidazole-5-carboximidamide P74.
Figure imgf000119_0001
P73 107
To a solution of 2-(5-hydroxy-6-p-toiyipyrimidin-4-yl)-1 H-benzo[cQimidazole-5- carbonitriie P73 (16 mg, 0.049 mmol) in absolute ethanol (2 ml_) cooled in an ice bath was added acetyl chloride (2 mi_). The reaction mixture was stirred at room temperature for 18 hours. The organic solvent was evaporated under reduced pressure. A methanolic ammonia solution (7 N, 5 mL) was added to the intermediate. The reaction mixture was stirred at room temperature for 18 hours. The organic solvent was evaporated under reduced pressure. The crude product was purified by RP-HPLC to afford the desired 2-(5-hydroxy-6-p-tolylpyrimidin-4- yl)-1 H-benzo[d]imidazole-5-carboximidamide 107 (3 mg, 0.0087 mmol).
LCMS: 345 (MH+)
Example 108
2-(5-hydroxy-6-phenyl-4-pyrimidinyl)-1 h-benzimidazole-6-carboximidamide
Figure imgf000119_0002
108
Example 107 was prepared using a procedure similar to the preparation of 106.
LSMS: 331 (MH+) The following compounds were synthesized using analogous procedures from the appropriate starting material.
Utility
The compounds of this invention are inhibitors of factor IXa and are useful as anticoagulants for the treatment or prevention of thromboembolic disorders in mammals (i.e., factor IXa-associated disorders). In general, a thromboembolic disorder is a circulatory disease caused by blood clots (i.e., diseases involving fibrin formation, platelet activation, and/or platelet aggregation).
The term "thromboembolic disorders" as used herein includes arterial cardiovascular thromboembolic disorders, venous cardiovascular or
cerebrovascular thromboembolic disorders, and thromboembolic disorders in the chambers of the heart. The term "thromboembolic disorders" as used herein also includes specific disorders selected from, but not limited to, unstable angina or other acute coronary syndromes, first or recurrent myocardial infarction, ischemic sudden death, transient ischemic attack, stroke, atherosclerosis, peripheral occlusive arterial disease, venous thrombosis, deep vein thrombosis,
thrombophlebitis, arterial embolism, coronary arterial thrombosis, cerebral arterial thrombosis, cerebral embolism, kidney embolism, pulmonary embolism, and thrombosis resulting from (a) prosthetic valves or other implants, (b) indwelling catheters, (c) stents, (d) cardiopulmonary bypass, (e) hemodialysis, or (f) other procedures in which blood is exposed to an artificial surface that promotes thrombosis. It is noted that thrombosis includes occlusion (e.g., after a bypass) and reocclusion (e.g., during or after percutaneous transluminal coronary angioplasty).
The thromboembolic disorders may result from conditions including but not limited to atherosclerosis, surgery or surgical complications, prolonged immobilization, arterial fibrillation, congenital thrombophilia, cancer, diabetes, effects of medications or hormones, and complications of pregnancy. The anticoagulant effect of compounds of the present invention is believed to be due to inhibition of serine proteases involved in the coagulation cascade and/or contact activation system, more specifically, inhibition of the coagulation factors: factor XIa, factor Vila, factor IXa, factor Xa, plasma kallikrein or thrombin.
The compounds of this invention also are inhibitors of plasma kallikrein and are useful as anti-inflammatory agents for the treatment or prevention of diseases associated with an activation of the contact activation system (i.e., plasma kallikrein associated disorders). In general, a contact activation system disorder is a disease caused by activation of blood on artificial surfaces, including prosthetic valves or other implants, indwelling catheters, stents, cardiopulmonary bypass, hemodialysis, microorganism (e.g., bacteria, virus), or other procedures in which blood is exposed to an artificial surface that promotes contact activation, blood clots (i.e., diseases involving fibrin formation, platelet activation, and/or platelet aggregation). It also includes systemic inflammatory response syndrome, sepsis, acute respiratory dystress syndrome, hereditary angioedema or other inherited or aquired deficencies of contact activation components or their inhibitors (plasma kallikrein, factor XIIa, high molecular weight kininogen, C1 - esterase inhibitor). It may also include acute and chronic inflammations of joints, vessels, or other mammalian organs.
The effectiveness of compounds of the present invention as inhibitors of the coagulation factors XIa, Vila, IXa, Xa, plasma kallikrein or thrombin, can be determined using a relevant purified serine protease, respectively, and an appropriate synthetic substrate. The rate of hydrolysis of the chromogenic or fluorogenic substrate by the relevant serine protease was measured both in the absence and presence of compounds of the present invention. Hydrolysis of the substrate resulted in the release of pNA (para nitroaniline), which was monitored spectrophotometrically by measuring the increase in absorbance at 405 nm, or the release of AMC (amino methylcoumarin, which was monitored spectrofluorometrically by measuring the increase in emission at 460 nm with excitation at 380 nm. A decrease in the rate of absorbance or fluorescence change in the presence of inhibitor is indicative of enzyme inhibition. Such methods are known to one skilled in the art. The results of this assay are expressed as the inhibitory constant, K1.
Factor XIa determinations can be made in 50 mM HEPES buffer at pH 7.4 containing 145 mM NaCI, 5 mM KCI, and 0.1% PEG 8000 (polyethylene glycol; JT Baker or Fisher Scientific). Determinations can be made using purified human Factor XIa at a final concentration of 75-200 pM (Haematologic Technologies) and the synthetic substrate S-2366 (pyroGlu-Pro-Arg-pNA; Chromogenix) at a concentration of 0.0002-0.00025 M. Compounds tested in the Factor XIa assay are considered to be active if they exhibit a K, of equal to or less than 15 μM. Preferred compounds of the present invention have K,'s of equal to or less than 1 μM. More preferred compounds of the present invention have K ,'s of equal to or less than 0.1 μM. Even more preferred compounds of the present invention have K1 1S of equal to or less than 0.01 μM.
