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WO2023114733A1 - Kras modulators and uses thereof - Google Patents

Kras modulators and uses thereof Download PDF

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Publication number
WO2023114733A1
WO2023114733A1 PCT/US2022/081393 US2022081393W WO2023114733A1 WO 2023114733 A1 WO2023114733 A1 WO 2023114733A1 US 2022081393 W US2022081393 W US 2022081393W WO 2023114733 A1 WO2023114733 A1 WO 2023114733A1
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alkyl
compound
salt
optionally substituted
halogen
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Hong Lin
Juan Luengo
Neil Johnson
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Quanta Therapeutics Inc
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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • KRAS MODULATORS AND USES THEREOF CROSS-REFERENCE [0001] This application claims the benefit of U.S. Provisional Patent Applications Nos. 63/288,970, filed on December 13, 2021; 63/367,560 filed on July 1, 2022; and 63/371,987 filed on August 19, 2022; the entire contents of each of which are incorporated herein by reference. BACKGROUND OF THE INVENTION [0002]
  • the small GTPase protein Kirsten Rat Sarcoma 2 Viral Oncogene Homolog (KRAS) is a member of the Ras family of cell signaling switches, regulating growth and survival of normal and cancerous cells (e.g., see Cully, M. and J.
  • KRAS mutations drive approximately 25% of human cancers by aberrant regulation of the mitogen-activated protein kinase (MAPK) signaling cascade and other effector pathways (e.g., see Stephen, A.G., et al., Dragging ras back in the ring. Cancer Cell, 2014.25(3): p.272-81).
  • MAPK mitogen-activated protein kinase
  • Ras has been recognized as a target in cancer for about 40 years, Ras-driven cancers remain among the most difficult to treat due to insensitivity to available targeted therapies.
  • Ras encoded by the three major genes KRAS, NRAS and HRAS, has the highest frequency of mutation of any oncogene.
  • Ras mutations All oncogenic Ras mutations drive the switch to accumulate in the active GTP-bound state.
  • the most common Ras mutation found across human tumor types is KRAS G12D (e.g., see The AACR Project GENIE Consortium. Cancer Discovery, 2017.7(8): p.818-831. Dataset Version 4).
  • Activating mutations in codon 12 impair the small GTPases’ ability to perform their role in hydrolyzing GTP. This regulatory impairment is fundamental for initiating and maintaining tumor progression.
  • GAP GTPase activating protein
  • GEF guanine nucleotide exchange factor
  • SOS guanine nucleotide exchange factor
  • KRAS G12C mutations most common in lung adenocarcinoma, have been clinically shown to be susceptible to direct inhibition by covalent modification with small molecule inhibitors trapping the protein in the inactive GDP-bound state.
  • KRAS G12D mutation confers a significantly slower intrinsic rate of GTP hydrolysis than G12C, resulting in more constitutive activation.
  • the present disclosure relates to Formula (I),Formula (II), Formula (III), or Formula (IV), including stereoisomers, tautomers, solvates, and pharmaceutically acceptable salts thereof, and to uses thereof in, for example, inhibiting KRas G12D and/or other G12 mutants.
  • Formula (I) is represented by Formula (I-A), Formula (V), or Formula (VI).
  • the disclosure provides a pharmaceutical composition comprising a compound or salt of Formula (I) and a pharmaceutically acceptable excipient.
  • the disclosure provides a method of treating a disease or disorder, using a compound or salt of Formula (I).
  • the disclosure provides a method of treating a disease or disorder, using a compound or salt of Formula (I) and a pharmaceutically acceptable excipient.
  • the disclosure provides a method of inhibiting KRas G12D and/or other G12 mutants, using a compound or salt of Formula (I).
  • the disclosure provides a method of inhibiting KRas G12D and/or other G12 mutants, using a compound or salt of Formula (I) and a pharmaceutically acceptable excipient.
  • the disclosure provides a pharmaceutical composition comprising a compound or salt of Formula (I-A) and a pharmaceutically acceptable excipient.
  • the disclosure provides a method of treating a disease or disorder, using a compound or salt of Formula (I-A).
  • the disclosure provides a method of treating a disease or disorder, using a compound or salt of Formula (I) and a pharmaceutically acceptable excipient.
  • the disclosure provides a method of inhibiting KRas G12D and/or other G12 mutants, using a compound or salt of Formula (I-A). In certain embodiments, the disclosure provides a method of inhibiting KRas G12D and/or other G12 mutants, using a compound or salt of Formula (I-A) and a pharmaceutically acceptable excipient. [0020] In certain embodiments, the disclosure provides a pharmaceutical composition comprising a compound or salt of Formula (II) and a pharmaceutically acceptable excipient. [0021] In certain embodiments, the disclosure provides a method of treating a disease or disorder, using a compound or salt of Formula (II).
  • the disclosure provides a method of treating a disease or disorder, using a compound or salt of Formula (II) and a pharmaceutically acceptable excipient.
  • the disclosure provides a method of inhibiting KRas G12D and/or other G12 mutants, using a compound or salt of Formula (II).
  • the disclosure provides a method of inhibiting KRas G12D and/or other G12 mutants, using a compound or salt of Formula (II) and a pharmaceutically acceptable excipient.
  • the disclosure provides a pharmaceutical composition comprising a compound or salt of Formula (III) and a pharmaceutically acceptable excipient.
  • the disclosure provides a method of treating a disease or disorder, using a compound or salt of Formula (III). In certain embodiments, the disclosure provides a method of treating a disease or disorder, using a compound or salt of Formula (III) and a pharmaceutically acceptable excipient. [0025] In certain embodiments, the disclosure provides a method of inhibiting KRas G12D and/or other G12 mutants, using a compound or salt of Formula (III). In certain embodiments, the disclosure provides a method of inhibiting KRas G12D and/or other G12 mutants, using a compound or salt of Formula (III) and a pharmaceutically acceptable excipient.
  • the disclosure provides a pharmaceutical composition comprising a compound or salt of Formula (IV) and a pharmaceutically acceptable excipient.
  • the disclosure provides a method of treating a disease or disorder, using a compound or salt of Formula (IV).
  • the disclosure provides a method of treating a disease or disorder, using a compound or salt of Formula (IV) and a pharmaceutically acceptable excipient.
  • the disclosure provides a method of inhibiting KRas G12D and/or other G12 mutants, using a compound or salt of Formula (IV).
  • the disclosure provides a method of inhibiting KRas G12D and/or other G12 mutants, using a compound or salt of Formula (IV) and a pharmaceutically acceptable excipient.
  • the disclosure provides a pharmaceutical composition comprising a compound or salt of Formula (V) and a pharmaceutically acceptable excipient.
  • the disclosure provides a method of treating a disease or disorder, using a compound or salt of Formula (V).
  • the disclosure provides a method of treating a disease or disorder, using a compound or salt of Formula (V) and a pharmaceutically acceptable excipient.
  • the disclosure provides a method of inhibiting KRas G12D and/or other G12 mutants, using a compound or salt of Formula (V). In certain embodiments, the disclosure provides a method of inhibiting KRas G12D and/or other G12 mutants, using a compound or salt of Formula (V) and a pharmaceutically acceptable excipient. [0032] In certain embodiments, the disclosure provides a pharmaceutical composition comprising a compound or salt of Formula (VI) and a pharmaceutically acceptable excipient. [0033] In certain embodiments, the disclosure provides a method of treating a disease or disorder, using a compound or salt of Formula (VI).
  • the disclosure provides a method of treating a disease or disorder, using a compound or salt of Formula (VI) and a pharmaceutically acceptable excipient.
  • the disclosure provides a method of inhibiting KRas G12D and/or other G12 mutants, using a compound or salt of Formula (VI).
  • the disclosure provides a method of inhibiting KRas G12D and/or other G12 mutants, using a compound or salt of Formula (VI) and a pharmaceutically acceptable excipient.
  • Alkyl refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, and preferably having from one to fifteen carbon atoms (i.e., C 1 -C 15 alkyl). In certain embodiments, an alkyl comprises one to thirteen carbon atoms (i.e., C 1 -C 13 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., C 1 -C 5 alkyl). In other embodiments, an alkyl comprises one to four carbon atoms (i.e., C 1 -C 4 alkyl). In other embodiments, an alkyl comprises one to three carbon atoms (i.e., C 1 -C 3 alkyl). In other embodiments, an alkyl comprises one to two carbon atoms (i.e., C 1 -C 2 alkyl). In other embodiments, an alkyl comprises one carbon atom (i.e.,C 1 alkyl).
  • an alkyl comprises five to fifteen carbon atoms (i.e., C 5 -C 15 alkyl). In other embodiments, an alkyl comprises five to eight carbon atoms (i.e., C 5 -C 8 alkyl). In other embodiments, an alkyl comprises two to five carbon atoms (i.e., C 2 -C 5 alkyl). In other embodiments, an alkyl comprises three to five carbon atoms (i.e., C 3 -C 5 alkyl).
  • the alkyl group is selected from 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).
  • the alkyl is attached to the rest of the molecule by a single bond.
  • C x-y when used in conjunction with a chemical moiety, such as alkyl, alkenyl, or alkynyl is meant to include groups that contain from x to y carbons in the chain.
  • C 1-6 alkyl refers to substituted or unsubstituted saturated hydrocarbon groups, including straight-chain alkyl and branched-chain alkyl groups that contain from 1 to 6 carbons.
  • the term –C x-y alkylene- refers to a substituted or unsubstituted alkylene chain with from x to y carbons in the alkylene chain.
  • alkylene- may be selected from methylene, ethylene, propylene, butylene, pentylene, and hexylene, any one of which is optionally substituted.
  • Alkoxy refers to a radical bonded through an oxygen atom of the formula –O-alkyl, where alkyl is an alkyl chain as defined above.
  • Alkenyl refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and preferably having from two to twelve carbon atoms (i.e., C 2 -C 12 alkenyl).
  • an alkenyl comprises two to eight carbon atoms (i.e., C 2 -C 8 alkenyl). 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., C 2 -C 4 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.
  • 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., C 2 -C 12 alkynyl).
  • an alkynyl comprises two to eight carbon atoms (i.e., C 2 -C 8 alkynyl).
  • an alkynyl comprises two to six carbon atoms (i.e., C 2 -C 6 alkynyl).
  • an alkynyl comprises two to four carbon atoms (i.e., C 2 -C 4 alkynyl).
  • the alkynyl is attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.
  • C x-y alkenyl and C x-y alkynyl refer to substituted or unsubstituted 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 –C x-y alkenylene- refers to a substituted or unsubstituted alkenylene chain with from x to y carbons in the alkenylene chain.
  • –C 2-6 alkenylene- may be selected from ethenylene, propenylene, butenylene, pentenylene, and hexenylene, any one of which is optionally substituted.
  • An alkenylene chain may have one double bond or more than one double bond in the alkenylene chain.
  • the term –C x-y alkynylene- refers to a substituted or unsubstituted alkynylene chain with from x to y carbons in the alkenylene chain.
  • alkenylene- 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.
  • "Alkylene” or “alkylene chain” refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing no unsaturation, and preferably having from one to twelve carbon atoms, for example, methylene, ethylene, propylene, n-butylene, and the like.
  • an 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 may be through any two carbons within the chain.
  • an alkylene comprises one to ten carbon atoms (i.e., C 1 -C 8 alkylene).
  • an alkylene comprises one to eight carbon atoms (i.e., C 1 -C 8 alkylene).
  • an alkylene comprises one to five carbon atoms (i.e., C 1 -C 5 alkylene).
  • an alkylene comprises one to four carbon atoms (i.e., C 1 -C 4 alkylene). In other embodiments, an alkylene comprises one to three carbon atoms (i.e., C 1 -C 3 alkylene). In other embodiments, an alkylene comprises one to two carbon atoms (i.e., C 1 -C 2 alkylene). In other embodiments, an alkylene comprises one carbon atom (i.e., 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., C 2 -C 5 alkylene).
  • an alkylene comprises three to five carbon atoms (i.e., C 3 -C 5 alkylene).
  • "Alkenylene” or “alkenylene chain” refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon double bond, and 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 may be through any two carbons within the chain.
  • an alkenylene comprises two to ten carbon atoms (i.e., C 2 -C 10 alkenylene). In certain embodiments, an alkenylene comprises two to eight carbon atoms (i.e., C 2 -C 8 alkenylene). In other embodiments, an alkenylene comprises two to five carbon atoms (i.e., C 2 -C 5 alkenylene). In other embodiments, an alkenylene comprises two to four carbon atoms (i.e., C 2 -C 4 alkenylene). In other embodiments, an alkenylene comprises two to three carbon atoms (i.e., C2-C 3 alkenylene).
  • an alkenylene comprises two carbon atom (i.e., C 2 alkenylene). In other embodiments, an alkenylene comprises five to eight carbon atoms (i.e., C 5 -C 8 alkenylene). In other embodiments, an alkenylene comprises three to five carbon atoms (i.e., C 3 -C 5 alkenylene).
  • Alkynylene or “alkynylene chain” refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon triple bond, and preferably having from two to twelve carbon atoms.
  • an 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 may be through any two carbons within the chain.
  • 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., C 2 -C 5 alkynylene).
  • an alkynylene comprises two to four carbon atoms (i.e., C 2 -C 4 alkynylene). In other embodiments, an alkynylene comprises two to three carbon atoms (i.e., C 2 -C 3 alkynylene). In other embodiments, an alkynylene comprises two carbon atom (i.e., C 2 alkynylene). In other embodiments, an alkynylene comprises five to eight carbon atoms (i.e., C 5 -C 8 alkynylene). In other embodiments, an alkynylene comprises three to five carbon atoms (i.e., C 3 -C 5 alkynylene).
  • 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.
  • Alkyl refers to a radical of the formula -R c -aryl where R c is an alkylene chain as defined above, for example, methylene, ethylene, and the like.
  • Alkenyl refers to a radical of the formula –R d -aryl where R d is an alkenylene chain as defined above.
  • Alkynyl refers to a radical of the formula -R e -aryl, where R e is an alkynylene chain as defined above.
  • Carbocycle refers to a saturated, unsaturated or aromatic rings in which each atom of the ring is carbon.
  • Carbocycle may include 3- to 10-membered monocyclic rings, 6- to 12- membered bicyclic rings, and 6- to 12-membered bridged rings.
  • Each ring of a bicyclic carbocycle may be selected from saturated, unsaturated, and aromatic rings.
  • 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.
  • Bicyclic carbocycles may be fused, bridged or spiro-ring systems. In some cases, spiro-ring carbocycles have at least two molecular rings with only one common atom.
  • unsaturated carbocycle refers to carbocycles with at least one degree of unsaturation and excluding aromatic carbocycles. Examples of unsaturated carbocycles include cyclohexadiene, cyclohexene, and cyclopentene.
  • Cycloalkyl refers to a 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. In certain embodiments, a cycloalkyl comprises three to ten carbon atoms. In other embodiments, a cycloalkyl comprises five to seven carbon atoms. The cycloalkyl may be attached to the rest of the molecule by a single bond.
  • Examples of monocyclic cycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • Polycyclic cycloalkyl radicals include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like.
  • Cycloalkenyl refers to an 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.
  • a cycloalkenyl comprises three to ten carbon atoms.
  • a cycloalkenyl comprises five to seven carbon atoms.
  • the cycloalkenyl may be attached to the rest of the molecule by a single bond.
  • Examples of monocyclic cycloalkenyls includes, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.
  • Cycloalkylalkyl refers to a radical of the formula –R c -cycloalkyl where R c is an alkylene chain as described above.
  • Cycloalkylalkoxy refers to a radical bonded through an oxygen atom of the formula – O-R c -cycloalkyl where R c is an alkylene chain as described 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, I, etc.).
  • halogen substituted alkanes e.g., Cl, Br, F, I, etc.
  • each halogen may be independently selected e.g., 1-chloro,2-fluoroethane.
  • fluoroalkyl refers to an alkyl radical, as defined above, that is substituted by one or more fluoro radicals, for example, trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like.
  • Aminoalkyl refers to an alkyl radical, as defined above, that is substituted by one or more amine radicals, for example, propan-2-amine, butane-1,2-diamine, pentane-1,2,4-triamine and the like.
  • Aminoalkyl refers to an alkyl radical, as defined above, that is substituted by one or more alkoxy radicals, for example, methoxymethane, 1,3-dimethoxybutane, 1-methoxypropane, 2-ethoxypentane, and the like.
  • Cyanoalkyl refers to an alkyl radical, as defined above, that is substituted by one or more cyano radicals, for example, acetonitrile, 2-ethyl-3-methylsuccinonitrile, butyronitrile, and the like.
  • Hydroalkyl refers to an alkyl radical, as defined above, that is substituted by one or more hydroxy radicals, for example, propan-1-ol, butane-1,4-diol, pentane-1,2,4-triol, and the like.
  • Heterocycle refers to a saturated or unsaturated or aromatic ring comprising one or more heteroatoms.
  • heteroatoms include N, O, Si, P, B, and S atoms.
  • Heterocycles include 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, and 6- to 12- membered bridged rings. Each ring of a bicyclic heterocycle may be selected from saturated, unsaturated, and aromatic rings. Bicyclic heterocycles may be fused, bridged or spiro-ring systems. In some cases, spiro-ring heterocycles have at least two molecular rings with only one common atom. The spiro-ring heterocycle includes at least one heteroatom. [0065] “Heterocyclene” refers to a divalent heterocycle linking the rest of the molecule to a radical group.
  • Heteroaryl or “aromatic heterocycle” refers to a radical derived from a heteroaromatic ring radical that comprises one to eleven carbon atoms and at least one heteroatom wherein each heteroatom may be selected from N, O, and S.
  • the heteroaryl ring may be selected from monocyclic or bicyclic and fused or bridged ring systems rings wherein at least one of the rings in the ring system is aromatic, i.e., it contains a cyclic, delocalized (4n+2) ⁇ – electron system in accordance with the Hückel theory.
  • the heteroatom(s) in the heteroaryl radical may be optionally oxidized.
  • One or more nitrogen atoms, if present, are optionally quaternized.
  • 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.
  • heteroaryls include, but are not limited to, pyridine, pyrimidine, oxazole, furan, pyran, thiophene, isoxazole, benzimidazole, benzthiazole, and imidazopyridine.
  • An “X-membered heteroaryl” 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.
  • the term “unsaturated heterocycle” refers to heterocycles with at least one degree of unsaturation and excluding aromatic heterocycles. Examples of unsaturated heterocycles include dihydropyrrole, dihydrofuran, oxazoline, pyrazoline, and dihydropyridine. Heterocycles may be optionally substituted by one or more substituents such as those substituents described herein.
  • substituted refers to moieties having substituents replacing a hydrogen on one or more carbons or substitutable heteroatoms, e.g., NH, of the structure. 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.
  • the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms.
  • 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.
  • Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
  • Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.
  • Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.
  • Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like.
  • Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine.
  • the pharmaceutically acceptable base addition salt is chosen from ammonium, potassium, sodium, calcium, and magnesium salts.
  • parenteral administration and “administered parenterally” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.
  • phrases “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable excipient or “pharmaceutically acceptable carrier” as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
  • materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide;
  • 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.
  • the terms “treat,” “treating” or “treatment,” as used herein, may include alleviating, abating or ameliorating a disease or condition symptoms, preventing additional symptoms, ameliorating or preventing the underlying causes of symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition either prophylactically and/or therapeutically.
  • G12 mutants refers to other oncogenic alleles of KRAS at amino acid position 12 (ie. G12X).
  • Formula (I) is represented by Formula (I-A), Formula (V), or Formula (VI).
  • the present disclosure provides a compound represented by the structure of Formula (I-A): ( ), or a pharmaceutically acceptable salt thereof, wherein: Y is O; R 2 is selected from -L-heterocycle, and -L-heteroaryl, wherein the heterocycle portion of -L- heterocycle, is optionally substituted with one or more R 6 , and wherein the heteroaryl of the -L- heteroaryl is optionally substituted with one or more R 7 ; each L is independently selected from a C 1 -C 4 alkylene optionally substituted with one or more substituents independently selected from -OH, C 1 -C 4 hydroxyalkyl, C 1 -C 4 alkyl, C 3 -C 6 carbocycle, or 3- to 8-membered heterocycle, wherein the C 3 -C 6 carbocycle and 3- to 8-membered heterocycle, wherein the C 3 -C 6
  • Y is O, R 2 is , R 9 is selected from pyrrolidine and thiazole, the pyrrolidine and thiazole are each optionally substituted with one or more R 49 .
  • Y is O. In some cases, Y is a bond. In some cases, Y is -NR 5 -.
  • L is selected from optionally substituted C1-C4 alkylene.
  • L is selected from optionally substituted C 1 -C 2 alkylene. In some cases, L is selected from optionally substituted C 1 alkylene. In some cases L is selected from unsubstituted C 1 -C 4 alkylene. [0086] In some embodiments, for a compound or salt of Formula (I), (I-A), (V), or (VI), L is selected from unsubstituted C 1 -C 4 alkylene. In some cases, L is selected from unsubstituted C 1 -C2 alkylene. In some cases, L is selected from unsubstituted C 1 alkylene. In some cases, L is selected from methylene and ethylene. In some cases, L is methylene.
  • the optional substituents of L are selected from C 1 -C 4 hydroxyalkyl, C 1 -C 4 alkyl, C 3 -C 6 carbocycle, wherein the C 3 -C 6 carbocycle is optionally substituted with one or more substituents selected from halogen.
  • optionally two substituents on the same carbon atom of L come together to form a C 3 carbocycle wherein the C 3 carbocycle is optionally substituted with one or more substituents selected from halogen.
  • optionally two hydrogens on the same carbon atom of L come together to form a C 3 carbocycle wherein the C 3 carbocycle is optionally substituted with one or more substituents selected from halogen.
  • R 2 is selected from optionally substituted -L-heterocycle, optionally substituted -L-heteroaryl, optionally substituted -L-aryl, -L-N(R 5 ) 2 , and -L-O-R 5 .
  • R 2 is selected from optionally substituted -L-5- to 12-membered heterocycle, optionally substituted -L-5- to 12-membered heteroaryl, optionally substituted -L-C6-C 12 aryl, -L- N(R 5 ) 2 , and -L-O-R 5 .
  • R 2 is selected from optionally substituted -L-heterocycle, optionally substituted -L-heteroaryl, and -L-N(R 5 ) 2 .
  • R 2 is selected from optionally substituted -L-5- to 12-membered heterocycle, optionally substituted -L-5- to 12-membered heteroaryl, and -L-N(R 5 ) 2 . In some cases, R 2 is selected from optionally substituted -L-heterocycle and -L-N(R 5 ) 2 . In some cases, R 2 is selected from optionally substituted -L-5- to 12-membered heterocycle and -L-N(R 5 ) 2 . In some cases, R 2 is selected from optionally substituted -L-5- to 12- membered heterocycle. In some cases, R 2 is selected from optionally substituted -L-heterocycle.
  • the heterocycle is selected from pyrrolidine, hexahydro-1H-pyrrolizine, pyrazolidine, imidazolidine, tetrahydrofuran, piperidine, piperazine, morpholine, azocane, and azonane.
  • the heterocycle is selected from pyrrolidine, hexahydro-1H-pyrrolizine, pyrazolidine, imidazolidine, piperidine, piperazine, azocane, and azonane.
  • the heteroaryl is selected from pyrrole, pyrazole, furan, thiohene, oxazole, isoxazole, isothiazole, thiazole, pyridine, pyrazine, and triazine.
  • the heteroaryl or heterocycle has at most 1 nitrogen atom.
  • the heteroaryl or heterocycle has at least 1 nitrogen atom.
  • the heterocycle of R 2 is a 5- to 12-membered heterocycle, 6- to 12-membered heterocycle, 7- to 12-membered heterocycle, or 8- to 12-membered heterocycle.
  • the heterocycle of R 2 is a 5- to 11- membered heterocycle, 5- to 10-membered heterocycle, 5- to 9-membered heterocycle, or 5- to 8- membered heterocycle.
  • the heterocycle of R 2 is a 6- to 11-membered heterocycle, 6- to 10-membered heterocycle, 6- to 9-membered heterocycle, or 6- to 8-membered heterocycle.
  • the heterocycle of R 2 is a 7- to 11-membered heterocycle, 7- to 10-membered heterocycle, 7- to 9-membered heterocycle, or 7- to 8-membered heterocycle.
  • the heterocycle of R 2 is a 5- to 6-membered heterocycle or 5- to 9-membered heterocycle. In some cases, the heterocycle of R 2 is an 8- to 9-membered heterocycle. In some embodiments, for a compound of Formula (I), the heterocycle of R 2 is saturated. The heterocycle may be optionally substituted as described elsewhere herein.
  • the optional substituents of L are selected from C 1 -C 4 hydroxyalkyl, C 1 - C 4 alkyl, C 3 -C 6 carbocycle; and wherein optionally two substituents on the same carbon atom of L come together to form a C 3 -C 6 carbocycle or 3- to 8-membered heterocycle wherein the C 3 -C 6 carbocycle and 3- to 8-membered heterocycle are optionally substituted with one or more substituents selected from halogen and C 1-6 haloalkyl.
  • each L is independently selected from a substituted C 1 -C 4 alkylene, wherein two substituents on the same carbon atom of L come together to form a C 3 -C 6 carbocycle.
  • each L is independently selected from a substituted C 1 -C 4 alkylene, and wherein two substituents on the same carbon atom of L come together to form a C 3 -C 6 carbocycle. In some cases, each L is independently selected from a substituted C 3 alkylene, and wherein two substituents on the same carbon atom of L come together to form a C 3 carbocycle.
  • each L is independently selected from [0096]
  • R 2 is selected from -L-heterocycle, wherein the heterocycle portion of -L-heterocycle is optionally substituted with one or more R 6 .
  • the heterocycle is a saturated heterocycle.
  • the heterocycle has at least one nitrogen atom and at least one sulfur atom.
  • the heterocycle has at least one nitrogen atom.
  • the heterocycle has at least one sulfur atom.
  • R 2 is selected from wherein the heterocycle portion is optionally substituted with one or more R 6 .
  • Y-R 2 is selected from , wherein the heterocycle portion is optionally substituted with one or more R 6 .
  • Y-R 2 is selected from wherein the heterocycle portion is optionally substituted with one or more R 6 .
  • Y-R 2 is selected fro and , wherein the heterocycle portion is optionally substituted with one or more R 6 .
  • R 2 is selected from -L-saturated heterocycle, wherein the saturated heterocycle portion of the -L- saturated heterocycle is optionally substituted with one or more R 6 , and contains one nitrogen atom and one sulfur atom.
  • Y-R 2 is selected from , and , wherein the heterocycle portion is optionally substituted with one or more R 6 .
  • each R 6 is independently selected from halogen, -OH, C 1 -C 3 hydroxyalkyl, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 1 - C 3 alkoxy, -CN, C 1 -C 3 aminoalkyl, -Q-phenyl, -Q-phenylSO 2 F, -NHC(O)phenyl, - NHC(O)phenylSO 2 F, C 1 -C 3 alkyl substituted pyrazolyl, -N(R 5
  • each R 6 is independently selected from halogen, -OH, C 1 -C 3 hydroxyalkyl, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C1- C 3 alkoxy, -CN, and C 1 -C 3 aminoalkyl.
  • each R 6 is independently selected from halogen, -OH, C 1 -C 3 hydroxyalkyl, C 1 -C 3 alkyl, C 1 -C 3 aminoalkyl, C 1 -C 3 haloalkyl, C 1 -C 3 alkoxy, -N(R 5 ) 2 , and oxo. In some cases, each R 6 is independently selected from -OH, C 1 -C 3 hydroxyalkyl, C 1 -C 3 alkyl, C 1 -C 3 aminoalkyl, C 1 -C 3 alkoxy, and -N(R 5 ) 2 .
  • each R 6 is independently selected from C 1 -C 3 alkyl, C 1 -C 3 alkoxy, and -N(R 5 ) 2 .
  • R 6 is selected from halogen, -OH, C 1 -C 3 hydroxyalkyl, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 alkoxy, - CN, and C 1 -C 3 aminoalkyl.
  • R 6 is selected from halogen and C 1 -C 3 alkyl.
  • R 6 is halogen.
  • R 6 is C 1 -C 3 alkyl. In some cases, R 6 is selected from halogen and C 1 -C 3 alkyl. In some cases, R 6 is selected from methyl and fluorine. [00106] In some embodiments, for a compound or salt of Formula (I), (I-A), (V), or (VI), R 2 is selected from [00107] In some embodiments, for a compound or salt of Formula (I), (I-A), (V), or (VI), Y-R 2 is selected from [00108] In some embodiments, for a compound or salt of Formula (I), (I-A), (V), or (VI), Y- R 2 is selected from , , [00109] In some embodiments, for a compound or salt of Formula (I), (I-A), (V), or (VI), Y-R 2 i s .
  • R 50 is selected from hydrogen, halogen, C 1 -C 3 cyanoalkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, and C 3 -C 6 carbocycle. In some cases, R 50 is selected from hydrogen, Cl 5 In some cases, R 0 is hydrogen.
  • R 4 is selected from halogen and hydrogen. In some cases, R 4 is selected from halogen. In some cases, R 4 is selected from chloride and fluorine. In some cases, R 4 is fluorine. In some cases, R 4 is hydrogen.
  • R 4 is selected from hydrogen, halogen, C 1 -C 3 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, and -O-C 1-6 alkyl, wherein the alkyl portion of -O-C 1-6 alkyl is substituted with one or more halogen substituents.
  • R 4 is selected from C 1-6 haloalkyl, C 1-6 alkoxy, and -O-C 1-6 alkyl, wherein the alkyl portion of -O-C 1-6 alkyl is substituted with one or more halogen substituents.
  • R 4 is selected from C 1-6 alkoxy, and -O-C 1-6 alkyl, wherein the alkyl portion of -O-C 1-6 alkyl is substituted with one or more halogen substituents. In some cases, R 4 is selected from -O-C 1-6 alkyl, wherein the alkyl portion of -O-C 1-6 alkyl is substituted with one or more halogen substituents.
  • the carbocycle of R 9 is selected from C 3 -C 12 carbocycle, C 3 -C 10 carbocycle, C 3 -C 9 carbocycle, C 3 -C 8 carbocycle, or C 3 -C 6 carbocycle.
  • the carbocycle of R 9 is selected from C 3 -C 12 carbocycle, C 4 -C 12 carbocycle, C 5 -C 12 carbocycle, C 6 -C 12 carbocycle, C 7 -C 12 carbocycle, C 8 -C 12 carbocycle, or C 9 -C 12 carbocycle.
  • the heterocycle of R 9 is a 5- to 12-membered heterocycle, 6- to 12-membered heterocycle, 7- to 12-membered heterocycle, or 8- to 12-membered heterocycle.
  • the heterocycle of R 9 is a 5- to 11- membered heterocycle, 5- to 10-membered heterocycle, 5- to 9-membered heterocycle, or 5- to 8- membered heterocycle.
  • the heterocycle of R 9 is a 6- to 11-membered heterocycle, 6- to 10-membered heterocycle, 6- to 9-membered heterocycle, or 6- to 8-membered heterocycle.
  • the heterocycle of R 9 is a 7- to 11-membered heterocycle, 7- to 10-membered heterocycle, 7- to 9-membered heterocycle, or 7- to 8-membered heterocycle. In some cases, the heterocycle of R 9 is a 5- to 6-membered heterocycle or 5- to 9-membered heterocycle. In some cases, the heterocycle of R 9 is an 8- to 9-membered heterocycle. In some embodiments, for a compound of Formula (I), the heterocycle of R 9 is saturated. The heterocycle may be optionally substituted as described elsewhere herein.
  • the heterocycle of R 9 is a 5- to 12-membered monocyclic heterocycle, 6- to 12-membered monocyclic heterocycle, 7- to 12-membered monocyclic heterocycle, or 8- to 12-membered monocyclic heterocycle.
  • the heterocycle of R 9 is a 5- to 11-membered monocyclic heterocycle, 5- to 10- membered monocyclic heterocycle, 5- to 9-membered monocyclic heterocycle, or 5- to 8- membered monocyclic heterocycle.
  • the heterocycle of R 9 is a 6- to 11-membered monocyclic heterocycle, 6- to 10-membered monocyclic heterocycle, 6- to 9-membered monocyclic heterocycle, or 6- to 8-membered monocyclic heterocycle.
  • the heterocycle of R 9 is a monocyclic 7- to 11-membered heterocycle, 7- to 10-membered monocyclic heterocycle, 7- to 9-membered monocyclic heterocycle, or 7- to 8-membered monocyclic heterocycle.
  • the heterocycle of R 9 is a 5- to 6-membered monocyclic heterocycle or 5- to 9-membered monocyclic heterocycle.
  • the heterocycle of R 9 is an 8- to 9- membered monocyclic heterocycle.
  • the heterocycle of R 9 is saturated.
  • the monocyclic heterocycle may be optionally substituted as described elsewhere herein.
  • the fused heterocycle of R 9 is a 6- to 12-membered fused heterocycle, 6- to 12- membered fused heterocycle, 7- to 12-membered fused heterocycle, or 8- to 12-membered fused heterocycle.
  • the fused heterocycle of R 9 is a 6- to 11-membered fused heterocycle, 6- to 10-membered fused heterocycle, 6- to 9-membered fused heterocycle, or 6- to 8-membered fused heterocycle.
  • the fused heterocycle of R 9 is a 7- to 11-membered fused heterocycle, 7- to 10-membered fused heterocycle, 7- to 9-membered fused heterocycle, or 7- to 8-membered fused heterocycle.
  • the fused heterocycle of R 9 is an 8- to 11-membered fused heterocycle.
  • the fused heterocycle of R 9 is a 10-membered fused heterocycle.
  • the fused heterocycle of R 9 is a 6-membered fused heterocycle.
  • the fused heterocycle may be optionally substituted as described elsewhere herein.
  • R 9 is selected from 7- to 8-membered spiro heterocycle. In some cases, R 9 is selected from 7-membered spiro heterocycle. In some cases, R 9 is selected from 8-membered spiro heterocycle. In some cases, R 9 is selected from 9-membered spiro heterocycle. In some cases, R 9 is selected from 10-membered spiro heterocycle.
  • R 9 is selected from 11-membered spiro heterocycle.
  • the spiro heterocycle may be substituted as described elsewhere herein.
  • the spiro heterocycle of R 9 contains at most 1 nitrogen atom.
  • the spiroheterocycle of R 9 contains at most 2 heteroatom atoms.
  • the spiroheterocycle of R 9 contains at most 3 heteroatom atoms.
  • the spiroheterocycle of R 9 contains at most 1 heteroatom atom.
  • the spiroheterocycle of R 9 contains at least 2 heteroatom atoms. In some cases, the spiroheterocycle of R 9 contains at least 3 heteroatom atoms. In some cases, the spiroheterocycle of R 9 contains at least 4 heteroatom atoms. In some cases, the spiroheterocycle of R 9 contains at least 2 nitrogen atoms. In some embodiments, the spiroheterocycle of R 9 contains at most 1 heteroatom atom. In some cases, the spiroheterocycle of R 9 contains at most 1 sulfur atom. In some cases, the heteroatom is selected from nitrogen, oxygen, and sulfur.
  • the spiro heterocycle of R 9 is selected from , In some embodiments, the spiro heterocycle of R 9 is selected from , .
  • the spiroheterocycle may be substituted as described elsewhere herein.
  • the 5- to 12-membered heterocycle of R 1 is an unsaturated heterocycle.
  • the 5- to 12-membered heterocycle of R 1 is a saturated heterocycle.
  • the 5- to 12-membered heterocycle of R 1 is a fused heterocycle.
  • the 5- to 12-membered heterocycle of R 1 is a bridged heterocycle.
  • the 5- to 12-membered heterocycle of R 1 is a non-bridged heterocycle.
  • the 5- to 12-membered heterocycle of R 1 is a monocyclic heterocycle.
  • the 5- to 12-membered heterocycle of R 1 is a bicyclic heterocycle.
  • the 5- to 12-membered heterocycle of R 1 is a spiro heterocycle.
  • R 9 is selected from 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle is substituted with one or more substituents independently selected from -OR 20 and -CN.
  • R 9 is selected from an optionally substituted 6- to 10-membered heterocycle.
  • R 9 is selected from , .
  • R 9 is selected from an optionally substituted 6- to 7-membered heterocycle.
  • the 6- to 7- membered heterocycle is a saturated heterocycle. In some cases, the 6- to 7-membered heterocycle is an unsaturated heterocycle.
  • R 9 is selected from and , each of which is substituted with one or more substituents independently selected from halogen, -OR 20 and -CN. In some cases, R 9 is selected from each of which is substituted with one or more substituents independently selected from -OR 20 and -CN. In some cases, R 9 is selected from , each of which is substituted with one or more substituents independently selected from -OH and -CN.
  • R 9 is selected fro m , each of which is substituted with one or more substituents independently selected from -OH and -CN, and further optionally substituted with C 1-6 alkyl. In some cases, R 9 is selected from some cases, R 9 is selected from 9 In some cases, the heterocycle of R is not piperazine. [00132] In some embodiments, for a compound or salt of Formula (I) or (I-A), R 9 is selected
  • each R 20 is independently selected from hydrogen; and C 1-6 alkyl, C 3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO 2 , -NH2, C 1-10 alkyl, -C 1-10 haloalkyl, -O-C 1-10 alkyl.
  • R 9 is selected from 5- to 12-membered unsaturated heterocycle, wherein the 5- to 12- membered unsaturated heterocycle is optionally substituted with one or more substituents independently selected from halogen, -OR 20 , -N(R 20 ) 2 , C 1-6 aminoalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 haloalkyl.
  • R 9 is selected from a 7-membered unsaturated heterocycle, wherein the 5- to 12-membered unsaturated heterocycle is optionally substituted with one or more substituents independently selected from halogen, -OR 20 , -N(R 20 ) 2 , C 1-6 aminoalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 haloalkyl. In some cases, R 9 is selected from which is optionally substituted with one or more substituents independently selected from halogen, -OR 20 and -CN.
  • R 9 is selected from which is substituted with one or more substituents independently selected from halogen, -OR 20 and -CN. In some cases, R 9 is selected which is substituted with one or more substituents independently selected from halogen. [00136] In some embodiments, for a compound or salt of Formula (I) or (I-A), R 9 is selected from an optionally substituted 5- to 12-membered unsaturated heterocycle, wherein the heterocycle has as most one nitrogen atom. In some cases, the 5- to 12-membered unsaturated heterocycle has at least one nitrogen atom.
  • R 9 is selected from 6- to 7-membered heterocycle. In some cases, R 9 is selected from 7-membered heterocycle. In some cases, R 9 is selected from 6-membered heterocycle. In some cases, the 6- to 7-membered heterocycle contains only 1 nitrogen atom and optionally one or more additional heteroatoms selected from oxygen, and sulfur. In some cases, the optionally one or more additional heteroatoms are selected from sulfur. In some cases, the optionally one or more additional heteroatoms are selected from oxygen.
  • the 6- to 7-membered heterocycle contains only 1 nitrogen atom and no further additional heteroatoms. In some cases, the 6- to 7-membered heterocycle is a non-aromatic 6- to 7-membered heterocycle. In some cases, the 6- to 7-membered heterocycle of R 9 is bound to Formula (I), (I-A), or (VI) via the only 1 nitrogen atom. In some cases, R 9 is selected from , , each of which is substituted. In some 9 cases, R is selected from , each of which is substituted.
  • R 9 is selected from , , some cases, R 9 i [00138]
  • the heterocycle of R 9 is not piperazine.
  • the heterocycle of R 9 is not morpholine.
  • R 9 is selected from pyrrolidine and thiazole.
  • R 9 is selected from pyrrolidine and thiazole, each of which is substituted with -NH2. In some cases, R 9 is selected from pyrrolidine. In some cases, R 9 is selected from thiazole. In some cases, the heterocycle of R 9 is not substituted with -N(R 20 ) 2 . In some cases, the heterocycle of R 9 is not substituted with -NH2. [00139] In some embodiments, for a compound or salt of Formula (I), (I-A), or (VI), Q is a bond. In some cases, Q is O.
  • the one or more substituents of R 9 are independently selected from halogen, -OR 20 , -N(R 20 ) 2 , -NO 2 , C 1-6 aminoalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, and C 1-6 alkyl.
  • the one or more substituents of R 9 are independently selected from halogen, -OR 20 , -N(R 20 ) 2 , -NO 2 , C 1-6 aminoalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, and C 1-6 alkyl. In some cases, the one or more substituents of R 9 are independently selected from -OR 20 , -N(R 20 ) 2 , C 1-6 aminoalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, and C 1-6 alkyl.
  • the one or more optional substituents of R 9 are independently selected from -OR 20 , -N(R 20 ) 2 , C 1-6 aminoalkyl, and C 1-6 hydroxyalkyl. In some cases, the one or more optional substituents of R 9 are independently selected from -OR 20 , - N(R 20 ) 2 , C 1-6 aminoalkyl, C 1-6 alkyl, and C 1-6 hydroxyalkyl. In some cases, the one or more optional substituents of R 9 are independently selected from -OR 20 , -N(R 20 ) 2 , and C 1-6 alkyl.
  • R 9 when R 9 is substituted with at least one -N(R 20 ) 2 , and R 2 is -L-heterocycle, the heterocycle of -L-heterocycle is a bicyclic heterocycle. In some cases, when R 9 is substituted with at least one -N(R 20 ) 2 , R 2 not , or Y- R 2 is not . In some cases, when 9 R is substituted with at least one -N(R 20 ) 2 , R 3 is not benzothiazole. In some cases, when R 9 is substituted with at least one -N(R 20 ) 2 , R 3 is selected from an optionally substituted aryl.
  • R 9 when R 9 is substituted with at least one -N(R 20 ) 2 , R 4 is hydrogen. In some cases, when R 9 is substituted with at least one -N(R 20 ) 2 , R 50 is hydrogen.
  • each R 20 is independently selected from hydrogen; and C 1-6 alkyl.
  • R 3 is selected from optionally substituted C6-C10 aryl.
  • the C6-C10 aryl is optionally substituted with one or more substituents independently selected from halogen, -OH, -NO 2 , C 1 -C 4 alkyl, C 1-6 aminoalkyl, C 1 -C 3 haloalkyl, -O-C 1 -C 3 haloalkyl, C 1 -C 3 alkoxy, C 1 -C 3 hydroxyalkyl, and -N(R 5 ) 2 .
  • the C6-C10 aryl is optionally substituted with one or more substituents independently selected from - OH, C 1-6 aminoalkyl, C 1 -C 3 alkoxy, C 1 -C 3 hydroxyalkyl, and -N(R 5 ) 2 .
  • the C 6 -C 10 aryl is optionally substituted with one or more substituents independently selected from -OH, C 1 - C 3 alkoxy, C 2-6 alkynyl, and C 1 -C 3 hydroxyalkyl.
  • the C6-C10 aryl is optionally substituted with one or more substituents independently selected from -OH, C 2-6 alkynyl, fluorine, and C 1 -C 4 alkyl. In some cases, the C 6 -C 10 aryl is selected from phenyl and naphthalene.
  • R 3 is not benzothiazole. In some cases, R 3 is not benzothiazole substituted with at least one -NH2.
  • R 3 is selected from an optionally substituted heterocycle. In some cases, the heterocycle is an 8- to 12- membered heterocycle. In some cases, R 3 is selected from an optionally substituted unsaturated 8- to 12- membered heterocycle. In some cases, R 3 is selected from an optionally substituted unsaturated 10-membered heterocycle.
  • the heterocycle is partially unsaturated. In some cases, the unsaturated heterocycle contains at most one nitrogen atom. In some cases, the unsaturated heterocycle contains at least one nitrogen atom. In some cases, the unsaturated heterocycle contains at least one oxygen atom. In some cases, the unsaturated heterocycle contains at least one nitrogen atom and at least one oxygen atom. In some cases, R 3 is selected from , which is optionally substituted.
  • R 3 is selected from [00148]
  • R 3 is selected from optionally substituted C 6 -C 10 aryl and optionally substituted 6- to 12-membered heteroaryl.
  • R 3 is selected from optionally substituted C6-C10 aryl and optionally substituted 6- to 12-membered heteroaryl.
  • substituents selected from halogen, -CN,
  • the naphthalene is optionally substituted with one or more substituents independently selected from fluorine, C 2-6 alkynyl, - OH, and C 1-3 alkyl.
  • R 3 is optionally substituted naphthalene.
  • the naphthalene is optionally substituted with one or more substituents selected from -OH, and C 1 -C 6 alkyl.
  • R 3 is selected from some cases, R 3 is selected from [00149]
  • R 3 is selected from an optionally substituted heteroaryl.
  • R 3 is selected from an optionally substituted tricyclic heteroaryl.
  • R 3 is selected from an optionally substituted 10- to 15-membered heteroaryl.
  • R 3 is selected from an optionally substituted 12- to 13- membered heteroaryl.
  • R 3 is selected from an optionally substituted 12-membered heteroaryl. In some cases, R 3 is selected from an optionally substituted 13-membered heteroaryl. In some cases, the heteroaryl has at least one nitrogen atom. In some cases, the heteroaryl has at least sulfur atom. In some cases, the heteroaryl has at least one nitrogen atom and is bound to Formula (I), (V), or (VI), via the at least one nitrogen atom. In some cases, the heteroaryl has at least one sulfur atom. In some cases, heteroaryl of R 3 is substituted with at least one substituent. In some cases, heteroaryl of R 3 is substituted with at least two substituents.
  • R 3 is selected from , and , each of which are optionally substituted.
  • R 3 is selected from [00150]
  • R 3 is selected from an optionally substituted tricyclic heteroaryl.
  • the tricyclic heteroaryl has at least one nitrogen atom and one sulfur atom.
  • R 3 is selected from which is optionally substituted with one or more substitutents selected from halogen, C 1 -C 3 haloalkyl, C 3 -C 6 cycloalkyl, and C 2-6 alkynyl. In some cases, R 3 is selected from , , , , . In some case 3 s, R is some cases, R 3 is . In some cases, R 3 is some cases, R 3 is 3 . In some cases, R is .
  • R 3 is selected from a phenyl, which is optionally substituted with one or more substituents independently selected from halogen, C 1 -C 3 haloalkyl, and -N(R 5 ) 2 . In some cases, R 3 is .
  • R 9 is selected from a substituted saturated 6- to 7-membered heterocycle. In some cases, R 9 is selected from a d , each of which is substituted. In some cases, R 9 is selected from which is substituted. In some cases, the one or more substituents are independently selected from halogen, -CN, -NHCN, and C 1-6 alkyl, and further optionally substituted with one or more C 1-6 alkyl. In some cases, the optional one or more substituents are independently selected from -CN, -NHCN, C 1-6 cyanoalkyl, and C 1-6 alkyl.
  • the one or more substituents are independently selected from -NHCN, and further optionally substituted with one or more C 1-6 alkyl.
  • R 1 is selected from , which is substituted with one or more substituents selected from -NHCN, and further optionally substituted with one or more C 1-6 alkyl.
  • R 1 is selected from some cases, R 1 is . In some cases, R 1 is .
  • R 4 is halogen;
  • R 3 is naphthalene substituted with one or more substituents independently selected from halogen, -OH, C 2 -C 4 alkynyl, and C1-3 alkyl;
  • R 50 is hydrogen;
  • Y is O;
  • R 2 is -L- heterocycle, wherein the heterocycle portion is optionally substituted with one or more substituents independently selected from halogen, oxo, and C 1 -C 3 alkyl; and
  • L is independently selected from an optionally substituted C 1 -C 4 alkylene.
  • L is C 1 -C 4 alkylene.
  • the heterocycle of -L-heterocycle is a bicyclic heterocycle.
  • the 10- membered heterocycle is a spiroheterocycle.
  • the 10-membered heterocycle is a saturated 10-membered heterocycle.
  • the 10-membered heterocycle is a non- aromatic 10-membered heterocycle.
  • the 10-membered heterocycle is selected from each of which is substituted.
  • the 10-membered heterocycle is selected from , which is substituted.
  • R 9 is selected from a substituted 6-membered heterocycle, wherein the one or more substituents are independently selected from halogen, -CN, -OH, C 1-6 fluoroalkyl, -NHCN, and C 1-6 alkoxy, and further substituted with one or more substituents independently selected from C 1-6 cyanoalkyl, and C 1-6 alkyl;
  • R 4 is halogen;
  • R 3 is naphthalene substituted with one or more substituents independently selected from halogen, -OH, C 2 -C 4 alkynyl, and C 1-3 alkyl;
  • R 50 is hydrogen;
  • Y is O;
  • R 2 is -L-heterocycle, wherein the heterocycle portion is optionally substituted with one or more substituents independently selected from halogen, oxo, and C 1 -C 3 alkyl; and
  • L is independently selected from an optionally substituted
  • the 6- membered heterocycle is a saturated 6-membered heterocycle. In some cases, the 6-membered heterocycle is selected from and , which is substituted. In some cases, the one or more substituents of R 9 are independently selected from one or more hydroxy and -NHCN, and further substituted with one or more C 1-6 alkyl. In some cases, the 6-membered heterocycle is substituted with at least one hydroxy. In some cases, the one or more substituents of R 9 are independently selected from one or more hydroxy, and further substituted with one or more C 1-6 alkyl. In some heterocycle of -L-heterocycle contains at least one nitrogen atom and one oxygen atom.
  • the heterocycle of -L-heterocycle is .
  • each L is independently selected from a substituted C 3 alkylene, and wherein two substituents on the same carbon atom of L come together to form a C 3-6 carbocycle.
  • L is .
  • the heterocycle of -L-heterocycle is a monocyclic heterocycle.
  • Y-R 2 is selected from .
  • Y-R 2 is selected from .
  • R 3 is selected from a phenyl, which is optionally substituted with one or more substituents independently selected from halogen, C 1 -C 3 haloalkyl, and -N(R 5 ) 2 . In some cases, .
  • the 5- to 12-membered heterocycle is a non-bridged heterocycle.
  • the present disclosure provides a compound represented by the structure of Formula (II): , or a pharmaceutically acceptable salt thereof, wherein: Y is selected from a bond, O and NR 5 ; R 2 is selected from L-pyrrolizine, wherein the pyrrolizine is optionally substituted with one or more R 6 ; each L is independently selected from a C 1 -C 4 alkylene optionally substituted with one or more substituents selected from -OH, C 1 -C 4 hydroxyalkyl, and C 1 -C 4 alkyl; and wherein optionally two substituents on the same carbon atom of L come together to form a C 3 -C 6 carbocycle or 3- to 8-membered heterocycle wherein the C 3 -C 6 carbocycle and 3- to 8-membered heterocycle are optionally substituted with one or more substituents selected from
  • Y is O. In some cases, Y is a bond. In some cases, Y is -NR 5 -.
  • L is selected from optionally substituted C1-C4 alkylene. In some cases, L is selected from optionally substituted C 1 - C 2 alkylene. In some cases, L is selected from optionally substituted C 1 alkylene. In some cases L is selected from unsubstituted C1-C4 alkylene. [00165] In some embodiments, for a compound of Formula (II), L is selected from unsubstituted C 1 -C 4 alkylene.
  • L is selected from unsubstituted C 1 -C 2 alkylene. In some cases, L is selected from unsubstituted C 1 alkylene. In some cases, L is selected from methylene and ethylene. In some cases, L is methylene.
  • the optional substituents of L are selected from C 1 -C 4 hydroxyalkyl, C 1 -C 4 alkyl, C 3 -C 6 carbocycle, wherein the C 3 -C 6 carbocycle is optionally substituted with one or more substituents selected from halogen.
  • L is selected from optionally substituted C1-C4 alkylene.
  • the optional substituents of L are selected from C 1 -C 4 hydroxyalkyl, and C 1 -C 4 alkyl.
  • optionally two substituents on the same carbon atom of L come together to form a C 3 carbocycle wherein the C 3 carbocycle is optionally substituted with one or more substituents selected from halogen.
  • optionally two hydrogens on the same carbon atom of L come together to form a C 3 carbocycle wherein the C 3 carbocycle is optionally substituted with one or more substituents selected from halogen.
  • R 2 is selected from , wherein the heterocycle portion is optionally substituted with one or more R 6 .
  • Y-R 2 is selected from , wherein the heterocycle portion is optionally substituted with one or more R 6 .
  • R 6 is independently selected from halogen, -OH, C 1 -C 3 hydroxyalkyl, C 1 -C 3 alkyl, C 1 -C 3 aminoalkyl, C 1 -C 3 haloalkyl, C 1 -C 3 alkoxy, -N(R 5 ) 2 , and oxo.
  • the R 6 is independently selected from -OH, C 1 -C 3 hydroxyalkyl, C 1 -C 3 alkyl, C 1 -C 3 aminoalkyl, C 1 -C 3 alkoxy, and -N(R 5 ) 2 .
  • each R 6 is independently selected from C 1 -C 3 alkyl, C 1 -C 3 alkoxy, and -N(R 5 ) 2 .
  • R 6 is selected from halogen, -OH, C 1 -C 3 hydroxyalkyl, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 alkoxy, -CN, and C 1 -C 3 aminoalkyl. In some cases, R 6 is selected from halogen and C 1 -C 3 alkyl. In some cases, R 6 is halogen. In some cases, R 6 is C 1 -C 3 alkyl. In some cases, R 6 is selected from halogen and C 1 -C 3 alkyl. In some cases, R 6 is selected from methyl and fluorine.
  • R 6 is selected from halogen, -OH, C 1 -C 3 hydroxyalkyl, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 alkoxy, -CN, and C 1 -C 3 aminoalkyl. In some cases, R 6 is selected from halogen and C 1 -C 3 alkyl.
  • R 2 is selected from [00179]
  • Y-R 2 is selected from [00180]
  • R 50 is selected from hydrogen, halogen, C 1 -C 3 cyanoalkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, and C 3 -C 6 carbocycle. In some cases, R 50 is selected from hydrogen, Cl, . [00181] In some embodiments, for a compound or salt of Formula (II), R 4 is selected from halogen and hydrogen.
  • R 4 is selected from halogen. In some cases, R 4 is fluorine. [00182] In some embodiments, for a compound or salt of Formula (II), R 4 is selected from hydrogen, halogen, C 1 -C 3 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, and -O-C 1-6 alkyl, wherein the alkyl portion of -O-C 1-6 alkyl is substituted with one or more halogen substituents.
  • R 4 is selected from C 1-6 haloalkyl, C 1-6 alkoxy, and -O-C 1-6 alkyl, wherein the alkyl portion of -O-C 1-6 alkyl is substituted with one or more halogen substituents. In some cases, R 4 is selected from C 1-6 alkoxy, and -O-C 1-6 alkyl, wherein the alkyl portion of -O-C 1-6 alkyl is substituted with one or more halogen substituents. In some cases, R 4 is selected from -O-C 1-6 alkyl, wherein the alkyl portion of -O-C 1-6 alkyl is substituted with one or more halogen substituents.
  • the carbocycle of R 9 is selected from C 3 -C 12 carbocycle, C 3 -C 10 carbocycle, C 3 -C 9 carbocycle, C 3 -C 8 carbocycle, or C 3 -C 6 carbocycle.
  • the carbocycle of R 9 is selected from C 3 -C 12 carbocycle, C 4 -C 12 carbocycle, C5-C 12 carbocycle, C6-C 12 carbocycle, C7-C 12 carbocycle, C8-C 12 carbocycle, or C9-C 12 carbocycle.
  • the heterocycle of R 9 is a 5- to 12-membered heterocycle, 6- to 12-membered heterocycle, 7- to 12-membered heterocycle, or 8- to 12-membered heterocycle.
  • the heterocycle of R 9 is a 5- to 11-membered heterocycle, 5- to 10-membered heterocycle, 5- to 9-membered heterocycle, or 5- to 8-membered heterocycle.
  • the heterocycle of R 9 is a 6- to 11-membered heterocycle, 6- to 10- membered heterocycle, 6- to 9-membered heterocycle, or 6- to 8-membered heterocycle.
  • the heterocycle of R 9 is a 7- to 11-membered heterocycle, 7- to 10-membered heterocycle, 7- to 9-membered heterocycle, or 7- to 8-membered heterocycle. In some cases, the heterocycle of R 9 is a 5- to 6-membered heterocycle or 5- to 9-membered heterocycle. In some cases, the heterocycle of R 9 is an 8- to 9-membered heterocycle. In some embodiments, for a compound of Formula (II), the heterocycle of R 9 is saturated. The heterocycle may be optionally substituted as described elsewhere herein.
  • the heterocycle of R 9 is a 5- to 12-membered monocyclic heterocycle, 6- to 12-membered monocyclic heterocycle, 7- to 12- membered monocyclic heterocycle, or 8- to 12-membered monocyclic heterocycle.
  • the heterocycle of R 9 is a 5- to 11-membered monocyclic heterocycle, 5- to 10-membered monocyclic heterocycle, 5- to 9-membered monocyclic heterocycle, or 5- to 8-membered monocyclic heterocycle.
  • the heterocycle of R 9 is a 6- to 11-membered monocyclic heterocycle, 6- to 10-membered monocyclic heterocycle, 6- to 9-membered monocyclic heterocycle, or 6- to 8-membered monocyclic heterocycle.
  • the heterocycle of R 9 is a monocyclic 7- to 11-membered heterocycle, 7- to 10-membered monocyclic heterocycle, 7- to 9-membered monocyclic heterocycle, or 7- to 8-membered monocyclic heterocycle.
  • the heterocycle of R 9 is a 5- to 6-membered monocyclic heterocycle or 5- to 9-membered monocyclic heterocycle.
  • the heterocycle of R 9 is an 8- to 9-membered monocyclic heterocycle.
  • the heterocycle of R 9 is saturated.
  • the monocyclic heterocycle may be optionally substituted as described elsewhere herein.
  • the one or more optional substituents of R 9 are independently selected from halogen, -OR 20 , -N(R 20 ) 2 , -NO 2 , C 1-6 aminoalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, and C 1-6 alkyl.
  • R 9 is selected from 5- to 12-membered unsaturated heterocycle, wherein the 5- to 12-membered unsaturated heterocycle is optionally substituted with one or more substituents independently selected from halogen, -OR 20 , -N(R 20 ) 2 , C 1-6 aminoalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 haloalkyl.
  • R 9 is selected from a 7-membered unsaturated heterocycle, wherein the 5- to 12-membered unsaturated heterocycle is optionally substituted with one or more substituents independently selected from halogen, - OR 20 , -N(R 20 ) 2 , C 1-6 aminoalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 haloalkyl.
  • R 9 is selected from which is optionally substituted with one or more substituents independently selected from halogen, -OR 20 and -CN.
  • R 9 is selected from which is substituted with one or more substituents independently selected from halogen, -OR 20 and -CN. In some cases, R 9 is selected from which is substituted with one or more substituents independently selected from halogen. [00194] In some embodiments, for a compound or salt of Formula (II), R 9 is selected from optionally substituted with one or more substituents.
  • R 1 is selected from , , , [00195]
  • R 9 is selected from an optionally substituted 5- to 12-membered unsaturated heterocycle, wherein the heterocycle has as most one nitrogen atom. In some cases, the 5- to 12-membered unsaturated heterocycle has at least one nitrogen atom.
  • the one or more optional substituents of R 9 are independently selected from halogen and -C(O)N(R 20 ) 2 . In some cases, R 9 is substituted with at least one -C(O)N(R 20 ) 2 . In some cases, R 9 is substituted with at least one halogen. [00198] In some embodiments, for a compound of Formula (II), the one or more optional substituents of R 9 are independently selected from halogen, -OR 20 , -N(R 20 ) 2 , -NO 2 , C 1-6 aminoalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, and C 1-6 alkyl.
  • the one or more optional substituents of R 9 are independently selected from -OR 20 , -N(R 20 ) 2 , C 1-6 aminoalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, and C 1-6 alkyl. In some cases, the one or more optional substituents of R 9 are independently selected from -OR 20 , -N(R 20 ) 2 , C 1-6 aminoalkyl, and C 1-6 hydroxyalkyl. In some cases, the one or more optional substituents of R 9 are independently selected from -OR 20 , -N(R 20 ) 2 , C 1-6 aminoalkyl, C 1-6 alkyl, and C 1-6 hydroxyalkyl.
  • the one or more optional substituents of R 9 are independently selected from -OR 20 , -N(R 20 ) 2 , and C 1-6 alkyl. In some cases, R 9 is not piperazine. [00199] In some embodiments, for a compound or salt of Formula (II), each R 20 is independently selected from hydrogen; and C 1-6 alkyl.
  • R 9 is selected from 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle is optionally substituted with one or more substituents independently selected from -OR 20 and -CN. In some cases, R 9 is selected from 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle is substituted with one or more substituents independently selected from -OR 20 and -CN.
  • each R 20 is independently selected from hydrogen; and C 1-6 alkyl.
  • R 9 is selected from 5- to 12-membered unsaturated heterocycle, wherein the 5- to 12-membered unsaturated heterocycle contains at least 1 nitrogen atom and optionally one or more additional heteroatoms selected from oxygen, boron, and sulfur, wherein the 5- to 12-membered unsaturated heterocycle of R 9 is bound to Formula (II) via the at least 1 nitrogen atom, and wherein 5- to 12-membered unsaturated heterocycle is optionally substituted with one or more substituents independently selected from halogen, -B(OR 20 ) 2 , –(CO)N(R 20 ) 2 , -OR 20 , -SR 20 , -S(O) 2 (R 20 ), -C(O)N(R 20 ) 2 , - N(R 20 )C(O)R 20 , -N(R 20 )C(O)N(R 20 ) 2 , -N(R 20 )C(O)N(R 20 ) 2 , -N(R 20
  • each R 20 is independently selected from hydrogen; and C 1-6 alkyl, C 3 -12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, - CN, -NO 2 , -NH 2 , C 1-10 alkyl, -C 1-10 haloalkyl, -O-C 1-10 alkyl.
  • R 9 is selected from 6- to 7-membered heterocycle.
  • the 6- to 7-membered heterocycle contains only 1 nitrogen atom, and the 6- to 7-membered heterocycle is optionally substituted; and wherein the 6- to 7-membered heterocycle of R 9 is bound to Formula (II) via the only 1 nitrogen atom.
  • R 9 is selected from an optionally substituted unsaturated 6-membered heterocycle.
  • R 9 is selected from an optionally substituted unsaturated 7-membered heterocycle.
  • R 9 is selected from , any of which is optionally substituted.
  • R 9 is selected from , any of which is optionally substituted.
  • R 9 is selected from 6- to 7-membered heterocycle, wherein the 6- to 7-membered heterocycle contains only 1 nitrogen atom and optionally one or more additional heteroatoms selected from oxygen, and sulfur. In some cases, the optionally one or more additional heteroatoms are selected from sulfur.
  • the 6- to 7-membered heterocycle contains only 1 nitrogen atom and no further additional heteroatoms. In some cases, the 6- to 7-membered heterocycle is an unsaturated 6- to 7-membered heterocycle.
  • R 9 is selected from , , , , , and , each of which is optionally substituted. In some cases, the one or more optional substituents of R 9 are each independently selected from halogen, -OH, -CN, C 1-6 cyanoalkyl, C 1-6 alkyl, and C 2-6 alkynyl. [00206] In some embodiments, for a compound or salt of Formula (II), R 9 is selected from an optionally substituted unsaturated 6- to 8-membered heterocycle.
  • R 9 is selected from a substituted unsaturated 6- to 8-membered heterocycle. In some cases, R 9 is selected from an optionally substituted unsaturated 6-membered heterocycle. In some cases, R 9 is selected from an optionally substituted unsaturated 7-membered heterocycle. In some cases, R 9 is selected from wherein each is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH 2 , -NO 2 , C 1-6 aminoalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, and C 1-6 alkyl.
  • R 9 is selected from selected from , wherein each is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH2, -NO 2 , C 1-6 aminoalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, and C 1-6 alkyl. In some cases, R 9 is selected from , wherein each is substituted with one or more substituents independently selected from halogen, -OH, -NH 2 , -NO 2 , C 1-6 aminoalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, and C 1-6 alkyl.
  • R 9 is selected from , and , wherein each is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH2, -NO 2 , C 1-6 aminoalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, and C 1-6 alkyl. In some cases, R 9 is selected from , wherein each is optionally substituted with one or more substituents independently selected from halogen, and C 1-6 haloalkyl. In some cases, R 9 is selected from , , , and [00207] In some embodiments, for a compound or salt of Formula (II), R 9 is not .
  • R 9 is selected from an optionally substituted 6- to 10-membered heterocycle.
