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WO2025160190A1 - Composés inhibiteurs thérapeutiques - Google Patents

Composés inhibiteurs thérapeutiques

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Publication number
WO2025160190A1
WO2025160190A1 PCT/US2025/012612 US2025012612W WO2025160190A1 WO 2025160190 A1 WO2025160190 A1 WO 2025160190A1 US 2025012612 W US2025012612 W US 2025012612W WO 2025160190 A1 WO2025160190 A1 WO 2025160190A1
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WO
WIPO (PCT)
Prior art keywords
optionally substituted
pharmaceutically acceptable
compound
acceptable salt
methyl
Prior art date
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Pending
Application number
PCT/US2025/012612
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English (en)
Inventor
Andrew I. Mcdonald
Shawn QIAN
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Retune Pharma Inc
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Retune Pharma Inc
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Application filed by Retune Pharma Inc filed Critical Retune Pharma Inc
Publication of WO2025160190A1 publication Critical patent/WO2025160190A1/fr
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Anticipated expiration legal-status Critical

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Classifications

    • 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
    • C07D401/14—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 three or more hetero rings
    • 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
    • A61P7/10—Antioedematous agents; Diuretics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • 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
    • C07D401/06—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 carbon chain containing only aliphatic carbon atoms
    • 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
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • diseases and disorders include, but are not limited to, angioedema, macular edema and brain edema.
  • heterocyclic derivative compounds and pharmaceutical compositions comprising said compounds.
  • the subject compounds and compositions are useful for inhibiting plasma kallikrein.
  • One embodiment provides a compound, or a pharmaceutically acceptable salt thereof, having the structure of Formula (I): wherein,
  • Ring A is 1,3-disubstituted pyridine or 1,3-disubstituted, 5-membered heteroaryl;
  • R 1 is hydrogen, halo, cyano, or optionally substituted C1-C5 alkyl
  • R 3 is hydrogen, cyano, C1-C3 optionally substituted alkoxy, or optionally substituted C1-C5 alkyl;
  • R 4 and R 5 are independently hydrogen, cyano, halo, hydroxy, C1-C3 optionally substituted alkoxy, or optionally substituted C1-C5 alkyl;
  • R 6 and R 7 are independently hydrogen, or optionally substituted C1-C5 alkyl
  • XI is G, or *J-CH2-K, wherein the * denotes attachment to -C(R 4 )(R 5 )-Ring A;
  • G is optionally substituted bicyclic heteroaryl ring
  • W is independently N, C-H, or C-F;
  • X is independently N, C-H, or C-F;
  • Y is independently N, C-H, or C-F;
  • Z is independently N, C-H, or C-F
  • K is selected from optionally substituted oxopyrimidinyl, or optionally substituted oxopyridinyl.
  • One embodiment provides a compound of Formula (I), or pharmaceutically acceptable salt thereof, having the structure of Formula (la): wherein,
  • Ring A is 1,3-disubstituted pyridine or 1,3-disubstituted, 5-membered heteroaryl;
  • R 1 is hydrogen, halogen, cyano, or optionally substituted C1-C5 alkyl
  • R 2 is hydrogen, cyano, optionally substituted C1-C5 alkyl, or C1-C3 optionally substituted alkoxy;
  • R 3 is hydrogen, cyano, C1-C3 optionally substituted alkoxy, or optionally substituted C1-C5 alkyl;
  • R 4 and R 5 are independently hydrogen, cyano, halo, hydroxy, C1-C3 optionally substituted alkoxy, or optionally substituted C1-C5 alkyl;
  • XI is G, or *J-CH2-K, wherein the * denotes attachment to -C(R 4 )(R 5 )-Ring A;
  • G is optionally substituted bicyclic heteroaryl ring
  • W is independently N, C-H, or C-F;
  • X is independently N, C-H, or C-F;
  • Y is independently N, C-H, or C-F;
  • Z is independently N, C-H, or C-F
  • K is selected from optionally substituted oxopyrimidinyl, or optionally substituted oxopyridinyl.
  • One embodiment provides a method of treating angioedema, including hereditary and non- hereditary, or macular edema, including diabetic macular edema, in a patient in need thereof, comprising administering to the patient a compound of Formula (I) or (la), or a pharmaceutically acceptable salt or solvate thereof.
  • One embodiment provides a method of prophylaxis to prevent attacks of angioedema in a patient in need thereof, the method comprising administering to the patient a compound as described in Formula (I) or (la), or a pharmaceutically acceptable salt thereof.
  • Amino refers to the -NH2 radical.
  • Cyano refers to the -CN radical.
  • Niro refers to the -NO2 radical.
  • Oxa refers to the -O- radical.
  • Alkyl refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to fifteen carbon atoms (e.g., C1-C15 alkyl).
  • an alkyl comprises one to thirteen carbon atoms (e.g., C1-C13 alkyl).
  • an alkyl comprises one to eight carbon atoms (e.g., Ci- Cs alkyl).
  • an alkyl comprises one to five carbon atoms (e.g., C1-C5 alkyl).
  • an alkyl comprises one to four carbon atoms (e.g., C1-C4 alkyl). In other embodiments, an alkyl comprises one to three carbon atoms (e.g., C1-C3 alkyl). In other embodiments, an alkyl comprises one to two carbon atoms (e.g., C1-C2 alkyl). In other embodiments, an alkyl comprises one carbon atom (e.g., Ci alkyl). In other embodiments, an alkyl comprises five to fifteen carbon atoms (e.g., C5-C15 alkyl). In other embodiments, an alkyl comprises five to eight carbon atoms (e.g., Cs-Cs alkyl).
  • an alkyl comprises two to five carbon atoms (e.g., C2-C5 alkyl). In other embodiments, an alkyl comprises three to five carbon atoms (e.g., C3-C5 alkyl).
  • the alkyl group is selected from methyl, ethyl, 1 -propyl (zz-propyl), 1 -methylethyl (z.w-propyl), 1 -butyl (zz-butyl), 1 -methylpropyl ( ec-butyl), 2-methylpropyl (z.w-butyl), 1,1 -dimethylethyl (tert-butyl), 1 -pentyl (zz-pentyl).
  • alkyl is attached to the rest of the molecule by a single bond.
  • an alkyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR a , -SIU, -OC(O)-R a , -N(R a ) 2 , -C(O)R a , -C(O)OR a , -C(O)N(R a ) 2 , - N(R a )C(O)OR a , -OC(O)-N(R a ) 2 , -N(R a )C(O)R a , -N(R a )S(O) t R a (where t is 1 or 2), -S(O)tOR a (where t is 1 or 2), -
  • an optionally substituted alkyl is a haloalkyl. In other embodiments, an optionally substituted alkyl is a fluoroalkyl. In other embodiments, an optionally substituted alkyl is a -CF3 group.
  • Alkoxy refers to a radical bonded through an oxygen atom of the formula -O-alkyl, where alkyl is an alkyl chain as defined above.
  • alkenyl refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and having from two to twelve carbon atoms. In certain embodiments, an alkenyl comprises two to eight carbon atoms. In other embodiments, an alkenyl comprises two to four carbon atoms. The alkenyl is attached to the rest of the molecule by a single bond, for example, ethenyl (z.e., vinyl), prop-l-enyl (z.e., allyl), but-l-enyl, pent-l-enyl, penta- 1,4-dienyl, and the like.
  • an alkenyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR a , -SIU, -OC(O)-R a , -N(R a ) 2 , -C(O)R a , -C(O)OR a , -C(O)N(R a ) 2 , - N(R a )C(O)OR a , -OC(O)-N(R a ) 2 , -N(R a )C(O)R a , -N(R a )S(O) t R a (where t is 1 or 2), -S(O)tOR a (where t is 1 or 2), -S(O)tOR a (where t is 1 or 2), -
  • Alkynyl refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, having from two to twelve carbon atoms.
  • an alkynyl comprises two to eight carbon atoms.
  • an alkynyl comprises two to six carbon atoms.
  • an alkynyl comprises two to four carbon atoms.
  • the alkynyl is attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.
  • an alkynyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR a , -SR a , -OC(O)-R a , -N(R a ) 2 , -C(O)R a , -C(O)OR a , - C(O)N(R a ) 2 , -N(R a )C(O)OR a , -OC(O)-N(R a ) 2 , -N(R a )C(O)R a , -N(R a )S(O)tR a (where t is 1 or 2), -S(O)tOR a (where t is 1 or 2), -S(O)tOR a (where t is 1 or 2),
  • Alkylene or "alkylene chain” refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing no unsaturation, and having from one to twelve carbon atoms, for example, methylene, ethylene, propylene, ⁇ -butylene, and the like.
