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WO2023225001A1 - Modulateurs d'enpp1 à base de naphtyridine et leurs utilisations - Google Patents

Modulateurs d'enpp1 à base de naphtyridine et leurs utilisations Download PDF

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WO2023225001A1
WO2023225001A1 PCT/US2023/022395 US2023022395W WO2023225001A1 WO 2023225001 A1 WO2023225001 A1 WO 2023225001A1 US 2023022395 W US2023022395 W US 2023022395W WO 2023225001 A1 WO2023225001 A1 WO 2023225001A1
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optionally substituted
alkyl
halogen
compound
independently selected
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Roland D. Saito
Winston C. Tse
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Vir Biotechnology Inc
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Vir Biotechnology Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders

Definitions

  • ENPP1 degrades cyclic guanosine monophosphate-adenosine monophosphate (cGAMP), a secondary messenger molecule that mediates the upregulation of type I interferons and other inflammatory cytokines and chemokines by activating stimulator of interferon genes (STING).
  • cGAMP cyclic guanosine monophosphate-adenosine monophosphate
  • STING stimulator of interferon genes
  • the present disclosure provides a compound represented by the structure of Formula (I): or a pharmaceutically acceptable salt thereof, wherein: X 2 is selected from -O-, -S-, -C(R 3 ) 2 -, -N(R 4 )-, and -C(R 18 ) 2 N(R 4 )-; Z 1 is absent, or selected from O and NR 5 ; G is N(H), X 1 is C(O), and is represented by: or G is N, X 1 is selected from C(H) and C-OR A , and is represented by R A is selected from: hydrogen and C 1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR 10 , -SR 10 , -N(R 10 ) 2 , -C(O)R 10 , -C(O)N(R 10 ) 2 , -N(R 10 )C(O)R 10
  • G is N(H).
  • a compound or salt of Formula (I) is represented by the structure of Formula (Ia): pharmaceutically acceptable salt thereof.
  • a compound or salt of Formula (I) is represented by the structure of Formula (Ib): , wherein X 1 is selected from C(H) and C-OR A , or a pharmaceutically acceptable salt thereof.
  • a compound or salt of Formula (I) is represented by the structure of Formula (I-1): pharmaceutically acceptable salt thereof.
  • a compound or salt of Formula (I) or (I-1) is represented by the structure of Formula (I-1a): 1a), or a pharmaceutically acceptable salt thereof.
  • a compound or salt of Formula (I) or (I-1) is represented by the structure of Formula (I-1b): -1b), wherein X 1 is selected from C(H) and C-OR A , or a pharmaceutically acceptable salt thereof.
  • a compound or salt of Formula (I) is represented by the structure of Formula (I-2): pharmaceutically acceptable salt thereof.
  • a compound or salt of Formula (I) or (I-2) is represented by the structure of Formula (I-2a): pharmaceutically acceptable salt thereof.
  • a compound or salt of Formula (I) or (I-2) is represented by the structure of Formula (I-2b): wherein X 1 is selected from C(H) and C-OR A , or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides a pharmaceutical composition comprising a compound or salt of Formula (I), (Ia), (Ib), (I-1), (I-1a), (I-1b), (I-2), (I-2a), or (I- 2b), and a pharmaceutically acceptable excipient.
  • the present disclosure provides a method of inhibiting ENPP1 in a subject in need thereof, comprising administering to the subject a compound or salt of Formula (I), (Ia), (Ib), (I-1), (I-1a), (I-1b), (I-2), (I-2a), or (I-2b).
  • INCORPORATION BY REFERENCE All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. To the extent publications and patents or patent applications incorporated by reference contradict the disclosure contained in the specification, the specification is intended to supersede and/or take precedence over any such contradictory material.
  • Alkyl refers to a straight or branched hydrocarbon chain monovalent radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, and preferably having from one to twelve carbon atoms (i.e., C1-C12 alkyl). The alkyl is attached to the remainder of the molecule through a single bond. In certain embodiments, an alkyl comprises one to twelve carbon atoms (i.e., C1-C12 alkyl).
  • an alkyl comprises one to eight carbon atoms (i.e., C1-C8 alkyl). In other embodiments, an alkyl comprises one to five carbon atoms (i.e., C 1 -C 5 alkyl). In other embodiments, an alkyl comprises one to four carbon atoms (i.e., C 1 - C4 alkyl). In other embodiments, an alkyl comprises one to three carbon atoms (i.e., C1-C3 alkyl). In other embodiments, an alkyl comprises one to two carbon atoms (i.e., C1-C2 alkyl). In other embodiments, an alkyl comprises one carbon atom (i.e., C 1 alkyl).
  • an alkyl comprises five to fifteen carbon atoms (i.e., C5-C15 alkyl). In other embodiments, an alkyl comprises five to eight carbon atoms (i.e., C5-C8 alkyl). In other embodiments, an alkyl comprises two to five carbon atoms (i.e., C 2 -C 5 alkyl). In other embodiments, an alkyl comprises three to five carbon atoms (i.e., C 3 -C 5 alkyl).
  • the alkyl group may be attached to the rest of the molecule by a single bind, such as, methyl, ethyl, 1-propyl (n-propyl), 1- methylethyl (iso-propyl), 1-butyl (n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (iso- butyl), 1,1-dimethylethyl (tert-butyl), 1-pentyl (n-pentyl), and the like.
  • a single bind such as, methyl, ethyl, 1-propyl (n-propyl), 1- methylethyl (iso-propyl), 1-butyl (n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (iso- butyl), 1,1-dimethylethyl (tert-butyl), 1-pentyl (n-pentyl), and the like.
  • 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 preferably having from two to twelve carbon atoms (i.e., C2-C12 alkenyl).
  • an alkenyl comprises two to eight carbon atoms (i.e., C 2 -C 8 alkenyl).
  • an alkenyl comprises two to six carbon atoms (i.e., C2-C6 alkenyl).
  • an alkenyl comprises two to four carbon atoms (i.e., C2-C4 alkenyl).
  • alkenyl is attached to the rest of the molecule by a single bond, for example, ethenyl (i.e., vinyl), prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like.
  • ethenyl i.e., vinyl
  • prop-1-enyl i.e., allyl
  • but-1-enyl but-1-enyl
  • pent-1-enyl penta-1,4-dienyl
  • alkenyl is attached to the rest of the molecule by a single bond, for example, ethenyl (i.e., vinyl), prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like.
  • Alkynyl refers to a straight or branched hydrocarbon chain
  • an alkynyl comprises two to eight carbon atoms (i.e., C2-C8 alkynyl). In other embodiments, an alkynyl comprises two to six carbon atoms (i.e., C2-C6 alkynyl). In other embodiments, an alkynyl comprises two to four carbon atoms (i.e., C 2 -C 4 alkynyl).
  • the alkynyl is attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.
  • Alkylene refers to a straight divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing no unsaturation, and preferably 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 the terminal carbons respectively.
  • Alkylene chain may be optionally substituted by one or more substituents such as those substituents described herein.
  • an alkylene comprises one to ten carbon atoms (i.e., C1-C10 alkylene). In certain embodiments, an alkylene comprises one to eight carbon atoms (i.e., C1-C8 alkylene). In other embodiments, an alkylene comprises one to five carbon atoms (i.e., C 1 -C 5 alkylene). In other embodiments, an alkylene comprises one to four carbon atoms (i.e., C1-C4 alkylene). In other embodiments, an alkylene comprises one to three carbon atoms (i.e., C1-C3 alkylene).
  • an alkylene comprises one to two carbon atoms (i.e., C 1 -C 2 alkylene). In other embodiments, an alkylene comprises one carbon atom (i.e., C 1 alkylene). In other embodiments, an alkylene comprises five to eight carbon atoms (i.e., C 5 -C 8 alkylene). In other embodiments, an alkylene comprises two to five carbon atoms (i.e., C 2 -C 5 alkylene). In other embodiments, an alkylene comprises three to five carbon atoms (i.e., C 3 -C 5 alkylene).
  • Alkenylene refers to a straight 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 preferably 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.
  • the points of attachment of the alkenylene chain to the rest of the molecule and to the radical group are through the terminal carbons respectively.
  • Alkenylene chain may be optionally substituted by one or more substituents such as those substituents described herein.
  • an alkenylene comprises two to ten carbon atoms (i.e., C 2 -C 10 alkenylene). In certain embodiments, an alkenylene comprises two to eight carbon atoms (i.e., C 2 -C 8 alkenylene). In other embodiments, an alkenylene comprises two to five carbon atoms (i.e., C 2 -C 5 alkenylene). In other embodiments, an alkenylene comprises two to four carbon atoms (i.e., C 2 -C 4 alkenylene). In other embodiments, an alkenylene comprises two to three carbon atoms (i.e., C 2 -C 3 alkenylene).
  • an alkenylene comprises two carbon atom (i.e., C 2 alkenylene). In other embodiments, an alkenylene comprises five to eight carbon atoms (i.e., C 5 -C 8 alkenylene). In other embodiments, an alkenylene comprises three to five carbon atoms (i.e., C 3 -C 5 alkenylene).
  • Alkynylene refers to a straight 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 preferably having from two to twelve carbon atoms.
  • alkynylene 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 alkynylene chain to the rest of the molecule and to the radical group are through the terminal carbons respectively.
  • Alkynylene chain may be optionally substituted by one or more substituents such as those substituents described herein.
  • an alkynylene comprises two to ten carbon atoms (i.e., C 2 -C 10 alkynylene).
  • an alkynylene comprises two to eight carbon atoms (i.e., C 2 -C 8 alkynylene).
  • an alkynylene comprises two to five carbon atoms (i.e., C 2 -C 5 alkynylene). In other embodiments, an alkynylene comprises two to four carbon atoms (i.e., C 2 -C 4 alkynylene). In other embodiments, an alkynylene comprises two to three carbon atoms (i.e., C 2 -C 3 alkynylene). In other embodiments, an alkynylene comprises two carbon atom (i.e., C2 alkynylene). In other embodiments, an alkynylene comprises five to eight carbon atoms (i.e., C 5 -C 8 alkynylene).
  • an alkynylene comprises three to five carbon atoms (i.e., C 3 -C 5 alkynylene).
  • Cx-y when used in conjunction with a chemical moiety, such as alkyl, alkenyl, or alkynyl is meant to include groups that contain from x to y carbons in the chain.
  • C 1-6 alkyl refers to substituted or unsubstituted saturated hydrocarbon groups, including straight-chain alkyl and branched-chain alkyl groups that contain from 1 to 6 carbons.
  • -Cx-y alkylene- refers to a substituted or unsubstituted alkylene chain with from x to y carbons in the alkylene chain.
  • -C 1-6 alkylene- may be selected from methylene, ethylene, propylene, butylene, pentylene, and hexylene, any one of which is optionally substituted.
  • C x-y alkenyl and “C x-y alkynyl” refer to unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond, respectively.
  • -Cx-y alkenylene- refers to a substituted or unsubstituted alkenylene chain with from x to y carbons in the alkenylene chain.
  • - C 2-6 alkenylene- may be selected from ethenylene, propenylene, butenylene, pentenylene, and hexenylene, any one of which is optionally substituted.
  • An alkenylene chain may have one double bond or more than one double bond in the alkenylene chain.
  • -Cx-yalkynylene- refers to a substituted or unsubstituted alkynylene chain with from x to y carbons in the alkynylene chain.
  • -C 2-6 alkynylene- may be selected from ethynylene, propynylene, butynylene, pentynylene, and hexynylene, any one of which is optionally substituted.
  • An alkynylene chain may have one triple bond or more than one triple bond in the alkynylene chain.
