[go: up one dir, main page]
More Web Proxy on the site http://driver.im/

WO2023114733A1 - Modulateurs de kras et leurs utilisations - Google Patents

Modulateurs de kras et leurs utilisations Download PDF

Info

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
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
compound
salt
optionally substituted
halogen
Prior art date
Application number
PCT/US2022/081393
Other languages
English (en)
Inventor
Hong Lin
Juan Luengo
Neil Johnson
Original Assignee
Quanta Therapeutics, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Quanta Therapeutics, Inc. filed Critical Quanta Therapeutics, Inc.
Publication of WO2023114733A1 publication Critical patent/WO2023114733A1/fr

Links

Classifications

    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D487/00Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02Heterocyclic 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
    • C07D487/04Ortho-condensed systems
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D401/00Heterocyclic 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
    • C07D401/14Heterocyclic 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
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D403/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14Heterocyclic 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
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D413/00Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14Heterocyclic 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
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D417/00Heterocyclic 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
    • C07D417/14Heterocyclic 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
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D519/00Heterocyclic 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.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

L'invention concerne des composés de modulation de KRAS, tels que des composés de formule (I) et diverses sous-formules ou des sels, des solvates, des stéréoisomères, des composés marqués par atomes ou des tautomères pharmaceutiquement acceptables de ceux-ci, utiles pour moduler KRAS GD12 et/ou d'autres mutants de G12.
PCT/US2022/081393 2021-12-13 2022-12-12 Modulateurs de kras et leurs utilisations WO2023114733A1 (fr)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
US202163288970P 2021-12-13 2021-12-13
US63/288,970 2021-12-13
US202263367560P 2022-07-01 2022-07-01
US63/367,560 2022-07-01
US202263371987P 2022-08-19 2022-08-19
US63/371,987 2022-08-19

Publications (1)

Publication Number Publication Date
WO2023114733A1 true WO2023114733A1 (fr) 2023-06-22

Family

ID=85018340

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2022/081393 WO2023114733A1 (fr) 2021-12-13 2022-12-12 Modulateurs de kras et leurs utilisations

Country Status (1)

Country Link
WO (1) WO2023114733A1 (fr)

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023215802A1 (fr) * 2022-05-04 2023-11-09 Kumquat Biosciences Inc. Composés hétérocycliques et leurs utilisations
US11912723B2 (en) 2022-02-09 2024-02-27 Quanta Therapeutics, Inc. KRAS modulators and uses thereof
WO2024112654A1 (fr) 2022-11-21 2024-05-30 Treeline Biosciences, Inc. Inhibiteurs de kras spirocycliques de dihydropyranopyrimidine
US12059425B2 (en) 2022-08-05 2024-08-13 Kumquat Biosciences Inc. Heterocyclic compounds and uses thereof
WO2024206858A1 (fr) 2023-03-30 2024-10-03 Revolution Medicines, Inc. Compositions pour induire une hydrolyse de ras gtp et leurs utilisations
WO2024229406A1 (fr) 2023-05-04 2024-11-07 Revolution Medicines, Inc. Polythérapie pour une maladie ou un trouble lié à ras
US12145947B2 (en) 2022-05-25 2024-11-19 Quanta Therapeutics, Inc. Pyrimidine based modulators and uses thereof
WO2025034702A1 (fr) 2023-08-07 2025-02-13 Revolution Medicines, Inc. Rmc-6291 destiné à être utilisé dans le traitement d'une maladie ou d'un trouble lié à une protéine ras
WO2025038936A1 (fr) 2023-08-17 2025-02-20 Treeline Biosciences, Inc. Inhibiteurs de dihydropyranopyrimidine kras spirocycliques
WO2025064848A1 (fr) 2023-09-21 2025-03-27 Treeline Biosciences, Inc. Inhibiteurs de kras de type dihydropyranopyrimidines spirocycliques
WO2025076044A1 (fr) 2023-10-03 2025-04-10 PAQ Therapeutics Inc. Chimères ciblant la protéolyse kras
WO2025080946A2 (fr) 2023-10-12 2025-04-17 Revolution Medicines, Inc. Inhibiteurs de ras