  • R 9 is selected [00209]
  • R 9 is selected from an optionally substituted 6- to 10-membered heterocycle.
  • R 9 is selected from , , each of which is substituted with one or more substituents independently selected from -OR 20 and -CN. In some cases, R 9 is selected [00211] In some embodiments, for a compound or salt of Formula (II), R 9 is selected from , each of which is optionally substituted with one or more substituents independently selected from -OR 20 and -CN. In some cases, R 9 is selected from , . [00212] In some embodiments, for a compound or salt of Formula (II), the heterocycle of R 9 is not piperazine. In some cases, the heterocycle of R 9 is not morpholine. [00213] In some embodiments, for a compound or salt of Formula (II), Q is a bond.
  • R 3 is selected from optionally substituted C6-C10 aryl and optionally substituted 6- to 12-membered heteroaryl.
  • R 3 is selected from optionally substituted C 6 -C 10 aryl and optionally substituted 6- to 12-membered heteroaryl. In some cases, R 3 is selected from optionally substituted C 10 aryl and optionally substituted 9- membered heteroaryl. In some cases, R 3 is selected from optionally substituted C6-C10 aryl and optionally substituted 8- to 10-membered heteroaryl.
  • R 3 is selected from optionally substituted naphthalene and optionally substituted indazole.
  • the naphthalene is optionally substituted with one or more substituents independently selected from fluorine, C 2-6 alkynyl, -OH, and C1-3 alkyl.
  • R 3 is optionally substituted naphthalene.
  • the naphthalene is optionally substituted with one or more substituents selected from -OH, and C 1 -C 6 alkyl.
  • R 3 is optionally substituted naphthalene.
  • the naphthalene is optionally substituted with one or more substituents selected from -OH and C 1 -C 6 alkyl.
  • R 3 is selected from .
  • R 4 is halogen;
  • R 3 is naphthalene substituted with one or more substituents independently selected from halogen, -OH, C 2 -C 4 alkynyl, and C 1-3 alkyl;
  • R 50 is hydrogen;
  • Y is O;
  • R 2 is -L-heterocycle, wherein the heterocycle portion is optionally substituted with one or more substituents independently selected from halogen, oxo, and C 1 -C 3 alkyl; and
  • L is independently selected from an optionally substituted C 1 -C 4 alkylene.
  • L is C 1 -C 4 alkylene.
  • the heterocycle of -L-heterocycle is a bicyclic heterocycle.
  • the 10-membered heterocycle is a spiroheterocycle.
  • the 10-membered heterocycle is a saturated 10-membered heterocycle.
  • the 10-membered heterocycle is a non- aromatic 10-membered heterocycle.
  • the 10-membered heterocycle is selected from f which is optionally substituted.
  • R 3 is selected from a substituted tricyclic heteroaryl. In some cases, R 3 is selected from an optionally substituted 10- to 15-membered heteroaryl. In some cases, R 3 is selected from an optionally substituted 12- to 13-membered heteroaryl. In some cases, R 3 is selected from an optionally substituted 12-membered heteroaryl. In some cases, R 3 is selected from an optionally substituted 13-membered heteroaryl. In some cases, the heteroaryl has at least one nitrogen atom. In some cases, the heteroaryl has at least sulfur atom. In some cases, the heteroaryl has at least one nitrogen atom and is bound to Formula (II) via the at least one nitrogen atom.
  • the heteroaryl has at least one sulfur atom.
  • heteroaryl of R 3 is substituted with at least one substituent.
  • heteroaryl of R 3 is substituted with at least two substituents.
  • R 3 is selected from , each of which are optionally substituted.
  • R 3 is selected from , which is optionally substituted with one or more substitutents selected from halogen, C 1 -C 3 haloalkyl, C 3 - C 6 cycloalkyl, and C 2-6 alkynyl.
  • R 3 is selected from , [00223]
  • the optional substituents of L are selected from C 1 -C 4 hydroxyalkyl, C 1 -C 4 alkyl, C 3 -C 6 carbocycle; and wherein optionally two substituents on the same carbon atom of L come together to form a C 3 -C 6 carbocycle or 3- to 8-membered heterocycle wherein the C 3 -C 6 carbocycle and 3- to 8- membered heterocycle are optionally substituted with one or more substituents selected from halogen and C 1-6 haloalkyl.
  • R 2 is selected from -L- heterocycle, wherein the heterocycle portion of -L-heterocycle is optionally substituted with one or more R 6 .
  • the heterocycle portion of -L-heterocycle is a saturated heterocycle.
  • the heterocycle portion of -L-heterocycle contains at least one nitrogen atom.
  • the heterocycle portion of -L-heterocycle contains at least one oxygen atom.
  • the heterocycle portion of -L-heterocycle contains at least one sulfur atom.
  • the heterocycle portion of -L-heterocycle contains at least one sulfur atom and one nitrogen atom.
  • the heterocycle portion of -L-heterocycle is a bicyclic heterocycle. In some cases, the heterocycle portion of -L-heterocycle is a monocyclic heterocycle. In some cases, the heterocycle , wherein the heterocycle portion is optionally substituted with one or more R 6 .
  • R 6 is selected from halogen, -OH, C 1 -C 3 hydroxyalkyl, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 alkoxy, oxo, -CN, and C 1 -C 3 aminoalkyl. In some cases, R 6 is selected from halogen and C 1 -C 3 alkyl.
  • R 2 is selected from -L- heterocycle, wherein the heterocycle portion of -L-heterocycle is optionally substituted with one or more R 6 .
  • Y-R 2 is selected from , and , wherein the heterocycle portion is optionally substituted with one or more R 6 .
  • R 6 is selected from halogen, -OH, C 1 -C 3 hydroxyalkyl, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 alkoxy, -CN, and C 1 -C 3 aminoalkyl.
  • R 6 is selected from halogen and C 1 -C 3 alkyl.
  • Y-R 2 is selected from , , . [00227]
  • R 2 is selected from -L- saturated heterocycle, wherein the saturated heterocycle portion of the -L-saturated heterocycle is optionally substituted with one or more R 6 , and contains one nitrogen atom and one sulfur atom.
  • Y-R 2 is selected from , wherein the heterocycle portion is optionally substituted with one or more R 6 .
  • Y-R 2 is selected from , wherein the heterocycle portion is optionally substituted with one or more substituents selected from C 1 -C 3 alkyl and oxo. In some cases, Y-R 2 is selected from cases, Y-R 2 is selected from [00228] In some embodiments, for a compound or salt of Formula (III), R 2 is selected from -L- heterocycle, wherein the heterocycle portion of -L-heterocycle is optionally substituted with one or more R 6 .
  • each L is independently selected from a substituted C 1 -C 4 alkylene, and wherein two substituents on the same carbon atom of L come together to form a C 3 -C 6 carbocycle. In some cases, each L is independently selected from a substituted C 3 alkylene, and wherein two substituents on the same carbon atom of L come together to form a C 3 carbocycle. In some cases, each L is independently selected from . , . [00230] In some embodiments, for a compound or salt of Formula (III), R 9 is selected from an optionally substituted unsaturated 6- to 8-membered heterocycle.
  • R 9 is selected from an optionally substituted unsaturated 6-membered heterocycle. In some cases, R 9 is selected from an optionally substituted unsaturated 7-membered heterocycle. In some cases, R 9 is selected from , wherein each is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH2, -NO 2 , C 1-6 aminoalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, and C 1-6 alkyl.
  • R 9 is selected from , , , , , cases, R 9 is selected from , wherein each is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH2, -NO 2 , C 1-6 aminoalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, and C 1-6 alkyl.
  • R 9 is selected from , wherein each is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH2, -NO 2 , C 1-6 aminoalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, and C 1-6 alkyl. In some cases, R 9 is selected from , and , wherein each is optionally substituted with one or more substituents independently selected from halogen, and C 1-6 haloalkyl. In some cases, R 9 is selected from , some cases, R 9 is selected from . [00231] In some embodiments, for a compound or salt of Formula (III), R 9 is selected from a non-bridged heterocycle.
  • R 3 is selected from an optionally substituted 9- to 15-membered heteroaryl and optionally substituted C 6 -C 10 aryl.
  • R 3 is selected from an optionally substituted 12- to 13-membered heteroaryl.
  • R 3 is selected from , [00234]
  • R 3 is selected from an optionally substituted tricyclic heteroaryl.
  • the tricyclic heteroaryl has at least one nitrogen atom and one sulfur atom.
  • R 3 is selected from , which is optionally substituted with one or more substitutents selected from halogen, C 1 -C 3 haloalkyl, C 3 -C 6 cycloalkyl, and C 2-6 [00235]
  • R 3 is naphthalene, wherein the naphthalene is optionally substituted with one or more substituents independently selected from halogen, -OH, C 2 -C 4 alkynyl, and C 1-3 alkyl. In some cases, R 3 is , In some cases, R 3 is naphthalene, and the naphthalene is substituted with one or more substituents independently selected from fluorine, C 2 -C 4 alkynyl, and hydroxy. In some cases, .
  • R 3 is selected from a phenyl, which is optionally substituted with one or more substituents independently selected from halogen, C 1 -C 3 haloalkyl, and -N(R 5 ) 2 . In some cases, . [00237] In some embodiments, for a compound or salt of Formula (III), R 50 is selected from hydrogen and halogen. In some cases, R 50 is selected from halogen. [00238] In some embodiments, for a compound or salt of Formula (III), R 4 is selected from hydrogen and halogen. In some cases, R 4 is halogen.
  • Y is O. in some cases, Y is a bond. In some cases, Y is NR 5 .
  • the optional substituents of L are selected from C 1 -C 4 hydroxyalkyl, C 1 -C 4 alkyl, C 3 -C 6 carbocycle; and wherein optionally two substituents on the same carbon atom of L come together to form a C 3 -C 6 carbocycle or 3- to 8-membered heterocycle wherein the C 3 -C 6 carbocycle and 3- to 8- membered heterocycle are optionally substituted with one or more substituents selected from halogen and C 1-6 haloalkyl.
  • each L is independently selected from a C 1 -C 4 alkylene.
  • R 2 is selected from -L- heterocycle, wherein the heterocycle portion of -L-heterocycle is optionally substituted with one or more R 6 .
  • the heterocycle portion of -L-heterocycle is a saturated heterocycle.
  • the heterocycle portion of -L-heterocycle contains at least one nitrogen atom.
  • the heterocycle portion of -L-heterocycle contains at least one oxygen atom.
  • the heterocycle portion of -L-heterocycle contains at least one sulfur atom.
  • the heterocycle portion of -L-heterocycle contains at least one sulfur atom and one nitrogen atom.
  • the heterocycle portion of -L-heterocycle is a bicyclic heterocycle. In some cases, the heterocycle portion of -L-heterocycle is a monocyclic heterocycle. In some cases, the heterocycle , wherein the heterocycle portion is optionally substituted with one or more R 6 .
  • R 6 is selected from halogen, -OH, C 1 -C 3 hydroxyalkyl, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 alkoxy, oxo, -CN, and C 1 -C 3 aminoalkyl. In some cases, R 6 is selected from halogen and C 1 -C 3 alkyl.
  • Y-R 2 is selected from - O-L-heterocycle, wherein the heterocycle portion of -O-L-heterocycle is optionally substituted with one or more R 6 .
  • Y-R 2 is selected from , and , wherein the heterocycle portion is optionally substituted with one or more R 6 .
  • R 6 is selected from halogen, -OH, C 1 -C 3 hydroxyalkyl, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 alkoxy, -CN, and C 1 -C 3 aminoalkyl.
  • R 6 is selected from halogen and C 1 -C 3 alkyl.
  • Y-R 2 is selected from , , .
  • R 2 is selected from -L- saturated heterocycle, wherein the saturated heterocycle portion of the -L-saturated heterocycle is optionally substituted with one or more R 6 , and contains one nitrogen atom and one sulfur atom.
  • Y-R 2 is selected from the heterocycle portion is optionally substituted with one or more R 6 .
  • Y-R 2 is selected from , wherein the heterocycle portion is optionally substituted with one or more substituents selected from C 1 -C 3 alkyl and oxo. In some cases, Y-R 2 is selected from cases, Y-R 2 is selected from [00245] In some embodiments, for a compound or salt of Formula (IV), R 2 is selected from -L- heterocycle, wherein the heterocycle portion of -L-heterocycle is optionally substituted with one or more R 6 .
  • each L is independently selected from a substituted C 1 -C 4 alkylene, and wherein two substituents on the same carbon atom of L come together to form a C 3 -C 6 carbocycle. In some cases, each L is independently selected from a substituted C 3 alkylene, and wherein two substituents on the same carbon atom of L come together to form a C 3 carbocycle. In some cases, each L is independently selected from . In some cases, Y-R 2 is . [00246] In some embodiments, for a compound or salt of Formula (IV), R 9 is selected from 6- to 7-membered heterocycle.
  • the 6- to 7-membered heterocycle contains only 1 nitrogen atom, and the 6- to 7-membered heterocycle is optionally substituted. In some cases, the 6- to 7-membered heterocycle of R 9 is bound to Formula (IV) via the only 1 nitrogen atom. In some cases, R 9 is selected from an optionally substituted saturated 6-membered heterocycle. In some cases, R 9 is selected from an optionally substituted unsaturated 6-membered heterocycle. In some cases, R 9 is selected from an optionally substituted saturated 7-membered heterocycle. In some cases, R 9 is selected from an optionally substituted unsaturated 7-membered heterocycle. In some cases, the heterocycle of R 9 is monocyclic.
  • R 9 is selected from 6- to 7-membered heterocycle, wherein the 6- to 7-membered heterocycle contains only 1 nitrogen atom and optionally one or more additional heteroatoms selected from oxygen, and sulfur, wherein the 6- to 7-membered heterocycle. In some cases, the optionally one or more additional heteroatoms are selected from sulfur. In some cases, the 6- to 7-membered heterocycle contains only 1 nitrogen atom and no further additional heteroatoms. In some cases, the 6- to 7-membered heterocycle is an unsaturated 6- to 7-membered heterocycle. In some cases, the 6- to 7-membered heterocycle is an saturated 6- to 7-membered heterocycle.
  • R 9 is selected from each of which is optionally substituted.
  • the one or more optional substituents of R 9 are each independently selected from halogen, -OH, -CN, C 1-6 cyanoalkyl, C 1-6 alkyl, and C 2-6 alkynyl.
  • R 9 is selected from an optionally substituted unsaturated 6- to 8-membered heterocycle. In some cases, R 9 is selected from an optionally substituted unsaturated 6-membered heterocycle.
  • R 9 is selected from an optionally substituted unsaturated 7-membered heterocycle.
  • R 9 is selected from wherein each is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH2, -NO 2 , C 1-6 aminoalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, and C 1-6 alkyl. In some cases, R 9 is selected from more substituents independently selected from halogen, -OH, -NH 2 , -NO 2 , C 1-6 aminoalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, and C 1-6 alkyl.
  • R 9 is selected from wherein each is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH2, -NO 2 , C 1-6 aminoalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, and C 1-6 alkyl. In some cases, R 9 is selected from , and , wherein each is optionally substituted with one or more substituents independently selected from halogen, and C 1-6 haloalkyl. In some cases, R 9 is selected from , R 9 is selected from . [00250] In some embodiments, for a compound or salt of Formula (IV), R 9 is selected from an optionally substituted 6- to 10-membered heterocycle.
  • R 9 is selected [00251]
  • R 9 is selected from an optionally substituted 6- to 10-membered heterocycle.
  • R 9 is selected from 6- to 7-membered heterocycle. In some cases, R 9 is selected from 7-membered heterocycle. In some cases, R 9 is selected from 6-membered heterocycle.
  • the 6- to 7-membered heterocycle contains only 1 nitrogen atom and optionally one or more additional heteroatoms selected from oxygen, and sulfur. In some cases, the optionally one or more additional heteroatoms are selected from sulfur. In some cases, the 6- to 7-membered heterocycle contains only 1 nitrogen atom and no further additional heteroatoms. In some cases, the 6- to 7-membered heterocycle is a non-aromatic 6- to 7-membered heterocycle. In some cases, the 6- to 7- membered heterocycle of R 9 is bound to Formula (IV) via the only 1 nitrogen atom. In some , and , each of which is substituted. In some cases, R 9 is selected from , each of which is substituted.
  • R 9 is selected from , [00253]
  • R 9 is selected from an optionally substituted 6- to 10-membered bridged heterocycle.
  • R 9 is selected from an optionally substituted 7- to 8-membered bridged heterocycle.
  • R 9 is selected from an optionally substituted 8-membered bridged heterocycle.
  • the bridged heterocycle has at least one nitrogen atom.
  • the bridged heterocycle has at least two nitrogen atoms.
  • the bridged heterocycle has at only two nitrogen atoms and no further heteroatoms.
  • R 20 is independently selected from hydrogen; and C 1-6 alkyl, C 3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO 2 , -NH2, C 1-10 alkyl, -C 1-10 haloalkyl, -O-C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3 -12 carbocycle, and 3- to 12-membered heterocycle.
  • R 20 is independently selected from hydrogen; and C 1-6 alkyl, C 3-12 carbocycle, and 3- to 12-membered heterocycle. In some cases, R 20 is independently selected from hydrogen; and C 1-6 alkyl. [00256] In some embodiments, for a compound or salt of Formula (IV), R 3 is selected from an optionally substituted 9- to 15-membered heteroaryl and optionally substituted C 6 -C 10 aryl.
  • R 3 is selected from an optionally substituted 12- to 13-membered heteroaryl.
  • R 3 is selected from an optionally substituted tricyclic heteroaryl.
  • the tricyclic heteroaryl has at least one nitrogen atom and one sulfur atom.
  • R 3 is selected from , which is optionally substituted with one or more substitutents selected from halogen, C 1 -C 3 haloalkyl, C 3 -C 6 cycloalkyl, and C 2-6 [00260]
  • R 3 is naphthalene, wherein the naphthalene is optionally substituted with one or more substituents independently selected from halogen, -OH, C 2 -C 4 alkynyl, and C 1-3 alkyl. In some cases, R 3 is , , In some cases, R 3 is naphthalene, and the naphthalene is substituted with one or more substituents independently selected from fluorine, C 2 -C 4 alkynyl, and hydroxy. In some cases, R 3 is selected from .
  • R 4 is selected from hydrogen, halogen, C 1 -C 3 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, and -O-C 1-6 haloalkyl. In some cases, R 4 is selected from hydrogen, halogen, C 1 -C 3 alkyl, C 1-6 haloalkyl, and C 1-6 alkoxy. In some cases, R 4 is selected from hydrogen and halogen. In some cases, R 4 is selected from hydrogen. In some cases, R 4 is halogen. [00262] In some embodiments, for a compound or salt of Formula (IV), each R 5 is independently selected from hydrogen.
  • each R 5 is independently selected from hydrogen.
  • R 50 is selected from hydrogen and halogen. In some cases, R 50 is selected from halogen.
  • L is C 1 -C 4 alkylene.
  • the heterocycle of - L-heterocycle is a bicyclic heterocycle.
  • the 10-membered heterocycle is a spiroheterocycle.
  • the 10-membered heterocycle is a saturated 10-membered heterocycle.
  • the 10-membered heterocycle is a non-aromatic 10-membered H heterocycle.
  • the 10-membered heterocycle is selected from and , each of which is substituted.
  • R 2 is selected from .
  • R 2 is selected .
  • R 9 is selected from .
  • R 9 is .
  • R 9 is .
  • the 10-membered heterocycle of R 9 contains at least 3 nitrogen atoms.
  • the 10-membered heterocycle of R 9 contains 3 nitrogen atoms and no other heteroatoms.
  • R 4 is fluorine.
  • R 4 is hydrogen.
  • R 4 is selected from hydrogen and halogen. In some cases, R 4 is selected from halogen. In some cases, R 4 is hydrogen. [00268] In some embodiments, for a compound or salt of Formula (V), R 3 is selected from aryl and heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, C 1 -C 4 alkyl, and C 2 -C 4 alkynyl.
  • R 50 is selected from hydrogen, halogen, C 1 -C 3 cyanoalkyl, and C 2 -C 4 alkenyl. In some cases, R 50 is hydrogen.
  • L is selected from C1-C4 alkylene. In some cases, L is selected from unsubstituted C1-C4 alkylene.
  • Y-R 2 is selected from R 6 .
  • R 6 is selected from halogen, -OH, C 1 -C 3 hydroxyalkyl, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 alkoxy, -CN, and C 1 -C 3 aminoalkyl.
  • Y-R 2 is selected from , [00272]
  • R 9 is selected from a 6- to 7- membered heterocycle, each of which is substituted. In some cases, R 9 is selected from each of which is substituted. In some cases, the one or more substituents are independently selected from -OH, -CN, and -NHCN; and further optionally substituted with one or more substituents independently selected from C 1-6 alkyl. In some cases, R 9 is selected from some cases, the one or more substituents are independently selected from -OH, and further optionally substituted with one or more substituents independently selected from C 1-6 alkyl.
  • R 9 is selected from some cases, the one or more substituents are independently selected from -CN and -NHCN, and further optionally substituted with one or more substituents independently selected from C 1-6 alkyl. In some cases, R 9 is selected from and . [00274] In some embodiments, for a compound or salt of (VI), R 4 is selected from hydrogen and halogen. In some cases, R 4 is selected from halogen. In some cases, R 4 is fluorine.
  • R 3 is selected from aryl and heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, C 1 -C 4 alkyl, and C 2 -C 4 alkynyl.
  • R 50 is selected from hydrogen, halogen, C 1 -C 3 cyanoalkyl, and C 2 -C 4 alkenyl.
  • L is selected from C 1 -C 4 alkylene.
  • L is selected from unsubstituted C 1 -C 4 alkylene.
  • R 6 is selected from halogen, -OH, C 1 -C 3 hydroxyalkyl, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 alkoxy, -CN, and C 1 -C 3 aminoalkyl.
  • R 3 is selected from optionally substituted aryl.
  • R 3 is not optionally substituted pyridine. In some cases, R 3 is not benzothiazole. In some cases, R 3 is not optionally substituted benzothiazole. In some cases, when R 9 is substituted with -CN, R 3 is not optionally substituted pyridine. In some cases, when R 9 is substituted with -CN, R 3 is not optionally substituted benzothiazole. In some cases, R 3 is not substituted with -N(R 20 ) 2 . In some cases, R 3 is not substituted with -NH 2 .
  • R 2 is selected from -L-6- to 8-membered heterocycle, wherein the heterocycle portion of -L-6- to 8-membered heterocycle is optionally substituted with one or more R 6 .
  • R 2 is selected from -L-6-membered heterocycle, wherein the heterocycle portion of -L-6-membered heterocycle is optionally substituted with one or more R 6 .
  • R 2 is selected from -L-8- membered heterocycle, wherein the heterocycle portion of -L-8-membered heterocycle is optionally substituted with one or more R 6 .
  • the heterocycle is bicyclic.
  • the heterocycle is monocyclic.
  • the heterocycle is a saturated heterocycle.
  • the heterocycle of R 2 has at least one sulfur atom.
  • the heterocycle of R 2 has at least one nitrogen atom.
  • the heterocycle of R 9 is substituted with at least one C 1-6 alkyl-N(R 20 ) 2 .
  • the compound is not a Michael acceptor.
  • the compound does not include an electrophilic substituent for a compound or salt of Formula (I), (I-A), (II), (III), (IV), (V), or (VI).
  • the compound or salt does not include an electrophilic substituent.
  • the R 9 does not include an electrophilic substituent.
  • the compound or salt does not form a covalent bond with any of the KRAS G12D and/or other G12 mutants.
  • the compound or salt is not a covalent modifier of KRAS G12D and/or other G12 mutants.
  • the compound or salt is not a covalent modifier of KRAS G12D and/or other G12 mutants.
  • salts particularly pharmaceutically acceptable salts, of the compounds described herein.
  • compounds that are inherently charged can form a salt with an appropriate counterion, e.g., a halide such as bromide, chloride, or fluoride, particularly bromide.
  • an appropriate counterion e.g., a halide such as bromide, chloride, or fluoride, particularly bromide.
  • 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 described herein are intended to include all Z-, E- and tautomeric forms as well.
  • 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 presented herein exist as tautomers. In circumstances where tautomerization is possible, a chemical equilibrium of the tautomers will exist. The exact ratio of the tautomers depends on several factors, including physical state, temperature, solvent, and pH. Some examples of tautomeric equilibrium include: .
  • the compounds disclosed herein, in some embodiments are used in different enriched isotopic forms, e.g., enriched in the content of 2 H, 3 H, 11 C, 13 C and/or 14 C.
  • the compound is deuterated in at least one position. 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.
  • compounds described herein are intended to include compounds which differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by 13 C- or 14 C-enriched carbon are within the scope of the present disclosure.
  • the compounds of the present disclosure optionally contain unnatural proportions of atomic isotopes at one or more atoms that constitute such compounds.
  • the compounds may be labeled with isotopes, such as for example, deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C).
  • isotopes such as for example, deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C).
  • Isotopic substitution with 2 H, 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. All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.
  • 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.
  • 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.
  • Compounds of the present invention 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.
  • the compounds described herein may in some cases exist as diastereomers, enantiomers, or other stereoisomeric forms. Where absolute stereochemistry is not specified, the compounds presented herein include all diastereomeric, enantiomeric, and epimeric forms as well as the appropriate mixtures thereof.
  • 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. [00300]
  • the methods and compositions described herein 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 or salts of the compounds 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
  • Prodrug forms of the herein described compounds, wherein the prodrug is metabolized in vivo to produce a compound as set forth herein are included within the scope of the claims. In some cases, some of the herein-described compounds may be a prodrug for another derivative or active compound.
  • 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. [00304] 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.
  • the present disclosure provides methods of producing the above-defined 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.
  • compositions comprising a therapeutically effective amount of any compound or salt of any one of Formulas (I), (I-A), (II), (III), (IV), (V), and (VI) (also referred to herein as “a pharmaceutical agent”).
  • a pharmaceutical agent also referred to herein as “a pharmaceutical agent”.
  • Pharmaceutical compositions may be formulated using one or more physiologically acceptable carriers including excipients and auxiliaries which facilitate processing of the pharmaceutical agent into preparations which are used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.
  • compositions and methods of the present disclosure may be utilized to treat an individual in need thereof.
  • the individual is a mammal such as a human, or a non-human mammal.
  • the composition or the pharmaceutical agent When administered to an animal, such as a human, the composition or the pharmaceutical agent, is preferably administered as a pharmaceutical composition comprising, for example, a pharmaceutical agent and a pharmaceutically acceptable carrier or excipient.
  • Pharmaceutically acceptable carriers are well known in the art and include, for example, aqueous solutions such as water or physiologically buffered saline or other solvents or vehicles such as glycols, glycerol, oils such as olive oil, or injectable organic esters.
  • aqueous solutions such as water or physiologically buffered saline or other solvents or vehicles such as glycols, glycerol, oils such as olive oil, or injectable organic esters.
  • the aqueous solution is pyrogen-free, or substantially pyrogen-free.
  • the excipients can be chosen, for example, to effect delayed release of an agent or to selectively target one or more cells, tissues or organs.
  • the pharmaceutical composition can be in dosage unit form such as tablet, capsule, granule, lyophile for reconstitution, powder, solution, syrup, suppository, injection or the like.
  • the composition can also be present in a transdermal delivery system, e.g., a skin patch.
  • the composition can also be present in a solution suitable for topical administration, such as an eye drop.
  • a pharmaceutically acceptable excipient can contain physiologically acceptable agents that act, for example, to stabilize, increase solubility or to increase the absorption of a compound such as a pharmaceutical agent.
  • physiologically acceptable agents include, for example, carbohydrates, such as glucose, sucrose or dextrans, antioxidants, such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins or other stabilizers or excipients.
  • carbohydrates such as glucose, sucrose or dextrans
  • antioxidants such as ascorbic acid or glutathione
  • chelating agents low molecular weight proteins or other stabilizers or excipients.
  • the choice of a pharmaceutically acceptable excipient, including a physiologically acceptable agent depends, for example, on the route of administration of the composition.
  • the preparation or pharmaceutical composition can be a self emulsifying drug delivery system or a self microemulsifying drug delivery system.
  • the pharmaceutical composition (preparation) also can be a liposome or other polymer matrix, which can have incorporated therein, for example, a compound of the invention.
  • Liposomes for example, which comprise phospholipids or other lipids, are nontoxic, physiologically acceptable and metabolizable carriers that are relatively simple to make and administer.
  • a pharmaceutical composition can be administered to a subject by any of a number of routes of administration including, for example, orally, for example, drenches as in aqueous or non-aqueous solutions or suspensions, tablets, capsules, including sprinkle capsules and gelatin capsules, boluses, powders, granules, pastes for application to the tongue; absorption through the oral mucosa, e.g., sublingually; anally, rectally or vaginally, for example, as a pessary, cream or foam; parenterally, including intramuscularly, intravenously, subcutaneously or intrathecally as, for example, a sterile solution or suspension; nasally; intraperitoneally; subcutaneously; transdermally, for example, as a patch applied to the skin; and topically,
  • a pharmaceutical composition may be a sterile aqueous or non-aqueous solution, suspension or emulsion, e.g., a microemulsion.
  • the excipients described herein are examples and are in no way limiting.
  • An effective amount or therapeutically effective amount refers to an amount of the one or more pharmaceutical agents administered to a subject, either as a single dose or as part of a series of doses, which is effective to produce a desired therapeutic effect.
  • Subjects may generally be monitored for therapeutic effectiveness using assays and methods suitable for the condition being treated, which assays will be familiar to those having ordinary skill in the art and are described herein.
  • Pharmacokinetics of a pharmaceutical agent, or one or more metabolites thereof, that is administered to a subject may be monitored by determining the level of the pharmaceutical agent or metabolite in a biological fluid, for example, in the blood, blood fraction, e.g., serum, and/or in the urine, and/or other biological sample or biological tissue from the subject. Any method practiced in the art and described herein to detect the agent may be used to measure the level of the pharmaceutical agent or metabolite during a treatment course.
  • the dose of a pharmaceutical agent described herein for treating a disease or disorder may depend upon the subject’s condition, that is, stage of the disease, severity of symptoms caused by the disease, general health status, as well as age, gender, and weight, and other factors apparent to a person skilled in the medical art.
  • Pharmaceutical compositions may be administered in a manner appropriate to the disease to be treated as determined by persons skilled in the medical arts.
  • suitable duration and frequency of administration of the pharmaceutical agent may also be determined or adjusted by such factors as the condition of the patient, the type and severity of the patient’s disease, the particular form of the active ingredient, and the method of administration.
  • Optimal doses of an agent may generally be determined using experimental models and/or clinical trials.
  • the optimal dose may depend upon the body mass, weight, or blood volume of the subject. The use of the minimum dose that is sufficient to provide effective therapy is usually preferred. Design and execution of pre-clinical and clinical studies for a pharmaceutical agent, including when administered for prophylactic benefit, described herein are well within the skill of a person skilled in the relevant art.
  • the optimal dose of each pharmaceutical agent may be different, such as less than when either agent is administered alone as a single agent therapy.
  • two pharmaceutical agents in combination may act synergistically or additively, and either agent may be used in a lesser amount than if administered alone.
  • An amount of a pharmaceutical agent that may be administered per day may be, for example, between about 0.01 mg/kg and 100 mg/kg, e.g., between about 0.1 to 1 mg/kg, between about 1 to 10 mg/kg, between about 10-50 mg/kg, between about 50-100 mg/kg body weight. In other embodiments, the amount of a pharmaceutical agent that may be administered per day is between about 0.01 mg/kg and 1000 mg/kg, between about 100-500 mg/kg, or between about 500-1000 mg/kg body weight.
  • the optimal dose, per day or per course of treatment may be different for the disease or disorder to be treated and may also vary with the administrative route and therapeutic regimen.
  • compositions comprising a pharmaceutical agent can be formulated in a manner appropriate for the delivery method by using techniques routinely practiced in the art.
  • the composition may be in the form of a solid, e.g., tablet, capsule, semi-solid, e.g., gel, liquid, or gas, e.g., aerosol.
  • the pharmaceutical composition is administered as a bolus infusion.
  • Pharmaceutical acceptable excipients are well known in the pharmaceutical art and described, for example, in Rowe et al., Handbook of Pharmaceutical Excipients: A Comprehensive Guide to Uses, Properties, and Safety, 5 th Ed., 2006, and in Remington: The Science and Practice of Pharmacy (Gennaro, 21 st Ed. Mack Pub.
  • compositions described herein may be formulated as a lyophilizate.
  • a composition described herein may be lyophilized or otherwise formulated as a lyophilized product using one or more appropriate excipient solutions for solubilizing and/or diluting the pharmaceutical agent(s) of the composition upon administration.
  • the pharmaceutical agent may be encapsulated within liposomes using technology known and practiced in the art.
  • a pharmaceutical agent is not formulated within liposomes for application to a stent that is used for treating highly, though not totally, occluded arteries.
  • Pharmaceutical compositions may be formulated for any appropriate manner of administration described herein and in the art.
  • a pharmaceutical composition e.g., for oral administration or for injection, infusion, subcutaneous delivery, intramuscular delivery, intraperitoneal delivery or other method, may be in the form of a liquid.
  • a liquid pharmaceutical composition may include, for example, one or more of the following: a sterile diluent such as water, saline solution, preferably physiological saline, Ringer’s solution, isotonic sodium chloride, fixed oils that may serve as the solvent or suspending medium, polyethylene glycols, glycerin, propylene glycol or other solvents; antibacterial agents; antioxidants; chelating agents; buffers and agents for the adjustment of tonicity such as sodium chloride or dextrose.
  • a parenteral composition can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic. The use of physiological saline is preferred, and an injectable pharmaceutical composition is preferably sterile.
  • a liquid pharmaceutical composition for treatment of an ophthalmological condition or disease, may be applied to the eye in the form of eye drops.
  • a liquid pharmaceutical composition may be delivered orally.
  • at least one of the pharmaceutical agents described herein can be used alone or in combination with appropriate additives to make tablets, powders, granules or capsules, and if desired, with diluents, buffering agents, moistening agents, preservatives, coloring agents, and flavoring agents.
  • the pharmaceutical agents may be formulated with a buffering agent to provide for protection of the compound from low pH of the gastric environment and/or an enteric coating.
  • a pharmaceutical agent included in a pharmaceutical composition may be formulated for oral delivery with a flavoring agent, e.g., in a liquid, solid or semi-solid formulation and/or with an enteric coating.
  • a pharmaceutical composition comprising any one of the pharmaceutical agents described herein may be formulated for sustained or slow release, also called timed release or controlled release.
  • sustained or slow release also called timed release or controlled release.
  • Such compositions may generally be prepared using well known technology and administered by, for example, oral, rectal, intradermal, or subcutaneous implantation, or by implantation at the desired target site.
  • Sustained-release formulations may contain the compound dispersed in a carrier matrix and/or contained within a reservoir surrounded by a rate controlling membrane.
  • compositions comprising a pharmaceutical agent are formulated for transdermal, intradermal, or topical administration.
  • the compositions can be administered using a syringe, bandage, transdermal patch, insert, or syringe-like applicator, as a powder/talc or other solid, liquid, spray, aerosol, ointment, foam, cream, gel, paste.
  • the active compositions can also be delivered via iontophoresis. Preservatives can be used to prevent the growth of fungi and other microorganisms.
  • Suitable preservatives include, but are not limited to, benzoic acid, butylparaben, ethyl paraben, methyl paraben, propylparaben, sodium benzoate, sodium propionate, benzalkonium chloride, benzethonium chloride, benzyl alcohol, cetypyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol, thimerosal, and combinations thereof.
  • Pharmaceutical compositions comprising a pharmaceutical agent can be formulated as emulsions for topical application. An emulsion contains one liquid distributed in the body of a second liquid.
  • the emulsion may be an oil-in-water emulsion or a water-in-oil emulsion.
  • Either or both of the oil phase and the aqueous phase may contain one or more surfactants, emulsifiers, emulsion stabilizers, buffers, and other excipients.
  • the oil phase may contain other oily pharmaceutically approved excipients.
  • Suitable surfactants include, but are not limited to, anionic surfactants, non-ionic surfactants, cationic surfactants, and amphoteric surfactants.
  • Compositions for topical application may also include at least one suitable suspending agent, antioxidant, chelating agent, emollient, or humectant.
  • Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents.
  • Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents.
  • Liquid sprays may be delivered from pressurized packs, for example, via a specially shaped closure.
  • Oil-in-water emulsions can also be used in the compositions, patches, bandages and articles. These systems are semisolid emulsions, micro-emulsions, or foam emulsion systems.
  • the pharmaceutical agent described herein can be formulated as in inhalant. Inhaled methods can deliver medication directly to the airway.
  • the pharmaceutical agent can be formulated as aerosols, microspheres, liposomes, or nanoparticles.
  • the pharmaceutical agent can be formulated with solvents, gases, nitrates, or any combinations thereof.
  • Compositions described herein are optionally formulated for delivery as a liquid aerosol or inhalable dry powder. Liquid aerosol formulations are optionally nebulized predominantly into particle sizes that can be delivered to the terminal and respiratory bronchioles.
  • Liquid aerosol and inhalable dry powder formulations are preferably delivered throughout the endobronchial tree to the terminal bronchioles and eventually to the parenchymal tissue.
  • Aerosolized formulations described herein are optionally delivered using an aerosol forming device, such as a jet, vibrating porous plate or ultrasonic nebulizer, preferably selected to allow the formation of aerosol particles having with a mass medium average diameter predominantly between 1 to 5 ⁇ .
  • the formulation preferably has balanced osmolarity ionic strength and chloride concentration, and the smallest aerosolizable volume able to deliver effective dose of the pharmaceutical agent.
  • the aerosolized formulation preferably does not impair negatively the functionality of the airways and does not cause undesirable side effects.
  • Aerosolization devices suitable for administration of aerosol formulations described herein include, for example, jet, vibrating porous plate, ultrasonic nebulizers and energized dry powder inhalers, that are able to nebulize the formulation into aerosol particle size predominantly in the size range from 1-5 ⁇ . Predominantly in this application means that at least 70% but preferably more than 90% of all generated aerosol particles are within 1-5 ⁇ range.
  • a jet nebulizer works by air pressure to break a liquid solution into aerosol droplets. Vibrating porous plate nebulizers work by using a sonic vacuum produced by a rapidly vibrating porous plate to extrude a solvent droplet through a porous plate.
  • An ultrasonic nebulizer works by a piezoelectric crystal that shears a liquid into small aerosol droplets.
  • a variety of suitable devices are available, including, for example, AeroNeb ⁇ ⁇ and AeroDose ⁇ ⁇ ⁇ vibrating porous plate nebulizers (AeroGen, Inc., Sunnyvale, California), Sidestream ⁇ nebulizers (Medic-Aid Ltd., West Wales, England), Pari LC ⁇ and Pari LC Star ⁇ jet nebulizers (Pari Respiratory Equipment, Inc., Richmond, Virginia), and Aerosonic ⁇ ⁇ (DeVilbiss Medizinische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische Kunststoffische
  • the pharmaceutical agent(s) can be formulated with oleaginous bases or ointments to form a semisolid composition with a desired shape
  • these semisolid compositions can contain dissolved and/or suspended bactericidal agents, preservatives and/or a buffer system.
  • a petrolatum component that may be included may be any paraffin ranging in viscosity from mineral oil that incorporates isobutylene, colloidal silica, or stearate salts to paraffin waxes.
  • Absorption bases can be used with an oleaginous system.
  • Additives may include cholesterol, lanolin (lanolin derivatives, beeswax, fatty alcohols, wool wax alcohols, low HLB (hydrophobellipophobe balance) emulsifiers, and assorted ionic and nonionic surfactants, singularly or in combination.
  • Controlled or sustained release transdermal or topical formulations can be achieved by the addition of time-release additives, such as polymeric structures, matrices, that are available in the art.
  • the compositions may be administered through use of hot-melt extrusion articles, such as bioadhesive hot-melt extruded film.
  • the formulation can comprise a cross-linked polycarboxylic acid polymer formulation.
  • a cross-linking agent may be present in an amount that provides adequate adhesion to allow the system to remain attached to target epithelial or endothelial cell surfaces for a sufficient time to allow the desired release of the compound.
  • An insert, transdermal patch, bandage or article can comprise a mixture or coating of polymers that provide release of the pharmaceutical agents at a constant rate over a prolonged period of time.
  • the article, transdermal patch or insert comprises water- soluble pore forming agents, such as polyethylene glycol (PEG) that can be mixed with water insoluble polymers to increase the durability of the insert and to prolong the release of the active ingredients.
  • PEG polyethylene glycol
  • Transdermal devices may also comprise a water insoluble polymer.
  • Rate controlling polymers may be useful for administration to sites where pH change can be used to effect release. These rate controlling polymers can be applied using a continuous coating film during the process of spraying and drying with the active compound.
  • the coating formulation is used to coat pellets comprising the active ingredients that are compressed to form a solid, biodegradable insert.
  • a polymer formulation can also be utilized to provide controlled or sustained release. Bioadhesive polymers described in the art may be used. By way of example, a sustained-release gel and the compound may be incorporated in a polymeric matrix, such as a hydrophobic polymer matrix.
  • Examples of a polymeric matrix include a microparticle.
  • the microparticles can be microspheres, and the core may be of a different material than the polymeric shell.
  • the polymer may be cast as a thin slab or film, a powder produced by grinding or other standard techniques, or a gel such as a hydrogel.
  • the polymer can also be in the form of a coating or part of a bandage, stent, catheter, vascular graft, or other device to facilitate delivery of the pharmaceutical agent.
  • the matrices can be formed by solvent evaporation, spray drying, solvent extraction and other methods known to those skilled in the art.
  • kits may include a container containing the unit dose, an informational package insert describing the use and attendant benefits of the drugs in treating disease, and optionally an appliance or device for delivery of the composition.
  • Methods of Treatment [00331]
  • the present disclosure provides compounds that inhibit KRas G12 mutants.
  • the method may inhibit KRas G12 mutants activity in a cell.
  • inhibitng KRas G12 mutants activity in a cell may include contacting the cell in which inhibition of KRas G12 mutants activity is desired with an effective amount of a compound of Formulas (I), (I-A), (II), (III), (IV), (V), (VI), or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing the compound or pharmaceutically acceptable salt thereof.
  • the contacting is in vitro.
  • the contacting is in vivo.
  • the term "contacting" refers to the bringing together of indicated moieties in an in vitro system or an in vivo system.
  • contacting" a KRas G12D and/or other G12 mutants with a compound provided herein includes the administration of a compound provided herein to an individual or patient, such as a human, having KRas G12D and/or other G12 mutants, as well as, for example, introducing a compound provided herein into a sample containing a cellular or purified preparation containing the KRas G12D and/or other G12 mutants.
  • a cell in which inhibition of KRas G12D and/or other G12 mutants activity is desired is contacted with an effective amount of a compound of Formulas (I), (I-A), (II), (III), (IV), (V), (VI), or pharmaceutically acceptable salt thereof to negatively modulate the activity of KRas G12D and/or other G12 mutants.
  • a compound of Formulas (I), (I-A), (II), (III), (IV), (V), (VI), or pharmaceutically acceptable salt thereof to negatively modulate the activity of KRas G12D and/or other G12 mutants.
  • the methods described herein are designed to inhibit undesired cellular proliferation resulting from enhanced KRas G12D and/or other G12 mutants activity within the cell.
  • the cells may be contacted in a single dose or multiple doses in accordance with a particular treatment regimen to effect the desired negative modulation of KRas G12D and/or other G12 mutants.
  • the ability of compounds to bind KRas G12D and/or other G12 mutants may be monitored in vitro using well known methods.
  • the inhibitory activity of exemplary compounds in cells may be monitored, for example, by measuring the inhibition of KRas G12D and/or other G12 mutants activity of the amount of phosphorylated ERK.
  • methods of treating cancer in a patient in need thereof comprising administering to said patient a therapeutically effective amount of a compound of Formulas (I), (I- A), (II), (III), (IV), (V), (VI), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound or pharmaceutically acceptable salt thereof are provided.
  • compositions and methods provided herein may be used for the treatment of a KRas G12D and/or other G12 mutants-associated cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formulas (I), (I-A), (II), (III), (IV), (V), (VI), or a pharmaceutically acceptable salt of any one thereof, or a pharmaceutical composition comprising the compound or pharmaceutically acceptable salt thereof are provided.
  • the KRas G12D and/or other G12 mutants -associated cancer is lung cancer.
  • compositions and methods provided herein may be used for the treatment of a wide variety of cancers including tumors such as lung, prostate, breast, brain, skin, cervical carcinomas, testicular carcinomas, etc. More particularly, cancers that may be treated by the compositions and methods of the invention include, but are not limited to tumor types such as astrocytic, breast, cervical, colorectal, endometrial, esophageal, gastric, head and neck, hepatocellular, laryngeal, lung, oral, ovarian, prostate and thyroid carcinomas and sarcomas.
  • tumor types such as astrocytic, breast, cervical, colorectal, endometrial, esophageal, gastric, head and neck, hepatocellular, laryngeal, lung, oral, ovarian, prostate and thyroid carcinomas and sarcomas.
  • these compounds can be used to treat: Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinom
  • the cancer is non-small cell lung cancer, small cell lung cancer, colorectal cancer, rectal cancer or pancreatic cancer. In some cases, the cancer is non-small cell lung cancer.
  • the concentration and route of administration to the patient will vary depending on the cancer to be treated.
  • the compounds, pharmaceutically acceptable salts thereof and pharmaceutical compositions comprising such compounds and salts also may be co-administered with other anti-neoplastic compounds, e.g., chemotherapy, or used in combination with other treatments, such as radiation or surgical intervention, either as an adjuvant prior to surgery or post- operatively.
  • a compound of Formula (I), Formula (I-A), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), or a pharmaceutically acceptable salt thereof as defined herein in the manufacture of a medicament for the treatment of cancer.
  • a use of a compound of Formula (I), Formula (I-A), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), or a pharmaceutically acceptable salt thereof as defined herein in the manufacture of a medicament for the inhibition of activity of KRas G12D and/or other G12 mutants.
  • Also provided herein is the use of a compound of Formula (I), Formula (I-A), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), or a pharmaceutically acceptable salt thereof, as defined herein, in the manufacture of a medicament for the treatment of a KRas G12D and/or other G12 mutants-associated disease or disorder.
  • the present disclosure provides a method for treating cancer in a patient in need thereof, the method comprising (a) determining that cancer is associated with a KRas G12D mutation and/or other G12 mutants (e.g., a KRas G12D and/or other G12 mutants- associated cancer) (e.g., as determined using a regulatory agency-approved, e.g., FDA- approved, assay or kit); and (b) administering to the patient a therapeutically effective amount of a compound of Formula (I), Formula (I-A), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • a KRas G12D mutation and/or other G12 mutants e.g., a KRas G12D and/or other G12 mutants- associated cancer
  • a regulatory agency-approved e.g., FDA- approved, assay or kit
  • the compounds described herein can be used in the preparation of medicaments for the prevention or treatment of diseases or conditions.
  • a method for treating any of the diseases or conditions described herein in a subject in need of such treatment involves administration of pharmaceutical compositions containing at least one compound described herein, or a pharmaceutically acceptable salt, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof, in therapeutically effective amounts to said subject.
  • the compositions containing the compound(s) described herein can be administered for prophylactic and/or therapeutic treatments. In therapeutic applications, the compositions are administered to a patient already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest the symptoms of the disease or condition.
  • compositions containing the compounds described herein are administered to a patient susceptible to or otherwise at risk of a particular disease, disorder or condition. Such an amount is defined to be a "prophylactically effective amount or dose.”
  • prophylactically effective amount or dose In this use, the precise amounts also depend on the patient's state of health, weight, and the like.
  • effective amounts for this use will depend on the severity and course of the disease, disorder or condition, previous therapy, the patient's health status and response to the drugs, and the judgment of the treating physician.
  • the administration of the compounds may be administered chronically, that is, for an extended period of time, including throughout the duration of the patient’s life in order to ameliorate or otherwise control or limit the symptoms of the patient’s disease or condition.
  • a maintenance dose is administered if necessary.
  • the dosage or the frequency of administration, or both can be reduced, as a function of the symptoms, to a level at which the improved disease, disorder or condition is retained. Patients can, however, require intermittent treatment on a long-term basis upon any recurrence of symptoms.
  • the amount of a given agent that will correspond to such an amount will vary depending upon factors such as the particular compound, disease or condition and its severity, the identity (e.g., weight) of the subject or host in need of treatment, but can nevertheless be determined in a manner recognized in the field according to the particular circumstances surrounding the case, including, e.g., the specific agent being administered, the route of administration, the condition being treated, and the subject or host being treated. In general, however, doses employed for adult human treatment will typically be in the range of about 0.02 - about 5000 mg per day, in some embodiments, about 1 – about 1500 mg per day.
  • the desired dose may conveniently be presented in a single dose or as divided doses administered simultaneously (or over a short period of time) or at appropriate intervals, for example as two, three, four or more sub-doses per day.
  • the pharmaceutical composition described herein may be in unit dosage forms suitable for single administration of precise dosages.
  • the formulation is divided into unit doses containing appropriate quantities of one or more compound.
  • the unit dosage may be in the form of a package containing discrete quantities of the formulation.
  • Non-limiting examples are packaged tablets or capsules, and powders in vials or ampoules.
  • Aqueous suspension compositions can be packaged in single-dose non-reclosable containers.
  • multiple-dose reclosable containers can be used, in which case it is typical to include a preservative in the composition.
  • formulations for parenteral injection may be presented in unit dosage form, which include, but are not limited to ampoules, or in multi-dose containers, with an added preservative.
  • Toxicity and therapeutic efficacy of such therapeutic regimens can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, the determination of the LD 50 (the dose lethal to 50% of the population) and the ED 50 (the dose therapeutically effective in 50% of the population).
  • the dose ratio between the toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio between LD50 and ED 50 .
  • the invention provides a method of treating or preventing a disease, state or condition in a patient in need thereof comprising administering to the patient an effective amount of a compound of any one of embodiments of the invention or a pharmaceutically acceptable salt thereof.
  • the disease, state or condition may be selected from a group as described elsewhere herein.
  • compounds herein can adopt to selectively eliminate an over activated KRas signaling which is induced by KRas mutations by directly binding with the mutated KRas protein, either by stabilizing its GDP bound form (the inactive form) or by blocking the interaction between GTP bound form and its downstream target protein.
  • another way is to hijack the protein degradation mechanism in a cell and leverage E3 ligases’ (like VHL, CRBN or IAPs) substrate specificity through a bi-functional molecule called Proteolysis targeting chimera (PROTAC) (Winter GE, Buckley DL, Paulk J, Roberts JM, Souza A, Dhe- Paganon S, Bradner JE. DRUG DEVELOPMENT. Phthalimide conjugation as a strategy for in vivo target protein degradation. Science.2015 Jun 19; 348 (6241): 1376-81), which can bind with both mutated KRas protein and E3 ligase, create interactions between those two proteins and induce KRas degradation.
  • E3 ligases like VHL, CRBN or IAPs
  • a bifunctional compound composed of a target protein (i.e., KRAS G12D)-binding moiety and an E3 ubiquitin ligase-binding moiety, which may induce proteasome- mediated degradation of selected proteins.
  • the bifunctional compound comprises a target protein (i.e., KRAS G12D)-binding moiety and an E3 ubiquitin ligase-binding moiety known in the art.
  • disclosed herein is the use of the compound disclosed herein in the preparation of degrading a target protein compound by using chemical modification of the compound disclosed herein.
  • the target protein-binding moiety is derived from a compound of Formula (I), Formula (I-A), Formula (II), Formula (III), Formula (IV), Formula (V), or Formula (VI).
  • the compounds of the present disclosure can generally be prepared in a number of ways well known to those skilled in the art of organic synthesis. By way of example, compounds of the present disclosure can be synthesized using the methods described herein, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereof as appreciated by those skilled in the art. [00355] The compounds of the present disclosure may be prepared as described in the schemes and examples described elsewhere herein. EXAMPLES [00356] The following synthetic schemes are provided for purposes of illustration, not limitation.
  • Example 2 Exemplary synthesis of compound 2 [00361] Step 1. To a solution of 7-bromo-2,4,6-trichloro-8-fluoro-quinazoline (580 mg, 1.76 mmol) and DIEA (680.68 mg, 5.27 mmol) in DCM (1 mL) was added azepane-4- carbonitrile;hydrochloride (282.02 mg, 1.76 mmol) at 0 o C. The mixture was stirred at 25 o C for 2 h. The mixture was concentrated to afford a crude product.
  • Step 4 The mixture of 1-[6-chloro-7-[7,8-difluoro-3-(methoxymethoxy)-1-naphthyl]- 8-fluoro-2-[[(2R,8S) -2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy] quinazolin-4- yl]azepane-4-carbonitrile (100 mg, 0.15 mmol), and HCl (5 mL, 2mol/L in dioxane ) was stirred at 25 o C for 1 h.
  • Example 3 Exemplary synthesis of compound 3 [00365] Step 1. To a solution of compound 2-amino-4-bromo-3-fluorobenzoic acid (20 g, 0.09 mol) in DMF (200 ml) was added NIS (21.1 g, 0.09 mol). The mixture was then stirred at 50 °C overnight. HPLC-MS showed that the starting material was consumed. The mixture was then cooled down to r.t. and poured into ice water slowly.
  • Step 2 To a solution of 2-amino-4-bromo-3-fluoro-5-iodobenzoic acid (5 g, 13.9 mmol) in DMF (10 mL) were added Pd(OAc) 2 (311.5 mg, 1.4 mmol), tir-o-tolyphosphine (845.0 mg, 2.8 mmol), triethylamine ( 3.86 mL, 9.3 mmol) and acrylonitrile (2.43 mL, 27.8 mmol). The mixture was degassed with N 2 for 5 min and stirred at 80 °C overnight. HPLC-MS showed that around 44% starting material was consumed.
  • Step 6 To a solution of 3-(7-bromo-8-fluoro-2,4-dihydroxyquinazolin-6- yl)propanenitrile (280 mg, 0.9 mmol) in POCl3 (5 mL) was slowly added DIEA (465.3 mg, 4.5 mmol). The mixture was then stirred at 100 °C for 3 h. HPLC-MS showed that the starting material was consumed. The solvent was co-evaporated with toluene. The resulting residue 3-(7-bromo- 2,4-dichloro-8-fluoroquinazolin-6-yl)propanenitrile (340 mg) was directly used in the next step without further purification.
  • Example 4 Compound 4 [00375] Synthesized in a fashion similar to example 3 using ((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methanol to afford 3-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-7-(3-hydroxynaphthalen-1-yl)-4-(4-hydroxypiperidin-1- yl)quinazolin-6-yl)propanenitrile (compound 4, 19.4 mg) as a pale white solid.
  • LC-MS calc.
  • Example 5 Synthesis of Compound 5 [00376] Step 1. To a solution of 7-bromo-2,4,6-trichloro-8-fluoro-quinazoline (600 mg, 1.82 mmol) and DIEA (0.9 mL, 5.45 mmol) in DCM (10 mL) was added azepane-4- carbonitrile;hydrochloride (306.33 mg, 1.91 mmol) at 0 o C. The mixture was stirred at 25 o C for 2 h.
  • Example 6 Synthesis of Compounds 6 and 7 [00379] The mixture of 1-[7-bromo-6-chloro-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin -8-yl]methoxy]quinazolin-4-yl]azepane-4-carbonitrile (200 mg, 0.37 mmol), 1,2,3,4-tetrahydro- quinoline (1.5 mL, 0.14 mmol), Pd(OAc) 2 (16.64 mg, 0.07 mmol), Xantphos (42.82 mg, 0.07 mmol) and Cs2CO3 (361.46 mg, 1.11 mmol) was stirred at 100 o C for 8 h (neat condition) under argon.
  • Example 7 Compound 8 [00380] Compound 8 was synthesized in a similar fashion to Compound 4.
  • 1-(8-Fluoro-7-(3- hydroxynaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6-vinylquinazolin-4- yl)azepan-4-ol: LCMS calculated for C 3 2H36FN4O3 (M+H) + m/z 543.66, found 543.12.
  • the mixture was diluted with EA (50 mL), washed with H2O (2x10 mL) and brine (10 mL), dried over Na2SO4, and concentrated.
  • the crude product was purified by silica gel chromatography (eluted with EtOAc in petroleum ether from 10% to 50%).
  • Step 3 The mixture of 1-[6-chloro-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-7-[7-fluoro-3-hydroxy-8-(2-triisopropylsilylethynyl)-1- naphthyl]quinazolin-4-yl]azepane-4-carbonitrile (20.mg, 0.02mmol)1-[8-fluoro-2-[[(2R,8S)-2- fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7-[7-fluoro-3-hydroxy-8-(2- triisopropylsilylethynyl)-1-na
  • Example 9 Synthesis of compounds 11 and 12 [00386] Compounds 11 and 12 were synthesized in a similar fashion to Example 8 using 4-((1- (( ⁇ 1-oxidaneyl)methyl)cyclopropyl)methyl)morpholine instead of [(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methanol.
  • Step 3 preparation of 7-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)quinazolin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione (14c).
  • Step 4 preparation of 7-(8-fluoro-7-(7-fluoro-3-hydroxy-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)quinazolin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione (14d).
  • Step 1 preparation of (5R)-3-(2,2-dimethylpropanoyloxymethyl)-2,4-dioxo-1,3,9- triazaspiro[4.5]decane-9-carboxylate (18a).
  • benzyl (5R)-2,4-dioxo-1,3,9- triazaspiro[4.5]decane-9-carboxylate 5000 mg, 16.48 mmol
  • K 2 CO 3 4784.56 mg, 34.62 mmol
  • chloromethyl 2,2-dimethylpropanoate 2979.13 mg, 19.78 mmol
  • Step 2 preparation of [(5R)-2,4-dioxo-1,3,9-triazaspiro[4.5]decan-3-yl]methyl 2,2- dimethylpropanoate (18b).
  • the resulting mixture was recharged with H2 then stirred at 25 °C under H 2 for 16h.
  • Step 7 preparation of (5R)-9-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazolin-4-yl]-1,3,9- triazaspiro[4.5]decane-2,4-dione.
  • Example 13 Nucleotide Exchange Assay: [00409] Ras proteins cycle between an active, GTP bound state, and an inactive GDP-bound state. This activity is tightly regulated by GTPase activating proteins (GAPs) and guanine nucleotide exchange factors (GEFs). GEFs, such as SOS1/2, activate Ras proteins by exchanging GDP for GTP, thus returning Ras to its active conformation (Simanshu, Nissley, & McCormick, 2017). Therefore, a small molecule that binds K-Ras in a manner that prevents SOS-mediated nucleotide exchange locks KRas in its inactive state.
  • GAPs GTPase activating proteins
  • GEFs guanine nucleotide exchange factors
  • HTRF Homogenous time resolved fluorescence
  • 5X compound was added to the protein mixture and incubated for 1 h at RT.
  • 2.5X acceptor solution containing SOS1 cat (564-1049, Reaction Biology MSC-11-502) and GTP-DY-647P1 were then added to the donor KRAS mixture such that the final concentration of the reaction contained 5 nM GST-tagged KRAS G12D (2-169), 20 nM SOScat, and 150 nM GTP.
  • NEA KRAS G12D IC 50 (uM) values of selected compounds are depicted in Table 2 with compounds having a value ⁇ 0.01 uM as ++++; > 0.01 uM to 0.1 uM as +++; > 0.1 uM to 1 uM as ++; > 1 uM to 20 uM as +; and >20 uM as NA.
  • Example 14 Protein Constructs for Protein-Protein Interaction: Table 1: Assay, Protein construct, and protein construct sequences Example 15.
  • KRAS wt and KRAS G12D/V proteins were expressed and purified in conditions similar to those previously reported (Tran, et al., 2021) (Zhang, et al., 2020). Briefly, KRAS (1-169) proteins were expressed in E. coli at 18°C with an upstream TEV cleavage site (ENLFYQS) followed an Avi tag sequence (GLNDIFEAQKIEWHE). KRAS expression constructs contained both a His6 and maltose-binding protein (MBP) tags at the N-terminus for Ni-NTA column purification prior to overnight TEV cleavage and MBP column purification.
  • MBP maltose-binding protein
  • the avi-tagged NRAS expression construct contained both a His6 tag and SUMO cleavage sige at the N-terminus for Ni-NTA column purification followed by His-ULP1 digestion overnight. All avi- tagged RAS proteins were dialyzed into buffer containing ATP, biotin, and BirA followed by purification over a second Ni-NTA column and then run over a size exclusion HiLoad TM 26/600 Superdex TM column in 20 mM HEPES, pH 7.5, 300 mM NaCl, 5 mM MgCl2, and 1 mM TCEP. Fractions containing the protein of interest were pooled, concentrated, and confirmed by intact mass spectrometry.
  • His-tagged RAF1 expression construct contained both a His6 and MBP tags at the N-terminus for Ni-NTA column purification followed by MBP-tagged TEV digestion overnight.
  • RAF1 protein samples were further purified over a MBP column followed by a Ni-NTA column and a second MBP column.
  • the fractions containing the protein of interest were pooled, concentrated, and further purified over a HiLoad TM 16/600 Superdex TM 75 pg size exclusion column into 20mM HEPES, pH8.0, 200mM NaCl, 5mM TCEP.
  • Example 16 Protein-Protein Interaction (PPI) Assay: [00413] When RAS proteins are in the active GTP-bound conformation, they bind the effector protein RAF1 at the N-terminus Ras-binding domain (RBD, residues 52-131) (Tran, et al., 2021). Homogenous time resolved fluorescence (HTRF) was used to monitor the interaction between wt or mutant KRAS and RAF1 or wt NRAS and RAF1. Compounds were assayed in the presence of KRAS G12D/V and RAF1 versus wt KRAS to assess activity against mutant and w.t. KRAS. Similarly, compounds were then assayed in the presence of w.t.
  • HTRF Homogenous time resolved fluorescence
  • RAF1 NRAS and RAF1 to assess RAS isoform selectivity.
  • His-tagged RAF1 protein was incubated with the HTRF donor, anti-6His Tb Cryptate gold (Cisbio 61DB10RDF), and biotinylated RAS proteins were incubated with the HTRF acceptor, streptavidin-d2 (CisBio 610SADLA). The intensity of the fluorescence signal emitted is proportional to binding between the two proteins.
  • the donor solution was prepared by mixing 16 nM His-tagged RAF1 in protein dilution buffer with 1:100 anti-6His Tb cryptate in PPI-Terbium detection buffer.
  • 16 nM biotinylated RAS protein was diluted into protein dilution buffer (50 mM Tris-HCl pH 7.5, 150 mM NaCl, 0.1 mM MgCl2, 1 mM TCEP, 0.005% Tween20) and mixed with 1:2000 Streptavidin-d2 diluted in PPI-Terbium detection buffer (CisBio 61DB10RDF).50X compound in DMSO was mixed with 16 nM KRAS-acceptor solution and incubated for 30 minutes at room temperature. After compound pre-incubation with KRAS, the RAF1 donor solution was added to the KRAS-acceptor solution and incubated for 1 hour at room temperature.
  • protein dilution buffer 50 mM Tris-HCl pH 7.5, 150 mM NaCl, 0.1 mM MgCl2, 1 mM TCEP, 0.005% Tween20
  • PPI-Terbium detection buffer CisBio 61DB10RDF
  • the fluorescence signal emitted was monitored at 665 nm and 615 nm using an Envision multimode plate reader.
  • the HTRF ratio (665/615) was calculated and normalized to 0% inhibition in the absence of compound and 100% inhibition in the presence of untagged RAF1 protein.
  • PPI KRAS G12D/RAF1, KRAS G12V/RAF1, w.t.KRAS/RAF1 and NRAS/RAF1 IC 50 (uM) values of selected compounds are depicted in Table 2 and Table 3 with compounds having a value ⁇ 0.1 uM as ++++; > 0.1 uM to 1 uM as +++; > 1 uM to 10 uM as ++; > 10 uM to 100 uM as +; and >100 uM as NA.
  • AGS cells (ATCC CRL-1739) are cultured in the complete medium containing 10% fetal bovine serum and 1x Penicillin/Streptomycin at 37 o C in a humid atmosphere of 5% CO 2 in the air (AGS cells: RPMI 1640 medium).
  • AGS cells RPMI 1640 medium
  • the cells are plated in tissue-culture treated 96-well plates at the specified densities and allowed to attach for overnight (AGS: 30,000 cells/well).
