EP4448105A1 - Dérivés hétérocycliques pour le traitement d'une maladie - Google Patents

Dérivés hétérocycliques pour le traitement d'une maladie

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Publication number
EP4448105A1
EP4448105A1 EP22850824.8A EP22850824A EP4448105A1 EP 4448105 A1 EP4448105 A1 EP 4448105A1 EP 22850824 A EP22850824 A EP 22850824A EP 4448105 A1 EP4448105 A1 EP 4448105A1
Authority
EP
European Patent Office
Prior art keywords
optionally substituted
independently selected
alkyl
halogen
substituents independently
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Application number
EP22850824.8A
Other languages
German (de)
English (en)
Inventor
Rohit Ranjan
Belinda HETZLER
Joseph E. Pero
James Cassidy
Nathan Shapiro
Haiying CAI
Zachary NEWBY
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Glaxo Wellcome Uk Ltd
Vir Biotechnology Inc
Original Assignee
Glaxo Wellcome Uk Ltd
Vir Biotechnology Inc
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Publication date
Application filed by Glaxo Wellcome Uk Ltd, Vir Biotechnology Inc filed Critical Glaxo Wellcome Uk Ltd
Publication of EP4448105A1 publication Critical patent/EP4448105A1/fr
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • 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
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/10—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring

Definitions

  • the membrane protein STT3 is a highly conserved subunit of the oligosaccharyltransferase and contains the active site of the complex. STT3 transfers oligosaccharides onto the asparagine residues of sequons (N-X ⁇ P-T/S/C) in nascent glycoproteins.
  • the two alternate STT3 proteins, STT3A and STT3B are widely expressed in a variety of human tissues and are encoded by different genes. STT3A and STT3B exist in distinct OST complexes, possess different kinetic properties, and have different substrate preferences, in spite of their partially overlapping roles in glycosylation.
  • STT3A complex generally promotes co-translational glycosylation
  • STT3B complex generally promotes post-translational glycosylation.
  • oligosaccharyltransferase complex has been implicated in several diseases, few compounds have been identified that inhibit the function of this complex. There is a need in the art to identify compounds that inhibit the function of the STT3A and/or STT3B complexes.
  • the present disclosure provides a compound represented by the structure of Formula (II): or a pharmaceutically acceptable salt thereof, wherein: A is selected from 4- to 10-membered heterocycle and C 3-10 carbocycle optionally substituted with one or more substituents independently selected from halogen, -OR 11 , -N(R 11 ) 2 , -C(O)R 11 , -C(O)OR 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 , -C(O)OR 11 , -NO 2 , and - CN; B is selected from Y 1 is selected from N and CH; each Y 2 is independently selected from N and C(R 5 ); X is selected from -OR 6 , -N(R 7 )(R 8 ), and -C(R
  • the present disclosure provides a pharmaceutical composition comprising a compound of Formula (I) or (II), and a pharmaceutically acceptable excipient.
  • the present disclosure provides a method of treating a disease in a subject in need thereof, comprising administering to the subject a compound of Formula (I) or (II), or a pharmaceutically composition thereof.
  • the disease is caused by a respiratory virus.
  • the respiratory virus is selected from an influenza virus, a rhinovirus, a coronavirus, a metapneumovirus, an adenoviruses, a syncytial virus, a bocaviruses, and a parainfluenza virus.
  • the present disclosure provides a method of inhibiting STT3 in a subject in need thereof, comprising administering to the subject a compound of Formula (I) or (II), or a pharmaceutically composition thereof.
  • 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., C 1 -C 12 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., C 1 -C 12 alkyl). In certain embodiments, an alkyl comprises one to eight carbon atoms (i.e., C 1- C 8 alkyl). In other embodiments, an alkyl comprises one to five carbon atoms (i.e., C 1 -C 5 alkyl).
  • an alkyl comprises one to four carbon atoms (i.e., C 1 -C 4 alkyl). In other embodiments, an alkyl comprises one to three carbon atoms (i.e., C 1 -C 3 alkyl). In other embodiments, an alkyl comprises one to two carbon atoms (i.e., C 1 -C 2 alkyl). In other embodiments, an alkyl comprises one carbon atom (i.e., C 1 alkyl). In other embodiments, an alkyl comprises five to fifteen carbon atoms (i.e., C 5 -C 15 alkyl). In other embodiments, an alkyl comprises five to eight carbon atoms (i.e., C 5 -C 8 alkyl).
  • 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., C 2 -C 12 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., C 2 -C 6 alkenyl).
  • an alkenyl comprises two to four carbon atoms (i.e., C 2 -C 4 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., C 2 -C 8 alkynyl). In other embodiments, an alkynyl comprises two to six carbon atoms (i.e., C 2 -C 6 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., C 1 -C 10 alkylene). In certain embodiments, an alkylene comprises one to eight carbon atoms (i.e., C 1 -C 8 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., C 1 -C 4 alkylene). In other embodiments, an alkylene comprises one to three carbon atoms (i.e., C 1- C 3 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., C 2 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).
  • C x-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.
  • C x-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.
  • -C x-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.
  • -C x-y alkynylene- 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.
  • 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., C 3-10 cycloalkyl). In other embodiments, 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. Examples of 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., C 3-12 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., C 5-7 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.
  • C x-y carbocycle is meant to include groups that contain from x to y carbons in a ring.
  • 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.
  • heterocycle 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 1, 2, 3, or 4 heteroatoms selected from oxygen, nitrogen, sulfur, or any combination thereof.
  • the heterocycle comprises 1 or 2 heteroatoms 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 1, 2, 3, or 4 heterocycloalkyl selected from oxygen, nitrogen, sulfur, or any combination thereof.
  • the heteroaryl comprises 1 or 2 heteroatoms selected from oxygen, nitrogen, sulfur, or any combination thereof.
  • the heterocycloalkyl comprises at least one heteroatom selected from oxygen, nitrogen, or any combination thereof. In some embodiments, the heterocycloalkyl comprises at least one heteroatom selected from oxygen, sulfur, or any combination thereof. In some embodiments, 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.
  • 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, thi
  • 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 1, 2, 3, or 4 heteroatoms selected from oxygen, nitrogen, sulfur, or any combination thereof.
  • the heteroaryl comprises 1 or 2 heteroatoms selected from oxygen, nitrogen, sulfur, or any combination thereof.
  • the heteroaryl comprises at least one heteroatom selected from oxygen, nitrogen, or any combination thereof. In some embodiments, the heteroaryl comprises at least one heteroatom selected from oxygen, sulfur, or any combination thereof. In some embodiments, 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.
  • 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 NH 2 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.
  • treatment 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.
  • B is selected from In some embodiments, B is In some embodiments, B is [0043] In some embodiments, for the compound or salt of Formula (I), n is selected from 0, 1, 2, and 3. In some embodiments, n is selected from 0, 1, and 2. In some embodiments, n is 0 or 1. In some embodiments, n is 0.
  • each R 2 is independently selected from halogen, -OR 13 , -N(R 13 ) 2 , -C(O)R 13 , -C(O)OR 13 , -NO 2 , -CN, and C 1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR 13 , -N(R 13 ) 2 , and -CN; and R 13 is independently selected at each occurrence from hydrogen and C 1-4 alkyl.
  • each R 2 is independently selected from halogen, -OR 13 , -N(R 13 ) 2 , - NO 2 , -CN, and C 1-6 alkyl; and R 13 is independently selected at each occurrence from hydrogen and C 1-4 alkyl. In some embodiments, each R 2 is independently selected from halogen, -OR 13 , -N(R 13 ) 2 , and C 1-6 alkyl; and R 13 is independently selected at each occurrence from hydrogen and C 1-4 alkyl. In some embodiments, each R 2 is independently selected from halogen and C 1-6 alkyl. [0045] In some embodiments, for the compound or salt of Formula (I), B is selected from , , , , , and .
  • each Y 1 is independently selected from N, CH, and CR 10 . In some embodiments, at least one Y 1 is N. In some embodiments, at least one Y 1 is CH. In some embodiments, at least one Y 1 is CR 10 . In some embodiments, each Y 1 is independently selected from CH and CR 10 . In some embodiments, each Y 1 is independently selected from N and CR 10 .
  • each Y 1 is selected from N and CH. In some embodiments, each Y 1 is N. In some embodiments, each Y 1 is CH. In some embodiments, each Y 1 is independently selected from CH, C-F, and C-O-C 1-4 alkyl. In some embodiments, each Y 1 is independently selected from CH, C-F, and C-O-CH 3 . In In some embodiments, each Y 1 is independently CH or C-F. In some embodiments, each Y 1 is independently CH or C-O-C 1-4 alkyl. In some embodiments, each Y 1 is independently CH or C-O- CH 3 .
  • R 1 and R 10 are each independently selected at each occurrence from halogen, -OR 12 , -N(R 12 ) 2 , -C(O)R 12 , - C(O)OR 12 , -NO 2 , -CN, and C 1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR 12 , -N(R 12 ) 2 , -C(O)R 12 , -C(O)OR 12 , -NO 2 , and -CN; and R 12 is independently selected at each occurrence from hydrogen and C 1-4 alkyl.
  • R 1 and R 10 are each independently selected at each occurrence from halogen and - OR 12 ; and R 12 is independently selected at each occurrence from hydrogen and C 1-4 alkyl. In some embodiments, R 1 and R 10 are each independently selected at each occurrence from halogen and - O-C 1-4 alkyl. In some embodiments, R 1 and R 10 are each independently selected at each occurrence from halogen and -O-C 1-4 alkyl. In some embodiments, R 1 and R 10 are each independently selected at each occurrence from fluor, and methoxy.
  • each R 10 is independently selected from halogen, -OR 12 , -N(R 12 ) 2 , -C(O)R 12 , -C(O)OR 12 , -NO 2 , -CN, and C 1- 6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR 12 , -N(R 12 ) 2 , and -CN; and R 12 is independently selected at each occurrence from hydrogen and C 1-4 alkyl.