Citations (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5846514A (en) 1994-03-25 1998-12-08 Isotechnika, Inc. Enhancement of the efficacy of nifedipine by deuteration
US6334997B1 (en) 1994-03-25 2002-01-01 Isotechnika, Inc. Method of using deuterated calcium channel blockers
WO2017087528A1 (fr) * 2015-11-16 2017-05-26 Araxes Pharma Llc Composés quinazoline substitués en position 2 comprenant un groupe hétérocyclique substitué et leur méthode d'utilisation
WO2022105857A1 (fr) * 2020-11-20 2022-05-27 Jacobio Pharmaceuticals Co., Ltd. Inhibiteurs de kras g12d
WO2022105859A1 (fr) * 2020-11-20 2022-05-27 Jacobio Pharmaceuticals Co., Ltd. Inhibiteurs de kras g12d
WO2022135470A1 (fr) * 2020-12-22 2022-06-30 上海科州药物研发有限公司 Préparation et procédé d'application d'un composé hétérocyclique utilisé en tant qu'inhibiteur de kras
CN114685460A (zh) * 2020-12-31 2022-07-01 贝达药业股份有限公司 Kras g12c抑制剂及其在医药上的应用
WO2022148422A1 (fr) * 2021-01-08 2022-07-14 Beigene, Ltd. Composés pontés en tant qu'inhibiteur et dégradeur de kras g12d et leur utilisation
WO2022173870A1 (fr) * 2021-02-09 2022-08-18 Kumquat Biosciences Inc. Composés hétérocycliques et leurs utilisations
WO2022177917A2 (fr) * 2021-02-16 2022-08-25 Theras, Inc. Compositions et procédés d'inhibition de ras
WO2022184178A1 (fr) * 2021-03-05 2022-09-09 Jacobio Pharmaceuticals Co., Ltd. Inhibiteurs de kras g12d
WO2022187527A1 (fr) * 2021-03-05 2022-09-09 Nikang Therapeutics, Inc Dérivés de quinazoline nitrile en tant qu'inhibiteurs de kras
WO2022187528A1 (fr) * 2021-03-05 2022-09-09 Nikang Therapeutics, Inc Dérivés de quinazoline amine en tant qu'inhibiteurs de kras
WO2022192794A1 (fr) * 2021-03-12 2022-09-15 Bristol-Myers Squibb Company Inhibiteurs de kras g12d
WO2022192790A1 (fr) * 2021-03-12 2022-09-15 Bristol-Myers Squibb Company Inhibiteurs de kras
WO2022194066A1 (fr) * 2021-03-15 2022-09-22 贝达药业股份有限公司 Inhibiteur de kras g12d et ses applications en médecine
WO2022193982A1 (fr) * 2021-03-15 2022-09-22 药雅科技(上海)有限公司 Préparation et utilisation d'un inhibiteur de la mutéine krasg12c
WO2022194191A1 (fr) * 2021-03-16 2022-09-22 Guangdong Newopp Biopharmaceuticals Co., Ltd. Composés hétérocycliques utilisés en tant qu'inhibiteurs de kras g12d
WO2022214102A1 (fr) * 2021-04-09 2022-10-13 杭州英创医药科技有限公司 Composé hétérocyclique agissant comme inhibiteur de kras g12d
WO2022221386A1 (fr) * 2021-04-14 2022-10-20 Erasca, Inc. Inhibiteurs sélectifs de kras
WO2022232331A1 (fr) * 2021-04-29 2022-11-03 Amgen Inc. Composés hétérocycliques et procédés d'utilisation
WO2022251576A1 (fr) * 2021-05-28 2022-12-01 Merck Sharp & Dohme Corp. Petites molécules inhibitrices du mutant g12c kras
WO2022247760A1 (fr) * 2021-05-22 2022-12-01 上海科州药物研发有限公司 Composés hétérocycliques utiles en tant qu'inhibiteurs de kras, leur préparation et leur utilisation thérapeutique