  • the cells are treated with the serially diluted compound solutions in a final concentration of 0.5 % DMSO. After the treatment for the specified time (AGS cells: 3 hours), the supernatant is removed, and the cells are lysed by the lysis buffer supplied with the kit.
  • pERK ICW is a high throughput screening assay to evaluate the cellular potency of mutant KRAS small molecule inhibitors.
  • KRAS mutant cell line AGS (KRAS G12D ) were purchased from ATCC and maintained in DMEM and RPMI medium supplemented with 10% fetal bovine serum and Penicillin/Streptomycin. [00418] Cells grown in exponential phase were trypsinized, resuspended in fresh media, and viable cells were counted using a cell counter with Trypan Blue (BioRad TC20). Cells were seeded into 384-well plate (Greiner 781091) at density of 5,000 cells/well for AGS and allowed to grow overnight in a 37 ⁇ C CO 2 incubator.
  • IC50 half-maximal inhibitory concentrations
  • Z-factor for each plate was computed from signals derived from wells treated with either DMSO or 5 ⁇ M of Trametinib.
  • AGS pERK ICW (Method B) IC 50 (uM) values of selected compounds are depicted in Table 2 with compounds having a value 0.001 uM to 0.01 uM as ++++; > 0.01 uM to 0.1 uM as +++; > 0.1 uM to 1 uM as ++; 1 uM to 10 uM as + and > 10 uM as NA.
  • Table 2 includes NEA KRAS G12D IC 50 (uM) values ( ⁇ 0.01 uM as ++++; > 0.01 uM to 0.1 uM as +++; > 0.1 uM to 1 uM as ++; > 1 uM to 20 uM as +; and >20 uM as NA), PPI KRAS G12D/RAF1 IC50 (uM) values ( ⁇ 0.1 uM as ++++; > 0.1 uM to 1 uM as +++; > 1 uM to 10 uM as ++; > 10 uM to 100 uM as +; and >100 uM as NA), AGS pERK HTRF (Method A) IC50 (uM) values ( ⁇ 0.01 uM as ++++; > 0.01 uM to 0.1 uM as +++; 0.1 uM to 1 uM as ++; 1 uM to 20 uM as + and >20 uM as NA), PPI
  • Table 3 includes KRASG12V/RAF1, wtKRAS/RAF1 and wtNRAS/RAF1 PPI IC 50 (uM) values of selected compounds; with compounds having a value ⁇ 0.1 uM as ++++; 0.1 uM to 1 uM as +++; >1 uM to 10 uM as ++; >10 uM to 100 uM as +; and >100 uM as NA.
  • uM KRASG12V/RAF1, wtKRAS/RAF1 and wtNRAS/RAF1 PPI IC 50 (uM) values of selected compounds; with compounds having a value ⁇ 0.1 uM as ++++; 0.1 uM to 1 uM as +++; >1 uM to 10 uM as ++; >10 uM to 100 uM as +; and >100 uM as NA.

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Abstract

Provided herein are KRAS modulating compounds, such as compounds of Formula (I) and various Sub Formulas or pharmaceutically acceptable salts, solvates, stereoisomers, atom labelled, or tautomers of any of the foregoing, useful for modulating KRAS GD12 and/or other G12 mutants.

Description

KRAS MODULATORS AND USES THEREOF CROSS-REFERENCE [0001] This application claims the benefit of U.S. Provisional Patent Applications Nos. 63/288,970, filed on December 13, 2021; 63/367,560 filed on July 1, 2022; and 63/371,987 filed on August 19, 2022; the entire contents of each of which are incorporated herein by reference. BACKGROUND OF THE INVENTION [0002] The small GTPase protein Kirsten Rat Sarcoma 2 Viral Oncogene Homolog (KRAS) is a member of the Ras family of cell signaling switches, regulating growth and survival of normal and cancerous cells (e.g., see Cully, M. and J. Downward, SnapShot: Ras Signaling. Cell, 2008. 133(7): p.1292-1292 e1). KRAS mutations drive approximately 25% of human cancers by aberrant regulation of the mitogen-activated protein kinase (MAPK) signaling cascade and other effector pathways (e.g., see Stephen, A.G., et al., Dragging ras back in the ring. Cancer Cell, 2014.25(3): p.272-81). Though Ras has been recognized as a target in cancer for about 40 years, Ras-driven cancers remain among the most difficult to treat due to insensitivity to available targeted therapies. Ras, encoded by the three major genes KRAS, NRAS and HRAS, has the highest frequency of mutation of any oncogene. All oncogenic Ras mutations drive the switch to accumulate in the active GTP-bound state. The most common Ras mutation found across human tumor types is KRAS G12D (e.g., see The AACR Project GENIE Consortium. Cancer Discovery, 2017.7(8): p.818-831. Dataset Version 4). Activating mutations in codon 12 impair the small GTPases’ ability to perform their role in hydrolyzing GTP. This regulatory impairment is fundamental for initiating and maintaining tumor progression. [0003] Despite extensive efforts, small molecules have not been identified which block effector binding or restore GTPase activating protein (GAP) sensitivity, though some have been found which block interaction of Ras with the guanine nucleotide exchange factor (GEF), SOS, which activates Ras at the plasma membrane. KRAS G12C mutations, most common in lung adenocarcinoma, have been clinically shown to be susceptible to direct inhibition by covalent modification with small molecule inhibitors trapping the protein in the inactive GDP-bound state. KRAS G12D mutation confers a significantly slower intrinsic rate of GTP hydrolysis than G12C, resulting in more constitutive activation. Thus, pharmacological targeting the of inactive state is unlikely to achieve similar results against G12D, despite the existence of a similar binding pocket in the GDP-state. Additionally, a cysteine present at the site of the activating mutation yields itself to covalent chemistry, while aspartic acid does not provide typical medicinal chemistry approaches for selective covalent modification. [0004] In order to potentially exploit the accumulation of KRAS G12D and other mutant variants in the GTP-bound state as a vulnerability to achieve selective inhibition of cancer cells while sparing normal Ras function, it is attractive for small molecule inhibitors to bind selectively to the GTP-state and stabilize a conformation that is incompetent for oncogenic signaling interactions with effector proteins. Furthermore, it has been shown that only constitutive activation of Raf, MEK and ERK kinases in the MAPK cascade downstream of Ras can bypass the requirement for Ras proteins in proliferative signaling (e.g., see Drosten, M., et al., Genetic analysis of Ras signalling pathways in cell proliferation, migration and survival. EMBO J, 2010.29(6): p.1091- 104). As all evidence has indicated that MAPK signaling is essential for the growth effects of Ras in cancer, KRAS-mutant-selective inhibition in this pathway is considered the critical functional readout for potential clinical benefit of novel therapeutic approaches. Thus, there is a need to develop new inhibitors for KRAS-driven cancers that demonstrate inhibition of MAPK signals via a mechanism of action that is selective for binding to the active GTP-bound state over the inactive GDP-bound state. SUMMARY OF THE INVENTION [0005] The present disclosure relates to Formula (I),Formula (II), Formula (III), or Formula (IV), including stereoisomers, tautomers, solvates, and pharmaceutically acceptable salts thereof, and to uses thereof in, for example, inhibiting KRas G12D and/or other G12 mutants. [0006] In an aspect, the present disclosure provides a compound represented by the structure of Formula (I):
Figure imgf000003_0001
or a pharmaceutically acceptable salt thereof, wherein: Y is selected from a bond, O and NR5; R2 is selected from hydrogen, -N(R5)2, -L-N(R5)2, -L-OR5, heterocycle, C1-C6 alkyl, -L- heterocycle, -L-aryl, -L-heteroaryl, -L-cycloalkyl, -L-N(R5)2, -L-NHC(=NH)NH2, -L-C(O)N(R5)2, -L-C1-C6 haloalkyl, -L-OR5, -L-NR5C(O)-aryl, -L-COOH, and -LC(=O)OC1-C6 alkyl, wherein the heterocycle, the aryl portion of -L-NR5C(O)-aryl, the heterocycle portion of -L-heterocycle, and the cycloalkyl portion of the -L-cycloalkyl are each optionally substituted with one or more R6, and wherein the aryl of the -L- aryl and heteroaryl of the -L-heteroaryl are each optionally substituted with one or more R7; each L is independently selected from a C1-C4 alkylene optionally substituted with one or more substituents independently selected from -OH, C1-C4 hydroxyalkyl, C1-C4 alkyl, C3-C6 carbocycle, and 3- to 8-membered heterocycle, wherein the C3-C6 carbocycle and 3- to 8- membered heterocycle are optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle wherein the C3-C6 carbocycle and the 3- to 8- membered heterocycle are optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl; R3 is selected from aryl and heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, =O, -NO2,C1-C4 alkyl, C1-6 aminoalkyl, -S- C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 hydroxyalkynyl, C1-C3 cyanoalkyl, triazolyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, -S-C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, -CH2C(=O)N(R5)2, -C3-C4 alkynyl(NR5)2, -N(R5)2, (C1-C3 alkoxy)haloC1-C3 alkyl- , and C3-C6 cycloalkyl, wherein the C3-C6 cycloalkyl is optionally substituted with one or more substituents selected from halogen and C1-C3 alkyl; and wherein when R3 is benzothiazole, the benzothiazole is optionally substituted with one or more R49; R4 is selected from hydrogen, halogen, C1-C3 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and -O-C1- 6 haloalkyl; each R5 is independently selected from hydrogen and C1-C3 alkyl; each R6 is independently selected from halogen, -OH, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1- C3 haloalkyl, C1-C3 alkoxy, -CN, C1-C3 aminoalkyl, -Q-phenyl, -Q-phenylSO2F, -NHC(O)phenyl, - NHC(O)phenylSO2F, C1-C3 alkyl substituted pyrazolyl, -N(R5)2, (C1-C3 alkoxy)C1-C3 alkyl-, ( C1-C3 alkyl)C(=O), oxo, (C1-C3 haloalkyl)C(=O)-, -SO2F, (C1-C3 alkoxy)C1-C3 alkoxy, - CH2OC(O)N(R5)2, -CH2NHC(O)OC1-C6 alkyl, -CH2NHC(O)N(R5)2, -CH2NHC(O)C1-C6 alkyl, - CH2(pyrazolyl), -CH2NHSO2C1-C6 alkyl, -CH2OC(O)heterocycle, -OC(O)N(R5)2, - OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl), -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl(C1-C3 alkyl)N(CH3)2, -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl, -OC(O)heterocycle, and - CH2heterocycle, wherein the phenyl of -NHC(O)phenyl and -OC(O)NH(C1-C3 alkyl)(C1-C3 alkyl)phenyl are each optionally substituted with -C(O)H and OH, and wherein the heterocycle of -CH2heterocyclyl is optionally substituted with oxo; each Q is independently selected from a bond and O; each R7 is independently selected from halogen, -OH, HC(=O)-, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, and -N(R5)2; R9 is selected from C3-C12 carbocycle and 5- to 12-membered heterocycle, wherein the C3-C12 carbocycle and the 5- to 12-membered heterocycle are each substituted with one or more substituents independently selected from halogen, -B(OR20)2, -OR20, -SR20, -N(R20)2, -NHCN, - NO2, =O, =S, =N(R20), -CN, C1-6 fluoroalkyl, C1-6 alkoxy, and C2-6 alkynyl; and further optionally substituted with one or more substituents independently selected from -C(O)N(R20)2, -C(O)NR20- OR20, C1-6 alkyl-O-C(O)C1-6 alkyl, C1-6 aminoalkyl, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 alkyl, and C2-6 alkenyl; each R20 is independently selected from hydrogen; and C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbocycle, and 3- to 12- membered heterocycle; each R49 is independently selected from halogen, -CN, -OH, =O, -NO2, C1-C4 alkyl, C1-6 aminoalkyl, -S-C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 hydroxyalkynyl, C1-C3 cyanoalkyl, triazolyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, -S-C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, -CH2C(=O)N(R5)2, -C3-C4 alkynyl(NR5)2, (C1-C3 alkoxy)haloC1-C3 alkyl-, and C3- C6 cycloalkyl, wherein the C3-C6 cycloalkyl is optionally substituted with one or more substituents selected from halogen and C1-C3 alkyl; and R50 is selected from hydrogen, halogen, -OH, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, -CN, C1-C3 cyanoalkyl, C1-C3 aminoalkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 hydroxyalkynyl, and C3-C6 carbocycle; and wherein when Y is O, R2 is
Figure imgf000005_0002
and R9 is selected from pyrrolidine and thiazole, the pyrrolidine and thiazole are each optionally substituted with one or more R49. [0007] In an aspect, the present disclosure provides a compound represented by the structure of Formula (I-A):
Figure imgf000005_0001
or a pharmaceutically acceptable salt thereof, wherein: Y is O; R2 is selected from -L-heterocycle, and -L-heteroarylwherein the heterocycle portion of - L-heterocycle, is optionally substituted with one or more R6, and wherein the heteroaryl of the -L- heteroaryl is optionally substituted with one or more R7; each L is independently selected from a C1-C4 alkylene optionally substituted with one or more substituents independently selected from -OH, C1-C4 hydroxyalkyl, C1-C4 alkyl, C3-C6 carbocycle, or 3- to 8-membered heterocycle, wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle wherein the C3-C6 carbocycle and the 3- to 8- membered heterocycle are optionally substituted with one or more substituents independently selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl; R3 is selected from aryl and heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, =O, -NO2, C1-C4 alkyl, C1-6 aminoalkyl, -S-C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 hydroxyalkynyl, C1-C3 cyanoalkyl, triazolyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, -S-C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, -CH2C(=O)N(R5)2, -C3-C4 alkynyl(NR5)2, -N(R5)2, (C1-C3 alkoxy)haloC1-C3 alkyl- , and C3-C6 cycloalkyl, wherein the C3-C6 cycloalkyl is optionally substituted with one or more substituents selected from halogen and C1-C3 alkyl; and wherein when R3 is benzothiazole or pyridine, the benzothiazole or pyridine is optionally substituted with one or more R49; R4 is selected from hydrogen, halogen, C1-C3 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and -O-C1- 6 haloalkyl; each R5 is independently selected from hydrogen and C1-C3 alkyl; each R6 is independently selected from halogen, -OH, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1- C3 haloalkyl, C1-C3 alkoxy, -CN, C1-C3 aminoalkyl, -Q-phenyl, -Q-phenylSO2F, -NHC(O)phenyl, - NHC(O)phenylSO2F, C1-C3 alkyl substituted pyrazolyl, -N(R5)2, (C1-C3 alkoxy)C1-C3 alkyl-, (C1-C3 alkyl)C(=O), oxo, =CH2, (C1-C3 haloalkyl)C(=O)-, -SO2F, (C1-C3 alkoxy)C1-C3 alkoxy, - CH2OC(O)N(R5)2, -CH2NHC(O)OC1-C6 alkyl, -CH2NHC(O)N(R5)2, -CH2NHC(O)C1-C6 alkyl, - CH2(pyrazolyl), -CH2NHSO2C1-C6 alkyl, -CH2OC(O)heterocycle, -OC(O)N(R5)2, - OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl), -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl(C1-C3 alkyl)N(CH3)2, -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl, -OC(O)heterocycle, and - CH2heterocycle, wherein the phenyl of -NHC(O)phenyl and -OC(O)NH(C1-C3 alkyl)(C1-C3 alkyl)phenyl are each optionally substituted with -C(O)H and OH, and wherein the heterocycle of -CH2heterocyclyl is optionally substituted with oxo; each Q is independently selected from a bond and O; each R7 is independently selected from halogen, -OH, HC(=O)-, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, and -N(R5)2; R9 is selected from C3-C12 carbocycle and 5- to 12-membered heterocycle, wherein the C3- C12 carbocycle and 5- to 12-membered heterocycle are each substituted with one or more substituents independently selected from halogen, -B(OR20)2, -OR20, -SR20, -NHCN, -NO2, =O, =S, =N(R20), -CN, C1-6 fluoroalkyl, C1-6 alkoxy, and C2-6 alkynyl; and further optionally substituted with one or more substituents independently selected from -C(O)N(R20)2, -C(O)NR20-OR20, C1-6 aminoalkyl, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 alkyl, C1-6 alkyl-O-C(O)C1-6 alkyl, and C2-6 alkenyl; wherein when R9 is substituted with at least one -OH, =O, or C1-6 alkoxy, the 5- to 12- membered heterocycle is a non-bridged heterocycle;each R20 is independently selected from hydrogen; and C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle; each R49 is independently selected from halogen, -CN, -OH, =O, -NO2, C1-C4 alkyl, C1-6 aminoalkyl, -S-C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 hydroxyalkynyl, C1-C3 cyanoalkyl, triazolyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, -S-C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, -CH2C(=O)N(R5)2, -C3-C4 alkynyl(NR5)2, (C1-C3 alkoxy)haloC1-C3 alkyl-, and C3- C6 cycloalkyl, wherein the C3-C6 cycloalkyl is optionally substituted with one or more substituents independently selected from halogen and C1-C3 alkyl; R50 is selected from hydrogen, halogen, -OH, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, -CN, C1-C3 cyanoalkyl, C1-C3 aminoalkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 hydroxyalkynyl, and C3-C6 carbocycle; and wherein when Y is O, R2 is 9
Figure imgf000007_0002
, R is selected from pyrrolidine and thiazole, the pyrrolidine and thiazole are each optionally substituted with one or more R49. [0008] In an aspect, the present disclosure provides a compound represented by the structure of Formula (II):
Figure imgf000007_0001
or a pharmaceutically acceptable salt thereof, wherein: Y is selected from a bond, O and NR5; R2 is selected from L-pyrrolizine, wherein the pyrrolizine is optionally substituted with one or more R6; each L is independently selected from a C1-C4 alkylene optionally substituted with one or more substituents selected from -OH, C1-C4 hydroxyalkyl, and C1-C4 alkyl; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl; R3 is selected from aryl and heteroaryl, wherein the aryl and the heteroaryl are each optionally substituted with one or more substituents independently selected from halogen, -CN, - OH, =O, -NO2, C1-C4 alkyl, C1-6 aminoalkyl, -S-C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 hydroxyalkynyl, C1-C3 cyanoalkyl, triazolyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, -S- C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, -CH2C(=O)N(R5)2, -C3-C4 alkynyl(NR5)2, -N(R5)2, (C1-C3 alkoxy)haloC1-C3 alkyl-, and C3-C6 cycloalkyl, wherein the C3-C6 cycloalkyl is optionally substituted with one or more substituents selected from halogen and C1-C3 alkyl; R4 is selected from hydrogen, halogen, C1-C3 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and -O-C1- 6 haloalkyl; each R5 is independently selected from hydrogen and C1-C3 alkyl; each R6 is independently selected from halogen, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkyl, oxo, C1-C3 haloalkyl, C1-C3 alkoxy, cyano, =CH2, =NO-C1-C3 alkyl, C1-C3 aminoalkyl, - N(R5)S(O)2(R5), -Q-phenyl, -Q-phenylSO2F, -NHC(O)phenyl, - NHC(O)phenylSO2F, C1-C3 alkyl substituted pyrazolyl, tert-butyldimethylsilyloxyCH2- , -N(R5)2, (C1-C3 alkoxy)C1-C3 alkyl-, (C1- C3 alkyl)C(=O), oxo, (C1-C3 haloalkyl)C(=O)-, -SO2F, (C1-C3 alkoxy)C1-C3 alkoxy, - CH2OC(O)N(R5)2, -CH2NHC(O)OC1-C6 alkyl, -CH2NHC(O)N(R5)2, -CH2NHC(O)C1-C6 alkyl, - CH2(pyrazolyl), -CH2NHSO2C1-C6 alkyl, -CH2OC(O)heterocycle, -OC(O)N(R5)2, - OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl), -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl(C1-C3 alkyl)N(CH3)2, -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl, - OC(O)heterocycle, -O-C1-C3 alkyl, and -CH2heterocycle, wherein the phenyl of -NHC(O)phenyl and -OC(O)NH(C1-C3 alkyl)(C1-C3 alkyl)phenyl are optionally substituted with one or more substituents selected from - C(O)H and OH, and wherein the alkyl of -O-C1-C3 alkyl is optionally substituted with substituents selected from heterocycle, oxo and hydroxy; and wherein the heterocycle of -CH2heterocyclyl is optionally substituted with oxo; Q is selected from a bond and O; R9 is selected from C3-C12 carbocycle and 5- to 12-membered heterocycle, each of which are optionally substituted with one or more substituents independently selected from halogen, - B(OR20)2, -OR20, -SR20, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), - NR20S(O)2R20, -C(O)N(R20)2, -C(=NR20)N(R20)2, -C(O)NR20OR20, -N(R20)C(O)R20, - N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, -C(O)R20, -C(O)OR20, -OC(O)R20, - OC(O)N(R20)2, -NO2, =O, =N(R20), =NO(R20), -CN, -NHCN, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-C12 carbocycle and 5- to 12-membered heterocycle, wherein the C3-C12 carbocycle and 5- to 12-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -B(OR20)2, -OR20, -SR20, -S(O)2(R20), -S(O)2N(R20)2, - S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, -C(O)NR20OR20, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, -C(O)R20, -C(O)OR20, -OC(O)R20, - OC(O)N(R20)2, -NO2, =O, =N(R20), =NO(R20), -CN, -NHCN, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C3-C12 carbocycle; each R20 is independently selected from hydrogen; and C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbocycle, and 3- to 12- membered heterocycle; and R50 is selected from hydrogen, halogen, -OH, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, -CN, C1-C3 cyanoalkyl, C1-C3 aminoalkyl, C2-C4 alkenyl, C2-C4 alkynyl, and C2-C4 hydroxyalkynyl. [0009] In an aspect, the present disclosure provides a compound represented by Formula (III):
Figure imgf000009_0001
or a pharmaceutically acceptable salt thereof, wherein: Y is selected from a bond, O and NR5; R2 is selected from hydrogen, -N(R5)2, -L-N(R5)2, -L-OR5, heterocycle, C1-C6 alkyl, -L- heterocycle, -L-aryl, -L-heteroaryl, -L-cycloalkyl, -L-N(R5)2, -L-NHC(=NH)NH2, -L-C(O)N(R5)2, -L-C1-C6 haloalkyl, -L-OR5, -L-NR5C(O)-aryl, -L-COOH, and -LC(=O)OC1-C6 alkyl, wherein the heterocycle, the aryl portion of -L-NR5C(O)-aryl, the heterocycle portion of -L-heterocycle, and the cycloalkyl portion of the -L-cycloalkyl are each optionally substituted with one or more R6, and wherein the aryl of the -L- aryl and heteroaryl of the -L-heteroaryl are each optionally substituted with one or more R7; each L is independently selected from a C1-C4 alkylene optionally substituted with one or more substituents independently selected from -OH, C1-C4 hydroxyalkyl, C1-C4 alkyl, C3-C6 carbocycle, and 3- to 8-membered heterocycle, wherein the C3-C6 carbocycle and 3- to 8- membered heterocycle are optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle wherein the C3-C6 carbocycle and the 3- to 8- membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, and C1-6 haloalkyl; R3 is selected from aryl and heteroaryl, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, =O, -NO2, C1-C4 alkyl, C1-6 aminoalkyl, -S-C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 hydroxyalkynyl, C1-C3 cyanoalkyl, triazolyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, -S-C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, -CH2C(=O)N(R5)2, -C3-C4 alkynyl(NR5)2, -N(R5)2, (C1-C3 alkoxy)haloC1-C3 alkyl- , and C3-C6 cycloalkyl, wherein the C3-C6 cycloalkyl is optionally substituted with one or more substituents independently selected from halogen and C1-C3 alkyl; R4 is selected from hydrogen, halogen, C1-C3 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and -O-C1- 6 haloalkyl; each R5 is independently selected from hydrogen and C1-C3 alkyl; each R6 is independently selected from halogen, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, cyano, =CH2, =NO-C1-C3 alkyl, C1-C3 aminoalkyl, - N(R5)S(O)2(R5), -Q-phenyl, -Q-phenylSO2F, -NHC(O)phenyl, - NHC(O)phenylSO2F, C1-C3 alkyl substituted pyrazolyl, tert-butyldimethylsilyloxyCH2- , -N(R5)2, (C1-C3 alkoxy)C1-C3 alkyl-, (C1- C3 alkyl)C(=O), oxo, (C1-C3 haloalkyl)C(=O)-, -SO2F, (C1-C3 alkoxy)C1-C3 alkoxy, - CH2OC(O)N(R5)2, -CH2NHC(O)OC1-C6 alkyl, -CH2NHC(O)N(R5)2, -CH2NHC(O)C1-C6 alkyl, - CH2(pyrazolyl), -CH2NHSO2C1-C6 alkyl, -CH2OC(O)heterocycle, -OC(O)N(R5)2, - OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl), -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl(C1-C3 alkyl)N(CH3)2, -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl, - OC(O)heterocycle, -O-C1-C3 alkyl, and -CH2heterocycle, wherein the phenyl of -NHC(O)phenyl and -OC(O)NH(C1-C3 alkyl)(C1-C3 alkyl)phenyl are each optionally substituted with one or more substituents independently selected from -C(O)H and OH, and wherein the alkyl of -O-C1-C3 alkyl is optionally substituted with substituents selected from heterocycle, oxo and hydroxy; and wherein the heterocycle of -CH2heterocyclyl is optionally substituted with oxo; each Q is independently selected from a bond and O; each R7 is independently selected from halogen, -OH, HC(=O)-, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, and -N(R5)2; R9 is selected from unsaturated 5- to 12-membered heterocycle, wherein the unsaturated 5- to 12-membered heterocycle contains at least 1 nitrogen atom and optionally one or more additional heteroatoms selected from oxygen, boron, and sulfur, and wherein the unsaturated 5- to 12-membered heterocycle of R9 is bound to Formula (III) via the at least 1 nitrogen atom, and wherein the unsaturated 5- to 12-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -B(OR20)2, -OR20, -SR20, - N(R20)S(O)2(R20), -S(O)2(R20), -S(O)2N(R20)2, -C(O)N(R20)2, -C(O)NR20-OR20, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)2, -C(O)R20, -C(O)OR20, -OC(O)R20, -NO2, =O, =S, =N(R20), -CN, C1-6 alkyl-O-C(O)C1-6 alkyl, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl; each R20 is independently selected from hydrogen; and C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbocycle, and 3- to 12- membered heterocycle; and R50 is selected from hydrogen, halogen, -OH, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, -CN, C1-C3 cyanoalkyl, C1-C3 aminoalkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 hydroxyalkynyl, and C3-C6 carbocycle. [0010] In an aspect, the present disclosure provides a compound represented by Formula (IV):
Figure imgf000011_0001
or a pharmaceutically acceptable salt thereof, wherein: Y is selected from a bond, O and NR5; R2 is selected from hydrogen, -N(R5)2, -L-N(R5)2, -L-OR5, heterocycle, C1-C6 alkyl, -L- heterocycle, -L-aryl, -L-heteroaryl, -L-cycloalkyl, -L-N(R5)2, -L-NHC(=NH)NH2, -L-C(O)N(R5)2, -L-C1-C6 haloalkyl, -L-OR5, -L-NR5C(O)-aryl, -L-COOH, and -LC(=O)OC1-C6 alkyl, wherein the heterocycle, the aryl portion of -L-NR5C(O)-aryl, the heterocycle portion of -L-heterocycle, and the cycloalkyl portion of the -L-cycloalkyl are each optionally substituted with one or more R6, and wherein the aryl of the -L-aryl and heteroaryl of the -L-heteroaryl are each optionally substituted with one or more R7; each L is independently selected from a C1-C4 alkylene optionally substituted with one or more substituents independently selected from -OH, C1-C4 hydroxyalkyl, C1-C4 alkyl, C3-C6 carbocycle, and 3- to 8-membered heterocycle, wherein the C3-C6 carbocycle and 3- to 8- membered heterocycle are optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle wherein the C3-C6 carbocycle and 3- to 8- membered heterocycle are optionally substituted with one or more substituents independently selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl; R3 is selected from tricyclic aryl and tricyclic heteroaryl, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, =O, - NO2, C1-C4 alkyl, C1-6 aminoalkyl, -S-C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 hydroxyalkynyl, C1-C3 cyanoalkyl, triazolyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, -S-C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, -CH2C(=O)N(R5)2, -C3-C4 alkynyl(NR5)2, -N(R5)2, (C1-C3 alkoxy)haloC1-C3 alkyl-, and C3-C6 cycloalkyl, wherein the C3-C6 cycloalkyl is optionally substituted with one or more substituents selected from halogen and C1-C3 alkyl; R4 is selected from hydrogen, halogen, C1-C3 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and -O-C1- 6 haloalkyl; each R5 is independently selected from hydrogen and C1-C3 alkyl; each R6 is independently selected from halogen, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkyl, oxo, C1-C3 haloalkyl, C1-C3 alkoxy, cyano, =NO-C1-C3 alkyl, C1-C3 aminoalkyl, -N(R5)S(O)2(R5), -Q-phenyl, -Q-phenylSO2F, -NHC(O)phenyl, - NHC(O)phenylSO2F, C1-C3 alkyl substituted pyrazolyl, tert-butyldimethylsilyloxyCH2- , -N(R5)2, (C1-C3 alkoxy)C1-C3 alkyl-, (C1-C3 alkyl)C(=O), (C1-C3 haloalkyl)C(=O)-, -SO2F, (C1-C3 alkoxy)C1-C3 alkoxy, -CH2OC(O)N(R5)2, - CH2NHC(O)OC1-C6 alkyl, -CH2NHC(O)N(R5)2, -CH2NHC(O)C1-C6 alkyl, -CH2(pyrazolyl), - CH2NHSO2C1-C6 alkyl, -CH2OC(O)heterocycle, -OC(O)N(R5)2, -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl), -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl(C1-C3 alkyl)N(CH3)2, -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl, - OC(O)heterocycle, -O-C1-C3 alkyl, and -CH2heterocycle, wherein the phenyl of -NHC(O)phenyl and -OC(O)NH(C1-C3 alkyl)(C1-C3 alkyl)phenyl are optionally substituted with one or more substituents selected from -C(O)H and OH, and wherein the alkyl of -O-C1-C3 alkyl is optionally substituted with substituents selected from heterocycle, oxo and hydroxy; and wherein the heterocycle of -CH2heterocyclyl is optionally substituted with oxo; each Q is independently selected from a bond and O; each R7 is independently selected from halogen, -OH, HC(=O)-, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, and -N(R5)2; R9 is selected from 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -B(OR20)2, -OR20, -SR20, -S(O)2(R20), -S(O)2N(R20)2, -N(R20)S(O)2(R20), -C(O)N(R20)2, -C(O)NR20-OR20, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)2, -S(O)2R20, - C(O)R20, -C(O)OR20, -OC(O)R20, -NO2, =O, =S, =N(R20), -CN, C1-6 alkyl-O-C(O)C1-6 alkyl, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl; each R20 is independently selected from hydrogen; and C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbocycle, and 3- to 12- membered heterocycle; and R50 is selected from hydrogen, halogen, -OH, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, -CN, C1-C3 cyanoalkyl, C1-C3 aminoalkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 hydroxyalkynyl, and C3-C6 carbocycle. [0011] In an aspect, the present disclosure provides a compound represented by Formula (V)
Figure imgf000013_0001
or a pharmaceutically acceptable salt thereof, wherein: Y is O; R2 is selected from -L-heterocycle, wherein the heterocycle portion of -L-heterocycle is optionally substituted with one or more R6; each L is independently selected from a C1-C4 alkylene optionally substituted with one or more substituents independently selected from -OH, C1-C4 hydroxyalkyl, C1-C4 alkyl, C3-C6 carbocycle, and 3- to 8-membered heterocycle, wherein the C3-C6 carbocycle and 3- to 8- membered heterocycle are optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle wherein the C3-C6 carbocycle and the 3- to 8- membered heterocycle are optionally substituted with one or more substituents independently selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl; R3 is selected from aryl and heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, =O, -NO2, C1-C4 alkyl, C1-6 aminoalkyl, -S-C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 hydroxyalkynyl, C1-C3 cyanoalkyl, triazolyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, -S-C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, -CH2C(=O)N(R5)2, -C3-C4 alkynyl(NR5)2, -N(R5)2, (C1-C3 alkoxy)haloC1-C3 alkyl- , and C3-C6 cycloalkyl, wherein the C3-C6 cycloalkyl is optionally substituted with one or more substituents selected from halogen and C1-C3 alkyl; R4 is selected from hydrogen, halogen, C1-C3 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and -O-C1- 6 haloalkyl; each R5 is independently selected from hydrogen and C1-C3 alkyl; each R6 is independently selected from halogen, -OH, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1- C3 haloalkyl, C1-C3 alkoxy, -CN, =CH2, C1-C3 aminoalkyl, -Q-phenyl, -Q-phenylSO2F, - NHC(O)phenyl, - NHC(O)phenylSO2F, C1-C3 alkyl substituted pyrazolyl, -N(R5)2, (C1-C3 alkoxy)C1-C3 alkyl-, (C1-C3 alkyl)C(=O), oxo, (C1-C3 haloalkyl)C(=O)-, -SO2F, (C1-C3 alkoxy)C1- C3 alkoxy, -CH2OC(O)N(R5)2, -CH2NHC(O)OC1-C6 alkyl, -CH2NHC(O)N(R5)2, - CH2NHC(O)C1-C6 alkyl, -CH2(pyrazolyl), -CH2NHSO2C1-C6 alkyl, -CH2OC(O)heterocycle, - OC(O)N(R5)2, -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl), -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl(C1-C3 alkyl)N(CH3)2, -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl, - OC(O)heterocycle, and -CH2heterocycle, wherein the phenyl of -NHC(O)phenyl and - OC(O)NH(C1-C3 alkyl)(C1-C3 alkyl)phenyl are each optionally substituted with -C(O)H and OH, and wherein the heterocycle of -CH2heterocyclyl is optionally substituted with oxo; each Q is independently selected from a bond and O; each R20 is independently selected from hydrogen; and C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbocycle, and 3- to 12- membered heterocycle; R50 is selected from hydrogen, halogen, -OH, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, -CN, C1-C3 cyanoalkyl, C1-C3 aminoalkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 hydroxyalkynyl, and C3-C6 carbocycle. [0012] In an aspect, the present disclosure provides a compound represented by Formula (VI):
Figure imgf000015_0001
Formula (VI), or a pharmaceutically acceptable salt thereof, wherein: Y is O; R2 is selected from -L-heterocycle, wherein the heterocycle portion of -L-heterocycle, is optionally substituted with one or more R6; each L is independently selected from a C1-C4 alkylene optionally substituted with one or more substituents independently selected from -OH, C1-C4 hydroxyalkyl, C1-C4 alkyl, C3-C6 carbocycle, or 3- to 8-membered heterocycle, wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle wherein the C3-C6 carbocycle and the 3- to 8- membered heterocycle are optionally substituted with one or more substituents independently selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl; R3 is selected from aryl and heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, =O, -NO2, C1-C4 alkyl, C1-6 aminoalkyl, -S-C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 hydroxyalkynyl, C1-C3 cyanoalkyl, triazolyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, -S-C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, -CH2C(=O)N(R5)2, -C3-C4 alkynyl(NR5)2, -N(R5)2, (C1-C3 alkoxy)haloC1-C3 alkyl- , and C3-C6 cycloalkyl, wherein the C3-C6 cycloalkyl is optionally substituted with one or more substituents selected from halogen and C1-C3 alkyl; and wherein when R3 is benzothiazole or pyridine, the benzothiazole or pyridine is optionally substituted with one or more R49; R4 is selected from hydrogen, halogen, C1-C3 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and -O-C1- 6 haloalkyl; each R5 is independently selected from hydrogen and C1-C3 alkyl; each R6 is independently selected from halogen, -OH, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1- C3 haloalkyl, C1-C3 alkoxy, -CN, =CH2, C1-C3 aminoalkyl, -Q-phenyl, -Q-phenylSO2F, - NHC(O)phenyl, - NHC(O)phenylSO2F, C1-C3 alkyl substituted pyrazolyl, -N(R5)2, (C1-C3 alkoxy)C1-C3 alkyl-, (C1-C3 alkyl)C(=O), oxo, (C1-C3 haloalkyl)C(=O)-, -SO2F, (C1-C3 alkoxy)C1- C3 alkoxy, -CH2OC(O)N(R5)2, -CH2NHC(O)OC1-C6 alkyl, -CH2NHC(O)N(R5)2, - CH2NHC(O)C1-C6 alkyl, -CH2(pyrazolyl), -CH2NHSO2C1-C6 alkyl, -CH2OC(O)heterocycle, - OC(O)N(R5)2, -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl), -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl(C1-C3 alkyl)N(CH3)2, -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl, - OC(O)heterocycle, and -CH2heterocycle, wherein the phenyl of -NHC(O)phenyl and - OC(O)NH(C1-C3 alkyl)(C1-C3 alkyl)phenyl are each optionally substituted with -C(O)H and OH, and wherein the heterocycle of -CH2heterocyclyl is optionally substituted with oxo; each Q is independently selected from a bond and O; R9 is selected from a 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle is substituted with one or more substituents independently selected from -OH, - NHCN, -CN, C1-6 alkoxy; and further optionally substituted with one or more substituents independently selected from halogen, -C(O)N(R20)2, -C(O)NR20-OR20, C1-6 haloalkyl, -SR20, =O, =S, =N(R20), -B(OR20)2, -N(R20)2, -NO2, C1-6 aminoalkyl, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 alkyl, C1-6 alkyl-O-C(O)C1-6 alkyl, C2-6 alkynyl and C2-6 alkenyl; wherein when R9 is substituted with at least one -OH or C1-6 alkoxy, the 5- to 12-membered heterocycle is an non-bridged heterocycle; each R20 is independently selected from hydrogen; and C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbocycle, and 3- to 12- membered heterocycle; each R49 is independently selected from halogen, -CN, -OH, =O, -NO2, C1-C4 alkyl, C1-6 aminoalkyl, -S-C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 hydroxyalkynyl, C1-C3 cyanoalkyl, triazolyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, -S-C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, -CH2C(=O)N(R5)2, -C3-C4 alkynyl(NR5)2, (C1-C3 alkoxy)haloC1-C3 alkyl-, and C3- C6 cycloalkyl, wherein the C3-C6 cycloalkyl is optionally substituted with one or more substituents independently selected from halogen and C1-C3 alkyl; R50 is selected from hydrogen, halogen, -OH, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, -CN, C1-C3 cyanoalkyl, C1-C3 aminoalkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 hydroxyalkynyl, and C3-C6 carbocycle. [0013] In certain embodiments, Formula (I) is represented by Formula (I-A), Formula (V), or Formula (VI). [0014] In certain embodiments, the disclosure provides a pharmaceutical composition comprising a compound or salt of Formula (I) and a pharmaceutically acceptable excipient. [0015] In certain embodiments, the disclosure provides a method of treating a disease or disorder, using a compound or salt of Formula (I). In certain embodiments, the disclosure provides a method of treating a disease or disorder, using a compound or salt of Formula (I) and a pharmaceutically acceptable excipient. [0016] In certain embodiments, the disclosure provides a method of inhibiting KRas G12D and/or other G12 mutants, using a compound or salt of Formula (I). In certain embodiments, the disclosure provides a method of inhibiting KRas G12D and/or other G12 mutants, using a compound or salt of Formula (I) and a pharmaceutically acceptable excipient. [0017] In certain embodiments, the disclosure provides a pharmaceutical composition comprising a compound or salt of Formula (I-A) and a pharmaceutically acceptable excipient. [0018] In certain embodiments, the disclosure provides a method of treating a disease or disorder, using a compound or salt of Formula (I-A). In certain embodiments, the disclosure provides a method of treating a disease or disorder, using a compound or salt of Formula (I) and a pharmaceutically acceptable excipient. [0019] In certain embodiments, the disclosure provides a method of inhibiting KRas G12D and/or other G12 mutants, using a compound or salt of Formula (I-A). In certain embodiments, the disclosure provides a method of inhibiting KRas G12D and/or other G12 mutants, using a compound or salt of Formula (I-A) and a pharmaceutically acceptable excipient. [0020] In certain embodiments, the disclosure provides a pharmaceutical composition comprising a compound or salt of Formula (II) and a pharmaceutically acceptable excipient. [0021] In certain embodiments, the disclosure provides a method of treating a disease or disorder, using a compound or salt of Formula (II). In certain embodiments, the disclosure provides a method of treating a disease or disorder, using a compound or salt of Formula (II) and a pharmaceutically acceptable excipient. [0022] In certain embodiments, the disclosure provides a method of inhibiting KRas G12D and/or other G12 mutants, using a compound or salt of Formula (II). In certain embodiments, the disclosure provides a method of inhibiting KRas G12D and/or other G12 mutants, using a compound or salt of Formula (II) and a pharmaceutically acceptable excipient. [0023] In certain embodiments, the disclosure provides a pharmaceutical composition comprising a compound or salt of Formula (III) and a pharmaceutically acceptable excipient. [0024] In certain embodiments, the disclosure provides a method of treating a disease or disorder, using a compound or salt of Formula (III). In certain embodiments, the disclosure provides a method of treating a disease or disorder, using a compound or salt of Formula (III) and a pharmaceutically acceptable excipient. [0025] In certain embodiments, the disclosure provides a method of inhibiting KRas G12D and/or other G12 mutants, using a compound or salt of Formula (III). In certain embodiments, the disclosure provides a method of inhibiting KRas G12D and/or other G12 mutants, using a compound or salt of Formula (III) and a pharmaceutically acceptable excipient. [0026] In certain embodiments, the disclosure provides a pharmaceutical composition comprising a compound or salt of Formula (IV) and a pharmaceutically acceptable excipient. [0027] In certain embodiments, the disclosure provides a method of treating a disease or disorder, using a compound or salt of Formula (IV). In certain embodiments, the disclosure provides a method of treating a disease or disorder, using a compound or salt of Formula (IV) and a pharmaceutically acceptable excipient. [0028] In certain embodiments, the disclosure provides a method of inhibiting KRas G12D and/or other G12 mutants, using a compound or salt of Formula (IV). In certain embodiments, the disclosure provides a method of inhibiting KRas G12D and/or other G12 mutants, using a compound or salt of Formula (IV) and a pharmaceutically acceptable excipient. [0029] In certain embodiments, the disclosure provides a pharmaceutical composition comprising a compound or salt of Formula (V) and a pharmaceutically acceptable excipient. [0030] In certain embodiments, the disclosure provides a method of treating a disease or disorder, using a compound or salt of Formula (V). In certain embodiments, the disclosure provides a method of treating a disease or disorder, using a compound or salt of Formula (V) and a pharmaceutically acceptable excipient. [0031] In certain embodiments, the disclosure provides a method of inhibiting KRas G12D and/or other G12 mutants, using a compound or salt of Formula (V). In certain embodiments, the disclosure provides a method of inhibiting KRas G12D and/or other G12 mutants, using a compound or salt of Formula (V) and a pharmaceutically acceptable excipient. [0032] In certain embodiments, the disclosure provides a pharmaceutical composition comprising a compound or salt of Formula (VI) and a pharmaceutically acceptable excipient. [0033] In certain embodiments, the disclosure provides a method of treating a disease or disorder, using a compound or salt of Formula (VI). In certain embodiments, the disclosure provides a method of treating a disease or disorder, using a compound or salt of Formula (VI) and a pharmaceutically acceptable excipient. [0034] In certain embodiments, the disclosure provides a method of inhibiting KRas G12D and/or other G12 mutants, using a compound or salt of Formula (VI). In certain embodiments, the disclosure provides a method of inhibiting KRas G12D and/or other G12 mutants, using a compound or salt of Formula (VI) and a pharmaceutically acceptable excipient. INCORPORATION BY REFERENCE [0035] 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. DETAILED DESCRIPTION OF THE INVENTION [0036] The following description sets forth numerous exemplary configurations, methods, parameters, and the like. It should be recognized, however, that such description is not intended as a limitation on the scope of the present disclosure, but is instead provided as a description of exemplary embodiments. [0037] In the following description, certain specific details are set forth in order to provide a thorough understanding of various embodiments of the disclosure. However, one skilled in the art will understand that the disclosure may be practiced without these details. Definitions [0038] 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. [0039] "Alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, and preferably having from one to fifteen carbon atoms (i.e., C1-C15 alkyl). In certain embodiments, an alkyl comprises one to thirteen carbon atoms (i.e., C1-C13 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). In certain embodiments, the alkyl group is selected from 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). The alkyl is attached to the rest of the molecule by a single bond. [0040] 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, the term “C1-6alkyl” 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-yalkylene- refers to a substituted or unsubstituted alkylene chain with from x to y carbons in the alkylene chain. For example –C1-6alkylene- may be selected from methylene, ethylene, propylene, butylene, pentylene, and hexylene, any one of which is optionally substituted. [0041] "Alkoxy" refers to a radical bonded through an oxygen atom of the formula –O-alkyl, where alkyl is an alkyl chain as defined above. [0042] "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. [0043] "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. [0044] The terms “Cx-yalkenyl” and “Cx-yalkynyl” refer to substituted or unsubstituted 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-yalkenylene- refers to a substituted or unsubstituted alkenylene chain with from x to y carbons in the alkenylene chain. For example, –C2-6alkenylene- 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 alkenylene chain. For example, –C2-6alkenylene- 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. [0045] "Alkylene" or "alkylene chain" refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing no unsaturation, and preferably having from one to twelve carbon atoms, for example, methylene, ethylene, propylene, n-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 may be through any two carbons within the chain. In certain embodiments, an alkylene comprises one to ten carbon atoms (i.e., C1-C8 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). [0046] "Alkenylene" or "alkenylene chain" refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon double bond, and 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 may be through any two carbons within the chain. 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). [0047] "Alkynylene" or "alkynylene chain" refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon triple bond, and 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 may be through any two carbons within the chain. 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). [0048] "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. [0049] "Aralkyl" refers to a radical of the formula -Rc-aryl where Rc is an alkylene chain as defined above, for example, methylene, ethylene, and the like. [0050] "Aralkenyl" refers to a radical of the formula –Rd-aryl where Rd is an alkenylene chain as defined above. "Aralkynyl" refers to a radical of the formula -Re-aryl, where Re is an alkynylene chain as defined above. [0051] “Carbocycle” refers to a saturated, unsaturated or aromatic rings in which each atom of the ring is carbon. Carbocycle may include 3- to 10-membered monocyclic rings, 6- to 12- membered bicyclic rings, and 6- to 12-membered bridged rings. Each ring of a bicyclic carbocycle may be selected from saturated, unsaturated, and aromatic rings. 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. Bicyclic carbocycles may be fused, bridged or spiro-ring systems. In some cases, spiro-ring carbocycles have at least two molecular rings with only one common atom. [0052] The term “unsaturated carbocycle” refers to carbocycles with at least one degree of unsaturation and excluding aromatic carbocycles. Examples of unsaturated carbocycles include cyclohexadiene, cyclohexene, and cyclopentene. [0053] "Cycloalkyl" refers to a 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. In certain embodiments, a cycloalkyl comprises three to ten carbon atoms. In other embodiments, a cycloalkyl comprises five to seven carbon atoms. The cycloalkyl may be attached to the rest of the molecule by a single bond. Examples of monocyclic cycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl radicals include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. [0054] "Cycloalkenyl" refers to an 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. In certain embodiments, a cycloalkenyl comprises three to ten carbon atoms. In other embodiments, a cycloalkenyl comprises five to seven carbon atoms. The cycloalkenyl may be attached to the rest of the molecule by a single bond. Examples of monocyclic cycloalkenyls includes, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. [0055] "Cycloalkylalkyl" refers to a radical of the formula –Rc-cycloalkyl where Rc is an alkylene chain as described above. [0056] "Cycloalkylalkoxy" refers to a radical bonded through an oxygen atom of the formula – O-Rc-cycloalkyl where Rc is an alkylene chain as described above. [0057] "Halo" or "halogen" refers to halogen substituents such as bromo, chloro, fluoro and iodo substituents. [0058] 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, I, etc.). When an alkyl group is substituted with more than one halogen radicals, each halogen may be independently selected e.g., 1-chloro,2-fluoroethane. [0059] "Fluoroalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more fluoro radicals, for example, trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like. [0060] "Aminoalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more amine radicals, for example, propan-2-amine, butane-1,2-diamine, pentane-1,2,4-triamine and the like. [0061] "Alkoxyalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more alkoxy radicals, for example, methoxymethane, 1,3-dimethoxybutane, 1-methoxypropane, 2-ethoxypentane, and the like. [0062] "Cyanoalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more cyano radicals, for example, acetonitrile, 2-ethyl-3-methylsuccinonitrile, butyronitrile, and the like. [0063] "Hydroxyalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more hydroxy radicals, for example, propan-1-ol, butane-1,4-diol, pentane-1,2,4-triol, and the like. [0064] “Heterocycle” refers to a saturated or unsaturated 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, 6- to 12-membered bicyclic rings, and 6- to 12- membered bridged rings. Each ring of a bicyclic heterocycle may be selected from saturated, unsaturated, and aromatic rings. Bicyclic heterocycles may be fused, bridged or spiro-ring systems. In some cases, spiro-ring heterocycles have at least two molecular rings with only one common atom. The spiro-ring heterocycle includes at least one heteroatom. [0065] “Heterocyclene” refers to a divalent heterocycle linking the rest of the molecule to a radical group. [0066] "Heteroaryl" or “aromatic heterocycle” refers to a radical derived from a heteroaromatic ring radical that comprises one to eleven carbon atoms and at least one heteroatom wherein each heteroatom may be selected from N, O, and S. As used herein, the heteroaryl ring may be selected from monocyclic or bicyclic and fused or bridged ring systems rings wherein at least one of the rings in the ring system is aromatic, i.e., it contains a cyclic, delocalized (4n+2) ^– electron system in accordance with the Hückel theory. The heteroatom(s) in the heteroaryl radical may be optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. 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. Examples of heteroaryls include, but are not limited to, pyridine, pyrimidine, oxazole, furan, pyran, thiophene, isoxazole, benzimidazole, benzthiazole, and imidazopyridine. [0067] An “X-membered heteroaryl” 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. [0068] The term “unsaturated heterocycle” refers to heterocycles with at least one degree of unsaturation and excluding aromatic heterocycles. Examples of unsaturated heterocycles include dihydropyrrole, dihydrofuran, oxazoline, pyrazoline, and dihydropyridine. Heterocycles may be optionally substituted by one or more substituents such as those substituents described herein. [0069] The term “substituted” refers to moieties having substituents replacing a hydrogen on one or more carbons or substitutable heteroatoms, e.g., NH, of the structure. 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. For purposes of this disclosure, the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. [0070] 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, -R b-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, and heterocycle, 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, -R b-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, -R b-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. [0071] As used in the specification and claims, the singular form “a”, “an” and “the” includes plural references unless the context clearly dictates otherwise. [0072] 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. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salt is chosen from ammonium, potassium, sodium, calcium, and magnesium salts. [0073] The phrases “parenteral administration” and “administered parenterally” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion. [0074] 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. [0075] 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 must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen- free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations. [0076] 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. [0077] The terms “treat,” “treating” or “treatment,” as used herein, may include alleviating, abating or ameliorating a disease or condition symptoms, preventing additional symptoms, ameliorating or preventing the underlying causes of symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition either prophylactically and/or therapeutically. [0078] The term “G12 mutants”, as used herein, refers to other oncogenic alleles of KRAS at amino acid position 12 (ie. G12X). Compounds of the disclosure [0079] The following is a discussion of compounds and salts thereof that may be used in the methods of the disclosure. [0080] In some aspects, the present disclosure provides a compound represented by the structure of Formula (I):
Figure imgf000028_0001
or a pharmaceutically acceptable salt thereof, wherein: Y is selected from a bond, O and NR5; R2 is selected from hydrogen, -N(R5)2, -L-N(R5)2, -L-OR5, heterocycle, C1-C6 alkyl, -L- heterocycle, -L-aryl, -L-heteroaryl, -L-cycloalkyl, -L-N(R5)2, -L-NHC(=NH)NH2, -L-C(O)N(R5)2, -L-C1-C6 haloalkyl, -L-OR5, -L-NR5C(O)-aryl, -L-COOH, and -LC(=O)O C1-C6 alkyl, wherein the heterocycle, the aryl portion of -L-NR5C(O)-aryl, the heterocycle portion of -L-heterocycle, and the cycloalkyl portion of the -L-cycloalkyl are each optionally substituted with one or more R6, and wherein the aryl of the -L- aryl and heteroaryl of the -L-heteroaryl are each optionally substituted with one or more R7; each L is independently selected from a C1-C4 alkylene optionally substituted with one or more substituents independently selected from -OH, C1-C4 hydroxyalkyl, C1-C4 alkyl, C3-C6 carbocycle, or 3- to 8-membered heterocycle, wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle wherein the C3-C6 carbocycle and the 3- to 8- membered heterocycle are optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl; R3 is selected from aryl and heterocycle, wherein each is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, =O, -NO2, C1-C4 alkyl, C1-6 aminoalkyl, -S-C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 hydroxyalkynyl, C1-C3 cyanoalkyl, triazolyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, -S-C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, -CH2C(=O)N(R5)2, -C3-C4 alkynyl(NR5)2, -N(R5)2, (C1-C3 alkoxy)haloC1-C3 alkyl- , and C3-C6 cycloalkyl, wherein the C3-C6 cycloalkyl is optionally substituted with one or more substituents selected from halogen and C1-C3 alkyl; and wherein when R3 is benzothiazole, the benzothiazole is optionally substituted with one or more R49; R4 is selected from hydrogen, halogen, C1-C3 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and -O-C1- 6 haloalkyl; each R5 is independently selected from hydrogen and C1-C3 alkyl; each R6 is independently selected from halogen, -OH, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1- C3 haloalkyl, C1-C3 alkoxy, -CN, C1-C3 aminoalkyl, -Q-phenyl, -Q-phenylSO2F, -NHC(O)phenyl, - NHC(O)phenylSO2F, C1-C3 alkyl substituted pyrazolyl, -N(R5)2, (C1-C3 alkoxy)C1-C3 alkyl-, (C1-C3 alkyl)C(=O), oxo, (C1-C3 haloalkyl)C(=O)-, -SO2F, (C1-C3 alkoxy)C1-C3 alkoxy, - CH2OC(O)N(R5)2, -CH2NHC(O)OC1-C6 alkyl, -CH2NHC(O)N(R5)2, -CH2NHC(O)C1-C6 alkyl, - CH2(pyrazolyl), -CH2NHSO2C1-C6 alkyl, -CH2OC(O)heterocycle, -OC(O)N(R5)2, - OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl), -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl(C1-C3 alkyl)N(CH3)2, -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl, -OC(O)heterocycle, and - CH2heterocycle, wherein the phenyl of -NHC(O)phenyl and -OC(O)NH(C1-C3 alkyl)(C1-C3 alkyl)phenyl are each optionally substituted with -C(O)H and OH, and wherein the heterocycle of -CH2heterocyclyl is optionally substituted with oxo; each Q is independently selected from a bond and O; each R7 is independently selected from halogen, -OH, HC(=O)-, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, and -N(R5)2; R9 is selected from C3-C12 carbocycle and 5- to 12-membered heterocycle, wherein the C3- C12 carbocycle and 5- to 12-membered heterocycle are each substituted with one or more substituents independently selected from halogen, -B(OR20)2, -OR20, -SR20, -N(R20)2, -NHCN, - NO2, =O, =S, =N(R20), -CN, C1-6 fluoroalkyl, C1-6 alkoxy, and C2-6 alkynyl; and further optionally substituted with one or more substituents independently selected from -C(O)N(R20)2, -C(O)NR20- OR20, C1-6 alkyl-O-C(O)C1-6 alkyl, C1-6 aminoalkyl, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 alkyl, and C2-6 alkenyl; each R20 is independently selected from hydrogen; and C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbocycle, and 3- to 12- membered heterocycle; each R49 is independently selected from halogen, -CN, -OH, =O, -NO2, C1-C4 alkyl, C1-6 aminoalkyl, -S-C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 hydroxyalkynyl, C1-C3 cyanoalkyl, triazolyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, -S-C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, -CH2C(=O)N(R5)2, -C3-C4 alkynyl(NR5)2, (C1-C3 alkoxy)haloC1-C3 alkyl-, and C3- C6 cycloalkyl, wherein the C3-C6 cycloalkyl is optionally substituted with one or more substituents selected from halogen and C1-C3 alkyl; R50 is selected from hydrogen, halogen, -OH, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, -CN, C1-C3 cyanoalkyl, C1-C3 aminoalkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 hydroxyalkynyl, and C3-C6 carbocycle; and wherein when Y is O, R2 is , R9 is selected from pyrrolidine and thiazole, the
Figure imgf000030_0002
pyrrolidine and thiazole are each optionally substituted with one or more R49. [0081] In some embodiments, Formula (I) is represented by Formula (I-A), Formula (V), or Formula (VI). [0082] In some aspects, the present disclosure provides a compound represented by the structure of Formula (I-A):
Figure imgf000030_0001
( ), or a pharmaceutically acceptable salt thereof, wherein: Y is O; R2 is selected from -L-heterocycle, and -L-heteroaryl, wherein the heterocycle portion of -L- heterocycle, is optionally substituted with one or more R6, and wherein the heteroaryl of the -L- heteroaryl is optionally substituted with one or more R7; each L is independently selected from a C1-C4 alkylene optionally substituted with one or more substituents independently selected from -OH, C1-C4 hydroxyalkyl, C1-C4 alkyl, C3-C6 carbocycle, or 3- to 8-membered heterocycle, wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle wherein the C3-C6 carbocycle and the 3- to 8- membered heterocycle are optionally substituted with one or more substituents independently selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl; R3 is selected from aryl and heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, =O, -NO2, C1-C4 alkyl, C1-6 aminoalkyl, -S-C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 hydroxyalkynyl, C1-C3 cyanoalkyl, triazolyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, -S-C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, -CH2C(=O)N(R5)2, -C3-C4 alkynyl(NR5)2, -N(R5)2, (C1-C3 alkoxy)haloC1-C3 alkyl- , and C3-C6 cycloalkyl, wherein the C3-C6 cycloalkyl is optionally substituted with one or more substituents selected from halogen and C1-C3 alkyl; and wherein when R3 is benzothiazole or pyridine, the benzothiazole or pyridine is optionally substituted with one or more R49; R4 is selected from hydrogen, halogen, C1-C3 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and -O-C1-6 haloalkyl; each R5 is independently selected from hydrogen and C1-C3 alkyl; each R6 is independently selected from halogen, -OH, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1- C3 haloalkyl, C1-C3 alkoxy, -CN, C1-C3 aminoalkyl, -Q-phenyl, -Q-phenylSO2F, -NHC(O)phenyl, - NHC(O)phenylSO2F, C1-C3 alkyl substituted pyrazolyl, -N(R5)2, (C1-C3 alkoxy)C1-C3 alkyl-, (C1-C3 alkyl)C(=O), oxo, =CH2, (C1-C3 haloalkyl)C(=O)-, -SO2F, (C1-C3 alkoxy)C1-C3 alkoxy, - CH2OC(O)N(R5)2, -CH2NHC(O)OC1-C6 alkyl, -CH2NHC(O)N(R5)2, -CH2NHC(O)C1-C6 alkyl, - CH2(pyrazolyl), -CH2NHSO2C1-C6 alkyl, -CH2OC(O)heterocycle, -OC(O)N(R5)2, - OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl), -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl(C1-C3 alkyl)N(CH3)2, -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl, -OC(O)heterocycle, and - CH2heterocycle, wherein the phenyl of -NHC(O)phenyl and -OC(O)NH(C1-C3 alkyl)(C1-C3 alkyl)phenyl are each optionally substituted with -C(O)H and OH, and wherein the heterocycle of -CH2heterocyclyl is optionally substituted with oxo; each Q is independently selected from a bond and O; each R7 is independently selected from halogen, -OH, HC(=O)-, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, and -N(R5)2; R9 is selected from C3-C12 carbocycle and 5- to 12-membered heterocycle, wherein the C3- C12 carbocycle and 5- to 12-membered heterocycle are each substituted with one or more substituents independently selected from halogen, -B(OR20)2, -OR20, -SR20, -NHCN, -NO2, =O, =S, =N(R20), -CN, C1-6 fluoroalkyl, C1-6 alkoxy, and C2-6 alkynyl; and further optionally substituted with one or more substituents independently selected from -C(O)N(R20)2, -C(O)NR20-OR20, C1-6 aminoalkyl, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 alkyl, C1-6 alkyl-O-C(O)C1-6 alkyl, and C2-6 alkenyl; wherein when R9 is substituted with at least one -OH, =O, or C1-6 alkoxy, the 5- to 12- membered heterocycle is a non-bridged heterocycle;each R20 is independently selected from hydrogen; and C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle; each R49 is independently selected from halogen, -CN, -OH, =O, -NO2, C1-C4 alkyl, C1-6 aminoalkyl, -S-C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 hydroxyalkynyl, C1-C3 cyanoalkyl, triazolyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, -S-C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, -CH2C(=O)N(R5)2, -C3-C4 alkynyl(NR5)2, (C1-C3 alkoxy)haloC1-C3 alkyl-, and C3- C6 cycloalkyl, wherein the C3-C6 cycloalkyl is optionally substituted with one or more substituents independently selected from halogen and C1-C3 alkyl; R50 is selected from hydrogen, halogen, -OH, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, -CN, C1-C3 cyanoalkyl, C1-C3 aminoalkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 hydroxyalkynyl, and C3-C6 carbocycle. [0083] In some embodiments, for a compound or salt of Formula (I) or (I-A), when Y is O, R2 is , R9 is selected from pyrrolidine and thiazole, the pyrrolidine and thiazole are each optionally substituted with one or more R49. [0084] In some embodiments, for a compound or salt of Formula (I), (I-A), (V), or (VI), Y is O. In some cases, Y is a bond. In some cases, Y is -NR5-. [0085] In some embodiments, for a compound or salt of Formula (I), (I-A), (V), or (VI), L is selected from optionally substituted C1-C4 alkylene. In some cases, L is selected from optionally substituted C1-C2 alkylene. In some cases, L is selected from optionally substituted C1 alkylene. In some cases L is selected from unsubstituted C1-C4 alkylene. [0086] In some embodiments, for a compound or salt of Formula (I), (I-A), (V), or (VI), L is selected from unsubstituted C1-C4 alkylene. In some cases, L is selected from unsubstituted C1-C2 alkylene. In some cases, L is selected from unsubstituted C1 alkylene. In some cases, L is selected from methylene and ethylene. In some cases, L is methylene. [0087] In some embodiments, for a compound or salt of Formula (I), (I-A), (V), or (VI), optional substituents of L are selected from C1-C4 hydroxyalkyl, C1-C4 alkyl, C3-C6 carbocycle, wherein the C3-C6 carbocycle is optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, and C1-6 haloalkyl. [0088] In some embodiments, for a compound or salt of Formula (I), (I-A), (V), or (VI), the optional substituents of L are selected from C1-C4 hydroxyalkyl, C1-C4 alkyl, C3-C6 carbocycle, wherein the C3-C6 carbocycle is optionally substituted with one or more substituents selected from halogen. [0089] In some embodiments, for a compound or salt of Formula (I), (I-A), (V), or (VI), optionally two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl. In some cases, optionally two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle wherein the C3-C6 carbocycle is optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl. In some cases, optionally two substituents on the same carbon atom of L come together to form a C3 carbocycle wherein the C3 carbocycle is optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl. In some cases, optionally two substituents on the same carbon atom of L come together to form a C3 carbocycle wherein the C3 carbocycle is optionally substituted with one or more substituents selected from halogen. [0090] In some embodiments, for a compound or salt of Formula (I), (I-A), (V), or (VI), optionally two hydrogens on the same carbon atom of L come together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl. In some cases, optionally two hydrogens on the same carbon atom of L come together to form a C3-C6 carbocycle wherein the C3-C6 carbocycle is optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl. In some cases, optionally two hydrogens on the same carbon atom of L come together to form a C3 carbocycle wherein the C3 carbocycle is optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl. In some cases, optionally two hydrogens on the same carbon atom of L come together to form a C3 carbocycle wherein the C3 carbocycle is optionally substituted with one or more substituents selected from halogen. [0091] In some embodiments, for a compound or salt of Formula (I), (I-A), (V), or (VI), R2 is selected from optionally substituted -L-heterocycle, optionally substituted -L-heteroaryl, optionally substituted -L-aryl, -L-N(R5)2, and -L-O-R5. In some embodiments, for a compound of Formula (I), R2 is selected from optionally substituted -L-5- to 12-membered heterocycle, optionally substituted -L-5- to 12-membered heteroaryl, optionally substituted -L-C6-C12aryl, -L- N(R5)2, and -L-O-R5. In some cases, R2 is selected from optionally substituted -L-heterocycle, optionally substituted -L-heteroaryl, and -L-N(R5)2. In some cases, R2 is selected from optionally substituted -L-5- to 12-membered heterocycle, optionally substituted -L-5- to 12-membered heteroaryl, and -L-N(R5)2. In some cases, R2 is selected from optionally substituted -L-heterocycle and -L-N(R5)2. In some cases, R2 is selected from optionally substituted -L-5- to 12-membered heterocycle and -L-N(R5)2. In some cases, R2 is selected from optionally substituted -L-5- to 12- membered heterocycle. In some cases, R2 is selected from optionally substituted -L-heterocycle. In some cases, the heterocycle is selected from pyrrolidine, hexahydro-1H-pyrrolizine, pyrazolidine, imidazolidine, tetrahydrofuran, piperidine, piperazine, morpholine, azocane, and azonane. In some cases, the heterocycle is selected from pyrrolidine, hexahydro-1H-pyrrolizine, pyrazolidine, imidazolidine, piperidine, piperazine, azocane, and azonane. In some cases, the heteroaryl is selected from pyrrole, pyrazole, furan, thiohene, oxazole, isoxazole, isothiazole, thiazole, pyridine, pyrazine, and triazine. In some cases, the heteroaryl or heterocycle has at most 1 nitrogen atom. In some cases, the heteroaryl or heterocycle has at least 1 nitrogen atom. [0092] In some embodiments, for a compound or salt of Formula (I) or (I-A), the heterocycle of R2 is a 5- to 12-membered heterocycle, 6- to 12-membered heterocycle, 7- to 12-membered heterocycle, or 8- to 12-membered heterocycle. In some cases, the heterocycle of R2 is a 5- to 11- membered heterocycle, 5- to 10-membered heterocycle, 5- to 9-membered heterocycle, or 5- to 8- membered heterocycle. In some cases, the heterocycle of R2 is a 6- to 11-membered heterocycle, 6- to 10-membered heterocycle, 6- to 9-membered heterocycle, or 6- to 8-membered heterocycle. In some cases, the heterocycle of R2 is a 7- to 11-membered heterocycle, 7- to 10-membered heterocycle, 7- to 9-membered heterocycle, or 7- to 8-membered heterocycle. In some cases, the heterocycle of R2 is a 5- to 6-membered heterocycle or 5- to 9-membered heterocycle. In some cases, the heterocycle of R2 is an 8- to 9-membered heterocycle. In some embodiments, for a compound of Formula (I), the heterocycle of R2 is saturated. The heterocycle may be optionally substituted as described elsewhere herein. [0093] In some embodiments, for a compound or salt of Formula (I), (I-A), (V), or (VI), each L is independently selected from an optionally substituted C1-C4 alkylene; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle, wherein the C3-C6 carbocycle is optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl. In some cases, the optional substituents of L are selected from C1-C4 hydroxyalkyl, C1- C4 alkyl, C3-C6 carbocycle; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are optionally substituted with one or more substituents selected from halogen and C1-6 haloalkyl. [0094] In some embodiments, for a compound or salt of Formula (I), (I-A), (V), or (VI), each L is independently selected from a substituted C1-C4 alkylene, wherein two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle. In some cases, the C3-C6 carbocycle is optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl. [0095] In some embodiments, for a compound or salt of Formula (I), (I-A), (V), or (VI), each L is independently selected from a substituted C1-C4 alkylene, and wherein two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle. In some cases, each L is independently selected from a substituted C3 alkylene, and wherein two substituents on the same carbon atom of L come together to form a C3 carbocycle. In some cases, each L is independently selected from
Figure imgf000035_0001
[0096] In some embodiments, for a compound or salt of Formula (I), (I-A), (V), or (VI), R2 is selected from -L-heterocycle, wherein the heterocycle portion of -L-heterocycle is optionally substituted with one or more R6. In some cases, the heterocycle is a saturated heterocycle. In some cases, the heterocycle has at least one nitrogen atom and at least one sulfur atom. In some cases, the heterocycle has at least one nitrogen atom. In some cases, the heterocycle has at least one sulfur atom. [0097] In some embodiments, for a compound or salt of Formula (I), (I-A), (V), or (VI), R2 is selected from wherein the heterocycle portion is optionally
Figure imgf000035_0002
substituted with one or more R6. [0098] In some embodiments, for a compound or salt of Formula (I), (I-A), (V), or (VI), Y-R2 is selected from
Figure imgf000035_0003
, wherein the heterocycle portion is optionally substituted with one or more R6. [0099] In some embodiments, for a compound or salt of Formula (I), (I-A), (V), or (VI), Y-R2 is selected from wherein the heterocycle
Figure imgf000036_0001
portion is optionally substituted with one or more R6. [00100] In some embodiments, for a compound or salt of Formula (I), (I-A), (V), or (VI), Y-R2 is selected fro
Figure imgf000036_0002
and
Figure imgf000036_0003
, wherein the heterocycle portion is optionally substituted with one or more R6. [00101] In some embodiments, for a compound or salt of Formula (I), (I-A), (V), or (VI), R2 is selected from -L-saturated heterocycle, wherein the saturated heterocycle portion of the -L- saturated heterocycle is optionally substituted with one or more R6, and contains one nitrogen atom and one sulfur atom. In some cases, Y-R2 is selected from , and
Figure imgf000036_0004
, wherein the heterocycle portion is optionally substituted with one or more R6. In
Figure imgf000036_0005
some cases, Y-R2 is selected from
Figure imgf000036_0006
, , , wherein the heterocycle portion is optionally substituted with one or more substituents selected from C1- C3 alkyl and oxo. In some cases, Y-R2 is selected fro , and
Figure imgf000036_0008
Figure imgf000036_0007
In some cases, Y-R2 is selected from , , and
Figure imgf000036_0009
[00102] In some embodiments, for a compound or salt of Formula (I), (V), or (VI), each R6 is independently selected from halogen, -OH, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1- C3 alkoxy, -CN, C1-C3 aminoalkyl, -Q-phenyl, -Q-phenylSO2F, -NHC(O)phenyl, - NHC(O)phenylSO2F, C1-C3 alkyl substituted pyrazolyl, -N(R5)2, (C1-C3 alkoxy)C1-C3 alkyl-, (C1-C3 alkyl)C(=O), oxo, (C1-C3 haloalkyl)C(=O)-, -SO2F, (C1-C3 alkoxy)C1-C3 alkoxy, - CH2OC(O)N(R5)2, -CH2NHC(O)OC1-C6 alkyl, -CH2NHC(O)N(R5)2, -CH2NHC(O)C1-C6 alkyl, - CH2(pyrazolyl), -CH2NHSO2C1-C6 alkyl, -CH2OC(O)heterocycle, -OC(O)N(R5)2, - OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl), -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl(C1-C3 alkyl)N(CH3)2, -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl, -OC(O)heterocycle, and - CH2heterocycle, wherein the phenyl of -NHC(O)phenyl and -OC(O)NH(C1-C3 alkyl)(C1-C3 alkyl)phenyl are each optionally substituted with -C(O)H and OH, and wherein the heterocycle of -CH2heterocyclyl is optionally substituted with oxo. [00103] In some embodiments, for a compound or salt of Formula (I) or (I-A), each R6 is independently selected from halogen, -OH, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1- C3 alkoxy, -CN, and C1-C3 aminoalkyl. [00104] In some embodiments, for a compound or salt of Formula (I), (I-A), (V), or (VI), each R6 is independently selected from halogen, -OH, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 aminoalkyl, C1-C3 haloalkyl, C1-C3 alkoxy, -N(R5)2, and oxo. In some cases, each R6 is independently selected from -OH, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 aminoalkyl, C1-C3 alkoxy, and -N(R5)2. In some cases, each R6 is independently selected from C1-C3 alkyl, C1-C3 alkoxy, and -N(R5)2. [00105] In some embodiments, for a compound or salt of Formula (I), (I-A), (V), or (VI), R6 is selected from halogen, -OH, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, - CN, and C1-C3 aminoalkyl. In some cases, R6 is selected from halogen and C1-C3 alkyl. In some cases, R6 is halogen. In some cases, R6 is C1-C3 alkyl. In some cases, R6 is selected from halogen and C1-C3 alkyl. In some cases, R6 is selected from methyl and fluorine. [00106] In some embodiments, for a compound or salt of Formula (I), (I-A), (V), or (VI), R2 is selected from
Figure imgf000037_0001
[00107] In some embodiments, for a compound or salt of Formula (I), (I-A), (V), or (VI), Y-R2 is selected from
Figure imgf000037_0002
[00108] In some embodiments, for a compound or salt of Formula (I), (I-A), (V), or (VI), Y- R2 is selected from ,
Figure imgf000038_0001
,
Figure imgf000038_0003
[00109] In some embodiments, for a compound or salt of Formula (I), (I-A), (V), or (VI), Y-R2 i
Figure imgf000038_0004
s . [00110] In some embodiments, for a compound or salt of Formula (I), (I-A), (V), or (VI), R50 is selected from hydrogen, halogen, C1-C3 cyanoalkyl, C2-C4 alkenyl, C2-C4 alkynyl, and C3-C6 carbocycle. In some cases, R50 is selected from hydrogen, Cl 5