  • each R 10 is independently selected from halogen, -OR 12 , - N(R 12 ) 2 , -CN, and C 1-6 alkyl; and R 12 is independently selected at each occurrence from hydrogen and C 1-4 alkyl. In some embodiments, each R 10 is independently selected from halogen and -OR 12 ; and R 12 is selected from hydrogen and C 1-4 alkyl. In some embodiments, each R 10 is independently selected from fluoro and methoxy. In some embodiments, each R 10 is fluoro. In some embodiments, each R 10 is methoxy.
  • the present disclosure provides a compound represented by the structure of Formula (I-B): or a pharmaceutically acceptable salt thereof.
  • m is selected from 0, 1, 2, and 3.
  • m is selected from 0, 1, and 2.
  • m is 0 or 1.
  • m is 0.
  • m is 1.
  • each R 1 is independently selected from halogen, -OR 12 , -N(R 12 ) 2 , -C(O)R 12 , -C(O)OR 12 , -NO 2 , -CN, and C 1- 6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR 12 , -N(R 12 ) 2 , -C(O)R 12 , -C(O)OR 12 , -NO 2 , and -CN; and R 12 is independently selected at each occurrence from hydrogen and C 1-4 alkyl.
  • each R 1 is independently selected from halogen, -OR 12 , -N(R 12 ) 2 , -CN, and C 1-6 alkyl; and R 12 is independently selected at each occurrence from om hydrogen and C 1-4 alkyl. In some embodiments, each R 1 is independently selected from halogen and -OR 12 ; and R 12 is selected from hydrogen and C 1-4 alkyl. In some embodiments, each R 1 is independently selected from fluoro and methoxy. In some embodiments, each R 1 is fluoro. In some embodiments, each R 1 is methoxy.
  • the present disclosure provides a compound represented by the structure of Formula (I-C): , or a pharmaceutically acceptable salt thereof.
  • R 3 is selected from hydrogen, halogen, -OR 14 , -N(R 14 ) 2 , -C(O)R 14 , -C(O)OR 14 , -NO 2 , -CN, and C 1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, - OR 14 , -N(R 14 ) 2 , -C(O)R 14 , -C(O)OR 14 , -NO 2 , and -CN; and R 14 is independently selected at each occurrence from hydrogen and C 1-4 alkyl.
  • R 3 is selected from hydrogen, halogen, -OR 14 , -N(R 14 ) 2 , and C 1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR 14 , -N(R 14 ) 2 , -C(O)R 14 , -C(O)OR 14 , -NO 2 , and -CN; and R 14 is independently selected at each occurrence from hydrogen and C 1-4 alkyl.
  • R 3 is selected from hydrogen and halogen.
  • R 3 is hydrogen.
  • R 3 is halogen.
  • R 3 is fluoro.
  • R 4 is selected from hydrogen, -C(O)R 15 , -C(O)OR 15 , and C 1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR 15 , -N(R 15 ) 2 , -C(O)R 15 , -C(O)OR 15 , - NO 2 , and -CN; and R 15 is independently selected at each occurrence from hydrogen and C 1-4 alkyl.
  • R 4 is selected from hydrogen, -C(O)R 15 , -C(O)OR 15 , and C 1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR 15 , -N(R 15 ) 2 , and -C(O)OR 15 ;and R 15 is independently selected at each occurrence from hydrogen and C 1-4 alkyl.
  • R 4 is selected from hydrogen, -C(O)OR 15 , and C 1-6 alkyl; R 15 is independently selected at each occurrence from C 1-4 alkyl.
  • R 4 is hydrogen.
  • R 4 is C 1-6 alkyl, In some embodiments, R 4 -C(O)OR 15 ; and R 15 is independently selected from C 1-4 alkyl. In some embodiments, R 4 is -C(O)O-t-butyl.
  • each Y 2 is independently selected from N and C(R 5 ). In some embodiments, at least two Y 2 is C(R 5 ). In some embodiments, each Y 2 is N. In some embodiments, each Y 2 is C(R 5 ).
  • each R 5 is independently selected from: hydrogen, halogen, -OR 16 , -N(R 16 ) 2 , -C(O)R 16 , -C(O)OR 16 , -NO 2 , and -CN; C 1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR 16 , -N(R 16 ) 2 , -C(O)R 16 , -C(O)OR 16 , -NO 2 , and -CN; and C 3-6 carbocycle and 4- to 6-membered heterocycle, any of which is optionally substituted with one or more substituents independently selected from halogen, -OR 16 , -N(R 16 ) 2 , - C(O)R 16 , -C(O)OR 16 , -NO 2 , and -CN;
  • each R 5 is independently selected from: hydrogen, halogen, -OR 16 , -CN, C 3-6 carbocycle, C 1-6 alkyl optionally substituted with one or more substituents independently selected from halogen and - OR 16 ; and R 16 is independently selected at each occurrence from hydrogen and C 1-4 alkyl.
  • each R 5 is independently selected from: hydrogen, halogen, -OH, -OC 1-6 alkyl, -CN, C 3-6 carbocycle, C 1-6 alkyl optionally substituted with one or more substituents independently selected from halogen and -OC 1-6 alkyl.
  • each R 5 is independently selected from hydrogen, halogen, -OC 1-6 alkyl., -CN, C 1-6 alkyl, C 1-6 haloalkyl and C 3-6 cycloalkyl, wherein the C 1-6 alkyl and C 3-6 cycloalkyl, are each optionally substituted with one or more substituents independently selected from halogen and OC 1-6 alkyl.
  • each R 5 is independently selected from hydrogen, fluoro, chloro, bromo, iodo, methyl, ethyl, 2-methoxymethyl, difluoromethyl, trifluoromethyl, and cyclopropyl. In some embodiments, each R 5 is independently selected from hydrogen, fluoro, chloro, bromo, methyl, ethyl, 2-methoxymethyl, difluoromethyl, trifluoromethyl, and cyclopropyl. In some embodiments, each R 5 is hydrogen. In some embodiments, each R 5 is fluoro. In some embodiments, each R 5 is chloro. In some embodiments, each R 5 is bromo. In some embodiments, each R 5 is iodo.
  • each R 5 is methyl. In some embodiments, each R 5 is ethyl. In some embodiments, each R 5 is 2-methoxymethyl. In some embodiments, each R 5 is difluoromethyl. In some embodiments, each R 5 is trifluoromethyl. In some embodiments, each R 5 is cyclopropyl. [0061] In some embodiments, for the compound or salt of Formula (I), (I-A), (I-B), or (I-C), B is selected from:
  • B is [0062]
  • A is selected from -L-A’ and -N(R A ) 2 .
  • A is -L-A’.
  • A is -N(R A ) 2 .
  • L is selected from a bond, -O-, -N(R B )-, and -C(O)-;
  • A’ is selected from 4- to 10-membered heterocycle and C 3-10 carbocycle, any of which is optionally substituted with one or more substituents independently selected from halogen, -OR 11 , -N(R 11 ) 2 , -C(O)R 11 , -C(O)N(R 11 ) 2 , -C(O)OR 11 , -S(
  • A is selected from -L-A’ and -N(R A ) 2 ;
  • L is selected from a bond, -O-, -N(R B )-, and -C(O)-;
  • R B is selected from hydrogen and C 1-4 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR 11 and C 3-6 carbocycle;
  • each R A is independently selected from hydrogen 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 , -C(O)OR 11 , - NO 2 , -CN, 3- to 6-membered heterocycle, and C 3-6 carbocycle, wherein the 3- to 6-membered heterocycle and C 3-6 carbocycle are each optionally substituted with one or more substituents independently selected from halogen, -OR 11 , -N(R 11 ) 2 , -C(O)R 11 , -C(O)OR 11 , -NO 2 , -CN, C 1-4 alkyl, and C 1-4 haloalkyl.
  • each R A is independently selected from hydrogen and C 1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR 11 , -N(R 11 ) 2 , -NO 2 , -CN, 3- to 6-membered heterocycle, and C 3-6 carbocycle, wherein the 3- to 6-membered heterocycle and C 3-6 carbocycle are each optionally substituted with one or more substituents independently selected from halogen, -OR 11 , -N(R 11 ) 2 , -NO 2 , -CN, C 1-4 alkyl, and C 1-4 haloalkyl.
  • each R A is independently selected from hydrogen and C 1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR 11 , 3- to 6-membered heterocycle, and C 3-6 carbocycle, wherein the 3- to 6-membered heterocycle and C 3-6 carbocycle are each optionally substituted with one or more substituents independently selected from halogen, -OR 11 , C 1-4 alkyl, and C 1-4 haloalkyl; and R 11 is independently selected at each occurrence from hydrogen, C 1-4 alkyl, and C 1-4 haloalkyl.
  • each R A is independently selected from hydrogen and C 1-6 alkyl optionally substituted with one or more substituents independently selected from -OR 11 , 3- to 6-membered heterocycle, and C 3-6 carbocycle, wherein the 3- to 6-membered heterocycle and C 3-6 carbocycle are each optionally substituted with one or more substituents independently selected from halogen and -OR 11 ; and R 11 is independently selected at each occurrence from hydrogen, C 1-4 alkyl, and C 1-4 haloalkyl.
  • each R A is independently selected from hydrogen and C 1-4 alkyl optionally substituted with one or more substituents independently selected from -OH and cyclopropyl optionally substituted with one or more substituents independently selected from halogen and -OH.
  • L is selected from a bond, -O-, -N(R B )-, and -C(O)-. In some embodiments, L is selected from a bond, -O-, -N(R B )-, and -C(O)-; and R B is selected from hydrogen and C 1-4 alkyl. In some embodiments, L is selected from a bond, -O-, -N(C 1-4 alkyl)-, and -C(O)-.