  • the alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond.
  • the points of attachment of the alkylene chain to the rest of the molecule and to the radical group are through one carbon in the alkylene chain or through any two carbons within the chain.
  • an alkylene comprises one to eight carbon atoms (e.g., Ci-Cs alkylene). In other embodiments, an alkylene comprises one to five carbon atoms (e.g., C1-C5 alkylene). In other embodiments, an alkylene comprises one to four carbon atoms (e.g., C1-C4 alkylene). In other embodiments, an alkylene comprises one to three carbon atoms (e.g., C1-C3 alkylene). In other embodiments, an alkylene comprises one to two carbon atoms (e.g., C1-C2 alkylene). In other embodiments, an alkylene comprises one carbon atom (e.g., Ci alkylene).
  • an alkylene comprises five to eight carbon atoms (e.g., Cs-Cs alkylene). In other embodiments, an alkylene comprises two to five carbon atoms (e.g., C2-C5 alkylene). In other embodiments, an alkylene comprises three to five carbon atoms (e.g., C3-C5 alkylene).
  • an alkylene chain is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR a , - SR a , -OC(O)-R a , -N(R a ) 2 , -C(O)R a , -C(O)OR a , -C(O)N(R a ) 2 , -N(R a )C(O)OR a , -OC(O)-N(R a ) 2 , - N(R a )C(O)R a , -N(R a )S(O)tR a (where t is 1 or 2), -S(O)tOR a (where t is 1 or 2), -S(O)tOR a (where t is 1 or 2),
  • alkenylene or "alkenylene chain” refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon double bond, and having from two to twelve carbon atoms.
  • the alkenylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond.
  • an alkenylene comprises two to eight carbon atoms (e.g., C2-C8 alkenylene).
  • an alkenylene comprises two to five carbon atoms (e.g., C2-C5 alkenylene).
  • an alkenylene comprises two to four carbon atoms (e.g., C2-C4 alkenylene). In other embodiments, an alkenylene comprises two to three carbon atoms (e.g., C2-C3 alkenylene). In other embodiments, an alkenylene comprises two carbon atoms (e.g., C2 alkenylene). In other embodiments, an alkenylene comprises five to eight carbon atoms (e.g., Cs-Cs alkenylene). In other embodiments, an alkenylene comprises three to five carbon atoms (e.g., C3-C5 alkenylene).
  • an alkenylene chain is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR a , -SIU, -OC(O)-R a , -N(R a ) 2 , -C(O)R a , -C(O)OR a , -C(O)N(R a ) 2 , - N(R a )C(O)OR a , -OC(O)-N(R a ) 2 , -N(R a )C(O)R a , -N(R a )S(O) t R a (where t is 1 or 2), -S(O)tOR a (where t is 1 or 2), -S(O)tOR a (where t is 1 or 2), -
  • Alkynylene or “alkynylene chain” refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon triple bond, and having from two to twelve carbon atoms.
  • the alkynylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond.
  • an alkynylene comprises two to eight carbon atoms (e.g., C2-C8 alkynylene).
  • an alkynylene comprises two to five carbon atoms (e.g., C2-C5 alkynylene).
  • an alkynylene comprises two to four carbon atoms (e.g., C2-C4 alkynylene). In other embodiments, an alkynylene comprises two to three carbon atoms (e.g., C2-C3 alkynylene). In other embodiments, an alkynylene comprises two carbon atoms (e.g., C2 alkynylene). In other embodiments, an alkynylene comprises five to eight carbon atoms (e.g., Cs-Cs alkynylene). In other embodiments, an alkynylene comprises three to five carbon atoms (e.g., C3-C5 alkynylene).
  • an alkynylene chain is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethyl silanyl, -OR a , -SIU, -OC(O)-R a , -N(R a ) 2 , -C(O)R a , -C(O)OR a , -C(O)N(R a ) 2 , - N(R a )C(O)OR a , -OC(O)-N(R a ) 2 , -N(R a )C(O)R a , -N(R a )S(O) t R a (where t is 1 or 2), -S(O)tOR a (where t is 1 or 2), -S(O)tOR a (where t is 1 or 2),
  • Aryl refers to a radical derived from an aromatic monocyclic or multicyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom.
  • the aromatic monocyclic or multicyclic hydrocarbon ring system contains only hydrogen and carbon from five to eighteen carbon atoms, where at least one of the rings in the ring system is fully unsaturated, z.e., it contains a cyclic, delocalized (4n+2) ⁇ -electron system in accordance with the Huckel theory.
  • the ring system from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin and naphthalene.
  • aryl or the prefix “ar-” (such as in “aralkyl”) is meant to include aryl radicals optionally substituted by one or more substituents independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, halo, cyano, nitro, -R b -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)-N(R a ) 2 , -R b -N(R a ) 2 , - R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a ) 2 , -R b -O-R c -C(O)N(R a
  • Aralkyl refers to a radical of the formula -R c -aryl where R c is an alkylene chain as defined above, for example, methylene, ethylene, and the like.
  • the alkylene chain part of the aralkyl radical is optionally substituted as described above for an alkylene chain.
  • the aryl part of the aralkyl radical is optionally substituted as described above for an aryl group.
  • alkenyl refers to a radical of the formula -R d -aryl where R d is an alkenylene chain as defined above.
  • the aryl part of the aralkenyl radical is optionally substituted as described above for an aryl group.
  • the alkenylene chain part of the aralkenyl radical is optionally substituted as defined above for an alkenylene group.
  • Aralkynyl refers to a radical of the formula -R e -aryl, where R e is an alkynylene chain as defined above.
  • the aryl part of the aralkynyl radical is optionally substituted as described above for an aryl group.
  • the alkynylene chain part of the aralkynyl radical is optionally substituted as defined above for an alkynylene chain.
  • Aralkoxy refers to a radical bonded through an oxygen atom of the formula -O-R c -aryl where R c is an alkylene chain as defined above, for example, methylene, ethylene, and the like.
  • R c is an alkylene chain as defined above, for example, methylene, ethylene, and the like.
  • the alkylene chain part of the aralkyl radical is optionally substituted as described above for an alkylene chain.
  • the aryl part of the aralkyl radical is optionally substituted as described above for an aryl group.
  • Carbocyclyl refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which includes fused or bridged ring systems, having from three to fifteen carbon atoms.
  • a carbocyclyl comprises three to ten carbon atoms.
  • a carbocyclyl comprises five to seven carbon atoms.
  • the carbocyclyl is attached to the rest of the molecule by a single bond. Carbocyclyl is saturated (z.e., containing single C-C bonds only) or unsaturated (z.e., containing one or more double bonds or triple bonds).
  • a fully saturated carbocyclyl radical is also referred to as "cycloalkyl.”
  • monocyclic cycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • An unsaturated carbocyclyl is also referred to as "cycloalkenyl.”
  • Examples of monocyclic cycloalkenyls include, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.
  • Polycyclic carbocyclyl radicals include, for example, adamantyl, norbornyl (z.e., bicyclo[2.2.1]heptanyl), norbomenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like.
  • carbocyclyl is meant to include carbocyclyl radicals that are optionally substituted by one or more substituents independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, halo, oxo, thioxo, cyano, nitro, -R b -0R a , -R b -0C(0)-R a , -R b -0C(0)-0R a , -R b -0C(0)-0R a , -R b -0C(0)-N(R a ) 2 , -R b - N(R a ) 2 , -R b -C(0)R a , -R b -C(0)0R a , -R b -C(0)N(R a ) 2 , -R b -0-R c -C(0)N(R a ) 2
  • Carbocyclylalkyl refers to a radical of the formula -R c -carbocyclyl where R c is an alkylene chain as defined above. The alkylene chain and the carbocyclyl radical is optionally substituted as defined above.
  • Carbocyclylalkynyl refers to a radical of the formula -R c -carbocyclyl where R c is an alkynylene chain as defined above. The alkynylene chain and the carbocyclyl radical is optionally substituted as defined above.
  • Carbocyclylalkoxy refers to a radical bonded through an oxygen atom of the formula -O- R c -carbocyclyl where R c is an alkylene chain as defined above.
  • R c is an alkylene chain as defined above.
  • the alkylene chain and the carbocyclyl radical is optionally substituted as defined above.
  • Halo or "halogen” refers to bromo, chloro, fluoro or iodo substituents.
