WO2024263753A1 - Sulfoximine based stt3a/b modulators for the treatment of disease - Google Patents

Sulfoximine based stt3a/b modulators for the treatment of disease Download PDF

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WO2024263753A1
WO2024263753A1 PCT/US2024/034785 US2024034785W WO2024263753A1 WO 2024263753 A1 WO2024263753 A1 WO 2024263753A1 US 2024034785 W US2024034785 W US 2024034785W WO 2024263753 A1 WO2024263753 A1 WO 2024263753A1
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independently selected
halogen
alkyl
optionally substituted
substituents independently
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PCT/US2024/034785
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French (fr)
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James S. CASSIDY
Belinda E. HETZLER
Rohit Ranjan
Nathan Shapiro
Vladimir SOFIYEV
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Vir Biotechnology, Inc.
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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
    • C07D403/14—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
    • 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
    • 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
    • C07D403/02—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
    • 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
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms 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
    • 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 (I): or a pharmaceutically acceptable salt thereof, wherein: Ring A is 3- to 12-membered heterocycle; X 1 is selected from N and C(H); each R 1 is independently selected at each occurrence from: WSGR Docket No.58296-711601 halogen, -OR 11 , -SR 11 , -N(R 11 )2, -C(O)R 11 , -C(O)N(R 11 )2, -C(O)OR 11 , -OC(O)R 11 , -N(R 11 )C(O)R 11 , -N(R 11 )C(O)OR 11 , -N(R 11 )S(O) 2 R 11 , -S(O) 2 N(R 11 ) 2 , -S(O)R 11 , - S(O) 2 R 11 , -NO 2 ,
  • the present disclosure provides a pharmaceutical composition comprising a compound or salt of Formula (I) and at least one pharmaceutically acceptable excipient.
  • 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).
  • the present disclosure can be used as a method of modulating STT3 in a subject in need thereof, comprising administering to the subject: a compound of Formula (I) or a pharmaceutically acceptable salt thereof; or a pharmaceutical composition WSGR Docket No.58296-711601 comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • the present disclosure can be used as a method of inhibiting STT3 in a subject in need thereof, comprising administering to the subject: a compound of Formula (I) or a pharmaceutically acceptable salt thereof; or a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • the present disclosure can be used as a method of modulating replication of a respiratory virus in a subject in need thereof, comprising administering to the subject: a compound of Formula (I) or a pharmaceutically acceptable salt thereof; or a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • the respiratory virus is selected from influenza virus, a rhinovirus, a coronavirus, a metapneumovirus, an adenovirus, a syncytial virus, a bocaviruses, and a parainfluenza virus.
  • the present disclosure can be used as a method of inhibiting replication of a respiratory virus in a subject in need thereof, comprising administering to the subject: a compound of Formula (I) or a pharmaceutically acceptable salt thereof; or a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • the respiratory virus is selected from influenza virus, a rhinovirus, a coronavirus, a metapneumovirus, an adenovirus, a syncytial virus, a bocaviruses, and a parainfluenza virus.
  • the present disclosure can be used as a method of treating a respiratory virus in a subject in need thereof (e.g., treating a subject infected by a respiratory virus), comprising administering to the subject: a compound of Formula (I) or a pharmaceutically acceptable salt thereof; or a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • the respiratory virus is selected from influenza virus, a rhinovirus, a coronavirus, a metapneumovirus, an adenovirus, a syncytial virus, a bocaviruses, and a parainfluenza virus.
  • Alkyl refers to a straight or branched hydrocarbon chain monovalent radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, and preferably having from one to twelve carbon atoms (i.e., C1-C12 alkyl). The alkyl is attached to the remainder of the molecule through a single bond. In certain embodiments, an alkyl comprises one to twelve carbon atoms (i.e., C 1 -C 12 alkyl).
  • 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., C1-C5 alkyl). In other embodiments, an alkyl comprises one to four carbon atoms (i.e., C1- C4 alkyl). In other embodiments, an alkyl comprises one to three carbon atoms (i.e., C1-C3 alkyl). In other embodiments, an alkyl comprises one to two carbon atoms (i.e., C 1 -C 2 alkyl). In other embodiments, an alkyl comprises one carbon atom (i.e., C1 alkyl).
  • an alkyl comprises five to fifteen carbon atoms (i.e., C5-C15 alkyl). In other embodiments, an alkyl comprises five to eight carbon atoms (i.e., C 5 -C 8 alkyl). In other embodiments, an alkyl comprises two to five carbon atoms (i.e., C2-C5 alkyl). In other embodiments, an alkyl comprises three to five carbon atoms (i.e., C3-C5 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., C2-C8 alkenyl).
  • an alkenyl comprises two to six carbon atoms (i.e., C2-C6 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., C2-C4 alkynyl).
  • the alkynyl is attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.
  • Alkylene refers to a straight divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing no unsaturation, and preferably having from one to twelve carbon atoms, for example, methylene, ethylene, propylene, butylene, and the like.
  • the alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond.
  • the points of attachment of the alkylene chain to the rest of the molecule and to the radical group are through the terminal carbons respectively.
  • Alkylene chain may be optionally substituted by one or more substituents such as those substituents described herein.
  • an alkylene comprises one to ten carbon atoms (i.e., C1-C10 alkylene). In certain embodiments, an alkylene comprises one to eight carbon atoms (i.e., C 1 -C 8 alkylene). In other embodiments, an alkylene comprises one to five carbon atoms (i.e., C1-C5 alkylene). In other embodiments, an alkylene comprises one to four carbon atoms (i.e., C1-C4 alkylene). In other embodiments, an alkylene comprises one to three carbon atoms (i.e., C 1 -C 3 alkylene).
  • an alkylene comprises one to two carbon atoms (i.e., C1-C2 alkylene). In other embodiments, an alkylene comprises one carbon atom (i.e., C1 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., C2-C5 alkylene). In other embodiments, an alkylene comprises three to five carbon atoms (i.e., C3-C5 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., C2-C8 alkenylene). In other embodiments, an alkenylene comprises two to five carbon atoms (i.e., C2-C5 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., C2 alkenylene). In other embodiments, an alkenylene comprises five to eight carbon atoms (i.e., C5-C8 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., C2-C10 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., C2-C5 alkynylene). In other embodiments, an alkynylene comprises two to four carbon atoms (i.e., C2-C4 alkynylene). In other embodiments, an alkynylene comprises two to three carbon atoms (i.e., C 2 -C 3 alkynylene). In other embodiments, an alkynylene comprises two carbon atom (i.e., C2 alkynylene). In other embodiments, an alkynylene comprises five to eight carbon atoms (i.e., C5-C8 alkynylene).
  • an alkynylene comprises three to five carbon atoms (i.e., C 3 -C 5 alkynylene).
  • Cx-y when used in conjunction with a chemical moiety, such as alkyl, alkenyl, or alkynyl is meant to include groups that contain from x to y carbons in the chain.
  • C1-6 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.
  • -C1-6 alkylene- may be selected from methylene, ethylene, propylene, butylene, pentylene, and hexylene, any one of which is optionally substituted.
  • Cx-y alkenyl and “Cx-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.
  • - C2-6 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.
  • -C2-6 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., C3-10 cycloalkyl). In other embodiments, a cycloalkyl comprises five to seven carbon atoms (i.e., C5-7 cycloalkyl).
  • the WSGR Docket No.58296-711601 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., C3-12 cycloalkenyl).
  • a cycloalkenyl comprises three to ten carbon atoms (i.e., C3-10 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.
  • Cx-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 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. In some embodiments, 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. In some embodiments, 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.
  • the heterocycloalkyl is attached to the rest of the molecule through any atom of the heterocycloalkyl, valence permitting, such as any carbon or nitrogen atoms of the heterocycloalkyl.
  • heterocycloalkyl radicals include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, WSGR Docket No.58296-711601 thiomorpholinyl, 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 5- to 12-membered aromatic ring radical whose ring structure comprise at least one heteroatom, preferably between one to four heteroatoms.
  • the heteroaryl comprises at least one heteroatom selected from oxygen, nitrogen, sulfur, or any combination thereof.
  • the heteroaryl comprises at least one heteroatom selected from oxygen, nitrogen, or any combination thereof.
  • the heteroaryl comprises at least one heteroatom selected from oxygen, sulfur, or any combination thereof.
  • the heteroaryl comprises at least one heteroatom selected from nitrogen, sulfur, or any combination thereof.
  • One or more nitrogen atoms, if present, are optionally quaternized.
  • the 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.
  • the heteroaryl ring may be selected from monocyclic or polycyclic (bicyclic and fused or bridged) 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.
  • 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.
  • An “X-membered heterocycle” refers to the number of endocylic atoms, i.e., X, in the ring.
  • a 5-membered heteroaryl ring or 5-membered aromatic heterocycle has 5 endocyclic atoms, e.g., triazole, oxazole, thiophene, etc.
  • Alkoxy refers to a radical bonded through an oxygen atom of the formula –O-alkyl, where alkyl is an alkyl chain as defined above.
  • Halo or “halogen” refers to halogen substituents such as bromo, chloro, fluoro and iodo substituents.
  • haloalkyl or “haloalkane” refers to an alkyl radical, as defined above, that is substituted by one or more halogen radicals, for example, trifluoromethyl, dichloromethyl, bromomethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like.
  • the alkyl part of the fluoroalkyl radical is optionally further substituted.
  • haloalkanes examples include halomethane (e.g., chloromethane, bromomethane, fluoromethane, iodomethane), di-and trihalomethane (e.g., trichloromethane, tribromomethane, trifluoromethane, triiodomethane), 1-haloethane, 2- haloethane, 1,2-dihaloethane, 1-halopropane, 2-halopropane, 3-halopropane, 1,2-dihalopropane, 1,3-dihalopropane, 2,3-dihalopropane, 1,2,3-trihalopropane, and any other suitable combinations of alkanes (or substituted alkanes) and halogens (e.g., Cl, Br, F, and I).
  • halomethane e.g., chloromethane, bromomethane, fluoromethane, iodomethane
  • each halogen may be independently selected for example, 1-chloro,2-fluoroethane.
  • substituted refers to moieties having substituents replacing a hydrogen on one or more carbons or substitutable heteroatoms, e.g., an NH or NH2 of a compound. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, i.e., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.
  • substituted refers to moieties having substituents replacing two hydrogen atoms on the same carbon atom, such as substituting the two hydrogen atoms on a single carbon with an oxo, imino or thioxo group.
  • substituted is contemplated to include all permissible substituents of organic compounds.
  • the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds.
  • the permissible substituents can be one or more and the same or different for appropriate organic compounds.
  • salts or “pharmaceutically acceptable salt” refers to salts derived from a variety of organic and inorganic counter ions well known in the art.
  • Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids.
  • Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.
  • phrases “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable excipient or “pharmaceutically acceptable carrier” as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material.
  • Each carrier WSGR Docket No.58296-711601 must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
  • the terms "subject,” “individual,” and “patient” may be used interchangeably and refer to humans, the as well as non-human mammals (e.g., non-human primates, canines, equines, felines, porcines, bovines, ungulates, lagomorphs, and the like).
  • the subject can be a human (e.g., adult male, adult female, adolescent male, adolescent female, male child, female child) under the care of a physician or other health worker in a hospital, as an outpatient, or other clinical context. In certain embodiments, the subject may not be under the care or prescription of a physician or other health worker.
  • a subject in need thereof refers to a subject, as described infra, that suffers from, or is at risk for, a pathology to be prophylactically or therapeutically treated with a compound or salt described herein.
  • administer are defined as providing a composition to a subject via a route known in the art, including but not limited to intravenous, intraarterial, oral, parenteral, buccal, topical, transdermal, rectal, intramuscular, subcutaneous, intraosseous, transmucosal, or intraperitoneal routes of administration.
  • oral routes of administering a composition can be used.
  • administered should be understood to mean providing a compound of the invention or a prodrug of a compound of the invention to the individual in need.
  • 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.
  • a therapeutic benefit may be achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder, such as observing an improvement in the subject, notwithstanding that the subject may still be afflicted with the underlying disorder.
  • the compositions are administered to a subject at risk of developing a particular disease, or to a subject reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made.
  • Treating can include, for example, reducing, delaying or alleviating the severity of one or more symptoms of the disease or condition, or it can include reducing the frequency with which symptoms of a disease, defect, disorder, or adverse condition, and the like, WSGR Docket No.58296-711601 are experienced by a patient. Treating can be used herein to refer to a method that results in some level of treatment or amelioration of the disease or condition, and can contemplate a range of results directed to that end, including but not restricted to prevention of the condition entirely.
  • the term “prevent” or “preventing” as related to a disease or disorder may refer to a compound that, in a statistical sample, reduces the occurrence of the disorder or condition in the treated sample relative to an untreated control sample, or delays the onset or reduces the severity of one or more symptoms of the disorder or condition relative to the untreated control sample.
  • “modulate” refers to alteration of the activity or the expression of target protein/gene in the presence of an exogenous compound, relative to the comparable conditions in the absence of the exogenous compound.
  • the term “modulate” can be up- regulation (e.g., activation or stimulation) or down-regulation (e.g., inhibition or suppression).
  • Ring A is 3- to 12-membered heterocycle comprising one or more heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, for the compound or salt or salt of Formula (I), Ring A is 3- to 12-membered saturated heterocycle comprising one or more heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, for the compound or salt or salt of Formula (I), Ring A is 3- to 12-membered unsaturated heterocycle comprising one or more heteroatoms selected from nitrogen, oxygen, and sulfur.
  • Ring A is selected from 3- to 4- membered heterocycle, 3- to 5-membered heterocycle, 3- to 6-membered heterocycle, 3- to 7- membered heterocycle, 3- to 8-membered heterocycle, 3- to 9-membered heterocycle, 3- to 10- membered heterocycle, 3- to 11-membered heterocycle, and 3- to 12-membered heterocycle, any of which is optionally substituted with R 1 as defined in Formula (I).
  • Ring A is selected from 3-membered heterocycle, 4-membered heterocycle, 5-membered heterocycle, 6-membered heterocycle, 7-membered heterocycle, 8-membered heterocycle, 9-membered heterocycle, 10-membered heterocycle, 11-membered heterocycle, and 12-membered heterocycle, any of which is optionally substituted with R 1 as defined in Formula (I).
  • Ring A is 5- to 12- membered heteroaryl comprising one or more heteroatoms selected from nitrogen, oxygen, and WSGR Docket No.58296-711601 sulfur.
  • Ring A is selected from 5- to 6-membered heteroaryl, 5- to 9- membered heteroaryl, and 5- to 10-membered heteroaryl, any of which is optionally substituted with R 1 as defined in Formula (I). In some embodiments, Ring A is selected from 5-membered heteroaryl, 6-membered heteroaryl, 9-membered heteroaryl, and 10-membered heteroaryl, any of which is optionally substituted with R 1 as defined in Formula (I). [0050] In some embodiments, for the compound or salt of Formula (I), Ring A is selected from 3- to 6-membered monocyclic heterocycle and 6- to 12-membered bicyclic heterocycle, any of which comprises at least one heteroatom selected from nitrogen, oxygen, and sulfur.
  • Ring A is 3- to 6- membered monocyclic heterocycle comprising one heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is 5- to 6-membered heteroaryl. In some embodiments, Ring A is 5-membered heteroaryl selected from pyrrolyl and thiophenyl. In some embodiments, Ring A is selected from pyrrolyl and thiophenyl; and n is 0. [0052] In some embodiments, for the compound or salt of Formula selected from [0053] In some embodiments, for the compound or salt of Formula (I), Ring A is 6- to 12- membered bicyclic heterocycle comprising at least one heteroatom selected from nitrogen, oxygen, and sulfur.
  • the 6- to 12-membered bicyclic heterocycle of Ring A is selected from a 6- to 12-membered bridged heterocycle, 6- to 12-membered fused heterocycle, and 6- to 12-membered spirocyclic heterocycle.
  • Ring A is 6- to 12- membered fused heterocycle.
  • Ring A is selected from 1H-indolyl, indolinyl, benzo[b]thiophenyl, 1H-pyrrolo[2,3-b]pyridinyl, 1H-pyrrolo[3,2-b]pyridinyl, 1H- pyrrolo[3,2-c]pyridinyl, 1H-benzo[d]imidazolyl, 4,7-dihydro-1H-pyrrolo[3,2-b]pyridinyl, 6,7- dihydro-1H-pyrrolo[2,3-c]pyridinyl, 5H-pyrrolo[3,2-d]pyrimidinyl, 7H-pyrrolo[2,3- c]pyridazinyl, 1H-pyrrolo[2,3-d]pyridazinyl, 5H-pyrrolo[2,3-b]pyrazinyl, 7H-pyrrolo[2,3- d]pyrimidinyl, and 3,7-dihydro-2
  • Ring A is selected from 1H-indolyl and indolinyl. In some embodiments, Ring A is benzo[b]thiophenyl. In some embodiments, Ring A is selected from 1H-pyrrolo[2,3-b]pyridinyl, 1H-pyrrolo[3,2- b]pyridinyl, and 1H-pyrrolo[3,2-c]pyridinyl. In some embodiments, Ring A is 1H- WSGR Docket No.58296-711601 benzo[d]imidazolyl.
  • Ring A is selected from 4,7-dihydro-1H-pyrrolo[3,2- b]pyridinyl and 6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl. In some embodiments, Ring A is selected from 5H-pyrrolo[3,2-d]pyrimidinyl, 7H-pyrrolo[2,3-c]pyridazinyl, 1H-pyrrolo[2,3- d]pyridazinyl, 5H-pyrrolo[2,3-b]pyrazinyl, and 7H-pyrrolo[2,3-d]pyrimidinyl.
  • Ring A is 3,7-dihydro-2H-pyrrolo[2,3-d]pyrimidinyl.
  • Ring A is selected from benzo[b]thiophenyl, 1H-indolyl, 5H-pyrrolo[3,2-d]pyrimidinyl, 7H- pyrrolo[2,3-c]pyridazinyl, and 1H-pyrrolo[2,3-d]pyridazinyl; and n is 0.
  • n is 1, 2, or 3. In some embodiments, n is 3. In some embodiments, n is 1 or WSGR Docket No.58296-711601 2. In some embodiments, n is 1. In some embodiments, n is 2, 3, or 4. In some embodiments, n is 2 or 3. In some embodiments, Ring A is 6- to 10-membered bicyclic heteroaryl comprising at least one heteroatom selected from nitrogen, oxygen, and sulfur.
  • n is 1, 2, or 3. In some embodiments, n is 3. In some embodiments, n is 1 or 2. In some embodiments, n is 1. In some embodiments, n is 2, 3, or 4. In some embodiments, n is 2 or 3.
  • Ring A is selected from 1H-indolyl, indolinyl, benzo[b]thiophenyl, 1H-pyrrolo[2,3-b]pyridinyl, 1H-pyrrolo[3,2- b]pyridinyl, 1H-pyrrolo[3,2-c]pyridinyl, 1H-benzo[d]imidazolyl, 4,7-dihydro-1H-pyrrolo[3,2- b]pyridinyl, 6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl, 5H-pyrrolo[3,2-d]pyrimidinyl, 7H- pyrrolo[2,3-c]pyridazinyl, 1H-pyrrolo[2,3-d]pyridazinyl, 5H-pyrrolo[2,3-b]pyrazinyl, 7H- pyrrolo[2,3-d
  • n is 1, 2, or 3. In some embodiments, n is 3. In some embodiments, n is 1 or 2. In some embodiments, n is 1. In some embodiments, n is 2, 3, or 4. In some embodiments, n is 2 or 3.
  • n is selected from 1, 2, 3, and 4; each R 1 is independently selected at each occurrence from C 3-6 saturated carbocycle, 3- to 6-membered saturated heterocycle, and 5- to 6-membered heteroaryl, each 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, -N(R 11 )C(O)R 11 , -N(R 11 )C(O)OR 11 , -N(R 11 )S(O)2R 11 , -NO2, -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR 11 , -N(R 11 ) 2 , -C(O)R 11 , -C(O)N(R 11 ) 2 , -N(R 11 )C(O)R 11 ,
  • n is selected from 1 and 2; each R 1 is independently selected at each occurrence from cyclopropyl, oxetanyl, thiophenyl, pyrazolyl, and triazolyl, each 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 , -N(R 11 )C(O)R 11 , - N(R 11 )C(O)OR 11 , -N(R 11 )S(O)2R 11 , -NO2, -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR 11 , -N(R 11 )2, -C(O)R 11 , - WSGR Docket No.58296-711601 C(O)N(R 11 )2,
  • n is 1, 2, or 3. In some embodiments, n is 3. In some embodiments, n is 1 or 2. In some embodiments, n is 1. In some embodiments, n is 2, 3, or 4. In some embodiments, n is 2 or 3. In some embodiments, Ring A is 6- to 10-membered bicyclic heteroaryl comprising at least one heteroatom selected from nitrogen, oxygen, and sulfur.
  • n is selected from 1, 2, 3, and 4; each R 1 is independently selected at each occurrence from C3-6 saturated carbocycle, 3- to 6-membered saturated heterocycle, and 5- to 6-membered heteroaryl, each 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, -N(R 11 )C(O)R 11 , -N(R 11 )C(O)OR 11 , -N(R 11 )S(O)2R 11 , -NO2, -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR 11 , -N(R 11 ) 2 , -C(O)R 11 , -C(O)N(R 11 ) 2 , -N(R 11 )C(O)R 11 ,
  • n is selected from 1 and 2; each R 1 is independently selected at each occurrence from cyclopropyl, oxetanyl, thiophenyl, pyrazolyl, and triazolyl, each 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 , -N(R 11 )C(O)R 11 , - N(R 11 )C(O)OR 11 , -N(R 11 )S(O)2R 11 , -NO2, -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR 11 , -N(R 11 )2, -C(O)R 11 , - WSGR Docket No.58296-711601 C(O)N(R 11 )2,
  • n is 1, 2, or 3. In some embodiments, n is 3. In some embodiments, n is 1 or 2. In some embodiments, n is 1. In some embodiments, n is 2, 3, or 4. In some embodiments, n is 2 or 3.
  • Ring A is selected from 1H-indolyl, indolinyl, benzo[b]thiophenyl, 1H-pyrrolo[2,3-b]pyridinyl, 1H-pyrrolo[3,2- b]pyridinyl, 1H-pyrrolo[3,2-c]pyridinyl, 1H-benzo[d]imidazolyl, 4,7-dihydro-1H-pyrrolo[3,2- b]pyridinyl, 6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl, 5H-pyrrolo[3,2-d]pyrimidinyl, 7H- pyrrolo[2,3-c]pyridazinyl, 1H-pyrrolo[2,3-d]pyridazinyl, 5H-pyrrolo[2,3-b]pyrazinyl, 7H- pyrrolo[2,3-d
  • n is selected from 1, 2, 3, and 4; each R 1 is independently selected at each occurrence from C3-6 saturated carbocycle, 3- to 6-membered saturated heterocycle, and 5- to 6-membered heteroaryl, each 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, -N(R 11 )C(O)R 11 , -N(R 11 )C(O)OR 11 , - N(R 11 )S(O)2R 11 , -NO2, -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR 11 , -N(R 11 ) 2 , -C(O)R 11 , -C(O)N(R 11 ) 2 , -N(R 11 )C(O)R 11 ,
  • n is selected from 1 and 2; each R 1 is independently selected at each occurrence from cyclopropyl, oxetanyl, thiophenyl, pyrazolyl, and triazolyl, each of which is optionally WSGR Docket No.58296-711601 substituted with one or more substituents independently selected from halogen, -OR 11 , -N(R 11 )2, 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)N(R 11 )2, -N(R 11 )C(O)R 11 , -N(R 11 )C(O)OR 11 , - N(R 11 )S(O)2R 11 , -NO2, and -CN; and R 11 is independently selected at each occurrence from hydrogen and C 1-6 alkyl optionally substituted with one more
  • n is 1, 2, or 3. In some embodiments, n is 3. In some embodiments, n is 1 or 2. In some embodiments, n is 1. In some embodiments, n is 2, 3, or 4. In some embodiments, n is 2 or 3.
  • Ring A is selected from pyrrolyl, thiophenyl, 1H-indolyl, indolinyl, benzo[b]thiophenyl, 1H-pyrrolo[2,3-b]pyridinyl, 1H- pyrrolo[3,2-b]pyridinyl, 1H-pyrrolo[3,2-c]pyridinyl, 1H-benzo[d]imidazolyl, 4,7-dihydro-1H- pyrrolo[3,2-b]pyridinyl, 6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl, 5H-pyrrolo[3,2-d]pyrimidinyl, 7H-pyrrolo[2,3-c]pyridazinyl, 1H-pyrrolo[2,3-d]pyridazinyl, 5H
  • WSGR Docket No.58296-711601 WSGR Docket No.58296-711601
  • WSGR Docket No.58296-711601 WSGR Docket No.58296-711601
  • a 3- to 12-membered heterocycle is a 3- to 12-membered saturated heterocycle. In some embodiments, is a 3- to 12-membered unsaturated heterocycle.
  • for the compound or salt of Formula (I) is selected from 3- to 7-membered monocyclic heterocycle and 6- to 12-membered bicyclic heterocycle.
  • the 6- to 12-membered bicyclic heterocycle of is selected from a 6- to 12-membered bridged heterocycle, 6- to 12-membered fused heterocycle, and 6- to 12-membered spirocyclic heterocycle.
  • the 6- to 12-membered bicyclic heterocycle of is a 6- to 12-membered bridged heterocycle.
  • the 6- to 12-membered fused heterocycle of is a 6- to 12-membered bridged heterocycle.
  • the 6- to 12-membered bicyclic is a 6- to 12-membered spirocyclic heterocycle.
  • heterocycloalkyl is a 6- to 12-membered spirocyclic heterocycle.
  • m is selected from 0, 1, 2, and 3.
  • for the compound or salt of Formula (I), is selected from 3- to 7-membered monocyclic heterocycle and 6- to 12-membered bicyclic heterocycle; m is selected from 0, 1, and 2; each R 2 is independently selected at each occurrence from: halogen, - OR 12 , -SR 12 , -N(R 12 ) 2 , -C(O)R 12 , -C(O)N(R 12 ) 2 , -C(O)OR 12 , -OC(O)R 12 , -N(R 12 )C(O)R 12 , - N(R 12 )C(O)OR 12 , -N(R 12 )S(O) 2 R 12 , -S(O) 2 N(R 12 ) 2 , -S(O) 2 N(R 12 ) 2 , -S(O) 2 N(R 12 ) 2 , -S(O) 2 N(R 12 )
  • m is selected from 0, 1, and 2; each R 2 is independently selected at each occurrence from: halogen, -OR 12 , -N(R 12 )2, -C(O)R 12 , -C(O)N(R 12 )2, -C(O)OR 12 , -N(R 12 )C(O)R 12 , -N(R 12 )C(O)OR 12 , -NO 2 , and -CN; and C 1-6 alkyl optionally substituted with WSGR Docket No.58296-711601 one or more substituents independently selected from halogen, -OR 12 , -N(R 12 )2, -C(O)R 12 , - C(O)N(R 12 ) 2 , -C(O)OR 12 , -N(R 12 )C(O)R 12 , -N(R 12 )C(O)OR 12 , -NO 2 , and -CN; and R
  • m is 0 or 1. In some embodiments, m is 1 or 2. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. [0069] In some embodiments, for the compound or salt of Formula (I), is 3- to 7- membered monocyclic heterocycle; m is selected from 0, 1, and 2; each R 2 is independently selected at each occurrence from: halogen, -OR 12 , -SR 12 , -N(R 12 ) 2 , -C(O)R 12 , - C(O)N(R 12 )2, -C(O)OR 12 , -OC(O)R 12 , -N(R 12 )C(O)R 12 , -N(R 12 )C(O)OR 12 , -N(R 12 )S(O)2R 12 , - S(O)2N(R 12 )2, -S(O)R 12 , -S(O)2
  • m is selected from 0, 1, and 2; each R 2 is independently selected at each occurrence from: halogen, - OR 12 , -N(R 12 ) 2 , -C(O)R 12 , -C(O)N(R 12 ) 2 , -C(O)OR 12 , -N(R 12 )C(O)R 12 , -N(R 12 )C(O)OR 12 , -NO 2 , and -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR 12 , -N(R 12 ) 2 , -C(O)R 12 , -C(O)N(R 12 ) 2 , -C(O)OR 12 , -N(R 12 )C(O)R 12 , - N(R 12 )C(O)OR 12 , -NO 2 , and -CN; and R 12 is selected at each occurrence from: halogen
  • m is 0 or 1. In some embodiments, m is 1 or 2. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. [0070] In some embodiments, for the compound or salt of Formula (I), is 4- to 6- membered heterocycloalkyl; m is selected from 0, 1, and 2; each R 2 is independently selected at each occurrence from: halogen, -OR 12 , -SR 12 , -N(R 12 )2, -C(O)R 12 , -C(O)N(R 12 )2, -C(O)OR 12 , - OC(O)R 12 , -N(R 12 )C(O)R 12 , -N(R 12 )C(O)OR 12 , -N(R 12 )S(O)2R 12 , -S(O)2N(R 12 )2, -S(O)R 12 , - S(O) 2 R
  • m is selected from 0, 1, and 2; each R 2 is independently selected at each occurrence from: halogen, -OR 12 , -N(R 12 )2, - C(O)R 12 , -C(O)N(R 12 )2, -C(O)OR 12 , -N(R 12 )C(O)R 12 , -N(R 12 )C(O)OR 12 , -NO2, and -CN; and C1- 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)N(R 12 )2, -C(O)OR 12 , -N(R 12 )C(O)R 12 , -N(R 12 )C(O)OR 12 , -NO2, and -CN; and R 12 is selected at each occurrence from hydrogen and C1-6 alkyl optionally substitute
  • m is 0 or 1. In some embodiments, m is 1 or 2. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. [0071] In some embodiments, for the compound or salt of Formula (I), is selected from azetidinyl, pyrrolidinyl, and piperidinyl; m is selected from 0, 1, and 2; each R 2 is independently selected at each occurrence from: halogen, -OR 12 , -SR 12 , -N(R 12 )2, -C(O)R 12 , - C(O)N(R 12 ) 2 , -C(O)OR 12 , -OC(O)R 12 , -N(R 12 )C(O)R 12 , -N(R 12 )C(O)OR 12 , -N(R 12 )S(O) 2 R 12 , - S(O) 2 N(R 12 ) 2 , - -
  • m is selected from 0, 1, and 2; each R 2 is independently selected at each occurrence from: halogen, - OR 12 , -N(R 12 )2, -C(O)R 12 , -C(O)N(R 12 )2, -C(O)OR 12 , -N(R 12 )C(O)R 12 , -N(R 12 )C(O)OR 12 , -NO2, and -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)N(R 12 ) 2 , -C(O)OR 12 , -N(R 12 )C(O)R 12 , - N(R 12 )C(O)OR 12 , -NO2, and -CN; and R 12 is selected at each occurrence from hydrogen and C1-6 alkyl
  • m is 0 or 1. In some WSGR Docket No.58296-711601 embodiments, m is 1 or 2. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. [0072] In some embodiments, for the compound or salt of Formula (I), is selected WSGR Docket No.58296-711601 [0073] In some embodiments, for the compound or salt of Formula (I), is selected from 3- to 7-membered monocyclic heterocycle and 6- to 12-membered bicyclic heterocycle; m is selected from 0, 1, and 2; each R 2 is independently selected at each occurrence from: halogen, - OR 12 , -SR 12 , -N(R 12 )2, -C(O)R 12 , -C(O)N(R 12 )2, -C(O)OR 12 , -OC(O)R 12 , -N(R 12 )C(O)R 12 , - N(R
  • m is 0 or 1. In some embodiments, m is 1 or 2. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. [0074] In some embodiments, for the compound or salt of Formula (I), is 3- to 7- membered monocyclic heterocycle; m is selected from 0, 1, and 2; each R 2 is independently selected at each occurrence from: halogen, -OR 12 , -SR 12 , -N(R 12 ) 2 , -C(O)R 12 , - C(O)N(R 12 ) 2 , -C(O)OR 12 , -OC(O)R 12 , -N(R 12 )C(O)R 12 , -N(R 12 )C(O)OR 12 , -N(R 12 )S(O) 2 R 12 , - S(O)2N(R 12 )2, -S(O)R 12 , -S(O)
  • m is 0 or 1. In some embodiments, m is 1 or 2. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. [0075] In some embodiments, for the compound or salt of Formula (I), is 4- to 6- membered heterocycloalkyl; m is selected from 0, 1, and 2; each R 2 is independently selected at each occurrence from: halogen, -OR 12 , -SR 12 , -N(R 12 )2, -C(O)R 12 , -C(O)N(R 12 )2, -C(O)OR 12 , - OC(O)R 12 , -N(R 12 )C(O)R 12 , -N(R 12 )C(O)OR 12 , -N(R 12 )S(O) 2 R 12 , -S(O) 2 N(R 12 ) 2 , -S(O)R 12 , - S(O)
  • m is 0 or 1. In some embodiments, m is 1 or 2. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. [0076] In some embodiments, for the compound or salt of Formula (I), is selected from azetidinyl, pyrrolidinyl, and piperidinyl; m is selected from 0, 1, and 2; each R 2 is independently selected at each occurrence from: halogen, -OR 12 , -SR 12 , -N(R 12 )2, -C(O)R 12 , - C(O)N(R 12 )2, -C(O)OR 12 , -OC(O)R 12 , -N(R 12 )C(O)R 12 , -N(R 12 )C(O)OR 12 , -N(R 12 )S(O)2R 12 , - S(O) 2 N(R 12 ) 2 , -S(
  • m is 0 or 1. In some embodiments, m is 1 or 2. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. WSGR Docket No.58296-711601 [0077] In some embodiments, for the compound or salt of Formula selected [0078] In some embodiments, for the compound or salt of Formula (I), is a 6- to 12- membered bridged heterocycle; and m is 0.
  • azabicyclo[3.1.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 7-azabicyclo[2.2.1]heptanyl, and 2- oxa-5-azabicyclo[2.2.1]heptanyl; and m is 0.
  • azabicyclo[3.1.1]heptanyl; and m is 0.
  • is 2,5- diazabicyclo[2.2.1]heptanyl; and m is 0.
  • is 2-oxa-5- azabicyclo[2.2.1]heptanyl; and m is 0.
  • azabicyclo[2.2.1]heptanyl; and m is 0.
  • the compound or salt of Formula (I) is a 6- to 12- membered spirocyclic heterocycle; and m is 0.
  • R 3 is selected from: hydrogen, -C(O)R 13 , -S(O)2R 13 , and -CN; C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR 13 , -N(R 13 ) 2 , -C(O)R 13 , - C(O)N(R 13 )2, -C(O)OR 13 , -N(R 13 )C(O)R 13 , -NO2, and -CN; and C3-6 carbocycle and 3- to 6- membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 13 , -N(R 13 ) 2 , -C(
  • R 3 is hydrogen.
  • R 3 is C1-6 alkyl. In some embodiments, R 3 is 5- to 6-membered heteroaryl. In some embodiments, R 3 is selected from hydrogen, , -CN, methyl, ethyl, -S(O 2 )CH 3 , , and .
  • R 4 is selected from: 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)N(R 14 )2, -C(O)OR 14 , -NO2, -CN, C3-6 carbocycle and 3- to 6-membered heterocycle, the C 3-6 carbocycle and 3- to 6-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OR 14 , -N(R 14 )2, -C(O)R 14 , -C(O)N(R 14 )2, -C(O)OR 14 , -NO2, -CN, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkyl-OR 14 , C1-6 alkyl-C 3-6 carbocycle, and C 1-6 alkyl-C 3-6 heterocycle; and R 14 is independently
  • R 4 is selected from: C1-6 alkyl optionally substituted with one or more substituents independently selected from -OR 14 , -C(O)R 14 , C 3-6 carbocycle and 3- to 6- membered heterocycle, the C 3-6 carbocycle and 3- to 6-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OR 14 , -N(R 14 )2, -C(O)R 14 , -C(O)N(R 14 )2, -C(O)OR 14 , -NO2, -CN, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkyl- WSGR Docket No.58296-711601 OR 14 , C1-6 alkyl-C3-6 carbocycle, and C1-6 alkyl-C3-6 heterocycle; and R 14 is independently selected at each occurrence from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 carbocycle and 3- to
  • R 4 is selected from: 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)N(R 14 )2, -C(O)OR 14 , -NO2, and -CN; and R 14 is independently selected at each occurrence from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 carbocycle and 3- to 10-membered heterocycle.
  • R 4 is C1-6 alkyl substituted with one substituent selected from C3-6 carbocycle and 3- to 6-membered heterocycle, the C3-6 carbocycle and 3- to 6-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OR 14 , -N(R 14 )2, -C(O)R 14 , -C(O)N(R 14 )2, -C(O)OR 14 , -NO2, -CN, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkyl-OR 14 , C1-6 alkyl-C3-6 carbocycle, and C1-6 alkyl-C3-6 heterocycle; and R 14 is independently selected at each occurrence from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 carbocycle and 3- to 10-membered heterocycle.
  • R 4 is C 1-6 alkyl. In some embodiments, R 4 is selected from: methyl, ethyl, propyl, isopropyl, , [0086] In some embodiments, for the compound or salt of Formula (I), R 4 is selected from: C3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 14 , -SR 14 , -N(R 14 )2, -C(O)R 14 , - C(O)N(R 14 )2, -C(O)OR 14 , -OC(O)R 14 , -N(R 14 )C(O)R 14 , -N(R 14 )C(O)OR 14 , -N(R 14 )S(O)2R 14 , - S(O) 2 N(R 14 ) 2 , -S(O)R 14 , -S(O)
  • R 4 is selected from: cyclobutyl, phenyl, and bicyclo[1.1.1]pentanyl. In some embodiments, R 4 is selected from: [0087] In some embodiments, for the compound or salt of Formula (I), R 4 is selected from: 3- to 6-membered monocyclic heterocycle and 8- to 10-membered fused heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 14 , -SR 14 , -N(R 14 )2, -C(O)R 14 , -C(O)N(R 14 )2, -C(O)OR 14 , -OC(O)R 14 , -N(R 14 )C(O)R 14 , - N(R 14 )C(O)OR 14 , -N(R 14 )S(O)2R 14 , -S(O)2N(R 14 )2, -S(O)R 14 ,
  • R 4 is selected from: 3- to 6-membered monocyclic heterocycle and 8- to 10- membered fused heterocycle. In some embodiments, R 4 is selected from: oxetanyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, 6,7-dihydro-5H-cyclopenta[b]pyridinyl, and 2,3-dihydro- [1,4]dioxino[2,3-b]pyridinyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 14 , -SR 14 , -N(R 14 )2, -C(O)R 14 , - C(O)N(R 14 )2, -C(O)OR 14 , -OC(O)R 14 , -N(R 14 )C(O)R 14 , -N(R 14 )C(O)OR 14 ,
  • R 4 is selected from: oxetanyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, 6,7-dihydro-5H- cyclopenta[b]pyridinyl, and 2,3-dihydro-[1,4]dioxino[2,3-b]pyridinyl.
  • Ring A is 8- to 10-membered heterocycle;
  • X 1 is selected from N and C(H);
  • n is selected from 0, 1, and 2; each R 1 is independently selected at each occurrence from: halogen, -OR 11 , -SR 11 , -N(R 11 ) 2 , -C(O)R 11 , -C(O)N(R 11 ) 2 , -C(O)OR 11 , -OC(O)R 11 , -N(R 11 )C(O)R 11 , -N(R 11 )C(O)OR 11 , -N(R 11 )S(O)
  • Ring A is indolyl;
  • X 1 is selected from N and C(H);
  • n is selected from 0, 1, and 2;
  • Formula (I) is represented by the structure of Formula (I-a): or a pharmaceutically acceptable salt thereof, wherein each of A 1 , A 2 , A 3 , and A 4 are independently selected at each occurrence from C(R 1 ), C(H), and N; R A is halogen or hydrogen; and X 1 , R 1 , R 2 , R 3 , R 4 , m, and are as defined in Formula (I).
  • Formula (I) or Formula (I-a) is represented by the structure of Formula (I-b): or a pharmaceutically acceptable salt thereof, wherein each of A 1 , A 2 , A 3 , and A 4 are independently selected at each occurrence from C(R 1 ), C(H), and N; R A is halogen or hydrogen; and are as defined in Formula (I).
  • Formula (I), Formula (I-a), or Formula (I-b) is represented by the structure of Formula (I-c): or a pharmaceutically acceptable salt thereof, wherein each of A 1 , A 2 , A 3 , and A 4 are independently selected at each occurrence from C(R 1 ), C(H), and N; q is 1 or 2; R A is halogen or hydrogen; and X 1 , R 1 , R 2 , R 4 , and m are as defined in Formula (I).
  • each R 2 is independently selected at each occurrence from -OH, -F, -CN, methyl, -O-(methyl), and fluoromethyl.
  • Formula (I), Formula (I-a), Formula (I-b), or Formula (I-c) is represented by the structure of Formula (I-d): or a pharmaceutically acceptable salt thereof, wherein each of A 1 and A 4 are independently selected at each occurrence from C(R 1 ), C(H), and N; n is 0 or 1 or 2; q is 1 or 2; R A is halogen or hydrogen; and X 1 , R 1 , R 2 , R 4 , and m are as defined in Formula (I).
  • each R 2 is independently selected at each occurrence from -OH, -F, -CN, methyl, -O-(methyl), and fluoromethyl.
  • Formula (I), Formula (I-a), Formula (I-b), Formula (I-c), or Formula (I- d) is represented by the structure of Formula (I-e): or a pharmaceutically acceptable salt thereof, wherein each of A 1 and A 4 are independently selected at each occurrence from C(R 1 ), C(H), and N; n is 0 or 1 or 2; q is 1 or 2; R A is halogen or hydrogen; and X 1 , R 1 , R 2 , R 4 , and m are as defined in Formula (I).
  • each R 2 is independently selected at each occurrence from -OH, -F, -CN, methyl, -O-(methyl), and fluoromethyl.
  • R 4 is selected from methyl, ethyl, and 5- to 10-membered heteroaryl.
  • Ring A is selected from: [0097]
  • the compound or salt of Formula (I), Formula (I-a), Formula (I-b), Formula (I-c), Formula (I-d), or Formula (I-e) is selected from: WSGR Docket No.58296-711601 [0098]
  • the compound or salt of Formula (I) is a compound displayed in Table 1, or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides a compound of Formula (II): or a pharmaceutically acceptable salt thereof, wherein: X 2 is N, C(H), or C(R 8 ); each R 8 is independently selected from halogen, -OR 20 , -SR 20 , -N(R 20 ) 2 , -C(O)R 20 , - C(O)N(R 20 ) 2 , -C(O)OR 20 , -OC(O)R 20 , -N(R 20 )C(O)R 20 , -N(R 20 )C(O)OR 20 , -N(R 20 )S(O) 2 R 20 , - S(O)2N(R 20 )2, -NO2, and -CN; WSGR Docket No.58296-711601 z is selected from 1 and 2; R 20 is independently selected at each occurrence from: hydrogen; C1-6 alkyl optionally substituted with one more substituents independently selected
  • the present disclosure provides a compound of Formula (III): or a pharmaceutically acceptable salt thereof, wherein: X 3 is N, C(H), or C(R 38 ); each R 38 is independently selected from halogen, -OR 40 , -SR 40 , -N(R 40 ) 2 , -C(O)R 40 , - C(O)N(R 40 )2, -C(O)OR 40 , -OC(O)R 40 , -N(R 40 )C(O)R 40 , -N(R 40 )C(O)OR 40 , -N(R 20 )S(O)2R 40 , - S(O)2N(R 40 )2, -NO2, and -CN; y is selected from 0, 1, and 2; Z is 5- to 10-membered heteroaryl, 3- to 15-membered carbocycle, or -N(R 36 )2, wherein the 5- to 10-membered heteroaryl
  • “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.
  • 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)-.
  • 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), herein may in some cases exist as diastereomers, enantiomers, or other stereoisomeric forms.
  • the compounds presented herein include all diastereomeric, enantiomeric, and epimeric forms as well as the racemates, mixtures of diastereomers, and other mixtures thereof, to the extent they can be made by one of ordinary skill in the art by routine experimentation. Separation of stereoisomers may be performed by chromatography or by forming diastereomers and separating by recrystallization, or chromatography, or any combination thereof. (Jean Jacques, Andre Collet, Samuel H.
  • 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) 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).
  • Racemic mixtures of chiral compounds can be separated and isolated by any suitable method, including, but not limited to: (1) formation of ionic, diastereomeric salts with chiral compounds and separation by fractional crystallization or other methods, (2) formation of diastereomeric compounds with chiral derivatizing reagents, separation of the diastereomers, and conversion to the pure stereoisomers, and (3) separation of the substantially pure or enriched stereoisomers directly under chiral conditions.
  • Another approach for separation of the enantiomers is to use a Diacel chiral column and elution using an organic mobile phase such as done by Chiral Technologies (www.chiraltech.com) on a fee for service basis.
  • a "tautomer” refers to a molecule wherein a proton shift from one atom of a molecule to another atom of the same molecule is possible.
  • the compounds or salts for Formula (I) exist as tautomers. In circumstances where tautomerization is possible, a chemical equilibrium of the tautomers may exist. The exact ratio of the tautomers depends on WSGR Docket No.58296-711601 several factors, including physical state, temperature, solvent, and pH.
  • 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.
  • the methods of synthesis for deuterium-containing compounds are known in the art and include, by way of non-limiting example only, the following synthetic methods.
  • Deuterated starting materials are readily available and are subjected to the synthetic methods described herein to provide for the synthesis of deuterium-containing compounds.
  • WSGR Docket No.58296-711601 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).
  • 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, such as those with a quaternary nitrogen can form a salt with an appropriate counterion, e.g., a halide such as bromide, chloride, or fluoride, particularly bromide.
  • compositions of Formula (I) include the use of amorphous forms as well as crystalline forms (also known as polymorphs).
  • the compounds described herein may be in the form of pharmaceutically acceptable salts.
  • active metabolites of these compounds having the same type of activity are included in the scope of the present disclosure.
  • the compounds described herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like.
  • the solvated forms of the compounds presented herein are also considered to be disclosed herein.
  • Compounds of Formula (I) also include crystalline and amorphous forms of those compounds, pharmaceutically acceptable salts, and active metabolites of these compounds having the same type of activity, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of the compounds, as well as mixtures thereof.
  • compounds or salts of Formula (I) may be prodrugs, e.g., wherein a hydroxyl in the parent compound is presented as an ester or a carbonate, or carboxylic acid present in the parent compound is presented as an ester.
  • prodrug is intended to encompass compounds which, under physiologic conditions, are converted into pharmaceutical agents of the present disclosure.
  • One method for making a prodrug is to include one or more selected moieties which are hydrolyzed under physiologic conditions to reveal the desired molecule.
  • the prodrug is converted by an enzymatic activity of the host animal such as specific target cells in the host animal.
  • esters or carbonates e.g., esters or carbonates of alcohols or carboxylic acids and esters of phosphonic acids
  • Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent is not.
  • Prodrugs may help enhance the cell permeability of a compound relative to the parent drug.
  • the prodrug may also have improved solubility in pharmaceutical compositions over the parent drug.
  • Prodrugs may be designed as reversible drug derivatives, for use as modifiers to enhance drug transport to site-specific tissues or to increase drug residence inside of a cell.
  • the prodrug may be converted, e.g., enzymatically or chemically, to the parent compound under the conditions within a cell.