Figure imgf000038_0002
In some cases, R 0 is hydrogen. [00111] In some embodiments, for a compound or salt of Formula (I), (I-A), (V), or (VI), R49 is independently selected from at each occurrence from halogen, -CN, -OH, =O, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 hydroxyalkynyl, C1-C3 cyanoalkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl. [00112] In some embodiments, for a compound or salt of Formula (I), (I-A), (V), or (VI), R4 is selected from halogen and hydrogen. In some cases, R4 is selected from halogen. In some cases, R4 is selected from chloride and fluorine. In some cases, R4 is fluorine. In some cases, R4 is hydrogen. [00113] In some embodiments, for a compound or salt of Formula (I), (I-A), (V), or (VI), R4 is selected from hydrogen, halogen, C1-C3 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and -O-C1-6 alkyl, wherein the alkyl portion of -O-C1-6 alkyl is substituted with one or more halogen substituents. In some cases, R4 is selected from C1-6 haloalkyl, C1-6 alkoxy, and -O-C1-6 alkyl, wherein the alkyl portion of -O-C1-6 alkyl is substituted with one or more halogen substituents. In some cases, R4 is selected from C1-6 alkoxy, and -O-C1-6 alkyl, wherein the alkyl portion of -O-C1-6 alkyl is substituted with one or more halogen substituents. In some cases, R4 is selected from -O-C1-6 alkyl, wherein the alkyl portion of -O-C1-6 alkyl is substituted with one or more halogen substituents. [00114] In some embodiments, for a compound of Formula (I) or (I-A), the carbocycle of R9 is selected from C3-C12 carbocycle, C3-C10 carbocycle, C3-C9 carbocycle, C3-C8 carbocycle, or C3-C6 carbocycle. In some cases, the carbocycle of R9 is selected from C3-C12 carbocycle, C4-C12 carbocycle, C5-C12 carbocycle, C6-C12 carbocycle, C7-C12 carbocycle, C8-C12 carbocycle, or C9-C12 carbocycle. [00115] In some embodiments, for a compound of Formula (I), (I-A), or (VI), the heterocycle of R9 is a 5- to 12-membered heterocycle, 6- to 12-membered heterocycle, 7- to 12-membered heterocycle, or 8- to 12-membered heterocycle. In some cases, the heterocycle of R9 is a 5- to 11- membered heterocycle, 5- to 10-membered heterocycle, 5- to 9-membered heterocycle, or 5- to 8- membered heterocycle. In some cases, the heterocycle of R9 is a 6- to 11-membered heterocycle, 6- to 10-membered heterocycle, 6- to 9-membered heterocycle, or 6- to 8-membered heterocycle. In some cases, the heterocycle of R9 is a 7- to 11-membered heterocycle, 7- to 10-membered heterocycle, 7- to 9-membered heterocycle, or 7- to 8-membered heterocycle. In some cases, the heterocycle of R9 is a 5- to 6-membered heterocycle or 5- to 9-membered heterocycle. In some cases, the heterocycle of R9 is an 8- to 9-membered heterocycle. In some embodiments, for a compound of Formula (I), the heterocycle of R9 is saturated. The heterocycle may be optionally substituted as described elsewhere herein. [00116] In some embodiments, for a compound of Formula (I), (I-A), or (VI), the heterocycle of R9 is a 5- to 12-membered monocyclic heterocycle, 6- to 12-membered monocyclic heterocycle, 7- to 12-membered monocyclic heterocycle, or 8- to 12-membered monocyclic heterocycle. In some cases, the heterocycle of R9 is a 5- to 11-membered monocyclic heterocycle, 5- to 10- membered monocyclic heterocycle, 5- to 9-membered monocyclic heterocycle, or 5- to 8- membered monocyclic heterocycle. In some cases, the heterocycle of R9 is a 6- to 11-membered monocyclic heterocycle, 6- to 10-membered monocyclic heterocycle, 6- to 9-membered monocyclic heterocycle, or 6- to 8-membered monocyclic heterocycle. In some cases, the heterocycle of R9 is a monocyclic 7- to 11-membered heterocycle, 7- to 10-membered monocyclic heterocycle, 7- to 9-membered monocyclic heterocycle, or 7- to 8-membered monocyclic heterocycle. In some cases, the heterocycle of R9 is a 5- to 6-membered monocyclic heterocycle or 5- to 9-membered monocyclic heterocycle. In some cases, the heterocycle of R9 is an 8- to 9- membered monocyclic heterocycle. In some embodiments, for a compound of Formula (I), (I-A), or (VI), the heterocycle of R9 is saturated. The monocyclic heterocycle may be optionally substituted as described elsewhere herein. [00117] In some embodiments, for a compound or salt of Formula (I), Formula (I-A), or Formula (VI), the fused heterocycle of R9 is a 6- to 12-membered fused heterocycle, 6- to 12- membered fused heterocycle, 7- to 12-membered fused heterocycle, or 8- to 12-membered fused heterocycle. In some cases, the fused heterocycle of R9 is a 6- to 11-membered fused heterocycle, 6- to 10-membered fused heterocycle, 6- to 9-membered fused heterocycle, or 6- to 8-membered fused heterocycle. In some cases, the fused heterocycle of R9 is a 7- to 11-membered fused heterocycle, 7- to 10-membered fused heterocycle, 7- to 9-membered fused heterocycle, or 7- to 8-membered fused heterocycle. In some cases, the fused heterocycle of R9 is an 8- to 11-membered fused heterocycle. In some cases, the fused heterocycle of R9 is a 10-membered fused heterocycle. In some cases, the fused heterocycle of R9 is a 6-membered fused heterocycle. The fused heterocycle may be optionally substituted as described elsewhere herein. [00118] In some embodiments, for a compound or salt of Formula (I), Formula (I-A), or Formula (VI), R9 is selected from 7- to 8-membered spiro heterocycle. In some cases, R9 is selected from 7-membered spiro heterocycle. In some cases, R9 is selected from 8-membered spiro heterocycle. In some cases, R9 is selected from 9-membered spiro heterocycle. In some cases, R9 is selected from 10-membered spiro heterocycle. In some cases, R9 is selected from 11-membered spiro heterocycle. The spiro heterocycle may be substituted as described elsewhere herein. [00119] In some embodiments, for a compound or salt of Formula (I), Formula (I-A), or Formula (VI), the spiro heterocycle of R9 contains at most 1 nitrogen atom. In some embodiments, the spiroheterocycle of R9 contains at most 2 heteroatom atoms. In some embodiments, the spiroheterocycle of R9 contains at most 3 heteroatom atoms. In some embodiments, the spiroheterocycle of R9 contains at most 1 heteroatom atom. In some cases, the spiroheterocycle of R9 contains at least 2 heteroatom atoms. In some cases, the spiroheterocycle of R9 contains at least 3 heteroatom atoms. In some cases, the spiroheterocycle of R9 contains at least 4 heteroatom atoms. In some cases, the spiroheterocycle of R9 contains at least 2 nitrogen atoms. In some embodiments, the spiroheterocycle of R9 contains at most 1 heteroatom atom. In some cases, the spiroheterocycle of R9 contains at most 1 sulfur atom. In some cases, the heteroatom is selected from nitrogen, oxygen, and sulfur. In some embodiments, the spiro heterocycle of R9 is selected from
Figure imgf000040_0002
,
Figure imgf000040_0001
In some embodiments, the spiro
Figure imgf000040_0003
heterocycle of R9 is selected from
Figure imgf000041_0001
, . The spiroheterocycle may be substituted as described elsewhere herein. [00120] In some embodiments, for a compound or salt of Formula (I), (I-A), or (VI), the 5- to 12-membered heterocycle of R1 is an unsaturated heterocycle. [00121] In some embodiments, for a compound or salt of Formula (I), (I-A), or (VI), the 5- to 12-membered heterocycle of R1 is a saturated heterocycle. [00122] In some embodiments, for a compound or salt of Formula (I), (I-A), or (VI), the 5- to 12-membered heterocycle of R1 is a fused heterocycle. [00123] In some embodiments, for a compound or salt of Formula (I), (I-A), or (VI), the 5- to 12-membered heterocycle of R1 is a bridged heterocycle. [00124] In some embodiments, for a compound or salt of Formula (I), (I-A), or (VI), the 5- to 12-membered heterocycle of R1 is a non-bridged heterocycle. [00125] In some embodiments, for a compound or salt of Formula (I), (I-A), or (VI), the 5- to 12-membered heterocycle of R1 is a monocyclic heterocycle. [00126] In some embodiments, for a compound or salt of Formula (I), (I-A), or (VI), the 5- to 12-membered heterocycle of R1 is a bicyclic heterocycle. [00127] In some embodiments, for a compound or salt of Formula (I), (I-A), or (VI), the 5- to 12-membered heterocycle of R1 is a spiro heterocycle. [00128] In some embodiments, for a compound or salt of Formula (I), (I-A), or (VI), R9 is selected from 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle is substituted with one or more substituents independently selected from halogen, -B(OR20)2, - OR20, -SR20, -N(R20)2, -S(O)2(R20), -NO2, =O, =S, =N(R20), -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl. In some cases, R9 is selected from 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle is substituted with one or more substituents independently selected from halogen, -OR20, -N(R20)2, -NO2, =O, =S, =N(R20), -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, and C1-6 haloalkyl. In some cases, R9 is selected from 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle is substituted with one or more substituents independently selected from -OR20 and -CN. [00129] In some embodiments, for a compound or salt of Formula (I), (I-A), or (VI), R9 is selected from 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle are each substituted with one or more substituents independently selected from halogen, -B(OR20)2, - OR20, -SR20, -N(R20)2, -NHCN, -NO2, =O, =S, =N(R20), -CN, C1-6 fluoroalkyl, C1-6 alkoxy, and C2-6 alkynyl; and further optionally substituted with one or more substituents independently selected from –C(O)N(R20)2, C1-6 aminoalkyl, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl. In some cases, R9 is selected from 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle is substituted with one or more substituents independently selected from halogen, -OH, -N(R20)2, -NHCN, =O, -CN, C1-6 fluoroalkyl, C1-6 alkoxy, and C2-6 alkynyl; and further optionally substituted with one or more substituents independently selected from -C(O)N(R20)2, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, and C1-6 alkyl. In some cases, R9 is selected from 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle is substituted with one or more substituents independently selected from halogen, - OH, -NH2, -NHCN, =O, -CN, C1-6 alkoxy, and C2-6 alkynyl. [00130] In some embodiments, for a compound or salt of Formula (I), (I-A), or (VI), R9 is selected from an optionally substituted 6- to 10-membered heterocycle. In some cases, R9 is selected from
Figure imgf000042_0001
, each of which is substituted with one or more substituents independently selected from halogen, =O, - OH, and -CN; and further optionally substituted with one or more substituents independently selected from -C(O)N(R20)2, C1-6 aminoalkyl, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, and C1-6 alkyl. In some cases, R9 is selected from
Figure imgf000042_0003
Figure imgf000042_0002
, . [00131] In some embodiments, for a compound or salt of Formula (I), (I-A), or (VI), R9 is selected from an optionally substituted 6- to 7-membered heterocycle. In some cases, the 6- to 7- membered heterocycle is a saturated heterocycle. In some cases, the 6- to 7-membered heterocycle is an unsaturated heterocycle. In some cases, R9 is selected from
Figure imgf000042_0004
and , each of which is substituted with one or more substituents independently selected from
Figure imgf000043_0008
halogen, -OR20 and -CN. In some cases, R9 is selected from
Figure imgf000043_0007
each of which is substituted with one or more substituents independently selected from -OR20 and -CN. In some cases, R9 is selected from , each of which is substituted with one or more
Figure imgf000043_0005
substituents independently selected from -OH and -CN. In some cases, R9 is selected fro
Figure imgf000043_0006
m
Figure imgf000043_0001
, each of which is substituted with one or more substituents independently selected from -OH and -CN, and further optionally substituted with C1-6 alkyl. In some cases, R9 is selected from
Figure imgf000043_0002
some cases, R9 is selected from 9
Figure imgf000043_0004
In some cases, the heterocycle of R is not piperazine. [00132] In some embodiments, for a compound or salt of Formula (I) or (I-A), R9 is selected
Figure imgf000043_0003
Figure imgf000044_0001
of which is substituted with one or more substituents. [00133] In some embodiments, for a compound or salt of Formula (I), (I-A), or (VI), R9 is selected from 5- to 12-membered unsaturated heterocycle, wherein the 5- to 12-membered unsaturated heterocycle is substituted with one or more substituents independently selected from halogen, -B(OR20)2, -OR20, -SR20, -N(R20)2, -NHCN, -NO2, =O, =S, =N(R20), -CN, C1-6 fluoroalkyl, C1-6 alkoxy, and C2-6 alkynyl; and further optionally substituted with one or more substituents independently selected from -C(O)N(R20)2, C1-6 aminoalkyl, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl. In some cases, the 5- to 12-membered unsaturated heterocycle is optionally substituted with one or more substituents independently selected from halogen, -B(OR20)2, -OH, -SR20, -N(R20)2, -NHCN, -NO2, =O, -CN, and C1-6 alkoxy; and further optionally substituted with one or more substituents independently selected from -C(O)N(R20)2, C1-6 aminoalkyl, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, and C1-6 alkyl. In some cases, each R20 is independently selected from hydrogen; and C1-6 alkyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl. [00134] In some embodiments, for a compound or salt of Formula (I), (I-A), or (VI), R9 is selected from 5- to 12-membered unsaturated heterocycle, wherein the 5- to 12-membered unsaturated heterocycle is optionally substituted with one or more substituents independently selected from halogen, -B(OR20)2, -OR20, -SR20, -N(R20)2, -S(O)2(R20), -NO2, =O, =S, =N(R20), -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl. In some cases, R9 is selected from 5- to 12-membered unsaturated heterocycle, wherein the 5- to 12-membered unsaturated heterocycle is optionally substituted with one or more substituents independently selected from halogen, -OR20, -N(R20)2, -NO2, =O, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl. In some cases, R9 is selected from 5- to 12-membered unsaturated heterocycle, wherein the 5- to 12- membered unsaturated heterocycle is optionally substituted with one or more substituents independently selected from halogen, -OR20, -N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl. In some cases, R9 is selected from a 7-membered unsaturated heterocycle, wherein the 5- to 12-membered unsaturated heterocycle is optionally substituted with one or more substituents independently selected from halogen, -OR20, -N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl. In some cases, R9 is selected from
Figure imgf000045_0003
which is optionally substituted with one or more substituents independently selected from halogen, -OR20 and -CN. [00135] In some embodiments, for a compound or salt of Formula (I), (I-A), or (VI), R9 is selected from
Figure imgf000045_0002
which is substituted with one or more substituents independently selected from halogen, -OR20 and -CN. In some cases, R9 is selected
Figure imgf000045_0001
which is substituted with one or more substituents independently selected from halogen. [00136] In some embodiments, for a compound or salt of Formula (I) or (I-A), R9 is selected from an optionally substituted 5- to 12-membered unsaturated heterocycle, wherein the heterocycle has as most one nitrogen atom. In some cases, the 5- to 12-membered unsaturated heterocycle has at least one nitrogen atom. In some cases, the 5- to 12-membered unsaturated heterocycle has at most one nitrogen atom. [00137] In some embodiments, for a compound or salt of Formula (I), (I-A), or (VI), R9 is selected from 6- to 7-membered heterocycle. In some cases, R9 is selected from 7-membered heterocycle. In some cases, R9 is selected from 6-membered heterocycle. In some cases, the 6- to 7-membered heterocycle contains only 1 nitrogen atom and optionally one or more additional heteroatoms selected from oxygen, and sulfur. In some cases, the optionally one or more additional heteroatoms are selected from sulfur. In some cases, the optionally one or more additional heteroatoms are selected from oxygen. In some cases, the 6- to 7-membered heterocycle contains only 1 nitrogen atom and no further additional heteroatoms. In some cases, the 6- to 7-membered heterocycle is a non-aromatic 6- to 7-membered heterocycle. In some cases, the 6- to 7-membered heterocycle of R9 is bound to Formula (I), (I-A), or (VI) via the only 1 nitrogen atom. In some cases, R9 is selected from
Figure imgf000046_0001
, , each of which is substituted. In some 9
Figure imgf000046_0003
cases, R is selected from
Figure imgf000046_0005
Figure imgf000046_0004
, each of which is substituted. In some cases, the substituents of R9 are each selected from one or more halogen, -OR20, -SR20, -N(R20)2, -NHCN, -NO2, =O, -CN, C1-6 fluoroalkyl, and C2-6 alkynyl; and further optionally substituted with one or more substituents independently selected from -C(O)N(R20)2, C1-6 aminoalkyl, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 alkyl, and C2-6 alkenyl. In some cases, the substituents of R9 are each selected from one or more halogen, -OR20, -N(R20)2, -NHCN, =O, -CN, and C2-6 alkynyl; and further optionally substituted with one or more substituents independently selected from -C(O)N(R20)2, C1-6 aminoalkyl, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, and C1-6 alkyl. In some cases, the substituents of R9 are each selected from one or more halogen, -OH, -NHCN, =O, -CN, and C2-6 alkynyl; and further optionally substituted with one or more substituents independently selected from C1-6 alkyl. In some cases, R9 is selected from
Figure imgf000046_0006
, ,
Figure imgf000046_0002
some cases, R9 i
Figure imgf000046_0007
[00138] In some embodiments, for a compound or salt of Formula (I), (I-A), or (VI), the heterocycle of R9 is not piperazine. In some cases, the heterocycle of R9 is not morpholine. In some cases, R9 is selected from pyrrolidine and thiazole. In some cases, R9 is selected from pyrrolidine and thiazole, each of which is substituted with -NH2. In some cases, R9 is selected from pyrrolidine. In some cases, R9 is selected from thiazole. In some cases, the heterocycle of R9 is not substituted with -N(R20)2. In some cases, the heterocycle of R9 is not substituted with -NH2. [00139] In some embodiments, for a compound or salt of Formula (I), (I-A), or (VI), Q is a bond. In some cases, Q is O. [00140] In some embodiments, for a compound of Formula (I), (I-A), or (VI), the one or more substituents of R9 are independently selected from halogen, -OR20, -N(R20)2, -NO2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl, and C1-6 alkyl. [00141] In some embodiments, for a compound of Formula (I), (I-A), or (VI), the one or more substituents of R9 are independently selected from halogen, -OR20, -N(R20)2, -NO2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl, and C1-6 alkyl. In some cases, the one or more substituents of R9 are independently selected from -OR20, -N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, and C1-6 alkyl. In some cases, the one or more optional substituents of R9 are independently selected from -OR20, -N(R20)2, C1-6 aminoalkyl, and C1-6 hydroxyalkyl. In some cases, the one or more optional substituents of R9 are independently selected from -OR20, - N(R20)2, C1-6 aminoalkyl, C1-6 alkyl, and C1-6 hydroxyalkyl. In some cases, the one or more optional substituents of R9 are independently selected from -OR20, -N(R20)2, and C1-6 alkyl. [00142] In some embodiments, for a compound or salt of Formula (I), (I-A), or (VI), the one or more substituents of R9 are independently selected from halogen, -B(OR20)2, -OR20, -SR20, - N(R20)2, -NHCN, -N(R20)2, -NO2, =O, =S, =N(R20), -CN, C1-6 fluoroalkyl, C1-6 alkoxy, and C2-6 alkynyl; and further optionally substituted with one or more substituents independently selected from -C(O)N(R20)2, -C(O)NR20-OR20, C1-6 alkyl-O-C(O)C1-6 alkyl, C1-6 aminoalkyl, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 alkyl, and C2-6 alkenyl. In some cases, when R9 is substituted with at least one -N(R20)2, and R2 is -L-heterocycle, the heterocycle of -L-heterocycle is a bicyclic heterocycle. In some cases, when R9 is substituted with at least one -N(R20)2, R2 not
Figure imgf000047_0001
, or Y- R2 is not . In some cases, when 9
Figure imgf000047_0002
R is substituted with at least one -N(R20)2, R3 is not benzothiazole. In some cases, when R9 is substituted with at least one -N(R20)2, R3 is selected from an optionally substituted aryl. In some cases, when R9 is substituted with at least one -N(R20)2, R4 is hydrogen. In some cases, when R9 is substituted with at least one -N(R20)2, R50 is hydrogen. [00143] In some embodiments, for a compound or salt of Formula (I), (I-A), (V), or (VI), each R20 is independently selected from hydrogen; and C1-6 alkyl. [00144] In some embodiments, for a compound of Formula (I), (I-A), (V), or (VI), R3 is selected from optionally substituted C6-C10 aryl. In some cases, the C6-C10 aryl is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, =O, -NO2, C1-C4 alkyl, C1-6 aminoalkyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, C2- 6 alkynyl, and -N(R5)2. In some cases, the C6-C10 aryl is optionally substituted with one or more substituents independently selected from halogen, -OH, -NO2, C1-C4 alkyl, C1-6 aminoalkyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, and -N(R5)2. In some cases, the C6-C10 aryl is optionally substituted with one or more substituents independently selected from - OH, C1-6 aminoalkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, and -N(R5)2. In some cases, the C6-C10 aryl is optionally substituted with one or more substituents independently selected from -OH, C1- C3 alkoxy, C2-6 alkynyl, and C1-C3 hydroxyalkyl. In some cases, the C6-C10 aryl is optionally substituted with one or more substituents independently selected from -OH, C2-6 alkynyl, fluorine, and C1-C4 alkyl. In some cases, the C6-C10 aryl is selected from phenyl and naphthalene. [00145] In some embodiments, for a compound or salt of Formula (I), (I-A), (V), or (VI), R3 is selected from aryl and heteroaryl, wherein each is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, =O, -NO2, C1-C4 alkyl, C1-6 aminoalkyl, -S-C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 hydroxyalkynyl, C1-C3 cyanoalkyl, triazolyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, -S-C1-C3 haloalkyl, C1-C3 alkoxy, C1- C3 hydroxyalkyl, -CH2C(=O)N(R5)2, -C3-C4 alkynyl(NR5)2, -N(R5)2, (C1-C3 alkoxy)haloC1-C3 alkyl-, and C3-C6 cycloalkyl, wherein the C3-C6 cycloalkyl is optionally substituted with one or more substituents selected from halogen and C1-C3 alkyl; and when R3 is benzothiazole, the benzothiazole is optionally substituted with one or more R49. [00146] In some embodiments, for a compound or salt of Formula (I), (I-A), (V), or (VI), R3 is not benzothiazole. In some cases, R3 is not benzothiazole substituted with at least one -NH2. [00147] In some embodiments, for a compound or salt of Formula (I), (I-A), (V), or (VI), R3 is selected from an optionally substituted heterocycle. In some cases, the heterocycle is an 8- to 12- membered heterocycle. In some cases, R3 is selected from an optionally substituted unsaturated 8- to 12- membered heterocycle. In some cases, R3 is selected from an optionally substituted unsaturated 10-membered heterocycle. In some cases, the heterocycle is partially unsaturated. In some cases, the unsaturated heterocycle contains at most one nitrogen atom. In some cases, the unsaturated heterocycle contains at least one nitrogen atom. In some cases, the unsaturated heterocycle contains at least one oxygen atom. In some cases, the unsaturated heterocycle contains at least one nitrogen atom and at least one oxygen atom. In some cases, R3 is selected from
Figure imgf000049_0001
, which is optionally substituted. In some cases, the optional substituents are selected from halogen, cyano, hydroxy, =O, -NO2, C1-C4 alkyl, C3-C6 cycloalkyl, C1-6 aminoalkyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, C2-6 alkynyl, and -N(R5)2. In some cases, the optional substituents are selected from halogen, cyano, hydroxy, =O, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C3 haloalkyl, C2-6 alkynyl, and -NH2. In some cases, R3 is selected from
Figure imgf000049_0002
[00148] In some embodiments, for a compound or salt of Formula (I), (I-A), (V), or (VI), R3 is selected from optionally substituted C6-C10 aryl and optionally substituted 6- to 12-membered heteroaryl. In some cases, R3 is selected from optionally substituted C6-C10 aryl and optionally substituted 6- to 12-membered heteroaryl. In some cases, R3 is selected from optionally substituted C10 aryl and optionally substituted 9-membered heteroaryl. In some cases, R3 is selected from optionally substituted naphthalene and optionally substituted indazole. In some cases, the naphthalene and indazole are optionally substituted with one or more substituents selected from halogen, -CN, -OH, =O, -NO2, C1-C4 alkyl, C1-6 aminoalkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 hydroxyalkynyl, C1-C3 cyanoalkyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, and N(R5)2. In some cases, indazole is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH2, -NO2, =O, C1-6 alkyl, C2-6 alkynyl, C1-6 aminoalkyl, C1-6 hydroxyalkyl, and C1-6 haloalkyl. In some cases, the naphthalene is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH2, -NO2, =O, C1-6 alkyl, C2-6 alkynyl, C1-6 aminoalkyl, C1-6 hydroxyalkyl, and C1-6 haloalkyl. In some cases, the naphthalene is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH2, -NO2, =O, C1-6 alkyl, C1-6 aminoalkyl, C1-6 hydroxyalkyl, and C1-6 haloalkyl. In some cases, the naphthalene is optionally substituted with one or more substituents independently selected from fluorine, C2-6 alkynyl, - OH, and C1-3 alkyl. In some cases, R3 is optionally substituted naphthalene. In some cases, the naphthalene is optionally substituted with one or more substituents selected from -OH, and C1-C6 alkyl. In some cases, R3 is selected from
Figure imgf000049_0003
Figure imgf000050_0001
some cases, R3 is selected from
Figure imgf000050_0005
[00149] In some embodiments, for a compound or salt of Formula (I), (I-A), (V), or (VI), R3 is selected from an optionally substituted heteroaryl. In some cases, R3 is selected from an optionally substituted tricyclic heteroaryl. In some cases, R3 is selected from an optionally substituted 10- to 15-membered heteroaryl. In some cases, R3 is selected from an optionally substituted 12- to 13- membered heteroaryl. In some cases, R3 is selected from an optionally substituted 12-membered heteroaryl. In some cases, R3 is selected from an optionally substituted 13-membered heteroaryl. In some cases, the heteroaryl has at least one nitrogen atom. In some cases, the heteroaryl has at least sulfur atom. In some cases, the heteroaryl has at least one nitrogen atom and is bound to Formula (I), (V), or (VI), via the at least one nitrogen atom. In some cases, the heteroaryl has at least one sulfur atom. In some cases, heteroaryl of R3 is substituted with at least one substituent. In some cases, heteroaryl of R3 is substituted with at least two substituents. In some cases, the substituents are selected from halogen, cyano, hydroxy, =O, -NO2, C1-C4 alkyl, C3-C6 cycloalkyl, C1-6 aminoalkyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, C2-6 alkynyl, and -N(R5)2. In some cases, the substituents are selected from halogen, cyano, hydroxy, =O, -NO2, hydroxy, C1-C4 alkyl, C3-C6 cycloalkyl, C1-6 aminoalkyl, C1-C3 haloalkyl, and -NH2. In some cases, R3 is selected from
Figure imgf000050_0002
, and
Figure imgf000050_0006
Figure imgf000050_0003
, each of which are optionally substituted. In some cases, R3 is selected from
Figure imgf000050_0004
each of which are optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, =O, - NO2, C1-C4 alkyl, C3-C6 cycloalkyl, C1-6 aminoalkyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, C2-6 alkynyl, and -N(R5)2. In some cases, R3 is selected from
Figure imgf000051_0001
each of which are optionally substituted with one or more substituents independently selected from -CN, -OH, =O, C3-C6 cycloalkyl, C2-6 alkynyl, and -NH2. In some cases, R3 is selected from , ,
Figure imgf000051_0002
some cases, R3 is selected from
Figure imgf000051_0004
Figure imgf000051_0005
Figure imgf000051_0006
In some cases, R3 is selected from an unsubstituted heteroaryl. In some cases, R3 is selected from
Figure imgf000051_0003
, which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, =O, -NO2, C1-C4 alkyl, C3-C6 cycloalkyl, C1-6 aminoalkyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, C2-6 alkynyl, and -N(R5)2. In some cases, R3 is selected from
Figure imgf000052_0001
, which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, =O, hydroxy, C3-C6 cycloalkyl, C1-6 aminoalkyl, C2-6 alkynyl, and -N(R5)2. In some cases, R3 is selected from
Figure imgf000052_0003
. In some cases, R3 is selected from
Figure imgf000052_0004
, which is optionally substituted with one or more substituents independently selected from halogen. In some cases, R3 is selected
Figure imgf000052_0005
, which is optionally substituted with one or more substituents independently selected from chlorine and fluorine. In some cases, R3 is selected from . In some cases, R3 is selected from
Figure imgf000052_0006
Figure imgf000052_0007
,a d . In some cases, R3 is selected from
Figure imgf000052_0008
. In some cases, R3 is selected from . In some cases, R3 is selected from
Figure imgf000052_0002
Figure imgf000052_0009
, which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, =O, -NO2, C1-C4 alkyl, C3-C6 cycloalkyl, C1-6 aminoalkyl, C1-C3 haloalkyl, - O-C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, C2-6 alkynyl, and -N(R5)2. In some cases, R3 is selected from
Figure imgf000052_0010
which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, =O, hydroxy, C3-C6 cycloalkyl, C1-6 aminoalkyl, C2-6 alkynyl, and -N(R5)2. In some cases, R3 is selected from
Figure imgf000052_0011
[00150] In some embodiments, for a compound or salt of Formula (I), (I-A), (V), or (VI), R3 is selected from an optionally substituted tricyclic heteroaryl. In some cases, the tricyclic heteroaryl has at least one nitrogen atom and one sulfur atom. In some cases, R3 is selected from
Figure imgf000053_0004
, which is optionally substituted with one or more substituents independently selected from halogen, C1-C3 haloalkyl, -CN, -OH, =O, hydroxy, C3-C6 cycloalkyl, C1-6 aminoalkyl, C2-6 alkynyl, and -N(R5)2. In some cases, R3 is selected from
Figure imgf000053_0001
, which is optionally substituted with one or more substitutents selected from halogen, hydroxy, =O, -NO2, C1-C4 alkyl, C3-C6 cycloalkyl, C1-6 aminoalkyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, and C2-6 alkynyl. In some cases, R3 is selected from
Figure imgf000053_0002
which is optionally substituted with one or more substitutents selected from halogen, C1-C3 haloalkyl, C3-C6 cycloalkyl, and C2-6 alkynyl. In some cases, R3 is selected from
Figure imgf000053_0005
, , , , . In some case 3
Figure imgf000053_0006
s, R is some cases, R3 is
Figure imgf000053_0007
. In some cases, R3 is
Figure imgf000053_0008
some cases, R3 is 3
Figure imgf000053_0009
. In some cases, R is
Figure imgf000053_0003
. [00151] In some embodiments, for a compound or salt of Formula (I), (I-A), (V), or (VI), R3 is selected from a phenyl, which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, =O, -NO2, C1-C4 alkyl, C1-6 aminoalkyl, -S-C1- C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 hydroxyalkynyl, C1-C3 cyanoalkyl, triazolyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, -S-C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, - CH2C(=O)N(R5)2, -C3-C4 alkynyl(NR5)2, -N(R5)2, (C1-C3 alkoxy)haloC1-C3 alkyl-, and C3-C6 cycloalkyl, wherein the C3-C6 cycloalkyl is optionally substituted with one or more substituents selected from halogen and C1-C3 alkyl. In some cases, R3 is selected from a phenyl, which is optionally substituted with one or more substituents independently selected from halogen, C1-C3 haloalkyl, and -N(R5)2. In some cases, R3 is
Figure imgf000054_0001
. [00152] In some embodiments, for a compound or salt of Formula (I) or (I-A), R3 is selected from aryl and heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, =O, -NO2, C1-C4 alkyl, C1-6 aminoalkyl, -S-C1- C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 hydroxyalkynyl, C1-C3 cyanoalkyl, triazolyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, -S-C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, - CH2C(=O)N(R5)2, -C3-C4 alkynyl(NR5)2, -N(R5)2, (C1-C3 alkoxy)haloC1-C3 alkyl-, and C3-C6 cycloalkyl, wherein the C3-C6 cycloalkyl is optionally substituted with one or more substituents selected from halogen and C1-C3 alkyl; and wherein when R3 is benzothiazole, the benzothiazole is optionally substituted with one or more R49. [00153] In some embodiments, for a compound or salt of Formula (I), (I-A), or (VI), R9 is selected from a substituted saturated 6- to 7-membered heterocycle. In some cases, R9 is selected from
Figure imgf000054_0003
a d , each of which is substituted. In some cases, R9 is selected from
Figure imgf000054_0002
which is substituted. In some cases, the one or more substituents are independently selected from halogen, -CN, -NHCN, and C1-6 alkyl, and further optionally substituted with one or more C1-6 alkyl. In some cases, the optional one or more substituents are independently selected from -CN, -NHCN, C1-6 cyanoalkyl, and C1-6 alkyl. In some cases, the one or more substituents are independently selected from -NHCN, and further optionally substituted with one or more C1-6 alkyl. In some cases, R1 is selected from
Figure imgf000054_0004
, which is substituted with one or more substituents selected from -NHCN, and further optionally substituted with one or more C1-6 alkyl. In some cases, R1 is selected from
Figure imgf000055_0001
some cases, R1 is
Figure imgf000055_0005
. In some cases, R1 is
Figure imgf000055_0002
. [00154] In some embodiments, for a compound or salt of Formula (I) or (I-A), R9 is selected from a substituted 10-membered spiro heterocycle, wherein the one or more substituents are independently selected from halogen, -NHCN, =O, -CN, C1-6 alkoxy and further optionally substituted with one or more substituents independently selected from C1-6 cyanoalkyl, and C1-6 alkyl. In some cases, the one or more substituents are independently selected from =O. [00155] In some embodiments, for a compound or salt of Formula (I), (I-A), or (VI), R9 is selected from a substituted 10-membered heterocycle, wherein the one or more substituents are independently selected from halogen, -NHCN, =O, -CN, C1-6 alkoxy and further optionally substituted with one or more substituents independently selected from C1-6 cyanoalkyl, and C1-6 alkyl; R4 is halogen; R3 is naphthalene substituted with one or more substituents independently selected from halogen, -OH, C2-C4 alkynyl, and C1-3 alkyl; R50 is hydrogen; Y is O; R2 is -L- heterocycle, wherein the heterocycle portion is optionally substituted with one or more substituents independently selected from halogen, oxo, and C1-C3 alkyl; and L is independently selected from an optionally substituted C1-C4 alkylene. In some cases, L is C1-C4 alkylene. In some cases, the heterocycle of -L-heterocycle is a bicyclic heterocycle. In some cases, the 10- membered heterocycle is a spiroheterocycle. In some cases, the 10-membered heterocycle, is a saturated 10-membered heterocycle. In some cases, the 10-membered heterocycle, is a non- aromatic 10-membered heterocycle. In some cases, the 10-membered heterocycle is selected from
Figure imgf000055_0003
each of which is substituted. In some cases, the 10-membered heterocycle is selected from
Figure imgf000055_0004
, which is substituted. In some cases, the one or more substituents of R9 are independently selected from one or more halogen, -NHCN, =O, -CN, and C1-6 alkoxy In some cases the one or more substituents of R9 are independently selected from
Figure imgf000056_0001
some cases,
Figure imgf000056_0002
. some cases, the 10-membered heterocycle of R9 contains at least 3 nitrogen atoms. In some cases, the 10-membered heterocycle of R9 contains 3 nitrogen atoms and no other heteroatoms. In some cases, R4 is fluorine. In some cases, R4 is hydrogen. [00156] In some embodiments, for a compound or salt of Formula (I), (I-A), or (VI), R9 is selected from a substituted 6-membered heterocycle, wherein the one or more substituents are independently selected from halogen, -CN, -OH, C1-6 fluoroalkyl, -NHCN, and C1-6 alkoxy, and further substituted with one or more substituents independently selected from C1-6 cyanoalkyl, and C1-6 alkyl; R4 is halogen; R3 is naphthalene substituted with one or more substituents independently selected from halogen, -OH, C2-C4 alkynyl, and C1-3 alkyl; R50 is hydrogen; Y is O; R2 is -L-heterocycle, wherein the heterocycle portion is optionally substituted with one or more substituents independently selected from halogen, oxo, and C1-C3 alkyl; and L is independently selected from an optionally substituted C1-C4 alkylene. In some cases, the 6- membered heterocycle, is a saturated 6-membered heterocycle. In some cases, the 6-membered heterocycle is selected from and
Figure imgf000056_0003
, which is substituted. In some cases, the one or more substituents of R9 are independently selected from one or more hydroxy and -NHCN, and further substituted with one or more C1-6 alkyl. In some cases, the 6-membered heterocycle is substituted with at least one hydroxy. In some cases, the one or more substituents of R9 are independently selected from one or more hydroxy, and further substituted with one or more C1-6 alkyl. In some
Figure imgf000057_0001
heterocycle of -L-heterocycle contains at least one nitrogen atom and one oxygen atom. In some cases, the heterocycle of -L-heterocycle is
Figure imgf000057_0005
. In some cases, each L is independently selected from a substituted C3 alkylene, and wherein two substituents on the same carbon atom of L come together to form a C3-6 carbocycle. In some cases, L is
Figure imgf000057_0002
. In some cases, the heterocycle of -L-heterocycle is a monocyclic heterocycle. In some cases, Y-R2 is selected from
Figure imgf000057_0004
. In some cases, Y-R2 is selected from
Figure imgf000057_0003
. [00157] In some embodiments, for a compound or salt of Formula (I), (I-A), (V), or (VI), R3 is selected from a phenyl, which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, =O, -NO2, C1-C4 alkyl, C1-6 aminoalkyl, -S-C1- C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 hydroxyalkynyl, C1-C3 cyanoalkyl, triazolyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, -S-C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, - CH2C(=O)N(R5)2, -C3-C4 alkynyl(NR5)2, -N(R5)2, (C1-C3 alkoxy)haloC1-C3 alkyl-, and C3-C6 cycloalkyl, wherein the C3-C6 cycloalkyl is optionally substituted with one or more substituents selected from halogen and C1-C3 alkyl. In some cases, R3 is selected from a phenyl, which is optionally substituted with one or more substituents independently selected from halogen, C1-C3 haloalkyl, and -N(R5)2. In some cases,
Figure imgf000058_0001
. [00158] In some embodiments, for a compound or salt of Formula (I) or (I-A), R9 is selected from C3-C12 carbocycle and 5- to 12-membered heterocycle, wherein the C3-C12 carbocycle and 5- to 12-membered heterocycle are each substituted with one or more substituents independently selected from halogen, -B(OR20)2, -OR20, -SR20, -N(R20)2, -NHCN, -NO2, =O, =S, =N(R20), -CN, C1-6 fluoroalkyl, C1-6 alkoxy, and C2-6 alkynyl; and further optionally substituted with one or more substituents independently selected from -C(O)N(R20)2, -C(O)NR20-OR20, C1-6 aminoalkyl, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 alkyl, C1-6 alkyl-O-C(O)C1-6 alkyl, and C2-6 alkenyl; Y is selected from a bond, O and NR5; and R2 is selected from hydrogen, -N(R5)2, -L-N(R5)2, -L- OR5, heterocycle, C1-C6 alkyl, -L-heterocycle, -L-aryl, -L-heteroaryl, -L-cycloalkyl, -L-N(R5)2, - L-NHC(=NH)NH2, -L-C(O)N(R5)2, -L-C1-C6 haloalkyl, -L-OR5, -L-NR5C(O)-aryl, -L-COOH, and -LC(=O)OC1-C6 alkyl, wherein the heterocycle, the aryl portion of -L-NR5C(O)-aryl, the heterocycle portion of -L-heterocycle, and the cycloalkyl portion of the -L-cycloalkyl are each optionally substituted with one or more R6, and wherein the aryl of the -L- aryl and heteroaryl of the -L-heteroaryl are each optionally substituted with one or more R7. [00159] In some embodiments, for a compound or salt of Formula (I) or (I-A), R9 is selected from C3-C12 carbocycle and 5- to 12-membered heterocycle, wherein the C3-C12 carbocycle and 5- to 12-membered heterocycle are each substituted with one or more substituents independently selected from halogen, -B(OR20)2, -OR20, -SR20, -NHCN, -NO2, =O, =S, =N(R20), -CN, C1-6 fluoroalkyl, C1-6 alkoxy, and C2-6 alkynyl; and further optionally substituted with one or more substituents independently selected from -C(O)N(R20)2, -C(O)NR20-OR20, C1-6 aminoalkyl, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 alkyl, C1-6 alkyl-O-C(O)C1-6 alkyl, and C2-6 alkenyl; wherein when R9 is substituted with at least one -OH, =O, or C1-6 alkoxy, the 5- to 12-membered heterocycle is a non-bridged heterocycle. [00160] In some embodiments, for a compound or salt of Formula (I), (I-A), or (VI), when R9 is substituted with at least one -OH, =O, or C1-6 alkoxy, the 5- to 12-membered heterocycle is a non-bridged heterocycle. [00161] In some embodiments, for a compound or salt of Formula (I) or (I-A), the compound
Figure imgf000059_0001
[00162] In some aspects, the present disclosure provides a compound represented by the structure of Formula (II):
Figure imgf000059_0002
, or a pharmaceutically acceptable salt thereof, wherein: Y is selected from a bond, O and NR5; R2 is selected from L-pyrrolizine, wherein the pyrrolizine is optionally substituted with one or more R6; each L is independently selected from a C1-C4 alkylene optionally substituted with one or more substituents selected from -OH, C1-C4 hydroxyalkyl, and C1-C4 alkyl; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl; R3 is selected from aryl and heteroaryl, wherein the aryl and the heteroaryl are each optionally substituted with one or more substituents independently selected from halogen, -CN, - OH, =O, -NO2, C1-C4 alkyl, C1-6 aminoalkyl, -S-C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 hydroxyalkynyl, C1-C3 cyanoalkyl, triazolyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, -S- C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, -CH2C(=O)N(R5)2, -C3-C4 alkynyl(NR5)2, -N(R5)2, (C1-C3 alkoxy)haloC1-C3 alkyl-, and C3-C6 cycloalkyl, wherein the C3-C6 cycloalkyl is optionally substituted with one or more substituents selected from halogen and C1-C3 alkyl; R4 is selected from hydrogen, halogen, C1-C3 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and -O-C1- 6 haloalkyl; each R5 is independently selected from hydrogen and C1-C3 alkyl; each R6 is independently selected from halogen, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkyl, oxo, C1-C3 haloalkyl, C1-C3 alkoxy, cyano, =CH2, =NO-C1-C3 alkyl, C1-C3 aminoalkyl, - N(R5)S(O)2(R5), -Q-phenyl, -Q-phenylSO2F, -NHC(O)phenyl, - NHC(O)phenylSO2F, C1-C3 alkyl substituted pyrazolyl, tert-butyldimethylsilyloxyCH2- , -N(R5)2, (C1-C3 alkoxy)C1-C3 alkyl-, (C1- C3 alkyl)C(=O), oxo, (C1-C3 haloalkyl)C(=O)-, -SO2F, (C1-C3 alkoxy)C1-C3 alkoxy, - CH2OC(O)N(R5)2, -CH2NHC(O)OC1-C6 alkyl, -CH2NHC(O)N(R5)2, -CH2NHC(O)C1-C6 alkyl, - CH2(pyrazolyl), -CH2NHSO2C1-C6 alkyl, -CH2OC(O)heterocycle, -OC(O)N(R5)2, - OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl), -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl(C1-C3 alkyl)N(CH3)2, -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl, - OC(O)heterocycle, -O-C1-C3 alkyl, and -CH2heterocycle, wherein the phenyl of -NHC(O)phenyl and -OC(O)NH(C1-C3 alkyl)(C1-C3 alkyl)phenyl are optionally substituted with one or more substituents selected from - C(O)H and OH, and wherein the alkyl of -O-C1-C3 alkyl is optionally substituted with substituents selected from heterocycle, oxo and hydroxy; and wherein the heterocycle of -CH2heterocyclyl is optionally substituted with oxo; Q is selected from a bond and O; R9 is selected from C3-C12 carbocycle and 5- to 12-membered heterocycle, each of which are optionally substituted with one or more substituents independently selected from halogen, - B(OR20)2, -OR20, -SR20, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), - NR20S(O)2R20, -C(O)N(R20)2, -C(=NR20)N(R20)2, -C(O)NR20OR20, -N(R20)C(O)R20, - N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, -C(O)R20, -C(O)OR20, -OC(O)R20, - OC(O)N(R20)2, -NO2, =O, =N(R20), =NO(R20), -CN, -NHCN, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-C12 carbocycle and 5- to 12-membered heterocycle, wherein the C3-C12 carbocycle and 5- to 12-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -B(OR20)2, -OR20, -SR20, -S(O)2(R20), -S(O)2N(R20)2, - S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, -C(O)NR20OR20, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, -C(O)R20, -C(O)OR20, -OC(O)R20, - OC(O)N(R20)2, -NO2, =O, =N(R20), =NO(R20), -CN, -NHCN, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C3-C12 carbocycle; each R20 is independently selected from hydrogen; and C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbocycle, and 3- to 12- membered heterocycle; and R50 is selected from hydrogen, halogen, -OH, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, -CN, C1-C3 cyanoalkyl, C1-C3 aminoalkyl, C2-C4 alkenyl, C2-C4 alkynyl, and C2-C4 hydroxyalkynyl. [00163] In some embodiments, for a compound of Formula (II), Y is O. In some cases, Y is a bond. In some cases, Y is -NR5-. [00164] In some embodiments, for a compound or salt of Formula (II), L is selected from optionally substituted C1-C4 alkylene. In some cases, L is selected from optionally substituted C1- C2 alkylene. In some cases, L is selected from optionally substituted C1 alkylene. In some cases L is selected from unsubstituted C1-C4 alkylene. [00165] In some embodiments, for a compound of Formula (II), L is selected from unsubstituted C1-C4 alkylene. In some cases, L is selected from unsubstituted C1-C2 alkylene. In some cases, L is selected from unsubstituted C1 alkylene. In some cases, L is selected from methylene and ethylene. In some cases, L is methylene. [00166] In some embodiments, for a compound or salt of Formula (II), optional substituents of L are selected from C1-C4 hydroxyalkyl, C1-C4 alkyl, C3-C6 carbocycle, wherein the C3-C6 carbocycle is optionally substituted with one or more substituents selected from halogen, -OH, - NO2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, and C1-6 haloalkyl. [00167] In some embodiments, for a compound or salt of Formula (II), the optional substituents of L are selected from C1-C4 hydroxyalkyl, C1-C4 alkyl, C3-C6 carbocycle, wherein the C3-C6 carbocycle is optionally substituted with one or more substituents selected from halogen. [00168] In some embodiments, for a compound or salt of Formula (II), L is selected from optionally substituted C1-C4 alkylene. [00169] In some embodiments, for a compound or salt of Formula (II), the optional substituents of L are selected from C1-C4 hydroxyalkyl, and C1-C4 alkyl. [00170] In some embodiments, for a compound or salt of Formula (II), optionally two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle or 3- to 8- membered heterocycle wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl. In some cases, optionally two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle wherein the C3-C6 carbocycle is optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl. In some cases, optionally two substituents on the same carbon atom of L come together to form a C3 carbocycle wherein the C3 carbocycle is optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl. In some cases, optionally two substituents on the same carbon atom of L come together to form a C3 carbocycle wherein the C3 carbocycle is optionally substituted with one or more substituents selected from halogen. [00171] In some embodiments, for a compound or salt of Formula (II), optionally two hydrogens on the same carbon atom of L come together to form a C3-C6 carbocycle or 3- to 8- membered heterocycle wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl. In some cases, optionally two hydrogens on the same carbon atom of L come together to form a C3-C6 carbocycle wherein the C3-C6 carbocycle is optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl. In some cases, optionally two hydrogens on the same carbon atom of L come together to form a C3 carbocycle wherein the C3 carbocycle is optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl. In some cases, optionally two hydrogens on the same carbon atom of L come together to form a C3 carbocycle wherein the C3 carbocycle is optionally substituted with one or more substituents selected from halogen. [00172] In some embodiments, for a compound or salt of Formula (II), R2 is selected from
Figure imgf000062_0001
, wherein the heterocycle portion is optionally substituted with one or more R6. [00173] In some embodiments, for a compound or salt of Formula (II), Y-R2 is selected from
Figure imgf000062_0002
, wherein the heterocycle portion is optionally substituted with one or more R6. [00174] In some embodiments, for a compound or salt of Formula (II), R6 is independently selected from halogen, -OH, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 aminoalkyl, C1-C3 haloalkyl, C1-C3 alkoxy, -N(R5)2, and oxo. In some cases, the R6 is independently selected from -OH, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 aminoalkyl, C1-C3 alkoxy, and -N(R5)2. In some cases, the R6 is independently selected from C1-C3 alkyl, C1-C3 alkoxy, and -N(R5)2. [00175] In some embodiments, for a compound or salt of Formula (II), each R6 is independently selected from halogen, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkyl, oxo, C1-C3 haloalkyl, C1-C3 alkoxy, cyano, =NO-C1-C3 alkyl, C1-C3 aminoalkyl, -N(R5)S(O)2(R5), -Q- phenyl, -Q-phenylSO2F, -NHC(O)phenyl, - NHC(O)phenylSO2F, C1-C3 alkyl substituted pyrazolyl, tert-butyldimethylsilyloxyCH2- , -N(R5)2, (C1-C3 alkoxy)C1-C3 alkyl-, (C1-C3 alkyl)C(=O), oxo, (C1-C3 haloalkyl)C(=O)-, -SO2F, (C1-C3 alkoxy)C1-C3 alkoxy, - CH2OC(O)N(R5)2, -CH2NHC(O)OC1-C6 alkyl, -CH2NHC(O)N(R5)2, -CH2NHC(O)C1-C6 alkyl, - CH2(pyrazolyl), -CH2NHSO2C1-C6 alkyl, -CH2OC(O)heterocycle, -OC(O)N(R5)2, - OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl), -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl(C1-C3 alkyl)N(CH3)2, -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl, - OC(O)heterocycle, -O-C1-C3 alkyl, and -CH2heterocycle, wherein the phenyl of -NHC(O)phenyl and -OC(O)NH(C1-C3 alkyl)(C1-C3 alkyl)phenyl are optionally substituted with one or more substituents selected from - C(O)H and OH, and wherein the alkyl of -O-C1-C3 alkyl is optionally substituted with substituents selected from heterocycle, oxo and hydroxy; and wherein the heterocycle of - CH2heterocyclyl is optionally substituted with oxo. [00176] In some embodiments, for a compound or salt of Formula (II), R6 is selected from halogen, -OH, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, -CN, and C1-C3 aminoalkyl. In some cases, R6 is selected from halogen and C1-C3 alkyl. In some cases, R6 is halogen. In some cases, R6 is C1-C3 alkyl. In some cases, R6 is selected from halogen and C1-C3 alkyl. In some cases, R6 is selected from methyl and fluorine. [00177] In some embodiments, for a compound or salt of Formula (II), R6 is selected from halogen, -OH, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, -CN, and C1-C3 aminoalkyl. In some cases, R6 is selected from halogen and C1-C3 alkyl. [00178] In some embodiments, for a compound or salt of Formula (II), R2 is selected from
Figure imgf000063_0001
[00179] In some embodiments, for a compound or salt of Formula (II), Y-R2 is selected from
Figure imgf000063_0002
[00180] In some embodiments, for a compound or salt of Formula (II), R50 is selected from hydrogen, halogen, C1-C3 cyanoalkyl, C2-C4 alkenyl, C2-C4 alkynyl, and C3-C6 carbocycle. In some cases, R50 is selected from hydrogen, Cl,
Figure imgf000064_0001
. [00181] In some embodiments, for a compound or salt of Formula (II), R4 is selected from halogen and hydrogen. In some cases, R4 is selected from halogen. In some cases, R4 is fluorine. [00182] In some embodiments, for a compound or salt of Formula (II), R4 is selected from hydrogen, halogen, C1-C3 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and -O-C1-6 alkyl, wherein the alkyl portion of -O-C1-6 alkyl is substituted with one or more halogen substituents. In some cases, R4 is selected from C1-6 haloalkyl, C1-6 alkoxy, and -O-C1-6 alkyl, wherein the alkyl portion of -O-C1-6 alkyl is substituted with one or more halogen substituents. In some cases, R4 is selected from C1-6 alkoxy, and -O-C1-6 alkyl, wherein the alkyl portion of -O-C1-6 alkyl is substituted with one or more halogen substituents. In some cases, R4 is selected from -O-C1-6 alkyl, wherein the alkyl portion of -O-C1-6 alkyl is substituted with one or more halogen substituents. [00183] In some embodiments, for a compound of Formula (II), the carbocycle of R9 is selected from C3-C12 carbocycle, C3-C10 carbocycle, C3-C9 carbocycle, C3-C8 carbocycle, or C3-C6 carbocycle. In some cases, the carbocycle of R9 is selected from C3-C12 carbocycle, C4-C12 carbocycle, C5-C12 carbocycle, C6-C12 carbocycle, C7-C12 carbocycle, C8-C12 carbocycle, or C9-C12 carbocycle. [00184] In some embodiments, for a compound of Formula (II), the heterocycle of R9 is a 5- to 12-membered heterocycle, 6- to 12-membered heterocycle, 7- to 12-membered heterocycle, or 8- to 12-membered heterocycle. In some cases, the heterocycle of R9 is a 5- to 11-membered heterocycle, 5- to 10-membered heterocycle, 5- to 9-membered heterocycle, or 5- to 8-membered heterocycle. In some cases, the heterocycle of R9 is a 6- to 11-membered heterocycle, 6- to 10- membered heterocycle, 6- to 9-membered heterocycle, or 6- to 8-membered heterocycle. In some cases, the heterocycle of R9 is a 7- to 11-membered heterocycle, 7- to 10-membered heterocycle, 7- to 9-membered heterocycle, or 7- to 8-membered heterocycle. In some cases, the heterocycle of R9 is a 5- to 6-membered heterocycle or 5- to 9-membered heterocycle. In some cases, the heterocycle of R9 is an 8- to 9-membered heterocycle. In some embodiments, for a compound of Formula (II), the heterocycle of R9 is saturated. The heterocycle may be optionally substituted as described elsewhere herein. [00185] In some embodiments, for a compound of Formula (II), the heterocycle of R9 is a 5- to 12-membered monocyclic heterocycle, 6- to 12-membered monocyclic heterocycle, 7- to 12- membered monocyclic heterocycle, or 8- to 12-membered monocyclic heterocycle. In some cases, the heterocycle of R9 is a 5- to 11-membered monocyclic heterocycle, 5- to 10-membered monocyclic heterocycle, 5- to 9-membered monocyclic heterocycle, or 5- to 8-membered monocyclic heterocycle. In some cases, the heterocycle of R9 is a 6- to 11-membered monocyclic heterocycle, 6- to 10-membered monocyclic heterocycle, 6- to 9-membered monocyclic heterocycle, or 6- to 8-membered monocyclic heterocycle. In some cases, the heterocycle of R9 is a monocyclic 7- to 11-membered heterocycle, 7- to 10-membered monocyclic heterocycle, 7- to 9-membered monocyclic heterocycle, or 7- to 8-membered monocyclic heterocycle. In some cases, the heterocycle of R9 is a 5- to 6-membered monocyclic heterocycle or 5- to 9-membered monocyclic heterocycle. In some cases, the heterocycle of R9 is an 8- to 9-membered monocyclic heterocycle. [00186] In some embodiments, for a compound of Formula (II), the heterocycle of R9 is saturated. The monocyclic heterocycle may be optionally substituted as described elsewhere herein. [00187] In some embodiments, for a compound or salt of Formula (II), R9 is selected from 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -B(OR20)2, -OR20, -SR20, S(O)2(R20), -C(O)N(R20)2, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)2, -C(O)R20, -C(O)OR20, -OC(O)R20, -NO2, =O, =S, =N(R20), -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl. [00188] In some embodiments, for a compound or salt of Formula (II), R9 is selected from 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle is substituted with one or more substituents independently selected from halogen, -B(OR20)2, -OR20, -SR20, S(O)2(R20), -C(O)N(R20)2, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)2, -C(O)R20, -C(O)OR20, -OC(O)R20, -NO2, =O, =S, =N(R20), -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl. [00189] In some embodiments, for a compound or salt of Formula (II), R9 is selected from 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle is substituted with one or more substituents independently selected from halogen, -B(OR20)2, -OR20, -SR20, -N(R20)2, - S(O)2(R20), -NO2, =O, =S, =N(R20), -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl. [00190] In some embodiments, for a compound or salt of Formula (II), R9 is selected from 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -OR20, -N(R20)2, -NO2, =O, =S, =N(R20), -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, and C1-6 haloalkyl. [00191] In some embodiments, for a compound of Formula (II), the one or more optional substituents of R9 are independently selected from halogen, -OR20, -N(R20)2, -NO2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl, and C1-6 alkyl. [00192] In some embodiments, for a compound or salt of Formula (II), R9 is selected from 5- to 12-membered unsaturated heterocycle, wherein the 5- to 12-membered unsaturated heterocycle is optionally substituted with one or more substituents independently selected from halogen, -B(OR20)2, -OR20, -SR20, S(O)2(R20), -C(O)N(R20)2, -N(R20)C(O)R20, - N(R20)C(O)N(R20)2, -N(R20)2, -C(O)R20, -C(O)OR20, -OC(O)R20, -NO2, =O, =S, =N(R20), -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl. In some cases, R9 is selected from 5- to 12-membered unsaturated heterocycle, wherein the 5- to 12-membered unsaturated heterocycle is optionally substituted with one or more substituents independently selected from halogen, -B(OR20)2, -OR20, -SR20, - N(R20)2, -S(O)2(R20), -NO2, =O, =S, =N(R20), -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl. In some cases, R9 is selected from 5- to 12-membered unsaturated heterocycle, wherein the 5- to 12-membered unsaturated heterocycle is optionally substituted with one or more substituents independently selected from halogen, -OR20, -N(R20)2, -NO2, =O, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl. In some cases, R9 is selected from 5- to 12-membered unsaturated heterocycle, wherein the 5- to 12-membered unsaturated heterocycle is optionally substituted with one or more substituents independently selected from halogen, -OR20, -N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl. In some cases, R9 is selected from a 7-membered unsaturated heterocycle, wherein the 5- to 12-membered unsaturated heterocycle is optionally substituted with one or more substituents independently selected from halogen, - OR20, -N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl. In some cases, R9 is selected from
Figure imgf000066_0001
which is optionally substituted with one or more substituents independently selected from halogen, -OR20 and -CN. [00193] In some embodiments, for a compound or salt of Formula (II), R9 is selected from
Figure imgf000066_0002
which is substituted with one or more substituents independently selected from halogen, -OR20 and -CN. In some cases, R9 is selected from
Figure imgf000067_0001
which is substituted with one or more substituents independently selected from halogen. [00194] In some embodiments, for a compound or salt of Formula (II), R9 is selected from
Figure imgf000067_0002
Figure imgf000067_0003
optionally substituted with one or more substituents. In some cases, the one or more of the optional substituents are independently selected from halogen, -OH, -N(R20)2, -B(OH)2, -C(O)N(R20)2, - NHCN, -NO2, C1-6 alkoxy, =O, -CN, C1-6 alkyl, C2-6 alkenyl, C1-6 aminoalkyl, C1-6 hydroxyalkyl, and C1-6 haloalkyl. In some cases, R1 is selected from
Figure imgf000067_0004
,
Figure imgf000068_0001
Figure imgf000069_0001
Figure imgf000070_0001
, ,
Figure imgf000071_0001
[00195] In some embodiments, for a compound or salt of Formula (II), R9 is selected from C3- C12 carbocycle and 5- to 12-membered heterocycle, each of which are optionally substituted with one or more substituents independently selected from halogen, -B(OR20)2, -OR20, -SR20, - N(R20)2, S(O)2(R20), -C(O)N(R20)2, -C(O)NR20-OR20, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, - C(O)R20, -C(O)OR20, -OC(O)R20, -NO2, =O, =S, =N(R20), -CN, -NHCN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl-O-C(O)C1-6 alkyl, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl. [00196] In some embodiments, for a compound or salt of Formula (II), R9 is selected from an optionally substituted 5- to 12-membered unsaturated heterocycle, wherein the heterocycle has as most one nitrogen atom. In some cases, the 5- to 12-membered unsaturated heterocycle has at least one nitrogen atom. [00197] In some embodiments, for a compound of Formula (II), the one or more optional substituents of R9 are independently selected from halogen, -S(O)2(R20), -S(O)2N(R20)2, - S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, -C(=NR20)N(R20)2, - C(O)NR20OR20, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -C(O)R20, - C(O)OR20, -OC(O)R20, -OC(O)N(R20)2, =N(R20), =NO(R20), -CN, -NHCN, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-C12 carbocycle and 5- to 12-membered heterocycle. In some cases, the one or more optional substituents of R9 are independently selected from halogen, -S(O)2(R20), - S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, - C(=NR20)N(R20)2, -C(O)NR20OR20, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, - C(O)R20, -C(O)OR20, -OC(O)R20, -OC(O)N(R20)2, =N(R20), =NO(R20), -CN, -NHCN, C1-6 alkyl- N(R20)2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-C12 carbocycle and 5- to 12-membered heterocycle. In some cases, the one or more optional substituents of R9 are independently selected from halogen, -C(O)N(R20)2, C1-6 alkyl, C2-6 alkynyl, -S(O)2(R20), -S(O)2N(R20)2, - S(O)N(R20)2, -S(O)R20(=NR20), -C(O)N(R20)2, -C(=NR20)N(R20)2, -C(O)OR20, -C(O)NHOR20, - C(O)R20, and C1-6 alkyl-N(R20)2. In some cases, the one or more optional substituents of R9 are independently selected from halogen and -C(O)N(R20)2. In some cases, R9 is substituted with at least one -C(O)N(R20)2. In some cases, R9 is substituted with at least one halogen. [00198] In some embodiments, for a compound of Formula (II), the one or more optional substituents of R9 are independently selected from halogen, -OR20, -N(R20)2, -NO2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl, and C1-6 alkyl. In some cases, the one or more optional substituents of R9 are independently selected from -OR20, -N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, and C1-6 alkyl. In some cases, the one or more optional substituents of R9 are independently selected from -OR20, -N(R20)2, C1-6 aminoalkyl, and C1-6 hydroxyalkyl. In some cases, the one or more optional substituents of R9 are independently selected from -OR20, -N(R20)2, C1-6 aminoalkyl, C1-6 alkyl, and C1-6 hydroxyalkyl. In some cases, the one or more optional substituents of R9 are independently selected from -OR20, -N(R20)2, and C1-6 alkyl. In some cases, R9 is not piperazine. [00199] In some embodiments, for a compound or salt of Formula (II), each R20 is independently selected from hydrogen; and C1-6 alkyl. [00200] In some embodiments, for a compound or salt of Formula (II), R9 is selected from 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -OR20, -N(R20)2, -NO2, =O, =S, =N(R20), -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, and C1-6 haloalkyl. [00201] In some embodiments, for a compound or salt of Formula (II), R9 is selected from 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle is optionally substituted with one or more substituents independently selected from -OR20 and -CN. In some cases, R9 is selected from 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle is substituted with one or more substituents independently selected from -OR20 and -CN. [00202] In some embodiments, for a compound or salt of Formula (II), each R20 is independently selected from hydrogen; and C1-6 alkyl. [00203] In some embodiments, for a compound or salt of Formula (II), R9 is selected from 5- to 12-membered unsaturated heterocycle, wherein the 5- to 12-membered unsaturated heterocycle contains at least 1 nitrogen atom and optionally one or more additional heteroatoms selected from oxygen, boron, and sulfur, wherein the 5- to 12-membered unsaturated heterocycle of R9 is bound to Formula (II) via the at least 1 nitrogen atom, and wherein 5- to 12-membered unsaturated heterocycle is optionally substituted with one or more substituents independently selected from halogen, -B(OR20)2, –(CO)N(R20)2, -OR20, -SR20, -S(O)2(R20), -C(O)N(R20)2, - N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)2, -C(O)R20, -C(O)OR20, -OC(O)R20, -NO2, =O, =S, =N(R20), -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, and C2-6 alkynyl. In some cases, each R20 is independently selected from hydrogen; and C1-6 alkyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, - CN, -NO2, -NH2, C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl. [00204] In some embodiments, for a compound or salt of Formula (II), R9 is selected from 6- to 7-membered heterocycle. In some cases, the 6- to 7-membered heterocycle contains only 1 nitrogen atom, and the 6- to 7-membered heterocycle is optionally substituted; and wherein the 6- to 7-membered heterocycle of R9 is bound to Formula (II) via the only 1 nitrogen atom. In some cases, R9 is selected from an optionally substituted unsaturated 6-membered heterocycle. In some cases, R9 is selected from an optionally substituted unsaturated 7-membered heterocycle. In some cases, R9 is selected from
Figure imgf000073_0001
, any of which is optionally substituted. In some cases, R9 is selected from
Figure imgf000073_0002
Figure imgf000073_0003
, any of which is optionally substituted. In some cases, the one or more optional substituents of R9 are each independently selected from halogen, -OR20, -N(R20)2, =O, -CN, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 alkyl, and C2-6 alkynyl. [00205] In some embodiments, for a compound or salt of Formula (II), R9 is selected from 6- to 7-membered heterocycle, wherein the 6- to 7-membered heterocycle contains only 1 nitrogen atom and optionally one or more additional heteroatoms selected from oxygen, and sulfur. In some cases, the optionally one or more additional heteroatoms are selected from sulfur. In some cases, the 6- to 7-membered heterocycle contains only 1 nitrogen atom and no further additional heteroatoms. In some cases, the 6- to 7-membered heterocycle is an unsaturated 6- to 7-membered heterocycle. In some cases, R9 is selected from
Figure imgf000073_0004
, , , , , and
Figure imgf000073_0005
, each of which is optionally substituted. In some cases, the one or more optional substituents of R9 are each independently selected from halogen, -OH, -CN, C1-6 cyanoalkyl, C1-6 alkyl, and C2-6 alkynyl. [00206] In some embodiments, for a compound or salt of Formula (II), R9 is selected from an optionally substituted unsaturated 6- to 8-membered heterocycle. In some cases, R9 is selected from a substituted unsaturated 6- to 8-membered heterocycle. In some cases, R9 is selected from an optionally substituted unsaturated 6-membered heterocycle. In some cases, R9 is selected from an optionally substituted unsaturated 7-membered heterocycle. In some cases, R9 is selected from
Figure imgf000074_0001
wherein each is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH2, -NO2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl, and C1-6 alkyl. In some cases, R9 is selected from
Figure imgf000074_0002
selected from
Figure imgf000074_0003
, wherein each is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH2, -NO2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl, and C1-6 alkyl. In some cases, R9 is selected from
Figure imgf000074_0004
, wherein each is substituted with one or more substituents independently selected from halogen, -OH, -NH2, -NO2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6
Figure imgf000074_0005
hydroxyalkyl, C1-6 haloalkyl, and C1-6 alkyl. In some cases, R9 is selected from , and
Figure imgf000075_0001
, wherein each is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH2, -NO2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl, and C1-6 alkyl. In some cases, R9 is selected from
Figure imgf000075_0002
, wherein each is optionally substituted with one or more substituents independently selected from halogen, and C1-6 haloalkyl. In some cases, R9 is selected from
Figure imgf000075_0003
, , , and
Figure imgf000075_0004
[00207] In some embodiments, for a compound or salt of Formula (II), R9 is not
Figure imgf000075_0005
. [00208] In some embodiments, for a compound or salt of Formula (II), R9 is selected from an optionally substituted 6- to 10-membered heterocycle. In some cases, R9 is selected from
Figure imgf000075_0006
,
Figure imgf000075_0007
one or more substituents independently selected from halogen, =O, -OH, and -CN; and further optionally substituted with one or more substituents independently selected from -C(O)N(R20)2, C1-6 aminoalkyl, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, and C1-6 alkyl. In some cases, R9 is selected
Figure imgf000075_0008
[00209] In some embodiments, for a compound or salt of Formula (II), R9 is selected from an
Figure imgf000076_0001
optionally substituted 6- to 10-membered heterocycle. In some cases, R9 is selected from ,
Figure imgf000076_0002
substituted with one or more substituents independently selected from halogen, =O, - OH, -CN, -C(O)N(R20)2, C1-6 aminoalkyl, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, and C1-6 alkyl. In some cases, R9 is selected from
Figure imgf000076_0003
Figure imgf000076_0004
. [00210] In some embodiments, for a compound or salt of Formula (II), R9 is selected from 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle is optionally substituted with one or more substituents independently selected from -OR20 and -CN. In some cases, R9 is selected from
Figure imgf000076_0005
, , each of which is substituted with one or more substituents independently selected from -OR20 and -CN. In some cases, R9 is selected
Figure imgf000076_0006
[00211] In some embodiments, for a compound or salt of Formula (II), R9 is selected from
Figure imgf000076_0007
, each of which is optionally substituted with one or more substituents independently selected from -OR20 and -CN. In some cases, R9 is selected from
Figure imgf000077_0001
,
Figure imgf000077_0002
. [00212] In some embodiments, for a compound or salt of Formula (II), the heterocycle of R9 is not piperazine. In some cases, the heterocycle of R9 is not morpholine. [00213] In some embodiments, for a compound or salt of Formula (II), Q is a bond. In some cases, Q is O. [00214] In some embodiments, for a compound or salt of Formula (II), R3 is selected from optionally substituted C6-C10 aryl and optionally substituted 6- to 12-membered heteroaryl. [00215] In some embodiments, for a compound or salt of Formula (II), R3 is selected from optionally substituted C6-C10 aryl and optionally substituted 6- to 12-membered heteroaryl. In some cases, R3 is selected from optionally substituted C10 aryl and optionally substituted 9- membered heteroaryl. In some cases, R3 is selected from optionally substituted C6-C10 aryl and optionally substituted 8- to 10-membered heteroaryl. In some cases, R3 is selected from optionally substituted naphthalene and optionally substituted indazole. In some cases, the naphthalene and indazole are optionally substituted with one or more substituents selected from halogen, -CN, -OH, =O, -NO2, C1-C4 alkyl, C1-6 aminoalkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 hydroxyalkynyl, C1-C3 cyanoalkyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, and N(R5)2. In some cases, indazole is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH2, -NO2, =O, C1-6 alkyl, C2-6 alkynyl, C1-6 aminoalkyl, C1-6 hydroxyalkyl, and C1-6 haloalkyl. In some cases, the naphthalene is optionally substituted with one or more substituents independently selected from halogen, -OH, - NH2, -NO2, =O, C1-6 alkyl, C2-6 alkynyl, C1-6 aminoalkyl, C1-6 hydroxyalkyl, and C1-6 haloalkyl. In some cases, the naphthalene is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH2, -NO2, =O, C1-6 alkyl, C1-6 aminoalkyl, C1-6 hydroxyalkyl, and C1-6 haloalkyl. In some cases, the naphthalene is optionally substituted with one or more substituents independently selected from fluorine, C2-6 alkynyl, -OH, and C1-3 alkyl. In some cases, R3 is optionally substituted naphthalene. In some cases, the naphthalene is optionally substituted with one or more substituents selected from -OH, and C1-C6 alkyl. [00216] In some embodiments, for a compound or salt of Formula (II), R3 is selected from naphthalene and indazole, wherein the naphthalene and indazole are optionally substituted with one or more substituents selected from halogen, -CN, -OH, =O, -NO2, C1-C4 alkyl, C1-6 aminoalkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 hydroxyalkynyl, C1-C3 cyanoalkyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, and N(R5)2. [00217] In some embodiments, for a compound or salt of Formula (II), R3 is optionally substituted naphthalene. The naphthalene is optionally substituted with one or more substituents selected from -OH and C1-C6 alkyl. [00218] In some embodiments, for a compound or salt of Formula (II), R3 is selected from
Figure imgf000078_0001
. [00219] In some embodiments, for a compound or salt of Formula (II), R9 is selected from an optionally substituted 10-membered heterocycle, wherein the optional one or more substituents are independently selected from halogen, =O, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 cyanoalkyl, C1-6 haloalkyl, and C1-6 alkyl; R4 is halogen; R3 is naphthalene substituted with one or more substituents independently selected from halogen, -OH, C2-C4 alkynyl, and C1-3 alkyl; R50 is hydrogen; Y is O; R2 is -L-heterocycle, wherein the heterocycle portion is optionally substituted with one or more substituents independently selected from halogen, oxo, and C1-C3 alkyl; and L is independently selected from an optionally substituted C1-C4 alkylene. In some cases, L is C1-C4 alkylene. In some cases, the heterocycle of -L-heterocycle is a bicyclic heterocycle. In some cases, the 10-membered heterocycle is a spiroheterocycle. In some cases, the 10-membered heterocycle, is a saturated 10-membered heterocycle. In some cases, the 10-membered heterocycle, is a non- aromatic 10-membered heterocycle. In some cases, the 10-membered heterocycle is selected from
Figure imgf000078_0002
f which is optionally substituted. In some cases, the one or more substituents of R9 are independently selected from one or more halogen, -NHCN, =O, -CN, and C1-6 alkoxy. In some cases, the one or more substituents of R9 are independently selected from =O.