  • L is selected from a bond, -O-, -N(CH 3 )-, and -C(O)-. In some embodiments, L is -O-. In some embodiments, L is -N(R B )-. In some embodiments, L is -N(C 1-4 alkyl)-. In some embodiments, L is -N(CH 3 )-. In some embodiments, L is -C(O)-. In some embodiments, L is a bond.
  • A is L-A’; and L is -O- and -N(R B )-, and -C(O)-; R B is selected from C 1-4 alkyl; and A’ is selected from cyclobutyl, azetidinyl, pyrrolidinyl, any of which is optionally substituted with one or more -OH.
  • A is selected from: .
  • A is -N(R A ) 2 ; and each R A is independently selected from hydrogen 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 , -C(O)OR 11 , -NO 2 , -CN, 3- to 6-membered heterocycle, and C 3-6 carbocycle, wherein the 3- to 6-membered heterocycle and C 3-6 carbocycle are each optionally substituted with one or more substituents independently selected from halogen, -OR 11 , -N(R 11 ) 2 , -C(O)R 11 , -C(O)OR 11 , -NO 2 , - CN, C 1-4 alkyl, and C 1-4 haloalkyl.
  • A is -N(R A ) 2 ; and each R A is independently selected from hydrogen and C 1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR 11 , -N(R 11 ) 2 , -NO 2 , -CN, 3- to 6-membered heterocycle, and C 3-6 carbocycle, wherein the 3- to 6-membered heterocycle and C 3-6 carbocycle are each optionally substituted with one or more substituents independently selected from halogen, -OR 11 , -N(R 11 ) 2 , -NO 2 , -CN, C 1-4 alkyl, and C 1-4 haloalkyl and R 11 is independently selected at each occurrence from hydrogen, C 1-4 alkyl, and C 1-4 haloalkyl.
  • A is - N(R A ) 2 ; and each R A is independently selected from hydrogen and C 1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR 11 , 3- to 6-membered heterocycle, and C 3-6 carbocycle, wherein the 3- to 6-membered heterocycle and C 3-6 carbocycle are each optionally substituted with one or more substituents independently selected from halogen, -OR 11 , C 1-4 alkyl, and C 1-4 haloalkyl; and R 11 is independently selected at each occurrence from hydrogen, C 1-4 alkyl, and C 1-4 haloalkyl.
  • A is -N(R A ) 2 ; and each R A is independently selected from hydrogen and C 1-6 alkyl optionally substituted with one or more substituents independently selected from -OR 11 , 3- to 6-membered heterocycle, and C 3-6 carbocycle, wherein the 3- to 6-membered heterocycle and C 3-6 carbocycle are each optionally substituted with one or more substituents independently selected from halogen and -OR 11 ; and R 11 is independently selected at each occurrence from hydrogen, C 1-4 alkyl, and C 1-4 haloalkyl.
  • A is -N(R A ) 2 ; and each R A is independently selected from hydrogen and C 1-4 alkyl optionally substituted with one or more substituents independently selected from -OH and cyclopropyl optionally substituted with one or more substituents independently selected from fluoro and -OH.
  • A is selected from: and [0073]
  • L is a bond;
  • L is a bond
  • L is a bond
  • substituents independently selected from fluoro,
  • L is a bond
  • L is a bond;
  • (I) is selected from 4- to 9-membered heterocyclo
  • L is a bond; and A’ is selected from azetidine, pyrrolidine, thiophene, thiazole, piperidine, 2- azabicyclo[2.2.1]heptane, 3-azabicyclo[3.1.0]hexane, 1,6-diazaspiro[3.4]octane, 1,7- diazaspiro[4.4]nonane, octahydropyrrolo[3,4-b]pyrrole, octahydropyrrolo[3,4-c]pyrrole, cyclobutene, cyclopentene, 2,5-dihydrofuran, cyclopentane, cyclohexane, tetrahydrofuran, isoxazolidine, 2-azabicyclo[2.1.1]hexane, 7-azabicyclo[2.2.1]h
  • substituents independently selected from fluoro, -OH, methoxy
  • L is a bond; and A’ is selected from azetidine, pyrrolidine, thiophene, thiazole, piperidine, 2- azabicyclo[2.2.1]heptane, 3-azabicyclo[3.1.0]hexane, cyclobutene, cyclopentene, 2,5- dihydrofuran, cyclopentane, cyclohexane, tetrahydrofuran, isoxazolidine, 2- azabicyclo[2.1.1]hexane, 7-azabicyclo[2.2.1]heptane, 2-azabicyclo[2.2.1]heptane, 7- azabicyclo[2.2.1]heptane, and pyridine, any of which is optionally substituted with one or more substituents independently selected from fluoro, -OH, methoxy, methyl, trifluorine, 2- azabicyclo[2.2.1]heptane, and pyridine, any of which is optionally substituted with one or
  • A is selected from:
  • X is selected from -OR 6 , -N(R 7 )(R 8 ), and -C(R 7 )(R 8 )(R 9 ). In some embodiments, X is selected from - N(R 7 )(R 8 ) and -C(R 7 )(R 8 )(R 9 ). In some embodiments, X is selected from -OR 6 and -C(R 7 )(R 8 )(R 9 ). In some embodiments, X is selected from -OR 6 and -N(R 7 )(R 8 ).
  • X is selected from -OR 6 . In some embodiments, X is selected from -N(R 7 )(R 8 ). In some embodiments, X is selected from -C(R 7 )(R 8 )(R 9 ).
  • X is selected from -OR 6 , -N(R 7 )(R 8 ), and -C(R 7 )(R 8 )(R 9 ), and each of R 7 , R 8 , and R 9 is independently selected from: hydrogen, -OR 18 , -OC(O)R 18 , -C(O)R 18 , -C(O)OR 18 , and -C(O)N(R 18 ) 2 ; C 1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR 18 , -N(R 18 ) 2 , -C(O)R 18 , -C(O)OR 18 , -OC(O)R 18 , -C(O)N(R 18 ) 2 , - N(R 18 )C(O)R 18 ,
  • X is selected from -OR 6 , -N(R 7 )(R 8 ), and -C(R 7 )(R 8 )(R 9 ), and each of R 7 , R 8 , and R 9 is independently selected from: hydrogen, -OR 18 , -OC(O)R 18 , -C(O)R 18 , -C(O)OR 18 , and -C(O)N(R 18 ) 2 ; C 1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR 18 , -N(R 18 ) 2 , -C(O)R 18 , -C(O)OR 18 , -OC(O)R 18 , -C(O)N(R 18 ) 2 , - N(R 18 )C(O)R 18 ,
  • X is selected from -N(R 7 )(R 8 ) and -C(R 7 )(R 8 )(R 9 ), and wherein each of R 7 , R 8 , and R 9 is independently selected from: hydrogen; -OR 18 , -OC(O)R 18 , -C(O)R 18 , -C(O)OR 18 , and -C(O)N(R 18 ) 2 ; C 1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR 18 , -N(R 18 ) 2 , -C(O)R 18 , -C(O)OR 18 , -OC(O)R 18 , -C(O)N(R 18 ) 2 , - N(R 18 )C(O)R 18 , -N(R
  • X is selected from -N(R 7 )(R 8 ) and -C(R 7 )(R 8 )(R 9 ), wherein each of R 7 , R 8 , and R 9 is independently selected from: hydrogen; -OR 18 , -C(O)R 18 , -OC(O)R 18 , -C(O)OR 18 , and -C(O)N(R 18 ) 2 ; C 1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR 18 , -N(R 18 ) 2 , -C(O)R 18 , -C(O)OR 18 , -OC(O)R 18 , -C(O)N(R 18 ) 2 , - N(R 18 )C(O)R 18 , -N(R 18
  • X is selected from -N(R 7 )(R 8 ) and -C(R 7 )(R 8 )(R 9 ); wherein R 7 and R 8 of -N(R 7 )(R 8 ) come together to form a 4- to 12-membered heterocycle or R 7 and R 8 of -C(R 7 )(R 8 )(R 9 ) come together to form a C 3 - 6 carbocycle, wherein the 4- to 12-membered heterocycle and the C 3-6 carbocycle are each optionally substituted with one or more substituents independently selected from: halogen, -OR 19 , -N(R 19 ) 2 , -C(O)R 19 , -C(O)OR 19 , -C(O)N(R 19 ) 2 , -N(R 19 )C(O)R 19 ,
  • X is selected from -N(R 7 )(R 8 ) and -C(R 7 )(R 8 )(R 9 ); wherein R 7 and R 8 of -N(R 7 )(R 8 ) come together to form a 4- to 12-membered heterocycle selected from azetidine, 1,6-diazaspiro[3.3]heptane, pyrrolidine, 3-azabicyclo[3.1.0]hexane, piperazine, morpholine, 2-oxa-5- azabicyclo[2.2.1]heptane, 2-ethylmorpholine, 8-azabicyclo[3.2.1]octane, decahydro-1,6- naphthyridine, and 1,4,7-trioxa-10-azacyclododecane, any of which is optionally substituted with one or more substituents
  • X is N(R 7 )(R 8 ), and R 7 and R 8 of -N(R 7 )(R 8 ) come together to form a 4- to 12-membered heterocycle.