  • the term “carbocycle” as used herein refers to a saturated, unsaturated or aromatic ring in which each atom of the ring is carbon. Carbocycle include 3- to 10-membered monocyclic rings and 6- to 12-membered bicyclic rings. Each ring of a bicyclic carbocycle may be selected from saturated, unsaturated, and aromatic rings.
  • Bicyclic carbocycles may be fused, bridged or spiro- ring systems.
  • the carbocycle is an aryl.
  • the carbocycle is a cycloalkyl.
  • the carbocycle is a cycloalkenyl.
  • an aromatic ring e.g., phenyl
  • carbocycles include cyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl, indanyl, and naphthyl. Carbocycle may be optionally substituted by one or more substituents such as those substituents described herein.
  • the term “carbocyclene” refers to a divalent ring, linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen atoms. The carbocyclene is attached to the rest of the molecule through a single bond and to the radical group through a single bond.
  • Carbocyclene includes arylene and cycloalkylene. The term therefore distinguishes “carbocyclene” from “heterocyclene” in which the divalent ring comprises at least one atom that is different from a carbon atom.
  • the “heterocyclene” 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 heterocyclene are to the rest of the molecule and to the radical group through any two atoms respectively, valency permitting.
  • Heterocyclene includes heteroarylene and heterocycloalkylene.
  • Carbocyclene and heterocyclene may each be optionally substituted by one or more substituents such as those substituents described herein.
  • Cycloalkyl refers to a stable fully saturated monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which includes fused or bridged ring systems, and preferably having from three to twelve carbon atoms (i.e., C 3-12 cycloalkyl).
  • a cycloalkyl comprises three to ten carbon atoms (i.e., C3-10 cycloalkyl).
  • a cycloalkyl comprises five to seven carbon atoms (i.e., C5-7 cycloalkyl).
  • the cycloalkyl may be attached to the rest of the molecule by a single bond.
  • monocyclic cycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • Polycyclic cycloalkyl radicals include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like.
  • Cycloalkyl may be optionally substituted by one or more substituents such as those substituents described herein.
  • Cycloalkenyl refers to a stable unsaturated non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which includes fused or bridged ring systems, preferably having from three to twelve carbon atoms and comprising at least one double bond (i.e., C3-12 cycloalkenyl).
  • a cycloalkenyl comprises three to ten carbon atoms (i.e., C 3-10 cycloalkenyl).
  • a cycloalkenyl comprises five to seven carbon atoms (i.e., C5-7 cycloalkenyl).
  • the cycloalkenyl may be attached to the rest of the molecule by a single bond.
  • monocyclic cycloalkenyls include, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.
  • Cycloalkenyl may be optionally substituted by one or more substituents such as those substituents described herein.
  • Aryl refers to a radical derived from an aromatic monocyclic or aromatic multicyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom.
  • the aromatic monocyclic or aromatic multicyclic hydrocarbon ring system contains only hydrogen and carbon and from five to eighteen carbon atoms, where at least one of the rings in the ring system is aromatic, i.e., it contains a cyclic, delocalized (4n+2) ⁇ –electron system in accordance with the Hückel 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 may be optionally substituted by one or more substituents such as those substituents described herein.
  • a “Cx-y carbocycle” is meant to include groups that contain from x to y carbons in a ring.
  • the term “C 3-6 carbocycle” can be a saturated, unsaturated or aromatic ring system that contains from 3 to 6 carbon atoms ⁇ any of which is optionally substituted as provided herein.
  • the term “heterocycle” as used herein refers to a saturated, unsaturated, non-aromatic or aromatic ring comprising one or more heteroatoms. Exemplary heteroatoms include N, O, Si, P, B, and S atoms.
  • Heterocycles include 3- to 10-membered monocyclic rings and 6- to 12- membered bicyclic rings. Each ring of a bicyclic heterocycle may be selected from saturated, unsaturated, and aromatic rings.
  • the heterocycle comprises at least one heteroatom selected from oxygen, nitrogen, sulfur, or any combination thereof.
  • the heterocycle comprises at least one heteroatom selected from oxygen, nitrogen, or any combination thereof.
  • the heterocycle comprises at least one heteroatom selected from oxygen, sulfur, or any combination thereof.
  • the heterocycle comprises at least one heteroatom selected from nitrogen, sulfur, or any combination thereof.
  • the heterocycle may be attached to the rest of the molecule through any atom of the heterocycle, valence permitting, such as a carbon or nitrogen atom of the heterocycle.
  • the heterocycle is a heteroaryl.
  • the heterocycle is a heterocycloalkyl.
  • Exemplary heterocycles include pyrrolidinyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, piperidinyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, thiophenyl, oxazolyl, thiazolyl, morpholinyl, indazolyl, indolyl, and quinolinyl.
  • Heterocycle may be optionally substituted by one or more substituents such as those substituents described herein.
  • Bicyclic heterocycles may be fused, bridged or spiro-ring systems.
  • a heterocycle e.g., pyridyl
  • a saturated or unsaturated ring e.g., cyclohexane, cyclopentane, or cyclohexene.
  • Heterocycle may be optionally substituted by one or more substituents such as those substituents described herein.
  • Heterocycloalkyl refers to a stable 3- to 12-membered non-aromatic ring radical that comprises two to twelve carbon atoms and at least one heteroatom wherein each heteroatom may be selected from N, O, Si, P, B, and S atoms.
  • the heterocycloalkyl comprises at least one heteroatom selected from oxygen, nitrogen, sulfur, or any combination thereof.
  • the heterocycloalkyl comprises at least one heteroatom selected from oxygen, nitrogen, or any combination thereof.
  • the heterocycloalkyl comprises at least one heteroatom selected from oxygen, sulfur, or any combination thereof.
  • the heterocycloalkyl comprises at least one heteroatom selected from nitrogen, sulfur, or any combination thereof.
  • the heterocycloalkyl may be selected from monocyclic or bicyclic, and fused or bridged ring systems.
  • the heteroatoms in the heterocycloalkyl radical are optionally oxidized.
  • One or more nitrogen atoms, if present, are optionally quaternized.
  • the heterocycloalkyl radical is partially or fully saturated.
  • the heterocycloalkyl is attached to the rest of the molecule through any atom of the heterocycloalkyl, valence permitting, such as any carbon or nitrogen atoms of the heterocycloalkyl.
  • heterocycloalkyl radicals include, but are not limited to, dioxolanyl, thienyl[1,3]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
  • Heterocycloalkyl may be optionally substituted by one or more substituents such as those substituents described herein.
  • the term “heteroaryl” refers to a radical derived from a 3- to 12-membered aromatic ring radical that comprises one to eleven carbon atoms and at least one heteroatom wherein each heteroatom may be selected from N, O, and S.
  • the heteroaryl comprises at least one heteroatom selected from oxygen, nitrogen, sulfur, or any combination thereof.
  • the heteroaryl comprises at least one heteroatom selected from oxygen, nitrogen, or any combination thereof.
  • the heteroaryl comprises at least one heteroatom selected from oxygen, sulfur, or any combination thereof.
  • the heteroaryl comprises at least one heteroatom selected from nitrogen, sulfur, or any combination thereof.
  • the heteroaryl ring may be selected from monocyclic or bicyclic and fused or bridged ring systems rings wherein at least one of the rings in the ring system is aromatic, i.e., it contains a cyclic, delocalized (4n+2) ⁇ –electron system in accordance with the Hückel theory.
  • the heteroatom(s) in the heteroaryl radical may be optionally oxidized.
  • One or more nitrogen atoms, if present, are optionally quaternized.
  • heteroaryl may be attached to the rest of the molecule through any atom of the heteroaryl, valence permitting, such as a carbon or nitrogen atom of the heteroaryl.
  • Heteroaryl includes aromatic single ring structures, preferably 5- to 6-membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms.
  • Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine, and the like.
  • Heteroaryl may be optionally substituted by one or more substituents such as those substituents described herein.
  • Heteroaryl also includes polycyclic ring systems having two or more rings in which two or more atoms are common to two adjoining rings wherein at least one of the rings is heteroaromatic, e.g., the other rings can be aromatic or non-aromatic carbocyclic, or heterocyclic.
  • Heteroaryl may be optionally substituted by one or more substituents such as those substituents described herein.
  • An “X-membered heterocycle” refers to the number of endocylic atoms, i.e., X, in the ring.
  • a 5-membered heteroaryl ring or 5-membered aromatic heterocycle has 5 endocyclic atoms, e.g., triazole, oxazole, thiophene, etc.
  • Alkoxy refers to a radical bonded through an oxygen atom of the formula –O-alkyl, where alkyl is an alkyl chain as defined above.
  • Halo or “halogen” refers to halogen substituents such as bromo, chloro, fluoro and iodo substituents.
  • haloalkyl or “haloalkane” refers to an alkyl radical, as defined above, that is substituted by one or more halogen radicals, for example, trifluoromethyl, dichloromethyl, bromomethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like.
  • the alkyl part of the fluoroalkyl radical is optionally further substituted.
  • haloalkanes examples include halomethane (e.g., chloromethane, bromomethane, fluoromethane, iodomethane), di-and trihalomethane (e.g., trichloromethane, tribromomethane, trifluoromethane, triiodomethane), 1-haloethane, 2- haloethane, 1,2-dihaloethane, 1-halopropane, 2-halopropane, 3-halopropane, 1,2-dihalopropane, 1,3-dihalopropane, 2,3-dihalopropane, 1,2,3-trihalopropane, and any other suitable combinations of alkanes (or substituted alkanes) and halogens (e.g., Cl, Br, F, and I).
  • halomethane e.g., chloromethane, bromomethane, fluoromethane, iodomethane
  • each halogen may be independently selected for example, 1-chloro,2-fluoroethane.
  • substituted refers to moieties having substituents replacing a hydrogen on one or more carbons or substitutable heteroatoms, e.g., an NH or NH2 of a compound. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, i.e., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.
  • substituted refers to moieties having substituents replacing two hydrogen atoms on the same carbon atom, such as substituting the two hydrogen atoms on a single carbon with an oxo, imino or thioxo group.
  • substituted is contemplated to include all permissible substituents of organic compounds.
  • the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds.
  • the permissible substituents can be one or more and the same or different for appropriate organic compounds.
  • salts or “pharmaceutically acceptable salt” refers to salts derived from a variety of organic and inorganic counter ions well known in the art.
  • Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids.
  • Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.
  • phrases “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable excipient or “pharmaceutically acceptable carrier” as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
  • the terms "subject,” “individual,” and “patient” may be used interchangeably and refer to humans, as well as non-human mammals (e.g., non-human primates, canines, equines, felines, porcines, bovines, ungulates, lagomorphs, and the like).
  • the subject can be a human (e.g., adult male, adult female, adolescent male, adolescent female, male child, female child) under the care of a physician or other health worker in a hospital, as an outpatient, or other clinical context.
  • the subject may not be under the care or prescription of a physician or other health worker.
  • a subject in need thereof refers to a subject, as described herein, that suffers from, or is at risk for, a pathology to be prophylactically or therapeutically treated with a compound or salt described herein.
  • the terms “administer”, “administered”, “administers” and “administering” are defined as providing a composition to a subject via a route known in the art, including but not limited to intravenous, intraarterial, oral, parenteral, buccal, topical, transdermal, rectal, intramuscular, subcutaneous, intraosseous, transmucosal, or intraperitoneal routes of administration.
  • oral routes of administering a composition can be used.
  • the terms “administer”, “administered”, “administers” and “administering” a compound should be understood to mean providing a compound of the disclosure or a salt of a compound of the disclosure to the individual in need.