  • Fluoroalkyl refers to an alkyl radical, as defined above, that is substituted by one or more fluoro radicals, as defined above, for example, trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, l-fluoromethyl-2-fluoroethyl, and the like.
  • the alkyl part of the fluoroalkyl radical is optionally substituted as defined above for an alkyl group.
  • Heterocyclyl refers to a stable 3- to 18-membered non-aromatic ring radical that comprises two to twelve carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur. Unless stated otherwise specifically in the specification, the heterocyclyl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which optionally includes fused or bridged ring systems. The heteroatoms in the heterocyclyl radical are optionally oxidized. One or more nitrogen atoms, if present, are optionally quatemized. The heterocyclyl radical is partially or fully saturated. The heterocyclyl is attached to the rest of the molecule through any atom of the ring(s).
  • heterocyclyl radicals include, but are not limited to, dioxolanyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thio
  • heterocyclyl is meant to include heterocyclyl radicals as defined above that are optionally substituted by one or more substituents selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, - R b -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)-N(R a ) 2 , -R b -N(R a ) 2 , -R b -C(O)R a , -R b - C(O)OR a , -R b -C(O)N(R a ) 2 , -R b -O-R c -
  • A-heterocyclyl or “N-attached heterocyclyl” refers to a heterocyclyl radical as defined above containing at least one nitrogen and where the point of attachment of the heterocyclyl radical to the rest of the molecule is through a nitrogen atom in the heterocyclyl radical.
  • An ⁇ '-heterocyclyl radical is optionally substituted as described above for heterocyclyl radicals.
  • Examples of such A-heterocyclyl radicals include, but are not limited to, 1-morpholinyl, 1- piperidinyl, 1-piperazinyl, 1-pyrrolidinyl, pyrazolidinyl, and imidazolidinyl.
  • C-heterocyclyl or “C-attached heterocyclyl” refers to a heterocyclyl radical as defined above containing at least one heteroatom and where the point of attachment of the heterocyclyl radical to the rest of the molecule is through a carbon atom in the heterocyclyl radical.
  • a C-heterocyclyl radical is optionally substituted as described above for heterocyclyl radicals.
  • C-heterocyclyl radicals include, but are not limited to, 2-morpholinyl, 2- or 3- or 4-piperidinyl, 2-piperazinyl, 2- or 3-pyrrolidinyl, and the like.
  • Heterocyclylalkyl refers to a radical of the formula -R c -heterocyclyl where R c is an alkylene chain as defined above. If the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl is optionally attached to the alkyl radical at the nitrogen atom.
  • the alkylene chain of the heterocyclylalkyl radical is optionally substituted as defined above for an alkylene chain.
  • the heterocyclyl part of the heterocyclylalkyl radical is optionally substituted as defined above for a heterocyclyl group.
  • Heterocyclylalkoxy refers to a radical bonded through an oxygen atom of the formula -O- R c -heterocyclyl where R c is an alkylene chain as defined above. If the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl is optionally attached to the alkyl radical at the nitrogen atom.
  • the alkylene chain of the heterocyclylalkoxy radical is optionally substituted as defined above for an alkylene chain.
  • the heterocyclyl part of the heterocyclylalkoxy radical is optionally substituted as defined above for a heterocyclyl group.
  • Heteroaryl refers to a radical derived from a 3 - to 18-membered aromatic ring radical that comprises two to seventeen carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the heteroaryl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, wherein at least one of the rings in the ring system is fully unsaturated, z.e., it contains a cyclic, delocalized (4n+2) ⁇ -electron system in accordance with the Hiickel theory.
  • Heteroaryl includes fused or bridged ring systems.
  • the heteroatom(s) in the heteroaryl radical is optionally oxidized.
  • heteroaryl is attached to the rest of the molecule through any atom of the ring(s).
  • heteroaryls include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[Z>][l,4]dioxepinyl, benzo[b][l,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodi oxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl
  • heteroaryl is meant to include heteroaryl radicals as defined above which are optionally substituted by one or more substituents selected from optionally substituted alkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclylalkyl, optionally substituted alkenyl, optionally substituted alkynyl, halo, optionally substituted fluoroalkyl, optionally substituted haloalkenyl, optionally substituted haloalkynyl, oxo, thioxo, cyano, nitro, -R b -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , - R b -OC(O)-N(R a ) 2 , -R b -N(R a ) 2 , -R b -C(O)R a
  • A-heteroaryl refers to a heteroaryl radical as defined above containing at least one nitrogen and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a nitrogen atom in the heteroaryl radical.
  • An A-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.
  • C-heteroaryl refers to a heteroaryl radical as defined above and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a carbon atom in the heteroaryl radical.
  • a C-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.
  • Heteroarylalkyl refers to a radical of the formula -R c -heteroaryl, where R c is an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heteroaryl alkyl radical is optionally substituted as defined above for an alkylene chain. The heteroaryl part of the heteroarylalkyl radical is optionally substituted as defined above for a heteroaryl group.
  • Heteroarylalkoxy refers to a radical bonded through an oxygen atom of the formula -O- R c -heteroaryl, where R c is an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom.
  • the alkylene chain of the heteroarylalkoxy radical is optionally substituted as defined above for an alkylene chain.
  • the heteroaryl part of the heteroaryl alkoxy radical is optionally substituted as defined above for a heteroaryl group.
  • the compounds disclosed herein in some embodiments, contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that are defined, in terms of absolute stereochemistry, as (R)- or (5 -. Unless stated otherwise, it is intended that all stereoisomeric forms of the compounds disclosed herein are contemplated by this disclosure. When the compounds described herein contain alkene double bonds, and unless specified otherwise, it is intended that this disclosure includes both E and Z geometric isomers (e.g., cis or trans.) Likewise, all possible isomers, as well as their racemic and optically pure forms, and all tautomeric forms are also intended to be included.
  • geometric isomer refers to E or Z geometric isomers (e.g., cis or trans) of an alkene double bond.
  • positional isomer refers to structural isomers around a central ring, such as ortho-, meta-, and para- isomers around a benzene ring.
  • a "tautomer” refers to a molecule wherein a proton shift from one atom of a molecule to another atom of the same molecule is possible.
  • the compounds disclosed herein are used in different enriched isotopic forms, e.g., enriched in the content of 2 H, 3 H, n C, 13 C and/or 14 C.
  • the compound is deuterated in at least one position.
  • deuterated forms can be made by the procedure described in, for example, U.S. Patent Nos. 5,846,514 and 6,334,997.
  • deuteration can, in some instances, improve the metabolic stability and or efficacy, thus increasing the duration of action of drugs.
  • structures depicted herein are intended to include compounds which differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by 13 C- or 14 C-enriched carbon are within the scope of the present disclosure.
  • the compounds of the present disclosure optionally contain unnatural proportions of atomic isotopes at one or more atoms that constitute such compounds.
  • the compounds may be labeled with isotopes, such as for example, deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C).
  • isotopes such as for example, deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C).
  • Isotopic substitution with 2 H, n C, 13 C, 14 C, 15 C, 12 N, 13 N, 15 N, 16 N, 16 O, 1 7 O, 14 F, 15 F, 16 F, 17 F, 18 F, 33 S, 34 S, 35 S, 36 S, 35 C1, 37 C1, 79 Br, 81 Br, 125 I are all contemplated.
  • isotopic substitution with 18 F is contemplated. All isotopic variations of the compounds of the present invention, whether radio
  • the compounds disclosed herein have some or all of the J H atoms replaced with 2 H atoms.
  • the methods of synthesis for deuterium-containing compounds are known in the art and include, by way of non-limiting example only, the following synthetic methods.
  • Deuterium substituted compounds are synthesized using various methods such as described in: Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [Curr., Pharm. Des., 2000; 6(10)] 2000, 110 pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32.
  • Deuterated starting materials are readily available and are subjected to the synthetic methods described herein to provide for the synthesis of deuterium-containing compounds.
  • Large numbers of deuterium-containing reagents and building blocks are available commercially from chemical vendors, such as Aldrich Chemical Co.
  • CD3I iodomethane-ds
  • LiAlD4 lithium aluminum deuteride
  • Deuterium gas and palladium catalyst are employed to reduce unsaturated carbon-carbon linkages and to perform a reductive substitution of aryl carbon-halogen bonds as illustrated, by way of example only, in the reaction schemes below.