  • the parent compound comprises an acidic moiety, e.g., resulting from the hydrolysis of the prodrug, which may be charged under the conditions within the cell.
  • the prodrug is converted to the parent compound once it has passed through the cell membrane into a cell.
  • the parent compound has diminished cell membrane permeability properties relative to the prodrug, such as decreased lipophilicity and increased hydrophilicity.
  • the design of a prodrug increases the lipophilicity of the pharmaceutical agent.
  • the design of a prodrug increases the effective water solubility. See, e.g., Fedorak et al., Am. J. Physiol., 269:G210-218 (1995); McLoed et al., Gastroenterol, 106:405-413 (1994); Hochhaus et al., Biomed.
  • the present disclosure provides methods of producing the above-defined WSGR Docket No.58296-711601 compounds.
  • the compounds may be synthesized using conventional techniques.
  • these compounds are conveniently synthesized from readily available starting materials.
  • Synthetic chemistry transformations and methodologies useful in synthesizing the compounds described herein are known in the art and include, for example, those described in R. Larock, Comprehensive Organic Transformations (1989); T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2d. Ed. (1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis (1994); and L.
  • compositions comprising a compound or salt of Formula (I) and at least one pharmaceutically acceptable excipient.
  • Pharmaceutical compositions can be formulated using one or more physiologically- acceptable carriers comprising excipients and auxiliaries. Formulation can be modified depending upon the route of administration chosen.
  • Pharmaceutical compositions comprising a compound, salt or conjugate can be manufactured, for example, by lyophilizing the compound, salt or conjugate, mixing, dissolving, emulsifying, encapsulating or entrapping the conjugate.
  • the pharmaceutical compositions can also include the compounds, salts or conjugates in a free- base form or pharmaceutically-acceptable salt form.
  • Methods for formulation of the conjugates can include formulating any of the compounds, salts or conjugates with one or more inert, pharmaceutically-acceptable excipients or carriers to form a solid, semi-solid, or liquid composition.
  • Solid compositions can include, for example, powders, tablets, dispersible granules and capsules, and in some aspects, the solid compositions further contain nontoxic, auxiliary substances, for example wetting or emulsifying agents, pH buffering agents, and other pharmaceutically-acceptable additives.
  • compositions can comprise at least one active ingredient (e.g., a compound, salt or conjugate).
  • the active ingredients can be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization (e.g., hydroxymethylcellulose or gelatin microcapsules and poly-(methylmethacylate) microcapsules, WSGR Docket No.58296-711601 respectively), in colloidal drug-delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules) or in macroemulsions.
  • Pharmaceutical compositions as often further can comprise more than one active compound (e.g., a compound, salt or conjugate and other agents) as necessary for the particular indication being treated.
  • the active compounds can have complementary activities that do not adversely affect each other.
  • the composition can also comprise a chemotherapeutic agent, cytotoxic agent, cytokine, growth-inhibitory agent, anti-hormonal agent, anti-angiogenic agent, and/or cardioprotectant.
  • chemotherapeutic agent cytotoxic agent, cytokine, growth-inhibitory agent, anti-hormonal agent, anti-angiogenic agent, and/or cardioprotectant.
  • Such molecules can be present in combination in amounts that are effective for the purpose intended.
  • the compositions and formulations can be sterilized. Sterilization can be accomplished by filtration through sterile filtration.
  • the compositions can be formulated for administration as an injection.
  • Non-limiting examples of formulations for injection can include a sterile suspension, solution or emulsion in oily or aqueous vehicles.
  • Suitable oily vehicles can include, but are not limited to, lipophilic solvents or vehicles such as fatty oils or synthetic fatty acid esters, or liposomes.
  • Aqueous injection suspensions can contain substances which increase the viscosity of the suspension.
  • the suspension can also contain suitable stabilizers.
  • Injections can be formulated for bolus injection or continuous infusion.
  • the compositions can be lyophilized or in powder form for reconstitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
  • a suitable vehicle e.g., sterile pyrogen-free water
  • the compounds, salts or conjugates can be formulated in a unit dosage injectable form (e.g., solution, suspension, emulsion) in association with a pharmaceutically acceptable parenteral vehicle.
  • Vehicles can be water, saline, Ringer’s solution, dextrose solution, and 5% human serum albumin.
  • Non-aqueous vehicles such as fixed oils and ethyl oleate can also be used.
  • Liposomes can be used as carriers.
  • the vehicle can contain minor amounts of additives such as substances that enhance isotonicity and chemical stability (e.g., buffers and preservatives).
  • Sustained-release preparations can also be prepared.
  • sustained-release preparations can include semipermeable matrices of solid hydrophobic polymers that can contain the compound, salt or conjugate, and these matrices can be in the form of shaped articles (e.g., films or microcapsules).
  • sustained-release matrices can include polyesters, hydrogels (e.g., poly(2-hydroxyethyl-methacrylate), or poly (vinyl alcohol)), polylactides, copolymers of L-glutamic acid and ⁇ ethyl-L-glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as the LUPRON DEPO TM (i.e., injectable WSGR Docket No.58296-711601 microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), and poly- D-( –)-3-hydroxybutyric acid.
  • LUPRON DEPO TM
  • compositions can be prepared for storage by mixing a compound, salt or conjugate with a pharmaceutically acceptable carrier, excipient, and/or a stabilizer.
  • This formulation can be a lyophilized formulation or an aqueous solution.
  • Acceptable carriers, excipients, and/or stabilizers can be nontoxic to recipients at the dosages and concentrations used.
  • Acceptable carriers, excipients, and/or stabilizers can include buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives, polypeptides; proteins, such as serum albumin or gelatin; hydrophilic polymers; amino acids; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counter-ions such as sodium; metal complexes; and/or non- ionic surfactants or polyethylene glycol.
  • buffers such as phosphate, citrate, and other organic acids
  • antioxidants including ascorbic acid and methionine
  • preservatives polypeptides
  • proteins such as serum albumin or gelatin
  • hydrophilic polymers amino acids
  • a compound or salt of any one of Formula (I) may be formulated in any suitable pharmaceutical formulation.
  • a pharmaceutical formulation of the present disclosure typically contains an active ingredient (e.g., compound or salt of any one of Formula (I)), 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.
  • a compound or salt of Formula (I) is formulated with a chelating agent or other material capable of binding metal ions, such as ethylene diamine tetra acetic acid (EDTA) and its salts are capable of enhancing the stability of a compound or salt of Formula (I).
  • EDTA ethylene diamine tetra acetic acid
  • Pharmaceutical formulations may be provided in any suitable form, which may depend on the route of administration. In some embodiments, the pharmaceutical composition disclosed herein can be formulated in dosage form for administration to a subject.
  • the pharmaceutical composition is formulated for oral, intravenous, intraarterial, aerosol, parenteral, buccal, topical, transdermal, rectal, intramuscular, subcutaneous, intraosseous, intranasal, intrapulmonary, transmucosal, inhalation, and/or intraperitoneal administration.
  • the dosage form is formulated for oral administration.
  • the pharmaceutical composition can be formulated in the form of a pill, a tablet, a capsule, an inhaler, a liquid suspension, a liquid emulsion, a gel, or a powder.
  • the pharmaceutical composition can be formulated as a unit dosage in liquid, gel, semi-liquid, semi- solid, or solid form.
  • the disclosure provides a pharmaceutical composition for oral administration containing at least one compound or salt of any one of Formula (I) and a pharmaceutical excipient suitable for oral administration.
  • the composition may be in the form of a solid, liquid, gel, semi-liquid, or semi-solid.
  • the composition further comprises a second agent.
  • compositions of the disclosure suitable for oral administration can be presented as discrete dosage forms, such as hard or soft capsules, cachets, troches, lozenges, or tablets, or liquids or aerosol sprays each containing a predetermined amount of an active ingredient as a powder or in granules, a solution, or a suspension in an aqueous or non-aqueous liquid, an oil-in-water emulsion, or a water-in-oil liquid emulsion, or dispersible powders or granules, or syrups or elixirs.
  • Such dosage forms can be prepared by any of the methods of pharmacy, which typically include the step of bringing the active ingredient(s) into association with the carrier.
  • the composition are prepared by uniformly and intimately admixing the active ingredient(s) with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation.
  • a tablet can be prepared by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets can be prepared by compressing in a suitable machine the active ingredient(s) in a free-flowing form such as powder or granules, optionally mixed with an excipient such as, but not limited to, a binder, a lubricant, an inert diluent, and/or a surface active or dispersing agent.
  • Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound or salt of any one of Formula (I) moistened with an inert liquid diluent.
  • the disclosure provides a pharmaceutical composition for injection containing a compound or salt of any one of Formula (I) disclosed herein and a pharmaceutical excipient suitable for injection. Components and amounts of agents in the composition are as described herein.
  • the compound or salt of any one of Formula (I) may be formulated for injection as aqueous or oil suspensions, emulsions, with sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueous solution, and similar pharmaceutical vehicles.
  • WSGR Docket No.58296-711601 Aqueous solutions in saline are also conventionally used for injection. Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, and the like (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils may also be employed.
  • compositions may also be prepared from a compound or salt of any one of Formula (I) and one or more pharmaceutically acceptable excipients suitable for transdermal, inhalative, sublingual, buccal, rectal, intraosseous, intraocular, intranasal, epidural, or intraspinal administration.
  • the compounds described herein can be used in the preparation of medicaments for the prevention or treatment of diseases or conditions.
  • a method for treating any of the diseases or conditions described herein in a subject in need of such treatment involves administration of pharmaceutical compositions containing at least one compound described herein, or a pharmaceutically acceptable salt, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof, in therapeutically effective amounts to said subject.
  • the compositions containing the compound(s) described herein can be administered for prophylactic and/or therapeutic treatments. In therapeutic applications, the compositions are administered to a patient already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest the symptoms of the disease or condition.
  • compositions containing the compounds described herein are administered to a patient susceptible to or otherwise at risk of a particular disease, disorder or condition. Such an amount is defined to be a "prophylactically effective amount or dose.” In this use, the precise amounts also depend on the patient's state of health, weight, and the like.
  • 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).
  • the present disclosure provides a method of modulating of N- glycosylation.
  • the method of modulating of N-glycosylation comprises administering to a subject in need thereof an effective amount of a compound or salt of Formula (I).
  • the present disclosure provides a method of inhibiting N- glycosylation.
  • the method of inhibiting N-glycosylation comprises administering to a subject in need thereof an effective amount of a compound or salt of Formula (I).
  • the present disclosure can be used as a method of modulating STT3 in a subject in need thereof, comprising administering to the subject: a compound of Formula (I) or a pharmaceutically acceptable salt thereof; or a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • the present disclosure can be used as a method of inhibiting STT3 in a subject in need thereof, comprising administering to the subject: a compound of Formula (I) or a pharmaceutically acceptable salt thereof; or a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • the present disclosure can be used as a method of modulating replication of a respiratory virus in a subject in need thereof, comprising administering to the subject: a compound of Formula (I) or a pharmaceutically acceptable salt thereof; or a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • the WSGR Docket No.58296-711601 respiratory virus is selected from influenza virus, a rhinovirus, a coronavirus, a metapneumovirus, an adenovirus, a syncytial virus, a bocaviruses, and a parainfluenza virus.
  • the present disclosure can be used as a method of inhibiting replication of a respiratory virus in a subject in need thereof, comprising administering to the subject: a compound of Formula (I) or a pharmaceutically acceptable salt thereof; or a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • the respiratory virus is selected from influenza virus, a rhinovirus, a coronavirus, a metapneumovirus, an adenovirus, a syncytial virus, a bocaviruses, and a parainfluenza virus.
  • the present disclosure can be used as a method of treating a respiratory virus in a subject in need thereof (e.g., treating a subject infected by a respiratory virus), comprising administering to the subject: a compound of Formula (I) or a pharmaceutically acceptable salt thereof; or a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • the respiratory virus is selected from influenza virus, a rhinovirus, a coronavirus, a metapneumovirus, an adenovirus, a syncytial virus, a bocaviruses, and a parainfluenza virus.
  • the present disclosure can be used as a method of treating cancer in a subject in need thereof, comprising administering to the subject: a compound of Formula (I) or a pharmaceutically acceptable salt thereof; or a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • the method of treating cancer in a subject in need thereof leads to modulation of STT3 in the subject.
  • the method of treating cancer in a subject in need thereof comprises inhibition of N-glycosylation in the subject.
  • N-glycosylation is a common post-translational modification in eukaryotic cells, which is essential for the proper folding, stability, and function of many secreted proteins.
  • N- glycosylation in humans is mediated exclusively by the oligosaccharyltransferase (OST) complex which catalyzes the transfer of glycans onto the asparagine residues of sequons (N-X- S/T) on nascent glycoproteins.
  • OST oligosaccharyltransferase
  • Dysregulation of N- glycosylation has been implicated in various diseases, including cancer (Hu, M.; Zhang, R.; Yang, J.; Zhao, C.; Liu, W.; Huang, Y.; Lyu, H.; Xiao, S.; Guo, D.; Zhou, C.; Tang, J.
  • cancer Hu, M.; Zhang, R.; Yang, J.; Zhao, C.; Liu, W.; Huang, Y.; Lyu, H.; Xiao, S.; Guo, D.; Zhou, C.; Tang, J.
  • neurodegenerative disorders Pradeep, P.; Kang, H.; Lee, B. Glycosylation and behavioral WSGR Docket No.58296-711601 symptoms in neurological disorders.
  • Examples 1-32 show general and exemplary procedures for the preparation of some embodiments of the claimed compounds of Formula (I).
  • Example 33 shows how exemplary compounds of the disclosure were prepared.
  • Example 34 shows how exemplary compounds of the disclosure are effective at modulating (e.g., inhibiting) N-glycosylation activity.
  • Step 2 Preparation of 3-bromo-4-fluorophenyl)(cyclopropyl)(imino)-l6-sulfanone
  • 3-bromo-4-fluorophenyl)(cyclopropyl)sulfane 3.2 g, 12.95 mmol
  • ammonium carbonate 3.2 g, 33.3 mmol
  • dichloromethane 10 mL
  • methanol 20 mL
  • PhI(OAc)2 14 g, 43.5 mmol
  • Step 3 Preparation of tert-butyl 2-(5-(cyclopropanesulfonimidoyl)-2-fluorophenyl)-1H-indole-1- carboxylate [0160] To a solution of (3-bromo-4-fluorophenyl)(cyclopropyl)(imino)-l6-sulfanone (1g, 3.60 mmol) in water (1 mL) and 1,4-dioxane (10 mL) were added (1-(tert-butoxycarbonyl)-1H-indol- 2-yl)boronic acid (1.033 g, 3.95 mmol), PdCl 2 (dppf)-CH 2 Cl 2 adduct (0.147 g, 0.180 mmol) and K2CO3 (1.491 g, 10.79 mmol) under N2.
  • Step 4 Preparation of cyclopropyl(4-((S)-3-hydroxypyrrolidin-1-yl)-3-(1H-indol-2- yl)phenyl)(imino)-l6-sulfanone [0161]
  • the reaction mixture was filtered to give filtrate.
  • the filtrate was purified by prep-HPLC to give cyclopropyl(4-((S)-3-hydroxypyrrolidin-1-yl)-3-(1H-indol-2-yl)phenyl)(imino)-l6-sulfanone (200 mg, 0.480 mmol, 28.4 % yield) as a white solid.
  • Step 2 Preparation of tert-butyl cyclopropyl(4-((S)-3-hydroxypyrrolidin-1-yl)-3-(1H-indol-2- yl)phenyl)(methylimino)-l6-sulfanone: (4) [0166] A solution of tert-butyl 2-(2-fluoro-5-(N-methylcyclopropanesulfonimidoyl)phenyl)-1H- indole-1-carboxylate (150 mg, 0.350 mmol), (S)-pyrrolidin-3-ol (91 mg, 1.050 mmol) and potassium carbonate (145 mg, 1.050 mmol) in Dimethyl Sulfoxide (1 mL) was stirred at 90 °C for 12 hours.
  • Example 7 General Scheme – Synthesis of Compound (5)
  • Example 8. Exemplary Scheme – Synthesis of Compound (5) Step 1: Preparation of tert-butyl 2-(5-(N-cyanocyclopropanesulfonimidoyl)-2-fluorophenyl)-1H- indole-1-carboxylate [0167] To a solution of tert-butyl 2-(5-(cyclopropanesulfonimidoyl)-2-fluorophenyl)-1H-indole- 1-carboxylate (200 mg, 0.483 mmol) in Acetonitrile (6 mL) were added AIBN (119 mg, 0.724 WSGR Docket No.58296-711601 mmol), copper(I) iodide (18.38 mg, 0.097 mmol) and K2CO3 (133 mg, 0.965 mmol) at 25 °C.
  • AIBN 119 mg, 0.724 WSGR Docke
  • reaction mixture was purified by prep-HPLC to give N-(cyclopropyl(4-((S)-3- hydroxypyrrolidin-1-yl)-3-(1H-indol-2-yl)phenyl)(oxo)-l6-sulfaneylidene)cyanamide (75 mg, 0.177 mmol, 38.8 % yield) as a white solid.
  • LC-MS m/z [M+H] + 407.1.
  • Step 1 Preparation of tert-butyl (3-((3-bromo-4-fluorophenyl)thio)cyclobutyl)carbamate
  • 3-bromo-4-fluorobenzenethiol 4.4 g, 21.25 mmol
  • NaOH 1.700 g, 42.5 mmol
  • Methanol 40 mL
  • 3-((tert-butoxycarbonyl)amino)cyclobutyl 4- methylbenzenesulfonate (5.08 g, 14.87 mmol)
  • Step 5 Preparation of ((3-aminocyclobutyl)(4-(3,3-difluoropyrrolidin-1-yl)-3-(1H-indol-2- yl)phenyl)(imino)-l6-sulfanone (6)
  • tert-butyl 2-(5-(3-((tert-butoxycarbonyl)amino)cyclobutane-1- sulfonimidoyl)-2-(3,3-difluoropyrrolidin-1-yl)phenyl)-1H-indole-1-carboxylate 900 mg, 1.427 mmol
  • Ethyl acetate 4.5 mL
  • HCl 4.5 mL, 18.00 mmol
  • Step 6 Preparation of (4-(3,3-difluoropyrrolidin-1-yl)-3-(1H-indol-2-yl)phenyl)(3- (dimethylamino)cyclobutyl)(imino)-l6-sulfanone (7)
  • [0175] To a solution of (3-aminocyclobutyl)(4-(3,3-difluoropyrrolidin-1-yl)-3-(1H-indol-2- yl)phenyl)(imino)-l6-sulfanone (500 mg, 1.071 mmol) in Methanol (5 mL) was added TEA (0.149 mL, 1.071 mmol).
  • Step 7 Preparation of (4-(3,3-difluoropyrrolidin-1-yl)-3-(1H-indol-2-yl)phenyl)((3- (dimethylamino)cyclobutyl)(imino)-l6-sulfanone, isomer 1 (8) and (4-(3,3-difluoropyrrolidin-1- yl)-3-(1H-indol-2-yl)phenyl)((3-(dimethylamino)cyclobutyl)(imino)-l6-sulfanone, isomer 2 (9) [0176] (4-(3,3-difluoropyrrolidin-1-yl)-3-(1H-indol-2-yl)phenyl)((3- (dimethylamino)cyclobutyl)(imino)-l6-sulfanone (40 mg,
  • Step 3 Preparation of (R)-(4-(3,3-difluoropyrrolidin-1-yl)-3-(5-hydroxy-1H-indol-2- [0179] To a solution of (R)-(4-(3, 3-difluoropyrrolidin-1-yl)-3-(5-methoxy-1H-indol-2-yl) phenyl) (ethyl) (imino)-l6-sulfanone (520 mg, 1.240 mmol) in Dichloromethane (DCM) (10 mL) was added BBr3 (0.703 mL, 7.44 mmol) at -60 °C. The mixture was stirred at -60 °C for 1 hr.
  • DCM Dichloromethane
  • Example 15 General Scheme – Synthesis of Compounds (13 and 14) WSGR Docket No.58296-711601
  • Example 16 Exemplary Scheme – Synthesis of Compounds (13 and 14) Preparation of 3-azidopropyl 4-methylbenzenesulfonate [0184] To a solution of 3-azidopropan-1-ol (2.35 g, 23.24 mmol) in Dichloromethane (DCM) (25 mL) were added pyridine (2.256 mL, 27.9 mmol) and 4-methylbenzenesulfonyl chloride (TsCl, TosCl) (5.32 g, 27.9 mmol). The mixture was stirred at 20 °C for 12 hours under N2.
  • DCM Dichloromethane
  • TsCl, TosCl 4-methylbenzenesulfonyl chloride
  • Step 1 Preparation of (3-azidopropyl)(3-bromo-4-fluorophenyl)sulfane [0185] To a solution of 3-bromo-4-fluorobenzenethiol (2 g, 9.66 mmol) and NaOH (0.773 g, 19.32 mmol) in Methanol (20 mL) was added 3-azidopropyl 4-methylbenzenesulfonate (2.466 g, 9.66 mmol). The mixture was stirred at 20 °C for 12 hours. The reaction mixture was concentrated under reduced pressure to remove Methanol.
  • Step 2 Preparation of 4-((3-azidopropyl)sulfinyl)-2-bromo-1-fluorobenzene [0186] To a solution of (3-azidopropyl)(3-bromo-4-fluorophenyl)sulfane (1.58 g, 5.45 mmol) in Dichloromethane (16 mL) was added slowly m-CPBA (meta-chloro peroxybenzoic acid) (1.057 g, 4.90 mmol) at 0 °C, and the mixture was stirred at 20 °C for 12 hours. The resultant mixture was filtered and the filter cake was washed with DCM (20 mL x 3).
  • m-CPBA metal-chloro peroxybenzoic acid
  • reaction mixture was used directly for purification.
  • the reaction mixture was purified by prep-HPLC to give tert-butyl 2-(2-((S)-3-hydroxypyrrolidin-1- yl)-5-(1-oxido-4,5-dihydro-3H-1l6-isothiazol-1-yl)phenyl)-1H-indole-1-carboxylate (270 mg, 0.554 mmol, 31.0 % yield) as a yellow solid.
  • Example 17 General Scheme – Synthesis of Compounds (15 and 16) WSGR Docket No.58296-711601
  • Example 18 Exemplary Scheme – Synthesis of Compounds (15 and 16) Step 1: Preparation of tert-butyl ((3-bromo-4-fluorophenyl) (ethyl) (oxo)-l6-sulfaneylidene) carbamate [0191] To a stirred (3-bromo-4-fluorophenyl)(ethyl)(imino)-l6-sulfanone (4.00 g, 15.03 mmol) in Tetrahydrofuran (40 mL) was added NaH (1.2 g, 30.10 mmol) at 0 °C and the mixture was stirred at 0 °C for 30 minutes.
  • Step 3 Preparation of 2-(2-((3-bromo-4-fluorophenyl)thio)ethyl)-1-(2-methoxyethyl)-1H- imidazole [0200] To a solution of 3-bromo-4-fluorobenzenethiol (3.06 g, 14.80 mmol) and NaOH (1.480 g, 37.0 mmol) in Methanol (15 mL) was added 2-(1-(2-methoxyethyl)-1H-imidazol-2- yl)ethyl 4-methylbenzenesulfonate (6 g, 18.50 mmol). The mixture was stirred at 60 °C for 12 hours.
  • Step 4 Preparation of (3-bromo-4-fluorophenyl)(imino)(2-(1-(2-methoxyethyl)-1H-imidazol-2- yl)ethyl)-l6-sulfanone [0201] To a solution of 2-(2-((3-bromo-4-fluorophenyl)thio)ethyl)-1-(2-methoxyethyl)-1H- imidazole (1.4 g, 3.90 mmol) in Dichloromethane (4.50 mL) and Methanol (9 mL) were added PhI(OAc)2 (3.77 g, 11.69 mmol) and (NH4)2CO3 (1.123 g, 11.69 mmol).
  • Step 5 Preparation of (3-bromo-4-(3,3-difluoropyrrolidin-1-yl)phenyl)(imino)(2-(1-(2- methoxyethyl)-1H-imidazol-2-yl)ethyl)-l6-sulfanone [0202] To a solution of (3-bromo-4-fluorophenyl)(imino)(2-(1-(2-methoxyethyl)-1H- imidazol-2-yl)ethyl)-l6-sulfanone (720 mg, 1.845 mmol) in Dimethyl Sulfoxide (8 mL) were added 3,3-difluoropyrrolidine, Hydrochloride (1324 mg, 9.22 mmol) and K2CO3 (1275 mg, 9.22 mmol).
  • reaction mixture was purified by prep-HPLC to give (3-bromo-4-(3,3- difluoropyrrolidin-1-yl)phenyl)(imino)(2-(1-(2-methoxyethyl)-1H-imidazol-2-yl)ethyl)-l6- sulfanone (410 mg, 0.830 mmol, 45.0 % yield) as a yellow solid.
  • LC-MS m/z [M+H] + 479.1.
  • Step 6 Preparation of tert-butyl 2-(2-(3,3-difluoropyrrolidin-1-yl)-5-(2-(1-(2-methoxyethyl)-1H- [0203] A mixture of (3-bromo-4-(3,3-difluoropyrrolidin-1-yl)phenyl)(imino)(2-(1-(2- methoxyethyl)-1H-imidazol-2-yl)ethyl)-l6-sulfanone (360 mg, 0.754 mmol), (1-(tert- butoxycarbonyl)-1H-indol-2-yl)boronic acid (236 mg, 0.905 mmol), K 2 CO 3 (313 mg, 2.262 mmol) and PdCl2(dppf)-CH2Cl2 adduct (61.6 mg, 0.075 mmol) in 1,4-Dioxane
  • Step 7 Preparation of (4-(3,3-difluoropyrrolidin-1-yl)-3-(1H-indol-2-yl)phenyl)(imino)(2-(1-(2- [0204]
  • tert-butyl 2-(2-(3,3-difluoropyrrolidin-1-yl)-5-(2-(1-(2- methoxyethyl)-1H-imidazol-2-yl)ethylsulfonimidoyl)phenyl)-1H-indole-1-carboxylate 380 mg, 0.619 mmol
  • Dichloromethane 4 mL
  • TFA 0.8 mL, 10.38 mmol
  • Step 8 Preparation of (4-(3,3-difluoropyrrolidin-1-yl)-3-(1H-indol-2-yl)phenyl)(imino)(2-(1-(2- methoxyethyl)-1H-imidazol-2-yl)ethyl)-l6-sulfanone, isomer 1 (17) and(4-(3,3- difluoropyrrolidin-1-yl)-3-(1H-indol-2-yl)phenyl)(imino)(2-(1-(2-methoxyethyl)-1H-imidazol-2- [0205] (4-(3,3-difluoropyrrolidin-1-yl)-3-(1H-indol-2-yl)phenyl)(imino)(2-(1-(2- methoxyethyl)-1H-imidazol-2-yl)
  • Step 2 Preparation of tert-butyl (S)-3-((R)-1-hydroxyethyl)pyrrolidine-1-carboxylate [0207] To a solution of tert-butyl (S)-3-formylpyrrolidine-1-carboxylate (2 g, 10.04 mmol) in Tetrahydrofuran (20 mL) was added methylmagnesium bromide (5.02 mL, 15.06 mmol) at - 78 °C under N 2 atmosphere, after 1 hour, the reaction mixture was heated to 0 °C for 1 hour under N 2 atmosphere.
  • Step 4 Preparation of (R)-(3-bromo-4-((S)-3-((S)-1-hydroxyethyl)pyrrolidin-1- yl)phenyl)(ethyl)(imino)-l6-sulfanone [0209] To a solution of (R)-(3-bromo-4-fluorophenyl)(ethyl)(imino)-l6-sulfanone (500 mg, 1.879 mmol) in Dimethyl Sulfoxide (5 mL) were added (R)-1-((S)-pyrrolidin-3-yl)ethan-1-ol, Trifluoroacetate salt (857 mg, 3.76 mmol) and DIEA (1.641 mL, 9.39 mmol).
  • Step 7 Preparation of (1R)-(4-(3-acetylpyrrolidin-1-yl)-3-(1H-indol-2-yl)phenyl)(ethyl)(imino)- l6-sulfanone (19) [0212] To a solution of tert-butyl 2-(2-(3-acetylpyrrolidin-1-yl)-5-((R)- ethylsulfonimidoyl)phenyl)-1H-indole-1-carboxylate (50 mg, 0.101 mmol) in Dichloromethane (0.5 mL) was added TFA (0.1 ml, 1.298 mmol).
  • Example 23 General Scheme – Synthesis of Compounds (20 and 21) WSGR Docket No.58296-711601
  • Example 24 Exemplary Scheme – Synthesis of Compounds (20 and 21) Step 1: Preparation of (1R)-ethyl(4-((3S)-3-(1-hydroxyethyl)pyrrolidin-1-yl)-3-(1H-indol-2- yl)phenyl)(imino)-l6-sulfanone, isomer 1 (20) and (1R)-ethyl(4-((3S)-3-(1- hydroxyethyl)pyrrolidin-1-yl)-3-(1H-indol-2-yl)phenyl)(imino)-l6-sulfanone, isomer 2 (21) [0213] To a solution of tert-butyl 2-(5-((R)-ethylsulfonimidoyl)-2-((S)-3
  • the three batches were each stirred at 25 °C for 16 hours under N2 with 34W blue LED.
  • the three batches were combined and diluted with water (10 mL) and extracted with EtOAc (15 mL * 3).
  • the combined organic layers were dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue.
  • Step 2 Preparation of (R)-(4-(3,3-difluoropyrrolidin-1-yl)-3-(5-(oxetan-3-yl)-1H-indol-2- yl)phenyl)(ethyl)(imino)-l6-sulfanone (23) [0218] To a solution of tert-butyl (R)-2-(2-(3,3-difluoropyrrolidin-1-yl)-5- (ethylsulfonimidoyl)phenyl)-5-(oxetan-3-yl)-1H-indole-1-carboxylate (53 mg, 0.097 mmol) in Dichloromethane (1 mL) was added TFA (0.25 mL, 3.24 mmol).
  • Step 2 Preparation of diethyl-1- (2-bromo-4-(N-(tert-butoxycarbonyl) ethylsulfonimidoyl) phenyl) azetidine-3, 3-dicarboxylate
  • tert-butyl ((3-bromo-4-fluorophenyl) (ethyl) (oxo)-l6-sulfaneylidene) carbamate 1.5g, 4.10 mmol
  • diethyl azetidine-3, 3-dicarboxylate Trifluoroacetic acid salt (1.549 g, 4.91 mmol) in Dimethyl Sulfoxide (30 mL) was added DIEA (diisopropylethylamine) (3.58 mL, 20.48 mmol).
  • Step 3 Preparation of diethyl 1-(2-(1-(tert-butoxycarbonyl)-1H-indol-2-yl)-4-(N-(tert- butoxycarbonyl) ethylsulfonimidoyl) phenyl) azetidine-3, 3-dicarboxylate [0221] To a solution of diethyl 1-(2-bromo-4-(N-(tert- butoxycarbonyl)ethylsulfonimidoyl)phenyl)azetidine-3,3-dicarboxylate ( 1.5g, 2.74 mmol) in Water (5 mL) and Tetrahydrofuran (20 mL) were added (1-(tert-butoxycarbonyl)-1H-indol-2- yl)boronic acid (1.073 g, 4.11 mmol), DTBPF PdCl 2 (0.179 g, 0.274 m
  • reaction mixture was concentrated under reduced pressure to give a residue.
  • residue was purified by column chromatography to give tert-butyl ((4-(3, 3-dicarbamoylazetidin- WSGR Docket No.58296-711601 1-yl)-3-(1H-indol-2-yl) phenyl) (ethyl) (oxo)-l6-sulfaneylidene) carbamate (500 mg, 0.340 mmol, 23.25 % yield) as a pale pink solid.
  • Step 8 Preparation of 1-(4-(ethylsulfonimidoyl)-2-(1H-indol-2-yl) phenyl) azetidine-3, 3- dicarbonitrile, isomer 1 (first eluted peak) (24) and 1-(4-(ethylsulfonimidoyl)-2-(1H-indol-2-yl) [0226] 1-(4-(ethylsulfonimidoyl)-2-(1H-indol-2-yl) phenyl) azetidine-3, 3-dicarbonitrile (30 mg, 0.077 mmol) was purified by SFC (supercritical fluid chromatography) to give 1-(4- (ethylsulfonimidoyl)-2-(1H-indol-2-yl) phenyl) azetidine-3, 3-d
  • Step 5 Preparation of (R)-(3-(5-(1H-1,2,3-triazol-5-yl)-1H-indol-2-yl)-4-(3,3- difluoropyrrolidin-1-yl)phenyl)(ethyl)(imino)-l6-sulfanone (26) [0231] A mixture of tert-butyl (R)-2-(2-(3,3-difluoropyrrolidin-1-yl)-5- (ethylsulfonimidoyl)phenyl)-5-(1H-1,2,3-triazol-5-yl)-1H-indole-1-carboxylate (180 mg, 0.323 mmol) in Ethyl acetate (2 mL) and HCl/EtOAc (2 ml, 2M, 8.00 mmol) was stirred at 15 °C for 0.5 hour.
  • Example 33 Example Compounds of the Disclosure.
  • Compounds 27-78 (Table 1) were synthesized according to the general scheme in Example 1 using similar procedures described for Compounds 1 and 2 with appropriate reagents and intermediates.
  • Compounds 79-102 (Table 1) were synthesized according to the general scheme in Example 3 using similar procedures described for Compound 3 with appropriate reagents and intermediates.
  • Compounds 103-108 and 110 (Table 1) were synthesized according to the general scheme in Example 9 using similar procedures described for Compounds 6, 7, 8, and 9 with appropriate reagents and intermediates.
  • 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. [0239] Putative inhibitors were assayed as follows.
  • ERLuc cells were plated in DMEM (Dulbecco’s Modified Eagle Medium) media with 10% FBS (fetal bovine serum) and incubated overnight at 37 degrees Celsius, 5% CO 2 . 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 (dimethyl sulfoxide). Negative controls (DMSO only) and positive controls (2.8uM NGI-1, N-linked glycosylation inhibitor 1) were included on every assay plate.
  • DMEM Dulbecco’s Modified Eagle Medium
  • FBS fetal bovine serum
  • the NanoLuc luminescence was then similarly detected.
  • the maximum and minimum levels of ERLuc activity were established using the Firefly luminescence of the positive and negative controls, respectively.
  • the ERLuc activity observed using putative inhibitors was quantified as the percent of Firefly luminescence relative to these controls.
  • EC 50 values were calculated using CDDVault by fitting a sigmoidal variable slope nonlinear regression model to the data.
  • Table 2 provides data for the biological evaluation of some embodiments of the present disclosure, including EC 50 values for the ERLuc assay described above.
  • ERLuc EC 50 values are categorized as follows: A is ⁇ 10 nM; B is > 10 nM and ⁇ 50 nM; C is > 50 nM and ⁇ 100 nM; D is > 100 nM and ⁇ 1000 nM; and E is > 1000 nM .
  • Table 2 WSGR Docket No.58296-711601 WSGR Docket No.58296-711601 WSGR Docket No.58296-711601 WSGR Docket No.58296-711601 WSGR Docket No.58296-711601 [0243] While preferred embodiments of the present disclosure have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. It is not intended that the disclosure be limited by the specific examples provided within the specification.

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Abstract

The disclosure provides sulfoximine based modulators of Formula (I), or pharmaceutically acceptable salts thereof, for the inhibition of the oligosaccharyltransferase complex. Further, the present disclosure provides methods for the treatment of disease using the sulfoximine based modulators of Formula (I), or pharmaceutically acceptable salts thereof. In another aspect, the present disclosure provides methods for the modulation of N-glycosylation using the sulfoximine based modulators of Formula (I), or pharmaceutically acceptable salts thereof.