Factor Vila determinations can be made in 0.005 M calcium chloride, 0.15 M sodium chloride, 0.05 M HEPES buffer containing 0.5% PEG 8000 at a pH of 7.4. Determinations can be made using purified human Factor Vila
(Haematologic Technologies) or recombinant human Factor Vila (Novo Nordisk) at a final assay concentration of 2-5 nM, recombinant soluble tissue factor at a concentration of 18-35 nM and the synthetic substrate H-D-lle-Pro-Arg-pNA (S- 2288; Chromogenix or BMPM-2; AnaSpec) at a concentration of 0.001 M.
Compounds tested in the Factor Vila assay are considered to be active if they exhibit a K, of equal to or less than 15 μM.
Factor IXa determinations were made according to the following assay procedure: Buffer:
50 mM Tris pH 8.0
5 mM CaCI2-2H20
10O mM NaCI
15% vol/vol Ethylene Glycol
Enzyme:
Human plasma factor IXa. (American Diagnostica Inc. product)
Enzyme is diluted 1 :800 in buffer to achieve 0.0057 ug/ml working stock for use in assay. Mix by inversion.
Substrate:
Spectrozyme factor IXa Fluorogenic substrate (American Diagnostica Inc.) The substrate (l Oumoles lyophilized) is reconstituted with 1 ml water to give a 1OmM stock. The substrate is then further diluted to 300 uM in buffer for use in assay. Mix by inversion.
Procedure in 384 well plate:
Add 10 ul vehicle or compound
Add 10 ul Factor IXa enzyme.
Add 10 ul Fluorogenic substrate.
Incubate reaction at room temperature for 2h.
Quench with 5 ul 50% acetic acid.
Read Fluorescence - Absorbance 360nm; Emission 440nm Factor Xa determinations are made according to the following assay procedure:
Buffer:
20 mM Tris pH 8.0
2.5 mM CaCI2-2H20 200 mM NaCI
Enzyme:
Human plasma factor Xa. (American Diagnostica Inc.)
Resuspend enyme in water to 80 ug/ml.
Enzyme is diluted to 0.133 ug/ml in buffer. Mix by inversion.
Substrate:
Spectrozyme factor IXa Fluorogenic substrate (American Diagnostica Inc.) Reconstitute with 1 ml water to give a 1OmM stock. The substrate is then further diluted to 30OuM in buffer for use in assay. Mix by inversion.
Procedure in 384 well plate:
Add 10 ul vehicle or compound
Add 10 ul Factor Xa enzyme.
Add 10 ul Fluorogenic substrate.
Incubate reaction at room temperature for 2h.
Quench with 5 ul 50% acetic acid.
Read Fluorescence - Absorbance 360nm; Emission 440nm
IC50 determinations for factor IXa and Xa were made for the present clompounds as described below
IC50 calculation
Compounds were tested at multiple concentrations beginning at 100 uM and decreasing at half log intervals. IC50 values for compounds at each coagulation factor were then generated using nonlinear curvefit software within ActivityBase (IDBS software). Each compound that was tested was tested in at least 2 separate assays (4 replicates per experiment). The final IC50 values obtained represent the average of all determinations. In one embodiment, the compounds of the present invention have factor IXa IC50 (nM; nanomolar) values ranging from about 10 nM to greater than 25,000 nM. In another embodiment, for some of the compounds, the values range from about 10 nM to about 20,000 nM, and in another embodiment from about 20 nM to about 10,000 nM, and in another embodiment from about 20 nM to about 1000 M, and in another embodiment from about 20 nM to about 500 nM, and in another embodiment from about 20 nM to about 100 nM, and in another embodiment from about 5 nM to about 100 nM.
In one embodiment, some of the compounds of the present invention are selective factor IXa inhibitors, i.e., selective for factor IXa over other coagulation factors, such as factor Xa.
Selectivity calculation
Selectivity for Factor IXa activity over Factor Xa activity can be determined by the following calculation.: (IC50 Factor Xa) / (IC50 Factor IXa). Similar calculations can be made for selectivity of compounds for Factor IX compared to other coagulation factors.
Plasma kallikrein determinations can be made in 0.1 M sodium phosphate buffer at a pH of 7.4 containing 0.2 M sodium chloride and 0.5% PEG 8000.
Determinations can be made using purified human kallikrein (Enzyme Research Laboratories) at a final assay concentration of 200 pM and the synthetic substrate S-2302 (H-(D)-Pro-Phe-Arg-pNA; Chromogenix) at a concentration of 0.00008-0.0004 M. The Km value useful for calculation of K, is 0.00005 to
0.00007 M. Compounds tested in the plasma kallikrein assay are considered to be active if they exhibit a K, of equal to or less than 15 μM. Preferred compounds of the present invention have K1 1S of equal to or less than 1 μM. More preferred compounds of the present invention have K1 1S of equal to or less than 0.1 μM. Even more preferred compounds of the present invention have K,'s of equal to or less than 0.01 μM. Thrombin determinations can be made in 0.1 M sodium phosphate buffer at a pH of 7.4 containing 0.2 M sodium chloride and 0.5% PEG 8000.
Determinations are made using purified human alpha thrombin (Haematologic Technologies or Enzyme Research Laboratories) at a final assay concentration of 200-250 μM and the synthetic substrate S-2366 (pyroGlu-Pro-Arg-pNA;
Chromogenix) at a concentration of 0.0002 M. Compounds tested in the thrombin assay are considered to be active if they exhibit a K, of equal to or less than 15 μM.
Compounds of the present invention are useful as effective inhibitors of the coagulation cascade and/or contact activation system, and useful as anticoagulants for the prevention or treatment of thromboembolic disorders in mammals and/or as anti-inflammatory agents for the prevention or treatment of inflammatory disorders in mammals.