  • the compounds disclosed herein contain one deuterium atom. In another embodiment, the compounds disclosed herein contain two deuterium atoms. In another embodiment, the compounds disclosed herein contain three deuterium atoms. In another embodiment, the compounds disclosed herein contain four deuterium atoms. In another embodiment, the compounds disclosed herein contain five deuterium atoms. In another embodiment, the compounds disclosed herein contain six deuterium atoms. In another embodiment, the compounds disclosed herein contain more than six deuterium atoms. In another embodiment, the compound disclosed herein is fully substituted with deuterium atoms and contains no non-exchangeable J H hydrogen atoms. In one embodiment, the level of deuterium incorporation is determined by synthetic methods in which a deuterated synthetic building block is used as a starting material.
  • “Pharmaceutically acceptable salt” includes both acid and base addition salts.
  • a pharmaceutically acceptable salt of any one of the kallikrein inhibitory compounds described herein is intended to encompass any and all pharmaceutically suitable salt forms.
  • Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
  • “Pharmaceutically acceptable acid addition salt” refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like.
  • salts that are formed with organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and. aromatic sulfonic acids, etc.
  • acetic acid trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.
  • Exemplary salts thus include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinate suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, and the like.
  • Acid addition salts of basic compounds are, in some embodiments, prepared by contacting the free base forms with a sufficient amount of the desired acid to produce the salt according to methods and techniques with which a skilled artisan is familiar.
  • “Pharmaceutically acceptable base addition salt” refers to those salts that retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. Pharmaceutically acceptable base addition salts are, in some embodiments, formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like.
  • Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N,N- dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, 7V-methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. See Berge et al
  • solvates refers to a composition of matter that is the solvent addition form.
  • solvates contain either stoichiometric or non- stoichiometric amounts of a solvent, and are formed during the process of making with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of compounds described herein are conveniently prepared or formed during the processes described herein. The compounds provided herein exist in either unsolvated or solvated forms.
  • subject or “patient” encompasses mammals.
  • mammals include, but are not limited to, any member of the Mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like.
  • the mammal is a human.
  • treatment or “treating,” or “palliating” or “ameliorating” are used interchangeably. These terms refer to an approach for obtaining beneficial or desired results including but not limited to therapeutic benefit and/or a prophylactic benefit.
  • therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated.
  • a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient is still afflicted with the underlying disorder.
  • the compositions are, in some embodiments, administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease has not been made.
  • vascular permeability is important in regulating the passage of small molecules or blood cells between blood vessels and surrounding tissues.
  • Vascular permeability depends upon the physiological states of tissues such as during inflammation, changes in blood pressure, and fluctuations in ion and nutrient gradients.
  • the junctions between the endothelial cells that line blood vessels are the immediate controllers of vascular permeability.
  • the strength of these junctions is tightly regulated by the kinin-kallikrein system of polypeptides and enzymes. Abnormalities in the kinin-kallikrein system lead to a range of pathologies including angioedema, macular edema and brain edema.
  • Angioedema is a potentially fatal blood disorder characterized by swelling that may occur in the face, gastrointestinal tract, extremities, genitals and upper airways. Genetic hereditary angioedema attacks result from the unregulated activation of the kallikrein system with uncontrolled increases in vascular permeability. Currently there is a need for agents that are useful for the treatment of angioedema and for agents that inhibit plasma kallikrein.
  • the kallikrein-kinin system represents a metabolic cascade that, when activated, triggers the release of vasoactive kinins.
  • the kinin-kallikrein system (KKS) consists of serine proteases involved in the production of kinins, principally bradykinin and Lys-bradykinin (kallidin).
  • the KKS contributes to a variety of physiological processes including inflammation, blood pressure control and coagulation.
  • the activation of this system is particularly important in blood pressure regulation and in inflammatory reactions, due to the ability of bradykinin to elevate vascular permeability and to cause vasodilatation of arteries and veins of the gut, aorta, uterus and urethra.
  • the kinin-kallikrein system also referred to as the contact system, consists of three serine proenzymes (factor XII (FXII) or Hageman factor, factor IX (FIX), and prekallikrein), and the kinin precursor high molecular weight kinin (HK).
  • FXII factor XII
  • FIX factor IX
  • HK kinin precursor high molecular weight kinin
  • Kallikrein can further convert a-FXIIa to P-FXIIa by an additional cleavage at R334-N335, a positive feedback mechanism that leads to sufficient kallikrein production to drive downstream processes.
  • a-FXIIa consists of a heavy and light chain that are disulphide linked, whereas P-FXIIa lacks the heavy chain and loses its capacity to bind to negatively charged surfaces (Stavrou E, Schmaier AH., Thrombosis Research, 2010, 125(3) pp. 210-215).
  • FXIIa heavy chain shows strong homology with tissue-type plasminogen activator (tPA), with the presence of fibronectin type I, epidermal growth factor, and Kringle domains (Ny et al., Proc Natl Acad Sci USA, 1984, 81(17) pp. 5355-5359; Cool DE, MacGillivray RT, The Journal of Biological Chemistry, 1987, 262(28) pp. 13662-13673).
  • Kallikrein is a trypsin-like serine protease enzyme that cleaves high molecular weight kinin (HK) to produce bradykinin. Bradykinin then binds to the bradykinin 2R receptors (BK2R) on endothelial cells to trigger an increase in vascular permeability.
  • Protease inhibitors regulate the activation of the contact system.
  • Several known serpins of plasma are Cl-inhibitor (CHNH), antithrombin III, a2 -macroglobulin, al-protease inhibitor, and a2-antiplasmin (Kaplan et al., Advances in Immunology, 1997 (66) pp.225-72; Pixley et al., The Journal of Biological Chemistry, 1985, 260(3) pp. 1723-9).
  • CHNH is the major regulator of the intrinsic system, interfering with the activities of factor Xlla and of kallikrein (Cugno et al., The Journal of Laboratory and Clinical Medicine, 1993, 121(1) pp. 38-43).
  • Both CHNH and a2 -macroglobulin account for more than 90% of the kallikrein inhibitory activity of plasma.
  • the FXII-dependent kallikrein-kinin system is tightly regulated by the CINH and when regulation of the FXII-dependent kallikrein-kinin system fails, in a subject, the subject is believed to suffer from hereditary angioedema (HAE) that is characterized by invalidating edema attacks.
  • HAE hereditary angioedema
  • Angioedema is a potentially fatal blood disorder characterized by swelling that may occur in the face, gastrointestinal tract, extremities, genitals and upper airways. Angioedema attacks begin in the deeper layers of the skin and mucous membranes with localized blood vessel dilatation and increased permeability. Symptoms of the disease result from the leakage of plasma from blood vessels into surrounding tissues. Genetic hereditary angioedema attacks result from unregulated activation of the kallikrein system with consequent overproduction of bradykinin and uncontrolled increases in vascular permeability. As vascular permeability rises beyond normal, plasma leaks out of the vasculature into surrounding tissue, causing swelling (Mehta D and Malik AB, Physiol.
  • HAE results from mutations in the genes that code for elements of the coagulation and inflammation pathways.
  • the three forms of HAE are distinguished by their underlying causes and levels of the Cl -esterase inhibitor (Cl INH, serpin peptidase inhibitor, clade G, member 1) protein in the blood, which inhibits the activity of plasma kallikrein.
  • Cl -esterase inhibitor Cl INH, serpin peptidase inhibitor, clade G, member 1
  • type I patients have insufficient levels of functional CHNH
  • type II patients have dysfunctional CHNH.
  • type I and II affect men and women at equal rates
  • type III which primarily affects women, results from a mutation in coagulation factor XII (Hageman factor; HAE-FXII).
  • the underlying causes of type I and II HAE are autosomal dominant mutations in CHNH gene (SERPING1 gene) on chromosome 11 (1 Iql2-ql3.1).
  • CHNH accounts for 90% of inhibition of FXIIa and 50% of inhibition of plasma kallikrein (Pixley RA et al., J. Biol. Chem., 260, 1723-9, 1985; Schapira M et al., Biochemistry, 20, 2738- 43, 1981).
  • CHNH also inactivates prekallikrein (Colman RW et al, Blood, 65, 311- 8, 1985).
  • CHNH levels are normal, its activity blocks FXIIa from converting prekallikrein to kallikrein and blocks kallikrein's conversion to HK, thus preventing the production of bradykinin and the edemic episodes.
  • CHNH levels are low, or levels of dysfunctional CHNH are high, this inhibition fails and the pathogenic process ensues.