Figure imgf000079_0001
is selected from
Figure imgf000079_0003
some cases,
Figure imgf000079_0002
. some cases,
Figure imgf000079_0004
. some cases, the 10-membered heterocycle of R9 contains at least 3 nitrogen atoms. In some cases, the 10-membered heterocycle of R9 contains 3 nitrogen atoms and no other heteroatoms. In some cases, R4 is fluorine. In some cases, Y-R2 is selected from
Figure imgf000079_0005
[00220] In some embodiments, for a compound or salt of Formula (II), the compound is
Figure imgf000080_0001
. [00221] In some embodiments, for a compound or salt of Formula (II), R3 is selected from an optionally substituted heteroaryl. In some cases, R3 is selected from an optionally substituted tricyclic heteroaryl.. In some cases, R3 is selected from a substituted tricyclic heteroaryl. In some cases, R3 is selected from an optionally substituted 10- to 15-membered heteroaryl. In some cases, R3 is selected from an optionally substituted 12- to 13-membered heteroaryl. In some cases, R3 is selected from an optionally substituted 12-membered heteroaryl. In some cases, R3 is selected from an optionally substituted 13-membered heteroaryl. In some cases, the heteroaryl has at least one nitrogen atom. In some cases, the heteroaryl has at least sulfur atom. In some cases, the heteroaryl has at least one nitrogen atom and is bound to Formula (II) via the at least one nitrogen atom. In some cases, the heteroaryl has at least one sulfur atom. In some cases, heteroaryl of R3 is substituted with at least one substituent. In some cases, heteroaryl of R3 is substituted with at least two substituents. In some cases, the substituents are selected from halogen, cyano, hydroxy, =O, -NO2, C1-C4 alkyl, C3-C6 cycloalkyl, C1-6 aminoalkyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, C2-6 alkynyl, and -N(R5)2. In some cases, the substituents are selected from halogen, cyano, hydroxy, =O, -NO2, hydroxy, C1-C4 alkyl, C3-C6 cycloalkyl, C1-6 aminoalkyl, C1-C3 haloalkyl, and -NH2. In some cases, R3 is selected from
Figure imgf000080_0002
, each of which are optionally substituted. In some cases, R3
Figure imgf000080_0003
is selected from
Figure imgf000080_0004
, , , , each of which are optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, =O, -NO2, C1-C4 alkyl, C3-C6 cycloalkyl, C1-6 aminoalkyl, C1-C3 haloalkyl, - O-C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, C2-6 alkynyl, and -N(R5)2. In some cases, R3 is selected from
Figure imgf000081_0001
, each of which are optionally substituted with one or more substituents independently selected from -CN, -OH, =O, C3-C6 cycloalkyl, C2-6
Figure imgf000081_0002
unsubstituted heteroaryl. In some cases, R3 is selected from
Figure imgf000081_0003
, which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, =O, - NO2, C1-C4 alkyl, C3-C6 cycloalkyl, C1-6 aminoalkyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, C2-6 alkynyl, and -N(R5)2. In some cases, R3 is selected from
Figure imgf000082_0001
, which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, =O, hydroxy, C3-C6 cycloalkyl, C1-6 aminoalkyl, C2-6 alkynyl, some cases, R3 is selected from
Figure imgf000082_0002
. some cases, R3 is selected from
Figure imgf000082_0003
, which is optionally substituted with one or more substituents independently selected from halogen. In some cases, R3 is selected from
Figure imgf000082_0004
, which is optionally substituted with one or more substituents independently selected from chlorine and fluorine. In
Figure imgf000082_0005
from
Figure imgf000082_0006
. In some cases, R3 is selected from
Figure imgf000082_0007
. some cases, R3 is selected from
Figure imgf000082_0008
, which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, =O, -NO2, C1-C4 alkyl, C3-C6 cycloalkyl, C1-6 aminoalkyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, C2-6 alkynyl, and -N(R5)2. In some cases, R3 is selected from
Figure imgf000082_0009
, which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, =O, hydroxy, C3-C6 cycloalkyl, C1-6 aminoalkyl, C2-6 alkynyl, and -N(R5)2. In some cases, R3 is selected from
Figure imgf000083_0001
. [00222] In some embodiments, for a compound or salt of Formula (II), R3 is selected from an optionally substituted tricyclic heteroaryl. In some cases, the tricyclic heteroaryl has at least one nitrogen atom and one sulfur atom. In some cases, R3 is selected from
Figure imgf000083_0002
, which is optionally substituted with one or more substituents independently selected from halogen, C1- C3 haloalkyl, -CN, -OH, =O, hydroxy, C3-C6 cycloalkyl, C1-6 aminoalkyl, C2-6 alkynyl, and - N(R5)2. In some cases, R3 is selected from
Figure imgf000083_0003
, which is optionally substituted with one or more substitutents selected from halogen, hydroxy, =O, -NO2, C1-C4 alkyl, C3-C6 cycloalkyl, C1-6 aminoalkyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, and C2-6 alkynyl. In some cases, R3 is selected from
Figure imgf000083_0004
, which is optionally substituted with one or more substitutents selected from halogen, C1-C3 haloalkyl, C3- C6 cycloalkyl, and C2-6 alkynyl. In some cases, R3 is selected from
Figure imgf000083_0005
,
Figure imgf000083_0006
Figure imgf000084_0001
[00223] In another aspect, the present disclosure provides a compound of Formula (III):
Figure imgf000084_0002
Formula (III), or a pharmaceutically acceptable salt thereof, wherein: Y is selected from a bond, O and NR5; R2 is selected from hydrogen, -N(R5)2, -L-N(R5)2, -L-OR5, heterocycle, C1-C6 alkyl, -L- heterocycle, -L-aryl, -L-heteroaryl, -L-cycloalkyl, -L-N(R5)2, -L-NHC(=NH)NH2, -L-C(O)N(R5)2, -L-C1-C6 haloalkyl, -L-OR5, -L-NR5C(O)-aryl, -L-COOH, and -LC(=O)OC1-C6 alkyl, wherein the heterocycle, the aryl portion of -L-NR5C(O)-aryl, the heterocycle portion of -L-heterocycle, and the cycloalkyl portion of the -L-cycloalkyl are each optionally substituted with one or more R6, and wherein the aryl of the -L- aryl and heteroaryl of the -L-heteroaryl are each optionally substituted with one or more R7; each L is independently selected from a C1-C4 alkylene optionally substituted with one or more substituents independently selected from -OH, C1-C4 hydroxyalkyl, C1-C4 alkyl, C3-C6 carbocycle, or 3- to 8-membered heterocycle, wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle wherein the C3-C6 carbocycle and the 3- to 8- membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, and C1-6 haloalkyl; R3 is selected from aryl and heteroaryl, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, =O, -NO2, C1-C4 alkyl, C1-6 aminoalkyl, -S-C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 hydroxyalkynyl, C1-C3 cyanoalkyl, triazolyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, -S-C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, -CH2C(=O)N(R5)2, -C3-C4 alkynyl(NR5)2, -N(R5)2, (C1-C3 alkoxy)haloC1-C3 alkyl- , and C3-C6 cycloalkyl, wherein the C3-C6 cycloalkyl is optionally substituted with one or more substituents independently selected from halogen and C1-C3 alkyl; R4 is selected from hydrogen, halogen, C1-C3 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and -O-C1- 6 haloalkyl; each R5 is independently selected from hydrogen and C1-C3 alkyl; each R6 is independently selected from halogen, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, cyano, =CH2, =NO-C1-C3 alkyl, C1-C3 aminoalkyl, - N(R5)S(O)2(R5), -Q-phenyl, -Q-phenylSO2F, -NHC(O)phenyl, -NHC(O)phenylSO2F, C1-C3 alkyl substituted pyrazolyl, tert-butyldimethylsilyloxyCH2- , -N(R5)2, (C1-C3 alkoxy)C1-C3 alkyl-, (C1- C3 alkyl)C(=O), oxo, (C1-C3 haloalkyl)C(=O)-, -SO2F, (C1-C3 alkoxy)C1-C3 alkoxy, - CH2OC(O)N(R5)2, -CH2NHC(O)OC1-C6 alkyl, -CH2NHC(O)N(R5)2, -CH2NHC(O)C1-C6 alkyl, - CH2(pyrazolyl), -CH2NHSO2C1-C6 alkyl, -CH2OC(O)heterocycle, -OC(O)N(R5)2, - OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl), -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl(C1-C3 alkyl)N(CH3)2, -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl, - OC(O)heterocycle, -O-C1-C3 alkyl, and -CH2heterocycle, wherein the phenyl of -NHC(O)phenyl and -OC(O)NH(C1-C3 alkyl)(C1-C3 alkyl)phenyl are each optionally substituted with one or more substituents independently selected from -C(O)H and OH, and wherein the alkyl of -O-C1-C3 alkyl is optionally substituted with substituents independently selected from heterocycle, oxo and hydroxy; and wherein the heterocycle of -CH2heterocyclyl is optionally substituted with oxo; each Q is independently selected from a bond and O; each R7 is independently selected from halogen, -OH, HC(=O)-, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, and -N(R5)2; R9 is selected from unsaturated 5- to 12-membered heterocycle, wherein the unsaturated 5- to 12-membered heterocycle contains at least 1 nitrogen atom and optionally one or more additional heteroatoms selected from oxygen, boron, and sulfur, and wherein the unsaturated 5- to 12-membered heterocycle of R9 is bound to Formula (III) via the at least 1 nitrogen atom, and wherein the unsaturated 5- to 12-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -B(OR20)2, -OR20, -SR20, - N(R20)S(O)2(R20), -S(O)2(R20), -S(O)2N(R20)2, -C(O)N(R20)2, -C(O)NR20-OR20, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)2, -C(O)R20, -C(O)OR20, -OC(O)R20, -NO2, =O, =S, =N(R20), -CN, C1-6 alkyl-O-C(O)C1-6 alkyl, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl; each R20 is independently selected from hydrogen; and C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbocycle, and 3- to 12- membered heterocycle; and R50 is selected from hydrogen, halogen, -OH, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, -CN, C1-C3 cyanoalkyl, C1-C3 aminoalkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 hydroxyalkynyl, and C3-C6 carbocycle. [00224] In some embodiments, for a compound or salt of Formula (III), each L is independently selected from a C1-C4 alkylene optionally substituted; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle, wherein the C3-C6 carbocycle is optionally substituted with one or more substituents selected from halogen, -OH, - NO2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl. In some cases, the optional substituents of L are selected from C1-C4 hydroxyalkyl, C1-C4 alkyl, C3-C6 carbocycle; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle wherein the C3-C6 carbocycle and 3- to 8- membered heterocycle are optionally substituted with one or more substituents selected from halogen and C1-6 haloalkyl. [00225] In some embodiments, for a compound or salt of Formula (III), R2 is selected from -L- heterocycle, wherein the heterocycle portion of -L-heterocycle is optionally substituted with one or more R6. In some cases, the heterocycle portion of -L-heterocycle is a saturated heterocycle. In some cases, the heterocycle portion of -L-heterocycle contains at least one nitrogen atom. In some cases, the heterocycle portion of -L-heterocycle contains at least one oxygen atom. In some cases, the heterocycle portion of -L-heterocycle contains at least one sulfur atom. In some cases, the heterocycle portion of -L-heterocycle contains at least one sulfur atom and one nitrogen atom. In some cases, the heterocycle portion of -L-heterocycle is a bicyclic heterocycle. In some cases, the heterocycle portion of -L-heterocycle is a monocyclic heterocycle. In some cases, the heterocycle
Figure imgf000086_0001
, wherein the heterocycle portion is optionally substituted with one or more R6. In some cases, R6 is selected from halogen, -OH, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, oxo, -CN, and C1-C3 aminoalkyl. In some cases, R6 is selected from halogen and C1-C3 alkyl. In
Figure imgf000087_0001
[00226] In some embodiments, for a compound or salt of Formula (III), R2 is selected from -L- heterocycle, wherein the heterocycle portion of -L-heterocycle is optionally substituted with one or more R6. In some cases, Y-R2 is selected from
Figure imgf000087_0002
, and
Figure imgf000087_0003
, wherein the heterocycle portion is optionally substituted with one or more R6. In some cases, R6 is selected from halogen, -OH, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, -CN, and C1-C3 aminoalkyl. In some cases, R6 is selected from halogen and C1-C3 alkyl. In some cases, Y-R2 is selected from
Figure imgf000087_0004
, ,
Figure imgf000087_0005
. [00227] In some embodiments, for a compound or salt of Formula (III), R2 is selected from -L- saturated heterocycle, wherein the saturated heterocycle portion of the -L-saturated heterocycle is optionally substituted with one or more R6, and contains one nitrogen atom and one sulfur atom. In some cases, Y-R2 is selected from
Figure imgf000087_0006
, wherein the heterocycle portion is optionally substituted with one or more R6. In some cases, Y-R2 is selected from
Figure imgf000087_0007
, wherein the heterocycle portion is optionally substituted with one or more substituents selected from C1-C3 alkyl and oxo. In some cases, Y-R2 is selected from
Figure imgf000088_0001
cases, Y-R2 is selected from
Figure imgf000088_0002
[00228] In some embodiments, for a compound or salt of Formula (III), R2 is selected from -L- heterocycle, wherein the heterocycle portion of -L-heterocycle is optionally substituted with one or more R6. In some cases, each L is independently selected from a substituted C1-C4 alkylene, and wherein two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle, wherein the C3-C6 carbocycle is optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl. [00229] In some embodiments, for a compound or salt of Formula (III), each L is independently selected from a substituted C1-C4 alkylene, and wherein two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle. In some cases, each L is independently selected from a substituted C3 alkylene, and wherein two substituents on the same carbon atom of L come together to form a C3 carbocycle. In some cases, each L is independently selected from
Figure imgf000088_0003
. , . [00230] In some embodiments, for a compound or salt of Formula (III), R9 is selected from an optionally substituted unsaturated 6- to 8-membered heterocycle. In some cases, R9 is selected from an optionally substituted unsaturated 6-membered heterocycle. In some cases, R9 is selected from an optionally substituted unsaturated 7-membered heterocycle. In some cases, R9 is selected from
Figure imgf000088_0004
, wherein each is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH2, -NO2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl, and C1-6 alkyl. In some cases, R9 is selected from
Figure imgf000088_0005
, , , , ,
Figure imgf000089_0001
cases, R9 is selected from
Figure imgf000089_0002
, , wherein each is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH2, -NO2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl, and C1-6 alkyl. In some cases, R9 is selected from
Figure imgf000089_0003
, wherein each is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH2, -NO2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl, and C1-6 alkyl. In some cases, R9 is selected from
Figure imgf000089_0004
, and
Figure imgf000089_0005
, wherein each is optionally substituted with one or more substituents independently selected from halogen, and C1-6 haloalkyl. In some cases, R9 is selected from
Figure imgf000089_0006
,
Figure imgf000089_0007
some cases, R9 is selected from
Figure imgf000089_0008
. [00231] In some embodiments, for a compound or salt of Formula (III), R9 is selected from a non-bridged heterocycle. In some cases, the heterocycle of R9 only has 1 nitrogen atom and no other heteroatoms. [00232] In some embodiments, for a compound or salt of Formula (III), R3 is selected from an optionally substituted 9- to 15-membered heteroaryl and optionally substituted C6-C10 aryl. In some cases, the C6-C10 aryl is optionally substituted with one or more substituents independently selected from halogen, cyano, hydroxy, =O, -NO2, C1-C4 alkyl, C1-6 aminoalkyl, C1-C3 haloalkyl, - O-C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, C2-6 alkynyl, and -N(R5)2; and the 9- to 15- membered heteroaryl is optionally substituted with one or more substituents independently selected from halogen, cyano, hydroxy, =O, -NO2, C1-C4 alkyl, C3-C6 cycloalkyl, C1-6 aminoalkyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, C2-6 alkynyl, and -N(R5)2.
Figure imgf000090_0001
[00233] In some embodiments, for a compound or salt of Formula (III), R3 is selected from an optionally substituted 12- to 13-membered heteroaryl. In some cases, the substituents are selected from halogen, hydroxy, cyano, =O, -NO2, C1-C4 alkyl, C3-C6 cycloalkyl, C1-6 aminoalkyl, C1-C3 haloalkyl, C1-C3 hydroxyalkyl, C2-C4 alkynyl, and -N(R20)2. In some cases, the substituents are selected from halogen, hydroxy, =O, -NO2, C1-C4 alkyl, C3-C6 cycloalkyl, C1-6 aminoalkyl, C1-C3 haloalkyl, C2-C4 alkynyl, and -NH2. In some cases, R3 is selected from
Figure imgf000091_0001
, each of which are optionally substituted with one or more substituents independently selected from halogen, hydroxy, =O, -NO2, C1-C4 alkyl, C3-C6 cycloalkyl, C1-6 aminoalkyl, C1-C3 haloalkyl, C1-C3 hydroxyalkyl, C2-6 alkynyl, and -N(R20)2. In some cases, R3 is selected from
Figure imgf000091_0002
with one or more substituents independently selected from cyano, hydroxy, =O, C3-C6 cycloalkyl, C2-6 alkynyl, and -NH2. In some cases, R3 is selected from
Figure imgf000091_0003
,
Figure imgf000091_0004
[00234] In some embodiments, for a compound or salt of Formula (III), R3 is selected from an optionally substituted tricyclic heteroaryl. In some cases, the tricyclic heteroaryl has at least one nitrogen atom and one sulfur atom. In some cases, R3 is selected from
Figure imgf000091_0005
, which is optionally substituted with one or more substituents independently selected from halogen, C1-C3 haloalkyl, -CN, -OH, =O, hydroxy, C3-C6 cycloalkyl, C1-6 aminoalkyl, C2-6 alkynyl, and -N(R5)2. In some cases, R3 is selected from
Figure imgf000092_0001
, which is optionally substituted with one or more substitutents selected from halogen, hydroxy, =O, -NO2, C1-C4 alkyl, C3-C6 cycloalkyl, C1-6 aminoalkyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, and C2-6 alkynyl. In some cases, R3 is selected from
Figure imgf000092_0002
, which is optionally substituted with one or more substitutents selected from halogen, C1-C3 haloalkyl, C3-C6 cycloalkyl, and C2-6
Figure imgf000092_0003
[00235] In some embodiments, for a compound or salt of Formula (III), R3 is naphthalene, wherein the naphthalene is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH2, -NO2, =O, C1-6 alkyl, C1-6 aminoalkyl, C1-6 hydroxyalkyl, C2- C4 alkynyl, and C1-6 haloalkyl. In some cases, R3 is naphthalene, wherein the naphthalene is optionally substituted with one or more substituents independently selected from halogen, -OH, C2-C4 alkynyl, and C1-3 alkyl. In some cases, R3 is
Figure imgf000093_0001
,
Figure imgf000093_0002
In some cases, R3 is naphthalene, and the naphthalene is substituted with one or more substituents independently selected from fluorine, C2-C4 alkynyl, and hydroxy. In some cases,
Figure imgf000093_0003
Figure imgf000093_0004
. [00236] In some embodiments, for a compound or salt of Formula (III), R3 is selected from a phenyl, which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, =O, -NO2, C1-C4 alkyl, C1-6 aminoalkyl, -S-C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 hydroxyalkynyl, C1-C3 cyanoalkyl, triazolyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, -S-C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, -CH2C(=O)N(R5)2, -C3-C4 alkynyl(NR5)2, -N(R5)2, (C1-C3 alkoxy)haloC1-C3 alkyl-, and C3-C6 cycloalkyl, wherein the C3-C6 cycloalkyl is optionally substituted with one or more substituents selected from halogen and C1- C3 alkyl. In some cases, R3 is selected from a phenyl, which is optionally substituted with one or more substituents independently selected from halogen, C1-C3 haloalkyl, and -N(R5)2. In some cases,
Figure imgf000093_0005
. [00237] In some embodiments, for a compound or salt of Formula (III), R50 is selected from hydrogen and halogen. In some cases, R50 is selected from halogen. [00238] In some embodiments, for a compound or salt of Formula (III), R4 is selected from hydrogen and halogen. In some cases, R4 is halogen. [00239] In an aspect, the present disclosure provides a compound of Formula (IV):
Figure imgf000094_0001
Formula (IV), or a pharmaceutically acceptable salt thereof, wherein: Y is selected from a bond, O and NR5; R2 is selected from hydrogen, -N(R5)2, -L-N(R5)2, -L-OR5, heterocycle, C1-C6 alkyl, -L- heterocycle, -L-aryl, -L-heteroaryl, -L-cycloalkyl, -L-N(R5)2, -L-NHC(=NH)NH2, -L-C(O)N(R5)2, -L-C1-C6 haloalkyl, -L-OR5, -L-NR5C(O)-aryl, -L-COOH, or -LC(=O)OC1-C6 alkyl, wherein the heterocycle, the aryl portion of -L-NR5C(O)-aryl, the heterocycle portion of -L-heterocycle, and the cycloalkyl portion of the -L-cycloalkyl are each optionally substituted with one or more R6, and wherein the aryl of the -L-aryl and heteroaryl of the -L-heteroaryl are each optionally substituted with one or more R7; each L is independently selected from a C1-C4 alkylene optionally substituted with one or more substituents independently selected from -OH, C1-C4 hydroxyalkyl, C1-C4 alkyl, C3-C6 carbocycle, and 3- to 8-membered heterocycle, wherein the C3-C6 carbocycle and 3- to 8- membered heterocycle are optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle wherein the C3-C6 carbocycle and 3- to 8- membered heterocycle are optionally substituted with one or more substituents independently selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl; R3 is selected from tricyclic aryl and tricyclic heteroaryl, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, =O, - NO2, C1-C4 alkyl, C1-6 aminoalkyl, -S-C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 hydroxyalkynyl, C1-C3 cyanoalkyl, triazolyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, -S-C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, -CH2C(=O)N(R5)2, -C3-C4 alkynyl(NR5)2, -N(R5)2, (C1-C3 alkoxy)haloC1-C3 alkyl-, and C3-C6 cycloalkyl, wherein the C3-C6 cycloalkyl is optionally substituted with one or more substituents selected from halogen and C1-C3 alkyl; R4 is selected from hydrogen, halogen, C1-C3 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and -O-C1- 6 haloalkyl; each R5 is independently selected from hydrogen and C1-C3 alkyl; each R6 is independently selected from halogen, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkyl, oxo, C1-C3 haloalkyl, C1-C3 alkoxy, cyano, =NO-C1-C3 alkyl, C1-C3 aminoalkyl, -N(R5)S(O)2(R5), -Q-phenyl, -Q-phenylSO2F, -NHC(O)phenyl, - NHC(O)phenylSO2F, C1-C3 alkyl substituted pyrazolyl, tert-butyldimethylsilyloxyCH2- , -N(R5)2, (C1-C3 alkoxy)C1-C3 alkyl-, (C1-C3 alkyl)C(=O), (C1-C3 haloalkyl)C(=O)-, -SO2F, (C1-C3 alkoxy)C1-C3 alkoxy, -CH2OC(O)N(R5)2, - CH2NHC(O)OC1-C6 alkyl, -CH2NHC(O)N(R5)2, -CH2NHC(O)C1-C6 alkyl, -CH2(pyrazolyl), - CH2NHSO2C1-C6 alkyl, -CH2OC(O)heterocycle, -OC(O)N(R5)2, -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl), -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl(C1-C3 alkyl)N(CH3)2, -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl, - OC(O)heterocycle, -O-C1-C3 alkyl, and -CH2heterocycle, wherein the phenyl of -NHC(O)phenyl and -OC(O)NH(C1-C3 alkyl)(C1-C3 alkyl)phenyl are optionally substituted with one or more substituents selected from -C(O)H and OH, and wherein the alkyl of -O-C1-C3 alkyl is optionally substituted with substituents selected from heterocycle, oxo and hydroxy; and wherein the heterocycle of -CH2heterocyclyl is optionally substituted with oxo; each Q is independently selected from a bond and O; each R7 is independently selected from halogen, -OH, HC(=O)-, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, and -N(R5)2; R9 is selected from 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -B(OR20)2, -OR20, -SR20, -S(O)2(R20), -S(O)2N(R20)2, -N(R20)S(O)2(R20), -C(O)N(R20)2, -C(O)NR20-OR20, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)2, -S(O)2R20, - C(O)R20, -C(O)OR20, -OC(O)R20, -NO2, =O, =S, =N(R20), -CN, C1-6 alkyl-O-C(O)C1-6 alkyl, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl; each R20 is independently selected from hydrogen; and C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbocycle, and 3- to 12- membered heterocycle; and R50 is selected from hydrogen, halogen, -OH, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, -CN, C1-C3 cyanoalkyl, C1-C3 aminoalkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 hydroxyalkynyl, and C3-C6 carbocycle. [00240] In some embodiments, for a compound or salt of Formula (IV), Y is O. in some cases, Y is a bond. In some cases, Y is NR5. [00241] In some embodiments, for a compound or salt of Formula (IV), each L is independently selected from a C1-C4 alkylene optionally substituted; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle, wherein the C3-C6 carbocycle is optionally substituted with one or more substituents selected from halogen, -OH, - NO2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl. In some cases, the optional substituents of L are selected from C1-C4 hydroxyalkyl, C1-C4 alkyl, C3-C6 carbocycle; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle wherein the C3-C6 carbocycle and 3- to 8- membered heterocycle are optionally substituted with one or more substituents selected from halogen and C1-6 haloalkyl. In some cases, each L is independently selected from a C1-C4 alkylene. [00242] In some embodiments, for a compound or salt of Formula (IV), R2 is selected from -L- heterocycle, wherein the heterocycle portion of -L-heterocycle is optionally substituted with one or more R6. In some cases, the heterocycle portion of -L-heterocycle is a saturated heterocycle. In some cases, the heterocycle portion of -L-heterocycle contains at least one nitrogen atom. In some cases, the heterocycle portion of -L-heterocycle contains at least one oxygen atom. In some cases, the heterocycle portion of -L-heterocycle contains at least one sulfur atom. In some cases, the heterocycle portion of -L-heterocycle contains at least one sulfur atom and one nitrogen atom. In some cases, the heterocycle portion of -L-heterocycle is a bicyclic heterocycle. In some cases, the heterocycle portion of -L-heterocycle is a monocyclic heterocycle. In some cases, the heterocycle
Figure imgf000096_0001
, wherein the heterocycle portion is optionally substituted with one or more R6. In some cases, R6 is selected from halogen, -OH, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, oxo, -CN, and C1-C3 aminoalkyl. In some cases, R6 is selected from halogen and C1-C3 alkyl. In
Figure imgf000096_0002
[00243] In some embodiments, for a compound or salt of Formula (IV), Y-R2 is selected from - O-L-heterocycle, wherein the heterocycle portion of -O-L-heterocycle is optionally substituted with one or more R6. In some cases, Y-R2 is selected from
Figure imgf000097_0001
, and
Figure imgf000097_0002
, wherein the heterocycle portion is optionally substituted with one or more R6. In some cases, R6 is selected from halogen, -OH, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, -CN, and C1-C3 aminoalkyl. In some cases, R6 is selected from halogen and C1-C3 alkyl. In some cases, Y-R2 is selected from
Figure imgf000097_0003
, ,
Figure imgf000097_0004
. [00244] In some embodiments, for a compound or salt of Formula (IV), R2 is selected from -L- saturated heterocycle, wherein the saturated heterocycle portion of the -L-saturated heterocycle is optionally substituted with one or more R6, and contains one nitrogen atom and one sulfur atom. In some cases, Y-R2 is selected from
Figure imgf000097_0005
the heterocycle portion is optionally substituted with one or more R6. In some cases, Y-R2 is selected from
Figure imgf000097_0006
, wherein the heterocycle portion is optionally substituted with one or more substituents selected from C1-C3 alkyl and oxo. In some cases, Y-R2 is selected from
Figure imgf000097_0007
cases, Y-R2 is selected from
Figure imgf000097_0008
[00245] In some embodiments, for a compound or salt of Formula (IV), R2 is selected from -L- heterocycle, wherein the heterocycle portion of -L-heterocycle is optionally substituted with one or more R6. In some cases, each L is independently selected from a substituted C1-C4 alkylene, and wherein two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle, wherein the C3-C6 carbocycle is optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl. In some cases, each L is independently selected from a substituted C1-C4 alkylene, and wherein two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle. In some cases, each L is independently selected from a substituted C3 alkylene, and wherein two substituents on the same carbon atom of L come together to form a C3 carbocycle. In some cases, each L is independently selected from
Figure imgf000098_0002
. In some cases, Y-R2 is
Figure imgf000098_0001
. [00246] In some embodiments, for a compound or salt of Formula (IV), R9 is selected from 6- to 7-membered heterocycle. In some cases, the 6- to 7-membered heterocycle contains only 1 nitrogen atom, and the 6- to 7-membered heterocycle is optionally substituted. In some cases, the 6- to 7-membered heterocycle of R9 is bound to Formula (IV) via the only 1 nitrogen atom. In some cases, R9 is selected from an optionally substituted saturated 6-membered heterocycle. In some cases, R9 is selected from an optionally substituted unsaturated 6-membered heterocycle. In some cases, R9 is selected from an optionally substituted saturated 7-membered heterocycle. In some cases, R9 is selected from an optionally substituted unsaturated 7-membered heterocycle. In some cases, the heterocycle of R9 is monocyclic. In some cases, R9 is selected from , ,
Figure imgf000098_0003
, any of which is optionally substituted. In some cases, R9 is selected from
Figure imgf000098_0004
, any of which is optionally substituted. In some cases, the one or more optional substituents of R9 are each independently selected from halogen, -OR20, -N(R20)2, =O, -CN, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 alkyl, and C2-6 alkynyl. [00247] In some embodiments, for a compound or salt of Formula (IV), R9 is selected from 6- to 7-membered heterocycle, wherein the 6- to 7-membered heterocycle contains only 1 nitrogen atom and optionally one or more additional heteroatoms selected from oxygen, and sulfur, wherein the 6- to 7-membered heterocycle. In some cases, the optionally one or more additional heteroatoms are selected from sulfur. In some cases, the 6- to 7-membered heterocycle contains only 1 nitrogen atom and no further additional heteroatoms. In some cases, the 6- to 7-membered heterocycle is an unsaturated 6- to 7-membered heterocycle. In some cases, the 6- to 7-membered heterocycle is an saturated 6- to 7-membered heterocycle. In some cases, R9 is selected from
Figure imgf000099_0001
each of which is optionally substituted. In some cases, the one or more optional substituents of R9 are each independently selected from halogen, -OR20, -C(O)N(R20)2, , -N(R20)2, -C(O)R20, -C(O)OR20, -OC(O)R20, -NO2, =O, =S, =N(R20), -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1- 6 alkyl, C2-6 alkenyl, and C2-6 alkynyl. In some cases, the one or more optional substituents of R9 are each independently selected from halogen, -OH, -CN, C1-6 cyanoalkyl, C1-6 alkyl, and C2-6 alkynyl. [00248] In some embodiments, for a compound or salt of Formula (IV), R9 is selected from an optionally substituted unsaturated 6- to 8-membered heterocycle. In some cases, R9 is selected from an optionally substituted unsaturated 6-membered heterocycle. [00249] In some embodiments, for a compound or salt of Formula (IV), R9 is selected from an optionally substituted unsaturated 7-membered heterocycle. In some cases, R9 is selected from
Figure imgf000099_0002
wherein each is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH2, -NO2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl, and C1-6 alkyl. In some cases, R9 is selected from
Figure imgf000099_0003
more substituents independently selected from halogen, -OH, -NH2, -NO2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl, and C1-6 alkyl. In some cases, R9 is selected from
Figure imgf000100_0001
wherein each is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH2, -NO2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl, and C1-6 alkyl. In some cases, R9 is selected from
Figure imgf000100_0002
, and
Figure imgf000100_0003
, wherein each is optionally substituted with one or more substituents independently selected from halogen, and C1-6 haloalkyl. In some cases, R9 is selected from
Figure imgf000100_0004
, R9 is selected from
Figure imgf000100_0005
. [00250] In some embodiments, for a compound or salt of Formula (IV), R9 is selected from an optionally substituted 6- to 10-membered heterocycle. In some cases, R9 is selected from
Figure imgf000100_0006
,
Figure imgf000100_0007
one or more substituents independently selected from halogen, =O, -OH, and -CN; and further optionally substituted with one or more substituents independently selected from -C(O)N(R20)2, C1-6 aminoalkyl, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, and C1-6 alkyl. In some cases, R9 is selected
Figure imgf000100_0008
[00251] In some embodiments, for a compound or salt of Formula (IV), R9 is selected from an
Figure imgf000101_0001
optionally substituted 6- to 10-membered heterocycle. In some cases, R9 is selected from ,
Figure imgf000101_0002
optionally substituted with one or more substituents independently selected from halogen, =O, - OH, -CN, -C(O)N(R20)2, C1-6 aminoalkyl, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, and C1-6 alkyl. In
Figure imgf000101_0003
. [00252] In some embodiments, for a compound or salt of Formula (IV), R9 is selected from 6- to 7-membered heterocycle. In some cases, R9 is selected from 7-membered heterocycle. In some cases, R9 is selected from 6-membered heterocycle. In some cases, the 6- to 7-membered heterocycle contains only 1 nitrogen atom and optionally one or more additional heteroatoms selected from oxygen, and sulfur. In some cases, the optionally one or more additional heteroatoms are selected from sulfur. In some cases, the 6- to 7-membered heterocycle contains only 1 nitrogen atom and no further additional heteroatoms. In some cases, the 6- to 7-membered heterocycle is a non-aromatic 6- to 7-membered heterocycle. In some cases, the 6- to 7- membered heterocycle of R9 is bound to Formula (IV) via the only 1 nitrogen atom. In some
Figure imgf000101_0004
Figure imgf000101_0005
Figure imgf000101_0006
, and , each of which is substituted. In some cases, R9 is selected from ,
Figure imgf000102_0001
each of which is substituted. In some cases, the substituents of R9 are each selected from one or more halogen, -OR20, -SR20, -N(R20)2, -NHCN, -NO2, =O, -CN, C1-6 fluoroalkyl, -C(O)N(R20)2, C1-6 aminoalkyl, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 alkyl, C2-6 alkynyl, and C2-6 alkenyl. In some cases, the substituents of R9 are each selected from one or more halogen, -OR20, -N(R20)2, -NHCN, =O, -CN, C1-6 alkyl, C2-6 alkynyl, C1-6 aminoalkyl, C1-6 hydroxyalkyl, and C1-6 cyanoalkyl. In some cases, the substituents of R9 are each selected from one or more halogen, -OH, -NHCN, =O, -CN, C1-6 alkyl and C2-6 alkynyl. In some cases, R9 is selected from
Figure imgf000102_0002
,
Figure imgf000102_0003
[00253] In some embodiments, for a compound or salt of Formula (IV), R9 is selected from an optionally substituted 6- to 10-membered bridged heterocycle. In some cases, R9 is selected from an optionally substituted 7- to 8-membered bridged heterocycle. In some cases, R9 is selected from an optionally substituted 8-membered bridged heterocycle. In some cases, the bridged heterocycle has at least one nitrogen atom. In some cases, the bridged heterocycle has at least two nitrogen atoms. In some cases, the bridged heterocycle has at only two nitrogen atoms and no further heteroatoms. In some cases, R9 is selected from
Figure imgf000102_0004
, which is optionally substituted with one or more substituents independently selected from halogen, =O, -OH, -CN, -C(O)N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl, C1-6 cyanoalkyl, and C1-6 alkyl. In some cases,
Figure imgf000102_0005
. [00254] In some embodiments, for a compound or salt of Formula (IV), the heterocycle of R9 is substituted with one or more substituents independently selected from halogen, -B(OR20)2, - OR20, -SR20, -N(R20)S(O)2(R20), -S(O)2R20, -C(O)N(R20)2, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)2, -C(O)R20, -C(O)OR20, -OC(O)R20, -NO2, =O, =S, =N(R20), -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl. In some cases, the heterocycle of R9 is substituted with one or more substituents independently selected from halogen, -OR20, -SR20, -NO2, =O, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl. In some cases, the heterocycle of R9 is substituted with one or more substituents independently selected from halogen, -OH, -NO2, =O, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, and C2-6 alkynyl. [00255] In some embodiments, for a compound or salt of Formula (IV), R20 is independently selected from hydrogen; and C1-6 alkyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle. In some cases, R20 is independently selected from hydrogen; and C1-6 alkyl, C3-12 carbocycle, and 3- to 12-membered heterocycle. In some cases, R20 is independently selected from hydrogen; and C1-6 alkyl. [00256] In some embodiments, for a compound or salt of Formula (IV), R3 is selected from an optionally substituted 9- to 15-membered heteroaryl and optionally substituted C6-C10 aryl. In some cases, the C6-C10 aryl is optionally substituted with one or more substituents independently selected from halogen, cyano, hydroxy, =O, -NO2, C1-C4 alkyl, C1-6 aminoalkyl, C1-C3 haloalkyl, - O-C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, C2-6 alkynyl, and -N(R5)2; and the 9- to 15- membered heteroaryl is optionally substituted with one or more substituents independently selected from halogen, cyano, hydroxy, =O, -NO2, C1-C4 alkyl, C3-C6 cycloalkyl, C1-6 aminoalkyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, C2-6 alkynyl, and -N(R5)2.