  • “treatment” or “treating” refers to an approach for obtaining beneficial or desired results with respect to a disease, disorder, or medical condition including, but not limited to, a therapeutic benefit and/or a prophylactic benefit.
  • treatment or treating involves administering a compound or composition disclosed herein to a subject.
  • a therapeutic benefit may include the eradication or amelioration of the underlying disorder being treated.
  • compositions are administered to a subject at risk of developing a particular disease, or to a subject reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made. Treating can include, for example, reducing, delaying or alleviating the severity of one or more symptoms of the disease or condition, or it can include reducing the frequency with which symptoms of a disease, defect, disorder, or adverse condition, and the like, are experienced by a patient.
  • Treating can be used herein to refer to a method that results in some level of treatment or amelioration of the disease or condition, and can contemplate a range of results directed to that end, including but not restricted to prevention of the condition entirely.
  • the term “prevent” or “preventing” as related to a disease or disorder may refer to a compound that, in a statistical sample, reduces the occurrence of the disorder or condition in the treated sample relative to an untreated control sample, or delays the onset or reduces the severity of one or more symptoms of the disorder or condition relative to the untreated control sample.
  • a “therapeutic effect,” as used herein, encompasses a therapeutic benefit and/or a prophylactic benefit as described above.
  • a prophylactic effect includes delaying or eliminating the appearance of a disease or condition, onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.
  • the present disclosure provides a compound represented by the structure of Formula (I): or a pharmaceutically acceptable salt thereof, wherein: X 2 is selected from -O-, -S-, -C(R 3 ) 2 -, -N(R 4 )-, and -C(R 18 ) 2 N(R 4 )-; Z 1 is absent, or selected from O and NR 5 ; G is N(H), X 1 is C(O), and is represented by: or G is N, X 1 is selected from C(H) and C-OR A , and is represented by R A is selected from: hydrogen and C 1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR 10 , -SR 10 , -N(R 10 ) 2 , -C(O)R 10 , -C(O)N(R 10 ) 2 , -N(R 10 )C(O)R 10 , -C(O)OR
  • G is N(H).
  • a compound or salt of Formula (I) is represented by the structure of Formula (Ia): pharmaceutically acceptable salt thereof.
  • a compound or salt of Formula (I) is represented by the structure of Formula (Ib): wherein X 1 is selected from C(H) and C-OR A , or a pharmaceutically acceptable salt thereof.
  • a compound or salt of Formula (I) is represented by the structure of Formula (I-1): pharmaceutically acceptable salt thereof.
  • a compound or salt of Formula (I) or (I-1) is represented by the structure of Formula (I-1a): 1a), or a pharmaceutically acceptable salt thereof.
  • a compound or salt of Formula (I) or (I-1) is represented by the structure of Formula (I-1b): -1b), wherein X 1 is selected from C(H) and C-OR A , or a pharmaceutically acceptable salt thereof.
  • a compound or salt of Formula (I) is represented by the structure of Formula (I-2): pharmaceutically acceptable salt thereof.
  • a compound or salt of Formula (I) or (I-2) is represented by the structure of Formula (I-2a): pharmaceutically acceptable salt thereof.
  • a compound or salt of Formula (I) or (I-2) is represented by the structure of Formula (I-2b): wherein X 1 is selected from C(H) and C-OR A , or a pharmaceutically acceptable salt thereof.
  • z is selected from 0 and 1. In some embodiments, z is selected from 1 and 2.
  • z is 0. In some embodiments, z is 1. In some embodiments, z is 2. [0061] In some embodiments, for a compound or salt of Formula (I), (Ia), (Ib), (I-1), (I-1a), (I- 1b), (I-2), (I-2a), (I-2b), or (Ic), m is selected from 0 and 1. In some embodiments, m is selected from 1 and 2. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2.
  • each R 1 is independently selected from halogen, -OR 11 , -SR 11 , - N(R 11 ) 2 , -C(O)R 11 , -C(O)N(R 11 ) 2 , -N(R 11 )C(O)R 11 , -C(O)OR 11 , -OC(O)R 11 , -S(O)R 11 , -S(O) 2 R 11 , -S(O) 2 N(R 11 ) 2 , -N(R 11 )S(O) 2 R 11 , -S(O)(NR 11 )R 11 , -S(NR 11 ) 2 R 11 , -NO 2 , -CN, and C 1-6 alky
  • each R 1 is independently selected from halogen, -OR 11 , -SR 11 , -N(R 11 ) 2 , -C(O)R 11 , -C(O)N(R 11 ) 2 , -N(R 11 )C(O)R 11 , -C(O)OR 11 , - OC(O)R 11 , -S(O)R 11 , -S(O) 2 R 11 , -S(O) 2 N(R 11 ) 2 , -N(R 11 )S(O) 2 R 11 , -S(O)(NR 11 )R 11 , - S(NR 11 ) 2 R 11 , -NO 2 , and -CN.
  • each R 1 is independently C 1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR 11 , -N(R 11 ) 2 , -C(O)R 11 , -NO 2 , -CN.
  • each R 1 is independently selected from: halogen, -OR 11 , - N(R 11 ) 2 , -C(O)R 11 , -NO 2 , -CN, and C 1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR 11 , -N(R 11 ) 2 , -C(O)R 11 , -NO 2 , and -CN.
  • each R 1 is independently selected from: halogen, -OR 11 , -N(R 11 ) 2 , -C(O)R 11 , -NO 2 , -CN, and C 1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR 11 , -N(R 11 ) 2 , -C(O)R 11 , -NO 2 , and -CN.
  • each R 1 is independently C 1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR 11 , -N(R 11 ) 2 , -C(O)R 11 , -NO 2 , and -CN.
  • each R 1 is independently C 1-6 alkyl optionally substituted with one or more halogen substituents. In some embodiments, each R 1 is independently C 1-6 alkyl. [0064] In some embodiments, for a compound or salt of Formula (I), (Ia), (Ib), (I-1), (I-1a), (I- 1b), (I-2), (I-2a), (I-2b), or (Ic), and R 1 is selected from halogen, -OR 11 , -SR 11 , -N(R 11 ) 2 , - C(O)R 11 , -C(O)N(R 11 ) 2 , -N(R 11 )C(O)R 11 , -C(O)OR 11 , -OC(O)R 11 , -S(O)R 11 , -S(O) 2 R 11 , - S(O) 2 N(R 11 ) 2 , -N(R 11 )S(O) 2 R
  • each R 1 is independently selected from -OR 11 , -SR 11 , and -N(R 11 ) 2 . In some embodiments, each R 1 is independently selected from -OR 11 , -SR 11 , and -N(R 11 ) 2 .
  • each R 1 is -OR 11 [0065]
  • z is 1, and R 1 is selected from halogen, -OR 11 , -SR 11 , -N(R 11 ) 2 , - C(O)R 11 , -C(O)N(R 11 ) 2 , -N(R 11 )C(O)R 11 , -C(O)OR 11 , -OC(O)R 11 , -S(O)R 11 , -S(O) 2 R 11 , - S(O) 2 N(R 11 ) 2 , -N(R 11 )S(O) 2 R 11 , -S(O)(NR 11 )R 11 , -S(NR 11 ) 2 R 11 ,
  • z is 1, and each R 1 is independently selected from -OR 11 , -SR 11 , and -N(R 11 ) 2 . In some embodiments, z is 1, and each R 1 is independently selected from -OR 11 , -SR 11 , and - N(R 11 ) 2 . In some embodiments, z is 1, and each R 1 is -OR 11 . In some embodiments, z is 1, and each R 1 is -F.
  • each R 2 is independently selected from: halogen, -OR 12 , -SR 12 , - N(R 12 ) 2 , -C(O)R 12 , -C(O)N(R 12 ) 2 , -N(R 12 )C(O)R 12 , -C(O)OR 12 , -OC(O)R 12 , -S(O)R 12 , -S(O) 2 R 12 , -S(O) 2 N(R 12 ) 2 , -N(R 12 )S(O) 2 R 12 , -S(O)(NR 12 )R 12 , -S(NR 12 ) 2 R 12 , -NO 2 , -CN; and C 1-6 al
  • each R 2 is independently selected from halogen, -OR 12 , -SR 12 , -N(R 12 ) 2 , -C(O)R 12 , -C(O)N(R 12 ) 2 , - N(R 12 )C(O)R 12 , -C(O)OR 12 , -OC(O)R 12 , -S(O)R 12 , -S(O) 2 R 12 , -S(O) 2 N(R 12 ) 2 , -N(R 12 )S(O) 2 R 12 , - S(O)(NR 12 )R 12 , -S(NR 12 ) 2 R 12 , -NO 2 , and -CN.
  • each R 2 is independently selected from: halogen, -OR 12 , -SR 12 , - N(R 12 ) 2 , -NO 2 , -CN; and C 1-6 alkyl optionally substituted with one or more halogen substituents.
  • m is 1, and R 2 is selected from: halogen, -OR 12 , -SR 12 , -N(R 12 ) 2 , - NO 2 , -CN; and C 1-6 alkyl optionally substituted with one or more halogen substituents.
  • m is 1, and R 2 is -CN.
  • m is 1, and R 2 is selected from C 1-6 alkyl optionally substituted with one or more halogen substituents.
  • m is 1, and R 2 is selected from C 1-6 alkyl.
  • m is 1, and R 2 is selected from C 1-6 alkyl optionally substituted with one or more halogen substituents.
  • m is 1, and each R 2 is independently selected from: halogen, - OR 12 , -SR 12 , -N(R 12 ) 2 , -NO 2 , -CN; and C 1-6 alkyl optionally substituted with one or more halogen substituents.
  • m is 1, each R 2 is independently selected from: halogen, - OR 12 , -SR 12 , -N(R 12 ) 2 , -NO 2 , and -CN.
  • m is 1, and R 2 is -CN. In some embodiments, m is 1, R 2 is selected from C 1-6 alkyl optionally substituted with one or more halogen substituents. In some embodiments, m is 1, R 2 is selected from C 1-6 alkyl. [0069] In some embodiments, for a compound or salt of Formula (I), (Ia), (Ib), (I-1), (I-1a), (I- 1b), (I-2), (I-2a), (I-2b), or (Ic), X 2 is selected from -O-, -S-, -C(R 3 ) 2 -, -N(R 4 )-, and - C(R 18 ) 2 N(R 4 )-.
  • X 2 is selected from -O-, -S-, -C(R 3 ) 2 -, and -N(R 4 )-. In some embodiments, X 2 is selected from -O-, -S-, and -N(R 4 )-. In some embodiments, X 2 is selected from -O-, -S-, and -N(H)-.
  • X 2 is selected from -O-, -S-, -N(R 4 )-, and -C(R 18 ) 2 N(R 4 )-. In some embodiments, X 2 is selected from -O-, -N(R 4 )-, and -C(R 18 ) 2 N(R 4 )-. In some embodiments, X 2 is selected from -O-, -N(H)-, and -CH 2 N(H)-.
  • X 2 is selected from -O- and -N(R 4 )-. In some embodiments, X 2 is selected from -O- and -N(H)-. In some embodiments, X 2 is -O-. [0071] In some embodiments, for a compound or salt of Formula (I), (Ia), (Ib), (I-1), (I-1a), (I- 1b), (I-2), (I-2a), (I-2b), or (Ic), X 2 is -N(R 4 )-.
  • X 2 is -N(R 4 )-, wherein R 4 is selected from hydrogen, C 1-6 alkyl, and C 3-6 carbocycle, wherein the C 1-6 alkyl and C 3-6 carbocycle are each optionally substituted with one or more substituents independently selected from: halogen, -OR 14 , -SR 14 , -N(R 14 ) 2 , -NO 2 , and -CN.