  • plasma kallikrein also contributes to non-hereditary angioedema, high altitude cerebral edema, cytotoxic cerebral edema, osmotic cerebral edema, diabetic macular edema (DME), clinically significant macular edema, cystoid macular edema (CME, Gao BB, Nat Med., 13(2), 181-8, 2007), retinal edema, radiation induced edema, lymph edema, glioma- associated edema, allergic edema e.g. airflow obstruction in chronic allergic sinusitis or perennial rhinitis.
  • retinopathy and diabetic retinopathy include retinopathy and diabetic retinopathy (Liu J and Feener EP, Biol. Chem. 394(3), 319-28, 2013), proliferative and non-proliferative retinopathy (Liu J et al, Invest. Ophthalmol. Vis.
  • CME following cataract extraction
  • CME induced by cryotherapy CME induced by uveitis
  • CME following vascular occlusion e.g., central retinal vein occlusion, branch retinal vein occlusion or hemiretinal vein occlusion
  • complications related to cataract surgery in diabetic retinopathy hypertensive retinopathy (JA Phillips et al., Hypertension, 53, 175-181, 2009)
  • retinal trauma dry and wet age-related macular degeneration (AMD), ischemic reperfusion injuries (C Storoni et al., JPET, 381, 849-954, 2006), e.g., in a variety of contexts associated with tissue and/or organ transplantation.
  • AMD age-related macular degeneration
  • ischemic reperfusion injuries C Storoni et al., JPET, 381, 849-954, 2006
  • kallikrein inhibitors inactivate both a-FXIIa and P-FXIIa molecules active early in the HAE pathway that catalyze the production of kallikrein (Muller F and Renne T, Curr. Opin. Hematol., 15, 516-21, 2008; Cugno M et al., Trends Mol. Med. 15(2):69-78, 2009).
  • plasma kallikrein inhibitors are considered to be useful in the treatment of other edemas such as macular edema and brain edema, and retinopathy, e.g., retinopathy associated with diabetes and/or hypertension.
  • bradykinin receptors antagonists prevent bradykinin from activating the vascular permeability pathway and stop the initiation of swelling.
  • heterocyclic derivative compounds and pharmaceutical compositions comprising said compounds.
  • the subject compounds and compositions are useful for inhibiting plasma kallikrein.
  • One embodiment provides a compound, or a pharmaceutically acceptable salt thereof, having the structure of Formula (I): wherein,
  • Ring A is 1,3-disubstituted pyridine or 1,3-disubstituted, 5-membered heteroaryl;
  • R 1 is hydrogen, halo, cyano, or optionally substituted C1-C5 alkyl
  • R 2 is hydrogen, cyano, optionally substituted C1-C5 alkyl, or C1-C3 optionally substituted alkoxy;
  • R 3 is hydrogen, cyano, C1-C3 optionally substituted alkoxy, or optionally substituted C1-C5 alkyl;
  • R 4 and R 5 are independently hydrogen, cyano, halo, hydroxy, C1-C3 optionally substituted alkoxy, or optionally substituted C1-C5 alkyl;
  • R 6 and R 7 are independently hydrogen, or optionally substituted C1-C5 alkyl
  • XI is G, or *J-CH2-K, wherein the * denotes attachment to -C(R 4 )(R 5 )-Ring A;
  • G is optionally substituted bicyclic heteroaryl ring
  • W is independently N, C-H, or C-F;
  • X is independently N, C-H, or C-F;
  • Y is independently N, C-H, or C-F;
  • Z is independently N, C-H, or C-F
  • K is selected from optionally substituted oxopyrimidinyl, or optionally substituted oxopyridinyl.
  • One embodiment provides a compound of Formula (I), or pharmaceutically acceptable salt thereof, having the structure of Formula (la): wherein,
  • Ring A is 1,3-disubstituted pyridine or 1,3-disubstituted, 5-membered heteroaryl;
  • R 1 is hydrogen, halo, cyano, or optionally substituted C1-C5 alkyl
  • R 2 is hydrogen, cyano, optionally substituted C1-C5 alkyl, or C1-C3 optionally substituted alkoxy
  • R 3 is hydrogen, cyano, C1-C3 optionally substituted alkoxy, or optionally substituted C1-C5 alkyl;
  • R 4 and R 5 are independently hydrogen, cyano, halo, hydroxy, C1-C3 optionally substituted alkoxy, or optionally substituted C1-C5 alkyl;
  • XI is G, or *J-CH2-K, wherein the * denotes attachment to -C(R 4 )(R 5 )-Ring A;
  • G is optionally substituted bicyclic heteroaryl ring
  • W is independently N, C-H, or C-F;
  • X is independently N, C-H, or C-F;
  • Y is independently N, C-H, or C-F;
  • Z is independently N, C-H, or C-F
  • K is selected from optionally substituted oxopyrimidinyl, or optionally substituted oxopyridinyl.
  • Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 are independently selected from hydrogen, fluoromethyl, hydroxymethyl, and methyl. Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R 6 is hydrogen, and R 7 is hydrogen, hydroxymethyl, or methyl. Another embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R 6 is hydrogen, and R 7 is hydrogen.
  • Another embodiment provides the compound of Formula (I) or (la), or a pharmaceutically acceptable salt thereof, wherein XI is G.
  • Another embodiment provides the compound of Formula (I) or (la), or a pharmaceutically acceptable salt thereof, wherein G is selected from optionally substituted quinolyl, optionally substituted indolyl, optionally substituted indazolyl, optionally substituted benzimidazolyl, optionally substituted isoquinolyl, optionally substituted cinnolinyl, optionally substituted phthalazinyl, optionally substituted quinazolinyl, optionally substituted naphthyridinyl, or optionally substituted benzoisoxazolyl.
  • G is selected from optionally substituted quinolyl, optionally substituted indolyl, optionally substituted indazolyl, optionally substituted benzimidazolyl, optionally substituted isoquinolyl, optionally substituted cinnolinyl, optionally substituted phthalazinyl, optionally substituted quinazolinyl, optionally substituted naphthyridinyl, or optionally substituted benzo
  • Another embodiment provides the compound of Formula (I) or (la), or a pharmaceutically acceptable salt thereof, wherein G is selected from optionally substituted quinolin-3-yl, or optionally substituted quinolin-6-yl.
  • Another embodiment provides the compound, or a pharmaceutically acceptable salt thereof, wherein the optionally substituted quinolin-6-yl, or optionally substituted quinolin-3-yl is substituted with at least one substituent selected from optionally substituted C1-C3 alkyl, halogen, -CN, -SChMe, -SO2NH2, -CONH2, -CH2NHAC, - CChMe, -CO2H, -CH2OH, -CH2NH2, -NH2, -OH, or -OMe.
  • Another embodiment provides the compound, or a pharmaceutically acceptable salt thereof, wherein the optionally substituted quinolin-6-yl is substituted at least at the 3-position.
  • Another embodiment provides the compound, or a pharmaceutically acceptable salt thereof, wherein the quinolin-6-yl is selected from 3-chloroquinolin-6-yl, 3-methylquinolin-6-yl, 3-trifluoromethylquinolin-6-yl, 3- fluoroquinolin-6-yl, or 3-cyanoquinolin-6-yl.
  • Another embodiment provides the compound, or a pharmaceutically acceptable salt thereof, wherein the optionally substituted quinolin-3-yl is substituted at least at the 6-position or the 7-position.
  • Another embodiment provides the compound of Formula (I) or (la), or a pharmaceutically acceptable salt thereof, wherein G is 3- chloroquinolin-6-yl.
  • Another embodiment provides the compound of Formula (I) or (la), or a pharmaceutically acceptable salt thereof, wherein XI is *J-CH2-K, wherein the * denotes attachment to - C(R 4 )(R 5 )-Ring A.
  • Another embodiment provides the compound of Formula (I) or (la), or a pharmaceutically acceptable salt thereof, wherein J is
  • W is independently C-H, or C-F
  • X is independently C-H, or C-F
  • Y is independently C-H, or C-F
  • Z is independently C-H, or C-F.
  • Another embodiment provides the compound, or a pharmaceutically acceptable salt thereof, wherein:
  • W is independently C-H, or C-F
  • X is independently C-H, or C-F
  • Y is independently C-H, or C-F.
  • Another embodiment provides the compound of Formula (I) or (la), or a pharmaceutically acceptable salt thereof, wherein J is W-X
  • Another embodiment provides the compound, or a pharmaceutically acceptable salt thereof, wherein:
  • W is independently C-H, or C-F
  • X is independently C-H, or C-F
  • Z is independently C-H, or C-F.