Description

WSGR Docket No.58296-711601 SULFOXIMINE BASED STT3A/B MODULATORS FOR THE TREATMENT OF DISEASE CROSS-REFERENCE [0001] This application claims the benefit of U.S. Provisional Application Serial No. 63/522,360 filed June 21, 2023, which is hereby incorporated by reference in its entirety. BACKGROUND OF THE INVENTION [0002] The oligosaccharyltransferase complex, localized in the endoplasmic reticulum (ER) of eukaryotic cells, is responsible for the N-linked glycosylation of numerous protein substrates. 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. While the STT3A complex generally promotes co-translational glycosylation, the STT3B complex generally promotes post-translational glycosylation. Although the 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. SUMMARY OF THE INVENTION [0003] In some aspects, the present disclosure provides a compound represented by the structure of Formula (I):
Figure imgf000002_0001
or a pharmaceutically acceptable salt thereof, wherein: Ring A is 3- to 12-membered heterocycle; X1 is selected from N and C(H); each R1 is independently selected at each occurrence from: WSGR Docket No.58296-711601 halogen, -OR11, -SR11, -N(R11)2, -C(O)R11, -C(O)N(R11)2, -C(O)OR11, -OC(O)R11, -N(R11)C(O)R11, -N(R11)C(O)OR11, -N(R11)S(O)2R11, -S(O)2N(R11)2, -S(O)R11, - S(O)2R11, -NO2, , =S, =N(R11), and -CN; C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR11, -SR11, - N(R11)2, -C(O)R11, -C(O)N(R11)2, -C(O)OR11, -OC(O)R11, -N(R11)C(O)R11, -
Figure imgf000003_0001
C3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR11, -
Figure imgf000003_0002
each R2 is independently selected at each occurrence from: halogen, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)N(R12)2, -C(O)OR12, -OC(O)R12, -N(R12)C(O)R12, -N(R12)C(O)OR12, -N(R12)S(O)2R12, -S(O)2N(R12)2, -S(O)R12, - S(O)2R12, -NO2, =O, =S, =N(R12), and -CN; C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)N(R12)2, -C(O)OR12, - OC(O)R12, -N(R12)C(O)R12, -N(R12)C(O)OR12, -N(R12)S(O)2R12, -S(O)2N(R12)2, - S(O)R12, -S(O)2R12, -NO2, =O, =S, =N(R12), and -CN; and C3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR12, - SR12, -N(R12)2, -C(O)R12, -C(O)N(R12)2, -C(O)OR12, -OC(O)R12, -N(R12)C(O)R12, - N(R12)C(O)OR12, -N(R12)S(O)2R12, -S(O)2N(R12)2, -S(O)R12, -S(O)2R12, -NO2, =O, =S, =N(R12), -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected halogen, -OR12, -SR12, -N(R12)2, -C(O)R12, - C(O)N(R12)2, -C(O)OR12, -OC(O)R12, -N(R12)C(O)R12, -N(R12)C(O)OR12, - N(R12)S(O)2R12, -S(O)2N(R12)2, -S(O)R12, -S(O)2R12, -NO2, =O, =S, =N(R12), and -CN; WSGR Docket No.58296-711601 R3 is selected from: hydrogen, -C(O)R13, -S(O)2R13, and -CN; C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)N(R13)2, -C(O)OR13, - OC(O)R13, -N(R13)C(O)R13, -N(R13)C(O)OR13, -N(R13)S(O)2R13, -S(O)2N(R13)2, - S(O)R13, -S(O)2R13, -NO2, =O, =S, =N(R13), and -CN; and C3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, - SR13, -N(R13)2, -C(O)R13, -C(O)N(R13)2, -C(O)OR13, -OC(O)R13, -N(R13)C(O)R13, - N(R13)C(O)OR13, -N(R13)S(O)2R13, -S(O)2N(R13)2, -S(O)R13, -S(O)2R13, -NO2, =O, =S, =N(R13), -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, - C(O)N(R13)2, -C(O)OR13, -OC(O)R13, -N(R13)C(O)R13, -N(R13)C(O)OR13, - N(R13)S(O)2R13, -S(O)2N(R13)2, -S(O)R13, -S(O)2R13, -NO2, =O, =S, =N(R13), and -CN; R4 is selected from: C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR14, -SR14, -N(R14)2, -C(O)R14, -C(O)N(R14)2, -C(O)OR14, - OC(O)R14, -N(R14)C(O)R14, -N(R14)C(O)OR14, -N(R14)S(O)2R14, -S(O)2N(R14)2, - S(O)R14, -S(O)2R14, -NO2, =O, =S, =N(R14), -CN, C3-6 carbocycle and 3- to 6-membered heterocycle, the C3-6 carbocycle and 3- to 6-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OR14, - SR14, -N(R14)2, -C(O)R14, -C(O)N(R14)2, -C(O)OR14, -OC(O)R14, -N(R14)C(O)R14, - N(R14)C(O)OR14, -N(R14)S(O)2R14, -S(O)2N(R14)2, -S(O)R14, -S(O)2R14, -NO2, =O, =S, =N(R14), -CN, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkyl-OR14, C1-6 alkyl-C3-6 carbocycle, and C1-6 alkyl-C3-6 heterocycle ; and C3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR14, - SR14, -N(R14)2, -C(O)R14, -C(O)N(R14)2, -C(O)OR14, -OC(O)R14, -N(R14)C(O)R14, - N(R14)C(O)OR14, -N(R14)S(O)2R14, -S(O)2N(R14)2, -S(O)R14, -S(O)2R14, -NO2, =O, =S, =N(R14), -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR14, -SR14, -N(R14)2, -C(O)R14, - C(O)N(R14)2, -C(O)OR14, -OC(O)R14, -N(R14)C(O)R14, -N(R14)C(O)OR14, - N(R14)S(O)2R14, -S(O)2N(R14)2, -S(O)R14, -S(O)2R14, -NO2, =O, =S, =N(R14), and -CN; or WSGR Docket No.58296-711601 R3 and R4 come together with the atoms to which they are each bound to form a 4- to 6- membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR15, -SR15, -N(R15)2, -C(O)R15, -C(O)N(R15)2, -C(O)OR15, -OC(O)R15, -N(R15)C(O)R15, -N(R15)C(O)OR15, -N(R15)S(O)2R15, -S(O)2N(R15)2, -S(O)R15, - S(O)2R15, -NO2, =O, =S, =N(R15), and -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR15, -SR15, -N(R15)2, -C(O)R15, -C(O)N(R15)2, -C(O)OR15, - OC(O)R15, -N(R15)C(O)R15, -N(R15)C(O)OR15, -N(R15)S(O)2R15, -S(O)2N(R15)2, - S(O)R15, -S(O)2R15, -NO2, =O, =S, =N(R15), and -CN; R11, R12, R13, R14, and R15 are each independently selected at each occurrence from: hydrogen; C1-6 alkyl optionally substituted with one more substituents independently selected from halogen, -O-C1-6 alkyl, -O-C1-6 haloalkyl, -NH2, -NO2, =O, -CN, -S(O)2OH, -S-C1-6 alkyl, -S(O)-C1-6 alkyl, -S(O)2-C1-6 alkyl, -P(O)(OH)2, -P(-C1-6 alkyl)2, -P(-C1-6 alkyl)(-O-C1-6 alkyl) -P(-O-(C1-6 alkyl))2, -P(=O)(-C1-6 alkyl)2, -P(=O)(-C1-6 alkyl)(-O- (C1-6 alkyl), -P(O)(-O-(C1-6 alkyl))2, C3-10 carbocycle and 3- to 10-membered heterocycle, wherein each C3-10 carbocycle, and 3- to 10-membered heterocycle are optionally substituted with one or more substituents independently selected from: halogen, -OH, -O- C1-6 alkyl, -O-C1-6 haloalkyl, -NH2, -NO2, =O, and -CN; and C3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OH, -O- C1-6 alkyl, -O-C1-6 haloalkyl, -NH2, -NO2, =O, and -CN; n is selected from 0, 1, 2, 3, and 4; and m is selected from 0, 1, 2, 3, and 4. [0004] In some aspects, the present disclosure provides a pharmaceutical composition comprising a compound or salt of Formula (I) and at least one pharmaceutically acceptable excipient. [0005] In some aspects, 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). [0006] In certain embodiments, the present disclosure can be used as a method of modulating STT3 in a subject in need thereof, comprising administering to the subject: a compound of Formula (I) or a pharmaceutically acceptable salt thereof; or a pharmaceutical composition WSGR Docket No.58296-711601 comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. [0007] In certain embodiments, the present disclosure can be used as a method of inhibiting STT3 in a subject in need thereof, comprising administering to the subject: a compound of Formula (I) or a pharmaceutically acceptable salt thereof; or a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. [0008] In certain embodiments, the present disclosure can be used as a method of modulating replication of a respiratory virus in a subject in need thereof, comprising administering to the subject: a compound of Formula (I) or a pharmaceutically acceptable salt thereof; or a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In some embodiments, the respiratory virus is selected from influenza virus, a rhinovirus, a coronavirus, a metapneumovirus, an adenovirus, a syncytial virus, a bocaviruses, and a parainfluenza virus. [0009] In certain embodiments, the present disclosure can be used as a method of inhibiting replication of a respiratory virus in a subject in need thereof, comprising administering to the subject: a compound of Formula (I) or a pharmaceutically acceptable salt thereof; or a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In some embodiments, the respiratory virus is selected from influenza virus, a rhinovirus, a coronavirus, a metapneumovirus, an adenovirus, a syncytial virus, a bocaviruses, and a parainfluenza virus. [0010] In certain embodiments, the present disclosure can be used as a method of treating a respiratory virus in a subject in need thereof (e.g., treating a subject infected by a respiratory virus), comprising administering to the subject: a compound of Formula (I) or a pharmaceutically acceptable salt thereof; or a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In some embodiments, the respiratory virus is selected from influenza virus, a rhinovirus, a coronavirus, a metapneumovirus, an adenovirus, a syncytial virus, a bocaviruses, and a parainfluenza virus. INCORPORATION BY REFERENCE [0011] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. To the extent publications and patents or patent applications incorporated by reference contradict the WSGR Docket No.58296-711601 disclosure contained in the specification, the specification is intended to supersede and/or take precedence over any such contradictory material. DETAILED DESCRIPTION OF THE INVENTION [0012] While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby. Definitions [0013] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference. [0014] As used in the specification and claims, the singular form “a”, “an” and “the” includes plural references unless the context clearly dictates otherwise. [0015] "Alkyl" refers to a straight or branched hydrocarbon chain monovalent radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, and preferably having from one to twelve carbon atoms (i.e., C1-C12 alkyl). The alkyl is attached to the remainder of the molecule through a single bond. In certain embodiments, an alkyl comprises one to twelve carbon atoms (i.e., C1-C12 alkyl). In certain embodiments, an alkyl comprises one to eight carbon atoms (i.e., C1-C8 alkyl). In other embodiments, an alkyl comprises one to five carbon atoms (i.e., C1-C5 alkyl). In other embodiments, an alkyl comprises one to four carbon atoms (i.e., C1- C4 alkyl). In other embodiments, an alkyl comprises one to three carbon atoms (i.e., C1-C3 alkyl). In other embodiments, an alkyl comprises one to two carbon atoms (i.e., C1-C2 alkyl). In other embodiments, an alkyl comprises one carbon atom (i.e., C1 alkyl). In other embodiments, an alkyl comprises five to fifteen carbon atoms (i.e., C5-C15 alkyl). In other embodiments, an alkyl comprises five to eight carbon atoms (i.e., C5-C8 alkyl). In other embodiments, an alkyl comprises two to five carbon atoms (i.e., C2-C5 alkyl). In other embodiments, an alkyl comprises three to five carbon atoms (i.e., C3-C5 alkyl). For example, 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. WSGR Docket No.58296-711601 [0016] "Alkenyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and preferably having from two to twelve carbon atoms (i.e., C2-C12 alkenyl). In certain embodiments, an alkenyl comprises two to eight carbon atoms (i.e., C2-C8 alkenyl). In certain embodiments, an alkenyl comprises two to six carbon atoms (i.e., C2-C6 alkenyl). In other embodiments, an alkenyl comprises two to four carbon atoms (i.e., C2-C4 alkenyl). The 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. [0017] "Alkynyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, and preferably having from two to twelve carbon atoms (i.e., C2-C12 alkynyl). In certain embodiments, an alkynyl comprises two to eight carbon atoms (i.e., C2-C8 alkynyl). In other embodiments, an alkynyl comprises two to six carbon atoms (i.e., C2-C6 alkynyl). In other embodiments, an alkynyl comprises two to four carbon atoms (i.e., C2-C4 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. [0018] "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. In certain embodiments, an alkylene comprises one to ten carbon atoms (i.e., C1-C10 alkylene). In certain embodiments, an alkylene comprises one to eight carbon atoms (i.e., C1-C8 alkylene). In other embodiments, an alkylene comprises one to five carbon atoms (i.e., C1-C5 alkylene). In other embodiments, an alkylene comprises one to four carbon atoms (i.e., C1-C4 alkylene). In other embodiments, an alkylene comprises one to three carbon atoms (i.e., C1-C3 alkylene). In other embodiments, an alkylene comprises one to two carbon atoms (i.e., C1-C2 alkylene). In other embodiments, an alkylene comprises one carbon atom (i.e., C1 alkylene). In other embodiments, an alkylene comprises five to eight carbon atoms (i.e., C5-C8 alkylene). In other embodiments, an alkylene comprises two to five carbon atoms (i.e., C2-C5 alkylene). In other embodiments, an alkylene comprises three to five carbon atoms (i.e., C3-C5 alkylene). WSGR Docket No.58296-711601 [0019] "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. In certain embodiments, an alkenylene comprises two to ten carbon atoms (i.e., C2-C10 alkenylene). In certain embodiments, an alkenylene comprises two to eight carbon atoms (i.e., C2-C8 alkenylene). In other embodiments, an alkenylene comprises two to five carbon atoms (i.e., C2-C5 alkenylene). In other embodiments, an alkenylene comprises two to four carbon atoms (i.e., C2-C4 alkenylene). In other embodiments, an alkenylene comprises two to three carbon atoms (i.e., C2-C3 alkenylene). In other embodiments, an alkenylene comprises two carbon atom (i.e., C2 alkenylene). In other embodiments, an alkenylene comprises five to eight carbon atoms (i.e., C5-C8 alkenylene). In other embodiments, an alkenylene comprises three to five carbon atoms (i.e., C3-C5 alkenylene). [0020] "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. The 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. In certain embodiments, an alkynylene comprises two to ten carbon atoms (i.e., C2-C10 alkynylene). In certain embodiments, an alkynylene comprises two to eight carbon atoms (i.e., C2-C8 alkynylene). In other embodiments, an alkynylene comprises two to five carbon atoms (i.e., C2-C5 alkynylene). In other embodiments, an alkynylene comprises two to four carbon atoms (i.e., C2-C4 alkynylene). In other embodiments, an alkynylene comprises two to three carbon atoms (i.e., C2-C3 alkynylene). In other embodiments, an alkynylene comprises two carbon atom (i.e., C2 alkynylene). In other embodiments, an alkynylene comprises five to eight carbon atoms (i.e., C5-C8 alkynylene). In other embodiments, an alkynylene comprises three to five carbon atoms (i.e., C3-C5 alkynylene). [0021] The term “Cx-y” when used in conjunction with a chemical moiety, such as alkyl, alkenyl, or alkynyl is meant to include groups that contain from x to y carbons in the chain. For example, WSGR Docket No.58296-711601 the term “C1-6 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. The term -Cx-y alkylene- refers to a substituted or unsubstituted alkylene chain with from x to y carbons in the alkylene chain. For example, -C1-6 alkylene- may be selected from methylene, ethylene, propylene, butylene, pentylene, and hexylene, any one of which is optionally substituted. [0022] The terms “Cx-y alkenyl” and “Cx-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. The term -Cx-y alkenylene- refers to a substituted or unsubstituted alkenylene chain with from x to y carbons in the alkenylene chain. For example, - C2-6 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. The term -Cx-yalkynylene- refers to a substituted or unsubstituted alkynylene chain with from x to y carbons in the alkynylene chain. For example, -C2-6 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. [0023] 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. In some embodiments, the carbocycle is an aryl. In some embodiments, the carbocycle is a cycloalkyl. In some embodiments, the carbocycle is a cycloalkenyl. In an exemplary embodiment, an aromatic ring, e.g., phenyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene. Any combination of saturated, unsaturated and aromatic bicyclic rings, as valence permits, are included in the definition of carbocyclic. Exemplary 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. [0024] "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., C3-12 cycloalkyl). In certain embodiments, a cycloalkyl comprises three to ten carbon atoms (i.e., C3-10 cycloalkyl). In other embodiments, a cycloalkyl comprises five to seven carbon atoms (i.e., C5-7 cycloalkyl). The WSGR Docket No.58296-711601 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. [0025] "Cycloalkenyl" refers to a stable unsaturated non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which includes fused or bridged ring systems, preferably having from three to twelve carbon atoms and comprising at least one double bond (i.e., C3-12 cycloalkenyl). In certain embodiments, a cycloalkenyl comprises three to ten carbon atoms (i.e., C3-10 cycloalkenyl). In other embodiments, a cycloalkenyl comprises five to seven carbon atoms (i.e., C5-7 cycloalkenyl). The cycloalkenyl may be attached to the rest of the molecule by a single bond. Examples of 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. [0026] "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. [0027] A “Cx-y carbocycle” is meant to include groups that contain from x to y carbons in a ring. For example, the term “C3-6 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. [0028] The term “heterocycle” as used herein refers to a saturated, unsaturated, non-aromatic or aromatic ring comprising one or more heteroatoms. Exemplary heteroatoms include N, O, Si, P, B, and S atoms. Heterocycles include 3- to 10-membered monocyclic rings and 6- to 12- membered bicyclic rings. Each ring of a bicyclic heterocycle may be selected from saturated, unsaturated, and aromatic rings. In some embodiments, the heterocycle comprises at least one heteroatom selected from oxygen, nitrogen, sulfur, or any combination thereof. In some WSGR Docket No.58296-711601 embodiments, the heterocycle comprises at least one heteroatom selected from oxygen, nitrogen, or any combination thereof. In some embodiments, the heterocycle comprises at least one heteroatom selected from oxygen, sulfur, or any combination thereof. In some embodiments, 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. In some embodiments, the heterocycle is a heteroaryl. In some embodiments, 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. In an exemplary embodiment, a heterocycle, e.g., pyridyl, may be fused to 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. [0029] "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. In some embodiments, the heterocycloalkyl comprises at least one heteroatom selected from oxygen, nitrogen, sulfur, or any combination thereof. In some embodiments, 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. The heterocycloalkyl is attached to the rest of the molecule through any atom of the heterocycloalkyl, valence permitting, such as any carbon or nitrogen atoms of the heterocycloalkyl. Examples of heterocycloalkyl radicals include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, WSGR Docket No.58296-711601 thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Heterocycloalkyl may be optionally substituted by one or more substituents such as those substituents described herein. [0030] The term “heteroaryl” refers to a radical derived from a 5- to 12-membered aromatic ring radical whose ring structure comprise at least one heteroatom, preferably between one to four heteroatoms. In some embodiments, the heteroaryl comprises at least one heteroatom selected from oxygen, nitrogen, sulfur, or any combination thereof. In some embodiments, 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. One or more nitrogen atoms, if present, are optionally quaternized. The 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. [0031] As used herein, the heteroaryl ring may be selected from monocyclic or polycyclic (bicyclic and fused or bridged) 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. 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. [0032] An “X-membered heterocycle” refers to the number of endocylic atoms, i.e., X, in the ring. For example, a 5-membered heteroaryl ring or 5-membered aromatic heterocycle has 5 endocyclic atoms, e.g., triazole, oxazole, thiophene, etc. [0033] "Alkoxy" refers to a radical bonded through an oxygen atom of the formula –O-alkyl, where alkyl is an alkyl chain as defined above. [0034] "Halo" or "halogen" refers to halogen substituents such as bromo, chloro, fluoro and iodo substituents. WSGR Docket No.58296-711601 [0035] As used herein, the term "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. In some embodiments, the alkyl part of the fluoroalkyl radical is optionally further substituted. Examples of halogen substituted alkanes (“haloalkanes”) 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). When an alkyl group is substituted with more than one halogen radicals, each halogen may be independently selected for example, 1-chloro,2-fluoroethane. [0036] The term “substituted” refers to moieties having substituents replacing a hydrogen on one or more carbons or substitutable heteroatoms, e.g., an NH or NH2 of a compound. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, i.e., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. In certain embodiments, 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. As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds. In a broad aspect, 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. [0037] In some embodiments, substituents may include any substituents described herein, for example: halogen, hydroxy, oxo (=O), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=N-H), oximo (=N-OH), hydrazino (=N-NH2), -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)- N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb- N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb-N(Ra)S(O)tRa (where t is 1 or 2), -Rb-S(O)tRa (where t is 1 or 2), -Rb-S(O)tORa (where t is 1 or 2), and -Rb-S(O)tN(Ra)2 (where t is 1 or 2); and alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, WSGR Docket No.58296-711601 heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl any of which may be optionally substituted by alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=O), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=N-H), oximo(=N-OH), hydrazine(=N-NH2), -Rb-ORa, -Rb-OC(O)- Ra, -Rb-OC(O)- ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb- C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb-N(Ra)S(O)tRa (where t is 1 or 2), -Rb-S(O)tRa (where t is 1 or 2), -Rb-S(O)tORa (where t is 1 or 2) and -Rb-S(O)tN(Ra)2 (where t is 1 or 2); wherein each Ra is independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, wherein each Ra, valence permitting, may be optionally substituted with alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=O), thioxo (=S), cyano (- CN), nitro (-NO2), imino (=N-H), oximo (=N-OH), hydrazine(=N-NH2), -Rb-ORa, -Rb-OC(O)- Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc- C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb-N(Ra)S(O)tRa (where t is 1 or 2), -Rb-S(O)tRa (where t is 1 or 2), -Rb-S(O)tORa (where t is 1 or 2) and -Rb-S(O)tN(Ra)2 (where t is 1 or 2); and wherein each Rb is independently selected from a direct bond or a straight or branched alkylene, alkenylene, or alkynylene chain, and each Rc is a straight or branched alkylene, alkenylene or alkynylene chain. It will be understood by those skilled in the art that substituents can themselves be substituted, if appropriate. [0038] The term “salt” 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. [0039] The phrase “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. [0040] The phrase “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 WSGR Docket No.58296-711601 must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. [0041] The terms "subject," "individual," and "patient" may be used interchangeably and refer to humans, the as well as non-human mammals (e.g., non-human primates, canines, equines, felines, porcines, bovines, ungulates, lagomorphs, and the like). In various embodiments, the subject can be a human (e.g., adult male, adult female, adolescent male, adolescent female, male child, female child) under the care of a physician or other health worker in a hospital, as an outpatient, or other clinical context. In certain embodiments, the subject may not be under the care or prescription of a physician or other health worker. [0042] As used herein, the phrase "a subject in need thereof" refers to a subject, as described infra, that suffers from, or is at risk for, a pathology to be prophylactically or therapeutically treated with a compound or salt described herein. [0043] The terms “administer”, “administered”, “administers” and “administering” are defined as providing a composition to a subject via a route known in the art, including but not limited to intravenous, intraarterial, oral, parenteral, buccal, topical, transdermal, rectal, intramuscular, subcutaneous, intraosseous, transmucosal, or intraperitoneal routes of administration. In certain embodiments, oral routes of administering a composition can be used. The terms ““administer”, “administered”, “administers” and “administering” a compound should be understood to mean providing a compound of the invention or a prodrug of a compound of the invention to the individual in need. [0044] As used herein, “treatment” or “treating” refers to an approach for obtaining beneficial or desired results with respect to a disease, disorder, or medical condition including, but not limited to, a therapeutic benefit and/or a prophylactic benefit. In certain embodiments, 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. Also, a therapeutic benefit may be achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder, such as observing an improvement in the subject, notwithstanding that the subject may still be afflicted with the underlying disorder. In certain embodiments, for prophylactic benefit, the compositions are administered to a subject at risk of developing a particular disease, or to a subject reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made. Treating can include, for example, reducing, delaying or alleviating the severity of one or more symptoms of the disease or condition, or it can include reducing the frequency with which symptoms of a disease, defect, disorder, or adverse condition, and the like, WSGR Docket No.58296-711601 are experienced by a patient. Treating can be used herein to refer to a method that results in some level of treatment or amelioration of the disease or condition, and can contemplate a range of results directed to that end, including but not restricted to prevention of the condition entirely. [0045] In certain embodiments, the term “prevent” or “preventing” as related to a disease or disorder may refer to a compound that, in a statistical sample, reduces the occurrence of the disorder or condition in the treated sample relative to an untreated control sample, or delays the onset or reduces the severity of one or more symptoms of the disorder or condition relative to the untreated control sample. [0046] As used herein, “modulate” refers to alteration of the activity or the expression of target protein/gene in the presence of an exogenous compound, relative to the comparable conditions in the absence of the exogenous compound. As used herein, the term “modulate” can be up- regulation (e.g., activation or stimulation) or down-regulation (e.g., inhibition or suppression). Compounds [0047] In some aspects, the present disclosure provides a compound represented by the structure of Formula (I):
Figure imgf000017_0001
or a pharmaceutically acceptable salt thereof, wherein: Ring A is 3- to 12-membered heterocycle; X1 is selected from N and C(H); each R1 is independently selected at each occurrence from: halogen, -OR11, -SR11, -N(R11)2, -C(O)R11, -C(O)N(R11)2, -C(O)OR11, -OC(O)R11, -N(R11)C(O)R11, -N(R11)C(O)OR11, -N(R11)S(O)2R11, -S(O)2N(R11)2, -S(O)R11, - S(O)2R11, -NO2, =S, =N(R11), and -CN; C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR11, -SR11, - N(R11)2, -C(O)R11, -C(O)N(R11)2, -C(O)OR11, -OC(O)R11, -N(R11)C(O)R11, -
Figure imgf000017_0002
WSGR Docket No.58296-711601 C3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR11, -
Figure imgf000018_0001
each R2 is independently selected at each occurrence from: halogen, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)N(R12)2, -C(O)OR12, -OC(O)R12, -N(R12)C(O)R12, -N(R12)C(O)OR12, -N(R12)S(O)2R12, -S(O)2N(R12)2, -S(O)R12, - S(O)2R12, -NO2, =O, =S, =N(R12), and -CN; C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)N(R12)2, -C(O)OR12, - OC(O)R12, -N(R12)C(O)R12, -N(R12)C(O)OR12, -N(R12)S(O)2R12, -S(O)2N(R12)2, - S(O)R12, -S(O)2R12, -NO2, =O, =S, =N(R12), and -CN; and C3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR12, - SR12, -N(R12)2, -C(O)R12, -C(O)N(R12)2, -C(O)OR12, -OC(O)R12, -N(R12)C(O)R12, - N(R12)C(O)OR12, -N(R12)S(O)2R12, -S(O)2N(R12)2, -S(O)R12, -S(O)2R12, -NO2, =O, =S, =N(R12), -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected halogen, -OR12, -SR12, -N(R12)2, -C(O)R12, - C(O)N(R12)2, -C(O)OR12, -OC(O)R12, -N(R12)C(O)R12, -N(R12)C(O)OR12, - N(R12)S(O)2R12, -S(O)2N(R12)2, -S(O)R12, -S(O)2R12, -NO2, =O, =S, =N(R12), and -CN; R3 is selected from: hydrogen, -C(O)R13, -S(O)2R13, and -CN; C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)N(R13)2, -C(O)OR13, - OC(O)R13, -N(R13)C(O)R13, -N(R13)C(O)OR13, -N(R13)S(O)2R13, -S(O)2N(R13)2, - S(O)R13, -S(O)2R13, -NO2, =O, =S, =N(R13), and -CN; and C3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, - WSGR Docket No.58296-711601 SR13, -N(R13)2, -C(O)R13, -C(O)N(R13)2, -C(O)OR13, -OC(O)R13, -N(R13)C(O)R13, - N(R13)C(O)OR13, -N(R13)S(O)2R13, -S(O)2N(R13)2, -S(O)R13, -S(O)2R13, -NO2, =O, =S, =N(R13), -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, - C(O)N(R13)2, -C(O)OR13, -OC(O)R13, -N(R13)C(O)R13, -N(R13)C(O)OR13, - N(R13)S(O)2R13, -S(O)2N(R13)2, -S(O)R13, -S(O)2R13, -NO2, =O, =S, =N(R13), and -CN; R4 is selected from: C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR14, -SR14, -N(R14)2, -C(O)R14, -C(O)N(R14)2, -C(O)OR14, - OC(O)R14, -N(R14)C(O)R14, -N(R14)C(O)OR14, -N(R14)S(O)2R14, -S(O)2N(R14)2, - S(O)R14, -S(O)2R14, -NO2, =O, =S, =N(R14), -CN, C3-6 carbocycle and 3- to 6-membered heterocycle, the C3-6 carbocycle and 3- to 6-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OR14, - SR14, -N(R14)2, -C(O)R14, -C(O)N(R14)2, -C(O)OR14, -OC(O)R14, -N(R14)C(O)R14, - N(R14)C(O)OR14, -N(R14)S(O)2R14, -S(O)2N(R14)2, -S(O)R14, -S(O)2R14, -NO2, =O, =S, =N(R14), -CN, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkyl-OR14, C1-6 alkyl-C3-6 carbocycle, and C1-6 alkyl-C3-6 heterocycle ; and C3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR14, - SR14, -N(R14)2, -C(O)R14, -C(O)N(R14)2, -C(O)OR14, -OC(O)R14, -N(R14)C(O)R14, - N(R14)C(O)OR14, -N(R14)S(O)2R14, -S(O)2N(R14)2, -S(O)R14, -S(O)2R14, -NO2, =O, =S, =N(R14), -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR14, -SR14, -N(R14)2, -C(O)R14, - C(O)N(R14)2, -C(O)OR14, -OC(O)R14, -N(R14)C(O)R14, -N(R14)C(O)OR14, - N(R14)S(O)2R14, -S(O)2N(R14)2, -S(O)R14, -S(O)2R14, -NO2, =O, =S, =N(R14), and -CN; or R3 and R4 come together with the atoms to which they are each bound to form a 4- to 6- membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR15, -SR15, -N(R15)2, -C(O)R15, -C(O)N(R15)2, -C(O)OR15, -OC(O)R15, -N(R15)C(O)R15, -N(R15)C(O)OR15, -N(R15)S(O)2R15, -S(O)2N(R15)2, -S(O)R15, - S(O)2R15, -NO2, =O, =S, =N(R15), and -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR15, -SR15, -N(R15)2, -C(O)R15, -C(O)N(R15)2, -C(O)OR15, - WSGR Docket No.58296-711601 OC(O)R15, -N(R15)C(O)R15, -N(R15)C(O)OR15, -N(R15)S(O)2R15, -S(O)2N(R15)2, - S(O)R15, -S(O)2R15, -NO2, =O, =S, =N(R15), and -CN; R11, R12, R13, R14, and R15 are each independently selected at each occurrence from: hydrogen; C1-6 alkyl optionally substituted with one more substituents independently selected from halogen, -O-C1-6 alkyl, -O-C1-6 haloalkyl, -NH2, -NO2, =O, -CN, -S(O)2OH, -S-C1-6 alkyl, -S(O)-C1-6 alkyl, -S(O)2-C1-6 alkyl, -P(O)(OH)2, -P(-C1-6 alkyl)2, -P(-C1-6 alkyl)(-O-C1-6 alkyl) -P(-O-(C1-6 alkyl))2, -P(=O)(-C1-6 alkyl)2, -P(=O)(-C1-6 alkyl)(-O- (C1-6 alkyl), -P(O)(-O-(C1-6 alkyl))2, C3-10 carbocycle and 3- to 10-membered heterocycle, wherein each C3-10 carbocycle, and 3- to 10-membered heterocycle are optionally substituted with one or more substituents independently selected from: halogen, -OH, -O- C1-6 alkyl, -O-C1-6 haloalkyl, -NH2, -NO2, =O, and -CN; and C3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OH, -O- C1-6 alkyl, -O-C1-6 haloalkyl, -NH2, -NO2, =O, and -CN; n is selected from 0, 1, 2, 3, and 4; and m is selected from 0, 1, 2, 3, and 4. [0048] In some embodiments, for the compound or salt or salt of Formula (I), Ring A is 3- to 12-membered heterocycle comprising one or more heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, for the compound or salt or salt of Formula (I), Ring A is 3- to 12-membered saturated heterocycle comprising one or more heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, for the compound or salt or salt of Formula (I), Ring A is 3- to 12-membered unsaturated heterocycle comprising one or more heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is selected from 3- to 4- membered heterocycle, 3- to 5-membered heterocycle, 3- to 6-membered heterocycle, 3- to 7- membered heterocycle, 3- to 8-membered heterocycle, 3- to 9-membered heterocycle, 3- to 10- membered heterocycle, 3- to 11-membered heterocycle, and 3- to 12-membered heterocycle, any of which is optionally substituted with R1 as defined in Formula (I). In some embodiments, Ring A is selected from 3-membered heterocycle, 4-membered heterocycle, 5-membered heterocycle, 6-membered heterocycle, 7-membered heterocycle, 8-membered heterocycle, 9-membered heterocycle, 10-membered heterocycle, 11-membered heterocycle, and 12-membered heterocycle, any of which is optionally substituted with R1 as defined in Formula (I). [0049] In some embodiments, for the compound or salt or salt of Formula (I), Ring A is 5- to 12- membered heteroaryl comprising one or more heteroatoms selected from nitrogen, oxygen, and WSGR Docket No.58296-711601 sulfur. In some embodiments, Ring A is selected from 5- to 6-membered heteroaryl, 5- to 9- membered heteroaryl, and 5- to 10-membered heteroaryl, any of which is optionally substituted with R1 as defined in Formula (I). In some embodiments, Ring A is selected from 5-membered heteroaryl, 6-membered heteroaryl, 9-membered heteroaryl, and 10-membered heteroaryl, any of which is optionally substituted with R1 as defined in Formula (I). [0050] In some embodiments, for the compound or salt of Formula (I), Ring A is selected from 3- to 6-membered monocyclic heterocycle and 6- to 12-membered bicyclic heterocycle, any of which comprises at least one heteroatom selected from nitrogen, oxygen, and sulfur. [0051] In some embodiments, for the compound or salt of Formula (I), Ring A is 3- to 6- membered monocyclic heterocycle comprising one heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is 5- to 6-membered heteroaryl. In some embodiments, Ring A is 5-membered heteroaryl selected from pyrrolyl and thiophenyl. In some embodiments, Ring A is selected from pyrrolyl and thiophenyl; and n is 0. [0052] In some embodiments, for the compound or salt of Formula
Figure imgf000021_0001
selected from
Figure imgf000021_0002
[0053] In some embodiments, for the compound or salt of Formula (I), Ring A is 6- to 12- membered bicyclic heterocycle comprising at least one heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, the 6- to 12-membered bicyclic heterocycle of Ring A is selected from a 6- to 12-membered bridged heterocycle, 6- to 12-membered fused heterocycle, and 6- to 12-membered spirocyclic heterocycle. [0054] In some embodiments, for the compound or salt of Formula (I), Ring A is 6- to 12- membered fused heterocycle. In some embodiments, Ring A is selected from 1H-indolyl, indolinyl, benzo[b]thiophenyl, 1H-pyrrolo[2,3-b]pyridinyl, 1H-pyrrolo[3,2-b]pyridinyl, 1H- pyrrolo[3,2-c]pyridinyl, 1H-benzo[d]imidazolyl, 4,7-dihydro-1H-pyrrolo[3,2-b]pyridinyl, 6,7- dihydro-1H-pyrrolo[2,3-c]pyridinyl, 5H-pyrrolo[3,2-d]pyrimidinyl, 7H-pyrrolo[2,3- c]pyridazinyl, 1H-pyrrolo[2,3-d]pyridazinyl, 5H-pyrrolo[2,3-b]pyrazinyl, 7H-pyrrolo[2,3- d]pyrimidinyl, and 3,7-dihydro-2H-pyrrolo[2,3-d]pyrimidinyl. In some embodiments, Ring A is selected from 1H-indolyl and indolinyl. In some embodiments, Ring A is benzo[b]thiophenyl. In some embodiments, Ring A is selected from 1H-pyrrolo[2,3-b]pyridinyl, 1H-pyrrolo[3,2- b]pyridinyl, and 1H-pyrrolo[3,2-c]pyridinyl. In some embodiments, Ring A is 1H- WSGR Docket No.58296-711601 benzo[d]imidazolyl. In some embodiments, Ring A is selected from 4,7-dihydro-1H-pyrrolo[3,2- b]pyridinyl and 6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl. In some embodiments, Ring A is selected from 5H-pyrrolo[3,2-d]pyrimidinyl, 7H-pyrrolo[2,3-c]pyridazinyl, 1H-pyrrolo[2,3- d]pyridazinyl, 5H-pyrrolo[2,3-b]pyrazinyl, and 7H-pyrrolo[2,3-d]pyrimidinyl. In some embodiments, Ring A is 3,7-dihydro-2H-pyrrolo[2,3-d]pyrimidinyl. In some embodiments, Ring A is selected from benzo[b]thiophenyl, 1H-indolyl, 5H-pyrrolo[3,2-d]pyrimidinyl, 7H- pyrrolo[2,3-c]pyridazinyl, and 1H-pyrrolo[2,3-d]pyridazinyl; and n is 0. [0055] In some embodiments, for the compound or salt of Formula
Figure imgf000022_0001
selected from
Figure imgf000022_0002
[0056] In some embodiments, for the compound or salt of Formula (I), Ring A is 6- to 12- membered bicyclic heterocycle comprising at least one heteroatom selected from nitrogen, oxygen, and sulfur; n is selected from 1, 2, 3, and 4; each R1 is independently selected at each occurrence from: halogen, -OR11, -SR11, -N(R11)2, -C(O)R11, -C(O)N(R11)2, -C(O)OR11, - OC(O)R11, -N(R11)C(O)R11, -N(R11)C(O)OR11, -N(R11)S(O)2R11, -S(O)2N(R11)2, -S(O)R11, - S(O)2R11, -NO2=S, =N(R11), and -CN; and C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR11, -SR11, -N(R11)2, -C(O)R11, -C(O)N(R11)2, -C(O)OR11, -OC(O)R11, - N(R11)C(O)R11, -N(R11)C(O)OR11, -N(R11)S(O)2R11, -S(O)2N(R11)2, -S(O)R11, -S(O)2R11, -NO2, =O, =S, =N(R11), and -CN; and R11 is independently selected at each occurrence from hydrogen and C1-6 alkyl optionally substituted with one more substituents independently selected from halogen, -O-C1-6 alkyl, -O-C1-6 haloalkyl, -NH2, -NO2, =O, -CN, C3-10 carbocycle, and 3- to 10- membered heterocycle. In some embodiments, n is selected from 1, 2, 3, and 4; each R1 is independently selected at each occurrence from: halogen, -OR11, -N(R11)2, -C(O)R11, - C(O)N(R11)2, -C(O)OR11, -N(R11)C(O)R11, -N(R11)S(O)2R11, -NO2, =S, and -CN; and C1-6 alkyl and C2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, -C(O)R11, -C(O)N(R11)2, -C(O)OR11, - N(R11)C(O)R11, -N(R11)S(O)2R11, -NO2, =O, =S, and -CN; and R11 is independently selected at each occurrence from hydrogen and C1-6 alkyl optionally substituted with one more substituents independently selected from halogen, -O-C1-6 alkyl, -O-C1-6 haloalkyl, -NH2, -NO2, and -CN. In some embodiments, n is 1, 2, or 3. In some embodiments, n is 3. In some embodiments, n is 1 or WSGR Docket No.58296-711601 2. In some embodiments, n is 1. In some embodiments, n is 2, 3, or 4. In some embodiments, n is 2 or 3. In some embodiments, Ring A is 6- to 10-membered bicyclic heteroaryl comprising at least one heteroatom selected from nitrogen, oxygen, and sulfur. [0057] In some embodiments, for the compound or salt of Formula (I), Ring A is 6- to 12- membered fused heterocycle; n is selected from 1, 2, 3, and 4; each R1 is independently selected at each occurrence from: halogen, -OR11, -SR11, -N(R11)2, -C(O)R11, -C(O)N(R11)2, -C(O)OR11, - OC(O)R11, -N(R11)C(O)R11, -N(R11)C(O)OR11, -N(R11)S(O)2R11, -S(O)2N(R11)2, -S(O)R11, - S(O)2R11, -NO2, =S, =N(R11), and -CN; and C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR11, -SR11, -N(R11)2, -C(O)R11, -C(O)N(R11)2, -C(O)OR11, -OC(O)R11, - N(R11)C(O)R11, -N(R11)C(O)OR11, -N(R11)S(O)2R11, -S(O)2N(R11)2, -S(O)R11, -S(O)2R11, -NO2, =O, =S, =N(R11), and -CN; and R11 is independently selected at each occurrence from hydrogen and C1-6 alkyl optionally substituted with one more substituents independently selected from halogen, -O-C1-6 alkyl, -O-C1-6 haloalkyl, -NH2, -NO2, =O, -CN, C3-10 carbocycle, and 3- to 10- membered heterocycle. In some embodiments, n is selected from 1, 2, 3, and 4; each R1 is independently selected at each occurrence from: halogen, -OR11, -N(R11)2, -C(O)R11, - C(O)N(R11)2, -C(O)OR11, -N(R11)C(O)R11, -N(R11)S(O)2R11, -NO2, =S, and -CN; and C1-6 alkyl and C2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, -C(O)R11, -C(O)N(R11)2, -C(O)OR11, - N(R11)C(O)R11, -N(R11)S(O)2R11, -NO2, =O, =S, and -CN; and R11 is independently selected at each occurrence from hydrogen and C1-6 alkyl optionally substituted with one more substituents independently selected from halogen, -O-C1-6 alkyl, -O-C1-6 haloalkyl, -NH2, -NO2, and -CN. In some embodiments, n is 1, 2, or 3. In some embodiments, n is 3. In some embodiments, n is 1 or 2. In some embodiments, n is 1. In some embodiments, n is 2, 3, or 4. In some embodiments, n is 2 or 3. [0058] In some embodiments, for the compound or salt of Formula (I), Ring A is selected from 1H-indolyl, indolinyl, benzo[b]thiophenyl, 1H-pyrrolo[2,3-b]pyridinyl, 1H-pyrrolo[3,2- b]pyridinyl, 1H-pyrrolo[3,2-c]pyridinyl, 1H-benzo[d]imidazolyl, 4,7-dihydro-1H-pyrrolo[3,2- b]pyridinyl, 6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl, 5H-pyrrolo[3,2-d]pyrimidinyl, 7H- pyrrolo[2,3-c]pyridazinyl, 1H-pyrrolo[2,3-d]pyridazinyl, 5H-pyrrolo[2,3-b]pyrazinyl, 7H- pyrrolo[2,3-d]pyrimidinyl, and 3,7-dihydro-2H-pyrrolo[2,3-d]pyrimidinyl; n is selected from 1, 2, 3, and 4; each R1 is independently selected at each occurrence from: halogen, -OR11, -SR11, - N(R11)2, -C(O)R11, -C(O)N(R11)2, -C(O)OR11, -OC(O)R11, -N(R11)C(O)R11, -N(R11)C(O)OR11, - N(R11)S(O)2R11, -S(O)2N(R11)2, -S(O)R11, -S(O)2R11, -NO2, =S, =N(R11), and -CN; and C1-6 WSGR Docket No.58296-711601 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR11, -SR11, -N(R11)2, -C(O)R11, - S(O)2R11, -
Figure imgf000024_0001
independently selected at each occurrence from hydrogen and C1-6 alkyl optionally substituted with one more substituents independently selected from halogen, -O-C1-6 alkyl, -O-C1-6 haloalkyl, -NH2, -NO2, =O, -CN, C3-10 carbocycle, and 3- to 10-membered heterocycle. In some embodiments, n is selected from 1, 2, 3, and 4; each R1 is independently selected at each occurrence from: halogen, -OR11, -N(R11)2, -C(O)R11, -C(O)N(R11)2, -C(O)OR11, -N(R11)C(O)R11, -N(R11)S(O)2R11, -NO2, =S, and -CN; and C1-6 alkyl and C2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, -C(O)R11, - C(O)N(R11)2, -C(O)OR11, -N(R11)C(O)R11, -N(R11)S(O)2R11, -NO2, =O, =S, and -CN; and R11 is independently selected at each occurrence from hydrogen and C1-6 alkyl optionally substituted with one more substituents independently selected from halogen, -O-C1-6 alkyl, -O-C1-6 haloalkyl, -NH2, -NO2, and -CN. In some embodiments, n is 1, 2, or 3. In some embodiments, n is 3. In some embodiments, n is 1 or 2. In some embodiments, n is 1. In some embodiments, n is 2, 3, or 4. In some embodiments, n is 2 or 3. [0059] In some embodiments, for the compound or salt of Formula
Figure imgf000024_0002
selected from
Figure imgf000024_0003
WSGR Docket No.58296-711601
Figure imgf000025_0001
WSGR Docket No.58296-711601
Figure imgf000026_0001
[0060] In some embodiments, for the compound or salt of Formula (I), Ring A is 6- to 12- membered bicyclic heterocycle comprising at least one heteroatom selected from nitrogen, oxygen, and sulfur; n is selected from 1, 2, 3, and 4; each R1 is independently selected at each occurrence from C3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR11,
Figure imgf000026_0002
=N(R11), -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR11, -SR11, -N(R11)2, -C(O)R11, -C(O)N(R11)2, -C(O)OR11, -OC(O)R11, -N(R11)C(O)R11, -N(R11)C(O)OR11, -N(R11)S(O)2R11, -S(O)2N(R11)2, -S(O)R11, -S(O)2R11, -NO2, =O, =S, =N(R11), and -CN; and R11 is independently selected at each occurrence from hydrogen and C1-6 alkyl optionally substituted with one more substituents independently selected from halogen, -O-C1-6 alkyl, -O-C1-6 haloalkyl, -NH2, -NO2, =O, -CN, C3-10 carbocycle, and 3- to 10- membered heterocycle. In some embodiments, n is selected from 1, 2, 3, and 4; each R1 is independently selected at each occurrence from C3-6 saturated carbocycle, 3- to 6-membered saturated heterocycle, and 5- to 6-membered heteroaryl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, -C(O)R11, - C(O)N(R11)2, -N(R11)C(O)R11, -N(R11)C(O)OR11, -N(R11)S(O)2R11, -NO2, -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, -C(O)R11, -C(O)N(R11)2, -N(R11)C(O)R11, -N(R11)C(O)OR11, -N(R11)S(O)2R11, -NO2, and -CN; and R11 is independently selected at each occurrence from hydrogen and C1-6 alkyl optionally substituted with one more substituents independently selected from halogen, -O-C1-6 alkyl, and -O-C1-6 haloalkyl. In some embodiments, n is selected from 1 and 2; each R1 is independently selected at each occurrence from cyclopropyl, oxetanyl, thiophenyl, pyrazolyl, and triazolyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, -C(O)R11, -C(O)N(R11)2, -N(R11)C(O)R11, - N(R11)C(O)OR11, -N(R11)S(O)2R11, -NO2, -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, -C(O)R11, - WSGR Docket No.58296-711601 C(O)N(R11)2, -N(R11)C(O)R11, -N(R11)C(O)OR11, -N(R11)S(O)2R11, -NO2, and -CN; and R11 is independently selected at each occurrence from hydrogen and C1-6 alkyl optionally substituted with one more substituents independently selected from halogen, -O-C1-6 alkyl, and -O-C1-6 haloalkyl. In some embodiments, n is 1, 2, or 3. In some embodiments, n is 3. In some embodiments, n is 1 or 2. In some embodiments, n is 1. In some embodiments, n is 2, 3, or 4. In some embodiments, n is 2 or 3. In some embodiments, Ring A is 6- to 10-membered bicyclic heteroaryl comprising at least one heteroatom selected from nitrogen, oxygen, and sulfur. [0061] In some embodiments, for the compound or salt of Formula (I), Ring A is 6- to 12- membered fused heterocycle; n is selected from 1, 2, 3, and 4; each R1 is independently selected at each occurrence from C3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR11,