  • X 2 is -N(R 4 )-, wherein R 4 is selected from C 1-6 alkyl, and C 3-6 carbocycle, wherein the C 1-6 alkyl and C 3-6 carbocycle are each optionally substituted with one or more substituents independently selected from: halogen, -OR 14 , -SR 14 , -N(R 14 ) 2 , -NO 2 , and -CN.
  • X 2 is -N(R 4 )-, wherein R 4 is hydrogen.
  • X 2 is -N(H)-.
  • X 2 is -C(R 18 ) 2 N(R 4 )-.
  • X 2 is - C(R 18 ) 2 N(R 4 )-, wherein R 4 is selected from hydrogen, C 1-6 alkyl, and C 3-6 carbocycle, wherein C 1-6 alkyl and C 3-6 carbocycle are each optionally substituted with one or more substituents independently selected from: halogen, -OR 14 , -SR 14 , -N(R 14 ) 2 , -NO 2 , and -CN; and R 18 is hydrogen, C(O)R 17 , -NO 2 , CN or C 2-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR 17 , -SR 17 , -N(R 17 ) 2 , -C(O)R 17 , - NO 2 , and CN.
  • X 2 is -CH2N(R 4 )-.
  • X 2 is -CH2N(R 4 )-, wherein R 4 is selected from hydrogen, C 1-6 alkyl, and C 3-6 carbocycle, wherein the C 1-6 alkyl and C 3-6 carbocycle are each optionally substituted with one or more substituents independently selected from: halogen, -OR 14 , -SR 14 , -N(R 14 ) 2 , -NO 2 , and -CN.
  • X 2 is - CH2N(R 4 )-, wherein R 4 is selected from C 1-6 alkyl and C 3-6 carbocycle, wherein the C 1-6 alkyl and C 3-6 carbocycle are each optionally substituted with one or more substituents independently selected from: halogen, -OR 14 , -SR 14 , -N(R 14 ) 2 , -NO 2 , and -CN.
  • X 2 is - CH2N(R 4 )-, wherein R 4 is hydrogen.
  • X 2 is -C(R 18 ) 2 N(H)-.
  • X 2 is -C(R 18 ) 2 N(H)-, wherein each R 18 is selected from hydrogen, C(O)R 17 , -NO 2 , -CN, and C 2-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR 17 , -SR 17 , -N(R 17 ) 2 , -C(O)R 17 , -NO 2 , and CN.
  • X 2 is - C(R 18 ) 2 N(H)-,wherein each R 18 is independently hydrogen.
  • X 2 is - CH 2 N(H)-.
  • R A is selected from hydrogen and C 1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -CN, C 3-6 carbocycle, and 3- to 6-membered heterocycle.
  • R A is C 1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -CN, C 3-6 carbocycle, and 3- to 6-membered heterocycle.
  • R A is selected from hydrogen and C 1-6 alkyl, wherein C 1-6 alkyl is optionally substituted with one or more halogen substituents. In some embodiments, R A is C 1-6 alkyl optionally substituted with one or more halogen substituents. In some embodiments, R A is selected from hydrogen, methyl, and ethyl. In some embodiments, R A is selected from methyl, ethyl, and cyclopropylmethyl. In some embodiments, R A is selected from methyl and ethyl. In some embodiments, R A is methyl. In some embodiments, R A is ethyl. In some embodiments, R A is hydrogen. In some embodiments, R A is cyclopropylmethyl.
  • a compound or salt of Formula (I), (Ia), (Ib), (I-1), (I-1a), (I- 1b), (I-2), (I-2a), (I-2b), or (Ic) is selected from optionally substituted C3-9 carbocyclene, optionally substituted C 3 - 8 carbocyclene, optionally substituted C 3 - 7 carbocyclene, optionally substituted C 3 - 6 carbocyclene, optionally substituted C 3 - 5 carbocyclene, and optionally substituted C 3 - 4 carbocyclene.
  • A is selected from optionally substituted C4-10 carbocyclene, optionally substituted C5-10 carbocyclene, optionally substituted C6-10 carbocyclene, optionally substituted C 7 - 10 carbocyclene, optionally substituted C 8 - 10 carbocyclene, and optionally substituted C9-10 carbocyclene.
  • is C 3-10 carbocyclene optionally substituted with one or more substituents independently selected from: halogen, -OR 15 , -N(R 15 ) 2 , -C(O)R 15 , -NO 2 , O, and -CN; and C 1-6 alkyl optionally substituted with one or more halogen substituents.
  • is C 3-6 carbocyclene optionally substituted with one or more substituents independently selected from: halogen, -OR 15 , -N(R 15 ) 2 , -C(O)R 15 , -NO 2 , O, and -CN; and C 1-6 alkyl optionally substituted with one or more halogen substituents.
  • is phenylene or 5- to 6-membered heteroarylene, any of which is optionally substituted with one or more substituents independently selected from: halogen, -OR 15 , -N(R 15 ) 2 , -C(O)R 15 , -NO 2 , O, and -CN; and C 1-6 alkyl optionally substituted with one or more halogen substituents.
  • A is unsubstituted phenylene or 5- to 6- membered heteroarylene.
  • is phenylene optionally substituted with one or more substituents independently selected from: halogen, -OR 15 , -N(R 15 ) 2 , -C(O)R 15 , -NO 2 , O, and -CN; and C 1-6 alkyl optionally substituted with one or more halogen substituents.
  • A is unsubstituted phenylene.
  • A is an optionally substituted 5- to 10-membered heterocyclene comprising at least one heteroatom selected from nitrogen, oxygen, and sulfur.
  • A is selected from an optionally substituted 5- to 9-membered heterocyclene, an optionally substituted 5- to 8-membered heterocyclene, an optionally substituted 5- to 7-membered heterocyclene, and an optionally substituted 5 or 6-membered heterocyclene.
  • A is selected from an optionally substituted 5- to 10-membered saturated heterocyclene and optionally substituted 5- to 10-membered unsaturated heterocyclene.
  • A is selected from an optionally substituted 5- to 6-membered heteroarylene.
  • Z 1 is absent.
  • Z 1 is selected from O and NR 5 .
  • Z 1 is O.
  • Z 1 is NR 5 .
  • Z 1 is NR 5 .
  • Z 1 is NR 5 , wherein R 5 is selected from hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 3-12 carbocycle, and optionally substituted 3- to 12-membered heterocycle, wherein the substituents on R 5 are independently selected at each occurrence from halogen, -OR 16 , -SR 16 , -N(R 16 ) 2 , -C(O)R 16 , - C(O)N(R 16 ) 2 , -N(R 16 )C(O)R 16 , -N(R 16 )C(O)OR 16 , -C(O)OR 16 , -OC(O)R 16 , -S(O)R 16 , -S(O) 2 R 16 , - S(O) 2 N(R 16 ) 2 , -N(R 16 )S(O) 2 R 16 , -S(O)(NR 16 )R 16 , -S(NR 16 )R 16
  • Z 1 is NR 5 , wherein R 5 is C 1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR 16 , -SR 16 , -N(R 16 ) 2 , -C(O)R 16 , -C(O)N(R 16 ) 2 , -N(R 16 )C(O)R 16 , -N(R 16 )C(O)OR 16 , -C(O)OR 16 , -OC(O)R 16 , -S(O)R 16 , -S(O) 2 R 16 , -S(O) 2 N(R 16 ) 2 , -N(R 16 )S(O) 2 R 16 , -
  • Z 1 is NR 5 , wherein R 5 is C 1-6 alkyl optionally substituted with one or more substituents independently selected from -OR 16 , -N(R 16 ) 2 , halogen, - C3-12 carbocycle, and 3- to 12-membered heterocycle. In some embodiments, Z 1 is NR 5 , wherein R 5 is C 1-6 alkyl optionally substituted with one or more substituents independently selected from -OH, halogen, phenyl, -NH2, -NMe2, and pyridyl.
  • Z 1 is NR 5 , wherein R 5 is C 1-6 alkyl optionally substituted with one or more substituents independently selected from -OH, fluoro, phenyl, -NMe 2 , and pyrid-4-yl. In some embodiments, Z 1 is NR 5 , wherein R 5 is C 1-6 alkyl substituted with -OH. In some embodiments, Z 1 is NR 5 , wherein R 5 is C 1-6 alkyl substituted with phenyl. In some embodiments, Z 1 is NR 5 , wherein R 5 is C 1-6 alkyl substituted with -NMe2.
  • Z 1 is NR 5 , wherein R 5 is C 1-6 alkyl substituted with pyrid-4-yl. In some embodiments, Z 1 is NR 5 , wherein R 5 is C 1-6 alkyl substituted with one or more halogen. In some embodiments, Z 1 is NR 5 , wherein R 5 is C 1-6 alkyl substituted with one or more fluorine atoms. In some embodiments, Z 1 is NR 5 , wherein R 5 is , Z 1 is NR 5 , wherein R 5 is hydrogen.
  • Z 1 is NR 5 , wherein two of R 5 , R 6 , and R 7 are selected from hydrogen and the other of R 5 , R 6 , and R 7 is selected from hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C3-12 carbocycle, and optionally substituted 3- to 12-membered heterocycle, wherein the substituents on R 5 are independently selected at each occurrence from halogen, -OR 16 , -SR 16 , -N(R 16 ) 2 , -C(O)R 16 , -C(O)N(R 16 ) 2 , -N(R 16 )C(O)R 16 , - N(R 16 )C(O)OR 16 , -C(O)OR 16 , -C(O)OR 16 , -C(O)OR 16 , -C(O)OR 16 , -C(O)OR 16 , -C(O)OR 16 , -C(O)OR 16 ,
  • Z 1 is NR 5 , wherein two of R 5 , R 6 , and R 7 are selected from hydrogen and the other of R 5 , R 6 , and R 7 is C 1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR 16 , -SR 16 , -N(R 16 ) 2 , -C(O)R 16 , - C(O)N(R 16 ) 2 , -N(R 16 )C(O)R 16 , -N(R 16 )C(O)OR 16 , -C(O)OR 16 , -OC(O)R 16 , -S(O)R 16 , -S(O) 2 R 16 , - S(O)
  • Z 1 is NR 5 , wherein two of R 5 , R 6 , and R 7 are selected from hydrogen and the other of R 5 , R 6 , and R 7 is C 1-6 alkyl optionally substituted with one or more substituents independently selected from -OR 16 , - N(R 16 ) 2 , halogen, - C3-12 carbocycle, and 3- to 12-membered heterocycle.
  • Z 1 is NR 5 , wherein two of R 5 , R 6 , and R 7 are selected from hydrogen and the other of R 5 , R 6 , and R 7 is C 1-6 alkyl optionally substituted with one or more substituents independently selected from -OH, halogen, phenyl, -NH2, -NMe2, and pyridyl.
  • Z 1 is NR 5 , wherein two of R 5 , R 6 , and R 7 are selected from hydrogen and the other of R 5 , R 6 , and R 7 is C 1-6 alkyl optionally substituted with one or more substituents independently selected from -OH, fluoro, phenyl, -NMe2, and pyrid-4-yl.
  • Z 1 is NR 5 , wherein two of R 5 , R 6 , and R 7 are selected from hydrogen and the other of R 5 , R 6 , and R 7 is C 1-6 alkyl substituted with -OH.