Figure imgf000103_0001
,
Figure imgf000104_0001
[00257] In some embodiments, for a compound or salt of Formula (IV), R3 is selected from an optionally substituted 12- to 13-membered heteroaryl. In some cases, the substituents are selected from halogen, hydroxy, cyano, =O, -NO2, C1-C4 alkyl, C3-C6 cycloalkyl, C1-6 aminoalkyl, C1-C3 haloalkyl, C1-C3 hydroxyalkyl, C2-C4 alkynyl, and -N(R20)2. In some cases, the substituents are selected from halogen, hydroxy, =O, -NO2, C1-C4 alkyl, C3-C6 cycloalkyl, C1-6 aminoalkyl, C1-C3 haloalkyl, C2-C4 alkynyl, and -NH2. [00258] In some embodiments, for a compound or salt of Formula (IV), R3 is selected from
Figure imgf000104_0002
of which are optionally substituted with one or more substituents independently selected from halogen, hydroxy, =O, -NO2, C1-C4 alkyl, C3-C6 cycloalkyl, C1-6 aminoalkyl, C1-C3 haloalkyl, C1- C3 hydroxyalkyl, C2-6 alkynyl, and -N(R20)2. In some cases, R3 is selected from
Figure imgf000104_0003
,
Figure imgf000104_0004
, each of which are optionally substituted with one or more substituents independently selected from cyano, hydroxy, =O, C3-C6 cycloalkyl, C2-6 alkynyl, and
Figure imgf000105_0001
[00259] In some embodiments, for a compound or salt of Formula (IV), R3 is selected from an optionally substituted tricyclic heteroaryl. In some cases, the tricyclic heteroaryl has at least one nitrogen atom and one sulfur atom. In some cases, R3 is selected from , which is optionally substituted with one or more substituents independently selected from halogen, C1-C3 haloalkyl, -CN, -OH, =O, hydroxy, C3-C6 cycloalkyl, C1-6 aminoalkyl, C2-6 alkynyl, and -N(R5)2. In some cases, R3 is selected from , which is optionally substituted with one or more substitutents selected from halogen, hydroxy, =O, -NO2, C1-C4 alkyl, C3-C6 cycloalkyl, C1-6 aminoalkyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, and C2-6 alkynyl. In some cases, R3 is selected from
Figure imgf000105_0002
, which is optionally substituted with one or more substitutents selected from halogen, C1-C3 haloalkyl, C3-C6 cycloalkyl, and C2-6
Figure imgf000105_0003
Figure imgf000106_0004
[00260] In some embodiments, for a compound or salt of Formula (IV), R3 is naphthalene, wherein the naphthalene is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH2, -NO2, =O, C1-6 alkyl, C1-6 aminoalkyl, C1-6 hydroxyalkyl, C2- C4 alkynyl, and C1-6 haloalkyl. In some cases, R3 is naphthalene, wherein the naphthalene is optionally substituted with one or more substituents independently selected from halogen, -OH, C2-C4 alkynyl, and C1-3 alkyl. In some cases, R3 is
Figure imgf000106_0001
, ,
Figure imgf000106_0002
In some cases, R3 is naphthalene, and the naphthalene is substituted with one or more substituents independently selected from fluorine, C2-C4 alkynyl, and hydroxy. In some cases, R3 is selected from
Figure imgf000106_0003
. [00261] In some embodiments, for a compound or salt of Formula (IV), R4 is selected from hydrogen, halogen, C1-C3 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and -O-C1-6 haloalkyl. In some cases, R4 is selected from hydrogen, halogen, C1-C3 alkyl, C1-6 haloalkyl, and C1-6 alkoxy.. In some cases, R4 is selected from hydrogen and halogen. In some cases, R4 is selected from hydrogen. In some cases, R4 is halogen. [00262] In some embodiments, for a compound or salt of Formula (IV), each R5 is independently selected from hydrogen. In some cases, each R5 is independently selected from hydrogen. [00263] In some embodiments, for a compound or salt of Formula (IV), R50 is selected from hydrogen and halogen. In some cases, R50 is selected from halogen. [00264] In some embodiments, a compound or salt of Formula (IV), R9 is selected from an optionally substituted 10-membered heterocycle, wherein the optional one or more substituents are independently selected from halogen, =O, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 cyanoalkyl, C1-6 haloalkyl, and C1-6 alkyl; R4 is halogen; R3 is an optionally substituted tricyclic aryl and optionally substituted tricyclic heteroaryl; R50 is hydrogen; Y is O; R2 is -L-heterocycle, wherein the heterocycle portion is optionally substituted with one or more substituents independently selected from halogen, oxo, and C1-C3 alkyl; and L is independently selected from an optionally substituted C1-C4 alkylene. In some cases, L is C1-C4 alkylene. In some cases, the heterocycle of - L-heterocycle is a bicyclic heterocycle. In some cases, the 10-membered heterocycle is a spiroheterocycle. In some cases, the 10-membered heterocycle, is a saturated 10-membered heterocycle. In some cases, the 10-membered heterocycle, is a non-aromatic 10-membered H heterocycle. In some cases, the 10-membered heterocycle is selected from
Figure imgf000107_0001
and
Figure imgf000107_0002
, each of which is substituted. In some cases, the one or more substituents of R9 are independently selected from one or more halogen, -NHCN, =O, -CN, and C1-6 alkoxy. In some cases, the one or more substituents of R9 are independently selected from =O. In some cases, R2 is selected from
Figure imgf000107_0004
. some cases, R2 is selected
Figure imgf000107_0003
. In some cases, R9 is selected from
Figure imgf000107_0005
. In some cases, R9 is
Figure imgf000108_0001
. , . some cases, the 10-membered heterocycle of R9 contains at least 3 nitrogen atoms. In some cases, the 10-membered heterocycle of R9 contains 3 nitrogen atoms and no other heteroatoms. In some cases, R4 is fluorine. In some R4 is hydrogen. [00265] In an aspect, the present disclosure provides a compound of Formula (VI):
Figure imgf000108_0002
Formula (V), or a pharmaceutically acceptable salt thereof, wherein: Y is O; R2 is selected from -L-heterocycle, wherein the heterocycle portion of -L-heterocycle is optionally substituted with one or more R6; each L is independently selected from a C1-C4 alkylene optionally substituted with one or more substituents independently selected from -OH, C1-C4 hydroxyalkyl, C1-C4 alkyl, C3-C6 carbocycle, and 3- to 8-membered heterocycle, wherein the C3-C6 carbocycle and 3- to 8- membered heterocycle are optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle wherein the C3-C6 carbocycle and the 3- to 8- membered heterocycle are optionally substituted with one or more substituents independently selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl; R3 is selected from aryl and heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, =O, -NO2, C1-C4 alkyl, C1-6 aminoalkyl, -S-C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 hydroxyalkynyl, C1-C3 cyanoalkyl, triazolyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, -S-C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, -CH2C(=O)N(R5)2, -C3-C4 alkynyl(NR5)2, -N(R5)2, (C1-C3 alkoxy)haloC1-C3 alkyl- , and C3-C6 cycloalkyl, wherein the C3-C6 cycloalkyl is optionally substituted with one or more substituents selected from halogen and C1-C3 alkyl; R4 is selected from hydrogen, halogen, C1-C3 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and -O-C1- 6 haloalkyl; each R5 is independently selected from hydrogen and C1-C3 alkyl; each R6 is independently selected from halogen, -OH, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1- C3 haloalkyl, C1-C3 alkoxy, -CN, =CH2, C1-C3 aminoalkyl, -Q-phenyl, -Q-phenylSO2F, - NHC(O)phenyl, - NHC(O)phenylSO2F, C1-C3 alkyl substituted pyrazolyl, -N(R5)2, (C1-C3 alkoxy)C1-C3 alkyl-, (C1-C3 alkyl)C(=O), oxo, (C1-C3 haloalkyl)C(=O)-, -SO2F, (C1-C3 alkoxy)C1- C3 alkoxy, -CH2OC(O)N(R5)2, -CH2NHC(O)OC1-C6 alkyl, -CH2NHC(O)N(R5)2, - CH2NHC(O)C1-C6 alkyl, -CH2(pyrazolyl), -CH2NHSO2C1-C6 alkyl, -CH2OC(O)heterocycle, - OC(O)N(R5)2, -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl), -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl(C1-C3 alkyl)N(CH3)2, -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl, - OC(O)heterocycle, and -CH2heterocycle, wherein the phenyl of -NHC(O)phenyl and - OC(O)NH(C1-C3 alkyl)(C1-C3 alkyl)phenyl are each optionally substituted with -C(O)H and OH, and wherein the heterocycle of -CH2heterocyclyl is optionally substituted with oxo; each Q is independently selected from a bond and O; each R20 is independently selected from hydrogen; and C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbocycle, and 3- to 12- membered heterocycle; R50 is selected from hydrogen, halogen, -OH, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, -CN, C1-C3 cyanoalkyl, C1-C3 aminoalkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 hydroxyalkynyl, and C3-C6 carbocycle. [00266] In an aspect, the present disclosure provides a compound of Formula (V):
Figure imgf000109_0001
Formula (V), or a pharmaceutically acceptable salt thereof, wherein: Y is O; R2 is selected from -L-heterocycle, wherein the heterocycle portion of -L-heterocycle, is optionally substituted with one or more R6; each L is independently selected from a C1-C4 alkylene optionally substituted with one or more substituents independently selected from -OH, C1-C4 hydroxyalkyl, C1-C4 alkyl, C3-C6 carbocycle, or 3- to 8-membered heterocycle, wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle wherein the C3-C6 carbocycle and the 3- to 8- membered heterocycle are optionally substituted with one or more substituents independently selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl; R3 is selected from aryl and heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, =O, -NO2, C1-C4 alkyl, C1-6 aminoalkyl, -S-C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 hydroxyalkynyl, C1-C3 cyanoalkyl, triazolyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, -S-C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, -CH2C(=O)N(R5)2, -C3-C4 alkynyl(NR5)2, -N(R5)2, (C1-C3 alkoxy)haloC1-C3 alkyl- , and C3-C6 cycloalkyl, wherein the C3-C6 cycloalkyl is optionally substituted with one or more substituents selected from halogen and C1-C3 alkyl; and wherein when R3 is benzothiazole or pyridine, the benzothiazole or pyridine is optionally substituted with one or more R49; R4 is selected from hydrogen, halogen, C1-C3 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and -O-C1- 6 haloalkyl; each R5 is independently selected from hydrogen and C1-C3 alkyl; each R6 is independently selected from halogen, -OH, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1- C3 haloalkyl, C1-C3 alkoxy, -CN, =CH2, C1-C3 aminoalkyl, -Q-phenyl, -Q-phenylSO2F, - NHC(O)phenyl, - NHC(O)phenylSO2F, C1-C3 alkyl substituted pyrazolyl, -N(R5)2, (C1-C3 alkoxy)C1-C3 alkyl-, (C1-C3 alkyl)C(=O), oxo, (C1-C3 haloalkyl)C(=O)-, -SO2F, (C1-C3 alkoxy)C1- C3 alkoxy, -CH2OC(O)N(R5)2, -CH2NHC(O)OC1-C6 alkyl, -CH2NHC(O)N(R5)2, - CH2NHC(O)C1-C6 alkyl, -CH2(pyrazolyl), -CH2NHSO2C1-C6 alkyl, -CH2OC(O)heterocycle, - OC(O)N(R5)2, -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl), -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl(C1-C3 alkyl)N(CH3)2, -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl, - OC(O)heterocycle, and -CH2heterocycle, wherein the phenyl of -NHC(O)phenyl and - OC(O)NH(C1-C3 alkyl)(C1-C3 alkyl)phenyl are each optionally substituted with -C(O)H and OH, and wherein the heterocycle of -CH2heterocyclyl is optionally substituted with oxo; each Q is independently selected from a bond and O; R9 is selected from a 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle is substituted with one or more substituents independently selected from -OH, - NHCN, -CN, C1-6 alkoxy; and further optionally substituted with one or more substituents independently selected from halogen, -C(O)N(R20)2, -C(O)NR20-OR20, C1-6 haloalkyl, -SR20, =O, =S, =N(R20), -B(OR20)2, -N(R20)2, -NO2, C1-6 aminoalkyl, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 alkyl, C1-6 alkyl-O-C(O)C1-6 alkyl, C2-6 alkynyl and C2-6 alkenyl; wherein when R9 is substituted with at least one -OH or C1-6 alkoxy, the 5- to 12-membered heterocycle is an non-bridged heterocycle; each R20 is independently selected from hydrogen; and C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbocycle, and 3- to 12- membered heterocycle; each R49 is independently selected from halogen, -CN, -OH, =O, -NO2, C1-C4 alkyl, C1-6 aminoalkyl, -S-C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 hydroxyalkynyl, C1-C3 cyanoalkyl, triazolyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, -S-C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, -CH2C(=O)N(R5)2, -C3-C4 alkynyl(NR5)2, (C1-C3 alkoxy)haloC1-C3 alkyl-, and C3- C6 cycloalkyl, wherein the C3-C6 cycloalkyl is optionally substituted with one or more substituents independently selected from halogen and C1-C3 alkyl; each R49 is independently selected from halogen, -CN, -OH, =O, -NO2, C1-C4 alkyl, C1-6 aminoalkyl, -S-C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 hydroxyalkynyl, C1-C3 cyanoalkyl, triazolyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, -S-C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, -CH2C(=O)N(R5)2, -C3-C4 alkynyl(NR5)2, (C1-C3 alkoxy)haloC1-C3 alkyl-, and C3- C6 cycloalkyl, wherein the C3-C6 cycloalkyl is optionally substituted with one or more substituents independently selected from halogen and C1-C3 alkyl; R50 is selected from hydrogen, halogen, -OH, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, -CN, C1-C3 cyanoalkyl, C1-C3 aminoalkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 hydroxyalkynyl, and C3-C6 carbocycle. [00267] In some embodiments, for a compound or salt of Formula (V), R4 is selected from hydrogen and halogen. In some cases, R4 is selected from halogen. In some cases, R4 is hydrogen. [00268] In some embodiments, for a compound or salt of Formula (V), R3 is selected from aryl and heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, C1-C4 alkyl, and C2-C4 alkynyl. [00269] In some embodiments, for a compound or salt of Formula (V), R50 is selected from hydrogen, halogen, C1-C3 cyanoalkyl, and C2-C4 alkenyl. In some cases, R50 is hydrogen. [00270] In some embodiments, for a compound or salt of Formula (V), L is selected from C1-C4 alkylene. In some cases, L is selected from unsubstituted C1-C4 alkylene. In some cass, each L is independently selected from a C1-C4 alkylene optionally substituted; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle, wherein the C3-C6 carbocycle is optionally substituted with one or more substituents selected from halogen, - OH, -NO2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl. [00271] In some embodiments, for a compound or salt of Formula (V), Y-R2 is selected from
Figure imgf000112_0001
R6. In some cases, R6 is selected from halogen, -OH, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, -CN, and C1-C3 aminoalkyl. In some cases, Y-R2 is selected from ,
Figure imgf000112_0002
[00272] In an aspect, the present disclosure provides a compound of Formula (VI):
Figure imgf000112_0003
Formula (VI), or a pharmaceutically acceptable salt thereof, wherein: Y is O; R2 is selected from -L-heterocycle, wherein the heterocycle portion of -L-heterocycle, is optionally substituted with one or more R6; each L is independently selected from a C1-C4 alkylene optionally substituted with one or more substituents independently selected from -OH, C1-C4 hydroxyalkyl, C1-C4 alkyl, C3-C6 carbocycle, or 3- to 8-membered heterocycle, wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle wherein the C3-C6 carbocycle and the 3- to 8- membered heterocycle are optionally substituted with one or more substituents independently selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl; R3 is selected from aryl and heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, =O, -NO2, C1-C4 alkyl, C1-6 aminoalkyl, -S-C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 hydroxyalkynyl, C1-C3 cyanoalkyl, triazolyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, -S-C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, -CH2C(=O)N(R5)2, -C3-C4 alkynyl(NR5)2, -N(R5)2, (C1-C3 alkoxy)haloC1-C3 alkyl- , and C3-C6 cycloalkyl, wherein the C3-C6 cycloalkyl is optionally substituted with one or more substituents selected from halogen and C1-C3 alkyl; and wherein when R3 is benzothiazole or pyridine, the benzothiazole or pyridine is optionally substituted with one or more R49; R4 is selected from hydrogen, halogen, C1-C3 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and -O-C1- 6 haloalkyl; each R5 is independently selected from hydrogen and C1-C3 alkyl; each R6 is independently selected from halogen, -OH, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1- C3 haloalkyl, C1-C3 alkoxy, -CN, =CH2, C1-C3 aminoalkyl, -Q-phenyl, -Q-phenylSO2F, - NHC(O)phenyl, - NHC(O)phenylSO2F, C1-C3 alkyl substituted pyrazolyl, -N(R5)2, (C1-C3 alkoxy)C1-C3 alkyl-, (C1-C3 alkyl)C(=O), oxo, (C1-C3 haloalkyl)C(=O)-, -SO2F, (C1-C3 alkoxy)C1- C3 alkoxy, -CH2OC(O)N(R5)2, -CH2NHC(O)OC1-C6 alkyl, -CH2NHC(O)N(R5)2, - CH2NHC(O)C1-C6 alkyl, -CH2(pyrazolyl), -CH2NHSO2C1-C6 alkyl, -CH2OC(O)heterocycle, - OC(O)N(R5)2, -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl), -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl(C1-C3 alkyl)N(CH3)2, -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl, - OC(O)heterocycle, and -CH2heterocycle, wherein the phenyl of -NHC(O)phenyl and - OC(O)NH(C1-C3 alkyl)(C1-C3 alkyl)phenyl are each optionally substituted with -C(O)H and OH, and wherein the heterocycle of -CH2heterocyclyl is optionally substituted with oxo; each Q is independently selected from a bond and O; R9 is selected from a 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle is substituted with one or more substituents independently selected from -OH, - NHCN, -CN, C1-6 alkoxy; and further optionally substituted with one or more substituents independently selected from halogen, -C(O)N(R20)2, -C(O)NR20-OR20, C1-6 haloalkyl, -SR20, =O, =S, =N(R20), -B(OR20)2, -N(R20)2, -NO2, C1-6 aminoalkyl, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 alkyl, C1-6 alkyl-O-C(O)C1-6 alkyl, C2-6 alkynyl and C2-6 alkenyl; wherein when R9 is substituted with at least one -OH or C1-6 alkoxy, the 5- to 12-membered heterocycle is an non-bridged heterocycle; each R20 is independently selected from hydrogen; and C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbocycle, and 3- to 12- membered heterocycle; each R49 is independently selected from halogen, -CN, -OH, =O, -NO2, C1-C4 alkyl, C1-6 aminoalkyl, -S-C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 hydroxyalkynyl, C1-C3 cyanoalkyl, triazolyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, -S-C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, -CH2C(=O)N(R5)2, -C3-C4 alkynyl(NR5)2, (C1-C3 alkoxy)haloC1-C3 alkyl-, and C3- C6 cycloalkyl, wherein the C3-C6 cycloalkyl is optionally substituted with one or more substituents independently selected from halogen and C1-C3 alkyl; R50 is selected from hydrogen, halogen, -OH, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, -CN, C1-C3 cyanoalkyl, C1-C3 aminoalkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 hydroxyalkynyl, and C3-C6 carbocycle. [00273] In some embodiments, for a compound or salt of (VI), R9 is selected from a 6- to 7- membered heterocycle, each of which is substituted. In some cases, R9 is selected from
Figure imgf000114_0001
Figure imgf000114_0002
each of which is substituted. In some cases, the one or more substituents are independently selected from -OH, -CN, and -NHCN; and further optionally substituted with one or more substituents independently selected from C1-6 alkyl. In some cases, R9 is selected from
Figure imgf000114_0003
some cases, the one or more substituents are independently selected from -OH, and further optionally substituted with one or more substituents independently selected from C1-6 alkyl. In some cases, R9 is selected from
Figure imgf000114_0004
Figure imgf000115_0001
some cases, the one or more substituents are independently selected from -CN and -NHCN, and further optionally substituted with one or more substituents
Figure imgf000115_0002
independently selected from C1-6 alkyl. In some cases, R9 is selected from and
Figure imgf000115_0003
. [00274] In some embodiments, for a compound or salt of (VI), R4 is selected from hydrogen and halogen. In some cases, R4 is selected from halogen. In some cases, R4 is fluorine. [00275] In some embodiments, for a compound or salt of (VI), R3 is selected from aryl and heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, C1-C4 alkyl, and C2-C4 alkynyl. [00276] In some embodiments, for a compound or salt of (VI), R50 is selected from hydrogen, halogen, C1-C3 cyanoalkyl, and C2-C4 alkenyl. [00277] In some embodiments, for a compound or salt of (VI), L is selected from C1-C4 alkylene. In some cases, L is selected from unsubstituted C1-C4 alkylene. In some cases, each L is independently selected from a C1-C4 alkylene optionally substituted; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle, wherein the C3-C6 carbocycle is optionally substituted with one or more substituents selected from halogen, - OH, -NO2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl. In some ,
Figure imgf000115_0004
, , ,
Figure imgf000115_0005
wherein the heterocycle portion is optionally substituted with one or more R6. In some cases, R6 is selected from halogen, -OH, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, -CN, and C1-C3 aminoalkyl. In some
Figure imgf000116_0001
[00278] In some embodiments, for a compound or salt of Formula (I), (I-A), (II), (III), (IV), (V), or (VI), when R9 is substituted with -CN, R3 is selected from optionally substituted aryl. In some cases, when R9 is substituted with -CN and when R3 is pyridine, the pyridine is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, =O, - NO2, C1-C4 alkyl, C1-6 aminoalkyl, -S-C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 hydroxyalkynyl, C1-C3 cyanoalkyl, triazolyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, -S-C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, -CH2C(=O)N(R5)2, -C3-C4 alkynyl(NR5)2, (C1-C3 alkoxy)haloC1-C3 alkyl-, and C3-C6 cycloalkyl, wherein the C3-C6 cycloalkyl is optionally substituted with one or more substituents selected from halogen and C1-C3 alkyl. In some cases, when R9 is substituted with -CN, and when R3 is heterocycle, the heterocycle is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, =O, - NO2, C1-C4 alkyl, C1-6 aminoalkyl, -S-C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 hydroxyalkynyl, C1-C3 cyanoalkyl, triazolyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, -S-C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, -CH2C(=O)N(R5)2, -C3-C4 alkynyl(NR5)2, (C1-C3 alkoxy)haloC1-C3 alkyl-, and C3-C6 cycloalkyl, wherein the C3-C6 cycloalkyl is optionally substituted with one or more substituents selected from halogen and C1-C3 alkyl. In some cases, R3 is not optionally substituted pyridine. In some cases, R3 is not benzothiazole. In some cases, R3 is not optionally substituted benzothiazole. In some cases, when R9 is substituted with -CN, R3 is not optionally substituted pyridine. In some cases, when R9 is substituted with -CN, R3 is not optionally substituted benzothiazole. In some cases, R3 is not substituted with -N(R20)2. In some cases, R3 is not substituted with -NH2. [00279] In some embodiments, for a compound or salt of Formula (I), (I-A), (II), (III), (IV), (V), or (VI), R2 is selected from -L-6- to 8-membered heterocycle, wherein the heterocycle portion of -L-6- to 8-membered heterocycle is optionally substituted with one or more R6. In some cases, R2 is selected from -L-6-membered heterocycle, wherein the heterocycle portion of -L-6-membered heterocycle is optionally substituted with one or more R6. In some cases, R2 is selected from -L-8- membered heterocycle, wherein the heterocycle portion of -L-8-membered heterocycle is optionally substituted with one or more R6. In some cases, the heterocycle is bicyclic. In some cases, the heterocycle is monocyclic. In some cases, the heterocycle is a saturated heterocycle. In some cases, the heterocycle of R2 has at least one sulfur atom. In some cases, the heterocycle of R2 has at least one nitrogen atom. [00280] In some embodiments, for a compound or salt of Formula (I), (I-A), (II), (III), (IV), (V), or (VI), the heterocycle of R2 is optionally substituted with one or more substituents selected from halogen, hydroxy, C1-C3 alkyl, -N(R5)S(O)2(R5), -OC(O)N(R5)2, =CH2, oxo, =NO-C1-C3 alkyl, - CH2OC(O)heterocycle, -CH2heterocycle, -CH2OC(O)N(R5)2, and -O-C1-C3 alkyl, wherein the alkyl of -O-C1-C3 alkyl is optionally substituted with substituents selected from heterocycle, oxo,
Figure imgf000117_0001
[00281] In some embodiments, for a compound or salt of Formula (I), (I-A), (II), (III), (IV), or (VI), the heterocycle of R9 is substituted with at least one C1-6 alkyl-N(R20)2. [00282] In some embodiments, for a compound or salt of Formula (II), (III), (IV), or (VI), the heterocycle of R9 is substituted with at least one C1-6 alkyl-N(R20)2. [00283] In some embodiments, for a compound or salt of Formula (I), (I-A), (II), (III), (IV), (V), or (VI), the compound is not a Michael acceptor. [00284] In some embodiments, for a compound or salt of Formula (I), (I-A), (II), (III), (IV), (V), or (VI), the compound does not include an electrophilic substituent. [00285] In some embodiments, for a compound or salt of Formula (I), (I-A), (II), (III), (IV), (V), or (VI), the compound or salt does not include an electrophilic substituent. [00286] In some embodiments, for a compound or salt of Formula (I), (I-A), (II), (III), (IV), (V), or (VI), the R9 does not include an electrophilic substituent. [00287] In some embodiments, for a compound or salt of Formula (I), (I-A), (II), (III), (IV), (V), or (VI), the compound or salt does not form a covalent bond with any of the KRAS G12D and/or other G12 mutants. [00288] In some embodiments, for a compound or salt of Formula (I), (I-A), (II), (III), (IV), (V), or (VI), the compound or salt is not a covalent modifier of KRAS G12D and/or other G12 mutants. [00289] Included in the present disclosure are salts, particularly pharmaceutically acceptable salts, of the compounds described herein. The compounds of the present invention that 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. [00290] 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 described herein are intended to include all Z-, E- and tautomeric forms as well. [00291] 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 presented herein, in certain embodiments, exist as tautomers. In circumstances where tautomerization is possible, a chemical equilibrium of the tautomers will exist. The exact ratio of the tautomers depends on several factors, including physical state, temperature, solvent, and pH. Some examples of tautomeric equilibrium include:
Figure imgf000119_0001
. [00292] 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. [00293] 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. [00294] 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. [00295] 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. [00296] 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. [00297] Deuterated starting materials are readily available and are subjected to the synthetic methods described herein to provide for the synthesis of deuterium-containing compounds. Large numbers of deuterium-containing reagents and building blocks are available commercially from chemical vendors, such as Aldrich Chemical Co. [00298] Compounds of the present invention 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. [00299] The compounds described herein may in some cases exist as diastereomers, enantiomers, or other stereoisomeric forms. Where absolute stereochemistry is not specified, the compounds presented herein include all diastereomeric, enantiomeric, and epimeric forms as well as the appropriate mixtures thereof. 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. [00300] The methods and compositions described herein 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. [00301] In certain embodiments, compounds or salts of the compounds 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. [00302] Prodrug forms of the herein described compounds, wherein the prodrug is metabolized in vivo to produce a compound as set forth herein are included within the scope of the claims. In some cases, some of the herein-described compounds may be a prodrug for another derivative or active compound. [00303] 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. [00304] 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 compounds. The compounds may be synthesized using conventional techniques. Advantageously, these compounds are conveniently synthesized from readily available starting materials. [00305] 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 [00306] Provided herein, in certain embodiments, are compositions comprising a therapeutically effective amount of any compound or salt of any one of Formulas (I), (I-A), (II), (III), (IV), (V), and (VI) (also referred to herein as “a pharmaceutical agent”). [00307] Pharmaceutical compositions may be formulated using one or more physiologically acceptable carriers including excipients and auxiliaries which facilitate processing of the pharmaceutical agent into preparations which are used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. A summary of pharmaceutical compositions is found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa., Mack Publishing Company, 1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins, 1999). [00308] The compositions and methods of the present disclosure may be utilized to treat an individual in need thereof. In certain embodiments, the individual is a mammal such as a human, or a non-human mammal. When administered to an animal, such as a human, the composition or the pharmaceutical agent, is preferably administered as a pharmaceutical composition comprising, for example, a pharmaceutical agent and a pharmaceutically acceptable carrier or excipient. Pharmaceutically acceptable carriers are well known in the art and include, for example, aqueous solutions such as water or physiologically buffered saline or other solvents or vehicles such as glycols, glycerol, oils such as olive oil, or injectable organic esters. In a preferred embodiment, when such pharmaceutical compositions are for human administration, particularly for invasive routes of administration, e.g., routes, such as injection or implantation, that circumvent transport or diffusion through an epithelial barrier, the aqueous solution is pyrogen-free, or substantially pyrogen-free. The excipients can be chosen, for example, to effect delayed release of an agent or to selectively target one or more cells, tissues or organs. The pharmaceutical composition can be in dosage unit form such as tablet, capsule, granule, lyophile for reconstitution, powder, solution, syrup, suppository, injection or the like. The composition can also be present in a transdermal delivery system, e.g., a skin patch. The composition can also be present in a solution suitable for topical administration, such as an eye drop. [00309] A pharmaceutically acceptable excipient can contain physiologically acceptable agents that act, for example, to stabilize, increase solubility or to increase the absorption of a compound such as a pharmaceutical agent. Such physiologically acceptable agents include, for example, carbohydrates, such as glucose, sucrose or dextrans, antioxidants, such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins or other stabilizers or excipients. The choice of a pharmaceutically acceptable excipient, including a physiologically acceptable agent, depends, for example, on the route of administration of the composition. The preparation or pharmaceutical composition can be a self emulsifying drug delivery system or a self microemulsifying drug delivery system. The pharmaceutical composition (preparation) also can be a liposome or other polymer matrix, which can have incorporated therein, for example, a compound of the invention. Liposomes, for example, which comprise phospholipids or other lipids, are nontoxic, physiologically acceptable and metabolizable carriers that are relatively simple to make and administer. [00310] A pharmaceutical composition (preparation) can be administered to a subject by any of a number of routes of administration including, for example, orally, for example, drenches as in aqueous or non-aqueous solutions or suspensions, tablets, capsules, including sprinkle capsules and gelatin capsules, boluses, powders, granules, pastes for application to the tongue; absorption through the oral mucosa, e.g., sublingually; anally, rectally or vaginally, for example, as a pessary, cream or foam; parenterally, including intramuscularly, intravenously, subcutaneously or intrathecally as, for example, a sterile solution or suspension; nasally; intraperitoneally; subcutaneously; transdermally, for example, as a patch applied to the skin; and topically, for example, as a cream, ointment or spray applied to the skin, or as an eye drop. The compound may also be formulated for inhalation. In certain embodiments, a compound may be simply dissolved or suspended in sterile water. [00311] A pharmaceutical composition may be a sterile aqueous or non-aqueous solution, suspension or emulsion, e.g., a microemulsion. The excipients described herein are examples and are in no way limiting. An effective amount or therapeutically effective amount refers to an amount of the one or more pharmaceutical agents administered to a subject, either as a single dose or as part of a series of doses, which is effective to produce a desired therapeutic effect. [00312] Subjects may generally be monitored for therapeutic effectiveness using assays and methods suitable for the condition being treated, which assays will be familiar to those having ordinary skill in the art and are described herein. Pharmacokinetics of a pharmaceutical agent, or one or more metabolites thereof, that is administered to a subject may be monitored by determining the level of the pharmaceutical agent or metabolite in a biological fluid, for example, in the blood, blood fraction, e.g., serum, and/or in the urine, and/or other biological sample or biological tissue from the subject. Any method practiced in the art and described herein to detect the agent may be used to measure the level of the pharmaceutical agent or metabolite during a treatment course. [00313] The dose of a pharmaceutical agent described herein for treating a disease or disorder may depend upon the subject’s condition, that is, stage of the disease, severity of symptoms caused by the disease, general health status, as well as age, gender, and weight, and other factors apparent to a person skilled in the medical art. Pharmaceutical compositions may be administered in a manner appropriate to the disease to be treated as determined by persons skilled in the medical arts. In addition to the factors described herein and above related to use of pharmaceutical agent for treating a disease or disorder, suitable duration and frequency of administration of the pharmaceutical agent may also be determined or adjusted by such factors as the condition of the patient, the type and severity of the patient’s disease, the particular form of the active ingredient, and the method of administration. Optimal doses of an agent may generally be determined using experimental models and/or clinical trials. The optimal dose may depend upon the body mass, weight, or blood volume of the subject. The use of the minimum dose that is sufficient to provide effective therapy is usually preferred. Design and execution of pre-clinical and clinical studies for a pharmaceutical agent, including when administered for prophylactic benefit, described herein are well within the skill of a person skilled in the relevant art. When two or more pharmaceutical agents are administered to treat a disease or disorder, the optimal dose of each pharmaceutical agent may be different, such as less than when either agent is administered alone as a single agent therapy. In certain particular embodiments, two pharmaceutical agents in combination may act synergistically or additively, and either agent may be used in a lesser amount than if administered alone. An amount of a pharmaceutical agent that may be administered per day may be, for example, between about 0.01 mg/kg and 100 mg/kg, e.g., between about 0.1 to 1 mg/kg, between about 1 to 10 mg/kg, between about 10-50 mg/kg, between about 50-100 mg/kg body weight. In other embodiments, the amount of a pharmaceutical agent that may be administered per day is between about 0.01 mg/kg and 1000 mg/kg, between about 100-500 mg/kg, or between about 500-1000 mg/kg body weight. The optimal dose, per day or per course of treatment, may be different for the disease or disorder to be treated and may also vary with the administrative route and therapeutic regimen. [00314] Pharmaceutical compositions comprising a pharmaceutical agent can be formulated in a manner appropriate for the delivery method by using techniques routinely practiced in the art. The composition may be in the form of a solid, e.g., tablet, capsule, semi-solid, e.g., gel, liquid, or gas, e.g., aerosol. In other embodiments, the pharmaceutical composition is administered as a bolus infusion. [00315] Pharmaceutical acceptable excipients are well known in the pharmaceutical art and described, for example, in Rowe et al., Handbook of Pharmaceutical Excipients: A Comprehensive Guide to Uses, Properties, and Safety, 5th Ed., 2006, and in Remington: The Science and Practice of Pharmacy (Gennaro, 21st Ed. Mack Pub. Co., Easton, PA (2005)). Exemplary pharmaceutically acceptable excipients include sterile saline and phosphate buffered saline at physiological pH. Preservatives, stabilizers, dyes, buffers, and the like may be provided in the pharmaceutical composition. In addition, antioxidants and suspending agents may also be used. In general, the type of excipient is selected based on the mode of administration, as well as the chemical composition of the active ingredient(s). Alternatively, compositions described herein may be formulated as a lyophilizate. A composition described herein may be lyophilized or otherwise formulated as a lyophilized product using one or more appropriate excipient solutions for solubilizing and/or diluting the pharmaceutical agent(s) of the composition upon administration. In other embodiments, the pharmaceutical agent may be encapsulated within liposomes using technology known and practiced in the art. In certain particular embodiments, a pharmaceutical agent is not formulated within liposomes for application to a stent that is used for treating highly, though not totally, occluded arteries. Pharmaceutical compositions may be formulated for any appropriate manner of administration described herein and in the art. [00316] A pharmaceutical composition, e.g., for oral administration or for injection, infusion, subcutaneous delivery, intramuscular delivery, intraperitoneal delivery or other method, may be in the form of a liquid. A liquid pharmaceutical composition may include, for example, one or more of the following: a sterile diluent such as water, saline solution, preferably physiological saline, Ringer’s solution, isotonic sodium chloride, fixed oils that may serve as the solvent or suspending medium, polyethylene glycols, glycerin, propylene glycol or other solvents; antibacterial agents; antioxidants; chelating agents; buffers and agents for the adjustment of tonicity such as sodium chloride or dextrose. A parenteral composition can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic. The use of physiological saline is preferred, and an injectable pharmaceutical composition is preferably sterile. In another embodiment, for treatment of an ophthalmological condition or disease, a liquid pharmaceutical composition may be applied to the eye in the form of eye drops. A liquid pharmaceutical composition may be delivered orally. [00317] For oral formulations, at least one of the pharmaceutical agents described herein can be used alone or in combination with appropriate additives to make tablets, powders, granules or capsules, and if desired, with diluents, buffering agents, moistening agents, preservatives, coloring agents, and flavoring agents. The pharmaceutical agents may be formulated with a buffering agent to provide for protection of the compound from low pH of the gastric environment and/or an enteric coating. A pharmaceutical agent included in a pharmaceutical composition may be formulated for oral delivery with a flavoring agent, e.g., in a liquid, solid or semi-solid formulation and/or with an enteric coating. [00318] A pharmaceutical composition comprising any one of the pharmaceutical agents described herein may be formulated for sustained or slow release, also called timed release or controlled release. Such compositions may generally be prepared using well known technology and administered by, for example, oral, rectal, intradermal, or subcutaneous implantation, or by implantation at the desired target site. Sustained-release formulations may contain the compound dispersed in a carrier matrix and/or contained within a reservoir surrounded by a rate controlling membrane. Excipients for use within such formulations are biocompatible, and may also be biodegradable; preferably the formulation provides a relatively constant level of active component release. The amount of pharmaceutical agent contained within a sustained release formulation depends upon the site of implantation, the rate and expected duration of release, and the nature of the condition, disease or disorder to be treated or prevented. [00319] In certain embodiments, the pharmaceutical compositions comprising a pharmaceutical agent are formulated for transdermal, intradermal, or topical administration. The compositions can be administered using a syringe, bandage, transdermal patch, insert, or syringe-like applicator, as a powder/talc or other solid, liquid, spray, aerosol, ointment, foam, cream, gel, paste. This preferably is in the form of a controlled release formulation or sustained release formulation administered topically or injected directly into the skin adjacent to or within the area to be treated, e.g., intradermally or subcutaneously. The active compositions can also be delivered via iontophoresis. Preservatives can be used to prevent the growth of fungi and other microorganisms. Suitable preservatives include, but are not limited to, benzoic acid, butylparaben, ethyl paraben, methyl paraben, propylparaben, sodium benzoate, sodium propionate, benzalkonium chloride, benzethonium chloride, benzyl alcohol, cetypyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol, thimerosal, and combinations thereof. [00320] Pharmaceutical compositions comprising a pharmaceutical agent can be formulated as emulsions for topical application. An emulsion contains one liquid distributed in the body of a second liquid. The emulsion may be an oil-in-water emulsion or a water-in-oil emulsion. Either or both of the oil phase and the aqueous phase may contain one or more surfactants, emulsifiers, emulsion stabilizers, buffers, and other excipients. The oil phase may contain other oily pharmaceutically approved excipients. Suitable surfactants include, but are not limited to, anionic surfactants, non-ionic surfactants, cationic surfactants, and amphoteric surfactants. Compositions for topical application may also include at least one suitable suspending agent, antioxidant, chelating agent, emollient, or humectant. [00321] Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents. Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents. Liquid sprays may be delivered from pressurized packs, for example, via a specially shaped closure. Oil-in-water emulsions can also be used in the compositions, patches, bandages and articles. These systems are semisolid emulsions, micro-emulsions, or foam emulsion systems. [00322] In some embodiments, the pharmaceutical agent described herein can be formulated as in inhalant. Inhaled methods can deliver medication directly to the airway. The pharmaceutical agent can be formulated as aerosols, microspheres, liposomes, or nanoparticles. The pharmaceutical agent can be formulated with solvents, gases, nitrates, or any combinations thereof. Compositions described herein are optionally formulated for delivery as a liquid aerosol or inhalable dry powder. Liquid aerosol formulations are optionally nebulized predominantly into particle sizes that can be delivered to the terminal and respiratory bronchioles. Liquid aerosol and inhalable dry powder formulations are preferably delivered throughout the endobronchial tree to the terminal bronchioles and eventually to the parenchymal tissue. [00323] Aerosolized formulations described herein are optionally delivered using an aerosol forming device, such as a jet, vibrating porous plate or ultrasonic nebulizer, preferably selected to allow the formation of aerosol particles having with a mass medium average diameter predominantly between 1 to 5 ^. Further, the formulation preferably has balanced osmolarity ionic strength and chloride concentration, and the smallest aerosolizable volume able to deliver effective dose of the pharmaceutical agent. Additionally, the aerosolized formulation preferably does not impair negatively the functionality of the airways and does not cause undesirable side effects. [00324] Aerosolization devices suitable for administration of aerosol formulations described herein include, for example, jet, vibrating porous plate, ultrasonic nebulizers and energized dry powder inhalers, that are able to nebulize the formulation into aerosol particle size predominantly in the size range from 1-5 ^. Predominantly in this application means that at least 70% but preferably more than 90% of all generated aerosol particles are within 1-5 ^ range. A jet nebulizer works by air pressure to break a liquid solution into aerosol droplets. Vibrating porous plate nebulizers work by using a sonic vacuum produced by a rapidly vibrating porous plate to extrude a solvent droplet through a porous plate. An ultrasonic nebulizer works by a piezoelectric crystal that shears a liquid into small aerosol droplets. A variety of suitable devices are available, including, for example, AeroNeb ^ ^ and AeroDose ^ ^ ^vibrating porous plate nebulizers (AeroGen, Inc., Sunnyvale, California), Sidestream ^ nebulizers (Medic-Aid Ltd., West Sussex, England), Pari LC ^ and Pari LC Star ^ jet nebulizers (Pari Respiratory Equipment, Inc., Richmond, Virginia), and Aerosonic ^ ^ (DeVilbiss Medizinische Produkte (Deutschland) GmbH, Heiden, Germany) and UltraAire ^ (Omron Healthcare, Inc., Vernon Hills, Illinois) ultrasonic nebulizers. [00325] In some embodiments, the pharmaceutical agent(s) can be formulated with oleaginous bases or ointments to form a semisolid composition with a desired shape In addition to the pharmaceutical agent, these semisolid compositions can contain dissolved and/or suspended bactericidal agents, preservatives and/or a buffer system. A petrolatum component that may be included may be any paraffin ranging in viscosity from mineral oil that incorporates isobutylene, colloidal silica, or stearate salts to paraffin waxes. Absorption bases can be used with an oleaginous system. Additives may include cholesterol, lanolin (lanolin derivatives, beeswax, fatty alcohols, wool wax alcohols, low HLB (hydrophobellipophobe balance) emulsifiers, and assorted ionic and nonionic surfactants, singularly or in combination. [00326] Controlled or sustained release transdermal or topical formulations can be achieved by the addition of time-release additives, such as polymeric structures, matrices, that are available in the art. For example, the compositions may be administered through use of hot-melt extrusion articles, such as bioadhesive hot-melt extruded film. The formulation can comprise a cross-linked polycarboxylic acid polymer formulation. A cross-linking agent may be present in an amount that provides adequate adhesion to allow the system to remain attached to target epithelial or endothelial cell surfaces for a sufficient time to allow the desired release of the compound. [00327] An insert, transdermal patch, bandage or article can comprise a mixture or coating of polymers that provide release of the pharmaceutical agents at a constant rate over a prolonged period of time. In some embodiments, the article, transdermal patch or insert comprises water- soluble pore forming agents, such as polyethylene glycol (PEG) that can be mixed with water insoluble polymers to increase the durability of the insert and to prolong the release of the active ingredients. [00328] Transdermal devices (inserts, patches, bandages) may also comprise a water insoluble polymer. Rate controlling polymers may be useful for administration to sites where pH change can be used to effect release. These rate controlling polymers can be applied using a continuous coating film during the process of spraying and drying with the active compound. In one embodiment, the coating formulation is used to coat pellets comprising the active ingredients that are compressed to form a solid, biodegradable insert. [00329] A polymer formulation can also be utilized to provide controlled or sustained release. Bioadhesive polymers described in the art may be used. By way of example, a sustained-release gel and the compound may be incorporated in a polymeric matrix, such as a hydrophobic polymer matrix. Examples of a polymeric matrix include a microparticle. The microparticles can be microspheres, and the core may be of a different material than the polymeric shell. Alternatively, the polymer may be cast as a thin slab or film, a powder produced by grinding or other standard techniques, or a gel such as a hydrogel. The polymer can also be in the form of a coating or part of a bandage, stent, catheter, vascular graft, or other device to facilitate delivery of the pharmaceutical agent. The matrices can be formed by solvent evaporation, spray drying, solvent extraction and other methods known to those skilled in the art. [00330] Kits with unit doses of one or more of the agents described herein, usually in oral or injectable doses, are provided. Such kits may include a container containing the unit dose, an informational package insert describing the use and attendant benefits of the drugs in treating disease, and optionally an appliance or device for delivery of the composition. Methods of Treatment [00331] In an aspect, the present disclosure provides compounds that inhibit KRas G12 mutants. In some cases, the method may inhibit KRas G12 mutants activity in a cell. In some cases, inhibitng KRas G12 mutants activity in a cell may include contacting the cell in which inhibition of KRas G12 mutants activity is desired with an effective amount of a compound of Formulas (I), (I-A), (II), (III), (IV), (V), (VI), or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing the compound or pharmaceutically acceptable salt thereof. In some cases, the contacting is in vitro. In some cases, the contacting is in vivo. As used herein, the term "contacting" refers to the bringing together of indicated moieties in an in vitro system or an in vivo system. For example, "contacting" a KRas G12D and/or other G12 mutants with a compound provided herein includes the administration of a compound provided herein to an individual or patient, such as a human, having KRas G12D and/or other G12 mutants, as well as, for example, introducing a compound provided herein into a sample containing a cellular or purified preparation containing the KRas G12D and/or other G12 mutants. In some cases, a cell in which inhibition of KRas G12D and/or other G12 mutants activity is desired is contacted with an effective amount of a compound of Formulas (I), (I-A), (II), (III), (IV), (V), (VI), or pharmaceutically acceptable salt thereof to negatively modulate the activity of KRas G12D and/or other G12 mutants. In some cases, by negatively modulating the activity of KRas G12D and/or other G12 mutants, the methods described herein are designed to inhibit undesired cellular proliferation resulting from enhanced KRas G12D and/or other G12 mutants activity within the cell. The cells may be contacted in a single dose or multiple doses in accordance with a particular treatment regimen to effect the desired negative modulation of KRas G12D and/or other G12 mutants. The ability of compounds to bind KRas G12D and/or other G12 mutants may be monitored in vitro using well known methods. [00332] In some embodiments, the inhibitory activity of exemplary compounds in cells may be monitored, for example, by measuring the inhibition of KRas G12D and/or other G12 mutants activity of the amount of phosphorylated ERK. [00333] In another aspect, methods of treating cancer in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a compound of Formulas (I), (I- A), (II), (III), (IV), (V), (VI), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound or pharmaceutically acceptable salt thereof are provided. The compositions and methods provided herein may be used for the treatment of a KRas G12D and/or other G12 mutants-associated cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formulas (I), (I-A), (II), (III), (IV), (V), (VI), or a pharmaceutically acceptable salt of any one thereof, or a pharmaceutical composition comprising the compound or pharmaceutically acceptable salt thereof are provided. In some cases, the KRas G12D and/or other G12 mutants -associated cancer is lung cancer. The compositions and methods provided herein may be used for the treatment of a wide variety of cancers including tumors such as lung, prostate, breast, brain, skin, cervical carcinomas, testicular carcinomas, etc. More particularly, cancers that may be treated by the compositions and methods of the invention include, but are not limited to tumor types such as astrocytic, breast, cervical, colorectal, endometrial, esophageal, gastric, head and neck, hepatocellular, laryngeal, lung, oral, ovarian, prostate and thyroid carcinomas and sarcomas. More specifically, these compounds can be used to treat: Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); Genitourinary tract: kidney (adenocarcinoma, Wilm's tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); Liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Biliary tract: gall bladder carcinoma, ampullary carcinoma, cholangiocarcinoma; Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors; Nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal cord neurofibroma, meningioma, glioma, sarcoma); Gynecological: uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervical dysplasia), ovaries (ovarian carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tubes (carcinoma); Hematologic: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis; and Adrenal glands: neuroblastoma. In some cases, the cancer is non-small cell lung cancer, small cell lung cancer, colorectal cancer, rectal cancer or pancreatic cancer. In some cases, the cancer is non-small cell lung cancer. In some cases, the concentration and route of administration to the patient will vary depending on the cancer to be treated. The compounds, pharmaceutically acceptable salts thereof and pharmaceutical compositions comprising such compounds and salts also may be co-administered with other anti-neoplastic compounds, e.g., chemotherapy, or used in combination with other treatments, such as radiation or surgical intervention, either as an adjuvant prior to surgery or post- operatively. [00334] Also provided herein is a compound of Formula (I), Formula (I-A), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein for use in therapy. [00335] Also provided herein is a compound of Formula (I), Formula (I-A), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein for use in the treatment of cancer. [00336] Also provided herein is a compound of Formula (I), Formula (I-A), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for use in the inhibition of KRas G12D and/or other G12 mutants. [00337] Also provided herein is a compound of Formula (I), Formula (I-A), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein, for use in the treatment of a KRas G12D and/or other G12 mutants -associated disease or disorder. [00338] Also provided herein is the use of a compound of Formula (I), Formula (I-A), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), or a pharmaceutically acceptable salt thereof, as defined herein in the manufacture of a medicament for the treatment of cancer. [00339] Also provided herein is a use of a compound of Formula (I), Formula (I-A), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), or a pharmaceutically acceptable salt thereof, as defined herein in the manufacture of a medicament for the inhibition of activity of KRas G12D and/or other G12 mutants. [00340] Also provided herein is the use of a compound of Formula (I), Formula (I-A), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), or a pharmaceutically acceptable salt thereof, as defined herein, in the manufacture of a medicament for the treatment of a KRas G12D and/or other G12 mutants-associated disease or disorder. [00341] In another aspect, the present disclosure provides a method for treating cancer in a patient in need thereof, the method comprising (a) determining that cancer is associated with a KRas G12D mutation and/or other G12 mutants (e.g., a KRas G12D and/or other G12 mutants- associated cancer) (e.g., as determined using a regulatory agency-approved, e.g., FDA- approved, assay or kit); and (b) administering to the patient a therapeutically effective amount of a compound of Formula (I), Formula (I-A), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. [00342] 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. [00343] 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. [00344] 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. [00345] In the case wherein the patient’s condition does not improve, upon the doctor’s discretion the administration of the compounds may be administered chronically, that is, for an extended period of time, including throughout the duration of the patient’s life in order to ameliorate or otherwise control or limit the symptoms of the patient’s disease or condition. [00346] Once improvement of the patient's conditions has occurred, a maintenance dose is administered if necessary. Subsequently, the dosage or the frequency of administration, or both, can be reduced, as a function of the symptoms, to a level at which the improved disease, disorder or condition is retained. Patients can, however, require intermittent treatment on a long-term basis upon any recurrence of symptoms. [00347] The amount of a given agent that will correspond to such an amount will vary depending upon factors such as the particular compound, disease or condition and its severity, the identity (e.g., weight) of the subject or host in need of treatment, but can nevertheless be determined in a manner recognized in the field according to the particular circumstances surrounding the case, including, e.g., the specific agent being administered, the route of administration, the condition being treated, and the subject or host being treated. In general, however, doses employed for adult human treatment will typically be in the range of about 0.02 - about 5000 mg per day, in some embodiments, about 1 – about 1500 mg per day. The desired dose may conveniently be presented in a single dose or as divided doses administered simultaneously (or over a short period of time) or at appropriate intervals, for example as two, three, four or more sub-doses per day. [00348] The pharmaceutical composition described herein may be in unit dosage forms suitable for single administration of precise dosages. In unit dosage form, the formulation is divided into unit doses containing appropriate quantities of one or more compound. The unit dosage may be in the form of a package containing discrete quantities of the formulation. Non-limiting examples are packaged tablets or capsules, and powders in vials or ampoules. Aqueous suspension compositions can be packaged in single-dose non-reclosable containers. Alternatively, multiple-dose reclosable containers can be used, in which case it is typical to include a preservative in the composition. By way of example only, formulations for parenteral injection may be presented in unit dosage form, which include, but are not limited to ampoules, or in multi-dose containers, with an added preservative. [00349] Toxicity and therapeutic efficacy of such therapeutic regimens can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, the determination of the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between the toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio between LD50 and ED50. Compounds exhibiting high therapeutic indices are preferred. The data obtained from cell culture assays and animal studies can be used in formulating a range of dosage for use in human. The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50 with minimal toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. [00350] In certain embodiments, the invention provides a method of treating or preventing a disease, state or condition in a patient in need thereof comprising administering to the patient an effective amount of a compound of any one of embodiments of the invention or a pharmaceutically acceptable salt thereof. The disease, state or condition may be selected from a group as described elsewhere herein. [00351] The following examples further illustrate the invention but, of course, should not be construed as in any way limiting its scope Bifunctional Compounds [00352] In some embodiments, compounds herein can adopt to selectively eliminate an over activated KRas signaling which is induced by KRas mutations by directly binding with the mutated KRas protein, either by stabilizing its GDP bound form (the inactive form) or by blocking the interaction between GTP bound form and its downstream target protein. In some embodiments, another way is to hijack the protein degradation mechanism in a cell and leverage E3 ligases’ (like VHL, CRBN or IAPs) substrate specificity through a bi-functional molecule called Proteolysis targeting chimera (PROTAC) (Winter GE, Buckley DL, Paulk J, Roberts JM, Souza A, Dhe- Paganon S, Bradner JE. DRUG DEVELOPMENT. Phthalimide conjugation as a strategy for in vivo target protein degradation. Science.2015 Jun 19; 348 (6241): 1376-81), which can bind with both mutated KRas protein and E3 ligase, create interactions between those two proteins and induce KRas degradation. [00353] Disclosed herein is a bifunctional compound composed of a target protein (i.e., KRAS G12D)-binding moiety and an E3 ubiquitin ligase-binding moiety, which may induce proteasome- mediated degradation of selected proteins. In some embodiments, the bifunctional compound comprises a target protein (i.e., KRAS G12D)-binding moiety and an E3 ubiquitin ligase-binding moiety known in the art. In some embodiments, disclosed herein is the use of the compound disclosed herein in the preparation of degrading a target protein compound by using chemical modification of the compound disclosed herein. In some cases, the target protein-binding moiety is derived from a compound of Formula (I), Formula (I-A), Formula (II), Formula (III), Formula (IV), Formula (V), or Formula (VI). Preparation of Compounds [00354] The compounds of the present disclosure can generally be prepared in a number of ways well known to those skilled in the art of organic synthesis. By way of example, compounds of the present disclosure can be synthesized using the methods described herein, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereof as appreciated by those skilled in the art. [00355] The compounds of the present disclosure may be prepared as described in the schemes and examples described elsewhere herein. EXAMPLES [00356] 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. [00357] The present disclosure provides processes for preparing compounds described herein (described in greater detail below). Example 1. Exemplary synthesis of compound 1
Figure imgf000135_0001