  • X is -N(R 7 )(R 8 ), and wherein R 7 and R 8 of -N(R 7 )(R 8 ) come together to form a 4- to 12-membered heterocycle selected from azetidine, 1,6-diazaspiro[3.3]heptane, pyrrolidine, 3- azabicyclo[3.1.0]hexane, piperazine, morpholine, 2-oxa-5-azabicyclo[2.2.1]heptane, 2- ethylmorpholine, 8-azabicyclo[3.2.1]octane, decahydro-1,6-naphthyridine, and 1,4,7-trioxa-10- azacyclododecane, any of which is optionally substituted with one or more substituents independently selected from: -OR 19 , -C(O)
  • R 7 and R 8 of -N(R 7 )(R 8 ) come together to form a 4- to 12-membered heterocycle selected from azetidine, 1,6-diazaspiro[3.3]heptane, pyrrolidine, 3-azabicyclo[3.1.0]hexane, piperazine, morpholine, 2-oxa-5-azabicyclo[2.2.1]heptane, 2-ethylmorpholine, 8-azabicyclo[3.2.1]octane, decahydro-1,6-naphthyridine, and 1,4,7-trioxa-10-azacyclododecane, any of which is optionally substituted with one or more substituents independently selected from: fluoro, -OR 19 , -C(O)R 19 , -C(O)OR 19 ,
  • X is C(R 7 )(R 8 )(R 9 ).
  • X is -C(R 7 )(R 8 )(R 9 ), and each of R 7 , R 8 , and R 9 is independently selected from: hydrogen, -OC(O)R 18 , -C(O)R 18 , -C(O)OR 18 , and -C(O)N(R 18 ) 2 ; C 1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -N(R 18 ) 2 , -C(O)R 18 , -C(O)OR 18 , -OC(O)R 18 , -C(O)N(R 18 )
  • X is selected from -C(R 7 )(R 8 )(R 9 ), wherein each of R 7 , R 8 , and R 9 is independently selected from: hydrogen -C(O)R 18 and -OC(O)R 18 ; C 1-4 alkyl optionally substituted with one or more substituents independently selected from: -N(R 18 ) 2 , -C(O)R 18 , -N(R 18 )C(O)R 18 , -C(O)N(R 18 ) 2 , -N(R 18 )C(O)OR 18 ; and phenyl, morpholinyl, piperazinyl, and 4-oxa-7-azaspiro[2.5]octanyl, any of which is optionally substituted with one or more C 1-4 alkyl; and cyclopropyl optionally substituted
  • X is selected from -C(R 7 )(R 8 )(R 9 ), wherein each of R 7 and R 8 is independently selected from hydrogen and C 1-4 alkyl; and R 9 is selected from: -C(O)R 18 and -OC(O)R 18 ; C 1-4 alkyl optionally substituted with one or more substituents independently selected from: -N(R 18 ) 2 , -C(O)R 18 , -N(R 18 )C(O)R 18 , -C(O)N(R 18 ) 2 , -N(R 18 )C(O)OR 18 ; and phenyl, morpholinyl, piperazinyl, and 4-oxa-7-azaspiro[2.5]octanyl, any of which is optionally substituted with one or more C 1-4 alkyl; and
  • X is selected from -C(R 7 )(R 8 )(R 9 ), wherein each of R 7 and R 8 is independently selected from hydrogen and methyl; and R 9 is selected from: -C(O)R 18 and -OC(O)R 18 ; C 1-2 alkyl optionally substituted with one or more substituents independently selected from: -N(R 18 ) 2 , -C(O)R 18 , -N(R 18 )C(O)R 18 , -C(O)N(R 18 ) 2 , -N(R 18 )C(O)OR 18 ; and phenyl, morpholinyl, piperazinyl, and 4-oxa-7-azaspiro[2.5]octanyl, any of which is optionally substituted with one or more C 1-4 alkyl; and cyclopropyl
  • X is selected from: methyl, ethyl, , , , , , , , [0118]
  • R 7 and R 8 of -C(R 7 )(R 8 )(R 9 ) come together to form a C 3-6 carbocycle.
  • R 7 and R 8 of -C(R 7 )(R 8 )(R 9 ) come together to form a C 3-6 carbocycle optionally substituted with one or more -C(O)R 19 , and R 19 is 3- to 10-membered heterocycle.
  • R 7 and R 8 of -C(R 7 )(R 8 )(R 9 ) come together to form a C 3-4 carbocycle optionally substituted with one or more - C(O)R 19 , and R 19 is 3- to 6-membered heterocycle.
  • R 7 and R 8 of - C(R 7 )(R 8 )(R 9 ) come together to form a C 3-4 carbocycle optionally substituted with one or more - C(O)R 19 , and R 19 is morpholinyl.
  • X is selected from cyclopropyl and cyclobutyl, each of which is optionally substituted with -C(O)R 19 ; and wherein R 19 is morpholinyl. [0120]
  • X is selected from: .
  • X is -OR 6 , wherein R 6 is selected from hydrogen and C 1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR 17 , -N(R 17 ) 2 , -C(O)R 17 , -C(O)OR 17 , -NO 2 , and -CN.
  • X is -OR 6 , wherein R 6 is selected from hydrogen and C 1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR 17 , -N(R 17 ) 2 , -NO 2 , and -CN. In some embodiments, X is -OR 6 , wherein R 6 is selected from hydrogen and C 1-6 alkyl optionally substituted with halogen. In some embodiments, X is selected from -OH and -O-C 1-4 alkyl optionally substituted with one or more halogen. In some embodiments, X is selected from: -OH and 2,2,2-trifluoroethoxy.
  • X is selected from -OR 6 , -N(R 7 )(R 8 ), and -C(R 7 )(R 8 )(R 9 ), and each of R 7 , R 8 , and R 9 is independently selected from: hydrogen, -OR 18 , -OC(O)R 18 , -C(O)R 18 , -C(O)OR 18 , and -C(O)N(R 18 ) 2 ; C 1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR 18 , -N(R 18 ) 2 , -C(O)R 18 , -C(O)OR 18 , -OC(O)R 18 , -C(O)N(R 18 ) 2 , - N(R 18 )C(O)R 18 ,
  • X is selected from -OR 6 , -N(R 7 )(R 8 ), and -C(R 7 )(R 8 )(R 9 ), and each of R 7 , R 8 , and R 9 is independently selected from: hydrogen, -OR 18 , -OC(O)R 18 , -C(O)R 18 , -C(O)OR 18 , and -C(O)N(R 18 ) 2 ; C 1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR 18 , -N(R 18 ) 2 , -C(O)R 18 , -C(O)OR 18 , -OC(O)R 18 , -C(O)N(R 18 ) 2 , - N(R 18 )C(O)R 18 ,
  • each R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , and R 17 are independently selected at each occurrence from: hydrogen, C 1-4 alkyl, and C 1-4 haloalkyl.
  • R 11 is independently selected at each occurrence from hydrogen, C 1-6 alkyl, and C 1-6 haloalkyl; and each R 12 , R 13 , R 14 , R 15 , R 16 , and R 17 are independently selected at each occurrence at each occurrence from: hydrogen and C 1-4 alkyl.
  • R 11 is selected from hydrogen, methyl, ethyl, and 2,2,2-tifluoroethyl; each R 12 , R 13 , R 14 , R 15 , R 16 , and R 17 are independently selected at each occurrence at each occurrence from: hydrogen, methyl, and ethyl.
  • R 11 is independently selected at each occurrence from hydrogen, C 1-4 alkyl, and C 1-4 haloalkyl.
  • R 12 is independently selected at each occurrence from hydrogen and C 1-4 alkyl.
  • R 13 is independently selected at each occurrence from hydrogen and C 1-4 alkyl.
  • R 14 is independently selected at each occurrence from hydrogen and C 1-4 alkyl.
  • R 15 is independently selected at each occurrence from C 1-4 alkyl.
  • R 16 is independently selected at each occurrence from hydrogen and C 1-4 alkyl.
  • R 17 is independently selected at each occurrence from hydrogen and C 1-4 alkyl.
  • the present disclosure provides a compound represented by Formula (II): or a pharmaceutically acceptable salt thereof, wherein: A is selected from 4- to 10-membered heterocycle and C 3-10 carbocycle optionally substituted with one or more substituents independently selected from halogen, -OR 11 , -N(R 11 ) 2 , -C(O)R 11 , -C(O)OR 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 , -C(O)OR 11 , -NO 2 , and - CN; B is selected from Y 1 is selected from N and CH; each Y 2 is independently selected from N and C(R 5 ); X is selected from -OR 6 , -N(R 7 )(R 8 ), and -C(R 7
  • Y 1 is N. In some embodiments, Y 1 is CH.
  • R 1 is selected from halogen, C 1-6 alkyl, and 4- to 8-membered heterocycle, wherein C 1-6 alkyl and 4- to 8-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OR 12 , -N(R 12 ) 2 , -C(O)R 12 , -C(O)OR 12 , -NO 2 , and -CN.
  • R 1 is selected from chloro, fluoro, bromo, and C 1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR 12 , -N(R 12 ) 2 , -C(O)R 12 , -C(O)OR 12 , -NO 2 , and -CN.
  • R 1 is selected from chloro, fluoro, bromo, and 4- to 8-membered heterocycle optionally substituted with one or more substituents independently selected from halogen, -OR 12 , -N(R 12 ) 2 , -C(O)R 12 , -C(O)OR 12 , -NO 2 , and -CN.
  • R 1 is selected from chloro, fluoro, bromo, and optionally substituted 4- to 6-membered saturated heterocycle.
  • A is selected from 3- to 10-membered saturated heterocycle, any one of which is optionally substituted with one or more substituents independently selected from halogen, -OR 11 , and C 1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR 11 , -N(R 11 ) 2 , -NO 2 , and -CN.
  • A is selected from a 3- to 10-membered saturated heterocycle comprising at least one nitrogen heteroatom and optionally substituted with one or more substituents independently selected from halogen, -OR 11 , and C 1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR 11 , -N(R 11 ) 2 , -NO 2 , and -CN.
  • A is selected from 6- to 10-membered bicyclic heterocycle optionally substituted with one or more substituents independently selected from halogen, -OR 11 , and C 1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR 11 , -N(R 11 ) 2 , -NO 2 , and -CN.