Patent Citations (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5846514A (en) 1994-03-25 1998-12-08 Isotechnika, Inc. Enhancement of the efficacy of nifedipine by deuteration
US6334997B1 (en) 1994-03-25 2002-01-01 Isotechnika, Inc. Method of using deuterated calcium channel blockers
WO2017087528A1 (fr) * 2015-11-16 2017-05-26 Araxes Pharma Llc Composés quinazoline substitués en position 2 comprenant un groupe hétérocyclique substitué et leur méthode d'utilisation
WO2022105857A1 (fr) * 2020-11-20 2022-05-27 Jacobio Pharmaceuticals Co., Ltd. Inhibiteurs de kras g12d
WO2022105859A1 (fr) * 2020-11-20 2022-05-27 Jacobio Pharmaceuticals Co., Ltd. Inhibiteurs de kras g12d
WO2022135470A1 (fr) * 2020-12-22 2022-06-30 上海科州药物研发有限公司 Préparation et procédé d'application d'un composé hétérocyclique utilisé en tant qu'inhibiteur de kras
CN114685460A (zh) * 2020-12-31 2022-07-01 贝达药业股份有限公司 Kras g12c抑制剂及其在医药上的应用
WO2022148422A1 (fr) * 2021-01-08 2022-07-14 Beigene, Ltd. Composés pontés en tant qu'inhibiteur et dégradeur de kras g12d et leur utilisation
WO2022173870A1 (fr) * 2021-02-09 2022-08-18 Kumquat Biosciences Inc. Composés hétérocycliques et leurs utilisations
WO2022177917A2 (fr) * 2021-02-16 2022-08-25 Theras, Inc. Compositions et procédés d'inhibition de ras
WO2022184178A1 (fr) * 2021-03-05 2022-09-09 Jacobio Pharmaceuticals Co., Ltd. Inhibiteurs de kras g12d
WO2022187527A1 (fr) * 2021-03-05 2022-09-09 Nikang Therapeutics, Inc Dérivés de quinazoline nitrile en tant qu'inhibiteurs de kras
WO2022187528A1 (fr) * 2021-03-05 2022-09-09 Nikang Therapeutics, Inc Dérivés de quinazoline amine en tant qu'inhibiteurs de kras
WO2022192794A1 (fr) * 2021-03-12 2022-09-15 Bristol-Myers Squibb Company Inhibiteurs de kras g12d
WO2022192790A1 (fr) * 2021-03-12 2022-09-15 Bristol-Myers Squibb Company Inhibiteurs de kras
WO2022194066A1 (fr) * 2021-03-15 2022-09-22 贝达药业股份有限公司 Inhibiteur de kras g12d et ses applications en médecine
WO2022193982A1 (fr) * 2021-03-15 2022-09-22 药雅科技(上海)有限公司 Préparation et utilisation d'un inhibiteur de la mutéine krasg12c
WO2022194191A1 (fr) * 2021-03-16 2022-09-22 Guangdong Newopp Biopharmaceuticals Co., Ltd. Composés hétérocycliques utilisés en tant qu'inhibiteurs de kras g12d
WO2022214102A1 (fr) * 2021-04-09 2022-10-13 杭州英创医药科技有限公司 Composé hétérocyclique agissant comme inhibiteur de kras g12d
WO2022221386A1 (fr) * 2021-04-14 2022-10-20 Erasca, Inc. Inhibiteurs sélectifs de kras
WO2022232331A1 (fr) * 2021-04-29 2022-11-03 Amgen Inc. Composés hétérocycliques et procédés d'utilisation
WO2022247760A1 (fr) * 2021-05-22 2022-12-01 上海科州药物研发有限公司 Composés hétérocycliques utiles en tant qu'inhibiteurs de kras, leur préparation et leur utilisation thérapeutique
WO2022251576A1 (fr) * 2021-05-28 2022-12-01 Merck Sharp & Dohme Corp. Petites molécules inhibitrices du mutant g12c kras

Non-Patent Citations (25)