Figure imgf000027_0001
=N(R11), -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR11, -SR11, -N(R11)2, -C(O)R11, -C(O)N(R11)2, -C(O)OR11, -OC(O)R11, -N(R11)C(O)R11, -N(R11)C(O)OR11, -N(R11)S(O)2R11, -S(O)2N(R11)2, -S(O)R11, -S(O)2R11, -NO2, =O, =S, =N(R11), and -CN; and R11 is independently selected at each occurrence from hydrogen and C1-6 alkyl optionally substituted with one more substituents independently selected from halogen, -O-C1-6 alkyl, -O-C1-6 haloalkyl, -NH2, -NO2, =O, -CN, C3-10 carbocycle, and 3- to 10- membered heterocycle. In some embodiments, n is selected from 1, 2, 3, and 4; each R1 is independently selected at each occurrence from C3-6 saturated carbocycle, 3- to 6-membered saturated heterocycle, and 5- to 6-membered heteroaryl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, -C(O)R11, - C(O)N(R11)2, -N(R11)C(O)R11, -N(R11)C(O)OR11, -N(R11)S(O)2R11, -NO2, -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, -C(O)R11, -C(O)N(R11)2, -N(R11)C(O)R11, -N(R11)C(O)OR11, -N(R11)S(O)2R11, -NO2, and -CN; and R11 is independently selected at each occurrence from hydrogen and C1-6 alkyl optionally substituted with one more substituents independently selected from halogen, -O-C1-6 alkyl, and -O-C1-6 haloalkyl. In some embodiments, n is selected from 1 and 2; each R1 is independently selected at each occurrence from cyclopropyl, oxetanyl, thiophenyl, pyrazolyl, and triazolyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, -C(O)R11, -C(O)N(R11)2, -N(R11)C(O)R11, - N(R11)C(O)OR11, -N(R11)S(O)2R11, -NO2, -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, -C(O)R11, - WSGR Docket No.58296-711601 C(O)N(R11)2, -N(R11)C(O)R11, -N(R11)C(O)OR11, -N(R11)S(O)2R11, -NO2, and -CN; and R11 is independently selected at each occurrence from hydrogen and C1-6 alkyl optionally substituted with one more substituents independently selected from halogen, -O-C1-6 alkyl, and -O-C1-6 haloalkyl. In some embodiments, n is 1, 2, or 3. In some embodiments, n is 3. In some embodiments, n is 1 or 2. In some embodiments, n is 1. In some embodiments, n is 2, 3, or 4. In some embodiments, n is 2 or 3. [0062] In some embodiments, for the compound or salt of Formula (I), Ring A is selected from 1H-indolyl, indolinyl, benzo[b]thiophenyl, 1H-pyrrolo[2,3-b]pyridinyl, 1H-pyrrolo[3,2- b]pyridinyl, 1H-pyrrolo[3,2-c]pyridinyl, 1H-benzo[d]imidazolyl, 4,7-dihydro-1H-pyrrolo[3,2- b]pyridinyl, 6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl, 5H-pyrrolo[3,2-d]pyrimidinyl, 7H- pyrrolo[2,3-c]pyridazinyl, 1H-pyrrolo[2,3-d]pyridazinyl, 5H-pyrrolo[2,3-b]pyrazinyl, 7H- pyrrolo[2,3-d]pyrimidinyl, and 3,7-dihydro-2H-pyrrolo[2,3-d]pyrimidinyl; n is selected from 1, 2, 3, and 4; each R1 is independently selected at each occurrence from C3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR11, -SR11, -N(R11)2, -C(O)R11, -C(O)N(R11)2, -
Figure imgf000028_0001
S(O)R11, -S(O)2R11, -NO2, =O, =S, =N(R11), -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR11, -SR11, -N(R11)2, -C(O)R11, - S(O)2R11, -
Figure imgf000028_0002
independently selected at each occurrence from hydrogen and C1-6 alkyl optionally substituted with one more substituents independently selected from halogen, -O-C1-6 alkyl, -O-C1-6 haloalkyl, -NH2, -NO2, =O, -CN, C3-10 carbocycle, and 3- to 10-membered heterocycle. In some embodiments, n is selected from 1, 2, 3, and 4; each R1 is independently selected at each occurrence from C3-6 saturated carbocycle, 3- to 6-membered saturated heterocycle, and 5- to 6-membered heteroaryl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, -C(O)R11, -C(O)N(R11)2, -N(R11)C(O)R11, -N(R11)C(O)OR11, - N(R11)S(O)2R11, -NO2, -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, -C(O)R11, -C(O)N(R11)2, -N(R11)C(O)R11, -N(R11)C(O)OR11, -N(R11)S(O)2R11, -NO2, and -CN; and R11 is independently selected at each occurrence from hydrogen and C1-6 alkyl optionally substituted with one more substituents independently selected from halogen, -O-C1-6 alkyl, and -O-C1-6 haloalkyl. In some embodiments, n is selected from 1 and 2; each R1 is independently selected at each occurrence from cyclopropyl, oxetanyl, thiophenyl, pyrazolyl, and triazolyl, each of which is optionally WSGR Docket No.58296-711601 substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2,
Figure imgf000029_0001
C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, -C(O)R11, -C(O)N(R11)2, -N(R11)C(O)R11, -N(R11)C(O)OR11, - N(R11)S(O)2R11, -NO2, and -CN; and R11 is independently selected at each occurrence from hydrogen and C1-6 alkyl optionally substituted with one more substituents independently selected from halogen, -O-C1-6 alkyl, and -O-C1-6 haloalkyl. In some embodiments, n is 1, 2, or 3. In some embodiments, n is 3. In some embodiments, n is 1 or 2. In some embodiments, n is 1. In some embodiments, n is 2, 3, or 4. In some embodiments, n is 2 or 3. [0063] In some embodiments, for the compound or salt of Formula
Figure imgf000029_0002
Figure imgf000029_0003
[0064] In some embodiments, for the compound or salt of Formula (I), Ring A is selected from pyrrolyl, thiophenyl, 1H-indolyl, indolinyl, benzo[b]thiophenyl, 1H-pyrrolo[2,3-b]pyridinyl, 1H- pyrrolo[3,2-b]pyridinyl, 1H-pyrrolo[3,2-c]pyridinyl, 1H-benzo[d]imidazolyl, 4,7-dihydro-1H- pyrrolo[3,2-b]pyridinyl, 6,7-dihydro-1H-pyrrolo[2,3-c]pyridinyl, 5H-pyrrolo[3,2-d]pyrimidinyl, 7H-pyrrolo[2,3-c]pyridazinyl, 1H-pyrrolo[2,3-d]pyridazinyl, 5H-pyrrolo[2,3-b]pyrazinyl, 7H- pyrrolo[2,3-d]pyrimidinyl, and 3,7-dihydro-2H-pyrrolo[2,3-d]pyrimidinyl; n selected from 1, 2, 3, and 4; each R1 is independently selected at each occurrence from: halogen, -OR11, -N(R11)2, - C(O)R11, -C(O)N(R11)2, -C(O)OR11, -N(R11)C(O)R11, -N(R11)S(O)2R11, -NO2, =S, and -CN; and C1-6 alkyl and C2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, -C(O)R11, -C(O)N(R11)2, -C(O)OR11, - N(R11)C(O)R11, -N(R11)S(O)2R11, -NO2, =O, =S, and -CN; and C3-6 saturated carbocycle, 3- to 6- membered saturated heterocycle, and 5- to 6-membered heteroaryl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, WSGR Docket No.58296-711601 -C(O)R11, -C(O)N(R11)2, -N(R11)C(O)R11, -N(R11)C(O)OR11, -N(R11)S(O)2R11, -NO2, -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, -C(O)R11, -C(O)N(R11)2, -N(R11)C(O)R11, -N(R11)C(O)OR11, - N(R11)S(O)2R11, -NO2, and -CN; and R11 is independently selected at each occurrence from hydrogen and C1-6 alkyl optionally substituted with one more substituents independently selected from halogen, -O-C1-6 alkyl, -O-C1-6 haloalkyl, -NH2, -NO2, and -CN. [0065] In some embodiments, for the compound or salt of Formula
Figure imgf000030_0001
selected from
Figure imgf000030_0002
WSGR Docket No.58296-711601
Figure imgf000031_0001
WSGR Docket No.58296-711601
Figure imgf000032_0001
[0066] In some embodiments, for the compound or salt of Formula (I),
Figure imgf000032_0002
is a 3- to 12- membered heterocycle. In some embodiments,
Figure imgf000032_0003
is a 3- to 12-membered saturated heterocycle. In some embodiments,
Figure imgf000032_0004
is a 3- to 12-membered unsaturated heterocycle. In some embodiments,
Figure imgf000032_0005
is selected from 3- to 4-membered saturated heterocycle, 3- to 5- membered saturated heterocycle, 3- to 6-membered saturated heterocycle, 3- to 7-membered saturated heterocycle, 3- to 8-membered saturated heterocycle, 3- to 9-membered saturated heterocycle, 3- to 10-membered saturated heterocycle, 3- to 11-membered saturated heterocycle, and 3- to 12-membered saturated heterocycle, any of which is optionally substituted with R2 as defined in Formula (I). In some embodiments, is selected from 3-membered saturated heterocycle, 4-membered saturated heterocycle, 5-membered saturated heterocycle, 6-membered saturated heterocycle, 7-membered saturated heterocycle, 8-membered saturated heterocycle, 9- membered saturated heterocycle, 10-membered saturated heterocycle, 11-membered saturated heterocycle, and 12-membered saturated heterocycle, any of which is optionally substituted with R2 as defined in Formula (I). [0067] In some embodiments, for the compound or salt of Formula (I),
Figure imgf000032_0006
is selected from 3- to 7-membered monocyclic heterocycle and 6- to 12-membered bicyclic heterocycle. In some WSGR Docket No.58296-711601 embodiments,
Figure imgf000033_0001
is 3- to 7-membered monocyclic heterocycle. In some embodiments,
Figure imgf000033_0002
is 6- to 12-membered bicyclic heterocycle. In some embodiments, the 6- to 12-membered bicyclic heterocycle of
Figure imgf000033_0003
is selected from a 6- to 12-membered bridged heterocycle, 6- to 12-membered fused heterocycle, and 6- to 12-membered spirocyclic heterocycle. In some embodiments, the 6- to 12-membered bicyclic heterocycle of is a 6- to 12-membered bridged heterocycle. In some embodiments, the 6- to 12-membered fused heterocycle of
Figure imgf000033_0004
is a 6- to 12-membered bridged heterocycle. In some embodiments, the 6- to 12-membered bicyclic is a 6- to 12-membered spirocyclic heterocycle. In some embodiments,
Figure imgf000033_0005
heterocycloalkyl. In some embodiments,
Figure imgf000033_0006
selected from azetidinyl, pyrrolidinyl, and piperidinyl. In some embodiments, m is selected from 0, 1, 2, and 3. [0068] In some embodiments, for the compound or salt of Formula (I), is selected from 3- to 7-membered monocyclic heterocycle and 6- to 12-membered bicyclic heterocycle; m is selected from 0, 1, and 2; each R2 is independently selected at each occurrence from: halogen, - OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)N(R12)2, -C(O)OR12, -OC(O)R12, -N(R12)C(O)R12, - N(R12)C(O)OR12, -N(R12)S(O)2R12, -S(O)2N(R12)2, -S(O)R12, -S(O)2R12, -NO2, =O, =S, =N(R12), and -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)N(R12)2, -C(O)OR12, -OC(O)R12, -N(R12)C(O)R12, -N(R12)C(O)OR12, -N(R12)S(O)2R12, -S(O)2N(R12)2, -S(O)R12, -S(O)2R12, -NO2, =O, =S, =N(R12), and -CN; and R12 is selected at each occurrence from hydrogen and C1-6 alkyl optionally substituted with one more substituents independently selected from halogen, -O-C1-6 alkyl, -O-C1-6 haloalkyl, -NH2, -NO2, =O, -CN, C3-10 carbocycle, and 3- to 10-membered heterocycle. In some embodiments, m is selected from 0, 1, and 2; each R2 is independently selected at each occurrence from: halogen, -OR12, -N(R12)2, -C(O)R12, -C(O)N(R12)2, -C(O)OR12, -N(R12)C(O)R12, -N(R12)C(O)OR12, -NO2, and -CN; and C1-6 alkyl optionally substituted with WSGR Docket No.58296-711601 one or more substituents independently selected from halogen, -OR12, -N(R12)2, -C(O)R12, - C(O)N(R12)2, -C(O)OR12, -N(R12)C(O)R12, -N(R12)C(O)OR12, -NO2, and -CN; and R12 is selected at each occurrence from hydrogen and C1-6 alkyl optionally substituted with one more substituents independently selected from halogen, -O-C1-6 alkyl, -O-C1-6 haloalkyl, -NH2, and - NO2. In some embodiments, m is 0 or 1. In some embodiments, m is 1 or 2. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. [0069] In some embodiments, for the compound or salt of Formula (I),
Figure imgf000034_0001
is 3- to 7- membered monocyclic heterocycle; m is selected from 0, 1, and 2; each R2 is independently selected at each occurrence from: halogen, -OR12, -SR12, -N(R12)2, -C(O)R12, - C(O)N(R12)2, -C(O)OR12, -OC(O)R12, -N(R12)C(O)R12, -N(R12)C(O)OR12, -N(R12)S(O)2R12, - S(O)2N(R12)2, -S(O)R12, -S(O)2R12, -NO2, =O, =S, =N(R12), and -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR12, -SR12, - N(R12)2, -C(O)R12, -C(O)N(R12)2, -C(O)OR12, -OC(O)R12, -N(R12)C(O)R12, -N(R12)C(O)OR12, - N(R12)S(O)2R12, -S(O)2N(R12)2, -S(O)R12, -S(O)2R12, -NO2, =O, =S, =N(R12), and -CN; and R12 is selected at each occurrence from hydrogen and C1-6 alkyl optionally substituted with one more substituents independently selected from halogen, -O-C1-6 alkyl, -O-C1-6 haloalkyl, -NH2, -NO2, =O, -CN, C3-10 carbocycle, and 3- to 10-membered heterocycle. In some embodiments, m is selected from 0, 1, and 2; each R2 is independently selected at each occurrence from: halogen, - OR12, -N(R12)2, -C(O)R12, -C(O)N(R12)2, -C(O)OR12, -N(R12)C(O)R12, -N(R12)C(O)OR12, -NO2, and -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR12, -N(R12)2, -C(O)R12, -C(O)N(R12)2, -C(O)OR12, -N(R12)C(O)R12, - N(R12)C(O)OR12, -NO2, and -CN; and R12 is selected at each occurrence from hydrogen and C1-6 alkyl optionally substituted with one more substituents independently selected from halogen, -O- C1-6 alkyl, -O-C1-6 haloalkyl, -NH2, and -NO2. In some embodiments, m is 0 or 1. In some embodiments, m is 1 or 2. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. [0070] In some embodiments, for the compound or salt of Formula (I),
Figure imgf000034_0002
is 4- to 6- membered heterocycloalkyl; m is selected from 0, 1, and 2; each R2 is independently selected at each occurrence from: halogen, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)N(R12)2, -C(O)OR12, - OC(O)R12, -N(R12)C(O)R12, -N(R12)C(O)OR12, -N(R12)S(O)2R12, -S(O)2N(R12)2, -S(O)R12, - S(O)2R12, -NO2, =O, =S, =N(R12), and -CN; and C1-6 alkyl optionally substituted with one or WSGR Docket No.58296-711601 more substituents independently selected from halogen, -OR12, -SR12, -N(R12)2, -C(O)R12, - C(O)N(R12)2, -C(O)OR12, -OC(O)R12, -N(R12)C(O)R12, -N(R12)C(O)OR12, -N(R12)S(O)2R12, - S(O)2N(R12)2, -S(O)R12, -S(O)2R12, -NO2, =O, =S, =N(R12), and -CN; and R12 is selected at each occurrence from hydrogen and C1-6 alkyl optionally substituted with one more substituents independently selected from halogen, -O-C1-6 alkyl, -O-C1-6 haloalkyl, -NH2, -NO2, =O, -CN, C3- 10 carbocycle, and 3- to 10-membered heterocycle. In some embodiments, m is selected from 0, 1, and 2; each R2 is independently selected at each occurrence from: halogen, -OR12, -N(R12)2, - C(O)R12, -C(O)N(R12)2, -C(O)OR12, -N(R12)C(O)R12, -N(R12)C(O)OR12, -NO2, and -CN; and C1- 6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR12, -N(R12)2, -C(O)R12, -C(O)N(R12)2, -C(O)OR12, -N(R12)C(O)R12, -N(R12)C(O)OR12, -NO2, and -CN; and R12 is selected at each occurrence from hydrogen and C1-6 alkyl optionally substituted with one more substituents independently selected from halogen, -O-C1-6 alkyl, -O- C1-6 haloalkyl, -NH2, and -NO2. In some embodiments, m is 0 or 1. In some embodiments, m is 1 or 2. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. [0071] In some embodiments, for the compound or salt of Formula (I), is selected from azetidinyl, pyrrolidinyl, and piperidinyl; m is selected from 0, 1, and 2; each R2 is independently selected at each occurrence from: halogen, -OR12, -SR12, -N(R12)2, -C(O)R12, - C(O)N(R12)2, -C(O)OR12, -OC(O)R12, -N(R12)C(O)R12, -N(R12)C(O)OR12, -N(R12)S(O)2R12, - S(O)2N(R12)2, -S(O)R12, -S(O)2R12, -NO2, =O, =S, =N(R12), and -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR12, -SR12, - N(R12)2, -C(O)R12, -C(O)N(R12)2, -C(O)OR12, -OC(O)R12, -N(R12)C(O)R12, -N(R12)C(O)OR12, - N(R12)S(O)2R12, -S(O)2N(R12)2, -S(O)R12, -S(O)2R12, -NO2, =O, =S, =N(R12), and -CN; and R12 is selected at each occurrence from hydrogen and C1-6 alkyl optionally substituted with one more substituents independently selected from halogen, -O-C1-6 alkyl, -O-C1-6 haloalkyl, -NH2, -NO2, =O, -CN, C3-10 carbocycle, and 3- to 10-membered heterocycle. In some embodiments, m is selected from 0, 1, and 2; each R2 is independently selected at each occurrence from: halogen, - OR12, -N(R12)2, -C(O)R12, -C(O)N(R12)2, -C(O)OR12, -N(R12)C(O)R12, -N(R12)C(O)OR12, -NO2, and -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR12, -N(R12)2, -C(O)R12, -C(O)N(R12)2, -C(O)OR12, -N(R12)C(O)R12, - N(R12)C(O)OR12, -NO2, and -CN; and R12 is selected at each occurrence from hydrogen and C1-6 alkyl optionally substituted with one more substituents independently selected from halogen, -O- C1-6 alkyl, -O-C1-6 haloalkyl, -NH2, and -NO2. In some embodiments, m is 0 or 1. In some WSGR Docket No.58296-711601 embodiments, m is 1 or 2. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. [0072] In some embodiments, for the compound or salt of Formula (I), is selected
Figure imgf000036_0001
WSGR Docket No.58296-711601 [0073] In some embodiments, for the compound or salt of Formula (I),
Figure imgf000037_0001
is selected from 3- to 7-membered monocyclic heterocycle and 6- to 12-membered bicyclic heterocycle; m is selected from 0, 1, and 2; each R2 is independently selected at each occurrence from: halogen, - OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)N(R12)2, -C(O)OR12, -OC(O)R12, -N(R12)C(O)R12, - N(R12)C(O)OR12, -N(R12)S(O)2R12, -S(O)2N(R12)2, -S(O)R12, -S(O)2R12, -NO2, =O, =S, =N(R12), and -CN; and C3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR12, -SR12, - N(R12)2, -C(O)R12, -C(O)N(R12)2, -C(O)OR12, -OC(O)R12, -N(R12)C(O)R12, -N(R12)C(O)OR12, - N(R12)S(O)2R12, -S(O)2N(R12)2, -S(O)R12, -S(O)2R12, -NO2, =O, =S, =N(R12), -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected halogen, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)N(R12)2, -C(O)OR12, -OC(O)R12, -N(R12)C(O)R12, - N(R12)C(O)OR12, -N(R12)S(O)2R12, -S(O)2N(R12)2, -S(O)R12, -S(O)2R12, -NO2, =O, =S, =N(R12), and -CN; and R12 is selected at each occurrence from hydrogen and C1-6 alkyl optionally substituted with one more substituents independently selected from halogen, -O-C1-6 alkyl, -O- C1-6 haloalkyl, -NH2, -NO2, =O, -CN, C3-10 carbocycle, and 3- to 10-membered heterocycle. m is selected from 0 and 1; each R2 is independently selected at each occurrence from: halogen, - OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -NO2, =O, =S, -CN; and C3-6 carbocycle and 3- to 6- membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -NO2, =O, =S, -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected halogen, -OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -NO2, =O, =S, and -CN; and R12 is selected at each occurrence from hydrogen, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, m is 0 or 1. In some embodiments, m is 1 or 2. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. [0074] In some embodiments, for the compound or salt of Formula (I), is 3- to 7- membered monocyclic heterocycle; m is selected from 0, 1, and 2; each R2 is independently selected at each occurrence from: halogen, -OR12, -SR12, -N(R12)2, -C(O)R12, - C(O)N(R12)2, -C(O)OR12, -OC(O)R12, -N(R12)C(O)R12, -N(R12)C(O)OR12, -N(R12)S(O)2R12, - S(O)2N(R12)2, -S(O)R12, -S(O)2R12, -NO2, =O, =S, =N(R12), and -CN; and C3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR12, -SR12, -N(R12)2, -C(O)R12, - WSGR Docket No.58296-711601 C(O)N(R12)2, -C(O)OR12, -OC(O)R12, -N(R12)C(O)R12, -N(R12)C(O)OR12, -N(R12)S(O)2R12, - S(O)2N(R12)2, -S(O)R12, -S(O)2R12, -NO2, =O, =S, =N(R12), -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected halogen, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)N(R12)2, -C(O)OR12, -OC(O)R12, -N(R12)C(O)R12, -N(R12)C(O)OR12, - N(R12)S(O)2R12, -S(O)2N(R12)2, -S(O)R12, -S(O)2R12, -NO2, =O, =S, =N(R12), and -CN; and R12 is selected at each occurrence from hydrogen and C1-6 alkyl optionally substituted with one more substituents independently selected from halogen, -O-C1-6 alkyl, -O-C1-6 haloalkyl, -NH2, -NO2, =O, -CN, C3-10 carbocycle, and 3- to 10-membered heterocycle. m is selected from 0 and 1; each R2 is independently selected at each occurrence from: halogen, -OR12, -N(R12)2, - C(O)R12, -C(O)OR12, -NO2, =O, =S, -CN; and C3-6 carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -NO2, =O, =S, -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected halogen, -OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -NO2, =O, =S, and -CN; and R12 is selected at each occurrence from hydrogen, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, m is 0 or 1. In some embodiments, m is 1 or 2. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. [0075] In some embodiments, for the compound or salt of Formula (I),
Figure imgf000038_0001
is 4- to 6- membered heterocycloalkyl; m is selected from 0, 1, and 2; each R2 is independently selected at each occurrence from: halogen, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)N(R12)2, -C(O)OR12, - OC(O)R12, -N(R12)C(O)R12, -N(R12)C(O)OR12, -N(R12)S(O)2R12, -S(O)2N(R12)2, -S(O)R12, - S(O)2R12, -NO2, =O, =S, =N(R12), and -CN; and C3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)N(R12)2, -C(O)OR12, -OC(O)R12, -N(R12)C(O)R12, -N(R12)C(O)OR12, -N(R12)S(O)2R12, -S(O)2N(R12)2, -S(O)R12, -S(O)2R12, -NO2, =O, =S, =N(R12), -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected halogen, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)N(R12)2, -C(O)OR12, - OC(O)R12, -N(R12)C(O)R12, -N(R12)C(O)OR12, -N(R12)S(O)2R12, -S(O)2N(R12)2, -S(O)R12, - S(O)2R12, -NO2, =O, =S, =N(R12), and -CN; and R12 is selected at each occurrence from hydrogen and C1-6 alkyl optionally substituted with one more substituents independently selected from halogen, -O-C1-6 alkyl, -O-C1-6 haloalkyl, -NH2, -NO2, =O, -CN, C3-10 carbocycle, and 3- to 10-membered heterocycle. m is selected from 0 and 1; each R2 is independently selected at each occurrence from: halogen, -OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -NO2, =O, =S, -CN; and C3-6 WSGR Docket No.58296-711601 carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR12, -N(R12)2, - C(O)R12, -C(O)OR12, -NO2, =O, =S, -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected halogen, -OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -NO2, =O, =S, and -CN; and R12 is selected at each occurrence from hydrogen, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, m is 0 or 1. In some embodiments, m is 1 or 2. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. [0076] In some embodiments, for the compound or salt of Formula (I),
Figure imgf000039_0001
is selected from azetidinyl, pyrrolidinyl, and piperidinyl; m is selected from 0, 1, and 2; each R2 is independently selected at each occurrence from: halogen, -OR12, -SR12, -N(R12)2, -C(O)R12, - C(O)N(R12)2, -C(O)OR12, -OC(O)R12, -N(R12)C(O)R12, -N(R12)C(O)OR12, -N(R12)S(O)2R12, - S(O)2N(R12)2, -S(O)R12, -S(O)2R12, -NO2, =O, =S, =N(R12), and -CN; and C3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR12, -SR12, -N(R12)2, -C(O)R12, - C(O)N(R12)2, -C(O)OR12, -OC(O)R12, -N(R12)C(O)R12, -N(R12)C(O)OR12, -N(R12)S(O)2R12, - S(O)2N(R12)2, -S(O)R12, -S(O)2R12, -NO2, =O, =S, =N(R12), -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected halogen, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)N(R12)2, -C(O)OR12, -OC(O)R12, -N(R12)C(O)R12, -N(R12)C(O)OR12, - N(R12)S(O)2R12, -S(O)2N(R12)2, -S(O)R12, -S(O)2R12, -NO2, =O, =S, =N(R12), and -CN; and R12 is selected at each occurrence from hydrogen and C1-6 alkyl optionally substituted with one more substituents independently selected from halogen, -O-C1-6 alkyl, -O-C1-6 haloalkyl, -NH2, -NO2, =O, -CN, C3-10 carbocycle, and 3- to 10-membered heterocycle. m is selected from 0 and 1; each R2 is independently selected at each occurrence from: halogen, -OR12, -N(R12)2, - C(O)R12, -C(O)OR12, -NO2, =O, =S, -CN; and C3-6 carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -NO2, =O, =S, -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected halogen, -OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -NO2, =O, =S, and -CN; and R12 is selected at each occurrence from hydrogen, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, m is 0 or 1. In some embodiments, m is 1 or 2. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. WSGR Docket No.58296-711601 [0077] In some embodiments, for the compound or salt of Formula
Figure imgf000040_0001
selected
Figure imgf000040_0002
[0078] In some embodiments, for the compound or salt of Formula (I),
Figure imgf000040_0003
is a 6- to 12- membered bridged heterocycle; and m is 0. In some embodiments,
Figure imgf000040_0004
azabicyclo[3.1.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 7-azabicyclo[2.2.1]heptanyl, and 2- oxa-5-azabicyclo[2.2.1]heptanyl; and m is 0. In some embodiments,
Figure imgf000040_0005
azabicyclo[3.1.1]heptanyl; and m is 0. In some embodiments,
Figure imgf000040_0006
is 2,5- diazabicyclo[2.2.1]heptanyl; and m is 0. In some embodiments,
Figure imgf000040_0007
is 2-oxa-5- azabicyclo[2.2.1]heptanyl; and m is 0. In some embodiments,
Figure imgf000040_0008
azabicyclo[2.2.1]heptanyl; and m is 0. [0079] In some embodiments, for the compound or salt of Formula
Figure imgf000040_0009
selected
Figure imgf000040_0010
WSGR Docket No.58296-711601 [0080] In some embodiments, for the compound or salt of Formula (I),
Figure imgf000041_0001
is a 6- to 12- membered spirocyclic heterocycle; and m is 0. In some embodiments,
Figure imgf000041_0002
2- oxa-6-azaspiro[3.3]heptanyl, 1-oxa-6-azaspiro[3.3]heptanyl, and 1-thia-6-azaspiro[3.3]heptanyl; and m is 0. In some embodiments,
Figure imgf000041_0003
is 2-oxa-6-azaspiro[3.3]heptanyl; and m is 0. In some embodiments,
Figure imgf000041_0004
is 1-oxa-6-azaspiro[3.3]heptanyl; and m is 0. In some embodiments,
Figure imgf000041_0005
is 1-thia-6-azaspiro[3.3]heptanyl; and m is 0. [0081] In some embodiments, for the compound or salt of Formula
Figure imgf000041_0006
selected from
Figure imgf000041_0007
[0082] In some embodiments, for the compound or salt of Formula (I), is selected from azetidinyl, pyrrolidinyl, piperidinyl, 6-azabicyclo[3.1.1]heptanyl, 2,5- diazabicyclo[2.2.1]heptanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 1-oxa-6-azaspiro[3.3]heptanyl, and 1-thia-6-azaspiro[3.3]heptanyl; m is selected from 0, 1, and 2; each R2 is independently selected at each occurrence from: halogen, -OR12, -N(R12)2, - C(O)R12, -C(O)N(R12)2, -C(O)OR12, -N(R12)C(O)R12, -N(R12)C(O)OR12, -NO2, and -CN; and C1- 6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR12, -N(R12)2, -C(O)R12, -C(O)N(R12)2, -C(O)OR12, -N(R12)C(O)R12, -N(R12)C(O)OR12, -NO2, and -CN; and C3-6 carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -NO2, =O, =S, -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected halogen, -OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -NO2, =O, =S, and -CN; and R12 is selected at each occurrence from hydrogen and C1-6 alkyl optionally substituted with one more substituents independently selected from halogen, -O-C1-6 alkyl, -O- C1-6 haloalkyl, -NH2, -NO2, =O, -CN, C3-10 carbocycle, and 3- to 10-membered heterocycle. WSGR Docket No.58296-711601 [0083] In some embodiments, for the compound or salt of Formula
Figure imgf000042_0001
selected
Figure imgf000042_0002
WSGR Docket No.58296-711601
Figure imgf000043_0001
. [0084] In some embodiments, for the compound or salt of Formula (I), R3 is selected from: hydrogen, -C(O)R13, -S(O)2R13, and -CN; C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, -C(O)R13, - C(O)N(R13)2, -C(O)OR13, -N(R13)C(O)R13, -NO2, and -CN; and C3-6 carbocycle and 3- to 6- membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, -C(O)R13, -C(O)N(R13)2, -C(O)OR13, - N(R13)C(O)R13, -NO2, and -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected halogen, -OR13, -N(R13)2, -C(O)R13, - C(O)N(R13)2, -C(O)OR13, -N(R13)C(O)R13, -NO2, and -CN; and R13 is selected from hydrogen and C1-6 alkyl optionally substituted with one more substituents independently selected from halogen, -O-C1-6 alkyl, -O-C1-6 haloalkyl, -NH2, -NO2, =O, -CN, C3-10 carbocycle, and 3- to 10- membered heterocycle. In some embodiments, R3 is selected from: hydrogen, -C(O)R13, -CN, and -S(O)2R13; C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, -C(O)N(R13)2, -N(R13)C(O)R13, -NO2, and -CN; and 5- to 6-membered heteroaryl optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, -C(O)R13, -NO2, and -CN; and R13 is selected from hydrogen and C1-6 alkyl optionally substituted with one more substituents independently selected from halogen, -O-C1-6 alkyl, -O-C1-6 haloalkyl, -NH2, -NO2, =O, -CN, C3-10 carbocycle, and 3- to 10-membered heterocycle. In some embodiments, R3 is selected from: hydrogen, -C(O)R13, -CN, and -S(O)2R13; and R13 is selected from hydrogen and C1-6 alkyl optionally substituted with one more substituents independently selected from halogen, -O-C1-6 alkyl, -O-C1-6 haloalkyl, -NH2, - NO2, =O, -CN, C3-10 carbocycle, and 3- to 10-membered heterocycle. In some embodiments, R3 is selected from: C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, -C(O)N(R13)2, -N(R13)C(O)R13, -NO2, and -CN; and R13 is selected from hydrogen and C1-6 alkyl optionally substituted with one more substituents independently selected from halogen, -O-C1-6 alkyl, -O-C1-6 haloalkyl, -NH2, -NO2, =O, -CN, C3- 10 carbocycle, and 3- to 10-membered heterocycle. In some embodiments, R3 is selected from: 5- to 6-membered heteroaryl optionally substituted with one or more substituents independently WSGR Docket No.58296-711601 selected from halogen, -OR13, -N(R13)2, -C(O)R13, -NO2, and -CN; and R13 is selected from hydrogen and C1-6 alkyl optionally substituted with one more substituents independently selected from halogen, -O-C1-6 alkyl, -O-C1-6 haloalkyl, -NH2, -NO2, =O, -CN, C3-10 carbocycle, and 3- to 10-membered heterocycle. In some embodiments, R3 is hydrogen. In some embodiments, R3 is C1-6 alkyl. In some embodiments, R3 is 5- to 6-membered heteroaryl. In some embodiments, R3
Figure imgf000044_0001
is selected from hydrogen, , -CN, methyl, ethyl, -S(O2)CH3, , and
Figure imgf000044_0002
. [0085] In some embodiments, for the compound or salt of Formula (I), R4 is selected from: C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, - OR14, -SR14, -N(R14)2, -C(O)R14, -C(O)N(R14)2, -C(O)OR14, -OC(O)R14, -N(R14)C(O)R14, - N(R14)C(O)OR14, -N(R14)S(O)2R14, -S(O)2N(R14)2, -S(O)R14, -S(O)2R14, -NO2, =O, =S, =N(R14), -CN, C3-6 carbocycle and 3- to 6-membered heterocycle, the C3-6 carbocycle and 3- to 6- membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OR14, -SR14, -N(R14)2, -C(O)R14, - C(O)N(R14)2, -C(O)OR14, -OC(O)R14, -N(R14)C(O)R14, -N(R14)C(O)OR14, -N(R14)S(O)2R14, - S(O)2N(R14)2, -S(O)R14, -S(O)2R14, -NO2, =O, =S, =N(R14), -CN, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkyl-OR14, C1-6 alkyl-C3-6 carbocycle, and C1-6 alkyl-C3-6 heterocycle; and R14 is independently selected at each occurrence from hydrogen, C1-6 alkyl, C1-6 haloalkyl, C3-10 carbocycle and 3- to 10-membered heterocycle. In some embodiments, R4 is selected from: C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR14, -N(R14)2, -C(O)R14, -C(O)N(R14)2, -C(O)OR14, -NO2, -CN, C3-6 carbocycle and 3- to 6-membered heterocycle, the C3-6 carbocycle and 3- to 6-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OR14, -N(R14)2, -C(O)R14, -C(O)N(R14)2, -C(O)OR14, -NO2, -CN, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkyl-OR14, C1-6 alkyl-C3-6 carbocycle, and C1-6 alkyl-C3-6 heterocycle; and R14 is independently selected at each occurrence from hydrogen, C1-6 alkyl, C1-6 haloalkyl, C3-10 carbocycle and 3- to 10-membered heterocycle. In some embodiments, R4 is selected from: C1-6 alkyl optionally substituted with one or more substituents independently selected from -OR14, -C(O)R14, C3-6 carbocycle and 3- to 6- membered heterocycle, the C3-6 carbocycle and 3- to 6-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OR14, -N(R14)2, -C(O)R14, -C(O)N(R14)2, -C(O)OR14, -NO2, -CN, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkyl- WSGR Docket No.58296-711601 OR14, C1-6 alkyl-C3-6 carbocycle, and C1-6 alkyl-C3-6 heterocycle; and R14 is independently selected at each occurrence from hydrogen, C1-6 alkyl, C1-6 haloalkyl, C3-10 carbocycle and 3- to 10-membered heterocycle. In some embodiments, R4 is selected from: C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR14, -N(R14)2, -C(O)R14, -C(O)N(R14)2, -C(O)OR14, -NO2, and -CN; and R14 is independently selected at each occurrence from hydrogen, C1-6 alkyl, C1-6 haloalkyl, C3-10 carbocycle and 3- to 10-membered heterocycle. In some embodiments, R4 is C1-6 alkyl substituted with one substituent selected from C3-6 carbocycle and 3- to 6-membered heterocycle, the C3-6 carbocycle and 3- to 6-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OR14, -N(R14)2, -C(O)R14, -C(O)N(R14)2, -C(O)OR14, -NO2, -CN, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkyl-OR14, C1-6 alkyl-C3-6 carbocycle, and C1-6 alkyl-C3-6 heterocycle; and R14 is independently selected at each occurrence from hydrogen, C1-6 alkyl, C1-6 haloalkyl, C3-10 carbocycle and 3- to 10-membered heterocycle. In some embodiments, R4 is C1-6 alkyl. In some embodiments, R4 is selected from: methyl, ethyl, propyl, isopropyl,
Figure imgf000045_0001
,
Figure imgf000045_0002
[0086] In some embodiments, for the compound or salt of Formula (I), R4 is selected from: C3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR14, -SR14, -N(R14)2, -C(O)R14, - C(O)N(R14)2, -C(O)OR14, -OC(O)R14, -N(R14)C(O)R14, -N(R14)C(O)OR14, -N(R14)S(O)2R14, - S(O)2N(R14)2, -S(O)R14, -S(O)2R14, -NO2, =O, =S, =N(R14), -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR14, -SR14, - N(R14)2, -C(O)R14, -C(O)N(R14)2, -C(O)OR14, -OC(O)R14, -N(R14)C(O)R14, -N(R14)C(O)OR14, - N(R14)S(O)2R14, -S(O)2N(R14)2, -S(O)R14, -S(O)2R14, -NO2, =O, =S, =N(R14), and -CN; and R14 is independently selected at each occurrence from hydrogen, C1-6 alkyl, C1-6 haloalkyl, C3-10 WSGR Docket No.58296-711601 carbocycle and 3- to 10-membered heterocycle. In some embodiments, R4 is selected from: C3-6 monocyclic carbocycle and C5-8 bridged carbocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR14, -SR14, -N(R14)2, -C(O)R14, -C(O)N(R14)2, -C(O)OR14, -OC(O)R14, -N(R14)C(O)R14, -N(R14)C(O)OR14, -N(R14)S(O)2R14, - S(O)2N(R14)2, -S(O)R14, -S(O)2R14, -NO2, =O, =S, =N(R14), -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR14, -SR14, - N(R14)2, -C(O)R14, -C(O)N(R14)2, -C(O)OR14, -OC(O)R14, -N(R14)C(O)R14, -N(R14)C(O)OR14, - N(R14)S(O)2R14, -S(O)2N(R14)2, -S(O)R14, -S(O)2R14, -NO2, =O, =S, =N(R14), and -CN; and R14 is independently selected at each occurrence from hydrogen, C1-6 alkyl, C1-6 haloalkyl, C3-10 carbocycle and 3- to 10-membered heterocycle. In some embodiments, R4 is selected from: C3-6 monocyclic carbocycle that is optionally substituted with one or more substituents independently selected from halogen, -OR14, -SR14, -N(R14)2, -C(O)R14, -C(O)N(R14)2, -C(O)OR14, -OC(O)R14, -N(R14)C(O)R14, -N(R14)C(O)OR14, -N(R14)S(O)2R14, -S(O)2N(R14)2, -S(O)R14, -S(O)2R14, -NO2, =O, =S, =N(R14), -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR14, -SR14, -N(R14)2, -C(O)R14, -C(O)N(R14)2, - C(O)OR14, -OC(O)R14, -N(R14)C(O)R14, -N(R14)C(O)OR14, -N(R14)S(O)2R14, -S(O)2N(R14)2, - S(O)R14, -S(O)2R14, -NO2, =O, =S, =N(R14), and -CN; and R14 is independently selected at each occurrence from hydrogen, C1-6 alkyl, C1-6 haloalkyl, C3-10 carbocycle and 3- to 10-membered heterocycle. In some embodiments, R4 is selected from: C5-8 bridged carbocycle that is optionally substituted with one or more substituents independently selected from halogen, -OR14, -SR14, - N(R14)2, -C(O)R14, -C(O)N(R14)2, -C(O)OR14, -OC(O)R14, -N(R14)C(O)R14, -N(R14)C(O)OR14, - N(R14)S(O)2R14, -S(O)2N(R14)2, -S(O)R14, -S(O)2R14, -NO2, =O, =S, =N(R14), -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, - OR14, -SR14, -N(R14)2, -C(O)R14, -C(O)N(R14)2, -C(O)OR14, -OC(O)R14, -N(R14)C(O)R14, - N(R14)C(O)OR14, -N(R14)S(O)2R14, -S(O)2N(R14)2, -S(O)R14, -S(O)2R14, -NO2, =O, =S, =N(R14), and -CN; and R14 is independently selected at each occurrence from hydrogen, C1-6 alkyl, C1-6 haloalkyl, C3-10 carbocycle and 3- to 10-membered heterocycle. In some embodiments, R4 is selected from: C3-6 monocyclic carbocycle and C5-8 bridged carbocycle, each of which is substituted with one or more substituents independently selected from halogen, -OR14, -SR14, - N(R14)2, -C(O)R14, -C(O)N(R14)2, -C(O)OR14, -OC(O)R14, -N(R14)C(O)R14, -N(R14)C(O)OR14, - N(R14)S(O)2R14, -S(O)2N(R14)2, -S(O)R14, -S(O)2R14, -NO2, =O, =S, =N(R14), -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, - OR14, -SR14, -N(R14)2, -C(O)R14, -C(O)N(R14)2, -C(O)OR14, -OC(O)R14, -N(R14)C(O)R14, - N(R14)C(O)OR14, -N(R14)S(O)2R14, -S(O)2N(R14)2, -S(O)R14, -S(O)2R14, -NO2, =O, =S, =N(R14), WSGR Docket No.58296-711601 and -CN; and R14 is independently selected at each occurrence from hydrogen, C1-6 alkyl, C1-6 haloalkyl, C3-10 carbocycle and 3- to 10-membered heterocycle. In some embodiments, R4 is selected from: C3-6 monocyclic carbocycle and C5-8 bridged carbocycle. In some embodiments, R4 is selected from: cyclobutyl, phenyl, and bicyclo[1.1.1]pentanyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR14, -SR14, - N(R14)2, -C(O)R14, -C(O)N(R14)2, -C(O)OR14, -OC(O)R14, -N(R14)C(O)R14, -N(R14)C(O)OR14, - N(R14)S(O)2R14, -S(O)2N(R14)2, -S(O)R14, -S(O)2R14, -NO2, =O, =S, =N(R14), -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, - OR14, -SR14, -N(R14)2, -C(O)R14, -C(O)N(R14)2, -C(O)OR14, -OC(O)R14, -N(R14)C(O)R14, - N(R14)C(O)OR14, -N(R14)S(O)2R14, -S(O)2N(R14)2, -S(O)R14, -S(O)2R14, -NO2, =O, =S, =N(R14), and -CN; and R14 is independently selected at each occurrence from hydrogen, C1-6 alkyl, C1-6 haloalkyl, C3-10 carbocycle and 3- to 10-membered heterocycle. In some embodiments, R4 is selected from: cyclobutyl, phenyl, and bicyclo[1.1.1]pentanyl, each of which is substituted with one or more substituents independently selected from halogen, -OR14, -SR14, -N(R14)2, -C(O)R14, -C(O)N(R14)2, -C(O)OR14, -OC(O)R14, -N(R14)C(O)R14, -N(R14)C(O)OR14, -N(R14)S(O)2R14, - S(O)2N(R14)2, -S(O)R14, -S(O)2R14, -NO2, =O, =S, =N(R14), -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR14, -SR14, - N(R14)2, -C(O)R14, -C(O)N(R14)2, -C(O)OR14, -OC(O)R14, -N(R14)C(O)R14, -N(R14)C(O)OR14, - N(R14)S(O)2R14, -S(O)2N(R14)2, -S(O)R14, -S(O)2R14, -NO2, =O, =S, =N(R14), and -CN; and R14 is independently selected at each occurrence from hydrogen, C1-6 alkyl, C1-6 haloalkyl, C3-10 carbocycle and 3- to 10-membered heterocycle. In some embodiments, R4 is selected from: cyclobutyl, phenyl, and bicyclo[1.1.1]pentanyl. In some embodiments, R4 is selected from:
Figure imgf000047_0001
[0087] In some embodiments, for the compound or salt of Formula (I), R4 is selected from: 3- to 6-membered monocyclic heterocycle and 8- to 10-membered fused heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR14, -SR14, -N(R14)2, -C(O)R14, -C(O)N(R14)2, -C(O)OR14, -OC(O)R14, -N(R14)C(O)R14, - N(R14)C(O)OR14, -N(R14)S(O)2R14, -S(O)2N(R14)2, -S(O)R14, -S(O)2R14, -NO2, =O, =S, =N(R14), -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR14, -SR14, -N(R14)2, -C(O)R14, -C(O)N(R14)2, -C(O)OR14, -OC(O)R14, -N(R14)C(O)R14, -N(R14)C(O)OR14, -N(R14)S(O)2R14, -S(O)2N(R14)2, -S(O)R14, -S(O)2R14, -NO2, WSGR Docket No.58296-711601 =O, =S, =N(R14), and -CN; and R14 is independently selected at each occurrence from hydrogen, C1-6 alkyl, C1-6 haloalkyl, C3-10 carbocycle and 3- to 10-membered heterocycle. In some embodiments, R4 is selected from: 3- to 6-membered monocyclic heterocycle and 8- to 10- membered fused heterocycle. In some embodiments, R4 is selected from: oxetanyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, 6,7-dihydro-5H-cyclopenta[b]pyridinyl, and 2,3-dihydro- [1,4]dioxino[2,3-b]pyridinyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR14, -SR14, -N(R14)2, -C(O)R14, - C(O)N(R14)2, -C(O)OR14, -OC(O)R14, -N(R14)C(O)R14, -N(R14)C(O)OR14, -N(R14)S(O)2R14, - S(O)2N(R14)2, -S(O)R14, -S(O)2R14, -NO2, =O, =S, =N(R14), -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR14, -SR14, - N(R14)2, -C(O)R14, -C(O)N(R14)2, -C(O)OR14, -OC(O)R14, -N(R14)C(O)R14, -N(R14)C(O)OR14, - N(R14)S(O)2R14, -S(O)2N(R14)2, -S(O)R14, -S(O)2R14, -NO2, =O, =S, =N(R14), and -CN; and R14 is independently selected at each occurrence from hydrogen, C1-6 alkyl, C1-6 haloalkyl, C3-10 carbocycle and 3- to 10-membered heterocycle. In some embodiments, R4 is selected from: oxetanyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, 6,7-dihydro-5H- cyclopenta[b]pyridinyl, and 2,3-dihydro-[1,4]dioxino[2,3-b]pyridinyl. In some embodiments, R4
Figure imgf000048_0001
[0088] In some embodiments, for the compound or salt of Formula (I), R3 and R4 come together with the atoms to which they are each bound to form a 4- to 6-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR15, -SR15, - N(R15)2, -C(O)R15, -C(O)N(R15)2, -C(O)OR15, -OC(O)R15, -N(R15)C(O)R15, -N(R15)C(O)OR15, - N(R15)S(O)2R15, -S(O)2N(R15)2, -S(O)R15, -S(O)2R15, -NO2, =O, =S, =N(R15), and -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, - OR15, -SR15, -N(R15)2, -C(O)R15, -C(O)N(R15)2, -C(O)OR15, -OC(O)R15, -N(R15)C(O)R15, - N(R15)C(O)OR15, -N(R15)S(O)2R15, -S(O)2N(R15)2, -S(O)R15, -S(O)2R15, -NO2, =O, =S, =N(R15), and -CN. In some embodiments, R3 and R4 come together with the atoms to which they are each bound to form a 4- to 6-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR15, -N(R15)2, -C(O)R15, -C(O)N(R15)2, - WSGR Docket No.58296-711601 NO2, =O, and -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR15, -N(R15)2, -C(O)R15, -C(O)N(R15)2, -NO2, =O, and -CN; and R15 is independently selected at each occurrence from hydrogen, C1-6 alkyl, and C1- 6 haloalkyl. In some embodiments, R3 and R4 come together with the atoms to which they are each bound to form a 4- to 6-membered heterocycle. In some embodiments, when R3 and R4 come together with the atoms to which they are each bound to form a 4- to 6-membered heterocycle,
Figure imgf000049_0001
[0089] In some embodiments, for the compound or salt of Formula (I), Ring A is 8- to 10-membered heterocycle; X1 is selected from N and C(H); n is selected from 0, 1, and 2; each R1 is independently selected at each occurrence from: halogen, -OR11, -SR11, -N(R11)2, -C(O)R11, -C(O)N(R11)2, -C(O)OR11, -OC(O)R11, -N(R11)C(O)R11, -N(R11)C(O)OR11, -N(R11)S(O)2R11, -S(O)2N(R11)2, -S(O)R11, - S(O)2R11, -NO2, =S, =N(R11), and -CN; C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR11, -SR11, - N(R11)2, -C(O)R11, -C(O)N(R11)2, -C(O)OR11, -OC(O)R11, -N(R11)C(O)R11, -
Figure imgf000049_0002
is 3- to 6-membered heterocycloalkyl; m is selected from 0, 1, and 2; each R2 is independently selected at each occurrence from: halogen, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)N(R12)2, -C(O)OR12, -OC(O)R12, -N(R12)C(O)R12, -N(R12)C(O)OR12, -N(R12)S(O)2R12, -S(O)2N(R12)2, -S(O)R12, - S(O)2R12, -NO2, =O, =S, =N(R12), and -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)N(R12)2, -C(O)OR12, - OC(O)R12, -N(R12)C(O)R12, -N(R12)C(O)OR12, -N(R12)S(O)2R12, -S(O)2N(R12)2, - S(O)R12, -S(O)2R12, -NO2, =O, =S, =N(R12), and -CN; R3 is hydrogen; and WSGR Docket No.58296-711601 R4 is selected from: C1-3 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR14, -SR14, -N(R14)2, -C(O)R14, -C(O)N(R14)2, -C(O)OR14, - OC(O)R14, -N(R14)C(O)R14, -N(R14)C(O)OR14, -N(R14)S(O)2R14, -S(O)2N(R14)2, - S(O)R14, -S(O)2R14, -NO2, =O, =S, =N(R14), and -CN; and C3-6 carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR14, - SR14, -N(R14)2, -C(O)R14, -C(O)N(R14)2, -C(O)OR14, -OC(O)R14, -N(R14)C(O)R14, - N(R14)C(O)OR14, -N(R14)S(O)2R14, -S(O)2N(R14)2, -S(O)R14, -S(O)2R14, -NO2, =O, =S, =N(R14), -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR14, -SR14, -N(R14)2, -C(O)R14, -C(O)N(R14)2, - C(O)OR14, -OC(O)R14, -N(R14)C(O)R14, -N(R14)C(O)OR14, -N(R14)S(O)2R14, - S(O)2N(R14)2, -S(O)R14, -S(O)2R14, -NO2, =O, =S, =N(R14), and -CN. [0090] In some embodiments, for the compound or salt of Formula (I), Ring A is indolyl; X1 is selected from N and C(H); n is selected from 0, 1, and 2; each R1 is independently selected at each occurrence from: halogen, -OR11, -SR11, -N(R11)2, -C(O)R11, -C(O)N(R11)2, -C(O)OR11, -OC(O)R11, -N(R11)C(O)R11, -N(R11)C(O)OR11, -N(R11)S(O)2R11, -S(O)2N(R11)2, -S(O)R11, - S(O)2R11, -NO2, =S, =N(R11), and -CN; C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR11, -SR11, -
Figure imgf000050_0001
Figure imgf000050_0002
selected from azetindyl and pyrrolidinyl; m is selected from 0, 1, and 2; each R2 is independently selected at each occurrence from: halogen, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)N(R12)2, -C(O)OR12, -OC(O)R12, -N(R12)C(O)R12, -N(R12)C(O)OR12, -N(R12)S(O)2R12, -S(O)2N(R12)2, -S(O)R12, - S(O)2R12, -NO2, =O, =S, =N(R12), and -CN; and WSGR Docket No.58296-711601 C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)N(R12)2, -C(O)OR12, - OC(O)R12, -N(R12)C(O)R12, -N(R12)C(O)OR12, -N(R12)S(O)2R12, -S(O)2N(R12)2, - S(O)R12, -S(O)2R12, -NO2, =O, =S, =N(R12), and -CN; R3 is hydrogen; and R4 is selected from: C1-3 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR14, -SR14, -N(R14)2, -C(O)R14, -C(O)N(R14)2, -C(O)OR14, - OC(O)R14, -N(R14)C(O)R14, -N(R14)C(O)OR14, -N(R14)S(O)2R14, -S(O)2N(R14)2, - S(O)R14, -S(O)2R14, -NO2, =O, =S, =N(R14), and -CN; and C3-6 carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR14, - SR14, -N(R14)2, -C(O)R14, -C(O)N(R14)2, -C(O)OR14, -OC(O)R14, -N(R14)C(O)R14, - N(R14)C(O)OR14, -N(R14)S(O)2R14, -S(O)2N(R14)2, -S(O)R14, -S(O)2R14, -NO2, =O, =S, =N(R14), -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR14, -SR14, -N(R14)2, -C(O)R14, -C(O)N(R14)2, - C(O)OR14, -OC(O)R14, -N(R14)C(O)R14, -N(R14)C(O)OR14, -N(R14)S(O)2R14, - S(O)2N(R14)2, -S(O)R14, -S(O)2R14, -NO2, =O, =S, =N(R14), and -CN. [0091] In some aspects, Formula (I) is represented by the structure of Formula (I-a):