The Michaelis constant, Km, for substrate hydrolysis by each protease can be determined at 25° C. using the method of Lineweaver and Burk. Values of K, are determined by allowing the protease to react with the substrate in the presence of the inhibitor. Reactions are allowed to go for periods of 20-180 minutes (depending on the protease) and the velocities (rate of absorbance or fluorescence change versus time) are measured. The following relationships were used to calculate K, values: o (vo-vs)/vs=l/(Kι(1+ S/Km)) for a competitive inhibitor with one binding site; or
o Vs/vo=A+((B-A)/1 +((IC50/(l) n))) and
o K,=lC5o/(1 +S/Km) for a competitive inhibitor
o where:
o V0 is the velocity of the control in the absence of inhibitor; o vs is the velocity in the presence of inhibitor;
o I is the concentration of inhibitor; o A is the minimum activity remaining (usually locked at zero);
o B is the maximum activity remaining (usually locked at 1.0) ;
o n is the Hill coefficient, a measure of the number and cooperativity of potential inhibitor binding sites;
o IC50 is the concentration of inhibitor that produces 50% inhibition under the assay conditions;
0 Ki is the dissociation constant of the enzyme:inhibitor complex; 0 S is the concentration of substrate; and
0 Km is the Michaelis constant for the substrate. The effectiveness of compounds of the present invention as inhibitors of the coagulation factors XIa1 Vila, IXa, Xa1 or thrombin, can be determined using relevant in vivo thrombosis models, including In Vivo Electrically-induced Carotid Artery Thrombosis Models and In Vivo Rabbit Arterio-venous Shunt Thrombosis Models. In Vivo Electrically-induced Carotid Artery Thrombosis Model: The
antithrombotic effect of compounds of the present invention can be demonstrated in the electrically-induced carotid artery thrombosis (ECAT) model in rabbits. In this model, rabbits are anesthetized with a mixture of ketamine (50 mg/kg i.m.) and xylazine (10 mg/kg i.m.). A femoral vein and a femoral artery are isolated and catheterized. The carotid artery is also isolated such that its blood flow can be measured with a calibrated flow probe that is linked to a flowmeter. A stainless steel bipolar hook electrode is placed on the carotid artery and positioned caudally in relationship to the flow probe as a means of applying electrical stimulus. In order to protect the surrounding tissue, a piece of Parafilm is placed under the electrode.
Test compounds are considered to be effective as anticoagulants based on their ability to maintain blood flow in the carotid artery following the induction of thrombosis by an electrical stimulus. A test compound or vehicle is given as continuous intravenous infusion via the femoral vein, starting 1 hour before electrical stimulation and continuing to the end of the test. Thrombosis is induced by applying a direct electrical current of 4 mA for 3 min to the external arterial surface, using a constant current unit and a d.c. stimulator. The carotid blood flow is monitored and the time to occlusion (decrease of blood flow to zero following induction of thrombosis) in minutes is noted. The change in observed blood flow is calculated as a percentage of the blood flow prior to induction of thrombosis and provides a measure of the effect of a test compound when compared to the case where no compound is administered. This information is used to estimate the ED50 value, the dose that increases blood flow to 50% of the control (blood flow prior to induction of thrombosis) and is accomplished by nonlinear least square regression.
In Vivo Rabbit Arterio-venous Shunt Thrombosis Model: The
antithrombotic effect of compounds of the present invention can be demonstrated in a rabbit arterio-venous (AV) shunt thrombosis model. In this model, rabbits weighing 2-3 kg anesthetized with a mixture of xylazine (10 mg/kg i.m.) and ketamine (50 mg/kg i.m.) are used. A saline-filled AV shunt device is connected between the femoral arterial and the femoral venous cannulae. The AV shunt device consists of a piece of 6-cm tygon tubing that contains a piece of silk thread. Blood will flow from the femoral artery via the AV-shunt into the femoral vein. The exposure of flowing blood to a silk thread will induce the formation of a significant thrombus. After forty minutes, the shunt is disconnected and the silk thread covered with thrombus is weighed. Test agents or vehicle will be given (i.v., i.p., s. c, or orally) prior to the opening of the AV shunt. The percentage inhibition of thrombus formation is determined for each treatment group. The ID5O values (dose which produces 50% inhibition of thrombus formation) are estimated by linear regression.
The anti-inflammatory effect of these compounds can be demonstrated in an Evans Blue dye extravasation assay using C1 -esterase inhibitor deficient mice. In this model, mice are dosed with a compound of the present invention, Evans Blue is injected via the tail vein, and extravasation of the blue dye is determined by spectrophotometric means from tissue extracts.
The ability of the compounds of the current invention to reduce or prevent the systemic inflammatory response syndrome, for example, as observed during on-pump cardiovascular procedures, can be tested in in vitro perfusion systems, or by on-pump surgical procedures in larger mammals, including dogs and baboons. Read-outs to assess the benefit of the compounds of the present invention include for example reduced platelet loss, reduced platelet/white blood cell complexes, reduced neutrophil elastase levels in plasma, reduced activation of complement factors, and reduced activation and/or consumption of contact activation proteins (plasma kallikrein, factor XII, factor Xl, high molecular weight kininogen, C1 -esterase inhibitors).
The utility of the compounds of the current invention to reduce or prevent the morbidity and/or mortality of sepsis can be assessed by injecting a mammalian host with bacteria or viruses or extracts there of and compounds of the present invention. Typical read-outs of the efficacy include changes in the LD50 and blood pressure preservation.
The compounds of the present invention may also be useful as inhibitors of additional serine proteases, notably human thrombin, human plasma kallikrein and human plasmin. Because of their inhibitory action, these compounds are indicated for use in the prevention or treatment of physiological reactions, including blood coagulation, fibrinolysis, blood pressure regulation and inflammation, and wound healing catalyzed by the aforesaid class of enzymes. Specifically, the compounds have utility as drugs for the treatment of diseases arising from elevated thrombin activity of the aforementioned serine proteases, such as myocardial infarction, and as reagents used as anticoagulants in the processing of blood to plasma for diagnostic and other commercial purposes. The compounds of the present invention can be administered alone or in combination with one or more additional therapeutic agents. These include other anti-coagulant or coagulation inhibitory agents, anti-platelet or platelet inhibitory agents, anti-inflammatory agents, thrombin inhibitors, or thrombolytic or fibrinolytic agents.
The compounds are administered to a mammal in a therapeutically effective amount. By "therapeutically effective amount" it is meant an amount of a compound of the present invention that, when administered alone or in combination with an additional therapeutic agent to a mammal, is effective to treat (i.e. prevent, inhibit or ameliorate) the thromboembolic and/or inflammatory disease condition or treat the progression of the disease in a host.