* Cited by examiner, † Cited by third party
Title
"Curr., Pharm. Des", vol. 6, 2000, article "Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development", pages: 110
"Pharmaceutical Dosage Forms and Drug Delivery Systems", 1999, LIPPINCOTT WILLIAMS & WILKINS
"Pharmaceutical Dosage Forms", 1980, MARCEL DECKER
CANCER DISCOVERY, vol. 7, no. 8, 2017, pages 818 - 831
CULLY, M.J. DOWNWARD, SNAPSHOT: RAS SIGNALING. CELL, vol. 133, no. 7, 2008, pages 1292 - 1292
DROSTEN, M ET AL.: "Genetic analysis of Ras signalling pathways in cell proliferation, migration and survival", EMBO J, vol. 29, no. 6, 2010, pages 1091 - 104
EDWARD B. ROCHE: "Bioreversible Carriers in Drug Design", 1987, AMERICAN PHARMACEUTICAL ASSOCIATION AND PERGAMON PRESS
EVANS, E. ANTHONY: "Synthesis of radiolabeled compounds", J. RADIOANAL. CHEM., vol. 64, no. 1-2, 1981, pages 9 - 32
FEDORAK ET AL., AM. J. PHYSIOL., vol. 269, 1995, pages G210 - 218
GENNARO: "Remington: The Science and Practice of Pharmacy", 2005, MACK PUBLISHING COMPANY
GEORGE WVARMA, RAJENDER S: "The Synthesis of Radiolabeled Compounds via Organometallic Intermediates", TETRAHEDRON, vol. 45, no. 21, 1989, pages 6601 - 21
HOCHHAUS ET AL., BIOMED. CHROM, vol. 6, 1992, pages 283 - 286
HOOVER, JOHN E: "Remington's Pharmaceutical Sciences", 1975, MACK PUBLISHING CO.
J. LARSEN ET AL., INT. J. PHARMACEUTICS, vol. 47, 1988, pages 103
J. LARSENH. BUNDGAARD, INT. J. PHARMACEUTICS, vol. 37, 1987, pages 87
JEAN JACQUESANDRE COLLETSAMUEL H. WILEN: "Enantiomers, Racemates and Resolutions", 1981, JOHN WILEY AND SONS, INC.
L. FIESERM. FIESER, FIESER AND FIESER'S REAGENTS FOR ORGANIC SYNTHESIS, 1994
MCLOED ET AL., GASTROENTEROL, vol. 106, 1994, pages 405 - 413
P. G. M. WUTS: "T. W. Greene", 1991, article "Protective Groups in Organic Synthesis"
R. LAROCK, COMPREHENSIVE ORGANIC TRANSFORMATIONS, 1989
ROWE ET AL.: "Handbook of Pharmaceutical Excipients: A Comprehensive Guide to Uses, Properties, and Safety", 2006
SINKULA ET AL., J. PHARM. SCI., vol. 64, 1975, pages 181 - 210
STEPHEN, A.G. ET AL.: "Dragging ras back in the ring", CANCER CELL, vol. 25, no. 3, 2014, pages 272 - 81, XP028633347, DOI: 10.1016/j.ccr.2014.02.017
T. HIGUCHIV. STELLA: "Pro-drugs as Novel Delivery Systems", A.C.S. SYMPOSIUM SERIES, vol. 14
WINTER GEBUCKLEY DLPAULK JROBERTS JMSOUZA ADHE-PAGANON SBRADNER JE: "DRUG DEVELOPMENT", PHTHALIMIDE CONJUGATION AS A STRATEGY FOR IN VIVO TARGET PROTEIN DEGRADATION. SCIENCE, vol. 348, no. 6241, 19 June 2015 (2015-06-19), pages 1376 - 81