Figure imgf000051_0001
or a pharmaceutically acceptable salt thereof, wherein each of A1, A2, A3, and A4 are independently selected at each occurrence from C(R1), C(H), and N; RA is halogen or hydrogen; and X1, R1, R2, R3, R4, m, and are as defined in Formula (I). WSGR Docket No.58296-711601 [0092] In some aspects, Formula (I) or Formula (I-a) is represented by the structure of Formula (I-b):
Figure imgf000052_0001
or a pharmaceutically acceptable salt thereof, wherein each of A1, A2, A3, and A4 are independently selected at each occurrence from C(R1), C(H), and N; RA is halogen or hydrogen; and
Figure imgf000052_0002
are as defined in Formula (I). [0093] In some aspects, Formula (I), Formula (I-a), or Formula (I-b) is represented by the structure of Formula (I-c):
Figure imgf000052_0003
or a pharmaceutically acceptable salt thereof, wherein each of A1, A2, A3, and A4 are independently selected at each occurrence from C(R1), C(H), and N; q is 1 or 2; RA is halogen or hydrogen; and X1, R1, R2, R4, and m are as defined in Formula (I). In some embodiments, each R2 is independently selected at each occurrence from -OH, -F, -CN, methyl, -O-(methyl), and fluoromethyl. WSGR Docket No.58296-711601 [0094] In some aspects, Formula (I), Formula (I-a), Formula (I-b), or Formula (I-c) is represented by the structure of Formula (I-d):
Figure imgf000053_0001
or a pharmaceutically acceptable salt thereof, wherein each of A1 and A4 are independently selected at each occurrence from C(R1), C(H), and N; n is 0 or 1 or 2; q is 1 or 2; RA is halogen or hydrogen; and X1, R1, R2, R4, and m are as defined in Formula (I). In some embodiments, each R2 is independently selected at each occurrence from -OH, -F, -CN, methyl, -O-(methyl), and fluoromethyl. [0095] In some aspects, Formula (I), Formula (I-a), Formula (I-b), Formula (I-c), or Formula (I- d) is represented by the structure of Formula (I-e):
Figure imgf000053_0002
or a pharmaceutically acceptable salt thereof, wherein each of A1 and A4 are independently selected at each occurrence from C(R1), C(H), and N; n is 0 or 1 or 2; q is 1 or 2; RA is halogen or hydrogen; and X1, R1, R2, R4, and m are as defined in Formula (I). In some embodiments, each R2 is independently selected at each occurrence from -OH, -F, -CN, methyl, -O-(methyl), and fluoromethyl. In some embodiments, R4 is selected from methyl, ethyl, and 5- to 10-membered heteroaryl. WSGR Docket No.58296-711601 [0096] In some embodiments, for the compound or salt of Formula (I), Formula (I-a), Formula (I-b), Formula (I-c), Formula (I-d), or Formula (I-e), Ring A is selected from:
Figure imgf000054_0001
[0097] In some embodiments, for the compound or salt of Formula (I), Formula (I-a), Formula (I-b), Formula (I-c), Formula (I-d), or Formula (I-e),
Figure imgf000054_0002
is selected from: WSGR Docket No.58296-711601
Figure imgf000055_0001
[0098] In some embodiments, for the compound or salt of Formula (I), the compound is a compound displayed in Table 1, or a pharmaceutically acceptable salt thereof. [0099] In certain embodiments, the present disclosure provides a compound of Formula (II):
Figure imgf000055_0002
or a pharmaceutically acceptable salt thereof, wherein: X2 is N, C(H), or C(R8); each R8 is independently selected from halogen, -OR20, -SR20, -N(R20)2, -C(O)R20, - C(O)N(R20)2, -C(O)OR20, -OC(O)R20, -N(R20)C(O)R20, -N(R20)C(O)OR20, -N(R20)S(O)2R20, - S(O)2N(R20)2, -NO2, and -CN; WSGR Docket No.58296-711601 z is selected from 1 and 2; R20 is independently selected at each occurrence from: hydrogen; C1-6 alkyl optionally substituted with one more substituents independently selected from halogen, -O-C1-6 alkyl, -O-C1-6 haloalkyl, -NH2, -NO2, =O, -CN, C3-10 carbocycle and 3- to 10-membered heterocycle, wherein each C3-10 carbocycle, and 3- to 10-membered heterocycle are optionally substituted with one or more substituents independently selected from: halogen, -OH, -O-C1-6 alkyl, -O-C1-6 haloalkyl, -NH2, -NO2, =O, and -CN; and C3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OH, -O- C1-6 alkyl, -O-C1-6 haloalkyl, -NH2, -NO2, =O, and -CN; and Ring A, R1, R2, R3, R4, n, m, and are as defined in Formula (I). [0100] In certain embodiments, the present disclosure provides a compound of Formula (III):
Figure imgf000056_0001
or a pharmaceutically acceptable salt thereof, wherein: X3 is N, C(H), or C(R38); each R38 is independently selected from halogen, -OR40, -SR40, -N(R40)2, -C(O)R40, - C(O)N(R40)2, -C(O)OR40, -OC(O)R40, -N(R40)C(O)R40, -N(R40)C(O)OR40, -N(R20)S(O)2R40, - S(O)2N(R40)2, -NO2, and -CN; y is selected from 0, 1, and 2; Z is 5- to 10-membered heteroaryl, 3- to 15-membered carbocycle, or -N(R36)2, wherein the 5- to 10-membered heteroaryl or 3- to 12-membered carbocycle are each optionally substituted with 1, 2, 3, or 4 occurrences of R32; Ring C is 3- to 12-membered heterocycle; each R31 is independently selected at each occurrence from: WSGR Docket No.58296-711601 halogen, -OR41, -SR41, -N(R41)2, -C(O)R41, -C(O)N(R41)2, -C(O)OR41, -OC(O)R41, -N(R41)C(O)R41, -N(R41)C(O)OR41, -N(R41)S(O)2R41, -S(O)2N(R41)2, -S(O)R41, - S(O)2R41, -NO2, , =S, =N(R41), and -CN; C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR41, -SR41, - N(R41)2, -C(O)R41, -C(O)N(R41)2, -C(O)OR41, -OC(O)R41, -N(R41)C(O)R41, - N(R41)C(O)OR41, -N(R41)S(O)2R41, -S(O)2N(R41)2, -S(O)R41, -S(O)2R41, -NO2, , =O, =S, =N(R41), and -CN; and C3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR41, - SR41, -N(R41)2, -C(O)R41, -C(O)N(R41)2, -C(O)OR41, -OC(O)R41, -N(R41)C(O)R41, - N(R41)C(O)OR41, -N(R41)S(O)2R41, -S(O)2N(R41)2, -S(O)R41, -S(O)2R41, -NO2, , =O, =S, =N(R41), and -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR41, -SR41, -N(R41)2, -C(O)R41, - C(O)N(R41)2, -C(O)OR41, -OC(O)R41, -N(R41)C(O)R41, -N(R41)C(O)OR41, - N(R41)S(O)2R41, -S(O)2N(R41)2, -S(O)R41, -S(O)2R41, -NO2, , =O, =S, =N(R41), and -CN; each R32 is independently selected at each occurrence from: halogen, -OR42, -SR42, -N(R42)2, -C(O)R42, -C(O)N(R42)2, -C(O)OR42, -OC(O)R42, -N(R42)C(O)R42, -N(R42)C(O)OR42, -N(R42)S(O)2R42, -S(O)2N(R42)2, -S(O)R42, - S(O)2R42, -NO2, =O, =S, =N(R42), and -CN; C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR42, -SR42, -N(R42)2, -C(O)R42, -C(O)N(R42)2, -C(O)OR42, - OC(O)R42, -N(R42)C(O)R42, -N(R42)C(O)OR42, -N(R42)S(O)2R42, -S(O)2N(R42)2, - S(O)R42, -S(O)2R42, -NO2, =O, =S, =N(R42), and -CN; and C3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR42, - SR42, -N(R42)2, -C(O)R42, -C(O)N(R42)2, -C(O)OR42, -OC(O)R42, -N(R42)C(O)R42, - N(R42)C(O)OR42, -N(R42)S(O)2R42, -S(O)2N(R42)2, -S(O)R42, -S(O)2R42, -NO2, =O, =S, =N(R42), and -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected halogen, -OR42, -SR42, -N(R42)2, -C(O)R42, - C(O)N(R42)2, -C(O)OR42, -OC(O)R42, -N(R42)C(O)R42, -N(R42)C(O)OR42, - N(R42)S(O)2R42, -S(O)2N(R42)2, -S(O)R42, -S(O)2R42, -NO2, =O, =S, =N(R42), and -CN; R33 is selected from: hydrogen, -C(O)R43, -S(O)2R43, and -CN; WSGR Docket No.58296-711601 C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR43, -SR43, -N(R43)2, -C(O)R43, -C(O)N(R43)2, -C(O)OR43, - OC(O)R43, -N(R43)C(O)R43, -N(R43)C(O)OR43, -N(R43)S(O)2R43, -S(O)2N(R43)2, - S(O)R43, -S(O)2R43, -NO2, =O, =S, =N(R43), and -CN; and C3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR43, - SR43, -N(R43)2, -C(O)R43, -C(O)N(R43)2, -C(O)OR43, -OC(O)R43, -N(R43)C(O)R43, - N(R43)C(O)OR43, -N(R43)S(O)2R43, -S(O)2N(R43)2, -S(O)R43, -S(O)2R43, -NO2, =O, =S, =N(R43), and -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected halogen, -OR43, -SR43, -N(R43)2, -C(O)R43, - C(O)N(R43)2, -C(O)OR43, -OC(O)R43, -N(R43)C(O)R43, -N(R43)C(O)OR43, - N(R43)S(O)2R43, -S(O)2N(R43)2, -S(O)R43, -S(O)2R43, -NO2, =O, =S, =N(R43), and -CN; R34 is selected from: C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR44, -SR44, -N(R44)2, -C(O)R44, -C(O)N(R44)2, -C(O)OR44, - OC(O)R44, -N(R44)C(O)R44, -N(R44)C(O)OR44, -N(R44)S(O)2R44, -S(O)2N(R44)2, - S(O)R44, -S(O)2R44, -NO2, =O, =S, =N(R44), -CN, C3-6 carbocycle and 3- to 6-membered heterocycle, the C3-6 carbocycle and 3- to 6-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OR44, - SR44, -N(R44)2, -C(O)R44, -C(O)N(R44)2, -C(O)OR44, -OC(O)R44, -N(R44)C(O)R44, - N(R44)C(O)OR44, -N(R44)S(O)2R44, -S(O)2N(R44)2, -S(O)R44, -S(O)2R44, -NO2, =O, =S, =N(R44), -CN, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkyl-OR44, C1-6 alkyl-C3-6 carbocycle, and C1-6 alkyl-C3-6 heterocycle ; and C3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR44, - SR44, -N(R44)2, -C(O)R44, -C(O)N(R44)2, -C(O)OR44, -OC(O)R44, -N(R44)C(O)R44, - N(R44)C(O)OR44, -N(R44)S(O)2R44, -S(O)2N(R44)2, -S(O)R44, -S(O)2R44, -NO2, =O, =S, =N(R44), -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR44, -SR44, -N(R44)2, -C(O)R44, - C(O)N(R44)2, -C(O)OR44, -OC(O)R44, -N(R44)C(O)R44, -N(R44)C(O)OR44, - N(R44)S(O)2R44, -S(O)2N(R44)2, -S(O)R44, -S(O)2R44, -NO2, =O, =S, =N(R44), -CN; or R33 and R34 come together with the atoms to which they are each bound to form a 4- to 6- membered heterocycle optionally substituted with one or more substituents independently selected from: WSGR Docket No.58296-711601 halogen, -OR45, -SR45, -N(R45)2, -C(O)R45, -C(O)N(R45)2, -C(O)OR45, -OC(O)R45, -N(R45)C(O)R45, -N(R45)C(O)OR45, -N(R45)S(O)2R45, -S(O)2N(R45)2, -S(O)R45, - S(O)2R45, -NO2, =O, =S, =N(R45), and -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR45, -SR45, -N(R45)2, -C(O)R45, -C(O)N(R45)2, -C(O)OR45, - OC(O)R45, -N(R45)C(O)R45, -N(R45)C(O)OR45, -N(R45)S(O)2R45, -S(O)2N(R45)2, - S(O)R45, -S(O)2R45, -NO2, =O, =S, =N(R45), and -CN; each R36 is independently selected at each occurrence from: hydrogen; C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR46, -SR46, -N(R46)2, -C(O)R46, -C(O)N(R46)2, -C(O)OR46, - OC(O)R46, -N(R46)C(O)R46, -N(R46)C(O)OR46, -N(R46)S(O)2R46, -S(O)2N(R46)2, - S(O)R46, -S(O)2R46, -NO2, =O, =S, =N(R46), and -CN; and C3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR46, - SR46, -N(R46)2, -C(O)R46, -C(O)N(R46)2, -C(O)OR46, -OC(O)R46, -N(R46)C(O)R46, - N(R46)C(O)OR46, -N(R46)S(O)2R46, -S(O)2N(R46)2, -S(O)R46, -S(O)2R46, -NO2, =O, =S, =N(R46), and -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected halogen, -OR46, -SR46, -N(R46)2, -C(O)R46, - C(O)N(R46)2, -C(O)OR46, -OC(O)R46, -N(R46)C(O)R46, -N(R46)C(O)OR46, - N(R46)S(O)2R46, -S(O)2N(R46)2, -S(O)R46, -S(O)2R46, -NO2, =O, =S, =N(R46), and -CN; R40, R41, R42, R43, R44, R45, and R46 are each independently selected at each occurrence from: hydrogen; C1-6 alkyl optionally substituted with one more substituents independently selected from halogen, -O-C1-6 alkyl, -O-C1-6 haloalkyl, -NH2, -NO2, =O, -CN, -S(O)2OH, -S-C1-6 alkyl, -S(O)-C1-6 alkyl, -S(O)2-C1-6 alkyl, -P(O)(OH)2, -P(-C1-6 alkyl)2, -P(-C1-6 alkyl)(-O-C1-6 alkyl) -P(-O-(C1-6 alkyl))2, -P(=O)(-C1-6 alkyl)2, -P(=O)(-C1-6 alkyl)(-O- (C1-6 alkyl), -P(O)(-O-(C1-6 alkyl))2, C3-10 carbocycle and 3- to 10-membered heterocycle, wherein each C3-10 carbocycle, and 3- to 10-membered heterocycle are optionally substituted with one or more substituents independently selected from: halogen, -OH, -O- C1-6 alkyl, -O-C1-6 haloalkyl, -NH2, -NO2, =O, and -CN; and C3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OH, -O- C1-6 alkyl, -O-C1-6 haloalkyl, -NH2, -NO2, =O, and -CN; and WSGR Docket No.58296-711601 [0101] n is selected from 0, 1, 2, 3, and 4.While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby. [0102] Chemical entities having carbon-carbon double bonds or carbon-nitrogen double bonds may exist in Z- or E- form (or cis- or trans- form). Furthermore, some chemical entities may exist in various tautomeric forms. Unless otherwise specified, compounds or salts of Formula (I), are intended to include all Z-, E- and tautomeric forms as well. [0103] “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. WSGR Docket No.58296-711601 [0104] The compounds or salts for Formula (I), herein may in some cases exist as diastereomers, enantiomers, or other stereoisomeric forms. The compounds presented herein include all diastereomeric, enantiomeric, and epimeric forms as well as the racemates, mixtures of diastereomers, and other mixtures thereof, to the extent they can be made by one of ordinary skill in the art by routine experimentation. Separation of stereoisomers may be performed by chromatography or by forming diastereomers and separating by recrystallization, or chromatography, or any combination thereof. (Jean Jacques, Andre Collet, Samuel H. Wilen, “Enantiomers, Racemates and Resolutions”, John Wiley And Sons, Inc., 1981, herein incorporated by reference for this disclosure). Stereoisomers may also be obtained by stereoselective synthesis. 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. [0105] In certain embodiments, compounds or salts for Formula (I), 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. For example, a single stereoisomer, e.g., an enantiomer, substantially free of its stereoisomer may be obtained by resolution of the racemic mixture using a method such as formation of diastereomers using optically active resolving agents (Stereochemistry of Carbon Compounds, (1962) by E. L. Eliel, McGraw Hill; Lochmuller (1975) J. Chromatogr., 113(3): 283-302). Racemic mixtures of chiral compounds can be separated and isolated by any suitable method, including, but not limited to: (1) formation of ionic, diastereomeric salts with chiral compounds and separation by fractional crystallization or other methods, (2) formation of diastereomeric compounds with chiral derivatizing reagents, separation of the diastereomers, and conversion to the pure stereoisomers, and (3) separation of the substantially pure or enriched stereoisomers directly under chiral conditions. Another approach for separation of the enantiomers is to use a Diacel chiral column and elution using an organic mobile phase such as done by Chiral Technologies (www.chiraltech.com) on a fee for service basis. [0106] 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. In certain embodiments, the compounds or salts for Formula (I), exist as tautomers. In circumstances where tautomerization is possible, a chemical equilibrium of the tautomers may exist. The exact ratio of the tautomers depends on WSGR Docket No.58296-711601 several factors, including physical state, temperature, solvent, and pH. Some non–limiting
Figure imgf000062_0001
[0107] The compounds disclosed herein, in some embodiments, are used in different enriched isotopic forms, e.g., enriched in the content of 2H, 3H, 11C, 13C and/or 14C. In one particular embodiment, the compound is deuterated in at least one position. Such deuterated forms can be made by the procedure described in U.S. Patent Nos.5,846,514 and 6,334,997. As 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. [0108] In certain embodiments, the compounds disclosed herein have some or all of the 1H atoms replaced with 2H atoms. The methods of synthesis for deuterium-containing compounds are known in the art and include, by way of non-limiting example only, the following synthetic methods. [0109] 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. [0110] Deuterated starting materials are readily available and are subjected to the synthetic methods described herein to provide for the synthesis of deuterium-containing compounds. WSGR Docket No.58296-711601 Large numbers of deuterium-containing reagents and building blocks are available commercially from chemical vendors, such as Aldrich Chemical Co. [0111] Unless otherwise stated, 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 13C- or 14C-enriched carbon are within the scope of the present disclosure. [0112] The compounds of the present disclosure optionally contain unnatural proportions of atomic isotopes at one or more atoms that constitute such compounds. For example, the compounds may be labeled with isotopes, such as for example, deuterium (2H), tritium (3H), iodine-125 (125I) or carbon-14 (14C). Isotopic substitution with 2H, 11C, 13C, 14C, 15C, 12N, 13N, 15N, 16N, 16O, 17O, 14F, 15F, 16F, 17F, 18F, 33S, 34S, 35S, 36S, 35Cl, 37Cl, 79Br, 81Br, and 125I are all contemplated. All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention. [0113] Included in the present disclosure are salts, particularly pharmaceutically acceptable salts, of the compounds of Formula (I). 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. Alternatively, compounds that are inherently charged, such as those with a quaternary nitrogen, can form a salt with an appropriate counterion, e.g., a halide such as bromide, chloride, or fluoride, particularly bromide. [0114] The methods and compositions of Formula (I), include the use of amorphous forms as well as crystalline forms (also known as polymorphs). The compounds described herein may be in the form of pharmaceutically acceptable salts. As well, in some embodiments, active metabolites of these compounds having the same type of activity are included in the scope of the present disclosure. In addition, the compounds described herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. The solvated forms of the compounds presented herein are also considered to be disclosed herein. [0115] Compounds of Formula (I), also include crystalline and amorphous forms of those compounds, pharmaceutically acceptable salts, and active metabolites of these compounds having the same type of activity, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of the compounds, as well as mixtures thereof. WSGR Docket No.58296-711601 [0116] In certain embodiments, compounds or salts of Formula (I), may be prodrugs, e.g., wherein a hydroxyl in the parent compound is presented as an ester or a carbonate, or carboxylic acid present in the parent compound is presented as an ester. The term “prodrug” is intended to encompass compounds which, under physiologic conditions, are converted into pharmaceutical agents of the present disclosure. One method for making a prodrug is to include one or more selected moieties which are hydrolyzed under physiologic conditions to reveal the desired molecule. In other embodiments, the prodrug is converted by an enzymatic activity of the host animal such as specific target cells in the host animal. For example, esters or carbonates (e.g., esters or carbonates of alcohols or carboxylic acids and esters of phosphonic acids) are preferred prodrugs of the present disclosure. [0117] Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent is not. Prodrugs may help enhance the cell permeability of a compound relative to the parent drug. The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug. Prodrugs may be designed as reversible drug derivatives, for use as modifiers to enhance drug transport to site-specific tissues or to increase drug residence inside of a cell. [0118] In certain embodiments, the prodrug may be converted, e.g., enzymatically or chemically, to the parent compound under the conditions within a cell. In certain embodiments, the parent compound comprises an acidic moiety, e.g., resulting from the hydrolysis of the prodrug, which may be charged under the conditions within the cell. In particular embodiments, the prodrug is converted to the parent compound once it has passed through the cell membrane into a cell. In certain embodiments, the parent compound has diminished cell membrane permeability properties relative to the prodrug, such as decreased lipophilicity and increased hydrophilicity. [0119] In some embodiments, the design of a prodrug increases the lipophilicity of the pharmaceutical agent. In some embodiments, the design of a prodrug increases the effective water solubility. See, e.g., Fedorak et al., Am. J. Physiol., 269:G210-218 (1995); McLoed et al., Gastroenterol, 106:405-413 (1994); Hochhaus et al., Biomed. Chrom., 6:283-286 (1992); J. Larsen and H. Bundgaard, Int. J. Pharmaceutics, 37, 87 (1987); J. Larsen et al., Int. J. Pharmaceutics, 47, 103 (1988); Sinkula et al., J. Pharm. Sci., 64:181-210 (1975); T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol.14 of the A.C.S. Symposium Series; and Edward B. Roche, Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, all incorporated herein for such disclosure). According to another embodiment, the present disclosure provides methods of producing the above-defined WSGR Docket No.58296-711601 compounds. The compounds may be synthesized using conventional techniques. Advantageously, these compounds are conveniently synthesized from readily available starting materials. [0120] Synthetic chemistry transformations and methodologies useful in synthesizing the compounds described herein are known in the art and include, for example, those described in R. Larock, Comprehensive Organic Transformations (1989); T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2d. Ed. (1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis (1995). Pharmaceutical Formulations [0121] In some aspects, the present disclosure provides a pharmaceutical composition comprising a compound or salt of Formula (I) and at least one pharmaceutically acceptable excipient. [0122] Pharmaceutical compositions can be formulated using one or more physiologically- acceptable carriers comprising excipients and auxiliaries. Formulation can be modified depending upon the route of administration chosen. Pharmaceutical compositions comprising a compound, salt or conjugate can be manufactured, for example, by lyophilizing the compound, salt or conjugate, mixing, dissolving, emulsifying, encapsulating or entrapping the conjugate. The pharmaceutical compositions can also include the compounds, salts or conjugates in a free- base form or pharmaceutically-acceptable salt form. [0123] Methods for formulation of the conjugates can include formulating any of the compounds, salts or conjugates with one or more inert, pharmaceutically-acceptable excipients or carriers to form a solid, semi-solid, or liquid composition. Solid compositions can include, for example, powders, tablets, dispersible granules and capsules, and in some aspects, the solid compositions further contain nontoxic, auxiliary substances, for example wetting or emulsifying agents, pH buffering agents, and other pharmaceutically-acceptable additives. Alternatively, the compounds, salts or conjugates can be lyophilized or in powder form for re-constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use. [0124] Pharmaceutical compositions can comprise at least one active ingredient (e.g., a compound, salt or conjugate). The active ingredients can be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization (e.g., hydroxymethylcellulose or gelatin microcapsules and poly-(methylmethacylate) microcapsules, WSGR Docket No.58296-711601 respectively), in colloidal drug-delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules) or in macroemulsions. [0125] Pharmaceutical compositions as often further can comprise more than one active compound (e.g., a compound, salt or conjugate and other agents) as necessary for the particular indication being treated. The active compounds can have complementary activities that do not adversely affect each other. For example, the composition can also comprise a chemotherapeutic agent, cytotoxic agent, cytokine, growth-inhibitory agent, anti-hormonal agent, anti-angiogenic agent, and/or cardioprotectant. Such molecules can be present in combination in amounts that are effective for the purpose intended. [0126] The compositions and formulations can be sterilized. Sterilization can be accomplished by filtration through sterile filtration. [0127] The compositions can be formulated for administration as an injection. Non-limiting examples of formulations for injection can include a sterile suspension, solution or emulsion in oily or aqueous vehicles. Suitable oily vehicles can include, but are not limited to, lipophilic solvents or vehicles such as fatty oils or synthetic fatty acid esters, or liposomes. Aqueous injection suspensions can contain substances which increase the viscosity of the suspension. The suspension can also contain suitable stabilizers. Injections can be formulated for bolus injection or continuous infusion. Alternatively, the compositions can be lyophilized or in powder form for reconstitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use. [0128] For parenteral administration, the compounds, salts or conjugates can be formulated in a unit dosage injectable form (e.g., solution, suspension, emulsion) in association with a pharmaceutically acceptable parenteral vehicle. Such vehicles can be inherently non-toxic, and non-therapeutic. Vehicles can be water, saline, Ringer’s solution, dextrose solution, and 5% human serum albumin. Non-aqueous vehicles such as fixed oils and ethyl oleate can also be used. Liposomes can be used as carriers. The vehicle can contain minor amounts of additives such as substances that enhance isotonicity and chemical stability (e.g., buffers and preservatives). [0129] Sustained-release preparations can also be prepared. Examples of sustained-release preparations can include semipermeable matrices of solid hydrophobic polymers that can contain the compound, salt or conjugate, and these matrices can be in the form of shaped articles (e.g., films or microcapsules). Examples of sustained-release matrices can include polyesters, hydrogels (e.g., poly(2-hydroxyethyl-methacrylate), or poly (vinyl alcohol)), polylactides, copolymers of L-glutamic acid and γ ethyl-L-glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as the LUPRON DEPOTM (i.e., injectable WSGR Docket No.58296-711601 microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), and poly- D-( –)-3-hydroxybutyric acid. [0130] Pharmaceutical formulations can be prepared for storage by mixing a compound, salt or conjugate with a pharmaceutically acceptable carrier, excipient, and/or a stabilizer. This formulation can be a lyophilized formulation or an aqueous solution. Acceptable carriers, excipients, and/or stabilizers can be nontoxic to recipients at the dosages and concentrations used. Acceptable carriers, excipients, and/or stabilizers can include buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives, polypeptides; proteins, such as serum albumin or gelatin; hydrophilic polymers; amino acids; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counter-ions such as sodium; metal complexes; and/or non- ionic surfactants or polyethylene glycol. [0131] A compound or salt of any one of Formula (I) may be formulated in any suitable pharmaceutical formulation. A pharmaceutical formulation of the present disclosure typically contains an active ingredient (e.g., compound or salt of any one of Formula (I)), 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. [0132] In certain embodiments, a compound or salt of Formula (I) is formulated with a chelating agent or other material capable of binding metal ions, such as ethylene diamine tetra acetic acid (EDTA) and its salts are capable of enhancing the stability of a compound or salt of Formula (I). [0133] Pharmaceutical formulations may be provided in any suitable form, which may depend on the route of administration. In some embodiments, the pharmaceutical composition disclosed herein can be formulated in dosage form for administration to a subject. In some embodiments, the pharmaceutical composition is formulated for oral, intravenous, intraarterial, aerosol, parenteral, buccal, topical, transdermal, rectal, intramuscular, subcutaneous, intraosseous, intranasal, intrapulmonary, transmucosal, inhalation, and/or intraperitoneal administration. In some embodiments, the dosage form is formulated for oral administration. For example, the pharmaceutical composition can be formulated in the form of a pill, a tablet, a capsule, an inhaler, a liquid suspension, a liquid emulsion, a gel, or a powder. In some embodiments, the pharmaceutical composition can be formulated as a unit dosage in liquid, gel, semi-liquid, semi- solid, or solid form. WSGR Docket No.58296-711601 [0134] The amount of compound or salt of any one of Formula (I) will be dependent on the mammal being treated, the severity of the disorder or condition, the rate of administration, the disposition of the compound or salt of any one of Formula (I) and the discretion of the prescribing physician. [0135] In some embodiments, the disclosure provides a pharmaceutical composition for oral administration containing at least one compound or salt of any one of Formula (I) and a pharmaceutical excipient suitable for oral administration. The composition may be in the form of a solid, liquid, gel, semi-liquid, or semi-solid. In some embodiments, the composition further comprises a second agent. [0136] Pharmaceutical compositions of the disclosure suitable for oral administration can be presented as discrete dosage forms, such as hard or soft capsules, cachets, troches, lozenges, or tablets, or liquids or aerosol sprays each containing a predetermined amount of an active ingredient as a powder or in granules, a solution, or a suspension in an aqueous or non-aqueous liquid, an oil-in-water emulsion, or a water-in-oil liquid emulsion, or dispersible powders or granules, or syrups or elixirs. Such dosage forms can be prepared by any of the methods of pharmacy, which typically include the step of bringing the active ingredient(s) into association with the carrier. In general, the composition are prepared by uniformly and intimately admixing the active ingredient(s) with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation. For example, a tablet can be prepared by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing in a suitable machine the active ingredient(s) in a free-flowing form such as powder or granules, optionally mixed with an excipient such as, but not limited to, a binder, a lubricant, an inert diluent, and/or a surface active or dispersing agent. Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound or salt of any one of Formula (I) moistened with an inert liquid diluent. [0137] In some embodiments, the disclosure provides a pharmaceutical composition for injection containing a compound or salt of any one of Formula (I) disclosed herein and a pharmaceutical excipient suitable for injection. Components and amounts of agents in the composition are as described herein. [0138] In certain embodiments, the compound or salt of any one of Formula (I) may be formulated for injection as aqueous or oil suspensions, emulsions, with sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueous solution, and similar pharmaceutical vehicles. WSGR Docket No.58296-711601 [0139] Aqueous solutions in saline are also conventionally used for injection. Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, and the like (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils may also be employed. The proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, for the maintenance of the required particle size in the case of dispersion and by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. [0140] Pharmaceutical compositions may also be prepared from a compound or salt of any one of Formula (I) and one or more pharmaceutically acceptable excipients suitable for transdermal, inhalative, sublingual, buccal, rectal, intraosseous, intraocular, intranasal, epidural, or intraspinal administration. Preparations for such pharmaceutical composition are well-known in the art. See, e.g., Anderson, Philip O.; Knoben, James E.; Troutman, William G, eds., Handbook of Clinical Drug Data, Tenth Edition, McGraw-Hill, 2002; Pratt and Taylor, eds., Principles of Drug Action, Third Edition, Churchill Livingston, New York, 1990; Katzung, ed., Basic and Clinical Pharmacology, Ninth Edition, McGraw Hill, 2003; Goodman and Gilman, eds., The Pharmacological Basis of Therapeutics, Tenth Edition, McGraw Hill, 2001; Remingtons Pharmaceutical Sciences, 20th Ed., Lippincott Williams & Wilkins., 2000; Martindale, The Extra Pharmacopoeia, Thirty-Second Edition (The Pharmaceutical Press, London, 1999). Methods of Treatment [0141] The compounds described herein can be used in the preparation of medicaments for the prevention or treatment of diseases or conditions. In addition, 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. [0142] 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. Amounts effective for this use will depend on the severity and course of the disease or condition, previous therapy, the patient's health status, weight, and response to the drugs, and the judgment of the treating physician. WSGR Docket No.58296-711601 [0143] In prophylactic applications, compositions containing the compounds described herein are administered to a patient susceptible to or otherwise at risk of a particular disease, disorder or condition. Such an amount is defined to be a "prophylactically effective amount or dose." In this use, the precise amounts also depend on the patient's state of health, weight, and the like. When used in a patient, effective amounts for this use will depend on the severity and course of the disease, disorder or condition, previous therapy, the patient's health status and response to the drugs, and the judgment of the treating physician. [0144] In some aspects, 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). [0145] In certain aspects, the present disclosure provides a method of modulating of N- glycosylation. In some embodiments, the method of modulating of N-glycosylation comprises administering to a subject in need thereof an effective amount of a compound or salt of Formula (I). [0146] In certain aspects, the present disclosure provides a method of inhibiting N- glycosylation. In some embodiments, the method of inhibiting N-glycosylation comprises administering to a subject in need thereof an effective amount of a compound or salt of Formula (I). [0147] In certain embodiments, the present disclosure can be used as a method of modulating STT3 in a subject in need thereof, comprising administering to the subject: a compound of Formula (I) or a pharmaceutically acceptable salt thereof; or a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. [0148] In certain embodiments, the present disclosure can be used as a method of inhibiting STT3 in a subject in need thereof, comprising administering to the subject: a compound of Formula (I) or a pharmaceutically acceptable salt thereof; or a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. [0149] In certain embodiments, the present disclosure can be used as a method of modulating replication of a respiratory virus in a subject in need thereof, comprising administering to the subject: a compound of Formula (I) or a pharmaceutically acceptable salt thereof; or a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In some embodiments, the WSGR Docket No.58296-711601 respiratory virus is selected from influenza virus, a rhinovirus, a coronavirus, a metapneumovirus, an adenovirus, a syncytial virus, a bocaviruses, and a parainfluenza virus. [0150] In certain embodiments, the present disclosure can be used as a method of inhibiting replication of a respiratory virus in a subject in need thereof, comprising administering to the subject: a compound of Formula (I) or a pharmaceutically acceptable salt thereof; or a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In some embodiments, the respiratory virus is selected from influenza virus, a rhinovirus, a coronavirus, a metapneumovirus, an adenovirus, a syncytial virus, a bocaviruses, and a parainfluenza virus. [0151] In certain embodiments, the present disclosure can be used as a method of treating a respiratory virus in a subject in need thereof (e.g., treating a subject infected by a respiratory virus), comprising administering to the subject: a compound of Formula (I) or a pharmaceutically acceptable salt thereof; or a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In some embodiments, the respiratory virus is selected from influenza virus, a rhinovirus, a coronavirus, a metapneumovirus, an adenovirus, a syncytial virus, a bocaviruses, and a parainfluenza virus. [0152] In certain embodiments, the present disclosure can be used as a method of treating cancer in a subject in need thereof, comprising administering to the subject: a compound of Formula (I) or a pharmaceutically acceptable salt thereof; or a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In some embodiments, the method of treating cancer in a subject in need thereof leads to modulation of STT3 in the subject. In some embodiments, the method of treating cancer in a subject in need thereof comprises inhibition of N-glycosylation in the subject. N-glycosylation is a common post-translational modification in eukaryotic cells, which is essential for the proper folding, stability, and function of many secreted proteins. N- glycosylation in humans is mediated exclusively by the oligosaccharyltransferase (OST) complex which catalyzes the transfer of glycans onto the asparagine residues of sequons (N-X- S/T) on nascent glycoproteins. Dysregulation of N- glycosylation has been implicated in various diseases, including cancer (Hu, M.; Zhang, R.; Yang, J.; Zhao, C.; Liu, W.; Huang, Y.; Lyu, H.; Xiao, S.; Guo, D.; Zhou, C.; Tang, J. The role of N-glycosylation modification in the pathogenesis of liver cancer. Cell Death Dis.2023, 14, doi.org/10.1038/s41419-023-05733-z) and neurodegenerative disorders (Pradeep, P.; Kang, H.; Lee, B. Glycosylation and behavioral WSGR Docket No.58296-711601 symptoms in neurological disorders. Transl. Psychiatry 2023, doi.org/10.1038/s41398-023- 02446-x). EXAMPLES [0153] The invention now being generally described, it will be more readily understood by reference to the following examples which are included merely for purposes of illustration of certain aspects and embodiments of the present invention, and are not intended to limit the invention in any way. [0154] The following synthetic schemes are provided for purposes of illustration, not limitation. The following examples illustrate the various methods of making compounds described herein. It is understood that one skilled in the art may be able to make these compounds by similar methods or by combining other methods known to one skilled in the art. It is also understood that one skilled in the art would be able to make, in a similar manner as described below by using the appropriate starting materials and modifying the synthetic route as needed. In general, starting materials and reagents can be obtained from commercial vendors or synthesized according to sources known to those skilled in the art or prepared as described herein. [0155] Examples 1-32 show general and exemplary procedures for the preparation of some embodiments of the claimed compounds of Formula (I). [0156] Example 33 shows how exemplary compounds of the disclosure were prepared. [0157] Example 34 shows how exemplary compounds of the disclosure are effective at modulating (e.g., inhibiting) N-glycosylation activity.
WSGR Docket No.58296-711601 Example 1. General Scheme – Synthesis of Compounds (1 and 2)
Figure imgf000073_0001
WSGR Docket No.58296-711601 Example 2. Exemplary Scheme – Synthesis of Compounds (1 and 2)
Figure imgf000074_0001
Figure imgf000074_0003
Step 1: Preparation of (3-bromo-4-fluorophenyl)(cyclopropyl)sulfane
Figure imgf000074_0002
[0158] To a solution of 3-bromo-4-fluorobenzenethiol (4 g, 19.32 mmol) in 1,2-Dichloroethane (40 mL) were added copper (II) acetate (3.51 g, 19.32 mmol), cyclopropylboronic acid (2.489 g, 29.0 mmol), 2,2'-bipyridine (3.02 g, 19.32 mmol) and Cs2CO3 (6.29 g, 19.32 mmol). The mixture was stirred at 70 °C for 12 hours. The reaction mixture was concentrated to give a residue. The residue was purified by column chromatography to give (3-bromo-4- fluorophenyl)(cyclopropyl)sulfane (4.2 g, 12.00 mmol, 62.1 % yield) as yellow oil. WSGR Docket No.58296-711601 Step 2: Preparation of 3-bromo-4-fluorophenyl)(cyclopropyl)(imino)-l6-sulfanone
Figure imgf000075_0001
[0159] To a solution of (3-bromo-4-fluorophenyl)(cyclopropyl)sulfane (3.2 g, 12.95 mmol) and ammonium carbonate (3.2 g, 33.3 mmol) in dichloromethane (10 mL) and methanol (20 mL) was added PhI(OAc)2 (14 g, 43.5 mmol). The mixture was stirred at 20 °C for 1 hour. The reaction mixture was concentrated to give a residue. The residue was purified by column chromatography to give (3-bromo-4-fluorophenyl)(cyclopropyl)(imino)-l6-sulfanone (3 g, 9.70 mmol, 74.9 % yield) as yellow oil. LC-MS: m/z [M+H]+ 277.9, [M+H+2]+ 279.9 Step 3: Preparation of tert-butyl 2-(5-(cyclopropanesulfonimidoyl)-2-fluorophenyl)-1H-indole-1- carboxylate
Figure imgf000075_0002
[0160] To a solution of (3-bromo-4-fluorophenyl)(cyclopropyl)(imino)-l6-sulfanone (1g, 3.60 mmol) in water (1 mL) and 1,4-dioxane (10 mL) were added (1-(tert-butoxycarbonyl)-1H-indol- 2-yl)boronic acid (1.033 g, 3.95 mmol), PdCl2(dppf)-CH2Cl2 adduct (0.147 g, 0.180 mmol) and K2CO3 (1.491 g, 10.79 mmol) under N2. The mixture was stirred at 80 °C for 12 hours under N2. The reaction mixture was concentrated under pressure to give a residue. The residue was purified by column chromatography to give tert-butyl 2-(5-(cyclopropanesulfonimidoyl)-2- fluorophenyl)-1H-indole-1-carboxylate (1.2g, 2.83 mmol, 79 % yield) as yellow oil. LC-MS: m/z [M+H]+ 415.2 WSGR Docket No.58296-711601 Step 4: Preparation of cyclopropyl(4-((S)-3-hydroxypyrrolidin-1-yl)-3-(1H-indol-2- yl)phenyl)(imino)-l6-sulfanone
Figure imgf000076_0001
[0161] A solution of tert-butyl 2-(5-(cyclopropanesulfonimidoyl)-2-fluorophenyl)-1H-indole-1- carboxylate (700 mg, 1.689 mmol), (S)-pyrrolidin-3-ol (441 mg, 5.07 mmol) and potassium carbonate (700 mg, 5.07 mmol) in dimethyl sulfoxide (10 mL) was stirred at 90 °C for 12 hours. The reaction mixture was filtered to give filtrate. The filtrate was purified by prep-HPLC to give cyclopropyl(4-((S)-3-hydroxypyrrolidin-1-yl)-3-(1H-indol-2-yl)phenyl)(imino)-l6-sulfanone (200 mg, 0.480 mmol, 28.4 % yield) as a white solid. LC-MS: m/z [M+H]+ 382.1 Step 5: Preparation of (S)-cyclopropyl(4-((S)-3-hydroxypyrrolidin-1-yl)-3-(1H-indol-2- yl)phenyl)(imino)-l6-sulfanone (1) and (R)-cyclopropyl(4-((S)-3-hydroxypyrrolidin-1-yl)-3-(1H- indol-2-yl)phenyl)(imino)-l6-sulfanone (2)
Figure imgf000076_0002
[0162] Cyclopropyl(4-((S)-3-hydroxypyrrolidin-1-yl)-3-(1H-indol-2-yl)phenyl)(imino)-l6- sulfanone (200 mg, 0.524 mmol) was separated by chiral SFC (Instrument: PREP-SFC-9; Column: ChiralPak IH, 250*30mm, 10um; Mobile phase: A for CO2 and B for MeOH(0.1%NH3H2O); Gradient: B%=27%~50% ; Flow rate: 70mL/min; Wavelength:220 nm; Column temperature: 35 degrees centigrade; System back pressure: 150 bar) to give cyclopropyl(4-((S)-3-hydroxypyrrolidin-1-yl)-3-(1H-indol-2-yl)phenyl)(imino)-l6-sulfanone, isomer 1 (65.8 mg, 0.172 mmol, 32.9 % yield) (first eluted peak) as a white solid and WSGR Docket No.58296-711601 cyclopropyl(4-((S)-3-hydroxypyrrolidin-1-yl)-3-(1H-indol-2-yl)phenyl)(imino)-l6-sulfanone, isomer 2 (63.9 mg, 0.167 mmol, 32.0 % yield) (second eluted peak) as a white solid. LC-MS: m/z [M+H]+ 382.1. Example 3. General Scheme – Synthesis of Compound (3)
Figure imgf000077_0001
Example 4. Exemplary Scheme – Synthesis of Compound
Figure imgf000077_0003
Figure imgf000077_0002
Step 1: Preparation of ethyl(4-((S)-3-hydroxypyrrolidin-1-yl)-3-(1H-indol-2-yl)phenyl)(imino)- l6-sulfanone
Figure imgf000077_0004
[0163] To a solution of (S)-pyrrolidin-3-ol (0.346 g, 3.98 mmol) and tert-butyl 2-(5- (ethylsulfonimidoyl)-2-fluorophenyl)-1H-indole-1-carboxylate (0.8 g, 1.988 mmol) in Dimethyl Sulfoxide (8 mL) was added K2CO3 (1.099 g, 7.95 mmol), then the mixture was stirred at 100 °C for 24 hours. The mixture was diluted with H2O (10 mL) and the aqueous phase was extracted with EtOAc (10 mL*3). The combined organic layers were dried over anhydrous Na2SO4, WSGR Docket No.58296-711601 filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue The residue was purified by column chromatography to give ethyl(4-((S)-3-hydroxypyrrolidin-1- yl)-3-(1H-indol-2-yl)phenyl)(imino)-l6-sulfanone (870 mg, 1.586 mmol, 80 % yield) as yellow oil. LC-MS: m/z [M+H]+ 370.3 Step 2: Preparation of (3-(3-chloro-1H-indol-2-yl)-4-((S)-3-hydroxypyrrolidin-1-
Figure imgf000078_0001
[0164] To a solution of ethyl(4-((S)-3-hydroxypyrrolidin-1-yl)-3-(1H-indol-2-yl)phenyl)(imino)- l6-sulfanone (200 mg, 0.363 mmol) in N,N-Dimethylformamide (DMF) (2 mL) was added NCS (N-chlorosuccinimide) (33.9 mg, 0.254 mmol) at 0 °C. The mixture was stirred at 20 °C for 1 hours. The reaction mixture was purified by prep-HPLC to give (3-(3-chloro-1H-indol-2-yl)-4- ((S)-3-hydroxypyrrolidin-1-yl)phenyl)(ethyl)(imino)-l6-sulfanone (32.3 mg, 0.080 mmol, 22.05 % yield) as a light-yellow solid. LC-MS: m/z [M+H]+=404.1.1H NMR (400 MHz, DMSO-d6) δ = 11.75 (s, 1H), 7.70 (dd, J = 2.4, 9.2 Hz, 1H), 7.61 (d, J = 2.4 Hz, 1H), 7.48 (d, J = 8.0 Hz, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.20 (dt, J = 1.2, 7.6 Hz, 1H), 7.17 - 7.11 (m, 1H), 6.94 (d, J = 8.8 Hz, 1H), 4.87 (d, J = 3.6 Hz, 1H), 4.15 (br d, J = 2.8 Hz, 1H), 3.87 (s, 1H), 3.30 - 3.22 (m, 1H), 3.15 (dt, J = 3.6, 8.8 Hz, 1H), 3.09 - 2.98 (m, 3H), 2.72 - 2.66 (m, 1H), 1.91 - 1.80 (m, 1H), 1.78 - 1.69 (m, 1H), 1.09 (t, J = 7.6 Hz, 3H).