The compounds of the invention are preferably administered alone to a mammal in a therapeutically effective amount. However, the compounds of the invention can also be administered in combination with an additional therapeutic agent, as define below, to a mammal in a therapeutically effective amount. When administered in a combination, the combination of compounds is preferably, but not necessarily, a synergistic combination. Synergy, as described for example by Chou and Talalay, Adv. Enzyme Regui 1984, 22, 27-55, occurs when the effect (in this case, inhibition of the desired target) of the compounds when
administered in combination is greater than the additive effect of the compounds when administered alone as a single agent. In general, a synergistic effect is most clearly demonstrated at suboptimal concentrations of the compounds. Synergy can be in terms of lower cytotoxicity, increased anticoagulant effect, or some other beneficial effect of the combination compared with the individual components.
By "administered in combination" or "combination therapy" it is meant that the compound of the present invention and one or more additional therapeutic agents are administered concurrently to the mammal being treated. When administered in combination each component may be administered at the same time or sequentially in any order at different points in time. Thus, each
component may be administered separately but sufficiently closely in time so as to provide the desired therapeutic effect. Compounds which can be administered in combination with the
compounds of the present invention include, but are not limited to,
anticoagulants, anti-thrombin agents, anti-platelet agents, fibrinolytics,
hypolipidemic agents, antihypertensive agents, and anti-ischemic agents.
Other anticoagulant agents (or coagulation inhibitory agents) that may be used in combination with the compounds of this invention include warfarin, heparin (either unfractionated heparin or any commercially available low molecular weight heparin, for example LOVANOX®) , aprotinin, synthetic pentasaccharide, direct acting thrombin inhibitors including hirudin and
argatroban, as well as other factor Vila, Villa, IXa, Xa, XIa, thrombin, TAFI, and fibrinogen inhibitors known in the art. Factor IXa inhibitors different from the compounds of Formulae l-lll include monoclonal antibodies, synthetic active-site blocked competitive inhibitors, oral inhibitors and RNA aptamers. These are described in the previously cited Howard et al. reference (Howard, EL, Becker KC, Rusconi, CP, Becker RC. Factor IXa Inhibitors as Novel Anticoagulents. Arterioscler Thmmb Vase Biol. 2007; 27: 722-727.)
The term anti-platelet agents (or platelet inhibitory agents), as used herein, denotes agents that inhibit platelet function, for example, by inhibiting the aggregation, adhesion or granular secretion of platelets. Such agents include, but are not limited to, the various known non-steroidal anti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, sulindac, indomethacin, mefenamate, droxicam, diclofenac, sulfinpyrazone, and piroxicam, including pharmaceutically acceptable salts or prodrugs thereof. Of the NSAIDS, aspirin (acetylsalicylic acid or ASA), and piroxicam are preferred. Other suitable platelet inhibitory agents include llb/llla antagonists (e.g., tirofiban, eptifibatide, and abciximab), thromboxane-A2-receptor antagonists (e.g., ifetroban), thromboxane- A2-synthetase inhibitors, phosphodiesterase-lll (PDE-III) inhibitors (e.g., dipyridamole, cilostazol), and PDE V inhibitors (such as sildenafil), and
pharmaceutically acceptable salts or prodrugs thereof.
The term anti-platelet agents (or platelet inhibitory agents), as used herein, is also intended to include ADP (adenosine diphosphate) receptor antagonists, preferably antagonists of the purinergic receptors P2Y1 and P2Y12, with P2Y12 being even more preferred. Preferred P 2Y12 receptor antagonists include ticlopidine and clopidogrel, including pharmaceutically acceptable salts or prodrugs thereof. Clopidogrel is an even more preferred agent. Ticlopidine and clopidogrel are also preferred compounds since they are known to be gentle on the gastro-intestinal tract in use. The compounds of the present invention may also be dosed in combination with aprotinin. The term thrombin inhibitors (or anti-thrombin agents), as used herein, denotes inhibitors of the serine protease thrombin. By inhibiting thrombin, various thrombin-mediated processes, such as thrombin-mediated platelet activation (that is, for example, the aggregation of platelets, and/or the granular secretion of plasminogen activator inhibitor-l and/or serotonin), endothelial cell activation, inflammatory reactions, and/or fibrin formation are disrupted. A number of thrombin inhibitors are known to one of skill in the art and these inhibitors are contemplated to be used in combination with the present compounds. Such inhibitors include, but are not limited to, boroarginine derivatives, boropeptides, heparins, hirudin and argatroban, including pharmaceutically acceptable salts and prodrugs thereof. Boroarginine derivatives and boropeptides include N-acetyl and peptide derivatives of boronic acid, such as C-terminal alpha-aminoboronic acid derivatives of lysine, ornithine, arginine, homoarginine and corresponding isothiouronium analogs thereof. The term hirudin, as used herein, includes suitable derivatives or analogs of hirudin, referred to herein as hirulogs, such as disulfatohirudin.
The term "thrombin receptor antagonists", also known as protease activated receptor (PAR) antagonists or PAR-1 antagonists, are useful in the treatment of thrombotic, inflammatory, atherosclerotic and fibroproliferative disorders, as well as other disorders in which thrombin and its receptor play a pathological role.
Thrombin receptor antagonist peptides have been identified based on structure-activity studies involving substitutions of amino acids on thrombin receptors. In Bernatowicz et al, J. Med. Chem., vol. 39, pp. 4879-4887 (1996), tetra-and pentapeptides are disclosed as being potent thrombin receptor antagonists, for example N-trans-cinnamoyl-p-fluoroPhe-p-guanidinoPhe-Leu- Arg-NH2 and N-trans-cinnamoyl-p-fluoroPhe-p-guanidinoPhe-Leu-Arg-Arg-NHa. Peptide thrombin receptor antagonists are also disclosed in WO 94/03479, published Feb. 17, 1994.
Substituted tricyclic thrombin receptor antagonists are disclosed in U.S. Pat. Nos. 6,063,847, 6,326,380 and WO 01/96330 and 10/271 ,715.
Other thrombin receptor antagonists include those disclosed in U.S. Pat. Nos. 7,304,078; 7,235,567; 7,037920; 6,645,987; and EP Patent Nos.
EP1495018 and EP1294714.