[00358] Step 1. The mixture of 7-bromo-2,4,6-trichloro-8-fluoro-quinazoline (100 mg, 0.3 mmol), azepan-4-ol (41.83 mg, 0.36 mmol), and DIEA (0.15 mL, 0.91 mmol) in DCM (3 mL) was stirred at 25 oC for 2 h. The mixture was concentrated to afford a crude product. The crude product was purified by silica gel chromatography (PE: EA=5:1 to 3:1) to obtain 1-(7-bromo-2, 6-dichloro- 8-fluoro-quinazolin-4-yl) azepan-4-ol (110 mg, 0.267 mmol, 89 % yield) as a pale-yellow solid. LCMS m/z calcd for C14H13BrCl2FN3O+H: 410.1, found 410.1. [00359] Step 2. The mixture of 1-(7-bromo-2,6-dichloro-8-fluoro-quinazolin-4-yl) azepan-4-ol (150 mg, 0.37 mmol), [(2S)-1-methylpyrrolidin-2-yl]methanol (84.46 mg, 0.73 mmol), and DIEA (142.17 mg, 1.1 mmol) in dioxane (1 mL) was stirred at 80 oC for 16 h. The mixture was concentrated and purified by prep-TLC (DCM/EA = 1:1, v/v) to obtain 1-[7-bromo-6-chloro-8- fluoro-2-[[(2S)-1-methylpyrrolidin-2-yl] methoxy] quinazolin-4-yl] azepan-4-ol (80 mg, 0.1640 mmol, 45% yield) as yellow solid. LCMS (ESI): m/z calcld for C20H25BrClFN4O2+H: 488.8, found: 489.0. [00360] Step 3. The mixture of 1-[7-bromo-6-chloro-8-fluoro-2-[[(2S)-1-methylpyrrolidin-2-yl] methoxy] quinazolin -4-yl]azepan-4-ol (150 mg, 0.31 mmol), (5-methyl-1H-indazol-4-yl)boronic acid (59.53 mg, 0.34 mmol ), Ruphos Pd G3 (38.58 mg, 0.05 mmol), and K3PO4 (195.82 mg, 0.92 mmol) in dioxane (2 mL) and water (0.40 mL) was stirred at 90 oC for 2 h under argon. The mixture was extracted with EtOAc (10 mL), dried over Na2SO4, concentrated. The crude product was purified by prep-HPLC (H2O:CH3CN = 90:10 to 50:50, 0.1% TFA as additive) to obtain 1-[6- chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl] methoxy] quinazolin-4-yl] azepan-4-ol;2,2,2-trifluoroacetic acid, compound 1 (40.11 mg, 0.0487 mmol, 16% yield) as pink solid. LCMS (ESI) m/z calcd for C28H32ClFN6O2+H: 539.2, found 539.2.1H NMR (400 MHz, DMSO) δ 8.13 (s, 1H), 7.59 (d, J = 8.8 Hz, 1H), 7.54 (s, 1H), 7.39 (d, J = 8.6 Hz, 1H), 4.72 (d, J = 12.3 Hz, 1H), 4.62 – 4.54 (m, 1H), 3.99 (s, 3H), 3.83 (s, 3H), 3.59 (s, 1H), 3.14 (s, 1H), 2.96 (d, J = 4.3 Hz, 3H), 2.26 (d, J = 7.5 Hz, 1H), 2.17 (s, 3H), 2.09 (s, 3H), 1.92 (d, J = 13.1 Hz, 3H), 1.77 (d, J = 11.5 Hz, 2H), 1.63 (s, 1H). Example 2. Exemplary synthesis of compound 2
Figure imgf000136_0001
Figure imgf000137_0001
[00361] Step 1. To a solution of 7-bromo-2,4,6-trichloro-8-fluoro-quinazoline (580 mg, 1.76 mmol) and DIEA (680.68 mg, 5.27 mmol) in DCM (1 mL) was added azepane-4- carbonitrile;hydrochloride (282.02 mg, 1.76 mmol) at 0 oC. The mixture was stirred at 25 oC for 2 h. The mixture was concentrated to afford a crude product. The crude product was purified by silica gel chromatography (PE: EA=10:1 to 3:1) to obtain 1-(7-bromo-2,6-dichloro-8-fluoro- quinazolin-4-yl) azepane-4-carbonitrile (639 mg, 1.3371 mmol, 76% yield) as a pale-yellow solid. LCMS (ESI) calcd for C15H12BrCl2FN4+H: 417.0, found 417.0. [00362] Step 2. The mixture of 1-(7-bromo-2,6-dichloro-8-fluoro-quinazolin-4-yl) azepane-4- carbonitrile (200 mg, 0.48 mmol) and [(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl] methanol (228.47 mg, 1.44 mmol) was stirred at 140 oC for 0.5 h. The crude product was purified by flash chromatography (H2O:CH3CN = 90:10 to 50:50) to obtain 1-[7-bromo-6-chloro-8-fluoro- 2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazolin-4-yl]azepane-4- carbonitrile (120 mg, 0.22 mmol, 46% yield) as white solid. LCMS (ESI) m/z calcd for C23H25BrClF2N5O+H: 542.2, found 542.1. [00363] Step 3. The mixture of 1- [7-bromo-6-chloro-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin -8-yl]methoxy] quinazolin-4-yl] azepane-4-carbonitrile (120 mg, 0.22 mmol), 2-[7,8-difluoro-3- (methoxymethoxy)-1-naphthyl]-4,4,5,5-tetramethyl-1,3,2- dioxaborolane (97.12 mg, 0.28 mmol), cataCXium A-Pd (29.72 mg, 0.04 mmol), and K3PO4 (141.29 mg, 0.67 mmol) in dioxane (10 mL) and water (2 mL) was stirred at 80 oC for 3 h under argon. The mixture was filtered and concentrated. The crude product was purified by prep-TLC (PE:EA = 1:1 ) to obtain 1-[6-chloro-7-[7,8-difluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro- 2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazolin-4-yl]azepane-4- carbonitrile (100 mg, 0.15 mmol, 66% yield) as pale-yellow solid. LCMS (ESI) m/z calcd for C35H34ClF4N5O3+H: 684.2, found 684.2. [00364] Step 4. The mixture of 1-[6-chloro-7-[7,8-difluoro-3-(methoxymethoxy)-1-naphthyl]- 8-fluoro-2-[[(2R,8S) -2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy] quinazolin-4- yl]azepane-4-carbonitrile (100 mg, 0.15 mmol), and HCl (5 mL, 2mol/L in dioxane ) was stirred at 25 oC for 1 h. The mixture was concentrated to afford a crude product. The crude product was purified by prep-HPLC (H2O:CH3CN = 90:10 to 50:50, 0.1% NH4HCO3 as additive) to obtain 1- [6-chloro-7-(7,8-difluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro -1, 2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]quinazolin-4-yl]azepane-4-carbonitrile, compound 2 (17.62 mg, 0.0271 mmol, 18.521% yield) as a white solid. MS (EIS) m/z calcd for C33H30ClF4N5O2+H: 640.2, found: 640.3.1H NMR (400 MHz, DMSO) δ 10.31 (s, 1H), 8.00 (s, 1H), 7.74 (dd, J = 8.8, 4.5 Hz, 1H), 7.57 (dd, J = 17.3, 9.5 Hz, 1H), 7.39 (s, 1H), 7.10 (s, 1H), 5.28 (d, J = 53.9 Hz, 1H), 4.15 – 4.02 (m, 2H), 3.99 (dd, J = 11.3, 5.1 Hz, 4H), 3.19 (s, 1H), 3.07 (t, J = 10.8 Hz, 2H), 3.01 (s, 1H), 2.84 (t, J = 7.1 Hz, 1H), 2.26 (s, 2H), 2.12 (dd, J = 16.4, 9.6 Hz, 2H), 2.05 (s, 2H), 2.01 (s, 2H), 1.90 – 1.81 (m, 2H), 1.81 – 1.72 (m, 2H). Example 3. Exemplary synthesis of compound 3
Figure imgf000138_0001
[00365] Step 1. To a solution of compound 2-amino-4-bromo-3-fluorobenzoic acid (20 g, 0.09 mol) in DMF (200 ml) was added NIS (21.1 g, 0.09 mol). The mixture was then stirred at 50 °C overnight. HPLC-MS showed that the starting material was consumed. The mixture was then cooled down to r.t. and poured into ice water slowly. The formed precipitate was then filtered and washed with heptane (100 mL x 3) to provide desired product 2-amino-4-bromo-3-fluoro-5- iodobenzoic acid (27.8 g, 89.6% yield) as a pale white solid. LC-MS calc. for C7H5BrFINO2 [M+H]+: m/z = 359.9/361.9; Found 359.8/361.8; HPLC: C18 column (4.6 x 150 mm, 5 μm); flow rate = 1 mL/ min; mobile phase: 5% MeCN/H2O (with 0.1% TFA) to 95% 10 min, 95% 5 min; λ = 220 nm. tR = 5.81 min. [00366] Step 2. To a solution of 2-amino-4-bromo-3-fluoro-5-iodobenzoic acid (5 g, 13.9 mmol) in DMF (10 mL) were added Pd(OAc)2 (311.5 mg, 1.4 mmol), tir-o-tolyphosphine (845.0 mg, 2.8 mmol), triethylamine ( 3.86 mL, 9.3 mmol) and acrylonitrile (2.43 mL, 27.8 mmol). The mixture was degassed with N2 for 5 min and stirred at 80 °C overnight. HPLC-MS showed that around 44% starting material was consumed. The reaction did not improve upon adding extra catalyst and acrylonitrile. The mixture was then cooled down to r.t. and purified by prep-HPLC on C18 column (30 x 250 mm, 10 μm) using mobile phase 0 to 100% MeCN/H2O (tR = 15 min) to afford (E)-2- amino-4-bromo-5-(2-cyanovinyl)-3-fluorobenzoic acid (1.89 g). LC-MS calc. for C10H7BrFN2O2 [M+H]+: m/z = 285.0/287.0; Found 284.9/286.9; HPLC: C18 column (4.6 x 150 mm, 5 μm); flow rate = 1 mL/ min; mobile phase: 5% MeCN/H2O (with 0.1% TFA) to 95% 10 min, 95% 5 min; λ = 220 nm. tR = 5.31 min. [00367] Step 3. To a solution of (E)-2-amino-4-bromo-5-(2-cyanovinyl)-3-fluorobenzoic acid (750 mg, 2.63 mmol) in dry THF (8 mL) at -40 °C was dropwise added superhydride (1 N, 13.2 mL, 13.16 mmol). The mixture was stirred at -40 °C for 10 min and then slowly warmed to r.t. in 30 min. HPLC-MS showed that the starting material was consumed. Meanwhile, about 53% over- reduced by-product was observed. The reaction was then quenched with the addition of sat. NaHCO3 solution. The crude was purified by prep-HPLC on C18 column (30 x 250 mm, 10 μm) using mobile phase 0 to 80% MeCN/H2O (tR = 20 min) to afford 2-amino-4-bromo-5-(2- cyanoethyl)-3-fluorobenzoic acid (210 mg). LC-MS calc. for C10H9BrFN2O2 [M+H]+: m/z = 287.0/289.0; Found 287.0/289.0; HPLC: C18 column (4.6 x 150 mm, 5 μm); flow rate = 1 mL/ min; mobile phase: 5% MeCN/H2O (with 0.1% TFA) to 95% 10 min, 95% 5 min; λ = 220 nm. tR = 5.31 min. [00368] Step 4. To a solution of 2-amino-4-bromo-5-(2-cyanoethyl)-3-fluorobenzoic acid (100 mg, 0.35 mmol) in dry THF (8 mL) was added triphosgene (52 mg, 0.18 mmol). The mixture was then stirred at 60 °C for 3 h. HPLC-MS showed that the starting material was completely consumed. The reaction was then cooled down to r.t. and quenched with the addition of solid Na2CO3. The solvent was then removed under reduced pressure to provide 3-(7-bromo-8-fluoro- 2,4-dioxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)propanenitrile (150 mg), which was directly used in the next step without further purification. LC-MS calc. for C11H7BrFN2O3 [M+H]+: m/z = 313.0/315.0; Found 312.9/315.0. [00369] Step 5. To a solution of 3-(7-bromo-8-fluoro-2,4-dioxo-1,4-dihydro-2H- benzo[d][1,3]oxazin-6-yl)propanenitrile (150 mg, 0.48 mmol) in THF (10 mL) was added NH4OH (1.5 mL). The mixture was stirred at r.t. for 3 h. HPLC-MS showed that the starting material was completely consumed. The solvent was then removed under reduced pressure. The resulting solid was then dissolved in THF (10 mL), followed by the addition of CDI (155.7mg, 0.96 mmol). The mixture was then stirred at 75 °C for 12 h. HPL-s showed that the starting material was consumed. The reaction was concentrated and the resulting solid was then filtered, washed with DCM (5 mL x 2) and heptane (5 mL x 2) to afford the desired product 3-(7-bromo-8-fluoro-2,4- dihydroxyquinazolin-6-yl)propanenitrile (146 mg). LC-MS calc. for C11H8BrFN3O2 [M+H]+: m/z = 312.0/314.0; Found 312.0/314.0; HPLC: C18 column (4.6 x 150 mm, 5 μm); flow rate = 1 mL/ min; mobile phase: 5% MeCN/H2O (with 0.1% TFA) to 95% 10 min, 95% 5 min; λ = 220 nm. tR = 4.64 min. [00370] Step 6. To a solution of 3-(7-bromo-8-fluoro-2,4-dihydroxyquinazolin-6- yl)propanenitrile (280 mg, 0.9 mmol) in POCl3 (5 mL) was slowly added DIEA (465.3 mg, 4.5 mmol). The mixture was then stirred at 100 °C for 3 h. HPLC-MS showed that the starting material was consumed. The solvent was co-evaporated with toluene. The resulting residue 3-(7-bromo- 2,4-dichloro-8-fluoroquinazolin-6-yl)propanenitrile (340 mg) was directly used in the next step without further purification. By-product will be observed if the reaction was treated by acid-base aqueous work-up. LC-MS calc. for C11H6BrCl2FN3 [M+H]+: m/z = 347.9/349.9; Found 347.9/349.9; HPLC: C18 column (4.6 x 150 mm, 5 μm); flow rate = 1 mL/ min; mobile phase: 5% MeCN/H2O (with 0.1% TFA) to 95% 10 min, 95% 5 min; λ = 220 nm. tR = 6.10 min. [00371] Step 7. The crude 3-(7-bromo-2,4-dichloro-8-fluoroquinazolin-6-yl)propanenitrile (340 mg, 0.98 mmol) from previous step in DCM/THF (8 mL, 1:1) was neutralized by DIPEA to basic at -60 °C. To this basic solution, piperidin-4-one (300.1 mg, 1.96 mmol) was then added. The resulting mixture was then slowly warmed to r.t. and stirred for another 1 h. HPLC-MS showed that the starting material was consumed. The residue was purified by prep-HPLC on C18 column (30 x 250 mm, 10 μm) using mobile phase 10 to 100% MeCN/H2O (tR = 20 min) to afford 3-(7-bromo-2-chloro-8-fluoro-4-(4-oxopiperidin-1-yl)quinazolin-6-yl)propanenitrile (310 mg). LC-MS calc. for C16H14BrClFN4O [M+H]+: m/z = 411.0/413.0; Found 411.0/413.0; HPLC: C18 column (4.6 x 150 mm, 5 μm); flow rate = 1 mL/ min; mobile phase: 5% MeCN/H2O (with 0.1% TFA) to 95% 10 min, 95% 5 min; λ = 220 nm. tR = 5.72 min. [00372] Step 8. To a solution of 3-(7-bromo-2-chloro-8-fluoro-4-(4-oxopiperidin-1- yl)quinazolin-6-yl)propanenitrile (50 mg, 0.12 mmol) in dioxane (5 mL) was added (S)-(1- methylpyrrolidin-2-yl)methanol (70.1 mg, 0.61 mmol) and DIPEA (78.8 mg, 0.61 mmol). The mixture was stirred at 90 °C in a sealed tube for 2 days. HPLC showed that about 60% starting material was consumed. The mixture was then purified by prep-HPLC on C18 column (30 x 250 mm, 10 μm) using mobile phase 10 to 80% MeCN/H2O (tR = 20 min) to afford (S)-3-(7-bromo- 8-fluoro-2-((1-methylpyrrolidin-2-yl)methoxy)-4-(4-oxopiperidin-1-yl)quinazolin-6- yl)propanenitrile (19.2 mg). LC-MS calc. for C22H26BrFN5O2 [M+H]+: m/z = 490.1/492.1; Found 490.1/492.1. [00373] Step 9. To a solution of (S)-3-(7-bromo-8-fluoro-2-((1-methylpyrrolidin-2- yl)methoxy)-4-(4-oxopiperidin-1-yl)quinazolin-6-yl)propanenitrile (19.2 mg, 0.04 mmol) in MeOH (4 mL) was added NaBH4 (4.5 mg, 0.12 mmol). The reaction was stirred at r.t. for 1 h. HPLC-MS showed that the starting material was consumed completely. The crude was then purified by prep-HPLC on C18 column (30 x 250 mm, 10 μm) using mobile phase 10 to 80% MeCN/H2O (tR = 20 min) to afford (S)-3-(7-bromo-8-fluoro-4-(4-hydroxypiperidin-1-yl)-2-((1- methylpyrrolidin-2-yl)methoxy)quinazolin-6-yl)propanenitrile (14 mg). LC-MS calc. for C22H28BrFN5O2 [M+H]+: m/z = 492.1/494.1; Found 492.1/494.1. [00374] Step 10. To a solution of (S)-3-(7-bromo-8-fluoro-4-(4-hydroxypiperidin-1-yl)-2-((1- methylpyrrolidin-2-yl)methoxy)quinazolin-6-yl)propanenitrile (14 mg, 0.03 mmol) in dioxane/H2O (5 ml, 4:1) were added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen- 2-ol (11.5 mg, 0.05 mmol), Pd(dppf)Cl2 (4.2 mg, 0.2 eq), Cs2CO3 (27.8 mg, 0.15 mmol). The mixture was degassed with N2 for 2 min. The mixture was then stirred at 100 °C for 12 h. The residue was then purified by prep-HPLC on C18 column (30 x 250 mm, 10 μm) using mobile phase 10 to 80% MeCN/H2O (tR = 20 min) to afford the desired product with minor impurity. The solid was then purified by normal phase on Prep silica (100 x 21.2 mm) using mobile phase 0 to 10% MTBE:MeOH (1:1)/Hexane:MTBE (1:1) to afford 3-(8-fluoro-7-(3-hydroxynaphthalen-1- yl)-4-(4-hydroxypiperidin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-6- yl)propanenitrile (compound 3, 3.6 mg) as a pale white solid. LC-MS calc. for C32H35FN5O3 [M+H]+: m/z = 556.3/557.3; Found 556.2/557.3; HPLC: C18 column (4.6 x 150 mm, 5 μm); flow rate = 1 mL/ min; mobile phase: 5% MeCN/H2O (with 0.1% TFA) to 95% 25 min, 95% 5 min; λ = 220 nm. tR = 10.54 min; 1H NMR (300 MHz, MeOD) δ 7.93 (s, 1H), 7.81 (d, J = 8.3 Hz, 1H), 7.46 (dd, J = 10.2, 4.1 Hz, 1H), 7.32 (d, J = 2.2 Hz, 1H), 7.24 (d, J = 5.9 Hz, 2H), 7.11 (d, J = 2.3 Hz, 1H), 4.63 (s, 3H), 4.42 (d, J = 13.1 Hz, 2H), 4.07 (d, J = 3.9 Hz, 1H), 3.80 – 3.69 (m, 3H), 3.02 (s, 3H), 2.86 (dd, J = 14.0, 6.8 Hz, 2H), 2.73 (d, J = 7.6 Hz, 1H), 2.47 – 2.38 (m, 2H), 2.09 (d, J = 13.3 Hz, 4H), 1.81 (s, 2H), 1.63 (s, 2H). Example 4: Compound 4
Figure imgf000142_0001
[00375] Synthesized in a fashion similar to example 3 using ((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methanol to afford 3-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-7-(3-hydroxynaphthalen-1-yl)-4-(4-hydroxypiperidin-1- yl)quinazolin-6-yl)propanenitrile (compound 4, 19.4 mg) as a pale white solid. LC-MS calc. for C34H36F2N5O3 [M+H]+: m/z = 600.3/601.3; Found 600.3/601.3; HPLC: C18 column (4.6 x 150 mm, 5 μm); flow rate = 1 mL/ min; mobile phase: 5% MeCN/H2O (with 0.1% TFA) to 95% 10 min, 95% 5 min; λ = 220 nm. tR = 4.70 min; 1H NMR (300 MHz, MeOD) δ 7.94 (s, 1H), 7.81 (d, J = 8.3 Hz, 1H), 7.47 (ddd, J = 8.1, 6.0, 2.0 Hz, 1H), 7.32 (d, J = 2.3 Hz, 1H), 7.29 – 7.17 (m, 2H), 7.13 – 7.07 (m, 1H), 5.63 – 5.45 (m, 1H), 4.66 (qd, J = 12.6, 4.3 Hz, 2H), 4.43 (d, J = 13.9 Hz, 2H), 4.11 – 4.02 (m, 1H), 3.79 (dd, J = 23.8, 13.4 Hz, 4H), 3.47 – 3.38 (m, 1H), 2.86 (dd, J = 14.3, 7.6 Hz, 1H), 2.78 – 2.62 (m, 2H), 2.55 (t, J = 5.5 Hz, 1H), 2.51 – 2.25 (m, 5H), 2.09 (d, J = 16.2 Hz, 3H), 1.79 (dt, J = 12.9, 8.8 Hz, 2H). Example 5: Synthesis of Compound 5
Figure imgf000142_0002
[00376] Step 1. To a solution of 7-bromo-2,4,6-trichloro-8-fluoro-quinazoline (600 mg, 1.82 mmol) and DIEA (0.9 mL, 5.45 mmol) in DCM (10 mL) was added azepane-4- carbonitrile;hydrochloride (306.33 mg, 1.91 mmol) at 0 oC. The mixture was stirred at 25 oC for 2 h. The mixture was concentrated to afford a crude product which was purified by silica gel chromatography eluted with EtOAc in petroleum ether from 10% to 30% to afford 5a 1-(7-bromo- 2,6-dichloro-8-fluoro-quinazolin-4-yl) azepane-4-carbonitrile (720 mg,1.72 mmol, 94.8 % yield) as a pale yellow solid. LCMS calculated for C15H12BrCl2FN4 (M+H)+ m/z = 417.0, found: 417.0. [00377] Step 2. The mixture of 1-(7-bromo-2,6-dichloro-8-fluoro-quinazolin-4-yl)azepane-4- carbonitrile (360 mg, 0.86 mmol) and [(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methanol (411.24 mg, 2.58 mmol) was stirred at 140 oC for 0.5 h. The crude product was purified by silica gel chromatography eluted with MeOH in DCM from 2% to 6% to afford 5b 1- [7-bromo-6-chloro-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]quinazolin-4-yl]azepane-4-carbonitrile (470 mg, 0.869 mmol, crude) as pale yellow solid. LCMS calculated for C23H25BrClF2N5O(M+H)+ m/z= 540.1, found 540.2. [00378] Step 3. The mixture of 1-[7-bromo-6-chloro-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydro- pyrrolizin-8-yl]methoxy]quinazolin-4-yl]azepane-4-carbonitrile (100 mg, 0.18 mmol), 3,4-dihydro-2H-1,4-benzoxazine (50 mg, 0.37 mmol), Pd(OAc)2 (8.3 mg, 0.04 mmol), Cs2CO3 (180.7 mg, 0.55 mmol) and Xantphos (21.4 mg, 0.04 mmol) in 1,4-Dioxane (10 mL) was stirred at 140 oC for 1 h under argon. The mixture was diluted with EtOAc (25 mL), washed with water (2 x 10 mL) and brine (10 ml), dried over Na2SO4, concentrated. The crude product was purified by prep-HPLC eluted with CH3CN in H2O (0.1 % TFA) from 5.0% to 95% to afford 1- [6-chloro-7-(2,3-dihydro-1,4-benzoxazin-4-yl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]quinazolin-4-yl]azepane-4-carbonitrile;2,2,2-trifluoroacetic acid (21.68 mg, 0.0214 mmol) as yellow solid. LCMS calculated for C31H33ClF2N6O2(M+H)+ m/z = 595.2, found: 595.1.1H NMR (400 MHz,CD3OD) δ 8.13 (s, 1H), 6.84 (dd, 1H), 6.69 – 6.67 (m, 2H), 6.27 – 6.20 (m, 1H), 5.62 -5.49 (m, 1H), 4.73 – 4.57 (m, 2H), 4.42 – 4.33 (m, 2H), 4.23 – 4.21 (m, 2H), 4.07 – 3.73 (m, 7H), 3.50 – 3.41 (m, 1H), 3.18– 3.16 (m, 1H), 2.73 – 2.61 (m, 1H), 2.58 – 2.50 (m, 1H), 2.40 – 2.38 (m, 1H), 2.37 – 3.412.30 (m, 5H), 2.13 – 1.94 (m, 4H). Example 6: Synthesis of Compounds 6 and 7
Figure imgf000143_0001
[00379] The mixture of 1-[7-bromo-6-chloro-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin -8-yl]methoxy]quinazolin-4-yl]azepane-4-carbonitrile (200 mg, 0.37 mmol), 1,2,3,4-tetrahydro- quinoline (1.5 mL, 0.14 mmol), Pd(OAc)2 (16.64 mg, 0.07 mmol), Xantphos (42.82 mg, 0.07 mmol) and Cs2CO3 (361.46 mg, 1.11 mmol) was stirred at 100 oC for 8 h (neat condition) under argon. The mixture was filtered and concentrated. The crude product was purified by prep-HPLC eluted with CH3CN in H2O (0.1 % FA) from 5.0% to 95% to afford 1-[6- chloro-7-(3,4-dihydro-2H-quinolin-1-yl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]quinazolin-4-yl] azepane-4-carbonitrile;formic acid (10.48 mg, 0.0159 mmol) (6) as yellow solid; LCMS calculated for C32H35ClF2N6O (M+H)+ m/z = 593.3, found: 593.1; 1H NMR (400 MHz, CD3OD) δ 8.52 (s, 1H), 8.07 (d, J = 1.8 Hz, 1H), 7.02 (d, J = 6.7 Hz, 1H), 6.83 (t, J = 7.3 Hz, 1H), 6.64 (t, J = 7.1 Hz, 1H), 6.04 (d, J = 8.4 Hz, 1H), 5.36 – 3.99 (m, 1H), 4.30 – 4.20 (m, 2H), 4.10 – 3.97 (m, 4H), 3.62 – 3.60 (m, 2H), 3.48 – 2.90 (m, 8H), 2.39 –1.97 (m, 13H); and (7) 1-[7-(3,4-Dihydro-2H-quinolin-1-yl)-8-fluoro-2-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7-hexahydro- pyrrolizin-8-yl]methoxy]quinazolin-4-yl]azepane-4-carbonitrile;formic acid (8.13 mg, 0.0116 mmol) (7) as yellow solid. LCMS calc for C32H36F2N6O (M+H)+ m/z = 559.3, found: 559.4; 1H NMR (400 MHz, CD3OD) δ 8.50 (s, 1H), 7.88 (d, 1H), 7.27 (t, 1H), 7.07 (d, 1H), 6.91 (t, 1H), 6.76 (t, 1H), 6.58 (d, 1H), 5.46 (m, 1H), 4.57 – 4.42 (m, 2H), 4.15 - 3.95 (m, 4H), 3.73 - 3.66 (m, 6H), 3.14 (m, 1H), 2.90-2.88 (m, 2H), 2.62- 1.92 (m, 14H). Example 7: Compound 8
Figure imgf000144_0001
[00380] Compound 8 was synthesized in a similar fashion to Compound 4. 1-(8-Fluoro-7-(3- hydroxynaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6-vinylquinazolin-4- yl)azepan-4-ol: LCMS calculated for C32H36FN4O3 (M+H)+ m/z = 543.66, found 543.12. 1H NMR (300 MHz, MeOD) δ 8.36 (s, 1H), 7.80 (d, 1H), 7.46 (dt, 1H), 7.31 (d, 1H), 7.22 (d, 1H), 7.13 (s, 1H), 7.04 (t, 1H), 6.85 (s, 1H), 6.32 (dd, 1H), 5.80 (d, 1H), 5.22 (d, 1H), 4.30 – 4.24 (m, 2H), 4.22 – 3.92 (m, 5H), 3.78 (s, 1H), 3.12 (s, 3H), 2.40 (m, 4H), 2.17 (m, 6H), 1.63 (s, 3H). Example 8: Synthesis of compounds 9 and 10
Figure imgf000145_0001
[00381] Step 1. The mixture of 1-[7-bromo-6-chloro-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]quinazolin-4-yl]azepane-4-carbonitrile (100.mg, 0.18mmol) 2-[2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1- naphthyl]ethynyl-triisopropyl-silane (284.31mg, 0.55mmol), CataCxium A Pd G3 (20.2mg, 0.03mmol), water (2mL), toluene (8mL) and Cs2CO3 (180.73mg, 0.55mmol) was stirred at 100 oC for 4 h under argon. The mixture was diluted with EA (50 mL), washed with H2O (2x10 mL) and brine (10 mL), dried over Na2SO4, and concentrated. The crude product was purified by silica gel chromatography (eluted with EtOAc in petroleum ether from 10% to 50%). The mixture of product 1-[6-chloro-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7-[7- fluoro-3-(methoxymethoxy)-8-(2-triisopropylsilylethynyl)-1-naphthyl]quinazolin-4-yl]azepane- 4-carbonitrile (9a, 60mg, 0.0709mmol, 38% yield) were obtained as brown solid. LCMS calc for C46H55ClF3N5O3Si (M+H)+ m/z = 846.4, found: 846.4. 1-[8-Fluoro-2-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7-[7-fluoro-3-(methoxymethoxy)-8-(2- triisopropylsilylethynyl)-1-naphthyl]quinazolin-4-yl]azepane-4-carbonitrile (10a, 60mg, 0.0739mmol, 39.96% yield)LCMS cal for C46H55F3N5O3Si (M+H)+ m/z = 812.4, found: 812.4. [00382] Step 2. The mixture of 1-[6-chloro-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-7-[7-fluoro-3-(methoxymethoxy)-8-(2- triisopropylsilylethynyl)-1-naphthyl]quinazolin-4-yl]azepane-4-carbonitrile (30.mg, 0.04mmol), 1-[8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7-[7-fluoro-3- (methoxymethoxy)-8-(2-triisopropylsilylethynyl)-1-naphthyl]quinazolin-4-yl]azepane-4- carbonitrile (30.mg, 0.04mmol) 4M HCl in 1,4-dioxane (0.5mL, 0.04mmol), MeCN (2mL) was stirred at 25 oC for 1 h. The mixture was basified with saturated aqueous NaHCO3 to pH=9, extracted with DCM (2 x 10mL), dried over Na2SO4, concentrated. [00383] Step 3. The mixture of 1-[6-chloro-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-7-[7-fluoro-3-hydroxy-8-(2-triisopropylsilylethynyl)-1- naphthyl]quinazolin-4-yl]azepane-4-carbonitrile (20.mg, 0.02mmol)1-[8-fluoro-2-[[(2R,8S)-2- fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7-[7-fluoro-3-hydroxy-8-(2- triisopropylsilylethynyl)-1-naphthyl]quinazolin-4-yl]azepane-4-carbonitrile (20.mg, 0.03mmol), CsF (18.93mg, 0.12mmol), DMF (1.5mL), was stirred at 50 oC for 1 h. The crude product was purified by Prep-HPLC (eluted with CH3CN in H2O (0.1 % TFA) from 5.0% to 95%); [00384] Compound 9: 1-[6-chloro-7-(8-ethynyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazolin-4-yl]azepane-4- carbonitrile;2,2,2-trifluoroacetic acid (5.6 mg, 0.0068mmol, 27% yield) was obtained as a brown solid. LCMS calc for C35H31ClF3N5O2 (M+H)+ m/z =646.2, found: 646.2. 1H NMR (400 MHz, MeOD) δ 8.08 – 8.05 (m, 1H), 7.86 (dd, J = 9.0, 5.9 Hz, 1H), 7.36 – 7.28 (m, 2H), 7.07 – 7.04 (m, 1H), 5.62 – 5.44 (m, 1H), 4.82 – 4.53 (m, 2H), 4.42 – 4.24 (m, 2H), 4.20 – 3.76 (m, 5H), 3.49 – 3.38 (m, 2H), 3.27 – 3.20 (m, 2H), 2.68 – 2.53 (m, 2H), 2.49 – 2.21 (m, 6H), 2.19 – 1.94 (m, 6H). [00385] Compound 10: 1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)azepane-4- carbonitrile (3 mg, 0.004mmol) was obtained as a brown solid. LCMS calc for C35H32F3N5O2 (M+H)+ m/z = 612.3, found: 612.3. 1H NMR (400 MHz, MeOD) δ 7.90 – 7.79 (m, 2H), 7.58 – 7.49 (m, 1H), 7.38 – 7.23 (m, 2H), 7.14 – 7.04 (m, 1H), 5.68 – 5.48 (m, 1H), 4.77 – 4.61 (m, 2H), 4.30 – 4.13 (m, 2H), 4.12 – 3.78 (m, 5H), 3.55 – 3.45 (m, 2H), 2.79 – 2.56 (m, 2H), 2.47 – 2.16 (m, 7H), 2.08 – 1.79 (m, 4H). Example 9: Synthesis of compounds 11 and 12
Figure imgf000146_0001
[00386] Compounds 11 and 12 were synthesized in a similar fashion to Example 8 using 4-((1- ((λ1-oxidaneyl)methyl)cyclopropyl)methyl)morpholine instead of [(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methanol. Compound 11 1-(6-Chloro-7-(8-ethynyl-7-fluoro-3- hydroxynaphthalen-1-yl)-8-fluoro-2-((1-(piperidin-4-ylmethyl)cyclopropyl)methoxy)quinazolin- 4-yl)azepane-4-carbonitrile; LCMS calc for C36H34ClF2N5O3 (M+H)+ m/z =658.2, found: 658.3. 1H NMR (400 MHz, MeOD) δ 8.07 – 8.03 (m, 1H), 7.86 (dd, 1H), 7.36 – 7.27 (m, 2H), 7.08 – 7.03 (m, 1H), 4.52 (d, 1H), 4.43 (d, 1H), 4.37 – 4.24 (m, 2H), 4.23 – 3.83 (m, 6H), 3.38-3.33 (m, 4H), 3.27 – 3.20 (m, 3H), 2.45 – 2.27 (m, 4H), 2.17 – 2.10 (m, 1H), 2.08 – 1.99 (m, 2H), 0.99 (m, 2H), 0.88 (m, 2H). [00387] Compound 12 1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((1- (morpholinomethyl)cyclopropyl)methoxy)quinazolin-4-yl)azepane-4-carbonitrile; LCMS calc for C36H35F2N5O3 (M+H)+ m/z = 624.3, found: 624.3. 1H NMR (400 MHz, MeOD) δ 7.90 (s, 1H), 7.84 (dd, 1H), 7.67 – 7.59 (m, 1H), 7.36 – 7.25 (m, 2H), 7.10 (dd, 1H), 4.63 (d, 1H), 4.55 (d, 1H), 4.48 (d, 1H), 4.33 – 4.07 (m, 3H), 4.06 – 3.85 (m, 5H), 3.54 – 3.43 (m, 2H), 3.42 – 3.36 (m, 2H), 3.23 – 3.05 (m, 2H), 2.34 – 2.17 (m, 3H), 2.08 – 1.83 (m, 4H), 1.09 – 0.98 (m, 4H). Synthesis of compound 13
Figure imgf000147_0001
[00388] Compound 13 was synthesized in a similar fashion to example 8. 5-Ethynyl-6-fluoro- 4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,3,6,7- tetrahydro-1H-azepin-1-yl)quinazolin-7-yl)naphthalen-2-ol. LCMS calc for C34H32F3N4O2 (M+H)+ m/z = 585.2; found: 585.4. 1H NMR (400 MHz, MeOD) δ 7.78 - 7.91 (m, 2H), 7.25 - 7.33 (m, 2H), 7.19 (dd, 1H), 7.08 (d, 1H), 5.72 - 5.84 (m, 2H), 5.30 (d, J = 54.0 Hz, 1H), 4.01- 4.47 (m, 6H), 3.09 - 3.28 (m, 4H), 2.95 - 3.05 (m, 1H), 2.60 - 2.70 (m, 3H),1.79 - 2.42 (m, 7H). Example 10. Exemplary Synthesis of 7-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)- 1,3,7-triazaspiro[4.5]decane-2,4-dione (Compound 14) and 7-(7-(8-ethyl-7-fluoro-3- hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)quinazolin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione (compound 15)
Figure imgf000147_0002
[00389] Step 1. preparation of 7-(7-bromo-2-chloro-8-fluoroquinazolin-4-yl)-1,3,7- triazaspiro[4.5]decane-2,4-dione (14a). The mixture of 7-bromo-2,4-dichloro-8-fluoro- quinazoline (600.0 mg, 2.03 mmol), 1,3,9-triazaspiro[4.5]decane-2,4-dione (377.33 mg, 2.23 mmol), DIEA (0.71 mL, 4.06 mmol) in DCM (10 mL) was stirred at 25 oC for 2 h. The mixture was concentrated. The crude was purified by flash chromatography column (eluted with MeCN in H2O from 0% to 100%). 9-(7-bromo-2-chloro-8-fluoro-quinazolin-4-yl)-1,3,9- triazaspiro[4.5]decane-2,4-dione (14a, 850 mg, 1.98 mmol, 97.8%) was obtained as a yellow solid. LCMS calcld for C15H12BrClFN5O2 (M+H)+ m/z = 428.2, found: 428.2. [00390] Step 2. preparation of 7-(7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione (14b). The mixture of 9-(7-bromo-2-chloro-8-fluoro-quinazolin-4-yl)-1,3,9-triazaspiro[4.5]decane- 2,4- dione (14a, 500.0 mg, 1.17 mmol), Cs2CO3 (210.14mg, 3.5mmol), DABCO (65.42 mg, 0.58 mmol) and [(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methanol (371.41 mg, 2.33 mmol) in DMF (10 mL) and THF (10 mL) was stirred at 25 oC for 16 h. The mixture was diluted with EtOAC (20 mL), washed with water (20 mL) and brine (20 ml), dried over Na2SO4, filtered and concentrated. The crude product was purified by silica gel chromatography (eluted with EtOAc in petroleum ether from 5% to 90%) to give 9-[7-bromo-8-fluoro-2-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazolin-4-yl]-1,3,9-triazaspiro[4.5]decane-2,4- dione (14b, 180 mg, 0.3265 mmol, 27.9%) as a yellow solid. LCMS calcld for C23H25BrF2N6O3 (M+H)+ m/z = 551.2, found: 551.2. [00391] Step 3. preparation of 7-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)quinazolin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione (14c). To a solution of 9-[7-bromo-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin -8- yl]methoxy]quinazolin-4-yl]-1,3,9-triazaspiro[4.5]decane-2,4-dione (14b, 150.0 mg, 0.27 mmol) in 1,4-Dioxane (5 mL) and Water (1 mL) were added 2-[2-fluoro-6-(methoxymethoxy) -8- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-naphthyl]ethynyl-triisopropyl-silane (167.32mg, 0.33mmol), K3PO4 (173.23 mg, 0.82 mmol) and [2-(2-aminophenyl)phenyl]palladium (1+);bis(1- adamantyl)-butyl-phosphane;methanesulfonate (19.81 mg, 0.03 mmol) at rt under nitrogen. The mixture was stirred at 100 °C for 4 h. The reaction mixture was quenched with water (20 mL), extracted with EtOAc (20 mL×3), washed with brine (20 mL), dried over Na2SO4, filtered, concentrated. The crude was purified by flash chromatography column (eluted with MeCN in H2O from 0% to 100%) to give 9-[8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]-7-[7-fluoro-3-(methoxymethoxy)-8-(2-triisopropylsilylethynyl)-1- naphthyl]quinazolin-4-yl]-1,3,9-triazaspiro[4.5]decane-2,4-dione (14c, 100 mg, 0.1167 mmol, 42.9% yield) as a yellow solid. LCMS calcd for C46H55F3N6O5Si(M+H)+: 857.4, found: 857.4. [00392] Step 4. preparation of 7-(8-fluoro-7-(7-fluoro-3-hydroxy-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)quinazolin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione (14d). To a solution of 9-[8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl] methoxy]-7-[7-fluoro- 3-(methoxymethoxy)-8-(2-triisopropylsilylethynyl)-1-naphthyl]quinazolin-4-yl]-1,3,9- triazaspiro[4.5]decane-2,4-dione (14c,40.0 mg, 0.05 mmol) in DCM (2 mL) was added 4 M HCl in dioxane (2.0 mL, 0.05 mmol) at 25 °C. The reaction mixture was then stirred at 25 °C for 30 min. The mixture was concentrated to afford the crude product 14d, which was used for next step without further purification. LCMS calcd for C44H51F3N6O4Si(M+H)+: 813.4, found: 813.4. [00393] Step 5. preparation of 7-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-1,3,7- triazaspiro[4.5]decane-2,4-dione (14). To a solution of 9-[8-fluoro-2-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy] -7-[7-fluoro-3-hydroxy-8-(2- triisopropylsilylethynyl)-1-naphthyl]quinazolin-4-yl]-1,3,9-triazaspiro[4.5]decane-2,4-dione (14d, 35 mg, 0.04 mmol) in DMF (2 mL) was added CsF (32.7 mg, 0.22 mmol) at rt. The mixture was stirred at 60 °C for 4 h. The mixture was filtered and was purified by Flash eluting with 0- 90% ACN in water (0.1% TFA) to obtain 9-[7-(8-ethynyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro -2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazolin-4-yl]- 1,3,9-triazaspiro[4.5]decane-2,4-dione;2,2,2-trifluoroacetic acid (14, 4.44 mg, 0.0067 mmol, 15.5 % yield) as a yellow solid. LCMS calcld. for C35H31F3N6O4 (M+H)+ m/z =657.3, found: 657.3. 1HNMR (400 MHz, CD3OD) δ 7.94-7.81 (m, 2H), 7.45-7.27 (m, 3H), 7.14-7.07 (m, 1H), 5.65- 5.45 (m, 1H), 4.80-4.26 (m, 4H), 4.10-3.64 (m, 5H), 3.52-3.38 (m, 1H), 3.24-3.16 (m, 1H), 2.76- 1.90 (m, 11H). [00394] Step 6. preparation of 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-1,3,7- triazaspiro[4.5]decane-2,4-dione (15). To a solution of 9-[7-(8-ethynyl-7-fluoro-3-hydroxy-1- naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]quinazolin-4-yl]-1,3,9-triazaspiro[4.5]decane-2,4-dione (14, 20.mg, 0.03mmol) in Methanol (2 mL) was added Pd/C (4.0 mg, 0.03mmol) at 25 oC, The mixture was stirred at 25 oC for 16 h under H2 (1 atm). LCMS showed the desired product. The mixture was filtered and concentrated. The mixture was purified by Prep-HPLC (eluted with CH3CN in H2O (0.1 % TFA) from 5.0% to 95%) to obtain 9-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)- 2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazolin-4-yl]-1,3,9- triazaspiro[4.5]decane-2,4-dione;2,2,2-trifluoroacetic acid (15, 3.85mg, 0.0041mmol, 13.6% yield) as a white solid. LCMS calcld for C35H35F3N6O4 (M+H)+ m/z = 661.3, found: 661.3. 1HNMR (400 MHz, CD3OD): δ 8.47 (s, 1H), 7.96-7.89 (m, 1H), 7.70-7.61 (m, 1H), 7.43-7.34 (m, 1H), 7.28-7.21 (m, 2H), 7.02-6.92 (m, 1H), 5.60-5.41 (m, 1H), 4.67-4.37 (m, 5H), 3.82-3.62 (m, 4H), 3.42-3.32 (m, 1H), 2.61-1.91 (m, 13H), 0.82-0.71 (m, 3H). Compound 16 and Compound 17. (R)-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fl uoro-2-((1-(morpholinomethyl)cyclopropyl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (1 6) and (R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((1-(morpholinomethyl) cyclopropyl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (17)
Figure imgf000150_0001
[00395] Compounds 16 and 17 were prepared similarly to those described in Ex.10. Compound 16: LCMS calcld for C35H36F2N4O4 (M+H)+ m/z = 615.28 , found: 615.2; 1HNMR (400 MHz, CD3OD) δ 8.12 (dd, J = 15.7, 8.6 Hz, 1H), 7.86 (dd, J = 9.1, 5.8 Hz, 1H), 7.50 (t, J = 7.6 Hz, 1H), 7.38 – 7.28 (m, 2H), 7.14 (dd, J = 8.7, 2.4 Hz, 1H), 4.95 (s, 1H), 4.72 (m, 2H), 4.61 – 4.38 (m, 2H), 4.14 – 3.60 (m, 7H), 3.55 – 3.32 (m, 4H), 3.18 – 3.07 (m, 1H), 2.24 – 2.08 (m, 1H), 1.93 – 1.76 (m, 3H), 1.31 (d, J = 8.8 Hz, 3H), 1.10 – 0.90 (m, 4H). Compound 17: LCMS calcld for C35H40F2N4O4 (M+H)+ m/z = 619.31 , found: 619.1; 1HNMR (400 MHz, CD3OD) δ 7.93 (dd, J = 8.4, 3.7 Hz, 1H), 7.64 (dd, J = 9.0, 5.9 Hz, 1H), 7.30 – 7.17 (m, 3H), 6.95 (d, J = 2.6 Hz, 1H), 4.57 (s, 2H), 4.48 – 4.37 (m, 2H), 4.19 – 4.17 (m, 1H), 4.03 (d, J = 11.9 Hz, 1H), 3.63 (t, J = 4.5 Hz, 4H), 2.49 – 2.43 (m, 8H), 2.17 – 2.13 (m, 1H), 1.82 – 1.73 (m, 3H), 1.25 (d, J = 7.7 Hz, 3H), 0.78 (td, J = 7.3, 4.5 Hz, 3H), 0.70 (m, 2H), 0.48 (m, 2H). Example 11. Exemplary Synthesis of (5R)-9-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazolin-4-yl]- 1,3,9-triazaspiro[4.5]decane-2,4-dione (Compound 18)
Figure imgf000151_0001
[00396] Step 1. preparation of (5R)-3-(2,2-dimethylpropanoyloxymethyl)-2,4-dioxo-1,3,9- triazaspiro[4.5]decane-9-carboxylate (18a). To a solution of benzyl (5R)-2,4-dioxo-1,3,9- triazaspiro[4.5]decane-9-carboxylate (5000 mg, 16.48 mmol) and K2CO3 (4784.56 mg, 34.62 mmol) in DMF (40 mL) was added chloromethyl 2,2-dimethylpropanoate (2979.13 mg, 19.78 mmol) at 25 °C and Ar. The mixture was stirred at 25 °C overnight. The reaction mixture was diluted with ethyl acetate. The organic phase was washed with water, brine solution, dried over anhydrous Na2SO4, and then concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, eluting with 10% to 50% EtOAc/PE) to afford benzyl (5R)-3-(2,2-dimethylpropanoyloxymethyl)-2,4-dioxo-1,3,9-triazaspiro[4.5]decane-9-carboxylate (18a, 5600 mg,13.41 mmol, 81.38% yield) as white solid. LCMS calculated for C21H28N3O6 (M+H)+ m/z = 418.2; found: 418.2. [00397] Step 2. preparation of [(5R)-2,4-dioxo-1,3,9-triazaspiro[4.5]decan-3-yl]methyl 2,2- dimethylpropanoate (18b). A mixture of benzyl (5R)-3-(2,2-dimethylpropanoyloxymethyl)-2,4- dioxo-1,3,9-triazaspiro[4.5]decane-9-carboxylate (18a, 4750 mg, 11.38 mmol) in Ethanol (100 mL) was added Pd/C (1046.81 mg, 9.1 mmol). The resulting mixture was recharged with H2 then stirred at 25 °C under H2 for 16h. the reaction mixture is filtered and concentrated to give crude [(5R)-2,4-dioxo-1,3,9-triazaspiro[4.5]decan-3-yl]methyl 2,2-dimethylpropanoate (18b, 3200 mg,11.30 mmol, 99.27% yield) as a colorless oil. LCMS calculated for C13H22N3O4(M+H)+ m/z = 284.2; found:284.2 [00398] Step 3. preparation of [(5R)-9-(7-bromo-2-chloro-8-fluoro-quinazolin-4-yl)-2,4-dioxo- 1,3,9-triazaspiro[4.5]decan-3-yl]methyl 2,2-dimethylpropanoate (18c). To a solution of 7-bromo- 2,4-dichloro-8-fluoro-quinazoline (3373.65 mg, 11.4 mmol) and [(5R)-2,4-dioxo-1,3,9- triazaspiro[4.5]decan-3-yl]methyl 2,2-dimethylpropanoate (18b, 3230 mg, 11.4 mmol) in DCM (50mL) was added DIEA (4.96mL, 28.5mmol) at -70 °C under N2. The mixture was stirred at RT for 2h. The mixture was concentrated and purified by flash silica gel column chromatography (DCM/MeOH=20:1) to afford [(5R)-9-(7-bromo-2-chloro-8-fluoro-quinazolin-4-yl)-2,4-dioxo- 1,3,9-triazaspiro[4.5]decan-3-yl]methyl 2,2-dimethylpropanoate (18c, 6156 mg,11.34 mmol, 99.48% yield) as a light-yellow solid. LCMS calculated for C21H23BrClFN5O4 (M+H)+ m/z = 542.05; found: 542.0/544.0 [00399] Step 4. preparation of [(5R)-9-[7-bromo-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]quinazolin-4-yl]-2,4-dioxo-1,3,9-triazaspiro[4.5]decan-3- yl]methyl 2,2-dimethylpropanoate (18d). A solution of [(5R)-9-(7-bromo-2-chloro-8-fluoro- quinazolin-4-yl)-2,4-dioxo-1,3,9-triazaspiro[4.5]decan-3-yl]methyl 2,2-dimethylpropanoate (18c 5000 mg, 9.21mmol) and [(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl] methanol (5132.74 mg, 32.24 mmol) in 1,4-Dioxane (10 mL) was added DIEA (3571.55 mg, 27.63 mmol). The resulting mixture was stirred at 115 °C in a sealed tube overnight. The resulting mixture was concentrated and purified by flash column chromatography (silica gel, eluting with 0% to 10% MeOH/DCM) to afford [(5R)-9-[7-bromo-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]quinazolin-4-yl]-2,4-dioxo-1,3,9-triazaspiro[4.5]decan-3- yl]methyl 2,2-dimethylpropanoate (18d, 3240 mg,4.87 mmol, 52.85 % yield) as a white solid. LCMS calculated for C29H36BrF2N6O5 (M+H)+ m/z = 665.2; found: 665.4 [00400] Step 5. preparation of [(5R)-9-[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]- 8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazolin-4-yl]- 2,4-dioxo-1,3,9-triazaspiro[4.5]decan-3-yl]methyl 2,2-dimethylpropanoate (18e). The mixture of [(5R)-9-[7-bromo-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]quinazolin-4-yl]-2,4-dioxo-1,3,9-triazaspiro[4.5]decan-3-yl]methyl 2,2- dimethylpropanoate (18d, 1500 mg, 2.25 mmol), 2-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1- naphthyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1055.47 mg, 2.93 mmol), and Cs2CO3 (2203.04 mg, 6.76 mmol) in 1,4-Dioxane (12 mL)/Water (1.2 mL) was recharged with Ar. Then CataCXium A Pd G3 (328.28mg, 0.45mmol) was added under Ar and the reaction was microwaved at 85 °C for 2.5h. Then the mixture was filtered and concentrated. The residue was purified by flash column chromatography (silica gel, eluting with 4% MeOH/DCM) to afford [(5R)-9-[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-2-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazolin-4-yl]-2,4-dioxo-1,3,9- triazaspiro[4.5]decan-3-yl]methyl 2,2-dimethylpropanoate (18e, 1680 mg, 2.05 mmol, 91.02% yield) as a brown solid. LCMS calculated for C43H50F3N6O7 (M+H)+ m/z = 819.4; found:819.5 [00401] Step 6. preparation of (5R)-9-[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazolin-4-yl]- 1,3,9-triazaspiro[4.5]decane-2,4-dione (18f). To a solution of [(5R)-9-[7-[8-ethyl-7-fluoro-3- (methoxymethoxy)-1-naphthyl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin- 8-yl]methoxy]quinazolin-4-yl]-2,4-dioxo-1,3,9-triazaspiro[4.5]decan-3-yl]methyl 2,2- dimethylpropanoate (18e,1680 mg, 2.05 mmol) in THF (25 mL)/Methanol (2.5 mL) was added Lithium Hydroxide (294.81 mg, 12.31 mmol) and the reaction was stirred at rt for 2h. HCl- dioxane(4 M) was added to the mixture until the pH was weak acid. The mixture was concentrated and residue was purified with pre-HPLC on a C18 column with a mobile phase (H2O- NH4HCO3/ACN) to afford (5R)-9-[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazolin-4-yl]- 1,3,9-triazaspiro[4.5]decane-2,4-dione (18f, 1100 mg,1.56 mmol, 76.08% yield) as a white solid. LCMS calculated for C37H40F3N6O5 (M+H)+ m/z = 705.3; found: 705.5. [00402] Step 7. preparation of (5R)-9-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazolin-4-yl]-1,3,9- triazaspiro[4.5]decane-2,4-dione. To a solution of (5R)-9-[7-[8-ethyl-7-fluoro-3- (methoxymethoxy)-1-naphthyl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin- 8-yl]methoxy]quinazolin-4-yl]-1,3,9-triazaspiro[4.5]decane-2,4-dione (18f, 340 mg, 0.48 mmol) in MeCN (12 mL) was added HCl in Dioxane (1.45mL, 5.79mmol) and the reaction was stirred at RT for 2h. Then the mixture was concentrated and purified by Prep-HPLC on a C18 column (5 uM, 50 x 150 mm) with mobile phase: H2O (0.1% NH4HCO3) / MeCN at flow rate : 35 mL/min to afford (5R)-9-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazolin-4-yl]-1,3,9-triazaspiro[4.5]decane-2,4- dione (Compound 18, 240 mg, 0.36 mmol, 74.77% yield) as a white solid. LCMS calculated for C35H36F3N6O4 (M+H)+ m/z =661.3; found: 661.2.1H NMR (400 MHz, CD3OD) δ 7.88 (d, J = 8.8 Hz, 1H), 7.65 (dd, J = 8.8, 5.6 Hz, 1H), 7.31 (dd, J = 8.8, 7.2 Hz, 1H), 7.18 – 7.26 (m, 2H), 6.95 (d, J = 2.8 Hz, 1H), 5.31 (d, J = 54.0 Hz, 1H), 4.34 – 4.49 (m, 2H), 4.26 (s, 2H), 3.50 – 3.71 (m, 2H), 3.14 – 3.29 (m, 3H), 2.96 – 3.06 (m, 1H), 2.29 – 2.52 (m, 3H), 2.14 – 2.28 (m, 3H), 1.88 – 2.08 (m, 6H), 0.76 (td, J = 7.6, 2.0 Hz, 3H). Compound 19. (3R)-1-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[(2-methyl-1,1- dioxo-thiazinan-3-yl)methoxy]quinazolin-4-yl]-3-methyl-piperidin-3-ol
Figure imgf000153_0001
[00403] Compounds 19 was prepared similarly to those described in Ex.11. LCMS calculated for C32H37F2N4O5S (M+H)+ m/z =627.3; found:627.4.1H NMR (400 MHz, CD3OD) δ 7.95 (d, J = 8.8 Hz, 1H), 7.64 (dd, J = 9.2, 6.0 Hz, 1H), 7.17 – 7.33 (m, 3H), 6.95 (d, J = 2.4 Hz, 1H), 4.61 – 4.66 (m, 2H), 4.17 – 4.28 (m, 2H), 4.09 (d, J = 13.2 Hz, 1H), 3.43 – 3.63 (m, 2H), 2.99 – 3.14 (m, 2H), 2.89 (s, 3H), 2.23 – 2.54 (m, 2H), 2.11 – 2.27 (m, 3H), 1.66 – 1.90 (m, 5H), 1.27 (dd, J = 14.0, 1.6 Hz, 3H), 0.78 (dd, J = 12.4, 7.2 Hz, 3H). Example 12. Exemplary Synthesis of [1-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazolin-4-yl]-3-methyl-3- piperidyl]cyanamide (Compound 20).
Figure imgf000154_0001
[00404] Step 1. preparation of tert-butyl N-[1-(7-bromo-2-chloro-8-fluoro-quinazolin-4-yl)-3- methyl-3-piperidyl]carbamate (20a). A solution of 7-bromo-2,4-dichloro-8-fluoro-quinazoline (450 mg, 1.52 mmol) in DMF (2 mL) was added DIEA (393.07 mg, 3.04 mmol) at 0 °C. Then the mixture was added dropwise a solution of tert-butyl N-(3-methyl-3-piperidyl)carbamate (325.88 mg, 1.52 mmol) in DMF (2 mL) at 0 °C. The mixture was stirred at 0 °C for 30 mins. The solution was extracted with EtOAc (10 ml x3), dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography (eluted with EtOAc in petroleum ether from 5% to 12%). The product of tert-butyl N-[1-(7-bromo-2-chloro-8-fluoro-quinazolin-4-yl)-3-methyl-3- piperidyl]carbamate (20a, 450 mg, 0.95 mmol, 62.46% yield) was obtained as a white solid. LCMS calculated for C19H23BrClFN4O2 (M+H)+ m/z =473.77, found: 473.1. [00405] Step 2. preparation of 1-(7-bromo-2-chloro-8-fluoro-quinazolin-4-yl)-3-methyl- piperidin-3-amine;hydrochloride (20b). A solution of tert-butyl N-[1-(7-bromo-2-chloro-8-fluoro- quinazolin-4-yl)-3-methyl-3-piperidyl]carbamate (20a, 180 mg, 0.38 mmol) in HCl in Dioxane (1 mL, 4.mmol) was stirred at 25 °C for 0.5 h. The solution was concentrated. The crude was used to next step directly. LCMS calculated for C14H15BrClFN4 (M+H)+ m/z =373.65, found: 373.1. [00406] Step 3. preparation of [1-(7-bromo-2-chloro-8-fluoro-quinazolin-4-yl)-3-methyl-3- piperidyl]cyanamide (20c). A solution of 1-(7-bromo-2-chloro-8-fluoro-quinazolin-4-yl)-3- methyl-piperidin-3-amine (20b, 90 mg, 0.24 mmol) in THF (1 mL) was added NaOAc (39.51 mg, 0.48 mmol) and carbononitridic bromide (25.51 mg, 0.24 mmol) at 25 °C. The solution was stirred at 25 °C for 1 h. The solution was extrated with Ethyl acetate (3 ml x3), dried over Na2SO4 and concentrated. The crude was purified by prep-TLC (DCM:MeOH=50:1). The product of [1-(7- bromo-2-chloro-8-fluoro-quinazolin-4-yl)-3-methyl-3-piperidyl]cyanamide (20c 85 mg, 0.21 mmol, 88.52% yield) was obtained as a white solid. LCMS calculated for C15H14BrClFN5 (M+H)+ m/z =398.66, found: 398.2. [00407] Step 4. preparation of [1-[7-bromo-8-fluoro-2-[[rac-(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]quinazolin-4-yl]-3-methyl-3-piperidyl]cyanamide (20d). A solution of [(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methanol (159.74 mg, 1 mmol) in DMSO (0.2 mL) was added NaH (10.03 mg, 0.25 mmol) at 25 °C for 30 mins, Then a solution [1-(7-bromo-2-chloro-8-fluoro-quinazolin-4-yl)-3-methyl-3-piperidyl]cyanamide (20c, 20 mg, 0.05 mmol) in DMSO (0.2 mL) was added to the above solution at 25 °C for 30 mins. The solution was quenched with CH3COOH until the solution became cleared. The solution was purified by prep-HPLC (eluting with CH3CN in H2O from 5 % to 95 %). The product of [1-[7- bromo-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazolin- 4-yl]-3-methyl-3-piperidyl]cyanamide (20d, 70 mg,0.13 mmol, 66.90% yield) was obtained as a brown oil. LCMS calculated for C23H27BrF2N6O (M+H)+ m/z =521.4, found: 521.2. [00408] Step 5. preparation of [1-[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]- 8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazolin-4-yl]-3- methyl-3-piperidyl]cyanamide (20e). A solution of [1-[7-bromo-8-fluoro-2-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazolin-4-yl]-3-methyl-3-piperidyl]cyanamide (20d, 30 mg, 0.06 mmol) in 1,4-Dioxane (0.2 mL) and Water (0.1 mL) was added 2-[8-ethyl-7- fluoro-3-(methoxymethoxy)-1-naphthyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (24.87 mg, 0.07mmol), cataxium A Pd (4.19 mg, 0.01 mmol) and CS2CO3 (18.76 mg, 0.06 mmol) at 25 °C, Then the mixture was stirred at 100 °C for 1 h. The solution was extracted with Ethyl Acetate (1 ml x3), dried over Na2SO4 and concentrated. The residue was purified by prep-TLC (DCM:MeOH=20:1). The product of [1-[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8- fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazolin-4-yl]-3- methyl-3-piperidyl]cyanamide (20e, 25 mg, 0.031 mmol, 64.40% yield) was obtained as a brown solid. LCMS calculated for C37H41F3N6O3 (M+H)+ m/z =675.76, found: 675.3. Step 6. preparation of [1-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2- fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazolin-4-yl]-3-methyl-3- piperidyl]cyanamide (Compound 20). A solution of [1-[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)- 1-naphthyl]-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]quinazolin-4-yl]-3-methyl-3-piperidyl]cyanamide (20e, 25 mg, 0.04 mmol) in MeCN (0.5 mL) was added HCl in Dioxane (0.2 mL, 0.8 mmol) at 25 °C for 1 h. The solution was purified by prep-HPLC (eluting with CH3CN (0.1 % TFA) in H2O from 5% to 95 %). The product of [1- [7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]quinazolin-4-yl]-3-methyl-3-piperidyl]cyanamide;2,2,2- trifluoroacetic acid (20, 4.35 mg,0.0046 mmol, 12.31% yield) was obtained as a yellow solid. LCMS calculated for C35H37F3N6O2 (M+H)+ m/z =631.3, found: 631.4. 1H NMR (400 MHz, CD3OD) δ 7.975 (d, J=8.8 Hz, 1 H), 7.708-7.670 (m, 1 H), 7.505-7.435 (m, 1 H), 7.292-7.243 (m, 2 H), 6.986-6.967 (m, 1 H), 5.578 (d, J=52.8 Hz, 1 H), 4.773-4.7644 (m, 2 H), 4.585-4.407 (m, 2 H), 4.098-3.838 (m, 3 H), 3.692-3.572 (m, 2 H), 3.510-3.433 (m, 1 H), 2.7922.327 ((m, 7 H), 2.233-1.871 (m, 5 H), 1.415–1.397 (m, 3 H), 0.840-0.781 (m, 3 H). Example 13: Nucleotide Exchange Assay: [00409] Ras proteins cycle between an active, GTP bound state, and an inactive GDP-bound state. This activity is tightly regulated by GTPase activating proteins (GAPs) and guanine nucleotide exchange factors (GEFs). GEFs, such as SOS1/2, activate Ras proteins by exchanging GDP for GTP, thus returning Ras to its active conformation (Simanshu, Nissley, & McCormick, 2017). Therefore, a small molecule that binds K-Ras in a manner that prevents SOS-mediated nucleotide exchange locks KRas in its inactive state. Homogenous time resolved fluorescence (HTRF) was used to detect SOS-mediated binding of a fluorescent GTP analog, GTP-DY-647P1 (Jena Biosciences NU-820-647P1) to GST-tagged KRASG12D (2-169, Reaction Biology, MSC-11- 539). [00410] GST-tagged KRASG12D (2-169) and anti-GST MAb Tb Cryptate Gold (CisBio 61GSTTLB) were diluted into assay buffer (20 mM HEPES, pH 7.3, 150 mM NaCl, 5 mM MgCl2, 0.05% BSA 0.0025% NP40, 1 mM DTT) to prepare a 2.5X donor solution. 5X compound was added to the protein mixture and incubated for 1 h at RT. 2.5X acceptor solution containing SOS1cat (564-1049, Reaction Biology MSC-11-502) and GTP-DY-647P1 were then added to the donor KRAS mixture such that the final concentration of the reaction contained 5 nM GST-tagged KRASG12D (2-169), 20 nM SOScat, and 150 nM GTP. The reaction was monitored using at RT with the Envision multimode plate reader (Ex/Em 337/665, 620 nM) up to 90 minutes at 5-minute intervals. Data was blanked to reactions without SOS1 and % inhibition was calculated such that DMSO and blank = 100%. Curve fitting was done using a 4-parameter fit. NEA KRAS G12D IC50 (uM) values of selected compounds are depicted in Table 2 with compounds having a value <0.01 uM as ++++; > 0.01 uM to 0.1 uM as +++; > 0.1 uM to 1 uM as ++; > 1 uM to 20 uM as +; and >20 uM as NA. Example 14: Protein Constructs for Protein-Protein Interaction: Table 1: Assay, Protein construct, and protein construct sequences
Figure imgf000157_0001
Example 15. Recombinant Protein Production: [00411] Biotinylated KRAS wt and KRAS G12D/V proteins were expressed and purified in conditions similar to those previously reported (Tran, et al., 2021) (Zhang, et al., 2020). Briefly, KRAS (1-169) proteins were expressed in E. coli at 18°C with an upstream TEV cleavage site (ENLFYQS) followed an Avi tag sequence (GLNDIFEAQKIEWHE). KRAS expression constructs contained both a His6 and maltose-binding protein (MBP) tags at the N-terminus for Ni-NTA column purification prior to overnight TEV cleavage and MBP column purification. The avi-tagged NRAS expression construct contained both a His6 tag and SUMO cleavage sige at the N-terminus for Ni-NTA column purification followed by His-ULP1 digestion overnight. All avi- tagged RAS proteins were dialyzed into buffer containing ATP, biotin, and BirA followed by purification over a second Ni-NTA column and then run over a size exclusion HiLoadTM 26/600 SuperdexTM column in 20 mM HEPES, pH 7.5, 300 mM NaCl, 5 mM MgCl2, and 1 mM TCEP. Fractions containing the protein of interest were pooled, concentrated, and confirmed by intact mass spectrometry. To prepare ‘GTP’ loaded KRAS and NRAS, biotinylated KRAS or NRAS was nucleotide exchanged from GDP-bound protein to GppNHp-bound (Jena Biosciences, NU-401- 50) protein in the presence of alkaline phosphatase and excess GppNHp as previously described and the resulting nucleotide content was confirmed by HPLC reverse phase analytical chromatography (Donohue, et al., 2019) (Tran, et al., 2021). [00412] His-tagged RAF1 (52-131) was similarly expressed in E. coli at 18°C overnight with an upstream TEV cleavage site. His-tagged RAF1 expression construct contained both a His6 and MBP tags at the N-terminus for Ni-NTA column purification followed by MBP-tagged TEV digestion overnight. RAF1 protein samples were further purified over a MBP column followed by a Ni-NTA column and a second MBP column. The fractions containing the protein of interest were pooled, concentrated, and further purified over a HiLoadTM 16/600 SuperdexTM 75 pg size exclusion column into 20mM HEPES, pH8.0, 200mM NaCl, 5mM TCEP. Example 16: Protein-Protein Interaction (PPI) Assay: [00413] When RAS proteins are in the active GTP-bound conformation, they bind the effector protein RAF1 at the N-terminus Ras-binding domain (RBD, residues 52-131) (Tran, et al., 2021). Homogenous time resolved fluorescence (HTRF) was used to monitor the interaction between wt or mutant KRAS and RAF1 or wt NRAS and RAF1. Compounds were assayed in the presence of KRAS G12D/V and RAF1 versus wt KRAS to assess activity against mutant and w.t. KRAS. Similarly, compounds were then assayed in the presence of w.t. NRAS and RAF1 to assess RAS isoform selectivity. In all assay formats, His-tagged RAF1 protein was incubated with the HTRF donor, anti-6His Tb Cryptate gold (Cisbio 61DB10RDF), and biotinylated RAS proteins were incubated with the HTRF acceptor, streptavidin-d2 (CisBio 610SADLA). The intensity of the fluorescence signal emitted is proportional to binding between the two proteins. The donor solution was prepared by mixing 16 nM His-tagged RAF1 in protein dilution buffer with 1:100 anti-6His Tb cryptate in PPI-Terbium detection buffer. 16 nM biotinylated RAS protein was diluted into protein dilution buffer (50 mM Tris-HCl pH 7.5, 150 mM NaCl, 0.1 mM MgCl2, 1 mM TCEP, 0.005% Tween20) and mixed with 1:2000 Streptavidin-d2 diluted in PPI-Terbium detection buffer (CisBio 61DB10RDF).50X compound in DMSO was mixed with 16 nM KRAS-acceptor solution and incubated for 30 minutes at room temperature. After compound pre-incubation with KRAS, the RAF1 donor solution was added to the KRAS-acceptor solution and incubated for 1 hour at room temperature. The fluorescence signal emitted was monitored at 665 nm and 615 nm using an Envision multimode plate reader. The HTRF ratio (665/615) was calculated and normalized to 0% inhibition in the absence of compound and 100% inhibition in the presence of untagged RAF1 protein. PPI KRAS G12D/RAF1, KRAS G12V/RAF1, w.t.KRAS/RAF1 and NRAS/RAF1 IC50 (uM) values of selected compounds are depicted in Table 2 and Table 3 with compounds having a value <0.1 uM as ++++; > 0.1 uM to 1 uM as +++; > 1 uM to 10 uM as ++; > 10 uM to 100 uM as +; and >100 uM as NA. [00414] Compounds described herein are active against KRAS G12 mutant and other alleles representative by PPI-G12D, PPI-G12V and PPI-w.t.KRAS potency for broad activity against mutant KRAS and wtKRAS amplification driven malignancies. Example 17. pERK Inhibition cellular HTRF assay in AGS Cell Lines (Method A) [00415] The Phospho-ERK cellular HTRF assay measures ERK protein phosphorylated at Thr202/Tyr204 as a readout of MAPK pathway activation (Cisbio 64ERKPEH). AGS cells (ATCC CRL-1739) are cultured in the complete medium containing 10% fetal bovine serum and 1x Penicillin/Streptomycin at 37oC in a humid atmosphere of 5% CO2 in the air (AGS cells: RPMI 1640 medium). [00416] On day 1, the cells are plated in tissue-culture treated 96-well plates at the specified densities and allowed to attach for overnight (AGS: 30,000 cells/well). On day 2, the cells are treated with the serially diluted compound solutions in a final concentration of 0.5 % DMSO. After the treatment for the specified time (AGS cells: 3 hours), the supernatant is removed, and the cells are lysed by the lysis buffer supplied with the kit. Then, the cell lysates are treated with the detection reagents overnight at 4oC in darkness. On day 3, the fluorescence intensities at the wavelengths 665 and 620 nm are measured by the Envision plate reader (Perkin Elmer). The data are processed and fitted to a 4-parameter logistic model for IC50 calculations (GraphPad Prism 9). Example 18. pERK In Cell Western (ICW) assay (Method B) [00417] pERK ICW is a high throughput screening assay to evaluate the cellular potency of mutant KRAS small molecule inhibitors. KRAS mutant cell line AGS (KRASG12D) were purchased from ATCC and maintained in DMEM and RPMI medium supplemented with 10% fetal bovine serum and Penicillin/Streptomycin. [00418] Cells grown in exponential phase were trypsinized, resuspended in fresh media, and viable cells were counted using a cell counter with Trypan Blue (BioRad TC20). Cells were seeded into 384-well plate (Greiner 781091) at density of 5,000 cells/well for AGS and allowed to grow overnight in a 37˚C CO2 incubator. The next day, compounds were dispensed into wells with a ½ log, 10-point serial dilution and top concentration of 10 µM using Tecan D300e dispenser and incubated for 3 hours in a 37 ˚C CO2 incubator. Cells were then fixed with paraformaldehyde (Electron Microscopy Sciences, 15710, 4% final concentration) for 30 min, permeabilized with wash buffer (1X PBS + 0.1% Triton X-100) for 30 min and blocked with Odyssey blocking buffer (Li-COR 927-70001) for 1 hour, all at room temperature (RT). Phospho-ERK antibody (CST 4370L) was diluted 1:500 in Odyssey blocking + 0.2% Tween 20 and incubated with cells overnight at 4 ˚C. The next day, plates were washed 5x with wash buffer, incubated with IRDye 800 CW, Goat anti-Rabbit secondary antibody (Li-COR 926-32211, 1:500) and DRAQ5 (CST 4084L, 1:5,000) diluted in in Odyssey blocking + 0.2% Tween 20 for 1 hour, washed 5x, and imaged on an Odyssey CLx imaging system. [00419] For data analysis, signal intensities from 800 (phosphor-ERK) and 700 (DRAQ5) channels were extracted, and phospho-ERK signals were normalized to DRAQ5 signals for each well and percent of DMSO control values were computed. Data were then imported into Graphpad Prism to compute half-maximal inhibitory concentrations (IC50) using a 4-parameter variable slope model. Z-factor for each plate was computed from signals derived from wells treated with either DMSO or 5 µM of Trametinib. AGS pERK ICW (Method B) IC50 (uM) values of selected compounds are depicted in Table 2 with compounds having a value 0.001 uM to 0.01 uM as ++++; > 0.01 uM to 0.1 uM as +++; > 0.1 uM to 1 uM as ++; 1 uM to 10 uM as + and > 10 uM as NA. [00420] Table 2 includes NEA KRAS G12D IC50 (uM) values (<0.01 uM as ++++; > 0.01 uM to 0.1 uM as +++; > 0.1 uM to 1 uM as ++; > 1 uM to 20 uM as +; and >20 uM as NA), PPI KRAS G12D/RAF1 IC50 (uM) values (<0.1 uM as ++++; > 0.1 uM to 1 uM as +++; > 1 uM to 10 uM as ++; > 10 uM to 100 uM as +; and >100 uM as NA), AGS pERK HTRF (Method A) IC50 (uM) values (<0.01 uM as ++++; > 0.01 uM to 0.1 uM as +++; 0.1 uM to 1 uM as ++; 1 uM to 20 uM as + and >20 uM as NA), and AGS pERK ICW (Method B) IC50 (uM) values (0.001 uM to 0.01 uM as ++++; > 0.01 uM to 0.1 uM as +++; > 0.1 uM to 1 uM as ++; 1 uM to 10 uM as + and > 10 uM as NA) of selected compounds. ND indicates not determined.
Figure imgf000160_0001
Figure imgf000161_0001
[00421] Table 3 includes KRASG12V/RAF1, wtKRAS/RAF1 and wtNRAS/RAF1 PPI IC50 (uM) values of selected compounds; with compounds having a value <0.1 uM as ++++; 0.1 uM to 1 uM as +++; >1 uM to 10 uM as ++; >10 uM to 100 uM as +; and >100 uM as NA.
Figure imgf000161_0002
[00422] 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.

Claims

CLAIMS WHAT IS CLAIMED IS: 1. A compound of Formula (I-A):
Figure imgf000162_0001
Formula (I-A), or a pharmaceutically acceptable salt thereof, wherein: Y is O; R2 is selected from -L-heterocycle, and -L-heteroaryl, wherein the heterocycle portion of - L-heterocycle, is optionally substituted with one or more R6, and wherein the heteroaryl of the -L- heteroaryl is optionally substituted with one or more R7; each L is independently selected from a C1-C4 alkylene optionally substituted with one or more substituents independently selected from -OH, C1-C4 hydroxyalkyl, C1-C4 alkyl, C3-C6 carbocycle, or 3- to 8-membered heterocycle, wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle wherein the C3-C6 carbocycle and the 3- to 8- membered heterocycle are optionally substituted with one or more substituents independently selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl; R3 is selected from aryl and heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, =O, -NO2, C1-C4 alkyl, C1-6 aminoalkyl, -S-C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 hydroxyalkynyl, C1-C3 cyanoalkyl, triazolyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, -S-C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, -CH2C(=O)N(R5)2, -C3-C4 alkynyl(NR5)2, -N(R5)2, (C1-C3 alkoxy)haloC1-C3 alkyl- , and C3-C6 cycloalkyl, wherein the C3-C6 cycloalkyl is optionally substituted with one or more substituents selected from halogen and C1-C3 alkyl; and wherein when R3 is benzothiazole or pyridine, the benzothiazole or pyridine is optionally substituted with one or more R49; R4 is selected from hydrogen, halogen, C1-C3 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and -O-C1- 6 haloalkyl; each R5 is independently selected from hydrogen and C1-C3 alkyl; each R6 is independently selected from halogen, -OH, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1- C3 haloalkyl, C1-C3 alkoxy, -CN, C1-C3 aminoalkyl, -Q-phenyl, -Q-phenylSO2F, -NHC(O)phenyl, - NHC(O)phenylSO2F, C1-C3 alkyl substituted pyrazolyl, -N(R5)2, (C1-C3 alkoxy)C1-C3 alkyl-, (C1-C3 alkyl)C(=O), oxo, =CH2, (C1-C3 haloalkyl)C(=O)-, -SO2F, (C1-C3 alkoxy)C1-C3 alkoxy, - CH2OC(O)N(R5)2, -CH2NHC(O)OC1-C6 alkyl, -CH2NHC(O)N(R5)2, -CH2NHC(O)C1-C6 alkyl, - CH2(pyrazolyl), -CH2NHSO2C1-C6 alkyl, -CH2OC(O)heterocycle, -OC(O)N(R5)2, - OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl), -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl(C1-C3 alkyl)N(CH3)2, -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl, -OC(O)heterocycle, and - CH2heterocycle, wherein the phenyl of -NHC(O)phenyl and -OC(O)NH(C1-C3 alkyl)(C1-C3 alkyl)phenyl are each optionally substituted with -C(O)H and OH, and wherein the heterocycle of -CH2heterocyclyl is optionally substituted with oxo; each Q is independently selected from a bond and O; each R7 is independently selected from halogen, -OH, HC(=O)-, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, and -N(R5)2; R9 is selected from C3-C12 carbocycle and 5- to 12-membered heterocycle, wherein the C3- C12 carbocycle and 5- to 12-membered heterocycle are each substituted with one or more substituents independently selected from halogen, -B(OR20)2, -OR20, -SR20, -NHCN, -NO2, =O, =S, =N(R20), -CN, C1-6 fluoroalkyl, C1-6 alkoxy, and C2-6 alkynyl; and further optionally substituted with one or more substituents independently selected from -C(O)N(R20)2, -C(O)NR20-OR20, C1-6 aminoalkyl, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 alkyl, C1-6 alkyl-O-C(O)C1-6 alkyl, and C2-6 alkenyl; wherein when R9 is substituted with at least one -OH, =O, or C1-6 alkoxy, the 5- to 12- membered heterocycle is a non-bridged heterocycle;each R20 is independently selected from hydrogen; and C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle; each R49 is independently selected from halogen, -CN, -OH, =O, -NO2, C1-C4 alkyl, C1-6 aminoalkyl, -S-C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 hydroxyalkynyl, C1-C3 cyanoalkyl, triazolyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, -S-C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, -CH2C(=O)N(R5)2, -C3-C4 alkynyl(NR5)2, (C1-C3 alkoxy)haloC1-C3 alkyl-, and C3- C6 cycloalkyl, wherein the C3-C6 cycloalkyl is optionally substituted with one or more substituents independently selected from halogen and C1-C3 alkyl; R50 is selected from hydrogen, halogen, -OH, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, -CN, C1-C3 cyanoalkyl, C1-C3 aminoalkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 hydroxyalkynyl, and C3-C6 carbocycle; and wherein when Y is O, R2 is
Figure imgf000164_0001
, R9 is selected from pyrrolidine and thiazole, the pyrrolidine and thiazole are each optionally substituted with one or more R49. 2. The compound or salt of claim 1, wherein each L is independently selected from a optionally substituted C1-C4 alkylene; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle, wherein the C3-C6 carbocycle is optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl. 3. The compound or salt of claims 2, wherein the optional substituents of L are selected from C1-C4 hydroxyalkyl, C1-C4 alkyl, C3-C6 carbocycle; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are optionally substituted with one or more substituents selected from halogen and C1-6 haloalkyl. 4. The compound or salt of any one of claims 1 to 3, wherein R2 is selected from -L- heterocycle, wherein the heterocycle portion of -L-heterocycle is optionally substituted with one or more R6. 5. The compound or salt of any one of claims 1 to 4, wherein Y-R2 is selected from
Figure imgf000164_0002
, , wherein the heterocycle portion is optionally substituted with one or more R6. 6. The compound or salt of claim 5, wherein R6 is selected from halogen, -OH, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, -CN, and C1-C3 aminoalkyl. 7. The compound or salt of claim 6, wherein R6 is selected from halogen and C1-C3 alkyl.
Figure imgf000164_0003
9. The compound or salt of claim 1, wherein L is selected from optionally substituted C1-C4 alkylene. 10. The compound or salt of claim 9, wherein the optional substituents of L are selected from C1-C4 hydroxyalkyl, C1-C4 alkyl, C3-C6 carbocycle, wherein the C3-C6 carbocycle is optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, and C1-6 haloalkyl. 11. The compound or salt of claim 10, wherein the optional substituents of L are selected from C1-C4 hydroxyalkyl, C1-C4 alkyl, C3-C6 carbocycle; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are optionally substituted with one or more substituents selected from halogen and C1-6 haloalkyl. 12. The compound or salt of any one of claims 9 to 11, wherein R2 is selected from -L- heterocycle, wherein the heterocycle portion of -L-heterocycle is optionally substituted with one or more R6. 13. The compound or salt of claim 12, wherein Y-R2 is selected from
Figure imgf000165_0001
Figure imgf000165_0002
, wherein the heterocycle portion is optionally substituted with one or more R6. 14. The compound or salt of claim 13, wherein R6 is selected from halogen, -OH, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, -CN, and C1-C3 aminoalkyl. 15. The compound or salt of claim 14, wherein R6 is selected from halogen and C1-C3 alkyl. 16. The compound or salt of claim 15, wherein Y-R2 is selected from
Figure imgf000165_0003
,
Figure imgf000165_0004
17. The compound or salt of any one of claims 1 to 16, wherein R3 is selected from an optionally substituted 12- to 13-membered heteroaryl. 18. The compound or salt of claim 17, wherein the optional substituents of R3 are selected from halogen, hydroxy, cyano, =O, -NO2, C1-C4 alkyl, C3-C6 cycloalkyl, C1-6 aminoalkyl, C1-C3 haloalkyl, C1-C3 hydroxyalkyl, C2-C4 alkynyl, and -N(R20)2. 19. The compound or salt of claim 18, wherein the optional substituents of R3 are selected from halogen, hydroxy, =O, -NO2, C1-C4 alkyl, C3-C6 cycloalkyl, C1-6 aminoalkyl, C1-C3 haloalkyl, C2-C4 alkynyl, and -NH2.