WSGR Docket No.58296-711601 Example 5. General Scheme – Synthesis of Compound (4)
Figure imgf000079_0001
Example 6. Exemplary Scheme – Synthesis of Compound (4)
Figure imgf000079_0002
WSGR Docket No.58296-711601 Step 1: Preparation of tert-butyl 2-(2-fluoro-5-(N-methylcyclopropanesulfonimidoyl)phenyl)-1H- indole-1-carboxylate
Figure imgf000080_0001
[0165] To a solution of tert-butyl 2-(5-(cyclopropanesulfonimidoyl)-2-fluorophenyl)-1H-indole- 1-carboxylate (150 mg, 0.362 mmol) in 1,4-Dioxane (1 mL) were added Py (0.070 mL, 0.869 mmol) and Cu(OAc)2 (108 mg, 0.543 mmol) at 20 °C. After addition, the mixture was stirred at this temperature for 10 min, and then methylboronic acid (43.3 mg, 0.724 mmol) was added dropwise at 20 °C. The resulting mixture was stirred at 100 °C for 1 hour. The reaction mixture was quenched by addition H2O 3 mL at 25 °C, and then extracted with EtOAc (2 mL * 3). The combined organic layers were washed with brine (2 mL * 1), dried over Na2SO4, filtered and concentrated under reduced pressure to give a crude material. The crude material was purified by prep-TLC to give tert-butyl 2-(2-fluoro-5-(N-methylcyclopropanesulfonimidoyl)phenyl)-1H- indole-1-carboxylate (150 mg, 0.296 mmol, 82 % yield) as colorless oil. LC-MS: m/z [M+H]+ 429.2 Step 2: Preparation of tert-butyl cyclopropyl(4-((S)-3-hydroxypyrrolidin-1-yl)-3-(1H-indol-2- yl)phenyl)(methylimino)-l6-sulfanone: (4)
Figure imgf000080_0002
[0166] A solution of tert-butyl 2-(2-fluoro-5-(N-methylcyclopropanesulfonimidoyl)phenyl)-1H- indole-1-carboxylate (150 mg, 0.350 mmol), (S)-pyrrolidin-3-ol (91 mg, 1.050 mmol) and potassium carbonate (145 mg, 1.050 mmol) in Dimethyl Sulfoxide (1 mL) was stirred at 90 °C for 12 hours. The reaction mixture was filtered to give filtrate. The filtrate was purified by prep- HPLC to give cyclopropyl (4-((S)-3-hydroxypyrrolidin-1-yl)-3-(1H-indol-2-yl) phenyl) WSGR Docket No.58296-711601 (methylimino)-l6-sulfanone (22 mg, 0.056 mmol, 15.89 % yield) as a white solid. LC-MS: m/z [M+H] + 396.10, 394.05 [M-H]-.1H NMR (400 MHz, DMSO-d6) δ ppm 11.40 (br s, 1H), 7.50 - 7.60 (m, 3H), 7.36 (d, J = 8.0 Hz, 1H), 7.05 - 7.12 (m, 1H), 6.92 - 7.04 (m, 2H), 6.42 (s, 1H), 4.83 (t, J = 2.8 Hz, 1H), 4.16 (br d, J = 2.4 Hz, 1H), 3.26 - 3.31 (m, 1H), 3.08 - 3.22 (m, 2H), 2.72 - 2.84 (m, 1H), 2.57 - 2.67 (m, 1H), 2.52 (d, J = 7.2 Hz, 3H), 2.07 (s, 1H), 1.81 - 1.91 (m, 1H), 1.68 - 1.79 (m, 1H), 1.06 - 1.16 (m, 1H), 0.94 - 1.04 (m, 1H), 0.72 - 0.92 (m, 2H). Example 7. General Scheme – Synthesis of Compound (5)
Figure imgf000081_0001
Example 8. Exemplary Scheme – Synthesis of Compound (5)
Figure imgf000081_0002
Step 1: Preparation of tert-butyl 2-(5-(N-cyanocyclopropanesulfonimidoyl)-2-fluorophenyl)-1H- indole-1-carboxylate
Figure imgf000081_0003
[0167] To a solution of tert-butyl 2-(5-(cyclopropanesulfonimidoyl)-2-fluorophenyl)-1H-indole- 1-carboxylate (200 mg, 0.483 mmol) in Acetonitrile (6 mL) were added AIBN (119 mg, 0.724 WSGR Docket No.58296-711601 mmol), copper(I) iodide (18.38 mg, 0.097 mmol) and K2CO3 (133 mg, 0.965 mmol) at 25 °C. The resulting mixture was stirred at 75 °C for 12 hours under O2. The mixtures was diluted with H2O 5 mL, and extracted with EtOAc (5 mL * 2). The combined organic layers were washed with saturated NaCl solution (10 mL * 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by Prep-TLC to give tert-butyl 2- (5-(N-cyanocyclopropanesulfonimidoyl)-2-fluorophenyl)-1H-indole-1-carboxylate (250 mg, 0.469 mmol, 97 % yield) as a yellow solid. LC-MS: m/z [M+H-56]+ 384.1 Step 2: Preparation of N-(cyclopropyl(4-((S)-3-hydroxypyrrolidin-1-yl)-3-(1H-indol-2- yl)phenyl)(oxo)-l6-sulfaneylidene)cyanamide (5)
Figure imgf000082_0001
[0168] A solution of tert-butyl 2-(5-(N-cyanocyclopropanesulfonimidoyl)-2-fluorophenyl)- 1H-indole-1-carboxylate (200 mg, 0.455 mmol), (S)-pyrrolidin-3-ol (119 mg, 1.365 mmol) and potassium carbonate (252 mg, 1.820 mmol) in Dimethyl Sulfoxide (3 mL) was stirred at 100 °C for 12 hours. The reaction mixture was purified by prep-HPLC to give N-(cyclopropyl(4-((S)-3- hydroxypyrrolidin-1-yl)-3-(1H-indol-2-yl)phenyl)(oxo)-l6-sulfaneylidene)cyanamide (75 mg, 0.177 mmol, 38.8 % yield) as a white solid. LC-MS: m/z [M+H]+ 407.1.1H NMR (400 MHz, DMSO-d6) δ = 11.49 (s, 1H), 7.75 (dd, J = 2.4, 9.1 Hz, 1H), 7.70 (d, J = 2.4 Hz, 1H), 7.54 (d, J = 7.8 Hz, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.15 - 7.07 (m, 1H), 7.06 - 6.98 (m, 2H), 6.46 (s, 1H), 4.88 (t, J = 3.4 Hz, 1H), 4.17 (br s, 1H), 3.42 - 3.35 (m, 1H), 3.32 - 3.27 (m, 1H), 3.26 - 3.14 (m, 2H), 2.91 - 2.74 (m, 1H), 1.96 - 1.66 (m, 2H), 1.40 - 1.22 (m, 2H), 1.16 - 1.05 (m, 2H). WSGR Docket No.58296-711601 Example 9. General Scheme – Synthesis of Compounds (6, 7, 8, and 9)
Figure imgf000083_0001
WSGR Docket No.58296-711601 Example 10. Exemplary Scheme – Synthesis of Compounds (6, 7, 8, and 9)
Figure imgf000084_0001
Figure imgf000084_0002
Preparation of 3-((tert-butoxycarbonyl)amino)cyclobutyl 4-methylbenzenesulfonate [0169] To a solution of tert-butyl (3-hydroxycyclobutyl)carbamate (2 g, 10.68 mmol) in Dichloromethane (20 mL) were added pyridine (1.037 mL, 12.82 mmol) and 4- methylbenzenesulfonyl chloride (TsCl, TosCl) (2.240 g, 11.75 mmol) at 0 °C. The mixture was stirred at 15 °C for 12 hours. The reaction mixture was quenched by addition H2O 30mL, and WSGR Docket No.58296-711601 then extracted with EtOAc (20 mL * 3). The combined organic layers were washed with brine (15 mL * 1), dried over Na2SO4, filtered and concentrated under reduced pressure to give 3- ((tert-butoxycarbonyl)amino)cyclobutyl 4-methylbenzenesulfonate (4.94 g, 12.06 mmol, 113 % yield) as a green solid. This compound has no M/Z in LCMS. Step 1: Preparation of tert-butyl (3-((3-bromo-4-fluorophenyl)thio)cyclobutyl)carbamate
Figure imgf000085_0001
[0170] To a solution of 3-bromo-4-fluorobenzenethiol (4.4 g, 21.25 mmol) and NaOH (1.700 g, 42.5 mmol) in Methanol (40 mL) was added 3-((tert-butoxycarbonyl)amino)cyclobutyl 4- methylbenzenesulfonate (5.08 g, 14.87 mmol) at 15 °C. Then, the mixture was stirred at 60 °C for 12 hours. The reaction mixture was concentrated under reduced pressure to remove MeOH to give a residue. The residue was diluted with H2O 50 mL and extracted with EtOAc ( 50 mL * 3). The combined organic layers were washed with brine (20 mL * 1), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to give tert-butyl (3-((3-bromo-4- fluorophenyl)thio)cyclobutyl)carbamate (1.48 g, 3.60 mmol, 16.95 % yield) as a yellow solid. LC-MS: m/z [M+H-56]+ 320.0, 322.0 [M+2+H-56]+ Step 2: Preparation of tert-butyl (3-(3-bromo-4-fluorophenylsulfonimidoyl)cyclobutyl)carbamate
Figure imgf000085_0002
[0171] To a solution of tert-butyl (3-((3-bromo-4-fluorophenyl)thio)cyclobutyl)carbamate (1.48 g, 3.93 mmol) in Methanol (15 mL) and Dichloromethane (2.498 mL) were added PhI(OAC)2 (3.80 g, 11.80 mmol) and Ammonium carbonate (1.134 g, 11.80 mmol) at 20 °C. Then, the mixture was stirred at 20 °C for 12 hours. Some solids appeared in the reaction mixture. The solids were collected by filtration, then it was washed with DCM (5 mL x 3) and WSGR Docket No.58296-711601 dried under reduced pressure to give tert-butyl (3-(3-bromo-4- fluorophenylsulfonimidoyl)cyclobutyl)carbamate (940 mg, 2.212 mmol, 56.2 % yield) as a white solid. LC-MS: m/z [M+H]+ 407.0, 409.0 [M+2+H] + Step 3: Preparation of tert-butyl(3-(3-bromo-4-(3,3-difluoropyrrolidin-1- yl)phenylsulfonimidoyl)cyclobutyl)carbamate
Figure imgf000086_0001
[0172] To a solution of tert-butyl (3-(3-bromo-4- fluorophenylsulfonimidoyl)cyclobutyl)carbamate (910 mg, 2.234 mmol) in Dimethyl Sulfoxide (10 mL) were added 3,3-difluoropyrrolidine, Hydrochloride (3208 mg, 22.34 mmol) and DIEA (3.90 mL, 22.34 mmol). The mixture was stirred at 120 °C for 24 hours. The reaction mixture was diluted with water 50 mL and extracted with EtOAc (40 mL * 3). The combined organic layers were washed with brine (20 mL * 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to give tert-butyl (3-(3-bromo-4-(3,3-difluoropyrrolidin-1-yl)phenylsulfonimidoyl)cyclobutyl)carbamate (920 mg, 1.534 mmol, 68.6 % yield) as a yellow solid. LC-MS: m/z [M+H]+ 494.1496.1 [M+2+H] + Step 4: Preparation of tert-butyl 2-(5-(3-((tert-butoxycarbonyl)amino)cyclobutane-1- sulfonimidoyl)-2-(3,3-difluoropyrrolidin-1-yl)phenyl)-1H-indole-1-carboxylate
Figure imgf000086_0002
[0173] A mixture of tert-butyl (3-(3-bromo-4-(3,3-difluoropyrrolidin-1- yl)phenylsulfonimidoyl)cyclobutyl)carbamate (870 mg, 1.760 mmol), (1-(tert-butoxycarbonyl)- WSGR Docket No.58296-711601 1H-indol-2-yl)boronic acid (689 mg, 2.64 mmol), K2CO3 (730 mg, 5.28 mmol) and PdCl2(dppf)- CH2Cl2adduct (144 mg, 0.176 mmol) in 1,4-Dioxane (9 mL) and Water (0.900 mL) was degassed and purged with N2 for 3 times, and then the reaction mixture was stirred at 80 °C for 12 hours under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to remove 1,4-Dioxane to give a residue. The residue was purified by column chromatography to give tert-butyl 2-(5-(3-((tert-butoxycarbonyl)amino)cyclobutane-1-sulfonimidoyl)-2-(3,3- difluoropyrrolidin-1-yl)phenyl)-1H-indole-1-carboxylate (950 mg, 1.382 mmol, 79 % yield) as brown oil. LC-MS: m/z [M+H]+ 631.3. Step 5: Preparation of ((3-aminocyclobutyl)(4-(3,3-difluoropyrrolidin-1-yl)-3-(1H-indol-2- yl)phenyl)(imino)-l6-sulfanone (6)
Figure imgf000087_0001
[0174] To a solution of tert-butyl 2-(5-(3-((tert-butoxycarbonyl)amino)cyclobutane-1- sulfonimidoyl)-2-(3,3-difluoropyrrolidin-1-yl)phenyl)-1H-indole-1-carboxylate (900 mg, 1.427 mmol) in Ethyl acetate (4.5 mL) was added HCl (4.5 mL, 18.00 mmol). The mixture was stirred at 25 °C for 12 hours. Some solids appeared in the reaction mixture. The solids were collected by filtration, then it was washed with EtOAc (5 mL x 3) and dried under reduced pressure to provide ((3-aminocyclobutyl)(4-(3,3-difluoropyrrolidin-1-yl)-3-(1H-indol-2-yl)phenyl)(imino)- l6-sulfanone, Hydrochloride (1.06 g, 2.098 mmol, 147 % yield) as a purple solid. A part of the solid was purified by prep-HPLC give ((3-aminocyclobutyl)(4-(3,3-difluoropyrrolidin-1-yl)-3- (1H-indol-2-yl)phenyl)(imino)-l6-sulfanone (7 mg, 0.016 mmol, 18.98 % yield) as a white solid. LC-MS: m/z [M+H]+ 431.10, 429.10 [M-H]-.1H NMR (400 MHz, DMSO-d6) δ = 11.46 (s, 1H), 7.73 (d, J = 2.4 Hz, 1H), 7.67 (dd, J = 2.0, 8.4 Hz, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.14 - 6.98 (m, 3H), 6.54 (d, J = 1.2 Hz, 1H), 4.02 - 3.88 (m, 1H), 3.47 - 3.34 (m, 3H), 3.30 (br s, 2H), 3.16 - 3.04 (m, 1H), 2.46 - 2.31 (m, 3H), 2.31 - 2.14 (m, 2H), 2.01 - 1.87 (m, 3H). WSGR Docket No.58296-711601 Step 6: Preparation of (4-(3,3-difluoropyrrolidin-1-yl)-3-(1H-indol-2-yl)phenyl)(3- (dimethylamino)cyclobutyl)(imino)-l6-sulfanone (7)
Figure imgf000088_0001
[0175] To a solution of (3-aminocyclobutyl)(4-(3,3-difluoropyrrolidin-1-yl)-3-(1H-indol-2- yl)phenyl)(imino)-l6-sulfanone (500 mg, 1.071 mmol) in Methanol (5 mL) was added TEA (0.149 mL, 1.071 mmol). The mixture was stirred at 20 °C for 10 min. Then Acetic Acid (0.05 mL) and formaldehyde (0.319 mL, 4.28 mmol) were added to the mixture and the mixture was stirred at 20 °C for 30 min. Then sodium triacetoxyborohydride (340 mg, 1.606 mmol) was added to the mixture, the mixture was stirred at 20 °C for 2 hours. The reaction mixture was quenched by the addition of H2O (1 mL) to give a solution. The solution was purified by prep- HPLC to give (4-(3,3-difluoropyrrolidin-1-yl)-3-(1H-indol-2-yl)phenyl)(3- (dimethylamino)cyclobutyl)(imino)-l6-sulfanone (18.5 mg, 0.040 mmol, 3.77 % yield) as a white solid. LC-MS: m/z [M+H]+ 459.10, 457.10 [M-H]-.1H NMR (400 MHz, DMSO-d6) δ = 11.47 (s, 1H), 7.74 (d, J = 2.0 Hz, 1H), 7.69 (dd, J = 2.0, 8.8 Hz, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.14 - 6.99 (m, 3H), 6.55 (d, J = 1.2 Hz, 1H), 3.97 (s, 1H), 3.59 - 3.49 (m, 1H), 3.39 - 3.34 (m, 2H), 3.31 (br s, 2H), 2.54 (br s, 1H), 2.38 (tt, J = 7.2, 14.4 Hz, 2H), 2.15 - 2.01 (m, 4H), 1.98 (s, 6H).
WSGR Docket No.58296-711601 Step 7: Preparation of (4-(3,3-difluoropyrrolidin-1-yl)-3-(1H-indol-2-yl)phenyl)((3- (dimethylamino)cyclobutyl)(imino)-l6-sulfanone, isomer 1 (8) and (4-(3,3-difluoropyrrolidin-1- yl)-3-(1H-indol-2-yl)phenyl)((3-(dimethylamino)cyclobutyl)(imino)-l6-sulfanone, isomer 2 (9)
Figure imgf000089_0001
[0176] (4-(3,3-difluoropyrrolidin-1-yl)-3-(1H-indol-2-yl)phenyl)((3- (dimethylamino)cyclobutyl)(imino)-l6-sulfanone (40 mg, 0.087 mmol) was separated by chiral SFC Instrument: Waters SFC150AP Preparative SFC System; Column: DAICEL CHIRALPAK AD(250mm*30mm,10um); Mobile phase: A for CO2 and B for IPA(0.1% NH3H2O); Gradient: B%=40.00% isocratic elution mode; Flow rate: 70.00g/min; Monitor wavelength: 220&254nm; Column temperature: 40℃; System back pressure: 100 bar) to give (4-(3,3-difluoropyrrolidin-1- yl)-3-(1H-indol-2-yl)phenyl)((3-(dimethylamino)cyclobutyl)(imino)-l6-sulfanone, isomer 1 (12.8 mg, 0.028 mmol, 32.0 % yield) as a white solid and (4-(3,3-difluoropyrrolidin-1-yl)-3-(1H-indol- 2-yl)phenyl)((3-(dimethylamino)cyclobutyl)(imino)-l6-sulfanone, isomer 2 (6.1 mg, 0.013 mmol, 15.25 % yield) as a white solid. LC-MS: m/z [M+H]+ 459.15, 457.15 [M-H]-.1H NMR (400 MHz, DMSO-d6) δ = 11.47 (s, 1H), 7.74 (d, J = 2.4 Hz, 1H), 7.69 (dd, J = 2.4, 8.8 Hz, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.14 - 6.99 (m, 3H), 6.55 (d, J = 1.2 Hz, 1H), 4.13 - 3.87 (m, 1H), 3.60 - 3.48 (m, 1H), 3.42 - 3.33 (m, 3H), 3.31 (br s, 1H), 2.56 - 2.52 (m, 1H), 2.38 (tt, J = 7.2, 14.0 Hz, 2H), 2.17 - 2.04 (m, 4H), 1.99 (s, 6H).1H NMR (400 MHz, DMSO-d6) δ = 11.47 (s, 1H), 7.74 (d, J = 2.4 Hz, 1H), 7.69 (dd, J = 2.0, 8.8 Hz, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.14 - 6.99 (m, 3H), 6.55 (d, J = 1.2 Hz, 1H), 4.03 - 3.93 (m, 1H), 3.54 (quin, J = 8.8 Hz, 1H), 3.39 - 3.33 (m, 3H), 3.31 (br s, 1H), 2.53 - 2.51 (m, 1H), 2.38 (tt, J = 7.2, 14.4 Hz, 2H), 2.14 - 2.01 (m, 4H), 1.98 (s, 6H). WSGR Docket No.58296-711601 Example 11. General Scheme – Synthesis of Compounds (10 and 11)
Figure imgf000090_0001
Figure imgf000090_0002
Figure imgf000090_0003
Figure imgf000090_0004
Example 12. Exemplary Scheme – Synthesis of Compounds (10 and 11)
Figure imgf000090_0005
WSGR Docket No.58296-711601 Step 1: Preparation of tert-butyl (R)-2-(2-(3,3-difluoropyrrolidin-1-yl)-5- (ethylsulfonimidoyl)phenyl)-5-methoxy-1H-indole-1-carboxylate
Figure imgf000091_0001
[0177] To a solution of (R)-(3-bromo-4-(3,3-difluoropyrrolidin-1-yl)phenyl)(ethyl)(imino)- l6-sulfanone (500 mg, 1.416 mmol) in Water (1.000 mL) and 1,4-Dioxane (5 mL) were added (1-(tert-butoxycarbonyl)-5-methoxy-1H-indol-2-yl)boronic acid (618 mg, 2.123 mmol), PdCl2(dppf)-CH2Cl2adduct (116 mg, 0.142 mmol) and K2CO3 (587 mg, 4.25 mmol) under N2. The mixture was stirred at 80 °C for 12 hours. The reaction mixture was diluted with water 5 mL and extracted with EtOAc (5 mL * 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to give tert-butyl (R)-(2-(2-(3,3-difluoropyrrolidin-1-yl)-5- (ethylsulfonimidoyl)phenyl)-5-methoxy-1H-indole-1-carboxylate (750 mg, 1.261 mmol, 89 % yield) as brown oil. LC-MS: m/z [M+H]+ 520.2, 521.3 [M+2+H]+ Step 2: Preparation of (R)-(4-(3,3-difluoropyrrolidin-1-yl)-3-(5-methoxy-1H-indol-2- yl)phenyl)(ethyl)(imino)-l6-sulfanone (10)
Figure imgf000091_0002
[0178] A mixture of tert-butyl 2-(2-(3,3-difluoropyrrolidin-1-yl)-5- (ethylsulfonimidoyl)phenyl)-5-methoxy-1H-indole-1-carboxylate (750mg, 1.443 mmol) in HCl (10 mL, 40.0 mmol) was stirred at 15 °C for 1 hours. The reaction mixture was concentrated under reduced pressure to give (4-(3,3-difluoropyrrolidin-1-yl)-3-(5-methoxy-1H-indol-2- yl)phenyl)(ethyl)(imino)-l6-sulfanone (680 mg, 1.179 mmol, 82 % yield) as a brown solid. A part of solid was purified by prep-HPLC to give (R)-(4-(3,3-difluoropyrrolidin-1-yl)-3-(5- WSGR Docket No.58296-711601 methoxy-1H-indol-2-yl)phenyl)(ethyl)(imino)-l6-sulfanone (30.1 mg, 0.072 mmol, 39.2 % yield) was obtained as an off-white solid. LC-MS: m/z [M+H] + 420.05, 418.10 [M-H]-.1H NMR (400 MHz, DMSO-d6) δ = 11.30 (s, 1H), 7.77 (d, J = 2.25 Hz, 1H), 7.72 (dd, J = 8.63, 2.25 Hz, 1H), 7.28 (d, J = 8.63 Hz, 1H), 7.02 - 7.11 (m, 2H), 6.75 (dd, J = 8.82, 2.44 Hz, 1H), 6.48 (d, J = 1.38 Hz, 1H), 3.99 (s, 1H), 3.76 (s, 3H), 3.34 - 3.43 (m, 3H), 3.31 (br s, 1H), 3.10 (q, J = 7.34 Hz, 2H), 2.38 (tt, J = 14.15, 6.93 Hz, 2H), 1.08 (t, J = 7.38 Hz, 3 H). Step 3: Preparation of (R)-(4-(3,3-difluoropyrrolidin-1-yl)-3-(5-hydroxy-1H-indol-2-
Figure imgf000092_0001
[0179] To a solution of (R)-(4-(3, 3-difluoropyrrolidin-1-yl)-3-(5-methoxy-1H-indol-2-yl) phenyl) (ethyl) (imino)-l6-sulfanone (520 mg, 1.240 mmol) in Dichloromethane (DCM) (10 mL) was added BBr3 (0.703 mL, 7.44 mmol) at -60 °C. The mixture was stirred at -60 °C for 1 hr. The reaction mixture was quenched by addition H2O 5 mL at 0 °C, and then was adjusted to PH= 6 with saturated NaHCO33 mL at 0 °C, and then extracted with EtOAc (5 mL * 3). The combined organic layers were dried over [Na2SO4], filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC to give (R)-(4-(3, 3- difluoropyrrolidin-1-yl)-3-(5-hydroxy-1H-indol-2-yl) phenyl) (ethyl) (imino)-l6-sulfanone (18.2 mg, 0.045 mmol, 3.62 % yield) as a light yellow solid. LC-MS: m/z [M+H] + 406.10, 404.05 [M-H]-.1H NMR (400 MHz, DMSO-d6) δ = 11.13 (s, 1H), 8.68 (s, 1H), 7.75 (d, J = 2.0 Hz, 1H), 7.70 (dd, J = 2.2.6 Hz, 1H), 7.23 - 7.12 (m, 1H), 7.06 (d, J = 8.8 Hz, 1H), 6.85 (d, J = 1.9 Hz, 1H), 6.63 (dd, J = 2.28.6 Hz, 1H), 6.37 (d, J = 1.4 Hz, 1H), 3.97 (s, 1H), 3.43 - 3.35 (m, 4H), 3.09 (q, J = 7.4 Hz, 2H), 2.40 - 2.34 (m, 2H), 1.08 (t, J = 7.4Hz, 3H). WSGR Docket No.58296-711601 Example 13. General Scheme – Synthesis of Compound (12)
Figure imgf000093_0001
Example 14. Exemplary Scheme – Synthesis of Compound (12)
Figure imgf000093_0002
WSGR Docket No.58296-711601 Step 1: Preparation of 1-(2-bromo-4-(ethylsulfonimidoyl)phenyl)-3-methylazetidine-3- carbonitrile
Figure imgf000094_0001
[0180] To a solution of (3-bromo-4-fluorophenyl)(ethyl)(imino)-l6-sulfanone, isomer 2 (500 mg, 1.879 mmol) in Dimethyl Sulfoxide (DMSO) (5 mL) were added DIEA (1.313 mL, 7.52 mmol) and 3-ethynyl-3-methylazetidine, Hydrochloride (495 mg, 3.76 mmol). Then the mixture was stirred at 100 °C for 12 hours. The mixture was diluted with H2O 10 mL and extracted with EtOAc (15 mL * 3). The combined organic layers were washed with brine (20 mL * 1), dried over Na2SO4, filtered and concentrated under reduced pressure to give 1-(2-bromo-4- (ethylsulfonimidoyl)phenyl)-3-methylazetidine-3-carbonitrile (1.26 g, 3.22 mmol, 171 % yield) as yellow oil. LC-MS: m/z [M+H]+ 342.0, 344.0 [M+2+H]+ Step 2: Preparation of tert-butyl-2-(2-(3-cyano-3-methylazetidin-1-yl)-5- (ethylsulfonimidoyl)phenyl)-1H-indole-1-carboxylate
Figure imgf000094_0002
[0181] A mixture of 1-(2-bromo-4-(ethylsulfonimidoyl)phenyl)-3-methylazetidine-3- carbonitrile (1.2 g, 3.51 mmol), (1-(tert-butoxycarbonyl)-1H-indol-2-yl)boronic acid (1.098 g, 4.21 mmol), K2CO3 (1.454 g, 10.52 mmol) and PdCl2(dppf) -CH2Cl2adduct (0.286 g, 0.351 mmol) in 1,4-Dioxane (12 mL) and Water (1.200 mL) was degassed and purged with N2 for 3 times, and then the reaction mixture was stirred at 80 °C for 12 hours under N2 atmosphere. The reaction mixture was filtered and the filter cake was washed with EtOAc (5 mL x 3). Then the combined filtrates were concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to give tert-butyl-2-(2-(3-cyano-3-methylazetidin-1-yl)-5- WSGR Docket No.58296-711601 (ethylsulfonimidoyl)phenyl)-1H-indole-1-carboxylate (1.09 g, 2.217 mmol, 63.2 % yield) as brown gum. LC-MS: m/z [M+H]+ 479.3 Step 3: Preparation of 1-(4-(ethylsulfonimidoyl)-2-(1H-indol-2-yl)phenyl)-3-methylazetidine-3- carbonitrile
Figure imgf000095_0001
[0182] To a solution of tert-butyl-2-(2-(3-cyano-3-methylazetidin-1-yl)-5- (ethylsulfonimidoyl)phenyl)-1H-indole-1-carboxylate (1.04 g, 2.173 mmol) in Dichloromethane (10 mL) was added Trifluoroacetic acid (TFA) (2.5 mL). The mixture was stirred at 15 °C for 12 hours. The reaction mixture was concentrated under reduced pressure to remove DCM to give a residue. The residue was diluted with H2O 20 mL and extracted with EtOAc (10 mL * 3). The combined organic layers were washed with NaHCO3 (10 mL * 1), dried over Na2SO4, filtered and concentrated under reduced pressure to give 1-(4-(ethylsulfonimidoyl)-2-(1H-indol- 2-yl)phenyl)-3-methylazetidine-3-carbonitrile (800 mg, 1.403 mmol, 64.6 % yield) as brown gum. LC-MS: m/z [M+H]+ 379.2 Step 4: Preparation of (R)-1-(4-(ethylsulfonimidoyl)-2-(3-fluoro-1H-indol-2-yl)phenyl)-3- methylazetidine-3-carbonitrile (12)
Figure imgf000095_0002
[0183] To a solution of 1-(4-(ethylsulfonimidoyl)-2-(1H-indol-2-yl)phenyl)-3- methylazetidine-3-carbonitrile (300 mg, 0.526 mmol) in Acetonitrile (12 mL) was added a mixture of selectfluor (1-(Chloromethyl)-4-fluoro-1,4-diazabicyclo[2.2.2]octane-1,4-diium WSGR Docket No.58296-711601 ditetrafluoroborate) (149 mg, 0.421 mmol) in Acetonitrile (4.00 mL) at 0 °C , the reaction mixture was stirred at 0 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to remove ACN to give a residue. The residue was purified by prep-HPLC to give (R)- 1-(4-(ethylsulfonimidoyl)-2-(3-fluoro-1H-indol-2-yl)phenyl)-3-methylazetidine-3-carbonitrile (76.6 mg, 0.184 mmol, 35.1 % yield) as a rufous solid. LC-MS: m/z [M+H]+=397.1.1H NMR (400 MHz, DMSO-d6) δ = 11.49 (s, 1H), 7.76 - 7.69 (m, 2H), 7.57 (d, J = 8.0 Hz, 1H), 7.41 (d, J = 8.0 Hz, 1H), 7.12 (t, J = 7.2 Hz, 1H), 7.05 - 6.99 (m, 1H), 6.77 (d, J = 9.2 Hz, 1H), 6.50 (d, J = 1.2 Hz, 1H), 4.24 - 3.99 (m, 1H), 3.96 (dd, J = 2.8, 8.0 Hz, 2H), 3.62 (t, J = 8.8 Hz, 2H), 3.10 (q, J = 7.2 Hz, 2H), 1.52 (s, 3H), 1.09 (t, J = 7.2 Hz, 3H). Example 15. General Scheme – Synthesis of Compounds (13 and 14)
Figure imgf000096_0001
WSGR Docket No.58296-711601 Example 16. Exemplary Scheme – Synthesis of Compounds (13 and 14)
Figure imgf000097_0001
Preparation of 3-azidopropyl 4-methylbenzenesulfonate [0184] To a solution of 3-azidopropan-1-ol (2.35 g, 23.24 mmol) in Dichloromethane (DCM) (25 mL) were added pyridine (2.256 mL, 27.9 mmol) and 4-methylbenzenesulfonyl chloride (TsCl, TosCl) (5.32 g, 27.9 mmol).The mixture was stirred at 20 °C for 12 hours under N2. The reaction mixture was diluted with water 50 mL and extracted with DCM (50 mL * 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to give 3- azidopropyl 4-methylbenzenesulfonate (4.8 g, 18.33 mmol, 79 % yield) as colorless oil. The desired M/Z didn’t response in LCMS. WSGR Docket No.58296-711601 Step 1: Preparation of (3-azidopropyl)(3-bromo-4-fluorophenyl)sulfane
Figure imgf000098_0001
[0185] To a solution of 3-bromo-4-fluorobenzenethiol (2 g, 9.66 mmol) and NaOH (0.773 g, 19.32 mmol) in Methanol (20 mL) was added 3-azidopropyl 4-methylbenzenesulfonate (2.466 g, 9.66 mmol). The mixture was stirred at 20 °C for 12 hours. The reaction mixture was concentrated under reduced pressure to remove Methanol. The residue was diluted with H2O (50 mL) and the aqueous phase was extracted with DCM (30 mL*3). The combined organic layers were washed brine (30 mL*3) and dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to give (3-azidopropyl)(3-bromo-4-fluorophenyl)sulfane (1.58 g, 4.59 mmol, 47.5 % yield) as yellow oil. The desired M/Z didn’t response in LCMS. Step 2: Preparation of 4-((3-azidopropyl)sulfinyl)-2-bromo-1-fluorobenzene
Figure imgf000098_0002
[0186] To a solution of (3-azidopropyl)(3-bromo-4-fluorophenyl)sulfane (1.58 g, 5.45 mmol) in Dichloromethane (16 mL) was added slowly m-CPBA (meta-chloro peroxybenzoic acid) (1.057 g, 4.90 mmol) at 0 °C, and the mixture was stirred at 20 °C for 12 hours. The resultant mixture was filtered and the filter cake was washed with DCM (20 mL x 3). Then the combined filtrates were washed with Na2SO3 (20 mL*2), brine (20 mL*2), dried over Na2SO4 and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to give 4-((3-azidopropyl)sulfinyl)-2-bromo-1-fluorobenzene (1.3 g, 3.94 mmol, 72.3 % yield) as colorless oil. LC-MS: m/z [M+H]+ 306.0, [M+2+H]+ 308.0 WSGR Docket No.58296-711601 Step 3: Preparation of 1-(3-bromo-4-fluorophenyl)-4,5-dihydro-3H-isothiazole 1-oxide
Figure imgf000099_0001
Figure imgf000099_0002
[0187] To a solution of 4-((3-azidopropyl)sulfinyl)-2-bromo-1-fluorobenzene (700 mg, 2.286 mmol) in Toluene (10 mL) was added Iron(II) phthalocyanine (650 mg, 1.143 mmol). The mixture was stirred at 120 °C for 12 hours under N2. The reaction mixture was filtered and the filter cake was washed with EtOAc (20 mL x 3). Then the combined filtrates were concentrated under reduced pressure to provide a residue. The residue was purified by column chromatography to give 1-(3-bromo-4-fluorophenyl)-4,5-dihydro-3H-isothiazole 1-oxide (523mg, 1.724 mmol, 75 % yield) as blue gum. LC-MS: m/z [M+H]+ 277.0, [M+2+H]+ 279.0 Step 4: Preparation of tert-butyl 2-(2-fluoro-5-(1-oxido-4,5-dihydro-3H-1l6-isothiazol-1- yl)phenyl)-1H-indole-1-carboxylate
Figure imgf000099_0003
[0188] To a solution of 1-(3-bromo-4-fluorophenyl)-4,5-dihydro-3H-isothiazole 1-oxide (470 mg, 1.690 mmol) in Water (2 mL) and 1,4-Dioxane (10 mL) were added (1-(tert- butoxycarbonyl)-1H-indol-2-yl)boronic acid (662 mg, 2.53 mmol), PdCl2(dppf)-CH2Cl2adduct (69.0 mg, 0.084 mmol) and K2CO3 (701 mg, 5.07 mmol) under N2. The mixture was stirred at 80 °C for 12 hours. The reaction mixture was diluted with water 10 mL and extracted with EtOAc (5 mL * 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to give tert-butyl 2-(2-fluoro-5-(1-oxido-4,5-dihydro-3H-1l6-isothiazol-1- yl)phenyl)-1H-indole-1-carboxylate (740 mg, 1.674 mmol, 99 % yield) as green oil. LC-MS: m/z [M+H]+ 415.1, [M+H-56]+ 359.1 WSGR Docket No.58296-711601 Step 5: Preparation of tert-butyl 2-(2-((S)-3-hydroxypyrrolidin-1-yl)-5-(1-oxido-4,5-dihydro-3H- 1l6-isothiazol-1-yl)phenyl)-1H-indole-1-carboxylate
Figure imgf000100_0001
[0189] To a solution of (S)-pyrrolidin-3-ol (311 mg, 3.57 mmol) and tert-butyl 2-(2-fluoro-5- (1-oxido-4,5-dihydro-3H-1l6-isothiazol-1-yl)phenyl)-1H-indole-1-carboxylate (740 mg, 1.785 mmol) in Dimethyl Sulfoxide (8 mL) was added K2CO3 (987 mg, 7.14 mmol), then the mixture was stirred at 100 °C for 36 hours. The reaction mixture was used directly for purification. The reaction mixture was purified by prep-HPLC to give tert-butyl 2-(2-((S)-3-hydroxypyrrolidin-1- yl)-5-(1-oxido-4,5-dihydro-3H-1l6-isothiazol-1-yl)phenyl)-1H-indole-1-carboxylate (270 mg, 0.554 mmol, 31.0 % yield) as a yellow solid. LC-MS: m/z [M+H]+ 382.1, [M-H]- 380.1 Step 6: Preparation of 1-(4-((S)-3-hydroxypyrrolidin-1-yl)-3-(1H-indol-2-yl)phenyl)-4,5- dihydro-3H-isothiazole 1-oxide, isomer 1 (13) & 1-(4-((S)-3-hydroxypyrrolidin-1-yl)-3-(1H- dihydro-3H-isothiazole 1-oxide, isomer 2 (14)
Figure imgf000100_0002
Figure imgf000100_0003
[0190] 1-(4-((S)-3-hydroxypyrrolidin-1-yl)-3-(1H-indol-2-yl)phenyl)-4,5-dihydro-3H- isothiazole 1-oxide (270 mg, 0.708 mmol) was separated by SFC to give 1-(4-((S)-3- hydroxypyrrolidin-1-yl)-3-(1H-indol-2-yl)phenyl)-4,5-dihydro-3H-isothiazole 1-oxide, isomer 1 (74.4 mg, 0.195 mmol, 27.6 % yield) as a white solid and 1-(4-((S)-3-hydroxypyrrolidin-1-yl)-3- (1H-indol-2-yl)phenyl)-4,5-dihydro-3H-isothiazole 1-oxide, isomer 2 (60.6 mg, 0.159 mmol, 22.44 % yield) as a white solid. LC-MS: m/z [M+H]+ 382.1, 384.1 [M+2+H]+.1H NMR (400 MHz, DMSO-d6) δ ppm 11.40 (s, 1 H) 7.59 - 7.67 (m, 2 H) 7.52 (d, J=7.6 Hz, 1 H) 7.36 (d, J=8.0 Hz, 1 H) 7.06 - 7.12 (m, 1 H) 6.98 - 7.04 (m, 1 H) 6.94 (d, J=8.8 Hz, 1 H) 6.40 (d, J=1.6 WSGR Docket No.58296-711601 Hz, 1 H) 4.83 (d, J=3.6 Hz, 1 H) 4.16 (br d, J=2.0 Hz, 1 H) 3.68 - 3.78 (m, 1 H) 3.63 (dt, J=10.4, 6.4 Hz, 1 H) 3.28 (t, J=8.0 Hz, 3 H) 3.11 - 3.19 (m, 2 H) 2.77 (br d, J=10.4 Hz, 1 H) 2.11 - 2.31 (m, 2 H) 1.85 (ddt, J=12.4, 8.4, 4.0, 4.0 Hz, 1 H) 1.68 - 1.78 (m, 1 H).1H NMR (400 MHz, DMSO-d6) δ ppm 11.42 (s, 1 H) 7.59 - 7.67 (m, 2 H) 7.52 (d, J=8.0 Hz, 1 H) 7.35 (d, J=8.0 Hz, 1 H) 7.05 - 7.12 (m, 1 H) 6.97 - 7.04 (m, 1 H) 6.94 (d, J=9.6 Hz, 1 H) 6.40 (d, J=1.2 Hz, 1 H) 4.84 (d, J=3.6 Hz, 1 H) 4.15 (br d, J=1.6 Hz, 1 H) 3.68 - 3.77 (m, 1 H) 3.63 (dt, J=10.0, 6.4 Hz, 1 H) 3.28 (br t, J=7.2 Hz, 3 H) 3.15 (br dd, J=10.8, 4.8 Hz, 2 H) 2.77 (br d, J=11.2 Hz, 1 H) 2.09 - 2.29 (m, 2 H) 1.80 - 1.92 (m, 1 H) 1.66 - 1.79 (m, 1 H). Example 17. General Scheme – Synthesis of Compounds (15 and 16)
Figure imgf000101_0001
WSGR Docket No.58296-711601 Example 18. Exemplary Scheme – Synthesis of Compounds (15 and 16)
Figure imgf000102_0001
Step 1: Preparation of tert-butyl ((3-bromo-4-fluorophenyl) (ethyl) (oxo)-l6-sulfaneylidene) carbamate
Figure imgf000102_0002
[0191] To a stirred (3-bromo-4-fluorophenyl)(ethyl)(imino)-l6-sulfanone (4.00 g, 15.03 mmol) in Tetrahydrofuran (40 mL) was added NaH (1.2 g, 30.10 mmol) at 0 °C and the mixture was stirred at 0 °C for 30 minutes. (Boc)2O (di-tert-butyl dicarbonate) (6.98 mL, 30.1 mmol) was added and the mixture was stirred at 15 °C for 16 hours. The reaction mixture was quenched by addition H2O (50 mL) at 0 °C, and then extracted with EtOAc (50 mL * 3). The combined organic layers were washed with brine (50 mL * 1), dried over Na2SO4, filtered and concentrated WSGR Docket No.58296-711601 under reduced pressure to give a residue. The residue was purified by column chromatography to give tert-butyl ((3-bromo-4-fluorophenyl) (ethyl) (oxo)-l6-sulfaneylidene) carbamate (6.00 g, 14.48 mmol, 96 % yield) as colourless oil. LC-MS: m/z [M+H-100]+ 266.1, 268.1[M+2+H- 100]+ Step 2: Preparation of 1-(2-bromo-4-(N-(tert-butoxycarbonyl) ethylsulfonimidoyl) phenyl)-3- (trifluoromethyl) azetidine-3-carboxylic acid, Potassium salt
Figure imgf000103_0001
K salt [0192] To a solution of tert-butyl ((3-bromo-4-fluorophenyl) (ethyl) (oxo)-l6-sulfaneylidene) carbamate (267 mg, 0.730 mmol) in Dimethyl Sulfoxide (1 mL) were added K2CO3 (403 mg, 2.92 mmol) and 3-(trifluoromethyl) azetidine-3-carboxylic acid, Hydrochloride (100 mg, 0.486 mmol). The mixture was stirred at 100 °C for 12 hours. The reaction mixture was quenched by addition H2O (3 mL) at 15 °C. The reaction mixture was purified by reverse phase column to give 1-(2-bromo-4-(N-(tert-butoxycarbonyl)ethylsulfonimidoyl)phenyl)-3-(trifluoromethyl) azetidine-3-carboxylic acid, Potassium salt (400 mg, 0.692 mmol, 142 % yield) as a white solid. LC-MS: m/z [M+H]+ 515.1/517.1; [M+H-56]+ , 459.1/461.0; [M+H-100]+ 415.0/417.0 Step 3: Preparation of tert-butyl ((3-bromo-4-(3-carbamoyl-3-(trifluoromethyl) azetidin-1-yl) phenyl) (ethyl) (oxo)-l6-sulfaneylidene) carbamate
Figure imgf000103_0002
[0193] 1-(2-bromo-4-(N-(tert-butoxycarbonyl)ethylsulfonimidoyl)phenyl)-3- (trifluoromethyl)azetidine-3-carboxylic acid (150 mg, 0.291 mmol), HOBt·NH3 (1- WSGR Docket No.58296-711601 hydroxybenzotriazole ammonia) (177 mg, 1.164 mmol) and EDCI (1-Ethyl-3-(3- dimethylaminopropyl)carbodiimide) (112 mg, 0.582 mmol) were dissolved in a mixture of Tetrahydrofuran (3 mL) and TEA (triethylamine) (0.162 mL, 1.164 mmol), then the mixture was stirred under nitrogen atmosphere at 40 °C for 6 hours. The reaction mixture was added MeOH (2 mL * 7). The combined organic layers were concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to give tert-butyl ((3-bromo-4-(3- carbamoyl-3-(trifluoromethyl) azetidin-1-yl) phenyl) (ethyl) (oxo)-l6-sulfaneylidene) carbamate (300 mg, 0.538 mmol, 185 % yield) as yellow oil. LC-MS: m/z [M+H]+ 514.1/516.1; [M+H- 56]+, 458.0/460.0; [M+H-100]+ 414.0/416.0 Step 4: Preparation of tert-butyl ((3-bromo-4-(3-cyano-3-(trifluoromethyl) azetidin-1-yl) phenyl) (ethyl) (oxo)-l6-sulfaneylidene) carbamate
Figure imgf000104_0001
[0194] To a solution of tert-butyl ((3-bromo-4-(3-carbamoyl-3-(trifluoromethyl)azetidin-1- yl)phenyl)(ethyl)(oxo)-l6-sulfaneylidene)carbamate (280 mg, 0.544 mmol) in Dichloromethane (4 mL) were added TEA (0.607 mL, 4.35 mmol) and TFAA (trifluoroacetic anhydride) (0.308 mL, 2.177 mmol) at 0 °C was stirred at 15 °C for 1 h. The reaction mixture was concentrated under reduced pressure give a residue. The residue was purified by column chromatography to give tert-butyl ((3-bromo-4-(3-cyano-3-(trifluoromethyl) azetidin-1-yl) phenyl) (ethyl) (oxo)-l6- sulfaneylidene) carbamate (260 mg, 0.507 mmol, 93 % yield) as a yellow solid. LC-MS: m/z [M+H]+ 496.1/496.1; [M+H-56]+, 440.0/442.0; [M+H-100]+ 396.0/398.0 WSGR Docket No.58296-711601 Step 5: Preparation of tert-butyl 2-(5-(N-(tert-butoxycarbonyl)ethylsulfonimidoyl)-2-(3-cyano-3- (trifluoromethyl)azetidin-1-yl)phenyl)-1H-indole-1-carboxylate
Figure imgf000105_0001
[0195] To a solution of tert-butyl ((3-bromo-4-(3-cyano-3-(trifluoromethyl)azetidin-1- yl)phenyl)(ethyl)(oxo)-l6-sulfaneylidene)carbamate (180 mg, 0.363 mmol) in Tetrahydrofuran (3 mL) and Water (0.6 mL) were added (1-(tert-butoxycarbonyl)-1H-indol-2-yl)boronic acid (284 mg, 1.088 mmol), K3PO4 (308 mg, 1.451 mmol) and DTBPF PdCl2 (47.3 mg, 0.073 mmol) under N2. The mixture was stirred at 80 °C for 2 hours. The reaction mixture was quenched by addition H2O (5 mL) at 0 °C, and then extracted with EtOAc (4 mL * 3). The combined organic layers were washed with brine (2 mL * 1), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to give tert-butyl 2-(5-(N-(tert-butoxycarbonyl) ethylsulfonimidoyl)-2-(3-cyano-3-(trifluoromethyl) azetidin-1-yl)phenyl)-1H-indole-1-carboxylate (300 mg, 0.449 mmol, 124 % yield) as yellow oil. LC-MS: m/z [M+H]+ 633.4 Step 6: Preparation of 1-(4-(ethylsulfonimidoyl)-2-(1H-indol-2-yl)phenyl)-3- (trifluoromethyl)azetidine-3-carbonitrile
Figure imgf000105_0002
[0196] To a solution of tert-butyl 2-(5-(N-(tert-butoxycarbonyl)ethylsulfonimidoyl)-2-(3- cyano-3-(trifluoromethyl)azetidin-1-yl)phenyl)-1H-indole-1-carboxylate (280 mg, 0.443 mmol) in Dichloromethane (3 mL) was added TFA (trifluoroacetic acid) (0.3 ml, 3.89 mmol). The mixture was stirred at 15 °C for 12 hours. The reaction mixture was basified by TEA till pH = 7 at 0 °C and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to give 1-(4-(ethylsulfonimidoyl)-2-(1H-indol-2-yl)phenyl)-3- WSGR Docket No.58296-711601 (trifluoromethyl)azetidine-3-carbonitrile (150 mg, 0.326 mmol, 73.6 % yield) as a yellow solid. LC-MS: m/z [M+H]+ 433.2 Step 7: Preparation of 1-(4-(ethylsulfonimidoyl)-2-(1H-indol-2-yl)phenyl)-3- (trifluoromethyl)azetidine-3-carbonitrile, isomer 1 (15) and 1-(4-(ethylsulfonimidoyl)-2-(1H-
Figure imgf000106_0001
[0197] 1-(4-(ethylsulfonimidoyl)-2-(1H-indol-2-yl)phenyl)-3-(trifluoromethyl)azetidine-3- carbonitrile (150 mg, 0.347 mmol) was used for separation by SFC to give 1-(4- (ethylsulfonimidoyl)-2-(1H-indol-2-yl)phenyl)-3-(trifluoromethyl)azetidine-3-carbonitrile, isomer 1 (44.8 mg, 0.101 mmol, 29.1 % yield) (first eluted peak) as an off-white solid (Note: ee%=100.00%) LC-MS: m/z [M+H]+ 433.15, 431.00 [M-H]-.1H NMR (400 MHz, DMSO-d6) δ ppm 11.54 (br s, 1 H), 7.71 - 7.88 (m, 2 H), 7.59 (br d, J = 7.6 Hz, 1 H), 7.43 (br d, J = 8.0 Hz, 1 H), 7.09 - 7.19 (m, 1 H), 7.01 - 7.08 (m, 1 H), 6.90 (br d, J = 8.4 Hz, 1 H), 6.52 (s, 1 H), 4.23 - 4.37 (m, 2 H), 4.07 - 4.14 (m, 2 H), 4.04 (s, 1 H), 3.06 - 3.18 (m, 2 H), 1.06 - 1.15 (m, 3 H).1-(4- (ethylsulfonimidoyl)-2-(1H-indol-2-yl) phenyl)-3-(trifluoromethyl) azetidine-3-carbonitrile, isomer 2 (41.7 mg, 0.096 mmol, 27.8 % yield) (second eluted peak) as a white solid (Note: ee%= 99.60%). LC-MS: m/z [M+H]+ 433.10, 431.00 [M-H]-.1H NMR (400 MHz, DMSO-d6) δ ppm 11.53 (br d, J = 6.0 Hz, 1 H), 7.69 - 7.84 (m, 2 H), 7.51 - 7.63 (m, 1 H), 7.36 - 7.47 (m, 1 H), 7.08 - 7.20 (m, 1 H), 6.98 - 7.07 (m, 1 H), 6.86 - 6.93 (m, 1 H), 6.51 (br d, J = 8.8 Hz, 1 H), 4.22 - 4.36 (m, 2 H), 3.98 - 4.15 (m, 3 H), 3.05 - 3.16 (m, 2 H), 1.04 - 1.13 (m, 3 H). WSGR Docket No.58296-711601 Example 19. General Scheme – Synthesis of Compounds (17 and 18)
Figure imgf000107_0001
WSGR Docket No.58296-711601 Example 20. Exemplary Scheme – Synthesis of Compounds (17 and 18)
Figure imgf000108_0001
WSGR Docket No.58296-711601
Figure imgf000109_0001
[0198] To a solution of 2-(1H-imidazol-2-yl)ethan-1-ol (1 g, 8.92 mmol) in Acetonitrile (10 mL) was added K2CO3 (3.70 g, 26.8 mmol) at 15 °C. After addition, the mixture was stirred at this temperature for 0.5 hour, and then 1-bromo-2-methoxyethane (1.363 g, 9.81 mmol) and KI (0.296 g, 1.784 mmol) were added at 15 °C. The resulting mixture was stirred at 80 °C for 12 hours. The reaction mixture was filtered and the filter cake was washed with ACN (20 mL * 3). Then the combined filtrates were concentrated under reduced pressure to give 2-(1-(2- methoxyethyl)-1H-imidazol-2-yl)ethan-1-ol (1.4 g, 5.00 mmol, 56.1 % yield) as yellow oil. LC- MS: m/z [M+H]+ 171.2.