The term thrombolytic (or fibrinolytic) agents (or thrombolytics or fibrinolytics), as used herein, denotes agents that lyse blood clots (thrombi). Such agents include tissue plasminogen activator (TPA, natural or recombinant) and modified forms thereof, anistreplase, urokinase, streptokinase, tenecteplase (TNK), lanoteplase (nPA), factor Vila inhibitors, PAI-I inhibitors (i.e., inactivators of tissue plasminogen activator inhibitors), alpha-2-antiplasmin inhibitors, and anisoylated plasminogen streptokinase activator complex, including pharmaceutically acceptable salts or prodrugs thereof. The term anistreplase, as used herein, refers to anisoylated plasminogen streptokinase activator complex, as described, for example, in European Patent Application No. 028,489, the disclosure of which is hereby incorporated herein by reference herein. The term urokinase, as used herein, is intended to denote both dual and single chain urokinase, the latter also being referred to herein as prourokinase.
Examples of suitable anti-arrythmic agents for use in combination with the present compounds include: Class I agents (such as propafenone); Class Il agents (such as carvadiol and propranolol); Class III agents (such as sotalol, dofetilide, amiodarone, azimilide and ibutilide); Class IV agents (such as ditiazem and verapamil); K+ channel openers such as Uch inhibitors, and lκUr inhibitors (e.g., compounds such as those disclosed in WO01/40231).
The term antihypertensive agents, as used herein, include: alpha adrenergic blockers; beta adrenergic blockers; calcium channel blockers (e.g., diltiazem, verapamili nifedipine, amlodipine and mybefradil); diruetics (e.g., chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide,
bendroflumethiazide, methylchlorothiazide, trichloromethiazide, polythiazide, benzthiazide, ethacrynic acid tricrynafen, chlorthalidone, furosemide, musolimine, bumetanide, triamtrenene, amiloride, spironolactone); renin inhibitors;
angiotensin-converting enzyme (ACE) inhibitors (e.g., captopril, lisinopril, fosinopril, enalapril, ceranopril, cilazopril, delapril, pentopril, quinapril, ramipril, lisinopril); angiotensin-ll receptor antagonists (e.g., irbestatin, losartan,
valsartan); ET receptor antagonists (e.g., sitaxsentan, atrsentan and compounds disclosed in U.S. Pat. Nos. 5,612,359 and 6,043,265); Dual ET/AII antagonist (e.g., compounds disclosed in WO 00/01389); neutral endopeptidase (NEP) inhibitors; vasopepsidase inhibitors (dual ACE/NEP inhibitors, e.g., omapatrilat, gemopatrilat, nitrates); and β-blockers (e.g., propanolol, nadolo, or carvedilol). Examples of suitable cardiac glycosides for use in combination with the compounds of the present invention include digitalis and ouabain.
Examples of suitable mineralocorticoid receptor antagonists for use in combination with the compounds of the present invention include sprionolactone and eplirinone.
Examples of suitable cholesterol/lipid lowering agents and lipid profile therapies for use in combination with the compounds of the present invention include: HMG-CoA reductase inhibitors (e.g., pravastatin, lovastatin, atorvastatin, simvastatin, fluvastatin, NK-104 (a.k.a. itavastatin, or nisvastatin or nisbastatin) and ZD-4522 (a.k.a. rosuvastatin, or atavastatin or visastatin)); squalene synthetase inhibitors; fibrates; bile acid sequestrants (such as questran); ACAT inhibitors; MTP inhibitors; lipooxygenase inhibitors; choesterol absorption inhibitors; and cholesterol ester transfer protein inhibitors (e.g., CP-529414).
Examples of suitable anti-diabetic agents for use in combination with the compounds of the present invention include: biguanides (e.g., metformin);
glucosidase inhibitors (e.g., acarbose); insulins (including insulin secretagogues or insulin sensitizers); meglitinides (e.g., repaglinide); sulfonylureas (e.g., glimepiride, glyburide and glipizide); biguanide/glyburide combinations (e.g., glucovance), thiozolidinediones (e.g., troglitazone, rosiglitazone and
pioglitazone), PPAR-alpha agonists, PPAR-gamma agonists, PPAR
alpha/gamma dual agonists, SGLT2 inhibitors, inhibitors of fatty acid binding protein (aP2) such as those disclosed in WO00/59506, glucagon-like peptide-1 (GLP-1 ), and dipeptidyl peptidase IV (DP4) inhibitors.
Examples of suitable anti-depressant agents for use in combination with the compounds of the present invention include nefazodone and sertraline.
Examples of suitable anti-inflammatory agents for use in combination with the compounds of the present invention include: prednisone; dexamethasone; enbrel; protein tyrosine kinase (PTK) inhibitors; cyclooxygenase inhibitors (including NSAIDs, and COX-1 and/or COX-2 inhibitors); aspirin; indomethacin; ibuprofen; prioxicam; naproxen; celecoxib; and/or rofecoxib.
Examples of suitable anti-osteoporosis agents for use in combination with the compounds of the present invention include alendronate and raloxifene.
Examples of suitable hormone replacement therapies for use in combination with the compounds of the present invention include estrogen (e.g., congugated estrogens) and estradiol.
Examples of suitable anti-obesity agents for use in combination with the compounds of the present invention include orlistat and aP2 inhibitors (such as those disclosed in WO00/59506).
Examples of suitable anti-anxiety agents for use in combination with the compounds of the present invention include diazepam, lorazepam, buspirone, and hydroxyzine pamoate. Examples of suitable anti-anxiety agents for use in combination with the compounds of the present invention include diazepam, lorazepam, buspirone, and hydroxyzine pamoate.
Examples of suitable anti-proliferative agents for use in combination with the compounds of the present invention include cyclosporin A, paclitaxel, adriamycin; epithilones, cisplatin, and carboplatin.
Examples of suitable anti-ulcer and gastroesophageal reflux disease agents for use in combination with the compounds of the present invention include famotidine, ranitidine, and omeprazole.
Administration of the compounds of the present invention (i. e., a first therapeutic agent) in combination with at least one additional therapeutic agent (i.e., a second therapeutic agent), preferably affords an efficacy advantage over the compounds and agents alone, preferably while permitting the use of lower doses of each. A lower dosage minimizes the potential of side effects, thereby providing an increased margin of safety. It is preferred that at least one of the therapeutic agents is administered in a sub-therapeutic dose. It is even more preferred that all of the therapeutic agents be administered in sub-therapeutic doses. Sub-therapeutic is intended to mean an amount of a therapeutic agent that by itself does not give the desired therapeutic effect for the condition or disease being treated. Synergistic combination is intended to mean that the observed effect of the combination is greater than the sum of the individual agents administered alone.