  • Another embodiment provides the compound of Formula (I) or (la), or a pharmaceutically acceptable salt thereof, wherein J is Another embodiment provides the compound, or a pharmaceutically acceptable salt thereof, wherein:
  • W is independently C-H, or C-F
  • Y is independently C-H, or C-F
  • Z is independently C-H, or C-F.
  • Another embodiment provides the compound of Formula (I) or (la), or a pharmaceutically acceptable salt thereof, wherein J is N — X
  • Another embodiment provides the compound, or a pharmaceutically acceptable salt thereof, wherein:
  • X is independently C-H, or C-F
  • Y is independently C-H, or C-F; and Z is independently C-H, or C-F.
  • Another embodiment provides the compound of Formula (I) or (la), or a pharmaceutically acceptable salt thereof, wherein K is optionally substituted oxopyrimidinyl.
  • Another embodiment provides the compound, or a pharmaceutically acceptable salt thereof, wherein the optionally substituted oxopyrimidinyl is optionally substituted with at least one fluoro.
  • Another embodiment provides the compound, or a pharmaceutically acceptable salt thereof, wherein the optionally substituted oxopyrimidinyl is optionally substituted 2-oxopyrimidin-l-yl.
  • Another embodiment provides the compound, or a pharmaceutically acceptable salt thereof, wherein the optionally substituted oxopyrimidinyl is optionally substituted 6-oxopyrimidin-l-yl.
  • Another embodiment provides the compound of Formula (I) or (la), or a pharmaceutically acceptable salt thereof, wherein K is optionally substituted oxopyridinyl.
  • Another embodiment provides the compound, or a pharmaceutically acceptable salt thereof, wherein the optionally substituted oxopyridinyl is optionally substituted 2-oxopyridin-l-yl.
  • Another embodiment provides the compound, or a pharmaceutically acceptable salt thereof, wherein the optionally substituted 2-oxopyridin-l-yl is optionally substituted with at least one fluoro.
  • Ring A is a 1,3 -di substituted pyridine having the structure:
  • Another embodiment provides the compound of Formula (I) or (la), or a pharmaceutically acceptable salt thereof, wherein Ring A is a 1,3 -di substituted, 5-membered heteroaryl.
  • Another embodiment provides the compound, or a pharmaceutically acceptable salt thereof, wherein the 1,3 -di substituted, 5-membered heteroaryl is selected from optionally substituted imidazolyl, optionally substituted pyrazolyl, optionally substituted triazole, optionally substituted oxazole, or optionally substituted oxadiazole.
  • Another embodiment provides the compound or a pharmaceutically acceptable salt thereof, wherein the 1,3 -di substituted, 5-membered heteroaryl is selected from optionally substituted triazole, optionally substituted oxazole, or optionally substituted oxadi azole.
  • Another embodiment provides the compound of Formula (I) or (la), or a pharmaceutically acceptable salt thereof, wherein R 1 is fluoro.
  • Another embodiment provides the compound of Formula (I) or (la), or a pharmaceutically acceptable salt thereof, wherein R 2 is C1-C3 optionally substituted alkoxy. Another embodiment provides the compound, or a pharmaceutically acceptable salt thereof, wherein R 2 is -OCH3, - OCF3, -OCHF2, or -OCH2F. Another embodiment provides the compound, or a pharmaceutically acceptable salt thereof, wherein R 2 is -OCH3.
  • Another embodiment provides the compound of Formula (I) or (la), or a pharmaceutically acceptable salt thereof, wherein R 3 is hydrogen.
  • Another embodiment provides the compound of Formula (I) or (la), or a pharmaceutically acceptable salt thereof, wherein R 4 and R 5 are hydrogen.
  • One embodiment provides a kallikrein inhibitory compound, or a pharmaceutically acceptable salt or solvate thereof, having a structure presented in Table 1.
  • Suitable reference books and treatise that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation include for example, "Synthetic Organic Chemistry", John Wiley & Sons, Inc., New York; S. R. Sandler et al., "Organic Functional Group Preparations,” 2nd Ed., Academic Press, New York, 1983; H. O. House, “Modern Synthetic Reactions", 2nd Ed., W. A. Benjamin, Inc. Menlo Park, Calif. 1972; T. L. Gilchrist, "Heterocyclic Chemistry", 2nd Ed., John Wiley & Sons, New York, 1992; J.
  • the kallikrein inhibitory compound described herein is administered as a pure chemical.
  • the kallikrein inhibitory compound described herein is combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, physiologically suitable (or acceptable) excipient, or physiologically suitable (or acceptable) carrier) selected on the basis of a chosen route of administration and standard pharmaceutical practice as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21 st Ed. Mack Pub. Co., Easton, PA (2005)).
  • a pharmaceutical composition comprising at least one kallikrein inhibitory compound as described herein, or a stereoisomer, pharmaceutically acceptable salt, hydrate, or solvate thereof, together with one or more pharmaceutically acceptable carriers.
  • the carrier(s) or excipient(s) is acceptable or suitable if the carrier is compatible with the other ingredients of the composition and not deleterious to the recipient (i.e., the subject or the patient) of the composition.
  • One embodiment provides a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (I) or (la), or a pharmaceutically acceptable salt or solvate thereof.
  • One embodiment provides a method of preparing a pharmaceutical composition comprising mixing a compound of Formula (I) or (la), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.
  • the kallikrein inhibitory compound as described by Formula (I) or (la), or a pharmaceutically acceptable salt or solvate thereof is substantially pure, in that it contains less than about 5%, or less than about 2%, or less than about 1%, or less than about 0.5%, or less than about 0.1%, of other organic small molecules, such as unreacted intermediates or synthesis by-products that are created, for example, in one or more of the steps of a synthesis method.
  • One embodiment provides a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof.
  • One embodiment provides a method of preparing a pharmaceutical composition comprising mixing a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.
  • the kallikrein inhibitory compound as described by Table 1, or a pharmaceutically acceptable salt or solvate thereof is substantially pure, in that it contains less than about 5%, or less than about 2%, or less than about 1%, or less than about 0.5%, or less than about 0.1%, of other organic small molecules, such as unreacted intermediates or synthesis by-products that are created, for example, in one or more of the steps of a synthesis method.
  • Suitable oral dosage forms include, for example, tablets, pills, sachets, or capsules of hard or soft gelatin, methylcellulose or of another suitable material easily dissolved in the digestive tract.
  • suitable nontoxic solid carriers include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate, and the like. See, e.g., Remington: The Science and Practice of Pharmacy (Gennaro, 21 st Ed. Mack Pub. Co., Easton, PA (2005)).
  • the kallikrein inhibitory compound as described by Formula (I) or (la), or Table 1, or pharmaceutically acceptable salt or solvate thereof is formulated for administration by injection.
  • the injection formulation is an aqueous formulation.
  • the injection formulation is a non-aqueous formulation.
  • the injection formulation is an oil-based formulation, such as sesame oil, or the like.
  • the dose of the composition comprising at least one kallikrein inhibitory compound as described herein differs depending upon the subject or patient's (e.g., human) condition. In some embodiments, such factors include general health status, age, and other factors.
  • compositions are administered in a manner appropriate to the disease to be treated (or prevented).
  • An appropriate dose and a suitable duration and frequency of administration will be determined by such factors as the condition of the patient, the type and severity of the patient's disease, the particular form of the active ingredient, and the method of administration.
  • an appropriate dose and treatment regimen provides the composition(s) in an amount sufficient to provide therapeutic and/or prophylactic benefit (e.g., an improved clinical outcome, such as more frequent complete or partial remissions, or longer disease-free and/or overall survival, or a lessening of symptom severity.
  • Optimal doses are generally determined using experimental models and/or clinical trials. The optimal dose depends upon the body mass, weight, or blood volume of the patient.
  • Oral doses typically range from about 0.01 mg to about 1000 mg, one to four times, or more, per day.
  • One embodiment provides a compound of Formula (I) or (la), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of the human or animal body.
  • One embodiment provides a compound of Formula (I) or (la), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treating angioedema, including hereditary and non-hereditary, or macular edema, including diabetic macular edema.
  • One embodiment provides a method of treating angioedema, including hereditary and non- hereditary, or macular edema, including diabetic macular edema, in a patient in need thereof, comprising administering to the patient a compound of Formula (I) or (la), or a pharmaceutically acceptable salt or solvate thereof.
  • One embodiment provides a method of treating angioedema, including hereditary and non- hereditary, or macular edema, including diabetic macular edema, in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a compound of Formula (I) or (la), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.
  • a pharmaceutical composition comprising a compound of Formula (I) or (la), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.