Figure imgf000109_0002
[0199] To a solution of 2-(1-(2-methoxyethyl)-1H-imidazol-2-yl)ethan-1-ol (1.4 g, 8.23 mmol) in Dichloromethane (15 mL) were added pyridine (3.99 mL, 49.4 mmol) and 4- methylbenzenesulfonyl chloride (3.14 g, 16.45 mmol) at 0 °C. The mixture was stirred at 15 °C for 12 hours. The reaction mixture was concentrated under reduced pressure to remove DCM to give 2-(1-(2-methoxyethyl)-1H-imidazol-2-yl)ethyl 4-methylbenzenesulfonate (6 g, 6.02 mmol, 73.2 % yield) as brown oil. LC-MS: m/z [M+H]+ 325.1. WSGR Docket No.58296-711601 Step 3: Preparation of 2-(2-((3-bromo-4-fluorophenyl)thio)ethyl)-1-(2-methoxyethyl)-1H- imidazole
Figure imgf000110_0001
[0200] To a solution of 3-bromo-4-fluorobenzenethiol (3.06 g, 14.80 mmol) and NaOH (1.480 g, 37.0 mmol) in Methanol (15 mL) was added 2-(1-(2-methoxyethyl)-1H-imidazol-2- yl)ethyl 4-methylbenzenesulfonate (6 g, 18.50 mmol). The mixture was stirred at 60 °C for 12 hours. The reaction mixture was concentrated under reduced pressure to remove MeOH to give a residue. The residue was dissolved in MeOH (1 mL) and the resulting solution purified by prep-HPLC to give 2-(2-((3-bromo-4-fluorophenyl)thio)ethyl)-1-(2-methoxyethyl)-1H-imidazole (1.5 g, 4.11 mmol, 22.21 % yield) as orange oil. LC-MS: m/z [M+H]+ 361.1. Step 4: Preparation of (3-bromo-4-fluorophenyl)(imino)(2-(1-(2-methoxyethyl)-1H-imidazol-2- yl)ethyl)-l6-sulfanone
Figure imgf000110_0002
[0201] To a solution of 2-(2-((3-bromo-4-fluorophenyl)thio)ethyl)-1-(2-methoxyethyl)-1H- imidazole (1.4 g, 3.90 mmol) in Dichloromethane (4.50 mL) and Methanol (9 mL) were added PhI(OAc)2 (3.77 g, 11.69 mmol) and (NH4)2CO3 (1.123 g, 11.69 mmol). The mixture was stirred at 15 °C for 12 hours. The reaction mixture was concentrated under reduced pressure to remove DCM and MeOH to give a residue. The residue was dissolved in MeOH (5 mL) and the resulting solution was purified by prep-HPLC to give (3-bromo-4-fluorophenyl)(imino)(2-(1-(2- WSGR Docket No.58296-711601 methoxyethyl)-1H-imidazol-2-yl)ethyl)-l6-sulfanone (720 mg, 1.821 mmol, 46.7 % yield) as yellow oil. LC-MS: m/z [M+H]+ 392.1. Step 5: Preparation of (3-bromo-4-(3,3-difluoropyrrolidin-1-yl)phenyl)(imino)(2-(1-(2- methoxyethyl)-1H-imidazol-2-yl)ethyl)-l6-sulfanone
Figure imgf000111_0001
[0202] To a solution of (3-bromo-4-fluorophenyl)(imino)(2-(1-(2-methoxyethyl)-1H- imidazol-2-yl)ethyl)-l6-sulfanone (720 mg, 1.845 mmol) in Dimethyl Sulfoxide (8 mL) were added 3,3-difluoropyrrolidine, Hydrochloride (1324 mg, 9.22 mmol) and K2CO3 (1275 mg, 9.22 mmol). The mixture was stirred at 100 °C for 12 hours. Then K2CO3 (1275 mg, 9.22 mmol) and 3,3-difluoropyrrolidine, Hydrochloride (1324 mg, 9.22 mmol) were added to the mixture, the mixture was stirred at 100 °C for another 12 hours. Then, the reaction mixture was stirred at 120 °C for 12 hours. The reaction mixture was purified by prep-HPLC to give (3-bromo-4-(3,3- difluoropyrrolidin-1-yl)phenyl)(imino)(2-(1-(2-methoxyethyl)-1H-imidazol-2-yl)ethyl)-l6- sulfanone (410 mg, 0.830 mmol, 45.0 % yield) as a yellow solid. LC-MS: m/z [M+H]+ 479.1.
WSGR Docket No.58296-711601 Step 6: Preparation of tert-butyl 2-(2-(3,3-difluoropyrrolidin-1-yl)-5-(2-(1-(2-methoxyethyl)-1H-
Figure imgf000112_0001
[0203] A mixture of (3-bromo-4-(3,3-difluoropyrrolidin-1-yl)phenyl)(imino)(2-(1-(2- methoxyethyl)-1H-imidazol-2-yl)ethyl)-l6-sulfanone (360 mg, 0.754 mmol), (1-(tert- butoxycarbonyl)-1H-indol-2-yl)boronic acid (236 mg, 0.905 mmol), K2CO3 (313 mg, 2.262 mmol) and PdCl2(dppf)-CH2Cl2 adduct (61.6 mg, 0.075 mmol) in 1,4-Dioxane (4 mL) and Water (0.400 mL) was degassed and purged with N2 for 3 times, and then the reaction mixture was stirred at 80 °C for 12 hours under N2 atmosphere. The mixture was filtered through a Celite pad, and the filtrate was concentrated to give a residue. The residue was purified by column chromatography to give tert-butyl 2-(2-(3,3-difluoropyrrolidin-1-yl)-5-(2-(1-(2-methoxyethyl)- 1H-imidazol-2-yl)ethylsulfonimidoyl)phenyl)-1H-indole-1-carboxylate (430 mg, 0.607 mmol, 81 % yield) as brown oil. LC-MS: m/z [M+H]+ 614.3.
WSGR Docket No.58296-711601 Step 7: Preparation of (4-(3,3-difluoropyrrolidin-1-yl)-3-(1H-indol-2-yl)phenyl)(imino)(2-(1-(2-
Figure imgf000113_0001
[0204] To a solution of tert-butyl 2-(2-(3,3-difluoropyrrolidin-1-yl)-5-(2-(1-(2- methoxyethyl)-1H-imidazol-2-yl)ethylsulfonimidoyl)phenyl)-1H-indole-1-carboxylate (380 mg, 0.619 mmol) in Dichloromethane (4 mL) was added TFA (0.8 mL, 10.38 mmol). The mixture was stirred at 15 °C for 12 hours. The reaction mixture was adjusted pH to 10 by TEA and concentrated to remove DCM to give a residue. The residue was dissolved in MeOH (5mL) and the resulting solution was purified by prep-HPLC to give (4-(3,3-difluoropyrrolidin-1-yl)-3-(1H- indol-2-yl)phenyl)(imino)(2-(1-(2-methoxyethyl)-1H-imidazol-2-yl)ethyl)-l6-sulfanone (160 mg, 0.285 mmol, 46.0 % yield) as a yellow solid. LC-MS: m/z [M+H]+ 514.25.
WSGR Docket No.58296-711601 Step 8: Preparation of (4-(3,3-difluoropyrrolidin-1-yl)-3-(1H-indol-2-yl)phenyl)(imino)(2-(1-(2- methoxyethyl)-1H-imidazol-2-yl)ethyl)-l6-sulfanone, isomer 1 (17) and(4-(3,3- difluoropyrrolidin-1-yl)-3-(1H-indol-2-yl)phenyl)(imino)(2-(1-(2-methoxyethyl)-1H-imidazol-2-
Figure imgf000114_0001
[0205] (4-(3,3-difluoropyrrolidin-1-yl)-3-(1H-indol-2-yl)phenyl)(imino)(2-(1-(2- methoxyethyl)-1H-imidazol-2-yl)ethyl)-l6-sulfanone (90 mg, 0.175 mmol) was used to be separated by chiral SFC to give (4-(3,3-difluoropyrrolidin-1-yl)-3-(1H-indol-2- yl)phenyl)(imino)(2-(1-(2-methoxyethyl)-1H-imidazol-2-yl)ethyl)-l6-sulfanone, isomer 1 (38.3 mg, 0.075 mmol, 42.6 % yield) (peak 1) was obtained as a white solid. ee%=100%. LC-MS: m/z [M+H]+ 514.2.1H NMR (400 MHz, DMSO-d6) δ = 11.50 (s, 1H), 7.85 (s, 1H), 7.79 (br d, J = 8.4 Hz, 1H), 7.56 (d, J = 8.0 Hz, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.16 - 7.08 (m, 2H), 7.06 - 6.98 (m, 2H), 6.71 (s, 1H), 6.57 (s, 1H), 4.28 (s, 1H), 3.99 (br t, J = 4.8 Hz, 2H), 3.49 (br t, J = 4.8 Hz, 4H), 3.40 (br s, 2H), 3.33 (br s, 2H), 3.14 (s, 3H), 2.93 (br dd, J = 6.0, 10.0 Hz, 2H), 2.39 (tt, J = 7.2, 14.0 Hz, 2H). (4-(3,3-difluoropyrrolidin-1-yl)-3-(1H-indol-2-yl)phenyl)(imino)(2-(1-(2- methoxyethyl)-1H-imidazol-2-yl)ethyl)-l6-sulfanone, isomer 2 (44.4 mg, 0.086 mmol, 49.3 % yield) (peak 2) was obtained as a light-yellow solid. ee%= 99.62%. LC-MS: m/z [M+H]+ 514.2. 1H NMR (400 MHz, DMSO-d6) δ = 11.51 (br s, 1H), 7.86 (br s, 1H), 7.80 (br d, J = 8.4 Hz, 1H), 7.57 (br d, J = 7.2 Hz, 1H), 7.41 (br d, J = 7.2 Hz, 1H), 7.12 (br d, J = 8.4 Hz, 2H), 7.05 (br d, J = 2.8 Hz, 2H), 6.73 (br s, 1H), 6.59 (br s, 1H), 4.29 (br s, 1H), 4.00 (br d, J = 4.0 Hz, 2H), 3.51 (br s, 5H), 3.43 - 3.37 (m, 3H), 3.15 (br s, 3H), 2.94 (br s, 2H), 2.42 (br d, J = 6.4 Hz, 2H). WSGR Docket No.58296-711601 Example 21. General Scheme – Synthesis of Compound (19)
Figure imgf000115_0001
Figure imgf000115_0002
Figure imgf000115_0003
Figure imgf000115_0004
Figure imgf000115_0005
WSGR Docket No.58296-711601 Example 22. Exemplary Scheme – Synthesis of Compound (19)
Figure imgf000116_0002
Step 1: Preparation of tert-butyl (S)-3-formylpyrrolidine-1-carboxylate
Figure imgf000116_0001
[0206] To a solution of tert-butyl (S)-3-(hydroxymethyl)pyrrolidine-1-carboxylate (5 g, 24.84 mmol) in Dichloromethane (50 mL) was added DMP (12.64 g, 29.8 mmol) at 0 °C . The mixture was stirred at 20 °C for 3 hours. The reaction mixture was filtered and the filter cake was washed with EtOAc (100 mL * 3). The combined organic layers were washed with Na2SO3 (aq.) (50 mL * 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to give tert-butyl (S)-3- formylpyrrolidine-1-carboxylate (4 g, 7.01 mmol, 28.2 % yield) as colorless oil. This compound has no M/Z appear. WSGR Docket No.58296-711601 Step 2: Preparation of tert-butyl (S)-3-((R)-1-hydroxyethyl)pyrrolidine-1-carboxylate
Figure imgf000117_0001
[0207] To a solution of tert-butyl (S)-3-formylpyrrolidine-1-carboxylate (2 g, 10.04 mmol) in Tetrahydrofuran (20 mL) was added methylmagnesium bromide (5.02 mL, 15.06 mmol) at - 78 °C under N2 atmosphere, after 1 hour, the reaction mixture was heated to 0 °C for 1 hour under N2 atmosphere. The reaction mixture was quenched by addition NH4Cl (aq.) (40 mL) at 0 °C, and then diluted with H2O (100 mL) and extracted with EtOAc (100 mL * 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to give tert-butyl (S)-3-((R)-1- hydroxyethyl)pyrrolidine-1-carboxylate (1.33 g, 2.83 mmol, 28.2 % yield) as colorless oil . LC- MS: m/z [M+H-56]+ 160.2 Step 3: Preparation of (R)-1-((S)-pyrrolidin-3-yl)ethan-1-ol, Trifluoroacetate salt
Figure imgf000117_0002
[0208] To a solution of tert-butyl (S)-3-((R)-1-hydroxyethyl)pyrrolidine-1-carboxylate (1.33 g, 6.18 mmol) in Dichloromethane (13 mL) was added TFA (2.6 mL, 33.7 mmol) at 15 °C . Then, the mixture was stirred at 15 °C for 12 h. The reaction mixture was concentrated under reduced pressure to give (R)-1-((S)-pyrrolidin-3-yl)ethan-1-ol, Trifluoroacetate salt (1.2 g, 1.058 mmol, 17.13 % yield) as yellow oil. LC-MS: m/z [M+H-56]+ 116.2
WSGR Docket No.58296-711601 Step 4: Preparation of (R)-(3-bromo-4-((S)-3-((S)-1-hydroxyethyl)pyrrolidin-1- yl)phenyl)(ethyl)(imino)-l6-sulfanone
Figure imgf000118_0001
Figure imgf000118_0002
[0209] To a solution of (R)-(3-bromo-4-fluorophenyl)(ethyl)(imino)-l6-sulfanone (500 mg, 1.879 mmol) in Dimethyl Sulfoxide (5 mL) were added (R)-1-((S)-pyrrolidin-3-yl)ethan-1-ol, Trifluoroacetate salt (857 mg, 3.76 mmol) and DIEA (1.641 mL, 9.39 mmol). The mixture was stirred at 120 °C for 12 hours. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (15 mL * 3). The combined organic layers were washed with brine (10 mL * 3), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to give (R)-(3-bromo-4-((S)-3- ((S)-1-hydroxyethyl)pyrrolidin-1-yl)phenyl)(ethyl)(imino)-l6-sulfanone (500 mg, 0.670 mmol, 35.7 % yield) as yellow oil. LC-MS: m/z [M+H]+ 361.1 Step 5: Preparation of tert-butyl 2-(5-((R)-ethylsulfonimidoyl)-2-((S)-3-((S)-1- hydroxyethyl)pyrrolidin-1-yl)phenyl)-1H-indole-1-carboxylate
Figure imgf000118_0003
[0210] To a solution of (R)-(3-bromo-4-((S)-3-((S)-1-hydroxyethyl)pyrrolidin-1- yl)phenyl)(ethyl)(imino)-l6-sulfanone (480 mg, 1.329 mmol) in Tetrahydrofuran (5 mL) and Water (1.25 mL) were added (1-(tert-butoxycarbonyl)-1H-indol-2-yl)boronic acid (694 mg, 2.66 mmol), DTBPF PdCl2 (87 mg, 0.133 mmol) and tripotassium phosphate (846 mg, 3.99 mmol) under N2 atmosphere. The mixture was stirred at 80 °C for 12 hours under N2 atmosphere. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (5 mL * 3). The WSGR Docket No.58296-711601 combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to give tert-butyl 2-(5-((R)-ethylsulfonimidoyl)-2-((S)-3-((S)-1-hydroxyethyl)pyrrolidin-1-yl)phenyl)- 1H-indole-1-carboxylate (437 mg, 0.441 mmol, 33.2 % yield) as a brown solid. LC-MS: m/z [M+H]+ 498.3 Step 6: Preparation of tert-butyl 2-(2-((S)-3-acetylpyrrolidin-1-yl)-5-((R)- ethylsulfonimidoyl)phenyl)-1H-indole-1-carboxylate
Figure imgf000119_0001
[0211] To a solution of tert-butyl 2-(5-((R)-ethylsulfonimidoyl)-2-((S)-3-((S)-1- hydroxyethyl)pyrrolidin-1-yl)phenyl)-1H-indole-1-carboxylate (220 mg, 0.442 mmol) in Dichloromethane (6.6 mL) was added PCC (pyridinium chlorochromate) (143 mg, 0.663 mmol). The mixture was stirred at 15 °C for 12 h. The reaction mixture was filtered, the filter cake was washed with EtOAc (5 mL * 5), and the filtrate was washed with Na2SO3 (aq.) (10 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to give tert- butyl 2-(2-((S)-3-acetylpyrrolidin-1-yl)-5-((R)-ethylsulfonimidoyl)phenyl)-1H-indole-1- carboxylate (50 mg, 0.070 mmol, 15.82 % yield) as yellow oil. LC-MS: m/z [M+H]+ 496.2
WSGR Docket No.58296-711601 Step 7: Preparation of (1R)-(4-(3-acetylpyrrolidin-1-yl)-3-(1H-indol-2-yl)phenyl)(ethyl)(imino)- l6-sulfanone (19)
Figure imgf000120_0001
[0212] To a solution of tert-butyl 2-(2-(3-acetylpyrrolidin-1-yl)-5-((R)- ethylsulfonimidoyl)phenyl)-1H-indole-1-carboxylate (50 mg, 0.101 mmol) in Dichloromethane (0.5 mL) was added TFA (0.1 ml, 1.298 mmol). The mixture was stirred at 15 °C for 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was dissolved in ACN and the resulting solution was purified was purified by prep-HPLC to give (1R)-(4-(3-acetylpyrrolidin-1-yl)-3-(1H-indol-2-yl)phenyl)(ethyl)(imino)-l6-sulfanone (7.3 mg, 0.018 mmol, 17.95 % yield) as a yellow solid. LC-MS: m/z [M+H]+ 396.15.1H NMR (400 MHz, DMSO-d6) δ = 11.38 (s, 1H), 7.72 (d, J = 2.4 Hz, 1H), 7.67 (dd, J = 2.4, 8.8 Hz, 1H), 7.52 (d, J = 8.0 Hz, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.11 - 7.05 (m, 1H), 7.03 - 6.96 (m, 2H), 6.45 (d, J = 1.2 Hz, 1H), 3.87 (s, 1H), 3.25 - 3.15 (m, 3H), 3.13 - 3.01 (m, 4H), 2.11 - 2.02 (m, 4H), 1.98 - 1.86 (m, 1H), 1.08 (t, J = 7.2 Hz, 3H). Example 23. General Scheme – Synthesis of Compounds (20 and 21)
Figure imgf000120_0002
WSGR Docket No.58296-711601 Example 24. Exemplary Scheme – Synthesis of Compounds (20 and 21)
Figure imgf000121_0001
Step 1: Preparation of (1R)-ethyl(4-((3S)-3-(1-hydroxyethyl)pyrrolidin-1-yl)-3-(1H-indol-2- yl)phenyl)(imino)-l6-sulfanone, isomer 1 (20) and (1R)-ethyl(4-((3S)-3-(1- hydroxyethyl)pyrrolidin-1-yl)-3-(1H-indol-2-yl)phenyl)(imino)-l6-sulfanone, isomer 2 (21) [0213] To a solution of tert-butyl 2-(5-((R)-ethylsulfonimidoyl)-2-((S)-3-((S)-1- hydroxyethyl)pyrrolidin-1-yl)phenyl)-1H-indole-1-carboxylate (50 mg, 0.100 mmol) in Dichloromethane (0.5 mL) was added TFA (0.1 mL, 1.298 mmol). The mixture was stirred at 15 °C for 12 hours. The reaction mixture was filtered and the combined filtrates were purified by prep-HPLC to give (1R)-ethyl(4-((3S)-3-(1-hydroxyethyl)pyrrolidin-1-yl)-3-(1H-indol-2- yl)phenyl)(imino)-l6-sulfanone, isomer 1 (3.6 mg, 8.59 µmol, 8.55 % yield) as a white solid. LC- MS: m/z [M+H]+ 398.4, [M-H]- 396.1.1H NMR (400 MHz, DMSO-d6) δ = 11.36 (s, 1H), 7.69 (d, J = 2.4 Hz, 1H), 7.65 (dd, J = 2.4, 8.8 Hz, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.10 - 7.04 (m, 1H), 7.02 - 6.97 (m, 1H), 6.94 (d, J = 8.8 Hz, 1H), 6.43 (d, J = 1.6 Hz, 1H), 4.52 (d, J = 4.8 Hz, 1H), 3.47 - 3.36 (m, 1H), 3.24 - 3.14 (m, 2H), 3.13 - 2.95 (m, 5H), 2.07 - 1.96 (m, 1H), 1.81 - 1.69 (m, 1H), 1.56 - 1.41 (m, 1H), 1.13 - 0.97. (1R)-ethyl(4-((3S)-3-(1- hydroxyethyl)pyrrolidin-1-yl)-3-(1H-indol-2-yl)phenyl)(imino)-l6-sulfanone, isomer 2 (3.4 mg, 8.05 µmol, 8.01 % yield) was obtained as a white solid. LC-MS: m/z [M+H]+ 398.5, [M-H]- 396.1.1H NMR (400 MHz, DMSO-d6) δ = 11.24 (br s, 1H), 7.64 - 7.59 (m, 2H), 7.51 (br d, J = 7.2 Hz, 1H), 7.36 (br d, J = 8.0 Hz, 1H), 7.10 - 7.04 (m, 1H), 7.02 - 6.90 (m, 2H), 6.41 (s, 1H), 3.43 - 3.32 (m, 1H), 3.13 - 2.93 (m, 5H), 2.80 (br t, J = 9.6 Hz, 1H), 2.07 - 1.76 (m, 2H), 1.61 - 1.50 (m, 1H), 1.08 - 0.85 (m, 6H). WSGR Docket No.58296-711601 Example 25. General Scheme – Synthesis of Compound (22)
Figure imgf000122_0002
Example 26. Exemplary Scheme – Synthesis of Compound (22)
Figure imgf000122_0001
WSGR Docket No.58296-711601 Step 1: Preparation of tert-butyl (R)-5-bromo-2-(2-(3,3-difluoropyrrolidin-1-yl)-5- (ethylsulfonimidoyl)phenyl)-1H-indole-1-carboxylate
Figure imgf000123_0001
[0214] To a solution of (R)-(3-bromo-4-(3,3-difluoropyrrolidin-1-yl)phenyl)(ethyl)(imino)- l6-sulfanone (500 mg, 1.416 mmol) in Water (2.000 mL) and 1,4-Dioxane (10 mL) were added (5-bromo-1-(tert-butoxycarbonyl)-1H-indol-2-yl)boronic acid (578 mg, 1.699 mmol), PdCl2(dppf)-CH2Cl2 adduct (116 mg, 0.142 mmol) and K2CO3 (587 mg, 4.25 mmol) under N2. The mixture was stirred at 80 °C for 12 hours under N2. The residue was diluted with water 5 mL and extracted with EtOAc (10 mL * 3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to give tert-butyl (R)-5-bromo-2-(2-(3,3- difluoropyrrolidin-1-yl)-5-(ethylsulfonimidoyl)phenyl)-1H-indole-1-carboxylate (460 mg, 0.607 mmol, 42.9 % yield) as brown oil. LC-MS: m/z [M+H]+ 568.1, 570.0[M+2+H]+ Step 2: Preparation of tert-butyl (R)-2-(2-(3,3-difluoropyrrolidin-1-yl)-5- (ethylsulfonimidoyl)phenyl)-5-((trimethylsilyl)ethynyl)-1H-indole-1-carboxylate
Figure imgf000123_0002
[0215] To a solution of tert-butyl (R)-5-bromo-2-(2-(3,3-difluoropyrrolidin-1-yl)-5- (ethylsulfonimidoyl)phenyl)-1H-indole-1-carboxylate (350 mg, 0.616 mmol) in TEA (5441 µl, 39.0 mmol) were added ethynyltrimethylsilane (181 mg, 1.847 mmol), CuI (11.73 mg, 0.062 mmol) and Pd(PPh3)2Cl2 (64.8 mg, 0.092 mmol) under N2. The mixture was stirred at 80 °C for 12 hours under N2. The reaction mixture was purified by column chromatography to give tert- butyl (R)-2-(2-(3,3-difluoropyrrolidin-1-yl)-5-(ethylsulfonimidoyl)phenyl)-5- WSGR Docket No.58296-711601 ((trimethylsilyl)ethynyl)-1H-indole-1-carboxylate (384 mg, 0.360 mmol, 58.5 % yield) as brown oil. LC-MS: m/z [M+H]+ 586.1, [M+H-56]+ =530.1 Step 3: Preparation of (R)-(4-(3,3-difluoropyrrolidin-1-yl)-3-(5-ethynyl-1H-indol-2- yl)phenyl)(ethyl)(imino)-l6-sulfanone (22)
Figure imgf000124_0001
[0216] To a solution of tert-butyl (R)-2-(2-(3,3-difluoropyrrolidin-1-yl)-5- (ethylsulfonimidoyl)phenyl)-5-((trimethylsilyl)ethynyl)-1H-indole-1-carboxylate (130 mg, 0.222 mmol) in Methanol (1.5 mL) was added K2CO3 (61.3 mg, 0.444 mmol). The mixture was stirred at 15 °C for 12 hours. The residue was diluted with water (2 mL) and extracted with EtOAc (4 mL * 3). The combined organic layers were washed with brine (3 mL * 3), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude material was purified by column chromatography to give (R)-(4-(3,3-difluoropyrrolidin-1-yl)-3-(5- ethynyl-1H-indol-2-yl)phenyl)(ethyl)(imino)-l6-sulfanone (8.8 mg, 0.021 mmol, 9.33 % yield) as a brown solid. LC-MS: m/z [M+H]+ 414.1.1H NMR (400 MHz, DMSO-d6) δ = 11.70 (s, 1H), 7.78 (d, J = 2.4 Hz, 1H), 7.74 (dd, J = 2.4, 8.4 Hz, 1H), 7.71 (s, 1H), 7.38 (d, J = 8.4 Hz, 1H), 7.20 (dd, J = 1.6, 8.4 Hz, 1H), 7.10 (d, J = 8.8 Hz, 1H), 6.58 (d, J = 1.6 Hz, 1H), 4.00 (s, 1H), 3.92 (s, 1H), 3.42 - 3.33 (m, 3H), 3.30 (d, J = 2.4 Hz, 1H), 3.10 (q, J = 7.6 Hz, 2H), 2.45 - 2.35 (m, 2H), 1.08 (t, J = 7.6 Hz, 3H).
WSGR Docket No.58296-711601 Example 27. General Scheme – Synthesis of Compound (23)
Figure imgf000125_0001
Example 28. Exemplary Scheme – Synthesis of Compound (23)
Figure imgf000125_0002
WSGR Docket No.58296-711601 Step 1: Preparation of tert-butyl (R)-2-(2-(3,3-difluoropyrrolidin-1-yl)-5- (ethylsulfonimidoyl)phenyl)-5-(oxetan-3-yl)-1H-indole-1-carboxylate
Figure imgf000126_0001
[0217] Three batches were set in parallel. To a solution of tert-butyl (R)-5-bromo-2-(2-(3,3- difluoropyrrolidin-1-yl)-5-(ethylsulfonimidoyl)phenyl)-1H-indole-1-carboxylate (280 mg, 0.493 mmol) (93 mg * 3) 3-bromooxetane (101 mg, 0.739 mmol) (33.5 mg * 3) in 1,2- Dimethoxyethane (9 mL) (3 mL * 3) were added Na2CO3 (104 mg, 0.985 mmol) (34.6 mg * 3), NiCl2(glyme) (0.541 mg, 2.463 µmol) (0.18 mg * 3), TTMSS (tris-trimethylsilyl silane) (122 mg, 0.493 mmol) (40.6 mg * 3), dtbbpy (4,4’-di-tert-butyl 2,2’-bipyridine) (0.661 mg, 2.463 µmol) (0.22 mg * 3) and (Ir(dF(CF3)ppy)2(bpy)PF6 (5.53 mg, 4.93 µmol) (1.84 mg * 3) at 25 °C under N2. The three batches were each stirred at 25 °C for 16 hours under N2 with 34W blue LED. The three batches were combined and diluted with water (10 mL) and extracted with EtOAc (15 mL * 3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to give tert-butyl (R)-2-(2-(3,3-difluoropyrrolidin-1-yl)-5- (ethylsulfonimidoyl)phenyl)-5-(oxetan-3-yl)-1H-indole-1-carboxylate (53 mg, 0.065 mmol, 13.12 % yield) as a brown solid. LC-MS: m/z [M+H]+ 546.2, [M+H-56] + 490.2, [M+H-100]+ 346.2
WSGR Docket No.58296-711601 Step 2: Preparation of (R)-(4-(3,3-difluoropyrrolidin-1-yl)-3-(5-(oxetan-3-yl)-1H-indol-2- yl)phenyl)(ethyl)(imino)-l6-sulfanone (23)
Figure imgf000127_0001
[0218] To a solution of tert-butyl (R)-2-(2-(3,3-difluoropyrrolidin-1-yl)-5- (ethylsulfonimidoyl)phenyl)-5-(oxetan-3-yl)-1H-indole-1-carboxylate (53 mg, 0.097 mmol) in Dichloromethane (1 mL) was added TFA (0.25 mL, 3.24 mmol). The mixture was stirred at 15 °C for 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was dissolved in HPLC-ACN (1 ml) and the resulting solution was purified by prep-HPLC (FA condition) to give (R)-(4-(3,3-difluoropyrrolidin-1-yl)-3-(5-(oxetan-3-yl)- 1H-indol-2-yl)phenyl)(ethyl)(imino)-l6-sulfanone (2.9 mg, 6.09 µmol, 6.27 % yield) as a pale pink solid. LC-MS: m/z [M+H] + 446.15, 444.05 [M-H]-.1H NMR (400 MHz, DMSO-d6) δ = 11.45 (s, 1H), 7.78 (d, J = 2.4 Hz, 1H), 7.73 (dd, J = 2.4, 8.4 Hz, 1H), 7.55 (s, 1H), 7.40 (d, J = 8.4 Hz, 1H), 7.20 (dd, J = 1.2, 8.4 Hz, 1H), 7.09 (d, J = 8.8 Hz, 1H), 6.54 (d, J = 1.6 Hz, 1H), 4.97 (dd, J = 6.0, 8.4 Hz, 2H), 4.68 (t, J = 6.4 Hz, 2H), 4.31 (quin, J = 7.6 Hz, 1H), 3.99 (s, 1H), 3.40 - 3.33 (m, 3H), 3.26 (br d, J = 1.2 Hz, 1H), 3.10 (q, J = 7.2 Hz, 2H), 2.40 (td, J = 7.2, 14.0 Hz, 2H), 1.08 (t, J = 7.2 Hz, 3H).
WSGR Docket No.58296-711601 Example 29. General Scheme – Synthesis of Compounds (24
Figure imgf000128_0001
Figure imgf000128_0004
Figure imgf000128_0002
Figure imgf000128_0003
Figure imgf000128_0005
WSGR Docket No.58296-711601 Example 30. Exemplary Scheme – Synthesis of Compounds (24 and 25)
Figure imgf000129_0001
Figure imgf000129_0003
Step 1: Preparation of diethyl azetidine-3, 3-dicarboxylate
Figure imgf000129_0002
[0219] To a solution of 1-(tert-butyl) 3, 3-diethyl azetidine-1, 3, 3-tricarboxylate (1.8g, 5.97 mmol) in Dichloromethane (20 mL) was added TFA (4 mL, 51.9 mmol). The mixture was WSGR Docket No.58296-711601 stirred at 15 °C for 12 hours. The reaction mixture was concentrated under reduced pressure to give diethyl azetidine-3, 3-dicarboxylate, Trifluoroacetic acid salt (3.4g, 8.41 mmol, 141 % yield) as yellow oil. LC-MS: m/z [M+H]+ 202.1. Step 2: Preparation of diethyl-1- (2-bromo-4-(N-(tert-butoxycarbonyl) ethylsulfonimidoyl) phenyl) azetidine-3, 3-dicarboxylate
Figure imgf000130_0001
[0220] To a solution of tert-butyl ((3-bromo-4-fluorophenyl) (ethyl) (oxo)-l6-sulfaneylidene) carbamate (1.5g, 4.10 mmol) and diethyl azetidine-3, 3-dicarboxylate, Trifluoroacetic acid salt (1.549 g, 4.91 mmol) in Dimethyl Sulfoxide (30 mL) was added DIEA (diisopropylethylamine) (3.58 mL, 20.48 mmol). The mixture was stirred at 100 °C for 12 hours under N2. After cooling to 15 °C, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was diluted with H2O (20 mL) and the aqueous phase was extracted with EtOAc (15 mL * 3). The combined organic layers were dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to give diethyl 1-(2-bromo-4-(N-(tert-butoxycarbonyl) ethylsulfonimidoyl) phenyl) azetidine-3, 3-dicarboxylate (1.5 g, 2.486 mmol, 60.7 % yield) as pale yellow oil. LC- MS: m/z [M+H]+ 547.2, 549.2 [M+2+H]+
WSGR Docket No.58296-711601 Step 3: Preparation of diethyl 1-(2-(1-(tert-butoxycarbonyl)-1H-indol-2-yl)-4-(N-(tert- butoxycarbonyl) ethylsulfonimidoyl) phenyl) azetidine-3, 3-dicarboxylate
Figure imgf000131_0001
[0221] To a solution of diethyl 1-(2-bromo-4-(N-(tert- butoxycarbonyl)ethylsulfonimidoyl)phenyl)azetidine-3,3-dicarboxylate ( 1.5g, 2.74 mmol) in Water (5 mL) and Tetrahydrofuran (20 mL) were added (1-(tert-butoxycarbonyl)-1H-indol-2- yl)boronic acid (1.073 g, 4.11 mmol), DTBPF PdCl2 (0.179 g, 0.274 mmol) and tripotassium phosphate (1.745 g, 8.22 mmol) under N2. The mixture was stirred at 90 °C for 10 hours. The reaction mixture was diluted with H20 (20 mL) and extracted with EtOAc (15 mL * 3). The combined organic layers were washed with brine (50 mL * 1), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to give diethyl 1-(2-(1-(tert-butoxycarbonyl)-1H-indol-2-yl)-4-(N-(tert- butoxycarbonyl) ethylsulfonimidoyl) phenyl) azetidine-3, 3-dicarboxylate (1.5g, 2.063 mmol, 75 % yield) as brown oil. LC-MS: m/z [M+H]+ 684.3 Step 4: Preparation of tert-butyl ((4-(3, 3-dicarbamoylazetidin-1-yl) -3- (1H-indol-2-yl) phenyl)
Figure imgf000131_0002
[0222] A mixture of diethyl 1-(2-(1-(tert-butoxycarbonyl)-1H-indol-2-yl)-4-(N-(tert- butoxycarbonyl) ethylsulfonimidoyl) phenyl) azetidine-3, 3-dicarboxylate (1000 mg, 1.462 mmol), ammonia (898 µl, 6.29 mmol), formamide (171 mg, 0.951mmol) was stirred at 15 °C for 2 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to give tert-butyl ((4-(3, 3-dicarbamoylazetidin- WSGR Docket No.58296-711601 1-yl)-3-(1H-indol-2-yl) phenyl) (ethyl) (oxo)-l6-sulfaneylidene) carbamate (500 mg, 0.340 mmol, 23.25 % yield) as a pale pink solid. LC-MS: m/z [M+H]+ 526.3 Step 5: Preparation of tert-butyl 2-(5-(N-(tert-butoxycarbonyl) ethylsulfonimidoyl) -2-(3, 3- dicarbamoylazetidin-1-yl) phenyl) -1H-indole-1-carboxylate
Figure imgf000132_0001
[0223] To a solution of tert-butyl ((4-(3,3-dicarbamoylazetidin-1-yl)-3-(1H-indol-2- yl)phenyl)(ethyl)(oxo)-l6-sulfaneylidene)carbamate (400 mg, 0.761 mmol) in Tetrahydrofuran (5 mL) was added triethylamine (231 mg, 2.283 mmol) at 40 °C, then di-tert-butyl dicarbonate (332 mg, 1.522 mmol) and N,N-dimethylpyridin-4-amine (DMAP) (9.30 mg, 0.076 mmol) were added to the mixture. The mixture was stirred at 40 °C for 2 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by Prep-TLC (SiO2, methyl alcohol/Ethyl acetate = 1/7) to give tert-butyl 2-(5-(N-(tert- butoxycarbonyl)ethylsulfonimidoyl)-2-(3,3-dicarbamoylazetidin-1-yl)phenyl)-1H-indole-1- carboxylate (200 mg, 0.277 mmol, 36.4 % yield) as a white solid. LC-MS: m/z [M+H]+ 626.3 Step 6: Preparation of tert-butyl 2-(5-(N-(tert-butoxycarbonyl) ethylsulfonimidoyl) -2 - (3, 3-
Figure imgf000132_0002
[0224] To a solution of tert-butyl 2-(5-(N-(tert-butoxycarbonyl)ethylsulfonimidoyl)-2-(3,3- dicarbamoylazetidin-1-yl)phenyl)-1H-indole-1-carboxylate (150 mg, 0.240 mmol) in Dichloromethane (2 mL) were added TEA (0.200 mL, 1.438 mmol) and TFAA (0.152 mL, 1.079 mmol) at 0 °C, then the mixtue was stirred at 15 °C for 12 hours. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by Prep-TLC (SiO2, WSGR Docket No.58296-711601 Petroleum ether/Ethyl acetate = 2/1) to give tert-butyl 2-(5-(N-(tert-butoxycarbonyl) ethylsulfonimidoyl) -2- (3, 3-dicyanoazetidin-1-yl) phenyl) -1H -indole-1-carboxylate (120 mg, 0.198 mmol, 82 % yield) as a white solid. LC-MS: m/z [M+H]+ 590.4 Step 7: Preparation of 1-(4-(ethylsulfonimidoyl)-2-(1H-indol-2-yl) phenyl) azetidine-3, 3- dicarbonitrile
Figure imgf000133_0001
[0225] To a solution of tert-butyl 2-(5-(N-(tert-butoxycarbonyl)ethylsulfonimidoyl)-2-(3,3- dicyanoazetidin-1-yl)phenyl)-1H-indole-1-carboxylate ( 120mg, 0.203 mmol) in Dichloromethane (1mL) was added TFA (0.1 ml, 1.298 mmol). The mixture was stirred at 15 °C for 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was dissolved in ACN (1 mL), and the resulting solution was purified by prep- HPLC to give 1-(4-(ethylsulfonimidoyl)-2-(1H-indol-2-yl) phenyl) azetidine-3, 3-dicarbonitrile (30 mg, 0.064 mmol, 31.5 % yield) as a pale yellow solid. LC-MS: m/z [M+H]+ 390.3 Step 8: Preparation of 1-(4-(ethylsulfonimidoyl)-2-(1H-indol-2-yl) phenyl) azetidine-3, 3- dicarbonitrile, isomer 1 (first eluted peak) (24) and 1-(4-(ethylsulfonimidoyl)-2-(1H-indol-2-yl)
Figure imgf000133_0002
[0226] 1-(4-(ethylsulfonimidoyl)-2-(1H-indol-2-yl) phenyl) azetidine-3, 3-dicarbonitrile (30 mg, 0.077 mmol) was purified by SFC (supercritical fluid chromatography) to give 1-(4- (ethylsulfonimidoyl)-2-(1H-indol-2-yl) phenyl) azetidine-3, 3-dicarbonitrile, isomer 1 (7.5 mg, 0.019 mmol, 24.44 % yield) (first eluted peak) as a white solid. LC-MS: m/z [M+H]+ 390.05.1H WSGR Docket No.58296-711601 NMR (400 MHz, DMSO-d6) δ ppm 11.55 (s, 1 H) 7.69 - 7.82 (m, 2 H) 7.59 (d, J=7.6 Hz, 1 H) 7.43 (d, J=7.6 Hz, 1 H) 7.11 - 7.18 (m, 1 H) 7.00 - 7.07 (m, 1 H) 6.86 (d, J=9.2 Hz, 1 H) 6.54 (d, J=1.2 Hz, 1 H) 4.14 - 4.22 (m, 4 H) 4.06 (s, 1 H) 3.11 (q, J=7.2 Hz, 2 H) 1.09 (t, J=7.2 Hz, 3 H). And 1-(4-(ethylsulfonimidoyl)-2-(1H-indol-2-yl) phenyl) azetidine-3, 3-dicarbonitrile, isomer 1 (7.5 mg, 0.019 mmol, 24.44 % yield) (second eluted peak) was obtained as a white solid. LC- MS: m/z [M+H] + 390.05.1H NMR (400 MHz, DMSO-d6) δ ppm 11.54 (s, 1 H) 7.73 - 7.79 (m, 2 H) 7.59 (d, J=7.6 Hz, 1 H) 7.43 (d, J=8.0 Hz, 1 H) 7.14 (t, J=7.6 Hz, 1 H) 7.00 - 7.09 (m, 1 H) 6.86 (d, J=9.2 Hz, 1 H) 6.54 (s, 1 H) 4.15 - 4.22 (m, 4 H) 4.04 (s, 1 H) 3.11 (q, J=7.2 Hz, 2 H) 1.09 (t, J=7.2 Hz, 3 H). Example 31. General Scheme – Synthesis of Compound (26)
Figure imgf000134_0001
WSGR Docket No.58296-711601 Example 32. Exemplary Scheme – Synthesis of Compound (26)
Figure imgf000135_0001
Step 1: Preparation of tert-butyl (R)-5-bromo-2-(2-(3,3-difluoropyrrolidin-1-yl)-5- (ethylsulfonimidoyl)phenyl)-1H-indole-1-carboxylate
Figure imgf000135_0002
[0227] To a solution of (R)-(3-bromo-4-(3,3-difluoropyrrolidin-1-yl)phenyl)(ethyl)(imino)- l6-sulfanone (790 mg, 2.237 mmol) in Water (2.00 mL) and 1,4-Dioxane (10 mL) were added (5-bromo-1-(tert-butoxycarbonyl)-1H-indol-2-yl)boronic acid (912 mg, 2.68 mmol), PdCl2(dppf)-CH2Cl2adduct (183 mg, 0.224 mmol) and K2CO3 (927 mg, 6.71 mmol) under N2. The mixture was stirred at 80 °C for 12 hours under N2. The reaction mixture was diluted with water (8 mL) and extracted with EtOAc (5 mL * 3). The combined organic layers were dried WSGR Docket No.58296-711601 over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to give tert-butyl (R)-5-bromo-2-(2-(3,3- difluoropyrrolidin-1-yl)-5-(ethylsulfonimidoyl)phenyl)-1H-indole-1-carboxylate (780 mg, 0.958 mmol, 42.8 % yield) as brown oil. LC-MS: m/z [M+H]+ 568.1, 570.1 [M+2+H]+ Step 2: Preparation of tert-butyl (R)-2-(2-(3,3-difluoropyrrolidin-1-yl)-5- (ethylsulfonimidoyl)phenyl)-5-((trimethylsilyl)ethynyl)-1H-indole-1-carboxylate
Figure imgf000136_0001
[0228] To a solution of tert-butyl (R)-5-bromo-2-(2-(3,3-difluoropyrrolidin-1-yl)-5- (ethylsulfonimidoyl)phenyl)-1H-indole-1-carboxylate (680 mg, 1.196 mmol) in TEA (8 mL, 57.4 mmol) were added ethynyltrimethylsilane (352 mg, 3.59 mmol), CuI (22.78 mg, 0.120 mmol) and Pd(PPh3)2Cl2 (126 mg, 0.179 mmol) under N2. The mixture was stirred at 80 °C for 8 hours under N2. The reaction mixture was purified by column chromatography to give tert-butyl (R)-2-(2-(3,3-difluoropyrrolidin-1-yl)-5-(ethylsulfonimidoyl)phenyl)-5-((trimethylsilyl)ethynyl)- 1H-indole-1-carboxylate (800 mg, 0.929 mmol, 78 % yield) as brown oil. LC-MS: m/z [M+H]+ 586.1 Step 3: Preparation of tert-butyl (R)-2-(2-(3,3-difluoropyrrolidin-1-yl)-5- (ethylsulfonimidoyl)phenyl)-5-ethynyl-1H-indole-1-carboxylate
Figure imgf000136_0002
[0229] To a solution of tert-butyl (R)-2-(2-(3,3-difluoropyrrolidin-1-yl)-5- (ethylsulfonimidoyl)phenyl)-5-((trimethylsilyl)ethynyl)-1H-indole-1-carboxylate (300 mg, 0.512 mmol) in Tetrahydrofuran (5 mL) was added TBAF (tetrabutylammonium fluoride) (0.512 mL, 0.512 mmol). The mixture was stirred at 20 °C for 12 hours. The reaction mixture was diluted WSGR Docket No.58296-711601 with water (3 mL) and extracted with EtOAc (2 mL * 3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by Prep-TLC (SiO2, Ethyl acetate/Methyl alcohol = 20/1) to give tert- butyl (R)-2-(2-(3,3-difluoropyrrolidin-1-yl)-5-(ethylsulfonimidoyl)phenyl)-5-ethynyl-1H-indole- 1-carboxylate (146 mg, 0.224 mmol, 43.7 % yield) as a yellow solid. LC-MS: m/z [M+H]+ 514.2 Step 4: Preparation of tert-butyl (R)-2-(2-(3,3-difluoropyrrolidin-1-yl)-5- (ethylsulfonimidoyl)phenyl)-5-(1H-1,2,3-triazol-5-yl)-1H-indole-1-carboxylate
Figure imgf000137_0001
[0230] To a solution of tert-butyl (R)-2-(2-(3,3-difluoropyrrolidin-1-yl)-5- (ethylsulfonimidoyl)phenyl)-5-ethynyl-1H-indole-1-carboxylate (230 mg, 0.448 mmol) in Tert- Butanol (3 mL) and Water (3.00 mL) were added CuSO4.5H2O (55.9 mg, 0.224 mmol), sodium azide (87 mg, 1.343 mmol) and sodium ascorbate (44.4 mg, 0.224 mmol). The mixture was stirred at 60 °C for 12 hours. The reaction mixture was diluted with H2O (2 mL), some solids appeared, the solids were collected by filtration and the filter cake was washed with H2O (5 mL) and dried to give tert-butyl (R)-2-(2-(3,3-difluoropyrrolidin-1-yl)-5-(ethylsulfonimidoyl)phenyl)- 5-(1H-1,2,3-triazol-5-yl)-1H-indole-1-carboxylate (200 mg, 0.232 mmol, 51.9 % yield) as a green solid. LC-MS: m/z [M+H]+ 557.1
WSGR Docket No.58296-711601 Step 5: Preparation of (R)-(3-(5-(1H-1,2,3-triazol-5-yl)-1H-indol-2-yl)-4-(3,3- difluoropyrrolidin-1-yl)phenyl)(ethyl)(imino)-l6-sulfanone (26)
Figure imgf000138_0001
[0231] A mixture of tert-butyl (R)-2-(2-(3,3-difluoropyrrolidin-1-yl)-5- (ethylsulfonimidoyl)phenyl)-5-(1H-1,2,3-triazol-5-yl)-1H-indole-1-carboxylate (180 mg, 0.323 mmol) in Ethyl acetate (2 mL) and HCl/EtOAc (2 ml, 2M, 8.00 mmol) was stirred at 15 °C for 0.5 hour. The reaction mixture was concentrated to give a residue. The residue was dissolved in DMSO (5 mL) and purified by prep-HPLC to give (R)-(3-(5-(1H-1,2,3-triazol-5-yl)-1H-indol-2- yl)-4-(3,3-difluoropyrrolidin-1-yl)phenyl)(ethyl)(imino)-l6-sulfanone (12.5 mg, 0.027 mmol, 8.31 % yield) as a light yellow solid. LC-MS: m/z [M+H]+ 457.1.1H NMR (400 MHz, DMSO- d6) δ = 14.92 - 14.63 (m, 1H), 11.78 - 11.46 (m, 1H), 8.32 - 8.10 (m, 1H), 8.09 - 8.00 (m, 1H), 7.81 (d, J = 2.4 Hz, 1H), 7.74 (dd, J = 2.0, 8.8 Hz, 1H), 7.70 - 7.59 (m, 1H), 7.46 (br d, J = 8.4 Hz, 1H), 7.10 (d, J = 8.8 Hz, 1H), 6.66 - 6.59 (m, 1H), 4.00 (s, 1H), 3.44 - 3.33 (m, 4H), 3.11 (q, J = 7.2 Hz, 2H), 2.45 - 2.33 (m, 2H), 1.09 (t, J = 7.2 Hz, 3H). Example 33. Example Compounds of the Disclosure. [0232] Compounds 27-78 (Table 1) were synthesized according to the general scheme in Example 1 using similar procedures described for Compounds 1 and 2 with appropriate reagents and intermediates. [0233] Compounds 79-102 (Table 1) were synthesized according to the general scheme in Example 3 using similar procedures described for Compound 3 with appropriate reagents and intermediates. [0234] Compounds 103-108 and 110 (Table 1) were synthesized according to the general scheme in Example 9 using similar procedures described for Compounds 6, 7, 8, and 9 with appropriate reagents and intermediates. [0235] Compounds 111-124 (Table 1) were synthesized according to the general scheme in Example 13 using similar procedures described for Compound 12 with appropriate reagents and intermediates. WSGR Docket No.58296-711601 [0236] Compound 125 (Table 1) was synthesized according to the general scheme in Example 21 using similar procedures described for Compound 19 with appropriate reagents and intermediates. Table 1. Structure and Spectroscopic Data for Compounds 1-108, 110-346, 348-359, 361- 367, 369, 371-387, 389-395, and 397-399.