The compounds of the present invention are also useful as standard or reference compounds, for example as a quality standard or control, in tests or assays involving the inhibition of thrombin, Factor Vila, IXa, Xa, XIa, and/or plasma kallikrein. Such compounds may be provided in a commercial kit, for example, for use in pharmaceutical research involving thrombin, Factor Vila, IXa, Xa, XIa, and/or plasma kallikrein. XIa. For example, a compound of the present invention could be used as a reference in an assay to compare its known activity to a compound with an unknown activity. This would ensure the experimentor that the assay was being performed properly and provide a basis for comparison, especially if the test compound was a derivative of the reference compound. When developing new assays or protocols, compounds according to the present invention could be used to test their effectiveness.
The compounds of the present invention may also be used in diagnostic assays involving thrombin, Factor Vila, IXa, Xa, XIa, and/or plasma kallikrein. For example, the presence of thrombin, Factor Vila, IXa, Xa XIa, and/or plasma kallikrein in an unknown sample could be determined by addition of the relevant chromogenic substrate, for example S2366 for Factor XIa, to a series of solutions containing test sample and optionally one of the compounds of the present invention. If production of pNA is observed in the solutions containing test sample, but not in the presence of a compound of the present invention, then one would conclude Factor XIa was present.
Extremely potent and selective compounds of the present invention, those having K1 values less than or equal to 0.001 μM against the target protease and greater than or equal to 0.1 μM against the other proteases, may also be used in diagnostic assays involving the quantitation of thrombin, Factor Vila, IXa, Xa, XIa, and/or plasma kallikrein in serum samples. For example, the amount of Factor IXa in serum samples could be determined by careful titration of protease activity in the presence of the relevant chromogenic substrate, S2366, with a potent and selective Factor IXa inhibitor of the present invention.
The present invention also encompasses an article of manufacture. As used herein, article of manufacture is intended to include, but not be limited to, kits and packages. The article of manufacture of the present invention, comprises: (a) a first container; (b) a pharmaceutical composition located within the first container, wherein the composition, comprises: a first therapeutic agent, comprising: a compound of the present invention or a pharmaceutically acceptable salt form thereof; and, (c) a package insert stating that the
pharmaceutical composition can be used for the treatment of a thromboembolic and/or inflammatory disorder (as defined previously). In another embodiment, the package insert states that the pharmaceutical composition can be used in combination (as defined previously) with a second therapeutic agent to treat a thromboembolic and/or inflammatory disorder. The article of manufacture can further comprise: (d) a second container, wherein components (a) and (b) are located within the second container and component (c) is located within or outside of the second container. Located within the first and second containers means that the respective container holds the item within its boundaries. The first container is a receptacle used to hold a pharmaceutical composition. This container can be for manufacturing, storing, shipping, and/or individual/bulk selling. First container is intended to cover a bottle, jar, vial, flask, syringe, tube (e.g., for a cream preparation), or any other container used to manufacture, hold, store, or distribute a pharmaceutical product.
The second container is one used to hold the first container and, optionally, the package insert. Examples of the second container include, but are not limited to, boxes (e.g., cardboard or plastic), crates, cartons, bags (e.g., paper or plastic bags), pouches, and sacks. The package insert can be physically attached to the outside of the first container via tape, glue, staple, or another method of attachment, or it can rest inside the second container without any physical means of attachment to the first container. Alternatively, the package insert is located on the outside of the second container. When located on the outside of the second container, it is preferable that the package insert is physically attached via tape, glue, staple, or another method of attachment.
Alternatively, it can be adjacent to or touching the outside of the second container without being physically attached.
The package insert is a label, tag, marker, etc. that recites information relating to the pharmaceutical composition located within the first container. The information recited will usually be determined by the regulatory agency governing the area in which the article of manufacture is to be sold (e.g., the United States Food and Drug Administration). Preferably, the package insert specifically recites the indications for which the pharmaceutical composition has been approved. The package insert may be made of any material on which a person can read information contained therein or thereon. Preferably, the package insert is a printable material (e.g., paper, plastic, cardboard, foil, adhesive-backed paper or plastic, etc.) on which the desired information has been formed (e.g., printed or applied). Dosage and Formulation
The compounds of this invention can be administered in such oral dosage forms as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. They may also be administered in intravenous (bolus or infusion), intraperitoneal, subcutaneous, or intramuscular form, all using dosage forms well known to those of ordinary skill in the pharmaceutical arts. They can be administered alone, but generally will be administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.
The dosage regimen for the compounds of the present invention will, of course, vary depending upon known factors, such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration; the species, age, sex, health, medical condition, and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment; the frequency of treatment; the route of administration, the renal and hepatic function of the patient, and the effect desired. A physician or veterinarian can determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progress of the thromboembolic disorder. By way of general guidance, the daily oral dosage of each active ingredient, when used for the indicated effects, will range between about 0.001 to 1000 mg/kg of body weight, preferably between about 0.01 to 100 mg/kg of body weight per day, and most preferably between about 1.0 to 20 mg/kg/day.
Intravenously, the most preferred doses will range from about 1 to about 10 mg/kg/minute during a constant rate infusion. Compounds of this invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three, or four times daily. Compounds of this invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using transdermal skin patches. When administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
The compounds are typically administered in admixture with suitable pharmaceutical diluents, excipients, or carriers (collectively referred to herein as pharmaceutical carriers) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices.
For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic,
pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like; for oral administration in liquid form, the oral drug components can be combined with any oral, non-toxic,
pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents, and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.
The compounds of the present invention 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.
Compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include
polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide- phenol, polyhydroxyethylaspartamidephenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues. Furthermore, the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, and crosslinked or amphipathic block copolymers of hydrogels. Dosage forms (pharmaceutical compositions) suitable for administration may contain from about 1 milligram to about 100 milligrams of active ingredient per dosage unit. In these pharmaceutical compositions the active ingredient will ordinarily be present in an amount of about 0.5-95% by weight based on the total weight of the composition. Gelatin capsules may contain the active ingredient and powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective
disintegration in the gastrointestinal tract. Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance.