  • A is selected from azetidine, pyrrolidine, pyrazolidine, imidazolidine, piperidine, piperazine, morpholine, thiomorpholine, azepane, azocane, azabicyclo[3.1.0]hexane, and azabicyclo[2.2.1]heptane, and azaspiro[3.3]heptane, any of which is optionally substituted.
  • A is selected from azetidine, pyrrolidine, azabicyclo[3.1.0]hexane, and azabicyclo[2.2.1]heptane, any of which is optionally substituted with one or more substituents independently selected from chlorine, fluorine, -OH, C 1-6 haloalkyl, and -O-C 1-6 alkyl.
  • R 4 is hydrogen.
  • R 4 is C 1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR 15 , -N(R 15 ) 2 , -C(O)R 15 , -C(O)OR 15 , -NO 2 , and -CN.
  • B is In some embodiments, B is 2 In some embodiments, Y is N. In some embodiments, one of Y 2 is N. In some embodiments, two of Y 2 are N. In some embodiments, a most one of Y 2 is N. In some embodiments, at most two of Y 2 are N. In some embodiments, Y 2 is C(R 5 ).
  • Y 2 is selected from C(R 5 ) at each instance.
  • R 5 is selected from hydrogen, halogen, C 1-6 haloalkyl, and -O-C 1-6 alkyl.
  • R 5 is selected from fluorine, methyl, -OMe, and -OCF 3 .
  • one of R 5 is selected from fluorine, methyl, -OMe, and -OCF 3 , and each remaining R 5 is hydrogen.
  • B is selected from: , , , , , , In some embodiments, B is , embodiments, R 3 is selected from hydrogen, halogen, -OR 14 , -CN, C 1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR 14 , -NO 2 , and -CN. In some embodiments, R 3 is selected from hydrogen and C 1-6 alkyl optionally substituted with halogen and -OR 14 . [0141] In some embodiments, for the compound or salt of Formula (II), wherein B is In some embodiments, n is selected from 0 and 1. In some embodiments, n is 0.
  • n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is C 1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR 14 , -N(R 14 ) 2 , -C(O)R 14 , - C(O)OR 14 , -NO 2 , -CN. In some embodiments, R 2 is independently selected from halogen, -OR 13 , -N(R 13 ) 2 , -C(O)R 13 , -C(O)OR 13 , -NO 2 , -CN.
  • R 2 is independently selected from C 1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR 13 , -N(R 13 ) 2 , -C(O)R 13 , -C(O)OR 13 , -NO 2 , and -CN.
  • R 4 is hydrogen, and n is selected from 0 and 1.
  • X is -OR 6 .
  • R 6 is selected from hydrogen and C 1-6 haloalkyl.
  • R 9 is hydrogen.
  • X is -N(R 7 )(R 8 ).
  • each of R 7 and R 8 is selected from: hydrogen; C 1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR 18 , -N(R 18 ) 2 , -C(O)R 18 , -C(O)OR 18 , -C(O)N(R 18 ) 2 , -N(R 18 )C(O)R 18 , -NO 2 , and -CN; and C 3-10 carbocycle and 3- to10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 18 , -N(R 18 ) 2 , -C(O)R 18 , -C(O)OR 18 , -C(O)N(R 18 ) 2 , -N(R 18
  • each of R 7 and R 8 is hydrogen.
  • each of R 7 and R 8 is C 1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR 18 , -N(R 18 ) 2 , -C(O)R 18 , -C(O)OR 18 , -C(O)N(R 18 ) 2 , -N(R 18 )C(O)R 18 , -NO 2 , and -CN.
  • each of R 7 and R 8 is selected from methyl, ethyl, isopropyl, propyl, any of which is optionally substituted.
  • m is selected from 0 and 1. In some embodiments, m is 0. In some embodiments, m is 1. [0146] In some embodiments, for the compound or salt of Formula (II), X is -C(R 7 )(R 8 )(R 9 ).
  • each of R 7 , R 8 , and R 9 is selected from: hydrogen; C 1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR 18 , -N(R 18 ) 2 , -C(O)R 18 , -C(O)OR 18 , -C(O)N(R 18 ) 2 , -N(R 18 )C(O)R 18 , -NO 2 , and -CN; and C 3-10 carbocycle and 3- to10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 18 , -N(R 18 ) 2 , -C(O)R 18 , -C(O)OR 18 , -C(O)N(R 18 ) 2 , -N(R 18 )C(O)R 18 , -NO 2 , -CN, and C 1-6 alkyl optionally substitute
  • R 7 and R 8 can come together to form a 4- to 12-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR 19 , -N(R 19 ) 2 , -C(O)R 19 , -C(O)OR 19 , - C(O)N(R 19 ) 2 , -N(R 19 )C(O)R 19 , -NO 2 , -CN, and C 1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR 19 , -N(R 19 ) 2 , -C(O)R 19 , -C(O)OR 19 , -C(O)N(R 19 ) 2 , -N(R 19 )C(O)R 19 , -NO 2 , and -CN.
  • R 7 and R 8 can come together to form a 4- to 6-membered heterocycle selected from azetidine, pyrrolidine, pyrazolidine, imidazolidine, piperidine, piperazine, morpholine, and thiomorpholine, any of which is optionally substituted.
  • Formula (II) is selected from:
  • Formula (II) is selected from: [0150] In some embodiments, for the compound or salt of Formula (II), Formula (II) is selected from: , , , , ,
  • the compound is a compound set forth in Table A, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound set forth in Table B, or a pharmaceutically acceptable salt thereof.
  • Table B
  • compounds or salts of Formula (I), (I-A), (I-B), (I-C), or (II) 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.
  • the term “( ⁇ )” 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), (I-A), (I-B), (I-C), or (II) 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.
  • 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. Furthermore, a mixture of two enantiomers enriched in one of the two can be purified to provide further optically enriched form of the major enantiomer by recrystallization and/or trituration.
  • compounds or salts for Formula (I), (I-A), (I-B), (I-C), or (II) may comprise two or more enantiomers or diatereomers 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.
  • Methods of producing substantially pure enantiomers are well known to those of skill in the art.
  • 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).
  • 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 of Formula (I), (I-A), (I-B), (I-C), or (II) 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. Chem., 1981, 64(1-2), 9-32.
  • Deuterated starting materials are readily available and are subjected to the synthetic methods described herein to provide for the synthesis of deuterium-containing compounds. Large numbers of deuterium-containing reagents and building blocks are available commercially from chemical vendors, such as Aldrich Chemical Co.
  • 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), (I-A), (I-B), (I-C), or (II).
  • 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.
  • an appropriate counterion e.g., a halide such as bromide, chloride, or fluoride, particularly bromide.
  • compositions comprising a compound or salt of Formula (I), (I-A), (I-B), (I-C), or (II) and at least one pharmaceutically acceptable excipient.
  • a compound or salt of Formula (I), (I-A), (I-B), (I-C), or (II) can 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 Formula (I), (I-A), (I-B), (I-C), or (II), 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. 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.
  • 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), (I-A), (I-B), (I-C), or (II).
  • the present disclosure provides a method for treating a disease caused by a virus.
  • the present disclosure provides a method for treating a disease caused by a respiratory virus.
  • the respiratory virus is selected from an influenza virus, a rhinovirus, a coronavirus, a metapneumovirus, an adenoviruses, a syncytial virus, a bocaviruses, and a parainfluenza virus.
  • the present discloses a method of inhibiting STT3 in a subject in need thereof, comprising administering to the subject a compound of Formula (I), (I-A), (I-B), (I- C), or (II).
  • Step 2 Preparation of 3-bromo-2-fluoro-N,N-dimethyl-4-(pyrrolidin-1-yl) benzene sulfonamide
  • K 2 CO 3 potassium carbonate
  • pyrrolidine 30 ul, 1.5 eq
  • Step 3 Preparation of 2-fluoro-3-(1H-indol-2-yl)-N, N- dimethyl-4-(pyrrolidin-1-yl)benzene sulfonamide
  • 3-bromo-2-fluoro-N,N-dimethyl-4-(pyrrolidin-1-yl)benzene sulfonamide 35 mg, 0.12 mmol
  • tert-butyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-1- carboxylate 100 mg, 2 eq
  • Pd(dppf)Cl 2 ⁇ DCM 10 mg, 0.05 eq) in dioxane/water(9/1) (1 ml) was added K 2 CO 3 (40mg, 2eq).
  • Step 2 Preparation of 5-bromo-N, N-dimethyl-6-(pyrrolidin-1-yl)pyridine-3-sulfonamide [0177] To a solution of 5-bromo-6-chloro-N,N-dimethylpyridine-3-sulfonamide (210 mg, 0.70 mmol) in dioxane (5 ml), TEA (207ul, 2 eq) and pyrrolidine (73 ul, 1.3 eq) were added.
  • Step 3 Preparation of 5-(1H-indol-2-yl)-N,N-dimethyl-6-(pyrrolidin-1-yl)pyridine-3- sulfonamide
  • 5-bromo-N,N-dimethyl-6-(pyrrolidin-1-yl)pyridine-3-sulfonamide 70 mg, 0.21 mmol
  • tert-butyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-1- carboxylate 86 mg, 1.2 eq
  • Xphos-G4 9 mg, 0.05 eq) in dioxane/water(4/1) (2 ml) was added K 3 PO 4 (89mg, 2 eq).
  • the reaction was degassed with N 2 and heated at 90 °C for 16 hours. The solid was filtered. The filtrate was concentrated.
  • the Boc-protected product was purified by flash chromatography at 0-30% EtOAc/hexane, concentrated and treated with TFA (1 ml) for 30 minutes.
  • the reaction mixture was purified by reverse-phase HPLC [eluent: water / acetonitrile with 0.1 % trifluoracetic acid (TFA)] to give 5-(1H-indol-2-yl)-N,N-dimethyl-6-(pyrrolidin-1- yl)pyridine-3-sulfonamide.
  • LC-MS m/z [M+H] + 371.19.