  • One embodiment provides a method of prophylaxis to prevent attacks of angioedema in a patient in need thereof, the method comprising administering to the patient a compound of Formula (I) or (la), or a pharmaceutically acceptable salt thereof.
  • One embodiment provides a method of prophylaxis to prevent attacks of angioedema in a patient in need thereof, the method comprising administering to the patient a pharmaceutical composition comprising a compound of Formula (I) or (la), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • One embodiment provides a method of prophylaxis to prevent attacks of angioedema in a patient in need thereof, the method comprising administering to the patient a compound as described in Table 1, or a pharmaceutically acceptable salt thereof.
  • One embodiment provides a method of prophylaxis to prevent attacks of angioedema in a patient in need thereof, the method comprising administering to the patient a pharmaceutical composition comprising a compound as described in Table 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • Another embodiment provides the method wherein the angioedema is hereditary angioedema. Another embodiment provides the method wherein the angioedema is acute angioedema.
  • One embodiment provides a method of inhibiting kallikrein protein activity comprising contacting the kallikrein protein with a compound of Formula (I) or (la), or Table 1. Another embodiment provides the method of inhibiting kallikrein protein activity, wherein the kallikrein protein is contacted in an in vivo setting. Another embodiment provides the method of inhibiting kallikrein protein activity, wherein the kallikrein protein is contacted in an in vitro setting.
  • the kallikrein inhibitory compounds disclosed herein are synthesized according to the following examples. As used below, and throughout the description of the invention, the following abbreviations, unless otherwise indicated, shall be understood to have the following meanings: ACN acetonitrile °C degrees Celsius
  • NMR nuclear magnetic resonance pH potential of hydrogen a measure of the acidity or basicity of an aqueous solution
  • Example 1 Preparation of N-((5-aminopyri din-2 -yl)methyl)-2-((3 -chi oroquinolin-6- yl)methyl)isonicotinamide
  • Example 3 Preparation of N-((5-amino-3-fluoropyridi n -2-yl)methyl)-2-((3-chloroquinolin-6- yl)methyl)isonicotinamide
  • Example 4 Preparation of N-((5-amino-3 -fluoro-4-m ethoxypyri din-2 -yl)methyl)-2-((3 - chloroquinolin-6-yl)methyl)isonicotinamide
  • Example 5 Preparation of N-((5-amino-3 -fluoro-4-m ethoxypyri din-2 -yl)methyl)-2-((3 -chi oro- 8-fiuo r oquinolin-6-yl)methyl)oxazole-5-carboxamide
  • Example 6 Preparation of N-((5-amino-4-(difluoromethoxy)-3-fluoropyri din-2 -yl)methyl)-2- ((3-chloroquinolin-6-yl)methyl)isonicotinamide
  • tert-butyl (6-(((tert-butoxycarbonyl)amino)methyl)-4-(difluoromethoxy)-5- fluoropyri din-3 -yl)carbamate (80 mg, 0.20 mmol, 1.0 eq) in DCM (10 mL) was added TFA (3 mL) at rt. The mixture was stirred at rt for 2 h. The mixture was concentrated to yield tert-butyl (6-(aminomethyl)-4-(difluoromethoxy)-5-fluoropyridin-3-yl)carbamate trifluoroacetate (50 mg, quant.), which was used in the next step without further purification.
  • Example 7 Preparation of N-((5-amino-3 -fluoro-4-methoxypyri din-2 -yl)methyl)-2-((6-((2- oxopyridin-l(2H)-yl)methyl)pyridin-3-yl)methyl)oxazole-5-carboxamide
  • SOCh 53.4 g, 0.45 mol, 1.5 eq
  • Example 8 Preparation of N-((5-amino-3 -fluoro-4-(fluorom ethoxy )pyri din-2-yl)methyl)-2-((3 - chloroquinolin-6-yl)methyl)isonicotinamide
  • tert-butyl (6-cyano-5-fluoro-4-methoxypyridin-3-yl)carbamate 800 mg, 3.0 mmol, 1.0 eq
  • MeOH 50 mL
  • NH3 H2O 5mL
  • Raney Ni 80 mg
  • the mixture was stirred under H2 (0.5 MPa) at 30 °C for 16 h, cooled to rt and filtered.
  • the filtrate was concentrated under reduced pressure to yield tert-butyl (6-(aminomethyl)-5-fluoro-4- methoxypyri din-3 -yl)carbamate (780 mg, 88.0%), which was used in the next step without further purification.
  • Example 10 Preparation of N-((5-amino-3-fluoro-4-methoxypyridin-2-yl)methyl)-2-((6-((3- fluoro-2-oxopyri din- l(2H)-yl)methyl)pyri din-3 -yl)methyl)oxazole-5 -carboxamide
  • Example 11 Preparation of N-((5-amino-3-fluoro-4-methoxypyridin-2-yl)methyl)-2-(4-((3- fluoro-2-oxopyridin-l(2H)-yl)methyl)benzyl)oxazole-5-carboxamide
  • Example 12 Preparation of N-((5-amino-3 -fluoro-4-methoxypyri din-2 -yl)methyl)-2-((6-((2- oxopyridin.l(2H)-yl)methyl)pyri din-3 -yl)methyl)isonicotinamide
  • Example 13 Preparation of N-((5-amino-3 -fluoro-4-m ethoxypyri din-2 -yl)methyl)-2-(3 -fluoro- 4-((2-oxopyridin-l(2H)-yl)methyl)benzyl)oxazole-5-carboxamide
  • Example 14 Preparation of N-((5-amino-3-fluoro-4-methoxypyridin-2-yl)methyl)-5-((6-((2- oxopyri din- l(2H)-yl)methyl)pyri din-3 -yl)m ethyl)- 1, 3, 4-oxadiazole-2-carboxamide
  • tert-butyl (6-(aminomethyl)-5-fluoro-4-methoxypyridin-3-yl)carbamate 300 mg, 1.11 mmol, 1.0 eq) and K2CO3 (459 mg, 3.33 mmol, 3 eq) in MeCN (10 mL) was added ethyl 2-chloro-2-oxoacetate (227 mg, 1.66 mmol, 1.5 eq) at rt.
  • Example 15 Preparation of N-((5-amino-3 -fluoro-4-m ethoxypyri din-2 -yl)methyl)-2-(3 -fluoro- 4-((3-fluoro-2-oxopyridin-l(2H)-yl)methyl)benzyl)oxazole-5-carboxamide
  • Example 16 Preparation of N-((5-amino-3 -fluoro-4-m ethoxypyri din-2 -yl)methyl)-2-(3 -fhioro- 4-((5-fluoro-2-oxopyridin-l(2H)-yl)methyl)benzyl)oxazole-5-carboxamide
  • Example 17 Preparation of N-((5-amino-3 -fluoro-4-m ethoxypyri din-2 -yl)methyl)-2-(4-((2- oxopyridin-l(2H)-yl)methyl)benzyl)oxazole-5-carboxamide
  • Example 18 Preparation of N-((5-amino-3-fluoro-4-methoxypyridin-2-yl)methyl)-2-((6-((5- fluoro-2-oxopyri din- l(2H)-yl)methyl)pyri din-3 -yl)methyl)oxazole-5 -carboxamide
  • Example 19 Preparation of N-((5-amino-3-fluoro-4-methoxypyridin-2-yl)methyl)-5-((6-((2- oxopyri din- l(2H)-yl)methyl)pyri din-3 -yl)methyl)-4H-l, 2, 4-triazole-3 -carboxamide
  • E Ethyl (E)-2-amino-3-(2-(2-(6-((2-oxopyri din- l(2H)-yl)m ethyl)pyri din-3 - yl)acetyl)hydrazineylidene)propanoate (300 mg, 0.84 mmol, 1.0 eq) and molecular sieve (4A, 100 mg) in xylene (10 mL) was stirred at 170 °C for 16 h.
  • Example 20 Preparation of N-((5-amino-3-fluoro-4-methoxypyridin-2-yl)methyl)-2-(2,3- difluoro-4-((2-oxopyridin-l(2H)-yl)methyl)benzyl)oxazole-5 -carboxamide
  • reaction mixture was stirred at rt for 1 h, quenched with NH4CI aqueous (30 mL), extracted with EA (30 mL x 3). The combined organic layers were washed with brine and dried over Na2SO4, filtered and concentrated.