In general, water, a suitable oil, saline, aqueous dextrose (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions. Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances. Antioxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or combined, are suitable stabilizing agents. Also used are citric acid and its salts and sodium EDTA, In addition, parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl-or propyl-paraben, and chlorobutanol.
Suitable pharmaceutical carriers are described in Remington's
Pharmaceutical Sciences, Mack Publishing Company, a standard reference text in this field. Where the compounds of this invention are combined with other anticoagulant agents, for example, a daily dosage may be about 0.1 to 100 milligrams of the compound of the present invention and about 1 to 7.5 milligrams of the second anticoagulant, per kilogram of patient body weight. For a tablet dosage form, the compounds of this invention generally may be present in an amount of about 5 to 10 milligrams per dosage unit, and the second anticoagulant in an amount of about 1 to 5 milligrams per dosage unit.
Where the compounds of the present invention are administered in combination with an anti-platelet agent, by way of general guidance, typically a daily dosage may be about 0.01 to 25 milligrams of the compound of the present invention and about 50 to 150 milligrams of the anti-platelet agent, preferably about 0.1 to 1 milligrams of the compound of the present invention and about 1 to 3 milligrams of antiplatelet agents, per kilogram of patient body weight. Where the compounds of the present invention are administered in combination with thrombolytic agent, typically a daily dosage may be about 0.1 to 1 milligrams of the compound of the present invention, per kilogram of patient body weight and, in the case of the thrombolytic agents, the usual dosage of the thrombotic agent when administered alone may be reduced by about 70-80% when administered with a compound of the present invention.
Where two or more of the foregoing second therapeutic agents are administered with the compound of the present invention, generally the amount of each component in a typical daily dosage and typical dosage form may be reduced relative to the usual dosage of the agent when administered alone, in view of the additive or synergistic effect of the therapeutic agents when
administered in combination.
Particularly when provided as a single dosage unit, the potential exists for a chemical interaction between the combined active ingredients. For this reason, when the compound of Formula I and a second therapeutic agent are combined in a single dosage unit they are formulated such that although the active ingredients are combined in a single dosage unit, the physical contact between the active ingredients is minimized (that is, reduced). For example, one active ingredient may be enteric coated. By enteric coating one of the active
ingredients, it is possible not only to minimize the contact between the combined active ingredients, but also, it is possible to control the release of one of these components in the gastrointestinal tract such that one of these components is not released in the stomach but rather is released in the intestines. One of the active ingredients may also be coated with a material that affects a sustained-release throughout the gastrointestinal tract and also serves to minimize physical contact between the combined active ingredients. Furthermore, the sustained-released component can be additionally enteric coated such that the release of this component occurs only in the intestine. Still another approach would involve the formulation of a combination product in which the one component is coated with a sustained and/or enteric release polymer, and the other component is also coated with a polymer such as a low viscosity grade of hydroxypropyl
methylcellulose (HPMC) or other appropriate materials as known in the art, in order to further separate the active components. The polymer coating serves to form an additional barrier to interaction with the other component.
These as well as other ways of minimizing contact between the
components of combination products of the present invention, whether administered in a single dosage form or administered in separate forms but at the same time by the same manner, will be readily apparent to those skilled in the art, once armed with the present disclosure.
The present invention is not to be limited in scope by the specific embodiments disclosed in the examples which are intended as illustrations of a few aspects of the invention and any embodiments that are functionally equivalent are within the scope of this invention. Indeed, various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the relevant art and are intended to fall within the scope of the appended claims.
A number of references have been cited, the entire disclosures of which have been incorporated herein in their entirety.

Claims

What is claimed is:
1. A compound of Formula (I)
Figure imgf000146_0001
Formula (I)
or a pharmaceutically acceptable salt or solvate thereof, wherein;
X1 is selected from the group consisting of a covalent bond, -S- and -O-;
R1 is selected from the group consisting of halo, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein when each of said cycloalkyl, heterocyclyl, aryl and heteroaryl has substitutents on adjacent carbon atoms, said substituents can optionally be taken together with the carbon atoms to which they are attached to form a first five- or six-membered cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein when said first five- or six-membered cycloalkyl, heterocyclyl, aryl or heteroaryl has substitutents on adjacent carbon atoms, said substituents can optionally be taken together with the carbon atoms to which they are attached to form a second five- or six-membered cycloalkyl, heterocyclyl, aryl or heteroaryl;
X2 is selected from the group consisting of a covalent bond, and -O-;
R2 is selected from the group consisting of H, halogen and alkyl, with the proviso that when X2 is a covalent bond, R2 is halogen;
X3 is selected from the group consisting of a covalent bond, -N(R)- and -O-;
R is H or alkyl; R3 is selected from the group consisting of halo, alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein when each of said cycloalkyl, heterocyclyl, aryl and heteroaryl has substitutents on adjacent carbon atoms, said substituents can optionally be taken together with the carbon atoms to which they are attached to form a first five- or six-membered cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein when said first five- or six-membered cycloalkyl, heterocyclyl, aryl or heteroaryl has substitutents on adjacent carbon atoms, said substituents can optionally be taken together with the carbon atoms to which they are attached to form a second five- or six-membered cycloalkyl, heterocyclyl, aryl or heteroaryl; and
R4 is selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
with the proviso that when X1 and X3 are both -O-, then -X2-R2 is other than -halo.
2. The compound of claim 1 , wherein X2 is -O- and R2 is H or alkyl.
3. The compound of claim 1 , wherein X2 is a covalent bond, and R2 is halo.
4. The compound of claim 1 , wherein -X2R2 is selected from the group consisting of hydroxyl, methoxy, and fluoro.
5. The compound of claim 1 , wherein X1 is selected from the group consisting of a covalent bond and -O-.
6. The compound of claim 1 , wherein X1 is a covalent bond, and R1 is halo.
7. The compound of claim 1 , wherein R1 aryl is phenyl which is unsubstituted or substituted with at least one ring system substituent selected from the group consisting of halo, alkyl, haloalkyl, haloalkoxy, -C(=O)OH, and - C(=NH)NH2.