20. The compound or salt of claim 19, wherein R3 is selected from
Figure imgf000166_0001
,
Figure imgf000166_0002
, each of which are optionally substituted. 21. The compound or salt of claim 20, wherein R3 is selected from
Figure imgf000166_0003
, and
Figure imgf000166_0004
, each of which are optionally substituted with one or more substituents independently selected from halogen, hydroxy, =O, -NO2, C1-C4 alkyl, C3-C6 cycloalkyl, C1-6 aminoalkyl, C1-C3 haloalkyl, C1-C3 hydroxyalkyl, C2-6 alkynyl, and -N(R20)2. 22. The compound or salt of claim 21, wherein R3 is selected from
Figure imgf000166_0005
,
Figure imgf000166_0006
, each of which are optionally substituted with one or more substituents independently selected from halogen, cyano, C1-C3 haloalkyl, hydroxy, =O, C3-C6 cycloalkyl, C2-6 alkynyl, and -NH2. 23. The compound or salt of any one of claims 17 to 22, wherein R3 is selected from
Figure imgf000166_0007
Figure imgf000167_0001
. 24. The compound or salt of any one of claims 1 to 16, wherein R3 is selected from
Figure imgf000167_0002
, which is optionally substituted with one or more substitutents selected from halogen, C1-C3 haloalkyl, C3-C6 cycloalkyl, and C2-6 alkynyl. 25. The compound or salt of claim 24, wherein R3 is naphthalene, wherein the naphthalene is optionally substituted with one or more substituents independently selected from halogen, -OH, C2-C4 alkynyl, and C1-3 alkyl. 26. The compound or salt of claim 25, wherein
Figure imgf000167_0003
,
Figure imgf000167_0004
27. The compound or salt of claim 26, wherein R3 is naphthalene, and the naphthalene is substituted with one or more substituents independently selected from fluorine, C2-C4 alkynyl, and hydroxy. 28. The compound or salt of claim 27, wherein R3 is selected from
Figure imgf000167_0005
Figure imgf000167_0006
. 29. The compound or salt of any one of claims 1 to 28, wherein R50 is selected from hydrogen, halogen, C1-C3 cyanoalkyl, C2-C4 alkenyl, C2-C4 alkynyl, and C3-C6 carbocycle.
30. The compound or salt of claim 29, wherein R50 is selected from hydrogen, Cl,
Figure imgf000168_0001
31. The compound or salt of claims 29 or 30, wherein R4 is selected from halogen and hydrogen. 32. The compound or salt of claim 31, wherein R4 is selected from halogen. 33. The compound or salt of any one of claims 1 to 32, wherein R9 is selected from 6- to 7- membered heterocycle. 34. The compound or salt of claim 33, wherein the 6- to 7-membered heterocycle contains only 1 nitrogen atom and optionally one or more additional heteroatoms selected from oxygen, and sulfur. 35. The compound or salt of claim 34, wherein the optionally one or more additional heteroatoms are selected from sulfur. 36. The compound or salt of claim 35, wherein the 6- to 7-membered heterocycle contains only 1 nitrogen atom and no further additional heteroatoms. 37. The compound or salt of any one of claims 33 to 36, wherein the 6- to 7-membered heterocycle is a non-aromatic 6- to 7-membered heterocycle. 38. The compound or salt of any one of claims 34 to 36, wherein the 6- to 7-membered heterocycle of R9 is bound to Formula (I-A) via the only 1 nitrogen atom. 39. The compound or salt of claims 37 or 38, wherein R9 is selected from
Figure imgf000168_0002
, ,
Figure imgf000168_0003
40. The compound or salt of claims 37 or 38, wherein R9 is selected from
Figure imgf000168_0004
,
Figure imgf000168_0005
each of which is substituted. 41. The compound or salt of any one of claims 1 to 32, wherein R9 is selected from a substituted unsaturated 6- to 8-membered heterocycle. 42. The compound or salt of claim 41, wherein R9 is selected from a substituted unsaturated 6-membered heterocycle.
43. The compound or salt of claim 41, wherein R9 is selected from a substituted unsaturated 7-membered heterocycle. 44. The compound or salt of any one of claims 41 to 43 , wherein R9 is selected from
Figure imgf000169_0001
, wherein each is substituted. 45. The compound or salt of claim 44, wherein R9 is selected from
Figure imgf000169_0002
,
Figure imgf000169_0003
46. The compound or salt of claim 44, wherein R9 is selected from
Figure imgf000169_0004
Figure imgf000169_0005
, each of which is substituted. 47. The compound or salt of claim 46, wherein R9 is selected from
Figure imgf000169_0006
, each of which is substituted with one or more fluorine.
Figure imgf000170_0001
48. The compound or salt of claim 47, wherein R9 is selected from , and
Figure imgf000170_0002
. 49. The compound or salt of any one of claims 1 to 32, wherein R9 is selected from 5- to 12- membered heterocycle, wherein the 5- to 12-membered heterocycle is substituted with one or more substituents independently selected from halogen, -B(OR20)2, -OR20, -SR20, -N(R20)2, - NHCN, -NO2, =O, -CN, C1-6 alkoxy, C2-6 alkenyl, and C2-6 alkynyl. 50. The compound or salt of claim 49, wherein R9 is selected from 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle is substituted with one or more substituents independently selected from -OR20 and -CN. 51. The compound or salt of claims 49 or 50, wherein each R20 is independently selected from hydrogen; and C1-6 alkyl. 52. The compound or salt of any one of claims 49 to 51, wherein R9 is selected from
Figure imgf000170_0003
,
Figure imgf000170_0004
, each of which is substituted with one or more substituents independently selected from halogen, -OR20 and -CN. 53. The compound or salt of claim 52, wherein R9 is selected from
Figure imgf000170_0005
Figure imgf000170_0006
. 54. The compound or salt of any one of claims 1 to 32, wherein R9 is selected from an optionally substituted 6- to 10-membered heterocycle. 55. The compound or salt of claim 54, R9 is selected from
Figure imgf000171_0001
,
Figure imgf000171_0002
, each of which is substituted with one or more substituents independently selected from halogen, =O, -OH, C2-6 alkynyl, -NHCN, and -CN; and further optionally substituted with one or more substituents independently selected from C1-6 aminoalkyl, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, and C1-6 alkyl. 56. The compound or salt of claim 55, wherein R9 is selected from
Figure imgf000171_0003
, ,
Figure imgf000171_0004
57. The compound or salt of claim 56, wherein R9 is from
Figure imgf000171_0005
. . The compound or salt of claim 56, wherein R9 is from
Figure imgf000171_0006
. 59. The compound or salt of any one of claims 1 to 58, wherein R3 is selected from optionally substituted C6-C10 aryl and optionally substituted 6- to 12-membered heteroaryl. 60. The compound or salt of claim 59, wherein R3 is selected from naphthalene and indazole, wherein the naphthalene and indazole are optionally substituted with one or more substituents selected from halogen, -CN, -OH, =O, -NO2, C1-C4 alkyl, C1-6 aminoalkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 hydroxyalkynyl, C1-C3 cyanoalkyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, and N(R5)2. 61. The compound or salt of claim 60, wherein R3 is naphthalene, wherein the naphthalene is optionally substituted with one or more substituents selected from -OH, and C1-C6 alkyl.
62. The compound or salt of any one of claims 59 to 61, wherein R3 is selected from
Figure imgf000172_0001
. 63. The compound or salt of any one of claims 1 to 60, wherein R3 is selected from
Figure imgf000172_0002
or a pharmaceutically acceptable salt thereof, wherein: Y is selected from a bond, O and NR5; R2 is selected from L-pyrrolizine, wherein the pyrrolizine is optionally substituted with one or more R6; each L is independently selected from a C1-C4 alkylene optionally substituted with one or more substituents selected from -OH, C1-C4 hydroxyalkyl, and C1-C4 alkyl; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl; R3 is selected from aryl and heteroaryl, wherein the aryl and the heteroaryl are each optionally substituted with one or more substituents independently selected from halogen, -CN, - OH, =O, -NO2, C1-C4 alkyl, C1-6 aminoalkyl, -S-C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 hydroxyalkynyl, C1-C3 cyanoalkyl, triazolyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, -S- C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, -CH2C(=O)N(R5)2, -C3-C4 alkynyl(NR5)2, -N(R5)2, (C1-C3 alkoxy)haloC1-C3 alkyl-, and C3-C6 cycloalkyl, wherein the C3-C6 cycloalkyl is optionally substituted with one or more substituents selected from halogen and C1-C3 alkyl; R4 is selected from hydrogen, halogen, C1-C3 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and -O-C1- 6 haloalkyl; each R5 is independently selected from hydrogen and C1-C3 alkyl; each R6 is independently selected from halogen, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkyl, oxo, C1-C3 haloalkyl, C1-C3 alkoxy, cyano, =CH2, =NO-C1-C3 alkyl, C1-C3 aminoalkyl, - N(R5)S(O)2(R5), -Q-phenyl, -Q-phenylSO2F, -NHC(O)phenyl, - NHC(O)phenylSO2F, C1-C3 alkyl substituted pyrazolyl, tert-butyldimethylsilyloxyCH2- , -N(R5)2, (C1-C3 alkoxy)C1-C3 alkyl-, (C1- C3 alkyl)C(=O), oxo, (C1-C3 haloalkyl)C(=O)-, -SO2F, (C1-C3 alkoxy)C1-C3 alkoxy, - CH2OC(O)N(R5)2, -CH2NHC(O)OC1-C6 alkyl, -CH2NHC(O)N(R5)2, -CH2NHC(O)C1-C6 alkyl, - CH2(pyrazolyl), -CH2NHSO2C1-C6 alkyl, -CH2OC(O)heterocycle, -OC(O)N(R5)2, - OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl), -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl(C1-C3 alkyl)N(CH3)2, -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl, - OC(O)heterocycle, -O-C1-C3 alkyl, and -CH2heterocycle, wherein the phenyl of -NHC(O)phenyl and -OC(O)NH(C1-C3 alkyl)(C1-C3 alkyl)phenyl are optionally substituted with one or more substituents selected from - C(O)H and OH, and wherein the alkyl of -O-C1-C3 alkyl is optionally substituted with substituents selected from heterocycle, oxo and hydroxy; and wherein the heterocycle of -CH2heterocyclyl is optionally substituted with oxo; Q is selected from a bond and O; R9 is selected from C3-C12 carbocycle and 5- to 12-membered heterocycle, each of which are optionally substituted with one or more substituents independently selected from halogen, - B(OR20)2, -OR20, -SR20, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), - NR20S(O)2R20, -C(O)N(R20)2, -C(=NR20)N(R20)2, -C(O)NR20OR20, -N(R20)C(O)R20, - N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, -C(O)R20, -C(O)OR20, -OC(O)R20, - OC(O)N(R20)2, -NO2, =O, =N(R20), =NO(R20), -CN, -NHCN, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-C12 carbocycle and 5- to 12-membered heterocycle, wherein the C3-C12 carbocycle and 5- to 12-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -B(OR20)2, -OR20, -SR20, -S(O)2(R20), -S(O)2N(R20)2, - S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, -C(O)NR20OR20, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, -C(O)R20, -C(O)OR20, -OC(O)R20, - OC(O)N(R20)2, -NO2, =O, =N(R20), =NO(R20), -CN, -NHCN, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C3-C12 carbocycle; each R20 is independently selected from hydrogen; and C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbocycle, and 3- to 12- membered heterocycle; and R50 is selected from hydrogen, halogen, -OH, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, -CN, C1-C3 cyanoalkyl, C1-C3 aminoalkyl, C2-C4 alkenyl, C2-C4 alkynyl, and C2-C4 hydroxyalkynyl. 65. The compound or salt of claims 64, wherein L is selected from optionally substituted C1- C4 alkylene. 66. The compound or salt of claims 65, wherein the optional substituents of L are selected from C1-C4 hydroxyalkyl, C1-C4 alkyl, C3-C6 carbocycle, wherein the C3-C6 carbocycle is optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, and C1-6 haloalkyl. 67. The compound or salt of claims 66, wherein the optional substituents of L are selected from C1-C4 hydroxyalkyl, and C1-C4 alkyl, and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl. 68. The compound or salt of any one of claims 64 to 67, wherein Y-R2 is selected from
Figure imgf000174_0001
, wherein the heterocycle portion is optionally substituted with one or more R6. 69. The compound or salt of claim 68, wherein R6 is selected from halogen, -OH, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, -CN, and C1-C3 aminoalkyl. 70. The compound or salt of claim 69, wherein R6 is selected from halogen and C1-C3 alkyl. 71. The compound or salt of claim 70, wherein Y-R2 is selected from
Figure imgf000174_0002
, and
Figure imgf000174_0003
. 72. The compound or salt of any one of claims 64 to 71, wherein R50 is selected from hydrogen, halogen, C1-C3 cyanoalkyl, C2-C4 alkenyl, C2-C4 alkynyl, and C3-C6 carbocycle. 73. The compound or salt of claim 72, wherein R50 is selected from hydrogen, Cl,
Figure imgf000174_0004
74. The compound or salt of any one of claims 64 to 73, wherein R4 is selected from halogen and hydrogen. 75. The compound or salt of claim 74, wherein R4 is selected from halogen.
76. The compound or salt of any one of claims 64 to 75, wherein R9 is selected from 5- to 12- membered heterocycle, wherein the 5- to 12-membered heterocycle is substituted with one or more substituents independently selected from halogen, -B(OR20)2, -OR20, -SR20, -N(R20)2, - S(O)2(R20), -NO2, =O, =S, =N(R20), -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl. 77. The compound or salt of claim 76, wherein R9 is selected from 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle is substituted with one or more substituents independently selected from halogen, -OR20, -N(R20)2, -NO2, =O, =S, =N(R20), -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, and C1-6 haloalkyl. 78. The compound or salt of claim 77, wherein R9 is selected from 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle is substituted with one or more substituents independently selected from -OR20 and -CN. 79. The compound or salt of any one of claims 64 to 78, wherein each R20 is independently selected from hydrogen; and C1-6 alkyl. 80. The compound or salt of claim 76, wherein R9 is selected from
Figure imgf000175_0001
Figure imgf000175_0002
, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR20 and -CN. 81. The compound or salt of claim 80, wherein R9 is selected from
Figure imgf000175_0003
, each of which is optionally substituted with one or more substituents independently selected from - OR20 and -CN. 82. The compound or salt of claim 81, wherein R9 is selected from
Figure imgf000175_0004
Figure imgf000175_0005
.
83. The compound or salt of any one of claims 64 to 75, wherein R9 is selected from 6- to 7- membered heterocycle. 84. The compound or salt of claim 83, wherein the 6- to 7-membered heterocycle contains only 1 nitrogen atom and optionally one or more additional heteroatoms selected from oxygen, and sulfur. 85. The compound or salt of claim 84, wherein the optionally one or more additional heteroatoms are selected from sulfur. 86. The compound or salt of claim 85, wherein the 6- to 7-membered heterocycle contains only 1 nitrogen atom and no further additional heteroatoms. 87. The compound or salt of any one of claims 83 to 86, wherein the 6- to 7-membered heterocycle is a non-aromatic 6- to 7-membered heterocycle. 88. The compound or salt of any one of claims 83 to 87, wherein the 6- to 7-membered heterocycle of R9 is bound to Formula (II) via the only 1 nitrogen atom. 89. The compound or salt of claim 88, wherein R9 is selected from
Figure imgf000176_0001
, , ,
Figure imgf000176_0002
, each of which is optionally substituted. 90. The compound or salt of claim 89, wherein R9 is selected from
Figure imgf000176_0003
, which is substituted with at least one -NHCN and further optionally substituted with one or more C1-6 alkyl. 91. The compound or salt of any one of claims 83 to 88, wherein R9 is selected from
Figure imgf000176_0004
,
Figure imgf000176_0005
each of which is optionally substituted. 92. The compound or salt of any one of claims 83 to 91, wherein the substituents of R9 are selected at each occurrence from one or more substituents selected from halogen, -OR20, - N(R20)2, -S(O)2(R20), -C(O)N(R20)2, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, - C(O)R20, -C(O)OR20, -OC(O)R20, -NO2, =O, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl.
93. The compound or salt of claim 92, wherein the substituents of R9 are selected at each occurrence from one or more substituents selected from halogen, -OH, -N(R20)2, =O, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, and C2-6 alkynyl. 94. The compound or salt of any one of claims 64 to 75, wherein R9 is selected from an unsaturated 6- to 8-membered heterocycle. 95. The compound or salt of claim 94, wherein R9 is selected from an unsaturated 6- membered heterocycle. 96. The compound or salt of claim 95, wherein R9 is selected from an unsaturated 7- membered heterocycle. 97. The compound or salt of any one of claims 94 to 96, wherein R9 is selected from
Figure imgf000177_0001
, wherein each is optionally substituted. 98. The compound or salt of any one of claims 94 to 96, wherein R9 is selected from
Figure imgf000177_0002
99. The compound or salt of any one of claims 94 to 98, wherein the substituents of R9 are selected at each occurrence from one or more substituents selected from halogen, -OH, -N(R20)2, =O, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, and C2-6 alkynyl. 100. The compound or salt of claim 99, wherein R9 is selected from
Figure imgf000177_0003
,
Figure imgf000177_0004
101. The compound or salt of claim 98, wherein R9 is selected from
Figure imgf000178_0001
Figure imgf000178_0002
, each of which is substituted. 102. The compound or salt of claim 98, wherein R9 is selected from
Figure imgf000178_0003
, each of which is substituted with one or more fluorine. 103. The compound or salt of claim 102, wherein R9 is selected from
Figure imgf000178_0004
,
Figure imgf000178_0005
. 104. The compound or salt of any one of claims 64 to 103, wherein R3 is selected from optionally substituted C6-C10 aryl and optionally substituted 6- to 12-membered heteroaryl. 105. The compound or salt of claim 104, wherein R3 is selected from naphthalene and indazole, wherein the naphthalene and indazole are optionally substituted with one or more substituents selected from halogen, -CN, -OH, =O, -NO2, C1-C4 alkyl, C1-6 aminoalkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 hydroxyalkynyl, C1-C3 cyanoalkyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, and N(R5)2. 106. The compound or salt of claim 105, wherein R3 is naphthalene, wherein the naphthalene is optionally substituted with one or more substituents selected from -OH and C1-C6 alkyl. 107. The compound or salt of any one of claims 104 to 106, wherein R3 is selected from
Figure imgf000178_0006
.
108. The compound or salt of any one of claims 104 to 106, wherein R3 is selected from
Figure imgf000179_0001
109. The compound or salt of any one of claims 64 to 103, wherein R3 is selected from an optionally substituted 12- to 13-membered heteroaryl. 110. The compound or salt of claim 109, wherein the optional substituents of R3 are selected from halogen, hydroxy, cyano, =O, -NO2, C1-C4 alkyl, C3-C6 cycloalkyl, C1-6 aminoalkyl, C1-C3 haloalkyl, C1-C3 hydroxyalkyl, C2-C4 alkynyl, and -N(R20)2. 111. The compound or salt of claim 110, wherein the optional substituents of R3 are selected from halogen, hydroxy, =O, -NO2, C1-C4 alkyl, C3-C6 cycloalkyl, C1-6 aminoalkyl, C1-C3 haloalkyl, C2-C4 alkynyl, and -NH2. 112. The compound or salt of any one of claims 109 to 111, wherein R3 is selected from
Figure imgf000179_0002
optionally substituted. 113. The compound or salt of claim 112, wherein R3 is selected from
Figure imgf000179_0003
, and
Figure imgf000179_0004
, each of which are optionally substituted with one or more substituents independently selected from halogen, hydroxy, =O, -NO2, C1-C4 alkyl, C3-C6 cycloalkyl, C1-6 aminoalkyl, C1-C3 haloalkyl, C1-C3 hydroxyalkyl, C2-6 alkynyl, and -N(R20)2. 114. The compound or salt of claim 113, wherein R3 is selected from
Figure imgf000179_0005
,
Figure imgf000179_0006
, each of which are optionally substituted with one or more substituents independently selected from halogen, cyano, C1-C3 haloalkyl, hydroxy, =O, C3-C6 cycloalkyl, C2-6 alkynyl, and -NH2.
115. The compound or salt of any one of claims 64 to 114, wherein R3 is selected from
Figure imgf000180_0001
. nd or salt of any one of claims 64 to 114, wherein R3 is selected from
Figure imgf000180_0002
, which is optionally substituted with one or more substitutents selected from halogen, C1-C3 haloalkyl, C3-C6 cycloalkyl, and C2-6 alkynyl. 117. The compound or salt of any one of claims 64 to 114, wherein the compound is selected from
Figure imgf000180_0003
118. A compound of Formula (III):
Figure imgf000180_0004
or a pharmaceutically acceptable salt thereof, wherein: Y is selected from a bond, O and NR5; R2 is selected from hydrogen, -N(R5)2, -L-N(R5)2, -L-OR5, heterocycle, C1-C6 alkyl, -L- heterocycle, -L-aryl, -L-heteroaryl, -L-cycloalkyl, -L-N(R5)2, -L-NHC(=NH)NH2, -L-C(O)N(R5)2, -L-C1-C6 haloalkyl, -L-OR5, -L-NR5C(O)-aryl, -L-COOH, and -LC(=O)OC1-C6 alkyl, wherein the heterocycle, the aryl portion of -L-NR5C(O)-aryl, the heterocycle portion of -L-heterocycle, and the cycloalkyl portion of the -L-cycloalkyl are each optionally substituted with one or more R6, and wherein the aryl of the -L- aryl and heteroaryl of the -L-heteroaryl are each optionally substituted with one or more R7; each L is independently selected from a C1-C4 alkylene optionally substituted with one or more substituents independently selected from -OH, C1-C4 hydroxyalkyl, C1-C4 alkyl, C3-C6 carbocycle, and 3- to 8-membered heterocycle, wherein the C3-C6 carbocycle and the 3- to 8- membered heterocycle are optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle wherein the C3-C6 carbocycle and the 3- to 8- membered heterocycle are optionally substituted with one or more substituents independently selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, and C1-6 haloalkyl; R3 is selected from aryl and heteroaryl, wherein each is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, =O, -NO2, C1-C4 alkyl, C1-6 aminoalkyl, -S-C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 hydroxyalkynyl, C1-C3 cyanoalkyl, triazolyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, -S-C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, -CH2C(=O)N(R5)2, -C3-C4 alkynyl(NR5)2, -N(R5)2, (C1-C3 alkoxy)haloC1-C3 alkyl- , and C3-C6 cycloalkyl, wherein the C3-C6 cycloalkyl is optionally substituted with one or more substituents independently selected from halogen and C1-C3 alkyl; R4 is selected from hydrogen, halogen, C1-C3 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and -O-C1- 6 haloalkyl; each R5 is independently selected from hydrogen and C1-C3 alkyl; each R6 is independently selected from halogen, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, cyano, =CH2, =NO-C1-C3 alkyl, C1-C3 aminoalkyl, - N(R5)S(O)2(R5), -Q-phenyl, -Q-phenylSO2F, -NHC(O)phenyl, -NHC(O)phenylSO2F, C1-C3 alkyl substituted pyrazolyl, tert-butyldimethylsilyloxyCH2- , -N(R5)2, (C1-C3 alkoxy)C1-C3 alkyl-, (C1- C3 alkyl)C(=O), oxo, (C1-C3 haloalkyl)C(=O)-, -SO2F, (C1-C3 alkoxy)C1-C3 alkoxy, - CH2OC(O)N(R5)2, -CH2NHC(O)OC1-C6 alkyl, -CH2NHC(O)N(R5)2, -CH2NHC(O)C1-C6 alkyl, - CH2(pyrazolyl), -CH2NHSO2C1-C6 alkyl, -CH2OC(O)heterocycle, -OC(O)N(R5)2, - OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl), -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl(C1-C3 alkyl)N(CH3)2, -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl, - OC(O)heterocycle, -O-C1-C3 alkyl, and -CH2heterocycle, wherein the phenyl of -NHC(O)phenyl and -OC(O)NH(C1-C3 alkyl)(C1-C3 alkyl)phenyl are each optionally substituted with one or more substituents independently selected from -C(O)H and OH, and wherein the alkyl of -O-C1-C3 alkyl is optionally substituted with one or more substituents independently selected from heterocycle, oxo and hydroxy; and wherein the heterocycle of -CH2heterocyclyl is optionally substituted with oxo; each Q is independently selected from a bond and O; each R7 is independently selected from halogen, -OH, HC(=O)-, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, and -N(R5)2; R9 is selected from unsaturated 5- to 12-membered heterocycle, wherein the unsaturated 5- to 12-membered heterocycle contains at least 1 nitrogen atom and optionally one or more additional heteroatoms selected from oxygen, boron, and sulfur, and wherein the unsaturated 5- to 12-membered heterocycle of R9 is bound to Formula (III) via the at least 1 nitrogen atom, and wherein the unsaturated 5- to 12-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -B(OR20)2, -OR20, -SR20, - N(R20)S(O)2(R20), -S(O)2(R20), -S(O)2N(R20)2, -C(O)N(R20)2, -C(O)NR20-OR20, - N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)2, -C(O)R20, -C(O)OR20, -OC(O)R20, -NO2, =O, =S, =N(R20), -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl; each R20 is independently selected from hydrogen; and C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbocycle, and 3- to 12- membered heterocycle; and R50 is selected from hydrogen, halogen, -OH, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, -CN, C1-C3 cyanoalkyl, C1-C3 aminoalkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 hydroxyalkynyl, and C3-C6 carbocycle. 119. The compound or salt of claims 118, wherein each L is independently selected from a C1- C4 alkylene optionally substituted; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle, wherein the C3-C6 carbocycle is optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl. 120. The compound or salt of claims 119, wherein the optional substituents of L are selected from C1-C4 hydroxyalkyl, C1-C4 alkyl, C3-C6 carbocycle; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are optionally substituted with one or more substituents selected from halogen and C1-6 haloalkyl. 121. The compound or salt of any one of claims 118 to 120, wherein R2 is selected from -L- heterocycle, wherein the heterocycle portion of -L-heterocycle is optionally substituted with one or more R6. 122. The compound or salt of any one of claims 118 to 121, wherein Y is O. 123. The compound or salt of any one of claims 118 to 122, wherein Y-R2 is selected from
Figure imgf000183_0001
124. The compound or salt of claim 123, wherein R6 is selected from halogen, -OH, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, oxo, C1-C3 alkoxy, -CN, and C1-C3 aminoalkyl. 125. The compound or salt of claim 124, wherein R6 is selected from halogen and C1-C3 alkyl. 126. The compound or salt of claim 125, wherein Y-R2 is selected from
Figure imgf000183_0002
,
Figure imgf000183_0003
127. The compound or salt of any one of claims 118 to 120, wherein R2 is selected from -L- heterocycle, wherein the heterocycle portion of -L-heterocycle is optionally substituted with one or more R6. 128. The compound or salt of claim 127, wherein each L is independently selected from a substituted C1-C4 alkylene, and wherein two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle, wherein the C3-C6 carbocycle is optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl. 129. The compound or salt of claim 128, wherein each L is independently selected from a substituted C1-C4 alkylene, and wherein two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle.
130. The compound or salt of claim 129, wherein each L is independently selected from a substituted C3 alkylene, and wherein two substituents on the same carbon atom of L come together to form a C3 carbocycle. 131. The compound or salt of claim 130, wherein each L is independently selected from
Figure imgf000184_0001
. 132. The compound or salt of claim 131, wherein Y-R2 is
Figure imgf000184_0002
. 133. The compound or salt of any one of claims 118 to 132, wherein R9 is selected from an optionally substituted unsaturated 6- to 8-membered heterocycle. 134. The compound or salt of claim 133, wherein R9 is selected from an optionally substituted unsaturated 6-membered heterocycle. 135. The compound or salt of claim 134, wherein R9 is selected from an optionally substituted unsaturated 7-membered heterocycle. 136. The compound or salt of claims 133 to 135, wherein R9 is selected from
Figure imgf000184_0003
,
Figure imgf000184_0004
wherein each is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH2, -NO2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl, and C1-6 alkyl.
137. The compound or salt of claim 136, wherein R9 is selected from
Figure imgf000185_0001
,
Figure imgf000185_0002
138. The compound or salt of claims 133 to 135, wherein R9 is selected from
Figure imgf000185_0003
,
Figure imgf000185_0004
, wherein each is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH2, -NO2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl, and C1-6 alkyl. 139. The compound or salt of claim 138, wherein R9 is selected from
Figure imgf000185_0005
, wherein each is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH2, -NO2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl, and C1-6 alkyl. 140. The compound or salt of claim 139, wherein R9 is selected from
Figure imgf000185_0006
, wherein each is optionally substituted with one or more substituents independently selected from halogen, and C1-6 haloalkyl.
141. The compound or salt of claim 140, wherein R9 is selected from
Figure imgf000186_0001
,
Figure imgf000186_0002
142. The compound or salt of claim 140, wherein R9 is selected from
Figure imgf000186_0003
. 143. The compound or salt of any one of claims 118 to 132, wherein R9 is selected from an optionally substituted unsaturated 9- to 11-membered heterocycle. 144. The compound or salt of claim 143, wherein R9 is selected from an optionally substituted unsaturated 10-membered heterocycle. 145. The compound or salt of claim 144, wherein
Figure imgf000186_0004
, which is optionally substituted. 146. The compound or salt of claim 144, wherein
Figure imgf000186_0005
, which is optionally substituted with one or more substituents selected from halogen, -OH, -C(O)N(R20)2, - C(O)NR20-OR20, -N(R20)2, -C(O)R20, -NO2, =O, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, and C2-6 alkynyl. 147. The compound or salt of claim 144, wherein
Figure imgf000186_0006
each R20 is independently selected from hydrogen; and C1-6 alkyl, and C3-12 carbocycle, and each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, - CN, -NO2, -NH2, C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbocycle and 3- to 12-membered heterocycle
148. The compound or salt of claim 147, wherein each R20 is independently selected from hydrogen; and C1-6 alkyl. 149. The compound or salt of any one of claims 118 to 148, wherein R3 is selected from an optionally substituted 9- to 15-membered heteroaryl optionally substituted C6-C10 aryl. 150. The compound or salt of claim 149, wherein the C6-C10 aryl is optionally substituted with one or more substituents independently selected from halogen, cyano, hydroxy, =O, -NO2, C1-C4 alkyl, C1-6 aminoalkyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, C2-6 alkynyl, and -N(R5)2; and the 9- to 15-membered heteroaryl is optionally substituted with one or more substituents independently selected from halogen, cyano, hydroxy, =O, -NO2, C1-C4 alkyl, C3-C6 cycloalkyl, C1-6 aminoalkyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, C1-C3 alkoxy, C1- C3 hydroxyalkyl, C2-6 alkynyl, and -N(R5)2.
Figure imgf000187_0001
Figure imgf000188_0001
. 152. The compound or salt of claim 118, wherein R3 is selected from an optionally substituted 12- to 13-membered heteroaryl. 153. The compound or salt of claim 152, the substituents are selected from halogen, hydroxy, cyano, =O, -NO2, C1-C4 alkyl, C3-C6 cycloalkyl, C1-6 aminoalkyl, C1-C3 haloalkyl, C1-C3 hydroxyalkyl, C2-C4 alkynyl, and -N(R20)2. 154. The compound or salt of claim 153, the substituents are selected from halogen, hydroxy, =O, -NO2, C1-C4 alkyl, C3-C6 cycloalkyl, C1-6 aminoalkyl, C1-C3 haloalkyl, C2-C4 alkynyl, and - NH2. 155. The compound or salt of any one of claims 152 to 154, wherein R3 is selected from
Figure imgf000188_0002
optionally substituted. 156. The compound or salt of claim 155, wherein R3 is selected from
Figure imgf000188_0003
,
Figure imgf000188_0004
, each of which are optionally substituted with one or more substituents independently selected from halogen, hydroxy, =O, -NO2, C1-C4 alkyl, C3-C6 cycloalkyl, C1-6 aminoalkyl, C1-C3 haloalkyl, C1-C3 hydroxyalkyl, C2-6 alkynyl, and -N(R20)2.
157. The compound or salt of claim 156, wherein R3 is selected from
Figure imgf000189_0001
,
Figure imgf000189_0002
, each of which are optionally substituted with one or more substituents independently selected from cyano, hydroxy, =O, C3-C6 cycloalkyl, C2-6 alkynyl, and -NH2. 158. The compound or salt of claim 157, wherein R3 is selected from
Figure imgf000189_0003
, ,
Figure imgf000189_0004
159. The compound or salt of claim 118, wherein R3 is selected from
Figure imgf000189_0005
, which is optionally substituted with one or more substituents independently selected from halogen, -CN, - OH, =O, -NO2, C1-C4 alkyl, C3-C6 cycloalkyl, C1-6 aminoalkyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, C2-6 alkynyl, and -N(R5)2. 160. The compound or salt of claim 159, wherein R3 is selected from
Figure imgf000189_0006
, which is optionally substituted with one or more substituents independently selected from halogen, -CN, - OH, =O, hydroxy, C3-C6 cycloalkyl, C1-6 aminoalkyl, C2-6 alkynyl, and -N(R5)2.
161. The compound or salt of claim 160, wherein R3 is selected from
Figure imgf000190_0001
,
Figure imgf000190_0002
162. The compound or salt of claim 118, wherein R3 is selected from an optionally substituted tricyclic heteroaryl. 163. The compound or salt of claim 162, wherein R3 is a tricyclic heteroaryl that has at least one nitrogen atom and one sulfur atom. 164. The compound or salt of claim 163, wherein R3 is selected from
Figure imgf000190_0003
, which is optionally substituted with one or more substituents independently selected from halogen, C1-C3 haloalkyl, -CN, -OH, =O, hydroxy, C3-C6 cycloalkyl, C1-6 aminoalkyl, C2-6 alkynyl, and -N(R5)2. 165. The compound or salt of claim 164, wherein R3 is selected from
Figure imgf000190_0004
, which is optionally substituted with one or more substitutents selected from halogen, hydroxy, =O, -NO2, C1-C4 alkyl, C3-C6 cycloalkyl, C1-6 aminoalkyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, and C2-6 alkynyl. 166. The compound or salt of claim 165, wherein R3 is selected from
Figure imgf000190_0005
, which is optionally substituted with one or more substitutents selected from halogen, C1-C3 haloalkyl, C3-C6 cycloalkyl, and C2-6 alkynyl.
Figure imgf000191_0001
168. The compound or salt of claim 118, wherein R3 is naphthalene, wherein the naphthalene is optionally substituted with one or more substituents independently selected from halogen, - OH, -NH2, -NO2, =O, C1-6 alkyl, C1-6 aminoalkyl, C1-6 hydroxyalkyl, C2-C4 alkynyl, and C1-6 haloalkyl. 169. The compound or salt of claim 168, wherein R3 is naphthalene, wherein the naphthalene is optionally substituted with one or more substituents independently selected from halogen, - OH, C2-C4 alkynyl, and C1-3 alkyl.
Figure imgf000191_0002
171. The compound or salt of claim 169, wherein R3 is naphthalene, and the naphthalene is substituted with one or more substituents independently selected from fluorine, C2-C4 alkynyl, and hydroxy.
Figure imgf000191_0003
.
173. The compound or salt of any one of claims 118 to 172, wherein R50 is selected from hydrogen and halogen. 174. The compound or salt of claim 173, R50 is selected from halogen. 175. The compound or salt of any one of claims 118 to 174, wherein R4 is selected from hydrogen and halogen. 176. The compound or salt of claim 175, wherein R4 is halogen. 177. A compound of Formula (IV):
Figure imgf000192_0001
Formula (IV), or a pharmaceutically acceptable salt thereof, wherein: Y is selected from a bond, O and NR5; R2 is selected from hydrogen, -N(R5)2, -L-N(R5)2, -L-OR5, heterocycle, C1-C6 alkyl, -L- heterocycle, -L-aryl, -L-heteroaryl, -L-cycloalkyl, -L-N(R5)2, -L-NHC(=NH)NH2, -L-C(O)N(R5)2, -L-C1-C6 haloalkyl, -L-OR5, -L-NR5C(O)-aryl, -L-COOH, and -LC(=O)OC1-C6 alkyl, wherein the heterocycle, the aryl portion of -L-NR5C(O)-aryl, the heterocycle portion of -L-heterocycle, and the cycloalkyl portion of the -L-cycloalkyl are each optionally substituted with one or more R6, and wherein the aryl of the -L-aryl and heteroaryl of the -L-heteroaryl are each optionally substituted with one or more R7; each L is independently selected from a C1-C4 alkylene optionally substituted with one or more substituents independently selected from -OH, C1-C4 hydroxyalkyl, C1-C4 alkyl, C3-C6 carbocycle, and 3- to 8-membered heterocycle, wherein the C3-C6 carbocycle and the 3- to 8- membered heterocycle are optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle wherein the C3-C6 carbocycle and the 3- to 8- membered heterocycle are optionally substituted with one or more substituents independently selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, and C1-6 haloalkyl; R3 is selected from tricyclic aryl and tricyclic heteroaryl, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, =O, - NO2, C1-C4 alkyl, C1-6 aminoalkyl, -S-C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 hydroxyalkynyl, C1-C3 cyanoalkyl, triazolyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, -S-C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, -CH2C(=O)N(R5)2, -C3-C4 alkynyl(NR5)2, -N(R5)2, (C1-C3 alkoxy)haloC1-C3 alkyl-, and C3-C6 cycloalkyl, wherein the C3-C6 cycloalkyl is optionally substituted with one or more substituents independently selected from halogen and C1-C3 alkyl; R4 is selected from hydrogen, halogen, C1-C3 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and -O-C1- 6 haloalkyl; each R5 is independently selected from hydrogen and C1-C3 alkyl; each R6 is independently selected from halogen, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkyl, oxo, C1-C3 haloalkyl, C1-C3 alkoxy, cyano, =NO-C1-C3 alkyl, C1-C3 aminoalkyl, -N(R5)S(O)2(R5), -Q-phenyl, -Q-phenylSO2F, -NHC(O)phenyl, - NHC(O)phenylSO2F, C1-C3 alkyl substituted pyrazolyl, tert-butyldimethylsilyloxyCH2- , -N(R5)2, (C1-C3 alkoxy)C1-C3 alkyl-, (C1-C3 alkyl)C(=O), (C1-C3 haloalkyl)C(=O)-, -SO2F, (C1-C3 alkoxy)C1-C3 alkoxy, -CH2OC(O)N(R5)2, - CH2NHC(O)OC1-C6 alkyl, -CH2NHC(O)N(R5)2, -CH2NHC(O)C1-C6 alkyl, -CH2(pyrazolyl), - CH2NHSO2C1-C6 alkyl, -CH2OC(O)heterocycle, -OC(O)N(R5)2, -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl), -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl(C1-C3 alkyl)N(CH3)2, -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl, - OC(O)heterocycle, -O-C1-C3 alkyl, and -CH2heterocycle, wherein the phenyl of -NHC(O)phenyl and -OC(O)NH(C1-C3 alkyl)(C1-C3 alkyl)phenyl are optionally substituted with one or more substituents selected from -C(O)H and OH, and wherein the alkyl of -O-C1-C3 alkyl is optionally substituted with substituents selected from heterocycle, oxo and hydroxy; and wherein the heterocycle of -CH2heterocyclyl is optionally substituted with oxo; each Q is independently selected from a bond and O; each R7 is independently selected from halogen, -OH, HC(=O)-, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, and -N(R5)2; R9 is selected from 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -B(OR20)2, -OR20, -SR20, -S(O)2(R20), -S(O)2N(R20)2, -N(R20)S(O)2(R20), -C(O)N(R20)2, -C(O)NR20-OR20, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)2, -S(O)2R20, - C(O)R20, -C(O)OR20, -OC(O)R20, -NO2, =O, =S, =N(R20), -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl; each R20 is independently selected from hydrogen; and C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbocycle, and 3- to 12- membered heterocycle; and R50 is selected from hydrogen, halogen, -OH, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, -CN, C1-C3 cyanoalkyl, C1-C3 aminoalkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 hydroxyalkynyl, and C3-C6 carbocycle.
178. The compound or salt of claims 177, wherein each L is independently selected from a C1- C4 alkylene optionally substituted; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle, wherein the C3-C6 carbocycle is optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl. 179. The compound or salt of claim 178, wherein the optional substituents of L are selected from C1-C4 hydroxyalkyl, C1-C4 alkyl, C3-C6 carbocycle; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are optionally substituted with one or more substituents selected from halogen and C1-6 haloalkyl. 180. The compound or salt of any one of claims 177 to 179, wherein Y is O. 181. The compound or salt of any one of claims 177 to 180, wherein R2 is selected from -L- heterocycle, wherein the heterocycle portion of -L-heterocycle may be optionally substituted with one or more R6. 182. The compound or salt of any one of claims 177 to 181, wherein Y-R2 is selected from
Figure imgf000194_0001
wherein the heterocycle portion is optionally substituted with one or more R6. 183. The compound or salt of claim 182, wherein R6 is selected from halogen, -OH, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, -CN, and C1-C3 aminoalkyl. 184. The compound or salt of claim 183, wherein R6 is selected from halogen and C1-C3 alkyl. 185. The compound or salt of claim 184, wherein Y-R2 is selected from
Figure imgf000194_0002
,
Figure imgf000194_0003
186. The compound or salt of claim 177, wherein R2 is selected from -L-heterocycle, wherein the heterocycle portion of -L-heterocycle is optionally substituted with one or more R6. 187. The compound or salt of claim 186, wherein each L is independently selected from a substituted C1-C4 alkylene, and wherein two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle, wherein the C3-C6 carbocycle is optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl.
188. The compound or salt of claim 187, wherein each L is independently selected from a substituted C1-C4 alkylene, and wherein two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle. 189. The compound or salt of claims 188, wherein each L is independently selected from a substituted C3 alkylene, and wherein two substituents on the same carbon atom of L come together to form a C3 carbocycle. 190. The compound or salt of claim 189, wherein each L is independently selected from
Figure imgf000195_0001
. 191. The compound or salt of claim 190, wherein Y-R2 is
Figure imgf000195_0002
. 192. The compound or salt of any one of claims 177 to 191, wherein R9 is selected from 6- to 7-membered heterocycle. 193. The compound or salt of claim 192, wherein the 6- to 7-membered heterocycle contains only 1 nitrogen atom, and wherein the 6- to 7-membered heterocycle is optionally substituted. 194. The compound or salt of 193, wherein the 6- to 7-membered heterocycle of R9 is bound to Formula (IV) via the only 1 nitrogen atom. 195. The compound or salt of any one of claims 192 to 194, wherein R9 is selected from an optionally substituted unsaturated 6-membered heterocycle. 196. The compound or salt of any one of claims 192 to 194, wherein R9 is selected from an optionally substituted unsaturated 7-membered heterocycle. 197. The compound or salt of any one of claims 192 to 196, wherein R9 is selected from
Figure imgf000195_0003
, , r s
Figure imgf000195_0004
,
Figure imgf000195_0005
y of which is optionally substituted. 199. The compound or salt of any one of claims 192 to 198, wherein the one or more optional substituents of R9 are each independently selected from halogen, -OR20, -N(R20)2, =O, -CN, C1-6 hydroxyalkyl C16 cyanoalkyl C16 alkyl and C26 alkynyl
200. The compound or salt of any one of claims 177 to 194, wherein R9 is selected from 6- to 7-membered heterocycle, wherein the 6- to 7-membered heterocycle contains only 1 nitrogen atom and optionally one or more additional heteroatoms selected from oxygen, and sulfur. 201. The compound or salt of claim 200, wherein the optionally one or more additional heteroatoms are selected from sulfur. 202. The compound or salt of claim 201, wherein the 6- to 7-membered heterocycle contains only 1 nitrogen atom and no further additional heteroatoms. 203. The compound or salt of any one of claims 200 to 202, wherein the 6- to 7-membered heterocycle is an unsaturated 6- to 7-membered heterocycle. 204. The compound or salt of claim 203, wherein R9 is selected from
Figure imgf000196_0001
,
Figure imgf000196_0002
205. The compound or salt of claim 204, wherein the one or more optional substituents of R9 are each independently selected from halogen, -OH, -CN, C1-6 cyanoalkyl, C1-6 alkyl, and C2-6 alkynyl. 206. The compound or salt of any one of claims 177 to 194, wherein R9 is selected from an optionally substituted unsaturated 6- to 8-membered heterocycle. 207. The compound or salt of claim 206, wherein R9 is selected from an optionally substituted unsaturated 6-membered heterocycle. 208. The compound or salt of claim 206, wherein R9 is selected from an optionally substituted unsaturated 7-membered heterocycle. 209. The compound or salt of any one of claims 206 to 208, wherein R9 is selected from
Figure imgf000196_0003
wherein each is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH2, -NO2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl, and C1-6 alkyl.
210. The compound or salt of claim 209, wherein R9 is selected from
Figure imgf000197_0001
,
Figure imgf000197_0002
211. The compound or salt of any one of claims 206 to 208, wherein R9 is selected from
Figure imgf000197_0003
wherein each is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH2, -NO2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl, and C1-6 alkyl. 212. The compound or salt of claim 211, wherein R9 is selected from
Figure imgf000197_0004
, wherein each is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH2, -NO2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl, and C1-6 alkyl. 213. The compound or salt of claim 212, wherein R9 is selected from
Figure imgf000197_0005
, wherein each is optionally substituted with one or more substituents independently selected from halogen, and C1-6 haloalkyl.
214. The compound or salt of claim 213, wherein R9 is selected from
Figure imgf000198_0001
, ,
Figure imgf000198_0002
215. The compound or salt of claim 214, wherein R9 is selected from
Figure imgf000198_0003
, , 216. The compound or salt of any one of claims 177 to 190, wherein R9 is selected from 6- to 7-membered heterocycle. 217. The compound or salt of claim 216, wherein the 6- to 7-membered heterocycle contains only 1 nitrogen atom and optionally one or more additional heteroatoms selected from oxygen, and sulfur. 218. The compound or salt of claim 217, wherein the optionally one or more additional heteroatoms are selected from sulfur. 219. The compound or salt of claim 218, wherein the 6- to 7-membered heterocycle contains only 1 nitrogen atom and no further additional heteroatoms. 220. The compound or salt of any one of claims 216 to 219, wherein the 6- to 7-membered heterocycle is a non-aromatic 6- to 7-membered heterocycle. 221. The compound or salt of any one of claims 216 to 220, wherein the 6- to 7-membered heterocycle of R9 is bound to Formula (IV) via the only 1 nitrogen atom. 222. The compound or salt of claim 221, wherein R9 is selected from
Figure imgf000198_0004
, , ,
Figure imgf000198_0005
, , , each of which is optionally substituted.
223. The compound or salt of claim 222, wherein R9 is selected from
Figure imgf000199_0001
,
Figure imgf000199_0002
, , , each of which is substituted. 224. The compound or salt of any one of claims 177 to 194, wherein R9 is selected from an optionally substituted 6- to 10-membered heterocycle. 225. The compound or salt of claim 224, R9 is selected from
Figure imgf000199_0003
,
Figure imgf000199_0004
substituted with one or more substituents independently selected from halogen, =O, - OH, -C(O)N(R20)2, C2-6 alkynyl, -NHCN, -CN, C1-6 aminoalkyl, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, and C1-6 alkyl. 226. The compound or salt of claim 225, wherein R9 is selected from
Figure imgf000199_0005
, ,
Figure imgf000199_0006
227. The compound or salt of any one of claims 177 to 194, wherein R9 is selected from an optionally substituted unsaturated 9- to 11-membered heterocycle. 228. The compound or salt of claim 227, wherein R9 is selected from an optionally substituted unsaturated 10-membered heterocycle. 229. The compound or salt of claim 228, wherein
Figure imgf000199_0007
, which is optionally substituted.
230. The compound or salt of claim 229, wherein
Figure imgf000200_0001
, which is optionally substituted with one or more substituents selected from halogen, -OH, -C(O)N(R20)2, - C(O)NR20-OR20, -N(R20)2, -C(O)R20, -NO2, =O, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, and C2-6 alkynyl. 231. The compound or salt of claim 230, wherein
Figure imgf000200_0002
each R20 is independently selected from hydrogen; and C1-6 alkyl, and C3-12 carbocycle, and each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, - CN, -NO2, -NH2, C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle. 232. The compound or salt of claim 231, wherein each R20 is independently selected from hydrogen; and C1-6 alkyl. 233. The compound or salt of claim 118, wherein R3 is selected from an optionally substituted tricyclic 12- to 13-membered heteroaryl. 234. The compound or salt of claim 233, the substituents are selected from halogen, hydroxy, cyano, =O, -NO2, C1-C4 alkyl, C3-C6 cycloalkyl, C1-6 aminoalkyl, C1-C3 haloalkyl, C1-C3 hydroxyalkyl, C2-C4 alkynyl, and -N(R20)2. 235. The compound or salt of claim 234, the substituents are selected from halogen, hydroxy, =O, -NO2, C1-C4 alkyl, C3-C6 cycloalkyl, C1-6 aminoalkyl, C1-C3 haloalkyl, C2-C4 alkynyl, and - NH2. 236. The compound or salt of any one of claims 233 to 235, wherein R3 is selected from
Figure imgf000200_0003
optionally substituted.
237. The compound or salt of claim 236, wherein R3 is selected from
Figure imgf000201_0001
Figure imgf000201_0002
, each of which are optionally substituted with one or more substituents independently selected from halogen, hydroxy, =O, -NO2, C1-C4 alkyl, C3-C6 cycloalkyl, C1-6 aminoalkyl, C1-C3 haloalkyl, C1-C3 hydroxyalkyl, C2-6 alkynyl, and -N(R20)2. 238. The compound or salt of claim 237, wherein R3 is selected from
Figure imgf000201_0003
,
Figure imgf000201_0004
, each of which are optionally substituted with one or more substituents independently selected from cyano, hydroxy, =O, C3-C6 cycloalkyl, C2-6 alkynyl, and . 239. The compound or salt of claim 238, wherein R3 is selected from
Figure imgf000201_0005
,
Figure imgf000201_0006
240. The compound or salt of claim 238, wherein R3 is selected from
Figure imgf000202_0001
, which is optionally substituted with one or more substituents independently selected from halogen, -CN, - OH, =O, -NO2, C1-C4 alkyl, C3-C6 cycloalkyl, C1-6 aminoalkyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, C2-6 alkynyl, and -N(R5)2. 241. The compound or salt of claim 240, wherein R3 is selected from
Figure imgf000202_0002
, which is optionally substituted with one or more substituents independently selected from halogen, -CN, - OH, =O, hydroxy, C3-C6 cycloalkyl, C1-6 aminoalkyl, C2-6 alkynyl, and -N(R5)2.
Figure imgf000202_0003
243. The compound or salt of claims 118 or 233, wherein R3 is a tricyclic heteroaryl that has at least one nitrogen atom and one sulfur atom. 244. The compound or salt of claim 243, wherein R3 is selected from
Figure imgf000202_0004
, which is optionally substituted with one or more substituents independently selected from halogen, C1-C3 haloalkyl, -CN, -OH, =O, hydroxy, C3-C6 cycloalkyl, C1-6 aminoalkyl, C2-6 alkynyl, and -N(R5)2. 245. The compound or salt of claim 244, wherein R3 is selected from
Figure imgf000202_0005
, which is optionally substituted with one or more substitutents selected from halogen, hydroxy, =O, -NO2, C1-C4 alkyl, C3-C6 cycloalkyl, C1-6 aminoalkyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, and C2-6 alkynyl.
246. The compound or salt of claim 245, wherein R3 is selected from
Figure imgf000203_0001
, which is optionally substituted with one or more substitutents selected from halogen, C1-C3 haloalkyl, C3-C6 cycloalkyl, and C2-6 alkynyl.
Figure imgf000203_0002
248. The compound or salt of any one of claims 177 to 247, wherein R50 is selected from hydrogen and halogen. 249. The compound or salt of claim 248, wherein R50 is selected from halogen. 250. The compound or salt of any one of claims 177 to 249, wherein R4 is selected from hydrogen and halogen. 251. The compound or salt of claim 250, wherein R4 is halogen. 252. A compound of Formula (V):
Figure imgf000203_0003
Formula (V), or a pharmaceutically acceptable salt thereof, wherein: Y is O; R2 is selected from -L-heterocycle, wherein the heterocycle portion of -L-heterocycle is optionally substituted with one or more R6; each L is independently selected from a C1-C4 alkylene optionally substituted with one or more substituents independently selected from -OH, C1-C4 hydroxyalkyl, C1-C4 alkyl, C3-C6 carbocycle, and 3- to 8-membered heterocycle, wherein the C3-C6 carbocycle and 3- to 8- membered heterocycle are optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle wherein the C3-C6 carbocycle and the 3- to 8- membered heterocycle are optionally substituted with one or more substituents independently selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl; R3 is selected from aryl and heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, =O, -NO2, C1-C4 alkyl, C1-6 aminoalkyl, -S-C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 hydroxyalkynyl, C1-C3 cyanoalkyl, triazolyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, -S-C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, -CH2C(=O)N(R5)2, -C3-C4 alkynyl(NR5)2, -N(R5)2, (C1-C3 alkoxy)haloC1-C3 alkyl- , and C3-C6 cycloalkyl, wherein the C3-C6 cycloalkyl is optionally substituted with one or more substituents selected from halogen and C1-C3 alkyl; R4 is selected from hydrogen, halogen, C1-C3 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and -O-C1- 6 haloalkyl; each R5 is independently selected from hydrogen and C1-C3 alkyl; each R6 is independently selected from halogen, -OH, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1- C3 haloalkyl, C1-C3 alkoxy, -CN, =CH2, C1-C3 aminoalkyl, -Q-phenyl, -Q-phenylSO2F, - NHC(O)phenyl, - NHC(O)phenylSO2F, C1-C3 alkyl substituted pyrazolyl, -N(R5)2, (C1-C3 alkoxy)C1-C3 alkyl-, (C1-C3 alkyl)C(=O), oxo, (C1-C3 haloalkyl)C(=O)-, -SO2F, (C1-C3 alkoxy)C1- C3 alkoxy, -CH2OC(O)N(R5)2, -CH2NHC(O)OC1-C6 alkyl, -CH2NHC(O)N(R5)2, - CH2NHC(O)C1-C6 alkyl, -CH2(pyrazolyl), -CH2NHSO2C1-C6 alkyl, -CH2OC(O)heterocycle, - OC(O)N(R5)2, -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl), -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl(C1-C3 alkyl)N(CH3)2, -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl, - OC(O)heterocycle, and -CH2heterocycle, wherein the phenyl of -NHC(O)phenyl and - OC(O)NH(C1-C3 alkyl)(C1-C3 alkyl)phenyl are each optionally substituted with -C(O)H and OH, and wherein the heterocycle of -CH2heterocyclyl is optionally substituted with oxo; each Q is independently selected from a bond and O; each R20 is independently selected from hydrogen; and C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbocycle, and 3- to 12- membered heterocycle; R50 is selected from hydrogen, halogen, -OH, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, -CN, C1-C3 cyanoalkyl, C1-C3 aminoalkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 hydroxyalkynyl, and C3-C6 carbocycle. 253. The compound or salt of claim 252, wherein R4 is selected from hydrogen and halogen. 254. The compound or salt of claims 252 or 253, wherein R4 is selected from halogen. 255. The compound or salt of any one of claims 252 to 254, wherein R4 is hydrogen. 256. The compound or salt of any one of claims 252 to 255, wherein R3 is selected from aryl and heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, C1-C4 alkyl, and C2-C4 alkynyl. 257. The compound or salt of any one of claims, wherein R50 is selected from hydrogen, halogen, C1-C3 cyanoalkyl, and C2-C4 alkenyl. 258. The compound or salt of claim 257, wherein R50 is hydrogen. 259. The compound or salt of any one of claims 252 to 258, wherein L is selected from C1-C4 alkylene. 260. The compound or salt of any one of claims 252 to 259, wherein L is selected from unsubstituted C1-C4 alkylene. 261. The compound or salt of any one of claims 252 to 260, wherein each L is independently selected from a C1-C4 alkylene optionally substituted; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle, wherein the C3-C6 carbocycle is optionally substituted with one or more substituents selected from halogen, -OH, - NO2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl. 262. The compound or salt of any one of claims 252 to 261, wherein Y-R2 is selected from
Figure imgf000205_0001
Figure imgf000205_0002
, wherein the heterocycle portion is optionally substituted with one or more R6.
263. The compound or salt of any one of claims 252 to 262, wherein R6 is selected from halogen, -OH, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, -CN, and C1-C3 aminoalkyl. 264. The compound or salt of any one of claims 252 to 264, wherein Y-R2 is selected from
Figure imgf000206_0001
or a pharmaceutically acceptable salt thereof, wherein: Y is O; R2 is selected from -L-heterocycle, wherein the heterocycle portion of -L-heterocycle, is optionally substituted with one or more R6; each L is independently selected from a C1-C4 alkylene optionally substituted with one or more substituents independently selected from -OH, C1-C4 hydroxyalkyl, C1-C4 alkyl, C3-C6 carbocycle, or 3- to 8-membered heterocycle, wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle wherein the C3-C6 carbocycle and the 3- to 8- membered heterocycle are optionally substituted with one or more substituents independently selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl; R3 is selected from aryl and heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, =O, -NO2, C1-C4 alkyl, C1-6 aminoalkyl, -S-C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 hydroxyalkynyl, C1-C3 cyanoalkyl, triazolyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, -S-C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, -CH2C(=O)N(R5)2, -C3-C4 alkynyl(NR5)2, -N(R5)2, (C1-C3 alkoxy)haloC1-C3 alkyl- , and C3-C6 cycloalkyl, wherein the C3-C6 cycloalkyl is optionally substituted with one or more substituents selected from halogen and C1-C3 alkyl; and wherein when R3 is benzothiazole or pyridine, the benzothiazole or pyridine is optionally substituted with one or more R49; R4 is selected from hydrogen, halogen, C1-C3 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and -O-C1- 6 haloalkyl; each R5 is independently selected from hydrogen and C1-C3 alkyl; each R6 is independently selected from halogen, -OH, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1- C3 haloalkyl, C1-C3 alkoxy, -CN, =CH2, C1-C3 aminoalkyl, -Q-phenyl, -Q-phenylSO2F, - NHC(O)phenyl, - NHC(O)phenylSO2F, C1-C3 alkyl substituted pyrazolyl, -N(R5)2, (C1-C3 alkoxy)C1-C3 alkyl-, (C1-C3 alkyl)C(=O), oxo, (C1-C3 haloalkyl)C(=O)-, -SO2F, (C1-C3 alkoxy)C1- C3 alkoxy, -CH2OC(O)N(R5)2, -CH2NHC(O)OC1-C6 alkyl, -CH2NHC(O)N(R5)2, - CH2NHC(O)C1-C6 alkyl, -CH2(pyrazolyl), -CH2NHSO2C1-C6 alkyl, -CH2OC(O)heterocycle, - OC(O)N(R5)2, -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl), -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl(C1-C3 alkyl)N(CH3)2, -OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl, - OC(O)heterocycle, and -CH2heterocycle, wherein the phenyl of -NHC(O)phenyl and - OC(O)NH(C1-C3 alkyl)(C1-C3 alkyl)phenyl are each optionally substituted with -C(O)H and OH, and wherein the heterocycle of -CH2heterocyclyl is optionally substituted with oxo; each Q is independently selected from a bond and O; R9 is selected from a 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle is substituted with one or more substituents independently selected from -OH, - NHCN, -CN, C1-6 alkoxy; and further optionally substituted with one or more substituents independently selected from halogen, -C(O)N(R20)2, -C(O)NR20-OR20, C1-6 haloalkyl, -SR20, =O, =S, =N(R20), -B(OR20)2, -N(R20)2, -NO2, C1-6 aminoalkyl, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 alkyl, C1-6 alkyl-O-C(O)C1-6 alkyl, C2-6 alkynyl and C2-6 alkenyl; wherein when R9 is substituted with at least one -OH or C1-6 alkoxy, the 5- to 12-membered heterocycle is a non-bridged heterocycle; each R20 is independently selected from hydrogen; and C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbocycle, and 3- to 12- membered heterocycle; each R49 is independently selected from halogen, -CN, -OH, =O, -NO2, C1-C4 alkyl, C1-6 aminoalkyl, -S-C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 hydroxyalkynyl, C1-C3 cyanoalkyl, triazolyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, -S-C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, -CH2C(=O)N(R5)2, -C3-C4 alkynyl(NR5)2, (C1-C3 alkoxy)haloC1-C3 alkyl-, and C3- C6 cycloalkyl, wherein the C3-C6 cycloalkyl is optionally substituted with one or more substituents independently selected from halogen and C1-C3 alkyl; R50 is selected from hydrogen, halogen, -OH, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, -CN, C1-C3 cyanoalkyl, C1-C3 aminoalkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 hydroxyalkynyl, and C3-C6 carbocycle. 266. The compound or salt of claim 265, wherein R9 is selected from a 6- to 7-membered heterocycle, each of which is substituted. 267. The compound or salt of claim 266, wherein R9 is selected from
Figure imgf000208_0001
each of which is substituted. 268. The compound or salt of claims 266 or 267, wherein the one or more substituents are independently selected from -OH, -CN, and -NHCN; and further optionally substituted with one or more substituents independently selected from C1-6 alkyl. 269. The compound or salt of claim 268, wherein R9 is selected from
Figure imgf000208_0002
, ,
Figure imgf000208_0003
270. The compound or salt of claim 268, wherein the one or more substituents are independently selected from -OH, and further optionally substituted with one or more substituents independently selected from C1-6 alkyl.
271. The compound or salt of claim 270, wherein R9 is selected from
Figure imgf000209_0001
Figure imgf000209_0002
. 272. The compound or salt of claim 268, wherein the one or more substituents are independently selected from -CN and -NHCN, and further optionally substituted with one or more substituents independently selected from C1-6 alkyl. 273. The compound or salt of claim 272, wherein R9 is selected from
Figure imgf000209_0003
Figure imgf000209_0004
. 274. The compound or salt of any one of claims 265 to 273, wherein R4 is selected from hydrogen and halogen. 275. The compound or salt of claim 274, wherein R4 is selected from halogen. 276. The compound or salt of claim 275, wherein R4 is fluorine. 277. The compound or salt of any one of claims 265 to 276, wherein R3 is selected from aryl and heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, C1-C4 alkyl, and C2-C4 alkynyl. 278. The compound or salt of any one of claims 265 to 273, wherein R50 is selected from hydrogen, halogen, C1-C3 cyanoalkyl, and C2-C4 alkenyl.
279. The compound or salt of any one of claims 265 to 278, wherein L is selected from C1-C4 alkylene. 280. The compound or salt of any one of claims 265 to 279, wherein L is selected from unsubstituted C1-C4 alkylene. 281. The compound or salt of any one of claims 265 to 280, wherein each L is independently selected from a C1-C4 alkylene optionally substituted; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle, wherein the C3-C6 carbocycle is optionally substituted with one or more substituents selected from halogen, -OH, - NO2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl. 282. The compound or salt of any one of claims 265 to 281, wherein Y-R2 is selected from
Figure imgf000210_0001
Figure imgf000210_0002
, wherein the heterocycle portion is optionally substituted with one or more R6. 283. The compound or salt of any one of claims 265 to 282, wherein R6 is selected from halogen, -OH, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, -CN, and C1-C3 aminoalkyl. 284. The compound or salt of any one of claims 265 to 283, wherein Y-R2 is selected from ,
Figure imgf000210_0003
285. A pharmaceutical composition comprising a compound or salt of any one of claims 1 to 284 and a pharmaceutically acceptable excipient. 286. A method of treating a disease or disorder, using a compound or salt of any one of claims 1 to 284 or a pharmaceutical composition of claim 285.
287. A method of inhibiting KRas G12D and/or other G12 mutants, using a compound or salt of any one of claims 1 to 284 or a pharmaceutical composition of claim 285. 288. A method of inhibiting KRas G12D and/or other G12 alleles, using a compound or salt of any one of claims 1 to 284 or a pharmaceutical composition of claim 285. 289. A method of inhibiting KRas G12D and/or other alleles, using a compound or salt of any one of claims 1 to 284 or a pharmaceutical composition of claim 285. 290. Use of a compound of any one of Claims 1-284 thereof in the preparation of a target protein degrading compound by using chemical modification of compound of any one of Claims 1-284. 291. A bifunctional compound composed of a target protein-binding moiety and an E3 ubiquitin ligase-binding moiety, wherein the target protein-binding moiety is derived from the compound of any of claims 1-284.
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