  • Example 3 Step 1 Preparation of 3-(1-hydroxypropyl)-N,N-dimethyl-4-(pyrrolidin-1-yl)benzene sulfonamide [0179] To a solution of 3-formyl-N,N-dimethyl-4-(pyrrolidin-1-yl)benzene sulfonamide (100 mg, 0.35 mmol, 1 eq) in THF (1 mL) at 0 °C , bromo(ethyl)magnesium (3 M, 0.6 mL, 5 eq) was added. The reaction mixture was degassed, purged with nitrogen, and stirred at 0 °C for 1-2 h under N 2 atmosphere.
  • Step 2 Preparation of N,N-dimethyl-3-propionyl-4-(pyrrolidin-1-yl)benzene sulfonamide
  • DMP Dess-Martin periodinane
  • Step 3 Preparation of N,N-dimethyl-3-(3-methyl-1H-indol-2-yl)-4-(pyrrolidin-1- yl)benzenesulfonamide
  • N,N-dimethyl-3-propionyl-4-(pyrrolidin-1-yl)benzene sulfonamide 22 mg, 0.07 mmol, 1 eq
  • acetic acid 1 mL
  • phenyl hydrazine 15 mg, 2 eq
  • Step 2 Preparation of 3-bromo-N,N-dimethyl-4-(pyrrolidin-1-yl)benzene sulfonamide
  • pyrrolidine 3.37 g, 2 eq
  • 3-bromo-4-chloro-N,N- dimethylbenzenesulfonamide 6.71 g, 1 eq
  • DMSO 50 ml
  • K 2 CO 3 6.57 g, 2 eq
  • the reaction mixture was stirred at 50 °C for 12 hrs.
  • the reaction mixture was poured into water (500 mL) and EtOAc (500 mL).
  • the organic layer was concentrated and triturated by MTBE.
  • the title compound was obtained.
  • Step 1 Preparation of tert-butyl 2-(5-(N,N-dimethylsulfamoyl)-2-fluorophenyl)-lH-indole-l- carb oxy late [0188] A mixture of 3-bromo-4-fluoro-N,N-dimethylbenzenesulfonamide (1.95 g, 6.89 mmol, 1 eq), (1-tert-butoxycarbonylindol-2-yl)boronic acid (1.8 g, 6.89 mmol, 1 eq), diacetoxypalladium (77 mg, 0.05 eq), XPhos (283 mg, 0.1 eq) and K 3 PO 4 (2.20 g, 1.5 eq) in 1,4-dioxane/H 2 O (9/1) (20 ml) was purged with N 2 , and then stirred at 80 °C for 12 h under N 2 .
  • reaction mixture was quenched by H 2 O (30 ml) and extracted by EtOAc (3x30 ml). The organic phases were combined, washed with brine (2x15 ml), dried over Na 2 SO 4 , concentrated in vacuo, and purified by flash chromatography (SiO 2 , 0-17% of ethyl acetate in petroleum ether) to give a title compound.
  • Step 1 Preparation of 2,2,2-trifluoroethyl 3-bromo-4-fluorobenzenesulfonate [0191] To a solution of 3-bromo-4-fluorobenzenesulfonyl chloride (14 g, 1 eq) in DCM (300 ml) was added CF 3 CH 2 OH (6.14 g, 1.2 eq) and DABCO (17.25 g, 3 eq). The mixture was stirred at 25 °C for 2 hr. The reaction mixture was diluted with water (50 ml) and extracted with ethyl acetate (3x50 ml).
  • Step 2 Preparation of 2,2,2-trifluoroethyl 3-bromo-4-(pyrrolidin-1-yl)benzene sulfonate
  • 2,2,2-trifluoroethyl 3-bromo-4-fluorobenzenesulfonate 6 g, 1 eq
  • DMF 60 ml
  • K 2 CO 3 7.38 g, 3 eq
  • pyrrolidine 2.532 g, 2 eq
  • the mixture was stirred at 50 °C for 2 h, diluted with water (50 ml), and extracted with ethyl acetate (3x50 ml).
  • reaction mixture was stirred at 100 °C for 12 hr. After cooling to room temperature, the reaction mixture was diluted with water (50 ml) and extracted with ethyl acetate (3 x 50 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate. The filtrate was concentrated. The residue was purified by reverse-phase HPLC (eluent: water / acetonitrile with 10mM NH 4 HCO 3 ) to obtain title compound. LCMS: m/z [M+H] + 443.1.
  • Step 2 Preparation of tert-butyl 2-(5-(chlorosulfonyl)-2-(pyrrolidin-1-yl)phenyl)-1H-indole-1- carboxylate [0196] To a solution of 3-(1-(tert-butoxycarbonyl)-1H-indol-2-yl)-4-(pyrrolidin-1- yl)benzenesulfonic acid (50 mg, 1 eq) in DMF (1 ml) was added a solutkon of oxalyl chloride in DCM (1 ml, 29 mg, 2 eq) at 0 °C. The mixture was stirred at 25 °C for 2 h.
  • Step 3 Preparation of 4-((3-(1H-indol-2-yl)-4-(pyrrolidin-1-yl)phenyl) sulfonyl) morpholine
  • the tert-butyl 2-(5-(chlorosulfonyl)-2-(pyrrolidin-1-yl)phenyl)-1H-indole-1-carboxylate (50 mg, 1 eq) was mixed with morpholine (95 mg, 10 eq) at 0 °C. Then reaction was stirred at 25 °C for 3 h.
  • Example 8 Step 1 Preparation of 3-(1H-indol-2-yl)-4-(pyrrolidin-1-yl)benzenesulfonic acid [0199] To a solution of 3-(1-(tert-butoxycarbonyl)-1H-indol-2-yl)-4-(pyrrolidin-1- yl)benzenesulfonic acid (50 mg, 1 eq) in DCM (1 mL) was added TFA (1 ml). The reaction mixture was stirred at 50 °C for 12 h. After cooling to room temperature, the reaction mixture was concentrated in vacuo.
  • Step 1 Preparation of 3-acetyl-4-bromo-N,N-dimethylbenzenesulfonamide [0200] To a solution of 3-acetyl-4-bromobenzenesulfonyl chloride (450 mg, 1 eq) and Et 3 N (306 mg, 2 eq) in DCM (4.5 mL), N,N-dimethylamine (2 M, 1.51 ml, 2 eq) was added at 0 °C over 10 minutes. The mixture was stirred at 20 °C for 2 hours, diluted with DCM (30 mL) and quenched with 1 M HCl (3 mL). The organic phase was washed with saturated aq.
  • Step 2 Preparation of 3-acetyl-N,N-dimethyl-4-(thiophen-2-yl)benzene sulfonamide [0201] A mixture of 3-acetyl-4-bromo-N,N-dimethylbenzenesulfonamide (260 mg, 1 eq), diacetoxypalladium (9.53 mg, 0.05 eq), 4,4,5,5-tetramethyl-2-(2-thienyl)-1,3,2-dioxaborolane (178 mg, 1 eq), XPhos (35 mg, 0.1 eq) and K 3 PO 4 (270 mg, 1.5 eq) in 1,4-dioxane
  • Step 3 Preparation of (E)-N,N-dimethyl-3-(1-(2-phenylhydrazineylidene)ethyl)-4-(thiophen-2- yl)benzenesulfonamide [0202] To a solution of 3-acetyl-N,N-dimethyl-4-(thiophen-2-yl)benzene sulfonamide (50 mg, 1 eq) in acetic acid (2 ml) was added phenyl hydrazine (52 mg, 3 eq). The mixture was stirred at 140 °C for 1 h.
  • Step 4 Preparation of 3-(1H-indol-2-yl)-N,N-dimethyl-4-(thiophen-2-yl)benzene sulfonamide
  • Step 2 Preparation of 3-ethynyl-N,N-dimethyl-4-(pyrrolidin-1-yl)benzene sulfonamide
  • N,N-dimethyl-4-(pyrrolidin-1-yl)-3-((trimethylsilyl) ethynyl) benzene sulfonamide 550 mg, 1 eq
  • MeOH 4.2 mL
  • K 2 CO 3 216.84 mg, 1 eq
  • Step 3 Preparation of 3-((2-amino-6-methylpyridin-3-yl)ethynyl)-N,N-dimethyl-4-(pyrrolidin-1- yl) benzene sulfonamide
  • Pd(PPh 3 ) 2 Cl 2 25.21 mg, 0.1 eq
  • CuI 6.84 mg, 0.1 eq
  • Et 3 N 545.26 mg, 15 eq
  • 3- iodo-6-methylpyridin-2-amine 100 mg, 1 eq
  • Step 4 Preparation of N,N-dimethyl-3-(6-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-4-(pyrrolidin-1- yl)benzene sulfonamide
  • NMP 3-((2-amino-6-methylpyridin-3-yl)ethynyl)-N,N-dimethyl-4-(pyrrolidin- 1-yl) benzene sulfonamide (100 mg, 1 eq) in NMP (1.5 ml) was added the solution of t-BuOK (58.37 mg, 2 eq) in NMP (1.5 ml) under nitrogen atmosphere, purged with N 2 .
  • Example 11 Step 1 Preparation of 3-((3-aminopyridin-4-yl)ethynyl)-N,N-dimethyl-4-(pyrrolidin-1-yl) benzene sulfonamide
  • Step 2 Preparation of N,N-dimethyl-4-(pyrrolidin-1-yl)-3-(1H-pyrrolo[2,3-c]pyridin-2-yl) benzene sulfonamide
  • KOtBu 34.83 mg, 2.3 eq
  • 18-CROWN-6 3.92 mg, 0.11 eq
  • Example 12 Step 1 Preparation of 3-(5-hydroxy-1H-pyrrolo[3,2-b]pyridin-2-yl)-N,N-dimethyl-4-(pyrrolidin- 1-yl)benzenesulfonamide [0210] To a solution of 3-acetyl-N,N-dimethyl-4-(pyrrolidin-1-yl)benzene sulfonamide (170 mg, 1 eq) in HOAc (3 ml) was added 5-hydrazineyl-2-methoxypyridine (159.63 mg, 2 eq) at 25°C. The resulting mixture was stirred at 110°C for 3 hr at microwave and then concentrated.