8. The compound of claim 5, wherein X1 is -O- and R1 is phenyl which is substituted with a ring system substituent selected from the group consisting of fluoro, chloro, trifluoromethyl, trifluoromethoxy, methyl, ethyl, and -C(=NH)NH2.
9. The compound of claim 1 , wherein X3 is NH, and R3 is selected from the group consisting of alkyl, cylcloalkyl, heterocyclyl, and aryl, wherein when each of said cycloalkyl, heterocyclyl, and aryl has substitutents on adjacent carbon atoms, said substituents can optionally be taken together with the carbon atoms to which they are attached to form a five- or six-membered aryl or heteroaryl.
10. The compound of claim 9, wherein R3 is alkyl which is unsubstituted or substituted with an aryl substituent, wherein when said aryl has substitutents on adjacent carbon atoms, said substituents can optionally be taken together with the carbon atoms to which they are attached to form a five- or six-membered aryl or heteroaryl.
11. The compound of claim 10, wherein R3 is alkyl-benzopyridyl, wherein the benzopyridyl is attached to the alkyl through the benzene ring of said benzopyridyl, wherein said benzopyridyl is unsubstituted or substituted with a ring system substitutent that is -NH2.
12. The compound of claim 9, wherein R3 is cycloalkyl, wherein when said cycloalkyl has substitutents on adjacent carbon atoms, said substituents can optionally be taken together with the carbon atoms to which they are attached to form a five- or six-membered aryl or heteroaryl.
13. The compound of claim 12, wherein said R3 cycloalkyl is selected from the group consisting of cyclohexyl, and thiazolyl-fused cyclohexyl, each of which unsubstituted or substituted with a ring system substituent selected from the group consisting of alkyl, -NH2, aminoalkyl-, -alkyl-NH-C(=O)O-alkyl, -NH- C(=O)O-alkyl.
14. The compound of claim 9, wherein R3 is heterocyclyl, wherein wherein when said heterocyclyl has substitutents on adjacent carbon atoms, said substituents can optionally be taken together with the carbon atoms to which they are attached to form a five- or six-membered aryl or heteroaryl.
15. The compound of claim 14, wherein said R3 heterocyclyl is piperidinyl which is unsubstituted or substituted with at least one ring system substituent that is -C(=O)-O-alkyl.
16. The compound of claim 9, wherein R3 is aryl, wherein when said aryl has substitutents on adjacent carbon atoms, said substituents can optionally be taken together with the carbon atoms to which they are attached to form a five- or six-membered cyclohexyl, aryl, or heteroaryl.
17. The compound of claim 16, wherein said R3 aryl is selected from the
group consisting of phenyl,
Figure imgf000149_0001
isoindolinyl, benzoimidazolyl, benzoxazolyl, benzopyrrolyl, benzopyrrazolyl,
Figure imgf000149_0002
each of which is independently unsubstituted or substituted with at least one ring system substituent selected from the group consisting of alkyl, aminoalkyl, -NH2, -C(=NH)NH2, cyano, halo, -C(=O)O-alkyl, alkoxy, haloalkoxy, heteroaryl, hydroxyl, and -C(=O)NH2, and wherein
Figure imgf000149_0003
indicates the point of attachment of the R3 aryl.
18. The compound of claim 1 , wherein X3 is a covalent bond, and R is heteroaryl, wherein when said heteroaryl has substitutents on adjacent carbon atoms, said substituents can optionally be taken together with the carbon atoms to which they are attached to form a five- or six-membered aryl or heteroaryl.
19. The compound of claim 18, wherein said R3 heteroaryl is selected benzopyrrolidinyl which is unsubstituted or substituted with at least one ring system substituent selected from the group consisting of cyano, alkyl, and aminoalkyk
20. The compound of claim 1 , wherein X3 is a covalent bond, and R3 is halo.
21. The compound of claim 1 , wherein X1 and X3 are both -O-, and R1 and R3 are both H or aryl.
22. The compound of claim 1 , wherein R4 is alkyl and is f-butyl.
23. The compound of claim 1 , wherein R4 is cycloalkyl and is selected from the group consisting of cyclopropyl and cyclohexyl.
24. The compound of claim 1 , wherein R4 is aryl and is phenyl.
25. The compound of claim 1 , selected from the group consisting of:
Figure imgf000150_0001
Figure imgf000151_0001
Figure imgf000152_0001
Figure imgf000153_0001
ı52
Figure imgf000154_0001
Figure imgf000155_0001
and or a pharmaceutically acceptable salt or solvate thereof.
26. A pharmaceutical composition comprising at least one compound of claim 1 , or a pharmaceutically acceptable salt, solvate or ester thereof and at least one pharmaceutically acceptable carrier.
27. A method of treating a disorder or disease mediated by factor IXa, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or ester thereof.
28. A method for treating a thromboembolic disorder, comprising:
administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt, solvate, or ester thereof.
29. The method of claim 28, wherein the thromboembolic disorder is selected from the group consisting of arterial cardiovascular thromboembolic disorders, venous cardiovascular thromboembolic disorders, and
thromboembolic disorders in the chambers of the heart.
30. The method of claim 29, wherein the thromboembolic disorder is selected from unstable angina, an acute coronary syndrome, atrial fibrillation, first myocardial infarction, recurrent myocardial infarction, ischemic sudden death, transient ischemic attack, stroke, atherosclerosis, peripheral occlusive arterial disease, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary arterial thrombosis, cerebral arterial thrombosis, cerebral embolism, kidney embolism, pulmonary embolism, and thrombosis resulting from (a) prosthetic valves or other implants, (b) indwelling catheters, (c) stents, (d) cardiopulmonary bypass, (e) hemodialysis, or (f) other procedures in which blood is exposed to an artificial surface that promotes thrombosis.
31. The method of claim 29, further comprising administering to said patient an anticoagulant agent(s) independently selected from a group consisting of a thrombin inhibitor, a thrombin receptor (PAR-1 ) antagonist, a factor IXa inhibitor different from the compound of claim 1 , a factor Vila inhibitor, factor Villa inhibitor, a factor Xa inhibitor, Aspirin®, and Plavix®.
32. The method of claim 31 , wherein said factor IX a inhibitor is selected from the group consisting of monoclonal antibodies, synthetic active site-blocked competitive inhibitors, oral inhibitors, and RNA aptamers.
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