  • Z 1 is NR 5 , wherein two of R 5 , R 6 , and R 7 are selected from hydrogen and the other of R 5 , R 6 , and R 7 is C 1-6 alkyl substituted with phenyl. In some embodiments, Z 1 is NR 5 , wherein two of R 5 , R 6 , and R 7 are selected from hydrogen and the other of R 5 , R 6 , and R 7 is C 1-6 alkyl substituted with -NMe 2 .
  • Z 1 is NR 5 , wherein two of R 5 , R 6 , and R 7 are selected from hydrogen and the other of R 5 , R 6 , and R 7 is C 1-6 alkyl substituted with pyrid-4- yl. In some embodiments, Z 1 is NR 5 , wherein two of R 5 , R 6 , and R 7 are selected from hydrogen and the other of R 5 , R 6 , and R 7 is C 1-6 alkyl substituted with one or more halogen.
  • Z 1 is NR 5 , wherein two of R 5 , R 6 , and R 7 are selected from hydrogen and the other of R 5 , R 6 , and R 7 is C 1-6 alkyl substituted with one or more fluorine atoms.
  • Z 1 is NR 5 , wherein two of R 5 , R 6 , and R 7 are selected from hydrogen and the other of R 5 , R 6 , and R 7 is selected from: hydrogen, methyl, cyclopropyl, phenyl, , , , some embodiments, Z 1 is NR 5 , wherein R 5 is hydrogen.
  • R 5 , R 6 , and R 7 are hydrogen, and the other R 5 , R 6 , and R 7 is selected from C 3-6 carbocycle and C 1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -N(R 16 ) 2 , -OR 16 , wherein R 16 is selected from hydrogen and -O-C 1-6 alkyl.
  • R 5 , R 6 , and R 7 is hydrogen.
  • each R 6 and R 7 is hydrogen.
  • R 7 is C3-12 carbocycle optionally substituted with one or more substituents independently selected from: halogen, -OR 16 , -SR 16 , -N(R 16 ) 2 , -C(O)R 16 , -C(O)N(R 16 ) 2 , -N(R 16 )C(O)R 16 , -N(R 16 )C(O)OR 16 , -C(O)OR 16 , -OC(O)R 16 , -S(O)R 16 , -S(O) 2 R 16 , -S(O) 2 N(R 16 ) 2 , -N(R 16 )S(O) 2 R 16 , -S(O)(NR 16 )
  • R 7 is C 3-6 carbocycle optionally substituted with one or more substituents independently selected from: halogen, -OR 16 , -SR 16 , -N(R 16 ) 2 , -C(O)R 16 , -C(O)N(R 16 ) 2 , -N(R 16 )C(O)R 16 , -N(R 16 )C(O)OR 16 , -C(O)OR 16 , -OC(O)R 16 , -S(O)R 16 , -S(O) 2 R 16 , -S(O) 2 N(R 16 ) 2 , -N(R 16 )S(O) 2 R 16 , -S(O)(NR 16 )
  • R 7 is phenyl.
  • R 7 is selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • R 7 is cyclopropyl.
  • R 7 is C 1-6 alkyl optionally substituted with one or more substituents independently selected from -OR 16 , -SR 16 , -N(R 16 ) 2 , -C(O)R 16 , -C(O)N(R 16 ) 2 , - N(R 16 )C(O)R 16 , -N(R 16 )C(O)OR 16 , -C(O)OR 16 , -OC(O)R 16 , -S(O)R 16 , -S(O) 2 R 16 , -S(O) 2 N(R 16 ) 2 , -N(R 16 )S(O) 2 R 16 , -S(O)(NR 16 )R 16 ,
  • R 7 is C 1-6 alkyl optionally substituted with one or more substituents independently selected from -OR 16 , -N(R 16 ) 2 , halogen, -C 3-12 carbocycle, and 3- to 12-membered heterocycle. In some embodiments, R 7 is C 1-6 alkyl optionally substituted with one or more substituents independently selected from -OR 16 , -N(R 16 ) 2 , halogen, C3-12 carbocycle, and 3- to 12-membered heterocycle.
  • R 7 is C 1-6 alkyl optionally substituted with one or more substituents independently selected from -OH, halogen, phenyl, -NH 2 , -NMe 2 , and pyridyl. In some embodiments, R 7 is C 1-6 alkyl optionally substituted with one or more substituents independently selected from -OH, fluoro, phenyl, -NMe2, and pyrid-4-yl. In some embodiments, R 7 is C 1-6 alkyl substituted with -OH. In some embodiments, R 7 is C 1-6 alkyl substituted with phenyl. In some embodiments, R 7 is C 1-6 alkyl substituted with -NMe2.
  • R 7 is C 1-6 alkyl substituted with pyrid-4-yl. In some embodiments, R 7 is C 1-6 alkyl substituted with one or more halogen. In some embodiments, R 7 is C 1-6 alkyl substituted with one or more fluorine atoms.
  • R 7 is selected from: hydrogen, methyl, cyclopropyl, phenyl, and [0106] In some embodiments, for a compound or salt of Formula (I), (Ia), (Ib), (I-1), (I-1a), (I- 1b), (I-2), (I-2a), (I-2b), or (Ic), R 7 is selected from: hydrogen, methyl, , In some embodiments, R 7 is selected from: cyclopropyl, phenyl, In some embodiments, R 7 is selected from: and .
  • R 5 and R 6 are each hydrogen and R 7 is selected from C 1-6 alkyl optionally substituted with one or more substituents independently selected from: -OR 16 , and R 16 is selected from hydrogen and -O-C 1-6 alkyl.
  • R 5 and R 6 are each hydrogen and R 7 is C 1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR 16 , -SR 16 , - N(R 16 ) 2 , -C(O)R 16 , -C(O)N(R 16 ) 2 , -N(R 16 )C(O)R 16 , -N(R 16 )C(O)OR 16 , -C(O)OR 16 , -OC(O)R 16 , - S(O)R 16 , -S(O) 2 R 16 , -S(O) 2 N(R 16 ) 2 , -N(R 16 )S(O) 2 R 16 , -S
  • R 5 and R 6 are each hydrogen and R 7 is C 1-6 alkyl optionally substituted with one or more substituents independently selected from -OR 16 , -N(R 16 ) 2 , halogen,- C 3-12 carbocycle, and 3- to 12-membered heterocycle.
  • R 5 and R 6 are each hydrogen and R 7 is C 1-6 alkyl optionally substituted with one or more substituents independently selected from -OR 16 , - N(R 16 ) 2 , halogen, C 3-12 carbocycle, and 3- to 12-membered heterocycle.
  • R 5 and R 6 are each hydrogen and R 7 is C 1-6 alkyl optionally substituted with one or more substituents independently selected from -OH, halogen, phenyl, -NH2, -NMe2, and pyridyl. In some embodiments, R 5 and R 6 are each hydrogen and R 7 is C 1-6 alkyl optionally substituted with one or more substituents independently selected from -OH, fluoro, phenyl, -NMe2, and pyrid-4- yl. In some embodiments, R 5 and R 6 are each hydrogen and R 7 is C 1-6 alkyl substituted with -OH.
  • R 5 and R 6 are each hydrogen and R 7 is C 1-6 alkyl substituted with phenyl. In some embodiments, R 5 and R 6 are each hydrogen and R 7 is C 1-6 alkyl substituted with -NMe 2 In some embodiments, R 5 and R 6 are each hydrogen and R 7 is C 1-6 alkyl substituted with pyrid- 4-yl. In some embodiments, R 5 and R 6 are each hydrogen and R 7 is C 1-6 alkyl substituted with one or more halogen. In some embodiments, R 5 and R 6 are each hydrogen and R 7 is C 1-6 alkyl substituted with one or more fluorine atoms.
  • R 5 and R 6 are each hydrogen and R 7 is selected from: hydrogen, methyl, cyclopropyl, phenyl, , , , , , [0111]
  • R 5 and R 6 are each hydrogen and R 7 is selected from: hydrogen, methyl, cyclopropyl, phenyl, , , , , [0112]
  • R 5 and R 6 are each hydrogen and R 7 is selected from: hydrogen, methyl, cyclopropyl, phenyl, , , , , , [0112]
  • R 5 and R 6 are each hydrogen and R 7 is selected from: hydrogen, methyl, cyclopropyl, phenyl, , , , , , [0112]
  • R and R are each hydrogen and R 7 is selected from: cyclopropyl, phenyl, , and .
  • R 5 and R 6 are each hydrogen and R 7 is selected from: and [0113]
  • R 6 and R 7 together with the nitrogen atom to which R 6 and R 7 are attached, form a 3- to 12-membered heterocycle optionally substituted with one or more W 1
  • R 5 is selected from hydrogen, C 1-6 alkyl, C 3-12 carbocycle, and 3- to 12-membered heterocycle, wherein C 1-6 alkyl, C3-12 carbocycle , and 3- to 12-membered heterocycle are each optionally substituted with one or more W 2 .
  • R 6 and R 7 together with the nitrogen atom to which R 6 , and R 7 are attached, form a 3- to 12-membered heterocycle optionally substituted with one or more W 1 , and R 5 is selected from hydrogen and C 1-6 alkyl optionally substituted with one or more W 2 .
  • R 6 and R 7 together with the nitrogen atom to which R 6 , and R 7 are attached, form a 3- to 12-membered heterocycle optionally substituted with one or more W 1 , and R 5 is hydrogen.
  • R 6 and R 7 together with the nitrogen atom to which R 6 , and R 7 are attached, form a 3- to 12-membered heterocycle optionally substituted with one or more W 1 .
  • R 6 and R 7 together with the nitrogen atom to which R 6 , and R 7 are attached, form a 3- to 8-membered heterocycle optionally substituted with one or more W 1 .
  • R 6 and R 7 together with the nitrogen atom to which R 6 , and R 7 are attached, form an aziridine ring, an azetidine ring, a pyrrole ring, a pyrrolidine ring, a pyrazole ring, a pyrazolidine ring, a thiazoline ring, a thiazolidine ring, an oxazoline ring, an oxazolidine ring, an oxadiazoline ring, an oxadiazolidine ring, an imidazole ring, an imidazoline ring, an imidazolidine ring, a piperidine ring, a piperazine ring, a thiomorpholine ring, a morpholine ring, an azepane ring, an oxazepane ring, and a thiazepine ring, each of which is optionally substituted with one or more W 1 .
  • R 6 and R 7 together with the nitrogen atom to which R 6 , and R 7 are attached, form a pyrrolidine ring. In some embodiments, R 6 and R 7 , together with the nitrogen atom to which R 6 , and R 7 are attached, form a morpholine ring. In some embodiments, R 6 and R 7 , together with the nitrogen atom to which R 6 , and R 7 are attached, form a piperidine ring. In some embodiments, R 6 and R 7 , together with the nitrogen atom to which R 6 , and R 7 are attached, form a piperazine ring.
  • R 6 and R 7 together with the nitrogen atom to which R 6 , and R 7 are attached, form a thiomorpholine ring.
  • R 6 and R 7 together with the nitrogen atom to which R 6 , and R 7 are attached, form a 5- to 8-membered heterocycle optionally substituted with one or more W 1 .
  • R 6 and R 7 together with the nitrogen atom to which R 6 , and R 7 are attached, form a pyrrole ring, a pyrrolidine ring, a pyrazole ring, a pyrazolidine ring, a thiazoline ring, a thiazolidine ring, an oxazoline ring, an oxazolidine ring, an oxadiazoline ring, an oxadiazolidine ring, an imidazole ring, an imidazoline ring, an imidazolidine ring, a piperidine ring, a piperazine ring, a thiomorpholine ring, a morpholine ring, an azepane ring, an oxazepane ring, and a thiazepine ring, each of which is optionally substituted with one or more W 1 .