  • Step 2 Preparation of tert-butyl 2-(5-(N-methyl-N-(2-morpholinoethyl)sulfamoyl)-2-(pyrrolidin- 1-yl)phenyl)-1H-indole-1-carboxylate [0212] To a solution of N-methyl-2-morpholino-ethanamine (0.9 g, 95.89 eq) in DCM (3 ml) was added tert-butyl 2-(5-(chlorosulfonyl)-2-(pyrrolidin-1-yl)phenyl)-1H-indole-1-carboxylate (30 mg, 1 eq) at 25°C.
  • Step 3 Preparation of 3-(1H-indol-2-yl)-N-methyl-N-(2-morpholinoethyl)-4-(pyrrolidin-1- yl)benzene sulfonamide [0213] To a solution of tert-butyl 2-(5-(N-methyl-N-(2-morpholinoethyl)sulfamoyl)-2- (pyrrolidin-1-yl)phenyl)-1H-indole-1-carboxylate (30 mg, 1 eq) in DMSO (1 ml) was added t- BuOK (1 M, 2 mL, 37.92 eq).
  • Example 15 Synthesis of Intermediate Compound I-2 tert-butyl (2-((2-methoxyethyl)(methyl)amino)-2-oxoethyl)carbamate: [0215] A mixture of (tert-butoxycarbonyl)glycine (10.61 g, 56.09 mmol, 1 eq), HATU (25.59 g, 67.31 mmol, 1.2 eq) and DIEA (18.12 g, 140.24 mmol, 24.43 mL, 2.5 eq) in DCM (120 mL) was stirred at 20°C for 20 min.
  • the resulting mixture was stirred at 20°C for 12 h. LCMS analysis showed starting material was consumed completely and one main peak with desired mass was detected.
  • the resulting mixture was diluted with water 100 mL and extracted with ethyl acetate 180 mL (3 ⁇ 60 mL). The combined organic layers were washed with water 120 mL (2 ⁇ 60 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue.
  • Step 2 Preparation of (R)-3-bromo-4-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)-N-methyl- N-(2-morpholino-2-oxoethyl)benzenesulfonamide (compound I-11) [0222] To a solution of (R)-3-bromo-4-(3-hydroxypyrrolidin-1-yl)-N-methyl-N-(2-morpholino-2- oxoethyl)benzenesulfonamide (1.7 g, 3.68 mmol, 1 eq) in DCM (17 mL) were added TBSCl (0.66 g, 4.41 mmol, 1.2 eq) and imidazole (0.3 g, 4.41 mmol, 1.2 eq) at 20°C.
  • Step 4 Preparation of tert-butyl (S)-2-(2-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)-5- sulfamoylphenyl)-1H-indole-1-carboxylate (compound I-12) [0226] A mixture of (S)-3-bromo-4-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1- yl)benzenesulfonamide (1.45 g, 3.33 mmol, 1 eq), (1-tert-butoxycarbonylindol-2-yl)boronic acid (1.74 g, 6.66 mmol, 2 eq), Pd(PPh 3 ) 2 Cl 2 (233.72 mg, 332.99 umol, 0.1 eq) and Na 2 CO 3 (1.06 g, 9.99 mmol, 3 eq) in Dioxane (20 mL)
  • Example 19 Synthesis of Intermediate Compound I-13 tert-butyl 6-methyl-2-(2-(pyrrolidin-1-yl)-5-((2,2,2-trifluoroethoxy)sulfonyl)phenyl)-1H- indole-1-carboxylate [0227] To a solution of 2,2,2-trifluoroethyl 3-bromo-4-(pyrrolidin-1-yl)benzenesulfonate (5 g, 12.88 mmol, 1 eq) in dioxane (25 mL) were added (1-tert-butoxycarbonyl-6-methyl-indol-2- yl)boronic acid (4.25 g, 15.46 mmol, 1.2 eq) and Na 2 CO 3 (4.10 g, 38.64 mmol, 3 eq) and H 2 O (5 mL) at 20°C, then added Pd(PPh 3 ) 2 Cl 2 (904.04 mg, 1.29 mmol, 0.1
  • Example 20 Synthesis of Intermediate Compound I-14 methyl ((4-(azetidin-1-yl)-3-bromophenyl)sulfonyl)glycinate [0230] In a 250 mL round bottom flask, methyl glycinate hydrochloride (918 mg, 7.31 mmol, 1 eq) was dissolved in DCM (30 mL), and DIPEA (3.8 mL, 21.9 mmol, 3 eq) was added. Under vigorous stirring, 3-bromo-4-fluorobenzenesulfonyl chloride (1.1 mL, 7.31 mmol, 1 eq) was added dropwise under slight warming of the reaction mixture.
  • Example 22 Synthesis of Intermediate Compound I-16 trans-4-(3-cyano-4-hydroxypyrrolidin-1-yl)-3-(1H-indol-2-yl)-N,N- dimethylbenzenesulfonamide (Compound I-16) [0234] 4-(3-cyano-4-hydroxypyrrolidin-1-yl)-3-(1H-indol-2-yl)-N,N- dimethylbenzenesulfonamide was synthesized analogous to Compound 428, set forth below, substituting trans-4-hydroxypyrrolidine-3-carbonitrile for (4,4-difluoropyrrolidin-3-yl)methanol hydrochloride. LC-MS: m/z [M+H] + 411.2.
  • Example 23 Synthesis of Intermediate Compound I-17
  • Example 24 Synthesis of Intermediate Compound I-18 N-methyl-N-((3-(6-methyl-1H-indol-2-yl)-4-(pyrrolidin-1-yl)phenyl)sulfonyl)glycine (Compound I-18) [0236] N-methyl-N-((3-(6-methyl-1H-indol-2-yl)-4-(pyrrolidin-1-yl)phenyl)sulfonyl)glycine was synthesized analogous to Compound 406 substituting methyl glycinate for methyl (S)-azetidine- 2-carboxylate. LC-MS: m/z [M+H] + 485.2.
  • Example 25 Synthesis of Compound 428
  • tert-butyl 2-((3-bromo-4-fluorophenyl)thio)acetate Material does not ionize.
  • tert-butyl 2-(3-bromo-4-fluorobenzenesulfonyl)acetate [0254] A flask containing tert-butyl 2-[(3-bromo-4-fluorophenyl)sulfanyl]acetate (500 mg, 1.56 mmol) in water, acetonitrile, and THF at rt had Oxone (2.87 mg, 4.67 mmol) added.
  • tert-butyl 2-[3-bromo-4-(pyrrolidin-1-yl)benzenesulfonyl]acetate [0255] A flask containing tert-butyl 2-(3-bromo-4-fluorobenzenesulfonyl)acetate ( 410 mg, 1.16 mmol) and DIPEA (0.61 mL, 3.48 mmol) in DMSO had pyrrolidine (0.11 mL, 1.39 mmol) added. The solution was heated to 90 °C overnight.
  • Example 32 Synthesis of Compound 509 tert-butyl 1-((3-bromo-4-fluorophenyl)sulfonyl)-1,6-diazaspiro[3.3]heptane-6-carboxylate: [0275] To a solution of tert-butyl 1,6-diazaspiro[3.3]heptane-6-carboxylate, 0.5 Oxalic acid salt (3 g, 12.33 mmol) in Dichloromethane (40 mL) were added TEA (5.16 mL, 37.0 mmol) and 3-bromo- 4-fluorobenzenesulfonyl chloride (4.05 g, 14.8 mmol) at 0 °C, the mixture was stirred at 20 °C for 2 hours under N 2 .
  • reaction mixture was quenched by H 2 O, and then diluted with DCM and extracted with DCM. The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a crude material.
  • the crude material was purified by column chromatography to give tert-butyl 1-((3-bromo-4-fluorophenyl)sulfonyl)-1,6- diazaspiro[3.3]heptane-6-carboxylate as a white solid.
  • Example 38 Synthesis of Compound 237 [0292] To a solution of 4-[3,3-difluoro-4-(hydroxymethyl)pyrrolidin-1-yl]-3-(1H-indol-2-yl)- N,N-dimethylbenzenesulfonamide (60 mg, 0.10 mmol) in DMF was added sodium 2-chloro-2,2- difluoroacetate (16 mg, 0.10 mmol) and cesium carbonate (67 mg, 0.21 mmol).
  • Table 16 includes spectroscopic data for compounds that were prepared in a manner analogous to Compound 221.
  • Table 16 Example 40: Synthesis of Compound 385 3-bromo-4-fluoro-N,N-dimethylbenzenesulfonamide [0296] To a solution of dimethylamine, hydrochloride (5.96 g, 73.1 mmol) in Dichloromethane (300 mL) were added TEA (30.6 mL, 219 mmol) and 3-bromo-4-fluorobenzenesulfonyl chloride (20 g, 73.1 mmol) at 0 °C, the mixture was stirred at 20 °C for 12 hours under N 2 .
  • Table 17 includes spectroscopic data for compounds that were prepared in a manner analogous to Compound 385.
  • Table 17 Example 41: Synthesis of Compound 373 3-(3-chloro-1H-indol-2-yl)-4-fluoro-N,N-dimethylbenzenesulfonamide: [0302] To a solution of 4-fluoro-3-(1H-indol-2-yl)-N,N-dimethylbenzenesulfonamide (200 mg, 0.63 mmol) in N,N-dimethylformamide was added NCS (84 mg, 0.628 mmol) at 0 °C, and the mixture was stirred at 20 °C for 12 hours.