Figure imgf000139_0001
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Example 34. Inhibition of N-Glycosylation in H1 HeLa Cells. [0237] Inhibition of N-glycosylation was tested in a luminescence-based cellular assay (ERLuc). This assay was based on the ER-LucT reporter described in publication PMID 20413434. Reporter luciferase activity is inhibited by N-glycosylation, and inhibition of N-glycosylation therefore results in increased luminescence signal. [0238] 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. [0239] Putative inhibitors were assayed as follows. One day prior to small molecule treatment, ERLuc cells were plated in DMEM (Dulbecco’s Modified Eagle Medium) media with 10% FBS (fetal bovine serum) and incubated overnight at 37 degrees Celsius, 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 (dimethyl sulfoxide). Negative controls (DMSO only) and positive controls (2.8uM NGI-1, N-linked glycosylation inhibitor 1) were included on every assay plate. [0240] After 18 hours incubation at 37 degrees Celsius and 5% CO2, assay plates were assayed for Firefly luciferase activity using the Promega Nano-Glo® Dual-Luciferase® Reporter assay system according to the manufacturer’s protocol. First, ONE-Glo™ EX Reagent was added to assay wells, and assay plates were shaken to mix for over 3 minutes. Luminescence of the Firefly luciferase was detected on a Perkin Elmer EnSight® plate reader. Second, NanoDLR™ Stop & WSGR Docket No.58296-711601 Glo® Reagent was added to assay wells, and assay plates were shaken to mix for over 15 minutes. The NanoLuc luminescence was then similarly detected. [0241] The maximum and minimum levels of ERLuc activity were established using the Firefly luminescence of the positive and negative controls, respectively. The ERLuc activity observed using putative inhibitors was quantified as the percent of Firefly luminescence relative to these controls. EC50 values were calculated using CDDVault by fitting a sigmoidal variable slope nonlinear regression model to the data. [0242] Table 2 provides data for the biological evaluation of some embodiments of the present disclosure, including EC50 values for the ERLuc assay described above. ERLuc EC50 values are categorized as follows: A is < 10 nM; B is > 10 nM and < 50 nM; C is > 50 nM and < 100 nM; D is > 100 nM and < 1000 nM; and E is > 1000 nM . Table 2.
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[0243] While preferred embodiments of the present disclosure have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. It is not intended that the disclosure be limited by the specific examples provided within the specification. While the disclosure has been described with reference to the aforementioned specification, the descriptions and illustrations of the embodiments herein are not meant to be construed in a limiting sense. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the disclosure. Furthermore, it shall be understood that all aspects of the disclosure are not limited to the specific depictions, configurations or relative proportions set forth herein which depend upon a variety of conditions and variables. It should be understood that various alternatives to the embodiments of the disclosure described herein may be employed in practicing the disclosure. It is therefore contemplated that the invention shall also cover any such alternatives, modifications, variations or equivalents. It is intended that the following claims define the scope of the disclosure and that methods and structures within the scope of these claims and their equivalents be covered thereby.

Claims

WSGR Docket No.58296-711601 CLAIMS WHAT IS CLAIMED IS: 1. A compound represented by the structure of Formula (I):
Figure imgf000238_0001
or a pharmaceutically acceptable salt thereof, wherein: Ring A is 3- to 12-membered heterocycle; X1 is selected from N and C(H); each R1 is independently selected at each occurrence from: halogen, -OR11, -SR11, -N(R11)2, -C(O)R11, -C(O)N(R11)2, -C(O)OR11, -OC(O)R11, -N(R11)C(O)R11, -N(R11)C(O)OR11, -N(R11)S(O)2R11, -S(O)2N(R11)2, -S(O)R11, - S(O)2R11, -NO2, =S, =N(R11), and -CN; C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR11, -SR11, - N(R11)2, -C(O)R11, -C(O)N(R11)2, -C(O)OR11, -OC(O)R11, -N(R11)C(O)R11, -
Figure imgf000238_0002
C3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR11, -
Figure imgf000238_0003
each R2 is independently selected at each occurrence from: WSGR Docket No.58296-711601 halogen, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)N(R12)2, -C(O)OR12, -OC(O)R12, -N(R12)C(O)R12, -N(R12)C(O)OR12, -N(R12)S(O)2R12, -S(O)2N(R12)2, -S(O)R12, - S(O)2R12, -NO2, =O, =S, =N(R12), and -CN; C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)N(R12)2, -C(O)OR12, - OC(O)R12, -N(R12)C(O)R12, -N(R12)C(O)OR12, -N(R12)S(O)2R12, -S(O)2N(R12)2, - S(O)R12, -S(O)2R12, -NO2, =O, =S, =N(R12), and -CN; and C3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR12, - SR12, -N(R12)2, -C(O)R12, -C(O)N(R12)2, -C(O)OR12, -OC(O)R12, -N(R12)C(O)R12, - N(R12)C(O)OR12, -N(R12)S(O)2R12, -S(O)2N(R12)2, -S(O)R12, -S(O)2R12, -NO2, =O, =S, =N(R12), -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected halogen, -OR12, -SR12, -N(R12)2, -C(O)R12, - C(O)N(R12)2, -C(O)OR12, -OC(O)R12, -N(R12)C(O)R12, -N(R12)C(O)OR12, - N(R12)S(O)2R12, -S(O)2N(R12)2, -S(O)R12, -S(O)2R12, -NO2, =O, =S, =N(R12), and -CN; R3 is selected from: hydrogen, -C(O)R13, -S(O)2R13, and -CN; C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)N(R13)2, -C(O)OR13, - OC(O)R13, -N(R13)C(O)R13, -N(R13)C(O)OR13, -N(R13)S(O)2R13, -S(O)2N(R13)2, - S(O)R13, -S(O)2R13, -NO2, =O, =S, =N(R13), and -CN; and C3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, - SR13, -N(R13)2, -C(O)R13, -C(O)N(R13)2, -C(O)OR13, -OC(O)R13, -N(R13)C(O)R13, - N(R13)C(O)OR13, -N(R13)S(O)2R13, -S(O)2N(R13)2, -S(O)R13, -S(O)2R13, -NO2, =O, =S, =N(R13), -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, - C(O)N(R13)2, -C(O)OR13, -OC(O)R13, -N(R13)C(O)R13, -N(R13)C(O)OR13, - N(R13)S(O)2R13, -S(O)2N(R13)2, -S(O)R13, -S(O)2R13, -NO2, =O, =S, =N(R13), and -CN; R4 is selected from: C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR14, -SR14, -N(R14)2, -C(O)R14, -C(O)N(R14)2, -C(O)OR14, - OC(O)R14, -N(R14)C(O)R14, -N(R14)C(O)OR14, -N(R14)S(O)2R14, -S(O)2N(R14)2, - S(O)R14, -S(O)2R14, -NO2, =O, =S, =N(R14), -CN, C3-6 carbocycle and 3- to 6-membered WSGR Docket No.58296-711601 heterocycle, the C3-6 carbocycle and 3- to 6-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OR14, - SR14, -N(R14)2, -C(O)R14, -C(O)N(R14)2, -C(O)OR14, -OC(O)R14, -N(R14)C(O)R14, - N(R14)C(O)OR14, -N(R14)S(O)2R14, -S(O)2N(R14)2, -S(O)R14, -S(O)2R14, -NO2, =O, =S, =N(R14), -CN, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkyl-OR14, C1-6 alkyl-C3-6 carbocycle, and C1-6 alkyl-C3-6 heterocycle ; and C3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR14, - SR14, -N(R14)2, -C(O)R14, -C(O)N(R14)2, -C(O)OR14, -OC(O)R14, -N(R14)C(O)R14, - N(R14)C(O)OR14, -N(R14)S(O)2R14, -S(O)2N(R14)2, -S(O)R14, -S(O)2R14, -NO2, =O, =S, =N(R14), -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR14, -SR14, -N(R14)2, -C(O)R14, - C(O)N(R14)2, -C(O)OR14, -OC(O)R14, -N(R14)C(O)R14, -N(R14)C(O)OR14, - N(R14)S(O)2R14, -S(O)2N(R14)2, -S(O)R14, -S(O)2R14, -NO2, =O, =S, =N(R14), and -CN; or R3 and R4 come together with the atoms to which they are each bound to form a 4- to 6- membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR15, -SR15, -N(R15)2, -C(O)R15, -C(O)N(R15)2, -C(O)OR15, -OC(O)R15, -N(R15)C(O)R15, -N(R15)C(O)OR15, -N(R15)S(O)2R15, -S(O)2N(R15)2, -S(O)R15, - S(O)2R15, -NO2, =O, =S, =N(R15), and -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR15, -SR15, -N(R15)2, -C(O)R15, -C(O)N(R15)2, -C(O)OR15, - OC(O)R15, -N(R15)C(O)R15, -N(R15)C(O)OR15, -N(R15)S(O)2R15, -S(O)2N(R15)2, - S(O)R15, -S(O)2R15, -NO2, =O, =S, =N(R15), and -CN; R11, R12, R13, R14, and R15 are each independently selected at each occurrence from: hydrogen; C1-6 alkyl optionally substituted with one more substituents independently selected from halogen, -O-C1-6 alkyl, -O-C1-6 haloalkyl, -NH2, -NO2, =O, -CN, -S(O)2OH, -S-C1-6 alkyl, -S(O)-C1-6 alkyl, -S(O)2-C1-6 alkyl, -P(O)(OH)2, -P(-C1-6 alkyl)2, -P(-C1-6 alkyl)(-O-C1-6 alkyl) -P(-O-(C1-6 alkyl))2, -P(=O)(-C1-6 alkyl)2, -P(=O)(-C1-6 alkyl)(-O- (C1-6 alkyl), -P(O)(-O-(C1-6 alkyl))2, C3-10 carbocycle and 3- to 10-membered heterocycle, wherein each C3-10 carbocycle, and 3- to 10-membered heterocycle are optionally WSGR Docket No.58296-711601 substituted with one or more substituents independently selected from: halogen, -OH, -O- C1-6 alkyl, -O-C1-6 haloalkyl, -NH2, -NO2, =O, and -CN; and C3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OH, -O- C1-6 alkyl, -O-C1-6 haloalkyl, -NH2, -NO2, =O, and -CN; n is selected from 0, 1, 2, 3, and 4; and m is selected from 0, 1, 2, 3, and 4. 2. The compound or salt of claim 1, wherein X1 is C(H). 3. The compound or salt of claim 1, wherein X1 is N. 4. The compound or salt of any one of claims 1 to 3, wherein Ring A is selected from 3- to 6-membered monocyclic heterocycle and 6- to 12-membered bicyclic heterocycle, any of which comprises at least one heteroatom selected from nitrogen, oxygen, and sulfur. 5. The compound or salt of claim 4, wherein Ring A is 3- to 6-membered monocyclic heterocycle comprising one heteroatom selected from nitrogen, oxygen, and sulfur. 6. The compound or salt of claim 5, wherein Ring A is 5- to 6-membered heteroaryl. 7. The compound or salt of claim 6, wherein Ring A is 5-membered heteroaryl selected from pyrrolyl and thiophenyl. 8. The compound or salt of claim 7, wherein n is 0 and Ring A is selected from pyrrolyl and thiophenyl. 9. The compound or salt of claim 8, wherein
Figure imgf000241_0001
selected from and
Figure imgf000241_0002
. 10. The compound or salt of claim 4, wherein Ring A is 6- to 12-membered bicyclic heterocycle comprising at least one heteroatom selected from nitrogen, oxygen, and sulfur. WSGR Docket No.58296-711601 11. The compound or salt of claim 10, wherein the 6- to 12-membered bicyclic heterocycle of Ring A is selected from a 6- to 12-membered bridged heterocycle, 6- to 12-membered fused heterocycle, and 6- to 12-membered spirocyclic heterocycle. 12. The compound or salt of claim 11, wherein Ring A is 6- to 12-membered fused heterocycle. 13. The compound or salt of claim 12, wherein Ring A is selected from 1H-indolyl, indolinyl, benzo[b]thiophenyl, 1H-pyrrolo[2,3-b]pyridinyl, 1H-pyrrolo[3,2-b]pyridinyl, 1H- pyrrolo[3,2-c]pyridinyl, 1H-benzo[d]imidazolyl, 4,7-dihydro-1H-pyrrolo[3,2-b]pyridinyl, 6,7- dihydro-1H-pyrrolo[2,3-c]pyridinyl, 5H-pyrrolo[3,2-d]pyrimidinyl, 7H-pyrrolo[2,3- c]pyridazinyl, 1H-pyrrolo[2,3-d]pyridazinyl, 5H-pyrrolo[2,3-b]pyrazinyl, 7H-pyrrolo[2,3- d]pyrimidinyl, and 3,7-dihydro-2H-pyrrolo[2,3-d]pyrimidinyl. 14. The compound or salt of claim 13, wherein n is 0 and Ring A is selected from benzo[b]thiophenyl, 1H-indolyl, 5H-pyrrolo[3,2-d]pyrimidinyl, 7H-pyrrolo[2,3-c]pyridazinyl, and 1H-pyrrolo[2,3-d]pyridazinyl. 15. The compound or salt of claim 14, wherein
Figure imgf000242_0001
selected from
Figure imgf000242_0002
,
Figure imgf000242_0003
16. The compound or salt of any one of claims 10 to 13, wherein: n selected from 1, 2, 3, and 4; each R1 is independently selected at each occurrence from: halogen, -OR11, -SR11, -N(R11)2, -C(O)R11, -C(O)N(R11)2, -C(O)OR11, -OC(O)R11, -N(R11)C(O)R11, -N(R11)C(O)OR11, -N(R11)S(O)2R11, -S(O)2N(R11)2, -S(O)R11, - S(O)2R11, -NO2, =S, =N(R11), and -CN; and C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR11, -SR11, -
Figure imgf000242_0004
=N(R11), and -CN; and WSGR Docket No.58296-711601 R11 is independently selected at each occurrence from hydrogen and C1-6 alkyl optionally substituted with one more substituents independently selected from halogen, -O-C1-6 alkyl, -O-C1-6 haloalkyl, -NH2, -NO2, =O, -CN, C3-10 carbocycle, and 3- to 10-membered heterocycle. 17. The compound or salt of claim 16, wherein: n selected from 1, 2, 3, and 4; each R1 is independently selected at each occurrence from: halogen, -OR11, -N(R11)2, -C(O)R11, -C(O)N(R11)2, -C(O)OR11, -N(R11)C(O)R11, - N(R11)S(O)2R11, -NO2, =S, and -CN; and C1-6 alkyl and C2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, -C(O)R11, - C(O)N(R11)2, -C(O)OR11, -N(R11)C(O)R11, -N(R11)S(O)2R11, -NO2, =O, =S, and -CN; and R11 is independently selected at each occurrence from hydrogen and C1-6 alkyl optionally substituted with one more substituents independently selected from halogen, -O-C1-6 alkyl, -O-C1-6 haloalkyl, -NH2, -NO2, and -CN. 18. The compound or salt of claim 17, wherein
Figure imgf000243_0001
selected from
Figure imgf000243_0002
,
WSGR Docket No.58296-711601
Figure imgf000244_0001
WSGR Docket No.58296-711601
Figure imgf000245_0001
19. The compound or salt of any one of claims 10 to 13, wherein: n selected from 1, 2, 3, and 4; each R1 is independently selected at each occurrence from C3-10 carbocycle and 3- to 10- membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR11, -SR11, -N(R11)2, -C(O)R11, -
Figure imgf000245_0002
C1-6 alkyl optionally substituted with one or more substituents independently selected
Figure imgf000245_0003
R11 is independently selected at each occurrence from hydrogen and C1-6 alkyl optionally substituted with one more substituents independently selected from halogen, -O-C1-6 alkyl, -O-C1-6 haloalkyl, -NH2, -NO2, =O, -CN, C3-10 carbocycle, and 3- to 10-membered heterocycle. 20. The compound or salt of claim 19, wherein: n selected from 1, 2, 3, and 4; each R1 is independently selected at each occurrence from C3-6 saturated carbocycle, 3- to 6- membered saturated heterocycle, and 5- to 6-membered heteroaryl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, -C(O)R11, -C(O)N(R11)2, -N(R11)C(O)R11, -N(R11)C(O)OR11, - N(R11)S(O)2R11, -NO2, -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, -C(O)R11, - C(O)N(R11)2, -N(R11)C(O)R11, -N(R11)C(O)OR11, -N(R11)S(O)2R11, -NO2, and -CN; and R11 is independently selected at each occurrence from hydrogen and C1-6 alkyl optionally substituted with one more substituents independently selected from halogen, -O-C1-6 alkyl, and -O-C1-6 haloalkyl. WSGR Docket No.58296-711601 21. The compound or salt of claim 20, wherein: n selected from 1 and 2; each R1 is independently selected at each occurrence from cyclopropyl, oxetanyl, thiophenyl, pyrazolyl, and triazolyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, -C(O)R11, -
Figure imgf000246_0001
alkyl optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, -C(O)R11, -C(O)N(R11)2, -N(R11)C(O)R11, -N(R11)C(O)OR11, - N(R11)S(O)2R11, -NO2, and -CN; and R11 is independently selected at each occurrence from hydrogen and C1-6 alkyl optionally substituted with one more substituents independently selected from halogen, -O-C1-6 alkyl, and -O-C1-6 haloalkyl.
Figure imgf000246_0002
23. The compound or salt of claim 4, wherein: Ring A is selected from pyrrolyl, thiophenyl, 1H-indolyl, indolinyl, benzo[b]thiophenyl, 1H- pyrrolo[2,3-b]pyridinyl, 1H-pyrrolo[3,2-b]pyridinyl, 1H-pyrrolo[3,2-c]pyridinyl, 1H- benzo[d]imidazolyl, 4,7-dihydro-1H-pyrrolo[3,2-b]pyridinyl, 6,7-dihydro-1H- pyrrolo[2,3-c]pyridinyl, 5H-pyrrolo[3,2-d]pyrimidinyl, 7H-pyrrolo[2,3-c]pyridazinyl, 1H-pyrrolo[2,3-d]pyridazinyl, 5H-pyrrolo[2,3-b]pyrazinyl, 7H-pyrrolo[2,3- d]pyrimidinyl, and 3,7-dihydro-2H-pyrrolo[2,3-d]pyrimidinyl; n selected from 1, 2, 3, and 4; each R1 is independently selected at each occurrence from: WSGR Docket No.58296-711601 halogen, -OR11, -N(R11)2, -C(O)R11, -C(O)N(R11)2, -C(O)OR11, -N(R11)C(O)R11, - N(R11)S(O)2R11, -NO2, =S, and -CN; and C1-6 alkyl and C2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, -C(O)R11, - C(O)N(R11)2, -C(O)OR11, -N(R11)C(O)R11, -N(R11)S(O)2R11, -NO2, =O, =S, and -CN; and C3-6 saturated carbocycle, 3- to 6-membered saturated heterocycle, and 5- to 6- membered heteroaryl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, -C(O)R11, - C(O)N(R11)2, -N(R11)C(O)R11, -N(R11)C(O)OR11, -N(R11)S(O)2R11, -NO2, -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR11, -N(R11)2, -C(O)R11, -C(O)N(R11)2, -N(R11)C(O)R11, -N(R11)C(O)OR11, - N(R11)S(O)2R11, -NO2, and -CN; and R11 is independently selected at each occurrence from hydrogen and C1-6 alkyl optionally substituted with one more substituents independently selected from halogen, -O-C1-6 alkyl, -O-C1-6 haloalkyl, -NH2, -NO2, and -CN. 24. The compound or salt of claim 23, wherein
Figure imgf000247_0001
selected from
Figure imgf000247_0002
,
Figure imgf000247_0003
WSGR Docket No.58296-711601 ,
Figure imgf000248_0001
WSGR Docket No.58296-711601
Figure imgf000249_0001
25. The compound or salt of any one of claims 1 to 24, wherein
Figure imgf000249_0002
is selected from 3- to 7-membered monocyclic heterocycle and 6- to 12-membered bicyclic heterocycle. 26. The compound or salt of claim 25, wherein
Figure imgf000249_0003
is 3- to 7-membered monocyclic heterocycle. 27. The compound or salt of claim 26, wherein
Figure imgf000249_0004
is 4- to 6-membered heterocycloalkyl. 28. The compound or salt of claim 27, wherein
Figure imgf000249_0005
selected from azetidinyl, pyrrolidinyl, and piperidinyl. 29. The compound or any one of claims 25 to 28, wherein m is selected from 0, 1, 2, and 3. 30. The compound or salt of claim 29, wherein: m is selected from 0, 1, and 2; each R2 is independently selected at each occurrence from: halogen, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)N(R12)2, -C(O)OR12, -OC(O)R12, - N(R12)C(O)R12, -N(R12)C(O)OR12, -N(R12)S(O)2R12, -S(O)2N(R12)2, -S(O)R12, -S(O)2R12, -NO2, =O, =S, =N(R12), and -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)N(R12)2, -C(O)OR12, -OC(O)R12, - WSGR Docket No.58296-711601 N(R12)C(O)R12, -N(R12)C(O)OR12, -N(R12)S(O)2R12, -S(O)2N(R12)2, -S(O)R12, -S(O)2R12, -NO2, =O, =S, =N(R12), and -CN; and R12 is selected at each occurrence from hydrogen and C1-6 alkyl optionally substituted with one more substituents independently selected from halogen, -O-C1-6 alkyl, -O-C1-6 haloalkyl, - NH2, -NO2, =O, -CN, C3-10 carbocycle, and 3- to 10-membered heterocycle. 31. The compound or salt of claim 30, wherein: m is selected from 0, 1, and 2; each R2 is independently selected at each occurrence from: halogen, -OR12, -N(R12)2, -C(O)R12, -C(O)N(R12)2, -C(O)OR12, -N(R12)C(O)R12, - N(R12)C(O)OR12, -NO2, and -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR12, -N(R12)2, -C(O)R12, -C(O)N(R12)2, -C(O)OR12, -N(R12)C(O)R12, - N(R12)C(O)OR12, -NO2, and -CN; and R12 is selected at each occurrence from hydrogen and C1-6 alkyl optionally substituted with one more substituents independently selected from halogen, -O-C1-6 alkyl, -O-C1-6 haloalkyl, - NH2, and -NO2.
Figure imgf000250_0001
WSGR Docket No.58296-711601
Figure imgf000251_0001
33. The compound or salt of claim 29, wherein: m is selected from 0, 1, and 2; each R2 is independently selected at each occurrence from: halogen, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)N(R12)2, -C(O)OR12, -OC(O)R12, - N(R12)C(O)R12, -N(R12)C(O)OR12, -N(R12)S(O)2R12, -S(O)2N(R12)2, -S(O)R12, -S(O)2R12, -NO2, =O, =S, =N(R12), and -CN; and C3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR12, - SR12, -N(R12)2, -C(O)R12, -C(O)N(R12)2, -C(O)OR12, -OC(O)R12, -N(R12)C(O)R12, - N(R12)C(O)OR12, -N(R12)S(O)2R12, -S(O)2N(R12)2, -S(O)R12, -S(O)2R12, -NO2, =O, =S, =N(R12), -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected halogen, -OR12, -SR12, -N(R12)2, -C(O)R12, - C(O)N(R12)2, -C(O)OR12, -OC(O)R12, -N(R12)C(O)R12, -N(R12)C(O)OR12, - N(R12)S(O)2R12, -S(O)2N(R12)2, -S(O)R12, -S(O)2R12, -NO2, =O, =S, =N(R12), and -CN; and R12 is selected at each occurrence from hydrogen and C1-6 alkyl optionally substituted with one more substituents independently selected from halogen, -O-C1-6 alkyl, -O-C1-6 haloalkyl, - NH2, -NO2, =O, -CN, C3-10 carbocycle, and 3- to 10-membered heterocycle. WSGR Docket No.58296-711601 34. The compound or salt of claim 33, wherein: m is selected from 0 and 1; each R2 is independently selected at each occurrence from: halogen, -OR12, -N(R12)2, -C(O)R12, -C(O)OR12, -NO2, =O, =S, -CN; and C3-6 carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR12, - N(R12)2, -C(O)R12, -C(O)OR12, -NO2, =O, =S, -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected halogen, -OR12, -N(R12)2, - C(O)R12, -C(O)OR12, -NO2, =O, =S, and -CN; and R12 is selected at each occurrence from hydrogen, C1-6 alkyl, and C1-6 haloalkyl. 35. The compound or salt of claim 34, wherein
Figure imgf000252_0002
selected from
Figure imgf000252_0001
,
Figure imgf000252_0003
36. The compound or salt of claim 25, wherein
Figure imgf000252_0004
is 6- to 12-membered bicyclic heterocycle. 37. The compound or salt of claim 36, wherein the 6- to 12-membered bicyclic heterocycle
Figure imgf000252_0005
is selected from a 6- to 12-membered bridged heterocycle, 6- to 12-membered fused heterocycle, and 6- to 12-membered spirocyclic heterocycle. 38. The compound or salt of claim 37, wherein m is 0 and
Figure imgf000252_0006
is 6- to 12-membered bridged heterocycle. WSGR Docket No.58296-711601 39. The compound or salt of claim 38, wherein m is 0 and
Figure imgf000253_0001
is selected from 6- azabicyclo[3.1.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 7-azabicyclo[2.2.1]heptanyl, and 2- oxa-5-azabicyclo[2.2.1]heptanyl. 40. The compound or salt of claim 39, wherein
Figure imgf000253_0002
selected from
Figure imgf000253_0003
, ,
Figure imgf000253_0004
41. The compound or salt of claim 37, wherein m is 0 and
Figure imgf000253_0005
is 6- to 12-membered spirocyclic heterocycle. 42. The compound or salt of claim 41, wherein m is 0 and
Figure imgf000253_0006
is selected from 2-oxa-6- azaspiro[3.3]heptanyl, 1-oxa-6-azaspiro[3.3]heptanyl, and 1-thia-6-azaspiro[3.3]heptanyl. 43. The compound or salt of claim 42, wherein is selected from
Figure imgf000253_0007
,
Figure imgf000253_0008
44. The compound or salt of claim 25, wherein:
Figure imgf000253_0009
is selected from azetidinyl, pyrrolidinyl, piperidinyl, imidazolidinyl, 6- azabicyclo[3.1.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2-oxa-5- azabicyclo[2.2.1]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 1-oxa-6-azaspiro[3.3]heptanyl, 7-azabicyclo[2.2.1]heptanyl, and 1-thia-6-azaspiro[3.3]heptanyl; WSGR Docket No.58296-711601 m is selected from 0, 1, and 2; each R2 is independently selected at each occurrence from: halogen, -OR12, -N(R12)2, -C(O)R12, -C(O)N(R12)2, -C(O)OR12, -N(R12)C(O)R12, - N(R12)C(O)OR12, -NO2, =O, and -CN; C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR12, -N(R12)2, -C(O)R12, -C(O)N(R12)2, -C(O)OR12, - N(R12)C(O)R12, -N(R12)C(O)OR12, -NO2, and -CN; and C3-6 carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR12, - N(R12)2, -C(O)R12, -C(O)OR12, -NO2, =O, =S, -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected halogen, -OR12, -N(R12)2, - C(O)R12, -C(O)OR12, -NO2, =O, =S, and -CN; and R12 is selected at each occurrence from hydrogen and C1-6 alkyl optionally substituted with one more substituents independently selected from halogen, -O-C1-6 alkyl, -O-C1-6 haloalkyl, - NH2, -NO2, =O, -CN, C3-10 carbocycle, and 3- to 10-membered heterocycle.
Figure imgf000254_0001
WSGR Docket No.58296-711601
Figure imgf000255_0001
46. The compound or salt of any one of claims 1 to 45, wherein: R3 is selected from: hydrogen, -C(O)R13, -CN, and -S(O)2R13; C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, -C(O)R13, -C(O)N(R13)2, -C(O)OR13, - N(R13)C(O)R13, -NO2, and -CN; and C3-6 carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR13, - N(R13)2, -C(O)R13, -C(O)N(R13)2, -C(O)OR13, -N(R13)C(O)R13, -NO2, and -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected halogen, -OR13, -N(R13)2, -C(O)R13, -C(O)N(R13)2, -C(O)OR13, -N(R13)C(O)R13, -NO2, and -CN; and R13 is selected from hydrogen and C1-6 alkyl optionally substituted with one more substituents independently selected from halogen, -O-C1-6 alkyl, -O-C1-6 haloalkyl, -NH2, -NO2, =O, -CN, C3- 10 carbocycle, and 3- to 10-membered heterocycle. 47. The compound or salt of claim 46, wherein R3 is selected from: hydrogen, -C(O)R13, -CN, and -S(O)2R13; WSGR Docket No.58296-711601 C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, -C(O)N(R13)2, -N(R13)C(O)R13, -NO2, and -CN; and 5- to 6-membered heteroaryl optionally substituted with one or more substituents independently selected from halogen, -OR13, -N(R13)2, -C(O)R13, -NO2, and -CN; and R13 is selected from hydrogen and C1-6 alkyl optionally substituted with one more substituents independently selected from halogen, -O-C1-6 alkyl, -O-C1-6 haloalkyl, -NH2, -NO2, =O, -CN, C3- 10 carbocycle, and 3- to 10-membered heterocycle. 48. The compound or salt of claim 47, wherein R3 is selected from hydrogen,
Figure imgf000256_0001
, -CN, methyl, ethyl,
Figure imgf000256_0002
49. The compound or salt of any one of claims 1 to 48, wherein R4 is selected from: C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR14, -SR14, -N(R14)2, -C(O)R14, -C(O)N(R14)2, -C(O)OR14, - OC(O)R14, -N(R14)C(O)R14, -N(R14)C(O)OR14, -N(R14)S(O)2R14, -S(O)2N(R14)2, - S(O)R14, -S(O)2R14, -NO2, =O, =S, =N(R14), -CN, C3-6 carbocycle and 3- to 6-membered heterocycle, the C3-6 carbocycle and 3- to 6-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OR14, - SR14, -N(R14)2, -C(O)R14, -C(O)N(R14)2, -C(O)OR14, -OC(O)R14, -N(R14)C(O)R14, - N(R14)C(O)OR14, -N(R14)S(O)2R14, -S(O)2N(R14)2, -S(O)R14, -S(O)2R14, -NO2, =O, =S, =N(R14), -CN, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkyl-OR14, C1-6 alkyl-C3-6 carbocycle, and C1-6 alkyl-C3-6 heterocycle; and R14 is independently selected at each occurrence from hydrogen, C1-6 alkyl, C1-6 haloalkyl, C3-10 carbocycle and 3- to 10-membered heterocycle. 50. The compound or salt of claim 49, wherein: R4 is selected from: C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR14, -N(R14)2, -C(O)R14, -C(O)N(R14)2, -C(O)OR14, -NO2, -CN, C3-6 carbocycle and 3- to 6-membered heterocycle, the C3-6 carbocycle and 3- to 6-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OR14, -N(R14)2, -C(O)R14, -C(O)N(R14)2, -C(O)OR14, -NO2, -CN, WSGR Docket No.58296-711601 C1-6 alkyl, C1-6 haloalkyl, C1-6 alkyl-OR14, C1-6 alkyl-C3-6 carbocycle, and C1-6 alkyl-C3-6 heterocycle; and R14 is independently selected at each occurrence from hydrogen, C1-6 alkyl, C1-6 haloalkyl, C3-10 carbocycle and 3- to 10-membered heterocycle. 51. The compound or salt of claim 50, wherein R4 is selected from: methyl, ethyl, propyl,
Figure imgf000257_0001
52. The compound or salt of any one of claims 1 to 48, wherein: R4 is selected from: C3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR14, - SR14, -N(R14)2, -C(O)R14, -C(O)N(R14)2, -C(O)OR14, -OC(O)R14, -N(R14)C(O)R14, - N(R14)C(O)OR14, -N(R14)S(O)2R14, -S(O)2N(R14)2, -S(O)R14, -S(O)2R14, -NO2, =O, =S, =N(R14), -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR14, -SR14, -N(R14)2, -C(O)R14, -C(O)N(R14)2, - C(O)OR14, -OC(O)R14, -N(R14)C(O)R14, -N(R14)C(O)OR14, -N(R14)S(O)2R14, - S(O)2N(R14)2, -S(O)R14, -S(O)2R14, -NO2, =O, =S, =N(R14), and -CN; and R14 is independently selected at each occurrence from hydrogen, C1-6 alkyl, C1-6 haloalkyl, C3-10 carbocycle and 3- to 10-membered heterocycle. 53. The compound or salt of claim 52, wherein: R4 is selected from: C3-6 monocyclic carbocycle and C5-8 bridged carbocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR14, -SR14, -N(R14)2, -C(O)R14, -C(O)N(R14)2, -C(O)OR14, -OC(O)R14, - N(R14)C(O)R14, -N(R14)C(O)OR14, -N(R14)S(O)2R14, -S(O)2N(R14)2, -S(O)R14, -S(O)2R14, -NO2, =O, =S, =N(R14), -CN; and C1-6 alkyl optionally substituted with one or more WSGR Docket No.58296-711601 substituents independently selected from halogen, -OR14, -SR14, -N(R14)2, -C(O)R14, - C(O)N(R14)2, -C(O)OR14, -OC(O)R14, -N(R14)C(O)R14, -N(R14)C(O)OR14, - N(R14)S(O)2R14, -S(O)2N(R14)2, -S(O)R14, -S(O)2R14, -NO2, =O, =S, =N(R14), and -CN; and R14 is independently selected at each occurrence from hydrogen, C1-6 alkyl, C1-6 haloalkyl, C3-10 carbocycle and 3- to 10-membered heterocycle. 54. The compound or salt of claim 53, wherein: R4 is selected from: cyclobutyl, phenyl, and bicyclo[1.1.1]pentanyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR14, - SR14, -N(R14)2, -C(O)R14, -C(O)N(R14)2, -C(O)OR14, -OC(O)R14, -N(R14)C(O)R14, - N(R14)C(O)OR14, -N(R14)S(O)2R14, -S(O)2N(R14)2, -S(O)R14, -S(O)2R14, -NO2, =O, =S, =N(R14), -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR14, -SR14, -N(R14)2, -C(O)R14, -C(O)N(R14)2, - C(O)OR14, -OC(O)R14, -N(R14)C(O)R14, -N(R14)C(O)OR14, -N(R14)S(O)2R14, - S(O)2N(R14)2, -S(O)R14, -S(O)2R14, -NO2, =O, =S, =N(R14), and -CN; and R14 is independently selected at each occurrence from hydrogen, C1-6 alkyl, C1-6 haloalkyl, C3-10 carbocycle and 3- to 10-membered heterocycle.
Figure imgf000258_0001
56. The compound or salt of claim 52, wherein: R4 is selected from: 3- to 6-membered monocyclic heterocycle and 8- to 10-membered fused heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR14, -SR14, -N(R14)2, -C(O)R14, - C(O)N(R14)2, -C(O)OR14, -OC(O)R14, -N(R14)C(O)R14, -N(R14)C(O)OR14, - N(R14)S(O)2R14, -S(O)2N(R14)2, -S(O)R14, -S(O)2R14, -NO2, =O, =S, =N(R14), -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR14, -SR14, -N(R14)2, -C(O)R14, -C(O)N(R14)2, -C(O)OR14, -OC(O)R14, - WSGR Docket No.58296-711601 N(R14)C(O)R14, -N(R14)C(O)OR14, -N(R14)S(O)2R14, -S(O)2N(R14)2, -S(O)R14, -S(O)2R14, -NO2, =O, =S, =N(R14), and -CN; and R14 is independently selected at each occurrence from hydrogen, C1-6 alkyl, C1-6 haloalkyl, C3-10 carbocycle and 3- to 10-membered heterocycle. 57. The compound or salt of claim 56, wherein: R4 is selected from: oxetanyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, 6,7-dihydro-5H- cyclopenta[b]pyridinyl, and 2,3-dihydro-[1,4]dioxino[2,3-b]pyridinyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR14, -SR14, -N(R14)2, -C(O)R14, -C(O)N(R14)2, -C(O)OR14, -OC(O)R14, - N(R14)C(O)R14, -N(R14)C(O)OR14, -N(R14)S(O)2R14, -S(O)2N(R14)2, -S(O)R14, -S(O)2R14, -NO2, =O, =S, =N(R14), -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR14, -SR14, -N(R14)2, -C(O)R14, - C(O)N(R14)2, -C(O)OR14, -OC(O)R14, -N(R14)C(O)R14, -N(R14)C(O)OR14, - N(R14)S(O)2R14, -S(O)2N(R14)2, -S(O)R14, -S(O)2R14, -NO2, =O, =S, =N(R14), and -CN; and R14 is independently selected at each occurrence from hydrogen, C1-6 alkyl, C1-6 haloalkyl, C3-10 carbocycle and 3- to 10-membered heterocycle. 58. The compound or salt of claim 57,wherein R4 is selected from
Figure imgf000259_0001
, , ,
Figure imgf000259_0002
59. The compound or salt of any one of claims 1 to 45, wherein R3 and R4 come together with the atoms to which they are each bound to form a 4- to 6-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR15, -SR15, -N(R15)2, -C(O)R15, -C(O)N(R15)2, -C(O)OR15, -OC(O)R15, -N(R15)C(O)R15, -N(R15)C(O)OR15, -N(R15)S(O)2R15, -S(O)2N(R15)2, -S(O)R15, - S(O)2R15, -NO2, =O, =S, =N(R15), and -CN; and WSGR Docket No.58296-711601 C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR15, -SR15, -N(R15)2, -C(O)R15, -C(O)N(R15)2, -C(O)OR15, - OC(O)R15, -N(R15)C(O)R15, -N(R15)C(O)OR15, -N(R15)S(O)2R15, -S(O)2N(R15)2, - S(O)R15, -S(O)2R15, -NO2, =O, =S, =N(R15), and -CN. 60. The compound or salt of claim 59, wherein R3 and R4 come together with the atoms to which they are each bound to form a 4- to 6-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, -OR15, -N(R15)2, -C(O)R15, - C(O)N(R15)2, -NO2, =O, and -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR15, -N(R15)2, -C(O)R15, -C(O)N(R15)2, - NO2, =O, and -CN; and R15 is independently selected at each occurrence from hydrogen, C1-6 alkyl, and C1-6 haloalkyl. 61. The compound or salt of claim 60, wherein when R3 and R4 come together with the atoms to which they are each bound to form a 4- to 6-membered heterocycle,
Figure imgf000260_0001
. 62. The compound or salt of any one of claims 1 to 3, wherein Ring A is 8- to 10-membered heterocycle. 63. The compound or salt of claim 62, wherein Ring A is indolyl. 64. The compound or salt of claim 62 or claim 63, wherein: n is selected from 0, 1, and 2; and each R1 is independently selected at each occurrence from: halogen, -OR11, -SR11, -N(R11)2, -C(O)R11, -C(O)N(R11)2, -C(O)OR11, -OC(O)R11, -N(R11)C(O)R11, -N(R11)C(O)OR11, -N(R11)S(O)2R11, -S(O)2N(R11)2, -S(O)R11, - S(O)2R11, -NO2, =S, =N(R11), and -CN; and C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR11, -SR11, -
Figure imgf000260_0002
=N(R11), and -CN. WSGR Docket No.58296-711601 65. The compound or salt of any one of claims 62 to 64, wherein
Figure imgf000261_0001
3- to 6-membered heterocycloalkyl. 66. The compound or salt of claim 65, wherein
Figure imgf000261_0002
is selected from azetindyl and pyrrolidinyl. 67. The compound or salt of any one of claims 62 to 66, wherein: m is selected from 0, 1, and 2; and each R2 is independently selected at each occurrence from: halogen, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)N(R12)2, -C(O)OR12, -OC(O)R12, -N(R12)C(O)R12, -N(R12)C(O)OR12, -N(R12)S(O)2R12, -S(O)2N(R12)2, -S(O)R12, - S(O)2R12, -NO2, =O, =S, =N(R12), and -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR12, -SR12, -N(R12)2, -C(O)R12, -C(O)N(R12)2, -C(O)OR12, - OC(O)R12, -N(R12)C(O)R12, -N(R12)C(O)OR12, -N(R12)S(O)2R12, -S(O)2N(R12)2, - S(O)R12, -S(O)2R12, -NO2, =O, =S, =N(R12), and -CN. 68. The compound or salt of any one of claims 62 to 67, wherein R3 is hydrogen. 69. The compound or salt of any one of claims 62 to 68, wherein R4 is selected from: C1-3 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR14, -SR14, -N(R14)2, -C(O)R14, -C(O)N(R14)2, -C(O)OR14, - OC(O)R14, -N(R14)C(O)R14, -N(R14)C(O)OR14, -N(R14)S(O)2R14, -S(O)2N(R14)2, - S(O)R14, -S(O)2R14, -NO2, =O, =S, =N(R14), and -CN; and C3-6 carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR14, - SR14, -N(R14)2, -C(O)R14, -C(O)N(R14)2, -C(O)OR14, -OC(O)R14, -N(R14)C(O)R14, - N(R14)C(O)OR14, -N(R14)S(O)2R14, -S(O)2N(R14)2, -S(O)R14, -S(O)2R14, -NO2, =O, =S, =N(R14), -CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR14, -SR14, -N(R14)2, -C(O)R14, -C(O)N(R14)2, - C(O)OR14, -OC(O)R14, -N(R14)C(O)R14, -N(R14)C(O)OR14, -N(R14)S(O)2R14, - S(O)2N(R14)2, -S(O)R14, -S(O)2R14, -NO2, =O, =S, =N(R14), and -CN. WSGR Docket No.58296-711601 70. The compound or salt of claim 1, wherein the structure of Formula (I) is selected from the compounds provided in Table 1 or a pharmaceutically acceptable salt thereof. 71. A pharmaceutical composition, comprising a compound or salt of any one of claims 1 to 70, and a pharmaceutically acceptable excipient. 72. A method of modulating STT3 in a subject in need thereof, comprising administering to the subject a compound of any one of claims 1 to 70, or a pharmaceutical composition of claim 71. 73. A method of inhibiting STT3 in a subject in need thereof, comprising administering to the subject a compound of any one of claims 1 to 70, or a pharmaceutical composition of claim 71. 74. A method of modulating replication of a respiratory virus in subject in need thereof, comprising administering to the subject a compound of any one of claims 1 to 70, or a pharmaceutical composition of claim 71. 75. A method of inhibiting replication of a respiratory virus in subject in need thereof, comprising administering to the subject a compound of any one of claims 1 to 70, or a pharmaceutical composition of claim 71. 76. A method of treating a respiratory virus in subject in need thereof, comprising administering to the subject a compound of any one of claims 1 to 70, or a pharmaceutical composition of claim 71. 77. The method of any one of claims 74 to 76, wherein the respiratory virus is selected from influenza virus, a rhinovirus, a coronavirus, a metapneumovirus, an adenovirus, a syncytial virus, a bocaviruses, and a parainfluenza virus.
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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5846514A (en) 1994-03-25 1998-12-08 Isotechnika, Inc. Enhancement of the efficacy of nifedipine by deuteration
US6334997B1 (en) 1994-03-25 2002-01-01 Isotechnika, Inc. Method of using deuterated calcium channel blockers
WO2017019540A2 (en) * 2015-07-24 2017-02-02 Yale University Inhibitors of n-linked glycosylation and methods using same
WO2018130174A1 (en) * 2017-01-11 2018-07-19 江苏豪森药业集团有限公司 Pyrrolo[2,3-c]pyridine derivative, preparation method therefor, and use thereof in medicine

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5846514A (en) 1994-03-25 1998-12-08 Isotechnika, Inc. Enhancement of the efficacy of nifedipine by deuteration
US6334997B1 (en) 1994-03-25 2002-01-01 Isotechnika, Inc. Method of using deuterated calcium channel blockers
WO2017019540A2 (en) * 2015-07-24 2017-02-02 Yale University Inhibitors of n-linked glycosylation and methods using same
WO2018130174A1 (en) * 2017-01-11 2018-07-19 江苏豪森药业集团有限公司 Pyrrolo[2,3-c]pyridine derivative, preparation method therefor, and use thereof in medicine

Non-Patent Citations (24)

* Cited by examiner, † Cited by third party
Title
"Basic and Clinical Pharmacology", 2003, MCGRAW HILL
"Curr., Pharm. Des.", vol. 6, 2000, article "Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development.", pages: 110
"Encyclopedia of Reagents for Organic Synthesis", 1995
"Handbook of Clinical Drug Data", 2002, MCGRAW-HILL
"Principles of Drug Action", 1990, CHURCHILL LIVINGSTON
"Remingtons Pharmaceutical Sciences", 2000, LIPPINCOTT WILLIAMS & WILKINS.
"The Pharmacological Basis of Therapeutics", 2001, MCGRAW HILL
E. L. ELIEL: "Stereochemistry of Carbon Compounds", 1962, MCGRAW HILL
EVANS, E. ANTHONY.: "Synthesis of radiolabeled compounds", J. RADIOANAL. CHEM, vol. 64, no. 1-2, 1981, pages 9 - 32
FEDORAK ET AL., AM. J. PHYSIOL., vol. 269, 1995, pages 210 - 218
GEORGE W.VARMA, RAJENDER S.: "The Synthesis of Radiolabeled Compounds via Organometallic Intermediates", TETRAHEDRON, vol. 45, no. 21, 1989, pages 6601 - 21
HOCHHAUS ET AL., BIOMED. CHROM., vol. 6, 1992, pages 283 - 286
HU, M.ZHANG, R.YANG, J.ZHAO, C.LIU, W.HUANG, Y.LYU, H.XIAO, S.GUO, D.ZHOU, C.: "The role of N-glycosylation modification in the pathogenesis of liver cancer", CELL DEATH DIS., vol. 14, 2023
J. LARSEN ET AL., INT. J. PHARMACEUTICS, vol. 47, 1988, pages 103
J. LARSENH. BUNDGAARD, INT. J. PHARMACEUTICS, vol. 37, 1987, pages 87
L. FIESERM. FIESER, FIESER AND FIESER'S REAGENTS FOR ORGANIC SYNTHESIS, 1994
LOCHMULLER, J. CHROMATOGR., vol. 113, no. 3, 1975, pages 283 - 302
MARTINDALE: "The Extra Pharmacopoeia", 1999, THE PHARMACEUTICAL PRESS
MCLOED ET AL., GASTROENTEROL, vol. 106, 1994, pages 405 - 413
PRADEEP, PKANG, H.LEE, B.: "Glycosylation and behavioral symptoms in neurological disorders", TRANSL. PSYCHIATRY, 2023
RINIS NATALIA ET AL: "Editing N-Glycan Site Occupancy with Small-Molecule Oligosaccharyltransferase Inhibitors", CELL CHEMICAL BIOLOGY, ELSEVIER, AMSTERDAM, NL, vol. 25, no. 10, 2 August 2018 (2018-08-02), pages 1231, XP085531595, ISSN: 2451-9456, DOI: 10.1016/J.CHEMBIOL.2018.07.005 *
SINKULA ET AL., J. PHARM. SCI., vol. 64, 1975, pages 181 - 210
T. HIGUCHIV. STELLA: "Bioreversible Carriers in Drug Design", vol. 14, 1987, AMERICAN PHARMACEUTICAL ASSOCIATION AND PERGAMON PRESS
WUTS, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS, 1991

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