  • R 6 and R 7 together with the nitrogen atom to which R 6 , and R 7 are attached, form a 5- or 6-membered heterocycle optionally substituted with one or more W 1 .
  • R 6 and R 7 together with the nitrogen atom to which R 6 , and R 7 are attached, form a pyrrole ring, a pyrrolidine ring, a pyrazole ring, a pyrazolidine ring, a thiazoline ring, a thiazolidine ring, an oxazoline ring, an oxazolidine ring, an oxadiazoline ring, an oxadiazolidine ring, an imidazole ring, an imidazoline ring, an imidazolidine ring, a piperidine ring, a piperazine ring, a thiomorpholine ring, and a morpholine ring, each of which is optionally substituted with one or more W 1 .
  • R 6 and R 7 together with the nitrogen atom to which R 6 , and R 7 are attached, form a 3- to 8-membered saturated heterocycle optionally substituted with one or more W 1 .
  • R 6 and R 7 together with the nitrogen atom to which R 6 , and R 7 are attached, form an aziridine ring, an azetidine ring, a pyrrolidine ring, a pyrazolidine ring, a thiazolidine ring, an oxazolidine ring, an oxadiazolidine ring, an imidazolidine ring, a piperidine ring, a piperazine ring, a thiomorpholine ring, a morpholine ring, an azepane ring, an oxazepane ring, and a thiazepine ring, each of which is optionally substituted with one or more W 1 .
  • R 6 and R 7 together with the nitrogen atom to which R 6 , and R 7 are attached, form a 5- to 8-membered saturated heterocycle optionally substituted with one or more W 1 .
  • R 6 and R 7 together with the nitrogen atom to which R 6 , and R 7 are attached, form a pyrrolidine ring, a pyrazolidine ring, a thiazolidine ring, an oxazolidine ring, an oxadiazolidine ring, an imidazolidine ring, a piperidine ring, a piperazine ring, a thiomorpholine ring, a morpholine ring, an azepane ring, an oxazepane ring, and a thiazepine ring, each of which is optionally substituted with one or more W 1 .
  • R 6 and R 7 together with the nitrogen atom to which R 6 , and R 7 are attached, form a 5- or 6-membered saturated heterocycle optionally substituted with one or more W 1 .
  • R 6 and R 7 together with the nitrogen atom to which R 6 , and R 7 are attached, form a pyrrolidine ring, a pyrazolidine ring, a thiazolidine ring, an oxazolidine ring, an oxadiazolidine ring, an imidazolidine ring, a piperidine ring, a piperazine ring, a thiomorpholine ring, and a morpholine ring, each of which is optionally substituted with one or more W 1 .
  • the compound of Formula (I), (Ia), (Ib), (I-1), (I-1a), (I-1b), (I-2), (I-2a), (I-2b), or (Ic) is selected from: , , , , , , , ,
  • the compound of Formula (I), (Ia), (Ib), (I-1), (I-1a), (I-1b), (I-2), (I-2a), (I-2b), or (Ic) is selected from: ,
  • the compound of Formula (I), (Ia), (Ib), (I-1), (I-1a), (I-1b), or (Ic) is selected from: ,
  • the compound of Formula (I), (Ia), (Ib), (I-2), (I-2a), (I-2b), or (Ic) is selected from:
  • the compound of Formula (I), (Ia), (Ib), (I-2), (I-2a), (I-2b), or (Ic) is selected from:
  • the compound of Formula (I) is represented by the structure of Formula (Ic): ( ), or a pharmaceutically acceptable salt thereof, wherein: X 2 is selected from -O-, -S-, -C(R 3 ) 2 -, -N(R 4 )-, and -C(R 18 ) 2 N(R 4 )-; Z 1 is absent, or selected from O and NR 5 ; G is N(H), X 1 is C(O), and is represented by: ; or G is N, X 1 is selected from C(H) and C-OR A , and is represented by ; R A is selected from: hydrogen and C 1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR 10 , -SR 10 , -N(R 10 ) 2 , -C(O)R 10 , -C(O)N(R 10 ) 2 , -N
  • compounds or salts of Formula (I), (Ia), (Ib), (I-1), (I-1a), (I-1b), (I-2), (I-2a), (I-2b), or (Ic) are intended to include all Z-, E- and tautomeric forms as well.
  • “Isomers” are different compounds that have the same molecular formula.
  • “Stereoisomers” are isomers that differ only in the way the atoms are arranged in space.
  • Enantiomers are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a “racemic” mixture.
  • ( ⁇ ) is used to designate a racemic mixture where appropriate.
  • “Diastereoisomers” or “diastereomers” are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other.
  • the absolute stereochemistry is specified according to the Cahn-Ingold-Prelog R-S system. When a compound is a pure enantiomer, the stereochemistry at each chiral carbon can be specified by either R or S.
  • Resolved compounds whose absolute configuration is unknown can be designated (+) or (-) depending on the direction (dextro- or levorotatory) in which they rotate plane polarized light at the wavelength of the sodium D line.
  • Certain compounds described herein contain one or more asymmetric centers and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms, the asymmetric centers of which can be defined, in terms of absolute stereochemistry, as (R)- or (S)-.
  • the present chemical entities, pharmaceutical compositions and methods are meant to include all such possible stereoisomers, including racemic mixtures, optically pure forms, mixtures of diastereomers and intermediate mixtures.
  • Optically active (R)- and (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques.
  • the optical activity of a compound can be analyzed via any suitable method, including but not limited to chiral chromatography and polarimetry, and the degree of predominance of one stereoisomer over the other isomer can be determined.
  • the compounds or salts for Formula (I), (Ia), (Ib), (I-1), (I-1a), (I-1b), (I-2), (I-2a), (I-2b), or (Ic) herein may in some cases exist as diastereomers, enantiomers, or other stereoisomeric forms.
  • the compounds presented herein include all diastereomeric, enantiomeric, and epimeric forms as well as the racemates, mixtures of diastereomers, and other mixtures thereof, to the extent they can be made by one of ordinary skill in the art by routine experimentation. Separation of stereoisomers may be performed by chromatography or by forming diastereomers and separating by recrystallization, or chromatography, or any combination thereof. (Jean Jacques, Andre Collet, Samuel H. Wilen, “Enantiomers, Racemates and Resolutions”, John Wiley And Sons, Inc., 1981, herein incorporated by reference for this disclosure). Stereoisomers may also be obtained by stereoselective synthesis.
  • compounds or salts for Formula (I), (Ia), (Ib), (I-1), (I-1a), (I- 1b), (I-2), (I-2a), (I-2b), or (Ic) may comprise two or more enantiomers or diastereomers of a compound wherein a single enantiomer or diastereomer accounts for at least about 70% by weight, at least about 80% by weight, at least about 90% by weight, at least about 98% by weight, or at least about 99% by weight or more of the total weight of all stereoisomers.
  • a single stereoisomer e.g., an enantiomer, substantially free of its stereoisomer may be obtained by resolution of the racemic mixture using a method such as formation of diastereomers using optically active resolving agents (Stereochemistry of Carbon Compounds, (1962) by E. L. Eliel, McGraw Hill; Lochmuller (1975) J. Chromatogr., 113(3): 283-302).
  • Racemic mixtures of chiral compounds can be separated and isolated by any suitable method, including, but not limited to: (1) formation of ionic, diastereomeric salts with chiral compounds and separation by fractional crystallization or other methods, (2) formation of diastereomeric compounds with chiral derivatizing reagents, separation of the diastereomers, and conversion to the pure stereoisomers, and (3) separation of the substantially pure or enriched stereoisomers directly under chiral conditions.
  • Another approach for separation of the enantiomers is to use a Diacel chiral column and elution using an organic mobile phase such as done by Chiral Technologies (www.chiraltech.com) on a fee for service basis.
  • 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 or salts for Formula (I), (Ia), (Ib), (I-1), (I-1a), (I-1b), (I-2), (I-2a), (I-2b), or (Ic) exist as tautomers.
  • a chemical equilibrium of the tautomers may exist. The exact ratio of the tautomers depends on several factors, including physical state, temperature, solvent, and pH.
  • the compounds disclosed herein are used in different enriched isotopic forms, e.g., enriched in the content of 2 H, 3 H, 11 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 U.S. Patent Nos.5,846,514 and 6,334,997.
  • deuteration can improve the metabolic stability and or efficacy, thus increasing the duration of action of drugs.
  • the compounds disclosed herein have some or all of the 1 H atoms replaced with 2 H atoms.
  • 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. [In: 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.
  • 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.
  • compounds described herein are intended to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, 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, 11 C, 13 C, 14 C, 15 C, 12 N, 13 N, 15 N, 16 N, 16 O, 17 O, 14 F, 15 F, 16 F, 17 F, 18 F, 33 S, 34 S, 35 S, 36 S, 35 Cl, 37 Cl, 79 Br, 81 Br, and 125 I are all contemplated.
  • salts particularly pharmaceutically acceptable salts, of the compounds of Formula (I), (Ia), (Ib), (I-1), (I-1a), (I-1b), (I-2), (I-2a), (I-2b), or (Ic).
  • the compounds of the present disclosure may possess a sufficiently acidic, a sufficiently basic, or both functional groups, can react with any of a number of inorganic bases, and inorganic and organic acids, to form a salt.
  • compounds that are inherently charged can form a salt with an appropriate counterion, e.g., a halide such as bromide, chloride, or fluoride, particularly bromide, trifluoracetic acid, or formic acid.
  • an appropriate counterion e.g., a halide such as bromide, chloride, or fluoride, particularly bromide, trifluoracetic acid, or formic acid.
  • the present disclosure provides a pharmaceutical composition comprising a compound or salt of Formula (I), (Ia), (Ib), (I-1), (I-1a), (I-1b), (I-2), (I-2a), (I-2b), or (Ic), and at least one pharmaceutically acceptable excipient.
  • Pharmaceutical compositions can be formulated using one or more physiologically- acceptable carriers comprising excipients and auxiliaries. Formulation can be modified depending upon the route of administration chosen.
  • compositions comprising a compound, salt or conjugate can be manufactured, for example, by lyophilizing the compound, salt or conjugate, mixing, dissolving, emulsifying, encapsulating or entrapping the conjugate.
  • the pharmaceutical compositions can also include the compounds, salts or conjugates in a free- base form or pharmaceutically-acceptable salt form.
  • a compound or salt of any one of Formula (I), (Ia), (Ib), (I-1), (I-1a), (I-1b), (I-2), (I-2a), (I-2b), or (Ic), may be formulated in any suitable pharmaceutical formulation.
  • a pharmaceutical formulation of the present disclosure typically contains an active ingredient (e.g., compound or salt of any one of Formula (I), (Ia), (Ib), (I-1), (I-1a), (I-1b), (I-2), (I-2a), (I-2b), or (Ic), and one or more pharmaceutically acceptable excipients or carriers, including but not limited to: inert solid diluents and fillers, diluents, sterile aqueous solution and various organic solvents, permeation enhancers, antioxidents, solubilizers, and adjuvants.
  • an active ingredient e.g., compound or salt of any one of Formula (I), (Ia), (Ib), (I-1), (I-1a), (I-1b), (I-2), (I-2a), (I-2b), or (Ic)
  • one or more pharmaceutically acceptable excipients or carriers including but not limited to: inert solid diluents and fillers, diluents,
  • compositions may also be prepared from a compound or salt of any one of Formula (I), (Ia), (Ib), (I-1), (I-1a), (I-1b), (I-2), (I-2a), (I-2b), or (Ic), and one or more pharmaceutically acceptable excipients suitable for transdermal, inhalative, sublingual, buccal, rectal, intraosseous, intraocular, intranasal, epidural, or intraspinal administration. Preparations for such pharmaceutical composition are well-known in the art.