  • NCS 84 mg, 0.628 mmol
  • Example 43 Synthesis of Compound 318 1-((4-bromo-3-chlorophenyl)sulfonyl)azetidine: [0311] To a solution of 4-bromo-3-chlorobenzenesulfonyl chloride (5 g, 17.24 mmol) and azetidine hydrochloride (1.936 g, 20.69 mmol) in dichloromethane (50 mL) was added DIEA (9.04 mL, 51.7 mmol) at 0 °C. The mixture was stirred at 0 °C for 1 hour. The residue was diluted with H 2 O (50 mL) and the aqueous phase was extracted with DCM (30 mL).
  • Table 23 includes spectroscopic data for compound that were prepared in a manner analogous to Compound 226.
  • Table 23 Example 49: Synthesis of Compound 233 3-iodo-N,N-dimethyl-4-(pyrrolidin-1-yl)benzenesulfonamide [0344] A mixture of compound I-9 (2 g, 6.00 mmol, 1 eq), NaI (3.61 g, 24.1 mmol, 4.01 eq), CuI (240.0 mg, 1.26 mmol, 0.21 eq) and N,N'-dimethylethane-1,2-diamine (190.5 mg, 2.16 mmol, 232.5 uL, 0.36 eq) in dioxane (20 mL) was degassed and purged with N 2 for 3 times at 25°C, and then the resulting mixture was heated to 140°C and stirred at 140°C for 12 h under N 2 atmosphere.
  • tert-butyl 6-bromo-2-(5-(N,N-dimethylsulfamoyl)-2-(pyrrolidin-1-yl)phenyl)-1H- pyrrolo[3,2-b]pyridine-1-carboxylate A mixture of 3-iodo-N,N-dimethyl-4-(pyrrolidin-1-yl)benzenesulfonamide (300 mg, 788.97 umol, 1 eq), tert-butyl 6-bromo-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- pyrrolo[3,2-b]pyridine-1-carboxylate (807.03 mg, 2.37 mmol, 3 eq), K 3 PO 4 (334.95 mg, 1.58 mmol, 2 eq), BrettPhos Pd G3 (125.35 mg, 157.79 umol, 0.2 eq) in THF (4 mL
  • Table 27 includes spectroscopic data for compounds that were prepared in a manner analogous to Compound 430.
  • Table 27 Example 54 Synthesis of Compound 422 N-((4-(azetidin-1-yl)-3-(6-methyl-1H-indol-2-yl)phenyl)sulfonyl)-N-(2-oxo-2-(4-oxa-7- azaspiro[2.5]octan-7-yl)ethyl)acetamide: (Compound 422) [0356] In a 4 mL glass vial, 4-(azetidin-1-yl)-3-bromo-N-(2-oxo-2-(4-oxa-7-azaspiro[2.5]octan-7- yl)ethyl)benzenesulfonamide compound I-14 (36 mg, 0.081 mmol, 1 eq) was dissolved in DCM (200 uL).
  • Example 56 Synthesis of Compound 248 tert-butyl 6-methoxy-1H-pyrrolo[3,2-b]pyridine-1-carboxylate [0360] To a solution of 6-methoxy-1H-pyrrolo[3,2-b]pyridine (500 mg, 3.37 mmol, 1 eq) and Boc2O (1.10 g, 5.06 mmol, 1.16 mL, 1.5 eq) in DCM (50 mL) were added DMAP (412.28 mg, 3.37 mmol, 1 eq) and TEA (341.48 mg, 3.37 mmol, 469.71 uL, 1 eq). The resulting mixture was stirred at 25°C for 12 h.
  • tert-butyl 6-methoxy-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[3,2- b]pyridine-1-carboxylate 400 mg, 1.61 mmol, 1 eq
  • i-PrBPin 449.32 mg, 2.42 mmol, 492.68 uL, 1.5 eq
  • THF 20 mL
  • LDA 2 M, 1.61 mL, 2 eq
  • Table 29 includes spectroscopic data for compounds that were prepared in a manner analogous to Compound 248 Table 29 Example 57: Synthesis of Compound 139 N,N-dimethyl-3-(6-methyl-1H-pyrrolo[3,2-c]pyridin-2-yl)-4-(pyrrolidin-1- yl)benzenesulfonamide (Compound 139) [0365] A mixture of 5-iodo-2-methylpyridin-4-amine (27.7 mg, 0.12mmol), Pd(PPh 3 ) 2 Cl 2 (3.78 mg, 0.005mmol) and CuI (1.03 mg, 0.005mmol) in DMF (1.5 mL) were added Et 3 N (218.1mg, 2.16 mmol) and 3-ethynyl-N,N-dimethyl-4-(pyrrolidin-1-yl)benzenesulfonamide (30 mg, 0.108mmol) at 20°C, the resulting reaction mixture was degassed and p
  • N-(2-((3-bromo-4-(pyrrolidin-1-yl)phenyl)sulfonamido)ethyl)morpholine-4-carboxamide [0368] To a vial of N-(2-aminoethyl)-3-bromo-4-fluorobenzenesulfonamide (105mg, 0.35mmol) in DCM (4ml) was added morpholine-4-carbonyl chloride (60mg, 0.4mmol) and triethylamine (50mg, 0.5 mmol).
  • Example 61 Synthesis of Compound 336 2-(azidomethyl)-1-((3-bromo-4-fluorophenyl)sulfonyl)azetidine [0379] To a vial of 3-bromo-4-fluorobenzenesulfonyl chloride (450mg, 1.64mmol) in DCM (6ml) was added triethylamine (218mg, 2.2mmol) and azetidin-2-ylmethanol (150mg, 1.72mmol). The mixture was stirred at room temperature for 2 hours then concentrated to an oil under vacuum.
  • Example 62 Synthesis of Compound 507 3-(azetidin-1-ylsulfonyl)-2,6-dichloropyridine [0383] To a solution of 2,6-dichloropyridine-3-sulfonyl chloride (3.5 g, 14.20 mmol) and Azetidine hydrochloride (1.063 g, 11.36 mmol) in Dichloromethane (30 mL) was added TEA (5.94 mL, 42.6 mmol) at 0 °C. The mixture was stirred at 20 °C for 1 hour. The mixture was diluted with H 2 O (30 mL) and the aqueous phase was extracted with DCM (30 mL * 2).
  • the reaction mixture was diluted with water (100 mL) and extracted with EtOAc (150 mL * 2). The combined organic layers were washed with brine (500 mL * 2), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue.
  • the residue was dissolved in DCM (20 mL), and loaded to Biotage using 80 g Agela flash silica gel column, eluted with 0% to 50% ethyl acetate in petroleum ether with the flowing rate of 100 ml/min.
  • the ERLuc reporter cell line was generated as follows: A lentiviral construct was generated to encode Firefly luciferase with three potential N-glycosylation sites, with an EGFR secretion signal fused to the N-terminus, along with an internal expression control NanoLuc luciferase linked at the C-terminus via a P2A ribosomal skipping sequence.
  • the construct was introduced via lentiviral transduction into H1 Hela cells, and a single cell clone of the transduced cells was isolated via limiting dilution and established as the ERLuc reporter cell line.
  • Putative inhibitors were assayed as follows. One day prior to small molecule treatment, ERLuc cells were plated in DMEM media with 10% FBS and incubated overnight at 37C, 5% CO2. Putative inhibitors were diluted in DMEM with 10% FBS, and the supernatant on ERLuc cells was replaced with the treatments. All treatments were normalized to 0.5% DMSO. Negative controls (DMSO only) and positive controls (2.8uM NGI-1) were included on every assay plate.
  • HUCOV229e virus was obtained from and ATCC and propagated in low passage MRC5 cells for 2-7 days at 35C, 5% CO2 until 80-90% CPE was observed. Supernatants were isolated, clarified, filtered, and submitted to Tangential Flow filtration for concentration. Virus was quantitated by plaque assay on MRC5 cells using standard methods. In infectious assays, virus was applied to cells at MOI observed to yield 70-80% cell death relative to control at 3 days post infection. [0400] Putative inhibitors were assayed as follows.
  • PIV3-GFP assay in A549 cells [0403] Inhibition of PIV3-GFP reporter expression and compound cytotoxic effects in A549 cells were measured in fluorescent cell imaging assays. Viral GFP was detected as a measure of infection and nuclei were counted as a measure of cell viability. [0404] PIV3-GFP virus was obtained from and ViraTree and propagated in LLC-MK2 cells for 2- 3 days at 37C, 5% CO2 until 80-90% CPE was observed. Supernatants were isolated, clarified, and quantified by TCID50 assay using standard methods.
  • virus was applied to A549 cells at a target MOI observed to yield 40-60% infection of cells by GFP fluorescence two days after infection.
  • Putative inhibitors were assayed as follows. Serial dilutions of compounds, negative controls (DMSO) and positive controls (remdesivir) were applied to assay plates. All treatments were normalized to 0.5% DMSO in 50 uL final volumes. A549 cells were harvested, counted and resuspended in phenol red-free DMEM containing 10% FBS, HEPES, glutamine and pyruvate. PIV3 virus was added to cell suspension at target MOI prior to seeding in assay plates.
  • Table 34 provides data for the biological evaluation of some embodiments of the present disclosure, including EC50 and/or CC50 values for ERluc, 229e, MRC, PIV3, and A549 obtained using the assays described above. Assay values are categorized as follows: A is ⁇ 100 nM; B is 100 nM – 2 uM; C is 2.01 uM – 10 uM; D is > 10 uM Table 34

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Abstract

L'invention concerne des dérivés hétérocycliques de formule (I) pour inhiber le complexe oligosaccharyltransférase et traiter une maladie.
EP22850824.8A 2021-12-16 2022-12-15 Dérivés hétérocycliques pour le traitement d'une maladie Withdrawn EP4448105A1 (fr)

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