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11912723B2 (en) 2022-02-09 2024-02-27 Quanta Therapeutics, Inc. KRAS modulators and uses thereof
WO2023215802A1 (fr) * 2022-05-04 2023-11-09 Kumquat Biosciences Inc. Composés hétérocycliques et leurs utilisations
US12145947B2 (en) 2022-05-25 2024-11-19 Quanta Therapeutics, Inc. Pyrimidine based modulators and uses thereof
US12059425B2 (en) 2022-08-05 2024-08-13 Kumquat Biosciences Inc. Heterocyclic compounds and uses thereof
WO2024112654A1 (fr) 2022-11-21 2024-05-30 Treeline Biosciences, Inc. Inhibiteurs de kras spirocycliques de dihydropyranopyrimidine
WO2024206858A1 (fr) 2023-03-30 2024-10-03 Revolution Medicines, Inc. Compositions pour induire une hydrolyse de ras gtp et leurs utilisations
WO2024229406A1 (fr) 2023-05-04 2024-11-07 Revolution Medicines, Inc. Polythérapie pour une maladie ou un trouble lié à ras
WO2025034702A1 (fr) 2023-08-07 2025-02-13 Revolution Medicines, Inc. Rmc-6291 destiné à être utilisé dans le traitement d'une maladie ou d'un trouble lié à une protéine ras
WO2025038936A1 (fr) 2023-08-17 2025-02-20 Treeline Biosciences, Inc. Inhibiteurs de dihydropyranopyrimidine kras spirocycliques
WO2025064848A1 (fr) 2023-09-21 2025-03-27 Treeline Biosciences, Inc. Inhibiteurs de kras de type dihydropyranopyrimidines spirocycliques
WO2025076044A1 (fr) 2023-10-03 2025-04-10 PAQ Therapeutics Inc. Chimères ciblant la protéolyse kras
WO2025080946A2 (fr) 2023-10-12 2025-04-17 Revolution Medicines, Inc. Inhibiteurs de ras

Similar Documents

Publication Publication Date Title
WO2023114733A1 (fr) Modulateurs de kras et leurs utilisations
US11912723B2 (en) KRAS modulators and uses thereof
WO2022256459A1 (fr) Modulateurs de kras et leurs utilisations
US12145947B2 (en) Pyrimidine based modulators and uses thereof
JP7395730B2 (ja) ヘテロ環式rip1阻害化合物
JP2024026193A (ja) Rho関連プロテインキナーゼのモジュレーター
WO2022261210A1 (fr) Modulateurs de kras et leurs utilisations
EA029768B1 (ru) Гетероциклильные соединения
JP2024543497A (ja) ユビキチン特異的プロテアーゼ1(usp1)の小分子阻害剤及びその使用
TW202327602A (zh) 泛素特異性蛋白酶1 (usp1)之小分子抑制劑及其用途
CA3199496A1 (fr) Derives heterocycliques pour le traitement de troubles a mediation par trpm3
CA3208490A1 (fr) Analogues pour le traitement d'une maladie
TW202334142A (zh) 泛素特異性蛋白酶1(usp1)之小分子抑制劑及其用途
EP4298094A1 (fr) Analogues pour le traitement d'une maladie
KR20240024948A (ko) 질환의 치료를 위한 베타-락탐 유도체
US20250051365A1 (en) Kras modulators and uses thereof
WO2024112895A1 (fr) Composés et compositions pour le traitement d'états associés à l'activité du récepteur de lpa
TW202317586A (zh) 治療性化合物及方法
WO2025049402A1 (fr) Modulateurs de kras et leurs utilisations
WO2025049619A1 (fr) Modulateurs de kras et leurs utilisations
US20050004200A1 (en) Pyrazole compounds as integrin receptor antagonists derivatives
WO2025034883A1 (fr) Polythérapies avec modulateurs de kras
WO2023078337A1 (fr) Inhibiteurs doubles de cdk8/19 et leurs procédés d'utilisation
WO2025034919A1 (fr) Polythérapies avec des modulateurs de kras
WO2025106901A1 (fr) Polythérapies anticancéreuses avec un modulateur de kras et un inhibiteur de la voie rtk-mapk

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 22847093

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

32PN Ep: public notification in the ep bulletin as address of the adressee cannot be established

Free format text: NOTING OF LOSS OF RIGHTS PURSUANT TO RULE 112(1) EPC (EPO FORM 1205A DATED 15/11/2024)