  • the compounds described herein can be used in the preparation of medicaments for the prevention or treatment of diseases or conditions.
  • a method for treating any of the diseases or conditions described herein in a subject in need of such treatment involves administration of pharmaceutical compositions containing at least one compound described herein, or a pharmaceutically acceptable salt, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof, in therapeutically effective amounts to said subject.
  • the compositions containing the compound(s) described herein can be administered for prophylactic and/or therapeutic treatments. In therapeutic applications, the compositions are administered to a patient already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest the symptoms of the disease or condition.
  • compositions containing the compounds described herein are administered to a patient susceptible to or otherwise at risk of a particular disease, disorder or condition. Such an amount is defined to be a "prophylactically effective amount or dose.”
  • prophylactically effective amount or dose In this use, the precise amounts also depend on the patient's state of health, weight, and the like.
  • effective amounts for this use will depend on the severity and course of the disease, disorder or condition, previous therapy, the patient's health status and response to the drugs, and the judgment of the treating physician.
  • the present disclosure provides a method for treatment, comprising administering to a subject in need thereof an effective amount of a compound or salt of Formula (I), (Ia), (Ib), (I-1), (I-1a), (I-1b), (I-2), (I-2a), (I-2b), or (Ic).
  • a method for immunotherapeutic treatment comprising administering to a subject in need thereof an effective amount of a compound or salt of Formula (I), (Ia), (Ib), (I-1), (I-1a), (I-1b), (I-2), (I-2a), (I-2b), or (Ic).
  • immunotherapeutic treatment may be used to treat disorders resulting from a virus, bacteria, cancer, or tumor.
  • the present disclosure can be used as a method for immunotherapeutic treatment in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising a compound or salt of Formula (I), (Ia), (Ib), (I-1), (I-1a), (I-1b), (I-2), (I-2a), (I-2b), or (Ic), and a pharmaceutically acceptable excipient.
  • a pharmaceutical composition comprising a compound or salt of Formula (I), (Ia), (Ib), (I-1), (I-1a), (I-1b), (I-2), (I-2a), (I-2b), or (Ic), and a pharmaceutically acceptable excipient may be used as an immunological adjuvant.
  • the immunological adjuvant of the present disclosure may be used in combination with a vaccine for the treatment or prevention a disease, state or condition in a patient in need thereof.
  • immunological adjuvant may be as described Gutjahr, A., et al. Triggering Intracellular Receptors for Vaccine Adjuvantation. Trends in Immunology, 37(9), 573–587 (2016).
  • the present disclosure can be used as a method of activating an immune response to a pathogen in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising a compound or salt of Formula (I), (Ia), (Ib), (I-1), (I-1a), (I-1b), (I-2), (I-2a), (I-2b), or (Ic), and a pharmaceutically acceptable excipient.
  • a pharmaceutical composition comprising a compound or salt of Formula (I), (Ia), (Ib), (I-1), (I-1a), (I-1b), (I-2), (I-2a), (I-2b), or (Ic), and a pharmaceutically acceptable excipient.
  • the present disclosure can be used as a method of inhibiting ENPP1 in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising a compound or salt of Formula (I), (Ia), (Ib), (I-1), (I-1a), (I-1b), (I-2), (I-2a), (I-2b), or (Ic), and a pharmaceutically acceptable excipient.
  • a pharmaceutical composition comprising a compound or salt of Formula (I), (Ia), (Ib), (I-1), (I-1a), (I-1b), (I-2), (I-2a), (I-2b), or (Ic), and a pharmaceutically acceptable excipient.
  • the present disclosure can be used as a method of activating STING activity in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising a compound or salt of Formula (I), (Ia), (Ib), (I-1), (I- 1a), (I-1b), (I-2), (I-2a), (I-2b), or (Ic), and a pharmaceutically acceptable excipient.
  • a pharmaceutical composition comprising a compound or salt of Formula (I), (Ia), (Ib), (I-1), (I- 1a), (I-1b), (I-2), (I-2a), (I-2b), or (Ic), and a pharmaceutically acceptable excipient.
  • Examples 1-13 show general and exemplary procedures for the preparation of the claimed ENPP1 modulators.
  • Example 14 provides selected compounds of the disclosure with associated 1 H NMR and mass spectroscopy data.
  • Example 15 provides bioassay procedures and associated data for the enzymatic inhibition of ENPP1 of selected ENPP1 modulators as described herein.
  • Step 2 Preparation of (R)-4-amino-N-(1-(4-methoxyphenyl)ethyl)benzenesulfonamide.
  • [0158] To a flask purged with inert gas was added 20% Pd(OH) 2 on carbon (2.1 g) followed by a solution of (R)-N-(1-(4-methoxyphenyl)ethyl)-4-nitrobenzenesulfonamide (40.4 g, 120 mmol) in EtOH (200 mL) and THF (200 mL).
  • Step 4 Preparation of (R)-4-((8-methoxy-1,7-naphthyridin-4-yl)amino)-N-(1-(4- [0160] To a solution of 4-chloro-8-methoxy-1,7-naphthyridine (333 mg, 1.71 mmol) and (R)-4- amino-N-(1-(4-methoxyphenyl)ethyl)benzenesulfonamide (577 mg, 1.88 mmol) in THF (20 mL) was added RuPhos Pd G3 (143 mg, 171 ⁇ mol) and t-BuONa (329 mg, 3.42 mmol).
  • Step 5 Preparation of (R)-N-((R)-2-hydroxypropyl)-4-((8-methoxy-1,7-naphthyridin-4- yl)amino)-N'-((R)-1-(4-methoxyphenyl)ethyl)benzenesulfonimidamide and (S)-N-((R)-2- hydroxypropyl)-4-((8-methoxy-1,7-naphthyridin-4-yl)amino)-N'-((R)-1-(4-methoxyphenyl)ethyl) [0161] To a solution of (R)-4-((8-methoxy-1,7-naphthyridin-4-yl)amino)-N-(1-(4- methoxyphenyl)ethyl)benzenesulfonamide (400 mg, 861 ⁇ mol) and triethylamine (1.31
  • Step 6 Preparation of (R)-N-((R)-2-hydroxypropyl)-4-((8-methoxy-1,7-naphthyridin-4- yl)amino)benzenesulfonimidamide (1).
  • Step 2 Preparation of 4-((8-methoxy-1,7-naphthyridin-4-yl)amino)benzenesulfonimidamide [0165]
  • the title compound was synthesized using a similar procedure described in Example 2, step 6.
  • the product was purified by preparative HPLC (eluent: water / acetonitrile w/ 0.1% formic acid).
  • Example 5 Exemplary Scheme—Synthesis of Compounds (23) Preparation of 4-(((8-methoxy-1,7-naphthyridin-4-yl)amino)methyl)benzenesulfonamide (23). [0167] To a solution of 4-chloro-8-methoxy-1,7-naphthyridine (100 mg, 515 ⁇ mol) and 4- (aminomethyl)benzenesulfonamide (149 mg, 668 ⁇ mol) in 1-methoxy 2-propanol (5 mL) was added TsOH (44 mg, 2571 ⁇ mol) at 20 °C.
  • Step 2 Preparation of tert-butyl (4-(2-cyanoacetyl)-2-methoxypyridin-3-yl)carbamate. [0169] To a solution of acetonitrile (2.04 g, 49.59 mmol, 2.61 mL) in THF (35 mL) was added dropwise n-butyllithium (2.5 M in hexanes, 19.8 mL) at -78°C over 5 min.
  • Step 3 Preparation of 4-hydroxy-8-methoxy-1,7-naphthyridine-3-carbonitrile [0170]
  • a mixture of tert-butyl (4-(2-cyanoacetyl)-2-methoxypyridin-3-yl)carbamate (3.26 g, 11.2 mmol) and DMF-DMA (9.73 g, 81.7 mmol) in DMF (11 mL) was purged with N2 and stirred at 20 °C for 1 h. The resulting mixture was filtered and concentrated under reduced pressure. After extracting with ethyl acetate and water, the organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure.
  • Step 5 Preparation of 4-((3-cyano-8-methoxy-1,7-naphthyridin-4-yl)amino)benzenesulfonamide (24).
  • Step 1 Preparation of 4-((1,7-naphthyridin-4-yl)amino)benzenesulfonamide.
  • Step 2 Preparation of 4-((1,7-naphthyridin-4-yl)amino)benzenesulfonamide.
  • the title compound was synthesized using a similar procedure described in Example 2, step 6.
  • the product was purified by preparative HPLC (eluent: water / acetonitrile w/ 0.1% TFA).
  • Step 1 Preparation of (R)-4-hydroxy-N-(1-(4-methoxyphenyl)ethyl)benzenesulfonamide.
  • Step 2 Preparation of (R)-4-((8-methoxy-1,7-naphthyridin-4-yl)oxy)-N-(1-(4- methoxyphenyl)ethyl)benzenesulfonamide.
  • (R)-4-hydroxy-N-(1-(4-methoxyphenyl)ethyl)benzenesulfonamide (1.26 g, 4.10 mmol) in MeOH (12 mL) was added 10M sodium hydroxide (aq, 410 ⁇ L) at 20 °C. After stirring for 10 min, the mixture was concentrated, and dissolved in N,N-dimethylacetamide (12 mL).
  • Step 3 Preparation of (R)-N-((R)-2-hydroxypropyl)-4-((8-methoxy-1,7-naphthyridin-4-yl)oxy)- N'-((R)-1-(4-methoxyphenyl)ethyl)benzenesulfonimidamide and (S)-N-((R)-2-hydroxypropyl)-4- ((8-methoxy-1,7-naphthyridin-4-yl)oxy)-N'-((R)-1-(4- methoxyphenyl)ethyl)benzenesulfonimidamide.
  • Step 4 Preparation of (S)-N-((R)-2-hydroxypropyl)-4-((8-methoxy-1,7-naphthyridin-4- yl)oxy)benzenesulfonimidamide (32).
  • the title compound was synthesized using a similar procedure described in Example 2, step 6.
  • the product was purified by preparative HPLC (eluent: water / acetonitrile w/ 0.1% formic acid).
  • LC-MS m/z [M+H] + : 389.1.
  • Example 12 Exemplary Scheme—Synthesis of Compound (52). Step 1: Preparation of 6-fluoro-2-methoxy-3-nitropyridine [0181] A flame dried 100 mL RBF equipped with a magnetic stirrer bar was charged with 6- chloro-2-methoxy-3-nitropyridine (4.00 g, 1.0 equiv, 20.2 mmol) and tetramethylammonium fluoride (2.52 g, 1.3 equiv, 26.3 mmol). The reaction media was flushed with N2 and dry DMF (50 mL) was then added to the reaction media which was stirred at ambient temperature for 6h. At this point the reaction media was filtrated and the solid was washed once with AcOEt.
  • 6- chloro-2-methoxy-3-nitropyridine 4.00 g, 1.0 equiv, 20.2 mmol
  • tetramethylammonium fluoride 2.52 g, 1.3 equiv, 26.3 mmol
  • Step 2 Preparation of 6-fluoro-2-methoxypyridin-3-amine [0182] A 100 mL RBF equipped with a magnetic stirrer bar was charged with 6-fluoro-2- methoxy-3-nitropyridine (1.70 g, 1 equiv, 9.9 mmol). MeOH (33 mL) was added followed by Pt/V (2%) (482 mg, 5 mol%, 49.4 ⁇ mol) and the reaction media was flushed with N 2 and then purged with H2. The reaction media was kept under H2 atmosphere (1 atm) and stirred until full reduction of the nitro group was observed. After 5h of stirring the reaction media was purged with N 2 , and then filtrated with a syringe filter.