  • Example 22 Preparation of N-((5-amino-3 -fluoro-4-methoxypyri din-2 -yl)methyl)-2-((6-((2- oxopyridin-l(2H)-yl)methyl)pyridazin-3-yl)methyl)oxazole-5-carboxamide
  • Example 23 Preparation of N-((5-amino-3 -fluoro-4-m ethoxypyri din-2 -yl)methyl)-2-(4-((2- oxopyrimidin-l(2H)-yl)methyl)benzyl)oxazole-5-carboxamide
  • Example 24 Preparation of N-((5-amino-3 -fluoro-4-m ethoxypyri din-2 -yl)methyl)-2-((6-((2- oxopyrimidin-l(2H)-yl)methyl)pyridin-3-yl)methyl)oxazole-5-carboxamide
  • Example 25 Preparation of N-((5-amino-3 -fluoro-4-m ethoxypyri din-2 -yl)methyl)-2-(4-((6- oxopyrimidin-l(6H)-yl)methyl)benzyl)oxazole-5-carboxamide
  • a 10 mM solution of the test compound was made in DMSO. This solution was serially diluted 1 :5 in DMSO to yield 2000, 400, 80, 16, 3.2, 0.64, 0.128, 0.0256 and 0.00512 pM compound test solutions. A control tube containing only DMSO is included. 16 pL of each compound test solution was combined with 384 pL of assay buffer (50 mM Tris-HCl pH 7.5, 150 mM NaCl, 0.01% Triton X-100) to yield a “4X test compound buffer stock”.
  • assay buffer 50 mM Tris-HCl pH 7.5, 150 mM NaCl, 0.01% Triton X-100
  • Example 2 In vitro cellular assay
  • Plasma kallikrein inhibitor C1NH (Athens Research & Technology, Cat#16-16-031509); DXS (Sigma, Cat#31395); FXIIa (Enzyme Research Laboratories, Cat#FXIIa 3850AL); Substrate Z- FR-2-AMC (GL Biochem, Cat#55352); Thermo ScientificTM NuncTM 96-Well Polypropylene MicroWell Plates (Thermo Scientific, Cat#267342).
  • An assay buffer was prepared comprising 50 mM Tris-HCl pH 7.2, 150 mM NaCl, and 0.01% Triton X-100.
  • a 10 mg/mL stock solution of DXS was diluted to 1.25 mg/mL, lul of this DXS was mixed with 47ul of 100% human plasma in assay plate. The plate was incubated for 7 min at 4 °C.
  • a 16000 nM stock solution of FXIIa was diluted to 500 nM, lul of this FXIIa was mixed with 47 pl of 100% human plasma in assay plate. The plate was incubated for 30 min at 4 °C.
  • test compound at various concentrations, prepared by serial dilutions as described above, was added to the test wells.
  • the volume of the test compound added to each test well was 1 pL, to yield final concentrations of 2000 nM, 500 nM, 125 nM, 31.25 nM, 7.81 nM and 1.95 nM. Each test compound concentration was tested in duplicate.
  • the 96-well assay plate included positive control wells which contain the mixture of human plasma and DXS/FXIIa without test compound, and background wells which contain neither the mixture of human plasma and DXS/FXIIa nor test compound.
  • the total volume of liquid in positive control and background wells was brought up to 49 pL, using the assay buffer.
  • test compound mixed with human plasma and ellagic acid and appropriate controls, was incubated at 37 °C for 5 min.
  • a 10 mM stock solution of substrate Z-FR-2-AMC was diluted to 2000 pM in the assay buffer, and 1 pL of the diluted substrate was added to each well, to yield a final substrate concentration of 40 pM in each well.
  • the reagents were mixed well by shaking the plate gently for 30 sec.
  • the enzyme reaction was quantified by immediate kinetic reading of the assay plate using excitation/emission wavelengths of 330 nm/440 nm respectively. Fluorescence intensity was recorded for 60 min, using a time interval of 43 sec. The highest mean velocity for 10 reads within the first 30 minutes was used to calculate the ECso and EC90 values. [00322] The inhibition activity of compounds was evaluated using the EC50 and EC90 values, calculated according to the dose-response curve of compounds, fitted using the “log (inhibitor)-response (variable slope)” equation in GraphPad Prism software (GraphPad Software, Inc.).
  • Mean(BG) is the average value of the fluorescence intensity of the background wells and Mean (PC) is the average value of the fluorescence intensity of the positive control wells.
  • Biochemical assay (hPK IC50) data are designated within the following ranges:
  • Celluar assay (plasma EC50) data are designated within the following ranges: A: ⁇ 0.20 pM C: > 1.0 pM to ⁇ 10 pM
  • Example 1 Oral capsule
  • the active ingredient is a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof.
  • a capsule for oral administration is prepared by mixing 1-1000 mg of active ingredient with starch or other suitable powder blend. The mixture is incorporated into an oral dosage unit such as a hard gelatin capsule, which is suitable for oral administration.
  • Example 2 Solution for injection
  • the active ingredient is a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof, and is formulated as a solution in sesame oil at a concentration of 50 mg-eq/mL.

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Abstract

L'invention concerne des composés dérivés hétérocycliques et des compositions pharmaceutiques comprenant lesdits composés qui sont utiles pour inhiber la kallicréine plasmatique. En outre, les composés et compositions de l'invention sont utiles pour le traitement de maladies impliquant l'inhibition de la kallicréine plasmatique, notamment l'angio-œdème et analogue.
PCT/US2025/012612 2024-01-23 2025-01-22 Composés inhibiteurs thérapeutiques Pending WO2025160190A1 (fr)

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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013111108A1 (fr) * 2012-01-27 2013-08-01 Novartis Ag Dérivés hétéroarylcarboxamide à 5 chaînons comme inhibiteurs de la kallikréine plasmatique
WO2015103317A1 (fr) * 2013-12-30 2015-07-09 Lifesci Pharmaceuticals, Inc. Composés inhibiteurs thérapeutiques
WO2017001926A2 (fr) * 2015-07-01 2017-01-05 Lifesci Pharmaceuticals, Inc Composés inhibiteurs thérapeutiques
WO2018011628A1 (fr) * 2016-07-11 2018-01-18 Lifesci Pharmaceuticals, Inc. Composés inhibiteurs thérapeutiques
US20210078999A1 (en) * 2019-09-18 2021-03-18 Shire Human Genetic Therapies, Inc. Plasma kallikrein inhibitors and uses thereof
WO2024059186A1 (fr) * 2022-09-15 2024-03-21 Takeda Pharmaceutical Company Limited Dérivés de n-((isoquinolin-6-yl)méthyl)-1 h-pyrazole-4-carboxamide en tant qu' inhibiteurs de la kallicréine plasmatique pour le traitement de l'angioœdème héréditaire
WO2025001956A1 (fr) * 2023-06-30 2025-01-02 远森制药（杭州）有限公司 Composés formamide hétéroaromatiques et leurs utilisations en médecine

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Publication number Priority date Publication date Assignee Title
WO2013111108A1 (fr) * 2012-01-27 2013-08-01 Novartis Ag Dérivés hétéroarylcarboxamide à 5 chaînons comme inhibiteurs de la kallikréine plasmatique
WO2015103317A1 (fr) * 2013-12-30 2015-07-09 Lifesci Pharmaceuticals, Inc. Composés inhibiteurs thérapeutiques
WO2017001926A2 (fr) * 2015-07-01 2017-01-05 Lifesci Pharmaceuticals, Inc Composés inhibiteurs thérapeutiques
WO2018011628A1 (fr) * 2016-07-11 2018-01-18 Lifesci Pharmaceuticals, Inc. Composés inhibiteurs thérapeutiques
US20210078999A1 (en) * 2019-09-18 2021-03-18 Shire Human Genetic Therapies, Inc. Plasma kallikrein inhibitors and uses thereof
WO2024059186A1 (fr) * 2022-09-15 2024-03-21 Takeda Pharmaceutical Company Limited Dérivés de n-((isoquinolin-6-yl)méthyl)-1 h-pyrazole-4-carboxamide en tant qu' inhibiteurs de la kallicréine plasmatique pour le traitement de l'angioœdème héréditaire
WO2025001956A1 (fr) * 2023-06-30 2025-01-02 远森制药（杭州）有限公司 Composés formamide hétéroaromatiques et leurs utilisations en médecine

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Title
DAVIE, R. L. ET AL.: "Sebetralstat (KVD900): a potent and selective small molecule plasma kallikrein inhibitor featuring a novel P 1 group as a potential oral on-demand treatment for hereditary angioedema.", JOURNAL OF MEDICINAL CHEMISTRY, vol. 65, no. 20, 2022, pages 13629 - 13644, XP093268255, DOI: 10.1021/acs.jmedchem.2c00921 *

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