  • Step 3 Preparation of 5-(((6-fluoro-2-methoxypyridin-3-yl)amino)methylene)-2,2-dimethyl-1,3- dioxane-4,6-dione [0183] A 50 mL RBF equipped with a magnetic stirrer bar was charged with 6-fluoro-2- methoxypyridin-3-amine (1.0 g, 1.0 equiv, 9.85 mmol).
  • Step 4 Preparation of 6-fluoro-8-methoxy-1,7-naphthyridin-4(1H)-one
  • Dowtherm A 124 mL
  • the reaction media was allowed to stir at 220 °C for further 10 minutes.
  • the reaction media was allowed to cool down to room temperature at which point copious amount of hexanes was added.
  • Step 5 Preparation of Preparation of 4-chloro-6-fluoro-8-methoxy-1,7-naphthyridine [0185] A 100 mL RBF equipped with a magnetic stirrer bar was charged with 6-fluoro-8- methoxy-1,7-naphthyridin-4(1H)-one (820 mg, 1.0 equiv, 4.22 mmol).
  • Step 6 Preparation of (R)-4-((6-fluoro-8-methoxy-1,7-naphthyridin-4-yl)amino)-N-(1-(4- methoxyphenyl)ethyl)benzenesulfonamide [0186] To a flame dried 10 mL RBF equipped with a magnetic stirrer bar was added 4-chloro-6- fluoro-8-methoxy-1,7-naphthyridine (200 mg, 1.0 equiv, 941 ⁇ mol), RuPhos Pd G4 (40.8 mg, 5 mol%, 47.0 ⁇ mol), (R)-4-Amino-N-(1-(4-methoxyphenyl)ethyl)benzenesulfonamide (320 mg, 1.0 equiv, 941 ⁇ mol) and potassium phosphate tribasic (306 mg, 1.5 equiv, 1.41 mmol).
  • Step 7 Preparation of 4-((6-fluoro-8-methoxy-1,7-naphthyridin-4-yl)amino)benzenesulfonamide (52) [0187] To a 25 mL RBF equipped with a magnetic stirrer bar was added (R)-4-((6-fluoro-8- methoxy-1,7-naphthyridin-4-yl)amino)-N-(1-(4-methoxyphenyl)ethyl)benzenesulfonamide (200 mg, 1 equiv, 414 ⁇ mol).
  • the RBF was evacuated and backfilled with nitrogen 3 times, then dried THF (5.00 mL) was added.
  • the reaction vessel was purged with N2 for one more minute and the resulting mixture was stirred and heated at 75 °C under N2 atmosphere for 24h.
  • the reaction was cooled down to room temperature and was quenched with aq. NH 4 Cl (5 mL) and diluted with ethyl acetate.
  • Organic layer was separated and the aq. layer was extracted three times with ethyl acetate. Organics layers were combined, washed with brine and dried over anhydrous Na2SO4.
  • Step 3 Preparation of (R)-4-((8-(cyclopropylmethoxy)-6-fluoro-1,7-naphthyridin-4-yl)amino)- [0190] To a 5 mL RBF equipped with a magnetic stirrer bar was added (R)-4-((8- (cyclopropylmethoxy)-6-fluoro-1,7-naphthyridin-4-yl)amino)-N-((R)-2-hydroxypropyl)-N'-((R)- 1-(4-methoxyphenyl)ethyl)benzenesulfonimidamide (15 mg, 1 equiv, 25.9 ⁇ mol).
  • Example 14 Example Compounds of the Disclosure. [0191] Compounds 3-20 (TABLE 1) were synthesized according to the general scheme in Example 1 using similar procedures described for compounds 1 and 2 replacing (R)-1- aminopropan-2-ol with the appropriate amine in step 5.
  • Compound 30 (TABLE 1) was synthesized using similar procedures described in Example 4 for compound 22 replacing 4-((8-methoxy-1,7-naphthyridin-4- yl)amino)benzenesulfonamide with (R)-4-((8-methoxy-1,7-naphthyridin-4-yl)oxy)-N-(1-(4- methoxyphenyl)ethyl)benzenesulfonamide [0194] Compound 33-34 (TABLE 1) were synthesized according to the general scheme in Example 9 using similar procedures described for compounds 1 and 2 replacing sodium methoxide in methanol with sodium ethoxide in step 3.
  • Compound 35-36 (TABLE 1) were synthesized according to the general scheme in Example 9, compounds 31 and 32 using similar procedures described for compounds 1 and 2 replacing sodium methoxide in methanol with sodium phenylmethanolate in step 3 and heating the reaction in step 6 at 50 °C in a sealed vessel.
  • Compounds 37-47 and 50 (TABLE 1) were synthesized according to the general scheme in Example 1 using similar procedures described for compounds 1 and 2 replacing (R)-1- aminopropan-2-ol with the appropriate amine in step 5.
  • Example 15 ENPP1 Enzymatic Inhibition Assay.
  • the inhibition of ENPP1’s phosphodiesterase activity was tested in a purified enzymatic assay using 2’3’-cyclic GAMP as a substrate which allowed for the release of cleaved AMP to be monitored using a luminescent assay. Inhibition of ENPP1 activity by small molecules resulted in a dose-dependent reduction in luminescence.
  • Putative inhibitors were diluted in assay buffer (50 mM Tris pH 8.0, 250 mM NaCl, 0.5 mM CaCl2, 1 ⁇ M ZnCl2, 1% DMSO) and pre-incubated for 15 minutes at 37 °C with recombinant protein containing the human ENPP1 enzymatic domain (Viva Biotech). The enzymatic reaction was initiated upon addition of the 2’3’-cGAMP substrate. The final reaction concentrations were 1 nM ENPP1 and 20 ⁇ M 2’3’-cGAMP substrate in a 25 ⁇ L volume. Inhibitor concentrations ranged from 10 ⁇ M to 0.056 nM. The reaction was incubated for 30 minutes at 37 °C.
  • the amount of AMP generated from the cleavage of 2’3’- cGAMP was determined using the Promega AMP-Glo method according to the manufacturer’s protocol.
  • AMP-Glo reagent 1 was added and incubated with the reaction mix for 1 hour at room temperature.
  • AMP Detection solution was added and the mixture was incubated for an additional hour. The luminescence of the mixture was read on a Perkin Elmer Ensight TM plate reader.
  • the maximum and minimum levels of ENPP1 activity were established using no inhibitor and no enzyme controls, respectively. The activity observed using ENPP1 inhibitors was quantified as the percent of activity relative to these controls.
  • IC50 values were calculated using CDD Vault by fitting a sigmoidal variable slope nonlinear regression model to the data. [0202] TABLE 2 includes IC50 values for ENPP1 inhibition of selected compounds; with compounds having an IC50 of less than 10 nM as A, 10 nM ⁇ B ⁇ 100 nM as B, and greater than 100 nM as C. Table 2. ENPP1 IC50 values for selected compounds

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Abstract

La divulgation concerne des modulateurs d'ENPP1 à base de naphtyridines de formule (I), (Ia), (Ib), (I-1), (I-1a), (I-1b), (I-2), (I-2a), (I-2b) ou (Ic) et des sels de ceux-ci, et leur utilisation pour la modulation de l'activité de l'ENPP1.
PCT/US2023/022395 2022-05-16 2023-05-16 Modulateurs d'enpp1 à base de naphtyridine et leurs utilisations Ceased WO2023225001A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5846514A (en) 1994-03-25 1998-12-08 Isotechnika, Inc. Enhancement of the efficacy of nifedipine by deuteration
US6334997B1 (en) 1994-03-25 2002-01-01 Isotechnika, Inc. Method of using deuterated calcium channel blockers
WO2019046778A1 (fr) * 2017-08-31 2019-03-07 Mavupharma, Inc. Inhibiteurs de l'ectonucléotide pyrophosphatase-phosphodiestérase (enpp-1) et utilisations de ces derniers
WO2021225969A1 (fr) * 2020-05-04 2021-11-11 Volastra Therapeutics, Inc. Inhibiteurs imino sulfanone de l'enpp1

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5846514A (en) 1994-03-25 1998-12-08 Isotechnika, Inc. Enhancement of the efficacy of nifedipine by deuteration
US6334997B1 (en) 1994-03-25 2002-01-01 Isotechnika, Inc. Method of using deuterated calcium channel blockers
WO2019046778A1 (fr) * 2017-08-31 2019-03-07 Mavupharma, Inc. Inhibiteurs de l'ectonucléotide pyrophosphatase-phosphodiestérase (enpp-1) et utilisations de ces derniers
WO2021225969A1 (fr) * 2020-05-04 2021-11-11 Volastra Therapeutics, Inc. Inhibiteurs imino sulfanone de l'enpp1

Non-Patent Citations (19)

* Cited by examiner, † Cited by third party
Title
"Basic and Clinical Pharmacology", 2003, MCGRAW HILL
"Encyclopedia of Reagents for Organic Synthesis", 1995
"Handbook of Clinical Drug Data", 2002, MCGRAW-HILL
"Principles of Drug Action", 1990, CHURCHILL LIVINGSTON
"Remingtons Pharmaceutical Sciences", 2000, LIPPINCOTT WILLIAMS & WILKINS
"The Pharmacological Basis of Therapeutics", 2001, MCGRAW HILL
CHIRAL TECHNOLOGIES, Retrieved from the Internet <URL:www.chiraltech.com>
CURR., PHARM. DES., vol. 6, no. 10, 2000
DATABASE Registry [online] Chemical Abstracts Service; 20 December 2019 (2019-12-20), ANONYMOUS: "3-[(1,2-dihydro-2-oxo-1,7-naphthyridin-4-yl)amino]- N,N-dimethyl-1-azetidinesulfonamide", XP093067997, retrieved from STN Database accession no. 2395811-69-3 *
DATABASE Registry [online] Chemical Abstracts Service; 5 June 2020 (2020-06-05), ANONYMOUS: "N,N-dimethyl-3-[1-(1,7-naphthyridin-4-ylamino)ethyl]-Benzenesulfonamide", XP093067995, retrieved from STN Database accession no. 2419508-30-6 *
E. L. ELIEL: "Stereochemistry of Carbon Compounds", 1962, MCGRAW HILL
EVANS, E. ANTHONY: "Synthesis of radiolabeled compounds", J. RADIOANAL. CHEM., vol. 64, no. 1-2, 1981, pages 9 - 32
GEORGE W.VARMA, RAJENDER S.: "The Synthesis of Radiolabeled Compounds via Organometallic Intermediates", TETRAHEDRON, vol. 45, no. 21, 1989, pages 6601 - 21
GUTJAHR, A. ET AL.: "Triggering Intracellular Receptors for Vaccine Adjuvantation", TRENDS IN IMMUNOLOGY, vol. 37, no. 9, 2016, pages 573 - 587, XP029706574, DOI: 10.1016/j.it.2016.07.001
L. FIESERM. FIESER, FIESER AND FIESER'S REAGENTS FOR ORGANIC SYNTHESIS, 1994
LOCHMULLER, J. CHROMATOGR., vol. 113, no. 3, 1975, pages 283 - 302
MARTINDALE: "The Extra Pharmacopoeia", 1999, THE PHARMACEUTICAL PRESS
R. LAROCK, COMPREHENSIVE ORGANIC TRANSFORMATIONS, 1989
T. W. GREENEP. G. M. WUTS: "Protective Groups in Organic Synthesis", 1991

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